CN116098910A - Compound for treating cerebral edema - Google Patents

Compound for treating cerebral edema Download PDF

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CN116098910A
CN116098910A CN202111332225.3A CN202111332225A CN116098910A CN 116098910 A CN116098910 A CN 116098910A CN 202111332225 A CN202111332225 A CN 202111332225A CN 116098910 A CN116098910 A CN 116098910A
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党永军
俞飚
王瑞娜
裴成锋
蒋维
徐鹏
李增霞
朱蒂
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Shanghai Institute of Organic Chemistry of CAS
Fudan University
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Abstract

The invention relates to the technical field of biological medicine, in particular to application of a compound shown in a formula (I) or pharmaceutically acceptable salt thereof in preparation of a medicament for treating cerebral edema.
Figure DDA0003349323460000011

Description

Compound for treating cerebral edema
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to application of a compound shown in a formula (I) or pharmaceutically acceptable salt thereof in preparation of a medicament for treating cerebral edema.
Background
Cerebral edema refers to a pathological phenomenon in which water content in the brain increases, resulting in an increase in brain volume, and can be classified into vascular origin, cellular origin, osmotic origin and interstitial origin according to the cause of formation thereof. Cerebral edema is a reaction of brain tissue to various pathogenic factors, such as brain trauma, intracranial lesions (encephalitis, meningitis, etc.), cerebrovascular diseases, obstructive hydrocephalus, epileptic seizures, and systemic diseases such as toxic dysentery, severe pneumonia, etc., all cause cerebral edema.
Cerebral edema increases intracranial pressure, which can aggravate cerebral edema and develop to a certain extent, and can cause damage to brain tissues in function and structure. If not diagnosed and treated in time, cerebral edema aggravates or develops from limitation to diffusion, serious damage is caused to brain, irreversible secondary pathological changes are formed, and brain death occurs.
The mechanism of Cerebral Edema (CE) is quite complex, and includes ionic edema, cell/cytotoxic edema, vascular edema, etc. (see, e.g., ruchira M.Jha et al, neuropharmacology, 2019 February;145 (Pt B): 230-246.). In view of the large number of clinical resources dedicated to this situation, special attention to CE is becoming a critical requirement.
Disclosure of Invention
The invention relates to application of a compound shown in a formula (I) or pharmaceutically acceptable salt thereof in preparation of a medicament for treating cerebral edema:
Figure BDA0003349323440000021
n is 0 or 1;
R 1 selected from hydrogen, C 2-10 Alkanoyl, unsubstituted or para-substituted benzoyl, tris (C) 1-10 Alkyl) silyl, tri (C) 6-20 Aryl) silicon-based, allyl, and substituted or unsubstituted benzyl;
R 2 selected from hydrogen, hydroxy, halogen; wherein the hydroxyl group optionally has a protecting group selected from C 2-10 Alkanoyl, unsubstituted or para-substituted benzoyl, tris (C) 1-10 Alkyl) silyl, tri (C) 6-20 Aryl) silicon-based, allyl, and substituted or unsubstituted benzyl;
wherein,,
the substituent of the benzoyl is selected from methoxy, nitro, azido and halogen;
the substituent of the benzyl is selected from naphthylmethylene, p-methoxyphenyl, p-methylphenyl, p-nitrobenzyl and p-halogen substituted benzyl.
In one embodiment, R 1 Selected from acetyl, unsubstituted benzoyl and para methoxy substituted benzoyl.
In one embodiment, the cerebral edema includes cerebral edema associated with: a decline or loss of consciousness level, memory loss, a change in mental state, a short or long term neurological deficit, or an intracranial lesion.
In one embodiment, the medicament may be used to reduce cerebral edema, and thereby reduce neuronal apoptosis.
In a specific embodiment, the compound of formula (I) has the following formula (also referred to herein as compound P57 or P57):
Figure BDA0003349323440000022
drawings
Fig. 1: water content of brain tissue of each group of mice in the brain edema model. After 6-8 weeks male C57BL/6J mice were subjected to TBI molding, 25mg/kg of P57 was intraperitoneally injected, and after 24 hours, the water content of the brain tissue of the mice was measured, and the solvent group was used as a blank control, the hibernation mixture was used as a positive control, and n=8.
Detailed Description
The invention will be described in further detail below with the understanding that the terminology is intended to be in the nature of words of description rather than of limitation.
Unless otherwise defined, the technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. If there is a conflict, the present application provides definitions. When an amount, concentration, or other value or parameter is expressed as a range, a preferred range, or an upper preferable range value, and a lower preferable range value, this is to be understood as equivalent to any range specifically disclosed by combining any pair of upper range values or preferred range values with any lower range value or preferred range value, regardless of whether the range is specifically disclosed. Unless otherwise indicated, the numerical ranges set forth herein are intended to include the endpoints of the ranges and all integers and fractions (fractions) within the range.
The terms "about", "about" when used in conjunction with a numerical variable generally refer to the value of the variable and all values of the variable being within experimental error (e.g., within a confidence interval of 95% for the average) or within + -10% of the specified value, or more broadly.
The term "optional" or "optionally present" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, when a group is described as optionally substituted, it may be unsubstituted or substituted, e.g., with one or more substituents independently selected from those described herein. It will be understood by those skilled in the art that the meaning of the type and number of substituents can be arbitrarily selected and combined, as long as the compounds formed are stable.
The expression "comprising" or similar expressions "including", "containing" and "having" etc. synonymously therewith are open ended and do not exclude additional unrecited elements, steps or components. The expression "consisting of …" excludes any element, step or ingredient not specified. The expression "consisting essentially of …" means that the scope is limited to the specified elements, steps, or components, plus any elements, steps, or components that are optionally present that do not materially affect the basic and novel characteristics of the claimed subject matter. It should be understood that the expression "comprising" encompasses the expressions "consisting essentially of …" and "consisting of …".
The term "one(s)" or "at least one(s)" may mean one(s), two(s), three(s), four(s), five(s), six(s), seven(s), eight(s), nine(s) or more(s).
The term "pharmaceutically acceptable salt" refers to the relatively non-toxic, inorganic or organic acid addition salts of the compounds of the present invention. Suitable pharmaceutically acceptable salts of the compounds of the invention may be acid addition salts of the compounds of the invention which contain a nitrogen atom in the chain or ring, for example, with sufficiently basic properties, for example with the following inorganic acids: such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid or nitric acid; or an acid addition salt with an organic acid of: for example formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2- (4-hydroxybenzoyl) benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectate acid, persulphuric acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, fatty acid, alginic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptonic acid, glycerophosphate, aspartic acid, sulfosalicylic acid, hemisulphonic acid, semi-sulfuric acid or thiocyanic acid.
The term "alkyl",by independently or in combination with other groups is meant branched and straight chain saturated aliphatic hydrocarbon groups having a specific number of carbon atoms. "alkyl" may be C 1-10 An alkyl group. For example, C 1-6 、C 2-6 、C 3-9 Alkyl groups such as those containing a linear or branched arrangement of 1,2, 3,4, 5,6, 7, 8, 9, 10 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and the like. Examples of alkyl groups are C 2-6 Alkyl, C 3-9 Alkyl groups, and the like.
The term "alkanoyl" refers to a radical of an alkyl oxy acid remaining after removal of one or more hydroxy groups and having the general formula R-C (O) -, wherein alkyl is as described above. For example, acetyl, propionyl, butyryl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, and the like. Examples of alkanoyl groups are C 2-10 Alkanoyl, C 2-6 Alkanoyl and the like.
