CN116891424A - Isothiocyanate derivative, preparation method and application thereof - Google Patents

Isothiocyanate derivative, preparation method and application thereof Download PDF

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CN116891424A
CN116891424A CN202310735071.5A CN202310735071A CN116891424A CN 116891424 A CN116891424 A CN 116891424A CN 202310735071 A CN202310735071 A CN 202310735071A CN 116891424 A CN116891424 A CN 116891424A
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substituted
unsubstituted
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heterocycloalkyl
saturated
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刘进军
王凤亮
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Qingdao Zhenxing Pharmaceutical Technology Co ltd
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Abstract

The invention provides an isothiocyanate derivative, a preparation method and application thereof. The isothiocyanate derivative, especially the aryloxy alkyl substituted isothiocyanate compound, has broad-spectrum anti-tumor activity and strong drug-forming property.

Description

Isothiocyanate derivative, preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicines, and relates to an isothiocyanate derivative, a preparation method and application thereof.
Background
Malignant tumor has become the second leading cause of death in humans, and is a serious disease that threatens human health at present, and small molecule chemotherapeutic drugs and targeted drugs are still the main means for treating malignant tumor at present. One of the important sources of small molecule drugs is the discovery of new molecules or backbone structures from nature, especially from plants. The natural medicines in China are rich in resources, active monomers are screened from the traditional Chinese medicines, and structural modification and transformation are carried out by utilizing a medicinal chemical means, so that the method has great significance in finding out novel antitumor medicines. Isothiocyanate compounds represented by Sulforaphane (Sulforaphane) are chemical substances which are found in plants and take isothiocyanato as main functional groups, and are widely distributed in plants. The compound is one of active substances with anticancer effect found in vegetables, has the effect of preventing and controlling various aging diseases, and has good medicinal value. The isothiocyanate compounds found so far have more than 100 kinds, and mainly comprise Sulforaphane (SFN), allyl isothiocyanate (allyl isothiocyanate, AITC), benzyl isothiocyanate (Benzyl isothiocyanate, BITC) and other various organic compounds such as isothiocyanato alkanes, alkenes, phenols and the like which are artificially synthesized or extracted in plants. Sulforaphane is the most representative compound among isothiocyanate compounds, mainly exists in cruciferous plants, has remarkable anti-tumor and anti-aging effects and extremely small toxic and side effects, and is therefore widely focused (Springer TA. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm [ J ]. Cell,1994, 76, 301-314). It has been found in 1992 that it has antioxidant, antitumor and other effects, and has become a research hotspot. The research shows that the sulforaphane can effectively prevent the occurrence of cancers such as liver cancer, lung cancer, prostate cancer, breast cancer, rectal cancer, gastric cancer, adenocarcinoma, skin cancer and the like. The sulforaphane also has the activities of resisting oxidation, repairing DNA damage, inhibiting I phase metabolic enzyme, inducing II phase metabolic enzyme expression, eliminating infection and the like, and plays an important role in inhibiting growth-promoting signal paths, blocking cell cycle, inducing apoptosis, inhibiting the metabolic activation of various chemical cancerogenic substances, inhibiting inflammation and the like. Sulforaphane is currently considered as a potential tumor therapeutic drug.
However, natural isothiocyanates lack a safer and more efficient method of acquisition. The isothiocyanate compounds in plants generally exist in the form of their precursor substances, namely glucoside, which has no pharmacodynamic effect and needs to be hydrolyzed by enzymes such as myrosinase to exert the pharmacodynamic function. Enzymes such as myrosinase are difficult to extract, difficult to store and denatured by heat, so that transportation, sales, storage and use of glucosides and isothiocyanates are limited. In addition, many biological activity studies remain at the enzyme and cellular level. Therefore, the compounds are used as lead compounds for structural transformation and modification, and the development of novel antitumor drugs has important theoretical and practical significance.
Disclosure of Invention
The invention aims to take sulforaphane as a lead compound, and design and synthesize a novel isothiocyanate derivative by carrying out structural transformation on the sulforaphane. By researching the structure-activity relationship of the compounds, new anticancer drugs with high biological activity and good drug-forming property are searched, and a preparation method easy to realize is provided.
In one aspect, the invention provides an isothiocyanate derivative, which is characterized in that the compound is an aryloxy alkyl substituted isothiocyanate compound, and has a structure shown in a general formula I:
Wherein:
R 1 ,R 2 can occupy any position in the ring 2,3,4 and is independently selected from the group consisting of H, OH, F, cl, br, I, CF 3 ,OR 3 ,SR 3 ,NR 4 R 5 ,CN,N 3 ,NCS,NCO,SO 2 Cl,SO 2 F,CONR 4 R 5 ,SO 2 NR 4 R 5 ,COOR 3 ,NO 2 ,CHO,CF 3 ,SO 3 H,OP(O)(O H) 2 Si (alkyl) 3 Fluoroalkyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 alkenyl, substituted or unsubstituted C1-C10 alkinyl, C1-C10 cycloalkyl, C6-C10 aryl, C6-C10 heteroaryl, C3-C20 heterocycloalkyl; alternatively, R 1 And R is 2 Adjacent may be linked to form a substituted or unsubstituted C5-C12 aromatic ring, a substituted or unsubstituted C5-C12 heteroaromatic ring, a substituted or unsubstituted C3-C10 saturated or unsaturated cycloalkyl ring, a substituted or unsubstituted saturated or unsaturated C3-C10 heterocycloalkyl ring, a substituted or unsubstituted C3-C10 spirocycloalkyl ring, a substituted or unsubstituted C3-C10 spiroheterocycloalkyl ring;
R 3 ,R 4 ,R 5 each independently selected from H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 alkenyl, substituted or unsubstituted C1-C10 alkinyl, C1-C10 cycloalkyl, C6-C10 aryl, C6-C10 heteroaryl, C3-C20 heterocycloalkyl; or R is 4 And R is 5 Can be linked to each other to form an aromatic ring, a heteroaromatic ring, or a saturated or unsaturated heterocycloalkyl ring;
W 1 ,W 2 ,W 3 each independently is C or N;
x is O, N or C;
Y 1 ,Y 2 independently selected from the group consisting of H, OH, F, cl, br, CF 3 ,OR 3 ,NR 4 R 5 Substituted or unsubstituted C1-C10 alkyl, C1-C10 cycloalkyl, C6-C10 aryl, C6-C10 heteroaryl, C3-C20 heterocycloalkyl; alternatively, Y 1 And Y 2 Are linked to each other to form a substituted or unsubstituted C5-C12 aromatic ring, a substituted or unsubstituted C5-C12 heteroaromatic ring, a substituted or unsubstituted aromatic ringAn unsubstituted saturated or unsaturated C3-C10 cycloalkyl ring, a substituted or unsubstituted saturated or unsaturated C3-C10 heterocycloalkyl ring, a substituted or unsubstituted C3-C10 spirocycloalkyl ring, or a substituted or unsubstituted C3-C10 spiroheterocycloalkyl ring;
the heteroatoms are 1 or more N, S, O atoms;
l=1 or 2;
n＝1-3；
m＝1-5。
according to some embodiments, the isothiocyanate derivative, in formula I:
R 1 ,R 2 independently selected from the group consisting of H, OH, F, cl, br, CF 3 ,OR 3 ,NR 4 R 5 Substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 alkenyl, substituted or unsubstituted C1-C10 alkinyl, C1-C10 cycloalkyl, C6-C10 aryl, C6-C10 heteroaryl, C3-C20 heterocycloalkyl; alternatively, R 1 And R is 2 Adjacent may be linked to a substituted or unsubstituted aromatic ring, a substituted or unsubstituted heteroaromatic ring, a substituted or unsubstituted saturated or unsaturated heterocyclic ring;
W 1 ,W 2 ,W 3 each independently is C or N;
x is O;
Y 1 ,Y 2 independently selected from the group consisting of H, OH, F, cl, br, CF 3 ,OR 3 ,NR 4 R 5 Substituted or unsubstituted C1-C10 alkyl, C1-C10 cycloalkyl, C6-C10 aryl, C6-C10 heteroaryl, C3-C20 heterocycloalkyl; or Y 1 And Y 2 Are linked to each other to form a substituted or unsubstituted aromatic ring, a substituted or unsubstituted heteroaromatic ring, or a substituted or unsubstituted saturated or unsaturated heterocycloalkyl ring;
l＝1；
n=1 or 2;
m＝1-5。
according to other embodiments, in formula I:
l＝1；
n=1 or 2;
m＝1-5。
according to other embodiments, in formula I:
Y 1 ,Y 2 are linked to each other to form a substituted or unsubstituted aromatic ring, a substituted or unsubstituted heteroaromatic ring, or a substituted or unsubstituted saturated or unsaturated heterocycloalkyl ring;
