CN114716496B - Fulvestrant derivative, preparation method and application thereof - Google Patents

Fulvestrant derivative, preparation method and application thereof Download PDF

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CN114716496B
CN114716496B CN202210464096.1A CN202210464096A CN114716496B CN 114716496 B CN114716496 B CN 114716496B CN 202210464096 A CN202210464096 A CN 202210464096A CN 114716496 B CN114716496 B CN 114716496B
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CN114716496A (en
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王攀
李闯创
刘鑫
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Southwest University of Science and Technology
Chinese University of Hong Kong Shenzhen
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Southwest University of Science and Technology
Chinese University of Hong Kong Shenzhen
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0051—Estrane derivatives
    • C07J1/0081—Substituted in position 17 alfa and 17 beta
    • C07J1/0088—Substituted in position 17 alfa and 17 beta the substituent in position 17 alfa being an unsaturated hydrocarbon group
    • C07J1/0096—Alkynyl derivatives
    • 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
    • A61P5/30—Oestrogens
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention relates to a fulvestrant derivative, a preparation method and application thereof, wherein the fulvestrant derivative has a structure shown in a formula (I) or a formula (II):

Description

Fulvestrant derivative, preparation method and application thereof
Technical Field
The invention relates to the technical field of pharmaceutical chemistry, in particular to fulvestrant derivatives, a preparation method and application of fulvestrant derivatives.
Background
ICI 164,384 is the first selective estrogen antagonist and has no estrogenic effect. On the basis, the medicine fulvestrant is developed. Fulvestrant is a treatment developed by Astrazeneca for post-menopausal advanced breast cancer that is ineffective in antiestrogen therapy and positive for estrogen receptors. Is the only antiestrogen which can be widely used in clinic after the failure of the action of tamoxifen. Fulvestrant is a brand-new breast cancer endocrine treatment drug, binds with high affinity, blocks and down regulates the number of estrogen receptors, accelerates the loss of estrogen receptor functions, plays a role of pure antiestrogen and has no receptor agonism, so fulvestrant is not only an estrogen receptor antagonist, but also an estrogen receptor down regulator. The FDA approves the market in 2002, 4; 4 months in the united kingdom, 2004, was approved for marketing, 10 countries such as europe now, and 6 months in the country. Under the trade name of Fushide, the intramuscular injection is administered once a month, and each dose is 250mg or 500mg.
In the clinical use and biological activity research process of fulvestrant, people gradually find that the bioavailability of fulvestrant is lower and seriously influences the curative effect, so how to improve the bioavailability becomes the main direction of structural modification of the main compound.
Disclosure of Invention
Based on this, it is necessary to provide fulvestrant derivatives and fulvestrant derivative preparation methods and applications that can improve bioavailability.
A fulvestrant derivative having a structure represented by formula (I) or formula (II):
x is S or s=o;
R 1 selected from: substituted or unsubstituted C 1-16 Alkyl, substituted or unsubstituted C 1-16 Alkoxy, substituted or unsubstituted 3-20 membered cycloalkyl, substituted or unsubstituted C 2-16 Alkenyl, substituted or unsubstituted C 2-16 Alkynyl, substituted or unsubstituted 3-20 membered heterocyclyl, substituted or unsubstituted 5-20 membered aryl, or substituted or unsubstituted 5-20 membered heteroaryl;
R 2 and R is 5 Each independently selected from: H. substituted or unsubstituted C 1-16 Alkyl or-COR 6 ；
R 3 And R is 4 Each independently is H or a hydroxyl protecting group;
R 6 is H or C 1-16 An alkyl group;
l is
The preparation method of fulvestrant derivatives comprises the following steps:
oxidizing the compound shown in the formula (III-1) to obtain a compound shown in the formula (III-2);
the OH protecting group of the compound shown in the formula (III-2) is protected to obtain a compound shown in the formula (III-3);
reacting a compound shown in a formula (III-3) with an alkynyl format reagent to obtain a compound shown in the formula (III);
wherein,x is S or s=o; r is R 3 ' is a hydroxyl protecting group.
The fulvestrant derivative, the fulvestrant derivative prepared by the preparation method, the pharmaceutically acceptable salt of the fulvestrant derivative, or the pharmaceutically acceptable salt of the fulvestrant derivative prepared by the preparation method is applied to the preparation of estrogen receptor antagonistic drugs and/or estrogen receptor down-regulation drugs.
A pharmaceutical composition comprising a first drug and a second drug, wherein the first drug comprises the fulvestrant derivative, the fulvestrant derivative prepared by the preparation method, a pharmaceutically acceptable salt of the fulvestrant derivative, or a pharmaceutically acceptable salt of the fulvestrant derivative prepared by the preparation method; the second agent is an EGFR inhibitor and/or a HER2 inhibitor.
The beneficial effects are that:
researchers of the invention find that the 17 beta hydroxyl group of fulvestrant has an indispensable effect in the binding process of the fulvestrant and ER, but the 17 beta hydroxyl group can be oxidized by 17 beta-HSD 2 oxidase in vivo to generate 17-carbonyl compound without biological activity, so that the bioavailability of fulvestrant is influenced. The fulvestrant derivative is designed, so that on one hand, the 17 beta hydroxyl of fulvestrant is reserved, and the fulvestrant derivative still has the potential of combining with ER receptors; on the other hand C17 position R 1 The introduction of the group avoids 17 beta-HSD 2 oxidation, thereby achieving the aim of improving bioavailability.
The preparation method of the Fulvestrant derivative takes the Fulvestrant (Fulvestrant) shown in the formula (III-1) as a starting material, firstly converts the 17-hydroxyl into carbonyl through oxidation reaction, then protects the hydroxyl and adopts a format reagent to react, so that a product with a required configuration can be obtained in high yield, and key active group hydroxyl is introduced into the derivative again to obtain a key intermediate, thereby not only ensuring the activity of the compound, but also avoiding low bioavailability caused by oxidation of the 17-hydroxyl. After the key intermediate of the structural compound shown in the formula (III) is obtained, various fulvestrant derivatives can be obtained through simple reaction, so that the construction of a fulvestrant derivative compound library is facilitated, further, the screening of lead compounds with application potential is facilitated, and a foundation is laid for improving the activity of fulvestrant compounds, improving the bioavailability, reducing side effects and the like.
Detailed Description
The present invention will be described more fully hereinafter in order to facilitate an understanding of the present invention, and preferred embodiments of the present invention are set forth. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "and/or" as used herein includes any and all combinations of one or more of the associated listed items.
Terminology
Unless otherwise indicated or contradicted, terms or phrases used herein have the following meanings:
"substituted" as used herein means replaced by one or more groups. When multiple groups are selected from the same series of candidate substituents, they may be the same or different.
"optionally" as used herein means that the defined group may or may not be selected from a range of candidate groups.