The term "halogen" refers to fluorine, chlorine, bromine, iodine.
The term "aryl" refers to any functional group or substituent derived from an aromatic ring. "aryl" may contain 6 to 20 carbon atoms (C 6-20 Aryl), for example 6 to 14 carbon atoms (C 6-14 Aryl) or 6-10 carbon atoms (C 6-10 Aryl) or 9-16 carbon atoms (C 9-16 Aryl) and the like, for example, phenyl, naphthyl, indanyl, fluorenyl and the like.
The term "protecting group" (Pg) refers to a class of substituents that are used to react with other functional groups on a compound to block or protect a particular functional group. For example, "amino protecting group" refers to a substituent attached to an amino group that blocks or protects an amino function on a compound. Suitable amino protecting groups include, but are not limited to, acetyl, trifluoroacetyl, t-Butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and-9-fluorenylmethoxycarbonyl (Fmoc). Similarly, "hydroxy protecting group" refers to a class of hydroxy substituents that effectively block or protect the function of a hydroxy group. Suitable protecting groups include, but are not limited to, acetyl and silyl. "carboxy protecting group" refers to a class of carboxy substituents that effectively block or protect a carboxy group. Commonly usedThe carboxyl protecting group includes-CH 2 CH 2 SO 2 Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphine) -ethyl, nitroethyl, and the like. For general description and instructions for use of protecting groups, see references: T.W. Greene, protective Groups in Organic Synthesis, john Wiley&Sons,New York,1991。
OH protecting groups or SH protecting groups include, but are not limited to, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3, 4-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, 1-dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutoxycarbonyl, diphenylmethoxycarbonyl, 2-trichloroethoxycarbonyl, 2-tribromoethoxycarbonyl, 2- (trimethylsilane) ethoxycarbonyl, 2- (benzenesulfonyl) ethoxycarbonyl, 2- (triphenylphosphine onium) ethoxycarbonyl, 2-furfuryl oxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, 4-ethoxy-1-naphthyloxycarbonyl, 8-quinolinyloxycarbonyl, acetyl, formyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, pivaloyl, benzoyl, C 1-10 Alkyl (e.g., methyl, t-butyl), 2-trichloroethyl, 2-trimethylsilylethyl, 1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, benzyl (phenylmethyl), p-methoxybenzyl, 3, 4-dimethoxybenzyl, diphenylmethyl, triphenylmethyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2-trichloro-ethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, 1-ethoxyethyl, methanesulfonyl, p-toluenesulfonyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, diphenylmethylsilyl, phenyltrimethylsilyl and t-butylmethoxyphenylsilyl. In particular, hydroxy protectionBases include, but are not limited to: c (C) 2-10 Alkanoyl, unsubstituted or para-substituted benzoyl, tris (C) 1-10 Alkyl) silyl, tri (C) 6-20 Aryl) silicon-based, allyl, and substituted or unsubstituted benzyl. Examples of substituents include, but are not limited to: methoxy, nitro, azido, halogen, naphthylene, p-methoxyphenyl, p-methylphenyl, p-nitrobenzyl, and p-halogen substituted benzyl.
Cerebral edema and its treatment
The invention relates to application of a compound shown in a formula (I) or pharmaceutically acceptable salt thereof in preparation of a medicament for treating cerebral edema:
Figure BDA0003349323440000061
n is 0 or 1;
R 1 selected from hydrogen, C 2-10 Alkanoyl, unsubstituted or para-substituted benzoyl, tris (C) 1-10 Alkyl) silyl, tri (C) 6-20 Aryl) silicon-based, allyl, and substituted or unsubstituted benzyl;
R 2 selected from hydrogen, hydroxy, halogen.
In one embodiment, the substituent of the benzoyl group is selected from methoxy, nitro, azido and halogen.
In one embodiment, the substituents of the benzyl group are selected from the group consisting of naphthylmethylene, p-methoxyphenyl, p-methylphenyl, p-nitrobenzyl, and p-halogen substituted benzyl.
In one embodiment, the hydroxyl group may optionally have a protecting group. The protecting group may be selected from C 2-10 Alkanoyl, unsubstituted or para-substituted benzoyl, tris (C) 1-10 Alkyl) silyl, tri (C) 6-20 Aryl) silicon-based, allyl, and substituted or unsubstituted benzyl.
In one embodiment, R 1 Selected from acetyl, unsubstituted benzoyl and para methoxy substituted benzoyl.
In yet another aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of cerebral edema.
In a further aspect, the present invention also relates to a method of treating cerebral edema comprising administering to a subject in need thereof a compound of formula (I) or a pharmaceutically acceptable salt thereof.
In one embodiment, the compound of formula (I) is selected from:
Figure BDA0003349323440000062
/>
Figure BDA0003349323440000071
/>
Figure BDA0003349323440000081
or a pharmaceutically acceptable salt thereof.
In a specific embodiment, the compound of formula (I) has the following formula (also referred to herein as compound P57 or P57):
Figure BDA0003349323440000082
in one embodiment of the invention, the cerebral edema includes cerebral edema associated with: a decline or loss of consciousness level, memory loss, a change in mental state, a short or long term neurological deficit, or an intracranial lesion.
Pharmaceutical composition and administration
The compounds used in the present invention may be administered in a therapeutically effective amount via any means known to be acceptable in the art, alone or in combination with one or more other therapeutic agents. The therapeutically effective amount may vary depending on factors such as the severity of the disease, age and health, potency, the particular condition being treated, and the desired effect.
The compounds used in the present invention may be administered in the form of pharmaceutical compositions by any conventional route including, but not limited to, oral, rectal, transmucosal, nasal or enteral administration, parenteral delivery.
Pharmaceutical compositions for oral administration may be prepared, for example, by mixing the active ingredient with one or more carriers, granulating the resulting mixture, if desired, and processing the mixture or granules by adding other excipients to obtain tablets or cores. Suitable carriers include, but are not limited to, fillers such as sugars, e.g., lactose, sucrose, mannitol, or sorbitol; calcium phosphates, such as tricalcium phosphate or calcium hydrogen phosphate; binders, for example starches, such as corn, wheat, rice or potato starch, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone; if desired, disintegrants may also be used.
Pharmaceutical compositions for oral administration may also include capsules, such as sealed capsules of glycerol or sorbitol. Capsules may contain the active ingredient in the form of granules, for example, in admixture with fillers such as cornstarch, binders and/or glidants such as talc or magnesium stearate, and optionally stabilizers. In capsules, the active ingredient may be dissolved or suspended in suitable liquid excipients such as fatty oils, paraffinic oils, which may contain stabilizers.
Pharmaceutical compositions suitable for rectal administration, such as suppositories, comprise a combination of the active ingredient and a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.
Pharmaceutical compositions suitable for parenteral delivery may comprise the active ingredient in water-soluble form, for example water-soluble salts or aqueous injection suspensions comprising viscosity-increasing substances, for example sodium carboxymethylcellulose, aqueous solutions of sorbitol and/or dextran and/or stabilizers. Parenteral administration may also use infusion solutions.
Advantageous effects
The invention discloses important roles of the compounds in cerebral edema treatment, and demonstrates the prospect of the application of the compounds in cerebral edema treatment.
Examples
The technical scheme of the invention will be further described through specific examples. It should be noted that the described embodiments are only exemplary and are not limiting to the scope of the invention. The invention is capable of other embodiments or of being practiced or carried out in various ways.
