CN1319971C - Camptothecine derivatives and their use - Google Patents

Camptothecine derivatives and their use Download PDF

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Publication number
CN1319971C
CN1319971C CNB2005100983920A CN200510098392A CN1319971C CN 1319971 C CN1319971 C CN 1319971C CN B2005100983920 A CNB2005100983920 A CN B2005100983920A CN 200510098392 A CN200510098392 A CN 200510098392A CN 1319971 C CN1319971 C CN 1319971C
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camptothecine
open loop
acid amides
lactonic ring
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CN1821247A (en
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尤田耙
袁胜涛
王涛
张陆勇
王宗贵
耿燕
李明宗
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Hefei Keda Biological Technology Co., Ltd.
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HEFEI ZHONGKEDA BIO-TECHNOLOGY Co Ltd
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Abstract

The present invention relates to camptothecin derivatives represented by formula (1) and salts thereof. In the formula, R1 represents 0 to 3 identical or different substituent radicals on 9, 10, 11-site, and the substituent radicals comprise halogen atoms, hydroxy and alkoxyl; R2 represents straight chains of C2 to C5 or branched chains of alkylene; R3 represents hydrogen atoms or R4CO-, wherein R4 represents low-grade alkyl, low-grade alkamino alkyl or low-grade alkoxyl alkyl; Y represents heterocyclic basic radicals or hydrogenated heterocyclic basic radicals. The present invention also comprises a preparing method of the compound shown as the formula (1) and applications thereof in treating cancer.

Description

Camptothecin derivative and uses thereof
Technical field:
The present invention relates to a kind of novel derivative of new antitumour drug compounds, particularly a kind of camptothecine, their preparation and application.
Background technology:
Found in the compound of the E lactonic ring open loop of camptothecine some activity and camptothecine quite or better, novel derivative that toxicity is littler than camptothecine.The water soluble that wherein has, thereby be suitable for making injection etc. and use formulation more easily.For example, Japanese first drugmaker once used NH 2CH 2CH 2N (CH 3) 2E ring is carried out ring-opening reaction, and then the new compound of a series of E ring open loop that 17-hydroxyl acylations is obtained (referring to J.P.A, H1 131179; CN1126212A).Gondola Indena S.P.A. company makes the E ring open loop of camptothecine generate alkali metal carboxylate by alkaline hydrolysis, again with 17-hydroxyl acylations, also obtain a series of water soluble camptothecin novel derivatives (referring to US006,121,277A).But the anti-tumor activity of these camptothecine novel derivatives and hypotoxicity are still not ideal enough.
The invention provides the new E ring opened loop compound that the end of the chain contains heterocyclic base or hydrogenation heterocyclic base, or further the hydroxyl on the 17-position of these opened loop compounds is carried out the compound of acidylate with different acylating reagents.These compounds are owing to contain heterocyclic base (imidazoles, pyridine, pyrimidine, pyrazine etc.) or hydrogenation heterocyclic base (piperidines, piperazine, morpholine etc.) and easy and HCl, CF on the end group 3COOH, RSO 3H etc. form soluble salt, thereby preparation is simple, and good water solubility, antitumour activity height, toxicity are little.
Summary of the invention:
The invention provides a kind of novel derivative of camptothecine, its chemical structure is as follows:
Wherein
R 1Represent 9,10 or the 11-position on do not replace or 0-3 identical or different substituting group arranged on these, these substituting groups are selected from halogen atom, hydroxyl, alkoxyl group; As: F, Cl, Br, OH, OMe, OEt etc.
R 2Represent C 2-C 5The straight or branched alkylidene group; As :-CH 2CH 2-,-CH 2CH 2CH 2-,-CH 2(CH 2) 2CH 2-,-CH 2CH (CH 3) CH 2-wait .R 3Represent hydrogen atom or R 4CO-,
R 4Represent low alkyl group, lower alkyl amino alkylidene group or lower alkoxy alkylidene group; As :-CH 3-CH 2CH 3,-(CH 2) nCH 3,-(CH 2) nOCH 3,-(CH 2) nNHCH 3,-(CH 2) nN (CH 3) 2Deng (n=1-3)
Y represents heterocyclic base or hydrogenation heterocyclic bases such as imidazoles, pyridine, pyrimidine, pyrazine, as piperidines, piperazine, morpholine.
Preferred compound is:
R 1Represent 9,10 or the 11-position on be arbitrarily H, OH
R 2Representative-CH 2CH 2CH 2-
R 3Represent H, R 4CO
R 4Representative-CH 3,-CH 2CH 3.-(CH 2) nNR 2
Y represents 1-imidazolyl, 1-morpholinyl
Most preferred is:
R 1Represent H
R 2Representative-CH 2CH 2CH 2-
R 3Represent H, R 4CO
R 4Representative-CH 3,-CH 2CH 3
Y represents 1-imidazolyl, 1-morpholinyl
The chemical name of most preferred is:
21-N[3-(1-morpholinyl) propyl group] acid amides-17-hydroxyl E lactonic ring open loop camptothecine (R 1=H, R 2=-CH 2CH 2CH 2-, R 3=H, the Y=1-morpholinyl); 21-N[3-(1-morpholinyl) propyl group] acid amides-17-acetoxyl group E lactonic ring open loop camptothecine (R 1=H, R 2=-CH 2CH 2CH 2-, R 3=R 4CO, R 4=-CH 3, the Y=1-morpholinyl); 21-N[3-(1-morpholinyl) propyl group] acid amides-17-propionyloxy E lactonic ring open loop camptothecine (R 1=H, R 2=-CH 2CH 2CH 2-, R 3=R 4CO, R 4=-CH 2CH 3, the Y=1-morpholinyl); 21-N[3-(1-imidazolyl) propyl group] acid amides-17-hydroxyl E lactonic ring open loop camptothecine (R 1=H, R 2=-CH 2CH 2CH 2-, R 3=H, the Y=1-imidazolyl); 21-N[3-(1-imidazolyl) propyl group] acid amides-17-acetoxyl group E lactonic ring open loop camptothecine (R 1=H, R 2=-CH 2CH 2CH 2-, R 3=R 4CO, R 4=-CH 3, the Y=1-imidazolyl); 21-N[3-(1-imidazolyl) propyl group] acid amides-17-propionyloxy E lactonic ring open loop camptothecine (R 1=H, R 2=-CH 2CH 2CH 2-, R 3=R 4CO, R 4=-CH 2CH 3, the Y=1-imidazolyl).
