WO2023020135A1 - 阿比特龙衍生物及其制备与应用 - Google Patents

阿比特龙衍生物及其制备与应用 Download PDF

Info

Publication number
WO2023020135A1
WO2023020135A1 PCT/CN2022/103497 CN2022103497W WO2023020135A1 WO 2023020135 A1 WO2023020135 A1 WO 2023020135A1 CN 2022103497 W CN2022103497 W CN 2022103497W WO 2023020135 A1 WO2023020135 A1 WO 2023020135A1
Authority
WO
WIPO (PCT)
Prior art keywords
abiraterone
dimethyl
pyridin
decahydro
phenanthrenyl
Prior art date
Application number
PCT/CN2022/103497
Other languages
English (en)
French (fr)
Inventor
王伟
陆永章
谭进辉
Original Assignee
广东中科药物研究有限公司
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 广东中科药物研究有限公司 filed Critical 广东中科药物研究有限公司
Publication of WO2023020135A1 publication Critical patent/WO2023020135A1/zh

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • 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
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention belongs to the field of medicine, and specifically relates to abiraterone derivatives and their preparation and application.
  • the chemical name is 17-(3-pyridyl)androst-5,16-dien-3 ⁇ -ol, which is a CYP17 inhibitor. It is mainly used in combination with prednisone in the treatment of metastases previously treated with docetaxel-containing chemotherapy. Abiraterone acetate (ZYTIGA) is converted in vivo to abiraterone, an androgen biosynthesis inhibitor, inhibits 17 ⁇ -hydroxylase/C17,20-lyase (CYP17) in patients with castration-resistant prostate cancer . This enzyme is expressed in testicular, adrenal, and prostate tumor tissues and is required for androgen biosynthesis.
  • Abiraterone is clinically used in the form of abiraterone acetate, and abiraterone acetate needs to be taken on an empty stomach, because food has a greater impact on the absorption of abiraterone acetate, and there are also differences between individuals bigger.
  • M1 One of the metabolites of abiraterone acetate, referred to as M1, the chemical name is:
  • 17-(3-pyridine)-4, (16-dieneandrost-3-one, English name: 17-(3-pyridine)-4,16-dieneandrost-3-one), is the compound of abiraterone acetate one of the metabolites.
  • the present invention provides an abiraterone derivative and a preparation method thereof.
  • the abiraterone derivative provided by the present invention exhibits relatively less abdominal distension and has better efficacy and tolerance.
  • Kinetic experiments showed that the plasma concentration of M1 was significantly higher than that of abiraterone acetate after intragastric administration of equimolar doses, and M2 was detected in the metabolites, while there was no M2 in the metabolites of abiraterone acetate. It has the effect of inhibiting prostate cancer significantly better than that of abiraterone, and has less gastrointestinal side effects than abiraterone.
  • the compound provided by the invention has the effect of treating acne at the same time.
  • Abiraterone derivatives provided by the present invention have a structural formula as shown in formula I:
  • R is selected from: (Ar represents a substituted or unsubstituted aromatic ring, specifically a benzene ring or a pyridine ring; a substituent can be a C1-C8 alkyl group, a C1-C8 alkoxy group, or a halogen);
  • R 1 and R 2 are independently selected from any of the following groups: H, (C3-C8) carbocycloalkyl, substituted or unsubstituted (C1-C18) (specifically C2-C6 ) alkane (wherein, the substituent can be amino (amino group does not contain active hydrogen at the end), carboxyl (carboxyl does not contain active hydrogen at the end), halogen, (C3-C8) heterocycloalkyl), (C2-C8 ) alkenyl or substituted (C2-C8) alkenyl, (C2-C8) alkynyl or substituted (C2-C8) alkynyl, (C6-C20) aryl or substituted (C6 -C20) aryl, (C2-C20) heterocyclic group or (C2-C20) heterocyclic group containing substituents;
  • R 1 and R 2 form a ring with each other as (C3-C8) heterocycloalkyl or substituted (C3-C8) heterocycloalkyl, (C6-C20) heteroaryl or substituted (C6-C20) heteroaryl;
  • R is: , R 1 and R 2 cannot be unsubstituted alkanes with 1 or more carbon atoms;
  • the substituents of the compound do not include the terminal substituents being hydroxyl, amino, carboxyl, phosphoryl and sulfonyl, but include compounds in which the active hydrogen of hydroxyl, amino, carboxyl, phosphoryl and sulfonyl is substituted. It has been proved by experiments that the compounds with active hydrogen groups at the end are unstable. It is found in the experiment that when R1 and R2 are unsubstituted amino groups or the ends of R1 and R2 are unsubstituted amino groups, stable compound samples cannot be obtained. When the ends of R1 and R2 are carboxyl groups, stable compound samples cannot be obtained.
  • the compounds shown below can be obtained and have the characteristics described in the present invention.
  • the terminal is a carboxyl group
  • the compound sample cannot be obtained due to stability reasons, but when the carboxyl group forms an ester with an alcohol or a substituted alcohol, and forms an amide with an amine or a substituted amine, and the terminal is not replaced by an amino group or a carboxyl group, a stable sample can be obtained , and has the characteristics of the invention.
  • R2 is H
  • R1 is a straight-chain alkyl group greater than/equal to 1 C, such as: when R1 is -CH3 , the drug concentration of M1 and M2 (see Pharmacokinetic Examples for structure) in vivo is significantly lower than that of other Compounds, this is due to the high fat solubility of straight-chain alkyl groups, which is difficult to absorb and difficult to hydrolyze in vivo.
  • compound b directly reacts with the carbonyl compound of fragment R to obtain the abiraterone derivative shown in I; or compound b forms an active product with carbonyldiimidazole, and then condenses with the corresponding alcohol and ammonia of fragment R to obtain the abiraterone derivative shown in I. Derivatives of abiraterone.
  • the eukaryote is a mammal
  • the tumor cells are cancer cells
  • the cancer cells are prostate cancer cells
  • the tumor is carcinoma; the carcinoma is prostate cancer.
  • the prostate cancer was castration-resistant prostate cancer previously received chemotherapy containing docetaxel.
  • the present invention also provides an inhibitor of eukaryotic tumor cell proliferation, which comprises the abiraterone derivative shown in formula I.
  • the present invention also provides a medicine for treating acne, which comprises the abiraterone derivative shown in formula I.
  • the abiraterone derivatives provided by the present invention show relatively less abdominal distension than abiraterone, and have better drug efficacy and tolerance.
  • Pharmacokinetic experiments show that the M1 The plasma concentration was significantly higher than that of abiraterone acetate, and M2 was detected in the metabolites, while there was no M2 in the metabolites of abiraterone acetate. It has the effect of inhibiting prostate cancer significantly better than that of abiraterone, and has less gastrointestinal side effects than abiraterone.
  • the compound provided by the invention also has the effect of treating acne.
  • abiraterone (35.0g, 100mmol, 1.0eq.), aluminum isopropoxide (20.5g, 100mmol, 1.0eq.), cyclohexanone (29.5g, 300mmol, 3.0eq.) in a round bottom reaction flask , add toluene (210mL), protect with nitrogen, and heat at 100°C for 16h.
