CA2469224A1 - Trioxane derivatives - Google Patents
Trioxane derivatives Download PDFInfo
- Publication number
- CA2469224A1 CA2469224A1 CA002469224A CA2469224A CA2469224A1 CA 2469224 A1 CA2469224 A1 CA 2469224A1 CA 002469224 A CA002469224 A CA 002469224A CA 2469224 A CA2469224 A CA 2469224A CA 2469224 A1 CA2469224 A1 CA 2469224A1
- Authority
- CA
- Canada
- Prior art keywords
- compound
- iron
- treatment
- compound according
- pharmaceutically acceptable
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 150000004901 trioxanes Chemical class 0.000 title claims description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 142
- 150000003839 salts Chemical class 0.000 claims abstract description 20
- 125000004429 atom Chemical group 0.000 claims abstract description 3
- BGJSXRVXTHVRSN-UHFFFAOYSA-N 1,3,5-trioxane Chemical compound C1OCOCO1 BGJSXRVXTHVRSN-UHFFFAOYSA-N 0.000 claims abstract 2
- 238000000034 method Methods 0.000 claims description 71
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 52
- BJDCWCLMFKKGEE-ISOSDAIHSA-N artenimol Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@H](O)[C@@H]4C BJDCWCLMFKKGEE-ISOSDAIHSA-N 0.000 claims description 37
- 229920000768 polyamine Polymers 0.000 claims description 36
- 230000008878 coupling Effects 0.000 claims description 30
- 238000010168 coupling process Methods 0.000 claims description 30
- 238000005859 coupling reaction Methods 0.000 claims description 30
- 238000011282 treatment Methods 0.000 claims description 30
- 229960002521 artenimol Drugs 0.000 claims description 26
- 229930016266 dihydroartemisinin Natural products 0.000 claims description 26
- 229910052742 iron Inorganic materials 0.000 claims description 26
- -1 alcohol methyl ester Chemical class 0.000 claims description 25
- 206010028980 Neoplasm Diseases 0.000 claims description 21
- 201000011510 cancer Diseases 0.000 claims description 17
- 239000003814 drug Substances 0.000 claims description 16
- 230000008569 process Effects 0.000 claims description 16
- 238000004519 manufacturing process Methods 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 11
- 201000004792 malaria Diseases 0.000 claims description 10
- 150000001412 amines Chemical class 0.000 claims description 9
- 241001465754 Metazoa Species 0.000 claims description 8
- 230000037396 body weight Effects 0.000 claims description 8
- 150000001735 carboxylic acids Chemical class 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 6
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 claims description 3
- 229940127089 cytotoxic agent Drugs 0.000 claims description 3
- 239000002254 cytotoxic agent Substances 0.000 claims description 3
- 231100000599 cytotoxic agent Toxicity 0.000 claims description 3
- 150000002505 iron Chemical class 0.000 claims description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 3
- 239000012038 nucleophile Substances 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 150000003141 primary amines Chemical class 0.000 claims description 3
- 238000011321 prophylaxis Methods 0.000 claims description 3
- WNDUPUMWHYAJOR-SADXPQEKSA-K (2r,3r,4r,5s)-hexane-1,2,3,4,5,6-hexol;2-hydroxypropane-1,2,3-tricarboxylate;iron(3+) Chemical compound [Fe+3].OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O WNDUPUMWHYAJOR-SADXPQEKSA-K 0.000 claims description 2
- 125000001140 1,4-phenylene group Chemical group [H]C1=C([H])C([*:2])=C([H])C([H])=C1[*:1] 0.000 claims description 2
- ZITFTYGHYGPDAV-UHFFFAOYSA-L 2-aminoacetic acid;iron(2+);sulfate Chemical compound [H+].[Fe+2].NCC([O-])=O.[O-]S([O-])(=O)=O ZITFTYGHYGPDAV-UHFFFAOYSA-L 0.000 claims description 2
- UQSASSBWRKBREL-UHFFFAOYSA-K 2-hydroxyethyl(trimethyl)azanium;iron(3+);2-oxidopropane-1,2,3-tricarboxylate;trihydrate Chemical compound O.O.O.[Fe+3].C[N+](C)(C)CCO.[O-]C(=O)CC([O-])(C([O-])=O)CC([O-])=O UQSASSBWRKBREL-UHFFFAOYSA-K 0.000 claims description 2
- 229920002307 Dextran Polymers 0.000 claims description 2
- 239000004277 Ferrous carbonate Substances 0.000 claims description 2
- PMVSDNDAUGGCCE-TYYBGVCCSA-L Ferrous fumarate Chemical compound [Fe+2].[O-]C(=O)\C=C\C([O-])=O PMVSDNDAUGGCCE-TYYBGVCCSA-L 0.000 claims description 2
- 102000003886 Glycoproteins Human genes 0.000 claims description 2
- 108090000288 Glycoproteins Proteins 0.000 claims description 2
- 108010035210 Iron-Binding Proteins Proteins 0.000 claims description 2
- 102000008133 Iron-Binding Proteins Human genes 0.000 claims description 2
- XMUZQOKACOLCSS-UHFFFAOYSA-N [2-(hydroxymethyl)phenyl]methanol Chemical compound OCC1=CC=CC=C1CO XMUZQOKACOLCSS-UHFFFAOYSA-N 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 239000003098 androgen Substances 0.000 claims description 2
- 150000008064 anhydrides Chemical class 0.000 claims description 2
- 229940046836 anti-estrogen Drugs 0.000 claims description 2
- 230000001833 anti-estrogenic effect Effects 0.000 claims description 2
- 230000000340 anti-metabolite Effects 0.000 claims description 2
- 229940100197 antimetabolite Drugs 0.000 claims description 2
- 239000002256 antimetabolite Substances 0.000 claims description 2
- FWZTTZUKDVJDCM-CEJAUHOTSA-M disodium;(2r,3r,4s,5s,6r)-2-[(2s,3s,4s,5r)-3,4-dihydroxy-2,5-bis(hydroxymethyl)oxolan-2-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol;iron(3+);oxygen(2-);hydroxide;trihydrate Chemical compound O.O.O.[OH-].[O-2].[O-2].[O-2].[O-2].[O-2].[O-2].[O-2].[O-2].[Na+].[Na+].[Fe+3].[Fe+3].[Fe+3].[Fe+3].[Fe+3].O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 FWZTTZUKDVJDCM-CEJAUHOTSA-M 0.000 claims description 2
- 239000000328 estrogen antagonist Substances 0.000 claims description 2
- 229950003601 ferrocholinate Drugs 0.000 claims description 2
- RAQDACVRFCEPDA-UHFFFAOYSA-L ferrous carbonate Chemical compound [Fe+2].[O-]C([O-])=O RAQDACVRFCEPDA-UHFFFAOYSA-L 0.000 claims description 2
- 235000019268 ferrous carbonate Nutrition 0.000 claims description 2
- 229960004652 ferrous carbonate Drugs 0.000 claims description 2
- 235000019850 ferrous citrate Nutrition 0.000 claims description 2
- 239000011640 ferrous citrate Substances 0.000 claims description 2
- 235000002332 ferrous fumarate Nutrition 0.000 claims description 2
- 239000011773 ferrous fumarate Substances 0.000 claims description 2
- 229960000225 ferrous fumarate Drugs 0.000 claims description 2
- 239000004222 ferrous gluconate Substances 0.000 claims description 2
- 235000013924 ferrous gluconate Nutrition 0.000 claims description 2
- 229960001645 ferrous gluconate Drugs 0.000 claims description 2
- 235000013925 ferrous lactate Nutrition 0.000 claims description 2
- 239000004225 ferrous lactate Substances 0.000 claims description 2
- 229940037907 ferrous lactate Drugs 0.000 claims description 2
- 235000003891 ferrous sulphate Nutrition 0.000 claims description 2
- 239000011790 ferrous sulphate Substances 0.000 claims description 2
- 229940083124 ganglion-blocking antiadrenergic secondary and tertiary amines Drugs 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 239000003112 inhibitor Substances 0.000 claims description 2
- 229940074445 iron sorbitex Drugs 0.000 claims description 2
- 229910000015 iron(II) carbonate Inorganic materials 0.000 claims description 2
- APVZWAOKZPNDNR-UHFFFAOYSA-L iron(ii) citrate Chemical compound [Fe+2].OC(=O)CC(O)(C([O-])=O)CC([O-])=O APVZWAOKZPNDNR-UHFFFAOYSA-L 0.000 claims description 2
- VRIVJOXICYMTAG-IYEMJOQQSA-L iron(ii) gluconate Chemical compound [Fe+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O VRIVJOXICYMTAG-IYEMJOQQSA-L 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 125000003107 substituted aryl group Chemical group 0.000 claims description 2
- 150000003461 sulfonyl halides Chemical class 0.000 claims description 2
- DEQJBORXLQWRGV-UHFFFAOYSA-N 2-hydroxypropanoic acid;iron Chemical compound [Fe].CC(O)C(O)=O.CC(O)C(O)=O DEQJBORXLQWRGV-UHFFFAOYSA-N 0.000 claims 1
- 150000004698 iron complex Chemical class 0.000 claims 1
- 125000001424 substituent group Chemical group 0.000 claims 1
- 125000004433 nitrogen atom Chemical group N* 0.000 abstract description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 97
- 125000003118 aryl group Chemical group 0.000 description 63
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 60
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 59
- 239000000047 product Substances 0.000 description 35
- 101150041968 CDC13 gene Proteins 0.000 description 32
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 32
- 230000015572 biosynthetic process Effects 0.000 description 26
- 238000003786 synthesis reaction Methods 0.000 description 26
- 238000005160 1H NMR spectroscopy Methods 0.000 description 25
- 239000000203 mixture Substances 0.000 description 24
- 210000004027 cell Anatomy 0.000 description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 150000001408 amides Chemical class 0.000 description 16
- KIDHWZJUCRJVML-UHFFFAOYSA-N putrescine Chemical compound NCCCCN KIDHWZJUCRJVML-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 230000000078 anti-malarial effect Effects 0.000 description 11
- BLUAFEHZUWYNDE-NNWCWBAJSA-N artemisinin Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2OC(=O)[C@@H]4C BLUAFEHZUWYNDE-NNWCWBAJSA-N 0.000 description 11
- VHRGRCVQAFMJIZ-UHFFFAOYSA-N cadaverine Chemical compound NCCCCCN VHRGRCVQAFMJIZ-UHFFFAOYSA-N 0.000 description 11
- 239000003430 antimalarial agent Substances 0.000 description 10
- 238000009472 formulation Methods 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 239000004615 ingredient Substances 0.000 description 9
- 229930101531 artemisinin Natural products 0.000 description 8
- 239000006260 foam Substances 0.000 description 8
- 244000045947 parasite Species 0.000 description 8
- 239000005700 Putrescine Substances 0.000 description 7
- 229960004191 artemisinin Drugs 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- 150000003254 radicals Chemical class 0.000 description 7
- 229940079593 drug Drugs 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 5
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 5
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- ATHGHQPFGPMSJY-UHFFFAOYSA-N spermidine Chemical compound NCCCCNCCCN ATHGHQPFGPMSJY-UHFFFAOYSA-N 0.000 description 5
- 108010078791 Carrier Proteins Proteins 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
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- 231100000135 cytotoxicity Toxicity 0.000 description 4
- SXYIRMFQILZOAM-HVNFFKDJSA-N dihydroartemisinin methyl ether Chemical compound C1C[C@H]2[C@H](C)CC[C@H]3[C@@H](C)[C@@H](OC)O[C@H]4[C@]32OO[C@@]1(C)O4 SXYIRMFQILZOAM-HVNFFKDJSA-N 0.000 description 4
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- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 3
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- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 150000004985 diamines Chemical class 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 229950010286 diolamine Drugs 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
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- 230000002222 downregulating effect Effects 0.000 description 1
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- 210000003743 erythrocyte Anatomy 0.000 description 1
- 229950000206 estolate Drugs 0.000 description 1
- BENASNHJHCMGTI-SGEMFXFFSA-N ethylperoxyartemisitene Chemical compound C1C[C@H]2[C@H](C)CC[C@H]3C(=C)[C@@H](OOCC)O[C@H]4[C@]32OO[C@]1(C)O4 BENASNHJHCMGTI-SGEMFXFFSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000010408 film Substances 0.000 description 1
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- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 229940050411 fumarate Drugs 0.000 description 1
- 229960001731 gluceptate Drugs 0.000 description 1
- KWMLJOLKUYYJFJ-VFUOTHLCSA-N glucoheptonic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)C(O)=O KWMLJOLKUYYJFJ-VFUOTHLCSA-N 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 229940097042 glucuronate Drugs 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 229960003242 halofantrine Drugs 0.000 description 1
- 238000005534 hematocrit Methods 0.000 description 1
- 125000004404 heteroalkyl group Chemical group 0.000 description 1
- 108010045676 holotransferrin Proteins 0.000 description 1
- 229950011479 hyclate Drugs 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 229940099584 lactobionate Drugs 0.000 description 1
- JYTUSYBCFIZPBE-AMTLMPIISA-N lactobionic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O JYTUSYBCFIZPBE-AMTLMPIISA-N 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical class ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- 229960004961 mechlorethamine Drugs 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 229940120152 methyl 3-hydroxybenzoate Drugs 0.000 description 1
- VBWFYEFYHJRJER-UHFFFAOYSA-N methyl 4-(hydroxymethyl)benzoate Chemical compound COC(=O)C1=CC=C(CO)C=C1 VBWFYEFYHJRJER-UHFFFAOYSA-N 0.000 description 1
- 229940102396 methyl bromide Drugs 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- UMJJGDUYVQCBMC-UHFFFAOYSA-N n-ethyl-n'-[3-[3-(ethylamino)propylamino]propyl]propane-1,3-diamine Chemical compound CCNCCCNCCCNCCCNCC UMJJGDUYVQCBMC-UHFFFAOYSA-N 0.000 description 1
- QXOCYGPVDXDFLC-UHFFFAOYSA-N n-ethyl-n'-[4-[4-(ethylamino)butylamino]butyl]butane-1,4-diamine Chemical compound CCNCCCCNCCCCNCCCCNCC QXOCYGPVDXDFLC-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229950004864 olamine Drugs 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- UNEIHNMKASENIG-UHFFFAOYSA-N para-chlorophenylpiperazine Chemical compound C1=CC(Cl)=CC=C1N1CCNCC1 UNEIHNMKASENIG-UHFFFAOYSA-N 0.000 description 1
- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229960003975 potassium Drugs 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- XNSAINXGIQZQOO-SRVKXCTJSA-N protirelin Chemical compound NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)[C@H]1NC(=O)CC1)CC1=CN=CN1 XNSAINXGIQZQOO-SRVKXCTJSA-N 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 229930183339 qinghaosu Natural products 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- MOODSJOROWROTO-UHFFFAOYSA-N salicylsulfuric acid Chemical compound OC(=O)C1=CC=CC=C1OS(O)(=O)=O MOODSJOROWROTO-UHFFFAOYSA-N 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229940083542 sodium Drugs 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 229940063675 spermine Drugs 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229940014800 succinic anhydride Drugs 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 229940071103 sulfosalicylate Drugs 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000003239 susceptibility assay Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- KKEYFWRCBNTPAC-UHFFFAOYSA-L terephthalate(2-) Chemical compound [O-]C(=O)C1=CC=C(C([O-])=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-L 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000007723 transport mechanism Effects 0.000 description 1
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- MBYLVOKEDDQJDY-UHFFFAOYSA-N tris(2-aminoethyl)amine Chemical compound NCCN(CCN)CCN MBYLVOKEDDQJDY-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
- C07D493/18—Bridged systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P33/06—Antimalarials
-
- 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
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The present invention relates to compounds of general formula (13), and pharmaceutically acceptable salts thereof, in which: n = an integer of from 1 to 4; A represents a trioxane-containing residue; B represents a group having the general formula: -D-E-F-, in which D is linked to A and represents an atom or group selected from the following (a, b, c, d), E represents a bivalent, optionally substituted organic radical; and F is linked to C and represents a group selected from the following: (e, f, g, h) and C represents a group containing at least two nitrogen atoms, (13).
Description
TRIOXANE DERIVATIVES
The present invention relates to certain compounds containing a trioxane moiety that have potent antimalarial activity and antiturnour activity.
Artemisinin (1), which is also known as qinghaosu, is a tetracyclic 1,2,4-trioxane occurring in Artemisia au.nua. Artemisinin and its derivatives dihydroartemisinin (DHA)
The present invention relates to certain compounds containing a trioxane moiety that have potent antimalarial activity and antiturnour activity.
Artemisinin (1), which is also known as qinghaosu, is a tetracyclic 1,2,4-trioxane occurring in Artemisia au.nua. Artemisinin and its derivatives dihydroartemisinin (DHA)
(2), artemether (3) and sodium artesunate (4) are used routinely in the treatment of malaria and have been found to be particularly effective against cerebral malaria.
4 5 H a H = H = H _ .,,~Oz - ,,,v0 ,,,v0 .,v0 O ~Oli, 8a 8 O Oim O ~ O O/~~ ~ i O/~.
H =~2~2a ~.,H H __ '~iH H .,H H ~~H
O s O O~~ O _ to ' O OH OCH3 Na+-O II
O
Different mechanisms of action have been proposed to account fox the antimalarial action of artemisinin and its derivatives (Posner et al., J. Am.
Chem. Soc.
1996, 118; 3537; Posner et al., J. Am. Chem. Soc. 1995, 117, 5885; Posner et al., J. Med.
Chem. 1995, 38, 2273). Whilst the mechanism of action of artemisinin as an antimalarial has not been unequivocally established, it has been shown that the peroxide linkage is essential for antimalarial activity.
Certain artemisinin derivatives containing a peroxide moiety have also been tested for biological activity other than antimalarial activity. For example, the cytoxicity to Ehrlich ascites tumour cells of artemisinin, dihydroartemisinin, artemisitene, arteether, ethylperoxyartemisitene and an ether dimer of artemisinin has been demonstrated (Beekman et al., PlaytotlZer. Res., 1996, 10, 140; Woerdenberg et al., J. Nat.
Prod., 1993, 56, 849).
Selective cancer cell cytoxicity from exposure to dihydroartemisinin and holotransferrin, a non heme iron transport protein saturated with iron, has also been disclosed (Lai et al., Ca~icer Lett., 1995, 91, 41 and US Patent No. 5578637), with the drug combination being approximately 100 times more effective on molt-4 cells than lymphocytes.
It is known that some biologically active molecules contain chemical groups which enable them to bind to DNA. The method by which DNA binding occurs depends upon the overall structure of the molecule and the nature of the chemical groups contained within the molecule. For instance, the major and minor grooves of the double helical DNA are occupied by water under physiological conditions. However, certain oligopeptidic compounds such as netropscin and disamycin can displace water molecules and form strong hydrogen bonds with hydrophilic groups along the DNA strands.
Alternatively, some compounds contain groups which are capable of intercalating with DNA. Intercalators are compounds which insert between the bases of DNA.
Well characterised examples of intercalators are provided by anthracyclines, such as adriamycin and daunomycin, which are used for the treatment of cancer, and acridines, such as amascrine, which is used for treating acute leukaemia and malignant lymphomas.
The antiturnour activity is associated with the intercalating property of these compounds.
Naturally occurring polyamines, such as the tetra-amine spermine (5) and the triamine spermidine (6) occur in cells at micromolar concentrations, and may even rise to millimolar levels in certain cancer cells (Tabor & Tabor, Afzn. Rev. Biocheni, 1984, 53, 749). The biosynthetic building blocks for these and closely related polyamines are the alpha amino acids ornithine and lysine, affording the diamines putrescine (7) (1,4-diaminobutane) and cadaverine (8) (1,5-diamino pentane) respectively.
H2N~N~N~.NH2 H2N~H~NH2 H
H2N~NH2 H2N NH2 In recent years, it has been established that polyamines and polyamine amides have potential as novel therapeutic lead compounds in the design of anti-tumour agents.
