WO2024262969A1 - Compound having novel structure in which hair loss treatment component is immobilized and method for producing same - Google Patents
Compound having novel structure in which hair loss treatment component is immobilized and method for producing same Download PDFInfo
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- WO2024262969A1 WO2024262969A1 PCT/KR2024/008561 KR2024008561W WO2024262969A1 WO 2024262969 A1 WO2024262969 A1 WO 2024262969A1 KR 2024008561 W KR2024008561 W KR 2024008561W WO 2024262969 A1 WO2024262969 A1 WO 2024262969A1
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- minoxidil
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
Definitions
- 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.
- minoxidil is used as an external agent applied to the scalp, but it can cause side effects if it comes into contact with areas other than the scalp. Therefore, in order to make minoxidil work only on the target area, fixation of minoxidil is an important issue, but there is a problem that the structure of minoxidil is greatly changed during fixation, which reduces the efficacy.
- the present invention provides a compound in which a 4-azasteroid derivative or minoxidil and a polymer are chemically bound.
- the polymer may be directly bound to the 4-azasteroid derivative or the minoxidil or may be bound via a spacer.
- the minoxidil may include a carboxyl group or an amine group bonded to a secondary carbon.
- 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.
- 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 polymer may include at least one selected from the group consisting of hyaluronic acid, alginate, cellulose, chitosan, gelatin, starch, chitin, collagen, and heparin.
- the spacer may be any one of an alkyl chain including at least one selected from the group consisting of -NH 2 , -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.
- 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.
- the compound may be any one of the following chemical formulas 6 to 9.
- Ra is NH, O, , , , , , , , and One of them,
- Rb is CH 2 , NH , O , , and At least one of the following,
- Rc is , , and At least one of the following,
- Re is , , , , , , , and One of them,
- Rb is CH 2 , NH , O , , and At least one of the following,
- Rc is , and At least one of the following,
- n can be 10 to 10,000
- A can be a 4-azasteroid derivative or minoxidil
- x can be 0 to 40
- y can be 1 to 40
- z can be 1 to 40.
- 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.
- 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.
- 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.
- a method for preparing a compound comprising a step of directly bonding a 4-azasteroid derivative or minoxidil to a polymer or via a spacer.
- the method for preparing the compound according to one example of the present invention may further comprise, prior to 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.
- the method for preparing the compound according to one example of the present invention may further include, prior to the modifying step, a step of protecting the primary amine contained in the minoxidil with an amine protecting group.
- another aspect of the present disclosure 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 piperidine derivative according to one example of the present invention may contain a carboxyl group or an amine group.
- the polymer may be deacetylated.
- the compound of the present invention can stably fix an hair loss treatment component by binding to a polymer without significantly changing the structure of the hair loss treatment component.
- the hair loss treatment component When the compound of the present invention is absorbed into the body, the hair loss treatment component is separated from the compound within the cell and can only act on the scalp. Therefore, the side effects of the hair loss treatment component can be reduced through the local action of the effective ingredient.
- the composition containing the compound of the present invention can be utilized as a long-term formulation.
- the cell absorption rate can be improved depending on the type of polymer constituting the compound.
- the present invention provides a compound in which a 4-azasteroid derivative or minoxidil and a polymer are chemically bound.
- 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.
- the above minoxidil represents 3-hydroxy-2-imino-6-piperidin-1-ylpyrimidin-4-amine, and can be represented by the following chemical formula 4.
- 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.
- 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 a functional group included in the 4-azasteroid derivative or the minoxidil, or may react with a spacer.
- the polymer may include at least one selected from the group consisting of hyaluronic acid, alginate, cellulose, chitosan, gelatin, starch, chitin, collagen, and heparin.
- the polymer may be hyaluronic acid represented by the following chemical formula 5.
- the polymer may be deacetylated.
- an amide group contained in the polymer may be converted 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.
- the polymer may be halogenated.
- a hydroxyl group of a primary alcohol contained in the polymer may be converted 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.
- the compound of the present invention may be a polymer directly bonded to the minoxidil by reaction between a carboxyl group contained in the polymer and an amine group contained in the minoxidil.
- the minoxidil may include a carboxyl group or an amine group bonded to a secondary carbon.
- 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.
- the amine group bonded to the secondary carbon can be obtained by amination of the substituted carboxyl group.
- the spacer may be an alkyl chain comprising at least one selected from the group consisting of -NH 2 , -COOH, -OH, aldehyde, epoxide, halogen elements (F, Cl, Br, I), succinimide, an alkene, and an alkyne at at least one of both terminals.
- 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.
- the spacer may be a peptide.
- 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.
- the compound according to various embodiments of the present invention may be any one of the following chemical formulas 6 to 9.
- Ra is NH, O, (alkane) , (alkane), (Cleavable) , (Cleavable), (ADH), (PEG), (PEG), and (Peptide) is one of them,
- Rb is CH 2 , NH , O , , and At least one of the following,
- Rc is , , and At least one of the following,
- Re is , (alkane), (alkane), (Cleavable), (Cleavable), (PEG), (PEG) and (Peptide) is one of them,
- Rb is CH 2 , NH , O , , and At least one of the following,
- Rc is , and At least one of the following,
- n can be 10 to 10,000
- A may be a 4-azasteroid derivative or minoxidil
- x may be 0 to 40
- y may be 1 to 40
- z may be 1 to 40.
- 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.
- Ra is NH, , and It can be either of the following,
- Rb is , and It can be at least one of the following.
- Rc is , and It can be either of the following,
- Rb is , and It can be at least one of the following.
- Rd is , , , and It can be either of the following,
- Rb is , and It can be at least one of the following.
- A may be a 4-azasteroid derivative or minoxidil.
- 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 an example and is not limited thereto.
- 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.
- 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.
- n can be 10 to 10,000
- 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.
- the spacer is cleaved within the cell and the hair loss treatment component is separated from the compound so that it can act only on the scalp. Therefore, side effects can be reduced through the local action of the effective ingredient.
- a composition including the compound of the present invention can be utilized as a long-term preparation.
- the cell absorption rate can be improved depending on the type of polymer to be bound.
- one embodiment of the present invention can provide a skin external 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.
- the present invention provides a method for preparing a compound in which a 4-azasteroid derivative or minoxidil and a polymer are chemically bonded.
- 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 overlapping extent.
- 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 through a spacer.
- 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.
- the modified minoxidil may add a functional group capable of reacting with the polymer or the spacer.
- the secondary hydrogen contained in minoxidil can be replaced with a carboxyl group to transform the minoxidil into a modified minoxidil, specifically, carboxylated minoxidil.
- carboxylated minoxidil can be modified into aminated minoxidil by amination.
- 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.
- 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.
- a step of protecting the primary amine contained in the minoxidil with an amine protecting group.
- 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.
- the compound of the present invention can be prepared 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.
- the 4-azasteroid derivative or the minoxidil, and the polymer can be combined via the spacer.
- modified minoxidil and hyaluronic acid can be combined by adding a diamine that can act as a spacer, as in the following reaction formula.
- the present invention 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.
- the description of the compound of the present invention and the description of the method for preparing the compound can be applied equally to the extent that they overlap.
- 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.
- 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.
- the piperidine derivative in the step of combining the polymer and 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).
- the polymer and the piperidine derivative can be linked directly or via a spacer.
- the step of directly bonding the polymer and the piperidine derivative can proceed as in the following reaction scheme.
- 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.
- the step of bonding the polymer and the piperidine derivative through the spacer can be performed by reacting the spacer and the piperidine derivative as shown in the following reaction formula.
- 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.
- the above 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 and the above polymer may be added.
- the deacetylation may be performed without particular limitation by any method known in the art, but as a specific example, it may be performed as in the following reaction scheme.
- the method for producing the compound using the deacetylated polymer can be performed as in the following reaction scheme.
- the step of combining the piperidine derivative to which the deacetylated polymer is combined and the pyrimidine derivative can be performed as shown in the following reaction formula.
- 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.
- 0.05 g piperidin-4-amine was slowly added and stirred for 3 hours. After completion of the reaction, it was extracted with ethanol. By-products were removed by washing with ethanol and vacuum dried.
- minoxidil-HA was synthesized.
- the specific synthesis method is as follows.
- 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. After that, 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. Next, the mixture was washed with methanol and ethanol to remove by-products, and dried under vacuum.
- 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 and stirred for 3 hours. After completion of the reaction, it was extracted with ethanol. By-products were removed by washing with ethanol and dried under vacuum.
- minoxidil-spacer-HA was synthesized.
- the specific synthesis method is as follows.
- Tetrabutylammonium (TBA)-HA was dissolved in DMSO to prepare solution 1.
- 0.065 g piperidin-4-carboxylic acid was dissolved in DMSO to prepare solution 2.
- 0.123 g DMAP and 0.208 g DCC were added to solution 2 and stirred for 30 minutes.
- the HA solution of solution 1 was slowly added to solution 3 and stirred for 3 hours. After completion of the reaction, it was extracted with ethanol. The by-products were removed by washing with ethanol and dried under vacuum.
- minoxidil-HA was synthesized.
- the specific synthesis method is as follows.
- TBA-HA 0.1 g TBA-HA was dissolved in DMSO to prepare solution 1.
- 0.093 g (piperidine-4-carbonyl)glycine was dissolved in DMSO to prepare solution 2.
- 0.122 g DMAP and 0.206 g DCC were added to solution 2 and stirred for 30 minutes.
- the HA solution of solution 1 was slowly added to solution 3 and stirred for 3 hours. After completion of the reaction, it was extracted with ethanol. By-products were removed by washing with ethanol and dried under vacuum.
- minoxidil-spacer-HA was synthesized.
- the specific synthesis method is as follows.
- Deacetylated HA was synthesized according to the following reaction scheme 11.
- the specific synthesis method is as follows.
- 0.1 g HA was dissolved in distilled water. NH2OH was added to make 50 wt% and stirred at 40°C for 24 hours. After completion of the reaction, it was extracted with ethanol. By-products were removed by washing with ethanol and dried under vacuum.
- Piperidine-HA was synthesized according to the following reaction scheme 12.
- the specific synthesis method is as follows.
- 0.1 g deacetylated HA was dissolved in distilled water to prepare solution 1.
- 0.065 g piperidin-4-carboxylic acid was dissolved in distilled water to prepare solution 2.
- 0.191 g EDC ⁇ HCl and 0.115 g NHS were added to solution 2 and stirred for 30 minutes.
- the HA solution of solution 1 was slowly added to solution 2 and stirred for 3 hours. After completion of the reaction, it was extracted with ethanol. By-products were removed by washing with ethanol and dried under vacuum.
- minoxidil-HA was synthesized.
- the specific synthesis method is as follows.
- 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. After dissolving 0.15 g of glycine in distilled water, it was slowly added to Solution 2 and stirred for 3 hours. After completion of the reaction, it was extracted with ethanol. By-products were removed by washing with ethanol and dried under vacuum.
- Deacetylated HA was synthesized according to the following reaction scheme 15.
- the specific synthesis method is as follows.
- 0.1 g HA was dissolved in distilled water. NH2OH was added to make 50 wt% and stirred at 40°C for 24 hours. After completion of the reaction, it was extracted with ethanol. By-products were removed by washing with ethanol and dried under vacuum.
- 0.1 g deacetylated HA was dissolved in distilled water to prepare solution 1.
- 0.093 g (piperidine-4-carbonyl)glycine was dissolved in distilled water to prepare solution 2.
- 0.191 g EDC ⁇ HCl and 0.115 g NHS were added to solution 2 and stirred for 30 minutes to prepare solution 3.
- 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. By-products were removed by washing with ethanol and dried under vacuum.
- minoxidil-spacer-HA was synthesized.
- the specific synthesis method is as follows.
- minoxidil-HA was synthesized.
- the specific synthesis method is as follows.
- 0.1 g HA was dissolved in distilled water to prepare Solution 1.
- 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 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 by-products and dried under vacuum.
- 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, it was extracted with ethanol. By-products were removed by washing with ethanol and dried under vacuum.
- minoxidil-spacer-HA was synthesized.
- the specific synthesis method is as follows.
- Step 2 0.1 g of the prepared 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. The mixture was washed with methanol and ethanol to remove by-products, and dried under vacuum.
- TBA-HA 0.1 g TBA-HA was dissolved in DMF, and 2.5 mmol 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 freeze-dried and stored.
- Step 2 0.1 g of the prepared Chlorinated HA was dissolved in distilled water. 0.12 g of the prepared piperidine derivative-spacer in Step 1 was slowly added and stirred for 24 hours. After completion of the reaction, it was extracted with ethanol. By-products were removed by washing with ethanol and dried under vacuum.
- minoxidil-spacer-HA was synthesized.
- the specific synthesis method is as follows.
- Step 3 0.1 g of the prepared piperidine derivative-spacer-HA was dissolved in distilled water, and potassium carbonate was added to prepare solution 1. 0.08 g of 2,6-Diamino-4-chloropyrimidine 1-oxide was dissolved in methanol to prepare solution 2. 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. The mixture was washed with methanol and ethanol to remove by-products, and dried under vacuum.
- Deacetylated HA was synthesized according to the following reaction scheme 27.
- the specific synthesis method is as follows.
- 0.1 g HA was dissolved in distilled water. NH2OH was added to make 50 wt% and stirred at 40°C for 24 hours. After completion of the reaction, it was extracted with ethanol. By-products were removed by washing with ethanol and dried under vacuum.
- 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, it was extracted with ethanol. By-products were removed by washing with ethanol and dried under vacuum.
- minoxidil-spacer-HA was synthesized.
- the specific synthesis method is as follows.
- Step 3 0.1 g of the prepared piperidine derivative-spacer-HA was dissolved in distilled water, and potassium carbonate was added to prepare solution 1. 0.08 g of 2,6-Diamino-4-chloropyrimidine 1-oxide was dissolved in methanol to prepare solution 2. 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. The mixture was washed with methanol and ethanol to remove by-products, and dried under vacuum.
- spacer-HA was synthesized.
- the specific synthesis 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. By-products were removed by washing with ethanol, and dried under vacuum.
