Patent EP0617034A1 successfully refreshed from Google Patents.
EP0617034A1
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2-Debenzoyl-2-acyl taxol derivatives and methods for making same
Assignee: Virginia Tech Intellectual Properties Inc
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Filing: 1994-03-09
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Granted: —
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Expires: 2014-03-09
Abstract
Abstract The present invention relates to 2-debenzoyl-2-acyl taxol derivatives, analogues thereof and methods for making same. Compounds of the present invention include compounds having the general formula: wherein R₁ is an alkyl or substituted alkyl; R₂ is selected from the group consisting of H and C(O)R a ; R₃ is selected from the group consisting of H, protecting groups, R b , and C(O)R b ; R₄ is selected from the group consisting of H and C(O)R c , and wherein R a , R b , and R c are independently selected from the group consisting of alkyls, substituted alkyls, alkenyls, alkynyls, aryls, and substituted aryls; provided that R a is other than phenyl and 3-hydroxyphenyl.
Inventors
- 👤 David G.K. Kingston
- 👤 Ashok Gopal Chaudhary
- 👤 Milind Moreshwar Gharpure
- 👤 John Matthew Rimoldi
- 👤 Leslie A. A. Gunatilaka
Bibliographic Details
Application Number
—
Jurisdiction
EP
Data Source
google_patents
Last Synchronized
2026-11-08 07:16
CPC Classifications
C; C07; C07D; C07D405/00; C07D405/02; C07D405/12; A; A61; A61P; A61P35/00; C07D305/00; C07D305/14; C07D409/00; C07D409/02; C07D409/12; C07F; C07F7/00; C07F7/02; C07F7/08; C07F7/18; C07F7/1804; Y; Y02; Y02P; Y02P20/00; Y02P20/50; Y02P20/55
Claims Analysis
Total Claims: 78
Claim 1
Independent Claim
53 words
Analogues of taxol having biological activity and comprising a substituted benzoyloxy group at the C-2 position of the B-ring of the tetracyclic taxane nucleus provided that, when the para-substituent, the ortho-substituents and one meta-substituent is H, the other meta-substituent is other than a substituent selected from the group consisting of H and OH.
Claim 2
Dependent Claim
23 words
The analogues of claim 1, wherein said substituents are independently selected from the group consisting of hydrogen, halogens, alkoxys, diatomics, and linear triatomics.
Claim 3
Dependent Claim
12 words
The analogues of claim 2, wherein neither of said meta-substituents are H.
Claim 4
Dependent Claim
39 words
The analogues of claim 2, wherein one of said substituents on the meta positions of the C-2 benzoyloxy group is H, and the other meta-substituent is selected from the group consisting of nitro, fluoro, methoxy, chloro, cyano, and azido.
Claim 5
Dependent Claim
40 words
The analogues of claim 4, wherein the ortho substituents and the para substituents are H and wherein one of said substituents on the meta positions of the C-2 benzoyloxy group is H, and the other meta-substituent comprises an azido moiety.
Claim 6
Dependent Claim
75 words
Compounds having antineoplastic activity and having the general formula: wherein R₁ is a substituted alkyl; R₅ is selected from the group consisting of H and acyls; R₂ is selected from the group consisting of H, OH, oxyprotecting groups and acyls; R₃ is selected from the group consisting of H, OH, and acyls, wherein said acyls are the same or different; R₄ is H or OH; and provided that R₅ is other than C(O)C₆H₅ and C(O)-3-hydroxyphenyl.
Claim 7
Dependent Claim
20 words
The compounds of claim 6, wherein R₄ is OH and R₂ is OH or an oxyprotecting group or an acyl.
Claim 8
Dependent Claim
61 words
The compounds of claim 7, wherein R₁ has the general formula: wherein Ar is an aryl or substituted aryl; Z is selected from the group consisting of substituted alkyls, alkenyls, alkoxys, aryls and substituted aryls; X is H or a protecting group; and Y is selected from the group consisting of H, protecting groups, alkyloyls, substituted alkyloyls, substituted aryloyls, and aryloyls.
Claim 9
Dependent Claim
24 words
The compounds of claim 8, wherein X is H and R₅ is C(O)R a and R a is an alkyl or a substituted alkyl.
