WO2009006839A1

WO2009006839A1 - Substituted indol-3-yl oxalylpodophyllotoxin derivates, their salts, and application thereof

Info

Publication number: WO2009006839A1
Application number: PCT/CN2008/071573
Authority: WO
Inventors: Hong Chen; Zhiyong Lei; Pengfei Yu; Maosheng Cheng; Bo Cao; Shufang Bai; Min Feng
Original assignee: Medical College Of Chinese People`S Armed Police Force
Priority date: 2007-07-11
Filing date: 2008-07-08
Publication date: 2009-01-15
Also published as: CN101085779A

Abstract

Substituted indol-3-yl oxalylpodophyllotoxin derivates and their salts comprise the following general formula (I). These compounds are effective against many drug-resistant tumors.

Description

Substituted 吲哚-3-3-oxalyl epipodophyllotoxin derivative and salt thereof and use thereof

Technical field

The present invention relates to a substituted indole-3-yloxalyl glycoside derivative, an inorganic acid salt thereof and an organic acid salt, and to use in the preparation of an antitumor drug.

Background technique

吲哚-3-Glyceramide has a variety of biological activities and has been demonstrated by considerable literature and published patent records. For example, in the Netherlands patent application 6502481, the indole-3-oxalic acid amide derivative is a class of compounds having anti-inflammatory, antipyretic and analgesic activities. In the British patent application GB-B1028 812, an indole-3-yloxacin derivative as an analgesic, anticonvulsant and β-adrenergic compound is described. G. Domschke et al. (Ber. 94, 2353 (196 1)) describe indole-3-yloxacin derivatives having certain pharmacological properties. E. Walson, J. Med. Chem., 11 , 1252 (1968), describes indole-3-yl oxalic acid amide derivatives which have an inhibitory effect on glycerophosphate dehydrogenase and lactate dehydrogenase.

The European Patent Specification ΕΡ 675110 describes that indole-3-yloxazamide derivatives can be used as sPLA2 inhibitors and can be used for the treatment of toxic shock in pancreatitis and for the treatment of allergic arthritis and rheumatoid arthritis. . The compound of the prior patent DE-A 19636150 A1 has been proposed for use as an anti-tumor in the German patent application No. 19,814,838. Summary of the invention

It is an object of the present invention to provide substituted indole-3-yloxalyl glycoside derivatives having good antitumor biological activity.

A second object of the present invention is to provide an inorganic or organic salt which replaces the indole-3-yloxalyl glycoside derivative. A third object of the present invention is to provide a use of a substituted indole-3-yloxalyl glycoside derivative for the preparation of an antitumor drug.

A fourth object of the present invention is to provide an inorganic salt or an organic salt of a substituted indolin-3-yloxalyl glycoside derivative for use in the preparation of an antitumor drug.

The technical solution of the present invention is summarized as follows:

Substituted indole-3-yl oxalyl glucoside derivative, having the following general formula (I):

Wherein R represents hydrogen or methyl;

among them! ^ represents hydrogen, an alkyl group, C ₃ 〜(: ₇ cycloalkyl, (^~(: ₆ aralkyl, ~(: ₆ alkylsulfonyl, haloacyl, halosulfonyl, ethoxy) a carbonyl group, an alkoxycarbonyl group having an alkyl moiety of 1 to 18 carbon atoms, an alkoxysulfonyl group having an alkyl moiety of 1 to 18 carbon atoms, a benzene ring, a substituted benzene ring, a pyridine ring, a substituted pyridine ring, a pyrimidine ring a substituted pyrimidine ring, a quinoline ring, a substituted quinoline ring, a benzyl group, a substituted benzyl group, a benzoyl group, a substituted benzoyl group, a cinnamyl group, a substituted cinnamyl group, a cinnamoyl group or a substituted cinnamoyl group, the substituted benzene ring, Substituents in the substituted pyridine ring, the substituted pyrimidine ring, the substituted quinoline ring, the substituted benzyl group, the substituted benzoyl group, the substituted cinnamyl group, and the substituted cinnamoyl group are: (^~(: ₆ alkyl group, c ₃ ～c ₇₎ Cycloalkyl, (~(: ₆ alkoxy, (~ ₆ : alkanesulfonylamino, nitro, amino, hydroxy, cyano, halogen, trifluoromethyl, ethoxycarbonyl, alkyl) a portion of an alkoxycarbonyl or alkyl moiety having from 1 to 18 carbon atoms having from 1 to 18 carbon atoms Oxygen sulfonyl group;

or! ^ represents a substituted benzyl group represented by the formula (Π):

