Use of wez series compounds for the preparation of a product for the prevention or / and treatment of hair loss

Abstract

The application discloses use of WEZ series compounds in preparation of products for preventing or / and treating alopecia. By establishing an animal model of alopecia, it is found that the compounds shown in formulas IV, V and VI have effects in treating alopecia and other similar hair loss diseases, including but not limited to androgen source alopecia (AGA) (also known as seborrheic alopecia) and alopecia areata.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical chemistry, and particularly relates to the use of a WEZ series compound in the preparation of a product for preventing or / and treating alopecia. BACKGROUND

[0002] Alopecia areata (AA) is a non-scarring hair loss, with normal skin in the affected area. It usually presents as sudden hair loss in patches, and can involve the entire scalp in severe cases, which is called alopecia totalis (AT), and when all body hair including axillary and pubic hair is involved, it is called alopecia universalis (AU), which can seriously affect the appearance and psychology of patients. The etiology is not fully understood, and autoimmune dysfunction or instability, and neurosychological factors are considered to be important related factors. The cure rate of alopecia areata is relatively high, but the cure rate of alopecia areata caused by different etiologies is quite different. Some alopecia areata patients can recover naturally, and some alopecia areata patients can last for several years. Minoxidil is a common topical drug for treating alopecia areata, which can promote skin vasodilation, improve local blood circulation, and promote hair growth. The commonly used glucocorticoids for severe alopecia areata include prednisolone, compound betamethasone, etc., which can be taken orally, topically or intradermally injected. For patients who are not suitable for glucocorticoid drugs, immunosuppressants can be used for treatment, and common drugs include cyclosporine, methotrexate, glucocorticoids and immunosuppressants, which have many side effects.

[0003] Androgenetic alopecia (AGA) is also known as seborrheic alopecia, which is a hereditary androgen-dependent hair loss. It is a common and frequently-occurring disease. It mainly occurs in men aged 20-30 years. The hair loss is mainly on the top of the head, and it often starts from the hairline on both sides of the forehead, or it can also start from the top. The hair loss area gradually extends upward, and the hair becomes sparse and thin, and eventually most or all of the hair on the top of the head is lost, but the hair on the back of the neck and the bilateral temporal upper parts remains, showing a horseshoe-shaped appearance. The hair in the belt-shaped area remains normal. The skin in the hair loss area is shiny, and the pores are small or only a few fine and soft downy hairs are left. The speed, range and severity of hair loss are affected by genetics and individual factors. Generally, the fastest development occurs at the age of 30, and severe total baldness is rare. Women often have diffuse hair loss on the top of the head, and the hair on the top of the head becomes sparse. Epidemiological surveys in China show that the prevalence of androgenetic alopecia in men is 21.3%, and in women it is 6.0%. The cause and pathogenesis of androgenetic alopecia are not clear. It is generally believed that androgens and their receptors play a key role in the occurrence of the disease, and type II 5a-reductase is an important factor in the occurrence of the disease. Under normal physiological conditions, androgens stimulate the growth and development of hair in the body, but in some specific parts, they can induce hair loss. Testosterone is the main androgen in the body, which is converted to dihydrotestosterone by 5a-reductase, and the latter can induce the transformation of terminal hair into downy hair, eventually leading to hair loss. There is no ideal treatment method at present, and it is a refractory type of alopecia. Minoxidil is a non-specific treatment for hair loss, and it is the first-line external drug approved by FDA for the treatment of hair loss, but it can cause facial and limb hirsutism during use, and the therapeutic effect gradually disappears after discontinuation. Since androgens play a great role in the pathogenesis, recent new treatment methods attempt to stop the miniaturization of hair follicles through the effect of anti-androgens. Finasteride is a selective inhibitor of type II 5a-reductase, and it has been found in recent years that finasteride is effective in treating AGA and can continuously improve the growth of hair. However, finasteride has adverse reactions such as sexual dysfunction, temporary reduction of sperm and abnormal development of male breasts, and it has been found in animal experiments that it has teratogenic effects, so it is not suitable for children and women of childbearing age. Cimetidine needs to be taken for 5 months or more, and the side effects are male breast development, impotence, and decreased sexual desire. Oral contraceptives: mainly have ethinyl estradiol, levonorgestrel (left-handed methyl levonorgestrel), norgestrel, norethindrone, norethisterone, norgestimate (oxime norethisterone), double ester norethindrone and acetoxynorgestrel, etc. It is often used to treat female AGA, and the hair will improve after 6-12 months of treatment.