Other workers, (Bergeron et al., Med. Chem., 1987, 31, 1183, Bergeron et al., CahceY
Res., 1989, 49, 2959) have addressed the usefulness of polyamines in cancer chemotherapy. In more recent studies, polyarnines have been identified as novel leads for the design of antidiarrhoeal agents and antimalarials and as ion chelators.
There is ever increasing realisation of the biological effects of polyamines, particularly in cellular pxocesses, including growth and replication (Heby &
Persson, Tre~.ds Bio. Sci., 1990, 15, 153). Thus, it is not surprising that polyamine conjugates continue to be the focus of significant attention as potential anticancer agents. It has been shown that a polyamine transporter specifically mediates the uptake of extracellular polyamines into cells (Seiler & Dezeure, Int. J. Biochem., 1990, 22, 211), and rapidly dividing tumour cells require large quantities of polyamines. Consequently, this polyamine transporter is up-regulated in tumour cells more so than in normal cells (Seiler et al., CatzceY Res., 1990, 50, 5077). Polyamines bind to DNA via either the major or the minor groove (Rodger et al., Biopolymers, 1994, 34, 1583, Rogers et al., Bio, org. Med.
Chem., 1995, 3, 861) and it is thought that endogenous polyamines also effect chromatin stability and structure (Basu et al., Bioclzem.J., 1992, 282, 723). Taking these aspects into account when designing polyamine based anticancer agents, there exists a potential uptake mechanism with selectivity for cancer cells (Cohen & Smith, Bioclzem.
Soc.
TYans., 1990, 18, 743) and two possible modes of cytotoxicity. This cytotoxicity may be mediated either by DNA binding and hence disruption of transcription (Feuerstein et al.,
4 5 H a H = H = H _ .,,~Oz - ,,,v0 ,,,v0 .,v0 O ~Oli, 8a 8 O Oim O ~ O O/~~ ~ i O/~.
H =~2~2a ~.,H H __ '~iH H .,H H ~~H
O s O O~~ O _ to ' O OH OCH3 Na+-O II
O
Different mechanisms of action have been proposed to account fox the antimalarial action of artemisinin and its derivatives (Posner et al., J. Am.
Chem. Soc.
1996, 118; 3537; Posner et al., J. Am. Chem. Soc. 1995, 117, 5885; Posner et al., J. Med.
Chem. 1995, 38, 2273). Whilst the mechanism of action of artemisinin as an antimalarial has not been unequivocally established, it has been shown that the peroxide linkage is essential for antimalarial activity.
Certain artemisinin derivatives containing a peroxide moiety have also been tested for biological activity other than antimalarial activity. For example, the cytoxicity to Ehrlich ascites tumour cells of artemisinin, dihydroartemisinin, artemisitene, arteether, ethylperoxyartemisitene and an ether dimer of artemisinin has been demonstrated (Beekman et al., PlaytotlZer. Res., 1996, 10, 140; Woerdenberg et al., J. Nat.
Prod., 1993, 56, 849).
Selective cancer cell cytoxicity from exposure to dihydroartemisinin and holotransferrin, a non heme iron transport protein saturated with iron, has also been disclosed (Lai et al., Ca~icer Lett., 1995, 91, 41 and US Patent No. 5578637), with the drug combination being approximately 100 times more effective on molt-4 cells than lymphocytes.
It is known that some biologically active molecules contain chemical groups which enable them to bind to DNA. The method by which DNA binding occurs depends upon the overall structure of the molecule and the nature of the chemical groups contained within the molecule. For instance, the major and minor grooves of the double helical DNA are occupied by water under physiological conditions. However, certain oligopeptidic compounds such as netropscin and disamycin can displace water molecules and form strong hydrogen bonds with hydrophilic groups along the DNA strands.
Alternatively, some compounds contain groups which are capable of intercalating with DNA. Intercalators are compounds which insert between the bases of DNA.
Well characterised examples of intercalators are provided by anthracyclines, such as adriamycin and daunomycin, which are used for the treatment of cancer, and acridines, such as amascrine, which is used for treating acute leukaemia and malignant lymphomas.
The antiturnour activity is associated with the intercalating property of these compounds.
Naturally occurring polyamines, such as the tetra-amine spermine (5) and the triamine spermidine (6) occur in cells at micromolar concentrations, and may even rise to millimolar levels in certain cancer cells (Tabor & Tabor, Afzn. Rev. Biocheni, 1984, 53, 749). The biosynthetic building blocks for these and closely related polyamines are the alpha amino acids ornithine and lysine, affording the diamines putrescine (7) (1,4-diaminobutane) and cadaverine (8) (1,5-diamino pentane) respectively.
H2N~N~N~.NH2 H2N~H~NH2 H
H2N~NH2 H2N NH2 In recent years, it has been established that polyamines and polyamine amides have potential as novel therapeutic lead compounds in the design of anti-tumour agents.
Other workers, (Bergeron et al., Med. Chem., 1987, 31, 1183, Bergeron et al., CahceY
Res., 1989, 49, 2959) have addressed the usefulness of polyamines in cancer chemotherapy. In more recent studies, polyarnines have been identified as novel leads for the design of antidiarrhoeal agents and antimalarials and as ion chelators.
There is ever increasing realisation of the biological effects of polyamines, particularly in cellular pxocesses, including growth and replication (Heby &
Persson, Tre~.ds Bio. Sci., 1990, 15, 153). Thus, it is not surprising that polyamine conjugates continue to be the focus of significant attention as potential anticancer agents. It has been shown that a polyamine transporter specifically mediates the uptake of extracellular polyamines into cells (Seiler & Dezeure, Int. J. Biochem., 1990, 22, 211), and rapidly dividing tumour cells require large quantities of polyamines. Consequently, this polyamine transporter is up-regulated in tumour cells more so than in normal cells (Seiler et al., CatzceY Res., 1990, 50, 5077). Polyamines bind to DNA via either the major or the minor groove (Rodger et al., Biopolymers, 1994, 34, 1583, Rogers et al., Bio, org. Med.
Chem., 1995, 3, 861) and it is thought that endogenous polyamines also effect chromatin stability and structure (Basu et al., Bioclzem.J., 1992, 282, 723). Taking these aspects into account when designing polyamine based anticancer agents, there exists a potential uptake mechanism with selectivity for cancer cells (Cohen & Smith, Bioclzem.
Soc.
TYans., 1990, 18, 743) and two possible modes of cytotoxicity. This cytotoxicity may be mediated either by DNA binding and hence disruption of transcription (Feuerstein et al.,
3 Nucleic Acids Res., 1990, 18, 1271), or by interference with polyamine biosynthetic pathways thereby modulating the cellular concentrations of endogenous polyamines.
To date, some of the simplest and most effective synthetic polyamines to display anticancer activity have been developed by Porter, Bergeron and their co-workers. They initially found activity with spermidine and spermine analogues which are N-alkylated (Porter et al., Cancer Res., 1982, 42, 4072, Porter et al., Cancer Res., 1985, 45, 2050).
Further studies showed the best analogues to be tetra-amines which have been bis-ethylated on the terminal, primary amines (e.g. compounds 9, 10 and 11) (Bergeron et al., J. Med. Chern., 1987, 31, 1183, Porter et al., Cancer Res., 1987, 47, 2821).
H
/~N~N~N~Nw/ /~H~H~N~H~
H H H
H
~N~N~N N~
H H H
These compounds are recognised and taken into cells by the polyamine transporter. Once inside the cells, they deplete intracellular pools by down-regulating the enzyme ornithine decarboxylase (ODC), the first enzyme in the polyamine synthesis pathway, and up regulating the spermine-spermidine N1-acetyltransferase (SSAT) enzyme which works in the back conversion pathway (Bergeron et al., Cancer Res., 1989, 49, 2959). The cytotoxic effects of the analogues DENSPM (9), DESPM (10) and DEHSPM (11) in the in vitro culture of L1210 cells, over 96 h, were l.3uM, 0.2uM and 0.06~.M respectively.
Many polyamine or polyamide moeities, for example desferrioxamine B (12), are low molecular weight ion chelating compounds. They facilitate iron solublization and transport.
To date, some of the simplest and most effective synthetic polyamines to display anticancer activity have been developed by Porter, Bergeron and their co-workers. They initially found activity with spermidine and spermine analogues which are N-alkylated (Porter et al., Cancer Res., 1982, 42, 4072, Porter et al., Cancer Res., 1985, 45, 2050).
Further studies showed the best analogues to be tetra-amines which have been bis-ethylated on the terminal, primary amines (e.g. compounds 9, 10 and 11) (Bergeron et al., J. Med. Chern., 1987, 31, 1183, Porter et al., Cancer Res., 1987, 47, 2821).
H
/~N~N~N~Nw/ /~H~H~N~H~
H H H
H
~N~N~N N~
H H H
These compounds are recognised and taken into cells by the polyamine transporter. Once inside the cells, they deplete intracellular pools by down-regulating the enzyme ornithine decarboxylase (ODC), the first enzyme in the polyamine synthesis pathway, and up regulating the spermine-spermidine N1-acetyltransferase (SSAT) enzyme which works in the back conversion pathway (Bergeron et al., Cancer Res., 1989, 49, 2959). The cytotoxic effects of the analogues DENSPM (9), DESPM (10) and DEHSPM (11) in the in vitro culture of L1210 cells, over 96 h, were l.3uM, 0.2uM and 0.06~.M respectively.
Many polyamine or polyamide moeities, for example desferrioxamine B (12), are low molecular weight ion chelating compounds. They facilitate iron solublization and transport.
4 Another approach to the development of antitumour compounds is the covalent linking of cytotoxic agents, whose activity is mediated through direct interaction with DNA, to a polyamine. The resulting conjugate will be transported into the cell through the polyamine transport mechanism (if recognised) and the polyamine should further aid DNA binding of the cytotoxic component as its DNA target site. In line with this, Cullis has demonstrated that polyamines conjugated to the nitrogen mustard chlorambucil increase the efficiency of DNA alkylation at the N7 of guanine by factors in the range of 103 to 104 (Cullis et al., J. Am. Chem. Soc., 1995, 117, X033).
It has now been discovered that artemisinin and synthetic trioxane derivatives can be chemically modified by the attachment of a polyamine residue to form analogues of arternisinin and synthetic trioxane derivatives which exhibit antimalarial, cytotoxic and antitumour activity.
According to a first aspect of the present invention therefore there is provided a compound of general formula 13 A--f -B o,~ C
n or a pharmaceutically acceptable salt thereof, in which:
n = an integer of from 1 to 4;
A represents a trioxane-containing residue;
B represents a group having the general formula:
-D-E-F-in which:
D is linked to A and represents an atom or group selected from the following:
O O O H
-o- -oJ.l- -o~o- -p-L~-N- , E represents a bivalent, optionally substituted organic radical; and F is linked to C and represents a group selected from the following:
O O O
-N-ll- ~ ; and C represents a group containing at least two nitrogen atoms.
In a preferred embodiment of the present invention, A represents the following trioxane-containing residue:
u....
H
With regard to the optionally substituted organic radical E, this preferably comprises an organic radical of 2-50 carbon atoms, more preferably 1-20 carbon atoms.
The optionally substituted organic radical E may comprise, for example, an optionally substituted alkyl, aryl, acyl, heteroalkyl or heteroacyl group. The organic radical E may optionally be substituted by groups including, but not limited to, primary, secondary and tertiary amines; halogen-containing groups, such as bromide, chloride and fluoride;
alcohols and derivatives thereof, including ethers and esters; and carboxylic acids and derivatives thereof, including esters and amides. Examples of organic radicals comprising Group E include -CH2-CHZ-, p-phenylene and pyridine.
With regard to group C, this may be, for example, a natural or synthetic polyamine residue and is preferably of 2-50 carbon atoms. Preferably also, group C
comprises. at least two amino groups, each of which is independently a primary or secondary group, after linking to group F through the same or different amino groups of the polyamine.
Those salts comprising pharmaceutically acceptable salts as referred to herein will be readily apparent to a skilled person. These salts include, but are not limited to acetate, adipate, besylate, bromide, camsylate, chloride, citrate, edisylate, estolate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hyclate, hydrobromide, hydrochloride, iodide, isethionate, lactate, lactobionate, maleate, mesylate, methylbromide, methylsulfate, napsylate, nitrate, oleate, pamoate, phosphate, polygalacturonate, stearate, succinate, sulfate, sulfosalicylate, tannate, tartrate, terephthalate, tosylate, triethiodide, benzathine, calcium, diolamine, meglumine, olamine, potassium, procaine, sodium, tromethamine, and zinc.
Apart from imparting selectivity against cancer cells, the incorporation of amine functionality into an endoperoxide was seen as a useful strategy for enhancing antimalarial activity, since the amine peroxide should be concentrated in the acidic vacuole of the malaria parasite by ion-trapping (Vennerstrom et al., J. Med.
Chern., 1989, 32, 64, O' Neill et al., J. Med. Chem., 1996, 39, 4511). Intraparasitic accumulation in the haem "rich" food vacuole is considered to be key to the action of all basic quinoline antimalarial agents (O' Neill, Phartn. e~ Therapeutics, 1998, 77, 29). For example, chloroquine is a dibasic drug with pI~s of 8.1 (quinoline ring nitrogen) and 10.2 (diethylamino side chain) and accumulates in acidic vesicles to the square of the monobasic antimalarials such as mefloquine. Experiments on the pH gradient between the external medium and the parasite food vacuole have shown that the value is around 2.2. On this basis, Ginsburg and co-workers suggested that chloroquine would be expected to accumulate 2.5 x 104 compared with 160 fold for the mono-basic antimalarials such as mefloquine (Ginsburg et al., Biochem. Phar»zacol., 1989, 38, 2645).
It follows that the introduction of two basic amino groups into an artemisinin derivative would be expected to increase significantly the cellular accumulation of drug in the ferrous rich parasite food vacuole. This approach should provide analogues with increased antimalarial potency, since more drug will be available for reductive endoperoxide bioactivation to radical species.
One preferred embodiment of the present invention provides compounds having the structure 13n.
13n, G = substituted aryl ring Specific examples of such compounds are included in Chart 1.
s CHART 1- C-10-Ether Linked Diamino Analogues N
R1 / \ N I i 13a-13d (R2= H, N02, F, CF3) .""O
O O""..
R = / \ ~N~
N
~O~R_1 13e R1= \ / ~~.R2 ~N ~
13f-13j (R2=H,p-N02,p-Cl,rn-CFg, p-F
This series of preferred compounds was prepared as shown in Scheme 1.
Dihydroartemisinin (2) was coupled with 1,4-benzenedimethanol to give the corresponding alcohol (12a) in high yield with excellent diastereoselectivity ((3/oc 5:1).
The alcohol was then converted into the mesylate (12b) in high yield by treatment with mesyl chloride and triethylamine. The key mesylate was then allowed to react with a range of diamino nucleophiles to provide compounds (13a-13d). As shown in Scheme 1, DHA was also coupled with 1,3-benzenedimethanol to provide the alcohol which could then be transformed into target analogues (13f-13j) using the same chemistry described for the para substituted analogues.
Scheme 1 ~N w HN~ I ~
_ R2 1. BF3.Et20 2 ~ --\ ene HO OH
2. MsCl 12a (R3= H) 13a-13d (R2= H, N02, F, CF3) 12b (R3= Ms) 1. BF3. Et20 -HO / \ benzene OH
HN N I \ Ph 2. MsCl Benzene 13e _ ~N~ H
.. O
O 0.,..
benzene O~ / \ ~N
\~N~ I = R2 M ~s 13f 13j (R2= H, p-NO2, pCl, m-CF3, p-F) Thus, and in accordance with a further aspect of the present invention there is provided a process for the production of a compound of general formula 13 as hereinbefore defined, said process comprising the steps of coupling dihydroartemisinin with benzenedimethanol, converting the resultant alcohol into the corresponding sulfonate by treatment with a sulfonyl halide, and reacting said sulfonate with a diamino nucleophile.
Most preferably, the resultant alcohol is converted into the corresponding mesylate by treatment with mesyl chloride.
to This process is particularly advantageous with regard to the production of trioxane derivatives of the type exemplified by compounds 13a-13j.
Further preferred compounds of the present invention were prepared according to Schemes 2 to 5 as shown below. Dihydroartemisinin (2) was coupled with a variety of alcohol methyl esters. These were then hydrolysed to give carboxylic acids, which were coupled with a number of polyamines and amines. Under standard conditions compounds with two artemisinin groups in the molecule were formed. If an excess of amine was used at 0°C, this gave the desired monomers.
.",o ..",o ..".o 0 Om" O AgC104 O On.,. 0 On".
0 HO \ / OMe DM~ O O
_ _ \~ \
O OMe O OMe O~~".
2.5% IfOH O iqR a Met O
O
O OH
Scheme 2 .,~no 0 O On".
b p O
O
OH
Scheme 3 .",~o O Oi",.
EDCI
O H2N~NH2 HOBT, DCM' O
O OH
Scheme 4 H
N ~~
,,,, .""o 0 0.,.,.
~NHZ EDC~ O
O H2N HOBT, DCM ; 'O~ ~ \
O O O I H
O ~~N~/\/~NHZ
I'v~~~I I('O
OOH
Scheme 5 According to a further aspect of the present invention therefore there is provided a process for the production of a compound of general formula 13 as hereinbefore described, said process comprising the steps of coupling dihydroartemisinin with an alcohol methyl ester, hydrolysing the resultant compound to produce the corresponding carboxylic acid, and coupling said carboxylic acid with a polyamine or amine.
Alternatively, a further aspect of the invention provides a process for the production of a compound of general formula 13 as hereinbefore described, said process comprising the steps of coupling dihydroartemisinin with an anhydride, forming a carboxylic acid, and coupling said carboxylic acid with a polyamine or amine.
Preferably, coupling of the carboxylic acid and polyamine or amine is carried out at a temperature of between -20 and +40 ° C.
These processes are particularly advantageous with regard to the production of trioxane derivatives of the type exemplified by Examples 20 to 35.
The antimalarial activity of the new compounds was assessed using two strains of P. falciparum from Thailand: (a) the uncloned I~1 strain which is known to be CQ
resistant and (b) the HB3 strain which is sensitive to all antimalarials.
Parasites were maintained in continuous culture using the method of Trager and Jenson (J.
Parasitol., 1977, 63, 883-886). Cultures were grown in flasks containing human erythrocytes (2-5%) with parasitemia in the range of 1% to 10% suspended in RPMI 1640 medium supplemented with 25 mM HEPES and 32 mM NaHC03, and 10% human serum (complete medium). Cultures were gassed with a mixture of 3% 02, 4% C02 and 93% N2.
Antimalarial activity was assessed with an adaption of the 48-h sensitivity assay of Desjardins et al. (Aratimicrob. Agents. Chemother., 1979, 16, 710-718) using [3H~-hypoxanthine incorporation as an assessment of parasite growth. Stock drug solutions were prepared in 100% dimethylsulphoxide (DMSO) and diluted to the appropriate concentration using complete medium. Assays were performed in sterile 96-well microtitre-plates, each plate containing 200 ~,1 of parasite culture (2%
parasitemia, 0.5%
haematocrit) with or without 10 ~,l drug dilutions. Each drug was tested in triplicate and parasite growth was compared to control wells (which constituted 100 %
parasite growth).
After 24-h incubation at 37°C, 0.5 ~,Ci hypoxanthine was added to each well. Cultures were incubated for a further 24 h before they were harvested onto filter-mats, dried for 1 h at 55°C and counted using a Wallac 1450 Microbeta Trilux Liquid scintillation and luminescence counter. ICso values were calculated by interpolation of the probit transformation of the log dose - response curve.
The results of these experiments axe contained in Table 1, which shows the of compounds of the present invention versus the K1 strain of P. falciparum ifi vitro.
