[go: up one dir, main page]

WO2023101256A1 - Inhibiteur de 5-alpha-réductase, sel pharmaceutiquement acceptable de celui-ci et utilisation associée - Google Patents

Inhibiteur de 5-alpha-réductase, sel pharmaceutiquement acceptable de celui-ci et utilisation associée Download PDF

Info

Publication number
WO2023101256A1
WO2023101256A1 PCT/KR2022/017724 KR2022017724W WO2023101256A1 WO 2023101256 A1 WO2023101256 A1 WO 2023101256A1 KR 2022017724 W KR2022017724 W KR 2022017724W WO 2023101256 A1 WO2023101256 A1 WO 2023101256A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
pharmaceutically acceptable
acceptable salt
composition
Prior art date
Application number
PCT/KR2022/017724
Other languages
English (en)
Korean (ko)
Inventor
양재성
윤성화
Original Assignee
주식회사 팜어스바이오사이언스
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from KR1020220149149A external-priority patent/KR102829242B1/ko
Application filed by 주식회사 팜어스바이오사이언스 filed Critical 주식회사 팜어스바이오사이언스
Publication of WO2023101256A1 publication Critical patent/WO2023101256A1/fr

Links

Images

Classifications

    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q7/00—Preparations for affecting hair growth
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/18—Ring systems of four or more rings

