CN101619085B - Erythromycin derivative and application as tumor cell proliferation inhibitor thereof - Google Patents

Abstract

The invention belongs to the technical field of medicine, and relates to a kind of erythromycin derivative, its structure is as shown in (I): In the above structural formula (I), a and e may be selected from 0 and 1, b, c, and d may be selected from 0, 1, 2, and 3, but a, b, c, d, and e are not 0 at the same time. The present invention also provides pharmaceutically acceptable non-toxic salts and hydrates thereof formed by the derivatives represented by the above structural formulas. The derivatives have better antitumor activity and can be used for the application of tumor cell proliferation inhibitors in the preparation of tumor drugs.

Description

Erythromycin derivatives and their use as tumor cell proliferation inhibitors

technical field

The invention belongs to the technical field of medicine, and relates to an erythromycin derivative and its application as a tumor cell proliferation inhibitor in the preparation of antitumor drugs.

Background technique

Malignant tumor is a serious disease that threatens human health and life, and it is the leading cause of death in China. Finding and discovering new drugs for the treatment of tumors is a major issue at present.

Erythromycin (erythromycin) is the first macrolide antibiotic with clinical practical value discovered by human beings. It is mainly used to treat various infections caused by Gram-positive bacteria; ), telithromycin (telithromycin) and other erythromycin derivatives have good antibacterial activity, and are commonly used clinical anti-infective drugs. In addition to antibacterial activity, erythromycin derivatives also exhibit other biological activities, including promoting digestive tract motility, anti-inflammatory activity, antagonizing luteinizing hormone releasing hormone activity, and the like. Drugs such as erythromycin have certain adjuvant therapeutic effects on malignant tumors. For related reports, see Agouridas C., et al.J.Med.Chem., 1998, 41(10): 1651-1659; Faghih R., et al.J.Med.Chem., 1998, 41(17): 3402 -3408; Mereu A., et al.Bioorg.Med.Chem.Lett., 2006, 16(22):5801-5804; Randolph J.T., et al.J.Med.Chem., 2004, 47(5): 1085-10997; Hamada K., et al. Chemotherapy, 2000, 46(1):49-61. The relationship between erythromycin derivatives and tumor therapy has attracted people's attention, but the activity of erythromycin derivatives to directly inhibit the proliferation of tumor cells has not been reported in the literature.

Contents of the invention

The purpose of the present invention is to design and synthesize erythromycin derivatives with good tumor cell proliferation inhibitory activity; the prepared compounds show good results in anti-tumor activity tests in vivo and in vitro.

The present invention relates to the compound of formula (I) or its optical isomer, corresponding body, non-corresponding body, racemate or racemic mixture, or its pharmaceutically acceptable salt, hydrate (the number of water of crystallization is 0～ any real number in 16), ester or prodrug:

In the above structural formula (I), a and e can be selected from 0 and 1, b, c, and d can be selected from 0, 1, 2, and 3, but a, b, c, d, and e cannot be 0 at the same time. R _alone represents a hydroxyl group, or a group of formula (II) or formula (III).

In formula (II), f is selected from 0 and 1, R ₅ is selected from hydrogen, optionally substituted -CR _a R _b (C ₁ -C ₈ ) alkyl, optionally substituted -CR _a R _b (C ₂ -C ₈ ) alkenyl, optionally substituted -CR _a R _b (C ₂ -C ₈ ) alkynyl, optionally substituted cycloalkyl, optionally substituted (C ₅ -C ₇ ) cycloalkenyl, And optionally substituted -NR _a (C ₁ -C ₈ ) alkyl, optionally substituted -NR _a (C ₂ -C ₈ ) alkenyl, optionally substituted -NR _a (C ₂ -C ₈ ) Alkynyl. Wherein the substituent is selected from halogen, alkyl, alkenyl, alkynyl, cycloalkyl, oxo, aryl, heteroaryl, heterocyclyl, CN, nitro, -COOR _c , -OCOR _c , - OR _c , -SR _c , -SOR _c , -SO ₂ R _c , -NR _c R _d , -CONR _c R _d , -OCONR _c R _d , -NHCOR _c , -NHCOOR _c and -NHCONR _c R _d ; where , R _a and R _b are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkane Base, COOR _c and CONR _c R _d ; R _c and R _d are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, Heteroaralkyl and heterocyclylalkyl. In formula (III), R ₆ is selected from hydrogen, optionally substituted -CR _a R _b (C ₁ -C ₈ ) alkyl, optionally substituted -CR _a R _b (C ₂ -C ₈ ) alkenyl , optionally substituted -CR _a R _b (C ₂ -C ₈ ) alkynyl, optionally substituted cycloalkyl, optionally substituted (C ₅ -C ₇ ) cycloalkenyl, and optionally substituted -NR _a (C ₁ -C ₈ )alkyl, optionally substituted -NR _a (C ₂ -C ₈ )alkenyl, optionally substituted -NR _a (C ₂ -C ₈ )alkynyl. Wherein the substituent is selected from halogen, alkyl, alkenyl, alkynyl, cycloalkyl, oxo, aryl, heteroaryl, heterocyclyl, CN, nitro, -COOR _c , -OCOR _c , - OR _c , -SR _c , -SOR _c , -SO ₂ R _c , -NR _c R _d , -CONR _c R _d , -OCONR _c R _d , -NHCOR _c , -NHCOOR _c and -NHCONR _c R _d ; where , R _a and R _b are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkane Base, COOR _c and CONR _c R _d ; R _c and R _d are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, Heteroaralkyl and heterocyclylalkyl.

When R ₁ alone represents a hydroxyl group, or a group of formula (II) or formula (III), R ₂ represents hydrogen; or, R ₂ and R ₁ together represent a carbonyl group.

R ₃ is selected from hydrogen, optionally substituted -CR _a R _b (C ₁ -C ₈ ) alkyl, optionally substituted -CR _a R _b (C ₂ -C ₈ ) alkenyl, optionally substituted - CR _a R _b (C ₂ -C ₈ )alkynyl, optionally substituted cycloalkyl, and optionally substituted (C ₅ -C ₇ )cycloalkenyl. Wherein the substituent is selected from halogen, alkyl, alkenyl, alkynyl, cycloalkyl, oxo, aryl, heteroaryl, heterocyclyl, CN, nitro, -COOR _c , -OCOR _c , - OR _c , -SR _c , -SOR _c , -SO ₂ R _c , -NR _c R _d , -CONR _c R _d , -OCONR _c R _d , -NHCOR _c , -NHCOOR _c and -NHCONR _c R _d ; where , R _a and R _b are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkane Base, COOR _c and CONR _c R _d ; R _c and R _d are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, Heteroaralkyl and heterocyclylalkyl.

R ₄ represents hydrogen or a hydroxyl protecting group.

X ₁ represents CH-OH, C=O or a group of formula (IV).

In formula (IV), h, i, m can be selected from 0 and 1, g, j, k, l can be selected from 0, 1, 2 and 3; Y represents methylene, oxygen or NH; Z independently represents Hydrogen or -N(CO) _s R ₁₁ R ₁₂ or -O(CO) _t R ₁₃ or formula (V). wherein s and t are selected from 0 or 1, each of R ₁₁ , R ₁₂ , and R ₁₃ is independently selected from hydrogen, optionally substituted -CR _a R _b (C ₁ -C ₈ ) alkyl, optionally substituted -CR _a R _b (C ₂ -C ₈ ) alkenyl, optionally substituted -CR _a R _b (C ₂ -C ₈ ) alkynyl, optionally substituted cycloalkyl, optionally substituted (C ₅ -C ₇ ) cycloalkenyl, and optionally substituted -NR _a (C ₁ -C ₈ ) alkyl, optionally substituted -NR _a (C ₂ -C ₈ ) alkenyl, optionally substituted -NR _a (C ₂ -C ₈ )alkynyl. Wherein the substituent is selected from halogen, alkyl, alkenyl, alkynyl, cycloalkyl, oxo, aryl, heteroaryl, heterocyclyl, CN, nitro, -COOR _c , -OCOR _c , - OR _c , -SR _c , -SOR _c , -SO ₂ R _c , -NR _c R _d , -CONR _c R _d , -OCONR _c R _d , -NHCOR _c , -NHCOOR _c and -NHCONR _c R _d ; where , R _a and R _b are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkane Base, COOR _c and CONR _c R _d ; R _c and R _d are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, Heteroaralkyl and heterocyclylalkyl;

In formula (V), n and r are selected from 0 or 1, and o, p, q can be selected from 0, 1, 2 and 3.

