WO2000076487A2 - Use of paclitaxel and steriod derivatives as aromatase inhibitors for the treatment of cancer - Google Patents
Use of paclitaxel and steriod derivatives as aromatase inhibitors for the treatment of cancer Download PDFInfo
- Publication number
- WO2000076487A2 WO2000076487A2 PCT/GB2000/002186 GB0002186W WO0076487A2 WO 2000076487 A2 WO2000076487 A2 WO 2000076487A2 GB 0002186 W GB0002186 W GB 0002186W WO 0076487 A2 WO0076487 A2 WO 0076487A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- use according
- sulphamate
- compound
- ring
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K31/566—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol having an oxo group in position 17, e.g. estrone
-
- 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 inhibition of tumour necrosis factor ⁇ stimulated aromatase activity.
- oestrone from androstenedione, by the aromatase enzyme complex is an important source of oestrogen available to support the growth of hormone-dependent tumours (1).
- Cytokines such as interleukin 6 (IL-6) and tumour necrosis factor ⁇ (TNF ⁇ ) and Prostaglandin E (PGE 2 ), can all stimulate aromatase activity (2-4).
- IL-6 interleukin 6
- TNF ⁇ tumour necrosis factor ⁇
- PGE 2 Prostaglandin E
- Many breast tumours are infiltrated by macrophages and lymphocytes and there is evidence that these cells may be an important source of the factors that can stimulate aromatase activity (5-6).
- CM conditioned medium
- TNF ⁇ has an important role in regulating aromatase activity.
- TNF ⁇ acts by interacting with cell-surface receptors (10).
- paclitaxel a compound that stabilises microtubules, was found to rapidly down-regulate TNF ⁇ receptors (11).
- the present invention provides use of a material selected from (i) microtubule stabilising agent; (ii) microtubule disrupter, preferably Paclitaxel; (iii) a compound of the formula A-B wherein A is an oxyhydrocarbyl group and B is a cyclic group, preferably 2-meOE2; and (iv) a compound of the formula C-D wherein C is an sulphamate group and D is a cyclic group, preferably MeOEMATE; for the manufacture of a medicament for the inhibition of tumour necrosis factor ⁇ (TNF ⁇ ) stimulated aromatase activity.
- 2-meOE2 is a preferred and is exemplary of a compound of the formula A-B wherein A is an oxyhydrocarbyl group and B is a cyclic group
- 2-MeOEMATE is a preferred and is exemplary of a compound of the formula C-D wherein C is an sulphamate group and D is a cyclic group.
- 2- MeOEMATE is exemplary of a compound of the formula C-D-E wherein C is an sulphamate group, D is a cyclic group, and E is an oxyhydrocarbyl group
- Paclitaxel is a preferred and is exemplary of a microtubule disrupter
- the aromatase enzyme which converts androstenedione to oestrone, regulates the availability of oestrogen to support the growth of hormone-dependent breast tumours.
- Biological response modifiers including cytokines, such as interleukin 6 (IL-6) and tumour necrosis factor ⁇ (TNF ⁇ ) or prostaglandin E 2 (PGE ) can stimulate aromatase activity.
- IL-6 interleukin 6
- TNF ⁇ tumour necrosis factor ⁇
- PGE prostaglandin E 2
- Paclitaxel which is used in the treatment of breast cancer, stabilises microtubules and has previously been shown to rapidly down-regulate TNF-receptors on human macrophages.
- (2-meOE2) also acts to stabilise microtubules.
- paclitaxel, 2-meOE2 and 2-methoxyoestrone-3-O-sulphamate (2- meOEMATE) to antagonise TNF ⁇ -stimulated aromatase activity in stromal fibroblasts derived from normal or malignant breast tissues.
- Paclitaxel inhibited basal and TNF ⁇ -stimulated aromatase activities by 88% and 91% respectively.
- MeOE2 also reduced basal and TNF ⁇ -stimulated aromatase activities by 46% and 56% respectively.
- 2-MeOEMATE also reduced basal and TNF ⁇ -stimulated aromatase activities.
- Paclitaxel, 2-meOE2 and 2-MeOEMATE also inhibited stimulation of aromatase activity by IL-6 plus its soluble receptor and PGE .
- the cyclic group may be a single ring or it is a polycyclic ring structure.
- polycyclic includes fused and non-fused ring structures including combinations thereof.
- the cyclic group may contain any one or more of C, H, O, N, P, halogen (including Cl, Br and I), S and P.
- At least one of the cyclic groups may be a heterocyclic group (a heterocycle) or a non- heterocyclic group.
- At least one of the cyclic groups may be a saturated ring structure or an unsaturated ring structure (such as an aryl group).
- at least one of the cyclic groups is an aryl ring.
- Group A and/or Group C and/or Group E is linked or attached to the aryl
- cyclic group is polycyclic some or all of the ring components of the compound may be fused together or joined via one or more suitable spacer groups.
- the polycyclic compound may comprise a number of fused rings.
