SK594A3 - Method of preparation of sulfur imidazole derivatives and intermediates - Google Patents
Method of preparation of sulfur imidazole derivatives and intermediates Download PDFInfo
- Publication number
- SK594A3 SK594A3 SK5-94A SK594A SK594A3 SK 594 A3 SK594 A3 SK 594A3 SK 594 A SK594 A SK 594A SK 594 A3 SK594 A3 SK 594A3
- Authority
- SK
- Slovakia
- Prior art keywords
- formula
- alkyl
- carbon atoms
- radical
- butyl
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims description 47
- 238000000034 method Methods 0.000 title claims description 36
- 239000000543 intermediate Substances 0.000 title description 4
- RLYNUCZWGJPITA-UHFFFAOYSA-N [S].C1=CNC=N1 Chemical class [S].C1=CNC=N1 RLYNUCZWGJPITA-UHFFFAOYSA-N 0.000 title description 2
- -1 mercapto, formyl Chemical group 0.000 claims description 204
- 125000004432 carbon atom Chemical group C* 0.000 claims description 58
- 150000003254 radicals Chemical class 0.000 claims description 48
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 43
- 150000003839 salts Chemical class 0.000 claims description 42
- 125000000217 alkyl group Chemical group 0.000 claims description 40
- 125000003545 alkoxy group Chemical group 0.000 claims description 39
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 39
- 238000006243 chemical reaction Methods 0.000 claims description 35
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 34
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 32
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 30
- 125000004414 alkyl thio group Chemical group 0.000 claims description 29
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 27
- 150000001875 compounds Chemical class 0.000 claims description 26
- 239000002253 acid Substances 0.000 claims description 25
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 24
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 23
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 23
- 239000011707 mineral Substances 0.000 claims description 23
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 22
- 125000005843 halogen group Chemical group 0.000 claims description 22
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 22
- 230000008569 process Effects 0.000 claims description 21
- 229910052717 sulfur Inorganic materials 0.000 claims description 20
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 18
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 16
- 125000004423 acyloxy group Chemical group 0.000 claims description 15
- 235000010290 biphenyl Nutrition 0.000 claims description 15
- 125000000524 functional group Chemical group 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 150000007524 organic acids Chemical class 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 12
- 150000007522 mineralic acids Chemical class 0.000 claims description 12
- 125000004076 pyridyl group Chemical group 0.000 claims description 12
- 125000004434 sulfur atom Chemical group 0.000 claims description 12
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 11
- 125000003342 alkenyl group Chemical group 0.000 claims description 11
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 11
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 11
- 239000011593 sulfur Substances 0.000 claims description 11
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 11
- 125000002252 acyl group Chemical group 0.000 claims description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 10
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 150000007530 organic bases Chemical class 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 8
- 235000005985 organic acids Nutrition 0.000 claims description 8
- 150000003462 sulfoxides Chemical class 0.000 claims description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 7
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 7
- 125000005842 heteroatom Chemical group 0.000 claims description 7
- KKFDJZZADQONDE-UHFFFAOYSA-N (hydridonitrato)hydroxidocarbon(.) Chemical compound O[C]=N KKFDJZZADQONDE-UHFFFAOYSA-N 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 6
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 6
- 239000004305 biphenyl Substances 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 239000001301 oxygen Chemical group 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 6
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 5
- 230000003647 oxidation Effects 0.000 claims description 5
- 238000007254 oxidation reaction Methods 0.000 claims description 5
- 125000006239 protecting group Chemical group 0.000 claims description 5
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 5
