Compound having novel structure in which hair loss treatment component is immobilized and method for producing same

Abstract

Various embodiments of the present invention relate to a compound in which a 4-azasteroid derivative or minoxidil and a polymer are chemically bonded, wherein the polymer is directly bonded to or bonded through a spacer to the 4-azasteroid derivative or the minoxidil. The method for manufacturing a compound according to various embodiments of the present invention may comprise a step of directly bonding or bonding through a spacer a 4-azasteroid derivative or minoxidil to a polymer. The method for manufacturing a compound according to various embodiments of the present invention may comprise the steps of: bonding a polymer to a piperidine derivative; and bonding the piperidine derivative, to which the polymer is bound, to a pyrimidine derivative.

Description

Compound having a novel structure in which a hair loss treatment ingredient is fixed and a method for producing the same

[0001] Various embodiments of the present invention relate to a compound having a novel structure in which a hair loss treatment ingredient is immobilized and a method for producing the same.

[0002] Minoxidil is a representative example of a drug used to treat scalp hair loss. Approved by the U.S. FDA, minoxidil acts as a unique potassium channel opener, dilating blood vessels. In addition, it has been reported to induce hair from the telogen phase to the anagen phase and maintain the induced anagen phase.

[0003] Meanwhile, minoxidil is used as a topical medication applied to the scalp, but contact with other areas can cause adverse effects. Therefore, immobilization of minoxidil is crucial for ensuring its action is limited to the target area. However, immobilization significantly alters the structure of minoxidil, reducing its efficacy.

[0004] In various embodiments of the present invention, it is intended to provide a compound capable of stably fixing a hair loss treatment component, including minoxidil, which is widely used as a scalp hair loss treatment agent, and inducing a local action to reduce side effects, and a method for preparing the same.

[0005] To achieve the above purpose, the present invention provides a compound in which a 4-azasteroid derivative or minoxidil and a polymer are chemically bonded.

[0006] According to an example of the present invention, the polymer may be directly bonded to the 4-azasteroid derivative or the minoxidil or may be bonded via a spacer.

[0007] According to an example of the present invention, the minoxidil may include a carboxyl group or an amine group bonded to a secondary carbon.

[0008] The 4-azasteroid derivative according to an example of the present invention may contain at least one functional group selected from the group consisting of an amide group, a carboxyl group, and a thioester group.

[0009] According to an example of the present invention, the polymer may include at least one functional group selected from the group consisting of a hydroxyl group, a carboxyl group, an acetyl group, an amide group, and an amine group.

[0010] According to an example of the present invention, the polymer may include at least one selected from the group consisting of hyaluronic acid, alginate, cellulose, chitosan, gelatin, starch, chitin, collagen, and heparin.

[0011] According to one example of the present invention, the polymer may be deacetylated.

[0012] According to an example of the present invention, the spacer may be any one of an alkyl chain including at least one selected from the group consisting of -NH2, -COOH, -OH, aldehyde, epoxide, halogen elements (F, Cl, Br, I), succinimide, alkene, and alkyne at at least one of both terminals, an alkyl chain including at least one selected from the group consisting of a disulfide bond, an ester bond, and an amide bond, and a peptide.

[0013] According to an example of the present invention, the compound may be any one of the following chemical formulas 6 to 9.

[0014] [Chemical Formula 6]

[0015]

[0016] [Chemical Formula 7]

[0017]

[0018] In the above chemical formulas 6 and 7,

[0019] Ra is NH, O, , , , , , , , and One of them,

[0020] Rb is CH2, NH, O, , and At least one of them,

[0021] Rc is , , and At least one of them,

[0022] Rd is H, CH3, CH(CH3)2, CH2-CH(CH3)2, CH2-CH2-S-CH3, CH(CH3)-CH2-CH3, CH2-OH, CH(CH3)-OH, CH2-SH, CH2-CONH2, CH2-CH2-CONH2, CH2-CH2-CH2-CH2-NH2, CH2-CH2-CH2-NH-C(NH2)=NH, CH2-COOH, CH2-CH2-COOH, , , , and It is one of them.

[0023] [Chemical Formula 8]

[0024]

[0025] In the above chemical formula 8,

[0026] Re is , , , , , , , and One of them,

[0027] Rb is CH2, NH, O, , and At least one of them,

[0028] Rc is , and At least one of them,

[0029] Rd is H, CH3, CH(CH3)2, CH2-CH(CH3)2, CH2-CH2-S-CH3, CH(CH3)-CH2-CH3, CH2-OH, CH(CH3)-OH, CH2-SH, CH2-CONH2, CH2-CH2-CONH2, CH2-CH2-CH2-CH2-NH2, CH2-CH2-CH2-NH-C(NH2)=NH, CH2-COOH, CH2-CH2-COOH, , , , and It can be any one of the following.

[0030] [Chemical Formula 9]

[0031]

[0032] In the above chemical formulas 6 to 9, n may be 10 to 10,000, in the above chemical formulas 6 to 8, A may be a 4-azasteroid derivative or minoxidil, x may be 0 to 40, y may be 1 to 40, and z may be 1 to 40.

[0033] According to an example of the present invention, the compound represented by the above-described [chemical formula 6] may be any one of the compounds shown in the following [Table 1], wherein n may be 10 to 10,000, and X may be 0 to 40.

[0034] [Table 1]

[0035] [Correction pursuant to Rule 91, 04.09.2024]

[0036] [Correction pursuant to Rule 91, 04.09.2024]

[0037] According to an example of the present invention, the compound represented by the above-described [chemical formula 7] may be any one of the compounds shown in the following [Table 2], wherein n may be 10 to 10,000, and X may be 0 to 40.

[0038] [Table 2]

[0039] [Correction pursuant to Rule 91, 04.09.2024]

[0040] [Correction pursuant to Rule 91, 04.09.2024]

[0041] According to an example of the present invention, the compound represented by the above-described [chemical formula 8] may be any one of the compounds shown in the following [Table 3], wherein n may be 10 to 10,000, and X may be 0 to 40.

[0042] [Table 3]

[0043] [Correction pursuant to Rule 91, 04.09.2024]

[0044] [Correction pursuant to Rule 91, 04.09.2024]

[0045] In another aspect of the present invention, a method for preparing a compound is provided, comprising a step of directly bonding a 4-azasteroid derivative or minoxidil to a polymer or bonding it through a spacer. According to an example of the present invention, the method for preparing the compound may further comprise, before the bonding step, a step of modifying the minoxidil by replacing a secondary hydrogen contained in the minoxidil with a carboxyl group or an amine group.

[0046] The method for preparing the compound according to an example of the present invention may further include, before the modifying step, a step of protecting the primary amine contained in the minoxidil with an amine protecting group.

[0047] In addition, another aspect of the present disclosure provides a method for preparing a compound, comprising the steps of: combining a polymer and a piperidine derivative; and combining the piperidine derivative to which the polymer is combined with a pyrimidine derivative.

[0048] The piperidine derivative according to an example of the present invention may contain a carboxyl group or an amine group.

[0049] According to one example of the present invention, the polymer may be deacetylated.

[0050] The compound of the present invention can stably fix a hair loss treatment component by being bound to a polymer without significantly changing the structure of the hair loss treatment component.

[0051] When the compound of the present invention is absorbed into the body, the hair loss treatment component dissociates from the compound within the cells and can only act on the scalp. Therefore, the localized action of the active ingredient can reduce side effects of the hair loss treatment component. Furthermore, a composition containing the compound of the present invention can be utilized as a long-acting formulation. Furthermore, depending on the type of polymer constituting the compound, cellular uptake can be enhanced.

[0052] Below, various embodiments of this document are described. The embodiments and terminology used herein are not intended to limit the technology described in this document to specific embodiments, but should be understood to encompass various modifications, equivalents, and / or alternatives of the embodiments.

[0053]

[0054] compound

[0055] The present invention provides a compound in which a 4-azasteroid derivative or minoxidil and a polymer are chemically bonded.

