Transdermal delivery forms of a dual-positive deep 5 inhibitor / organic nitric

Abstract

The present invention relates to a transdermal delivery form of a double-effect PDE5 inhibitor / organic nitrate for enhancing local blood flow, and more particularly, to a transdermal delivery form of a double-effect PDE5 inhibitor / organic nitrate, the present invention relates to the use of a compound or a pharmaceutically acceptable salt thereof for the prevention or treatment of a variety of symptoms or diseases including alopecia using a dual action of a soluble guanylate cyclase activator and a phosphodiesterase inhibitor to enhance local blood flow, and a transdermal delivery form thereof. The compound enhances local blood flow, thereby exhibiting an excellent effect of preventing and treating alopecia and other various diseases caused by a decrease in local blood flow without side effects, and can be easily applied to a patient only with less treatment frequency when intradermal injection is performed using a microneedle compared to application therapy. The present invention relates to a pharmaceutical composition and a cosmetic composition for relieving alopecia and promoting hair growth, which can exhibit a significantly improved effect of preventing and treating alopecia and other various diseases caused by reduced local blood flow, and can be effectively used as a pharmaceutical composition and a cosmetic composition for relieving alopecia and promoting hair growth instead of a conventional alopecia therapeutic agent to which the application thereof is limited. The traditional Chinese medicine composition can also be used for treating various diseases caused by local blood flow reduction.

Description

Technical Field

[0001] The present invention relates to a transdermal administration form of a dual-acting PDE5 inhibitor / organic nitrate for increasing local blood flow, and more particularly, to a compound or a pharmaceutically acceptable salt thereof having a dual pharmacological effect of inhibiting PDE5 and releasing NO in order to increase local blood flow, for use in preventing or treating a variety of symptoms or diseases including hair loss, and to a transdermal administration form thereof. Background Art

[0002] Phosphodiesterase (PDE) is an enzyme that regulates the intracellular levels of second messengers by catalyzing the hydrolysis and corresponding degradation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Inhibition of PDE can increase the intracellular concentration of endogenous cAMP / cGMP. Therefore, inhibition of PDE can mediate various physiological mechanisms at different cellular and organ levels. Phosphodiesterase type 5 (PDE5) specifically hydrolyzes cyclic guanylate monophosphate (cGMP) to 5'-guanylate (5'GMP). Selective inhibition of PDE5 has been validated by related methods, and strategies for promoting inhibition of PDE5 activity are used as therapeutic tools, especially in neurological, vascular and cardiovascular diseases and disorders. Moreover, the introduction of PDE5 inhibitors has revolutionized the treatment of male impotence (Andersson KE, British Journal of Pharmacology (2018) 175: 2554-2565; Das A et al. Pharmacol Ther. (2015) 147: 12-21; Dobhal T et al. Critical Review in Pharmaceutical Sciences (2012) 1 (3): 13-27). The most notable examples of PDE5 inhibitors are sildenafil, tadalafil and vardenafil, for example, described in WO 99 / 24433, WO 01 / 60825, EP 995751 and WO 2011 / 075655. Recently, in addition to PDE5 inhibition, novel PDE5 inhibitors with dual pharmacology were described in WO / 2018 / 215433, which release NO in an additive manner.

[0003] On the other hand, alopecia is a symptom of abnormal loss of a lot of hair. It is more common in cases of main hair loss, but abnormal loss of hair in the beard, eyebrows, pubic hair, armpit hair, and other parts of the body is also called alopecia.

[0004] Hair is produced from follicles, which are located in the dermis above the subcutaneous fat below the epidermis. Follicles are located on all parts of the body except the lips, palms, and soles of the feet, and new hair is made from the hair matrix at the base of the follicle. The living cells in the hair matrix proliferate and push upward, and when these cells quickly dry and die, they are compressed into a dense and hard mass to form the hair shaft. The hair shaft, composed of dead proteins, is covered with a delicate layer (cuticle) formed by plate-like scales.

[0005] The hair growth cycle consists of three phases: the anagen phase, when hair growth is most active, the catagen phase, when hair begins to regress, and the telogen phase, when hair growth stops. At the end of the telogen phase, new hair grows from the follicle as the hair falls out, and the cycle begins anew. The growth phase of eyebrows and eyelashes is about 1 to 6 months, and the growth phase of hair is about 2 to 6 years. Usually, about 50 to 100 hairs fall out at the end of the telogen phase every day.

[0006] The most common type of hair loss in men is male pattern baldness or alopecia, which occurs gradually over years, starting most noticeably at the top of the head and progressing to the forehead. For female hair loss, the hairs become thinner in thickness and more diffuse, usually after menopause.

[0007] In order to alleviate or treat hair loss, many studies are being conducted. In particular, the cosmetics and pharmaceutical industries have been conducting studies for a long time to develop new substances that stimulate hair growth or alleviate hair loss, and thus drug therapies using female hormones, blood flow enhancers, and hair transplantation methods are being developed. Currently, the most commonly used drugs for treating hair loss include FDA-approved 2,4-diamino-6-piperidinylpyridine-3-oxide (also known as "minoxidil", see U.S. Patents 4,139,619 and 4,596,812) and finasteride, a specific inhibitor of type II 5α-reductase.

[0008] Minoxidil preparations are reported to be drugs that increase blood flow and supply nutrients to the hair roots to induce hair growth by dilating blood vessels. In particular, they are very effective in relieving hair loss symptoms in the whorl area. Pharmaceuticals using them as active ingredients are marketed under the trade name of Rogaine (a trademark of Pharmacia & Upjohn Company). It is reported that for men with male pattern baldness, Rogaine can reduce hair loss to 10% and promote hair growth, but the disadvantage is that it must be applied directly to the scalp from the outside and used regularly for a long time, and it does not have a very good effect on hair loss in areas other than the whorl area.

[0009] It is reported that the pharmaceutical product with finasteride as the active ingredient is marketed under the trade name of Propecia (a trademark of Merck & Co., Inc. in the United States). As an oral pill, it inhibits the function of type II 5α-reductase to prevent testosterone from being converted into dihydrotestosterone (DHT), thereby inhibiting hair loss. However, this also requires continuous and regular use, and some patients have side effects such as decreased libido and impotence, and there is a problem that it can only be used for adult men.

[0010] On the other hand, in order to effectively deliver the above-mentioned drugs into the human body and improve the stability to the external environment, various drug delivery methods have been developed, but there is currently the inconvenience that minoxidil preparations need to be applied twice a day and Propecia preparations need to be taken every day.

[0011] Therefore, the present inventors have made great efforts to develop a new hair growth agent with improved efficacy compared with the existing hair growth agents. As a result, it was found that the compound according to the present invention has excellent therapeutic effects, especially compared with minoxidil, which is the most recently used and commercially available, and has an effect on female pattern hair loss at a low dose, and also has a hair loss prevention effect. At the same time, when the compound according to the present invention is loaded on microneedles and applied, it is also confirmed that the application once every two days can exert a better effect than the existing hair growth agent, compared with the application twice a day of the existing hair growth agent. In addition, when the molded dissolving microneedles are directly administered percutaneously to the main action site, it is confirmed that the therapeutic dose that exerts the effect can be significantly reduced compared with minoxidil, thereby confirming that the present invention can be administered at a local dose.

[0012] Furthermore, transdermal administration using shaped dissolving microneedles of the compounds and compositions of the present invention can avoid or reduce the likelihood of systemic drug exposure with side effects such as systemic arterial hypotension. Summary of the invention

[0013] Technical issues

[0014] The object of the present invention is to provide a novel use of a compound or a pharmaceutically acceptable salt thereof for enhancing local blood flow through the dual effects of inhibiting PDE5 and releasing NO, and to provide an effective administration method thereof.

[0015] Solutions to the problem

[0016] In order to achieve the above object, the present invention provides a pharmaceutical composition for transdermal administration comprising a compound of Chemical Formula I or a pharmaceutically acceptable salt thereof:

[0017] Chemical formula I

[0018]

[0019] Among them, in the compound,

[0020] R1 is a C1-C3 alkyl group, preferably a methyl group or an ethyl group, more preferably an ethyl group;

[0021] R2 is H, CHO or CH=N-OH, preferably H, CHO or (E)-CH=N-OH, more preferably H;

[0022] R3 is a C1-C4 alkyl group, preferably an ethyl group or a propyl group, more preferably an n-propyl group;

[0023] R4 is a C1-C6 alkyl group, preferably an ethyl group or a propyl group, more preferably an n-propyl group;

[0024] R5 is SO2NR6R7, wherein R6 and R7 together with the nitrogen atom to which they are attached form a heterocyclic ring selected from piperidine and piperazine, the heterocyclic ring being substituted by at least one R8 independently selected from C1-C6 alkyl optionally substituted by OH or ONO2, at least one of the at least one R8 comprising at least one ONO2 moiety.

[0025] In the present invention, the compound of the chemical formula I may be a compound wherein R1 is a methyl group or an ethyl group; R2 is H; R3 is an ethyl group or an n-propyl group; and R4 is an ethyl group or an n-propyl group.

[0026] In the present invention, the compound of the chemical formula I may be a compound wherein R1 is an ethyl group; R2 is H; R3 is an n-propyl group; and R4 is an n-propyl group.