[0004] For the above diseases, the current treatment methods cannot meet the clinical needs, and more new drugs with good efficacy, fewer side effects and low prices are needed to control the progression of the disease and reduce the occurrence of recurrence and complications. SUMMARY

[0005] The present application aims to provide the use of WEZ series compounds or pharmaceutically acceptable salts thereof in the preparation of products for preventing or / and treating hair loss.

[0006] The WEZ series compounds of the present application are compounds having the structure of Formula I or Formula II or Formula III:

[0007] wherein: R1, R2, R3 are independently selected from hydrogen, halogen, hydroxyl, amino, methoxyl, aminomethyl;

[0008] R4 is independently selected from hydrogen, methyl, ethyl, carboxyl, hydroxyl; R5 is ; wherein R6 and R8 are each independently selected from H, halogen or (C1-C4) alkyl, provided that R6 and R8 are not halogen at the same time.

[0009] In some specific examples, the WEZ series compounds of the present application are compounds having the structure of Formula IV or Formula V or Formula VI: .

[0010] In one aspect, the present application provides the use of WEZ series compounds or pharmaceutically acceptable salts thereof in the preparation of products for preventing or / and treating hair loss.

[0011] In some embodiments, the hair loss of the present application is hair loss, including physiological hair loss and pathological hair loss. The physiological hair loss is well known in the art, such as natural hair loss, senile hair loss, postpartum hair loss, etc. The pathological hair loss refers to abnormal or excessive hair loss, such as hair loss caused by infection, endocrine disease, immune system disease and nutritional deficiency, etc., such as androgenetic alopecia (AGA) (also known as seborrheic alopecia), alopecia areata, etc.

[0012] In some specific embodiments, the hair loss of the present application is pathological hair loss, and in some more specific examples, androgenetic alopecia (AGA) (also known as seborrheic alopecia) or alopecia areata.

[0013] In another aspect, the present application also provides the use of WEZ series compounds or pharmaceutically acceptable salts thereof in the preparation of products for promoting hair growth.

[0014] The products of the present application include, but are not limited to, pharmaceutical products, washing and caring products or health care products.

[0015] The WEZ series compound or pharmaceutically acceptable salt thereof can be prepared into any dosage form permitted by pharmacy, such as preparations suitable for oral, parenteral, intraperitoneal, intravenous, intra-arterial, transdermal, sublingual, intramuscular, rectal, transbuccal, intranasal, inhalation, vaginal, intraocular, topical, skin, subcutaneous, intra-adipose, intra-articular, intraperitoneal or intrathecal administration.

[0016] For example, in a preferred embodiment, the dosage form is a cream, paste, tablet, granule, oral liquid, capsule, drop pill, enema, film or injection.

[0017] The WEZ series compound or pharmaceutically acceptable salt thereof can also be prepared into a washing and caring product, such as shampoo, hair conditioner and the like.

[0018] The WEZ series compound or pharmaceutically acceptable salt thereof can also be prepared into a health care product for preventing hair loss or promoting hair growth.

[0019] The present application discovers the effect of the compounds shown in formula IV, V and VI in treating hair loss and other similar hair loss diseases, including but not limited to androgenetic alopecia (AGA) (also known as seborrheic alopecia) and alopecia areata, by establishing a hair loss animal model. BRIEF DESCRIPTION OF DRAWINGS

[0020] Figure 1 The WEZ compound can significantly promote the hair growth of the hair loss model mice. DETAILED DESCRIPTION

[0021] The present application will be further described below in conjunction with examples. It should be understood that the specific examples described herein are only used to explain the present application and are not used to limit the present application. Any simple improvement on the preparation method of the present application within the concept of the present application falls within the protection scope of the present application. The experimental method not specified in the following examples is generally according to the known method in the art. The test materials used in the following examples are commercially available from the conventional biochemical reagent store, unless otherwise specified.

