CN113698415A - Novel oridonin analogue and derivative, preparation method and medical application thereof - Google Patents

Novel oridonin analogue and derivative, preparation method and medical application thereof Download PDF

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CN113698415A
CN113698415A CN202110548952.7A CN202110548952A CN113698415A CN 113698415 A CN113698415 A CN 113698415A CN 202110548952 A CN202110548952 A CN 202110548952A CN 113698415 A CN113698415 A CN 113698415A
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sulfonyl
acyl
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徐进宜
姚鸿
徐盛涛
马晓倩
谢绍文
刘俊凯
吴宏玉
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China Pharmaceutical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/08—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
    • C07C69/12—Acetic acid esters
    • C07C69/18—Acetic acid esters of trihydroxylic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring
    • C07F9/65517—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring condensed with carbocyclic rings or carbocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms

Abstract

The invention discloses a novel oridonin analogue and derivative, a preparation method and medical application thereof, wherein the oridonin analogue and the derivative are shown in general formulas I and II. The invention also discloses a preparation method of the B epoxy bridge modified oridonin analogues and 14-hydroxy derivatives thereof and application of the analogues in the field of treating tumor diseases.

Description

Novel oridonin analogue and derivative, preparation method and medical application thereof
Technical Field
The invention relates to the field of natural medicines and pharmaceutical chemistry, in particular to a novel oridonin analogue obtained by modifying an epoxy bridge B and a 14-hydroxyl derivative thereof. The invention also discloses a preparation method of the B epoxy bridge modified oridonin analogues and 14-hydroxy derivatives thereof and application of the analogues in the field of treating tumor diseases.
Background
Oridonin is a main active ingredient of Rabdosia rubescens of Rabdosia (Rabdosia) of Labiatae and has a wide range of physiological activities such as anti-tumor, anti-inflammatory and antibacterial activities (see Liu Z, Ouyang L, Peng H, et al. cell Proliferat,2012,45, 499). In the earlier studies, researchers at home and abroad and the subject group find that oridonin A ring, D ring and hydroxyl at C-14 position are subjected to esterification derivatization (see ZL 201611034438.7; ZL200710133915. X; ZL 201010509348.5; ZL201110178862. X; ZL 201310423035.1; Ding Y, Li D, Ding C, et al. journal of Medicinal Chemistry,2018,61,2737), and the derivatives show obvious antitumor activity in vitro and in vivo.
Figure BDA0003073481740000011
Although more reports are made on oridonin-based modification, the modification research results on the oxygen bridge on the B ring are rare. The oxygen bridge on the B ring and the 7-hydroxyl form a hemiacetal structure, and the structure causes the oridonin to be easy to open in an acid solution, and then reacts with the 1-hydroxyl or Michael acceptor of the oridonin, so that the activity is reduced.
Disclosure of Invention
The invention obtains the novel analogs and derivatives of oridonin with better antitumor activity and drug property by opening or displacing an oxygen bridge at the 7-position of the B ring of the oridonin, eliminating the 1-position hydroxyl of the oridonin and carrying out structural modification on the 14-position hydroxyl, and provides the preparation methods of the derivatives.
The invention is realized by the following technical scheme.
Oridonin analogs and derivatives, optically active forms or racemates, diastereomer mixtures thereof, or pharmaceutically acceptable salts thereof, represented by general formulas I and II:
Figure BDA0003073481740000012
wherein, A can be hydrogen, hydroxy, halogen or sulfonyl; U-Y can be a carbon-carbon single bond or a carbon-carbon double bond; x is O, M is any one of the following groups: (1) a hydrogen or deuterium atom, (2) a C1-16 aliphatic chain acyl or sulfonyl group, (3) a C3-10 carbocyclic acyl or sulfonyl group, (4) a C1-6 haloalkanoyl or sulfonyl group (5) a C6-10 aroyl or sulfonyl group which is unsubstituted or substituted by 1,2, 3, 4 substituents, (6) an unsubstituted or 1, 2. a heteroaroyl or sulfonyl group of 5-10 atoms substituted with 3, 4 substituents, (7) a C2-6 alkenoyl or sulfonyl group, (8) a C2-6 alkynoyl or sulfonyl group, (9) an amino acid, (10) a phosphoryl group, (11) an acyl group of the formula- (O) C-L-Ph substituted or unsubstituted on the phenyl ring, (12) an acyl group of the formula- (O) C-L-Ar substituted or unsubstituted on the aromatic ring; l denotes any of the following groups: - (CH)2)m-、-C≡C-、-CH＝CH-、-CH2-O-CH2-、-CH2-S-CH2-、-CH2-NH-CH2-、-(CH2)m-Ar-(CH2)m-or- (CH)2)m-Z-(CH2)m-; m is equal to 1,2, 3, 4, 5, 6; ar represents an aromatic group consisting of 5 to 10 atoms which is unsubstituted or substituted by 1,2, 3 or 4 substituents; z represents a carbocyclic or heteroatom-containing cyclic group consisting of 3 to 6 atoms; each R1、R2Independently any one of the following groups: (1) hydrogen or deuterium atom, (2) C1-16Fatty alkanyl radical, (3) C1-16Fatty chain acyl or sulfonyl, (4) C3-10Carbocyclyl or sulfonyl, (5) C1-6Haloalkyl, acyl or sulfonyl, (6) heteroatom-containing alkyl, cyclic, acyl or sulfonyl consisting of 2 to 16 atoms, (7) unsubstituted or substituted by 1,2, 3 or 4 substituents6-10Aryl, heteroaryl, and heteroaryl,Acyl or sulfonyl, (8) heteroaryl, acyl or sulfonyl consisting of 5 to 10 atoms which are unsubstituted or substituted by 1,2, 3, 4 substituents, (9) C2-6Alkenyl, acyl or sulfonyl, (10) C2-6Alkynyl, acyl or sulfonyl, (11) a glycoside group, (12) an amino acid, (13) a phosphoryl group.
According to a preferred aspect of the invention, a is preferably hydrogen or hydroxy; U-Y is preferably a carbon-carbon single bond or a carbon-carbon double bond; x is O, M is preferably: (1) hydrogen, (2) C1-16Fatty chain acyl or sulfonyl, (3) C3-10Carbocyclic acyl or sulfonyl, (4) C unsubstituted or substituted by 1,2, 3, 4 substituents6-10Aroyl or sulfonyl, (5) heteroaroyl or sulfonyl of 5-10 atoms unsubstituted or substituted by 1,2, 3, 4 substituents, (6) C2-6Alkenoyl or sulfonyl, (7) amino acid, (8) phosphoryl, (9) acyl of the general formula- (O) C-L-Ph substituted or unsubstituted on the phenyl ring, (10) acyl of the general formula- (O) C-L-Ar substituted or unsubstituted on the aromatic ring; l denotes any of the following groups: - (CH)2)m-、-C≡C-、-CH＝CH-、-CH2-O-CH2-、-CH2-S-CH2-、-CH2-NH-CH2-、-(CH2)m-Ar-(CH2)m-or- (CH)2)m-Z-(CH2)m-; m is equal to 1,2, 3, 4, 5, 6; ar represents an aromatic group consisting of 5 to 10 atoms which is unsubstituted or substituted by 1,2, 3 or 4 substituents; z represents a carbocyclic or heteroatom-containing cyclic group consisting of 3 to 6 atoms; each R1、R2Preferably: (1) hydrogen, (2) C1-16Fatty alkanyl radical, (3) C1-16Fatty chain acyl or sulfonyl, (4) heteroatom-containing alkyl, cyclic, acyl or sulfonyl consisting of 2 to 16 atoms, (5) unsubstituted or substituted C with 1,2, 3, 4 substituents6-10Aryl, acyl or sulfonyl.