Compound of the present invention is the reagent N H that contains two basic groups with a series of 2-(CH 2) n-Y (Y represents heterocyclic base or hydrogenation heterocyclic base) carries out to the E of camptothecine ring that ring-opening reaction obtains.
The preparation method is listed in the following reaction formula: wherein, the compound of formula (1) representative is by the camptothecine (CPT) of formula (2) definition, 10-hydroxyl CPT, 10 or crude substance such as 11-methoxyl group CPT or by semisynthetic 9,10,11-contains the substituent CPT derivative that defines in (1) formula and separates reagent ammonia through the ammonia of formula (3) definition and separate open loop on the position, or further the 17-hydroxy esterification is prepared, reaction formula is as follows:
R in the formula 1, R 2, R 3, R 4, Y definition cotype (1) compound.
The R of reaction formula below 2The compound of representing with Y is a most preferred of the present invention.
Though separating open loop reaction, ammonia also can adopt solubilizing agent not directly to separate the CPT derivative raw material reaction that reagent and formula (2) define with excess of ammonia.But because of the ammonia that uses among the present invention separate the reagent boiling point higher, should not remove excess of ammonia with the method for underpressure distillation and separate reagent, bring difficulty can for ensuing separation and purification of products, therefore adopt slightly excess of ammonia to separate reagent and in appropriate solvent, react with the raw material that formula (2) defines.After the reaction reaction mixture is poured in ether or sherwood oil or the mixed solvent of the two, made the product precipitation, the precipitation that leaches further gets product with column chromatography purification.
The esterification of open-loop products 17-position hydroxyl, available corresponding acylating agent carries out under pyridine, DCC or DMAP catalysis as acid anhydrides, acyl chlorides or other suitable acylating agent.
For example open-loop products and acid anhydrides can be spent the night at heated and stirred in the presence of pyridine, the gained reaction mixture is poured in the sherwood oil, and the yellow solid that leaches separates through silica gel column chromatography, obtains very pure acylate.
Various CPT novel derivatives that the present invention obtains and the various acid that wait the medicinal permission of mole, example hydrochloric acid, methylsulfonic acid or trifluoroacetic acid reaction can get various soluble salts.
The present invention also comprises, the application of formula of the present invention (1) camptothecin derivative in the preparation antitumor drug, and described tumour is solid tumor and non-solid tumor.
Following data by experiment illustrate beneficial effect of the present invention:
One, XY-8 is to the antitumor action of vitro culture human tumor cells
1.XY-8 anti tumor activity in vitro screening
1.1 tried thing
XY-8 (for the compound of the embodiment of the invention one preparation) Hefei ZhongKeDa Bioisystech Co., Ltd provides.Positive drug alkyl camptothecine injection (HCPT), 2ml:2mg, Huangshi Feiyun Pharmaceutical Co., Ltd., lot number: 041001.
1.2 subject cell strain
Select the human lung cancer cell A549 for use, the low differentiation of people adenocarcinoma of stomach cell BGC-823, human liver cancer cell SMMC-7721, four cell strains of human promyelocytic leukemia cell HL-60.
1.3 test method
Get and be in one bottle in cell in good condition exponential phase of growth, add 0.25% tryptic digestive juice, digestion comes off attached cell, counting 2～4 * 10 4Individual/ml, make cell suspension.Obtained cell suspension is inoculated on 96 orifice plates, and constant temperature CO is put in 180 μ l/ holes 2Cultivated 24 hours in the incubator.Change liquid, adding is subjected to the reagent thing, and cultivated 48 hours in 20 μ l/ holes.MTT is added in 96 orifice plates, 20 μ l/ holes, reaction is 4 hours in the incubator.Supernatant liquor is removed in suction, adds DMSO, 150 μ l/ holes, and jolting is 5 minutes on the dull and stereotyped shaking table.Tried thing and investigated three concentration (1 * 10 -7, 1 * 10 -6, 1 * 10 -5Mol/L), be the light absorption value that the 570nm place measures every hole with enzyme-linked immunosorbent assay instrument at wavelength, calculate the cell inhibitory rate under each concentration respectively.
Cell inhibitory rate %=(negative control group OD value-susceptibility group OD value)/negative control group OD value * 100%
1.4 antitumor activity screening judging criterion
In the extracorporeal anti-tumor function screening, the dissimilar positive effect judging criterions of being tried thing see the following form:
Known molecular quantizes compound mol/L Unknown compound μ g/ml Crude extract μ g/ml Cell inhibitory rate % Active
1×10 -7 1×10 -6 1×10 -5 1 10 100 2 20 200 ≥50 ≥50 ≥50 +++potent
1×10 -7 1×10 -6 1×10 -5 1 10 100 2 20 200 ＜50 ≥50 ≥50 ++ middle effect
1×10 -7 1×10 -6 1×10 -5 1 10 100 2 20 200 ＜50 ＜50 ≥50 + weak effect
1.5 The selection result
XY-8 sees Table 1 to the antitumor action The selection result of vitro culture human tumor cells.Wherein XY-8 has weak effect to the low differentiation of people adenocarcinoma of stomach cell BGC-823; Have potent to human promyelocytic leukemia cell HL-60 and human lung cancer cell A549.