R ₇ independently represents a hydroxyl group, or a group of formula (II) or formula (III). In formula (II), f is selected from 0 and 1, R ₅ is selected from hydrogen, optionally substituted -CR _a R _b (C ₁ -C ₈ ) alkyl, optionally substituted -CR _a R _b (C ₂ -C ₈ ) alkenyl, optionally substituted -CR _a R _b (C ₂ -C ₈ ) alkynyl, optionally substituted cycloalkyl, optionally substituted (C ₅ -C ₇ ) cycloalkenyl, And optionally substituted -NR _a (C ₁ -C ₈ ) alkyl, optionally substituted -NR _a (C ₂ -C ₈ ) alkenyl, optionally substituted -NR _a (C ₂ -C ₈ ) Alkynyl. Wherein the substituent is selected from halogen, alkyl, alkenyl, alkynyl, cycloalkyl, oxo, aryl, heteroaryl, heterocyclyl, CN, nitro, -COOR _c , -OCOR _c , - OR _c , -SR _c , -SOR _c , -SO ₂ R _c , -NR _c R _d , -CONR _c R _d , -OCONR _c R _d , -NHCOR _c , -NHCOOR _c and -NHCONR _c R _d ; where , R _a and R _b are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkane Base, COOR _c and CONR _c R _d ; R _c and R _d are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, Heteroaralkyl and heterocyclylalkyl. In formula (III), R ₆ is selected from hydrogen, optionally substituted -CR _a R _b (C ₁ -C ₈ ) alkyl, optionally substituted -CR _a R _b (C ₂ -C ₈ ) alkenyl , optionally substituted -CR _a R _b (C ₂ -C ₈ ) alkynyl, optionally substituted cycloalkyl, optionally substituted (C ₅ -C ₇ ) cycloalkenyl, and optionally substituted -NR _a (C ₁ -C ₈ )alkyl, optionally substituted -NR _a (C ₂ -C ₈ )alkenyl, optionally substituted -NR _a (C ₂ -C ₈ )alkynyl. Wherein the substituent is selected from halogen, alkyl, alkenyl, alkynyl, cycloalkyl, oxo, aryl, heteroaryl, heterocyclyl, CN, nitro, -COOR _c , -OCOR _c , - OR _c , -SR _c , -SOR _c , -SO ₂ R _c , -NR _c R _d , -CONR _c R _d , -OCONR _c R _d , -NHCOR _c , -NHCOOR _c , and -NHCONR _c R _d ; where , R _a and R _b are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkane Base, COOR _c and CONR _c R _d ; R _c and R _d are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, Heteroaralkyl and heterocyclylalkyl.

When R ₇ alone represents a hydroxyl group, or a group of formula (II) or formula (III), R ₈ represents hydrogen; or, R ₈ and R ₇ together represent a carbonyl group.

R ₉ is selected from hydrogen, optionally substituted -CR _a R _b (C ₁ -C ₈ ) alkyl, optionally substituted -CR _a R _b (C ₂ -C ₈ ) alkenyl, optionally substituted - CR _a R _b (C ₂ -C ₈ )alkynyl, optionally substituted cycloalkyl, and optionally substituted (C ₅ -C ₇ )cycloalkenyl. Wherein the substituent is selected from halogen, alkyl, alkenyl, alkynyl, cycloalkyl, oxo, aryl, heteroaryl, heterocyclyl, CN, nitro, -COOR _c , -OCOR _c , - OR _c , -SR _c , -SOR _c , -SO ₂ R _c , -NR _c R _d , -CONR _c R _d , -OCONR _c R _d , -NHCOR _c , -NHCOOR _c and -NHCONR _c R _d ; where , R _a and R _b are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkane Base, COOR _c and CONR _c R _d ; R _c and R _d are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, Heteroaralkyl and heterocyclylalkyl.

R ₁₀ represents hydrogen or a hydroxyl protecting group.

X ₃ independently represents hydrogen or -N(CO) _u R ₁₄ R ₁₅ or -O(CO) _v R ₁₆ . wherein u and v are selected from 0 or 1, each of R ₁₄ , R ₁₅ , and R ₁₆ is independently selected from hydrogen, optionally substituted -CR _a R _b (C ₁ -C ₈ ) alkyl, optionally substituted -CR _a R _b (C ₂ -C ₈ ) alkenyl, optionally substituted -CR _a R _b (C ₂ -C ₈ ) alkynyl, optionally substituted cycloalkyl, optionally substituted (C ₅ -C ₇ ) cycloalkenyl, and optionally substituted -NR _a (C ₁ -C ₈ ) alkyl, optionally substituted -NR _a (C ₂ -C ₈ ) alkenyl, optionally substituted -NR _a (C ₂ -C ₈ )alkynyl. Wherein the substituent is selected from halogen, alkyl, alkenyl, alkynyl, cycloalkyl, oxo, aryl, heteroaryl, heterocyclyl, CN, nitro, -COOR _c , -OCOR _c , - OR _c , -SR _c , -SOR _c , -SO ₂ R _c , -NR _c R _d , -CONR _c R _d , -OCONR _c R _d , -NHCOR _c , -NHCOOR _c and -NHCONR _c R _d ; where , R _a and R _b are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkane Base, COOR _c and CONR _c R _d ; R _c and R _d are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, Heteroaralkyl and heterocyclylalkyl.

X ₂ independently represents hydrogen or -N(CO) _w R ₁₇ R ₁₈ or -O(CO) _x R ₁₉ . wherein w and x are selected from 0 or 1, each of R ₁₇ , R ₁₈ , and R ₁₉ is independently selected from hydrogen, optionally substituted -CR _a R _b (C ₁ -C ₈ ) alkyl, optionally substituted -CR _a R _b (C ₂ -C ₈ ) alkenyl, optionally substituted -CR _a R _b (C ₂ -C ₈ ) alkynyl, optionally substituted cycloalkyl, optionally substituted (C ₅ -C ₇ ) cycloalkenyl, and optionally substituted -NR _a (C ₁ -C ₈ ) alkyl, optionally substituted -NR _a (C ₂ -C ₈ ) alkenyl, optionally substituted -NR _a (C ₂ -C ₈ )alkynyl. Wherein the substituent is selected from halogen, alkyl, alkenyl, alkynyl, cycloalkyl, oxo, aryl, heteroaryl, heterocyclyl, CN, nitro, -COOR _c , -OCOR _c , - OR _c , -SR _c , -SOR _c , -SO ₂ R _c , -NR _c R _d , -CONR _c R _d , -OCONR _c R _d , -NHCOR _c , -NHCOOR _c and -NHCONR _c R _d ; where , R _a and R _b are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkane Base, COOR _c and CONR _c R _d ; R _c and R _d are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, Heteroaralkyl and heterocyclylalkyl.

When X ₁ represents CH-OH or C=O, c is selected from 0 and 1. Wherein, when c is 1, the remaining groups are defined as above; when c is 0, then a, b are both 1, d, e are both 0, R ₁ is formula (II) and R ₂ is hydrogen or R ₁ and R ₂ together represent a carbonyl group and R ₃ , R ₄ , X ₂ , Y and Z are as defined above.