Table 1 Compound Number IC50 (nM) SD
(13a) 8.2 2.7 (13b) 138.1 11.1 (13c) 6.3 0.7 (13d) 12.5 1.6 (13e) 3.8 0.1 (13f) 6.6 0.7 (13g) 4.3 0.30 (13h) 13.3 0.6 (13i) 22.5 1.9 (13j) 12.6 17 Artemether 6.5 2 Chloroquine 255 10 Table 2 shows the IC50 of compounds of the invention versus the HB3 strain of P. falciparu»z in vitro.
Table 2 Compound Number IC50 (nM) SD
(13c) 2.3 0.7 (13d) 8.1 1.2 (13e) 1.8 0.2 (13f) 3.4 0.7 (13g) 4.3 0.30 (13j) 12.6 17 Artemether 9.2 0.2 The anticancer activity of these compounds of the present invention was also assessed, by NCI 3-cell line anticancer assay. In this protocol, each cell line is inoculated and preincubated on a microtiter plate. Test agents are then added at a single concentration and the culture incubated for 48 hours. End-point determinations are made with sulforhodamine B, a protein-binding dye. Results for each test agent are reported as the percentage of growth of the treated cells when compared to the untreated control cells. Compounds which reduce the growth of any one of the cells lines to 32%
or less (negative numbers indicate cell kill) are passed on for evaluation in the full panel of 60 cell lines over a 5-log dose range.
The results of these assays are shown in Table 3 below.
Table 3 Compound Number ConcentrationNCI-H460 MCF7 SF-268 (Lung) (Breast)(CNS) (13h) 1.OOE-04Molar22 11 31 (13i) 1.OOE-04Molar15 10 29 (13c) 1.OOE-04Molar12 13 27 According to a further aspect of the present invention there is provided a compound of general formula 13 as hereinbefore defined, or a pharmaceutically acceptable salt thereof, for use as a medicament.
Compounds of the present invention may be used particularly, but not exclusively, as medicaments for the treatment of malaria or cancer. Whilst the currently preferred use of peroxides is for treatment, it cannot be ruled out that these compounds would have a use in the prophylaxis of malaria.
A therapeutically effective non-toxic amount of a compound of general formula 13 as hereinbefore defined may be administered in any suitable manner, including orally, parenterally (including subcutaneously, intramuscularly and intravenously), or topically.
The administration will generally be carried out repetitively at intervals, for example once or several times a day.
The amount of the compound of general formula 13 that is required in order to be effective as an antimalarial or anticancer agent for treating human or animal subjects will of course vary and is ultimately at the discretion of the medical or veterinary practitioner treating the human or animal in each particular case. The factors to be considered by such a practitioner, e.g. a physician, include the route of administration and pharmaceutical formulation; the subject's body weight, surface area, age and general condition; and the chemical form of the compound to be administered.
In daily treatment, for example, the total daily dose may be given as a single dose, multiple doses, e.g. two to six times per day, or by intravenous infusion for any selected duration.
The compound of general formula 13 may be presented, for example, in the form of a tablet, capsule, liquid (e.g. syrup) or injection.
While it may be possible for the compounds of general formula 13 to be administered alone as the active pharmaceutical ingredient, it is preferable to present the compounds in a pharmaceutical composition.
According to a further aspect of the present invention therefore there is provided a pharmaceutical composition containing a compound of general formula 13 as hereinbefore defined, or a pharmaceutically acceptable salt thereof, as an active ingredient.
Such pharmaceutical compositions for medical use will be formulated in accordance with any of the methods well known in the art of pharmacy for administration in any convenient manner. The compounds of the invention will usually be admixed with at least one other ingredient providing a compatible pharmaceutically acceptable additive, carrier, diluent or excipient, and may be presented in unit dosage form.
The carriers) must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The possible formulations include those suitable for oral, rectal, topical and parenteral (including subcutaneous, intramuscular and intravenous) administration or for administration to the lung or another absorptive site such as the nasal passages.
All methods of formulation in making up such pharmaceutical compositions will generally include the step of bringing the compound of general formula 13 into association with a carrier which constitutes one or more accessory ingredients. Usually, the formulations are prepared by uniformly and intimately bringing the compound of general formula 13 into association with a liquid carrier or with a finely divided solid carrier or with both and then, if necessary, shaping the product into desired formulations.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets or lozenges, each containing a predetermined amount of the compound of general formula 13; as a powder or granules;
or a suspension in an aqueous liquid or non-aqueous liquid such as a syrup, an elixir, an emulsion or a draught. The compound of general formula 13 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 compound of general formula 13 in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Moulded tablets may be made by moulding, in a suitable machine, a mixture of the powdered compound of general formula 13 with any suitable carrier.
A syrup may be made by adding the compound of general formula 13 to a concentrated, aqueous solution of a sugar, for example sucrose, to which may be added any desired accessory ingredient. Such accessory ingredients) may include flavourings, an agent to retard crystallisation of the sugar or an agent to increase the solubility of any other ingredient, such as a polyhydric alcohol, for example glycerol or sorbitol.
Formulations for rectal administration may be presented as a suppository with a usual carrier such as cocoa butter.
Formulations suitable for parental administration conveniently comprise a sterile aqueous preparation of the compound of general formula 13 which is preferably isotonic with the blood of the recipient.
In addition to the aforementioned ingredients, formulations of this invention, for example ointments, creams and the like, may include one or more accessory ingredients, for example a diluent, buffer, flavouring agent, binder, surface active agent, thickener, lubricant and/or a preservative (including an antioxidant) or other pharmaceutically inert excipient.
The compounds of this invention may also be made up for administration in liposomal formulations which can be prepared by methods well-known in the art.
A further aspect of the present invention provides the use of a compound of general formula 13 as hereinbefore defined, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prophylaxis of malaria.
A further aspect of the present invention provides the use of a compound of general formula 13 as hereinbefore defined, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.
It has further surprisingly been found that exposure of tumour cells to iron potentiates the anticancer effect of the compounds of the present invention.
This finding is supported by the observation that cultured cancer cell lines were more readily destroyed by compounds of the present invention following exposure to culture medium having an elevated iron concentration.
According to a further aspect of the present invention therefore there is provided a product containing a first compound of general formula 13 as hereinbefore defined, or a pharmaceutically acceptable salt thereof, and a second, iron-containing, compound as a combined preparation for simultaneous, separate or sequential use in the treatment of cancers.
Preferably, the first and second compounds are used sequentially, the second, iron-containing, compound being used first.
The first compound may be presented in any of the forms described above.
Administration of the first compound may be in any suitable manner, including intravenously, intraarterially, intralesionally, topically, intracavitarily or orally. Any suitable dosage of the compound may be used. Preferably, a dosage within the range of 0.1 to SOOmg/kg body weight is used, more preferably within the range of 0.5 to 300mg/kg body weight, such as 1 to 50 mg/kg body weight.
With regard to the iron-containing compound, this may take any suitable form.
Preferred agents for enhancing intracellular iron levels for use in the present invention include pharmaceutically acceptable iron salts and iron complexes. Iron salts useful in the present invention include ferrous fumarate, ferrous sulphate, ferrous carbonate, ferrous citrate, ferrous gluconate, ferrous lactate and ferrous maleate. Iron complexes useful in the present invention include ferrocholinate, ferroglycine sulphate, dextran iron complex, peptonized iron, iron sorbitex, saccharated iron, iron complexed with iron binding proteins and glycoproteins such as the holoferritins and holotransferrins.
The iron-containing compound may be presented in any of the forms described above in relation to the compound of general formula 13. Administration of the iron-containing compound may be achieved via any of the possible routes of administration of the first compound. The first and second compounds may be administered via the same or different routes.
The iron-containing compound may be used ay any appropriate dosage, but is preferably used at a dosage within the range of 0.01 to 1000 mg iron/kg body weight.
The product of the invention may further comprise one or more other agents known to be useful in the treatment of tumours. Such agents may include, for example, androgen inhibitors, antiestrogens, antimetabolites and cytotoxic agents.
According to a further aspect of the present invention there is provided a method of treatment of malaria which comprises administering to an animal in need of such treatment a therapeutically effective amount of a compound of general formula 13 as hereinbefore defined, or a pharmaceutically acceptable salt thereof.
In terms of suitable dosages for the treatment of malaria, the preferred amount of compounds of the present invention is between l0mg to 5g, preferably 50 to 1000mg, administered over a period of 2-5 days, alone or in combination with other antimalarial drugs, such as, for example, the class II blood schizonticides or halofantrine (Looaeesuwan, Am. J. Trop. Med., 1999, 60, 238).
According to a further aspect of the present invention there is provided a method of treatment of cancer which comprises administering to an animal in need of such treatment a therapeutically effective amount of a compound of general formula 13 as hereinbefore defined, or a pharmaceutically acceptable salt thereof.
The method may further comprise the simultaneous, separate or sequential administration to the said animal an effective amount of an iron-containing compound as hereinbefore described.
The invention will now be illustrated by the following non-limiting examples.
Examples Experimental Section Merck Kieselgel 60 F 254 pre-coated silica plates for TLC were obtained from BDH, Poole, Dorset, U.K. Column chromatography was carried out on Merck 9385 silica gel.
Infra red (IR) spectra were recorded in the range 4000-600 cm 1 using a Perkin Elmer 298 infrared spectrometer. Spectra of liquids were taken as films. Sodium chloride plates (nujol mull) , solution cells (dichloromethane) and KBr discs were used as indicated.
1H NMR spectra were recorded using a Perkin Elmer R34 (220 MHz) and Bruker (300 MHz and 200 MHz) spectrometers. Solvents are indicated in the text and tetramethylsilane was used as the internal reference. Mass spectra were recorded at 70eV
using a VG7070E mass spectrometer. The samples were introduced using a direct-insertion probe. In the text the parent ion (M+) is given, followed by peaks corresponding to major fragment losses with intensities in parentheses.
General Procedure 1. Synthesis of Ether Derivatives Dihydroartemisinin (2.00 g, 7.04 mmol) was dissolved in anhydrous diethyl ether (200 mL) under N2. BF3.Et20 (1.03 mL, 8.10 mmol) was added to the solution, followed by the appropriate (hydroxymethyl) benzyl alcohol (1.46 g, 10.56 mmol). The mixture was allowed to stir at room temperature for 20 h and then quenched with water. The organic phase was washed with Na2S04 solution (30 % w/v), dried over MgS04, filtered and the solvent was removed under reduced pressure to the give the crude product as an oil.
Purification by silica gel chromatography using ethyl acetate/nhexane (40/60) as the eluent gave the corresponding ether products.
10(3-[[4-(Hydroxymethyl)benzyl]oxy]dihydroartemisinin (12a) This compound was prepared using general procedure 1 to give the product as a colourless syrup (78 % yield): 1H NMR (300 MHz, CDC13) 8 7.20-7.08 (4 H, m, aromatic), 5.44 (1 H, s), 4.88 (1 H, d, J = 3.80 Hz), 4.85 (1 H, d, J = 12.19 Hz), 4.69 (2 H, s), 4.51 (1 H, d, J = 12.19 Hz), 2.67 (1 H, sex), 2.38 (1 H, dt, J = 13.46, 3.98 Hz), 2.07-1.20 (10 H, m), 1.46 (3 H, s) and 0.94 (6 H, d, J = 7.17 Hz); 13C NMR (75 MHz, CDC13) 8 140.20, 137.88, 127.59, 127.05, 104.21, 101.45, 88.09, 81.18, 69.57, 65.11, 52.62, 44.45, 37.43, 36.46, 34.64, 30.94, 26.16, 24.69, 24.52, 20.32 and 13.06; IR (thin film)/crri 1 3476, 2924, 1612, 1516, 1458, 1377, 1194, 1101, 1011, 876 (O-O) and 826 (O-O); MS m/z (CI) [M + NH4]+ 422 (8), 359 (100), 284 (39), 221 (96) and 138 (33).
10(3-[[3-(Hydroxymethyl)benzyl]oxy]dihydroartemisinin This compound was prepared using general procedure 1 to give the product as a colourless solid (68 % yield): m.p. 118-120 °C; 1H NMR (300 MHz, CDC13) 8 7.34-7.26 (4 H, m, aromatic), 5.40 (1 H, s), 4.92 (1 H, d, J = 3.80 Hz), 4.88 (1 H, d, J
= 12.20 Hz), 4.70 (2 H, s), 4.55 (1 H, d, J = 12.20 Hz), 2.67 (1 H, sex), 2.38 (1 H, dt, J
= 13.50, 3.80 Hz), 2.07-1.20 (10 H, m), 1.45 (3 H, s), 0.96 (3 H, d, J = 6.00 Hz) and 0.88 (3 H, d, J =
7.60 Hz); 13C NMR (75 MHz, CDC13) 8 141.05, 138.93, 128.64, 126.80, 126.15, 104.21, 101.65, 88.06, 81.17, 69.90, 65.37, 52.62, 44.47, 37.43, 36.46, 34.65, 30.97, 26.16, 24.70, 24.51, 20.31 and 13.07; IR (Nujol)/crri 13507, 2924, 1611, 1462, 1378, 1227,1192, 1104, 1011, 874 (O-O) and 823 (O-O); Anal. C23Hsa06 requires C 68.29 %, H 7.97 %, found C
68.01%,H8.14%.
General Procedure 2. Synthesis of C-10 Oxo Derivatives To a solution of the appropriate (hydroxymethyl) benzyl alcohol (0.20 g, 0.50 mmol) in anhydrous DCM (10 mL) under NZ was added triethylamine (0.08 mL, 0.55 mmol), followed by mesyl chloride (0.06 mL, 0.74 mmol) at 0 °C. The mixture was stirred at 0 °C for 2 h and then quenched with water (10 mL). The organic phase was extracted with DCM (3 x 10 mL) and then dried over MgS04, filtered and the solvent was removed under reduced pressure. The crude mesylate and the appropriate substituted piperazine derivative (4.11 mmol) were dissolved in anhydrous benzene (10 mL) under NZ
atmosphere. The mixture was heated at reflux for 5 h. After allowing to cool to room temperature, the mixture was quenched with saturated NaHC03 solution and the organic phase was extracted with diethyl ether (3 x 10 mL). The organic extracts were washed with brine, dried over MgS04, filtered and the solvent was removed under reduced pressure. Purification by silica gel chromatography using ethyl acetate/nhexane (40/60) as the eluent gave the corresponding piperazine products.
10(3-[[4-[Phenylpiperazyl)methyl]benzyl]oxy]dihydroartemisinin (13a) This compound was prepared from 1-phenyl piperazine using general procedure 2 to give the product as a yellow oil (84 % yield): 1H (300 MHz, CDCl3) b 7.30-7.28 (4 H, d, J =
4.5 Hz, aromatic), 7.00-6.90 (5 H, m, aromatic), 5.45 (1 H, s), 4.90 (1 H, d, J = 3.80 Hz), 4.86 (1 H, d, J = 12.20 Hz), 4.50 (1 H, d, J =12.20 Hz), 3.53 (2 H, s, CH2), 2.69 (1 H, m, CH), 2.51 (8 H, m, CH2), 2.38 (1 H, dt, J = 13.32, 4.12 Hz), 2.07-1.20 (10 H, m), 1.45 (3 H, s, CH3), 0.95-0.93 (6 H, 2 x CH3); isC (75 MHz, CDC13) 8 129.34, 128.28, 127.19, 104.16, 101.51, 88.08, 81.18, 69.67, 62.98, 62.68, 52.92, 52.66, 44.49, 37.43, 36.49, 34.67, 30.97, 26.19, 24.71, 24.52, 20.31, 13.06; LC/MS (NH3); m/z 563[M + H+, (100)], 279 (17).
10[3-[[4-[(4-Nitrophenylpiperazyl)methyl]benzyl]oxy]dihydroartemisinin (13b) This compound was prepared from 1-(4-nitrophenyl)piperazine using general procedure 2 to give the product as an orange solid (68 % yield): 1H (300 MHz, CDCl3) ~
8.12 (2 H, d, J = 9.48 Hz, aromatic), 7.35-7.27 (4 H, m, aromatic), 6.82 (2 H, d, J = 9.48 Hz, aromatic), 5.47 (1 H, s), 4.91 (1 H, d, J = 3.90 Hz), 4.90 (1 H, d, J = 12.50 Hz), 4.53 (1 H, d, J = 12.50 Hz), 3.58 (2 H, s), 3.47-3.42 (4 H, m), 2.68 (1 H, m), 2.64-2.59 (4 H, m), 2.38 (1 H, dt, J = 13.32, 4.12 Hz), 2.07-1.20 (10 H, m), 1.46 (3 H, s) and 0.95 (6 H, d, J =
6.70 Hz); 13C (75 MHz, CDC13) ~ 154.96, 129.17, 127.34, 125.99, 112.70, 104.19, 101.43, 88.09, 81.16, 69.54, 62.61, 52.63, 52.48, 47.08, 44.46, 37.46, 36.47, 34.67, 30.94, 26.18, 24.71, 24.53, 20.31 and 13.06; IR (Nujol)/crri 1 2927, 1597, 1493, 1462, 1377, 1327, 1251, 1231, 1099, 1010, 876 (O-O) and 828 (O-O); MS m/z (EI) [M]+ 593 (1), 264 (98), 218 (34), 104 (100) and 56 (58).
10[3-[[4-[(4-Fluorophenylpiperazyl)methyl]benzyl]oxy]dihydroartemisinin (13c) This compound was prepared from 1-(4-fluorophenyl)piperazine using general procedure 2 to give the product as a yellow oil (64 % yield): 1H (300 MHz, CDCl3) 8 7.35-7.28 (4 H, m, aromatic), 6.99-6.85 (4 H, m, aromatic), 5.46 (1 H, s), 4.91 (1 H, d, J
= 3.90 Hz), 4.90 (1 H, d, J = 12.45 Hz), 4.52 (1 H, d, J =12.45 Hz), 3.58 (2 H, s), 3.16-3.11 (4 H, m), 2.68-2.63 (5 H, m), 2.38 (1 H, dt, J = 13.50, 3.90 Hz), 2.07-1.20 (10 H, m), 1.46 (3 H, s), 0.95 (3 H, d, J = 6.00 Hz) and 0.94 (3H, d, J = 6.60 Hz); 13C (75 MHz, CDC13) b 141.05, 138.93, 128.64, 126.80, 126.15, 104.21, 101.65, 88.06, 81.17, 69.90, 65.37, 52.62, 44.47, 37.43, 36.46, 34.65, 30.97, 26.16, 24.70, 24.51, 20.10 and 13.07; IR (thin film)/crri 1 2945, 1633, 1510, 1455, 1374, 1359, 1240, 1142, 1099, 1011, 876 (O-O) and 825 (O-O);
HRMS (EI) C33H43FN2O5 [M~+ requires 566.31561, found 566.31493.
10(i-[[4-[(4-Trifluoromethylphenylpiperazyl)methyl]benzyl]oxy]dihydroartemisinin (13d) This compound was prepared from 1-(4-trifluoromethyl phenyl)piperazine using general procedure 2 to give the product as a yellow oil (64 % yield): 1H, (300 MHz, CDCl3) 8 7.35-7.28 (5 H, m, aromatic), 7.10-7.03 (3 H, m, aromatic), 5.46 (1 H, s)~
4.92 (1 H, d, J
=12.30 Hz), 4.88 (1 H, d, J = 3.80 Hz), 4.52, (1 H, d, J = 12.30 Hz), 3.61 (2 H, m, CH2), 3.27 (4 H, m, CH2), 2.70-2.65 (5 H, m, CH2), 2.39 (1 H, m, CH2), 2.07-1.20 (10 H, m), 1.45 (3 H, s, CH3), 0.97-0.94 (6 H, d, 2 xCH3); 13C (75 MHz, CDCl3) 8 129.59, 129.32, 127.33, 118.78, 112.29, 104.19, 101.50, 88.09, 81.17, 69.61, 62.58, 52.73, 48.55, 44.48, 37.46, 36.48, 34.67, 30.96,26.18, 24.71, 24.54, 20.31, 13.06; IR (thin film)/crri 1 (2925), (1454), (1136), (1011). LC/MS (NH3); m/z 618 [M + H+, (100)], 603 (100), 333 (7).
