US4981968A
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Synthesis of camptothecin and analogs thereof
Assignee: RTI International
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Filing: 1988-09-28
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Granted: 1991-01-01
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Expires: 2008-09-28
Abstract
Abstract A method for synthesizing camptothecin and camptothecin analogs using a novel hydroxyl-containing tricyclic intermediate and the camptothecin analogs produced by the process. The camptothecin analogs are effective inhibitors of topoisomerase I and show anti-leukemic and anti-tumor activity.
Inventors
- 👤 Monroe E. Wall
- 👤 Mansukh C. Wani
- 👤 Allan W. Nicholas
- 👤 Govindarajan Manikumar
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-29 03:25
CPC Classifications
C; C07; C07D; C07D491/00; C07D491/22
Claims Analysis
Total Claims: 30
Claim 1
Independent Claim
177 words
A method for synthesizing camptothecin compounds comprising the steps of: cyclizing a compound of the formula shown below, wherein X is an organic group which is converted to a carbonyl group when treated with an acid; in the presence of a basic catalyst, and a source of oxygen, ##STR11## to form a lactone having the formula ##STR12## deprotecting said lactone to form a hydroxyl-containing tricyclic compound having the formula shown below ##STR13## reacting said hydroxyl-containing tricyclic compound in the presence of an acid or base catalyst, with a substituted ortho-amino compound of the formula ##STR14## wherein n=1, R is an amino or hydroxy group and R 2 is H or C 1-8 alkyl; and wherein R is an amino group, reacting said amino group with (a) the carboxylic acid group of an amino acid or carboxylic acid derivative thereon, a C 4-10 saturated or unsaturated carboxylic acid anhydride, (c) with phosgene and then with a diamine or a tertiary amino alcohol; and when R is a hydroxy group, reacting the hydroxy group with a dialkylamino alkyl halide.
Claim 2
Independent Claim
177 words
A method for synthesizing camptothecin compounds comprising the steps of: cyclizing a compound of the formula shown below, wherein X is an organic group which is converted to a carbonyl group when treated with an acid; in the presence of a basic catalyst, and a source of oxygen, ##STR11## to form a lactone having the formula ##STR12## deprotecting said lactone to form a hydroxyl-containing tricyclic compound having the formula shown below ##STR13## reacting said hydroxyl-containing tricyclic compound in the presence of an acid or base catalyst, with a substituted ortho-amino compound of the formula ##STR14## wherein n=1, R is an amino or hydroxy group and R 2 is H or C 1-8 alkyl; and wherein R is an amino group, reacting said amino group with (a) the carboxylic acid group of an amino acid or carboxylic acid derivative thereon, a C 4-10 saturated or unsaturated carboxylic acid anhydride, (c) with phosgene and then with a diamine or a tertiary amino alcohol; and when R is a hydroxy group, reacting the hydroxy group with a dialkylamino alkyl halide.
Claim 3
Independent Claim
130 words
A method for synthesizing camptothecin compounds, comprising the steps of: cyclizing a compound of the formula shown below, wherein X is an organic group which is converted to a carbonyl group when treated with an acid; in the presence of a basic catalyst, and a source of oxygen, ##STR15## to form a lactone having the formula ##STR16## deprotecting said lactone to form a hydroxyl-containing tricyclic compound having the formula shown below ##STR17## reacting said hydroxyl-containing tricyclic compound in the presence of an acid or base catalyst, with a substituted ortho-amino compound of the formula ##STR18## wherein n=1, R is an aminomethyl or a hydrazino group, and R 2 is H or C 1-8 alkyl; and reacting said aminomethyl or hydrazino group with an acid to form an acid addition salt.
Claim 4
Independent Claim
130 words
A method for synthesizing camptothecin compounds, comprising the steps of: cyclizing a compound of the formula shown below, wherein X is an organic group which is converted to a carbonyl group when treated with an acid; in the presence of a basic catalyst, and a source of oxygen, ##STR15## to form a lactone having the formula ##STR16## deprotecting said lactone to form a hydroxyl-containing tricyclic compound having the formula shown below ##STR17## reacting said hydroxyl-containing tricyclic compound in the presence of an acid or base catalyst, with a substituted ortho-amino compound of the formula ##STR18## wherein n=1, R is an aminomethyl or a hydrazino group, and R 2 is H or C 1-8 alkyl; and reacting said aminomethyl or hydrazino group with an acid to form an acid addition salt.
Claim 5
Dependent Claim
31 words
The method of claim 1, wherein said cyclizing step is performed in the presence of a basic catalyst selected from the group consisting of sodium carbonate, potassium carbonate, triethylamine and diisopropylamine.
Claim 6
Dependent Claim
29 words
The method of claim 1, wherein said cyclizing step is performed in the presence of a polar organic solvent selected from the group consisting of methanol, ethanol and dimethylformamide.
Claim 7
Dependent Claim
28 words
The method of claim 1, wherein said reacting step is catalyzed by a basic compound selected from the group consisting of sodium carbonate, potassium carbonate, triethylamine and diisopropylamine.
Claim 8
Dependent Claim
27 words
The method of claim 1, wherein said source of oxygen is selected from the group consisting of oxygen gas, air, hydrogen peroxide, lead tetraacetate and selenium dioxide.