- Step 1 was prepared by dissolving 0.1 g spacer-HA in distilled water to prepare Solution 1.
- Solution 2 was prepared by dissolving 0.079 g 3-Oxo-4-aza-5 ⁇ -androst-1-ene-17 ⁇ -carboxylic Acid in methanol.
- 0.191 g EDC ⁇ HCl and 0.115 g NHS were added to Solution 2 and stirred for 30 minutes to prepare Solution 3.
- 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. The by-products were removed by washing with ethanol and dried under vacuum.
- spacer-HA was synthesized.
- the specific synthesis 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. By-products were removed by washing with ethanol, and vacuum dried.
- Step 1 was prepared by dissolving 0.1 g spacer-HA in distilled water to prepare Solution 1.
- Solution 2 was prepared by dissolving 0.079 g 3-Oxo-4-aza-5 ⁇ -androst-1-ene-17 ⁇ -carboxylic Acid in methanol.
- 0.191 g EDC ⁇ HCl and 0.115 g NHS were added to Solution 2 and stirred for 30 minutes to prepare Solution 3.
- 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. The by-products were removed by washing with ethanol and dried under vacuum.
- Dutasteride substituted with a carboxyl group was synthesized according to the following reaction scheme 34.
- the specific synthetic method is as follows.
- spacer-HA was synthesized.
- the specific synthesis 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. By-products were removed by washing with ethanol, and vacuum dried.
- dutasteride-spacer-HA was synthesized.
- the specific synthesis method is as follows.
- step 2 0.1 g of spacer-HA synthesized was dissolved in distilled water, 0.191 g of EDC ⁇ HCl and 0.115 g of NHS were added to 1, and stirred for 30 minutes.
- step 2 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. By-products were removed by washing with ethanol, and dried under vacuum.
- spacer-HA was synthesized.
- the specific synthesis 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. By-products were removed by washing with ethanol, and vacuum dried.
- hyaluronic acid 0.1 g 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 by-products, and vacuum dried.
- finasteride-spacer-HA was synthesized.
- the specific synthesis method is as follows.
- Step 1 was prepared by dissolving 0.1 g spacer-HA in distilled water to prepare solution 1.
- Solution 2 was prepared by dissolving 0.1 g 2-Pyridyl 3-oxo-4-aza-5 ⁇ -androst-1-ene-17 ⁇ -carbothioate in methanol. After mixing solutions 1 and 2, NaH was added and stirred for 3 hours. After completion of the reaction, it was extracted with ethanol. The mixture was washed with ethanol to remove by-products and dried under vacuum.
- TBA-HA was dissolved in DMSO to prepare solution 1.
- 0.079 g 3-Oxo-4-aza-5 ⁇ -androst-1-ene-17 ⁇ -carboxylic Acid was dissolved in DMSO to prepare solution 2.
- 0.122 g DMAP and 0.206 g DCC were added to solution 2 and stirred for 30 minutes.
- the HA solution of solution 1 was slowly added to solution 2 and stirred for 3 hours. After completion of the reaction, it was extracted with ethanol. The by-products were removed by washing with ethanol and dried under vacuum.
- TBA-HA 0.1 g TBA-HA was dissolved in DMF, and 2.5 mmol 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 freeze-dried and stored.
- Step 1 0.1 g of chlorinated HA prepared was dissolved in distilled water.
- Step 2 0.22 g of 4-azasteroid derivative-spacer prepared was dissolved in methanol and added to the HA solution. After stirring for 24 hours, it was extracted with ethanol. It was washed with ethanol, by-products were removed, and vacuum dried.
- Deacetylated HA was synthesized according to the following reaction scheme 44.
- the specific synthesis method is as follows.
- 0.1 g HA was dissolved in distilled water. NH2OH was added to make 50 wt% and stirred at 40°C for 24 hours. After completion of the reaction, it was extracted with ethanol. By-products were removed by washing with ethanol and dried under vacuum.
- 0.1 g deacetylated HA was dissolved in distilled water to prepare solution 1.
- 0.079 g 3-Oxo-4-aza-5 ⁇ -androst-1-ene-17 ⁇ -carboxylic Acid was dissolved in methanol to prepare solution 2.
- 0.191 g EDC ⁇ HCl and 0.115 g NHS were added to solution 2 and stirred for 30 minutes to prepare solution 3.
- 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. The by-products were removed by washing with ethanol and dried under vacuum.
- Deacetylated HA was synthesized according to the following reaction scheme 47.
- the specific synthesis method is as follows.
- 0.1 g HA was dissolved in distilled water. NH2OH was added to make 50 wt% and stirred at 40°C for 24 hours. After completion of the reaction, it was extracted with ethanol. By-products were removed by washing with ethanol and dried under vacuum.
- 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 was dissolved in methanol and added to the HA solution. After stirring for 24 hours, it was extracted with ethanol. It was washed with ethanol, by-products were removed, and vacuum dried.
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Abstract
Description
본 발명의 다양한 실시예는 탈모 치료 성분이 고정화된 신규한 구조를 가지는 화합물 및 이의 제조 방법에 관한 것이다. 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.
두피 탈모 치료에 사용되는 의약품의 대표적인 예로 미녹시딜이 있다. 미녹시딜은 미국 FDA에서 허가되었으며, 고유한 칼륨 통로 개방제(Potassium channel opener)로서의 혈관 확장 기능 외에 휴지기의 모발주기에서 성장기로 유도하고, 유도된 성장기 모발주기를 계속 유지시키는 활성이 보고되었다.A representative example of a drug used to treat scalp hair loss is minoxidil. Minoxidil has been approved by the US FDA, and in addition to its vasodilating function as a unique potassium channel opener, it has been reported to have the activity of inducing hair from the resting phase to the growth phase and maintaining the induced growth phase hair cycle.
한편, 미녹시딜은 두피에 바르는 외용제로 사용되고 있으나, 두피가 아닌 다른 부위에 접촉하게 될 경우 부작용을 일으킬 수 있다. 따라서, 타겟 부위에만 미녹시딜을 작용시키기 위해서는 미녹시딜의 고정화가 중요한 문제인데, 고정화 시 미녹시딜의 구조가 많이 변형되어 약효가 떨어진다는 문제가 있다.Meanwhile, minoxidil is used as an external agent applied to the scalp, but it can cause side effects if it comes into contact with areas other than the scalp. Therefore, in order to make minoxidil work only on the target area, fixation of minoxidil is an important issue, but there is a problem that the structure of minoxidil is greatly changed during fixation, which reduces the efficacy.
본 발명의 다양한 실시예에서는, 두피 탈모치료제로 널리 사용되는 미녹시딜을 비롯한 탈모 치료 성분을 안정적으로 고정화할 수 있고, 국소 작용을 유도하여 부작용을 감소시킬 수 있는 화합물 및 이의 제조방법을 제공하고자 한다.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 producing the same.
상기 목적을 달성하기 위하여, 본 발명은 4-아자스테로이드(4-azasteroid) 유도체 또는 미녹시딜, 및 고분자가 화학적으로 결합된 화합물을 제공한다.To achieve the above purpose, the present invention provides a compound in which a 4-azasteroid derivative or minoxidil and a polymer are chemically bound.
본 발명의 일 예에 따른 상기 고분자는, 상기 4-아자스테로이드(4-azasteroid) 유도체 또는 상기 미녹시딜과 직접 결합 또는 스페이서를 통해 결합되는 것일 수 있다.According to one example of the present invention, the polymer may be directly bound to the 4-azasteroid derivative or the minoxidil or may be bound via a spacer.
본 발명의 일 예에 따른 상기 미녹시딜은 2차 탄소(secondary carbon)에 결합된 카복실기 또는 아민기를 포함하는 것일 수 있다.According to an example of the present invention, the minoxidil may include a carboxyl group or an amine group bonded to a secondary carbon.
본 발명의 일 예에 따른 상기 4-아자스테로이드(4-azasteroid) 유도체는 아마이드기, 카복실기 및 싸이오에스터기(thioester)로 이루어진 군에서 선택된 어느 하나 이상의 작용기를 함유하는 것일 수 있다.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.
본 발명의 일 예에 따른 상기 고분자는 하이드록시기, 카복실기, 아세틸기, 아마이드기 및 아민기 중 적어도 어느 하나 이상의 작용기를 포함하는 것일 수 있다.According to one 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.
본 발명의 일 예에 따른 상기 고분자는 히알루론산, 알지네이트, 셀룰로오스, 카이토산, 젤라틴, 전분, 키틴, 콜라겐 및 헤파린으로 이루어진 군에서 선택된 적어도 어느 하나를 포함할 수 있다.According to one 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.
본 발명의 일 예에 따른 상기 고분자는 탈아세틸화(deacetylated)된 것일 수 있다.According to one example of the present invention, the polymer may be deacetylated.
본 발명의 일 예에 따른 상기 스페이서는, 양 말단 중 적어도 어느 하나에 -NH2, -COOH, -OH, 알데하이드(aldehyde), 에폭사이드(epoxide), 할로겐 원소(F, Cl, Br, I), 석신이미드(succinimide), 알켄(alkene), 및 알카인(alkyne)으로 이루어진 군에서 선택된 적어도 어느 하나를 포함하는 알킬체인, 디설파이드(Disulfide) 결합, 에스터(Ester) 결합 및 아마이드(Amide) 결합으로 이루어진 군에서 선택된 적어도 어느 하나를 포함하는 알킬체인, 및 펩타이드 중 어느 하나인 것일 수 있다.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 -NH 2 , -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.
본 발명의 일 예에 따른 상기 화합물은 하기 화학식 6 내지 9 중 어느 하나인 것일 수 있다.According to an example of the present invention, the compound may be any one of the following chemical formulas 6 to 9.
[화학식 6][Chemical formula 6]
[화학식 7][Chemical formula 7]
상기 화학식 6 및 7에서,In the above chemical formulas 6 and 7,
Ra는 NH, O,
Rb는 CH2, NH, O,
Rc는
Rd는 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,
[화학식 8][Chemical formula 8]
상기 화학식 8에서, In the above chemical formula 8,
Re는
Rb는 CH2, NH, O,
Rc는
Rd는 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,
[화학식 9][Chemical formula 9]
상기 화학식 6 내지 9에서 n은 10 내지 10,000일 수 있고, 상기 화학식 6 내지 8에서 A는 4-아자스테로이드(4-azasteroid) 유도체 또는 미녹시딜일 수 있으며, x는 0 내지 40일 수 있고, y는 1 내지 40일 수 있으며, z는 1 내지 40일 수 있다.In the above chemical formulas 6 to 9, n can be 10 to 10,000, in the above chemical formulas 6 to 8, A can be a 4-azasteroid derivative or minoxidil, x can be 0 to 40, y can be 1 to 40, and z can be 1 to 40.
본 발명의 일 예에 따른 상기 [화학식 6]로 표시되는 화합물은 하기 [표 1]에 표시된 화합물 중 어느 하나인 것일 수 있고, 여기서, n은 10 내지 10,000일 수 있고, X는 0 내지 40일 수 있다.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.
[표 1][Table 1]
[규칙 제91조에 의한 정정 04.09.2024]
[규칙 제91조에 의한 정정 04.09.2024]
본 발명의 일 예에 따른 상기 [화학식 7]로 표시되는 화합물은 하기 [표 2]에 표시된 화합물 중 어느 하나인 것일 수 있고, 여기서, n은 10 내지 10,000일 수 있고, X는 0 내지 40일 수 있다.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.
[표 2][Table 2]
[규칙 제91조에 의한 정정 04.09.2024]
[규칙 제91조에 의한 정정 04.09.2024]
본 발명의 일 예에 따른 상기 [화학식 8]으로 표시되는 화합물은 하기 [표 3]에 표시된 화합물 중 어느 하나인 것일 수 있고, 여기서, n은 10 내지 10,000일 수 있고, X는 0 내지 40일 수 있다.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.
[표 3][Table 3]
[규칙 제91조에 의한 정정 04.09.2024]
[규칙 제91조에 의한 정정 04.09.2024]
본 발명의 다른 일 측면에서는 4-아자스테로이드(4-azasteroid) 유도체 또는 미녹시딜을 고분자와 직접 결합 또는 스페이서를 통해 결합하는 단계;를 포함하는, 화합물의 제조방법을 제공한다.본 발명의 일 예에 따른 상기 화합물의 제조방법은 상기 결합하는 단계 전, 상기 미녹시딜이 함유하는 2차 수소를 카복실기 또는 아민기로 치환하여 상기 미녹시딜을 변형하는 단계;를 더 포함할 수 있다.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 via a spacer. The method for preparing the compound according to one example of the present invention may further comprise, prior to 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.
본 발명의 일 예에 따른 상기 화합물의 제조방법은 상기 변형하는 단계 전, 상기 미녹시딜이 함유하는 1차 아민을 아민 보호기로 보호화(protection)하는 단계;를 더 포함할 수 있다.The method for preparing the compound according to one example of the present invention may further include, prior to the modifying step, a step of protecting the primary amine contained in the minoxidil with an amine protecting group.
또한, 본 개시의 또 다른 일 측면에서는 고분자와 피페리딘 유도체를 결합하는 단계; 및 상기 고분자가 결합된 상기 피페리딘 유도체와 피리미딘 유도체를 결합하는 단계;를 포함하는, 화합물의 제조방법을 제공한다.In addition, another aspect of the present disclosure 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.
본 발명의 일 예에 따른 상기 피페리딘 유도체는 카복실기 또는 아민기를 함유하는 것일 수 있다.The piperidine derivative according to one example of the present invention may contain a carboxyl group or an amine group.
본 발명의 일 예에 따른 상기 고분자는 탈아세틸화(deacetylated)된 것일 수 있다.According to one example of the present invention, the polymer may be deacetylated.
본 발명의 화합물은, 탈모 치료 성분의 구조가 크게 변형되지 않으면서도 고분자에 결합됨으로써, 탈모 치료 성분을 안정적으로 고정화할 수 있다. The compound of the present invention can stably fix an hair loss treatment component by binding to a polymer without significantly changing the structure of the hair loss treatment component.
