WO2008070908A1 - Chemical compounds and processes - Google Patents
Chemical compounds and processes Download PDFInfo
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- WO2008070908A1 WO2008070908A1 PCT/AU2007/001908 AU2007001908W WO2008070908A1 WO 2008070908 A1 WO2008070908 A1 WO 2008070908A1 AU 2007001908 W AU2007001908 W AU 2007001908W WO 2008070908 A1 WO2008070908 A1 WO 2008070908A1
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- alkyl
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- 0 CCCC1C(CCC)C(*)=C(*)*1 Chemical compound CCCC1C(CCC)C(*)=C(*)*1 0.000 description 13
- MIMWDGDLJCJLQS-UHFFFAOYSA-N CC(C=C1)=C(C)NC1=O Chemical compound CC(C=C1)=C(C)NC1=O MIMWDGDLJCJLQS-UHFFFAOYSA-N 0.000 description 1
- YIJYGMPPWWXWLA-UHFFFAOYSA-N CC(C=N1)=C(C)NC1=O Chemical compound CC(C=N1)=C(C)NC1=O YIJYGMPPWWXWLA-UHFFFAOYSA-N 0.000 description 1
- PTURTHBRTGJYRN-UHFFFAOYSA-N CC1=C(C)NC=CC1=O Chemical compound CC1=C(C)NC=CC1=O PTURTHBRTGJYRN-UHFFFAOYSA-N 0.000 description 1
- NAXVHUMRNKLTEH-UHFFFAOYSA-N COc(cc1)ccc1-c([o]c1nc(OC)ncc11)c1-c(cc1OC)cc(OC)c1OC Chemical compound COc(cc1)ccc1-c([o]c1nc(OC)ncc11)c1-c(cc1OC)cc(OC)c1OC NAXVHUMRNKLTEH-UHFFFAOYSA-N 0.000 description 1
- FPQBSLROBCTRKR-UHFFFAOYSA-N C[n]1ncc(-c([o]c2cc(OC)cnc22)c2I)c1 Chemical compound C[n]1ncc(-c([o]c2cc(OC)cnc22)c2I)c1 FPQBSLROBCTRKR-UHFFFAOYSA-N 0.000 description 1
- GONPAYHDXQDYIW-UHFFFAOYSA-N C[n]1ncc(C#Cc(c(OC)c2)ncc2OC)c1 Chemical compound C[n]1ncc(C#Cc(c(OC)c2)ncc2OC)c1 GONPAYHDXQDYIW-UHFFFAOYSA-N 0.000 description 1
- OXQOBQJCDNLAPO-UHFFFAOYSA-N Cc1c(C)nccn1 Chemical compound Cc1c(C)nccn1 OXQOBQJCDNLAPO-UHFFFAOYSA-N 0.000 description 1
- XPCYMUBTCGGWOH-UHFFFAOYSA-N Cc1cncnc1C Chemical compound Cc1cncnc1C XPCYMUBTCGGWOH-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Definitions
- the present invention relates generally to chemical compounds and methods for their use and preparation.
- the invention relates to chemical compounds which may possess useful therapeutic activity, use of these compounds in methods of therapy and the manufacture of medicaments as well as compositions containing these compounds.
- Tubulin is an important target in controlling disease states associated with cell proliferation such as cancer and inflammation (eg, psoriasis).
- Tubulin is composed of a heterodimer of two related proteins called ⁇ and ⁇ tubulin.
- Tubulin polymerises to form structures called microtubules.
- Compounds that inhibit tubulin's ability to polymerise to form microtubules interrupt cell division which is dependent on the formation of microtubules to form mitotic spindles. Examples of such compounds include the Vinca alkaloids such as vincristine and vinblastine.
- compounds that inhibit the depolymerisation of microtubules can also prevent cell division since they often disrupt the proper formation of mitotic spindles which must also disassemble in order for cell division to be completed. Interruption of the mitotic process in this manner often induces cell death by an apoptotic mechanism.
- compounds which act in this manner include the taxoids such as paclitaxel.
- diseased tissue is generally more sensitive to the effect of these agents because it is more likely to be in a state of mitosis which is the stage of a cell's life cycle affected by agents that target tubulin.
- a number of normal, healthy tissues also have quite high rates of proliferation (for example hair follicles and the lining of the gastro-intestinal tract) and accordingly, these tissues can be damaged during chemotherapy with these agents.
- Tubulin is also a target for treating disease states that are dependent or result from the abnormal formation of blood vessels (neovascularisation) such as in cancerous tumours and in ocular myopathy.
- neovascularisation blood vessels
- the cytoskeleton of the vascular endothelial cells are disrupted through depolymerisation of microtubles, which results from inhibiting the polymerisation of tubulin to form microtubules.
- Microtubule length is dependent on the rate of depolymerisation versus polymerisation. Depolymerising microtubles through inhibition of polymerisation leads to a change in endothelial cell morphology, which then causes a blockage or shutdown in blood flow.
- Neovascular systems are more sensitive to these agents because they are more dependent on microtubule cytoskeletons than normal, healthy, vascular endothelial cells which are also supported by actin based cytoskeletal structures.
- TPIs tubulin polymerisation inhibitors
- the vascular targeting modality can be achieved at a lower in vivo concentration than the antiproliferative modality.
- agents that target the colchicine binding domain of tubulin are potentially dual mode agents (ie. antimitotic and antivascular).
- CA4 combretastatin A4
- CA4P disodium phosphate
- the present invention provides compounds of formula (I) and salts thereof;
- X represents O, S, SO, SO 2 , Se, SeO, or SeO 2 ;
- Y represents a group of formula (i) or (ii);
- each R 1 ⁇ -R 1D independently represents H, carboxyl, cyano, dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, phosphono, phosphorylamino, phosphinyl, sulfo, trihaloethenyl, trihalomethanethio, trihalomethoxy, trihalomethyl, optionally substituted acyl, optionally substituted acylamino, optionally substituted acylimino, optionally substituted acyliminoxy, optionally substituted acyloxy, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted alkenyl, optionally substituted alkenyloxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted aminoacyl, optionally substituted aminoacyloxy, optionally substituted aminoacy
- Q represents H, CN, halogen, trialkylsilyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted acyl, optionally substituted oxyacyl, optionally substituted acylamino, optionally substituted aminoacylamino, OR", SR" or NR"R", where each R" independently represents, H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl and optionally substituted oxyacyl, or NR 11 TSfR", where each R'" independently represents H, optionally substituted alkyl, optionally substituted alkenyl,
- the present invention also provides a method for treating a disease state by inhibiting tubulin polymerisation including the step of administering to a patient in need thereof a compound of formula (II) or a pharmaceutically acceptable salt thereof;
- X represents O, S, SO, SO 2 , Se, SeO, SeO 2 or NR where R is selected from H, O, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkenyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, and optionally substituted sulfonyl;
- Y represents a group of formula (i) or (ii);
- each R 1 -R D independently represents H, carboxyl, cyano, dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, phosphono, phosphorylamino, phosphinyl, sulfo, trihaloethenyl, trihalomethanethio, trihalomethoxy, trihalomethyl, optionally substituted acyl, optionally substituted acylamino, optionally substituted acylimino, optionally substituted acyliminoxy, optionally substituted acyloxy, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted alkenyl, optionally substituted alkenyloxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted aminoacyl, optionally substituted aminoacyloxy, optionally substituted aminosulf
- Z' is H, optionally substituted alkyl, optionally substituted aryl or optionally substituted amino
- R' is selected from H, O, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkenyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted sulfonyl; and
- Q represents H, CN, halogen, trialkylsilyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted acyl, optionally substituted oxyacyl, optionally substituted acylamino, optionally substituted aminoacylamino, OR", SR" or NR 11 R", where each R" independently represents, H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl and optionally substituted oxyacyl, or NR 111 NR'", where each R" 1 independently represents H, optionally substituted alkyl, optionally substituted alkenyl,
- the present invention also provides the use of a compound of formula (II) or a salt thereof:
- X represents O 5 S, SO, SO 2 , Se, SeO, SeO 2 or NR where R is selected from H, O, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkenyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted sulfonyl;
- Y represents a group of formula (i) or (ii);
- each R 1A -R 1D independently represents H, carboxyl, cyano, dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, phosphono, phosphorylamino, phosphinyl, sulfo, trihaloethenyl, trihalomethanethio, trihalomethoxy, trihalomethyl, optionally substituted acyl, optionally substituted acylamino, optionally substituted acyliniino, optionally substituted acyliminoxy, optionally substituted acyloxy, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted alkenyl, optionally substituted alkenyloxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted aminoacyl, optionally substituted aminoacyl, optionally substituted aminoacyl
- Alkyl refers to monovalent alkyl groups which may be straight chained or branched and preferably have from 1 to 10 carbon atoms or more preferably 1 to 6 carbon atoms. Examples of such alkyl groups include methyl, ethyl, ⁇ -propyl, /jo-propyl, n-butyl, iso- butyl, «-hexyl, and the like. Especially preferred are “lower alkyl” groups which have 1 to 4 carbon atoms.
