WO2022008639A1 - Analogues d'hexahydropyrimidine antipaludiques - Google Patents
Analogues d'hexahydropyrimidine antipaludiques Download PDFInfo
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- WO2022008639A1 WO2022008639A1 PCT/EP2021/068951 EP2021068951W WO2022008639A1 WO 2022008639 A1 WO2022008639 A1 WO 2022008639A1 EP 2021068951 W EP2021068951 W EP 2021068951W WO 2022008639 A1 WO2022008639 A1 WO 2022008639A1
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- compound
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- DKYBVKMIZODYKL-UHFFFAOYSA-N 1,3-diazinane Chemical class C1CNCNC1 DKYBVKMIZODYKL-UHFFFAOYSA-N 0.000 title description 3
- 230000000078 anti-malarial effect Effects 0.000 title description 2
- 239000003430 antimalarial agent Substances 0.000 title description 2
- 238000011282 treatment Methods 0.000 claims abstract description 20
- 201000004792 malaria Diseases 0.000 claims abstract description 14
- -1 methoxy, difluoromethoxy Chemical group 0.000 claims description 223
- 150000001875 compounds Chemical class 0.000 claims description 164
- 238000000034 method Methods 0.000 claims description 68
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 57
- 125000001424 substituent group Chemical group 0.000 claims description 51
- 150000003839 salts Chemical class 0.000 claims description 26
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 23
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 21
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- 239000001257 hydrogen Substances 0.000 claims description 19
- 229910052736 halogen Inorganic materials 0.000 claims description 15
- 150000002367 halogens Chemical group 0.000 claims description 15
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 15
- 125000003118 aryl group Chemical group 0.000 claims description 14
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
- 125000001072 heteroaryl group Chemical group 0.000 claims description 11
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 150000001602 bicycloalkyls Chemical group 0.000 claims description 8
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 8
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 8
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 7
- 125000004043 oxo group Chemical group O=* 0.000 claims description 7
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 6
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 230000002265 prevention Effects 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 5
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 3
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 3
- 238000002560 therapeutic procedure Methods 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000003112 inhibitor Substances 0.000 abstract description 9
- 241000223960 Plasmodium falciparum Species 0.000 abstract description 8
- 244000045947 parasite Species 0.000 abstract description 8
- 230000003389 potentiating effect Effects 0.000 abstract description 7
- 210000004369 blood Anatomy 0.000 abstract description 6
- 239000008280 blood Substances 0.000 abstract description 6
- BNHBTRHDCIHBAU-UHFFFAOYSA-N 2-amino-4,5-dihydro-1h-pyrimidin-6-one Chemical class NC1=NCCC(=O)N1 BNHBTRHDCIHBAU-UHFFFAOYSA-N 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 204
- 238000007429 general method Methods 0.000 description 109
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 76
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 58
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 56
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 53
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 39
- 239000011541 reaction mixture Substances 0.000 description 38
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 37
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
- 235000019439 ethyl acetate Nutrition 0.000 description 36
- 239000002904 solvent Substances 0.000 description 36
- 239000000243 solution Substances 0.000 description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 33
- 239000007787 solid Substances 0.000 description 31
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 28
- 238000006243 chemical reaction Methods 0.000 description 24
- 239000000203 mixture Substances 0.000 description 24
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 22
- 239000012044 organic layer Substances 0.000 description 22
- 238000004440 column chromatography Methods 0.000 description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 17
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 17
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 15
- 125000004432 carbon atom Chemical group C* 0.000 description 15
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 239000007788 liquid Substances 0.000 description 13
- 230000002829 reductive effect Effects 0.000 description 13
- 239000000377 silicon dioxide Substances 0.000 description 13
- 229910052938 sodium sulfate Inorganic materials 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 239000007832 Na2SO4 Substances 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 11
- 238000002360 preparation method Methods 0.000 description 11
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 10
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- 239000012267 brine Substances 0.000 description 9
- 125000001153 fluoro group Chemical group F* 0.000 description 9
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
- CQOUAQUBJPKQON-UHFFFAOYSA-N 3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid Chemical compound C1C2(F)CC1(C(=O)O)C2 CQOUAQUBJPKQON-UHFFFAOYSA-N 0.000 description 8
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical group FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 description 7
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 7
- 150000002391 heterocyclic compounds Chemical class 0.000 description 7
- 229910052757 nitrogen Chemical group 0.000 description 7
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 7
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 6
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 6
- PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 6
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 125000004429 atom Chemical group 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 6
- 125000001309 chloro group Chemical group Cl* 0.000 description 6
- 239000007822 coupling agent Substances 0.000 description 6
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- QEYKZNBKTNESNT-UHFFFAOYSA-N 3-chlorobicyclo[1.1.1]pentane-1-carboxylic acid Chemical compound C1C2(Cl)CC1(C(=O)O)C2 QEYKZNBKTNESNT-UHFFFAOYSA-N 0.000 description 5
- CJJMAWPEZKYJAP-UHFFFAOYSA-N 3-hydroxyadamantane-1-carboxylic acid Chemical compound C1C(C2)CC3CC2(O)CC1(C(=O)O)C3 CJJMAWPEZKYJAP-UHFFFAOYSA-N 0.000 description 5
- 239000004215 Carbon black (E152) Substances 0.000 description 5
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 5
- 150000001448 anilines Chemical class 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- BVCRERJDOOBZOH-UHFFFAOYSA-N bicyclo[2.2.1]heptanyl Chemical group C1C[C+]2CC[C-]1C2 BVCRERJDOOBZOH-UHFFFAOYSA-N 0.000 description 5
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 5
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 5
- 125000000723 dihydrobenzofuranyl group Chemical group O1C(CC2=C1C=CC=C2)* 0.000 description 5
- 229930195733 hydrocarbon Natural products 0.000 description 5
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
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- 238000002953 preparative HPLC Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 125000004750 (C1-C6) alkylaminosulfonyl group Chemical group 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 4
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- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 241001505483 Plasmodium falciparum 3D7 Species 0.000 description 4
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- 239000002253 acid Substances 0.000 description 4
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 description 4
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- 239000012298 atmosphere Substances 0.000 description 4
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- 230000009286 beneficial effect Effects 0.000 description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 4
- 229910002092 carbon dioxide Inorganic materials 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 125000006622 cycloheptylmethyl group Chemical group 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
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- 125000005842 heteroatom Chemical group 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
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- 238000000746 purification Methods 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
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- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 238000001851 vibrational circular dichroism spectroscopy Methods 0.000 description 4
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 description 3
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 description 3
- ABFPKTQEQNICFT-UHFFFAOYSA-M 2-chloro-1-methylpyridin-1-ium;iodide Chemical compound [I-].C[N+]1=CC=CC=C1Cl ABFPKTQEQNICFT-UHFFFAOYSA-M 0.000 description 3
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- 125000004122 cyclic group Chemical group 0.000 description 3
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 3
