A macrocyclic lactam compound, a preparation method and application thereof

Abstract

The application provides a macrocyclic lactam compound, a preparation method and application thereof. The application provides a macrocyclic lactam compound as shown in formula 1 or a pharmaceutically acceptable salt thereof. The compound is novel in structure, has good inflammation inhibiting activity, and provides a new candidate compound for developing anti-inflammatory drugs.

Description

TECHNICAL FIELD

[0001] The present application relates to a kind of macrocylic lactam compounds, its preparation method and application. BACKGROUND

[0002] Inflammation is a defense mechanism of the body to infection, mainly manifested as redness, pain, etc. There are two main types of drugs for the treatment of inflammation in clinical: one is glucocorticoid anti-inflammatory drugs with steroid structure, and the other is non-steroidal anti-inflammatory drugs.

[0003] Glucocorticoid anti-inflammatory drugs represented by cortisone were introduced in the 1940s, and achieved remarkable efficacy in the treatment of arthritis and other diseases, but long-term use can produce dependence and some serious side effects including adrenal cortical function, limiting its wide use in clinical.

[0004] The concept of non-steroidal anti-inflammatory drugs can be traced back to the 1950s, that is, it does not contain a steroid structure in its structure. Subsequently, anti-inflammatory drug research and development became a hot spot, and a series of non-steroidal anti-inflammatory drugs were developed and marketed, mainly including pyrazolone, anthranilic acid, indole acetic acid, aryl alkanoic acid, etc. SUMMARY

[0005] The technical problem to be solved by the present application is the single structure of existing anti-inflammatory drugs. To this end, the present application provides a kind of macrocylic lactam compound, its preparation method and application. The compound has a novel structure and good inflammation inhibitory activity, providing a new candidate compound for the development of anti-inflammatory drugs.

[0006] The present application provides a kind of macrocylic lactam compound as shown in formula 1 or its pharmaceutically acceptable salt:

[0007]

[0008] Among them, R 1 is hydrogen, hydroxyl, amino, cyano, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-6 membered cycloalkyl, C6-C 10 aryl, 3-6 membered heterocycloalkyl or 5-10 membered heteroaryl;

[0009] R 2 is hydrogen, hydroxyl, amino, cyano, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-6 membered cycloalkyl, C6-C 10 aryl, 3-6 membered heterocycloalkyl or 5-10 membered heteroaryl;

[0010] R 3It can be hydrogen, hydroxyl, amino, cyano, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-6 membered cycloalkyl, C6-C 10 Aryl, 3-6 membered heterocyclic alkyl or 5-10 membered heteroaryl;

[0011] R 4 It can be hydrogen, hydroxyl, amino, cyano, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-6 membered cycloalkyl, C6-C 10 Aryl, 3-6 membered heterocyclic alkyl or 5-10 membered heteroaryl;

[0012] L 1 for Where end a and R 5 Connected to the same carbon atom;

[0013] X 1 For O, S, or NH;

[0014] X 2 For O, S, or NH;

[0015] R 7-1 It can be hydrogen, hydroxyl, amino, cyano, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-6 membered cycloalkyl, C6-C 10 Aryl, 3-6 membered heterocyclic alkyl or 5-10 membered heteroaryl;

[0016] R 7-2 It can be hydrogen, hydroxyl, amino, cyano, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-6 membered cycloalkyl, C6-C 10 Aryl, 3-6 membered heterocyclic alkyl or 5-10 membered heteroaryl;

[0017] R 7-3 It can be hydrogen, hydroxyl, amino, cyano, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-6 membered cycloalkyl, C6-C 10 Aryl, 3-6 membered heterocyclic alkyl or 5-10 membered heteroaryl;

[0018] R 7-4 It can be hydrogen, hydroxyl, amino, cyano, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-6 membered cycloalkyl, C6-C 10 Aryl, 3-6 membered heterocyclic alkyl or 5-10 membered heteroaryl;

[0019] R 7-5It can be hydrogen, hydroxyl, amino, cyano, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-6 membered cycloalkyl, C6-C 10 Aryl, 3-6 membered heterocyclic alkyl or 5-10 membered heteroaryl;

[0020] R 7-6 It can be hydrogen, hydroxyl, amino, cyano, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-6 membered cycloalkyl, C6-C 10 Aryl, 3-6 membered heterocyclic alkyl or 5-10 membered heteroaryl;

[0021] R 7-7 It can be hydrogen, hydroxyl, amino, cyano, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-6 membered cycloalkyl, C6-C 10 Aryl, 3-6 membered heterocyclic alkyl or 5-10 membered heteroaryl;

[0022] R 7-8 It can be hydrogen, hydroxyl, amino, cyano, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-6 membered cycloalkyl, C6-C 10 Aryl, 3-6 membered heterocyclic alkyl or 5-10 membered heteroaryl;

[0023] X 3 For O, S, or NH;

[0024] X 4 For O, S, or NH;

[0025] R 8-1 It can be hydrogen, hydroxyl, amino, cyano, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-6 membered cycloalkyl, C6-C 10 Aryl, 3-6 membered heterocyclic alkyl or 5-10 membered heteroaryl;

[0026] R 8-2 It can be hydrogen, hydroxyl, amino, cyano, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-6 membered cycloalkyl, C6-C 10 Aryl, 3-6 membered heterocyclic alkyl or 5-10 membered heteroaryl;

[0027] R 8-3 It can be hydrogen, hydroxyl, amino, cyano, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-6 membered cycloalkyl, C6-C 10 Aryl, 3-6 membered heterocyclic alkyl or 5-10 membered heteroaryl;