  • reaction solution was extracted with water, the organic phase was concentrated, and column chromatography was used to obtain (8S,9S,10R,13S,14S)-10,13-dimethyl-17-(pyridin-3-yl)-6,7,8,9 ,10,11,12,13,14,15-Decahydro-1H-cyclopenteno[a]phenanthrene-3(2H)-one O-(1H-imidazole-1-carbonyl)oxime (2.0g, 79.5 %).
  • reaction solution was concentrated and purified by column chromatography to obtain solid (8S,9S,10R,13S,14S)-10,13-dimethyl-17-(pyridin-3-yl)-6,7,8,9,10, 11,12,13,14,15-Decahydro-1H-cyclopenteno[a]phenanthrene-3(2H)-one O-((2-(dimethylamino)ethyl)carbamoyl)oxime ( 1.5 g, 7.8%).
  • test compounds ZONK1901 series compounds (invention compounds) and ZONK1901-10 (abiraterone acetate) inhibit the growth of human prostate cancer cell VCaP nude mouse xenograft tumor model in vivo.
  • Test sample Example 1 compound (B), Example 2 compound (C), Example 3 compound (D), Example 4 (E), Example 5 (F), Example 6 (G), Embodiment 7 (H) and ZONK1901-19, ZONK1901-10 (I) (abiraterone acetate)
  • DMEM culture medium fetal bovine serum; trypsin; blue-chain double antibody; dimethyl sulfoxide (DMSO); TPGS; Matrigel; PBS (pH7.4, 0.01M)
  • mice Male BALB/c nude mice (number: 90; age: 6-7 weeks) were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., and were raised in the SPF animal room of Suzhou Shengsu New Drug Development Co., Ltd. at a temperature of 20 ⁇ 25°C, relative humidity 40% ⁇ 70%, light and dark lighting for 12 hours each; animals had free access to water and food. After normal feeding for about 6 days, mice with good signs and conditions can be selected for this experiment after veterinary inspection. Before grouping, use a marker pen to mark the base of the tail of the animals, and after grouping, each animal is marked by ear clipping.
  • Human prostate cancer cells VCaP were obtained from the Shanghai Cell Bank of the Chinese Academy of Sciences (CAS, cryopreserved in liquid nitrogen in our laboratory)
  • VCaP cells were routinely cultured in DMEM medium containing 10% fetal bovine serum under 5% CO2 and 37°C culture conditions. Digested with 0.25% trypsin for passage, according to the cell growth, passage 2-3 times a week, the passage ratio is 1:3 to 1:5.
  • VCaP cells Collect the VCaP cells in the logarithmic growth phase, count the cells, and resuspend them in 50% DMEM basal medium and 50% Matrigel Matrix, adjust the cell concentration to 5 ⁇ 107 cells/mL; place the cells in an ice box, and use
  • the cell suspension was sucked into a 1mL syringe and injected subcutaneously into the anterior right armpit of nude mice.
  • Each animal was inoculated with 200 ⁇ L (1 ⁇ 107 cells/mouse) to establish a VCaP xenograft tumor model. Observe the state of the animals regularly, measure the diameter of the tumor with an electronic vernier caliper, input the data into an Excel spreadsheet, calculate the volume of the tumor, and monitor the growth of the tumor.
  • the day of grouping was taken as the first day of the experiment (D1). After the experiment started, the tumor diameter was measured twice a week, and the tumor volume was calculated. At the same time, the body weight of the animals was weighed and recorded.
  • the tumor volume (TV) calculation formula is as follows:
  • DMSO&PEG400&PG (v:v:v, 10:60:30) preparation: draw appropriate volumes of DMSO, PEG400 and PG respectively, and mix well.
  • the ratio of DMSO PEG400 and PG in the mixture is 10:60:30 (v:v:v), which is used as a blank solvent and stored at room temperature.
  • test compound weigh an appropriate amount of the test compound into a glass bottle, add an appropriate volume of solvent DMSO, vortex and sonicate, then add appropriate volumes of PEG400 and PG in turn, vortex and mix to obtain a drug preparation with a final concentration of 0.05M.
  • solvent DMSO solvent-free water
  • PEG400 and PG appropriate volumes of PEG400 and PG in turn, vortex and mix to obtain a drug preparation with a final concentration of 0.05M.
  • the animal groups and dosing regimen are shown in Table 1.
  • the test samples were administered on the day of grouping, and the experiment was ended 28 days later or when the tumor volume of the solvent control group reached 2000 mm3 (whichever was reached earlier), and the administration volume was 10 mL ⁇ kg-1.
  • Group A was the blank solvent group, and the blank solvent (DMSO&PEG400&PG(v:v:v, 10:60:30)) was administered intragastrically, once a day (QD).
  • the other groups were intragastrically administered the test compound, once a day (QD).
  • Group I was intragastrically administered ZONK1901-10 at a dose of 195.8 mg ⁇ kg-1 (0.5 mmol ⁇ kg-1), once a day (QD).
  • the animals were euthanized (CO2) after weighing the body weight and measuring the tumor diameter.
  • the tumor tissue was stripped, weighed and photographed, and the tumor weight and tumor inhibition rate were calculated.
  • the animals were dissected grossly, and the internal organs were observed with naked eyes for abnormalities. Animal carcasses and tumor tissues were stored in the refrigerator for unified treatment.
  • RTV relative tumor volume
  • TVinitial is the tumor volume measured during group administration
  • TVt is the tumor volume at each measurement during administration.
  • RTVT represents the RTV of the treatment group
  • RTVC represents the RTV of the solvent control group
  • TGI (%) The calculation formula of tumor growth inhibition rate TGI (%) is:
  • TGI 100% ⁇ [1-(TV t(T) -TV initial(T) )/(TV t(C) -TV initial(C) )]
  • TV t (T) represents the tumor volume measured each time in the treatment group
  • TV initial (T) represents the tumor volume of the treatment group when administered in groups
  • TV t (C) represents the tumor volume measured each time in the solvent control group
  • TV initial (C) represents the tumor volume of the solvent control group at the time of group administration.
  • the formula for calculating the weight loss rate of animals is:
  • Animal weight loss rate 100% ⁇ (BW initial - BW t )/BW initial
  • BW t represents the animal body weight measured each time during the administration period
  • BW initial represents the animal body weight at the time of group administration.
  • the formula for calculating tumor weight inhibition rate IR (%) is:
  • W C represents the tumor weight in the control group
  • W T represents the tumor weight in the treatment group
  • Embodiment 20 pharmacokinetic experiment
  • mice To study the pharmacokinetic properties after intragastric administration in mice.
  • mice are randomly divided into 9 groups (each group contains 5), embodiment 1 compound (B), embodiment 2 compound (C), embodiment 3 compound (D), embodiment 4 (E), implement Example 5(F), Example 6(G), and ZONK1901-19(H), ZONK1901-10(I) (abiraterone acetate).
  • the main pharmacokinetic parameters of the metabolites ZONK1901-1 and ZONK1901-2 after intragastric administration in each group are as follows:
  • Embodiment 21 acne pharmacodynamics test
  • each dose group continued to apply coal tar in the morning, and after removing the coal tar in the afternoon, smear the test drug or control drug on the lesion (0.01%/10g ointment, smear 1g ointment/piece), 1 time/ day, for 2 consecutive weeks (the model control group and the normal control group were coated with the same amount of matrix).
  • the animals were sacrificed by air embolism, and the skin (full thickness) of the ear where the administration was administered was taken, fixed with 4% paraformaldehyde solution, stained with HE, and routinely observed for pathology.

