POLAR MARINE-DERIVED MACROCYCLIC LACTAM COMPOUND, AND PREPARATION METHOD THEREFOR AND USE THEREOF
20250114326 ยท 2025-04-10
Assignee
Inventors
Cpc classification
A61P29/00
HUMAN NECESSITIES
A61K31/395
HUMAN NECESSITIES
C12P17/188
CHEMISTRY; METALLURGY
International classification
A61K31/395
HUMAN NECESSITIES
A61P29/00
HUMAN NECESSITIES
Abstract
Provided in the present invention are a polar marine-derived macrocyclic lactam compound, and a preparation method therefor and the use thereof. Provided in the present invention is a macrocyclic lactam compound as represented by formula 1 or a pharmaceutically acceptable salt thereof. The compound has a novel structure and good inflammation inhibitory activity, and provides a new candidate compound for developing an anti-inflammatory drug.
Claims
1. A macrocyclic lactam compound as represented by formula 1 or a pharmaceutically acceptable salt thereof: ##STR00017## wherein R.sup.1 is hydrogen, hydroxyl, amino, cyano, halogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, 3- to 6-membered cycloalkyl, C.sub.6-C.sub.10 aryl, 3- to 6-membered heterocycloalkyl or 5- to 10-membered heteroaryl; R.sup.2 is hydrogen, hydroxyl, amino, cyano, halogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, 3- to 6-membered cycloalkyl, C.sub.6-C.sub.10 aryl, 3- to 6-membered heterocycloalkyl or 5- to 10-membered heteroaryl; R.sup.3 is hydrogen, hydroxyl, amino, cyano, halogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, 3- to 6-membered cycloalkyl, C.sub.6-C.sub.10 aryl, 3- to 6-membered heterocycloalkyl or 5- to 10-membered heteroaryl; R.sup.4 is hydrogen, hydroxyl, amino, cyano, halogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, 3- to 6-membered cycloalkyl, C.sub.6-C.sub.10 aryl, 3- to 6-membered heterocycloalkyl or 5- to 10-membered heteroaryl; L.sup.1 is ##STR00018## wherein the terminal a and R.sup.5 are connected to the same carbon atom; X.sup.1 is O, S or NH; X.sup.2 is O, S or NH; R.sup.7-1 is hydrogen, hydroxyl, amino, cyano, halogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, 3- to 6-membered cycloalkyl, C.sub.6-C.sub.10 aryl, 3- to 6-membered heterocycloalkyl or 5- to 10-membered heteroaryl; R.sup.7-2 is hydrogen, hydroxyl, amino, cyano, halogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, 3- to 6-membered cycloalkyl, C.sub.6-C.sub.10 aryl, 3- to 6-membered heterocycloalkyl or 5- to 10-membered heteroaryl; R.sup.7-3 is hydrogen, hydroxyl, amino, cyano, halogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, 3- to 6-membered cycloalkyl, C.sub.6-C.sub.10 aryl, 3- to 6-membered heterocycloalkyl or 5- to 10-membered heteroaryl; R.sup.7-4 is hydrogen, hydroxyl, amino, cyano, halogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, 3- to 6-membered cycloalkyl, C.sub.6-C.sub.10 aryl, 3- to 6-membered heterocycloalkyl or 5- to 10-membered heteroaryl; R.sup.7-5 is hydrogen, hydroxyl, amino, cyano, halogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, 3- to 6-membered cycloalkyl, C.sub.6-C.sub.10 aryl, 3- to 6-membered heterocycloalkyl or 5- to 10-membered heteroaryl; R.sup.7-6 is hydrogen, hydroxyl, amino, cyano, halogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, 3- to 6-membered cycloalkyl, C.sub.6-C.sub.10 aryl, 3- to 6-membered heterocycloalkyl or 5- to 10-membered heteroaryl; R.sup.7-7 is hydrogen, hydroxyl, amino, cyano, halogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, 3- to 6-membered cycloalkyl, C.sub.6-C.sub.10 aryl, 3- to 6-membered heterocycloalkyl or 5- to 10-membered heteroaryl; R.sup.7-8 is hydrogen, hydroxyl, amino, cyano, halogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, 3- to 6-membered cycloalkyl, C.sub.6-C.sub.10 aryl, 3- to 6-membered heterocycloalkyl or 5- to 10-membered heteroaryl; X.sup.3 is O, S or NH; X.sup.4 is O, S or NH; R.sup.8-1 is hydrogen, hydroxyl, amino, cyano, halogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, 3- to 6-membered cycloalkyl, C.sub.6-C.sub.10 aryl, 3- to 6-membered heterocycloalkyl or 5- to 10-membered heteroaryl; R.sup.8-2 is hydrogen, hydroxyl, amino, cyano, halogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, 3- to 6-membered cycloalkyl, C.sub.6-C.sub.10 aryl, 3- to 6-membered heterocycloalkyl or 5- to 10-membered heteroaryl; R.sup.8-3 is hydrogen, hydroxyl, amino, cyano, halogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, 3- to 6-membered cycloalkyl, C.sub.6-C.sub.10 aryl, 3- to 6-membered heterocycloalkyl or 5- to 10-membered heteroaryl; R.sup.8-4 is hydrogen, hydroxyl, amino, cyano, halogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, 3- to 6-membered cycloalkyl, C.sub.6-C.sub.10 