Homocamptoth-ecine compounds, their preparation process and use

Abstract

The present invention relates to medicine technology, and is homocamptothecine compound with antitumor activity and its use and preparation process. The preparation process has low cost and high yield. The compound of the present invention has topoisomerase inhibiting effect, antitumor activity and antiviral activity, and may be used as topoisomerase inhibitor and in preparing antitumor and antiviral medicines.

Description

technical field

[0001] The invention relates to the technical field of medicine, and relates to a new homocamptothecin compound with antitumor activity and its preparation method and application. Background technique

[0002] Camptothecin (camtptothecin, CPT) is a natural alkaloid extracted from camptotheca japonica, which has a five-ring structure. The natural camptothecin structure is shown below:

[0003]

[0004] Camptothecin exhibits antiproliferative activity against a variety of human tumor cell lines, and its antitumor activity is achieved by inhibiting DNA topoisomerase I.

[0005] The six-membered α-hydroxylactone ring E ring of camptothecin is easily hydrolyzed into an inactive carboxylate form in vivo, which greatly reduces its activity in vivo. After transforming its six-membered α-hydroxylactone ring structure into a seven-membered β-hydroxylactone ring analogue, a new camptothecin analogue, called homocamptothecin (hCPT) com...

Examples

Embodiment 1

[0055] Embodiment 1 prepares compound N

[0056] Synthesis of A, 1,1-ethylenedioxy-6-formyloxymethyl-7-propionyl-5-oxygen-1,2,3,5-tetrahydroindolizine (compound L)

[0057] Referring to the literature method (Wani et al. J.Med.Chem.23:554 (1980); Wall et al. J.Med.Chem.29:1553 (1986)) to obtain the starting material 1,1-ethylenedioxy-5- O-(5'-ethyl-5'-hydroxy-2'H, 5'H, 6'H-6-oxypyran)[3',4'-f]Δ 6(8) Tetrahydroindolizine (compound K). Dissolve 8g of compound K in 170ml of methanol, add 0.96g of potassium borohydride, heat and stir in an oil bath at 50°C for 20 minutes, then add 120ml of acetic acid and 30ml of aqueous solution containing 7.2g of sodium periodate, continue to stir for 20 minutes and pour into 600ml of water, extracted with 100ml of dichloromethane x 5, dried, and evaporated to dryness in vacuo to obtain 7.5g of compound L. Recrystallized from tetrahydrofuran, mp: 126-7°C.

[0058] 1 HNMR (CDCl 3 ): 1.19(t, 3H), 2.41(t, 2H), 2.8(q, 2H), 4.1(m, 6H), 5.2(s, 2...

Embodiment 2

[0071] Preparation of 7-chloromethyl-10-chlorohomocamptothecin (general formula II compound, wherein R 1 , R 2 , R 3 , R 4 The sequence is the synthesis of chloromethyl, H, Cl, H)A, 2'-amino-2,4'-dichloroacetophenone

[0072] 25ml two-neck bottle, add 3ml of 1M BCl 3 For n-hexane solution, put 0.32g of p-chloroaniline in 3ml of benzene solution dropwise under cooling in an ice bath, remove the ice bath after the addition, add 0.19ml of chloroacetonitrile and 0.37g of anhydrous aluminum trichloride, and reflux with nitrogen for 6 hours , remove the oil bath, add 3ml of 2N hydrochloric acid under cooling in an ice bath, reheat until the solid dissolves, extract with 8ml of dichloromethane x 3, wash the organic layer with 20ml of water, dry over anhydrous magnesium sulfate and evaporate to dryness to obtain 2'- Amino-2,4'-dichloroacetophenone 0.2 g.

[0073] Synthesis of B, 7-chloromethyl-10-chlorohomocamptothecin

[0074] Take 45mg of 2'-amino-2,4'-dichloroacetophenone, 60...

Embodiment 3

[0077] Preparation of 7-chloromethyl-10-fluorohomocamptothecin (general formula II compound, wherein R 1 , R 2 , R 3 , R 4 followed by chloromethyl, H, F, H)A, 2'-amino-2-chloro-4'-fluoroacetophenone

[0078] According to the method of Example 2A, p-fluoroaniline was used instead of p-chloroaniline to obtain 2'-amino-2-chloro-4'-fluoroacetophenone.

[0079] B. 7-Chloromethyl-10-fluorohomocamptothecin

[0080] According to the method of Example 2B, 2'-amino-2-chloro-4'-fluoroacetophenone was used instead of 2'-amino-2,4'-dichloroacetophenone to obtain 7-chloromethyl-10- Fluorocamptothecin is a yellow solid.

