CN1319970C - Camptothecin derivative used as anti-tumor agent and preparation method thereof - Google Patents
Camptothecin derivative used as anti-tumor agent and preparation method thereof Download PDFInfo
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- CN1319970C CN1319970C CNB200510135329XA CN200510135329A CN1319970C CN 1319970 C CN1319970 C CN 1319970C CN B200510135329X A CNB200510135329X A CN B200510135329XA CN 200510135329 A CN200510135329 A CN 200510135329A CN 1319970 C CN1319970 C CN 1319970C
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Abstract
The present invention discloses a camptothecin derivative used as antitumor agent and a preparing thereof. A general formula (I) represents the camptothecin derivative.
Description
Invention field:
The present invention relates to a kind of as antineoplastic agent camptothecine novel derivative, its preparation method and as the purposes of antineoplastic agent.
Background of invention:
Camptothecine is to extract a kind of alkaloid that obtains from China arch paulownia section plant, has very strong anti-tumor activity.Its structure is as follows:
Formula (II)
But camptothecine itself is because toxic side effect is bigger, and its application is restricted, and existing various active height in its derivative, and the little new compound of toxicity has been approved for clinical treatment.For example irinotecan (Irrinotican) and topotecan (Topotican) etc.Also find some active and camptothecine in the derivative of the E lactonic ring open loop of camptothecine quite or better, and the toxicity new compound 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)
2The E of camptothecine ring is carried out ring-opening reaction, then with 17-position hydroxyl acylations, obtain the open loop of a series of E ring new compound (referring to J.P.A.H1,131,179; CN 1126212A).Gondola Indena S.P.A company makes the E ring open loop of camptothecine generate an alkali metal salt by the alkaline hydrolysis of camptothecine, again with 17-position hydroxyl acylations, also obtain a series of water soluble camptothecin derivatives (referring to (and US006,121,277A).But the anti-tumor activity of these camptothecine novel derivatives and hypotoxicity are still not ideal enough.
The purpose of this invention is to provide a kind of antineoplastic new camptothecin derivative and preparation method thereof, this derivative has high reactivity and hypotoxic characteristics.
Summary of the invention:
The invention provides a kind of new camptothecin derivative.
The present invention screens from a series of end of the chains contain the camptothecin derivative of E lactonic ring open loop of heterocyclic base or hydrogenation heterocyclic base.
Its chemical structure of camptothecin derivative of E lactonic ring open loop that the above end of the chain contains heterocyclic base or hydrogenation heterocyclic base is as follows:
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, alkoxyl group; As: F, Cl, Br, OH, OMe, OEt ,-OCH
2O-,-OCH
2CH
2O-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-etc.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 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
Easy and the HCl of these compounds, CF
3COOH, RSO
3Acid such as H forms the acceptable soluble salt of physiology.Its preparation is simple, good water solubility, but need further study their antitumor activity activity and toxicity.
The present invention finds that unexpectedly following formula (I) compound is that anti-tumor activity is the highest in this series compound, and of toxicity minimum.
Formula (I)
For this reason, claimed this compound of the present invention and pharmacy acceptable salt thereof, ester, solvate, the material of crystal habit.
Described pharmacy acceptable salt can be: the salt of mineral acid example hydrochloric acid, Hydrogen bromide, phosphoric acid, sulfuric acid etc., with organic acid such as acetate, trifluoroacetic acid, citric acid, toxilic acid, oxalic acid, succsinic acid, phenylformic acid, tartrate, fumaric acid, amygdalic acid, xitix or malate, and resemble amino acid saltss such as L-Ala, aspartic acid, Methionin or with the salt of sulfonic acid such as methylsulfonic acid, tosic acid etc.
