WO2005044821A1

WO2005044821A1 - New camptothecin derivatives and processes of the preparation thereof and the use of the same

Info

Publication number: WO2005044821A1
Application number: PCT/CN2004/000490
Authority: WO
Inventors: Wei Lu; Heyong Gao; Xiongwen Zhang; Jian Ding
Original assignee: Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences
Priority date: 2003-11-10
Filing date: 2004-05-17
Publication date: 2005-05-19
Also published as: CN1616460A; CN100406460C

Abstract

The present invention disclosed new camptothecin derivatives, processes of the preparation thereof, and the use of the same. The present invention relates to the camptothecin derivatives represented by the following formula (F): Etherification of 10-hydroxy-camptothecin and corresponding substituted allyl bromide, obtained the etherized compounds, and then subjected them to a Claisen rearrangement to obtain allyl substituted compounds. Hydrogenation of the allyl camptothecin compounds gives the 9-substituted 10-hydroxy camptothecin derivatives. The antineoplastic effects of the present compounds have been observed in pharmacological screening.

Description

New derivative of camptothecin, preparation method and application thereof

The present invention relates to novel camptothecin derivatives with improved antitumor activity, intermediates for preparing these derivatives, and methods for preparing these derivatives. More specifically, the present invention relates to a 9-fluorenyl-10-hydroxy substituted camptothecin derivative, a method for preparing the same, and applications of these compounds in the field of antitumor. Background of the invention

Malignant tumors are the second leading cause of death in humans in the world. Cancer chemotherapy is an important method for the treatment of malignant tumors. Among them, topoisomerase inhibitors are widely used in clinical practice, and the topoisomerase I inhibitors used in clinical applications are camptothecin drugs.

Camptothecin (CPT) is a toxic alkaloid. It was isolated from Chinese plant Camptotheca acuminata by American scientist Wall in 1966. Camptothecin has significant activity on rat leukemia L1210 system. Camptothecin is an alkaloid with an indole structure in structure. The specific structure is shown below, compound 1:

This structure contains a pentacyclic structure, in which the E ring is a six-membered lactone ring, and the lactone ring contains an a hydroxyl group whose absolute configuration is S. After the isolation of camptothecin, it has a great interest because of its good anti-leukemia L1210 activity. However, camptothecin cannot be entered into clinical studies because of its poor water solubility. In the 1970s, China opened the lactone ring with NaOH to prepare a water-soluble sodium salt for clinical research, but the effect was not good and it was very toxic and terminated.

Since the discovery of camptothecin as a specific inhibitor of topoisomerase I in 1985, a large number of derivatives of camptothecin have been studied. Great results. For example, 10-hydroxycamptothecin (Compound 2) has lower toxicity and higher antitumor activity than camptothecin, and has been widely used in clinical practice in China.

Starting from hydroxycamptothecin, the use of Manich reaction to introduce amine methyl group at the 9-position has better water solubility. And antitumor activity, of which 10-hydroxy-9 ~~ dimethylaminomethylcamptothecin (Compound 3, Topotecan) was marketed in 1996 and used as a second-line treatment for ovarian cancer patients. Approved as a second-line treatment for small cell lung cancer (SCLC).

Compound 4 (SN-38) obtained by introducing an ethyl group at the 7-position of 10-hydroxycamptothecin has excellent antitumor activity. Its water-soluble prodrug Irinotecan (Compound 5) was marketed in 1994 for colorectal use. Cancer treatment.

In addition, there are some camptothecin compounds in clinical research, but the existing results show that these compounds are not as effective as Topotecan and Irinotecan. Therefore, there is a need to invent new camptothecin derivatives with better curative effects. Summary of the invention

The object of the present invention is to find a new type of hydroxycamptothecin, which has an antitumor drug with little toxic and side effects and strong activity.

Another object of the present invention is to provide a method for preparing a hydroxycamptothecin derivative.

A further object of the present invention is its application in antitumor drugs.

The present invention relates to new camptothecin derivatives. These compounds are compounds substituted at the hydroxyl group at the 10-position and alkyl groups at the 9-position of the camptothecin. They have better antitumor activity.

The specific structural formula of the present invention is-

Where R is H; ~ C ₆ linear or branched alkyl, alkenyl and alkynyl, hydroxy-substituted alkyl, alkoxy-substituted alkyl, amine-substituted alkyl, where amine is primary Amine, secondary amine or aromatic amine; X is H, alkyl of ¾, alkoxy substituted alkyl and Ph-, PhCH _2- _;

M is alkyl with ₆ dC, dC hydroxyl, amine, alkoxy-substituted alkyl with _6.

The first type of compound is a derivative of 10-hydroxy-9-fluorenylcamptothecin, which has the following structure (Structural Formula A), and a method for preparing these compounds.

Where R is H, ^ to ¾ straight or branched fluorenyl; alkenyl and alkynyl; where R is hydroxy-substituted alkyl (such as methylol, hydroxyethyl), alkoxy-substituted alkyl base. Or amine-substituted alkyl (such as aminomethyl, aminoethyl, etc.), wherein the amine group is a primary, secondary or aromatic amine. X is H, C to ₆ alkyl, and substituted alkyl groups containing embankment.