Table 1.XY-8 is to the antitumor action The selection result of vitro culture human tumor cells
Cell strain Tried thing Final concentration mol/L Cell inhibitory rate % Active
A549 XY-8 1×10 -7 1×10 -6 1×10 -5 53.88 a 87.35 99.59 +++
Mitomycin 1×10 -7 1×10 -6 1×10 -5 18.42 41.93 89.46 +
BGC-823 XY-8 1×10 -7 1×10 -6 1×10 -5 31.28 44.70 50.66 +
Cis-platinum 1×10 -7 1×10 -6 1×10 -5 11.00 10.90 92.94 +
HL-60 XY-8 1×10 -7 1×10 -6 1×10 -5 70.41 91.82 97.32 +++
Cis-platinum 1×10 -7 1×10 -6 1×10 -5 24.82 46.37 96.79 +
SMMC-7721 XY-8 1×10 -7 27.63 _
1×10 -6 1×10 -5 17.40 33.45
Mitomycin 1×10 -7 1×10 -6 1×10 -5 5.03 49.14 61.68 +
A: the antitumor drug primary-screened sample is counted n=3
2.XY-8 to the inhibiting IC of vitro culture human lung cancer cell A549 50Value
2.1 tried thing
XY-8 Hefei ZhongKeDa Bioisystech Co., Ltd provides.Positive drug alkyl camptothecine injection (HCPT), 2ml:2mg, Huangshi Feiyun Pharmaceutical Co., Ltd., lot number: 041001.
2.2 subject cell strain
Select the human lung cancer cell A549 for use.
2.3 test method
Get and be in one bottle in cell in good condition exponential phase of growth, add 0.25% tryptic digestive juice, digestion comes off attached cell, counting 2～4 * 10 4Individual/ml, make cell suspension.Obtained cell suspension is inoculated on 96 orifice plates, and constant temperature CO is put in 180 μ l/ holes 2Cultivated 24 hours in the incubator.Change liquid, adding is subjected to the reagent thing, and cultivated 48 hours in 20 μ l/ holes.MTT is added in 96 orifice plates, 20 μ l/ holes, reaction is 4 hours in the incubator.Supernatant liquor is removed in suction, adds DMSO, 150 μ l/ holes, and jolting is 5 minutes on the dull and stereotyped shaking table.Tried thing and investigated 6 concentration (1 * 10 -8～1 * 10 -5Mol/L), be the light absorption value that the 570nm place measures every hole with enzyme-linked immunosorbent assay instrument at wavelength, calculate cell inhibitory rate under each concentration respectively, use IC 50Software for calculation calculates test-compound IC 50
Cell inhibitory rate %=(negative control group OD value-susceptibility group OD value)/negative control group OD value * 100%
2.4 result
Tried thing Final concentration mol/L IC 50 μmol/L Tried thing Final concentration mol/L IC 50 μmol/L
HCPT 1×10 -7 3×10 -7 1×10 -6 3×10 -6 1×10 -5 3×10 -5 13.8±8.6 XY-8 1×10 -8 3×10 -8 1×10 -7 3×10 -7 1×10 -6 1×10 -5 8.1±3.2
Annotate: each sample IC50 repetition measurement frequency n 〉=3.
Two, XY-8 is to the experimental therapy effect of mice transplanted tumor
1. materials and methods
1.1 animal
50 of ICR mouse, female, 18-22g is provided by animal housing of China Medicine University, conformity certification number: kinoplaszm SCXK (Soviet Union) 2002--0011 of Soviet Union.
1.2 knurl kind
Mouse S180 sarcoma and H22 liver cancer are provided by institute of materia medica, Chinese Academy of Sciences Shanghai.
1.3 tried thing
XY-8 Hefei ZhongKeDa Bioisystech Co., Ltd provides.Positive drug alkyl camptothecine injection (HCPT), 2ml:2mg, Huangshi Feiyun Pharmaceutical Co., Ltd., lot number: 041001.
2. test method
2.1XY-8 experimental therapy effect to mouse S180 sarcoma
Select well-grown 7～11 days S180 knurl kind for use, it is subcutaneous to be inoculated in the right side of mice armpit, and about 4.5～5 * 10 6Cell/only, inoculate and divide cage at random after 24 hours, intravenously administrable, administration volume are 0.4ml/.Tried thing XY-8 and established 10,5, three dosage groups of 2.5mg/kg, positive drug HCPT establishes 8mg/kg, each is organized in inoculation back administration in the 2nd, 5 day.Measure body weight every day during the administration, put to death animal on the 8th day, claims knurl heavy, and it is heavy that average knurl is respectively organized in calculating, presses formula and obtain tumor control rate and carry out the t check.
Figure C20051009839200091
2.2XY-8 experimental therapy effect to mouse H22 liver cancer
Test method is with S180 sarcoma test, tried thing XY-8 and establishes 10,5, three dosage groups of 2.5mg/kg, and positive drug HCPT establishes 8mg/kg.
3. result
3.1XY-8 experimental therapy effect to mouse S180 sarcoma
The results are shown in Table 4.Compare with the physiological saline control group, three dosage groups of XY-8 10,5,2.5mg/kg all can significantly suppress tumor growth (P＜0.01), and wherein the effect of XY-8 10mg/kg obviously is better than HCPT8mg/kg (P＜0.01).