aryl, 3- to 6-membered heterocycloalkyl or 5- to 10-membered heteroaryl; R.sup.8-5 is hydrogen, hydroxyl, amino, cyano, halogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, 3- to 6-membered cycloalkyl, C.sub.6-C.sub.10 aryl, 3- to 6-membered heterocycloalkyl or 5- to 10-membered heteroaryl; R.sup.8-6 is hydrogen, hydroxyl, amino, cyano, halogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, 3- to 6-membered cycloalkyl, C.sub.6-C.sub.10 aryl, 3- to 6-membered heterocycloalkyl or 5- to 10-membered heteroaryl; R.sup.8-7 is hydrogen, hydroxyl, amino, cyano, halogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, 3- to 6-membered cycloalkyl, C.sub.6-C.sub.10 aryl, 3- to 6-membered heterocycloalkyl or 5- to 10-membered heteroaryl; R.sup.8-8 is hydrogen, hydroxyl, amino, cyano, halogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, 3- to 6-membered cycloalkyl, C.sub.6-C.sub.10 aryl, 3- to 6-membered heterocycloalkyl or 5- to 10-membered heteroaryl; R.sup.8-9 is hydrogen, hydroxyl, amino, cyano, halogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, 3- to 6-membered cycloalkyl, C.sub.6-C.sub.10 aryl, 3- to 6-membered heterocycloalkyl or 5- to 10-membered heteroaryl; X.sup.5 is O, S or NH; R.sup.9-1 is hydrogen, hydroxyl, amino, cyano, halogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, 3- to 6-membered cycloalkyl, C.sub.6-C.sub.10 aryl, 3- to 6-membered heterocycloalkyl or 5- to 10-membered heteroaryl; R.sup.9-2 is hydrogen, hydroxyl, amino, cyano, halogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, 3- to 6-membered cycloalkyl, C.sub.6-C.sub.10 aryl, 3- to 6-membered heterocycloalkyl or 5- to 10-membered heteroaryl; R.sup.9-3 is hydrogen, hydroxyl, amino, cyano, halogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, 3- to 6-membered cycloalkyl, C.sub.6-C.sub.10 aryl, 3- to 6-membered heterocycloalkyl or 5- to 10-membered heteroaryl; R.sup.9-4 is hydrogen, hydroxyl, amino, cyano, halogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, 3- to 6-membered cycloalkyl, C.sub.6-C.sub.10 aryl, 3- to 6-membered heterocycloalkyl or 5- to 10-membered heteroaryl; R.sup.5 is hydrogen, hydroxyl, amino, cyano, halogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, 3- to 6-membered cycloalkyl, C.sub.6-C.sub.10 aryl, 3- to 6-membered heterocycloalkyl or 5- to 10-membered heteroaryl; R.sup.6 is hydrogen, hydroxyl, amino, cyano, halogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, 3- to 6-membered cycloalkyl, C.sub.6-C.sub.10 aryl, 3- to 6-membered heterocycloalkyl or 5- to 10-membered heteroaryl; L.sup.2 is ##STR00019## wherein the terminal c and R.sup.6 are connected to the same carbon atom; X.sup.6 is O, S or NH; R.sup.10-1 is hydrogen, hydroxyl, amino, cyano, halogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, 3- to 6-membered cycloalkyl, C.sub.6-C.sub.10 aryl, 3- to 6-membered heterocycloalkyl or 5- to 10-membered heteroaryl; R.sup.10-2 is hydrogen, hydroxyl, amino, cyano, halogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, 3- to 6-membered cycloalkyl, C.sub.6-C.sub.10 aryl, 3- to 6-membered heterocycloalkyl or 5- to 10-membered heteroaryl; R.sup.10-3 is hydrogen, hydroxyl, amino, cyano, halogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, 3- to 6-membered cycloalkyl, C.sub.6-C.sub.10 aryl, 3- to 6-membered heterocycloalkyl or 5- to 10-membered heteroaryl; R.sup.10-4 is hydrogen, hydroxyl, amino, cyano, halogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, 3- to 6-membered cycloalkyl, C.sub.6-C.sub.10 aryl, 3- to 6-membered heterocycloalkyl or 5- to 10-membered heteroaryl; R.sup.10-5 is hydrogen, hydroxyl, amino, cyano, halogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, 3- to 6-membered cycloalkyl, C.sub.6-C.sub.10 aryl, 3- to 6-membered heterocycloalkyl or 5- to 10-membered heteroaryl; L.sup.3 is a bond or methylene; R.sup.11 is hydrogen, hydroxyl, amino, cyano, halogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, 3- to 6-membered cycloalkyl, C.sub.6-C.sub.10 aryl, 3- to 6-membered heterocycloalkyl or 5- to 10-membered heteroaryl; R.sup.12 is hydroxyl, C.sub.1-C.sub.6 alkoxy or C.sub.1-C.sub.6 alkyl substituted by hydroxyl; the above-mentioned 3- to 6-membered heterocycloalkyl independently contains 1, 2 or 3 heteroatoms; the above-mentioned 3- to 6-membered heterocycloalkyl contains 1, 2 or 3 heteroatoms independently selected from N, O and S; the above-mentioned 5- to 10-membered heteroaryl independently contains 1, 2 or 3 heteroatoms; the above-mentioned 5- to 10-membered heteroaryl contains 1, 2 or 3 heteroatoms independently selected from N, O and S.