"substituted or unsubstituted" as used herein means that the defined groups may or may not be substituted. When a defined group is substituted, it is understood to be optionally substituted with groups acceptable in the art, including but not limited to: c (C) 1-30 Alkyl, cycloalkyl containing 3 to 20 ring atoms, heterocyclyl containing 3 to 20 ring atoms, aryl containing 5 to 20 ring atoms, heteroaryl containing 5 to 20 ring atoms, silyl, carbonyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, haloformyl, formyl, -NRR', cyano, isocyano, thiocyanate, isothiocyanate, hydroxy, trifluoromethyl, nitro or halogen, and which may be further substituted with substituents acceptable in the art; it is understood that R 'and R "in-NR' R" are each independently substituted with a group acceptable in the art, including but not limited to H, C 1-6 Alkyl, cycloalkyl having 3 to 8 ring atoms, heterocyclyl having 3 to 8 ring atoms, aryl having 5 to 20 ring atoms or heteroaryl having 5 to 10 ring atoms; the C is 1-6 Alkyl, cycloalkyl having 3 to 8 ring atoms, heterocyclyl having 3 to 8 ring atoms, aryl having 5 to 20 ring atoms, or heteroaryl having 5 to 10 ring atoms is optionally further substituted with one or more of the following groups: c (C) 1-6 Alkyl, cycloalkyl having 3 to 8 ring atoms, heterocyclyl having 3 to 8 ring atoms, halogen, hydroxy, nitro or amino.
The term "x" in the present invention means a linking site, e.gTwo alkynyl groups are linked to C at position 17 of the two parent nuclei, respectively, (-) ->
The term "alkyl" refers to a radical containing primary (plus) carbon atoms, or secondarySaturated hydrocarbons of carbon atoms, or tertiary carbon atoms, or quaternary carbon atoms, or combinations thereof. Phrases containing this term, e.g., "C 1 ～C 16 Alkyl "refers to an alkyl group containing 1 to 16 carbon atoms, suitable examples include, but are not limited to: methyl (Me, -CH) 3 ) Ethyl (Et, -CH) 2 CH 3 ) 1-propyl (n-Pr, n-propyl, -CH 2 CH 2 CH 3 ) 2-propyl (i-Pr, i-propyl, -CH (CH) 3 ) 2 ) 1-butyl (n-Bu, n-butyl, -CH) 2 CH 2 CH 2 CH 3 ) 2-methyl-1-propyl (i-Bu, i-butyl, -CH) 2 CH(CH 3 ) 2 ) 2-butyl (s-Bu, s-butyl, -CH (CH) 3 )CH 2 CH 3 ) 2-methyl-2-propyl (t-Bu, t-butyl, -C (CH) 3 ) 3 ) 1-pentyl (n-pentyl, -CH) 2 CH 2 CH 2 CH 2 CH 3 ) 2-pentyl (-CH (CH 3) CH2CH2CH 3), 3-pentyl (-CH (CH) 2 CH 3 ) 2 ) 2-methyl-2-butyl (-C (CH) 3 ) 2 CH 2 CH 3 ) 3-methyl-2-butyl (-CH (CH) 3 )CH(CH 3 ) 2 ) 3-methyl-1-butyl (-CH) 2 CH 2 CH(CH 3 ) 2 ) 2-methyl-1-butyl (-CH) 2 CH(CH 3 )CH 2 CH 3 ) 1-hexyl (-CH) 2 CH 2 CH 2 CH 2 CH 2 CH 3 ) 2-hexyl (-CH (CH) 3 )CH 2 CH 2 CH 2 CH 3 ) 3-hexyl (-CH (CH) 2 CH 3 )(CH 2 CH 2 CH 3 ) 2-methyl-2-pentyl (-C (CH) 3 ) 2 CH 2 CH 2 CH 3 ) 3-methyl-2-pentyl (-CH (CH) 3 )CH(CH 3 )CH 2 CH 3 ) 4-methyl-2-pentyl (-CH (CH) 3 )CH 2 CH(CH 3 ) 2 ) 3-methyl-3-pentyl (-C (CH) 3 )(CH 2 CH 3 ) 2 ) 2-methyl-3-pentyl (-CH (CH) 2 CH 3 )CH(CH 3 ) 2 ) 2, 3-dimethyl-2-butyl (-C (CH) 3 ) 2 CH(CH 3 ) 2 ) 3, 3-dimethyl-2-butyl (-CH (CH) 3 )C(CH 3 ) 3 And octyl (- (CH) 2 ) 7 CH 3 )。
The term "cycloalkyl" refers to a non-aromatic hydrocarbon containing a ring carbon atom, which may be a monocyclic alkyl, or a spirocycloalkyl, or a bridged cycloalkyl. Phrases containing this term, e.g., "C 3 ～C 9 Cycloalkyl "means cycloalkyl containing 3 to 9 carbon atoms, and each occurrence may be, independently of the other, C 3 Cycloalkyl, C 4 Cycloalkyl, C 5 Cycloalkyl, C 6 Cycloalkyl, C 7 Cycloalkyl, C 8 Cycloalkyl or C 9 Cycloalkyl groups. Suitable examples include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. In addition, "cycloalkyl" may also contain one or more double bonds, and representative examples of cycloalkyl groups containing a double bond include cyclopentenyl, cyclohexenyl, cyclohexadienyl, and cyclobutenyl.
The term "alkoxy" refers to a group having an-O-alkyl group, i.e. an alkyl group as defined above, attached to the parent core structure via an oxygen atom. Phrases containing this term, e.g., "C 1 ～C 9 Alkoxy "means that the alkyl moiety contains from 1 to 9 carbon atoms and, at each occurrence, can be independently of one another C 1 Alkoxy, C 4 Alkoxy, C 5 Alkoxy, C 6 Alkoxy, C 7 Alkoxy, C 8 Alkoxy or C 9 An alkoxy group. Suitable examples include, but are not limited to: methoxy (-O-CH) 3 or-OMe), ethoxy (-O-CH 2 CH 3 or-OEt) and t-butoxy (-O-C (CH) 3 ) 3 or-OtBu).
"alkenyl" is intended to mean comprising a moiety having at least one unsaturation, i.e., carbon-carbon sp 2 A hydrocarbon of a normal carbon atom, a secondary carbon atom, a tertiary carbon atom or a cyclic carbon atom of the double bond. Phrases containing this term, e.g., "C 2 ～ 16 Alkenyl "refers to alkenyl groups containing 2 to 16 carbon atoms, suitable examples include, but are not limited to: vinyl (-ch=ch) 2 ) Allyl (-CH) 2 CH＝CH 2 ) Cyclopentenyl (-C) 5 H 7 ) And 5-hexenyl (-CH) 2 CH 2 CH 2 CH 2 CH＝CH 2 )。
"alkynyl" refers to a hydrocarbon containing a normal carbon atom, a secondary carbon atom, a tertiary carbon atom, or a cyclic carbon atom with at least one site of unsaturation, i.e., a carbon-carbon sp triple bond. Phrases containing this term, e.g., "C 2 ～ 16 Alkynyl "refers to alkynyl groups containing 2 to 16 carbon atoms, with suitable examples at each occurrence including, but not limited to: ethynyl (-C≡CH) and propargyl (-CH) 2 C≡CH)。
"aryl" refers to an aromatic hydrocarbon radical derived from the removal of one hydrogen atom on the basis of an aromatic ring compound, which may be a monocyclic aryl radical, or a fused ring aryl radical, or a polycyclic aryl radical, at least one of which is an aromatic ring system for a polycyclic species. For example, "5-20 membered aryl" refers to an aryl group containing 5 to 20 ring atoms, suitable examples include, but are not limited to: benzene, biphenyl, naphthalene, anthracene, phenanthrene, perylene, triphenylene, and derivatives thereof.
