CN109180478B - Diphenheptane compounds, preparation method and application thereof - Google Patents
Diphenheptane compounds, preparation method and application thereof Download PDFInfo
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- CN109180478B CN109180478B CN201811032569.0A CN201811032569A CN109180478B CN 109180478 B CN109180478 B CN 109180478B CN 201811032569 A CN201811032569 A CN 201811032569A CN 109180478 B CN109180478 B CN 109180478B
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- 238000002360 preparation method Methods 0.000 title claims description 35
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- -1 diphenylheptane compound Chemical class 0.000 claims abstract description 19
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- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims abstract description 4
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 147
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 81
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- OAVCWZUKQIEFGG-UHFFFAOYSA-O 2-(5-methyl-2H-tetrazol-1-ium-1-yl)-1,3-thiazole Chemical compound CC1=NN=N[NH+]1C1=NC=CS1 OAVCWZUKQIEFGG-UHFFFAOYSA-O 0.000 description 1
- DTJVECUKADWGMO-UHFFFAOYSA-N 4-methoxybenzenesulfonyl chloride Chemical compound COC1=CC=C(S(Cl)(=O)=O)C=C1 DTJVECUKADWGMO-UHFFFAOYSA-N 0.000 description 1
- JXRGUPLJCCDGKG-UHFFFAOYSA-N 4-nitrobenzenesulfonyl chloride Chemical compound [O-][N+](=O)C1=CC=C(S(Cl)(=O)=O)C=C1 JXRGUPLJCCDGKG-UHFFFAOYSA-N 0.000 description 1
- VQDQISMDUHBUFF-UHFFFAOYSA-N 4-phenylbutanoyl chloride Chemical compound ClC(=O)CCCC1=CC=CC=C1 VQDQISMDUHBUFF-UHFFFAOYSA-N 0.000 description 1
- GQJMIKVSYWHDMK-UHFFFAOYSA-N 7-phenylheptylbenzene Chemical compound C=1C=CC=CC=1CCCCCCCC1=CC=CC=C1 GQJMIKVSYWHDMK-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
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- 235000014375 Curcuma Nutrition 0.000 description 1
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- RRSNDVCODIMOFX-MPKOGUQCSA-N Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O Chemical compound Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O RRSNDVCODIMOFX-MPKOGUQCSA-N 0.000 description 1
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
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- 235000013976 turmeric Nutrition 0.000 description 1
- 235000019509 white turmeric Nutrition 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/14—Preparation of carboxylic acid esters from carboxylic acid halides
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
- C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- Health & Medical Sciences (AREA)
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- Bioinformatics & Cheminformatics (AREA)
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- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Immunology (AREA)
- Mycology (AREA)
- Polymers & Plastics (AREA)
- Food Science & Technology (AREA)
- Nutrition Science (AREA)
- Dermatology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention relates to the technical field of compound synthesis, in particular to a diphenylheptane compound and application thereof, wherein the structural formula of the compound is as follows:
wherein R is1、R2Are all cyclopropane formyl; or R1Is H, R2Is cyclopropanecarbonyl; or R1Is H, R2Is m-chlorobenzoyl; or R1Is H, R2Is composed of
Or R1 and R2 are both
Or R1Is H, R2Is composed of
R3F, Br, trifluoromethyl or tert-butyl; or R1、R2Are all made of
R3Is an acetamido group. The compound of the invention has psoriasis bioactivity and has therapeutic effect on some immunosuppressive diseases. The compound of the invention is prepared into various pharmaceutically acceptable forms, such as tablets, pills, capsules, injections, suspending agents or emulsions, and hopefully replaces part of the existing psoriasis treatment medicines in the future.
Description
Technical Field
The invention relates to the technical field of compound synthesis, in particular to a diphenylheptane compound and a preparation method and application thereof.
Background
The diphenyl heptane compounds are general names of natural compounds with 1, 7-diphenyl heptane parent nucleus, can be divided into linear and cyclic compounds according to the structure, are compounds with special structures mainly existing in Zingiberaceae plants, and have various physiological activities such as hepatotoxicity resistance, tumor resistance, inflammation elimination, bile excretion, disinsection, oxidation resistance and the like. The natural linear diphenylheptane compounds have typical structures, various and remarkable physiological activities, and are focused on people in recent years. The constitution of rhizoma Alpiniae Officinarum is chemically reduced and phthalylated by chemical modification technology to obtain new series of diphenylheptane derivatives, and the physiological activity of the derivatives is studied.
Patent CN101003500A discloses a diphenyl heptane compound, which is a new compound of two sodium sulfonate substituted diphenyl heptanes obtained from ginger, turmeric, curcuma aromatica, curcuma zedoary and galangal of zingiberaceae, and can be used for preparing medicines for resisting physiological changes or diseases caused by oxygen free radicals or related to the oxygen free radicals, such as liver-protecting medicines, anti-senile dementia medicines, cardiovascular and cerebrovascular disease treatment medicines, anti-aging medicines, diabetes complication medicines and the like.
