NO890521L - SUBSTITUTED PYRIMIDINES. - Google Patents
SUBSTITUTED PYRIMIDINES.Info
- Publication number
- NO890521L NO890521L NO89890521A NO890521A NO890521L NO 890521 L NO890521 L NO 890521L NO 89890521 A NO89890521 A NO 89890521A NO 890521 A NO890521 A NO 890521A NO 890521 L NO890521 L NO 890521L
- Authority
- NO
- Norway
- Prior art keywords
- substituted
- aryl
- formula
- trifluoromethyl
- alkyl
- Prior art date
Links
- 150000003230 pyrimidines Chemical class 0.000 title claims description 23
- 238000002360 preparation method Methods 0.000 claims abstract description 11
- -1 dialkylsulfamoyl Chemical group 0.000 claims description 170
- 125000000217 alkyl group Chemical group 0.000 claims description 81
- 125000003118 aryl group Chemical group 0.000 claims description 81
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 71
- 125000003545 alkoxy group Chemical group 0.000 claims description 65
- 125000004414 alkyl thio group Chemical group 0.000 claims description 59
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 58
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 56
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 46
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 43
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 42
- 229910052736 halogen Inorganic materials 0.000 claims description 41
- 150000002367 halogens Chemical group 0.000 claims description 41
- 125000005110 aryl thio group Chemical group 0.000 claims description 39
- 125000004104 aryloxy group Chemical group 0.000 claims description 39
- 125000001072 heteroaryl group Chemical group 0.000 claims description 37
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 37
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 36
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 36
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 34
- 239000000460 chlorine Chemical group 0.000 claims description 34
- 229910052801 chlorine Inorganic materials 0.000 claims description 34
- 125000005034 trifluormethylthio group Chemical group FC(S*)(F)F 0.000 claims description 34
- 125000004659 aryl alkyl thio group Chemical group 0.000 claims description 32
- 229910052731 fluorine Inorganic materials 0.000 claims description 30
- 239000011737 fluorine Substances 0.000 claims description 30
- 238000000034 method Methods 0.000 claims description 28
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 25
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 25
- 229910052794 bromium Inorganic materials 0.000 claims description 25
- 229910052739 hydrogen Inorganic materials 0.000 claims description 23
- 239000001257 hydrogen Substances 0.000 claims description 23
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 22
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 21
- 125000005140 aralkylsulfonyl group Chemical group 0.000 claims description 21
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 21
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 20
- 125000005117 dialkylcarbamoyl group Chemical group 0.000 claims description 20
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 20
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 19
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 19
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 18
- 125000004076 pyridyl group Chemical group 0.000 claims description 17
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 17
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 16
- 125000002252 acyl group Chemical group 0.000 claims description 16
- 150000001299 aldehydes Chemical class 0.000 claims description 16
- 125000001153 fluoro group Chemical group F* 0.000 claims description 15
- 125000002541 furyl group Chemical group 0.000 claims description 15
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 15
- 125000005493 quinolyl group Chemical group 0.000 claims description 15
- 125000001544 thienyl group Chemical group 0.000 claims description 15
- 150000002431 hydrogen Chemical class 0.000 claims description 14
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims description 14
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 13
- 125000004744 butyloxycarbonyl group Chemical group 0.000 claims description 13
- 150000002596 lactones Chemical class 0.000 claims description 13
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 13
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 13
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 12
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 11
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 11
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 11
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 11
- 125000006125 ethylsulfonyl group Chemical group 0.000 claims description 11
- 125000005929 isobutyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])OC(*)=O 0.000 claims description 11
- 150000002576 ketones Chemical class 0.000 claims description 11
- 125000002971 oxazolyl group Chemical group 0.000 claims description 11
- 239000011734 sodium Substances 0.000 claims description 11
- 125000000335 thiazolyl group Chemical group 0.000 claims description 11
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 10
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 10
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 10
- 239000012442 inert solvent Substances 0.000 claims description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 9
- 125000001041 indolyl group Chemical group 0.000 claims description 9
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 claims description 9
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 9
- 125000004742 propyloxycarbonyl group Chemical group 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- 150000001735 carboxylic acids Chemical class 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 8
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 8
- 150000007513 acids Chemical class 0.000 claims description 7
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 7
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 7
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 7
- 150000001768 cations Chemical class 0.000 claims description 7
- 125000002883 imidazolyl group Chemical group 0.000 claims description 7
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 7
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 7
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 7
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 7
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 6
- 229910052708 sodium Inorganic materials 0.000 claims description 6
- 239000012312 sodium hydride Substances 0.000 claims description 6
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 claims description 5
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 claims description 5
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 125000001624 naphthyl group Chemical group 0.000 claims description 5
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 5
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 claims description 5
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 5
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 5
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 4
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 4
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 claims description 4
- 239000011591 potassium Substances 0.000 claims description 4
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 3
- 239000011575 calcium Substances 0.000 claims description 3
- 229910052791 calcium Inorganic materials 0.000 claims description 3
- 125000004672 ethylcarbonyl group Chemical group [H]C([H])([H])C([H])([H])C(*)=O 0.000 claims description 3
- 239000011777 magnesium Substances 0.000 claims description 3
- 229910052749 magnesium Inorganic materials 0.000 claims description 3
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical class C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 2
- 239000005977 Ethylene Substances 0.000 claims description 2
- 229940079593 drug Drugs 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- MUMHLNVTWIKASW-UHFFFAOYSA-N benzyl hypofluorite Chemical compound FOCC1=CC=CC=C1 MUMHLNVTWIKASW-UHFFFAOYSA-N 0.000 claims 1
- 150000004677 hydrates Chemical class 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 45
- 230000000694 effects Effects 0.000 abstract description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 39
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 38
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 31
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- 238000005160 1H NMR spectroscopy Methods 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- 239000002904 solvent Substances 0.000 description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 239000000203 mixture Substances 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 14
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 13
- 235000019441 ethanol Nutrition 0.000 description 12
- 150000002430 hydrocarbons Chemical group 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 239000003960 organic solvent Substances 0.000 description 9
- 235000015424 sodium Nutrition 0.000 description 9
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 8
- 150000002170 ethers Chemical class 0.000 description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Inorganic materials [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 8
- 238000007127 saponification reaction Methods 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 102100029077 3-hydroxy-3-methylglutaryl-coenzyme A reductase Human genes 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 5
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 5
- 229960000583 acetic acid Drugs 0.000 description 5
- 239000003513 alkali Substances 0.000 description 5
- 239000000969 carrier Substances 0.000 description 5
- 239000003638 chemical reducing agent Substances 0.000 description 5
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 5
- 229930195733 hydrocarbon Natural products 0.000 description 5
- 238000006798 ring closing metathesis reaction Methods 0.000 description 5
- 229910052717 sulfur Inorganic materials 0.000 description 5
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 5
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 5
- 239000008096 xylene Substances 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- 125000001931 aliphatic group Chemical group 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 150000001718 carbodiimides Chemical class 0.000 description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
- 150000002168 ethanoic acid esters Chemical class 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 229910052987 metal hydride Inorganic materials 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 235000011121 sodium hydroxide Nutrition 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- CABVTRNMFUVUDM-VRHQGPGLSA-N (3S)-3-hydroxy-3-methylglutaryl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C[C@@](O)(CC(O)=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 CABVTRNMFUVUDM-VRHQGPGLSA-N 0.000 description 3
- 241000282472 Canis lupus familiaris Species 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 108090000895 Hydroxymethylglutaryl CoA Reductases Proteins 0.000 description 3
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 3
- WGLPBDUCMAPZCE-UHFFFAOYSA-N Trioxochromium Chemical compound O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 229950005499 carbon tetrachloride Drugs 0.000 description 3
- 229960001701 chloroform Drugs 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 3
- 239000012280 lithium aluminium hydride Substances 0.000 description 3
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 3
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 description 3
- 150000004681 metal hydrides Chemical class 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 125000004430 oxygen atom Chemical group O* 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000001632 sodium acetate Substances 0.000 description 3
- 235000017281 sodium acetate Nutrition 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 125000004434 sulfur atom Chemical group 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 3
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- 125000004185 ester group Chemical group 0.000 description 1
- WCQOBLXWLRDEQA-UHFFFAOYSA-N ethanimidamide;hydrochloride Chemical compound Cl.CC(N)=N WCQOBLXWLRDEQA-UHFFFAOYSA-N 0.000 description 1
- XRQAZXMSTPXVCD-UHFFFAOYSA-N ethyl 4-(4-fluorophenyl)-2,6-dimethyl-1,4-dihydropyrimidine-5-carboxylate Chemical compound CCOC(=O)C1=C(C)NC(C)=NC1C1=CC=C(F)C=C1 XRQAZXMSTPXVCD-UHFFFAOYSA-N 0.000 description 1
- ILJPHPVLMYMDTN-UHFFFAOYSA-N ethyl 4-(4-fluorophenyl)-2,6-dimethylpyrimidine-5-carboxylate Chemical compound CCOC(=O)C1=C(C)N=C(C)N=C1C1=CC=C(F)C=C1 ILJPHPVLMYMDTN-UHFFFAOYSA-N 0.000 description 1
- PKYAJIKGVYYYLK-UHFFFAOYSA-N ethyl 4-(4-fluorophenyl)-2-phenyl-6-propan-2-ylpyrimidine-5-carboxylate Chemical compound CCOC(=O)C1=C(C(C)C)N=C(C=2C=CC=CC=2)N=C1C1=CC=C(F)C=C1 PKYAJIKGVYYYLK-UHFFFAOYSA-N 0.000 description 1
- DVVAGJCGTFTZJN-UHFFFAOYSA-N ethyl 4-(4-fluorophenyl)-6-methyl-2-phenyl-1,4-dihydropyrimidine-5-carboxylate Chemical compound CCOC(=O)C1=C(C)N=C(C=2C=CC=CC=2)NC1C1=CC=C(F)C=C1 DVVAGJCGTFTZJN-UHFFFAOYSA-N 0.000 description 1
- RKAAEZSKIBVVGC-UHFFFAOYSA-N ethyl 4-(4-fluorophenyl)-6-methyl-2-phenylpyrimidine-5-carboxylate Chemical compound CCOC(=O)C1=C(C)N=C(C=2C=CC=CC=2)N=C1C1=CC=C(F)C=C1 RKAAEZSKIBVVGC-UHFFFAOYSA-N 0.000 description 1
- XCLDSQRVMMXWMS-UHFFFAOYSA-N ethyl 4-methyl-3-oxopentanoate Chemical compound CCOC(=O)CC(=O)C(C)C XCLDSQRVMMXWMS-UHFFFAOYSA-N 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 235000019264 food flavour enhancer Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000004362 fungal culture Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000005826 halohydrocarbons Chemical class 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 150000002440 hydroxy compounds Chemical class 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000006328 iso-butylcarbonyl group Chemical group [H]C([H])([H])C([H])(C(*)=O)C([H])([H])[H] 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 229920005610 lignin Polymers 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- HZRMTWQRDMYLNW-UHFFFAOYSA-N lithium metaborate Chemical compound [Li+].[O-]B=O HZRMTWQRDMYLNW-UHFFFAOYSA-N 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- ORVKLMUCEUFGET-BUHFOSPRSA-N methyl (e)-7-[4-(4-fluorophenyl)-2-phenyl-6-propan-2-ylpyrimidin-5-yl]-5-hydroxy-3-oxohept-6-enoate Chemical compound COC(=O)CC(=O)CC(O)\C=C\C1=C(C(C)C)N=C(C=2C=CC=CC=2)N=C1C1=CC=C(F)C=C1 ORVKLMUCEUFGET-BUHFOSPRSA-N 0.000 description 1
- LAMGLADUERXMPQ-OUKQBFOZSA-N methyl (e)-7-[4-(4-fluorophenyl)-6-methyl-2-phenylpyrimidin-5-yl]-5-hydroxy-3-oxohept-6-enoate Chemical compound COC(=O)CC(=O)CC(O)\C=C\C1=C(C)N=C(C=2C=CC=CC=2)N=C1C1=CC=C(F)C=C1 LAMGLADUERXMPQ-OUKQBFOZSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- XMSZANIMCDLNKA-UHFFFAOYSA-N methyl hypofluorite Chemical compound COF XMSZANIMCDLNKA-UHFFFAOYSA-N 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical compound [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- GCOCYGLSBKOTBU-ZHACJKMWSA-N n-[(e)-2-diethoxyphosphorylethenyl]cyclohexanamine Chemical compound CCOP(=O)(OCC)\C=C\NC1CCCCC1 GCOCYGLSBKOTBU-ZHACJKMWSA-N 0.000 description 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- 125000005186 naphthyloxy group Chemical group C1(=CC=CC2=CC=CC=C12)O* 0.000 description 1
- 125000005146 naphthylsulfonyl group Chemical group C1(=CC=CC2=CC=CC=C12)S(=O)(=O)* 0.000 description 1
- 125000005029 naphthylthio group Chemical group C1(=CC=CC2=CC=CC=C12)S* 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- QYSGYZVSCZSLHT-UHFFFAOYSA-N octafluoropropane Chemical compound FC(F)(F)C(F)(F)C(F)(F)F QYSGYZVSCZSLHT-UHFFFAOYSA-N 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 description 1
- 125000004344 phenylpropyl group Chemical group 0.000 description 1
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 239000006187 pill Substances 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
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- JVUYWILPYBCNNG-UHFFFAOYSA-N potassium;oxido(oxo)borane Chemical compound [K+].[O-]B=O JVUYWILPYBCNNG-UHFFFAOYSA-N 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000011533 pre-incubation Methods 0.000 description 1
- GVIIRWAJDFKJMJ-UHFFFAOYSA-N propan-2-yl 3-oxobutanoate Chemical compound CC(C)OC(=O)CC(C)=O GVIIRWAJDFKJMJ-UHFFFAOYSA-N 0.000 description 1
- DHGFMVMDBNLMKT-UHFFFAOYSA-N propyl 3-oxobutanoate Chemical compound CCCOC(=O)CC(C)=O DHGFMVMDBNLMKT-UHFFFAOYSA-N 0.000 description 1
- 125000004673 propylcarbonyl group Chemical group 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 239000003352 sequestering agent Substances 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- NVIFVTYDZMXWGX-UHFFFAOYSA-N sodium metaborate Chemical compound [Na+].[O-]B=O NVIFVTYDZMXWGX-UHFFFAOYSA-N 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical compound [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- YFNKIDBQEZZDLK-UHFFFAOYSA-N triglyme Chemical compound COCCOCCOCCOC YFNKIDBQEZZDLK-UHFFFAOYSA-N 0.000 description 1
- XREXPQGDOPQPAH-QKUPJAQQSA-K trisodium;[(z)-18-[1,3-bis[[(z)-12-sulfonatooxyoctadec-9-enoyl]oxy]propan-2-yloxy]-18-oxooctadec-9-en-7-yl] sulfate Chemical compound [Na+].[Na+].[Na+].CCCCCCC(OS([O-])(=O)=O)C\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CC(CCCCCC)OS([O-])(=O)=O)COC(=O)CCCCCCC\C=C/CC(CCCCCC)OS([O-])(=O)=O XREXPQGDOPQPAH-QKUPJAQQSA-K 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- PZRXQXJGIQEYOG-UHFFFAOYSA-N zinc;oxido(oxo)borane Chemical compound [Zn+2].[O-]B=O.[O-]B=O PZRXQXJGIQEYOG-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- 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
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, 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
- C07D405/06—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 linked by a carbon chain containing only aliphatic carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Diabetes (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Substituerte pyrlaldlner med formel. der. K, X og A kan ha forskjellige betydninger.Forbindelsene rapporteres å ha blant annet serum-kolesterln-senkende virkning.Forbindelsenes fremstilling beskrives.Substituted pyrlaldins of formula there. K, X and A can have different meanings. The compounds are reported to have, among other things, a serum-cholesterol-lowering effect. The preparation of the compounds is described.
Description
Foreliggende oppfinnelse angår substituerte pyrimidiner , mellomforbindelser for deres fremstilling, deres fremstilling og deres anvendelse i legemidler. The present invention relates to substituted pyrimidines, intermediate compounds for their preparation, their preparation and their use in pharmaceuticals.