[0027] In the present invention, the compound of Chemical Formula I may be a compound selected from the group consisting of the following compounds:

[0028]

[0029] In the present invention, the compound of Chemical Formula I may be a compound selected from the group consisting of the following compounds:

[0030] (1) (1-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperidine-4,4-diyl)bis(ethane-2,1-diyl)di nitrate);

[0031] (2) 2-(4-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphen yl)sulfonyl)piperazin-1-yl)ethyl nitrate;

[0032] (3) 2-(1-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphen yl)sulfonyl)piperidin-4-yl)ethyl nitrate;

[0033] (4) 3-(1-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphen yl)sulfonyl)piperidin-4-yl)propyl nitrate;

[0034] (5) (R)-1-(1-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4-yl)ethane-1,2-diyl dinitrate;

[0035] (6) (S)-1-(1-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4-yl)ethane-1,2-diyl dinitrate;

[0036] (7) ((2R,6S)-4-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)-1-methylpiperazine-2,6-diyl)bis(ethane-2,1-diyl)dinitrate);

[0037] (8) ((2S,6S)-4-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)-1-methylpiperazine-2,6-diyl)bis(ethane-2,1-diyl)dinitrate);

[0038] (9) 3-(1-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4-yl)-3-hydroxypentane-1,5-diyl din itrate; and

[0039] (10) 2-(1-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4-yl)-2-hydroxypropane-1,3-dinitrate.

[0040] In the present invention, preferably, the compound of the chemical formula I may be the following compound 1 (Cp1) or compound 2 (Cp2):

[0041]

[0042] From the most preferred perspective, the compound of Formula I may be Compound 1.

[0043] In the present invention, the pharmaceutical composition for transdermal administration may be a pharmaceutical composition for preventing or treating hair loss for topical administration.

[0044] In the present invention, the composition for transdermal administration may contain 0.00005% (w / w) to 0.5% (w / w) of the compound of Formula I, preferably, the compound represented by Compound 1 or Compound 2 or a pharmaceutically acceptable salt thereof.

[0045] In the present invention, a transdermal composition comprising a compound of formula I, preferably a compound represented by compound 1 or compound 2, or a pharmaceutically acceptable salt thereof, can be used to prevent, improve or treat one or more diseases or disorders selected from the group consisting of skin diseases, skin aging, steroid-induced skin atrophy; impotence; and hair loss or hair growth.

[0046] The present invention is characterized in that the disease or disorder may be hair loss, and the pharmaceutical composition can prevent hair loss or promote hair growth by (i) inducing anagen induction, (ii) promoting melanogenesis, (iii) increasing the number of hair follicles, (iv) increasing skin thickness, (v) promoting angiogenesis, (vi) outer root sheath cell proliferation and / or (vii) enhancing blood flow in hair follicles.

[0047] The present invention is characterized in that the hair loss can be androgenic alopecia (AGA), chemotherapy-induced alopecia (CIA) or alopecia areata.

[0048] As another embodiment, the present invention provides a transdermal administration method of a compound of Formula I or a pharmaceutically acceptable salt thereof:

[0049] Chemical formula I

[0050]

[0051] Among them, in the compound,

[0052] R1 is a C1-C3 alkyl group, preferably a methyl group or an ethyl group, more preferably an ethyl group;

[0053] R2 is H, CHO or CH=N-OH, preferably H, CHO or (E)-CH=N-OH, more preferably H;

[0054] R3 is a C1-C4 alkyl group, preferably an ethyl group or a propyl group, more preferably an n-propyl group;

[0055] R4 is a C1-C6 alkyl group, preferably an ethyl group or a propyl group, more preferably an n-propyl group;

[0056] R5 is SO2NR6R7, wherein R6 and R7 together with the nitrogen atom to which they are attached form a heterocyclic ring selected from piperidine and piperazine, the heterocyclic ring being substituted by at least one R8 independently selected from C1-C6 alkyl optionally substituted by OH or ONO2, at least one of the at least one R8 comprising at least one ONO2 moiety.

[0057] In the present invention, the transdermal administration may be for preventing, improving or treating one or more diseases or disorders selected from the group consisting of skin diseases, skin aging, steroid-induced skin atrophy, impotence, and hair loss or hair growth.

[0058] As another embodiment, the present invention provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof or the composition for preparing a drug for transdermal administration:

[0059] Chemical formula I

[0060]

[0061] Among them, in the compound,

[0062] R1 is a C1-C3 alkyl group, preferably a methyl group or an ethyl group, more preferably an ethyl group;

[0063] R2 is H, CHO or CH=N-OH, preferably H, CHO or (E)-CH=N-OH, more preferably H;

[0064] R3 is a C1-C4 alkyl group, preferably an ethyl group or a propyl group, more preferably an n-propyl group;

[0065] R4 is a C1-C6 alkyl group, preferably an ethyl group or a propyl group, more preferably an n-propyl group;

[0066] R5 is SO2NR6R7, wherein R6 and R7 together with the nitrogen atom to which they are attached form a heterocyclic ring selected from piperidine and piperazine, the heterocyclic ring being substituted by at least one R8 independently selected from C1-C6 alkyl optionally substituted by OH or ONO2, at least one of the at least one R8 comprising at least one ONO2 moiety.

[0067] In the present invention, the drug may be a drug for preventing, improving or treating one or more diseases or disorders selected from the group consisting of skin diseases, skin aging, steroid-induced skin atrophy; impotence; and hair loss or hair growth.

[0068] As another embodiment, the present invention provides a transdermal administration method, which comprises the step of applying the compound of Formula I or a pharmaceutically acceptable salt thereof or the composition to a subject in need thereof:

[0069] Chemical formula I

[0070]

[0071] Among them, in the compound,

[0072] R1 is a C1-C3 alkyl group, preferably a methyl group or an ethyl group, more preferably an ethyl group;

[0073] R2 is H, CHO or CH=N-OH, preferably H, CHO or (E)-CH=N-OH, more preferably H;

[0074] R3 is a C1-C4 alkyl group, preferably an ethyl group or a propyl group, more preferably an n-propyl group;

[0075] R4 is a C1-C6 alkyl group, preferably an ethyl group or a propyl group, more preferably an n-propyl group;

[0076] R5 is SO2NR6R7, wherein R6 and R7 together with the nitrogen atom to which they are attached form a heterocyclic ring selected from piperidine and piperazine, the heterocyclic ring being substituted by at least one R8 independently selected from C1-C6 alkyl optionally substituted by OH or ONO2, at least one of the at least one R8 comprising at least one ONO2 moiety.

[0077] In the present invention, the transdermal administration method may be a method for preventing, improving or treating one or more diseases or disorders selected from the group consisting of skin diseases, skin aging, steroid-induced skin atrophy; impotence; and hair loss or hair growth.

[0078] As another embodiment, the present invention can provide a cosmetic composition for transdermal administration or transdermal application comprising the compound of Formula I as an active ingredient.

[0079] The present invention also provides a kit, which comprises:

[0080] (i) a first kit component comprising the pharmaceutical composition; and

[0081] (ii) A second kit component comprising an adhesive or non-adhesive patch or device suitable for applying the pharmaceutical composition to the skin.

[0082] The present invention also provides a solid composition, which is a solid composition for preparing the pharmaceutical composition, wherein the solid composition is dissolved in a liquid solvent, and the liquid composition in which the solid composition is dissolved contains 0.00005% (w / w) to 0.5% (w / w) of the compound of Chemical Formula I or a pharmaceutically acceptable salt thereof.

[0083] The present invention also provides a microneedle structure carrying the pharmaceutical composition or cosmetic composition.

[0084] The present invention is characterized in that the microneedle structure can be a microneedle patch or a microneedle applicator.

[0085] The present invention is characterized in that the microneedle structure may include solid microneedles, coated microneedles, dissolving microneedles, hollow microneedles or candle-shaped microneedles.

[0086] The present invention is characterized in that the microneedle may contain a biocompatible polymer selected from the group consisting of hyaluronic acid, collagen, polyvinyl pyrrolidone, polylactic acid, polylactic acid glycolic acid, polylactide, polyglycolic acid, polyethylene glycol, polycaprolactone, polyamino acid, polypropylene fumarate, γ-polyglutamic acid, polyvinyl alcohol, polyethylene imine, albumin, dextran, fibrin, elastin, gelatin, alginate, polyacrylic acid, carboxymethyl cellulose and mixtures or copolymers thereof.

[0087] The present invention is characterized in that the pharmaceutical composition or cosmetic composition is injected once within 2 to 15 days.

[0088] Effects of the Invention

[0089] The compound according to the present invention has a dual effect of enhancing local blood flow by releasing NO and inhibiting PDE5, thereby exerting an excellent effect of preventing and treating hair loss and other various diseases caused by reduced local blood flow without side effects. Compared with application treatment, when transdermal injection is performed using microneedles, only a less frequent treatment can be performed to exert a significantly improved effect of preventing and treating hair loss and other various diseases caused by reduced local blood flow. The compound can be effectively used as a transdermal composition for alleviating hair loss and promoting hair growth that can replace existing hair loss therapeutic agents with limited application, and can be used for the treatment of various diseases caused by reduced local blood flow. BRIEF DESCRIPTION OF THE DRAWINGS

[0090] Figure 1 shows the hair growth effect and skin tissue development effect of applying compound 1 or using microneedle injection ( Figure 1a ), growth period conversion rate ( Figure 1b ), hair growth rate( Figure 1c ), each hair growth cycle distribution rate ( Figure 1d ), skin thickness( Figure 1e ) and changes in hair thickness ( Figure 1f , Figure 1g ) comparison results.

