US4399282A
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Camptothecin derivatives
Assignee: Yakult Honsha Co Ltd
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Filing: 1980-07-08
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Granted: 1983-08-16
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Expires: 2000-07-08
Abstract
Abstract New camptothecin derivatives possessing either or both of high anti-tumor activity and slight toxicity, represented by the general formula: <IMAGE> wherein X is H, CH2OH, COOH, an alkyl group, an aralkyl group or the grouping CH2OR1 or COOR2 wherein R1 is an alkyl group or an acyl group and R2 is a lower alkyl group, Y is H, OH or the grouping OR3 wherein R3 is a lower alkyl group or an acyl group, and Z is H or an acyl group, with the proviso that when X is CH2OH, an alkyl group or an aralkyl group, both Y and Z are H, that when X is the grouping CH2OR1 or COOR2, Y is H, that when Y is OH, both X and Z are H, and that when Y is the grouping OR3, X is H, and water-soluble alkali metal salts thereof. These camptothecin derivatives are prepared by treating camptothecin with sulfuric acid and a persulfate or with sulfuric acid and a peroxide, if necessary, with an organic compound corresponding to the organic moiety of the substituent to be introduced directly into camptothecin, in an aqueous medium in the presence or absence of a transition metal ion, and optionally treating the resultant products, if necessary, after oxidation of the introduced substituent, with an alkylating agent or an acylating agent.
Inventors
- 👤 Tadashi Miyasaka
- 👤 Masahiko Mutai
- 👤 Seigo Sawada
- 👤 Kenichiro Nokata
- 👤 Hisao Hagiwara
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-27 11:48
CPC Classifications
C; C07; C07D; C07D491/00; C07D491/22; A; A61; A61P; A61P35/00
Claims Analysis
Total Claims: 55
Claim 1
Independent Claim
234 words
A camptothecin derivative of the formula: ##STR9## wherein X is H, CH 2 OH, COOH, a straight or branched chain alkyl group with 1-18 carbon atoms, a cycloalkyl group with 5-7 carbon atoms, a phenylalkyl group having 1 to 3 carbon atoms in the alkylene portion thereof, or the group CH 2 OCOR 1 or COOR 2 where R 1 is a straight or branched chain alkyl group with 1-17 carbon atoms, trifluoromethyl, phenyl, a phenylalkyl group having 1 to 2 carbon atoms in the alkylene portion thereof or the group HOOC--(CH 2 ) n where n is an integer of 2 to 4 and where R 2 is a lower alkyl group; Y is H, OH or OR 3 , where R 3 is a lower alkyl group, an alkanoyl group with 1-5 carbon atoms, benzoyl or a phenylalkanoyl group with 1-2 carbon atoms in the alkylene portion thereof; and Z is H, acetyl or trifluoroacetyl; with the proviso (1) that when X is CH 2 OH, the straight or branched alkyl group, the cycloalkyl group or the phenylalkyl group, both Y and Z are H, (2) that when X is CH 2 OCOR 1 or COOR 2 , Y is H, (3) that when Y is OH, both X and Z are H, and (4) that when Y is OR 3 , X is H; or a water-soluble alkali metal salt thereof.
Claim 2
Dependent Claim
234 words
A camptothecin derivative of the formula: ##STR9## wherein X is H, CH 2 OH, COOH, a straight or branched chain alkyl group with 1-18 carbon atoms, a cycloalkyl group with 5-7 carbon atoms, a phenylalkyl group having 1 to 3 carbon atoms in the alkylene portion thereof, or the group CH 2 OCOR 1 or COOR 2 where R 1 is a straight or branched chain alkyl group with 1-17 carbon atoms, trifluoromethyl, phenyl, a phenylalkyl group having 1 to 2 carbon atoms in the alkylene portion thereof or the group HOOC--(CH 2 ) n where n is an integer of 2 to 4 and where R 2 is a lower alkyl group; Y is H, OH or OR 3 , where R 3 is a lower alkyl group, an alkanoyl group with 1-5 carbon atoms, benzoyl or a phenylalkanoyl group with 1-2 carbon atoms in the alkylene portion thereof; and Z is H, acetyl or trifluoroacetyl; with the proviso (1) that when X is CH 2 OH, the straight or branched alkyl group, the cycloalkyl group or the phenylalkyl group, both Y and Z are H, (2) that when X is CH 2 OCOR 1 or COOR 2 , Y is H, (3) that when Y is OH, both X and Z are H, and (4) that when Y is OR 3 , X is H; or a water-soluble alkali metal salt thereof.