"heteroaryl" means that at least one carbon atom is replaced by a non-carbon atom on the basis of an aryl group, which may be an N atom, an O atom, an S atom, etc. For example, "5-20 membered heteroaryl" refers to heteroaryl groups containing 5 to 20 ring atoms, suitable examples include, but are not limited to: furan, benzofuran, thiophene, benzothiophene, pyrrole, pyrazole, triazole, imidazole, oxazole, oxadiazole, thiazole, tetrazole, indole, carbazole, pyrroloimidazole, pyrrolopyrrole, thienopyrrole, thienothiophene, furopyrrole, furofuran, thienofuran, benzisoxazole, benzisothiazole, benzimidazole, pyridine, pyrazine, pyridazine, pyrimidine, triazine, quinoline, isoquinoline, naphthyridine, quinoxaline, phenanthridine, primary pyridine, quinazoline, and quinazolinone.
"Heteroalkyl" means that at least one carbon atom is replaced by a non-carbon atom on the basis of alkyl, which may be an N atom, an O atom, an S atom, etc. For example, if the carbon atom in the alkyl group attached to the parent core structure is replaced by a non-carbon atom, the resulting heteroalkyl groups are each alkoxy groups (e.g., -OCH 3 Etc.), amines (e.g.,-NHCH 3 、-N(CH 3 ) 2 etc.) or thioalkyl (e.g., -SCH) 3 ). If the carbon atoms of the alkyl group not attached to the parent core structure are replaced by non-carbon atoms, the resulting heteroalkyl groups are each alkyl ethers (e.g., -CH 2 CH 2 -O-CH 3 Etc.), alkylamines (e.g., -CH 2 NHCH 3 、-CH 2 N(CH 3 ) 2 Etc.) or thioalkyl ethers (e.g., -CH 2 -S-CH 3 ). If the terminal carbon atom of the alkyl group is replaced by a non-carbon atom, the resulting heteroalkyl groups are each hydroxyalkyl groups (e.g., -CH 2 CH 2 -OH), aminoalkyl groups (e.g., -CH 2 NH 2 ) Or an alkylmercapto group (e.g., -CH) 2 CH 2 -SH)。
"heterocyclyl" means a cycloalkyl group in which at least one carbon atom is replaced by a non-carbon atom, which may be an N atom, an O atom, an S atom, etc., and may be a saturated or partially unsaturated ring. Phrases containing this term, for example, "3-20 membered heterocyclyl" refers to heterocyclyl groups containing 3 to 20 ring atoms, suitable examples at each occurrence include, but are not limited to: dihydropyridinyl, tetrahydropyridinyl (piperidinyl), tetrahydrothienyl, thioxotetrahydrothienyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolinyl.
"amino" refers to a derivative of ammonia having the formula-N (X) 2 Wherein each "X" is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, or the like. Non-limiting types of amino groups include-NH 2 -N (alkyl) 2 -NH (alkyl), -N (cycloalkyl) 2 -NH (cycloalkyl), -N (heterocyclyl) 2 -NH (heterocyclyl), -N (aryl) 2 -NH (aryl), -N (alkyl) (heterocyclyl), -N (cycloalkyl) (heterocyclyl), -N (aryl) (heteroaryl), -N (alkyl) (heteroaryl), and the like.
"halogen" or "halo" refers to F, cl, br or I.
As used herein, "prodrug" refers to any compound that when administered to an organism produces a drug, i.e., an active ingredient, as a result of spontaneous chemical reactions, enzyme-catalyzed chemical reactions, photolysis, and/or metabolic chemical reactions. Prodrugs are thus covalently modified analogues or potential forms of the therapeutically active compound. Suitable examples include, but are not limited to: carboxylic acid esters, carbonates, phosphates, nitrates, sulfates, sulfones, sulfoxides, amino compounds, carbamates, azo compounds, phosphoramides, glucosides, ethers, acetals, etc. of the compounds.
By "pharmaceutically acceptable" is meant those ligands, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for administration to patients and commensurate with a reasonable benefit/risk ratio.
"pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. As used herein, the language "pharmaceutically acceptable carrier" includes buffers compatible with pharmaceutical administration, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. Each carrier must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the patient. Suitable examples include, but are not limited to: (1) sugars such as lactose, glucose and sucrose; (2) Starches, such as corn starch, potato starch, and substituted or unsubstituted beta-cyclodextrin; (3) Cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) Oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) Polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) ringer's solution; (19) ethanol; (20) phosphate buffer; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.
By "pharmaceutically acceptable salt" is meant a salt of any of the compounds of the indicated structure with an acid or base, which is suitable for use as a medicament. Pharmaceutically acceptable salts include inorganic and organic salts. One type of salt is a salt of a compound of the invention with an acid. Suitable salts forming acids include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, and the like; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, and the like; amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid. Another class of salts are salts of the compounds of the present invention with bases, suitable for forming the salts include, but are not limited to: alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., magnesium or calcium salts), ammonium salts (e.g., lower alkanolammonium salts and other pharmaceutically acceptable amine salts), such as methylamine, ethylamine, propylamine, dimethylamine, trimethylamine, diethylamine, triethylamine, t-butylamine, ethylenediamine, hydroxyethylamine, dihydroxyethylamine, triethylamine, and amine salts formed from morpholine, piperazine, lysine, respectively.
"solvate" refers to a compound of formula (I) that coordinates to a solvent molecule to form a complex in a specific ratio. "hydrate" refers to a complex of the compound of the present invention coordinated to water.
Mode of administration
The dosage form and the mode of administration of the compound of the present invention or the pharmaceutical composition thereof are not particularly limited.
Representative modes of administration include, but are not limited to: oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) injection, and topical administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, e.g., glycerin; (d) Disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent, such as paraffin; (f) an absorption accelerator, e.g., a quaternary amine compound; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) an adsorbent, for example, kaolin; and (i) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents. Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active compound may also be in the form of microcapsules with one or more of the above excipients, if desired.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances. In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. Such as suspensions, may contain suspending agents as, for example, particularly ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous or nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms for topical administration include ointments, powders, patches, sprays and inhalants. Is prepared by mixing the active ingredient under aseptic condition with pharmaceutically acceptable carrier and any preservative, buffer or propellant as required.