Det er kjent at laktonderivater som er isolert fra sopp-kulturer er inhibitorer for 3-hydroksy-3-metyl-glutaryl-koenzym A-reduktase (HMG-CoA-reduktase) [EP-A 22 478; US-PS Lactone derivatives isolated from fungal cultures are known to be inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoA reductase) [EP-A 22 478; US PS
4 231 938]. Utover dette er også bestemte indolderivater henholdsvis pyrazolderivater inhibitorer for HMG-CoA-reduktase [EP-A 1 114 027; US-PS 4 613 610]. Det er nu funnet substituerte pyrimidiner med den generelle formel (I) 4,231,938]. In addition to this, certain indole derivatives or pyrazole derivatives are also inhibitors of HMG-CoA reductase [EP-A 1 114 027; US-PS 4,613,610]. Substituted pyrimidines with the general formula (I) have now been found
der there
R<1>- betyr cykloalkyl, ellerR<1>- means cycloalkyl, or
- betyr alkyl som kan være substituert med halogen, cyano, alkoksy, alkyltio, alkylsulfonyl, trifluormetyl, trifluormetoksy, trifluormetyltio, trifluormetylsulfonyl, alkoksykarbonyl, acyl eller en gruppe med formelen -NR4R^, der - means alkyl which may be substituted with halogen, cyano, alkoxy, alkylthio, alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfonyl, alkoxycarbonyl, acyl or a group of the formula -NR4R^, where
R<4>, r<5>- er like eller forskjellige og betyr aryl, R<4>, r<5>- are the same or different and mean aryl,
aralkyl, acyl, alkylsulfonyl eller arylsulfonyl, aralkyl, acyl, alkylsulfonyl or arylsulfonyl,
eller kan være substituert med karbamoyl, dialkylkarbamoyl, sulfamoyl, dialkylsulfamoyl, heteroaryl, aryl, aryloksy, aryltio, arylsulfonyl, aralkoksy, aralkyltio eller aralkylsulfonyl, hvorved heteroaryl- og or may be substituted with carbamoyl, dialkylcarbamoyl, sulfamoyl, dialkylsulfamoyl, heteroaryl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyloxy, aralkylthio or aralkylsulfonyl, whereby heteroaryl- and
arylrestene i de sistnevnte substituenter kan være substituert opptil tre ganger, likt eller forskjellig, med halogen, cyano, trifluormetyl, trifluormetoksy, alkyl, alkoksy, alkyltio eller alkylsulfonyl, the aryl residues in the last-mentioned substituents can be substituted up to three times, identically or differently, with halogen, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, alkylthio or alkylsulfonyl,
r<2>betyr heteroaryl som kan være substituert opptil tre ganger, likt eller forskjellig, med halogen, alkyl, alkoksy, alkyltio, alkylsulfonyl, aryl, aryloksy, aryltio, arylsulfonyl, trifluormetyl, trifluormetoksy, trifluormetyltio, alkoksykarbonyl eller med en gruppe med formelen -NR<4>R^, der R<4>og R<5>har den ovenfor angitte betydning, eller r<2>means heteroaryl which may be substituted up to three times, identically or differently, with halogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or with a group of the formula -NR<4>R^, where R<4>and R<5> have the meaning indicated above, or
R<2>- betyr aryl som kan være substituert opptil fem ganger, R<2>- means aryl which can be substituted up to five times,
likt eller forskjellig, med alkyl, alkoksy, alkyltio, alkylsulfonyl, aryl, aryloksy, aryltio, arylsulfonyl, aralkyl, aralkoksy, aralkyltio, aralkylsulfonyl, halogen, cyano, nitro, trifluormetyl, trifluormetoksy, trifluormetyltio, alkoksykarbonyl, sulfamoyl, dialkylsulfamoyl, karbamoyl, dialkylkarbamoyl eller med en gruppe med formelen -NR<4>R<5>, derR<4>ogR<5>har den ovenfor angitte betydning, the same or different, with alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyl, aralkyl, aralkylthio, aralkylsulfonyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl, sulfamoyl, dialkylsulfamoyl, carbamoyl, dialkylcarbamoyl or with a group of the formula -NR<4>R<5>, where R<4>and R<5> have the meaning indicated above,
R<3>- betyr hydrogen, ellerR<3>- means hydrogen, or
- betyr cykloalkyl, eller- means cycloalkyl, or
- betyr alkyl som kan være substituert med halogen, cyano, alkoksy, alkyltio, alkylsulfonyl, trifluormetyl, trifluormetoksy, trifluormetyltio, trifluormetylsulfonyl, alkoksykarbonyl, acyl eller en gruppe med formelen -NR<4>R<5>, der R<4>og R<5>har den ovenfor angitte betydning, - means alkyl which may be substituted with halogen, cyano, alkoxy, alkylthio, alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfonyl, alkoxycarbonyl, acyl or a group of the formula -NR<4>R<5>, where R<4>and R<5> has the meaning given above,
eller med karbamoyl, dialkylkarbamoyl, sulfamoyl, dialkylsulfamoyl, heteroaryl, aryl, aryloksy, aryltio, arylsulfonyl, aralkoksy, aralkyltio eller aralkylsulfonyl, hvorved heteroaryl- og arylrestene i de sistnevnte substituenter kan være substituert opptil tre or with carbamoyl, dialkylcarbamoyl, sulfamoyl, dialkylsulfamoyl, heteroaryl, aryl, aryloxy, arylthio, arylsulfonyl, aralkylthio, aralkylthio or aralkylsulfonyl, whereby the heteroaryl and aryl residues in the latter substituents may be substituted up to three
ganger, likt eller forskjellig, med halogen, cyano, trifluormetyl, trifluormetoksy, alkyl, alkoksy, alkyltio eller alkylsulfonyl, eller times, equally or differently, with halogen, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, alkylthio or alkylsulfonyl, or
R<3>- betyr heteroaryl som kan være substituert opptil tre ganger, likt eller forskjellig, med halogen, alkyl, alkoksy, alkyltio, alkylsulfonyl, aryl, aryloksy, aryltio, arylsulfonyl, trifluormetyl, trifluormetoksy, trifluormetyltio, alkoksykarbonyl eller med en gruppe med formelen -NR<4>R<5>, derR<4>og R<5>har den ovenfor angitte betydning, eller R<3>- means heteroaryl which may be substituted up to three times, identically or differently, with halogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl or with a group of the formula -NR<4>R<5>, where R<4>and R<5> have the above meaning, or
R<3>- betyr aryl som kan være substituert opptil fem ganger, R<3>- means aryl which can be substituted up to five times,
likt eller forskjellig, med alkyl, alkoksy, alkyltio, alkylsulfonyl, aryl, aryloksy, aryltio, arylsulfonyl, aralkyl, aralkoksy, aralkyltio, aralkylsulfonyl, halogen, cyano, nitro, trifluormetyl, trifluormetoksy, trifluormetyltio, alkoksykarbonyl, sulfamoyl, dialkylsulfamoyl, karbamoyl, dialkylkarbamoyl eller med en gruppe med formelen -NR<4>R<5>, der R<4>og R<5>har den ovenfor angitte betydning, eller the same or different, with alkyl, alkoxy, alkylthio, alkylsulfonyl, aryl, aryloxy, arylthio, arylsulfonyl, aralkyl, aralkyl, aralkylthio, aralkylsulfonyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkoxycarbonyl, sulfamoyl, dialkylsulfamoyl, carbamoyl, dialkylcarbamoyl or with a group of the formula -NR<4>R<5>, where R<4>and R<5> have the above meaning, or
R<3>- betyr alkoksy, aryloksy, aralkoksy, alkyltio, aryltio, R<3>- means alkoxy, aryloxy, aralkyloxy, alkylthio, arylthio,
aralkyltio eller en gruppe med formelen -NR<4>R^, der R<4>og r<5>har den ovenfor angitte betydning, aralkylthio or a group with the formula -NR<4>R^, where R<4> and r<5> have the meaning indicated above,
X - betyr en gruppe med formelen -CH2-CH2- eller -CH=CH- og A - betyr en gruppe med formelen X - means a group with the formula -CH2-CH2- or -CH=CH- and A - means a group with the formula
der there
r<6>- betyr hydrogen eller alkyl og r<6>- means hydrogen or alkyl and
R<7>- betyr hydrogen,R<7>- means hydrogen,
- en alkyl-, aryl- eller aralkylrest, eller- an alkyl, aryl or aralkyl residue, or
- betyr et kation.- means a cation.
Overraskende viser oppfinnelsens substituerte pyrimidiner en god inhibitorisk virkning på HMG-CoA-reduktase (3-hydroksy-3-metylglutaryl-koenzym-A-reduktase). Surprisingly, the substituted pyrimidines of the invention show a good inhibitory effect on HMG-CoA reductase (3-hydroxy-3-methylglutaryl-coenzyme-A-reductase).
C<y>kloalk<y>l betyr generelt en cyklisk hydrokarbonrest med 3 til 8 karbonatomer. Foretrukket er cyklopropyl-, cyklopentyl-og cykloheksylringen. Som eksempler skal nevnes cyklopropyl, cyklopentyl, cykloheksyl, cykloheptyl og cyklooktyl. C<y>chloalk<y>l generally means a cyclic hydrocarbon residue of 3 to 8 carbon atoms. Preferred are the cyclopropyl, cyclopentyl and cyclohexyl rings. Examples include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
Alkyl betyr generelt en rettkjedet eller forgrenet hydrokarbonrest med 1 til 12 karbonatomer og foretrukket er lavalkyl med 1 til ca. 6 karbonatomer. Som eksempler skal nevnes metyl, etyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, heksyl, isoheksyl, heptyl, isoheptyl, oktyl og isooktyl. Alkyl generally means a straight-chain or branched hydrocarbon residue with 1 to 12 carbon atoms and is preferably lower alkyl with 1 to approx. 6 carbon atoms. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl, octyl and isooctyl.
Alkoksy betyr generelt en via et oksygenatom bundet rettkjedet eller forgrenet hydrokarbonrest med 1 til 12 karbonatomer. Foretrukket er lavalkoksy med 1 til ca. 6 karbonatomer. Spesielt foretrukket er en alkoksyrest med 1 til 4 karbonatomer. Som eksempel skal nevnes metoksy, etoksy, propoksy, isopropoksy, butoksy, isobutoksy, pentoksy, isopentoksy, heksoksy, isoheksoksy, heptoksy, isoheptoksy, oktoksy og isooktoksy. Alkoxy generally means a straight-chain or branched hydrocarbon residue with 1 to 12 carbon atoms attached via an oxygen atom. Preferred is low alcohol with 1 to approx. 6 carbon atoms. Particularly preferred is an carboxylic acid residue with 1 to 4 carbon atoms. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, isopentoxy, hexoxy, isohexoxy, heptoxy, isoheptoxy, octoxy and isooctoxy.
Alkyltio betyr generelt en via et svovelatom bundet rettkjedet eller forgrenet hydrokarbonrest med 1 til 12 karbonatomer. Foretrukket er lavalkyltio med 1 til ca. 6 karbonatomer. Spesielt foretrukket er en alkyltiorest med 1 til 4 karbonatomer. Som eksempler skal nevnes metyltio, etyltio, propyltio, isopropyltio, butyltio, isobutyltio, pentyltio, isopentyltio, heksyltio, isoheksyltio, heptyltio, isoheptyl-tio, oktyltio og isooktyltio. Alkylthio generally means a straight-chain or branched hydrocarbon residue with 1 to 12 carbon atoms attached via a sulfur atom. Preferred is lower alkylthio with 1 to approx. 6 carbon atoms. Particularly preferred is an alkylthio residue with 1 to 4 carbon atoms. Examples include methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, pentylthio, isopentylthio, hexylthio, isohexylthio, heptylthio, isoheptylthio, octylthio and isooctylthio.
Alk<y>lsulfonyl betyr generelt en rettkjedet eller forgrenet hydrokarbonrest med 1 til 12 karbonatomer som er bundet via en S02~gruppe. Foretrukket er lavalkylsulfonyl med 1 til ca. 6 karbonatomer. Som eksempler skal nevnes metylsulfonyl, etylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, pentylsulfonyl, isopentyl-sulfonyl, heksylsulfonyl, isoheksylsulfonyl. Alk<y>lsulfonyl generally means a straight-chain or branched hydrocarbon residue with 1 to 12 carbon atoms which is attached via a SO2~ group. Preferred is lower alkylsulfonyl with 1 to approx. 6 carbon atoms. Examples include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, pentylsulfonyl, isopentylsulfonyl, hexylsulfonyl, isohexylsulfonyl.
Ar<y>l betyr generelt en aromatisk rest med 6 til ca. 12 karbonatomer. Foretrukne arylrester er fenyl, naftyl og bifenyl. Ar<y>l generally means an aromatic residue with 6 to about 12 carbon atoms. Preferred aryl radicals are phenyl, naphthyl and biphenyl.
Aryloksy betyr generelt en aromatisk rest med 6 til ca. 12 karbonatomer som er bundet via et oksygenatom. Foretrukne aryloksyrester er fenoksy og naftyloksy. Aryloxy generally means an aromatic residue with 6 to approx. 12 carbon atoms which are bound via an oxygen atom. Preferred aryloxy radicals are phenoxy and naphthyloxy.
Ar<y>ltio betyr generelt en aromatisk rest med 6 til ca. 12 karbonatomer som er bundet via et svovelatom. Foretrukne aryltiorester er fenyltio eller naftyltio. Ar<y>ltio generally means an aromatic residue with 6 to about 12 carbon atoms which are bound via a sulfur atom. Preferred arylthio residues are phenylthio or naphthylthio.
Arylsulfonyl betyr generelt en aromatisk rest med 6 til ca. 12 karbonatomer som er bundet via en S02-gruppe. Eksempler er fenylsulfonyl, naftylsulfonyl og bifenylsulfonyl. Arylsulfonyl generally means an aromatic residue with 6 to about 12 carbon atoms which are bound via a SO2 group. Examples are phenylsulfonyl, naphthylsulfonyl and biphenylsulfonyl.
Aralk<y>l betyr generelt en via en alkylenkjede bundet arylrest med 7 til 14 karbonatomer. Foretrukket er aralkylrester med 1 til 6 karbonatomer i den alifatiske del og 6 til 12 karbonatomer i den aromatiske del. Som eksempler skal nevnes benzyl, naftylmetyl, fenetyl og fenylpropyl. Aralk<y>1 generally means an aryl residue with 7 to 14 carbon atoms attached via an alkylene chain. Preferred are aralkyl residues with 1 to 6 carbon atoms in the aliphatic part and 6 to 12 carbon atoms in the aromatic part. Examples include benzyl, naphthylmethyl, phenethyl and phenylpropyl.
Aralkoksy betyr generelt en aralkylrest med 7 til 14 karbonatomer hvorved alkylenkjeden er bundet via et oksygenatom. Foretrukket er aralkoksyrester med 1 til 6 karbonatomer i den alifatiske del og 6 til 12 karbonatomer i den aromatiske del. Som eksempler skal nevnes benzyloksy, naftyl-metoksy, fenetoksy og fenylpropoksy. Aralkyl generally means an aralkyl residue with 7 to 14 carbon atoms whereby the alkylene chain is bound via an oxygen atom. Aralkoc acid residues with 1 to 6 carbon atoms in the aliphatic part and 6 to 12 carbon atoms in the aromatic part are preferred. Examples include benzyloxy, naphthylmethoxy, phenethoxy and phenylpropoxy.
Aralk<y>ltio betyr generelt en aralkylrest med 7 til ca. 14 karbonatomer hvorved alkylkjeden er bundet via et svovelatom. Foretrukket er aralkyltiorester med 1 til 6 karbonatomer i den alifatiske del og 6 til 12 karbonatomer i den aromatiske del. Som eksempler skal nevnes benzyltio, naftylmetyltio, fenetyltio og fenylpropyltio. Aralk<y>ltio generally means an aralkyl residue with 7 to about 14 carbon atoms whereby the alkyl chain is bound via a sulfur atom. Preferred are aralkylthio residues with 1 to 6 carbon atoms in the aliphatic part and 6 to 12 carbon atoms in the aromatic part. Examples include benzylthio, naphthylmethylthio, phenethylthio and phenylpropylthio.
Aralkvlsulfon<y>l betyr generelt en aralkylrest med 7 til ca. 14 karbonatomer hvorved alkylresten er bundet via en S0£-kjede. Foretrukket er aralkylsulfonylrester med 1 til 6 karbonatomer i den alifatiske del og 6 til 12 karbonatomer i den aromatiske del. Som eksempler skal nevnes benzylsulfonyl, naftylmetylsulfonyl, fenetylsulfonyl og fenylpropylsulfonyl. Alkoksykarbonyl kan for eksempel beskrives ved formelen Aralkylsulfon<y>1 generally means an aralkyl radical with 7 to about 14 carbon atoms whereby the alkyl residue is bound via an S0£ chain. Preferred are aralkylsulfonyl residues with 1 to 6 carbon atoms in the aliphatic part and 6 to 12 carbon atoms in the aromatic part. Examples include benzylsulfonyl, naphthylmethylsulfonyl, phenethylsulfonyl and phenylpropylsulfonyl. Alkoxycarbonyl can, for example, be described by the formula
Alkyl betyr herved en rettkjedet eller forgrenet hydrokarbonrest med 1 til 12 karbonatomer. Foretrukket er lavalkoksykarbonyl med 1 til ca. 6 karbonatomer i alkyldelen. Spesielt foretrukket er et alkoksykarbonyl med 1 til 4 karbonatomer i alkyldelen og spesielt skal nevnes metoksykarbonyl, etoksykarbonyl, propoksykarbonyl, isopropoksykarbonyl, butoksykarbonyl eller isobutoksykarbonyl. Alkyl here means a straight-chain or branched hydrocarbon residue with 1 to 12 carbon atoms. Preferred is lower alkoxycarbonyl with 1 to approx. 6 carbon atoms in the alkyl part. Particularly preferred is an alkoxycarbonyl with 1 to 4 carbon atoms in the alkyl part and particular mention should be made of methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl or isobutoxycarbonyl.
Acyl betyr generelt fenyl eller rettkjedet eller forgrenet lavalkyl med 1 til ca. 6 karbonatomer som er bundet via en karbonylgruppe. Foretrukket er fenyl- og alkylrester med opptil 4 karbonatomer. Spesielt skal nevnes benzoyl, acetyl, etylkarbonyl, propylkarbonyl, isopropylkarbonyl, butyl-karbonyl og isobutylkarbonyl. Acyl generally means phenyl or straight-chain or branched lower alkyl with 1 to about 6 carbon atoms which are bound via a carbonyl group. Preference is given to phenyl and alkyl residues with up to 4 carbon atoms. Particular mention should be made of benzoyl, acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl and isobutylcarbonyl.
Halogen betyr generelt fluor, klor, brom eller jod, foretrukket er fluor, klor og brom. Spesielt foretrukket er fluor og klor. Halogen generally means fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine and bromine. Particularly preferred are fluorine and chlorine.
Heteroaryl innenfor rammen av den ovenfor angitte definisjon betyr generelt en 5- til 6-leddet aromatisk ring som som heteroatomer kan inneholde oksygen, svovel og/eller nitrogen og som på de ytterligere aromatiske ringer kan være påkonden-sert. Foretrukket er 5- og 6-leddede aromatiske ringer som inneholder et oksygen-, et svovel- og/eller opptil to nitrogenatomer og som eventuelt er benzokondensert. Som spesielt foretrukne heteroarylrester skal nevnes tienyl, furyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, kinolyl, isokinolyl, kinazolyl, kinoksalyl, ftalazinyl, cinnolyl, tiazolyl, benzotiazolyl, isotiazolyl, oksazolyl, benzoksazolyl, isoksazolyl, imidazolyl, benzimidazolyl, pyrazolyl, indolyl og isoindolyl. Heteroaryl within the framework of the definition given above generally means a 5- to 6-membered aromatic ring which as heteroatoms can contain oxygen, sulfur and/or nitrogen and which can be condensed onto the further aromatic rings. Preferred are 5- and 6-membered aromatic rings which contain one oxygen, one sulfur and/or up to two nitrogen atoms and which are optionally benzo-condensed. Particularly preferred heteroaryl residues are thienyl, furyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, quinazolyl, quinoxalyl, phthalazinyl, cinnolyl, thiazolyl, benzothiazolyl, isothiazolyl, oxazolyl, benzoxazolyl, isoxazolyl, imidazolyl, benzimidazolyl, pyrazolyl, indolyl and isoindolyl.
Hvis R<7>er en alkyl-, aryl- eller aralkylrest danner det seg en estergruppe. If R<7> is an alkyl, aryl or aralkyl residue, an ester group is formed.
Foretrukket er fysiologisk godtagbare estre som in vivo lett hydrolyseres til en fri karboksylgruppe og en tilsvarende godtagbar alkohol. Hertil hører for eksempel alkylestre (C1_6~aryl (C^j^)» og aralkylestre (C7_1Q), fortrinnsvis lavalkylestre som benzylester. Spesielt foretrukket er metylester, etylester, propylester, benzylester. Physiologically acceptable esters are preferred which are easily hydrolyzed in vivo to a free carboxyl group and a correspondingly acceptable alcohol. These include, for example, alkyl esters (C1-6~aryl (C^j^)' and aralkyl esters (C7-1Q), preferably lower alkyl esters such as benzyl ester. Particularly preferred are methyl ester, ethyl ester, propyl ester, benzyl ester.