[0022] Unless otherwise specified, the structure of the compound WEZ-4 described in the following examples is shown in formula IV, the structure of the compound WEZ-5 is shown in formula V, and the structure of the compound WEZ-6 is shown in formula VI:

[0023] .

[0024] Example 1: Effect of the compound WEZ series on the rat hair loss model

[0025] 1. Experimental method

[0026] 1.1 Materials

[0027] (1) Preparation method of compound WEZ-4, WEZ-5, WEZ-6 tincture: 75% ethanol is mixed with an appropriate amount of the above compound to prepare tincture of different concentrations.

[0028] (2) Positive treatment drug: 5% minoxidil tincture (trade name: Minoxidil, Zhejiang Wanma Pharmaceutical Co., Ltd.)

[0029] (3) Experimental animals: SPF Wistar rats, male, from Shanghai Slac Animal Feed Co., Ltd.

[0030] 1.2 Animal grouping and modeling

[0031] Wistar rats were randomly divided into negative control group (75% ethanol for external use), model group (75% ethanol for external use), positive control group (5% minoxidil tincture for external use), WEZ-4 external treatment group (5% WEZ-4 tincture for external use), WEZ-5 external treatment group (5% WEZ-5 tincture for external use), WEZ-6 external treatment group (5% WEZ-6 tincture for external use), WEZ-4 intravenous injection group (2 mg / kg.d), WEZ-5 intravenous injection group (2 mg / kg.d), WEZ-6 intravenous injection group (2 mg / kg.d), 10 rats in each group. Before the experiment, the back of each rat was selected as the observation area with an area of 4 cm x 5 cm. Except for the negative control group, the rats were subcutaneously injected with testosterone propionate injection [5 ml / (kg·d)] on the back of the neck, once a day, for 60 consecutive days, to establish androgenetic alopecia (AGA), also known as seborrheic alopecia (SA) model. After 4 weeks of continuous subcutaneous injection of testosterone propionate, the rats gradually developed hair loss, and the remaining hair became fine and brittle, indicating that the alopecia model was successfully established. At the same time, the skin was smeared with the drug, and the corresponding drug groups of rats were smeared on the observation area of the back, 2 mL / (rat·time), twice a day, with an interval of 8 h. Intravenous administration was once a day. The negative control group and the model control group were smeared with 75% ethanol solution, 2 mL / (rat·time), twice a day, for 60 consecutive days.

[0032] 1.3 Observation index and test method

[0033] The length of 10 hairs was measured with vernier caliper in the observation area of the back of each rat every 15 days. After 60 days of administration, the skin in the observation area was taken, and routine histological dehydration, paraffin embedding, HE staining, and light microscopy were performed to observe the histopathological changes of the rat skin hair follicle and sebaceous gland. Semi-quantitative analysis was performed on the lesions in each group. The grading criteria are as follows: the normal structure of the skin dermis tissue cells and subcutaneous hair follicle and sebaceous gland is recorded as "1"; no dermal tissue proliferation is observed in the skin, and the lesions of the hair follicle and sebaceous gland are limited, and no inflammation is observed in the subcutaneous tissue, which is recorded as "±"; no obvious proliferation is observed in the dermal tissue of the skin, and the hair follicle is obviously cystic, the sebaceous gland is not obviously proliferated, and no inflammation is observed in the subcutaneous tissue, which is recorded as "+"; the skin dermal tissue has segmental proliferation, and a small part of the hair follicle has cystic change, the sebaceous gland has mild proliferation and hypertrophy, and no obvious inflammation is observed in the subcutaneous tissue, which is recorded as "++"; the skin dermal tissue cells have different degrees of segmental proliferation, and part of the hair follicle has cystic change, showing uneven size of the hair follicle, and no cells are observed in the peripheral part. The sebaceous gland has proliferation, and the cells in the proliferated glands have fewer nuclei, and a small part of the rats has mild inflammatory proliferation in the subcutaneous tissue, which is recorded as "+++".

