CN1781922A - Camptothecine derivative, preparing method and use - Google Patents
Camptothecine derivative, preparing method and use Download PDFInfo
- Publication number
- CN1781922A CN1781922A CN 200410089053 CN200410089053A CN1781922A CN 1781922 A CN1781922 A CN 1781922A CN 200410089053 CN200410089053 CN 200410089053 CN 200410089053 A CN200410089053 A CN 200410089053A CN 1781922 A CN1781922 A CN 1781922A
- Authority
- CN
- China
- Prior art keywords
- compound
- camptothecine
- alkyl
- dihydrofuran
- coo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Abstract
The present invention discloses a kind of new camptothecine derivatives and their preparation process and use. The camptothecine derivatives include 9, 10-dihydro furan ring camptothecine derivative obtained with 10-hydroxy-9-allyl/substituted allyl camptothecine through oxidation to break double bond, acid catalyzed addition other reaction; corresponding furan ring camptothecine derivative obtained through dewatering; and dihydro furan ring camptothecine derivative with NBS treated 9-allyl radical or 10-hydroxy clip ring. Pharmacological screening shows that all the compounds have excellent antitumor activity.
Description
Technical field
The present invention relates to improve the preparation method of novel camptothecin derivatives He these derivatives of anti-tumor activity.In particular, the present invention relates to 9,10 and form furans, dihydrofuran and furan nucleuss thereof and replace various substituent camptothecin derivatives, and their preparation method and these compounds are in antitumor Application for Field.
Background of invention
Malignant tumour is the human in the world second largest cause of the death, and chemotherapy of tumors is an important means for the treatment of malignant tumor.Wherein topology isomerase inhibitors series antineoplastic medicament is widely used clinically, and the inhibitor medicaments of the topology isomerase I that uses clinically all is camptothecines.
Camptothecine (CPT) is a kind of deleterious alkaloid, and U.S. scientist Wall obtained by separating in the distinctive plant camptotheca acuminata of China in 1966, and camptothecine has significant activity to big murine leukemia L1210 system.Camptothecine structurally is a kind of alkaloid that contains indole structure, and concrete structure is as follows, compound 1:
Contain a five rings structure in this structure, E ring is the lactonic ring of a six-ring in its structure, a hydroxyl that to contain an absolute configuration on lactonic ring be S.After isolating camptothecine,, cause the interest that people are very big because it has good leukemia L1210 activity.But camptothecine can not enter clinical study owing to poorly water-soluble.In the seventies, China opens lactonic ring with NaOH, be prepared into water miscible sodium salt and carry out clinical study, but effect is bad, and have very big toxicity and stop.
After discovery camptothecine in 1985 is the single-minded inhibitor of topoisomerase I, camptothecine has been carried out the research of a large amount of derivatives, its purpose is to improve its water-soluble and raising activity and reduction toxicity, and has obtained very big achievement.For example 10-hydroxycamptothecine (compound 2) has lower toxicity and higher anti-tumor activity than camptothecine, has been widely used in clinical in China.
From hydroxycamptothecine, application Manich is reflected at 9 last amine methyl of introducing and has better water solubility and anti-tumor activity, 10-hydroxyl-9-dimethylamino methyl camptothecine (compound 3 wherein, Topotecan) in listing in 1996, as ovarian cancer patient's second line treatment medicine, U.S. FDA was ratified its two wires smelting as small cell lung cancer (SCLC) again and is treated medicine in 1999.
The compound 4 (SN-38) that the introducing ethyl obtains on 7 of 10-hydroxycamptothecine has fabulous anti-tumor activity, and its water-soluble prodrug Irinotecan (compound 5) is used for the treatment of colorectal cancer in listing in 1994.
In addition, also have some camptothecine compounds just in clinical study, but existing result shows that these compound curative effects are all not as Topotecan and Irinotecan.Wherein Exatecan (compound 5-1) and compound 5-2 have the camptothecin structure of six rings, have shown the good anticancer activity, all are in the clinical study stage.This patent provides a kind of six ring camptothecine compounds of synthetic another class novelty, and has shown good antitumour activity, has further research, DEVELOPMENT PROSPECT.