- Alkylene refers to divalent alkyl groups preferably having from 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms. Examples of such alkylene groups include methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), and the propylene isomers (e.g., -CH 2 CH 2 CH 2 - and -CH(CH 3 )CH 2 -), and the like.
- Aryl refers to an unsaturated aromatic carbocyclic group having a single ring (eg. phenyl) or multiple condensed rings (eg. naphthyl or anthryl), preferably having from 6 to 14 carbon atoms. Examples of aryl groups include phenyl, naphthyl and the like.
- Arylene refers to a divalent aryl group wherein the aryl group is as described above.
- Aryloxy refers to the group aryl-O- wherein the aryl group is as described above.
- Arylalkyl refers to — alkylene-aryl groups preferably having from 1 to 10 carbon atoms in the alkylene moiety and from 6 to 10 carbon atoms in the aryl moiety. Such arylalkyl groups are exemplified by benzyl, phenethyl and the like.
- Arylalkoxy refers to the group arylalkyl-O- wherein the arylalkyl group are as described above. Such arylalkoxy groups are exemplified by benzyloxy and the like.
- Alkoxy refers to the group alkyl-O- where the alkyl group is as described above. Examples include, methoxy, ethoxy, rc-propoxy, wo-propoxy, w-butoxy, tert-butoxy, sec- butoxy, /7-pentoxy, «-hexoxy, 1,2-dimethylbutoxy, and the like.
- Alkenyloxy refers to the group alkenyl-O- wherein the alkenyl group is as described above.
- Alkenylene refers to divalent alkenyl groups preferably having from 2 to 8 carbon atoms and more preferably 2 to 6 carbon atoms. Examples include ethenylene
- Alkynyl refers to alkynyl groups preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1, and preferably from 1-2, carbon to carbon, triple bonds.
- alkynyl groups include ethynyl (-C ⁇ CH), propargyl (-CH 2 C ⁇ CH), pent-2-ynyl (-CH 2 C ⁇ CCH 2 -CH 3 ), and the like.
- Alkynyloxy refers to the group alkynyl-O- wherein the alkynyl groups is as described above.
- Alkynylene refers to the divalent alkynyl groups preferably having from 2 to 8 carbon atoms and more preferably 2 to 6 carbon atoms. Examples include ethynylene (-C ⁇ C-), propynylene (-CH 2 -C ⁇ C-), and the like.
- Acyl refers to groups H-C(O)-, alkyl-C(O)-, cycloalkyl-C(O)-, aryl-C(O)-, heteroaryl- C(O)- and heterocyclyl-C(O)-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
- Oxyacyl refers to groups alkyl-OC(O)-, cycloalkyl-OC(O)-, aryl-OC(O)-, heteroaryl- OC(O)-, and heterocyclyl-OC(O)-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
- Amino refers to the group -NR*R* where each R* is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
- Aminoacyl refers to the group -C(0)NR*R* where each R* is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
- Acylamino refers to the group -NR 515 C(O)R* where each R* is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are as described herein.
- Acyloxy refers to the groups -OC(O)-alkyl, -OC(O)-aryl, -C(O)O-heteroaryl, and -C(O)O-heterocyclyl where alkyl, aryl, heteroaryl and heterocyclyl are as described herein.
- Aminoacyloxy refers to the groups -OC(O)NR* -alkyl, -OC(O)NR* -aryl, -OC(O)NR*-heteroaryl, and -OC(O)NR* -heterocyclyl where R* is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
- Oxyacylamino refers to the groups -NR*C(O)O-alkyl, -NR*C(O)O-aryl, -NR*C(O)O-heteroaryl, and NR*C(O)O-heterocyclyl where R* is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
- Oxyacyloxy refers to the groups -OC(O)O-alkyl, -O-C(O)O-aryl, -OC(O)O- heteroaryl, and -OC(O)O-heterocyclyl where alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are as described herein.
- Acylimino refers to the groups -C(NR*)-R* where each R* is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are as described herein.
- Acyliminoxy refers to the groups -0-C(NR*)-R* where each R* is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are as described herein.
- Oxyacylimino refers to the groups -C(NR*)-OR* where each R* is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are as described herein.
- Cycloalkyl refers to cyclic alkyl groups having a single cyclic ring or multiple condensed rings, preferably incorporating 3 to 8 carbon atoms.
- Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, and the like.
- Cycloalkenyl refers to cyclic alkenyl groups having a single cyclic ring and at least one point of internal unsaturation, preferably incorporating 4 to 8 carbon atoms.
- suitable cycloalkenyl groups include, for instance, cyclobut-2-enyl, cyclopent-3-enyl, cyclohex-4-enyl, cyclooct-3-enyl and the like.
- Halo or halogen refers to fluoro, chloro, bromo and iodo.
- Heteroaryl refers to a monovalent aromatic heterocyclic group which fulfils the H ⁇ ckel criteria for aromaticity (ie. contains 4n + 2 ⁇ electrons) and preferably has from 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen, selenium, and sulfur within the ring (and includes oxides of sulfur, selenium and nitrogen).
- Such heteroaryl groups can have a single ring (eg. pyridyl, pyrrolyl or N-oxides thereof or furyl) or multiple condensed rings (eg. indolizinyl, benzoimidazolyl, coumarinyl, quinolinyl, isoquinolinyl or benzothienyl).
- Heterocyclyl refers to a monovalent saturated or unsaturated group having a single ring or multiple condensed rings, preferably from 1 to 8 carbon atoms and from 1 to 4 hetero atoms selected from nitrogen, sulfur, oxygen, selenium or phosphorous within the ring. The most preferred heteroatom is nitrogen.
- heterocyclyl and heteroaryl groups include, but are not limited to, oxazole, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, isothiazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6, 7
- the heteroaryl or heterocyclyl group can be connected to the core molecule of the compounds of the present invention, as represented by formulae (I) (Ia) (Ib) and (II), through a C-C or C- heteroatom bond, in particular a C-N bond.