본 발명의 화합물이 체내에 흡수되었을 때, 세포 내에서 탈모 치료 성분이 화합물로부터 분리되어 두피에서만 작용할 수 있다. 따라서, 유효성분의 국소 작용을 통해 탈모 치료 성분의 부작용을 줄일 수 있다. 또한, 본 발명의 화합물을 포함하는 조성물은 장기 지속형 제제로 활용가능하다. 또한, 화합물을 구성하는 고분자 종류에 따라 세포 흡수율을 향상시킬 수 있다.When the compound of the present invention is absorbed into the body, the hair loss treatment component is separated from the compound within the cell and can only act on the scalp. Therefore, the side effects of the hair loss treatment component can be reduced through the local action of the effective ingredient. In addition, the composition containing the compound of the present invention can be utilized as a long-term formulation. In addition, the cell absorption rate can be improved depending on the type of polymer constituting the compound.
이하, 본 문서의 다양한 실시예들이 기재된다. 실시예 및 이에 사용된 용어들은 본 문서에 기재된 기술을 특정한 실시 형태에 대해 한정하려는 것이 아니며, 해당 실시예의 다양한 변경, 균등물, 및/또는 대체물을 포함하는 것으로 이해되어야 한다. Below, various embodiments of this document are described. It should be understood that the embodiments and terms used herein are not intended to limit the technology described in this document to specific embodiments, but rather include various modifications, equivalents, and/or substitutes of the embodiments.
화합물compound
본 발명은 4-아자스테로이드(4-azasteroid) 유도체 또는 미녹시딜, 및 고분자가 화학적으로 결합된 화합물을 제공한다.The present invention provides a compound in which a 4-azasteroid derivative or minoxidil and a polymer are chemically bound.
상기 4-아자스테로이드(4-azasteroid) 유도체는 스테로이드 고리 시스템의 4번 탄소 원자가 질소 원자로 대체된 스테로이드 유도체일 수 있고, 구체적으로 하기 화학식 1, 화학식 2 또는 화학식 3으로 표시되는 스테로이드 유도체일 수 있다.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.
[화학식 1][Chemical Formula 1]
[화학식 2][Chemical formula 2]
[화학식 3][Chemical Formula 3]
상기 미녹시딜은 3-하이드록시-2-이미노-6-피페리딘-1-일피리미딘-4-아민(3-hydroxy-2-imino-6-piperidin-1-ylpyrimidin-4-amine)을 나타내는 것으로서, 하기 화학식 4로 표시될 수 있다.The above minoxidil represents 3-hydroxy-2-imino-6-piperidin-1-ylpyrimidin-4-amine, and can be represented by the following chemical formula 4.
[화학식 4][Chemical Formula 4]
본 발명의 화합물은 상기 고분자가 상기 4-아자스테로이드(4-azasteroid) 유도체 또는 상기 미녹시딜과 직접 결합 또는 스페이서를 통해 결합되는 것일 수 있다.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.
일 실시예에 따르면, 상기 고분자는 하이드록시기, 카복실기, 아세틸기, 아마이드기 및 아민기 중 적어도 어느 하나 이상의 작용기를 포함하는 것일 수 있다. 상기 고분자가 포함하는 작용기는 상기 4-아자스테로이드(4-azasteroid) 유도체 또는 상기 미녹시딜이 포함하는 작용기와 반응하거나, 스페이서와 반응할 수 있다. 예를 들면, 고분자는 히알루론산, 알지네이트, 셀룰로오스, 카이토산, 젤라틴, 전분, 키틴, 콜라겐 및 헤파린 이루어진 군에서 선택된 적어도 어느 하나를 포함할 수 있다. 구체적으로 상기 고분자는 하기 화학식 5의 히알루론산일 수 있다.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 a functional group included in the 4-azasteroid derivative or the minoxidil, or may react 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.
[화학식 5][Chemical Formula 5]
일 실시예에 따르면, 상기 고분자는 탈아세틸화(deacetylated)된 것일 수 있다. 일 실시예에 따르면, 상기 탈아세틸화에 의하여 상기 고분자가 함유하는 아마이드기가 아민기로 전환될 수 있고, 전환된 아민기는 상기 4-아자스테로이드(4-azasteroid) 유도체, 상기 미녹시딜 또는 스페이서와 반응할 수 있는 새로운 반응 지점이 될 수 있다.In one embodiment, the polymer may be deacetylated. In one embodiment, by the deacetylation, an amide group contained in the polymer may be converted 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.
일 실시예에 따르면, 상기 고분자는 할로젠화(halogenated)된 것일 수 있다. 일 실시예에 따르면, 상기 할로젠화에 의하여 상기 고분자가 함유하는 1차 알콜(primary alcohol)의 하이드록시기가 할로젠기로 전환될 수 있고, 전환된 할로젠기는 상기 4-아자스테로이드(4-azasteroid) 유도체, 상기 미녹시딜 또는 스페이서가 함유하는 친핵성 부분과 치환 반응을 할 수 있는 새로운 반응 지점이 될 수 있다.In one embodiment, the polymer may be halogenated. In one embodiment, by the halogenation, a hydroxyl group of a primary alcohol contained in the polymer may be converted 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.
일 실시예에 따르면, 본 발명의 화합물은 상기 고분자가 함유하는 카복실기와 상기 미녹시딜이 함유하는 아민기가 반응함으로써 상기 고분자가 상기 미녹시딜과 직접 결합된 것일 수 있다.According to one embodiment, the compound of the present invention may be a polymer directly bonded to the minoxidil by reaction between a carboxyl group contained in the polymer and an amine group contained in the minoxidil.
일 실시예에 따르면, 상기 미녹시딜은 2차 탄소(secondary carbon)에 결합된 카복실기 또는 아민기를 포함할 수 있다. 구체적으로 상기 2차 탄소(secondary carbon)에 결합된 카복실기는 상기 미녹시딜이 함유하는 2차 수소(secondary hydrogen)를 치환 반응을 통해 카복실기로 치환하여 얻을 수 있다. 또한, 상기 2차 탄소(secondary carbon)에 결합된 아민기는, 상기 치환된 카복실기를 아미노화(amination)하여 얻을 수 있다.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. In addition, the amine group bonded to the secondary carbon can be obtained by amination of the substituted carboxyl group.
일 실시예에 따르면, 상기 스페이서는 양 말단 중 적어도 어느 하나에 -NH2, -COOH, -OH, 알데하이드(aldehyde), 에폭사이드(epoxide), 할로겐 원소(F, Cl, Br, I), 석신이미드(succinimide), 알켄(alkene), 및 알카인(alkyne)으로 이루어진 군에서 선택된 적어도 어느 하나를 포함하는 알킬체인일 수 있다. 또는, 상기 스페이서는 디설파이드(Disulfide) 결합, 에스터(Ester) 결합 및 아마이드(Amide) 결합으로 이루어진 군에서 선택된 적어도 어느 하나를 포함하는 알킬체인일 수 있다. 또는 상기 스페이서는 펩타이드일 수 있다. 일 실시예에 따르면, 상기 스페이서는 체내와 같은 특정 조건에서 절단 가능한 링커일 수 있다. 따라서, 상기 화합물이 체내에 흡수되었을 때, 세포 내에서 상기 스페이서가 절단되고 탈모 치료 성분이 화합물로부터 분리되어 두피에서만 작용할 수 있다. 따라서, 유효성분의 국소 작용을 통해 부작용을 줄일 수 있다. In one embodiment, the spacer may be an alkyl chain comprising at least one selected from the group consisting of -NH 2 , -COOH, -OH, aldehyde, epoxide, halogen elements (F, Cl, Br, I), succinimide, an alkene, and an alkyne at at least one of both terminals. 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.
구체적으로, 본 발명의 다양한 실시예에 따른 화합물은 하기 화학식 6 내지 9 중 어느 하나일 수 있다.Specifically, the compound according to various embodiments of the present invention may be any one of the following chemical formulas 6 to 9.
[화학식 6][Chemical formula 6]
[화학식 7][Chemical formula 7]
상기 화학식 6 및 7에서,In the above chemical formulas 6 and 7,
Ra는 NH, O,
Rb는 CH2, NH, O,
Rc는
Rd는 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,
[화학식 8][Chemical formula 8]
상기 화학식 8에서, In the above chemical formula 8,
Re는
Rb는 CH2, NH, O,
Rc는
Rd는 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,
[화학식 9][Chemical formula 9]
상기 화학식 6 내지 9에서 n은 10 내지 10,000 일 수 있고,In the above chemical formulas 6 to 9, n can be 10 to 10,000,
상기 화학식 6 내지 8에서, 상기 A는 4-아자스테로이드(4-azasteroid) 유도체 또는 미녹시딜일 수 있고, x는 0 내지 40 일 수 있으며, y는 1 내지 40일 수 있고, z는 1 내지 40일 수 있다.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.
한편, 본 발명의 다양한 실시예에 따른 화합물은 하기 화학식 6-1, 화학식 7-1, 화학식 8-1 및 화학식 9 중 어느 하나일 수 있다. 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.
[화학식 6-1][Chemical Formula 6-1]
상기 화학식 6-1에서, Ra는 NH,
Rb는
[화학식 7-1][Chemical Formula 7-1]
[규칙 제91조에 의한 정정 04.09.2024]
상기 화학식 7-1에서, Rc는
Rb는
[화학식 8-1][Chemical Formula 8-1]
상기 화학식 8-1에서, Rd는
Rb는
상기 화학식 6-1 내지 8-1에서, 상기 A는 4-아자스테로이드(4-azasteroid) 유도체 또는 미녹시딜일 수 있다.In the above chemical formulas 6-1 to 8-1, A may be a 4-azasteroid derivative or minoxidil.
[화학식 9][Chemical formula 9]
보다 구체적으로, 상기 [화학식 6] 또는 [화학식 6-1]로 표시되는 화합물은 하기 [표 1]에 표시된 화합물 중 어느 하나일 수 있으나, 이는 구체적인 예시를 나타내는 것일 뿐 이에 제한되는 것은 아니다. 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 an example and is not limited thereto.
[규칙 제91조에 의한 정정 04.09.2024]
[Correction under Rule 91 04.09.2024]
상기 [화학식 7] 또는 [화학식 7-1]로 표시되는 화합물은 하기 [표 2]에 표시된 화합물 중 어느 하나일 수 있으나, 이는 구체적인 예시를 나타내는 것일 뿐 이에 제한되는 것은 아니다.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.
상기 [화학식 8] 또는 [화학식 8-1]으로 표시되는 화합물은 하기 [표 3]에 표시된 화합물 중 어느 하나일 수 있으나, 이는 구체적인 예시를 나타내는 것일 뿐 이에 제한되는 것은 아니다.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.
상기 표 1 내지 표 3에 표시된 화학식에서 n은 10 내지 10,000 일 수 있고, X는 0 내지 40 일 수 있다. 본 발명의 화합물은, 탈모 치료 성분의 구조가 크게 변형되지 않고 고분자에 결합됨으로써, 탈모 치료 성분을 안정적으로 고정화할 수 있다. 또한, 고분자와 탈모 치료 성분이 스페이서를 통해 결합된 경우에도, 화합물이 체내에 흡수되었을 때, 세포 내에서 스페이서가 절단되고 탈모 치료 성분이 화합물로부터 분리되어 두피에서만 작용할 수 있다. 따라서, 유효성분의 국소 작용을 통해 부작용을 줄일 수 있다. 또한, 본 발명의 화합물을 포함하는 조성물은 장기 지속형 제제로 활용가능하다. 또한, 결합하는 고분자 종류에 따라 세포 흡수율을 향상할 수 있다. 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 so that it can act only on the scalp. Therefore, side effects can be reduced through the local action of the effective ingredient. In addition, a composition including the compound of the present invention can be utilized as a long-term preparation. In addition, the cell absorption rate can be improved depending on the type of polymer to be bound.
한편, 본 발명의 일 실시예는, 상술한 화합물을 포함하는 피부 외용제 조성물 또는 주사제 조성물을 제공할 수 있다. 구체적으로, 본 발명의 일 실시예는 상술한 화합물을 포함하는 탈모 방지용 조성물을 제공할 수 있다. Meanwhile, one embodiment of the present invention can provide a skin external 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.
화합물의 제조방법Method for preparing a compound
본 발명은 4-아자스테로이드(4-azasteroid) 유도체 또는 미녹시딜, 및 고분자가 화학적으로 결합된 화합물을 제조하는 방법을 제공한다. 상술한 본 발명의 상기 화합물에 대한 설명은 중복되는 범위에서 본 발명의 제조방법에 대하여 동일하게 적용될 수 있다.The present invention provides a method for preparing a compound in which a 4-azasteroid derivative or minoxidil and a polymer are chemically bonded. 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 overlapping extent.
본 발명의 일 실시예에 따른 상기 화합물의 제조방법은 4-아자스테로이드(4-azasteroid) 유도체 또는 미녹시딜을 고분자와 직접 결합 또는 스페이서를 통해 결합하는 단계;를 포함할 수 있다. 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 through a spacer.
일 실시예에 따르면, 상기 화합물의 제조방법은 상기 결합하는 단계 전, 상기 미녹시딜이 함유하는 2차 수소를 카복실기 또는 아민기로 치환하여 상기 미녹시딜을 변형하는 단계;를 더 포함할 수 있다. 상기 변형하는 단계를 통하여 변형된 미녹시딜은 상기 고분자 또는 상기 스페이서와 반응할 수 있는 작용기를 추가할 수 있다.According to 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.
예를 들면, 하기 반응식과 같이 미녹시딜이 함유하는 2차 수소를 카복실기로 치환하여 상기 미녹시딜을 변형된 미녹시딜, 구체적으로 카복실화된 미녹시딜(Carboxylated minoxidil)로 변형할 수 있다.For example, as shown in the following reaction formula, the secondary hydrogen contained in minoxidil can be replaced with a carboxyl group to transform the minoxidil into a modified minoxidil, specifically, carboxylated minoxidil.