Landscapes

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

Abstract

本发明公开一种阿比特龙衍生物及其制备方法，本发明所提供的阿比特龙衍生物相对于阿比特龙表现相对较少的腹胀现象，具有更好药效和耐受性，药代动力学实验表明，等摩尔剂量灌胃给药后M1的血药浓度显著高于阿比特龙醋酸酯。具有显著优于阿比特龙的抑制***癌的作用，并且胃肠道副作用较阿比特龙小。本发明所提供的化合物同时具有治疗痤疮的作用。

Description

阿比特龙衍生物及其制备与应用 技术领域
本发明属于医药领域，具体涉及阿比特龙衍生物及其制备与应用。
背景技术
阿比特龙(Abiraterone)，其结构式为：
Figure PCTCN2022103497-appb-000001
化学名称17-(3-吡啶基)雄甾-5,16-二烯-3β-醇，为CYP17抑制剂，临床上主要适用于与***联用为治疗既往接受含多烯紫杉醇化疗转移去势难治性***癌患者，醋酸阿比特龙(ZYTIGA)在体内被转化为阿比特龙，一种雄激素生物合成抑制剂，抑制17α-羟化酶/C17,20-裂解酶(CYP17)。在睾丸，肾上腺，和***肿瘤组织中表达此酶，为雄激素生物合成所需。阿比特龙在临床上是以阿比特龙醋酸酯的形式使用，阿比特龙醋酸酯需要在空腹时服用，这是由于食物对于醋酸阿比特龙酯的吸收影响较大，个体之间的差异也比较大。阿比特龙醋酸酯的代谢物之一，简称M1,化学名为：
17-(3-吡啶)-4，(16-二烯雄-3-酮，英文名为：17-(3-pyridine)-4,16-dieneandrost-3-one)，为醋酸阿比特龙的代谢物之一。
在我们的前期研究中发现，腹腔注射醋酸阿比特龙的Vcap(人***癌细胞)接种的肿瘤模型小鼠在接受腹腔注射药物后部分出现腹胀，并出现死亡现象，解剖后发现部分药物未吸收。
发明内容
本发明提供一种阿比特龙衍生物及其制备方法，本发明所提供的阿比特龙衍生物相对于阿比特龙表现相对较少的腹胀现象，具有更好药效和耐受性，药代动力学实验表明，等摩尔剂量灌胃给药后M1的血药浓度显著高于阿比特龙醋酸酯，代谢物中检测到有M2，而醋酸阿比特龙的代谢物中则没有M2。具有显著优于阿比特龙的抑制***癌的作用，并且胃肠道副作用较阿比特龙小。本发 明所提供的化合物同时具有治疗痤疮的作用。
Figure PCTCN2022103497-appb-000002
本发明所提供的阿比特龙衍生物，其结构式如式I所示：
Figure PCTCN2022103497-appb-000003
式I中，R选自：
Figure PCTCN2022103497-appb-000004
(Ar表示取代或未取代的芳香环，具体可为苯环、吡啶环；取代基可为C1-C8的烷基、C1-C8的烷氧基、卤素)；
其中，R 1、R 2独立地选自下述基团中的任意一种：H、(C3-C8)碳环烷基、取代或未取代的(C1-C18)(具体可为C2-C6)烷烃(其中，取代基可为氨基(氨基在末端时不含活泼氢)、羧基(羧基在末端时不含活泼氢)、卤素、(C3-C8)杂环烷基)、(C2-C8)烯基或含有取代基的(C2-C8)烯基、(C2-C8)炔基或含有取代基的(C2-C8)炔基、(C6-C20)芳基或含有取代基的(C6-C20)芳基、(C2-C20)杂环基或含有取代基的(C2-C20)杂环基；
或R 1、R 2相互成环为(C3-C8)杂环烷基或取代(C3-C8)杂环烷基、(C6-C20)杂芳基或取代(C6-C20)杂芳基；
R为：
Figure PCTCN2022103497-appb-000005
时，R 1、R 2不可为未取代的碳原子数大于等于1的烷烃；
所述化合物的取代基不包括末端取代基为羟基、氨基、羧基、磷酰基、磺酰基，但包括羟基、氨基、羧基、磷酰基，磺酰基活泼氢被取代的化合物。通过实验证明，末端带活泼氢基团的化合物均不稳定，在实验中发现，R1、R2为未取代的氨基或R1、R2的末端为未取代的氨基时，不能够得到稳定的化合物样品，R1和R2的末端为羧基时同样不能得到稳定的化合物样品。
末端氨基被取代或成酰胺键时，如下所示化合物则可以得到，并具有本发明所述特征。末端为羧基时，也由于稳定性原因不能得到化合物样品，但当羧基与醇或取代的醇成酯、与胺或取代的胺成酰胺，末端不为氨基、羧基的取代，能够得到稳定的样品，并具有发明所述特征。
Figure PCTCN2022103497-appb-000006
Figure PCTCN2022103497-appb-000007
Figure PCTCN2022103497-appb-000008
中R 2为H，R 1为大于/等于1个C的直链烷基，如：R 1为-CH 3时，体内M1和M2(结构见药代实施例)的药物浓度显著低于其它化合物，这是由于直链烷基的脂溶性较大难于吸收且在体内较难水解。
具体地，上述式I所示阿比特龙衍生物具有代表意义的形式如下：
Figure PCTCN2022103497-appb-000009
Figure PCTCN2022103497-appb-000010
Figure PCTCN2022103497-appb-000011
Figure PCTCN2022103497-appb-000012
Figure PCTCN2022103497-appb-000013
Figure PCTCN2022103497-appb-000014
Figure PCTCN2022103497-appb-000015
Figure PCTCN2022103497-appb-000016
上述式I所示阿比特龙衍生物根据图1所示的反应流程图，通过包括如下步骤的方法制备得到：
Figure PCTCN2022103497-appb-000017
1)以阿比特龙为原料，在异丙醇铝和环己酮存在下，氧化反应得到化合物a；
2)在碱性条件下，使化合物a与盐酸羟胺发生缩合反应，得到化合物b；
3)化合物b与片段R的羰基化合物直接酯化反应，得到I所示阿比特龙衍生物；或者化合物b与羰基二咪唑形成活化物，然后与片段R相应的醇、氨缩合，得到I所示阿比特龙衍生物。
上述式I所示阿比特龙衍生物在如下方面的应用也属于本发明的保护范围：
1)在制备真核生物肿瘤细胞增殖抑制剂中的应用；
2)在制备预防和/或***药物中的应用。
所述真核生物为哺乳动物；
所述肿瘤细胞为癌细胞；
所述癌细胞为***癌细胞；
所述肿瘤为癌；所述癌为***癌。
所述***癌为既往接受含多烯紫杉醇化疗转移去势难治性***癌。
本发明还提供一种真核生物肿瘤细胞增殖抑制剂，其包含式I所示阿比特龙衍生物。
式I所示化合物在制备治疗痤疮药物中的应用也属于本发明的保护范围。
本发明还提供一种治疗痤疮的药物，其包含式I所示阿比特龙衍生物。
本发明所提供的阿比特龙衍生物相对于阿比特龙表现相对较少的腹胀现象，具有更好药效和耐受性，药代动力学实验表明，等摩尔剂量灌胃给药后M1的血药浓度显著高于阿比特龙醋酸酯，代谢物中检测到有M2，而醋酸阿比特龙的代谢物中则没有M2。具有显著优于阿比特龙的抑制***癌的作用，并且胃肠道副作用较阿比特龙小。本发明所提供的化合物同时具有治疗痤疮的作用。
具体实施方式
下面通过具体实施例对本发明进行说明，但本发明并不局限于此。
下述实施例中所使用的实验方法如无特殊说明，均为常规方法；下述实施例中所用的试剂、材料等，如无特殊说明，均可从商业途径得到。
实施例1
(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲-3(2H)-酮O-((2-(二甲氨基)乙基)氨基甲酰基)肟的合成
Figure PCTCN2022103497-appb-000018
1)(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮
Figure PCTCN2022103497-appb-000019
分别称量阿比特龙(35.0g，100mmol，1.0eq.)、异丙醇铝(20.5g，100mmol，1.0eq.),环己酮(29.5g，300mmol,3.0eq.)于圆底反应瓶中,加入甲苯(210mL)，氮气保护，100℃加热反应16h。冷却反应液，加入食盐水，硅藻土过滤不溶物，分离有机层，柱层析纯化得到白色固体(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮(30.2g，87.0％)。 1H NMR(DMSO-d6 400MHz)δ8.47(s,1H),8.33(d,1H),7.77-7.29(m,2H),5.96(m,1H),5.85(s,1H),2.99(m,2H),2.37-1.27(m,21H).ESI-MS m/z:348.1[M+H]+.
2)(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮肟
Figure PCTCN2022103497-appb-000020
称量(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮(30.0g，86.5mmol，1.0eq.)溶解于无水乙醇(250mL)中，然后加入盐酸羟胺(12.0g，173mmol，2.0eq.)、乙酸钠(21.3g，260mmol，3.0eq.)，室温反应3h。向反应液中加入过量水，析出白色固体。过滤粗品，乙醇重结晶得到(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮肟(25.0g，80.0％)。1H NMR(DMSO-d6 400MHz)δ8.47(s,1H),8.33(d,1H),7.77-7.29(m,2H),5.96(m,1H),5.85(s,1H),4.62(s,1H),2.99(m,2H),2.37-1.27(m,21H).ESI-MS m/z:363.1[M+H]+.