10(3-[[4-[(Benzylpiperazyl)methyl]benzyl]oxy]dihydroartemisinin (13c) This compound was prepared from 1-benzylpiperazine using general procedure 2 to give the product as a yellow oil (72 % yield): 1H NMR (300 MHz, CDC13) 8 7.32-7.20 (9 H, m, aromatic), 5.45 (1 H, s), 4.91 (1 H, d, J = 3.90 Hz), 4.90 (1 H, d, J =
12.50 Hz), 4.52 (1 H, d, J = 12.50 Hz), 3.54 (4 H, br s), 2.68 (1 H, m), 2.54-2.49 (8 H, m), 2.38 (1 H, dt, J
= 14.10, 3.90 Hz), 2.07-1.20 (10 H, m), 1.45 (3 H, s), 0.94 (3 H, d, J = 5.70 Hz) and 0.94 (3H, d, J = 7.2 Hz); 13C (75 MHz, CDCl3) 8 129.34, 128.28, 127.19, 104.16, 101.51, 88.08, 81.18, 69.67, 62.98, 62.68, 52.92, 52.66, 44.49, 37.43, 36.49, 34.67, 30.97, 26.19, 24.71, 24.52, 20.31 and 13.06; IR (thin film)/cni 1 2938, 1609, 1495, 1457, 1374, 1344, 1227, 1099, 1010, 876 (O-O) and 826 (O-O).
10/3-[[3-[(Phenylpiperazyl)methyl]benzyl]oxy]dihydroartemisinin (l3fj This compound was prepared from 1-phenylpiperazine using general procedure 2 to give the product as a brown foam (59 % yield): 1H NMR (300 MHz, CDC13) 8 7.30-7.22 (4 H, m, aromatic), 6.94-6.85 (5 H, m, aromatic), 5.47 (1 H, s), 4.91 (1 H, d, J =
3.70 Hz), 4.90 (1 H, d, J = 12.20 Hz), 4.55 (1 H, d, J = 12.20 Hz), 3.59 (2 H, br s), 3.27-3.21 (4 H, m), 2.69-2.61 (5 H, m), 2.38 (1 H, dt, J = 13.30, 3.80 Hz), 2.07-1.20 (10 H, m), 1.46 (3 H, s), 0.95 (3 H, d, J = 7.40 Hz) and 0.94 (3H, d, J = 6.00 Hz); 13C (75 MHz, CDC13) ~ 139.10, 129.17, 128.38, 116.16, 104.19, 101.40, 88.10, 81.18, 69.68, 52.65, 44.47, 37.45, 36.48, 34.69, 30.96, 26.19, 24.71, 24.53, 20.32 and 13.10; IR (Nujol)/cni 1 2925, 1601, 1504, 1455, 1375, 1228, 1101, 1013, 875 (O-O) and 825 (O-O); HRMS (EI) C33H44N2O5 [M]+
requires 548.32501, found 548.32604.
10(3-[[3-[(4-Nitrophenylpiperazyl)methyl]benzyl]oxy]dihydroartemisinin (13g) This compound was prepared from 1-(4-nitrophenyl)piperazine using general procedure 2 to give the product as an orange foam (85 % yield): 1H (300 MHz, CDC13) 8 8.13 (2 H, d, J = 9.50 Hz, aromatic), 7.36-7.25 (4 H, m, aromatic), 6.82 (2 H, d, J = 9.50 Hz, aromatic), 5.47 (1 H, s), 4.91 (1 H, d, J = 5.00 Hz), 4.90 (1 H, d, J = 12.30 Hz), 4.56 (1 H, d, J = 12.30 Hz), 3.61 (2 H, s), 3.49-3.43 (4 H, m), 2.71 (1 H, rn), 2.69-2.63 (4 H, m), 2.39 (1 H, dt, J = 13.87, 3.98 Hz), 2.07-1.20 (10 H, m), 1.45 (3 H, s) and 0.94 (6H, d, J =
7.40 Hz); 13C (75 MHz, CDCl3) b 151.00, 128.50, 128.00, 125.99, 112.79, 104.00, 101.00, 88.09, 81.50, 69.56, 60.38, 52.61, 52.20, 46.96, 44.20, 37.47, 36.45, 34.50, 30.93, 26.00, 24.70, 24.55, 20.32 and 13.00; IR (Nujol)/crri 1 2923, 1598, 1506, 1456, 1378, 1328, 1248, 1099, 1010, 875 (O-O) and 826 (O-O); MS m/z (EI) [M~+ 593 (1), 264 (43), 219 (18), 105 (100) and 56 (30).
10(3-[[3-[(4-Chlorophenylpiperazyl)methyl]benzyl]oxy]dihydroartemisinin (13h) This compound was prepared from 1-(4-chlorophenyl)piperazine using general procedure 2 to give the product as a brown foam (64 % yield): 1H (300 MHz, CDCl3) b 7.32-7.06 (6 H, m, aromatic), 6.83 (2 H, d, J = 9.06, aromatic), 5.47 (1 H, s), 4.92 (1 H, d, J = 4.10 Hz), 4.90 (1 H, d, J = 12.01 Hz), 4.55 (1 H, d, J = 12.01 Hz), 3.61 (2 H, br s), 3.22-3.17 (4 H, m), 2.69-2.61 (5 H, m), 2.39 (1 H, dt, J =13.50, 3.85 Hz), 2.07-1.20 (10 H, m), 1.46 (3 H, s) and 0.94 (3H, d, J = 6.60 Hz); 13C (75 MHz, CDC13) 8 138.50, 129.03, 128.44, 117.35, 104.19, 101.37, 88.09, 81.17, 69.64, 52.81, 49.03, 44.45, 37.45, 36.47, 34.68, 30.94, 26.19, 24.71, 24.53, 20.32 and 13.10; IR (Nujol)/crri 1 2927, 1616, 1496, 1459, 1378, 1225, 1102, 1032, 874 (O-O) and 815 (O-O); MS m/z (EI) [M]+ 422 (1), 300 (26), 193 (19), 131 (14) and 105 (100).
10(3-[[3-[(3-Trifluoromethylphenylpiperazyl)methyl]benzyl]oxy]dihydroartemisinin (13i) This compound was prepared from 1-[(3-trifluoromethyl)phenyl]piperazine using general procedure 2 to give the product as a brown foam (66 % yield): 1H (300 MHz, CDC13) ~
7.37-7.23 (4 H, rn, aromatic), 7.10-7.06 (4 H, m, aromatic), 5.47 (1 H, s), 4.92 (1 H, d, J
= 3.98 Hz), 4.90 (1 H, d, J = 12.16 Hz), 4.52 (1 H, d, J = 12.16 Hz), 3.58 (2 H, s), 3.16-3.11 (4 H, m), 2.68-2.63 (5 H, m), 2.38 (1 H, dt, J =13.48, 4.02 Hz), 2.07-1.20 (10 H, m), 1.45 (3 H, s), 0.95 (3 H, d, J = 7.20 Hz) and 0.94 (3H, d, J = 6.00 Hz); 13C
NMR (75 MHz, CDC13) 8 151.49, 138.65, 129.59, 128.40, 118.74, 115.81, 112.22, 104.19, 101.38, 88.09, 81.17, 69.68, 62.81, 52.80, 52.64, 48.64, 44.46, 37.46, 36.46, 34.69, 30.95, 26.19, 24.71, 24.53, 20.31 and 13.10; IR (Nujol)/crri 1 2921, 1612, 1496, 1454, 1350, 1228, 1120, 1011, 875 (O-O) and 826 (O-O); MS m/z (EI) [M]+ 616 (1), 334 (11), 227 (7), 105 (100) and 56 (10).
10(3-[[3-[(4-Fluorophenylpiperazyl)methyl]benzyl]oxy]dihydroartemisinin (13j) This compound was prepared from 1-(4-fluorophenyl)piperazine using general procedure 2 to give the product as an off-white foam (69 % yield): 1H (300 MHz, CDC13) 8 7.36-7.27 (4 H, m, aromatic), 6.98-6.84 (4 H, m, aromatic), 5.47 (1 H, s), 4.91 (1 H, d, J = 3.43 Hz), 4.90 (1 H, d, J = 12.29 Hz), 4.54 (1 H, d, J =12.29 Hz), 3.58 (2 H, s), 3.12 (4 H, t, J
= 4.81 Hz), 2.63 (1 H, m), 2.62 (4 H, t, J = 13.80 Hz), 2.38 (1 H, dt, J =
13.40, 3.90 Hz), 2.07-1.20 (10 H, m), 1.45 (3 H, s), 0.94 (3 H, d, J = 6.00 Hz) and 0.93 (3 H, d, J = 6.00 Hz); 13C (75 MHz, CDC13) 8 148.04, 138.62, 128.40, 126.34, 117.89, 115.70, 115.40, 104.19, 101.36, 88.09, 81.18, 69.65, 62.82, 52.99, 52.64, 50.07, 44.46, 37.45, 36.47, 34.69, 30.95, 26.19, 24.71, 24.53, 20.32 and 13.10; IR (Nujol)/crri 1 2924, 1510, 1460, 1377, 1229, 1160, 1102, 1012, 875 (O-O) and 826 (O-O); HRMS (EI) C33Hq.3FN2O5 [M~+
xequires 566.31561, found 566.31437; C33H4sFNzOs requires C 69.97 %, H 7.60 %, N
4.97 %, found C 69.67 %, H 7.72 %, N 4.82 %.
Procedure 1. Synthesis of ~3 methyl-p-[(10-dihydroartemisininoxy)methyl]benzoate (14) A solution of dihydroartemisinin (5 g, 17.6 mmol) in anhydrous dichloromethane (40 ml) was stirred at room temperature. Methyl 4-(hydroxymethyl)-benzoate (6.7 g, 40 mmol) and silver perchlorate (0.73 g, 3.52 mrnol) were added. The reaction was cooled to -78 °C
and stirred under N2. Trimethylsilyl triflate was added dropwise and the reaction mixture was stirred under N2 at -78 °C for 2 hours. The reaction was quenched with triethylamine (20 ml) and allowed to warm to room temperature. Any resulting precipitate was removed by filtration and the reaction mixture was evaporated to dryness.
Purification of the crude mixture by flash column chromatography, using 10% ethyl acetate/n-hexane as the eluent, gave the (3 (14) and a-isomers in 47% and 14% yield respectively.
Data for [3-isomer 14 1H NMR (250 MHz, CDCl3) 7.95 (2H, d, J = 8.3 Hz, aromatic), 7.31 (2H, d, J = 8.3 Hz, aromatic), 5.38 (1H, s), 4.89 (1H, d, J = 13.2 Hz, AB
coupling), 4.85 (1H, d, J = 3.7 Hz), 4.50 (1H, d, J =13.2 Hz, AB coupling), 3.84 (3H, s, OMe), 2.62 (1H, m, CH), 2.28 (1H, dt, J =13.4, 4.0 Hz), 2.00-1.16 (10H, m), 1.45 (3H, s, CH3), 0.91-0.86 (6H, 2 x CH3).
Procedure 2. Synthesis of (3-artelinic acid (15) A suspension of 14[3 (3.65 g, 8,42 mmol) in aqueous potassium hydroxide and methanol (2.5 % KOH/MeOH, 1/1 mixture, 350 rnl) was stirred for 24 hours at room temperature.
After this time the methanol was removed in vacuo and the aqueous mixture was cooled to 0 °C. The mixture was acidified to pH 2 by dropwise addition of dilute hydrochloric acid, then extracted with diethyl ether (3 x 200 ml). The organic extracts were dried over anhydrous MgS04 and the solution was evaporated to dryness. This gave pure product 2 as a white foam in a 92% yield: 1H NMR (250 MHz, CDC13) 8.90 (2H, d, J = 8.3 Hz, aromatic), 7.44 (2H, d, J = 8.3 Hz, aromatic), 5.47 (1H, s), 5.00 (1H, d, J =
13.3 Hz, AB
coupling), 4.90 (1H, d, J = 3.4 Hz), 4.62 (1H, d, J = 13.3 Hz, AB coupling), 2.72 (1H, m, CH), 2.38 (1H, dt, J = 13.4, 4.0 Hz), 2.08-1.20 (11H, m), 1.47 (3H, s, CH3), 1.01-0.95 (6H, 2 x CH3).
Synthesis of Example 16 This compound was prepared from methyl 3-hydroxybenzoate using procedure 1 and procedure 2 to give the product as a yellow foam (77 % yield): 1H NMR (250 MHz, CDC13) 7.80 (1H, s, aromatic), 7.75 (1H, m, aromatic), 7.43-7.40 (2H, 2 x d, J
= 5.4 Hz, aromatic), 5.59 (1H, d, J = 2.8 Hz), 5.51 (1H, s), 2.86 (1H, rn, CH), 2.40 (1H, dt, J =
13.2, 3.9 Hz), 2.08-1.20 (11H, m), 1.47 (3H, s, CH3), 1.07-0.98 (6H, 2 x CH3).
Synthesis of Example 17 This compound was prepared from methyl 4-hydroxybenzoate using procedure 1 and procedure 2 to give the product as a yellow foam (45 % yield).
Hydrolysis of the ester was carried out by the same procedure as for the synthesis of 15 but using a solvent mix of 2.5 % aqueous KOH, MeOH and THF in a 2/1/1 ratio:
NMR (250 MHz, CDC13) 8.07 (2H, d, J = 8.7 Hz, aromatic), 7.18 (2H, d, J = 8.7 Hz, aromatic), 5.62 (1H, d, J = 3.2 Hz), 5.46 (1H, s), 2.85 (1H, m, CH), 2.39 (1H, dt, J =
14.2, 4.0 Hz), 2.13-1.20 (11H, m), 1.46 (3H, s, CH3), 1.05-0.95 (6H, 2 x CH3).
Procedure 3. Synthesis of 10 succinyl dihydroartemisinin (18) A solution of dihydroartemisinin (1.5 g, 5.28 mmol) in anhydrous dichloromethane (75 ml) was stirred at room temperature. Succinic anhydride (0.63 g, 6.33 mmol) and triethyl amine (3.7 ml, 26.4 mmol) were added and the solution was stirred at room temperature for 1 hour. The reaction mixture was washed with aqueous citric acid (pH 2, 2 x 20 ml), dried over MgS04 and evaporated to dryness. Purification of the crude mixture by flash column chromatography, using 2-5% methanol/dichloromethane as the eluent, gave 18 in a 65 % yield: 1H NMR (250 MHz, CDCl3) 5.73 (1H, d, J = 9.9 Hz), 5.36 (1H, s), 2.62 (2H, m), 2.64 (4H, dd, J = 4.4, 1.9 Hz), 2.30 (1H, dt, J = 13.3, 4.0 Hz), 1.99-1.18 (10H, m), 1.36 (3H, s, CH3), 0.89 (3H, d, J = 5.8 Hz, CH3), 0.78 (3H, d, J = 7.1 Hz, CH3).
Synthesis of Example 19 .",.o 0 0.,,..
'OH
This compound was prepared from phthalic anhydride using procedure 3 to give 19 in a 70 % yield: 1H NMR (250 MHz, CDC13) 7.78 (2H, m, aromatic), 7.52 (2H, m, aromatic),
It has now been discovered that artemisinin and synthetic trioxane derivatives can be chemically modified by the attachment of a polyamine residue to form analogues of arternisinin and synthetic trioxane derivatives which exhibit antimalarial, cytotoxic and antitumour activity.
According to a first aspect of the present invention therefore there is provided a compound of general formula 13 A--f -B o,~ C
n or a pharmaceutically acceptable salt thereof, in which:
n = an integer of from 1 to 4;
A represents a trioxane-containing residue;
B represents a group having the general formula:
-D-E-F-in which:
D is linked to A and represents an atom or group selected from the following:
O O O H
-o- -oJ.l- -o~o- -p-L~-N- , E represents a bivalent, optionally substituted organic radical; and F is linked to C and represents a group selected from the following:
O O O
-N-ll- ~ ; and C represents a group containing at least two nitrogen atoms.
In a preferred embodiment of the present invention, A represents the following trioxane-containing residue:
u....
H
With regard to the optionally substituted organic radical E, this preferably comprises an organic radical of 2-50 carbon atoms, more preferably 1-20 carbon atoms.
The optionally substituted organic radical E may comprise, for example, an optionally substituted alkyl, aryl, acyl, heteroalkyl or heteroacyl group. The organic radical E may optionally be substituted by groups including, but not limited to, primary, secondary and tertiary amines; halogen-containing groups, such as bromide, chloride and fluoride;
alcohols and derivatives thereof, including ethers and esters; and carboxylic acids and derivatives thereof, including esters and amides. Examples of organic radicals comprising Group E include -CH2-CHZ-, p-phenylene and pyridine.
With regard to group C, this may be, for example, a natural or synthetic polyamine residue and is preferably of 2-50 carbon atoms. Preferably also, group C
comprises. at least two amino groups, each of which is independently a primary or secondary group, after linking to group F through the same or different amino groups of the polyamine.
Those salts comprising pharmaceutically acceptable salts as referred to herein will be readily apparent to a skilled person. These salts include, but are not limited to acetate, adipate, besylate, bromide, camsylate, chloride, citrate, edisylate, estolate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hyclate, hydrobromide, hydrochloride, iodide, isethionate, lactate, lactobionate, maleate, mesylate, methylbromide, methylsulfate, napsylate, nitrate, oleate, pamoate, phosphate, polygalacturonate, stearate, succinate, sulfate, sulfosalicylate, tannate, tartrate, terephthalate, tosylate, triethiodide, benzathine, calcium, diolamine, meglumine, olamine, potassium, procaine, sodium, tromethamine, and zinc.
Apart from imparting selectivity against cancer cells, the incorporation of amine functionality into an endoperoxide was seen as a useful strategy for enhancing antimalarial activity, since the amine peroxide should be concentrated in the acidic vacuole of the malaria parasite by ion-trapping (Vennerstrom et al., J. Med.
Chern., 1989, 32, 64, O' Neill et al., J. Med. Chem., 1996, 39, 4511). Intraparasitic accumulation in the haem "rich" food vacuole is considered to be key to the action of all basic quinoline antimalarial agents (O' Neill, Phartn. e~ Therapeutics, 1998, 77, 29). For example, chloroquine is a dibasic drug with pI~s of 8.1 (quinoline ring nitrogen) and 10.2 (diethylamino side chain) and accumulates in acidic vesicles to the square of the monobasic antimalarials such as mefloquine. Experiments on the pH gradient between the external medium and the parasite food vacuole have shown that the value is around 2.2. On this basis, Ginsburg and co-workers suggested that chloroquine would be expected to accumulate 2.5 x 104 compared with 160 fold for the mono-basic antimalarials such as mefloquine (Ginsburg et al., Biochem. Phar»zacol., 1989, 38, 2645).
It follows that the introduction of two basic amino groups into an artemisinin derivative would be expected to increase significantly the cellular accumulation of drug in the ferrous rich parasite food vacuole. This approach should provide analogues with increased antimalarial potency, since more drug will be available for reductive endoperoxide bioactivation to radical species.
One preferred embodiment of the present invention provides compounds having the structure 13n.
13n, G = substituted aryl ring Specific examples of such compounds are included in Chart 1.
s CHART 1- C-10-Ether Linked Diamino Analogues N
R1 / \ N I i 13a-13d (R2= H, N02, F, CF3) .""O
O O""..
R = / \ ~N~
N
~O~R_1 13e R1= \ / ~~.R2 ~N ~
13f-13j (R2=H,p-N02,p-Cl,rn-CFg, p-F
This series of preferred compounds was prepared as shown in Scheme 1.
Dihydroartemisinin (2) was coupled with 1,4-benzenedimethanol to give the corresponding alcohol (12a) in high yield with excellent diastereoselectivity ((3/oc 5:1).