2. The macrocyclic lactam compound as represented by formula 1 or the pharmaceutically acceptable salt thereof of claim 1, wherein, the macrocyclic lactam compound as represented by formula 1 satisfies one or more of the following conditions: ##STR00020## ##STR00021## (vi) the C.sub.1-C.sub.6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or 2-methylbutyl; (vii) the C.sub.2-C.sub.6 alkenyl is ethenyl, 1-propenyl or 2-propenyl; (viii) the C.sub.2-C.sub.6 alkynyl is ethynyl, 1-propynyl or 2-propynyl; (ix) the C.sub.1-C.sub.6 alkoxy is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, secbutoxy or tert-butoxy; (x) the 3- to 6-membered cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (xi) the C.sub.6-C.sub.10 aryl is phenyl or naphthyl; (xii) the 3- to 6-membered heterocycloalkyl is tetrahydropyrrolyl, tetrahydrofuryl, morpholinyl, piperidyl or piperazinyl; (xiii) the 5- to 10-membered heteroaryl is pyrrolyl, furyl, pyridyl, indolyl or quinolyl; (ix) the C.sub.1-C.sub.6 alkyl substituted by hydroxyl is hydroxymethyl; (xv) the macrocyclic lactam compound as represented by formula 1 is ##STR00022##
3. The macrocyclic lactam compound as represented by formula 1 or the pharmaceutically acceptable salt thereof of claim 1, wherein, the macrocyclic lactam compound as represented by formula 1 is: ##STR00023## R.sup.1 is C.sub.1-C.sub.6 alkoxy; R.sup.2 is hydroxyl; R.sup.3 is hydroxyl; R.sup.4 is C.sub.1-C.sub.6 alkyl; L.sup.1 is ##STR00024## wherein the terminal a and R.sup.5 are connected to the same carbon atom; X.sup.1 is O; R.sup.7-1 is hydrogen; R.sup.7-2 is hydroxyl; X.sup.2 is O; R.sup.7-3 is C.sub.1-C.sub.6 alkyl; R.sup.7-4 is hydrogen; R.sup.7-5 is C.sub.1-C.sub.6 alkyl; R.sup.7-6 is hydrogen; R.sup.7-7 is C.sub.1-C.sub.6 alkyl; R.sup.7-8 is hydrogen; X.sup.3 is O; R.sup.8-1 is hydroxyl; R.sup.8-2 is hydrogen; R.sup.8-3 is hydrogen; R.sup.8-4 is C.sub.1-C.sub.6 alkyl; R.sup.8-5 is hydrogen; R.sup.8-6 is C.sub.1-C.sub.6 alkyl; R.sup.8-7 is hydrogen; R.sup.8-8 is C.sub.1-C.sub.6 alkyl; R.sup.8-9 is hydrogen; X.sup.5 is O; R.sup.9-1 is hydroxyl; R.sup.9-2 is hydrogen; R.sup.9-3 is hydroxyl; R.sup.9-4 is C.sub.1-C.sub.6 alkyl; R.sup.5 is hydrogen or C.sub.1-C.sub.6 alkyl; R.sup.6 is hydrogen or C.sub.1-C.sub.6 alkyl; L.sup.2 is ##STR00025## wherein the terminal c and R.sup.6 are connected to the same carbon atom; X.sup.6 is O; R.sup.10-1 is C.sub.1-C.sub.6 alkyl; R.sup.10-2 is C.sub.1-C.sub.6 alkyl; R.sup.10-3 is C.sub.1-C.sub.6 alkyl; R.sup.10-4 is hydrogen; R.sup.10-5 is hydrogen; R.sup.11 is hydrogen; R.sup.12 is hydroxyl or C.sub.1-C.sub.6 alkyl substituted by hydroxyl; L.sup.3 is a bond or methylene.
4. The macrocyclic lactam compound as represented by formula 1 or the pharmaceutically acceptable salt thereof of claim 1, wherein, the macrocyclic lactam compound as represented by formula 1 is any one of the following structures: ##STR00026## ##STR00027##
5. A method for preparing the macrocyclic lactam compound as represented by formula 1 as defined in claim 1, comprising the following step: isolating the compound from the fermentation culture of Streptomyces somaliensis.
6. The method for preparing the macrocyclic lactam compound as represented by formula 1 of claim 5, wherein, the method satisfies one or more of the following conditions: (i) the strain Streptomyces somaliensis used in the method is purchased from Shanghai Boliang Sci & Tech Co., Ltd; (ii) the fermentation culture is obtained using a medium having the following formula: 4 g of yeast extract, 10 g of malt extract, 4 g of glucose, 2.5 g of sea salt, 0.02% anti-forming agent, and 1 L of distilled water; (iii) the fermentation temperature for the fermentation culture in the preparation method is 28 C.; (iv) the fermentation conditions for the fermentation culture in the preparation method is 28 C., 220 rpm; (v) the fermentation time for the fermentation culture in the preparation method ranges from 3 to 7 days; (vi) the isolation in the preparation method sequentially comprises filtration, extraction, and column chromatography; (vii) the filtration in the preparation method is gauze filtration, as long as a fermentation broth is obtained; (viii) the extraction in the preparation method is performed with ethyl acetate; (ix) the extraction in the preparation method is performed three times with an equal volume of ethyl acetate; (x) the column chromatography in the preparation method is performed once, twice, or three times.
7. (canceled)
8. A pharmaceutical composition, comprising the macrocyclic lactam compound as represented by formula 1 or the pharmaceutically acceptable salt thereof as defined in claim 1 and a pharmaceutical adjuvant.
9-10. (canceled)
11. A pharmaceutical composition, comprising the macrocyclic lactam compound defined in claim 4 and a pharmaceutical adjuvant.
12. An IL-6 inhibitor, comprising the macrocyclic lactam compound as represented by formula 1 or the pharmaceutically acceptable salt thereof as defined in claim 1.
13. The IL-6 inhibitor of claim 12, wherein the IL-6 inhibitor is used therein is an IL-6 inhibitor for use in vitro.
14. An IL-6 inhibitor, comprising the macrocyclic lactam compound or the pharmaceutically acceptable salt thereof as defined in claim 4.