l＝1；
n＝1；
m＝3。
according to other embodiments, in formula I:
R 1 ,R 2 independently selected from the group consisting of H, OH, F, cl, br, CF 3 ,OCH 3 ,NR 4 R 5 ；
W 1 ,W 2 ,W 3 Each independently is C or N;
x is O;
Y 1 ,Y 2 are linked to each other to form a substituted or unsubstituted aromatic ring, a substituted or unsubstituted heteroaromatic ring, or a substituted or unsubstituted saturated or unsaturated heterocycloalkyl ring;
l＝1；
n＝1；
m＝3。
according to other embodiments, Y in formula I 1a And Y 2a Are linked to each other to form a substituted or unsubstituted C6 aromatic ring or C6 heteroaromatic ring, i.e., the isothiocyanate derivative has the structure of formula II:
wherein R is 1 ,R 2 ，R 6 Can occupy any position on the respective ring, and is independently selected from the group consisting of H, F, cl, br, I, OR 3 ,SR 3 ,NR 4 R 5 ,CN,N 3 ,NCS,NCO,SO 2 Cl,SO 2 F,CONR 4 R 5 ,SO 2 NR 4 R 5 ,COOR 3 ,NO 2 ,CHO,CF 3 ,SO 3 H,O-P(O)(O H) 2 Si (alkyl)) 3 Fluoroalkyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 alkenyl, substituted or unsubstituted C1-C10 alkinyl, C1-C10 cycloalkyl, C6-C10 aryl, C6-C10 heteroaryl, C3-C20 heterocycloalkyl; alternatively, R 1 And R is 2 Adjacent may be linked to form a substituted or unsubstituted C5-C12 aromatic ring, a substituted or unsubstituted C5-C12 heteroaromatic ring, a substituted or unsubstituted saturated or unsaturated C3-C10 cycloalkyl ring, a substituted or unsubstituted saturated or unsaturated C3-C10 heterocycloalkyl ring, a substituted or unsubstituted C3-C10 spirocycloalkyl ring, a substituted or unsubstituted C3-C10 spiroheterocycloalkyl ring, a substituted or unsubstituted C3-C10 bridged cycloalkyl ring, a substituted or unsubstituted C3-C10 bridged heterocycloalkyl ring; wherein the heteroatom is N, S, O or a combination thereof;
wherein R is 3 ,R 4 ,R 5 Each independently selected from H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 alkenyl, substituted or unsubstituted C1-C10 alkinyl, C1-C10 cycloalkyl, C6-C10 aryl, C6-C10 heteroaryl, C3-C20 heterocycloalkyl; or R is 4 And R is 5 Can be linked to each other to form an aromatic ring, a heteroaromatic ring, a saturated or unsaturated heterocycloalkyl ring;
W 1 ,W 2 ,W 3 ,W 4 ,W 5 ,W 6 ,W 7 each independently is C or N;
x is O, N or C;
l=1 or 2;
n＝1-3；
m＝1-5。
according to other embodiments, the isothiocyanate derivative has the structure of formula III:
wherein R is 1 ,R 2 ，R 7 Can occupy any position on the respective ring, and is independently selected from the group consisting of H, F, cl, br, I, OR 3 ,SR 3 ,NR 4 R 5 ,CN,N 3 ,NCS,NCO,SO 2 Cl,SO 2 F,CONR 4 R 5 ,SO 2 NR 4 R 5 ,COOR 3 ,NO 2 ,CHO,CF 3 ,SO 3 H,O-P(O)(OH) 2 (Si) alkyl group 3 Fluoroalkyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 alkenyl, substituted or unsubstituted C1-C10 alkinyl, C1-C10 cycloalkyl, C6-C10 aryl, C6-C10 heteroaryl, C3-C20 heterocycloalkyl; alternatively, R 1 R 2 Adjacent may be linked to form a substituted or unsubstituted C5-C12 aromatic ring, a substituted or unsubstituted C5-C12 heteroaromatic ring, a substituted or unsubstituted saturated or unsaturated C3-C10 cycloalkyl ring, a substituted or unsubstituted saturated or unsaturated C3-C10 heterocycloalkyl ring, a substituted or unsubstituted C3-C10 spirocycloalkyl ring, a substituted or unsubstituted C3-C10 spiroheterocycloalkyl ring, a substituted or unsubstituted C3-C10 bridged cycloalkyl ring, a substituted or unsubstituted C3-C10 bridged heterocycloalkyl ring; wherein the heteroatom is N, S or O or a combination thereof;
wherein R is 3 ,R 4 ,R 5 Each independently selected from H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 alkenyl, substituted or unsubstituted C1-C10 alkinyl, C1-C10 cycloalkyl, C6-C10 aryl, C6-C10 heteroaryl, C3-C20 heterocycloalkyl; or R is 4 And R is 5 Can be linked to each other to form an aromatic ring, a heteroaromatic ring, a saturated or unsaturated heterocycloalkyl ring;
x is O, N or C;
l=1 or 2;
n＝1-3；
m＝1-5。
in another aspect, the present invention provides a method for preparing the isothiocyanate derivative, comprising the steps of:
(1) Under the catalysis of triphenylphosphine and DIAD, M1 and G-XH undergo Mitsunobu etherification reaction to produce an intermediate M3;
(2) M3 is hydrolyzed by catalytic amide, and phthalic acid structure is removed to obtain an intermediate M4;
(3) Catalyzing M4 and thiocarbonyldiimidazole by triethylamine to carry out nucleophilic substitution reaction to obtain an intermediate M5;
(4) M5 and H 2 O 2 Performing oxidation reaction to prepare a target product:
in one embodiment, the steps (1) to (4) include:
(1) Weighing a proper amount of G-X, placing the mixture into a double-neck flask, adding triphenylphosphine (3 eq) at room temperature, adding a proper amount of dichloromethane with proper volume, replacing with nitrogen, transferring to an ice bath (0 ℃), dropwise adding DIAD (3 eq) while stirring when the system temperature is stable, discharging a large amount of heat, slowly dropwise adding a dichloromethane solution of M1 (1.3 eq), and stirring overnight in an ice bath; adding a proper amount of 1N hydrochloric acid solution into the reaction solution, extracting with dichloromethane twice, mixing the organic phases, washing the organic phases with saturated saline solution, drying with anhydrous sodium sulfate, and purifying to obtain a product (M3) for the next reaction;
(2) Weighing the product (M3) of the previous step into a round-bottom flask, adding an appropriate volume of ethanolamine, adding a 20% NaOH aqueous solution, replacing with nitrogen, transferring to 50 ℃ for reaction, stirring for 5 hours, and stopping the reaction after LC-MS detection shows that the reaction is complete; adding proper volume of ethyl acetate and water, regulating pH to 10, separating, extracting the water phase with proper volume of ethyl acetate for the second time, mixing the organic phases, washing twice with half-saturated saline solution, and drying with anhydrous sodium sulfate to obtain a product M4;
(3) Dissolving the product M4 of the previous step by using a proper volume of dichloromethane, adding triethylamine (1.0 eq), displacing nitrogen, transferring to an ice bath for stirring, dissolving thiocarbonyldiimidazole (1.0 eq) by using a proper volume of dichloromethane, dropwise adding into a dichloromethane system of the M4 in the ice bath, continuing to stir in the ice bath for 20min after adding, transferring to room temperature for stirring overnight, and stopping the reaction after the LC-MS detection shows that the reaction is complete; post-treatment, namely adding a proper volume of dichloromethane into the reaction solution, washing twice with half-saturated saline solution, drying with anhydrous sodium sulfate, and concentrating to obtain a product M5;
(4) Dissolving the product M5 in proper volumes of ethanol and acetic acid (5/1, v/v), stirring in an ice bath, slowly dropwise adding hydrogen peroxide (4.0 eq), transferring to room temperature, stirring for reaction, stirring overnight, performing LC-MS monitoring, drying most of the ethanol in a water bath at 45 ℃ in a spinning way, adding a proper volume of dichloromethane for extraction, extracting the aqueous phase again, merging the organic phases, washing with half-saturated salt water for 4-5 times, washing with saturated salt water, drying with anhydrous sodium sulfate, spinning, and purifying by a high-pressure reverse phase chromatographic column to obtain the target compound (I').
In yet another aspect, the invention provides the use of said isothiocyanate derivative in the treatment or prophylaxis of a disease, wherein said disease is cancer. The use in treating a disease comprises administering a therapeutically effective amount of the isothiocyanate derivative or pharmaceutical composition thereof to a patient in need thereof.
In addition, the invention also provides the use of the isothiocyanate derivative in the manufacture of a medicament comprising a therapeutically effective amount of the isothiocyanate derivative or a pharmaceutical composition thereof. The medicament is for the treatment or prevention of a disease, wherein the disease is cancer.
The cancer includes solid tumors such as pancreatic cancer, liver cancer, lung cancer, breast cancer, melanoma, multiple myeloma, gastric cancer, colorectal cancer, or non-solid tumors such as hematological tumors.
Detailed Description
The present invention will be further described in connection with the examples which follow, to provide a more complete understanding of the invention to those skilled in the art, but are not to be construed as limiting the invention in any way. The starting materials used for the experiments in the present invention were either purchased from reagent suppliers or prepared from known starting materials via methods well known in the art.
The following definitions are provided to clarify their specific usage in the context of this document.
