NZ517069A - New stilbenes with vascular damaging activity - Google Patents
New stilbenes with vascular damaging activityInfo
- Publication number
- NZ517069A NZ517069A NZ517069A NZ51706900A NZ517069A NZ 517069 A NZ517069 A NZ 517069A NZ 517069 A NZ517069 A NZ 517069A NZ 51706900 A NZ51706900 A NZ 51706900A NZ 517069 A NZ517069 A NZ 517069A
- Authority
- NZ
- New Zealand
- Prior art keywords
- stilbene
- cis
- prodrug
- alkyl
- treatment
- Prior art date
Links
- 230000002792 vascular Effects 0.000 title description 11
- 230000000254 damaging effect Effects 0.000 title description 10
- 235000021286 stilbenes Nutrition 0.000 title description 4
- 150000001629 stilbenes Chemical class 0.000 title description 3
- PJANXHGTPQOBST-QXMHVHEDSA-N cis-stilbene Chemical compound C=1C=CC=CC=1/C=C\C1=CC=CC=C1 PJANXHGTPQOBST-QXMHVHEDSA-N 0.000 claims abstract description 36
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 32
- 229940002612 prodrug Drugs 0.000 claims abstract description 28
- 239000000651 prodrug Substances 0.000 claims abstract description 28
- 238000011282 treatment Methods 0.000 claims abstract description 24
- 239000000203 mixture Substances 0.000 claims abstract description 22
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 16
- -1 alkythio Chemical group 0.000 claims abstract description 15
- 201000010099 disease Diseases 0.000 claims abstract description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 11
- 206010029113 Neovascularisation Diseases 0.000 claims abstract description 10
- 125000004414 alkyl thio group Chemical group 0.000 claims abstract description 7
- 239000003814 drug Substances 0.000 claims abstract description 7
- 239000001257 hydrogen Substances 0.000 claims abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 7
- 201000011510 cancer Diseases 0.000 claims abstract description 6
- 206010012689 Diabetic retinopathy Diseases 0.000 claims abstract description 5
- 201000004681 Psoriasis Diseases 0.000 claims abstract description 5
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 5
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 5
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 5
- 208000002780 macular degeneration Diseases 0.000 claims abstract description 5
- 206010039073 rheumatoid arthritis Diseases 0.000 claims abstract description 5
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims abstract description 4
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims abstract description 4
- 125000001188 haloalkyl group Chemical group 0.000 claims abstract description 4
- 230000007062 hydrolysis Effects 0.000 claims abstract description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 4
- 238000001727 in vivo Methods 0.000 claims abstract description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 3
- 125000001475 halogen functional group Chemical group 0.000 claims abstract 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 230000000259 anti-tumor effect Effects 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 229910019142 PO4 Inorganic materials 0.000 claims description 3
- UAXYYNUZYVSJKT-FPLPWBNLSA-N [2-methyl-5-[(z)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenyl] dihydrogen phosphate Chemical compound COC1=C(OC)C(OC)=CC(\C=C/C=2C=C(OP(O)(O)=O)C(C)=CC=2)=C1 UAXYYNUZYVSJKT-FPLPWBNLSA-N 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 201000001320 Atherosclerosis Diseases 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 238000001959 radiotherapy Methods 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims 1
- 150000001733 carboxylic acid esters Chemical class 0.000 claims 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 claims 1
- 229910021653 sulphate ion Inorganic materials 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 4
- 150000001875 compounds Chemical class 0.000 description 51
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 44
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
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- 210000005166 vasculature Anatomy 0.000 description 10
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 238000000034 method Methods 0.000 description 8
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- 230000015572 biosynthetic process Effects 0.000 description 7
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- 150000003839 salts Chemical class 0.000 description 7
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- HVXBOLULGPECHP-UHFFFAOYSA-N combretastatin A4 Natural products C1=C(O)C(OC)=CC=C1C=CC1=CC(OC)=C(OC)C(OC)=C1 HVXBOLULGPECHP-UHFFFAOYSA-N 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 239000012267 brine Substances 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- 125000005843 halogen group Chemical group 0.000 description 5
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
- 238000011321 prophylaxis Methods 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
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- 238000004587 chromatography analysis Methods 0.000 description 3
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 3
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- 238000000746 purification Methods 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
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- 125000004665 trialkylsilyl group Chemical group 0.000 description 3
- 239000001431 2-methylbenzaldehyde Substances 0.000 description 2
- LGZKGOGODCLQHG-CYBMUJFWSA-N 5-[(2r)-2-hydroxy-2-(3,4,5-trimethoxyphenyl)ethyl]-2-methoxyphenol Chemical compound C1=C(O)C(OC)=CC=C1C[C@@H](O)C1=CC(OC)=C(OC)C(OC)=C1 LGZKGOGODCLQHG-CYBMUJFWSA-N 0.000 description 2
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- 239000004215 Carbon black (E152) Substances 0.000 description 2
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- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
- C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/52—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an inorganic compound, e.g. an inorganic ion that is complexed with the active ingredient
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/12—Esters of phosphoric acids with hydroxyaryl compounds
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The specification relates to a cis-stilbene prodrug (as shown below) where, R1, R2 and R3 are each independently alkyl; R4 is alkyl, haloalkyl, alkenyl, alkynyl, alkythio, alkylsulphinyl, alkylsulphonyl or halo; R5 is hydrogen, alkoxy, alkyl, alkylthio, hydroxyl or halo; and X is a group that can be removed in vivo by hydrolysis. The composition of this drug can be used in the treatment of diseases involving neovascularisation including, cancer, diabetic retinopathy, psoriasis, rheumatoid arthritis, artherosclerosis or macular degeneration.