15. The IL-6 inhibitor of claim 14, wherein the IL-6 inhibitor is used therein is an IL-6 inhibitor for use in vitro.
16. A method for treating an anti-inflammatory, comprising the macrocyclic lactam compound as represented by formula 1 or the pharmaceutically acceptable salt thereof as defined in claim 1.
17. A method for treating an anti-inflammatory, comprising the macrocyclic lactam compound or the pharmaceutically acceptable salt thereof as defined in claim 4.
18. The method of claim 6, wherein, the method satisfies one or more of the following conditions: (i) in the preparation method, if the column chromatography is performed three times, the stationary-phase column for the first column chromatography is a gel column; (ii) in the preparation method, if the column chromatography is performed three times, the stationary-phase column for the first column chromatography is a Sephadex LH-20 gel column; (iii) in the preparation method, if the column chromatography is performed three times, the stationary-phase column for the first column chromatography has the following size: diameter: 6 cm, and length: 150 cm; (iv) in the preparation method, if the column chromatography is performed three times, the mobile phase for the first column chromatography is dichloromethane and methanol; (v) in the preparation method, if the column chromatography is performed three times, the mobile phase for the first column chromatography is CH.sub.2Cl.sub.2:MeOH=1:1; (vi) in the preparation method, if the column chromatography is performed three times, the stationary-phase column for the second column chromatography is a medium-pressure normal-phase silica gel column or medium-pressure reversed-phase silica gel column; (vii) in the preparation method, if the column chromatography is performed three times, the stationary-phase column for the second column chromatography is SEPAFLASH Silica Flash Column or SEPAFLASH SW 120 Bonded Spherical C18, 15 m, 100 A [SW-5223-120-SP]; (viii) in the preparation method, if the column chromatography is performed three times, the mobile phase for the second column chromatography is dichloromethane and methanol, or methanol and water; (ix) in the preparation method, if the column chromatography is performed three times, the mobile phase for the second column chromatography is dichloromethane-methanol (100:0, 30 min; 100:0-95:5, 210 min; 95:5-50:50, 30 min; 50:50-0:100, 30 min; and finally, flushing the column with pure methanol), or, 10%-100% for 5 h, then flushing the column with 100% methanol for 30 min); (x) in the preparation method, if the column chromatography is performed three times, the stationary-phase column for the third column chromatography is a reversed-phase semi-preparative high performance liquid phase column; in the preparation method, if the column chromatography is performed three times, the stationary-phase column for the third column chromatography can be YMC-Pack Pro C18 RS 250*10.0 mm L.D. S-5 m, 8 nm, YMC-Pack Pro C18 RS 250*4.6 mm L.D. S-5 m, 8 nm or Atlantis Prep T3 5 m 10250 mm column; (xi) in the preparation method, if the column chromatography is performed three times, the mobile phase for the third column chromatography is acetonitrile and water; (xii) in the preparation method, if the column chromatography is performed three times, the mobile phase for the third column chromatography is 45% acetonitrile/water (0.1% HCOOH), 42% acetonitrile/water, 55% acetonitrile/water or 90% acetonitrile/water.
19. A method for preparing the macrocyclic lactam compound of claim 4, comprising the following step: isolating the compound from the fermentation culture of Streptomyces somaliensis.
20. The method of claim 19, wherein, the method satisfies one or more of the following conditions: (i) the strain Streptomyces somaliensis used in the method is purchased from Shanghai Boliang Sci & Tech Co., Ltd; (ii) the fermentation culture is obtained using a medium having the following formula: 4 g of yeast extract, 10 g of malt extract, 4 g of glucose, 2.5 g of sea salt, 0.02% anti-forming agent, and 1 L of distilled water; (iii) the fermentation temperature for the fermentation culture in the preparation method is 28 C.; (iv) the fermentation conditions for the fermentation culture in the preparation method is 28 C., 220 rpm; (v) the fermentation time for the fermentation culture in the preparation method ranges from 3 to 7 days; (vi) the isolation in the preparation method sequentially comprises filtration, extraction, and column chromatography; (vii) the filtration in the preparation method is gauze filtration, as long as a fermentation broth is obtained; (viii) the extraction in the preparation method is performed with ethyl acetate; (ix) the extraction in the preparation method is performed three times with an equal volume of ethyl acetate; (x) the column chromatography in the preparation method is performed once, twice, or three times.