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- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 3
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
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- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 2
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- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 2
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- QBRDOUHHJWRTHN-UHFFFAOYSA-N 3,5,7-trifluoroadamantane-1-carboxylic acid Chemical compound C1C(C2)(F)CC3(F)CC2(F)CC1(C(=O)O)C3 QBRDOUHHJWRTHN-UHFFFAOYSA-N 0.000 description 2
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- CGISBZCYXGUFNK-UHFFFAOYSA-N 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid Chemical compound C1C2(C(F)(F)F)CC1(C(=O)O)C2 CGISBZCYXGUFNK-UHFFFAOYSA-N 0.000 description 2
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- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
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- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
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- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000003965 isoxazolidinyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- IXHBTMCLRNMKHZ-LBPRGKRZSA-N levobunolol Chemical compound O=C1CCCC2=C1C=CC=C2OC[C@@H](O)CNC(C)(C)C IXHBTMCLRNMKHZ-LBPRGKRZSA-N 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 229910052808 lithium carbonate Inorganic materials 0.000 description 1
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 229960001962 mefloquine Drugs 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- GRWIABMEEKERFV-UHFFFAOYSA-N methanol;oxolane Chemical compound OC.C1CCOC1 GRWIABMEEKERFV-UHFFFAOYSA-N 0.000 description 1
- IEMUIDNPKOVDKO-JPQMRUPTSA-N methyl (3S)-3-[[(R)-tert-butylsulfinyl]amino]-3-[2-chloro-3-(phenylmethoxycarbonylamino)phenyl]butanoate Chemical compound C(C1=CC=CC=C1)OC(=O)NC=1C(=C(C=CC=1)[C@@](CC(=O)OC)(C)N[S@](=O)C(C)(C)C)Cl IEMUIDNPKOVDKO-JPQMRUPTSA-N 0.000 description 1
- DZMFHKDVJVNOBP-IBGZPJMESA-N methyl (3S)-3-amino-3-[2-chloro-3-(phenylmethoxycarbonylamino)phenyl]butanoate Chemical compound N[C@](CC(=O)OC)(C)C1=C(C(=CC=C1)NC(=O)OCC1=CC=CC=C1)Cl DZMFHKDVJVNOBP-IBGZPJMESA-N 0.000 description 1
- VMVNZNXAVJHNDJ-UHFFFAOYSA-N methyl 2,2,2-trifluoroacetate Chemical compound COC(=O)C(F)(F)F VMVNZNXAVJHNDJ-UHFFFAOYSA-N 0.000 description 1
- YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical compound COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 description 1
- CWOBWCDFHUNRGG-UHFFFAOYSA-N methyl 3-methoxyadamantane-1-carboxylate Chemical compound C1C(C2)CC3CC2(OC)CC1(C(=O)OC)C3 CWOBWCDFHUNRGG-UHFFFAOYSA-N 0.000 description 1
- CLYOOVNORYNXMD-UHFFFAOYSA-N methyl adamantane-1-carboxylate Chemical compound C1C(C2)CC3CC2CC1(C(=O)OC)C3 CLYOOVNORYNXMD-UHFFFAOYSA-N 0.000 description 1
- SOHCYNFHNYKSTM-UHFFFAOYSA-N methylsulfinylmethane;oxolane Chemical compound CS(C)=O.C1CCOC1 SOHCYNFHNYKSTM-UHFFFAOYSA-N 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 229940042472 mineral oil Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- WWECJGLXBSQKRF-UHFFFAOYSA-N n,n-dimethylformamide;methanol Chemical compound OC.CN(C)C=O WWECJGLXBSQKRF-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 239000002687 nonaqueous vehicle Substances 0.000 description 1
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 1
- 229940006093 opthalmologic coloring agent diagnostic Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- AHVQYHFYQWKUKB-UHFFFAOYSA-N oxan-4-amine Chemical compound NC1CCOCC1 AHVQYHFYQWKUKB-UHFFFAOYSA-N 0.000 description 1
- 125000005961 oxazepanyl group Chemical group 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 229940066842 petrolatum Drugs 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000002831 pharmacologic agent Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 229960003424 phenylacetic acid Drugs 0.000 description 1
- 239000003279 phenylacetic acid Substances 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- PDTFCHSETJBPTR-UHFFFAOYSA-N phenylmercuric nitrate Chemical compound [O-][N+](=O)O[Hg]C1=CC=CC=C1 PDTFCHSETJBPTR-UHFFFAOYSA-N 0.000 description 1
- 125000004344 phenylpropyl group Chemical group 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 108010020708 plasmepsin Proteins 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229940113124 polysorbate 60 Drugs 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- MCSINKKTEDDPNK-UHFFFAOYSA-N propyl propionate Chemical compound CCCOC(=O)CC MCSINKKTEDDPNK-UHFFFAOYSA-N 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 239000002287 radioligand Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- VILMUCRZVVVJCA-UHFFFAOYSA-M sodium glycolate Chemical compound [Na+].OCC([O-])=O VILMUCRZVVVJCA-UHFFFAOYSA-M 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000001587 sorbitan monostearate Substances 0.000 description 1
- 235000011076 sorbitan monostearate Nutrition 0.000 description 1
- 229940035048 sorbitan monostearate Drugs 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000003019 stabilising effect Effects 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- CVCASMHLTDLRLF-UHFFFAOYSA-N tert-butyl N-(cyclohexylcarbamothioyl)carbamate Chemical compound CC(C)(C)OC(=O)NC(=S)NC1CCCCC1 CVCASMHLTDLRLF-UHFFFAOYSA-N 0.000 description 1
- YFEMBBPMLYBDTN-UHFFFAOYSA-N tert-butyl N-[(2-methyloxan-4-yl)carbamothioyl]carbamate Chemical compound CC1OCCC(C1)NC(=S)NC(OC(C)(C)C)=O YFEMBBPMLYBDTN-UHFFFAOYSA-N 0.000 description 1
- YNACLTGJTBBXJM-NRFANRHFSA-N tert-butyl N-[(4S)-4-(3-amino-2-chlorophenyl)-1-(4,4-difluorocyclohexyl)-4-methyl-6-oxo-5H-pyrimidin-2-yl]carbamate Chemical compound NC=1C(=C(C=CC=1)[C@]1(N/C(/N(C(C1)=O)C1CCC(CC1)(F)F)=N\C(OC(C)(C)C)=O)C)Cl YNACLTGJTBBXJM-NRFANRHFSA-N 0.000 description 1
- QGZMXOAAWAJJSW-QFIPXVFZSA-N tert-butyl N-[(4S)-4-(3-amino-2-chlorophenyl)-1-cyclohexyl-4-methyl-6-oxo-5H-pyrimidin-2-yl]carbamate Chemical compound NC=1C(=C(C=CC=1)[C@]1(NC(N(C(C1)=O)C1CCCCC1)=NC(OC(C)(C)C)=O)C)Cl QGZMXOAAWAJJSW-QFIPXVFZSA-N 0.000 description 1
- WYVFPGFWUKBXPZ-UHFFFAOYSA-N tert-butyl n-(4-oxocyclohexyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1CCC(=O)CC1 WYVFPGFWUKBXPZ-UHFFFAOYSA-N 0.000 description 1
- MHXBHWLGRWOABW-UHFFFAOYSA-N tetradecyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCC MHXBHWLGRWOABW-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- UJJLJRQIPMGXEZ-SCSAIBSYSA-N tetrahydrofuran-2-carboxylic acid Chemical compound OC(=O)[C@H]1CCCO1 UJJLJRQIPMGXEZ-SCSAIBSYSA-N 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- LALRXNPLTWZJIJ-UHFFFAOYSA-N triethylborane Chemical compound CCB(CC)CC LALRXNPLTWZJIJ-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- 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
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/08—Bridged systems
-
- 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
Definitions
- the present invention relates to a class of heterocyclic compounds, and to their use in therapy. More particularly, this invention is concerned with pharmacologically active substituted hexahydropyrimidine derivatives, and analogues thereof. These compounds are potent inhibitors of the growth and propagation of the Plasmodium falciparum parasite in human blood, and are accordingly of benefit as pharmaceutical agents, especially in the treatment of malaria. Malaria is a mosquito-borne infectious disease, caused by a parasite of the genus Plasmodium, which has devastating consequences.
- the compounds in accordance with the present invention being potent inhibitors of the growth and propagation of the P. falciparum parasite in human blood, are therefore beneficial in the treatment of malaria.
- the compounds in accordance with the present invention may be beneficial as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents.
- the compounds of this invention may be useful as radioligands in assays for detecting pharmacologically active compounds.
- WO 2019/192992 co-pending international patent application PCT/EP2020/063083 (published on 19 November 2020 as WO 2020/229427), and co-pending international patent application PCT/EP2020/073011 (published on 25 February 2021 as WO 2021/032687, and claiming priority from United Kingdom patent applications 1911865.2 and 1913759.5), describe certain classes of heterocyclic compounds which are stated to be potent inhibitors of the growth and propagation of the P. falciparum parasite in human blood, and therefore to be beneficial in the treatment of malaria.
- WO 2017/142825 describes a family of heterocyclic compounds which are stated to be potent inhibitors of P. falciparum growth in vitro that may be useful for the treatment of malaria.
- WO 2017/089453 and WO 2017/144517 describe heterocyclic compounds which are stated to be potent and selective inhibitors of plasmepsin V activity that are beneficial in the treatment of malaria.
- WO 2016/172255, WO 2016/118404 and WO 2011/044181 describe certain classes of heterocyclic compounds which are stated to be BACE inhibitors that may be useful for treating A ⁇ -related pathologies including Alzheimer’s disease.
- WO 2012/019966 describes 1,4,5,6-tetrahydropyrimidin-2-ylamine derivatives which are stated to have BACE2 inhibitory properties that may be useful in the treatment of metabolic disorders (including type 2 diabetes), and cardiovascular disorders.
- WO 2008/103351, WO 2006/065277 and WO 2005/058311 describe a family of heterocyclic compounds that are stated to be aspartyl protease inhibitors.