Description
New Zealand Paient Spedficaiion for Paient Number 517069
PCT/G800/03067
5170
NEW STILBENES WITH VASCULAR DAMAGING ACTIVITY
Formation of new vasculature by angiogenesis is a key pathological feature of several diseases (J Folkman, New England Journal of Medicine 333, 1757-1763 (1995)). For example, for a solid tumour to grow it must develop its own blood supply upon which it depends critically for the provision of oxygen and nutrients; if this blood supply is mechanically shut off the tumour undergoes necrotic death. Neovascularisation is also a clinical feature of skin lesions in psoriasis, of the invasive pannus in the joints of rheumatoid arthritis patients and of atherosclerotic plaques. Retinal neovascularisation is pathological in macular degeneration and in diabetic retinopathy. In all these diseases reversal of neovascularisation by damaging the newly-formed vascular endothelium is expected to have a beneficial therapeutic effect.
Compounds able to damage neovasculature have advantages in the treatment of disease. For example, attacking tumour vasculature has several important advantages over a direct attack on the tumour. In particular the endothelial cells of tumour vasculature are more genetically stable than those of the tumour itself and are therefore less likely to become resistant to the damaging agent. Thus a major problem in conventional anti-tumour chemotherapy, that of drug resistance, is circumvented by this approach. Furthermore, since the endothelial cells of the tumour vasculature, unlike the tumour cells themselves, are similar between different solid tumour types, vascular damaging agents are able to attack a wide range of tumour types.
A number of tubulin-binding agents including the stilbenes combretastatin Al, combretastatin A4 (D. J. Chaplin et a/.,British J. Cancer 27, S86-S88 (1996))and combretastatin A4 phosphate (D.J. Chaplin et al., Anticancer Research .19, 189-196, (1999)) are known to selectively damage neovasculature of solid tumours in animal models. While there are reports of the activity of other analogues of combretastatin A4 in tubulin binding assays, in cytotoxicity assays and in tumour models there have been no reports of the vascular damaging activities of analogues. Since the activity of
tubulin-binding compounds against in vitro assays are poor predictors of selective vascular damaging activity and activity of such compounds in vivo can also be mediated by direct antimitotic effects on the tumour itself, no prediction can be made of the selective vascular damaging activity of known or novel analogues of the 5 combretastatins from published reports. Thus compounds which have the advantages of a selective anti-vascular mechanism given above, rather than acting through a direct effect on the tumour tissue itself are not apparent.
We have found a series of novel c/s-stilbenes with vascular damaging activity. These 10 compounds specifically damage newly-formed vascular endothelium, especially that associated with solid tumours, without affecting the normal, established vascular endothelium of the host species. Such compounds are of use in the prophylaxis and treatment of cancers involving solid tumours and in other diseases where there is inappropriate formation of new vasculature such as diabetic retinopathy, psoriasis, 15 rheumatoid arthritis, macular degeneration and the formation of atherosclerotic plaques.
Known vascular-damaging stilbenes, combretastatin Al, combretastatin A4 and combretastatin A4 phosphate have a 4-methoxy group in the "B" ring. The 20 compounds of the invention lack a 4-methoxy group in the ring corresponding to the "B" ring of combretastatin A4. Several studies suggest that substituting alternative groups for the 4-methoxy group in the B-ring of combretastatin A4 would considerably reduce biological activity:
In J. Med. Chem 1991, 34, 2579-2588, Cushman et al. state, regarding analogues of combretastatin A4: "the presence of a 4-methoxy group in the B-ring plays a very important role for this compound to be highly cytotoxic". Replacement of the 4-methoxy group with chlorine, for example, gave compounds that were three to four orders of magnitude less potent against a panel of five different cell lines.
3
(followed by page 3a)
In J. Med. Chem. 1998, 41, 3022-3032 Ohsumi et al disclose anilino analogues of combretastatin A4 in which the replacement of the B-ring 4-methoxy group by either a methyl group or a chlorine atom gave a reduction in biological potency of 8.5-fold and 13.5-fold respectively.
Similarly in Brit. J. Cancer 1995, 71, 705-711 Woods et al. disclose analogues of combretastatin with reduced potency. For example the 4-methyl compound shows 3.5 to 36-fold reduction in potency against four cell lines compared to the 4-methoxy compound.