[0028] R 8-4 hydrogen, hydroxyl, amino, cyano, halogen, Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Ci-C6-alkoxy, 3- to 6-membered cycloalkyl, C6-Ci0-aryl, 3- to 10-membered heteroaryl or 3- to 6-membered heterocycloalkyl; 10 C6-Ci0-aryl, 3- to 10-membered heteroaryl or 3- to 6-membered heterocycloalkyl;

[0029] R 8-5 hydrogen, hydroxyl, amino, cyano, halogen, Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Ci-C6-alkoxy, 3- to 6-membered cycloalkyl, C6-Ci0-aryl, 3- to 10-membered heteroaryl or 3- to 6-membered heterocycloalkyl; 10 C6-Ci0-aryl, 3- to 10-membered heteroaryl or 3- to 6-membered heterocycloalkyl;

[0030] R 8-6 hydrogen, hydroxyl, amino, cyano, halogen, Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Ci-C6-alkoxy, 3- to 6-membered cycloalkyl, C6-Ci0-aryl, 3- to 10-membered heteroaryl or 3- to 6-membered heterocycloalkyl; 10 C6-Ci0-aryl, 3- to 10-membered heteroaryl or 3- to 6-membered heterocycloalkyl;

[0031] R 8-7 hydrogen, hydroxyl, amino, cyano, halogen, Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Ci-C6-alkoxy, 3- to 6-membered cycloalkyl, C6-Ci0-aryl, 3- to 10-membered heteroaryl or 3- to 6-membered heterocycloalkyl; 10 C6-Ci0-aryl, 3- to 10-membered heteroaryl or 3- to 6-membered heterocycloalkyl;

[0032] R 8-8 hydrogen, hydroxyl, amino, cyano, halogen, Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Ci-C6-alkoxy, 3- to 6-membered cycloalkyl, C6-Ci0-aryl, 3- to 10-membered heteroaryl or 3- to 6-membered heterocycloalkyl; 10 C6-Ci0-aryl, 3- to 10-membered heteroaryl or 3- to 6-membered heterocycloalkyl;

[0033] R 8-9 hydrogen, hydroxyl, amino, cyano, halogen, Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Ci-C6-alkoxy, 3- to 6-membered cycloalkyl, C6-Ci0-aryl, 3- to 10-membered heteroaryl or 3- to 6-membered heterocycloalkyl; 10 C6-Ci0-aryl, 3- to 10-membered heteroaryl or 3- to 6-membered heterocycloalkyl;

[0034] X 5 O, S or NH;

[0035] R 9-1 hydrogen, hydroxyl, amino, cyano, halogen, Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Ci-C6-alkoxy, 3- to 6-membered cycloalkyl, C6-Ci0-aryl, 3- to 10-membered heteroaryl or 3- to 6-membered heterocycloalkyl; 10 C6-Ci0-aryl, 3- to 10-membered heteroaryl or 3- to 6-membered heterocycloalkyl;

[0036] R 9-2 is hydrogen, hydroxyl, amino, cyano, halogen, Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Ci-C6-alkoxy, 3- to 6-membered cycloalkyl, C6-Ci0-aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; 10 is hydrogen, hydroxyl, amino, cyano, halogen, Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Ci-C6-alkoxy, 3- to 6-membered cycloalkyl, C6-Ci0-aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl;

[0037] R 9-3 is hydrogen, hydroxyl, amino, cyano, halogen, Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Ci-C6-alkoxy, 3- to 6-membered cycloalkyl, C6-Ci0-aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; 10 is hydrogen, hydroxyl, amino, cyano, halogen, Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Ci-C6-alkoxy, 3- to 6-membered cycloalkyl, C6-Ci0-aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl;

[0038] R 9-4 is hydrogen, hydroxyl, amino, cyano, halogen, Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Ci-C6-alkoxy, 3- to 6-membered cycloalkyl, C6-Ci0-aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; 10 is hydrogen, hydroxyl, amino, cyano, halogen, Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Ci-C6-alkoxy, 3- to 6-membered cycloalkyl, C6-Ci0-aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl;

[0039] R 5 is hydrogen, hydroxyl, amino, cyano, halogen, Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Ci-C6-alkoxy, 3- to 6-membered cycloalkyl, C6-Ci0-aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; 10 is hydrogen, hydroxyl, amino, cyano, halogen, Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Ci-C6-alkoxy, 3- to 6-membered cycloalkyl, C6-Ci0-aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl;

[0040] R 6 is hydrogen, hydroxyl, amino, cyano, halogen, Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Ci-C6-alkoxy, 3- to 6-membered cycloalkyl, C6-Ci0-aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; 10 is hydrogen, hydroxyl, amino, cyano, halogen, Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Ci-C6-alkoxy, 3- to 6-membered cycloalkyl, C6-Ci0-aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl;

[0041] L 2 is wherein c is 1, 2, 3, 4, 5 or 6; 6 are connected to the same carbon atom;

[0042] X 6 is O, S or NH;

[0043] R 10-1 is hydrogen, hydroxyl, amino, cyano, halogen, Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Ci-C6-alkoxy, 3- to 6-membered cycloalkyl, C6-Ci0-aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; 10 is hydrogen, hydroxyl, amino, cyano, halogen, Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Ci-C6-alkoxy, 3- to 6-membered cycloalkyl, C6-Ci0-aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl;

[0044] R 10-2hydrogen, hydroxyl, amino, cyano, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, 3-6 membered cycloalkyl, C6-C10aryl, 3-6 membered heterocycloalkyl, or 5-10 membered heteroaryl; 10 hydrogen, hydroxyl, amino, cyano, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, 3-6 membered cycloalkyl, C6-C10aryl, 3-6 membered heterocycloalkyl, or 5-10 membered heteroaryl;