Patent CN101979366A provides 25 new dibenzoheptane compounds, which are extracted and separated from Curcuma kwangsiensis as raw material with organic solvent and/or water, and can prevent and treat inflammation and diseases related to nitric oxide signal transmission.
The patent CN105732379A discloses a diphenylheptane compound (E) -3-acetoxyl-1, 7-di (4-hydroxyphenyl) -6-heptene with biological activity, which can be extracted from plants or prepared by a synthetic method, and the diphenylheptane compound has better proliferation inhibiting effect and dose-effect relationship by in vitro test on the proliferation of human T cell lymphoma cell line HH, thereby being applicable to the preparation of medicaments or foods for preventing and treating psoriasis.
Patent CN105732380A discloses a diphenylheptane compound 3, 5-diacetoxy-1, 7-bis (4-hydroxyphenyl) heptane, which can be extracted from plants or prepared by synthetic method, has biological activity of inhibiting human T cell lymphoma cell line HH cell proliferation, and can be used for preparing medicine or food for preventing and treating psoriasis.
Although patents CN105732379A and CN105732380A disclose two diphenylheptane compounds and their use in preparing drugs or foods for preventing and treating psoriasis, the two disclosed substances have poor water solubility and poor activity, and the preparation method is complicated, which is not suitable for the wide-scale popularization of the drugs. Therefore, there is a great need for the development of commercially available diphenannes for the treatment of psoriasis.
Disclosure of Invention
The invention aims to provide a diphenylheptane compound with psoriasis bioactivity and a preparation method and application thereof, so as to solve one or more of the problems.
According to one aspect of the present invention, there is provided a compound of the dibenzoheptane type having psoriasis biological activity, the structural formula of which is as follows:
wherein R is1、R2Are all cyclopropane formyl; or R1Is H, R2Is cyclopropanecarbonyl; or
According to another object of the present invention, there is provided a process for producing the above-mentioned diphenanne-based compound,
when R is1Is H or cyclopropanecarbonyl, R2In the case of cyclopropanecarbonyl, the preparation method comprises the following steps:
1) weighing 1, 7-di (4-phenylhydroxy) heptyl-3, 5-diol ester, cyclopropyl formyl chloride and triethylamine, mixing, adding dichloromethane serving as a solvent,
2) spin-drying the dichloromethane solution to obtain a yellowish viscous crude product,
3) loading the light yellow crude product obtained in the step 2) on a column by a dry method, wherein the light yellow crude product is firstly prepared by petroleum ether: ethyl acetate ═ 5: 1, eluting, collecting eluent, and then spin-drying to obtain a first product; and then continuing to reuse petroleum ether: ethyl acetate 4: 1, eluting, collecting eluent, and spin-drying to obtain a second product; the chemical reaction formula is as follows:
when R is1Is H, R2When it is m-chlorobenzoyl, its preparationThe method comprises the following steps:
dissolving 1, 7-di (4-phenylhydroxy) heptyl-3, 5-diol ester and triethylamine serving as a catalyst in dichloromethane or dioxane or chloroform serving as a solvent, dropwise adding m-chlorobenzoyl chloride at normal temperature, reacting for 2-24h, performing TLC detection reaction, adding water and ethyl acetate for extraction, removing ethyl acetate under reduced pressure after the solution is layered, and performing column chromatography to obtain a product, wherein the chemical reaction formula is as follows:
when R is1Is H or
R2Is composed of
The preparation method comprises the following steps:
dissolving 1, 7-di (4-phenylhydroxy) heptyl-3, 5-diol ester and triethylamine serving as a catalyst in dichloromethane or dioxane or chloroform serving as a solvent, dropwise adding benzylsulfonyl chloride at normal temperature, reacting at normal temperature for 2-24h, adding water and ethyl acetate for extraction after TLC detection reaction is finished, removing ethyl acetate under reduced pressure after the solution is layered, and carrying out column chromatography to obtain the product. The reaction formula of the preparation process is shown as follows:
when R is1Is H, R2Is composed of
R3When F is used, the preparation method comprises the following steps:
dissolving 1, 7-di (4-phenylhydroxy) heptyl-3, 5-diol ester and triethylamine serving as a catalyst in dichloromethane or dioxane or chloroform serving as a solvent, dropwise adding p-fluorobenzenesulfonyl chloride at normal temperature, reacting at normal temperature for 2-24h, adding water and ethyl acetate for extraction after TLC detection reaction is finished, removing ethyl acetate under reduced pressure after the solution is layered, and performing column chromatography to obtain a product; the reaction formula of the preparation process is shown as follows:
when R is1Is H, R2Is composed of
R3When Br is used, the preparation method comprises the following steps:
dissolving 1, 7-di (4-phenylhydroxy) heptyl-3, 5-diol ester and triethylamine serving as a catalyst in dichloromethane or dioxane or chloroform serving as a solvent, dropwise adding p-bromobenzenesulfonyl chloride at normal temperature, reacting at normal temperature for 2-24h, adding water and ethyl acetate for extraction after TLC detection reaction is finished, removing ethyl acetate under reduced pressure after the solution is layered, and performing column chromatography to obtain a product; the reaction formula of the preparation process is shown as follows:
when R is1Is H, R2Is composed of
R3When the compound is trifluoromethyl, the preparation method comprises the following steps:
dissolving 1, 7-di (4-phenylhydroxy) heptyl-3, 5-diol ester and triethylamine serving as a catalyst in dichloromethane or dioxane or chloroform serving as a solvent, dropwise adding p-trifluoromethylbenzenesulfonyl chloride at normal temperature, reacting at normal temperature for 2-24h, adding water and ethyl acetate for extraction after TLC detection reaction is finished, removing ethyl acetate under reduced pressure after the solution is layered, and carrying out column chromatography to obtain a product; the reaction formula of the preparation process is shown as follows:
when R is1Is H, R2Is composed of
R3When the tert-butyl is adopted, the preparation method comprises the following steps:
dissolving 1, 7-di (4-phenylhydroxy) heptyl-3, 5-diol ester and triethylamine serving as a catalyst in dichloromethane or dioxane or chloroform serving as a solvent, dropwise adding p-tert-butylbenzene sulfonyl chloride at normal temperature, reacting at normal temperature for 2-24h, adding water and ethyl acetate for extraction after TLC detection reaction is finished, removing ethyl acetate under reduced pressure after the solution is layered, and performing column chromatography to obtain the product.
When R1 and R2 are both
R3When the compound is acetamido, the preparation method comprises the following steps:
dissolving raw materials 1, 7-di (4-phenylhydroxy) heptyl-3, 5-diol ester and a catalyst triethylamine in a solvent dichloromethane or dioxane or chloroform, dropwise adding p-acetamido benzenesulfonyl chloride at normal temperature, reacting at normal temperature for 2-24h, after TLC detection reaction is finished, adding water and ethyl acetate for extraction, after the solution is layered, removing ethyl acetate under reduced pressure, and carrying out column chromatography to obtain a product.
According to a further object of the invention, the application of the dibenzoheptane compounds in preparing medicines or foods for preventing and treating psoriasis and immunosuppressive diseases is provided.
In some embodiments, the diphenylheptanes comprise at least one of compounds 1-7, wherein,
the compound 2 is 1-cyclopropane formyl phenoxy-7- (4-phenylhydroxy) heptyl-3, 5-diol ester, and the chemical formula is as follows:
the compound 3 is 1-m-chlorophenyl formylphenoxy-7- (4-phenylhydroxy) heptyl-3, 5-diol ester, and has the chemical formula:
compound 4-1, having the structural formula:
the compound 5 is 1-p-fluorobenzenesulfonyl phenoxy-7- (4-phenylhydroxy) heptyl-3, 5-diol ester, and has a chemical formula as follows:
the compound 6 is 1-p-bromophenylsulfonylphenoxy-7- (4-phenylhydroxy) heptyl-3, 5-diol ester, and has the chemical formula:
the compound 7 is 1- (4-trifluoromethyl) benzenesulfonylphenoxy-7- (4-phenylhydroxy) heptyl-3, 5-diol ester, and has the chemical formula:
in some embodiments, the medicament contains one or more pharmaceutically acceptable carriers or excipients.
In some embodiments, the medicament may be a tablet, pill, capsule, injection, suspension, or emulsion.
The compound has the advantages of simple structure, short synthetic path, simple synthetic process and high yield. Experiments prove that the compound has the biological activity of psoriasis and has the treatment effect on some immunosuppressive diseases; compared with the dibenzoheptane compounds with psoriasis bioactivity in the prior art, the compound of the invention has greatly improved bioactivity. The compounds of the invention are prepared in various pharmaceutically acceptable forms, such as: tablets, pills, capsules, injections, suspensions or emulsions are promising as replacements for some of the existing psoriasis treatment drugs in the future.