The second class of compounds are derivatives of camptothecin at the 10-position oxo and 9-position at the 9-position, and have the following structure (Structural Formula B), and their preparation methods.

Wherein R and X are the same as those represented by the general formula (A); M is a fluorenyl group to ¾, or a hydroxy-substituted fluorenyl group and an alkoxy-substituted fluorenyl group, or an amine-substituted alkyl group, in which amine The radical is a primary, secondary or aromatic amine. In addition, R and M may also form a cyclic compound, such as a five-membered furan ring and a six-membered pyran ring. Many of the compounds involved in the present invention contain hydroxyl groups, phenolic hydroxyl groups, and these compounds can be converted into corresponding ester compounds. The compounds shown in the present invention are fatty acid esters, aromatic acid esters, carbonates and the like.

The preparation method of the present invention can be obtained through the following reactions:

The 9-position of the 10-hydroxycamptothecin structure is more active. For example, a Mannich reaction can be introduced to introduce an amine methyl group, and the antitumor drug Topotecan is prepared by this method. But Mannich reaction can only introduce one carbon methyl group. In this patent we provide a method for introducing an alkyl group at the 9-position of 10-hydroxycamptothecin through the Claisen rearrangement reaction. The specific reaction formula is as follows −

10-Hydroxycamptothecin and the corresponding substituted allyl bromide are subjected to etherification to obtain the general formula (C), and then the Claisen rearrangement is carried out. The alkylation reaction occurs at the 9 position to obtain the allyl substituted structure. The compound of the general formula (D) undergoes a hydrogenation reaction to obtain a 10-hydroxycamptothecin compound substituted with a fluorenyl group at the 9-position. Where X represents the same as the above, specifically H, CH _3- , CH ₃ C¾- ₅ CH ₃ CH ₂ CH _2- , CH ₃ (CH ₂ ) ₂ CH _2- , CH ₃ (CH ₂ ) ₃ CH ₂ _{_{_{- 5 CH 3 (CH 2)}}} 4 CH 2 -, Ph-, PhCH 2 - 3 CH3OCH2-, CH3CH2OCH2-, CH3OCH2CH2-, CH 3 CH 2 OC¾CH 2 - and the like. The catalyst for the hydrogenation reaction may be other conventional hydrogenation catalysts such as Raney nickel, palladium carbon, platinum black, and the like. The hydrogen source may be hydrogen, hydrogen formate, cyclohexadiene and other hydrogen atom donors. The Claisen rearrangement reaction can be carried out according to conventional reaction conditions. The solvent can be a solvent with a higher boiling point, such as DMF, DMA, DMSO, dimethylpyrrolidone, N, N-diethylaniline, N, N-dimethylaniline. Wait.

For example, when X is H, 10-hydroxycamptothecin and allyl bromide are reacted in the presence of potassium carbonate to obtain allyl ether compound (6). Compound (6) is heated in DMF solution, and Claisen weight 10-Hydroxy-9-allyl camptothecin (7) is obtained, and then compound (7) is hydrogenated in the presence of palladium carbon to obtain compound (8).

The compound having the structure (D) can be neutralized with the compound of the general formula (E) to further react at the hydroxyl group at position 10. If an etherification reaction is performed, a compound having the general formula (F) and the general formula (G) can be obtained. As follows:

Where X is the same as the one represented above. M stands for-. ₆ fluorenyl group, QC ₆ hydroxy group, amine group, fluorenyloxy-substituted alkyl group, specifically CH _3- , CH ₃ C¾-, CH3CH2CH2-, CH ₃ CH ₂ CH ₂ CH _2- , (CH ₃ ) ₂ NCH _2- , (Et) ₂ NCH _2- , (CH ₃ ) ₂ NCH ₂ CH _2- , (Et) ₂ NCH ₂ CH ₂ -HOCH ₂ CH _2- , HOCH2CH2CH2-, HOCH ₂ CH ₂ CH ₂ CH ₂ -, CH ₃ OCH _2- , CH ₃ OCH ₂ CH _2- , EtOCH _2- , EtOCH ₂ C¾- and so on. Y represents Cl, Br, I, OTs, OMs, OTf and other groups which can be used as leaving groups. Among them, Base represents an inorganic base that can be used as an etherification reaction, such as K ₂ CO ₃ , Na ₂ CO ₃ , NaOH, KOH, etc .; an organic base such as pyridine, triethylamine, and the like.

For example, when M is CH ₃ and X is H atom, corresponding compounds (9) and (10) can be obtained, as follows:

Compound (9) can also be obtained by Kumada reaction. Using 10-methoxy-9-bromocamptothecin under normal reaction conditions, compound (9) can be obtained, such as (Bu) 3SnCH2CHCH2- under palladium catalysis. Reaction with 10-methoxy-9-bromocamptothecin gives compound (9), and hydrogenation of compound (9) also gives compound (10). as follows:

A series of reactions can be performed using compound (9) to obtain new camptothecin derivatives. For example, using the classic borohydride and hydrogen peroxide oxidation reactions, the allyl at position 9 can be converted into a hydroxypropyl compound (11). The compound (11) can be demethylated by a classic demethylation method to obtain the compound (12). The demethylation reagent can be Me ₃ SiI, HBr, A1C1 ₃ and the like.