- the fused rings may comprise any combination of different size rings, such as 3 six- membered rings (6,6,6), a six-membered ring, a seven-membered ring and a six- membered ring (6,7,6), a six-membered ring and two eight-membered rings (6,8,8) etc.
- cyclic group is polycyclic
- Group A and/or Group C and/or Group E are attached to the same ring of the polycyclic compound.
- the compound is a polycyclic compound.
- the polycyclic compound will contain, inclusive of all substituents, no more than 50 about carbon atoms, more usually no more than about 30 to 40 carbon atoms.
- the polycyclic compound can comprise at least two ring components, or at least three ring components, or at least four ring components.
- the polycyclic compound comprises four ring components.
- Preferred polycyclic compounds have a steroidal ring component - that is to say a cyclopentanophenanthrene skeleton, or bio-isosteres thereof.
- bio-isostere is when any one or more of rings A, B, C and D is a heterocyclic ring and/or when any one or more of rings A, B, C and D has been substituted and/or when any one or more of rings A, B, C and D has been modified; but wherein the bio-isostere in the absence of the sulphamate group has steroidal properties.
- each ring A', B', C and D' independently represents a heterocyclic ring or a non-heterocyclic ring, which rings may be independently substituted or unsubstituted, saturated or unsaturated.
- any one or more of rings A', B', C and D' may be independently substituted with suitable groups - such as an alkyl group, an aryl group, a hydroxy group, a halo group, a hydrocarbyl group, an oxyhydrocarbyl group etc.
- D' is a five or six membered non-heterocyclic ring having at least one substituent.
- the ring D' is substituted with a ethinyl group.
- heterocyclic ring comprises a combination of C atoms and at least one N atom and/or at least one O atom.
- Other heterocyclic atoms may be present in the ring.
- Suitable, preferred steroidal nuclei rings A'-D' of the compounds of the present invention include rings A-D of dehydroepiandrosterone and oestrogens including oestrone.
- Preferred steroidal nuclei rings A'-D' of the compounds of the present invention include rings A-D of:
- dehvdroepiandrosterones and substituted dehvdroepiandrosterones. viz: dehydroepiandrosterones 6 ⁇ -OH-dehydroepiandrosterone 7 ⁇ -OH-dehydroepiandrosterone 16 ⁇ -OH-dehydroepiandrosterone 16 ⁇ -OH-dehydroepiandrosterone
- the ring system A'B'C'D' may contain a variety of non-interfering substituents.
- the ring system A'B'C'D' may contain one or more hydroxy, alkyl especially lower ( -C ⁇ ) alkyl, e.g. methyl, ethyl, n-propyl, isopropyl, n- butyl, sec-butyl, tert-butyl, n-pentyl and other pentyl isomers, and n-hexyl and other hexyl isomers, alkoxy especially lower (C*-C 6 ) alkoxy, e.g. methoxy, ethoxy, propoxy etc., alkinyl, e.g. ethinyl, or halogen, e.g. fluoro substituents.
- the polycyclic compound may not contain or be based on a steroid nucleus.
- the polycyclic compound may contain or be based on a non-steroidal ring system - such as diethylstilboestrol, stilboestrol, coumarins, flavonoids, combrestatin and other ring systems.
- a non-steroidal ring system such as diethylstilboestrol, stilboestrol, coumarins, flavonoids, combrestatin and other ring systems.
- Other suitable non-steroidal compounds for use in or as the composition of the present invention may be found in
- Group A or Group C and/or Group E are attached to the same ring of the cyclic compound of the present invention at positions ortho with respect to each other.
- the polycyclic compound has a steroidal structure and Group A or Group E is attached to the A ring.
- the Group A or Group E is attached to the 2 position of the A ring of the steroidal structure.
- the polycyclic compound has a steroidal structure and Group C is attached to the A ring.
- the Group C is attached to the 3 position of the A ring of the steroidal structure.
- Group A is a oxyhydrocarbyl group.
- oxyhydrocarbyl group means a group comprising at least C, H and O and may optionally comprise one or more other suitable substituents. Examples of such substituents may include halo-, alkoxy-, nitro-, an alkyl group, a cyclic group etc. In addition to the possibility of the substituents being a cyclic group, a combination of substituents may form a cyclic group. If the oxyhydrocarbyl group comprises more than one C then those carbons need not necessarily be linked to each other. For example, at least two of the carbons may be linked via a suitable element or group. Thus, the oxyhydrocarbyl group may contain hetero atoms. Suitable hetero atoms will be apparent to those skilled in the art and include, for instance, sulphur and nitrogen. In one preferred embodiment of the present invention, the oxyhydrocarbyl group is a oxyhydrocarbon group.
- oxyhydrocarbon means any one of an alkoxy group, an oxyalkenyl group, an oxyalkynyl group, which groups may be linear, branched or cyclic, or an oxyaryl group.
- the term oxyhydrocarbon also includes those groups but wherein they have been optionally substituted. If the oxyhydrocarbon is a branched structure having substituent(s) thereon, then the substitution may be on either the hydrocarbon backbone or on the branch; alternatively the substitutions may be on the hydrocarbon backbone and on the branch.