[0091] FIG2 is a fluorescence microscope observation of the expression levels of β-catenin, proliferating cell nuclear antigen (PCNA), MECA32, and VCAN, which are skin tissue development markers, when applying compound 1 or using microneedle injection (respectively Figure 2a , Figure 2d , Figure 2f ) and quantitatively analyzed them (respectively Figure 2b , Figure 2c , Figure 2e , Figure 2g ) results. DETAILED DESCRIPTION

[0092] Unless otherwise defined, all technical terms and scientific terms used in this specification have the same meaning as those commonly understood by those of ordinary skill in the art to which the present invention belongs. Generally, the nomenclature used in this specification and the experimental methods described below are well-known and commonly used methods in the art.

[0093] In the present invention, it has been confirmed that the compound represented by Chemical Formula I has the effect of inhibiting PDE5 (Phosphodiesterase) while releasing NO, and through this mechanism, it shows excellent therapeutic effects not only in male pattern hair loss but also in female pattern hair loss, and also exhibits significantly excellent effects in hair loss induced by chemotherapy used for cancer treatment, etc., compared with minoxidil, one of the latest hair growth agents on the market.

[0094] Furthermore, it has been confirmed that the compound represented by Chemical Formula I according to the present invention can also simultaneously exert the effect of preventing hair loss when administered at a stage before hair loss occurs.

[0095] Therefore, from one perspective, the present invention relates to a pharmaceutical composition for transdermal administration comprising a compound of Formula I or a pharmaceutically acceptable salt thereof:

[0096] Chemical formula I

[0097]

[0098] Among them, in the compound,

[0099] R1 is a C1-C3 alkyl group, preferably a methyl group or an ethyl group, more preferably an ethyl group;

[0100] R2 is H, CHO or CH=N-OH, preferably H, CHO or (E)-CH=N-OH, more preferably H;

[0101] R3 is a C1-C4 alkyl group, preferably an ethyl group or a propyl group, more preferably an n-propyl group;

[0102] R4 is a C1-C6 alkyl group, preferably an ethyl group or a propyl group, more preferably an n-propyl group;

[0103] R5 is SO2NR6R7, wherein R6 and R7 together with the nitrogen atom to which they are attached form a heterocyclic ring selected from piperidine and piperazine, the heterocyclic ring being substituted by at least one R8, the R8 being independently selected from C1-C6 alkyl, selectively substituted by OH or ONO2, at least one of the at least one R8 comprising at least one ONO2 moiety.

[0104] In the present invention, the compound of the chemical formula I may be a compound wherein R1 is a methyl group or an ethyl group; R2 is H; R3 is an ethyl group or an n-propyl group; and R4 is an ethyl group or an n-propyl group.

[0105] In the present invention, the compound of the chemical formula I may be a compound wherein R1 is ethyl; R2 is H; R3 is n-propyl; and R4 is n-propyl.

[0106] In the present invention, the compound of Chemical Formula I may be a compound selected from the group consisting of the following compounds:

[0107]

[0108] In the present invention, the compound of Chemical Formula I may be a compound selected from the group consisting of the following compounds:

[0109] (1) (1-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-pr opoxyphenyl)sulfonyl)piperidine-4,4-diyl)bis(ethane-2,1-diyl)dinitrate);

[0110] (2) 2-(4-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperazin-1-yl)ethyl nitrate;

[0111] (3) 2-(1-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4-yl)ethyl nitrate;

[0112] (4) 3-(1-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4-yl)propyl nitrate;

[0113] (5) (R)-1-(1-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxy phenyl)sulfonyl)piperidin-4-yl)ethane-1,2-diyl dinitrate;

[0114] (6) (S)-1-(1-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4-yl)ethane-1,2-diyl dinitrate;

[0115] (7) ((2R,6S)-4-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)-1-methylpiperazine-2,6-diyl)bis(ethane-2,1-diyl)dinitrate);

[0116] (8) ((2S,6S)-4-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)-1-methylpiperazine-2,6-diyl)bis(ethane-2,1-diyl)dinitrate);

[0117] (9) 3-(1-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4-yl)-3-hydroxypentane-1,5-diyl dinitrate; and

[0118] (10) 2-(1-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-prop oxyphenyl)sulfonyl)piperidin-4-yl)-2-hydroxypropane-1,3-dinitrate.

[0119] In the present invention, the compound of Chemical Formula I or a pharmaceutically acceptable salt thereof may include all compounds represented by Chemical Formula I, their prodrugs, their solvates, their hydrates, their metabolites or their pharmaceutically acceptable salts.

[0120] Preferably, the compound of Formula I is Compound 1 (Cp1) or Compound 2 (Cp2).

[0121]

[0122] In the most preferred embodiment, the compound of formula I is compound 1.

[0123] For example, compound 1 represented by chemical formula I may undergo the following metabolic process in vivo. In the present invention, the effect of the present invention may be exerted by administering the following primary or secondary metabolites instead of the compound represented by chemical formula I, which is obvious to a person skilled in the art to which the present invention belongs.

[0124]

[0125] In addition, compound 2 (TOP-M111) represented by chemical formula I can undergo the following metabolic process in vivo. In the present invention, the following corresponding metabolite (Mir odenafil) is administered to replace the compound represented by chemical formula I to enable the effect of the present invention to be exerted, which is obvious to ordinary technicians in the technical field to which the present invention belongs.

[0126]

[0127] The present invention is characterized in that the pharmaceutical composition can be used to prevent, improve or treat one or more diseases or disorders selected from the group consisting of skin diseases, skin aging, steroid-induced skin atrophy; impotence; and hair loss or hair growth, but is not limited thereto.

[0128] The present invention is characterized in that the pharmaceutical composition can be used for topical administration, preferably, can be used for transdermal administration, but is not limited thereto.

[0129] The present invention is characterized in that the pharmaceutical composition can be formulated in a manner containing 0.00005% (w / w) to 0.5% (w / w) of a compound represented by chemical formula I, preferably compound 1 or compound 2, or a pharmaceutically acceptable salt thereof, but is not limited thereto. For example, it is characterized in that it may contain 0.00005 to 0.5%, 0.0001 to 0.04%, 0.0002 to 0.03% or 0.0004 to 0.02% of the compound represented by chemical formula I, or a pharmaceutically acceptable salt thereof, but is not limited thereto. For example, the pharmaceutical composition can be formulated in a manner containing 0.0005% to 0.05% or 0.0008 to 0.004% (w / w) of a compound represented by chemical formula I, preferably compound 1 or compound 2, or a pharmaceutically acceptable salt thereof.

[0130] The present invention is characterized in that the compound represented by Chemical Formula I, preferably Compound 1 or Compound 2, or a pharmaceutically acceptable salt thereof can be formulated for male administration at 0.0005 to 0.02% (w / w), but is not limited thereto.

[0131] The present invention is characterized in that the compound represented by Chemical Formula I, preferably Compound 1 or Compound 2, or a pharmaceutically acceptable salt thereof can be formulated for administration to women at 0.00005 to 0.01% (w / w), but is not limited thereto.

[0132] The present invention is characterized in that the compound represented by chemical formula I, preferably compound 1 or compound 2, or a pharmaceutically acceptable salt thereof can prevent hair loss or promote hair growth by (i) inducing anagen induction, (ii) promoting melanogenesis, (iii) increasing the number of hair follicles, (iv) increasing skin thickness, (v) promoting angiogenesis, (vi) outer root sheath cell proliferation and / or (vii) increasing blood flow in hair follicles, but is not limited thereto.

[0133] The present invention is characterized in that the hair loss can be androgenic alopecia, chemotherapy-induced alopecia, or alopecia areata, but is not limited thereto.

[0134] As another embodiment, the present invention provides a transdermal administration method of a compound of Formula I or a pharmaceutically acceptable salt thereof:

[0135] Chemical formula I

[0136]

[0137] Among them, in the compound,

[0138] R1 is a C1-C3 alkyl group, preferably a methyl group or an ethyl group, more preferably an ethyl group;

[0139] R2 is H, CHO or CH=N-OH, preferably H, CHO or (E)-CH=N-OH, more preferably H;

[0140] R3 is a C1-C4 alkyl group, preferably an ethyl group or a propyl group, more preferably an n-propyl group;

[0141] R4 is a C1-C6 alkyl group, preferably an ethyl group or a propyl group, more preferably an n-propyl group;

[0142] R5 is SO2NR6R7, wherein R6 and R7 together with the nitrogen atom to which they are attached form a heterocyclic ring selected from piperidine and piperazine, the heterocyclic ring being substituted by at least one R8 independently selected from C1-C6 alkyl optionally substituted by OH or ONO2, at least one of the at least one R8 comprising at least one ONO2 moiety.

[0143] In the present invention, the transdermal administration may be for preventing, improving or treating one or more diseases or disorders selected from the group consisting of skin diseases, skin aging, steroid-induced skin atrophy, impotence, and hair loss or hair growth.

[0144] As another embodiment, the present invention provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof or the composition for preparing a drug for transdermal administration:

[0145] Chemical formula I

[0146]

[0147] Among them, in the compound,

[0148] R1 is a C1-C3 alkyl group, preferably a methyl group or an ethyl group, more preferably an ethyl group;

[0149] R2 is H, CHO or CH=N-OH, preferably H, CHO or (E)-CH=N-OH, more preferably H;

[0150] R3 is a C1-C4 alkyl group, preferably an ethyl group or a propyl group, more preferably an n-propyl group;

[0151] R4 is a C1-C6 alkyl group, preferably an ethyl group or a propyl group, more preferably an n-propyl group;

[0152] R5 is SO2NR6R7, wherein R6 and R7 together with the nitrogen atom to which they are attached form a heterocyclic ring selected from piperidine and piperazine, the heterocyclic ring being substituted by at least one R8 independently selected from C1-C6 alkyl optionally substituted by OH or ONO2, at least one of the at least one R8 comprising at least one ONO2 moiety.