[0056] The above 4-azasteroid derivative may be a steroid derivative in which the 4th carbon atom of the steroid ring system is replaced with a nitrogen atom, and specifically may be a steroid derivative represented by the following chemical formula 1, chemical formula 2, or chemical formula 3.

[0057] [Chemical Formula 1]

[0058]

[0059] [Chemical Formula 2]

[0060]

[0061] [Chemical Formula 3]

[0062]

[0063] The above minoxidil represents 3-hydroxy-2-imino-6-piperidin-1-ylpyrimidin-4-amine, and can be represented by the following chemical formula 4.

[0064] [Chemical Formula 4]

[0065]

[0066] The compound of the present invention may be one in which the polymer is directly bonded to the 4-azasteroid derivative or the minoxidil or is bonded via a spacer.

[0067] In one embodiment, the polymer may include at least one functional group selected from the group consisting of a hydroxyl group, a carboxyl group, an acetyl group, an amide group, and an amine group. The functional group included in the polymer may react with the functional group included in the 4-azasteroid derivative or the minoxidil, or with a spacer. For example, the polymer may include at least one selected from the group consisting of hyaluronic acid, alginate, cellulose, chitosan, gelatin, starch, chitin, collagen, and heparin. Specifically, the polymer may be hyaluronic acid represented by the following chemical formula 5.

[0068] [Chemical Formula 5]

[0069]

[0070] In one embodiment, the polymer may be deacetylated. In one embodiment, the deacetylation may convert an amide group contained in the polymer into an amine group, and the converted amine group may become a new reaction site capable of reacting with the 4-azasteroid derivative, the minoxidil, or the spacer.

[0071] In one embodiment, the polymer may be halogenated. In one embodiment, the halogenation may convert a hydroxyl group of a primary alcohol contained in the polymer into a halogen group, and the converted halogen group may become a new reaction site capable of undergoing a substitution reaction with a nucleophilic moiety contained in the 4-azasteroid derivative, the minoxidil, or the spacer.

[0072] According to one embodiment, the compound of the present invention may be a polymer directly bonded to the minoxidil by reacting the carboxyl group contained in the polymer with the amine group contained in the minoxidil.

[0073] In one embodiment, the minoxidil may include a carboxyl group or an amine group bonded to a secondary carbon. Specifically, the carboxyl group bonded to the secondary carbon can be obtained by substituting a secondary hydrogen contained in the minoxidil with a carboxyl group through a substitution reaction. Additionally, the amine group bonded to the secondary carbon can be obtained by amination of the substituted carboxyl group.

[0074] In one embodiment, the spacer may be an alkyl chain comprising at least one selected from the group consisting of -NH2, -COOH, -OH, aldehyde, epoxide, halogen elements (F, Cl, Br, I), succinimide, alkene, and alkyne at at least one of both ends. Alternatively, the spacer may be an alkyl chain comprising at least one selected from the group consisting of a disulfide bond, an ester bond, and an amide bond. Alternatively, the spacer may be a peptide. In one embodiment, the spacer may be a linker that is cleavable under specific conditions, such as in the body. Therefore, when the compound is absorbed into the body, the spacer is cleaved within the cell, and the hair loss treatment ingredient is separated from the compound and can act only on the scalp. Therefore, side effects can be reduced through the local action of the active ingredient.

[0075] Specifically, the compound according to various embodiments of the present invention may be any one of the following chemical formulas 6 to 9.

[0076] [Chemical Formula 6]

[0077]

[0078] [Chemical Formula 7]

[0079]

[0080] In the above chemical formulas 6 and 7,

[0081] Ra is NH, O, (alkane) , (alkane), (Cleavable) , (Cleavable), (ADH), (PEG), (PEG), and (Peptide) is one of them,

[0082] Rb is CH2, NH, O, , and At least one of them,

[0083] Rc is , , and At least one of them,

[0084] Rd is H, CH3, CH(CH3)2, CH2-CH(CH3)2, CH2-CH2-S-CH3, CH(CH3)-CH2-CH3, CH2-OH, CH(CH3)-OH, CH2-SH, CH2-CONH2, CH2-CH2-CONH2, CH2-CH2-CH2-CH2-NH2, CH2-CH2-CH2-NH-C(NH2)=NH, CH2-COOH, CH2-CH2-COOH, , , , and It is one of them.

[0085] [Chemical Formula 8]

[0086]

[0087] In the above chemical formula 8,

[0088] Re is , , (alkane), (alkane), (Cleavable), (Cleavable), (PEG), (PEG) and (Peptide) is one of them,

[0089] Rb is CH2, NH, O, , and At least one of them,

[0090] Rc is , and At least one of them,

[0091] Rd is H, CH3, CH(CH3)2, CH2-CH(CH3)2, CH2-CH2-S-CH3, CH(CH3)-CH2-CH3, CH2-OH, CH(CH3)-OH, CH2-SH, CH2-CONH2, CH2-CH2-CONH2, CH2-CH2-CH2-CH2-NH2, CH2-CH2-CH2-NH-C(NH2)=NH, CH2-COOH, CH2-CH2-COOH, , , , and It can be any one of the following.

[0092] [Chemical Formula 9]

[0093]

[0094] In the above chemical formulas 6 to 9, n may be 10 to 10,000,

[0095] In the above chemical formulas 6 to 8, A may be a 4-azasteroid derivative or minoxidil, x may be 0 to 40, y may be 1 to 40, and z may be 1 to 40.

[0096] Meanwhile, the compound according to various embodiments of the present invention may be any one of the following chemical formulas 6-1, 7-1, 8-1, and 9.

[0097] [Chemical Formula 6-1]

[0098]

[0099] In the above chemical formula 6-1, Ra is NH, , , and It can be either of the following:

[0100] Rb is , and It can be at least one of the following:

[0101] [Chemical Formula 7-1]

[0102] [Correction pursuant to Rule 91, 04.09.2024]

[0103] In the above chemical formula 7-1, Rc is , , and It can be either of the following:

[0104] Rb is , and It can be at least one of the following:

[0105] [Chemical Formula 8-1]

[0106]

[0107] In the above chemical formula 8-1, Rd is , , , and It can be either of the following:

[0108] Rb is , and It can be at least one of the following:

[0109] In the above chemical formulas 6-1 to 8-1, A may be a 4-azasteroid derivative or minoxidil.

[0110] [Chemical Formula 9]

[0111]

[0112] More specifically, the compound represented by the above [Chemical Formula 6] or [Chemical Formula 6-1] may be any one of the compounds shown in [Table 1] below, but this is only a specific example and is not limited thereto.

[0113] [Correction pursuant to Rule 91, 04.09.2024]

[0114]

[0115] The compound represented by the above [Chemical Formula 7] or [Chemical Formula 7-1] may be any one of the compounds shown in [Table 2] below, but this is only a specific example and is not limited thereto.

[0116] 9 10 11 12 13 14

[0117]

[0118] The compound represented by the above [chemical formula 8] or [chemical formula 8-1] may be any one of the compounds shown in [Table 3] below, but this is only a specific example and is not limited thereto.

[0119] 15 16 17 18 19 20

[0120]

[0121] In the chemical formulas shown in Tables 1 to 3 above, n can be 10 to 10,000, and X can be 0 to 40. The compound of the present invention can stably fix the hair loss treatment component by being bound to a polymer without significantly changing the structure of the hair loss treatment component. In addition, even when the polymer and the hair loss treatment component are bound through a spacer, when the compound is absorbed into the body, the spacer is cleaved within the cell, and the hair loss treatment component is separated from the compound and can act only on the scalp. Therefore, side effects can be reduced through the local action of the active ingredient. In addition, a composition including the compound of the present invention can be utilized as a long-lasting formulation. In addition, the cell absorption rate can be improved depending on the type of polymer to be bound.

[0122] Meanwhile, one embodiment of the present invention can provide a skin topical composition or an injection composition comprising the compound described above. Specifically, one embodiment of the present invention can provide a hair loss prevention composition comprising the compound described above.