Definitions

  • the present invention is a novel compound capable of improving the effect of preventing hair loss and promoting hair growth by selectively inhibiting 5-alpha-reductase while minimizing side effects due to oral administration, and preventing hair loss or hair growth including the same. It relates to a composition for promotion.
  • the present invention inhibits 5-alpha-reductase only on the scalp in order to eliminate the side effects of existing 5-alpha-reductase inhibitors and interferes with the production of dihydrotestosterone (DHT) in the body during systemic absorption. It relates to a novel compound capable of minimizing systemic side effects by rapidly excreting the compound and a composition for external application for preventing hair loss or stimulating hair growth comprising the same.
  • DHT dihydrotestosterone
  • Hair is made in hair follicles, and each hair follicle periodically goes through stages of activity and quiescence.
  • the time interval of this hair cycle varies depending on the body part. In the case of hair, it goes through a growth period (anagen phase) of about 26 years, a regression period of 2 to 4 weeks, and a rest period of about 3 to 4 months.
  • Each hair follicle has 10 to 20 hair follicle growth cycles during its lifetime.
  • the number of hairs (hair) is about 100,000, and they grow an average of 1 cm per month.
  • 85-90% of all normal hair is in the anagen phase, and the number of anagen follicles decreases with age.
  • 10 to 15% of hair follicles are in the catagen or telogen phase, and an average of 50 to 150 hairs are normally lost per day depending on the hair cycle and season. If more hair is lost, it can be seen as alopecia.
  • Hair loss can be divided into telogen hair loss and anagen hair loss according to the growth cycle, and telogen hair loss includes androgen-induced male pattern baldness, female postpartum hair loss, and the like. In addition, it is known that hair loss occurs due to local infection, endocrine disorders, genetic factors, and autoimmunity.
  • Alopecia means a condition in which there is no hair where hair should normally be. Hair plays a large role in terms of beauty, and in addition, it has functions such as UV protection and hair protection.
  • Representative drugs conventionally used for alopecia include preparations such as minoxidil for external use and oral finasteride. Although the mechanism of action of minoxidil is not clear, it was first developed for the purpose of lowering blood pressure in hypertensive patients, and hirsutism was discovered in patients who took it, and it is currently used as an external agent for hair loss and hair growth treatment. However, various side effects such as hypotension, edema, angina pectoris, dermatitis and itching have been reported, and there is a problem that the effect is significantly weaker than finasteride. Oral finasteride is a drug that inhibits 5-alpha-reductase, which converts testosterone, a type of male hormone, into dihydrotestosterone (DHT).
  • DHT dihydrotestosterone
  • compositions that exhibits a strong DHT inhibitory effect only at the application site while avoiding the side effects of existing drugs by minimizing exposure of the drug to the body as a 5-alpha-reductase inhibitor and exhibiting an effect of suppressing hair loss and promoting hair growth.
  • Finasteride which is currently used for hair loss treatment, has excellent drug efficacy, but has side effects, so its use is limited. Since this side effect is caused by inhibiting 5-alpha-reductase in the body as well as the scalp, the development of a drug that does not inhibit this enzyme in the body is required.
  • the object of the present invention is to maximize the effect of preventing hair loss and promoting hair growth by selectively inhibiting 5-alpha-reductase in the scalp while minimizing systemic exposure of this drug compared to conventional oral therapeutic agents, and It is intended to provide a novel drug capable of avoiding side effects and a composition for external application containing the same.
  • the present invention used a retrometabolic drug design technology to eliminate toxicity caused by long-term systemic exposure of existing drugs by using metabolites that rapidly escape outside the body.
  • the present invention also intends to selectively inhibit 5-alpha-reductase only in the scalp using a linker that is easily degraded by metabolic enzymes outside the target local area or can have a slightly longer degradation time in the target local area.
  • a compound of formula 1 or a pharmaceutically acceptable salt thereof is provided.
  • a is 1 or 2;
  • R 1 is OH, NH 2 , OR 2 or NHR 3 ;
  • R 2 and R 3 are each independently a substituent represented by Formula 2:
  • l and m are each independently 0 or 1;
  • n is an integer from 0 to 3;
  • A is -CH 2 -, -NH-, -O- or -CH 2 O-;
  • R 4 is NO 2 , -NHCOR 5 (where R 5 is C 1-5 alkyl), halogenosulfonyl, halogen atom, C 1-5 halogenoalkyl, C 1-5 halogenoalkoxy, C 1-5 alkoxy or C 1-5 alkyl.
  • R 4 is NO 2 , -NHCOR 5 (where R 5 is C 1-3 alkyl), halogenosulfonyl, a halogen atom, C 1-3 halogenoalkyl, C 1-3 halogenoalkoxy, C 1-3 alkoxy or C 1-3 alkyl.
