CN102010418A - High-camptothecin compounds and use thereof as medicaments - Google Patents

Abstract

The invention relates to the technical field of medicine, in particular to a new class of homocamptothecin compounds and their use as antitumor drugs. The structure of the compound of the present invention is shown in the general formula (I), including its optical isomers, racemates, cis-trans isomers and any mixture of these forms or pharmaceutically acceptable salts thereof. The compound of the invention has the effect of inhibiting the activity of topoisomerase I, and can be used for preparing antitumor drugs.

Description

Homocamptothecin compounds and their use as medicine

technical field

The invention relates to the technical field of medicine, in particular to a homocamptothecin compound and its application as an antitumor drug.

Background technique

Camptothecin (Camptothecin) is an alkaloid extracted from the Chinese Davidiaceae plant Camptotheca acuminata by American chemist Wall et al. Camptothecin is a five-ring rigid structure composed of indolizine[1,2-b]quinoline fragments fused with six-membered-hydroxylactone. The 20th carbon with-hydroxyl is asymmetrical, which endows the molecule with Optical properties. Its structure is as follows:

Camptothecin is the earliest discovered, most studied, and most widely used specific topoisomerase I inhibitor (Topo I), and is also the most classic Topo I specific inhibitor. exhibited good antitumor activity. After years of research on the structure-activity relationship, a large number of camptothecin derivatives with application value have been developed, among which Irinotecan (CPT-11) and Topotecan (Topotecan, TPT) have been approved by the FDA for marketing, Benoy Tecan was approved for marketing in South Korea in 2004.

A large number of studies have shown that camptothecin compounds have many advantages such as high efficiency, broad spectrum, and good selectivity. However, camptothecin still has disadvantages such as unstable metabolism in the body, low water solubility, toxicity, and species differences. At first, researchers prepared camptothecin E ring ring-opening into carboxylate form to improve water solubility, however, this change significantly reduced the activity of camptothecin, and caused its serious toxic side effects (CancerChemother.Rpt. 1972, 56, 95). In order to improve the stability of camptothecin compounds in vivo and enhance the activity, the researchers esterified the 20-hydroxyl into a prodrug, which can effectively prevent the formation of hydrogen bonds between the 20-hydroxyl and the adjacent carbonyl molecule to inhibit Hydrolysis of the lactone ring. In 1985, with the discovery of the mechanism of action of camptothecin, it can specifically act on DNA topoisomerase I, which triggered the second wave of researchers' in-depth research on camptothecin. In 1997, Olivier Lavergne et al. proposed a new class of camptothecin analogs with a β-hydroxy seven-membered lactone ring in WO97/00876, also known as homocamptothecin (hCPT). It not only enhances the anti-tumor activity, but also has the advantages of small species difference, low toxicity and side effects, and high activity against drug-resistant tumor cells, which has attracted the attention of researchers. Currently, BN809915 (diflomotecan) (Expert Opin. Investig.Drugs.2009, 18, 69), BN80927 (elomotecan) (Cancer Res. 2004, 64, 4942), etc., have entered Phase II and Phase I clinical stages respectively.

According to the structure-activity relationship of camptothecin compounds, the 7th position is the key region that affects their activity. Studies have shown that introducing an appropriate group at the 7th position of homocamptothecin can significantly improve the antitumor activity of homocamptothecin compounds in vivo and in vitro (ZL200510110903 .6; Eur. J. Med. Chem. 2010, 45, 2726).

Contents of the invention

The present invention combines the characteristics of high anti-tumor activity of homocamptothecin, small species difference, and low toxicity and side effects, and the diverse biological activities of compounds such as dihydropyrimidines and dihydropyridines, and combines these active groups with homocamptothecin. Proper combination of the parent skeleton, thus discovering novel homocamptothecin derivatives with better anti-tumor activity, including optical isomers, racemates, cis-trans isomers and any mixture or mixture of these forms Its medicinal salt, structure such as general formula (I):

in:

In general formula (I):

或

或

或(CH₂)_mC(O)R₁₀基团，其中R₆表示氢、羟基、氨基、低级烷基氨基、低级烷基、低级卤代烷基、低级烷氧基、低级链烯基、氰基、低级氰基烷基、硝基、低级硝基烷基、酰胺基、低级酰胺基烷基、肼基、低级肼基烷基、叠氮基、低级叠氮基烷基、苯基，所述苯基至少具有一个或多个下列取代基团：氢、羟基、氨基、低级烷基氨基、低级烷基、卤素、低级卤代烷基、低级烷氧基、低级链烯基、氰基、低级氰基烷基、硝基、低级硝基烷基、酰胺基、低级酰胺基烷基、肼基、低级肼基烷基、叠氮基、低级叠氮基烷基；R ₁ : means

or

or

Or (CH ₂ ) _m C (O) R ₁₀ group, wherein R ₆ represents hydrogen, hydroxyl, amino, lower alkylamino, lower alkyl, lower haloalkyl, lower alkoxy, lower alkenyl, cyano , lower cyanoalkyl, nitro, lower nitroalkyl, amido, lower amidoalkyl, hydrazino, lower hydrazinoalkyl, azido, lower azidoalkyl, phenyl, said Phenyl has at least one or more of the following substituents: hydrogen, hydroxyl, amino, lower alkylamino, lower alkyl, halogen, lower haloalkyl, lower alkoxy, lower alkenyl, cyano, lower cyano Alkyl, nitro, lower nitroalkyl, amido, lower amidoalkyl, hydrazino, lower hydrazinoalkyl, azido, lower azidoalkyl;

Preferably wherein _R represents hydrogen, hydroxy, amino, lower alkylamino, lower alkyl, lower haloalkyl, lower alkoxy, lower alkenyl, cyano, lower cyanoalkyl, nitro, lower nitroalkane group, amide group, lower amidoalkyl group, hydrazino group, lower hydrazinoalkyl group, azido group, lower azidoalkyl group, phenyl group, said phenyl group has at least one or more of the following substituent groups: hydrogen , hydroxy, halogen, lower alkyl, lower alkoxy, cyano, nitro;

_R represents hydrogen, hydroxy, lower hydroxyalkyl, lower alkyl, lower haloalkyl, lower alkoxy, lower alkenyl, cyano, lower cyanoalkyl, nitro, lower nitroalkyl, amino, Lower alkylamino, lower aminoalkyl, alkylamido, lower amidoalkyl, hydrazino, lower hydrazinoalkyl, azido, lower azidoalkyl, phenyl, said phenyl having at least One or more of the following substituents: hydrogen, hydroxy, amino, lower alkylamino, lower alkyl, halogen, lower haloalkyl, lower alkoxy, lower alkenyl, cyano, lower cyanoalkyl, nitr group, lower nitroalkyl group, amido group, lower amidoalkyl group, hydrazino group, lower hydrazinoalkyl group, azido group, lower azidoalkyl group;

Preferably _R represents lower alkyl, lower haloalkyl, cyano, lower cyanoalkyl, nitro, lower nitroalkyl, amino, lower aminoalkyl, hydroxyl, lower hydroxyalkyl;

_R represents hydrogen, hydroxy, lower alkyl, lower hydroxyalkyl, lower haloalkyl, lower amidoalkyl, lower alkoxy, lower alkenyl, cyano, lower cyanoalkyl, nitro, lower nitro Alkyl, amino, lower alkylamino, lower aminoalkyl, alkylamido, hydrazino, lower hydrazinoalkyl, azido, lower azidoalkyl, phenyl;

Preferably _R represents hydrogen, lower alkyl, lower haloalkyl, lower amidoalkyl, lower hydrazinoalkyl, lower azidoalkyl, phenyl;

_R represents hydrogen, hydroxy, lower alkyl, lower hydroxyalkyl, lower haloalkyl, lower amidoalkyl, lower alkoxy, lower alkenyl, cyano, lower cyanoalkyl, nitro, lower nitro Alkyl, amino, lower alkylamino, lower aminoalkyl, alkylamido, hydrazino, lower hydrazinoalkyl, azido, lower azidoalkyl, phenyl, the phenyl has at least One or more of the following substituents: hydrogen, hydroxy, amino, lower alkylamino, lower alkyl, halogen, lower haloalkyl, lower alkoxy, lower alkenyl, cyano, lower cyanoalkyl, nitr group, lower nitroalkyl group, amido group, lower amidoalkyl group, hydrazino group, lower hydrazinoalkyl group, azido group, lower azidoalkyl group;

Preferably _R represents hydrogen, lower alkyl, lower haloalkyl, phenyl, and said phenyl has at least one or more of the following substituent groups: hydrogen, hydroxyl, halogen, lower alkyl, lower alkoxy, cyano, nitro;

R ₁₀ represents lower alkyl, cycloalkyl, [N=X], aryl, and has at least one or more of the following substituent groups: hydrogen, hydroxyl, halogen, lower alkyl, lower alkoxy, cyano, nitro;

R ₂ , R ₃ , and R ₄ independently represent the following groups: hydrogen, halogen, lower haloalkyl, lower alkyl, lower alkenyl, amino, lower alkylamino, nitro, lower nitroalkyl, cyano , lower cyanoalkyl, amido, lower amidoalkyl, hydrazino, lower hydrazinoalkyl, azido, lower azidoalkyl, (CH ₂ ) _m NR ₁₁ R ₁₂ , (CH ₂ ) _m OR ₁₃ , (CH ₂ ) _m SR ₁₄ , (CH ₂ ) _m O ₂ R ₁₄ , (CH ₂ ) _m NR ₈ C(O)R ₁₅ , (CH ₂ ) _m C(O)R ₁₅ , (CH ₂ ) _m OC(O)R ₁₅ , O(CH ₂ ) _m NR ₁₁ R ₁₂ , OC(O)NR ₁₁ R ₁₂ , OC(O)(CH ₂ ) _m CO ₂ R ₁₃ or (CH ₂ ) _n [ N=X], OC(O)[N=X], (CH ₂ ) _m OC(O)[N=X], substituted or unsubstituted lower aralkyl, wherein the substituent is lower alkyl, hydroxyl, Halogen, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy, lower alkoxy lower alkyl; or _R and _R together form a 3- or 4-membered chain, or R ₃ and R ₄ together form a 3- or 4-membered chain, wherein the units of the chain are selected from CH, CH ₂ , O, S or NR ₁₅ ;

Preferably R ₂ , R ₃ , R ₄ independently represent the following groups: hydrogen, halogen, lower alkyl, nitro, amino, (CH ₂ ) _m NR ₁₁ R ₁₂ , (CH ₂ ) _m OR ₁₃ , (CH ₂ ) _m C(O)R ₁₄ , (CH ₂ ) _m OC(O)R ₁₄ , substituted or unsubstituted lower aralkyl, wherein the substituent is lower alkyl, hydroxy, halogen, nitro, amino, lower alkane ylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy, lower alkoxy lower alkyl, or _R2 and _R3 together form a 3- or 4-membered chain, wherein the units of the chain are selected from CH, CH ₂ , O, S or NR ₁₅ ;

_R represents lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, lower alkoxy lower alkyl or lower alkylthio lower alkyl;

Preferably R represents _ethyl ;

R ₁₁ and R ₁₂ independently represent hydrogen, lower alkyl, lower hydroxyalkyl, lower alkyl lower aminoalkyl, lower aminoalkyl, cycloalkyl, cycloalkyl lower alkyl, lower alkenyl, Lower alkoxy lower alkyl, lower haloalkyl or substituted or unsubstituted lower aralkyl, wherein the substituents are lower alkyl, halogen, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkane Oxygen or lower alkoxy lower alkyl;

R ₁₃ and R ₁₄ represent hydrogen, lower alkyl, lower hydroxyalkyl, amino, lower alkylamino, lower alkyl lower aminoalkyl, lower aminoalkyl, cycloalkyl, cycloalkyl lower alkyl, Lower alkenyl, lower alkoxy, lower alkoxy lower alkyl, lower haloalkyl and either substituted or unsubstituted lower aralkyl, wherein the substituents are lower alkyl, hydroxy, halogen, nitro, amino, lower Alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy or lower alkoxy lower alkyl;