A fulvestrant derivative having a structure represented by formula (I) or formula (II):
x is S or s=o; further, X is s=o;
R 1 selected from: substituted or unsubstituted C 1-16 Alkyl, substituted or unsubstituted C 1-16 Alkoxy, substituted or unsubstituted 3-20 membered cycloalkyl, substituted or unsubstituted C 2-16 Alkenyl, substituted or unsubstituted C 2-16 Alkynyl, substituted or unsubstituted 3-20 membered heterocyclyl, substituted or unsubstituted 5-20 membered aryl, or substituted or unsubstituted 5-20 membered heteroaryl;
further, when C 1-16 Alkyl, C 1-16 Alkoxy, 3-20 membered cycloalkyl, C 2-16 Alkenyl, C 2-16 Alkynyl, 3-20 membered heterocyclyl, 5-20 membered aryl, and 5-20 membered heteroaryl are substituted with groups selected from the group consisting of: c (C) 1-4 Alkyl, C 1-4 Alkoxy, halogen, hydroxy, nitro, 3-8 membered cycloalkyl, 3-8 membered heterolepticCyclic groups, 5-10 membered aryl groups, 5-10 membered heterocyclic groups, -COR 10 、-COOR 10 、-CONR 10 R 11 、-OCOR 10 、-NR 10 R 11 or-NCOR 10 ；R 10 And R is 11 Each independently is C 1-4 Alkyl, 3-8 membered cycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl;
further, R 1 Selected from: substituted or unsubstituted C 1-8 Alkyl, substituted or unsubstituted C 1-8 Alkoxy, substituted or unsubstituted 3-8 membered cycloalkyl, substituted or unsubstituted C 2-8 Alkenyl, substituted or unsubstituted C 2-8 Alkynyl, substituted or unsubstituted 3-10 membered heterocyclyl, substituted or unsubstituted 5-10 membered aryl, or substituted or unsubstituted 5-10 membered heteroaryl;
further, when C 1-8 Alkyl, C 1-8 Alkoxy, 3-8 membered cycloalkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, 3-10 membered heterocyclyl, 5-10 membered aryl, or 5-10 membered heteroaryl, when substituted, is selected from the group consisting of: c (C) 1-4 Alkyl, C 1-4 Alkoxy, halogen, hydroxy, nitro, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered aryl, 5-10 membered heterocyclyl, -COR 10 、-COOR 10 、-CONR 10 R 11 、-OCOR 10 、-NR 10 R 11 or-NCOR 10 ；R 10 And R is 11 Each independently is C 1-4 Alkyl, 3-8 membered cycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl;
further, R 1 Selected from: c (C) 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, R 7 Substitution C 2-8 Alkenyl or R 7 Substitution C 2-8 Alkynyl;
R 7 selected from: 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered aryl, 5-10 membered heteroaryl, R 8 Substituted 3-8 membered cycloalkyl, R 8 Substituted 3-8 membered heterocyclyl, R 8 Substituted 5-10 membered aryl, or R 8 Substituted 5-10 membered heteroaryl;
R 8 selected from: c (C) 1-4 Alkyl, C 1-4 Alkoxy, halogen,hydroxyl or amino.
Further, R 1 Selected from: c (C) 1-4 Alkyl, vinyl, ethynyl, propynyl, or 5-6 membered aryl substituted ethynyl.
Further, R 1 Selected from: methyl, ethyl, ethynyl, propynyl, phenyl substituted ethynyl or vinyl;
R 2 and R is 5 Each independently selected from: H. substituted or unsubstituted C 1-16 Alkyl or-COR 6 ；
Further, R 2 And R is 5 Each independently selected from: H. substituted or unsubstituted C 1-8 Alkyl or-COR 6 ；
Further, R 2 And R is 5 Each independently selected from: H. or-COR 6 ；
R 6 Is H or C 1-16 An alkyl group; further, R 6 Is H or C 1-4 An alkyl group; further, R 6 Is H or methyl;
R 3 and R is 4 Each independently selected from: h or a hydroxyl protecting group;
further, R 3 And R is 4 Each independently selected from: h or TBS;
l is
Further, the fulvestrant derivative is selected from any of the following compounds:
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researchers of the invention find that the 17 beta hydroxyl group of fulvestrant has an indispensable effect in the binding process of the fulvestrant and ER, but the 17 beta hydroxyl group can be oxidized by 17 beta-HSD 2 oxidase in vivo to generate 17-carbonyl compound without biological activity, so that the bioavailability of fulvestrant is influenced. The fulvestrant derivative is designed, so that on one hand, the 17 beta hydroxyl of fulvestrant is reserved, and the fulvestrant derivative still has the potential of combining with ER receptor, and on the other hand, R at C17 position 1 The introduction of the group avoids 17 beta-HSD 2 oxidation, thereby achieving the aim of improving bioavailability.
Further, structural analysis, fulvestrant consisted of estradiol units and side chains at the C7 position, i.e. introduction of specific side chains at the C7 position of estradiol resulted in therapeutically effective fulvestrant. Another pharmaceutical molecule, estrinol (ethinyl estradiol, is also obtained after the introduction of an alkynyl group at the C17 position of estradiol, and is mainly used clinically for supplementing estrogen deficiency and other diseases). The clinical effect of the estrinol proves that the C17 position of the estradiol is a modification site worthy of research, so that the molecule contains a parent structure of fulvestrant by introducing alkynyl into the C17 position, and meanwhile, 17 beta hydroxyl is reserved, so that the activity is very likely to be influenced newly, and a brand new research direction is provided for structural modification of fulvestrant derivatives.
The invention also provides a preparation method of the fulvestrant derivative, which comprises the following steps:
s101: providing a compound represented by the formula (I-1);
wherein,
the compounds of formula (I-1) are each as defined above and will not be described in detail herein.
It will be appreciated that the compound of formula (I-1) may be a commercially available starting material or may be synthesized by conventional methods, and further, step S101 includes the steps of:
s1011: providing a compound represented by the formula (I-2);
the compound shown in the formula (I-2), namely Fulvestrant, can be prepared from commercial raw materials or by an existing method.
S1012: oxidizing the hydroxyl group at 17 beta position of the compound shown in the formula (I-2) to generate R 3 A compound of formula (I-1) which is H;
specifically, PCC oxidation, answerer oxidation, oppenauer oxidation, etc., may be employed in step S1012, and further, oxidation is preferably performed by Oppenauer oxidation; further, the oxidation was performed using the following conditions:
dissolving a compound shown in a formula (I-2), aluminum isopropoxide and cyclohexanone in an organic solvent, refluxing, and separating to obtain the compound shown in the formula (I-1) after the reaction is completed;
further, the molar ratio of the compound shown in the formula (I-2) to the aluminum isopropoxide is 1 (0.7-0.9);
s1013: r is R 3 R is prepared by protecting group on hydroxyl of compound shown in formula (I-1) with H 3 A compound represented by the formula (I-1) which is a hydroxyl protecting group.