(II)

Where q is 1 or 2;

The other substitution sites H of the benzene ring in the substituted benzyl group represented by the formula (Π) are substituted by the same or different substituents of (^~(: ₆ alkyl group, C _{3 to} C ₇ Cycloalkyl, (^~(: ₆ alkoxy, (^~(: ₆ alkylsulfonylamino, nitro, amino, hydroxy, cyano, halogen, trifluoromethyl, ethoxycarbonyl, alkane Alkoxycarbonyl group having 1 to 18 carbon atoms in the base portion and alkoxysulfonyl group having 1 to 18 carbon atoms in the alkyl moiety;

R ₄ , R ₆ , and R _{7 of} the above formula (I) are the same or different, and R ₄ , R ₆ , and R ₇ represent hydrogen, (^~(: ₆ alkyl group, C ₃ ～C) ₇ cycloalkyl, (^~(: ₆ alkoxy, (^~(: ₆ alkylsulfonylamino, nitro, amino, hydroxy, cyano, halogen, trifluoromethyl, ethoxycarbonyl) An alkoxycarbonyl group having an alkyl moiety of 1 to 18 carbon atoms, an alkoxysulfonyl group having an alkyl moiety of 1 to 18 carbon atoms, a benzene ring, a substituted benzene ring, a pyridine ring, a substituted pyridine ring, a pyrimidine ring, a substitution a pyrimidine ring, a quinoline ring, a substituted quinoline ring, a benzyloxy group, a substituted benzyloxy group, a substituted benzene ring, a substituted pyridine ring, a substituted pyrimidine ring, a substituted quinoline ring, or a substituted benzyloxy group The base is: (^~(: ₆ alkyl, C ₃ -C ₇ cycloalkyl, ~(: ₆ alkoxy, ~(: ₆ alkanesulfonylamino, nitro, amino, hydroxy, cyanide) a halogen, a trifluoromethyl group, an ethoxycarbonyl group, an alkoxycarbonyl group having an alkyl moiety of 1 to 18 carbon atoms, and an alkoxy group having an alkyl moiety of 1 to 18 carbon atoms Acyl;

In the formula (I), X is an oxygen or an imino group.

Preferably:

In the formula (I), R represents a methyl group, ! ^ represents p-chlorobenzyl, R ₂ = R ₄ = R ₅ = R ₆ = R ₇ represents hydrogen, X represents oxygen, chemical name: 4- [1_ (p-chlorobenzyl) indol-3-yl] Acyl epipodophyllotoxin (YB-B1EP0). In the formula (I), R represents a methyl group, which represents a 3,4-dichlorobenzyl group, R ₂ = R ₄ = R ₅ = R ₆ = R ₇ represents hydrogen, X represents oxygen, and the chemical name is: 4-[1 -(3,4-Dichlorobenzyl)indol-3-yl]oxalyl epipodophyllotoxin (YB-F1EP0).

In the formula (I), R represents a methyl group, which represents a 3,4-methylenedioxybenzyl group, R ₂ = R ₄ = R ₅ = R ₆ = R ₇ represents hydrogen, X represents oxygen, and the chemical name is: 4 -[1-(3,4-Methylenedioxybenzyl)indol-3-yl]oxalyl epipodophyllotoxin (YB-L1EP0).

In the formula (I), R represents a methyl group, ! ^ represents p-chlorobenzyl, R ₂ = R ₄ = R ₅ = R ₆ = R ₇ represents hydrogen, X represents an imino group, chemical name: 4-[1-(p-chlorobenzyl)indol-3-yl Oxaloylamino-4-deoxyepidetoxin (YB-B1EPN).

In the formula (I), R represents a methyl group, and represents a 3,4-methylenedioxybenzyl group, R ₂ = R ₄ = R ₅ = R ₆ = R ₇ represents hydrogen, and X represents an imino group, and the chemical name is: 4-[1-(3,4-Methylenedioxybenzyl)indol-3-yl]oxalylamino-4-deoxyepidetoxin (YB-L1EPN).

In the formula (I), R represents a methyl group, represents a bromine, represents hydrogen, and X represents an imino group, and the chemical name is: 4-(5-bromoindol-3-yl)oxalylamino-4-deoxyepidetoxin ( YB-XB1EPN).

In the formula (I), R represents a methyl group, represents a methoxy group, represents hydrogen, and X represents an imino group, and the chemical name is: 4-(5-methoxyindol-3-yl)oxalylamino-4-deoxy table Ghost white toxin (YB-X31EPN).