Its prerequisites are:

When X ₁ is carbonyl, R ₁ is formula (II) (f is 0, R ₅ is hydrogen), R ₂ , R ₃ , R ₄ are all hydrogen, c, d, e are all 0, a, b are all 1, then X ₂ is not -NHCOCH ₂ NHCOOBn at the same time.

When X ₁ is carbonyl, R ₁ is formula (II) (f is 0, R ₅ is hydrogen), R ₂ , R ₃ , R ₄ are all hydrogen, c, d, e are all 0, a, b are all 1, then X ₂ is not -NHCOOPh at the same time.

When X ₁ is carbonyl, R ₁ is formula (II) (f is 0, R ₅ is hydrogen), R ₂ , R ₃ , R ₄ are all hydrogen, c, d, e are all 0, a, b are all 1, then X ₂ is not -NHBu-t at the same time.

When X ₁ is carbonyl, R ₁ is formula (II) (f is 0, R ₅ is hydrogen), R ₂ , R ₃ , R ₄ are all hydrogen, c, d, e are all 0, a, b are all 1, then _X2 is not hydrogen at the same time.

When X ₁ is carbonyl, R ₁ is formula (II) (f is 0, R ₅ is hydrogen), R ₂ and R ₄ are both hydrogen, R ₃ is methyl, c, d, e are both 0, a, b are both 1, then X ₂ is not hydrogen at the same time.

When X ₁ is carbonyl, R ₁ is formula (II) (f is 0, R ₅ is hydrogen), R ₂ , R ₃ , R ₄ are all hydrogen, c, d, e are all 0, a, b are all 1, then X ₂ is not methyl at the same time.

When X ₁ is carbonyl, R ₁ is formula (II) (f is 0, R ₅ is hydrogen), R ₂ , R ₃ , R ₄ are all hydrogen, c, d, e are all 0, a, b are all 1, then X ₂ is not -CH ₂ CH ₂ N(COCH) ₂ at the same time.

In addition, when _X1 is formula (IV) and c and k are both 0, then a and b are both 1, d and e are both 0, _R1 is formula (II) and _R2 is hydrogen or _R1 and R ₂ together represent a carbonyl group and R ₃ , R ₄ , X ₂ , Y and Z are as defined above.

Its prerequisites are:

When X ₁ is formula (IV) (g, h, i, j, m are both 0, k, l are 1, Y is methylene, Z is hydrogen), R ₁ is formula (II) (f is 0, R ₅ is hydrogen), R ₂ , R ₃ , R ₄ are all hydrogen, a, e are both 0, b, c, d are both 1, then X ₂ is not -NHCH ₂ CH ₂ NH ₂ at the same time.

When X ₁ is formula (IV) (g, h, i, j, m are both 0, k, l are 1, Y is methylene, Z is hydrogen), R ₁ is formula (II) (f is 0, R ₅ is hydrogen), R ₂ , R ₃ , R ₄ are all hydrogen, a, e are both 0, b, c, d are both 1, then X ₂ is not -N(CH ₂ CH ₂ ) ₂ NH.

When _X1 is formula (IV) [(g, h, i, j, m are 0, k, l are 1, Y is methylene, Z is formula (V) (n, p, q, r are the same is 0, o is 1, R ₈ , R ₉ , R ₁₀ are all hydrogen, X ₃ is hydrogen)], R ₁ is formula (II) (f is 0, R ₅ is hydrogen), R ₂ , R ₃ , R ₄ are both hydrogen, a, c, d, e are all 0, b is 1, then X ₂ is not hydrogen at the same time.

When _R1 is formula (II) (f is 0, _R5 is hydrogen), _X1 is formula (IV) (g, h, i, j, k, l, m are all 0, Y is methylene, Z is 2-chlorobenzyl), R ₂ , R ₃ , and R ₄ are all hydrogen, c, d, e are all 0, a, b are both 1, and X ₂ is not -COCH ₃ at the same time.

When _R1 is formula (II) (f is 0, _R5 is hydrogen), _X1 is formula (IV) (g, h, i, j, k, l, m are all 0, Y is methylene, Z is 1-isopropoxycyclohexyl), R ₂ , R ₃ , and R ₄ are all hydrogen, c, d, and e are all 0, a, b are both 1, and X ₂ is not -COCH ₃ at the same time.

When _R1 is formula (II) (f is 0, _R5 is hydrogen), _X1 is formula (IV) (g, h, i, j, k, l, m are all 0, Y is methylene, Z is 2-chlorobenzyl), R ₂ and R ₃ are both hydrogen, R ₄ is acetyl, c, d, e are both 0, a and b are both 1, then X ₂ is not -COCH at the same time ₃ .

Detailed description of the invention

In terms of the above description, certain definitions are explained below.

Unless otherwise indicated, under the standard nomenclature used in the disclosure herein, the terminal portion of the designated side chain is described first, followed by the adjacent functional group attached to the attachment site.

Unless otherwise specified, the terms "alkyl", "alkenyl" and "alkynyl", whether used alone or as part of a substituent, include groups having from 1 to 8 carbon atoms or any number within that range. Straight and branched chains of carbon atoms. The term "alkyl" refers to straight or branched chain hydrocarbons. "Alkenyl" means a straight or branched chain hydrocarbon containing at least one carbon-carbon double bond. "Alkynyl" means a straight or branched chain hydrocarbon containing at least one carbon-carbon triple bond. For example, alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl and 2-methylpentyl. "Alkoxy" means an oxygen ether formed from the aforementioned linear or branched alkyl groups. "Cycloalkyl" contains 3-8 ring carbon atoms, preferably 5-7 ring carbon atoms. "Cycloalkenyl" contains 5-8 ring carbon atoms and at least one carbon-carbon double bond. These alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and alkoxy groups may be independently substituted with one or more groups including, but not limited to, halogen, alkyl, alkenyl, Alkynyl, cycloalkyl, alkoxy, oxo, heteroaryl, heterocyclyl, CN, nitro, -OCOR _a , -OR _a , -SR _a , -SOR _a , -COOR _a , -NR _a R _b , -CONR _a R _b , -OCONR _a R _b , -NHCOR _a , -NHCOOR _a , and -NHCONR _a R _b ; wherein R _a and R _b are independently selected from H, alkyl, alkenyl, alkyne radical, cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl and heterocyclylalkyl. "Aralkyl", "heteroaralkyl" and "heterocyclylalkyl" refer to alkyl substituted by aryl, heteroaryl and heterocyclyl, respectively. "Arylalkenyl", "heteroarylalkenyl" and "heterocyclylalkenyl" refer to alkenyl substituted by aryl, heteroaryl and heterocyclyl, respectively. "Arylalkynyl", "heteroarylalkynyl" and "heterocyclylalkynyl" refer to alkynyl groups substituted by aryl, heteroaryl and heterocyclyl, respectively.

The term "acyl" as used herein, whether used alone or as part of a substituent, refers to an organic group of 2 to 6 carbon atoms (branched or straight) formed from an organic acid by removal of a hydroxyl group. The term "Ac" as used herein, whether used alone or as part of a substituent, refers to an acetyl group.

The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine. (Mono-, di-, tri- and per-)halo-alkyl refers to an alkyl group in which a hydrogen atom is replaced by a halogen by independent replacement.