[0123]

[0124] Method for preparing a compound

[0125] The present invention provides a method for preparing a compound comprising a 4-azasteroid derivative or minoxidil and a polymer chemically bound thereto. The description of the compound of the present invention described above can be equally applied to the preparation method of the present invention to the extent that it overlaps.

[0126]

[0127] A method for preparing the compound according to one embodiment of the present invention may include a step of directly bonding a 4-azasteroid derivative or minoxidil to a polymer or bonding it through a spacer.

[0128] In one embodiment, the method for preparing the compound may further include, prior to the combining step, a step of modifying the minoxidil by replacing a secondary hydrogen contained in the minoxidil with a carboxyl group or an amine group. Through the modifying step, the modified minoxidil may add a functional group capable of reacting with the polymer or the spacer.

[0129] For example, the minoxidil can be transformed into a modified minoxidil, specifically, carboxylated minoxidil, by replacing the secondary hydrogen contained in the minoxidil with a carboxyl group as shown in the reaction formula below.

[0130] [Correction pursuant to Rule 91, 04.09.2024]

[0131] Additionally, the carboxylated minoxidil can be modified into aminated minoxidil by amination.

[0132] According to one embodiment, the method for preparing the compound of the present invention can prepare the compound by reacting the modified minoxidil with the polymer as shown in the following reaction formula.

[0133] [Correction pursuant to Rule 91, 04.09.2024]

[0134] In one embodiment, the method for preparing the compound may further include, prior to the modifying step, a step of protecting the primary amine contained in the minoxidil with an amine protecting group. Through the protecting step, when the minoxidil is modified into aminated minoxidil, the reaction site bonded to the polymer or the spacer can be designated by the amine group added through the modifying step.

[0135] Specifically, the primary amine contained in minoxidil can be protected with acetic anhydride as shown in the following reaction formula, and the protected minoxidil can be modified.

[0136] [Correction pursuant to Rule 91, 04.09.2024]

[0137] Next, the compound of the present invention can be manufactured by reacting the amine group added by modification of minoxidil with the carboxyl group of hyaluronic acid as shown in the following reaction formula, followed by deprotection.

[0138] [Correction pursuant to Rule 91, 04.09.2024]

[0139] According to one embodiment, in the combining step, the 4-azasteroid derivative or the minoxidil, and the polymer may be combined via the spacer.

[0140] For example, modified minoxidil and hyaluronic acid can be combined by adding a diamine that can act as a spacer, as shown in the reaction formula below.

[0141] [Correction pursuant to Rule 91, 04.09.2024]

[0142] In addition, the present invention provides a method for preparing a compound, comprising the steps of: combining a polymer with a piperidine derivative; and combining the piperidine derivative to which the polymer is combined with a pyrimidine derivative. The description of the compound of the present invention and the description of the method for preparing the compound may be applied equally to the extent that they overlap.

[0143] The above piperidine derivative may refer to a compound that has been changed by introduction of a functional group, oxidation, reduction, or substitution of atoms, as long as the structure and properties of piperidine are not significantly changed.

[0144] The above pyrimidine derivative may refer to a compound that has been changed by introduction of a functional group, oxidation, reduction, or substitution of atoms, as long as the structure and properties of pyrimidine are not significantly changed.

[0145] [Revised on 04.09.2024 by Rule 91] According to an embodiment, in the step of combining the polymer and the piperidine derivative, the piperidine derivative may contain a carboxyl group or an amine group, and specifically (Piperidin-4-amine) or It may be (piperidine-4-carboxylic acid).

[0146] In one embodiment, the polymer and the piperidine derivative may be bonded directly or via a spacer.

[0147] According to one embodiment, the step of directly bonding the polymer and the piperidine derivative may proceed as in the following reaction formula.

[0148] [Correction pursuant to Rule 91, 04.09.2024]

[0149] Next, the step of combining the piperidine derivative to which the polymer is directly bound and the pyrimidine derivative can proceed as shown in the following reaction formula.

[0150] [Correction pursuant to Rule 91, 04.09.2024]

[0151] According to one embodiment, the step of bonding the polymer and the piperidine derivative through a spacer can be performed by reacting the spacer and the piperidine derivative as shown in the following reaction formula.

[0152] [Correction pursuant to Rule 91, 04.09.2024]

[0153] Next, the spacer combined with the piperidine derivative can be reacted with the polymer to form a bond, as shown in the following reaction formula.

[0154] [Correction pursuant to Rule 91, 04.09.2024]

[0155] Next, the step of combining the piperidine derivative and the pyrimidine derivative to which the polymer is bound through the spacer can proceed as shown in the following reaction formula.

[0156] [Correction pursuant to Rule 91, 04.09.2024]

[0157] The polymer may be a deacetylated polymer. Through the deacetylation, a reaction site capable of reacting with the carboxyl group contained in the 4-azasteroid derivative or minoxidil may be added to the polymer. The deacetylation may be performed without particular limitation by any method known in the art, but as a specific example, it may be performed according to the following reaction scheme.

[0158]

[0159] According to one embodiment, the method for preparing the compound using the deacetylated polymer can be performed as in the following reaction formula.

[0160] [Correction pursuant to Rule 91, 04.09.2024]

[0161] Next, the step of combining the piperidine derivative to which the deacetylated polymer is bound and the pyrimidine derivative can be performed as shown in the following reaction formula.

[0162] [Correction pursuant to Rule 91, 04.09.2024]

[0163] Meanwhile, the above description described a method of binding to a polymer through some modification of minoxidil, but the example is not limited thereto, and a polymer can be bound without modifying minoxidil.

[0164]

[0165] Hereinafter, the present invention will be described in detail through examples and experimental examples. However, the following examples and experimental examples are only intended to illustrate the present invention, and the present invention is not limited to the following examples and experimental examples.

[0166]

[0167] Example 1: Synthesis of a compound included in chemical formula 6

[0168] Step 1. Synthesis of piperidine derivative-HA

[0169] According to the following reaction scheme 1, a piperidine derivative-HA was synthesized. The specific synthesis method is as follows.

[0170] 0.1 g hyaluronic acid was dissolved in distilled water. 0.191 g EDC·HCl and 0.115 g NHS were added to the hyaluronic acid dissolved in distilled water and stirred for 30 minutes. Next, 0.05 g piperidin-4-amine was slowly added and stirred for 3 hours. After completion of the reaction, the mixture was extracted with ethanol. Byproducts were removed by washing with ethanol and vacuum-dried.

[0171] <Reaction schematic 1>

[0172] [Correction pursuant to Rule 91, 04.09.2024]

[0173] Step 2. Minoxidil-HA synthesis

[0174] Minoxidil-HA was synthesized according to the following reaction scheme 2. The specific synthesis method is as follows.

[0175] Step 1: 0.1 g of the synthesized piperidine derivative-HA was dissolved in distilled water, and potassium carbonate was added to prepare solution 1. Solution 2 was prepared by dissolving 0.08 g of 2,6-Diamino-4-chloropyrimidine 1-oxide in methanol. Solution 1 was then heated to 55–60°C, and solution 2 was added under reflux. After 12 hours of reaction, the pH was adjusted to neutral, and the mixture was extracted with ethanol. Next, the mixture was washed with methanol and ethanol to remove byproducts, and vacuum-dried.

[0176] <Reaction schematic 2>

[0177] [Correction pursuant to Rule 91, 04.09.2024]

[0178] Example 2: Synthesis of a compound included in chemical formula 6

[0179] Step 1. Piperidine derivative-spacer synthesis

[0180] According to the following reaction scheme 3, 2-amino-N-(piperidin-4-yl)acetamide, in which a piperidine derivative and a spacer are combined, was synthesized. The specific synthetic method is as follows.