Hvis R<7>betyr et kation, foretrekkes spesielt et fysiologisk godtagbart metall- eller ammoniumkation. Foretrukket er herved alkali- henholdsvis jordalkalimetallkationer som for eksempel natrium-, kalium-, magnesium- eller kalsiumkationer samt aluminium- eller ammoniumkationer, videre ikke-toksiske substituerte ammoniumkationer fra aminer som dilavalkyl-aminer (Cg til ca. C^,), trilavalkylaminer (C^til ca. C5), dibenzylamin, N,N'-dibenzyletylendiamin, N-benzyl-P-fenyl-etylamin, N-metylmorfolin eller N-etylmorfolin, dihydro-abietylamin, N,N'-bis-dihydroabietyletylendiamin, N—lav-alkylpiperidin og andre aminer, som kan anvendes for dannelse av salter. If R<7> is a cation, a physiologically acceptable metal or ammonium cation is particularly preferred. Preferred here are alkali or alkaline earth metal cations such as sodium, potassium, magnesium or calcium cations as well as aluminum or ammonium cations, further non-toxic substituted ammonium cations from amines such as di-lower alkyl amines (Cg to approx. C^,), tri-lower alkyl amines ( C^ to about C5), dibenzylamine, N,N'-dibenzylethylenediamine, N-benzyl-P-phenyl-ethylamine, N-methylmorpholine or N-ethylmorpholine, dihydro-abiethylamine, N,N'-bis-dihydroabiethylethylenediamine, N— lower alkyl piperidine and other amines, which can be used to form salts.
Foretrukket er substituerte pyrimidiner med formel (I), hvori Preferred are substituted pyrimidines of formula (I), in which
r! - er cyklopropyl, cyklopentyl eller cykloheksyl ellerr! - is cyclopropyl, cyclopentyl or cyclohexyl or
- er lavalkyl som kan være substituert med fluor, klor, brom, cyano, lavalkoksy, lavalkyltio, lavalkylsulfonyl, trifluormetyl, trifluormetoksy, trifluormetylsulfonyl, lavalkoksykarbonyl, benzoyl, lavalkylkarbonyl med en gruppe med formelen -NR4R5 , der - is lower alkyl which may be substituted by fluorine, chlorine, bromine, cyano, lower alkoxy, lower alkylthio, lower alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylsulfonyl, lower alkoxycarbonyl, benzoyl, lower alkylcarbonyl with a group of the formula -NR4R5, where
R<4>og R<5>kan være like eller forskjellige og betyr lavalkyl, fenyl, benzyl, acetyl, benzoyl, fenylsulfonyl eller lavalkylsulfonyl, R<4> and R<5> can be the same or different and mean lower alkyl, phenyl, benzyl, acetyl, benzoyl, phenylsulfonyl or lower alkylsulfonyl,
eller med pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, kinolyl, isokinolyl, pyrryl, indolyl, tienyl, furyl, imidazolyl, oksazolyl, tiazolyl, fenyl, fenoksy, fenyltio, fenylsulfonyl, benzyloksy, benzyltio, benzylsulfonyl, fenyletoksy, fenyletyltio eller fenyletylsulfonyl, hvorved de nevnte heteroaryl- og arylrester kan være substituert opptil to ganger, likt eller forskjellig, med fluor, klor, brom, lavalkyl, lavalkoksy, trifluormetyl eller trifluormetoksy, or with pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, pyrryl, indolyl, thienyl, furyl, imidazolyl, oxazolyl, thiazolyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, benzyloxy, benzylthio, benzylsulfonyl, phenylethoxy, phenylethylthio or phenylethylsulfonyl, whereby they said heteroaryl and aryl residues may be substituted up to twice, identically or differently, with fluorine, chlorine, bromine, lower alkyl, lower alkoxy, trifluoromethyl or trifluoromethoxy,
R<2>- betyr tienyl, furyl, tiazolyl, isotiazolyl, oksazolyl, R<2>- means thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl,
isoksazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, kinolyl, isokinolyl, ftalazinyl, kinoksalinyl, kinazolinyl, cinnolinyl, benzotiazolyl, benzoksazolyl eller benzimidazolyl, som kan være substituert opptil to ganger, likt eller forskjellig, med fluor, klor, brom, lavalkyl, lavalkoksy, fenyl, fenoksy, trifluormetyl, trifluormetoksy eller lavalkoksykarbonyl, eller isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzothiazolyl, benzoxazolyl or benzimidazolyl, which may be substituted up to twice, identically or differently, with fluorine, chlorine, bromine , lower alkyl, lower alkoxy, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy or lower alkoxycarbonyl, or
betyr fenyl eller naftyl, som kan være substituert opptil fire ganger, likt eller forskjellig, med lavalkyl, lavalkoksy, lavalkyltio, lavalkylsulfonyl, fenyl, fenyloksy, fenyltio, fenylsulfonyl, benzyl, benzyloksy, benzyltio, benzylsulfonyl, fenetyl, fenyletoksy, fenyletyltio, fenyletylsulfonyl, fluor, means phenyl or naphthyl, which may be substituted up to four times, identically or differently, with lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfonyl, phenyl, phenyloxy, phenylthio, phenylsulfonyl, benzyl, benzyloxy, benzylthio, benzylsulfonyl, phenethyl, phenylethoxy, phenylethylthio, phenylethylsulfonyl, fluoride,
klor, brom eller cyano, trifluormetyl, trifluormetoksy, trifluormetyltio, lavalkoksykarbonyl eller med en gruppe med formelen —NR<4>R^, der R<4>og R^ har den ovenfor angitte betydning, chlorine, bromine or cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, lower alkoxycarbonyl or with a group of the formula —NR<4>R^, where R<4> and R^ have the above meaning,
R<3>- betyr hydrogen, ellerR<3>- means hydrogen, or
- betyr cyklopropyl, cyklopentyl eller cykloheksyl, eller - betyr lavalkyl som kan være substituert med fluor, klor, brom, cyano, lavalkoksy, lavalkyltio, lavalkylsulfonyl, trifluormetyl, trifluormetoksy, trifluormetylsulfonyl, lavalkoksykarbonyl, benzoyl, lavalkylkarbonyl med en gruppe med formelen -NR<4>R^, der R<4>og R^ har den ovenfor angitte betydning, - means cyclopropyl, cyclopentyl or cyclohexyl, or - means lower alkyl which may be substituted by fluorine, chlorine, bromine, cyano, lower alkoxy, lower alkylthio, lower alkylsulfonyl, trifluoromethyl, trifluoromethoxy, trifluoromethylsulfonyl, lower alkoxycarbonyl, benzoyl, lower alkylcarbonyl with a group of the formula -NR< 4>R^, where R<4>and R^ have the meaning indicated above,
eller med pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, kinolyl, isokinolyl, pyrrolyl, indolyl, tienyl, furyl, imidazolyl, oksazolyl, tiazolyl, fenyl, fenoksy, fenyltio, fenylsulfonyl, benzyloksy, benzyltio, benzylsulfonyl, fenyletoksy, fenyletyltio eller fenyletylsulfonyl, hvorved de nevnte heteroaryl- og arylrester kan være substituert opptil to ganger, likt eller forskjellig, med fluor, klor, brom, lavalkyl, lavalkoksy, trifluormetyl eller trifluormetoksy, eller or with pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, pyrrolyl, indolyl, thienyl, furyl, imidazolyl, oxazolyl, thiazolyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, benzyloxy, benzylthio, benzylsulfonyl, phenylethoxy, phenylethylthio or phenylethylsulfonyl, whereby they said heteroaryl and aryl residues may be substituted up to twice, identically or differently, by fluorine, chlorine, bromine, lower alkyl, lower alkoxy, trifluoromethyl or trifluoromethoxy, or
R<3>- betyr tienyl, furyl, tiazolyl, isotiazolyl, oksazolyl, R<3>- means thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl,
isoksazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, kinolyl, isokinolyl, ftalazinyl, kinoksalinyl, kinazolinyl, cinnolinyl, benzotiazolyl, benzoksazolyl eller benzimidazolyl, som kan være substituert opptil to ganger, likt eller forskjellig, med fluor, klor, brom, lavalkyl, lavalkoksy, fenyl, fenoksy, trifluormetyl, trifluormetoksy eller lavalkoksykarbonyl, eller isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzothiazolyl, benzoxazolyl or benzimidazolyl, which may be substituted up to twice, identically or differently, with fluorine, chlorine, bromine , lower alkyl, lower alkoxy, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy or lower alkoxycarbonyl, or
R<3>- betyr fenyl eller naftyl som kan være substituert opptil fire ganger, likt eller forskjellig, med lavalkyl, lavalkoksy, lavalkyltio, lavalkylsulfonyl, fenyl, fenyloksy, fenyltio, fenylsulfonyl, benzyl, benzyloksy, benzyltio, benzylsulfony1, fenetyl, fenyletoksy, fenyletyltio, fenyletylsulfonyl, fluor, klor, brom, cyano, trifluormetyl, trifluormetoksy, trifluormetyltio, lavalkoksykarbonyl eller med en gruppe med formelen R<3>- means phenyl or naphthyl which may be substituted up to four times, identically or differently, with lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfonyl, phenyl, phenyloxy, phenylthio, phenylsulfonyl, benzyl, benzyloxy, benzylthio, benzylsulfony1, phenethyl, phenylethoxy, phenylethylthio, phenylethylsulfonyl, fluorine, chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, lower alkoxycarbonyl or with a group of the formula
-NR<4>R<5>, derR<4>ogR<5>har den ovenfor angitte betydning, eller -NR<4>R<5>, where R<4>and R<5> have the meaning stated above, or
R<3>- betyr alkoksy, aryloksy, aralkoksy, alkyltio, aryltio, R<3>- means alkoxy, aryloxy, aralkyloxy, alkylthio, arylthio,
aralkyltio eller en gruppe med formelen -NR<4>R<5>, der R<4>og R<5>har den ovenfor angitte betydning, aralkylthio or a group with the formula -NR<4>R<5>, where R<4> and R<5> have the meaning stated above,
X - betyr en gruppe med formelen -CH2-CH2- eller -CH=CH- og A - betyr en gruppe med formelen X - means a group with the formula -CH2-CH2- or -CH=CH- and A - means a group with the formula
der there
R^ - betyr hydrogen eller lavalkyl ogR^ - means hydrogen or lower alkyl and
R<7>- betyr alkyl C^-alkyl, C6_12-aryl eller C7_1Q-aralkyl, eller - betyr et fysiologisk godtagbart kation derav. R<7>- means alkyl C1-alkyl, C6-12-aryl or C7-10-aralkyl, or - means a physiologically acceptable cation thereof.
Spesielt foretrukket er forbindelser med den generelle formel (I) der: R<1>- betyr cyklopropyl, cyklopentyl eller cykloheksyl, eller - betyr metyl, etyl, propyl, isopropyl, butyl, sek-butyl eller tert-butyl, som kan være substituert med fluor, klor, brom, cyano, metoksy, etoksy, propoksy, isopropoksy, butoksy, sek-butoksy, tert-butoksy, metyltio, etyltlo, propyltio, isopropyltio, metylsulfonyl, etylsulfonyl, propylsulfonyl, isopropylsulfonyl, trifluormetyl, trifluormetoksy, metoksykarbonyl, etoksykarbonyl, butoksykarbonyl, isobutoksykarbonyl, tert-butoksykarbonyl, benzoyl, acetyl, pyridyl, pyrimidyl, tienyl, furyl, fenyl, fenoksy, fenyltio, fenylsulfonyl, benzyloksy, benzyltio eller benzylsulfonyl, Particularly preferred are compounds of the general formula (I) where: R<1>- means cyclopropyl, cyclopentyl or cyclohexyl, or - means methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl, which may be substituted with fluorine, chlorine, bromine, cyano, methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, methylthio, ethyltlo, propylthio, isopropylthio, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, benzoyl, acetyl, pyridyl, pyrimidyl, thienyl, furyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, benzyloxy, benzylthio or benzylsulfonyl,
R<2>- betyr pyridyl, pyrimidyl, kinolyl eller isokinolyl, som kan være substituert med fluor, klor, metyl, metoksy eller trifluormetyl, eller R<2>- means pyridyl, pyrimidyl, quinolyl or isoquinolyl, which may be substituted by fluorine, chlorine, methyl, methoxy or trifluoromethyl, or
- betyr fenyl, som kan være substituert opptil tre ganger, likt eller forskjellig, med metyl, etyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, metoksy, etoksy, propoksy, isopropoksy, butoksy, isobutoksy, tert-butoksy, metyltio, etyltio, propyltio, isopropyltio, metylsulfonyl, etylsulfonyl, propylsulfonyl, isopropylsulfonyl, fenyl, fenoksy, benzyl, benzyloksy, fluor, klor, brom, cyano, trifluormetyl, trifluormetoksy, metoksykarbonyl, etoksykarbonyl, propoksykarbonyl, isopropoksykarbonyl, butoksykarbonyl, isobutoksykarbonyl eller tert-butoksykarbonyl, eller - means phenyl, which may be substituted up to three times, identically or differently, by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, methylthio , ethylthio, propylthio, isopropylthio, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, phenyl, phenoxy, benzyl, benzyloxy, fluoro, chloro, bromo, cyano, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl or tert-butoxycarbonyl , or
R<3>- betyr hydrogen, cyklopropyl, cyklopentyl eller cykloheksyl, eller R<3>- means hydrogen, cyclopropyl, cyclopentyl or cyclohexyl, or
- betyr metyl, etyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, heksyl eller isoheksyl, som kan være substituert med fluor, klor, brom, cyano, metoksy, etoksy, propoksy, isopropoksy, butoksy, isobutoksy, tert-butoksy, metyltio, etyltio, propyltio, isopropyltio, butyltio, isobutyltio, tert-butyltio, metylsulfonyl, etylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, tert-butylsulfonyl, trifluormetyl, trifluormetoksy, metoksykarbonyl, etoksykarbonyl, propoksykarbonyl, isopropoksykarbonyl, butoksykarbonyl, isobutoksykarbonyl, tert-butoksykarbonyl, benzoyl,acetyl, etylkarbonyl eller substituert med en gruppe -NR<4>R<5>, der - means methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl or isohexyl, which may be substituted with fluorine, chlorine, bromine, cyano, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy , tert-butoxy, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert-butylthio, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, tert-butylsulfonyl, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl , isobutoxycarbonyl, tert-butoxycarbonyl, benzoyl, acetyl, ethylcarbonyl or substituted with a group -NR<4>R<5>, where
R<4>og R<5>er like eller forskjellige ogR<4>and R<5>are the same or different and
betyr metyl, etyl, propyl, isopropyl, butyl, isobutyl, tert-butyl,,fenyl, benzyl, acetyl, metylsulfonyl, etylsulfonyl, propylsulfonyl, isopropylsulfonyl eller fenylsulfonyl, means methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl,,phenyl, benzyl, acetyl, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl or phenylsulfonyl,
eller med pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, kinolyl, isokinolyl, tienyl, furyl, fenyl, fenoksy, fenyltio, fenylsulfonyl, benzyloksy, benzyltio eller benzylsulfonyl, hvorved de nevnte heteroaryl- og arylrester kan være substituert med fluor, klor, metyl, etyl, propyl, isopropyl, isobutyl, tert-butyl, metoksy, etoksy, propoksy, isopropoksy, butoksy, isobutoksy, or with pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, thienyl, furyl, phenyl, phenoxy, phenylthio, phenylsulfonyl, benzyloxy, benzylthio or benzylsulfonyl, whereby the aforementioned heteroaryl and aryl residues can be substituted with fluorine, chlorine, methyl, ethyl , propyl, isopropyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,
tert-butoksy, trifluormetyl eller trifluormetoksy, eller - betyr tienyl, furyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, oksazolyl, isooksazolyl, imidazolyl, pyrazolyl, tiazolyl, isotiazolyl, kinolyl, isokinolyl, benzoksazolyl, benzimidazolyl eller benztiazolyl, hvorved de nevnte rester kan være substituert med fluor, klor, metyl, etyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, metoksy, etoksy, propoksy, isopropoksy, butoksy, isobutoksy, tert-butoksy, fenyl, fenoksy, trifluormetyl, trifluormetoksy, metoksykarbonyl, etoksykarbonyl, isopropoksykarbonyl, propoksykarbonyl, butoksykarbonyl, isobutoksykarbonyl eller tert.butoksykarbonyl , eller - betyr fenyl som kan være substituert opptil tre ganger, likt eller forskjellig, med metyl, etyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, heksyl, isoheksyl, metoksy, etoksy, propoksy, isopropoksy, butoksy, isobutoksy, tert-butoksy, metyltio, etyltio, propyltio, isopropyltio, butyltio, isobutyltio, tert-butyltio, metylsulfonyl, etylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, tert-butylsulfonyl, fenyl, fenoksy, fentyltio, fenylsulfonyl, benzyl, benzyloksy, benzyltio, benzylsulfonyl, fluor, klor, brom, cyano, trifluormetyl, tert-butoxy, trifluoromethyl or trifluoromethoxy, or - means thienyl, furyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, quinolyl, isoquinolyl, benzoxazolyl, benzimidazolyl or benzthiazolyl, whereby the said residues can be substituted with fluorine, chlorine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy, methoxycarbonyl, ethoxycarbonyl , isopropoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl or tert.butoxycarbonyl , or - means phenyl which may be substituted up to three times, identically or differently, with methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert-butylthio, me tylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, tert-butylsulfonyl, phenyl, phenoxy, phentylthio, phenylsulfonyl, benzyl, benzyloxy, benzylthio, benzylsulfonyl, fluorine, chlorine, bromine, cyano, trifluoromethyl,
trifluormetoksy, trifluormetyltio, metoksykarbonyl, etoksykarbonyl, propoksykarbonyl, isopropoksykarbonyl, butoksykarbonyl, isobutoksykarbonyl, tert-butoksykarbonyl, eller kan være substituert med en gruppe med formelen -NR<4>R^, der R<4>og R^ har den ovenfor angitte betydning, eller - betyr alkoksy, aryloksy, aralkoksy, alkyltio, aryltio, aralkyltio eller en gruppe med formelen -NR<4>R^, der R<4>og r<5>har den ovenfor angitte betydning, X - betyr en gruppe med formelen -CH2-CH2- eller -CH=CH- og A - betyr en gruppe med formelen trifluoromethoxy, trifluoromethylthio, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, or may be substituted with a group of the formula -NR<4>R^, where R<4> and R^ have the above meaning . the formula -CH2-CH2- or -CH=CH- and A - means a group with the formula
der there
R^ - betyr hydrogen, metyl, etyl, propyl, isopropyl, R^ - means hydrogen, methyl, ethyl, propyl, isopropyl,
butyl, isobutyl eller tert-butyl, ogbutyl, isobutyl or tert-butyl, and
R<7>- betyr hydrogen, metyl, etyl, propyl, isopropyl, R<7>- means hydrogen, methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, tert-butyl eller benzyl, eller et natrium-, kalium-, kalsium- eller magnesium- eller ammoniumion. butyl, isobutyl, tert-butyl or benzyl, or a sodium, potassium, calcium or magnesium or ammonium ion.