It cannot be anticipated from the above studies that compounds in which the B-ring 4-methoxy group is replaced would retain anti-vascular activity. It is particularly unexpected that replacing the B-ring methoxy group of combretastatin A4 would result in a compound with similar potency as a vascular damaging agent.
Thus according to one aspect of the invention we provide a compound of formula (1):
Wherein:
R',R2 and R3 are each independently alkyl,
R4 is alkyl, haloalkyl, alkenyl, alkynyl, alkylthio, alkylsulphinyl, alkylsulphonyl or halo, R5 is hydrogen, alkoxy, alkyl, alkylthio, hydroxy or halo,
and the pharmaceutical^ acceptable salts, solvates, hydrates and prodrugs thereof.
intellectual property office of n.z.
2 9 JAN 2004 RECEIVED
3a
In a particular aspect, the present invention provides a cis-stilbene prodrug of formula:
wherein:
R1, R2 and R3 are each independently alkyl;
R4 is alkyl, haloalkyl, alkenyl, alkynyl, alkylthio, alkylsulphinyl, alkylsulphonyl or halo;
R5 is hydrogen, alkoxy, alkyl, alkylthio, hydroxyl or halo; and X is a group which can be removed in vivo by hydrolysis.
In another aspect, the present invention provides a composition for use in the treatment of neovascularisation which composition contains an effective amount of the cis-stilbene prodrug of the present invention and a pharmaceutical^ acceptable excipient.
In still another aspect, the present invention provides a use of a cis-stilbene prodrug of the present invention in the manufacture of a medicament for the treatment of a disease involving neovascularisation.
4
As used herein the term "alkyl", alone or in combinations, means a straight or branched-chain alkyl group containing from one to seven, preferably a maximum of four, carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl and pentyl. Examples of alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, 5 butoxy and t-butoxy.
The term "halogen" means fluorine, chlorine, bromine or iodine.
An alkenyl group may be for example an olefinic group containing from two to seven 10 carbon atoms for example methylene, ethylene, n-propylene, i-propylene, n-butylene, i-butylene, s-butylene and t-butylene. An alkynyl group may be for example an ethynyl, propynyl or butynyl group.
Where one or more functional groups in compounds of formula (1) are sufficiently 15 basic or acidic the formation of salts is possible. Suitable salts include pharmaceutically acceptable salts for example acid addition salts including hydrochlorides, hydrobromides, phosphates, sulphates, hydrogen sulphates, alkylsulphonates, arylsulphonates, acetates, benzoates, citrates, maleates, fiimarates, succinates, lactates and tartrates, salts derived from inorganic bases including alkali metal salts such as 20 sodium or potassium salts, alkaline earth metal salts such as magnesium or calcium salts, and salts derived from organic amines such as morpholine, piperidine or dimethylamine salts.
Prodrugs of the invention are compounds which upon administration to a mammal 25 produce compounds of formula (1). Such prodrugs can be for example converted within the mammal by hydrolysis. Prodrugs are preferably ester derivatives of the phenolic hydroxy group contained in compounds of formula (1) such as, for example, phosphate esters, carboxylate esters, sulphate esters and carbonates.
Preferred compounds of the invention are those of formula 1 in which R1, R2 and R3 are all methyl, and prodrugs thereof
PCT/G B00/03067
Further preferred compounds of the invention are those of formula 1 in which R1, R2 and R3 are all methyl and R5 is hydrogen and prodrugs thereof
Still further preferred compounds of the invention are those of formula 1 in which R1, R2 and R3 are all methyl, R5 is hydrogen and R4 is alkyl or halo and prodrugs thereof
Preferred prodrugs of the invention are phosphate esters. Particularly preferred prodrugs of the invention are dihydrogen phosphate esters.
Specifically preferred compounds of the invention are:
(Z)-l-(3-hydroxy-4-methylphenyI)-2-(3,4,5-trimethoxyphenyl)ethene
(Z)-2-methyl-5-[2-(3,4,5-trimethoxyphenyl)ethenyl]phenyl dihydrogen phosphate
Compounds of the invention can be prepared by any process known to a person skilled in the art. Compounds of formulae (1) can be prepared by a number of processes as generally described hereinbelow and more specifically in the Examples hereinafter. In the general preparations described below it may be necessary to employ protecting groups which are then removed during the final stages of the synthesis. The appropriate use of such protecting groups and processes for their removal will be readily apparent to those skilled in the art. In the following process description, the symbols R1, R2, R\ R4 and R5, when used in the formulae depicted are to be understood to represent those groups described above in relation to formula (1) unless otherwise indicated
In one general example compounds of formula (1) can be prepared by Wittig olefin synthesis involving reaction of a phosphonium salt of formula (2) with a strong base, for example an alkyllithium such as n-butyllithium or t-butyllithium or a metal hydride such as sodium hydride in a solvent such as an ether solvent for example diethyl ether
6
or tetrahydrofuran or in a solvent such as a hydrocarbon solvent for example toluene at a temperature of between about -I00°C to about 30°C followed by treatment with an aldehyde of formula (3) in which R6 is a protecting group, to give an intermediate of formula (4). The synthesis of compounds of formula (1) is then completed by removal of the group R6. Suitable protecting groups R6 include trialkylsilyl, for example t-butyldimethylsilyl, and allyl. Where R6 is a trialkylsilyl group it may be removed, for example, by treatment with a quaternary ammonium fluoride such as tetrabutylammonium fluoride in an ether solvent such as tetrahydrofuran at a temperature of about -30°C to about 40°C conveniently at or near ambient temperature. Where R6 is an allyl group it may be removed for example by treatment with a palladium(O) complex such as tetrakis(triphenylphosphine)Pd(0) in a solvent such as a chlorinated solvent, for example dichloromethane, at a temperature of about -40°C to about 40°C conveniently at or near ambient temperature, in the presence of an allyl scavenger such as morpholine.