In the formula (I), R represents a methyl group, represents a methyl group, represents hydrogen, and X represents an imino group, and the chemical name is: 4-[2-methylindol-3-yl]oxalylamino-4-deoxyepide White toxin (YB-V81EPN).

In the formula (I), R represents a methyl group, R ₆ represents a fluorine, represents hydrogen, and X represents an imino group, and the chemical name is: 4-(6-fluoroindol-3-yl)oxalylamino-4-deoxyepide White toxin (YB-Y11EPN).

In the formula (I), R represents a methyl group, R ₆ represents a methoxy group, represents hydrogen, and X represents an imino group, and the chemical name is: 4-(6-methoxyindol-3-yl)oxalylamino-4 - Deoxyepoxyphoratoxin (YB-Y31EPN).

In the general formula (I), R represents hydrogen, represents hydrogen, and X represents an imino group, and the chemical name is: 4β-((吲哚-3-yl)oxalylamino)-4-deoxy-demethylepipodophyllotoxin (FM- PN5).

In the formula (I), R represents hydrogen, represents methoxy, = =1? ₄ = =1? ₇ represents hydrogen, X represents an imino group, represents a methoxy group, represents hydrogen, and X represents an imino group, and the chemical name is: 4-(6-Methoxyindole-3-yl)oxalylamino-4-deoxy-demethylepipodophyllotoxin (FM-PN7).

Any one of the above substituted inorganic or organic acid salts of an indole-3-yloxalyl glycoside derivative, the inorganic acid being hydrochloric acid, sulfuric acid or phosphoric acid; the organic acid being acetic acid, lactic acid or C Diacid, maleic acid, fumaric acid, gluconic acid, glucuronic acid, citric acid, ascorbic acid, pamoic acid, methanesulfonic acid, trifluoroacetic acid, succinic acid, 2-hydroxyethanesulfonic acid, nicotinic acid or p-toluene acid.

The use of any of the above to replace the indole-3-yloxalyl glycoside derivative for the preparation of an antitumor drug. The use of any of the above to replace the inorganic or organic acid salt of the indole-3-yloxalyl glycoside derivative for the preparation of an antitumor drug.

The invention utilizes the existing natural resource ghost white toxin in our country to synthesize a series of compounds with anti-tumor activity, in order to find anti-tumor drugs with high anti-tumor activity and effective against multi-drug resistant tumors. The structural modification of the natural product, ghost white toxin, is expected to make the newly synthesized compound effective against multiple drug-resistant tumors while retaining its anti-tumor activity.

DRAWINGS

Figure 1 is a nuclear magnetic resonance spectrum of 4-[1-(p-chlorobenzyl)indol-3-yl]oxalylpodophyllotoxin (YB-B1EP0); Figure 2 is a nuclear magnetic resonance spectrum of 4-[l-(3,4-dichlorobenzyl)indol-3-yl]oxalylpodophyllotoxin (YB-F1EP0); Figure 3 is 4-[1-( Nuclear magnetic resonance spectrum of 3,4-methylenedioxybenzyl)indol-3-yl]oxalylpodophyllotoxin (YB-L1EP0);

Figure 4 is a nuclear magnetic resonance spectrum of 4-[1-(p-chlorobenzyl)indol-3-yl]oxalylamino-4-deoxyepidetoxin (YB-B1EPN);

Figure 5 is a nuclear magnetic resonance spectrum of 4-[1-(3,4-methylenedioxybenzyl)indol-3-yl]oxalylamino-4-deoxyepipodophyllotoxin (YB-L1EPN);

Figure 6 is a nuclear magnetic resonance spectrum of 4-(5-bromoindol-3-yl)oxalylamino-4-deoxyepipodophyllotoxin (YB-XB1EPN); Figure 7 is 4-(5-methoxyindole) Nuclear magnetic resonance spectrum of -3-yl) oxalylamino-4-deoxyepipodophyllotoxin (YB-X31EPN);

Figure 8 is a nuclear magnetic resonance spectrum of 4-[2-methylindol-3-yl]oxalylamino-4-deoxyepipodophyllotoxin (YB-V81EPN); Figure 9 is 4-(6-fluoroindole- Nuclear magnetic resonance spectrum of 3-yl) oxalylamino-4-deoxyepipodophyllotoxin (YB-Y11EPN); Figure 10 is 4-(6-methoxyindol-3-yl)oxalylamino-4-deoxy Nuclear magnetic resonance spectrum of epipodophyllotoxin (¥13 315?^).

