Patent US3406378A successfully refreshed from Google Patents.
Patent EP0056692A1 successfully refreshed from Google Patents.
EP0056692A1
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EP
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7-Substituted camptothecin derivatives and process for their preparation
Assignee: Yakult Honsha Co Ltd
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Filing: 1982-01-08
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Granted: —
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Expires: 2002-01-08
Abstract
Abstract 7-substituted camptothecin derivatives of the general formula wherein R represents-CHO,-CH 2 OR',-CH(OR') 2 or-CH=N-X where R' is a lower alkyl group having from 1 to 6 carbon atoms or a phenylalkyl group having from 1 to 3 carbon atoms in the alkylene moiety thereof, and X is a hydroxyl group or -NR 1 R 2 where R 1 and R are the same or different and each represent hydrogen atom or a lower alkyl group having from 1 to 6 carbon atoms, or when R' is hydrogen, R 2 may be a lower alkyl group having from 1 to 6 carbon atoms, a substituted or unsubstituted aryl group, a carbamoyl group, an acyl group, an aminoalkyl group or an amidino group, or when R' is a lower alkyl group, R 2 may be an aminoalkyl group, or R 1 and R 2 may be combined together with the nitrogen atom to which they are attached to form a heterocyclic group which may be interrupted by one or two nitrogen, oxygen and/or sulfur atoms, and the quaternary salts thereof.
Inventors
- 👤 Tadashi Miyasaka
- 👤 Masahiko Mutai
- 👤 Seigo Sawada
- 👤 Kenichiro Nokata
Bibliographic Details
Application Number
—
Jurisdiction
EP
Data Source
google_patents
Last Synchronized
2026-10-27 10:56
CPC Classifications
C; C07; C07D; C07D491/00; C07D491/22
Claims Analysis
Total Claims: 55
Claim 1
Independent Claim
183 words
7-substituted camptothecin derivatives of the general formula: wherein R represents -CHO, -CH 2 OR', -CH(OR') 2 or -CH=N-X where R' is a lower alkyl group having from 1 to 6 carbon atoms or a phenylalkyl group having from 1 to 3 carbon atoms in the alkylene moiety thereof, and X is a hydroxyl group or -NR 1 R 2 where Rand R 2 are the same or different and each represent hydrogen atom or a lower alkyl group having from 1 to 6 carbon atoms, or when R 1 is hydrogen, R 2 may be a lower alkyl group having from 1 to 6 carbon atoms, a substituted or unsubstituted aryl group, a carbamoyl group, an acyl group, an aminoalkyl group or an amidino group, or when R 1 is a lower alkyl group, R 2 may be an aminoalkyl group, or R 1 and R 2 may be combined together with the nitrogen atom to which they are attached to form a heterocyclic group which may be interrupted by one or two nitrogen, oxygen and/or sulfur atoms, and the quaternary salts thereof.
Claim 2
Dependent Claim
183 words
7-substituted camptothecin derivatives of the general formula: wherein R represents -CHO, -CH 2 OR', -CH(OR') 2 or -CH=N-X where R' is a lower alkyl group having from 1 to 6 carbon atoms or a phenylalkyl group having from 1 to 3 carbon atoms in the alkylene moiety thereof, and X is a hydroxyl group or -NR 1 R 2 where Rand R 2 are the same or different and each represent hydrogen atom or a lower alkyl group having from 1 to 6 carbon atoms, or when R 1 is hydrogen, R 2 may be a lower alkyl group having from 1 to 6 carbon atoms, a substituted or unsubstituted aryl group, a carbamoyl group, an acyl group, an aminoalkyl group or an amidino group, or when R 1 is a lower alkyl group, R 2 may be an aminoalkyl group, or R 1 and R 2 may be combined together with the nitrogen atom to which they are attached to form a heterocyclic group which may be interrupted by one or two nitrogen, oxygen and/or sulfur atoms, and the quaternary salts thereof.
Claim 3
Dependent Claim
33 words
7-substituted camptothecin derivatives as claimed. in Claim 1 wherein R represents the group -CH 2 OR' where R'' is a straight or branched chain alkyl group having from 1 to 6 carbon atoms.