Summary of the invention
The objective of the invention is to seek the novel camptothecine of a class, make it become little, the active strong antitumor drug of toxic side effect.
Another object of the present invention provides a kind of method for preparing this camptothecin derivative.
A further object of the present invention is that it is used in antitumor drug.
The present invention is about the camptothecine novel derivative, and these compounds are that 9,10 formation of camptothecine furans, dihydrofuran and furan nucleus thereof have various substituting groups, and 7 is the compound of various alkyl.They have better anti-tumor activity.
Concrete structure formula general formula of the present invention is:
Wherein:
R
1Be H, hydroxyl, methylol, alkoxyl group, alkanoyloxy, alkoxyl-methyl, alkyloyloxyethyl methyl; R
2Be H, C
1~C
6Alkyl; X is C
1~C
6Alkyl, halogen.
R more specifically
1Be H, HO-, HOCH
2-, CH
3O-, CH
3CH
2O-, CH
3CH
2CH
2O-, CH
3(CH
2)
2CH
2O-, CH
3(CH
2)
3CH
2O-, CH
3(CH
2)
4CH
2O-, CH
3(CH
2)
5CH
2O-, PhCH
2-, (CH
3)
2CHO-, HCOO-, CH
3COO-, CH
3CH
2COO-, CH
3(CH
2)
2COO-, CH
3(CH
2)
3COO-, CH
3(CH
2)
4COO-, PhCOO-, CH
3OCH
2-, CH
3CH
2OCH
2-, CH
3CH
2CH
2OCH
2-, CH
3(CH
2)
2CH
2OCH
2-, CH
3(CH
2)
3CH
2OCH
2-, HCOOCH
2-, CH
3COOCH
2-, CH
3CH
2COOCH
2-, CH
3CH
2CH
2COOCH
2-, CH
3(CH
2)
3COOCH
2-.
Corresponding R
2Be H, CH
3-, CH
3CH
2-, CH
3CH
2CH
2-, CH
3(CH
2)
2CH
2-, CH
3(CH
2)
3CH
2-.
Corresponding X is CH
3-, CH
3CH
2-, CH
3CH
2CH
2-, CH
3(CH
2)
2CH
2-.
R wherein
1Be H, HO, HOCH
2-, R
3O, R
4OCH
2, R
5COO, R
6COOCH
2, NH
2, R
7(R
8) N, R
9CONH; R wherein
3, R
4, R
5, R
6, R
7, R
8, R
9Be various alkyl; R
2Be H, C
1~C
6Alkyl; X is H, C
1~C
6Alkyl, halogen.
When R is H, CH
3CH
2The time,
R
1Be H, perhaps C
1~C
6Alkyl, perhaps contain C
1~C
6Acyl group
When R is H, CH
3CH
2The time,
R
1Be H, perhaps C
1~C
6Alkyl, perhaps contain C
1~C
6Acyl group
When R is H, CH3CH2,
X is H or C
1~C
6Alkyl;
Preparation method of the present invention can make by following reaction
Method one,
Wherein R is various alkyl, as methyl, ethyl, propyl group etc.; R
1Be R
2O, R
3CO, wherein R
2Be various alkyl, as methyl, ethyl, propyl group, butyl etc., R3 is methyl, ethyl, propyl group, butyl etc.; X is C
1~C
4Alkyl.