- Heteroarylene refers to a divalent heteroaryl group wherein the heteroaryl group is as described above.
- Heterocyclylene refers to a divalent heterocyclyl group wherein the heterocyclyl group is as described above.
- Thio refers to groups H-S-, alkyl-S-, cycloalkyl-S-, aryl-S-, heteroaryl-S- ; and heterocyclyl-S-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
- Thioacyl refers to groups H-C(S)-, alkyl-C(S)-, cycloalkyl-C(S)-, aryl-C(S)-, heteroaryl-C(S)-, and heterocyclyl-C(S)-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
- Oxythioacyl refers to groups HO-C(S)-, alkylO-C(S)-, cycloalkylO-C(S)-, arylO- C(S)-, heteroarylO-C(S)-, and heterocyclylO-C(S)-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
- Oxythioacyloxy refers to groups HO-C(S)-O-, alkylO-C(S)-O-, cycloalkylO-C(S)-O-, arylO-C(S)-O-, heteroarylO-C(S)-O-, and heterocyclylO-C(S)-O-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
- Phosphorylamino refers to the groups -NR*-P(0)(R**)(0R***) where R* represents H, alkyl, cycloalkyl, alkenyl, or aryl, R** represents OR*** or is hydroxy or amino and R*** is alkyl, cycloalkyl, aryl or arylalkyl, where alkyl, amino, alkenyl, aryl, cycloalkyl, and arylalkyl are as described herein.
- Thioacyloxy refers to groups H-C(S)-O-, alkyl-C(S)-O-, cycloalkyl-C(S)-O-, aryl- C(S)-O-, heteroaryl-C(S)-O-, and heterocyclyl-C(S)-O-, where alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are as described herein.
- Sulfmyl refers to groups H-S(O)-, alkyl-S(O)-, cycloalkyl-S(O)-, aryl-S(O)-, heteroaryl-S(O)-, and heterocyclyl-S(O)-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
- Sulfonyl refers to groups H-S(O) 2 -, alkyl-S(O) 2 -, cycloalkyl-S(O) 2 -, aryl-S(O) 2 -, heteroaryl-S(O) 2 -, and heterocyclyl-S(O) 2 -, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
- “Sulfinylamino” refers to groups H-S(O)-NR*-, alkyl-S (O)-NR*-, cycloalkyl-S(O)- NR*-, aryl-S(O)-NR*-, heteroaryl-S (O)-NR*-, and heterocyclyl-S(O)-NR*-, where R* is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
- “Sulfonylamino” refers to groups H-S(O) 2 -NR*-, alkyl-S(O) 2 -NR*-, cycloalkyl-S(O) 2 - NR*-, aryl-S(O) 2 -NR*-, heteroaryl-S(O) 2 -NR*-, and heterocyclyl-S(O) 2 -NR*-, where R* is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
- Oxysulfinylamino refers to groups HO-S(O)-NR*-, alkylO-S(O)-NR*-, cycloalkylO- S(O)-NR*-, arylO-S(O)-NR*-, heteroarylO-S(O)-NR% and heterocyclylO-S(O)-NR*-, where R* is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
- Oxysulfonylamino refers to groups HO-S(O) 2 -NR*-, alkylO-S(O) 2 -NR*-, cycloalkylO-S(O) 2 -NR*-, arylO-S(O) 2 -NR*-, heteroarylO-S(O) 2 -NR*-, and heterocyc IyIO-S(O) 2 -NR*-, where R* is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
- Aminothioacyl refers to groups R*R*N-C(S)-, where each R* is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
- Thioacylamino refers to groups H-C(S)-NR*-, alkyl-C(S)-NR*-, cycloalkyl-C(S)- NR*-, aryl-C(S)-NR*-, heteroaryl-C(S)-NR*-, and heterocyclyl-C(S)-NR*-, where R* is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
- Aminyl refers to groups R*R*N-S(0)-, where each R* is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
- Aminosulfonyl refers to groups R*R*N-S(O) 2 -, where each R* is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
- a group may or may not be further substituted or fused (so as to form a condensed polycyclic group) with one or more groups selected from hydroxyl, acyl, alkyl (which may be further substituted by amino, aminoacyl, oxyacyl, hydroxy, aryl and nitro), alkoxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy, amino, aminoacyl, thio, arylalkyl, arylalkoxy (which may be further substituted by halogen, hydroxy, alkyl, nitro, alkoxy, acyl and amino), aryl (which may be further substituted by halogen, hydroxy, alkyl, nitro, alkoxy, acyl and amino), aryloxy (which may be further substituted by halogen, hydroxy, alkyl, nitro, alkoxy, acyl and amino), carboxyl, acylamino,
- R 1A -R 1D includes the following groups:
- alkyl group preferably methyl and ethyl
- substituted alkyl group preferably 1-hydroxyethyl, 1-thioethyl, methoxyiminomethyl, ethoxyiminomethyl, l-(hydroxyimino)ethyl, l-(hydroxyimino)propyl, 1- hydrazinoethyl, 1-hydrazinopropyl, hydroxyiminomethyl, 2-oxopropyl, 2-oxobutyl, 3-oxobutyl, 3-oxopentyl, nitromethyl, 1-riitromethyl, and 2-nitroethyl;
- acyl group preferably formyl acetyl, propionyl, benzoyl (optionally substituted with methyl, methoxy, halogen, nitro, trifluoromethyl or cyano);
- alkoxy group preferably methoxy and ethoxy
- oxyacyl group preferably methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butyloxycarbonyl, isobutyloxycarbonyl;
- acyloxy group preferably acetoxy and propioxy
- substituted arylalkyl group preferably 1-hydroxybenzyl, and 1 -thiobenzyl;
- sulfinyl group preferably methylsulf ⁇ nyl, ethylsulf ⁇ nyl, benzene sulfinyl (optionally substituted with methyl, methoxy, halogen, nitro, trifluoromethane or cyano), methoxysulfmyl, ethoxy sulfinyl;
- sulfonyl group preferably methylsulfonyl, ethylsulfonyl, benzenesulfonyl (optionally substituted with methyl, methoxy, halogen, nitro, trifluoromethane or cyano);
- oxyacylamino group preferably methoxy carbonylamido, and ethoxycarbonyl amido
- oxythioacyl group preferably methoxythiocarbonyl and ethoxythiocarbonyl
- thioacyloxy group preferably thionoacetoxy and thionopropionoxy
- sulphinylamino group preferably methylsulfinylamino, ethylsulfinylamino, and benzenesulfinylamino (optionally substituted with methyl, methoxy, halogen, nitro, trifluoromethane or cyano); amino group, preferably N-methylamino, and N,N'-dimethylamino;
- substituted amino groups preferably residues of L-valine, D-valine, L-alanine, D-alanine, aspartic acid, and alanylserine;
- sulphonylamino group preferably methylsulfonylamino, ethylsulfonylamino and benzene sulfonylamino (optionally substituted with methyl, methoxy, halogen, nitro, trifluoromethane or cyano);
- substituted thio group preferably alkylthio
- oxysulfinylamino group preferably methoxysulfinylamino and ethoxysulfinylamino
- oxysulfonylamino group preferably methoxysulfonylamino and ethoxysulfonylamino
- alkenyl group preferably, 1-propenyl, vinyl, nitrovinyl, cyano vinyl, or trifiuorovinyl and styryl (optionally substituted with methyl, methoxy, halogen, nitro, trifluoromethane or cyano);
- alkynyl group preferably 1-propynyl, ethynyl or trimethylsilylethynyl.