Table 4.XY-8 is to the tumor growth restraining effect of mouse S180 sarcoma (x ± sd)
Group Dosage mg/kg Number of animals Body weight (g) Knurl heavy (g) Inhibition rate of tumor growth (%)
d1 d7 d1 d7
Physiological saline HCPT XY-8 XY-8 XY-8 8 10 5 2.5 10 10 10 10 10 10 10 10 10 10 24.4±1.0 24.3±1.7 24.5±1.1 25.2±1.0 23.8±1.1 29.1±0.7 28.4±1.9 28.0±1.3 28.4±0.9 28.5±0.7 1.09±0.52 0.31±0.21 ** 0.10±0.08 **，## 0.18±0.12 ** 0.32±0.10 ** 71.3 90.7 83.4 70.4
D1, d7: inoculation back the 1st, 7 day;
*Compare with the physiological saline group P＜0.01; ##Compare with the HCPT group P＜0.01.
3.2XY-8 experimental therapy effect to mouse H22 liver cancer
The results are shown in Table 5.Compare with the physiological saline control group, three dosage groups of XY-8 10,5,2.5mg/kg all can significantly suppress tumor growth (P＜0.01), and wherein the effect of XY-8 10,5mg/kg obviously is better than HCPT8mg/kg (P＜0.01, P＜0.05).
Table 5.XY-8 is to the tumor growth restraining effect of mouse H22 liver cancer (x ± sd)
Group Dosage mg/kg Number of animals Body weight (g) Knurl heavy (g) Inhibition rate of tumor growth (%)
d1 d7 d1 d7
Physiological saline HCPT XY-8 XY-8 XY-8 8 10 5 2.5 10 10 10 10 10 10 10 10 10 10 20.2±0.8 20.1±0.7 19.7±0.8 20.1±0.8 19.6±0.9 27.0±2.8 25.2±1.5 21.0±1.9 23.2±1.3 24.4±1.5 1.12±0.45 ** 0.77±0.63 ** 0.18±0.11 **，## 0.24±0.17 **，# 0.42±0.23 ** 30.7 83.8 78.6 62.3
D1, d7: inoculate the 1st, 7 day;
*Compare with the physiological saline group P＜0.01; #P＜0.05, ##Compare with the HCPT group P＜0.01.
Three, XY-8 is to the experimental therapy effect of people's cancer Nude Mice
1. purpose
Investigate new compound XY-8 people's cancer Nude Mice is had or not growth-inhibiting effect and action intensity
2. materials and methods
2.1 tried thing
New compound XY-8 is provided by Hefei ZhongKeDa Bioisystech Co., Ltd, is pale yellow powder, and is soluble in water, prepares desired concn with physiological saline before the administration; Positive drug alkyl camptothecine injection (HCPT), 2ml:2mg, Huangshi Feiyun Pharmaceutical Co., Ltd., lot number: 041001, be diluted to desired concn with physiological saline before each administration.
2.2 transplanted tumor
Select human lung adenocarcinoma A-549 Nude Mice, people's adenocarcinoma of stomach BGC-823 Nude Mice, people's adenocarcinoma of stomach SGC-7901 Nude Mice for use, it is subcutaneous and set up to be inoculated in nude mouse by human lung adenocarcinoma A-549, people's adenocarcinoma of stomach BGC-823 and people's adenocarcinoma of stomach SGC-7901 cell strain respectively.The cell inoculation amount is 2 * 10 6, inoculation is used after forming and passing for 3 generations again in the nude mouse body behind the transplanted tumor.
2.3 animal
Female BALB/cA nude mouse, age in days 35-40 days, body weight 18-22g was provided by Chinese Academy of Sciences's Shanghai Experimental Animal Center.The conformity certification numbering: Shanghai is moving closes the card word No. 122.10 of the negative control groups of every treated animal number, 5 of administration groups.
2.4 test method
The tumor tissue of getting the growth animated period cuts into 1.5mm 3About, under aseptic condition, it is subcutaneous to be inoculated in nude mouse right side armpit.Nude Mice is treated tumor growth to 100～300mm with vernier caliper measurement transplanted tumor diameter 3After with the animal random packet.Use the method for measuring the knurl footpath, dynamic observe the antineoplastic effect of tested thing.The measurement number of times of diameter of tumor is that each the measurement also need claim mouse heavy simultaneously 3 times weekly.The administration group is intravenously administrable 3 times weekly, and positive controls is intravenously administrable 2 times weekly, and negative control group is given equivalent physiological saline simultaneously.
2.5 detect index and method of calculation
(1) gross tumor volume (tumor volume, TV), calculation formula is:
TV＝1/2×a×b 2
Wherein a, b represent length and width respectively.
(2) relative tumour volume (relative tumor volume, RTV), calculation formula is:
RTV＝TV t/TV 0。
TV wherein 0(d during for minute cage administration 0) gross tumor volume, TV tGross tumor volume when measuring each time.
(3) relative tumor proliferation rate T/C (%), calculation formula is:
T RTV
T/C(％)＝——×100
C RTV
T RTV: treatment group RTV; C RTV: negative control group RTV.
Test-results is with the evaluation index of relative tumor proliferation rate T/C (%) as anti-tumor activity.
3. result
3.1XY-8 experimental therapy effect to human lung adenocarcinoma A-549 Nude Mice
XY-8 sees Table 6 and Fig. 1 to the experimental treatment result of human lung adenocarcinoma A-549.XY-8 has certain growth-inhibiting effect to human lung adenocarcinoma A-549 Nude Mice.It is 60.7,103.6 and 53.6 that XY-8 2.5,5 and 10mg/kg dosage group are respectively the T/C (%) of A-549, and HCPT 8mg/kg dosage group T/C (%) is 71.4.Experimental group does not have obvious toxicity.