[0181] 0.075 g glycine was dissolved in distilled water. 0.382 g EDC·HCl and 0.23 g NHS were added to the glycine dissolved in distilled water and stirred for 30 minutes. Next, 0.2 g piperidin-4-amine was slowly added and stirred for 3 hours. After completion of the reaction, the mixture was extracted with ethanol. Byproducts were removed by washing with ethanol and vacuum-dried.

[0182] <Reaction schematic diagram 3>

[0183] [Correction pursuant to Rule 91, 04.09.2024]

[0184] Step 2. Piperidine derivative-spacer-HA synthesis

[0185] According to the following reaction scheme 4, piperidine derivative-spacer-HA was synthesized. The specific synthetic method is as follows.

[0186] 0.1 g HA was dissolved in distilled water. 0.191 g EDC·HCl and 0.115 g NHS were added to the HA dissolved in distilled water and stirred for 30 minutes. 0.078 g 2-amino-N-(piperidin-4-yl)acetamide was dissolved in distilled water and slowly added, followed by stirring for 3 hours. After completion of the reaction, it was extracted with ethanol. Byproducts were removed by washing with ethanol and vacuum-dried.

[0187] <Reaction schematic diagram 4>

[0188] [Correction pursuant to Rule 91, 04.09.2024]

[0189] Step 3. Minoxidil-Spacer-HA Synthesis

[0190] According to the following reaction scheme 5, minoxidil-spacer-HA was synthesized. The specific synthesis method is as follows.

[0191] 0.1 g of piperidine derivative-spacer-HA was dissolved in distilled water, and potassium carbonate was added to prepare solution 1. Solution 2 was prepared by dissolving 0.08 g of 2,6-Diamino-4-chloropyrimidine 1-oxide in methanol. Solution 1 was heated to 55-60°C, and solution 2 was added under reflux. After 12 hours of reaction, the pH was adjusted to neutral, and the mixture was extracted with ethanol. Byproducts were removed by washing with methanol and ethanol, and the mixture was vacuum-dried.

[0192] <Reaction schematic 5>

[0193] [Correction pursuant to Rule 91, 04.09.2024]

[0194] Example 3: Synthesis of a compound included in chemical formula 7

[0195] Step 1. Synthesis of piperidine derivative-HA

[0196] According to the following reaction scheme 6, a piperidine derivative-HA was synthesized. The specific synthesis method is as follows.

[0197] Solution 1 was prepared by dissolving 0.1 g of Tetrabutylammonium (TBA)-HA in DMSO. Solution 2 was prepared by dissolving 0.065 g of piperidin-4-carboxylic acid in DMSO. 0.123 g of DMAP and 0.208 g of DCC were added to Solution 2 and stirred for 30 minutes. The HA solution in Solution 1 was slowly added to Solution 3 and stirred for 3 hours. After the reaction was completed, the mixture was extracted with ethanol. Byproducts were removed by washing with ethanol and dried under vacuum.

[0198] <Reaction schematic diagram 6>

[0199] [Correction pursuant to Rule 91, 04.09.2024]

[0200] Step 2. Minoxidil-HA synthesis

[0201] Minoxidil-HA was synthesized according to the following reaction scheme 7. The specific synthesis method is as follows.

[0202] 0.1 g of piperidine derivative-HA was dissolved in distilled water, and potassium carbonate was added to prepare solution 1. Solution 2 was prepared by dissolving 0.08 g of 2,6-Diamino-4-chloropyrimidine 1-oxide in methanol. Solution 1 was heated to 55-60°C, and solution 2 was added under reflux. After 12 hours of reaction, the pH was adjusted to neutral, and the mixture was extracted with ethanol. Byproducts were removed by washing with methanol and ethanol, and the mixture was vacuum-dried.

[0203] <Reaction schematic 7>

[0204] [Correction pursuant to Rule 91, 04.09.2024]

[0205] Example 4: Synthesis of a compound included in chemical formula 7

[0206] Step 1. Piperidine derivative-spacer synthesis

[0207] According to the following reaction scheme 8, a piperidine derivative-spacer was synthesized. The specific synthetic method is as follows.

[0208] 0.13 g piperidine-4-carboxylic acid was dissolved in distilled water. 0.385 g EDC·HCl and 0.232 g NHS were added to the piperidine derivative dissolved in distilled water and stirred for 30 minutes. 0.15 g glycine was dissolved in distilled water and slowly added, followed by stirring for 3 hours. After completion of the reaction, the mixture was extracted with ethanol. Byproducts were removed by washing with ethanol and vacuum-dried.

[0209] <Reaction schematic 8>

[0210] [Correction pursuant to Rule 91, 04.09.2024]

[0211] Step 2. Piperidine derivative-spacer-HA synthesis

[0212] According to the following reaction scheme 9, piperidine derivative-spacer-HA was synthesized. The specific synthetic method is as follows.

[0213] Solution 1 was prepared by dissolving 0.1 g of TBA-HA in DMSO. Solution 2 was prepared by dissolving 0.093 g of (piperidine-4-carbonyl)glycine in DMSO. 0.122 g of DMAP and 0.206 g of DCC were added to Solution 2 and stirred for 30 minutes. The HA solution in Solution 1 was slowly added to Solution 3 and stirred for 3 hours. After the reaction was completed, the mixture was extracted with ethanol. Byproducts were removed by washing with ethanol and dried under vacuum.

[0214] <Reaction schematic 9>

[0215] [Correction pursuant to Rule 91, 04.09.2024]

[0216] Step 3. Minoxidil-Spacer-HA Synthesis

[0217] According to the following reaction scheme 10, minoxidil-spacer-HA was synthesized. The specific synthesis method is as follows.

[0218] 0.1 g of piperidine derivative-HA was dissolved in distilled water, and potassium carbonate was added to prepare solution 1. Solution 2 was prepared by dissolving 0.08 g of 2,6-Diamino-4-chloropyrimidine 1-oxide in methanol. Solution 1 was heated to 55-60°C, and solution 2 was added under reflux. After 12 hours of reaction, the pH was adjusted to neutral, and the mixture was extracted with ethanol. Byproducts were removed by washing with methanol and ethanol, and the mixture was vacuum-dried.

[0219] <Reaction schematic 10>

[0220] [Correction pursuant to Rule 91, 04.09.2024]

[0221] Example 5: Synthesis of a compound included in chemical formula 8

[0222] Step 1. Deacetylated HA synthesis

[0223] Deacetylated HA was synthesized according to the following reaction scheme 11. The specific synthesis method is as follows.

[0224] 0.1 g HA was dissolved in distilled water. NH2OH was added to a concentration of 50 wt% and stirred at 40°C for 24 hours. After completion of the reaction, the mixture was extracted with ethanol. Byproducts were removed by washing with ethanol and dried under vacuum.

[0225] <Reaction schematic 11>

[0226]

[0227] Step 2. Synthesis of piperidine derivative-HA

[0228] Piperidine-HA was synthesized according to the following reaction scheme 12. The specific synthesis method is as follows.

[0229] Solution 1 was prepared by dissolving 0.1 g of deacetylated HA in distilled water. Solution 2 was prepared by dissolving 0.065 g of piperidin-4-carboxylic acid in distilled water. 0.191 g of EDC·HCl and 0.115 g of NHS were added to Solution 2 and stirred for 30 minutes. The HA solution in Solution 1 was slowly added to Solution 2 and stirred for 3 hours. After the reaction was completed, the mixture was extracted with ethanol. Byproducts were removed by washing with ethanol and dried under vacuum.

[0230] <Reaction schematic 12>

[0231] [Correction pursuant to Rule 91, 04.09.2024]

[0232] Step 3. Minoxidil-HA synthesis

[0233] Minoxidil-HA was synthesized according to the following reaction scheme 13. The specific synthesis method is as follows.

[0234] 0.1 g of piperidine derivative-HA was dissolved in distilled water, and potassium carbonate was added to prepare solution 1. Solution 2 was prepared by dissolving 0.08 g of 2,6-Diamino-4-chloropyrimidine 1-oxide in methanol. Solution 1 was heated to 55-60°C, and solution 2 was added under reflux. After 12 hours of reaction, the pH was adjusted to neutral, and the mixture was extracted with ethanol. Byproducts were removed by washing with methanol and ethanol, and the mixture was vacuum-dried.