Claim 10
Dependent Claim
13 words
The compounds of claim 8, wherein X is H and R₅ is H.
Claim 11
Dependent Claim
18 words
The compounds of claim 8, wherein Y and X are C(O)OC(CH₃)₃ and wherein Z and Ar are C₆H₅.
Claim 12
Dependent Claim
32 words
The compounds of claim 8, wherein X is H, R₃ is OC(O)CH₃, Ar is phenyl or substituted phenyl, and Z is selected from the group consisting of phenyl, substituted phenyl and OC(CH₃)₃.
Claim 13
Dependent Claim
18 words
The compound of claim 12, wherein R₂ is selected from the group consisting of OH and protecting groups.
Claim 14
Dependent Claim
44 words
Compounds having the formula: wherein R is selected from the group consisting of H and C(O)R a wherein R a is selected from the group consisting of alkyls, substituted alkyls, aryls, and substituted aryls; provided that R a is other than phenyl and 3-hydroxyphenyl.
Claim 15
Dependent Claim
50 words
Compounds having the general formula: wherein Z is C(O)OC(CH₃)₃; R₁ is C(O)OC(CH₃)₃; R₂ is selected from the group consisting of H and C(O)R a , wherein R a is selected from the group consisting of alkyls, substituted alkyls, aryls, and substituted aryls; and R₃ is a protecting group or hydrogen.
Claim 16
Dependent Claim
23 words
The compounds of claim 15, wherein R₂ is C(O)C₆H₅ and wherein R₃ is selected from the group consisting of H, Si(C₂H₅)₃, and C(O)OC(CH₃)₃.
Claim 17
Dependent Claim
57 words
The compounds of claim 6 having the general formula: wherein T, U, V, W, and X are any substituents provided that T, U, V, W, and X are not all H and when T, U, V, and W are H, X is not OH, and when T, U, V, and X are H, W is not OH.
Claim 18
Dependent Claim
58 words
The compound of claim 17, wherein R₄ is OH and R₁ has the general formula: wherein Ar is an aryl or substituted aryl; Z is selected from the group consisting of substituted alkyls, alkenyls, alkoxys, aryls and substituted aryls; and Y is selected from the group consisting of H, protecting groups, alkyloyls, substituted alkyloyls, substituted aryloyls, and aryloyls.
Claim 19
Dependent Claim
36 words
The compounds of claim 18, wherein Ar is phenyl or substituted phenyl and further wherein T, U, W, V, and X are independently selected from the group consisting of hydrogen, halogens, alkoxys, diatomics, and linear triatomics.
Claim 20
Dependent Claim
23 words
The compounds of claim 19, wherein R₃ is OC(O)CH₃ and wherein R₂ is selected from the group consisting of OH, triethylsilyloxy, and t-butoxycarbonyloxy.
Claim 21
Dependent Claim
17 words
The compounds of claim 20, wherein X is N₃ and T, U, W, and V are H.
Claim 22
Dependent Claim
19 words
The compounds of claim 20, wherein T, U, and W are H, V is Cl, and X is Cl.
Claim 23
Dependent Claim
9 words
The compounds of claim 20, wherein X is N₃.
Claim 24
Dependent Claim
11 words
The compounds of claim 20, wherein X comprises an azido moiety.
Claim 25
Dependent Claim
21 words
The compounds of claim 20, wherein Z is selected from the group consisting of C₆H₅ and OC(CH)₃, and Ar is C₆H₅.
Claim 26
Dependent Claim
29 words
The compounds of claim 25, wherein T, U, and V are H and W and X are independently selected from the group consisting of chloro, azido, fluoro, and cyano.
Claim 27
Dependent Claim
53 words
Compounds having the general formula: wherein T, U, V, W, and X are any substituents provided that T, U, V, W, and X are not all H and when T, U, V, and W are H, X is not OH, and when T, U, V, and X are H, W is not OH.
Claim 28
Dependent Claim
27 words
The compounds of claim 27, wherein T, U, W, V, and X are independently selected from the group consisting of hydrogen, halogens, alkoxys, diatomics, and linear triatomics.
Claim 29
Dependent Claim
19 words
The compounds of claim 28, wherein V, W, and X are alkoxy groups and T and U are hydrogen.
