WO2024103494A1 - 一种局部作用的雄激素受体拮抗剂及其应用 - Google Patents

一种局部作用的雄激素受体拮抗剂及其应用 Download PDF

Info

Publication number
WO2024103494A1
WO2024103494A1 PCT/CN2022/141920 CN2022141920W WO2024103494A1 WO 2024103494 A1 WO2024103494 A1 WO 2024103494A1 CN 2022141920 W CN2022141920 W CN 2022141920W WO 2024103494 A1 WO2024103494 A1 WO 2024103494A1
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
unsubstituted
alkyl
butyl
hydrogen
Prior art date
Application number
PCT/CN2022/141920
Other languages
English (en)
French (fr)
Inventor
陆鹏
王玉斌
张英
王亮
Original Assignee
南京思聚生物医药有限公司
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
Application filed by 南京思聚生物医药有限公司 filed Critical 南京思聚生物医药有限公司
Publication of WO2024103494A1 publication Critical patent/WO2024103494A1/zh

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
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • A61P17/10—Anti-acne agents
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/28—Antiandrogens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/86—Oxygen and sulfur atoms, e.g. thiohydantoin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel substituted thioimidazolidinone compounds as topically acting androgen receptor antagonists, and pharmaceutical compositions comprising such compounds for the treatment of androgen receptor-related diseases or conditions, such as androgenic alopecia and acne.
  • AGA Androgenic alopecia
  • AGA also known as seborrheic alopecia and premature baldness, is divided into male pattern alopecia and female pattern alopecia. It is the most common non-scarring hair loss in clinical practice.
  • AGA mainly occurs in late adolescence and is characterized by atrophy between hair follicles. The disease is mainly manifested by a receding hairline or a decrease and thinning of hair on the top of the head in male patients; female patients are mainly manifested by a decrease and thinning of hair on the top of the head. A few patients show diffuse thinning of hair without affecting the hairline.
  • AGA Alzheimer's disease
  • Androgenic alopecia is an androgen-dependent multi-gene genetic disease. Since Hamilton Norwood first proposed in 1942 that the occurrence of AGA is related to androgens, domestic and foreign researchers have focused their research on AGA on androgens and their metabolic enzymes in the scalp. However, the exact cause and pathogenesis of this disease have not yet been clarified. Some researchers have found that the incidence of the disease is also related to race, ethnicity, age, gender, living environment, living habits, mental and psychological factors, and bacterial infection (pityrosporum, Corynebacterium acnes, etc.). In recent years, the incidence of AGA has continued to increase and has shown a younger age. Therefore, treatment is urgently needed.
  • Male androgens are mainly synthesized by the testicles, including testosterone, dihydrotestosterone (DHT), androstenedione (DHEA) and dehydroepiandrosterone (ASD).
  • Female androgens are mainly derived from the adrenal cortex. Testosterone and androstenedione can be reduced to DHT by 5 ⁇ -reductase, and the affinity of DHT for androgen receptor (AR) is 5+ times that of testosterone.
  • 5 ⁇ -reductase I is mainly distributed in the sebaceous glands and liver; 5 ⁇ -reductase II is mainly distributed in the scalp hair follicles, epididymis, vas deferens, seminal vesicles, prostate and fetal genital skin.
  • scalp hair follicles are one of the target organs of androgens. Hair biopsy specimens of male AGA patients were taken, and it was found that the activity of 5 ⁇ -reductase in the hair loss area on the top of the head was significantly higher than that in the non-hair loss area on the occipital part.
  • DHT has a strong affinity for AR. After binding to AR, it enters the cell nucleus, inhibits the adenylate cyclase of the hair follicles, reduces the synthesis of cyclic nucleotides and related proteins, and causes the hair to enter the resting phase early. It also inhibits the growth of hair follicles, shrinks them, stimulates the proliferation of sebaceous glands and oil secretion, further reduces the volume of hair follicles and gradually disappears, thereby promoting hair shedding.
  • the technical problem to be solved by the present invention is to provide a compound represented by formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof in view of the deficiencies in the prior art.
  • Another technical problem to be solved by the present invention is to provide a composition containing the above compound, or its stereoisomer, or its pharmaceutically acceptable salt.
  • a further technical problem to be solved by the present invention is to provide the above-mentioned compound, or its stereoisomer, or its pharmaceutically acceptable salt, or the use of the above-mentioned composition.
  • a further technical problem to be solved by the present invention is to provide a method for preventing diseases or conditions mediated by androgen or androgen receptor activity in mammals, reducing the progression of diseases or conditions mediated by androgen or androgen receptor activity in mammals, and treating diseases or conditions mediated by androgen or androgen receptor activity in mammals.
  • the present invention discloses a compound represented by formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from substituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted C 5 to C 10 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted -(CH 2 ) n -cycloalkyl, substituted or unsubstituted -(CH 2 ) n -heterocycloalkyl, substituted or unsubstituted -CH(R 7 )OC(O)OR 8 or substituted or unsubstituted -CH(R 7 )OC(O)NH(R 8 ); wherein in the substituted ethyl, the substitution is substituted by one or more hydroxyl,
  • R 4 , R 5 , R 7 , and R 8 are each independently selected from hydrogen or C 1 -C 8 alkyl
  • n is selected from 0, 1, 2, 3, 4, 5 or 6;
  • R 2 and R 3 are each independently selected from cyano, nitro, alkyl, haloalkyl, hydroxyl, mercapto, halogen, C 1 ⁇ C 8 alkoxy or C 1 ⁇ C 8 haloalkoxy;
  • X and Y are each independently selected from N or CR 6 ;
  • R6 is selected from hydrogen, halogen, C1 - C8 alkyl, cycloalkyl or heterocyclic group.
  • R 1 is selected from substituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted C 5 to C 8 alkyl, substituted or unsubstituted C 2 to C 8 alkenyl, substituted or unsubstituted C 2 to C 8 alkynyl, substituted or unsubstituted -(CH 2 ) n -3 to 8 membered cycloalkyl, substituted or unsubstituted -(CH 2 ) n -3 to 8 membered heterocycloalkyl, substituted or unsubstituted -CH(R 7 )OC(O)OR 8 , or substituted or unsubstituted -CH(R 7 )OC(O)NH(R 8 ); where
  • R 1 is selected from substituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted C 5 ⁇ C 6 alkyl, substituted or unsubstituted C 2 ⁇ C 6 alkenyl, substituted or unsubstituted C 2 ⁇ C 6 alkynyl, substituted or unsubstituted -(CH 2 ) n -3 ⁇ 6 membered cycloalkyl, substituted or unsubstituted -(CH 2 ) n -3 ⁇ 6 membered heterocycloalkyl, substituted or unsubstituted -CH(R 7 )OC(O)OR 8 or substituted or unsubstituted -CH(R 7 )OC(O)NH(R 8
  • R 1 is selected from substituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted C 5 ⁇ C 6 alkyl, substituted or unsubstituted C 2 ⁇ C 4 alkenyl, substituted or unsubstituted C 2 ⁇ C 4 alkynyl, substituted or unsubstituted -(CH 2 ) n -3 ⁇ 6 membered cycloalkyl, substituted or unsubstituted -(CH 2 ) n -3 ⁇ 6 membered heterocycloalkyl, substituted or unsubstituted -CH(R 7 )OC(O)OR 8 or substituted or unsubstituted -CH(R 7 )OC(O)NH(R 8
  • R 1 is selected from substituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted C 5 ⁇ C 6 alkyl, substituted or unsubstituted C 2 ⁇ C 4 alkenyl, substituted or unsubstituted C 2 ⁇ C 4 alkynyl, substituted or unsubstituted -(CH 2 ) n -3 ⁇ 6 membered cycloalkyl, substituted or unsubstituted -(CH 2 ) n -3 ⁇ 6 membered heterocycloalkyl, substituted or unsubstituted -CH(R 7 )OC(O)OR 8 , or substituted or unsubstituted -CH(R 7 )OC(O)NH(
  • R is selected from substituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted allyl, substituted or unsubstituted propargyl, substituted or unsubstituted cyclopropyl, substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsub
  • R 1 is selected from n-propyl, n-butyl, isobutyl, allyl, propargyl, cyclopropyl,
  • R is selected from
  • R 7 and R 8 are each independently selected from hydrogen or C 1 -C 6 alkyl.
  • R 7 and R 8 are each independently selected from hydrogen or C 1 -C 4 alkyl.
  • R 7 , R 8 are each independently selected from hydrogen, methyl, ethyl, or isopropyl.
  • R 7 is selected from hydrogen, methyl, or isopropyl.
  • R 8 is selected from methyl, ethyl or isopropyl.
  • n is selected from 0, 1, 2, 3, or 4.
  • n is selected from 0, 1 or 2.
  • R 4 and R 5 are each independently selected from hydrogen or C 1 -C 6 alkyl.
  • R 4 and R 5 are each independently selected from hydrogen or C 1 -C 4 alkyl.
  • R 4 and R 5 are each independently selected from hydrogen, methyl or ethyl.
  • R 2 and R 3 are each independently selected from cyano, nitro, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, hydroxyl, mercapto, halogen, C 1 -C 4 alkoxy, or halogenated C 1 -C 4 alkoxy.
  • R 2 and R 3 are each independently selected from C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, mercapto, cyano, and halogen.
  • R 2 and R 3 are each independently selected from cyano, methyl, trifluoromethyl, fluoro, or chloro.
  • R 2 and R 3 are each independently selected from cyano, trifluoromethyl, fluoro, or chloro.
  • R 2 is selected from cyano and R 3 is selected from trifluoromethyl.
  • X and Y are each independently selected from N or CR 6 .
  • X and Y are both selected from CR 6 .
  • R6 is selected from hydrogen, halogen, C1 ⁇ C8 alkyl, cycloalkyl or heterocyclyl; in some embodiments, R6 is selected from hydrogen, halogen, C1 ⁇ C4 alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocyclyl; in some embodiments, R6 is selected from hydrogen or halogen; in some embodiments, R6 is selected from hydrogen, fluorine or chlorine; in some embodiments, R6 is selected from hydrogen or fluorine.
  • X is selected from CH.
  • Y is selected from CF.
  • the compound represented by formula (I) is a compound represented by formula (II),
  • R 1 is selected from substituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted C 5 to C 10 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted -(CH 2 ) n -cycloalkyl, substituted or unsubstituted -(CH 2 ) n -heterocycloalkyl, substituted or unsubstituted -CH(R 7 )OC(O)OR 8 or substituted or unsubstituted -CH(R 7 )OC(O)NH(R 8 ); wherein in the substituted ethyl, the substitution is substituted by one or more hydroxyl,
  • R 4 , R 5 , R 7 , and R 8 are each independently selected from hydrogen or C 1 -C 8 alkyl
  • n is selected from 0, 1, 2, 3, 4, 5 or 6;
  • R 2 and R 3 are each independently selected from cyano, nitro, alkyl, haloalkyl, hydroxyl, mercapto, halogen, C 1 ⁇ C 8 alkoxy or C 1 ⁇ C 8 haloalkoxy;
  • R6 is selected from hydrogen, halogen, C1 - C8 alkyl, cycloalkyl or heterocyclic group.
  • R 1 is selected from substituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted C 5 to C 8 alkyl, substituted or unsubstituted C 2 to C 8 alkenyl, substituted or unsubstituted C 2 to C 8 alkynyl, substituted or unsubstituted -(CH 2 ) n -3 to 8 membered cycloalkyl, substituted or unsubstituted -(CH 2 ) n -3 to 8 membered heterocycloalkyl, substituted or unsubstituted -CH(R 7 )OC(O)OR 8 , or substituted or unsubstituted -CH(R 7 )OC(O)NH(R 8 ); where
  • R 1 is selected from substituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted C 5 ⁇ C 6 alkyl, substituted or unsubstituted C 2 ⁇ C 6 alkenyl, substituted or unsubstituted C 2 ⁇ C 6 alkynyl, substituted or unsubstituted -(CH 2 ) n -3 ⁇ 6 membered cycloalkyl, substituted or unsubstituted -(CH 2 ) n -3 ⁇ 6 membered heterocycloalkyl, substituted or unsubstituted -CH(R 7 )OC(O)OR 8 or substituted or unsubstituted -CH(R 7 )OC(O)NH(R 8
  • R 1 is selected from substituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted C 5 ⁇ C 6 alkyl, substituted or unsubstituted C 2 ⁇ C 4 alkenyl, substituted or unsubstituted C 2 ⁇ C 4 alkynyl, substituted or unsubstituted -(CH 2 ) n -3 ⁇ 6 membered cycloalkyl, substituted or unsubstituted -(CH 2 ) n -3 ⁇ 6 membered heterocycloalkyl, substituted or unsubstituted -CH(R 7 )OC(O)OR 8 or substituted or unsubstituted -CH(R 7 )OC(O)NH(R 8
  • R 1 is selected from substituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted C 5 ⁇ C 6 alkyl, substituted or unsubstituted C 2 ⁇ C 4 alkenyl, substituted or unsubstituted C 2 ⁇ C 4 alkynyl, substituted or unsubstituted -(CH 2 ) n -3 ⁇ 6 membered cycloalkyl, substituted or unsubstituted -(CH 2 ) n -3 ⁇ 6 membered heterocycloalkyl, substituted or unsubstituted -CH(R 7 )OC(O)OR 8 , or substituted or unsubstituted -CH(R 7 )OC(O)NH(
  • R is selected from substituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted allyl, substituted or unsubstituted propargyl, substituted or unsubstituted cyclopropyl, substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsub
  • R 1 is selected from n-propyl, n-butyl, isobutyl, allyl, propargyl, cyclopropyl,
  • R is selected from
  • R 7 and R 8 are each independently selected from hydrogen or C 1 -C 6 alkyl.
  • R 7 and R 8 are each independently selected from hydrogen or C 1 -C 4 alkyl.
  • R 7 , R 8 are each independently selected from hydrogen, methyl, ethyl, or isopropyl.
  • R 7 is selected from hydrogen, methyl, or isopropyl.
  • R 8 is selected from methyl, ethyl or isopropyl.
  • n is selected from 0, 1, 2, 3, or 4.
  • n is selected from 0, 1 or 2.
  • R 4 and R 5 are each independently selected from hydrogen or C 1 -C 6 alkyl.
  • R 4 and R 5 are each independently selected from hydrogen or C 1 -C 4 alkyl.
  • R 4 and R 5 are each independently selected from hydrogen, methyl or ethyl.
  • R 2 and R 3 are each independently selected from cyano, nitro, C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, hydroxyl, mercapto, halogen, C 1 -C 4 alkoxy, or halogenated C 1 -C 4 alkoxy.
  • R 2 and R 3 are each independently selected from C 1 -C 4 alkyl, halogenated C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, mercapto, cyano, and halogen.
  • R 2 and R 3 are each independently selected from cyano, methyl, trifluoromethyl, fluoro, or chloro.
  • R 2 and R 3 are each independently selected from cyano, trifluoromethyl, fluoro, or chloro.
  • R 2 is selected from cyano and R 3 is selected from trifluoromethyl.
  • R 6 is selected from hydrogen, halogen, C 1 -C 8 alkyl, cycloalkyl, or heterocyclyl.
  • R 6 is selected from hydrogen, halogen, C 1 -C 4 alkyl, 3-6 membered cycloalkyl, or 3-6 membered heterocyclyl.
  • R 6 is selected from hydrogen or halogen; in some embodiments, R 6 is selected from hydrogen, fluorine, or chlorine.
  • R 6 is selected from hydrogen or fluoro.
  • the compound represented by formula (I) is a compound represented by formula (III),
  • R 1 is selected from substituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted C 5 to C 10 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted -(CH 2 ) n -cycloalkyl, substituted or unsubstituted -(CH 2 ) n -heterocycloalkyl, substituted or unsubstituted -CH(R 7 )OC(O)OR 8 or substituted or unsubstituted -CH(R 7 )OC(O)NH(R 8 ); wherein in the substituted ethyl, the substitution is substituted by one or more hydroxyl,
  • R 1 is selected from substituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted C 5 to C 8 alkyl, substituted or unsubstituted C 2 to C 8 alkenyl, substituted or unsubstituted C 2 to C 8 alkynyl, substituted or unsubstituted -(CH 2 ) n -3 to 8 membered cycloalkyl, substituted or unsubstituted -(CH 2 ) n -3 to 8 membered heterocycloalkyl, substituted or unsubstituted -CH(R 7 )OC(O)OR 8 , or substituted or unsubstituted -CH(R 7 )OC(O)NH(R 8 ); where
  • R 1 is selected from substituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted C 5 ⁇ C 6 alkyl, substituted or unsubstituted C 2 ⁇ C 6 alkenyl, substituted or unsubstituted C 2 ⁇ C 6 alkynyl, substituted or unsubstituted -(CH 2 ) n -3 ⁇ 6 membered cycloalkyl, substituted or unsubstituted -(CH 2 ) n -3 ⁇ 6 membered heterocycloalkyl, substituted or unsubstituted -CH(R 7 )OC(O)OR 8 or substituted or unsubstituted -CH(R 7 )OC(O)NH(R 8
  • R 1 is selected from substituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted C 5 ⁇ C 6 alkyl, substituted or unsubstituted C 2 ⁇ C 4 alkenyl, substituted or unsubstituted C 2 ⁇ C 4 alkynyl, substituted or unsubstituted -(CH 2 ) n -3 ⁇ 6 membered cycloalkyl, substituted or unsubstituted -(CH 2 ) n -3 ⁇ 6 membered heterocycloalkyl, substituted or unsubstituted -CH(R 7 )OC(O)OR 8 or substituted or unsubstituted -CH(R 7 )OC(O)NH(R 8
  • R 1 is selected from substituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted C 5 ⁇ C 6 alkyl, substituted or unsubstituted C 2 ⁇ C 4 alkenyl, substituted or unsubstituted C 2 ⁇ C 4 alkynyl, substituted or unsubstituted -(CH 2 ) n -3 ⁇ 6 membered cycloalkyl, substituted or unsubstituted -(CH 2 ) n -3 ⁇ 6 membered heterocycloalkyl, substituted or unsubstituted -CH(R 7 )OC(O)OR 8 , or substituted or unsubstituted -CH(R 7 )OC(O)NH(
  • R is selected from substituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted allyl, substituted or unsubstituted propargyl, substituted or unsubstituted cyclopropyl, substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsub
  • R 1 is selected from n-propyl, n-butyl, isobutyl, allyl, propargyl, cyclopropyl,
  • R is selected from
  • the compound represented by formula (I) is selected from the following compounds:
  • the compound represented by formula (I) is selected from the following compounds:
  • the compound represented by formula (I) is selected from the following compounds:
  • the compound represented by formula (I) is selected from the following compounds:
  • the present invention discloses a pharmaceutical composition, which comprises (i) a compound of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as described in the above-mentioned first technical problem, and (ii) a pharmaceutically acceptable carrier, diluent or excipient.
  • the present invention discloses the use of the compound of formula (I) or its stereoisomer, or its pharmaceutically acceptable salt, described in the first technical problem mentioned above, or the pharmaceutical composition described in the second technical problem mentioned above in the preparation of a drug for preventing diseases or conditions mediated by androgen or androgen receptor activity, reducing the progression of diseases or conditions mediated by androgen or androgen receptor activity, or treating diseases or conditions mediated by androgen or androgen receptor activity.
  • the disease or condition mediated by androgen or androgen receptor activity is selected from prostate cancer, acne, or alopecia.
  • the present invention discloses a method for preventing diseases or conditions mediated by androgen or androgen receptor activity in mammals, reducing the progression of diseases or conditions mediated by androgen or androgen receptor activity in mammals, and treating diseases or conditions mediated by androgen or androgen receptor in mammals, comprising administering to a mammal in need of such treatment a therapeutically effective amount of the compound of formula (I) or its stereoisomer, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in the second technical problem, as described above in the first technical problem.