A compound having the general formula (F) can break a double bond to obtain an aldehyde compound having the general formula (H), and then reduce the aldehyde group to a hydroxy compound having the general formula (I), and remove the M group To obtain a 10-hydroxycamptothecin derivative (J). Where X and M are the same as those represented by the general formula (F).

For example, when X is H and M is CH ₃ , the compound (9) can be double-cleaved to obtain an aldehyde compound (13). The double bond can be broken by classical methods in organic synthesis, such as: Os0 ₄ / aI0 ₄ System, KMn0 ₄ / NaI0 ₄ and other systems. Subsequently the aldehyde may be reduced to the alcohol (14), the method may be a borohydride reduction (e.g. NaBH _4, LiBH4, B¾), aluminum isopropoxide and the like of the reducing agent used. In the same manner as above, the methyl group on the methoxy group can be removed to obtain the compound (15).

In an acid-catalyzed method and a hydrogen reduction method, the hydroxyethyl group in the compound (14) can be converted into ethyl to obtain the ethyl compound (16). The acid used can be sulfuric acid, hydrochloric acid, p-toluenesulfonic acid, and methanesulfonic acid Acid, trifluoromethanesulfonic acid, etc. The catalyst for hydrogenation may be palladium black, palladium carbon, platinum black, etc., and palladium carbon is commonly used. According to the above-mentioned demethylation method, 10-hydroxy-9-ethylcamptothecin (17) can be obtained.

Starting from compound (11) and compound (14), a series of derivatizations can be performed to obtain a series of compounds. First, the primary hydroxyl group on the compound (11) and the compound (14) is etherified to obtain a compound having the general formula (K), and then the methyl group on the phenolic hydroxyl group is demethylated according to the method for preparing the compound (12) to obtain Compounds of general formula (M).

Where n is 1 or 2. R is an alkyl group, an aromatic group, or an alkyl group containing an amine group or a hydroxyl group, and specifically may be CH ₃ , CH ₃ CH ₂ , CH ₃ CH ₂ CH ₂ , CH ₃ C¾CH ₂ CH ₂ , Ph, Bn, and the like.

The compound (11) and the primary hydroxyl group on the compound (14) are converted into an active leaving group, and then reacted with the corresponding amine compound to obtain a compound having the general formula (0). Demethylation can be performed by the above-mentioned demethylation method to obtain a compound having a general formula (P).

Where n is 1 or 2. R is Cl, Br, I, OTs, OMs, OTf leaving group. R1 and R2 are H, -C ₆ alkyl group, C ₃ -C ₈ cyclofluorenyl group, oxygen-containing fluorenyl group, and aromatic group, specifically H, CH ₃ , CH ₃ CH ₂ , CH ₃ CH ₂ CH ₂ CH ₂ , C¾CH ₂ OCH ₂ CH ₂ , CH ₂ CH ₂ NCH ₂ CH ₂ , CH ₂ C¾N (CH ₃ ) CH ₂ C¾, Ph, Bn and so on.

The above compounds can also be converted into 9- and 10-position ring-closed compounds. For example, a compound containing a hydroxyalkyl group at the 9-position can form a furan ring or a pyran ring under the action of an acid with a phenolic hydroxyl group at the 10-position. ) And compounds of the general formula (S), where the acid referred to is an inorganic or organic acid, such as sulfuric acid, hydrochloric acid, acetic acid, and trifluoroacetic acid.

Where X is the same as that represented by the general formula (A). R is H, CH ₃ , CH ₂ OH. Many of the compounds involved in the present invention contain a hydroxyl group, a phenolic hydroxyl group.

The effect is transformed into the corresponding ester compound. The compounds shown in the present invention are fatty acid esters, aromatic acid esters, carbonates and the like.

The compound of the present invention has good antitumor activity, and can be applied clinically by oral administration, intravenous injection, intramuscular injection and the like.

The present invention tested the in vitro activity of some compounds, and the activity data showed that the growth inhibition rates of A-549 human lung adenocarcinoma cells and P388 mouse leukemia cells were very high, and showed good antitumor activity.

Table 1:% inhibition of growth of A—549 human lung adenocarcinoma cells No. 1 (H 10 10 " ⁶ If) ^-7 10" ⁸

95. 96.2 96. 94.2 91.

95. 95.0 97. 95.6 96.

95, 94.9 96. 93.1 90.

96. 94.4 93. 89.5 87.

91. 93.5 88. 83.9 81.

93, 94.0 90. 83.9 79.

94. 93.5 94. 91.5 85.