The ester class of described formula of the present invention (I) compound not only comprises and replacing or unsubstituted fatty acid ester, especially 1-6 carbon atom, as lower alkyl esters such as methyl esters, and comprise by intravital chemical hydrolysis or enzymic hydrolysis, at least can partly be converted into the ester class of formula (I) compound, as acetyl oxygen methyl esters, pivalyl oxygen methyl esters, the ethoxycarbonyl 2-ethoxyethyl acetate, cholinesterase, amino ethyl ester (as: diformazan ammonia ethyl ester or 1-piperazinyl ethyl ester), 5-2,3-indanyl ester, phthalidyl ester and hydroxy alkyl ester (as: 2-hydroxyl ethyl ester or 2,3-two hydroxypropyl acrylates), 5-methyl-2-oxo-1,3-dioxane penta-4-alkene methyl ester.
The present invention also provides and contains The compounds of this invention or its respective substance is the pharmaceutical composition of active constituents of medicine, and said composition contains the medicine acceptable carrier in case of necessity.
Composition of the present invention, it preferably is the pharmaceutical dosage forms of unitary dose, can make any pharmaceutically useful formulation when making pharmaceutical preparation, these formulations are selected from: tablet, sugar coated tablet, film coated tablet, enteric coated tablet, capsule, hard capsule, soft capsule, oral liquid, suck agent, granule, electuary, pill, powder, paste, sublimed preparation, suspensoid, solution, injection, suppository, ointment, plaster, creme, sprays, drops, patch.
When being prepared into medicament, can add the medicine acceptable carrier, described medicine acceptable carrier can be: carrier is selected from: N.F,USP MANNITOL, sorbyl alcohol, Sorbic Acid or sylvite, Sodium Pyrosulfite, sodium bisulfite, Sulfothiorine, cysteine hydrochloride, Thiovanic acid, methionine(Met), vitamin A, vitamins C, vitamin-E, vitamins D, azone, the EDTA disodium, EDTA calcium sodium, the alkali-metal carbonate of monovalence, acetate, phosphoric acid salt or its aqueous solution, hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid, amino acid, sodium-chlor, Repone K, Sodium.alpha.-hydroxypropionate, Xylitol, maltose, glucose, fructose, dextran, glycine, starch, sucrose, lactose, mannitol, silicon derivative, Mierocrystalline cellulose and derivative thereof, alginate, gelatin, polyvinylpyrrolidone, glycerine, propylene glycol, ethanol, soil temperature 60-80, span-80, beeswax, lanolin, whiteruss, hexadecanol, gallate ester, agar, trolamine, basic aminoacids, urea, wallantoin, lime carbonate, Calcium hydrogen carbonate, tensio-active agent, polyoxyethylene glycol, cyclodextrin, beta-cyclodextrin, the phospholipid material, kaolin, talcum powder, calcium stearate, Magnesium Stearate etc.
Pharmaceutical preparation of the present invention is determined usage and dosage according to patient's situation in use.
Pharmaceutical composition of the present invention, when making medicament, the medicament of unitary dose can contain compound 0.1-1000mg of the present invention, and all the other are pharmaceutically acceptable carrier.Pharmaceutically acceptable carrier can be the 0.1-99.9% of total formulation weight amount by weight.
The present invention can adopt following method preparation:
Another aspect of the present invention relates to the preparation method of formula (I) compound, and the preparation feedback formula is as follows:
Formula (II) formula (III) formula (I)
Obtain formula (I) compound by formula (II) compound and the reaction of formula (III) compound, this preparation method may further comprise the steps:
(1), formula (II) compound is dissolved in earlier in a kind of strong polar solvent, the compound that adds formula (III) again reacts.
(2), be reflected under heating (70-80 ℃) condition and carry out, clarify until system.
(3), the reaction mixture that obtains in (2) is poured in a kind of solvent of low-pole, product is separated out with precipitation mode.
(4), with the solid that is settled out in (3), use the alumina column chromatography purifying, can obtain formula (I) compound of purity＞98%.
(5), the intensive polar solvent described in (1) comprises methyl alcohol, ethanol, but be not limited to this two kinds of solvents.
(6), the weak polar solvent described in (3) comprises ether, sherwood oil, but is not limited to this two kinds of solvents.