The "alkyl" refers to a saturated or unsaturated, straight or branched chain of up to 12 carbon atoms, such as an alkyl group containing 1 to 12, 1 to 10, 1 to 8, 1 to 6, or 1 to 4 carbon atoms, and the alkyl group may have one or more substituents, such as containing 1 to 12, 1 to 10, 1 to 8, 1 to 6, or 1 to 4 carbon atoms, and the alkyl group may have one or more substituents; examples of such alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl (isopropyl), 1-butyl, 2-methyl-1-propyl (isobutyl), 2-butyl (sec-butyl), -2-methyl-2-propyl (tert-butyl), 1-pentyl, 2-pentyl, 3-pentyl, -2-methyl-2-butyl, 3-ethyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 2-methyl-3-pentyl, 2, 3-dimethyl-2-butyl, 3-dimethyl-2-butyl, hexyl, octyl, decyl, dodecyl, and the like. "cycloalkyl" refers to a monocyclic or bicyclic alkyl, saturated or unsaturated but not having aromatic character, e.g., containing 3 to 10 carbon atoms, and which cycloalkyl may have one or more substituents selected from halogen, C1-C6 linear or branched alkyl, C1-C6 linear or branched trihaloalkyl, hydroxyl, amine, C1-C6 linear or branched alkylamino, C1-C6 dialkylamino wherein each alkyl moiety may be linear or branched. The "aryl" refers to an aromatic hydrocarbon group resulting from the removal of at least one hydrogen atom from a single carbon atom of a parent aromatic ring system, which may have 6 to 30 carbon atoms, for example about 6-10 carbon atoms, such as phenyl, benzyl, optionally bearing one or more different substituents at the 2,3,4,5,6 position, and which may have one or more substituents selected from halogen, hydroxy, C1-C6 linear or branched alkyl, C1-C6 linear or branched alkoxy, cyano, nitro, amino, C1-C6 linear or branched alkylamino, dialkylamino wherein each alkyl moiety may be linear or branched, carboxy, C1-C6 linear or branched alkoxycarbonyl, C1-C6 linear or branched alkylcarbonyl, aminocarbonyl wherein the amino moiety is optionally substituted by one or two identical or different C1-C6 linear or branched alkyl groups. "heteroaryl" means an aromatic monocyclic group, an aromatic bicyclic group, or a bicyclic group wherein one ring is aromatic and the other is partially hydrogenated, containing 5 to 12 ring atoms, and wherein the ring system contains one, two, or three heteroatoms selected from oxygen, nitrogen, or sulfur; and the aryl-heteroaryl groups may bear one or more identical or different substituents selected from halogen, hydroxy, C1-C6 linear or branched alkyl, C1-C6 linear or branched alkoxy, cyano, nitro, amino, C1-C6 linear or branched alkylamino, C1-C6 dialkylamino in which each alkyl moiety may be linear or branched, carboxy, C1-C6 linear or branched alkoxycarbonyl, C1-C6 linear or branched alkylcarbonyl, aminocarbonyl in which the amino moiety is optionally substituted by one or two identical or different C1-C6 linear or branched alkyl groups. "heterocycloalkyl" means a mono-or bicyclic group containing one or two heteroatoms selected from oxygen, sulfur or nitrogen in the ring system, which are saturated or unsaturated but not of aromatic character, which contain 3 to 10 carbon atoms, and which may have one or more identical or different substituents selected from halogen, C1-C6 linear or branched alkyl, C1-C6 linear or branched trihaloalkyl, hydroxy, amino, C1-C6 linear or branched alkylamino, C1-C6 dialkylamino wherein each alkyl moiety may be linear or branched, said heterocycloalkyl being optionally substituted with one or more of those substituents recited in cycloalkyl.
The term "substituted" or "substituent" is used herein to mean that one or more (e.g., 1-20 in some embodiments, 1-10 in other embodiments, 1, 2, 3, 4, or 5 in some embodiments, 1, 2, or 3 in some embodiments, and 1 or 2) hydrogens on the group represented therewith are replaced with a selection from the specified substituents or suitable groups known to those skilled in the art. Such substituents include, for example, alkyl, alkenyl, alkynyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, alkylamino, dialkylamino, trifluoromethylthio, difluoromethyl, acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thio, alkylthio, alkylsulfinyl, alkylsulfonyl and cyano. For example, in some embodiments, the substituents include OH, NH 2 ，N(CH 3 ) 2 ，F，Cl，Br，I，CF 3 ，OCH 3 ，CO 2 H，CO 2 CH 3 ，CN，NCS,SO 3 H,SO 2 Cl,SO 2 F，Si(CH 3 ) 3 ，OP(O)(OH) 2 Aryl and heteroaryl.
The term "effective amount" herein refers to an amount that is effective to treat a disease or condition. For example, the "effective amount" may be a dose effective to slow the progression or extent of the treated disease or condition being treated. Therapeutically effective amounts are well within the ability of those skilled in the art. The term "effective amount" is meant to include the amount of a compound described herein or a pharmaceutical composition thereof.
The term "treating" herein includes (i) preventing or preventing the occurrence of a disease or condition, inhibiting or preventing the development of a disease or condition, and/or reducing or alleviating the extent of a disease or condition.
In an embodiment of the present invention, the present invention provides a preparation method of the above isothiocyanate derivative as shown in formula (I), wherein the compound of formula (II) can be prepared by referring to the following method:
synthetic route 1:
the synthesis steps are as follows:
synthesis of M1
An appropriate amount of compound 1 and cesium carbonate (2.5 eq) are weighed, placed in a round bottom flask, an appropriate amount of acetonitrile is added, nitrogen is replaced for 3 times, the mixture is transferred to an ice bath (0 ℃) for stirring, 2-mercaptoethanol (2.0 eq) is dropwise added when the system temperature is stable, and the mixture is continuously stirred at 0 ℃ for reaction for two hours. LC-MS detection showed that the reaction was stopped after completion.
Post-treatment: quenching with 6N hydrochloric acid solution to pH=2-3 in ice bath, spin drying most acetonitrile, extracting twice with proper amount of ethyl acetate, mixing organic phases, washing twice with water to remove 2-mercaptoethanol, washing with half saturated sodium bicarbonate solution to remove acid with half of the protection group of imide, washing with saturated saline solution, drying with anhydrous sodium sulfate, and spin drying to obtain M1 with purity of more than 98%.
ESI-MS：m/z[M+H]+＝280.4。
Synthesis of M3a
An appropriate amount of M2a was weighed into a two-necked flask, triphenylphosphine (3 eq) was added at room temperature, an appropriate amount of dichloromethane was added, the mixture was replaced with nitrogen, and then the mixture was transferred to an ice bath (0 ℃ C.) until the system temperature was stable, DIAD (3 eq) was added dropwise with stirring, a large amount of heat was released, and a dichloromethane solution of M1 (1.3 eq) was slowly added dropwise, and the mixture was stirred overnight in an ice bath.
Post-treatment: the reaction solution is added with a proper amount of 1N hydrochloric acid solution, dichloromethane is used for extraction twice, the organic phases are combined, the saturated saline water is used for washing the organic phases, anhydrous sodium sulfate is used for drying, and M3 is obtained after purification.
Synthesis of M4a
Weighing a proper amount of M3a into a round-bottom flask, adding a proper amount of ethanolamine, adding a 20% aqueous solution of NaOH, replacing with nitrogen, transferring to 50 ℃ for reaction, stirring for 5 hours, and stopping the reaction after LC-MS detection shows that the reaction is complete.
Post-treatment: adding proper volume of ethyl acetate and water, regulating pH to 10, separating liquid, extracting water phase with proper volume of ethyl acetate for the second time, combining organic phases, washing twice with half-saturated saline solution, drying with anhydrous sodium sulfate, and obtaining a product M4a which is directly used for the next reaction without further purification.
Synthesis of M5a
Dissolving the M4a in the last step by using a proper volume of dichloromethane (the equivalent weight is calculated as M3 a), adding triethylamine (1.0 eq), replacing nitrogen, transferring to an ice bath for stirring, dissolving thiocarbonyldiimidazole (1.0 eq) by using a proper volume of dichloromethane, dropwise adding the mixture into a dichloromethane system of the M4a in the ice bath, continuing to stir in the ice bath for 20min after adding, transferring to room temperature for stirring overnight, and stopping the reaction after the LC-MS detection shows that the reaction is complete. After-treatment, the reaction solution was added with an appropriate volume of dichloromethane, washed twice with half-saturated saline solution, dried over anhydrous sodium sulfate, and concentrated to give M5a, which was used directly in the next step.
5. Synthesis of Compound (I' a)
Dissolving M5a into proper volumes of ethanol and acetic acid (5/1, v/v), stirring under ice bath, slowly dropwise adding hydrogen peroxide (4.0 eq), transferring to room temperature, stirring for reaction, standing overnight, performing LC-MS detection on the fact that the M5a shows that the reaction is complete, spin-drying most of the ethanol in a water bath at 45 ℃, adding a proper volume of dichloromethane for extraction, extracting water phase again, combining organic phases, washing with half-saturated salt water for 4-5 times, washing with saturated salt water, drying with anhydrous sodium sulfate, spin-drying, and purifying by a high-pressure reverse phase chromatographic column to obtain the compound (I).
Example 1: preparation of the Compound 2'- (2- ((4-isothiocyanatobutyl) sulfanyl) ethoxy) - [1,1' -biphenyl ] -2-ol
The synthetic route is as follows:
the synthesis steps are as follows:
1. synthesis of Compound 2- (4- ((2 '-hydroxy- [1,1' -biphen-2-yl) oxy) ethyl) thio) butyl) isolinoline-1, 3-dione
The starting compound 1,1' -biphenyl ] -2,2' -diol (M2 ') (2.00 g,10.74 mmol) was weighed into a two-necked flask, triphenylphosphine (3.84 g,14.65 mmol) was added, 20mL of dichloromethane was added, nitrogen was substituted, the mixture was transferred to ice bath (0 ℃), DIAD (2.96 g,14.65 mmol) was added dropwise after the system temperature had stabilized, a large amount of heat was released, and a solution of M1 (2.73 g,9.76 mmol) in dichloromethane (10 mL) was slowly added dropwise after the addition, and the mixture was stirred overnight in ice bath.
Post-treatment: the reaction mixture was extracted twice with 20mL of 1N hydrochloric acid, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by high-pressure reverse phase chromatography to give 3.22g of 2- (4- ((2 ' -hydroxy- [1,1' -biphen-2-yl) oxy) ethyl) thio) butanolide-1, 3-dione (M3 ') as an oil in a yield of 74.35%. Without further purification, it was used directly in the next step.
ESI-MS：m/z[M+H] + ＝448.15。
2. Synthesis of the Compound 2'- (2- ((4-aminobutyl) thio) ethoxy) - [1,1' -biphenyl ] -2-ol.
2- (4- ((2 ' -hydroxy- [1,1' -biphen-2-yl) oxy) ethyl) thio) butyl) isoiindoline-1, 3-dione (M3 ') (1.00 g,2.24 mmol) was weighed into a round bottom flask, 5mL of ethanol amine was added, replaced with nitrogen, and the mixture was transferred to 50℃for reaction. Reaction was complete as indicated by detection of LC-MS from 5 h.