In some more specific preferred embodiments, formula i is preferably selected from the following subformulae:
Figure BDA0003073481740000021
wherein X is O, and each M is preferably: (1) hydrogen, (2) C1-8Fatty chain acyl group, (3) C3-8Carbocyclic acyl group, (4) C unsubstituted or substituted by 1,2, 3, 4 substituents6-10Aroyl, (5) heteroaroyl of 5-10 atoms unsubstituted or substituted with 1,2, 3, 4 substituents, (6) C2-6Alkenoyl, (7) amino acid, (8) phosphoryl, (9) acyl of the general formula- (O) C-L-Ph substituted or unsubstituted on the phenyl ring, (10) acyl of the general formula- (O) C-L-Ar substituted or unsubstituted on the aromatic ring; l denotes any of the following groups: - (CH)2)m-、-C≡C-、-CH＝CH-、-CH2-O-CH2-、-CH2-S-CH2-、-CH2-NH-CH2-、-(CH2)m-Ar-(CH2)m-or- (CH)2)m-Z-(CH2)m-; m is equal to 1,2, 3, 4, 5, 6; ar represents an aromatic group consisting of 5 to 10 atoms which is unsubstituted or substituted by 1,2, 3 or 4 substituents; z represents a carbocyclic or heteroatom-containing cyclic group consisting of 3 to 6 atoms.
In some embodiments, in formula I-1, I-2, or I-3, M is selected from H, methylsulfonyl, or-K-R3Wherein: k is selected from the group consisting of-C (O) -, -S (O)2-、-C(O)CH2CH2-、-C(O)CH＝CH-、-C(O)CH＝C(CH3)-；R3Selected from H or substituted or unsubstituted: c1-C3Alkyl radical, C3-C6Cycloalkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C6-C10Aryl radical, C4-C10Heterocyclic group, C4-C10A heteroaryl group; the substituent is selected from H, halogen, -CN, -SO2、-NH2、C1-C3Alkyl radical, C1-C3An alkoxy group.
In some more specific preferred embodiments, formula ii is preferably selected from the following subformulae:
Figure BDA0003073481740000031
wherein each R is1、R2Preferably: (1) c1-6Fatty chain acyl, (2) heteroatom-containing alkyl, cyclic, acyl or sulfonyl groups consisting of 2 to 8 atoms; x is O, each M is preferably: (1) hydrogen, (2) C1-8Fatty chain acyl, (3) C unsubstituted or substituted by 1,2, 3, 4 substituents6-10Aroyl, (4) heteroaroyl or sulfonyl of 5-10 atoms unsubstituted or substituted with 1,2, 3, 4 substituents.
In some embodiments, R in formula II-1 or formula II-21、R2Is acetyl.
In some embodiments, in formula II-1 or formula II-2, M is hydrogen, formyl, acetyl, or propionyl.
According to the invention, the structures of the representative B-ring modified novel oridonin analogues and derivatives and partial compounds thereof are as follows:
Figure BDA0003073481740000041
Figure BDA0003073481740000051
the oridonin derivative with the general formula I-1 can be prepared by the following method:
a) when M is H, dissolving oridonin in dry acetone, adding catalyst p-toluenesulfonic acid, dripping 2, 2-dimethoxypropane, and refluxing and stirring at 65 ℃ for 1H;
b) dissolving the product of a in dry dichloromethane, stirring in an ice bath, and adding triethylamine; diluting methanesulfonyl chloride with dry dichloromethane, slowly adding the diluted solution into the reaction system by using a constant-pressure dropping funnel, and continuously stirring for 2 hours in an ice bath;
c) dissolving the product of the step b in dry DMF, heating the solution to 110 ℃ in an oil bath, adding lithium carbonate and lithium bromide, and stirring the solution in the oil bath for 1 hour;
d) dissolving the product of c in anhydrous dichloromethane, stirring at-20 ℃, diluting DAST with anhydrous dichloromethane, slowly dripping into the reaction liquid containing the product of b, and reacting at low temperature for 20 min;
e) and d, washing the product with water, and performing column chromatography to obtain the compound shown in the general formula I-1.
f) When M is acyl, dissolving the product of e in dry methane, adding organic base, condensing agent such as DMAP and EDCI, and excessive acid, acid anhydride or acyl chloride, and reacting at room temperature for 6-72 h;
g) washing with water, and performing column chromatography to obtain the compound of the general formula I-1.
The oridonin derivative with the general formula I-2 can be prepared by the following method:
a) when M is H, dissolving oridonin in dry acetone, adding p-toluenesulfonic acid as catalyst, dripping 2, 2-dimethoxypropane, and stirring at 65 deg.C under reflux for 1H;
b) dissolving the product of a in methanol, slowly dripping NaOH solution at the temperature of 0-5 ℃, uniformly stirring, slowly dripping hydrogen peroxide solution, and continuing to react for 2 hours at low temperature;
c) dissolving the product of the step b in dry dichloromethane, slowly adding pyridine under the protection of inert gas, then slowly adding phenyl thiocarbamate, and reacting for 20-30 hours;
d) dissolving the product c in dry toluene, adding azodiisobutyronitrile as a catalyst, adding tri-n-butyltin hydride under the protection of inert gas, and heating and refluxing for 1-2 h;
e) dissolving the product d in dry dichloromethane, slowly dripping triethylamine at 0 ℃, diluting methylsulfonyl chloride with dry dichloromethane after the system is uniformly mixed, slowly dripping the diluted methylsulfonyl chloride into reaction liquid, and reacting for 1-2 h;
f) dissolving the product e in dry DMF, adding lithium carbonate and lithium bromide, heating to 110 ℃, and stirring in an oil bath for 1-2 hours;
g) dissolving the product of f in anhydrous dichloromethane, stirring at-20 ℃, diluting DAST with anhydrous dichloromethane, slowly dripping into the reaction liquid containing the product of c, and reacting at low temperature for 20 min;
h) washing with water, and performing column chromatography to obtain the compound of the general formula I-2.
i) When M is acyl, dissolving the product of h in dry methane, adding organic base, condensing agent such as DMAP and EDCI, and excessive acid, acid anhydride or acyl chloride, and reacting at room temperature for 6-72 h;
j) and (4) washing the product of the i with water, and carrying out column chromatography to obtain the compound of the general formula I-2.