- the oxyhydrocarbyl group is of the formula C*- 6 O (such as a C*- 3 O).
- the compound comprises a steroidal nucleus, preferably the A ring has an oxyhydrocarbyl group at the 2 position.
- the group C*- 6 O is attached to the 2 position of the A ring of a steroidal nucleus.
- the oxyhydrocarbyl group is an alkoxy.
- the alkyl group of the alkoxy substituent is preferably a lower alkyl group containing from 1 to 5 carbon atoms, that is to say methyl, ethyl, propyl etc.
- the alkyl group is methyl.
- the A ring has an methoxy substituent at the 2 position.
- a preferred compound of the present invention has the formula:
- rings A, B, C and D are independently optionally substituted.
- Group A or Group E is in the 2-position.
- Group C is in the 3-position.
- Group C is a "sulphamate group”.
- a “sulphamate group” is a group of the formula
- each of R* and R 2 is independently selected from H or a hydrocarbyl group.
- hydrocarbyl group means a group comprising at least C and H and may optionally comprise one or more other suitable substituents. Examples of such substituents may include halo-, alkoxy-, nitro-, a hydrocarbon group, an N-acyl group, a cyclic group etc. In addition to the possibility of the substituents being a cyclic group, a combination of substituents may form a cyclic group. If the hydrocarbyl group comprises more than one C then those carbons need not necessarily be linked to each other. For example, at least two of the carbons may be linked via a suitable element or group. Thus, the hydrocarbyl group may contain hetero atoms. Suitable hetero atoms will be apparent to those skilled in the art and include, for instance, sulphur, nitrogen and oxygen.
- R* and R 2 are independently selected from H or alkyl, cycloalkyl, alkenyl and aryl, or together represent alkylene, wherein the or each alkyl or cycloalkyl or alkenyl or optionally contain one or more hetero atoms or groups.
- the N-substituted sulphamate compound may contain one or two N- alkyl, N-alkenyl, N-cycloalkyl, N-acyl, or N-aryl substituents, preferably containing or each containing a maximum of 10 carbon atoms.
- R* and/or R is alkyl
- the preferred values are those where R* and R 2 are each independently selected from lower alkyl groups containing from 1 to 5 carbon atoms, that is to say methyl, ethyl, propyl etc.
- Ri and R are both methyl.
- R* and/or R 2 When R* and/or R 2 is aryl, typical values are phenyl and tolyl (-PhCH 3 ; o-, m- or p-). Where Ri and R represent cycloalkyl, typical values are cyclopropyl, cyclopentyl, cyclohexyl etc.
- R * and R 2 When joined together R * and R 2 typically represent an alkylene group providing a chain of 4 to 6 carbon atoms, optionally interrupted by one or more hetero atoms or groups, e.g. -0- or -NH- to provide a 5-, 6- or 7- membered heterocycle, e.g. morpholino, pyrrolidino or piperidino.
- alkyl, cycloalkyl, alkenyl, acyl and aryl we include substituted groups containing as substituents therein one or more groups which do not interfere with the activity of the compound in question.
- exemplary non-interfering substituents include hydroxy, amino, halo, alkoxy, alkyl and aryl.
- a non-limiting example of a hydrocarbyl group is an acyl group.
- At least one of R* and R 2 is H.
- suitable sulphamate compounds for use in the present invention or examples of suitable compounds that can be converted to suitable sulphamate compounds for use in the present invention, can be found in the art - such as PCT/GB92/01587, PCT/GB97/03352, PCT/GB97/00444, GB 9725749.7, GB 9725750.5, US-A-5567831, US-A-5677292, US-A-5567831, WO-A-96/05216, and WO-A-96/05217.
- PCT/GB92/01587 teaches novel sulphamate compounds and pharmaceutical compositions containing them for use in the treatment of oestrone dependent tumours, especially breast cancer.
- These sulphamate compounds are sulphamate esters.
- Examples of such inhibitors are sulphamate ester derivatives of steroids.
- Another compound suitable for use in the present invention has at least the following skeletal structure:
- At least one of R* and R is H.
- Another compound suitable for use in the present invention has at least the following skeletal structure:
- rings A, B, C and D are independently optionally substituted.
- a preferred compound of the present invention has the formula:
- rings A, B, C and D are independently optionally substituted.
- Group E is in the 2-position.
- Group C is in the 3-position.
- the sulphamate compound is an oxyhydrocarbyl steroidal sulphamate compound, in particular 2-methoxyoestrone-3-O-sulphamate, or a pharmaceutically active salt thereof, including analogues thereof.
- 2-methoxyoestrone-3-O-sulphamate is an analogue of oestrone-3-O-sulphamate (otherwise known as "EMATE”), which has the following structure:
- 2-methoxy EMATE is the sulphamoylated derivative of a naturally occurring oestrogen metabolite of the present invention, 2-methoxyoestrone. This compound is formed in the liver by the hydroxylation of oestrone by a 2-hydroxylase, with subsequent metabolism to the methoxy derivative by catechol oestrogen methyl transferase.