M3' may also be weighed into a round bottom flask, added with 20% NaOH aqueous solution, replaced with nitrogen, transferred to 50 ℃ for reaction, stirred for 5 hours, and after LC-MS detection shows complete reaction, the reaction is stopped.
Post-treatment: 20mL of ethyl acetate and 20mL of water were added, the aqueous phase was extracted a second time with 20mL of ethyl acetate, the organic phases were combined, washed twice with half-saturated brine, and dried over anhydrous sodium sulfate to give 2'- (2- ((4-aminobutyl) thio) ethoxy) - [1,1' -biphenyl ] -2-ol as an oil.
Without further purification, it was used directly in the next step.
ESI-MS：m/z[M+H] + ＝318.15。
3. Synthesis of Compound 2'- (2- ((4-isothiocyanatobutyl) thio) methoxy) - [1,1' -biphenyl ] -2-ol
The previous 2'- (2- ((4-aminobutyl) thio) method) - [1,1' -biphenyl ] -2-ol (M4 ') (equivalents calculated as M3') was dissolved with 10mL of dichloromethane, triethylamine (226 mg,2.23 mmol) was added, nitrogen was displaced, and the mixture was transferred to stirring under ice bath, thiocarbonyldiimidazole (0.40 g,2.23 mmol) was dissolved with 5mL of dichloromethane, dropwise added to the dichloromethane system of M4 under ice bath, after addition, stirring under ice bath was continued for 20min, and the mixture was transferred to room temperature overnight until LC-MS detection showed complete reaction.
After the reaction mixture was washed twice with 10mL of half-saturated brine and dried over anhydrous sodium sulfate, 10mL of methylene chloride was added to the mixture, followed by spin-drying to give 2' - (2- ((4-isothiocyanatobutyl) thio) ethoxy) - [1,1' -biphenyl ] -2-ol (M5 '). Without further purification, it was used directly in the next step.
ESI-MS：m/z[M+H] + ＝360.10。
4. Synthesis of the Compound 2'- (2- ((4-isothiocyanatobutyl) sulfanyl) ethoxy) - [1,1' -biphenyl ] -2-ol
To 2' - (2- ((4-isothiocyanatobutyl) thio) method) - [1,1' -biphenyl ] -2-ol (M5 ') obtained in the above step were added 10mL of ethanol and 2mL of acetic acid, stirred in an ice bath, slowly dropped with hydrogen peroxide (321.45 mg,9.45 mmol), transferred to room temperature and stirred for reaction, stirred overnight, medium control MS showed complete reaction, spin-dry most of the ethanol at 45 ℃, add 20mL of dichloromethane and 20mL of water for extraction, 20mL of dichloromethane re-extract the aqueous phase, combine the organic phases, wash with half saturated brine 4-5 times, wash with saturated brine, dry with anhydrous sodium sulfate, spin-dry, purification by high pressure reverse phase chromatography to give 2' - (2- ((4-isothiocyanato) method) - [1,1' -biphenyl ] -2-ol as an oil. The purity is more than 97 percent, and the yield is 71 percent.
ESI-MS：m/z[M+H] + ＝376.11；
1 H NMR(400MHz,cdcl 3 )δ7.43–7.36(m,1H),7.35–7.27(m,2H),7.21(dd,J＝7.5,1.3Hz,1H),7.15(t,J＝7.5Hz,1H),7.08(d,J＝8.3Hz,1H),7.04–6.97(m,2H),4.58–4.39(m,2H),3.47(dd,J＝13.2,7.8Hz,2H),3.20–3.09(m,1H),2.96(ddd,J＝13.9,5.6,3.2Hz,1H),2.62(dt,J＝13.5,6.7Hz,1H),2.50–2.38(m,1H),1.78–1.65(m,4H)。
Example 2: preparation of the Compound 4- (2- ((4-isothiocyanatobutyl) sulfanyl) methoxy) quinone
Starting from the corresponding starting material, the preparation was carried out analogously to compound example 1 above to give the compound 4- (2- ((4-isothioyanatobutyl) sulfofinyl) ethoxy) quinone:
the synthetic route is as follows:
the synthesis steps are as follows:
1. synthesis of Compound 2- (4- ((2- (4-yloxy) ethyl) thio) butyl) isoinoline-1, 3-dione
In a two-necked flask, 2.00g (13.78 mmol) of quinolin-4-ol (M2') (2.00 g (41.33 mmol) was weighed, triphenylphosphine (10.84 g (41.33 mmol)) was added, and 20mL of dichloromethane was added and replaced with nitrogen, and the mixture was transferred to an ice bath (0 ℃ C.) until the system temperature was stable, DIAD (8.36 g (41.33 mmol)) was added dropwise with a large amount of heat released, and a solution of M1 (5.00 g (17.91 mmol)) in dichloromethane (5 mL) was slowly added dropwise, and the mixture was stirred overnight in an ice bath.
Post-treatment: the reaction mixture was extracted twice with 20mL of 1N hydrochloric acid, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by high pressure reverse phase chromatography to give 3.40g of M3' as an oil in a yield of about 60.71%.
ESI-MS：m/z[M+H]+＝407.137。
2. Synthesis of Compound 4- ((2- (quinoin-4-yloxy) ethyl) thio) batan-1-amine
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M3-015 (1.00 g,2.46 mmol) was weighed into a round bottom flask, 5mL of ethanolamine was added, nitrogen was displaced, the reaction was transferred to 50℃and stirred for 5h, and after stirring the reaction, the reaction was stopped as indicated by a medium MS.
M3 "may also be weighed into a round bottom flask, added with 20% naoh aqueous solution, replaced with nitrogen, transferred to 50 ℃ for reaction, stirred for 5h, and after LC-MS detection showed complete reaction, the reaction was stopped.
Post-treatment: 20mL of ethyl acetate and 20mL of water were added, pH was adjusted to 10, the solution was separated, the aqueous phase was extracted a second time with 10mL, the organic phases were combined, washed twice with half-saturated brine, dried over anhydrous sodium sulfate to give an oil M4', immediately following.
ESI-MS：m/z[M+H]+＝277.13
3. Synthesis of Compound 4- (2- ((4-isothiocyanatobutyl) thio) methoxy) quinone
The last step of M4 "(equivalent weight is calculated as M3") was dissolved with 20mL of dichloromethane, triethylamine (226 mg,2.46 mmol) was added, nitrogen was displaced, transferred to stirring under ice bath, thiocarbonyldiimidazole (0.40 g,2.46 mmol) was dissolved with 10mL of dichloromethane, added dropwise to the dichloromethane system of M4' under ice bath, stirring under ice bath was continued for 20min, transferred to stirring overnight at room temperature, LC-MS was controlled completely and the reaction was stopped.
After the reaction mixture was washed twice with 10mL of methylene chloride and 10mL of half-saturated brine, dried over anhydrous sodium sulfate, and spin-dried to give M5' which was used directly in the next step.
ESI-MS：m/z[M+H]+＝318.10。
4. Synthesis of the Compound 4- (2- ((4-isothiocyanatobutyl) sulfanyl) methoxy) quinone
Adding 10mL of ethanol and 2mL of acetic acid into the solution obtained in the previous step, stirring the solution in an ice bath, slowly dropwise adding hydrogen peroxide (251.03 mg,7.38 mmol), transferring the solution to room temperature, stirring the solution for reaction, stirring the solution overnight, performing medium-control MS to show that the reaction is complete, performing spin-drying on most of the ethanol at 45 ℃, adding 20mL of dichloromethane for extraction, extracting the aqueous phase again by 10mL of dichloromethane, combining the organic phases, washing the organic phases with half-saturated salt water for 4-5 times, washing the saturated salt water, drying the solution by anhydrous sodium sulfate, performing spin-drying, and purifying the solution by high-pressure reverse phase chromatography to obtain the API with the purity of more than 99 percent and the yield of about 76 percent.
ESI-MS：m/z[M+H]+＝335.10；
1H NMR(400MHz,d2o)δ8.75(d,J＝6.7Hz,1H),8.28(d,J＝8.5Hz,1H),7.91(d,J＝3.0Hz,2H),7.73–7.67(m,1H),7.31(d,J＝6.8Hz,1H),3.51–3.30(m,4H),1.84–1.67(m,4H),1.08(d,J＝6.4Hz,4H)。
Example 3: preparation of the Compound 5,5' -dially-2, 2' -bis (2- ((4-isothiocyanatobutyl) sulfanyl) -1,1' -biphen yl) ethoxy
Starting from the corresponding starting material, the preparation was carried out analogously to compound example 1 described above, to give the compound 5,5' -dially-2, 2' -bis (2- ((4-isothiocyanatobutyl) sulfanyl) -1,1' -biphenyl:
the synthetic route is as follows:
the synthesis steps are as follows:
1. synthesis of the Compound 2,2'- ((5, 5' -dialkylene- [1,1'-biphen ] -2,2' -diyl) bis (oxy)) bis (ethane-2, 1-diyl)) bis (sulfanediyl)) bis (butane-4, 1-diyl)) bis (isoinoline-1, 3-dione)
5,5'-diallyl- [1,1' -biphenyl ] -2,2'-diol (M2') (0.86 g,3.22 mmol) was weighed into a two-necked flask, triphenylphosphine (2.82 g,10.74 mmol) was added, 20mL of toluene was added, nitrogen was substituted, and the mixture was transferred to ice bath (0 ℃ C.), DIAD (2.18 g,10.74 mmol) was added dropwise until the system temperature was stable, 2- (4- ((2-hydroxylethyl) thio) isoindole-1, 3-dione (M1) (2.00 g,7.12 mmol) was slowly added dropwise, and after the addition, the mixture was transferred to 80 ℃ C. Reflux for 5h, LC-MS was completely controlled, and the reaction was stopped.