[0153] In the present invention, the drug may be a drug for preventing, improving or treating one or more diseases or disorders selected from the group consisting of skin diseases, skin aging, steroid-induced skin atrophy; impotence; and hair loss or hair growth.

[0154] As another embodiment, the present invention provides a transdermal administration method, which comprises the step of applying the compound of Formula I or a pharmaceutically acceptable salt thereof or the composition to a subject in need thereof:

[0155] Chemical formula I

[0156]

[0157] Among them, in the compound,

[0158] R1 is a C1-C3 alkyl group, preferably a methyl group or an ethyl group, more preferably an ethyl group;

[0159] R2 is H, CHO or CH=N-OH, preferably H, CHO or (E)-CH=N-OH, more preferably H;

[0160] R3 is a C1-C4 alkyl group, preferably an ethyl group or a propyl group, more preferably an n-propyl group;

[0161] R4 is a C1-C6 alkyl group, preferably an ethyl group or a propyl group, more preferably an n-propyl group;

[0162] R5 is SO2NR6R7, wherein R6 and R7 together with the nitrogen atom to which they are attached form a heterocyclic ring selected from piperidine and piperazine, the heterocyclic ring being substituted by at least one R8 independently selected from C1-C6 alkyl optionally substituted by OH or ONO2, at least one of the at least one R8 comprising at least one ONO2 moiety.

[0163] In the present invention, the transdermal administration method may be a method for preventing, improving or treating one or more diseases or disorders selected from the group consisting of skin diseases, skin aging, steroid-induced skin atrophy; impotence; and hair loss or hair growth.

[0164] The use, use of the drug preparation, and detailed description of the transdermal administration method should refer to the description of the composition unless there is a conflict between them.

[0165] The compounds according to the present invention can treat, suppress or inhibit hair loss, characterized in that, for example, in individuals with hair loss, by (i) inducing the growth phase of hair follicles, (ii) promoting melanin production, (iii) increasing the number of hair follicles, (iv) increasing skin thickness (including the development of skin tissue), (v) promoting angiogenesis, (vi) promoting the proliferation of outer root sheath cells and / or (vii) increasing blood flow in hair follicles, to prevent hair loss or promote hair growth. In the present invention, the hair loss may be caused by androgenic alopecia (AGA), and the hair loss may be caused by male pattern baldness or female pattern baldness. In another example, the hair loss may be the result of skin damage, for example, the hair loss may be alopecia treated by drugs or chemotherapy.

[0166] As one aspect, the hair loss is scarring (in another example, scarring) alopecia, which is hair loss caused by scarring of the scalp area. The scarring alopecia typically occurs at the very top of the scalp, primarily in women. This condition is commonly seen in African-American women and is thought to be related to continued forceful tying or "corn-rowing" of the hair. In addition, forms of scarring alopecia may also occur in menopausal women associated with inflammation of the hair follicles and resulting scarring.

[0167] As yet another embodiment, the hair loss includes known baldness. As another embodiment, the present invention is alopecia areata, which is an autoimmune disorder that causes widespread hair loss or uneven hair loss, ranging from widespread thinning of hair to "islands" of remaining hair.

[0168] As still another aspect, the hair loss includes hair loss caused by compulsive hair pulling.

[0169] As another aspect, the hair loss includes triangular alopecia, which is a hair loss in the temporal lobe area since childhood. In the hair loss, hair loss may be complete, or some fine and small-diameter hair may remain.

[0170] As yet another approach, the hair loss includes telogen effluvium, a common type of hair loss caused when a high percentage of hair enters a "shedding" phase. The causes of telogen effluvium can be hormonal, nutritional, drug-related, or stress-related.

[0171] As another way, the hair loss includes loose-anagen syndrome, which is a condition that occurs primarily in blonde hair, where the scalp hair is loose in the follicles and is easily pulled out by combing or pulling. This condition may appear in childhood.

[0172] As yet another approach, the hair loss may be caused by a fungal infection, in one example, Tinea Capitis (Scalp Ringworm) can be treated which is characterized by patches of dandruff that spread from the scalp, where broken hairs, redness, swelling, and oozing may occur.

[0173] As yet another aspect, the hair loss includes hair loss associated with a specific disease state such as cancer, thyroid disease, insufficient protein in the diet, low iron concentration in the serum, or associated with a specific environmental stimulus such as chemotherapy or other radiation therapy.

[0174] As yet another aspect, the present invention can treat all diseases, disorders or symptoms associated with baldness. As yet another aspect, the present invention can treat all diseases, disorders or symptoms associated with degenerative skin disorders. As yet another aspect, the present invention can treat all diseases, disorders or symptoms associated with hair loss. Each disease, disorder or symptom is an individual embodiment of the present invention.

[0175] In the present invention, "treatment" refers to a therapeutic treatment or preventive or preventive measure for preventing or weakening the pathological morbidity or disorder as a target. Therefore, in one aspect, treatment may include acting directly on the disease, disorder or morbidity, or the symptoms related to the combination thereof, curing, inhibiting, suppressing, preventing, reducing the severity, delaying the start, and reducing the relevant symptoms. That is, in one aspect, "treatment" refers in particular to delaying progression, promoting decline, inducing decline, increasing decline, promoting recovery, increasing the efficacy of alternative therapeutic agents or reducing drug resistance, or a combination thereof. In one aspect, "prevention" refers in particular to delaying the start of symptoms, preventing recurrence, reducing the frequency or number of recurrences, increasing the latency between symptom occurrences, or a combination thereof. In an example, "suppression" or "suppression" refers in particular to reducing the severity of symptoms, reducing the severity of current events, reducing the number of symptoms, reducing the incidence of symptoms (incidence), reducing the latency of symptoms, alleviating symptoms, reducing secondary symptoms, reducing secondary infections, or a combination thereof.

[0176] In one aspect, the symptom is primary, in another aspect, the symptom is secondary. In one aspect, "primary" refers to symptoms that are a direct result of hair loss, in one aspect, "secondary" refers to symptoms that arise from or are a result of a primary cause. In one aspect, the compositions and strains used in the present invention together treat hair loss, in one aspect, primary or secondary symptoms, or secondary complications associated with seborrheic dermatitis.

[0177] In another aspect, the "symptoms" may be all symptoms of hair loss, including alopecia, baldness, temporary hair loss, patchy hair loss, degenerative skin disorders, or a combination thereof.

[0178] Methods for determining the presence and severity of hair loss described in the present invention are well known in the relevant art. Each method is an individual embodiment of the present invention.

[0179] In one aspect, the methods of the invention are used to treat an individual with hair loss. In one aspect, the hair loss is hair loss on the individual's scalp. In another aspect, the hair loss is hair loss on the individual's eyebrows. In another example, the hair loss refers to hair loss in the individual's scarring skin tissue, which in one example may be the individual's scalp, eyebrows, arms, or legs. In another example, any other area or region of skin having body hair is treated using the methods of the invention. Each possibility is an individual embodiment of the invention.

[0180] In some embodiments of the present invention, the pharmaceutical composition containing the compound represented by Chemical Formula I, or a pharmaceutically acceptable salt thereof as an active ingredient can be used in any dosage form selected from the group consisting of injection, granules, gel, suspension, emulsion, drops or liquid according to conventional methods, and more preferably, can be used as an external agent or injection.

[0181] In another aspect of the present invention, the pharmaceutical composition containing the compound represented by Chemical Formula I, or a pharmaceutically acceptable salt thereof as an active ingredient may further include one or more additives selected from the group consisting of appropriate carriers, excipients, disintegrants, sweeteners, coating agents, expanders, lubricants, lubricants, flavoring agents, antioxidants, buffers, antibacterial agents, diluents, dispersants, surfactants, binders and lubricants commonly used in the preparation of pharmaceutical compositions.

[0182] Specifically, the carrier, excipient and diluent can use lactose, glucose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talcum powder, magnesium stearate and mineral oil, and the solid preparation for oral administration includes tablets, pills, powders, granules, capsules, etc. These solid preparations can be mixed with at least one excipient in the composition, such as starch, calcium carbonate, sucrose or lactose, gelatin, etc. In addition, in addition to simple excipients, lubricants such as magnesium stearate and talcum powder can also be used.

[0183] In some aspects of the present invention, the pharmaceutical composition can be administered to a subject via a transdermal route in a conventional manner, preferably, can be administered to a subject via hypodermic injection.

[0184] The preferred dosage of the compound represented by Chemical Formula I, or a pharmaceutically acceptable salt thereof, or a precursor of the compound may vary depending on the state and weight of the subject, the type and severity of the disease, the drug form, the route of administration, and the duration, and may be appropriately selected by a person skilled in the art to which the present invention belongs.

[0185] As one aspect of the present invention, although not limited thereto, the daily dosage of the pharmaceutical composition for administration by smearing is 0.1 mg / kg to 1 mg / kg, preferably 1 ug / kg to 100 ug / kg, and most preferably 5 ug / kg to 50 ug / kg. In this case, about 0.1% to 10% of the drug can be administered in vivo.