Figure 11 is a nuclear magnetic resonance spectrum of 4?-((1-(4-cyanobenzyl)-indol-3-yl)-oxalylamino)-epipodophyllotoxin (FM-PN1).

Figure 12 is a nuclear magnetic resonance spectrum of 4β-(indol-3-acetyl)-epipodophyllotoxin (FM-PN2).

Figure 13 is a nuclear magnetic resonance spectrum of 4?-((1-benzyl-indol-3-yl)-oxalylamino)-epipodophyllotoxin (FM-PN3). Figure 14 is a nuclear magnetic resonance spectrum (FM-PN4) of 4?-((1-(3-cyanobenzyl)-indol-3-yl)-oxalylamino)-epenophorin.

Figure 15 is a nuclear magnetic resonance spectrum of 4β-((吲哚-3-yl)-oxalylamino)-4-deoxydemethylepipodophyllotoxin (FM-PN5).

Figure 16 is a nuclear magnetic resonance spectrum of 4?-((1-benzyl-indol-3-yl)-oxalylamino)-4-deoxydemethylepipodophyllotoxin (FM-PN6).

Figure 17 is a nuclear magnetic resonance spectrum of 4-(6-methoxyindol-3-yl)oxalylamino-4-deoxydemethylepipodophyllotoxin (FM-PN7).

detailed description

The synthetic process of the invention is:

Option One

Synthetic formula:

General formula 1

First step:

(1) Dissolving the mono- or poly-substituted anthracene derivative I in isopropanol (other solvents such as isoprotic alcohol, aprotic polar solvent or non-polar organic solvent may be used in addition to isopropanol). Such as tetrahydrofuran, dimethyl sulfoxide, hydrazine, hydrazine-dimethylformamide, hydrazine, hydrazine-dimethylacetamide, hydrazine-methylpyrrolidone, dioxane, toluene or dichloromethane, etc.;

(2) dropping the above solution into a vessel containing a suspension of alkali by nitrogen gas protection by using 1 molar equivalent or an excess of sodium hydroxide (may also be selected as potassium hydroxide, unbranched Potassium butoxide, pyridine or sodium amide) is added to isopropanol (solvent can also be used: tetrahydrofuran, dimethyl sulfoxide, hydrazine, hydrazine-dimethylformamide, hydrazine, hydrazine-dimethylacetamide, hydrazine Prepared with -methylpyrrolidone, dioxane, toluene or dichloromethane;

(3) Adding compound II, adding copper catalyst, reacting at 50-65 ° C for 6 hours (the temperature and time of the reaction can also be selected: at 110 ° C - 12 (TC reaction for 30 minutes, or 90 ° C - 11 ( TC reaction for 2 hours, or 80 ° C -10 (TC reaction for 3 hours, or 60 ° C-8 (TC reaction for 4 hours, or 0 ° C-2 (TC reaction for 12 hours, or 20 ° C to 40 ° C reaction) 10 hours, or 40 ° C -65 ° C reaction for 7 hours);

(4) The reaction mixture is added to water, and the obtained aqueous solution is extracted with diethyl ether (an organic solvent such as dichloromethane, chloroform, methyl t-butyl ether or tetrahydrofuran); the organic phase is combined, and then anhydrous sodium sulfate is used. The organic phase is concentrated under reduced pressure, and the remaining residue or oily residue is crystallized by trituration or recrystallization, distillation or purification by silica gel or alumina column chromatography or flash column chromatography to give intermediate III, eluent used A mixture of acetone:ethyl ether having a volume ratio of 8:2 or acetone:ethanol mixture having a volume ratio of 9:1;

Step 2:

(1) The intermediate product III is dissolved in toluene under nitrogen protection (other than a toluene solvent, other aprotic or non-polar organic solvents such as xylene, dichloromethane, diethyl ether, tert-butyl methyl ether) may be used. , tetrahydrofuran, dioxane Ring or chloroform);

(2) Under nitrogen protection, add the above solution to a solution of excess oxalyl chloride dissolved in toluene at -5-20 °C (except for toluene, the solvent can also be used: xylene, dichloromethane, ether) , tert-butyl methyl ether, tetrahydrofuran, dioxane or chloroform, etc., heated to 30 ° C -50 ° C, reaction for 3 hours (reaction temperature and reaction time can also be used: 20 ° C - 30 ° C, reaction 5 Hour, 50 ° C - 60 ° C, reaction for 2 hours, 60 ° C - 8 (TC reaction for 30 minutes), distill off the solvent to give the crude product;