Further, the step of step S1013 includes the steps of: r is R 3 Is HDissolving the compound shown in (I-1) in an organic solvent, adding imidazole and TBSCl, and separating after the reaction is completed to obtain R 3 A compound represented by the formula (I-1) which is a hydroxyl protecting group. It is understood that, if it is desired to obtain a compound free of a protecting group, the protecting group may be removed after introducing a predetermined group through a desired reaction after step S1013, and the specific conditions for removing the protecting group are not particularly limited herein, and may be selected according to the kind of the protecting group, and are understood to be within the scope of the present invention.
In one embodiment, the protecting group is-TBS, and the deprotection method is: the compound containing the group to be deprotected was dissolved in THF, TBAF was added thereto, and the reaction was stirred until complete isolation was performed.
S102, mixing a compound represented by formula (I-1) and a compound containing R 1 Reacting the group-forming reagent to obtain R 2 A compound of formula (I) which is H;
in the step S102, the Grignard reagent is adopted for reaction, so that the product with the required configuration can be obtained in high yield, the reaction condition is mild, the reagent is cheap, and the preparation is convenient for large-scale preparation, and is particularly suitable for industrial production application.
Further, in step S102, a compound represented by the formula (I-1) and a compound containing R 1 The molar ratio of the formative reagent of the group is 1: (1.8-2.2).
Further, in step S102, a compound represented by the formula (I-1) is reacted with an alkynyl-containing Grignard reagent to obtain R 1 Is a compound shown in a formula (I) containing alkynyl;
another pharmaceutical molecule, estrinol (ethinyl estradiol, is also obtained after the introduction of an alkynyl group at the C17 position of estradiol, and is mainly used clinically for supplementing estrogen deficiency and other diseases). The clinical effect of estradiol proves that the C17 position of estradiol is a modification site worthy of research, so that the molecule comprises a parent structure of fulvestrant by introducing alkynyl into the C17 position, meanwhile, 17 beta hydroxyl is reserved, the activity is very likely to be influenced newly, and the derivative of fulvestrant containing ethynyl at the C17 position can be used as a basic compound to further prepare other derivatives, so that the screening range of the compound is widened.
Further, R is 1 The compound shown in the formula (I) containing alkynyl is subjected to catalytic hydrogenation reduction reaction, and R is prepared by controlling the reduction degree 1 Is substituted or unsubstituted C 1-16 A compound of formula (I) of alkyl, and R 1 Is substituted or unsubstituted C 2-16 A compound of formula (I) of alkenyl.
S103, R is as follows 2 A compound of formula (I) and a halogenated C 1-16 Alkyl reaction to obtain R 2 Is substituted or unsubstituted C 1-16 A compound of formula (I) of alkyl; or R is to 2 A compound of formula (I) which is HReacting to obtain R 2 is-COR 6 A compound of formula (I);
s104, R is taken as 1 Coupling reaction of the compound shown in the formula (I) in the ethynyl to obtain R 1 A compound represented by formula (I) or a compound represented by formula (II) which is substituted alkynyl.
It will be appreciated that when R is employed 1 Performing self-coupling reaction on a compound shown in a formula (I) which is ethynyl to obtain a compound shown in a formula (II); when R is adopted 1 Coupling of compounds of formula (I) which are ethynyl groups with, for example, iodinated aryl groups, to give R 1 A compound of formula (I) which is substituted alkynyl.
The invention also provides a preparation method of the fulvestrant derivative, which comprises the following steps:
s201 providing a structural compound represented by formula (III):
/>
wherein,x is S or s=o;
further, step S201 includes the steps of:
s2011: oxidizing the compound shown in the formula (III-1) to obtain a compound shown in the formula (III-2);
in the step S2011, PCC oxidation, answer oxidation, oppenauer oxidation, etc. may be adopted, and further, the oxidation is preferably performed by adopting Oppenauer oxidation, so as to improve the yield and reduce the production cost; further, the oxidation was performed using the following conditions:
dissolving a compound shown in a formula (III-1), aluminum isopropoxide and cyclohexanone in an organic solvent, refluxing, and separating to obtain a compound shown in a formula (III-2) after the reaction is completed;
further, the molar ratio of the compound shown in the formula (III-1) to the aluminum isopropoxide is 1 (0.7-0.9);
s2012: the OH protecting group of the compound shown in the formula (III-2) is protected to obtain a compound shown in the formula (III-3);
R 3 ' is a hydroxyl protecting group; further, R 3 ' is-TBS.
S2013: reacting a compound shown in a formula (III-3) with an alkynyl format reagent to obtain a compound shown in the formula (III);
R 11 h, C of a shape of H, C 1-16 Alkyl, 5-10 membered aryl or 5-10 membered heteroaryl; further, R 11 H, C of a shape of H, C 1-4 Alkyl, 5-6 membered aryl or 5-6 membered heteroaryl; further, R 11 Is H, methyl or phenyl.
The Grignard reagent is adopted for reaction, so that the product with the required configuration can be obtained in high yield, the reaction condition is mild, the reagent is cheap, and the preparation is convenient for large-scale production, and is particularly suitable for industrial production application.
S202a, carrying out hydrogenation reduction on the structural compound shown in the formula (III) to obtain the structural compound shown in the formula (III-4) and/or the formula (III-5);
it will be appreciated that the above formulas are not to be construed as limiting the invention and that the alkene may be E or Z after reduction of the alkynyl group to the alkene.
S202b: structural compound shown in formula (III)Reacting to obtain a structural compound shown in a formula (III-6);
S202c：R 11 a structural compound of formula (III) which is H andreacting to obtain a structural compound shown in a formula (III-7);
Ar 1 is a 5-10 membered aryl group;
S202d：R 11 carrying out self-coupling reaction on the structural compound shown in the formula (III) which is H to prepare the structural compound shown in the formula (IV);
s203: removing the protecting group of the structural compound shown in (III-4) to (III-7) or (IV) to obtain the corresponding compound (III-4 ') to (III-7 ') or (IV ') with the protecting group removed;
the preparation method of the Fulvestrant derivative takes the Fulvestrant (Fulvestrant) shown in the formula (III-1) as a starting material, firstly converts the 17-hydroxyl into carbonyl through oxidation reaction, then protects the hydroxyl and adopts a format reagent to react, so that a product with a required configuration can be obtained in high yield, and key active group hydroxyl is introduced into the derivative again to obtain a key intermediate, thereby not only ensuring the activity of the compound, but also avoiding low bioavailability caused by oxidation of the 17-hydroxyl. After the key intermediate of the structural compound shown in the formula (III) is obtained, various fulvestrant derivatives can be obtained through simple reaction, so that the construction of a fulvestrant derivative compound library is facilitated, further, the screening of lead compounds with application potential is facilitated, and a foundation is laid for improving the activity of fulvestrant compounds, improving the bioavailability, reducing side effects and the like.