90 .: 93.2 92. 87. 63. Table 2: Inhibition rate of leukemia cell growth in P388 mice%

Sample concentration (M)

Evaluation

7 100 100 100 95.5 84.1 Strong

8 100 100 100 95.7 95.9 Strong

9 100 100 100 93.4 86.3 Strong

10 100 100 94.3 82.9 77.4 Strong

13 100 100 93.3 73.7 71.8 Strong

14 100 100 89.2 72.3 68.3 Strong

16 100 100 96.4 82.2 76,9 Strong

17 100 100 93.2 77.3 59.8 Strong The present invention focuses on the in vitro activity of compound (7) against various tumor cells. From the data in Table 3, it can be seen that most of IC _5Q of compound (7) on various tumor cells Level or more than a dozen nM levels, the overall activity is better than TPT (topotecan), 9NC (9-nitrocamptothecin), and HCPT (9-hydroxycamptothecin), even for most cells The activity of the strain was also better than that of SN-38.

HL-60 35.60 ± 4.11 7.94 ± 2.68 10.18 ± 0.92 5.86 ± 1.48 4.45

A549 28.09 ± 6.80 5.90 ± 1.61 31.95 ± 3.72 16.48 ± 2.16 4.68 ± 1.32

BEL-7402 420.33 ± 79.66 135.63 ± 34.72 58.80 ± 10.65 141.33 ± 10.97 313.00 soil 24.04

SGC-7901 488,67 ± 96.52 465.00 ± 75.35 9 ± 6.87 536 ± 60.85 318.00 ± 51.39

HO-8910 1379.71 ± 44.42 1119.11 ± 170.95 226,68 ± 40.76 2288.18 ± 376.45 238.50 ± 161.36

435 49.71 ± 6.05 3.42 ± 1.53 18.50 ± 6.14 11.08 ± 1.26 9.89 ± 0.25

468 176.45 ± 97.46 95.64 ± 36.91 64.87 ± 29.65 88.22 ± 18.77 17.28 soil 8.84

MCF-7 386.95 ± 45.61 72.95 ± 15.56 62 · 59 ± 19.76 51.80 ± 10.05 35.41 ± 25.15

HCT-15 14.40 soil 4.41 6.13 ± 4.07 9.59 ± 0.48 14.71 ± 3.79 10.40 ± 1.52

HCT-116 38.02 ± 2.19 12,87 ± 5.40 13.71 ± 1.40 6,54 ± 0,22 7,20 ± 37

WI-38 255.67 ± 29.52 86.83 ± 16.07 86.25 ± 15.67 371.75 ± 66.23 14.28 ± 1.65

HMEC 16.75 ± 5.86 1.65 ± 0.10 12.20 ± 1.82 2.75 ± 1.21 8.96 ± 1.98 The present invention also studied the in vivo activity of compound (7). Compound (7) in two in vivo models S- 180 solid tumor and liver activity data for display ¾ _2: considerable activity and HPCT, Slightly lower than TPT, but from the pre- and post-body weights of experimental mice, it can be seen that the toxicity of this compound is significantly less than

HCPT and TP.

Table 4: In vivo activity of compound (7) on S-180 malignant solid tumors

Dosage Number of animals Body weight Tumor weight

Group Inhibition rate (%)

(mg / kg) X ± SD

Way to start: after start last

NS i.p 16 16 21.9 31.9 1.82 ± 0.43

HCPT 4 i.p 8 8 22.0 17.1 0.51 ± 0.43 72.0 <0.01

7 1 i.p 8 8 22.0 28.3 1.23 ± 0 · 39 32.4 <0.01

7 2 i.p 8 8 22.1 26.0 0.87 + 0.65 52.2 <0.01

7 4 ip 8 8 22.0 22.3 0.18 ± 0.11 90.1 <0.01 Table 5: In vivo activity of compound (7) on H ₂₂ liver cancer

Dosage Number of animals Body weight Tumor weight

Group Inhibition rate (%)

(mg kg) X ± SD

Way start last start last

NS i.p 16 16 19.9 31.8 2.18 ± 0.49

ΤΡΤ 4 i.p 8 8 20.1 16.1 0.18 ± 0.11 91.7 <0.01

HCPT 4 i.p 8 8 19.9 16.3 0.40 + 0.24 81.7 <0.01

7 1 i.p 8 8 20.0 27.3 1 · 14 ± 0 · 57 47.7 <0.01

7 2 i-P 8 8 20.0 26.8 0.64 + 0.20 70.6 <0.01

7 4 i.p 8 8 20.1 22.3 0.41 ± 0.19 81.2 <0.01

detailed description

The derivatives and preparation methods of the present invention are described in more detail in the following examples, but the examples do not limit the present invention.

Example 1

9-allyl-10-hydroxycamptothecin

1) Preparation of 10-allyloxycamptothecin

Dissolve 5 g (13.7 mass) of 10-hydroxycamptothecin and 3.31 g (27.4 mmol) allyl bromide in 80 mL of DMF, add 5.7 g (41.1 mmol) of potassium carbonate, heat and reflux for 2 h, cool, and recover Part of the solvent, the residual liquid was added to ice water, a large amount of yellow solid was precipitated, extracted with chloroform (50 mL * 3), washed with water, It was dried over anhydrous sodium sulfate, filtered, and chloroform was distilled off. The residue was subjected to silica gel column chromatography (chloroform / acetone = 3/1) to obtain 4.48 g of yellow 10-allyloxycamptothecin with a yield of 81%. 1HNMR (CDC1 ₃ ) ^ (ppm): 1.04 (3H, t), 1.95 (2H, m), 3.78 (IH, s), 4.71 (2H, m), 5.27 (2H, s), 5.31 (IH, d ), 5.38 (IH, dd), 5.52 (IH, dd), 5.74 (IH, d), 6.13 (IH, m), 7.16 (IH, d), 7.49 (IH, dd), 7.64 (IH, s) , 8.14 (lH, d), 8.25 (IH, s).