- 2-methoxy EMATE has the formula presented as formula below:
- the sulphamate compound is an oxyhydrocarbyl derivative of oestrone-3-O-sulphamate.
- the sulphamate compound is a C-- 6 (such as a C*. ) alkoxy derivative of oestrone-3-O- sulphamate.
- the sulphamate compound is a 2-C ⁇ - 6 (such as a C*. 3 ) alkoxy derivative of oestrone-3-O-sulphamate.
- the sulphamate compound is 2-methoxyoestrone-3- O-sulphamate.
- paclitaxel Inhibition of basal and TNF ⁇ -stimulated aromatase activity by paclitaxel (Pax) in breast tissue fibroblasts.
- Paclitaxel was added to cells which were cultured for 24h in 2% stripped foetal calf serum.
- TNF ⁇ was added, in the presence of dexamethasone (l ⁇ nmol/1) and cells cultured for a further 48h in the same medium. Controls and cells with paclitaxel, but not TNF ⁇ , were also cultured in the presence of dexamethasone for a 48h period.
- Dose response for inhibition of TNF ⁇ -stimulated aromatase activity (expressed as % of TNF ⁇ -stimulated activity) by paclitaxel (Pax), 2-methoxyoestradiol (2-meOE2) or
- Samples of breast adipose or tumour tissue were obtained from women undergoing reduction mammoplasty or lumpectomy after obtaining their informed consent.
- Fibroblasts were cultured as previously described (2). Briefly, they were cultured in Eagles' modified minimal essential medium containing Hepes buffer (20mmol/l), 10% foetal calf serum (FCS) and supplements. Cells were routinely passaged 2-3 times after which replicate 25cm flasks were seeded with fibroblasts and grown to confluency. 2-MeOEMATE was prepared in as described in Appendix I. (For experiments, cells were cultured in phenol red-free medium containing 2% stripped FCS for 24h in the presence of paclitaxel, 2-meOE2 or 2-MeOEMATE before the addition of TNF ⁇ , IL-6 plus IL-6 soluble receptor (IL-6sR) or PGE and cultured for a further 48h in this medium.
- IL-6sR IL-6 soluble receptor
- TNF ⁇ , IL-6 and IL-6sR were used in the presence of dexamethasone (lOOnmol/l, Sigma).
- Paclitaxel, 2-meOE2 and other chemicals were also obtained from Sigma.
- aromatase activity was measured in intact monolayers using [l ⁇ - 3 H] androstenedione (15-30Ci/mmol, NEN-Du Pont, Stevenage, Herts, UK) over a 3-20h period (2,3).
- the number of cells was measured by counting cell nuclei using a Coulter counter.
- paclitaxel to inhibit TNF ⁇ stimulated aromatase activity was initially examined using fibroblasts derived from reduction mammoplasty tissue (Fig 1). In these cells TNF ⁇ , in the presence of dexamethasone, stimulated aromatase activity by
- TNF ⁇ , IL-6 plus IL-6sR or PGE 2 all significantly enhanced aromatase activity in tumour-derived fibroblasts.
- Paclitaxel, 2-meOE2 and 2-MeOEMATE inhibited basal aromatase activity and TNF ⁇ stimulated activity. In addition, however, they were also found to antagonise stimulation of aromatase activity by IL-6 plus IL-6sR or PGE 2 .
- paclitaxel While paclitaxel, 2-meOE2 and 2-MeOEMATE inhibited TNF ⁇ stimulated aromatase, it was evident that paclitaxel is a more potent antagonist. At 0.1 ⁇ M paclitaxel inhibited stimulation by 90% whereas 2-meOE2 at this concentration only 25 reduced the stimulation by 51%. 2-MeOE3, while showing some inhibitory effect at the highest concentration tested did not significantly reduce TNF ⁇ stimulation of aromatase activity at 5 ⁇ M.
- results from this investigation have revealed agents that alter microtubule stability, paclitaxel, 2-meOE2 and 2-MeOEMATE, not only inhibit basal aromatase activity but greatly reduce TNF ⁇ stimulated activity.
- Paclitaxel is used in the treatment of breast cancer but, as far as we are aware, this is the first report demonstrating its ability to inhibit basal and cytokine stimulated aromatase activity. This property is restricted microtubule stabilising agents as colchicine or cytocholasin B, which have different effects on the microskeleton, were unable to inhibit TNF ⁇ stimulated aromatase activity.
- TNF ⁇ , IL-6 plus IL6sR and PGE2 are the three main factors identified so far that can regulate aromatase activity in fibroblasts derived from subcutaneous adipose or breast tissues. Microtubules may be required for the synthesis of cytokine receptors or for their translocation to the plasma membrane (15). It is likely, therefore, that the effect that paclitaxel, 2-meOE2 and 2-MeOEMATE have on the ability of TNF ⁇ , IL- 6 or PGE 2 to stimulate aromatase activity may also result from an effect on the synthesis/translocation of the receptors involved in their signalling. The ability of paclitaxel, 2-meOE2 and 2-MeOEMATE to reduce basal (i.e. unstimulated) aromatase activity may result from blocking the autocrine/ paracrine action of cytokines and PGE 2 , which are known to be produced by these fibroblasts, on aromatase activity (6, 16).