[규칙 제91조에 의한 정정 04.09.2024]
또한, 추가적으로 상기 카복실화된 미녹시딜을 아미노화(amination)하여 상기 미녹시딜을 아미노화된 미녹시딜로 변형할 수 있다.Additionally, the carboxylated minoxidil can be modified into aminated minoxidil by amination.
일 실시예에 따르면, 본 발명의 상기 화합물의 제조방법은 상기 변형된 미녹시딜을 하기 반응식과 같이 상기 고분자와 반응시켜 상기 화합물을 제조할 수 있다.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.
[규칙 제91조에 의한 정정 04.09.2024]
일 실시예에 따르면, 상기 화합물의 제조방법은 상기 변형하는 단계 전, 상기 미녹시딜이 함유하는 1차 아민을 아민 보호기로 보호화(protection)하는 단계;를 더 포함할 수 있다. 상기 보호화하는 단계를 통해, 상기 미녹시딜이 아미노화된 미녹시딜로 변형된 경우, 상기 고분자 또는 상기 스페이서와 결합되는 반응 지점을 상기 변형하는 단계를 통해 추가된 아민기로 지정할 수 있다.According to 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.
구체적으로, 하기 반응식과 같이 미녹시딜이 함유하는 1차 아민을 무수 아세트산(acetic anhydride)으로 보호화하고, 상기 보호화된 미녹시딜을 변형할 수 있다.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.
[규칙 제91조에 의한 정정 04.09.2024]
다음, 하기 반응식과 같이 미녹시딜의 변형에 의해 추가된 아민기와 히알루론산의 카복실기를 반응시킨 후, 탈보호화(deprotection)하여 본 발명의 화합물을 제조할 수 있다.Next, the compound of the present invention can be prepared 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.
[규칙 제91조에 의한 정정 04.09.2024]
일 실시예에 따르면, 상기 결합하는 단계에서, 상기 4-아자스테로이드(4-azasteroid) 유도체 또는 상기 미녹시딜, 및 상기 고분자는 상기 스페이서를 통해 결합될 수 있다.According to one embodiment, in the combining step, the 4-azasteroid derivative or the minoxidil, and the polymer can be combined via the spacer.
예를 들면, 하기 반응식과 같이 변형된 미녹시딜 및 히알루론산을 스페이서 역할을 할 수 있는 다이아민(Diamine)을 추가하여 결합할 수 있다.For example, modified minoxidil and hyaluronic acid can be combined by adding a diamine that can act as a spacer, as in the following reaction formula.
[규칙 제91조에 의한 정정 04.09.2024]
또한, 본 발명은 고분자와 피페리딘 유도체를 결합하는 단계; 및 상기 고분자가 결합된 피페리딘 유도체와 피리미딘 유도체를 결합하는 단계;를 포함하는, 화합물의 제조방법을 제공한다. 상술한 본 발명의 상기 화합물에 대한 설명 및 상기 화합물의 제조방법에 대한 설명이 중복되는 범위에서 동일하게 적용될 수 있다.In addition, the present invention 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. The description of the compound of the present invention and the description of the method for preparing the compound can be applied equally to the extent that they overlap.
상기 피페리딘(Piperidine) 유도체는 피페리딘의 구조와 성질을 대폭 변화시키지 않는 한도 내에서 작용기의 도입, 산화, 환원 또는 원자의 치환 등에 의하여 변화된 화합물을 의미할 수 있다.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.
상기 피리미딘(Pyrimidine) 유도체는 피리미딘의 구조와 성질을 대폭 변화시키지 않는 한도 내에서 작용기의 도입, 산화, 환원 또는 원자의 치환 등에 의하여 변화된 화합물을 의미할 수 있다.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.
[규칙 제91조에 의한 정정 04.09.2024]
일 실시예에 따르면, 상기 고분자와 피페리딘 유도체를 결합하는 단계에서, 상기 피페리딘 유도체는 카복실기 또는 아민기를 함유하는 것일 수 있고, 구체적으로
According to one 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,
일 실시예에 따르면, 상기 고분자와 상기 피페리딘 유도체는 직접 결합 또는 스페이서를 통해 결합될 수 있다.In one embodiment, the polymer and the piperidine derivative can be linked directly or via a spacer.
일 실시예에 따르면, 상기 고분자와 피페리딘 유도체를 직접 결합하는 단계는 하기 반응식과 같이 진행될 수 있다.According to one embodiment, the step of directly bonding the polymer and the piperidine derivative can proceed as in the following reaction scheme.
[규칙 제91조에 의한 정정 04.09.2024]
다음, 상기 고분자가 직접 결합된 피페리딘 유도체와 상기 피리미딘 유도체를 결합하는 단계는 하기 반응식과 같이 진행될 수 있다.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.
[규칙 제91조에 의한 정정 04.09.2024]
일 실시예에 따르면, 상기 고분자와 피페리딘 유도체를 스페이서를 통해 결합하는 단계는, 하기 반응식과 같이 상기 스페이서와 상기 피페리딘 유도체를 반응시켜 결합할 수 있다.According to one embodiment, the step of bonding the polymer and the piperidine derivative through the spacer can be performed by reacting the spacer and the piperidine derivative as shown in the following reaction formula.
[규칙 제91조에 의한 정정 04.09.2024]
다음, 하기 반응식과 같이 상기 피페리딘 유도체와 결합된 스페이서를 상기 고분자와 반응시켜 결합할 수 있다.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.
[규칙 제91조에 의한 정정 04.09.2024]
다음, 상기 스페이서를 통해 상기 고분자가 결합된 피페리딘 유도체와 피리미딘 유도체를 결합하는 단계는 하기 반응식과 같이 진행될 수 있다.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.
[규칙 제91조에 의한 정정 04.09.2024]
상기 고분자는 탈아세틸화(deacetylated)된 고분자일 수 있다. 상기 탈아세틸화를 통하여 상기 4-아자스테로이드(4-azasteroid) 유도체 또는 미녹시딜이 함유하는 카복실기와 상기 고분자가 반응할 수 있는 반응 지점을 추가할 수 있다. 상기 탈아세틸화는 당업계에서 공지된 방법이라면 특별히 제한되지 않고 사용될 수 있으나, 구체적인 일 예로, 하기 반응식과 같이 수행될 수 있다.The above 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 and the above polymer may be added. The deacetylation may be performed without particular limitation by any method known in the art, but as a specific example, it may be performed as in the following reaction scheme.
일 실시예에 따르면, 상기 탈아세틸화된 고분자를 사용한 상기 화합물의 제조방법은 하기 반응식과 같이 수행될 수 있다.According to one embodiment, the method for producing the compound using the deacetylated polymer can be performed as in the following reaction scheme.
[규칙 제91조에 의한 정정 04.09.2024]
다음, 상기 탈아세틸화된 고분자가 결합된 피페리딘 유도체와 상기 피리미딘 유도체를 결합하는 단계는 하기 반응식과 같이 수행될 수 있다.Next, the step of combining the piperidine derivative to which the deacetylated polymer is combined and the pyrimidine derivative can be performed as shown in the following reaction formula.
[규칙 제91조에 의한 정정 04.09.2024]
한편, 앞선 설명에서는 미녹시딜의 일부 변형을 통해 고분자에 결합하는 방법으로 설명했으나, 실시예가 이에 한정되는 것은 아니고 미녹시딜의 변형없이 고분자를 결합시킬 수도 있다. Meanwhile, in the above description, a method of binding to a polymer through some modification of minoxidil was described, but the example is not limited thereto, and a polymer can also be bound without modifying minoxidil.
이하, 본 발명은 실시예 및 실험예에 의해서 상세히 설명한다. 단, 하기 실시예 및 실험예는 본 발명을 예시하기 위한 것일 뿐 본 발명이 하기 실시예 및 실험예에 의해서 한정되는 것은 아니다.Hereinafter, the present invention will be described in detail by 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.
실시예 1: 화학식 6에 포함되는 화합물의 합성Example 1: Synthesis of a compound included in chemical formula 6
Step 1. 피페리딘 유도체-HA 합성Step 1. Synthesis of piperidine derivative-HA
하기 반응 모식도 1에 따라, 피페리딘 유도체-HA를 합성하였다. 구체적인 합성 방법은 다음과 같다.According to the following reaction scheme 1, piperidine derivative-HA was synthesized. The specific synthesis method is as follows.
0.1 g 히알루론산을 증류수에 용해하였다. 0.191 g EDC·HCl과 0.115 g NHS를 증류수에 용해한 히알루론산에 넣고 30분간 교반하였다. 다음으로, 0.05 g piperidin-4-amine을 서서히 투입하고 3시간 교반하였다. 반응종료 후 에탄올에 추출하였다. 에탄올로 세척하여 부산물을 제거하고 진공 건조하였다. 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, it was extracted with ethanol. By-products were removed by washing with ethanol and vacuum dried.
<반응 모식도 1><Reaction schematic diagram 1>
[규칙 제91조에 의한 정정 04.09.2024]
Step 2. 미녹시딜-HA 합성Step 2. Minoxidil-HA Synthesis
하기 반응 모식도 2에 따라, 미녹시딜-HA를 합성하였다. 구체적인 합성 방법은 다음과 같다.According to the following reaction scheme 2, minoxidil-HA was synthesized. The specific synthesis method is as follows.
Step 1에서 합성된 0.1 g의 피페리딘 유도체-HA을 증류수에 용해하고, potassium carbonate를 투입하여 1번 용액을 준비하였다. 0.08 g 2,6-Diamino-4-chloropyrimidine 1-oxide를 메탄올에 용해하여 2번 용액을 준비하였다. 이후, 1번 용액을 55~60℃로 가열하고 reflux 하에 2번 용액을 투입하였다. 12시간 반응 후, pH를 중성으로 맞추고 에탄올에 추출하였다. 다음으로, 메탄올 및 에탄올로 세척하여 부산물을 제거하고 진공 건조하였다.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. After that, 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. Next, the mixture was washed with methanol and ethanol to remove by-products, and dried under vacuum.
<반응 모식도 2><Reaction schematic diagram 2>
[규칙 제91조에 의한 정정 04.09.2024]
실시예 2: 화학식 6에 포함되는 화합물의 합성Example 2: Synthesis of a compound included in chemical formula 6
Step 1. 피페리딘 유도체-스페이서 합성Step 1. Piperidine derivative-spacer synthesis
하기 반응 모식도 3에 따라, 피페리딘 유도체와 스페이서가 결합된 2-amino-N-(piperidin-4-yl)acetamide를 합성하였다. 구체적인 합성 방법은 다음과 같다.According to the following reaction scheme 3, 2-amino-N-(piperidin-4-yl)acetamide was synthesized by combining a piperidine derivative and a spacer. The specific synthetic method is as follows.
0.075 g glycine을 증류수에 용해하였다. 0.382 g EDC·HCl과 0.23 g NHS를 증류수에 용해한 glycine에 넣고 30분간 교반하였다. 다음으로, 0.2 g piperidin-4-amine을 서서히 투입하고 3시간 교반하였다. 반응종료 후 에탄올에 추출하였다. 에탄올로 세척하여 부산물을 제거하고 진공 건조하였다.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, it was extracted with ethanol. By-products were removed by washing with ethanol and dried under vacuum.
<반응 모식도 3><Reaction schematic diagram 3>
[규칙 제91조에 의한 정정 04.09.2024]
Step 2. 피페리딘 유도체-스페이서-HA 합성Step 2. Piperidine derivative-spacer-HA synthesis
하기 반응 모식도 4에 따라, 피페리딘 유도체-스페이서-HA를 합성하였다. 구체적인 합성 방법은 다음과 같다.According to the following reaction scheme 4, piperidine derivative-spacer-HA was synthesized. The specific synthetic method is as follows.
0.1 g HA을 증류수에 용해하였다. 0.191 g EDC·HCl과 0.115 g NHS를 증류수에 용해한 HA에 넣고 30분간 교반하였다. 0.078 g 2-amino-N-(piperidin-4-yl)acetamide을 증류수에 용해 후 서서히 투입하고 3시간 교반하였다. 반응종료 후 에탄올에 추출하였다. 에탄올로 세척하여 부산물을 제거하고 진공 건조하였다. 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 and stirred for 3 hours. After completion of the reaction, it was extracted with ethanol. By-products were removed by washing with ethanol and dried under vacuum.
<반응 모식도 4><Reaction schematic diagram 4>
[규칙 제91조에 의한 정정 04.09.2024]
Step 3. 미녹시딜-스페이서-HA 합성Step 3. Minoxidil-Spacer-HA Synthesis
하기 반응 모식도 5에 따라, 미녹시딜-스페이서-HA를 합성하였다. 구체적인 합성 방법은 다음과 같다.According to the following reaction scheme 5, minoxidil-spacer-HA was synthesized. The specific synthesis method is as follows.
0.1 g 피페리딘 유도체-스페이서-HA을 증류수에 용해하고, potassium carbonate 투입하여 1번 용액을 준비하였다. 0.08 g 2,6-Diamino-4-chloropyrimidine 1-oxide를 메탄올에 용해하여 2번 용액을 준비하였다. 1번 용액을 55~60℃로 가열하고 reflux 하에 2번 용액을 투입하였다. 12시간 반응 후, pH를 중성으로 맞추고 에탄올에 추출하였다. 메탄올 및 에탄올로 세척하여 부산물을 제거하고 진공 건조하였다.0.1 g of piperidine derivative-spacer-HA was dissolved in distilled water, and potassium carbonate was added to prepare solution 1. 0.08 g of 2,6-Diamino-4-chloropyrimidine 1-oxide was dissolved in methanol to prepare solution 2. 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. The mixture was washed with methanol and ethanol to remove by-products, and dried under vacuum.
<반응 모식도 5><Reaction schematic diagram 5>
[규칙 제91조에 의한 정정 04.09.2024]
실시예 3: 화학식 7에 포함되는 화합물의 합성Example 3: Synthesis of a compound included in chemical formula 7
Step 1. 피페리딘 유도체-HA 합성Step 1. Synthesis of piperidine derivative-HA
하기 반응 모식도 6에 따라, 피페리딘 유도체-HA를 합성하였다. 구체적인 합성 방법은 다음과 같다.According to the following reaction scheme 6, piperidine derivative-HA was synthesized. The specific synthesis method is as follows.