Unless otherwise indicated, the compounds, instruments and reagent materials used herein are all commercially available or may be prepared by conventional methods known in the art. Unless indicated otherwise or clearly unsuitable, the proportions or percentages and the like described herein are by weight.
Synthetic examples
Example 1
Process for the preparation of compound P57
1.1 Synthesis of intermediates 1-4
Figure BDA0003349323440000101
According to the method of the literature (Angew.chem.int.ed.2009, 48,7911-7914; J.am.chem.Soc.2015,137, 13776-13779.) intermediate 1-2 is prepared by 3 steps of reaction using dehydroepiandrosterone as a raw material. 1 H NMR(400MHz,CDCl 3 )δ7.36-7.24(m,5H),5.37(brs,1H),4.56(s,2H),3.80(dd,J＝11.3,4.7Hz,1H),3.31-3.23(m,1H),3.10(s,1H),2.50-2.43(m,2H),2.31-2.26(m,1H),2.15-2.08(m,2H),2.04-1.94(m,2H),1.89-1.78(m,2H),1.68-1.40(m,5H),1.27-1.20(m,1H),1.13-1.00(m,2H),1.03(s,3H),0.95(s,3H)； 13 C NMR(100MHz,CDCl 3 )δ221.2,141.2,139.0,128.4,127.6,127.5,120.7,78.3,72.7,70.0,51.4,49.6,49.2,39.1,37.2,37.2,35.8,30.6,30.5,28.3,28.3,21.7,19.4,8.1；ESIMS 417.5[M+Na] + .
Add Ph to dry three-necked flask 3 PEtBur (28.5 g,76.8 mmol) and t-BuOK (8.60 g,76.8 mmol) were added with THF (200 mL), and the mixture was stirred at room temperature to react for 40min to give a blood-red turbid liquid, and thenCompounds 1-2 (10.1 g in 100mL THF, 25.6 mmol) were added and the temperature was raised to 70℃and the reaction stirred for 5h. After cooling, a saturated ammonium chloride solution was added and stirred for 30min, the aqueous phase was separated, extracted 3 times with n-hexane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and column chromatography (PE/etoac=10:1) afforded white solid 1-3 (8.8 g, 85%). [ alpha ]] 25 D ＝-47.5(c＝1.4,CHCl 3 )； 1 H NMR(400MHz,CDCl 3 )δ7.36-7.31(m,4H),7.28-7.24(m,1H),5.36(brs,1H),5.27-5.20(m,1H),4.56(s,2H),3.78(dt,J＝10.4,4.9Hz,1H),3.27(tt,J＝11.3,4.5Hz,1H),2.48-2.41(m,2H),2.32-2.16(m,3H),2.06-1.95(m,2H),1.89-1.79(m,5H),1.69(d,J＝5.3Hz,1H),1.67-1.59(m,1H),1.57-1.37(m,4H),1.32-1.26(m,1H),1.13-1.04(m,2H),1.03(s,3H),0.89(s,3H)； 13 C NMR(100MHz,CDCl 3 )δ148.6,140.9,139.1,128.5,127.6,127.5,121.5,115.1,78.5,74.7,70.0,55.0,49.3,48.9,39.1,37.2,37.0,33.3,31.9,31.4,30.4,28.4,23.5,19.4,14.6,11.8；HRMS(ESI)calcd for C 28 H 38 O 2 Na[M+Na] + 429.2764,found 429.2768.
Intermediate 1-3 (7.10 g,17.5 mmol) was dissolved in THF (100 mL), 9-BBN (100mL,0.5M in THF,50.0mmol) was added and the temperature was raised to 60℃for reaction for 5h. After cooling to room temperature, the mixture was transferred to an ice bath and cooled, and 10% NaOH (100 mL) and 30% H were slowly added in this order 2 O 2 (200 mL) and allowed to warm to room temperature, the reaction was stirred for 2h. TLC showed complete reaction, diluted with ethyl acetate, separated, ethyl acetate extracted the aqueous layer 3 times, combined organic phases, sequentially with saturated Na 2 S 2 O 3 The solution was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated, followed by column chromatography (PE/etoac=2:1) to give 1-4 (6.70 g, 91%) as a white solid. [ alpha ]] 25 D ＝-53.7(c＝1.0,CHCl 3 )； 1 H NMR(400MHz,CDCl 3 )δ7.34-7.31(m,4H),7.28-7.26(m,1H),5.35(brs,1H),4.56(s,2H),4.11-3.05(m,1H),3.36(dd,J＝11.2,4.5Hz,1H),3.31-3.23(m,1H),2.43(ddd,J＝13.1,4.6,2.1Hz,1H),2.31-2.24(m,1H),2.04-1.95(m,2H),1.90-1.85(m,1H),1.79-1.66(m,4H),1.58-1.38(m,6H),1.26(d,J＝6.8Hz,3H),1.08-1.00(m,2H),1.03(s,3H),0.98-0.93(m,1H),0.79(s,3H)； 13 C NMR(100MHz,CDCl 3 )δ141.1,139.1,128.5,127.7,127.5,121.5,78.6,78.3,70.0,68.9,56.7,55.1,49.6,48.2,39.2,37.3,37.1,31.6,30.3,29.3,28.5,24.3,23.7,20.5,19.4,9.2；HRMS(ESI)calcd for C 28 H 40 O 3 Na[M+Na] + 447.2870,found 447.2875.
1.2 Synthesis of intermediates 1-5
Figure BDA0003349323440000111
Intermediate 1-4 (6.70 g,15.8 mmol) was dissolved in dry DMF (150 mL), imidazole (3.23 g,47.4 mmol) and t-butyldimethylchlorosilane (3.57 g,23.7 mmol) were added and the reaction stirred at room temperature for 20h. TLC showed complete reaction, diluted with ethyl acetate, washed successively with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated, followed by column chromatography (PE/etoac=12:1) to give a white solid (8.2 g, 96%).
The above white solid (9.20 g,17.1 mmol) was dissolved in dry CH 2 Cl 2 (5 mL) was added dess-Martin oxidizer (DMP) (18.1 g,42.7 mmol) and NaHCO at room temperature 3 (5.0 g,59.9 mmol) and stirred for 2h. TLC showed complete reaction, diluted with EtOAc and successively saturated Na 2 SO 3 The solution, saturated aqueous sodium bicarbonate and saturated brine were washed, dried over anhydrous sodium sulfate and concentrated, followed by column chromatography (PE/etoac=15:1) to give 1-5 (8.4 g, 92%) as a white solid. [ alpha ]] 25 D ＝+21.9(c＝0.68,CHCl 3 )； 1 H NMR(400MHz,CDCl 3 )δ7.36-7.29(m,4H),7.28-7.22(m,1H),5.37(brs,1H),4.55(s,2H),3.91-3.85(m,1H),3.33-3.21(m,1H),2.59(t,J＝13.2Hz,1H),2.47(ddd,J＝13.3,4.6,2.1Hz,1H),2.27(t,J＝11.2Hz,1H),2.22-2.11(m,2H),2.10-1.93(m,2H),1.90-1.64(m,5H),1.62-1.49(m,2H),1.48-1.30(m,3H),1.16(d,J＝6.2Hz,3H),1.13-1.07(m,1H),1.10(s,3H),1.04(s,3H),0.87(s,9H),0.05(s,3H),0.02(s,3H)； 13 C NMR(100MHz,CDCl 3 )δ215.0,140.7,139.0,128.4,127.6,127.5,121.4,78.3,70.1,57.5,56.1,53.4,49.4,39.1,37.9,37.7,37.0,31.5,31.3,28.3,26.1,24.4,24.0,23.5,19.1,18.1,13.0,-3.3,-4.5；HRMS(ESI)calcd for C 34 H 53 O 3 Si[M+H] + 537.3758,found 537.3767.