  • the mammal is a human.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent as long as the valence state of the particular atom is normal and the compound after the substitution is stable.
  • an ethyl group is "optionally” substituted with a halogen, which means that the ethyl group may be unsubstituted (CH 2 CH 3 ), monosubstituted (such as CH 2 CH 2 F), polysubstituted (such as CHFCH 2 F, CH 2 CHF 2 , etc.) or fully substituted (CF 2 CF 3 ). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible and/or cannot be synthesized will be introduced.
  • C n to C m means that the moiety has an integer number of carbon atoms in a given range.
  • C 1 to C 6 means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.
  • C 1 to C 3 means that the group may have 1 carbon atom, 2 carbon atoms or 3 carbon atoms.
  • any variable e.g., R
  • its definition at each occurrence is independent.
  • each R has independent options.
  • linking group When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a covalent bond.
  • the substituent When a substituent's bond crosses two atoms in a ring, the substituent may be bonded to any atom in the ring. It means that it can be substituted at any position on the cyclohexyl group or cyclohexadiene.
  • halo or halogen refers to fluorine, chlorine, bromine and iodine.
  • hydroxy refers to an -OH group.
  • mercapto refers to a -SH group.
  • amino refers to a -NH2 group.
  • cyano refers to a -CN group.
  • nitro refers to the -NO2 group.
  • alkyl refers to a hydrocarbon group of the general formula CnH2n +1 .
  • the alkyl group may be straight or branched.
  • C1- C6 alkyl refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.).
  • alkyl portion i.e., alkyl
  • alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio has the same definition as above.
  • C1- C3 alkyl refers to an alkyl group containing 1 to 3 carbon atoms (e.g., methyl, ethyl, propyl, and isopropyl).
  • alkoxy refers to an alkyl group as described above with a specific number of carbon atoms connected by an oxygen bridge.
  • C1 - C6 alkoxy includes C1 , C2 , C3 , C4 , C5 and C6 alkoxy.
  • Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy and S-pentoxy.
  • alkenyl refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms having at least one double bond.
  • alkenyl include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, etc.
  • alkynyl refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one triple bond.
  • alkynyl include, but are not limited to, ethynyl (-C ⁇ CH), 1-propynyl (-C ⁇ C-CH 3 ), 2-propynyl (-CH 2 -C ⁇ CH), 1,3-butadiynyl (-C ⁇ CC ⁇ CH), and the like.
  • cycloalkyl refers to a carbocyclic ring that is fully saturated and can exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 3 to 10-membered ring.
  • Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, bicyclo[1.1.1]pent-1-yl, and the like.
  • C 3 to C 4 cycloalkyl includes cyclopropyl and cyclobutyl.
  • heterocyclic radical refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic) and can exist as a monocyclic, bridged or spirocyclic ring.
  • the heterocyclic ring is generally a 3 to 10 ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen, or a 4 to 6 ring.
  • heterocyclic radicals include but are not limited to oxirane, tetrahydrofuranyl, dihydrofuranyl, 3,4-dihydropyranyl, 3,6-dihydropyranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, 2-oxa-7-azaspiro [3.5] nonanyl, 2-oxa-6-azaspiro [3.3] heptane etc.
  • heterocycloalkyl refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 3 to 10 ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen, or a 4 to 6 ring. Examples of 3-membered heterocycloalkyl include, but are not limited to, oxirane, thioethane, and cyclonitroethane.
  • Non-limiting examples of 4-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxadiene, thiazolinyl, and oxetanyl.
  • Examples of 5-membered heterocycloalkyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, tetrahydropyrazolyl, and tetrahydrofuranyl.
  • 6-membered heterocycloalkyl examples include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxane, thiomorpholinyl, 1,3-dithianyl, and 1,4-dithianyl.
  • 7-membered heterocycloalkyl include, but are not limited to, azepanyl, oxepanyl, and thiepanyl.
  • the monocyclic heterocycloalkyl has 5 or 6 ring atoms.
  • treatment means administering the compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • prevention means administering the compounds or formulations described herein to prevent a disease or one or more symptoms associated with the disease, and includes preventing a disease or disease state from occurring in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.
  • terapéuticaally effective amount means an amount of the compound of the present application that (i) treats or prevents a specific disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein.
  • the amount of the compound of the present application that constitutes a “therapeutically effective amount” varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and the present disclosure.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to salts of compounds of the present application, prepared from compounds with specific substituents found in the present application and relatively non-toxic acids or bases.
  • base addition salts can be obtained by contacting a neutral form of such compounds with a suitable base.
  • acid addition salts can be obtained by contacting a neutral form of such compounds with a suitable acid.
  • Certain specific compounds of the present application contain basic and acidic functional groups, and thus can be converted into either base or acid addition salts.
  • composition refers to a mixture of one or more compounds of the present application or their salts and pharmaceutically acceptable excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.
  • pharmaceutically acceptable excipients refers to those excipients that have no significant irritation to the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.
  • pharmaceutically acceptable excipients refers to those excipients that have no significant irritation to the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present invention.
  • the key is a solid wedge. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond. and straight dashed key To indicate the relative configuration of a stereocenter, use a wavy line Denotes a solid wedge bond or dotted wedge key Or use a wavy line Represents a straight solid bond and straight dashed key
  • Optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer.
  • a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art, and then the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is usually accomplished by using chromatography, which uses a chiral stationary phase and is optionally combined with a chemical derivatization method (for example, a carbamate is generated from an amine).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more atoms constituting the compound.
  • compounds may be labeled with radioactive isotopes, such as tritium (3H), iodine-125 (125 I) or C-14 (14C).
  • deuterated drugs may be formed by replacing hydrogen with heavy hydrogen, such as d3-methyl, which means that all three hydrogen atoms on the methyl group are replaced by deuterium atoms. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon.
  • deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending the biological half-life of drugs.
  • the present application also includes isotope-labeled compounds of the present application that are identical to those described herein, but one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number commonly found in nature.
  • isotopes that can be incorporated into compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 31P, 32P, 35S, 18F, 123I, 125I, and 36Cl, etc.
  • Certain isotopically labeled compounds of the present invention can be used in compound and/or substrate tissue distribution analysis. Tritiated (i.e., 3H) and carbon-14 (i.e., 14C) isotopes are particularly preferred due to their ease of preparation and detectability.
  • Positron emitting isotopes, such as 15O, 13N, 11C, and 18F can be used in positron emission tomography (PET) studies to determine substrate occupancy.
  • Isotopically labeled compounds of the present invention can generally be prepared by replacing an isotopically labeled reagent with an isotopically labeled reagent by the following procedures similar to those disclosed in the schemes and/or embodiments below.
  • substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and thus may be preferred in some circumstances, wherein the deuterium substitution may be partial or full, partial deuterium substitution means that at least one hydrogen is replaced by at least one deuterium, and all such forms of compounds are included within the scope of the present application.
  • the compounds of the present application may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers are included, such as enantiomers and diastereomers.
  • the compounds of the present application containing asymmetric carbon atoms can be separated in optically pure form or racemic form. Optically pure forms can be separated from racemic mixtures or synthesized by using chiral raw materials or chiral reagents.
  • the pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
  • Typical routes of administration of the compounds of the present application or their pharmaceutically acceptable salts or their pharmaceutical compositions include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.
  • the pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.
  • the therapeutic dose of the compounds of the present application may be determined, for example, based on the specific use of the treatment, the method of administering the compound, the health and condition of the patient, and the judgment of the prescribing physician.
  • the ratio or concentration of the compounds of the present application in the pharmaceutical composition may not be fixed, depending on a variety of factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration.
  • the compounds of the present application may be provided by a physiologically buffered aqueous solution containing about 0.1 to 10% w/v of the compound for parenteral administration. Some typical dosage ranges are about 1 ⁇ g/kg to about 1 g/kg body weight/day.
  • the dosage range is about 0.01 mg/kg to about 100 mg/kg body weight/day.
  • the dosage is likely to depend on such variables as the type and degree of development of the disease or condition, the general health status of the specific patient, the relative biological efficacy of the selected compound, the excipient formulation, and its route of administration.
  • the effective dose can be obtained by extrapolation of a dose-response curve derived from an in vitro or animal model test system.
  • the compounds of the present application can be prepared by a variety of synthesis methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitution methods known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.
  • the present invention has the following advantages:
  • the compounds of the present application are locally acting androgen antagonists.
  • the compounds have good skin stability, slow metabolism, and play an anti-androgenic alopecia effect, but have extremely poor stability in plasma and can be directed and rapidly metabolized to an inactive metabolite, enzalutamide (CAS: 1242137-15-0), avoiding systemic androgen antagonism side effects caused by systemic distribution.
  • the provided compounds are administered transdermally and show a hair growth promoting effect in a mouse alopecia model.
  • Figure 1 shows the hair growth scores of C57BL/6 mice.
  • FIG. 2 shows the hair growth of mice (Application Example 5).
  • FIG3 is a graph showing the hair growth of mice on day 26 and a curve showing changes in body weight and hair coverage (Application Example 6).
  • step 5 of example 1 compound 2 was prepared by reacting compound 1-4 obtained in step 4 of example 1 with n-butanol.
  • step 5 of example 1 compound 3 was prepared by reacting compound 1-4 obtained in step 4 of example 1 with neobutanol.
  • step 5 of example 1 compound 4 was prepared by reacting compound 1-4 obtained in step 4 of example 1 with cyclopropylmethanol.
  • step 5 of example 1 compound 5 was prepared by reacting compound 1-4 obtained in step 4 of example 1 with cyclopropanol.
  • step 1 of example 6 compound 1-4 obtained in step 4 of example 1 was reacted with (R)-glycerol acetonide to prepare compound 7-1.
  • step 1 of Example 6 compound 7 was prepared by reacting compound 7-1 obtained in step 1 with trifluoroacetic acid.
  • step 8 compound 8 was prepared by reacting compound 1-4 obtained in step 4 of example 1 with N,N-dimethylethanolamine.
  • step 9 was prepared by reacting compound 1-4 obtained in step 4 of example 1 with N,N-diethylethanolamine.
  • step 1 of example 6 compound 10 was prepared by reacting compound 1-4 obtained in step 4 of example 1 with N-hydroxyethylmorpholine.
  • step 5 of example 1 compound 1-4 obtained in step 4 of example 1 was reacted with (S)-3-hydroxytetrahydrofuran to prepare compound 11.
  • step 5 of example 1 compound 1-4 obtained in step 4 of example 1 was reacted with (R)-3-hydroxytetrahydrofuran to prepare compound 12.
  • step 5 of example 1 compound 13 was prepared by reacting compound 1-4 obtained in step 4 of example 1 with 3-hydroxyoxetane.
  • step 5 of example 1 compound 14 was prepared by reacting compound 1-4 obtained in step 4 of example 1 with 3-hydroxymethyloxetane.
  • step 5 of example 1 compound 1-4 obtained in step 4 of example 1 was reacted with tetrahydropyran-4-ol to prepare compound 15.
  • step 5 of example 1 compound 17 was prepared by reacting compound 1-4 obtained in step 4 of example 1 with (R)-2-butanol.
  • step 5 of example 1 compound 18 was prepared by reacting compound 1-4 obtained in step 4 of example 1 with (S)-2-butanol.
  • step 5 of example 1 compound 20 was prepared by reacting compound 1-4 obtained in step 4 of example 1 with 3-pentanol.
  • step 1
  • step 1 of Example 21 compound 22 was prepared by reacting compound 1-4 obtained in step 4 of Example 1 with 3-methyl-3-pentanol.
  • step 1 of example 21 compound 23 was prepared by reacting compound 1-4 obtained in step 4 of example 1 with 3-ethyl-3-pentanol.
  • step 1 of example 21 compound 24 was prepared by reacting compound 1-4 obtained in step 4 of example 1 with 1-methylcyclobutanol.
  • step 1 of Example 21 compound 25 was prepared by reacting compound 1-4 obtained in step 4 of Example 1 with 1-methylcyclopentanol.
  • step 3 of Example 1 compound 26-1 was prepared by reacting compound 1-2 obtained in step 2 of Example 1 with 4-isothiocyanato-2-(trifluoromethyl)benzonitrile.
  • step 4 of Example 1 compound 26-2 was obtained by using compound 26-1 prepared in the previous step.
  • compound 26 was prepared by reacting compound 26-2 obtained in the previous step with 2-methyl-2-butanol.
  • test compounds were dissolved in DMSO to prepare a 15 mM solution, and then serially diluted 3-fold 10 times to prepare 15 mM, 5 mM, 1.6667 mM, 0.5576 mM, 0.1852 mM, 0.0617 mM, 0.0206 mM, 0.0069 mM, 0.0023 mM and 0.0008 mM solutions.
  • HEK293T cells (ATCC, CRL-3216) were cultured according to ATCC recommendations (https://www.atcc.org/). Cells were tested when they were in the exponential growth phase.
  • Plasmids (pGL4.36[luc2P/MMTV/Hygro], Promega, E1360; pBIND-AR Vector, Pharmaron; LTX&Plus Reagent, Invitrogen, 15338-100) was transfected into HEK293T cells and cultured at 37°C and 5% CO2 for 5-6 h.
  • HEK293T cells were seeded into a 384-well assay plate (25 ⁇ l) at 15,000 cells/well and a final concentration of 1 nM DHT (MCE, HY-A0120).
  • the cells were cultured at 37°C and 5% CO 2 for 18-20 hours.
  • Example IC 50 ( ⁇ M) 1 2.375 2 1.695 3 1.784 4 3.041 5 7.416 6 7.473 7 >10 8 >10 9 >10 10 >10 11 1.282 12 0.873 13 4.240 14 2.011 15 0.790 16 0.778 17 1.032 18 0.508 19 1.527 20 1.238 twenty one 0.871 twenty two 1.236 twenty three 2.141 twenty four 1.185 25 0.819 26 0.904 Enzalutamide 0.776 Enzalutamide >30
  • Preparation of incubation solution Add 10 mL of 0.02 M phosphate buffered saline (PBS) with a pH of 7.4 into 9.8 mL of DMSO. Cool in an ice bath and vortex for 30 seconds to prepare the incubation solution.
  • PBS phosphate buffered saline
  • the test compound was prepared into a 10mM stock solution with DMSO.
  • the test compound was diluted to 2mM with DMSO.
  • 15 ⁇ L of 2mM test compound solution was added to 1485 ⁇ L incubation solution, vortexed for 30s and allowed to stand at room temperature.
  • the test compound was prepared into a 10mM storage solution with DMSO.
  • the test compound was diluted to a 2mM working solution with DMSO.
  • 10 ⁇ L of 2mM working solution was added to 990 ⁇ L rat plasma, vortexed for 5s, and configured into a reaction system with an initial concentration of 20 ⁇ M.
  • Incubated at 37°C, 80 ⁇ L of plasma samples were taken at 0min, 10min, 20min, 30min, 1h, 2h, 4h and 6h.
  • the compounds provided by the present invention are extremely unstable in plasma. Most of the compounds can be almost completely degraded into inactive metabolites - enzalutamide after 5 minutes of plasma incubation, and the prototype compound cannot be detected at all after 15 minutes. Therefore, the compounds of the present invention are rapidly inactivated after entering the blood and cannot be distributed throughout the body, thereby failing to cause systemic androgen antagonism. Therefore, they will not cause side effects such as decreased libido, decreased sperm production, ED, etc., and can effectively solve the problem that existing drugs such as finasteride are systemically distributed, resulting in systemic androgen inhibition causing side effects such as decreased libido, decreased sperm production, ED, etc.
  • Some compounds of the present invention have a long half-life and good stability in skin homogenate and are slowly degraded into inactive metabolites such as enzalutamide.
  • mice with no damage to the back skin and pink skin color were selected and randomly divided into: blank control group and model combination treatment group.
  • Blank control group soybean oil was intraperitoneally injected every 2 days, and 20 ⁇ L of acetone was applied to the hair removal area twice a day;
  • Model group dihydrotestosterone soybean oil solution was intraperitoneally injected every 2 days at a dose of 1 mg/kg, and 20 ⁇ L of acetone was applied to the hair removal area twice a day;
  • Treatment group dihydrotestosterone soybean oil solution was intraperitoneally injected every 2 days at a dose of 1 mg/kg, and 20 ⁇ L of 5% (w/v) acetone solution of Example 16 was applied to the hair removal area twice a day.
  • the scoring system used for mouse hair growth is:
  • Example 16 has the effect of promoting hair growth.
  • mice with no damage to the back skin and pink skin color were selected and randomly divided into: blank control group and model combination treatment group, 6 mice in each group.
  • the present invention provides a locally acting androgen receptor antagonist and its application ideas and methods. There are many methods and ways to implement the technical solution. The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as the protection scope of the present invention. All components not specified in this embodiment can be implemented by existing technologies.