[0045] R 10-3 hydrogen, hydroxyl, amino, cyano, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, 3-6 membered cycloalkyl, C6-C10aryl, 3-6 membered heterocycloalkyl, or 5-10 membered heteroaryl; 10 hydrogen, hydroxyl, amino, cyano, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, 3-6 membered cycloalkyl, C6-C10aryl, 3-6 membered heterocycloalkyl, or 5-10 membered heteroaryl;

[0046] R 10-4 hydrogen, hydroxyl, amino, cyano, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, 3-6 membered cycloalkyl, C6-C10aryl, 3-6 membered heterocycloalkyl, or 5-10 membered heteroaryl; 10 hydrogen, hydroxyl, amino, cyano, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, 3-6 membered cycloalkyl, C6-C10aryl, 3-6 membered heterocycloalkyl, or 5-10 membered heteroaryl;

[0047] R 10-5 hydrogen, hydroxyl, amino, cyano, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, 3-6 membered cycloalkyl, C6-C10aryl, 3-6 membered heterocycloalkyl, or 5-10 membered heteroaryl; 10 hydrogen, hydroxyl, amino, cyano, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, 3-6 membered cycloalkyl, C6-C10aryl, 3-6 membered heterocycloalkyl, or 5-10 membered heteroaryl;

[0048] L 3 hydrogen, hydroxyl, amino, cyano, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, 3-6 membered cycloalkyl, C6-C10aryl, 3-6 membered heterocycloalkyl, or 5-10 membered heteroaryl;

[0049] the 3-6 membered heterocycloalkyl group contains independently 1, 2, or 3 heteroatoms; the heteroatoms in the 3-6 membered heterocycloalkyl group are independently selected from 1, 2, or 3 of N, O, and S; the 5-10 membered heteroaryl group contains independently 1, 2, or 3 heteroatoms; the heteroatoms in the 5-10 membered heteroaryl group are independently selected from 1, 2, or 3 of N, O, and S.

[0050] In a certain embodiment, the macrocyclic lactam compound of Formula 1 or a pharmaceutically acceptable salt thereof, wherein the definitions of certain groups are as described below, and the definitions of the remaining groups are as described in any of the remaining embodiments (hereinafter referred to as “in a certain embodiment”):

[0051] the macrocyclic lactam compound of Formula 1 is

[0052] In a certain embodiment, hydrogen, hydroxyl, amino, cyano, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, 3-6 membered cycloalkyl, C6-C10aryl, 3-6 membered heterocycloalkyl, or 5-10 membered heteroaryl;

[0053] In a certain embodiment, hydrogen, hydroxyl, amino, cyano, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, 3-6 membered cycloalkyl, C6-C10aryl, 3-6 membered heterocycloalkyl, or 5-10 membered heteroaryl;

[0054] In a certain embodiment, In a certain embodiment,

[0055] In a certain embodiment, In a certain embodiment,

[0056] In a certain embodiment, In a certain embodiment,

[0057] In a certain embodiment, the C1-C6alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl or 2-methylbutyl.

[0058] In a certain embodiment, the C2-C6alkenyl is ethenyl, 1-propenyl or 2-propenyl.

[0059] In a certain embodiment, the C2-C6alkynyl is ethynyl, 1-propynyl or 2-propynyl.

[0060] In a certain embodiment, the C1-C6alkoxy is methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy or t-butoxy.

[0061] In a certain embodiment, the 3-6 membered cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0062] In a certain embodiment, the C6-C10aryl is phenyl or naphthyl. 10 In a certain embodiment, the C6-C10aryl is phenyl or naphthyl.

[0063] In a certain embodiment, the 3-6 membered heterocycloalkyl is tetrahydropyrrolyl, tetrahydrofuranyl, morpholinyl, piperidinyl or piperazinyl.

[0064] In a certain embodiment, the 5-10 membered heteroaryl is pyrrolyl, furanyl, pyridinyl, indolyl or quinolinyl.

[0065] In a certain embodiment, the C1-C6alkyl substituted with hydroxy is hydroxymethyl.

[0066] In a certain embodiment, the macrocyclic lactam compound of Formula 1 is

[0067] R 1 is C1-C6alkoxy;

[0068] R 2 is hydroxy;

[0069] R 3 is hydroxy;

[0070] R 4 is C1-C6 alkyl;

[0071] L 1 is wherein a is attached to R 5 on the same carbon atom;

[0072] X 1 is O;

[0073] R 7-1 is hydrogen;

[0074] R 7-2 is hydroxyl;

[0075] X 2 is O;

[0076] R 7-3 is C1-C6 alkyl;

[0077] R 7-4 is hydrogen;

[0078] R 7-5 is C1-C6 alkyl;

[0079] R 7-6 is hydrogen;

[0080] R 7-7 is C1-C6 alkyl;

[0081] R 7-8 is hydrogen;

[0082] X 3 is O;

[0083] R 8-1 is hydroxyl;

[0084] R 8-2 is hydrogen;

[0085] R 8-3 is hydrogen;

[0086] R 8-4 is C1-C6 alkyl;

[0087] R 8-5 is hydrogen;

[0088] R 8-6 is C1-C6 alkyl;

[0089] R 8-7 is hydrogen;

[0090] R 8-8 is C1-C6 alkyl;

[0091] R8-9 is hydrogen;

[0092] X 5 is O;

[0093] R 9-1 is hydroxyl;

[0094] R 9-2 is hydrogen;

[0095] R 9-3 is hydroxyl;

[0096] R 9-4 is C1-C6 alkyl;

[0097] R 5 is hydrogen or C1-C6 alkyl;

[0098] R 6 is hydrogen or C1-C6 alkyl;

[0099] L 2 is wherein c is attached to R 6 is attached to the same carbon atom;

[0100] X 6 is O;

[0101] R 10-1 is C1-C6 alkyl;

[0102] R 10-2 is C1-C6 alkyl;

[0103] R 10-3 is C1-C6 alkyl;

[0104] R 10-4 is hydrogen;

[0105] R 10-5 is hydrogen;

[0106] R 11 is hydrogen;

[0107] R 12 is hydroxyl or C1-C6 alkyl substituted with hydroxyl;

[0108] L 3 is a bond or methylene.