1.3 Synthesis of intermediates 1-6
Figure BDA0003349323440000121
Compounds 1-5 (2.0 g,3.72 mmol) were dissolved in 1, 4-dioxane (80 mL), cooled in a liquid nitrogen bath, and purged 3 times. The reaction mixture was irradiated with a 125W high-pressure mercury lamp for 2.5h under ice bath, after which 75% acetic acid (100 mL) was added and stirred for 1h after the solvent was removed by spinning, the aqueous phase was extracted 2 times with dichloromethane, the organic phases were combined, washed successively with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate and concentrated, and column chromatographed (PE/etoac=15:1) to give colorless oily liquid 1-6 (1.68 g, 84%). [ alpha ]] 24 D ＝–4.9(c＝1.1,CHCl 3 )； 1 H NMR(400MHz,CDCl 3 )δ9.54(s,1H),7.39-7.31(m,4H),7.30-7.23(m,1H),5.43(brs,1H),4.57(s,2H),3.98(dd,J＝6.2,2.4Hz,1H),3.38-3.24(m,1H),2.68(dt,J＝16.2,8.0Hz,1H),2.53-2.36(m,2H),2.34-2.16(m,4H),2.14-1.94(m,3H),1.93-1.80(m,2H),1.75-1.70(m,2H),1.65(s,3H),1.62-1.49(m,2H),1.19-1.12(m,1H),1.05(s,6H),0.83(s,9H),0.01(s,3H),-0.04(s,3H)； 13 C NMR(100MHz,CDCl 3 )δ201.9,139.7,139.0,138.9,136.2,128.5,127.7,127.6,122.2,78.4,70.2,68.9,57.4,45.3,43.1,39.1,38.1,37.7,34.2,31.5,30.1,28.3,25.9,22.2,21.7,19.3,18.1,13.6,-4.2,-4.8；HRMS(ESI)calcd for C 34 H 52 O 3 SiNa[M+Na] + 559.3578,found 559.3580.
1.4 Synthesis of intermediates 1-8
Figure BDA0003349323440000131
Intermediate 1-6 (1.30 g,2.42 mmol) was dissolved in THF (8 mL), TBAF (7.3mL,1.0M in THF,7.3mmol) was added and the temperature was raised to 65℃for 18h. TLC showed complete reaction, cooled, diluted with dichloromethane, washed once with water, extracted the aqueous phase twice with dichloromethane, combined with saturated brine, dried over anhydrous sodium sulfate and concentrated, followed by column chromatography (PE/etoac=4:1) to give colorless oily liquid 1-7 (923 mg, 91%).
The above colorless oily liquid 1-7 (1.35 g,3.19 mmol) was dissolved in dry CH 2 Cl 2 (20 mL) was added dess-Martin oxidizer (DMP) (3.39 g,7.99 mmol) and NaHCO at room temperature 3 (938 mg,11.2 mmol) and stirred for 1h. TLC showed complete reaction, diluted with EtOAc and successively saturated Na 2 SO 3 The solution, saturated aqueous sodium bicarbonate and saturated brine were washed, dried over anhydrous sodium sulfate and concentrated, followed by column chromatography (PE/etoac=6:1) to give 1-8 (1.23 g, 92%) as a white solid. [ alpha ]] 30 D ＝–129.2(c＝1.6,CHCl 3 )； 1 H NMR(500MHz,CDCl 3 )δ9.60(d,J＝1.3Hz,1H),7.38-7.30(m,4H),7.29-7.25(m,1H),5.43(brs,1H),4.56(s,2H),3.36-3.26(m,2H),2.69(td,J＝11.2,5.0Hz,1H),2.53-2.39(m,2H),2.32-2.18(m,3H),2.15-2.07(m,3H),2.06(s,3H),2.03-1.96(m,1H),1.94-1.83(m,3H),1.71(dt,J＝13.1,3.5Hz,1H),1.65(s,3H),1.61-1.50(m,1H),1.16(td,J＝13.6,3.7Hz,1H),1.05(s,3H)； 13 C NMR(125MHz,CDCl 3 )δ211.0,201.4,142.0,139.9,138.9,133.5,128.4,127.6,127.6,121.6,78.2,70.1,64.2,44.5,43.3,39.0,38.1,37.5,34.5,31.7,30.1,28.2,27.3,25.5,19.2,13.6；HRMS(ESI)calcd for C 28 H 36 O 3 Na[M+Na] + 443.2557,found 443.2559.
1.5 Synthesis of P57 aglycone hoodiggenin A
Figure BDA0003349323440000141
Intermediate 1-8 (1.15 g,2.73 mmol) was dissolved in THF (80 mL) and acetic acid/water/trifluoroacetic acid (2.5/1/0.6) mixture (80 mL) was added and reacted at room temperature for 18h. TLC showed complete reaction, dilution with dichloromethane, washing with ice water once, extraction of aqueous phase with dichloromethane 2 times, combining organic phases, washing sequentially with saturated aqueous sodium bicarbonate and saturated brine, drying over anhydrous sodium sulfate, concentrating, column chromatography (PE/etoac=1.5:1) to give white solid 1-9 (890 mg, 75%). [ alpha ]] 27 D ＝+11.9(c＝1.0,CHCl 3 )； 1 H NMR(500MHz,CDCl 3 )δ7.38-7.30(m,4H),7.29-7.25(m,1H),5.40(brs,1H),4.58(d,J＝11.9Hz,1H),4.55(d,J＝11.9Hz,1H),4.39(s,1H),3.60(dd,J＝7.8,6.3Hz,1H),3.35-3.23(m,2H),2.49-2.41(m,1H),2.35-2.27(m,2H),2.27(s,3H),2.01-1.79(m,6H),1.78-1.68(m,3H),1.61-1.50(m,1H),1.45(q,J＝12.5Hz,1H),1.20(td,J＝12.3,4.1Hz,1H),1.08-1.02(m,1H),1.01(s,3H),0.93(s,3H)； 13 C NMR(125MHz,CDCl 3 )δ218.3,139.2,139.0,128.5,127.7,127.6,122.2,85.8,78.4,73.5,70.1,57.0,55.2,43.6,39.0,37.4,37.2,35.8,34.6,33.2,30.0,28.5,27.5,24.5,19.5,8.4；HRMS(ESI)calcd for C 28 H 38 O 4 Na[M+Na] + 461.2662,found 461.2665.