  • R 4 may be NO 2 , acetamido, fluorosulfonyl fluoride, fluoro, trifluoromethyl, methyl, or isopropyl.
  • the pharmaceutically acceptable salt may be an acid addition salt, a base addition salt, a metal salt, an amino acid salt, or an organic salt.
  • the half-life of the compound of Formula 1 may be 1 hour or less.
  • a 5-alpha-reductase inhibitor comprising a compound as described above or a pharmaceutically acceptable salt thereof is provided.
  • composition for preventing hair loss or promoting hair growth comprising the compound as described above or a pharmaceutically acceptable salt thereof.
  • the composition for preventing hair loss or promoting hair growth of the present invention may be a composition for external application.
  • the composition of the present invention is a tonic, treatment, lotion, cream, ointment, lotion, powder, essence, pack, hair dye, shampoo, rinse, lotion, gel, balm, foam, It may be in one or more formulations of a bar, patch, and spray.
  • the composition can be topically and directly applied to the affected area to inhibit the production of dihydrotestosterone (DHT) around the hair follicles, thereby maximizing the effect of preventing hair loss and promoting hair growth.
  • DHT dihydrotestosterone
  • the composition when the composition is exposed to the body systemically, it is quickly discharged from the body and does not inhibit the production of DHT in the body, thereby preventing the side effects of existing drugs.
  • Figure 3 shows the stability analysis results of Compound 1 and Compound 3 in rat plasma.
  • Figure 4 shows the stability analysis results of Compound 1 and Compound 3 in human plasma.
  • the term "pharmaceutically acceptable salt” may be used interchangeably with “pharmaceutical salt”, and is a salt that is relatively non-toxic and harmless to an administered subject and can have an effective action, and is derived from the salt. It can mean any organic or inorganic compound formulation that does not reduce the efficacy of the drug, does not cause serious irritation to the subject to which the compound is administered, and does not impair the biological activity and physical properties of the compound.
  • the present invention includes not only the compounds of Formula 1 and pharmaceutically acceptable salts thereof, but also possible solvates, hydrates, isomers, and the like that can be prepared therefrom.
  • the term "pharmaceutically acceptable carrier”, “pharmaceutically acceptable excipient”, “physiologically acceptable carrier” or “physiologically acceptable excipient” refers to a pharmaceutically acceptable substance, composition or a vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each ingredient must be “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of the pharmaceutical formulation. It should also be suitable for use in contact with the tissues or organs of humans and animals without undue toxicity, irritation, allergic reaction, immunogenicity or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • each constituent drug of the composition may be a separate agent or a single agent, and the constituent drugs may be administered simultaneously, sequentially or in reverse order.
  • the pharmaceutically effective amount, administration time, administration interval, administration route, treatment period, etc. of each constituent drug of the pharmaceutical combination in the present invention may be the same or different from each other.
  • 5-alpha-reductase is an enzyme involved in steroid metabolism and serves to catalyze the irreversible reduction of testosterone to dihydrotestosterone (DHT).
  • DHT Dihydrotestosterone
  • the produced various protein regulatory substances can accelerate the hair growth period by promoting the proliferation of hair stromal cells and accelerate hair loss by shortening the differentiation period of hair follicle cells. Excessive formation of DHT by 5-alpha-reductase can lead to androgenetic alopecia.
  • DHT also plays a role in maintaining male sexual characteristics such as beard, low voice, and muscle growth.
  • an oral anti-hair loss composition since the drug is exposed to the whole body, the drug is exposed to the whole body for a long time, and the drug acts on the whole body to suppress DHT, etc. It is known that it has side effects related to male dysfunction and birth defects. there is.
  • the compound of the present invention contains a soft linker structure in the form of an ester group, carbonate, carbamate or urea in a molecule so that it can be exposed to the blood or degraded by metabolic enzymes in the blood, and the compound of the present invention is Metabolites generated after exposure are characterized by rapid exit from the body.
  • the compound of the present invention may have a half-life of less than 1 hour at most.
  • the present invention provides a compound of Formula 1 and a pharmaceutically acceptable salt thereof.
  • a is 1 or 2;
  • R 1 is OH, NH 2 , OR 2 or NHR 3 ;
  • R 2 and R 3 are each independently a substituent represented by Formula 2:
  • l and m are each independently 0 or 1;