Landscapes

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

Abstract

公开了一种局部作用的雄激素受体拮抗剂及其应用，所述雄激素受体拮抗剂为式(I)所示的化合物，或其立体异构体，或其药学上可接受的盐；所提供的化合物的皮肤稳定性较好，代谢慢，发挥抗雄激素脱发作用，但在血浆内稳定性极差，可定向、快速代谢为非活性代谢产物恩杂鲁胺酸，避免全身性分布导致的全身雄激素拮抗副作用。同时，所提供的化合物经皮给药在小鼠脱发模型上表现出促毛发生长作用。

Description

一种局部作用的雄激素受体拮抗剂及其应用 技术领域
本发明涉及新的取代的硫代咪唑烷酮化合物作为局部作用的雄激素受体拮抗剂，以及包含这类化合物的药物组合物，用于治疗雄激素受体相关疾病或病症，如雄激素性脱发和痤疮。
背景技术
雄激素性脱发(AGA)，又被称为脂溢性脱发、早秃，分为男性型脱发和女性型脱发，是临床上最常见的非瘢痕脱发。AGA主要发生在青春期后期，以毛囊间进行萎缩为特征。该病在男性患者中主要表现为发际线后移或头顶毛发减少和变细；女性患者则主要表现为头顶部毛发减少与变细，少数患者表现为弥漫性头发变稀而发际线未受影响。2010年流行病调查显示，AGA在我国男性患病率为21.3％，女性为6.0％，其中有家族史的男性占29.7％，女性占19.2％。中国男性脱发发病率不断提高，并出现低龄化趋势，中青年成了“脱发大军”的主力。60％的男性在25岁前开始脱发，在30岁前开始脱发的比例近84％。Qi J，Ho CH等人报道，50％的男性与女性正遭受不同程度AGA的影响。雄激素性脱发常发于17～20岁的男青年，30岁左右为发病高峰，以后随年龄的增加，虽然发病率减少，但症状加重，最后变为全秃。虽然AGA对患者的身体健康不产生影响，但其影响着患者的心理健康和生活质量，严重者可导致患者抑郁、焦虑、人际关系紧张和敏感等。
雄激素性脱发是一种雄激素依赖的多基因遗传性疾病，自1942年Hamilton Norwood首次提出AGA的发生与雄激素有关，此后国内外学者对AGA的研究主要集中在头皮部的雄激素及其代谢酶。然而至今本病的确切病因及发病机制尚未明确。有学者发现，该病的发病率还与种族、民族、年龄、性别、生活环境、生活习惯、精神心理因素及病菌感染(糠秕孢子菌、痤疮棒状杆菌等)等因素有关。近年来，AGA发病率不断提高，并表现出低龄化。因此急切需要进行治疗。
男性的雄激素主要由睾丸合成，包括睾酮、二氢睾酮(DHT)、雄烯二酮(DHEA)及脱氢异雄酮(ASD)等。女性的雄激素则主要来源于肾上腺皮质。睾酮和雄烯二酮可被5α-还原酶还原成DHT，而DHT对雄激素受体(AR)的亲和力是睾酮的5+倍。人体有两种5α-还原酶同工酶：5α-还原酶I和5α-还原酶II。其中，5α-还原酶I主要分布于皮脂腺与肝脏；5α-还原酶II主要分布在头皮毛囊、附睾、输精管、精囊、前列腺及胎儿生殖器皮肤。研究表明，头皮毛囊是雄激素的靶器官之一。取男性AGA患者头发活检标本，可见头顶部脱发区5α-还原酶活性明显高于枕部非脱发区。另外也有研究表明头顶部脱发区毛囊AR高表达，从而加速了该区域的脱发。DHT具有强AR亲和力，其与AR结合后进入细胞核内，抑制毛囊的腺苷酸环化酶，减少环苷酸及相关蛋白的合成，使毛发提前进入休止期。并抑制毛囊的生长，使毛囊缩小，刺激皮脂腺的增生与油脂分泌，进一步使毛囊体积减小并逐渐消失进而促进毛发的脱落。
目前AGA患者众多，但针对AGA的药物仍很少，目前仅非那雄胺与米诺地尔被批准上市，用于治疗AGA，其他多数药物为超适应症应用。现有AGA疗法有效，但也带来诸多副作用，如非那雄胺的男性性功能障碍、米诺地尔的丙二醇过敏和直立性低血压等。这些副作用限制了对应药物在临床上的使用。因此，临床上仍亟需局部有效、避免系统性分布、副作用低、使用方便的AGA药物。
发明内容
发明目的：本发明所要解决的技术问题是针对现有技术的不足，提供一种式(I)所示的化合物，或其立体异构体，或其药学上可接受的盐。
本发明还要解决的技术问题是提供一种含有上述化合物，或其立体异构体，或其药学上可接受的盐的组合物。
本发明进一步要解决的技术问题是提供上述化合物，或其立体异构体，或其药学上可接受的盐，或上述组合物的应用。
本发明更进一步要解决的技术问题是提供了一种预防哺乳动物由雄激素或雄激素受体活性介导的疾病或病症、降低哺乳动物由雄激素或雄激素受体活性介导的疾病或病症进展、治疗哺乳动物由雄激素或雄激素受体介导的疾病或病症的方法。
为了解决上述第一个技术问题，本发明公开了式(I)所示的化合物，或其立体异构体，或其药学上可接受的盐，
Figure PCTCN2022141920-appb-000001
其中：
R 1选自取代的乙基、取代或非取代的正丙基、取代或非取代的正丁基、取代或非取代的异丁基、取代或非取代的仲丁基、取代或非取代的C 5～C 10烷基、取代或非取代的烯基、取代或非取代的炔基、取代或非取代的-(CH 2) n-环烷基、取代或非取代的-(CH 2) n-杂环烷基、取代或非取代的-CH(R 7)OC(O)OR 8或取代或非取代的-CH(R 7)OC(O)NH(R 8)；其中所述取代的乙基中，所述取代为被一个或多个羟基、巯基、氰基、卤素、烷氧基、环烷基、杂环烷基或NR 4(R 5)取代；其中所述取代的正丙基、取代的正丁基、取代的异丁基、取代的仲丁基、取代的C 5～C 10烷基、取代的烯基、取代的炔基、取代的-(CH 2) n-环烷基、取代的-(CH 2) n-杂环烷基、取代的-CH(R 7)OC(O)OR 8或取代的-CH(R 7)OC(O)NH(R 8)中，所述取代为被一个或多个氢、氘、卤素、羟基、巯基、氰基、烷基、烷氧基、环烷基、杂环烷基或NR 4(R 5)取代；
R 4、R 5、R 7、R 8各自独立地选自氢或C 1～C 8烷基；
n选自0、1、2、3、4、5或6；
R 2、R 3各自独立地选自氰基、硝基、烷基、卤代烷基、羟基、巯基、卤素、C 1～C 8烷氧基或C 1～C 8卤代烷氧基；
X、Y各自独立地选N或CR 6；
R 6选自氢、卤素、C 1～C 8烷基、环烷基或杂环基。
在一些实施方案中，R 1选自取代的乙基、取代或非取代的正丙基、取代或非取代的正丁基、取代或非取代的异丁基、取代或非取代的仲丁基、取代或非取代的C 5～C 8烷基、取代或非取代的C 2～C 8烯基、取代或非取代的C 2～C 8炔基、取代或非取代的-(CH 2) n-3～8元环烷基、取代或非取代的-(CH 2) n-3～8元杂环烷基、取代或非取代的-CH(R 7)OC(O)OR 8或取代或非取代的-CH(R 7)OC(O)NH(R 8)；其中所述取代的乙基中，所述取代为被一个或多个羟基、巯基、氰基、卤素、烷氧基、环烷基、杂环烷基或NR 4(R 5)取代；所述取代的正丙基、取代的正丁基、取代的异丁基、取代的仲丁基、取代的C 5～C 8烷基、取代的C 2～C 8烯基、取代的C 2～C 8炔基、取代的-(CH 2) n-3～8元环烷基、取代的-(CH 2) n-3～8元杂环烷基、取代的-CH(R 7)OC(O)OR 8或取代的-CH(R 7)OC(O)NH(R 8)中，所述取代为被一 个或多个氢、氘、卤素、羟基、巯基、氰基、烷基、烷氧基、环烷基、杂环烷基或NR 4(R 5)取代；其中R 4、R 5、R 7、R 8各自独立地选自氢或C 1～C 8烷基。
在一些实施方案中，R 1选自取代的乙基、取代或非取代的正丙基、取代或非取代的正丁基、取代或非取代的异丁基、取代或非取代的仲丁基、取代或非取代的C 5～C 6烷基、取代或非取代的C 2～C 6烯基、取代或非取代的C 2～C 6炔基、取代或非取代的-(CH 2) n-3～6元环烷基、取代或非取代的-(CH 2) n-3～6元杂环烷基、取代或非取代的-CH(R 7)OC(O)OR 8或取代或非取代的-CH(R 7)OC(O)NH(R 8)；其中所述取代的乙基中，所述取代为被一个或多个羟基、巯基、氰基、卤素、烷氧基、环烷基、杂环烷基或NR 4(R 5)取代；所述取代的正丙基、取代的正丁基、取代的异丁基、取代的仲丁基、取代的C 5～C 6烷基、取代的C 2～C 6烯基、取代的C 2～C 6炔基、取代的-(CH 2) n-3～6元环烷基、取代的-(CH 2) n-3～6元杂环烷基、取代的-CH(R 7)OC(O)OR 8或取代的-CH(R 7)OC(O)NH(R 8)中，所述取代为被一个或多个氢、氘、卤素、羟基、巯基、氰基、烷基、烷氧基、环烷基、杂环烷基或NR 4(R 5)取代；其中R 4、R 5、R 7、R 8各自独立地选自氢或C 1～C 8烷基。
在一些实施方案中，R 1选自取代的乙基、取代或非取代的正丙基、取代或非取代的正丁基、取代或非取代的异丁基、取代或非取代的仲丁基、取代或非取代的C 5～C 6烷基、取代或非取代的C 2～C 4烯基、取代或非取代的C 2～C 4炔基、取代或非取代的-(CH 2) n-3～6元环烷基、取代或非取代的-(CH 2) n-3～6元杂环烷基、取代或非取代的-CH(R 7)OC(O)OR 8或取代或非取代的-CH(R 7)OC(O)NH(R 8)；其中所述取代的乙基中，所述取代为被一个或多个羟基、巯基、氰基、卤素、烷氧基、环烷基、杂环烷基或NR 4(R 5)取代；所述取代的正丙基、取代的正丁基、取代的异丁基、取代的仲丁基、取代的C 5～C 6烷基、取代的C 2～C 4烯基、取代的C 2～C 4炔基、取代的-(CH 2) n-3～6元环烷基、取代的-(CH 2) n-3～6元杂环烷基、取代的-CH(R 7)OC(O)OR 8或取代的-CH(R 7)OC(O)NH(R 8)中，所述取代为被一个或多个氢、氘、卤素、羟基、巯基、氰基、烷基、烷氧基、环烷基、杂环烷基或NR 4(R 5)取代；其中R 4、R 5、R 7、R 8各自独立地选自氢或C 1～C 8烷基。
在一些实施方案中，R 1选自取代的乙基、取代或非取代的正丙基、取代或非取代的正丁基、取代或非取代的异丁基、取代或非取代的仲丁基、取代或非取代的C 5～C 6烷基、取代或非取代的C 2～C 4烯基、取代或非取代的C 2～C 4炔基、取代或非取代的-(CH 2) n-3～6元环烷基、取代或非取代的-(CH 2) n-3～6元杂环烷基、取代或非取代的-CH(R 7)OC(O)OR 8或取代或非取代的-CH(R 7)OC(O)NH(R 8)；其中所述取代的乙基中，所述取代为被一个或多个羟基、卤素、C 1～C 4烷氧基、3～6元环烷基、3～6元杂环烷基或NR 4(R 5)取代；所述取代的正丙基、取代的正丁基、取代的异丁基、取代的仲丁基、取代的C 5～C 6烷基、取代的C 2～C 4烯基、取代的C 2～C 4炔基、取代的-(CH 2) n-3～6元环烷基、取代的-(CH 2) n-3～6元杂环烷基、取代的-CH(R 7)OC(O)OR 8或取代的-CH(R 7)OC(O)NH(R 8)中，所述取代为被一个或多个氢、氘、卤素、羟基、氰基、C 1～C 4烷基、C 1～C 4烷氧基、3～6元环烷基、3～6元杂环烷基或NR 4(R 5)取代；其中R 4、R 5、R 7、R 8各自独立地选自氢或C 1～C 8烷基。
在一些实施方案中，R 1选自取代的乙基、取代或非取代的正丙基、取代或非取代的正丁基、取代或非取代的异丁基、取代或非取代的仲丁基、取代或非取代的烯丙基、取代或非取代的炔丙基、取代或非取代的环丙基、取代或非取代的
Figure PCTCN2022141920-appb-000002
取代或非取代的
Figure PCTCN2022141920-appb-000003
取代或非取代的
Figure PCTCN2022141920-appb-000004
取代或非取代的
Figure PCTCN2022141920-appb-000005
取代或非取代的
Figure PCTCN2022141920-appb-000006
取代或非取代的
Figure PCTCN2022141920-appb-000007
取代或非取代的
Figure PCTCN2022141920-appb-000008
取代或非取代的
Figure PCTCN2022141920-appb-000009
取代或非取代的
Figure PCTCN2022141920-appb-000010
取代或非取代的
Figure PCTCN2022141920-appb-000011
取代或非取代的
Figure PCTCN2022141920-appb-000012
取代或非取代的
Figure PCTCN2022141920-appb-000013
取代或非取代的
Figure PCTCN2022141920-appb-000014
取代或非取代的
Figure PCTCN2022141920-appb-000015
取代或非取代的
Figure PCTCN2022141920-appb-000016
或取代或非取代的
Figure PCTCN2022141920-appb-000017
其中所述取代的乙基中，所述取代为被一个或多个羟基、卤素、C 1～C 4烷氧基、3～6元环烷基、3～6元杂环烷基或NR 4(R 5)取代，所述取代的正丙基、取代的正丁基、取代的异丁基、取代的仲丁基、取代的环丙基、取代的
Figure PCTCN2022141920-appb-000018
取代的
Figure PCTCN2022141920-appb-000019
取代的
Figure PCTCN2022141920-appb-000020
取代的
Figure PCTCN2022141920-appb-000021
取代的
Figure PCTCN2022141920-appb-000022
取代的
Figure PCTCN2022141920-appb-000023
取代的
Figure PCTCN2022141920-appb-000024
取代的
Figure PCTCN2022141920-appb-000025
取代的
Figure PCTCN2022141920-appb-000026
取代的
Figure PCTCN2022141920-appb-000027
取代的
Figure PCTCN2022141920-appb-000028
取代的
Figure PCTCN2022141920-appb-000029
取代的
Figure PCTCN2022141920-appb-000030
取代的
Figure PCTCN2022141920-appb-000031
取代的
Figure PCTCN2022141920-appb-000032
或取代的
Figure PCTCN2022141920-appb-000033
中，所述取代为一个或多个氢、氘、卤素、羟基、氰基、C 1～C 4烷基、C 1～C 4烷氧基、3～6元环烷基、3～6元杂环烷基或NR 4(R 5)取代；其中R 4、R 5、R 8各自独立地选自氢或C 1～C 8烷基。
在一些实施方案中，R 1选自正丙基、正丁基、异丁基、烯丙基、炔丙基、环丙基、
Figure PCTCN2022141920-appb-000034
在一些实施方案中，R 1选自
Figure PCTCN2022141920-appb-000035
在一些实施方案中，R 7、R 8各自独立地选自氢或C 1～C 6烷基。
在一些实施方案中，R 7、R 8各自独立地选自氢或C 1～C 4烷基。
在一些实施方案中，R 7、R 8各自独立地选自氢、甲基、乙基或异丙基。
在一些实施方案中，R 7选自氢、甲基或异丙基。
在一些实施方案中，R 8选甲基、乙基或异丙基。
在一些实施方案中，n选自0、1、2、3或4。
在一些实施方案中，n选自0、1或2。
在一些实施方案中，R 4、R 5各自独立的选自氢或C 1～C 6烷基。
在一些实施方案中，R 4、R 5各自独立的选自氢或C 1～C 4烷基。
在一些实施方案中，R 4、R 5各自独立的选自氢、甲基或乙基。
在一些实施方案中，R 2、R 3各自独立地选自氰基、硝基、C 1～C 4烷基、卤代C 1～C 4烷基、羟基、巯基、卤素、C 1～C 4烷氧基或卤代C 1～C 4烷氧基。
在一些实施方案中，R 2、R 3各自独立地选自C 1～C 4烷基、卤代C 1～C 4烷基、C 1～C 4烷氧基、羟基、巯基、氰基、卤素。
在一些实施方案中，R 2、R 3各自独立地选自氰基、甲基、三氟甲基、氟或氯。
在一些实施方案中，R 2、R 3各自独立地选自氰基、三氟甲基、氟或氯。
在一些实施方案中，R 2选自氰基、R 3选自三氟甲基。
在一些实施方案中，X、Y各自独立地选N或CR 6。
在一些实施方案中，X、Y均选自CR 6。
在一些实施方案中，R 6选自氢、卤素、C 1～C 8烷基、环烷基或杂环基；在一些实施方案中，R 6选自氢、卤素、C 1～C 4烷基、3～6元环烷基或3～6元杂环基；在一些实施方案中，R 6选自氢或卤素；在一些实施方案中，R 6选自氢、氟或氯；在一些实施方案中，R 6选自氢或氟。
在一些实施方案中，X选自CH。
在一些实施方案中，Y选自CF。
在一些实施方案中，式(I)所示的化合物为式(II)所述化合物，
Figure PCTCN2022141920-appb-000036
其中：
R 1选自取代的乙基、取代或非取代的正丙基、取代或非取代的正丁基、取代或非取代的异丁基、取代或非取代的仲丁基、取代或非取代的C 5～C 10烷基、取代或非取代的烯基、取代或非取代的炔基、取代或非取代的-(CH 2) n-环烷基、取代或非取代的-(CH 2) n-杂环烷基、取代或非取代的-CH(R 7)OC(O)OR 8或取代或非取代的-CH(R 7)OC(O)NH(R 8)；其中所述取代的乙基中，所述取代为被一个或多个羟基、巯基、氰基、卤素、烷氧基、环烷基、杂环烷基或NR 4(R 5)取代；其中所述取代的正丙基、取代的正丁基、取代的异丁基、取代的仲丁基、取代的C 5～C 10烷基、取代的烯基、取代的炔基、取代的-(CH 2) n-环烷基、取代的-(CH 2) n-杂环烷基、取代的-CH(R 7)OC(O)OR 8或取代的-CH(R 7)OC(O)NH(R 8)中，所述取代为被一个或多个氢、氘、卤素、羟基、巯基、氰基、烷基、烷氧基、环烷基、杂环烷基或NR 4(R 5)取代；
R 4、R 5、R 7、R 8各自独立地选自氢或C 1～C 8烷基；
n选自0、1、2、3、4、5或6；
R 2、R 3各自独立地选自氰基、硝基、烷基、卤代烷基、羟基、巯基、卤素、C 1～C 8烷氧基或C 1～C 8卤代烷氧基；
R 6选自氢、卤素、C 1～C 8烷基、环烷基或杂环基。
在一些实施方案中，R 1选自取代的乙基、取代或非取代的正丙基、取代或非取代的正丁基、取代或非取代的异丁基、取代或非取代的仲丁基、取代或非取代的C 5～C 8烷基、取代或非取代的C 2～C 8烯基、取代或非取代的C 2～C 8炔基、取代或非取代的-(CH 2) n-3～8元环烷基、取代或非取代的-(CH 2) n-3～8元杂环烷基、取代或非取代的-CH(R 7)OC(O)OR 8或取代或非取代的-CH(R 7)OC(O)NH(R 8)；其中所述取代的乙基中，所述取代为被一个或多个羟基、巯基、氰基、卤素、烷氧基、环烷基、杂环烷基或NR 4(R 5)取代；所述取代的正丙基、取代的正丁基、取代的异丁基、取代的仲丁基、取代的C 5～C 8烷基、取代的C 2～C 8烯基、取代的C 2～C 8炔基、取代的-(CH 2) n-3～8元环烷基、取代的-(CH 2) n-3～8元杂环烷基、取代的-CH(R 7)OC(O)OR 8或取代的-CH(R 7)OC(O)NH(R 8)中，所述取代为被一个或多个氢、氘、卤素、羟基、巯基、氰基、烷基、烷氧基、环烷基、杂环烷基或NR 4(R 5)取代；其中R 4、R 5、R 7、R 8各自独立地选自氢或C 1～C 8烷基。
在一些实施方案中，R 1选自取代的乙基、取代或非取代的正丙基、取代或非取代的正丁基、取代或非取代的异丁基、取代或非取代的仲丁基、取代或非取代的C 5～C 6烷基、取代或非取代的C 2～C 6烯基、取代或非取代的C 2～C 6炔基、取代或非取代的-(CH 2) n-3～6元环烷基、取代或非取代的-(CH 2) n-3～6元杂环烷基、取代或非取代的-CH(R 7)OC(O)OR 8或取代或非取代的-CH(R 7)OC(O)NH(R 8)；其中所述取代的乙基中，所述取代为被一个或多个羟基、巯基、氰基、卤素、烷氧基、环烷基、杂环烷基或NR 4(R 5)取代；所述取代的正丙基、取代的正丁基、取代的异丁基、取代的仲丁基、取代的C 5～C 6烷基、取代的C 2～C 6烯基、取代的C 2～C 6炔基、取代的-(CH 2) n-3～6元环烷基、取代的-(CH 2) n-3～6元杂环烷基、取代的-CH(R 7)OC(O)OR 8或取代的-CH(R 7)OC(O)NH(R 8)中，所述取代为被一个或多个氢、氘、卤素、羟基、巯基、氰基、烷基、烷氧基、环烷基、杂环烷基或NR 4(R 5)取代；其中R 4、R 5、R 7、R 8各自独立地选自氢或C 1～C 8烷基。
在一些实施方案中，R 1选自取代的乙基、取代或非取代的正丙基、取代或非取代的正丁基、取代或非取代的异丁基、取代或非取代的仲丁基、取代或非取代的C 5～C 6烷基、取代或非取代的C 2～C 4烯基、取代或非取代的C 2～C 4炔基、取代或非取代的-(CH 2) n-3～6元环烷基、取代或非取代的-(CH 2) n-3～6元杂环烷基、取代或非取代的-CH(R 7)OC(O)OR 8或取代或非取代的-CH(R 7)OC(O)NH(R 8)；其中所述取代的乙基中，所述取代为被一个或多个羟基、巯基、氰基、卤素、烷氧基、环烷基、杂环烷基或NR 4(R 5)取代；所述取代的正丙基、取代的正丁基、取代的异丁基、取代的仲丁基、取代的C 5～C 6烷基、取代的C 2～C 4烯基、取代的C 2～C 4炔基、取代的-(CH 2) n-3～6元环烷基、取代的-(CH 2) n-3～6元杂环烷基、取代的-CH(R 7)OC(O)OR 8或取代的-CH(R 7)OC(O)NH(R 8)中，所述取代为被一个或多个氢、氘、卤素、羟基、巯基、氰基、烷基、烷氧基、环烷基、杂环烷基或NR 4(R 5)取代；其中R 4、R 5、R 7、R 8各自独立地选自氢或C 1～C 8烷基。
在一些实施方案中，R 1选自取代的乙基、取代或非取代的正丙基、取代或非取代的正丁基、取代或非取代的异丁基、取代或非取代的仲丁基、取代或非取代的C 5～C 6烷基、取代或非取代的C 2～C 4烯基、取代或非取代的C 2～C 4炔基、取代或非取代的-(CH 2) n-3～6元环烷基、取代或非取代的-(CH 2) n-3～6元杂环烷基、取代或非取代的-CH(R 7)OC(O)OR 8或取代或非取代的-CH(R 7)OC(O)NH(R 8)；其中所述取代的乙基中，所述取代为被一个或多个羟基、卤素、C 1～C 4烷氧基、3～6元环烷基、3～6元杂环烷基或NR 4(R 5)取代；所述 取代的正丙基、取代的正丁基、取代的异丁基、取代的仲丁基、取代的C 5～C 6烷基、取代的C 2～C 4烯基、取代的C 2～C 4炔基、取代的-(CH 2) n-3～6元环烷基、取代的-(CH 2) n-3～6元杂环烷基、取代的-CH(R 7)OC(O)OR 8或取代的-CH(R 7)OC(O)NH(R 8)中，所述取代为被一个或多个氢、氘、卤素、羟基、氰基、C 1～C 4烷基、C 1～C 4烷氧基、3～6元环烷基、3～6元杂环烷基或NR 4(R 5)取代；其中R 4、R 5、R 7、R 8各自独立地选自氢或C 1～C 8烷基。
