CN107903196A - Stimulate and strengthen protective immunological reaction compound, preparation method and its usage - Google Patents

Stimulate and strengthen protective immunological reaction compound, preparation method and its usage Download PDF

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Publication number
CN107903196A
CN107903196A CN201711090559.8A CN201711090559A CN107903196A CN 107903196 A CN107903196 A CN 107903196A CN 201711090559 A CN201711090559 A CN 201711090559A CN 107903196 A CN107903196 A CN 107903196A
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compound
organic phase
reaction
water
preparation
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韩建林
董磊
梅海波
张峻峰
潘毅
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Nanjing University
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Nanjing University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/03—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/30—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms
    • C07C233/31—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/76—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/03—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C311/04—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms to acyclic carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C313/00—Sulfinic acids; Sulfenic acids; Halides, esters or anhydrides thereof; Amides of sulfinic or sulfenic acids, i.e. compounds having singly-bound oxygen atoms of sulfinic or sulfenic groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C313/02—Sulfinic acids; Derivatives thereof
    • C07C313/06—Sulfinamides

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to organic synthesis and medicinal chemistry art, and in particular to series compound, preparation method and its stimulation and the purposes for strengthening protective immunological reaction.The general formula of series compound of the present invention is：

Description

Stimulate and strengthen protective immunological reaction compound, preparation method and its usage
Technical field
The present invention relates to organic synthesis and pharmaceutical chemistry, and immunological effect drug field, and in particular to series is new to be exempted from Epidemic disease effect compounds and the drug regimen comprising this compound, they show immunoregulation effect.
Background technology
Macrophage is considered to be very important immunocyte all the time, it is in body defenses and immune response Play an important role.Macrophage can offer antigen to activating T cell or effector T cell, in the same of further activating T cell When macrophage itself be also activated and can play cell immune response.M1 types macrophage can secrete substantial amounts of proinflammatory factor (IL-12 and TNF-α), produces substantial amounts of superoxide anion and NO, so as to improve the killing ability of macrophage, strengthens its anti-sense Dye ability.
Immunomodulatory compounds can such as strengthen macrophage activity, promote the synthesis of antibody by the different modes of action With secretion etc., enhancing body is non-specific and specific immunity.
Due to many reasons such as increasing environmental pollution, virus variation, in recent years in crowd immunocompromised incidence It is high, show as easily by virus or bacterium repeated infection, rehabilitation duration length etc. after illness.Therefore, domestic and foreign scholars are always Striving to find high specificity, efficient, stable, nontoxic immunomodulatory compounds.
The content of the invention
The purpose of the present invention is being to provide the immunity effect compounds of Novel series.
It is applied to improve the immunocompetence of body and is possibly used for it is a further object of the present invention to provide above-claimed cpd Disease of prevention and/or treatment pathogenic infection etc..
This invention carries out illustration by vitro and in vivo bioactivity.Animal herein includes but is not limited to：Mouse, Rat, performing animal include but is not limited to cat, dog, and some other animal for example but are not limited to ox, sheep, pig, horse, spirit Long class animal for example but is not limited to monkey and people.The vivo detection of mouse model is the internal medicine for being widely recognized as and being received The model of Activity determination, while for other biologies for example but people can also be not limited to reference is provided.
Above-mentioned purpose is to test to realize by vitro and in vivo biological activity determination, but is not to be construed as to this chemical combination The restriction of the envelop of function of thing.
The present invention relates to compound formula to be：
1#:R1=C6H5；R2=t-Bu-S (O)；R3=H；X1=H；X2=F；
2#:R1=4-F-C6H4；R2=t-Bu-S (O)；R3=H；X1=H；X2=F；
3#:R1=4-Cl-C6H4；R2=t-Bu-S (O)；R3=H；X1=H；X2=F；
4#:R1=4-Br-C6H4；R2=t-Bu-S (O)；R3=H；X1=H；X2=F；
5#:R1=4-Me-C6H4；R2=t-Bu-S (O)；R3=H；X1=H；X2=F；
6#:R1=4-MeO-C6H4；R2=t-Bu-S (O)；R3=H；X1=H；X2=F；
7#:R1=2-Cl-C6H4；R2=t-Bu-S (O)；R3=H；X1=H；X2=F；
8#:R1=2-Br-C6H4；R2=t-Bu-S (O)；R3=H；X1=H；X2=F；
9#:R1=2-Me-C6H4；R2=t-Bu-S (O)；R3=H；X1=H；X2=F；
10#:R1=3-Cl-C6H4；R2=t-Bu-S (O)；R3=H；X1=H；X2=F；
11#:R1=3-Br-C6H4；R2=t-Bu-S (O)；R3=H；X1=H；X2=F；
12#:R1=3-MeO-C6H4；R2=t-Bu-S (O)；R3=H；X1=H；X2=F；
13#:R1=2-Naphthyl；R2=t-Bu-S (O)；R3=H；X1=H；X2=F；
14#:R1=2-Thienyl；R2=t-Bu-S (O)；R3=H；X1=H；X2=F；
15#:R1=t-Bu；R2=t-Bu-S (O)；R3=H；X1=H；X2=F；
16#:R1=C6H5；R2=t-Bu-S (O)；R3=H；X1=F；X2=F；
17#:R1=4-F-C6H4；R2=t-Bu-S (O)；R3=H；X1=F；X2=F；
18#:R1=4-Cl-C6H4；R2=t-Bu-S (O)；R3=H；X1=F；X2=F；
19#:R1=4-Br-C6H4；R2=t-Bu-S (O)；R3=H；X1=F；X2=F；
20#:R1=4-Me-C6H4；R2=t-Bu-S (O)；R3=H；X1=F；X2=F；
21#：R1=4-MeO-C6H4；R2=t-Bu-S (O)；R3=H；X1=F；X2=F；
22#:R1=2-Cl-C6H4；R2=t-Bu-S (O)；R3=H；X1=F；X2=F；
23#:R1=2-Br-C6H4；R2=t-Bu-S (O)；R3=H；X1=F；X2=F；
24#:R1=2-Me-C6H4；R2=t-Bu-S (O)；R3=H；X1=F；X2=F；
25#:R1=3-Cl-C6H4；R2=t-Bu-S (O)；R3=H；X1=F；X2=F；
26#:R1=3-Br-C6H4；R2=t-Bu-S (O)；R3=H；X1=F；X2=F；
27#:R1=3-MeO-C6H4；R2=t-Bu-S (O)；R3=H；X1=F；X2=F；
28#:R1=2-Naphthyl；R2=t-Bu-S (O)；R3=H；X1=F；X2=F；
29#:R1=2-Thienyl；R2=t-Bu-S (O)；R3=H；X1=F；X2=F；
30#:R1=t-Bu；R2=t-Bu-S (O)；R3=H；X1=F；X2=F；
31#:R1=C6H5；R2=t-Bu-S (O)；R3=H；X1=Cl；X2=F；
32#:R1=4-F-C6H4；R2=t-Bu-S (O)；R3=H；X1=Cl；X2=F；
33#:R1=4-Cl-C6H4；R2=t-Bu-S (O)；R3=H；X1=Cl；X2=F；
34#:R1=4-Me-C6H4；R2=t-Bu-S (O)；R3=H；X1=Cl；X2=F；
35#:R1=4-MeO-C6H4；R2=t-Bu-S (O)；R3=H；X1=Cl；X2=F；
36#:R1=2-Cl-C6H4；R2=t-Bu-S (O)；R3=H；X1=Cl；X2=F；
37#:R1=3-Cl-C6H4；R2=t-Bu-S (O)；R3=H；X1=Cl；X2=F；
38#:R1=3-MeO-C6H4；R2=t-Bu-S (O)；R3=H；X1=Cl；X2=F；
39#:R1=2-Thienyl；R2=t-Bu-S (O)；R3=H；X1=Cl；X2=F；
40#:R1=t-Bu；R2=t-Bu-S (O)；R3=H；X1=Cl；X2=F；
41#:R1=C6H5；R2=t-Bu-S (O)；R3=H；X1=Br；X2=F；
42#:R1=4-F-C6H4；R2=t-Bu-S (O)；R3=H；X1=Br；X2=F；
43#:R1=4-Cl-C6H4；R2=t-Bu-S (O)；R3=H；X1=Br；X2=F；
44#:R1=4-Me-C6H4；R2=t-Bu-S (O)；R3=H；X1=Br；X2=F；
45#:R1=4-MeO-C6H4；R2=t-Bu-S (O)；R3=H；X1=Br；X2=F；
46#:R1=2-Cl-C6H4；R2=t-Bu-S (O)；R3=H；X1=Br；X2=F；
47#:R1=3-Cl-C6H4；R2=t-Bu-S (O)；R3=H；X1=Br；X2=F；
48#:R1=3-MeO-C6H4；R2=t-Bu-S (O)；R3=H；X1=Br；X2=F；
49#:R1=2-Thienyl；R2=t-Bu-S (O)；R3=H；X1=Br；X2=F；
50#:R1=t-Bu；R2=t-Bu-S (O)；R3=H；X1=Br；X2=F；
51#:R1=C6H5；R2=t-Bu-S (O)2；R3=H；X1=F；X2=F；
52#:R1=4-MeO-C6H4；R2=t-Bu-S (O)2；R3=H；X1=F；X2=F；
53#:R1=C6H5；R2=Me-C (O)；R3=H；X1=F；X2=F；
54#:R1=4-MeO-C6H4；R2=Me-C (O)；R3=H；X1=F；X2=F；
55#:R1=C6H5；R2=C6H5-C(O)；R3=H；X1=F；X2=F；
56#:R1=4-MeO-C6H4；R2=C6H5-C(O)；R3=H；X1=F；X2=F；
57#:R1=C6H5；R2=t-Bu-S (O)；R3=Me；X1=F；X2=F；
58#:R1=4-MeO-C6H4；R2=t-Bu-S (O)；R3=Me；X1=F；X2=F；
59#:R1=C6H5；R2=t-Bu-S (O)；R3=Bn；X1=F；X2=F；
60#:R1=4-MeO-C6H4；R2=t-Bu-S (O)；R3=Bn；X1=F；X2=F；
Or its pharmaceutically acceptable salt or its solvate.