Tiglic acid (346 mg,3.45 mmol) was dissolved in tolene (15 mL) followed by Et 3 N (1.3 mL,9.2 mmol) and 2,4, 6-trichlorobenzoyl chloride (0.54 mL,3.45 mmol) were stirred at room temperature for 2h, then a solution of 1-9 (1.01 g,2.30 mmol) and DMAP (140 mg,1.15 mmol) in tolene (10 mL) was added and the reaction was stirred at room temperature to 80℃for 2h. Cooled to room temperature, diluted with EtOAc, washed with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated, followed by column chromatography (PE/etoac=6:1) to give 1-10 (1.08 g, 90%) as a white solid. [ alpha ]] 28 D ＝+15.9(c＝0.73,CHCl 3 )； 1 H NMR(500MHz,CDCl 3 )δ7.38-7.29(m,4H),7.28-7.24(m,1H),6.95-6.91(m,1H),5.40(brs,1H),4.64(dd,J＝12.0,4.4Hz,1H),4.55(s,2H),4.25(s,1H),3.33-3.22(m,1H),3.18-3.09(m,1H),2.45(ddd,J＝13.2,4.7,2.3Hz,1H),2.38-2.23(m,2H),2.20(s,3H),2.03-1.92(m,4H),1.89(s,3H),1.84(d,J＝8.1Hz,3H),1.83-1.71(m,4H),1.60(s,1H),1.54-1.44(m,2H),1.32-1.26(m,1H),1.07(s,3H),1.00(s,3H)； 13 C NMR(125MHz,CDCl 3 )δ217.2,167.8,139.2,139.1,138.0,128.9,128.5,127.7,127.6,122.1,85.8,78.4,76.1,70.1,57.3,53.9,43.2,39.0,37.4,37.3,35.9,34.6,33.3,28.4,27.5,26.2,24.5,19.5,14.7,12.3,10.1；HRMS(ESI)calcd for C 33 H 48 O 5 N[M+NH 4 ] + 538.3527,found 538.3530.
Compounds 1 to 10 (1.08 g,2.07 mmol) were dissolvedTo a mixture of 1, 2-dichloroethane (20 mL) and phosphate buffer (2.4 mL) having ph=7.0 was added 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone (DDQ) (2.35 g,10.4 mmol), and the mixture was reacted at room temperature to 50 ℃ for 1.5 hours. TLC showed complete reaction, cooled to room temperature, diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated, followed by column chromatography (PE/etoac=2:1) to give hoodiggenin a (721 mg, 81%) as a white solid. [ alpha ]] 27 D ＝+16.8(c＝0.40,CHCl 3 )； 1 H NMR(500MHz,CDCl 3 )δ6.97-6.89(m,1H),5.41(m,1H),4.64(dd,J＝12.0,4.4Hz,1H),4.27(s,1H),3.52(ddd,J＝15.8,11.2,4.5Hz,1H),3.17-3.10(m,1H),2.32(ddd,J＝13.1,5.1,2.4Hz,2H),2.26-2.21(m,1H),2.20(s,3H),2.04-1.93(m,3H),1.89(s,3H),1.84(d,J＝8.0Hz,3H),1.82-1.72(m,5H),1.53-1.43(m,2H),1.33-1.28(m,2H),1.12(dd,J＝14.2,4.3Hz,1H),1.07(s,3H),0.99(s,3H)； 13 C NMR(125MHz,CDCl 3 )δ217.2,167.8,139.1,138.0,128.9,122.2,85.9,76.1,71.7,57.3,53.9,43.2,42.1,37.3,37.0,35.9,34.6,33.3,31.6,27.5,26.2,24.5,19.5,14.7,12.3,10.1；ESIMS 453.5[M+Na] + .
1.6 Synthesis of intermediates 1-11
Figure BDA0003349323440000151
Intermediate 1-4 (1.50 g,3.53 mmol) was dissolved in dichloromethane (60 mL) and dess-Martin oxidizer (DMP) (6.0 g,14.1 mmol) and NaHCO were added at room temperature 3 (1.50 g,17.9 mmol) and stirred for 3h. TLC showed complete reaction, diluted with EtOAc and successively saturated Na 2 SO 3 The solution, saturated aqueous sodium bicarbonate and saturated brine were washed, dried over anhydrous sodium sulfate and concentrated, followed by column chromatography (PE/etoac=4:1) to give 1-11 (1.4 g, 93%) as a white solid. [ alpha ]] 25 D ＝+74.2(c＝1.2,CHCl 3 )； 1 H NMR(400MHz,CDCl 3 )δ7.36-7.31(m,4H),7.30-7.24(m,1H),5.37(brs,1H),4.56(s,2H),3.34(dd,J＝9.8,8.7Hz,1H),3.31-3.23(m,1H),2.63(t,J＝13.2Hz,1H),2.48(ddd,J＝13.3,4.7,2.3Hz,1H),2.34-2.27(m,2H),2.26(s,3H),2.24-2.17(m,1H),2.16-2.04(m,1H),1.99(dt,J＝12.9,3.4Hz,1H),1.94-1.66(m,4H),1.65-1.42(m,5H),1.11(s,3H),1.06-1.02(m,1H),0.98(s,3H)； 13 C NMR(100MHz,CDCl 3 )δ213.5,209.6,140.7,138.9,128.4,127.6,127.5,121.1,78.1,70.0,57.9,57.8,54.2,53.2,39.0,37.7,37.7,36.9,31.4,31.4,31.3,28.2,24.2,22.6,19.0,13.4；HRMS(ESI)calcd for C 28 H 36 O 3 Na[M+Na] + 443.2557,found 443.2562.
1.7 Synthesis of intermediates 1-8
Figure BDA0003349323440000161
Compounds 1-11 (1.0 g,2.38 mmol) were dissolved in dichloromethane (50 mL), cooled in a liquid nitrogen bath, and purged 3 times. The reaction mixture was irradiated with a 125W high-pressure mercury lamp under ice bath for 20min, and after the solvent was removed by spin-drying, column chromatography (PE/etoac=6:1) gave 1-8 (370 mg, 37%) as white solid, while raw material 1-11 (600 mg) was recovered. If the same reaction operation is repeated once for the recovered raw materials 1 to 11 (600 mg), a white solid 1 to 8 (640 mg, 64%) can be obtained in total, while the raw materials 1 to 11 (250 mg) are recovered.
1.8 Synthesis of intermediates 1-7
Figure BDA0003349323440000162
Intermediate 1-5 (14 g,26.1 mmol) was dissolved in THF (140 mL), TBAF (78.2mL,1.0M in THF,78.2mmol) was added under ice-bath, and the temperature was raised to 65℃for 18h. TLC showed complete reaction, cooled, diluted with dichloromethane, aqueous phase extracted twice with water, combined organic phases washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give column chromatography (PE/etoac=5:1) as a white solid 1-12 (10.7 g, 97%). 1 H NMR(500MHz,CDCl 3 )δ7.37-7.30(m,4H),7.28-7.24(m,1H),5.38(brs,1H),4.56(s,2H),3.88(dd,J＝6.2,2.4Hz,1H),3.32-3.23(m,1H),2.61(dt,J＝16.2,8.0Hz,1H),2.51-2.44(m,1H),2.34-2.16(m,4H),2.14-1.94(m,3H),1.89-1.80(m,2H),1.76-1.68(m,2H),1.22(d,2H),1.11(s,3H),1.08(s,3H)； 13 C NMR(500MHz,CDCl 3 )δ215.3,140.8,139.0,138.9,136.2,128.5,127.7,127.6,121.3,78.3,70.1,69.4,57.3,53.4,48.7,39.1,38.2,37.9,37.8,37.0,31.5,31.3,28.3,24.0,23.7,23.0,19.1,18.1,13.0.
