MXPA00000297A - A process of manufacturing camptothecin derivatives - Google Patents

Abstract

This invention relates to a process of manufacturing the compound of general formula (1) from the compound of general formula (2):wherein Y and Z are the same or different and each represents a hydrogen atom, C1-C6 alkyl group, a C1-C3 hydroxyalkyl group, or a general protecting group of amine such as benzyloxycarbonyl, benzyl, etc.;R1 is a hydrogen atom, a C1-C6 alkyl group, or a hydroxy group;R2 and R3 are the same or different and each represents a hydrogen atom or a hydroxy group, or they may be attached together to form a cyclic moiety, which is a methylenedioxy or an ethylenedioxy group;R4 is a hydrogen atom or a C1-C6 alkyl group;and R5 is hydrogen, hydroxy, fluoro, chloro, bromo, iodo or amine.

Description

A PROCESS OF MANUFACTURING DERIVATIVES OF CAMPOTOTECINE DESCRIPTION Background and field of the invention This invention relates to a process for the manufacture of camptothecin derivatives represented by the general formula (1) or a pharmaceutically acceptable salt thereof: wherein Y and Z are the same or different and each represents a hydrogen atom, an alkyl group of 1 to 6 carbon atoms, a hydroxyalkyl group of 1 to 3 carbon atoms, or a general amine protecting group such as benzyloxycarbonyl, benzyl, etc .; Ri is a hydrogen atom, an alkyl group of 1 to 6 carbon atoms, or a hydroxy group; R2 and R3 are the same or different and each represents a hydrogen atom or a hydroxy group, or they may be joined together to form a cyclic part which is a methylenedioxy or an ethylenedioxy group; R4 is a hydrogen atom or a. alkyl group of 1 to 6 carbon atoms; and R5 is hydrogen, hydroxy, fluoro, chloro, bromo, iodo or amine. From the first isolation of camptothecin from wood and bark of Camptotheca acuminata by Wall et al [M. E. Wall et. Al., J. Am. Chem. Soc., 88, 3888 (1966)], there were many attempts to synthesize camptothecin. However, the development of camptothecin as an effective antineoplastic agent was unsuccessful due to its severe toxicity in the clinical trial in 1970. After this, Liu et al. reported in 1985 crue camptothecin had a specific mode of action to inhibit topoisomerase I. Thus, there is considerable interest in this compound. Recently, several studies have been proposed for the development of camptothecin derivatives to reduce the toxicity of camptothecin and to also allow its antineoplastic activities. Among these related studies, the clinical trial of CPTL-11 (irinotecan) synthesized by Yakurt-Honsha Co. from Japan in 1986 showed that it exhibited excellent antineoplastic activities with less toxicity (Japanese Patent Laid Open Publication No. 64-61482) and followed by other pharmaceutical companies such as Smithkline Beecham (mole ecan) and Glaxo (MDO-camptothecin and 9-amino camptothecin). Among them, CPT-11 and topotecan were launched. On the other hand, the inventors reported in the Korean patent application No. 95-269 and 96-248 the 7-aminoethyl camptothecin derivatives and the process to manufacture them through the total synthesis, which have strong antitumor activity, low toxicity, and a large region of safety. The above invention produces camptothecin derivatives having strong antitumor activity. However, the process for making them is complex since the total synthesis was adopted and a new intermediary material was used. Accordingly, there has been a strong need to develop a simple and convenient industrial process for the mass production of camptothecin derivatives.