- R 1D and R 1B independently represent hydroxy or an ether substituent.
- X represents O, S, SO, SO 2 , Se, SeO, or SeO 2 ;
- Y represents a group of formula (i)(a) or (ii);
- R 1A , R 1C and R 1E independently represents H, carboxyl, cyano, dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, phosphono, phosphorylamino, phosphinyl, sulfo, trihaloethenyl, trihalomethanethio, trihalomethoxy, trihalomethyl, optionally substituted acyl, optionally substituted acylamino, optionally substituted acylimino, optionally substituted acyliminoxy, optionally substituted acyloxy, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted alkenyl, optionally substituted alkenyloxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted aminoacyl, optionally substituted aminoacyloxy, optionally substitute
- R 1D and R 1B independently represent hydroxy, optionally substituted arylalkoxy, optionally substituted alkenyloxy, optionally substituted alkoxy, optionally substituted alkynyloxy, or optionally substituted aryloxy;
- Q represents H, CN, halogen, trialkylsilyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted acyl, optionally substituted oxyacyl, optionally substituted acylamino, optionally substituted aminoacylamino, OR", SR" or NR 11 R", where each R 1 independently represents, H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl and optionally substituted oxyacyl, or NR 111 NR"', where each R"' independently represents H, optionally substituted alkyl, optionally substituted alkenyl
- R 1A and R 1E represents H.
- R 1C represents H, halogen, or an alkoxy group and R ID and R 1B independently represent an alkoxy group.
- R 1D , R 1C and R 1B represent an alkoxy group, and even more preferably a methoxy group.
- Particularly preferred compounds of the present invention include those compounds where A is a bivalent linking group of 4 or 12 atoms selected from C, N, O and S. In that arrangement A and the atoms to which they are attached together form an optionally substituted heterocyclyl or heteroaryl ring having 6 to 14 ring atoms. Examples include where the substructure
- a together with the atoms to which it is attached forms an optionally substituted 6-membered heteroaryl or optionally substituted 6-membered heterocycyl ring which contains at least one N-atom.
- ring A is an optionally substituted phenyl, pyridyl, pyridinonyl, pyridazinyl, pyrimidinyl, pyrimidinonyl or pyrazinyl ring.
- ring A has the substructure:
- the rings which represent A may be further optionally substituted, preferably by no more than 3 substituents.
- substituents it is particular preferred to use 1 to 3 substituents (and preferably 1 substituent) selected from halo, lower alkyl, halogenated forms of lower alkyl, hydroxy, lower alkoxy, nitro, amino, thio, optionally substituted lower alkylaryl, loweralkylamino, carboxy, and optionally substituted phenyl.
- N-oxide forms of the nitrogen atoms of nitrogen containing rings are also preferred.
- the ring nitrogen may be in a N-oxide form, or the ring may be in the form of a pyridinium salt.
- X represents O, S, SO, SO 2 , Se, SeO, SeO 2 or NR where R is selected from H, O, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkenyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, and optionally substituted sulfonyl;
- a together with the atoms to which it is attached forms an optionally substituted 6- membered heteroaryl or optionally substituted 6-membered heterocyclyl which contains at least one N-atom;
- ⁇ represents an optional double bond
- Y represents a group of formula (i)(b) or (ii)(a);
- Q represents H, CN, halogen, trialkylsilyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted acyl, optionally substituted oxyacyl, optionally substituted acylamino, optionally substituted aminoacylamino, OR", SR" or NR 11 R", where each R independently represents, H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl and optionally substituted oxyacyl, or NR 111 NR'", where each R 1 " independently represents H, optionally substituted alkyl, optionally substituted alkenyl, optional
- ring A is an optionally substituted phenyl, pyridyl, pyridinonyl, pyridazinyl, pyrimidinyl, pyrimidinonyl or pyrazinyl ring.
- ring A has the substructure:
- ring A has the substructure:
- X represents O 3 S, SO, SO 2 , Se, SeO, SeO 2 or NR where R is selected from H, O, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkenyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, and optionally substituted sulfonyl;
- R 1F represents hydrogen, lower alkyl, lower alkylaryl, or optionally substituted phenyl
- R 1G represents hydrogen, lower alkyl, lower alkoxy, lower alkylaryl, or optionally substituted phenyl
- Y represents a group of formula (i)(b) or ( ⁇ )(a);
- Q represents H, CN, halogen, trialkylsilyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted acyl, optionally substituted oxyacyl, optionally substituted acylamino, optionally substituted aminoacylamino, OR", SR" or NR"R", where each R' independently represents, H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl and optionally substituted oxyacyl, or NR 11 TSfR'", where each R'" independently represents H, optionally substituted alkyl, optionally substituted alkenyl
- R 1F is hydrogen or lower alkyl and R 1G is hydrogen.
- X is preferably selected from O and S. More preferably X is O.
- Q represents an optionally substituted aryl or optionally substituted heteroaryl group.
- preferred compounds are represented by formulae (I), (Ia), and (Ib) where X is O, Y represents a group of formula (i)(b) or (ii)(a), A together with the atoms to which it is attached forms an optionally substituted 6-membered heteroaryl or optionally substituted 6-membered heterocyclyl which contains at least one N-atom, and Q represents an optionally substituted aryl group or an optionally substituted heteroaryl group (and wherein Y and Q are not the same group).
- Q more preferably represents an optionally substituted phenyl group or a 5 or 6 membered optionally substituted heteroaryl group, preferably having from 1 to 4 heteroatoms selected from O, S, Se, or N and mixtures thereof.
- Examples of preferred 5 membered optionally substituted heteroaryl groups include optionally substituted imidazolyl, optionally substituted triazolyl, optionally substituted pyrrolyl, optionally substituted pyrazolyl, optionally substituted thiazolyl, optionally substituted thiophenyl, optionally substituted furanyl, optionally substituted selenophenyl, optionally substituted oxazolyl, optionally substituted isoazolyl, optionally substituted isothiazolyl, optionally substituted oxadiazolyl, optionally substituted thiadiazolyl, optionally substituted tetrazolyl, optionally substituted oxatriazolyl, optionally substituted thiatriazolyl, optionally substituted indolyl, optionally substituted benzofuranyl and optionally substituted benzothiophenyl.
- Examples of preferred 6 membered optionally substituted heteroaryl groups include optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyronyl, optionally substituted coumarinyl, optionally substituted chromonyl, optionally substituted pyridonyl, optionally substituted purinyl (adeninyl and guaninyl), optionally substituted uracilyl, optionally substituted thymidinyl, optionally substituted cytosinyl, optionally substituted quinolinyl and optionally substituted isoquinolinyl.
- Examples of more preferred 5 to 6 membered heteroaryl groups include: indolyl, 1-methyl- indolyl, furanyl, pyrazolyl and pyridinyl.
- the compounds of the present invention can be prepared based on modification of the multicomponent reaction system which has been described in PCT/AU02/00099 (WO 02/060872), the entire contents of which is incorporated herein by reference.
- the compounds of the present invention can be prepared by the reaction sequences depicted in Scheme 1 below: Scheme 1
- a sufficiently reactive halogen preferably I
- These starting compounds can be coupled together under conditions known in the art, for example, using nickel or palladium based coupling agents such as Pd (PPh 3 ) 2 C1 2 or Pd (PPh 3 ) 4 .