R ₁₅ represents hydrogen, lower alkyl, lower haloalkyl, aryl, or aryl substituted by one or more of the following groups: lower alkyl, hydroxyl, halogen, nitro, amino, lower alkylamino, lower haloalkyl , lower hydroxyalkyl, lower alkoxy or lower alkoxy lower alkyl;

G means O, S, NH;

m is an integer between 0 and 6;

n is 1 or 2;

[N=X] represents a 4 to 7-membered heterocyclic group, and X represents the chain required to complete the heterocyclic group and is selected from O, S, CH ₂ , CH, NR ₁₂ , COR ₁₄ ;

In this context, the term "lower" in relation to alkyl, alkylthio and alkoxy refers to a straight or branched chain saturated aliphatic hydrocarbon group containing 1 to 6 carbon atoms, for example, methyl, ethyl, propyl , isopropyl, butyl, tert-butyl, methylthio, ethylthio, methoxy and ethoxy, the term "lower" in relation to the term alkenyl or alkynyl means Groups with atoms and one or more double or triple bonds, for example: vinyl, allyl, isoallyl, pentenyl, hexenyl, propenyl, ethynyl, propynyl, and butynyl . The term cycloalkyl refers to a ring containing 3 to 7 carbons, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. The term aryl refers to mono-, bi- or tricyclic hydrocarbon compounds in which at least one ring is aromatic and each ring contains up to 7 carbon atoms, eg, phenyl, naphthyl, anthracenyl, biphenyl or indenyl. The term halogen refers to chlorine, bromine, iodine or fluorine. Corresponding to the terms lower haloalkyl, lower cyanoalkyl, lower nitroalkyl, lower amidoalkyl, lower hydrazinoalkyl, lower alkoxy lower alkyl, lower azidoalkyl, lower aralkyl , lower hydroxyalkyl, lower alkylthio lower alkyl and lower alkyl lower sulfonylalkyl are respectively replaced by one to three halogen, cyano, nitro, amido, hydrazino, alkoxy, azide Substitution by nitrogen, aryl, hydroxy, lower alkylthio lower alkyl or lower sulfonylalkyl. A lower alkylamino group may contain one or two lower alkyl groups, for example representing NHCH ₃ , NHCH ₂ CH ₃ , N(CH ₃ ) ₂ or CH ₃ NCH ₂ CH ₃ .

Compounds of formula (I) are selected from:

7-{4-[6-(4-Methyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin,

7-{4-[6-(4-gem-hydroxy-trifluoromethyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin,

7-{3-[6-(4-methyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin,

7-{3-[6-(4-gem-hydroxy-trifluoromethyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin,

7-{4-[6-(4-Methyl-5-methoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin,

7-{4-[6-(4-Methyl-5-acetyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin,

7-{4-[6-(3-Ethyl-4-methyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin,

7-{4-[6-(3,4-Dimethyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin,

(R)-7-{4-[6-(3,4-Dimethyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin,

(S)-7-{4-[6-(3,4-Dimethyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin,

7-{4-[6-(3-Phenyl-4-methyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin,

7-{4-[6-(4-methyl-5-tert-butoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin,

7-{4-[6-(4-Methyl-5-isobutoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin,

7-{4-[6-(3-Ethyl-4-methyl-5-methoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin,

7-{4-[6-(3-Methyl-4-gem-hydroxy-trifluoromethyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin,

7-{4-[6-(3-Phenyl-4-gem-hydroxy-trifluoromethyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin,

7-{4-[6-(3-Ethyl-4-gem-hydroxy-trifluoromethyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin,

7-{4-[6-(3,4-Dimethyl-5-acetyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin,

7-{4-[6-(3-Ethyl-4-methyl-5-tert-butoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin,

7-{4-[6-(3,4-Dimethyl-5-isobutoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin,

7-{4-[6-(3-Phenyl-4-methyl-5-tert-butoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin,

7-{4-[6-(3-Ethyl-4-methyl-5-acetyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin,

7-{4-[4-(2,6-Dimethyl-3,5-diethoxycarbonyl)dihydropyridyl]phenyl}methyleneaminohomocamptothecin,

7-{4-[4-(2,6-Dimethyl-3,5-dimethoxycarbonyl)dihydropyridyl]phenyl}methyleneaminohomocamptothecin,

7-{4-[4-(2,6-Dimethyl-3,5-di-tert-butoxycarbonyl)dihydropyridyl]phenyl}methyleneaminohomocamptothecin,

7-{4-[4-(2,6-Dimethyl-3,5-diisobutoxycarbonyl)dihydropyridyl]phenyl}methyleneaminohomocamptothecin,

7-{4-[4-(2,6-Dimethyl-3,5-di-n-propoxycarbonyl)dihydropyridyl]phenyl}methyleneaminohomocamptothecin,

7-{4-[4-(2,6-Dimethyl-3,5-diallyloxycarbonyl)dihydropyridyl]phenyl}methyleneaminohomocamptothecin,

7-{4-[4-(2,6-Dimethyl-3,5-dimethoxyethoxycarbonyl)dihydropyridyl]phenyl}methyleneaminohomocamptothecin,

7-{3-[4-(2,6-Dimethyl-3,5-dimethoxycarbonyl)dihydropyridyl]phenyl}methyleneaminohomocamptothecin,

(R)-7-{3-[4-(2,6-Dimethyl-3,5-dimethoxycarbonyl)dihydropyridyl]phenyl}methyleneaminohomocamptothecin,

(S)-7-{3-[4-(2,6-Dimethyl-3,5-dimethoxycarbonyl)dihydropyridyl]phenyl}methyleneaminohomocamptothecin,

7-{3-[4-(2,6-Dimethyl-3,5-diisobutoxycarbonyl)dihydropyridyl]phenyl}methyleneaminohomocamptothecin,

7-{3-[4-(2,6-Dimethyl-3,5-diethoxycarbonyl)dihydropyridyl]phenyl}methyleneaminohomocamptothecin,

(R)-7-{3-[4-(2,6-Dimethyl-3,5-diethoxycarbonyl)dihydropyridyl]phenyl}methyleneaminohomocamptothecin,

(S)-7-{3-[4-(2,6-Dimethyl-3,5-diethoxycarbonyl)dihydropyridyl]phenyl}methyleneaminohomocamptothecin,

7-(2-furyl)formyl-10-methoxyhomocamptothecin,

(R)-7-(2-furyl)formyl-10-methoxyhomocamptothecin,

(S)-7-(2-furyl)formyl-10-methoxyhomocamptothecin,

7-(2-thiophene)formyl-10-methoxyhomocamptothecin,

7-benzoyl-10-methoxyhomocamptothecin,

7-p-Chlorobenzoyl-10-methoxyhomocamptothecin,

7-p-fluorobenzoyl-10-methoxyhomocamptothecin,

7-(4-Methyl)benzoyl-10-methoxyhomocamptothecin,

7-(4-trifluoromethyl)benzoyl-10-methoxyhomocamptothecin,

7-(4-Methoxy)benzoyl-10-methoxyhomocamptothecin,

7-(3,5-Dimethyl)benzoyl-10-methoxyhomocamptothecin,

7-(2-naphthalene)benzoyl-10-methoxyhomocamptothecin,

7-cyclopropanoyl-10-methoxyhomocamptothecin,

(R)-7-cyclopropanoyl-10-methoxyhomocamptothecin,

(S)-7-cyclopropanoyl-10-methoxyhomocamptothecin,

7-cyclopentanoyl-10-methoxyhomocamptothecin,

(R)-7-cyclopentanoyl-10-methoxyhomocamptothecin,

(S)-7-cyclopentanoyl-10-methoxyhomocamptothecin,

7-Cyclohexanoyl-10-methoxyhomocamptothecin,

7-propionyl-10-methoxyhomocamptothecin,

7-butyryl-10-methoxyhomocamptothecin,

7-pentanoyl-10-methoxyhomocamptothecin,

7-heptanoyl-10-methoxyhomocamptothecin,

7-Isobutyryl-10-methoxyhomocamptothecin.

The β-hydroxylactone ring of the compound of the present invention contains an asymmetric carbon atom and has two configurations of R and S. Its racemate can obtain the optically pure enantiomer by the method of resolution [such as the method of Olivier Lavergne etc.: J.Med.Chem.41:5410 (1998)], in the present invention, we adopt chiral half The optically pure isomers of some compounds were obtained by preparative column separation. In addition, the carbon-nitrogen double bond in the 7-position substitution has cis-trans isomers. The present invention includes these enantiomeric configurations, cis-trans isomers and their various combinations, as well as racemic compounds.

The invention also provides a preparation method of the homocamptothecin compounds. The synthetic route is as follows:

Reaction formula one:

Reaction two:

Compounds of formula (I) can be prepared by the methods described below and exemplified for preferred compounds of the invention.

In Reaction Formula 1, the starting key intermediate 7-aldehyde homocamptothecin can be obtained with reference to Chinese patent ZL200510110903.6, and the synthesis of dihydropyrimidine and dihydropyridine derivatives can refer to the method in the literature (J.Fluorine Chem.2008, 129 , 1083; Bioorg.Med.Chem.2009, 17, 1579) obtained. Then they are condensed under the condition of the catalyst to obtain derivatives of different substituted dihydropyrimidines and dihydropyridine derivatives combined with homocamptothecin. Taking 7-formaldehyde homocamptothecin as an example, the specific synthesis steps are described in detail below:

1. For dihydropyrimidine derivatives, the synthetic method is to obtain nitro-substituted benzaldehyde and β-ketoester, urea (or thiourea) through the classic Biginelli reaction under catalytic conditions, where the catalyst includes Hydrochloric acid, sulfuric acid, boric acid, Yb(OTf) ₃ , acetic acid, p-toluenesulfonic acid, TMSCl, zeolite, InBr ₃ , KHSO ₄ , Microwave, etc. Considering the ease of post-treatment, we prefer TMSCl as the catalyst.

2. Catalytic hydrogenation of nitrodihydropyrimidine derivatives to obtain aminodihydropyrimidine derivatives. Reduction conditions include H ₂ /Pd-C, Sn/HCl, hydrazine hydrate/Raney Ni, etc. Here we prefer H ₂ / Pd-C.

3. For dihydropyridine derivatives, the synthesis method is to obtain nitro-substituted benzaldehyde with β-ketoester and ammonia through the classic Hantzsch reaction under catalytic conditions. The catalysts here include triethylamine, Yb (OTf) ₃ , zeolite, InBr ₃ , KHSO ₄ , Microwave (microwave), DMAP, etc. Here we prefer DMAP as the catalyst.

4. Catalytic hydrogenation of nitrodihydropyridine derivatives to obtain aminodihydropyridine derivatives. Reduction conditions include H ₂ /Pd-C, Sn/HCl, hydrazine hydrate/Raney Ni, etc. Here we prefer H ₂ / Pd-C.

5. React 7-formaldehyde-based homocamptothecin with the corresponding aminodihydropyrimidine and aminodihydropyridine derivatives under acid catalysis to obtain a combination of homocamptothecin and dihydropyrimidine and dihydropyridine derivatives, where the acid includes Organic acids and inorganic acids, such as: acetic acid, p-toluenesulfonic acid, sulfuric acid, Yb(OTf) ₃ , etc., preferably Yb(OTf) ₃ . The solvent is selected from polar or non-polar solvents such as dichloromethane, chloroform, benzene, DMSO, etc., preferably chloroform.

In Reaction Scheme 2, the starting tricyclic key intermediate (9-ethyl-9-hydroxyl-2,3,8,9-tetrahydro-5H-6-oxa-3a-aza-cycloheptane- 1,4,7-triketone) can be obtained with reference to Chinese patent ZL200410016229.0, and differently substituted anthranilaldehydes can be obtained by referring to literature methods [Sugasawa et al. J.Org.Chem.44: 578 (1979); Sugasawa et al. J.Am .Chem.Soc.100:484(1978)] obtained. Then they are subjected to the classic Friedlander condensation reaction to obtain homocamptothecin derivatives with different substituents on the A ring. The specific synthesis steps are described in detail below:

1. For the compound of formula (I), R ₂ , R ₄ are all hydrogen, and when R ₃ methoxy, the Friedlander condensation reaction of the tricyclic key intermediate and 5-methoxy-2-aminobenzaldehyde is obtained: 10-methoxyhomocamptothecin usually adopts polar or nonpolar solvents such as benzene, toluene, ethanol, acetic acid, etc., preferably nonpolar solvents such as benzene and toluene. The catalyst used for the Friedlander condensation is an acidic catalyst, including organic acids and inorganic acids, preferably organic acids such as p-toluenesulfonic acid, acetic acid, formic acid, etc., particularly preferably p-toluenesulfonic acid.

