WO1994004142A1 - Novel metallocenes as anti-tumor drugs - Google Patents
Novel metallocenes as anti-tumor drugs Download PDFInfo
- Publication number
- WO1994004142A1 WO1994004142A1 PCT/US1993/007875 US9307875W WO9404142A1 WO 1994004142 A1 WO1994004142 A1 WO 1994004142A1 US 9307875 W US9307875 W US 9307875W WO 9404142 A1 WO9404142 A1 WO 9404142A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- bis
- titanium
- cyclopentadienyl
- titanocene
- novel
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F17/00—Metallocenes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the present invention relates to new titanocene com ⁇ pounds. More particularly the invention relates to new titanocene complexes and methods for their preparation, which possess chemotherapeutic activity being useful for the treatment of human tumors.
- Titanocene dichloride one of the first metallocene compounds which was tested, was found to be indeed a very reactive anti-tumor reagent. Due to its rapid hydrolysis to the corresponding dihydroxy derivative, it is quite reasonable to assume that this dihydroxy titanocene is the actual drug. Accordingly, many references can be found describing titanocene compounds which were tested in an attempt to possess an improved cytotoxity. Examples of such compounds include halides, pseudohal ides , carbo- xylates, and phenolates. However, no significant improve ⁇ ment over titanocene dichloride in the antitumor activity has been achieved.
- the metallocene diacido complexes having the general formula (C 5 H 5 ) 2 MX 2 are characterized by the following structural features:
- the geometry of the complexes is that of a distorted tetrahedron .
- the complexes contain two uninegative acido ligands X coordinated to the central metal atom and arranged in adjacent "cis-like" position.
- cytostatic pharmaceutical compositions based on titanocene complexes there are described cytostatic pharmaceutical compositions based on titanocene complexes.
- a group which is present in all these complexes is an amino or substituted amino bound to the titancceno moiety.
- These compounds are obtained by a reaction between a titanocene dihalogenide and an amino phenol, lithiurr a inophenolate, or lithiurr amino thiophe- nolate.
- the compounds have a better solubility in water than titanocene dichloride, fact which improves their application and dosing.
- Other titanocene complexes which were described differ by their ionic character from the neutral titanocene compounds.
- novel titanocene derivatives which comprise two cyclopentadiene rings linked tc titan ⁇ ium as a central atom, which are bound covalently to two phencxy groups which possess a substituent R which is selected from the group consisting of: C00CH 3 , C00C 2 H 5 , H, C00CH 2 CH 2 0CH 2 CH 2 0CH 3 being free from amino groups, nitro group, chloride and fluoride.
- the above novel titanocene derivatives represent a compromise between the two main properties required for an antitumor agent: electrophi 1 icity and stability. DETAILED DESCRIPTION OF THE INVENTION.
- titanocenes as well as other antitumor agents, do react with DNA in a similar manner. Therefore, the two main properties requi ⁇ red for the drugs, in addition to the water solubility, are electrophil icity and stability in order to survive the aqueous biological medium during the time required to reach the target.
- the inventor's approach was to synthe ⁇ size the new compounds which should possess these two main properties. Accordingly, the titanocene compounds envisaged should contain groups such as phenolates, having the role cf moderate leaving groups, and appropri ⁇ ate substituents on the phenyl rings which impart stabi ⁇ lity to these compounds.
- the titanocene compounds will contain leaving groups of modera ⁇ te reactivity, such as phenols substituted at their 4-position with C0OCH 3 , C0 2 CH 2 CH 2 CH 2 0CH ? CH 2 0CH 3 , CH 2 -CH 3 C0CH 3 , H and of course possessing a satisfactory hydrcly- tic stability.
- TPE Bis(4-methoxycarbonylphenolato)bis(n -cyclopentadi ⁇ enyl )titanium( IV) , hereinafter referred to as TPE
- TEE1 Bis(4-ethoxycarbonylphenolato)bis (n -cyclopentadi ⁇ enyl) hereinafter referred to as TEE1.
- TEG (n -cyclopentadienyl )titanium( IV) .hereinafter referred to as TEG. 5.
- Bis[4-(methoxy)ethoxycarbonylphenolato]bis (n cyclo ⁇ pentadienyl )titanium( IV) , hereinafter referred to as
- TCE (n cyclopentadienyl )titanium( IV) , hereinafter referred to as TCE.
- Cytotoxicity measurements carried out with the above compounds show significant growth inhibition properties of these compounds expressed in terms cf IC 50 [ ⁇ X] values.
- Table 1 are presented the results which show that these compound*; are much superior than the known titanocene dichloride (TDC) under the same conditi- ons.
- the value of the ratio Ti/Pt represents the relative activity of TPE as compared with that of cls-platlnura.
- the first four entries represent data of normal cell lines and the other ten entries represent the experiments with tumor cell lines.
- the titanocene derivatives according to the present invention may be employed as such or as pharmaceutical compositions containing at least one titanocene complex as described above in addi ⁇ tion to pharmaceutically acceptable excipients, diluents and/or auxiliary agents.
- the excipient can serve as an agent for promoting absorption of the medicament by the body or as formulation auxiliary, sweetener, flavouring agent, colourant or preservative.
- the pharmaceutical formulations of the active compounds are preferably in the form of unit doses matched to the particular mode of administration.
- the amount of the active compound is chosen so that one or more units are usually sufficient for an individual therapeutic administration.