Oppfinnelsens substituerte pyrimidiner med den generelle formel (I) har flere asymmetriske karbonatomer og kan derfor foreligge i flere stereokjemiske former. Både de enkelte isomerer og deres blandinger er gjenstander for oppfinnelsen. The substituted pyrimidines of the invention with the general formula (I) have several asymmetric carbon atoms and can therefore exist in several stereochemical forms. Both the individual isomers and their mixtures are objects of the invention.
Alt etter betydningen av gruppen X henholdsvis resten A gir det seg forskjellige stereoisomerer som skal forklares nærmere nedenfor: Depending on the meaning of the group X or the residue A, different stereoisomers result, which will be explained in more detail below:
a) Hvis gruppen -X- betyr en gruppe med formelen -CH=CH-, kan oppfinnelsens forbindelser foreligge i to stereoisomere former som på dobbeltbindingen er E-konfigurert (II) eller Z-konfigurert (III) a) If the group -X- means a group with the formula -CH=CH-, the compounds of the invention can exist in two stereoisomeric forms which on the double bond are E-configured (II) or Z-configured (III)
Foretrukket er de forbindelser med den generelle formel (I) som er E-konfigurert (II). Preferred are those compounds of the general formula (I) which are E-configured (II).
b) Betyr resten -A- for en gruppe med formelenb) Denote the remainder -A- for a group with the formula
har forbindelsene med den generelle formel (I) minst to asymmetriske karbonatomer, nemlig de to karbonatomer på hvilke hydroksygruppene er bundet. Alt etter den relative stilling til disse hydroksygrupper i forhold til hver-andre kan oppfinnelsens forbindelser foreligge i erytro-konfigurasjon (IV) eller i treo-konfigurasjon (V) the compounds with the general formula (I) have at least two asymmetric carbon atoms, namely the two carbon atoms to which the hydroxy groups are attached. Depending on the relative position of these hydroxy groups in relation to each other, the compounds of the invention can exist in erythro-configuration (IV) or in threo-configuration (V)
Både av forbindelsene i erytro- som i treo-konfigurasjonen foreligger det i sin tur nok to enantiomerer, nemlig 3R,5S-isomerer henholdsvis 3S,5R-isomerer (erytro-form) som 3R,5R-isomerer og 3S,5S-isomerer (treo-form). Of the compounds in both the erythro and threo configurations, there are in turn two enantiomers, namely 3R,5S isomers respectively 3S,5R isomers (erythro form) such as 3R,5R isomers and 3S,5S isomers ( treo form).
Foretrukket er herved de erytro-konfigurerte isomerer, spesielt foretrukket er 3R,5S-isomeren samt 3R,5S-3S,5R-racematet. Preference is hereby given to the erythro-configured isomers, particularly preferred is the 3R,5S isomer and the 3R,5S-3S,5R racemate.
c) Betyr resten -A- en gruppe med formelenc) Does the residue -A- mean a group with the formula
har de substituerte pyrimidiner minst to asymmetriske karbonatomer, nemlig karbonatomet på hvilket hydroksygruppen er bundet og karbonatomet på hvilket resten med formelen er bundet. Alt etter stillingen av hydroksygruppen til den frie valens på laktonringen kan de substituerte pyrimidiner foreligge som cis-laktoner (VI) eller som trans-laktoner (VII). the substituted pyrimidines have at least two asymmetric carbon atoms, namely the carbon atom to which the hydroxy group is attached and the carbon atom to which the residue with the formula is attached. Depending on the position of the hydroxy group of the free valence on the lactone ring, the substituted pyrimidines can exist as cis-lactones (VI) or as trans-lactones (VII).
Både av cis-laktonet og trans-laktonet foreligger det i sin tur nok to isomerer, nemlig 4R,6R-isomeren henholdsvis 4S,6S-isomeren (cis-lakton) og 4R,6S-isomeren henholdsvis 4S,6R-isomeren (trans-lakton). Foretrukne isomerer er trans-laktonene. Spesielt foretrukket er herved 4R,6S-isomeren (trans) samt 4R,6S-4S,6R-racematet. Of both the cis-lactone and the trans-lactone, there are in turn two isomers, namely the 4R,6R-isomer respectively the 4S,6S-isomer (cis-lactone) and the 4R,6S-isomer respectively the 4S,6R-isomer (trans- lactone). Preferred isomers are the trans-lactones. Particular preference is hereby given to the 4R,6S isomer (trans) and the 4R,6S-4S,6R racemate.
Eksempelvis skal nevnes følgende isomere former av de substituerte pyrimidiner: For example, the following isomeric forms of the substituted pyrimidines should be mentioned:
Spesielt foretrukket er forbindelsene med den generelle formel (I) der Particularly preferred are the compounds of the general formula (I) there
R<1>- betyr cyklopropyl, metyl, etyl, propyl, isopropyl, R<1>- means cyclopropyl, methyl, ethyl, propyl, isopropyl,
butyl, isobutyl eller tert-butyl,butyl, isobutyl or tert-butyl,
R<2>- betyr fenyl, som kan være substituert opptil to ganger, R<2>- means phenyl, which may be substituted up to twice,
likt eller forskjellig, med metyl, metoksy, fenoksy, fluor, klor eller trifluormetyl, the same or different, with methyl, methoxy, phenoxy, fluorine, chlorine or trifluoromethyl,
R<3>- betyr metyl, isopropyl, tert-butyl ellerR<3>- means methyl, isopropyl, tert-butyl or
- betyr fenyl, som kan være substituert opptil to ganger, likt eller forskjellig, med metyl, metoksy, fluor eller klor, 18 - means phenyl, which may be substituted up to twice, identically or differently, by methyl, methoxy, fluorine or chlorine, 18
X - betyr en gruppe med formelen X - means a group with the formula
(E-konfigurert) og A - betyr en gruppe med formelen (E-configured) and A - means a group with the formula
der there
R<k>_ betyr hydrogen ogR<k>_ means hydrogen and
R<7>- betyr hydrogen, metyl eller etyl ellerR<7>- means hydrogen, methyl or ethyl or
betyr et natrium- eller kaliumkation.means a sodium or potassium cation.
I tillegg er det funnet en fremgangsmåte for fremstilling av de substituerte pyrimidiner med den generelle formel (I) In addition, a method has been found for the preparation of the substituted pyrimidines with the general formula (I)
der there
R<*>, R<2>, R<3>, X og A har den ovenfor angitte betydning, og denne fremgangsmåte karakteriseres ved at man reduserer ketoner med den generelle formel (VIII) R<*>, R<2>, R<3>, X and A have the above meaning, and this method is characterized by reducing ketones with the general formula (VIII)
der there
R<1>,R<2>og R<3>har den ovenfor angitte betydning og R<7>' - betyr alkyl, aryl eller aralkyl, R<1>, R<2> and R<3> have the above meaning and R<7>' - means alkyl, aryl or aralkyl,
forsåper estrene for fremstilling av syrene,saponifies the esters to produce the acids,
ringslutter karboksyl syrene for fremstilling av laktonene, ring-closes the carboxylic acids to produce the lactones,
forsåper estrene eller laktonene for fremstilling av saltene, saponifies the esters or lactones to produce the salts,
hydrerer etter vanlige metoder etenforbindelsene (X = -CH=CH-) for fremstilling av etylenforbindelsen (X = -CH2-CH2-) og hydrogenates according to usual methods the ethylene compounds (X = -CH=CH-) to produce the ethylene compound (X = -CH2-CH2-) and
eventuelt separerer isomerene.optionally separates the isomers.
Oppfinnelsens fremgangsmåte kan forklares ved følgende formelskjema: The method of the invention can be explained by the following formula:
Reduksjonen kan gjennomføres med de vanlige reduksjonsmidler og fortrinnsvis med slike som er egnet for reduksjon av ketoner til hydroksyforbindelser. Spesielt egnet er herved reduksjon med metallhydrider eller komplekse metallhydrider i inerte oppløsningsmidler, eventuelt i nærvær av et trialkyl-boran. Foretrukket er reduksjonen med komplekse metallhydrider som for eksempel litiumboranat, natriumboranat, kaliumboranat, sinkboranat, litiumtrialkylhydridoborater , natriumtrialkylhydridoboranater, natriumcyanotrihydridoborat eller litiumaluminiumhydrid. Spesielt foretrukket er reduksjon med natriumborhydrid i nærvær av trietylboran. The reduction can be carried out with the usual reducing agents and preferably with those which are suitable for the reduction of ketones to hydroxy compounds. Particularly suitable is reduction with metal hydrides or complex metal hydrides in inert solvents, possibly in the presence of a trialkyl borane. The reduction with complex metal hydrides such as lithium boranate, sodium boranate, potassium boranate, zinc boranate, lithium trialkylhydridoborates, sodium trialkylhydridoborates, sodium cyanotrihydridoborate or lithium aluminum hydride is preferred. Particularly preferred is reduction with sodium borohydride in the presence of triethylborane.
Som oppløsningsmiddel egner seg herved de vanlige organiske oppløsningsmidler som ikke endrer seg under reaksjons-betingelsene. Hertil hører fortrinnsvis etre som for eksempel dietyleter, dioksan, tetrahydrofuran eller dimetoksyetan eller halogenhydrokarboner som for eksempel diklormetan, triklormetan, tetraklormetan, 1,2-dikloretan eller hydrokarboner som for eksempel benzen, toluen, eller xylen. Likeledes er det mulig å anvende blandinger av de nevnte oppløsningsmidler. Suitable solvents are the usual organic solvents which do not change under the reaction conditions. These preferably include ethers such as diethyl ether, dioxane, tetrahydrofuran or dimethoxyethane or halohydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane or hydrocarbons such as benzene, toluene or xylene. Likewise, it is possible to use mixtures of the mentioned solvents.
Spesielt foretrukket er det å gjennomføre reduksjonen av ketongruppen til hydroksygruppe under betingelser der de øvrige funksjonelle grupper som for eksempel alkoksykarbonyl-gruppen ikke endres. Spesielt egnet for dette formål er anvendelse av natriumborhydrid som reduksjonsmiddel i nærvær av trietylboran i et inert oppløsningsmiddel som fortrinnsvis etre. It is particularly preferred to carry out the reduction of the ketone group to a hydroxy group under conditions where the other functional groups, such as the alkoxycarbonyl group for example, are not changed. Particularly suitable for this purpose is the use of sodium borohydride as reducing agent in the presence of triethylborane in an inert solvent such as preferably ether.
Reduksjonen skjer generelt i et temperaturområde fra —80°C til romtemperatur, altså ca. 30°C, helst fra -78" C til CC. The reduction generally takes place in a temperature range from -80°C to room temperature, i.e. approx. 30°C, preferably from -78" C to CC.
Oppfinnelsens fremgangsmåte gjennomføres vanligvis ved vanlig trykk. Det er imidlertid også mulig å gjennomføre fremgangsmåten ved undertrykk eller overtrykk (for eksempel i et område fra 0,5 til 5 bar). The method of the invention is usually carried out by ordinary pressure. However, it is also possible to carry out the method under negative or positive pressure (for example in a range from 0.5 to 5 bar).
Generelt blir reduksjonsmidlet anvendt i en mengde av 1 til 2 mol og fortrinnsvis 1 til 1,5 mol, beregnet på 1 mol keto-forbindelse. In general, the reducing agent is used in an amount of 1 to 2 mol and preferably 1 to 1.5 mol, calculated on 1 mol of keto compound.
Blant de ovenfor angitte reaksjonsbetingelser blir karbonylgruppen redusert til hydroksygruppe uten at det skjer noen reduksjon av dobbeltbindingen til enkeltbinding. Among the reaction conditions stated above, the carbonyl group is reduced to a hydroxy group without any reduction of the double bond to a single bond.
For fremstilling av forbindelser med den generelle formel (I), der X betyr en etylengruppering, kan reduksjonen av ketonene (III) skje under slike betingelser der både karbonylgruppen og dobbeltbindingen blir redusert. For the preparation of compounds of the general formula (I), where X means an ethylene group, the reduction of the ketones (III) can take place under such conditions where both the carbonyl group and the double bond are reduced.
Utover dette er det også mulig å gjennomføre reduksjonen av karbonylgruppen og reduksjonen av dobbeltbindingen i to separate trinn. In addition to this, it is also possible to carry out the reduction of the carbonyl group and the reduction of the double bond in two separate steps.
Karboksylsyren innenfor rammen av den generelle formel (I) tilsvarer formel (Ic) The carboxylic acid within the framework of the general formula (I) corresponds to formula (Ic)
Karboksylsyreesteren innenfor rammen av formel (I) tilsvarer formelen (Id) Saltene av oppfinnelsens forbindelser innenfor rammen av den generelle formel (I) tilsvarer formel (le) The carboxylic acid ester within the framework of formula (I) corresponds to the formula (Id) The salts of the compounds of the invention within the framework of the general formula (I) correspond to formula (le)
hvori in which
M<n+>betyr et kation, med valensen n. Den foretrukne valens M<n+>means a cation, with valence n. The preferred valence
er 1 eller 2.is 1 or 2.
Laktonene innenfor rammen av den generelle formel (I) tilsvarer formel (If) The lactones within the framework of the general formula (I) correspond to formula (If)
For fremstilling av oppfinnelsens karboksyl syrer med den generelle formel (Ic) forsåpes generelt karboksylsyreestrene med den generelle formel (Id) eller laktonet med den generelle formel (If) i henhold til kjente metoder. Forsåpningen skjer generelt idet esteren eller laktonet behandles i inerte oppløsningsmidler med vanlige baser, hvorved i alminnelighet først oppstår salter med den generelle formel (le) som så deretter i et andre trinn kan overføres til de frie syrer med den generelle formel (Ic) ved behandling med syre. For the production of the carboxylic acids of the invention with the general formula (Ic), the carboxylic acid esters with the general formula (Id) or the lactone with the general formula (If) are generally saponified according to known methods. The saponification generally occurs when the ester or lactone is treated in inert solvents with common bases, whereby salts with the general formula (le) are generally first formed, which can then in a second step be transferred to the free acids with the general formula (Ic) by treatment with acid.
Som base egner seg for forsåpningen de vanlige uorganiske baser. Hertil hører fortrinnsvis alkali- eller jordalkali-hydroksyder som for eksempel natrium-, kalium- eller bariumhydroksyd, eller alkalikarbonater som natrium- eller kaliumkarbonat, eller natriumhydrogenkarbonatet, eller alkalialkoholater som natriumetanolat, natriummetanolat, kaliummetanolat, kaliumetanolat eller kalium-tert-butanolat. Spesielt foretrukket anvendes natrium- eller kaliumhydroksyd. The usual inorganic bases are suitable as a base for the saponification. These preferably include alkali or alkaline earth hydroxides such as sodium, potassium or barium hydroxide, or alkali carbonates such as sodium or potassium carbonate, or sodium bicarbonate, or alkali alcoholates such as sodium ethanolate, sodium methanolate, potassium methanolate, potassium ethanolate or potassium tert-butanolate. Sodium or potassium hydroxide is particularly preferably used.
Som oppløsningsmiddel for forsåpningen egner seg vann eller de for en forsåpning vanligvis benyttede organiske oppløs-ningsmidler. Hertil hører fortrinnsvis alkoholer som metanol, etanol, propanol, isopropanol eller butanol, eller etre som tetrahydrofuran eller dioksan, eller dimetylformamid eller dimetylsulfoksyd. Spesielt foretrukket er alkoholer som metanol, etanol, propanol eller isopropanol. Likeledes er det mulig å anvende blandinger av disse oppløsningsmidler. Suitable solvents for the saponification are water or the organic solvents usually used for saponification. These preferably include alcohols such as methanol, ethanol, propanol, isopropanol or butanol, or ethers such as tetrahydrofuran or dioxane, or dimethylformamide or dimethylsulfoxide. Particularly preferred are alcohols such as methanol, ethanol, propanol or isopropanol. Likewise, it is possible to use mixtures of these solvents.
Forsåpningen skjer vanligvis ved en temperatur fra 0°C til + 10CTC, og fortrinnsvis fra +20°C til +80"C. The saponification usually takes place at a temperature from 0°C to +10°C, and preferably from +20°C to +80°C.
Generelt blir forsåpningen gjennomført ved vanlig trykk. Det er imidlertid også mulig å arbeide ved under- eller overtrykk, for eksempel fra 0,5 til 5 bar. In general, the saponification is carried out at normal pressure. However, it is also possible to work at under or over pressure, for example from 0.5 to 5 bar.
Ved gjennomføring av forsåpningen blir basen generelt anvendt i en mengde fra 1 til 3 mol og fortrinnsvis fra 1 til 1,5 mol, beregnet på 1 mol ester, henholdsvis lakton. Spesielt foretrukket er det å anvende molare mengder av reaktantene. Ved gjennomføring av reaksjonen oppstår i første trinn saltene av oppfinnelsens forbindelser (le) som mellom-produkter og disse kan isoleres. Oppfinnelsens syrer (Ic) oppnår man ved behandling av saltene (le) med vanlige uorganiske syrer. Hertil hører fortrinnsvis mineralsyrer som for eksempel saltsyre, bromhydrogensyre, svovelsyre eller fosforsyre. Det har ved fremstilling av karboksylsyrene (Ic) herved vist seg fordelaktig å ansure den basiske reaksjons-blanding for forsåpningen i et andre trinn uten isolering av saltene. Syrene kan så isoleres på i og for seg kjent måte. When carrying out the saponification, the base is generally used in an amount of from 1 to 3 mol and preferably from 1 to 1.5 mol, calculated on 1 mol of ester, respectively lactone. It is particularly preferred to use molar amounts of the reactants. When carrying out the reaction, the salts of the compounds of the invention (le) are produced in the first step as intermediate products and these can be isolated. The acids (Ic) of the invention are obtained by treating the salts (le) with common inorganic acids. These preferably include mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid. In the preparation of the carboxylic acids (Ic), it has proven advantageous to anacidify the basic reaction mixture for the saponification in a second step without isolating the salts. The acids can then be isolated in a manner known per se.