Claim 30
Dependent Claim
17 words
The compound of claim 28, wherein T, U, V and W are H and X is N₃.
Claim 31
Dependent Claim
14 words
The compound of claim 28, wherein T, U, W, V, and X are fluorine.
Claim 32
Dependent Claim
18 words
The compounds of claim 28, wherein T, U, and V are H and W and X are halogens.
Claim 33
Dependent Claim
27 words
The compounds of claim 28, wherein T, U, V and W are H and X is selected from the group consisting of NO₂, Cl, F, and CN.
Claim 34
Dependent Claim
19 words
The compound of claim 28, wherein T, U, and W are H, V is Cl, and X is Cl.
Claim 35
Dependent Claim
19 words
The compound of claim 28, wherein W, V, and X are all methoxy and T and U are hydrogen.
Claim 36
Dependent Claim
18 words
The compound of claim 28, wherein T and U are hydrogen and W, V, and X are fluorine.
Claim 37
Dependent Claim
5 words
The compound having the formula:
Claim 38
Dependent Claim
27 words
Analogues of taxol in which the substituent at the C-2 position on the B-ring of the taxane tetracyclic nucleus is QC(O)O wherein Q is a heterocyclic compound.
Claim 39
Dependent Claim
9 words
The compounds of claim 38, wherein Q is thiophene.
Claim 40
Dependent Claim
44 words
Analogues of taxol in which the benzoyl group of taxol has been replaced by the acyl, C(O)R a , wherein R a is selected from the group consisting alkyl, substituted alkyl, aryl, and substituted aryl; provided that R a is not phenyl or 3-hydroxyphenyl.
Claim 41
Dependent Claim
12 words
The analogues of claim 40, wherein R a is a substituted alkyl.
Claim 42
Dependent Claim
13 words
The analogues of claim 41, wherein said acyl has the formula shown below:
Claim 43
Dependent Claim
18 words
A pharmaceutical composition, comprising an antineoplastically effective amount of at least one of the compounds of claim 1.
Claim 44
Dependent Claim
19 words
Use of the taxol analogues of claim 1 in formulating pharmaceutical preparations for administration to patients suffering from cancer.
Claim 45
Dependent Claim
19 words
Use of the taxol analogues of claim 6 in formulating pharmaceutical preparations for administration to patients suffering from cancer.
Claim 46
Dependent Claim
116 words
Use of taxol analogues having the general formula: in formulating pharmaceutical preparations for administration to patients suffering from cancer; wherein R₁ is a substituted alkyl, R₂ is selected from the group consisting of H, OH, alkoxy groups, oxyprotecting groups and acyls, and R₃ is selected from the group consisting of H, OH, and acyls, wherein said acyls are the same or different and R₄ is H or OH; wherein T, U, V, W, and X are any substituents provided that T, U, V, W, and X are not all H and when T, U, V, and W are H, X is not OH, and when T, U, V, and X are H, W is not OH.
Claim 47
Dependent Claim
70 words
The use of claim 46, wherein R₁ has the general formula: wherein Ar is an aryl; Z is selected from the group consisting of alkyls, alkenyls, alkoxys, and aryls; and Y is selected from the group consisting of H, alkyloyls, substituted alkyloyls, substituted aryloyls, and aryloyls and further, wherein R₄ is OH, R₃ is C(O)CH₃, R₂ is H, and Z is selected from the group consisting of C₆H₅ and OC(CH₃)₃.
Claim 48
Dependent Claim
26 words
The use of claim 47, wherein T, U, V, W, and X are independently selected from the group consisting of halogens, alkoxys, diatomics, and linear triatomics.
Claim 49
Dependent Claim
19 words
Use of the taxol analogues of claim 30 in formulating pharmaceutical preparations for administration to patients suffering from cancer.
Claim 50
Dependent Claim
19 words
Use of the taxol analogues of claim 37 in formulating pharmaceutical preparations for administration to patients suffering from cancer.