[0109] In one aspect, the macrocylic lactam compound of Formula 1 is any one of the following structures:

[0110]

[0111]

[0112] The present application also provides a preparation method of the above-mentioned macrocyclic lactone compound shown as Formula 1, which comprises the following steps: separating the fermentation culture of Streptomyces somaliensis.

[0113] In the preparation method, the Streptomyces somaliensis can be Streptomyces somaliensis purchased from Shanghai Bolvance Biotech Co., Ltd.

[0114] In the preparation method, the formula of the culture medium used in the fermentation culture can be: 4 g of yeast extract, 10 g of malt extract, 4 g of glucose, 2.5 g of sea salt, 0.02% antifoam agent, 1 L of distilled water per liter of culture medium.

[0115] In the preparation method, the formula of the culture medium used in the fermentation culture can be: 4 g of yeast extract (OXOID LP0021), 10 g of malt extract (OXOID LP0039), 4 g of glucose (Hongrunbao Shun Q007), 2.5 g of sea salt (Qingfengtang sea salt), 0.02% antifoam agent (Hengxin Chemical), 1 L of distilled water.

[0116] In the preparation method, the fermentation temperature of the fermentation culture can be 28°C.

[0117] In the preparation method, the fermentation condition of the fermentation culture can be 28°C, 220 rpm.

[0118] In the preparation method, the fermentation time of the fermentation culture can be 3-7 days.

[0119] In the preparation method, the separation can be filtration, extraction, and column chromatography in sequence.

[0120] In the preparation method, the filtration can be gauze filtration, and the fermentation liquid is obtained.

[0121] In the preparation method, the extraction can be ethyl acetate extraction.

[0122] In the preparation method, the extraction can be 3 times of equal volume ethyl acetate extraction.

[0123] In the preparation method, the number of column chromatography can be 1, 2 or 3 times.

[0124] In the preparation method, when the number of column chromatography is 3 times, the stationary phase of the first column chromatography can be a gel column.

[0125] In the preparation method, when the number of times of the column chromatography is 3, the stationary phase of the first column chromatography can be Sephadex LH-20 gel column.

[0126] In the preparation method, when the number of times of the column chromatography is 3, the size of the stationary phase of the first column chromatography can be 6 cm in diameter and 150 cm in length.

[0127] In the preparation method, when the number of times of the column chromatography is 3, the mobile phase of the first column chromatography can be dichloromethane and methanol.

[0128] In the preparation method, when the number of times of the column chromatography is 3, the mobile phase of the first column chromatography can be CH2Cl2:MeOH = 1:1.

[0129] In the preparation method, when the number of times of the column chromatography is 3, the stationary phase of the second column chromatography can be medium-pressure normal-phase silica gel column or reverse-phase medium-pressure silica gel column.

[0130] In the preparation method, when the number of times of the column chromatography is 3, the stationary phase of the second column chromatography can be SEPAFLASH Silica Flash Column or SEPAFLASH SW 120 Bonded Spherical C18, 15 μm, 100A [SW-5223-120-SP].

[0131] In the preparation method, when the number of times of the column chromatography is 3, the mobile phase of the second column chromatography can be dichloromethane and methanol, methanol and water.

[0132] In the preparation method, when the number of times of the column chromatography is 3, the mobile phase of the second column chromatography can be dichloromethane-methanol (100:0 30 min, 100:0-95:5 210 min, 95:5-50:5 30 min, 50:50-0:100 30 min, and finally, pure methanol is used to flush the column for 30 min), or 10%-100% 5 h, and then 100% methanol is used to flush the column for 30 min.

[0133] In the preparation method, when the number of times of the column chromatography is 3, the stationary phase of the third column chromatography can be reverse-phase semi-preparative high-performance liquid.

[0134] In the preparation method, when the number of column chromatography is 3, the stationary phase of the third column chromatography can be YMC-Pack Pro C18 RS 250*10.0mm L.D.S-5μm, 8nm, YMC-Pack Pro C18 RS 250*4.6mm L.D.S-5μm, 8nm or Atlantis Prep T3 5μm 10x250mm Column.

[0135] In the preparation method, when the number of column chromatography is 3, the mobile phase of the third column chromatography can be acetonitrile and water.

[0136] In the preparation method, when the number of column chromatography is 3, the mobile phase of the third column chromatography can be 45% acetonitrile / water (0.1% HCOOH), 42% acetonitrile / water, 55% acetonitrile / water or 90% acetonitrile / water.

