CN112898213B - Polysubstituted 1, 3-diene supported ring compound and application thereof - Google Patents

Polysubstituted 1, 3-diene supported ring compound and application thereof Download PDF

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CN112898213B
CN112898213B CN201911227614.2A CN201911227614A CN112898213B CN 112898213 B CN112898213 B CN 112898213B CN 201911227614 A CN201911227614 A CN 201911227614A CN 112898213 B CN112898213 B CN 112898213B
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杨伟波
楼丽广
许忠良
全海天
宋必超
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Shanghai Institute of Materia Medica of CAS
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Abstract

The invention relates to a polysubstituted 1, 3-diene supported ring compound and use thereof. In particular, the present invention provides a compound of formula I, or an isomer thereof, or a pharmaceutically acceptable salt thereof. The compound of the formula I, or the isomer thereof, or the pharmaceutically acceptable salt thereof can enhance the antitumor activity of antitumor drugs.

Description

Polysubstituted 1, 3-diene supported ring compound and application thereof
Technical Field
The invention relates to the field of medicines, in particular to a polysubstituted 1, 3-diene supported ring compound and application thereof.
Background
Cancer is one of the leading causes of death worldwide and is on an increasing trend year by year. The Multidrug Resistance (MDR) of tumors is one of the important causes of the worsening of tumor therapy, and clinical manifestations of the Multidrug Resistance (MDR) of tumors are that cancer cells show cross Resistance to chemotherapeutic drugs, so that the tumors are difficult to treat and easy to recur. According to the american cancer society, more than 90% of deaths from tumor patients are affected by varying degrees of drug resistance. Therefore, overcoming multidrug resistance of tumors is a problem to be solved urgently in clinic.
Among the numerous mechanisms of tumor MDR, overexpression of P-glycoprotein (P-gp) in the Adenosine Triphosphate (ATP) -binding (ABC) transporter family is currently the most extensively studied mechanism of tumor MDR resistance. Over-expression of P-glycoprotein can cause the efflux of antitumor drugs from cells, so that the drugs entering the cells are reduced, and the tumor cells generate multidrug resistance. Research shows that the inhibition of P-gp can raise the accumulation of medicine in cell, raise the killing effect of medicine on tumor cell, inhibit and kill tumor cell
However, in the prior art, there are few drugs capable of inhibiting tumor multidrug resistance, and the inhibitory activity is poor, so there is an urgent need in the art to develop a drug capable of inhibiting tumor multidrug resistance with high efficiency, so as to enhance the therapeutic effect of the antitumor drug.
Disclosure of Invention
An object of the present invention is to provide a novel compound of formula I having excellent antitumor activity of antitumor drugs
The invention also aims to provide a compound of formula II and a preparation method thereof, and the preparation method of the compound of formula II realizes the preparation of the polysubstituted compound of formula II in one step for the first time, and has the characteristics of high atomic benefit, economic steps, easily obtained raw materials and the like.
In a first aspect of the invention, there is provided a compound of formula I, or an isomer thereof, or a pharmaceutically acceptable salt thereof,
Figure BDA0002302678430000021
wherein,
r1, R2, R3, and R4 are each independently hydrogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C6-C20 aryl, or substituted or unsubstituted 5-12 membered heteroaryl;
r5, R6, R7, R8, R9, R10, R11 and R12 are each independently hydrogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C8 cycloalkyl;
x is absent (absent), substituted or unsubstituted C1-C8 alkylene, substituted or unsubstituted C3-C8 cycloalkylene, substituted or unsubstituted 3-12 membered heterocycloalkyl, substituted or unsubstituted C1-C6 alkylene-NH-, substituted or unsubstituted C6-C12 aryl-NH-, -substituted or unsubstituted 5-12 membered heteroaryl-NH-;
y is nothing, amino acid residue and polypeptide residue, wherein the polypeptide residue contains m amino acid residues, and m is a positive integer of 2-10;
n is a positive integer of 0 to 30;
wherein any "substitution" means that one or more (preferably 1,2,3 or 4) hydrogen atoms on the group are substituted with a substituent selected from the group consisting of: halogen, -CN, halogenated C1-C4 alkyl (such as-CF 3), cyano, hydroxy, amino, C1-C4 alkyl, C3-C8 cycloalkyl, C1-C7 alkoxy, C6-C12 aryl-C1-C4 alkyl-, C6-C12 aryl-C1-C4 alkoxy-, C1-C4 alkylthio, 5-12 membered heteroaryl, C2-C4 ester group, amino acid residue;
the heterocycloalkylene and heteroaryl rings each independently have 1-3 (preferably 1,2 or 3) heteroatoms selected from N, O and S.
In another preferred embodiment, the heterocycloalkylene and heteroaryl have 1-3 (preferably 1,2 or 3) heteroatoms independently selected from N, O and S on the heterocycle.
In another preferred embodiment, n is a positive integer from 2 to 25.
In another preferred embodiment, n is a positive integer from 3 to 25.
In another preferred embodiment, n is a positive integer from 5 to 20.
In another preferred embodiment, n is a positive integer from 5 to 15.
In another preferred example, n is a positive integer of 8 to 12.
In another preferred embodiment, n is 0, 1,2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 23, 24, 25, 26, 27, 28, 29 or 30.
In the present invention, it is understood that when n is greater than 1, each R10 is the same or different.
In the present invention, it is understood that when n is greater than 1, each R11 is the same or different.
In another preferred embodiment, R1, R2, R3, and R4 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C6-C12 aryl, or substituted or unsubstituted 5-10 membered heteroaryl.
In another preferred embodiment, R2 and R3 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl.
In another preferred embodiment, R2 and R3 are each independently hydrogen.
In another preferred embodiment, R1 and R4 are each independently substituted or unsubstituted C6-C12 aryl, or substituted or unsubstituted 5-10 membered heteroaryl.
In another preferred embodiment, R1 and R4 are each independently substituted or unsubstituted C6-C12 aryl (e.g., phenyl, naphthyl).
In another preferred embodiment, R1 and R4 are each independently phenyl, naphthyl.
In another preferred embodiment, R5, R6, R7, R8, R9, R10, R11 and R12 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl.
In another preferred embodiment, R5, R6, R7, R8, R9, R10, R11 and R12 are each independently hydrogen.
In another preferred embodiment, X is absent, substituted or unsubstituted C1-C6 alkylene, substituted or unsubstituted C3-C8 cycloalkylene, substituted or unsubstituted 3-12 membered heterocycloalkylene.
In another preferred embodiment, X is absent, substituted or unsubstituted C1-C6 alkylene, substituted or unsubstituted 3-12 membered heterocycloalkylene.
In another preferred embodiment, X is absent, substituted or unsubstituted C1-C4 alkylene, substituted or unsubstituted 4-to 10-membered heterocycloalkylene.
In another preferred embodiment, the substituted or unsubstituted 4-10 membered heterocycloalkylene group is a substituted or unsubstituted saturated or unsaturated 4-10 membered heterocycloalkylene group.
In another preferred embodiment, X is absent, substituted or unsubstituted C1-C4 alkylene, substituted or unsubstituted 5-7 membered heterocycloalkylene.
In another preferred embodiment, the substituted or unsubstituted 5-7 membered heterocycloalkylene group is a substituted or unsubstituted saturated or unsaturated 5-7 membered heterocycloalkylene group.
In another preferred embodiment, X is absent, substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted 6-membered heterocycloalkylene.
In another preferred embodiment, the substituted or unsubstituted 6-membered heterocycloalkylene group is a substituted or unsubstituted saturated or unsaturated 6-membered heterocycloalkylene group.
In another preferred embodiment, X is methylene, ethylene, propylene, butylene, or piperidylene.
In another preferred embodiment, the piperidylidene group is
Figure BDA0002302678430000041
Wherein positions 1 and 2 are attachment sites.
In a further preferred embodiment of the present invention,
Figure BDA0002302678430000042
the 2-position connecting point of (2) is connected to the N atom.
In another preferred embodiment, the amino acid residue is a natural amino acid residue.
In another preferred embodiment, the amino acid residue is an L-amino acid residue.
In another preferred embodiment, the amino acids are classified according to the chemical structure of the R group, and the amino acid residue is an aliphatic amino acid residue, an aromatic amino acid residue, or a heterocyclic amino acid residue.
In another preferred embodiment, the aliphatic amino acid residue is glycine residue, alanine residue, valine residue, leucine residue, isoleucine residue, serine residue, threonine residue, cysteine residue, methionine residue, aspartic acid residue, glutamic acid residue, asparagine, glutamine, lysine residue, arginine residue.
In another preferred embodiment, the aromatic amino acid residue is a phenylalanine residue, a tyrosine residue, or a tryptophan residue.
In another preferred embodiment, the heterocyclic amino acid residue is histidine residue or proline residue.
In another preferred embodiment, the amino acid residue is glycine residue, alanine residue, valine residue, leucine residue, isoleucine residue, serine residue, threonine residue, cysteine residue, methionine residue, aspartic acid residue, glutamic acid residue, asparagine residue, glutamine residue, lysine residue, arginine residue.
In another preferred embodiment, or a pharmaceutically acceptable salt thereof, the amino acid residues have the structure:
Figure BDA0002302678430000043
Figure BDA0002302678430000051
wherein, the 3-position and the 4-position are connecting sites, and R is the R group of the amino acid.
In another preferred embodiment, the 3-position is linked to the N-atom and the 4-position is linked to the carbonyl group (C = O).
In another preferred embodiment, the 3-position is linked to the N atom and the 4-position is linked to the carbonyl group (C = O).
In another preferred embodiment, the amino acid residue is a valine residue.
In another preferred embodiment, the polypeptide residue has the formula:
Figure BDA0002302678430000052
wherein positions 3 and 4 are attachment sites, R is the R group of the amino acid, preferably position 3 is attached to the N atom and position 4 is attached to the carbonyl group (C = O).
In the present invention, in the structures of amino acid residues and polypeptide residues, R is an R group of amino acids, and "R" and "R group" are used interchangeably.
In another preferred embodiment, the R group (or R) is hydrogen, isopropyl, benzyl.
In another preferred embodiment, the R group (or R) is hydrogen, isopropyl, methyl, benzyl, isopropyl-methyl-, (methyl) (ethyl) CH-, isopropyl, 2-cyclopentylamino, 2-methylpropyl, 2-butyl, methylthioethyl.
In another preferred embodiment, the individual amino acids in the polypeptide residues may be the same or different.
In another preferred embodiment, m is 2,3, 4, 5, 6, 7, 8, 9 or 10.
In another preferred embodiment, m is 2 to 6, preferably 2 to 4.
In another preferred embodiment, the compound of formula I is a compound of formula Ia:
Figure BDA0002302678430000053
Figure BDA0002302678430000061
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, X and n are as defined above, and R is the R group of an L-amino acid.
In another preferred embodiment, the L-amino acid is glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, aspartic acid, glutamic acid, asparagine, glutamine, lysine, arginine.
In another preferred embodiment, the R group (or R) is hydrogen, isopropyl, benzyl
In another preferred embodiment, the R group (or R) is hydrogen, isopropyl, methyl, benzyl, isopropyl-methyl-, (methyl) (ethyl) CH-, isopropyl, 2-cyclopentylamino, 2-methylpropyl, 2-butyl, methylthioethyl.
In another preferred embodiment, the compound of formula I is a compound of formula Ib:
Figure BDA0002302678430000062
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, X and n are as defined above.
In another preferred embodiment, the compound of formula I is selected from the group consisting of:
Figure BDA0002302678430000063
in a second aspect of the invention, there is provided a process for the preparation of a compound of formula I as described in the first aspect of the invention, or an isomer thereof, or a pharmaceutically acceptable salt thereof, which process comprises:
when Y is hydrogen, the process comprises step (a):
(a) The compound of formula F is subjected to an amide reaction to generate a compound of formula I;
Figure BDA0002302678430000071
when Y is other than hydrogen, the process comprises step (b):
(b) Reacting the compound of formula F with amino acid or polypeptide to generate a compound of formula I;
Figure BDA0002302678430000072
wherein Y is an amino acid residue or a polypeptide residue.
In a third aspect of the present invention, there is provided a pharmaceutical composition comprising: (a) A compound of formula I according to the first aspect of the invention, or an isomer thereof, or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable carrier.
In another preferred embodiment, the pharmaceutical composition further comprises an anti-tumor drug.
In another preferred embodiment, the anti-tumor drug is a drug of a P-glycoprotein substrate.
In another preferred embodiment, the anti-tumor drug is a drug of a P-glycoprotein substrate which is resistant to tumor cells.
In another preferred embodiment, the anti-tumor drug is selected from the group consisting of: paclitaxel, vinorelbine, docetaxel, gemcitabine, epirubicin, doxorubicin, colchicine, or combinations thereof.
In a fourth aspect of the invention, there is provided the use of a compound of formula I, or an isomer thereof, or a pharmaceutically acceptable salt thereof, as described in the first aspect of the invention, and/or a pharmaceutical composition as described in the third aspect of the invention, for (I) the manufacture of a medicament for inhibiting or reversing multi-drug resistance of a tumour to an anti-cancer drug; (2) preparing a medicament for inhibiting P-glycoprotein; and/or (3) preparing a medicament for enhancing the anti-tumor activity of the anti-tumor medicament.
In another preferred embodiment, the tumor is a P-glycoprotein high expression tumor.
In another preferred embodiment, the multidrug resistance is multidrug resistance caused by P-glycoprotein.
In another preferred embodiment, the P-glycoprotein is tumor P-glycoprotein.
In another preferred embodiment, the tumor is selected from the group consisting of: nasopharyngeal carcinoma, oral cancer, esophageal cancer, gastric cancer, intestinal cancer, gallbladder cancer, bile duct cancer, lung cancer, liver cancer, kidney cancer, breast cancer, bladder cancer, ovarian cancer, cervical cancer, endometrial cancer, lymphoma, leukemia, or a combination thereof.
In another preferred embodiment, the oral cancer is human oral epidermoid carcinoma.
In another preferred embodiment, the anti-tumor drug is selected from the group consisting of: paclitaxel, vinorelbine, docetaxel, gemcitabine, epirubicin, doxorubicin, colchicine, or combinations thereof.
In another preferred embodiment, the P-glycoprotein is tumor P-glycoprotein.
In a fifth aspect of the invention, there is provided a kit comprising:
(A) A first formulation comprising a compound of formula I as described in the first aspect of the invention, or an isomer thereof, or a pharmaceutically acceptable salt thereof;
(B) A second formulation comprising an anti-neoplastic agent; and
(D) Instructions for use.
In another preferred embodiment, the instructions specify that the first formulation and the second formulation are to be used in combination to enhance the anti-tumor activity of the anti-tumor agent.