- the compounds described in those publications are also stated to be effective in a method of inhibiting inter alia plasmepsins (specifically plasmepsins I and II) for treatment of malaria.
- WO 2006/041404 describes a family of heterocyclic compounds that are stated to be inhibitors of Beta site APP (amyloid precursor protein) Cleaving Enzyme (BACE).
- the compounds described in that publication are also stated to be effective in a method of modulating BACE activity; and in methods of treating or preventing an amyloid- ⁇ - protein-related (A ⁇ -related) pathology, including Downs syndrome and Alzheimer disease.
- the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof: wherein Z represents C 1-6 alkyl, C 3-9 cycloalkyl, C 3-9 cycloalkyl(C 1-6 )alkyl, C 4-9 cycloalkenyl, C 4-12 bicycloalkyl, C 5-9 spirocycloalkyl, C 5-9 spirocycloalkyl(C 1-6 )alkyl, C 8-11 tricycloalkyl, C 8-11 tricycloalkyl(C 1-6 )alkyl, C 7-13 dispirocycloalkyl, C 7-13 dispirocycloalkyl(C 1-6 )alkyl, aryl(C 1-6 )alkyl, C-
- the compounds in accordance with the present invention overlap with the broadest generic scope of WO 2016/172255, WO 2008/103351, WO 2006/065277, WO 2005/058311 and WO 2006/041404. There is, however, no specific disclosure in any of those publications of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof.
- the present invention also provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use in therapy.
- the present invention also provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of malaria.
- the present invention also provides a method for the treatment and/or prevention of malaria which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof.
- the present invention also provides the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and/or prevention of malaria.
- this group may be unsubstituted, or substituted by one or more substituents. Typically, such groups will be unsubstituted, or substituted by one, two or three substituents, generally by one or two substituents.
- the salts of the compounds of formula (I) will be pharmaceutically acceptable salts.
- Other salts may, however, be useful in the preparation of the compounds of use in the invention or of their pharmaceutically acceptable salts. Standard principles underlying the selection and preparation of pharmaceutically acceptable salts are described, for example, in Handbook of Pharmaceutical Salts: Properties, Selection and Use, ed. P.H. Stahl & C.G. Wermuth, Wiley-VCH, 2002.
- Suitable alkyl groups which may be present on the compounds of use in the invention include straight-chained and branched C 1-6 alkyl groups, for example C 1-4 alkyl groups.
- Typical examples include methyl and ethyl groups, and straight-chained or branched propyl, butyl and pentyl groups.
- Particular alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 2,2-dimethylpropyl and 3- methylbutyl.
- Derived expressions such as “C 1-6 alkoxy”, “C 1-6 alkylthio”, “C 1-6 alkylsulfonyl” and “C 1-6 alkylamino” are to be construed accordingly.
- C 3-9 cycloalkyl refers to monovalent groups of 3 to 9 carbon atoms derived from a saturated monocyclic hydrocarbon, and may comprise benzo-fused analogues thereof.
- SuitableC 3-9 cycloalkyl groups include cyclopropyl, cyclobutyl, benzocyclobutenyl, cyclopentyl, indanyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclononanyl.
- C 4-9 cycloalkenyl refers to monovalent groups of 4 to 9 carbon atoms derived from an unsaturated monocyclic hydrocarbon, and may comprise benzo-fused analogues thereof. Suitable C 4-9 cycloalkenyl groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.
- C 4-12 bicycloalkyl refers to monovalent groups of 4 to 12 carbon atoms derived from a saturated bicyclic hydrocarbon.
- Typical bicycloalkyl groups include bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[4.1.0]heptanyl and bicyclo[2.2.2]octanyl. Additional bicycloalkyl groups include bicyclo[2.1.1]hexanyl.
- C 5-9 spirocycloalkyl refers to saturated bicyclic ring systems containing 5 to 9 carbon atoms, in which the two rings are linked by a common atom.
- Suitable spirocycloalkyl groups include spiro[2.3]hexanyl, spiro[2.4]heptanyl, spiro[3.3]heptanyl, spiro[3.4]octanyl, spiro[3.5]nonanyl and spiro[4.4]nonanyl.
- C 8-11 tricycloalkyl refers to monovalent groups of 8 to 11 carbon atoms derived from a saturated tricyclic hydrocarbon. Typical tricycloalkyl groups include adamantanyl. Additional tricycloalkyl groups include cubanyl and tricyclo[3.3.1.0 3,7 ]nonanyl.
- C 7-13 dispirocycloalkyl refers to saturated tricyclic ring systems containing 7 to 13 carbon atoms, in which the three rings incorporate two spiro linkages. Suitable dispirocycloalkyl groups include dispiro[2.0.24.13]heptanyl.
- aryl refers to monovalent carbocyclic aromatic groups derived from a single aromatic ring or multiple condensed aromatic rings. Suitable aryl groups include phenyl and naphthyl, preferably phenyl. Suitable aryl(C 1-6 )alkyl groups include benzyl, phenylethyl, phenylpropyl and naphthylmethyl.
- C 3-7 heterocycloalkyl refers to saturated monocyclic rings containing 3 to 7 carbon atoms and at least one heteroatom selected from oxygen, sulphur and nitrogen, and may comprise analogues thereof fused to an aryl or heteroaryl ring.
- Suitable heterocycloalkyl groups include oxetanyl, azetidinyl, tetrahydrofuranyl, dihydrobenzofuranyl, dihydrobenzothienyl, pyrrolidinyl, indolinyl, isoindolinyl, 2,3- dihydropyrrolo[2,3-b]pyridinyl, 2,3-dihydropyrrolo[3,2-b]pyridinyl, 1,3-dihydropyrrolo- [3,4-b]pyridinyl, 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, imidazolidinyl, tetrahydropyranyl, chromanyl, dioxanyl, tetrahydrothiopyranyl, piperidinyl, 1,2,3,4
- C-linked denotes that the heterocycloalkyl moiety is linked to the remainder of the molecule via a carbon atom comprised within the heterocycloalkyl ring.
- C 4-9 heterobicycloalkyl refers to monovalent groups of 4 to 9 carbon atoms derived from a saturated bicyclic hydrocarbon, comprising one or more heteroatoms selected from oxygen, sulphur and nitrogen.
- Typical heterobicyclo- alkyl groups include 3-oxabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexanyl, 2-aza- bicyclo[2.2.1]heptanyl, 7-oxabicyclo[2.2.1]heptanyl, 7-azabicyclo[2.2.1]heptanyl, 2-oxa- 5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 6-azabicyclo[3.2.0]- heptanyl, 3-azabicyclo[3.1.1]heptanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 2-oxabicyclo- [4.1.0]heptanyl, 3-azabicyclo[4.1.0]heptanyl, 2-oxabicyclo[2.2.2]octanyl, quinuclidinyl, 2-oxa-5-azabicyclo[2.2.2]octanyl, 3-azabicyclo[3.
- Additional heterobicycloalkyl groups include 2-oxa- bicyclo[2.1.1]hexanyl.
- C-linked denotes that the heterobicycloalkyl moiety is linked to the remainder of the molecule via a carbon atom comprised within the heterobicycloalkyl ring system.
- C 4-9 spiroheterocycloalkyl refers to saturated bicyclic ring systems containing 4 to 9 carbon atoms and at least one heteroatom selected from oxygen, sulphur and nitrogen, in which the two rings are linked by a common atom.
- Suitable spiroheterocycloalkyl groups include 5-azaspiro[2.3]hexanyl, 5-azaspiro[2.4]- heptanyl, 2-oxaspiro[3.3]heptanyl, 1-azaspiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, 2- oxa-6-azaspiro[3.3]-heptanyl, 3-oxa-6-azaspiro[3.3]heptanyl, 6-thia-2-azaspiro[3.3]- heptanyl, 5-azaspiro[2.5]octanyl, 6-oxaspiro[2.5]octanyl, 6-azaspiro[3.4]octanyl, 2-oxa-6- azaspiro[3.4]octanyl, 2-oxa-6- azaspiro[3.4]octanyl, 2-oxa-6-azaspiro[3.4]octanyl, 2-oxa-6-azaspir
- C-linked denotes that the spiroheterocycloalkyl moiety is linked to the remainder of the molecule via a carbon atom comprised within the spiroheterocycloalkyl ring system.
- heteroaryl refers to monovalent aromatic groups containing at least five atoms derived from a single ring or multiple condensed rings, wherein one or more carbon atoms have been replaced by one or more heteroatoms selected from oxygen, sulfur and nitrogen.