Obtain aldehyde by compound (A) through the two keys of oxidation scission, form stable hemiacetal (C) with 10 hydroxyls of intramolecularly.The method of the two keys of general oxidation scission has: NaIO
4/ OsO
4System, NaIO
4/ KMnO
4System, wherein the former reaction conditions gentleness is easy to operate, OsO
4Be again catalytic amount, so this patent has been selected this method; Aldehyde and 10 hydroxyls of forming form the intramolecularly hemiacetal automatically.Compound (C) hemiacetal hydroxyl obtains compound (D) through etherificate and esterification, and its method is with suitable base catalysis, through corresponding halides (CH
3(CH
2) nX, n=0~6, X is Cl, I, Br.As CH
3I, CH
3CH
2Br, CH
2CH
2CH
2Br, CH
3CH
2CH
2CH
2Br, CH
3CH
2CH
2Cl, CH
3CH
2CH
2CH
2Cl etc.) be reacted into ether (I) and be processed into ether, corresponding acyl chlorides is (as CH
3COCl, CH
3CH
2COCl, CH
3CH
2CH
2COCl, CH
3CH
2CH
2CH
2COCl etc.) be processed into ester.Used alkali can be mineral alkali, as K
2CO
3, KOH, Na
2CO
3Deng; Can be organic bases also, as pyridine, triethylamine etc.Used solvent has DMF, DMSO, 1,4-dioxane, tetrahydrofuran (THF) etc.Compound (A) is under acid catalysis, and 10 hydroxyls obtain compound (B) to 9 allylic pair of key additions, and temperature of reaction is controlled at 25~100 ℃, and used acid is various mineral acids, as HCl, HBr, HI, H
2SO
4Deng.Compound (C) obtains compound (E) through the acid treatment dehydration, and used acid is concentrated hydrochloric acid, concentrated hydrobromic acid etc., and temperature of reaction is controlled at 25~100 ℃.
For example, when R is H, when X was H, 1, in the mixing solutions of 4-dioxane and water, compound (6) was through NaIO
4/ OsO
4Oxidation, the two keys of fracture become aldehyde, form hemiacetal (7) with 10 hydroxyls again; Compound (6) reflux in hydrochloric acid obtains compound (8); Compound (7) reflux in dense Hydrogen bromide obtains compound (9).
When R is an ethyl, when X was H, compound (10) was a raw material, with corresponding compound (11), (12), (13) of obtaining of above-mentioned same method.
Among the present invention, compound (F), (G), (H) are according to following synthetic method preparation
Method two,
Wherein R is H, various alkyl, as methyl, ethyl, propyl group etc.; X is a halogen, as Cl, Br, I; R
1For hydrogen or various alkyl, as methyl, ethyl, propyl group, butyl etc.; R
2Be C
1~C
6Alkyl is as methyl, ethyl, propyl group, butyl etc.; Y is C
1~C
4Alkyl.
Compound (A
1) under acid catalysis, obtaining compound (F) through NBS or NCS processing, used acid is HCl, HBr, H
2SO
4, HClO
4Deng mineral acid, corresponding solvent is DMF, 1,4-dioxane, DMSO etc.; Compound (F) obtains corresponding ester (G) with various carboxylate salt nucleo philic substitution reactions in DMF or DMSO, temperature of reaction is controlled at 25~100 ℃; Compound (G) obtains compound (H) through basic hydrolysis, and used alkali has NaOH, KOH, K
2CO
3Deng, temperature of reaction is controlled at 25~100 ℃; Compound (H) under the base catalysis, obtains corresponding ether (I) with various haloalkane reactions in DMF or DMFSO, temperature of reaction is controlled at 25~100 ℃, and alkali is K
2CO
3, Na
2CO
3, KOH, NaOH etc.
Method three,
Wherein R is H, various alkyl, as methyl, ethyl, propyl group etc.; X is a halogen, as Cl, Br, I; R
1For hydrogen or various alkyl, as methyl, ethyl, propyl group, butyl etc.; R
2Be C
1~C
6Alkyl is as methyl, ethyl, propyl group, butyl etc.; Y is C
1~C
4Alkyl.
We are again with an other paths synthetic compound (H), (G), (I).At room temperature, compound is through the oxygenant epoxidation, through acid treatment, forms the dihydrofuran ring, i.e. compound (H), and used oxygenant has superoxide such as Peracetic Acid, hydrogen peroxide, metachloroperbenzoic acid; Temperature of reaction is controlled at 25~100 ℃; Reaction solvent has: methylene dichloride, chloroform, benzene etc.Compound (H) and various acyl chlorides are (as CH
3COCl, CH
3CH
2COCl, CH
3CH
2CH
2COCl, CH
3CH
2CH
2CH
2COCl etc.) be reacted into ester and obtain compound (G), reaction solvent has: methylene dichloride, chloroform, ether, tetrahydrofuran (THF), DMF, DMSO or the like, temperature of reaction is controlled at 0~100 ℃.Compound (H) and various haloalkane (CH
3(CH
2) nX, n=0~6, X is Cl, I, Br.As CH
3I, CH
3CH
2Br, CH
2CH
2CH
2Br, CH
3CH
2CH
2CH
2Br, CH
3CH
2CH
2Cl, CH
3CH
2CH
2CH
2Cl etc.) be reacted into ether (I), reaction solvent has: methylene dichloride, chloroform, ether, tetrahydrofuran (THF), DMF, DMSO or the like, temperature of reaction is controlled at 0~100 ℃.This synthetic thinking has shortened step, is easy to handle and derivatize.