  • n is an integer from 0 to 3;
  • A is -CH 2 -, -NH-, -O- or -CH 2 O-;
  • R 4 is NO 2 , -NHCOR 5 (where R 5 is C 1-5 alkyl), halogenosulfonyl, halogen atom, C 1-5 halogenoalkyl, C 1-5 halogenoalkoxy, C 1-5 alkoxy or C 1-5 alkyl.
  • R 4 is NO 2 , -NHCOR 5 (where R 5 is C 1-3 alkyl), halogenosulfonyl, a halogen atom, C 1-3 halogenoalkyl, C 1 -3 halogenoalkoxy, C 1-3 alkoxy or C 1-3 alkyl.
  • R 4 may be NO 2 , acetamido, fluorosulfonyl, fluoro, trifluoromethyl, methyl, or isopropyl.
  • the compound of Formula 1 may be provided in the form of a pharmaceutically acceptable salt.
  • a pharmaceutically acceptable salt or the pharmaceutical salt may be a non-toxic acid addition salt, a base addition salt, a metal salt, an amino acid salt, or an organic salt containing a pharmaceutically acceptable anion, such as sulfuric acid, hydrochloric acid, or nitric acid.
  • inorganic acids such as phosphoric acid, hydrobromic acid, hydroiodic acid, tartaric acid, formic acid, citric acid, acetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, lactic acid, malonic acid, malic acid, salicylic acid, succinic acid, oxalic acid, propionic acid, acid addition salts formed with organic acids such as aspartic acid, glutamic acid, citric acid and the like, and sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and naphthalenesulfonic acid; base addition salts formed with bases such as ammonium; metal salts formed by metals such as lithium, sodium, potassium, calcium or magnesium; amino acid salts formed by amino acids such as lysine, arginine or guanidine; Or it may
  • acid addition salts formed by free acids are specifically, phosphate, tartrate, stearate, gluconate, fumarate, 1-hydroxy 1-hydroxy-2-naphthoate, chloride, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, Nitrate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, bromide, iodide, fluoride, acetate, pro Propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate , propiolate, oxalate, malonate, succinate, suberate, sebacate, maleate, butyne-1,4 -dioate (butyne-1,4-dioate), hexane-1,6-dioate (hexane-1,6-dioate), benzoate (benzoate,
  • the compound of Formula 1 may have a structure of Formula 3 below.
  • R may be selected from -OH, -NH 2 or a substituent having the following structural formula.
  • the compound of Formula 1 may have a structure of Formula 4 below.
  • R may be selected from OH or a substituent having the following structural formula.
  • the compound of Formula 1 may have a structure of Formula 5 below.
  • R may be selected from substituents having the following structural formula.
  • the compound of Formula 1 may have a structure of Formula 6.
  • R may be selected from substituents having the following structural formula.
  • the compound of Formula 1 may be selected from the group consisting of compounds of Formulas 1 to 31 and pharmaceutically acceptable salts thereof.
  • the compound of Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention has a half-life (T 1/2 ) in the body of 1 hour or less, for example, 50 minutes or less, 40 minutes or less, 35 minutes or less. It may be less than 30 minutes, less than 20 minutes, or less than 15 minutes.
  • T 1/2 half-life
  • the dose of the present invention may be less than conventional doses.
  • the composition for external application of the present invention can be applied once to five times a day as a 0.001 to 30 wt% solution.
  • the present invention can be mainly applied to, for example, androgenetic alopecia, and when used as a composition for preventing female pattern alopecia and hair growth, the concentration may be adjusted or estradiol may be further included.
  • estradiol may be further included.
  • alphatradiol (17 ⁇ -estradiol) may be further included.
  • Alphatradiol is an estrogen derivative that blocks the conversion of testosterone to dihydrotestosterone, thereby reducing the concentration of DHT present in the scalp.
  • it plays a role in converting testosterone to 17 ⁇ -estradiol, a female hormone.
  • estradiol can promote the proliferation of hair follicle cells, and in particular, can be used for the treatment of female hair loss patients.
  • the present invention may further include additives commonly used in skin external preparations or cosmetic compositions, for example, antioxidants, stabilizers, solubilizers, vitamins, pigments, fragrances, moisturizers, preservatives, and emulsifiers. Ordinary adjuvants, carriers, etc. may be included.
  • the additives of the present invention may include materials commonly used in the art depending on the formulation.
  • water, lower monoalcohol, polyhydric alcohol, glycerin, etc. can be used as the solvent of the present invention.
  • the lower monoalcohol may include alcohol having 1 to 4 carbon atoms, and specifically, for example, may include methanol, ethanol, isopropyl alcohol, butanol, and the like.
  • the polyhydric alcohol may include, for example, ethylene glycol, propylene glycol, and 1,3-butylene glycol.
  • Solvents that can be used in the present invention are not limited to those described above and can be used without particular limitation as long as they are commonly used in the art.