Claim 51
Independent Claim
199 words
A method for making a first taxol analogue compound having a hydroxy or acyloxy substituent at the C-2 position from a second taxol analogue compound having a benzoyloxy substituent at the C-2 position, comprising a step of base catalyzed hydrolysis under phase transfer conditions wherein the benzoyloxy substituent of said second compound is replaced by a hydroxyl; wherein said first compound has the formula: wherein R₁ is a substituted alkyl, R₅ is selected from the group consisting of H and C(O)R a , R₂ is selected from the group consisting of H, OH, oxyprotecting groups and acyloxys, and R₃ is selected from the group consisting of H, OH, and acyloxys, wherein R a is selected from the group consisting of alkyls, substituted alkyls, aryls, substituted aryls, and heterocyclic compounds; wherein said acyloxys can be the same or different, and R₄ is H or OH; and said second compound has the formula: wherein R₇ is a substituted alkyl, R₆ is selected from the group consisting of H, OH, oxyprotecting groups and acyloxys, and R₃ is selected from the group consisting of H, OH, and acyloxys, wherein said acyloxys can be the same or different, and R₄ is H or OH.
Claim 52
Dependent Claim
61 words
The method of claim 51, wherein R₄ is OH and R₁ and R₇ are the same or different and have the general formula: wherein Ar is an aryl or substituted aryl; Z is selected from the group consisting of alkyls, alkenyls, alkoxys, and aryls; and Y is selected from the group consisting of H, alkyloyls, substituted alkyloyls, substituted aryloyls, and aryloyls.
Claim 53
Dependent Claim
31 words
The method of claim 52, wherein R₅ is C(O)R a , and further comprising a reaction with an acylating agent occurring subsequently to the replacement of said benzoyl moiety by H.
Claim 54
Dependent Claim
71 words
The method of claim 53, wherein R₁ and R₇ are the same, Ar is phenyl or substituted phenyl, Y is H, R₃ is OC(O)CH₃, and R₆ is OH, and further comprising a step of protecting the hydroxyl groups at the C-2' and C-7 positions prior to said step of base catalyzed hydrolysis; and further comprising a step of deprotecting said C-2' and C-7 positions following said reaction with an acylating agent.
Claim 55
Dependent Claim
66 words
The method of claim 54, wherein Ar is C₆H₅, Z is selected from the group consisting of C₆H₅ and OC(CH₃)₃, and further wherein said step of protecting the hydroxyl groups comprises reacting with a trialkylsilylhalide, and wherein said base catalyzed hydrolysis consists of reacting a 2',7-trialkylsilyl-protected derivative of said second compound in a mixture comprising aqueous sodium hydroxide, an organic solvent and a phase transfer catalyst.
Claim 56
Dependent Claim
13 words
The method of claim 55, wherein said acylating agent comprises a carboxylic acid.
Claim 57
Dependent Claim
15 words
The method of claim 56, wherein R₅ is QC(O) and Q is a heterocyclic compound.
Claim 58
Dependent Claim
40 words
The method of claim 52, wherein Ar is phenyl or substituted phenyl, and R₅ is H, and further wherein said base catalyzed hydrolysis comprises reaction in a mixture comprising aqueous sodium hydroxide, an organic solvent and a phase transfer catalyst.
Claim 59
Dependent Claim
20 words
The method of claim 53, wherein R₅ has the formula: wherein T, U, W, V, and X are any substituents.
Claim 60
Dependent Claim
27 words
The method of claim 59, wherein T, U, W, V, and X are independently selected from the group consisting of hydrogen, halogens, alkoxys, diatomics, and linear triatomics.
Claim 61
Dependent Claim
35 words
The method of claim 60, wherein R₃ is C(O)CH₃, Ar is C₆H₅, Z is selected from the group consisting of C₆H₅ and OC(CH₃)₃, and Y is selected from the group consisting of H and triethylsilyl.
Claim 62
Dependent Claim
53 words
The method of claim 61, wherein Y in said second compound is triethylsilyl and R₆ is triethylsilyloxy and further wherein said second compound is debenzoylated via reaction in a mixture comprising aqueous sodium hydroxide, a phase transfer catalyst, and an organic solvent, to yield a compound having a hydroxyl at the C-2 position.
Claim 63
Dependent Claim
32 words
The method of claim 62, wherein T, U, W and V are H, and further comprising a step wherein said compound having a hydroxyl at the C-2 position is reacted with meta-C₆H₄X-COOH.