2) Preparation of 9-allyl-10-hydroxycamptothecin

4.5 g (11.2 mmol) of 10-allyloxycamptothecin was dissolved in 80 mL of DMF, heated under reflux for 48 h, filtered, and DMF was distilled off. The residue was subjected to silica gel column chromatography (chloroform / acetone = 2/1) to obtain Yellow 9-allyl-10-hydroxycamptothecin 2.93, yield 65%. Edge (DMSO- ^) (ppm): 0.96 (3H, t), 1.87 (2H, m), 3.22 (2H, d), 4.22 (2H, s), 4.75 (2H, s), 4.93 (IH, m ), 4.96 (IH, s), 6.30 (IH, m), 7.13 (IH, s), 7.25 (IH, d), 7.96 (IH, d), 8.59 (1H, s). Example 2

9-allyl-10-methoxycamptothecin

Dissolve 1.5 g (3.7 mmol) of 9-allyl-10-hydroxycamptothecin obtained in Example 1 in 30 mL of DMF, add 10 g (7.4 mmol) of methyl iodide, 1.5 g (11.1 mmol) of potassium carbonate, and heat Reflux for 2 h, filter, evaporate DMF, and use silica gel column chromatography (chloroform / acetone = 3/1) to obtain 1.4 g of yellow 9-allyl-10-methoxycamptothecin with a yield of 90 ° / . . ¹ HNMR (DMSO-i¾) (ppm): 0.96 (3H, t), 1.86 (2H, m), 3.18 (2H, d), 3.73 (3H, s), 4.20 (2H, s), 4.65 (2H, s), 4.91 (IH, s), 4.97 (IH, s), 6.05 (IH, m), 7.01 (IH, s), 7.16 (IH, d), 7.68 (IH, d), 8.12 (IH, s ), 10.5 (1H, s). Example 3

9-propyl-10-hydroxycamptothecin

Dissolve 75 nig (0.185 mmol) of 9-allyl-10-hydroxycamptothecin in 2 mL of 1,4-dioxane, add 10 mg of Pd / C, and pass in hydrogen at normal pressure for 0.5 h at room temperature. After the reaction was completed, filtration was performed to recover 1,4-dioxane. A yellow solid precipitated from the residual solution and was filtered with suction to obtain 53 mg of 9-propyl-10-hydroxycamptothecin with a yield of 70.3%. 1HNMR (DMSO- ^) (ppm): 0.99 (3H, t), 1.08 (3H, t), 1.66 (2H, m), 1.98 (2H, m), 2.55 (2H, t), 3.95 (IH, s ), 4.22 (2H, s), 4.75 (2H, s), 7.01 (IH, s), 7.12 (IH, d), 7.61 (IH, d), 7.85 (IH, s), 10.12 (IH, s) . n Example 4

9-propyl-10-methoxycamptothecin

The operation method is the same as that in Example 3. From 75 mg (0.179 mmol) of 9-allyl-10-methoxycamptothecin to obtain 9-propyl-10-methoxycamptothecin 57 mg, yield 75.6%. . ¹ HNMR (DMSO- ^) (ppm): 0.96 (3H, t), 1.02 (3H, t), 1.58 (2H, m), 1.87 (2H, m), 2.45 (2H, t), 3.73 (3H, s), 4.18 (2H, s), 4.86 (2H, s), 7.00 (IH, s), 7.12 (IH, d), 7.59 (IH, d), 7.78 (IH, s). Example 5

9-hydroxyethyl-10-methoxycamptothecin

1) Preparation of 9-acetaldehyde -10-methoxycamptothecin

Dissolve 1.2 g (2.87 mmol) of 9-allyl-10-methoxycamptothecin in 15 mL of 1,4-dioxane, add 11 mg of osmium tetroxide, stir for a while, and add 0.614 g in portions. (2.9 mmol) sodium periodate. After the addition, continue to stir for 2 h, add 50 mL of chloroform, stir, add 40 mL of water, separate the organic layer, extract the aqueous layer twice, combine chloroform, wash with water, and anhydrous sodium sulfate. It was dried, filtered, and the recovery was simulated. The residue was subjected to silica gel column chromatography (chloroform / acetone = 2/1) to obtain a yellow solid, 0.99 g of 9-acetaldehyde-10-methoxycamptothecin, with a yield of 82%. iHNMR (DMSO-i¾ (ppm): 1.03 (3H, t), 1.96 (2H, m), 3.66 (2H, d), 3.76 (3H, s) 4.32 (2H, s), 4.85 (2H, s), 7.11 (IH, s), 7.16 (IH, d), 7.67 (IH, d), 7.99 (IH, s): 9.72 (lH, t).