(3) Dissolve the crude product obtained in the previous step in toluene (except for toluene, the solvent may also be used: tetrahydrofuran, dioxane, diethyl ether, hydrazine, hydrazine-dimethylformamide, hydrazine, hydrazine-dimethyl ethane For amide or dimethyl sulfoxide, etc., cool it to -5 ° C to 0 ° C (also -15 ° C to -5 ° C, or 0 ° C to 10 ° C), add acid scavenger The solution in the diluent, the acid scavenger is triethylamine (may also use pyridine, pyridine, cation exchange resin, sodium carbonate, potassium carbonate or potassium hydroxide), the diluent is toluene (may also be selected as tetrahydrofuran) , dioxane or diethyl ether), the excess triethylamine used in the neutralization reaction

(or other acid scavenger); add podophyllotoxin, react at 2 ° C -60 ° C for 2 hours (reaction temperature and reaction time can also be: 0 ° C-4 (TC, reaction 1 _ 3 hours, 60 ° C - 8 (TC, reaction for 1 hour, at 20 ° C - 30 ° C, allowed to stand for 24 hours, filtered, the filtrate was concentrated in vacuo, the residue was recrystallized from organic solvent, or silica gel column chromatography or alumina Chromatographic purification affords a fine formula I, using a mixture of acetone:ethyl ether in a volume ratio of 8:2 or a mixture of acetone:ethanol in a volume ratio of 9:1.

The invention is further illustrated by the following specific examples:

Example 1

The following compounds were synthesized according to the general procedure in Scheme 1:

4- [1-(p-Chlorobenzyl)indole-3-yl]oxalylamino-4-deoxyepidetoxin (YB-B1EPN)

First step:

Preparation of 1-p-chlorobenzyl hydrazine

The solution of 5. 28 g of sodium hydride (0.22 mol, 50%) at 200 was prepared by using a solution of 24. 0 g (0.2 mol), dissolved in 100 mL of dimethyl sulfoxide. In a suspension of mL dimethyl sulfoxide, then add 35 g (0.22 mol) of p-chlorobenzyl chloride; heat the solution to 60 ° C, leave it at room temperature for 12 hours, then pour it to 700 with stirring. The mixture was extracted with a total of 300 mL of dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, filtered, evaporated and evaporated to silica. : acetone / diethyl ether = 1 : 9, v / v) to give 1- p-chlorobenzyl hydrazine, yield: 35. 9 g _;

Step 2:

Synthesis 4- [ 1-(p-Chlorobenzyl)indol-3-yl]oxalylamino-4-deoxyepidetoxin (YB-B1EPN)

Under a nitrogen atmosphere, 9.4 g (0.04 mol) of 1-p-chlorobenzyl hydrazine was dissolved in 50 mL of diethyl ether, and the solution was added dropwise at 0 ° C to 4. 50 mL of oxalyl chloride dissolved in 50 ml. The lyophilized solution at a temperature of 1. 5 g was added to the mixture at a temperature of 0. 5 g. (0. 05 mol) 4β-Aminoepipodophyllotoxin was dissolved in 400 mL of tetrahydrofuran, and the mixture was heated under reflux for 3 hours, allowed to stand at room temperature overnight, concentrated under reduced pressure, and the residue was crystallized from ethyl acetate. 4-[1-(p-Chlorobenzyl)indol-3-yl]oxalylamino-4-deoxyepidetoxin (YB-B1EPN). Yield: 10. 5 g, see Figure 4.

The following compounds were prepared in the same manner:

(I)

Wherein R represents hydrogen or methyl;