Table 6.XY-8 is to the experimental therapy effect of human lung adenocarcinoma A-549 Nude Mice
Group Dosage mg/kg Number of animals Body weight (g) TV RTV T/C (％)
Beginning At last Beginning At last d0 d17
NS HCPT XY-8 XY-8 XY-8 8 10 5 2.5 10 5 5 5 5 10 5 5 5 5 21.4±1.4 21.3±1.7 20.7±0.6 21.5±0.9 21.3±0.5 22.5±1.3 22.4±1.8 23.4±2.5 22.1±1.1 22.7±1.0 128±71 131±54 132±134 126±72 120±23 390±342 258±137 211±237 407±365 200±73 2.8±1.0 2.0±0.5 1.5±0.4 * 2.9±1.3 1.7±0.5 * 71.4 53.6 103.6 60.7
D0: divide the cage administration time
3.2XY-8 experimental therapy effect to people's adenocarcinoma of stomach BGC-823 Nude Mice
XY-8 sees Table 7 and Fig. 2 to the experimental treatment result of people's adenocarcinoma of stomach BGC-823.XY-8 has certain growth-inhibiting effect to people's adenocarcinoma of stomach BGC-823 Nude Mice.XY-8 2.5,5 and 10mg/kg dosage group are respectively 39.8,36.6 and 27.3 to the T/C (%) of A-549, and HCPT 8mg/kg dosage group T/C (%) is 37.3.Experimental group does not have obvious toxicity.
Table 7.XY-8 is to the experimental therapy effect of people's adenocarcinoma of stomach BGC-823 Nude Mice
Group Dosage mg/kg Number of animals Body weight (g) TV RTV T/C (％)
Beginning At last Beginning At last d0 d17
NS HCPT XY-8 XY-8 XY-8 8 10 5 2.5 10 5 5 5 5 10 5 5 5 5 20.4±1.3 20.5±3.6 20.0±0.8 20.6±0.8 21.0±1.0 22.9±1.3 21.8±3.2 21.0±1.1 21.6±1.1 22.6±1.3 190±83 185±90 184±20 187±67 181±61 2793±1117 1119±327 774±132 1054±415 1108±368 16.1±5.9** 6.0±1.1** 4.4±1.0** 5.9±2.2** 6.4±2.3** 37.3 27.3 36.6 39.8
D0: divide the cage administration time
3.3XY-8 experimental therapy effect to people's adenocarcinoma of stomach SGC-7901 Nude Mice
XY-8 sees Table 8 and Fig. 3 to the experimental treatment result of people's adenocarcinoma of stomach SGC-7901.XY-8 has certain growth-inhibiting effect to people's adenocarcinoma of stomach SGC-791 Nude Mice.XY-8 2.5,5 and 10mg/kg dosage group are respectively 82.2,62.5 and 43.3 to the T/C (%) of A-549, and HCPT 8mg/kg dosage group T/C (%) is 54.8.Experimental group does not have obvious toxicity.
Table 8.XY-8 is to the experimental therapy effect of people's adenocarcinoma of stomach SGC-7901 Nude Mice
Group Dosage mg/kg Number of animals Body weight (g) TV RTV T/C (％)
Beginning At last Beginning At last d0 d17
NS HCPT XY-8 XY-8 XY-8 8 10 5 2.5 10 5 5 5 5 10 5 5 5 5 19.7±1.1 19.5±0.7 19.7±1.2 19.7±0.7 20.0±0.6 23.5±1.6 22.2±1.3 20.5±1.7 20.2±2.8 23.4±1.1 263±98 283±140 272±56 273±146 251±42 5671±1701 3009±1419 2382±589 3241±1203 4510±727 20.8±5.7 11.4±2.9** 9.0±2.3** 13.0±3.8** 17.1±1.6 54.8 43.3 62.5 82.2
D0: divide the cage administration time
The anti-tumor activity experiment of other new camptothecin derivatives
1 experimental result
Sample number into spectrum Final concentration (mol/L) The low differentiation of people adenocarcinoma of stomach cell BGC-823 Human promyelocytic leukemia cell HL-60 The human lung cancer cell A549 Human liver cancer cell SMMC-7721
Inhibiting rate (%) Inhibiting rate (%) Inhibiting rate (%) Inhibiting rate (%)
XY-8 1×10 -7 1×10 -6 1×10 -5 31.28 44.70 50.66 70.41 91.82 97.32 53.88 87.35 99.59 27.63 17.40 33.45
Bam 1×10 -7 1×10 -6 1×10 -5 19.78 25.53 24.72 1.41 49.88 89.68 12.24 31.63 87.35 19.03 19.74 17.26
Ban 1×10 -7 1×10 -6 1×10 -5 12.51 29.16 53.48 28.91 80.54 95.86 41.84 85.71 95.71 23.07 22.94 55.33
Ab 1×10 -7 1×10 -6 33.20 35.72 55.72 85.50 17.14 85.51 29.62 33.88
1×10 -5 63.57 94.01 96.94 53.91
Bbm 1×10 -7 1×10 -6 1×10 -5 26.94 19.27 26.84 5.35. 26.28 74.21 5.71 12.24 63.27 13.14 14.70 17.26
Bbn 1×10 -7 1×10 -6 1×10 -5 19.78 11.81 17.76 0.00 58.35 91.48 6.37 28.37 90.20 14.91 21.38 4.05
Wherein XY-8 represents 21-N[3-(1-morpholinyl) propyl group] acid amides-17-hydroxyl E lactonic ring open loop camptothecine (R 1=H, R 2=-CH 2CH 2CH 2-, R 3=H, the Y=1-morpholinyl), Bam represents 21-N[3-(1-morpholinyl) propyl group] and acid amides-17-acetoxyl group E lactonic ring open loop camptothecine (R 1=H, R 2=-CH 2CH 2CH 2-, R 3=R 4CO, R 4=-CH 3, the Y=1-morpholinyl), Ban represents 21-N[3-(1-morpholinyl) propyl group] acid amides-17-propionyloxy E lactonic ring open loop camptothecine (R 1=H, R 2=-CH 2CH 2CH 2-, R 3=R 4CO, R 4=-CH 2CH 3, the Y=1-morpholinyl), Ab represents 21-N[3-(1-imidazolyl) propyl group] acid amides-17-hydroxyl E lactonic ring open loop camptothecine (R 1=H, R 2=-CH 2CH 2CH 2-, R 3=H, the Y=1-imidazolyl), Bbm represents 21-N[3-(1-imidazolyl) propyl group] and acid amides-17-acetoxyl group E lactonic ring open loop camptothecine (R 1=H, R 2=-CH 2CH 2CH 2-, R 3=R 4CO, R 4=-CH 3, the Y=1-imidazolyl), Bbn represents 21-N[3-(1-imidazolyl) propyl group] acid amides-17-propionyloxy E lactonic ring open loop camptothecine (R 1=H, R 2=-CH 2CH 2CH 2-, R 3=R 4CO, R 4=-CH 2CH 3, the Y=1-imidazolyl).