Post-treatment: toluene was dried by spinning, the reaction mixture was added with 20mL of dichloromethane and 20mL of 1N hydrochloric acid solution, the organic phases were combined, the saturated brine was used for washing the organic phase, dried over anhydrous sodium sulfate, dried by spinning, and purified by silica gel column chromatography to give 3.91g of M3' "oil with a yield of about 69.20%.
ESI-MS：m/z[M+H]+＝789.29。
2. Synthesis of the Compound 4,4'- ((5, 5' -dially- [1,1'-biphenyl ] -2,2' -diyl) bis (oxy)) bis (ethane-2, 1-diyl)) bis (sulfanediyl)) bis (batan-1-amine)
M3' (1.27 g,1.61 mmol) was weighed into a round bottom flask, 10mL of ethanolamine was added, 20% aqueous NaOH solution was added, nitrogen was purged, and the mixture was transferred to 50℃for reaction. After 5h of reaction, LC-MS was controlled to complete the reaction and stopped. Post-treatment: 20mL of ethyl acetate and 20mL of water were added, the aqueous phase was extracted twice with 20mL of ethyl acetate, the organic phases were combined, washed twice with half-saturated brine, and dried over anhydrous sodium sulfate to give an oil M4', which was used directly in the next step.
ESI-MS：m/z[M+H]+＝529.28。
3. Synthesis of the Compound ((5, 5' -dialkylyl- [1,1' -biphenyl ] -2,2' -dialkylyl) bis (oxy)) bis (ethane-2, 1-diyl)) bis (4-isothiocyanatobutyl) sulfane
The last M4 ' "(equivalent weights were calculated as M3 '") was dissolved with 20mL of dichloromethane, triethylamine (0.97 g,9.61 mmol) was added, displaced with nitrogen, transferred to stirring under ice bath, thiocarbonyldiimidazole (1.71 g,9.61 mmol) was dissolved with 10mL of dichloromethane, dropwise adding the mixture into a dichloromethane system of M4 ' in an ice bath, continuing stirring in the ice bath for 20min after adding, transferring to room temperature, stirring overnight, and stopping the reaction after the central control reaction is completed.
After the reaction mixture was washed twice with 10mL of methylene chloride and 10mL of half-saturated brine, dried over anhydrous sodium sulfate, and spin-dried to give M5' "which was used directly in the next step.
ESI-MS：m/z[M+H]+＝613.20；
4. Synthesis of the Compound 5,5' -dially-2, 2' -bis (2- ((4-isothiocyanatobutyl) sulfanyl) -1,1' -biphen yl) ethoxy
20mL of ethanol and 2mL of acetic acid were added, stirred in an ice bath, and hydrogen peroxide (1.00 g,
29.41 mmol) was transferred to room temperature and stirred for reaction overnight, the medium MS showed complete reaction, most of the ethanol was spin-dried at 45 ℃,20mL of dichloromethane and 20mL of water were added for extraction, 20mL of dichloromethane were used for re-extraction of the aqueous phase, the organic phases were combined, half-saturated brine was washed 4-5 times, saturated brine was washed, dried over anhydrous sodium sulfate, spin-dried, and purified by high pressure reverse phase chromatography to give the compound 5,5' -dially-2, 2' -bis (2- ((4-isothiocyanatobutyl) sulfanyl) -1,1' -biphenyl, 99% purity, three step yield about 62%.
ESI-MS：m/z[M+H]+＝645.18；
1H NMR(400MHz,cdcl3)δ7.14(d,J＝8.3Hz,2H),7.04(s,2H),6.91(dd,J＝8.4,3.2Hz,2H),5.95(ddt,J＝16.8,10.0,6.7Hz,2H),5.06(t,J＝12.7Hz,4H),4.41–4.20(m,4H),3.51(d,J＝5.7Hz,4H),3.35(d,J＝6.7Hz,4H),3.18–2.73(m,4H),2.61–2.27(m,4H),1.78–1.60(m,8H)。
Example 4: preparation of the Compound 2- (2- ((4-isothiocyanatobutyl) sulfanyl) ethol)
Starting from the corresponding starting material, the preparation was carried out analogously to compound example 1 above to give the compound 2- (2- ((4-isothioyacyanatobutyl) sulfofinyl) ethoxy) phenol:
ESI-MS：m/z[M+H]+＝300.00；
1H NMR(400MHz,DMSO-d6)δ8.979(s,1H),6.981(d,J＝8Hz,1H),6.814(d,J＝0.8Hz,2H),6.755–6.713(m,1H),4.343–4.305(m,2H),3.739(t,J＝6.0Hz,2H),3.259–3.211(m,1H),3.071-3.013(m,1H),2.969-2.833(m,2H),1.806–1.754(m,4H)。
Example 5: preparation of the Compound 4- (2- ((4-isothiocyanatobutyl) sulfanyl) ethoxy) pyridine
Starting from the corresponding starting material, the compound 4- (2- ((4-isothioyacyanatobutyl) sulfanyl) ethoxy) pyridine was obtained using a preparation method similar to that of compound example 1 described above:
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ESI-MS：m/z[M+H]+＝285.15；
1H NMR(400MHz,DMSO-d6)δ8.41(dd,J＝4.8,1.6Hz,2H),7.03(dd,J＝4.4,1.6Hz,2H),4.49–4.40(m,2H),3.74(t,J＝5.6Hz,2H),3.27–3.24(m,1H),3.11-3.05(m,1H),2.93-2.78(m,2H),1.79–1.76(m,4H)。
example 6: the preparation of compound 2- (2- (2- ((4-isothiocyanatobutyl) sulfanyl) ethoxy) benzol) phenol was started from the corresponding starting material and compound 2- (2- (2- ((4-isothiocyanatobutyl) sulfanyl) ethoxy) benzol) phenol was obtained by a similar preparation method to that of the above-described compound example 1.
ESI-MS：m/z[M+H]+＝390.00；
1 H NMR(400MHz,DMSO-d6)δ9.29(s,1H),7.174(td,J＝7.2,1.6Hz,1H),7.042-6.983(m,3H),6.914(d,J＝7.6Hz,1H),6.856(t,J＝7.6Hz,1H),6.796(d,J＝8Hz,1H),6.676(t,J＝7.6Hz,1H),4.411–4.282(m,2H),3.825(dd,J＝18.4,15.6Hz,2H),3.718(t,J＝6.0Hz,2H),3.274-3.205(m,1H),3.080-3.025(m,1H),2.888-2.730(m,2H),1.770-1.720(m,4H)。
Example 7: preparation of the Compound 5,5' -dially-2 ' - (2- ((4-isothiocyanatobutyl) sulfanyl) ethoxy) - [1,1' -biphenyl ] -2-yl dihydrogen phosphate
The synthetic route is as follows:
starting from the corresponding starting material, the preparation was carried out analogously to compound example 1 described above, 5'-diallyl-2' - (2- ((4-isothiocyanatobutyl) sulfanyl) method) - [1,1'-biphen yl ] -2-ol was obtained, a 250ml two-necked flask was taken, 5' -diallyl-2'- (2- ((4-isothiocyanato) sulfanyl) method) - [1,1' -biphen yl ] -2-ol (2 g,4.34 mmol), 50ml of dichloromethane was added, triethylamine (1.78 g,17.6 mmol) was added, nitrogen was displaced, the mixture was transferred to-20℃until the system temperature was stabilized, phosphorus oxychloride (0.81 g,5.27 mmol) was slowly added dropwise, the reaction was continued for 7h, pH was adjusted to about 8 with saturated aqueous sodium bicarbonate, the extract was extracted, and the organic phase was dried and purified by reverse phase chromatography to give a yield of more than about 20% purity by means of 400% at a target pressure.
ESI-MS：m/z[M+H]+＝536.13；
1H NMR(400MHz,CDCl3)δ7.50(d,J＝8Hz,1H),7.03(d,J＝8Hz,1H),6.96(s,3H),6.66(d,J＝8Hz,1H),5.99-5.80(m,2H),5.06(dd,J＝36,16Hz),4.06(s,1H),3.95(s,1H),3.34(d,J＝8Hz),3.25(s,1H),2.85(s,1H),2.52(s,1H),2.22(s,1H),1.43(s,4H)。
Example 8: preparation of the Compound 4- (2- ((4-isothiocyanatobutyl) sulfanyl) methoxy) -6, 7-dimthoxyquinone
Starting from the corresponding starting material, the compound 4- (2- ((4-isoxyanaetobutyl) sulfanyl) ethoxy) -6, 7-dimethoxyquinone is obtained using a preparation method analogous to that described above for compound example 1:
the synthetic route is as follows:
the synthesis steps are as follows:
1. synthesis of Compound 2- (4- ((2- ((6, 7-dimthoxyquinol-4-yl) oxy) ethyl) thio) butyl) isoinoline-1, 3-dione
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M2' (7.7 g,37.55 mmol) was taken in a three-necked flask, triphenylphosphine (14.77 g,56.32 mmol) was added, 100mL of dichloromethane was added, the mixture was displaced with nitrogen, the mixture was transferred to ice bath (0 ℃ C.), DIAD (11.39 g,56.32 mmol) was added dropwise, a solution of M1 (11.01 g,39.42 mmol) in dichloromethane (50 mL) was slowly added dropwise, and the mixture was stirred overnight in ice bath.
Post-treatment: 80mL of 1N hydrochloric acid solution was added to the reaction solution, the mixture was extracted twice with dichloromethane, the organic phases were combined, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and dried by spin-drying. 70mL of ethanol is added, the mixture is recrystallized in ice bath, overnight, filtered by suction, washed twice with a small amount of ethanol and dried by spin to obtain M3'. The yield thereof was found to be 78%.