[0235] <Reaction schematic 13>

[0236] [Correction pursuant to Rule 91, 04.09.2024]

[0237] Example 6: Synthesis of a compound included in chemical formula 8

[0238] Step 1. Piperidine derivative-spacer synthesis

[0239] According to the following reaction scheme 14, a piperidine derivative-spacer was synthesized. The specific synthetic method is as follows.

[0240] Solution 1 was prepared by dissolving 0.13 g of piperidine-4-carboxylic acid in distilled water. 0.385 g of EDC·HCl and 0.232 g of NHS were added to Solution 1 and stirred for 30 minutes to prepare Solution 2. 0.15 g of glycine was dissolved in distilled water and slowly added to Solution 2, followed by stirring for 3 hours. After completion of the reaction, the mixture was extracted with ethanol. Byproducts were removed by washing with ethanol, and the mixture was vacuum-dried.

[0241] <Reaction schematic 14>

[0242] [Correction pursuant to Rule 91, 04.09.2024]

[0243] Step 2. Deacetylated HA synthesis

[0244] Deacetylated HA was synthesized according to the following reaction scheme 15. The specific synthesis method is as follows.

[0245] 0.1 g HA was dissolved in distilled water. NH2OH was added to a concentration of 50 wt% and stirred at 40°C for 24 hours. After completion of the reaction, the mixture was extracted with ethanol. Byproducts were removed by washing with ethanol and dried under vacuum.

[0246] <Reaction schematic 15>

[0247]

[0248] Step 3. Piperidine derivative-spacer-HA synthesis

[0249] According to the following reaction scheme 16, piperidine derivative-spacer-HA was synthesized. The specific synthetic method is as follows.

[0250] Solution 1 was prepared by dissolving 0.1 g of deacetylated HA in distilled water. Solution 2 was prepared by dissolving 0.093 g of (piperidine-4-carbonyl)glycine in distilled water. Solution 3 was prepared by adding 0.191 g of EDC·HCl and 0.115 g of NHS to Solution 2 and stirring for 30 minutes. The HA solution in Solution 1 was slowly added to Solution 3 and stirred for 3 hours. After the reaction was completed, the mixture was extracted with ethanol. Byproducts were removed by washing with ethanol and dried under vacuum.

[0251] <Reaction schematic 16>

[0252] [Correction pursuant to Rule 91, 04.09.2024]

[0253] Step 4. Minoxidil-Spacer-HA Synthesis

[0254] According to the following reaction scheme 17, minoxidil-spacer-HA was synthesized. The specific synthesis method is as follows.

[0255] 0.1 g of piperidine derivative-spacer-HA was dissolved in distilled water, and potassium carbonate was added to prepare solution 1. Solution 2 was prepared by dissolving 0.08 g of 2,6-Diamino-4-chloropyrimidine 1-oxide in methanol. Solution 1 was heated to 55-60°C, and solution 2 was added under reflux. After 12 hours of reaction, the pH was adjusted to neutral, and the mixture was extracted with ethanol. Byproducts were removed by washing with methanol and ethanol, and the mixture was vacuum-dried.

[0256] <Reaction schematic 17>

[0257] [Correction pursuant to Rule 91, 04.09.2024]

[0258] Example 7: Synthesis of a compound included in chemical formula 9

[0259] Minoxidil-HA was synthesized according to the following reaction scheme 18. The specific synthesis method is as follows.

[0260] Solution 1 was prepared by dissolving 0.1 g HA in distilled water. 0.191 g 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide·HCl (EDC·HCl) and 0.115 g N-Hydroxysuccinimide (NHS) were added to Solution 1 and stirred for 30 minutes to prepare Solution 2. 0.1 g of minoxidil was dissolved in ethanol. The minoxidil solution was slowly added to Solution 2 and stirred for 3 hours. After the reaction was completed, it was extracted with ethanol. Next, it was washed with ethanol to remove byproducts and vacuum dried.

[0261] <Reaction schematic 18>

[0262] [Correction pursuant to Rule 91, 04.09.2024]

[0263] Example 8: Synthesis of a compound included in chemical formula 6

[0264] Step 1. Piperidine derivative-spacer synthesis

[0265] According to the following reaction scheme 19, a piperidine derivative-spacer was synthesized. The specific synthetic method is as follows.

[0266] 0.13 g piperidine-4-carboxylic acid was dissolved in distilled water. 0.385 g EDC·HCl and 0.232 g NHS were added and stirred for 30 minutes to prepare Solution 1. 0.63 g aminomethyldisulfanylmethanamine was dissolved in ethanol, slowly added to Solution 1, and stirred for 3 hours. After completion of the reaction, it was extracted with acetone. Byproducts were removed by washing with ethanol, and the mixture was vacuum-dried.

[0267] <Reaction schematic 19>

[0268] [Correction pursuant to Rule 91, 04.09.2024]

[0269] Step 2. Piperidine derivative-spacer-HA synthesis

[0270] According to the following reaction scheme 20, a piperidine derivative-spacer-HA was synthesized. The specific synthetic method is as follows.

[0271] 0.1 g HA was dissolved in distilled water. 0.191 g EDC·HCl and 0.115 g NHS were added and stirred for 30 minutes. 0.12 g of the piperidine derivative-spacer prepared in Step 1 was slowly added and stirred for 3 hours. After completion of the reaction, the mixture was extracted with ethanol. Byproducts were removed by washing with ethanol and vacuum-dried.

[0272] <Reaction schematic 20>

[0273] [Correction pursuant to Rule 91, 04.09.2024]

[0274] Step 3. Minoxidil-Spacer-HA Synthesis

[0275] According to the following reaction scheme 21, minoxidil-spacer-HA was synthesized. The specific synthesis method is as follows.

[0276] Step 2: Dissolve 0.1 g of the piperidine derivative-spacer-HA prepared in distilled water and add potassium carbonate to prepare solution 1. Solution 2 was prepared by dissolving 0.08 g of 2,6-Diamino-4-chloropyrimidine 1-oxide in methanol. Solution 1 was heated to 55-60°C and solution 2 was added under reflux. After 12 hours of reaction, the pH was adjusted to neutral and the mixture was extracted with ethanol. Byproducts were removed by washing with methanol and ethanol, and the mixture was vacuum-dried.

[0277] <Reaction schematic 21>

[0278] [Correction pursuant to Rule 91, 04.09.2024]

[0279] Example 9: Synthesis of a compound included in chemical formula 7

[0280] Step 1. Piperidine derivative-spacer synthesis

[0281] According to the following reaction scheme 22, a piperidine derivative-spacer was synthesized. The specific synthetic method is as follows.

[0282] 0.13 g piperidine-4-carboxylic acid was dissolved in distilled water. 0.385 g EDC·HCl and 0.232 g NHS were added and stirred for 30 minutes to prepare Solution 1. 0.63 g aminomethyldisulfanylmethanamine was dissolved in ethanol, slowly added to Solution 1, and stirred for 3 hours. After completion of the reaction, it was extracted with acetone. Byproducts were removed by washing with ethanol, and the mixture was vacuum-dried.

[0283] <Reaction schematic 22>

[0284] [Correction pursuant to Rule 91, 04.09.2024]

[0285] Step 2. Chlorinated HA synthesis

[0286] Chlorinated HA was synthesized according to the following reaction scheme 23. The specific synthesis method is as follows.

[0287] 0.1 g of TBA-HA was dissolved in DMF, and 2.5 mmol of methanesulfonyl chloride was slowly added. After stirring at 50°C for 24 hours, sodium methoxide was added, and stirring was continued for an additional 48 hours. After completion of the reaction, the mixture was extracted with ethanol and dialyzed to remove impurities. The obtained sample was lyophilized and stored.