- Paclitaxel is used for the treatment of breast cancer but its toxicity precludes its long- term use.
- 2-meOE2, an endogenous oestrogen metabolite, and 2- MeOEMATE may have similar properties to paclitaxel suggests they may have considerable therapeutic potential (17).
- Oral administration of 2-meOE2 to mice inoculated with B ⁇ 6 melanoma, Meth A sarcoma or MDA-MB-435 breast cancer cells significantly reduced tumour growth (18, 19).
- Stromal fibroblasts cultured from adipose tissue have the ability to differentiate into adipocytes. TNF ⁇ , while stimulating aromatase activity in fibroblasts, inhibits their differentiation into adipocytes.
- High concentrations of oestradiol (10-100 ⁇ M) can inhibit TNF ⁇ stimulated aromatase activity in adipose stromal cells and it has been postulated that a feed-back loop may exist to prevent excessive oestrogen synthesis in these cells (22).
- Peroxisome prolierator activated receptor ⁇ (PPAR ⁇ ) ligands such as thiozolidinedione, can also stimulate adipocyte differentiation and also inhibit TNF ⁇ stimulated aromatase activity.
- PPAR ⁇ peroxisome prolierator activated receptor ⁇
- Attalla, H., Makela, T.P., Adlercreutz, H., and Andersson, L.C. (1996) Biochem. Biophysc. Res. Comm. 228, 467-473.
- Attalla, H., Westberg, J.A., Andersson, L.C, Adlercreutz, H., and Makela, T.P. (1998) Biochem. Biophys. Res. Comm. 247, 616-619.
- 2-methoxy EMATE was synthesised by treating a solution of 2 methoxyoestrone in anhydrous dimethylformamide with sodium hydride at 0°C. After evolution of hydrogen had ceased sulphamoyl chloride (2 equiv.) was added and the reaction mixture was allowed to warm to room temperature overnight. The compound was purified by silica gel flash chromatography, was a single pure spot by TLC and exhibited satisfactory spectroscopic and microanalytical data.
Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP00937052A EP1207888A2 (en) | 1999-06-10 | 2000-06-05 | Use of paclitaxel and of steroid derivatives as aromatase inhibitors for the treatment of cancer |
AU52346/00A AU5234600A (en) | 1999-06-10 | 2000-06-05 | Use |
JP2001502821A JP2004513064A (en) | 1999-06-10 | 2000-06-05 | Use of paclitaxel and steroid derivatives as aromatase inhibitors for the treatment of cancer |
CA002376067A CA2376067A1 (en) | 1999-06-10 | 2000-06-05 | Use of paclitaxel and steroid derivatives as aromatase inhibitors for the treatment of cancer |
US10/013,798 US20020055462A1 (en) | 1999-06-10 | 2001-12-10 | Use |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB9913536.0A GB9913536D0 (en) | 1999-06-10 | 1999-06-10 | Use |
GB9913536.0 | 1999-06-10 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/013,798 Continuation-In-Part US20020055462A1 (en) | 1999-06-10 | 2001-12-10 | Use |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2000076487A2 true WO2000076487A2 (en) | 2000-12-21 |
WO2000076487A3 WO2000076487A3 (en) | 2001-08-09 |
Family
ID=10855114
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB2000/002186 WO2000076487A2 (en) | 1999-06-10 | 2000-06-05 | Use of paclitaxel and steriod derivatives as aromatase inhibitors for the treatment of cancer |
Country Status (7)
Country | Link |
---|---|
US (1) | US20020055462A1 (en) |
EP (1) | EP1207888A2 (en) |
JP (1) | JP2004513064A (en) |
AU (1) | AU5234600A (en) |
CA (1) | CA2376067A1 (en) |
GB (1) | GB9913536D0 (en) |
WO (1) | WO2000076487A2 (en) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000066095A2 (en) * | 1999-04-30 | 2000-11-09 | Sterix Limited | Use of estrone derivatives as antitumour agents |
WO2002003979A2 (en) * | 2000-07-12 | 2002-01-17 | Board Of Regents, The University Of Texas System | Combination of 2-methoxyestradiol and an agent that increases intracellular superoxide anion |
DE10307103A1 (en) * | 2003-02-19 | 2004-09-09 | Schering Ag | Anti-tumor effective 2-substituted D-homostra-1,3,5 (10) -trien-3-yl sulfamate |
US7078395B1 (en) | 1999-06-16 | 2006-07-18 | Sterix Limited | Methods for treating or preventing cancer by preventing, inhibiting or arresting cell cycling |
US8026229B2 (en) | 2001-08-13 | 2011-09-27 | Sterix Limited | Antitumor-active 2-alkoxyestradiol sulfamates |
US8492570B2 (en) | 2003-02-19 | 2013-07-23 | Sterix Limited | 2-substituted estra-1,3,5(10)-triene-3-yl sulfamate with an anti-tumor action |