Aldehydes of formula (3) can be prepared by any process known to a person skilled in the art. In one general example an aldehyde of formula (3) can be prepared from an alcohol of formula (5) by oxidation with a suitable oxidising agent. Suitable oxidising agents include the Dess-Martin reagent and manganese dioxide. Alcohols of formula (5) can be prepared by application of standard methods of organic synthesis including the selective protection of phenols of formula (6). Where the protecting group R6 is a trialkylsilyl group, for example t-butyldimethylsilyl, alcohols of formula (5) may be prepared, for example, by treatment of a phenol of formula (6) with a strong base, for example an alkyllithium such as n-butyllithium or t-butyllithium or a metal hydride such as sodium hydride in a solvent such as an ether solvent for example diethyl ether or tetrahydrofuran or in a solvent such as a hydrocarbon solvent for example toluene at a
(i)
7
temperature of between about -100°C to about 40°C followed by treatment with tert-butylchlorodimethylsilane.
Phenols of formula (6) are either known or may be prepared from known compounds 5 using standard methods of organic synthesis.
Compounds of formula (1) may also be prepared from other compounds of formula 10 (1) by chemical modification. Examples of such chemical modifications that may be applied are standard alkylation, halogenation, oxidation and coupling reactions. These reactions may be used to add new substituents or to modify existing substituents.
Prodrugs of compounds of formula (1) can be prepared by any process known to a 15 person skilled in the art. Processes for the preparation of prodrugs of compounds of formula 1 include standard acyiation, sulphation and phosphorylation reactions. In one general example dihydrogen phosphate esters of compounds of formula (1) can be prepared by treatment of the corresponding di-t-butylphosphate esters with an acid, for example hydrochloric acid or trifluoroacetic acid, in a solvent such as a chlorinated 20 solvent, for example dichloromethane, at a temperature of from about -20°C to about 40°C, conveniently at room temperature.
Compounds according to the invention are able to destroy tumour vasculature and vasculature that has been newly formed while leaving unaffected normal, mature 25 vasculature. The ability of the compounds to act in this way may be determined by the tests described hereinafter.
PCT/GBOO/03067
The compounds according to the invention are thus of particular use in the prophylaxis and treatment of cancers involving solid tumours and in the prophylaxis and treatment of diseases where inappropriate angiogenesis occurs such as diabetic retinopathy, psoriasis, rheumatoid arthritis, atherosclerosis and macular degeneration.
The compounds of the invention may be administered as a sole therapy or in combination with other treatments. Thus the invention includes compositions for the treatment of neovascularisation which compositions contain an effective amount of a cis-stilbene or prodrugs thereof as hereinbefore defined. The invention also includes 10 the use in the preparation of a composition for the treatment of neovascularisation of a cis-stilbene or prodrugs therof as hereinbefore defined. For the treatment of solid tumours compounds of the invention may be administered in combination with radiotherapy or in combination with other anti-tumour substances for example those selected from mitotic inhibitors, for example vinblastine, vincristine, vinorelbine, 15 paclitaxel and docetaxel; platinum derivatives for example cisplatin and carboplatin; alkylating agents, for example melphalan, chlorambucil, busulphan, ifosfamide and cyclophosphamide; antimetabolites, for example methotrexate, 5-fluorouracil, cytosine arabinoside, gemcitabine and hydroxyurea; antitumour antibiotics for example bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin,mitomycin-C, 20 dactinomycin and mithramycin ; enzymes, for example aspariginase; topoisomerase inhibitors for example etoposide,teniposide, topotecan and irinotecan; thymidylate synthase inhibitors for example raltitrexed; biological response modifiers for example interferon; antibodies for example edrecolomab and trastuzumab; anti-hormones for example tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfene, anastrozole, 25 letrazole, vorazole ,exemestane, flutamide, nilutamide and bicalutamide; anti-growth factor compounds for example EGFr tyrosine kinase inhibitors VEGFr kinase inhibitors and PDGFr tyrosine kinase inhibitors; and anti-angiogenesis agents such as angiostatin, endostatin and thalidomide. Such combination treatment may involve simultaneous or sequential application of the individual components of the treatment.