在一些实施方案中，R 1选自取代的乙基、取代或非取代的正丙基、取代或非取代的正丁基、取代或非取代的异丁基、取代或非取代的仲丁基、取代或非取代的烯丙基、取代或非取代的炔丙基、取代或非取代的环丙基、取代或非取代的
Figure PCTCN2022141920-appb-000037
取代或非取代的
Figure PCTCN2022141920-appb-000038
取代或非取代的
Figure PCTCN2022141920-appb-000039
取代或非取代的
Figure PCTCN2022141920-appb-000040
取代或非取代的
Figure PCTCN2022141920-appb-000041
取代或非取代的
Figure PCTCN2022141920-appb-000042
取代或非取代的
Figure PCTCN2022141920-appb-000043
取代或非取代的
Figure PCTCN2022141920-appb-000044
取代或非取代的
Figure PCTCN2022141920-appb-000045
取代或非取代的
Figure PCTCN2022141920-appb-000046
取代或非取代的
Figure PCTCN2022141920-appb-000047
取代或非取代的
Figure PCTCN2022141920-appb-000048
取代或非取代的
Figure PCTCN2022141920-appb-000049
取代或非取代的
Figure PCTCN2022141920-appb-000050
取代或非取代的
Figure PCTCN2022141920-appb-000051
或取代或非取代的
Figure PCTCN2022141920-appb-000052
其中所述取代的乙基中，所述取代为被一个或多个羟基、卤素、C 1～C 4烷氧基、3～6元环烷基、3～6元杂环烷基或NR 4(R 5)取代，所述取代的正丙基、取代的正丁基、取代的异丁基、取代的仲丁基、取代的环丙基、取代的
Figure PCTCN2022141920-appb-000053
取代的
Figure PCTCN2022141920-appb-000054
取代的
Figure PCTCN2022141920-appb-000055
取代的
Figure PCTCN2022141920-appb-000056
取代的
Figure PCTCN2022141920-appb-000057
取代的
Figure PCTCN2022141920-appb-000058
取代的
Figure PCTCN2022141920-appb-000059
取代的
Figure PCTCN2022141920-appb-000060
取代的
Figure PCTCN2022141920-appb-000061
取代的
Figure PCTCN2022141920-appb-000062
取代的
Figure PCTCN2022141920-appb-000063
取代的
Figure PCTCN2022141920-appb-000064
取代的
Figure PCTCN2022141920-appb-000065
取代的
Figure PCTCN2022141920-appb-000066
取代的
Figure PCTCN2022141920-appb-000067
或取代的
Figure PCTCN2022141920-appb-000068
中，所述取代为一个或多个氢、氘、卤素、羟基、氰基、C 1～C 4烷基、C 1～C 4烷氧基、3～6元环烷基、3～6元杂环烷基或NR 4(R 5)取代；其中R 4、R 5、R 8各自独立地选自氢或C 1～C 8烷基。
在一些实施方案中，R 1选自正丙基、正丁基、异丁基、烯丙基、炔丙基、环丙基、
Figure PCTCN2022141920-appb-000069
Figure PCTCN2022141920-appb-000070
在一些实施方案中，R 1选自
Figure PCTCN2022141920-appb-000071
在一些实施方案中，R 7、R 8各自独立地选自氢或C 1～C 6烷基。
在一些实施方案中，R 7、R 8各自独立地选自氢或C 1～C 4烷基。
在一些实施方案中，R 7、R 8各自独立地选自氢、甲基、乙基或异丙基。
在一些实施方案中，R 7选自氢、甲基或异丙基。
在一些实施方案中，R 8选甲基、乙基或异丙基。
在一些实施方案中，n选自0、1、2、3或4。
在一些实施方案中，n选自0、1或2。
在一些实施方案中，R 4、R 5各自独立的选自氢或C 1～C 6烷基。
在一些实施方案中，R 4、R 5各自独立的选自氢或C 1～C 4烷基。
在一些实施方案中，R 4、R 5各自独立的选自氢、甲基或乙基。
在一些实施方案中，R 2、R 3各自独立地选自氰基、硝基、C 1～C 4烷基、卤代C 1～C 4烷基、羟基、巯基、卤素、C 1～C 4烷氧基或卤代C 1～C 4烷氧基。
在一些实施方案中，R 2、R 3各自独立地选自C 1～C 4烷基、卤代C 1～C 4烷基、C 1～C 4烷氧基、羟基、巯基、氰基、卤素。
在一些实施方案中，R 2、R 3各自独立地选自氰基、甲基、三氟甲基、氟或氯。
在一些实施方案中，R 2、R 3各自独立地选自氰基、三氟甲基、氟或氯。
在一些实施方案中，R 2选自氰基、R 3选自三氟甲基。
在一些实施方案中，R 6选自氢、卤素、C 1～C 8烷基、环烷基或杂环基。
在一些实施方案中，R 6选自氢、卤素、C 1～C 4烷基、3～6元环烷基或3～6元杂环基。
在一些实施方案中，R 6选自氢或卤素；在一些实施方案中，R 6选自氢、氟或氯。
在一些实施方案中，R 6选自氢或氟。
在一些实施方案中，式(I)所示的化合物为式(III)所述化合物，
Figure PCTCN2022141920-appb-000072
其中：
R 1选自取代的乙基、取代或非取代的正丙基、取代或非取代的正丁基、取代或非取代的异丁基、取代或非取代的仲丁基、取代或非取代的C 5～C 10烷基、取代或非取代的烯 基、取代或非取代的炔基、取代或非取代的-(CH 2) n-环烷基、取代或非取代的-(CH 2) n-杂环烷基、取代或非取代的-CH(R 7)OC(O)OR 8或取代或非取代的-CH(R 7)OC(O)NH(R 8)；其中所述取代的乙基中，所述取代为被一个或多个羟基、巯基、氰基、卤素、烷氧基、环烷基、杂环烷基或NR 4(R 5)取代；其中所述取代的正丙基、取代的正丁基、取代的异丁基、取代的仲丁基、取代的C 5～C 10烷基、取代的烯基、取代的炔基、取代的-(CH 2) n-环烷基、取代的-(CH 2) n-杂环烷基、取代的-CH(R 7)OC(O)OR 8或取代的-CH(R 7)OC(O)NH(R 8)中，所述取代为被一个或多个氢、氘、卤素、羟基、巯基、氰基、烷基、烷氧基、环烷基、杂环烷基或NR 4(R 5)取代；R 4、R 5、R 7、R 8各自独立地选自氢或C 1～C 8烷基；n选自0、1、2、3、4、5或6。
在一些实施方案中，R 1选自取代的乙基、取代或非取代的正丙基、取代或非取代的正丁基、取代或非取代的异丁基、取代或非取代的仲丁基、取代或非取代的C 5～C 8烷基、取代或非取代的C 2～C 8烯基、取代或非取代的C 2～C 8炔基、取代或非取代的-(CH 2) n-3～8元环烷基、取代或非取代的-(CH 2) n-3～8元杂环烷基、取代或非取代的-CH(R 7)OC(O)OR 8或取代或非取代的-CH(R 7)OC(O)NH(R 8)；其中所述取代的乙基中，所述取代为被一个或多个羟基、巯基、氰基、卤素、烷氧基、环烷基、杂环烷基或NR 4(R 5)取代；所述取代的正丙基、取代的正丁基、取代的异丁基、取代的仲丁基、取代的C 5～C 8烷基、取代的C 2～C 8烯基、取代的C 2～C 8炔基、取代的-(CH 2) n-3～8元环烷基、取代的-(CH 2) n-3～8元杂环烷基、取代的-CH(R 7)OC(O)OR 8或取代的-CH(R 7)OC(O)NH(R 8)中，所述取代为被一个或多个氢、氘、卤素、羟基、巯基、氰基、烷基、烷氧基、环烷基、杂环烷基或NR 4(R 5)取代；其中R 4、R 5、R 7、R 8各自独立地选自氢或C 1～C 8烷基。
在一些实施方案中，R 1选自取代的乙基、取代或非取代的正丙基、取代或非取代的正丁基、取代或非取代的异丁基、取代或非取代的仲丁基、取代或非取代的C 5～C 6烷基、取代或非取代的C 2～C 6烯基、取代或非取代的C 2～C 6炔基、取代或非取代的-(CH 2) n-3～6元环烷基、取代或非取代的-(CH 2) n-3～6元杂环烷基、取代或非取代的-CH(R 7)OC(O)OR 8或取代或非取代的-CH(R 7)OC(O)NH(R 8)；其中所述取代的乙基中，所述取代为被一个或多个羟基、巯基、氰基、卤素、烷氧基、环烷基、杂环烷基或NR 4(R 5)取代；所述取代的正丙基、取代的正丁基、取代的异丁基、取代的仲丁基、取代的C 5～C 6烷基、取代的C 2～C 6烯基、取代的C 2～C 6炔基、取代的-(CH 2) n-3～6元环烷基、取代的-(CH 2) n-3～6元杂环烷基、取代的-CH(R 7)OC(O)OR 8或取代的-CH(R 7)OC(O)NH(R 8)中，所述取代为被一个或多个氢、氘、卤素、羟基、巯基、氰基、烷基、烷氧基、环烷基、杂环烷基或NR 4(R 5)取代；其中R 4、R 5、R 7、R 8各自独立地选自氢或C 1～C 8烷基。
在一些实施方案中，R 1选自取代的乙基、取代或非取代的正丙基、取代或非取代的正丁基、取代或非取代的异丁基、取代或非取代的仲丁基、取代或非取代的C 5～C 6烷基、取代或非取代的C 2～C 4烯基、取代或非取代的C 2～C 4炔基、取代或非取代的-(CH 2) n-3～6元环烷基、取代或非取代的-(CH 2) n-3～6元杂环烷基、取代或非取代的-CH(R 7)OC(O)OR 8或取代或非取代的-CH(R 7)OC(O)NH(R 8)；其中所述取代的乙基中，所述取代为被一个或多个羟基、巯基、氰基、卤素、烷氧基、环烷基、杂环烷基或NR 4(R 5)取代；所述取代的正丙基、取代的正丁基、取代的异丁基、取代的仲丁基、取代的C 5～C 6烷基、取代的C 2～C 4烯基、取代的C 2～C 4炔基、取代的-(CH 2) n-3～6元环烷基、取代的-(CH 2) n-3～6元杂环烷基、取代的-CH(R 7)OC(O)OR 8或取代的-CH(R 7)OC(O)NH(R 8)中，所述取代为被一个或多个氢、氘、卤素、羟基、巯基、氰基、烷基、烷氧基、环烷基、杂环烷基或NR 4(R 5)取代；其中R 4、R 5、R 7、R 8各自独立地选自氢或C 1～C 8烷基。
在一些实施方案中，R 1选自取代的乙基、取代或非取代的正丙基、取代或非取代的 正丁基、取代或非取代的异丁基、取代或非取代的仲丁基、取代或非取代的C 5～C 6烷基、取代或非取代的C 2～C 4烯基、取代或非取代的C 2～C 4炔基、取代或非取代的-(CH 2) n-3～6元环烷基、取代或非取代的-(CH 2) n-3～6元杂环烷基、取代或非取代的-CH(R 7)OC(O)OR 8或取代或非取代的-CH(R 7)OC(O)NH(R 8)；其中所述取代的乙基中，所述取代为被一个或多个羟基、卤素、C 1～C 4烷氧基、3～6元环烷基、3～6元杂环烷基或NR 4(R 5)取代；所述取代的正丙基、取代的正丁基、取代的异丁基、取代的仲丁基、取代的C 5～C 6烷基、取代的C 2～C 4烯基、取代的C 2～C 4炔基、取代的-(CH 2) n-3～6元环烷基、取代的-(CH 2) n-3～6元杂环烷基、取代的-CH(R 7)OC(O)OR 8或取代的-CH(R 7)OC(O)NH(R 8)中，所述取代为被一个或多个氢、氘、卤素、羟基、氰基、C 1～C 4烷基、C 1～C 4烷氧基、3～6元环烷基、3～6元杂环烷基或NR 4(R 5)取代；其中R 4、R 5、R 7、R 8各自独立地选自氢或C 1～C 8烷基。
在一些实施方案中，R 1选自取代的乙基、取代或非取代的正丙基、取代或非取代的正丁基、取代或非取代的异丁基、取代或非取代的仲丁基、取代或非取代的烯丙基、取代或非取代的炔丙基、取代或非取代的环丙基、取代或非取代的
Figure PCTCN2022141920-appb-000073
取代或非取代的
Figure PCTCN2022141920-appb-000074
取代或非取代的
Figure PCTCN2022141920-appb-000075
取代或非取代的
Figure PCTCN2022141920-appb-000076
取代或非取代的
Figure PCTCN2022141920-appb-000077
取代或非取代的
Figure PCTCN2022141920-appb-000078
取代或非取代的
Figure PCTCN2022141920-appb-000079
取代或非取代的
Figure PCTCN2022141920-appb-000080
取代或非取代的
Figure PCTCN2022141920-appb-000081
取代或非取代的
Figure PCTCN2022141920-appb-000082
取代或非取代的
Figure PCTCN2022141920-appb-000083
取代或非取代的
Figure PCTCN2022141920-appb-000084
取代或非取代的
Figure PCTCN2022141920-appb-000085
取代或非取代的
Figure PCTCN2022141920-appb-000086
取代或非取代的
Figure PCTCN2022141920-appb-000087
或取代或非取代的
Figure PCTCN2022141920-appb-000088
其中所述取代的乙基中，所述取代为被一个或多个羟基、卤素、C 1～C 4烷氧基、3～6元环烷基、3～6元杂环烷基或NR 4(R 5)取代，所述取代的正丙基、取代的正丁基、取代的异丁基、取代的仲丁基、取代的环丙基、取代的
Figure PCTCN2022141920-appb-000089
取代的
Figure PCTCN2022141920-appb-000090
取代的
Figure PCTCN2022141920-appb-000091
取代的
Figure PCTCN2022141920-appb-000092
取代的
Figure PCTCN2022141920-appb-000093
取代的
Figure PCTCN2022141920-appb-000094
取代的
Figure PCTCN2022141920-appb-000095
取代的
Figure PCTCN2022141920-appb-000096
取代的
Figure PCTCN2022141920-appb-000097
取代的
Figure PCTCN2022141920-appb-000098
取代的
Figure PCTCN2022141920-appb-000099
取代的
Figure PCTCN2022141920-appb-000100
取代的
Figure PCTCN2022141920-appb-000101
取代的
Figure PCTCN2022141920-appb-000102
取代的
Figure PCTCN2022141920-appb-000103
或取代的
Figure PCTCN2022141920-appb-000104
中，所述取代为一个或多个氢、氘、卤素、羟基、氰基、C 1～C 4烷基、C 1～C 4烷氧基、3～6元环烷基、3～6元杂环烷基或NR 4(R 5)取代；其中R 4、R 5、R 8各自独立地选自氢或C 1～C 8烷基。
在一些实施方案中，R 1选自正丙基、正丁基、异丁基、烯丙基、炔丙基、环丙基、
Figure PCTCN2022141920-appb-000105
在一些实施方案中，R 1选自
Figure PCTCN2022141920-appb-000106
在一些实施方案中，式(I)所示的化合物选自以下化合物：
Figure PCTCN2022141920-appb-000107
在一些实施方案中，式(I)所示的化合物选自以下化合物：
Figure PCTCN2022141920-appb-000108
在一些实施方案中，式(I)所示的化合物选自以下化合物：
Figure PCTCN2022141920-appb-000109
在一些实施方案中，式(I)所示的化合物选自以下化合物：
Figure PCTCN2022141920-appb-000110
为了解决上述第二个技术问题，本发明公开了一种药物组合物，其包括(i)上述第一个技术问题中所述的式(I)化合物或其立体异构体，或其药学上可接受的盐，和(ii)药学上可接受的载体、稀释剂或赋形剂。
为了解决上述第三个技术问题，本发明公开了上述第一个技术问题中所述的式(I)化合物或其立体异构体，或其药学上可接受的盐，或上述第二个技术问题中所述的药物组合物在制备用于预防雄激素或雄激素受体活性介导的疾病或病症、降低雄激素或雄激素受体活性介导的疾病或病症进展、或治疗雄激素或雄激素受体活性介导的疾病或病症的药物中的用途。
在一些实施方案中，所述雄激素或雄激素受体活性介导的疾病或病症选自前列腺癌、痤疮或脱发。
为了解决上述第四个技术问题，本发明公开了一种预防哺乳动物由雄激素或雄激素 受体活性介导的疾病或病症、降低哺乳动物由雄激素或雄激素受体活性介导的疾病或病症进展、治疗哺乳动物由雄激素或雄激素受体介导的疾病或病症的方法，包括对需要该治疗的哺乳动物给予治疗有效量的上述第一个技术问题中所述的式(I)化合物或其立体异构体，或其药学上可接受的盐，或上述第二个技术问题中所述的药物组合物。
在一些实施方案中，所述哺乳动物为人类。
除非另有说明，本申请中所用的下列术语具有下列含义。一个特定的术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照本领域普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
术语“被取代”是指特定原子上的任意一个或多个氢原子被取代基取代，只要特定原子的价态是正常的并且取代后的化合物是稳定的。
术语“任选”或“任选地”是指随后描述的事件或情况可以发生或不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。例如，乙基“任选”被卤素取代，指乙基可以是未被取代的(CH 2CH 3)、单取代的(如CH 2CH 2F)、多取代的(如CHFCH 2F、CH 2CHF 2等)或完全被取代的(CF 2CF 3)。本领域技术人员可理解，对于包含一个或多个取代基的任何基团，不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式。
本文中的C n～C m，是该部分具有给定范围中的整数个碳原子。例如“C 1～C 6”是指该基团可具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子或6个碳原子。例如C 1～C 3是指该基团可具有1个碳原子、2个碳原子、3个碳原子。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被2个R所取代，则每个R都有独立的选项。
当一个连接基团的数量为0时，比如-(CH2)0-，表示该连接基团为共价键。
当其中一个变量选自共价键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表共价键时表示该结构实际上是A-Z。
当一个取代基的键交叉连接到一个环上的两个原子时，这种取代基可以与这个环上的任意原子相键合。例如，结构单元
Figure PCTCN2022141920-appb-000111
表示其可在环己基或者环己二烯上的任意一个位置发生取代。
术语“卤”或“卤素”是指氟、氯、溴和碘。
术语“羟基”是指-OH基团。
术语“巯基”指-SH基团。
术语“氨基”是指-NH2基团。
术语“氰基”是指-CN基团。
术语“硝基”是指-NO 2基团。
术语“烷基”是指通式为C nH 2n+1的烃基。该烷基可以是直链或支链的。例如，术语“C 1-C 6烷基”指含有1至6个碳原子的烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、新戊基、己基、2-甲基戊基等)。类似地，烷氧基、烷基氨基、二烷基氨基、烷基磺酰基和烷硫基的烷基部分(即烷基)具有上述相同定义。又例如，术语“C 1-C 3烷基”指含有1至3个碳原子的烷基(例如甲基、乙基、丙基和异丙基)。
术语“烷氧基”是指通过氧桥连接的具有特定数目碳原子的上述烷基。C 1～C 6烷氧基 包括C 1、C 2、C 3、C 4、C 5和C 6的烷氧基。烷氧基的例子包括但不限于：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基和S-戊氧基。
术语“烯基”是指由碳原子和氢原子组成的直链或支链的具有至少一个双键的不饱和脂肪族烃基。烯基的非限制性实例包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、异丁烯基、1,3-丁二烯基等。
术语“炔基”是指由碳原子和氢原子组成的直链或支链的具有至少一个三键的不饱和脂肪族烃基。炔基的非限制性实例包括但不限于乙炔基(-C≡CH)、1-丙炔基(-C≡C-CH 3)、2-丙炔基(-CH 2-C≡CH)、1,3-丁二炔基(-C≡C-C≡CH)等。
术语“环烷基”指完全饱和的并且可以以呈单环、桥环或螺环存在的碳环。除非另有指示，该碳环通常为3至10元环。环烷基非限制性实例包括但不限于环丙基、环丁基、环戊基、环己基、降冰片基(双环[2.2.1]庚基)、双环[2.2.2]辛基、金刚烷基、二环[1.1.1]戊-1-基等。例如，C 3～C 4环烷基包括环丙基和环丁基。
术语“杂环基”是指完全饱和的或部分不饱和的(但不是完全不饱和的杂芳族)并且可以以单环、桥环或螺环存在的非芳族环。除非另有指示，该杂环通常为含有1至3个独立地选自硫、氧和/或氮的杂原子(优选1或2个杂原子)的3至10元环，或者4至6元环。杂环基的非限制性实例包括但不限于环氧乙烷基、四氢呋喃基、二氢呋喃基、3,4-二氢吡喃基、3,6-二氢吡喃基、吡咯烷基、N-甲基吡咯烷基、二氢吡咯基、哌啶基、哌嗪基、吡唑烷基、4H-吡喃基、吗啉基、硫代吗啉基、四氢噻吩基、2-氧杂-7-氮杂螺[3.5]壬烷基、2-氧杂-6-氮杂螺[3.3]庚烷基等。