In a sixth aspect of the invention, there is provided an active ingredient combination comprising the following components:
(1) A compound of formula I according to the first aspect of the invention, or an isomer thereof, or a pharmaceutically acceptable salt thereof; and
(2) An antitumor drug.
In a seventh aspect of the invention, there is provided a kit according to the fifth aspect of the invention and/or a use of a combination of active ingredients according to the sixth aspect of the invention for (i) the manufacture of a medicament for inhibiting or reversing multi-drug resistance of a tumour to an anti-cancer drug; (2) preparing a medicament for inhibiting P-glycoprotein; and/or (3) preparing a medicament for enhancing the anti-tumor activity of the anti-tumor medicament.
In another preferred embodiment, the tumor includes (but is not limited to): nasopharyngeal carcinoma, oral cancer, esophageal cancer, gastric cancer, intestinal cancer, gallbladder cancer, bile duct cancer, lung cancer, liver cancer, kidney cancer, breast cancer, bladder cancer, ovarian cancer, cervical cancer, endometrial cancer, lymphoma, leukemia, or a combination thereof.
In another preferred embodiment, the anti-tumor drugs include (but are not limited to): paclitaxel, vinorelbine, docetaxel, gemcitabine, epirubicin, doxorubicin, colchicine, or combinations thereof.
In another preferred embodiment, the tumor is a P-glycoprotein high expression tumor.
In an eighth aspect of the invention, there is provided an in vitro non-therapeutic and non-diagnostic method for inhibiting tumor P-glycoprotein activity, said method comprising the steps of: contacting a compound of formula I according to the first aspect of the invention, or an isomer thereof, or a pharmaceutically acceptable salt thereof, with a tumor cell in an in vitro culture system, thereby inhibiting tumor P-glycoprotein activity.
In a ninth aspect of the present invention, there is provided an in vitro non-therapeutic and non-diagnostic method for enhancing the anti-tumor activity of an anti-tumor drug, said method comprising the steps of: contacting a compound of formula I, or an isomer thereof, or a pharmaceutically acceptable salt thereof, according to the first aspect of the present invention and an anti-tumor drug with tumor cells in an in vitro culture system, thereby enhancing the anti-tumor activity of the anti-tumor drug.
In a tenth aspect of the present invention, there is provided a method for preventing and/or treating tumors, said method comprising the steps of: administering to a subject suffering from a tumor a compound of formula I as described in the first aspect of the invention, or an isomer thereof, or a pharmaceutically acceptable salt thereof, and an anti-tumor agent, thereby preventing and/or treating the tumor.
In another preferred embodiment, the tumor includes (but is not limited to): nasopharyngeal carcinoma, oral cancer, esophageal cancer, gastric cancer, intestinal cancer, gallbladder cancer, bile duct cancer, lung cancer, liver cancer, kidney cancer, breast cancer, bladder cancer, ovarian cancer, cervical cancer, endometrial cancer, lymphoma, leukemia, or a combination thereof.
In another preferred embodiment, the anti-tumor drugs include (but are not limited to): paclitaxel, vinorelbine, docetaxel, gemcitabine, epirubicin, doxorubicin, colchicine, or combinations thereof.
In another preferred embodiment, the subject includes human and non-human mammals (rodents, rabbits, monkeys, livestock, dogs, cats, etc.).
In another preferred embodiment, the tumor is a P-glycoprotein high expression tumor.
In an eleventh aspect of the invention, there is provided a compound of formula II, or an isomer thereof, or a pharmaceutically acceptable salt thereof,
Figure BDA0002302678430000101
wherein,
r1, R2, R3, and R4 are each independently hydrogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C6-C20 aryl, or substituted or unsubstituted 5-12 membered heteroaryl;
r5 and R6 are each independently hydrogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C8 cycloalkyl;
r13 is hydrogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C6-C12 aryl-substituted or unsubstituted C1-C8 alkyl-;
z is O, S, -N (R14) -;
r14 is hydrogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 cycloalkyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 5-12 membered heteroaryl, p-nitrobenzenesulfonyl, p-methylbenzenesulfonyl;
wherein any "substitution" means that one or more (preferably 1,2,3 or 4) hydrogen atoms on the group are substituted with a substituent selected from the group consisting of: halogen, -CN, halogenated C1-C4 alkyl (such as-CF 3), cyano, hydroxy, amino, C1-C4 alkyl, C3-C8 cycloalkyl, C1-C7 alkoxy, C6-C12 aryl-C1-C4 alkyl-, C6-C12 aryl-C1-C4 alkoxy-, C1-C4 alkylthio, 5-12 membered heteroaryl, C2-C4 ester group, amino acid residue;
the heterocyclic ring of the heteroaryl group has 1 to 3 (preferably 1,2 or 3) heteroatoms selected from N, O and S, independently from each other.
In another preferred embodiment, R1, R2, R3, R4, R5 and R6 are as described in the first aspect of the invention.
In another preferred embodiment, R13 is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C6-C12 aryl, or substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C6-C12 aryl-substituted or unsubstituted C1-C6 alkyl-.
In another preferred embodiment, the halogen is F, cl, br.
In another preferred embodiment, R1 is a substituted or unsubstituted C6-C12 aryl, or a substituted or unsubstituted 5-10 membered heteroaryl.
In another preferred embodiment, R1 is phenyl, naphthyl, methylphenyl, methoxyphenyl, and halophenyl (monofluorophenyl, monochlorophenyl).
In another preferred embodiment, the halophenyl is monohalophenyl.
In another preferred embodiment, R4 is hydrogen, substituted or unsubstituted C6-C12 aryl, or substituted or unsubstituted 5-10 membered heteroaryl.
In another preferred embodiment, R4 is hydrogen, phenyl, halophenyl- (monohalophenyl-, dihalophenyl-), cyanophenyl-, trihalomethyl (e.g., trifluoromethyl), methoxyphenyl-, benzyl-O-phenyl-, methylphenyl-, naphthyl.
In another preferred embodiment, the halophenyl group is a monohalophenyl group (e.g., monofluorophenyl, monochlorophenyl) or polyhalophenyl group (e.g., difluorophenyl, dichlorophenyl).
In another preferred embodiment, R13 is methyl or benzyl.
In another preferred embodiment, the compound of formula II is selected from the group consisting of:
Figure BDA0002302678430000111
Figure BDA0002302678430000121
in a twelfth aspect of the invention, there is provided a process for the preparation of a compound of formula II as described in the eleventh aspect of the invention, or an isomer thereof, or a pharmaceutically acceptable salt thereof, said process comprising the steps of:
(1) In a first solvent, under the action of a catalyst and a first alkaline reagent, a compound of a formula C1 and a compound of a formula C2 are subjected to a carbene insertion reaction catalyzed by a transition metal to generate a compound of a formula II;
Figure BDA0002302678430000131
in another preferred embodiment, in the step (1), the catalyst is selected from the group consisting of: palladium acetate (Pd (OAc) 2 ) Palladium trifluoroacetate (Pd (OTf) 2 ) Bis (triphenylphosphine) palladium dichloride (Pd (PPh) 3 )Cl 2 ) Allyl palladium chloride dimer ([ PdCl (C)) 3 H 5 )] 2 ) (1, 5-cyclooctadiene) palladium dichloride (PdCl) 2 (cod)), palladium chloride (PdCl) 2 ) Bis (acetonitrile) palladium dichloride (Pd (CH) 3 CN) 2 Cl 2 ) [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (Pd (dppf) Cl 2 ) 1, 2-bis (phenylsulfinyl) ethylpalladium (II) diacetate (alternative name: white catalyst, CAS number 858971-43-4, tris (dibenzylideneacetone) dipalladium-chloroform adduct ([ Pd) 2 (dba) 3 ]·CHCl 3 ) Tris (dibenzylideneacetone) dipalladium (Pd) 2 (dba) 3 ) Tetratriphenylphosphine palladium (Pd (PPh) 3 ) 4 ) Or a combination thereof.
In another preferred embodiment, in the step (1), the catalyst is selected from the group consisting of: tris (dibenzylideneacetone) dipalladium-chloroform adduct ([ Pd) 2 (dba) 3 ]·CHCl 3 ) Tris (dibenzylideneacetone) dipalladium (Pd) 2 (dba) 3 ) Or a combination thereof.
In another preferred embodiment, in the step (1), the first alkaline agent is a quaternary ammonium salt alkaline agent.
In another preferred embodiment, in the step (1), the first alkaline agent is selected from the group consisting of: tetrabutylammonium fluoride, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetramethylammonium bromide, tetraethylammonium bromide, or a combination thereof.
In another preferred embodiment, in the step (1), the first alkaline agent is selected from the group consisting of: tetrabutylammonium chloride, tetrabutylammonium bromide, or a combination thereof.
In another preferred embodiment, in the step (1), the first solvent used is selected from the group consisting of: methanol, tetrahydrofuran, dioxane, chloroform, dichloromethane, 1, 2-dichloroethane, acetone, acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, or hexamethylphosphoric triamide, or a combination thereof.
In another preferred embodiment, in the step (1), the first solvent used is N, N-dimethylformamide.
In another preferred embodiment, in the step (1), the molar ratio of the catalyst to the first alkaline agent is 1:10-80, preferably 1:10-60, more preferably 1:20-60, more preferably 1:30-50, optimally 1.
In another preferred example, in the step (1), the molar ratio of the catalyst to the first alkaline agent is 1:10-80, preferably 1:10-60, more preferably 1:20-60, more preferably 1:30-50, optimally 1.
In another preferred embodiment, in the step (1), the molar ratio of the catalyst to the compound of formula C1 is 1:10-80, preferably 1:10-60, more preferably 1:20-60, more preferably 1:30-50, optimally 1.
In another preferred embodiment, in said step (1), the molar ratio of said compound of formula C1 to said compound of formula C2 is 1.
In another preferred embodiment, in the step (1), the reaction temperature is 20-80 ℃, preferably 40-80 ℃, and more preferably 50-70 ℃.
In another preferred embodiment, in the step (1), the reaction time is 1 to 12 hours, preferably 1 to 8 hours, more preferably 2 to 6 hours, and most preferably 2 to 4 hours.
In a thirteenth aspect of the present invention, there is provided a pharmaceutical composition comprising: (a) A compound of formula II according to the eleventh aspect of the invention, or an isomer thereof, or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable carrier.
In a fourteenth aspect of the present invention, there is provided the use of a compound of formula II, or an isomer thereof, or a pharmaceutically acceptable salt thereof, as described in the eleventh aspect of the present invention, for (a) preparing a compound of formula I, or an isomer thereof, or a pharmaceutically acceptable salt thereof, as described in the first aspect of the present invention.
In a fifteenth aspect of the invention, there is provided a compound of formula 34,
Figure BDA0002302678430000151
in a sixteenth aspect of the invention, there is provided a compound of formula 35,
Figure BDA0002302678430000152
in a seventeenth aspect of the present invention, there is provided a compound represented by formula 36,
Figure BDA0002302678430000153
it is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Drawings
FIG. 1 is the results of testing compound 13a,14a,15a in example 1 to reverse the resistance of KBV200 to vinorelbine.
Detailed Description
The invention provides a compound of formula I, or an isomer thereof, or a pharmaceutically acceptable salt thereof, which can remarkably inhibit the multidrug resistance of tumor cells to antitumor drugs, thereby remarkably enhancing the treatment of the antitumor drugs to tumors. In addition, the application also provides a compound of formula II, or an isomer thereof, or a pharmaceutically acceptable salt thereof, and a preparation method of the compound of formula II, or the isomer thereof, or the pharmaceutically acceptable salt thereof, wherein the preparation method of the compound of formula II, or the isomer thereof, or the pharmaceutically acceptable salt thereof is implemented through carbene insertion reaction, and the preparation method of the compound of formula II realizes the polysubstituted compound of formula II for the first time, and has the characteristics of high atomic efficiency, economic steps, easily obtained raw materials and the like. On the basis of this, the inventors have completed the present invention.
Term(s) for
As used herein, the terms "comprises," "comprising," "includes," "including," and "including" are used interchangeably and include not only closed-form definitions, but also semi-closed and open-form definitions. In other words, the term includes "consisting of 8230; \8230; composition;" consisting essentially of 8230; \8230; composition 8230).
It is to be understood that substituents and substitution patterns on the compounds of the present invention may be selected by one of ordinary skill in the art to produce chemically stable compounds that may be synthesized by techniques known in the art as well as the methods set forth below. If substituted with more than one substituent group, it is understood that the multiple groups may be on the same carbon or on different carbons, so long as a stable structure results.
As used herein, the term "substituted" or "substituted" is a radical in which a hydrogen atom on the radical is replaced with a non-hydrogen atom, but which needs to satisfy its valence requirements and which results from the substitution into a chemically stable compound, i.e., a compound which does not spontaneously undergo a transformation such as cyclization, elimination, etc.
As used herein,' A "
Figure BDA0002302678430000161
"denotes the attachment site of a group.
As used herein, the term "alkyl" refers to a straight-chain (i.e., unbranched) or branched-chain saturated hydrocarbon group containing only carbon atoms, or a combination of straight-chain and branched-chain groups. When an alkyl group is preceded by a carbon atom number limitation (e.g., C1-C10 alkyl) means that the alkyl group contains 1-10 carbon atoms, for example, C1-C4 alkyl means an alkyl group containing 1-4 carbon atoms, representative examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or the like.
As used herein, the term "alkylene" is a divalent alkyl group (i.e., a divalent alkyl group formed by removing a hydrogen from an alkyl group), e.g., C1-C8 alkylene refers to a divalent C1-C8 alkyl group, the alkyl group being as defined above, preferably, divalent radicals of alkylene groups other than methylene are not located on the same carbon atom. The following are representative examples of alkylene groups, including but not limited to:
Figure BDA0002302678430000171
in the present invention, the term "halogen" means F, cl, br or I.
In the present invention, the term "halo" means substituted by halogen.
As used herein, the term "haloalkyl" means an alkyl group wherein one or more (preferably 1,2,3 or 4) hydrogens are replaced with a halogen, said alkyl and halogen being as defined above, when the alkyl group previously has a carbon atom number limitation (e.g., haloC 1-C10 alkyl) meaning that said alkyl group contains 1 to 10 carbon atoms, for example, haloC 1-C4 alkyl means a haloalkyl group containing 1 to 4 carbon atoms, representative examples include, but are not limited to, -CF 3 、-CHF 2 Monofluoroisopropyl, difluorobutyl, or the like.