For fremstilling av oppfinnelsens laktoner med formel (If) blir generelt oppfinnelsens karboksylsyrer (Ic) ringsluttet i henhold til vanlige metoder, for eksempel ved oppvarming av den tilsvarende syre i inerte organiske oppløsningsmidler, eventuelt i nærvær av molekylsikt. For the production of the invention's lactones with formula (If), the invention's carboxylic acids (Ic) are generally ring-closed according to common methods, for example by heating the corresponding acid in inert organic solvents, possibly in the presence of molecular sieves.
Som oppløsningsmiddel egner seg herved hydrokarboner som benzen, toluen, xylen, jordoljefraksjoner eller tetralin eller diglym eller triglym. Spesielt anvendes benzen, toluen eller xylen. Likeledes er det mulig å benytte blandinger av de nevnte oppløsningsmidler. Spesielt foretrukket er det å anvende hydrokarboner og aller helst anvendes toluen, i nærvær av molekylsikt. Suitable solvents are hydrocarbons such as benzene, toluene, xylene, petroleum fractions or tetralin or diglyme or triglyme. In particular, benzene, toluene or xylene are used. Likewise, it is possible to use mixtures of the mentioned solvents. It is particularly preferred to use hydrocarbons and most preferably to use toluene, in the presence of molecular sieves.
Ringslutningen skjer vanligvis innen et temperaturområde fra -40°C til +200°C, fortrinnsvis fra -25°C til +50°C. Ringslutningen gjennomføres vanligvis ved vanlig trykk, men det er også mulig å gjennomføre reaksjonen ved under- eller overtrykk, for eksempel innen området 0,5 til 5 bar. The ring closure usually takes place within a temperature range from -40°C to +200°C, preferably from -25°C to +50°C. The cyclization is usually carried out at normal pressure, but it is also possible to carry out the reaction at under or over pressure, for example within the range of 0.5 to 5 bar.
Utover dette blir ringslutningen også gjennomført i inerte organiske oppløsningsmidler ved hjelp av ringsluttende henholdsvis vannavspaltende midler. Som slike tjener herved fortrinnsvis karbodiimider. Som karbodiimid foretrekkes N ,N'-dicykloheksylkarbodiimid-paratoluensulfonat, N-cykloheksyl-N'-[2-(N''-metylmorfolinium)etyl]karbodiimid eller N—(3-dimetylaminopropyl)-N'-etylkarbodi imid-hydroklorid. In addition to this, the ring closure is also carried out in inert organic solvents using ring-closing or water-splitting agents. Carbodiimides are preferably used as such. As carbodiimide, N,N'-dicyclohexylcarbodiimide-paratoluenesulfonate, N-cyclohexyl-N'-[2-(N''-methylmorpholinium)ethyl]carbodiimide or N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride are preferred.
Som oppløsningsmiddel egner seg herved de vanlige organiske oppløsningsmidler. Til disse hører fortrinnsvis etre som dietyleter, tetrahydrofuran eller dioksan, eller klorhydrokarboner som metylenklorid, kloroform eller karbontetraklorid eller hydrokarboner som benzen, toluen, xylen eller jordoljefraksjoner. Spesielt foretrukket er klorhydrokarboner som for eksempel metylenklorid, kloroform eller karbontetraklorid. Reaksjonen gjennomføres generelt innen et temperaturområde fra 0 til +80°C og helst fra +10 til +50°C. As a solvent, the usual organic solvents are suitable. These preferably include ethers such as diethyl ether, tetrahydrofuran or dioxane, or chlorinated hydrocarbons such as methylene chloride, chloroform or carbon tetrachloride or hydrocarbons such as benzene, toluene, xylene or petroleum fractions. Particularly preferred are chlorohydrocarbons such as methylene chloride, chloroform or carbon tetrachloride. The reaction is generally carried out within a temperature range from 0 to +80°C and preferably from +10 to +50°C.
Ved gjennomføring av ringslutningen har det vist seg fordelaktig å gjennomføre ringslutningsmetoden ved hjelp av karbodiimider som dehydratiserende midler. When carrying out the ring closure, it has proven advantageous to carry out the ring closure method using carbodiimides as dehydrating agents.
Separeringen av isomerene i de stereoisomere enhetlige bestanddeler skjer generelt i henhold til vanlige metoder som for eksempel beskrevet av E.L. Eliel, "Stereochemistry of Carbon Compounds", McGraw Hill, 1962. Foretrukket er herved separering av isomerene på trinnet med racemisk lakton. Spesielt foretrukket er det herved å overføre den racemiske blanding av trans-laktonet (VII) ved behandling enten med D-( + )- eller L-(-)-a-metylbenzylamin i henhold til vanlige metoder til de diastereomere dihydroksyamider (lg) som så på vanlig måte ved kromatografi eller krystall isering kan separeres i de enkelte diastereomerer. Derpå følgende hydrolyse av de diastereomere amider i henhold til vanlige metoder, for eksempel ved behandling av de diastereomere amider med uorganiske baser som natriumhydroksyd eller kaliumhydroksyd i vann og/eller organiske oppløsningsmidler som alkoholer som metanol, etanol, propanol eller isopropanol, gir de tilsvarende enantiomer-rene dihydroksysyrer (Ic) som som beskrevet ovenfor ved ringslutning kan overføres til de enantiomer-rene laktoner. Generelt gjelder det for fremstilling av oppfinnelsens forbindelser med den generelle formel (I) i enantiomer-ren form at konfigurasjonene til sluttproduktet i henhold til den ovenfor beskrevne metode er avhengig av konfigurasjonen til utgangsstoffene. The separation of the isomers into the stereoisomeric unitary components generally takes place according to common methods as described, for example, by E.L. Eliel, "Stereochemistry of Carbon Compounds", McGraw Hill, 1962. Hereby, separation of the isomers at the racemic lactone step is preferred. It is particularly preferred here to transfer the racemic mixture of the trans-lactone (VII) by treatment either with D-( + )- or L-(-)-α-methylbenzylamine according to usual methods to the diastereomeric dihydroxyamides (Ig) which so in the usual way by chromatography or crystallization can be separated into the individual diastereomers. Then the following hydrolysis of the diastereomeric amides according to conventional methods, for example by treating the diastereomeric amides with inorganic bases such as sodium hydroxide or potassium hydroxide in water and/or organic solvents such as alcohols such as methanol, ethanol, propanol or isopropanol, gives the corresponding enantiomers -pure dihydroxy acids (Ic) which, as described above, by ring closure can be transferred to the enantiomerically pure lactones. In general, it applies to the preparation of the compounds of the invention with the general formula (I) in enantiomerically pure form that the configurations of the final product according to the method described above are dependent on the configuration of the starting materials.
Isomersepareringen skal forklares nærmere i det følgende skjema: The isomer separation must be explained in more detail in the following form:
De som utgangsstoffer anvendte ketoner (VIII) er nye. The ketones (VIII) used as starting materials are new.
Det er funnet en fremgangsmåte for fremstilling av oppfinnelsens ketoner med den generelle formel (VIII) A method has been found for the production of the invention's ketones with the general formula (VIII)
der there
R<1>,R<2>,R<3>og R<7>' har den ovenfor angitte betydning, R<1>, R<2>, R<3> and R<7>' have the meaning given above,
og denne fremgangsmåte karakteriseres vedand this method is characterized by
aldehyder med den generelle formel (IX) aldehydes of the general formula (IX)
der there
R<1>,R<2>og R<3>har den ovenfor angitte betydning,R<1>, R<2> and R<3> have the above meaning,
i inerte oppløsningsmidler omsettes med aceteddikester med den generelle formel (X) in inert solvents is reacted with acetic acid esters of the general formula (X)
der there
R<7>' har den ovenfor angitte betydning,R<7>' has the meaning given above,
i nærvær av baser.in the presence of bases.
Oppfinnelsens fremgangsmåte kan for eksempel forklares ved det følgende reaksjonsskjema: The method of the invention can be explained, for example, by the following reaction scheme:
Som baser kommer herved i betraktning de vanlige sterkt basiske forbindelser. Hertil hører fortrinnsvis litium-organiske forbindelser som for eksempel N-butyllitium, sek-butyllitium, tert-butyllitium eller fenyllitium eller amider som for eksempel litiumdiisopropylamid, natriumamid eller kaliumamid eller litiumheksametyldisilylamid eller alkali-hydrider som natrium- eller kaliumhydrid. Likeledes er det mulig å anvende blandinger av de nevnte baser. Spesielt foretrukket er N-butyllitium eller natriumhydrid eller blandinger derav. As bases, the usual strongly basic compounds come into consideration. These preferably include lithium-organic compounds such as N-butyllithium, sec-butyllithium, tert-butyllithium or phenyllithium or amides such as lithium diisopropylamide, sodium amide or potassium amide or lithium hexamethyldisilamide or alkali hydrides such as sodium or potassium hydride. Likewise, it is possible to use mixtures of the aforementioned bases. Particularly preferred is N-butyllithium or sodium hydride or mixtures thereof.
Som oppløsningsmidler egner seg herved de vanlige organiske oppløsningsmidler som ikke endrer seg under reaksjons-betingelsene. Hertil hører fortrinnsvis etre som dietyleter, tetrahydrofuran, dioksan eller dimetoksyetan, eller hydrokarboner som benzen, toluen, xylen, cykloheksan, heksan eller jordoljefraksjoner. Likeledes er det mulig å anvende blandinger av de nevnte oppløsningsmidler. Spesielt foretrukket er etre som dietyleter eller tetrahydrofuran. Suitable solvents are the usual organic solvents which do not change under the reaction conditions. These preferably include ethers such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane, or hydrocarbons such as benzene, toluene, xylene, cyclohexane, hexane or petroleum fractions. Likewise, it is possible to use mixtures of the mentioned solvents. Particularly preferred are ethers such as diethyl ether or tetrahydrofuran.
Reaksjonen gjennomføres generelt innen et temperaturområdet fra -80 til +50°C, og fortrinnsvis fra -20°C til romtemperatur . The reaction is generally carried out within a temperature range from -80 to +50°C, and preferably from -20°C to room temperature.
Fremgangsmåten blir vanligvis gjennomført ved normaltrykk, men det er også mulig å arbeide ved under- eller overtrykk, for eksempel innen området fra 0,5 til 5 bar. The procedure is usually carried out at normal pressure, but it is also possible to work at low or high pressure, for example within the range from 0.5 to 5 bar.
Ved gjennomføring av fremgangsmåten blir aceteddikesteren vanligvis benyttet i en mengde fra 1 til 2 mol, og fortrinnsvis 1 til 1,5 mol, beregnet på 1 mol aldehyd. When carrying out the method, the acetic acid ester is usually used in an amount of from 1 to 2 mol, and preferably 1 to 1.5 mol, calculated on 1 mol of aldehyde.
De som utgangsstoffer anvendte aceteddikestre med formel (X) er kjente eller kan fremstilles etter kjente metoder ["Beilstein' s Handbuch der organischen Chemie", III. 632; 438] . The acetic acid esters of formula (X) used as starting materials are known or can be prepared by known methods ["Beilstein's Handbuch der organischen Chemie", III. 632; 438].
Som aceteddikester for oppfinnelsens fremgangsmåte skal for eksempel nevnes: aceteddiksyremetylester, aceteddiksyreetylester, acet-eddiksyrepropylester, aceteddiksyreisopropylester. De som utgangsstoffer anvendte aldehyder med den generelle formel (IX) er nye. Det er videre funnet en fremgangsmåte for fremstilling av aldehyder med den generelle formel (IX) Examples of acetoacetic esters for the method of the invention are: acetoacetic acid methyl ester, acetoacetic acid ethyl ester, acetoacetic acid propyl ester, acetoacetic acid isopropyl ester. The aldehydes with the general formula (IX) used as starting materials are new. A method for the production of aldehydes with the general formula (IX) has also been found
der there
R<1>,R<2>ogR<3>har den ovenfor angitte betydning,R<1>, R<2> and R<3> have the above meaning,
og denne karakteriseres ved at man reduserer pyrimidiner med den generelle formel (XI) i temperaturområdet -70°C til +100°C til hydroksymetylforbindelser med formel (XII), deretter oksyderer disse til de tilsvarende aldehyder (XIII) og omsetter disse med dialkyl-(C1-4)-aminovinylfosfonater i nærvær av natriumhydrid i inerte oppløsningsmidler som etre, for eksempel dietyleter, tetrahydrofuran eller dioksan, fortrinnsvis tetrahydrofuran, i et temperaturområd.e fra -20° C til +40°C og fortrinnsvis -5°C til romtemperatur, til aldehyder (IX). and this is characterized by reducing pyrimidines with the general formula (XI) in the temperature range -70°C to +100°C to hydroxymethyl compounds with formula (XII), then oxidizing these to the corresponding aldehydes (XIII) and reacting these with dialkyl (C1-4)-aminovinylphosphonates in the presence of sodium hydride in inert solvents such as ethers, for example diethyl ether, tetrahydrofuran or dioxane, preferably tetrahydrofuran, in a temperature range from -20°C to +40°C and preferably -5°C to room temperature, to aldehydes (IX).
Fremstillingen skal i det følgende forklares med eksempel i forbindelser av typen (I). The preparation will be explained in the following with an example in compounds of type (I).
Herved blir i henhold til skjema A pyrimidiner med formel (XI ) der Hereby, according to scheme A, pyrimidines of formula (XI ) are there
R<8>er alkyl med opptil 6 karbonatomer, C^_12~aryl eller C7_lg-aralkyl, og R<8> is alkyl of up to 6 carbon atoms, C^_12~aryl or C7_12-aralkyl, and
r! og R<2>har den ovenfor angitte betydning,r! and R<2> has the above meaning,
i første trinn (1) i inerte oppløsningsmidler som etre, for eksempel dietyleter, tetrahydrofuran eller dioksan, fortrinnsvis tetrahydrofuran, redusert med metallhydrider, for eksempel 1 itiumaluminiumhydrid, natriumcyanoborhydrid, natriumaluminiumhydrid, diisobutylaluminiumhydrid eller natrium-bis-(2-metoksyetoksy)-dihydroaluminat som reduksjonsmiddel, i temperaturområdet fra -70 til +100°C, fortrinnsvis -70°C til romtemperatur, henholdsvis fra romtemperatur til +70°C, alt etter anvendt reduksjonsmiddel, til hydroksymetylforbindelsene (XII). Fortrinnsvis skjer reduksjonen med 1 itiumaluminiumhydrid i tetrahydrofuran i et temperaturområde fra romtemperatur til 80°C. in the first step (1) in inert solvents such as ethers, for example diethyl ether, tetrahydrofuran or dioxane, preferably tetrahydrofuran, reduced with metal hydrides, for example 1 lithium aluminum hydride, sodium cyanoborohydride, sodium aluminum hydride, diisobutylaluminum hydride or sodium bis-(2-methoxyethoxy)-dihydroaluminate which reducing agent, in the temperature range from -70 to +100°C, preferably -70°C to room temperature, respectively from room temperature to +70°C, depending on the reducing agent used, to the hydroxymethyl compounds (XII). Preferably, the reduction with 1 lithium aluminum hydride in tetrahydrofuran takes place in a temperature range from room temperature to 80°C.
Hydroksymetylforbindelsene (XII) blir i det andre trinn (2) oksydert til aldehydene (VII) etter vanlige metoder. Oksydasjonen kan for eksempel skje med pyridiniumklorkromat, eventuelt i nærvær av aluminiumoksyd, i inerte oppløsnings- midler som klorerte hydrokarboner, fortrinnsvis metylenklorid, i et temperaturområde fra 0 til +60°C, og fortrinnsvis ved romtemperatur, eller gjennomført med trifluor-eddiksyre/dimetylsulfoksyd i henhold til Swern-oksydasjonens vanlige metoder. The hydroxymethyl compounds (XII) are oxidized in the second step (2) to the aldehydes (VII) according to usual methods. The oxidation can, for example, take place with pyridinium chlorochromate, optionally in the presence of aluminum oxide, in inert solvents such as chlorinated hydrocarbons, preferably methylene chloride, in a temperature range from 0 to +60°C, and preferably at room temperature, or carried out with trifluoroacetic acid/dimethyl sulfoxide according to the usual methods of Swern oxidation.
Aldehydene (XIII) blir i det tredje trinn (3) fortrinnsvis omsatt med dietyl-2-(cykloheksylamino)-vinylfosfonat i nærvær av natriumhydrld i inerte oppløsningsmidler som etre, for eksempel dietyleter, tetrahydrofuran eller dioksan, og fortrinnsvis i tetrahydrofuran, innen et temperaturområde fra In the third step (3), the aldehydes (XIII) are preferably reacted with diethyl-2-(cyclohexylamino)-vinylphosphonate in the presence of sodium hydroxide in inert solvents such as ethers, for example diethyl ether, tetrahydrofuran or dioxane, and preferably in tetrahydrofuran, within a temperature range from
-20 til +40"C og fortrinnsvis fra -5°C til romtemperatur, til aldehydene (IX). De herved som utgangsstoffer anvendte pyrimidiner med formel (XI) oppnås herved generelt ifølge skjema B ved oksydasjon av dihydropyrimidiner (XIV). De herved som utgangsstoffer anvendte dihydropyrimidiner fremstilles i henhold til metoder som er kjent fra litteraturen, se DE-A 103 796. Oksydasjonen av dihydropyrimidinene (XIV) til pyrimidinene (XI) kan for eksempel skje med kromoksyd i iseddik ved en temperatur fra -20 til +150°C, og fortrinnsvis ved tilbakeløpstemperatur, eller med 2,3-diklor-5,6-dicyan-p-benzokinon som oksydasjons-middel i inerte oppløsningsmidler som klorhydrokarboner, og fortrinnsvis metylenklorid I et temperaturområde fra 0 til +100"C, og fortrinnsvis ved romtemperatur. -20 to +40°C and preferably from -5°C to room temperature, to the aldehydes (IX). The pyrimidines of formula (XI) used here as starting materials are generally obtained according to scheme B by oxidation of dihydropyrimidines (XIV). dihydropyrimidines used as starting materials are prepared according to methods known from the literature, see DE-A 103 796. The oxidation of the dihydropyrimidines (XIV) to the pyrimidines (XI) can for example take place with chromium oxide in glacial acetic acid at a temperature from -20 to +150 °C, and preferably at reflux temperature, or with 2,3-dichloro-5,6-dicyan-p-benzoquinone as oxidizing agent in inert solvents such as chlorohydrocarbons, and preferably methylene chloride in a temperature range from 0 to +100"C, and preferably at room temperature.