Claim 4
Dependent Claim
32 words
7-substituted camptothecin derivatives as claimed in Claim 1 wherein R represents the group -CH(OR') 2 where R' is a straight or branched chain alkyl group having from 1 to 6 carbon atoms.
Claim 5
Dependent Claim
33 words
7-substituted camptothecin derivatives as claimed in Claim 1 wherein R represents the group -CH 2 OR' where R' is a phenylalkyl group having from 1 to 3 carbon atoms in the alkylene moiety.
Claim 6
Dependent Claim
37 words
7-substituted camptothecin derivatives as claimed in Claim 1 wherein R represents the group -CH(OR') 2 where R' is a phenylalkyl group having from 1 to 3 carbon atoms in the alkylene moiety which is linear or branched.
Claim 7
Dependent Claim
1 words
Camptothecin-7-aldehyde.
Claim 8
Dependent Claim
1 words
Camptothecin-7-aldehyde.
Claim 9
Dependent Claim
2 words
Camptothecin-7-aldehyde oxime.
Claim 10
Dependent Claim
2 words
Camptothecin-7-aldehyde oxime.
Claim 11
Dependent Claim
2 words
Camptothecin-7-aldehyde hydrazone.
Claim 12
Dependent Claim
2 words
Camptothecin-7-aldehyde hydrazone.
Claim 13
Dependent Claim
46 words
7-substituted camptothecin derivatives as claimed in Claim 1 wherein R represents the group -CH=N-X and X is the group -NR 1 R 2 where R 1 is hydrogen and R 2 is a straight or branched chain alkyl group having from 1 to 6 carbon atoms.
Claim 14
Dependent Claim
53 words
7-substituted camptothecin derivatives as claimed in Claim 1 wherein R represents the group -CH=N-X and X is the group -NR 1 R 2 where R 1 is hydrogen and R 2 is an unsubstituted phenyl group or a phenyl group substituted by one or two nitro groups in the o- and/or p-positions thereof.
Claim 15
Dependent Claim
2 words
Camptothecin-7-aldehyde p-toluenesulfonylhydrazone.
Claim 16
Dependent Claim
2 words
Camptothecin-7-aldehyde p-toluenesulfonylhydrazone.
Claim 17
Dependent Claim
5 words
Camptothecin-7-CH=N-N=C(NH 2 ) 2 .
Claim 18
Dependent Claim
5 words
Camptothecin-7-CH=N-N=C(NH 2 ) 2 .
Claim 19
Dependent Claim
7 words
Camptothecin-7-CH=N-NHCOCH 2 N(CH 3 ) 2 ·HCl
Claim 20
Dependent Claim
7 words
Camptothecin-7-CH=N-NHCOCH 2 N(CH 3 ) 2 ·HCl
Claim 21
Dependent Claim
7 words
Camptothecin-7-CH=N-NHCOCH 2 N(CH 3 ) 3 ·Cl
Claim 22
Dependent Claim
7 words
Camptothecin-7-CH=N-NHCOCH 2 N(CH 3 ) 3 ·Cl
Claim 23
Dependent Claim
2 words
Camptothecin-7-aldehyde semicarbazone.
Claim 24
Dependent Claim
2 words
Camptothecin-7-aldehyde semicarbazone.
Claim 25
Dependent Claim
2 words
Camptothecin-7-aldehyde phenylsemicarbazone.
Claim 26
Dependent Claim
2 words
Camptothecin-7-aldehyde phenylsemicarbazone.
Claim 27
Dependent Claim
2 words
Camptothecin-7-aldehyde thiosemicarbazone.
Claim 28
Dependent Claim
2 words
Camptothecin-7-aldehyde thiosemicarbazone.
Claim 29
Dependent Claim
35 words
A process for the preparation of camptothecin-7-aldehyde from 7-hydroxymethylcamptothecin, which comprises treating 7-hydroxymethylcamptothecin with a cationic reagent which is an inorganic acid, organic acid, a Lewis acid, an organic acid halide or a halogenating agent.