  • the formulation of the present invention is an ointment, paste, cream or gel, animal oil, vegetable oil, wax, paraffin, starch, tracanth, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide are used as carrier components.
  • carrier components can include
  • the formulation of the present invention when it is a powder or spray, it may include lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder as a carrier component, and in particular, in the case of a spray, additionally chlorofluorohydrocarbon, Propellants such as propane/butane or dimethyl ether may be included.
  • the carrier component may include a solvent, a solubilizing agent, an emulsifying agent, and the like, such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene Glycol, 1,3-butyl glycol oil, etc. may be used, and examples thereof may include plant extract oil, glycerol aliphatic ester, polyethylene glycol, sorbitan fatty acid ester, and the like.
  • a solvent such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene Glycol, 1,3-butyl glycol oil, etc.
  • examples thereof may include plant extract oil, glycerol aliphatic ester, polyethylene glycol, sorbitan fatty acid ester, and the like.
  • the formulation of the present invention is a suspension
  • a liquid diluent such as water, ethanol or propylene glycol
  • a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester, polyoxyethylene sorbitan ester, and the like, microcrystals cellulose, aluminum metahydroxide, bentonite, agar, tracanth, and the like.
  • the formulation of the present invention is surfactant-containing cleansing, as carrier components, aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, sulfosuccinic acid monoester, isethionate, imidazolinium derivative, methyl taurate, sarcosinate, fatty acid amide ether sulfates, alkylamidobetaines, fatty alcohols, fatty acid glycerides, fatty acid diethanolamides, vegetable oils, lanolin derivatives or ethoxylated glycerol fatty acid esters, and the like.
  • the formulation of the present invention is a soap
  • alkali metal salts of fatty acids fatty acid hemiester salts, fatty acid protein hydrolyzates, isethionates, lanolin derivatives, fatty alcohols, vegetable oils, glycerol, sugars, etc. may be included as carrier components. there is.
  • composition of the present invention can be prepared in any formulation commonly prepared in the art, for example, solutions, suspensions, emulsions, emulsions, pastes, gels, packs, creams, lotions, powders, soaps, It may be formulated as a surfactant-containing cleanser, oil, powder, wax, spray, etc., but is not limited thereto.
  • the composition of the present invention can be formulated into any product that can be applied to the hair or scalp, such as essence, lotion, cream, pack, soap, shampoo, cleanser, rinse, treatment, spray, wax, gel, softener, etc. can
  • pharmaceutically acceptable additives such as diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants may be conventionally included.
  • diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants
  • sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, etc. may be used, and non-aqueous solvents or suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, ethyl oleate, and the like. there is.
  • composition of the present invention may further include excipients commonly used in the art within a range that does not impair the objects and effects of the present invention, preferably consisting of a pH adjuster, a solubilizer, and combinations thereof It may further include a pharmaceutically acceptable excipient selected from the group.
  • the pH adjusting agent may be selected from the group consisting of citric acid, malic acid, lactic acid, phosphoric acid, hydrochloric acid, sulfuric acid, and combinations thereof, but is not limited thereto.
  • the solubilizing agent may be selected from the group consisting of diethylene glycol monoethyl ether, benzyl alcohol, glycerin, octoxynol, propylene glycol, propylene carbonate, polyethylene glycol, and mixtures thereof, but is not limited thereto.
  • composition according to the present invention as described above effectively inhibits only 5-alpha-reductase only in the scalp, but is rapidly excreted in the body, thereby avoiding conventional side effects. Therefore, it can be applied in various ways as a composition for preventing hair loss and promoting hair growth, and specifically, it can be applied as an external composition to improve the effect of the present invention.
  • Reaction Scheme 1 a solution of the starting material (6.34 g, 20 mmol) in CH 2 Cl 2 :THF (tetrahydrofuran) (1:1, 100 mL) was dissolved in Et 3 N (6.0 g, 60.0 mmol) and iso-butyl chloroformate (3.0 g, 22.0 mmol) were added dropwise, and after 30 minutes, the cooling condition was removed, and the reaction solution was stirred at room temperature for 2 hours. After the reaction solution was cooled down to -10°C again, 2 M LiBH 4 in THF (15 mL, 30 mmol) was added dropwise. After stirring the reaction solution for 2 hours, water (100 mL) was added dropwise to terminate the reaction.
  • Et 3 N 6.0 g, 60.0 mmol