2. Formylate 10-methoxyhomocamptothecin with substituted aldehydes and a suitable oxidation system under acidic conditions to obtain different substituted formyl homocamptothecins. The acid here is an inorganic acid, including hydrochloric acid, sulfuric acid of different concentrations, etc., preferably concentrated sulfuric acid. The oxidation system includes a combination of a reducing agent (such as ferrous sulfate, ferrous oxide, etc.) and an oxidizing agent (such as hydrogen peroxide, peracetic acid, tert-butanol peroxide, etc.), preferably a ferrous sulfate/tert-butanol peroxide system.

IB(大赛璐)，柱规格(内径：20mm；外径：250mm)，能选用的色谱溶剂有甲醇、异丙醇、乙腈、四氢呋喃、二氧六环、氯仿、正己烷等，在此处我们优选异丙醇/正己烷体系，流动相中缓冲液可以使用乙酸、甲酸、磷酸等，我们优选磷酸的缓冲体系。3. In the chiral separation of some compounds, the model of the chiral semi-preparative column we used is

IB (Daicel), column specifications (inner diameter: 20mm; outer diameter: 250mm), the chromatographic solvents that can be selected are methanol, isopropanol, acetonitrile, tetrahydrofuran, dioxane, chloroform, n-hexane, etc. Here we The isopropanol/n-hexane system is preferred, and the buffer in the mobile phase can use acetic acid, formic acid, phosphoric acid, etc., and we prefer the buffer system of phosphoric acid.

Certain compounds of the present invention can be prepared in the form of pharmaceutically acceptable salts according to conventional methods. Including its organic acid salts and inorganic acid salts: inorganic acids include (but not limited to) hydrochloric acid, sulfuric acid, phosphoric acid, diphosphoric acid, hydrobromic acid, nitric acid, etc., organic acids include (but not limited to) acetic acid, maleic acid, fumaric acid acid, tartaric acid, succinic acid, lactic acid, p-toluenesulfonic acid, salicylic acid, oxalic acid, etc.

The compound of formula (I) of the present invention has the function of inhibiting topoisomerase and has antitumor activity. The prior art suggests that the compound of the present invention has antiviral activity [Chiang.J.Li etc., The Journal of Biological Chemistry, 269:7051 (1994)] and antifungal activity [Fostel J. etc., FEMS Microbiology Letters, 138:105 ( 1996)], so the compounds of the present invention can be used to prepare corresponding therapeutic drugs.

The compounds of the present invention have antitumor activity, and they can be used to treat tumors, including esophagus, stomach, intestine, rectum, oral cavity, pharynx, larynx, lung, colon, breast, uterus, endometrium, ovary, prostate, testis, bladder, Cancers of the kidney, liver, pancreas, bone, connective tissue, skin, eye, brain, and central nervous system, as well as thyroid cancer, leukemia, Hawking's disease, lymphoma, and myeloma.

The compounds of the invention are also useful in the treatment of viral and fungal infections.

The pharmacological activity of the compounds of the present invention makes them useful for the preparation of antitumor, antifungal and antiviral drugs, so the present invention also includes pharmaceutical compositions using these compounds and their pharmaceutically acceptable salts as active ingredients. The pharmaceutical composition can be in solid or liquid form.

The present invention also includes the use of the compound of formula (I) in the preparation of the following medicines: medicines for inhibiting topoisomerase, antitumor medicines, antifungal medicines and antiviral medicines.

Detailed ways

The present invention will be described in detail below in conjunction with the examples, but the implementation of the present invention is not limited thereto.

Example 1 7-{4-[6-(4-methyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin

100 mg 7-formyl homocamptothecin, 10 mg Yb(OTf) ₃ , 100 mg 4-[6-(4-methyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]aniline and 30 mL chloroform The reaction vial was reacted at room temperature, and the reaction was monitored by TLC. After the reaction was complete, the solvent was evaporated, and purified on a silica gel column (eluent: CH ₂ Cl ₂ /CH ₃ OH 100:2) to obtain 70 mg of yellow solid 7-{4- [6-(4-Methyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin.

¹ H-NMR (DMSO):

0.88(t, 3H), 1.18(t, 3H), 1.88(q, 2H), 2.29(s, 6H), 3.06-3.48(q, 2H), 4.03(q, 4H), 4.94(s, 1H) , 5.39-5.53(q, 2H), 5.55(s, 2H), 6.04(s, 1H), 7.29-7.44(dd, 4H), 7.42(s, 1H), 7.80(t, 1H), 7.93(t , 1H), 8.25(d, 1H), 8.87(s, 1H), 8.96(d, 1H), 9.65(s, 1H).

Example 2 7-{4-[6-(4-gem-hydroxy-trifluoromethyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin

According to the method of Example 1, replace 4-[6-(4 -Methyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]aniline to give 85 mg of yellow solid 7-{4-[6-(4-gem-hydroxy-trifluoromethyl-5-ethoxy Carbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin.

¹ H-NMR (DMSO):

0.88(t, 3H), 1.87(q, 2H), 2.29(s, 6H,), 3.06-3.48(q, 2H), 3.58(s, 6H), 4.96(s, 1H), 5.39-5.54(q , 2H), 5.55(s, 2H), 6.03(s, 1H), 7.28-7.42(dd, 4H), 7.44(s, 1H), 7.81(t, 1H), 7.94(t, 1H), 8.25( d, 1H), 8.93(s, 1H), 8.96(d, 1H), 9.65(s, 1H).

Example 3 7-{3-[6-(4-methyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin

According to the method of Example 1, replace 4-[6-(4-methyl-5- Ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]aniline to give 56 mg of yellow solid 7-{3-[6-(4-methyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl] Phenyl}methyleneamino homocamptothecin.

¹ H-NMR (DMSO):

0.89(t, 3H), 1.15(t, 3H), 2.28(q, 2H), 2.36(s, 3H), 3.04-3.48(q, 2H), 4.03(q, 2H), 5.28(s, 1H) , 5.53-5.58(q, 2H), 5.58(s, 2H), 6.04(s, 1H), 7.35(1H), 7.39(1H), 7.46(s, 1H), 7.48-7.50(2H), 7.84( s, 1H), 7.85(t, 1H), 8.03(t, 1H), 8.27(d, 1H), 8.96(d, 1H), 9.25(s, 1H), 9.67(s, 1H).

Example 4 7-{3-[6-(4-gem-hydroxyl-trifluoromethyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin

According to the method of Example 1, replace 4-[6-(4 -Methyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]aniline to give 65 mg of yellow solid 7-{3-[6-(4-gem-hydroxy-trifluoromethyl-5-ethoxy Carbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin.

¹ H-NMR (DMSO):

0.88(t, 3H), 0.91(t, 3H), 1.88(q, 2H), 3.08-3.49(q, 2H), 3.10(s, 1H), 3.87(q, 2H), 4.94(d, 1H) , 5.40-5.55(q, 2H), 5.56(s, 2H), 6.06(s, 1H), 7.35(1H), 7.37(s, 1H), 7.45(s, 2H), 7.48-7.59(m, 3H ), 7.73(s, 1H), 7.84(t, 1H), 7.93(t, 1H), 8.25(d, 1H), 8.94(d, 1H), 9.68(s, 1H).

Example 5 7-{4-[6-(4-methyl-5-methoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin

According to the method of Example 1, 4-[6-(4-methyl-5-methoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]aniline replaces 4-[6-(4-methyl-5-ethane Oxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]aniline, 81 mg of yellow solid 7-{4-[6-(4-methyl-5-methoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]benzene Base} methylene amino homocamptothecin.

¹ H-NMR (DMSO):

0.88(t, 3H), 1.86(q, 2H), 2.29(s, 3H), 3.07-3.48(q, 2H), 3.57(s, 3H), 5.23(d, 1H), 5.40-5.56(q, 2H), 5.57(s, 2H), 6.04(s, 1H), 7.38-7.54(dd, 4H), 7.45(s, 1H), 7.81(t, 1H), 7.82(s, 1H), 7.95(t , 1H), 8.26(d, 1H), 8.98(d, 1H), 9.27(s, 1H), 9.68(s, 1H).

Example 6 7-{4-[6-(4-methyl-5-acetyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin

According to the method of Example 1, replace 4-[6-(4-methyl-5-ethane) with 4-[6-(4-methyl-5-acetyl-2-oxycarbonyl)dihydropyrimidinyl]aniline Oxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]aniline to give 66 mg of yellow solid 7-{4-[6-(4-methyl-5-acetyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl } Methyleneamino homocamptothecin.

¹ H-NMR (DMSO):

0.88(t, 3H), 1.87(q, 2H), 2.16(s, 3H), 2.24(s, 3H), 3.06-3.48(q, 2H), 5.35(d, 1H), 5.40-5.56(q, 2H), 5.57(s, 2H), 6.04(s, 1H), 7.39-7.53(dd, 4H), 7.45(s, 1H), 7.82(t, 1H), 7.91(s, 1H), 7.95(t , 1H), 8.26(d, 1H), 8.98(d, 1H), 9.24(s, 1H), 9.68(s, 1H).

Example 7 7-{4-[6-(3-ethyl-4-methyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin

According to the method of Example 1, replace 4-[6-(4- Methyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]aniline to give 45 mg of yellow solid 7-{4-[6-(3-ethyl-4-methyl-5-ethoxycarbonyl- 2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin.

¹ H-NMR (DMSO):

0.88(t, 3H), 1.12(t, 3H), 1.17(t, 3H), 1.87(q, 2H), 2.54(s, 3H), 3.07-3.48(q, 2H), 4.01-4.05(dq, 2H), 4.06(q, 2H), 5.22(d, 1H), 5.40-5.56(q, 2H), 5.57(s, 2H), 6.03(s, 1H), 7.36-7.54(dd, 4H), 7.45 (s, 1H), 7.82(t, 1H), 7.95(t, 1H), 7.97(s, 1H), 8.26(d, 1H), 8.98(d, 1H), 9.69(s, 1H).

Example 8 7-{4-[6-(3,4-Dimethyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin

According to the method of Example 1, replace 4-[6-(4-methyl) with 4-[6-(3,4-dimethyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]aniline -5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]aniline to give 56 mg of yellow solid 7-{4-[6-(3,4-dimethyl-5-ethoxycarbonyl-2-oxycarbonyl ) dihydropyrimidinyl] phenyl} methyleneamino homocamptothecin.

¹ H-NMR (DMSO):

0.88(t, 3H), 1.18(t, 3H), 1.87(q, 2H), 2.52(s, 3H), 3.06-3.48(q, 2H), 3.28(s, 3H), 4.07(q, 2H) , 5.24(d, 1H), 5.40-5.56(q, 2H), 5.57(s, 2H), 6.03(s, 1H), 7.36-7.53(dd, 4H), 7.45(s, 1H), 7.82(t , 1H), 7.95(t, 1H), 8.04(d, 1H), 8.26(d, 1H), 8.98(d, 1H), 9.69(s, 1H).

Example 9 (R)-7-{4-[6-(3,4-Dimethyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin

The obtained racemate compound 7-{4-[6-(3,4-dimethyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin 100mg , using a chiral semi-preparative column to separate isomers, mobile phase: isopropanol/n-hexane (60/40), flow rate: 1ml/min, detection wavelength: 220nm, column temperature: 25°C, to obtain 49mg of ( R)-7-{4-[6-(3,4-Dimethyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin{[α] ^D ₂₅ =+51.8 (C=0.44, _CHCl3 / _CH3OH =4:1)}.