0.1 g Tetrabutylammonium (TBA)-HA를 DMSO에 용해하여 1번 용액을 준비하였다. 0.065 g piperidin-4-carboxylic acid을 DMSO에 용해하여 2번 용액을 준비하였다. 0.123 g DMAP과 0.208 g DCC를 2번 용액에 넣고 30분간 교반하였다. 1번 용액의 HA 용액을 3에 서서히 투입하고 3시간 교반하였다. 반응종료 후 에탄올에 추출하였다. 에탄올로 세척하여 부산물을 제거하고 진공 건조하였다.0.1 g Tetrabutylammonium (TBA)-HA was dissolved in DMSO to prepare solution 1. 0.065 g piperidin-4-carboxylic acid was dissolved in DMSO to prepare solution 2. 0.123 g DMAP and 0.208 g DCC were added to solution 2 and stirred for 30 minutes. The HA solution of solution 1 was slowly added to solution 3 and stirred for 3 hours. After completion of the reaction, it was extracted with ethanol. The by-products were removed by washing with ethanol and dried under vacuum.
<반응 모식도 6><Reaction schematic diagram 6>
[규칙 제91조에 의한 정정 04.09.2024]
Step 2. 미녹시딜-HA 합성Step 2. Minoxidil-HA Synthesis
하기 반응 모식도 7에 따라, 미녹시딜-HA를 합성하였다. 구체적인 합성 방법은 다음과 같다.According to the following reaction schematic diagram 7, minoxidil-HA was synthesized. The specific synthesis method is as follows.
0.1 g 피페리딘 유도체-HA을 증류수에 용해하고, potassium carbonate 투입하여 1번 용액을 준비하였다. 0.08 g 2,6-Diamino-4-chloropyrimidine 1-oxide를 메탄올에 용해하여 2번 용액을 준비하였다. 1번 용액을 55~60℃로 가열하고 reflux 하에 2번 용액을 투입하였다. 12시간 반응 후, pH를 중성으로 맞추고 에탄올에 추출하였다. 메탄올 및 에탄올로 세척하여 부산물을 제거하고 진공 건조하였다. 0.1 g of piperidine derivative-HA was dissolved in distilled water, and potassium carbonate was added to prepare solution 1. 0.08 g of 2,6-Diamino-4-chloropyrimidine 1-oxide was dissolved in methanol to prepare solution 2. 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. By-products were removed by washing with methanol and ethanol, and the mixture was vacuum-dried.
<반응 모식도 7><Reaction schematic diagram 7>
[규칙 제91조에 의한 정정 04.09.2024]
실시예 4: 화학식 7에 포함되는 화합물의 합성Example 4: Synthesis of a compound included in chemical formula 7
Step 1. 피페리딘 유도체-스페이서 합성Step 1. Piperidine derivative-spacer synthesis
하기 반응 모식도 8에 따라, 피페리딘 유도체-스페이서를 합성하였다. 구체적인 합성 방법은 다음과 같다.According to the following reaction scheme 8, a piperidine derivative-spacer was synthesized. The specific synthetic method is as follows.
0.13 g piperidine-4-carboxylic acid을 증류수에 용해하였다. 0.385 g EDC·HCl과 0.232 g NHS를 증류수에 용해한 피페리딘 유도체에 넣고 30분간 교반하였다. 0.15 g glycine을 증류수에 용해 후, 서서히 투입하고 3시간 교반하였다. 반응종료 후 에탄올에 추출하였다. 에탄올로 세척하여 부산물을 제거하고 진공 건조하였다.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 and stirred for 3 hours. After completion of the reaction, it was extracted with ethanol. By-products were removed by washing with ethanol and dried under vacuum.
<반응 모식도 8><Reaction schematic diagram 8>
[규칙 제91조에 의한 정정 04.09.2024]
Step 2. 피페리딘 유도체-스페이서-HA 합성Step 2. Piperidine derivative-spacer-HA synthesis
하기 반응 모식도 9에 따라, 피페리딘 유도체-스페이서-HA을 합성하였다. 구체적인 합성 방법은 다음과 같다.According to the following reaction scheme 9, piperidine derivative-spacer-HA was synthesized. The specific synthesis method is as follows.
0.1 g TBA-HA을 DMSO에 용해하여 1번 용액을 준비하였다. 0.093 g (piperidine-4-carbonyl)glycine을 DMSO에 용해하여 2번 용액을 준비하였다. 0.122 g DMAP과 0.206 g DCC를 2번 용액에 투입하고 30분간 교반하였다. 1번 용액의 HA 용액을 3번 용액에 서서히 투입하고 3시간 교반하였다. 반응종료 후 에탄올에 추출하였다. 에탄올로 세척하여 부산물을 제거하고 진공 건조하였다. 0.1 g TBA-HA was dissolved in DMSO to prepare solution 1. 0.093 g (piperidine-4-carbonyl)glycine was dissolved in DMSO to prepare solution 2. 0.122 g DMAP and 0.206 g DCC were added to solution 2 and stirred for 30 minutes. The HA solution of solution 1 was slowly added to solution 3 and stirred for 3 hours. After completion of the reaction, it was extracted with ethanol. By-products were removed by washing with ethanol and dried under vacuum.
<반응 모식도 9><Reaction schematic diagram 9>
[규칙 제91조에 의한 정정 04.09.2024]
Step 3. 미녹시딜-스페이서-HA 합성Step 3. Minoxidil-Spacer-HA Synthesis
하기 반응 모식도 10에 따라, 미녹시딜-스페이서-HA 을 합성하였다. 구체적인 합성 방법은 다음과 같다.According to the following reaction scheme 10, minoxidil-spacer-HA was synthesized. The specific synthesis method is as follows.
0.1 g 피페리딘 유도체-HA을 증류수에 용해하고, potassium carbonate 투입하여 1번 용액을 준비하였다. 0.08 g 2,6-Diamino-4-chloropyrimidine 1-oxide를 메탄올에 용해하여 2번 용액을 준비하였다. 1번 용액을 55~60℃로 가열하고 reflux 하에 2번 용액을 투입하였다. 12시간 반응 후, pH를 중성으로 맞추고 에탄올에 추출하였다. 메탄올 및 에탄올로 세척하여 부산물을 제거하고 진공 건조하였다.0.1 g of piperidine derivative-HA was dissolved in distilled water, and potassium carbonate was added to prepare solution 1. 0.08 g of 2,6-Diamino-4-chloropyrimidine 1-oxide was dissolved in methanol to prepare solution 2. 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. By-products were removed by washing with methanol and ethanol, and the mixture was vacuum-dried.
<반응 모식도 10><Reaction schematic diagram 10>
[규칙 제91조에 의한 정정 04.09.2024]
실시예 5: 화학식 8에 포함되는 화합물의 합성Example 5: Synthesis of a compound included in chemical formula 8
Step 1. Deacetylated HA 합성Step 1. Synthesis of Deacetylated HA
하기 반응 모식도 11에 따라, Deacetylated HA을 합성하였다. 구체적인 합성 방법은 다음과 같다.Deacetylated HA was synthesized according to the following reaction scheme 11. The specific synthesis method is as follows.
0.1 g HA을 증류수에 용해하였다. NH2OH를 50 wt%가 되도록 투입하고 40℃에서 24시간 교반하였다. 반응종료 후 에탄올에 추출하였다. 에탄올로 세척하여 부산물을 제거하고 진공 건조하였다.0.1 g HA was dissolved in distilled water. NH2OH was added to make 50 wt% and stirred at 40°C for 24 hours. After completion of the reaction, it was extracted with ethanol. By-products were removed by washing with ethanol and dried under vacuum.
<반응 모식도 11><Reaction schematic diagram 11>
Step 2. 피페리딘 유도체-HA 합성Step 2. Synthesis of piperidine derivative-HA
하기 반응 모식도 12에 따라, Piperidine-HA을 합성하였다. 구체적인 합성 방법은 다음과 같다.Piperidine-HA was synthesized according to the following reaction scheme 12. The specific synthesis method is as follows.
0.1 g Deacetylated HA을 증류수에 용해하여 1번 용액을 준비하였다. 0.065 g piperidin-4-carboxylic acid를 증류수에 용해하여 2번 용액을 준비하였다. 0.191 g EDC·HCl과 0.115 g NHS를 2번 용액에 넣고 30분간 교반하였다. 1번 용액의 HA 용액을 2번 용액에 서서히 투입하고 3시간 교반하였다. 반응종료 후 에탄올에 추출하였다. 에탄올로 세척하여 부산물을 제거하고 진공 건조하였다. 0.1 g deacetylated HA was dissolved in distilled water to prepare solution 1. 0.065 g piperidin-4-carboxylic acid was dissolved in distilled water to prepare solution 2. 0.191 g EDC·HCl and 0.115 g NHS were added to solution 2 and stirred for 30 minutes. The HA solution of solution 1 was slowly added to solution 2 and stirred for 3 hours. After completion of the reaction, it was extracted with ethanol. By-products were removed by washing with ethanol and dried under vacuum.
<반응 모식도 12><Reaction schematic diagram 12>
[규칙 제91조에 의한 정정 04.09.2024]
Step 3. 미녹시딜-HA 합성Step 3. Minoxidil-HA Synthesis
하기 반응 모식도 13에 따라, 미녹시딜-HA을 합성하였다. 구체적인 합성 방법은 다음과 같다.According to the following reaction scheme 13, minoxidil-HA was synthesized. The specific synthesis method is as follows.
0.1 g 피페리딘 유도체-HA을 증류수에 용해하고, potassium carbonate 투입하여 1번 용액을 준비하였다. 0.08 g 2,6-Diamino-4-chloropyrimidine 1-oxide를 메탄올에 용해하여 2번 용액을 준비하였다. 1번 용액을 55~60℃로 가열하고 reflux 하에 2번 용액을 투입하였다. 12시간 반응 후, pH를 중성으로 맞추고 에탄올에 추출하였다. 메탄올 및 에탄올로 세척하여 부산물을 제거하고 진공 건조하였다.0.1 g of piperidine derivative-HA was dissolved in distilled water, and potassium carbonate was added to prepare solution 1. 0.08 g of 2,6-Diamino-4-chloropyrimidine 1-oxide was dissolved in methanol to prepare solution 2. 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. By-products were removed by washing with methanol and ethanol, and the mixture was vacuum-dried.
<반응 모식도 13><Reaction schematic diagram 13>
[규칙 제91조에 의한 정정 04.09.2024]
실시예 6: 화학식 8에 포함되는 화합물의 합성Example 6: Synthesis of a compound included in chemical formula 8
Step 1. 피페리딘 유도체-스페이서 합성Step 1. Piperidine derivative-spacer synthesis
하기 반응 모식도 14에 따라, 피페리딘 유도체-스페이서를 합성하였다. 구체적인 합성 방법은 다음과 같다.According to the following reaction scheme 14, a piperidine derivative-spacer was synthesized. The specific synthetic method is as follows.
0.13 g piperidine-4-carboxylic acid을 증류수에 용해하여 1번 용액을 준비하였다. 0.385 g EDC·HCl과 0.232 g NHS를 1번 용액에 넣고 30분간 교반하여 2번 용액을 준비하였다. 0.15 g glycine을 증류수에 용해 후, 2번 용액에 서서히 투입하고 3시간 교반하였다. 반응종료 후 에탄올에 추출하였다. 에탄올로 세척하여 부산물을 제거하고 진공 건조하였다.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. After dissolving 0.15 g of glycine in distilled water, it was slowly added to Solution 2 and stirred for 3 hours. After completion of the reaction, it was extracted with ethanol. By-products were removed by washing with ethanol and dried under vacuum.
<반응 모식도 14><Reaction schematic diagram 14>
[규칙 제91조에 의한 정정 04.09.2024]
Step 2. Deacetylated HA 합성Step 2. Synthesis of Deacetylated HA
하기 반응 모식도 15에 따라, Deacetylated HA 을 합성하였다. 구체적인 합성 방법은 다음과 같다.Deacetylated HA was synthesized according to the following reaction scheme 15. The specific synthesis method is as follows.
0.1 g HA을 증류수에 용해하였다. NH2OH를 50 wt%가 되도록 투입하고 40℃에서 24시간 교반하였다. 반응종료 후 에탄올에 추출하였다. 에탄올로 세척하여 부산물을 제거하고 진공 건조하였다.0.1 g HA was dissolved in distilled water. NH2OH was added to make 50 wt% and stirred at 40°C for 24 hours. After completion of the reaction, it was extracted with ethanol. By-products were removed by washing with ethanol and dried under vacuum.
<반응 모식도 15><Reaction schematic diagram 15>
Step 3. 피페리딘 유도체-스페이서-HA 합성Step 3. Piperidine derivative-spacer-HA synthesis
하기 반응 모식도 16에 따라, 피페리딘 유도체-스페이서-HA 을 합성하였다. 구체적인 합성 방법은 다음과 같다.According to the following reaction scheme 16, piperidine derivative-spacer-HA was synthesized. The specific synthetic method is as follows.
0.1 g Deacetylated HA을 증류수에 용해하여 1번 용액을 준비하였다. 0.093 g (piperidine-4-carbonyl)glycine를 증류수에 용해하여 2번 용액을 준비하였다. 0.191 g EDC·HCl과 0.115 g NHS를 2번 용액에 넣고 30분간 교반하여 3번 용액을 준비하였다. 1번 용액의 HA 용액을 3번 용액에 서서히 투입하고 3시간 교반하였다. 반응종료 후 에탄올에 추출하였다. 에탄올로 세척하여 부산물을 제거하고 진공 건조하였다.0.1 g deacetylated HA was dissolved in distilled water to prepare solution 1. 0.093 g (piperidine-4-carbonyl)glycine was dissolved in distilled water to prepare solution 2. 0.191 g EDC·HCl and 0.115 g NHS were added to solution 2 and stirred for 30 minutes to prepare solution 3. 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. By-products were removed by washing with ethanol and dried under vacuum.