[0137] In the preparation method, the separation can be as any of the following:

[0138] (1) filtering with gauze to obtain a fermentation broth, extracting the fermentation broth with an equal volume of ethyl acetate three times, combining the extracts and concentrating to obtain an ethyl acetate extract fraction;

[0139] The ethyl acetate extract fraction is separated by Sephadex LH-20 gel column chromatography, eluted with CH2Cl2:MeOH = 1:1 as a solvent to obtain components Fr.A-Fr.E;

[0140] Fr.B is separated by medium-pressure normal-phase silica gel column chromatography, gradient eluted with dichloromethane-methanol to obtain components Fr.B1-Fr.B8, and Fr.B4 is purified by reversed-phase semi-preparative high-performance liquid chromatography (45% acetonitrile / water (0.1% HCOOH)) to obtain compound somalactam A;

[0141] (2) filtering with gauze to obtain a fermentation broth, extracting the fermentation broth with an equal volume of ethyl acetate three times, combining the extracts and concentrating to obtain an ethyl acetate extract fraction;

[0142] The ethyl acetate extract fraction is separated by Sephadex LH-20 gel column chromatography, eluted with CH2Cl2:MeOH = 1:1 as a solvent to obtain components Fr.A-Fr.E;

[0143] Fr.B is separated by medium-pressure normal-phase silica gel column chromatography, gradient eluted with dichloromethane-methanol to obtain components Fr.B1-Fr.B8, and Fr.B5 is purified by reversed-phase semi-preparative high-performance liquid chromatography (55% acetonitrile / water) to obtain compound somalactam B;

[0144] (3) filter the fermentation broth with gauze, extract the fermentation broth with equal volume of ethyl acetate for 3 times, combine the extracts and concentrate to obtain ethyl acetate extract fraction;

[0145] The ethyl acetate extract fraction is separated by Sephadex LH-20 gel column chromatography, and eluted with CH2Cl2:MeOH = 1:1 as a solvent to obtain components Fr.A-Fr.E;

[0146] Fr.B is separated by medium pressure normal phase silica gel column chromatography, and eluted with dichloromethane-methanol gradient to obtain components Fr.B1-Fr.B8, and Fr.B6 is purified by reversed-phase semi-preparative high performance liquid (90% acetonitrile / water) to obtain somalactam C or D, respectively;

[0147] (3) filter the fermentation broth with gauze, extract the fermentation broth with equal volume of ethyl acetate for 3 times, combine the extracts and concentrate to obtain ethyl acetate extract fraction;

[0148] The ethyl acetate extract fraction is separated by Sephadex LH-20 gel column chromatography, and eluted with CH2Cl2:MeOH = 1:1 as a solvent to obtain components Fr.A-Fr.E;

[0149] Fr.D is separated by reversed-phase medium pressure silica gel column chromatography, and eluted with methanol-water gradient to obtain components Fr.D1-Fr.D7, and Fr.D3 is purified by reversed-phase semi-preparative high performance liquid (42% acetonitrile water) to obtain compound somalactam C or D.

[0150] The application also provides a use of Streptomyces somaliensis in the preparation of the above-mentioned macrolactam compound as shown in formula 1.

[0151] In the use, the Streptomyces somaliensis can be Streptomyces somaliensis purchased from Shanghai Bolang Biotechnology Co., Ltd.

[0152] The application also provides a pharmaceutical composition comprising substance X and a pharmaceutically acceptable excipient; the substance X is the above-mentioned macrolactam compound as shown in formula 1 or a pharmaceutically acceptable salt thereof.

[0153] In the pharmaceutical composition, the pharmaceutical composition can be an anti-inflammatory pharmaceutical composition.

[0154] In the pharmaceutical composition, the pharmaceutical composition can be an IL-6 inhibiting pharmaceutical composition.

[0155] In the pharmaceutical composition, the substance X can be a therapeutically effective amount of the substance X.

[0156] The present application also provides a use of a substance X in the preparation of an anti-inflammatory drug, wherein the substance X is a macrocyclic lactam compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.

[0157] The present application also provides a use of a substance X in the preparation of an IL-6 inhibitor, wherein the substance X is a macrocyclic lactam compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.

[0158] In the use, the IL-6 inhibitor can be an IL-6 inhibitor used in vitro.

[0159] Unless otherwise specified, the terms used in the present application have the following meanings:

[0160] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0161] The term "alkyl" refers to a straight or branched chain alkyl group having a specified number of carbon atoms (e.g., C1-C6). Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, sec-butyl, n-pentyl, n-hexyl, and the like.

[0162] The term "alkoxy" refers to the group R X -O-, wherein R X is an alkyl group as defined above.

[0163] The term "cycloalkyl" refers to a saturated monocyclic ring group consisting only of carbon atoms having a specified number of carbon atoms (e.g., C3-C6). Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0164] The term "heterocycloalkyl" refers to a cyclic group having a specified number of ring atoms (e.g., 5-10 membered), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatoms (one or more of N, O, and S), which is a saturated monocyclic ring. Heterocycloalkyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, morpholinyl, piperidinyl, and the like.

[0165] The term "aryl" refers to a cyclic group consisting only of carbon atoms having a specified number of carbon atoms (e.g., C6-C 10 ) which is a monocyclic or polycyclic ring, and each ring has aromaticity (complying with Huckel's rule). Aryl groups include, but are not limited to, phenyl, naphthyl, and the like.

[0166] The term "heteroaryl" refers to a cyclic group having the specified number of ring atoms (e.g., 5-10 membered), the specified number of heteroatoms (e.g., 1, 2, or 3), the specified type of heteroatoms (one or more of N, O, and S), which is monocyclic or polycyclic, and each ring of which is aromatic (complies with Huckel's rule). Heteroaryl groups include, but are not limited to, furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, indolyl, and the like.