1. get and be in one bottle in cell in good condition exponential phase of growth, add 0.25% tryptic digestive juice, digestion comes off attached cell, counting 2～4 * 10 -4Individual/mL, make cell suspension.
2. obtained cell suspension is inoculated on 96 orifice plates, and constant temperature CO is put in 180 μ l/ holes 2Cultivated 24 hours in the incubator.
3. change liquid, adding is subjected to the reagent thing, and cultivated 48 hours in 20 μ l/ holes.
4. MTT is added in 96 orifice plates, 20 μ l/ holes, reaction is 4 hours in the incubator.
5. inhale and go supernatant, add DMSO, 150 μ l/ holes, jolting is 5 minutes on the dull and stereotyped shaking table.
6. be the light absorption value that the 570nm place measures every hole with enzyme-linked immunosorbent assay instrument at wavelength, and calculate cell and suppress.
The XY-8 intravenously administrable is to the acute toxicity test of mouse
The The acute toxicity tests of XY-8 shows: mouse mainline is the LD of administration (iv) 50Value is 269.7mg/kg.The toxicity symptom of mouse shows as the minimizing of ingesting, and spontaneous activity obviously descends, and abdomen crouches, blepharoptosis, and irritant reaction is blunt to external world, and animal is quiet and die.Animal dead promptly occurs behind the maximum dose level group administration 3h, each dosage treated animal death all occurs in the 48h, and after about 48 hours, the mouse activity begins to increase and recovers normal.Dead mouse gross necropsy, internal organs are not seen obvious pathology.
Test-results is pressed the Bliss method and is calculated, and records the LD of mouse iv XY-8 50Value is 269.7mg/kg, and its fiducial limit of 95% is 257.7～280.2mg/kg.
The present invention also comprises the pharmaceutical composition with camptothecin derivative preparation of the present invention, pharmaceutical composition of the present invention comprises camptothecin derivative of the present invention or its physiologically acceptable salt of medicine effective quantity, also can add the medicine acceptable carrier in case of necessity, described composition is a pharmaceutical dosage forms, adopt the preparation of technology of pharmaceutics routine techniques, preferred dosage form is the dosage form of the injection of unitary dose.
Description of drawings:
Fig. 1 .XY-8 is to the effect of people's lung cancer A-549 Nude Mice growth-inhibiting
Fig. 2 .XY-8 is to the effect of people's adenocarcinoma of stomach BGC-823 Nude Mice growth-inhibiting
Fig. 3 .XY-8 is to the effect of people's adenocarcinoma of stomach SGC-7901 Nude Mice growth-inhibiting
Embodiment:
Further specify the present invention by the following examples:
Embodiment one: N-(3-aminopropyl) morpholine is separated open loop product (1) XY-8 to the ammonia of CPT preparation
105mg (0.3mmol) CPT is dissolved in 15ml methyl alcohol, adds 1.2 normal ammonia and separates reagent N-(3-aminopropyl) morpholine (3) a, after reacting 14 hours under 75 ℃, system becomes clarification, and reaction mixture is poured in the ether, separates out yellow mercury oxide, leach precipitation, wash with cold diethyl ether.Can find out by TLC, contain unreacted CPT in the product.Product is dissolved in a small amount of CHCl 3, separate (eluent: ethyl acetate: sherwood oil=1: 1 → 4: 1) get pure open-loop products (1) XY-8 106mg, productive rate 88% with alumina column chromatography.