<반응 모식도 16><Reaction schematic diagram 16>
[규칙 제91조에 의한 정정 04.09.2024]
Step 4. 미녹시딜-스페이서-HA 합성Step 4. Minoxidil-Spacer-HA Synthesis
하기 반응 모식도 17에 따라, 미녹시딜-스페이서-HA을 합성하였다. 구체적인 합성 방법은 다음과 같다.According to the following reaction scheme 17, minoxidil-spacer-HA was synthesized. The specific synthesis method is as follows.
0.1 g 피페리딘 유도체-스페이서-HA을 증류수에 용해하고, potassium carbonate 투입하여 1번 용액을 준비하였다. 0.08 g 2,6-Diamino-4-chloropyrimidine 1-oxide를 메탄올에 용해하여 2번 용액을 준비하였다. 1번 용액을 55~60℃로 가열하고 reflux 하에 2번 용액을 투입하였다. 12시간 반응 후, pH를 중성으로 맞추고 에탄올에 추출하였다. 메탄올 및 에탄올로 세척하여 부산물을 제거하고 진공 건조하였다.0.1 g of piperidine derivative-spacer-HA was dissolved in distilled water, and potassium carbonate was added to prepare solution 1. 0.08 g of 2,6-Diamino-4-chloropyrimidine 1-oxide was dissolved in methanol to prepare solution 2. 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. The mixture was washed with methanol and ethanol to remove by-products, and dried under vacuum.
<반응 모식도 17><Reaction schematic diagram 17>
[규칙 제91조에 의한 정정 04.09.2024]
실시예 7: 화학식 9에 포함되는 화합물의 합성Example 7: Synthesis of a compound included in chemical formula 9
하기 반응 모식도 18에 따라, 미녹시딜-HA을 합성하였다. 구체적인 합성 방법은 다음과 같다.According to the following reaction scheme 18, minoxidil-HA was synthesized. The specific synthesis method is as follows.
0.1 g HA을 증류수에 용해하여 1번 용액을 준비하였다. 0.191 g 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide·HCl (EDC·HCl)과 0.115 g N-Hydroxysuccinimide (NHS)를 1번 용액에 넣고 30분간 교반하여 2번 용액을 준비하였다. 0.1 g의 미녹시딜을 에탄올에 용해하였다. 미녹시딜 용액을 2번 용액에 서서히 투입하고 3시간 교반하였다. 반응 종료 후 에탄올에 추출하였다. 다음으로, 에탄올로 세척하여 부산물을 제거하고 진공 건조하였다.0.1 g HA was dissolved in distilled water to prepare Solution 1. 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 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 by-products and dried under vacuum.
<반응 모식도 18><Reaction schematic diagram 18>
[규칙 제91조에 의한 정정 04.09.2024]
실시예 8: 화학식 6에 포함되는 화합물의 합성Example 8: Synthesis of a compound included in chemical formula 6
Step 1. 피페리딘 유도체-스페이서 합성Step 1. Piperidine derivative-spacer synthesis
하기 반응 모식도 19에 따라, 피페리딘 유도체-스페이서를 합성하였다. 구체적인 합성 방법은 다음과 같다.According to the following reaction scheme 19, a piperidine derivative-spacer was synthesized. The specific synthetic method is as follows.
0.13 g piperidine-4-carboxylic acid을 증류수에 용해하였다. 0.385 g EDC·HCl과 0.232 g NHS를 넣고 30분간 교반하여 1번 용액을 준비하였다. 0.63 g aminomethyldisulfanylmethanamine을 에탄올에 용해 후, 1번 용액에 서서히 투입하고 3시간 교반하였다. 반응종료 후 아세톤에 추출하였다. 에탄올로 세척하여 부산물을 제거하고 진공 건조하였다.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. By-products were removed by washing with ethanol, and vacuum dried.
<반응 모식도 19><Reaction schematic diagram 19>
[규칙 제91조에 의한 정정 04.09.2024]
Step 2. 피페리딘 유도체-스페이서-HA 합성Step 2. Piperidine derivative-spacer-HA synthesis
하기 반응 모식도 20에 따라, 피페리딘 유도체-스페이서-HA를 합성하였다. 구체적인 합성 방법은 다음과 같다.According to the following reaction scheme 20, piperidine derivative-spacer-HA was synthesized. The specific synthetic method is as follows.
0.1 g HA을 증류수에 용해하였다. 0.191 g EDC·HCl과 0.115 g NHS를 넣고 30분간 교반하였다. Step 1에서 준비된 피페리딘 유도체-스페이서 0.12 g을 서서히 투입하고 3시간 교반하였다. 반응종료 후 에탄올에 추출하였다. 에탄올로 세척하여 부산물을 제거하고 진공 건조하였다.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, it was extracted with ethanol. By-products were removed by washing with ethanol and dried under vacuum.
<반응 모식도 20><Reaction schematic diagram 20>
[규칙 제91조에 의한 정정 04.09.2024]
Step 3. 미녹시딜-스페이서-HA 합성Step 3. Minoxidil-Spacer-HA Synthesis
하기 반응 모식도 21에 따라, 미녹시딜-스페이서-HA 을 합성하였다. 구체적인 합성 방법은 다음과 같다.According to the following reaction scheme 21, minoxidil-spacer-HA was synthesized. The specific synthesis method is as follows.
Step 2에서 준비된 피페리딘 유도체-스페이서-HA 0.1 g을 증류수에 용해하고, potassium carbonate 투입하여 1번 용액을 준비하였다. 0.08 g 2,6-Diamino-4-chloropyrimidine 1-oxide를 메탄올에 용해하여 2번 용액을 준비하였다. 1번 용액을 55~60℃로 가열하고 reflux 하에 2번 용액을 투입하였다. 12시간 반응 후, pH를 중성으로 맞추고 에탄올에 추출하였다. 메탄올 및 에탄올로 세척하여 부산물을 제거하고 진공 건조하였다.Step 2: 0.1 g of the prepared 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. The mixture was washed with methanol and ethanol to remove by-products, and dried under vacuum.
<반응 모식도 21><Reaction schematic diagram 21>
[규칙 제91조에 의한 정정 04.09.2024]
실시예 9: 화학식 7에 포함되는 화합물의 합성Example 9: Synthesis of a compound included in chemical formula 7
Step 1. 피페리딘 유도체-스페이서 합성Step 1. Piperidine derivative-spacer synthesis
하기 반응 모식도 22에 따라, 피페리딘 유도체-스페이서를 합성하였다. 구체적인 합성 방법은 다음과 같다.According to the following reaction scheme 22, a piperidine derivative-spacer was synthesized. The specific synthetic method is as follows.
0.13 g piperidine-4-carboxylic acid을 증류수에 용해하였다. 0.385 g EDC·HCl과 0.232 g NHS를 넣고 30분간 교반하여 1번 용액을 준비하였다. 0.63 g aminomethyldisulfanylmethanamine을 에탄올에 용해 후, 1번 용액에 서서히 투입하고 3시간 교반하였다. 반응종료 후 아세톤에 추출하였다. 에탄올로 세척하여 부산물을 제거하고 진공 건조하였다.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. By-products were removed by washing with ethanol, and vacuum dried.
<반응 모식도 22><Reaction schematic diagram 22>
[규칙 제91조에 의한 정정 04.09.2024]
Step 2. Chlorinated HA 합성Step 2. Synthesis of Chlorinated HA
하기 반응 모식도 23에 따라, Chlorinated HA을 합성하였다. 구체적인 합성 방법은 다음과 같다.According to the following reaction scheme 23, chlorinated HA was synthesized. The specific synthesis method is as follows.
0.1 g TBA-HA을 DMF에 녹이고 2.5 mmol의 methanesulfonyl chloride를 서서히 추가하였다. 50℃ 에서 24시간 교반 후, sodium methoxide를 첨가하고 48시간 추가 교반하였다. 반응종료 후 에탄올에 추출하고 dialysis하여 불순물을 제거하였다. 얻어진 시료는 동결건조하여 보관하였다.0.1 g TBA-HA was dissolved in DMF, and 2.5 mmol methanesulfonyl chloride was slowly added. After stirring at 50℃ 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 freeze-dried and stored.
<반응 모식도 23><Reaction schematic diagram 23>
Step 3. 피페리딘 유도체-스페이서-HA 합성Step 3. Piperidine derivative-spacer-HA synthesis
하기 반응 모식도 24에 따라, 피페리딘 유도체-스페이서-HA를 합성하였다. 구체적인 합성 방법은 다음과 같다.According to the following reaction scheme 24, piperidine derivative-spacer-HA was synthesized. The specific synthetic method is as follows.
Step 2에서 준비된 Chlorinated HA 0.1 g을 증류수에 용해하였다. Step 1에서 준비된 피페리딘 유도체-스페이서 0.12 g을 서서히 투입하고 24시간 교반하였다. 반응종료 후 에탄올에 추출하였다. 에탄올로 세척하여 부산물을 제거하고 진공 건조하였다.In Step 2, 0.1 g of the prepared Chlorinated HA was dissolved in distilled water. 0.12 g of the prepared piperidine derivative-spacer in Step 1 was slowly added and stirred for 24 hours. After completion of the reaction, it was extracted with ethanol. By-products were removed by washing with ethanol and dried under vacuum.
<반응 모식도 24><Reaction schematic diagram 24>
[규칙 제91조에 의한 정정 04.09.2024]
Step 4. 미녹시딜-스페이서-HA 합성Step 4. Minoxidil-Spacer-HA Synthesis
하기 반응 모식도 25에 따라, 미녹시딜-스페이서-HA 을 합성하였다. 구체적인 합성 방법은 다음과 같다.According to the following reaction scheme 25, minoxidil-spacer-HA was synthesized. The specific synthesis method is as follows.
Step 3에서 준비된 피페리딘 유도체-스페이서-HA 0.1 g을 증류수에 용해하고, potassium carbonate 투입하여 1번 용액을 준비하였다. 0.08 g 2,6-Diamino-4-chloropyrimidine 1-oxide를 메탄올에 용해하여 2번 용액을 준비하였다. 1번 용액을 55~60℃로 가열하고 reflux 하에 2번 용액을 투입하였다. 12시간 반응 후, pH를 중성으로 맞추고 에탄올에 추출하였다. 메탄올 및 에탄올로 세척하여 부산물을 제거하고 진공 건조하였다.Step 3: 0.1 g of the prepared piperidine derivative-spacer-HA was dissolved in distilled water, and potassium carbonate was added to prepare solution 1. 0.08 g of 2,6-Diamino-4-chloropyrimidine 1-oxide was dissolved in methanol to prepare solution 2. 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. The mixture was washed with methanol and ethanol to remove by-products, and dried under vacuum.
<반응 모식도 25><Reaction schematic diagram 25>
[규칙 제91조에 의한 정정 04.09.2024]
실시예 10: 화학식 8에 포함되는 화합물의 합성Example 10: Synthesis of a compound included in chemical formula 8
Step 1. 피페리딘 유도체-스페이서 합성Step 1. Piperidine derivative-spacer synthesis
하기 반응 모식도 26에 따라, 피페리딘 유도체-스페이서를 합성하였다. 구체적인 합성 방법은 다음과 같다.According to the following reaction scheme 26, a piperidine derivative-spacer was synthesized. The specific synthetic method is as follows.
0.18 g dithiodiglycolic acid을 증류수에 용해하였다. 0.193 g EDC·HCl과 0.116 g NHS를 넣고 30분간 교반하여 1번 용액을 준비하였다. 0.05 g 4-Aminopiperidine을 서서히 투입하고 3시간 교반하였다. 반응종료 후 아세톤에 추출하였다. 에탄올로 세척하여 부산물을 제거하고 진공 건조하였다.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, it was extracted with acetone. By-products were removed by washing with ethanol and dried under vacuum.
<반응 모식도 26><Reaction schematic diagram 26>
[규칙 제91조에 의한 정정 04.09.2024]
Step 2. Deacetylated-HA 합성Step 2. Deacetylated-HA synthesis
하기 반응 모식도 27에 따라, Deacetylated HA 을 합성하였다. 구체적인 합성 방법은 다음과 같다.Deacetylated HA was synthesized according to the following reaction scheme 27. The specific synthesis method is as follows.
0.1 g HA을 증류수에 용해하였다. NH2OH를 50 wt%가 되도록 투입하고 40℃에서 24시간 교반하였다. 반응종료 후 에탄올에 추출하였다. 에탄올로 세척하여 부산물을 제거하고 진공 건조하였다.0.1 g HA was dissolved in distilled water. NH2OH was added to make 50 wt% and stirred at 40°C for 24 hours. After completion of the reaction, it was extracted with ethanol. By-products were removed by washing with ethanol and dried under vacuum.
<반응 모식도 27><Reaction schematic diagram 27>
Step 3. 피페리딘 유도체-스페이서-HA 합성Step 3. Piperidine derivative-spacer-HA synthesis
하기 반응 모식도 28에 따라, 피페리딘 유도체-스페이서-HA를 합성하였다. 구체적인 합성 방법은 다음과 같다.According to the following reaction scheme 28, piperidine derivative-spacer-HA was synthesized. The specific synthetic method is as follows.
0.1 g deacetylated-HA을 증류수에 용해하였다. 0.191 g EDC·HCl과 0.115 g NHS를 넣고 30분간 교반하였다. Step 1에서 준비된 피페리딘 유도체-스페이서 0.12 g을 서서히 투입하고 3시간 교반하였다. 반응종료 후 에탄올에 추출하였다. 에탄올로 세척하여 부산물을 제거하고 진공 건조하였다.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, it was extracted with ethanol. By-products were removed by washing with ethanol and dried under vacuum.
<반응 모식도 28><Reaction schematic diagram 28>
[규칙 제91조에 의한 정정 04.09.2024]
Step 4. 미녹시딜-스페이서-HA 합성Step 4. Minoxidil-Spacer-HA Synthesis
하기 반응 모식도 29에 따라, 미녹시딜-스페이서-HA 을 합성하였다. 구체적인 합성 방법은 다음과 같다.According to the following reaction scheme 29, minoxidil-spacer-HA was synthesized. The specific synthesis method is as follows.