[0167] in a structural fragment means that the structural fragment is connected to other fragments in the molecule through the site. For example, in a structural fragment means that the structural fragment is connected to other fragments in the molecule through the site. For example, in a structural fragment means that the structural fragment is connected to other fragments in the molecule through the site. For example,

[0168] The term "pharmaceutically acceptable salt" refers to a salt of a compound that is formed by the reaction of the compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for patient administration) acid or base. When a compound contains relatively acidic functionalities, base addition salts can be obtained by contacting the free form of the compound with a sufficient amount of the appropriate base to produce the salt. Pharmaceutically acceptable base addition salts include, but are not limited to, sodium, potassium, calcium, aluminum, magnesium, bismuth, ammonium, and the like. When a compound contains relatively basic functionalities, acid addition salts can be obtained by contacting the free form of the compound with a sufficient amount of the appropriate acid to produce the salt. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, sulfate, methanesulfonate, and the like. See, e.g., Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, 2002).

[0169] The term "therapeutically effective amount" refers to the amount of a compound that, when administered to a patient, is sufficient to effect treatment for a disease. The therapeutically effective amount will vary depending on the compound, the disease, the severity of the disease, the age of the patient, and the like, but can be adjusted by one of skill in the art as needed.

[0170] The term "treatment" refers to any one of the following: (1) alleviating one or more of the biological manifestations of a disease; (2) interfering with one or more points in the biological cascade that leads to the disease; (3) slowing the development of one or more of the biological manifestations of a disease.

[0171] The term "prevention" refers to reducing the risk of developing a disease.

[0172] The term "patient" refers to any animal, preferably a mammal, most preferably a human, who has been or is to be treated. Mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, and the like.

[0173] The term "pharmaceutically acceptable excipient" refers to excipients and additives used in the production of pharmaceuticals and dispensing of prescriptions, and all substances contained in pharmaceutical preparations other than active ingredients. See the People's Republic of China Pharmacopoeia (2020 edition) or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009) for details.

[0174] On the basis of not violating the common sense of the art, the above-mentioned preferred conditions can be combined arbitrarily, i.e. to obtain each preferred example of the present application.

[0175] The reagents and raw materials used in the present application are commercially available.

[0176] The positive progress effect of the present application is that the compounds have good inflammation inhibitory activity, providing new candidate compounds for the development of anti-inflammatory drugs. BRIEF DESCRIPTION OF DRAWINGS

[0177] Figure 1 Single crystal diffraction pattern of Somalactam A.

[0178] Figure 2 Single crystal diffraction pattern of Somalactam B.

[0179] Figure 3 Single crystal diffraction pattern of Somalactam C.

[0180] Figure 4 Single crystal diffraction pattern of Somalactam D. DETAILED DESCRIPTION

[0181] The present application will be further illustrated by the following examples, but the present application is not limited in the scope of the examples. The experimental methods in the following examples without specific conditions are selected according to conventional methods and conditions, or according to the instructions of the goods.

[0182] The Streptomyces somaliensis in the following examples was purchased from Shanghai Bolang Biotechnology Co., Ltd.

[0183] Preparation and separation of compounds of the present application

[0184] 1. Preparation of extract infusion

[0185] (1) Fermentation: Activated Streptomyces somaliensis was inoculated into 250 mL flask containing 100 mL seed medium, 28°C, 220 rpm, shaker culture for 72 h to obtain seed liquid. The seed liquid was inoculated into 1 L flask containing 500 mL fermentation medium at 10% inoculation amount, 48 flasks, 24 L, 28°C, 220 rpm, shaker culture for 7 days to obtain fermentation culture of the strain. The formula of the seed medium and fermentation medium was as follows: 4 g of yeast extract (OXOID LP0021), 10 g of malt extract (OXOID LP0039), 4 g of glucose (Hongrunbao Shun Q007), 2.5 g of sea salt (Qingfengtang sea salt), 0.02% antifoam agent (Hengxin Chemical), 1 L of distilled water per liter of medium.

[0186] (2) Extraction: The fermentation broth was collected, and the mycelium was separated from the fermentation broth by gauze filtration. The fermentation broth was extracted with an equal volume of ethyl acetate for 3 times, and the extracts were combined and concentrated to obtain the ethyl acetate extract fraction.

[0187] 2. Isolation and purification

[0188] The above ethyl acetate extract fraction was separated by Sephadex LH-20 gel column chromatography (diameter: 6 cm, length: 150 cm) eluted with CH2Cl2:MeOH = 1:1 as the solvent to obtain components Fr.A-Fr.E (control the flow rate to be 1 drop / s, and about 100 ml / 30 min was connected to each tube, a total of 40 tubes, according to TLC thin layer analysis, 1-9 tubes were combined as A fraction, 10-26 tubes were combined as B fraction, 27-30 tubes were combined as C fraction, 31-35 tubes were combined as D fraction, and 36-40 tubes were combined as E fraction).

[0189] Fr. B was separated by medium pressure normal phase silica gel column chromatography (SEPAFLASH Silica Flash Column 120 g) using a gradient elution of 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 pure methanol at a flow rate of 25 ml / min) and pooled based on thin layer chromatography (TLC) analysis results to obtain fractions Fr. B1-Fr. B8 (approximately 100 ml each, then TLC spotted and pooled, Fr. B4 (retention time 114 min-142 min, polarity position 2%-2.6% methanol / water), Fr. B5 (retention time 142 min-170 min, polarity position 2.6%-3.3% methanol / water), Fr. B6 (retention time 170 min-198 min, polarity position 3.3%-4% methanol / water). Fr. B4 was purified by reverse phase semi-preparative high performance liquid chromatography (YMC-Pack Pro C18 RS 250*4.6 mm L.D.S-5 μm, 8 nm) (45% acetonitrile / water (0.1% HCOOH), flow rate 1.0 mL / min, detection wavelength 210 nm) to obtain compound somalactam A (retention time 11 min); Fr. B5 was purified by reverse phase semi-preparative high performance liquid chromatography (Atlantis Prep T3 5 μm 10*250 mm Column) (55% acetonitrile / water, flow rate 3.0 mL / min, detection wavelength 210 nm) to obtain compound somalactam B (retention time 40 min); and Fr. B6 was purified by reverse phase semi-preparative high performance liquid chromatography (Atlantis Prep T3 5 μm 10*250 mm Column) (90% acetonitrile / water, flow rate 3.0 mL / min, detection wavelength 210 nm) to obtain 3 and 4 (retention times 6 min and 7 min, respectively), i.e., compounds somalactam C and D, respectively.