术语“杂环烷基”是指完全饱和的并且可以以单环、桥环或螺环存在的环状基团。除非另有指示，该杂环通常为含有1至3个独立地选自硫、氧和/或氮的杂原子(优选1或2个杂原子)的3至10元环，或者4至6元环。3元杂环烷基的实例包括但不限于环氧乙烷基、环硫乙烷基、环氮乙烷基，4元杂环烷基的非限制性实例包括但不限于吖丁啶基、噁丁环基、噻丁环基、氧杂环丁烷基，5元杂环烷基的实例包括但不限于四氢呋喃基、四氢噻吩基、吡咯烷基、异噁唑烷基、噁唑烷基、异噻唑烷基、噻唑烷基、咪唑烷基、四氢吡唑基、四氢呋喃基，6元杂环烷基的实例包括但不限于哌啶基、四氢吡喃基、四氢噻喃基、吗啉基、哌嗪基、1,4-噻噁烷基、1,4-二氧六环基、硫代吗啉基、1,3-二噻烷基、1,4-二噻烷基，7元杂环烷基的实例包括但不限于氮杂环庚烷基、氧杂环庚烷基、硫杂环庚烷基。优选为具有5或6个环原子的单环杂环烷基。
术语“治疗”意为将本申请所述化合物或制剂进行给药以改善或消除疾病或与所述疾病相关的一个或多个症状，且包括：
i.抑制疾病或疾病状态，即遏制其发展；
ii.缓解疾病或疾病状态，即使该疾病或疾病状态消退。
术语“预防”意为将本申请所述化合物或制剂进行给药以预防疾病或与所述疾病相关的一个或多个症状，且包括：预防疾病或疾病状态在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病状态，但尚未被诊断为已患有该疾病状态时。
术语“治疗有效量”意指(i)治疗或预防特定疾病、病况或障碍，(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状，或(iii)预防或延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作的本申请化合物的用量。构成“治疗有效量”的本申请化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。
术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在 可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本申请化合物的盐，由本申请发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本申请的化合物中含有相对酸性的功能团时，可以通过合适的碱与这类化合物的中性形式接触的方式获得碱加成盐。当本申请的化合物中含有相对碱性的官能团时，可以通过合适的酸与这类化合物的中性形式接触的方式获得酸加成盐。本申请的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
术语“药物组合物”是指一种或多种本申请的化合物或其盐与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对有机体给予本申请的化合物。
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。
词语“包括(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising应理解为开放的、非排他性的意义，即“包括但不限于”。
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
除非另有说明，“(D)”或者“(+)”表示右旋，“(L)”或者“(-)”表示左旋，“(DL)”或者“(±)”表示外消旋。
除非另有说明，用楔形实线键
Figure PCTCN2022141920-appb-000112
和楔形虚线键
Figure PCTCN2022141920-appb-000113
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2022141920-appb-000114
和直形虚线键
Figure PCTCN2022141920-appb-000115
表示立体中心的相对构型，用波浪线
Figure PCTCN2022141920-appb-000116
表示楔形实线键
Figure PCTCN2022141920-appb-000117
或楔形虚线键
Figure PCTCN2022141920-appb-000118
或用波浪线
Figure PCTCN2022141920-appb-000119
表示直形实线键
Figure PCTCN2022141920-appb-000120
和直形虚线键
Figure PCTCN2022141920-appb-000121
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚(3H)，碘-125(125 I)或C-14(14C)。又例如，可用重氢取代氢形成氘代药物，比如d3-甲基表示甲基上的三个氢原子全部被氘原子取代，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药 物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
本申请还包括与本文中记载的那些相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本申请化合物。可结合到本申请化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、31P、32P、35S、18F、123I、125I和36Cl等。
某些同位素标记的本申请化合物(例如用3H及14C标记的那些)可用于化合物和/或底物组织分布分析中。氚化(即3H)和碳-14(即14C)同位素对于由于它们易于制备和可检测性是尤其优选的。正电子发射同位素，诸如15O、13N、11C和18F可用于正电子发射断层扫描(PET)研究以测定底物占有率。通常可以通过与公开于下文的方案和/或实施例中的那些类似的下列程序，通过同位素标记试剂取代未经同位素标记的试剂来制备同位素标记的本申请化合物。
此外，用较重同位素(诸如氘(即 2H))取代可以提供某些由更高的代谢稳定性产生的治疗优点(例如增加的体内半衰期或降低的剂量需求)，并且因此在某些情形下可能是优选的，其中氘取代可以是部分或完全的，部分氘取代是指至少一个氢被至少一个氘取代，所有这样的形式的化合物包含于本申请的范围内。
本申请化合物可以是不对称的，例如，具有一个或多个立体异构体。除非另有说明，所有立体异构体都包括，如对映异构体和非对映异构体。本申请的含有不对称碳原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。
本申请的药物组合物可通过将本申请的化合物与适宜的药学上可接受的辅料组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。
给予本申请化合物或其药学上可接受的盐或其药物组合物的典型途径包括但不限于口服、直肠、局部、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。
本申请的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。
本申请化合物的治疗剂量可根据例如以下而定：治疗的具体用途、给予化合物的方式、患者的健康和状态，以及签处方医师的判断。本申请化合物在药用组合物中的比例或浓度可不固定，取决于多种因素，它们包括剂量、化学特性(例如疏水性)和给药途径。例如可通过含约0.1～10％w/v该化合物的生理缓冲水溶液提供本申请化合物，用于肠胃外给药。某些典型剂量范围为约1μg/kg～约1g/kg体重/日。在某些实施方案中，剂量范围为约0.01mg/kg～约100mg/kg体重/日。剂量很可能取决于此类变量，如疾病或病症的种类和发展程度、具体患者的一般健康状态、所选择的化合物的相对生物学效力、赋形剂制剂及其给药途径。可通过由体外或动物模型试验系统导出的剂量-反应曲线外推，得到有效剂量。
本申请的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本申请的实施例。
本申请具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本申请的化学变化及其所需的试剂和物料。为了获得本申请的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
有益效果：与现有技术相比，本发明具有如下优势：
本申请的化合物、其立体异构体及其药学上可接受的盐为局部作用的雄激素拮抗剂。同时化合物的皮肤稳定性较好，代谢慢，发挥抗雄激素脱发作用，但在血浆内稳定性极差，可定向、快速代谢为非活性代谢产物恩杂鲁胺酸(CAS:1242137-15-0)，避免全身性分布导致的全身雄激素拮抗副作用。所提供的化合物经皮给药在小鼠脱发模型上表现出促毛发生长作用。
附图说明
下面结合附图和具体实施方式对本发明做更进一步的具体说明，本发明的上述和/或其他方面的优点将会变得更加清楚。
图1为C57BL/6小鼠毛发生长评分。
图2为小鼠毛发生长情况(应用实施例5)。
图3为第26天小鼠毛发生长情况图以及体重与毛发覆盖率变化曲线图(应用实施例6)。
具体实施方式
为清楚起见，进一步用实施例来阐述本发明，但是实施例并非限制本申请的范围。对本领域的技术人员而言，在不脱离本发明精神和范围的情况下，针对本发明具体实施方式进行各种变化和改进将是显而易见的。本申请所使用的所有试剂是市售的，无需进一步纯化即可使用。
实施例1：4-(3-(4-氰基-3-(三氟甲基)苯基)-5,5-二甲基-4-氧代-2-硫代咪唑烷-1-基)-2-氟苯甲酸丙酯(化合物1)的制备
Figure PCTCN2022141920-appb-000122
步骤1：化合物1-1的合成
250mL三颈瓶中加入150mLN,N-二甲基甲酰胺和15mL水，依次加入2-氟-4-溴苯甲酸10g、2-甲基丙氨酸7.25g、碳酸钾15.8g、碘化亚铜1.7g、2-乙酰基环己酮1.2g和三乙胺0.8g。110℃加热搅拌反应6h，加入500mL水稀释，用柠檬酸调pH至3-4。用乙酸乙酯萃取3次，合并有机相，用饱和食盐水洗涤3次。有机相经无水硫酸钠干燥后浓缩，所得固体粗品中加入50mL二氯甲烷，室温搅拌1h后过滤，滤饼用二氯甲烷洗涤。收集并干燥滤饼，得9.3g化合物1-1。
步骤2：化合物1-2的合成
250mL三颈瓶中加入100mL甲醇和13g上述步骤1制备的化合物1-1，搅拌溶解后冰浴降温。在冰浴条件下缓慢滴加氯化亚砜25.6g，滴加完毕后加热回流反应。待反应完 毕后，关闭加热，待冷至室温后加入50mL甲苯，减压浓缩。所得残渣用300mL乙酸乙酯复溶，用饱和食盐水洗涤1次，接着用饱和碳酸氢钠水溶液洗涤3次。有机相用无水硫酸钠干燥后浓缩，得11.3g化合物1-2。
步骤3：化合物1-3的合成
50mL三颈瓶中依次加入5mL二甲亚砜、10mL醋酸异丙酯、5g上述步骤2制备的化合物1-2和8.9g 4-异硫氰基-2-(三氟甲基)苯甲腈，90℃加热搅拌反应20h。关闭加热，自然冷至室温，反应液中加入50mL水稀释，用乙酸乙酯萃取3次。合并有机相，用饱和食盐水洗涤3次，有机相经无水硫酸钠干燥后浓缩。所得油状物加入35mL甲醇并室温搅拌2h。过滤，收集滤饼并干燥，的5.8g化合物1-3。
步骤4：化合物1-4的合成
将3.8g上述步骤3制备的化合物1-3溶于15mL四氢呋喃中，加入溶有0.68g氢氧化钠的水溶液15mL，室温搅拌反应过夜。反应完毕后，加入50mL水稀释，用1M稀盐酸调pH至3-4后，用乙酸乙酯萃取3次。合并有机相用无水硫酸钠干燥，浓缩有机相得3.0g化合物1-4。
步骤5：化合物1的合成
25mL圆底烧瓶中加入0.2g上述步骤4制备的化合物1-4和5mL正丙醇，冰浴条件下滴加0.158g氯化亚砜，滴加完毕后撤除冰浴，加热至45℃搅拌反应6h。减压浓缩，所得油状物用30mL乙酸乙酯复溶，用饱和食盐水洗涤3次。有机相用无水硫酸钠干燥后浓缩，所得粗品经柱层析纯化得0.18g白色固体。
1H NMR(400MHz,Chloroform-d)δ8.15(t,J＝8.0Hz,1H),8.02(d,J＝8.3Hz,1H),7.97(s,1H),7.85(d,J＝8.3Hz,1H),7.25–7.15(m,2H),4.37(t,J＝6.6Hz,2H),1.90–1.77(m,2H),1.64(s,6H),1.07(t,J＝7.4Hz,3H).
MS(ESI,[M+H] +)m/z:494.2.
实施例2：4-(3-(4-氰基-3-(三氟甲基)苯基)-5,5-二甲基-4-氧代-2-硫代咪唑烷-1-基)-2-氟苯甲酸丁酯(化合物2)的制备
Figure PCTCN2022141920-appb-000123
参照实施例1步骤5的方法，使用实施例1步骤4所得化合物1-4与正丁醇反应制备得到化合物2。
1H NMR(400MHz,Chloroform-d)δ8.14(t,J＝8.0Hz,1H),8.02(d,J＝8.3Hz,1H),7.97(s,1H),7.85(dd,J＝8.3,1.7Hz,1H),7.26–7.15(m,2H),4.41(t,J＝6.6Hz,2H),1.86–1.73(m,2H),1.64(s,6H),1.56–1.47(m,2H),1.01(t,J＝7.4Hz,3H).
MS(ESI,[M+H] +)m/z:508.7.
实施例3：4-(3-(4-氰基-3-(三氟甲基)苯基)-5,5-二甲基-4-氧代-2-硫代咪唑烷-1-基)-2-氟苯甲酸异丁酯(化合物3)的制备
Figure PCTCN2022141920-appb-000124
参照实施例1步骤5的方法，使用实施例1步骤4所得化合物1-4与新丁醇反应制备得到化合物3。
1H NMR(400MHz,Chloroform-d)δ8.15(t,J＝8.0Hz,1H),8.02(d,J＝8.3Hz,1H),7.98(s,1H),7.86(d,J＝8.1Hz,1H),7.27–7.15(m,2H),4.19(d,J＝6.4Hz,2H),2.19–2.06(m,1H),1.64(s,6H),1.06(d,J＝6.7Hz,6H).
MS(ESI,[M+H] +)m/z:508.2.
实施例4：4-(3-(4-氰基-3-(三氟甲基)苯基)-5,5-二甲基-4-氧代-2-硫代咪唑烷-1-基)-2-氟苯甲酸环丙基甲基酯(化合物4)的制备
Figure PCTCN2022141920-appb-000125
参照实施例1步骤5的方法，使用实施例1步骤4所得化合物1-4与环丙基甲醇反应制备得到化合物4。
1H NMR(400MHz,Chloroform-d)δ8.16(t,J＝8.0Hz,1H),8.03–7.96(m,2H),7.85(d,J＝8.1Hz,1H),7.27–7.15(m,2H),4.25(d,J＝7.2Hz,2H),1.66(s,6H),1.35-1.30(m,1H),0.67(d,J＝7.9Hz,2H),0.42(d,J＝5.0Hz,2H).
MS(ESI,[M+H] +)m/z:506.1.
实施例5：4-(3-(4-氰基-3-(三氟甲基)苯基)-5,5-二甲基-4-氧代-2-硫代咪唑烷-1-基)-2-氟苯甲酸环丙基酯(化合物5)的制备
Figure PCTCN2022141920-appb-000126
参照实施例1步骤5的方法，使用实施例1步骤4所得化合物1-4与环丙醇反应制备得到化合物5。
1H NMR(400MHz,Chloroform-d)δ8.11(t,J＝8.0Hz,1H),8.01(d,J＝8.3Hz,1H),7.97(s,1H),7.85(d,J＝8.2Hz,1H),7.25–7.13(m,2H),4.51–4.40(m,1H),1.63(s,6H),0.93–0.81(m,4H).
MS(ESI,[M+H] +)m/z:492.3.
实施例6：(R)-2,3-二羟基丙基4-(3-(4-氰基-3-(三氟甲基)苯基)-5,5-二甲基-4-氧代-2-硫氧基咪唑烷-1-基)-2-氟苯甲酸酯(化合物6)的制备
Figure PCTCN2022141920-appb-000127
步骤1：化合物6-1的制备
25mL圆底烧瓶中依次加入5mL醋酸异丙酯、0.15g实施例1步骤4所得化合物1-4、1mL氯化亚砜，80℃加热搅拌反应2h，停止加热。反应液冷至室温后浓缩，所得残渣用5mL醋酸异丙酯复溶，加入0.19g二异丙基乙基胺和0.08g(S)-甘油缩丙酮，室温搅拌反应 过夜。反应完毕后，加入20mL乙酸乙酯稀释，用饱和食盐水洗涤3次。有机相用无水硫酸钠干燥后浓缩，所得油状粗品经柱层析纯化得0.13g化合物6-1。
MS(ESI,[M+H] +)m/z:566.2.
步骤2：化合物6的制备
25mL圆底烧瓶中加入0.13g上述步骤1得到的化合物6-1、5mL二氯甲烷和0.5mL三氟醋酸，室温搅拌2h。浓缩反应液，所得油状物经柱层析纯化得97mg化合物6。
1H NMR(400MHz,Chloroform-d)δ8.17(t,J＝8.0Hz,1H),8.02(d,J＝8.3Hz,1H),7.97(s,1H),7.85(d,J＝7.8Hz,1H),7.27–7.15(m,2H),4.54(dd,J＝11.5,4.5Hz,1H),4.47(dd,J＝11.5,6.0Hz,1H),4.17–4.09(m,1H),3.85(dd,J＝11.4,3.8Hz,1H),3.76(dd,J＝11.3,5.7Hz,1H),1.64(s,6H).
MS(ESI,[M+H] +)m/z:526.4.
实施例7：4-(3-(4-氰基-3-(三氟甲基)苯基)-5,5-二甲基-4-氧代-2-硫氧基咪唑烷-1-基)-2-氟苯甲酸(S)-2,3-二羟基丙基酯(化合物7)的制备
Figure PCTCN2022141920-appb-000128
步骤1：化合物7-1的制备
参照实施例6步骤1的方法，使用实施例1步骤4所得化合物1-4与(R)-甘油缩丙酮反应制备得到化合物7-1。
MS(ESI,[M+H] +)m/z:566.2.
步骤2：化合物7的制备
参照实施例6步骤1的方法，使用上述步骤1所得化合物7-1与三氟醋酸反应制备得到化合物7。
1H NMR(400MHz,Chloroform-d)δ8.17(t,J＝8.0Hz,1H),8.02(d,J＝8.4Hz,1H),7.97(s,1H),7.85(d,J＝8.3Hz,1H),7.27–7.16(m,2H),4.54(dd,J＝11.5,4.4Hz,1H),4.47(dd,J＝11.3,6.2Hz,1H),4.22–4.07(m,1H),3.85(dd,J＝11.4,3.6Hz,1H),3.76(dd,J＝11.2,5.6Hz,1H),1.65(s,6H).
MS(ESI,[M+H] +)m/z:526.6.
实施例8：4-(3-(4-氰基-3-(三氟甲基)苯基)-5,5-二甲基-4-氧代-2-硫氧基咪唑烷-1-基)-2-氟苯甲酸2-(二甲氨基)乙基酯(化合物8)的制备
Figure PCTCN2022141920-appb-000129
参照实施例6步骤1的方法，使用实施例1步骤4所得化合物1-4与N,N-二甲基乙醇胺反应制备得到化合物8。
1H NMR(400MHz,Chloroform-d)δ8.14(t,J＝8.0Hz,1H),8.02(d,J＝8.3Hz,1H),7.97(d,J＝1.9Hz,1H),7.85(dd,J＝8.3,2.0Hz,1H),7.24–7.14(m,2H),4.50(t,J＝5.7Hz,2H),2.75(t,J＝5.7Hz,2H),2.36(s,6H),1.63(s,6H).
MS(ESI,[M+H] +)m/z:523.3.
实施例9：4-(3-(4-氰基-3-(三氟甲基)苯基)-5,5-二甲基-4-氧代-2-硫氧基咪唑烷-1- 基)-2-氟苯甲酸2-(二乙氨基)乙基酯(化合物9)的制备
Figure PCTCN2022141920-appb-000130
参照实施例6步骤1的方法，使用实施例1步骤4所得化合物1-4与N,N-二乙基乙醇胺反应制备得到化合物9。
1H NMR(400MHz,Chloroform-d)δ8.14(t,J＝8.0Hz,1H),8.02(d,J＝8.3Hz,1H),7.97(d,J＝2.0Hz,1H),7.85(dd,J＝8.3,2.0Hz,1H),7.26–7.13(m,2H),4.46(t,J＝6.2Hz,2H),2.88(t,J＝6.2Hz,2H),2.66(q,J＝7.1Hz,4H),1.64(s,6H),1.09(t,J＝7.1Hz,6H).
MS(ESI,[M+H] +)m/z:551.2.
实施例10：4-(3-(4-氰基-3-(三氟甲基)苯基)-5,5-二甲基-4-氧代-2-硫氧基咪唑-1-基)-2-氟苯甲酸2-吗啉乙基酯(化合物10)的制备
Figure PCTCN2022141920-appb-000131
参照实施例6步骤1的方法，使用实施例1步骤4所得化合物1-4与N-羟乙基吗啉反应制备得到化合物10。
1H NMR(400MHz,Chloroform-d)δ8.14(t,J＝8.0Hz,1H),8.02(d,J＝8.3Hz,1H),7.97(s,1H),7.85(dd,J＝8.3,2.0Hz,1H),7.25–7.12(m,2H),4.54(t,J＝5.7Hz,2H),3.75(t,J＝4.7Hz,4H),2.80(t,J＝5.7Hz,2H),2.60(t,J＝4.6Hz,4H),1.64(s,6H).
MS(ESI,[M+H] +)m/z:565.1.
实施例11：(S)-四氢呋喃-3-基4-(3-(4-氰基-3-(三氟甲基)苯基)-5,5-二甲基-4-氧代-2-硫代咪唑啉-1-基)-2-氟苯甲酸酯(化合物11)的制备
Figure PCTCN2022141920-appb-000132
参照实施例1步骤5的方法，使用实施例1步骤4所得化合物1-4与(S)-3-羟基四氢呋喃反应制备得到化合物11。
1H NMR(400MHz,Chloroform-d)δ8.14(t,J＝8.0Hz,1H),8.02(d,J＝8.3Hz,1H),7.97(d,J＝2.0Hz,1H),7.85(dd,J＝8.3,2.1Hz,1H),7.26–7.14(m,2H),5.69–5.55(m,1H),4.13–3.90(m,4H),2.42–2.26(m,1H),2.25–2.15(m,1H),1.64(s,6H).
MS(ESI,[M+H] +)m/z:522.3.
实施例12：(R)-四氢呋喃-3-基4-(3-(4-氰基-3-(三氟甲基)苯基)-5,5-二甲基-4-氧代-2-硫代咪唑啉-1-基)-2-氟苯甲酸酯(化合物12)的制备
Figure PCTCN2022141920-appb-000133
参照实施例1步骤5的方法，使用实施例1步骤4所得化合物1-4与(R)-3-羟基四氢呋喃反应制备得到化合物12。
1H NMR(400MHz,Chloroform-d)δ8.14(t,J＝8.0Hz,1H),8.02(d,J＝8.3Hz,1H),7.97(d,J＝2.0Hz,1H),7.85(dd,J＝8.3,2.1Hz,1H),7.26–7.10(m,2H),5.62(ddt,J＝6.4,4.2,1.9Hz,1H),4.10–3.91(m,4H),2.40–2.26(m,1H),2.26–2.14(m,1H),1.64(s,6H).