- the medicaments with the active compound may contain also one or more other pharmacologically active constituents, such as: alkylating agents, antimetabol ites antibiotics, vitamins, enzymes and heavy metal compounds.
- the novel titanocene derivatives, according to the pre ⁇ sent invention can be prepared from common chemical rea ⁇ gents using standard equipment. It should be realized, that the Examples for their preparations presented hereinafter are only for illustration and many other routes may be conceived for their syntheses.
- step (b) In the second step, an amount of 418 mg (2 mmol) of the product obtained in step (a) was reacted with 249 mg (Immol) of titanocene dichloride, as described in Example
- TCA product as obtained in the previous Example 6 was treated with an excess of methyl iodide (10 equiv) in benzene for about 6 hours. A yellow solid of TCE is formed, collected by filtration, washed by benzene and ether and dried.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/387,785 US5496854A (en) | 1992-08-19 | 1993-08-19 | Metallocenes as anti-tumor drugs |
AU50854/93A AU5085493A (en) | 1992-08-19 | 1993-08-19 | Novel metallocenes as anti-tumor drugs |
EP94908077A EP0655913A4 (en) | 1992-08-19 | 1993-08-19 | Novel metallocenes as anti-tumor drugs. |
JP6506565A JPH08501289A (en) | 1992-08-19 | 1993-08-19 | Novel metallocenes as antitumor agents |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IL10286692A IL102866A (en) | 1992-08-19 | 1992-08-19 | Metallocenes as anti-tumor drugs |
IL102866 | 1992-08-19 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1994004142A1 true WO1994004142A1 (en) | 1994-03-03 |
Family
ID=11063923
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1993/007875 WO1994004142A1 (en) | 1992-08-19 | 1993-08-19 | Novel metallocenes as anti-tumor drugs |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0655913A4 (en) |
JP (1) | JPH08501289A (en) |
AU (1) | AU5085493A (en) |
IL (1) | IL102866A (en) |
WO (1) | WO1994004142A1 (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1065870C (en) * | 1998-05-20 | 2001-05-16 | 中国石油化工总公司 | Metallocene compound |
CN1065871C (en) * | 1998-05-20 | 2001-05-16 | 中国石油化工总公司 | Metallocene titanium compound |
CN1065872C (en) * | 1998-05-20 | 2001-05-16 | 中国石油化工总公司 | Cyclopentadiene titanium compound |
WO2004005305A1 (en) * | 2002-07-05 | 2004-01-15 | University Of Leeds | Functionalised metallocenes as anticancer drugs |
DE102006054690A1 (en) * | 2006-11-17 | 2008-05-21 | Charité - Universitätsmedizin Berlin | Carbonyl-substituted titanocenes |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5002969A (en) * | 1985-05-22 | 1991-03-26 | Koepf Maier Petra | Pharmaceutical compositions containing titanocene complexes and use of these complexes as cytostatic agents |
-
1992
- 1992-08-19 IL IL10286692A patent/IL102866A/en active IP Right Grant
-
1993
- 1993-08-19 WO PCT/US1993/007875 patent/WO1994004142A1/en not_active Application Discontinuation
- 1993-08-19 AU AU50854/93A patent/AU5085493A/en not_active Abandoned
- 1993-08-19 JP JP6506565A patent/JPH08501289A/en active Pending
- 1993-08-19 EP EP94908077A patent/EP0655913A4/en not_active Withdrawn
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5002969A (en) * | 1985-05-22 | 1991-03-26 | Koepf Maier Petra | Pharmaceutical compositions containing titanocene complexes and use of these complexes as cytostatic agents |
Non-Patent Citations (4)
Title |
---|
Journal of Organometallic Chemistry, Volume 11, No. 3, issued March 1968, K. ANDRA, "Dicyclopentadienyltitandiphenoxide", pages 567-570, see page 567, especially table I, compound (II). * |
P.C. WAILES et al., "Organometallic Chemistry of Titanium, Zirconium, and Hafnium", published 1974 by Academic Press (N.Y.), see pages 62-73. * |
R. FELD et al., "The Organic Chemistry of Titanium", published 1965 by Butterworths Inc. (Washington, D.C.), see pages 3-15, especially page 5, reaction equation No. 1.13. * |
See also references of EP0655913A4 * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1065870C (en) * | 1998-05-20 | 2001-05-16 | 中国石油化工总公司 | Metallocene compound |
CN1065871C (en) * | 1998-05-20 | 2001-05-16 | 中国石油化工总公司 | Metallocene titanium compound |
CN1065872C (en) * | 1998-05-20 | 2001-05-16 | 中国石油化工总公司 | Cyclopentadiene titanium compound |
WO2004005305A1 (en) * | 2002-07-05 | 2004-01-15 | University Of Leeds | Functionalised metallocenes as anticancer drugs |
DE102006054690A1 (en) * | 2006-11-17 | 2008-05-21 | Charité - Universitätsmedizin Berlin | Carbonyl-substituted titanocenes |
Also Published As
Publication number | Publication date |
---|---|
IL102866A (en) | 1998-08-16 |
EP0655913A1 (en) | 1995-06-07 |
JPH08501289A (en) | 1996-02-13 |
EP0655913A4 (en) | 1995-08-16 |
IL102866A0 (en) | 1993-01-31 |
AU5085493A (en) | 1994-03-15 |
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