Therefore, the inventors et al. have studied a convenient process by means of which camptothecin derivatives having excellent activities can be manufactured from a compound of general formula 2 such as (S) -7-methylcamptothecin [S. Sawada et al., Chem. Pharm. Bull. , 39 (1991) 2574-2580]. Thus, the present invention has been completed. A process for making a camptothecin derivative or a pharmaceutically acceptable salt thereof, in accordance with the practice of this invention is described in more detail. The process for making a camptothecin derivative or a pharmaceutically acceptable salt thereof according to the present invention is to produce the compound of general formula 1 through the Mannich reaction, ie a compound of general formula 2 is reacted with an amine or a salt thereof and with a formaldehyde source in the presence of acid (Scheme 1) • [Scheme 1] " wherein Y and Z are the same or different and each represents a hydrogen atom, an alkyl group of 1 to 6 carbon atoms, a hydroxyalkyl group of 1 to 3 carbon atoms, or a general amine protecting group such as benzyloxycarbonyl , benzyl, etc.; Ri is a hydrogen atom, an alkyl group of 1 to 6 carbon atoms, or a hydroxy group; R2 and R3 are the same or different and each represents a hydrogen atom or a hydroxy group, or they may be joined together to form a cyclic part which is a methylenedioxy group or an ethylenedioxy group; R is a hydrogen atom or an alkyl group of 1 to 6 carbon atoms; and R5 is hydrogen, hydroxy, fluoro, chloro, bromo, iodo or amine. Preferably, R1 R2, R3, R4, R5, and Y represent hydrogen atoms, and Z is isopropyl.

Examples of the formaldehyde sources comprise formalin solution, paraformaldehyde, trioxane, di-ethyl sulfoxide, etc. Examples of the amine include primary or secondary amines such as methylamine, ethylamine, propylamine, isopropylamine, butylamine, pentylamine, hexylamine, benzylamine, isopropylbenzylamine, dimethylamine, diethylamine, benzyloxycarbonylamine, hydroxymethylamine, hydroxyethylamine, hydroxypropylamine and the like. In this reaction, examples of a reaction solvent comprise water, methanol, ethanol, dioxane, acetic acid, dimethylformamide, dimethyl sulfoxide and the like. Examples of the acid include hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, boron trifluoride, tin chloride and the like. And the temperature of the reaction is from 20 to 150 ° C. According to the present invention, pharmaceutically acceptable salts of compounds represented by the general formula 1 are salts of inorganic acids such as hydrochloric, sulfate, phosphate, etc., or salts of organic acids such as p-toluenesulfonate, acetate, methanesulfonate, trifluoromethanesulfonate, etc. .

Best mode for carrying out the invention This invention is explained in more detail by means of the following examples but the claims are not limited to these examples.

Example 1: (S) -7- [2- (N-isopropylamino) ethyl) camp or ecina _ (S) -7-methylcamptothecin hydrochloride (8 g, 0.0221 mol), isopropylamine (3.91 g, 0.0662 mol) and HCl (6.93 mL, 0.0684 mol) were added to dimethylsulfoxide (80 mL). The reaction mixture was stirred at 140 ° C for one hour, and then cooled to room temperature. The solvent was removed from the reaction by distillation under reduced pressure and the residue, thus obtained, was purified by column chromatography with (methylene chloride: ethanol = 10: 1) to give the desired product (6.75 g, 65% ) as a pale yellow solid. R NMR (DMSO-d6, 400 MHz) d: 9.29 (brs, 1H), 8.39 (d, 1H, J = 8.3Hz), 8.13 (d, 1H, J = 8.3Hz), 7.83 (t, 1H, J = 7.1Hz), 7.72 (t, 1H, J = 7.1Hz), 7.29 (s) , 1H), 6.52 (s, 1H), 5.43 (s, 2H), 5.37 (s, 2H), 3.64-3.60 (m, 2H), 3.45-3.34 (m, 1H), 3.20-3.14 (m, 2H) ), 1.92-1.82 (m, 2H), 1.27 (d, 6H, J = 6.4Hz), 0.87 (t, 3H, J = 8.0Hz) Example 2: (S) -7- [2- (N) Hydrochloride -isopropylamino) ethyl) camptothecin (S) -7-methylcamptothecin (8g, 0.0221 mol) and isopropylamine (3.91 g, 0.0662 mol) were added neatly in a mixed solution of formalin solution (37%, 9.73 ml, 0.12 mol) and c-HCl (6.93 ml, 0.0684 mol). The reaction mixture was stirred under reflux for 12 hours, and then cooled to room temperature. The solvent was removed from the reaction by distillation under reduced pressure and the residue, thus obtained, was purified by column chromatography with (methylene chloride: ethanol = 10: 1) to give the desired product (6.23g, 60% ) as a pale yellow solid. The data of the product analysis are the same as those of example 1.