MS(ESI,[M+H] +)m/z:522.3
实施例13：氧杂环丁烷-3-基4-(3-(4-氰基-3-(三氟甲基)苯基)-5,5-二甲基-4-氧代-2-硫代咪唑啉-1-基)-2-氟苯甲酸酯(化合物13)的制备
Figure PCTCN2022141920-appb-000134
参照实施例1步骤5的方法，使用实施例1步骤4所得化合物1-4与3-羟基氧杂环丁烷反应制备得到化合物13。
1H NMR(400MHz,Chloroform-d)δ8.18(t,J＝8.0Hz,1H),8.02(d,J＝8.3Hz,1H),7.97(d,J＝2.0Hz,1H),7.85(dd,J＝8.3,2.1Hz,1H),7.24(m,2H),5.80–5.69(m,1H),5.04(m,2H),4.88–4.78(m,2H),1.65(s,6H).
MS(ESI,[M+H] +)m/z:508.6
实施例14：(氧杂环丁烷-3-基)甲基4-(3-(4-氰基-3-(三氟甲基)苯基)-5,5-二甲基-4-氧代-2-硫代咪唑啉-1-基)-2-氟苯甲酸酯(化合物14)的制备
Figure PCTCN2022141920-appb-000135
参照实施例1步骤5的方法，使用实施例1步骤4所得化合物1-4与3-羟基甲基氧杂环丁烷反应制备得到化合物14。
1H NMR(400MHz,Chloroform-d)δ8.16(t,J＝8.0Hz,1H),8.02(d,J＝8.3Hz,1H),7.97(d,J＝2.0Hz,1H),7.85(dd,J＝8.2,2.1Hz,1H),7.25–7.13(m,2H),4.90(dd,J＝7.9,6.3Hz,2H),4.69–4.55(m,4H),3.55–3.39(m,1H),1.64(s,6H).
MS(ESI,[M+H] +)m/z:522.4
实施例15：四氢吡喃-4-基4-(3-(4-氰基-3-(三氟甲基)苯基)-5,5-二甲基-4-氧代-2-硫氧基咪唑烷-1-基)-2-氟苯甲酸酯(化合物15)的制备
Figure PCTCN2022141920-appb-000136
参照实施例1步骤5的方法，使用实施例1步骤4所得化合物1-4与四氢吡喃-4-醇反应制 备得到化合物15。
1H NMR(400MHz,Chloroform-d)δ8.15(t,J＝8.0Hz,1H),8.02(d,J＝8.2Hz,1H),7.97(d,J＝2.0Hz,1H),7.85(dd,J＝8.2,2.1Hz,1H),7.25-7.17(m,2H),5.39–5.21(m,1H),4.09–3.92(m,2H),3.74–3.61(m,2H),2.15–2.02(m,2H),1.94–1.79(m,2H),1.64(s,6H).
MS(ESI,[M+H] +)m/z:536.1
实施例16：4-(3-(4-氰基-3-(三氟甲基)苯基)-5,5-二甲基-4-氧代-2-硫代咪唑啉-1-基)-2-氟苯甲酸仲丁酯(化合物16)的制备
Figure PCTCN2022141920-appb-000137
25mL圆底烧瓶中依次加入0.2g实施例1步骤4所得化合物1-4、5mL N,N-二甲基甲酰胺、0.25g 2-碘丁烷和0.15g碳酸钾，60℃加热反应过夜。反应完毕后，撤去加热，冷却至室温，加入25mL水稀释反应液。有乙酸乙酯萃取(15mL×3)，合并有机相，用饱和食盐水洗涤(15mL×3)。有机相用无水硫酸钠干燥后浓缩，所得粗品经柱层析纯化得0.34g白色固体。
1H NMR(400MHz,Chloroform-d)δ8.13(t,J＝8.0Hz,1H),8.02(d,J＝8.3Hz,1H),7.97(d,J＝2.0Hz,1H),7.85(dd,J＝8.3,2.1Hz,1H),7.25–7.11(m,2H),5.25–5.11(m,1H),1.85–1.67(m,2H),1.64(s,6H),1.39(d,J＝6.3Hz,3H),1.02(t,J＝7.5Hz,3H).
MS(ESI,[M+H] +)m/z:508.4.
实施例17：(R)-4-(3-(4-氰基-3-(三氟甲基)苯基)-5,5-二甲基-4-氧代-2-硫代咪唑啉-1-基)-2-氟苯甲酸仲丁酯(化合物17)的制备
Figure PCTCN2022141920-appb-000138
参照实施例1步骤5的方法，使用实施例1步骤4所得化合物1-4与(R)-2-丁醇反应制备得到化合物17。
1H NMR(400MHz,Chloroform-d)δ8.14(t,J＝8.0Hz,1H),8.02(d,J＝8.3Hz,1H),7.97(d,J＝2.0Hz,1H),7.85(dd,J＝8.2,2.1Hz,1H),7.25–7.11(m,2H),5.25–5.11(m,1H),1.85–1.67(m,2H),1.65(s,6H),1.38(d,J＝6.4Hz,3H),1.01(t,J＝7.3Hz,3H).
MS(ESI,[M+H] +)m/z:508.3.
实施例18：(S)-4-(3-(4-氰基-3-(三氟甲基)苯基)-5,5-二甲基-4-氧代-2-硫代咪唑啉-1-基)-2-氟苯甲酸仲丁酯(化合物18)的制备
Figure PCTCN2022141920-appb-000139
参照实施例1步骤5的方法，使用实施例1步骤4所得化合物1-4与(S)-2-丁醇反应制备得到化合物18。
1H NMR(400MHz,Chloroform-d)δ8.13(t,J＝8.0Hz,1H),8.02(d,J＝8.3Hz,1H),7.97(d,J＝2.0Hz,1H),7.85(dd,J＝8.3,2.1Hz,1H),7.25–7.10(m,2H),5.25–5.11(m, 1H),1.85–1.67(m,2H),1.64(s,6H),1.39(d,J＝6.3Hz,3H),1.02(t,J＝7.5Hz,3H).
MS(ESI,[M+H] +)m/z:508.3.
实施例20：4-(3-(4-氰基-3-(三氟甲基)苯基)-5,5-二甲基-4-氧代-2-硫代咪唑啉-1-基)-2-氟苯甲酸戊-3-基酯(化合物20)的制备
Figure PCTCN2022141920-appb-000140
参照实施例1步骤5的方法，使用实施例1步骤4所得化合物1-4与3-戊醇反应制备得到化合物20。
1H NMR(600MHz,Chloroform-d)δ8.14(t,J＝8.0Hz,1H),8.02(d,J＝8.3Hz,1H),7.97(s,1H),7.88–7.82(m,1H),7.25–7.14(m,2H),5.10(p,J＝6.3Hz,1H),1.81–1.70(m,4H),1.64(s,6H),1.00(t,J＝7.4Hz,6H).
MS(ESI,[M+H] +)m/z:522.4.
实施例21：4-(3-(4-氰基-3-(三氟甲基)苯基)-5,5-二甲基-4-氧代-2-硫代咪唑啉-1-基)-2-氟苯甲酸-2-甲基丁基-2-酯(化合物21)的制备
Figure PCTCN2022141920-appb-000141
步骤1：
25mL圆底烧瓶中加入0.5g实施例1步骤4所得化合物1-4和4mL氯化亚砜，加热回流反应2h。浓缩后复溶于2mL无水四氢呋喃，冰水浴条件下滴加至3mL溶有0.29g 2-甲基-2-丁醇和0.34g三乙胺的无水四氢呋喃溶液中。滴加完毕后，室温搅拌反应1h。加入30mL乙酸乙酯，用饱和食盐水洗涤3次。有机相用无水硫酸钠干燥后浓缩，所得黄色油状物经柱层析纯化得0.43g白色固体目标产物。
1H NMR(600MHz,Chloroform-d)δ8.07(t,J＝8.0Hz,1H),8.01(d,J＝8.3Hz,1H),7.97(s,1H),7.85(d,J＝8.3Hz,1H),7.19(d,J＝8.4Hz,1H),7.15(d,J＝10.3Hz,1H),1.95(q,J＝7.4Hz,2H),1.63(s,6H),1.61(s,6H),1.01(t,J＝7.5Hz,3H).
MS(ESI,[M+H] +)m/z:522.6.
实施例22：4-(3-(4-氰基-3-(三氟甲基)苯基)-5,5-二甲基-4-氧代-2-硫代咪唑啉-1-基)-2-氟苯甲酸-3-甲基戊基-3-酯(化合物22)的制备
Figure PCTCN2022141920-appb-000142
参照实施例21步骤1的方法，使用实施例1步骤4所得化合物1-4与3-甲基-3-戊醇反应制备得到化合物22。
1H NMR(400MHz,Chloroform-d)δ8.07(t,J＝8.1Hz,1H),8.01(d,J＝8.3Hz,1H),7.97(d,J＝2.0Hz,1H),7.85(dd,J＝8.3,2.1Hz,1H),7.22–7.12(m,2H),2.12–2.00(m,2H),1.99–1.86(m,2H), 1.63(s,6H),1.57(s,3H),0.98(t,J＝7.5Hz,6H).
MS(ESI,[M+H] +)m/z:536.1.
实施例23：4-(3-(4-氰基-3-(三氟甲基)苯基)-5,5-二甲基-4-氧代-2-硫代咪唑啉-1-基)-2-氟苯甲酸-3-乙基戊基-3-酯(化合物23)的制备
Figure PCTCN2022141920-appb-000143
参照实施例21步骤1的方法，使用实施例1步骤4所得化合物1-4与3-乙基-3-戊醇反应制备得到化合物23。
1H NMR(400MHz,Chloroform-d)δ8.06(t,J＝8.0Hz,1H),8.02(d,J＝8.3Hz,1H),7.97(d,J＝2.0Hz,1H),7.86(dd,J＝8.2,1.9Hz,1H),7.22–7.11(m,2H),2.01(q,J＝7.5Hz,6H),1.64(s,6H),0.94(t,J＝7.5Hz,9H).
MS(ESI,[M+H] +)m/z:550.4.
实施例24：4-(3-(4-氰基-3-(三氟甲基)苯基)-5,5-二甲基-4-氧代-2-硫代咪唑啉-1-基)-2-氟苯甲酸-1-甲基环丁基酯(化合物24)的制备
Figure PCTCN2022141920-appb-000144
参照实施例21步骤1的方法，使用实施例1步骤4所得化合物1-4与1-甲基环丁醇反应制备得到化合物24。
1H NMR(400MHz,Chloroform-d)δ8.11(t,J＝8.0Hz,1H),8.01(d,J＝8.3Hz,1H),7.97(d,J＝2.0Hz,1H),7.85(dd,J＝8.3,2.1Hz,1H),7.24–7.13(m,2H),2.55–2.43(m,2H),2.35–2.25(m,2H),1.97–1.86(m,1H),1.83–1.73(m,1H),1.71(s,3H),1.63(s,6H).
MS(ESI,[M+H] +)m/z:520.4.
实施例25：4-(3-(4-氰基-3-(三氟甲基)苯基)-5,5-二甲基-4-氧代-2-硫代咪唑啉-1-基)-2-氟苯甲酸-1-甲基环戊酯(化合物25)的制备
Figure PCTCN2022141920-appb-000145
参照实施例21步骤1的方法，使用实施例1步骤4所得化合物1-4与1-甲基环戊醇反应制备得到化合物25。
1H NMR(400MHz,Chloroform-d)δ8.08(t,J＝8.1Hz,1H),8.01(d,J＝8.2Hz,1H),7.97(d,J＝2.0Hz,1H),7.85(dd,J＝8.3,2.1Hz,1H),7.17(m,2H),2.37–2.25(m,2H),1.89–1.78(m,4H),1.74(s,5H),1.65–1.60(m,6H).
MS(ESI,[M+H] +)m/z:534.1.
实施例26：4-(3-(4-氰基-3-氯苯基)-5,5-二甲基-4-氧代-2-硫代咪唑啉-1-基)-2-氟苯甲酸-2-甲基丁基-2-酯(化合物26)的制备
Figure PCTCN2022141920-appb-000146
步骤1：化合物26-1的合成
参照实施例1步骤3的方法，使用实施例1步骤2所得化合物1-2与4-异硫氰基-2-(三氟甲基)苯甲腈反应制备得到化合物26-1。
步骤2：化合物26-2的合成
参照实施例1步骤4的方法，使用上步制得的化合物26-1反应得到化合物26-2。
步骤3：化合物26的合成
参照实施例21步骤1的方法，使用上步所得化合物26-2与2-甲基-2-丁醇反应制备得到化合物26。
1H NMR(400MHz,Chloroform-d)δ8.07(t,J＝8.1Hz,1H),7.84(d,J＝8.4Hz,1H),7.70(d,J＝1.9Hz,1H),7.53(dd,J＝8.4,2.0Hz,1H),7.21–7.11(m,2H),1.94(q,J＝7.5Hz,2H),1.62–1.59(m,12H),1.01(t,J＝7.5Hz,3H).
MS(ESI,[M+H] +)m/z:488.4.应用实验例1：化合物对雄激素受体的拮抗活性
1)所有测试化合物溶于DMSO中配置成15mM溶液，并且3倍连续稀释10次，配置成15mM、5mM、1.6667mM、0.5576mM、0.1852mM、0.0617mM、0.0206mM、0.0069mM、0.0023mM和0.0008mM溶液。
2)按照ATCC的建议(https://www.atcc.org/)培养HEK293T细胞(ATCC，CRL-3216)。细胞在指数生长期时进行检测。
3)从培养皿中去除培养基，用磷酸盐缓冲液冲洗细胞，向培养皿中加入胰蛋白酶溶液，使细胞分离。用完全培养基清洗细胞一次。
4)使用磷酸盐缓冲液将细胞洗涤两次，以去除酚红，并将其重新悬浮在培养基中至适当浓度。
5)将6*10 6HEK293T细胞播种到100毫米的培养皿中(只有存活率大于90％的细胞才用于分析)，并在37℃、5％CO 2条件下培养16h。
6)将质粒(pGL4.36[luc2P/MMTV/Hygro]，Promega，E1360；pBIND-AR Vector，康龙化成；
Figure PCTCN2022141920-appb-000147
LTX&Plus Reagent，Invitrogen，15338-100)转染到HEK293T细胞中，并在37℃和5％CO 2条件下培养5-6h。
7)使用非接触式纳升级声波移液系统(Labcyte，Echo550)将50nl化合物稀释液转移到384孔分析板中。
8)将HEK293T细胞以15000个细胞/孔和1nM DHT(MCE，HY-A0120)终浓度接种到384孔的分析板中(25μl)。
9)细胞在37℃、5％CO 2条件下培养18-20小时。
10)将25μl荧光素酶分析试剂(britelite plus，PerkinElmer，6066769)加入384孔分析板的每个孔中。
11)使用酶标仪(Envision 2105，PerkinElmer)记录发光值，并计算IC 50。
表1.化合物对雄激素受体的拮抗活性
实施例 IC 50(μM)
1 2.375
2 1.695
3 1.784
4 3.041
5 7.416
6 7.473
7 >10
8 >10
9 >10
10 >10
11 1.282
12 0.873
13 4.240
14 2.011
15 0.790
16 0.778
17 1.032
18 0.508
19 1.527
20 1.238
21 0.871
22 1.236
23 2.141
24 1.185
25 0.819
26 0.904
恩杂鲁胺 0.776
恩杂鲁胺酸 >30
结果说明，本发申请的化合物具有雄激素受体拮抗活性。
其中，所述化合物19为
Figure PCTCN2022141920-appb-000148
应用实验例2：化学稳定性
温孵液配置：10mL 0.02M pH＝7.4的磷酸盐缓冲液(PBS)加入9.8mL DMSO中，冰浴降温后震荡涡旋30s，配置成温孵液。
待测化合物用DMSO配制成10mM的储存液。用DMSO将待测化合物稀释至2mM。取15μL 2mM的待测化合物溶液，加至1485μL温孵液中，涡旋30s后室温静置。于0h、2h、4h、6h、8h，取样300μL，14400rpm离心3min后，吸取200μL上清液，HPLC检测，计算浓度，并按照公式T 1/2＝-0.693/k计算半衰期。
表2.化学稳定性
实施例 半衰期
1 NA a
2 NA
3 NA
4 NA
5 NA
6 231h
10 77h
11 NA
12 NA
13 11.6h
14 57h
15 NA
16 NA
17 NA
18 NA
19 NA
20 NA
21 NA
22 NA
23 NA
24 NA
25 NA
恩杂鲁胺 NA
a 8h仍未观察到明显降解，无法拟合计算半衰期
结果显示，本发明化合物在pH7.4条件下稳定性较好。
应用实验例3：大鼠血浆稳定性
待测化合物用DMSO配制成10mM的储存液。用DMSO将待测化合物稀释至2mM工作液。取10μL 2mM工作液，加至990μL大鼠血浆中，涡旋5s，配置成初始浓度为20μM的反应体系，37℃温孵，并分别在0min、10min、20min、30min、1h、2h、4h和6h取80μL血浆样品。血浆样品中加入240μL甲醇，涡旋3min后14400rpm离心3min，吸取200μL上清液，HPLC检测，计算浓度，并按照公式T 1/2＝-0.693/k计算半衰期，结果如表3所示。
表3.大鼠血浆半衰期及降解产物
实施例 半衰期 降解产物
1 <5min 恩杂鲁胺酸
2 <5min 恩杂鲁胺酸
3 <5min 恩杂鲁胺酸
4 <5min 恩杂鲁胺酸
11 <5min 恩杂鲁胺酸
12 <5min 恩杂鲁胺酸
13 <5min 恩杂鲁胺酸
14 <5min 恩杂鲁胺酸
15 <5min 恩杂鲁胺酸
16 <5min 恩杂鲁胺酸
17 <5min 恩杂鲁胺酸
18 <5min 恩杂鲁胺酸
19 <5min 恩杂鲁胺酸
21 11.4min 恩杂鲁胺酸
25 13.2min 恩杂鲁胺酸
恩杂鲁胺 NA a 无
a 6h仍未观察到明显降解，无法拟合计算半衰期
结果显示，本发明所提供的化合物在血浆中极不稳定，大部分化合物在血浆温孵5min即可几乎全部降解为非活性代谢产物-恩杂鲁胺酸，15min完全不能检测到原型化合物，因此，本发明化合物进入血液后迅速失活，不能在全身分布，从而无法引起全身的雄激素拮抗作用，故而不会造成性欲降低、精子生成减少、ED等副作用，可有效解决现有药物如非那雄胺等药物系统性分布，导致全身性的雄激素抑制引起性欲降低、精子生成减少、ED等副作用的问题。
应用实验例4：小鼠10％皮肤匀浆液稳定性
1)待测化合物用DMSO配制成10mM的储存液，取20μL待测化合物储备液，加至80μL DMSO中，涡旋10s，配置成2mM工作液；
2)C57BL/6雄性小鼠(许可证号SCXK(豫)2020-0005)经脱毛膏对背部进行脱毛；
3)在麻醉状态下剥取背部皮肤，剔除血管、皮下组织和脂肪，并用预冷的生理盐水漂洗干净；
4)取2.3g皮肤，加至23mL预冷生理盐水中，在冰浴条件下充分匀浆(每匀浆15s，暂停10s)，5000rpm离心5min，吸取上清液，即皮肤组织匀浆液，置于冰上待用；
5)取皮肤组织匀浆液990μL，加入10μL 2mM待测化合物工作液，涡旋5s，并置于37℃水浴锅中，温孵，于0min、5min、10min、15min、30min、1h和2h分别取样80μL，加入240μL甲醇；
6)涡旋震荡3min后，13000rpm离心5min；
7)吸取上清液200μL，用HPLC进样分析，计算浓度，并按照公式T 1/2＝-0.693/k计算半衰期，结果如表4所示。
表4.小鼠10％皮肤匀浆液稳定性及降解产物
实施例 半衰期 降解产物
1 4.15min 恩杂鲁胺酸
2 4.33min 恩杂鲁胺酸
3 4.44min 恩杂鲁胺酸
4 3.59min 恩杂鲁胺酸
11 4.35min 恩杂鲁胺酸
12 4.79min 恩杂鲁胺酸
13 4.56min 恩杂鲁胺酸
15 12.00min 恩杂鲁胺酸
16 57.75min 恩杂鲁胺酸
17 51.34min 恩杂鲁胺酸
18 62.71min 恩杂鲁胺酸
19 4.03min 恩杂鲁胺酸
21 13.4h 恩杂鲁胺酸
25 11.9h 恩杂鲁胺酸
恩杂鲁胺 NA a 无
a 2h仍未观察到明显降解，无法拟合计算半衰期
本发明部分化合物在皮肤匀浆液中半衰期较长，稳定性较好。被缓慢降解为非活性代谢产物恩杂鲁胺酸。
应用实验例5：C57BL/6小鼠毛发生长模型
购买6至7周龄的雄性C57BL/6小鼠，并在标准条件下饲养于群笼中一周。通过在轻度麻醉下用电动剃须刀给下背部剃毛，后用脱毛膏脱去背部毛发，裸露皮肤约2cm×2cm，次日，挑选背部皮肤无破损，且皮肤颜色呈粉红色的小鼠进行随机分组，分为：空白对照组、模型组合治疗组。
空白对照组：每2日腹腔注射大豆油，并且每日两次在脱毛部位涂抹丙酮20μL；
模型组：每2日腹腔注射二氢睾酮的大豆油溶液，剂量为1mg/kg，并且每日两次在脱毛部位涂抹丙酮20μL；
治疗组：每2日腹腔注射二氢睾酮的大豆油溶液，剂量为1mg/kg，并且每日两次在脱毛部位涂抹5％(w/v)实施例16的丙酮溶液20μL。
每两天记录毛发生长评分。
用于小鼠毛发生长的评分系统为：
a)0：没有毛发生长，粉色肤色；
b)1：剃毛区域的肤色从粉色变为灰色，没有可见的毛发生长，表明毛生长期启动；
c)2：剃毛区域的肤色为黑色，有微小的毛发；
d)3：剃毛区域短的黑色毛发；
e)4：剃毛区域的毛发几乎接近周边区域。
毛发评分如图1所示，代表小鼠毛发生长情况如图2所示。结果显示：经12天的治疗，实施例16具有的促进毛发生长的作用。
应用实验例6：C57BL/6小鼠毛发生长模型2
购买6至7周龄的雄性C57BL/6小鼠，并在标准条件下饲养于群笼中一周。通过在轻度麻醉下用电动剃须刀给下背部剃毛，后用脱毛膏脱去背部毛发，裸露皮肤约2cm×2cm，次日，挑选背部皮肤无破损，且皮肤颜色呈粉红色的小鼠进行随机分组，分为：空白对照组、模型组合治疗组，每组6只。
空白对照组：每日皮下注射DMSO:甘油＝1:1(v/v)的混合溶剂，剂量为每20g体重100μL，并且每日两次再脱毛部位涂抹乙醇:DMSO＝75:25的混合溶剂20μL；
模型组：每日皮下注射二氢睾酮溶液(6mg/mL，溶剂为DMSO:甘油＝1:1(v/v))，剂量为30mg/kg，并且每日两次再脱毛部位涂抹乙醇:DMSO＝75:25的混合溶剂20μL；
治疗组：每日皮下注射二氢睾酮溶液(6mg/mL，溶剂为DMSO:甘油＝1:1(v/v))，剂量为30mg/kg，并且每日两次再脱毛部位涂抹5％(w/v)实施例16溶液20μL(溶剂 为乙醇:DMSO＝75:25的混合溶剂)
每2-3天称量体重，拍摄照片，并用Image J计算毛发覆盖率。用graphpad制作体重变化和毛发覆盖率变化曲线。结果如图3所示。
本发明提供了一种局部作用的雄激素受体拮抗剂及其应用的思路及方法，具体实现该技术方案的方法和途径很多，以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。本实施例中未明确的各组成部分均可用现有技术加以实现。