3)(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲-3(2H)-酮O-(1H-咪唑-1-羰基)肟
Figure PCTCN2022103497-appb-000021
将(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮肟(2.0g，5.52mmol，1.0eq.)溶解于二氯甲烷(20mL)中，分别加入三乙胺(1.11g，11.0mmol。2.0eq.)、羰基二咪唑(1.78g，11.0mmol。2.0eq.)，室温搅拌8h。反应液加水萃取，浓缩有机相，柱层析得到(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲-3(2H)-酮O-(1H-咪唑-1-羰基)肟(2.0g，79.5％)。1H NMR(DMSO-d6 400MHz)δ8.47(s,1H),8.33(d,1H),8.14(s,1H),7.77-7.14(m,4H),5.96(m,1H),5.85(s,1 H),2.99(m,2H),2.37-1.27(m,21H).ESI-MS m/z:457.1[M+H]+.
4)(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲-3(2H)-酮O-((2-(二甲氨基)乙基)氨基甲酰基)肟
Figure PCTCN2022103497-appb-000022
将(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲-3(2H)-酮O-(1H-咪唑-1-羰基)肟(2.0g，4.39mmol，1.0eq.)溶解于二氯甲烷(10mL)中，滴加N，N-二甲基乙二胺(0.58g，6.58mmol，1.5eq.)，室温搅拌5h。反应液浓缩，柱层析纯化得到固体(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲-3(2H)-酮O-((2-(二甲氨基)乙基)氨基甲酰基)肟(1.5g，7.8％)。1H NMR(DMSO-d6 400MHz)δ8.47(s,1H),8.33(d,1H),7.77-7.29(m,2H),5.96(m,1H),5.85(s,1H),3.28-3.26(d,4H),2.36(s,6H),2.37-1.27(m,23H).ESI-MS m/z:477.1[M+H]+.
实施例2
(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲-3(2H)-酮O-二甲氨基甲酰基肟的合成
Figure PCTCN2022103497-appb-000023
将(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮肟(2.0g，5.52mmol，1.0eq.)、三乙胺(1.11g，11.0mmol。2.0eq.)分别溶解 于二氯甲烷(20mL)中，滴加入二甲氨基甲酰氯(1.19g，11.0mmol，2.0eq.)，室温反应5h。反应液浓缩，柱层析得到白色固体(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲-3(2H)-酮O-二甲氨基甲酰基肟(2.0g，83.7％)。1H NMR(DMSO-d6 400MHz)δ8.47(s,1H),8.33(d,1H),7.77-7.29(m,2H),5.96(m,1H),5.85(s,1H),3.47(s,6H),2.37-1.27(m,23H).ESI-MS m/z:434.1[M+H]+.
实施例3
(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮O-(双(2-氯乙基)氨基甲酰基)肟的合成
Figure PCTCN2022103497-appb-000024
综合实施例1-2的合成方法，双(2-氯乙基)氨基甲酰氯与中间体(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮肟酯化后得到白色固体(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮O-(双(2-氯乙基)氨基甲酰基)肟。1H NMR(DMSO-d6 400MHz)δ8.47(s,1H),8.33(d,1H),7.77-7.29(m,2H),5.96(m,1H),5.62(s,1H),3.64(m,4H),3.24(m,4H),2.37-1.27(m,23H).ESI-MS m/z:532.1[M+H]+.
实施例4
(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯[a]菲基-3(2H)-酮O-([1,4'-联哌啶]-1'-羰基)肟的合成
Figure PCTCN2022103497-appb-000025
综合实施例1-2的合成方法，[1,4'-联哌啶]-1'-碳酰氯与中间体(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮肟酯化后得到白色固体(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯[a]菲基-3(2H)-酮O-([1,4'-联哌啶]-1'-羰基)肟。1H NMR(DMSO-d6 400MHz)δ8.47(s,1H),8.33(d,1H),7.77-7.29(m,2H),5.96(m,1H),5.62(s,1H),3.39(m,4H),2.62-2.42(m,5H),2.37-1.27(m,33H).ESI-MS m/z:557.1[M+H]+.
实施例5
(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮O-(2-甲基苯甲酰基)肟的合成
Figure PCTCN2022103497-appb-000026
综合实施例1-2的合成方法，邻甲基苯甲酰氯与中间体(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮肟酯化后得到白色固体(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮O-(2-甲基苯甲酰基)肟。1H NMR(DMSO-d6 400MHz)δ8.47(s,1H),8.33(d,1H),7.88-7.29(m,6H),5.96(m,1H),5.62(s,1H),2.37-1.27(m,26H).ESI-MS m/z:481.1[M+H]+.
实施例6
(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮O-(3-(甲氨基)丙酰基)肟的合成
Figure PCTCN2022103497-appb-000027
综合实施例1-2的合成方法，3-甲氨基丙酸与中间体(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮肟酯化后脱保护得到白色固体(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮O-(3-(甲氨基)丙酰基)肟。1H NMR(DMSO-d6 400MHz)δ8.47(s,1H),8.33(d,1H),7.77-7.29(m,2H),5.96(m,1H),5.62(s,1H),3.62(s,3H),2.83-2.63(m,4H),2.37-1.27(m,23H).ESI-MS m/z:448.1[M+H]+.
实施例7
(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮O-乙酰肟的合成
Figure PCTCN2022103497-appb-000028
综合实施例1-2的合成方法，乙酸酐与中间体(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮肟酯化后脱保护得到白色固体(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮O-乙酰肟。1H NMR(DMSO-d6 400MHz)δ8.47(s,1H),8.33(d,1H),7.77-7.29(m,2H),5.96(m,1H),5.62(s,1H),2.37-1.27(m,26H).ESI-MS m/z:405.1[M+H]+.
实施例8
((((((8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-7,8,9,11,12,13,14,15-八氢-1H-环戊烯并[a]菲基-3(2H,6H,10H)-亚基)氨基)氧)羰基)氧)甲基异丁酸酯的合成
Figure PCTCN2022103497-appb-000029
综合实施例1-2的合成方法，氯甲酸氯甲酯与中间体(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮肟酯化，然后与异丁酸成酯得到白色固体((((((8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-7,8,9,11,12,13,14,15-八氢-1H-环戊烯并[a]菲基-3(2H,6H,10H)-亚基)氨基)氧)羰基)氧)甲基异丁酸酯。1H NMR(DMSO-d6 400MHz)δ8.47(s,1H),8.33(d,1H),7.70-7.29(m,2H),6.95(s,1H),5.96(m,1H),5.62(s,1H),2.67-1.14(m,30H).ESI-MS m/z:507.1[M+H]+.