[0288] <Reaction schematic 23>

[0289]

[0290] Step 3. Piperidine derivative-spacer-HA synthesis

[0291] According to the following reaction scheme 24, piperidine derivative-spacer-HA was synthesized. The specific synthetic method is as follows.

[0292] 0.1 g of the chlorinated HA prepared in Step 2 was dissolved in distilled water. 0.12 g of the piperidine derivative-spacer prepared in Step 1 was slowly added and stirred for 24 hours. After completion of the reaction, the mixture was extracted with ethanol. Byproducts were removed by washing with ethanol and dried under vacuum.

[0293] <Reaction schematic 24>

[0294] [Correction pursuant to Rule 91, 04.09.2024]

[0295] Step 4. Minoxidil-Spacer-HA Synthesis

[0296] According to the following reaction scheme 25, minoxidil-spacer-HA was synthesized. The specific synthesis method is as follows.

[0297] Step 3 prepared 0.1 g of the piperidine derivative-spacer-HA was dissolved in distilled water, and potassium carbonate was added to prepare solution 1. Solution 2 was prepared by dissolving 0.08 g of 2,6-Diamino-4-chloropyrimidine 1-oxide in methanol. Solution 1 was heated to 55-60°C, and solution 2 was added under reflux. After 12 hours of reaction, the pH was adjusted to neutral, and the mixture was extracted with ethanol. Byproducts were removed by washing with methanol and ethanol, and the mixture was vacuum-dried.

[0298] <Reaction schematic 25>

[0299] [Correction pursuant to Rule 91, 04.09.2024]

[0300] Example 10: Synthesis of a compound included in chemical formula 8

[0301] Step 1. Piperidine derivative-spacer synthesis

[0302] According to the following reaction scheme 26, a piperidine derivative-spacer was synthesized. The specific synthetic method is as follows.

[0303] 0.18 g dithiodiglycolic acid was dissolved in distilled water. 0.193 g EDC·HCl and 0.116 g NHS were added and stirred for 30 minutes to prepare Solution 1. 0.05 g 4-Aminopiperidine was slowly added and stirred for 3 hours. After completion of the reaction, the mixture was extracted with acetone. Byproducts were removed by washing with ethanol and vacuum-dried.

[0304] <Reaction schematic 26>

[0305] [Correction pursuant to Rule 91, 04.09.2024]

[0306] Step 2. Deacetylated-HA synthesis

[0307] Deacetylated HA was synthesized according to the following reaction scheme 27. The specific synthesis method is as follows.

[0308] 0.1 g HA was dissolved in distilled water. NH2OH was added to a concentration of 50 wt% and stirred at 40°C for 24 hours. After completion of the reaction, the mixture was extracted with ethanol. Byproducts were removed by washing with ethanol and dried under vacuum.

[0309] <Reaction schematic 27>

[0310]

[0311] Step 3. Piperidine derivative-spacer-HA synthesis

[0312] According to the following reaction scheme 28, piperidine derivative-spacer-HA was synthesized. The specific synthetic method is as follows.

[0313] 0.1 g deacetylated-HA was dissolved in distilled water. 0.191 g EDC·HCl and 0.115 g NHS were added and stirred for 30 minutes. 0.12 g of the piperidine derivative-spacer prepared in Step 1 was slowly added and stirred for 3 hours. After completion of the reaction, the mixture was extracted with ethanol. Byproducts were removed by washing with ethanol and dried under vacuum.

[0314] <Reaction schematic 28>

[0315] [Correction pursuant to Rule 91, 04.09.2024]

[0316] Step 4. Minoxidil-Spacer-HA Synthesis

[0317] According to the following reaction scheme 29, minoxidil-spacer-HA was synthesized. The specific synthesis method is as follows.

[0318] Step 3 prepared 0.1 g of the piperidine derivative-spacer-HA was dissolved in distilled water, and potassium carbonate was added to prepare solution 1. Solution 2 was prepared by dissolving 0.08 g of 2,6-Diamino-4-chloropyrimidine 1-oxide in methanol. Solution 1 was heated to 55-60°C, and solution 2 was added under reflux. After 12 hours of reaction, the pH was adjusted to neutral, and the mixture was extracted with ethanol. Byproducts were removed by washing with methanol and ethanol, and the mixture was vacuum-dried.

[0319] <Reaction schematic 29>

[0320] [Correction pursuant to Rule 91, 04.09.2024]

[0321] Example 11: Synthesis of a compound included in chemical formula 6

[0322] Step 1. Spacer-HA synthesis

[0323] Spacer-HA was synthesized according to the following reaction scheme 30. The specific synthesis method is as follows.

[0324] 0.1 g hyaluronic acid was dissolved in distilled water. 0.191 g EDC·HCl and 0.115 g NHS were added and stirred for 30 minutes. Next, 2.5 mmol 1,6-hexanediamine was slowly added and stirred for 3 hours. After completion of the reaction, the mixture was extracted with ethanol. Byproducts were removed by washing with ethanol and vacuum-dried.

[0325] <Reaction schematic 30>

[0326] [Correction pursuant to Rule 91, 04.09.2024]

[0327] Step 2. Synthesis of 4-azasteroid derivative-spacer-HA

[0328] According to the following reaction scheme 31, 4-azasteroid derivative-spacer-HA was synthesized. The specific synthetic method is as follows.

[0329] Solution 1 was prepared by dissolving 0.1 g of spacer-HA prepared in Step 1 in distilled water. Solution 2 was prepared by dissolving 0.079 g of 3-Oxo-4-aza-5α-androst-1-ene-17β-carboxylic acid in methanol. Solution 3 was prepared by adding 0.191 g of EDC·HCl and 0.115 g of NHS to Solution 2 and stirring for 30 minutes. The HA solution of Solution 1 was slowly added to Solution 3 and stirred for 3 hours. After the reaction was completed, it was extracted with ethanol. Byproducts were removed by washing with ethanol and dried under vacuum.

[0330] <Reaction schematic 31>

[0331] [Correction pursuant to Rule 91, 04.09.2024]

[0332] Example 12: Synthesis of a compound included in chemical formula 6

[0333] Step 1. Spacer-HA synthesis

[0334] Spacer-HA was synthesized according to the following reaction schematic. The specific synthetic method is as follows. 0.1 g hyaluronic acid was dissolved in distilled water. 0.191 g EDC·HCl and 0.115 g NHS were added and stirred for 30 minutes. Next, 2.5 mmol aminomethyldisulfanylmethanamine was slowly added and stirred for 3 hours. After completion of the reaction, it was extracted with ethanol. Byproducts were removed by washing with ethanol and dried under vacuum.

[0335] <Reaction schematic 32>

[0336] [Correction pursuant to Rule 91, 04.09.2024]

[0337] Step 2. Synthesis of 4-azasteroid derivative-spacer-HA

[0338] According to the following reaction scheme 33, 4-azasteroid derivative-spacer-HA was synthesized. The specific synthetic method is as follows.

[0339] Solution 1 was prepared by dissolving 0.1 g of spacer-HA prepared in Step 1 in distilled water. Solution 2 was prepared by dissolving 0.079 g of 3-Oxo-4-aza-5α-androst-1-ene-17β-carboxylic acid in methanol. Solution 3 was prepared by adding 0.191 g of EDC·HCl and 0.115 g of NHS to Solution 2 and stirring for 30 minutes. The HA solution of Solution 1 was slowly added to Solution 3 and stirred for 3 hours. After the reaction was completed, it was extracted with ethanol. Byproducts were removed by washing with ethanol and dried under vacuum.

[0340] <Reaction schematic 33>

[0341] [Correction pursuant to Rule 91, 04.09.2024]

[0342] Example 13: Synthesis of a compound included in chemical formula 6

[0343] Step 1. Synthesis of carboxyl-substituted dutasteride

[0344] Dutasteride with a carboxyl group substituted was synthesized according to the following reaction schematic diagram 34. The specific synthetic method is as follows.