"Aryl" or "Ar", whether used alone or as part of a substituent, refers to a carboaromatic ring group including, but not limited to, phenyl, 1- or 2-naphthyl, and the like. 1-3 hydrogen atoms in carbocyclic aryl are substituted by independent replacement by: halogen, OH, CN, mercapto, nitro, amine, C ₁ -C ₈ -alkyl, aryl, heteroaryl radical, heterocyclyl, C ₁ -C ₈ -alkoxy, C ₁ -C ₈ -alkylthio, C ₁ -C ₈ -alkyl-amino, di(C ₁ -C ₈ -alkyl)amine radical, (mono-, di-, tri- and per-)halogenated alkyl, formyl, carboxyl, alkoxycarbonyl, C ₁ -C ₈ -alkyl-CO-O-, C ₁ -C ₈ -Alkyl-CO-NH-, or carboxamide. Representative aryl groups include, for example, phenyl, naphthyl, biphenyl, difluorophenyl, benzyl, benzoyloxyphenyl, ethoxycarbonylphenyl, acetylphenyl, ethoxyphenyl , phenoxyphenyl, hydroxyphenyl, carboxyphenyl, trifluoromethylphenyl, methoxyethylphenyl, acetamidophenyl, tolyl, xylyl, dimethylcarbamoyl Phenyl, etc.

"Heteroaryl", whether used alone or as part of a substituent, means a fully unsaturated cyclic group having 5-10 ring atoms, one ring atom selected from S, O and N, 0-3 The ring atoms are further heteroatoms independently selected from S, O and N, the remaining ring atoms being carbon atoms. The group may be attached to the remainder of the molecule through any ring atom. Typical heteroaryl groups include, for example, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, triazole Base, triazinyl, oxadiazolyl, thienyl, furyl, quinolinyl, isoquinolyl, indolyl, isothiazolyl, N-pyridyl oxide, 1,1-dioxythiophenyl, benzene Andthiazolyl, benzoxazolyl, benzothienyl, N-quinolinyl oxide, benzimidazolyl, benzopyranyl, benzisothiazolyl, benzisoxazolyl, benzodiazine Base, benzofuryl, benzofuryl, quinoxalinyl, pyrrolopyridyl, furopyridyl (such as furo[2,3-c]pyridyl, furo[3,2-b]pyridine or furo[2,3-b]pyridyl), imidazopyridyl (such as imidazo[4,5-bpyridyl or imidazo[4,5-c]pyridyl), naphthyridyl, 2 , 3-diazanaphthyl, purinyl, pyridopyridyl, quinazolinyl, thienofuryl, thienopyridyl and thienothienyl. Heteroaryl can be represented by halogen, OH, CN, mercapto, nitro, amino, C ₁ -C ₈ -alkyl, aryl, heteroaryl, heterocyclyl, C ₁ -C ₈ -alkoxy, C ₁ -C ₈ -Alkylthio, C ₁ -C ₈ -Alkyl-amino, Di(C ₁ -C ₈ -Alkyl)amino, (mono-, di-, tri- and per-)haloalkyl , formyl, carboxyl, alkoxycarbonyl, C ₁ -C ₈ -alkyl-CO-O-, C ₁ -C ₈ -alkyl-CO-NH or carboxamide independently replace the above 1-3 hydrogen atoms are substituted. Heteroaryl groups can be substituted by monooxo groups to give, for example, 4-oxo-1H-quinolines.

The terms "heterocycle", "heterocyclic" and "heterocyclyl" refer to an optionally substituted fully saturated, partially saturated or non-aromatic cyclic group, such as a 3- to 7-membered monocyclic ring, 7 - to 11-membered bicyclic or 10- to 15-membered tricyclic ring systems containing at least one heteroatom in the ring containing at least one carbon atom. Each ring in the heteroatom-containing heterocyclic group has 1, 2 or 3 heteroatoms independently selected from nitrogen atoms, oxygen atoms and sulfur atoms, wherein the nitrogen and sulfur atoms may be optionally oxidized. The nitrogen atoms can be optionally quaternized. A heterocyclyl can be attached through a heteroatom or a carbon atom.

Typical monocyclic heterocyclyl groups include pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl , isothiazolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 4-piperidinonyl, tetrahydro Pyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl sulfone, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfone, thiomorpholinyl sulfoxide, 1,3-dioxolane Base, Dioxanyl, Thietanyl, 2-OxaZenyl, AzaZenyl, etc. Typical bicyclic heterocyclyl groups include quinuclidinyl, tetrahydroisoquinolinyl, dihydroisoindolyl, dihydroquinolazolyl (such as 3,4-dihydro-4-oxo-quinolinyl base), dihydrobenzofuryl, dihydrobenzothienyl, thiochromanyl, thiochromanyl, thiochromanyl sulfone, benzopyranyl, dihydrobenzo Pyranyl, indolinyl, chromonyl, coumarinyl, isochromanyl, isoindolinyl, piperonyl, tetrahydroquinolyl, etc. Heterocyclyl can be represented by OH, CN, mercapto, nitro, amino, C ₁ -C ₈ -alkyl, aryl, heteroaryl, heterocyclyl, C ₁ -C ₈ -alkoxy, C ₁ -C ₈ -Alkylthio, C ₁ -C ₈ -Alkyl-amino, Di(C ₁ -C ₈ -Alkyl)-amino, (mono-, di-, tri- and per-)haloalkyl , formyl, carboxyl, alkoxycarbonyl, C ₁ -C ₈ -alkyl-CO-O-, C ₁ -C ₈ -alkyl-CO-NH- or carboxamide independently replace 1 on -3 hydrogen atoms are substituted.

Substituted aryl, substituted heteroaryl and substituted heterocycle can also be substituted by another substituted aryl, another substituted heteroaryl or another substituted heterocycle to form, for example, 4-pyrazol-1-yl-phenyl or 4 -pyridin-2-yl-phenyl.

The indicated number of carbon atoms (e.g. C _1-8 ) refers independently to the number of carbon atoms in the alkyl or cycloalkyl moiety or to the alkyl moiety in larger substituents in which alkyl appears as the prefix, suffix number of carbon atoms.

Unless otherwise stated, the definition of a substituent or variable at a particular position on a molecule is independent of its definition at other positions on the molecule. It is understood that the substituents and substitution patterns on the compounds of the present invention can be selected by one skilled in the art to provide compounds that are chemically stable and readily synthesized by techniques known in the art and methods described herein.

The term "hydroxyl protecting group" refers to groups known in the art for this purpose. Commonly used hydroxyl protecting groups are described, for example, in T.H. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis", Second Edition, John Wiley & Sons, New York (1991), the contents of which are incorporated herein as refer to. Illustrative hydroxy protecting groups include, but are not limited to, tetrahydropyranyl, benzyl, methylthiomethyl, ethylthiomethyl, benzenesulfonyl, trityl, trisubstituted silyl groups such as trimethyl Silyl group, triethylsilyl group, tributylsilyl group, triisopropylsilyl group, tert-butyldimethylsilyl group, tri-tert-butylsilyl group, methyldiphenylsilyl group, Ethyldiphenylsilyl and tert-butyldiphenylsilyl; acyl and aroyl groups such as acetyl, pivaloyl, benzoyl, 4-methoxybenzoyl and 4-nitrobenzoyl acyl; and alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl.

When the compounds according to the invention possess at least one stereocenter, they may exist accordingly as enantiomers. Where the compounds of the invention possess two or more stereocenters, they may also exist in diastereomeric forms. Furthermore, some of the crystalline forms of the compounds may exist as polymorphs and such polymorphs are also included within the scope of the present invention. In addition, some compounds can form solvates with water (ie, hydrates) or common organic solvents, and these solvates are also included in the scope of the present invention.

Certain compounds of the present invention may have trans and cis isomers. Furthermore, when a mixture of stereoisomers results from the preparation of the compounds of the present invention, these isomers can be separated by conventional techniques such as preparative chromatography. These compounds can be prepared in single stereoisomeric form or in racemic form, such as mixtures of some possible stereoisomers. Nonracemic forms can be obtained by synthesis or resolution. For example, these compounds can be resolved into the different component enantiomers using standard techniques such as formation of diastereomeric pairs by salt formation. These compounds can also be linked to a chiral auxiliary through a covalent bond, followed by chromatographic separation and/or crystallization, and then resolved by removing the chiral auxiliary. On the other hand, these compounds can also be resolved by chiral chromatography.