The oridonin derivative with the general formula I-3 can be prepared by the following method:
a) when M is H, dissolving oridonin in dry acetone, adding p-toluenesulfonic acid as catalyst, dripping 2, 2-dimethoxypropane, and stirring at 65 deg.C under reflux for 1H;
b) dissolving the product of a in anhydrous dichloromethane, adding triethylamine and trifluoroacetic anhydride, and stirring for 5 hours at room temperature;
c) dissolving the product of b in anhydrous dichloromethane, stirring at-20 ℃, diluting diethylaminosulfur trifluoride (DAST) with anhydrous dichloromethane, slowly dripping into the reaction solution containing the product of b, and reacting at low temperature for 20 min;
d) dissolving the product of c in dichloromethane, adding TBAB and sodium hydroxide solution, and stirring at room temperature for 15 min;
e) and d, washing the product with water, and performing column chromatography to obtain the compound of the general formula I-3.
f) When M is acyl, dissolving the product of c in dry dichloromethane, adding organic base and condensing agent such as DMAP and EDCI, excessive acid, acid anhydride or acyl chloride, and reacting at room temperature for 6-72 h;
g) and (f) dissolving the product of the step (f) in dichloromethane, adding a sodium hydroxide solution, stirring at room temperature for 15min, washing with water, and carrying out column chromatography to obtain the compound of the general formula I-3.
The oridonin derivative with the general formula II-1 can be prepared by the following method:
a) when R is1、R2When M is acyl, dissolving oridonin in dry acetone, and adding p-toluenesulfonic acid as catalystAdding a reagent, dropwise adding 2, 2-dimethoxypropane, and refluxing and stirring at 65 ℃ for 1 h;
b) dissolving the product of a in dry dichloromethane, stirring in an ice bath, and adding triethylamine; diluting methanesulfonyl chloride with dry dichloromethane, slowly adding the diluted solution into the reaction system by using a constant-pressure dropping funnel, and continuously stirring for 2 hours in an ice bath;
c) dissolving the product of the step b in dry DMF, heating the solution to 110 ℃ in an oil bath, adding lithium carbonate and lithium bromide, and stirring the solution in the oil bath for 1 hour;
d) dissolving the product of c in anhydrous dichloromethane, stirring at-20 ℃, diluting DAST with anhydrous dichloromethane, slowly dripping into the reaction liquid containing the product of c, and reacting at low temperature for 20 min;
e) dissolving the product of d in anhydrous dichloromethane, adding p-toluenesulfonic acid and anhydride, heating to 40 ℃, and reacting for 2-48 h;
f) washing with water, and performing column chromatography to obtain the compound of the general formula II-1.
g) The product of f is dissolved in tetrahydrofuran, 10% hydrochloric acid is added and stirred for 0.5h at room temperature.
The oridonin derivative with the general formula II-2 can be prepared by the following method:
a) when M is H, dissolving oridonin in dry acetone, adding p-toluenesulfonic acid as catalyst, dripping 2, 2-dimethoxypropane, and stirring at 65 deg.C under reflux for 1H;
b) dissolving the product of a in methanol, slowly dripping NaOH solution at the temperature of 0-5 ℃, uniformly stirring, slowly dripping hydrogen peroxide solution, and continuing to react for 2 hours at low temperature;
c) dissolving the product of the step b in dry dichloromethane, slowly adding pyridine under the protection of inert gas, then slowly adding phenyl thiocarbamate, and reacting for 20-30 hours;
d) dissolving the product c in dry toluene, adding azodiisobutyronitrile as a catalyst, adding tri-n-butyltin hydride under the protection of inert gas, and heating and refluxing for 1-2 h;
e) dissolving the product d in dry dichloromethane, slowly dripping triethylamine at 0 ℃, diluting methylsulfonyl chloride with dry dichloromethane after the system is uniformly mixed, slowly dripping the diluted methylsulfonyl chloride into reaction liquid, and reacting for 1-2 h;
f) dissolving the product e in dry DMF, adding lithium carbonate and lithium bromide, heating to 110 ℃, and stirring in an oil bath for 1-2 hours;
g) dissolving the product of f in tetrahydrofuran, adding 10% hydrochloric acid, and stirring at room temperature for 0.5 h;
h) dissolving the product in g in anhydrous dichloromethane, adding p-toluenesulfonic acid and anhydride, heating to 40 ℃, and reacting for 2-48 h;
i) washing with water, and performing column chromatography to obtain the compound of the general formula II-2.
Physical and chemical property tests prove that the stability of the oridonin analogue in an acid solution is obviously superior to that of the oridonin.
The invention also provides a pharmaceutical composition, which comprises the oridonin analogue and the derivative shown in the general formulas I and II, and an optically active body or a racemate, a non-corresponding isomer mixture or a pharmaceutical salt thereof.
The invention also provides the oridonin analogue and derivative shown in the general formulas I and II, and the application of the optical active body or racemate, non-corresponding isomer mixture, or the pharmaceutical salt or the composition containing the oridonin analogue and derivative in preparing antitumor drugs.
The tumor is abnormal pathological changes formed by clonal abnormal hyperplasia of cells of local tissues which lose normal regulation and control on the growth of the cells at the gene level under the action of various carcinogenic factors of an organism, and comprises but is not limited to breast cancer, gastric cancer, leukemia, liver cancer and the like.
Definitions of terms used in connection with the present invention: unless otherwise indicated, the initial definitions provided for by a group or term herein apply to that group or term throughout the specification; for terms not specifically defined herein, the meanings that would be afforded to one skilled in the art should be given in light of the disclosure and the context. The term "substituted" refers to the replacement of a hydrogen atom or molecule in a molecule, including the case of a substituent or substituents.
The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), iodine (I), or astatine (At) ions.
The term "alkyl" denotes a straight or branched chain saturated hydrocarbon group having the stated number of carbon atoms. The term "C1-C6Alkyl "refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. C1-C6Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, 2-dimethylbutyl, and 2, 3-dimethylbutyl, and the like. The term "C1-C3Alkyl "refers to a straight or branched chain saturated hydrocarbon group having 1 to 3 carbon atoms.
The term "cycloalkyl" denotes a saturated monocyclic or polycyclic ring structure of all carbon atoms. The term "C3-C6Cycloalkyl "refers to a saturated monocyclic or polycyclic ring structure having a total of 3 to 6 carbon atoms. C3-C6Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
The term "alkenyl" refers to a straight, branched or cyclic non-aromatic hydrocarbon group having a main chain containing 2 to 8 carbon atoms and at least one carbon-carbon double bond. Thus, "C2-C6The alkenyl group means an alkenyl group having 2 to 6 carbon atoms in the main chain. Alkenyl groups include ethenyl, propenyl, butenyl, 2-methylbutenyl, cyclohexenyl and the like. The straight, branched, or cyclic portion of an alkenyl group can contain a double bond and this portion can be substituted if a substituted alkenyl group is indicated.
The term "alkynyl" refers to a straight, branched or cyclic non-aromatic hydrocarbon group having a main chain containing 2 to 8 carbon atoms and at least one carbon-carbon triple bond. Thus, "C2-C8The alkynyl group "means an alkynyl group having 2 to 8 carbon atoms. Alkynyl includes ethynyl, propynyl, butynyl, 3-methylbutynyl and the like. The straight, branched, or cyclic portion of the alkynyl group can contain triple bonds and this portion can be substituted if a substituted alkynyl group is indicated.