For the prophylaxis and treatment of disease the compounds according to the invention may be administered as pharmaceutical compositions selected with regard to the intended route of administration and standard pharmaceutical practice. Such pharmaceutical compositions may take a form suitable for oral, buccal, nasal, topical, 5 rectal or parenteral administration and may be prepared in a conventional manner using conventional excipients. For example for oral administration the pharmaceutical compositions may take the form of tablets or capsules. For nasal administration or administration by inhalation the compounds may be conveniently delivered as a powder or in solution. Topical administration may be as an ointment or cream and rectal 10 administration may be as a suppository. For parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) the composition may take the form of, for example, a sterile solution, suspension or emulsion.
The dose of a compound of the invention required for the prophylaxis or treatment of a 15 particular condition will vary depending on the compound chosen, the route of administration, the form and severity of the condition and whether the compound is to be administered alone or in combination with another drug. Thus the precise dose will be determined by the administering physician but in general daily dosages may be in the range 0.001 to lOOmg/kg preferably 0.1 to lOmg/kg.
BIOLOGICAL ACTIVITY
The following test was used to demonstrate the activity of compounds according to the invention.
Activity against tumour vasculature measured bv fluorescent dve.
The following experiment further demonstrates the ability of the compounds to damage tumour vasculature.
Tumour functional vascular volume in CaNT tumour-bearing mice was measured using 30 the fluorescent dye Hoechst 33342 according to the method of Smith el a! (Brit J Cancer 57, 247-253, 1988). At least three animals were used in control and treated
groups. The fluorescent dye was dissolved in saline at 6.25 mg/ml and injected intravenously at 10 mg/kg 24 hours after intraperitoneal drug treatment. One minute later, animals were killed and tumours excised and frozen; 10 sections were cut at 3 different levels and observed under UV illumination using an Olympus microscope 5 equipped with epifluorescence. Blood vessels were identified by their fluorescent outlines and vascular volume was quantified using a point scoring system based on that described by Chalkley, (J Natl Cancer Inst, 4, 47-53, 1943). All estimates were based on counting a minimum of 100 fields from sections cut at the 3 different levels. Examples of the activity of compounds of the invention in this test are given in the 10 table:
Compound of Example
Dose (mg/kg)
% Reduction in Functional Vascular Volume
1
50
88
3
50
27
50
The following non-limiting Examples illustrate the invention:
EXAMPLE 1
CZ)-l-<'3-hvdroxv-4-methvlphenvl)-2-G.4.5-trimethoxvphenvl')ethene
A solution of l-(3-/tv7-butyldimethylsilyloxy-4-methylphenyl)-2-(3,4,5-trimethoxyphenyl)ethene (491 mg) in anhydrous tetrahydrofuran (10ml) at room temperature was treated slowly with a 1.1M solution of tetrabutylammonium fluoride 25 in tetrahydrofuran (1.1 ml). After 30 minutes crushed ice (5ml) and diethylether (30ml)
were added and the aqueous phase extracted with diethylether (5 portions of 5ml). The combined extracts were washed with water (3 portions of 10ml) and brine (10ml), dried (MgS04) and concentrated under reduced pressure to give a solid. Recrystallisation from ethyl acetate/hexane gave the title compound (208mg) as a 5 white solid m.p. 123-125°C. nmr: 5H (500MHz, d6-DMSO) 2.07 (s, 3H), 3.57 (s, 6H), 3.62 (s, 3H), 6.40 (d, J = 12Hz, 1H), 6.46 (d, J = 12 Hz, 1H), 6.56 (s, 2H), 6.61 (dd, J = 8Hz, 2Hz, 1H), 6.76 (d, J= 1.7Hz, 1H), 6.98 (d, J = 8Hz, 1H), 9.21 (s 1H).
The l-(3-fcr/-butyldimethylsilyloxy-4-methylphenyl)-2-(3,4,5-trimethoxyphenyl)ethene 10 used as starting material in the above preparation was prepared as follows:
A suspension of 3,4,5-trimethoxybenzyltriphenylphosphonium bromide (848mg) in dry tetrahydrofuran (50ml) at -78°C was treated dropwise with n-butyllithium (0.9ml of a 1.8M solution in hexane) and the mixture allowed to warm to -40°C and stir for lh. The mixture was recooled to -78°C and a solution of 3-ter/-butyldimethylsilyIoxy-4-15 methylbenzaldehyde (390mg) in tetrahydrofuran (40ml) added slowly. After a further 2h the mixture was allowed to warm to room temperature before being poured into ice water (20ml). The aqueous phase was extracted with diethylether (5 portions of 20ml) and the combined extracts were washed with water (3 portions of 20ml) and brine (2 portions of 20ml), dried (MgS04) and concentrated under reduced pressure to give an 20 oil. Purification by chromatography on silica gel, eluting with petroleum ether / ethyl acetate (90:10) gave l-(3-/cj/7-butyldimethylsilyloxy-4-methylphenyl)-2-(3,4,5-trimethoxyphenyI)ethene (456mg) as a red oil.