- Suitable heteroaryl groups include furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, thieno[2,3-c]pyrazolyl, thieno[3,2-c]- pyridinyl, dibenzothienyl, pyrrolyl, indolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-c]- pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrazolyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[3,4-b]- pyridinyl, pyrazolo[3,4-d]pyrimidinyl, indazolyl, 4,5,6,7-tetrahydroindazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, iso
- halogen as used herein is intended to include fluorine, chlorine, bromine and iodine atoms, typically fluorine, chlorine or bromine.
- the absolute stereochemical configuration of the chiral carbon atom in the imino- tetrahydropyrimidinone nucleus of the compounds according to the invention is as depicted in formula (I) above.
- the compounds in accordance with the invention are at least 51% enantiomerically pure (by which it is meant that a sample thereof comprises a mixture of enantiomers containing 51% or more of the enantiomer depicted in formula (I) and 49% or less of the opposite antipode).
- the compounds in accordance with the invention are at least 60% enantiomerically pure.
- the compounds in accordance with the invention are at least 75% enantiomerically pure.
- the compounds in accordance with the invention are at least 80% enantiomerically pure. More suitably, the compounds in accordance with the invention are at least 85% enantiomerically pure. Still more suitably, the compounds in accordance with the invention are at least 90% enantiomerically pure. Even more suitably, the compounds in accordance with the invention are at least 95% enantiomerically pure.
- the compounds in accordance with the invention are at least 99% enantiomerically pure.
- the compounds in accordance with the invention are at least 99.9% enantiomerically pure.
- the compounds of formula (I) may accordingly exist as enantiomers.
- the compounds in accordance with the invention possess one or more additional asymmetric centres, they may also exist as diastereomers.
- the invention is to be understood to extend to the use of all such enantiomers and diastereomers, and to mixtures thereof in any proportion, including racemates.
- Formula (I) and the formulae depicted hereinafter are intended to represent all individual stereoisomers and all possible mixtures thereof, unless stated or shown otherwise.
- Formula (I) and the formulae depicted hereinafter are intended to represent all individual tautomers and all possible mixtures thereof, unless stated or shown otherwise.
- compounds of formula (I) may exist as atropisomers.
- Formula (I) and the formulae depicted hereinafter are intended to represent all individual atropisomers and all possible mixtures thereof, unless stated or shown otherwise. It is to be understood that each individual atom present in formula (I), or in the formulae depicted hereinafter, may in fact be present in the form of any of its naturally occurring isotopes, with the most abundant isotope(s) being preferred. Thus, by way of example, each individual hydrogen atom present in formula (I), or in the formulae depicted hereinafter, may be present as a 1 H, 2 H (deuterium; D) or 3 H (tritium; T) atom, preferably 1 H.
- each individual carbon atom present in formula (I), or in the formulae depicted hereinafter, may be present as a 12 C, 13 C or 14 C atom, preferably 12 C.
- Z represents C 1-6 alkyl, C 3-9 cycloalkyl, C 3-9 cycloalkyl(C 1-6 )alkyl, C 4-9 cycloalkenyl, C4-12 bicycloalkyl, C 8-11 tricycloalkyl, C 8-11 tricycloalkyl(C 1-6 )alkyl, aryl- (C 1-6 )alkyl, C-linkedC 3-7 heterocycloalkyl, C-linked C 4-9 heterobicycloalkyl, C-linked C 4-9 spiroheterocycloalkyl or heteroaryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents.
- Z represents optionally substituted C 1-6 alkyl.
- Z represents optionally substituted C 3-9 cycloalkyl.
- Z represents optionally substituted C 3-9 cycloalkyl(C 1-6 )alkyl.
- Z represents optionally substituted C 4-9 cycloalkenyl.
- Z represents optionally substituted C 4-12 bicycloalkyl.
- Z represents optionally substituted C 5-9 spirocycloalkyl.
- Z represents optionally substituted C 5-9 spirocycloalkyl(C 1-6 )alkyl.
- Z represents optionally substituted C 8-11 tricycloalkyl. In a ninth embodiment, Z represents optionally substituted C 8-11 tricycloalkyl(C 1-6 )alkyl. In a tenth embodiment, Z represents optionally substituted C 7-13 dispirocycloalkyl. In an eleventh embodiment, Z represents optionally substituted C 7-13 dispirocycloalkyl(C 1-6 )alkyl. In a twelfth embodiment, Z represents optionally substituted aryl(C 1-6 )alkyl. In a thirteenth embodiment, Z represents optionally substituted C-linked C 3-7 heterocycloalkyl.
- Z represents optionally substituted C 3-7 heterocycloalkyl(C 1-6 )alkyl. In a fifteenth embodiment, Z represents optionally substituted C-linked C 4-9 heterobicycloalkyl. In a sixteenth embodiment, Z represents optionally substituted C-linked C 4-9 spiroheterocycloalkyl. In a seventeenth embodiment, Z represents optionally substituted heteroaryl(C 1-6 )alkyl.
- Z include ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, indanyl, cyclohexyl, indanylmethyl, cycloheptylmethyl, cyclohexenyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[3.1.0]hexanyl, bicyclo[2.2.1]- heptanyl, cubanyl, tricyclo[3.3.1.0 3,7 ]nonanyl, adamantanyl, adamantanylmethyl, benzyl, tetrahydrofuranyl, dihydrobenzofuranyl, tetrahydropyranyl, 2-oxabicyclo[2.1.1]hexanyl, 3-oxabicyclo[3.1.0]hexanyl, 2-oxabicyclo[4.1.0]heptanyl, 3-oxabicyclo[3.3.0]octanyl
- Suitable examples of Z include ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, indanyl, cyclohexyl, indanylmethyl, cycloheptylmethyl, cyclohexenyl, bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, bicyclo[2.2.1]heptanyl, adamantanyl, adamantanylmethyl, benzyl, tetrahydrofuranyl, dihydrobenzofuranyl, 3-oxabicyclo- [3.1.0]hexanyl, 2-oxabicyclo[4.1.0]heptanyl, 3-oxabicyclo[3.3.0]octanyl, 6-oxaspiro[2.5]- octanyl and furylmethyl, any of which groups may be optionally substituted by one or more substituents.
- Typical examples of optional substituents on Z include one, two or three substituents independently selected from halogen, cyano, nitro, C 1-6 alkyl, trifluoro- methyl, phenyl, pyrazolyl, hydroxy, oxo, C 1-6 alkoxy, difluoromethoxy, trifluoromethoxy, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, amino, C 1-6 alkylamino, di(C 1-6 )alkyl- amino, C2-6 alkylcarbonylamino, C2-6 alkoxycarbonylamino, C 1-6 alkylsulfonylamino, formyl, C2-6 alkylcarbonyl, carboxy, C2-6 alkoxycarbonyl, aminocarbonyl, C 1-6 alkyl- aminocarbonyl, di(C 1-6 )alkylaminocarbonyl, aminosulfonyl,
- optional substituents on Z include one, two or three substituents independently selected from halogen, cyano, C 1-6 alkyl, trifluoromethyl, phenyl, pyrazolyl, hydroxy, oxo, C 1-6 alkoxy and di(C 1-6 )alkylamino.
- Suitable examples of optional substituents on Z include one, two or three substituents independently selected from halogen, cyano, C 1-6 alkyl, trifluoromethyl, phenyl, pyrazolyl, oxo, C 1-6 alkoxy and di(C 1-6 )alkylamino.
- substituents on Z include one, two or three substituents independently selected from fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, phenyl, pyrazolyl, hydroxy, oxo, methoxy, tert-butoxy, difluoromethoxy, trifluoromethoxy, methylthio, methylsulfinyl, methyl- sulfonyl, amino, methylamino, tert-butylamino, dimethylamino, acetylamino, methoxy- carbonylamino, methylsulfonylamino, formyl, acetyl, carboxy, methoxycarbonyl, ethoxy- carbonyl, tert-butoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylamino- carbonyl, amino
- Selected examples of particular substituents on Z include one, two or three substituents independently selected from fluoro, chloro, cyano, methyl, tert-butyl, trifluoromethyl, phenyl, pyrazolyl, hydroxy, oxo, methoxy and dimethylamino.
- Suitable examples of particular substituents on Z include one, two or three substituents independently selected from fluoro, cyano, methyl, trifluoromethyl, phenyl, pyrazolyl, oxo, methoxy and dimethylamino.