Claim 3
Dependent Claim
1 words
7-Hydroxymethylcamptothecin.
Claim 4
Dependent Claim
1 words
7-Hydroxymethylcamptothecin.
Claim 5
Dependent Claim
1 words
5-Hydroxycamptothecin.
Claim 6
Dependent Claim
1 words
5-Hydroxycamptothecin.
Claim 7
Dependent Claim
51 words
A camptothecin derivative of the formula: 7-(R'CO--OCH.sub.2)-camptothecin wherein R' is a straight or branched chain alkyl group with 1-10 carbon atoms, phenyl or a phenylalkyl group with 1-2 carbon atoms in the alkylene portion thereof or the group HOOC--(CH 2 ) n where n is an integer of 2 to 4.
Claim 8
Dependent Claim
51 words
A camptothecin derivative of the formula: 7-(R'CO--OCH.sub.2)-camptothecin wherein R' is a straight or branched chain alkyl group with 1-10 carbon atoms, phenyl or a phenylalkyl group with 1-2 carbon atoms in the alkylene portion thereof or the group HOOC--(CH 2 ) n where n is an integer of 2 to 4.
Claim 9
Dependent Claim
26 words
A camptothecin derivative of the formula: 7-(R.sup.5 CO--OCH.sub.2)-20-O-(R.sup.5 CO)-camptothecin wherein the two R 5 's are identical with each other and each represents methyl or trifluoromethyl.
Claim 10
Dependent Claim
26 words
A camptothecin derivative of the formula: 7-(R.sup.5 CO--OCH.sub.2)-20-O-(R.sup.5 CO)-camptothecin wherein the two R 5 's are identical with each other and each represents methyl or trifluoromethyl.
Claim 11
Dependent Claim
31 words
A camptothecin derivative of the formula: 7-R.sup.6 -camptothecin wherein R 6 is a straight or branched chain alkyl group with 1-10 carbon atoms or a cycloalkyl group with 5-7 carbon atoms.
Claim 12
Dependent Claim
31 words
A camptothecin derivative of the formula: 7-R.sup.6 -camptothecin wherein R 6 is a straight or branched chain alkyl group with 1-10 carbon atoms or a cycloalkyl group with 5-7 carbon atoms.
Claim 13
Dependent Claim
26 words
A camptothecin derivative of the formula: 7-R.sup.7 -camptothecin wherein R 7 is a phenylalkyl group having 1 to 3 carbon atoms in the alkylene portion thereof.
Claim 14
Dependent Claim
26 words
A camptothecin derivative of the formula: 7-R.sup.7 -camptothecin wherein R 7 is a phenylalkyl group having 1 to 3 carbon atoms in the alkylene portion thereof.
Claim 15
Dependent Claim
23 words
A camptothecin derivative of the formula: 5-(R.sup.8 O)-camptothecin wherein R 8 is a straight or branched chain alkyl group with 1-5 carbon atoms.
Claim 16
Dependent Claim
23 words
A camptothecin derivative of the formula: 5-(R.sup.8 O)-camptothecin wherein R 8 is a straight or branched chain alkyl group with 1-5 carbon atoms.
Claim 17
Dependent Claim
39 words
A camptothecin derivative of the formula: 5-(R.sup.9 COO)-camptothecin wherein R 9 is a straight or branched chain alkyl group with 1-4 carbon atoms, phenyl or a phenylalkyl group having 1 to 3 carbon atoms in the alkylene portion thereof.
Claim 18
Dependent Claim
39 words
A camptothecin derivative of the formula: 5-(R.sup.9 COO)-camptothecin wherein R 9 is a straight or branched chain alkyl group with 1-4 carbon atoms, phenyl or a phenylalkyl group having 1 to 3 carbon atoms in the alkylene portion thereof.
Claim 19
Dependent Claim
1 words
5-Acetyloxy-20-O-acetylcamptothecin.
Claim 20
Dependent Claim
1 words
5-Acetyloxy-20-O-acetylcamptothecin.
Claim 21
Dependent Claim
2 words
Camptothecin-7-carboxylic acid.