¹ H-NMR (DMSO):

0.87(t, 3H), 1.19(t, 3H), 1.87(q, 2H), 2.52(s, 3H), 3.06-3.48(q, 2H), 3.28(s, 3H), 4.07(q, 2H) , 5.24(d, 1H), 5.40-5.56(q, 2H), 5.57(s, 2H), 6.03(s, 1H), 7.36-7.53(dd, 4H), 7.45(s, 1H), 7.82(t , 1H), 7.95(t, 1H), 8.04(d, 1H), 8.26(d, 1H), 8.98(d, 1H), 9.69(s, 1H).

Example 10 (S)-7-{4-[6-(3,4-Dimethyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin

According to the method of Example 9, the racemic compound 7-{4-[6-(3,4-dimethyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl} was resolved Methyleneaminohomocamptothecin 100 mg to give 50 mg of (S)-7-{4-[6-(3,4-dimethyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl} Methyleneamino homocamptothecin {[α] ^D ₂₅ = -50.8 (C = 0.44, CHCl ₃ /CH ₃ OH = 4:1)}.

¹ H-NMR (DMSO):

0.88(t, 3H), 1.19(t, 3H), 1.87(q, 2H), 2.52(s, 3H), 3.06-3.48(q, 2H), 3.28(s, 3H), 4.07(q, 2H) , 5.24(d, 1H), 5.40-5.56(q, 2H), 5.57(s, 2H), 6.03(s, 1H), 7.36-7.53(dd, 4H), 7.45(s, 1H), 7.82(t , 1H), 7.95(t, 1H), 8.04(d, 1H), 8.26(d, 1H), 8.98(d, 1H), 9.69(s, 1H).

Example 11 7-{4-[6-(3-phenyl-4-methyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin

According to the method of Example 1, replace 4-[6-(4- Methyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]aniline to give 61 mg of yellow solid 7-{4-[6-(3-phenyl-4-methyl-5-ethoxycarbonyl- 2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin.

¹ H-NMR (DMSO):

0.89(t, 3H), 1.19(t, 3H), 1.88(q, 2H), 2.07(s, 3H), 3.07-3.46(q, 2H), 3.28(s, 3H), 4.09(q, 2H) , 5.37(d, 1H), 5.40-5.56(q, 2H), 5.58(s, 2H), 6.05(s, 1H), 7.26(d, 2H), 7.41-7.54(m, 3H), 7.46(s , 1H), 7.55-7.63(dd, 4H), 7.82(t, 1H), 7.95(t, 1H), 8.24(d, 1H), 8.26(d, 1H), 8.98(d, 1H), 9.72( s, 1H).

Example 12 7-{4-[6-(4-methyl-5-tert-butoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin

According to the method of Example 1, replace 4-[6-(4-methyl-5 -Ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]aniline to give 45 mg of yellow solid 7-{4-[6-(4-methyl-5-tert-butoxycarbonyl-2-oxycarbonyl)dihydropyrimidine Base] phenyl} methyleneamino homocamptothecin.

¹ H-NMR (DMSO):

0.88(t, 3H), 1.36(s, 9H), 1.87(q, 2H), 2.25(s, 3H), 3.07-3.49(q, 2H), 4.03(q, 2H), 5.18(d, 1H) , 5.40-5.56(q, 2H), 5.58(s, 2H), 6.03(s, 1H), 7.38-7.56(dd, 4H), 7.45(s, 1H), 7.74(s, 1H), 7.83(t , 1H), 7.94(t, 1H), 8.26(d, 1H), 8.99(d, 1H), 9.12(s, 1H), 9.70(s, 1H).

Example 13 7-{4-[6-(4-methyl-5-isobutoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin

According to the method of Example 1, replace 4-[6-(4-methyl-5 -Ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]aniline to give 44 mg of yellow solid 7-{4-[6-(4-methyl-5-isobutoxycarbonyl-2-oxycarbonyl)dihydropyrimidine Base] phenyl} methyleneamino homocamptothecin.

¹ H-NMR (DMSO):

0.81-0.83(dd, 6H), 0.88(t, 3H), 1.16(t, 3H), 1.85(m, 1H), 1.86(q, 2H), 2.31(s, 3H), 3.07-3.45(q, 2H), 3.78(d, 1H), 5.24(d, 1H), 5.40-5.57(q, 2H), 5.58(s, 2H), 6.03(s, 1H), 7.38-7.54(dd, 4H), 7.45 (s, 1H), 7.81(s, 1H), 7.84(t, 1H), 7.95(t, 1H), 8.26(d, 1H), 8.98(d, 1H,), 9.26(s, 1H), 9.68 (s, 1H).

Example 14 7-{4-[6-(3-Ethyl-4-methyl-5-methoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin

According to the method of Example 1, replace 4-[6-(4- Methyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]aniline to obtain 64 mg of yellow solid 7-(2-trifluoromethylphenyl)vinylhomocamptothecin.

¹ H-NMR (DMSO):

0.89(t, 3H), 1.12(t, 3H), 1.87(q, 2H), 2.54(s, 3H), 3.07-3.48(q, 2H), 3.61(s, 3H), 3.63-3.85(dq, 2H), 5.22(d, 1H), 5.39-5.55(q, 2H), 5.54(s, 2H), 6.03(s, 1H), 7.36-7.53(dd, 4H), 7.44(s, 1H), 7.81 (t, 1H), 7.93(t, 1H), 7.98(d, 1H), 8.23(d, 1H), 8.95(d, 1H), 9.66(s, 1H).

Example 15 7-{4-[6-(3-methyl-4-gem-hydroxyl-trifluoromethyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneamino homocamptothecin

According to the method of Example 1, replace 4-[6-(3-methyl-4-gem-hydroxyl-trifluoromethyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]aniline [6-(4-Methyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]aniline, 69 mg of yellow solid 7-{4-[6-(3-methyl-4-gem-hydroxyl) -trifluoromethyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin.

¹ H-NMR (DMSO):

0.89(t, 3H), 0.88(t, 3H), 1.87(q, 2H), 2.9(s, 3H), 3.07-3.49(q, 2H), 3.22(d, 1H), 3.84(q, 2H) , 4.77(d, 1H), 5.40-5.56(q, 2H), 5.60(s, 2H), 6.05(s, 1H), 7.46(s, 1H), 7.49(s, 1H), 7.50-7.61(dd , 4H), 7.81(s, 1H), 7.84(t, 1H), 7.96(t, 1H), 8.27(d, 1H), 9.01(d, 1H), 9.72(s, 1H).

Example 16 7-{4-[6-(3-phenyl-4-gem-hydroxyl-trifluoromethyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneamino homocamptothecin

According to the method of Example 1, replace 4-[6-(3-phenyl-4-gem-hydroxyl-trifluoromethyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]aniline [6-(4-Methyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]aniline to give 64 mg of yellow solid 7-{4-[6-(3-phenyl-4-gem-hydroxyl -trifluoromethyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin.

¹ H-NMR (DMSO):

0.89(t, 3H), 0.92(t, 3H), 1.87(q, 2H), 3.07-3.48(q, 2H), 3.86(q, 2H), 4.38(s, 1H, CHCO), 4.39(s, 1H), 5.40-5.56(q, 2H), 5.60(s, 2H), 6.04(s, 1H), 6.68(t, 1H), 6.90(t, 1H), 7.23(t, 2H), 7.41(d , 1H), 7.43(s, 1H), 7.45(s, 1H), 7.46-7.58(dd, 4H), 7.84(t, 1H), 7.95(t, 1H), 8.26(d, 1H), 8.60( s, 1H), 9.00 (d, 1H), 9.72 (s, 1H).

Example 17 7-{4-[6-(3-ethyl-4-gem-hydroxyl-trifluoromethyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneamino homocamptothecin

According to the method of Example 1, replace 4-[6-(3-ethyl-4-gem-hydroxyl-trifluoromethyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]aniline [6-(4-Methyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]aniline, 65 mg of yellow solid 7-{4-[6-(3-ethyl-4-gem-hydroxyl) -trifluoromethyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin.

¹ H-NMR (DMSO):

0.87(t, 3H), 0.89(t, 3H), 1.15(t, 3H), 1.87(q, 2H), 3.07-3.49(q, 2H), 3.06(d, 1H), 3.39-3.48(dq, 2H), 3.83(q, 2H), 4.76(d, 1H), 5.40-5.56(q, 2H), 5.60(s, 2H), 6.04(s, 1H), 7.44(s, 1H), 7.46(s , 1H), 7.48-7.61(dd, 4H), 7.75(s, 1H), 7.85(t, 1H), 7.94(t, 1H), 8.27(d, 1H), 9.01(d, 1H), 9.72( s, 1H).

Example 18 7-{4-[6-(3,4-Dimethyl-5-acetyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin

According to the method of Example 1, replace 4-[6-(4-methyl- 5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]aniline, to obtain 84 mg of yellow solid 7-{4-[6-(3,4-dimethyl-5-acetyl-2-oxycarbonyl) di Hydropyrimidinyl]phenyl}methyleneaminohomocamptothecin.

¹ H-NMR (DMSO):

0.88(t, 3H), 1.87(q, 2H), 2.17(s, 3H), 2.50(s, 3H), 3.06-3.48(q, 2H), 3.12(s, 3H, NCH ₃ ), 5.30(d , 1H), 5.39-5.52(q, 2H ₂ ), 5.54(s, 2H), 6.04(s, 1H), 7.39-7.52(dd, 4H), 7.45(s, 1H), 7.81(t, 1H) , 7.94(t, 1H), 8.13(d, 1H), 8.25(d, 1H), 8.96(d, 1H), 9.67(s, 1H).

Example 19 7-{4-[6-(3-ethyl-4-methyl-5-tert-butoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin

According to the method of Example 1, replace 4-[6-(4 -Methyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]aniline to give 94 mg of yellow solid 7-{4-[6-(3-ethyl-4-methyl-5-tert-butoxy Carbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin.

¹ H-NMR (DMSO):

0.89(t, 3H), 1.11(t, 3H), 1.37(s, 9H), 1.87(q, 2H), 2.54(s, 3H), 3.07-3.48(q, 2H), 3.60-3.86(dq, 2H), 5.17(d, 1H), 5.40-5.56(q, 2H), 5.58(s, 2H), 6.03(s, 1H), 7.36-7.57(dd, 4H), 7.45(s, 1H), 7.82 (t, 1H), 7.88(d, 1H), 7.94(t, 1H), 8.26(d, 1H), 8.99(d, 1H), 9.70(s, 1H).

Example 20 7-{4-[6-(3,4-Dimethyl-5-isobutoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin

According to the method of Example 1, replace 4-[6-(4-methanol) with 4-[6-(3,4-dimethyl-5-isobutoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]aniline yl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]aniline to give 67 mg of yellow solid 7-{4-[6-(3,4-dimethyl-5-isobutoxycarbonyl-2- Oxycarbonyl) dihydropyrimidinyl] phenyl} methyleneamino homocamptothecin.

¹ H-NMR (DMSO):

0.83(dd, 6H), 0.88(t, 3H), 1.83(m, 1H), 1.87(q, 2H), 2.50(s, 3H), 3.08-3.48(q, 2H), 3.14(s, 3H) , 3.83(d, 2H), 5.26(d, 1H), 5.39-5.55(q, 2H), 5.46(d, 2H), 6.05(s, 1H), 7.37-7.52(dd, 4H), 7.42(s , 1H), 7.71(t, 1H, 7.90(t, 1H), 8.05(d, 1H), 8.20(d, 1H), 8.89(d, 1H), 9.61(s, 1H).

Example 21 7-{4-[6-(3-phenyl-4-methyl-5-tert-butoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin

According to the method of Example 1, replace 4-[6-(4 -Methyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]aniline to give 88 mg of yellow solid 7-{4-[6-(3-phenyl-4-methyl-5-tert-butoxy Carbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin.

¹ H-NMR (DMSO):

0.89(t, 3H), 1.39(s, 9H), 1.88(q, 2H), 2.02(s, 3H), 3.07-3.49(q, 2H), 5.31(d, 1H), 5.44-5.57(q, 2H2), 5.61(s, 2H), 6.04(s, 1H), 6.87(t, 2H), 7.41-7.54(t, 2H), 7.38(d, 1H), 7.45(s, 1H), 7.53-7.65 (dd, 4H), 7.82(t, 1H), 7.95(t, 1H), 8.16(d, 1H), 8.27(d, 1H), 8.98(d, 1H), 9.75(s, 1H).