- Selected values of Z include cyanoethyl, dimethylaminopropyl, cyclopropyl, cyanocyclopropyl, trifluoromethylcyclopropyl, phenylcyclopropyl, (difluoro)(methyl)- cyclopropyl, tetramethylcyclopropyl, cyclobutyl, dimethylcyclobutyl, pyrazolyl- cyclobutyl, (difluoro)(methyl)cyclobutyl, cyclopentyl, indanyl, difluorocyclohexyl, methoxycyclohexyl, (difluoro)(methyl)cyclohexyl, indanylmethyl, cycloheptylmethyl, cyclohexenyl, bicyclo[1.1.1]pentanyl, fluorobicyclo[1.1.1]pentanyl, chlorobicyclo[1.1.1]- pentanyl, tert-butyl
- Suitable values of Z include cyanoethyl, dimethylaminopropyl, cyclopropyl, cyanocyclopropyl, trifluoromethylcyclopropyl, phenylcyclopropyl, (difluoro)(methyl)- cyclopropyl, cyclobutyl, dimethylcyclobutyl, pyrazolylcyclobutyl, cyclopentyl, indanyl, difluorocyclohexyl, methoxycyclohexyl, (difluoro)(methyl)cyclohexyl, indanylmethyl, cycloheptylmethyl, cyclohexenyl, bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, bicyclo- [2.2.1]heptanyl, (dimethyl)(oxo)bicyclo[2.2.1]heptanyl, adamantanyl, cyanoadamantanyl, tri
- R 1 represents C 3-7 cycloalkyl, aryl(C 1-6 )alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl(C 1-6 )alkyl or heteroaryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents.
- R 1 represents C 3-7 cycloalkyl, C 3-7 heterocycloalkyl or C 3-7 heterocycloalkyl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents.
- R 1 represents C 3-7 cycloalkyl or C 3-7 heterocycloalkyl, either of which groups may be optionally substituted by one or more substituents.
- R 1 represents C 3-7 heterocycloalkyl, which group may be optionally substituted by one or more substituents.
- R 1 Suitable examples of R 1 include cyclobutyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanylmethyl, tetrahydropyranylmethyl, 7-oxabicyclo[2.2.1]- heptanyl, 8-oxabicyclo[3.2.1]octanyl and 2-oxaspiro[3.3]heptanyl, any of which groups may be optionally substituted by one or more substituents. Additional examples include chromanyl, which group may be optionally substituted by one or more substituents.
- R 1 examples include cyclobutyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl and tetrahydropyranylmethyl, any of which groups may be optionally substituted by one or more substituents. Additional examples include chromanyl, which group may be optionally substituted by one or more substituents. Selected examples of R 1 include cyclohexyl, tetrahydropyranyl and chromanyl, any of which groups may be optionally substituted by one or more substituents. Illustrative examples of R 1 include cyclohexyl and tetrahydropyranyl, either of which groups may be optionally substituted by one or more substituents.
- R 1 is tetrahydropyranyl, which group may be optionally substituted by one or more substituents.
- substituents on R 1 include one, two or three substituents independently selected from halogen, cyano, nitro, C 1-6 alkyl, difluoromethyl, trifluoromethyl, hydroxy, hydroxy(C 1-6 )alkyl, oxo, C 1-6 alkoxy, difluoromethoxy, trifluoromethoxy, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, amino, C 1-6 alkylamino, di(C 1-6 )alkylamino, amino(C 1-6 )alkyl, di(C 1-6 )alkylamino(C 1-6 )alkyl, C 2-6 alkylcarbonylamino, C2-6 alkoxycarbonylamino, C 1-6 alkylsulfonyla
- optional substituents on R 1 include one, two or three substituents independently selected from halogen, C 1-6 alkyl and trifluoromethyl. Apposite examples of optional substituents on R 1 include one, two or three substituents independently selected from halogen and C 1-6 alkyl. Suitable examples of optional substituents on R 1 include one, two or three substituents independently selected from C 1-6 alkyl.
- substituents on R 1 include one, two or three substituents independently selected from fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, hydroxy, hydroxymethyl, hydroxyethyl, hydroxyisopropyl, oxo, methoxy, difluoromethoxy, trifluoromethoxy, methylthio, methylsulfinyl, methylsulfonyl, amino, methylamino, dimethylamino, aminomethyl, dimethylaminomethyl, acetylamino, methoxycarbonylamino, methylsulfonylamino, formyl, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methyl- aminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl
- Selected examples of particular substituents on R 1 include one, two or three substituents independently selected from fluoro, methyl and trifluoromethyl. Apposite examples of particular substituents on R 1 include one, two or three substituents independently selected from fluoro and methyl. Suitable examples of particular substituents on R 1 include one, two or three substituents independently selected from methyl.
- Typical values of R 1 include difluorocyclohexyl, (difluoro)(methyl)cyclohexyl, tetrahydropyranyl and methyltetrahydropyranyl. Additional values include cyclohexyl, trifluoromethyltetrahydropyranyl, chromanyl and difluorochromanyl.
- R 1 Selected values of R 1 include cyclohexyl, difluorocyclohexyl, (difluoro)- (methyl)cyclohexyl, tetrahydropyranyl, methyltetrahydropyranyl, trifluoromethyl- tetrahydropyranyl, chromanyl and difluorochromanyl. Suitable values of R 1 include difluorocyclohexyl and methyltetrahydropyranyl. In a first embodiment, R 1 represents difluorocyclohexyl, especially 4,4-difluoro- cyclohexyl.
- R 1 represents (difluoro)(methyl)cyclohexyl, especially 4,4-difluoro-3-methylcyclohexyl.
- R 1 represents tetrahydropyranyl.
- R 1 represents methyltetrahydropyranyl, especially 2-methyltetrahydropyran-4-yl.
- R 1 represents cyclohexyl.
- R 1 represents trifluoromethyltetrahydropyranyl, especially 2-(trifluoromethyl)tetrahydropyran-4-yl.
- R 1 represents chromanyl, especially chroman-4-yl.
- R 1 represents difluorochromanyl, especially 5,7-difluorochroman-4-yl.
- R 2 represents methyl.
- R 2 represents fluoromethyl.
- R 2 represents ethyl.
- R 3 represents hydrogen or halogen.
- R 3 represents hydrogen.
- R 3 represents halogen, especially fluoro or chloro.
- R 3 represents fluoro.
- R 3 represents chloro.
- R 3 represents methyl.
- R 3 represents ethyl.
- R 3 represents difluoromethyl.
- R 3 represents trifluoromethyl.
- R 3 represents cyclopropyl.
- R 3 represents methoxy.
- R 3 represents difluoro- methoxy.
- R 3 represents trifluoromethoxy.
- Illustrative values of R 3 include hydrogen, fluoro and chloro.
- R 3 represents chloro.
- One sub-class of compounds according to the invention is represented by the compounds of formula (IIA), and pharmaceutically acceptable salts thereof: wherein R 11 represents hydrogen, methyl or trifluoromethyl; R 12 represents hydrogen or methyl; and Z and R 3 are as defined above. In a first embodiment, R 11 represents hydrogen.
- R 11 represents methyl. In a third embodiment, R 11 represents trifluoromethyl. In a first embodiment, R 12 represents hydrogen. In a second embodiment, R 12 represents methyl. In a first embodiment, R 11 and R 12 both represent hydrogen. In a second embodiment, R 11 represents hydrogen and R 12 represents methyl. In a third embodiment, R 11 and R 12 both represent methyl. In a fourth embodiment, R 11 represents trifluoro- methyl and R 12 represents hydrogen.
- Another sub-class of compounds according to the invention is represented by the compounds of formula (IIB), and pharmaceutically acceptable salts thereof: wherein Z, R 3 and R 11 are as defined above.
- compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical, ophthalmic or rectal administration, or a form suitable for administration by inhalation or insufflation.
- pharmaceutical compositions may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g.
- pregelatinised maize starch polyvinylpyrrolidone or hydroxypropyl methyl cellulose
- fillers e.g. lactose, microcrystalline cellulose or calcium hydrogenphosphate
- lubricants e.g. magnesium stearate, talc or silica
- disintegrants e.g. potato starch or sodium glycollate
- wetting agents e.g. sodium lauryl sulfate
- the tablets may be coated by methods well known in the art.
- Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
- Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles or preservatives.
- the preparations may also contain buffer salts, flavouring agents, colouring agents or sweetening agents, as appropriate.
- Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
- the compositions may take the form of tablets or lozenges formulated in conventional manner.
- the compounds of formula (I) may be formulated for parenteral administration by injection, e.g. by bolus injection or infusion. Formulations for injection may be presented in unit dosage form, e.g. in glass ampoules or multi-dose containers, e.g. glass vials.