Claim 22
Dependent Claim
2 words
Camptothecin-7-carboxylic acid.
Claim 23
Dependent Claim
25 words
A camptothecin derivative of the formula: 7-(R.sup.10 --OOC)-camptothecin wherein R 10 is a straight or branched chain alkyl group with 1 to 4 carbon atoms.
Claim 24
Dependent Claim
25 words
A camptothecin derivative of the formula: 7-(R.sup.10 --OOC)-camptothecin wherein R 10 is a straight or branched chain alkyl group with 1 to 4 carbon atoms.
Claim 25
Dependent Claim
187 words
A process for the preparation of a camptothecin derivative of the formula: ##STR10## wherein X' is the group COOR 4 or CH 2 OR where R 4 is H, lower alkyl or benzyl and R is H or R'CO where R' is a straight or branched chain alkyl group with 1-17 carbon atoms, trifluoromethyl, phenyl, a phenylalkyl group having 1 to 2 carbon atoms in the alkylene portion thereof or the group HOOC(CH 2 ) n where n is an integer of 2 to 4, and Z is H, acetyl or trifluoroacetyl, or a water-soluble alkali metal salt thereof, which comprises subjecting camptothecin to a radical reaction with a hydroxymethyl compound of the general formula: A--CH.sub.2 OH (II) wherein A is H, COOH or CH 2 OH, by the aid of sulfuric acid and an inorganic or organic peroxide in an aqueous medium, the inorganic and organic peroxide being selected from the group consisting of hydrogen peroxide, persulfuric acid and ammonium and alkali metal salts thereof, Caro's acid and alkali metal salts thereof, alkali metal and alkaline earth metal peroxides, tert-butyl hydroperoxide, benzoyl peroxide and dialkanoyl peroxides.
Claim 26
Dependent Claim
187 words
A process for the preparation of a camptothecin derivative of the formula: ##STR10## wherein X' is the group COOR 4 or CH 2 OR where R 4 is H, lower alkyl or benzyl and R is H or R'CO where R' is a straight or branched chain alkyl group with 1-17 carbon atoms, trifluoromethyl, phenyl, a phenylalkyl group having 1 to 2 carbon atoms in the alkylene portion thereof or the group HOOC(CH 2 ) n where n is an integer of 2 to 4, and Z is H, acetyl or trifluoroacetyl, or a water-soluble alkali metal salt thereof, which comprises subjecting camptothecin to a radical reaction with a hydroxymethyl compound of the general formula: A--CH.sub.2 OH (II) wherein A is H, COOH or CH 2 OH, by the aid of sulfuric acid and an inorganic or organic peroxide in an aqueous medium, the inorganic and organic peroxide being selected from the group consisting of hydrogen peroxide, persulfuric acid and ammonium and alkali metal salts thereof, Caro's acid and alkali metal salts thereof, alkali metal and alkaline earth metal peroxides, tert-butyl hydroperoxide, benzoyl peroxide and dialkanoyl peroxides.
Claim 27
Dependent Claim
57 words
A process according to claim 13, further comprising the step of treating the resultant 7-hydroxymethylcamptothecin with a compound of the formula: R'COOH wherein R' has the same meaning as defined above, or an anhydride or acid halide thereof, to give the 7-R'COOCH 2 group wherein R' is as defined above with or without simultaneous acetylation or trifluoroacetylation.
Claim 28
Dependent Claim
33 words
A process according to claim 13, further comprising the step of oxidizing the resultant 7-hydroxymethylcamptothecin with an oxidizer selected from the group consisting of chromium trioxide, alkali metal dichromates and permanganates to 7-carboxycamptothecin.
Claim 29
Dependent Claim
54 words
A process according to claim 14 or 15, further comprising the step of esterifying the 7-carboxyl group with a compound of the formula: R.sup.4 --OH wherein R 4 has the same meaning as defined above, to form a 7-X"-camptothecin wherein X" is the group R 4 OCO-- where R 4 is as defined above.
Claim 30
Dependent Claim
59 words
A process according to claim 13, wherein the radical reaction is carried out in the presence of a metal ion supplied in the reaction medium from a transition metal salt selected from the group consisting of silver, iron (II), copper, cobalt, nickel, lead, mercury, cadmium, thallium and zinc salts in the form of halides, carbonates, nitrates, sulfates and acetates.