Drawings
FIG. 1 is a high resolution LC-MS spectrum of Compound 1;
FIG. 2 is a high resolution LC-MS spectrum of Compound 2;
FIG. 3 is a high resolution LC-MS spectrum of Compound 3;
FIGS. 4-5 are high resolution LC-MS and NMR spectra of Compound 4;
FIG. 6 is a high resolution LC-MS spectrum of Compound 4-1;
FIG. 7 is a high resolution LC-MS spectrum of Compound 5;
FIG. 8 is a high resolution LC-MS spectrum of Compound 5-1;
FIGS. 9-10 are high resolution LC-MS and NMR hydrogen spectra of Compound 6;
FIGS. 11-12 are high resolution LC-MS and NMR spectra of Compound 6-1;
FIGS. 13-14 are high resolution LC-MS and NMR hydrogen spectra of Compound 7;
FIGS. 15-16 are high resolution LC-MS and NMR spectra of Compound 7-1;
FIGS. 17-18 are high resolution LC-MS and NMR hydrogen spectra of Compound 8;
FIGS. 19-20 are LC-MS and NMR hydrogen spectra of Compound 8-1;
FIGS. 21-22 are LC-MS and NMR hydrogen spectra of Compound 9;
FIGS. 23-24 are high resolution LC-MS and NMR hydrogen spectra of Compound 9-1.
Detailed Description
The present invention will be described in further detail with reference to the accompanying drawings.
1. Preparation of diphenylheptanes
1, 7-bis (4-phenylhydroxy) heptyl-3, 5-diol ester 100mg, cyclopropylcarbonyl chloride 77.65mg, triethylamine 40.30mg, and 5ml of methylene chloride as a solvent were weighed out accurately. After reacting for 24h at normal temperature, the dichloromethane solution is dried by spinning to obtain a pale yellow viscous crude product 87.62 mg. And (3) putting the spin-dried light yellow powder on a column by a dry method, and firstly, adding petroleum ether: ethyl acetate (5: 1)100ml was eluted and the eluate was collected to give product 1, 16.2mg in weight. Continuing to use petroleum ether: eluting with 150ml ethyl acetate (4: 1), collecting eluent to obtain product 2 with weight of 34.4 mg.
The product 1 was analyzed to be compound 1 and the product 2 was compound 2. Wherein the high resolution LC-MS spectrum of compound 1 is shown in figure 1, in which [ M + Na ] of compound 1]+Peak value of 559.23218, molecular weight of 536.24102, and molecular formula of C31H36O8。
The high resolution LC-MS spectrum of compound 2 is shown in FIG. 2, in which [ M + Na ]]+Peak value of 491.20560, molecular weight of 468.21, and molecular formula of C27H32O7。
It is also known that cyclopropylcarbonyl chloride reacts with a hydroxyl group on the benzene ring in 1, 7-bis (4-phenylhydroxy) heptyl-3, 5-diol ester by the following reaction scheme:
2. preparation of diphenylheptanes
Dissolving raw material 1, 7-di (4-phenylhydroxy) heptyl-3, 5-diol ester 200mg (0.5mmol) and catalyst triethylamine (2mmol) in solvent dichloromethane or dioxane or chloroform, dropwise adding m-chlorobenzoyl chloride (2mmol) at normal temperature, reacting for 12h at normal temperature, after TLC detection reaction is finished, adding 20ml of water and 20ml of Ethyl Acetate (EA) for extraction, after the solution is layered, removing EA under reduced pressure, and carrying out column chromatography to obtain two compounds. Identified as compound 3 and compound 3-1.
Wherein, the high resolution LC-MS spectrum of the compound 3 is shown in figure 3, in which [ M + Na ] is shown]+Has a peak value of 561.16681, a molecular weight of 538.00841 and a molecular formula of C30H30O7Cl。
The above reaction formula is as follows:
3. preparation of diphenylheptanes
Dissolving raw material 1, 7-di (4-phenylhydroxy) heptyl-3, 5-diol ester 200mg (0.5mmol) and catalyst triethylamine (1.5mmol) in solvent dichloromethane or dioxane or chloroform, dropwise adding benzylsulfonyl chloride (1.5mmol) at normal temperature, reacting for 16h at normal temperature, after TLC detection reaction is finished, adding 20ml of water and 20ml of EA for extraction, after the solution is layered, removing EA under reduced pressure, and carrying out column chromatography to obtain two compounds. Identified as compound 4 and compound 4-1.
Wherein, the high resolution LC-MS spectrum of compound 4 is shown in figure 4, in which [ M + Na ] is shown]+Peak value of 577.18805, molecular weight of 554.19744, and molecular formula of C30H34O8S; the NMR spectrum of compound 4 is shown in FIG. 5, and it can be seen that the specific data are as follows: (CDCl)3,600MHz)δ7.71-7.10(2H,d,J＝6.0),7.32-7.30(4H,2H,d,J＝12.0)，7.02-6.99(4H,m),6.87(2H,m),6.75-6.72(2H,m),4.98-4.89(3H,m),2.57-2.45(4H,m),2.01(3H,s),1.99(3H,s),1.60(6H,m)。
The high resolution LC-MS spectrum of compound 4-1 is shown in FIG. 6, and its molecular weight is 554.19744 and molecular formula is C30H34O8S。
The above reaction formula is as follows:
4. preparation of diphenylheptanes
Dissolving raw material 1, 7-di (4-phenylhydroxy) heptyl-3, 5-diol ester 200mg (0.5mmol) and catalyst triethylamine (0.5mmol) in solvent dichloromethane or dioxane or chloroform, dropwise adding p-fluorobenzene sulfonyl chloride (1mmol) at normal temperature, reacting for 10h at normal temperature, after TLC detection reaction is finished, adding 20ml of water and 20ml of EA for extraction, after solution layering, removing EA under reduced pressure, and carrying out column chromatography to obtain two compounds. Identified as compound 5 and compound 5-1.