- compositions for injection may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising, preserving and/or dispersing agents.
- the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
- the compounds of formula (I) may also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation or by intramuscular injection.
- the compounds according to the present invention may be conveniently delivered in the form of an aerosol spray presentation for pressurised packs or a nebuliser, with the use of a suitable propellant, e.g. dichlorodifluoromethane, fluorotrichloromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
- a suitable propellant e.g. dichlorodifluoromethane, fluorotrichloromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
- the compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
- the pack or dispensing device may be accompanied by instructions for administration.
- the compounds of use in the present invention may be conveniently formulated in a suitable ointment containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers.
- Particular carriers include, for example, mineral oil, liquid petroleum, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax and water.
- the compounds of use in the present invention may be formulated in a suitable lotion containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers.
- Particular carriers include, for example, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, benzyl alcohol, 2-octyldodecanol and water.
- the compounds of use in the present invention may be conveniently formulated as micronized suspensions in isotonic, pH-adjusted sterile saline, either with or without a preservative such as a bactericidal or fungicidal agent, for example phenylmercuric nitrate, benzylalkonium chloride or chlorhexidine acetate.
- a preservative such as a bactericidal or fungicidal agent, for example phenylmercuric nitrate, benzylalkonium chloride or chlorhexidine acetate.
- compounds may be formulated in an ointment such as petrolatum.
- the compounds of use in the present invention may be conveniently formulated as suppositories.
- a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and so will melt in the rectum to release the active component.
- suitable non-irritating excipient include, for example, cocoa butter, beeswax and polyethylene glycols.
- the quantity of a compound of use in the invention required for the prophylaxis or treatment of a particular condition will vary depending on the compound chosen and the condition of the patient to be treated. In general, however, daily dosages may range from around 10 ng/kg to 1000 mg/kg, typically from 100 ng/kg to 100 mg/kg, e.g.
- the compounds in accordance with the invention may be prepared by a process which comprises reacting a compound of formula Z-COCl with a compound of formula (III): wherein Z, R 1 , R 2 and R 3 are as defined above, and R p represents hydrogen or an N- protecting group; followed, as necessary, by removal of the N-protecting group R p .
- the reaction between the compound of formula Z-COCl and compound (III) is conveniently accomplished at ambient temperature in the presence of pyridine.
- the N-protecting group R p is tert-butoxycarbonyl (BOC). Where the N-protecting group R p is BOC, subsequent removal of the BOC group may suitably be accomplished by treatment with an acid, e.g.
- the compounds in accordance with the invention may be prepared by a two-step process which comprises: (i) treating a compound of formula Z-CO 2 H with oxalyl chloride and N,N-dimethylformamide; and (ii) reacting the material thereby obtained with a compound of formula (III) as defined above; followed, as necessary, by removal of the N-protecting group R p .
- Step (i) is conveniently accomplished at ambient temperature in a suitable solvent, e.g. a chlorinated solvent such as dichloromethane.
- Step (ii) is conveniently carried out in the presence of a base, e.g. an organic base such as triethylamine.
- the reaction is typically performed at a temperature in the region of 0°C in a suitable solvent, e.g. a chlorinated solvent such as dichloromethane.
- the compounds in accordance with the invention may be prepared by a process which comprises reacting a carboxylic acid of formula Z-CO 2 H with a compound of formula (III) as defined above; in the presence of a coupling agent; followed, as necessary, by removal of the N-protecting group R p .
- the coupling agent may be chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate, in which case the reaction may generally be carried out in the presence of 1-methylimidazole.
- the reaction is conveniently performed at ambient temperature in a suitable solvent, e.g. a nitrile solvent such as acetonitrile.
- the coupling agent may be 2,4,6-tripropyl-1,3,5,2,4,6-trioxa- triphosphorinane 2,4,6-trioxide, in which case the reaction may generally be carried out in the presence of a base which may suitably include organic amines, e.g.
- a trialkylamine such as N,N-diisopropylethylamine, or an aromatic base such as pyridine.
- the reaction is conveniently performed at ambient temperature in a suitable solvent, e.g. a chlorinated solvent such as dichloromethane.
- the coupling agent may be 2-chloro-1-methylpyridinium iodide, in which case the reaction may generally be carried out in the presence of a base, e.g. a trialkylamine such as N,N-diisopropylethylamine.
- the reaction is conveniently performed at ambient or elevated temperature in a suitable solvent, e.g. a chlorinated solvent such as dichloromethane, or an organic nitrile solvent such as acetonitrile.
- the intermediates of formula (III) above may be prepared by treating a compound of formula (IV): wherein R 1 , R 2 , R 3 and R p are as defined above, R q represents an N-protecting group, and R w represents C 1-4 alkyl, especially methyl; with a base; followed by removal of the N- protecting group R q .
- the base of use in the above reaction is a C 1-4 alkoxide salt, typically an alkali metal alkoxide such as potassium tert-butoxide.
- the reaction is conveniently accomplished at ambient temperature in a suitable solvent, e.g. a cyclic ether such as tetrahydrofuran.
- the N-protecting group R q is benzyloxycarbonyl.
- subsequent removal of the benzyloxycarbonyl group may suitably be accomplished by catalytic hydrogenation. Typically, this will involve treatment with gaseous hydrogen in the presence of a hydrogenation catalyst such as palladium on charcoal.
- the intermediates of formula (IV) above may be prepared by reacting a compound of formula (V) with a compound of formula (VI): wherein R 1 , R 2 , R 3 , R p , R q and R w are as defined above. Generally, the reaction between compounds (V) and (VI) is performed in the presence of a coupling agent.
- a suitable coupling agent is N-(3-dimethylaminopropyl)- N ⁇ -ethylcarbodiimide hydrochloride (EDC.HCl).
- EDC.HCl N-(3-dimethylaminopropyl)- N ⁇ -ethylcarbodiimide hydrochloride
- the reaction is performed in the presence of a base, typically an organic base such as N,N-diisopropylethylamine.
- the reaction between compounds (V) and (VI) is conveniently accomplished at ambient temperature in a suitable solvent, e.g. a dipolar aprotic solvent such as N,N- dimethylformamide. Under certain circumstances, the reaction between compounds (V) and (VI) will proceed directly to the corresponding compound of formula (III).
- the intermediates of formula (III) above may be prepared by treating a compound of formula (VII):
- R 1 , R 2 , R 3 and R p are as defined above; with a reducing agent.
- the reducing agent of use in the above reaction may be a mixture of zinc and ammonium formate, in which case the reaction may conveniently be accomplished at ambient temperature in a suitable solvent, e.g. a C 1-4 alkanol such as methanol.
- the reducing agent may be tin(II) chloride, in which case the reaction may conveniently be accomplished at an elevated temperature in a suitable solvent, e.g. a C 1-4 alkanol such as ethanol.
- the compound of formula (VII) may be reduced by conventional catalytic hydrogenation, in which case the reaction may conveniently be accomplished by treating compound (VII) with hydrogen gas in the presence of a hydrogenation catalyst, e.g. palladium on charcoal.
- a hydrogenation catalyst e.g. palladium on charcoal.
- the reaction will typically be performed at ambient temperature in a suitable solvent, e.g. a C 1-4 alkanol such as methanol.
- the intermediates of formula (VII) above may be prepared by treating a compound of formula (VIII): wherein R 1 , R 2 , R 3 , R p and R w are as defined above; with a base; in a manner analogous to that described above for compound (IV).
- the intermediates of formula (VIII) above may be prepared by reacting a compound of formula (VI) as defined above with a compound of formula (IX): wherein R 2 , R 3 and R w are as defined above; employing conditions analogous to those described above for the reaction between compounds (V) and (VI). Where they are not commercially available, the starting materials of formula (V), (VI) and (IX) may be prepared by methods analogous to those described in the accompanying Examples, or by standard methods well known from the art. It will be understood that any compound of formula (I) initially obtained from any of the above processes may, where appropriate, subsequently be elaborated into a further compound of formula (I) by techniques known from the art.
- the desired product can be separated therefrom at an appropriate stage by conventional methods such as preparative HPLC; or column chromatography utilising, for example, silica and/or alumina in conjunction with an appropriate solvent system.
- these isomers may be separated by conventional techniques.
- it is desired to obtain a particular enantiomer of a compound of formula (I) this may be produced from a corresponding mixture of enantiomers using any suitable conventional procedure for resolving enantiomers.
- diastereomeric derivatives e.g.