- a copper co-catalyst such as CuI is added together with a suitable base such as a trialkylamine (ie under Sonogashira conditions).
- cyclisation can be afforded by reaction with a group Y- HaI (preferably Y-I) again under palladium catalysed coupling conditions.
- Y and Q are preferably optionally substituted phenyl groups.
- Q is an optionally substituted phenyl group and Y is an optionally substituted aroyl group.
- Route B depicts an alternative protocol to access compounds of formula (II) where X is O, S, Se, or NR.
- P is a suitable protective group.
- X when X is Se, O or S, P may be a methyl group.
- X is NR
- the nitrogen atom of the starting aniline is suitably protected by a nitrogen protecting group or as an imine.
- Suitable nitrogen protecting groups are known to those skilled in the art of organic synthesis and include acyl groups (eg acetyl, trifluoroacetyl), phenyl, benzyl and benzoyl.
- Other suitable nitrogen protecting groups may be found in Protective Groups in Organic Synthesis, T, W. Greene and P. Wutz, John Wiley & Son, 3 rd Edition.
- the compounds of formula (II) in which X is NR, O, Se or S can be prepared by reacting together a protected phenol, protected thiol, protected selenol, or protected amine and terminal alkyne respectively.
- the protected X group (which bears a suitably positioned adjacent halogen, preferably I) may be coupled together using, for instance, the Sonogashira methodology described above in Route A.
- the coupling may be carried out under Negishi conditions with the use of an alkyllithium, ZnBr 2 and a Pd catalyst.
- the coupling reaction may be performed under conditions which allow for heteroannulation to spontaneously occur so as to form the target hetero-fused furan, thiophene, etc in a "one-pot" synthetic strategy. This may involve the addition of iodine or another I ⁇ source after the initial coupling reaction to effect iodocyclisation.
- the Y group may be introduced again by suitable Pd based coupling chemistry.
- an aryl or aroyl group may be exchanged for the I atom or Sn group under Stille cross-coupling reactions using stannanes (eg, aryl or alkylstannanes), Suzuki conditions
- the Pd catalysed coupling reactions discussed above are generally performed at temperatures below room temperature, most preferably at O 0 C and below (for instance at - 78 0 C). It is also preferred that such reactions are carried out under an inert atmosphere of either nitrogen or argon.
- Suitable solvents include solvents such as THF, diethyl ether, DMSO, dioxane, acetonitrile, dichloromethane, etc.
- the intermediates can be reacted, in situ, with Halogen-Y in the presence of a palladium catalyst in an atmosphere of CO to compounds of formula (II) where Y is aroyl.
- This may be accomplished by evacuating the inert reaction gas present in the initial coupling step and replacing said gases with CO.
- the initial reaction solvent is replaced with a more polar solvent such as, for instance, DMSO. Removal of the initial reaction solvent may be achieved in vacuo.
- Examples of functional group inter-conversions are: -C(0)NR*R** from -CO 2 CH 3 by heating with or without catalytic metal cyanide, e.g. NaCN 3 and HNR*R** in CH 3 OH; -
- OC(O)R from -OH with e.g., ClC(O)R in pyridine; -NC(S)NR*R** from -NHR with an alkylisothiocyanate or thiocyanic acid; -NRC(O)OR* from -NHR with alkyl chloroformate; -NRC(0)NR*R** from -NHR by treatment with an isocyanate, e.g.
- An important aspect of the present invention relates to compounds which possess tubulin binding activity.
- the introduction of the hetero A ring system can give rise to improved pharmacological properties over the same compounds which are based on a benzofused framework (ie benzothiophenes, benzofurans, benzoselenophenes and indoles).
- a benzofused framework ie benzothiophenes, benzofurans, benzoselenophenes and indoles.
- such compounds possess better solubility and therefore possess improved pharmacokinetic properties over the benzofused analogues.
- preferred compounds of the invention having improved tubulin binding activity or anti-tumour vasculature activity, can be useful in methods of therapy.
- these compounds may be used for treating tumours.
- tumor is used to define any malignant cancerous growth, and may include leukemias, melanomas, colon, lung, ovarian, skin, breast, prostate, CNS, and renal cancers, as well as other cancers.
- the compounds of the invention having tubulin binding activity may also be used in the treatment of solid tumours, eg. breast cancer.
- the invention also provides for the use of a compound of formula (I), (Ia), (Ib), (Ic), or (II) in the manufacture of a medicament for treating tumours.
- the compounds of the invention may be particularly useful in combination therapy, eg. combining the treatment with other chemotherapeutic or radiation treatments.
- the compounds of the invention can be used in the treatment of any disease state for which tubulin polymerisation plays a crucial role.
- the present compounds can be used in treating inflammation.
- inflammatory conditions may include acute and chronic inflammatory conditions such as rheumatoid arthritis, inflammatory bowel disease, Crohn's disease, psoriasis, and the like.
- compositions which possess bioactivity, such as tubulin binding activity, can be formulated as a composition, particularly a pharmaceutical composition, together with a pharmaceutically acceptable additive.
- a treatment effective amount is intended to include at least partially attaining the desired effect, or delaying the onset of, or inhibiting the progression of, or halting or reversing altogether the onset or progression of the particular disease of condition being treated.
- the term "effective amount" relates to an amount of compound which, when administered according to a desired dosing regimen, provides the desired therapeutic activity. Dosing may occur at intervals of minutes, hours, days, weeks, months or years or continuously over any one of these periods. Suitable dosages lie within the range of about 0.1 ng per kg of body weight to 1 g per kg of body weight per dosage.
- the dosage may be in the range of 1 ⁇ g to 1 g per kg of body weight per dosage, such as is in the range of 1 mg to 1 g per kg of body weight per dosage. In one embodiment, the dosage may be in the range of 1 mg to 500 mg per kg of body weight per dosage.
- the dosage may be in the range of 1 mg to 250 mg per kg of body weight per dosage. In yet another preferred embodiment, the dosage may be in the range of 1 mg to 100 mg per kg of body weight per dosage, such as up to 50 mg per body weight per dosage.
- Suitable dosage amounts and dosing regimens can be determined by the attending physician and may depend on the particular condition being treated, the severity of the condition as well as the general age, health and weight of the subject.
- the active ingredient may be administered in a single dose or a series of doses. While it is possible for the active ingredient to be administered alone, it is preferable to present it as a composition, preferably as a pharmaceutical composition.
- the formulation of such compositions is well known to those skilled in the art.
- the composition may contain any suitable carriers, diluents or excipients. These include all conventional solvents, dispersion media, fillers, solid carriers, coatings, antifungal and antibacterial agents, dermal penetration agents, surfactants, isotonic and absorption agents and the like. It will be understood that the compositions of the invention may also include other supplementary physiologically active agents.
- compositions include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parental (including subcutaneous, intramuscular, intravenous and intradermal) administration.
- the compositions may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
- compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, sachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
- the active ingredient may also be presented as a bolus, electuary or paste.
- a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
- Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g inert diluent, preservative disintegrant (e.g. sodium starch glycolate, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose) surface- active or dispersing agent.
- a binder e.g inert diluent, preservative disintegrant (e.g. sodium starch glycolate, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose) surface- active or dispersing agent.
- Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
- the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
- compositions suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavoured base, usually sucrose and acacia or tragacanth gum; pastilles comprising the active ingredient in an inert basis such as gelatine and glycerin, or sucrose and acacia gum; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
- compositions suitable for topical administration to the skin may comprise the compounds dissolved or suspended in any suitable carrier or base and may be in the form of lotions, gel, creams, pastes, ointments and the like.
- suitable carriers include mineral oil, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
- Transdermal patches may also be used to administer the compounds of the invention.
- compositions for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter, glycerin, gelatine or polyethylene glycol.
- compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
- compositions suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain anti-oxidants, buffers, bactericides and solutes which render the composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
- the compositions may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
- Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
- Preferred unit dosage compositions are those containing a daily dose or unit, daily sub- dose, as herein above described, or an appropriate fraction thereof, of the active ingredient.
- compositions of this invention may include other agents conventional in the art having regard to the type of composition in question, for example, those suitable for oral administration may include such further agents as binders, sweeteners, thickeners, flavouring agents disintegrating agents, coating agents, preservatives, lubricants and/or time delay agents.
- suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharine.
- Suitable disintegrating agents include cornstarch, methylcellulose, polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid or agar.
- Suitable flavouring agents include peppermint oil, oil of wintergreen, cherry, orange or raspberry flavouring.
- Suitable coating agents include polymers or copolymers of acrylic acid and/or methacrylic acid and/or their esters, waxes, fatty alcohols, zein, shellac or gluten.
- Suitable preservatives include sodium benzoate, vitamin E, alpha-tocopherol, ascorbic acid, methyl paraben, propyl paraben or sodium bisulphite.
- Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc.
- Suitable time delay agents include glyceryl monostearate or glyceryl distearate.
- the compounds of the present invention may be administered to a subject as a pharmaceutically acceptable salt.
- a pharmaceutically acceptable salt also fall within the scope of the present invention since these may be useful as intermediates in the preparation of pharmaceutically acceptable salts.
- Suitable pharmaceutically acceptable salts include, but are not limited to salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, maleic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benezenesulphonic, salicyclic sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids.
- pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric
- Base salts include, but are not limited to, those formed with pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, ammonium and alkylammonium.
- the present invention includes within its scope cationic salts eg sodium or potassium salts, or alkyl esters (eg methyl, ethyl) of the phosphate group.
- Basic nitrogen-containing groups may be quarternised with such agents as lower alkyl halide, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl and diethyl sulfate; and others.
- prodrug is used in its broadest sense and encompasses those derivatives that are converted in vivo to the compounds of the invention. Such derivatives would readily occur to those skilled in the art, and include, for example, compounds where a free hydroxy group is converted into an ester, such as an acetate or phosphate ester, or where a free amino group is converted into an amide (eg. ⁇ -aminoacid amide). Procedures for esterifying, eg.
- acylating the compounds of the invention are well known in the art and may include treatment of the compound with an appropriate carboxylic acid, anhydride or chloride in the presence of a suitable catalyst or base.
- a particularly preferred prodrug is a disodium phosphate ester.
- the disodium phosphate ester of novel compounds of the invention may be useful in targeting tumour vasculature and thus may provide a means of selective delivery of the compounds to the body.
- the disodium phosphate ester may be prepared in accordance with the methodology described in Pettit, G. R., et al, Anticancer Drug Des., 1995, 10, 299.
- the compounds of the invention may be in crystalline form either as the free compounds or as solvates (e.g. hydrates) and it is intended that both forms are within the scope of the present invention. Methods of solvation are generally known within the art.
- compounds of the invention may possess asymmetric centres and are therefore capable of existing in more than one stereoisomeric form.
- the invention thus also relates to compounds in substantially pure isomeric form at one or more asymmetric centres eg., greater than about 90% ee, such as about 95% or 97% ee or greater than 99% ee, as well as mixtures, including racemic mixtures, thereof.
- Such isomers may be prepared by asymmetric synthesis, for example using chiral intermediates, or mixtures may be resolved by conventional methods, eg., chromatography, or use of a resolving agent.
- the compounds of the present invention may be capable of undergoing tautomerism. Accordingly, all possible tautomers of a compound of the present invention fall within the scope and spirit of the invention.
- the synthetic methods and processes described herein to prepare the compounds of the present invention are amenable to solid phase synthetic techniques and/or combinatorial chemistry to produce individual compounds or libraries of compounds.
- Solution phase libraries may be prepared via parallel syntheses wherein different compounds are synthesised in separate reaction vessels in parallel, often in an automated fashion.
- attachment of the individual components employed in a synthetic sequence to an appropriate solid phase support allows for the further creation of chemical diversity by utilising not only parallel synthesis but also split synthesis wherein the solid support containing the compounds prepared in the prior step can be split into a number of batches, treated with the appropriate reagent and recombined.
- the substrates can be attached to a solid support surface by any linkers known in the art.
- the linkers may be any component capable of being cleaved to release the substrate or final compound from the support.
- the solid support is a polymer support.
- polymeric supports currently used in solid phase synthesis include: alkenyl resins: eg. REM resins; BHA resins: eg. benzhydrylamine (polymer-bound hydrochloride, 2% crosslinked), benzhydryl chloride (polymer bound); Br- functionalised resins: eg. brominated PPOA resin, brominated Wang resin; Chloromethyl resins: eg. 4-methoxybenzhydryl chloride (polymer bound); CHO-functionalised resins: eg. indole resin, formylpolystyrene; Cl-functionalised resins: eg.
- OH- functionalised resins eg. 4-benzyloxybenzyl alcohol (polymer bound); Hydroxy methyl resins: eg. benzyl alcohol (polymer bound); HMBA resin; Oxime resins; Rink acid resin; Triazine-based resin; Trityl amine resins; Trityl resins: eg. trityl-chloride (polymer bound), 2-chlorotrityl alcohol, 1,3-diaminepropane trityl.
- OH- functionalised resins eg. 4-benzyloxybenzyl alcohol (polymer bound); Hydroxy methyl resins: eg. benzyl alcohol (polymer bound); HMBA resin; Oxime resins; Rink acid resin; Triazine-based resin; Trityl amine resins; Trityl resins: eg. trityl-chloride (polymer bound), 2-chlorotrityl alcohol, 1,3-diaminepropane
- individual compounds or libraries of compounds can be synthesised by initially attaching the first compound substrate to a solid support surface which can be performed by providing a plurality of solid support surfaces, suitably derivatising each of the surfaces with groups capable of reacting with either the compound substrate or a linker moiety attached thereto.
- the various support surfaces with the attached first compound substrate can then be subjected to various reaction conditions and second compound substrates to provide a library of attached compounds, which may, if necessary, be reacted further with third and subsequent compound substrates or varying reactions conditions.
- Attachment and detachment of substrates and products can be performed under conditions similar to those as described in Johnson, M.G., et al, Tetrahedron, 1999, 55, 11641; Han Y., et al Tetrahedron 1999, 55, 11669; and Collini, M.D., et al, Tetrahedron Lett, 1997, 58, 7963.
- Those skilled in the art will appreciate that the invention described herein in susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications which fall within the spirit and scope.
- the invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more of said steps or features.
- Table 1 In vitro Data for Compounds: Inhibition of tubulin polymerisation and/or Inhibition of Proliferation of activated HUVEC cells.