among them! ^ represents hydrogen, an alkyl group, C ₃ 〜(: ₇ cycloalkyl, (^~(: ₆ aralkyl, ~(: ₆ alkylsulfonyl, haloacyl, halosulfonyl, ethoxy) a carbonyl group, an alkoxycarbonyl group having an alkyl moiety of 1 to 18 carbon atoms, an alkoxysulfonyl group having an alkyl moiety of 1 to 18 carbon atoms, a benzene ring, a substituted benzene ring, a pyridine ring, a substituted pyridine ring, a pyrimidine ring a substituted pyrimidine ring, a quinoline ring, a substituted quinoline ring, a benzyl group, a substituted benzyl group, a benzoyl group, a substituted benzoyl group, a cinnamyl group, a substituted cinnamyl group, a cinnamoyl group or a substituted cinnamoyl group, the substituted benzene ring, Substituents in the substituted pyridine ring, the substituted pyrimidine ring, the substituted quinoline ring, the substituted benzyl group, the substituted benzoyl group, the substituted cinnamyl group, and the substituted cinnamoyl group are: (^~(: ₆ alkyl group, C ₃ ～ C ₇₎ Cycloalkyl, (^~(: ₆ alkoxy, (^~(: ₆ alkylsulfonylamino, nitro, amino, hydroxy, cyano, halogen, trifluoromethyl, ethoxycarbonyl, An alkoxycarbonyl group having an alkyl moiety having 1 to 18 carbon atoms or an alkyl moiety having 1 to 18 carbon atoms ! Alkoxy sulfonyl group; or ^ represents the general formula ([pi) substituted benzyl group represented by:

Where (1=1 or 2

(II)

Where q is 1 or 2;

The other substitution sites H of the benzene ring in the substituted benzyl group represented by the formula (Π) are substituted by the same or different substituents of (^~(: ₆ alkyl group, C _{3 to} C ₇ Cycloalkyl, (^~(: ₆ alkoxy, (^~(: ₆ alkylsulfonylamino, nitro, amino, hydroxy, cyano, halogen, trifluoromethyl, ethoxycarbonyl, alkane a base having an alkoxycarbonyl group of 1 to 18 carbon atoms, An alkoxysulfonyl group having an alkyl moiety of 1 18 carbon atoms;

R ₄ R ₅ R ₆ R _{7 of} the formula (I) is the same or different, and R ₄ R ₅ R ₆ R ₇ represents hydrogen, ^CM alkyl, C ₃ C ₇ cycloalkyl, (^ ~(: ₆ alkoxy, (^~(: ₆ alkylsulfonylamino, nitro, amino, hydroxy, cyano, halogen, trifluoromethyl, ethoxycarbonyl, alkyl moiety having 1 18 An alkoxycarbonyl group of a carbon atom, an alkoxysulfonyl group having an alkyl moiety of 1 18 carbon atoms, a benzene ring, a substituted benzene ring, a pyridine ring, a substituted pyridine ring, a pyrimidine ring, a substituted pyrimidine ring, a quinoline ring, a substituted quinoline a ring, a benzyloxy group, a substituted benzyloxy group, a substituent in the substituted benzene ring, a substituted pyridine ring, a substituted pyrimidine ring, a substituted quinoline ring, or a substituted benzyloxy group: (^~(: ₆ ) Alkyl, C ₃ ～(: ₇ cycloalkyl, (^~(: ₆ alkoxy, (^~(: ₆ alkylsulfonylamino, nitro, amino, hydroxy, cyano, halogen, tri a fluoromethyl group, an ethoxycarbonyl group, an alkoxycarbonyl group having an alkyl moiety of 1 18 carbon atoms, an alkoxysulfonyl group having an alkyl moiety of 1 18 carbon atoms;

Table 1 shows the structure and physical properties of derivatives of several substituted indole-3-yloxalyl glycoside derivatives