Compounds 1-12 (2.1 g,4.97 mmol) were dissolved in 1, 4-dioxane (70 mL) in a quartz tube, cooled in a liquid nitrogen bath, and purged 3 times. Put in a photoreactor for illumination, after 5h TLC showed a substantial portion of the conversion of starting material. Direct spin-drying, column chromatography (PE/etoac=5:1) afforded white solid 1-7 (1.28 g,61%, recovered starting material 248 mg, brsm 69%). 1 H NMR(500MHz,CDCl 3 )δ9.56(s,1H),7.37-7.30(m,4H),7.29-7.25(m,1H),5.43(brs,1H),4.56(s,2H),4.03(dd,J＝6.2,2.4Hz,1H),3.34-3.27(m,1H),2.72(dt,J＝16.2,8.0Hz,1H),2.51-2.45(m,1H),2.34-2.16(m,4H),2.10-1.93(m,3H),1.80-1.70(m,2H),1.68(s,3H),1.62-1.49(m,2H),1.19-1.12(d,4H),1.05(s,3H)； 13 C NMR(500MHz,CDCl 3 )δ201.8,141.0,139.9,139.0,135.1,128.5,127.7,127.6,121.8,78.3,70.2,67.2,56.8,44.8,43.2,39.0,38.2,37.7,34.3,31.3,30.4,28.3,21.1,20.5,19.3,13.0.
1.9 Synthesis of Compounds 1-17
Figure BDA0003349323440000171
Preparation of intermediates 1-13 reference (chem. Commun.2012,48, 8679-8681), preparation of intermediates 1-14 reference (Nat. Commun.2015,6,5879-5888, DOI:10.1038/ncomms6879 and references thereto). Known intermediates 1-13 (1.14 mg,2.00 mmol) and 1-14 (340 mg,0.82 mmol) were mixed and dissolved in toluene (4 mL) and activated was added
Figure BDA0003349323440000181
Molecular sieve, stirring at room temperature for 30min. Adding Ph at-20deg.C 3 PAuNTf 2 (180 mg,0.25 mmol) and allowed to spontaneously warm for 3 hours. Adding triethylamine to quench the reaction, filtering and concentrating. Column chromatography (PE/etoac=3:1) afforded white solid 1-15 (550 mg, 86%). [ alpha ]] 24 D ＝–9.2(c＝1.2,CHCl 3 )； 1 H NMR(500MHz,CDCl 3 )δ8.10-8.01(m,4H),7.62-7.55(m,2H),7.48-7.43(m,4H),6.94(d,J＝9.1Hz,2H),6.79(d,J＝9.1Hz,2H),5.34(dd,J＝9.6,7.9Hz,1H),5.28(d,J＝8.3Hz,1H),5.16(t,J＝9.5Hz,1H),4.77(dd,J＝9.7,2.1Hz,1H),4.70(d,J＝7.9Hz,1H),3.97(dd,J＝9.4,6.3Hz,1H),3.87-3.76(m,4H),3.75(s,3H),3.71(dd,J＝9.6,6.2Hz,1H),3.48(s,3H),3.39(s,3H),3.35(s,3H),3.26(dd,J＝9.4,3.0Hz,1H),3.22(dd,J＝9.5,2.8Hz,1H),2.30-2.24(m,1H),2.17-2.09(m,1H),1.78(ddd,J＝13.6,9.5,2.4Hz,1H),1.65(ddd,J＝12.4,9.7,2.4Hz,1H),1.32(d,J＝6.1Hz,3H),1.25(d,J＝6.7Hz,3H),0.97(d,J＝6.2Hz,3H)； 13 C NMR(125MHz,CDCl 3 )δ165.4,164.9,154.9,151.5,133.5,133.3,129.9,129.9,129.8,129.7,128.7,128.6,117.7,114.5,102.7,99.6,96.9,84.1,82.1,81.7,76.7,76.6,74.6,73.5,70.6,69.0,68.1,59.2,58.7,57.8,55.8,36.0,34.7,18.4,18.1,17.8；HRMS(ESI)calcd for C 42 H 52 O 14 Na[M+Na] + 803.3249,found 803.3246.
1-15 (500 mg,0.64 mmol) was dissolved in CH 3 CN (40 mL) and H 2 O (40 mL) was added Ag (DPAH) under ice bath 2 (650 mg,1.4 mmol). The reaction was stirred at room temperature for 1h. The mixture was filtered, diluted with methylene chloride, washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated. Column chromatography (PE: ea=1:1) afforded hemiacetal 1-16 (390 mg, 91%) as a white solid.
The above hemiacetal 1-16 (390 mg,0.58 mmol) was dissolved in dichloromethane (30 mL), and 2- (cyclopropylethynyl) benzoic acid (220 mg,1.2 mmol), 4-Dimethylaminopyridine (DMAP) (14 mg,0.12 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) (280 mg,1.5 mmol) were added sequentially. The reaction mixture was reacted at room temperature for 4 hours, diluted with methylene chloride, washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate and concentrated. Column chromatography (PE: ea=2:1) gave colorless syrup 1-17 (430 mg,90%, β/α=6.5/1). [ alpha ]] 27 D ＝+11.6(c＝0.98,CHCl 3 )； 1 H NMR(500MHz,CDCl 3 )δ8.09-8.04(m,4H),7.90(ddd,J＝7.9,1.4,0.6Hz,1H),7.62-7.54(m,2H),7.51-7.42(m,5H),7.39(td,J＝7.6,1.4Hz,1H),7.28-7.24(m,1H),6.20(dd,J＝9.4,2.3Hz,1H),5.34(dd,J＝9.6,7.9Hz,1H),5.16(t,J＝9.5Hz,1H),4.77(dd,J＝9.7,2.0Hz,1H),4.69(d,J＝7.9Hz,1H),4.13-4.04(m,1H),3.88-3.76(m,4H),3.72(dd,J＝9.6,6.2Hz,1H),3.48(s,3H),3.41(s,3H),3.35(s,3H),3.28(dd,J＝9.2,3.0Hz,1H),3.23(dd,J＝9.5,2.8Hz,1H),2.33-2.27(m,1H),2.17-2.10(m,1H),1.79-1.72(m,1H),1.70-1.63(m,1H),1.53-1.46(m,1H),1.32(d,J＝6.2Hz,3H),1.25(d,J＝6.3Hz,3H),0.96(d,J＝6.2Hz,3H),0.90-0.84(m,4H)； 13 C NMR(125MHz,CDCl 3 )δ165.4,164.9,164.5,134.3,133.5,133.3,131.9,131.3,130.7,129.9,129.9,129.8,129.7,128.7,128.6,127.0,125.0,102.7,99.7,99.6,92.0,84.2,81.8,81.7,76.7,76.1,74.6,73.5,70.6,70.1,68.1,59.2,58.7,57.6,35.9,33.3,18.3,18.1,17.8,9.0,0.8；HRMS(ESI)calcd for C 47 H 54 O 14 Na[M+Na] + 865.3406,found 865.3410.