Step 3에서 준비된 피페리딘 유도체-스페이서-HA 0.1 g을 증류수에 용해하고, potassium carbonate 투입하여 1번 용액을 준비하였다. 0.08 g 2,6-Diamino-4-chloropyrimidine 1-oxide를 메탄올에 용해하여 2번 용액을 준비하였다. 1번 용액을 55~60℃로 가열하고 reflux 하에 2번 용액을 투입하였다. 12시간 반응 후, pH를 중성으로 맞추고 에탄올에 추출하였다. 메탄올 및 에탄올로 세척하여 부산물을 제거하고 진공 건조하였다.Step 3: 0.1 g of the prepared piperidine derivative-spacer-HA was dissolved in distilled water, and potassium carbonate was added to prepare solution 1. 0.08 g of 2,6-Diamino-4-chloropyrimidine 1-oxide was dissolved in methanol to prepare solution 2. 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. The mixture was washed with methanol and ethanol to remove by-products, and dried under vacuum.
<반응 모식도 29><Reaction schematic diagram 29>
[규칙 제91조에 의한 정정 04.09.2024]
실시예 11: 화학식 6에 포함되는 화합물의 합성Example 11: Synthesis of a compound included in chemical formula 6
Step 1. 스페이서-HA 합성Step 1. Spacer-HA synthesis
하기 반응 모식도 30에 따라, 스페이서-HA를 합성하였다. 구체적인 합성 방법은 다음과 같다.According to the following reaction scheme 30, spacer-HA was synthesized. The specific synthesis method is as follows.
0.1 g 히알루론산을 증류수에 용해하였다. 0.191 g EDC·HCl과 0.115 g NHS를 투입 후, 30분간 교반하였다. 다음으로, 2.5 mmol 1,6-hexanediamine을 서서히 투입하고 3시간 교반하였다. 반응종료 후 에탄올에 추출하였다. 에탄올로 세척하여 부산물을 제거하고 진공 건조하였다.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. By-products were removed by washing with ethanol, and dried under vacuum.
<반응 모식도 30><Reaction schematic diagram 30>
[규칙 제91조에 의한 정정 04.09.2024]
Step 2. 4-아자스테로이드 유도체-스페이서-HA 합성Step 2. Synthesis of 4-azasteroid derivative-spacer-HA
하기 반응 모식도 31에 따라, 4-아자스테로이드 유도체-스페이서-HA 을 합성하였다. 구체적인 합성 방법은 다음과 같다.According to the following reaction scheme 31, 4-azasteroid derivative-spacer-HA was synthesized. The specific synthetic method is as follows.
Step 1에서 준비된 0.1 g 스페이서-HA을 증류수에 용해하여 1번 용액을 준비하였다. 0.079 g 3-Oxo-4-aza-5α-androst-1-ene-17β-carboxylic Acid를 methanol에 용해하여 2번 용액을 준비하였다. 0.191 g EDC·HCl과 0.115 g NHS를 2번 용액에 넣고 30분간 교반하여 3번 용액을 준비하였다. 1번 용액의 HA 용액을 3번 용액에 서서히 투입하고 3시간 교반하였다. 반응종료 후 에탄올에 추출하였다. 에탄올로 세척하여 부산물을 제거하고 진공 건조하였다.Step 1 was prepared by dissolving 0.1 g spacer-HA in distilled water to prepare Solution 1. Solution 2 was prepared by dissolving 0.079 g 3-Oxo-4-aza-5α-androst-1-ene-17β-carboxylic Acid in methanol. 0.191 g EDC·HCl and 0.115 g NHS were added to Solution 2 and stirred for 30 minutes to prepare Solution 3. 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. The by-products were removed by washing with ethanol and dried under vacuum.
<반응 모식도 31><Reaction schematic diagram 31>
[규칙 제91조에 의한 정정 04.09.2024]
실시예 12: 화학식 6에 포함되는 화합물의 합성Example 12: Synthesis of a compound included in chemical formula 6
Step 1. 스페이서-HA 합성Step 1. Spacer-HA synthesis
하기 반응 모식도에 따라, 스페이서-HA를 합성하였다. 구체적인 합성 방법은 다음과 같다. 0.1 g 히알루론산을 증류수에 용해하였다. 0.191 g EDC·HCl과 0.115 g NHS를 투입 후, 30분간 교반하였다. 다음으로, 2.5 mmol aminomethyldisulfanylmethanamine을 서서히 투입하고 3시간 교반하였다. 반응종료 후 에탄올에 추출하였다. 에탄올로 세척하여 부산물을 제거하고 진공 건조하였다.According to the following reaction schematic, spacer-HA was synthesized. The specific synthesis 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. By-products were removed by washing with ethanol, and vacuum dried.
<반응 모식도 32><Reaction schematic diagram 32>
[규칙 제91조에 의한 정정 04.09.2024]
Step 2. 4-아자스테로이드 유도체-스페이서-HA 합성Step 2. Synthesis of 4-azasteroid derivative-spacer-HA
하기 반응 모식도 33에 따라, 4-아자스테로이드 유도체-스페이서-HA를 합성하였다. 구체적인 합성 방법은 다음과 같다.According to the following reaction scheme 33, 4-azasteroid derivative-spacer-HA was synthesized. The specific synthetic method is as follows.
Step 1에서 준비된 0.1 g 스페이서-HA을 증류수에 용해하여 1번 용액을 준비하였다. 0.079 g 3-Oxo-4-aza-5α-androst-1-ene-17β-carboxylic Acid를 methanol에 용해하여 2번 용액을 준비하였다. 0.191 g EDC·HCl과 0.115 g NHS를 2번 용액에 넣고 30분간 교반하여 3번 용액을 준비하였다. 1번 용액의 HA 용액을 3번 용액에 서서히 투입하고 3시간 교반하였다. 반응종료 후 에탄올에 추출하였다. 에탄올로 세척하여 부산물을 제거하고 진공 건조하였다.Step 1 was prepared by dissolving 0.1 g spacer-HA in distilled water to prepare Solution 1. Solution 2 was prepared by dissolving 0.079 g 3-Oxo-4-aza-5α-androst-1-ene-17β-carboxylic Acid in methanol. 0.191 g EDC·HCl and 0.115 g NHS were added to Solution 2 and stirred for 30 minutes to prepare Solution 3. 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. The by-products were removed by washing with ethanol and dried under vacuum.
<반응 모식도 33><Reaction schematic diagram 33>
[규칙 제91조에 의한 정정 04.09.2024]
실시예 13: 화학식 6에 포함되는 화합물의 합성Example 13: Synthesis of a compound included in chemical formula 6
Step 1. 카복실기가 치환된 두타스테리드 합성Step 1. Synthesis of carboxyl-substituted dutasteride
하기 반응 모식도 34에 따라 카복실기가 치환된 두타스테리드를 합성하였다. 구체적인 합성 방법은 다음과 같다. Dutasteride substituted with a carboxyl group was synthesized according to the following reaction scheme 34. The specific synthetic method is as follows.
0.410 g 2-Pyridyl 3-oxo-4-aza-5α-androst-1-ene-17β-carbothioate을 methylene chloride 5 mL에 용해하였다. 0.256 g silver trifluoromethanesulfonate (AgOTf) 와 0.819 g 4-Amino-2,5-bis(trifluoromethyl)benzoic acid를 넣고 상온에서 12시간 교반하였다. 반응물을 필터하고 잔여물을 과량의 methylene chloride로 세척하였다. 1 M HCl과 brine으로 반응물을 추출한 후 진공건조 하였다. Column을 통해 부산물을 제거하였다.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 the mixture was stirred at room temperature for 12 h. The reaction mixture was filtered, and the residue was washed with excess methylene chloride. The reaction mixture was extracted with 1 M HCl and brine, and then dried in vacuo. The byproducts were removed using a column.
<반응 모식도 34><Reaction schematic diagram 34>
[규칙 제91조에 의한 정정 04.09.2024]
Step 2. 스페이서-HA 합성Step 2. Spacer-HA synthesis
하기 반응 모식도 35에 따라, 스페이서-HA를 합성하였다. 구체적인 합성 방법은 다음과 같다.According to the following reaction scheme 35, spacer-HA was synthesized. The specific synthesis method is as follows.
0.1 g 히알루론산을 증류수에 용해하였다. 0.191 g EDC·HCl과 0.115 g NHS를 투입 후, 30분간 교반하였다. 다음으로, 2.5 mmol 1,6-hexanediamine을 서서히 투입하고 3시간 교반하였다. 반응종료 후 에탄올에 추출하였다. 에탄올로 세척하여 부산물을 제거하고 진공 건조하였다.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. By-products were removed by washing with ethanol, and vacuum dried.
<반응 모식도 35><Reaction schematic diagram 35>
[규칙 제91조에 의한 정정 04.09.2024]
Step 3. 두타스테리드-스페이서-HA 합성 Step 3. Dutasteride-Spacer-HA Synthesis
하기 반응 모식도 36에 따라, 두타스테리드-스페이서-HA를 합성하였다. 구체적인 합성 방법은 다음과 같다. According to the following reaction scheme 36, dutasteride-spacer-HA was synthesized. The specific synthesis method is as follows.
Step 2에서 합성된 0.1 g의 스페이서-HA을 증류수에 용해하고, 0.191 g EDC·HCl과 0.115 g NHS를 1에 넣고 30분간 교반하였다. 다음으로, step 1에서 합성된 0.229 g의 카복실기가 치환된 두타스테리드를 서서히 투입하고 3시간 교반하였다. 반응종료 후 에탄올에 추출하였다. 에탄올로 세척하여 부산물을 제거하고 진공 건조하였다.In step 2, 0.1 g of spacer-HA synthesized was dissolved in distilled water, 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. By-products were removed by washing with ethanol, and dried under vacuum.
<반응 모식도 36><Reaction schematic diagram 36>
[규칙 제91조에 의한 정정 04.09.2024]
실시예 14: 화학식 6에 포함되는 화합물의 합성Example 14: Synthesis of a compound included in chemical formula 6
Step 1. 스페이서-HA 합성Step 1. Spacer-HA synthesis
하기 반응 모식도 37에 따라, 스페이서-HA를 합성하였다. 구체적인 합성 방법은 다음과 같다. 0.1 g 히알루론산을 증류수에 용해하였다. 0.191 g EDC·HCl과 0.115 g NHS를 투입 후, 30분간 교반하였다. 다음으로, 2.5 mmol 1,6-hexanediamine을 서서히 투입하고 3시간 교반하였다. 반응종료 후 에탄올에 추출하였다. 에탄올로 세척하여 부산물을 제거하고 진공 건조하였다.According to the following reaction scheme 37, spacer-HA was synthesized. The specific synthesis 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. By-products were removed by washing with ethanol, and vacuum dried.
<반응 모식도 37><Reaction schematic diagram 37>
[규칙 제91조에 의한 정정 04.09.2024]
수득한 히알루론산 0.1 g을 증류수에 용해하고 0.25 mmol N-(tert-butyl)-4-chlorobutanamide을 투입 후 24시간 교반하였다. 반응종료 후 에탄올에 추출하고, 에탄올로 세척하여 부산물을 제거하고 진공 건조하였다.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 by-products, and vacuum dried.
<반응 모식도 38><Reaction schematic diagram 38>
[규칙 제91조에 의한 정정 04.09.2024]
Step 2. 피나스테리드-스페이서-HA 합성Step 2. Finasteride-Spacer-HA Synthesis
하기 반응 모식도 39에 따라, 피나스테리드-스페이서-HA 을 합성하였다. 구체적인 합성 방법은 다음과 같다.According to the following reaction scheme 39, finasteride-spacer-HA was synthesized. The specific synthesis method is as follows.
Step 1에서 준비된 0.1 g 스페이서-HA을 증류수에 용해하여 1번 용액을 준비하였다. 0.1 g 2-Pyridyl 3-oxo-4-aza-5α-androst-1-ene-17β-carbothioate를 메탄올에 용해하여 2번 용액을 준비하였다. 1번 용액과 2번 용액을 혼합 후, NaH를 투입하고 3시간 교반하였다. 반응종료 후 에탄올에 추출하였다. 에탄올로 세척하여 부산물을 제거하고 진공 건조하였다.Step 1 was prepared by dissolving 0.1 g spacer-HA in distilled water to prepare solution 1. Solution 2 was prepared by dissolving 0.1 g 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, it was extracted with ethanol. The mixture was washed with ethanol to remove by-products and dried under vacuum.
<반응 모식도 39><Reaction schematic diagram 39>
[규칙 제91조에 의한 정정 04.09.2024]
실시예 15: 화학식 7에 포함되는 화합물의 합성Example 15: Synthesis of a compound included in chemical formula 7
Step 1. 4-아자스테로이드 유도체-HA 합성Step 1. Synthesis of 4-azasteroid derivative-HA
하기 반응 모식도 40에 따라, 4-아자스테로이드 유도체-HA을 합성하였다. 구체적인 합성 방법은 다음과 같다.According to the following reaction scheme 40, 4-azasteroid derivative-HA was synthesized. The specific synthesis method is as follows.
0.1 g TBA-HA을 DMSO에 용해하여 1번 용액을 준비하였다. 0.079 g 3-Oxo-4-aza-5α-androst-1-ene-17β-carboxylic Acid을 DMSO에 용해하여 2번 용액을 준비하였다. 0.122 g DMAP과 0.206 g DCC를 2번 용액에 투입하고 30분간 교반하였다. 1번 용액의 HA 용액을 2번 용액에 서서히 투입하고 3시간 교반하였다. 반응종료 후 에탄올에 추출하였다. 에탄올로 세척하여 부산물을 제거하고 진공 건조하였다.0.1 g TBA-HA was dissolved in DMSO to prepare solution 1. 0.079 g 3-Oxo-4-aza-5α-androst-1-ene-17β-carboxylic Acid was dissolved in DMSO to prepare solution 2. 0.122 g DMAP and 0.206 g DCC were added to solution 2 and stirred for 30 minutes. The HA solution of solution 1 was slowly added to solution 2 and stirred for 3 hours. After completion of the reaction, it was extracted with ethanol. The by-products were removed by washing with ethanol and dried under vacuum.