" pharmaceutically acceptable salt " is the compound comprising formula (1) and the product of salt-forming reaction occurs with acid, including nothing Machine hydrochlorate, such as hydrochloride, hydrobromate or sulfate；Acylate, such as acetate, lactate, succinate, fumaric acid Eye, maleate, citrate, benzoate, mesylate or paratolunitrile salt etc..
Pharmaceutical composition containing the compounds of this invention, the pharmaceutical composition include therapeutically effective amount free form or can The compound for meeting general formula (1) of acceptable salt is as active ingredient；One or more medicinal carrier substances and/or dilution Agent.
Technical scheme, but following method is not limited only to, its scheme is as follows：
For the synthetic method of compound 1-50：
At 0 DEG C, 0.5mmol together with glycol compound 1, the imines 2 and 1.5mmol of 0.6mmol (1.2equiv) The LiBr of (130.3mg, 3.0equiv) is dissolved in the THF of 5mL, and the Et of 1.0mmol is slowly added dropwise to reaction system3N (101.2mg, 2.0equiv).Continue after reacting 0.5h at 0 DEG C, it is water-soluble to add 5mL saturated ammonium chlorides successively to reaction system Liquid and 20mL water quenchings are gone out reaction.Liquid separation, water are mutually extracted 2 times with 20mL ethyl acetate, merge organic phase, and organic phase is washed with 50mL 2 times, 50mL saturation NaCl aqueous solutions wash 1 time, anhydrous Na2SO4Dry, filtering, is spin-dried for solvent, target is obtained through column chromatography for separation Product.
For the synthetic method of compound 51：
Be separately added into the round-bottomed flask of 25mL compound 16 0.5mmol, methanol 5mL and concentrated hydrochloric acid aqueous solution (36%, 1mL).After system stirs reaction 24h at 20 DEG C, solvent is removed with Rotary Evaporators.Remaining residue 10mL dichloromethane Dissolving, adds triethylamine (15mmol).At room temperature after stirring reaction 1h, 10mL water is added, extracts organic phase solution, and with water (2 × 10mL) washing.Filtered after organic phase is dried with anhydrous sodium sulfate, remove solvent on a rotary evaporator and obtain crude product. Column chromatography for separation is then passed through, purification obtains pure deprotection compound.
It will obtain compound to be dissolved in 5mL tetrahydrofurans, system temperature is down to 0 DEG C, and 2.0 equivalents are sequentially added to system The tert-butyl group sulfonic acid chloride of triethylamine and 1.05 equivalents, continues to keep 0 DEG C of reaction 12h, adds water quenching to go out reaction, liquid separation, water is mutually used 20mL ethyl acetate extracts 2 times, merges organic phase, and organic phase is washed 2 times with 50mL, and 50mL saturation NaCl aqueous solutions wash 1 time, nothing Water Na2SO4Dry, filtering, is spin-dried for solvent, target product 51 is obtained through column chromatography for separation.
For the synthetic method of compound 52：
Be separately added into the round-bottomed flask of 25mL compound 21 0.5mmol, methanol 5mL and concentrated hydrochloric acid aqueous solution (36%, 1mL).After system stirs reaction 24h at 20 DEG C, solvent is removed with Rotary Evaporators.Remaining residue 10mL dichloromethane Dissolving, adds triethylamine (15mmol).At room temperature after stirring reaction 1h, 10mL water is added, extracts organic phase solution, and with water (2 × 10mL) washing.Filtered after organic phase is dried with anhydrous sodium sulfate, remove solvent on a rotary evaporator and obtain crude product. Column chromatography for separation is then passed through, purification obtains pure deprotection compound.
It will obtain compound to be dissolved in 5mL tetrahydrofurans, system temperature is down to 0 DEG C, and 2.0 equivalents are sequentially added to system The tert-butyl group sulfonic acid chloride of triethylamine and 1.05 equivalents, continues to keep 0 DEG C of reaction 12h, adds water quenching to go out reaction, liquid separation, water is mutually used 20mL ethyl acetate extracts 2 times, merges organic phase, and organic phase is washed 2 times with 50mL, and 50mL saturation NaCl aqueous solutions wash 1 time, nothing Water Na2SO4Dry, filtering, is spin-dried for solvent, target product 52 is obtained through column chromatography for separation.
For the synthetic method of compound 53：
Be separately added into the round-bottomed flask of 25mL compound 16 0.5mmol, methanol 5mL and concentrated hydrochloric acid aqueous solution (36%, 1mL).After system stirs reaction 24h at 20 DEG C, solvent is removed with Rotary Evaporators.Remaining residue 10mL dichloromethane Dissolving, adds triethylamine (15mmol).At room temperature after stirring reaction 1h, 10mL water is added, extracts organic phase solution, and with water (2 × 10mL) washing.Filtered after organic phase is dried with anhydrous sodium sulfate, remove solvent on a rotary evaporator and obtain crude product. Column chromatography for separation is then passed through, purification obtains pure deprotection compound.
It will obtain compound to be dissolved in 5mL tetrahydrofurans, system temperature is down to 0 DEG C, and 2.0 equivalents are sequentially added to system The chloroacetic chloride of triethylamine and 1.05 equivalents, continues to keep 0 DEG C of reaction 12h, adds water quenching to go out reaction, liquid separation, water mutually uses 20mL acetic acid Ethyl ester extracts 2 times, merges organic phase, and organic phase is washed 2 times with 50mL, and 50mL saturation NaCl aqueous solutions wash 1 time, anhydrous Na2SO4 Dry, filtering, is spin-dried for solvent, target product 53 is obtained through column chromatography for separation.
For the synthetic method of compound 54：
Be separately added into the round-bottomed flask of 25mL compound 21 0.5mmol, methanol 5mL and concentrated hydrochloric acid aqueous solution (36%, 1mL).After system stirs reaction 24h at 20 DEG C, solvent is removed with Rotary Evaporators.Remaining residue 10mL dichloromethane Dissolving, adds triethylamine (15mmol).At room temperature after stirring reaction 1h, 10mL water is added, extracts organic phase solution, and with water (2 × 10mL) washing.Filtered after organic phase is dried with anhydrous sodium sulfate, remove solvent on a rotary evaporator and obtain crude product. Column chromatography for separation is then passed through, purification obtains pure deprotection compound.
It will obtain compound to be dissolved in 5mL tetrahydrofurans, system temperature is down to 0 DEG C, and 2.0 equivalents are sequentially added to system The chloroacetic chloride of triethylamine and 1.05 equivalents, continues to keep 0 DEG C of reaction 12h, adds water quenching to go out reaction, liquid separation, water mutually uses 20mL acetic acid Ethyl ester extracts 2 times, merges organic phase, and organic phase is washed 2 times with 50mL, and 50mL saturation NaCl aqueous solutions wash 1 time, anhydrous Na2SO4 Dry, filtering, is spin-dried for solvent, target product 54 is obtained through column chromatography for separation.