The alcohol was then converted into the mesylate (12b) in high yield by treatment with mesyl chloride and triethylamine. The key mesylate was then allowed to react with a range of diamino nucleophiles to provide compounds (13a-13d). As shown in Scheme 1, DHA was also coupled with 1,3-benzenedimethanol to provide the alcohol which could then be transformed into target analogues (13f-13j) using the same chemistry described for the para substituted analogues.
Scheme 1 ~N w HN~ I ~
_ R2 1. BF3.Et20 2 ~ --\ ene HO OH
2. MsCl 12a (R3= H) 13a-13d (R2= H, N02, F, CF3) 12b (R3= Ms) 1. BF3. Et20 -HO / \ benzene OH
HN N I \ Ph 2. MsCl Benzene 13e _ ~N~ H
.. O
O 0.,..
benzene O~ / \ ~N
\~N~ I = R2 M ~s 13f 13j (R2= H, p-NO2, pCl, m-CF3, p-F) Thus, and in accordance with a further aspect of the present invention there is provided a process for the production of a compound of general formula 13 as hereinbefore defined, said process comprising the steps of coupling dihydroartemisinin with benzenedimethanol, converting the resultant alcohol into the corresponding sulfonate by treatment with a sulfonyl halide, and reacting said sulfonate with a diamino nucleophile.
Most preferably, the resultant alcohol is converted into the corresponding mesylate by treatment with mesyl chloride.
to This process is particularly advantageous with regard to the production of trioxane derivatives of the type exemplified by compounds 13a-13j.
Further preferred compounds of the present invention were prepared according to Schemes 2 to 5 as shown below. Dihydroartemisinin (2) was coupled with a variety of alcohol methyl esters. These were then hydrolysed to give carboxylic acids, which were coupled with a number of polyamines and amines. Under standard conditions compounds with two artemisinin groups in the molecule were formed. If an excess of amine was used at 0°C, this gave the desired monomers.
.",o ..",o ..".o 0 Om" O AgC104 O On.,. 0 On".
0 HO \ / OMe DM~ O O
_ _ \~ \
O OMe O OMe O~~".
2.5% IfOH O iqR a Met O
O
O OH
Scheme 2 .,~no 0 O On".
b p O
O
OH
Scheme 3 .",~o O Oi",.
EDCI
O H2N~NH2 HOBT, DCM' O
O OH
Scheme 4 H
N ~~
,,,, .""o 0 0.,.,.
~NHZ EDC~ O
O H2N HOBT, DCM ; 'O~ ~ \
O O O I H
O ~~N~/\/~NHZ
I'v~~~I I('O
OOH
Scheme 5 According to a further aspect of the present invention therefore there is provided a process for the production of a compound of general formula 13 as hereinbefore described, said process comprising the steps of coupling dihydroartemisinin with an alcohol methyl ester, hydrolysing the resultant compound to produce the corresponding carboxylic acid, and coupling said carboxylic acid with a polyamine or amine.
Alternatively, a further aspect of the invention provides a process for the production of a compound of general formula 13 as hereinbefore described, said process comprising the steps of coupling dihydroartemisinin with an anhydride, forming a carboxylic acid, and coupling said carboxylic acid with a polyamine or amine.
Preferably, coupling of the carboxylic acid and polyamine or amine is carried out at a temperature of between -20 and +40 ° C.
These processes are particularly advantageous with regard to the production of trioxane derivatives of the type exemplified by Examples 20 to 35.
The antimalarial activity of the new compounds was assessed using two strains of P. falciparum from Thailand: (a) the uncloned I~1 strain which is known to be CQ
resistant and (b) the HB3 strain which is sensitive to all antimalarials.
Parasites were maintained in continuous culture using the method of Trager and Jenson (J.
Parasitol., 1977, 63, 883-886). Cultures were grown in flasks containing human erythrocytes (2-5%) with parasitemia in the range of 1% to 10% suspended in RPMI 1640 medium supplemented with 25 mM HEPES and 32 mM NaHC03, and 10% human serum (complete medium). Cultures were gassed with a mixture of 3% 02, 4% C02 and 93% N2.
Antimalarial activity was assessed with an adaption of the 48-h sensitivity assay of Desjardins et al. (Aratimicrob. Agents. Chemother., 1979, 16, 710-718) using [3H~-hypoxanthine incorporation as an assessment of parasite growth. Stock drug solutions were prepared in 100% dimethylsulphoxide (DMSO) and diluted to the appropriate concentration using complete medium. Assays were performed in sterile 96-well microtitre-plates, each plate containing 200 ~,1 of parasite culture (2%
parasitemia, 0.5%
haematocrit) with or without 10 ~,l drug dilutions. Each drug was tested in triplicate and parasite growth was compared to control wells (which constituted 100 %
parasite growth).
After 24-h incubation at 37°C, 0.5 ~,Ci hypoxanthine was added to each well. Cultures were incubated for a further 24 h before they were harvested onto filter-mats, dried for 1 h at 55°C and counted using a Wallac 1450 Microbeta Trilux Liquid scintillation and luminescence counter. ICso values were calculated by interpolation of the probit transformation of the log dose - response curve.
The results of these experiments axe contained in Table 1, which shows the of compounds of the present invention versus the K1 strain of P. falciparum ifi vitro.
Table 1 Compound Number IC50 (nM) SD
(13a) 8.2 2.7 (13b) 138.1 11.1 (13c) 6.3 0.7 (13d) 12.5 1.6 (13e) 3.8 0.1 (13f) 6.6 0.7 (13g) 4.3 0.30 (13h) 13.3 0.6 (13i) 22.5 1.9 (13j) 12.6 17 Artemether 6.5 2 Chloroquine 255 10 Table 2 shows the IC50 of compounds of the invention versus the HB3 strain of P. falciparu»z in vitro.
Table 2 Compound Number IC50 (nM) SD
(13c) 2.3 0.7 (13d) 8.1 1.2 (13e) 1.8 0.2 (13f) 3.4 0.7 (13g) 4.3 0.30 (13j) 12.6 17 Artemether 9.2 0.2 The anticancer activity of these compounds of the present invention was also assessed, by NCI 3-cell line anticancer assay. In this protocol, each cell line is inoculated and preincubated on a microtiter plate. Test agents are then added at a single concentration and the culture incubated for 48 hours. End-point determinations are made with sulforhodamine B, a protein-binding dye. Results for each test agent are reported as the percentage of growth of the treated cells when compared to the untreated control cells. Compounds which reduce the growth of any one of the cells lines to 32%
or less (negative numbers indicate cell kill) are passed on for evaluation in the full panel of 60 cell lines over a 5-log dose range.
The results of these assays are shown in Table 3 below.
Table 3 Compound Number ConcentrationNCI-H460 MCF7 SF-268 (Lung) (Breast)(CNS) (13h) 1.OOE-04Molar22 11 31 (13i) 1.OOE-04Molar15 10 29 (13c) 1.OOE-04Molar12 13 27 According to a further aspect of the present invention there is provided a compound of general formula 13 as hereinbefore defined, or a pharmaceutically acceptable salt thereof, for use as a medicament.
Compounds of the present invention may be used particularly, but not exclusively, as medicaments for the treatment of malaria or cancer. Whilst the currently preferred use of peroxides is for treatment, it cannot be ruled out that these compounds would have a use in the prophylaxis of malaria.
A therapeutically effective non-toxic amount of a compound of general formula 13 as hereinbefore defined may be administered in any suitable manner, including orally, parenterally (including subcutaneously, intramuscularly and intravenously), or topically.
The administration will generally be carried out repetitively at intervals, for example once or several times a day.
The amount of the compound of general formula 13 that is required in order to be effective as an antimalarial or anticancer agent for treating human or animal subjects will of course vary and is ultimately at the discretion of the medical or veterinary practitioner treating the human or animal in each particular case. The factors to be considered by such a practitioner, e.g. a physician, include the route of administration and pharmaceutical formulation; the subject's body weight, surface area, age and general condition; and the chemical form of the compound to be administered.
In daily treatment, for example, the total daily dose may be given as a single dose, multiple doses, e.g. two to six times per day, or by intravenous infusion for any selected duration.
The compound of general formula 13 may be presented, for example, in the form of a tablet, capsule, liquid (e.g. syrup) or injection.
While it may be possible for the compounds of general formula 13 to be administered alone as the active pharmaceutical ingredient, it is preferable to present the compounds in a pharmaceutical composition.
According to a further aspect of the present invention therefore there is provided a pharmaceutical composition containing a compound of general formula 13 as hereinbefore defined, or a pharmaceutically acceptable salt thereof, as an active ingredient.
Such pharmaceutical compositions for medical use will be formulated in accordance with any of the methods well known in the art of pharmacy for administration in any convenient manner. The compounds of the invention will usually be admixed with at least one other ingredient providing a compatible pharmaceutically acceptable additive, carrier, diluent or excipient, and may be presented in unit dosage form.
The carriers) must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The possible formulations include those suitable for oral, rectal, topical and parenteral (including subcutaneous, intramuscular and intravenous) administration or for administration to the lung or another absorptive site such as the nasal passages.
All methods of formulation in making up such pharmaceutical compositions will generally include the step of bringing the compound of general formula 13 into association with a carrier which constitutes one or more accessory ingredients. Usually, the formulations are prepared by uniformly and intimately bringing the compound of general formula 13 into association with a liquid carrier or with a finely divided solid carrier or with both and then, if necessary, shaping the product into desired formulations.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets or lozenges, each containing a predetermined amount of the compound of general formula 13; as a powder or granules;
or a suspension in an aqueous liquid or non-aqueous liquid such as a syrup, an elixir, an emulsion or a draught. The compound of general formula 13 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 compound of general formula 13 in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Moulded tablets may be made by moulding, in a suitable machine, a mixture of the powdered compound of general formula 13 with any suitable carrier.
A syrup may be made by adding the compound of general formula 13 to a concentrated, aqueous solution of a sugar, for example sucrose, to which may be added any desired accessory ingredient. Such accessory ingredients) may include flavourings, an agent to retard crystallisation of the sugar or an agent to increase the solubility of any other ingredient, such as a polyhydric alcohol, for example glycerol or sorbitol.
Formulations for rectal administration may be presented as a suppository with a usual carrier such as cocoa butter.
Formulations suitable for parental administration conveniently comprise a sterile aqueous preparation of the compound of general formula 13 which is preferably isotonic with the blood of the recipient.
In addition to the aforementioned ingredients, formulations of this invention, for example ointments, creams and the like, may include one or more accessory ingredients, for example a diluent, buffer, flavouring agent, binder, surface active agent, thickener, lubricant and/or a preservative (including an antioxidant) or other pharmaceutically inert excipient.
The compounds of this invention may also be made up for administration in liposomal formulations which can be prepared by methods well-known in the art.
A further aspect of the present invention provides the use of a compound of general formula 13 as hereinbefore defined, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prophylaxis of malaria.
A further aspect of the present invention provides the use of a compound of general formula 13 as hereinbefore defined, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.
It has further surprisingly been found that exposure of tumour cells to iron potentiates the anticancer effect of the compounds of the present invention.
This finding is supported by the observation that cultured cancer cell lines were more readily destroyed by compounds of the present invention following exposure to culture medium having an elevated iron concentration.
According to a further aspect of the present invention therefore there is provided a product containing a first compound of general formula 13 as hereinbefore defined, or a pharmaceutically acceptable salt thereof, and a second, iron-containing, compound as a combined preparation for simultaneous, separate or sequential use in the treatment of cancers.
Preferably, the first and second compounds are used sequentially, the second, iron-containing, compound being used first.
The first compound may be presented in any of the forms described above.
Administration of the first compound may be in any suitable manner, including intravenously, intraarterially, intralesionally, topically, intracavitarily or orally. Any suitable dosage of the compound may be used. Preferably, a dosage within the range of 0.1 to SOOmg/kg body weight is used, more preferably within the range of 0.5 to 300mg/kg body weight, such as 1 to 50 mg/kg body weight.
With regard to the iron-containing compound, this may take any suitable form.
Preferred agents for enhancing intracellular iron levels for use in the present invention include pharmaceutically acceptable iron salts and iron complexes. Iron salts useful in the present invention include ferrous fumarate, ferrous sulphate, ferrous carbonate, ferrous citrate, ferrous gluconate, ferrous lactate and ferrous maleate. Iron complexes useful in the present invention include ferrocholinate, ferroglycine sulphate, dextran iron complex, peptonized iron, iron sorbitex, saccharated iron, iron complexed with iron binding proteins and glycoproteins such as the holoferritins and holotransferrins.
The iron-containing compound may be presented in any of the forms described above in relation to the compound of general formula 13. Administration of the iron-containing compound may be achieved via any of the possible routes of administration of the first compound. The first and second compounds may be administered via the same or different routes.
The iron-containing compound may be used ay any appropriate dosage, but is preferably used at a dosage within the range of 0.01 to 1000 mg iron/kg body weight.
The product of the invention may further comprise one or more other agents known to be useful in the treatment of tumours. Such agents may include, for example, androgen inhibitors, antiestrogens, antimetabolites and cytotoxic agents.
According to a further aspect of the present invention there is provided a method of treatment of malaria which comprises administering to an animal in need of such treatment a therapeutically effective amount of a compound of general formula 13 as hereinbefore defined, or a pharmaceutically acceptable salt thereof.
In terms of suitable dosages for the treatment of malaria, the preferred amount of compounds of the present invention is between l0mg to 5g, preferably 50 to 1000mg, administered over a period of 2-5 days, alone or in combination with other antimalarial drugs, such as, for example, the class II blood schizonticides or halofantrine (Looaeesuwan, Am. J. Trop. Med., 1999, 60, 238).
According to a further aspect of the present invention there is provided a method of treatment of cancer which comprises administering to an animal in need of such treatment a therapeutically effective amount of a compound of general formula 13 as hereinbefore defined, or a pharmaceutically acceptable salt thereof.
The method may further comprise the simultaneous, separate or sequential administration to the said animal an effective amount of an iron-containing compound as hereinbefore described.
The invention will now be illustrated by the following non-limiting examples.
Examples Experimental Section Merck Kieselgel 60 F 254 pre-coated silica plates for TLC were obtained from BDH, Poole, Dorset, U.K. Column chromatography was carried out on Merck 9385 silica gel.
Infra red (IR) spectra were recorded in the range 4000-600 cm 1 using a Perkin Elmer 298 infrared spectrometer. Spectra of liquids were taken as films. Sodium chloride plates (nujol mull) , solution cells (dichloromethane) and KBr discs were used as indicated.
1H NMR spectra were recorded using a Perkin Elmer R34 (220 MHz) and Bruker (300 MHz and 200 MHz) spectrometers. Solvents are indicated in the text and tetramethylsilane was used as the internal reference. Mass spectra were recorded at 70eV
using a VG7070E mass spectrometer. The samples were introduced using a direct-insertion probe. In the text the parent ion (M+) is given, followed by peaks corresponding to major fragment losses with intensities in parentheses.
General Procedure 1. Synthesis of Ether Derivatives Dihydroartemisinin (2.00 g, 7.04 mmol) was dissolved in anhydrous diethyl ether (200 mL) under N2. BF3.Et20 (1.03 mL, 8.10 mmol) was added to the solution, followed by the appropriate (hydroxymethyl) benzyl alcohol (1.46 g, 10.56 mmol). The mixture was allowed to stir at room temperature for 20 h and then quenched with water. The organic phase was washed with Na2S04 solution (30 % w/v), dried over MgS04, filtered and the solvent was removed under reduced pressure to the give the crude product as an oil.
Purification by silica gel chromatography using ethyl acetate/nhexane (40/60) as the eluent gave the corresponding ether products.
10(3-[[4-(Hydroxymethyl)benzyl]oxy]dihydroartemisinin (12a) This compound was prepared using general procedure 1 to give the product as a colourless syrup (78 % yield): 1H NMR (300 MHz, CDC13) 8 7.20-7.08 (4 H, m, aromatic), 5.44 (1 H, s), 4.88 (1 H, d, J = 3.80 Hz), 4.85 (1 H, d, J = 12.19 Hz), 4.69 (2 H, s), 4.51 (1 H, d, J = 12.19 Hz), 2.67 (1 H, sex), 2.38 (1 H, dt, J = 13.46, 3.98 Hz), 2.07-1.20 (10 H, m), 1.46 (3 H, s) and 0.94 (6 H, d, J = 7.17 Hz); 13C NMR (75 MHz, CDC13) 8 140.20, 137.88, 127.59, 127.05, 104.21, 101.45, 88.09, 81.18, 69.57, 65.11, 52.62, 44.45, 37.43, 36.46, 34.64, 30.94, 26.16, 24.69, 24.52, 20.32 and 13.06; IR (thin film)/crri 1 3476, 2924, 1612, 1516, 1458, 1377, 1194, 1101, 1011, 876 (O-O) and 826 (O-O); MS m/z (CI) [M + NH4]+ 422 (8), 359 (100), 284 (39), 221 (96) and 138 (33).
10(3-[[3-(Hydroxymethyl)benzyl]oxy]dihydroartemisinin This compound was prepared using general procedure 1 to give the product as a colourless solid (68 % yield): m.p. 118-120 °C; 1H NMR (300 MHz, CDC13) 8 7.34-7.26 (4 H, m, aromatic), 5.40 (1 H, s), 4.92 (1 H, d, J = 3.80 Hz), 4.88 (1 H, d, J
= 12.20 Hz), 4.70 (2 H, s), 4.55 (1 H, d, J = 12.20 Hz), 2.67 (1 H, sex), 2.38 (1 H, dt, J
= 13.50, 3.80 Hz), 2.07-1.20 (10 H, m), 1.45 (3 H, s), 0.96 (3 H, d, J = 6.00 Hz) and 0.88 (3 H, d, J =
7.60 Hz); 13C NMR (75 MHz, CDC13) 8 141.05, 138.93, 128.64, 126.80, 126.15, 104.21, 101.65, 88.06, 81.17, 69.90, 65.37, 52.62, 44.47, 37.43, 36.46, 34.65, 30.97, 26.16, 24.70, 24.51, 20.31 and 13.07; IR (Nujol)/crri 13507, 2924, 1611, 1462, 1378, 1227,1192, 1104, 1011, 874 (O-O) and 823 (O-O); Anal. C23Hsa06 requires C 68.29 %, H 7.97 %, found C
68.01%,H8.14%.
General Procedure 2. Synthesis of C-10 Oxo Derivatives To a solution of the appropriate (hydroxymethyl) benzyl alcohol (0.20 g, 0.50 mmol) in anhydrous DCM (10 mL) under NZ was added triethylamine (0.08 mL, 0.55 mmol), followed by mesyl chloride (0.06 mL, 0.74 mmol) at 0 °C. The mixture was stirred at 0 °C for 2 h and then quenched with water (10 mL). The organic phase was extracted with DCM (3 x 10 mL) and then dried over MgS04, filtered and the solvent was removed under reduced pressure. The crude mesylate and the appropriate substituted piperazine derivative (4.11 mmol) were dissolved in anhydrous benzene (10 mL) under NZ
atmosphere. The mixture was heated at reflux for 5 h. After allowing to cool to room temperature, the mixture was quenched with saturated NaHC03 solution and the organic phase was extracted with diethyl ether (3 x 10 mL). The organic extracts were washed with brine, dried over MgS04, filtered and the solvent was removed under reduced pressure. Purification by silica gel chromatography using ethyl acetate/nhexane (40/60) as the eluent gave the corresponding piperazine products.