实施例9
(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮O-((2-吗啉乙氧基羰基)肟的合成
Figure PCTCN2022103497-appb-000030
综合实施例1-2的合成方法，2-吗啉乙醇与中间体(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮肟在三光气环境下形成碳酸酯(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮O-((2-吗啉乙氧基羰基)肟。1H NMR(DMSO-d6 400MHz)δ8.47(s,1H),8.33(d,1H),7.70-7.29(m,2H),5.96(m,1H),5.62(s,1H),4.43(m,2H),3.65(m,4H),2.97(m,2H),2.36(m,4H),2.12-1.12(m,23H).ESI-MS m/z:520.1[M+H]+.
实施例10
(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮O-哌啶-4-羰基肟的合成
Figure PCTCN2022103497-appb-000031
综合实施例1-2的合成方法，4-哌啶甲酸与中间体(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮肟酯化后得到白色固体(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮O-哌啶-4-羰基肟。1H NMR(DMSO-d6 400MHz)δ8.47(s,1H),8.33(d,1H),7.70-7.29(m,2H),5.96(m,1H),5.62(s,1H),2.79(m,4H),2.33-1.27(m,28H).ESI-MS m/z:474.1[M+H]+.
实施例11
(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮O-(1-甲基哌啶-4-羰基)肟的合成
Figure PCTCN2022103497-appb-000032
综合实施例1-2的合成方法，1-甲基哌啶-4-甲酸与中间体(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮肟酯化后得到白色固体8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮O-(1-甲基哌啶-4-羰基)肟。 1H NMR(DMSO-d6 400MHz)δ8.47(s,1H),8.33(d,1H),7.70-7.29(m,2H),5.96(m,1H),5.62(s,1H),2.79(m,4H),2.33-1.27(m,31H).ESI-MS m/z:488.1[M+H]+.
实施例12
1-(4-(((((8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-7,8,9,11,12,13,14,15-八氢-1H-环戊烯并[a]菲基-3(2H,6H,10H)-亚基)氨基)氧)羰基)哌啶-1-基)乙酮的合成
Figure PCTCN2022103497-appb-000033
综合实施例1-2的合成方法，1-乙酰基哌啶-4-甲酸与中间体(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮肟酯化后得到白色固体1-(4-(((((8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-7,8,9,11,12,13,14,15-八氢-1H-环戊烯并[a]菲基-3(2H,6H,10H)-亚基)氨基)氧)羰基)哌啶-1-基)乙酮。1H NMR(DMSO-d6 400MHz)δ8.47(s,1H),8.33(d,1H),7.70-7.29(m,2H),5.96(m,1H),5.62(s,1H),3.39(m,4H),2.33-1.27(m,31H).ESI-MS m/z:516.1[M+H]+.
实施例13
(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮O-(1-(2-(二甲氨基)乙基)哌啶-4-羰基)肟的合成
Figure PCTCN2022103497-appb-000034
综合实施例1-2的合成方法，1-(2-(二甲氨基)乙基)哌啶-4-甲酸与中间体(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮肟酯化后得到白色固体(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮O-(1-(2-(二甲氨基)乙基)哌啶-4-羰基)肟。1H NMR(DMSO-d6 400MHz)δ8.47(s,1H),8.33(d,1H),7.70-7.29(m,2H),5.96(m,1H),5.62(s,1H),2.66(m,6H),2.41-2.37(m,8H),2.36-1.27(m,28H).ESI-MS m/z:545.1[M+H]+.
实施例14
(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮O-(1-(环丙烷硫酰基)哌啶-4-羰基)肟的合成
Figure PCTCN2022103497-appb-000035
综合实施例1-2的合成方法，1-(环丙烷硫酰基)哌啶-4-甲酸与中间体(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮肟酯化后得到白色固体(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮O-(1-(环丙烷硫酰基)哌啶-4-羰基)肟。1H NMR(DMSO-d6 400MHz)δ8.47(s,1H),8.33(d,1H),7.70-7.29(m,2H),5.96(m,1H),5.62(s,1H),2.91(m,4H),2.36-1.27(m,33H).ESI-MS m/z:578.1[M+H]+.
实施例15
(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮O-(1-(环丙烷甲基)哌啶-4-羰基)肟的合成
Figure PCTCN2022103497-appb-000036
综合实施例1-2的合成方法，1-(环丙烷甲基)哌啶-4-甲酸与中间体(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮肟酯化后得到白色固体(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮O-(1-(环丙烷甲基)哌啶-4-羰基)肟。1H NMR(DMSO-d6 400MHz)δ8.47(s,1H),8.33(d,1H),7.70-7.29(m,2H),5.96(m,1H),5.62(s,1H),2.41(m,4H),2.36-1.27(m,35H).ESI-MS m/z:528.1[M+H]+.
实施例16
(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮O-((S)-1-甲基吡咯烷-2-羰基)肟的合成
Figure PCTCN2022103497-appb-000037
综合实施例1-2的合成方法，(S)-1-甲基吡咯烷-2-甲酸与中间体(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮肟酯化后得到白色固体(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3- 基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮O-((S)-1-甲基吡咯烷-2-羰基)肟。1H NMR(DMSO-d6 400MHz)δ8.47(s,1H),8.33(d,1H),7.70-7.29(m,2H),5.96(m,1H),5.62(s,1H),3.08(m,1H),2.36-1.27(m,32H).ESI-MS m/z:474.1[M+H]+.
实施例17
(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮O-四氢-2H-吡喃-4-羰基肟的合成
Figure PCTCN2022103497-appb-000038
综合实施例1-2的合成方法，四氢吡喃-4-甲酸与中间体(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮肟酯化后得到白色固体(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮O-四氢-2H-吡喃-4-羰基肟。1H NMR(DMSO-d6 400MHz)δ8.47(s,1H),8.33(d,1H),7.70-7.29(m,2H),5.96(m,1H),5.62(s,1H),3.55(m,4H),2.36-1.27(m,28H).ESI-MS m/z:475.1[M+H]+.
实施例18
(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮O-烟酰肟的合成
Figure PCTCN2022103497-appb-000039