The invention also provides the fulvestrant derivative and pharmaceutically acceptable salts of the fulvestrant derivative prepared by the preparation method.
The invention also provides application of the fulvestrant derivative, the fulvestrant derivative prepared by the preparation method, pharmaceutically acceptable salt of the fulvestrant derivative or pharmaceutically acceptable salt of the fulvestrant derivative prepared by the preparation method in preparation of estrogen receptor antagonistic drugs and/or estrogen receptor down-regulation drugs.
Further, the estrogen receptor antagonist and the estrogen receptor downregulating drug are drugs for treating breast cancer.
The invention also provides a medicine which comprises 1) the fulvestrant derivative or the pharmaceutically acceptable salt thereof and 2) pharmaceutically acceptable auxiliary materials.
The invention also provides a pharmaceutical composition, which comprises the fulvestrant derivative, the fulvestrant derivative prepared by the preparation method, the pharmaceutically acceptable salt of the fulvestrant derivative, or the pharmaceutically acceptable salt of the fulvestrant derivative prepared by the preparation method; the second drug is an EGFR inhibitor and/or a HER2 inhibitor; further, the second drug is gefitinib and/or trastuzumab.
The invention also provides a method of treating breast cancer comprising administering to a patient an effective amount of the above-described medicament or the above-described pharmaceutical composition.
The invention will now be illustrated by way of specific examples.
Example 1
Preparation of Compound 2
Fulvestrant 1 (2.47 mmol,1.0 eq), aluminum isopropoxide (1.73 mmol,0.7 eq) and cyclohexanone (5 mL) were dissolved in toluene (30 mL) and refluxed at 150 ℃ for 12h. Removing toluene and cyclohexanone under reduced pressure after the reaction is finished, and separating the residual part by a silica gel column to obtain a target product 2; the isolation yield was 85%.
13 C NMR(126MHz,CDCl 3 )δ221.1,153.6,136.6,131.9,126.8,121.0),117.5),52.8,51.1,48.2,47.2,41.7,38.3,35.9,34.6,32.9,31.9,30.,29.7,29.4,29.3,28.9,28.3,26.9,25.8,22.7,21.3,18.3,14.7,14.0,-4.3.HRMS(ESI)Calcd for:C 32 H 46 O 3 F 5 S[M]+H＝605.3082.Found:605.3078.。
Example 2
Preparation of Compound 10
Compound 2 (1.9 mmol,1.0 eq) was dissolved in DMF (9 mL) and imidazole (6.65 mmol,3.5 eq) and TBSCl (5.7 mmol,3.0 eq) were added sequentially. And (3) reacting for 5 hours at normal temperature, monitoring the reaction by TLC, and separating by a silica gel column to obtain a target product compound 10. The isolation yield was 90%.
1 H NMR(400MHz,CDCl 3 )δ7.10(s,1H),6.62(dd,J＝8.4,2.4Hz,1H),6.55(d,J＝2.3Hz,1H),2.89(dd,J＝16.7,5.0Hz,1H),2.79–2.68(m,4H),2.66–2.59(m,1H),2.49(dd,J＝19.2,8.1Hz,1H),2.38(dd,J＝11.9,6.6Hz,2H),2.23–2.12(m,4H),1.96–1.84(m,3H),1.81–1.63(m,7H),1.45(d,J＝10.1Hz,5H),1.28(d,J＝13.9Hz,10H),0.97(s,9H),0.90(s,3H),0.19(s,6H).
13 C NMR(126MHz,CDCl 3 )δ221.1,153.6,136.6,131.9,126.8,121.0,117.5,52.8,51.1,48.2,47.2,41.7,38.3,35.9,34.6,33.0,31.9,30.1,29.9,29.7,29.6,29.5,29.3,28.9,28.3,26.9,25.8,22.7,21.3,18.3,14.7,14.0,-4.3.
HRMS(ESI)Calcd for:C 38 H 60 O 3 F 5 SSi[M]+H＝719.3947.Found:719.3943
Example 3
Preparation of Compound 11
Compound 10 (0.1 mmol,1.0 eq) was dissolved in THF (1 mL), cooled to 0deg.C, and methyl Grignard reagent (0.2 mmol,2.0 eq) was added. The reaction was monitored on a silica gel plate. The reaction was quenched with saturated ammonium chloride. The solvent was removed under reduced pressure and column-separated on silica gel to give the target compound 11. The isolation yield was 72%.
Example 4
Preparation of Compound 12
Compound 10 (0.1 mmol,1.0 eq) was dissolved in THF (1 mL), cooled to 0deg.C, and propynyl grignard reagent (0.2 mmol,2.0 eq) was added. The reaction was monitored on a silica gel plate. The reaction was quenched with saturated ammonium chloride. The solvent was removed under reduced pressure and column-separated on silica gel to give the target compound 12. The isolation yield was 62%.
1 H NMR(500MHz,CDCl 3 )δ7.12(d,J＝8.5Hz,1H),6.64–6.58(m,1H),6.54(dd,J＝9.7,2.4Hz,1H),2.89–2.60(m,7H),2.39–2.12(m,9H),2.06–1.93(m,2H),1.90(s,3H),1.86–1.59(m,11H),1.51–1.36(m,6H),1.25–1.11(m,3H),0.97(s,9H),0.89–0.83(m,3H),0.19(d,J＝3.0Hz,6H).
13 C NMR(126MHz,CDCl 3 )δ153.4,136.9,132.5,126.9,120.9,117.4,83.0,81.9,80.3,77.4,77.2,76.9,52.8,51.1,47.5,46.1,42.7,39.1,38.0,34.8,33.4,33.2,30.1,29.8,29.5,29.3,29.0,28.4,27.4,27.3,25.8,22.7,22.5,18.3,14.8,13.0,4.0,-4.3.
Example 5
Preparation of Compound 13
Compound 10 (0.1 mmol,1.0 eq) was dissolved in THF (1 mL), cooled to 0deg.C, and ethynyl grignard reagent (0.2 mmol,2.0 eq) was added. The reaction was monitored on a silica gel plate. The reaction was quenched with saturated ammonium chloride. The solvent was removed under reduced pressure and the target compound 13 was obtained by silica gel column separation. The isolation yield was 83%.
1 H NMR(500MHz,CDCl 3 )δ7.12(d,J＝8.5Hz,1H),6.61(d,J＝8.4Hz,1H),6.54(d,J＝2.4Hz,1H),2.84(dd,J＝16.7,5.0Hz,1H),2.78–2.60(m,6H),2.39–2.12(m,8H),2.04–1.98(m,1H),1.92–1.61(m,9H),1.50—1.43(m,5H),1.35–1.12(m,13H),1.07–1.00(m,1H),0.97(s,9H),0.88(s,3H),0.19(s,6H).