- salts may be produced by reaction of a mixture of enantiomers of formula (I), e.g. a racemate, and an appropriate chiral compound, e.g. a chiral base.
- the diastereomers may then be separated by any convenient means, for example by crystallisation, and the desired enantiomer recovered, e.g. by treatment with an acid in the instance where the diastereomer is a salt.
- a racemate of formula (I) may be separated using chiral HPLC.
- a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described above.
- a particular enantiomer may be obtained by performing an enantiomer-specific enzymatic biotransformation, e.g. an ester hydrolysis using an esterase, and then purifying only the enantiomerically pure hydrolysed acid from the unreacted ester antipode. Chromatography, recrystallisation and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular geometric isomer of the invention.
- Chromatography, recrystallisation and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular geometric isomer of the invention.
- the protecting groups may be removed at any convenient subsequent stage utilising methods known from the art.
- the following Examples illustrate the preparation of compounds according to the invention.
- the compounds of the present invention are potent inhibitors of the growth and propagation of the Plasmodium falciparum parasite in human blood. As such, they are active in a P.
- falciparum 3D7 asexual blood stage assay, exhibiting IC50 values of 50 ⁇ M or less, generally of 20 ⁇ M or less, usually of 5 ⁇ M or less, typically of 1 ⁇ M or less, suitably of 500 nM or less, ideally of 100 nM or less, and preferably of 20 nM or less (the skilled person will appreciate that a lower IC 50 figure denotes a more active compound).
- IC50 values of 50 ⁇ M or less, generally of 20 ⁇ M or less, usually of 5 ⁇ M or less, typically of 1 ⁇ M or less, suitably of 500 nM or less, ideally of 100 nM or less, and preferably of 20 nM or less (the skilled person will appreciate that a lower IC 50 figure denotes a more active compound).
- Asexual Blood Stage Assay The assay used to measure the effect of test compounds on a bloodstream stage of Plasmodium falciparum 3D7 strain employs SYBR green as the readout.
- DNA double stranded deoxyribonucleic acid
- falciparum culture maintenance Erythrocytes (A+ blood) were prepared for both parasite culture and assay by washing 4 times with incomplete media (15.9 g RPMI 1640 (25 mM HEPES, L- glutamine), 1 g NaHCO 3 , 2 g glucose, 400 ⁇ L gentacin (500 mg/mL), 2 mL hypoxanthine solution (13.6 g/L in 0.1M NaOH pH 7.3) in 1 litre of media). The cells were centrifuged at 1800g for 5 minutes, before decanting the supernatant and re-suspending in fresh incomplete media.
- incomplete media 15.9 g RPMI 1640 (25 mM HEPES, L- glutamine), 1 g NaHCO 3 , 2 g glucose, 400 ⁇ L gentacin (500 mg/mL), 2 mL hypoxanthine solution (13.6 g/L in 0.1M NaOH pH 7.3) in 1 litre of media.
- the cells were centrifuged
- the cells were re-suspended in complete media (incomplete media with 5 g/L AlbumaxII), and centrifuged at 1800g for 3 minutes. This cell sediment was treated as 100% haematocrit.
- P. falciparum 3D7 was cultured in erythrocytes at 5% haematocrit in complete media at 37°C (1% O 2 , 3%CO 2 , balance N 2 ). Cultures were split on a weekly basis to achieve a 1% parasitaemia in erythrocites at 5% haematocrit in fresh media. Culture media is replaced by fresh media every other day (2 times during the week).
- test compounds were added to assay plates using Echo dispensing technology (1.5 fold dilution and 20 points titration). 50 nL of each compound dilution was added to 50 ⁇ L of culture (5% haematocrit, 0.5% parasitaemia) and incubated for 72 h at 37°C (1% O 2 , 3% CO 2 , balance N 2 ). Final concentrations of test compounds ranged from 50,000 nM to 15 nM, in 0.5% DMSO.
- Quality control criteria for passing plates were as follows: Z ⁇ > 0.5, S:B > 3, %CV (no inhibition control) ⁇ 15.
- the formula used to calculate Z ⁇ is: where ⁇ denotes the mean; ⁇ denotes the standard deviation; p denotes the positive control; and n denotes the negative control.
- IDBS XLfit model 300
- the reaction mixture was stirred at room temperature for 16 h, then filtered through a pad of Celite®. The filtrate was washed with brine (300 mL). The organic layer was separated and dried over anhydrous sodium sulfate, then concentrated in vacuo. The crude residue was purified by column chromatography (silica, 100-200 mesh, 40% EtOAc in hexanes) to afford the title compound (7.50 g, 70%) as a yellow liquid.
- reaction mixture was stirred at r.t. for 4 h, then diluted with ice-cold water (50 mL) and extracted with EtOAc (2 x 20 mL). The organic layer was separated and washed with brine (20 mL), then dried over Na 2 SO 4 and concentrated in vacuo to afford a dark oil (7.2 g crude). A portion of the oil (6.0 g) was dissolved in THF (100 mL), and potassium tert-butoxide (1M in THF, 10.4 mL, 10.4 mmol) was added at 0°C. The reaction mixture was stirred at r.t. for 2 h, then quenched with H 2 O (300 mL) and extracted with EtOAc (2 x 100 mL).
- reaction mixture was stirred at -78°C for 1 h, then iodomethane (14.94 mL, 234.74 mmol) solution in THF (30 mL) was added at -78°C.
- the reaction mixture was stirred at r.t. for 12 h, then quenched with 1N aqueous NaOH solution, stirred for 2 h, diluted with H 2 O and extracted with EtOAc. The organic layer was separated and washed with brine, then dried over anhydrous Na 2 SO 4 and concentrated under vacuum.
- the crude residue was purified by column chromatography on silica gel (100-200 mesh size), eluting with using 20% ethyl acetate in hexane.
- Example 1 was prepared from Intermediate 9 and 4-(dimethylamino)butyric acid hydrochloride in accordance with General Method 1.
- Example 2 was prepared from Intermediate 9 and 4,4-difluorocyclohexane- carboxylic acid in accordance with General Method 2 followed by General Method 3.
- Example 3 was prepared from Intermediate 9 and adamantane-1-carboxylic acid in accordance with General Method 4 followed by General Method 3.
- Example 4 was prepared from Intermediate 9 and 3,5,7-trifluoroadamantane-1- carboxylic acid in accordance with General Method 4 followed by General Method 3.
- Example 5 was prepared from Intermediate 9 and 2-(1-adamantyl)acetic acid in accordance with General Method 4 followed by General Method 3.
- Example 6 was prepared from Intermediate 9 and bicyclo[1.1.1]pentane-1- carboxylic acid in accordance with General Method 2 followed by General Method 3.
- Example 7 was prepared from Intermediate 9 and 3,3-dimethylcyclobutane- carboxylic acid in accordance with General Method 2 followed by General Method 3.
- Example 8 was prepared from Intermediate 9 and phenylacetic acid in accordance with General Method 2.
- Example 9 was prepared from Intermediate 9 and cycloheptylacetic acid in accordance with General Method 1.
- Example 10 was prepared from Intermediate 9 and (2R)-tetrahydrofuran-2- carboxylic acid in accordance with General Method 2.
- Example 11 was prepared from Intermediate 9 and indane-2-carboxylic acid in accordance with General Method 2.
- Example 12 was prepared from Intermediate 9 and 2-indan-1-ylacetic acid in accordance with General Method 1.
- Example 13 was prepared from Intermediate 9 and rac-(1S,2S)-2-(trifluoro- methyl)cyclopropanecarboxylic acid in accordance with General Method 2.
- Example 14 was prepared from Intermediate 9 and bicyclo[3.1.0]hexane-6- carboxylic acid in accordance with General Method 1.
- Example 15 was prepared from Intermediate 9 and 2-phenylcyclopropane- carboxylic acid in accordance with General Method 2.
- Example 16 was prepared from Intermediate 9 and 2,3-dihydrobenzofuran-2- carboxylic acid in accordance with General Method 2.
- Example 17 was prepared from Intermediate 9 and (3R,3aS,6aR)-3,3a,4,5,6,6a- hexahydro-1H-cyclopenta[c]furan-3-carboxylic acid in accordance with General Method 2.
- Example 18 was prepared from Intermediate 9 and cyclobutanecarboxylic acid in accordance with General Method 2.
- Example 19 was prepared from Intermediate 9 and 2-(pyrazol-1-yl)cyclobutane- carboxylic acid in accordance with General Method 2.