The term "heterocycle" denotes a saturated cyclic group of 3 to 8 ring atoms in which one or two ring atoms areSelected from N, O or S (O)m(wherein m is an integer from 0 to 2) and the remaining ring atoms are C, wherein one or two C atoms may optionally be replaced by a carbonyl group. The rings of the heterocyclyl may be optionally independently substituted with one, two or three substituents.
The term "aryl" denotes an all-carbon monocyclic or fused polycyclic group of 1 to 12 carbon atoms with a completely conjugated pi-electron system. Non-limiting examples of aryl groups are phenyl, naphthyl and anthracenyl.
The term "heteroaryl" denotes a monocyclic or fused ring group of 5 to 12 ring atoms, containing one, two, three or four ring heteroatoms selected from N, O or S, the remaining ring atoms being C, and additionally having a completely conjugated pi-electron system. Non-limiting examples of unsubstituted heteroaryl groups are pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyrimidine, quinoline, isoquinoline, purine, tetrazole, triazine and carbazole. Heteroaryl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more, more preferably one, two or three, and still more preferably one or two.
According to the invention, the 1-position hydroxyl and the 6-position hydroxyl of the oridonin are eliminated or removed, the oxygen bridge on the B ring is transferred to the 6 position or is subjected to ring opening and is sealed by other groups, and the 14-position hydroxyl is further derivatized at the same time, so that a novel oridonin analogue and a 14-position hydroxyl derivative thereof are obtained. The invention can solve the problem that oridonin is unstable when encountering acid on one hand, and on the other hand, a novel anti-tumor active molecule with excellent druggability is expected to be obtained through structure optimization.
Detailed Description
The following examples are given to facilitate a better understanding of the invention, but do not limit the invention. The experimental procedures in the following examples are conventional unless otherwise specified. The test materials used in the following examples were purchased from a conventional biochemical reagent store unless otherwise specified.
Example 1
[ Compound 1 ]
Figure BDA0003073481740000091
(a) Dissolving oridonin (2g) in 30mL of anhydrous acetone (treated with phosphorus pentoxide), adding 1mL of 2, 2-dimethoxypropane and catalytic amount of p-toluenesulfonic acid, protecting a drying tube, performing reflux reaction for 10min, clarifying the solution from white turbidity, supplementing 0.2mL of 2, 2-dimethoxypropane, performing TLC monitoring reaction until the raw materials disappear, cooling to room temperature, adding saturated NaHCO3The solution was extracted three times with 50mL of dichloromethane each time, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 2.10g of a white solid (yield 95%) which was used directly in the next reaction.
(b) Dissolving the product of (a) in 30mL of anhydrous dichloromethane, adding 2mL of triethylamine, stirring in an ice bath, dropwise adding 1mL of methanesulfonyl chloride within 20min, continuing stirring for 1 hour, detecting the disappearance of raw materials by TLC, adding 70mL of dichloromethane, washing twice, washing with saturated salt once and 20mL each time, drying with anhydrous sodium sulfate, and concentrating to obtain 2.01g of light yellow solid (yield 80%).
(c) Dissolving the product (2.01g) of (b) in 20mL of pre-dried DMF, adding lithium carbonate (3.08g) and lithium bromide (3.62), reacting at 110 ℃ for 1 hour, cooling to room temperature, filtering by a sand core funnel to remove the lithium carbonate and the lithium bromide, washing the solid with ethyl acetate for three times, combining organic layers, supplementing dichloromethane to 100mL, washing twice, washing with saturated salt water once, concentrating to obtain a crude product of 1.2g, and directly using the crude product in the next reaction without purification.
(d) 1.2g of the product of (c) are dissolved in 40mL of anhydrous dichloromethane, protected with argon and cooled to-20 ℃. 810 μ L of DAST was dissolved in 1.5mL of anhydrous dichloromethane, and slowly added dropwise to the reaction solution containing the product of (c), and the reaction was continued at low temperature for 20min after completion of the dropwise addition. The reaction solution was extracted three times with ethyl acetate, washed with saturated brine, dried, filtered, concentrated in vacuo, and subjected to column chromatography to give 0.82g of a compound (yield 70%).1HNMR(300MHz,CDCl3)δ6.13(s,1H),5.90–5.72(m,1H),5.65(d,J＝10.1Hz,1H),5.53(s,1H),4.63(s,1H),4.31(s,1H),4.13(d,J＝9.0Hz,1H),4.01(s,1H),3.72(d,J＝9.0Hz,1H),3.12(d,J＝8.9Hz,1H),2.47(dd,J＝20.3,8.1Hz,1H),2.14–2.04(m,1H),1.94(dd,J＝23.5,8.2Hz,2H),1.86–1.61(m,4H),1.06(d,J＝13.6Hz,6H)；13C NMR(75MHz,CDCl3)δ205.6,203.2,149.2,128.2,124.1,120.1,81.8,73.7,71.6,65.4,54.0,50.0,49.3,43.9,39.5,30.4,29.4,23.1,18.2；HR-MS(ESI)m/z:calcd for C20H25O4[M+H]+329.1747,found 329.1746.
Example 2
[ Compound 2 ]
Figure BDA0003073481740000101
(a) Intermediate I-1 a (2.8g) from example 1 was dissolved in 40mL of methanol, cooled to 0 ℃, added with 2.5mL of 30% aqueous hydrogen peroxide and 5mL of 6N aqueous sodium hydroxide, and stirred at low temperature for 2 h. The reaction mixture was diluted with water, extracted three times with ethyl acetate, washed with saturated brine, dried, filtered and concentrated in vacuo to give 0.82g of diastereomeric mixture I-2 a (yield 70%). The product is used for the next reaction without purification.1H NMR(300MHz,CDCl3)δ5.34(d,J＝11.8Hz,1H),4.93(d,J＝1.9Hz,1H),4.27(d,J＝9.9Hz,1H),4.09(dd,J＝16.7,8.6Hz,1H),3.89(dd,J＝11.7,7.6Hz,1H),3.48(dd,J＝11.2,5.5Hz,1H),3.16(d,J＝5.9Hz,1H),2.97(d,J＝5.9Hz,1H),2.60–2.39(m,1H),2.28(d,J＝9.8Hz,1H),1.97–1.59(m,10H),1.39–1.04(m,12H).
(b) The diastereomeric mixture I-2 a (2g) was dissolved in redistilled toluene (50mL), AIBN (200mg) was added in a catalytic amount and 3.8mL of tri-n-butyltin hydride under an inert gas atmosphere, and the reaction was refluxed for 2 hours. After concentration in vacuo, column chromatography purification afforded 1.5g (85% yield) of diastereomeric mixture I-2 b.1H NMR(300MHz,CDCl3)δ6.17(s,1H),5.83(d,J＝11.7Hz,1H),5.56(s,1H),4.74(s,1H),4.11(t,J＝10.3Hz,1H),3.98–3.83(m,1H),3.76(d,J＝9.7Hz,1H),3.06(d,J＝8.6Hz,1H),2.59–2.44(m,1H),1.46–1.32(m,8H),1.31–1.21(m,12H),1.15(d,J＝9.8Hz,4H).