For the synthetic method of compound 55：
Be separately added into the round-bottomed flask of 25mL compound 16 0.5mmol, methanol 5mL and concentrated hydrochloric acid aqueous solution (36%, 1mL).After system stirs reaction 24h at 20 DEG C, solvent is removed with Rotary Evaporators.Remaining residue 10mL dichloromethane Dissolving, adds triethylamine (15mmol).At room temperature after stirring reaction 1h, 10mL water is added, extracts organic phase solution, and with water (2 × 10mL) washing.Filtered after organic phase is dried with anhydrous sodium sulfate, remove solvent on a rotary evaporator and obtain crude product. Column chromatography for separation is then passed through, purification obtains pure deprotection compound.
It will obtain compound to be dissolved in 5mL tetrahydrofurans, system temperature is down to 0 DEG C, and 2.0 equivalents are sequentially added to system The chlorobenzoyl chloride of triethylamine and 1.05 equivalents, continues to keep 0 DEG C of reaction 12h, adds water quenching to go out reaction, liquid separation, water mutually uses 20mL second Acetoacetic ester extracts 2 times, merges organic phase, and organic phase is washed 2 times with 50mL, and 50mL saturation NaCl aqueous solutions are washed 1 time, anhydrous Na2SO4Dry, filtering, is spin-dried for solvent, target product 55 is obtained through column chromatography for separation.
For the synthetic method of compound 56：
Be separately added into the round-bottomed flask of 25mL compound 21 0.5mmol, methanol 5mL and concentrated hydrochloric acid aqueous solution (36%, 1mL).After system stirs reaction 24h at 20 DEG C, solvent is removed with Rotary Evaporators.Remaining residue 10mL dichloromethane Dissolving, adds triethylamine (15mmol).At room temperature after stirring reaction 1h, 10mL water is added, extracts organic phase solution, and with water (2 × 10mL) washing.Filtered after organic phase is dried with anhydrous sodium sulfate, remove solvent on a rotary evaporator and obtain crude product. Column chromatography for separation is then passed through, purification obtains pure deprotection compound.
It will obtain compound to be dissolved in 5mL tetrahydrofurans, system temperature is down to 0 DEG C, and 2.0 equivalents are sequentially added to system The chlorobenzoyl chloride of triethylamine and 1.05 equivalents, continues to keep 0 DEG C of reaction 12h, adds water quenching to go out reaction, liquid separation, water mutually uses 20mL second Acetoacetic ester extracts 2 times, merges organic phase, and organic phase is washed 2 times with 50mL, and 50mL saturation NaCl aqueous solutions are washed 1 time, anhydrous Na2SO4Dry, filtering, is spin-dried for solvent, target product 56 is obtained through column chromatography for separation.
For the synthetic method of compound 57：
It will obtain compound 16 to be dissolved in 5mL tetrahydrofurans, system temperature is down to 0 DEG C, and 2.0 equivalents are sequentially added to system Sodium hydride and 1.1 equivalents iodomethane, continue to keep 0 DEG C of reaction 2h, add water quenching to go out reaction, liquid separation, water mutually uses 20mL acetic acid Ethyl ester extracts 2 times, merges organic phase, and organic phase is washed 2 times with 50mL, and 50mL saturation NaCl aqueous solutions wash 1 time, anhydrous Na2SO4 Dry, filtering, is spin-dried for solvent, target product 57 is obtained through column chromatography for separation.
For the synthetic method of compound 58：
It will obtain compound 21 to be dissolved in 5mL tetrahydrofurans, system temperature is down to 0 DEG C, and 2.0 equivalents are sequentially added to system Sodium hydride and 1.1 equivalents iodomethane, continue to keep 0 DEG C of reaction 2h, add water quenching to go out reaction, liquid separation, water mutually uses 20mL acetic acid Ethyl ester extracts 2 times, merges organic phase, and organic phase is washed 2 times with 50mL, and 50mL saturation NaCl aqueous solutions wash 1 time, anhydrous Na2SO4 Dry, filtering, is spin-dried for solvent, target product 58 is obtained through column chromatography for separation.
For the synthetic method of compound 59：
It will obtain compound 16 to be dissolved in 5mL tetrahydrofurans, system temperature is down to 0 DEG C, and 2.0 equivalents are sequentially added to system Sodium hydride and 1.1 equivalents benzyl bromine, continue to keep 0 DEG C of reaction 2h, add water quenching to go out reaction, liquid separation, water mutually uses 20mL acetic acid second Ester extracts 2 times, merges organic phase, and organic phase is washed 2 times with 50mL, and 50mL saturation NaCl aqueous solutions wash 1 time, anhydrous Na2SO4It is dry Dry, filtering, is spin-dried for solvent, target product 59 is obtained through column chromatography for separation.
For the synthetic method of compound 60：
It will obtain compound 21 to be dissolved in 5mL tetrahydrofurans, system temperature is down to 0 DEG C, and 2.0 equivalents are sequentially added to system Sodium hydride and 1.1 equivalents benzyl bromine, continue to keep 0 DEG C of reaction 2h, add water quenching to go out reaction, liquid separation, water mutually uses 20mL acetic acid second Ester extracts 2 times, merges organic phase, and organic phase is washed 2 times with 50mL, and 50mL saturation NaCl aqueous solutions wash 1 time, anhydrous Na2SO4It is dry Dry, filtering, is spin-dried for solvent, target product 60 is obtained through column chromatography for separation.
Unless otherwise indicated, the following term being used in claims and specification has following implication：
" pharmaceutically acceptable salt " " pharmaceutically acceptable salt " is that the compound comprising formula (1) is formed with acid reaction Salt, represents to retain the biological effectiveness of parent compound and those salt of property, this kind of salt includes：Inorganic acid salt, as hydrochloride, Hydrobromate or sulfate；Acylate, such as acetate, lactate, succinate, fumaric acid eye, maleate, citric acid Salt, benzoate, mesylate or paratolunitrile salt etc..
" Pharmaceutical composition " refers to one or more compound described here or theirs is pharmaceutically acceptable Salt and prodrug and other chemical compositions, such as the mixture of pharmaceutically acceptable carrier and excipient, pharmaceutical composition Purpose is to promote the administration of compound on organism body.
" solvate " is the compound or its salt for meeting general formula (1) feature of the present invention, it is further included containing non-covalent The stoichiometric amount or the solvent of non stoichiometric amounts that molecular separating force combines.When the solvent is water, the solvate is Hydrate.
" hydrate " refers to that the compound for meeting general formula (1) feature of the present invention is consolidated with what is formed in water interaction process State crystalline material.
The compound of the present invention has new structure, can be applied to prevention and/or tumor or other and tumour The medicine of relevant disease.
Embodiment
The present invention is described in further details with specific embodiment below, but the present invention is not limited to specific following implementation Example.