As used herein, the term "cycloalkyl" refers to a monocyclic, bicyclic, or polycyclic (fused, bridged, or spiro) ring system radical having a saturated or partially saturated unit ring. When a cycloalkyl group is preceded by a carbon atom number limitation (e.g., C3-C8), it is intended that the cycloalkyl group has 3 to 8 ring carbon atoms. In some preferred embodiments, the term "C3-C8 cycloalkyl" refers to a saturated or partially saturated monocyclic or bicyclic alkyl group having 3 to 8 ring carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, or the like. "spirocycloalkyl" refers to a bicyclic or polycyclic group having a single ring with a common carbon atom (called the spiro atom) between them, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. "fused-ring alkyl" refers to an all-carbon bicyclic or polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, and in which one or more of the rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. "bridged cycloalkyl" refers to an all-carbon polycyclic group in which any two rings share two carbon atoms not directly connected, and these may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Representative examples of cycloalkyl groups include, but are not limited to:
Figure BDA0002302678430000181
the term "cycloalkylene" refers to a divalent cycloalkyl group in which one more hydrogen is removed from the cycloalkyl group to form a divalent cycloalkyl group, and the divalent group cannot be located on an aromatic ring (e.g., an aromatic ring or a heteroaromatic ring) at the same time. For example, C3-C8 cycloalkylene refers to divalent C3-C8 cycloalkyl groups, wherein the cycloalkyl groups are as defined above. Preferably, the divalent radicals of the cycloalkylene radicals are not located on the same carbon atom. Representative examples of cycloalkylene groups include, but are not limited to:
Figure BDA0002302678430000182
the term "alkoxy" refers to the group R-O-, wherein R is alkyl, alkyl is as defined herein, when alkoxy is previously defined by the number of carbon atoms, e.g., C1-C6 alkoxy means that the alkyl in the alkoxy group has from 1 to 6 carbon atoms. Representative examples of alkoxy groups include (but are not limited to): methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, or the like.
As used herein, the term "alkylthio" refers to the group R-O-wherein R is alkyl and alkyl is as defined herein above, when alkylthio has the carbon atom number limitation at the beginning, e.g., C1-C6 alkylthio means that the alkyl group in the alkoxy group in question has 1-6 carbon atoms. Representative examples of alkylthio groups include (but are not limited to): methylthio, ethylthio, n-propylthio, isopropylthio, tert-butylthio, or the like.
The term "heterocycloalkyl" refers to a fully saturated or partially unsaturated cyclic group (including but not limited to, for example, 4-7 membered monocyclic, 7-11 membered bicyclic, or 8-16 membered tricyclic ring systems) in which at least one heteroatom is present in the ring having at least one carbon atom. Where the heterocycloalkyl group is preceded by a finite number of elements, this refers to the number of ring atoms in the heterocycloalkyl group, for example, 3-12 membered heterocycloalkyl refers to a heterocycloalkyl group having 3-12 ring atoms, each heteroatom-containing heterocycle may carry one or more (e.g., 1,2,3, or 4) heteroatoms selected from nitrogen atoms, oxygen atoms, or sulfur atoms, where the nitrogen or sulfur atoms may be oxidized and the nitrogen atoms may be quaternized. The heterocycloalkyl group may be attached to the residue of any heteroatom or carbon atom of the ring or ring system molecule. Typical monocyclic heterocycloalkyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, hexahydroazepinyl, 4-piperidyl, tetrahydropyranyl, morphinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1, 3-dioxanyl, and tetrahydro-1, 1-dioxythiophene, and the like. Polycyclic heterocycloalkyl includes spiro, fused and bridged heterocyclic groups; wherein the heterocyclic groups of the spiro, fused and bridged rings are optionally linked to other groups by single bonds or further linked to other cycloalkyl, heterocyclic, aryl and heteroaryl groups by any two or more atoms in the ring.
The term "heterocycloalkylene" refers to a divalent heterocycloalkyl group, i.e., a divalent heterocycloalkyl group formed by removing a hydrogen from the heterocycloalkyl group, e.g., 3-12 membered heterocycloalkylene refers to a divalent 3-12 membered heterocycloalkyl group, wherein the heterocycloalkyl group is as defined above. Preferably, the divalent radicals of the heterocycloalkylene group are not located on the same carbon atom. Representative examples of heterocycloalkylene groups include, but are not limited to: azetidinylene, pyrrolidinylene, oxetanylene, pyrazolylene, imidazolinylene, imidazolidinylene, oxazolidinylene, or the like.
The term "aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, and is an aromatic cyclic hydrocarbon group, when an aryl group has a previously defined number of carbon atoms, such as C6-C12 aryl, then said aryl group has 6-12 ring carbon atoms, such as phenyl and naphthyl. The aryl ring may be fused to other cyclic groups (including saturated or unsaturated rings) but must not contain heteroatoms such as nitrogen, oxygen, or sulfur, while the point of attachment to the parent must be at a carbon atom on the ring with the conjugated pi-electron system. Representative examples of aryl groups include, but are not limited to:
Figure BDA0002302678430000191
the term "heteroaryl" refers to an aromatic heterocyclic group having one to more (preferably 1,2,3 or 4) heteroatoms, which may be monocyclic (monocyclic) or polycyclic (bicyclic, tricyclic or polycyclic) fused together or covalently linked, and each heteroatom-containing heterocyclic ring may carry one more (e.g., 1,2,3, 4) heteroatoms each independently selected from the group consisting of: oxygen, sulfur and nitrogen. When a heteroaryl group is preceded by a number of members, this refers to the number of ring atoms of the heteroaryl group, for example 5-12 membered heteroaryl refers to heteroaryl groups having 5-12 ring atoms, representative examples include, but are not limited to: pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, tetrazolyl, and the like.
<xnotran> , "" R-CO-O- -CO-O-R , R , , "C </xnotran> 2 by-C4 ester group "is meant C 1 -C 3 Radicals of alkyl-CO-O-structure or-CO-O-C 1 -C 3 Representative examples of alkyl structures, ester groups include (but are not limited to): CH (CH) 3 COO-、C 2 H 5 COO-、C 3 H 8 COO-、(CH 3 ) 2 CHCOO-、-COOCH 3 、-COOC 2 H 5 、-COOC 3 H 8 Or the like.
As used herein, the term "amino", alone or as part of another substituent, denotes — NH2.
As used herein, the term "nitro", alone or as part of another substituent, denotes — NO2.
As used herein, the term "cyano," alone or as part of another substituent, denotes — CN
As used herein, the term "hydroxy", alone or as part of another substituent, denotes — OH.
As used herein, "R 1 "," R1 "and" R 1 "has the same meaning as" and can be substituted for "another, and other similar definitions have the same meaning.
As used herein, the term "amino acid residue" refers to an amino acid lacking a hydrogen atom in the amino group and lacking a hydroxyl group in the carboxyl group, and groups formed by the loss of a hydrogen atom in the amino group and the loss of a hydroxyl group in the carboxyl group are capable of participating in the formation of a peptide bond, e.g., the L-glycine residue is-NH-CH 2 -C(O)-。
In another preferred embodiment, in the amino acid residue, the carboxyl group loses one hydroxyl group to form C (O) to be connected with N atom.
As used herein, the term "amino acid residue" refers to an amino acid lacking a hydrogen atom from the amino group and lacking a hydroxyl group from the carboxyl group. In amino acid residues, the groups formed after the amino group has lost one hydrogen and the carboxyl group has lost one hydroxyl group are capable of participating in the formation of peptide bonds. Typically, an amino acid residue (e.g., an L-amino acid residue) has the formula (-NH-CH (R) -C (O) -):
Figure BDA0002302678430000201
wherein, the 3-position and the 4-position are connecting sites, and R is the R group of amino acid. In a preferred embodiment, in said compound of formula I, or an isomer thereof, or a pharmaceutically acceptable salt thereof, the carboxyl group of said amino acid residue is deprived of a hydroxyl group to form a C (O) linkage to an O atom, i.e. the 3-position of the amino acid residue is linked to the N atom and the 4-position is linked to a carbonyl group (C = O).
As used herein, the term "polypeptide residue" refers to a plurality of amino acid residues (e.g., m amino acid residues, m being a positive integer from 2 to 10) linked by peptide bonds (-NH-C (O) -), typically the polypeptide residue has the formula:
Figure BDA0002302678430000211
wherein, the 3-position and the 4-position are connecting sites, R is the R group of amino acid, and m is a positive integer of 2-10. In a preferred embodiment, in said compound of formula I, or an isomer thereof, or a pharmaceutically acceptable salt thereof, the 3-position of said polypeptide residue is attached to the N-atom and the 4-position is attached to the carbonyl group (C = O). It will be appreciated that in the polypeptide residues described, the R groups of each amino acid residue may be the same or different. For example, a polypeptide residue is formed of m amino acid residues, m is a positive integer from 2 to 10, and the R groups of the respective amino acid residues may be the same or different.
The term "Ns" is an abbreviation for p-nitrobenzenesulfonyl,
the term "Ts" is an abbreviation for p-methylbenzenesulfonamide.
In this specification, it is to be construed that all substituents are unsubstituted, unless expressly described as "substituted" herein. The term "substituted" means that one or more hydrogen atoms on a specified group are replaced with a specified substituent. Particular substituents are those described correspondingly in the foregoing, or as appearing in the examples. Unless otherwise specified, an optionally substituted group may have a substituent selected from a specific group at any substitutable site of the group, and the substituents may be the same or different at each position. In a preferred embodiment of the present invention, any "substitution" means that one or more (preferably 1,2,3 or 4) hydrogen atoms on the group are replaced by a substituent selected from the group consisting of: halogen, -CN, halogenated C1-C4 alkyl (such as-CF 3), cyano, hydroxyl, amino, C1-C4 alkyl, C3-C8 cycloalkyl, C1-C7 alkoxy, C6-C12 aryl-C1-C4 alkyl-, C6-C12 aryl-C1-C4 alkoxy-, C1-C4 alkylthio, 5-12 membered heteroaryl, C2-C4 ester group, amino acid residue.
As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention with an acid or base that is suitable for use as a pharmaceutical. Pharmaceutically acceptable salts include inorganic and organic salts. One preferred class of salts is that formed with an acid of the compounds of the present invention, and suitable acids for forming salts include (but are not limited to): inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, etc., organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, phenylmethanesulfonic acid, benzenesulfonic acid, etc.; and acidic amino acids such as aspartic acid and glutamic acid. One preferred class of salts are metal salts of the compounds of the present invention formed with bases, suitable bases for forming the salts include (but are not limited to): inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogencarbonate and sodium phosphate, and organic bases such as ammonia, triethylamine and diethylamine. The compound of formula I of the present invention can be converted into a pharmaceutically acceptable salt thereof by a conventional method, for example, a solution of the corresponding acid can be added to a solution of the above compound, and the corresponding salt of the compound of the present invention can be obtained by removing the solvent after salt formation is completed.
In the present invention, the term "prevention" refers to a method of preventing the onset of a disease and/or its attendant symptoms or protecting a subject from acquiring a disease. As used herein, "preventing" also includes delaying the onset of a disease and/or its attendant symptoms and reducing the risk of acquiring a disease in a subject.
In the present invention, the term "treatment" refers to any treatment of a disease in a mammal, including (but not limited to): (a) Inhibiting the disease, i.e., slowing or arresting the development of clinical symptoms; and/or (b) relieving the disease, i.e., causing regression of clinical symptoms, and/or (c) alleviating or eliminating the disease and/or its attendant symptoms.
Compounds of formula I and processes for their preparation
As used herein, the terms "compound of formula I of the present invention", "compound of formula I", and the like, are used interchangeably to refer to a compound of formula I, or an isomer thereof, or a pharmaceutically acceptable salt thereof, with the understanding that the term also includes mixtures of the above:
Figure BDA0002302678430000221
in particular, the compound of formula I is as described above in the first aspect of the invention.
Typically, the compound of formula I is selected from the group consisting of:
Figure BDA0002302678430000231
the present invention also provides a process for the preparation of a compound of formula I of the present invention, or an isomer thereof, or a pharmaceutically acceptable salt thereof, said process comprising the steps of:
when Y is hydrogen, the process comprises step (a):
(a) The compound of formula F is subjected to an amide reaction to generate a compound of formula I;
Figure BDA0002302678430000232
when Y is other than hydrogen, the process comprises step (b):
(b) Reacting the compound of formula F with amino acid or polypeptide to generate a compound of formula I;
Figure BDA0002302678430000233
wherein Y is an amino acid residue or a polypeptide residue.
In the above formulae, the groups are as defined above. Reagents and conditions for each step may be selected from those conventional in the art for carrying out such preparation methods, and such selection may be made by those skilled in the art, after the structure of the compound of formula I of the present invention is disclosed, according to the knowledge in the art. More specifically, the compounds of formula I of the present invention may also be conveniently prepared by optionally combining various synthetic methods described in the present specification or known in the art, and such combinations may be readily prepared by those skilled in the art to which the present invention pertains.
Compounds of formula II and processes for their preparation
As used herein, the terms "compound of formula II of the present invention", "compound of formula II", and the like are used interchangeably to refer to a compound of formula II, or an isomer thereof, or a pharmaceutically acceptable salt thereof. It is understood that the term also includes mixtures of the above components;
Figure BDA0002302678430000241
in particular, the compound of formula II is as described above in the eleventh aspect of the invention.
Typically, the compound of formula II is selected from the group consisting of:
Figure BDA0002302678430000242
Figure BDA0002302678430000251
the present invention also provides a process for the preparation of a compound of formula II of the present invention, or an isomer thereof, or a pharmaceutically acceptable salt thereof, said process comprising the steps of:
(1) In a first solvent, under the action of a catalyst and a first alkaline reagent, a compound of a formula C1 and a compound of a formula C2 are subjected to a carbene insertion reaction catalyzed by a transition metal to generate a compound of a formula II;
Figure BDA0002302678430000261
in an alternative, in the step (1), the catalyst is selected from the group consisting of: palladium acetate (Pd (OAc) 2 ) Palladium trifluoroacetate (Pd (OTf) 2 ) Bis (triphenylphosphine) palladium dichloride (Pd (PPh) 3 )Cl 2 ) And allylpalladium chloride dimer ([ PdCl (C)) 3 H 5 )] 2 ) (1, 5-cyclooctadiene) Palladium dichloride (PdCl) 2 (cod)), palladium chloride (PdCl) 2 ) Bis-acetonitrile palladium dichloride (Pd (CH) 3 CN) 2 Cl 2 ) [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (Pd (dppf) Cl 2 ) 1, 2-bis (phenylsulfinyl) ethylpalladium (II) diacetate (alternative name: white catalyst, CAS number 858971-43-4, tris (dibenzylideneacetone) dipalladium-chloroform adduct ([ Pd) 2 (dba) 3 ]·CHCl 3 ) Tris (dibenzylideneacetone) dipalladium (Pd) 2 (dba) 3 ) Tetratriphenylphosphine palladium (Pd (PPh) 3 ) 4 ) Or a combination thereof.