13 C NMR(101MHz,CDCl 3 )δ153.4,136.8,132.4,126.9,120.9,117.4,87.8,80.0,74.1,52.8,51.1,47.4,46.1,42.7,39.0,38.0,34.7,33.4,33.1,31.7,29.9,29.3,28.9,28.3,27.4,25.8,25.7,22.8,22.7,22.5,21.2,18.2,14.8,14.7,14.7,12.81,-4.3.
HRMS(ESI)Calcd for:C 40 H 62 O 3 F 5 SSi[M]+H＝745.4104.Found:745.4090
Example 6
Preparation of Compounds 14 and 15
Compound 13 (0.142 mmol,1.0 eq) was dissolved in ethanol (2 mL), 42mg of 5% Pd/C was added, and the mixture was reacted at room temperature with hydrogen (hydrogen balloon) for 10 hours. Filtering Pd/C after the reaction is finished, decompressing to remove solvent, and separating by a silica gel column to obtain target compounds 14 and 15; the isolation yields were 80% and 81%, respectively.
Compound 14
1 H NMR(500MHz,CDCl 3 )δ7.13(d,J＝8.5Hz,1H),6.63(dd,J＝8.4,2.5Hz,1H),6.56(d,J＝2.4Hz,1H),2.93–2.83(m,1H),2.75(s,6H),2.39–2.13(m,7H),2.08–1.98(m,1H),1.86–1.72(m,5H),1.68–1.38(m,14H),1.25–1.16(m,4H),1.04(t,J＝7.3Hz,4H),1.00(s,9H),0.93(d,J＝3.1Hz,3H),0.92–0.83(m,2H),0.21(d,J＝2.0Hz,6H).
13 C NMR(126MHz,CDCl 3 )δ153.4,136.9,132.54,126.8,121.0,117.3,83.7,52.8,51.1,46.9,45.8,42.8,38.2,34.8,33.8,33.4,31.9,30.1,29.9,29.8,29.8,29.8,29.6,29.5,29.3,29.1,28.9,28.4,27.4,25.8,25.8,23.0,22.7,18.3,14.8,14.6,8.0.
HRMS(ESI)Calcd for:C 40 H 66 O 3 F 5 SSi[M]+H＝749.4417.Found:749.4400.
Compound 15
1 H NMR(500MHz,CDCl 3 )δ7.10(t,J＝8.7Hz,1H),6.60(d,J＝8.2Hz,1H),6.53(s,1H),6.12(dd,J＝17.0,11.0Hz,1H),5.17(dd,J＝24.9,14.0Hz,2H),2.85(d,J＝15.8Hz,1H),2.79–2.60(m,6H),2.34–2.10(m,8H),2.00(d,J＝7.8Hz,2H),1.91–1.82(m,2H),1.69–1.36(m,14H),1.17-1.1(m,4H),1.09–0.99(m,4H),0.97(d,J＝0.8Hz,9H),0.27–0.12(m,7H). 13 C NMR(126MHz,CDCl 3 )δ153.4,143.4,136.9,132.5,126.8,120.9,117.3,112.2,84.3,52.8,51.1,46.9,45.4,42.8,38.1,36.4,34.8,33.4,32.5,30.0,29.8,29.5,28.9,28.3,27.3,25.8,22.7,18.2,14.7,14.2,8.0,-4.3.
HRMS(ESI)Calcd for:C 40 H 62 O 3 F 5 SSi＝[M]-H＝745.4104.Found:745.4090
Example 7
Preparation of Compound 16
Compound 13 (0.136 mmol,1.0 eq), cuI (0.014 mmol,0.1 eq), pdCl 2 (PPh 3 ) 2 (0.007mmol,0.05eq)，Et 3 N (0.816 mmol,6 eq), DMF (1 mL), 10h of reaction, TLC monitoring reaction, silica gel column separation, yield the target product compound 16, isolated 75% yield.
1 H NMR(500MHz,CDCl 3 )δ7.45(d,J＝3.5Hz,2H),7.36–7.27(m,3H),7.13(d,J＝8.5Hz,1H),6.62(d,J＝8.2Hz,1H),6.55(s,1H),2.91-2.80(m,1H),2.78–2.53(m,6H),2.49–1.86(m,14H),1.79–1.63(m,9H),1.52–1.34(m,9H),0.98(s,9H),0.94(s,3H),0.19(s,6H).
13 C NMR(126MHz,CDCl 3 )δ153.4,136.9,132.4,131.7,128.4,128.4,126.9,123.2,121.0,117.4,93.1,86.0,80.5,52.8,51.1,48.0,46.4,42.7,39.1,38.1,34.8,33.4,30.0,29.9,29.8,29.8,29.8,29.6,29.5,29.3,28.9,28.3,27.5,25.8,25.7,22.7,22.6,18.3,14.7,14.7,13.0,-4.3.
Example 8
Preparation of Compound 18
Chemical combinationObject 13 (0.05 mmol,1.0 eq), cuI (0.01 mmol,0.2 eq), pdCl 2 (PPh 3 ) 2 (0.02 mmol,0.4 eq), reacting for 10h under oxygen condition (balloon), TLC monitoring reaction, and separating with silica gel column to obtain target product compound 18; the isolated yield was 48%.
1 H NMR(500MHz,CDCl 3 )δ7.11(d,J＝8.4Hz,2H),6.61(d,J＝8.3Hz,2H),6.54(s,2H),2.88–2.65(m,14H),2.42–2.11(m,16H),2.05-1.98(m,2H),1.86-1.79(m,4H),1.77-1.72(m,4H),1.66–1.58(m,4H),1.51–1.30(m,20H),1.26–1.15(m,10H),0.97(s,18H),0.88(s,6H),0.19(s,12H).
13 C NMR(126MHz,CDCl 3 )δ153.4,136.8,132.3,126.9,121.0,117.4,80.8,70.4,52.7,52.6,51.0,51.9,48.2,46.6,42.7,39.2,37.9,34.7,33.4,33.4,29.9,29.8,29.6,29.5,29.4,29.3,28.9,28.2,28.9,28.0,27.4,27.3,25.8,22.8,22.6,18.3,14.9,14.3,12.9,-4.24,-1.43.
HRMS(ESI)Calcd for:C80 H121 O 6F10 S 2 Si2＝[M]+H＝1487.7978.Found:1487.8011
Example 9
Preparation of Compound 19
Compound 18 (0.1 mmol,1 eq) was dissolved in THF (2 mL), TBAF solution (0.12 mmol,1.2 eq) was added, the reaction was carried out for 5h, tlc monitored the reaction, and silica gel column separation was performed to give the target product compound 19; the isolated yield was 73%.
Example 10
Preparation of Compound 3
Compound 11 (0.1 mmol,1 eq) was dissolved in THF (2 mL), TBAF solution (0.12 mmol,1.2 eq) was added, the reaction was carried out for 5h, tlc monitored the reaction, and silica gel column separation was performed to obtain the target product compound 3; the isolation yield was 85%.