US9776736B2 (en) | 2014-08-16 | 2017-10-03 | HÜBNER GmbH & Co. KG | Coupling module |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8293277B2 (en) * | 1998-10-01 | 2012-10-23 | Alkermes Pharma Ireland Limited | Controlled-release nanoparticulate compositions |
AU6283299A (en) * | 1998-10-01 | 2000-04-17 | Elan Pharma International Limited | Controlled release nanoparticulate compositions |
US8236352B2 (en) * | 1998-10-01 | 2012-08-07 | Alkermes Pharma Ireland Limited | Glipizide compositions |
US20040013613A1 (en) * | 2001-05-18 | 2004-01-22 | Jain Rajeev A | Rapidly disintegrating solid oral dosage form |
US7521068B2 (en) * | 1998-11-12 | 2009-04-21 | Elan Pharma International Ltd. | Dry powder aerosols of nanoparticulate drugs |
US20040115134A1 (en) * | 1999-06-22 | 2004-06-17 | Elan Pharma International Ltd. | Novel nifedipine compositions |
US20090104273A1 (en) * | 1999-06-22 | 2009-04-23 | Elan Pharma International Ltd. | Novel nifedipine compositions |
US7198795B2 (en) * | 2000-09-21 | 2007-04-03 | Elan Pharma International Ltd. | In vitro methods for evaluating the in vivo effectiveness of dosage forms of microparticulate of nanoparticulate active agent compositions |
PT1471887E (en) | 2002-02-04 | 2010-07-16 | Elan Pharma Int Ltd | Nanoparticulate compositions having lysozyme as a surface stabilizer |
US20040101566A1 (en) * | 2002-02-04 | 2004-05-27 | Elan Pharma International Limited | Novel benzoyl peroxide compositions |
US20080220075A1 (en) * | 2002-03-20 | 2008-09-11 | Elan Pharma International Ltd. | Nanoparticulate compositions of angiogenesis inhibitors |
ATE343376T1 (en) * | 2002-03-20 | 2006-11-15 | Elan Pharma Int Ltd | NANOPARTICLE COMPOSITIONS OF ANGIOGENESIS INHIBITORS |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1993005064A1 (en) * | 1991-08-29 | 1993-03-18 | Imperial College Of Science, Technology And Medicine | Steroid sulphatase inhibitors |
WO1993005063A1 (en) * | 1991-08-29 | 1993-03-18 | Imperial College Of Science, Technology And Medicine | Steroid sulphatase inhibitors |
WO1998024802A2 (en) * | 1996-12-05 | 1998-06-11 | Imperial College Of Science Technology And Medicine | Compound |
GB2331987A (en) * | 1997-12-04 | 1999-06-09 | Imperial College | Polycyclic sulphamate oxime inhibitors of oestrone sulphatase |
GB2331988A (en) * | 1997-12-04 | 1999-06-09 | Imperial College | Polycyclic sulphamate inhibitors of oestrone sulphatase |
WO1999064013A1 (en) * | 1998-06-10 | 1999-12-16 | Sterix Limited | Pharmaceutical composition with tumor necrosis factor a and 2-methoxyestrone-3-o-sulphamate for inhibition of estrone sulphatase |
WO2000066095A2 (en) * | 1999-04-30 | 2000-11-09 | Sterix Limited | Use of estrone derivatives as antitumour agents |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU6833994A (en) * | 1993-05-17 | 1994-12-12 | Liposome Company, Inc., The | Incorporation of taxol into liposomes and gels |
US5643900A (en) * | 1993-07-02 | 1997-07-01 | Fotsis; Theodore | Method for treatment of pathological conditions associated with angiogenesis and preparation therefor |
US5571933A (en) * | 1994-11-17 | 1996-11-05 | Duquesne University Of The Holy Ghost | Derivatives of estra 1,3,5(10)triene-17-one, 3-amino compounds and their use |
-
1999
- 1999-06-10 GB GBGB9913536.0A patent/GB9913536D0/en not_active Ceased
-
2000
- 2000-06-05 EP EP00937052A patent/EP1207888A2/en not_active Withdrawn
- 2000-06-05 JP JP2001502821A patent/JP2004513064A/en not_active Withdrawn
- 2000-06-05 CA CA002376067A patent/CA2376067A1/en not_active Abandoned
- 2000-06-05 WO PCT/GB2000/002186 patent/WO2000076487A2/en active Search and Examination
- 2000-06-05 AU AU52346/00A patent/AU5234600A/en not_active Abandoned
-
2001
- 2001-12-10 US US10/013,798 patent/US20020055462A1/en not_active Abandoned
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1993005064A1 (en) * | 1991-08-29 | 1993-03-18 | Imperial College Of Science, Technology And Medicine | Steroid sulphatase inhibitors |
WO1993005063A1 (en) * | 1991-08-29 | 1993-03-18 | Imperial College Of Science, Technology And Medicine | Steroid sulphatase inhibitors |
WO1998024802A2 (en) * | 1996-12-05 | 1998-06-11 | Imperial College Of Science Technology And Medicine | Compound |