  • iso-butyl chloroformate 3.0 g, 22.0 mmol
  • the water layer was extracted with CH 2 Cl 2 (200 mL x 3), and the organic layer was concentrated under reduced pressure.
  • the resulting solid was dispersed in DMF (dimethyl formamide) (10 mL) and H 2 O (100 mL), filtered, and washed with PE (2-phenoxyethanol):EA (ethyl acetate) (5:1, 100 mL). gave.
  • the filtered solid was dried to obtain the target compound of Formula 1 as a white solid (target, 5.2 g, yield: 86%).
  • reaction condition (a) After activating phenol or benzyl alcohol with NaH using reaction condition (a), phenoxy or benzyloxy acetate analogs were synthesized by reacting with ethyl bromoacetate. Through the reaction condition (b), the ester group is hydrolyzed to an acid group to synthesize a corresponding acid compound, and finally, the reaction condition (c) is used to react with an alcohol to obtain various ester analogs of the compounds of Formulas 2 to 9 (Compounds 2 to 9). 9) was synthesized.
  • Compound 24 was synthesized as follows through a conventional synthesis method.
  • Compound 28 was synthesized as follows through a conventional synthesis method.
  • the activity of 5-alpha-reductase was measured using the mouse liver microsomal fraction isolated from above.
  • 50 ⁇ M NADPH and 0.9 ⁇ M testosterone were added to a 40 mM potassium phosphate buffer solution (pH 6.5, including 1 mM dithiothreitol).
  • the reaction was initiated by adding the liver microsome fraction, and the reaction proceeded at 37°C for 30 minutes.
  • the testosterone concentration of the reaction solution was measured by Enzyme Immunoassay (EIA) to confirm the activity of 5-alpha-reductase.
  • EIA Enzyme Immunoassay
  • Table 1 shows the results of measuring the molecular weight, partition coefficient (CLogP) and 5-alpha-reductase inhibitory effect of Compounds 1 to 32.
  • CLogP is a value calculated with the ChemDraw program.
  • the compounds according to the present invention are excellent in absorption (large partition coefficient value) and 5-alpha-reductase inhibitory effect, so they are suitable for application as 5-alpha-reductase inhibitors can know that
  • compound 32 has a mechanism of blocking the androgen receptor, and is known as a drug that avoids DHT-induced hair follicle damage by preventing DHT from binding by the blocked androgen receptor.
  • compound 32 has a mechanism of blocking the androgen receptor, and is known as a drug that avoids DHT-induced hair follicle damage by preventing DHT from binding by the blocked androgen receptor.
  • Test content Rat 1-week repeated toxicity (i.v. non-GLP)
  • Body Weight Change % Calculated compared to day 1 for each interval of body weight for main groups Food Consumption (g/rat/day) Calculated for days 1 - 4 and 4 - 7 for main groups only Blood Collection for Toxicokinetics Blood was collected from all rats on day 1 and 7 at 0, 0.083, 0.25, 0.5, 1, 2, 4, and 24 h post dosing Serum DHT level On day 7 at approximately 30 minutes post dosing Clinical Pathology On day 8 Gross Pathological Examination On day 8 Absolute Organ Weight (g) Adrenals, brain, epididymis, heart, kidneys, liver, lungs, ovaries with oviduct, prostate, seminal vesicles and coagulating gland, spleen, testes, thymus, and uterus with cervix. Relative Organ Weight (%) Calculated as relative to
  • the compound according to the present invention since the compound according to the present invention has an excellent 5-alpha-reductase inhibitory effect, it can be applied to a composition for the purpose of preventing, improving and treating alopecia. In addition, it is rapidly discharged from the body, acts locally on the affected area, and excellent hair loss prevention and hair growth promoting effects can be expected while preventing side effects.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Dermatology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Birds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un nouveau composé et une composition le comprenant pour prévenir la chute des cheveux et favoriser la pousse des cheveux, le composé étant capable d'inhiber uniquement la 5-alpha-réductase autour du cuir chevelu et du follicule pileux, avec la réduction au minimum concomitante des effets secondaires attribués à l'administration orale, ce qui permet d'améliorer l'effet de prévenir la chute des cheveux et de favoriser la pousse des cheveux. La composition selon la présente invention peut être appliquée localement et directement à la zone affectée afin d'augmenter au maximum l'effet de prévenir la chute des cheveux et de favoriser la pousse des cheveux. De plus, une exposition systémique in vivo peut être réduite au minimum et des effets secondaires peuvent être empêchés par une excrétion rapide à l'extérieur du corps.
PCT/KR2022/017724 2021-12-03 2022-11-11 Inhibiteur de 5-alpha-réductase, sel pharmaceutiquement acceptable de celui-ci et utilisation associée WO2023101256A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR10-2021-0171391 2021-12-03
KR20210171391 2021-12-03
KR1020220149149A KR102829242B1 (ko) 2021-12-03 2022-11-10 5-알파-환원효소 억제제, 그의 약학적으로 허용 가능한 염 및 그 용도
KR10-2022-0149149 2022-11-10