[0190] Fr.D was separated into fractions Fr.D1-Fr.D7 by reversed-phase medium-pressure silica gel column chromatography (SEPAFLASH SW120 Bonded Spherical C18, 15μm, 100A [SW-5223-120-SP], mobile phase: methanol-water system, 10%-100% for 5 h, followed by 100% methanol column flushing for 30 min, flow rate 25 mL / min, peaks were combined). Fr.D3 (retention time 226 min, polarity range 78% methanol / water) was separated by reversed-phase semi-preparative high-performance liquid chromatography (YMC-Pack Pro C18 RS 250*10.0 mm L.DS-5μm, 8 nm) (42% acetonitrile-water, flow rate 3.0 mL / min, detection wavelength 210 nm) to obtain compounds somalactam C and D (retention times 18 min and 22 min, respectively).

[0191] 3. Structural identification

[0192] The NMR, HRESIMS, IR, and UV identification data of compound Somalactam AD are shown below:

[0193] Somalactam A(1): White amorphous solid; 0.53 (c 0.2, MeOH); UV(MeOH)λ max (logε)195(3.08)nm; HRESIMS m / z 580.3130[MH] - (C 30 H 46 NO 10 ,Calculated value 580.3122) and m / z 604.3107 [M+Na] + (C 30 H 47 NO 10 Na + Theoretical value 604.3098). IR(KBr)νmax: 3375, 2919, 1726, 1658, 1650, 1642, 1631, 1530, 1461, 1441, 1379, 1281, 1237, 1191, 1138, 1056, 982, 588, 538, 481, 461, 447, 415. 13 The 1000-2000 NMR data (DMSO-d6) are shown in the table below:

[0194]

[0195]

[0196] Somalactam B (2): white amorphous solid; 53(c 0.5, MeOH); UV (MeOH) λ max (log ε) 193 (2.48) nm; HRESIMS m / z 580.3136 [M-H] - (C 30 H 46 NO 10 , calcd. 580.3122). IR (KBr) v max: 3380, 2963, 2880, 2271, 2145, 1748, 1624, 1537, 1414, 1376, 1333, 1262, 1250, 1197, 1110, 1088, 1070, 1021, 867, 804, 686, 611, 529, 477. 1 H and 13 C NMR data (DMSO-d6) are shown in the following table:

[0197]

[0198]

[0199] Somalactam C (3): white amorphous solid; 27.5 (c 0.5, MeOH); UV (MeOH) λ max (log ε) 198 (2.46) nm; HRESIMS m / z 580.3127 [M-H] - (C 30 H 46 NO 10 , calcd. 580.3122) and m / z 604.3099 [M+Na] + (C 30 H 47 NO 10 Na + , calcd. 604.3098). IR (KBr) v max: 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. 1 H and 13 C NMR data (DMSO-d6) are shown in the following table:

[0200]

[0201]

[0202] Somalactam D (4): white amorphous solid; 15.5 (c 0.5, MeOH); HRESIMS m / z 566.2974 [M-H] - (C 29 H 44 NO 10 , calculated 566.2965); UV (MeOH) λ max (log ε) 200 (2.55) nm; IR (KBr) v max: 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. 1 H and 13 C NMR data (DMSO-d6) are shown in the following table:

[0203]

[0204]

[0205] Meanwhile, the above compounds Somalactam A-D were recrystallized using solvent (methanol / water 1:1) (Somalactam A: solvent system methanol:water 2:1, first dissolve sample in 800 μl of methanol in 10 ml vial, then add 400 μl of pure water, mix well and put in the cabinet (room temperature); Somalactam B: solvent system methanol:water 2:1, first dissolve sample in 800 μl of methanol in 10 ml vial, then add 400 μl of pure water, mix well and put in the -4 °C refrigerator; Somalactam C: solvent system dichloromethane:methanol:water 5:5:1, first dissolve sample in 500 μl of dichloromethane in 10 ml vial, then add 500 μl of methanol water and 100 μl of pure water, mix well and put in the cabinet (room temperature)), to obtain the corresponding single crystal, and perform single crystal diffraction, as shown in Figure 1 、 Figure 2 、 Figure 3 or Figure 4 shown. Further combined with nuclear magnetic technology ( 1 HNMR, 13The absolute configuration of compounds Somalactam A-D was determined by C NMR, DEPT, COSY, HSQC, HMBC, ROESY.

[0206] In summary, the chemical structures of Somalactam A-D are as follows:

[0207]

[0208]

[0209] Example 2 Anti-inflammatory activity experiment of compounds of the present application

[0210] Culture of THP-1 cells and LPS treatment combined with test compounds

[0211] THP-1 cells (Chinese Academy of Sciences Cell Bank) were cultured in RPMI-1640 medium containing 10% FBS and placed in a 37°C, 5% CO2 incubator. In each well of a 96-well plate, 100 μL of a cell suspension containing complete medium with antibiotics (100 μg / mL streptomycin, 100 U / mL penicillin) and PMA (final concentration 160 nM) was added, containing about 5 x 10 4 cells / well, and the cells were treated for 36 h to allow them to grow adherently.