[0186] In one aspect, based on the total volume of the composition, the concentration of the active ingredient can be 1 μM to 100 μM, for example, it can be 10 μM or more, 15 μM or more, 20 μM or more, 25 μM or more, 30 μM or more, 35 μM or more, or it can be 40 μM or more, 90 μM or less, 80 μM or less, 70 μM or less, or 60 μM or less. In one example of the present specification, preferably, the concentration of the active ingredient can be 50 μM.

[0187] As another preferred aspect, the composition can be prepared as a cosmetic composition or an external preparation for skin in addition to a pharmaceutical composition.

[0188] The present invention is characterized in that the cosmetic composition or external skin preparation can have the effects of preventing or improving hair loss, promoting hair growth, preventing or improving skin diseases, and preventing or improving impotence.

[0189] The present invention is characterized in that the composition can be formulated into at least one form selected from the group consisting of softening lotion, astringent lotion, nourishing lotion, nourishing cream, massage cream, essence, cleansing cream, cleansing milk, cleansing water, hair nourishing agent, hair conditioner, brightening agent, hair conditioner, nourishing hair conditioner, shampoo, conditioner, hair treatment cream, hair conditioner, nourishing hair conditioner, moisturizing hair conditioner, hair massage cream, hair wax, hair gel, hair mask, nourishing hair mask, shampoo soap, shampoo, hair oil, hair dryer, hair preservation treatment agent, hair dye, hair waving agent, hair bleaching agent, hair gel, hair care essential oil, hair styling agent, hair adhesive, leave-in conditioner, hair mousse and styling agent, but is not limited thereto.

[0190] The appearance of the cosmetic composition according to one embodiment of the present invention comprises an acceptable medium or matrix in cosmetics or dermatology. This is suitable for all dosage forms of topical application, for example, in the form of emulsions, suspensions, microemulsions, microcapsules, microspheres, or ionic (liposomes) and nonionic vesicle dispersants obtained by dispersing the oil phase in the aqueous phase, or in the form of pastes, toners, emulsions, powders, ointments, sprays or tapered strips. These compositions can be prepared according to the conventional methods of this area. Compositions according to the present invention can also be used in the form of foams or in the form of aerosol compositions further comprising compressed propellants.

[0191] As some embodiments of the present invention, the cosmetic composition is not particularly limited in dosage form. For example, it can be formulated into softening lotion, astringent lotion, nourishing lotion, nourishing cream, massage cream, essence, cleansing cream, facial cleanser, cleansing water, hair nourishing agent, hair conditioner, hair brightening agent, hair conditioner, nourishing hair conditioner, shampoo, conditioner, hair treatment cream, hair conditioner, nourishing hair conditioner, moisturizing hair conditioner, hair massage cream, hair wax, hair gel, hair mask, nourishing hair mask, shampoo soap, shampoo, hair oil, hair dryer, hair preservation treatment agent, hair dye, hair waving agent, hair bleaching agent, hair gel, hair care essential oil, hair styling agent, hair adhesive, leave-in conditioner, hair mousse or styling agent and other cosmetics.

[0192] When the dosage form of the present invention is a paste, cream or gel, animal fiber, plant fiber, wax, paraffin, starch, gum tragacanth, cellulose derivatives, polyethylene glycol, silicon, bentonite, silicon dioxide, talc or zinc oxide etc. can be used as the carrier component.

[0193] When the dosage form of the present invention is a powder or a spray, lactose, talc, silicon dioxide, aluminum hydroxide, calcium silicate or polyamide powder can be used as a carrier component. In particular, the spray may further contain a propellant such as chlorofluorocarbon, propane / butane or dimethyl ether.

[0194] When the dosage form of the present invention is a solution or an emulsion, a solvent, a solvating agent or an emulsifying agent is used as a carrier component, for example, water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol oil, glycerol aliphatic ester, polyethylene glycol or fatty acid ester of sorbitol.

[0195] When the dosage form of the present invention is a suspension, as the carrier component, liquid diluents such as water, ethanol or propylene glycol, ethoxylated isostearyl alcohol, polyoxyethylene sorbitan and suspending agents such as polyoxyethylene sorbitan, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar or tragacanth can be used.

[0196] When the dosage form of the present invention is a detergent containing a surfactant, as the carrier component, fatty alcohol sulfate, fatty alcohol ether sulfate, sulfosuccinic acid monoester, ethyl sulfonate, imidazoline derivative, methyl taurate, sarcosinate, fatty acid ether sulfate, alkylamide betaine, fatty alcohol, fatty acid glyceride, fatty acid diethanolamide, vegetable oil, lanolin derivative or ethylated glycerol fatty acid ester can be used.

[0197] As some embodiments of the present invention, the cosmetic composition may further include functional additives and ingredients contained in ordinary cosmetic compositions in addition to the active ingredients. As the functional additives, ingredients selected from the group consisting of water-soluble vitamins, oil-soluble vitamins, polymer peptides, polymer polysaccharides, sphingomyelin and seaweed extracts may be included, and other cosmetic compositions with confirmed hair loss prevention or hair growth effects may be further included.

[0198] In addition to the functional additives, the cosmetic composition of the present invention may be formulated with ingredients contained in ordinary cosmetic compositions as needed. Examples of the ingredients further included include oil components, moisturizers, emollients, surfactants, organic and inorganic pigments, organic powders, ultraviolet absorbers, preservatives, bactericides, antioxidants, plant extracts, pH adjusters, alcohols, pigments, fragrances, blood stimulants, cold agents, antiperspirants, purified water, and the like.

[0199] The composition according to one aspect of the present invention may be an external preparation for skin application. The external preparation for skin application is a general term for any external preparation applied to the outside of the skin, which may include cosmetics and pharmaceuticals in various dosage forms.

[0200] From another perspective, the pharmaceutical composition or cosmetic composition of the present invention relates to a kit for preparing a dosage form for topical skin administration, wherein the kit is a kit for preparing a dosage form for applying any of the compositions to the skin, preferably, to transdermal administration to human skin, and the kit may include an adhesive or non-adhesive patch or device.

[0201] In one aspect, the kit can be a kit comprising (i) a first kit component comprising the pharmaceutical composition, and (ii) a second kit component comprising an adhesive or non-adhesive patch or device suitable for applying the pharmaceutical composition to the skin.

[0202] From another perspective, the present invention relates to a solid composition formulated as a liquid composition, wherein the solid composition is soluble in an aqueous liquid solvent, and the liquid composition is characterized in that it contains 0.00005% (w / w) to 0.5% (w / w) of a compound represented by Chemical Formula I, a derivative thereof, or a pharmaceutically acceptable salt thereof.

[0203] On the other hand, the pharmaceutical composition or cosmetic composition according to the present invention can be applied in the form of microneedles to the skin and other parts of the scalp that are to be treated or where hair growth is required.

[0204] Therefore, the present invention, from another perspective, relates to a microneedle structure carrying the pharmaceutical composition or cosmetic composition.

[0205] In the present invention, the microneedle structure is not limited thereto, but may be a microneedle patch or a microneedle applicator. In the present invention, the microneedle is not limited thereto, but may include a biocompatible polymer selected from the group consisting of hyaluronic acid, collagen, polyvinyl pyrrolidone, polylactic acid, polylactic acid glycolic acid, polylactide, polyglycolic acid, polyethylene glycol, polycaprolactone, polyamino acid, polypropylene fumarate, γ-polyglutamic acid, polyvinyl alcohol, polyethylene imine, albumin, dextran, fibrin, elastin, gelatin, alginic acid, polyacrylic acid, carboxymethyl cellulose, and mixtures or copolymers thereof.

[0206] In the present invention, the term "biocompatible polymer" composition refers in particular to a substance that is non-toxic, chemically inert, and non-immunogenic to the human body. Preferably, a polymer composition that can be decomposed by body fluids or microorganisms in the body can be used.

[0207] The present invention is characterized in that the microneedle structure may include solid microneedles, coated microneedles, dissolving microneedles, hollow microneedles or candle-shaped microneedles, preferably candle-shaped microneedles, but not limited thereto.

[0208] In the present invention, the microneedle may further include an adhesive composition.

[0209] In the present invention, the term "viscous composition" refers to a composition having the ability to stretch in the direction of negative pressure formation to form a microstructure when the negative pressure used in the present invention is applied. The viscous material used in the present invention includes acrylic polymers, amide polymers, acetyl polymers, vinyl polymers, epoxy polymers, silicon polymers, sulfonic resins, polycarbonate polymers or copolymers thereof, but is not limited thereto, and all viscous materials conventionally used in the art can be used.

[0210] Preferably, the viscous material used in the present invention has viscosity when fluidized. This viscosity can be varied according to the type, concentration, temperature, organic solvent, etc. of the viscous material, and can be appropriately adjusted according to the purpose of the present invention. More preferably, the viscous material of the present invention exhibits a viscosity of 200,000 cSt (centistoke) or less when fluidized.

[0211] The viscosity of the viscous composition can be variously changed according to the type, concentration, temperature or addition of a thickener, etc. of the substance contained in the composition, and can be appropriately adjusted according to the purpose of the present invention. The viscosity of the viscous composition can be adjusted by the inherent viscosity of the viscous substance, and can also be adjusted by using an additional thickener in the viscous composition.

[0212] For example, a thickening agent conventionally used in the art, such as hyaluronic acid and salts thereof, polyvinyl pyrrolidone, cellulose polymer, dextran, gelatin, glycerin, polyethylene glycol, polysorbate, propylene glycol, povidone, carbomer, gum ghatti, guar gum, glucomannan, glucosamine, dammer resin, rennet casein, locust bean gum, microfibrillated cellulose, psyllium seed gum, xanthan gum, arabino ga lactan, gum arabic, alginic acid, gelatin, gellan gum, carrageenan, karaya gum, curdlan, chitosan, chitin, tara gum, tamarind gum, tragacanth gum, Thickeners such as gum, furcellan, pectin or pullulan are added to the main component of the solid microstructure, such as a composition containing a biocompatible substance, to adjust the viscosity to be suitable for the present invention.