Claims (13)

  1. 式(I)所示的化合物，或其立体异构体，或其药学上可接受的盐，
    Figure PCTCN2022141920-appb-100001
    其中：
    R 1选自取代的乙基、取代或非取代的正丙基、取代或非取代的正丁基、取代或非取代的异丁基、取代或非取代的仲丁基、取代或非取代的C 5～C 10烷基、取代或非取代的烯基、取代或非取代的炔基、取代或非取代的-(CH 2) n-环烷基、取代或非取代的-(CH 2) n-杂环烷基、取代或非取代的-CH(R 7)OC(O)OR 8或取代或非取代的-CH(R 7)OC(O)NH(R 8)；其中所述取代的乙基中，所述取代为被一个或多个羟基、巯基、氰基、卤素、烷氧基、环烷基、杂环烷基或NR 4(R 5)取代；其中所述取代的正丙基、取代的正丁基、取代的异丁基、取代的仲丁基、取代的C 5～C 10烷基、取代的烯基、取代的炔基、取代的-(CH 2) n-环烷基、取代的-(CH 2) n-杂环烷基、取代的-CH(R 7)OC(O)OR 8或取代的-CH(R 7)OC(O)NH(R 8)中，所述取代为被一个或多个氢、氘、卤素、羟基、巯基、氰基、烷基、烷氧基、环烷基、杂环烷基或NR 4(R 5)取代；
    R 4、R 5、R 7、R 8各自独立地选自氢或C 1～C 8烷基；
    n选自0、1、2、3、4、5或6；
    R 2、R 3各自独立地选自氰基、硝基、烷基、卤代烷基、羟基、巯基、卤素、C 1～C 8烷氧基或C 1～C 8卤代烷氧基；
    X、Y各自独立地选N或CR 6；
    R 6选自氢、卤素、C 1～C 8烷基、环烷基或杂环基。
  2. 如权利要求1所述的式(I)所示的化合物，或其立体异构体，或其药学上可接受的盐，其特征在于，
    R 1选自取代的乙基、取代或非取代的正丙基、取代或非取代的正丁基、取代或非取代的异丁基、取代或非取代的仲丁基、取代或非取代的C 5～C 8烷基、取代或非取代的C 2～C 8烯基、取代或非取代的C 2～C 8炔基、取代或非取代的-(CH 2) n-3～8元环烷基、取代或非取代的-(CH 2) n-3～8元杂环烷基、取代或非取代的-CH(R 7)OC(O)OR 8或取代或非取代的-CH(R 7)OC(O)NH(R 8)；其中所述取代的乙基中，所述取代为被一个或多个羟基、巯基、氰基、卤素、烷氧基、环烷基、杂环烷基或NR 4(R 5)取代；所述取代的正丙基、取代的正丁基、取代的异丁基、取代的仲丁基、取代的C 5～C 8烷基、取代的C 2～C 8烯基、取代的C 2～C 8炔基、取代的-(CH 2) n-3～8元环烷基、取代的-(CH 2) n-3～8元杂环烷基、取代的-CH(R 7)OC(O)OR 8或取代的-CH(R 7)OC(O)NH(R 8)中，所述取代为被一个或多个氢、氘、卤素、羟基、巯基、氰基、烷基、烷氧基、环烷基、杂环烷基或NR 4(R 5)取代；其中R 4、R 5、R 7、R 8各自独立地选自氢或C 1～C 8烷基；
    优选地，R 1选自取代的乙基、取代或非取代的正丙基、取代或非取代的正丁基、取代或非取代的异丁基、取代或非取代的仲丁基、取代或非取代的C 5～C 6烷基、取代或非取代的C 2～C 6烯基、取代或非取代的C 2～C 6炔基、取代或非取代的-(CH 2) n-3～6元环烷基、取代或非取代的-(CH 2) n-3～6元杂环烷基、取代或非取代的-CH(R 7)OC(O)OR 8或取代或非取代的-CH(R 7)OC(O)NH(R 8)；其中所述取代的乙基中，所述取代为被一个或多个羟基、巯基、氰基、卤素、烷氧基、环烷基、杂环烷 基或NR 4(R 5)取代；所述取代的正丙基、取代的正丁基、取代的异丁基、取代的仲丁基、取代的C 5～C 6烷基、取代的C 2～C 6烯基、取代的C 2～C 6炔基、取代的-(CH 2) n-3～6元环烷基、取代的-(CH 2) n-3～6元杂环烷基、取代的-CH(R 7)OC(O)OR 8或取代的-CH(R 7)OC(O)NH(R 8)中，所述取代为被一个或多个氢、氘、卤素、羟基、巯基、氰基、烷基、烷氧基、环烷基、杂环烷基或NR 4(R 5)取代；其中R 4、R 5、R 7、R 8各自独立地选自氢或C 1～C 8烷基；
    优选地，R 1选自取代的乙基、取代或非取代的正丙基、取代或非取代的正丁基、取代或非取代的异丁基、取代或非取代的仲丁基、取代或非取代的C 5～C 6烷基、取代或非取代的C 2～C 4烯基、取代或非取代的C 2～C 4炔基、取代或非取代的-(CH 2) n-3～6元环烷基、取代或非取代的-(CH 2) n-3～6元杂环烷基、取代或非取代的-CH(R 7)OC(O)OR 8或取代或非取代的-CH(R 7)OC(O)NH(R 8)；其中所述取代的乙基中，所述取代为被一个或多个羟基、巯基、氰基、卤素、烷氧基、环烷基、杂环烷基或NR 4(R 5)取代；所述取代的正丙基、取代的正丁基、取代的异丁基、取代的仲丁基、取代的C 5～C 6烷基、取代的C 2～C 4烯基、取代的C 2～C 4炔基、取代的-(CH 2) n-3～6元环烷基、取代的-(CH 2) n-3～6元杂环烷基、取代的-CH(R 7)OC(O)OR 8或取代的-CH(R 7)OC(O)NH(R 8)中，所述取代为被一个或多个氢、氘、卤素、羟基、巯基、氰基、烷基、烷氧基、环烷基、杂环烷基或NR 4(R 5)取代；其中R 4、R 5、R 7、R 8各自独立地选自氢或C 1～C 8烷基；
    优选地，R 1选自取代的乙基、取代或非取代的正丙基、取代或非取代的正丁基、取代或非取代的异丁基、取代或非取代的仲丁基、取代或非取代的C 5～C 6烷基、取代或非取代的C 2～C 4烯基、取代或非取代的C 2～C 4炔基、取代或非取代的-(CH 2) n-3～6元环烷基、取代或非取代的-(CH 2) n-3～6元杂环烷基、取代或非取代的-CH(R 7)OC(O)OR 8或取代或非取代的-CH(R 7)OC(O)NH(R 8)；其中所述取代的乙基中，所述取代为被一个或多个羟基、卤素、C 1～C 4烷氧基、3～6元环烷基、3～6元杂环烷基或NR 4(R 5)取代；所述取代的正丙基、取代的正丁基、取代的异丁基、取代的仲丁基、取代的C 5～C 6烷基、取代的C 2～C 4烯基、取代的C 2～C 4炔基、取代的-(CH 2) n-3～6元环烷基、取代的-(CH 2) n-3～6元杂环烷基、取代的-CH(R 7)OC(O)OR 8或取代的-CH(R 7)OC(O)NH(R 8)中，所述取代为被一个或多个氢、氘、卤素、羟基、氰基、C 1～C 4烷基、C 1～C 4烷氧基、3～6元环烷基、3～6元杂环烷基或NR 4(R 5)取代；其中R 4、R 5、R 7、R 8各自独立地选自氢或C 1～C 8烷基；
    优选地，R 1选自取代乙基、取代或非取代的正丙基、取代或非取代的正丁基、取代或非取代的异丁基、取代或非取代的仲丁基、取代或非取代的烯丙基、取代或非取代的炔丙基、取代或非取代的环丙基、取代或非取代的
    Figure PCTCN2022141920-appb-100002
    取代或非取代的
    Figure PCTCN2022141920-appb-100003
    取代或非取代的
    Figure PCTCN2022141920-appb-100004
    取代或非取代的
    Figure PCTCN2022141920-appb-100005
    取代或非取代的
    Figure PCTCN2022141920-appb-100006
    取代或非取代的
    Figure PCTCN2022141920-appb-100007
    取代或非取代的
    Figure PCTCN2022141920-appb-100008
    取代或非取代的
    Figure PCTCN2022141920-appb-100009
    取代或非取代的
    Figure PCTCN2022141920-appb-100010
    取代或非取代的
    Figure PCTCN2022141920-appb-100011
    取代或非取代的
    Figure PCTCN2022141920-appb-100012
    取代或非 取代的
    Figure PCTCN2022141920-appb-100013
    取代或非取代的
    Figure PCTCN2022141920-appb-100014
    取代或非取代的
    Figure PCTCN2022141920-appb-100015
    取代或非取代的
    Figure PCTCN2022141920-appb-100016
    或取代或非取代的
    Figure PCTCN2022141920-appb-100017
    其中所述取代的乙基中，所述取代为被一个或多个羟基、卤素、C 1～C 4烷氧基、3～6元环烷基、3～6元杂环烷基或NR 4(R 5)取代，所述取代的正丙基、取代的正丁基、取代的异丁基、取代的仲丁基、取代的环丙基、取代的
    Figure PCTCN2022141920-appb-100018
    取代的
    Figure PCTCN2022141920-appb-100019
    取代的
    Figure PCTCN2022141920-appb-100020
    取代的
    Figure PCTCN2022141920-appb-100021
    取代的
    Figure PCTCN2022141920-appb-100022
    取代的
    Figure PCTCN2022141920-appb-100023
    取代的
    Figure PCTCN2022141920-appb-100024
    取代的
    Figure PCTCN2022141920-appb-100025
    取代的
    Figure PCTCN2022141920-appb-100026
    取代的
    Figure PCTCN2022141920-appb-100027
    取代的
    Figure PCTCN2022141920-appb-100028
    取代的
    Figure PCTCN2022141920-appb-100029
    取代的
    Figure PCTCN2022141920-appb-100030
    取代的
    Figure PCTCN2022141920-appb-100031
    取代的
    Figure PCTCN2022141920-appb-100032
    或取代的
    Figure PCTCN2022141920-appb-100033
    中，所述取代为一个或多个氢、氘、卤素、羟基、氰基、C 1～C 4烷基、C 1～C 4烷氧基、3～6元环烷基、3～6元杂环烷基或NR 4(R 5)取代；其中R 4、R 5、R 8各自独立地选自氢或C 1～C 8烷基；
    更优选地，R 1选自正丙基、正丁基、异丁基、烯丙基、炔丙基、环丙基、
    Figure PCTCN2022141920-appb-100034
    Figure PCTCN2022141920-appb-100035
  3. 如权利要求1所述的式(I)所示的化合物，或其立体异构体，或其药学上可接受的盐，其特征在于，R 1选自
    Figure PCTCN2022141920-appb-100036
  4. 如权利要求1所述的式(I)所示的化合物，或其立体异构体，或其药学上可接受的盐，其特征在于，
    R 7、R 8各自独立地选自氢或C 1～C 6烷基；
    优选地，R 7、R 8各自独立地选自氢或C 1～C 4烷基；
    优选地，R 7、R 8各自独立地选自氢、甲基、乙基或异丙基；
    优选地，R 7选自氢、甲基或异丙基；
    优选地，R 8选甲基、乙基或异丙基。
  5. 如权利要求1所述的式(I)所示的化合物，或其立体异构体，或其药学上可接受的盐，其特征在于，
    n选自0、1、2、3或4；
    优选地，n选自0、1或2。
  6. 如权利要求1所述的式(I)所示的化合物，或其立体异构体，或其药学上可接受的盐，其特征在于，
    R 4、R 5各自独立的选自氢或C 1～C 6烷基；
    优选地，R 4、R 5各自独立的选自氢或C 1～C 4烷基；
    更优选地，R 4、R 5各自独立的选自氢、甲基或乙基。
  7. 如权利要求1所述的式(I)所示的化合物，或其立体异构体，或其药学上可接受的盐，其特征在于，
    R 2、R 3各自独立地选自氰基、硝基、C 1～C 4烷基、卤代C 1～C 4烷基、羟基、巯基、卤素、C 1～C 4烷氧基或卤代C 1～C 4烷氧基；
    优选地，R 2、R 3各自独立地选自C 1～C 4烷基、卤代C 1～C 4烷基、C 1～C 4烷氧基、羟基、巯基、氰基、卤素；
    优选地，R 2、R 3各自独立地选自氰基、甲基、三氟甲基、氟或氯；
    优选地，R 2、R 3各自独立地选自氰基、三氟甲基、氟或氯；
    更优选地，R 2选自氰基、R 3选自三氟甲基。
  8. 如权利要求1所述的式(I)所示的化合物，或其立体异构体，或其药学上可接受的盐，其特征在于，
    X、Y分别独立地选自N或CR 6；优选地，X、Y均选自CR 6；R 6选自氢、卤素、C 1～C 8烷基、环烷基或杂环基；优选地，R 6选自氢、卤素、C 1～C 4烷基、3～6元环烷基或3～6元杂环基；优选地，R 6选自氢或卤素；优选地，R 6选自氢、氟或氯；优选地，R 6选自氢或氟；
    优选地，X选自CH；
    优选地，Y选自CF。
  9. 如权利要求1所述的式(I)所示的化合物，或其立体异构体，或其药学上可接受的盐，其特征在于，式(I)所示的化合物选自：
    Figure PCTCN2022141920-appb-100037
  10. 如权利要求1所述的式(I)所示的化合物，或其立体异构体，或其药学上可接受的盐，其特征在于，式(I)所示的化合物选自：
    Figure PCTCN2022141920-appb-100038
  11. 如权利要求1所述的式(I)所示的化合物，或其立体异构体，或其药学上可接受的盐，其特征在于，式(I)所示的化合物选自：
    Figure PCTCN2022141920-appb-100039
  12. 一种药物组合物，其特征在于，包含(i)权利要求1～11中任意一项所述的式(I)化合物或其立体异构体，或其药学上可接受的盐，和(ii)药学上可接受的载体、稀释剂或赋形剂。
  13. 权利要求1～11中任意一项所述的式(I)化合物，或其立体异构体，或其药学上可接受的盐，或权利要求12所述药物组合物在制备用于预防雄激素或雄激素受体活性介导的疾病或病症、降低雄激素或雄激素受体活性介导的疾病或病症进展、或治疗雄激素或雄激素受体活性介导的疾病或病症的药物中的用途；优选地，所述雄激素或雄激素受体活性介导的疾病或病症选自前列腺癌、痤疮或脱发。
PCT/CN2022/141920 2022-01-28 2022-12-26 一种局部作用的雄激素受体拮抗剂及其应用 WO2024103494A1 (zh)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CN202210105159 2022-01-28
CN202211445988.3 2022-11-18
CN202211445988.3A CN117164520A (zh) 2022-01-28 2022-11-18 一种局部作用的雄激素受体拮抗剂及其应用