The phrase "pharmaceutically acceptable salt" refers to salts of one or more free bases which possess the desired pharmacological activity of the free bases and which are neither biologically nor otherwise undesirable. These salts may be derived from organic or inorganic acids. Examples of inorganic acids are hydrochloric acid, nitric acid, hydrobromic acid, sulfuric acid or phosphoric acid. Examples of organic acids are acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, Methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. In addition, suitable salts include salts of inorganic or organic bases, such as KOH, NaOH, Ca(OH) ₂ , Al(OH) ₃ , piperidine, morpholine, ethylamine, triethylamine and the like.

Also included within the scope of the present invention are hydrated forms of said compounds containing varying amounts of water, such as monohydrates, hemihydrates and sesquihydrates. The present invention also includes within its scope prodrugs of the compounds of the invention. Such prodrugs are generally functional derivatives of the compound which are readily converted in vivo to the desired compound. Thus, in the method of treatment of the present invention, the term "administration" shall include the treatment of the various diseases described with either a specifically disclosed compound or a compound which is not disclosed but which is converted in vivo to the specified compound after administration to a patient. Routine methods for selecting and preparing suitable prodrug derivatives are described, for example, in Design of Prodrugs (H. Bundgaard, Elsevier, 1985).

The preferred partial compound structure of the present invention is as follows:

Compound 1

Compound 2

Compound 3

Compound 4

Compound 5

Compound 6

Compound 7

Compound 8

Compound 9

Compound 10

Compound 11

Compound 12

Compound 13

Compound 14

Compound 15

Compound 16

Compound 17

Compound 18

Compound 19

Compound 20

Compound 21

Compound 22

Compound 23

Compound 24

Compound 25

Compound 26

Compound 27

Compound 28

Compound 29

Compound 30

Compound 31

Compound 32

Compound 33

Compound 34

Compound 35

Compound 36

Compound 37

Compound 38

Compound 39

Compound 40

Compound 41

Compound 42

Compound 43

Compound 44

Compound 45

Compound 46

Compound 47

Compound 48

Compound 49

Compound 50

Compound 51

Compound 52

Compound 53

Compound 54

Compound 55

Compound 56

Compound 57

Compound 58

Compound 59

Compound 60

Compound 61

Compound 62

Compound 63

Compound 64

Compound 65

Detailed ways

The following examples will help to understand the present invention, but the content of the present invention is not limited to the examples given. Wherein, no attempt has been taken to optimize the yields obtained in these reactions, but it will be obvious to those skilled in the art to increase the yields by changing the reaction time, temperature, solvent and/or reagents.

Reagents used in the present invention are all commercially available, nuclear magnetic resonance spectrum is measured by AVANCE-400, BrukerARX-300 Fourier transform nuclear magnetic resonance spectrometer, and mass spectrum is measured by Brukee Esqure 2000, Shimadzu GCMS-QP5050A type mass spectrometer.

Embodiment 1: the preparation of compound 1

Step A

Clarithromycin (12.00g, 16.05mmol), triethylamine (5.60mL, 40.13mmol) and hydroxylamine hydrochloride (5.65g, 80.98mmol) were dissolved in 150mL of methanol, stirred and refluxed for 24h. After the reaction, methanol was distilled off, and the solution was poured into water and extracted with chloroform, washed with water and dried over anhydrous sodium sulfate. The solution was then concentrated and evaporated to dryness, and the obtained crude product was purified by silica gel column chromatography (chloroform:methanol:ammonia=10:0.5:0.01～10:1:0.05) to obtain 7.71g of 9(E)-clarithromycin oxime, yield 63 %.

Step B

The product obtained in step A (3.00 g, 3.93 mmol), sodium acetate (2.70 g, 19.7 mmol) were dissolved in 150 mL of methanol and 30 mL of water. Then iodine (1.19 g, 4.72 mmol) was added, the reaction was stirred at 50°C for 6 h, and the pH of the solution was controlled to 8.0-9.0 with 1N NaOH. After the reaction, the methanol was distilled off, and then the solution was poured into water and extracted with chloroform, washed with water and dried over anhydrous sodium sulfate. Then the solution was concentrated and evaporated to dryness, and the obtained crude product was purified by silica gel column chromatography (chloroform:methanol:ammonia water=10:0.5:0.01～10:1:0.05) to obtain 2.29 g of white solid, yield 78%.

Step C

The product obtained in Step B (1.00 g, 1.34 mmol) was dissolved in 10 mL of anhydrous ether and 2 mL of DMF, and NaH (95%) (0.06 g, 2.50 mmol) was added to the solution. When there is no more gas generation in the solution, trans-1,4-dibromobutene (0.15g, 0.68mmol) is added thereto, stirred at room temperature for 80 minutes, then the reaction solution is poured into water, extracted three times with chloroform, Washed with water and dried over anhydrous sodium sulfate. Then the solution was concentrated and evaporated to dryness, and the resulting crude product was purified by silica gel column chromatography (chloroform:methanol:ammonia=10:0.5:0.01～10:1:0.05) to obtain the title compound 0.69g, yield 65%; MS 790.2 [M/ 2+H] ⁺ ; See Table-1 for compound ¹³ C-NMR.

Embodiment 2: the preparation of compound 2

Step A

Erythromycin (12.00g, 16.36mmol), triethylamine (5.71mL, 40.90mmol) and hydroxylamine hydrochloride (5.70g, 81.98mmol) were dissolved in 12mL of methanol, stirred and refluxed for 24h. Then the reaction solution was cooled to 0° C., at which time a solid precipitated out, which was filtered and the filter cake was washed twice with cold methanol. Dissolve the solid in 10 mL of methanol, add 4 mL of ammonia water to the solution, stir for 30 minutes, then add

4 mL of distilled water. Subsequently, crystals were precipitated, and 10 mL of distilled water was added, filtered with suction, and dried to obtain 6.36 g of 9(E)-erythromycin oxime as a white solid, with a yield of 52%.

Step B

The product obtained in step A (1.50 g, 2.01 mmol), sodium acetate (0.97 g, 10.03 mmol) were dissolved in 50 mL of methanol and 5 mL of water. Then iodine (0.60 g, 2.41 mmol) was added, the reaction was stirred at 50°C for 6 h, and the pH of the solution was controlled to 8.0-9.0 with NaOH. After the reaction, methanol was distilled off, and the solution was poured into water and extracted with chloroform, washed with water and dried over anhydrous sodium sulfate. Then the solution was concentrated and evaporated to dryness, and the obtained crude product was purified by silica gel column chromatography (chloroform:methanol:ammonia=10:0.5:0.01～10:1:0.05) to obtain 1.18 g of white solid, yield 80%.

Step C

The product obtained in Step B (1.00 g, 1.36 mmol) was dissolved in 15 mL of anhydrous DMF, followed by addition of ethyl chloride (0.10 mL, 1.50 mmol), N,N-diisopropylethylamine (0.36 mL, 2.04 mmol), Stir at room temperature for 72 hours. After the reaction, the solution was poured into water and extracted with ethyl acetate, washed with water and dried over anhydrous sodium sulfate. The solution was concentrated and evaporated to dryness. :0.01～10:1:0.05) to obtain 0.65g of white solid, yield 63%.

Step D

Using the product obtained in Step C as raw material, the title compound was prepared in the same manner as Step C in Example 1, with a yield of 56%; MS 1577.8 [M+H] ⁺ ; compound ¹³ C-NMR is shown in Table-1.