IR(KBr)ν：1620.61cm -1(-CONH-)。
1HNMR(CDCl 3，300MHz)δppm：1.07(t，J＝7.20Hz，3H，18-CH 3)，1.76(m，2H，19-CH 2)，2.25(m，1H，22-CH 2)，2.43(m，1H，22-CH 2)，2.44(m，6H，22-CH 2，and 2×24-CH 2)，3.41(m，2H，21-CH 2)，3.75(m，4H，2×25-CH 2)，4.88(q，J AB＝12.70Hz，2H，17-CH 2)，5.04(s，2H，5-CH 2)，7.47(t，J＝8.4Hz，1H，10-H)，7.48(s，1H，14-H)，7.56(d，J＝7.20Hz，1H，9-H)，7.67(t，J＝5.20Hz，2H，11-H)，7.87(s，1H，7-H)，7.97(d，J＝8.46Hz，1H，12-H)，8.20(s，1H，NH)。
The ammonia of embodiment two, CPT is separated the preparation of 17-glycoloyl product (1) Bam of open loop product (1) XY-8
CPT open-loop products (1) XY-8 (0.25mmol) of 126mg N-(3-aminopropyl) morpholine is dissolved in 2mL (24.8mmol) pyridine, adds 1mL (10.6mmol) diacetyl oxide, and heating makes temperature maintenance about 40 ℃, and stirring is spent the night.The pressure reducing and steaming solvent.The a spot of CHCl of residue 3Dissolving is poured in the mixed solution of 20mL sherwood oil ether equal-volume ratio, separates out precipitation, filters the cold diethyl ether washing.Use CHCl again 3Dissolving, purification by silica gel column chromatography (eluent: ethyl acetate: sherwood oil=2: 1 → pure ethyl acetate), get xanchromatic pressed powder (1) Bam 112mg.Productive rate 81.9%.
IR(KBr)ν：1733.69cm -1(-CO-CH 3)，1620.61cm -1(-CONH-)。
1HNMR(CDCl 3，300MHz)δppm：1.10(t，J＝7.17Hz，3H，18-CH 3)，1.77(m，2H，19-CH 2)，2.06(s，3H，-CO-CH 3)，2.30(m，1H，22-CH 2)，2.52～2.54(m，7H，23-CH 2，2×24-CH 2，1/2×22-CH 2)，3.31～3.42(m，2H，21-CH 2)，3.78(d，J＝4.38Hz，4H，25-CH 2)，5.15(q，J＝19.41Hz，2H，5-CH 2)，5.47(dd，J AB＝11.58Hz，2H，17-CH 2)，7.43(t，J＝7.42Hz，1H，10-H)，7.58(s，1H，14-H)，7.63(d，J＝8.11Hz，1H，9-H)，7.69(t，J＝7.23Hz，1H，11-H)，8.04(d，J＝8.34Hz，1H，12-H)，8.14(s，1H，7-H)，8.17(s，1H，NH)
The ammonia of embodiment three, CPT is separated the preparation of 17-hydroxyl propionyl product (1) Ban of open loop product (1) XY-8
CPT open-loop products (1) XY-8 of 150mg (0.30mmol) N-(3-aminopropyl) morpholine, 1.5mL pyridine (18.6mmol) and 1mL propionic anhydride (7.7mmol) are mixed and heated to 40 ℃, stirring is spent the night, boil off low boiling point solvent, residuum is poured the 50mL ether into, separate out faint yellow solid, be further purified (eluent: ethyl acetate: sherwood oil=1: 1 → 3: 1) get (1) Bam straight product 111mg, productive rate 66.4% through silica gel column chromatography.
IR(KBr)ν：1729.83cm -1(-COCH 2CH 3)，1654.52cm -1(-CONH-)
1HNMR.(CDCl 3，300MHz)δppm：1.11(t，J＝7.23Hz，3H，18-CH 3)，1.21(t，J＝7.05Hz，3H，-CO-C-CH 3)，1.77(m，2H，19-CH 2)，2.31(m，1H，1/2×22-CH 2)，2.40～2.15(m，1H，1/2×22-CH 2)，2.55～2.56(m，6H，23-CH 2 and 2×24-CH 2)，3.32(m，1H，1/2×21-CH 2)，3.44(m，1H，1/2×21-CH 2)，3.48(q，J＝6.99Hz，2H，-CO-CH 2-)，3.79(t，J＝4.50Hz，4H，2×25-CH 2)，5.13(q，J＝19.17Hz，2H，5-CH 2)，5.47(q，J＝ AB＝11.58Hz，2H，17-CH 2)，7.45(t，J＝7.41，1H，10-H)，7.57(s，1H，14-H)，7.60(d，J＝8.10，1H，9-H)，7.68(t，J＝7.51，1H，11-H)，8.03(d，J＝8.46，1H，12-H)，8.12(s，1H，7-H)，8.21(s，1H，NH)。
Embodiment four, 1-(3-aminopropyl) imidazoles is separated open loop product (1) Ab to the ammonia of CPT preparation: 639mg CPT (1.84mmol) and about 1.2 normal 1-(3-aminopropyl) imidazoles and 1mLCHCl 3, to stir, heating (about 60 ℃) to becoming clarification, boils off CHCl 3, debris is poured the NHCl of 40mL into 4Saturated solution is with the CHCl of 5 * 40mL 3Extraction merges organic phase, and anhydrous sodium sulfate drying concentrates, silica gel column chromatography purification (eluent: ethyl acetate: sherwood oil=2: 1 → pure ethyl acetate), finally obtain yellow powder shape solid (1) Ab 815mg.Productive rate 93.7%.