The synthesis of 1 series compound of embodiment
The structural information of the application compound 1-60# is as follows：
1#:R1=C6H5；R2=t-Bu-S (O)；R3=H；X1=H；X2=F；
2#:R1=4-F-C6H4；R2=t-Bu-S (O)；R3=H；X1=H；X2=F；
3#:R1=4-Cl-C6H4；R2=t-Bu-S (O)；R3=H；X1=H；X2=F；
4#:R1=4-Br-C6H4；R2=t-Bu-S (O)；R3=H；X1=H；X2=F；
5#:R1=4-Me-C6H4；R2=t-Bu-S (O)；R3=H；X1=H；X2=F；
6#:R1=4-MeO-C6H4；R2=t-Bu-S (O)；R3=H；X1=H；X2=F；
7#:R1=2-Cl-C6H4；R2=t-Bu-S (O)；R3=H；X1=H；X2=F；
8#:R1=2-Br-C6H4；R2=t-Bu-S (O)；R3=H；X1=H；X2=F；
9#:R1=2-Me-C6H4；R2=t-Bu-S (O)；R3=H；X1=H；X2=F；
10#:R1=3-Cl-C6H4；R2=t-Bu-S (O)；R3=H；X1=H；X2=F；
11#:R1=3-Br-C6H4；R2=t-Bu-S (O)；R3=H；X1=H；X2=F；
12#:R1=3-MeO-C6H4；R2=t-Bu-S (O)；R3=H；X1=H；X2=F；
13#:R1=2-Naphthyl；R2=t-Bu-S (O)；R3=H；X1=H；X2=F；
14#:R1=2-Thienyl；R2=t-Bu-S (O)；R3=H；X1=H；X2=F；
15#:R1=t-Bu；R2=t-Bu-S (O)；R3=H；X1=H；X2=F；
16#:R1=C6H5；R2=t-Bu-S (O)；R3=H；X1=F；X2=F；
17#:R1=4-F-C6H4；R2=t-Bu-S (O)；R3=H；X1=F；X2=F；
18#:R1=4-Cl-C6H4；R2=t-Bu-S (O)；R3=H；X1=F；X2=F；
19#:R1=4-Br-C6H4；R2=t-Bu-S (O)；R3=H；X1=F；X2=F；
20#:R1=4-Me-C6H4；R2=t-Bu-S (O)；R3=H；X1=F；X2=F；
21#：R1=4-MeO-C6H4；R2=t-Bu-S (O)；R3=H；X1=F；X2=F；
22#:R1=2-Cl-C6H4；R2=t-Bu-S (O)；R3=H；X1=F；X2=F；
23#:R1=2-Br-C6H4；R2=t-Bu-S (O)；R3=H；X1=F；X2=F；
24#:R1=2-Me-C6H4；R2=t-Bu-S (O)；R3=H；X1=F；X2=F；
25#:R1=3-Cl-C6H4；R2=t-Bu-S (O)；R3=H；X1=F；X2=F；
26#:R1=3-Br-C6H4；R2=t-Bu-S (O)；R3=H；X1=F；X2=F；
27#:R1=3-MeO-C6H4；R2=t-Bu-S (O)；R3=H；X1=F；X2=F；
28#:R1=2-Naphthyl；R2=t-Bu-S (O)；R3=H；X1=F；X2=F；
29#:R1=2-Thienyl；R2=t-Bu-S (O)；R3=H；X1=F；X2=F；
30#:R1=t-Bu；R2=t-Bu-S (O)；R3=H；X1=F；X2=F；
31#:R1=C6H5；R2=t-Bu-S (O)；R3=H；X1=Cl；X2=F；
32#:R1=4-F-C6H4；R2=t-Bu-S (O)；R3=H；X1=Cl；X2=F；
33#:R1=4-Cl-C6H4；R2=t-Bu-S (O)；R3=H；X1=Cl；X2=F；
34#:R1=4-Me-C6H4；R2=t-Bu-S (O)；R3=H；X1=Cl；X2=F；
35#:R1=4-MeO-C6H4；R2=t-Bu-S (O)；R3=H；X1=Cl；X2=F；
36#:R1=2-Cl-C6H4；R2=t-Bu-S (O)；R3=H；X1=Cl；X2=F；
37#:R1=3-Cl-C6H4；R2=t-Bu-S (O)；R3=H；X1=Cl；X2=F；
38#:R1=3-MeO-C6H4；R2=t-Bu-S (O)；R3=H；X1=Cl；X2=F；
39#:R1=2-Thienyl；R2=t-Bu-S (O)；R3=H；X1=Cl；X2=F；
40#:R1=t-Bu；R2=t-Bu-S (O)；R3=H；X1=Cl；X2=F；
41#:R1=C6H5；R2=t-Bu-S (O)；R3=H；X1=Br；X2=F；
42#:R1=4-F-C6H4；R2=t-Bu-S (O)；R3=H；X1=Br；X2=F；
43#:R1=4-Cl-C6H4；R2=t-Bu-S (O)；R3=H；X1=Br；X2=F；
44#:R1=4-Me-C6H4；R2=t-Bu-S (O)；R3=H；X1=Br；X2=F；
45#:R1=4-MeO-C6H4；R2=t-Bu-S (O)；R3=H；X1=Br；X2=F；
46#:R1=2-Cl-C6H4；R2=t-Bu-S (O)；R3=H；X1=Br；X2=F；
47#:R1=3-Cl-C6H4；R2=t-Bu-S (O)；R3=H；X1=Br；X2=F；
48#:R1=3-MeO-C6H4；R2=t-Bu-S (O)；R3=H；X1=Br；X2=F；
49#:R1=2-Thienyl；R2=t-Bu-S (O)；R3=H；X1=Br；X2=F；
50#:R1=t-Bu；R2=t-Bu-S (O)；R3=H；X1=Br；X2=F；
51#:R1=C6H5；R2=t-Bu-S (O)2；R3=H；X1=F；X2=F；
52#:R1=4-MeO-C6H4；R2=t-Bu-S (O)2；R3=H；X1=F；X2=F；
53#:R1=C6H5；R2=Me-C (O)；R3=H；X1=F；X2=F；
54#:R1=4-MeO-C6H4；R2=Me-C (O)；R3=H；X1=F；X2=F；
55#:R1=C6H5；R2=C6H5-C(O)；R3=H；X1=F；X2=F；
56#:R1=4-MeO-C6H4；R2=C6H5-C(O)；R3=H；X1=F；X2=F；
57#:R1=C6H5；R2=t-Bu-S (O)；R3=Me；X1=F；X2=F；
58#:R1=4-MeO-C6H4；R2=t-Bu-S (O)；R3=Me；X1=F；X2=F；
59#:R1=C6H5；R2=t-Bu-S (O)；R3=Bn；X1=F；X2=F；
60#:R1=4-MeO-C6H4；R2=t-Bu-S (O)；R3=Bn；X1=F；X2=F.
1st, the synthesis of compound 1-50#
For the synthetic method of compound 1-50：
At 0 DEG C, 0.5mmol together with glycol compound 1, the imines 2 and 1.5mmol of 0.6mmol (1.2equiv) The LiBr of (130.3mg, 3.0equiv) is dissolved in the THF of 5mL, and the Et of 1.0mmol is slowly added dropwise to reaction system3N (101.2mg, 2.0equiv).Continue after reacting 0.5h at 0 DEG C, it is water-soluble to add 5mL saturated ammonium chlorides successively to reaction system Liquid and 20mL water quenchings are gone out reaction.Liquid separation, water are mutually extracted 2 times with 20mL ethyl acetate, merge organic phase, and organic phase is washed with 50mL 2 times, 50mL saturation NaCl aqueous solutions wash 1 time, anhydrous Na2SO4Dry, filtering, is spin-dried for solvent, target is obtained through column chromatography for separation Product.
2nd, the synthesis of compound 51-60#
The synthesis of compound 51#
For the synthetic method of compound 51：
Be separately added into the round-bottomed flask of 25mL compound 16 0.5mmol, methanol 5mL and concentrated hydrochloric acid aqueous solution (36%, 1mL).After system stirs reaction 24h at 20 DEG C, solvent is removed with Rotary Evaporators.Remaining residue 10mL dichloromethane Dissolving, adds triethylamine (15mmol).At room temperature after stirring reaction 1h, 10mL water is added, extracts organic phase solution, and with water (2 × 10mL) washing.Filtered after organic phase is dried with anhydrous sodium sulfate, remove solvent on a rotary evaporator and obtain crude product. Column chromatography for separation is then passed through, purification obtains pure deprotection compound.
It will obtain compound to be dissolved in 5mL tetrahydrofurans, system temperature is down to 0 DEG C, and 2.0 equivalents are sequentially added to system The tert-butyl group sulfonic acid chloride of triethylamine and 1.05 equivalents, continues to keep 0 DEG C of reaction 12h, adds water quenching to go out reaction, liquid separation, water is mutually used 20mL ethyl acetate extracts 2 times, merges organic phase, and organic phase is washed 2 times with 50mL, and 50mL saturation NaCl aqueous solutions wash 1 time, nothing Water Na2SO4Dry, filtering, is spin-dried for solvent, target product 51 is obtained through column chromatography for separation.
The synthesis of compound 52#
For the synthetic method of compound 52：
Be separately added into the round-bottomed flask of 25mL compound 21 0.5mmol, methanol 5mL and concentrated hydrochloric acid aqueous solution (36%, 1mL).After system stirs reaction 24h at 20 DEG C, solvent is removed with Rotary Evaporators.Remaining residue 10mL dichloromethane Dissolving, adds triethylamine (15mmol).At room temperature after stirring reaction 1h, 10mL water is added, extracts organic phase solution, and with water (2 × 10mL) washing.Filtered after organic phase is dried with anhydrous sodium sulfate, remove solvent on a rotary evaporator and obtain crude product. Column chromatography for separation is then passed through, purification obtains pure deprotection compound.