<반응 모식도 40><Reaction schematic diagram 40>
[규칙 제91조에 의한 정정 04.09.2024]
실시예 16: 화학식 7에 포함되는 화합물의 합성Example 16: Synthesis of a compound included in chemical formula 7
Step 1. Chlorinated HA 합성Step 1. Synthesis of Chlorinated HA
하기 반응 모식도 41에 따라, Chlorinated HA을 합성하였다. 구체적인 합성 방법은 다음과 같다.According to the following reaction scheme 41, chlorinated HA was synthesized. The specific synthesis method is as follows.
0.1 g TBA-HA을 DMF에 녹이고 2.5 mmol의 methanesulfonyl chloride를 서서히 추가하였다. 50℃ 에서 24시간 교반 후, sodium methoxide를 첨가하고 48시간 추가 교반하였다. 반응종료 후 에탄올에 추출하고 dialysis하여 불순물을 제거하였다. 얻어진 시료는 동결건조하여 보관하였다.0.1 g TBA-HA was dissolved in DMF, and 2.5 mmol methanesulfonyl chloride was slowly added. After stirring at 50℃ 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 freeze-dried and stored.
<반응 모식도 41><Reaction schematic diagram 41>
Step 2. 4-아자스테로이드 유도체-스페이서 합성Step 2. 4-Azasteroid Derivative-Spacer Synthesis
하기 반응 모식도 42에 따라, 4-아자스테로이드 유도체-스페이서를 합성하였다. 구체적인 합성 방법은 다음과 같다.According to the following reaction scheme 42, 4-azasteroid derivative-spacer was synthesized. The specific synthetic method is as follows.
0.317 g 3-Oxo-4-aza-5α-androst-1-ene-17β-carboxylic Acid를 DMSO에 용해하였다. 0.38 g Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium (HATU)를 투입하고 30분간 교반하였다. 5 mmol의 1,6-hexanediamine을 서서히 투입하고 3시간 교반하였다. 반응종료 후 에탄올에 추출하였다. 에탄올로 세척하여 부산물을 제거하고 진공 건조하였다.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, it was extracted with ethanol. The mixture was washed with ethanol to remove by-products and dried under vacuum.
<반응 모식도 42><Reaction schematic diagram 42>
[규칙 제91조에 의한 정정 04.09.2024]
Step 3. 4-아자스테로이드 유도체-스페이서-HA 합성Step 3. Synthesis of 4-azasteroid derivative-spacer-HA
하기 반응 모식도 43에 따라, 4-아자스테로이드 유도체-스페이서-HA 을 합성하였다. 구체적인 합성 방법은 다음과 같다.According to the following reaction scheme 43, 4-azasteroid derivative-spacer-HA was synthesized. The specific synthetic method is as follows.
Step 1에서 준비된 chlorinated HA 0.1 g을 증류수에 용해하였다. Step 2에서 준비된 4-아자스테로이드 유도체-스페이서 0.22 g을 메탄올에 용해하고 HA 용액에 첨가하였다. 24시간 교반 후, 에탄올에 추출하였다. 에탄올로 세척하고 부산물을 제거하고 진공 건조하였다.In Step 1, 0.1 g of chlorinated HA prepared was dissolved in distilled water. In Step 2, 0.22 g of 4-azasteroid derivative-spacer prepared was dissolved in methanol and added to the HA solution. After stirring for 24 hours, it was extracted with ethanol. It was washed with ethanol, by-products were removed, and vacuum dried.
<반응 모식도 43><Reaction schematic diagram 43>
[규칙 제91조에 의한 정정 04.09.2024]
실시예 17: 화학식 8에 포함되는 화합물의 합성Example 17: Synthesis of a compound included in chemical formula 8
Step 1. Deacetylated HA 합성Step 1. Synthesis of Deacetylated HA
하기 반응 모식도 44에 따라, Deacetylated HA 을 합성하였다. 구체적인 합성 방법은 다음과 같다.Deacetylated HA was synthesized according to the following reaction scheme 44. The specific synthesis method is as follows.
0.1 g HA을 증류수에 용해하였다. NH2OH를 50 wt%가 되도록 투입하고 40℃에서 24시간 교반하였다. 반응종료 후 에탄올에 추출하였다. 에탄올로 세척하여 부산물을 제거하고 진공 건조하였다.0.1 g HA was dissolved in distilled water. NH2OH was added to make 50 wt% and stirred at 40°C for 24 hours. After completion of the reaction, it was extracted with ethanol. By-products were removed by washing with ethanol and dried under vacuum.
<반응 모식도 44><Reaction schematic diagram 44>
Step 2. 4-아자스테로이드 유도체-HA 합성Step 2. Synthesis of 4-azasteroid derivative-HA
하기 반응 모식도 45에 따라, 4-아자스테로이드 유도체-HA 을 합성하였다. 구체적인 합성 방법은 다음과 같다.According to the following reaction scheme 45, 4-azasteroid derivative-HA was synthesized. The specific synthesis method is as follows.
0.1 g Deacetylated HA을 증류수에 용해하여 1번 용액을 준비하였다. 0.079 g 3-Oxo-4-aza-5α-androst-1-ene-17β-carboxylic Acid를 메탄올에 용해하여 2번 용액을 준비하였다. 0.191 g EDC·HCl과 0.115 g NHS를 2번 용액에 넣고 30분간 교반하여 3번 용액을 준비하였다. 1번 용액의 HA 용액을 3번 용액에 서서히 투입하고 3시간 교반하였다. 반응종료 후 에탄올에 추출하였다. 에탄올로 세척하여 부산물을 제거하고 진공 건조하였다.0.1 g deacetylated HA was dissolved in distilled water to prepare solution 1. 0.079 g 3-Oxo-4-aza-5α-androst-1-ene-17β-carboxylic Acid was dissolved in methanol to prepare solution 2. 0.191 g EDC·HCl and 0.115 g NHS were added to solution 2 and stirred for 30 minutes to prepare solution 3. 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. The by-products were removed by washing with ethanol and dried under vacuum.
<반응 모식도 45><Reaction schematic diagram 45>
[규칙 제91조에 의한 정정 04.09.2024]
실시예 18: 화학식 8에 포함되는 화합물의 합성Example 18: Synthesis of a compound included in chemical formula 8
Step 1. Chlorine이 치환된 4-아자스테로이드 유도체 합성Step 1. Synthesis of 4-azasteroid derivatives substituted with chlorine
하기 반응 모식도 46에 따라, Chlorine이 치환된 4-아자스테로이드 유도체를 합성하였다. 구체적인 합성 방법은 다음과 같다.According to the following reaction scheme 46, a chlorine-substituted 4-azasteroid derivative was synthesized. The specific synthetic method is as follows.
0.317 g 3-Oxo-4-aza-5α-androst-1-ene-17β-carboxylic Acid를 DMSO에 용해하였다. 0.38 g Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium (HATU)를 투입하고 30분간 교반하였다. 1 mmol의 2-Chloroethylamine을 서서히 투입하고 3시간 교반하였다. 반응종료 후 에탄올에 추출하였다. 에탄올로 세척하여 부산물을 제거하고 진공 건조하였다.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, it was extracted with ethanol. By-products were removed by washing with ethanol and dried under vacuum.
<반응 모식도 46><Reaction schematic diagram 46>
[규칙 제91조에 의한 정정 04.09.2024]
Step 2. Deacetylated HA 합성Step 2. Synthesis of Deacetylated HA
하기 반응 모식도 47에 따라, Deacetylated HA 을 합성하였다. 구체적인 합성 방법은 다음과 같다.Deacetylated HA was synthesized according to the following reaction scheme 47. The specific synthesis method is as follows.
0.1 g HA을 증류수에 용해하였다. NH2OH를 50 wt%가 되도록 투입하고 40℃에서 24시간 교반하였다. 반응종료 후 에탄올에 추출하였다. 에탄올로 세척하여 부산물을 제거하고 진공 건조하였다.0.1 g HA was dissolved in distilled water. NH2OH was added to make 50 wt% and stirred at 40°C for 24 hours. After completion of the reaction, it was extracted with ethanol. By-products were removed by washing with ethanol and dried under vacuum.
<반응 모식도 47><Reaction schematic diagram 47>
Step 3. 4-아자스테로이드 유도체-스페이서-HA 합성Step 3. Synthesis of 4-azasteroid derivative-spacer-HA
하기 반응 모식도 48에 따라, 4-아자스테로이드 유도체-스페이서-HA 을 합성하였다. 구체적인 합성 방법은 다음과 같다.According to the following reaction scheme 48, 4-azasteroid derivative-spacer-HA was synthesized. The specific synthetic method is as follows.
Step 2에서 준비된 deacetylated HA 0.1 g을 증류수에 용해하였다. Step 1에서 준비된 4-아자스테로이드 유도체-스페이서 0.19 g을 메탄올에 용해하고 HA 용액에 첨가하였다. 24시간 교반 후, 에탄올에 추출하였다. 에탄올로 세척하고 부산물을 제거하고 진공 건조하였다.In Step 2, 0.1 g of the deacetylated HA prepared was dissolved in distilled water. In Step 1, 0.19 g of the 4-azasteroid derivative-spacer prepared was dissolved in methanol and added to the HA solution. After stirring for 24 hours, it was extracted with ethanol. It was washed with ethanol, by-products were removed, and vacuum dried.
<반응 모식도 48><Reaction schematic diagram 48>
[규칙 제91조에 의한 정정 04.09.2024]
상술한 실시예에 설명된 특징, 구조, 효과 등은 본 발명의 적어도 하나의 실시예에 포함되며, 반드시 하나의 실시예에만 한정되는 것은 아니다. 나아가, 각 실시예에서 예시된 특징, 구조, 효과 등은 실시예들이 속하는 분야의 통상의 지식을 가지는 자에 의하여 다른 실시예들에 대해서도 조합 또는 변형되어 실시 가능하다. 따라서 이러한 조합과 변형에 관계된 내용들은 본 발명의 범위에 포함되는 것으로 해석되어야 할 것이다. 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 only one embodiment. Furthermore, the features, structures, effects, etc. exemplified in each embodiment can be combined or modified and implemented in other embodiments by a person having ordinary knowledge in the field to which the embodiments belong. Therefore, the contents related to such combinations and modifications should be interpreted as being included in the scope of the present invention.
또한, 이상에서 실시예들을 중심으로 설명하였으나 이는 단지 예시일 뿐 본 발명을 한정하는 것이 아니며, 본 발명이 속하는 분야의 통상의 지식을 가진 자라면 본 실시예의 본질적인 특성을 벗어나지 않는 범위에서 이상에 예시되지 않은 여러 가지의 변형과 응용이 가능함을 알 수 있을 것이다. 예를 들어, 실시예들에 구체적으로 나타난 각 구성 요소는 변형하여 실시할 수 있는 것이다. 그리고 이러한 변형과 응용에 관계된 차이점들은 첨부한 청구 범위에서 규정하는 본 발명의 범위에 포함되는 것으로 해석되어야 할 것이다.In addition, although the above has been described with reference to embodiments, these are merely examples and do not limit the present invention, and those with ordinary skill in the art to which the present invention pertains will recognize 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, the differences related to such modifications and applications should be interpreted as being included in the scope of the present invention defined in the appended claims.
Claims (17)
제8항에 있어서,
상기 [화학식 6]으로 표시되는 화합물은 하기 [표 1]에 표시된 화합물 중 어느 하나인 것인, 화합물:
여기서, n은 10 내지 10,000 이고, X는 0 내지 40 이다.
In Article 8,
The compound represented by the above [chemical formula 6] is one of the compounds represented in the following [Table 1]:
Here, n is between 10 and 10,000, and X is between 0 and 40.
제8항에 있어서,
상기 [화학식 7]로 표시되는 화합물은 하기 [표 2]에 표시된 화합물 중 어느 하나인 것인, 화합물:
여기서, n은 10 내지 10,000 이고, X는 0 내지 40 이다.
In Article 8,
The compound represented by the above [chemical formula 7] is one of the compounds represented in the following [Table 2]:
Here, n is between 10 and 10,000, and X is between 0 and 40.
제8항에 있어서,
상기 [화학식 8]로 표시되는 화합물은 하기 [표 3]에 표시된 화합물 중 어느 하나인 것인, 화합물:
여기서, n은 10 내지 10,000 이고, X는 0 내지 40 이다.
In Article 8,
The compound represented by the above [chemical formula 8] is one of the compounds represented in the following [Table 3]:
Here, n is between 10 and 10,000, and X is between 0 and 40.
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| KR10-2023-0079062 | 2023-06-20 | ||
| KR20230079062 | 2023-06-20 | ||
| KR1020240080211A KR20240177731A (en) | 2023-06-20 | 2024-06-20 | A novel compound immobilized with hair loss treatment ingredients and method for preparing the same |
| KR10-2024-0080211 | 2024-06-20 |
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| KR20180112003A (en) * | 2016-03-18 | 2018-10-11 | (주)케어젠 | The combination of pinasteride and peptide |
| KR20220099934A (en) * | 2017-12-01 | 2022-07-14 | 주식회사 굳티셀 | Composition for preventing or treating hair loss |
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| HAEMA KAMONWON; PIROONPAN THANANCHAI; TAECHUTRAKUL SAOWALUK; KEMPANICHKUL ANAN; PASANPHAN WANVIMOL: "Piperidine-conjugated polyfunctional star-shaped PLLA as a novel bio-based antioxidant additive for bioplastics", POLYMER DEGRADATION AND STABILITY, vol. 143, 1 January 1900 (1900-01-01), GB , pages 145 - 154, XP085169646, ISSN: 0141-3910, DOI: 10.1016/j.polymdegradstab.2017.07.001 * |
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