Example 3: (S) -7- [2- (N-isopropylamino) ethyl) camptothecin (S) -7-methylcamptothecin hydrochloride (8g, 0.0221 mol), isopropylamine (3.91 g, 0.0662 mol) and paraformaldehyde (5 g) were added in order in a mixed solution of ethanol (30 ml), water (30 ml) and c-HCl (6.93 ml, 0.0684 mol).

Then, the reaction mixture was stirred under reflux for 20 hours, and then cooled to room temperature. The reaction solvent was removed by distillation under reduced pressure and the residue, thus obtained, was purified by column chromatography with (methylene chloride = 10: 1 methylene chloride) to give the desired product (6.35g, 61.1% ) as a pale yellow solid. The product analysis data are the same as those in Example 1.

Example 4: (S) -7- [2- (N-propylamino) ethyl) camptothecin hydrochloride. The same procedure as in Example 1 was applied for propylamine (496 mg, 0.0084 mol) and (S) -7- ethyl camptothecin (1,005 g, 0.0028 mol) to give the desired product (677 mg, 52%) as yellow solid pale. ^ -NMR (DMSO-d6) d: 9.26 (brs, 1H), 8.43-7.7 (m, 4H), 7.3 (s, 1H), 6.48 (s, 1H), 5.42 (s, 2H), 5.29 (s) , 2H), 3.64-3.37 (m, 2H), 3.2-3.11 (m, 4H), 1.92-1.82 (m, 2H), 1.27-1.11 (m, 8H), 0.88 (t, 3H, J = 7.2Hz ), 0.81 (t, 3H, J = 7.3Hz) Example 5: (S) -7- [2- (N-isopropylamino) ethyl] -10,11-methylenedioxycamptothecin Hydrochloride The same procedure as in Example 1 was applied to (S) -7-methyl-10, 11- methylenedioxicamptothecin (1 g, 0.00248 mol) and isopropylamine (440 mg, 0.00744 mol) to give the desired product (540 mg, 48%) as a pale yellow solid. aH NMR (DMS0-d6) d: 9.21 (brs, 1H), 7.6 (s, 1H), 7. 4 (S, 1H), 7.21 (s, 1H), 6.28 (s, 2H), 5.4 (s, 2H), 5.32 (s, 2H), 3.64-3.60 (m, 2H), 3.45-3.34 (m, 1H), 3.19-3.10 (m, 2H), 1.92-1.81 (m, 2H), 1.27 (d, 6H, J = 7.1Hz), 0.88 (t, 3H, J = 7.2Hz) Example 6: (S) -7- [2- (N-isopropylamino) ethyl] -10,11-methylenedioxycamptothecin hydrochloride The same procedure as in example 2 to (S) -7-methyl-10, 11- methylenedioxicamptothecin (lg, 0.00248 mol) and isopropylamine (440 mg, 0.00744 mol) to give the desired product (600 mg, 53%) as a pale yellow solid. The data of the product analysis are the same as those of example 5.

Example 7: (S) -7- [2- (N-isopropylamino) ethyl) -10,11-methylenedioxyamptothecin hydrochloride The same procedure as in Example 3 was applied to (S) -7-methyl-10, 11 methylenedioxicamptothecin (Ig, 0.00248 mol) and isopropylamine (440 mg, 0.00744 mol) to give the desired product (565 mg, 51%) as a pale yellow solid. The data of the product analysis are the same as those of example 5.