- TPI Tubulin polymerisation inhibitor
- IC 50 is the concentration required to inhibit proliferation by 50%, this value falls within the range of concentrations given or >1000 nM Synthetic Protocols
- Step 1 5-Iodouracil (1 mmol) was refluxed in hexamethyldisilazide (HMDS) (2 ml) and trimethylsilylchloride TMSCl (3 drops) in round bottom flask under a nitrogen atmosphere and until all solids had dissolved (ca. 2 h). The excess of HMDS was removed under vacuum and the oily residue was dried under high vacuum.
- HMDS hexamethyldisilazide
- TMSCl trimethylsilylchloride
- Step 2 The 5-alkynyluracil (1.0 mmol), anhydrous K 2 CO 3 (0.41 g, 3.0 mmol), aryliodide (1.1 mmol) and Pd(PPh 3 ) 2 Cl 2 (or Pd(PPh 3 ) 4 ) (5 mol%) were added to dry round bottom flask under N 2 atmosphere. The system was evacuated and back filled with N 2 and then anhydrous DMSO (10 ml) was added. The system was again evacuated and back-filled with N 2 three times and heated to 100-110 0 C with stirring overnight. The solvents were removed under vacuum and residue dissolved in EtOAc (50 ml) and washed with water (20 ml). The aqueous layer was further extracted with EtOAc (3 x 30 ml). The organic layers were collected, dried and evaporated. The residue was purified as described for each example (below).
- Step 1 5-iodouracil (0.5 g, 2.10 mmol) and l-ethynyl-4-methoxybenzene (0.8 Ig, 4.20 mmol).
- the crude reaction mixture was diluted with ethyl acetate (300 mL) and washed with H 2 O (2 x 300 mL, 50 mL brine added). The aqueous extracts were combined, and sat. NH 4 Cl solution (100 mL) added.
- Step 2 The product from step 1 (0.24g, 1.0 mmol), 3,4,5-trimethoxyiodobenzene (0.32g, 1.1 mmol) and Pd(PPh 3 ) 4 (57 mg, 0.05 mmol) were added followed by DMSO (10 mL). The stirred mixture was heated to 10O 0 C overnight, diluted with ethyl acetate (300 mL) and washed with sat. NH 4 Cl solution (5%, 20OmL).
- Step 1 5-iodouracil (2.10 mmol) and l-ethynyl-3,4,5-trimethoxybenzene (4.20 mmol).
- the crude reaction mixture was diluted with ethyl acetate (300 mL) and washed with H 2 O (2 x 300 mL, 50 mL brine added).
- the aqueous extracts were combined, and sat. NH 4 Cl solution (100 mL) added.
- the aqueous phase was then washed with ethyl acetate (2 x 350 mL), the organics combined, dried (MgSO 4 ), filtered and concentrated to give the coupled alkyne as a white cream solid (0.49 g, 78%).
- Step 2 The product from step 1 (0.32 mmol), 4-methoxyiodobenzene (0.35 mmol) The aqueous phase was washed with ethyl acetate (3 x 200 mL), the organic extracts combined, dried (MgSO 4 ), filtered and concentrated to give the desired cyclised product as a pale brown solid which was chromatographed on silica gel (CH 2 Cl 2 , EtOAc and methanol 10:10:1) to give the pure product (93 mg, 69%).
- Step 1 5-iodouracil was coupled to 2-ethynylfuran. After quenching the reaction with MeOH the yellow powder was washed with MeOH and then with CH 2 Cl 2 . The yellow powder was dried under vacuum and used as such without further purification Yield (65%).
- Step 2 The coupled product from Step 1 was coupled with 3,4,5-trimethoxyiodobenzene.
- EtOAc extract was evaporated and purified by silica gel column chromatography using increasing gradient of EtOAc in CH 2 Cl 2 (23%).
- Step 1 5-iodouracil was coupled to 5 -ethynyl-1 -methyl- lH-indole (see below). After quenching reaction mixture with MeOH, the yellowish solid was suspended in CH 2 Cl 2 sonicated, filtered and washed with CH 2 Cl 2 thoroughly.
- Step 2 The material from step 1 was coupled to 3,4,5-trimethoxyiodobenzene. After evaporation of DMSO 5 the reaction mixture was diluted with EtOAc and washed with small amount of water. The residue was purified by column chromatography using 5% MeOH in 1:1 mixture of EtOAc and CH 2 Cl 2 .
- 5-iodo-l-methyl-lH-indole 5-Iodoindole (4.8 g, 20 mmol) was stirred in dry DMF (20 ml) containing MeI (8.5 g, 60 mmol) and K 2 CO 3 (13.8 g, 100 mmol) for overnight at 55 0 C. The reaction mixture was diluted with EtOAc and passed through celite plug. The illiterate was evaporated to dryness and then oil was further purified by small flash column, Yield (90%).
- 5-ethynyl-l-methyl-lH-indole 5-iodo-l -methyl- lH-indole (1.5 g, 5.84 mmol) were dissolved in mixture of CH 2 Cl 2 (10 ml) and NEt 3 (5 ml) and the system was evacuated- back filled by N 2 thrice.
- Pd(PPh 3 ) 2 Cl 2 122 mg, 3% mol
- TMS-acetylene 0.58 g, 8.7 mmol
- reaction mixture was diluted with 10 ml of hexane and filtered through celite plug, purified by passing through small column and then suspended in MeOH (20 ml) containing 10 ml of THF. NaOH was added to reaction mixture and stirred at room temp until starting material consumed completely.
- the reaction mixture was concentrated to 10 ml and extracted with EtOAc from aqueous NH 4 Cl solution, which was purified by column chromatography.
- Step 1 5-Iodouracil was coupled to 4-ethynyl-2-methoxypyridine. After quenching the reaction with MeOH, the solid separated was filtered and washed thoroughly with mixture OfEt 2 O and MeOH.
- Step 2 The product from step 1 was coupled to 3,4,5-trimethoxyiodobenzene.
- the residue was purified by silica gel column chromatography using CH 2 Cl 2 , increasing gradient of EtOAc (to 1 : 1 mixture) and then 5% MeOH in 1 : 1 mixture of EtOAc and CH 2 Cl 2 as eluant.
- the isolated creamy semi-solid gum was further purified by precipitating from mixture of Et 2 O and EtOAc; Yield (62%).
- Step 1 5-Iodouracil was coupled to MEM protected 5-ethynyl-2-methoxyphenol (Organic & Biomolecular Chemistry (2005), 3(14), 2657-2660). The brownish residue was purified by silica gel column chromatography using 40% EtOAc to pure EtOAc.
- Step 1 5-Iodouracil was coupled to bis-MOM protected 5-ethynyl-2-methoxycatechol. The residue was precipitated from CH 2 Cl 2 by slow addition of MeOH and then concentrating the mixture under vacuum without heating. The white creamy solid was filtered and dried.
- Step 2 The product from step 1 was coupled with 3,4,5-trimethoxyiodobenzene and the crude material eluted through short plug silica gel with EtOAc (1 cm x 1 cm) and the eluant concentrated.
- the product was dissolved in mixture of THF (3ml) and MeOH (2 ml) and 0.2 ml of concentrated HCl was added slowly with stirring. The reaction mixture was stirred for overnight with slow evaporation of solvents. The residue was dissolved in EtOAc (50 ml) and washed with water (5 ml).
- Step 1 5-Iodouracil was coupled to Boc-protected protected 5-ethynyl-2-methoxyaniline. After quenching the reaction mixture with MeOH, the product was isolated by silica gel chromatography using increasing gradient of EtOAc in dichloromethane as off-white solid, yield (45%).
- Step 2 The product from step 1 was coupled to 3,4,5-trimethoxyiodobenzene.