2) Preparation of 9-hydroxyethyl-10-methoxycamptothecin

Dissolve 0.99 g (2.36 mmol) of 9-acetaldehyde-10-methoxycamptothecin in 20 mL of 1,4-dioxane, add 0.13 g (2.36 mmol) of potassium borohydride, and stir at room temperature for 4 h, adjust the reaction solution to acidic with dilute hydrochloric acid, extract with chloroform (100 mL * 3), wash with water, dry with anhydrous sodium sulfate, evaporate chloroform, and precipitate a yellow solid to obtain 9-hydroxyethyl-10-methoxyloxy Tree alkaloid 0.95 g, yield 95%. 1HNMR (DMSO-) (ppm): 0.96 (3H, t), 1.87 (2H, m), 2.34 (IH, s), 2.74 (2H, t), 3.65 (3H, s), 3.86 (2H, t) , 4.32 (2H, s), 4.83 (2H, s), 7.03 (IH, s), 7.14 (IH, d), 7.68 (IH, d), 7.85 (IH, s), 9.99 (lH, s). Example 6

9-hydroxyethyl-10-hydroxycamptothecin

Dissolve 80 mg (0.189 mmol) of 9-hydroxyethyl-10-methoxycamptothecin in 15 mL of 20% hydrobromic acid, heat to reflux for 5.5 h, and complete the hydrolysis. Use a 10% aqueous solution of sodium hydroxide. Adjust the pH of the reaction solution to 5-6, extract with chloroform, wash with water, dry with anhydrous sodium sulfate, filter, evaporate chloroform, and silica gel column chromatography of the residual liquid (chloroform / acetone = 2/1) to obtain yellow 9-hydroxyethyl- 10-hydroxycamptothecin 45 mg, yield 58%. ^ MR (DMSO- ^) (ppm): 0.97 (3H, t), 1.91 (2H, m), 2.74 (2H, t), 3.88 (2H, t), 4.26 (2H, s), 4.53 (1H, s), 4.75 (2H, s), 7.03 (1H, s), 7.21 (1H, d), 7.71 (1H, d), 7.89 (1H, s), 10.11 (1H, s). Example 7

9-ethyl-10-methoxycamptothecin

200 mg (0.474 mmol) of 9-hydroxyethyl-10-methoxycamptothecin was dissolved in glacial acetic acid, 40 mg of 10% Pd / C was added, the temperature was raised to about 45 ° C, hydrogen was passed in, and the reaction was 2.5. h. After the reaction, glacial acetic acid was distilled off. Ice water was added to the residue, extracted with chloroform, washed with water, dried over anhydrous sodium sulfate, filtered, and chloroform was distilled off. 131 mg of yellow 9-ethyl-10-methoxycamptothecin was obtained in a yield of 68%. iHNMR (OMSO-d ₆ ) (ppm): 0.96 (3H, t), 1.24 (3H, t), 1.87 (2H, m), 2.59 (2H, t), 3.73 (3H, s), 4.26 (2H, s), 4.75 (2H, s), 7.04 (1H, s), 7.16 (1H, d), 7.71 (1H, d), 7.83 (1H, s). Example 8

9-ethyl-10- light camptothecin

The hydrolysis method was the same as in Example 6. 52 mg was obtained from 84 mg (0.207 mmol) of 9-ethyl-10-methoxycamptothecin in a yield of 64%. ifiNMR (DMSO- ^) (ppm): 0.98 (3H, t), 1.25 (3H, t), 1.91 (2H, m), 2.53 (2H, q), 4.23 (2H, s), 4.78 (2H, s ), 7.11 (1H, s), 7.17 (1H, d), 7.76 (1H, d), 7.85 (lH, s), 10.07 (lH, s). Example 9

9- (N, N-dimethylamino) ethyl-10-methoxycamptothecin

Add 500 mg (1.19 mmol) of 9-acetaldehyde-10-methoxycamptothecin, 45 mL of DMF, and 2 mL of formic acid to a round bottom flask, heat to reflux for 3.5 h, and evaporate excess DMF and formic acid. The residual solution was added with ice TK and carefully adjusted to pH 6 with 10% sodium hydroxide. A yellow solid was precipitated, extracted with chloroform, washed with water, dried over anhydrous sodium sulfate, filtered, chloroform was distilled off, and silica gel column chromatography (chloroform / acetone = 4/1) to obtain 203 mg of 9- (N, N-dimethylamino) ethyl-10-methoxycamptothecin with a yield of 38%. 1HNMR (DMSO-) (ppm): 0.96 (3H, t), 1.97 (2H, m), 2.27 (6H, s), 2.65 (2H, t), 2.69 (2H, t), 3.73 (3H, s) ,

4.26 (2H, s), 4.79 (2H, s), 7.06 (1H, s), 7.18 (1H, d), 7.71 (1H, d), 7.98 (1H, s). Example 10