Embodiment 3: the preparation of compound 3

Except using the corresponding raw materials, the title compound was prepared by the same method as in Example 1, with a yield of 64%; MS 1627.8[M+Na] ⁺ ; compound ¹³ C-NMR is shown in Table-1.

Embodiment 4: the preparation of compound 4

Except using the corresponding raw materials, the title compound was prepared by the same method as in Example 1, with a yield of 48%; MS 1661.9 [M+H] ⁺ ; compound ¹³ C-NMR is shown in Table-1.

Embodiment 5: the preparation of compound 5

Except using the corresponding raw materials, the title compound was prepared by the same method as in Example 1, with a yield of 59%; MS 865.8 [M/2+H] ⁺ ; compound ¹³ C-NMR is shown in Table-1.

Embodiment 6: the preparation of compound 6

Step A

The product obtained in Step A of Example 2 (1.00 g, 1.34 mmol) was dissolved in 50 mL of methanol and 7 mL of water, and 36% hydrochloric acid was added dropwise to control the pH value to 4.0-5.0, and stirred at room temperature for 24 h. After the reaction, adjust the pH value to 8.0-9.0 with saturated Na ₂ CO ₃ , then extract with chloroform, wash with water and dry with anhydrous sodium sulfate. The solution was concentrated and evaporated to dryness, and the resulting crude product was purified by silica gel column chromatography (chloroform:methanol:ammonia=10:0.5:0.01~10:1:0.05) to obtain 0.65 g of white solid, with a yield of 61%.

Step B

Using the product obtained in Step A as the starting material, the title compound was prepared in the same manner as in Example 1, with a yield of 62%; MS 1233.8[M+H] ⁺ .

Embodiment 7: the preparation of compound 7

Except using the corresponding raw materials, the title compound was prepared by the same method as in Example 1, the yield was 59%; MS 1261.7[M+H] ⁺ .

Embodiment 8: the preparation of compound 8

Step A

Clarithromycin (5.00 g, 6.69 mmol), sodium acetate (2.75 g, 33.46 mmol) were dissolved in 100 mL of methanol and 20 mL of water. Then iodine (2.03 g, 8.03 mmol) was added, the reaction was stirred at 50°C for 6 h, and the pH of the solution was controlled to 8.0-9.0 with 1N NaOH. After the reaction, methanol was distilled off, and the solution was poured into water and extracted with chloroform, washed with water and dried over anhydrous sodium sulfate. Then the solution was concentrated and evaporated to dryness, and the obtained crude product was purified by silica gel column chromatography (chloroform:methanol:ammonia water=10:0.5:0.01～10:1:0.05) to obtain 4.12 g of white solid, yield 84%.

Step B

The product obtained in Step A (1.06g, 1.44mmol) was dissolved in 25mL of dry dichloromethane, and N,N-diisopropylethylamine (0.33mL, 1.88mmol), trans 1,4-dibromobutyl Alkene (0.31 g, 1.44 mmol) and piperidine (0.15 mL, 1.44 mmol). After stirring at room temperature for 60 hours, the reaction solution was poured into saturated brine, extracted with ethyl acetate, washed with water and dried by adding anhydrous sodium sulfate, and the solvent was concentrated and evaporated to dryness. The obtained crude product was purified by silica gel column chromatography (chloroform:methanol:ammonia water=10:0.5:0.01～10:1:0.05) to obtain the title 0.71g, yield 57%; MS 871.6[M+H] ⁺ .

Embodiment 9: the preparation of compound 9

Except using the corresponding raw materials, the title compound was prepared by the same method as in Example 8, with a yield of 62%; MS 900.5[M+H] ⁺ .

Embodiment 10: the preparation of compound 10

Except using the corresponding raw materials, the title compound was prepared in the same manner as in Example 8, with a yield of 56%; MS 991.8 [M+H] ⁺ .

Embodiment 11: Preparation of compound 11

Step A

Erythromycin (5.00 g, 6.81 mmol), sodium acetate (2.80 g, 34.06 mmol) were dissolved in 100 mL of methanol and 20 mL of water. Then iodine (2.07g, 8.18mmol) was added, the reaction was stirred at 50°C for 6h, and the pH of the solution was controlled to 8.0-9.0 with 1N NaOH. After the reaction, methanol was distilled off, and the solution was poured into water and extracted with chloroform, washed with water and dried over anhydrous sodium sulfate. Then the solution was concentrated and evaporated to dryness, and the obtained crude product was purified by silica gel column chromatography (chloroform:methanol:ammonia water=10:0.5:0.01～10:1:0.05) to obtain 3.84 g of white solid, yield 79%.

Step B

Dissolve the product obtained in step A (0.20g, 0.28mmol) in 10mL of dry dichloromethane, add N,N-diisopropylethylamine (0.98mL, 5.60mmol), and then add chloroacetyl chloride (0.02mL , 0.28mmol), stirred at room temperature for 12 hours, then added 3-43 (74.52mg, 0.28mmol), stirred at room temperature for 24 hours. After the reaction, the reaction solution was poured into saturated brine, extracted with dichloromethane, washed with water and dried by adding anhydrous sodium sulfate, and the solvent was evaporated to dryness. The obtained crude product was purified by silica gel column chromatography (chloroform:methanol:ammonia water=10:0.5 :0.01～10:1:0.05) to obtain 0.16g of the title compound, yield 54%; MS 1027.0 [M+H] ⁺ ; see Table-1 for compound ¹³ C-NMR.

Embodiment 12: the preparation of compound 12

Except using the corresponding raw materials, the title compound was prepared by the same method as in Example 11, with a yield of 64%; MS 847.8 [M+H] ⁺ ; compound ¹³ C-NMR is shown in Table-1.

Embodiment 13: Preparation of compound 13

Except using the corresponding starting materials, the title compound was prepared in the same manner as in Example 11, with a yield of 58%; MS 861.4 [M+H] ⁺ ; see Table-1 for C-NMR of compound ¹³ .

Embodiment 14: the preparation of compound 14

Except using the corresponding raw materials, the title compound was prepared in the same manner as in Example 11, with a yield of 60%; MS 1013.9 [M+H] ⁺ ; compound ¹³ C-NMR is shown in Table-1.

Embodiment 15: Preparation of compound 15

Except using the corresponding starting materials, the title compound was prepared in the same manner as in Example 11, with a yield of 43%; MS 860.9 [M+H] ⁺ ; compound ¹³ C-NMR is shown in Table-1.

Embodiment 16: the preparation of compound 16

Dissolve the product (0.20 g, 0.27 mmol) obtained in step A in Example 2 in 6 mL of ether and 2 mL of DMF, add NaH (95%) (20.21 mg, 0.80 mmol), and add trans 1,4- Dibromo-2-butene (60.99 mg, 0.27 mmol) was stirred at room temperature for 5 hours, methylpiperazine (0.03 mL, 0.27 mmol) was added to the reaction solution, and stirred at room temperature for 48 hours. After the reaction, diethyl ether was distilled off, and then the solution was poured into water and extracted with ethyl acetate, washed with water and dried with anhydrous sodium sulfate, and the solution was concentrated and evaporated to dryness. The obtained crude product was purified by silica gel column chromatography (chloroform:methanol:ammonia water=10:0.5:0.01～10:1:0.05) to obtain 0.13g of a white solid with a yield of 55%; MS 901.5[M+H] ⁺ ; Compound ¹³ See Table-1 for C-NMR.

Embodiment 17: the preparation of compound 17

Except using the corresponding raw materials, the title compound was prepared in the same manner as in Example 16, with a yield of 60%; MS 977.5 [M+H] ⁺ ; compound ¹³ C-NMR is shown in Table-1.