- the product was isolated by column chromatography using increasing gradient of EtOAc in dichloromethane as white solid (65%).
- Example 20 A mixture of Pd 2 dba 3 (4 mg, 7 ⁇ mol) and PPh 3 (7.5 mg, 29 ⁇ mol) in THF (2 mL) was stirred for 15 minutes at room temperature. 3,4,5-trimethoxybenzoyl chloride (40 mg, 0.17 mmol), S (60 mg, 0.14 mmol) and CuCl (11 mg, 0.12 mmol) were added and the mixture left to stir at room temperature overnight. The mixture was diluted with ethyl acetate and washed with H 2 O (2x) and brine then dried (MgSO 4 ), filtered and concentrated.
- Example 21 To a mixture of 0.0306 g (0.0787 mmol) of H, 0.0332 g (0.173 mmol) of 3,4,5-trimethoxyphenylboronic acid, 0.009g (0.0077 mmol) of tetrakis(triphenylphosphine)palladium (0) in 3 ml of anhydrous dioxane, a solution of 0.033 mg (0.39 mmol) of sodium hydrogen carbonate in 1 ml of water was added at reflux under nitrogen atmosphere.
- Example 22 and 23 A stirred mixture of N (0.10 g, 0.26 mmol), trimethyl(3,4,5- trimethoxyphenyl)stannane (0.10 g, 0.30 mmol) and Pd(PPh 3 ) 4 (15 mg, 13 ⁇ mol) in DMSO (4mL) was heated to 100 0 C overnight under an atmosphere of CO. The cooled reaction mixture was diluted with ethyl acetate and washed with H 2 O (2x) and brine, dried (MgSO 4 ), filtered and concentrated.
- 2,4-Dimethoxypyridine (Q): A mixture of 4-nitropyridine N-oxide O (21.6 g; 15.4 mmol) and P(O)Cl 3 (11.41 g; 21.5 mmol) was refluxed for 1Oh then the excess Of P(O)Cl 3 was removed under reduced pressure. The residue was treated with ice (10 g) and pH of resulting mixture was adjusted to ⁇ 5 with aqueous NaOH. This was extracted with diethyl ether (3 x 150 ml).
- 1,6-Dimethoxypyrazine (V) A mixture of 1,6-dichloropi ⁇ erazine U (3.9g; 26 mmol) and freshly prepared sodium methoxide (62 mmol) in anhydrous methanol (50 ml) was refluxed overnight and the solvent was removed under reduced pressure. The residue was diluted to 100 ml with CH 2 Cl 2 and the solution washed with water, brine and dried over anhydrous MgSO 4 and filtered off. The filtrate was evaporated under reduced pressure to give pure 1,6-dimethoxypiperazine V (3.6 g; 98%) as a colourless crystals.
- Example 25 Prepared and purified as described for example 22 giving 12 mg (27%), yellow solid.
- Example 27 A mixture of ⁇ (52 mg, 0.2 mmol), 3,4,5-trimethoxyiodobenzene (72 mg, 0.24 mmol) and anhydrous potassium carbonate (14 mg, 1.01 mmol) (dried at 13O 0 C under vacuum for 2 hours) and of dichlorobis(triphenylphosphine)palladium (9.0 mg, 0.013mmol) in anhydrous dimethylsulfoxide (3 ml) was degassed in vacuo and saturated with carbon monoxide. The resulting mixture was vigorously stirred overnight at 100 0 C under carbon monoxide atmosphere.
- bromine 25 ⁇ L, 0.50 mmol was added neat and the reaction was allowed to warm to room temperature and quenched by the addition of water (10 ml) and ethyl acetate (10 ml). The organic layer was washed with brine (10 ml), dried over MgSO 4 and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica-gel, eluted with hexanes : EtOAc, 3:1) to afford the product as a white solid (45 mg, 29%).
- Example 28 A mixture of 7-bromo-6-methoxy-2-(4-methoxyphenyl)-3-(3,4,5- trimethoxybenzoyl)-furo[3,2-b]pyridme ( ⁇ ) (140 mg, 0.304 mmol), dry K 2 CO 3 (s) (126 mg, 0.912 mmol), 3,4,5-trimethoxyphenylboronic acid (96 mg, 0.453 mmol) and Pd(Ph 3 P) 4 (30 mg) in dry anisole (12 ml) was placed in a high pressure reaction vessel and charged with a carbon monoxide atmosphere (180 psi). The reaction vessel was heated to 90 0 C for 72 hours.
- Example 29 A suspension of 3-iodo-6 ⁇ methoxy-2-(l-methyl-lH-pyrazol-4 ⁇ yl)furo[3,2- b]pyridine ( ⁇ ) (57.6 mg, 0.162 mmol), 3,4,5-trimethoxy ⁇ henyl boronic acid ( 0.058 g, 0.27 mmol), dry K 2 CO 3 (0.075 g, 0.55 mmol) and Pd(PPh 3 ) 2 Cl 2 (0.016 g, 0.014 mmol) in anhydrous anisole (8 ml) was placed in Parr mini bench top reactor (series 4561, 300 ml).
- the reactor was degassed under reduced pressure and flashed with dry N 2 than flashed three times with CO by pressurizing the reactor up to 180 psi and depressurizing. Finally, the reactor was pressurized to 180 psi and stirred at 85 0 C (the temperature of external oil bath) for ⁇ 30 h. The reactor was cooled down to room temperature and the reaction mixture was diluted to with CH 2 Cl 2 (20 ml) and filtered through celite. The celite pad was washed with fresh portion Of CH 2 Cl 2 (3 x 20 ml) and combined filtrates were evaporated to dryness under reduced pressure.
- Example 30 A mixture of 3 -iodo-6-methoxy-7-(4-methoxy-benzyloxy)-2-(l -methyl- IH- ⁇ yrazol-4-yl)-furo[3 5 2-b]pyridine (250 mg, 0.509 mmol), dry K 2 CO 3 (s) (211 mg, 1.53 mmol), 3,4,5-trimethoxyphenyl boronic acid (215 mg, 1.01 mmol) and Pd(Ph 3 P) 4 (45 mg) in dry anisole (18 ml) was placed in a high pressure reaction vessel and charged with a carbon monoxide atmosphere (180 psi). The reaction vessel was heated to 90 0 C for 48 hours.
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WO2011022772A1 (en) | 2009-08-27 | 2011-03-03 | Bionomics Limited | Combination therapy for treating proliferative diseases |
WO2012077135A2 (en) | 2010-12-09 | 2012-06-14 | Kasina Laila Innova Pharmaceuticals Private Limited | Substituted 4-(arylamino) selenophenopyrimidine compounds and methods of use thereof |
US8580803B2 (en) | 2009-12-30 | 2013-11-12 | Arqule, Inc. | Substituted pyrrolo-aminopyrimidine compounds |
WO2013177633A1 (en) | 2012-06-01 | 2013-12-05 | Bionomics Limited | Combination therapy involving a vascular disrupting agent and an agent which targets hypoxia |
US9156845B2 (en) | 2012-06-29 | 2015-10-13 | Pfizer Inc. | 4-(substituted amino)-7H-pyrrolo[2,3-d] pyrimidines as LRRK2 inhibitors |
US9630968B1 (en) | 2015-12-23 | 2017-04-25 | Arqule, Inc. | Tetrahydropyranyl amino-pyrrolopyrimidinone and methods of use thereof |
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US8466163B2 (en) | 2013-06-18 |
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