9- (N, N-dimethylamino) ethyl-10- light camptothecin

The method is the same as that in Example 6. 150 mg (0.334 mmol) of 9- (N, N-dimethylamino) ethyl-10-methoxycamptothecin was put in and subjected to silica gel column chromatography to obtain 9- (N, (N-dimethylamino) ethyl-10-hydroxycamptothecin 52 mg, yield 36%. ^ NMR ^ DMSO-i ^ Cppm): 0.99 (3H, t), 1.89 (2H, m),

2.27 (6H, s), 2.64 (2H, t), 2.71 (2H, t), 4.25 (2H, s), 4.82 (2H, s), 7.08 (1H, s), 7.16 (1H, d), 7.77 (1H, d), 7.98 (1H, s), 10.12 (1H, s). Example 11

9- (2-(morpholine-4-) ethyl))-10-methoxycamptothecin

Add 500 mg (1.19 mmol) of 9-acetaldehyde-10-methoxycamptothecin, 45 mL of morpholine-4-formaldehyde, and 2 mL of formic acid to a round bottom flask, heat to about 150 ° C, and maintain the temperature to react 3 h, evaporate excess morpholine-4-formaldehyde and formic acid, add ice water to the residue, carefully adjust the pH to 6 with 10% sodium hydroxide, precipitate a yellow solid, extract with chloroform, wash with water, and dry with anhydrous sodium sulfate, Filtration, evaporation of chloroform, silica gel column chromatography (chloroform / acetone = 4/1), 9- (2 '-(morpholine-4-) ethyl))-10-methoxycamptothecin 180 mg, Yield: 31%. iHNMR (DMSO- ^) (ppm): 0.99 (3H, t), 1.87 (2H, m), 2.37 (4H, m), 2.65 (2H, t), 2.71 (2H, t), 3.67 (4H, m ), 3.76 (3H, s), 4.26 (2H, s), 4.78 (2H, s), 7.06 (1H, s) _: 7.15 (1H, d), 7.90 (1H, d), 8.01 (1H, s) ,. Example 12

9- (2-(morpholine-4-) ethyl))-10-hydroxycamptothecin

The method is the same as that in Example 6. Put 150 mg (0.305) 9- (2 '-(morpholine-4-) ethyl))-10-methoxycamptothecin, and use silica gel column chromatography to obtain 9- ( 2- (morpholine-4-) 'ethyl))-10-hydroxycamptothecin 46 mg, yield 32%. iHNMR (DMSO- £ ¾) (ppm): 0.96 (3H, t), 1.89 (2H, m), 2.35 (4H, m), 2.61 (2H, t), 2.69 (2H, t), 3.68 (4H, m), 4.27 (2H, s), 4.81 (2H, s), 7.05 (1H, s), 7.14 (1H, d), 7.68 (1H, d), 7.89 (1H, s), 10.02 (1H, s) ). Example 13

9-hydroxypropyl-10-hydroxycamptothecin

Dissolve 350 mg (0.866 mmol) of 9-allyl-10-hydroxycamptothecin in 25 mL of 1,4-dioxane, and dropwise add 1 mL (1.04 mmol) of 1M borane 1,4-dioxy Hexacyclic solution, stirred at room temperature for 3 h, cooled in an ice bath, and added dropwise 124.8 mg of 30% hydrogen peroxide solution, stirred at room temperature for 5 h, adjusted the reaction solution to acidic with 1 M hydrochloric acid, extracted with chloroform, washed with water, and anhydrous sodium sulfate Dry, filter, and evaporate the chloroform. The residue was subjected to silica gel column chromatography (chloroform / acetone = 2/1). iHNMR (DMSO-i¾ (ppm): 0.96 (3H, t), 1.81 (2H, m), 1.89 (2H _: m), 2.55 (2H, t), 3.53 (2H, t), 3.76 (3H, s) , 4.25 (2H, s), 4.77 (2H, s), 7.04 (1H, s), 7.16 (1H, d), 7.77 (1H, d), 7.89 (1H, s). Example 14

9-hydroxypropyl-10-methoxycamptothecin

The method is the same as that in Example 2. 75 mg (0.178 mmol) of 9-hydroxypropyl-10-hydroxycamptothecin was added and methylated at the 10-position. After column chromatography, 42 mg was obtained with a yield of 54%. 1HNMR (DMSO-i¾ (ppm): 0.96 (3H, t), 1.80 (2H, m), 1,90 (2H, m), 2.54 (2H, t), 3.53 (2H, ΐ), 4.26 (2H, s), 4.75 (2H, s), 7.08 (1H, s), 7.18 (1H, d), 7.78 (1H, d), 7.98 (1H, s), 10.03 (1H).

Claims

Rights request

1. 9-Alkylcamptothecin derivatives having the following structure _:

Where R is H; ~ straight or branched-chain alkyl, alkenyl and alkynyl, hydroxy-substituted alkyl, alkoxy-substituted alkyl, amine-substituted alkyl, where amine is a primary amine, Secondary amine or aromatic amine; X is H, to fluorenyl, alkoxy-substituted alkyl and Ph-, PhCH _2- _;

M is. !! -^ Alkyl, C _r C ₆ hydroxy, amine, alkoxy substituted alkyl.