Claim 31
Dependent Claim
14 words
A process according to claim 17, wherein the transition metal salt is silver nitrate.
Claim 32
Dependent Claim
14 words
A process according to claim 17, wherein the transition metal salt is ferrous sulfate.
Claim 33
Dependent Claim
12 words
A process according to claim 13, wherein the peroxide is ammonium persulfate.
Claim 34
Dependent Claim
12 words
A process according to claim 13, wherein the peroxide is hydrogen peroxide.
Claim 35
Dependent Claim
35 words
A process according to claim 17, wherein the transition metal salt is used within the range from an almost equimolar amount to an about 30 molar amount with respect to the amount of camptothecin used.
Claim 36
Dependent Claim
27 words
A process according to claim 13, wherein the reaction is carried out at a temperature varying from room temperature to the boiling point of the reaction mixture.
Claim 37
Dependent Claim
12 words
A process according to claim 13, wherein the hydroxymethyl compound is methanol.
Claim 38
Dependent Claim
241 words
A process for the preparation of a camptothecin derivative of the formula: ##STR11## wherein X"' is a straight or branched chain alkyl group with 1-18 carbon atoms, a cycloalkyl group with 5-7 carbon atoms, a phenylalkyl group having 1 to 3 carbon atoms in the alkylene portion thereof, or the group --COOR 4 where R 4 is H or a lower alkyl group, or a water-soluble alkali metal salt thereof, which comprises subjecting camptothecin to a radical reaction with an organic compound of the general formula: X"--Q (II') wherein Q is --CH 2 OH, --COOH, --CHO, --COX" or ##STR12## and X" is a straight or branched chain alkyl group with 1-10 carbon atoms, a cycloalkyl group with 5-7 carbon atoms, or a phenylalkyl group having 1 to 3 carbon atoms in the alkylene portion thereof, by the aid of sulfuric acid and an inorganic or organic peroxide in an aqueous medium in the presence of a transition metal ion supplied in the medium from a transition metal salt selected from the group consisting of silver, iron (II), copper, cobat, nickel, lead, mercury, cadmium, thallium and zinc salts in the form of halides, carbonates, nitrates, sulfates and acetates, the inorganic or organic peroxide being selected from the group consisting of hydrogen peroxide, persulfuric acid and ammonium and alkali metal salts thereof, Caro's acid and alkali metal salts thereof, alkali metal and alkaline earth metal peroxides, tert-butyl hydroperoxide, benzoyl peroxide and dialkanoyl peroxides.
Claim 39
Dependent Claim
241 words
A process for the preparation of a camptothecin derivative of the formula: ##STR11## wherein X"' is a straight or branched chain alkyl group with 1-18 carbon atoms, a cycloalkyl group with 5-7 carbon atoms, a phenylalkyl group having 1 to 3 carbon atoms in the alkylene portion thereof, or the group --COOR 4 where R 4 is H or a lower alkyl group, or a water-soluble alkali metal salt thereof, which comprises subjecting camptothecin to a radical reaction with an organic compound of the general formula: X"--Q (II') wherein Q is --CH 2 OH, --COOH, --CHO, --COX" or ##STR12## and X" is a straight or branched chain alkyl group with 1-10 carbon atoms, a cycloalkyl group with 5-7 carbon atoms, or a phenylalkyl group having 1 to 3 carbon atoms in the alkylene portion thereof, by the aid of sulfuric acid and an inorganic or organic peroxide in an aqueous medium in the presence of a transition metal ion supplied in the medium from a transition metal salt selected from the group consisting of silver, iron (II), copper, cobat, nickel, lead, mercury, cadmium, thallium and zinc salts in the form of halides, carbonates, nitrates, sulfates and acetates, the inorganic or organic peroxide being selected from the group consisting of hydrogen peroxide, persulfuric acid and ammonium and alkali metal salts thereof, Caro's acid and alkali metal salts thereof, alkali metal and alkaline earth metal peroxides, tert-butyl hydroperoxide, benzoyl peroxide and dialkanoyl peroxides.
Claim 40
Dependent Claim
49 words
A process according to claim 25, further comprising the step of oxidizing the resultant 7-X"-camptothecin derivative wherein X" is an alkyl group with an oxidizing agent selected from the group consisting of chromium trioxide, alkali metal dichromates and permanganates to a 7-X"'-camptothecin derivative wherein X"' is a carboxy group.