综合实施例1-2的合成方法，烟酸与中间体(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮肟酯化后得到白色固体(8S,9S,10R,13S,14S)-10,13-二甲基-17-(吡啶-3-基)-6,7,8,9,10,11,12,13,14,15-十氢-1H-环戊烯并[a]菲基-3(2H)-酮O-烟酰肟。1H NMR(DMSO-d6 400MHz)δ8.88(s,1H),8.65(d,1H),8.47(s,1H),8.33(d,1H),7.70-7.29(m,4H),5.96(m,1H),5.62(s,1H),2.36-1.27(m,23H).ESI-MS m/z:468.1[M+H]+.
实施例19：***肿瘤药效学实验
测试化合物ZONK1901系列化合物(发明化合物)和ZONK1901-10(阿比特龙醋酸酯)对人***癌细胞VCaP裸鼠移植瘤模型肿瘤体内生长的抑制作用。
受试样品：实施例1化合物(B)、实施例2化合物(C)、实施例3化合物(D)、实施例4(E)、实施例5(F)、实施例6(G)、实施例7(H)及ZONK1901-19、ZONK1901-10(I)(醋酸阿比特龙)
Figure PCTCN2022103497-appb-000040
ZONK1901-19(J组)
试剂
DMEM培养液；胎牛血清；胰蛋白酶；青-链双抗；二甲基亚砜(DMSO)；TPGS；Matrigel；PBS(pH7.4，0.01M)
雄性BALB/c裸小鼠(只数：90只；周龄：6-7周)从北京维通利华实验动物技术有限公司购买，饲养于苏州圣苏新药开发有限公司SPF动物房，温度20～25℃，相对湿度40％～70％，明暗照明各12小时；动物自由饮水及采食。正常喂养约6天后，经兽医检验，体征状况良好的小鼠可入选本实验。分组前使用记号笔于动物尾根部进行标识，分组后每只动物均用耳部剪缺方式标识。
人***癌细胞VCaP，来源于中科院上海细胞库(CAS，本实验室液氮冻存)
在5％CO2、37℃培养条件下，VCaP细胞在含10％胎牛血清的DMEM培养基中进行常规细胞培养。以0.25％胰酶消化传代，根据细胞生长情况，每周传代 2-3次，传代比例为1:3至1:5。
收取对数生长期VCaP细胞，细胞计数后重悬于含50％的DMEM基础培养基和50％的Matrigel Matrix中，调整细胞浓度至5×107细胞/mL；将细胞置于冰盒中，用1mL注射器吸取细胞悬液，注射到裸鼠前右侧腋窝皮下，每只动物接种200μL(1×107细胞/只)，建立VCaP移植瘤模型。定期观察动物状态，使用电子游标卡尺测量瘤径，数据输入Excel电子表格，计算肿瘤体积，监测肿瘤生长情况。待肿瘤体积达到100～300mm3，挑选健康状况良好、肿瘤体积相近的动物60只，根据肿瘤体积采用随机区组法分为10组(n＝6)，同时尽量保证每组平均体重保持一致。以分组当天为实验第一天(D1)，实验开始后每周测量2次瘤径，计算肿瘤体积，同时称量动物体重并记录。
肿瘤体积(TV)计算公式如下：
TV(mm 3)＝l×w 2/2
其中，l表示肿瘤长径(mm)；w表示肿瘤短径(mm)。
DMSO&PEG400&PG(v:v:v，10:60:30)配制：分别吸取适量体积DMSO、PEG400和PG，混合均匀。混合液中DMSO PEG400和PG的比例为10:60:30(v:v:v)，作为空白溶媒，室温保存。
给药制剂配制
称取适量的受试化合物至玻璃瓶中，加入适量体积溶媒DMSO，涡旋超声，然后依次加入适量体积的PEG400和PG，涡旋混匀，得终浓度为0.05M的给药制剂。分装后保存于2-8oC冰箱，每次给药前涡旋振荡搅拌均匀。每7天配制一次，分装保存于4度冰箱。
ZONK1901-10给药制剂配制。
称取适量的ZONK1901-10至玻璃瓶中，加入适量体积的玉米油，涡旋振荡搅拌均匀，得终浓度为19.58mg·mL-1(0.05M)的给药制剂。分装后保存于2-8oC冰箱，每次给药前涡旋振荡搅拌均匀。每7天配制一次，分装保存于4度冰箱。
动物分组及给药方案见表1。于分组当天开始给予受试样品，28天后或溶剂对照组肿瘤体积达到2000mm3结束实验(以先达到指标为准)，给药体积均为10mL·kg-1。A组为空白溶剂组，灌胃给予空白溶媒(DMSO&PEG400&PG(v:v:v，10:60:30))，每天1次(QD)。其他组均灌胃给予受试化合物，每天1次(QD)。I组灌胃给予ZONK1901-10，给药剂量为195.8mg·kg-1(0.5mmol·kg-1)，每天1次(QD)。
表1.裸鼠移植瘤模型药效实验给药方案
Figure PCTCN2022103497-appb-000041
实验最后一天，称量体重、测量瘤径后动物安乐死(CO2)。剥取肿瘤组织、称重并拍照，计算瘤重抑瘤率。对动物进行大体解剖，肉眼观察内脏器官有无异常。动物尸体及瘤组织放入尸体存放冰箱统一处理。
数据记录、计算公式
相对肿瘤体积(RTV)的计算公式为：
RTV＝TVt/TVinitial
其中，TVinitial为分组给药时测量到的肿瘤体积；TVt为给药期间每一次测量时的肿瘤体积。
相对肿瘤增殖率(％T/C)的计算公式为：
％T/C＝100％×(RTVT/RTVC)
其中，RTVT表示治疗组RTV；RTVC表示溶剂对照组RTV。
肿瘤生长抑制率TGI(％)的计算公式为：
TGI＝100％×[1－(TV t(T)－TV initial(T))/(TV t(C)－TV initial(C))]
其中，TV t(T)表示治疗组每次测量的肿瘤体积；TV initial(T)表示分组给药时治疗组的肿瘤体积；TV t(C)表示溶剂对照组每次测量的肿瘤体积；TV initial(C)表示分组给药时溶剂对照组的肿瘤体积。
动物体重下降率的计算公式为：
动物体重下降率＝100％×(BW initial－BW t)/BW initial
其中，BW t表示给药期间每次测量的动物体重；BW initial表示分组给药时的动物体重。
瘤重抑瘤率IR(％)的计算公式为：
IR＝100％×(W C－W T)/W C
其中，W C表示对照组瘤重；W T表示治疗组瘤重。
给药期间各组动物肿瘤体积及肿瘤生长抑制率
给药期间各组动物肿瘤休积及肿瘤生长抑制率
组别 A(溶剂) B C D E F G H I J
第1天 226±12 228±14 230±12 225±7 238±16 280±15 227±21 228±14 274±18 252±21
第25天 1103±66 384±32** 393±25** 478±64** 377±37** 410±44** 405±15* 492±30** 765±46* 790±49*
抑瘤率(GI)   82.2％＊＊ 81.4％＊＊ 71.2％＊＊ 84.2％＊＊ 85.2％＊＊ 80.7％＊＊ 69.3％** 44.1％＊ 38.7％*
注：“*”表示肿瘤体积与溶剂对照组比较，存在显著性差异(P<0.05)；“**”表示肿瘤体积与溶剂对照组比较，存在极显著性差异(P<0.01)
实施例20：药代动力学实验
Figure PCTCN2022103497-appb-000042
ZONK1901-19(H组)
研究在小鼠体内灌胃给药后的药代动力学性质。
45只雄性小鼠随机分为9组(每组含5只)，实施例1化合物(B)、实施例2化合物(C)、实施例3化合物(D)、实施例4(E)、实施例5(F)、实施例6(G)、及ZONK1901-19(H)、ZONK1901-10(I)(醋酸阿比特龙)。
每只小鼠采集2-3个不连续的时间点。
建立测定小鼠全血中ZONK1901-1、ZONK1901-2浓度的LC-MS/MS分析方法。所得血药浓度数据同时采用药动学处理软件Pharsight Phoenix WinNonlin8.0非房室模型计算相关药代动力学参数。
Figure PCTCN2022103497-appb-000043
各组灌胃给药后代谢物ZONK1901-1和ZONK1901-2的主要药代动力学参数如下表：
Figure PCTCN2022103497-appb-000044
实施例21：痤疮药效学试验
健康日本大耳白兔140只，体重2.0～2.5kg，全雄。动物适应性饲养1周后按体重随机选取10只作为正常对照组，剩余130家兔于耳道口外2cm处2×2cm2范围，每日涂煤焦油一次，厚度约为0.5mm。(涂前先将煤焦油水浴加热融化，每次涂煤焦油前先将上次涂的煤焦油焦壳取下；正常对照组涂橄榄油，方法同前。)造模3周后，130只家兔按皮损程度轻重随机分为13组，分别为模型对照 组、实施例1化合物(1组)、实施例2化合物(2组)、实施例3化合物(3组)、实施例4(4组)、实施例5(5组)、实施例6(6组)、实施例7(7组)、实施例8(8组)、实施例9(9组)、实施例10(10组)、实施例11(11组)、实施例12(12组)、实施例13(13组)，每组10只。分组后，各剂量组每日上午继续涂煤焦油，下午去除煤焦油后在病损局部涂抹受试药物或对照药物(均为0.01％/10g膏，按1g膏/只涂抹)，1次/日，连续2周(模型对照组和正常对照组涂等量基质)。末次给药后24小时，空气栓塞处死动物，取耳部给药处皮肤(全层)，4％多聚甲醛溶液固定，HE染色，进行常规病理观察。
1、实验结果
对实验性兔耳痤疮模型毛囊内角化物的影响
Figure PCTCN2022103497-appb-000045
*表示与模型对照组相比，P<0.05； **表示与模型对照组相比，P<0.01；
由上表可知，与模型对照组相比，各组兔耳毛囊内角化物均有改善。
3. 2对实验性兔耳痤疮模型炎细胞浸润程度的影响
Figure PCTCN2022103497-appb-000046
Figure PCTCN2022103497-appb-000047
**表示与模型对照组相比，P<0.01；*表示与模型对照组相比，P<0.05
由上表可知，与模型对照组相比，各组兔耳炎细胞浸润程度有所改善。