Claim 30
Dependent Claim
35 words
A process for the preparation of camptothecin-7-aldehyde from 7-hydroxymethylcamptothecin, which comprises treating 7-hydroxymethylcamptothecin with a cationic reagent which is an inorganic acid, organic acid, a Lewis acid, an organic acid halide or a halogenating agent.
Claim 31
Dependent Claim
23 words
A process as claimed in Claim 23 wherein the inorganic acid is sulfuric acid, hydrochloric acid, hydrobromic acid, perchloric acid or hydroiodic acid.
Claim 32
Dependent Claim
29 words
A process as claimed in Claim 23 wherein the organic acid is acetic acid, propionic acid, benzoic acid, chloroacetic acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid or ethanesulfonic acid.
Claim 33
Dependent Claim
22 words
A process as claimed in Claim 23 hwerein the Lewis acid is boron trifluoride etherate, aluminium chloride, ferric chloride or stannic chloride.
Claim 34
Dependent Claim
18 words
A process as claimed in Claim 23 wherein the organic acid halide is p-toluenesulfonyl chloride or phenylacetyl chloride.
Claim 35
Dependent Claim
21 words
A process as claimed in Claim 23 wherein the halogenating agent is phosphorus oxychloride, phosphorus trichloride, thionyl chloride or triphenylphosphi.te-carbon tetrachloride.
Claim 36
Dependent Claim
29 words
A process as claimed in Claim 23 or Claim 24 wherein the inorganic acid is used as a 20-50% aqueous solution and the reaction is carried out under reflux.
Claim 37
Dependent Claim
20 words
A process as claimed in Claim 23 or Claim 25 wherein the organic acid is used in a polar solvent.
Claim 38
Dependent Claim
42 words
A process as claimed in Claim 23 or Claim 26 wherein the Lewis acid is used in a 5 to 10 molar amount to the 7-hydroxymethylcamptothecin and the reaction is carried out at a temperature of 90-100 C in an aprotic solvent.
Claim 39
Dependent Claim
43 words
A process as claimed in Claim 23 or Claim 27 wherein the organic acid halide is used in a 5 to 10 molar amount to the 7-hydroxymethylcamptothecin and the reaction is carried at a temperature of 90 to 100°C in a polar solvent.
Claim 40
Dependent Claim
41 words
A process as claimed in Claim 23 or Claim 28 wherein the halogenating agent is used in a 5 to 10 molar amount to the 7-hydroxymethylcamptothecin and the reaction is carried out at a temperature of about 100°C in a solvent.
Claim 41
Dependent Claim
193 words
A process for the preparation of new 7-substituted camptothecin derivatives of the general formula: wherein X is a hydroxyl group or the group -NR 1 R 2 where R and R 2 are the same or different and each represent a hydrogen atom or a lower alkyl group having from 1 to 6 carbon atoms, or when R 1 is a hydrogen atom, R 2 may be a lower alkyl group having from 1 to 6 carbon atoms, a substituted or unsubstituted aryl group, a carbamoyl group, an acyl group, an aminoalkyl group or an amidino group, or when R1 is a lower alkyl group, R 2 may be an aminoalkyl group, or R 1 and-R 2 may be combined together with the nitrogen atom to which they are attached to form a heterocyclic group which may be interrupted by one or two nitrogen, oxygen and/or sulfur atoms, and the quaternary salts thereof, which process comprises reacting camptothecin-7-aldehyde or an acetal thereof with an active amino compound of the general formula: wherein X is as defined above, in a manner known per se and optionally treating the resultant product with a quaternizing agent.
Claim 42
Dependent Claim
193 words
A process for the preparation of new 7-substituted camptothecin derivatives of the general formula: wherein X is a hydroxyl group or the group -NR 1 R 2 where R and R 2 are the same or different and each represent a hydrogen atom or a lower alkyl group having from 1 to 6 carbon atoms, or when R 1 is a hydrogen atom, R 2 may be a lower alkyl group having from 1 to 6 carbon atoms, a substituted or unsubstituted aryl group, a carbamoyl group, an acyl group, an aminoalkyl group or an amidino group, or when R1 is a lower alkyl group, R 2 may be an aminoalkyl group, or R 1 and-R 2 may be combined together with the nitrogen atom to which they are attached to form a heterocyclic group which may be interrupted by one or two nitrogen, oxygen and/or sulfur atoms, and the quaternary salts thereof, which process comprises reacting camptothecin-7-aldehyde or an acetal thereof with an active amino compound of the general formula: wherein X is as defined above, in a manner known per se and optionally treating the resultant product with a quaternizing agent.