Example 22 7-{4-[6-(3-Ethyl-4-methyl-5-acetyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin

According to the method of Example 1, with 4-[6-(3-ethyl-4-methyl-5-acetyl-2-oxycarbonyl)dihydropyrimidinyl]aniline instead of 4-[6-(4-methyl Base-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]aniline to give 56 mg of yellow solid 7-{4-[6-(3-ethyl-4-methyl-5-acetyl-2- Oxycarbonyl) dihydropyrimidinyl] phenyl} methyleneamino homocamptothecin.

¹ H-NMR (DMSO):

0.88(t, 3H), 1.11(t, 3H), 1.87(q, 2H), 2.16(s, 3H), 2.24(s, 3H), 3.06-3.48(q, 2H), 3.62-3.85(dq, 2H), 5.28(d, 1H), 5.40-5.56(q, 2H), 5.56(s, 2H), 6.04(s, 1H), 7.39-7.55(dd, 4H), 7.45(s, 1H), 7.82 (t, 1H), 7.94(t, 1H), 8.05(d, 1H), 8.26(d, 1H), 8.98(d, 1H), 9.69(s, 1H).

Example 23 7-{4-[4-(2,6-Dimethyl-3,5-diethoxycarbonyl)dihydropyridyl]phenyl}methyleneaminohomocamptothecin

According to the method of Example 1, replace 4-[6-(4-methyl-5 -ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]aniline to give 78 mg of yellow solid 7-{4-[4-(2,6-dimethyl-3,5-diethoxycarbonyl)dihydropyridine Base] phenyl} methyleneamino homocamptothecin.

¹ H-NMR (DMSO):

0.88(t, 3H), 1.18(t, 3H), 1.88(q, 2H), 2.29(s, 6H), 3.06-3.48(q, 2H), 4.03(q, 4H), 4.94(s, 1H) , 5.39-5.53(q, 2H), 5.55(s, 2H), 6.04(s, 1H), 7.29-7.44(dd, 4H), 7.42(s, 1H), 7.80(t, 1H), 7.93(t , 1H), 8.25(d, 1H), 8.87(s, 1H), 8.96(d, 1H), 9.65(s, 1H).

Example 24 7-{4-[4-(2,6-Dimethyl-3,5-dimethoxycarbonyl)dihydropyridyl]phenyl}methyleneaminohomocamptothecin

According to the method of Example 1, replace 4-[6-(4-methyl-5 -Ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]aniline to give 78 mg of yellow solid 7-{4-[4-(2,6-dimethyl-3,5-dimethoxycarbonyl)dihydropyridine Base] phenyl} methyleneamino homocamptothecin.

¹ H-NMR (DMSO):

0.88(t, 3H), 1.87(q, 2H), 2.29(s, 6H), 3.06-3.48(q, 2H), 3.58(s, 6H), 4.96(s, 1H), 5.39-5.54(q, 2H), 5.55(s, 2H), 6.03(s, 1H), 7.28-7.42(dd, 4H), 7.44(s, 1H), 7.81(t, 1H), 7.94(t, 1H), 8.25(d , 1H), 8.93(s, 1H), 8.96(d, 1H), 9.65(s, 1H).

Example 25 7-{4-[4-(2,6-Dimethyl-3,5-di-tert-butoxycarbonyl)dihydropyridyl]phenyl}methyleneaminohomocamptothecin

According to the method of Example 1, replace 4-[6-(4-methyl- 5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]aniline, to obtain 56 mg of yellow solid 7-{4-[4-(2,6-dimethyl-3,5-di-tert-butoxycarbonyl) di Hydropyridyl]phenyl}methyleneaminohomocamptothecin.

¹ H-NMR (DMSO):

0.88(t, 3H), 1.38(s, 18H), 1.87(q, 2H), 2.25(s, 6H), 3.06-3.48(q, 2H), 3.58(s, 6H), 4.87(s, 1H) , 5.40-5.56(q, 2H), 5.56(s, 2H), 6.04(s, 1H), 7.29-7.48(dd, 4H), 7.45(s, 1H, C14-H), 7.81(t, 1H) , 7.94(t, 1H), 8.25(d, 1H), 8.66(s, 1H), 8.98(d, 1H), 9.68(s, 1H).

Example 26 7-{4-[4-(2,6-Dimethyl-3,5-diisobutoxycarbonyl)dihydropyridyl]phenyl}methyleneaminohomocamptothecin

According to the method of Example 1, replace 4-[6-(4-methyl- 5-Ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]aniline to give 98 mg of yellow solid 7-{4-[4-(2,6-dimethyl-3,5-diisobutoxycarbonyl)di Hydropyridyl]phenyl}methyleneaminohomocamptothecin.

¹ H-NMR (DMSO):

0.88(t, 3H), 0.91(d, 12H), 1.87(q, 2H), 1.89(m, 2H), 2.31(s, 6H), 3.06-3.48(q, 2H), 3.79(m, 4H) , 5.03(s, 1H), 5.39-5.54(q, 2H), 5.57(s, 2H), 6.04(s, 1H), 7.30-7.44(dd, 4H), 7.44(s, 1H), 7.81(t , 1H), 7.93(t, 1H), 8.25(d, 1H), 8.95(s, 1H), 8.96(d, 1H), 9.65(s, 1H).

Example 27 7-{4-[4-(2,6-Dimethyl-3,5-di-n-propoxycarbonyl)dihydropyridyl]phenyl}methyleneaminohomocamptothecin

According to the method of Example 1, replace 4-[6-(4-methyl- 5-Ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]aniline, to obtain 48 mg of yellow solid 7-{4-[4-(2,6-dimethyl-3,5-di-n-propoxycarbonyl) di Hydropyridyl]phenyl}methyleneaminohomocamptothecin.

¹ H-NMR (DMSO):

0.88(t, 3H), 0.91(d, 6H), 1.60(m, 4H), 1.87(q, 2H), 2.30(s, 6H), 3.06-3.93(q, 2H), 3.94(t, 4H) , 4.98(s, 1H), 5.39-5.54(q, 2H), 5.55(s, 2H), 6.03(s, 1H), 7.29-7.44(dd, 4H), 7.44(s, 1H), 7.81(t , 1H), 7.94(t, 1H), 8.25(d, 1H), 8.90(s, 1H), 8.97(d, 1H), 9.66(s, 1H).

Example 28 7-{4-[4-(2,6-Dimethyl-3,5-diallyloxycarbonyl)dihydropyridyl]phenyl}methyleneaminohomocamptothecin

According to the method of Example 1, replace 4-[6-(4-methyl- 5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]aniline, to give 58 mg of yellow solid 7-{4-[4-(2,6-dimethyl-3,5-diallyloxycarbonyl)di Hydropyridyl]phenyl}methyleneaminohomocamptothecin.

¹ H-NMR (DMSO):

0.87(t, 3H), 1.88(q, 2H), 2.28(s, 6H), 3.06-3.48(q, 2H), 4.50(d, 4H), 4.82-4.87(m, 2H), 4.91(s, 1H), 5.15(m, 4H), 5.39-5.55(q, 2H), 5.75(s, 2H), 6.03(s, 1H), 7.29-7.44(dd, 4H), 7.44(s, 1H), 7.81 (t, 1H), 7.94(t, 1H), 8.25(d, 1H), 8.80(s, 1H), 8.97(d, 1H), 9.66(s, 1H).

Example 29 7-{4-[4-(2,6-Dimethyl-3,5-dimethoxyethoxycarbonyl)dihydropyridyl]phenyl}methyleneaminohomocamptothecin

According to the method of Example 1, replace 4-[6-(4-methyl) with 4-[4-(2,6-dimethyl-3,5-dimethoxyethoxycarbonyl)dihydropyridyl]aniline -5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]aniline to give 78 mg of yellow solid 7-{4-[4-(2,6-dimethyl-3,5-dimethoxyethoxycarbonyl ) dihydropyridyl] phenyl} methyleneamino homocamptothecin.

¹ H-NMR (DMSO):

0.86(t, 3H), 1.24(s, 6H), 1.87(q, 2H), 2.49(s, 6H), 3.06-3.50(q, 2H), 3.54(t, 4H), 4.10(t, 4H) , 4.96(s, 1H), 5.39-5.54(q, 2H), 5.55(s, 2H), 6.03(s, 1H), 7.32-7.42(dd, 4H), 7.44(s, 1H), 7.81(t , 1H), 7.94(t, 1H), 8.25(d, 1H), 8.93(s, 1H), 8.96(d, 1H), 9.65(s, 1H).

Example 30 7-{3-[4-(2,6-Dimethyl-3,5-dimethoxycarbonyl)dihydropyridyl]phenyl}methyleneaminohomocamptothecin

According to the method of Example 1, 4-[6-(4-methyl-5 -Ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]aniline to give 78 mg of yellow solid 7-{3-[4-(2,6-dimethyl-3,5-dimethoxycarbonyl)dihydropyridine Base] phenyl} methyleneamino homocamptothecin.

¹ H-NMR (DMSO):

0.88(t, 3H), 1.87(q, 2H), 2.30(d, 6H), 3.06-3.49(q, 2H), 3.61(s, 6H), 5.03(s, 1H), 5.40-5.57(q, 2H), 5.57(s, 2H), 6.03(s, 1H), 7.15(d, 1H), 7.25(s, 1H), 7.37-7.39(m, 2H), 7.45(s, 1H), 7.83(t , 1H), 7.95(t, 1H), 8.25(d, 1H), 8.94(d, 1H), 8.96(s, 1H), 9.62(s, 1H).

Example 31 (R)-7-{3-[4-(2,6-Dimethyl-3,5-dimethoxycarbonyl)dihydropyridyl]phenyl}methyleneaminohomocamptothecin

According to the method of Example 9, the racemic compound 7-{3-[4-(2,6-dimethyl-3,5-dimethoxycarbonyl)dihydropyridyl]phenyl}methylene was resolved Aminohomocamptothecin 100mg yields 51mg of (R)-7-{3-[4-(2,6-dimethyl-3,5-dimethoxycarbonyl)dihydropyridyl]phenyl}methyleneaminohomocamptothecin Base {[α] ^D ₂₅ =+51.8 (C=0.44, CHCl ₃ /CH ₃ OH=4:1)}.

¹ H-NMR (DMSO):

0.87(t, 3H), 1.88(q, 2H), 2.30(d, 6H), 3.06-3.49(q, 2H), 3.61(s, 6H), 5.03(s, 1H), 5.40-5.57(q, 2H), 5.57(s, 2H), 6.03(s, 1H), 7.15(d, 1H), 7.25(s, 1H), 7.37-7.39(m, 2H), 7.45(s, 1H), 7.83(t , 1H), 7.95(t, 1H), 8.25(d, 1H), 8.94(d, 1H), 8.96(s, 1H), 9.62(s, 1H).

Example 32 (S)-7-{3-[4-(2,6-Dimethyl-3,5-dimethoxycarbonyl)dihydropyridyl]phenyl}methyleneaminohomocamptothecin

According to the method of Example 9, the racemic compound 7-{3-[4-(2,6-dimethyl-3,5-dimethoxycarbonyl)dihydropyridyl]phenyl}methylene was resolved Aminohomocamptothecin 100mg to give 48mg of (S)-7-{3-[4-(2,6-dimethyl-3,5-dimethoxycarbonyl)dihydropyridyl]phenyl}methyleneaminohomocamptothecin Base {[α] ^D ₂₅ = -51.4 (C = 0.44, CHCl ₃ /CH ₃ OH = 4:1)}.

¹ H-NMR (DMSO):

0.88(t, 3H), 1.87(q, 2H), 2.30(d, 6H), 3.06-3.49(q, 2H), 3.61(s, 6H), 5.03(s, 1H), 5.40-5.57(q, 2H), 5.57(s, 2H), 6.03(s, 1H), 7.15(d, 1H), 7.25(s, 1H), 7.37-7.39(m, 2H), 7.45(s, 1H), 7.83(t , 1H), 7.95(t, 1H), 8.25(d, 1H), 8.94(d, 1H), 8.96(s, 1H), 9.62(s, 1H).