1 H NMR(500MHz,CDCl 3 )δ7.13(d,J＝8.3Hz,1H),6.64(d,J＝7.5Hz,1H),6.57(s,1H),2.91–2.60(m,6H),2.35–2.12(m,6H),1.93-1.68(m,7H),1.63-1.54(m,3H),1.50–1.23(m,21H),0.89(s,3H).
13 C NMR(126MHz,CDCl 3 )δ154.1,137.1,131.4,127.1,116.3,113.1,82.0,52.6,51.0,46.1,43.0,39.1,38.3,34.9,33.4,32.0,29.8,29.7,29.3,29.2,29.0,28.9,28.7,27.5,27.4,27.3,26.1,25.2,22.7,22.6,14.3,14.0.
HRMS(ESI)Calcd for:C 33 H 50 O 3 F 5 S[M]+H＝621.3395.Found:621.3391
Example 11
Preparation of Compound 4
Compound 12 (0.05 mmol,1 eq) was dissolved in THF (1 mL), TBAF solution (0.6 mmol,1.2 eq) was added, the reaction was carried out for 5h, tlc monitored the reaction, and silica gel column separation was performed to obtain the target product compound 4; the isolation yield was 81%.
Example 12
Preparation of Compound 5
Compound 13 (0.1 mmol,1 eq) was dissolved in THF (2 mL), TBAF solution (0.12 mmol,1.2 eq) was added, the reaction was carried out for 5h, tlc monitored the reaction, and silica gel column separation was performed to give the target product compound 5; the isolation yield was 80%.
1 H NMR(500MHz,CDCl 3 )δ7.13(d,J＝8.5Hz,1H),6.67–6.62(m,1H),6.56(s,1H),2.85–2.60(m,6H),2.40–2.10(m,6H),2.10–1.97(m,2H),1.89-1.8(m,2H),1.76–1.62(m,7H),1.52–1.41(m,3H),1.11–0.99(m,1H),0.88(s,3H).
13 C NMR(126MHz,CDCl 3 )δ154.2,137.0,131.3,127.2,116.3,113.2,87.7,80.1,74.2,52.6,51.0,47.5,46.1,42.8,39.0,38.1,34.8,33.5,33.4,33.1,29.7,29.3,28.9,28.7,28.5,27.4,27.3,25.1,25.2,22.7,22.2,22.5,14.8,12.8.
Example 13
Preparation of Compound 6
Compound 14 (0.1 mmol,1 eq) was dissolved in THF (2 mL), TBAF solution (0.12 mmol,1.2 eq) was added, the reaction was carried out for 5h, tlc monitoring the reaction, and silica gel column separation was performed to obtain the target product compound 6; the isolation yield was 80%.
Example 14
Preparation of Compound 7
Compound 15 (0.1 mmol,1 eq) was dissolved in THF (2 mL), TBAF solution (0.12 mmol,1.2 eq) was added, the reaction was carried out for 5h, tlc monitored the reaction, and silica gel column separation was performed to give the target product compound 7; the isolated yield was 82%.
Example 15
Preparation of Compound 8
Compound 16 (0.1 mmol,1 eq) was dissolved in THF (2 mL), TBAF solution (0.12 mmol,1.2 eq) was added, the reaction was carried out for 5h, tlc monitored the reaction, and silica gel column separation was performed to obtain the target product compound 8; the isolation yield was 81%.
The technical features of the above-described embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above-described embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.
The above examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.

Claims (1)

1. A preparation method of fulvestrant derivatives is characterized in that the fulvestrant derivatives are compounds shown in a formula (IV) and are subjected to protective group R removal 3 ' post compound;
the preparation method comprises the following steps:
s100: oxidizing the compound shown in the formula (III-1) to obtain a compound shown in the formula (III-2); the OH protecting group of the compound shown in the formula (III-2) is protected to obtain a compound shown in the formula (III-3); reacting a compound shown in a formula (III-3) with an alkynyl format reagent to obtain a compound shown in the formula (III);
s200: carrying out self-coupling reaction on the compound shown in the formula (III) to obtain a compound shown in the formula (IV);
s400: protecting group R of the compound represented by formula (IV) 3 ' removing to obtain the fulvestrant derivative;
wherein,
x is s=o and,
R 3 ' is tert-butyl dimethylsilyl group,
R 11 is H;
wherein:
the step S100 includes: dissolving 2.47mmol of fulvestrant, 1.73mmol of aluminum isopropoxide and 5mL of cyclohexanone in 30mL of toluene, refluxing at 150 ℃ for 12 hours, removing toluene and cyclohexanone under reduced pressure after the reaction is finished, and separating the residual part by a silica gel column to obtain a compound shown in a formula (III-2), wherein the separation yield is 85%;
dissolving 1.9mmol of the compound shown in the formula (III-2) in 9mL of DMF, sequentially adding 6.65mmol of imidazole and 5.7mmol of TBSCl, reacting for 5h at normal temperature, monitoring the reaction by TLC, separating by a silica gel column, and obtaining the compound shown in the formula (III-3), wherein the separation yield is 90%;
dissolving 0.1mmoL of a compound shown in a formula (III-3) in 1mL of THF, cooling to 0 ℃, adding 0.2mmoL of an ethynyl Grignard reagent, monitoring the reaction by a silica gel plate, quenching the reaction with saturated ammonium chloride, removing a solvent under reduced pressure, and separating by a silica gel column to obtain the compound shown in the formula (III), wherein the separation yield is 83%;
the step S200 includes: 0.05mmol of the compound represented by the formula (III), 0.01mmol of CuI,0.02mmol of PdCl 2 (PPh 3 ) 2 The reaction is carried out for 10 hours under the condition of oxygen, TLC monitors the reaction, the reaction is finished, a silica gel column is separated, and the compound shown in the formula (IV) is prepared, and the separation yield is 48%.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4659516A (en) * 1983-10-12 1987-04-21 Imperial Chemical Industries Plc Steroid derivatives
EP1491551A1 (en) * 2002-04-02 2004-12-29 Chugai Seiyaku Kabushiki Kaisha Estrone derivative and process for producing the same
CN103421069A (en) * 2013-05-23 2013-12-04 中国海洋大学 Fulvestrant phosphate derivative and preparation method and application thereof
WO2021100029A2 (en) * 2019-11-24 2021-05-27 Kashiv Biosciences, Llc Prodrugs of fulvestrant

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4659516A (en) * 1983-10-12 1987-04-21 Imperial Chemical Industries Plc Steroid derivatives
EP1491551A1 (en) * 2002-04-02 2004-12-29 Chugai Seiyaku Kabushiki Kaisha Estrone derivative and process for producing the same
CN103421069A (en) * 2013-05-23 2013-12-04 中国海洋大学 Fulvestrant phosphate derivative and preparation method and application thereof
WO2021100029A2 (en) * 2019-11-24 2021-05-27 Kashiv Biosciences, Llc Prodrugs of fulvestrant

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