GB2331987A (en) * | 1997-12-04 | 1999-06-09 | Imperial College | Polycyclic sulphamate oxime inhibitors of oestrone sulphatase |
GB2331988A (en) * | 1997-12-04 | 1999-06-09 | Imperial College | Polycyclic sulphamate inhibitors of oestrone sulphatase |
WO1999064013A1 (en) * | 1998-06-10 | 1999-12-16 | Sterix Limited | Pharmaceutical composition with tumor necrosis factor a and 2-methoxyestrone-3-o-sulphamate for inhibition of estrone sulphatase |
WO2000066095A2 (en) * | 1999-04-30 | 2000-11-09 | Sterix Limited | Use of estrone derivatives as antitumour agents |
Non-Patent Citations (8)
Title |
---|
CUSHMAN M ET AL: "SYNTHESIS, ANTITUBULIN AND ANTIMITOTIC ACTIVITY, AND CYTOTOXICITY OF ANALOGS OF 2-METHOXYESTRADIOL, AN ENDOGENOUS MAMMALIAN METABOLITE OF ESTRADIOL THAT INHIBITS TUBULIN POLYMERIZATION BY BINDING TO THE COLCHICINE BINDING SITE" JOURNAL OF MEDICINAL CHEMISTRY,US,AMERICAN CHEMICAL SOCIETY. WASHINGTON, vol. 38, no. 12, 1995, pages 2041-2049, XP002055798 ISSN: 0022-2623 * |
KLAUBER NANCY ET AL: "Inhibition of angiogenesis and breast cancer in mice by the microtubule inhibitors 2-methoxyestradiol and taxol." CANCER RESEARCH, vol. 57, no. 1, 1997, pages 81-86, XP002162122 ISSN: 0008-5472 * |
PUROHIT A ET AL: "RECENT ADVANCES IN THE DEVELOPMENT OF STEROID SULPHATASE INHIBITORS" JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY,GB,ELSEVIER SCIENCE LTD., OXFORD, vol. 69, no. 1/06, 1999, pages 227-238, XP000852540 ISSN: 0960-0760 & PROCEEDINGS OF THE 10TH INTERNATIONAL CONGRESS ON HORMONAL STEROIDS, QUEBEC, 17-21 JUNE 1998, * |
PUROHIT A ET AL: "THE DEVELOPMENT OF A-RING MODIFIED ANALOGUES OF OESTRONE-3-O- SULPHAMATE AS POTENT STEROID SULPHATASE INHIBITORS WITH REDUCED OESTROGENICITY" JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY,GB,ELSEVIER SCIENCE LTD., OXFORD, vol. 64, no. 5, 1998, pages 269-275, XP000852539 ISSN: 0960-0760 * |
PUROHIT A: "Inhibition of tumor necrosis factor a-stimulated aromatase activity by microtubule-stabilizing agents, paclitaxel and 2-methoxyestradiol" BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS,ACADEMIC PRESS INC. ORLANDO, FL,US, vol. 261, 1999, pages 214-217, XP002121930 ISSN: 0006-291X * |
SCHWARZ S ET AL: "Synthesis of estrogen sulfamates: Compounds with a novel endocrinological profile" STEROIDS: STRUCTURE, FUNCTION, AND REGULATION,US,ELSEVIER SCIENCE PUBLISHERS, NEW YORK, NY, vol. 61, no. 12, 1 December 1996 (1996-12-01), pages 710-717, XP004016631 ISSN: 0039-128X * |
WOO L W L ET AL: "ACTIVE SITE DIRECTED INHIBITION OF ESTRONE SULFATASE BY NONSTEROIDAL COUMARIN SULFAMATES" JOURNAL OF MEDICINAL CHEMISTRY,US,AMERICAN CHEMICAL SOCIETY. WASHINGTON, vol. 39, no. 7, 1996, pages 1349-1351, XP000652210 ISSN: 0022-2623 * |
WOO L W L ET AL: "Oestrone 3-O-(N-acetyl)sulphamate, a potential molecular probe of the active site of oestrone sulphatase" BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,GB,OXFORD, vol. 7, no. 24, 16 December 1997 (1997-12-16), pages 3075-3080, XP004136588 ISSN: 0960-894X * |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000066095A2 (en) * | 1999-04-30 | 2000-11-09 | Sterix Limited | Use of estrone derivatives as antitumour agents |
WO2000066095A3 (en) * | 1999-04-30 | 2001-08-09 | Sterix Ltd | Use of estrone derivatives as antitumour agents |
US8207152B2 (en) | 1999-04-30 | 2012-06-26 | Sterix Limited | Methods for treating or preventing cancer by preventing, inhibiting, or arresting cell cycling |
US7078395B1 (en) | 1999-06-16 | 2006-07-18 | Sterix Limited | Methods for treating or preventing cancer by preventing, inhibiting or arresting cell cycling |
WO2002003979A2 (en) * | 2000-07-12 | 2002-01-17 | Board Of Regents, The University Of Texas System | Combination of 2-methoxyestradiol and an agent that increases intracellular superoxide anion |
WO2002003979A3 (en) * | 2000-07-12 | 2003-07-24 | Univ Texas | Combination of 2-methoxyestradiol and an agent that increases intracellular superoxide anion |
US8026229B2 (en) | 2001-08-13 | 2011-09-27 | Sterix Limited | Antitumor-active 2-alkoxyestradiol sulfamates |
DE10307103A1 (en) * | 2003-02-19 | 2004-09-09 | Schering Ag | Anti-tumor effective 2-substituted D-homostra-1,3,5 (10) -trien-3-yl sulfamate |
DE10307103A8 (en) * | 2003-02-19 | 2004-12-16 | Schering Ag | Antitumor effective 2-substituted D-homoestra-1,3,5 (10) -trien-3-yl sulfamate |