Example 8: (S) -7- [2- (N-isopropylamino) ethyl] -10,11-ethylenedioxycamptothecin hydrochloride The same procedure as in Example 1 was applied to (S) -7-methyl-10, 11- ethylendioxicamptothecin (Ig, 0.00239 mol) and isopropylamine (440 mg, 0.00744 mol) to give the desired product (703 mg, 56%) as a pale yellow solid. aH NMR (DMSO-d6) d: 9.20 (brs, 1H), 7.58 (s, 1H), 7.4 (s, 1H), 7.23 (s, 1H), 6.31 (m, 2H), 5.8 (m, 2H) , 5.4 (s, 2H), 5.32 (s, 2H), 3.61-3.3 (m, 2H), 3.17-3.11 (m, 3H), 1.96-1.84 (m, 2H), 1.27 (d, 6H, J = 7.5Hz), 0.92 (t, 3H.J = 6.8Hz) Example 9: (S) -7- [2- (N-isopropylamino) ethyl] -10,11-ethylenedioxycamptothecin hydrochloride The same procedure as in example 2 to (S) -7-methyl-10, 11- was applied ethylendioxicamptothecin (1 g, 0.00239 mol) and isopropylamine (440 mg, 0.00744 mol) to give the desired product (579 mg, 46%) as a pale yellow solid. The product analysis data are the same as those in Example 8.

Example 10: (S) -7- [2- (N-isopropylamino) ethyl) -10,1-ethylenedioxycamptothecin hydrochloride The same procedure as in Example 3 was applied to (S) -7-methyl-10, 11- ethylendioxicamptotecipa (1 g, 0.00239 mol) and isopropylamine (440 mg, 0.00744 mol) to give the desired product (668 mg, 53%) as pale yellow solid. The data of the product analysis are the same as those of example 8.

Example 11: (S) -7- [2- (N-propylamino) ethyl) -10,1-methylenedioxycamptothecin Hydrochloride The same procedure as in Example 1 was applied to (S) -7-methyl-10, 11- methylenedioxicamptothecin (1 g, 0.00248 mol) and propylane (440 mg, 0.00744 mol) to give the desired product (466 mg, 42%) as a pale yellow solid. ! H MR (DMS0-d6) d: 7.6 (s, 1H), 7.38 (s, 1H), 7.21 (s, 1H), 6.26 (s, 2H), 5.4 (s, 2H), 5.29 (s, 2H), 3.56- 3.311 (m, 2H), 3.18-3.03 (m, 4H), 1.91-1.81 (m , 2H), 1.29- 1.04 (m, 8H), 0.87 (t, 3H, J = 6.8Hz), 0.74 (t, 3H, J = 7.1 Hz) Example 12: (S) -7- [2- (N-propylamino) ethyl-10,16-ethylenedioxycamptothecin Hydrochloride The same procedure as in Example 1 was applied to (S) -7-methyl-10,11-ethylenedioxicamptothecin (1 g, 0.00239 mol) and propylamine (440 mg, 0.00744 mol) to give the desired product (575 mg, 46%) as pale yellow solid.

XH NMR (DMSO-d6) d: 7.6 (s, 1H), 7.36 (s, 1H), 7.20 (s, 1H), 6.26 (s, 2H), 5.81 (s, 2H), 5.41 (s, 2H), 5.28 (s, 2H), 3.52-3.41 (m, 2H), 3.16-3.01 (m, 4H), 1.93-1.79 (m, 2H), 1.28-1.02 (m, 8H), 0.88 (t, 3H, J = 7.1Hz), 0.78 (t, 3H, J = 7.1Hz) Example 13: (S) -7- [2- (N-isopropylbenzylamino) ethyl) camptothecin (S) -7-methylcamptothecin hydrochloride (8 g, 0.0221 mol), isopropylbenzylamine (9.88 g, 0.0662 mol) and c-HCl. { 6. 93 mi, 0. 0684 mol) were added to the dimethylsulfoxide (80 ml).