For example, when R was H, compound (6) was dissolved in 1, in the mixing solutions of 4-dioxane and water, at HClO
4Under the catalysis, room temperature reaction obtains compound (14); Also can directly make solvent, handle to obtain compound (14) through NBS with acetate.Compound (14) is in DMF, and with anhydrous acetic acid potassium, nucleophilic substitution reaction obtains ester (15) temperature of reaction and is controlled at 40~100 ℃.With the NaOH aqueous solution handle compound (15) get final product compound (16).
When R is ethyl, be raw material with compound (10), promptly can obtain compound (17), (18), (19) through above-mentioned identical synthetic method.
Compound related among the present invention much contains hydroxyl, and phenolic hydroxyl group can be converted into these compounds corresponding ester cpds.Compound shown in the present is a fatty acid ester, aromatic esters, carbonic ether etc.
Compound involved in the present invention has good antineoplastic activity, can carry out clinically oral, intravenous injection, modes such as intramuscular injection are used.
The external activity of the part of compounds that we test, activity data shows: the growth to human body tumour cells such as HL-60 human leukaemia cell, BEL-7402 human liver cancer cell, HCT-116 human large intestine cancer cells all has very high inhibiting rate, has shown good antitumor activity.
Table 1: to HL-60, BEL-7402, HCT-116 growth of cancer cells restraining effect (IC
50)
The cell strain title | IC 50(nM) | |||||||||
7 | 8 | 9 | 11 | 12 | 13 | 15 | 16 | 18 | 19 | |
HL-60 BEL-7402 HCT-116 | 8.4 ---- 3.2 | 3.1 7.4 4.9 | 3.0 1.6 1.6 | 4.2 4.4 1.4 | 4.9 7.5 2.6 | 0.28 ---- 1.7 | 11 ---- 4.3 | 8.7 19 2.6 | 9.1 11 0.52 | 7.1 7.8 3.8 |
Derivative of the present invention and preparation method be narration in more detail in following embodiment, but embodiment is not construed as limiting the invention.
Example 1
5-hydroxyl dihydrofuran is [4,5-i] camptothecine (7) also
300mg (0.742mmol) 10-hydroxyl-bright basic camptothecine of 9-alkene is dissolved in 100mL 1, in 4 dioxane, add 30mL water and 2mg perosmic anhydride, behind the question response liquid overstrike, divide 5 times and add 349mg (1.632mmol) sodium periodate, finish, react 1.5h again, the direct silica gel mixed sample of reaction solution, column chromatography (chloroform/methanol=50/1), obtain also [4,5-i] camptothecine (7) 261mg of yellow 5-hydroxyl dihydrofuran, yield 86.6%.
1HNMR(DMSO-d
6)(ppm):0.88(3H,t),1.81~1.92(2H,m),3.23(1H,dd),3.66(1H,dd),5.25(2H,s),5.42(2H,s),6.28(1H,m),6.54(1H,s),7.27(1H,d),7.52(1H,d),7.58(1H,d),8.01(1H,d),8.42(1H,s)。
Example 2
5-methyl dihydrofuran is [4,5-i] camptothecine (8) also
150mg (0.371mmol) 9-allyl group-10-hydroxyl base camptothecine is dissolved in the 30mL concentrated hydrochloric acid, reflux 2h, aqueous sodium hydroxide solution conditioned reaction liquid pH=5~6 with 20%, chloroform extraction 3 times, saturated sodium-chloride water solution is washed, dried over mgso is considered and is removed sal epsom, reclaims chloroform, residue silica gel column chromatography (chloroform/methanol=150: 1), obtain also [4,5-i] camptothecine (8) 112mg of yellow 5-methyl dihydrofuran, yield 74.7%.