[0212] The PMA-containing medium was discarded, and the cells were washed with 1 x PBS solution and treated with serum-free RPMI-1640 (2 mL) for 12 h. The test active compounds were prepared into 5 concentration gradients and added to each well for 2 h. The medium containing the compounds was retained, and the cells were treated with LPS (1 mg / mL)-containing serum-free medium (2 μL) for 24 h.

[0213] Determination of cytokine content

[0214] The content of the cytokine IL-6 in the medium was determined according to the Human Inflammation Cytometric Bead Array (CBA) method described in the manufacturer's instructions. After determining the above-mentioned cytokine levels on a FACSCalibur flow cytometer, the results were analyzed using FCAP Array software, and the control drug was 6.02 ± 0.12 μM.

[0215] Half-effective inhibitory concentration IC50(μM) of compounds 1-4 on inflammatory cytokine IL-6 50

[0216] Compound IL-6 (μM) 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

[0217] ​As can be seen from the above table, the four compounds all have inhibitory activity on inflammatory cytokine IL-6, and are better than or comparable to the positive control drug Tocilizumab. The present application provides new lead compounds for the development of new anti-inflammatory drugs, which have the potential to become new anti-inflammatory drugs.

Claims

1. A macrocyclic lactam compound or a pharmaceutically acceptable salt thereof, characterized by, The macrocyclic lactam compound is any one of the following structures: 、 、 and 。 2. A process for the preparation of a macroiactam compound as claimed in claim 1, characterized in that, It comprises the following steps: separation of fermentation culture of Streptomyces somaliensis, which is any one of the following: ①Gauze filtration to obtain fermentation broth, extracting the fermentation broth with equal volume of ethyl acetate for 3 times, combining the extracts and concentrating to obtain ethyl acetate extraction part; The above ethyl acetate extraction part is separated by Sephadex LH-20 gel column chromatography, eluted with CH2Cl2:MeOH = 1:1 as solvent, to obtain components Fr. A-Fr. E; Fr. B is separated by medium-pressure normal-phase silica gel column chromatography, gradient eluted with dichloromethane-methanol, to obtain components Fr. B1-Fr. B8, Fr. B4 is purified by reversed-phase semi-preparative high-performance liquid chromatography, mobile phase is 45% acetonitrile / water containing 0.1% HCOOH, to obtain compound Somalactam A; ②Gauze filtration to obtain fermentation broth, extracting the fermentation broth with equal volume of ethyl acetate for 3 times, combining the extracts and concentrating to obtain ethyl acetate extraction part; The above ethyl acetate extraction part is separated by Sephadex LH-20 gel column chromatography, eluted with CH2Cl2:MeOH = 1:1 as solvent, to obtain components Fr. A-Fr. E; Fr. B is separated by medium-pressure normal-phase silica gel column chromatography, gradient eluted with dichloromethane-methanol, to obtain components Fr. B1-Fr. B8, Fr. B5 is purified by reversed-phase semi-preparative high-performance liquid chromatography, mobile phase is 55% acetonitrile / water, to obtain compound Somalactam B; ③Gauze filtration to obtain fermentation broth, extracting the fermentation broth with equal volume of ethyl acetate for 3 times, combining the extracts and concentrating to obtain ethyl acetate extraction part; The above ethyl acetate extraction part is separated by Sephadex LH-20 gel column chromatography, eluted with CH2Cl2:MeOH = 1:1 as solvent, to obtain components Fr. A-Fr. E; Fr. B is separated by medium-pressure normal-phase silica gel column chromatography, gradient eluted with dichloromethane-methanol, to obtain components Fr. B1-Fr. B8, Fr. B6 is purified by reversed-phase semi-preparative high-performance liquid chromatography, mobile phase is 90% acetonitrile / water, to obtain Somalactam C or D, respectively; ④Gauze filtration to obtain fermentation broth, extracting the fermentation broth with equal volume of ethyl acetate for 3 times, combining the extracts and concentrating to obtain ethyl acetate extraction part; The above ethyl acetate extraction part is separated by Sephadex LH-20 gel column chromatography, eluted with CH2Cl2:MeOH = 1:1 as solvent, to obtain components Fr. A-Fr. E; Fr. D is separated by reversed-phase medium-pressure silica gel column chromatography, gradient eluted with methanol-water, to obtain components Fr. D1-Fr. D7, Fr. D3 is purified by reversed-phase semi-preparative high-performance liquid chromatography, mobile phase is 42% acetonitrile / water, to obtain compound Somalactam C or D.

3. The method for preparing macrocyclic lactam compounds as described in claim 2, characterized in that, It meets one or both of the following conditions: (1) the Streptomyces somaliensis is Streptomyces somaliensis purchased from Shanghai Bolvance Biotech Co., Ltd.; (2) the formula of the culture medium used in the fermentation culture is: 4 grams of yeast extract OXOID LP0021, 10 grams of malt extract OXOID LP0039, 4 grams of glucose, 2.5 grams of sea salt, 0.02% antifoam agent, 1L of distilled water.

4. Use of Streptomyces somaliensis in the preparation of a macrolactin compound as claimed in claim 1.

5. The use according to claim 4, wherein the compound is ###0002### The Streptomyces somaliensis is Streptomyces somaliensis purchased from Shanghai Bolvance Biotech Co., Ltd.

6. A pharmaceutical composition comprising substance X and a pharmaceutically acceptable excipient; the substance X is a macrolactin compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof.

7. Use of substance X in the preparation of an anti-inflammatory drug, the substance X being a macrolactin compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof.

8. Use of substance X in the preparation of an IL-6 inhibitor for in vitro use, the substance X being a macrolactin compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof.

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