(7), the column chromatography eluent described in (4) can be ethyl acetate: sherwood oil=1: 4 → 1: 1, but be not limited to this eluent combined system.
The compounds of this invention is compared research experiment, and observed result is:
In the vitro inhibition tumor cell growth, suppress in the test of mouse, the growth of nude mice transplantation tumor, its anti-tumor activity is higher about 2-10 times than the antitumor drug that is used for clinical treatment such as 10-hydroxycamptothecine, mitomycin, cis-platinum isoreactivity usually.For example, in the growth inhibition test to tumor cell in vitro, formula (I) compound concentration is 1 * 10
-6During mol/L, the inhibiting rate of human lung carcinoma cell A-549 is reached 87.35%, and mitomycin concentration in contrast is high 10 times (1 * 10
-5Mol/L) time, inhibiting rate just reaches 89.46%.To the human promyelocytic leukemia cell, formula (I) compound concentration is 1 * 10
-7Inhibiting rate reaches 70.41% during mol/L, and cis-platinum in contrast, concentration is high 10 times (1 * 10
-6Mol/L) time, inhibiting rate ability 46.37%.
To mouse transplanting tumor such as S180 sarcoma, formula (I) compound is when dosage is 2.5mg/kg, and inhibiting rate promptly reaches 70.4%, and when dosage was 5mg/kg, inhibiting rate reached 83.4%, and 10-hydroxycamptothecine dosage is when being 8mg/kg, inhibiting rate just 30.7%.
In the therapeutic test to the transplanted tumor (as human lung adenocarcinoma A-549, people's adenocarcinoma of stomach BGC-823, people's adenocarcinoma of stomach SGC-7901) of nude mouse, it is excellent that the curative effect of formula (I) compound is all compared the 10-hydroxycamptothecine of photograph.For example, to people's lung adenoma A-549, formula (I) compound is when dosage is 2.5mg/kg, and T/C is 60.7%, has been that the T/C (71.4%) of the 10-hydroxycamptothecine of 8mg/kg is low than dosage just.
It should be noted that especially: in above-mentioned every experimentation on animals, use the highest therapeutic dose continuous use more than 17 days, do not find any experimental animal death.The body weight of experimental group animal is also low unlike negative control group.Show formula (I) compound under effective treatment concentration, no obvious toxic-side effects.
Embodiment:
The present invention is described further by the following examples, but not as limitation of the present invention.
Embodiment 1:
105mg (0.3mmol) camptothecine is dissolved in 15mL methyl alcohol earlier, add 1.2 normal ammonia then and separate reagent N-(3-propyl group amino) morpholine, reacted 14 hours down in 75 ℃, after system becomes clarification, reaction mixture is poured in the 80mL ether, separate out yellow mercury oxide, leach precipitation, with the cold diethyl ether washing crude product of 2 * 2mL.By TLC as can be seen, contain unreacted raw material of camptothecine in the crude product.Crude product is dissolved in a spot of CHCl
3In, with alumina column chromatography be further purified (eluent is: ethyl acetate: sherwood oil 1: 4-〉1: 1) the pure product 106g of formula (I) compound, productive rate 88%, HPLC show that its purity is 99.1%.
IR(KBr)ν：1620cm
-1(-CO-NH-)
1H?NMR：(CDCl
3，300MHz)δpm：1.07(t，J＝7.2Hz，3H，18-CH
3)；1.76(q，2H，19-CH
2)；2.25(m，1H，23-CH
2)，.2.43(m，1H，23-CH
2)；2.44(m，4H，2×25-CH
2)；3.41(m，2H，22-CH
2)；3.75(m，4H，2×26-CH
2)；4.88(q，J
AB＝12.70，2H，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＝7.2Hz，1H，9-H)；7.67(t，J＝5.2，1H，11-H)；7.87(s，1H，7-H)；7.97(d，J＝8.5Hz，1H，12-H)；8.20(s，1H，CO-NH)。
Claims (9)
1, formula (I) compound:
Formula (I)
Or its pharmacy acceptable salt.