1HNMR(CDCl
3)(ppm):0.89(3H,t),1.51(3H,d),152-1.93(2H,m),3.11~3.24(1H,m),3.67~3.73(1H,m),5.20~5.25(1H,m),5.25(2H,s),5.41(2H,d),6.40(1H,s),7.28(1H,s),7.45(1H,d),7.99(1H,d),8.37(1H,s)。
Example 3
Furo [4,5-i] camptothecine (9)
Compound (7) 150mg (0.369mmol) that example 1 is obtained is dissolved in the 25mL concentrated hydrobromic acid, reflux 6.5h, under the ice bath cooling, 20% aqueous sodium hydroxide solution conditioned reaction liquid is to slightly acidic, chloroform methanol mixing solutions extracted several times, saturated sodium-chloride water solution is washed, and dried over mgso is considered and removed siccative, residue silica gel column chromatography (chloroform/methanol=150: 1), obtain light yellow furo [4,5-i] camptothecine (9) 93mg, yield 64.9%.
1HNMR(CDCl
3)(ppm):1.05(3H,t),1.85~1.96(2H,m),3.81(1H,s),5.321H,d),5.33(2H,s),5.75(1H,d),7.32(1H,q),7.66(1H,s),7.89(1H,d),7.98(1H,q),8.10(1H,d),8.66(1H,d)。
Example 4
5-hydroxyl dihydrofuran is [4,5-i] 7-ethyl-camptothecin (11) also
Working method is the same with example 1, obtains also [4,5-i] 7-ethyl-camptothecin (11) 228mg of 5-hydroxyl dihydrofuran, yield 75.7% by 300mg (0.694mmol) 9-allyl group-10-hydroxyl-7-ethyl-camptothecin.
1HNMR(DMSO-d
6)(ppm):0.88(3H,t),1.28(3H,t),1.81~1.92(2H,m),3.06~3.29(2H,m),3.45(1H,d),3.99(1H,dd),5.30(2H,s),5.43(2H,d),6.18~6.21(1H,m),6.50(1H,s),7.25(1H,s),7.49(2H,m),8.03(1H,d)。
Example 5
5-methyl dihydrofuran is [4,5-i] 7-ethyl-camptothecin (12) also
Working method is the same with example 2, obtains also [4,5-i] 7-ethyl-camptothecin (11) 122mg of 5-methyl dihydrofuran, yield 81.3% by 150mg (0.347mmol) 9-allyl group-10-hydroxyl-7-ethyl-camptothecin.
1HNMR(CDCl
3)(ppm):1.04(3H,t),1.34(3H,t),1.55~1.60(3H,m),1.83~1.95(2H,m),3.09~3.18(2H,m),3.35~3.42(1H,m),3.79(1H,d),3.88~3.95(1H,m),5.12~5.19(1H,m),5.23(2H,s),5.28(1H,d),5.74(1H,d),7.37(1H,dd),8.06(1H,dd)。
Example 6
Furo [4,5-i] 7-ethyl-camptothecin (13)
Operating process is the same with example 3, by 140mg (0.322mmol) 5-hydroxyl dihydrofuran also [4,5-i] 7-ethyl-camptothecin reaction obtain furo [4,5-i] 7-ethyl-camptothecin (13) 87mg, yield 64.8%.
1HNMR(CDCl
3)(ppm):1.05(3H,t),1.47(3H,t),1.86~1.95(2,m),3.38(2H,q),3.81(1H,s),5.32(1H,d),5.30(2H,s),5.76(1H,d),7.26(1H,d),7.37(1H,s),7.64(1H,s),7.91(1H,d),7.98(1H,d),8.13(1H,d)。
Example 7
5-brooethyl dihydrofuran is [4,5-i] camptothecine (14) also
Bright base-the 10-hydroxycamptothecine of 600mg (1.484mmol) 9-alkene is dissolved in the 30mL acetic acid, adds 265mg (1.484mmol) N-bromo-succinimide, stirring at room 1.5h, add the 40mL dilution, chloroform, methanol mixed solution extraction repeatedly, saturated nacl aqueous solution is washed, anhydrous magnesium sulfate drying, consider and remove siccative, reclaim solvent, residue column chromatography (chloroform/methanol=100: 1) obtains deep yellow 5-brooethyl dihydrofuran also [4,5-i] camptothecine (14) 366mg, yield 51%.