Claim 64
Dependent Claim
9 words
The method of claim 63 where X is N₃.
Claim 65
Independent Claim
46 words
A method of debenzoylating the C-2 position of taxol or a taxol analogue bearing a benzoyloxy substituent at the C-2 position comprising the step of hydrolyzing said taxol or taxol analogue in a mixture comprising aqueous sodium hydroxide, an organic solvent and a phase transfer catalyst.
Claim 66
Dependent Claim
23 words
A method for reacylating the product of the method of claim 65 comprising a step of reacting said product with an acylating agent.
Claim 67
Independent Claim
80 words
A method of acylating the C-2 position of taxol or a taxol analogue bearing a benzoyloxy substituent at said C-2 position, wherein said taxol or taxol analogue comprises C-2' and C-7 hydroxyl substituents; and further comprising a step of protecting said hydroxyl substituents with trialkylsilyl groups, replacing said benzoyloxy substituent by a hydroxyl substituent via base catalyzed hydrolysis, and subsequent to said step of protecting, a step of reacylating to form an acyl at said C-2 position other than benzoyl.
Claim 68
Dependent Claim
23 words
The method of claim 67 further comprising deprotecting said hydroxyl groups at said C-2' and C-7 positions by removal of said trialkylsilyl groups.
Claim 69
Independent Claim
60 words
A method for making a taxol analogue having a hydroxy or acyloxy substituent, other than benzoyloxy and 3-hydroxybenzoyloxy, at the C-2 position of the B-ring of the taxane tetracyclic nucleus comprising the step of removing a benzoyl moiety from said C-2 position of a second compound having the tetracylic taxane nucleus and having a benzoyloxy group at said C-2 position.
Claim 70
Dependent Claim
38 words
The method of claim 69, wherein said taxol analogue has the formula: and said second compound has the formula: and further wherein said second compound is converted to said taxol analogue compound by the addition of lithium hydroxide.
Claim 71
Dependent Claim
114 words
The method of claim 69, wherein said second compound is taxol, comprising: a) reacting taxol with di-t-butyl dicarbonate in the presence of an activating agent; (b) reacting the product of step a) with a trialkylsilylhalide; c) reacting the product of step b) with di-t-butyl dicarbonate in the presence of an activating agent; d) reacting the product of step c) with lithium hydroxide to remove the benzoyl group from said C-2 position; and e) reacting the product of step d) with an acylating agent to yield a taxol analogue having the formula: wherein R₃ is a trialkylsilyl protecting group and R is selected from the group consisting of alkyl, substituted alkyl, aryl, and substituted aryl.
Claim 72
Dependent Claim
25 words
The method of claim 71, wherein said acylating agent comprises a reagent selected from the group consisting of acid halides, β-lactams, anhydrides, and carboxylic acids.
Claim 73
Dependent Claim
14 words
The method of claim 72, wherein said acylating agent further comprises an activating agent.
Claim 74
Dependent Claim
16 words
The method of claim 73, wherein said trialkylsilylhalide is triethylsilylchloride and said activating agent is dimethylaminopyridine.
Claim 75
Dependent Claim
65 words
The method of claim 71, wherein said second compound has the formula: and wherein R₃ is a trialkylsilyl and wherein said taxol analogue has the formula: wherein R is selected from the group consisting of alkyl, substituted alkyl, aryl, and substituted aryl; and wherein said method further comprises the step of deprotection; said deprotection step occurring subsequent to said step of adding an acylating agent.
Claim 76
Dependent Claim
15 words
The method of claim 75, wherein said deprotection step comprises the addition of formic acid.
Claim 77
Dependent Claim
69 words
The method of claim 69 wherein said second compound has C-2' and C-7 positions having hydroxyl substituents and has a C-3' position having an amide substituent, and comprising: a) protecting said hydroxyl and amide substituents, and b) removing said benzoyl at said C-2 position of the compound resulting from step a) by reacting with lithium hydroxide; and c) reacting the compound resulting from step b) with an acylating agent.
Claim 78
Dependent Claim
23 words
The method of claim 77 further comprising removing protecting groups from said hydroxyl and amide substituents of the compound resulting from step c).
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