It will obtain compound to be dissolved in 5mL tetrahydrofurans, system temperature is down to 0 DEG C, and 2.0 equivalents are sequentially added to system The tert-butyl group sulfonic acid chloride of triethylamine and 1.05 equivalents, continues to keep 0 DEG C of reaction 12h, adds water quenching to go out reaction, liquid separation, water is mutually used 20mL ethyl acetate extracts 2 times, merges organic phase, and organic phase is washed 2 times with 50mL, and 50mL saturation NaCl aqueous solutions wash 1 time, nothing Water Na2SO4Dry, filtering, is spin-dried for solvent, target product 52 is obtained through column chromatography for separation.
The synthesis of compound 53#
For the synthetic method of compound 53：
Be separately added into the round-bottomed flask of 25mL compound 16 0.5mmol, methanol 5mL and concentrated hydrochloric acid aqueous solution (36%, 1mL).After system stirs reaction 24h at 20 DEG C, solvent is removed with Rotary Evaporators.Remaining residue 10mL dichloromethane Dissolving, adds triethylamine (15mmol).At room temperature after stirring reaction 1h, 10mL water is added, extracts organic phase solution, and with water (2 × 10mL) washing.Filtered after organic phase is dried with anhydrous sodium sulfate, remove solvent on a rotary evaporator and obtain crude product. Column chromatography for separation is then passed through, purification obtains pure deprotection compound.
It will obtain compound to be dissolved in 5mL tetrahydrofurans, system temperature is down to 0 DEG C, and 2.0 equivalents are sequentially added to system The chloroacetic chloride of triethylamine and 1.05 equivalents, continues to keep 0 DEG C of reaction 12h, adds water quenching to go out reaction, liquid separation, water mutually uses 20mL acetic acid Ethyl ester extracts 2 times, merges organic phase, and organic phase is washed 2 times with 50mL, and 50mL saturation NaCl aqueous solutions wash 1 time, anhydrous Na2SO4 Dry, filtering, is spin-dried for solvent, target product 53 is obtained through column chromatography for separation.
The synthesis of compound 54#
For the synthetic method of compound 54：
Be separately added into the round-bottomed flask of 25mL compound 21 0.5mmol, methanol 5mL and concentrated hydrochloric acid aqueous solution (36%, 1mL).After system stirs reaction 24h at 20 DEG C, solvent is removed with Rotary Evaporators.Remaining residue 10mL dichloromethane Dissolving, adds triethylamine (15mmol).At room temperature after stirring reaction 1h, 10mL water is added, extracts organic phase solution, and with water (2 × 10mL) washing.Filtered after organic phase is dried with anhydrous sodium sulfate, remove solvent on a rotary evaporator and obtain crude product. Column chromatography for separation is then passed through, purification obtains pure deprotection compound.
It will obtain compound to be dissolved in 5mL tetrahydrofurans, system temperature is down to 0 DEG C, and 2.0 equivalents are sequentially added to system The chloroacetic chloride of triethylamine and 1.05 equivalents, continues to keep 0 DEG C of reaction 12h, adds water quenching to go out reaction, liquid separation, water mutually uses 20mL acetic acid Ethyl ester extracts 2 times, merges organic phase, and organic phase is washed 2 times with 50mL, and 50mL saturation NaCl aqueous solutions wash 1 time, anhydrous Na2SO4 Dry, filtering, is spin-dried for solvent, target product 54 is obtained through column chromatography for separation.
The synthesis of compound 55#
For the synthetic method of compound 55：
Be separately added into the round-bottomed flask of 25mL compound 16 0.5mmol, methanol 5mL and concentrated hydrochloric acid aqueous solution (36%, 1mL).After system stirs reaction 24h at 20 DEG C, solvent is removed with Rotary Evaporators.Remaining residue 10mL dichloromethane Dissolving, adds triethylamine (15mmol).At room temperature after stirring reaction 1h, 10mL water is added, extracts organic phase solution, and with water (2 × 10mL) washing.Filtered after organic phase is dried with anhydrous sodium sulfate, remove solvent on a rotary evaporator and obtain crude product. Column chromatography for separation is then passed through, purification obtains pure deprotection compound.
It will obtain compound to be dissolved in 5mL tetrahydrofurans, system temperature is down to 0 DEG C, and 2.0 equivalents are sequentially added to system The chlorobenzoyl chloride of triethylamine and 1.05 equivalents, continues to keep 0 DEG C of reaction 12h, adds water quenching to go out reaction, liquid separation, water mutually uses 20mL second Acetoacetic ester extracts 2 times, merges organic phase, and organic phase is washed 2 times with 50mL, and 50mL saturation NaCl aqueous solutions are washed 1 time, anhydrous Na2SO4Dry, filtering, is spin-dried for solvent, target product 55 is obtained through column chromatography for separation.
The synthesis of compound 56#
For the synthetic method of compound 56：
Be separately added into the round-bottomed flask of 25mL compound 21 0.5mmol, methanol 5mL and concentrated hydrochloric acid aqueous solution (36%, 1mL).After system stirs reaction 24h at 20 DEG C, solvent is removed with Rotary Evaporators.Remaining residue 10mL dichloromethane Dissolving, adds triethylamine (15mmol).At room temperature after stirring reaction 1h, 10mL water is added, extracts organic phase solution, and with water (2 × 10mL) washing.Filtered after organic phase is dried with anhydrous sodium sulfate, remove solvent on a rotary evaporator and obtain crude product. Column chromatography for separation is then passed through, purification obtains pure deprotection compound.
It will obtain compound to be dissolved in 5mL tetrahydrofurans, system temperature is down to 0 DEG C, and 2.0 equivalents are sequentially added to system The chlorobenzoyl chloride of triethylamine and 1.05 equivalents, continues to keep 0 DEG C of reaction 12h, adds water quenching to go out reaction, liquid separation, water mutually uses 20mL second Acetoacetic ester extracts 2 times, merges organic phase, and organic phase is washed 2 times with 50mL, and 50mL saturation NaCl aqueous solutions are washed 1 time, anhydrous Na2SO4Dry, filtering, is spin-dried for solvent, target product 56 is obtained through column chromatography for separation.
The synthesis of compound 57#
For the synthetic method of compound 57：
It will obtain compound 16 to be dissolved in 5mL tetrahydrofurans, system temperature is down to 0 DEG C, and 2.0 equivalents are sequentially added to system Sodium hydride and 1.1 equivalents iodomethane, continue to keep 0 DEG C of reaction 2h, add water quenching to go out reaction, liquid separation, water mutually uses 20mL acetic acid Ethyl ester extracts 2 times, merges organic phase, and organic phase is washed 2 times with 50mL, and 50mL saturation NaCl aqueous solutions wash 1 time, anhydrous Na2SO4 Dry, filtering, is spin-dried for solvent, target product 57 is obtained through column chromatography for separation.
The synthesis of compound 58#
For the synthetic method of compound 58：
It will obtain compound 21 to be dissolved in 5mL tetrahydrofurans, system temperature is down to 0 DEG C, and 2.0 equivalents are sequentially added to system Sodium hydride and 1.1 equivalents iodomethane, continue to keep 0 DEG C of reaction 2h, add water quenching to go out reaction, liquid separation, water mutually uses 20mL acetic acid Ethyl ester extracts 2 times, merges organic phase, and organic phase is washed 2 times with 50mL, and 50mL saturation NaCl aqueous solutions wash 1 time, anhydrous Na2SO4 Dry, filtering, is spin-dried for solvent, target product 58 is obtained through column chromatography for separation.
The synthesis of compound 59#
For the synthetic method of compound 59：
It will obtain compound 16 to be dissolved in 5mL tetrahydrofurans, system temperature is down to 0 DEG C, and 2.0 equivalents are sequentially added to system Sodium hydride and 1.1 equivalents benzyl bromine, continue to keep 0 DEG C of reaction 2h, add water quenching to go out reaction, liquid separation, water mutually uses 20mL acetic acid second Ester extracts 2 times, merges organic phase, and organic phase is washed 2 times with 50mL, and 50mL saturation NaCl aqueous solutions wash 1 time, anhydrous Na2SO4It is dry Dry, filtering, is spin-dried for solvent, target product 59 is obtained through column chromatography for separation.
The synthesis of compound 60#
For the synthetic method of compound 60：
It will obtain compound 21 to be dissolved in 5mL tetrahydrofurans, system temperature is down to 0 DEG C, and 2.0 equivalents are sequentially added to system Sodium hydride and 1.1 equivalents benzyl bromine, continue to keep 0 DEG C of reaction 2h, add water quenching to go out reaction, liquid separation, water mutually uses 20mL acetic acid second Ester extracts 2 times, merges organic phase, and organic phase is washed 2 times with 50mL, and 50mL saturation NaCl aqueous solutions wash 1 time, anhydrous Na2SO4It is dry Dry, filtering, is spin-dried for solvent, target product 60 is obtained through column chromatography for separation.