1.10 Synthesis of intermediates 1-18
Figure BDA0003349323440000191
Compounds 1-17 (1.95 g,2.3 mmol) and hoodiggenin A (900 mg,2.1 mmol) were mixed and dissolved in dichloromethane (40 mL) and activated was added
Figure BDA0003349323440000192
Molecular sieve, stirring at room temperature for 30min. At 10 ℃, add Ph 3 PAuOTf (125 mg,0.21 mmol), was allowed to react for 2 hours at natural temperature. Adding triethylamine to quench the reaction, filtering and concentrating. Column chromatography (PE/etoac=2:1) gave colorless syrup 1-18 β (1 (1275 mg, 56%) and 1-18 α (925 mg, 40%). Compound 1-18 β: [ α] 29 D ＝+4.0(c＝1.1,CHCl 3 )； 1 H NMR(500MHz,CDCl 3 )δ8.06-8.04(m,4H),7.62-7.53(m,2H),7.48-7.42(m,4H),6.95-6.89(m,1H),5.39(brs,1H),5.32(dd,J＝9.6,7.9Hz,1H),5.15(t,J＝9.5Hz,1H),4.81(dd,J＝9.6,2.0Hz,1H),4.71(dd,J＝9.6,2.0Hz,1H),4.68(d,J＝7.9Hz,1H),4.63(dd,J＝12.0,4.4Hz,1H),4.25(s,1H),3.84-3.75(m,4H),3.75-3.66(m,2H),3.55-3.49(m,1H),3.47(s,3H),3.37(s,3H),3.34(s,3H),3.20(dd,J＝9.5,2.8Hz,1H),3.17-3.10(m,2H),2.38-2.27(m,2H),2.19(s,3H),2.14-2.08(m,1H),2.07-1.91(m,5H),1.88(s,3H),1.83(d,J＝7.1Hz,3H),1.80-1.72(m,3H),1.67-1.60(m,2H),1.56-1.45(m,3H),1.30(d,J＝6.2Hz,3H),1.18(d,J＝6.2Hz,3H),1.09(dd,J＝13.7,3.6Hz,1H),1.05(s,3H),0.97(s,3H),0.94(d,J＝6.2Hz,3H)； 13 C NMR(125MHz,CDCl 3 )δ217.2,167.8,165.4,164.9,139.1,137.9,133.5,133.3,129.9,129.9,129.8,129.8,128.9,128.7,128.6,122.1,102.7,99.7,96.0,85.8,84.2,82.6,81.7,77.6,76.7,76.0,74.6,73.4,70.6,68.6,68.1,59.2,58.7,57.9,57.3,53.9,43.2,38.8,37.4,37.2,36.0,35.8,35.5,34.5,33.3,29.6,27.5,26.2,24.5,19.4,18.3,18.1,17.8,14.6,12.3,10.0；HRMS(ESI)calcd for C 61 H 86 O 17 N[M+NH 4 ] + 1104.5890,found 1104.5890 Compounds 1-18 alpha: [ alpha ]] 29 D ＝+44.9(c＝0.60,CHCl 3 )； 1 H NMR(500MHz,CDCl 3 )δ8.07-8.04(m,4H),7.62-7.54(m,2H),7.50-7.40(m,4H),6.96-6.87(m,1H),5.36(brs,1H),5.33(dd,J＝9.6,7.9Hz,1H),5.15(t,J＝9.5Hz,1H),4.85(d,J＝3.4Hz,1H),4.76(dd,J＝9.6,2.0Hz,1H),4.68(d,J＝7.9Hz,1H),4.63(dd,J＝11.9,4.4Hz,1H),4.23(s,1H),4.19(dd,J＝9.2,6.4Hz,1H),3.83-3.75(m,3H),3.73-3.64(m,2H),3.46(s,3H),3.41-3.37(m,1H),3.36(s,3H),3.35(s,3H),3.25(dd,J＝9.2,3.0Hz,1H),3.22(dd,J＝9.5,2.8Hz,1H),3.15-3.10(m,1H),2.35-2.25(m,3H),2.19(s,3H),2.17-2.06(m,2H),2.02-1.93(m,3H),1.88(s,3H),1.83(d,J＝7.1Hz,3H),1.80-1.73(m,4H),1.70-1.64(m,2H),1.53-1.42(m,2H),1.31(d,J＝6.2Hz,3H),1.16(d,J＝6.4Hz,3H),1.06(s,3H),1.03-1.00(m,1H),0.96(s,3H),0.94(d,J＝6.2Hz,3H)； 13 C NMR(100MHz,CDCl 3 )δ217.2,167.8,165.4,165.0,139.6,137.9,133.5,133.3,130.0,129.9,129.8,129.8,128.9,128.7,128.6,121.7,102.7,99.5,93.9,85.9,84.2,81.7,76.6,76.1,75.7,75.6,74.6,73.4,70.6,68.1,63.1,59.2,58.5,57.3,53.9,43.1,40.0,37.3,37.2,35.9,35.7,34.5,33.3,32.8,27.6,27.4,26.2,24.5,19.5,18.0,17.8,17.8,14.7,12.3,10.1；HRMS(ESI)calcd for C 61 H 86 O 17 N[M+NH 4 ] + 1104.5890,found 1104.5885.
1.11 Synthesis of Compound P57
Figure BDA0003349323440000211
Compound 1-18β (1.20 g,0.11 mmol) was dissolved in tolene (100 mL), and a solution of potassium hydroxide (110 mg) in methanol (10 mL) was added thereto and reacted at room temperature for 1.0h. Add acidic resin to neutralize to ph=7.0, filter, concentrate. Column Chromatography (CH) 2 Cl 2 Meoh=30:1) to give P57 (950 mg, 98%) as a white solid. Compound P57: [ alpha ]] 27 D ＝+6.5(c＝0.48,CHCl 3 )； 1 H NMR(500MHz,CDCl 3 )δ6.95-6.89(m,1H),5.41(d,J＝5.1Hz,1H),4.84(dd,J＝9.6,2.0Hz,1H),4.76(dd,J＝9.5,2.0Hz,1H),4.64(dd,J＝12.0,4.4Hz,1H),4.30(d,J＝7.7Hz,1H),4.25(s,1H),3.91(dd,J＝9.6,6.2Hz,1H),3.84(dd,J＝9.6,6.3Hz,1H),3.81-3.77(m,2H),3.65(s,3H),3.57-3.48(m,2H),3.44(s,3H),3.43(s,3H),3.37(dd,J＝9.2,6.1Hz,1H),3.27(dd,J＝9.5,3.0Hz,1H),3.23-3.16(m,2H),3.15-3.07(m,2H),2.37-2.30(m,4H),2.19(s,3H),2.15(ddd,J＝13.8,3.7,2.1Hz,1H),2.09(ddd,J＝13.7,3.6,2.0Hz,1H),2.03-1.90(m,4H),1.88(s,3H),1.83(d,J＝8.0Hz,3H),1.79-1.75(m,3H),1.65(ddd,J＝13.8,9.6,2.5Hz,1H),1.54-1.41(m,3H),1.31(d,J＝6.1Hz,3H),1.27(d,J＝6.2Hz,3H),1.21(d,J＝6.2Hz,3H),1.10(dd,J＝13.7,3.8Hz,1H),1.06(s,3H),0.98(s,3H)； 13 CNMR(125MHz,CDCl 3 )δ217.2,167.8,139.1,137.9,128.9,122.1,104.5,99.8,96.0,85.9,85.4,82.9,82.7,77.6,77.1,76.1,74.9,74.8,71.8,68.7,68.4,60.8,58.1,58.1,57.3,53.9,43.2,38.8,37.4,37.2,35.9,35.7,35.3,34.6,33.3,29.6,27.5,26.2,24.5,19.5,18.6,18.4,18.0,14.7,12.3,10.1；HRMS(ESI)calcd for C 47 H 74 O 15 Na[M+Na] + 901.4920,found 901.4916.