2. The 9-alkylcamptothecin derivative according to claim 1, wherein X is H, CH _3- , C¾CH _2- , C¾C¾CH _2- , CH ₃ (CH ₂ ) ₂ CH _2- , CH ₃ (CH ₂ ) ₃ CH _2- , CH ₃ (CH ₂ ) ₄ C¾-, Ph-, PhC¾-, CH ₃ OCH _2- , CH3CH2OCH2-, CH ₃ OCH ₂ CH _2- , CH ₃ CH ₂ OCH ₂ C¾-;

M is C¾-, CH ₃ CH _2- , CH ₃ CH ₂ CH _2- , CH ₃ CH ₂ CH ₂ CH _2- , (CH ₃ ) ₂ NCH _2- , (Et) ₂ NCH _2- , (CH ₃ ) ₂ NCH ₂ CH2-, (Et) ₂ NCH ₂ CH ₂ -HOCH ₂ CH _2- , HOC¾CH ₂ CH _2- , HOCH ₂ CH ₂ CH ₂ CH _2- , CH ₃ OCH _2- , CH ₃ OCH ₂ CH _2- ₅ EtOCH _2- , EtOCH ₂ CH _2- .

3. The 9-alkylcamptothecin derivative according to claim 1,

It is characterized in that when R is C¾CH _2- ,

X is H, fluorenyl to ^, fluorenyl substituted with fluorenyl and PhCH _2- _;

^ [^ Is alkyl with _6, ₆ dC hydroxy, amino, alkoxy-substituted alkyl group.

4. The 9-alkylcamptothecin derivative according to claim 1,

It is characterized in that when R is CH ₂ C¾OH or -CH ₂ OH,

X is H, an alkyl group to ^, an alkyl group substituted with fluorenyloxy group, and PhCH _2- _;

M is C ₁ -C ₆ alkyl, -C ₆ hydroxy, amine, alkoxy substituted alkyl.

5. The 9-alkylcamptothecin derivative according to claim 1,

It is characterized in that when X is H,

R is H _; ~ C ₆ linear or branched alkyl, alkenyl and alkynyl, hydroxy-substituted alkyl, alkoxy-substituted alkyl, amine-substituted alkyl, where amine is a primary amine , Secondary or aromatic amines;

^^ is an alkyl group, a hydroxy group of QC ₆ , an amine group, a fluorenyl group substituted with fluorenyl group;

, Is 11, C _r C ₆ alkyl group, C ₃ -C ₈ cycloalkyl group, oxygen-containing alkyl group, aromatic group, specifically H, CH ₃ , CH ₃ C¾, CH ₃ CH ₂ CH ₂ CH _2. CH ₂ CH ₂ OCH ₂ CH ₂ , CH ₂ C¾NC¾CH ₂ , CH ₂ C¾N (CH ₃ ) CH ₂ CH ₂ , Ph, Bn.

6. The 9-cynocamptothecin derivative according to claim 1,

It is characterized in that when 9-bit and 10-bit are closed-loop,

X is H, an alkyl group to ¾, containing an alkoxy-substituted fluorenyl group and PhCH _2- _;

R is H, CH ₃ , -CH ₂ OH.

7.The method for preparing a 9-alkenyl camptothecin derivative according to claim 1, comprising the following steps:

a. 10-Hydroxycamptothecin and the corresponding substituted allyl halide etherified to compound C;

b. Compound C is rearranged to D by Claisen;

c. The hydroxyl group of compound D is fluorinated to obtain compound F;

d. Compound F is reduced to compound E, and E is dephosphorylated to obtain compound 0.

8. The method for preparing a 9-alkylcamptothecin derivative according to claim 7, characterized in that:

b. Compound C is rearranged to D by Claisen;

c alkylation of the hydroxyl group of compound D to obtain compound F;

d. Compound F is reduced to compound G, and G is dephosphorylated to yield compound E or compound D to yield compounds.

9. The method for preparing a 9-alkylcamptothecin derivative according to claim 7, characterized in that:

a. Compound (9) is subjected to a borohydride oxidation reaction to obtain a hydroxypropyl compound (11);

b. Compound (11) demethylated compound (12);

c The aldehyde-based compound H in which the double bond in compound F is oxidatively cleaved;

d. reduced hydroxyethyl compound I of compound H;

e. Compound I is dealkylated compound J.

10. The method for preparing a 9-fluorenylcamptothecin derivative according to claim 7, wherein: when M is CH ₃ , and n is 1 or 2:

. a compound (11) or compound J (wherein M is ₃ CH) converting the hydroxyl group in a leaving group; and

b. Compound N (R is CI, Br, I, Ots, Oms, Otf) is reacted with amine compound to obtain compound 0; c Compound 0 is demethylated to obtain compound P.

The method for preparing a 9-alkylcamptothecin derivative according to claim 7, characterized in that a Claissen rearrangement reaction is used for the synthesis of the camptothecin derivative.

The use of a 9-alkylcamptothecin derivative according to claim 1 as a medicament for the prevention and treatment of tumor diseases.