2 series compound immunostimulation of embodiment and the detection of enhancing activity
1st, influence of the compound to mouse macrophage secretion proinflammatory factor (TNF-α and IL-12) and nitric oxide (NO).
1) experiment material：Mouse macrophage strain ANA-1 is purchased from Chinese Academy of Sciences's cell bank, in 37 DEG C, 5%CO2Under the conditions of often Rule culture, culture medium is the PRMI-1640 (Gibco) containing 10% hyclone (FBS)；Hyclone is purchased from Hyclone companies； LPS(Escherichia coli0111:B4), penicillin, streptomysin are purchased from Nanjing Sheng Xing bio-engineering corporations (Jiangsu, south Capital)；Mouse source TNF-α and IL-12 are purchased from four Zheng Bai bio tech ltd of Beijing；Nitric oxide (NO) detection kit is purchased from The green skies Bioisystech Co., Ltd in Shanghai；Chemical combination object is dissolved in dimethyl sulfoxide (DMSO) and is configured to 1000 × test liquid storage (50 μ g/μl)。
2) experimental procedure
ANA-1 cells are collected first, and then 1000rpm is centrifuged for 5 minutes, is washed once, is resuspended to small containing 10% with PBS In the 1640 culture medium of cow's serum, single cell suspension is gently blown and beaten into glass dropper, is remembered under microscope with blood cell counts plate Number living cells.(cell concentration is adjusted to 1x 10 to every 500 microlitres of the hole inoculating cell suspension of 12 well culture plates6A/ml), at 37 degree 100% relative humidity, containing 5%CO2Packet transaction, such as table 1 below after the incubator culture 24h of air：
1 experiment packet of table and processing
Concrete outcome is shown in Table 2, table 3 and table 4, as knowen from these results：Compound can improve macrophages secrete TNF-α With the ability of IL-12, and promote nitric oxide (NO) release, these the result shows that：Compound can improve macrophage Killing ability, strengthen its anti-infection ability.
2 Compound ira vitro stimulating expression of macrophage TNF-α of table generates
3 Compound ira vitro stimulating expression of macrophage IL-12 of table is generated
The NO generations of 4 Compound ira vitro stimulating expression of macrophage of table
2nd, influence of the compound to mouse immunity
1) experiment material：SPF grades of ICR mouse are purchased from Yangzhou University's animal experimental center.Mouse source TNF-α and IFN-γ are purchased from Four Zheng Bai bio tech ltd of Beijing；Chemical combination object is dissolved in dimethyl sulfoxide (DMSO) and is configured to 1000 × test liquid storage (20 μ g/μl)。
2) experimental procedure：
(1) weight is that the SPF level ICR mouse of 18-20g are randomly divided into DMSO groups and 1-60# compound groups, every group 10 small Mouse.
(2) 1-60# compounds are administered respectively according to the dosage of 20mg/kg by the way of intraperitoneal injection, every two days one It is secondary, mouse successive administration 8 days.
(3) after being administered 4 times, after last dose 48h, eyeball takes blood, and blood stands 30 minutes at room temperature, 1000 × g centrifugations 10 minutes, then careful separation serum, and being transferred in 1.5ml Ep pipes.
(4) content of TNF-α and IFN-γ in ELISA experimental analyses serum (according to the method for ELISA detection kit). Concrete outcome is shown in Table 5 and table 6.As knowen from these results：Compound can improve the ability of body secretes TNF-α and IFN-γ. These the result shows that：Compound can improve the immunocompetence of body.
The influence that 5 compound of table produces TNF-α in mice serum
The influence that 6 compound of table produces IFN-γ in mice serum

Claims (10)

1. stimulation and enhancing protective immunological reaction compound or its pharmaceutically acceptable salt or its solvate, its structure are led to Formula is：
2. it is as claimed in claim 1 stimulate and enhancing protective immunological reaction compound or its pharmaceutically acceptable salt or its Solvate, substitutes in its general structure any one of in form such as following 1#-60# compounds：
1#:R1=C6H5；R2=t-Bu-S (O)；R3=H；X1=H；X2=F；
2#:R1=4-F-C6H4；R2=t-Bu-S (O)；R3=H；X1=H；X2=F；
3#:R1=4-Cl-C6H4；R2=t-Bu-S (O)；R3=H；X1=H；X2=F；
4#:R1=4-Br-C6H4；R2=t-Bu-S (O)；R3=H；X1=H；X2=F；
5#:R1=4-Me-C6H4；R2=t-Bu-S (O)；R3=H；X1=H；X2=F；
6#:R1=4-MeO-C6H4；R2=t-Bu-S (O)；R3=H；X1=H；X2=F；
7#:R1=2-Cl-C6H4；R2=t-Bu-S (O)；R3=H；X1=H；X2=F；
8#:R1=2-Br-C6H4；R2=t-Bu-S (O)；R3=H；X1=H；X2=F；
9#:R1=2-Me-C6H4；R2=t-Bu-S (O)；R3=H；X1=H；X2=F；
10#:R1=3-Cl-C6H4；R2=t-Bu-S (O)；R3=H；X1=H；X2=F；
11#:R1=3-Br-C6H4；R2=t-Bu-S (O)；R3=H；X1=H；X2=F；
12#:R1=3-MeO-C6H4；R2=t-Bu-S (O)；R3=H；X1=H；X2=F；
13#:R1=2-Naphthyl；R2=t-Bu-S (O)；R3=H；X1=H；X2=F；
14#:R1=2-Thienyl；R2=t-Bu-S (O)；R3=H；X1=H；X2=F；
15#:R1=t-Bu；R2=t-Bu-S (O)；R3=H；X1=H；X2=F；
16#:R1=C6H5；R2=t-Bu-S (O)；R3=H；X1=F；X2=F；
17#:R1=4-F-C6H4；R2=t-Bu-S (O)；R3=H；X1=F；X2=F；
18#:R1=4-Cl-C6H4；R2=t-Bu-S (O)；R3=H；X1=F；X2=F；
19#:R1=4-Br-C6H4；R2=t-Bu-S (O)；R3=H；X1=F；X2=F；
20#:R1=4-Me-C6H4；R2=t-Bu-S (O)；R3=H；X1=F；X2=F；
21#：R1=4-MeO-C6H4；R2=t-Bu-S (O)；R3=H；X1=F；X2=F；
22#:R1=2-Cl-C6H4；R2=t-Bu-S (O)；R3=H；X1=F；X2=F；
23#:R1=2-Br-C6H4；R2=t-Bu-S (O)；R3=H；X1=F；X2=F；
24#:R1=2-Me-C6H4；R2=t-Bu-S (O)；R3=H；X1=F；X2=F；
25#:R1=3-Cl-C6H4；R2=t-Bu-S (O)；R3=H；X1=F；X2=F；
26#:R1=3-Br-C6H4；R2=t-Bu-S (O)；R3=H；X1=F；X2=F；
27#:R1=3-MeO-C6H4；R2=t-Bu-S (O)；R3=H；X1=F；X2=F；
28#:R1=2-Naphthyl；R2=t-Bu-S (O)；R3=H；X1=F；X2=F；
29#:R1=2-Thienyl；R2=t-Bu-S (O)；R3=H；X1=F；X2=F；
30#:R1=t-Bu；R2=t-Bu-S (O)；R3=H；X1=F；X2=F；
31#:R1=C6H5；R2=t-Bu-S (O)；R3=H；X1=Cl；X2=F；
32#:R1=4-F-C6H4；R2=t-Bu-S (O)；R3=H；X1=Cl；X2=F；
33#:R1=4-Cl-C6H4；R2=t-Bu-S (O)；R3=H；X1=Cl；X2=F；
34#:R1=4-Me-C6H4；R2=t-Bu-S (O)；R3=H；X1=Cl；X2=F；
35#:R1=4-MeO-C6H4；R2=t-Bu-S (O)；R3=H；X1=Cl；X2=F；
36#:R1=2-Cl-C6H4；R2=t-Bu-S (O)；R3=H；X1=Cl；X2=F；
37#:R1=3-Cl-C6H4；R2=t-Bu-S (O)；R3=H；X1=Cl；X2=F；
38#:R1=3-MeO-C6H4；R2=t-Bu-S (O)；R3=H；X1=Cl；X2=F；
39#:R1=2-Thienyl；R2=t-Bu-S (O)；R3=H；X1=Cl；X2=F；
40#:R1=t-Bu；R2=t-Bu-S (O)；R3=H；X1=Cl；X2=F；
41#:R1=C6H5；R2=t-Bu-S (O)；R3=H；X1=Br；X2=F；
42#:R1=4-F-C6H4；R2=t-Bu-S (O)；R3=H；X1=Br；X2=F；
43#:R1=4-Cl-C6H4；R2=t-Bu-S (O)；R3=H；X1=Br；X2=F；
44#:R1=4-Me-C6H4；R2=t-Bu-S (O)；R3=H；X1=Br；X2=F；
45#:R1=4-MeO-C6H4；R2=t-Bu-S (O)；R3=H；X1=Br；X2=F；
46#:R1=2-Cl-C6H4；R2=t-Bu-S (O)；R3=H；X1=Br；X2=F；
47#:R1=3-Cl-C6H4；R2=t-Bu-S (O)；R3=H；X1=Br；X2=F；
48#:R1=3-MeO-C6H4；R2=t-Bu-S (O)；R3=H；X1=Br；X2=F；
49#:R1=2-Thienyl；R2=t-Bu-S (O)；R3=H；X1=Br；X2=F；
50#:R1=t-Bu；R2=t-Bu-S (O)；R3=H；X1=Br；X2=F；
51#:R1=C6H5；R2=t-Bu-S (O)2；R3=H；X1=F；X2=F；
52#:R1=4-MeO-C6H4；R2=t-Bu-S (O)2；R3=H；X1=F；X2=F；
53#:R1=C6H5；R2=Me-C (O)；R3=H；X1=F；X2=F；
54#:R1=4-MeO-C6H4；R2=Me-C (O)；R3=H；X1=F；X2=F；
55#:R1=C6H5；R2=C6H5-C(O)；R3=H；X1=F；X2=F；
56#:R1=4-MeO-C6H4；R2=C6H5-C(O)；R3=H；X1=F；X2=F；
57#:R1=C6H5；R2=t-Bu-S (O)；R3=Me；X1=F；X2=F；
58#:R1=4-MeO-C6H4；R2=t-Bu-S (O)；R3=Me；X1=F；X2=F；
59#:R1=C6H5；R2=t-Bu-S (O)；R3=Bn；X1=F；X2=F；
60#:R1=4-MeO-C6H4；R2=t-Bu-S (O)；R3=Bn；X1=F；X2=F.
3. being used for the pharmaceutical composition for stimulating and strengthening protective immunological reaction, contain therapeutically effective amount in described pharmaceutical composition The stimulation of any one of claims 1 or 2 and enhancing protective immunological reaction compound or its pharmaceutically acceptable salt Or its solvate, and contain one or more pharmaceutically acceptable pharmaceutical adjuvants.