Wherein, the high resolution LC-MS spectrum of compound 5 is shown in FIG. 7, in which [ M + Na ] is shown]+Peak value of 581.16333, molecular weight of 558.17237, and molecular formula of C29H31FO8S；
The LC-MS spectrum of compound 5-1 is shown in FIG. 8, in which [ M + Na ]]+Peak value of 739.14697, molecular weight of 716.15615, and molecular formula of C35H34F2O10S2。
The above reaction formula is as follows:
5. preparation of diphenylheptanes
Dissolving a raw material 1, 7-di (4-phenylhydroxy) heptyl-3, 5-diol ester 200mg (0.5mmol) and a catalyst triethylamine (1mmol) in a solvent dichloromethane or dioxane or chloroform, dropwise adding p-bromobenzenesulfonyl chloride (1.5mmol) at normal temperature, reacting for 8 hours at normal temperature, after TLC detection reaction is finished, adding 20ml of water and 20ml of EA for extraction, after the solution is layered, removing EA under reduced pressure, and carrying out column chromatography to obtain two compounds. Identified as compound 6 and compound 6-1.
Wherein, the high resolution LC-MS spectrum of compound 6 is shown in FIG. 9, in which [ M + Na ]]+Peak value of 641.08, molecular weight of 618.09230, and molecular formula of C29H31BrO8S; the NMR spectrum of compound 6 is shown in FIG. 10, and the specific data is as follows: (CDCl)3,600MHz)δ7.67(4H,s),7.09-7.08(2H,d,J＝6.0),7.02-7.01(2H,d,J＝6.0),6.89-6.88(2H,d,J＝6.0),6.75-6.73(2H,d,J＝12.0),5.04(1H,s),4.98-4.95(2H,m),2.60-2.52(4H,m),2.02(3H,s),2.00(3H,s),1.86-1.77(6H,m)。
The high-resolution LC-MS spectrum of compound 6-1 is shown in FIG. 11, in which [ M + Na ]]+Peak value of 860.98645, molecular weight of 835.99601, and molecular formula of C35H34Br2O10S2(ii) a The NMR spectrum of Compound 6-1 is shown in FIG. 12.
The above reaction formula is as follows:
6. preparation of diphenylheptanes
Dissolving raw material 1, 7-di (4-phenylhydroxy) heptyl-3, 5-diol ester 200mg (0.5mmol) and catalyst triethylamine (1.5mmol) in solvent dichloromethane or dioxane or chloroform, dropwise adding p-trifluoromethyl benzene sulfonyl chloride (2mmol) at normal temperature, reacting for 6h, detecting by TLC, adding 20ml water and 20ml EA for extraction, after the solution is layered, removing EA under reduced pressure, and carrying out column chromatography to obtain two compounds. Identified as compound 7 and compound 7-1.
Wherein, the high resolution LC-MS spectrum of compound 7 is shown in FIG. 13, in which [ M + Na ]]+Peak value of 631.16.34, molecular weight of 608.16917, and molecular formula of C30H31F3O8S; NMR spectrum of Compound 7 such asAs shown in fig. 14, the specific data are as follows: (CDCl)3,600MHz)δ7.98-7.96(2H,d,J＝12.0),7.82-7.80(2H,d,J＝12.0),7.08-7.07(2H,d,J＝6.0),7.01-7.00(2H,d,J＝6.0),6.89-6.88(2H,d,J＝6.0),6.74-6.73(2H,d,J＝6.0),4.93-4.88(2H,m),4.81(1H,s),2.59-2.50(4H,m),2.02(3H,s),1.99(3H,s),1.95-1.1.72(6H,m)。
The high-resolution LC-MS spectrum of compound 7-1 is shown in FIG. 15, in which [ M + Na ]]+The peak value is 839.14099[ M + Na]+Molecular weight of 816.14976 and molecular formula C37H34F6O10S2(ii) a The NMR spectrum of Compound 7-1 is shown in FIG. 16.
The above reaction formula is as follows:
7. preparation of diphenylheptanes
Dissolving raw material 1, 7-di (4-phenylhydroxy) heptyl-3, 5-diol ester 200mg (0.5mmol) and catalyst triethylamine (1.5mmol) in solvent dichloromethane or dioxane or chloroform, dropwise adding p-tert-butylbenzene sulfonyl chloride (2mmol) at normal temperature, reacting for 14h, detecting by TLC, adding 20ml water and 20ml EA for extraction, after the solution is layered, removing EA under reduced pressure, and carrying out column chromatography to obtain two compounds. Identified as compound 8 and compound 8-1.