1HNMR(CDCl
3)(ppm):1.04(3H,t),1.84~1.95(2H,m),3.44~3.52(1H,m),3.63~3.80(3H,m),5.27(2H,s),5.29~5.35(1H,m),5.28(1H,d),5.74(1H,d),7.42(1H,d),7.61(1H,s),8.07(1H,s),8.11(1H,s)。
Example 8
5-acetyl-o-methyl dihydrofuran is [4,5-i] camptothecine (15) also
360mg (0.745mmol) the 5-brooethyl dihydrofuran that example 7 is obtained also [4,5-i] camptothecine is dissolved among the anhydrous 30mLDMF, add 183mg (2.235mmol) anhydrous sodium acetate, stirring heating, temperature is controlled at 110 ℃, reaction 1.5h, cooling, add entry 30mL, chloroform, methanol mixed solution extracts 3 times, and saturated sodium-chloride water solution is washed, anhydrous magnesium sulfate drying, consider and remove sal epsom, boil off solvent, residue column chromatography (chloroform/methanol=55: 1) obtains yellow 5-acetyl-o-methyl dihydrofuran also [4,5-i] camptothecine (15) 211mg, yield 61.3%.
1HNMR(CDCl
3)(ppm):1.03(3H,t),1.84~1.95(2H,m),2.10(3H,s),3.27~3.33(1H,m),3.49(1H,s),3.62~3.69(1H,m),3.81(1H,d),4.32~4.49(1H,m),5.27(2H,s),5.28~5.33(1H,m),5.29(1H,d),5.74(1H,d),7.43(1H,dd),7.61(1H,d),8.06~8.10(2H,m)。
Example 9
5-methylol dihydrofuran is [4,5-i] camptothecine (16) also
120mg (0.259mmol) the 5-acetyl-o-methyl dihydrofuran that example 8 is obtained also [4,5-i] camptothecine alkali is dissolved in the 30mL methyl alcohol, the aqueous sodium hydroxide solution 5mL of adding 20%, at stirring at room reaction 4h, with dilute hydrochloric acid conditioned reaction liquid to slightly acidic, the chloroform methanol mixing solutions extracts repeatedly, saturated sodium-chloride water solution is washed, anhydrous magnesium sulfate drying is considered and is removed siccative, boils off solvent, residue column chromatography (chloroform/methanol=45: 1), obtain also [4,5-i] camptothecine (16) 99mg of 5-methylol dihydrofuran, yield 90.7%.
1HNMR(CD
5N)(ppm):1.14(3H,t),2.08~2.15(2H,m),3.56~3.60(2H,m),4.08~4.23(2H,m),5.33~5.39(3H,m),5.58(1H,d),5.92(1H,dd),7.50(1H,d),8.00(1H,s),8.07(1H,s),8.28(1H,s)。
Example 10
5-brooethyl dihydrofuran is [4,5-i] 7-ethyl-camptothecin (17) also
Operating process is the same with example 7, obtains also [4,5-i] 7-ethyl-camptothecin (17) 358mg of 5-brooethyl dihydrofuran, yield 43.2% by 700mg (1.619mmol) 7-ethyl-bright base of 9-alkene-10-hydroxycamptothecine reaction.
1HNMR(CDCl
3)(ppm):1.04(3H,t),1.37(3H,t),1.83~1.95(2H,m),3.16(2H,q),3.65~3.99(4H,m),5.21~5.27(1H,m),5.22(2H,s),5.29(1H,d),5.74(1H,d),7.39(1H,d),7.57(1H,s),8.08(1H,d)。
Example 11
5-acetyl-o-methyl dihydrofuran is [4,5-i] 7-ethyl-camptothecin (18) also
Operating process is the same with example 8, by example 10 obtain 350mg (0.684mmol) 5-brooethyl dihydrofuran also [4,5-i] 7-ethyl-camptothecin reaction obtain also [4,5-i] 7-ethyl-camptothecin (18) 174mg of 5-acetyl-o-methyl dihydrofuran, yield 52%.