Claims (8)

  1. 式I所示化合物：
    Figure PCTCN2022103497-appb-100001
    式I中，R选自：
    Figure PCTCN2022103497-appb-100002
    Ar表示取代或未取代的芳香环，具体可为苯环、吡啶环；取代基可为C1-C8的烷基、C1-C8的烷氧基、卤素；
    其中，R 1、R 2独立地选自下述基团中的任意一种：H、(C3-C8)碳环烷基、取代或未取代的(C1-C18)烷烃、(C2-C8)烯基或含有取代基的(C2-C8)烯基、(C2-C8)炔基或含有取代基的(C2-C8)炔基、(C6-C20)芳基或含有取代基的(C6-C20)芳基、(C2-C20)杂环基或含有取代基的(C2-C20)杂环基；
    或R 1、R 2相互成环为(C3-C8)杂环烷基或取代(C3-C8)杂环烷基、(C6-C20)杂芳基或取代(C6-C20)杂芳基；
    R为：
    Figure PCTCN2022103497-appb-100003
    时，R 1、R 2不可为未取代的碳原子数大于等于1的烷烃。
  2. 权利要求1中式I所示阿比特龙衍生物为如下任意一种：
    Figure PCTCN2022103497-appb-100004
    Figure PCTCN2022103497-appb-100005
    Figure PCTCN2022103497-appb-100006
    Figure PCTCN2022103497-appb-100007
    Figure PCTCN2022103497-appb-100008
    Figure PCTCN2022103497-appb-100009
    Figure PCTCN2022103497-appb-100010
    Figure PCTCN2022103497-appb-100011
    Figure PCTCN2022103497-appb-100012
  3. 权利要求1或2所述的式I所示阿比特龙衍生物在如下方面的应用：
    1)在制备真核生物肿瘤细胞增殖抑制剂中的应用；
    2)在制备预防和/或***药物中的应用。
  4. 根据权利要求3所述的应用，其特征在于：所述真核生物为哺乳动物；
    所述肿瘤细胞为癌细胞；
    所述癌细胞为***癌细胞；
    所述肿瘤为癌；所述癌为***癌。
  5. 根据权利要求4所述的应用，其特征在于：所述***癌为既往接受含多烯紫杉醇化疗转移去势难治性***癌。
  6. 一种真核生物肿瘤细胞增殖抑制剂，其包含权利要求1或2中式I所示阿比特龙衍生物。
  7. 权利要求1或2所述化合物在制备治疗痤疮药物中的应用。
  8. 一种治疗痤疮的药物，其包含含权利要求1或2中式I所示阿比特龙衍生物。
PCT/CN2022/103497 2021-08-18 2022-07-02 阿比特龙衍生物及其制备与应用 WO2023020135A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202110948115.3 2021-08-18
CN202110948115.3A CN114106077B (zh) 2021-08-18 2021-08-18 阿比特龙衍生物及其制备与应用