IR(KBr)ν：1651.08cm -1(-CONH-)
1HNMR.(CDCl 3，300MHz)δppm：1.06(t，J＝6.44Hz，3H，18-CH 3)，2.05(m，2H，19-CH 2)，2.30～2.39(m，2H，22-CH 2)，3.33(m，2H，21-CH 2)，4.01(t，J＝6.97Hz，2H，23-CH 2)，4.92(dd，J AB＝12.64Hz，2H，17-CH 2)，5.04(s，2H，5-CH 2)，6.94(s，1H，)，7.01(s，1H，)，7.45(t，J＝7.23Hz，1H，10-H)，7.51(d，J＝7.10Hz，1H，9-H)，7.56(s，1H，14-H)，7.65(d，J＝9.11Hz，1H，12-H)，7.70(t，J＝7.42Hz，1H，11-H)，8.03(s，1H，)，8.05(s，1H，7-H)。
Preparation 153mg (0.32mmol) (1) Ab that the ammonia of embodiment five, CPT is separated 17-glycoloyl product (1) Bbm of open loop product (1) Ab is dissolved in the pyridine of 1.8mL (22.3mmol), adds the diacetyl oxide of 1.2mL (12.7mmol).Heating makes temperature about 50 ℃, spends the night.Cooling, rotation boils off partial solvent, uses ether sedimentation then, filters.Solid is at (the eluent: ethyl acetate: sherwood oil=2: 1 → pure ethyl acetate), finally obtain dry yellow solid powdered product (1) Bbm 123mg of purifying by silica gel column chromatography.Productive rate: 88.4%.
IR(KBr)ν：1722.12cm -1(-CO-CH 3)，1651.08cm -1(-CONH-)
1HNMR.(CDCl 3，300MHz)δppm：1.07(t，J＝7.20Hz，3H，18-CH 3)，2.06(s，3H，-CO-CH 3)，2.10(m，2H，19-CH 2)，2.32～2.46(m，2H，22-CH 2)，3.33(m，2H，21-CH 2)，4.07(t，J＝7.02Hz，2H，23-CH 2)，5.20(m，2H，5-CH 2)5.52(dd，J AB＝11.49Hz，2H，17-CH 2)，7.01(s，1H，)，7.10(s，1H，)，7.54(t，J＝7.23Hz，1H，10-H)，7.61(s，1H，14-H)，7.76(d，1H，J＝7.13，9-H)，7.79(t，J＝7.42Hz，1H，11-H)，7.82(s，1H，)，8.12(d，J＝9.11Hz，1H，12-H)，8.23(s，1H，7-H)。
The ammonia of embodiment six, CPT is separated the preparation of 17-hydroxyl propionyl product (1) Bbn of open loop product (1) Ab
127mg (0.27mmol) (1) Ab is dissolved in 1.5mL (18.6mmol) pyridine, adds 1.0mL (7.7mmol) propionic anhydride.Be heated to about 50 ℃, stirring is spent the night.The pressure reducing and steaming partial solvent is used sherwood oil-ether sedimentation then, filters.Solid is through purification by silica gel column chromatography (eluent: ethyl acetate: sherwood oil=2: 1 → pure ethyl acetate), get yellow solid powder (1) Bbn 103mg.Productive rate: 72.4%.
IR(KBr)ν：1726.12cm -1(-CO-C 2H 5)，1652.23cm -1(-CONH-)
1HNMR.(CDCl 3，300MHz)δppm：1.01(t，J＝7.13Hz，3H，18-CH 3)，1.23(t，J＝7.11，3H，-CO-C-CH 3)，2.04(m，2H，19-CH 2)，2.30～2.47(m，4H，-CO-CH 2-and 22-CH 2)，3.31(m，2H，21-CH 2)，4.04(t，J＝6.99Hz，2H，23-CH 2)，5.16(m，2H，5-CH 2)5.52(dd，J AB＝11.61Hz，2H，17-CH 2)，6.98(s，1H，)，7.06(s，1H，)，7.51(t，J＝7.18Hz，1H，10-H)，7.59(s，1H，14-H)，7.60(s，1H，)，7.67(d，1H，J＝7.07，9-H)，7.73(t，J＝7.42Hz，1H，11-H)，8.01(d，J＝9.02Hz，1H，12-H)，8.18(s，1H，7-H)。

Claims (3)

  1. A structure as shown in the formula the application of camptothecin derivative in the preparation antitumor drug
    Figure C2005100983920002C1
    Wherein:
    R 1Represent 9,10 or the 11-position on 0-3 identical or different substituting group, these substituting groups are selected from halogen atom, hydroxyl or alkoxyl group;
    R 2Represent C 2-C 5The straight or branched alkylidene group;
    R 3Represent hydrogen atom or R 4CO-, R 4Represent low alkyl group, lower alkyl amino alkylidene group or lower alkoxy alkylidene group; Be selected from-CH 3,-(CH 2) nCH 3,-(CH 2) nOCH 3,-(CH 2) nNHCH 3,-(CH 2) nN (CH 3) 2, n=1-3 wherein;
    Y represents alkaline heterocyclic radical or hydrogenant alkalescence heterocyclic radical, is selected from imidazoles, pyridine, pyrimidine, pyrazine, piperidines, piperazine, morpholine.
  2. 2. the application of claim 1, described camptothecin derivative is
    21-N[3-(1-morpholinyl) propyl group] acid amides-17-hydroxyl E lactonic ring open loop camptothecine;
    21-N[3-(1-morpholinyl) propyl group] acid amides-17-acetoxyl group E lactonic ring open loop camptothecine;
    21-N[3-(1-morpholinyl) propyl group] acid amides-17-propionyloxy E lactonic ring open loop camptothecine;
    21-N[3-(1-imidazolyl) propyl group] acid amides-17-hydroxyl E lactonic ring open loop camptothecine;
    21-N[3-(1-imidazolyl) propyl group] acid amides-17-acetoxyl group E lactonic ring open loop camptothecine;
    21-N[3-(1-imidazolyl) propyl group] acid amides-17-propionyloxy E lactonic ring open loop camptothecine.
  3. 3. the application of claim 1, described tumour are solid tumor and non-solid tumor.
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