Publications (1)

Publication Number Publication Date
WO2023101256A1 true WO2023101256A1 (fr) 2023-06-08

Family

ID=86612742

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2022/017724 WO2023101256A1 (fr) 2021-12-03 2022-11-11 Inhibiteur de 5-alpha-réductase, sel pharmaceutiquement acceptable de celui-ci et utilisation associée

Country Status (1)

Country Link
WO (1) WO2023101256A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0285383B1 (fr) * 1987-04-03 1994-03-16 Merck & Co. Inc. Traitement des carcinomes prostatiques avec des 17-bêta-n-monosubstitué-carbamoyl-4-aza-5-alpha-androst-1-en-ones
EP0641208B1 (fr) * 1992-05-20 2000-08-02 Merck & Co. Inc. INHIBITEURS DE 5-$g(a)-REDUCTASE A BASE DE 4-AZASTEROIDES
US20210353622A1 (en) * 2020-05-12 2021-11-18 Chemistryrx Methods for treating hair loss and compositions for same
US20210353643A1 (en) * 2020-05-13 2021-11-18 Varsona Therapeutics, Inc. Topical dutasteride emulsions for treating endocrine therapy-induced alopecia
CN113712968A (zh) * 2021-09-27 2021-11-30 上海中医药大学 一种包含米诺地尔的药物组合物在防治脱发中的用途

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0285383B1 (fr) * 1987-04-03 1994-03-16 Merck & Co. Inc. Traitement des carcinomes prostatiques avec des 17-bêta-n-monosubstitué-carbamoyl-4-aza-5-alpha-androst-1-en-ones
EP0641208B1 (fr) * 1992-05-20 2000-08-02 Merck & Co. Inc. INHIBITEURS DE 5-$g(a)-REDUCTASE A BASE DE 4-AZASTEROIDES
US20210353622A1 (en) * 2020-05-12 2021-11-18 Chemistryrx Methods for treating hair loss and compositions for same
US20210353643A1 (en) * 2020-05-13 2021-11-18 Varsona Therapeutics, Inc. Topical dutasteride emulsions for treating endocrine therapy-induced alopecia
CN113712968A (zh) * 2021-09-27 2021-11-30 上海中医药大学 一种包含米诺地尔的药物组合物在防治脱发中的用途