- Example 20 was prepared from Intermediate 9 and cyclopentanecarboxylic acid in accordance with General Method 2.
- Example 21 was prepared from Intermediate 9 and (2S)-tetrahydrofuran-2- carboxylic acid in accordance with General Method 1.
- Example 22 was prepared from Intermediate 9 and cyclopropanecarboxylic acid in accordance with General Method 1.
- Example 23 was prepared from Intermediate 9 and 3-cyanopropanoic acid in accordance with General Method 1.
- Example 24 was prepared from Intermediate 9 and norbornane-1-carboxylic acid in accordance with General Method 1.
- Example 25 was prepared from Intermediate 9 and 6-oxaspiro[2.5]octane-2- carboxylic acid in accordance with General Method 1.
- Example 26 was prepared from Intermediate 9 and rac-(1R,6R,7R)-2-oxabicyclo- [4.1.0]heptane-7-carboxylic acid in accordance with General Method 1.
- Example 27 was prepared from Intermediate 9 and 1-cyanocyclopropane- carboxylic acid in accordance with General Method 1.
- Example 28 was prepared from Intermediate 9 and 2,2-dimethyl-5-oxo- tetrahydrofuran-3-carboxylic acid in accordance with General Method 1.
- Example 29 was prepared from Intermediate 9 and 4-methoxycyclohexane- carboxylic acid in accordance with General Method 1.
- Example 30 was prepared from Intermediate 9 and 2,2-difluoro-1-methyl- cyclopropanecarboxylic acid in accordance with General Method 1.
- Example 31 was prepared from Intermediate 9 and cyclohex-3-ene-1-carboxylic acid in accordance with General Method 1.
- Example 32 was prepared from Intermediate 9 and 7,7-dimethyl-2-oxo- norbornane-1-carboxylic acid in accordance with General Method 1.
- Example 33 was prepared from Intermediate 9 and 2-(3-furyl)acetic acid in accordance with General Method 1.
- Example 34 was prepared from Intermediate 9 and rac-(1R,5R)-3-oxabicyclo- [3.1.0]hexane-1-carboxylic acid in accordance with General Method 1.
- Example 35 was prepared from Intermediate 9 and 4,4-difluoro-1-methyl- cyclohexanecarboxylic acid in accordance with General Method 4 followed by General Method 3.
- Example 36 was prepared from Intermediate 9 and Intermediate 11 in accordance with General Method 2.
- Example 37 was prepared from Intermediate 40 and 3-fluorobicyclo[1.1.1]- pentane-1-carboxylic acid in accordance with General Method 2 followed by General Method 3.
- Example 38 was prepared from Intermediate 48 and 3-fluorobicyclo[1.1.1]- pentane-1-carboxylic acid in accordance with General Method 2 followed by General Method 3.
- Example 39 was prepared from Intermediate 42 and 3-(trifluoromethyl)bicyclo- [1.1.1]pentane-1-carboxylic acid in accordance with General Method 2 followed by General Method 3.
- Example 40 was prepared from Intermediate 42 and 3-fluorobicyclo[1.1.1]- pentane-1-carboxylic acid in accordance with General Method 2 followed by General Method 3.
- Example 41 was prepared from Intermediate 42 and 3-chlorobicyclo[1.1.1]- pentane-1-carboxylic acid in accordance with General Method 2 followed by General Method 3.
- Example 42 was prepared from Intermediate 33 and 3-hydroxyadamantane-1- carboxylic acid in accordance with General Method 5 followed by General Method 3.
- Example 43 was prepared from Intermediate 33 and 3-fluorobicyclo[1.1.1]- pentane-1-carboxylic acid in accordance with General Method 2 followed by General Method 3.
- Example 44 was prepared from Intermediate 32 and 3-fluorobicyclo[1.1.1]- pentane-1-carboxylic acid in accordance with General Method 2 followed by General Method 3.
- Example 45 was prepared from Intermediate 21 and 3-fluorobicyclo[1.1.1]- pentane-1-carboxylic acid in accordance with General Method 2 followed by General Method 3.
- Example 46 was prepared from Intermediate 9 and Intermediate 53 in accordance with General Method 1 followed by General Method 3.
- Example 47 was prepared from Intermediate 45 and 3-chlorobicyclo[1.1.1]- pentane-1-carboxylic acid in accordance with General Method 2 followed by General Method 3.
- Example 48 was prepared from Intermediate 51 and 3-chlorobicyclo[1.1.1]- pentane-1-carboxylic acid in accordance with General Method 2 followed by General Method 3.
- Example 49 was prepared from Intermediate 14 and 3-hydroxyadamantane-1- carboxylic acid in accordance with General Method 5 followed by General Method 3.
- Example 50 was prepared from Intermediate 14 and 3-chlorobicyclo[1.1.1]- pentane-1-carboxylic acid in accordance with General Method 2 followed by General Method 3.
- Example 51 was prepared from Intermediate 9 and 3-(trifluoromethyl)- adamantane-1-carboxylic acid in accordance with General Method 1 followed by General Method 3.
- Example 52 was prepared from Intermediate 9 and tricyclo[3.3.1.0 3,7 ]nonane-3- carboxylic acid in accordance with General Method 1 followed by General Method 3.
- Example 53 was prepared from Intermediate 9 and 2,2-dimethyltetrahydropyran- 4-carboxylic acid in accordance with General Method 1 followed by General Method 3.
- Example 54 was prepared from Intermediate 9 and 3-tert-butylbicyclo[1.1.1]- pentane-1-carboxylic acid in accordance with General Method 6.
- Example 55 was prepared from Intermediate 9 and 3-methoxybicyclo[1.1.1]- pentane-1-carboxylic acid in accordance with General Method 6.
- Example 56 was prepared from Intermediate 9 and 3,3-difluoro-1-methyl- cyclobutanecarboxylic acid in accordance with General Method 6.
- Example 57 was prepared from Intermediate 9 and 2,2,3,3-tetramethyl- cyclopropanecarboxylic acid in accordance with General Method 2 followed by General Method 3.
- Example 58 was prepared from Intermediate 9 and cubane-1-carboxylic acid in accordance with General Method 2 followed by General Method 3.
- Example 59 was prepared from Intermediate 14 and 3,5,7-trifluoroadamantane-1- carboxylic acid in accordance with General Method 2 followed by General Method 3.
- Example 60 was prepared from Intermediate 9 and 3-hydroxyadamantane-1- carboxylic acid in accordance with General Method 5 followed by General Method 3.
- Example 61 was prepared from Intermediate 9 and 5,5-difluoro-2-methyl- tetrahydropyran-2-carboxylic acid in accordance with General Method 1.
- Example 62 was prepared from Intermediate 9 and 3-fluorobicyclo[1.1.1]- pentane-1-carboxylic acid in accordance with General Method 2 followed by General Method 3.
- Example 63 was prepared from Intermediate 9 and 4,4-difluoroadamantane-1- carboxylic acid in accordance with General Method 2 followed by General Method 3.
- Example 64 was prepared from Intermediate 9 and 3-chlorobicyclo[1.1.1]- pentane-1-carboxylic acid in accordance with General Method 6.
- Example 65 was prepared from Intermediate 9 and 3-(trifluoromethyl)bicyclo- [1.1.1]pentane-1-carboxylic acid in accordance with General Method 2 followed by General Method 3.
- Example 66 was prepared from Intermediate 32 and 3-hydroxyadamantane-1- carboxylic acid in accordance with General Method 5 followed by General Method 3.
- Example 67 was prepared from Intermediate 14 and 3-fluorobicyclo[1.1.1]- pentane-1-carboxylic acid in accordance with General Method 2 followed by General Method 3.
- Example 68 was prepared from Intermediate 9 and bicyclo[2.1.1]hexane-1- carboxylic acid in accordance with General Method 1.
- Example 69 was prepared from Intermediate 9 and 4-(trifluoromethyl)-2-oxa- bicyclo[2.1.1]hexane-1-carboxylic acid in accordance with General Method 1.
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Abstract
L'invention concerne des dérivés de 2-imino-hexahydropyrimidine-4-one de formule (I) qui sont des inhibiteurs puissants de la croissance et de la propagation du parasite Plasmodium falciparum dans le sang humain et donc utiles pour le traitement du paludisme.
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WO2023152042A1 (fr) | 2022-02-08 | 2023-08-17 | UCB Biopharma SRL | Analogues d'hexahydropyrimidine antipaludiques |
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- 2020-07-10 GB GBGB2010606.8A patent/GB202010606D0/en not_active Ceased
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