(c) Dissolving the diastereoisomeric mixture I-2 b (1.75g) in 40mL of anhydrous dichloromethane, adding 1.2mL of triethylamine, stirring in an ice bath, dropwise adding 0.4mL of methanesulfonyl chloride within 20min, continuing stirring for 1 hour, detecting the disappearance of raw materials by TLC, adding 70mL of dichloromethane, washing twice, washing once with saturated salt, washing once with 20mL each time, drying with anhydrous sodium sulfate, and concentrating to obtain a light yellow solid. The next reaction was carried out without purification.
(d) Dissolving the product of (c) in 25mL of pre-dried DMF, adding lithium carbonate (1g) and lithium bromide (1.2g), reacting for 2 hours at 110 ℃, cooling to room temperature, filtering by a sand core funnel to remove lithium carbonate and lithium bromide, washing the solid with ethyl acetate for three times, combining organic layers, washing with saturated salt water once, concentrating to obtain a crude product of 1.2g, and directly using the crude product in the next reaction without purification.
(e) The product of (d) (255mg) was dissolved in 5mL of anhydrous dichloromethane, protected with argon, and cooled to-20 ℃. 171. mu.L of DAST was dissolved in 0.5mL of anhydrous dichloromethane, and slowly added dropwise to the reaction solution containing the product of (d), and the reaction was continued at low temperature for 20min after completion of the dropwise addition. The reaction mixture was extracted three times with ethyl acetate, washed with saturated brine, dried, filtered, concentrated in vacuo, and subjected to column chromatography to give 183mg of the compound (yield 72%).1H NMR(300MHz,CDCl3)δ6.11(s,1H),5.49(s,1H),4.56(s,1H),4.17(s,1H),3.96(d,J＝9.2Hz,1H),3.79(d,J＝9.7Hz,2H),3.10(d,J＝8.0Hz,1H),2.38(tt,J＝8.5,4.8Hz,1H),2.00(dd,J＝14.6,7.0Hz,1H),1.81(d,J＝13.5Hz,1H),1.71–1.61(m,3H),1.61–1.47(m,4H),1.24–1.12(m,2H),1.00(t,J＝5.4Hz,6H)；13C NMR(75MHz,CDCl3)δ205.3,203.4,148.9,119.7,82.9,74.1,69.4,66.0,54.4,52.9,48.2,44.0,39.5,33.1,31.1,29.6,29.53,22.9,18.2,17.4；HR-MS(ESI)m/z:calcd for C20H27O4[M+Na]+371.1829,found 371.1828.
Example 3
[ Compound 3 ]
Figure BDA0003073481740000111
(a) I-2 a (2.1g) from example 1 was dissolved in 50mL of anhydrous dichloromethaneTo the alkane, 1.1mL of triethylamine and 1.1mL of trifluoroacetic anhydride were added, and the mixture was stirred at room temperature for 5 hours. The reaction solution is prepared from saturated NaHCO3The solution was quenched, extracted three times with ethyl acetate, washed with saturated brine, dried, filtered, concentrated in vacuo, and subjected to column chromatography to give 2.2g of the compound (yield 90%).1H NMR(300MHz,CDCl3)δ6.21(s,1H),5.86(d,J＝11.8Hz,1H),5.62(s,1H),4.92–4.76(m,2H),4.24(s,2H),3.98(dd,J＝11.8,7.4Hz,1H),3.11(d,J＝9.2Hz,1H),2.54(ddd,J＝14.6,7.7,5.0Hz,1H),1.88(dt,J＝6.3,5.9Hz,3H),1.76–1.54(m,6H),1.45–1.36(m,5H),1.29(s,1H),1.24(d,J＝3.1Hz,6H).
(b) 2.2g of the product of (a) are dissolved in 60mL of anhydrous dichloromethane, protected with argon and cooled to-20 ℃. 1.47mL of DAST was dissolved in 3mL of anhydrous dichloromethane, and slowly added dropwise to the reaction solution containing the product (b), and the reaction was continued at low temperature for 20min after completion of the dropwise addition. The reaction solution was extracted three times with ethyl acetate, washed with saturated brine, dried, filtered, concentrated in vacuo, and subjected to column chromatography to give 1.8g of a compound (yield 70%).1H NMR(300MHz,CDCl3)δ6.18(s,1H),5.58(s,1H),5.12(dd,J＝11.0,6.2Hz,1H),4.63(s,1H),4.32–4.11(m,3H),3.17(d,J＝8.7Hz,1H),2.54–2.37(m,1H),2.26(dd,J＝11.7,6.3Hz,1H),2.11(ddt,J＝12.9,6.3,3.3Hz,1H),1.98(s,1H),1.89–1.73(m,2H),1.72–1.57(m,2H),1.49(dd,J＝14.1,2.3Hz,1H),1.39–1.24(m,2H),1.10(d,J＝9.7Hz,6H)；13C NMR(75MHz,CDCl3)δ204.4,203.2,148.8,120.4,82.6,82.3,73.5,67.9,65.1,55.5,52.7,51.1,43.7,36.7,32.1,30.8,29.1,24.1,22.3,18.9.
(c) The product of (b) was dissolved in dichloromethane and 10.5mL of 0.5N NaOH solution, 180mg of TBAB, was added. Stir at room temperature for 15 min. The reaction solution was extracted three times with ethyl acetate, washed with saturated brine, dried, filtered, concentrated in vacuo, and subjected to column chromatography to give 1.1g of the compound (yield 75%).1H NMR(300MHz,DMSO-d6)δ5.91(s,1H),5.44(s,1H),5.23(d,J＝3.0Hz,1H),4.79(d,J＝4.6Hz,1H),4.57(s,1H),4.15–3.95(m,3H),3.72–3.59(m,1H),2.98(s,1H),2.14(dd,J＝13.7,6.9Hz,1H),2.02–1.95(m,1H),1.62(dd,J＝12.4,7.9Hz,3H),1.50–1.22(m,5H),0.97(s,3H),0.89(s,3H)；13C NMR(101MHz,DMSO-d6)δ203.5,202.3,149.3,117.2,84.7,74.4,72.3,69.9,68.5,59.0,54.7,54.2,45.3,37.2,32.6,31.6,30.6,29.1,22.2,18.9；HR-MS(ESI)m/z:calcd for C20H26NaO5[M+Na]+369.1672,found 369.1676.