21. The method of claim 20, wherein, the method satisfies one or more of the following conditions: (i) in the preparation method, if the column chromatography is performed three times, the stationary-phase column for the first column chromatography is a gel column; (ii) in the preparation method, if the column chromatography is performed three times, the stationary-phase column for the first column chromatography is a Sephadex LH-20 gel column; (iii) in the preparation method, if the column chromatography is performed three times, the stationary-phase column for the first column chromatography has the following size: diameter: 6 cm, and length: 150 cm; (iv) in the preparation method, if the column chromatography is performed three times, the mobile phase for the first column chromatography is dichloromethane and methanol; (v) in the preparation method, if the column chromatography is performed three times, the mobile phase for the first column chromatography is CH.sub.2Cl.sub.2:MeOH=1:1; (vi) in the preparation method, if the column chromatography is performed three times, the stationary-phase column for the second column chromatography is a medium-pressure normal-phase silica gel column or medium-pressure reversed-phase silica gel column; (vii) in the preparation method, if the column chromatography is performed three times, the stationary-phase column for the second column chromatography is SEPAFLASH Silica Flash Column or SEPAFLASH SW 120 Bonded Spherical C18, 15 m, 100 A [SW-5223-120-SP]; (viii) in the preparation method, if the column chromatography is performed three times, the mobile phase for the second column chromatography is dichloromethane and methanol, or methanol and water; (ix) in the preparation method, if the column chromatography is performed three times, the mobile phase for the second column chromatography is dichloromethane-methanol (100:0, 30 min; 100:0-95:5, 210 min; 95:5-50:50, 30 min; 50:50-0:100, 30 min; and finally, flushing the column with pure methanol), or, 10%-100% for 5 h, then flushing the column with 100% methanol for 30 min); (x) in the preparation method, if the column chromatography is performed three times, the stationary-phase column for the third column chromatography is a reversed-phase semi-preparative high performance liquid phase column; in the preparation method, if the column chromatography is performed three times, the stationary-phase column for the third column chromatography can be YMC-Pack Pro C18 RS 250*10.0 mm L.D. S-5 m, 8 nm, YMC-Pack Pro C18 RS 250*4.6 mm L.D. S-5 m, 8 nm or Atlantis Prep T3 5 m 10250 mm column; (xi) in the preparation method, if the column chromatography is performed three times, the mobile phase for the third column chromatography is acetonitrile and water; (xii) in the preparation method, if the column chromatography is performed three times, the mobile phase for the third column chromatography is 45% acetonitrile/water (0.1% HCOOH), 42% acetonitrile/water, 55% acetonitrile/water or 90% acetonitrile/water.
22. The method of claim 19, wherein, the isolation is any one of the following: (1) filtering the fermentation culture with a gauze to obtain the fermentation broth, extracting the fermentation broth three times with an equal volume of ethyl acetate, and combining the extracts and concentrating same to obtain the ethyl acetate extract fraction; subjecting the above-mentioned ethyl acetate extract fraction to chromatographic separation on a Sephadex LH-20 gel column with an elution solvent: CH.sub.2Cl.sub.2:MeOH=1:1 to obtain components Fr. A-Fr. E; subjecting the component Fr. B to chromatographic separation on a medium-pressure normal-phase silica gel column (gradient elution with dichloromethane-methanol) to obtain components Fr. B1-Fr. B8, and purifying the component Fr. B4 through a reversed-phase semi-preparative high performance liquid phase column with a mobile phase of 45% acetonitrile/water containing 0.1% HCOOH to obtain the compound somalactam C; (2) filtering the fermentation culture with a gauze to obtain the fermentation broth, extracting the fermentation broth three times with an equal volume of ethyl acetate, and combining the extracts and concentrating same to obtain the ethyl acetate extract fraction; subjecting the above-mentioned ethyl acetate extract fraction to chromatographic separation on a Sephadex LH-20 gel column with an elution solvent: CH.sub.2Cl.sub.2:MeOH=1:1 to obtain components Fr. A-Fr. E; subjecting the component Fr. B to chromatographic separation on a medium-pressure normal-phase silica gel column (gradient elution with dichloromethane-methanol) to obtain components Fr. B1-Fr. B8, and purifying the component Fr. B5 through a reversed-phase semi-preparative high performance liquid phase column with a mobile phase of 55% acetonitrile/water to obtain the compound somalactam B; (3) filtering the fermentation culture with a gauze to obtain the fermentation broth, extracting the fermentation broth three times with an equal volume of ethyl acetate, and combining the extracts and concentrating same to obtain the ethyl acetate extract fraction; subjecting the above-mentioned ethyl acetate extract fraction to chromatographic separation on a Sephadex LH-20 gel column with an elution solvent: CH.sub.2Cl.sub.2:MeOH=1:1 to obtain components Fr. A-Fr. E; subjecting the component Fr. B to chromatographic separation on a medium-pressure normal-phase silica gel column, gradient elution with dichloromethane-methanol, to obtain components Fr. B1-Fr. B8, and purifying the component Fr. B6 through a reversed-phase semi-preparative high performance liquid phase column with a mobile phase of 90% acetonitrile/water to obtain somalactams A and D, respectively; (4) filtering the fermentation culture with a gauze to obtain the fermentation broth, extracting the fermentation broth three times with an equal volume of ethyl acetate, and combining the extracts and concentrating same to obtain the ethyl acetate extract fraction; subjecting the above-mentioned ethyl acetate extract fraction to chromatographic separation on a Sephadex LH-20 gel column with an elution solvent: CH.sub.2Cl.sub.2:MeOH=1:1 to obtain components Fr. A-Fr. E; subjecting the component Fr. D to chromatographic separation on a medium-pressure reversed-phase silica gel column, gradient elution with methanol-water, to obtain components Fr. D1-Fr. D7, and purifying the component Fr. D3 through a reversed-phase semi-preparative high performance liquid phase column with a mobile phase of 42% acetonitrile/water to obtain somalactams A and D, respectively.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
[0174]
[0175]
[0176]
[0177]
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0178] The present disclosure is further described below by way of examples; however, the present disclosure is not limited to the scope of the described examples. For the experimental methods in which no specific conditions are specified in the following examples, selections are made according to conventional methods and conditions or according to the product instructions.
[0179] In the following examples, Streptomyces somaliensis is purchased from Shanghai Boliang Sci & Tech Co., Ltd.