US8492570B2 (en) | 2003-02-19 | 2013-07-23 | Sterix Limited | 2-substituted estra-1,3,5(10)-triene-3-yl sulfamate with an anti-tumor action |
US9776736B2 (en) | 2014-08-16 | 2017-10-03 | HÜBNER GmbH & Co. KG | Coupling module |
Also Published As
Publication number | Publication date |
---|---|
JP2004513064A (en) | 2004-04-30 |
GB9913536D0 (en) | 1999-08-11 |
WO2000076487A3 (en) | 2001-08-09 |
EP1207888A2 (en) | 2002-05-29 |
AU5234600A (en) | 2001-01-02 |
CA2376067A1 (en) | 2000-12-21 |
US20020055462A1 (en) | 2002-05-09 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2000076487A2 (en) | Use of paclitaxel and steriod derivatives as aromatase inhibitors for the treatment of cancer | |
Goss et al. | Aromatase inhibitors in the treatment and prevention of breast cancer | |
EP0615448B1 (en) | Sex steroid activity inhibitors | |
Purohit et al. | Inhibition of tumor necrosis factor α-stimulated aromatase activity by microtubule-stabilizing agents, paclitaxel and 2-methoxyestradiol | |
CA2200195C (en) | Use of aromatase inhibitors for the production of a pharmaceutical agentfor treating a relative androgen deficiency in men | |
EP0942919B1 (en) | Sulphatase Inhibitors | |
PH30747A (en) | Combination therapy for the treatment of estrogen sensitive disease. | |
PT1624878E (en) | Use of compositions comprising an estrogenic component for the treatment and prevention of musculoskeletal pain | |
Lundgren | Progestins in Breast Cancer Treatment: A Reveiw | |
AU765386B2 (en) | Pharmaceutical composition with tumor necrosis factor a and 2-methoxyestrone-3-(o)-sulphamate for inhibition of estrone sulphatase | |
Reed et al. | The role of cytokines and sulphatase inhibitors in regulating oestrogen synthesis in breast tumours | |
JP6025301B2 (en) | C-19 steroids for therapeutic use | |
US20020147183A1 (en) | Antiangiogenic agents | |
James et al. | Oestrogen uptake and metabolism in vivo | |
Khalil et al. | Effect of dexamethasone and cytochrome P 450 inhibitors on the formation of 7α-hydroxydehydroepiandrosterone by human adipose stromal cells | |
EP1901737A1 (en) | Use of a steroid sulphatase inhibitor for inhibiting the synthesis of androstenedione and/or testosterone | |
EA005945B1 (en) | Inhibition of the growth factor dependency of tumor cells | |
WO2004035089A1 (en) | Remedy for hormone-dependent cancer | |
JP2002506823A (en) | Preventive and / or therapeutic agent for breast cancer containing steroidal aromatase inhibitor | |
Reed et al. | The effect of glucocorticoids on the in vivo conversion of androstenedione to oestrone | |
US6642220B1 (en) | Compounds that inhibit oestrone sulphatase; compositions thereof; and methods employing the same | |
Bajetta et al. | Novel non-steroidal aromatase inhibitors: are there new perspectives in the treatment of breast cancer? | |
Harris | Aminoglutethimide–A New Endocrine Therapy in Breast Cancer: A Cancer Research Review | |
US20040127473A1 (en) | Compound | |
Brennan | Corticosteroids in the treatment of solid tumors |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A2 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
AK | Designated states |
Kind code of ref document: A3 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A3 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
WWE | Wipo information: entry into national phase |
Ref document number: 52346/00 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2000937052 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 2376067 Country of ref document: CA Ref country code: CA Ref document number: 2376067 Kind code of ref document: A Format of ref document f/p: F |
|
ENP | Entry into the national phase |
Ref country code: JP Ref document number: 2001 502821 Kind code of ref document: A Format of ref document f/p: F |
|
WWE | Wipo information: entry into national phase |
Ref document number: 10013798 Country of ref document: US |
|
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
WWP | Wipo information: published in national office |
Ref document number: 2000937052 Country of ref document: EP |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 2000937052 Country of ref document: EP |
|
DPE2 | Request for preliminary examination filed before expiration of 19th month from priority date (pct application filed from 20040101) |