Example 4
[ Compound 4 ]
Figure BDA0003073481740000121
Compound 1(180mg) from example 1 and p-toluenesulphonic acid (110mg) were dissolved in 5mL of a dry acetic anhydride solution, heated to 40 ℃ and stirred for 2 h. The reaction was quenched with saturated sodium carbonate solution, extracted three times with ethyl acetate, washed with saturated brine, dried, filtered, concentrated in vacuo, and subjected to column chromatography to give 230mg of the compound (yield 84%).1H NMR(300MHz,CDCl3)δ6.22(s,1H),6.02(s,1H),5.95–5.81(m,1H),5.74(d,J＝13.7Hz,1H),5.61(d,J＝9.8Hz,1H),5.50(s,1H),4.44(d,J＝12.9Hz,1H),4.28(d,J＝12.9Hz,1H),3.13(s,1H),2.26(d,J＝4.2Hz,1H),2.15(t,J＝6.4Hz,8H),2.02(d,J＝11.1Hz,4H),1.85(s,1H),1.68(s,1H),1.07(d,J＝20.9Hz,6H),0.86(d,J＝6.6Hz,2H)；13C NMR(75MHz,CDCl3)δ199.1,198.1,170.2,170.0,169.2,145.6,130.7,129.4,119.2,114.5,74.6,73.3,65.2,62.2,52.6,50.5,43.6,42.2,41.2,34.4,32.6,30.1,26.4,24.3,20.6,17.4；HR-MS(ESI)m/z:calcd for C26H32NaO8[M+Na]+495.1989,found 495.1991.
Example 5
[ Compound 5 ]
Figure BDA0003073481740000122
Referring to the method for synthesizing compound 4 in example 4, compound 5 was synthesized starting from compound 2 in example 2.1H NMR(300MHz,CDCl3)δ6.13(s,1H),5.54(s,1H),5.42(s,1H),4.64(d,J＝12.7Hz,1H),4.47(d,J＝12.6Hz,1H),3.01(s,1H),2.61–2.36(m,2H),2.24(s,1H),2.14–1.97(m,5H),1.92(s,5H),1.73(s,2H),1.47(dd,J＝40.7,17.5Hz,6H),1.17(d,J＝11.7Hz,2H),0.84(d,J＝10.6Hz,6H)；13C NMR(75MHz,CDCl3)δ205.7,201.5,200.3,171.0,170.7,146.6,119.0,75.7,68.1,63.2,55.4,51.0,43.0,41.4,41.0,40.7,38.3,35.5,33.2,32.8,30.9,29.7,21.2,21.1,18.4,17.4；HR-MS(ESI)m/z:calcd for C26H34NaO8[M+Na]+497.2146,found 497.2144.
Example 6
[ Compound 6 ]
Figure BDA0003073481740000123
Compound 1(50mg) of example 1 was dissolved in 5mL of anhydrous dichloromethane, and a catalytic amount of DMAP (5mg), 0.03mL of acetic anhydride, and 0.1mL of triethylamine were added thereto, followed by stirring at room temperature for 3 hours. The reaction was quenched by addition of a small amount of water, extracted three times with ethyl acetate, washed with saturated brine, dried, filtered, concentrated in vacuo, and subjected to column chromatography to give 44mg (yield 78%) of the compound.1H NMR(300MHz,CDCl3)δ7.20(s,1H),6.05(s,1H),5.78–5.65(m,1H),5.58(d,J＝13.6Hz,2H),5.38(s,1H),4.28–4.16(m,2H),3.74(d,J＝8.9Hz,1H),3.10(d,J＝7.7Hz,1H),2.43(dd,J＝16.9,7.8Hz,1H),2.06(t,J＝8.0Hz,1H),1.92(s,4H),1.87–1.81(m,1H),1.68(dd,J＝19.5,9.9Hz,3H),0.97(d,J＝3.2Hz,6H)；13C NMR(101MHz,CDCl3)δ202.8,199.9,170.0,147.6,128.7,123.6,118.8,82.7,75.6,72.1,65.2,56.4,51.4,50.3,42.2,39.6,30.4,30.1,22.9,21.0,17.8；HR-MS(ESI)m/z:calcd for C22H27O5[M+H]+371.1853,found 371.1851.
Example 7
[ Compound 7 ]
Figure BDA0003073481740000131
Compound 1 from example 1(50mg, 0.15mmol) was dissolved in 5mL of dichloromethane, and a catalytic amount of DMAP (5 m) was added to the cyclopropyl acid (20mg, 0.23mmol)g) EDCI (47mg, 0.3mmol), and reacted at room temperature for 24 h. The reaction was quenched by addition of a small amount of water, extracted three times with ethyl acetate, washed with saturated brine, dried, filtered, concentrated in vacuo, and subjected to column chromatography to give 25mg (yield 41%) of the compound.1H NMR(300MHz,CDCl3)δ6.16(s,1H),5.84(ddd,J＝10.0,5.8,1.9Hz,1H),5.76–5.61(m,2H),5.48(s,1H),4.41–4.25(m,2H),3.85(d,J＝9.1Hz,1H),3.19(d,J＝7.2Hz,1H),2.61–2.45(m,1H),2.31–2.16(m,2H),1.97(dd,J＝15.2,9.4Hz,3H),1.88–1.68(m,8H),1.40–1.26(m,5H),1.08(d,J＝2.8Hz,6H)；13C NMR(75MHz,CDCl3)δ202.9,199.8,175.0,147.5,128.7,123.6,118.6,82.8,75.3,72.1,65.3,56.7,51.5,50.4,42.8,42.3,39.6,30.4,30.0,28.6,25.6,25.3,22.9,17.7；HR-MS(ESI)m/z:calcd for C27H35O5[M+H]+439.2479,found 439.2478.
Example 8
[ Compound 8-40 ]
Referring to the method for synthesizing compound 7 in example 7, compounds 8 to 40 shown in table 3 below were synthesized.
[ TABLE 3 ]
Figure BDA0003073481740000132
Figure BDA0003073481740000141
Figure BDA0003073481740000151
Figure BDA0003073481740000161
Figure BDA0003073481740000171
Figure BDA0003073481740000181
Example 9
[ Compound 41 ]
Figure BDA0003073481740000182
Compound 1(50mg) in example 1 was dissolved in 5mL of anhydrous dichloromethane, 30. mu.L of triethylamine was added, the mixture was cooled to 0 ℃, 20. mu.L of methanesulfonyl chloride was added dropwise, and the reaction was carried out for 30 min. The reaction was quenched by addition of a small amount of water, extracted three times with ethyl acetate, washed with saturated brine, dried, filtered, concentrated in vacuo, and subjected to flash column chromatography to give 47mg of the compound (yield 76%). MS: 407[ M + H ] M/z]+。
Example 10
[ Compound 42 ]
Figure BDA0003073481740000183
Compound 42 was synthesized by starting from compound 2 in example 2, with reference to the method for synthesizing compound 6 in example 6. MS M/z 373[ M + H ]]+。
Example 11
[ Compounds 43-49 ]
Compounds 43 to 49 shown in table 4 below were synthesized by referring to the method for synthesizing compound 7 in example 7, starting from compound 2 in example 2.
[ TABLE 4 ]
Figure BDA0003073481740000184
Figure BDA0003073481740000191
Example 11
[ Compound 50-53 ]
Compounds 50 to 53 shown in table 5 below were synthesized by the method for synthesizing compound 7 in example 7, starting from compound 3 in example 3.
[ TABLE 5 ]
Figure BDA0003073481740000192
The following are the results of the acid stability experiments for some of the compounds of the present invention:
dissolving 1mg of the compound (oridonin, compound 1, compound 2, compound 3) in 10mL of tetrahydrofuran/concentrated hydrochloric acid (V/V ═ 1: 1), shaking at room temperature for 24h, and detecting the remaining content of the compound by HPLC. The experimental result shows that the content of the oridonin is less than 0.025mg after 24 hours, and the compounds 1,2 and 3 are still stable and unchanged.