[0213] The present invention is characterized in that the composition can be injected once within 2 to 30 days, for example, once in 2 days, once in 3 days, once in 4 days, once in 5 days, once in 6 days, once in 7 days, once in 8 days, once in 9 days, once in 10 days, once in 11 days, once in 12 days, once in 13 days, once in 14 days, once in 15 days or once in 30 days, but is not limited thereto.

[0214] In the present invention, Korean Patent Publication No. 10-2016-0024354, No. 10-2020-0024515, No. 10-2020-0085224, and Korean Patent Authorization No. 10-2175312 on microneedles are incorporated into this specification as references, and a person skilled in the art of the present invention can use the microneedles described in the above-mentioned patents and other well-known microneedles to easily apply the pharmaceutical composition or cosmetic composition according to the present invention to the part where hair growth is required. As a preferred embodiment, the microneedle can be a dissolving microneedle (DMN), but is not limited thereto.

[0215] In the present invention, the microneedles may be solid microneedles, coated microneedles, dissolving microneedles or hollow microneedles.

[0216] Solid microneedles are not limited to this, but can generally be used for skin pretreatment. After inoculation of solid microneedles, if micron-sized holes are formed on the skin surface, drugs can be applied to the holes or patches containing drugs can be used, and the drugs are absorbed into the body through the holes and delivered to the skin.

[0217] Coated microneedles are microneedles that are coated with drugs on the surface of microneedles using water-soluble agents such as viscosity increasing agents and surface treatment agents. When the drugs are injected into the skin, the coated drugs dissolve in the skin and are delivered. Coated microneedles usually use sharp metal microneedles, which can be effectively injected, but the amount of drugs injected is small, so they are not suitable for drugs that need to be used in large quantities. They are suitable for vaccines that can be effective with only a small amount of injection.

[0218] Dissolving microneedles use biodegradable polymers or sugars in the needles to carry drugs. They have the advantages of being completely dissolved in the injection site during transdermal injection and requiring no additional treatment after microneedle injection.

[0219] Hollow microneedles are hollow microneedles of the common syringe type, which can easily deliver liquid preparations or large amounts of drugs or vaccines.

[0220] In the present invention, as one form of microneedles for injecting the compound or pharmaceutical composition, in-plane microneedles can be used (Lin Liwei et al., "Silicon-processed Microneedles", Journal of microelectromechanical systems: a joint IEEE and ASME publication on microstructures, microactuators, microsensors, and microsystems 8(1):78-84(1999)).

[0221] As another means for injecting the compound or pharmaceutical composition, biodegradable polymer microneedles can be used (e.g., Jung-Hwan Park et al., "Biodegradable polymer microneedles: Fabrication, mechanics and transdermal drug delivery", Journal of Controlled Release 104(1):51-66(2005)).

[0222] As another means for injecting the compound or pharmaceutical composition, an absorption-type microneedle can be used (eg, Japanese Patent Application Publication No. 2005154321; and Takaya Mi yano et al., "Sugar Micro Needles as Transdermic Drug Delivery System", Biomedical Microdevices, 7(3): 185-188 (2005)).

[0223] As another means for injecting the compound or pharmaceutical composition, biodegradable microneedles can be used (eg, Sean P Sullivan et al., "Minimally Invasive Prot otein Delivery with Rapidly Dissolving Polymer Microneedles", Advanced Materials 20(5):933-938 (2008)).

[0224] As another method for injecting the compound or pharmaceutical composition, a hollow microneedle may be used (eg, Korean Patent Publication No. 10-2016-0024354).

[0225] As another means for injecting the compound or pharmaceutical composition, a biodegradable polymer microneedle suitable for quantitative delivery of a drug may be used (eg, Korean Patent Publication No. 10-2020-0024515).

[0226] Furthermore, as a form for injecting the compound or pharmaceutical composition, microneedles prepared using centrifugal force may be used (eg, PCT Patent PCT / KR2014 / 003964).

[0227] On the other hand, as the most preferred form for injecting the compound or pharmaceutical composition, candle-type microneedles (eg, Korean Patent No. 10-2175312) may be used.

[0228] The preferred candle-shaped microneedle according to the present invention includes: a tip portion, including a drug; a base portion, formed on one side of the tip portion; and a separation portion, formed between a substrate and the base portion. After the tip portion is inserted into the skin, the substrate and the base portion are separated, physically separated by external force or chemically separated by chemical substances. The base portion provides a supporting force so that the tip portion can be completely inserted into the skin. The tip portion can be a microstructure with a candle-shaped cross-section.

[0229] In the present invention, the drug may be the compound or the pharmaceutical composition or the cosmetic composition according to the present invention.

[0230] In the present invention, the separation part may be a microstructure including at least one selected from the group consisting of a biodegradable polymer and a sugar.

[0231] In the present invention, the time required for the separation portion to be dissolved by the chemical substance may be less than 5 minutes.

[0232] In the present invention, the separation part can dissolve more than 70% of the unit volume by the chemical substance within 3 minutes.

[0233] The present invention is characterized in that the chemical substance may be applied to the skin before flowing between the base plate and the skin or the tip portion is inserted into the skin.

[0234] The present invention is characterized in that the chemical substance comprises at least one selected from water, an aqueous solution, and an injectable ester, the aqueous solution comprises at least one selected from anhydrous or aqueous lower alcohols having a carbon number of 1 to 4, acetone, ethyl acetate, chloroform, 1,3-butanediol, nucleic acid, diethyl ether, and butyl acetate, the injectable ester comprises at least one selected from a water-insoluble agent, propylene glycol, polyethylene glycol, an oil phase component, and ethyl oleate, and the oil that can be used as the oil phase component comprises at least one selected from vegetable oil, mineral oil, silicone oil, and synthetic oil.

[0235] The present invention is characterized in that the cross section of the center of the separation portion has a smaller area than the cross sections on both sides of the separation portion.

[0236] The present invention is characterized in that the separation portion is broken by a force smaller than a bonding force between the separation portion and any one of the base portion and the substrate.

[0237] The present invention is characterized in that the separation portion is broken by a force smaller than a force with which the tip portion is detached from the skin.

[0238] The present invention is characterized in that the strength of the separation portion is 0.01 to 1N.

[0239] The present invention is characterized in that the external force is applied in a horizontal direction or a vertical direction relative to the separation portion.

[0240] The present invention is characterized in that the separation portion or the base portion contains a biodegradable substance.

[0241] The present invention is characterized in that the substrate has a protruding portion having a predetermined thickness formed at a portion corresponding to the separation portion formed on a portion of the substrate.

[0242] The present invention is characterized in that the protrusion is a horizontal straight line, an inclined oblique line, or a curved line with a central convexity or concavity in a cross section of a surface forming the separation portion.

[0243] As used in this specification, the term "effective amount" refers to the amount required or sufficient to achieve the desired biological effect. Preferably, the term "effective content" refers to the amount of the compound of formula I of the present invention that (i) treats or prevents a specific disease, medical morbidity or disorder, (ii) reduces, alleviates or eliminates one or more symptoms of a specific disease, medical morbidity, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, medical morbidity, or disorder recorded in this specification. The effective amount of the compound of the present invention of formula I, or the pharmaceutical composition, is the amount to achieve these selected results, and this amount can be determined by a person skilled in the art as a daily matter. Further preferably, the term "effective content", as used in this specification, is typically and preferably, the amount required or sufficient to effectively increase NO release and PDE5 inhibitory effect. The effective content may vary depending on the specific composition administered and the size of the subject. A person skilled in the art can experimentally determine the effective amount of a specific composition of the present invention without excessive experimental procedures.

[0244] As used in this specification, the term "mammal" includes, but is not limited to, humans, mice, rats, guinea pigs, monkeys, dogs, cats, horses, cows, pigs, and sheep. As used in this specification, the term "mammal" preferably refers to humans.

[0245] The term "pharmaceutically acceptable" refers to properties that do not impair the biological activity and physical properties of the compound.

[0246] The term "prevention" used in the present invention refers to all actions to prevent the onset of a disease or inhibit its progress by administering a composition containing the compound.

[0247] The term "improvement" of the present invention refers to all actions that at least reduce the parameters related to the therapeutic state of the disease, such as the extent of symptoms, by administering the composition comprising the compound.

[0248] Furthermore, the term "treatment" used in the present invention refers to all actions of improving or curing disease symptoms by administering a composition containing the compound.

[0249] The term "administration" of the present invention refers to the act of introducing the pharmaceutical composition of the present invention into an individual by any appropriate method, as long as it can reach the target tissue, and the administration route may be through various routes such as oral or parenteral administration.

[0250] The term "topical administration" of the present invention is used in a broad sense, including administration to body surfaces that are generally open to the surroundings. This includes not only the skin, but also the nasal cavity, oral routes and genitals. Therefore, topical administration includes skin application, nasal application, oral application (including upper throat) and administration to genital organs. Topical preparations can take various forms, creams, ointments, solutions, emulsions, suspensions, pastes, lotions, foams and others. Water-miscible creams are generally suitable for moist, purulent lesions, and ointments are generally selected for dry, lichenified or scaly lesions or wounds that require further sealing effects. Emulsions are generally useful when minimal application is required in large or hairy areas or for the treatment of exudative lesions. The term "topical administration" is used in this application for the purpose of proposing topical administration and eye drops in this application.