In another preferred embodiment, in the step (1), the catalyst is selected from the group consisting of: tris (dibenzylideneacetone) dipalladium-chloroform adduct ([ Pd) 2 (dba) 3 ]·CHCl 3 ) Tris (dibenzylideneacetone) dipalladium (Pd) 2 (dba) 3 ) Or a combination thereof.
In another preferred embodiment, in the step (1), the first alkaline agent is a quaternary ammonium salt alkaline agent.
In another preferred embodiment, in the step (1), the first alkaline agent is selected from the group consisting of: tetrabutylammonium fluoride, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetramethylammonium bromide, tetraethylammonium bromide, or a combination thereof.
In another preferred embodiment, in the step (1), the first alkaline agent is selected from the group consisting of: tetrabutylammonium chloride, tetrabutylammonium bromide, or a combination thereof.
In another preferred embodiment, in the step (1), the first solvent used is selected from the group consisting of: methanol, tetrahydrofuran, dioxane, chloroform, dichloromethane, 1, 2-dichloroethane, acetone, acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, or hexamethylphosphoric triamide, or a combination thereof.
In another preferred embodiment, in the step (1), the first solvent used is N, N-dimethylformamide.
In another preferred embodiment, in the step (1), the molar ratio of the catalyst to the first alkaline agent is 1:10-80, preferably 1:10-60, more preferably 1:20-60, more preferably 1:30-50, optimally 1.
In another preferred embodiment, in the step (1), the molar ratio of the catalyst to the first alkaline agent is 1:10-80, preferably 1:10-60, more preferably 1:20-60, more preferably 1:30-50, optimally 1.
In another preferred embodiment, in the step (1), the molar ratio of the catalyst to the compound of formula C1 is 1:10-80, preferably 1:10-60, more preferably 1:20-60, more preferably 1:30-50, optimally 1.
In another preferred embodiment, in said step (1), the molar ratio of said compound of formula C1 to said compound of formula C2 is 1.
In another preferred embodiment, in the step (1), the reaction temperature is 20 to 80 ℃, preferably 40 to 80 ℃, and more preferably 50 to 70 ℃.
In another preferred embodiment, in the step (1), the reaction time is 1 to 12 hours, preferably 1 to 8 hours, more preferably 2 to 6 hours, and most preferably 2 to 4 hours.
In the above formulae, the groups are as defined above. Reagents and conditions for each step may be selected from those conventional in the art for carrying out such preparation methods, and such selection may be made by one skilled in the art, based on the knowledge in the art, after the structure of the compound of formula I of the present invention is disclosed. More specifically, the compounds of formula I of the present invention may also be conveniently prepared by optionally combining the various synthetic procedures described in the specification or known in the art, such combinations being readily performed by those skilled in the art to which the invention pertains.
In the preparation method of the compound of the formula II, or the isomer thereof, or the pharmaceutically acceptable salt thereof, the preparation of the polysubstituted compound of the formula II is realized for the first time in one step, and the preparation method has the characteristics of high atomic efficiency, economic steps, easily obtained raw materials and the like, and the compound of the formula II cannot be simply, conveniently and quickly obtained by other methods before.
Use of
The present invention also provides the use of a compound of formula I, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the third aspect of the present invention as described above, for (I) inhibiting or reversing the multidrug resistance of a tumor against an anticancer drug; (2) inhibition of P-glycoprotein; and/or (3) preparing and enhancing the anti-tumor activity of the anti-tumor medicament.
In a preferred embodiment, the tumor includes (but is not limited to): nasopharyngeal carcinoma, oral cancer, esophageal cancer, gastric cancer, intestinal cancer, gallbladder cancer, bile duct cancer, lung cancer, liver cancer, kidney cancer, breast cancer, bladder cancer, ovarian cancer, cervical cancer, endometrial cancer, lymphoma, leukemia, or a combination thereof.
In another preferred embodiment, the anti-tumor drugs include (but are not limited to): paclitaxel, vinorelbine, docetaxel, gemcitabine, epirubicin, doxorubicin, colchicine, or combinations thereof.
Compositions and methods of administration
The present invention provides a method for (i) inhibiting or reversing the multidrug resistance of tumors to anticancer drugs; (2) inhibition of P-glycoprotein; and/or (3) preparing a composition for enhancing the antitumor activity of the antitumor drug. The composition includes (but is not limited to): pharmaceutical compositions, food compositions, dietary supplements, beverage compositions, and the like.
Typically, the composition is a pharmaceutical composition comprising a compound of formula I as described herein, or an isomer thereof, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
In the compositions of the present invention, the amount of the compound of formula I is a therapeutically effective amount, wherein "therapeutically effective amount" refers to an amount that is functional or active and acceptable to humans and/or animals. It will be understood by those skilled in the art that the "therapeutically effective amount" may vary with the form of the pharmaceutical composition, the route of administration, the excipients used, the severity of the disease, and the combination with other drugs.
In the present invention, the dosage form of the pharmaceutical composition includes (but is not limited to) oral preparations, injections, and external preparations.
Representative include (but are not limited to): tablet, injection, infusion solution, paste, gel, solution, microsphere, and pellicle.
The term "pharmaceutically acceptable carrier" refers to: one or more compatible solid, semi-solid, liquid or gel fillers which are suitable for human or animal use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant that the components of the pharmaceutical composition and the active ingredient of the drug are blended with each other and not significantly detract from the efficacy of the drug.
It is to be understood that, in the present invention, the carrier is not particularly limited and may be selected from materials commonly used in the art, or prepared by a conventional method, or commercially available. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., tween), wetting agents (e.g., sodium lauryl sulfate), buffers, chelating agents, thickeners, pH adjusters, transdermal enhancers, colorants, flavors, stabilizers, antioxidants, preservatives, bacteriostats, pyrogen-free water, etc.
Typically, liquid dosage forms may contain, in addition to the active pharmaceutical ingredient, inert diluents commonly employed in the art such as 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, especially cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like. In addition to these inert diluents, the compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents and the like
The pharmaceutical preparation should be compatible with the mode of administration. The agents of the invention may also be used (including before, during or after) with other co-therapeutic agents. In using the pharmaceutical compositions or formulations, a safe and effective amount of the drug, typically at least about 10 micrograms/kg body weight, and in most cases no more than about 8 mg/kg body weight, preferably from about 10 micrograms/kg body weight to about 1 mg/kg body weight, is administered to the subject (e.g., human or non-human mammal). Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.
The present invention also provides a kit comprising:
(A) A first formulation comprising a compound of formula I as described herein, or an isomer thereof, or a pharmaceutically acceptable salt thereof;
(B) A second formulation comprising an anti-neoplastic agent; and
(D) Instructions for use.
In another preferred embodiment, the instructions specify that the first formulation and the second formulation are to be used in combination to enhance the anti-tumor activity of the anti-tumor agent.
The invention also provides an active ingredient combination, which comprises the following components:
(1) The compound of formula I, or an isomer thereof, or a pharmaceutically acceptable salt thereof; and
(2) An antitumor drug.
In another preferred embodiment, at least one of the active ingredients in the active ingredient combination is independent.
In a preferred embodiment, the tumor is selected from the group consisting of: nasopharyngeal carcinoma, oral cancer, esophageal cancer, gastric cancer, intestinal cancer, gallbladder cancer, bile duct cancer, lung cancer, liver cancer, kidney cancer, breast cancer, bladder cancer, ovarian cancer, cervical cancer, endometrial cancer, lymphoma, leukemia, or a combination thereof.
In another preferred embodiment, the anti-tumor drug is selected from the group consisting of: paclitaxel, vinorelbine, docetaxel, gemcitabine, epirubicin, doxorubicin, colchicine, or combinations thereof.
The main advantages of the present invention include:
(a) The invention provides a compound of formula I which has a novel structure and excellent antitumor activity of an antitumor drug.
(d) The compound of the formula I has good pharmaceutical property.
(e) The invention also provides a compound of formula II and a preparation method thereof, the preparation method of the compound of formula II realizes the preparation of the polysubstituted compound of formula II in one step for the first time, and the compound of formula II has the characteristics of high atomic benefit, economic steps, easily available raw materials and the like, and the compound of formula II cannot be simply, conveniently and quickly obtained by other methods before.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
Examples
1H-NMR spectroscopic data measurements of the compounds were determined using Varian Mercury-400MHz, varian Mercury-500MHz nuclear magnetic resonance, mass Spectroscopy EI-MS using a Finnigan MAT95 mass spectrometer, ESI-MS using a Finnigan LCQ Deca mass spectrometer.
Example 1 (2E, 4E) -6-hydroxy-2, 5-diphenyl-2, 4-diene-hexanoic acid methyl ester (1)
Figure BDA0002302678430000311
Wherein Ph denotes phenyl
4-phenyl-4-vinyl-1, 3-dioxopentanone (i.e. phenylvinyl-vinylene carbonate)Ethyl ester) (19mg, 0.1mmol, see angelw. Chem. Int. Ed.2016,55, 11037.), 2-diazo-2-phenyl-acetic acid methyl ester (35.2 mg,0.2mmol, see synlett.2015,26, 1880.), [ Pd ] 2-diazo-2-phenyl-acetic acid methyl ester (see synlett.2015,26, 1880.), [ Pd ] 2 2 (dba) 3 ]·CHCl 3 (2.5mg, 2.5mol%), tetrabutylammonium bromide (32.3mg, 0.1mmol) was dissolved in 1mL of DMF and reacted at 60 ℃ for 2h. After the reaction was completed, a saturated NaCl solution was added, extracted 3 times with ethyl acetate, dried over anhydrous sodium sulfate, and then the organic phase was concentrated and separated by silica gel column (petroleum ether: ethyl acetate = 4.
1 H NMR(500MHz,CDCl 3 ):δ＝7.50(d,J＝11.85Hz,1H),7.46-7.34(m,6H),7.32-7.27(m,4H),6.39(dt,J＝11.80,1.50Hz,1H),4.40(s,2H),3.69(s,3H),1.55(broad,1H)；
13 C NMR(126MHz,CDCl 3 ):δ＝167.6,150.1,136.5,136.4,134.7,133.1,129.8,128.4,128.2,128.0,127.6,127.4,121.9,66.7,51.7.
HRMS(ESI):C 19 H 19 O 3 + ,calcd.295.1329,found295.1324.
Example 2 (2E, 4E) -6-hydroxy-5- (4-bromo-phenyl) -2-phenyl-2, 4-diene-methyl hexanoate (2)
Figure BDA0002302678430000312
Synthesis of Compound 2 see Compound 1 prepared in example 1, except that 4- (4-bromo-phenyl) -4-vinyl-1, 3-dioxolanone is used in place of 4-phenyl-4-vinyl-1, 3-dioxolanone for the reaction. Compound 2 was a yellow solid in 76% yield.
1 H NMR(400MHz,CDCl 3 ):δ＝7.58-7.56(m,2H),7.45-7.34(m,4H),7.27-7.25(m,2H),7.19-7.17(m,2H),6.39(d,J＝11.80Hz,1H),4.35(s,2H),3.70(s,3H),1.66(broad,1H)；
13 C NMR(101MHz,CDCl 3 ):δ＝167.9,149.0,136.2,136.0,134.9,134.1,131.9,130.5,130.2,128.1,127.9,123.0,122.7,66.9,52.2.
HRMS(ESI):C 19 H 18 BrO 3 + ,calcd.373.0434,found373.0438.
Example 3 (2E, 4E) -6-hydroxy-5- (4-cyano-phenyl) -2-phenyl-2, 4-diene-hexanoic acid methyl ester (3)
Figure BDA0002302678430000321
Synthesis of Compound 3 see Compound 1 prepared in example 1, except that 4- (4-cyano-phenyl) -4-vinyl-1, 3-dioxolanone is used in place of 4-phenyl-4-vinyl-1, 3-dioxolanone for the reaction. Compound 3 was a yellow solid in 74% yield.
1 H NMR(400MHz,CDCl 3 ):δ＝7.73-7.71(m,2H),7.44-7.33(m,6H),7.27-7.26(m,1H),7.25-7.24(m,1H),6.45(dt,J＝11.92,1.44Hz,1H),4.37(s,2H),3.70(s,3H),1.81(broad,1H)；
13 C NMR(101MHz,CDCl 3 ):δ＝167.7,148.0,142.1,135.3,135.1,134.6,132.4,130.1,129.6,128.1,128.1,124.3,118.5,112.1,66.7,52.3.
HRMS(ESI):C 20 H 18 NO 3 + ,calcd.320.1281,found320.1289.
Example 4 (2E, 4E) -6-hydroxy-5- (4-methoxycarbonyl-phenyl) -2-phenyl-2, 4-diene-hexanoic acid methyl ester (4)
Figure BDA0002302678430000331
Synthesis of Compound 4 see Compound 1 prepared in example 1, except that 4- (4-methoxycarbonyl-phenyl) -4-vinyl-1, 3-dioxolanone is used in place of 4-phenyl-4-vinyl-1, 3-dioxolanone for the reaction. Compound 4 was a pale yellow solid in 68% yield.
1 H NMR(400MHz,CDCl 3 ):δ＝8.10-8.08(m,2H),7.42-7.36(m,6H),7.27-7.26(m,1H),7.25-7.24(m,1H),6.44(dt,J＝11.88,1.52Hz,1H),4.38(s,2H),3.94(s,3H),3.68(s,3H)；
13 C NMR(101MHz,CDCl 3 ):δ＝167.8,166.7,149.2,141.9,136.0,134.9,134.4,130.2,130.0,129.8,128.9,128.1,127.9,123.4,66.8,52.2,52.2.
HRMS(ESI):C 21 H 21 O 5 + ,calcd.353.1384,found353.1373.
Example 5 (2E, 4E) -6-hydroxy-5- (4-trifluoromethyl-phenyl) -2-phenyl-2, 4-diene-hexanoic acid methyl ester (5)
Figure BDA0002302678430000332
Synthesis of Compound 5 see Compound 1 prepared in example 1, except that 4- (4-trifluoromethyl-phenyl) -4-vinyl-1, 3-dioxolanone is used in place of 4-phenyl-4-vinyl-1, 3-dioxolanone for the reaction. Compound 5 was a white solid in 65% yield.
1 H NMR(400MHz,CDCl 3 ):δ＝7.71-7.69(m,2H),7.44-7.37(m,6H),7.28-7.25(m,2H),6.45(dt,J＝11.88,1.52Hz,1H),4.39(s,2H),3.70(s,3H)；
13 C NMR(101MHz,CDCl 3 ):δ＝167.8,148.6,140.9,135.8,134.8,134.7,130.2,130.1(J CF ＝32.94Hz),129.2,128.1,128.0,124.0(J CF ＝272.81Hz),125.6(J CF ＝3.58Hz),123.7,66.9,52.3.
LC/MS(ESI):C 20 H 18 F 3 O 3 + ,calcd.363.1,found363.1.