Oppfinnelsens forbindelser med den generelle formel (I) har verdifulle farmakologiske egenskaper og kan anvendes som aktiv bestanddel i legemidler. Spesielt er de inhibitorer av 3-hydroksy-3-metylglutaryl-koenzym-A (HMG-CoA)-reduktase og som følge derav inhibitorer av kolesterolbiosyntesen. De kan derfor anvendes for behandling av hyperlipoproteinemi, lipoproteinemi eller arteriosklerose. The compounds of the invention with the general formula (I) have valuable pharmacological properties and can be used as an active ingredient in pharmaceuticals. In particular, they are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme-A (HMG-CoA) reductase and, consequently, inhibitors of cholesterol biosynthesis. They can therefore be used for the treatment of hyperlipoproteinaemia, lipoproteinaemia or arteriosclerosis.
De nye virksomme stoffer kan på kjent måte overføres til de vanlige formuleringer som tabletter, dragéer, piller, granulat, aerosoler, sirup, emulsjoner, suspensjoner eller oppløsninger under anvendelse av inerte, ikke-toksiske, farmasøytisk egnede bærere eller oppløsningsmidler. Herved bør den terapeutisk virksomme forbindelse foreligge i en konsentrasjon fra ca. 0,5 til 98 vekt-#, fortrinnsvis 1 til 90 vekt-# av den totale blanding, det vil si i mengder som er tilstrekkelige til å oppnå det angitte doseringsspillerom. The new active substances can be transferred in a known manner to the usual formulations such as tablets, dragées, pills, granules, aerosols, syrups, emulsions, suspensions or solutions using inert, non-toxic, pharmaceutically suitable carriers or solvents. Hereby, the therapeutically active compound should be present in a concentration of approx. 0.5 to 98 wt-#, preferably 1 to 90 wt-# of the total mixture, that is, in amounts sufficient to achieve the indicated dosage range.
Formuleringene fremstilles for eksempel ved drøying av det virksomme middel med oppløsningsmidler og/eller bærere, eventuelt under anvendelse av emulgeringsmidler og/eller dispergeringsmidler, hvorved det for eksempel under anvendelse av vann som fortynningsmiddel også kan benyttes organiske oppløsningsmidler som hjelpeoppløsningsmidler. The formulations are prepared, for example, by diluting the active agent with solvents and/or carriers, possibly using emulsifiers and/or dispersants, whereby, for example, using water as a diluent, organic solvents can also be used as auxiliary solvents.
Som hjelpestoffer skal her for eksempel nevnes vann, ikke-toksiske organiske oppløsningsmidler som: paraffiner som jordoljefraksjoner; planteoljer som jordnøtt/- sesamolje; alkoholer som etylalkohol eller glycerol; bærere som for eksempel naturlig stenmel i form av kaolin, leire, talkum eller kritt, eller syntetisk stenmel som for eksempel høydisperse silisiumdioksyd eller silikater; sukkere som rør—, melke- eller druesukker; emulgeringsmidler som for eksempel polyoksyetylen-fettsyreester, polyoksyetylen-fettalkoholeter, alkylsulfonater og arylsulfonater; disper-geringsmiddel som lignin-sulfittavlut, metylcellulose, stivelse eller polyvinylpyrrolidon; eller smøremidler som magnesiumstearat, talkum, stearinsyre eller natriumlaurylsulfat. Examples of excipients include water, non-toxic organic solvents such as: paraffins such as petroleum fractions; vegetable oils such as peanut/sesame oil; alcohols such as ethyl alcohol or glycerol; carriers such as natural stone flour in the form of kaolin, clay, talc or chalk, or synthetic stone flour such as highly dispersed silicon dioxide or silicates; sugars such as cane, milk or dextrose; emulsifiers such as polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, alkylsulfonates and arylsulfonates; dispersing agent such as lignin sulphite liquor, methyl cellulose, starch or polyvinylpyrrolidone; or lubricants such as magnesium stearate, talc, stearic acid or sodium lauryl sulfate.
Administrering skjer på vanlig måte, fortrinnsvis oralt, parenteralt, perlingualt eller intravenøst. Når det gjelder oral anvendelse, kan tablettene i tillegg til de nevnte bærere selvfølgelig også inneholde tilsetninger som natrium-citrat, kalsiumkarbonat og dikalsiumfosfat sammen med forskjellige tilslag som stivelse, fortrinnsvis potet-stivelse, gelatin og lignende. Videre kan smøremidler som magnesiumstearat, natriumlaurylsulfat og talkum medanvendes ved tabletteringen. Når det gjelder vandige suspensjoner, kan den aktive bestanddel ved siden av de ovenfor nevnte stoffer også benyttes sammen med forskjellige smaksforbedrere eller farvestoffer. Administration takes place in the usual way, preferably orally, parenterally, perlingually or intravenously. When it comes to oral use, in addition to the carriers mentioned, the tablets can of course also contain additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various aggregates such as starch, preferably potato starch, gelatin and the like. Furthermore, lubricants such as magnesium stearate, sodium lauryl sulfate and talc can also be used during tableting. In the case of aqueous suspensions, the active ingredient can also be used in addition to the above-mentioned substances together with various flavor enhancers or coloring agents.
Når det gjelder den parenteral anvendelse kan man benytte oppløsninger av den aktive bestanddel under anvendelse av egnede flytende bærere. As regards the parenteral application, solutions of the active ingredient can be used using suitable liquid carriers.
Generelt har det ved intravenøs administrering vist seg fordelaktig å benytte mengder på ca. 0,001 til 1 mg/kg og fortrinnsvis ca. 0,01 til 0,5 mg/kg kroppsvekt av den aktive bestanddel for å oppnå virksomme resultater, ved administreringen, og ved oral anvendelse utgjør doseringen ca. 0,01 til 20 mg/kg og fortrinnsvis 0,1 til 10 mg/kg kroppsvekt. In general, for intravenous administration, it has proven advantageous to use amounts of approx. 0.001 to 1 mg/kg and preferably approx. 0.01 to 0.5 mg/kg body weight of the active ingredient to achieve effective results, at the time of administration, and for oral use the dosage amounts to approx. 0.01 to 20 mg/kg and preferably 0.1 to 10 mg/kg body weight.
På tross av dette kan det eventuelt være nødvendig å avvike fra de nevnte mengder, dette i avhengighet av kroppsvekt henholdsvis administreringsmetode, av de individuelle forhold overfor det benyttede medikament, typen formulering og tids-punktet henholdsvis intervallet for administreringen. Despite this, it may be necessary to deviate from the amounts mentioned, depending on body weight or the method of administration, the individual conditions in relation to the drug used, the type of formulation and the time or the interval for the administration.
Således kan det i enkelte tilfeller være tilstrekkelig med mindre enn den ovenfor angitte minstemengde, mens den maksimale grense av og til må overskrides. Når det gjelder administrering av større mengder kan det være å anbefale å fordele disse 1 flere enkelt administreringer i løpet av dagen. Thus, in some cases it may be sufficient to use less than the minimum amount specified above, while the maximum limit must occasionally be exceeded. When it comes to the administration of larger quantities, it may be advisable to spread these over 1 several single administrations during the day.
Eksempel 1 Example 1
(E/Z )-4-etoksykarbony1-4-(4-fluorfenyl)-but-3-en-2-on(E/Z )-4-ethoxycarbonyl-4-(4-fluorophenyl)-but-3-en-2-one
62 g (0,5 mol) 4-fluorbenzaldehyd og 53,9 ml (0,5 mol) aceteddiksyreetylester settes til 300 ml isopropanol,, dertil settes en blanding av 2,81 ml (28 mmol ) piperidin og 1,66 ml (29 mmol) eddiksyre i 40 ml isopropanol og det hele omrøres i 48 timer ved romtemperatur. Blandingen dampes inn i vakuum og resten destilleres under høyvakuum. 62 g (0.5 mol) 4-fluorobenzaldehyde and 53.9 ml (0.5 mol) ethyl acetate are added to 300 ml isopropanol, to which is added a mixture of 2.81 ml (28 mmol) piperidine and 1.66 ml ( 29 mmol) of acetic acid in 40 ml of isopropanol and the whole is stirred for 48 hours at room temperature. The mixture is evaporated under vacuum and the residue is distilled under high vacuum.
Kokepunkt 0,5 mm: 138°CBoiling point 0.5 mm: 138°C
Utbytte: 50,5 g (45,5$ av det teoretiske).Yield: 50.5 g ($45.5 of the theoretical).
Eksempel 2 Example 2
1,4-dihydro-2,6-dimetyl-4-(4-fluorfenyl)-pyrimidin-5-karboksylsyreetylester 1,4-dihydro-2,6-dimethyl-4-(4-fluorophenyl)-pyrimidine-5-carboxylic acid ethyl ester
I 230 ml etanol oppvarmer man over natt under tilbakeløp 23,6 g (0,1 mol) av forbindelsen fra eksempel 1, 10,5 g (0,11 mol) acetamidinhydroklorid og 9,85 g (0,12 mol) natriumacetat, oppløsningsmidlet fjernes under vakuum, resten tilsettes eddiksyreetylester og 180 ml IN saltsyre, den organiske fase vaskes ytterligere to ganger med 100 ml IN saltsyre, de forenede vandige faser vaskes med eter, gjøres alkalisk med konsentrert natronlut og ekstraheres tre ganger eddikester. Eddikesterfasen vaskes med vann, tørkes over Na2SC>4og dampes inn under vakuum. In 230 ml of ethanol, 23.6 g (0.1 mol) of the compound from example 1, 10.5 g (0.11 mol) acetamidine hydrochloride and 9.85 g (0.12 mol) sodium acetate are heated under reflux overnight, the solvent is removed under vacuum, ethyl acetate and 180 ml 1N hydrochloric acid are added to the residue, the organic phase is washed twice more with 100 ml 1N hydrochloric acid, the combined aqueous phases are washed with ether, made alkaline with concentrated caustic soda and extracted three times with acetic acid. The acetate phase is washed with water, dried over Na2SC>4 and evaporated under vacuum.
Utbytte: 12,4 g tilsvarende 44,9$ av det teoretiske.Yield: 12.4 g corresponding to 44.9$ of the theoretical.
<i>H-NMR (CDC13): S = 1,15 (tr, 3H, CH3); 1,9 (s, 3H, CH3); <i>H-NMR (CDCl 3 ): S = 1.15 (tr, 3H, CH 3 ); 1.9 (s, 3H, CH3);
2,3 (s, 3H, CH3); 4,05 (m, 2H, CH2); 2.3 (s, 3H, CH3); 4.05 (m, 2H, CH2);
5,3, 5,5 (2s, 1H, CH); 6,9-7,4 (m, 4H, aromater-H) ppm. 5.3, 5.5 (2s, 1H, CH); 6.9-7.4 (m, 4H, aromatics-H) ppm.
Eksempel 3 Example 3
2,6-dimetyl-4-(4-fluorfenyl)-pyrimidin-5-karboksyl syreetyl-ester 2,6-dimethyl-4-(4-fluorophenyl)-pyrimidine-5-carboxylic acid ethyl ester
I 70 ml eddiksyre oppvarmes 12,4 g (45,1 mol) av forbindelsen fra eksempel 2 til koking og 4,6 g (46 mmol) kromtrioksyd tilsettes porsjonsvis. Etter en time lar man det hele avkjøle til 25°C, man heller på is/25 % ig vandig ammoniakk-oppløsning, gjør det hele alkalisk med ammoniakkoppløsning, ekstraherer med diklormetan, vasker den organiske fase med vann og oppnår etter tørking over NagSC^, inndamping i vakuum og filtrering over silikagel (diklormetan:metanol 10:1) 7,14 g. In 70 ml of acetic acid, 12.4 g (45.1 mol) of the compound from example 2 is heated to boiling and 4.6 g (46 mmol) chromium trioxide is added portionwise. After one hour, the whole is allowed to cool to 25°C, it is poured onto ice/25% aqueous ammonia solution, the whole is made alkaline with ammonia solution, extracted with dichloromethane, the organic phase is washed with water and obtained after drying over NaCl^ , evaporation in vacuo and filtration over silica gel (dichloromethane:methanol 10:1) 7.14 g.
Utbytte: 57,7$ av det teoretiske.Dividend: 57.7$ of the theoretical.
1-H-NMR (CDC13): S = 1,2 (tr, 3H, CH3); 2,65 (s, 3H, CH3); 1 H NMR (CDCl 3 ): S = 1.2 (tr, 3H, CH 3 ); 2.65 (s, 3H, CH3);
2,85 (s, 3H, CH3); 4,3 (q, 2H, CH2); 2.85 (s, 3H, CH3); 4.3 (q, 2H, CH2);
7,1-7,8 (m, 4H, aromater-H) ppm. 7.1-7.8 (m, 4H, aromatics-H) ppm.
Eksempel 4 Example 4
2 ,6-dimetyl-4-(4-fluorfenyl)-5-hydroksymetyl-pyrimidin 2,6-dimethyl-4-(4-fluorophenyl)-5-hydroxymethyl-pyrimidine
Til 5,66 g (20,6 mmol) av forbindelsen fra eksempel 3 i 100 ml toluen drypper man under nitrogen ved -78°C 27 ml (40 mmol) diisobutylaluminiumhydrid (1,5 m i toluen). Etter oppvarming til 25"C hydrolyseres det med 20 $-ig vandig kaliumhydroksydoppløsning, den vandige fase vaskes med eddikester, de forenede organiske faser tørkes over Na2S04og oppløsningsmidlet fjernes under vakuum. To 5.66 g (20.6 mmol) of the compound from example 3 in 100 ml of toluene, 27 ml (40 mmol) of diisobutylaluminum hydride (1.5 m in toluene) is added dropwise under nitrogen at -78°C. After heating to 25°C, it is hydrolysed with 20% aqueous potassium hydroxide solution, the aqueous phase is washed with ethyl acetate, the combined organic phases are dried over Na 2 SO 4 and the solvent is removed under vacuum.
Utbytte: 4,1 g tilsvarende 85,9$ av det teoretiske.Yield: 4.1 g corresponding to 85.9$ of the theoretical.
<1->H-NMR (CDCI3): 5 = 1,8 (tr, 1H, OH); 2,7 (2s, 6H, CH3); <1->H-NMR (CDCl3): δ = 1.8 (tr, 1H, OH); 2.7 (2s, 6H, CH3);
4,65 (d, 2H, CH2); 7,1-7,7 (m, 4H, aromater-H) ppm. 4.65 (d, 2H, CH2); 7.1-7.7 (m, 4H, aromatics-H) ppm.
Eksempel 5 Example 5
2,6-dimetyl-4-(4-fluorfenyl)-pyrimidin-5-karbaldehyd 2,6-dimethyl-4-(4-fluorophenyl)-pyrimidine-5-carbaldehyde
Til en oppløsning av 4,1 g (17,7 mol) av forbindelsen fra eksempel 4 i 100 ml diklormetan setter man ved romtemperatur porsjonsvis 6,06 g (28,1 mmol) pyrimidiniumklorkromat og omrører to timer. Oppløsningsmidlet fjernes under vakuum og resten filtreres over sillkagel (diklormetan:metanol 3:1). To a solution of 4.1 g (17.7 mol) of the compound from example 4 in 100 ml of dichloromethane, 6.06 g (28.1 mmol) of pyrimidinium chlorochromate are added in portions at room temperature and stirred for two hours. The solvent is removed under vacuum and the residue is filtered over silica gel (dichloromethane:methanol 3:1).
Utbytte: 3,8 g tilsvarende 93,4% av det teoretiske.Yield: 3.8 g corresponding to 93.4% of the theoretical.
1-H-NMR (CDC13): S = 2,8 (2s, 6H, CH3); 7,1-7,7 (m, 4H, 1-H-NMR (CDCl 3 ): S = 2.8 (2s, 6H, CH 3 ); 7.1-7.7 (m, 4H,
aromater-H); 10,0 (s, 1H, CHO) ppm. aromatics-H); 10.0 (s, 1H, CHO) ppm.
Eksempel 6 Example 6
(E)-3-[2,6-dimetyl-4-(4-fluorfenyl)-pyrimid-5-yl]-prop-2-enal (E)-3-[2,6-dimethyl-4-(4-fluorophenyl)-pyrimid-5-yl]-prop-2-enal
Til en suspensjon av 0,5 g (20,8 mmol) natriumhydrid i 20 ml To a suspension of 0.5 g (20.8 mmol) sodium hydride in 20 ml
tetrahydrofuran drypper man ved 0°C en oppløsning av 0,81 g [2-(cykloheksylamino)vinyl]-fosfonsyredietylester i 20 ml THF, omrører i 15 minutter og drypper så til en oppløsning av 0,63 g (2,72 mmol) av forbindelsen fra eksempel 5 i 15 ml tetrahydrofuran, a solution of 0.81 g of [2-(cyclohexylamino)vinyl]-phosphonic acid diethyl ester in 20 ml of THF is added dropwise at 0°C, stirred for 15 minutes and then added dropwise to a solution of 0.63 g (2.72 mmol) of the compound from example 5 in 15 ml
THF, omrører en time ved 0°C, en time ved 25°C, hydrolyserer med 20 ml vann, vasker med dietyleter, fjerner oppløsnings-midlet under vakuum, tar opp resten i 40 ml toluen og oppvarmer oppløsningen med 2 g oksalsyre og 40 ml vann i en time ved 60°C, vasker med dietyleter, tørker over Na2S04og oppnår 0,5 g etter fjerning av oppløsningsmidlet. THF, stir for one hour at 0°C, one hour at 25°C, hydrolyze with 20 ml of water, wash with diethyl ether, remove the solvent under vacuum, take up the residue in 40 ml of toluene and heat the solution with 2 g of oxalic acid and 40 ml of water for one hour at 60°C, washing with diethyl ether, drying over Na 2 SO 4 and obtaining 0.5 g after removal of the solvent.