[0345] 0.410 g of 2-Pyridyl 3-oxo-4-aza-5α-androst-1-ene-17β-carbothioate was dissolved in 5 mL of methylene chloride. 0.256 g of silver trifluoromethanesulfonate (AgOTf) and 0.819 g of 4-Amino-2,5-bis(trifluoromethyl)benzoic acid were added and stirred at room temperature for 12 h. The reaction product was filtered, and the residue was washed with excess methylene chloride. The reaction product was extracted with 1 M HCl and brine and then dried in vacuo. Byproducts were removed through a column.

[0346] <Reaction schematic 34>

[0347] [Correction pursuant to Rule 91, 04.09.2024]

[0348] Step 2. Spacer-HA synthesis

[0349] Spacer-HA was synthesized according to the following reaction scheme 35. The specific synthesis method is as follows.

[0350] 0.1 g hyaluronic acid was dissolved in distilled water. 0.191 g EDC·HCl and 0.115 g NHS were added and stirred for 30 minutes. Next, 2.5 mmol 1,6-hexanediamine was slowly added and stirred for 3 hours. After completion of the reaction, the mixture was extracted with ethanol. Byproducts were removed by washing with ethanol and vacuum-dried.

[0351] <Reaction schematic 35>

[0352] [Correction pursuant to Rule 91, 04.09.2024]

[0353] Step 3. Dutasteride-Spacer-HA Synthesis

[0354] According to the following reaction scheme 36, dutasteride-spacer-HA was synthesized. The specific synthesis method is as follows.

[0355] Step 2: 0.1 g of spacer-HA synthesized was dissolved in distilled water, and 0.191 g of EDC·HCl and 0.115 g of NHS were added to 1 and stirred for 30 minutes. Next, 0.229 g of carboxyl-substituted dutasteride synthesized in step 1 was slowly added and stirred for 3 hours. After completion of the reaction, it was extracted with ethanol. Byproducts were removed by washing with ethanol and dried under vacuum.

[0356] <Reaction schematic diagram 36>

[0357] [Correction pursuant to Rule 91, 04.09.2024]

[0358] Example 14: Synthesis of a compound included in chemical formula 6

[0359] Step 1. Spacer-HA synthesis

[0360] Spacer-HA was synthesized according to the following reaction scheme 37. The specific synthetic method is as follows. 0.1 g hyaluronic acid was dissolved in distilled water. 0.191 g EDC·HCl and 0.115 g NHS were added and stirred for 30 minutes. Next, 2.5 mmol 1,6-hexanediamine was slowly added and stirred for 3 hours. After completion of the reaction, it was extracted with ethanol. Byproducts were removed by washing with ethanol and dried under vacuum.

[0361] <Reaction schematic 37>

[0362] [Correction pursuant to Rule 91, 04.09.2024]

[0363] 0.1 g of the obtained hyaluronic acid was dissolved in distilled water, 0.25 mmol N-(tert-butyl)-4-chlorobutanamide was added, and the mixture was stirred for 24 hours. After completion of the reaction, the mixture was extracted with ethanol, washed with ethanol to remove byproducts, and vacuum dried.

[0364] <Reaction schematic 38>

[0365] [Correction pursuant to Rule 91, 04.09.2024]

[0366] Step 2. Finasteride-Spacer-HA Synthesis

[0367] According to the following reaction scheme 39, finasteride-spacer-HA was synthesized. The specific synthesis method is as follows.

[0368] Solution 1 was prepared by dissolving 0.1 g of spacer-HA prepared in Step 1 in distilled water. Solution 2 was prepared by dissolving 0.1 g of 2-Pyridyl 3-oxo-4-aza-5α-androst-1-ene-17β-carbothioate in methanol. After mixing Solutions 1 and 2, NaH was added and stirred for 3 hours. After completion of the reaction, the mixture was extracted with ethanol. Byproducts were removed by washing with ethanol and dried under vacuum.

[0369] <Reaction schematic 39>

[0370] [Correction pursuant to Rule 91, 04.09.2024]

[0371] Example 15: Synthesis of a compound included in chemical formula 7

[0372] Step 1. Synthesis of 4-azasteroid derivative-HA

[0373] According to the following reaction schematic diagram 40, 4-azasteroid derivative-HA was synthesized. The specific synthesis method is as follows.

[0374] Solution 1 was prepared by dissolving 0.1 g of TBA-HA in DMSO. Solution 2 was prepared by dissolving 0.079 g of 3-Oxo-4-aza-5α-androst-1-ene-17β-carboxylic acid in DMSO. 0.122 g of DMAP and 0.206 g of DCC were added to Solution 2 and stirred for 30 minutes. The HA solution in Solution 1 was slowly added to Solution 2 and stirred for 3 hours. After the reaction was completed, the mixture was extracted with ethanol. Byproducts were removed by washing with ethanol and dried under vacuum.

[0375] <Reaction schematic 40>

[0376] [Correction pursuant to Rule 91, 04.09.2024]

[0377] Example 16: Synthesis of a compound included in chemical formula 7

[0378] Step 1. Chlorinated HA synthesis

[0379] Chlorinated HA was synthesized according to the following reaction scheme 41. The specific synthesis method is as follows.

[0380] 0.1 g of TBA-HA was dissolved in DMF, and 2.5 mmol of methanesulfonyl chloride was slowly added. After stirring at 50°C for 24 hours, sodium methoxide was added, and stirring was continued for an additional 48 hours. After completion of the reaction, the mixture was extracted with ethanol and dialyzed to remove impurities. The obtained sample was lyophilized and stored.

[0381] <Reaction schematic 41>

[0382]

[0383] Step 2. Synthesis of 4-azasteroid derivative-spacer

[0384] According to the following reaction scheme 42, a 4-azasteroid derivative-spacer was synthesized. The specific synthetic method is as follows.

[0385] 0.317 g 3-Oxo-4-aza-5α-androst-1-ene-17β-carboxylic acid was dissolved in DMSO. 0.38 g Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium (HATU) was added and stirred for 30 minutes. 5 mmol of 1,6-hexanediamine was slowly added and stirred for 3 hours. After completion of the reaction, the mixture was extracted with ethanol. Byproducts were removed by washing with ethanol and dried under vacuum.

[0386] <Reaction schematic 42>

[0387] [Correction pursuant to Rule 91, 04.09.2024]

[0388] Step 3. Synthesis of 4-azasteroid derivative-spacer-HA

[0389] According to the following reaction scheme 43, 4-azasteroid derivative-spacer-HA was synthesized. The specific synthetic method is as follows.

[0390] 0.1 g of the chlorinated HA prepared in Step 1 was dissolved in distilled water. 0.22 g of the 4-azasteroid derivative-spacer prepared in Step 2 was dissolved in methanol and added to the HA solution. After stirring for 24 hours, the solution was extracted with ethanol. The mixture was washed with ethanol, byproducts were removed, and vacuum-dried.

[0391] <Reaction schematic 43>

[0392] [Correction pursuant to Rule 91, 04.09.2024]

[0393] Example 17: Synthesis of a compound included in chemical formula 8

[0394] Step 1. Deacetylated HA synthesis

[0395] Deacetylated HA was synthesized according to the following reaction scheme 44. The specific synthesis method is as follows.

[0396] 0.1 g HA was dissolved in distilled water. NH2OH was added to a concentration of 50 wt% and stirred at 40°C for 24 hours. After completion of the reaction, the mixture was extracted with ethanol. Byproducts were removed by washing with ethanol and dried under vacuum.

[0397] <Reaction schematic 44>

[0398]

[0399] Step 2. Synthesis of 4-azasteroid derivative-HA

[0400] According to the following reaction scheme 45, 4-azasteroid derivative-HA was synthesized. The specific synthesis method is as follows.