[0251] The term "% (w / w)" of the present invention means (mass of the corresponding ingredient / total mass of the composition) x100.

[0252] The term "transdermal" administration of the present invention refers to a method of administering a drug through the skin, and "hypodermic" injection refers to injection into the subcutaneous tissue for drug administration. According to the composition of the present invention, in order to prevent the side effect of circulatory hypotension caused by PDE5 inhibitors, it is preferably administered locally at the site of action of the drug, more preferably, transdermally, and most preferably, subcutaneously. Candle-shaped microneedles carrying compound 1 can be used in the most preferred manner of local administration, transdermal administration or subcutaneous injection.

[0253] The term "kit" of the present invention means that the components contained in the kit can be physically separated and provided as different components, but are provided or sold together for the purpose of joint administration or use.

[0254] Compound or composition according to the present invention can be administered by suitable approach, for example, by intradermal administration, preferably percutaneous administration, more preferably subcutaneous injection. As other approaches and well known in the art, and for example, can be applied by housing entrance. Therefore, according to drug delivery device, such as administration form and administration route, conventional needle and syringe, microneedle, patch (such as WO98 / 20734), needle-free injection system (such as WO1999027961A1), spray equipment and others can be used. Compound or pharmaceutical composition of the present invention can be pre-filled or applied in the device.

[0255] Example

[0256] The present invention is further described in detail below by way of examples. These examples are only used to illustrate the present invention, and should not be interpreted as limiting the scope of the present invention by these examples, which is obvious to those skilled in the art to which the present invention belongs.

[0257] Synthesis of the compound represented by Chemical Formula I

[0258] Compounds of Formula I and methods for synthesizing the same are disclosed in WO / 2018 / 215433, the entire disclosure of which is incorporated herein by reference. In particular, Examples 1n and 1i of WO / 2018 / 215433 include detailed descriptions of the preparation of preferred compounds of Formula I.

[0259] Example 1. Candle-shaped microneedles loaded with compound 1

[0260] Candlelit microneedles (CMNs) are made through two main stages of so-called base layer and head layer production. The base layer formed by a biodegradable polymer is made using a dry method. After a 20% (w / v) pharmaceutical grade hyaluronic acid aqueous solution (PHA, 30 kDa; Youthcarefarm, Suwon, South Korea) is dispensed into the substrate, the droplets are contacted with the cover plate. The droplets are naturally dried at a predetermined distance of 300 μm between the two plates to form a red wine glass shape. Next, 60% (w / v) PHA droplets are dispersed on a 4% (w / v) carboxymethyl cellulose coated film (CMC, 90 kDa; Sigma-Aldrich, St. Louis, MO, USA). CMNs were prepared by centrifugal lithography with a force of 202 g for one minute. In PHA droplets loaded with 0.027% (w / v) of compound and the final Cp1 CMNs prepared from this solution contained 2 μg of drug per 5×5 array.

[0261] Applicator: The microneedle applicator that supports CMN penetration is designed to be applied to the scalp in the hairy part of the skin. The device's micro-pillars are arranged in a 5×5 CMN array and provide insertion force for penetrating hairy skin.

[0262] Example 2. Preparation of conventional dissolving microneedles (conv-DMN) loaded with compound 1

[0263] 2-1. Conical Conv-DMNs loaded with Compound 1 (Cp1) were prepared using the same polymer, drug loading (2 μg / day), and height (700 μm) as in Example 1.

[0264] 2-2. Conical Conv-DMNs loaded with Compound 1 (Cp1) were prepared using the same polymer, drug loading (4 μg / day), and height (700 μm) as in Example 1.

[0265] HPLC conditions for CP1: For quantitative analysis of the amount of compound 1 loaded on CMN, a reversed-phase HPLC (Waters 600S; Waters, Milford, MA, USA) with a C18 column (150 mm×4.6 id, Cosmosil 5C18-AR-ⅡTesque Inc., Kyoto, Japan) was used. To establish a calibration curve, a stock solution of compound 1 was prepared from 1.5 mg / mL to 0 (R 2 ≥0.99) were diluted in turn. The mobile phase was prepared with 0% (v / v) acetonitrile and 50% (v / v) distilled water, and the flow rate was set to 1 mL / min. The detection wavelength of compound 1 was 254 nm. The residence time was determined to be 6.625 minutes.

[0266] Example 3. Enhancement of the effect of compound 1 injected using microneedles

[0267] 3-1. Experimental methods

[0268] Seven-week-old C57BL / 6 mice (Oriental Bio, Korea) with hair follicles in the resting phase were purchased and the experiment was performed. Four mice were used for each of the six experimental groups: the transfersome smear control group (topical control), the minoxidil smear positive control group (topicalminoxidil), the compound 1 smear group (topical compound 1), the candle-shaped microneedle control group (CMN control), the compound 1 microneedle administration group (compound 1conv-DMN), and the compound 1 candle-shaped microneedle administration group (compound 1CMN).

[0269] Table 1

[0270]

[0271]

[0272] Preparation of topical minoxidil (positive control group) and topical compound 1 (medium dose compound 1 application group) solutions: For the topical dosage form, a 50 μL solution of polyethylene glycol 400 (PEG 400; Sigma-Aldrich, St. Louis, MO, USA) and ethanol (99.5°; Sigma-Aldrich) containing 2% (w / v) minoxidil (Sigma-Aldrich) or 0.002% (w / v) compound 1 (2 μg / 1 day) was prepared in a 7:3 (v / v) ratio. The 50 μL solution of the topical dosage form group was administered twice a day.

[0273] The mice were depilated on their backs and the experiment was started when the skin was pink. The drug was applied twice a day for 21 days. When microneedle injection was used, the injection was performed once every two days, and no injection was performed on the 21st day.

[0274] 3-2. Hair growth effect and skin thickness

[0275] On the 21st day of administration, the back of each mouse was observed with the naked eye, and then the mice were killed, the dorsal tissues were separated, frozen tissue sections were made, and H&E staining was performed. As a result, in the minoxidil smear positive control group (topicalminoxidil), the compound 1 smear group (topical compound 1), the compound 1 microneedle administration group (compound 1conv-DMN), and the compound 1 candle-type microneedle administration group (compound 1CMN), it can be confirmed that the skin thickness thickened, the dermis located in the hair follicles developed, and the hair follicles developed along with the hair growth effect. In this case, compared with minoxidil treatment, the effect was better when treated with compound 1. For compound 1, the skin tissue development of the hair growth effect was better when microneedle injection was used than when applied. On the other hand, when candle-type microneedles are used, the effect is best ( Figure 1a ).

[0276] 3-3. Comparison of conversion rates during the growth period

[0277] The darkened area on the back of the mice on day 21 of administration, i.e., the area converted from the hairless area to the anagen area, was analyzed by naked eyes and Image J software (National Institutes of Health, Bethesda, MD, USA).

[0278] The results of quantifying the skin area that turned black as a percentage relative to the total hair removal skin area confirmed that the area of ​​the mouse back that turned black in the minoxidil positive control group (topical minoxidil) was 65.3±22.3%, while in the compound 1 application group (topical compound 1), 92.1±3.0% of the hair removal area turned black, indicating that the growth phase conversion effect was better when compound 1 was applied than when minoxidil was applied. On the other hand, when compound 1 was administered with microneedles, a similar degree of growth phase conversion effect was also shown as in the case of topical application of compound 1 ( Figure 1b ).

[0279] 3-4. Comparison of hair growth rate

[0280] On day 21 of administration, the proportion of hair actually grown on the back of the mice was analyzed by naked eye and image analysis program Image J software (National Institutes of Health, Bethesda, MD, USA).

[0281] The results of quantifying the percentage of the skin area where hair actually grew relative to the total hair removal skin area showed that hair grew at 38.4±17.1% in the minoxidil application positive control group (topical minoxidil) and at 61.0±14.0% in the compound 1 application group (topical compound 1). Compared with minoxidil, compound 1 showed an improved effect on hair growth. In the compound 1 candle-type microneedle administration group (compound 1CMN), actual hair growth was observed at 92.9±11.2%. Therefore, it can be confirmed that actual hair grows rapidly in most of the area converted to the growth phase ( Figure 1c ).

[0282] 3-5. Comparison of distribution rates of each hair growth cycle

[0283] The distribution rate of each hair growth cycle was compared in mice on the 21st day of administration. To this end, the hair cycle was analyzed based on the morphology of each stained hair follicle based on the H&E stained images in Example 4-2. Five tissue sections were separated from four mice in each experimental group for analysis, and the proportion of the resting phase (telogen) and the growth phase (alogen) was confirmed by the morphology of the hair follicles with reference to Lahiji, Shayan Fakhraei, et al. "Transcutaneous implantation of valproic acid-encapsulated dissolving microneedles induce shair regro wth." Biomaterials 167 (2018): 69-79.

[0284] As a result, 52.5±1.3% of the minoxidil-treated positive control group (topical minoxidil) were converted to the growth phase, whereas 59.3±3.0% of the compound 1-treated group (topical compound 1) were converted to the growth phase. It was confirmed that the efficiency of compound 1 in converting to the growth phase was superior to that of minoxidil. On the other hand, 66.0±3.4% of the compound 1 microneedle administration group (compound 1conv-DMN) were converted to the growth phase, and 72.3±2.5% of the compound 1 candle-type microneedle administration group (compound 1CMN) were converted to the growth phase. It was confirmed that the growth phase conversion effect was significantly increased during microneedle administration, especially by using the candle-type microneedle administration method ( Figure 1d ).