Embodiment 18: Preparation of compound 18

Except using the corresponding starting materials, the title compound was prepared in the same manner as in Example 16, with a yield of 58%; MS 991.4 [M+H] ⁺ ; compound ¹³ C-NMR is shown in Table-1.

Embodiment 19: Preparation of compound 19

Except using the corresponding raw materials, the title compound was prepared by the same method as in Example 16, with a yield of 64%; MS 964.3 [M+H] ⁺ ; compound ¹³ C-NMR is shown in Table-1.

Embodiment 20: Preparation of compound 20

Except using the corresponding starting materials, the title compound was prepared in the same manner as in Example 16, with a yield of 48%; MS 962.5 [M+H] ⁺ ; see Table-1 for C-NMR of compound ¹³ .

Embodiment 21: Preparation of compound 21

Except using the corresponding starting materials, the title compound was prepared in the same manner as in Example 16, with a yield of 50%; MS 1006.0 [M+H] ⁺ ; see Table-1 for C-NMR of compound ¹³ .

Embodiment 22: Preparation of compound 22

Except using the corresponding starting materials, the title compound was prepared in the same manner as in Example 16, with a yield of 51%; MS 1036.8 [M+H] ⁺ ; see Table-1 for C-NMR of compound ¹³ .

Embodiment 23: Preparation of compound 23

Except using the corresponding raw materials, the title compound was prepared by the same method as in Example 16, with a yield of 42%; MS 1065.9 [M+H] ⁺ ; compound ¹³ C-NMR is shown in Table-1.

Embodiment 24: Preparation of compound 24

Except using the corresponding raw materials, the title compound was prepared by the same method as in Example 16, with a yield of 39%; MS 1040.7 [M+H] ⁺ ; compound ¹³ C-NMR is shown in Table-1.

Embodiment 25: Preparation of compound 25

Except using the corresponding starting materials, the title compound was prepared in the same manner as in Example 16, with a yield of 59%; MS 1009.9 [M+H] ⁺ ; compound ¹³ C-NMR is shown in Table-1.

Embodiment 26: Preparation of compound 26

Except using the corresponding raw materials, the title compound was prepared by the same method as in Example 16, with a yield of 44%; MS 1047.9 [M+H] ⁺ ; compound ¹³ C-NMR is shown in Table-1.

Embodiment 27: Preparation of compound 27

Except using the corresponding raw materials, the title compound was prepared in the same manner as in Example 16, with a yield of 59%; MS 1014.6 [M+H] ⁺ ; compound ¹³ C-NMR is shown in Table-1.

Embodiment 28: Preparation of compound 28

Except using the corresponding raw materials, the title compound was prepared by the same method as in Example 16, with a yield of 40%; MS 1041.9 [M+H] ⁺ ; compound ¹³ C-NMR is shown in Table-1.

Embodiment 29: Preparation of compound 29

Except using the corresponding raw materials, the title compound was prepared by the same method as in Example 16, with a yield of 66%; MS 873 [M+H] ⁺ .

Embodiment 30: Preparation of compound 30

Except using the corresponding starting materials, the title compound was prepared by the same method as in Example 16, with a yield of 61%; MS 886 [M+H] ⁺ .

Embodiment 31: Preparation of compound 31

Except using the corresponding raw materials, the title compound was prepared in the same manner as in Example 11, with a yield of 55%; MS 905 [M+H] ⁺ ; compound ¹³ C-NMR is shown in Table-1.

Embodiment 32: the preparation of compound 32

Except using the corresponding starting materials, the title compound was prepared in the same manner as in Example 11, with a yield of 64%; MS 937 [M+H] ⁺ ; compound ¹³ C-NMR is shown in Table-1.

Embodiment 33: Preparation of compound 33

Except using the corresponding starting materials, the title compound was prepared in the same manner as in Example 8, with a yield of 56%; MS 1028 [M+H] ⁺ ; see Table-1 for C-NMR of compound ¹³ .

Embodiment 34: Preparation of compound 34

Except using the corresponding starting materials, the title compound was prepared in the same manner as in Example 8, with a yield of 58%; MS 549 [M/2+H] ⁺ ; compound ¹³ C-NMR is shown in Table-1.

Embodiment 35: Preparation of compound 35

Except using the corresponding starting materials, the title compound was prepared in the same manner as in Example 11, with a yield of 60%; MS 974 [M+H] ⁺ ; compound ¹³ C-NMR is shown in Table-1.

Embodiment 36: Preparation of compound 36

Except using the corresponding starting materials, the title compound was prepared in the same manner as in Example 11, with a yield of 62%; MS 994 [M+H] ⁺ ; compound ¹³ C-NMR is shown in Table-1.

Embodiment 37: Preparation of compound 37

Except using the corresponding raw materials, the title compound was prepared in the same manner as in Example 11, with a yield of 39%; MS 888 [M+H] ⁺ ; compound ¹³ C-NMR is shown in Table-1.

Embodiment 38: Preparation of compound 38

Except using the corresponding starting materials, the title compound was prepared in the same manner as in Example 11, with a yield of 58%; MS 875 [M+H] ⁺ ; compound ¹³ C-NMR is shown in Table-1.

Embodiment 39: Preparation of compound 39

Except using the corresponding starting materials, the title compound was prepared in the same manner as in Example 11, with a yield of 44%; MS 895 [M+H] ⁺ ; compound ¹³ C-NMR is shown in Table-1.

Embodiment 40: Preparation of Compound 40

Except using the corresponding raw materials, the title compound was prepared by the same method as in Example 11, the yield was 44%; MS 875[M+H] ⁺ .

Embodiment 41: Preparation of compound 41

Except using the corresponding raw materials, the title compound was prepared in the same manner as in Example 16, with a yield of 58%; MS 1050 [M+H] ⁺ ; compound ¹³ C-NMR is shown in Table-1.

Embodiment 42: Preparation of Compound 42

Except using the corresponding starting materials, the title compound was prepared by the same method as in Example 16 with a yield of 67%; MS 1036[M+H] ⁺ .

Embodiment 43: Preparation of Compound 43

Except using the corresponding raw materials, the title compound was prepared in the same manner as in Example 16, with a yield of 67%; MS 1070 [M+H] ⁺ ; see Table-1 for C-NMR of compound ¹³ .

Embodiment 44: Preparation of compound 44

Except using the corresponding raw materials, the title compound was prepared in the same manner as in Example 16, with a yield of 62%; MS 1083 [M+H] ⁺ ; compound ¹³ C-NMR is shown in Table-1.

Embodiment 45: Preparation of compound 45

Except using the corresponding raw materials, the title compound was prepared in the same manner as in Example 16, with a yield of 45%; MS 1061 [M+H] ⁺ ; compound ¹³ C-NMR is shown in Table-1.

Embodiment 46: Preparation of compound 46

Except using the corresponding starting materials, the title compound was prepared in the same manner as in Example 16 with a yield of 70%; MS 1078 [M+H] ⁺ ; compound ¹³ C-NMR is shown in Table-1.

Embodiment 47: Preparation of Compound 47

Except using the corresponding raw materials, the title compound was prepared by the same method as in Example 16, with a yield of 61%; MS 498 [M/2+H] ⁺ ; compound ¹³ C-NMR is shown in Table-1.

Embodiment 48: Preparation of compound 48

Except using the corresponding raw materials, the title compound was prepared by the same method as in Example 16, with a yield of 67%; MS 1035 [M+H] ⁺ ; compound ¹³ C-NMR is shown in Table-1.

Embodiment 49: Preparation of compound 49

Except using the corresponding raw materials, the title compound was prepared in the same manner as in Example 16, with a yield of 36%; MS 1067 [M+H] ⁺ ; see Table-1 for C-NMR of compound ¹³ .