Example 6 (2E, 4E) -6-hydroxy-5- (4-fluoro-phenyl) -2-phenyl-2, 4-diene-hexanoic acid methyl ester (6)
Figure BDA0002302678430000341
Synthesis of Compound 6 see Compound 1 prepared in example 1, except that 4- (4-fluoro-phenyl) -4-vinyl-1, 3-dioxolanone is used in place of 4-phenyl-4-vinyl-1, 3-dioxolanone for the reaction. Compound 6 was a pale yellow solid in 87% yield.
1 H NMR(400MHz,CDCl 3 ):δ＝7.46-7.36(m,4H),7.30-7.26(m,3H),7.26-7.25(m,1H),7.15-7.11(m,2H),6.39(dt,J＝11.72,1.52Hz,1H),4.35(s,2H),3.69(s,3H)；
13 C NMR(101MHz,CDCl 3 ):δ＝168.0,164.0(J CF ＝249.23Hz),149.3,136.5,135.0,133.8,133.0(J CF ＝3.38Hz),130.6(J CF ＝8.14Hz),130.2,128.1,127.9,122.8,115.7(J CF ＝21.44Hz),67.1,52.2.
HRMS(ESI):C 19 H 18 FO 3 + ,calcd.313.1234,found313.1227.
Example 7 (2E, 4E) -6-hydroxy-5- (4-methoxy-phenyl) -2-phenyl-2, 4-diene-hexanoic acid methyl ester (7)
Figure BDA0002302678430000342
Synthesis of Compound 7 see Compound 1 prepared in example 1, except that 4- (4-methoxy-phenyl) -4-vinyl-1, 3-dioxolanone is used in place of 4-phenyl-4-vinyl-1, 3-dioxolanone for the reaction. Compound 7 was a yellow solid in 74% yield.
1 H NMR(400MHz,CDCl 3 ):δ＝7.54(d,J＝11.72Hz,1H),7.42-7.33(m,3H),7.28-7.23(m,4H),6.98-6.95(m,2H),6.34(dt,J＝11.88,1.44Hz,1H),4.36(s,2H),3.85(s,3H),3.69(s,3H),1.66(broad,1H)；
13 C NMR(101MHz,CDCl 3 ):δ＝168.1,159.8,150.2,137.3,135.2,133.0,130.2,130.2,129.2,128.0,127.8,121.9,114.1,67.1,55.3,52.1.
HRMS(ESI):C 20 H 21 O 4 + ,calcd.325.1434,found325.1432.
Example 8 (2E, 4E) -6-hydroxy-5- (4-benzyloxy-phenyl) -2-phenyl-2, 4-diene-methyl hexanoate (8)
Figure BDA0002302678430000351
Bn is an abbreviation for benzyl.
Synthesis of Compound 8 referring to Compound 1 prepared in example 1, except that 4- (4-benzyloxy-phenyl) -4-vinyl-1, 3-dioxolanone is used in place of 4-phenyl-4-vinyl-1, 3-dioxolanone for the reaction. Compound 8 was a white solid in 80% yield.
1 H NMR(400MHz,CDCl 3 ):δ＝7.57-7.54(m,1H),7.48-7.46(m,2H),7.44-7.35(m,6H),7.29-7.24(m,4H),7.06-7.03(m,2H),6.34(dt,J＝11.72,1.44Hz,1H),5.12(s,2H),4.38(s,2H),3.70(s,3H)；
13 C NMR(101MHz,CDCl 3 ):δ＝168.1,159.1,150.2,137.3,136.8,135.2,133.1,130.2,130.2,129.5,128.7,128.1,128.1,127.8,127.6,122.0,115.0,70.1,67.1,52.1.
HRMS(ESI):C 26 H 25 O 4 + ,calcd.401.1747,found401.1743.
Example 9 (2E, 4E) -6-hydroxy-5- (4-methyl-phenyl) -2-phenyl-2, 4-diene-hexanoic acid methyl ester (9)
Figure BDA0002302678430000361
Synthesis of Compound 9 see Compound 1, prepared in example 1, except that 4- (4-methyl-phenyl) -4-vinyl-1, 3-dioxolanone is used in place of 4-phenyl-4-vinyl-1, 3-dioxolanone. Compound 9 was a yellow solid in 80% yield.
1 H NMR(400MHz,CDCl 3 ):δ＝7.55-7.52(d,J＝11.76Hz,1H),7.43-7.34(m,3H),7.28-7.26(m,2H),7.24-7.19(m,4H),6.36(d,J＝11.80Hz,1H),4.38(s,2H),3.69(s,3H),2.40(s,3H),1.60(broad,1H)；
13 C NMR(101MHz,CDCl 3 ):δ＝168.1,150.6,138.4,137.2,135.2,133.9,133.2,130.2,129.4,128.7,128.0,127.8,122.0,67.1,52.1,21.3.
HRMS(ESI):C 20 H 21 O 3 + ,calcd.309.1485,found309.1488.
Example 10 (2E, 4E) -6-hydroxy-5- (2-methyl-phenyl) -2-phenyl-2, 4-diene-hexanoic acid methyl ester (10)
Figure BDA0002302678430000362
Synthesis of Compound 10 see Compound 1 prepared in example 1, except that 4- (2-methyl-phenyl) -4-vinyl-1, 3-dioxolanone is used in place of 4-phenyl-4-vinyl-1, 3-dioxolanone for the reaction. Compound 10 was a pale yellow solid in 72% yield.
1 H NMR(400MHz,CDCl 3 ):δ＝7.43-7.33(m,3H),7.29-7.26(m,3H),7.25-7.21(m,2H),7.14-7.06(m,2H),6.44(dt,J＝11.76,1.72Hz,1H),4.27(s,2H),3.65(s,3H),2.24(s,3H),1.62(broad,1H)；
13 C NMR(101MHz,CDCl 3 ):δ＝168.0,151.1,136.6,136.4,135.9,135.1,133.1,130.5,130.2,128.8,128.2,128.1,127.8,125.9,122.1,66.9,52.1,19.6.
HRMS(ESI):C 20 H 21 O 3 + ,calcd.309.1485,found309.1486.
Example 11 (2E, 4E) -6-hydroxy-5- (3-methyl-phenyl) -2-phenyl-2, 4-diene-hexanoic acid methyl ester (11)
Figure BDA0002302678430000371
Synthesis of Compound 11 see Compound 1 prepared in example 1, except that 4- (3-methyl-phenyl) -4-vinyl-1, 3-dioxolanone is used in place of 4-phenyl-4-vinyl-1, 3-dioxolanone for the reaction. Compound 11 was a yellow solid in 86% yield.
1 H NMR(400MHz,CDCl 3 ):δ＝7.51(d,J＝11.84Hz,1H),7.43-7.26(m,6H),7.22-7.19(m,1H),7.11-7.08(m,2H),6.37(dt,J＝11.84,1.48Hz,1H),4.37(s,2H),3.69(s,3H),2.40(s,3H),1.64(broad,1H)；
13 C NMR(101MHz,CDCl 3 ):δ＝168.1,150.8,138.3,137.1,136.9,135.2,133.3,130.2,129.3,128.5,128.1,127.8,126.0,122.2,67.1,52.1,21.5.
HRMS(ESI):C 20 H 21 O 3 + ,calcd.309.1485,found309.1477.
Example 12 (2E, 4E) -6-hydroxy-5- (3-fluoro-phenyl) -2-phenyl-2, 4-diene-hexanoic acid methyl ester (12)
Figure BDA0002302678430000372
Synthesis of Compound 12 see Compound 1 prepared in example 1, except that 4- (3-fluoro-phenyl) -4-vinyl-1, 3-dioxolanone is used in place of 4-phenyl-4-vinyl-1, 3-dioxolanone for the reaction. Compound 12 was a white solid in 67% yield.
1 H NMR(400MHz,CDCl 3 ):δ＝7.47-7.36(m,5H),7.27-7.25(m,2H),7.11-7.06(m,2H),7.03-7.00(m,1H),6.40(dt,J＝11.80,1.52Hz,1H),4.35(s,2H),3.70(s,3H)；
13 C NMR(101MHz,CDCl 3 ):δ＝167.9,162.8(J CF ＝248.19Hz),148.9,139.3(J CF ＝7.49Hz),136.2,134.9,134.2,130.3,130.2,128.1,127.9,124.7(J CF ＝2.75Hz),123.1,115.6(J CF ＝34.48Hz),115.4(J CF ＝32.59Hz),66.9,52.2.
HRMS(ESI):C 19 H 18 FO 3 + ,calcd.313.1234,found313.1230.
Example 13 (2E, 4E) -6-hydroxy-5- (2-naphthalen-yl) -2-phenyl-2, 4-diene-methyl hexanoate (13)
Figure BDA0002302678430000381
Synthesis of Compound 13 see Compound 1 prepared in example 1, except that 4- (2-naphthyl) -4-vinyl-1, 3-dioxolanone is used in place of 4-phenyl-4-vinyl-1, 3-dioxolanone. (Compound 13 is a pale yellow solid, 72% yield.
1 H NMR(400MHz,CDCl 3 ):δ＝7.92-7.86(m,3H),7.78(m,1H),7.56-7.52(m,3H),7.45-7.35(m,4H),7.33-7.29(m,2H),6.48(dt,J＝11.80,1.44Hz,1H),4.47(s,2H),3.66(s,3H)；
13 C NMR(101MHz,CDCl 3 ):δ＝168.0,150.5,136.8,135.2,134.5,133.7,133.2,133.1,130.3,128.4,128.2,128.2,128.1,127.9,127.7,126.6,126.5,122.8,67.2,52.1.
HRMS(ESI):C 23 H 21 O 3 + ,calcd.345.1485,found345.1478.
Example 14 (2E, 4E) -6-hydroxy-2-phenyl-2, 4-diene-methyl hexanoate (14)
Figure BDA0002302678430000391
Synthesis of Compound 14 see Compound 1 prepared in example 1, except that 4-vinyl-1, 3-dioxolanone is used in place of 4-phenyl-4-vinyl-1, 3-dioxolanone. Compound 14 was a yellow oily liquid in 43% yield.
1 H NMR(400MHz,CDCl 3 ):δ＝7.49-7.46(m,1H),7.40-7.31(m,3H),7.22-7.20(m,2H),6.34-7.23(m,2H),4.20(m,2H),3.76(s,3H)；
13 C NMR(101MHz,CDCl 3 ):δ＝167.9,141.3,139.7,134.9,132.7,130.1,128.0,127.8,126.5,62.9,52.2.
HRMS(ESI):C 13 H 15 O 3 + ,calcd.219.1016,found219.1014.
Example 15 (2E, 4E) -6-hydroxy-5- (3, 4-dichloro-phenyl) -2-phenyl-2, 4-diene-hexanoic acid methyl ester (15)
Figure BDA0002302678430000392
Synthesis of Compound 15 referring to Compound 1 prepared in example 1, except that 4- (3, 4-dichloro-phenyl) -4-vinyl-1, 3-dioxolanone is used in place of 4-phenyl-4-vinyl-1, 3-dioxolanone for the reaction. Compound 15 was a white solid in 59% yield.
1 H NMR(400MHz,CDCl 3 ):δ＝7.52-7.50(m,1H),7.43-7.35(m,5H),7.27-7.25(m,1H),7.25-7.23(m,1H),7.16-7.13(m,1H),6.40(dt,J＝11.84,1.48Hz,1H),4.33(s,2H),3.71(s,3H)；
13 C NMR(101MHz,CDCl 3 ):δ＝167.8,147.5,137.2,135.6,134.8,134.8,132.9,132.6,130.6,130.5,130.1,128.4,128.1,128.0,123.9,66.8,52.3.
HRMS(ESI):C 19 H 17 Cl 2 O 3 + ,calcd.363.0549,found363.0548.
Example 16 (2E, 4E) -6-hydroxy-2, 5-diphenyl-2, 4-diene-benzyl hexanoate (16)
Figure BDA0002302678430000401
Bn refers to benzyl.
Synthetic method of compound 16 compound 1 prepared in example 1 was reacted with 2-diazo-2-phenyl-acetic acid benzyl ester instead of 2-diazo-2-phenyl-acetic acid methyl ester. Compound 16 was a white solid in 73% yield.
1 H NMR(400MHz,CDCl 3 ):δ＝7.60-7.57(m,1H),7.44-7.35(m,6H),7.32-7.27(m,7H),7.22-7.20(m,2H),6.44(dt,J＝11.84,1.56Hz,1H),5.16(s,2H),4.41(s,2H)；
13 C NMR(101MHz,CDCl 3 ):δ＝167.2,150.9,137.2,137.0,136.3,135.0,133.3,130.3,128.8,128.6,128.5,128.4,128.0,127.8,127.4,122.3,67.0,66.3.
HRMS(ESI):C 25 H 23 O 3 + ,calcd.371.1642,found371.1633.
Example 17 (2E, 4E) -6-hydroxy-2- (4-methyl-phenyl) -5-phenyl-2, 4-diene-hexanoic acid methyl ester (17)
Figure BDA0002302678430000402
Synthetic procedure for compound 17 see compound 1 prepared in example 1, except that 2-diazo-2- (4-methyl-phenyl) -acetic acid methyl ester is used instead of 2-diazo-2-phenyl-acetic acid methyl ester for the reaction. Compound 17 was a pale yellow solid in 56% yield.
1 H NMR(400MHz,CDCl 3 ):δ＝7.49-7.38(m,4H),7.31-7.29(m,2H),7.23-7.16(m,4H),6.41(dt,J＝11.76,1.52Hz,1H),4.40(d,J＝1.40Hz,2H),3.68(s,3H),2.40(s,3H)；
13 C NMR(101MHz,CDCl 3 ):δ＝168.2,150.2,137.6,137.1,136.6,133.5,132.1,130.1,128.8,128.8,128.6,128.4,122.6,67.1,52.1,21.3.
HRMS(ESI):C 20 H 21 O 3 + ,calcd.309.1485,found309.1482.
Example 18 (2E, 4E) -6-hydroxy-2- (4-methoxy-phenyl) -5-phenyl-2, 4-diene-methyl hexanoate (18)
Figure BDA0002302678430000411
Synthetic procedure for compound 18 see compound 1 prepared in example 1, except that 2-diazo-2- (4-methoxy-phenyl) -acetic acid methyl ester is used instead of 2-diazo-2-phenyl-acetic acid methyl ester. Compound 18 was a white solid in 44% yield.
1 H NMR(400MHz,CDCl 3 ):δ＝7.47-7.38(m,4H),7.32-7.29(m,2H),7.23-7.19(m,2H),6.96-6.93(m,2H),6.43(dt,J＝11.72,1.44Hz,1H),4.41(s,2H),3.85(s,3H),3.69(s,3H)；
13 C NMR(101MHz,CDCl 3 ):δ＝168.3,159.2,150.0,137.1,136.4,133.2,131.5,128.8,128.6,128.4,127.4,122.6,113.5,67.1,55.3,52.1.
HRMS(ESI):C 20 H 21 O 4 + ,calcd.325.1434,found325.1433.