10(3-[[4-[Phenylpiperazyl)methyl]benzyl]oxy]dihydroartemisinin (13a) This compound was prepared from 1-phenyl piperazine using general procedure 2 to give the product as a yellow oil (84 % yield): 1H (300 MHz, CDCl3) b 7.30-7.28 (4 H, d, J =
4.5 Hz, aromatic), 7.00-6.90 (5 H, m, aromatic), 5.45 (1 H, s), 4.90 (1 H, d, J = 3.80 Hz), 4.86 (1 H, d, J = 12.20 Hz), 4.50 (1 H, d, J =12.20 Hz), 3.53 (2 H, s, CH2), 2.69 (1 H, m, CH), 2.51 (8 H, m, CH2), 2.38 (1 H, dt, J = 13.32, 4.12 Hz), 2.07-1.20 (10 H, m), 1.45 (3 H, s, CH3), 0.95-0.93 (6 H, 2 x CH3); isC (75 MHz, CDC13) 8 129.34, 128.28, 127.19, 104.16, 101.51, 88.08, 81.18, 69.67, 62.98, 62.68, 52.92, 52.66, 44.49, 37.43, 36.49, 34.67, 30.97, 26.19, 24.71, 24.52, 20.31, 13.06; LC/MS (NH3); m/z 563[M + H+, (100)], 279 (17).
10[3-[[4-[(4-Nitrophenylpiperazyl)methyl]benzyl]oxy]dihydroartemisinin (13b) This compound was prepared from 1-(4-nitrophenyl)piperazine using general procedure 2 to give the product as an orange solid (68 % yield): 1H (300 MHz, CDCl3) ~
8.12 (2 H, d, J = 9.48 Hz, aromatic), 7.35-7.27 (4 H, m, aromatic), 6.82 (2 H, d, J = 9.48 Hz, aromatic), 5.47 (1 H, s), 4.91 (1 H, d, J = 3.90 Hz), 4.90 (1 H, d, J = 12.50 Hz), 4.53 (1 H, d, J = 12.50 Hz), 3.58 (2 H, s), 3.47-3.42 (4 H, m), 2.68 (1 H, m), 2.64-2.59 (4 H, m), 2.38 (1 H, dt, J = 13.32, 4.12 Hz), 2.07-1.20 (10 H, m), 1.46 (3 H, s) and 0.95 (6 H, d, J =
6.70 Hz); 13C (75 MHz, CDC13) ~ 154.96, 129.17, 127.34, 125.99, 112.70, 104.19, 101.43, 88.09, 81.16, 69.54, 62.61, 52.63, 52.48, 47.08, 44.46, 37.46, 36.47, 34.67, 30.94, 26.18, 24.71, 24.53, 20.31 and 13.06; IR (Nujol)/crri 1 2927, 1597, 1493, 1462, 1377, 1327, 1251, 1231, 1099, 1010, 876 (O-O) and 828 (O-O); MS m/z (EI) [M]+ 593 (1), 264 (98), 218 (34), 104 (100) and 56 (58).
10[3-[[4-[(4-Fluorophenylpiperazyl)methyl]benzyl]oxy]dihydroartemisinin (13c) This compound was prepared from 1-(4-fluorophenyl)piperazine using general procedure 2 to give the product as a yellow oil (64 % yield): 1H (300 MHz, CDCl3) 8 7.35-7.28 (4 H, m, aromatic), 6.99-6.85 (4 H, m, aromatic), 5.46 (1 H, s), 4.91 (1 H, d, J
= 3.90 Hz), 4.90 (1 H, d, J = 12.45 Hz), 4.52 (1 H, d, J =12.45 Hz), 3.58 (2 H, s), 3.16-3.11 (4 H, m), 2.68-2.63 (5 H, m), 2.38 (1 H, dt, J = 13.50, 3.90 Hz), 2.07-1.20 (10 H, m), 1.46 (3 H, s), 0.95 (3 H, d, J = 6.00 Hz) and 0.94 (3H, d, J = 6.60 Hz); 13C (75 MHz, CDC13) b 141.05, 138.93, 128.64, 126.80, 126.15, 104.21, 101.65, 88.06, 81.17, 69.90, 65.37, 52.62, 44.47, 37.43, 36.46, 34.65, 30.97, 26.16, 24.70, 24.51, 20.10 and 13.07; IR (thin film)/crri 1 2945, 1633, 1510, 1455, 1374, 1359, 1240, 1142, 1099, 1011, 876 (O-O) and 825 (O-O);
HRMS (EI) C33H43FN2O5 [M~+ requires 566.31561, found 566.31493.
10(i-[[4-[(4-Trifluoromethylphenylpiperazyl)methyl]benzyl]oxy]dihydroartemisinin (13d) This compound was prepared from 1-(4-trifluoromethyl phenyl)piperazine using general procedure 2 to give the product as a yellow oil (64 % yield): 1H, (300 MHz, CDCl3) 8 7.35-7.28 (5 H, m, aromatic), 7.10-7.03 (3 H, m, aromatic), 5.46 (1 H, s)~
4.92 (1 H, d, J
=12.30 Hz), 4.88 (1 H, d, J = 3.80 Hz), 4.52, (1 H, d, J = 12.30 Hz), 3.61 (2 H, m, CH2), 3.27 (4 H, m, CH2), 2.70-2.65 (5 H, m, CH2), 2.39 (1 H, m, CH2), 2.07-1.20 (10 H, m), 1.45 (3 H, s, CH3), 0.97-0.94 (6 H, d, 2 xCH3); 13C (75 MHz, CDCl3) 8 129.59, 129.32, 127.33, 118.78, 112.29, 104.19, 101.50, 88.09, 81.17, 69.61, 62.58, 52.73, 48.55, 44.48, 37.46, 36.48, 34.67, 30.96,26.18, 24.71, 24.54, 20.31, 13.06; IR (thin film)/crri 1 (2925), (1454), (1136), (1011). LC/MS (NH3); m/z 618 [M + H+, (100)], 603 (100), 333 (7).
10(3-[[4-[(Benzylpiperazyl)methyl]benzyl]oxy]dihydroartemisinin (13c) This compound was prepared from 1-benzylpiperazine using general procedure 2 to give the product as a yellow oil (72 % yield): 1H NMR (300 MHz, CDC13) 8 7.32-7.20 (9 H, m, aromatic), 5.45 (1 H, s), 4.91 (1 H, d, J = 3.90 Hz), 4.90 (1 H, d, J =
12.50 Hz), 4.52 (1 H, d, J = 12.50 Hz), 3.54 (4 H, br s), 2.68 (1 H, m), 2.54-2.49 (8 H, m), 2.38 (1 H, dt, J
= 14.10, 3.90 Hz), 2.07-1.20 (10 H, m), 1.45 (3 H, s), 0.94 (3 H, d, J = 5.70 Hz) and 0.94 (3H, d, J = 7.2 Hz); 13C (75 MHz, CDCl3) 8 129.34, 128.28, 127.19, 104.16, 101.51, 88.08, 81.18, 69.67, 62.98, 62.68, 52.92, 52.66, 44.49, 37.43, 36.49, 34.67, 30.97, 26.19, 24.71, 24.52, 20.31 and 13.06; IR (thin film)/cni 1 2938, 1609, 1495, 1457, 1374, 1344, 1227, 1099, 1010, 876 (O-O) and 826 (O-O).
10/3-[[3-[(Phenylpiperazyl)methyl]benzyl]oxy]dihydroartemisinin (l3fj This compound was prepared from 1-phenylpiperazine using general procedure 2 to give the product as a brown foam (59 % yield): 1H NMR (300 MHz, CDC13) 8 7.30-7.22 (4 H, m, aromatic), 6.94-6.85 (5 H, m, aromatic), 5.47 (1 H, s), 4.91 (1 H, d, J =
3.70 Hz), 4.90 (1 H, d, J = 12.20 Hz), 4.55 (1 H, d, J = 12.20 Hz), 3.59 (2 H, br s), 3.27-3.21 (4 H, m), 2.69-2.61 (5 H, m), 2.38 (1 H, dt, J = 13.30, 3.80 Hz), 2.07-1.20 (10 H, m), 1.46 (3 H, s), 0.95 (3 H, d, J = 7.40 Hz) and 0.94 (3H, d, J = 6.00 Hz); 13C (75 MHz, CDC13) ~ 139.10, 129.17, 128.38, 116.16, 104.19, 101.40, 88.10, 81.18, 69.68, 52.65, 44.47, 37.45, 36.48, 34.69, 30.96, 26.19, 24.71, 24.53, 20.32 and 13.10; IR (Nujol)/cni 1 2925, 1601, 1504, 1455, 1375, 1228, 1101, 1013, 875 (O-O) and 825 (O-O); HRMS (EI) C33H44N2O5 [M]+
requires 548.32501, found 548.32604.
10(3-[[3-[(4-Nitrophenylpiperazyl)methyl]benzyl]oxy]dihydroartemisinin (13g) This compound was prepared from 1-(4-nitrophenyl)piperazine using general procedure 2 to give the product as an orange foam (85 % yield): 1H (300 MHz, CDC13) 8 8.13 (2 H, d, J = 9.50 Hz, aromatic), 7.36-7.25 (4 H, m, aromatic), 6.82 (2 H, d, J = 9.50 Hz, aromatic), 5.47 (1 H, s), 4.91 (1 H, d, J = 5.00 Hz), 4.90 (1 H, d, J = 12.30 Hz), 4.56 (1 H, d, J = 12.30 Hz), 3.61 (2 H, s), 3.49-3.43 (4 H, m), 2.71 (1 H, rn), 2.69-2.63 (4 H, m), 2.39 (1 H, dt, J = 13.87, 3.98 Hz), 2.07-1.20 (10 H, m), 1.45 (3 H, s) and 0.94 (6H, d, J =
7.40 Hz); 13C (75 MHz, CDCl3) b 151.00, 128.50, 128.00, 125.99, 112.79, 104.00, 101.00, 88.09, 81.50, 69.56, 60.38, 52.61, 52.20, 46.96, 44.20, 37.47, 36.45, 34.50, 30.93, 26.00, 24.70, 24.55, 20.32 and 13.00; IR (Nujol)/crri 1 2923, 1598, 1506, 1456, 1378, 1328, 1248, 1099, 1010, 875 (O-O) and 826 (O-O); MS m/z (EI) [M~+ 593 (1), 264 (43), 219 (18), 105 (100) and 56 (30).
10(3-[[3-[(4-Chlorophenylpiperazyl)methyl]benzyl]oxy]dihydroartemisinin (13h) This compound was prepared from 1-(4-chlorophenyl)piperazine using general procedure 2 to give the product as a brown foam (64 % yield): 1H (300 MHz, CDCl3) b 7.32-7.06 (6 H, m, aromatic), 6.83 (2 H, d, J = 9.06, aromatic), 5.47 (1 H, s), 4.92 (1 H, d, J = 4.10 Hz), 4.90 (1 H, d, J = 12.01 Hz), 4.55 (1 H, d, J = 12.01 Hz), 3.61 (2 H, br s), 3.22-3.17 (4 H, m), 2.69-2.61 (5 H, m), 2.39 (1 H, dt, J =13.50, 3.85 Hz), 2.07-1.20 (10 H, m), 1.46 (3 H, s) and 0.94 (3H, d, J = 6.60 Hz); 13C (75 MHz, CDC13) 8 138.50, 129.03, 128.44, 117.35, 104.19, 101.37, 88.09, 81.17, 69.64, 52.81, 49.03, 44.45, 37.45, 36.47, 34.68, 30.94, 26.19, 24.71, 24.53, 20.32 and 13.10; IR (Nujol)/crri 1 2927, 1616, 1496, 1459, 1378, 1225, 1102, 1032, 874 (O-O) and 815 (O-O); MS m/z (EI) [M]+ 422 (1), 300 (26), 193 (19), 131 (14) and 105 (100).
10(3-[[3-[(3-Trifluoromethylphenylpiperazyl)methyl]benzyl]oxy]dihydroartemisinin (13i) This compound was prepared from 1-[(3-trifluoromethyl)phenyl]piperazine using general procedure 2 to give the product as a brown foam (66 % yield): 1H (300 MHz, CDC13) ~
7.37-7.23 (4 H, rn, aromatic), 7.10-7.06 (4 H, m, aromatic), 5.47 (1 H, s), 4.92 (1 H, d, J
= 3.98 Hz), 4.90 (1 H, d, J = 12.16 Hz), 4.52 (1 H, d, J = 12.16 Hz), 3.58 (2 H, s), 3.16-3.11 (4 H, m), 2.68-2.63 (5 H, m), 2.38 (1 H, dt, J =13.48, 4.02 Hz), 2.07-1.20 (10 H, m), 1.45 (3 H, s), 0.95 (3 H, d, J = 7.20 Hz) and 0.94 (3H, d, J = 6.00 Hz); 13C
NMR (75 MHz, CDC13) 8 151.49, 138.65, 129.59, 128.40, 118.74, 115.81, 112.22, 104.19, 101.38, 88.09, 81.17, 69.68, 62.81, 52.80, 52.64, 48.64, 44.46, 37.46, 36.46, 34.69, 30.95, 26.19, 24.71, 24.53, 20.31 and 13.10; IR (Nujol)/crri 1 2921, 1612, 1496, 1454, 1350, 1228, 1120, 1011, 875 (O-O) and 826 (O-O); MS m/z (EI) [M]+ 616 (1), 334 (11), 227 (7), 105 (100) and 56 (10).
10(3-[[3-[(4-Fluorophenylpiperazyl)methyl]benzyl]oxy]dihydroartemisinin (13j) This compound was prepared from 1-(4-fluorophenyl)piperazine using general procedure 2 to give the product as an off-white foam (69 % yield): 1H (300 MHz, CDC13) 8 7.36-7.27 (4 H, m, aromatic), 6.98-6.84 (4 H, m, aromatic), 5.47 (1 H, s), 4.91 (1 H, d, J = 3.43 Hz), 4.90 (1 H, d, J = 12.29 Hz), 4.54 (1 H, d, J =12.29 Hz), 3.58 (2 H, s), 3.12 (4 H, t, J
= 4.81 Hz), 2.63 (1 H, m), 2.62 (4 H, t, J = 13.80 Hz), 2.38 (1 H, dt, J =
13.40, 3.90 Hz), 2.07-1.20 (10 H, m), 1.45 (3 H, s), 0.94 (3 H, d, J = 6.00 Hz) and 0.93 (3 H, d, J = 6.00 Hz); 13C (75 MHz, CDC13) 8 148.04, 138.62, 128.40, 126.34, 117.89, 115.70, 115.40, 104.19, 101.36, 88.09, 81.18, 69.65, 62.82, 52.99, 52.64, 50.07, 44.46, 37.45, 36.47, 34.69, 30.95, 26.19, 24.71, 24.53, 20.32 and 13.10; IR (Nujol)/crri 1 2924, 1510, 1460, 1377, 1229, 1160, 1102, 1012, 875 (O-O) and 826 (O-O); HRMS (EI) C33Hq.3FN2O5 [M~+
xequires 566.31561, found 566.31437; C33H4sFNzOs requires C 69.97 %, H 7.60 %, N
4.97 %, found C 69.67 %, H 7.72 %, N 4.82 %.
Procedure 1. Synthesis of ~3 methyl-p-[(10-dihydroartemisininoxy)methyl]benzoate (14) A solution of dihydroartemisinin (5 g, 17.6 mmol) in anhydrous dichloromethane (40 ml) was stirred at room temperature. Methyl 4-(hydroxymethyl)-benzoate (6.7 g, 40 mmol) and silver perchlorate (0.73 g, 3.52 mrnol) were added. The reaction was cooled to -78 °C
and stirred under N2. Trimethylsilyl triflate was added dropwise and the reaction mixture was stirred under N2 at -78 °C for 2 hours. The reaction was quenched with triethylamine (20 ml) and allowed to warm to room temperature. Any resulting precipitate was removed by filtration and the reaction mixture was evaporated to dryness.
Purification of the crude mixture by flash column chromatography, using 10% ethyl acetate/n-hexane as the eluent, gave the (3 (14) and a-isomers in 47% and 14% yield respectively.
Data for [3-isomer 14 1H NMR (250 MHz, CDCl3) 7.95 (2H, d, J = 8.3 Hz, aromatic), 7.31 (2H, d, J = 8.3 Hz, aromatic), 5.38 (1H, s), 4.89 (1H, d, J = 13.2 Hz, AB
coupling), 4.85 (1H, d, J = 3.7 Hz), 4.50 (1H, d, J =13.2 Hz, AB coupling), 3.84 (3H, s, OMe), 2.62 (1H, m, CH), 2.28 (1H, dt, J =13.4, 4.0 Hz), 2.00-1.16 (10H, m), 1.45 (3H, s, CH3), 0.91-0.86 (6H, 2 x CH3).
Procedure 2. Synthesis of (3-artelinic acid (15) A suspension of 14[3 (3.65 g, 8,42 mmol) in aqueous potassium hydroxide and methanol (2.5 % KOH/MeOH, 1/1 mixture, 350 rnl) was stirred for 24 hours at room temperature.
After this time the methanol was removed in vacuo and the aqueous mixture was cooled to 0 °C. The mixture was acidified to pH 2 by dropwise addition of dilute hydrochloric acid, then extracted with diethyl ether (3 x 200 ml). The organic extracts were dried over anhydrous MgS04 and the solution was evaporated to dryness. This gave pure product 2 as a white foam in a 92% yield: 1H NMR (250 MHz, CDC13) 8.90 (2H, d, J = 8.3 Hz, aromatic), 7.44 (2H, d, J = 8.3 Hz, aromatic), 5.47 (1H, s), 5.00 (1H, d, J =
13.3 Hz, AB
coupling), 4.90 (1H, d, J = 3.4 Hz), 4.62 (1H, d, J = 13.3 Hz, AB coupling), 2.72 (1H, m, CH), 2.38 (1H, dt, J = 13.4, 4.0 Hz), 2.08-1.20 (11H, m), 1.47 (3H, s, CH3), 1.01-0.95 (6H, 2 x CH3).
Synthesis of Example 16 This compound was prepared from methyl 3-hydroxybenzoate using procedure 1 and procedure 2 to give the product as a yellow foam (77 % yield): 1H NMR (250 MHz, CDC13) 7.80 (1H, s, aromatic), 7.75 (1H, m, aromatic), 7.43-7.40 (2H, 2 x d, J
= 5.4 Hz, aromatic), 5.59 (1H, d, J = 2.8 Hz), 5.51 (1H, s), 2.86 (1H, rn, CH), 2.40 (1H, dt, J =
13.2, 3.9 Hz), 2.08-1.20 (11H, m), 1.47 (3H, s, CH3), 1.07-0.98 (6H, 2 x CH3).
Synthesis of Example 17 This compound was prepared from methyl 4-hydroxybenzoate using procedure 1 and procedure 2 to give the product as a yellow foam (45 % yield).
Hydrolysis of the ester was carried out by the same procedure as for the synthesis of 15 but using a solvent mix of 2.5 % aqueous KOH, MeOH and THF in a 2/1/1 ratio:
NMR (250 MHz, CDC13) 8.07 (2H, d, J = 8.7 Hz, aromatic), 7.18 (2H, d, J = 8.7 Hz, aromatic), 5.62 (1H, d, J = 3.2 Hz), 5.46 (1H, s), 2.85 (1H, m, CH), 2.39 (1H, dt, J =
14.2, 4.0 Hz), 2.13-1.20 (11H, m), 1.46 (3H, s, CH3), 1.05-0.95 (6H, 2 x CH3).
Procedure 3. Synthesis of 10 succinyl dihydroartemisinin (18) A solution of dihydroartemisinin (1.5 g, 5.28 mmol) in anhydrous dichloromethane (75 ml) was stirred at room temperature. Succinic anhydride (0.63 g, 6.33 mmol) and triethyl amine (3.7 ml, 26.4 mmol) were added and the solution was stirred at room temperature for 1 hour. The reaction mixture was washed with aqueous citric acid (pH 2, 2 x 20 ml), dried over MgS04 and evaporated to dryness. Purification of the crude mixture by flash column chromatography, using 2-5% methanol/dichloromethane as the eluent, gave 18 in a 65 % yield: 1H NMR (250 MHz, CDCl3) 5.73 (1H, d, J = 9.9 Hz), 5.36 (1H, s), 2.62 (2H, m), 2.64 (4H, dd, J = 4.4, 1.9 Hz), 2.30 (1H, dt, J = 13.3, 4.0 Hz), 1.99-1.18 (10H, m), 1.36 (3H, s, CH3), 0.89 (3H, d, J = 5.8 Hz, CH3), 0.78 (3H, d, J = 7.1 Hz, CH3).