4. the pharmaceutical composition as claimed in claim 3 for being used to stimulating and strengthening protective immunological reaction, described pharmaceutically The salt of receiving refer to any one of claims requirement 1 or 2 stimulation and enhancing protective immunological reaction compound with The product of salt-forming reaction, including inorganic acid salt occur for acid, such as hydrochloride, hydrobromate or sulfate；Acylate, such as acetic acid Salt, lactate, succinate, fumaric acid eye, maleate, citrate, benzoate, mesylate or paratolunitrile salt Deng.
5. the preparation method of the stimulation and enhancing protective immunological reaction compound described in claim 2,
Method is as follows：
1st, the preparation of compound 1-50#
For the preparation method of compound 1-50：
At 0 DEG C, 0.5mmol together with glycol compound 1, the imines 2 and 1.5mmol of 0.6mmol (1.2equiv) The LiBr of (130.3mg, 3.0equiv) is dissolved in the THF of 5mL, and the Et of 1.0mmol is slowly added dropwise to reaction system3N (101.2mg, 2.0equiv)；Continue after reacting 0.5h at 0 DEG C, it is water-soluble to add 5mL saturated ammonium chlorides successively to reaction system Liquid and 20mL water quenchings are gone out reaction；Liquid separation, water are mutually extracted 2 times with 20mL ethyl acetate, merge organic phase, and organic phase is washed with 50mL 2 times, 50mL saturation NaCl aqueous solutions wash 1 time, anhydrous Na2SO4Dry, filtering, is spin-dried for solvent, target is obtained through column chromatography for separation Product；
2nd, the preparation of compound 51-60#
The preparation of compound 51#
For the preparation method of compound 51：
Compound 16 0.5mmol, methanol 5mL and concentrated hydrochloric acid aqueous solution (36%, 1mL) are separately added into the round-bottomed flask of 25mL； After system stirs reaction 24h at 20 DEG C, solvent is removed with Rotary Evaporators；Remaining residue 10mL dichloromethane dissolves, Add triethylamine (15mmol)；At room temperature stirring reaction 1h after, add 10mL water, extract organic phase solution, and with water (2 × 10mL) wash；Filtered after organic phase is dried with anhydrous sodium sulfate, remove solvent on a rotary evaporator and obtain crude product；Connect And pass through column chromatography for separation, purification obtains pure deprotection compound；
It will obtain compound to be dissolved in 5mL tetrahydrofurans, system temperature is down to 0 DEG C, and three second of 2.0 equivalents are sequentially added to system The tert-butyl group sulfonic acid chloride of amine and 1.05 equivalents, continues to keep 0 DEG C of reaction 12h, adds water quenching to go out reaction, liquid separation, water mutually uses 20mL second Acetoacetic ester extracts 2 times, merges organic phase, and organic phase is washed 2 times with 50mL, and 50mL saturation NaCl aqueous solutions are washed 1 time, anhydrous Na2SO4Dry, filtering, is spin-dried for solvent, target product 51 is obtained through column chromatography for separation；
The preparation of compound 52#
For the preparation method of compound 52：
Compound 21 0.5mmol, methanol 5mL and concentrated hydrochloric acid aqueous solution (36%, 1mL) are separately added into the round-bottomed flask of 25mL； After system stirs reaction 24h at 20 DEG C, solvent is removed with Rotary Evaporators；Remaining residue 10mL dichloromethane dissolves, Add triethylamine (15mmol)；At room temperature stirring reaction 1h after, add 10mL water, extract organic phase solution, and with water (2 × 10mL) wash；Filtered after organic phase is dried with anhydrous sodium sulfate, remove solvent on a rotary evaporator and obtain crude product；Connect And pass through column chromatography for separation, purification obtains pure deprotection compound；
It will obtain compound to be dissolved in 5mL tetrahydrofurans, system temperature is down to 0 DEG C, and three second of 2.0 equivalents are sequentially added to system The tert-butyl group sulfonic acid chloride of amine and 1.05 equivalents, continues to keep 0 DEG C of reaction 12h, adds water quenching to go out reaction, liquid separation, water mutually uses 20mL second Acetoacetic ester extracts 2 times, merges organic phase, and organic phase is washed 2 times with 50mL, and 50mL saturation NaCl aqueous solutions are washed 1 time, anhydrous Na2SO4Dry, filtering, is spin-dried for solvent, target product 52 is obtained through column chromatography for separation；
The preparation of compound 53#
For the preparation method of compound 53：
Compound 16 0.5mmol, methanol 5mL and concentrated hydrochloric acid aqueous solution (36%, 1mL) are separately added into the round-bottomed flask of 25mL； After system stirs reaction 24h at 20 DEG C, solvent is removed with Rotary Evaporators；Remaining residue 10mL dichloromethane dissolves, Add triethylamine (15mmol)；At room temperature stirring reaction 1h after, add 10mL water, extract organic phase solution, and with water (2 × 10mL) wash；Filtered after organic phase is dried with anhydrous sodium sulfate, remove solvent on a rotary evaporator and obtain crude product；Connect And pass through column chromatography for separation, purification obtains pure deprotection compound；
It will obtain compound to be dissolved in 5mL tetrahydrofurans, system temperature is down to 0 DEG C, and three second of 2.0 equivalents are sequentially added to system The chloroacetic chloride of amine and 1.05 equivalents, continues to keep 0 DEG C of reaction 12h, adds water quenching to go out reaction, liquid separation, water mutually uses 20mL ethyl acetate Extraction 2 times, merges organic phase, and organic phase is washed 2 times with 50mL, and 50mL saturation NaCl aqueous solutions wash 1 time, anhydrous Na2SO4It is dry, Filtering, is spin-dried for solvent, target product 53 is obtained through column chromatography for separation；
The preparation of compound 54#
For the preparation method of compound 54：
Compound 21 0.5mmol, methanol 5mL and concentrated hydrochloric acid aqueous solution (36%, 1mL) are separately added into the round-bottomed flask of 25mL； After system stirs reaction 24h at 20 DEG C, solvent is removed with Rotary Evaporators；Remaining residue 10mL dichloromethane dissolves, Add triethylamine (15mmol)；At room temperature stirring reaction 1h after, add 10mL water, extract organic phase solution, and with water (2 × 10mL) wash；Filtered after organic phase is dried with anhydrous sodium sulfate, remove solvent on a rotary evaporator and obtain crude product；Connect And pass through column chromatography for separation, purification obtains pure deprotection compound；
It will obtain compound to be dissolved in 5mL tetrahydrofurans, system temperature is down to 0 DEG C, and three second of 2.0 equivalents are sequentially added to system The chloroacetic chloride of amine and 1.05 equivalents, continues to keep 0 DEG C of reaction 12h, adds water quenching to go out reaction, liquid separation, water mutually uses 20mL ethyl acetate Extraction 2 times, merges organic phase, and organic phase is washed 2 times with 50mL, and 50mL saturation NaCl aqueous solutions wash 1 time, anhydrous Na2SO4It is dry, Filtering, is spin-dried for solvent, target product 54 is obtained through column chromatography for separation；
The preparation of compound 55#
For the preparation method of compound 55：