[0034] 2. Experimental results

[0035] 2.1 Effect of WEZ on hair growth in rats

[0036] The length of the hair of the rats in each treatment group was longer than that of the model control group on days 15, 30, 45, and 60 of administration, and the difference was statistically significant (P<0.01), and the difference was statistically significant compared with the positive treatment group (P<0.05). See Table 1

[0037] Table 1 Effect of each group on the length of hair growth in rats

[0038]

[0039] *The difference was statistically significant compared with the model control group (P<0.01)

[0040] 2.2 Effect of WEZ on the morphology of the superficial dermis hair follicle in the observation area of the rat skin

[0041] The dermal tissue cells of the model group rats were partially thickened in different degrees, and the rats had mild lymphocyte proliferation in the subcutaneous tissue. The hair follicles of some rats had obvious cystic degeneration, and the size of the hair follicles was different. The size of the enlarged hair follicle cavity was increased, and there were keratinous exfoliation around the cavity. The periphery had mild fibrosis, and the cells around the hair follicle disappeared or the cell layer was obviously reduced. There were blue calcified substances in the cavity, the number of sebaceous glands increased, and some glands were hypertrophic. The number of normal hair follicles decreased. The dermal tissue cells of the rats in each treatment group and the hair follicles and sebaceous glands in the subcutaneous tissue were different degrees of lesions compared with the model group. The number of damaged hair follicles in the skin of the rats in each treatment group was significantly reduced compared with the model control group, and the difference was statistically significant (P<0.01). Compared with the model control group, the dermal tissue cells of the rats in each treatment group and the hair follicles and sebaceous glands in the subcutaneous tissue were significantly reduced, and the difference was statistically significant (P<0.01). Compared with the positive treatment group, the difference was statistically significant (P<0.05). See Table 2.

[0042] Table 2 Effects of each group on the skin hair follicles and sebaceous glands of rats

[0043]

[0044] Note: * indicates that the difference was statistically significant compared with the model control group (P<0.01)

[0045] 3. Experimental conclusion

[0046] WEZ-4, WEZ-5, and WEZ-6 can significantly promote hair growth in the rat alopecia model, reduce damage to the subcutaneous hair follicles and sebaceous glands, and have no obvious adverse reactions.

[0047] Example 2 Effects of compounds WEZ series on the mouse alopecia model

[0048] 1. Experimental method

[0049] 1.1 Materials

[0050] (1) Preparation method of compound WEZ-4, WEZ-5, and WEZ-6 tincture: 60% ethanol was mixed with the above compounds to prepare a 2% concentration tincture.

[0051] (2) Positive treatment drug: 2% minoxidil tincture (produced by the Institute of Dermatology, Chinese Academy of Medical Sciences)

[0052] (3) Experimental animals: SPF level male healthy C57BL / 6 mice, half male and half female, 6-8 weeks old, weighing 20-25g, provided by Chengdu Yakang Biotechnology Co., Ltd.

[0053] 1.2 Animal grouping and modeling

[0054] The animal room operated on a 12-hour day-night cycle, ensuring free access to water and food, and maintaining a temperature of 23-25℃. Experimental animals were introduced to the room after a week of acclimatization. Mice were divided into 11 groups: negative control group (60% ethanol applied topically), model group (60% ethanol applied topically), positive control group (2% minoxidil applied topically), WEZ-4 treatment group (2% WEZ-4 tincture applied topically), WEZ-5 treatment group (2% WEZ-5 tincture applied topically), and WEZ-6 treatment group (2% WEZ-6 tincture applied topically), with 6 mice in each group (half male and half female). A 4 cm × 5 cm area on the back of each mouse was dehaired, and the dehaired area was colored yellow with 3% picric acid solution to define the observation area for the hair removal experiment. Except for the negative control group, mice in the other groups received subcutaneous injections of testosterone propionate [8 ml / (kg·d)] into the nape of the neck once daily for 60 days to establish the SA model. Simultaneously with model establishment, the drug was applied to the dorsal observation area of ​​the corresponding drug group rats at a dose of 1 ml / (rat·time), twice daily with a 2-hour interval. The normal control group and the model control group were treated with the excipient (60% ethanol solution), 1 ml / (rat·time), twice daily for 60 consecutive days.