Similar Documents

Publication Publication Date Title
WO2018226053A1 (fr) Composé dérivé du cyclopropylamine et son utilisation
EP2760823A1 (fr) Nouveaux composés en tant qu'inhibiteurs du hif-1alpha , et leur procédé de fabrication
WO2014109530A1 (fr) Dérivé 2-(phényléthynyl)thiéno[3,4-b]pyrazine, et composition pharmaceutique comprenant ce dérivé et destinée à la prévention ou au traitement du cancer
WO2021137665A1 (fr) Composé dérivé de 1,2,3-triazole utilisé en tant qu'inhibiteur de hsp90, et son utilisation
WO2020222541A1 (fr) Promédicament d'inhibiteur de caspase
WO2013105753A1 (fr) Dérivés de pipéridine substituée et procédés pour les préparer
WO2023101256A1 (fr) Inhibiteur de 5-alpha-réductase, sel pharmaceutiquement acceptable de celui-ci et utilisation associée
WO2020036382A1 (fr) Procédé de production d'intermédiaire utile pour la synthèse d'un inhibiteur de sglt
WO2022050749A1 (fr) Nouveau dérivé biaryle utile en tant qu'inhibiteur de la diacylglycérol acyltransférase 2, et son utilisation
WO2022211420A1 (fr) Composition pour la prévention ou le traitement d'une maladie neurodégénérative comprenant un composé induisant l'expression d'un gène klotho antivieillissement
WO2011105643A1 (fr) Dérivé de sélénazole ayant un ligand qui active le récepteur activé de la prolifération des peroxysomes (ppar), son procédé de préparation et utilisation des composés chimiques
EP3060549A1 (fr) Nouveau dérivé oxodihydropyridinecarbohydrazide antifongique
WO2022177313A1 (fr) Dérivé de sesquiterpène ou sel de qualité pharmaceutique de celui-ci, et leur utilisation
WO2018164549A1 (fr) Nouveau composé ayant une activité inhibitrice de malate déshydrogénase et composition pharmaceutique destinée à prévenir ou à traiter le cancer le contenant à titre de principe actif
WO2012148140A2 (fr) Dérivés d'alcaloïdes à base d'imidazole ayant des effets d'inhibition de l'angiogenèse et antioxydants et leur procédé de préparation
WO2023059121A1 (fr) Nouveau composé dérivé de benzofuranyl-hydroxyphényl-méthanone ou sel pharmaceutiquement acceptable associé
WO2015115796A1 (fr) Dérivé pegylé de 7-déshydrocholestérol
WO2021215624A1 (fr) Nouveau dérivé de 2-arylthiazole ou sel de celui-ci, procédé de préparation associé et composition pharmaceutique les comprenant
WO2023224371A1 (fr) Nouveau composé dérivé d'oxadiazole, et composition pharmaceutique pour la prévention ou le traitement de maladies neuroinflammatoires le comprenant
WO2022086110A1 (fr) Dérivé de thiobenzimidazole ou sel pharmaceutiquement acceptable de celui-ci, et leur utilisation
WO2017119570A1 (fr) Dérivé de thiazolidinedione et son utilisation
WO2014185561A1 (fr) Nouveau composé ou son sel pharmaceutiquement acceptable et composition pharmaceutique pour la prévention ou le traitement de maladies associées à uch-l1, le contenant en tant que principe actif
WO2019093699A1 (fr) Sélénopsammapline a et dérivé de celle-ci, procédé de préparation associé, et composition pour la prévention ou le traitement du cancer les contenant en tant que principes actifs
WO2023074937A1 (fr) Composé utilisé en tant que ligand de domaine de boîte ubr
WO2024144371A1 (fr) Composés pharmaceutiquement actifs, compositions et procédés de modulation de la pendrine

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22901614

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 22/10/2024)

122 Ep: pct application non-entry in european phase

Ref document number: 22901614

Country of ref document: EP

Kind code of ref document: A1