2. Synthesis of Compound 4- ((2- ((6, 7-dimethoxyquinone-4-yl) oxy) ethyl) thio) batan-1-amine (M4-053).
M3"" (9.35 g,20 mmol) was weighed into a round bottom flask, 50mL of ethanolamine was added, replaced with nitrogen, and the reaction was transferred to 80 ℃. After 5 hours of reaction, LCMS was controlled until a small amount of the by-product was not reacted, the reaction was transferred to room temperature, 5mL of an aqueous solution of sodium hydroxide (1.14, 28.4 mmol) was added, nitrogen was replaced, and the reaction was stopped after stirring overnight at room temperature.
Post-treatment: 100mL of ethyl acetate and 100mL of water were added, the aqueous phase was extracted a second time with 100mL of ethyl acetate, the organic phases were combined, washed twice with half-saturated brine, and dried over anhydrous sodium sulfate to give an oil M4', immediately following the next step.
ESI-MS：m/z[M+H]+＝337.2。
3. Synthesis of the Compound 4- (2- ((4-isothiocyanatobutyl) thio) methoxy) -6, 7-dimthoxyquinone
The previous step M4 'was dissolved with 100mL of methylene chloride, triethylamine (1.92 g,18.9mmol, calculated as M1) was added, nitrogen was displaced, the mixture was transferred to stirring under ice bath, thiocarbonyldiimidazole (3.4 g,18.9mmol, calculated as M1) was dissolved with 40mL of methylene chloride, added dropwise to the methylene chloride system of M4' under ice bath, stirring under ice bath was continued for 20min after the addition, the mixture was transferred to stirring at room temperature overnight, LCMS was completed with a controlled reaction, and the reaction was stopped.
Post-treatment: the solution was washed twice with half-saturated saline (except imidazole), dried over anhydrous sodium sulfate, and spin-dried to give M5', which was used directly in the next step.
ESI-MS：m/z[M+H]+＝379.11。
4. Synthesis of the Compound 4- (2- ((4-isothiocyanatobutyl) thio) methoxy) -6, 7-dimthoxyquinone
100mL of ethanol and 10mL of acetic acid are added, stirred in an ice bath, hydrogen peroxide (4.3 g,37.9mmol calculated by M1) is slowly added dropwise, the mixture is transferred to room temperature for stirring reaction, stirring is carried out overnight, a central control MS shows that the reaction is complete, most of the ethanol is dried by spinning at 45 ℃, 100mL of dichloromethane and 30mL of water are added for extraction, 30mL of dichloromethane is used for extracting the water phase again, the organic phases are combined, half saturated salt water is washed for 4-5 times, saturated salt water is washed, anhydrous sodium sulfate is dried, the mixture is dried by spinning, 50mL of EA is used for recrystallization and purification in an ice bath, and the white solid 8g is obtained by suction filtration, wherein the purity is more than 99%.
ESI-MS：m/z[M+H]+＝395.10；
1H NMR(400MHz,cdcl3)δ7.18(dd,J＝8.4,2.3Hz,1H),7.14–7.05(m,1H),6.99(dd,J＝12.2,5.3Hz,2H),6.89(d,J＝8.2Hz,1H),6.09(s,1H),6.03–5.88(m,2H),5.16–4.99(m,3H),4.53–4.34(m,2H),3.46(dd,J＝9.2,3.8Hz,1H),3.36(dd,J＝8.3,6.7Hz,4H),3.12(ddd,J＝12.7,8.5,4.1Hz,1H),2.93(ddd,J＝13.9,5.5,3.4Hz,1H),2.62(dt,J＝13.6,6.8Hz,1H),2.46(dt,J＝13.3,7.5Hz,1H),1.79–1.56(m,4H)。
Example 9: preparation of the Compound 4- (2- ((4-isothiocyanatobutyl) sulfanyl) ethoxy) -1H-indole
Starting from the corresponding starting material, the preparation was carried out analogously to compound example 1 above to give the compound 4- (2- ((4-isothioyacyanatobutyl) sulfanyl) ethoxy) -1H-indole:
ESI-MS：m/z[M+H]+＝322.95；
1H NMR(400MHz,DMSO-d6)δ11.099(s,1H),7.229(t,J＝2.8Hz,1H),7.02(dd,J＝19.6,8.0Hz,1H),7.019(s,1H),6.566(d,J＝7.2Hz,1H),6.413(t,J＝2.0Hz,1H),4.520–4.393(m,2H),3.738(t,J＝6.0Hz,2H),3.319(dd,J＝9.2,5.2Hz,1H),3.147–3.091(dt,J＝13.6,4.0Hz,1H),2.989–2.892(m,1H),1.793(d,J＝3.6Hz,4H)。
example 10: preparation of the Compound 8- (2- ((4-isothiocyanatobutyl) sulfanyl) method) quinazolin-2-amine
Starting from the corresponding starting material, the preparation was carried out analogously to compound example 1 above to give the compound 8- (2- ((4-isothiocyanatobutyl) sulfofinyl) ethoxy) quinazolin-2-amine (ZXS-093):
ESI-MS：m/z[M+H]+＝351.15；
1H NMR(400MHz,DMSO-d6)δ9.072(s,1H),7.390(d,J＝7.2Hz,1H),7.266(d,J＝7.6Hz,1H),7.140(t,J＝7.6,1H),6.838(s,1H),4.549-4.465(m,2H),3.739(t,J＝6.0Hz,2H),3.379–3.274(m,1H),3.182-3.095(d,dt,J＝5.2,13.6,4.4Hz,1H),3.021-2.890(m,2H),1.794(s,4H))。
Example 11: preparation of the Compound 2,2'-bis (2- ((4-isothiocyanatobutyl) sulfofinyl) method) -1,1' -biphenyl
Starting from the corresponding starting material, the preparation was carried out analogously to compound example 1 described above, to give the compound 2,2'-bis (2- ((4-isothiocyanatobutyl) sulfanyl) -1,1' -biphenyl:
ESI-MS：m/z[M+H]+＝565.40，
1H NMR(400MHz,DMSO-d6)δ7.342(dd J＝15.6,1.6Hz,1H),7.342(s,1H),7.195-7.166(dt,J＝7.6,2.4Hz,2H),7.124(dd J＝8.0,2.8Hz,2H),7.014(t,J＝7.2,1H),4.387-4.238(m,4H),3.675(t,J＝5.8,4H),3.156-3.096(m,2H),2.981-2.907(m,2H),2.573(t,J＝6.6Hz,4H),1.703–1.563(m,8H)。
example 12: preparation of the Compound 4- (3- ((4-isothiocyanatobutyl) sulfanyl) proxy) quinone
Starting from the corresponding starting material, the compound 4- (3- ((4-isothioyacyanatobutyl) sulfanyl) proxy) quinone) was obtained using a preparation method similar to that described above for compound example 1:
ESI-MS：m/z[M+H]+＝349.45；
1H NMR(400MHz,DMSO-d6)δ8.734(d,J＝5.2Hz,1H),8.211(d,J＝8.4Hz,1H),7.952(d,J＝8.4Hz,1H),7.749(t,J＝8.0Hz,1H),7.572(t,J＝8.0Hz,1H),7.033(d J＝5.2Hz,1H),4.392(t,J＝4.4,1H),3.735(t,J＝4.4,1H),3.081-3.009(m,1H),2.947-2.839(m,1H),2.801-2.733(m,1H),2.316-2.317(m,1H),1.774(s,4H)。
example 13: preparation of the Compound 4- (2- ((2-isothiocyanatotoethyl) thio) methoxy) quinone
Starting from the corresponding starting material, the preparation was carried out analogously to compound example 1 above to give the compound 4- (2- ((2-isoxyanaethyl) thio) method) quinone:
ESI-MS：m/z[M+H]+＝291.15；
1H NMR(400MHz,DMSO-d6)δ8.747(d,J＝5.2Hz,1H),8.156(d,J＝8.4Hz,1H),7.962(d,J＝8.4Hz,1H),7.759(dd,t,J＝15.2,1.6,1.6Hz,1H),7.586(dd,t,J＝15.2,1.2,1H),7.069(d,J＝5.2Hz,1H),4.450(t,J＝6.4,2H),3.922(t,J＝6.4,2H),3.143(t,J＝6.4,2H),3.012(t,J＝6.8,2H)。
example 14: preparation of the Compound 4- (2- ((2-isothiocyanatotoethyl) sulfanyl) methoxy) quinone
Starting from the end product of example 13, the compound 4- (2- ((2-isoxyanaethyl) sulfanyl) ethoxy) quinone is obtained using an oxidation process similar to that described above for compound example 1:
ESI-MS：m/z[M+H]+＝307.40；
1H NMR(400MHz,DMSO-d6)δ8.771(d,J＝5.2,2.8Hz,1H),8.186-8.156(dd,J＝
8.4,3.6Hz,1H),7.975(d,J＝8.4Hz,1H),7.771(t,J＝8.0Hz,1H),7.596(td,J＝7.2,0.8Hz,1H),7.153(t,J＝4.4Hz,1H),4.765-4.569(m,2H),,3.598-3.458(m,2H),1.912-1.818(d,4H)。
example 15: preparation of the Compound 4- (2- ((6-isothiocyanatoxyl) sulfofinyl) method) quinone
Starting from the corresponding starting material, the compound 4- (2- ((6-isoxyyanatoxyl) sulfanyl) ethoxy) quinone) was obtained using a similar preparation method as that described above for compound example 1:
ESI-MS：m/z[M+H]+＝363.50；
1H NMR(400MHz,DMSO-d6)δ8.764(d,J＝5.2Hz,1H),8.161(d,J＝8.4Hz,1H),7.977(d,J＝8.4Hz,1H),7.769(t,J＝8.0Hz,1H),7.597(t,J＝8.0Hz,1H),7.141(d,J＝5.2Hz,1H),4.723-4.472(m,1H),4.634-4.575(td,J＝9.6,3.6Hz,1H),3.664(t,J＝6.4,2H),3.384-3.415(m,1H),3.258-3.203(dt,J＝14,4.4Hz,1H),2.964-2.798(m,2H),1.754-1.624(m,4H),1.482-1.380(m,4H)。