Claim 9
Dependent Claim
18 words
The method of claim 1, wherein R 2 is H, CH 3 or C 2 H 5 .
Claim 10
Dependent Claim
29 words
The method of claim 1, wherein said reacting step is catalyzed by an acid selected from the group consisting of arylsulfonic acids, acetic acid, formic acid and hydrochloric acid.
Claim 11
Dependent Claim
33 words
The method of claim 1, wherein R n is an amino group, and wherein the amino-camptothecin is further reacted with the carboxylic acid group of an amino acid or carboxylic acid derivative thereof.
Claim 12
Dependent Claim
28 words
The method of claim 1, wherein R n is an amino group, and wherein the amino-camptothecin is reacted with a C 4-10 saturated or unsaturated carboxylic acid anhydride.
Claim 13
Dependent Claim
28 words
The method of claim 1, wherein R n is an amino group at C-9 and wherein the 9-amino-camptothecin is reacted with phosgene and then reacted with a diamine.
Claim 14
Dependent Claim
11 words
The method of claim 11, wherein said diamine is a n-alkylpiperazine.
Claim 15
Dependent Claim
29 words
The method of claim 1, wherein R n is an amino group at C-9 and wherein the 9-amino-camptothecin is reacted with phosgene and then reacted with a tertiary-amino alcohol.
Claim 16
Dependent Claim
12 words
The method of claim 13, wherein said alcohol is a n-dialkylamino ethanol.
Claim 17
Dependent Claim
25 words
The method of claim 1, wherein R n is a hydroxy group at C-9 and wherein the 9-hydroxycamptothecin is reacted with a dialkylamino alkyl halide.
Claim 18
Dependent Claim
27 words
The method of claim 2, wherein R n is an aminomethyl group and wherein the aminomethylcamptothecin is reacted with an acid to form an acid addition salt.
Claim 19
Dependent Claim
16 words
The method of claim 16, wherein said acid addition salt is a hydrochloride, gluconate or phosphate.
Claim 20
Dependent Claim
27 words
The method of claim 2, wherein R n is a hydrazino group and wherein the hydrazino-camptothecin is reacted with an acid to form an acid addition salt.
Claim 21
Dependent Claim
16 words
The process of claim 18, wherein said acid addition salt is a hydrochloride, gluconate or phosphate.
Claim 22
Dependent Claim
113 words
A camptothecin having the structure shown below ##STR19## wherein R n is (a) amino acid amido group obtained by reaction of an amino group at the 9-position on the A-ring with the carboxylic acid group of a naturally occurring α-amino acid, (b) a C 4-10 carboxylic acid amido group, (c) a urea group obtained by reaction of an amino group at the 9, 10, 11 or 12-position of the A-ring with phosgene followed by reaction with a diamine, (d) a urethane group obtained by reaction of an amino group at the 9, 10, 11 or 12-position of the A-ring with phosgene followed by reaction with a tertiary-amino alcohol, or pharmaceutically acceptable salts thereof.
Claim 23
Dependent Claim
113 words
A camptothecin having the structure shown below ##STR19## wherein R n is (a) amino acid amido group obtained by reaction of an amino group at the 9-position on the A-ring with the carboxylic acid group of a naturally occurring α-amino acid, (b) a C 4-10 carboxylic acid amido group, (c) a urea group obtained by reaction of an amino group at the 9, 10, 11 or 12-position of the A-ring with phosgene followed by reaction with a diamine, (d) a urethane group obtained by reaction of an amino group at the 9, 10, 11 or 12-position of the A-ring with phosgene followed by reaction with a tertiary-amino alcohol, or pharmaceutically acceptable salts thereof.
Claim 24
Dependent Claim
20 words
The camptotecin of claim 20, wherein said amino acid amido group is the glycinamido group or pharmaceutically acceptable salts thereof.
Claim 25
Dependent Claim
20 words
The camptothecin of claim 20, wherein said carboxylic acid amido group is the succinamido group or pharmaceutically acceptable salts thereof.
Claim 26
Dependent Claim
42 words
The camptothecin of claim 20, wherein R n is a urea group obtained by reaction of an amino group at the 9, 10, 11 or 12-position of the A-ring with phosgene followed by reaction with a diamine or pharmaceutically acceptable salts thereof.
Claim 27
Dependent Claim
13 words
The camptothecin of claim 23, wherein said urea group is the N-methylpiperazinocarbonylamino group.
Claim 28
Dependent Claim
43 words
The camptothecin of claim 20, wherein R n is a urethane group obtained by reaction of an amino group at the 9, 10, 11 or 12-position of the A-ring with phosgene followed by reaction with a tertiary-amino alcohol or pharmaceutically acceptable salts thereof.
Claim 29
Dependent Claim
13 words
The camptothecin of claim 25, wherein the urethane group is the N,N-diethylaminoethoxycarbonylamino group.
Claim 30
Dependent Claim
25 words
The camptothecin of claim 20, selected from the group consisting of 9-glycinamido-20(RS)-camptothecin, 9- or 10-succinamido-20-(RS)-camptothecin, 9- or 10- (4-methylpiperazino) carbonylamino-20(RS)-camptothecin and 9- or 10-(N,N-diethylaminoethoxy) carbonylamino-20(RS)-camptothecin.
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