Embodiment 50: the preparation of compound 50

Except using the corresponding raw materials, the title compound was prepared by the same method as in Example 16, with a yield of 44%; MS 1058 [M+H] ⁺ ; compound ¹³ C-NMR is shown in Table-1.

Embodiment 51: Preparation of compound 51

Except using the corresponding raw materials, the title compound was prepared in the same manner as in Example 16, with a yield of 67%; MS 1042 [M+H] ⁺ ; compound ¹³ C-NMR is shown in Table-1.

Embodiment 52: Preparation of compound 52

Except using the corresponding starting materials, the title compound was prepared by the same method as in Example 16 with a yield of 44%; MS 885 [M+H] ⁺ .

Embodiment 53: Preparation of compound 53

Except using the corresponding starting materials, the title compound was prepared in the same manner as in Example 16 with a yield of 67%; MS 924[M+H] ⁺ .

Embodiment 54: Preparation of compound 54

Except using the corresponding starting materials, the title compound was prepared in the same manner as in Example 16, with a yield of 65%; MS 1072 [M+H] ⁺ ; see Table-1 for C-NMR of compound ¹³ .

Embodiment 55: Preparation of compound 55

Except using the corresponding starting materials, the title compound was prepared in the same manner as in Example 16, with a yield of 38%; MS 1056 [M+H] ⁺ ; compound ¹³ C-NMR is shown in Table-1.

Embodiment 56: Preparation of compound 56

Except using the corresponding raw materials, the title compound was prepared by the same method as in Example 16, with a yield of 41%; MS 1012 [M+H] ⁺ ; compound ¹³ C-NMR is shown in Table-1.

Embodiment 57: Preparation of compound 57

Except using the corresponding starting materials, the title compound was prepared in the same manner as in Example 16, with a yield of 59%; MS 998 [M+H] ⁺ ; compound ¹³ C-NMR is shown in Table-1.

Embodiment 58: Preparation of compound 58

Except using the corresponding raw materials, the title compound was prepared in the same manner as in Example 16, with a yield of 58%; MS 1052 [M+H] ⁺ ; compound ¹³ C-NMR is shown in Table-1.

Embodiment 59: Preparation of compound 59

Except using the corresponding starting materials, the title compound was prepared in the same manner as in Example 16, with a yield of 67%; MS 1036 [M+H] ⁺ ; compound ¹³ C-NMR is shown in Table-1.

Embodiment 60: the preparation of compound 60

Except using the corresponding starting materials, the title compound was prepared in the same manner as in Example 16, with a yield of 67%; MS 1022 [M+H] ⁺ ; compound ¹³ C-NMR is shown in Table-1.

Embodiment 61: the preparation of compound 61

Except using the corresponding starting materials, the title compound was prepared in the same manner as in Example 16, with a yield of 71%; MS 992 [M+H] ⁺ ; see Table-1 for C-NMR of compound ¹³ .

Embodiment 62: the preparation of compound 62

Step A

The product obtained in Step B in Example 1 (6.00 g, 8.01 mmol) was dissolved in 80 mL of methanol and 40 mL of water, 36% hydrochloric acid was added to control the pH value to 4.0-5.0, and stirred at room temperature for 24 h. After the reaction, adjust the pH value to 8.0-9.0 with saturated Na ₂ CO ₃ , then extract with chloroform, wash with water and dry with anhydrous sodium sulfate. The solution was concentrated and evaporated to dryness, and the obtained crude product was purified by silica gel column chromatography (chloroform:methanol:ammonia water=10:0.5:0.01～10:1:0.05) to obtain 2.65 g of white solid, yield 56%.

Step B

The product obtained in Step A (0.50 g, 0.85 mmol) was dissolved in 50 mL of dichloromethane dried over anhydrous magnesium sulfate, followed by the addition of N,N-diisopropylethylamine (0.86 mL, 4.23 mmol) and β-naphthalene Benzyl (0.75g, 4.23mmol) was stirred under reflux for 12h. After the reaction, dichloromethane was evaporated to dryness and extracted with chloroform, washed with water and dried over anhydrous sodium sulfate. The solution was concentrated and evaporated to dryness. The crude product obtained from the above reaction was purified by silica gel column chromatography (chloroform:methanol:ammonia water=10:0.5:0.01~10:1:0.05) to obtain 0.48 g of white solid.

Step C

The product obtained in step B was dissolved in 10mL of anhydrous ether and 3mL of DMF, then NaH (95%) (31.52mg, 1.31mmol) was added to the solution, and when there was no gas generation in the solution, reaction was added thereto. Formula 1, 4-dibromobutene (0.44g, 1.97mmol), stirred at room temperature for 60 minutes. Then N-methylpiperazine (28.40 mg, 0.33 mmol) was added to the reaction solution. After continuing to react at room temperature for 12 h, the reaction solution was poured into water, extracted with dichloromethane, washed with water and dried over anhydrous sodium sulfate. Then the solution was concentrated and evaporated to dryness, and the obtained crude product was purified by silica gel column chromatography (chloroform:methanol:ammonia water=10:0.5:0.01～10:1:0.05) to obtain 0.29 g of white foamy solid.

Step D

Dissolve this product in 30 mL of dichloromethane dried with anhydrous magnesium sulfate, add 4.24 mL of DMSO, DCC (0.75 g, 3.61 mmol), 0.42 mL of pyridine, and 0.21 mL of trifluoroacetic acid, react in an ice-water bath for 24 hours, and the reaction is complete Afterwards, dichloromethane was evaporated to dryness, followed by extraction with chloroform, washing with water and drying over anhydrous sodium sulfate. The solution was concentrated and evaporated to dryness, and the resulting crude product was purified by silica gel column chromatography (chloroform: methanol: ammonia water = 10: 0.5: 0.01 ~ 10: 1: 0.05) to obtain 0.19 g of the title compound with a yield of 41%; MS 441 [M/ 2+H] ⁺ .

Embodiment 63: the preparation of compound 63

The title compound was prepared in the same manner as in Example 62, except that the corresponding starting materials were used, with a yield of 58%; MS 921 [M+H] ⁺ .

Embodiment 64: the preparation of compound 64

Except using the corresponding raw materials, the title compound was prepared in the same manner as in Example 16, with a yield of 60%; MS 1012 [M+H] ⁺ ; compound ¹³ C-NMR is shown in Table-1.

Embodiment 65: the preparation of compound 65

Except using the corresponding starting materials, the title compound was prepared in the same manner as in Example 16, with a yield of 66%; MS 953 [M+H] ⁺ ; compound ¹³ C-NMR is shown in Table-1.

Table-1 Compound ¹³ C-NMR assignment

Table-1 Compound ¹³ C-NMR assignment

Table-1 Compound ¹³ C-NMR assignment

Table-1 Compound ¹³ C-NMR assignment

Table-1 Compound ¹³ C-NMR assignment

Table-1 Compound ¹³ C-NMR assignment

Table-1 Compound ¹³ C-NMR assignment

Table-1 Compound ¹³ C-NMR assignment

Table-1 Compound ¹³ C-NMR assignment

Table-1 Compound ¹³ C-NMR assignment

Table-1 Compound ¹³ C-NMR assignment

Embodiment 66: In vitro antitumor activity test of the compound of the present invention

The in vitro activity test method and results are as follows: Among them, cisplatin, a commonly used anti-tumor drug in clinical practice, is the positive control experimental group.

Antitumor activity in vitro screening test-1

Screening method: tetrazolium salt (micoculture tetrazolium, MTT) reduction method

Cell line: human colon cancer cell line LoVo cell line

Action time: 48h

The inhibition rate (%) of each compound on tumor cell proliferation at 1.0 μM is shown in Table-2.

Table 2

Claims (2)

1. Erythromycin derivatives, selected from: 2. the application of the erythromycin derivative described in claim 1 in the preparation of antineoplastic drugs.