Example 19 (2E, 4E) -6-hydroxy-2- (4-fluoro-phenyl) -5-phenyl-2, 4-diene-hexanoic acid methyl ester (19)
Figure BDA0002302678430000421
Synthetic procedure for compound 19 see compound 1 prepared in example 1, except that 2-diazo-2- (4-fluoro-phenyl) -acetic acid methyl ester is used instead of 2-diazo-2-phenyl-acetic acid methyl ester for the reaction. Compound 19 was a white solid in 68% yield.
1 H NMR(400MHz,CDCl 3 ):δ＝7.51-7.39(m,4H),7.30-7.23(m,4H),7.12-7.07(m,2H),6.37(dt,J＝11.76,1.56Hz,1H),4.40(s,2H),3.68(s,3H)；
13 C NMR(101MHz,CDCl 3 ):δ＝167.8,162.4(J CF ＝248.05Hz),151.0,137.2,136.9,132.3,132.0(J CF ＝8.15Hz),131.0(J CF ＝3.35Hz),128.8,128.7,128.5,121.9,115.1(J CF ＝21.40Hz),67.0,52.2.
HRMS(ESI):C 19 H 18 FO 3 + ,calcd.313.1234,found313.1228.
Example 20 (2E, 4E) -6-hydroxy-2- (4-chloro-phenyl) -5-phenyl-2, 4-diene-hexanoic acid methyl ester (20)
Figure BDA0002302678430000422
See compound 1 prepared in example 1 for a synthetic method for compound 20, except that the reaction was performed using 2-diazo-2- (4-chloro-phenyl) -acetic acid methyl ester instead of 2-diazo-2-phenyl-acetic acid methyl ester. Compound 20 was a white solid in 74% yield.
1 H NMR(400MHz,CDCl 3 ):δ＝7.50(d,J＝11.84Hz,1H),7.46-7.36(m,5H),7.30-7.27(m,2H),7.23-7.20(m,2H),6.37(dt,J＝11.84,1.56Hz,1H),4.40(s,2H),3.68(s,3H)；
13 C NMR(101MHz,CDCl 3 ):δ＝167.6,151.3,137.4,136.9,133.8,133.6,132.1,131.6,128.8,128.7,128.6,128.3,121.7,66.9,52.2.
HRMS(ESI):C 19 H 18 ClO 3 + ,calcd.329.0939,found329.0934.
Example 21 (2E, 4E) -6-hydroxy-2- (3-chloro-phenyl) -5-phenyl-2, 4-diene-hexanoic acid methyl ester (21)
Figure BDA0002302678430000431
Synthetic procedure for compound 21 see compound 1 prepared in example 1, except that the reaction is carried out using 2-diazo-2- (3-chloro-phenyl) -acetic acid methyl ester instead of 2-diazo-2-phenyl-acetic acid methyl ester. Compound 21 was a white solid in 85% yield.
1 H NMR(400MHz,CDCl 3 ):δ＝7.51(d,J＝11.88Hz,1H),7.46-7.39(m,3H),7.34-7.33(m,2H),7.29-7.26(m,3H),7.16-7.14(m,1H),6.35(dt,J＝11.88,1.56Hz,1H),4.40(s,2H),3.68(s,3H)；
13 C NMR(101MHz,CDCl 3 ):δ＝167.5,151.7,137.7,137.0,136.8,134.0,131.9,130.2,129.3,128.8,128.7,128.6,128.5,128.0,121.6,66.9,52.2.
HRMS(ESI):C 19 H 18 ClO 3 + ,calcd.329.0939,found329.0932.
Example 22 (2E, 4E) -6-hydroxy-2- (3-methyl-phenyl) -5-phenyl-2, 4-diene-hexanoic acid methyl ester (22)
Figure BDA0002302678430000432
Synthetic procedure for compound 22 see compound 1 prepared in example 1, except that 2-diazo-2- (3-methyl-phenyl) -acetic acid methyl ester is used instead of 2-diazo-2-phenyl-acetic acid methyl ester for the reaction. Compound 22 was a white solid in 78% yield.
1 H NMR(400MHz,CDCl 3 ):δ＝7.53(d,J＝11.76Hz,1H),7.46-7.36(m,3H),7.30-7.21(m,5H),7.11-7.09(m,1H),6.12(dt,J＝11.80,1.52Hz,1H),4.35(s,2H),3.66(s,3H),2.16(s,3H)；
13 C NMR(101MHz,CDCl 3 ):δ＝167.9,150.6,137.3,137.0,136.9,134.9,133.3,130.2,130.0,128.8,128.6,128.5,128.1,125.6,122.1,67.1,52.1,19.8.
HRMS(ESI):C 20 H 21 O 3 + ,calcd.309.1485,found309.1477.
Example 23 (2E, 4E) -6-hydroxy-2- (2-methyl-phenyl) -5-phenyl-2, 4-diene-hexanoic acid methyl ester (23)
Figure BDA0002302678430000441
Synthetic procedure for compound 23 see compound 1 prepared in example 1, except that 2-diazo-2- (2-methyl-phenyl) -acetic acid methyl ester is used instead of 2-diazo-2-phenyl-acetic acid methyl ester. Compound 23 was a white solid in 69% yield.
1 H NMR(400MHz,CDCl 3 ):δ＝7.53(d,J＝11.80Hz,1H),7.46-7.26(m,7H),7.25-7.22(m,1H),7.11-7.09(m,1H),6.12(dt,J＝11.84,1.48Hz,1H),4.35(s,2H),3.66(s,3H),2.16(s,3H)；
13 C NMR(101MHz,CDCl 3 ):δ＝167.9,150.6,137.3,137.0,136.9,134.9,133.3,130.2,130.0,128.8,128.8,128.6,128.5,128.1,125.6,122.1,67.1,52.1,19.8.
HRMS(ESI):C 20 H 21 O 3 + ,calcd.309.1485,found309.1480.
Example 24 (2E, 4E) -6-hydroxy-2- (2-naphthalen-yl) -5-phenyl-2, 4-diene-hexanoic acid methyl ester (24)
Figure BDA0002302678430000451
Synthetic procedure for compound 24 see compound 1 prepared in example 1, except that 2-diazo-2- (2-naphthyl) -acetic acid methyl ester is used instead of 2-diazo-2-phenyl-acetic acid methyl ester for the reaction. Compound 24 was a yellow solid in 74% yield.
1 H NMR(400MHz,CDCl 3 ):δ＝7.90-7.86(m,3H),7.76-7.75(m,1H),7.60-7.57(m,1H),7.54-7.49(m,2H),7.48-7.37(m,4H),7.34-7.31(m,2H),6.42(dt,J＝11.76,1.56Hz,1H),4.36(s,2H),3.70(s,3H)；
13 C NMR(101MHz,CDCl 3 ):δ＝168.1,150.9,137.3,137.0,133.4,133.1,132.8,132.7,129.4,128.8,128.7,128.5,128.2,128.1,127.7,127.6,126.3,126.2,122.4,67.0,52.2.
HRMS(ESI):C 23 H 21 O 3 + ,calcd.345.1485,found345.1483.
Example 25 (2E, 4E) -6- [ (4-Nitro-phenyl) -sulfonylamino ] -2, 5-diphenyl-2, 4-diene-hexanoic acid methyl ester (25)
Figure BDA0002302678430000452
Ns is abbreviation for p-nitrobenzenesulfonyl
3- (4-Nitro-benzenesulfonyl) -4-phenyl-4-vinyl-2-oxazolidinone (37.4 mg,0.1mmol, synthetic method see Nature chem.2014,6, 47.), 2-diazo-2-phenyl-acetic acid methyl ester (35.2mg, 0.2mmol, synthetic method see Synlett.2015,26, 1880.), [ Pd ], (4-Nitro-benzenesulfonyl) -4-phenyl-4-vinyl-2-oxazolidinone 2 (dba) 3 ]·CHCl 3 (2.5mg, 2.5mol%), tetrabutylammonium bromide (32.3mg, 0.1mmol) was dissolved in 1mL of DMF and reacted at room temperature for 12 hours. After the reaction is finished, adding a saturated NaCl solution, extracting for 3 times by ethyl acetate, drying by anhydrous sodium sulfate, concentrating an organic phase, and separating by a silica gel column to obtain a white solid compound 25 with the yield of 51%.
1 H NMR(400MHz,CDCl 3 ):δ＝8.21-8.18(m,2H),7.80-7.77(m,2H),7.45-7.39(m,3H),7.37-7.33(m,3H),7.31-7.28(m,1H),7.20-7.17(m,2H),7.08-7.05(m,2H),6.17(dt,J＝11.68,1.28Hz,1H),4.71(t,J＝6.12Hz,1H),4.02(d,J＝6.12Hz,2H),3.67(s,3H)；
13 C NMR(101MHz,CDCl 3 ):δ＝167.6,149.9,145.8,144.6,136.0,135.7,134.9,134.7,130.0,128.9,128.9,128.7,128.2,128.1,125.4,124.2,52.3,49.9.
HRMS(ESI):C 25 H 23 N 2 O 6 S + ,calcd.479.1271,found479.1277.
Example 26 (2E, 4E) -6- [ (4-Nitro-phenyl) -sulfonylamino ] -5- (4-fluoro-phenyl) -2-phenyl-2, 4-diene-hexanoic acid methyl ester (26)
Figure BDA0002302678430000461
Synthesis of Compound 26 see Compound 25, prepared in example 25, except that 3- (4-nitro-benzenesulfonyl) -4- (4-fluoro-phenyl) -4-vinyl-2-oxazolidinone is used instead of 3- (4-nitro-benzenesulfonyl) -4-phenyl-4-vinyl-2-oxazolidinone. (Compound 26 was a white solid, 64% yield.
1 H NMR(400MHz,(CD 3 ) 2 CO):δ＝8.34-8.32(m,2H),7.97-7.94(m,2H),7.45-7.39(m,3H),7.33-7.29(m,2H),7.26-7.22(m,3H),7.21-7.15(m,2H),6.31(dt,J＝11.72,1.36Hz,1H),4.08(d,J＝4.88Hz,2H),3.62(s,3H)；
13 C NMR(101MHz,(CD 3 ) 2 CO):δ＝166.9,149.9,146.8,145.6,135.5,135.0,135.0,134.1,133.4(J CF ＝4.16Hz),131.1(J CF ＝8.23Hz),130.2,128.1,127.9,127.8,124.7,124.3,115.3(J CF ＝21.76Hz),51.3,49.5.
HRMS(ESI):C 25 H 22 FN 2 O 6 S + ,calcd.497.1177,found497.1170.
Example 27 (2E, 4E) -6- [ (4-Nitro-phenyl) -sulfonylamino ] -5- (4-chloro-phenyl) -2-phenyl-2, 4-diene-hexanoic acid methyl ester (27)
Figure BDA0002302678430000471
Synthesis of Compound 27 see Compound 25, prepared in example 25, except that 3- (4-nitro-benzenesulfonyl) -4- (4-chloro-phenyl) -4-vinyl-2-oxazolidinone is used instead of 3- (4-nitro-benzenesulfonyl) -4-phenyl-4-vinyl-2-oxazolidinone. Compound 27 was a light pink solid with a yield of 50%.
1 H NMR(400MHz,CDCl 3 ):δ＝8.23-8.21(m,2H),7.81-7.79(m,2H),7.44-7.39(m,3H),7.33-7.31(m,2H),7.26-7.23(m,1H),7.19-7.17(m,2H),7.06-7.04(m,2H),6.19(dt,J＝11.60,1.28Hz,1H),4.75(broad,1H),3.98(d,J＝6.12Hz,2H),3.68(s,3H)；
13 C NMR(101MHz,CDCl 3 ):δ＝167.5,149.9,145.8,143.3,135.4,135.1,135.0,134.5,130.0,129.1,128.2,128.2,128.1,125.9,124.3,52.4,49.8.
LC/MS(ESI):C 25 H 22 ClN 2 O 6 S + ,calcd.513.1,found513.2.
Example 28 (2E, 4E) -6- [ (4-Nitro-phenyl) -sulfonylamino ] -5- (4-methyl-phenyl) -2-phenyl-2, 4-diene-hexanoic acid methyl ester (28)
Figure BDA0002302678430000472
Synthesis of Compound 28 see Compound 25, prepared in example 25, except that 3- (4-nitro-benzenesulfonyl) -4- (4-methyl-phenyl) -4-vinyl-2-oxazolidinone is used instead of 3- (4-nitro-benzenesulfonyl) -4-phenyl-4-vinyl-2-oxazolidinone. Compound 28 was a yellow solid in 57% yield.
1 H NMR(400MHz,CDCl 3 ):δ＝8.21-8.18(m,2H),7.80-7.76(m,2H),7.45-7.39(m,3H),7.33-7.30(m,1H),7.19-7.13(m,4H),6.95-6.93(m,2H),6.13(dt,J＝11.60,1.28Hz,1H),4.67(t,J＝6.08Hz,1H),4.01(d,J＝6.08Hz,2H),3.67(s,3H),2.37(s,3H)；
13 C NMR(101MHz,CDCl 3 ):δ＝167.7,149.8,145.9,144.6,139.1,136.0,134.7,134.6,132.9,130.0,129.5,128.6,128.2,128.1,125.1,124.2,52.2,49.9,21.2.
HRMS(ESI):C 26 H 25 N 2 O 6 S + ,calcd.493.1428,found493.1423.
Example 29 (2E, 4E) -6- [ (4-Nitro-phenyl) -sulfonylamino ] -5- (4-methoxy-phenyl) -2-phenyl-2, 4-diene-hexanoic acid methyl ester (29)
Figure BDA0002302678430000481
Synthesis of Compound 29 see Compound 25 prepared in example 25, except that 3- (4-nitro-benzenesulfonyl) -4- (4-methoxy-phenyl) -4-vinyl-2-oxazolidinone is used instead of 3- (4-nitro-benzenesulfonyl) -4-phenyl-4-vinyl-2-oxazolidinone. Compound 29 was a yellow solid in 60% yield.
1 H NMR(400MHz,CDCl 3 ):δ＝8.22-8.17(m,2H),7.80-7.76(m,2H),7.44-7.32(m,4H),7.19-7.17(m,2H),7.02-6.98(m,2H),6.87-6.83(m,2H),6.11(dt,J＝11.60,1.20Hz,1H),4.73(m,1H),4.00(d,J＝6.08Hz,2H),3.83(s,3H),3.68(s,3H)；
13 C NMR(101MHz,CDCl 3 ):δ＝167.7,160.1,149.8,145.9,144.3,136.1,134.8,134.4,130.0,128.1,128.1,128.0,124.8,124.2,114.2,55.3,52.2,49.9.