The 3-fcr/-butyldimethylsilyloxy-4-methylbenzaldehyde used as starting material in the 25 above preparation was prepared as follows:
A solution of Dess-Martin periodinane (187mg) in dichloromethane (4ml) was treated slowly with a solution of 3-te/7-butyidimethylsilyloxy-4-methylbenzyl alcohol (lOOmg) in dichloromethane (4ml) and the mixture stirred for lh at room temperature. Diethylether (10ml) was added followed by aqueous sodium thiosulphate solution 30 (10ml) and the mixture stirred for 15 minutes. The aqueous phase was extracted with diethylether (5 portions of 20ml) and the combined extracts were washed with aqueous
12
sodium thiosulphate solution (3 portions of lOml), water (3 portions of 10ml) and brine (2 portions of 10ml), dried (MgS04) and concentrated under reduced pressure to give a yellow solid. Purification by chromatography on silica gel, eluting with petroleum ether / diethyl ether (50:50) gave 3-te/7-butyldimethyIsilyIoxy-4-methylbenzaldehyde (85mg).
The 3-/e/7-butyldimethylsilyloxy-4-methylbenzyl alcohol used as starting material in the above preparation was prepared as follows:
A solution of 3-hydroxy-4-methylbenzyl alcohol (275mg) in dry tetrahydrofuran (15ml) at -78°C was treated slowly with n-butyllithium (1.2ml of a 1.8M solution in hexane) and the mixture stirred for 15minutes before being allowed to warm to room temperature and stir for a further 30minutes. A solution of tert-butylchlorodimethylsilane (287mg) in tertrahydrofuran (10ml) was added and the mixture stirred for 16h. Water (20ml) was added and the mixture extracted with diethylether (5 portions of 20ml) and the combined extracts were washed with water (2 portions of 10ml) and brine (20ml), dried (MgS04) and concentrated under reduced pressure. Purification by chromatography on silica gel, eluting with petroleum ether / diethyl ether (50:50) gave 3-/cj/7-butyldimethyIsilyloxy-4-methylbenzyl alcohol (390mg).
EXAMPLE 2
(Z)-2-methvl-5-[2-(3.4.5-trimethoxvphenvPethenvl'|phenvl dihydrogen phosphate
Trifluoroacetic acid (0.22mL, 2.95mmol) was added dropwise to a stirred solution of (Z)-2-methyl-5-[2-(3,4,5-trimethoxyphenyl)ethenyl]phenyl di-fcr/butyl phosphate (401mg, 0.82mmol) and dichloromethane (16mL). The mixture was stirred at room temperature overnight. Solvent was removed in vacuo, and the residue azeotroped four times with toluene. The colourless oil was triturated with ether to give the title compound as a white solid (181mg, 58%) m.p. 109-113°C. nmr: 5H (500MHz, d6-DMSO) 2.39 (s, 3H), 3.81 (s, 6H), 3.87 (s, 3H), 6.69 (d, J=12Hz, 1H), 6.74 (d,
PCT/GBOO/03067
13
j=12Hz, IH), 6.78 (s, 2H), 7.07 (d, J=8Hz, IH), 7.28 (d, J=8Hz, IH), 7.49 (s, IH), 9.0 (bs, 2H).
(Z)-2-methyl-5-[2-(3,4,5-trimethoxyphenyl)ethenyl]phenyI di-tertbutyl phosphate was prepared as follows:
Di-ter/-butylphosphoramidite (498mg, 2.00mmol) in dichloromethane (lmL) was added to a solution of (Z)-l-(3-hydroxy-4-methyIphenyI)-2-(3,4,5-trimethoxyphenyl)ethene (300mg, l.OOmmol), l//-tetrazole (182mg, 2.60mmol) in dichloromethane (3mL) under nitrogen. After 2h, magnesium monoperoxyphthalate hexahydrate (1.24g, 2.00mmol) was added in portions. After stirring for a further 2h, the reaction mixture was partitioned between ethyl acetate and water; the aqueous phase was extracted (ethyl acetate x2); the combined organic extracts were washed (water x2, brine xl); dried (MgS04) and concentrated in vacuo. Flash chromatography, eluting with 33% ethyl acetate/hexane, gave (Z)-2-methyl-5-[2-(3,4,5-trimethoxyphenyl)ethenyl]phenyl di-/er/butyl phosphate as a yellow oil (401mg, 82%).
EXAMPLE 3
(ZVl-(4-f]uoro-3-hvdroxvphenvP-2-f3.4.5-trimethoxvphenv0ethene
This compound was isolated directly from the Wittig reaction between 3,4,5-trimethoxybenzyltriphenylphosphoniurn bromide and 3-te/7-butyIdimethyIsilyloxy-4-fluorobenzaldehyde (340mg) performed in an analogous manner to that of Example 1. There was obtained the title compound (80mg) as a colourless oil. nmr: (300MHz, d6-DMSO) 3.59 (s, 6H), 3.63 (s, 3H), 6.46 (d, J=12Hz, IH), 6.48 (d, J=12Hz, IH), 6.54 (s, 2H), 6.68 (m, IH), 6.90 (dd, J=8.8, 2.1Hz, IH), 7.06 (dd, J=11.4, 8.4Hz, IH), 9.80 (s, IH).