Referring to the prior art PNAS, october 7,2014, vol.111, no.40,14571-14576, other compounds of the present invention were prepared. Some of the compound characterization data are as follows:
example 2
Figure BDA0003349323440000221
[α] D 27 ＝6.1(c 2.1,CHCl 3 )； 1 H NMR(400MHz,CDCl 3 )δ6.93(q,J＝6.8Hz,1H),5.41(brs,1H),4.84(d,J＝8.4Hz,1H),4.76(d,J＝7.6Hz,1H),4.74(d,J＝8.0Hz,1H),4.64(dd,J＝12.0,4.0Hz,1H),4.50(d,J＝8.4Hz,1H),4.26(brs,1H),3.92-3.78(m,6H),3.58-3.48(m,1H),3.45(s,6H),3.44(s,6H),3.39(s,3H),3.32-3.10(m,7H),2.59(brs,1H),2.40-2.26(m,3H),2.20(s,3H),2.14-2.09(m,1H),1.33-1.12(m,12H),1.06(s,3H),0.98(s,3H)； 13 CNMR(100MHz,CDCl 3 )δ217.0,167.6,138.9,137.7,128.7,121.9,101.4,99.7,99.6,95.8,85.6,82.5,82.42,82.38,80.5,77.2,76.9,75.8,75.3,71.5,68.5,68.3,68.2,58.1,58.0,57.9,57.1,56.2,53.7,43.0,38.6,37.2,37.0,35.6,35.5,35.4,35.3,35.2,34.3,33.1,29.6,29.4,27.3,26.0,24.3,19.2,18.2,18.14,18.11,17.9,14.4,12.1,9.8；HRMS(MALDI)m/z calcd C 54 H 86 O 17 Na[M+Na] + 1029.5757,found 1029.5758.
Example 3
Figure BDA0003349323440000222
[α] D 25 ＝+56.0(c 0.55,CHCl 3 )； 1 H NMR(400MHz,CDCl 3 )δ6.92(br d,J＝7.6Hz,1H),5.40(br,1H),4.91(d,J＝4Hz,1H),4.85(dd,J＝1.6,9.6Hz,1H),4.64(dd,J＝11.6,4.4Hz,1H),4.33(d,J＝7.6z,1H),4.27(s,1H),4.22(dd,J＝6.8,9.2Hz,1H),3.83-3.86(m,2H),3.75(d,J＝3.6Hz,1H),3.64(s,3H),3.52-3.58(m,2H),3.40(s,3H),3.39(s,3H),3.40-3.52(m,3H),3.19(t,J＝9.2Hz,1H),3.08-3.15(m,2H),2.53(s,1H),2.45(s,1H),2.27-2.34(m,2H),2.19-2.24(m,1H)2.19(s,1H),1.88(s,3H),1.27-1.31(m,7H),1.22-1.25(m,5H),1.05(s,3H)0.98(s,3H)； 13 C NMR(100MHz,CDCl 3 )δ217.1,167.7,138.0,137.8,128.7,122.0,104.2,95.7,91.2,85.7,85.2,77.0，76.9，75.9,75.1,74.7,74.5,74.4,72.4,71.7,68.9,63.3,60.6,57.4,57.2,56.6,53.7,43.0,38.6,37.2,37.1,35.7,34.6,34.4,33.1,31.2,29.5,27.3,26.0,24.4,19.3,18.5,17.8,17.7,14.5,12.1,9.9；LR-ESIMS Calcd for C 47 H 74 O 15 Na(M+Na + )901.5,found 901.2.
Biological examples
Cerebral edema model
Experimental materials: diethyl ether, phosphate Buffered Saline (PBS), nylon monofilament suture, 20g weight and 60cm PVC-U insulating flame-retardant electrical bushing.
Solution: compound P57 was dissolved in 1% dmso+9% castor oil+90% pbs solution.
The test steps are as follows:
1. mouse cerebral edema model establishment
The falling weight method has been used for TBI modeling to simulate focal cortical contusions. The weight loss method damages the closed cranium fixed by the metal plate through the guide device by using a weight or directly damages the brain model through craniotomy. The method has simple operation, easy quantification, and good repeatability, and can directly cause cerebral edema.
The test was performed after C57BL/6J 6-8 week old male adult mice were fed for suitability. Mice were randomized into sham control sham, TBI hibernating agent positive control, TBI control sham (injected solvent) and TBI drug intervention, 8 per group. After the mice were anesthetized with diethyl ether, one experimenter manually fixed the skull of the mice on a horizontal tabletop with the skull upward, and the other experimenter freely and vertically dropped a 20g weight from a 60cm PVC-U insulating flame-retardant electrical bushing to smash the brains of the mice, so as to prepare a model of closed cerebral edema of the mice.
2. Treatment of mice of each group
Mice subjected to TBI molding were grouped and then injected intraperitoneally with 25mg/kg of P57, and 100. Mu.l/mouse of the solvent and hibernating agent, respectively, and the water content of brain tissue was measured after 24 hours.
3. Mouse brain tissue water content determination
The brains and cerebellum of the mice were removed, weighed wet by an electronic balance, and the brains were transected with a 3-knife. Drying in a 100 ℃ incubator for 24 hours, and weighing the dry weight. Brain tissue water content= (wet weight-dry weight)/wet weight x100%.
4. Analysis of results
Data were analyzed using graphprism 8.3.1 statistical software and expressed as mean ± standard error. the t-test compares the differences between the groups.
The results of the water content of the brain tissue of the mice are shown in FIG. 1. We observed a significant decrease in water content in brain tissue of P57-dosed mice compared to control group (< P0.05, < P <0.01, < P <0.001, n=8). The results indicate that compound P57 can significantly reduce cerebral edema, exhibiting excellent effects of treating cerebral edema.

Claims (7)

1. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cerebral oedema:
Figure FDA0003349323430000011
wherein,,
n is 0 or 1;
R 1 selected from hydrogen, C 2-10 Alkanoyl, unsubstituted or para-substituted benzoyl, tris (C) 1-10 Alkyl) silyl, tri (C) 6-20 Aryl) silicon-based, allyl, and substituted or unsubstituted benzyl;
R 2 selected from hydrogen, hydroxy, halogen; wherein the hydroxyl group optionally has a protecting group selected from C 2-10 Alkanoyl, unsubstituted or para-substituted benzoyl, tris (C) 1-10 Alkyl) silyl, tri (C) 6-20 Aryl) silicon-based, allyl, and substituted or unsubstituted benzyl;
wherein,,
the substituent of the benzoyl is selected from methoxy, nitro, azido and halogen;
the substituent of the benzyl is selected from naphthylmethylene, p-methoxyphenyl, p-methylphenyl, p-nitrobenzyl and p-halogen substituted benzyl.
2. The use according to claim 1, wherein,
R 1 selected from acetyl, unsubstituted benzoyl and para methoxy substituted benzoyl.
3. The use according to claim 1, wherein,
the compound is selected from:
Figure FDA0003349323430000012
/>
Figure FDA0003349323430000021
/>
Figure FDA0003349323430000031
4. the use according to claim 1, characterized in that,
the compounds have the formula:
Figure FDA0003349323430000032
5. the use according to any one of claims 1 to 4, characterized in that,
the cerebral oedema includes cerebral oedema associated with: a decline or loss of consciousness level, memory loss, a change in mental state, a short or long term neurological deficit, or an intracranial lesion.
6. The use according to claim 1-5, characterized in that,
the route of administration of the drug includes oral, rectal, transmucosal, nasal or enteral administration and parenteral delivery.
7. The use according to claim 1-6, characterized in that,
the dosage form of the medicine is oral or injection preparation.
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