Publications (1)

Publication Number Publication Date
WO2024103494A1 true WO2024103494A1 (zh) 2024-05-23

Family

ID=88932370

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/141920 WO2024103494A1 (zh) 2022-01-28 2022-12-26 一种局部作用的雄激素受体拮抗剂及其应用

Country Status (2)

Country Link
CN (1) CN117164520A (zh)
WO (1) WO2024103494A1 (zh)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101817787A (zh) * 2009-02-26 2010-09-01 童友之 抗前列腺癌的雄性激素受体拮抗剂
WO2013067151A1 (en) * 2011-11-02 2013-05-10 Medivation Prostate Therapeutics, Inc. Treatment methods using diarylthiohydantoin derivatives
CN104803919A (zh) * 2014-01-26 2015-07-29 上海医药工业研究院 用于制备恩杂鲁胺中间体的方法
CN104803918A (zh) * 2014-01-26 2015-07-29 上海医药工业研究院 恩杂鲁胺的制备方法
CN106800536A (zh) * 2017-01-10 2017-06-06 南京慧博生物科技有限公司 一种恩杂鲁胺的制备方法

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101332924B1 (ko) * 2005-05-13 2013-11-26 더 리전트 오브 더 유니버시티 오브 캘리포니아 디아릴히단토인 화합물
CN102482230B (zh) * 2009-09-10 2016-01-06 苏州开拓药业有限公司 雄激素受体拮抗剂及其用途
CN104341352A (zh) * 2013-08-09 2015-02-11 南京衡杰生物科技有限公司 作为雄激素受体拮抗剂的二芳基乙内酰脲化合物及其应用

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101817787A (zh) * 2009-02-26 2010-09-01 童友之 抗前列腺癌的雄性激素受体拮抗剂
WO2013067151A1 (en) * 2011-11-02 2013-05-10 Medivation Prostate Therapeutics, Inc. Treatment methods using diarylthiohydantoin derivatives
CN104803919A (zh) * 2014-01-26 2015-07-29 上海医药工业研究院 用于制备恩杂鲁胺中间体的方法
CN104803918A (zh) * 2014-01-26 2015-07-29 上海医药工业研究院 恩杂鲁胺的制备方法
CN106800536A (zh) * 2017-01-10 2017-06-06 南京慧博生物科技有限公司 一种恩杂鲁胺的制备方法

Also Published As

Publication number Publication date
CN117164520A (zh) 2023-12-05

Similar Documents

Publication Publication Date Title
CN104718188B (zh) N-取代的苯甲酰胺类及其在治疗疼痛中的用途
CN104837843B (zh) 作为gabaa受体调节剂的咪唑并哒嗪衍生物
ES2352098T3 (es) Derivado de fenoxi-pirrolidina y su uso y composiciones.
CN101980709A (zh) 哒嗪衍生物及其作为治疗剂在治疗皮肤障碍中的用途
CN101119993A (zh) 作为选择性雄激素受体调节剂的氨基苯基衍生物
US20120329781A1 (en) Combinations comprising alpha-2-delta ligands
JP2003521513A (ja) 抗癌剤としてのアダマンチル誘導体
JP2021506920A (ja) 結晶性の置換シクロヘキシルピラゾロ［１，５−ａ］ピリミジニルカルボキサミド化合物およびその治療的使用
JP2009517453A (ja) Ｐｄｅ７阻害剤としてのスピロ環式キナゾリン誘導体
WO2016044951A1 (en) Compositions and methods for enhancing hair growth, promoting skin regeneration, and wound healing
KR20230041021A (ko) 이소퀴놀린 화합물 및 AhR 불균형 치료에 있어서 그의 용도
TWI314930B (en) Novel salt form of a dopamine agonist
WO2018037279A1 (en) Nitroalkene trolox derivatives and methods of use thereof in the treatment and prevention of inflammation related conditions
US7053122B2 (en) Therapeutic use of aryl amino acid derivatives
JP2021519276A (ja) Ｄ−β−ヒドロキシ酪酸の重水素化類似体およびその使用
EP3663299A1 (en) Bicyclic compound acting as ror inhibitor
WO2024103494A1 (zh) 一种局部作用的雄激素受体拮抗剂及其应用
WO2020177291A1 (zh) 法舒地尔复合盐及其制备方法和用途
KR20060114005A (ko) 모발 성장 촉진 방법
EP3773597A1 (en) Phenothiazine derivatives and uses thereof
WO2019099457A1 (en) Benzodioxinone compounds
CN105377838A (zh) 新抗疟剂
KR20200034723A (ko) 신규 스피로락톤 화합물
WO2020249120A1 (zh) 氨基硫醇类化合物作为脑神经或心脏保护剂的用途
US5902827A (en) Method for treating patients with psoriasis by administering substituted sulfonyl indenyl acetic acids, esters and alcohols