Publications (1)

Publication Number Publication Date
WO2023020135A1 true WO2023020135A1 (zh) 2023-02-23

Family

ID=80440925

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/103497 WO2023020135A1 (zh) 2021-08-18 2022-07-02 阿比特龙衍生物及其制备与应用

Country Status (2)

Country Link
CN (1) CN114106077B (zh)
WO (1) WO2023020135A1 (zh)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114106077B (zh) * 2021-08-18 2023-01-24 广东中科药物研究有限公司 阿比特龙衍生物及其制备与应用

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014111815A2 (en) * 2013-01-18 2014-07-24 Cortendo Ab (Publ) Abiraterone and analogs thereof for the treatment of diseases associated with cortisol overproduction
CN104974212A (zh) * 2014-04-02 2015-10-14 北京朗瑞邦科技有限公司 有抗癌作用的阿比特龙衍生物
CN106279343A (zh) * 2015-06-12 2017-01-04 郭明山 一种作为cyp11b、cyp17、cyp21抑制剂的化合物
CN106977577A (zh) * 2017-04-21 2017-07-25 湖南师范大学 两类阿比特龙衍生物的合成
CN107226834A (zh) * 2016-03-23 2017-10-03 李成凤 一种作为治疗***癌的化合物及其制备方法和用途
CN110272465A (zh) * 2019-07-15 2019-09-24 成都贝诺科成生物科技有限公司 阿比特龙衍生物、其制备方法与应用
CN114106077A (zh) * 2021-08-18 2022-03-01 广东中科药物研究有限公司 阿比特龙衍生物及其制备与应用

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW201307378A (zh) * 2010-12-16 2013-02-16 Biomarin Pharm Inc Ｃｙｐ１１ｂ、ｃｙｐ１７及／或ｃｙｐ２１抑制劑

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014111815A2 (en) * 2013-01-18 2014-07-24 Cortendo Ab (Publ) Abiraterone and analogs thereof for the treatment of diseases associated with cortisol overproduction
CN104974212A (zh) * 2014-04-02 2015-10-14 北京朗瑞邦科技有限公司 有抗癌作用的阿比特龙衍生物
CN106279343A (zh) * 2015-06-12 2017-01-04 郭明山 一种作为cyp11b、cyp17、cyp21抑制剂的化合物
CN107226834A (zh) * 2016-03-23 2017-10-03 李成凤 一种作为治疗***癌的化合物及其制备方法和用途
CN106977577A (zh) * 2017-04-21 2017-07-25 湖南师范大学 两类阿比特龙衍生物的合成
CN110272465A (zh) * 2019-07-15 2019-09-24 成都贝诺科成生物科技有限公司 阿比特龙衍生物、其制备方法与应用
CN114106077A (zh) * 2021-08-18 2022-03-01 广东中科药物研究有限公司 阿比特龙衍生物及其制备与应用

Also Published As

Publication number Publication date
CN114106077A (zh) 2022-03-01
CN114106077B (zh) 2023-01-24

Similar Documents

Publication Publication Date Title
US9216956B2 (en) Deuterium-enriched 4-hydroxy-5-methoxy-N,1-dimethyl-2-oxo-N-[(4-trifluoro-methyl)phenyl]-1,2-dihydroquinoline-3-carboxamide
BRPI0708331A2 (pt) compostos de pirimidinil sulfonamida que inibem a adesão leucocitária mediada por vla-4
CN108794555A (zh) 一种炔雌醇药物共晶及其制备方法
JP2002542162A (ja) 医薬化合物
WO2023160727A1 (zh) 吲唑类化合物用于治疗银屑病的用途
WO2023020135A1 (zh) 阿比特龙衍生物及其制备与应用
BR112013005843A2 (pt) derivativos de er-beta 6-substituído por desmetil-estradiol
BRPI0708657A2 (pt) utilização de pelo menos um composto
BR112020001362A2 (pt) derivados de ácido biliar isotopicamente marcados
JP2002505335A (ja) Ｓ−置換１１β−ベンズアルドキシム−エストラ−４，９−ジエン−炭酸チオールエステル、その製造法および該化合物を含有する製薬学的調剤
US20180319836A1 (en) Bile acid derivatives and methods for synthesis and use
US8030358B2 (en) Methods and pharmaceutical compositions for decorporation of radioactive compounds
WO2016141279A1 (en) Salicylate inhibitors of melk and methods of use
WO2021143954A2 (zh) 一种氟伐替尼或其甲磺酸盐的晶型及其制备方法
BR112019018418A2 (pt) formas cristalinas do ácido obeticólico
TW200835503A (en) Methods for improved stability of steroid derivatives
WO2018090976A1 (zh) 一种具有抗癌作用的化合物及其制备方法和应用
CA3207043A1 (en) Certain chemical entities, compositions, and methods
EP3543228B1 (en) Compound having anticancer activity, and preparation method and application thereof
JP2022538602A (ja) Ａｋｒ１ｃ３阻害剤およびその医学的使用
BRPI0721050A2 (pt) Derivados de 6-alquoxialquil estradiol e métodos de uso
EP0470995A1 (en) USE OF STEROIDS AS AN ANTI-FUNGI AGENT.
TW200845960A (en) Wortmannin-rapalog conjugate and uses thereof
WO2020023537A1 (en) Derivatives of papaverine that are effective hypoxic tumor radiosensitizers
WO2020108485A1 (zh) 一种fxr激动剂的固体形式、结晶形式、a晶型及其制备方法和应用

Legal Events

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

Ref document number: 22857448

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 2022857448

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2022857448

Country of ref document: EP

Effective date: 20240318