Pharmacological tests prove that the novel oridonin analogue and derivative have an anti-tumor effect and can be used for preparing anti-tumor drugs. Preferred tumor diseases to be treated are breast cancer, gastric cancer, leukemia and liver cancer; the corresponding tumor cell lines used for pharmacological tests are DU4475, HCC1806, MDA-MB-468 and MDA-MB-231 cell lines. In addition, the novel oridonin analogue and the derivative thereof also have the function of antagonizing NLRP3, and can be used for treating NLRP 3-mediated related inflammatory diseases.
The following are the results of pharmacological experiments with some of the compounds of the invention:
effect of partial Compounds on growth of triple negative Breast cancer cells
Experimental equipment and reagent
Instrument clean bench (Suzhou Aikelin purifying equipment Co., Ltd.)
Constant temperature CO2 incubator (Japan SANYO)
Enzyme-linked immunity detector (American BIO-RAD)
Inverted biomicroscope (Japan OLYMPUS)
Mixed solution of reagent cyan and streptomycin (Nanjing Kai base biotechnology development Co., Ltd.)
Trypsin digestive juice (Nanjing Kai base Biotech development Co., Ltd.)
PBS (Nanjing Kai base biotechnology development Co., Ltd.)
MTT(BIOSHARP)
DMSO(SIGMA)
Cell line human breast cancer cell DU4475
Human gastric cancer cell HCC1806
Human leukemia cell MDA-MB-468
Human liver cancer cell MDA-MB-231
Experimental methods
1. Digesting and counting cells to obtain the concentration of 5 × 104Cell suspension/mL, 100ul cell suspension per well in 96-well plate (5X 10 per well)3Individual cells);
2.96 well plates were placed at 37 ℃ in 5% CO2Culturing in an incubator for 24 hours;
3. diluting the medicine with complete culture medium to required concentration, adding 100 μ L of corresponding medicine-containing culture medium into each well, and simultaneously setting up negative control group, solvent control group, and positive control group;
4.96 well plates were incubated at 37 ℃ in a 5% CO2 incubator for 72 hours;
5. the 96-well plate was MTT stained at λ 490nm, and the OD value was measured.
1) Add 20. mu.L MTT (5mg/mL) per well and continue culturing in the incubator for 4 hours;
2) discarding the culture medium, adding 150 mu L DMSO into each hole for dissolving, and shaking for 10 minutes to mix gently; and lambda is 490nm, and the OD value of each hole is read by a microplate reader to calculate the inhibition rate.
Cell inhibition rate of 100% × (negative control group OD value-compound group OD value)/negative control group OD value
Experimental results of Effect of Compounds on growth of triple negative Breast cancer cells
TABLE 1 Effect of some Compounds on the growth of 4 triple-negative breast cancer cells in vitro (IC)50: unit μmol/ml)
Figure BDA0003073481740000211
Figure BDA0003073481740000221
Effect of some compounds on tumor growth in vivo:
female ICR mice (from shanghaisi laboratory animal center) weighing 18-22g and successfully inoculated with HCC1806 triple negative breast cancer tumor cells were selected and randomly grouped into 8 mice per group. One group was a blank control, and the same administration volume of physiological saline solution was injected; the other group was a positive drug control group, to which 6mg/kg of paclitaxel (purchased from Sichuan Tai Chi pharmaceutical Co., Ltd., cat # 17100021) was administered; the remaining groups were given doses of the compounds separately. The solvent for dissolving paclitaxel and the above compounds is DMF, Tween 80: 5% physiological saline solution 10:2:88(V: V: V), and the administration mode is once for 1 day and 21 days continuously. After the experiment was completed, the mice were sacrificed and the tumors were surgically removed and weighed. The data obtained were statistically analyzed using SPSS 17.0.
Figure BDA0003073481740000222
Results of inhibition of tumor growth in vivo for some compounds:
group of Medicine Dosage form Tumor inhibition rate
1 Physiological saline - -
2 Paclitaxel 6mg/kg 66.0％
3 Compound 1 25mg/kg 63.4％
4 Compound 2 25mg/kg 61.2％
5 Compound 3 25mg/kg 58.7％
6 Compound 4 25mg/kg 59.1％
7 Compound 5 25mg/kg 57.4％
8 Compound 32 12.5mg/kg 67.3％
9 Compound 32 25mg/kg 74.1％
10 Compound 44 25mg/kg 70.1％
11 Oridonin 25mg/kg 54.2％
The above description of the embodiments is only intended to facilitate the understanding of the method of the invention and its core idea. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention.

Claims (10)

1. Novel oridonin analogues and derivatives represented by general formulas I and II, and optically active forms or racemates, diastereomer mixtures thereof, or pharmaceutically acceptable salts thereof:
Figure FDA0003073481730000011
wherein:
a is hydrogen, hydroxy, halogen or sulfonyl;
the connection of U-Y is a carbon-carbon single bond or a carbon-carbon double bond;
x is O; m is any one of the following groups: (1) hydrogen or deuterogenSub, (2) C1-16Fatty chain acyl or sulfonyl, (3) C3-10Carbocyclic acyl or sulfonyl group, (4) C1-6Haloalkanoyl or sulfonyl (5) C unsubstituted or substituted by 1,2, 3, 4 substituents6-10Aroyl or sulfonyl, (6) heteroaroyl or sulfonyl of 5-10 atoms unsubstituted or substituted by 1,2, 3, 4 substituents, (7) C2-6Alkenoyl or sulfonyl, (8) C2-6Alkynoyl or sulfonyl, (9) amino acids, (10) phosphoryl, (11) acyl substituted or unsubstituted on the phenyl ring of the formula- (O) C-L-Ph, (12) acyl substituted or unsubstituted on the aromatic ring of the formula- (O) C-L-Ar;
l denotes any of the following groups: - (CH)2)m-、-C≡C-、-CH＝CH-、-CH2-O-CH2-、-CH2-S-CH2-、-CH2-NH-CH2-、-(CH2)m-Ar-(CH2)m-or- (CH)2)m-Z-(CH2)m-；
Ar represents an aromatic group consisting of 5 to 10 atoms which is unsubstituted or substituted by 1,2, 3 or 4 substituents;
z represents a carbocyclic or heteroatom-containing cyclic group consisting of 3 to 6 atoms;
m is equal to 1,2, 3, 4, 5, 6.
Each R1、R2Independently any one of the following groups: (1) hydrogen or deuterium atom, (2) C1-16Fatty alkanyl radical, (3) C1-16Fatty chain acyl or sulfonyl, (4) C3-10Carbocyclyl or sulfonyl, (5) C1-6Haloalkyl, acyl or sulfonyl, (6) heteroatom-containing alkyl, cyclic, acyl or sulfonyl consisting of 2 to 16 atoms, (7) unsubstituted or substituted by 1,2, 3 or 4 substituents6-10Aryl, acyl or sulfonyl, (8) heteroaryl, acyl or sulfonyl consisting of 5 to 10 atoms which are unsubstituted or substituted by 1,2, 3 or 4 substituents, (9) C2-6Alkenyl, acyl or sulfonyl, (10) C2-6Alkynyl, acyl or sulfonyl, (11) a glycoside group, (12) an amino acid, (13) a phosphoryl group.