Wherein, the high resolution LC-MS spectrum of compound 8 is shown in FIG. 17, in which [ M + Na ]]+Peak value of 619.23566, molecular weight of 596.24439, and molecular formula of C33H40O8S; the NMR spectrum of Compound 8 is shown in FIG. 18.
The high resolution LC-MS spectrum of compound 8-1 is shown in FIG. 19, and its molecular weight is 792.30019 and molecular formula is C43H52O10S2(ii) a The NMR spectrum of Compound 8-1 is shown in FIG. 20.
The above reaction formula is as follows:
8. preparation of diphenylheptanes
Dissolving raw material 1, 7-di (4-phenylhydroxy) heptyl-3, 5-diol ester 200mg (0.5mmol) and catalyst triethylamine (1.5mmol) in solvent dichloromethane or dioxane or chloroform, dropwise adding p-acetamido benzene sulfonyl chloride (2mmol) at normal temperature, reacting for 10h, detecting by TLC, adding 20ml water and 20ml EA for extraction, after the solution is layered, removing EA under reduced pressure, and carrying out column chromatography to obtain two compounds. Identified as compound 9 and compound 9-1.
Wherein the high resolution LC-MS spectrogram and nuclear magnetic resonance hydrogen spectrogram of compound 9 are shown in FIGS. 21-22; the high-resolution LC-MS spectrum and the nuclear magnetic resonance hydrogen spectrum of the compound 9-1 are respectively shown in FIG. 23 and FIG. 24.
The above reaction formula is as follows:
according to the above preparation scheme, different raw materials are respectively selected to perform substitution reaction with 1, 7-bis (4-phenylhydroxy) heptyl-3, 5-diol ester, for example, p-nitrobenzenesulfonyl chloride is used for reaction with 1, 7-bis (4-phenylhydroxy) heptyl-3, 5-diol ester to obtain a compound, which is analyzed to be compound 14;
p-methoxybenzenesulfonyl chloride reacts with 1, 7-bis (4-phenylhydroxy) heptyl-3, 5-diol ester to obtain a compound, which is analyzed to be a compound 12;
reacting 2-thiophenesulfonyl chloride with 1, 7-bis (4-phenylhydroxy) heptyl-3, 5-diol ester to obtain a compound, which is analyzed to be a compound 13;
reaction of 4-phenylbutyryl chloride with 1, 7-bis (4-phenylhydroxy) heptyl-3, 5-diol ester afforded a compound which was analyzed as compound 11. Meanwhile, the reaction formula of the above reaction is as follows:
the pharmacodynamic activity of the twenty compound products prepared by the method is verified through an MTT (methyl thiazolyl tetrazolium) experiment:
psoriasis is a common chronic inflammatory skin disease easy to recur and is characterized in that red papules or plaques are covered with multiple layers of silvery-white scales, one of the pathological features is abnormal hyperplasia of epidermal cells, and the entrance of researches on psoriasis by researchers is a multi-degree proliferation and regulation mechanism of keratinocytes.
Therefore, in order to further explain the application of the diphenyl heptane compound disclosed by the invention in medicines or foods for preventing and treating psoriasis and immunosuppressive diseases, 20 diphenyl heptane compounds prepared by the invention are respectively prepared into test medicines with a series of concentrations, and the MTT method is utilized to take the human immortalized epidermal keratinocyte cell line HaCaT cell and the human T cell lymphoma cell line HH cell as research models, examine the influence of the synthesized 20 compounds on the proliferation thereof, and then screen potential medicines for treating psoriasis.
Wherein, the sources of the biological materials in the experiment are as follows: human T cell lymphoma cell line HH cells were purchased from ATCC, and human immortalized epidermal keratinocyte cell line HaCaT cells were purchased from chinese type culture collection (CCTCC).
The method comprises the steps of adding 40 mu L of dimethyl sulfoxide (DMSO) into 2mg of the diphenylheptane compounds, fully dissolving to obtain a diphenylheptane compound-DMSO solution, adding 2 mu L of the diphenylheptane compound-DMSO solution into 2mL of DMEM (purchased from Gibco company) to obtain 100 mu g/mL of drug mother liquor, and diluting to obtain test drugs with a series of concentrations of 50, 25, 6.25, 1.5625 and the like. If IC50 is more than 100 mug/mL, the drug effect is considered to be poor, and if IC50 is less than 1.5625 mug/mL, the drug is diluted to low concentration and then is tested experimentally.
The activities of the 20 types of the dibenzoheptane compounds against HaCaT cells and HH cells are detected by an MTT method, and the IC50 values of the compounds are respectively obtained after 24h and 48h of administration.