1HNMR(CDCl
3)(ppm):1.04(3H,t),1.37(3H,t),1.83~1.95(2H,m),2.11(3H,d),3.12~3.18(2H,m),3.49~3.95(2H,m),4.32~4.48(2H.m),5.20~5.32(4H,m),5.74(1H,d),7.41(1H,dd),7.58(1H,d),8.08(1H,dd)。
Example 12
5-methylol dihydrofuran is [4,5-i] 7-ethyl-camptothecin (19) also
Operating process is the same with example 9, and 100mg (0.204mmol) the 5-acetyl-o-methyl dihydrofuran that is obtained by example 11 also [4,5-i] 7-ethyl-camptothecin reaction obtains also [4,5-i] 7-ethyl-camptothecin (19) 75mg of 5-methylol dihydrofuran, yield 82%.
1HNMR(DMSO-d
6)(ppm):1.16(3H,t),1.22(3H,t),2.01~2.17(2H,m),2.94~3.03(2H,m),3.81~4.26(4H,m),5.25~5.36(3H,m),5.62(1H,dd),5.96(H,dd),7.51(1H,dd),8.01(1H,d),8.16(1H,dd)。
Claims (6)
2, camptothecin derivative according to claim 1 is characterized in that R
1Be H, HO-, HOCH
2-, CH
3O-, CH
3CH
2O-, CH
3CH
2CH
2O-, CH
3(CH
2)
2CH
2O-, CH
3(CH
2)
3CH
2O-, CH
3(CH
2)
4CH
2O-, CH
3(CH
2)
5CH
2O-, PhCH
2-, (CH
3)
2CHO-, HCOO-, CH
3COO-, CH
3CH
2COO-, CH
3(CH
2)
2COO-, CH
3(CH
2)
3COO-, CH
3(CH
2)
4COO-, PhCOO-, CH
3OCH
2-, CH
3CH
2OCH
2-, CH
3CH
2CH
2OCH
2-, CH
3(CH
2)
2CH
2OCH
2-, CH
3(CH
2)
3CH
2OCH
2-, HCOOCH
2-, CH
3COOCH
2-, CH
3CH
2COOCH
2-, CH
3CH
2CH
2COOCH
2-, CH
3(CH
2)
3COOCH
2-;
R
2Be H, CH
3-, CH
3CH
2-, CH
3CH
2CH
2-, CH
3(CH
2)
2CH
2-, CH
3(CH
2)
3CH
2-;
X is CH
3-, CH
3CH
2-, CH
3CH
2CH
2-, CH
3(CH
2)
2CH
2-.
3, according to described 9,10 the camptothecin derivatives that form the dihydrofuran ring of claim 1,
It is characterized in that, when R is H, CH
3CH
2The time,
R
1Be H, perhaps C
1~C
6Alkyl, perhaps contain C
1~C
6Acyl group.
5,9,10 preparation methods that form furan nucleus, dihydrofuran ring camptothecin derivative as claimed in claim 1 are made up of following steps:
Method one,
A.10-hydroxyl-9-allyl-camptothecine compd A adopts NaIO
4/ OSO
4System gets Compound C through the two keys of oxidation scission under the room temperature reaction condition;
B. Compound C in DMF, THF or DMSO solvent, gets D with various halides etherificates through base catalysis;
C. compd A is under hydrochloric acid, Hydrogen bromide or sulfuric acid acid catalysis, and hydroxyl obtains compd B to allylic pair of key addition;
D. Compound C is under concentrated hydrochloric acid or concentrated hydrobromic acid acid catalysis, dewater compd E;
Method two,
A.10-hydroxyl-9-allyl-camptothecine through NBS or NCS handle compound F 17-hydroxy-corticosterone;
B. compound F 17-hydroxy-corticosterone obtains compound G through the nucleophilic substitution of various carboxylate salts;
C. compound G gets compound H through hydrolysis;
D. compound H gets Compound I through alkylation;
Method three,
A. compd A peroxidation agent forms epoxide, under acid catalysis, opens and also forms dihydrofuran lopps camptothecine H more again;