Example 1 Preparation and Isolation of the Compound of the Present Disclosure
1. Preparation of Extracts
[0180] (1) Fermentation: Activated Streptomyces somaliensis was inoculated into a 250 mL triangular flask containing 100 mL of seed medium, and cultured on a shaker at 28 C., 220 rpm for 72 h to obtain a seed liquid, which was then inoculated into 48 1-L triangular flasks (inoculation amount: 10%, each containing 500 mL of fermentation medium, 24 L in total) and cultured with shaking on a shaker at 28 C., 220 rpm for 7 days to obtain the fermentation culture of the strain. The formula of the seed medium and fermentation medium was as follows: each liter of the media contained: 4 g of yeast extract (OXOID LP0021), 10 g of malt extract (OXOID LP0039), 4 g of glucose (HRBS-Q007), 2.5 g of sea salt (sea salt from Qingfengtang Co., Ltd.), 0.02% anti-forming agent (Hengxin Chemical Co., Ltd.), and 1 L of distilled water.
[0181] (2) Extraction: the fermentation broth was collected by filtering the fermentation culture with a gauze to remove the mycelium, and then extracted three times with an equal volume of ethyl acetate, and the extracts were combined and concentrated to obtain the ethyl acetate extract fraction.
2. Isolation and Purification
[0182] The above-mentioned ethyl acetate extract fraction was subjected to chromatographic separation on a Sephadex LH-20 gel column (diameter: 6 cm, length: 150 cm), and then eluted (solvent: CH.sub.2Cl.sub.2:MeOH=1:1) to obtain components Fr. A-Fr. E (the flow rate was controlled at 1 drop/s; a total of 40 tubes were used for the eluate (about 100 ml/30 min per tube); based on the analysis through thin layer chromatography (TLC), the eluates in tubes 1-9 were combined as Fr. A, tubes 10-26 as Fr. B, tubes 27-30 as Fr. C, tubes 31-35 as Fr. D, and tubes 36-40 as Fr. E).
[0183] Fr. B was subjected to chromatographic separation on a medium-pressure normal-phase silica gel column (SEPAFLASH Silica Flash column, 120 g), and gradient elution was carried out using dichloromethane-methanol (100:0, 30 min; 100:0-95:5, 210 min; 95:5-50:50, 30 min; 50:50-0:100, 30 min; and finally, the column was flushed with pure methanol; flow rate: 25 mL/min). The eluates were combined based on the analysis results from thin layer chromatography (TLC) to obtain components Fr. B1-Fr. B8 (collecting about 100 mL each, and then combining the corresponding eluates after analysis with TLC plate). Fr. B4 (retention time: 114 min-142 min, polar position: 2%-2.6% methanol/water), Fr. B5 (retention time: 142 min-170 min, polar position: 2.6%-3.3% methanol/water), and Fr. B6 (retention time: 170 min-198 min, polar position: 3.3%-4% methanol/water). Fr. B4 was purified (45% acetonitrile/water (0.1% HCOOH), flow rate: 1.0 mL/min, detection wavelength: 210 nm) through a reversed-phase semi-preparative high performance liquid phase column (YMC-Pack Pro C18 RS 250*4.6 mm L.D. S-5 m, 8 nm) to obtain compound somalactam A (retention time: 11 min); Fr. B5 was purified (55% acetonitrile/water, flow rate: 3.0 mL/min, detection wavelength: 210 nm) through a reversed-phase semi-preparative high performance liquid phase column (Atlantis Prep T3 5 m 10250 mm column) to obtain compound somalactam B (retention time: 40 min); and Fr. B6 was purified (90% acetonitrile/water, flow rate: 3.0 mL/min, detection wavelength: 210 nm) through a reversed-phase semi-preparative high performance liquid phase column (Atlantis Prep T3 5 m 10250 mm Column) to respectively obtain compounds 3 and 4 (retention time: 6 min and 7 min), i.e., somalactams C and D.
[0184] Fr. D was subjected to chromatographic separation on a medium-pressure reversed-phase silica gel column to obtain components Fr. D1-Fr. D7 (SEPAFLASH SW 120 Bonded Spherical C18, 15 m, 100 A [SW-5223-120-SP], mobile phase: methanol-water system, 10%-100% for 5 h, then flushing the column with 100% methanol for 30 min, flow rate: 25 ml/min, and combining based on the peaks); and Fr. D3 (retention time: 226 min, polar range: 78% methanol/water) was separated (42% acetonitrile/water, flow rate: 3.0 mL/min, detection wavelength: 210 nm) through a reversed-phase semi-preparative high performance liquid phase column (YMC-Pack Pro C18 RS 250*10.0 mm L.D. S-5 m, 8 nm) to obtain somalactams C and D (retention time: 18 min and 22 min).