Utbytte: 71,7$ av det teoretiske.Dividend: 71.7$ of the theoretical.
l-H-NMR (CDC13): S - 2,7 (s, 3H, CH3); 2,8 (s, 3H, CH3) ; 6,4 (dd, 1H, CHCH0); 7,2 (d, 1H, CH); 7,1-7,7 (m, 4H, aromater-H); 9,6 (d, 1H, CHO) ppm. Eksempel 7 Metyl(E)-7-[2 ,6-dimetyl-4-(4-fluorfenyl)-pyrimid-5-yl]-5-hydroksy-3-okso-hept-6-enoat 1-H NMR (CDCl 3 ): S - 2.7 (s, 3H, CH 3 ); 2.8 (s, 3H, CH3); 6.4 (dd, 1H, CHCH0); 7.2 (d, 1H, CH); 7.1-7.7 (m, 4H, aromatics-H); 9.6 (d, 1H, CHO) ppm. Example 7 Methyl (E)-7-[2,6-dimethyl-4-(4-fluorophenyl)-pyrimid-5-yl]-5-hydroxy-3-oxo-hept-6-enoate
Til en suspensjon av 256 mg (10,7 mmol) natriumhydrid i 25 ml THF drypper man ved 0°C 1,11 ml (10,3 mmol) aceteddiksyremetylester. Etter 15 minutter drypper man i løpet av 10 minutter til 7,3 ml (10,7 mmol n-butyllitium (1,5 m i heksan), man omrører i 15 minutter ved 0°C, drypper til en oppløsning av 2,4 g (3,8 mmol) av forbindelsen fra eksempel 6 i 10 ml THF, omrører i 15 minutter ved 0°C, hydrolyserer med 30 ml mettet vandig ammoniumkloridoppløsning, vasker tre ganger med diklormetan, tørker over Na2S04, fjerner oppløs-ningsmidlet under vakuum og oppnår 2,47 g olje etter kromatografi over silikagel med eddiksyreetylester som elueringsmiddel. To a suspension of 256 mg (10.7 mmol) of sodium hydride in 25 ml of THF, 1.11 ml (10.3 mmol) of acetoacetic acid methyl ester is added dropwise at 0°C. After 15 minutes, 7.3 ml (10.7 mmol of n-butyllithium (1.5 m in hexane) are added dropwise over 10 minutes, stirred for 15 minutes at 0°C, added dropwise to a solution of 2.4 g (3.8 mmol) of the compound from example 6 in 10 ml THF, stir for 15 minutes at 0°C, hydrolyze with 30 ml saturated aqueous ammonium chloride solution, wash three times with dichloromethane, dry over Na 2 SO 4 , remove the solvent under vacuum and obtains 2.47 g of oil after chromatography over silica gel with ethyl acetate as eluent.
Utbytte: 73,$ av det teoretiske.Dividend: $73.00 of the theoretical.
<1>H-NMR (CDCI3): S - 2,55 (s, 3H, CH3); 2,7 (d, 2H, CH2-CHOH); 2,75 (s, 3H, CH3); 3,1 (br, s, 1H, OH); 3,5 (s, 2H, CH2); 3,75 (s, 3H, 0CH3); 4,65 (m, 1H, CHOH); 5,6 (dd, 1H, CHCHOH); 6,6 (d, 1H, CH); 7,0-7,6 (m, 4H, aromater-H) ppm. <1>H-NMR (CDCl 3 ): S - 2.55 (s, 3H, CH 3 ); 2.7 (d, 2H, CH2-CHOH); 2.75 (s, 3H, CH3); 3.1 (br, s, 1H, OH); 3.5 (s, 2H, CH2); 3.75 (s, 3H, 0CH3); 4.65 (m, 1H, CHOH); 5.6 (dd, 1H, CHCHOH); 6.6 (d, 1H, CH); 7.0-7.6 (m, 4H, aromatics-H) ppm.
Eksempel 8 Example 8
Metyl-erytro-(E)-3,5-dihydroksy-7-[2,6-dimetyl-4-(4-fluor-fenyl)-pyrimid-5-yl]-hept-6-enoat Methyl erythro-(E)-3,5-dihydroxy-7-[2,6-dimethyl-4-(4-fluoro-phenyl)-pyrimid-5-yl]-hept-6-enoate
Gjennom en oppløsning av 1,69 g (4,55 mmol) av forbindelsen fra eksempel 7 og 5,7 ml (5,7 mmol) trietylboran (1 m, THF) i 45 ml THF blåser man luft i 5 minutter, avkjøler til -30°C, setter til 215 mg (5,7 mmol) natriumborhydrid og langsomt 3,8 ml metanol, omrører i 30 minutter ved —30°C, tilsetter langsomt 15,2 ml 30 $-ig hydrogenperoksyd i 33,4 ml vann under 0°C, omrører i 30 minutter ved 0°C, tar opp det hele i eddiksyreester, vasker med vann, IN saltsyre, vandig natriumhydrogenkarbonatoppløsning, tørker over Na2SC>4 , fjerner oppløsningsmidlet under vakuum og oppnår etter kromatografi over silikagel (eddiksyreetylester) 1,08 g. Through a solution of 1.69 g (4.55 mmol) of the compound from example 7 and 5.7 ml (5.7 mmol) of triethylborane (1 m, THF) in 45 ml of THF, air is blown for 5 minutes, cooled to -30°C, add 215 mg (5.7 mmol) sodium borohydride and slowly 3.8 ml methanol, stir for 30 minutes at -30°C, slowly add 15.2 ml 30 µg hydrogen peroxide in 33.4 ml water below 0°C, stir for 30 minutes at 0°C, take up the whole in acetic acid ester, wash with water, IN hydrochloric acid, aqueous sodium bicarbonate solution, dry over Na2SC>4 , remove the solvent under vacuum and obtain after chromatography over silica gel (ethyl acetate ) 1.08 g.
Utbytte: 63$ av det teoretiske.Dividend: 63$ of the theoretical.
<i>H-NMR (CDCI3): å = 1,8 (br, s, 2H, OH); 2,5 (m, 2H, CH2); <i>H-NMR (CDCl 3 ): δ = 1.8 (br, s, 2H, OH); 2.5 (m, 2H, CH2);
2,55 (s, 3H, CH3); 2,7 (s, 3H, CH3); 2.55 (s, 3H, CH3); 2.7 (s, 3H, CH3);
3,7 (s, 3H, 0CH3); 4,2 (m, 1H, CHOH); 3.7 (s, 3H, 0CH3); 4.2 (m, 1H, CHOH);
4,45 (m, 1H, CHOH); 5,6 (dd, 1H, CH, CHOH); 6,5 (d, 1H, CH); 7,0-7,6 (m, 4H, aromater-H) ppm. 4.45 (m, 1H, CHOH); 5.6 (dd, 1H, CH, CHOH); 6.5 (d, 1H, CH); 7.0-7.6 (m, 4H, aromatics-H) ppm.
Eksempel 9 Example 9
1,4-dihydro-4-(4-fluorfenyl)-6-metyl-2-fenyl-pyrimidin-5-karboksylsyreetylester 1,4-dihydro-4-(4-fluorophenyl)-6-methyl-2-phenyl-pyrimidine-5-carboxylic acid ethyl ester
Analogt eksempel 2 oppnår man fra 103,6 g (0,56 mol) benzamidinhydroklorld, 121,5 g (0,5 mol) av forbindelsen fra eksempel 1 og 49,2 g (0,6 mol) natriumacetat 87,5 g. Analogous to example 2, 87.5 g is obtained from 103.6 g (0.56 mol) of benzamidine hydrochloride, 121.5 g (0.5 mol) of the compound from example 1 and 49.2 g (0.6 mol) of sodium acetate.
Utbytte: 25,9$ av det teoretiske.Dividend: 25.9$ of the theoretical.
^H-NMR (CDCI3): S = 1,15 (tr, 2H, CH3); 2,15 (br, s, NH); 1 H-NMR (CDCl 3 ): S = 1.15 (tr, 2H, CH 3 ); 2.15 (br, s, NH);
2,6 (s, 3H, CH3); 4,1 (q, 2H, CH2); 5,8 (s, 1H, CH); 7,1-8,0 (9H, aromater-H) ppm. 2.6 (s, 3H, CH3); 4.1 (q, 2H, CH2); 5.8 (s, 1H, CH); 7.1-8.0 (9H, aromatics-H) ppm.
Eksempel 10 Example 10
4-(4-fluorfenyl)-6-metyl-2-fenyl-pyrimidin-5-karboksylsyre-etylester 4-(4-Fluorophenyl)-6-methyl-2-phenyl-pyrimidine-5-carboxylic acid ethyl ester
Analogt eksempel 3 oppnår man fra 40 g (0,12 mol) av forbindelsen fra eksempel 9 og 11,8 g (0,12 mol) kromtrioksyd 34,9 g. Analogous to example 3, 34.9 g is obtained from 40 g (0.12 mol) of the compound from example 9 and 11.8 g (0.12 mol) chromium trioxide.
Utbytte: 87,9$ av det teoretiske.Dividend: 87.9$ of the theoretical.
<1>H-NMR (CDC13): S = 1,15 (tr, 2H, CH3); 2,7 (s, 3H, CH3); <1>H-NMR (CDCl 3 ): S = 1.15 (tr, 2H, CH 3 ); 2.7 (s, 3H, CH3);
4,25 (q, 2H, CH2); 7,1-8,6 (9H, aromater-H) ppm. 4.25 (q, 2H, CH2); 7.1-8.6 (9H, aromatics-H) ppm.
Eksempel 11 Example 11
4-(4-fluorfenyl)-5-hydroksymetyl-6-metyl-2-fenylpyrimidin 4-(4-fluorophenyl)-5-hydroxymethyl-6-methyl-2-phenylpyrimidine
Analogt eksempel 2 oppnår man fra 30 g (0,09 mol) av forbindelsen fra eksempel 10 23,1 g. Analogous to example 2, 23.1 g is obtained from 30 g (0.09 mol) of the compound from example 10.
Utbytte: 87,3$ av det teoretiske.Dividend: 87.3$ of the theoretical.
<i>H-NMR (CDCI3): S = 2,8 (s, 3H, CH3); 4,5 (br, OH); 4,65 <i>H-NMR (CDCl 3 ): S = 2.8 (s, 3H, CH 3 ); 4.5 (br, OH); 4.65
(s, 2H, CH2); 7,1-8,5 (9H, aromater-H) ppm. (s, 2H, CH2); 7.1-8.5 (9H, aromatics-H) ppm.
Eksempel 12 Example 12
4-(4-fluorfenyl)-6-metyl-2-fenyl-pyrimidin-5-karbaldehyd 4-(4-fluorophenyl)-6-methyl-2-phenyl-pyrimidine-5-carbaldehyde
Analogt eksempel 5 oppnår man fra 12,9 g (44 mmol) av forbindelsen fra eksempel 11 og 14,2 g (66 mmol) pyrimidin-klorkromat 11,9 g. Analogously to example 5, 11.9 g of pyrimidine chlorochromate is obtained from 12.9 g (44 mmol) of the compound from example 11 and 14.2 g (66 mmol).
Utbytte: 93% av det teoretiske.Yield: 93% of the theoretical.
1-H-NMR (CDCI3): S = 2,9 (s, 3H, CH3); 7,2-8,7 (9H, aromater-H); 10,1 (s, 1H, CHO) ppm. 1-H-NMR (CDCl 3 ): S = 2.9 (s, 3H, CH 3 ); 7.2-8.7 (9H, aromatics-H); 10.1 (s, 1H, CHO) ppm.
Eksempel 13 Example 13
E-3-[4-(4-fluorfenyl)-6-metyl-2-fenyl-pyrimid-5-yl]-prop-2-enal E-3-[4-(4-fluorophenyl)-6-methyl-2-phenyl-pyrimid-5-yl]-prop-2-enal
Analogt eksempel 6 oppnår man fra 8,0 g (27 mmol) av forbindelsen fra eksempel 12, 0,8 g (33,6 mmol) natriumhydrid og 8,0 g (32,4 mmol) [2-(cykloheksylamino)vinyl]fosfonsyre-dietylester 5,9 g. Analogous to example 6, one obtains from 8.0 g (27 mmol) of the compound from example 12, 0.8 g (33.6 mmol) sodium hydride and 8.0 g (32.4 mmol) [2-(cyclohexylamino)vinyl] phosphonic acid diethyl ester 5.9 g.
Utbytte: 68,7$ av det teoretiske.Dividend: 68.7$ of the theoretical.
<1>H-NMR (CDC13): S = 2,8 (s, 3H, CH3); 6,45 (dd, 1H, CHCHO); <1>H-NMR (CDCl 3 ): S = 2.8 (s, 3H, CH 3 ); 6.45 (dd, 1H, CHCHO);
7,1-8,6 (m, 10H, aromater-H, CH); 9,65 (d, 1H, CHO) ppm. 7.1-8.6 (m, 10H, aromatics-H, CH); 9.65 (d, 1H, CHO) ppm.
Eksempel 14 Example 14
Metyl-(E)-7-[4-(4-fluorfenyl)-6-metyl-2-fenyl-pyrimid-5-yl]-5-hydroksy-3-okso-hept-6-enoat Methyl-(E)-7-[4-(4-fluorophenyl)-6-methyl-2-phenyl-pyrimid-5-yl]-5-hydroxy-3-oxo-hept-6-enoate
Analogt eksempel 7 oppnår man fra 3,4 g (10,7 mmol) av forbindelsen fra eksempel 13 5,18 g råprodukt. Analogous to example 7, 5.18 g of crude product is obtained from 3.4 g (10.7 mmol) of the compound from example 13.
Råutbytte: 100$Raw yield: 100$
<1->H-NMR (CDClo): S = 2,65 (s, 3H, CHo ) ; 2,7 (d, 2H, <1>H-NMR (CDCl 2 ): S = 2.65 (s, 3H, CH 2 ); 2.7 (d, 2H,
2,9 (br, 1H, OH); 3,5 (s, 3H, 2.9 (br, 1H, OH); 3.5 (s, 3H,
CH3); 3,75 (s, 3H, 0CH3); 4,7 (m, 1H, CHOH); 6,65 (d, 1H, CH-Ar); 7,1-8,6 (m, 9H, aromater-H) ppm. CH3); 3.75 (s, 3H, 0CH3); 4.7 (m, 1H, CHOH); 6.65 (d, 1H, CH-Ar); 7.1-8.6 (m, 9H, aromatics-H) ppm.
Eksempel 15 Example 15
Metyl-erytro-(E)-3,5-dlhydroksy-7-[4-(4-fluorfenyl)-6-metyl-2-fenyl-pyrimid-5-yl]-hept-6-enoat Methyl erythro-(E)-3,5-dlhydroxy-7-[4-(4-fluorophenyl)-6-methyl-2-phenyl-pyrimid-5-yl]-hept-6-enoate
Analogt eksempel 8 oppnår man fra 8,26 g (16 mmol) av forbindelsen fra eksempel 14 4,03 g. Analogously to example 8, 4.03 g is obtained from 8.26 g (16 mmol) of the compound from example 14.
Utbytte: 57,7$ av det teoretiske.Dividend: 57.7$ of the theoretical.
<1>H-NMR (CDC13): § = 1,6 (m, 2H, CH2); 2,5 (m, 2H, CH2C=0): <1>H-NMR (CDCl 3 ): δ = 1.6 (m, 2H, CH 2 ); 2.5 (m, 2H, CH2C=0):
2,7 (s, 3H, CH3); 3,7 (s, 3H,CH30); 4,2 (m, 1H, CHOH); 4,5 (m, 1H, CHOH); 5,7 (dd, 1H, CH-CHOH); 6,6 (d, 1H, CH-Ar); 7,0-8,6 (m, 9H, aromater-H) ppm. Eksempel 16 (E/Z)-4-etoksykarbonyl-5-(4-fluorfenyl)-2-metyl-pent-4-en-3-on 62 g (0,5 mol) 4-fluorbenzaldehyd og 79 g (0,5 mol) iso-butyryleddiksyreetylester settes til 300 ml tørr isopropanol og dertil settes en blanding av 2,81 ml (28 mmol) piperidin og 1,66 ml (29 mmol) eddiksyre i 40 ml isopropanol. Det hele omrøres i 48 timer ved romtemperatur, man damper inn under vakuum og destillerer resten i høyvakuum. 2.7 (s, 3H, CH3); 3.7 (s, 3H, CH 3 O); 4.2 (m, 1H, CHOH); 4.5 (m, 1H, CHOH); 5.7 (dd, 1H, CH-CHOH); 6.6 (d, 1H, CH-Ar); 7.0-8.6 (m, 9H, aromatics-H) ppm. Example 16 (E/Z)-4-ethoxycarbonyl-5-(4-fluorophenyl)-2-methyl-pent-4-en-3-one 62 g (0.5 mol) of 4-fluorobenzaldehyde and 79 g (0. 5 mol) of iso-butyryl acetic acid ethyl ester is added to 300 ml of dry isopropanol and to this is added a mixture of 2.81 ml (28 mmol) of piperidine and 1.66 ml (29 mmol) of acetic acid in 40 ml of isopropanol. The whole is stirred for 48 hours at room temperature, evaporated under vacuum and the residue distilled under high vacuum.
Kokepunkt 0,5 mm: 127°CBoiling point 0.5 mm: 127°C
Utbytte: 108,7 g tilsvarende 82,3$ av det teoretiske. Yield: 108.7 g corresponding to 82.3$ of the theoretical.
Eksempel 17 Example 17
1,4-dihydro-4-(4-fluorfenyl)-6-isopropyl-2-fenylpyrimidln-S-karboksylsyreetylester 1,4-dihydro-4-(4-fluorophenyl)-6-isopropyl-2-phenylpyrimidin-S-carboxylic acid ethyl ester
Analogt eksempel 2 oppnår man fra 59,5 g (0,2 mol) benz-amidinhydroklorid, 79,2 g (0,3 mol) av forbindelsen fra eksempel 16 og 28,7 g (0,35 mol) natriumacetat i 500 ml etanol 39 g. Analogous to example 2, one obtains from 59.5 g (0.2 mol) benzamidine hydrochloride, 79.2 g (0.3 mol) of the compound from example 16 and 28.7 g (0.35 mol) sodium acetate in 500 ml ethanol 39 g.
Utbytte: 35,5$ av det teoretiske.Dividend: 35.5$ of the theoretical.
1-H-NMR (CDC13): S = 1,2 (m, 9H, CH3); 2,8 (m, 1H; CH); 4,1 1-H-NMR (CDCl 3 ): S = 1.2 (m, 9H, CH 3 ); 2.8 (m, 1H; CH); 4.1
(q, 2H, CH2); 4,2 (br, 1H, NH); 5,75 (s, 1H, CHAr); 6,9-8,1 (m, 9H, aromater-H) ppm. (q, 2H, CH2); 4.2 (br, 1H, NH); 5.75 (s, 1H, CHAr); 6.9-8.1 (m, 9H, aromatics-H) ppm.
Eksempel 18 Example 18
4-(4-fluorfenyl)-6-isopropyl-2-fenyl-pyr imidin-5-karboksyl-syreetylester 4-(4-Fluorophenyl)-6-isopropyl-2-phenyl-pyrimidine-5-carboxylic acid ethyl ester
Analogt eksempel 3 oppnår man fra 39,0 g (0,11 mol) av forbindelsen fra eksempel 17 20,6 g. Analogous to example 3, 20.6 g is obtained from 39.0 g (0.11 mol) of the compound from example 17.
Utbytte: 56,6$ av det teoretiske.Dividend: 56.6$ of the theoretical.