6

C.Sl.0/800ZN3/X3d 6C8900/600Z OAV Οΐ

C.Sl.0/800ZN3/X3d 6C8900/600Z OAV Ϊ́ΐ

C.Sl.0/800ZN3/X3d 6C8900/600Z OAV Εε ΊΖ ο

9Τ ' Ν

ΖΟ '9 Η ε ff ·69 3 6W H H H H HN 3⁄43

F9 'fZ 0

8Ζ · Ν

8 'f Η Z f '£9 J zn H H H H H HN 3⁄43

l £ S 0

SO ·9 N

'f H T Z9 "89 3 S9T H H H H HN 3⁄43

SO "9S 0

ZS · N

T6 · H NdHT OS · 9 3 OZT H H H H HN 3⁄43 SA-aA S9 · N

w τ ή

£9 'f H NdHT 11 "S9 3 S8T H ή H H H H HN 3⁄43 TA-9A

SO ' Z 0

69 · N

K) 'S H 3⁄4 NdHT ZZ "99 3 SZT H H H 3 H H HN 3⁄43 8Λ-9Α

SO '9Z 0

ZS 'f N

T6 · H NdHT OS · 9 3 H H 03⁄43 H H H HN 3⁄43 εχ-aA

U 'TS 0

\Z 'f N

SO 'Zl

IT 'f H NdHT

6ZT H H g H H H HN 3⁄43 ax-aA εε "ss o

06 τ N

SO 'S H Nda ZL "89 3 1ST H H H H . HN 3⁄43 n-aA τε S o

96 τ N

TO 'S 13

89 'f H Nda 0 "99 3 1ST H H H H HN 3⁄43 Ta-aA

C.Sl.0/800ZN3/X3d 6C8900/600Z OAV FM-PN CH ₃ NH HHHHH 160 C 68. 65 4 H 4. 76

N 6. 02 0 20. 57

FM-PN H NH H H H H H 141 C 65. 25 5 H 4. 58

N 4. 92 0 25. 25

FM-PN H NH H H H H 219 C 69. 23 6 H 4. 86

O N 4. 25

0 21. 80

FM-PN H NH HHHH CH ₃ H 183 C 63. 91 7 0 H 4. 72

N 4. 65 0 26. 64

FM-PN H NH HHHF ₃ CHHC 65. 06 8 H 4. 57

N 4. 93 0 25. 28

FM-PN H NH H H H H H H H C 61. 36 9 H 4. 19

CI 5. 83 N 4. 60 0 23. 76

FM-PN H NH HHH CH ₃ 0 HHHC 64. 09 10 H 4. 27

F 7. 85 N 3. 83 0 19. 73 The above compound is used to prepare a mineral acid salt or an organic acid salt, which is hydrochloric acid, sulfuric acid or phosphoric acid; the organic acid is acetic acid, lactic acid, malonic acid, horse Acid, fumaric acid, gluconic acid, glucuronic acid, citric acid, ascorbic acid, pamoic acid, methanesulfonic acid, trifluoroacetic acid, succinic acid, 2-hydroxyethanesulfonic acid, nicotinic acid or p-toluenesulfonic acid to increase Its solubility in water.

Pharmacological tests have demonstrated that the compounds of the present invention have antitumor, antiviral and anti-inflammatory activities.

Anti-tumor activity study: In vitro anti-tumor activity screening The cells in logarithmic growth phase were diluted to lx 10 ⁴ _C ell/ml, immediately seeded in 96-well culture plates, 0.1 ml/well, and then cultured with different concentrations in the experimental wells. Base, three wells per concentration, control group plus equal volume of solvent, set at 37 ° C C0 ₂ incubator 96, then centrifuge (l OOOr / min, 20min), discard the supernatant, add 0.2ml freshly configured per well 0.2mg/ml MTT serum-free medium, continue to culture at 37 °C for 4h, then centrifuge, pour out the serum, 0.2ml DMSO dissolved MTT formazan precipitate, shake with a micro-ultrasonic shaker for 5 min, in the MR700 enzyme The optical density at 570 nm was measured on a scaler and the growth rate of tumor cells was calculated. Table 2 Inhibition of Hela, KB tumor cells by indole-3-yl grass amide derivatives (x lO- ⁶ mol/L)

Claims

Rights request

1. A substituted indole-3-yloxalyl glycoside derivative characterized by having the following general formula (I):

(I)

Wherein R represents hydrogen or methyl;

Wherein ^ represents hydrogen, (^~(: ₆ alkyl, C ₃ ～(: ₇ cycloalkyl, (^~(: ₆ aralkyl, ~(: ₆ alkylsulfonyl, haloacyl, a halosulfonyl group, an ethoxycarbonyl group, an alkoxycarbonyl group having an alkyl moiety of 1 to 18 carbon atoms, an alkoxysulfonyl group having an alkyl moiety of 1 to 18 carbon atoms, a benzene ring, a substituted benzene ring, a pyridine ring , substituted pyridine ring, pyrimidine ring, substituted pyrimidine ring, quinoline ring, substituted quinoline ring, benzyl group, substituted benzyl group, benzoyl group, substituted benzoyl group, cinnamyl group, substituted cinnamyl group, cinnamoyl group or substituted cinnamoyl group The substituent in the substituted benzene ring, the substituted pyridine ring, the substituted pyrimidine ring, the substituted quinoline ring, the substituted benzyl group, the substituted benzoyl group, the substituted cinnamyl group, and the substituted cinnamoyl group is: (^~(: ₆ alkane) a C ₃ -C ₇ cycloalkyl group, (^~(: ₆ alkoxy group, (^~(: ₆ alkylsulfonylamino, nitro, amino, hydroxy, cyano, halogen, trifluoromethyl) Alkoxycarbonyl or alkyl moiety having 1 to 18 carbon atoms in the alkyl moiety having 1 to 18 Atoms, an alkoxy sulfonyl group;