Example 33 7-{3-[4-(2,6-Dimethyl-3,5-diisobutoxycarbonyl)dihydropyridyl]phenyl}methyleneaminohomocamptothecin

According to the method of Example 1, 4-[6-(4-methyl- 5-Ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]aniline, to give 78mg of yellow solid 7-{3-[4-(2,6-dimethyl-3,5-diisobutoxycarbonyl)di Hydropyridyl]phenyl}methyleneaminohomocamptothecin.

¹ H-NMR (DMSO):

0.88(t, 3H), 0.91(d, 12H), 1.84-1.91(m, 4H), 2.32(s, 6H), 3.08-3.49(q, 2H), 3.81(d, 4H), 5.07(s, 1H), 5.41-5.57(q, 2H), 5.49(s, 2H), 6.05(s, 1H), 7.19(d, 1H), 7.29(s, 1H), 7.34-7.40(m, 2H), 7.44 (s, 1H), 7.79(t, 1H), 7.92(t, 1H), 8.23(d, 1H), 8.87(d, 1H), 8.96(s, 1H), 9.56(s, 1H).

Example 34 7-{3-[4-(2,6-Dimethyl-3,5-diethoxycarbonyl)dihydropyridyl]phenyl}methyleneaminohomocamptothecin

According to the method of Example 1, 4-[6-(4-methyl-5 -ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]aniline to give 78 mg of yellow solid 7-{4-[4-(2,6-dimethyl-3,5-diethoxycarbonyl)dihydropyridine Base] phenyl} methyleneamino homocamptothecin.

¹ H-NMR (DMSO):

0.89(t, 3H), 1.19(t, 3H), 1.88(q, 2H), 2.29(s, 6H), 3.07-3.48(q, 2H), 4.03(m, 4H), 4.99(s, 1H) , 5.40-5.55(q, 2H), 5.56(s, 2H), 6.03(s, 1H), 7.18(d, 1H), 7.28(s, 1H), 7.36-7.39(m, 2H), 7.45(s , 1H), 7.82(t, 1H), 7.93(t, 1H), 8.26(d, 1H), 8.86(s, 1H), 8.93(d, 1H), 9.61(s, 1H).

Example 35 (R)-7-{3-[4-(2,6-Dimethyl-3,5-diethoxycarbonyl)dihydropyridyl]phenyl}methyleneaminohomocamptothecin

According to the method of Example 9, the racemic compound 7-{3-[4-(2,6-dimethyl-3,5-diethoxycarbonyl)dihydropyridyl]phenyl}methylene was resolved Aminohomocamptothecin 100mg yields 49mg of (R)-7-{3-[4-(2,6-dimethyl-3,5-diethoxycarbonyl)dihydropyridyl]phenyl}methyleneaminohomocamptothecin Base {[α] ^D ₂₅ =+51.0 (C=0.44, CHCl ₃ /CH ₃ OH=4:1)}.

¹ H-NMR (DMSO):

0.88(t, 3H), 1.19(t, 3H), 1.88(q, 2H), 2.29(s, 6H), 3.07-3.48(q, 2H), 4.03(m, 4H), 4.99(s, 1H) , 5.40-5.55(q, 2H), 5.56(s, 2H), 6.03(s, 1H), 7.18(d, 1H), 7.28(s, 1H), 7.36-7.39(m, 2H), 7.45(s , 1H), 7.82(t, 1H), 7.93(t, 1H), 8.26(d, 1H), 8.86(s, 1H), 8.93(d, 1H), 9.61(s, 1H).

Example 36 (S)-7-{3-[4-(2,6-Dimethyl-3,5-diethoxycarbonyl)dihydropyridyl]phenyl}methyleneaminohomocamptothecin

According to the method of Example 9, the racemic compound 7-{3-[4-(2,6-dimethyl-3,5-diethoxycarbonyl)dihydropyridyl]phenyl}methylene was resolved Aminohomocamptothecin 100 mg yielded 49 mg of (S)-7-{4-[6-(3,4-dimethyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methylene Aminohomocamptothecin {[α] ^D ₂₅ =+51.4 (C=0.44, CHCl ₃ /CH ₃ OH=4:1)}.

¹ H-NMR (DMSO):

0.87(t, 3H), 1.18(t, 3H), 1.88(q, 2H), 2.29(s, 6H), 3.07-3.48(q, 2H), 4.03(m, 4H), 4.99(s, 1H) , 5.40-5.55(q, 2H), 5.56(s, 2H), 6.03(s, 1H), 7.18(d, 1H), 7.28(s, 1H), 7.36-7.39(m, 2H), 7.45(s , 1H), 7.82(t, 1H), 7.93(t, 1H), 8.26(d, 1H), 8.86(s, 1H), 8.93(d, 1H), 9.61(s, 1H).

The synthesis of embodiment 37 10-methoxy homocamptothecin

With 6.07g 9-ethyl-9-hydroxyl-2,3,8,9-tetrahydro-5H-6-oxa-3a-aza-cycloheptane-1,4,7-trione and 5.30g 5-methoxy-2-aminobenzaldehyde in 500ml of toluene, reflux to separate water, after 30 minutes, add 1.25g of p-toluenesulfonic acid, continue to reflux for 4h, evaporate the solvent, wash with acetone and methanol to obtain 4.38g of yellow Solid 10-methoxyhomocamptothecin.

¹ H NMR (DMSO):

0.87(t, 3H), 1.86(q, 2H), 3.04-3.48(q, 2H), 3.95(s, 3H), 5.25(s, 2H), 5.37-5.54(q, 2H), 6.00(s, 1H), 7.35(s, 1H), 7.50(d, 1H), 7.51(d, 1H), 8.05(d, 1H), 8.54(s, 1H). ESI-MS: m/z, 391 [MH] ^- .

Example 38 Synthesis of 7-(2-furyl)formyl-10-methoxyhomocamptothecin

100mg of 10-methoxyhomocamptothecin and 142mg of ferrous sulfate heptahydrate were dissolved in 9ml of 50% acetic acid aqueous solution, cooled in an ice-salt bath, and 0.9ml of concentrated sulfuric acid and 1.27mmol of (2-furan)formaldehyde were added successively at 5°C , when the temperature dropped to 0°C, 0.07ml of 80% tert-butanol peroxide was added and stirred overnight at room temperature. The reaction mixture was diluted with ice water, extracted with dichloromethane, the organic phase was dried (anhydrous sodium sulfate), concentrated, and purified by silica gel column chromatography (CH ₂ Cl ₂ /MeOH 98/2) to obtain 39 mg of yellow solid 7-(2 -furyl)formyl-10-methoxyhomocamptothecin.

¹ H NMR (DMSO):

0.87(t, 3H), 1.86(q, 2H), 3.04-3.49(q, 2H), 3.83(s, 3H), 5.09(d, 2H), 5.35-5.49(q, 2H), 6.03(s, 1H), 6.85(d, 1H), 7.12(d, 1H), 7.40(s, 1H), 7.55(d, 1H), 7.60(dd, 1H), 8.19(d, 1H, 12H), 8.26(s , 1H).ESI-MS: m/z, 485[MH] ^- .

Synthesis of Example 39 (R)-7-(2-furyl)formyl-10-methoxyhomocamptothecin

According to the method of Example 9, the racemic compound 7-(2-furyl)formyl-10-methoxyhomocamptothecin 100mg was resolved to obtain 52mg of (R)-7-(2-furyl)formyl- 10-methoxyhomocamptothecin {[α] ^D ₂₅ =+52.8 (C=0.44, CHCl ₃ /CH ₃ OH=4:1)}.

¹ H NMR (DMSO):

0.88(t, 3H), 1.87(q, 2H), 3.04-3.49(q, 2H), 3.83(s, 3H), 5.09(d, 2H), 5.35-5.49(q, 2H), 6.03(s, 1H), 6.85(d, 1H), 7.12(d, 1H), 7.40(s, 1H), 7.55(d, 1H), 7.60(dd, 1H), 8.19(d, 1H, 12H), 8.26(s , 1H).

Example 40 Synthesis of (S)-7-(2-furyl)formyl-10-methoxyhomocamptothecin

According to the method of Example 9, the racemic compound 7-(2-furyl)formyl-10-methoxyhomocamptothecin 100mg was resolved to obtain 47mg of (S)-7-(2-furyl)formyl- 10-methoxyhomocamptothecin {[α] ^D ₂₅ = -52.7 (C = 0.44, CHCl ₃ /CH ₃ OH = 4:1)}.

¹ H NMR (DMSO):

0.87(t, 3H), 1.86(q, 2H), 3.04-3.49(q, 2H), 3.83(s, 3H), 5.09(d, 2H), 5.35-5.49(q, 2H), 6.03(s, 1H), 6.85(d, 1H), 7.12(d, 1H), 7.40(s, 1H), 7.55(d, 1H), 7.60(dd, 1H), 8.19(d, 1H, 12H), 8.26(s , 1H).

Example 41 Synthesis of 7-(2-thiophene)formyl-10-methoxyhomocamptothecin

According to the method of Example 38, (2-thiophene)formaldehyde was used instead of (2-furan)formaldehyde to obtain 39 mg of yellow solid 7-(2-thiophene)formyl-10-methoxyhomocamptothecin.

¹ H NMR (DMSO):

0.87(t, 3H), 1.86(q, 2H), 3.04-3.49(q, 2H), 3.82(s, 3H), 5.04(d, 2H), 5.34-5.50(q, 2H), 6.03(s, 1H), 7.11(d, 1H), 7.27(t, 1H), 7.41(s, 1H), 7.61(dd, 1H), 7.73(d, 1H), 8.20(d, 1H, 12H), 8.35(d , 1H).

Synthesis of Example 427-benzoyl-10-methoxyhomocamptothecin

According to the method of Example 38, benzaldehyde was used instead of (2-furan) formaldehyde to obtain 45 mg of yellow solid 7-benzoyl-10-methoxyhomocamptothecin.

¹ H NMR (DMSO):

0.87(t, 3H), 1.86(q, 2H), 3.03-3.48(q, 2H), 3.75(s, 3H), 4.93(d, 2H), 5.33-5.48(q, 2H), 6.03(s, 1H), 7.03(s, 1H), 7.41(s, 1H), 7.59-7.64(m, 3H), 7.80(t, 1H), 7.91(d, 2H), 8.20(d, 1H).

Example 43 Synthesis of 7-p-chlorobenzoyl-10-methoxyhomocamptothecin

According to the method of Example 38, p-chlorobenzaldehyde was used instead of (2-furan) formaldehyde to obtain 48 mg of yellow solid 7-p-chlorobenzoyl-10-methoxyhomocamptothecin.

¹ H NMR (DMSO):

0.87(t, 3H), 1.86(q, 2H), 3.03-3.49(q, 2H), 3.76(s, 3H), 4.95(d, 2Hz), 5.33-5.49(q, 2H), 6.03(s, 1H), 7.03(s, 1H), 7.41(s, 1H), 7.60(dd, 1H), 7.67(d, 2H), 7.92(d, 2H), 8.20(d, 1H).

Example 44 Synthesis of 7-p-fluorobenzoyl-10-methoxyhomocamptothecin

According to the method of Example 38, p-fluorobenzaldehyde was used instead of (2-furan) formaldehyde to obtain 46 mg of 7-p-fluorobenzoyl-10-methoxyhomocamptothecin as a yellow solid.

¹ H NMR (DMSO):

0.87(t, 3H), 1.86(q, 2H), 3.03-3.49(q, 2H), 3.76(s, 3H), 4.95(d, 2H), 5.33-5.49(q, 2H), 6.03(s, 1H), 7.01(d, 1H), 7.41(s, 1H), 7.42(d, 2H), 7.60(dd, 1H), 8.00(dd, 2H), 8.20(d, 1H).

Example 45 Synthesis of 7-(4-methyl)benzoyl-10-methoxyhomocamptothecin

According to the method of Example 38, 4-methylbenzaldehyde was used instead of (2-furan)formaldehyde to obtain 47 mg of yellow solid 7-(4-methyl)benzoyl-10-methoxyhomocamptothecin.