Meanwhile, methotrexate is an effective anti-psoriasis drug, is widely applied to psoriasis treatment at home and abroad, can prevent the synthesis of cell DNA, inhibit the proliferation of epidermal keratinocytes of patients with psoriasis, and is a cytotoxic immunosuppressant, so that methotrexate is taken as an experimental comparative example and is selected as a positive control drug.
The specific data of the results of the IC50 detection of HaCaT cells and HH cells by the 20 compounds and the control drug methotrexate 24h and 48h according to the present invention are shown in table 1:
TABLE 1 IC50 of twenty compounds 24h and 48h on HaCaT and HH cells
As can be seen from Table 1, the IC50 of the positive drug methotrexate is far greater than 100 mu g/mL, the screening of the anti-HaCaT cell activity of 20 synthesized compounds shows that the anti-HaCaT activity of the compounds 1, 4 and 6 is better, the IC50 is between 14.46 and 69.46 mu g/mL, and the IC50 of the compounds 2, 3,5 and 7 is reduced to be less than 100 mu g/mL after 48h of administration, so that the inhibition effect of the compounds on the HaCaT cells is better than that of the positive drugs, and the compounds can be used as potential compounds for treating psoriasis.
In the HH cell activity screening, the IC50 of methotrexate is more than 100 mu g/mL, while the compound 2, the compound 3, the compound 4-1, the compound 5, the compound 6, the compound 7, the compound 8 and the compound 9 in the synthesized compounds all show certain inhibitory activity, the IC50 is between 8.48 and 79.21 mu g/mL, wherein the IC50 of the compound 1 is about 51.93 mu g/mL after being administrated for 48 hours, and the compounds are all far superior to the positive drug methotrexate and can be used as a potential drug for treating psoriasis.
Therefore, the ten dibenzoheptane compounds, i.e., the compound 1, the compound 2, the compound 3, the compound 4-1, the compound 5, the compound 6, the compound 7, the compound 8 and the compound 9, can be preferably used as compounds for potentially treating psoriasis by analyzing and judging the activity of the 20 dibenzoheptane compounds prepared by a chemical synthesis method by using 1, 7-di (4-phenylhydroxy) heptyl-3, 5-diol ester as a raw material.
For the sake of economy, the spectrum of the inactive diphenanne compounds prepared by the present application is partially omitted from the description and the drawings.
What has been described above are merely some embodiments of the present invention. It will be apparent to those skilled in the art that various changes and modifications can be made without departing from the inventive concept thereof, and these changes and modifications can be made without departing from the spirit and scope of the invention.
Claims (6)
1. The diphenylheptane compounds are characterized in that the structural formula is as follows:
wherein R is1、R2Are all cyclopropane formyl; or R1Is H, R2Is cyclopropanecarbonyl; or R1Is H, R2Is m-chlorobenzoyl;
or R1Is H, R2Is composed of
Or R1、R2Are all made of
Or R1Is H, R2Is composed of
R3F, Br, trifluoromethyl or tert-butyl;
or R1、R2Are all made of
R3Is an acetamido group.
2. A process for producing a diheptane compound as described in claim 1, which comprises,
when R is1Is H or cyclopropanecarbonyl, R2In the case of cyclopropanecarbonyl, the preparation method comprises the following steps:
1) weighing 1, 7-di (4-phenylhydroxy) heptyl-3, 5-diol ester, cyclopropyl formyl chloride and triethylamine, mixing, adding dichloromethane serving as a solvent, and reacting at normal temperature for 2-24 hours;
2) spin-drying the dichloromethane solution to obtain a yellowish viscous crude product,
3) loading the light yellow crude product obtained in the step 2) on a column by a dry method, wherein the light yellow crude product is firstly prepared by petroleum ether: ethyl acetate ═ 5: 1, eluting, collecting eluent, and then spin-drying to obtain a first product; and then continuing to use petroleum ether: ethyl acetate 4: 1, eluting the column, collecting eluent, and then spin-drying to obtain a second product;
when R is1Is H, R2When the m-chlorobenzoyl is adopted, the preparation method comprises the following steps:
dissolving 1, 7-di (4-phenylhydroxy) heptyl-3, 5-diol ester and triethylamine serving as a catalyst in dichloromethane or dioxane or chloroform serving as a solvent, dropwise adding m-chlorobenzoyl chloride at normal temperature, reacting at normal temperature for 2-24h, adding water and ethyl acetate for extraction after TLC detection reaction is finished, removing ethyl acetate under reduced pressure after the solution is layered, and carrying out column chromatography to obtain a product;
when R is1Is H or
R2Is composed of
The preparation method comprises the following steps:
dissolving 1, 7-di (4-phenylhydroxy) heptyl-3, 5-diol ester and triethylamine serving as a catalyst in dichloromethane or dioxane or chloroform serving as a solvent, dropwise adding benzylsulfonyl chloride at normal temperature, reacting at normal temperature for 2-24h, adding water and ethyl acetate for extraction after TLC detection reaction is finished, removing ethyl acetate under reduced pressure after the solution is layered, and carrying out column chromatography to obtain a product;