Synthesis of Example 19 .",.o 0 0.,,..
'OH
This compound was prepared from phthalic anhydride using procedure 3 to give 19 in a 70 % yield: 1H NMR (250 MHz, CDC13) 7.78 (2H, m, aromatic), 7.52 (2H, m, aromatic),
5.91 (1H, d, J = 9.8), 5.56 (1H, s), 2.58 (1H, m, CH), 2.30 (1H, dt, J = 14.1, 3.9 Hz), 2.00-1.20 (11H, m), 1.36 (3H, s, CH3), 0.91-0.84 (6H, 2 x CH3).
Procedure 4. Synthesis of Example 20 A solution of 15 (100 mg, 0.24 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (46 mg, 0.24 mmol) and 1-hydroxybenzotriazole (32 mg, 0.24 mmol) in dichloromethane (2 ml) was stirred at room temperature. 1,5-diaminopentane (.14 ul, 0.12 mmol) was added and the reaction was stirred for 2 hours at room temperature.
After this time the reaction was washed with water (3 x 20 ml),the organic extracts dried over MgS04 and evaporated to dryness. Purification of the crude mixture, using preparative HPLC (C18, Luna, 100 x 21.2 mm, 10 micron), gave 20 in a 14 % yield: 1H NMR
(250 MHz, CDC13) 7.68 (4H, d, J = 8.2 Hz, aromatic), 7.28 (4H, d, J = 8.2 Hz, aromatic), 6.31 (2H, m, amide) 5.37 (2H, s), 4.89 (2H, d, J = 12.9 Hz, AB coupling), 4.83 (2H, s), 4.49 (2H, d, J =12.9 Hz, AB coupling), 3.40 (4H, m) 2.61 (2H, m, CH), 2.26 (2H, dt, J = 13.5, 4.0 Hz), 2.08-1.16 (26H, m), 1.38 (6H, s, CH3), 0.89-0.83 (12H, 2 x CH3).
Procedure 5. Synthesis of Example 21 A solution of 1,4-diaminobutane (0.17 g, 1.9 mmol) in dichloromethane (6 ml) was cooled to 0 °C. A pre-formed solution of 15 (200 mgs, 0.47 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (92 mg, 0.47 mmol) and 1-hydroxybenzotriazole (65 mg, 0.47 mmol) in dichloromethane (2 ml) was added dropwise over 1 hour. The reaction mixture was stirred at 0°C for a further hour, washed with water (3 x 20 ml), the organic extracts dried over MgSOø and evaporated to dryness.
Purification of the crude mixture by flash column chromatography, using 50%
methanol/dichloromethane as the eluent, gave product 21 in a 21% yield: 1H NMR
(250 MHz, CDC13) 7.70 (2H, d, J = 8.2 Hz, aromatic), 7.28 (2H, d, J = 8.2 Hz, aromatic), 7.00 (1H, m, amide) 5.37 (1H, s), 4.85 (1H, d, J = 12.7 Hz, AB coupling), 4.8 (1H, s), 4.48 (1H, d, J = 12.7 Hz, AB coupling), 3.38 (2H, m) 2.60 (2H, m, CH, NH), 2.26 (1H, dt, J =
14.3, 4.0 Hz), 2.01-1.15 (17H, m), 1.38 (3H, s, CH3), 0.89-0.83 (6H, 2 x CH3).
Synthesis of Example 22 This compound was prepared from compound 15 and 1,4-diaminobutane, using a similar procedure to 4. Purification of the crude material by preparative HPLC gave the product in a 31 % yield: 1H NMR (250 MHz, CDCl3) 7.80 (4H, d, J = 8.2 Hz, aromatic), 7.39 (4H, d, J = 8.2 Hz, aromatic), 6.61 (2H, m, amide) 5.46 (2H, s), 4.95 (2H, d, J = 12.7 Hz, AB coupling), 4.91 (2H, s), 4.57 (2H, d, J = 12.7 Hz, AB coupling), 3.52 (4H, m) 2.69 (2H, m, CH), 2.34 (2H, dt, J =13.6, 3.9 Hz), 2.10-1.24 (24H, m), 1.46 (6H, s, CH3), 0.98-0.94 (12H, 2 x CH3).
Synthesis of Example 23 N~
N~ J
This compound was prepared from compound 15 and 1,4-bis(3-aminopropyl)-piperazine, using a similar procedure to 4 to give the product in a 21 % yield: 1H NMR
(250 MHz, CDCl3) 8.12 (2H, m, amide), 7.80 (4H, d, J = 8.2 Hz, aromatic), 7.36 (4H, d, J
= 8.2 Hz, aromatic), 5.45 (2H, s), 4.92 (2H, d, J = 12.8 Hz, AB coupling), 4.88 (2H, s), 4.57 (2H, d, J =12.8 Hz, AB coupling), 3.57 (4H, m) 2.70-1.19 (40H, m) 1.45 (6H, s, CH3), 0.95-0.92 (12H, 2 x CH3).
Synthesis of Example 24 NON
This compound was prepared from compound 15 and 3,3'-diamino-N-methyldipropylamine, using a similar procedure to 4 to give the product in a 27 % yield:
1H NMR (250 MHz, CDCl3) 7.56 (4H, d, J = 8.2 Hz, aromatic), 7.16 (4H, d, J =
8.2 Hz, aromatic), 5.24 (2H, s), 4.72 (2H, d, J =13.3 Hz, AB coupling), 4.69 (2H, s), 4.36 (2H, d, J = 13.3 Hz, AB coupling), 3.33 (4H, m) 2.47 (2H, m) 2.3 (4H, t, J = 6.3 Hz), 2.15 (2H, dt, J = 14.2, 3.9 Hz), 2.07 (3H, s, NMe), 1.87-1.03 (26H, m) 1.25 (6H, s, CH3), 0.76-0.70 (12H, 2 x CH3).
Synthesis of Example 25 ,,,, o,a .0~0 o w W
This compound was prepared from compound 15 and benzylamine, using a similar procedure to 4 to give the product in a 20 % yield: 1H NMR (250 MHz, CDC13) 7.79 (2H, d, J = 8.2 Hz, aromatic), 7.44-7.28 (7H, m, aromatic), 6.46 (1H, m, amide) 5.46 (1H, s), 4.95 (1H, d, J = 12.8 Hz, AB coupling), 4.90 (1H, s), 4.66 (2H. d, J = 5.63 Hz, benzylic CH2), 4.57 (1H, d, J = 12.8 Hz, AB coupling), 2.68 (1H, m, CH), 2.38 (1H, dt, J = 13.54, 3.93 Hz), 2.08-1.24 (10H, m), 1.46 (3H, s, CH3), 0.97-0.89 (6H, 2 x CH3).
Synthesis of Example 26 This compound was prepared from compound 15 and tris(2-aminoethyl)amine, using a similar procedure to 4 to give the product in a 13 % yield: 1H NMR (250 MHz, CDC13) 7.69 (6H, d, J = 8.1 Hz, aromatic), 7.18 (6H, d, J = 8.1 Hz, aromatic), 5.43 (3H, s), 4.86 (3H, d, J =12.4 Hz, AB coupling), 4.86 (3H, s), 4.50 (3H, d, J = 12.4 Hz, AB
coupling), 3.56 (6H, m), 2.77 (6H, m), 2.67 (3H, m) 2.37 (3H, dt, J = 13.8, 3.8 Hz), 1.93-1.21 (33H, m) 1.46 (9H, s, CH3), 0.96-0.93 (18H, 2 x CH3).
Synthesis of Example 27 0 0 0 .
o ;
N I ,o,d ~N \
/ ~N
_O, ~ ~ I H 0 0 p 0 This compound was prepared from compound 17 and 1,4-diaminobutane, using a similar procedure to 4 to give the product in a 17 % yield: 1H NMR (250 MHz, CDC13) 7.79 (4H, d, J = 8.6 Hz, aromatic), 7.14 (4H, d, J = 8.6 Hz, aromatic), 6.66 (2H, m, amide), 5.57 (2H, d, J = 3.3 Hz), 5.46 (2H, s), 3.50 (4H, m), 2.83 (2H, m, CH), 2.39 (2H, dt, J = 13.9, 3.8 Hz), 2.07-1.22 (24H, m), 1.44 (6H, s, CH3), 1.04-0.93 (12H, 2 x CH3).
Synthesis of Example 28 2s This compound was prepared from compound 17 and 1,5-diaminopentane, using a similar procedure to 4 to give the product in a 25 % yield: 1H NMR (250 MHz, CDC13) 7.63 (4H, d, J = 8.8 Hz, aromatic), 7.03 (4H, d, J = 8.8 Hz, aromatic), 6.14 (2H, m, amide), 5.46 (2H, d, J = 3.2 Hz), 5.34 (2H, s), 3.35 (4H; m), 2.71 (2H, m, CH), 2.26 (2H, dt, J = 13.6, 4.0 Hz), 1.95-1.11 (26H, m), 1.32 (6H, s, CH3), 0.93-0.84 (12H, 2 x CH3).
Synthesis of Example 29 ''° o .. ~ o 0 0 O,~~ ~ \ I Fib ~N~N I / ~O O
O~O~O U
O
This compound was prepared from compound 17 and 1,4-bis(3-aminopropyl)-piperazine, using a similar procedure to 4 to give the product in a 28 % yield: 1H NMR
(250 MHz, CDC13) 7.97 (2H, m, amide), 7.79 (4H, d, J = 8.7 Hz, aromatic), 7.15 (4H, d, J
= 8.7 Hz, aromatic), 5.56 (2H, d, J = 3.4 Hz), 5.47 (2H, s), 3.58 (4H, m), 2.85 (2H, m, CH), 2.58 (10H, m), 2.40 (2H, dt, J = 14.0, 3.8 Hz), 2.08-1.15 (26H, m), 1.44 (6H, s, CH3), 1.05-0.97 (12H, 2 x CH3).
Synthesis of Example 30 O,Oo' \ I H~ I ~H ~ / O,O
O~O~O Ow, O O
This compound was prepared from compound 17 and 3,3'-diamino-N-methyldipropylamine, using a similar procedure to 4 to give the product in a 17 % yield:
1H NMR (250 MHz, CDC13) 7.78 (4H, d, J = 8.7 Hz, aromatic), 7.33 (2H, m, amide), 7.15 (4H, d, J = 8.7 Hz, aromatic), 5.56 (2H, d, J = 3.1 Hz), 5.46 (2H, s), 3.53 (4H, m), 2.83 (2H, m, CH), 2.51 (4H, m), 2.51-1.11 (33H, m), 1.44 (6H, s, CH3), 1.04-0.96 (12H, 2 x CH3).
Synthesis of Example 31 ,,,,, o o_o,~
o w This compound was prepared from compound 17 and benzylamine, using a similar procedure to 4 to give the product in a 54 % yield: 1H NMR (250 MHz, CDC13) 7.76 (2H, d, J = 8.8 Hz, aromatic), 7.38-7.28 (5H, m, aromatic), 7.16 (2H, d, J = 8.8 Hz, aromatic),
Procedure 4. Synthesis of Example 20 A solution of 15 (100 mg, 0.24 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (46 mg, 0.24 mmol) and 1-hydroxybenzotriazole (32 mg, 0.24 mmol) in dichloromethane (2 ml) was stirred at room temperature. 1,5-diaminopentane (.14 ul, 0.12 mmol) was added and the reaction was stirred for 2 hours at room temperature.
After this time the reaction was washed with water (3 x 20 ml),the organic extracts dried over MgS04 and evaporated to dryness. Purification of the crude mixture, using preparative HPLC (C18, Luna, 100 x 21.2 mm, 10 micron), gave 20 in a 14 % yield: 1H NMR
(250 MHz, CDC13) 7.68 (4H, d, J = 8.2 Hz, aromatic), 7.28 (4H, d, J = 8.2 Hz, aromatic), 6.31 (2H, m, amide) 5.37 (2H, s), 4.89 (2H, d, J = 12.9 Hz, AB coupling), 4.83 (2H, s), 4.49 (2H, d, J =12.9 Hz, AB coupling), 3.40 (4H, m) 2.61 (2H, m, CH), 2.26 (2H, dt, J = 13.5, 4.0 Hz), 2.08-1.16 (26H, m), 1.38 (6H, s, CH3), 0.89-0.83 (12H, 2 x CH3).
Procedure 5. Synthesis of Example 21 A solution of 1,4-diaminobutane (0.17 g, 1.9 mmol) in dichloromethane (6 ml) was cooled to 0 °C. A pre-formed solution of 15 (200 mgs, 0.47 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (92 mg, 0.47 mmol) and 1-hydroxybenzotriazole (65 mg, 0.47 mmol) in dichloromethane (2 ml) was added dropwise over 1 hour. The reaction mixture was stirred at 0°C for a further hour, washed with water (3 x 20 ml), the organic extracts dried over MgSOø and evaporated to dryness.
Purification of the crude mixture by flash column chromatography, using 50%
methanol/dichloromethane as the eluent, gave product 21 in a 21% yield: 1H NMR
(250 MHz, CDC13) 7.70 (2H, d, J = 8.2 Hz, aromatic), 7.28 (2H, d, J = 8.2 Hz, aromatic), 7.00 (1H, m, amide) 5.37 (1H, s), 4.85 (1H, d, J = 12.7 Hz, AB coupling), 4.8 (1H, s), 4.48 (1H, d, J = 12.7 Hz, AB coupling), 3.38 (2H, m) 2.60 (2H, m, CH, NH), 2.26 (1H, dt, J =
14.3, 4.0 Hz), 2.01-1.15 (17H, m), 1.38 (3H, s, CH3), 0.89-0.83 (6H, 2 x CH3).
Synthesis of Example 22 This compound was prepared from compound 15 and 1,4-diaminobutane, using a similar procedure to 4. Purification of the crude material by preparative HPLC gave the product in a 31 % yield: 1H NMR (250 MHz, CDCl3) 7.80 (4H, d, J = 8.2 Hz, aromatic), 7.39 (4H, d, J = 8.2 Hz, aromatic), 6.61 (2H, m, amide) 5.46 (2H, s), 4.95 (2H, d, J = 12.7 Hz, AB coupling), 4.91 (2H, s), 4.57 (2H, d, J = 12.7 Hz, AB coupling), 3.52 (4H, m) 2.69 (2H, m, CH), 2.34 (2H, dt, J =13.6, 3.9 Hz), 2.10-1.24 (24H, m), 1.46 (6H, s, CH3), 0.98-0.94 (12H, 2 x CH3).
Synthesis of Example 23 N~
N~ J
This compound was prepared from compound 15 and 1,4-bis(3-aminopropyl)-piperazine, using a similar procedure to 4 to give the product in a 21 % yield: 1H NMR
(250 MHz, CDCl3) 8.12 (2H, m, amide), 7.80 (4H, d, J = 8.2 Hz, aromatic), 7.36 (4H, d, J
= 8.2 Hz, aromatic), 5.45 (2H, s), 4.92 (2H, d, J = 12.8 Hz, AB coupling), 4.88 (2H, s), 4.57 (2H, d, J =12.8 Hz, AB coupling), 3.57 (4H, m) 2.70-1.19 (40H, m) 1.45 (6H, s, CH3), 0.95-0.92 (12H, 2 x CH3).
Synthesis of Example 24 NON
This compound was prepared from compound 15 and 3,3'-diamino-N-methyldipropylamine, using a similar procedure to 4 to give the product in a 27 % yield:
1H NMR (250 MHz, CDCl3) 7.56 (4H, d, J = 8.2 Hz, aromatic), 7.16 (4H, d, J =
8.2 Hz, aromatic), 5.24 (2H, s), 4.72 (2H, d, J =13.3 Hz, AB coupling), 4.69 (2H, s), 4.36 (2H, d, J = 13.3 Hz, AB coupling), 3.33 (4H, m) 2.47 (2H, m) 2.3 (4H, t, J = 6.3 Hz), 2.15 (2H, dt, J = 14.2, 3.9 Hz), 2.07 (3H, s, NMe), 1.87-1.03 (26H, m) 1.25 (6H, s, CH3), 0.76-0.70 (12H, 2 x CH3).
Synthesis of Example 25 ,,,, o,a .0~0 o w W
This compound was prepared from compound 15 and benzylamine, using a similar procedure to 4 to give the product in a 20 % yield: 1H NMR (250 MHz, CDC13) 7.79 (2H, d, J = 8.2 Hz, aromatic), 7.44-7.28 (7H, m, aromatic), 6.46 (1H, m, amide) 5.46 (1H, s), 4.95 (1H, d, J = 12.8 Hz, AB coupling), 4.90 (1H, s), 4.66 (2H. d, J = 5.63 Hz, benzylic CH2), 4.57 (1H, d, J = 12.8 Hz, AB coupling), 2.68 (1H, m, CH), 2.38 (1H, dt, J = 13.54, 3.93 Hz), 2.08-1.24 (10H, m), 1.46 (3H, s, CH3), 0.97-0.89 (6H, 2 x CH3).
Synthesis of Example 26 This compound was prepared from compound 15 and tris(2-aminoethyl)amine, using a similar procedure to 4 to give the product in a 13 % yield: 1H NMR (250 MHz, CDC13) 7.69 (6H, d, J = 8.1 Hz, aromatic), 7.18 (6H, d, J = 8.1 Hz, aromatic), 5.43 (3H, s), 4.86 (3H, d, J =12.4 Hz, AB coupling), 4.86 (3H, s), 4.50 (3H, d, J = 12.4 Hz, AB
coupling), 3.56 (6H, m), 2.77 (6H, m), 2.67 (3H, m) 2.37 (3H, dt, J = 13.8, 3.8 Hz), 1.93-1.21 (33H, m) 1.46 (9H, s, CH3), 0.96-0.93 (18H, 2 x CH3).
Synthesis of Example 27 0 0 0 .
o ;
N I ,o,d ~N \
/ ~N
_O, ~ ~ I H 0 0 p 0 This compound was prepared from compound 17 and 1,4-diaminobutane, using a similar procedure to 4 to give the product in a 17 % yield: 1H NMR (250 MHz, CDC13) 7.79 (4H, d, J = 8.6 Hz, aromatic), 7.14 (4H, d, J = 8.6 Hz, aromatic), 6.66 (2H, m, amide), 5.57 (2H, d, J = 3.3 Hz), 5.46 (2H, s), 3.50 (4H, m), 2.83 (2H, m, CH), 2.39 (2H, dt, J = 13.9, 3.8 Hz), 2.07-1.22 (24H, m), 1.44 (6H, s, CH3), 1.04-0.93 (12H, 2 x CH3).
Synthesis of Example 28 2s This compound was prepared from compound 17 and 1,5-diaminopentane, using a similar procedure to 4 to give the product in a 25 % yield: 1H NMR (250 MHz, CDC13) 7.63 (4H, d, J = 8.8 Hz, aromatic), 7.03 (4H, d, J = 8.8 Hz, aromatic), 6.14 (2H, m, amide), 5.46 (2H, d, J = 3.2 Hz), 5.34 (2H, s), 3.35 (4H; m), 2.71 (2H, m, CH), 2.26 (2H, dt, J = 13.6, 4.0 Hz), 1.95-1.11 (26H, m), 1.32 (6H, s, CH3), 0.93-0.84 (12H, 2 x CH3).