¹ H NMR (DMSO):

0.87(t, 3H), 1.86(q, 2H), 2.43(s, 3H), 3.03-3.48(q, 2H), 3.76(s, 3H), 4.90(d, 2H), 5.33-5.48(q, 2H), 6.02(s, 1H), 7.02(d, 1H), 7.40(s, 1H), 7.41(d, 2H), 7.59(dd, 1H), 7.82(d, 2H), 8.19(d, 1H ).

Example 46 Synthesis of 7-(4-trifluoromethyl)benzoyl-10-methoxyhomocamptothecin

According to the method of Example 38, 4-trifluoromethylbenzaldehyde was used instead of (2-furan)formaldehyde to obtain 51 mg of 7-(4-trifluoromethyl)benzoyl-10-methoxyhomocamptothecin as a yellow solid.

¹ H NMR (DMSO):

0.87(t, 3H), 1.86(q, 2H), 3.03-3.49(q, 2H), 3.74(s, 3H), 4.97(d, 2H), 5.33-5.48(q, 2H), 6.03(s, 1H), 7.04(d, 1H), 7.41(s, 1H), 7.61(dd, 1H), 7.96(d, 2H), 8.09(d, 2H), 8.21(d, 1H).

Example 47 Synthesis of 7-(4-methoxy)benzoyl-10-methoxyhomocamptothecin

According to the method of Example 38, 4-methoxybenzaldehyde was used instead of (2-furan)formaldehyde to obtain 48 mg of yellow solid 7-(4-methoxy)benzoyl-10-methoxycamptotree.

¹ H NMR (DMSO):

0.87(t, 3H), 1.86(q, 2H), 3.03-3.48(q, 2H), 3.77(s, 3H), 3.88(s, 3H), 4.92(d, 2H), 5.33-5.48(q, 2H), 6.03(s, 1H), 7.02(d, 1H), 7.10(d, 2H), 7.40(s, 1H), 7.59(dd, 1H), 7.89(d, 2H), 8.19(d, 1H ).

Example 48 Synthesis of 7-(3,5-dimethyl)benzoyl-10-methoxyhomocamptothecin

According to the method of Example 38, 3,5-dimethylbenzaldehyde was used instead of (2-furan) formaldehyde to obtain 48 mg of yellow solid 7-(3,5-dimethyl)benzoyl-10-methoxycamptophyllin alkali.

¹ H NMR (DMSO):

0.88(t, 3H), 1.86(q, 2H), 2.33(s, 6H), 3.04-3.47(q, 2H), 3.78(s, 3H), 4.87(d, 2H), 5.33-5.48(q, 2H), 6.01(s, 1H), 7.03(d, 1H), 7.40(s, 1H), 7.44(s, 1H), 7.55(s, 2H), 7.59(dd, 1H), 8.18(d, 1H ).

Example 49 Synthesis of 7-(2-naphthalene)benzoyl-10-methoxyhomocamptothecin

According to the method of Example 38, 2-naphthylbenzaldehyde was used instead of (2-furan) formaldehyde to obtain 45 mg of yellow solid 7-(2-naphthalene)formyl-10-methoxyhomocamptothecin.

¹ H NMR (DMSO):

0.88(t, 3H), 1.87(q, 2H), 3.03-3.48(q, 2H), 3.74(s, 3H), 4.94(d, 2H), 5.31-5.45(q, 2H), 6.03(s, 1H), 7.10(d, 1H), 7.44(s, 1H), 8.02-8.18(m, 4H), 8.23(d, 1H), 8.46(s, 1H).

Example 50 Synthesis of 7-cyclopropanoyl-10-methoxy homocamptothecin

According to the method of Example 38, cyclopropanaldehyde was used instead of (2-furan) formaldehyde to obtain 35 mg of yellow solid 7-cyclopropanoyl-10-methoxyhomocamptothecin.

¹ H-NMR (DMSO):

0.87(t, 3H), 1.33-1.46(m, 4H), 1.86(q, 2H), 2.75(t, 1H), 3.05-3.49(q, 2H), 3.94(s, 3H), 5.33(s, 2H), 5.38-5.54(q, 2H), 6.03(s, 1H), 7.38(s, 1H), 7.48(d, 1H), 7.61(dd, 1H), 8.17(d, 1H).

Synthesis of Example 51 (R)-7-cyclopropanoyl-10-methoxyl homocamptothecin

According to the method of Example 9, the racemic compound 7-cyclopropionyl-10-methoxyhomocamptothecin 100 mg was resolved to obtain 49 mg of (R)-7-cyclopropionyl-10-methoxyhomamptothecin { [α] ^D ₂₅ =+50.9 (C=0.44, CHCl ₃ /CH ₃ OH=4:1)}.

¹ H-NMR (DMSO):

0.87(t, 3H), 1.33-1.46(m, 4H), 1.86(q, 2H), 2.75(t, 1H), 3.05-3.49(q, 2H), 3.94(s, 3H), 5.33(s, 2H), 5.38-5.54(q, 2H), 6.03(s, 1H), 7.38(s, 1H), 7.48(d, 1H), 7.61(dd, 1H), 8.17(d, 1H).

Synthesis of Example 52 (S)-7-cyclopropanoyl-10-methoxyhomocamptothecin

According to the method of Example 9, the racemic compound 7-cyclopropionyl-10-methoxyhomocamptothecin 100 mg was resolved to obtain 47 mg of (S)-7-cyclopropionyl-10-methoxyhomocamptothecin { [α] ^D ₂₅ = -50.5 (C = 0.44, CHCl ₃ /CH ₃ OH = 4:1)}.

¹ H-NMR (DMSO):

0.87(t, 3H), 1.33-1.46(m, 4H), 1.86(q, 2H), 2.75(t, 1H), 3.05-3.49(q, 2H), 3.94(s, 3H), 5.33(s, 2H), 5.38-5.54(q, 2H), 6.03(s, 1H), 7.38(s, 1H), 7.48(d, 1H), 7.61(dd, 1H), 8.17(d, 1H).

Example 53 Synthesis of 7-cyclopentanoyl-10-methoxy homocamptothecin

According to the method of Example 38, cyclopentanaldehyde was used instead of (2-furan) formaldehyde to obtain 43 mg of 7-cyclopentanoyl-10-methoxyhomocamptothecin as a yellow solid.

¹ H-NMR (DMSO):

0.86(t, 3H), 1.63-1.93(m, 10H), 3.04-3.49(q, 2H), 3.74(t, 1H), 3.92(s, 3H), 5.28(s, 2H), 5.37-5.53( q, 2H), 6.03(s, 1H), 7.15(d, 1H), 7.37(s, 1H), 7.60(dd, 1H), 8.15(d, 1H).

Synthesis of Example 54 (R)-7-cyclopentanoyl-10-methoxy homocamptothecin

According to the method of Example 9, the racemic compound 7-cyclopentanoyl-10-methoxyhomocamptothecin 100 mg was resolved to obtain 48 mg of (R)-7-cyclopentanoyl-10-methoxyhomocamptothecin { [α] ^D ₂₅ =+52.3 (C=0.44, CHCl ₃ /CH ₃ OH=4:1)}.

¹ H-NMR (DMSO):

0.88(t, 3H), 1.63-1.93(m, 10H), 3.04-3.49(q, 2H), 3.74(t, 1H), 3.92(s, 3H), 5.28(s, 2H), 5.37-5.53( q, 2H), 6.03(s, 1H), 7.15(d, 1H), 7.37(s, 1H), 7.70(dd, 1H), 8.15(d, 1H).

Synthesis of Example 55 (S)-7-cyclopentanoyl-10-methoxy homocamptothecin

According to the method of Example 9, the racemic compound 7-cyclopentanoyl-10-methoxyhomocamptothecin 100 mg was resolved to obtain 50 mg of (S)-7-cyclopentanoyl-10-methoxyhomocamptothecin { [α] ^D ₂₅ = -52.0 (C = 0.44, CHCl ₃ /CH ₃ OH = 4:1)}.

¹ H-NMR (DMSO):

0.87(t, 3H), 1.63-1.93(m, 10H), 3.04-3.49(q, 2H), 3.74(t, 1H), 3.92(s, 3H), 5.28(s, 2H), 5.37-5.53( q, 2H), 6.03(s, 1H), 7.15(d, 1H), 7.37(s, 1H), 7.60(dd, 1H), 8.15(d, 1H).

Example 56 Synthesis of 7-cyclohexyl-10-methoxyhomocamptothecin

According to the method of Example 38, cyclohexanaldehyde was used instead of (2-furan) formaldehyde to obtain 46 mg of yellow solid 7-cyclohexanoyl-10-methoxyhomocamptothecin.

¹ H-NMR (DMSO):

0.86(t, 3H), 1.24-1.95(m, 12H), 3.04-3.49(q, 2H), 3.20(t, 1H), 3.92(s, 3H), 5.26(s, 2H), 5.37-5.53( q, 2H), 6.02(s, 1H), 7.10(d, 1H), 7.37(s, 1H), 7.59(dd, 1H), 8.15(d, 1H).

Example 57 Synthesis of 7-propionyl-10-methoxyhomocamptothecin

According to the method of Example 38, propionaldehyde was used instead of (2-furan) formaldehyde to obtain 41 mg of yellow solid 7-propionyl-10-methoxyhomocamptothecin.

¹ H-NMR (DMSO):

0.86(t, 3H), 1.23(t, 3H), 1.86(q, 2H), 3.04-3.49(q, 2H), 3.16(q, 2H), 3.94(s, 3H), 5.32(s, 2H) , 5.38-5.54(q, 2H), 6.02(s, 1H), 7.30(d, 1H), 7.37(s, 1H), 7.60(dd, 1H), 8.15(d, 1H).

Example 58 Synthesis of 7-butyryl-10-methoxyhomocamptothecin

According to the method of Example 38, butyraldehyde was used instead of (2-furan) formaldehyde to obtain 31 mg of yellow solid 7-butyryl-10-methoxyhomocamptothecin.

¹ H-NMR (DMSO):

0.86(t, 3H), 1.01(t, 3H), 1.79(q, 2H), 1.86(q, 2H), 3.04-3.49(q, 2H), 3.14(t, 2H), 3.93(s, 3H) , 5.31(s, 2H), 5.38-5.54(q, 2H), 6.03(s, 1H), 7.27(d, 1H), 7.37(s, 1H), 7.59(dd, 1H), 8.15(d, 1H ).

Example 59 Synthesis of 7-pentanoyl-10-methoxyhomocamptothecin

According to the method of Example 38, valeraldehyde was used instead of (2-furan) formaldehyde to obtain 37 mg of 7-pentanoyl-10-methoxyhomocamptothecin as a yellow solid.

¹ H-NMR (DMSO):

0.86(t, 3H), 0.93(t, 3H), 1.42(q, 2H), 1.74(t, 2H), 1.84(q, 2H), 3.04-3.49(q, 2H), 3.15(t, 2H) , 3.93(s, 3H), 5.31(s, 2H), 5.37-5.53(q, 2H), 6.03(s, 1H), 7.28(d, 1H), 7.37(s, 1H), 7.60(dd, 1H ), 8.15(d, 1H).

Example 60 Synthesis of 7-heptanoyl-10-methoxyhomocamptothecin

According to the method of Example 38, heptanal was used instead of (2-furan) formaldehyde to obtain 38 mg of yellow solid 7-heptanoyl-10-methoxyhomocamptothecin.

¹ H-NMR (DMSO):

0.86(m, 6H), 1.25(q, 2H), 1.39(t, 2H), 1.76(t, 2H), 1.85(q, 2H), 3.04-3.49(q, 2H), 3.14(t, 2H) , 3.93(s, 3H), 5.31(s, 2H), 5.37-5.53(q, 2H), 6.03(s, 1H), 7.28(d, 1H), 7.37(s, 1H), 7.60(dd, 1H ), 8.15(d, 1H).

Example 61 Synthesis of 7-isobutyryl-10-methoxyhomocamptothecin

According to the method of Example 38, isobutyraldehyde was used instead of (2-furan) formaldehyde to obtain 26 mg of yellow solid 7-isobutyryl-10-methoxyhomocamptothecin.