The following compounds were prepared in an analogous manner to that of Example 1:
14
EXAMPLE 4
fZ>-l-C4-chloro-3-hvdroxvphenvlV2-(3.4.5-trimethoxvphenvl')ethene
From (Z)-l-(3-te/7-butyldimethylsiiyloxy-4-chlorophenyl)-2-(3,4,5-trimethoxyphenyl)ethene (240mg) there was obtained the title compound (121mg) as a colourless oil. nmr: (300MHz, d6-DMSO) 3.59 (s, 6H), 3.63 (s, 3H), 6.49 (m, 2H), 6.54 (s, 2H), 6.71 (dd, J=8.2, 0.9Hz, IH), 6.93 (d, J=0.9Hz, IH), 7.25 (d, J=8.2Hz, IH), 10.11 (bs, lH).m/e 320 (M+).
EXAMPLE 5
(Z)-l-('4-ethvl-3-hvdroxvphenvn-2-f3.4.5-trimethoxvphenvnethene
From (Z)-l-(3-/c?/7-butyldimethylsilyloxy-4-ethylphenyl)-2-(3,4,5-trimethoxyphenyl)ethene (926mg) there was obtained the title compound (208mg) as a white solid m.p. 105-107°C, nmr: 5H (300MHz, CDC13) 1.02 (t, J=7.6Hz, 3H), 2.6 (q, J=7.5Hz, 2H) 3.7 (s, 6H), 3.8 (s, 3H), 4.6 (bs, IH), 6.4 (d, J = 12Hz, IH), 6.5 (d, J = 12 Hz, IH), 6.5 (s, 2H), 6.7 (s,lH), 6.8 (d, J= 7.6Hz, IH), 7.0 (d, J = 7.6Hz, IH).
Claims (19)
1. A cis-stilbene prodrug of formula: wherein: R1, R2 and R3 are each independently alkyl ; R4 is alkyl, haloalkyl, alkenyl, alkynyl, alkylthio, alkylsulphinyl, alkylsulphonyl or halo; R5 is hydrogen, alkoxy, alkyl, alkylthio, hydroxyl or halo; and X is a group which can be removed in vivo by hydrolysis.
2. A cis-stilbene prodrug according to claim 1 wherein: R1, R2 and R3 are all methyl.
3. A cis-stilbene prodrug according to claim 1 or 2, wherein: R5 is hydrogen and R4 is alkyl or halo.
4. A cis-stilbene prodrug according to claim 3 wherein R4 is methyl.
5. A cis-stilbene prodrug according to claim 1, 2, 3 or 4, which is a carboxylic ester, phosphate ester, sulphate ester or carbonate.
6. A cis-stilbene prodrug according to claim 5, which is a phosphate ester.
7. A cis-stilbene prodrug according to claim 5 or 6, which is a dihydrogen phosphate ester. intellectual property office of n.z. 2 9 JAN 2004 RECEIVED 16
8. (Z)-2-methyl-5-[2-(3,4,5-trimethoxyphenyl)ethenyl]phenyl dihydrogen phosphate.
9. A composition for use in the treatment of neovascularisation which composition contains an effective amount of the cis-stilbene dihydrogen phosphate according to claim 8 and a pharmaceutically acceptable excipient.
10. A composition for use in the treatment of neovascularisation which composition contains an effective amount of the cis-stilbene prodrug according to any one of claims 1 to 7 and a pharmaceutically acceptable excipient.
11. A composition as claimed in claim 9 or 10 in combination with at least one further anti-tumour substance.
12. A use of a cis-stilbene prodrug as defined in any one of claims 1 to 8 in the manufacture of a medicament for the treatment of a disease involving neovascularisation.
13. A use according to claim 12, wherein the disease is cancer involving a solid tumour.
14 A use according to claim 13, wherein said medicament is for administration in combination with radiotherapy or another anti-tumour substance.
15. A use according to claim 12, wherein the disease is diabetic retinopathy, psoriasis, rheumatoid arthritis, atherosclerosis or macular degeneration.
16. A use according to any one of claims 12 to 15, wherein the cis-stilbene prodrug is (Z)-2-methyl-5-[2-(3,4,5-trimethoxyphenyl)ethenyl]phenyl dihydrogen phosphate. | . .TELLErriiAL PROPERTY of:;scf of n.z. 13 FEB 2004 17