Compound 16 0.5mmol, methanol 5mL and concentrated hydrochloric acid aqueous solution (36%, 1mL) are separately added into the round-bottomed flask of 25mL； After system stirs reaction 24h at 20 DEG C, solvent is removed with Rotary Evaporators；Remaining residue 10mL dichloromethane dissolves, Add triethylamine (15mmol)；At room temperature stirring reaction 1h after, add 10mL water, extract organic phase solution, and with water (2 × 10mL) wash；Filtered after organic phase is dried with anhydrous sodium sulfate, remove solvent on a rotary evaporator and obtain crude product；Connect And pass through column chromatography for separation, purification obtains pure deprotection compound；
It will obtain compound to be dissolved in 5mL tetrahydrofurans, system temperature is down to 0 DEG C, and three second of 2.0 equivalents are sequentially added to system The chlorobenzoyl chloride of amine and 1.05 equivalents, continues to keep 0 DEG C of reaction 12h, adds water quenching to go out reaction, liquid separation, water mutually uses 20mL acetic acid second Ester extracts 2 times, merges organic phase, and organic phase is washed 2 times with 50mL, and 50mL saturation NaCl aqueous solutions wash 1 time, anhydrous Na2SO4It is dry Dry, filtering, is spin-dried for solvent, target product 55 is obtained through column chromatography for separation；
The preparation of compound 56#
For the preparation method of compound 56：
Compound 21 0.5mmol, methanol 5mL and concentrated hydrochloric acid aqueous solution (36%, 1mL) are separately added into the round-bottomed flask of 25mL； After system stirs reaction 24h at 20 DEG C, solvent is removed with Rotary Evaporators；Remaining residue 10mL dichloromethane dissolves, Add triethylamine (15mmol)；At room temperature stirring reaction 1h after, add 10mL water, extract organic phase solution, and with water (2 × 10mL) wash；Filtered after organic phase is dried with anhydrous sodium sulfate, remove solvent on a rotary evaporator and obtain crude product；Connect And pass through column chromatography for separation, purification obtains pure deprotection compound；
It will obtain compound to be dissolved in 5mL tetrahydrofurans, system temperature is down to 0 DEG C, and three second of 2.0 equivalents are sequentially added to system The chlorobenzoyl chloride of amine and 1.05 equivalents, continues to keep 0 DEG C of reaction 12h, adds water quenching to go out reaction, liquid separation, water mutually uses 20mL acetic acid second Ester extracts 2 times, merges organic phase, and organic phase is washed 2 times with 50mL, and 50mL saturation NaCl aqueous solutions wash 1 time, anhydrous Na2SO4It is dry Dry, filtering, is spin-dried for solvent, target product 56 is obtained through column chromatography for separation；
The preparation of compound 57#
For the preparation method of compound 57：
It will obtain compound 16 to be dissolved in 5mL tetrahydrofurans, system temperature is down to 0 DEG C, and the hydrogen of 2.0 equivalents is sequentially added to system Change the iodomethane of sodium and 1.1 equivalents, continue to keep 0 DEG C of reaction 2h, add water quenching to go out reaction, liquid separation, water mutually uses 20mL ethyl acetate Extraction 2 times, merges organic phase, and organic phase is washed 2 times with 50mL, and 50mL saturation NaCl aqueous solutions wash 1 time, anhydrous Na2SO4It is dry, Filtering, is spin-dried for solvent, target product 57 is obtained through column chromatography for separation；
The preparation of compound 58#
For the preparation method of compound 58：
It will obtain compound 21 to be dissolved in 5mL tetrahydrofurans, system temperature is down to 0 DEG C, and the hydrogen of 2.0 equivalents is sequentially added to system Change the iodomethane of sodium and 1.1 equivalents, continue to keep 0 DEG C of reaction 2h, add water quenching to go out reaction, liquid separation, water mutually uses 20mL ethyl acetate Extraction 2 times, merges organic phase, and organic phase is washed 2 times with 50mL, and 50mL saturation NaCl aqueous solutions wash 1 time, anhydrous Na2SO4It is dry, Filtering, is spin-dried for solvent, target product 58 is obtained through column chromatography for separation；
The preparation of compound 59#
For the preparation method of compound 59：
It will obtain compound 16 to be dissolved in 5mL tetrahydrofurans, system temperature is down to 0 DEG C, and the hydrogen of 2.0 equivalents is sequentially added to system Change the benzyl bromine of sodium and 1.1 equivalents, continue to keep 0 DEG C of reaction 2h, add water quenching to go out reaction, liquid separation, water is mutually with 20mL ethyl acetate extraction Take 2 times, merge organic phase, organic phase is washed 2 times with 50mL, and 50mL saturation NaCl aqueous solutions wash 1 time, anhydrous Na2SO4It is dry, mistake Filter, is spin-dried for solvent, target product 59 is obtained through column chromatography for separation；
The preparation of compound 60#
For the preparation method of compound 60：
It will obtain compound 21 to be dissolved in 5mL tetrahydrofurans, system temperature is down to 0 DEG C, and the hydrogen of 2.0 equivalents is sequentially added to system Change the benzyl bromine of sodium and 1.1 equivalents, continue to keep 0 DEG C of reaction 2h, add water quenching to go out reaction, liquid separation, water is mutually with 20mL ethyl acetate extraction Take 2 times, merge organic phase, organic phase is washed 2 times with 50mL, and 50mL saturation NaCl aqueous solutions wash 1 time, anhydrous Na2SO4It is dry, mistake Filter, is spin-dried for solvent, target product 60 is obtained through column chromatography for separation.
6. claims 1 or 2 any one of them compound is in stimulation and enhancing protective immunological reaction medicine is prepared Using.
7. compound as claimed in claim 7 protects body from caused by pathogen or in the infection medicine facilitated preparing Application, wherein the pathogen is virus, bacterium and fungi.
8. claims 1 or 2 any one of them compound is preparing the stimulation of up-regulation protective immunity and enhancer and thing Application in the expression of matter and the medicine of activity.
9. compound as claimed in claim 9 prepare up-regulation protective immunity stimulate and enhancer and material expression and Application in the medicine of activity, the protective immunity stimulation and enhancer are immune chemotactic factor (CF) and immunoinflammatory with material The factor.
10. claims 1 or 2 any one of them compound is preparing induction interleukin 12, tumor necrosis factor-alpha With the expression of interferon-γ, and induction NO generation medicine in application.
CN201711090559.8A 2017-11-08 2017-11-08 Stimulate and strengthen protective immunological reaction compound, preparation method and its usage Pending CN107903196A (en)

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Citations (2)

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Publication number Priority date Publication date Assignee Title
CN101203522A (en) * 2005-05-12 2008-06-18 遗传工程与生物技术中心 Antineoplastic compounds and pharmaceutical compositions thereof
CN101962350A (en) * 2010-08-13 2011-02-02 中国科学院上海有机化学研究所 Beta-aryl homoallylic amine compound with optical activity, synthesis method and application

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