HRMS(ESI):C 26 H 25 N 2 O 7 S + ,calcd.509.1377,found509.1363.
Example 30 (2E, 4E) -6- [ (4-methyl-phenyl) -sulfonylamino ] -5- (4-methyl-phenyl) -2-phenyl-2, 4-diene-hexanoic acid methyl ester (30)
Figure BDA0002302678430000491
Ts is an abbreviation for p-toluenesulfonyl.
Synthesis of Compound 30 see Compound 25 prepared in example 25, except that 3- (4-nitro-benzenesulfonyl) -4-phenyl-4-vinyl-2-oxazolidinone is replaced with 3- (4-methyl-benzenesulfonyl) -4- (4-methyl-phenyl) -4-vinyl-2-oxazolidinone. Compound 30 was a white solid in 78% yield.
1 H NMR(400MHz,CDCl 3 ):δ＝7.58-7.55(m,2H),7.44-7.35(m,4H),7.23-7.15(m,6H),6.98-6.96(m,2H),6.16(dt,J＝11.76,1.28Hz,1H),4.73(t,J＝4.84Hz,1H),3.90(d,J＝6.24Hz,2H),3.68(s,3H),2.43(s,3H),2.39(s,3H)；
13 C NMR(101MHz,CDCl 3 ):δ＝167.9,145.5,143.4,138.8,136.8,136.5,134.8,133.9,133.2,130.1,129.6,129.4,128.7,128.1,128.0,127.2,124.6,52.2,49.7,21.6,21.3.
HRMS(ESI):C 27 H 28 NO 4 S + ,calcd.462.1734,found462.1726.
Example 31 (2E, 4E) -6- [ (4-methyl-phenyl) -sulfonylamino ] -5- (4-methoxy-phenyl) -2-phenyl-2, 4-diene-hexanoic acid methyl ester (31)
Figure BDA0002302678430000492
Ts is an abbreviation for p-toluenesulfonyl.
Synthesis of Compound 31 see Compound 25 prepared in example 25, except that 3- (4-nitro-benzenesulfonyl) -4-phenyl-4-vinyl-2-oxazolidinone is replaced with 3- (4-methyl-benzenesulfonyl) -4- (4-methoxy-phenyl) -4-vinyl-2-oxazolidinone. Compound 31 was a white solid in 76% yield.
1 H NMR(400MHz,CDCl 3 ):δ＝7.58-7.56(m,2H),7.44-7.37(m,4H),7.24-7.19(m,4H),7.04-7.01(m,2H),6.90-6.86(m,2H),6.14(dt,J＝11.72,1.32Hz,1H),4.42(broad,1H),3.89(d,J＝6.20Hz,2H),3.85(s,3H),3.68(s,3H),2.43(s,3H)；
13 C NMR(101MHz,CDCl 3 ):δ＝167.9,160.0,145.0,143.5,136.8,136.7,134.9,133.8,130.2,130.1,129.6,128.4,128.1,128.0,127.1,124.4,114.2,55.4,52.2,49.7,21.6.
HRMS(ESI):C 27 H 28 NO 5 S + ,calcd.478.1683,found478.1676.
Example 32 (2E, 4E) -6- [ (4-nitro-phenyl) -sulfonylamino ] -2- (4-methyl-phenyl) -5-phenyl-2, 4-diene-hexanoic acid methyl ester (32)
Figure BDA0002302678430000501
See compound 25 prepared in example 25 for the synthesis of compound 32, except that the reaction was carried out with 2-diazo-2- (4-methyl-phenyl) -acetic acid methyl ester instead of 2-diazo-2-phenyl-acetic acid methyl ester. Compound 32 was a white solid in 41% yield.
1 H NMR(400MHz,CDCl 3 ):δ＝8.22-8.19(m,2H),7.81-7.77(m,2H),7.37-7.33(m,3H),7.28-7.22(m,3H),7.09-7.04(m,4H),6.19(dt,J＝11.68,1.24Hz,1H),4.69(broad,1H),4.03(d,J＝5.96Hz,2H),3.66(s,3H),2.43(s,3H)；
13 C NMR(101MHz,CDCl 3 ):δ＝167.8,149.9,145.8,144.1,138.1,136.1,135.4,134.9,131.6,129.9,128.9,128.9,128.7,128.2,125.6,124.2,52.3,49.9,21.4.
HRMS(ESI):C 26 H 25 N 2 O 6 S + ,calcd.493.1428,found493.1421.
Example 33 (2E, 4E) -6- [ (4-nitro-phenyl) -sulfonylamino ] -2, 5-diphenyl-2, 4-diene-benzyl hexanoate (33)
Figure BDA0002302678430000511
Synthetic procedure for compound 33 see compound 25 prepared in example 25, except that 2-diazo-2-phenyl-acetic acid benzyl ester is used instead of 2-diazo-2-phenyl-acetic acid methyl ester for the reaction. Compound 33 was a white solid in 37% yield.
1 H NMR(400MHz,CDCl 3 ):δ＝8.21-8.18(m,2H),7.82-7.77(m,2H),7.43-7.27(m,10H),7.22-7.16(m,4H),7.08-7.06(m,2H),6.21(dt,J＝11.72,1.24Hz,1H),5.13(s,2H),4.67(m,1H),4.03(d,J＝5.92Hz,2H)；
13 C NMR(101MHz,CDCl 3 ):δ＝166.8,149.9,145.8,144.8,136.0,136.0,136.0,134.7,134.5,130.1,128.9,128.8,128.7,128.4,128.2,128.1,127.9,127.5,125.3,124.2,66.5,49.8.
HRMS(ESI):C 31 H 27 N 2 O 6 S + ,calcd.555.1584,found555.1565.
Example 34 (2E, 4E) -6-carbonyl-2, 5-diphenyl-2, 4-diene-hexanoic acid methyl ester (34)
Figure BDA0002302678430000512
0.1mmol of compound 1 is dissolved in 1mL of dichloromethane and 0.13mmol of DMP oxidant is added at 0 ℃ under nitrogen. After stirring for 5 minutes, the reaction was slowly warmed to room temperature, followed by stirring for another 1 hour. Then the reaction solution is cooled to 0 ℃, and then NaHCO is used again 3 /Na 2 S 2 O 3 The solution was washed twice with (1. And finally, combining organic phases, drying by using anhydrous sodium sulfate, performing reduced pressure spin drying, and separating a product by using a flash chromatographic column to obtain a final product. The product was compound 34 as a yellow solid in 78% yield.
1 H NMR(400MHz,CDCl 3 ):δ＝9.60(s,1H),7.67(d,J＝11.76Hz,1H),7.50-7.44(m,6H),7.34-7.29(m,4H),7.06(d,J＝11.76Hz,1H),3.76(s,3H)；
13 C NMR(101MHz,CDCl 3 ):δ＝193.1,167.0,146.2,143.1,140.8,134.3,134.0,131.7,130.2,130.0,129.0,128.9,128.5,128.4,128.3,52.6.
HRMS(ESI):C 19 H 17 O 3 + ,calcd.293.1172,found293.1170.
Example 35 (2E, 4E) -6- (Phthalimido) -2, 5-diphenyl-2, 4-diene-methyl hexanoate (35)
Figure BDA0002302678430000521
0.1mmol of compound 1 is dissolved in 1.3mL of tetrahydrofuran and 0.2mmol of triphenylphosphine and 0.2mmol of phthalimide are added at 0 ℃ under nitrogen. After stirring for 5 minutes, 0.2mmol of diethyl azodicarbonate was slowly added. After stirring at 0 ℃ for 30 minutes, the reaction was slowly warmed to room temperature, followed by stirring until the reaction was complete (TLC detection). And then, spin-drying the reaction solution under a reduced pressure condition, and separating the product by using a flash chromatographic column to obtain the final product. The product was compound 35 as a pale yellow solid in 67% yield.
1 H NMR(400MHz,CDCl 3 ):δ＝7.77-7.67(m,4H),7.44-7.34(m,6H),7.24-7.12(m,5H),6.14(dt,J＝11.64,1.52Hz,1H),4.59(s,2H),3.67(s,3H)；
13 C NMR(101MHz,CDCl 3 ):δ＝167.8,167.6,144.6,136.5,136.3,134.8,133.9,133.8,131.7,130.2,128.8,128.6,128.5,127.7,127.6,123.8,123.3,52.1,43.9.
HRMS(ESI):C 27 H 22 NO 4 + ,calcd.424.1543,found424.1537.
Example 36 (2E, 4E) -2, 5-diphenyl-2, 4-diene-1, 6-hexanediol (36)
Figure BDA0002302678430000531
0.2mmol of compound 1 was dissolved in 3mL of super-dry tetrahydrofuran and a toluene solution of diisobutylaluminum hydride (DIBAL-H1 Mintoluene,0.7 mmol)) was slowly added dropwise under nitrogen. The reaction was then stirred overnight at ambient temperature. After the reaction is finished, the reaction solution is quenched by water, acidified by dilute hydrochloric acid and extracted by ethyl acetate. And finally, combining organic phases, drying, performing reduced pressure spin drying, and separating a product through a flash chromatography column to obtain a final product. The product was compound 36 as a yellow solid in 60% yield.
1 H NMR(600MHz,Acetone-d6):δ＝7.41-7.38(m,4H),7.35-7.30(m,6H),6.47(s,2H),4.28(d,J＝5.80Hz,4H),3.96(t,J＝5.84Hz,2H)；
13 C NMR(126MHz,Acetone-d6):δ＝143.5,139.2,128.9,128.1,127.1,122.3,66.2.
HRMS(ESI):C 18 H 17 O + [M–H 2 O+H + ],calcd.249.1274,found249.1261；C 18 H 15 + [M–2H 2 O+H + ],calcd.231.1168,found231.1159.
EXAMPLE 37 preparation of Compound 13a
Figure BDA0002302678430000541
Step 1: preparation of synthetic intermediate Int 1 from compound 25:
1mmol of compound 25 was dissolved in 4mL of methanol, and 4mL of 10% aqueous sodium hydroxide solution was added. Then, the reaction mixture was reacted at 80 ℃ for 2 hours. After the reaction, the reaction solution was adjusted to pH 7 with dilute hydrochloric acid and extracted with ethyl acetate. And finally, combining organic phases, drying, performing reduced pressure spin drying, and separating a product through a flash chromatography column to obtain a synthetic intermediate Int 1. The product was a white solid in 43% yield.
Preparation of intermediate Int 2
Preparation of intermediate Int 2 by step 2 or step 3
And 2, step: preparation of synthetic intermediate Int 2 from compound 35:
423mg of Compound 35 was dissolved in 13mL of acetic acid, and 20mL of 6N HCl aqueous solution was added. Then, the reaction mixture was reacted at 140 ℃ for 48 hours. After the reaction was completed, the reaction solution was spin-dried under reduced pressure, and the residue was used in the next step without further purification.
The residue was dissolved in 20mL of water and 20mL of acetone and NaHCO 3 The pH was adjusted to 7, after which 370mg of Fmoc-OSu and 168mg of NaHCO were added 3 Then, the reaction solution was reacted at room temperature for 18 hours. And after the reaction is finished, adjusting the pH value to be between 3 and 4 by using dilute hydrochloric acid, extracting by using ethyl acetate, finally combining organic phases, drying, performing reduced pressure spin drying, and separating a product by using a flash chromatographic column to obtain a synthetic intermediate Int 2. The product was a solid in 44% yield.
And 3, step 3: preparation of synthetic intermediate Int 2 from synthetic intermediate Int 1:
50mg of the synthetic intermediate Int 1, 15mg of potassium carbonate are dissolved in 5mL of methanol and 0.02mL of thioglycolic acid are added at 0 ℃. Then, the reaction mixture was slowly warmed to room temperature and reacted for 7 hours. After the reaction was completed, the reaction solution was dried under reduced pressure, and the residue was used in the next step without further purification.
The residue was dissolved in 3mL of water and 3mL of acetone and NaHCO 3 The pH was adjusted to 7, after which 50mg of Fmoc-OSu and 93mg of NaHCO were added 3 Then, the reaction solution was reacted at room temperature for 18 hours. And after the reaction is finished, adjusting the pH value to be between 3 and 4 by using dilute hydrochloric acid, extracting by using ethyl acetate, finally combining organic phases, drying, performing reduced pressure spin drying, and separating a product by using a flash chromatographic column to obtain a synthetic intermediate Int 2. The product was a solid in 74% yield.
And 4, step 4: preparation of synthetic intermediate Int 3 from synthetic intermediate Int 2:
200mg of the synthetic intermediate Int 2, 230mg of EDCI and 162mg of HOBt were dissolved in 15mL of dichloromethane, and 98mg of L-type valine benzyl ester hydrochloride was added. Then, the reaction mixture was reacted at room temperature for 12 hours. And after the reaction is finished, washing the reaction solution with water, performing pressure spin drying on the organic phase, and separating the product from the residue through a flash chromatographic column to obtain a synthetic intermediate Int 3. The product was a white solid in 37% yield.
And 5: preparation of synthetic intermediate Int 4 from synthetic intermediate Int 3:
54mg of the synthetic intermediate Int 3 was dissolved in 40mL of dichloromethane, and 0.12mL of DBU was added. Then, the reaction mixture was reacted at room temperature for 1 hour. After the reaction is finished, the reaction solution is acidified by hydrochloric acid dioxane solution, then the reaction solution is decompressed and dried in a spinning mode, and residues are directly used for the next step without further purification.
The residue was dissolved in 40mL of dichloromethane, and 90mg of EDCI and 32mg of HOBt, and 51mg of Fmoc-NH- (CH) 2 ) 11 -COOH. Then, the reaction solution was reacted at room temperature for 6 hours. And after the reaction is finished, washing the reaction solution with water, carrying out decompression and spin-drying on the organic phase, and separating the product from the residue through a flash chromatographic column to obtain a synthetic intermediate Int 4. The product is a white solid, and is producedThe ratio was 29%.
And 6: preparation of the final product, compound 13a, from the synthetic intermediate Int 4:
45mg of synthetic intermediate Int 4 was dissolved in 1mL of methanol, and 1mL of 10% aqueous sodium hydroxide solution was added. Then, the reaction mixture was reacted at room temperature for 12 hours. After the reaction, the reaction solution was acidified with dilute hydrochloric acid, and then the reaction solution was spin-dried under reduced pressure, and the residue was used in the next step without further purification.
The residue was dissolved in 40mL of dichloromethane, and 39mg of EDCI and 28mg of HOBt were added. Then, the reaction mixture was reacted at room temperature for 4 hours. After the reaction is finished, the reaction solution is washed by water, the organic phase is subjected to vacuum spin drying, and the residue is subjected to separation by a flash chromatographic column to obtain a product compound 13a. The product was a white solid in 24% yield.