when R is1Is H, R2Is composed of
R3When F is used, the preparation method comprises the following steps:
dissolving 1, 7-di (4-phenylhydroxy) heptyl-3, 5-diol ester and triethylamine serving as a catalyst in dichloromethane or dioxane or chloroform serving as a solvent, dropwise adding p-fluorobenzenesulfonyl chloride at normal temperature, reacting at normal temperature for 2-24h, adding water and ethyl acetate for extraction after TLC detection reaction is finished, removing ethyl acetate under reduced pressure after the solution is layered, and performing column chromatography to obtain a product;
when R is1Is H, R2Is composed of
R3When Br is used, the preparation method comprises the following steps:
dissolving 1, 7-di (4-phenylhydroxy) heptyl-3, 5-diol ester and triethylamine serving as a catalyst in dichloromethane or dioxane or chloroform serving as a solvent, dropwise adding p-bromobenzenesulfonyl chloride at normal temperature, reacting at normal temperature for 2-24h, adding water and ethyl acetate for extraction after TLC detection reaction is finished, removing ethyl acetate under reduced pressure after the solution is layered, and performing column chromatography to obtain a product;
when R is1Is H, R2Is composed of
R3When the compound is trifluoromethyl, the preparation method comprises the following steps:
dissolving 1, 7-di (4-phenylhydroxy) heptyl-3, 5-diol ester and triethylamine serving as a catalyst in dichloromethane or dioxane or chloroform serving as a solvent, dropwise adding p-trifluoromethylbenzenesulfonyl chloride at normal temperature, reacting at normal temperature for 2-24h, adding water and ethyl acetate for extraction after TLC detection reaction is finished, removing ethyl acetate under reduced pressure after the solution is layered, and carrying out column chromatography to obtain a product;
when R is1Is H, R2Is composed of
R3When the tert-butyl is adopted, the preparation method comprises the following steps:
dissolving 1, 7-di (4-phenylhydroxy) heptyl-3, 5-diol ester and triethylamine serving as a catalyst in dichloromethane or dioxane or chloroform serving as a solvent, dropwise adding p-tert-butylbenzene sulfonyl chloride at normal temperature, reacting at normal temperature for 2-24h, adding water and ethyl acetate for extraction after TLC detection reaction is finished, removing ethyl acetate under reduced pressure after the solution is layered, and performing column chromatography to obtain a product;
when R is1、R2Are all made of
R3When the compound is acetamido, the preparation method comprises the following steps:
dissolving raw materials 1, 7-di (4-phenylhydroxy) heptyl-3, 5-diol ester and a catalyst triethylamine in a solvent dichloromethane or dioxane or chloroform, dropwise adding p-acetamido benzenesulfonyl chloride at normal temperature, reacting at normal temperature for 2-24h, after TLC detection reaction is finished, adding water and ethyl acetate for extraction, after the solution is layered, removing ethyl acetate under reduced pressure, and carrying out column chromatography to obtain a product.
3. Use of the diphenylheptane compounds of claim 1 in the preparation of medicaments or foods for the prevention and treatment of psoriasis and immunosuppressive diseases.
4. Use according to claim 3, characterized in that said diphenylheptanes comprise at least one of the following ten compounds:
compound 1, having the structural formula:
compound 2, having the structural formula:
compound 3, having the structural formula:
compound 4, having the structural formula:
compound 4-1, having the structural formula:
compound 5, having the structural formula:
compound 6, having the structural formula:
compound 7, having the structural formula:
compound 8, having the structural formula:
compound 9, having the structural formula:
5. the use according to claim 4, wherein the medicament comprises one or more pharmaceutically acceptable carriers or excipients.
6. The use according to any one of claims 3 to 5, wherein the medicament is in the form of a tablet, pill, capsule, injection, suspension or emulsion.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105732380A (en) * | 2014-12-08 | 2016-07-06 | 广东省中医院 | Diarylheptanoid compound and its preparation method and use |
| CN108140783A (en) * | 2015-04-29 | 2018-06-08 | 三星Sdi株式会社 | The partition board and electrochemical cell of high heat resistance and anti-flammability |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105732380A (en) * | 2014-12-08 | 2016-07-06 | 广东省中医院 | Diarylheptanoid compound and its preparation method and use |
| CN108140783A (en) * | 2015-04-29 | 2018-06-08 | 三星Sdi株式会社 | The partition board and electrochemical cell of high heat resistance and anti-flammability |
Non-Patent Citations (1)
| Title |
|---|
| BIARYLHEPTANOIDS AND OTHER CONSTITUENTS FROM WOOD OF ALNUS JAPONICA;MASAYASU NOMURA等;《Phytochemistry》;19811231;第20卷(第5期);第1097-1104页 * |
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