¹ H-NMR (DMSO):

0.87(t, 3H), 1.21(d, 6H), 1.85(q, 2H), 3.05-3.49(q, 2H), 3.46-3.48(m, 1H), 3.93(s, 3H), 5.26(s, 2H), 5.37-5.53(q, 2H), 6.04(s, 1H), 7.10(d, 1H), 7.37(s, 1H), 7.59(dd, 1H), 8.14(d, 1H).

Antitumor activity test of the compound of the present invention

The compounds of the present invention were tested for inhibition of tumor cell proliferation, using the conventional MTT method (such as "New Drug Pharmacological Research Methods", edited by Lu Qiujun, 2007: 242-243). A549 (human lung cancer cells), MDA-MB-435 (human breast cancer cells) and HCT116 (human intestinal cancer cells) were selected as cell lines, which were cryopreserved and passaged by the pharmacology laboratory of Shanghai Institute of Pharmaceutical Industry. The culture medium is RPMI1640+15%NBS+double antibody.

Preparation of MTT solution: Weigh 0.5 g of MTT, dissolve in 100 ml of phosphate buffered solution (PBS) or phenol red-free medium, filter with a 0.22 μm filter membrane to remove bacteria in the solution, and store at 4°C in the dark.

Preparation of sample solution: after dissolving in DMSO (Merck), add PBS (-) to make a 100 μg/mL solution or a uniform suspension, then dilute with DMSO in PBS (-), the final concentrations are 10 μg/mL and 1 μg respectively /mL, 0.1μg/mL, 0.01μg/mL, 0.001μg/mL, 0.0001μg/mL. The listed antitumor drug topotecan (TPT) was formulated as a reference solution under the same conditions.

MTT method: 100 μl of cell suspension with a concentration of 4-6×10 ⁴ /ml was added to each well of a 96-well plate, and placed in a 37° C., 5% CO ₂ incubator. After 24 hours, add the sample solution, 10 μl/well, set up duplicate wells, and act at 37°C and 5% CO ₂ for 72 hours. Add 20 μl of 5 mg/ml MTT solution to each well, add the dissolving solution after 4 hours of action, 100 μl/well, put it in the incubator, measure the 570nmOD value with MK-2 automatic microplate reader after dissolving. Calculate the half inhibitory concentration IC ₅₀ .

The test results are shown in Table 1, wherein, the sample refers to the homocamptothecin compounds prepared in the corresponding examples (for example, 7-{4-[6-(4-methyl-5-ethoxycarbonyl-2-oxygen) in Example 1 carbonyl) dihydropyrimidinyl] phenyl} methyleneamino homocamptothecin).

Table 1 The half inhibitory concentration IC ₅₀ (unit: μg/mL) of test compounds to tumor cells

The above experimental results show that the compounds of the present invention have good anti-tumor activity, and the activity of several compounds is higher than that of the marketed drug topotecan. Therefore, the compounds of the present invention and their salts can be used to prepare anti-tumor drugs.

Claims (5)

1. Homocamptothecin compounds, including optical isomers, racemates, cis-trans isomers and any mixture of these forms or pharmaceutically acceptable salts thereof, with a structure such as general formula (I):

In general formula (I): R ₁ : means

or

or

Or (CH ₂ ) _m C (O) R ₁₀ group, wherein R ₆ represents hydrogen, hydroxyl, amino, lower alkylamino, lower alkyl, lower haloalkyl, lower alkoxy, lower alkenyl, cyano , lower cyanoalkyl, nitro, lower nitroalkyl, amido, lower amidoalkyl, hydrazino, lower hydrazinoalkyl, azido, lower azidoalkyl, phenyl, said Phenyl has at least one or more of the following substituents: hydrogen, hydroxyl, halogen, lower alkyl, lower alkoxy, cyano, nitro; _R represents lower alkyl, lower haloalkyl, cyano, lower cyanoalkyl, nitro, lower nitroalkyl, amino, lower aminoalkyl, hydroxyl, lower hydroxyalkyl; _R represents hydrogen, lower alkyl, lower haloalkyl, lower amidoalkyl, lower hydrazinoalkyl, lower azidoalkyl, phenyl; _R represents hydrogen, lower alkyl, lower haloalkyl, phenyl, and the phenyl has at least one or more of the following substituent groups: hydrogen, hydroxyl, halogen, lower alkyl, lower alkoxy, cyano, nitro base; R ₁₀ represents lower alkyl, cycloalkyl, [N=X], aryl, and has at least one or more of the following substituent groups: hydrogen, hydroxyl, halogen, lower alkyl, lower alkoxy, cyano, nitro; R ₂ , R ₃ , R ₄ independently represent the following groups: hydrogen, halogen, lower alkyl, nitro, amino, (CH ₂ ) _m NR ₁₁ R ₁₂ , (CH ₂ ) _m OR ₁₃ , (CH ₂ ) _m C(O)R ₁₄ , (CH ₂ ) _m OC(O)R ₁₄ , substituted or unsubstituted lower aralkyl, wherein the substituent is lower alkyl, hydroxyl, halogen, nitro, amino, lower alkyl Amino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy, lower alkoxy lower alkyl, or R ₂ and R ₃ together form a 3- or 4-membered chain, wherein the units of the chain are selected from CH, CH ₂ , O, S or NR ₁₅ ; R ₅ represents lower alkyl; R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ , R ₁₅ independently represent hydrogen or lower alkyl; The lower alkyl is straight chain or branched chain alkyl containing 1 to 6 carbon atoms; lower alkoxy is straight chain or branched chain alkoxy containing 1 to 6 carbon atoms; lower haloalkyl is containing 1 to 3 A lower alkyl group substituted by a halogen atom; a lower aralkyl group is a lower alkyl group connected with an aryl group; G means O, S, NH; m is an integer between 0 and 6; n is 1 or 2; [N=X] represents a 4- to 7-membered heterocyclic group, X represents the chain required to complete the heterocyclic group and is selected from O, S, CH ₂ , CH, NR ₁₂ , COR ₁₄ . 2. The compound of claim 1, wherein R _is ethyl. 3. compound as claimed in claim 2, is characterized in that, described compound is selected from: 7-{4-[6-(4-Methyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin, 7-{4-[6-(4-gem-hydroxy-trifluoromethyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin, 7-{3-[6-(4-methyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin, 7-{3-[6-(4-gem-hydroxy-trifluoromethyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin, 7-{4-[6-(4-Methyl-5-methoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin, 7-{4-[6-(4-Methyl-5-acetyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin, 7-{4-[6-(3-Ethyl-4-methyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin, 7-{4-[6-(3,4-Dimethyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin, (R)-7-{4-[6-(3,4-Dimethyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin, (S)-7-{4-[6-(3,4-Dimethyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin, 7-{4-[6-(3-Phenyl-4-methyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin, 7-{4-[6-(4-methyl-5-tert-butoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin, 7-{4-[6-(4-Methyl-5-isobutoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin, 7-{4-[6-(3-Ethyl-4-methyl-5-methoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin, 7-{4-[6-(3-Methyl-4-gem-hydroxy-trifluoromethyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin, 7-{4-[6-(3-Phenyl-4-gem-hydroxy-trifluoromethyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin, 7-{4-[6-(3-Ethyl-4-gem-hydroxy-trifluoromethyl-5-ethoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin, 7-{4-[6-(3,4-Dimethyl-5-acetyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin, 7-{4-[6-(3-Ethyl-4-methyl-5-tert-butoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin, 7-{4-[6-(3,4-Dimethyl-5-isobutoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin, 7-{4-[6-(3-Phenyl-4-methyl-5-tert-butoxycarbonyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin, 7-{4-[6-(3-Ethyl-4-methyl-5-acetyl-2-oxycarbonyl)dihydropyrimidinyl]phenyl}methyleneaminohomocamptothecin, 7-{4-[4-(2,6-Dimethyl-3,5-diethoxycarbonyl)dihydropyridyl]phenyl}methyleneaminohomocamptothecin, 7-{4-[4-(2,6-Dimethyl-3,5-dimethoxycarbonyl)dihydropyridyl]phenyl}methyleneaminohomocamptothecin, 7-{4-[4-(2,6-Dimethyl-3,5-di-tert-butoxycarbonyl)dihydropyridyl]phenyl}methyleneaminohomocamptothecin, 7-{4-[4-(2,6-Dimethyl-3,5-diisobutoxycarbonyl)dihydropyridyl]phenyl}methyleneaminohomocamptothecin, 7-{4-[4-(2,6-Dimethyl-3,5-di-n-propoxycarbonyl)dihydropyridyl]phenyl}methyleneaminohomocamptothecin, 7-{4-[4-(2,6-Dimethyl-3,5-diallyloxycarbonyl)dihydropyridyl]phenyl}methyleneaminohomocamptothecin, 7-{4-[4-(2,6-Dimethyl-3,5-dimethoxyethoxycarbonyl)dihydropyridyl]phenyl}methyleneaminohomocamptothecin, 7-{3-[4-(2,6-Dimethyl-3,5-dimethoxycarbonyl)dihydropyridyl]phenyl}methyleneaminohomocamptothecin, (R)-7-{3-[4-(2,6-Dimethyl-3,5-dimethoxycarbonyl)dihydropyridyl]phenyl}methyleneaminohomocamptothecin, (S)-7-{3-[4-(2,6-Dimethyl-3,5-dimethoxycarbonyl)dihydropyridyl]phenyl}methyleneaminohomocamptothecin, 7-{3-[4-(2,6-Dimethyl-3,5-diisobutoxycarbonyl)dihydropyridyl]phenyl}methyleneaminohomocamptothecin, 7-{3-[4-(2,6-Dimethyl-3,5-diethoxycarbonyl)dihydropyridyl]phenyl}methyleneaminohomocamptothecin, (R)-7-{3-[4-(2,6-Dimethyl-3,5-diethoxycarbonyl)dihydropyridyl]phenyl}methyleneaminohomocamptothecin, (S)-7-{3-[4-(2,6-Dimethyl-3,5-diethoxycarbonyl)dihydropyridyl]phenyl}methyleneaminohomocamptothecin, 7-(2-furyl)formyl-10-methoxyhomocamptothecin, (R)-7-(2-furyl)formyl-10-methoxyhomocamptothecin, (S)-7-(2-furyl)formyl-10-methoxyhomocamptothecin, 7-(2-thiophene)formyl-10-methoxyhomocamptothecin, 7-benzoyl-10-methoxyhomocamptothecin, 7-p-Chlorobenzoyl-10-methoxyhomocamptothecin, 7-p-fluorobenzoyl-10-methoxyhomocamptothecin, 7-(4-Methyl)benzoyl-10-methoxyhomocamptothecin, 7-(4-trifluoromethyl)benzoyl-10-methoxyhomocamptothecin, 7-(4-Methoxy)benzoyl-10-methoxyhomocamptothecin, 7-(3,5-Dimethyl)benzoyl-10-methoxyhomocamptothecin, 7-(2-naphthalene)benzoyl-10-methoxyhomocamptothecin, 7-cyclopropanoyl-10-methoxyhomocamptothecin, (R)-7-cyclopropanoyl-10-methoxyhomocamptothecin, (S)-7-cyclopropanoyl-10-methoxyhomocamptothecin, 7-cyclopentanoyl-10-methoxyhomocamptothecin, (R)-7-cyclopentanoyl-10-methoxyhomocamptothecin, (S)-7-cyclopentanoyl-10-methoxyhomocamptothecin, 7-Cyclohexanoyl-10-methoxyhomocamptothecin, 7-propionyl-10-methoxyhomocamptothecin, 7-butyryl-10-methoxyhomocamptothecin, 7-pentanoyl-10-methoxyhomocamptothecin, 7-heptanoyl-10-methoxyhomocamptothecin, 7-Isobutyryl-10-methoxyhomocamptothecin. 4. any compound in claims 1 to 3, including its optical isomers, racemates, cis-trans isomers and any mixture or pharmaceutically acceptable salt thereof of these forms, in the preparation of topoisomerase I application of inhibitors. 5. The application according to claim 4, characterized in that the application is in the preparation of medicines for treating tumor diseases.