1 H NMR(400MHz,MeOH-d4):δ＝7.55-7.39(m,9H),7.33-7.31(m,2H),6.32(d,J＝11.44Hz,1H),4.12-4.00(m,3H),3.49(m,1H),2.10(t,J＝6.60Hz,2H),1.87(m,1H),1.55-1.10(m,22H),0.87(d,J＝6.68Hz,3H),0.84(d,J＝6.68Hz,3H)；
13 C NMR(126MHz,MeOH-d4):δ＝174.73,172.03,138.30,130.19,128.80,128.58,128.24,128.09,128.02,122.67,60.19,44.66,38.25,35.53,29.87,29.65,29.51,28.90,28.80,28.51,26.41,25.84,18.20,17.62.
LC/MS(ESI):C 35 H 48 N 3 O 3 + ,calcd.558.4,found558.3.
EXAMPLE 38 preparation of Compound 14a
Figure BDA0002302678430000561
Step 1: preparation of synthetic intermediate Int 5 from starting material compound 1:
dissolving the raw material compound 1 in ether, cooling in an ice water bath, and slowly adding phosphorus tribromide. Then, the reaction mixture was reacted at 0 ℃ for 2 hours. After the reaction, the reaction solution was washed with water, and the organic phase was dried over anhydrous sodium sulfate and used in the next step without further purification.
4- (N-tert-Butoxycarbonyl-amino) -piperidine was dissolved in dichloromethane and the bromo-compound was added slowly in ether at-15 ℃. Then, the reaction mixture was reacted at 0 ℃ for 2 hours. And after the reaction is finished, washing the reaction solution with water, carrying out decompression and spin-drying on the organic phase, and separating the product from the residue through a flash chromatographic column to obtain a synthetic intermediate Int 5.
And 2, step: preparation of synthetic intermediate Int 6 from synthetic intermediate Int 5:
the synthetic intermediate Int 5 was dissolved in dichloromethane and trifluoroacetic acid was added slowly at 0 ℃. Then, the reaction mixture was reacted at room temperature for 2 hours. After the reaction, the reaction mixture was spin-dried under reduced pressure, and the residue was dissolved in ethyl acetate and washed with a saturated aqueous sodium carbonate solution. The combined organic phases were dried and concentrated under reduced pressure and the residue was used directly in the next step without further purification.
The residue was dissolved in dichloromethane, EDCI and HOBt added, and Fmoc-NH- (CH) 2 ) 11 -COOH. Then, the reaction solution was reacted at room temperature for 6 hours. And after the reaction is finished, washing the reaction solution with water, performing vacuum spin-drying on the organic phase, and separating the product from the residue through a flash chromatographic column to obtain a synthetic intermediate Int 6.
And 3, step 3: preparation of the final product, compound 14a, from the synthetic intermediate Int 6:
the synthesis intermediate Int 6 was dissolved in methanol and a 10% aqueous solution of lithium hydroxide (1. Then, the reaction mixture was reacted at 40 ℃ for 12 hours. After the reaction, the reaction solution was adjusted to pH 7 with dilute hydrochloric acid, and then the reaction solution was spin-dried under reduced pressure, and the residue was used in the next step without further purification.
The residue was dissolved with dichloromethane, followed by the addition of EDCI and HOBt. Then, the reaction solution was reacted at room temperature for 12 hours. After the reaction is finished, the reaction solution is washed by water, extracted by ethyl acetate, the organic phase is decompressed and dried, and the residue is separated from the product by a flash chromatographic column to obtain the product compound 14a. The product was a white solid.
1 H NMR(400MHz,CDCl 3 ):δ＝7.48-7.43(m,3H),7.42-7.33(m,4H),7.30-7.27(m,2H),7.25-7.23(m,2H),6.13(d,J＝11.73Hz,1H),5.40(d,J＝6.06Hz,1H),5.26(d,J＝6.99Hz,1H),3.89(d,J＝7.92Hz,4.20Hz,1H),3.31-3.18(m,3H),2.33-2.27(m,4H),2.15(t,J＝7.29Hz,2H),1.80-1.73(m,2H),1.68-1.63(m,3H),1.52-1.32(m,10H),1.21-1.13(m,8H)；
13 C NMR(126MHz,CDCl 3 ):δ＝172.50,166.72,140.15,135.90,133.10,130.08,129.00,128.67,128.56,128.31,128.25,63.95,47.17,43.08,39.49,37.21,30.21,29.81,29.33,29.01,28.96,28.83,28.24,28.16,26.64,26.03.
LC/MS(ESI):C 35 H 48 N 3 O 2 + ,calcd.542.4,found542.2.
EXAMPLE 39 preparation of Compound 15a
Figure BDA0002302678430000581
Step 1: preparation of synthetic intermediate Int 7 from synthetic intermediate Int 6:
the synthetic intermediate Int 6 was dissolved in dichloromethane and 10 equivalents of DBU were added. Then, the reaction mixture was reacted at room temperature for 1 hour. After the reaction is finished, the reaction solution is washed by water, extracted by ethyl acetate, combined with organic phases, dried and dried by decompression and spin-drying, and the residue is separated from the product by a flash chromatographic column and then carried out in the next step.
The product after column separation was dissolved in methylene chloride, EDCI and 51mg of Fmoc protected amino L-valine were added. Then, the reaction solution was reacted at room temperature for 4 hours. And after the reaction is finished, washing the reaction solution with water, performing pressure spin drying on the organic phase, and separating the product from the residue through a flash chromatographic column to obtain a synthetic intermediate Int 7.
Step 2: preparation of the final product, compound 15a, from the synthetic intermediate Int 7:
the synthesis intermediate Int 7 was dissolved in methanol and a 10% aqueous solution of lithium hydroxide (1. Then, the reaction mixture was reacted at 45 ℃ for 12 hours. After the reaction, the reaction solution was adjusted to pH 7 with dilute hydrochloric acid, and then the reaction solution was spin-dried under reduced pressure, and the residue was used in the next step without further purification.
The residue was dissolved with dichloromethane, followed by the addition of EDCI and HOBt. Then, the reaction solution was reacted at room temperature for 12 hours. After the reaction is finished, the reaction solution is washed by water, extracted by ethyl acetate, the organic phase is decompressed and dried, and the residue is separated from the product by a flash chromatographic column to obtain a product compound 15a. The product was a white solid.
1 H NMR(400MHz,CDCl 3 ):δ＝7.56(d,J＝12.11Hz,1H),7.51-7.45(m,3H),7.40-7.30(m,5H),7.23-7.20(m,2H),6.22(d,J＝12.11Hz,1H),6.09(dd,J＝8.55Hz,3.50Hz,1H),5.66(d,J＝9.29Hz,1H),5.24(d,J＝8.19Hz,1H),4.17(dd,J＝8.96Hz,4.59Hz,1H),3.82(tt,J＝8.96Hz,4.59Hz,1H),3.51(dtd,J＝13.77Hz,7.88Hz,5.90Hz,1H),3.33(d,J＝15.01Hz,1H),3.18(d,J＝15.01Hz,1H),2.68-2.58(m,2H),2.20-2.09(m,4H),2.04-1.90(m,2H),1.90-1.80(m,2H),1.70-1.56(m,2H),1.36-1.14(m,18H),0.88(d,J＝6.67Hz,3H),0.71(d,J＝6.81Hz,3H)；
13 C NMR(126MHz,CDCl 3 ):δ＝172.77,170.98,167.17,139.32,135.48,135.04,134.86,130.01,129.25,128.66,128.66,128.41,128.17,125.43,125.38,64.52,59.19,50.85,50.56,45.44,39.19,37.23,32.01,31.88,30.16,30.12,29.92,29.87,29.64,29.57,28.77,28.51,26.99,26.38,19.75,17.72.
LC/MS(ESI):C 40 H 57 N 4 O 3 + ,calcd.641.4,found641.3.
Test example 1:
compound reversing drug resistance of human oral epidermoid carcinoma drug-resistant cell line KBV200 cell to vinorelbine with high expression of P-gp
Cytotoxicity experiments were as follows: KBV200 cells were routinely cultured in RPMI-1640 medium containing 10% Fetal Bovine Serum (FBS) at 37 ℃ in an incubator containing 5% CO2. Cells were seeded in 96-well plates and cultured overnight, then Vinorelbine (VNR) at various concentrations, and compound 13a, compound 14a or compound 15a at 10 μ M were added and cultured for 72 hours. After the drug action is finished, fixing cells by trichloroacetic acid, then dyeing by an SRB solution, finally adding a Tris solution to dissolve the SRB, and measuring the OD value under the wavelength of 510nm by an enzyme-labeling instrument; the inhibition was calculated and the IC50 calculated using Graphpad prism5.0 software.
The inhibitory effect of vinorelbine on vinorelbine cells after the combination of vinorelbine with compound 13a, compound 14a and compound 15a, respectively, is shown in table 1 and figure 1:
TABLE 1 Compounds 13a,14a,15a reverse KBV200 resistance to vinorelbine
Figure BDA0002302678430000591
Figure BDA0002302678430000601
a Remarking: compound 13a, compound 14a, and compound 15a were prepared as above in examples 37-39; the fold reversal was the IC50 of Vinorelbine drug alone divided by the IC of Vinorelbine in combination with compound 13a,14a, or 15a 50 。
It can be concluded from table 1 and fig. 1 that 10 μ M compounds 13a,14a and 15a can remarkably reverse the drug resistance of P-gp highly expressed KBV200 cells to vinorelbine, and the reversing times are as high as 11.2-192.9, indicating that the compounds 13a,14a and 15a can efficiently reverse the drug resistance of KBV200 cells to vinorelbine, and remarkably improve the inhibition effect of vinorelbine to KBV200 cells.
All documents mentioned in this application are incorporated by reference in this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes or modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the appended claims of the present application.

Claims (10)

1. A compound of formula I, or a pharmaceutically acceptable salt thereof,
Figure FDA0003864630710000011
wherein,
r1 and R4 are each independently hydrogen, substituted or unsubstituted C6-C12 aryl, wherein R1 and R4 are not both hydrogen;
r2, R3, R5, R6, R7, R8, R9, R10, R11 and R12 are all hydrogen;
x is an unsubstituted or 5-7 membered saturated heterocycloalkylene group, wherein the heterocycloalkylene group has 1N atom in the heterocycle;
y is nothing or an amino acid residue, wherein the structure of the amino acid residue is as follows:
Figure FDA0003864630710000012
wherein, the 3-position and the 4-position are connecting sites, and R is the R group of amino acid;
and the 3-position is connected with N atom, and the 4-position is connected with C = O;
the amino acid is glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, aspartic acid, glutamic acid, asparagine, glutamine, lysine, arginine, phenylalanine, tyrosine, tryptophan, histidine, proline;
n is a positive integer of 6 to 12;
wherein any "substitution" means that one or more hydrogen atoms on the group are replaced with a substituent selected from the group consisting of: halogen, -CN, halogenated C1-C4 alkyl, cyano, hydroxy, amino, C1-C4 alkyl, C3-C8 cycloalkyl, C1-C7 alkoxy, C6-C12 aryl-C1-C4 alkyl-, C6-C12 aryl-C1-C4 alkoxy-, C1-C4 alkylthio, 5-12 membered heteroaryl, C2-C4 ester group, amino acid residue; the heteroaryl group has 1 to 3 heteroatoms selected from N, O and S in the heterocyclic ring.
2. The compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the amino acid residue is a glycine residue, an alanine residue, a valine residue, a leucine residue, an isoleucine residue, a methionine residue, an asparagine residue, a glutamine residue, a lysine residue, a phenylalanine residue, a tyrosine residue, a tryptophan residue, a proline residue, a histidine residue.
3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is a compound having the structure of formula Ia:
Figure FDA0003864630710000021
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, X and n are as defined in claim 1, R is the R group of an L-amino acid;
the L-amino acid is glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, aspartic acid, glutamic acid, asparagine, glutamine, lysine and arginine.
4. A compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X is piperidinyl.
5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is of formula Ib:
Figure FDA0003864630710000022
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, X and n are as defined in claim 1.
6. The compound of formula I of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
Figure FDA0003864630710000031
7. a pharmaceutical composition, said composition comprising: (a) A compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable carrier.
8. Use of a compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 7, for (1) the manufacture of a medicament for inhibiting or reversing the multidrug resistance of a tumor against an anticancer drug; (2) preparing a medicament for inhibiting P-glycoprotein; or (3) preparing the medicine for enhancing the anti-tumor activity of the anti-tumor medicine.
9. The use of claim 8, wherein the tumor is selected from the group consisting of: nasopharyngeal carcinoma, oral cancer, esophageal cancer, gastric cancer, intestinal cancer, gallbladder cancer, bile duct cancer, lung cancer, liver cancer, kidney cancer, breast cancer, bladder cancer, ovarian cancer, cervical cancer, endometrial cancer, lymphoma, leukemia; or
The anti-tumor drug is selected from the following groups: paclitaxel, vinorelbine, docetaxel, gemcitabine, epirubicin, doxorubicin, colchicine, or combinations thereof.
10. A process for preparing a compound of formula II, or a pharmaceutically acceptable salt thereof, comprising the steps of:
(1) In a first solvent, under the action of a catalyst and a first alkaline reagent, a compound of a formula C1 and a compound of a formula C2 are subjected to a carbene insertion reaction catalyzed by a transition metal to generate a compound of a formula II;
Figure FDA0003864630710000032
in the step (1), the catalyst is selected from the following group: tris (dibenzylideneacetone) dipalladium-chloroform adduct, tris (dibenzylideneacetone) dipalladium, or combinations thereof;
in the step (1), the first alkaline agent is selected from the group consisting of: tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetramethylammonium bromide, tetraethylammonium bromide, or a combination thereof;
r1 and R4 are each independently hydrogen, substituted or unsubstituted C6-C12 aryl, wherein R1 and R4 are not both hydrogen;
r2, R3, R5 and R6 are all hydrogen;
r13 is methyl or benzyl;
z is O, S or-N (R14) -;
r14 is p-nitrobenzenesulfonyl or p-methylbenzenesulfonyl;
wherein any "substitution" means that one or more hydrogen atoms on the group are replaced with a substituent selected from the group consisting of: halogen, -CN, halogenated C1-C4 alkyl, cyano, hydroxy, amino, C1-C4 alkyl, C3-C8 cycloalkyl, C1-C7 alkoxy, C6-C12 aryl-C1-C4 alkyl-, C6-C12 aryl-C1-C4 alkoxy-, C1-C4 alkylthio, 5-12 membered heteroaryl, C2-C4 ester group, amino acid residue; the heteroaryl group has 1 to 3 heteroatoms selected from N, O and S in the heterocyclic ring.
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