2, the compound of claim 1, wherein said pharmacy acceptable salt is: hydrochloride, hydrobromate, phosphoric acid salt, vitriol, acetate, trifluoroacetate, Citrate trianion, maleate, oxalate, succinate, benzoate, tartrate, fumarate, mandelate, ascorbate salt, malate, L-Ala salt, aspartate, lysine salt, mesylate or tosilate.
3, the pharmaceutical composition that contains the compound of claim 1.
4, the composition of claim 3, described composition contains the medicine acceptable carrier.
5, the composition of claim 4, described composition are injection or oral pharmaceutical preparation.
6, the preparation method of the compound of claim 1 is characterized in that, through the step of formula (II) compound and the reaction of formula (III) compound.
Formula (II) formula (III)
7, the preparation method of claim 6 is characterized in that,
The process following steps:
(1), the compound of formula (II) is dissolved in earlier in a kind of strong polar solvent, the compound that adds formula (III) again reacts;
(2), be reflected under the 70-80 ℃ of heating condition and carry out, clarify until system;
(3), the reaction mixture that obtains in (2) is poured in a kind of solvent of low-pole, product is separated out with precipitation mode;
(4), with the solid that is settled out in (3), use the alumina column chromatography purifying, can obtain formula (I) compound of purity＞98%;
(5), the intensive polar solvent described in (1) comprises methyl alcohol, ethanol;
(6), the weak polar solvent described in (3) comprises ether, sherwood oil;
(7), the column chromatography eluent described in (4) can be ethyl acetate: sherwood oil=1: 4 → 1: 1.
8, the application of the compound of claim 1 in the preparation antitumor drug.
9, the application of claim 8, described tumour is a lung cancer, liver cancer, cancer of the stomach, esophagus cancer, mammary cancer, ovarian cancer or leukemia.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200510135329XA CN1319970C (en) | 2005-12-30 | 2005-12-30 | Camptothecin derivative used as anti-tumor agent and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200510135329XA CN1319970C (en) | 2005-12-30 | 2005-12-30 | Camptothecin derivative used as anti-tumor agent and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1803799A CN1803799A (en) | 2006-07-19 |
| CN1319970C true CN1319970C (en) | 2007-06-06 |
Family
ID=36865971
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB200510135329XA Expired - Fee Related CN1319970C (en) | 2005-12-30 | 2005-12-30 | Camptothecin derivative used as anti-tumor agent and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1319970C (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1192740A (en) * | 1995-06-21 | 1998-09-09 | 科学研究与运用咨询公司 | Novel camptothecin analogues, prepn. method therefor, use thereof, and pharmaceutical compositions contg. same |
-
2005
- 2005-12-30 CN CNB200510135329XA patent/CN1319970C/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1192740A (en) * | 1995-06-21 | 1998-09-09 | 科学研究与运用咨询公司 | Novel camptothecin analogues, prepn. method therefor, use thereof, and pharmaceutical compositions contg. same |
Non-Patent Citations (1)
| Title |
|---|
| China Pharmacist 402.405,DNA拓扑异构酶I抑制药 2003 * |
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| Publication number | Publication date |
|---|---|
| CN1803799A (en) | 2006-07-19 |
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Owner name: HEFEI USTC BIOTECHNOLOGY CO., LTD. Free format text: FORMER NAME: HEFEI ZHONGKEDA BIO-TECHNOLOGY CO., LTD. |
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Address after: 230088, Anhui province high tech Zone, 425 innovation Avenue, Anhui province science and technology achievement demonstration base D, Hefei Patentee after: Hefei Keda Biological Technology Co., Ltd. Address before: 230027 West College of life science, No. 96 Jinzhai Road, Anhui, Hefei Patentee before: Hefei Zhongkeda Bio-technology Co., Ltd. |
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Granted publication date: 20070606 Termination date: 20151230 |
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