EP0473326A1
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Water soluble derivatives of taxol
Assignee: Virginia Tech Intellectual Properties Inc
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Filing: 1991-08-13
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Granted: —
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Expires: 2011-08-13
Abstract
Abstract Sulfonated 2′-acryloyltaxol and sulfonated 2′-O-acyl acid taxol derivatives are synthesized which have improved water solubility and stability while maintaining bio-activity. In particular, 2′-[(3-sulfo-1-oxopropyl)oxy] taxol sodium salt is synthesized by reacting taxol with acrylic acid, and subsequently reacting the 2′-acryloyltaxol with bisulfite in a Michael reaction. 2′-{[(4-((2-sulfoethyl)amino)-1,4-dioxobutyl)oxy}taxol sodium salt and 2′-{[4-((3-sulfopropyl)amino)-1,4-dioxobutyl]oxy} taxol sodium salt are synthesized by reacting 2′-succinyltaxol with the tetrabutylammonium salts of taurine and 3-amino-propyl sulfonic acid, respectively, and subsequently exchanging the ammonium with sodium. Glycol derivatives of 2′-O-acyl acid taxols with improved water solubility are synthesized by reaction of a glycol with 2′-O-acyl acid taxol.
Inventors
- 👤 David G.I. Davidson Hall Chem.Dep. Kingston
- 👤 Zhi-Yang Davidson Hall Chem.Dep. Zhao
Bibliographic Details
Application Number
—
Jurisdiction
EP
Data Source
google_patents
Last Synchronized
2026-11-07 16:21
CPC Classifications
C; C07; C07D; C07D305/00; C07D305/14; A; A61; A61P; A61P35/00
Claims Analysis
Total Claims: 17
Claim 1
Independent Claim
21 words
Derivatives of taxol having the following general structure: wherein: X is selected from the group consisting of H, alkyls, and aryls.
Claim 2
Dependent Claim
10 words
A compound according to claim 1, wherein: X is H
Claim 3
Dependent Claim
38 words
Water soluble derivatives of taxol having the following general structure: wherein: X is selected from the group consisting of H, alkyls, and aryls; and M is selected from the group consisting of H, alkaline metals, and ammonio groups.
Claim 4
Dependent Claim
14 words
A compound according to claim 3, wherein: X is H, and M is Na.
Claim 5
Dependent Claim
73 words
Water soluble derivatives of taxol having the following structure: wherein: R is selected from the group consisting of: -(CH y ) n -CO-NH-(CH₂) z SO₂O-M, and -(CH y ) n -CO-O-(CH₂) z -OH; wherein: M is selected from the group consisting of H, alkaline metals, and ammonio groups, n is 1 to 3, y is 1 to 2, provided y is not 1 when n is 1, and z is 2 to 3.
Claim 6
Dependent Claim
16 words
Compounds according to claim 5, wherein: Y is 2, n is 2, and z is 2.
Claim 7
Dependent Claim
16 words
Compounds according to claim 5, wherein: Y is 2, n is 2, and z is 3.
Claim 8
Dependent Claim
11 words
Compounds according to claim 5, wherein: M is a quaternary ammonium.
Claim 9
Dependent Claim
21 words
A process for producing 2′-acryloyltaxol derivatives, comprising the step of: (a) esterifying taxol with an acid of the acrylic acid family.
Claim 10
Dependent Claim
96 words
A process according to claim 9, further comprising the step of: (b) performing a Michael reaction at the β vinyl position of the 2′-acryloyl ester formed in step (a) with a nucleophile to form water soluble derivatives of taxol, wherein: said nucleophile is selected from the group consisting of bisulfite ion, and sulfite ion, and said water soluble derivatives have the following general structure: wherein: R is -CHX-CHX-SO₂O-M; and X is selected from the group consisting of H, alkyls, and aryls; and M is selected from the group consisting of H, alkaline metals and ammonio groups.
Claim 11
Dependent Claim
24 words
A process according to claim 10, wherein: said esterifying step (a) is carried out in the presence of isobutyl chloroformate as a coupling agent.
Claim 12
Dependent Claim
136 words
A process according to claim 11, wherein: step (a) comprises the steps of: (a1) dissolving triethylamine and said acrylic acid in tetrahydrofuran under argon atmosphere to form a first solution; (a2) cooling said first solution to about 0°C; (a3) combining said isobutyl chloroformate with said first solution to form a second solution, and warming said second solution to about room temperature; (a4) adding taxol to said second solution to form said 2′-acryloyl taxol derivatives; and (a5) precipitating and drying said 2′-acryloyl taxol derivatives; and wherein: step (b) comprises the steps of: (b1) dissolving said 2′-acryloyl taxol derivatives of step (a) in isopropanol to form a third solution; (b2) dissolving sodium meta-bisulfite in distilled water to form a fourth solution; and (b3) combining said third solution and said fourth solution to form said water soluble taxol derivatives.
Claim 13
Dependent Claim
77 words
A process for producing water soluble taxol derivatives, comprising the steps of: (a) reacting 2′-O-acyl acid taxol derivatives with an organic solvent soluble amino sulfonic acid salt to form 2′-O-acyl taxol derivatives having the following general structure: wherein: R is -(CH y ) n -CO-NH-(CH₂) z -SO₂O-M, wherein: M is an ammonio group, n is 1 to 3, y is 1 to 2, provided y is 2 when n is 1, and z is 2 to 3.
Claim 14
Dependent Claim
109 words
A process according to claim 13, wherein: said 2′-O-acyl acid taxol derivatives have the following general structure: wherein: R is -(CH y ) n -CO-OH, wherein: y is 1 to 2, and n is 1 to 3, provided y is 2 when n is 1, and wherein: step (a) comprises the steps of: (a1) combining compounds having the following general structure: NH₂-(CH₂) z -SO₃H with an aqueous solution of an ammonio compound to form salts having the following general structure: NH₂-(CH₂) z -SO₃-M, wherein: z is 2 to 3, and M is an ammonio compound; and (a2) reacting said 2′-O-acyl acid taxol derivatives with said salts of step (a1).
Claim 15
Dependent Claim
29 words
A process according to claim 14, further comprising the step of: (b) converting said ammonio group to a moiety selected from the group consisting of H, and alkaline metals.
Claim 16
Dependent Claim
114 words
A process for producing water soluble taxol derivatives, comprising the steps of: (a) reacting taxol with a compound having the following general structure: HOOC-(CH y ) n -CO-NH-(CH₂) z -SO₂O-M, wherein: M is an ammonio group, n is 1 to 3, y is 1 to 2, provided y is 2 when n is 1, and z is 2 to 3, said reaction resulting in the formation of taxol derivatives having the following general structure: wherein: R is -(CH y ) n -CO-NH-(CH₂) z -SO₂O-M, wherein: M is an ammonio group, n is 1 to 3, y is 1 to 2, provided y is 2 when n is 1, and z is 2 to 3.
Claim 17
Dependent Claim
29 words
A process according to claim 16, further comprising the step of: (b) converting said ammonio group to a moiety selected from the group consisting of H, and alkaline metals.
References Cited (Backward Citations)
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