[0401] Solution 1 was prepared by dissolving 0.1 g of deacetylated HA in distilled water. Solution 2 was prepared by dissolving 0.079 g of 3-Oxo-4-aza-5α-androst-1-ene-17β-carboxylic acid in methanol. Solution 3 was prepared by adding 0.191 g of EDC·HCl and 0.115 g of NHS to Solution 2 and stirring for 30 minutes. The HA solution in Solution 1 was slowly added to Solution 3 and stirred for 3 hours. After the reaction was completed, the mixture was extracted with ethanol. Byproducts were removed by washing with ethanol and dried under vacuum.

[0402] <Reaction schematic 45>

[0403] [Correction pursuant to Rule 91, 04.09.2024]

[0404] Example 18: Synthesis of a compound included in chemical formula 8

[0405] Step 1. Synthesis of chlorine-substituted 4-azasteroid derivatives

[0406] According to the following reaction scheme 46, a chlorine-substituted 4-azasteroid derivative was synthesized. The specific synthetic method is as follows.

[0407] 0.317 g 3-Oxo-4-aza-5α-androst-1-ene-17β-carboxylic Acid was dissolved in DMSO. 0.38 g Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium (HATU) was added and stirred for 30 minutes. 1 mmol of 2-Chloroethylamine was slowly added and stirred for 3 hours. After completion of the reaction, the mixture was extracted with ethanol. By-products were removed by washing with ethanol and dried under vacuum.

[0408] <Reaction schematic 46>

[0409] [Correction pursuant to Rule 91, 04.09.2024]

[0410] Step 2. Deacetylated HA synthesis

[0411] Deacetylated HA was synthesized according to the following reaction scheme 47. The specific synthesis method is as follows.

[0412] 0.1 g HA was dissolved in distilled water. NH2OH was added to a concentration of 50 wt% and stirred at 40°C for 24 hours. After completion of the reaction, the mixture was extracted with ethanol. Byproducts were removed by washing with ethanol and dried under vacuum.

[0413] <Reaction schematic 47>

[0414]

[0415] Step 3. Synthesis of 4-azasteroid derivative-spacer-HA

[0416] According to the following reaction scheme 48, 4-azasteroid derivative-spacer-HA was synthesized. The specific synthetic method is as follows.

[0417] Step 2: 0.1 g of the deacetylated HA prepared was dissolved in distilled water. Step 1: 0.19 g of the 4-azasteroid derivative-spacer prepared in step 1 was dissolved in methanol and added to the HA solution. After stirring for 24 hours, the solution was extracted with ethanol. The solution was washed with ethanol, byproducts were removed, and vacuum-dried.

[0418] <Reaction schematic 48>

[0419] [Correction pursuant to Rule 91, 04.09.2024]

[0420]

[0421] The features, structures, effects, etc. described in the above-described embodiments are included in at least one embodiment of the present invention, and are not necessarily limited to just one embodiment. Furthermore, the features, structures, effects, etc. exemplified in each embodiment can be combined or modified in other embodiments by those skilled in the art to which the embodiments pertain. Therefore, the contents related to such combinations and modifications should be construed as falling within the scope of the present invention.

[0422] In addition, although the above description focuses on embodiments, these are merely examples and do not limit the present invention. Those skilled in the art to which the present invention pertains will appreciate that various modifications and applications not exemplified above are possible without departing from the essential characteristics of the present embodiments. For example, each component specifically shown in the embodiments can be modified and implemented. In addition, differences related to such modifications and applications should be interpreted as being included within the scope of the present invention defined in the appended claims.

Claims

1. 4-Azasteroid derivative or minoxidil, and a compound chemically bonded with a polymer, A compound wherein the polymer is directly bonded to the 4-azasteroid derivative or the minoxidil or is bonded via a spacer.

2. In paragraph 1, The above minoxidil is a compound containing a carboxyl group or an amine group bonded to a secondary carbon.

3. In paragraph 1, A compound wherein the above 4-azasteroid derivative contains at least one functional group selected from the group consisting of an amide group, a carboxyl group, and a thioester group.

4. In paragraph 1, The above polymer is a compound containing at least one functional group selected from the group consisting of a hydroxyl group, a carboxyl group, an acetyl group, an amide group, and an amine group.

5. In paragraph 1, A compound wherein the polymer comprises at least one selected from the group consisting of hyaluronic acid, alginate, cellulose, chitosan, gelatin, starch, chitin, collagen, and heparin.

6. In paragraph 1, The above polymer is a deacetylated compound 7. In paragraph 1, The above spacer, A compound comprising an alkyl chain comprising at least one selected from the group consisting of -NH2, -COOH, -OH, aldehyde, epoxide, halogen elements (F, Cl, Br, I), succinimide, alkene, and alkyne at at least one of both terminals, an alkyl chain comprising at least one selected from the group consisting of a disulfide bond, an ester bond, and an amide bond, and a peptide.

8. In paragraph 1, The compound is any one of the following chemical formulas 6 to 9: [Chemical Formula 6] [Chemical Formula 7] In the above chemical formulas 6 and 7, Ra is NH, O, , , , , , , , and One of them, Rb is CH2, NH, O, , and At least one of them, Rc is , , and At least one of them, Rd is H, CH3, CH(CH3)2, CH2-CH(CH3)2, CH2-CH2-S-CH3, CH(CH3)-CH2-CH3, CH2-OH, CH(CH3)-OH, CH2-SH, CH2-CONH2, CH2-CH2-CONH2, CH2-CH2-CH2-NH2, CH2-CH2-CH2-NH-C(NH2)=NH, CH2-COOH, CH2-CH2-COOH, , , , and It is one of them. [Chemical Formula 8] In the above chemical formula 8, Re is , , , , , , , and One of them, Rb is CH2, NH, O, , and At least one of them, Rc is , and At least one of them, Rd is H, CH3, CH(CH3)2, CH2-CH(CH3)2, CH2-CH2-S-CH3, CH(CH3)-CH2-CH3, CH2-OH, CH(CH3)-OH, CH2-SH, CH2-CONH2, CH2-CH2-CONH2, CH2-CH2-CH2-NH2, CH2-CH2-CH2-NH-C(NH2)=NH, CH2-COOH, CH2-CH2-COOH, , , , and It is one of them. [Chemical Formula 9] In the above chemical formulas 6 to 9, n is 10 to 10,000, In the above chemical formulas 6 to 8, A is a 4-azasteroid derivative or minoxidil, x is 0 to 40, y is 1 to 40, and z is 1 to 40.

9. [Correction under Rule 91 04.09.2024] In paragraph 8, the compound represented by the above [chemical formula 6] is any one of the compounds represented in [Table 1] below: wherein, n is 10 to 10,000, and X is 0 to 40.

10. [Revision according to Rule 91 04.09.2024] In paragraph 8, the compound represented by the above [chemical formula 7] is any one of the compounds shown in [Table 2] below: wherein, n is 10 to 10,000, and X is 0 to 40.

11. [Correction pursuant to Rule 91 04.

09. [2024] In the 8th paragraph, the compound represented by the above [chemical formula 8] is any one of the compounds represented in the following [Table 3], wherein n is 10 to 10,000, and X is 0 to 40. A method for producing a compound, comprising the step of directly bonding a 12.4-azasteroid derivative or minoxidil to a polymer or bonding it through a spacer.

13. In paragraph 12, A method for producing a compound, further comprising, before the combining step, a step of modifying the minoxidil by replacing secondary hydrogen contained in the minoxidil with a carboxyl group or an amine group.

14. In paragraph 13, A method for producing a compound, further comprising, before the above-mentioned modifying step, a step of protecting the primary amine contained in the minoxidil with an amine protecting group.

15. A step of combining a polymer and a piperidine derivative; and A method for producing a compound, comprising the step of combining a piperidine derivative and a pyrimidine derivative to which the polymer is combined.

16. In paragraph 15, A method for producing a compound, wherein the above piperidine derivative contains a carboxyl group or an amine group.

17. In paragraph 12 or paragraph 15, A method for producing a compound, wherein the above polymer is deacetylated.

Images