Claim 43
Dependent Claim
46 words
A process as calimed in Claim 34 wherein the active amino compound of the general formula (II) is hydroxylamine, hydrazine, a lower alkylhydrazine, phenyl hydrazine which may be ring-substituted with one or two nitro groups in the o- and/or p-positions, semicarbazide, Girard reagents, thiosemicarbazide or N-aminohydantoin.
Claim 44
Dependent Claim
20 words
A process as claimed in Claim 34 wherein the quaternizing agent is a lower alkyl halide or a strong acid.
Claim 45
Dependent Claim
72 words
A process for the preparation of new 7-alkoxymethyl-and 7-dialkoxymethylcamptothecin derivatives of the general formulae : wherein R' is a lower alkyl group having from 1 to 6 carbon atoms or a phenyl-alkyl group having from 1 to 3 carbon atoms in the alkylene moiety thereof, which process comprises treating 7-hydroxymethylcamptothecin with an acid in the presence of a lower alkanol or phenylalkanol of the general formula: wherein R' is as defined above.
Claim 46
Dependent Claim
72 words
A process for the preparation of new 7-alkoxymethyl-and 7-dialkoxymethylcamptothecin derivatives of the general formulae : wherein R' is a lower alkyl group having from 1 to 6 carbon atoms or a phenyl-alkyl group having from 1 to 3 carbon atoms in the alkylene moiety thereof, which process comprises treating 7-hydroxymethylcamptothecin with an acid in the presence of a lower alkanol or phenylalkanol of the general formula: wherein R' is as defined above.
Claim 47
Dependent Claim
27 words
A process as claimed in Claim 37 wherein the acid is a mineral acid, a Lewis acid, a strong organic carboxylic acid or an organic sulfonic acid.
Claim 48
Dependent Claim
21 words
A process as claimed in Claim 38 wherein the mineral acid is sulfuric acid, hydrochloric acid, hydrobromic acid or perchloric acid.
Claim 49
Dependent Claim
21 words
A process as clained in Claim 38 wherein the Lewis acid is boron trifluoride, aluminium chloride, ferric chloride or stannic chloride.
Claim 50
Dependent Claim
19 words
A process as calimed in Claim 38 wherein the strong organic carboxylic acid is trifluoroacetic acid or trichloroacetic acid.
Claim 51
Dependent Claim
22 words
A process as claimed in Claim 38 wherein the organic sulfonic acid is benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid or ethanesulfonic acid.
Claim 52
Dependent Claim
32 words
A process as claimed in any one of Claims 37 to 42 wherein the lower alkanol is methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, n-amyl alcohol, isoamyl alcohol, tert-amyl alcohol, n-hexanol or 2-ethylbutanol.
Claim 53
Dependent Claim
40 words
A process as calimed in any one of Claims 37 to 43 wherein the 7-hydroxymethylcamptothecin is maintained in the lower alkanol or phenylalkanol as solvent in the presence of the acid at a temperature from room temperature to reflux temperature.
Claim 54
Dependent Claim
43 words
A process as claimed in any one of Claims 37 to 44 wherein the acid is used in a catalytic amount or in an amount of several molar equivalents to the 71 hydroxymethylcamptothecin to obtain 7-dialkoxymethyli camptothecin to obtain 7-alkoxymethylcamptothecins exclusively or preferentially.
Claim 55
Dependent Claim
32 words
A process as calimed in any one of claims 37 to 44 wherein the acid is used in a large exvess amount relative to the 7-hydroxymethylcamptothecin to obtain 7-aldoxymethylcamptothecins exclusively or preferentially.
References Cited (Backward Citations)
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