Claim 41
Dependent Claim
30 words
A process according to claim 26, further comprising the step of esterifying the 7-carboxy group with a lower alkanol to form a 7-X"'-camptothecin wherein X"' is a lower alkoxycarbonyl group.
Claim 42
Dependent Claim
14 words
A process according to claim 25, wherein the transition metal salt is silver nitrate.
Claim 43
Dependent Claim
14 words
A process according to claim 25, wherein the transition metal salt is ferrous sulfate.
Claim 44
Dependent Claim
12 words
A process according to claim 25, wherein the peroxide is ammonium persulfate.
Claim 45
Dependent Claim
12 words
A process according to claim 25, wherein the peroxide is hydrogen peroxide.
Claim 46
Dependent Claim
24 words
A process according to claim 25, wherein the organic compound is used in a large excess in molar ratio with respect to the camptothecin.
Claim 47
Dependent Claim
25 words
A process according to claim 32, wherein the organic compound is used in an amount of about 20 molar proportion with respect to the camptothecin.
Claim 48
Dependent Claim
32 words
A process according to claim 25, wherein the transition metal salt and the peroxide are used respectively in an amount of about 5 to 8 molar excess with respect to the camptothecin.
Claim 49
Dependent Claim
12 words
A process according to claim 25, wherein the peroxide is tert-butyl hydroperoxide.
Claim 50
Dependent Claim
138 words
A process for the preparation of a camptothecin derivative of the formula: ##STR13## wherein Y' is OH or the group OR 3 where R 3 is a lower alkyl group, a lower alkylcarbonyl group, benzoyl or a phenylalkyl group having 1 to 3 carbon atoms in the alkylene portion thereof, and Z is H or acetyl, or a water-soluble alkali metal salt thereof, which comprises treating camptothecin with sulfuric acid and a persulfate selected from the group consisting of ammonium persulfate, alkali metal persulfates, Caro's acid and alkali metal salts thereof in an aqueous medium containing a transition metal ion supplied in the medium from a transition metal salt selected from the group consisting of silver, iron (II), copper, cobalt, nickel, lead, mercury, cadmium, thallium and zinc salts in the form of halides, carbonates, nitrates, sulfates and acetates.
Claim 51
Dependent Claim
138 words
A process for the preparation of a camptothecin derivative of the formula: ##STR13## wherein Y' is OH or the group OR 3 where R 3 is a lower alkyl group, a lower alkylcarbonyl group, benzoyl or a phenylalkyl group having 1 to 3 carbon atoms in the alkylene portion thereof, and Z is H or acetyl, or a water-soluble alkali metal salt thereof, which comprises treating camptothecin with sulfuric acid and a persulfate selected from the group consisting of ammonium persulfate, alkali metal persulfates, Caro's acid and alkali metal salts thereof in an aqueous medium containing a transition metal ion supplied in the medium from a transition metal salt selected from the group consisting of silver, iron (II), copper, cobalt, nickel, lead, mercury, cadmium, thallium and zinc salts in the form of halides, carbonates, nitrates, sulfates and acetates.
Claim 52
Dependent Claim
95 words
A process according to claim 36, further comprising the step of treating the resultant 5-hydroxycamptothecin with a compound of the general formula: R.sup.3 --OH wherein R 3 has the same meaning as defined above, to convert the 5-hydroxy group into a 5-R 3' O group where R 3' is a lower alkyl group, or into a 5-R 3" O group where R 3" is a lower alkylcarbonyl group, a benzoyl group or a phenylalkylcarbonyl group having 1 to 3 carbon atoms in the alkylene portion thereof, with or without simultaneous acetylation of the 20-hydroxy group.
Claim 53
Dependent Claim
14 words
A process according to claim 36 wherein the transition metal salt is silver nitrate.
Claim 54
Dependent Claim
14 words
A process according to claim 36, wherein the transition metal salt is ferrous sulfate.
Claim 55
Dependent Claim
26 words
A process according to claim 36, wherein the persulfate is used in an amount within the range of 5-30 molar proportion with respect to the camptothecin.
References Cited (Backward Citations)
US3894029A
Cited
US4031098A
Cited
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| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
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