2. Oridonin analogues and derivatives, optically active forms or racemates, diastereomer mixtures or pharmaceutically acceptable salts thereof according to claim 1 of general formulae i and ii, wherein:
a is hydrogen or hydroxy;
the connection of U-Y is a carbon-carbon single bond or a carbon-carbon double bond;
m is any one of the following groups: (1) hydrogen or deuterium atom, (2) C1-16Fatty chain acyl or sulfonyl, (3) C3-10Carbocyclic acyl or sulfonyl group, (4) C1-6Haloalkanoyl or sulfonyl (5) C unsubstituted or substituted by 1,2, 3, 4 substituents6-10Aroyl or sulfonyl, (6) heteroaroyl or sulfonyl of 5-10 atoms unsubstituted or substituted by 1,2, 3, 4 substituents, (7) C2-6Alkenoyl or sulfonyl, (8) C2-6Alkynoyl or sulfonyl, (9) amino acids, (10) phosphoryl, (11) acyl substituted or unsubstituted on the phenyl ring of the formula- (O) C-L-Ph, (12) acyl substituted or unsubstituted on the aromatic ring of the formula- (O) C-L-Ar;
l denotes any of the following groups: - (CH)2)m-、-C≡C-、-CH＝CH-、-CH2-O-CH2-、-CH2-S-CH2-、-CH2-NH-CH2-、-(CH2)m-Ar-(CH2)m-or- (CH)2)m-Z-(CH2)m-；
Ar represents an aromatic group consisting of 5 to 10 atoms which is unsubstituted or substituted by 1,2, 3 or 4 substituents;
z represents a carbocyclic or heteroatom-containing cyclic group consisting of 3 to 6 atoms;
m is equal to 1,2, 3, 4, 5, 6.
Each R1、R2Comprises the following steps: (1) hydrogen, (2) C1-16Fatty alkanyl radical, (3) C1-16Fatty chain acyl or sulfonyl, (4) heteroatom-containing alkyl, cyclic, acyl or sulfonyl consisting of 2 to 16 atoms, (5) unsubstituted or substituted C with 1,2, 3, 4 substituents6-10Aryl, acyl or sulfonyl.
3. Oridonin analogues and derivatives, optically active forms or racemates, diastereomer mixtures or pharmaceutically acceptable salts thereof according to claim 1 of general formulae i and ii, wherein: formula I is selected from the following subformulae:
Figure FDA0003073481730000021
wherein:
x is-O-and each M is any one of the following groups: (1) hydrogen or deuterium atom, (2) C1-16Fatty chain acyl or sulfonyl, (3) C3-10Carbocyclic acyl or sulfonyl group, (4) C1-6Haloalkanoyl or sulfonyl (5) C unsubstituted or substituted by 1,2, 3, 4 substituents6-10Aroyl or sulfonyl, (6) heteroaroyl or sulfonyl of 5-10 atoms unsubstituted or substituted by 1,2, 3, 4 substituents, (7) C2-6Alkenoyl or sulfonyl, (8) C2-6Alkynoyl or sulfonyl, (9) amino acids, (10) phosphoryl, (11) acyl substituted or unsubstituted on the phenyl ring of the formula- (O) C-L-Ph, (12) acyl substituted or unsubstituted on the aromatic ring of the formula- (O) C-L-Ar;
l denotes any of the following groups: - (CH)2)m-、-C≡C-、-CH＝CH-、-CH2-O-CH2-、-CH2-S-CH2-、-CH2-NH-CH2-、-(CH2)m-Ar-(CH2)m-or- (CH)2)m-Z-(CH2)m-；
Ar represents an aromatic group consisting of 5 to 10 atoms which is unsubstituted or substituted by 1,2, 3 or 4 substituents;
z represents a carbocyclic or heteroatom-containing cyclic group consisting of 3 to 6 atoms;
m is equal to 1,2, 3, 4, 5, 6.
4. Oridonin analogues and derivatives, optically active forms or racemates, diastereomer mixtures or pharmaceutically acceptable salts thereof according to claim 3, of general formulae i and ii, wherein: in the general formula I-1, I-2 or I-3, M is selected from H, methylsulfonyl, or-K-R3Wherein: k is selected from the group consisting of-C (O) -, -S (O)2-、-C(O)CH2CH2-、-C(O)CH＝CH-、-C(O)CH＝C(CH3)-；R3Selected from H or substituted or unsubstituted: c1-C3Alkyl radical, C3-C6Cycloalkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C6-C10Aryl radical, C4-C10Heterocyclic group, C4-C10A heteroaryl group; the substituent is selected from H, halogen, -CN, -SO2、-NH2、C1-C3Alkyl radical, C1-C3An alkoxy group.
5. Oridonin analogues and derivatives, optically active forms or racemates, diastereomer mixtures or pharmaceutically acceptable salts thereof according to claim 1 of general formulae i and ii, wherein: formula II is selected from the following subformulae:
Figure FDA0003073481730000031
each R1、R2Comprises the following steps: (1) c1-6Fatty chain acyl, (2) heteroatom-containing alkyl, cyclic, acyl or sulfonyl groups consisting of 2 to 8 atoms;
each X is O;
each M is: (1) hydrogen, (2) C1-8Fatty chain acyl, (3) C unsubstituted or substituted by 1,2, 3, 4 substituents6-10Aroyl, (4) heteroaroyl or sulfonyl of 5-10 atoms unsubstituted or substituted with 1,2, 3, 4 substituents.
6. Oridonin analogues of general formulae I and II according to claim 5 and their useA derivative, and an optically active form or racemate, a mixture of diastereomers, or a pharmaceutically acceptable salt thereof, wherein: in the general formula II-1 or the general formula II-2, R1、R2Is acetyl.
7. The oridonin analogs and derivatives of formula i and ii, their optically active forms or racemates, diastereomer mixtures, or pharmaceutically acceptable salts thereof of claim 1, wherein the oridonin analogs and derivatives of formula i and ii are selected from the group consisting of:
Figure FDA0003073481730000051
Figure FDA0003073481730000061
8. a pharmaceutical composition, comprising the oridonin analogue and derivative shown in the general formulas I and II as claimed in any one of claims 1 to 7, and optically active substances or racemates, diastereoisomer mixtures thereof, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers.
9. An application of the oridonin analogue and the derivative shown in the general formulas I and II, the optically active body or the racemate or the diastereoisomer mixture thereof, or the pharmaceutically acceptable salt thereof or the composition of claim 8 in the preparation of antitumor drugs is disclosed in any one of claims 1 to 7.
10. The use of claim 9, wherein the tumor is breast cancer, gastric cancer, leukemia or liver cancer.
CN202110548952.7A 2020-05-22 2021-05-19 Novel oridonin analogue and derivative, preparation method and medical application thereof Pending CN113698415A (en)

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