<1>H-NMR (CDC13): S = 1,15 (tr, 3H, CH3); 1,4 (d, 6H, CH3) ; <1>H-NMR (CDCl 3 ): S = 1.15 (tr, 3H, CH 3 ); 1.4 (d, 6H, CH3);
3,3 (m, 1H, CH); 4,2 (q, 2H, CH2); 7,0-8,6 (m, 9H, aromater-H) ppm. 3.3 (m, 1H, CH); 4.2 (q, 2H, CH2); 7.0-8.6 (m, 9H, aromatics-H) ppm.
Eksempel 19 Example 19
4-(4-fluorfenyl)-5-hydroksymetyl-6-isopropyl-2-fenylpyrimidin 4-(4-fluorophenyl)-5-hydroxymethyl-6-isopropyl-2-phenylpyrimidine
Analogt eksempel 4 oppnår man fra 20,0 g (55 mmol) av forbindelsen fra eksempel 18 16,7 g av tittelforbindelsen. Analogous to example 4, 16.7 g of the title compound is obtained from 20.0 g (55 mmol) of the compound from example 18.
Utbytte: 94$ av det teoretiske.Dividend: 94$ of the theoretical.
<1>H-NMR (CDCI3): S = 1,4 (d, 6H, CH3); 1,7 (br, 1H, OH); <1>H-NMR (CDCl 3 ): S = 1.4 (d, 6H, CH 3 ); 1.7 (br, 1H, OH);
3,55 (m, 1H, CH): 4,7 (s, 2H, CH2); 3.55 (m, 1H, CH): 4.7 (s, 2H, CH2);
7,1-8,7 (m, 9H, aromater-H) ppm. 7.1-8.7 (m, 9H, aromatics-H) ppm.
Eksempel 20 Example 20
4-(4-fluorfenyl)-6-isopropyl-2-fenyl-pyrimidin-5-karbaldehyd 4-(4-fluorophenyl)-6-isopropyl-2-phenyl-pyrimidine-5-carbaldehyde
Analogt eksempel 5 oppnår man fra 16,3 g (50 mmol) av forbindelsen fra eksempel 19 7,9 av tittelforbindelsen. Analogous to example 5, 7.9 g of the title compound is obtained from 16.3 g (50 mmol) of the compound from example 19.
Utbytte: 49,4$ av det teoretiske.Dividend: 49.4$ of the theoretical.
<1>H-NMR (CDCI3): S = 1,4 (d, 6H, CH3 ); 4,0 (m, 1H, CH); 7,2-8,7 (m, 9H, aromater-H); 10,1 (s, 1H, CHO) ppm. <1>H-NMR (CDCl 3 ): S = 1.4 (d, 6H, CH 3 ); 4.0 (m, 1H, CH); 7.2-8.7 (m, 9H, aromatics-H); 10.1 (s, 1H, CHO) ppm.
Eksempel 21 Example 21
(E)-3-[4-(4-fluorfenyl)-6-isopropyl-2-fenyl-pyrimid-5-yl]-prop-2-enal (E)-3-[4-(4-fluorophenyl)-6-isopropyl-2-phenyl-pyrimid-5-yl]-prop-2-enal
Analogt eksempel 6 oppnår man fra 7,9 g (25 mmol) av forbindelsen fra eksempel 20 6,9 g av eksempel 21. Analogous to example 6, 6.9 g of example 21 is obtained from 7.9 g (25 mmol) of the compound from example 20.
Utbytte: 0% av det teoretiske.Yield: 0% of the theoretical.
1-H-NMR (CDC13): S 1,4 (d, 6H, CH3); 3,4 (m, 1H, CH); 6,3 1-H-NMR (CDCl 3 ): S 1.4 (d, 6H, CH 3 ); 3.4 (m, 1H, CH); 6.3
(dd, 1H, CHCHO); 7,1-8,7 (m, 9H, aromater-H); 7,6 (d, 1H, CHAr) ppm. (dd, 1H, CHCHO); 7.1-8.7 (m, 9H, aromatics-H); 7.6 (d, 1H, CHAr) ppm.
Eksempel 22 Example 22
Metyl-(E)-7-[4-(4-fluorfenyl)-6-isopropyl-2-fenylpyrimid-5-yl]-5-hydroksy-3-okso-hept-6-enoat Methyl-(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-phenylpyrimid-5-yl]-5-hydroxy-3-oxo-hept-6-enoate
Analogt eksempel 7 oppnår man fra 1,9 g (5,5 mmol) av forbindelsen fra eksempel 21 0,8 g av eksempel 22. Analogous to example 7, 0.8 g of example 22 is obtained from 1.9 g (5.5 mmol) of the compound from example 21.
Utbytte: 30,2 %Yield: 30.2%
1-H-NMR (CDCI3): S = 1,35 (d, 6H, CH3); 2,65 (d, 2H, CH2); 1-H-NMR (CDCl 3 ): S = 1.35 (d, 6H, CH 3 ); 2.65 (d, 2H, CH2);
3,4 (m, 1H, CH); 3,5 (s, 2H, CH2); 3,75 (s, 3H, CH3O); 4,65 (m, 1H, CHOH); 5,5 (dd, 1H, CH CHOH); 6,75 (d, 1H, CHAr); 3.4 (m, 1H, CH); 3.5 (s, 2H, CH2); 3.75 (s, 3H, CH 3 O); 4.65 (m, 1H, CHOH); 5.5 (dd, 1H, CH CHOH); 6.75 (d, 1H, CHAr);
7,1-8,6 (m, 9H, aromater-H) ppm. 7.1-8.6 (m, 9H, aromatics-H) ppm.
Eksempel 23 Example 23
Metyl-erytro-(E)-3, 5-dihydroksy-7-[4-(4-fluorfenyl)-6-isopropyl-2-fenyl-pyrimid-5-yl]-hept-6-enoat Methyl erythro-(E)-3, 5-dihydroxy-7-[4-(4-fluorophenyl)-6-isopropyl-2-phenyl-pyrimid-5-yl]-hept-6-enoate
Analogt eksempel 8 oppnår man fra 0,8 g (1,75 mmol) av forbindelsen fra eksempel 22 0,5 g av eksempel 23. Analogously to example 8, 0.8 g (1.75 mmol) of the compound from example 22 yields 0.5 g of example 23.
Utbytte: 62 $Dividend: $62
1-H-NMR (CDCI3)<:>S = 1,3 (d, 6H, CH3 ); 1,6 (m, 2H, CH2 ); 2,5 1-H-NMR (CDCl 3 )<:>S = 1.3 (d, 6H, CH 3 ); 1.6 (m, 2H, CH2 ); 2.5
(m, 2H, CH2C=0); 3,45 (m, 1H, CH); 3,7 (m, 2H, CH2C=O); 3.45 (m, 1H, CH); 3.7
(s, 3H, CH3O); 4,2 (m, 1H, CHOH); 4,5 (m, 1H, CHOH); 5,5 (dd, 1H, CH-CHOH); (s, 3H, CH3O); 4.2 (m, 1H, CHOH); 4.5 (m, 1H, CHOH); 5.5 (dd, 1H, CH-CHOH);
6,7 (d, 1H, CHAr); 7,1-8,6 (m, 9H, aromater-H) ppm. 6.7 (d, 1H, CHAr); 7.1-8.6 (m, 9H, aromatics-H) ppm.
AnvendelseseksemplerApplication examples
Eksempel 1Example 1
Enzymaktivitetsbestemmelsene ble modifisert i henhold til G.C. Ness et al. i "Archives of Biochemistry and Biophysics", 197. 493-499 (1979). Rico-hannrotter med kroppsvekt 300-400 g ble behandlet i 11 dager med altrominpulverfor hvortil det var satt 40 g kolestyramin pr. kg for. Etter dekapitering ble leveren fjernet fra dyrene og lagt på is. Leveren ble oppmalt og homogenisert i en Potter-Elvejem-homogenisator tre ganger i 3 volumer 0,1 m sakkarose, 0,05 m KC1, 0,04 m KxHy- fosfat, 0,03 m etylendiamintetraeddiksyre, 0,002 m ditiotreit (SPE)-buffer, pH 7,2. Deretter sentrifugerte man i 15 minutter ved 15 000 x g og sedimentet ble kastet. Superna-tanten ble sedimentert i 75 minutter ved 100 000 x g. Denne pellet ble tatt opp i et kvart volum SPE-buffer, homogenisert en gang til og deretter sentrifugert i 60 minutter ved 1 000 000 x g. Den oppnådde pellet ble tatt opp i det fem-dobbelte volum SPE-buffer, homogenisert og frosset inn og lagret ved -78°C (= enzymoppløsning). The enzyme activity assays were modified according to G.C. Ness et al. in "Archives of Biochemistry and Biophysics", 197. 493-499 (1979). Male Rico rats with a body weight of 300-400 g were treated for 11 days with altromin powder to which 40 g of cholestyramine had been added per kg for. After decapitation, the liver was removed from the animals and placed on ice. The liver was minced and homogenized in a Potter-Elvejem homogenizer three times in 3 volumes of 0.1 m sucrose, 0.05 m KC1, 0.04 m KxHy- phosphate, 0.03 m ethylenediaminetetraacetic acid, 0.002 m dithiothreitol (SPE)- buffer, pH 7.2. It was then centrifuged for 15 minutes at 15,000 x g and the sediment was discarded. The supernatant was pelleted for 75 minutes at 100,000 x g. This pellet was taken up in a quarter volume of SPE buffer, homogenized once more and then centrifuged for 60 minutes at 1,000,000 x g. The resulting pellet was taken up in the five-fold volume of SPE buffer, homogenized and frozen and stored at -78°C (= enzyme solution).
For prøving ble prøveforbindelsene (eller Mevinolin som referansesubstans) oppløst i dimetylformamid under tilsetning av 5 volum-% IN NaOH og benyttet i en mengde av 10 yl i forskjellige konsentrasjoner i enzymtesten. Denne startet etter 20 minutters forinkubering av forbindelsen med enzymet ved 37°C. Prøvesatsen utgjorde 0,380 ml og inneholdt 4 pmol glukose-6-fosfat, 1,1 mg storfealbumin, 2,1 pmol ditiotreit, 0,35 pmol NADP, 1 enhet glukose-6-fosfatdehydrogenase, 35 jjmol KxHy-fosfat pH 7,2, 20 pl enzympreparat og 56 nmol 3-hydroksy-3-metyl-glutaryl-koenzym A (glutaryl-3-<14>C) 1 000 000 ppm. For testing, the test compounds (or Mevinolin as a reference substance) were dissolved in dimethylformamide with the addition of 5% by volume IN NaOH and used in an amount of 10 µl in different concentrations in the enzyme test. This started after 20 minutes of pre-incubation of the compound with the enzyme at 37°C. The sample batch was 0.380 ml and contained 4 pmol glucose-6-phosphate, 1.1 mg bovine albumin, 2.1 pmol dithiothreitol, 0.35 pmol NADP, 1 unit glucose-6-phosphate dehydrogenase, 35 jjmol KxHy-phosphate pH 7.2, 20 pl enzyme preparation and 56 nmol 3-hydroxy-3-methyl-glutaryl-coenzyme A (glutaryl-3-<14>C) 1,000,000 ppm.
Man inkuberte i 60 minutter ved 37°C og stanset reaksjonen ved tilsetning av 300 pl 0,24 m HC1. Etter en etterinkubering på 60 minutter ved 37°C ble det hele sentrifugert og 600 pl supernatant bragt på en 0,7 cm x 4 cm søyle fylt med "Biorex" 5-klorid 100-200 mesh (anionbytter). Man vasket etter med 2 ml destillert vann og gjennomløpet pluss vaskevannet ble tilsatt 3 ml aquasol og tellet i en LKB-scintillasjonsteller. IC5Q-verdiene ble bestemt ved oppføring av den prosentuale hemming mot konsentrasjonen av forbindelsen i prøven ved intrapolering. For bestemmelse av den relative inhibitoriske potens ble ICsQ-verdien for referansesubstansen Mevinolin satt til 1 og sammenlignet med den simultanbestemte IC5Q-verdi til testforbindelsen. It was incubated for 60 minutes at 37°C and the reaction was stopped by the addition of 300 µl of 0.24 m HCl. After a post-incubation of 60 minutes at 37°C, the whole was centrifuged and 600 µl of supernatant was applied to a 0.7 cm x 4 cm column filled with "Biorex" 5-chloride 100-200 mesh (anion exchanger). One then washed with 2 ml of distilled water and the flow-through plus the wash water was added to 3 ml of aquasol and counted in an LKB scintillation counter. The IC5Q values were determined by plotting the percentage inhibition against the concentration of the compound in the sample by interpolation. To determine the relative inhibitory potency, the ICsQ value for the reference substance Mevinolin was set to 1 and compared with the simultaneously determined IC5Q value of the test compound.
De virksomme stoffer i eksemplene 1 til 23 viste en høyere virkning sammenlignet med Mevinolin. The active substances in examples 1 to 23 showed a higher effect compared to Mevinolin.
Eksempel 2Example 2
Den serum-kolesterin-senkende virkning for forbindelsene ifølge oppfinnelsen på blodkolesterinverdiene hos hunder og marsvin ble funnet ved et flere uker langt f6ringsforsøk. For dette formål ble stoffene som skulle undersøkes når det gjaldt hunder gitt til sunne Beagler i løpet av flere uker, en gang daglig, i en kapsel sammen med foret, per oralt. Til foret var det også under hele forsøksperioden, det vil si foran, under og etter administreringsperioden også tilsatt kolestyramin (4 g/100 g for som gallesyresekvestrerings-middel. The serum-cholesterol-lowering effect of the compounds according to the invention on the blood cholesterol values in dogs and guinea pigs was found in a feeding experiment lasting several weeks. For this purpose, the substances to be examined in the case of dogs were given to healthy Beagles during several weeks, once a day, in a capsule together with the feed, orally. Cholestyramine (4 g/100 g of feed as a bile acid sequestering agent) was also added to the feed during the entire experimental period, that is before, during and after the administration period.
To ganger i uken tappet man veneblod fra hundene og serum-kolesterin ble bestemt enzymatisk med kommersielt tilgjenge-lig testkit. Serumkolesterinverdiene under administreringsperioden ble sammenlignet med serumkolesterinverdiene før administreringsperioden (kontroller ). Twice a week, venous blood was drawn from the dogs and serum cholesterol was determined enzymatically with a commercially available test kit. The serum cholesterol values during the administration period were compared with the serum cholesterol values before the administration period (controls).
Marsvinene fikk prøvesubstansen i foret. Etter to uker tappet man blod og serumkolesterininnholdet ble bestemt. The guinea pigs received the test substance in their feed. After two weeks, blood was drawn and the serum cholesterol content was determined.
Claims (9)
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DE3805913A DE3805913A1 (en) | 1988-02-25 | 1988-02-25 | Substituted pyrimidines |
IT8822721A IT1227543B (en) | 1988-11-24 | 1988-11-24 | New 3-aryl-4-carboxy-di:hydroxy:alkyl-pyrimidine derivs. |
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NO890521D0 NO890521D0 (en) | 1989-02-08 |
NO890521L true NO890521L (en) | 1989-08-28 |
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NO89890521A NO890521L (en) | 1988-02-25 | 1989-02-08 | SUBSTITUTED PYRIMIDINES. |
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EP (1) | EP0330057A2 (en) |
JP (1) | JPH01261377A (en) |
CN (1) | CN1036954A (en) |
AU (1) | AU3020289A (en) |
DK (1) | DK88989D0 (en) |
FI (1) | FI890868A (en) |
IL (1) | IL89376A0 (en) |
NO (1) | NO890521L (en) |
PT (1) | PT89809A (en) |
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ATE132496T1 (en) * | 1987-07-10 | 1996-01-15 | Hoechst Ag | 3-DESMETHYL-MEVALONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, PHARMACEUTICAL PREPARATIONS BASED ON THESE COMPOUNDS, THEIR USE AND INTERMEDIATE PRODUCTS |
DE3826814A1 (en) * | 1988-08-06 | 1990-02-08 | Hoechst Ag | NEW 6-FLUORO-3,5-DIHYDROXYCARBONSAEURES AND THEIR DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, THEIR USE AS MEDICAMENTS, PHARMACEUTICAL PREPARATES AND INTERMEDIATE PRODUCTS |
DE3832570A1 (en) * | 1988-09-24 | 1990-03-29 | Hoechst Ag | 7-SUBSTITUTED DERIVATIVES OF 3,5-DIHYDROXYHEPT-6-ACID, METHODS FOR THE PRODUCTION THEREOF, THEIR USE AS MEDICINAL PRODUCTS AND INTERMEDIATE PRODUCTS |
JP2648897B2 (en) | 1991-07-01 | 1997-09-03 | 塩野義製薬株式会社 | Pyrimidine derivatives |
EP0705837B1 (en) | 1994-09-06 | 2002-08-07 | Ube Industries, Ltd. | Preparation of 3-Oxy-5-oxo-6-heptenoic acid derivatives |
AR008789A1 (en) | 1996-07-31 | 2000-02-23 | Bayer Corp | PIRIDINES AND SUBSTITUTED BIPHENYLS |
GB0001621D0 (en) | 2000-01-26 | 2000-03-15 | Astrazeneca Ab | Pharmaceutical compositions |
TW200614993A (en) | 2004-06-11 | 2006-05-16 | Akzo Nobel Nv | 4-phenyl-pyrimidine-2-carbonitrile derivatives |
US8372877B2 (en) | 2010-04-16 | 2013-02-12 | Cumberland Pharmaceuticals | Stabilized statin formulations |
CN103153299A (en) | 2010-10-06 | 2013-06-12 | 国立大学法人东京大学 | Prophylactic and/or therapeutic agent against lymphedema |
EP3184103A1 (en) | 2015-12-21 | 2017-06-28 | Hexal AG | Pharmaceutical composition comprising atorvastatin or a salt thereof |
-
1989
- 1989-02-08 NO NO89890521A patent/NO890521L/en unknown
- 1989-02-15 EP EP89102536A patent/EP0330057A2/en not_active Withdrawn
- 1989-02-22 JP JP1040462A patent/JPH01261377A/en active Pending
- 1989-02-22 IL IL89376A patent/IL89376A0/en unknown
- 1989-02-22 AU AU30202/89A patent/AU3020289A/en not_active Abandoned
- 1989-02-23 FI FI890868A patent/FI890868A/en not_active Application Discontinuation
- 1989-02-23 PT PT89809A patent/PT89809A/en not_active Application Discontinuation
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NO890521D0 (en) | 1989-02-08 |
AU3020289A (en) | 1989-08-31 |
FI890868A (en) | 1989-08-26 |
JPH01261377A (en) | 1989-10-18 |
CN1036954A (en) | 1989-11-08 |
FI890868A0 (en) | 1989-02-23 |
EP0330057A2 (en) | 1989-08-30 |
PT89809A (en) | 1989-10-04 |
DK88989D0 (en) | 1989-02-24 |
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