Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2002-03-21
2003-05-06
Wilson, James O. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S017700, C536S018700, C536S022100, C536S027110, C536S027120, C536S029100
Reexamination Certificate
active
06559299
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a novel process to make indolo-carbazole carbazole glycosides in high purity which inhibit the growth of tumor cells and are therefore useful in the treatment of cancer in mammals, and the like.
In the field of cancer chemotherapy, a large number of compounds have already been put to practical use as antitumor agents. However, a need continues for the development of more efficacious compounds that work against a variety of tumors (see the Proceedings of the 47th General Meeting of the Japan Cancer Society, pp. 12-15 (1988)). This need has led to the development of indolocarbazole derivatives. (See U.S. Pat. Nos. 4,487,925; 4,552,842; 4,785,085; 5,591,842 and 5,922,860; Japanese Patent No. 20277/91; Journal of Antibiotics, Vol. 44, pp. 723-728 (1991); W091/18003; WO 98/07433; and EP0545195 A1). These compounds have been shown to act as topoisomerase inhibitors and therefore useful in the treatment of cancer (Cancer Chemother. Pharmacol. 34 (suppl): S41-S45 (1994)).
The success of these compounds in treating numerous cancers has necessitated the development of improved methods for their syntheses. (see Bioorg. & Med. Chem. Letters 2000, 10, 419; Tetrahedron 1997, 53, 5937; Tetrahedron 1997, 53, 585; and Synthesis 1976, 414). The previously known methods, however, suffer from numerous problems, including the use of undesirable solvents, mercury or silver salts, low yields and formation of unwanted side-products necessitating tedious or protracted purification steps.
For example, the previously known methods of preparation of the indolocarbazole glycoside III in high purity require purification procedures, such as combinations of carbon treatment, chromatography and/or recrystallization of the crude material, that are tedious, time-consuming and dangerous, especially when performed on a commercial scale due to the highly cytotoxic nature of the product. (see Bioorg & Med Chem Letters 1999, 3307; and Tetrahedron 1997, 585 (describing synthesis of structurally similar compound, requiring re-dissolution of crude product to obtain pure material)).
An object of this invention therefore is to provide a novel route to these indolopyrrolocarbazole-derived antitumor substances while overcoming the problems inherent in the previously known syntheses, specifically a route producing the product in sufficient purity to allow for use “as is” in subsequent formulations.
SUMMARY OF THE INVENTION
The present invention relates to a novel process to make indolo-carbazole glycosides of Formula I in high purity which inhibit the growth of tumor cells and are therefore useful in the treatment of cancer in mammals, and the like.
DETAILED DESCRIPTION OF THE INVENTION
An embodiment of the present invention is illustrated by a process for the preparation of a compound of Formula I in high purity,
which comprises the steps of:
(a) adjusting the pH of an acidic mixture consisting essentially of an alcohol, an acid, water and compound I, by adding a base to produce a solution with a pH in the range of about 1.5 to about 6.5;
(b) keeping the temperature of the solution from step (a) in the range of about 50° C. to about 100° C. ; and
(c) isolating the crystals of compound I.
In a second embodiment of the instant invention, the process comprises the steps of:
(a) adjusting the pH of an acidic mixture consisting essentially of an acid, alcohol, water and compound I, by adding a base to produce a solution with a pH in the range of about 1.5 to about 6.5;
(b) adjusting the solution from step (a) with an alcohol so that the solution is about 10% w/v to about 30% w/v water in an alcohol and the concentration of compound I is about 10 mL/g to 20 mL/g;
(c) adjusting the temperature of the solution from step (b) to a temperature in the range of about 50° C. to about 100° C. ;
(d) adding an alcohol to the solution from (c) such that the solution is diluted to about 3:2 (solution: alcohol);
(e) aging the solution from (d) at a temperature in the range of about 50° C. to about 100° C. until crystals of compound I are formed to produce a slurry; and
(f) isolating the crystals of compound I.