B. compound H becomes ester G with various acyl chloride reactions;
C. compound H and various haloalkane are reacted into ether I.
6,9,10 purposes that form furan nucleus, dihydrofuran ring camptothecin derivative as claimed in claim 1 are as using in the anti-tumor medicine.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CNB2004100890531A CN100432076C (en) | 2004-12-03 | 2004-12-03 | Camptothecine derivative, preparing method and use |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CNB2004100890531A CN100432076C (en) | 2004-12-03 | 2004-12-03 | Camptothecine derivative, preparing method and use |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1781922A true CN1781922A (en) | 2006-06-07 |
CN100432076C CN100432076C (en) | 2008-11-12 |
Family
ID=36772591
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB2004100890531A Expired - Fee Related CN100432076C (en) | 2004-12-03 | 2004-12-03 | Camptothecine derivative, preparing method and use |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN100432076C (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101475574B (en) * | 2008-01-03 | 2012-07-04 | 江苏先声药物研究有限公司 | Camptothecin derivative, and preparation and use thereof |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5670500A (en) * | 1995-05-31 | 1997-09-23 | Smithkline Beecham Corporation | Water soluble camptothecin analogs |
-
2004
- 2004-12-03 CN CNB2004100890531A patent/CN100432076C/en not_active Expired - Fee Related
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101475574B (en) * | 2008-01-03 | 2012-07-04 | 江苏先声药物研究有限公司 | Camptothecin derivative, and preparation and use thereof |
Also Published As
Publication number | Publication date |
---|---|
CN100432076C (en) | 2008-11-12 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1043893C (en) | Pharmaceuticals | |
CN1298398A (en) | 12,13-modified epothilone derivatives | |
CN1029956C (en) | Process for resoluting folinic acid | |
CN1046283C (en) | Process for the preparation of 9-amino camptothecin | |
CN100335470C (en) | 10 -deacetylbaccatine III and 10 -deacetyl 14 'beta' -hydroxybaccatine III derivatives, process for preparation thereof and pharmaceutical compositions containing them | |
CN1070405A (en) | The diastereomer and the method for making thereof of 3-cephem-4-carbonic acid-1-(isopropoxy carbonyl oxygen) ethyl ester | |
EP1995249B1 (en) | Camptothecin derivatives and their use | |
CN102746314A (en) | Stable 7-membered lactonic ring-containing camptothecin compound and its preparation method and use | |
CN110143974B (en) | Novel artemisinin derivative, synthesis method and application thereof | |
CN87106996A (en) | Quinoline compound, their preparation method and with its carcinostatic agent as the active drug component | |
JPH04139177A (en) | Furalbenzoquinone derivative, its production and carcinostatic agent | |
CN1781922A (en) | Camptothecine derivative, preparing method and use | |
CN1520418A (en) | Process for prepn. of cefpodoxime acid | |
CN1616460A (en) | Novel derivative of camptothecine, preparing method and use | |
CN109153639B (en) | Trigonelline compounds | |
EP2588482B1 (en) | Preparation of tesetaxel and related compounds and corresponding synthesis intermediate | |
CN1409714A (en) | Pentacycle taxane compounds | |
CN1224626C (en) | B-D-5-thioxylose derivatives, preparation method and therapeutic use | |
CN100408582C (en) | Homocamptoth-ecine compounds, their preparation process and use | |
CN1235882C (en) | Aliphatic amino substituted indole quinoline derivatives, their preparation method and pharmaceutical application | |
CN1314675C (en) | Taxol derivatives | |
CN1440973A (en) | Optical pure analog of camptothecine | |
CN101591342B (en) | Method for synthesizing key intermediate for preparing camptothecine compounds | |
CN103288842B (en) | Fluorine replaces E ring camptothecin analogues and the purposes as medicine thereof | |
CN1673225A (en) | Carbonate medicine precursors of hydroxycamptothecine and its derivative and their prepn and application |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C17 | Cessation of patent right | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20081112 Termination date: 20111203 |