example 16: preparation of the Compound 2-chloro-2'- (2- ((4-isothiocyanatobutyl) sulfofinyl) methoxy) -1,1' -biphenyl
Starting from the corresponding starting material, the compound 2-chloro-2'- (2- ((4-isothiocyanatobutyl) sulfanyl) ethoxy) -1,1' -biphenyl) was obtained using a similar preparation method as described in compound example 1 above:
ESI-MS：m/z[M+H]+＝394.00；
1H NMR(400MHz,DMSO-d6)δ7.540-7.500(m,1H),7.426-7.367(m,3H),7.341-7.307(m,1H),7.718(t,J＝8.0Hz,2H),7.059(t,J＝7.2Hz,1H),4.405-4.276(m,2H),3.677(t,J＝5.6Hz,2H),3.139-3.072(m,1H),2.953-2.896(m,1H),2.580(t,J＝6.8,2H),1.699-1.581(m,4H)。
example 17: preparation of Compound 4- (2- ((4-isothiocyanatobutyl) sulfanyl) methoxy) -1H-indazole (ZXS-156)
Starting from the corresponding starting material, the preparation was carried out analogously to compound example 1 above to give the compound 4- (2- ((4-isothioyacyanatobutyl) sulfanyl) ethoxy) -1H-indazole:
ESI-MS：m/z[M+H]+＝324.35；
1H NMR(400MHz,DMSO-d6)δ13.07(s,1H),7.99(s,1H),7.26(t,J＝8.0Hz,1H),7.12(d,J＝8.0Hz,1H),6.63(d,J＝8.0Hz,1H),4.57-4.48(m,2H),3.74(t,J＝4.0Hz,2H),3.39-3.32(m,1H),3.18-3.11(m,1H),2.97-2.93(m,1H),2.89-2.84(m,1H),1.82-1.77(m,1H)。
example 18: preparation of the Compound (E) -4- (2- ((4-isothiocyanatobut-1-en-1-yl) sulfanyl) methoxy) quinone
Starting from the corresponding starting material, the preparation was carried out analogously to compound example 1 above to give the compound (E) -4- (2- ((4-isoxyanastabut-1-en-1-yl) sulfanyl) methoxy) quinone:
ESI-MS：m/z[M+H]+＝333.40；
1H NMR(400MHz,DMSO-d6)δ8.751(d,J＝5.2Hz,1H),8.178(dd,J＝7.6,4.8Hz,1H),7.966(d,J＝8.4Hz,1H),7.762(t,J＝7.6Hz,1H),7.595(td,J＝8.0,2.8Hz,1H),7.116(dd,J＝9.2,5.2Hz,1H),6.931-6.677(m,1H),6.346-6.266(m,1H),4.686-4.555(m,2H),3.839-3.740(m,2H),3.563-3.4343(m,2H),2.802-2.540(m,2H)。
example 19: preparation of Compound 4- ((5-isothiocyanatopentyl) oxy) quinone
Starting from the corresponding starting material, the preparation was carried out analogously to compound example 1 above to give the compound 4- ((5-isothioyacyanatopenyl) oxy) quinone:
ESI-MS：m/z[M+H]+＝273.10；
1H NMR(400MHz,DMSO-d6)δ8.196-8.172(dt,J＝8.0,0.8Hz,1H),8.008(d,J＝7.6Hz,1H),7.743-7.725(m,2H),7.398-7.358m,1H),6.049(d,J＝7.6Hz,1H),4.257(t,J＝7.2Hz,2H),3.668(t,J＝6.4Hz,2H),1.787-1.641(m,4H),1.437-1.360(m,2H)。
Example 20: preparation of the Compound 4- (2- (2-isothiocyanatotoethoxy) ethoxy) quinone
Starting from the corresponding starting material, the compound was obtained using a preparation method analogous to that of compound example 1 above:
ESI-MS：m/z[M+H]+＝275.08；
1H NMR(400MHz,DMSO-d6)δ8.741(d,J＝5.2Hz,1H),8.215(dd,J＝8.4,1.2Hz,1H),7.955(d,J＝8.4Hz,1H),7.752(td,J＝7.2,1.6Hz,1H),7.752(td,J＝6.8,1.2Hz,1H),7.050(d,J＝5.2Hz,1H),4.417(t,J＝4.4Hz,2H),3.980(t,J＝4.4Hz,2H),3.881(t,J＝4.8Hz,2H),3.781(t,J＝5.2Hz,2H)。
example 21: human tumor cell line proliferation Activity test
1) The effect of the compounds on proliferation activity of 10 tumor cell lines was determined using the CellTiter-Glo assay. Tumor cell lines A549 (lung cancer human alveolar basal epithelial cell), hep G2 (human liver cancer cell), mia PaCa-2 (human pancreatic cancer cell), THP-1 (human monocytic leukemia cell), SW1463 (KRAS mutant colorectal cancer), MM1R (multiple myeloma), MP41 (melanoma), BT-549 (human milk) were selectedAdeno-associated cancer cells), HCC 1806 (human breast cancer cells), MDA-MB-231 (human breast cancer cells), the in vitro antitumor activity of the synthesized compounds was evaluated by CellTiter-Glo method, and Staurosporine was used as a positive control. Taking tumor cells in logarithmic growth phase, adding a proper volume of culture medium into a centrifuge tube, and gently beating to make the cells re-suspended uniformly. Counts were performed using a Vi-Cell XR cytometer. The cell suspension was brought to the appropriate concentration. The cell suspension was added to a 96-well plate at 100. Mu.L/well. Labeling detailed information such as cell name, plate density, date, etc., placing the culture plate in CO 2 The incubator was left overnight.
2) The test compounds were prepared as 20mM stock solution in DMSO and added to the corresponding cell wells using an HPD300 automated drug feeder and incubated for 120 hours at 37℃in a 5% carbon dioxide incubator.
3) Examples of cell proliferation inhibition experiments section
4) The compound pairs in the examples were A549 (lung cancer human alveolar basal epithelial cells), hep G2 (human hepatoma cells), mia PaCa-2 (human pancreatic cancer cells), THP-1 (human monocytic leukemia cells), SW1463 (KRAS mutant colorectal cancer), MM1R (multiple myeloma), MP41 (melanoma), BT-549 (human breast ductal carcinoma cells), HCC
1806 Proliferation of (human breast cancer cells) and MDA-MB-231 (human breast cancer cells) showed an inhibitory effect. Wherein ZXS-055 shows obvious inhibition effect on SW1463 (KRAS mutant colorectal cancer), MM1R (multiple myeloma) and MP41 (melanoma), the IC50 values of the inhibition effect are respectively 0.265, 0.017 and 0.098, and the proliferation inhibition effect of ZXS-136 on Hep G2 (human hepatoma cells), mia PaCa-2 (human pancreatic cancer cells) and THP-1 (human monocytic leukemia cells) is obvious, and the IC50 values of the inhibition effect are respectively 0.308, 0.602, 0.227 and 0.628. Cell proliferation inhibition experimental data show that the inhibition effect of the series of compounds on A549 (lung cancer human alveolar basal epithelial cells) is weaker than that of the series of compounds on other tested tumor strains.
5) The structure-activity analysis was performed by cell proliferation inhibition experimental data. the-NCS structure in the compound should be a structure with efficacy or a structure with increased efficacy, wherein the inhibition of cell proliferation is significantly reduced after ZXS-059 loses the-NCS structure. In contrast to ZXS-136 and ZXS-015, proper extension of the side chain length of a compound is beneficial in increasing the cell proliferation inhibition of the compound.
6) In summary, by introducing other different groups into the structure of the sulforaphane, or modifying the structure of the sulforaphane, more derivatives with tumor cell proliferation inhibition effect are obtained. While retaining the-NCS structure, the trend of the antitumor activity of the compound is obvious when the side chain is prolonged. In the cyclic structure part of the compound, the compound with a coupled aromatic ring or aromatic heterocycle and parallel double-ring structure has better tumor cell proliferation inhibition activity than that of a single-ring structure. Therefore, compounds with better antitumor activity, higher selectivity and more advantageous patent drug properties are sought by further taking sulforaphane as a basic skeleton, and valuable information is provided.
Half Inhibitory Concentration (IC) of isothiocyanate derivative on tumor cells 50 )
Cytological IC50 data test compounds were derived from the compounds in the examples, in a non-one-to-one correspondence, and the positive control for the test was staurosporine.