[0055] 1.3 Observation Indicators and Testing Methods

[0056] Every 15 days after drug administration, 10 hairs were plucked from the observation area on the back of each mouse, and the hair length was measured using calipers. Sixty days after drug administration, skin samples from the experimental observation area were taken for routine tissue dehydration, paraffin embedding, HE staining, and light microscopic examination to observe the histopathological changes in the mouse skin hair follicles and sebaceous glands. Semi-quantitative analysis was performed on the lesions in each group. The grading criteria are as follows: "-" indicates normal dermal tissue cells and subcutaneous hair follicle and sebaceous gland structure; "±" indicates no dermal hyperplasia, localized lesions in hair follicles and sebaceous glands, and no subcutaneous inflammation; "+" indicates no significant dermal hyperplasia, significant cystic degeneration of hair follicles, no significant sebaceous gland hyperplasia, and no subcutaneous inflammation; "+" indicates segmental hyperplasia in the dermal tissue, not obvious, with a small number of hair follicles showing cystic degeneration, and mild hyperplasia and hypertrophy of sebaceous glands. No obvious inflammation under the skin is marked as "++": The dermal cells of the skin show segmental proliferation of varying degrees, and some hair follicles show cystic degeneration, resulting in uneven hair follicle size and absence of cells in the periphery. Sebaceous glands show hyperplasia, with fewer cell nuclei in the hyperplastic glands. Mild inflammatory hyperplasia in some subcutaneous tissues is marked as "+++".

[0057] 2. Experimental Results

[0058] 2.1 Effects of WEZ series on hair growth in mice

[0059] The length of the hair of each group of mice on the 15th, 30th, 45th, and 60th day of administration was longer than that of the model control group, and the difference was statistically significant (P<0.01), and the difference was statistically significant compared with the positive treatment group (P<0.05). See Table 3. The hair growth of each group of mice on the 30th day is shown in Figure 1 .

[0060] Table 3 Effect of each group on the length of hair growth of mice

[0061]

[0062] *The difference was statistically significant compared with the model control group (P<0.01)

[0063] 2.2 Effect of WEZ on the morphology of dermal superficial hair follicles in the observation area of mice

[0064] The dermal tissue cells of some skin of the model group of mice were thickened to varying degrees, and the subcutaneous lymphocytes of the mice were slightly proliferated; some subcutaneous hair follicles of the mice were obviously cystic, the size of the hair follicles was different, there were exfoliated keratin in the enlarged hair follicle cavity, the periphery had slight fibrosis, the cells around the hair follicle disappeared or the cell layers were obviously reduced, the cavity was similar to calcification and dyed blue, the number of sebaceous glands increased, some glands were hypertrophic, the nuclei of the hypertrophic gland cells were obviously reduced, and the number of normal hair follicles decreased. The skin dermal tissue cells and subcutaneous hair follicles and sebaceous glands of the mice in each treatment group were differentially reduced compared with the model group. The number of damaged hair follicles of the mice in each treatment group was significantly reduced compared with the model control group, and the difference was statistically significant (P<0.01). Compared with the model control group, the skin dermal tissue cells and subcutaneous hair follicles and sebaceous glands of the mice in each treatment group were obviously reduced, and the difference was statistically significant (P<0.01). See Table 4.

[0065] Table 4 Effect of each group on the skin hair follicles and sebaceous glands of mice

[0066]

[0067] Note: *The difference was statistically significant compared with the model control group (P<0.01)

[0068] 3. Experimental conclusion

[0069] WEZ-4, WEZ-5, and WEZ-6 can obviously promote the hair growth of the mouse alopecia model and reduce the damage to the subcutaneous hair follicles and sebaceous glands.

Claims

1. Use of a WEZ series compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament or a care product for preventing or / and treating hair loss, wherein the WEZ series compound is a compound of formula IV or formula V or formula VI: 。 2. Use according to claim 1, characterized in that, The hair loss is particularly hair loss.

3. Use according to claim 2, characterized in that, The hair loss is physiological hair loss or pathological hair loss.

4. Use according to claim 3, characterized in that, The physiological hair loss is natural hair loss, senile hair loss or postpartum hair loss; the pathological hair loss includes seborrheic alopecia or alopecia areata.

5. Use of a WEZ series compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament or a care product for promoting hair growth, wherein the WEZ series compound is a compound of formula IV or formula V or formula VI: 。

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