Or ! ^ represents a substituted benzyl group represented by the formula (II):

Where (1=1 or 2

(II)

Where q is 1 or 2;

The other substitution sites H of the benzene ring in the substituted benzyl group represented by the formula (Π) are substituted by the same or different substituents, The substituent is (^~(: ₆ alkyl, C ₃ -C ₇ cycloalkyl, (^~(: ₆ alkoxy, (^~(: ₆ sulfonamide, nitro) , amino, hydroxy, cyano, halogen, trifluoromethyl, ethoxycarbonyl, alkoxycarbonyl having 1 to 18 carbon atoms in the alkyl moiety, alkoxysulfonyl having 1 to 18 carbon atoms in the alkyl moiety ;

R ₄ , R ₆ , and R _{7 of} the above formula (I) are the same or different, and R ₄ , R ₆ , and R ₇ represent hydrogen, (^~(: ₆ alkyl group, C ₃ ～C) ₇ cycloalkyl, (^~(: ₆ alkoxy, (^~(: ₆ alkylsulfonylamino, nitro, amino, hydroxy, cyano, halogen, trifluoromethyl, ethoxycarbonyl) An alkoxycarbonyl group having an alkyl moiety of 1 to 18 carbon atoms, an alkoxysulfonyl group having an alkyl moiety of 1 to 18 carbon atoms, a benzene ring, a substituted benzene ring, a pyridine ring, a substituted pyridine ring, a pyrimidine ring, a substitution Pyrimidine ring, quinoline ring, substituted quinoline ring, benzyloxy group, substituted benzyloxy group, substituted phenyl ring, substituted pyridine ring, substituted pyrimidine ring, substituted quinoline ring, substituted benzyloxy group The base is: C Ce alkyl group, C ₃ 〜(: ₇ cycloalkyl group, (^~(: ₆ alkoxy group, (^~(: ₆ alkylsulfonylamino group, nitro group, amino group, hydroxyl group, a cyano group, a halogen, a trifluoromethyl group, an ethoxycarbonyl group, an alkoxycarbonyl group having an alkyl moiety of 1 to 18 carbon atoms, and an alkoxysulfonyl group having an alkyl moiety of 1 to 18 carbon atoms.

In the formula (I), X is an oxygen or an imino group.

2. A substituted indole-3-yloxalyl epihospiron derivative according to claim 1, characterized in that said R represents a methyl group, ! ^ represents p-chlorobenzyl or 3,4-dichlorobenzyl or 3,4-methylenedioxybenzyl, R ₂ = R ₄ = R ₅ = R ₆ = R ₇ represents hydrogen, and X represents oxygen.

3. A substituted indole-3-yloxalyl epihospiron derivative according to claim 1, characterized in that said R represents a methyl group, ! ^ represents p-chlorobenzyl or 3,4-methylenedioxybenzyl, R ₂ = R ₄ = R ₅ = R ₆ = R ₇ represents hydrogen, and X represents an imino group.

A substituted indole-3-yloxalyl epigalnotoxin derivative according to claim 1, wherein R represents a methyl group, represents a bromine or a methoxy group, represents hydrogen, and X represents an imino group.

A substituted indole-3-yloxalyl epihospiron derivative according to claim 1, wherein R represents a methyl group, represents a methyl group, represents hydrogen, and X represents an imino group.

A substituted indole-3-yloxalyl epihospiron derivative according to claim 1, wherein R represents a methyl group, represents a fluorine or a methoxy group, represents hydrogen, and X represents an imino group.

The inorganic or organic acid salt of a substituted indolin-3-yloxalyl glycoside derivative according to any one of claims 1 to 6, wherein the inorganic acid is hydrochloric acid, sulfuric acid or phosphoric acid; The organic acids are acetic acid, lactic acid, malonic acid, maleic acid, fumaric acid, gluconic acid, glucuronic acid, citric acid, ascorbic acid, pamoic acid, methanesulfonic acid, trifluoroacetic acid, succinic acid, 2-hydroxyethyl Sulfonic acid, nicotinic acid or p-toluenesulfonic acid.

The use of a substituted indole-3-yl oxalyl glucoside derivative according to any one of claims 1 to 6 for the preparation of an antitumor drug.

The use of a mineral acid salt or an organic acid salt of a substituted indole-3-yloxalyl glycoside derivative according to any one of claims 1 to 6 for the preparation of an antitumor drug.