Then, the same procedure as in Example 1 was carried out to give the desired product (9.27 g, 75%) as a pale yellow solid. aH NMR (DMSO-de, 400MHz) d 8. 38 (d, 1H, J = 8.5Hz), 8. 13 (d, 1H, J = 8.5Hz), 7.86 (dd, 1H, J = 8.5, 8.0Hz), 7.74 (dd, 1H, J = 8.5, 8.0HZ), 7.52-7.31 (m, 5H), 7.29 (s, 1H), 6. 52 (s, 1H), 5.43 (s, 2H), 5.35 (s, 2H), 3.66-359 Tm, 2H), 3. 54 (s, 2H), 3.45-3.34 (m, 1H), 3.21-3.16 (m, 2H), 1.92-1.82 (m, 2H), 1.26 (d, 6H, J = 6.4Hz), 0.88 (t, 3H, J = 8.0Hz) Example 14: (S) -7- [2- (N-isopropylamino) ethyl) camptothecin Hydrochloride Pd-C (10%, 500 mg), 4.4% formic acid (10 ml) and methanol (100 ml) were added to (S) -7- [2- (N-isopropylbenzylamino) ethyl] camptothecin hydrochloride (5 g, 0.0089 mol) and the reaction mixture was stirred at room temperature for 18 hours. Then, the reaction solution was filtered and the filtrate, thus obtained, was distilled under reduced pressure. The residue, thus obtained, was purified by column of vapor chromatography. (methylene chloride: methanol 10: 1) to give the desired product (3.6 g, 86%) as a pale yellow solid. The data of the product analysis are the same as those of Example 1. The present invention relates in particular to a process for the manufacture of a camptothecin derivative or the pharmaceutically acceptable salts thereof. Especially, substituted camptothecin derivatives having excellent antineoplastic activities can be manufactured easily and economically by means of such a process.

Claims (5)

1. A process for making the compound represented by general formula 1 or a pharmaceutically acceptable salt thereof, wherein the process comprises the step wherein a compound of general formula 2 is reacted with an amine or a salt thereof and with a source of formaldehyde in the presence of acid: wherein Y and Z are the same or different and each represents a hydrogen atom, an alkyl group of 1 to 6 carbon atoms, a hydroxyalkyl group of 1 to 3 carbon atoms, or a general amine protecting group such as benzyloxycarbonyl , benzyl, etc .; Ri is a hydrogen atom, an alkyl group of 1 to 6 carbon atoms, or a hydroxy group; R2 and R3 are the same or different and each represents a hydrogen atom or a hydroxy group, or they may be joined together to form a cyclic part, which is a methylenedioxy group or an ethylenedioxy group; R4 is a hydrogen atom or an alkyl group of 1 to 6 carbon atoms; and R5 is hydrogen, hydroxy, fluoro, chloro, bromo, iodo or amine.

2. A process according to claim 1 or 2, wherein Ri, R2, R3, R4, R5 and Y are the same and each represents a hydrogen atom; and Z is isopropyl.

3. A process according to claim 1 or 2, wherein the formaldehyde source is a solution of formalin, paraformaldehyde, trioxane or dimethylsulfoxide.

4. A process according to claim 1 or 2, wherein the amine is methylamine, ethylamine, propylamine, isopropylamine, butylamine, pentylamine, hexylamine, benzylamine, isopropylbenzylamine, dimethylamine, diethylamine, benzyloxycarbonylamine, hydroxymethylamine, hydroxyethylamine or hydroxypropylamine.

5. A process according to claim 1 or 2, wherein the solvent of the reaction is water, methanol, ethanol, dioxane, acetic acid, dimethylformamide or dimethylsulfoxide; the acid is hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, boron trifluoride or tin chloride; and the temperature of the reaction is from 20 to 150 ° C.