3. Structure Identification
[0185] The NMR, HRESIMS, IR, and UV determination data of compounds Somalactam A-D are as shown below:
[0186] Somalactam A (1): white amorphous solid; [].sub.D.sup.25 0.53 (c 0.2, MeOH); UV (MeOH) .sub.max (log ) 195 (3.08) nm; HRESIMS m/z 580.3130 [M-H].sup. (C.sub.30H.sub.46NO.sub.10, calculated value: 580.3122) and m/z 604.3107 [M+Na].sup.+ (C.sub.30H.sub.47NO.sub.10Na.sup.+, theoretical value: 604.3098). IR (KBr) vmax: 3375, 2919, 1726, 1658, 1650, 1642, 1631, 1530, 1461, 1441, 1379, 1281, 1237, 1191, 1138, 1056, 982, 588, 538, 481, 461, 447, 415. .sup.13C NMR data (DMSO-d.sub.6) are as shown in the table below:
TABLE-US-00001 Position .sub.C, type 1 170.7, C 2 83.7, C 3 207.6, C 4a 39.7, CH.sub.2 4b 5 70.3, CH 6 89.9, C 7 127.8, CH 8 137.1, C 9 92.2, CH 10 132.8, C 11 132.5, CH 12 134.0, C 13 124.9, CH 14a 28.8, CH.sub.2 14b 15 75.4, CH 16 169.7, C 17 82.2, CH 18 70.5, CH 19a 42.2, CH.sub.2 19b 20a 41.0, CH.sub.2 20b 21 29.3, CH 22a 29.8, CH.sub.2 22b 23 11.0, CH.sub.3 24 20.5, CH.sub.3 25 23.7, CH.sub.3 26 12.3, CH.sub.3 27 14.5, CH.sub.3 28 17.3, CH.sub.3 29 62.3, CH.sub.2 30 57.7, OCH.sub.3 2-OH 5-OH 18-OH 29-OH NH
[0187] Somalactam B (2): white amorphous solid; [].sub.D.sup.25 53 (c 0.5, MeOH); UV (MeOH) .sub.max (log ) 193 (2.48) nm; HRESIMS m/z 580.3136 [M-H].sup. (C.sub.30H.sub.46NO.sub.10, calculated value: 580.3122). IR (KBr) vmax: 3380, 2963, 2880, 2271, 2145, 1748, 1624, 1537, 1414, 1376, 1333, 1262, 1250, 1197, 1110, 1088, 1070, 1021, 867, 804, 686, 611, 529, 477. .sup.1H and .sup.13C NMR data (DMSO-d.sub.6) are as shown in the table below:
TABLE-US-00002 Position .sub.C .sub.H, mult. (J in Hz) 1 179.0, C 2 78.2, C 3 110.3, C 4a 38.4, CH.sub.2 2.36, d (15.1) 4b 2.02, dd (15.0, 4.3) 5 86.3, CH 4.38, d (4.7) 6 91.9, C 7 96.0, C 8 129.0 CH 5.40, s 9 146.8, C 10 58.4, CH 3.65, s 11 62.4, CH 2.06, d (3.9) 12 135.6, C 13 123.6, CH 5.50, dd (11.1, 4.2) 14a 36.8, CH.sub.2 2.56, t (12.6) 14b 1.90, m 15 68.0, CH 3.49, m 16a 69.6, CH.sub.2 4.14, dt (10.7, 2.2) 16b 3.89, t (10.1) 17 169.2 18 81.3, CH 3.76, br.s 19 73.0, CH 3.99, m 20a 42.6, CH.sub.2 3.47, m 20b 3.14, m 21a 41.5, CH.sub.2 1.89, dd (13.8, 5.4) 21b 1.18, dd, (11.5, 5.0) 22 29.9, CH 1.39, m 23a 29.8, CH.sub.2 1.15, m 23b 0.99, m 24 11.6, CH.sub.3 0.74, t (7.4) 25 21.8, CH.sub.3 0.90, d (6.5) 26 24.4, CH.sub.3 1.26, s 27 24.8, CH.sub.3 1.30, s 28 15.3, CH.sub.3 1.56, s 29 11.3, CH.sub.3 1.33, s 30 58.6, CH.sub.3 3.34, s 2-OH 3.75, s 3-OH 6.24, s 15-OH 5.07, br.s 19-OH 4.73, d (6.0) NH 8.62, t (6.3)
[0188] Somalactam C (3): white amorphous solid; [].sub.D.sup.25 27.5 (c 0.5, MeOH); UV (MeOH) .sub.max (log ) 198 (2.46) nm; HRESIMS m/z 580.3127 [M-H].sup. (C.sub.30H.sub.46NO.sub.10, calculated value: 580.3122) and m/z 604.3099 [M+Na].sup.+ (C.sub.30H.sub.47NO.sub.10Na.sup.+, calcd. 604.3098). IR (KBr) vmax: 3381, 2962, 2930, 2874, 2262, 2131, 1732, 1643, 1526, 1438, 1373, 1331, 1282, 1243, 1194, 1130, 1108, 1058, 1026, 993, 964, 930, 911, 857, 834, 768, 735, 700, 654, 604, 517, 485. .sup.1H and .sup.13C NMR data (DMSO-d.sub.6) are as shown in the table below:
TABLE-US-00003 Position .sub.C .sub.H, mult. (J in Hz) 1 176.7, C 2 78.3, C 3 109.9, C 4a 39.1, CH.sub.2 2.36, m 4b 2.02, dd, (12.0, 4.0) 5 84.7, CH 3.92, d, (4.0) 6 94.9, C 7 96.0, C 8 130.6, CH 5.22, s 9 143.0, C 10 58.4, CH 3.12, s 11 64.9, CH 1.89, br.s 12 138.4, C 13 123.8, CH 5.16, dd, (9.5, 3.0) 14a 30.5, CH.sub.2 2.39, m 14b 2.22, d (12.0) 15 73.8, CH 5.02, m 16 171.1, C 17 79.9, CH 3.76, br s 18 67.6, CH 4.22, m 19a 41.2, CH.sub.2 3.26, m 19b 2.96, m 20a 40.3, CH.sub.2 2.00, dd (11.5, 5.0) 20b 1.18, dd (11.5, 5.0) 21 30.0, CH 1.46, m 22a 29.2, CH.sub.2 1.25, m 22b 1.02, m 23 10.9, CH.sub.3 0.76, t (6.5) 24 20.6, CH.sub.3 0.90, d (5.5) 25 20.5, CH.sub.3 1.27, s 26 26.0, CH.sub.3 1.50, s 27 15.3, CH.sub.3 1.56, s 28 12.8, CH.sub.3 1.40, s 29 63.0, CH.sub.2 3.49, m 30 59.6, CH.sub.3 3.46, s 2-OH 4.12, s 29-OH 4.88, br.s 3-OH 6.02, s NH 8.52, t, (5.5) 18-OH 4.62, d, (6.1)
[0189] Somalactam D (4): white amorphous solid; [].sub.D.sup.25 15.5 (c 0.5, MeOH); HRESIMS m/z 566.2974 [M-H].sup. (C.sub.29H.sub.44NO.sub.10, calculated value: 566.2965); UV (MeOH) .sub.max (log ) 200 (2.55) nm; IR (KBr) vmax: 3384, 2957, 2871, 1735, 1646, 1525, 1497, 1440, 1373, 1332, 1283, 1248, 1194, 1130, 1108, 1076, 1055, 1005, 957, 931, 912, 858, 837, 809, 731, 695, 654, 598, 517, 485, 466, 437. .sup.1H and .sup.13C NMR data (DMSO-d.sub.6) are as shown in the table below:
TABLE-US-00004 Position .sub.C .sub.H, mult. (J in Hz) 1 176.9, C 2 78.9, C 3 108.6, C 4 42.6, CH.sub.2 2.27, m 5 75.2, CH 4.21, t (3.7) 6 87.7, C 7 134.2, CH 5.34, s 8 131.5 C 9 63.3, CH 3.35 10 146.6, C 11 130.4, CH 5.31, t (2.1) 12 82.3, C 13 43.0, CH 1.59, m 14a 23.0, CH.sub.2 1.94, m 14b 1.71, d (15.5) 15 68.3, CH 4.84, q (5.5) 16 169.7, C 17 79.6, CH 4.01, d (1.5) 18 71.8, CH 3.75, m 19a 40.6, CH 3.63, m 19b 2.99, m 20a 40.8, CH.sub.2 2.01, dd (5.8) 20b 1.22, m 21 29.8, CH 1.44, m 22a 29.3, CH.sub.2 1.24, m 22b 1.03, m 23 10.9, CH.sub.3 0.75, t (7.2) 24 20.8, CH.sub.3 0.91, d (6.7) 25 24.7, CH.sub.3 1.33, s 26 12.3, CH.sub.3 1.39, s 27 14.8, CH.sub.3 1.63, s 28 23.2, CH.sub.3 1.26, s 29a 61.3, CH.sub.2 3.82, dd 29b 3.30, m 30 57.8, CH.sub.3 3.36, s 2-OH 5.29, s 3-OH 5.88, s 5-OH 5.75, d (4.0) 18-OH 4.70, d (6.3) NH 8.55, dd (3.2)
[0190] Furthermore, solvents (methanol/water 1:1) were used for crystallization of the above-mentioned compounds, i.e., somalactams A-D (Somalactam A: solvent system: methanol:water 2:1; the sample was first dissolved in 800 l of methanol in a 10 mL vial and then 400 l of purified water was added dropwise; after the mixture was uniformly mixed, the vial was placed in a cabinet (at room temperature); Somalactam B: solvent system: methanol:water 2:1; the sample was first dissolved in 800 l of methanol in a 10 mL vial and then 400 l of purified water was added dropwise; after the mixture was uniformly mixed, the vial was placed in a refrigerator at 4 C.; Somalactam C: solvent system: dichloromethane:methanol:water 5:5:1; the sample was first dissolved in 500 l of dichloromethane in a 10 mL vial and then 500 l of methanol and 100 l of purified water were added dropwise; after the mixture was uniformly mixed, the vial was placed in a cabinet (at room temperature)). The respective single crystals were obtained, and single crystal diffraction was performed. The results were as shown in
[0191] To sum up, the chemical structures of Somalactams A-D are as follows:
##STR00016##
Example 2 Anti-Inflammatory Activity Experiment of the Compound of the Present Disclosure
[0192] Culture of THP-1 cells and treatment of THP-1 cells with test compounds in combination with LPS
[0193] THP-1 cells (from the Cell Bank of the Chinese Academy of Sciences) were cultured in RPMI-1640 medium containing 10% FBS in a 5% CO.sub.2 incubator at 37 C. 100 L of a cell suspension in a complete culture medium containing antibiotics (100 g/mL streptomycin and 100 U/mL penicillin) and PMA (final concentration: 160 nM) was added to each well in a 96-well plate (about 510.sup.4 cells/well). After 36 h of treatment, the cells achieved adherent growth.
[0194] The PMA-containing medium was discarded and then the cells were washed with 1PBS solution. Serum-free RPMI-1640 (2 mL) was added and the cells were treated for 12 h. The active compounds to be tested were diluted into five concentration gradients and added to each well for a 2-hour treatment. The culture solutions containing the compounds were retained and the cells were treated with a serum-free medium (2 L) containing LPS (1 mg/mL) for 24 h.
Cytokine Content Assay
[0195] The content assay for cytokine IL-6 in the culture solution was performed according to the Human Inflammation Cytometric Bead Array (CBA) method in the manufacturer's instructions. After the above-mentioned cytokine levels were determined on the FACSCalibur flow cytometer, the FCAP Array software was used to analyze the results. The IC.sub.50 value of the control drug was 6.020.12 M.
[0196] Half maximal inhibitory concentration (IC.sub.50) value (M) of compounds 1-4 on inflammatory cytokine IL-6
TABLE-US-00005 Compound IL-6 (M) 1 10.54 0.06 2 11.12 0.13 3 5.76 1.18 4 9.12 0.15 Control drug Tocilizumab 9.22 0.12
[0197] It can be seen from the Table above that the four compounds all have inhibitory activities against the inflammatory cytokine IL-6, which are superior to or equivalent to that of the positive control drug Tocilizumab. The present disclosure provides anew lead compound for the development of new anti-inflammatory drugs, which holds promise as a new anti-inflammatory drug.