[0285] 3-6. Changes in skin thickness and hair thickness

[0286] In order to compare the development degree of skin and hair tissue, the thickness of the skin stained with H&E in Example 4-2 was measured under a microscope, and 30 hairs were taken from each treatment group and the thickness of the hair was compared.

[0287] As a result, compared with the minoxidil positive control group (topical minoxidil), the compound 1 application experimental group (topical compound 1) was observed to have further improved skin thickening effect and hair thickness improvement effect. When microneedle administration was used, especially candle-type microneedle administration, further significantly improved skin thickening effect and hair thickness improvement effect were confirmed ( Figure 1e , 1f , 1g).

[0288] 3-7. Analysis of skin tissue development markers

[0289] The development of skin tissue as a surrounding support body during hair growth plays an important role in hair growth. In order to compare the degree of skin tissue development in the six experimental groups of the transfer body smear control group (topical control), minoxidil smear positive control group (topicalminoxidil), compound 1 smear group (topical compound 1), candle-type microneedle control group (CMN control), compound 1 microneedle administration group (compound 1conv-DMN), and compound 1 candle-type microneedle administration group (compound 1CMN), β-catenin (β-catenin) and proliferating cell nuclear antigen (PCNA) as biomarkers representing skin tissue proliferation, vascular endothelial cell marker MECA32 representing the development of the vascular network around mouse hair follicles, and versican (Versican, VCAN), a marker of hair papilla cells (DP) generated in the anagen phase (Anagen) showing the effect of inducing the anagen phase of hair follicles, were immunohistochemically stained and observed. For this purpose, as shown in Example 4-2, after collecting the dorsal tissue of mice on the 21st day, the tissue sections were frozen, and the fluorescent image was analyzed after the fluorescent substance-conjugated antibody was treated in the tissue. The antibodies used were β-catenin (BD Biosciences, San Jose, CA, USA), PCNA (LSBIO, Seattle, WA, USA), VCAN (LSBIO, Seattle, WA, USA), and MECA-32 (Novus Biologicals, CA, USA).

[0290] As a result, the expression of β-catenin was higher when Compound 1 was applied or administered with microneedles than when minoxidil was applied. In particular, the expression of β-catenin was highest when Compound 1 was administered with candle-shaped microneedles ( Figure 2a , Figure 2b On the other hand, PCNA was expressed at a higher level when microneedles were used, regardless of drug administration ( Figure 2a , Figure 2c ), which is believed to be the effect of microneedling to stimulate the skin.

[0291] For MECA 3, the expression level of MECA 3 increased in the order of minoxidil application, compound 1 application, compound 1 administration using ordinary microneedles, and M-19 administration using candle-type microneedles ( Figure 2d , Figure 2e ), compared with minoxidil, compound 1 has a higher effect of dilating blood vessels. Compared with applying compound 1, it can be confirmed that the use of microneedles, especially candle-shaped microneedles, further improves the effect of dilating blood vessels, thereby significantly promoting the supply of nutrients through the blood flow enhancement of hair follicles.

[0292] In addition, it was confirmed that for Versican (VCAN), the expression level of VCAN increased in the order of minoxidil application, compound 1 application, compound 1 administration using ordinary microneedles, and M-19 administration using candle-type microneedles ( Figure 2f , Figure 2g ), the growth phase (anagen) of hair follicles was promoted in the order of minoxidil application, compound 1 application, compound 1 administration using ordinary microneedles, and M-19 administration using candle-type microneedles, thereby actively generating hair papilla cells.

[0293] The above describes in detail the specific part of the content of the present invention. It is obvious to those skilled in the art that this specific technology is only a preferred embodiment, and the scope of the present invention is not limited thereto. Therefore, the essential scope of the present invention should be defined by the attached invention claims and their equivalents.

[0294] This research was supported by a grant from the Korea Health Industry Development Agency (HI20C2083) with financial resources from the Ministry of Health and Welfare of Korea.

[0295] chnology R&D Project through the Korea Health Industry Developme

[0296] nt Institute (KHDI), funded by the Ministry of Health&Welfare,

[0297] Republic of Korea (grant number: HI20C2083).

Claims

1. A pharmaceutical composition for transdermal administration comprising a compound of formula I or a pharmaceutically acceptable salt thereof: Chemical formula I in, R1 is a C1-C3 alkyl group; R2 is H, CHO or CH=N-OH; R3 is a C1-C4 alkyl group; R4 is a C1-C6 alkyl group; R5 is SO2NR6R7, wherein R6 and R7 together with the nitrogen atom to which they are attached form a heterocyclic ring selected from piperidine and piperazine, the heterocyclic ring being substituted by at least one R8, the R8 being independently selected from C1-C6 alkyl, selectively substituted by OH or ONO2, at least one of the at least one R8 comprising at least one ONO2 moiety.

2. The pharmaceutical composition according to claim 1, wherein R1 is methyl or ethyl; R2 is H; R3 is ethyl or n-propyl; and R4 is ethyl or n-propyl.

3. The pharmaceutical composition according to claim 1, wherein R1 is ethyl; R2 is H; R3 is n-propyl; and R4 is n-propyl.

4. The pharmaceutical composition according to claim 1, wherein The compound of formula I is a compound selected from the group consisting of the following compounds:

5. The pharmaceutical composition according to claim 1, wherein The compound of formula I is a compound selected from the group consisting of the following compounds: (1) (1-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4,4-diyl)bis(ethane-2,1-diyl) dinitrate; (1) (1-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4,4-diyl)bis(ethane-2,1-diyl) dinitrate; (2) 2-(4-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperazin-1-yl)ethyl nitrate; (3) 2-(1-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4-yl)ethyl nitrate; (4) 3-(1-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4-yl)propyl nitrate; (5) (R)-1-(1-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4-yl)ethylene glycol dinitrate; (6) (S)-1-(1-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4-yl)ethylene glycol dinitrate; (7) ((2R,6S)-4-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)-1-methylpiperazine-2,6-diyl)bis(ethane-2,1-diyl) dinitrate; (8) ((2S,6S)-4-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)-1-methylpiperazine-2,6-diyl)bis(ethane-2,1-diyl) dinitrate; (9) 3-(1-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4-yl)-3-hydroxypentane-1,5-dinitrate; and (10) 2-(1-((3-(5-ethyl-4-oxo-7-propyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-2-yl)-4-propoxyphenyl)sulfonyl)piperidin-4-yl)-2-hydroxypropane-1,3-dinitrate.

6. The pharmaceutical composition according to claim 1, wherein The compound of Chemical Formula I is a compound of Chemical Formula 1 or Chemical Formula 2:

7. The pharmaceutical composition according to claim 1, wherein The pharmaceutical composition comprises 0.00005% (w / w) to 0.5% (w / w) of the compound of Formula I or a pharmaceutically acceptable salt thereof.

8. The pharmaceutical composition according to claim 1, wherein The pharmaceutical composition is used for preventing, improving or treating one or more diseases or disorders selected from the group consisting of skin diseases, skin aging, steroid-induced skin atrophy, impotence, and hair loss or hair growth.

9. The pharmaceutical composition according to claim 8, wherein The disease or disorder is hair loss, The pharmaceutical composition prevents hair loss or promotes hair growth by (i) inducing the growth phase of hair follicles, (ii) promoting melanin production, (iii) increasing the number of hair follicles, (iv) increasing skin thickness, (v) promoting angiogenesis, (vi) outer root sheath cell proliferation and / or (vii) enhancing blood flow in hair follicles.

10. The pharmaceutical composition according to claim 8, wherein The hair loss is androgenic alopecia, chemotherapeutic drug-induced alopecia or alopecia areata.

11. A kit, wherein: include: (i) a first kit component comprising a pharmaceutical composition according to any one of claims 1 to 10; as well as (ii) a second kit component comprising an adhesive or non-adhesive patch or device suitable for applying the pharmaceutical composition to the skin.

12. A solid composition for preparing a pharmaceutical composition according to any one of claims 1 to 10, wherein: The solid composition is dissolved in a liquid solvent, and the liquid composition in which the solid composition is dissolved contains 0.00005% (w / w) to 0.5% (w / w) of the compound of Chemical Formula I or a pharmaceutically acceptable salt thereof.

13. A microneedle structure, wherein: The pharmaceutical composition according to any one of claims 1 to 10 is carried.

14. The microneedle structure according to claim 13, wherein The microneedle structure is a microneedle patch or a microneedle applicator.

15. The microneedle structure according to claim 13, wherein The microneedle structure includes solid microneedles, coated microneedles, dissolved microneedles, hollow microneedles or candle-shaped microneedles.

16. The microneedle structure according to claim 15, characterized in that: The microneedle structure comprises a biocompatible polymer selected from the group consisting of hyaluronic acid, collagen, polyvinyl pyrrolidone, polylactic acid, polylactic acid-co-glycolic acid, polylactide, polyglycolic acid, polyethylene glycol, polycaprolactone, polyamino acids, polypropylene fumarate, γ-polyglutamic acid, polyvinyl alcohol, polyethylene imine, albumin, dextran, fibrin, elastin, gelatin, alginate, polyacrylic acid, carboxymethyl cellulose, and mixtures or copolymers thereof.

17. The microneedle structure according to claim 13, characterized in that: The pharmaceutical composition is injected once within 2 to 15 days.

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