In a further embodiment of the second embodiment, the process further comprises deprotecting intermediate II:
(wherein R is independently a hydrogen or a substituted or unsubstituted benzyl protecting group, with the proviso that at least one R is a substituted or unsubstituted benzyl protecting group), via hydrogenation in the presence of a catalyst to produce a reaction mixture, followed by filtering the reaction mixture to afford the mixture of step (a).
In an alternative embodiment, R is benzyl in the process described above.
In a third embodiment of the instant invention, the process for the preparation of compound m in high purity
comprises the steps of:
(a) adjusting the pH of an acidic mixture consisting essentially of an acid, alcohol, water and compound III, by adding a base to produce a solution with a pH in the range of about 1.5 to about 6.5;
(b) adjusting the solution from step (a) with an alcohol so that the solution is about 10% w/v to about 30% w/v water in an alcohol and the concentration of compound III is about 10 mL/g to 20 mL/g;
(c) adjusting the temperature of the solution from step (b) to a temperature in the range of about 50° C. to about 100° C. ;
(d) seeding the solution;
(e) adding an alcohol to the solution such that the solution is diluted to about 3:2 (solution: alcohol);
(f) aging the solution from (e) at a temperature in the range of about 50° C. to about 100° C. until crystals of compound III are formed to produce a slurry; and
(g) isolating the crystals of compound III.
In a further embodiment of the third embodiment, the process further comprises deprotecting intermediate II:
(wherein R is independently a hydrogen or a substituted or unsubstituted benzyl protecting group, with the proviso that at least one R is a substituted or unsubstituted benzyl protecting group), via hydrogenation in the presence of a catalyst to produce a reaction mixture, followed by filtering the reaction mixture to afford the mixture of step (a).
And yet another embodiment is the process described immediately above wherein the pH in step (a) is adjusted to a pH in the range of about 1.5 to about 3.5; the solution in (b) is adjusted so that the solution is about 15% w/v to about 25% w/v water in alcohol and the concentration of compound III is about 12 mL/g to about 18 mL/g; and the temperature in step (c) is adjusted to about 70° C.
A further embodiment is the process above wherein the pH in step (a) is adjusted to a pH of about 2.5; the solution in (b) is adjusted so that the solution is about 20% w/v water in alcohol and the concentration of compound III is about 15 mL/g; and the temperature in step (c) is adjusted to about 70° C.
Also encompassed by the present invention is the process described above further comprising the step of adjusting the slurry after step (f) such that the water content is lowered to a range of about 1% w/v to about 10% w/v before isolating the crystals of compound III in step (g).
A preferred embodiment is a process for the preparation of compound III in high purity,
which comprises the steps of:
(a) adjusting the pH of an acidic mixture consisting essentially of an acid, alcohol, water and compound III, by adding a lower alkyl amine base to produce a solution with a pH of about 2.5;
(b) adjusting the solution from step (a) with isopropyl alcohol so that the solution is about 20% w/v water in isopropyl alcohol and the concentration of compound I is about 15 mL/g;
(c) adjusting the temperature of the solution from step (b) to a temperature of about 70° C. ;
(d) seeding the solution;
(e) adding isopropyl alcohol to the solution such that the solution is diluted to about 3:2 (solution:isopropyl alcohol);
(f) aging the solution from (e) at a temperature of about 70° C. until the crystals of compound I are formed to produce a slurry;
(g) adjusting the slurry so that the water content is about 3% w/v;
(h) aging the slurry at about 70° C
Hiraga Shouichi
Iida Takehiko
Kamatani Asayuki
Kawasaki Masashi
Tschaen David
Brown Dianne
Daniel Mark R.
McIntosh Traviss C.
Merck & Co. , Inc.
Wilson James O.
LandOfFree
Preparation and isolation of indolocarbazole glycosides does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Preparation and isolation of indolocarbazole glycosides, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Preparation and isolation of indolocarbazole glycosides will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3001024