Claims (11)

1. An isothiocyanate derivative having the structure of formula I:
wherein:
R 1 ，R 2 can occupy any position in the ring 2,3,4, each independently selected from the group consisting of: h, OH, F, cl, br, I, CF 3 ，OR 3 ，SR 3 ，NR 4 R 5 ，CN，N 3 ，NCS，NCO，SO 2 Cl，SO 2 F，CONR 4 R 5 ，SO 2 NR 4 R 5 ，COOR 3 ，NO 2 ，CHO，CF 3 ，SO 3 H，OP(O)(OH) 2 Si (alkyl) 3 Fluoroalkyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 alkenyl, substituted or unsubstituted C1-C10 alkinyl, C1-C10 cycloalkyl, C6-C10 aryl, C6-C10 heteroaryl, C3-C20 heterocycloalkyl; alternatively, R 1 And R is 2 Adjacent may be linked to form a substituted or unsubstituted C5-C12 aromatic ring, a substituted or unsubstituted C5-C12 heteroaromatic ring, a substituted or unsubstituted C3-C10 saturated or unsaturated cycloalkyl ring, a substituted or unsubstituted saturated or unsaturated C3-C10 heterocycloalkyl ring, a substituted or unsubstituted C3-C10 spirocycloalkyl ring, a substituted or unsubstituted C3-C10 spiroheterocycloalkyl ring;
R 3 ，R 4 ，R 5 each independently selected from the following groups: h, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 alkenyl, substituted or unsubstituted C1-C10 alkinyl, C1-C10 cycloalkyl, C6-C10 aryl, C6-C10 heteroaryl, C3-C20 heterocycloalkyl; or R is 4 And R is 5 Can be linked to each other to form an aromatic ring, a heteroaromatic ring, or a saturated or unsaturated heterocycloalkyl ring;
W 1 ，W 2 ，W 3 Each independently is C or N;
x is O, N or C;
Y 1 ，Y 2 each independently selected from the following groups: h, OH, F, cl, br, CF 3 ，OR 3 ，NR 4 R 5 Substituted or unsubstituted C1-C10 alkyl, C1-C10 cycloalkyl, C6-C10 aryl, C6-C10 heteroaryl, C3-C20 heterocycloalkyl; alternatively, Y 1 And Y 2 Are linked to each other to form a substituted or unsubstituted C5-C12 aromatic ring, substituted or unsubstituted CA 5-C12 heteroaryl ring, a substituted or unsubstituted saturated or unsaturated C3-C10 cycloalkyl ring, a substituted or unsubstituted saturated or unsaturated C3-C10 heterocycloalkyl ring, a substituted or unsubstituted C3-C10 spirocycloalkyl ring, or a substituted or unsubstituted C3-C10 spiroheterocycloalkyl ring;
the heteroatoms are 1 or more N, S, O atoms;
l=1 or 2;
n＝1-3；
m＝1-5。
2. the isothiocyanate derivative according to claim 1, in the general formula I:
R 1 ，R 2 each independently selected from the following groups: h, OH, F, cl, br, CF 3 ，OR 3 ，NR 4 R 5 Substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 alkenyl, substituted or unsubstituted C1-C10 alkinyl, C1-C10 cycloalkyl, C6-C10 aryl, C6-C10 heteroaryl, C3-C20 heterocycloalkyl; alternatively, R 1 And R is 2 Adjacent may be linked to a substituted or unsubstituted aromatic ring, a substituted or unsubstituted heteroaromatic ring, a substituted or unsubstituted saturated or unsaturated heterocyclic ring;
W 1 ，W 2 ，W 3 Each independently is C or N;
x is O;
Y 1 ，Y 2 each independently selected from the following groups: h, OH, F, cl, br, CF 3 ，OR 3 ，NR 4 R 5 Substituted or unsubstituted C1-C10 alkyl, C1-C10 cycloalkyl, C6-C10 aryl, C6-C10 heteroaryl, C3-C20 heterocycloalkyl; or Y 1 And Y 2 Are linked to each other to form a substituted or unsubstituted aromatic ring, a substituted or unsubstituted heteroaromatic ring, or a substituted or unsubstituted saturated or unsaturated heterocycloalkyl ring;
l＝1；
n=1 or 2;
m＝1-5。
3. the isothiocyanate derivative according to claim 2, in the general formula I:
l＝1；
n=1 or 2;
m＝1-5。
4. the isothiocyanate derivative according to claim 2, in the general formula I:
Y 1 ，Y 2 are linked to each other to form a substituted or unsubstituted aromatic ring, a substituted or unsubstituted heteroaromatic ring, or a substituted or unsubstituted saturated or unsaturated heterocycloalkyl ring;
l＝1；
n＝1；
m＝3。
5. the isothiocyanate derivative according to claim 2, in the general formula I:
R 1 ，R 2 each independently selected from the following groups: h, OH, F, cl, br, CF 3 ，OCH 3 ，NR 4 R 5 ；W 1 ，W 2 ，W 3 Each independently is C or N;
x is O;
Y 1 ，Y 2 are linked to each other to form a substituted or unsubstituted aromatic ring, a substituted or unsubstituted heteroaromatic ring, or a substituted or unsubstituted saturated or unsaturated heterocycloalkyl ring;
l＝1；
n＝1；
m＝3。
6. isothiocyanate derivative according to claim 1, characterized in that Y in formula I 1 And Y 2 Are linked to each other to form a substituted or unsubstituted C6 aromatic ring or C6 heteroaromatic ring, i.e., the isothiocyanate derivative has the structure of formula II:
wherein: r is R 1 ，R 2 ，R 6 Can occupy any position on the ring where each is located, each independently selected from the group consisting of: h, F, cl, br, I, OR 3 ，SR 3 ，NR 4 R 5 ，CN，N 3 ，NCS，NCO，SO 2 Cl，SO 2 F，CONR 4 R 5 ，SO 2 NR 4 R 5 ，COOR 3 ，NO 2 ，CHO，CF 3 ，SO 3 H，O-P(O)(OH) 2 Si (alkyl) 3 Fluoroalkyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 alkenyl, substituted or unsubstituted C1-C10 alkinyl, C1-C10 cycloalkyl, C6-C10 aryl, C6-C10 heteroaryl, C3-C20 heterocycloalkyl; alternatively, R 1 And R is 2 Adjacent may be linked to form a substituted or unsubstituted C5-C12 aromatic ring, a substituted or unsubstituted C5-C12 heteroaromatic ring, a substituted or unsubstituted saturated or unsaturated C3-C10 cycloalkyl ring, a substituted or unsubstituted saturated or unsaturated C3-C10 heterocycloalkyl ring, a substituted or unsubstituted C3-C10 spirocycloalkyl ring, a substituted or unsubstituted C3-C10 spiroheterocycloalkyl ring, a substituted or unsubstituted C3-C10 bridged cycloalkyl ring, a substituted or unsubstituted C3-C10 bridged heterocycloalkyl ring; wherein the heteroatom is N, S, O or a combination thereof;
wherein: r is R 3 ，R 4 ，R 5 Each independently selected from the following groups: h, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 alkenyl, substituted or unsubstituted C1-C10 alkinyl, C1-C10 cycloalkyl, C6-C10 aryl, C6-C10 heteroaryl, C3-C20 heterocycloalkyl; or R is 4 And R is 5 Can be linked to each other to form an aromatic ring, a heteroaromatic ring, a saturated or unsaturated heterocycloalkyl ring;
W 1 ，W 2 ，W 3 ，W 4 ，W 5 ，W 6 ，W 7 each independently is C or N;
x is O, N or C;
l=1 or 2;
n＝1-3；
m＝1-5。
7. the isothiocyanate derivative of claim 1, having the structure of formula III:
wherein: r is R 1 ，R 2 ，R 7 Can occupy any position on the ring where each is located, each independently selected from the group consisting of: h, F, cl, br, I, OR 3 ，SR 3 ，NR 4 R 5 ，CN，N 3 ，NCS，NCO，SO 2 Cl，SO 2 F，CONR 4 R 5 ，SO 2 NR 4 R 5 ，COOR 3 ，NO 2 ，CHO，CF 3 ，SO 3 H，O-P(O)(OH) 2 (Si) alkyl group 3 Fluoroalkyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 alkenyl, substituted or unsubstituted C1-C10 alkinyl, C1-C10 cycloalkyl, C6-C10 aryl, C6-C10 heteroaryl, C3-C20 heterocycloalkyl; alternatively, R 1 R 2 Adjacent may be linked to form a substituted or unsubstituted C5-C12 aromatic ring, a substituted or unsubstituted C5-C12 heteroaromatic ring, a substituted or unsubstituted saturated or unsaturated C3-C10 cycloalkyl ring, a substituted or unsubstituted saturated or unsaturated C3-C10 heterocycloalkyl ring, a substituted or unsubstituted C3-C10 spirocycloalkyl ring, a substituted or unsubstituted C3-C10 spiroheterocycloalkyl ring, a substituted or unsubstituted C3-C10 bridged cycloalkyl ring, a substituted or unsubstituted C3-C10 bridged heterocycloalkyl ring; wherein the heteroatom is N, S or O or a combination thereof;
Wherein: r is R 3 ，R 4 ，R 5 Each independently selected from the following groups: h, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 alkenyl, substituted or unsubstituted C1-C10 alkinyl, C1-C10 cycloalkyl, C6-C10 aryl, C6-C10 heteroaryl, C3-C20 heterocycloalkyl; or R is 4 And R is 5 Can be linked to each other to form an aromatic ring, a heteroaromatic ring, a saturated or unsaturated heterocycloalkyl ring;
x is O, N or C;
l=1 or 2;
n＝1-3；
m＝1-5。
8. the method of preparing an isothiocyanate derivative of any of claims 1-7, comprising the steps of:
1) Under the catalysis of triphenylphosphine and DIAD, M1 and G-XH undergo Mitsunobu etherification reaction to produce an intermediate M3;
2) M3 is hydrolyzed by catalytic amide, and phthalic acid structure is removed to obtain an intermediate M4;
3) Catalyzing M4 and thiocarbonyldiimidazole by triethylamine to carry out nucleophilic substitution reaction to obtain an intermediate M5;
4) M5 and H 2 O 2 Carrying out oxidation reaction to prepare a target product (I'):
9. a pharmaceutical composition comprising an effective dose of the isothiocyanate derivative of any one of claims 1-7 as a pharmaceutically active ingredient, together with pharmaceutically acceptable carriers and excipients.
10. Use of an isothiocyanate derivative of any of claims 1-7, or a pharmaceutical composition thereof, in the manufacture of a medicament for the prevention or treatment of cancer.
11. The use of claim 10, wherein the cancer is pancreatic cancer, liver cancer, lung cancer, breast cancer, melanoma, multiple myeloma, gastric cancer, colorectal cancer, or hematological tumor.
CN202310735071.5A 2023-06-20 2023-06-20 Isothiocyanate derivative, preparation method and application thereof Pending CN116891424A (en)

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