Synthesis of Example 29 ''° o .. ~ o 0 0 O,~~ ~ \ I Fib ~N~N I / ~O O
O~O~O U
O
This compound was prepared from compound 17 and 1,4-bis(3-aminopropyl)-piperazine, using a similar procedure to 4 to give the product in a 28 % yield: 1H NMR
(250 MHz, CDC13) 7.97 (2H, m, amide), 7.79 (4H, d, J = 8.7 Hz, aromatic), 7.15 (4H, d, J
= 8.7 Hz, aromatic), 5.56 (2H, d, J = 3.4 Hz), 5.47 (2H, s), 3.58 (4H, m), 2.85 (2H, m, CH), 2.58 (10H, m), 2.40 (2H, dt, J = 14.0, 3.8 Hz), 2.08-1.15 (26H, m), 1.44 (6H, s, CH3), 1.05-0.97 (12H, 2 x CH3).
Synthesis of Example 30 O,Oo' \ I H~ I ~H ~ / O,O
O~O~O Ow, O O
This compound was prepared from compound 17 and 3,3'-diamino-N-methyldipropylamine, using a similar procedure to 4 to give the product in a 17 % yield:
1H NMR (250 MHz, CDC13) 7.78 (4H, d, J = 8.7 Hz, aromatic), 7.33 (2H, m, amide), 7.15 (4H, d, J = 8.7 Hz, aromatic), 5.56 (2H, d, J = 3.1 Hz), 5.46 (2H, s), 3.53 (4H, m), 2.83 (2H, m, CH), 2.51 (4H, m), 2.51-1.11 (33H, m), 1.44 (6H, s, CH3), 1.04-0.96 (12H, 2 x CH3).
Synthesis of Example 31 ,,,,, o o_o,~
o w This compound was prepared from compound 17 and benzylamine, using a similar procedure to 4 to give the product in a 54 % yield: 1H NMR (250 MHz, CDC13) 7.76 (2H, d, J = 8.8 Hz, aromatic), 7.38-7.28 (5H, m, aromatic), 7.16 (2H, d, J = 8.8 Hz, aromatic),
6.37 (1H, m, amide), 5.56 (1H, d, J = 3.3 Hz), 5.46 (1H, s), 4.65 (2H, d, J =
5.6 Hz, benzylic), 2.84 (1H, m, CH), 2.39 (1H, dt, J = 13.3, 4.0 Hz), 2.08-1.22 (10H, m), 1.45 (3H, s, CH3), 1.04-0.96 (6H, 2 x CH3).
5.6 Hz, benzylic), 2.84 (1H, m, CH), 2.39 (1H, dt, J = 13.3, 4.0 Hz), 2.08-1.22 (10H, m), 1.45 (3H, s, CH3), 1.04-0.96 (6H, 2 x CH3).
7 PCT/GB02/05531 Synthesis of Example 32 ,,,, O,o~ ~ I N ~ o o_ °
' O~O 0 \ ~H I ~0~~
O
This compound was prepared from compound 16 and 1,4-diaminobutane, using a similar procedure to 4 to give the product in a 23 % yield: 1H NMR (250 MHz, CDCl3) 7.57-7.21 (8H, m, aromatic), 6.92 (2H, m, amide), 5.60 (2H, d, J = 3.2 Hz), 5.48 (2H, s), 3.46 (4H, m), 2.80 (2H, m, CH), 2.37 (2H, dt, J = 13.9, 3.6 Hz), 2.05-1.22 (24H, m), 1.38 (6H, s, CH3), 1.04-0.95 (12H, 2 x CH3).
Synthesis of Example 33 ,,,, ,,,.
O,~~~ ~ / I N N I / O,O
O~O O \ ~ O~~'~, O O
O O
This compound was prepared from compound 16 and 1,5-diaminopentane, using a similar procedure to 4 to give the product in a 28 % yield: 1H NMR (250 MHz, CDC13) 7.35-6.98 (8H, m, aromatic), 6.5 (2H, m, amide), 5.39 (2H, d, J = 3.2 Hz), 5.27 (2H, s), 3.21 (4H, m), 2.61 (2H, m, CH), 2.17 (2;H, dt, J = 13.9, 4.0 Hz), 1.85-1.02 (26H, m), 1.19 (6H, s, CH3), 0.83-0.75 (12H, 2 x CH3).
Synthesis of Example 34 ,,,, o 0 0 0 .
N~ ~N~H I
O.O~O~ H N
O
O ..","
This compound was prepared from compound 16 and 1,4-bis(3-aminopropyl)-piperazine, using a similar procedure to 4 to give the product in a 42 % yield: 1H NMR
(250 MHz, CDC13) 8:03 (2H, m, amide), 7.55-6.23 (8H, m, aromatic), 5.56 (2H, d, J = 3.1 Hz), 5.46 (2H, s), 3.53 (4H, m), 2.81 (2H, m, CH), 2.53-1.20 (42H, m), 1.41 (6H, s, CH3), 1.03-0.94 (12H, 2 x CH3).
Synthesis of Example 35 ,,,, O~O~~ ~O N~N~O O O
O O O I I H I I .O.O
O O
..."i This compound was prepared from compound 18 and 1,4-diaminobutane, using a similar procedure to 4 to give the product in a 14 % yield: 1H NMR (250 MHz, CDC13) 6.20 (2H, m, amide), 5.77 (2H, d, J = 9.9 Hz), 5.44 (2H, s), 3.25 (4H, m), 2.76 (4H, m, CH), 2.57-1.26 (32H, m), 1.43 (6H, s, CH3), 0.97 (6H, d, J = 5.7 Hz, CH3), 0.85 (6H, d, J = 7.09).
It is to be understood that the present invention is not intended to be restricted to the details of the above examples and embodiments, which are described by way of example only.
' O~O 0 \ ~H I ~0~~
O
This compound was prepared from compound 16 and 1,4-diaminobutane, using a similar procedure to 4 to give the product in a 23 % yield: 1H NMR (250 MHz, CDCl3) 7.57-7.21 (8H, m, aromatic), 6.92 (2H, m, amide), 5.60 (2H, d, J = 3.2 Hz), 5.48 (2H, s), 3.46 (4H, m), 2.80 (2H, m, CH), 2.37 (2H, dt, J = 13.9, 3.6 Hz), 2.05-1.22 (24H, m), 1.38 (6H, s, CH3), 1.04-0.95 (12H, 2 x CH3).
Synthesis of Example 33 ,,,, ,,,.
O,~~~ ~ / I N N I / O,O
O~O O \ ~ O~~'~, O O
O O
This compound was prepared from compound 16 and 1,5-diaminopentane, using a similar procedure to 4 to give the product in a 28 % yield: 1H NMR (250 MHz, CDC13) 7.35-6.98 (8H, m, aromatic), 6.5 (2H, m, amide), 5.39 (2H, d, J = 3.2 Hz), 5.27 (2H, s), 3.21 (4H, m), 2.61 (2H, m, CH), 2.17 (2;H, dt, J = 13.9, 4.0 Hz), 1.85-1.02 (26H, m), 1.19 (6H, s, CH3), 0.83-0.75 (12H, 2 x CH3).
Synthesis of Example 34 ,,,, o 0 0 0 .
N~ ~N~H I
O.O~O~ H N
O
O ..","
This compound was prepared from compound 16 and 1,4-bis(3-aminopropyl)-piperazine, using a similar procedure to 4 to give the product in a 42 % yield: 1H NMR
(250 MHz, CDC13) 8:03 (2H, m, amide), 7.55-6.23 (8H, m, aromatic), 5.56 (2H, d, J = 3.1 Hz), 5.46 (2H, s), 3.53 (4H, m), 2.81 (2H, m, CH), 2.53-1.20 (42H, m), 1.41 (6H, s, CH3), 1.03-0.94 (12H, 2 x CH3).
Synthesis of Example 35 ,,,, O~O~~ ~O N~N~O O O
O O O I I H I I .O.O
O O
..."i This compound was prepared from compound 18 and 1,4-diaminobutane, using a similar procedure to 4 to give the product in a 14 % yield: 1H NMR (250 MHz, CDC13) 6.20 (2H, m, amide), 5.77 (2H, d, J = 9.9 Hz), 5.44 (2H, s), 3.25 (4H, m), 2.76 (4H, m, CH), 2.57-1.26 (32H, m), 1.43 (6H, s, CH3), 0.97 (6H, d, J = 5.7 Hz, CH3), 0.85 (6H, d, J = 7.09).
It is to be understood that the present invention is not intended to be restricted to the details of the above examples and embodiments, which are described by way of example only.
Claims (39)
1. A compound of the following general formula:
or a pharmaceutically acceptable salt thereof, in which:
n = an integer of from 1 to 4;
A represents a trioxane-containing residue having the following structure;
B represents a group having the general formula:
-D-E-F-in which:
D is linked to A and represents an atom or group selected from the following:
E represents a bivalent, optionally substituted organic radical having at least 3 carbon atoms; and F is linked to C and represents a group selected from the following:
and C represents a group containing at least two amino groups.
or a pharmaceutically acceptable salt thereof, in which:
n = an integer of from 1 to 4;
A represents a trioxane-containing residue having the following structure;
B represents a group having the general formula:
-D-E-F-in which:
D is linked to A and represents an atom or group selected from the following:
E represents a bivalent, optionally substituted organic radical having at least 3 carbon atoms; and F is linked to C and represents a group selected from the following:
and C represents a group containing at least two amino groups.
2. A compound according to either of claim 1, wherein E comprises an organic radical of 3-50 carbon atoms.
3. A compound according to claim 2, wherein E comprises are organic radical of 3-20 carbon atoms.
4. A compound according to any of claims 1 to 3, wherein E has a substituent selected from primary, secondary and tertiary amines; halogen-containing groups;
alcohols and derivatives thereof, and carboxylic acids and derivatives thereof.
alcohols and derivatives thereof, and carboxylic acids and derivatives thereof.
5. A compound according to claim 3, wherein E is selected from -CH2-CH~-, p-phenylene and pyridine.
6. A compound according to any of clam 1 to 3, wherein C comprises a natural or synthetic polyamine residue of 2-50 carbon atoms.
7. A compound according to any of claims 1 to 6, wherein amino groups, are independently a primary or secondary group, after linking to group F through the same or different amino groups of the polyamine.
8, A compound of the following formula:
in which:
G represents a substituted aryl group.
in which:
G represents a substituted aryl group.
9. A compound according to Claim 8, wherein the compound comprises a compound of the following formula:
in which R2 is selected from H, NO2, F, and CF3.
in which R2 is selected from H, NO2, F, and CF3.
10. A compound according to claim 8, wherein the compound is:
11. A compound according to claim 8, wherein the compound comprises a compound of the following formula:
in which:
R2 is selected from H, pNO2, p-Cl, m-CF3, and p-F.
in which:
R2 is selected from H, pNO2, p-Cl, m-CF3, and p-F.
12. A compound according to claim 1, wherein the compound is selected from the following:
13. A compound of the following formula:
14. A process for the. production of a trioxane derivative, comprising the steps of coupling dihydroartemisinin with benzenedimethanol, converting the resultant alcohol into the corresponding sulfonate by treatment with a sulfonyl halide, and reacting said sulfonate with a diamino nucleophile.
15. A process according to claim 14, wherein the resultant alcohol is converted into the corresponding mesylate by treatment with mesyl chloride.
16. A process according to either of claims 14 or 15, wherein the trioxane derivative comprises a compound according to any of claims 9 to 11.
17. A process for the production of a trioxane derivative, comprising the steps of coupling dihy droartemisinin with an alcohol methyl ester, hydrolysing the resultant compound to produce the corresponding carboxylic acid, and coupling said carboxylic acid with a polyamine or amine.
18. A process according to claim 17, wherein coupling of the carboxylic acid and polyamine or amine is carried out at a temperature of between -20°C and +40°C.
19. A process according either of claims 17 or 18, wherein the trioxane derivative comprises a compound according to claim 12.
20. A process for the production of a trioxane derivative, comprising the steps of coupling dihydroartemisinin with an anhydride, forming a carboxylic acid, and coupling said carboxylic acid with a polyamine or amine.
21. A process according to claim 19, wherein the trioxane derivative comprises a compound according to claim 13.
22. A compound according to any of claims 1 to 13, or a pharmaceutically acceptable salt thereof, for use as a medicament.
23. A compound according to claim 22, wherein the medicament is a medicament for the treatment of malaria or cancer.
24. A pharmaceutical composition containing a compound according to any of claims 1 to 13, or a pharmaceutically acceptable salt thereof, as an active ingredient.
25. The use of a compound according to any of claims 1 to 13, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prophylaxis of malaria.
26. The use of a compound according to any of claims 1 to 13, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.
27. A product containing a first compound according to any of claims 1 to 13, or a pharmaceutically acceptable salt thereof a second, iron-containing compound as a combined preparation for simultaneous, separate or sequential use in the treatment of cancers.
28. A product according to claim 27, wherein the first and second compounds are for use sequentially, the second, iron-containing, compound being used first.
29. A product according to either of claims 27 or 28, wherein the second, iron-containing compound is an iron salt selected from ferrous fumarate, ferrous sulphate, ferrous carbonate, ferrous citrate, ferrous gluconate, ferrous lactate and ferrous maleate.
34. A product according to either of claims 27 or 28, wherein the second, iron-containing compound is an iron complex selected from ferrocholinate, ferroglycine sulphate, dextran iron complex, peptonized iron, iron sorbitex, saccharated iron; iron complexed with an iron binding protein, and iron complexed with a glycoprotein.
31. A product according to any of claims 27 to 29, wherein the product further comprises one or more other agents known to be useful in the treatment of tumours.
32. A product according to claim 31, wherein the one or more other agents are selected from androgen inhibitors, antiestrogens, antimetabolites and cytotoxic agents.
33. A method of treatment of malaria which comprises administering too an animal in net of such treatment a therapeutically effective amount of a compound according to any of claims 1 to 13, or a pharmaceutically acceptable salt thereof.
34. A method of treatment according to claim 33, wherein the compound is administered in an amount of 50 to 1000mg.
35. A method of treatment of cancer which comprises administering to an animal in need of such treatment a therapeutically effective amount of a first compound according to any of Claims 1 to 13, or a pharmaceutically acceptable salt thereof.
36. A method of treatment according to claim 35, wherein the method further comprises the simultaneous, separate or sequential administration to the said animal of an effective amount of a second, iron-containing, compound.
37. A method according to either of claims 35 or 36, wherein the first compound is administered at a dosage within the range of 0.5 to 300 mg/kg body weight.
38. A method according to claim 37, wherein the first compound is administered at a dosage within the range of 1 to 50 mg/kg body weight.
39. A method according to any of claims 35 to 38, wherein second, iron containing, compound is administered at a dosage within the range of 0.01 to 1000 mg iron/kg body weight.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB0129215.0A GB0129215D0 (en) | 2001-12-06 | 2001-12-06 | Trioxane derivatives |
GB0129215.0 | 2001-12-06 | ||
GB0217723A GB0217723D0 (en) | 2002-07-31 | 2002-07-31 | Trioxane derivatives |
GB0217723.6 | 2002-07-31 | ||
PCT/GB2002/005531 WO2003048167A1 (en) | 2001-12-06 | 2002-12-06 | Trioxane derivatives |
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CA2469224A1 true CA2469224A1 (en) | 2003-06-12 |
Family
ID=26246842
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CA002469224A Abandoned CA2469224A1 (en) | 2001-12-06 | 2002-12-06 | Trioxane derivatives |
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EP (1) | EP1465899A1 (en) |
JP (1) | JP2005515999A (en) |
AU (1) | AU2002352357A1 (en) |
CA (1) | CA2469224A1 (en) |
WO (1) | WO2003048167A1 (en) |
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CN115385929A (en) * | 2022-09-16 | 2022-11-25 | 延边大学 | Dihydroartemisinin derivative, preparation method and application |
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CN1814601A (en) * | 2005-02-04 | 2006-08-09 | 中国科学院上海药物研究所 | Artemisine derivative with immune suppression action and medicinal composition |
US8911751B2 (en) | 2005-10-11 | 2014-12-16 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Compositions for nasal delivery |
EP1933809B1 (en) * | 2005-10-11 | 2012-02-08 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Compositions for nasal delivery |
CN102010420B (en) * | 2010-10-12 | 2013-11-27 | 沈阳药科大学 | [(10S)-9,10-dihydroartemisinine-10-oxyl]benzaldehyde semicarbazones (sulfur) series substances as well as preparation method and application thereof |
CN102153564B (en) * | 2011-01-31 | 2013-07-24 | 中国科学院上海药物研究所 | Nitrogen-atom-containing arteannuin dimers, and preparation method and application thereof |
CN103570738B (en) * | 2012-08-07 | 2016-04-13 | 中国科学院上海生命科学研究院 | Artemisin derivant and method for making thereof and application |
CN103113386B (en) * | 2013-02-20 | 2015-12-23 | 沈阳药科大学 | Nitrogen heterocyclic substituted-dihydro artemisinin derivative and application thereof |
CN106588950B (en) * | 2016-12-13 | 2018-05-08 | 昆药集团股份有限公司 | artesunate derivative, its preparation method and its application |
JPWO2021132627A1 (en) * | 2019-12-26 | 2021-07-01 | ||
CN112694482B (en) * | 2020-12-29 | 2022-04-01 | 张家港威胜生物医药有限公司 | Method for preparing artesunate by using microchannel reactor |
WO2022230793A1 (en) * | 2021-04-26 | 2022-11-03 | 住友ファーマ株式会社 | Oxepin derivative |
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CN1041595A (en) * | 1988-10-04 | 1990-04-25 | 赫彻斯特股份公司 | New artemisin derivative, its method for making and as the application of antiprotozoan agent, |
CN1028294C (en) * | 1989-12-21 | 1995-04-26 | 中国科学院上海药物研究所 | Containing nitrogen green wormwood element derivative synthetizing and using |
CN1038416C (en) * | 1992-12-04 | 1998-05-20 | 中国科学院上海药物研究所 | Artemisin derivant and its preparation method |
US5726203A (en) * | 1993-07-19 | 1998-03-10 | Li; Zelin | Qinghaosu derivatives against AIDS |
US5677468A (en) * | 1995-06-29 | 1997-10-14 | Hauser, Inc. | Artemisinin dimer compounds having anticancer activity |
US6160004A (en) * | 1997-12-30 | 2000-12-12 | Hauser, Inc. | C-10 carbon-substituted artemisinin-like trioxane compounds having antimalarial, antiproliferative and antitumor activities |
CN1084333C (en) * | 1998-06-17 | 2002-05-08 | 中国科学院上海药物研究所 | Artemisine compounds, their preparing process and medicine composition containing them |
EP0974594A1 (en) * | 1998-07-14 | 2000-01-26 | The Hong Kong University of Science & Technology | Artemisinin derivatives as anti-infective agent |
EP1095043A1 (en) * | 1998-07-14 | 2001-05-02 | The Hong Kong University of Science & Technology | Trioxane derivatives |
US6297272B1 (en) * | 1999-01-12 | 2001-10-02 | Hauser, Inc. | Artemisinin analogs having antimalarial antiproliferative and antitumor activities and chemoselective methods of making the same |
CN1105722C (en) * | 1999-11-12 | 2003-04-16 | 中国科学院上海药物研究所 | Arteannuin derivant containing azacyclic radical and preparation process thereof |
WO2001062299A2 (en) * | 2000-02-28 | 2001-08-30 | Shearwater Corporation | Water-soluble polymer conjugates of artelinic acid |
-
2002
- 2002-12-06 CA CA002469224A patent/CA2469224A1/en not_active Abandoned
- 2002-12-06 EP EP02788077A patent/EP1465899A1/en not_active Withdrawn
- 2002-12-06 AU AU2002352357A patent/AU2002352357A1/en not_active Abandoned
- 2002-12-06 WO PCT/GB2002/005531 patent/WO2003048167A1/en active Application Filing
- 2002-12-06 JP JP2003549357A patent/JP2005515999A/en active Pending
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CN115385929A (en) * | 2022-09-16 | 2022-11-25 | 延边大学 | Dihydroartemisinin derivative, preparation method and application |
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JP2005515999A (en) | 2005-06-02 |
AU2002352357A1 (en) | 2003-06-17 |
WO2003048167A1 (en) | 2003-06-12 |
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