[0081] 1 HNMR(DMSO): 0.919(t, 3H), 1.9(q, 2H), 3.11-3.50(Abq, 2H), 5.42-5.59(m, 6H), 6.0(s, 1H), 7.45(s, 1H) 7.86(m, 1H), 8.21(m, 1H), 8.32(m, 1H)

technical field

[0001] The invention relates to the technical field of medicine, and relates to a new homocamptothecin compound with antitumor activity and its preparation method and application. Background technique

[0002] Camptothecin (camtptothecin, CPT) is a natural alkaloid extracted from camptotheca japonica, which has a five-ring structure. The natural camptothecin structure is shown below:

[0003]

[0004] Camptothecin exhibits antiproliferative activity against a variety of human tumor cell lines, and its antitumor activity is achieved by inhibiting DNA topoisomerase I.

[0005] The six-membered α-hydroxylactone ring E ring of camptothecin is easily hydrolyzed into an inactive carboxylate form in vivo, which greatly reduces its activity in vivo. After transforming its six-membered α-hydroxylactone ring structure into a seven-membered β-hydroxylactone ring analogue, a new camptothecin analogue, called homocamptothecin (hCPT) com...

Examples

Embodiment 1

[0055] Embodiment 1 prepares compound N

[0056] Synthesis of A, 1,1-ethylenedioxy-6-formyloxymethyl-7-propionyl-5-oxygen-1,2,3,5-tetrahydroindolizine (compound L)

[0057] Referring to the literature method (Wani et al. J.Med.Chem.23:554 (1980); Wall et al. J.Med.Chem.29:1553 (1986)) to obtain the starting material 1,1-ethylenedioxy-5- O-(5'-ethyl-5'-hydroxy-2'H, 5'H, 6'H-6-oxypyran)[3',4'-f]Δ 6(8) Tetrahydroindolizine (compound K). Dissolve 8g of compound K in 170ml of methanol, add 0.96g of potassium borohydride, heat and stir in an oil bath at 50°C for 20 minutes, then add 120ml of acetic acid and 30ml of aqueous solution containing 7.2g of sodium periodate, continue to stir for 20 minutes and pour into 600ml of water, extracted with 100ml of dichloromethane x 5, dried, and evaporated to dryness in vacuo to obtain 7.5g of compound L. Recrystallized from tetrahydrofuran, mp: 126-7°C.

[0058] 1 HNMR (CDCl 3 ): 1.19(t, 3H), 2.41(t, 2H), 2.8(q, 2H), 4.1(m, 6H), 5.2(s, 2...

Embodiment 2

[0071] Preparation of 7-chloromethyl-10-chlorohomocamptothecin (general formula II compound, wherein R 1 , R 2 , R 3 , R 4 The sequence is the synthesis of chloromethyl, H, Cl, H)A, 2'-amino-2,4'-dichloroacetophenone

[0072] 25ml two-neck bottle, add 3ml of 1M BCl 3 For n-hexane solution, put 0.32g of p-chloroaniline in 3ml of benzene solution dropwise under cooling in an ice bath, remove the ice bath after the addition, add 0.19ml of chloroacetonitrile and 0.37g of anhydrous aluminum trichloride, and reflux with nitrogen for 6 hours , remove the oil bath, add 3ml of 2N hydrochloric acid under cooling in an ice bath, reheat until the solid dissolves, extract with 8ml of dichloromethane x 3, wash the organic layer with 20ml of water, dry over anhydrous magnesium sulfate and evaporate to dryness to obtain 2'- Amino-2,4'-dichloroacetophenone 0.2 g.

[0073] Synthesis of B, 7-chloromethyl-10-chlorohomocamptothecin

[0074] Take 45mg of 2'-amino-2,4'-dichloroacetophenone, 60...

Embodiment 3

[0077] Preparation of 7-chloromethyl-10-fluorohomocamptothecin (general formula II compound, wherein R 1 , R 2 , R 3 , R 4 followed by chloromethyl, H, F, H)A, 2'-amino-2-chloro-4'-fluoroacetophenone

[0078] According to the method of Example 2A, p-fluoroaniline was used instead of p-chloroaniline to obtain 2'-amino-2-chloro-4'-fluoroacetophenone.

[0079] B. 7-Chloromethyl-10-fluorohomocamptothecin

[0080] According to the method of Example 2B, 2'-amino-2-chloro-4'-fluoroacetophenone was used instead of 2'-amino-2,4'-dichloroacetophenone to obtain 7-chloromethyl-10- Fluorocamptothecin is a yellow solid.

[0081] 1 HNMR(DMSO): 0.919(t, 3H), 1.9(q, 2H), 3.11-3.50(Abq, 2H), 5.42-5.59(m, 6H), 6.0(s, 1H), 7.45(s, 1H) 7.86(m, 1H), 8.21(m, 1H), 8.32(m, 1H)

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