17. A use according to any one of claims 12 to 16, substantially as herein described.
18. A composition according to claim 9, 10 or 11, substantially as herein described.
19. A cis-stilbene prodrug according to any one of claims 1 to 8, substantially as herein described. intellectual property office of n.z. 2 9 JAN 2004 RECEIVED
Applications Claiming Priority (2)
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GBGB9918912.8A GB9918912D0 (en) | 1999-08-12 | 1999-08-12 | New stilbenes with vascular damaging activity |
PCT/GB2000/003067 WO2001012579A2 (en) | 1999-08-12 | 2000-08-09 | New stilbenes with vascular damaging activity |
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EP (1) | EP1206429A2 (en) |
JP (1) | JP2003507356A (en) |
CA (1) | CA2379544A1 (en) |
GB (1) | GB9918912D0 (en) |
NZ (1) | NZ517069A (en) |
WO (1) | WO2001012579A2 (en) |
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HUP0102521A3 (en) | 1998-04-03 | 2003-08-28 | Ajinomoto Kk | Antitumor agents comprising a stilbene derivative and a platinum coordination compound |
GB0019944D0 (en) | 2000-08-15 | 2000-09-27 | Angiogene Pharm Ltd | Compositions with vascular damaging activity |
EP1351912A2 (en) * | 2000-12-21 | 2003-10-15 | Cancer Research Ventures Limited | Substituted stilbenes, their reactions and anticancer activity |
FR2838437B1 (en) | 2002-04-11 | 2004-06-04 | Aventis Pharma Sa | PROCESSES FOR THE PREPARATION OF COMBRETASTATINS |
GB0306908D0 (en) * | 2003-03-26 | 2003-04-30 | Angiogene Pharm Ltd | Bioreductively activated stilbene prodrugs |
TW200533636A (en) * | 2003-12-16 | 2005-10-16 | Gtx Inc | Prodrugs of selective androgen receptor modulators and methods of use thereof |
CN1723884A (en) | 2004-07-21 | 2006-01-25 | 中国人民解放军军事医学科学院放射医学研究所 | Cis-1, the diphenyl ethylene derivatives that 2-replaces are used to prepare the purposes of the medicine of treatment or prevent diabetes |
CN101085743B (en) * | 2006-06-06 | 2012-02-15 | 浙江大德药业集团有限公司 | Fluorine-containing alkoxy combretastatin derivative, preparation method and use thereof |
AU2008326251B2 (en) | 2007-11-21 | 2014-03-06 | Mateon Therapeutics, Inc. | Method for treating hematopoietic neoplasms |
JP2011016777A (en) * | 2009-07-10 | 2011-01-27 | Nipro Corp | New cysteine derivative |
EP2609089A1 (en) | 2010-08-27 | 2013-07-03 | Universität des Saarlandes | Selective 17beta-hydroxysteroid dehydrogenase type 1 inhibitors |
US9353150B2 (en) | 2012-12-04 | 2016-05-31 | Massachusetts Institute Of Technology | Substituted pyrazino[1′,2′:1 ,5]pyrrolo[2,3-b]-indole-1,4-diones for cancer treatment |
AU2014228822A1 (en) | 2013-03-15 | 2015-10-01 | Memorial Sloan-Kettering Cancer Center | HSP90-targeted cardiac imaging and therapy |
US11419934B2 (en) | 2015-08-18 | 2022-08-23 | Oncotelic Therapeutics, Inc. | Use of VDAS to enhance immunomodulating therapies against tumors |
US10918627B2 (en) | 2016-05-11 | 2021-02-16 | Massachusetts Institute Of Technology | Convergent and enantioselective total synthesis of Communesin analogs |
US11932650B2 (en) | 2017-05-11 | 2024-03-19 | Massachusetts Institute Of Technology | Potent agelastatin derivatives as modulators for cancer invasion and metastasis |
US10640508B2 (en) | 2017-10-13 | 2020-05-05 | Massachusetts Institute Of Technology | Diazene directed modular synthesis of compounds with quaternary carbon centers |
CN113227398A (en) | 2018-10-29 | 2021-08-06 | 塞弗德公司 | Exponential-base-3 nucleic acid amplification with nested overlapping primers at reduced amplification time |
WO2020247054A1 (en) | 2019-06-05 | 2020-12-10 | Massachusetts Institute Of Technology | Compounds, conjugates, and compositions of epipolythiodiketopiperazines and polythiodiketopiperazines and uses thereof |
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TW325458B (en) * | 1993-09-08 | 1998-01-21 | Ajinomoto Kk | Stilbene derivatives and pharmaceutical compositions comprising the same for anti-cancer |
US5561122A (en) * | 1994-12-22 | 1996-10-01 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Combretastatin A-4 prodrug |
GB9903403D0 (en) * | 1999-02-16 | 1999-04-07 | Angiogene Pharm Ltd | Substituted stilbene compounds with vascular damaging activity |
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- 2000-08-09 JP JP2001516880A patent/JP2003507356A/en active Pending
- 2000-08-09 EP EP00951727A patent/EP1206429A2/en not_active Withdrawn
- 2000-08-09 WO PCT/GB2000/003067 patent/WO2001012579A2/en not_active Application Discontinuation
- 2000-08-09 CA CA002379544A patent/CA2379544A1/en not_active Abandoned
- 2000-08-09 NZ NZ517069A patent/NZ517069A/en unknown
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GB9918912D0 (en) | 1999-10-13 |
WO2001012579A3 (en) | 2001-10-11 |
WO2001012579A2 (en) | 2001-02-22 |
JP2003507356A (en) | 2003-02-25 |
EP1206429A2 (en) | 2002-05-22 |
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