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical group [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 4
- 125000003158 alcohol group Chemical group 0.000 claims description 4
- 229910052796 boron Inorganic materials 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 125000002720 diazolyl group Chemical group 0.000 claims description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 150000002825 nitriles Chemical group 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 125000003386 piperidinyl group Chemical group 0.000 claims description 4
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 claims description 4
- 230000009467 reduction Effects 0.000 claims description 4
- 125000006413 ring segment Chemical group 0.000 claims description 4
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 4
- 150000003457 sulfones Chemical class 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 125000000335 thiazolyl group Chemical group 0.000 claims description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
- 125000005997 bromomethyl group Chemical group 0.000 claims description 3
- 125000004705 ethylthio group Chemical group C(C)S* 0.000 claims description 3
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 3
- 150000003536 tetrazoles Chemical class 0.000 claims description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 3
- 229920002554 vinyl polymer Polymers 0.000 claims description 3
- 125000000304 alkynyl group Chemical group 0.000 claims description 2
- 125000004185 ester group Chemical group 0.000 claims description 2
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 2
- 125000001188 haloalkyl group Chemical group 0.000 claims description 2
- 125000004995 haloalkylthio group Chemical group 0.000 claims description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- ORTFAQDWJHRMNX-UHFFFAOYSA-M oxidooxomethyl Chemical compound [O-][C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-M 0.000 claims description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 2
- 125000005415 substituted alkoxy group Chemical group 0.000 claims description 2
- 125000001174 sulfone group Chemical group 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims 1
- RRIPXSCKGCCVJA-UHFFFAOYSA-N CSC1=C(N(C=N1)CC2=CC=C(C=C2)C3=CC=CC=C3C4=NNN=N4)C(=O)O Chemical compound CSC1=C(N(C=N1)CC2=CC=C(C=C2)C3=CC=CC=C3C4=NNN=N4)C(=O)O RRIPXSCKGCCVJA-UHFFFAOYSA-N 0.000 claims 1
- 235000015429 Mirabilis expansa Nutrition 0.000 claims 1
- 244000294411 Mirabilis expansa Species 0.000 claims 1
- CXOFVDLJLONNDW-UHFFFAOYSA-N Phenytoin Chemical compound N1C(=O)NC(=O)C1(C=1C=CC=CC=1)C1=CC=CC=C1 CXOFVDLJLONNDW-UHFFFAOYSA-N 0.000 claims 1
- 125000005741 alkyl alkenyl group Chemical group 0.000 claims 1
- 125000004103 aminoalkyl group Chemical group 0.000 claims 1
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims 1
- ZPTIXGACNDKMFL-UHFFFAOYSA-N ethyl 2-butyl-3-[[4-(4,4-dimethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-5-methylsulfanylimidazole-4-carboxylate Chemical compound CCCCC1=NC(SC)=C(C(=O)OCC)N1CC1=CC=C(B2OC(C)(C)CO2)C=C1 ZPTIXGACNDKMFL-UHFFFAOYSA-N 0.000 claims 1
- BLNWTAHYTCHDJH-UHFFFAOYSA-O hydroxy(oxo)azanium Chemical compound O[NH+]=O BLNWTAHYTCHDJH-UHFFFAOYSA-O 0.000 claims 1
- TUJKJAMUKRIRHC-UHFFFAOYSA-N hydroxyl Chemical compound [OH] TUJKJAMUKRIRHC-UHFFFAOYSA-N 0.000 claims 1
- 235000013536 miso Nutrition 0.000 claims 1
- 239000007858 starting material Substances 0.000 claims 1
- 239000000047 product Substances 0.000 description 149
- 239000000203 mixture Substances 0.000 description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 229910052801 chlorine Inorganic materials 0.000 description 8
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 8
- 125000006308 propyl amino group Chemical group 0.000 description 8
- 239000000460 chlorine Substances 0.000 description 7
- 229910052763 palladium Inorganic materials 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- 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 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 229940024606 amino acid Drugs 0.000 description 5
- 235000001014 amino acid Nutrition 0.000 description 5
- 125000003277 amino group Chemical group 0.000 description 5
- 125000001309 chloro group Chemical group Cl* 0.000 description 5
- 229940093915 gynecological organic acid Drugs 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- KCIDZIIHRGYJAE-YGFYJFDDSA-L dipotassium;[(2r,3r,4s,5r,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] phosphate Chemical class [K+].[K+].OC[C@H]1O[C@H](OP([O-])([O-])=O)[C@H](O)[C@@H](O)[C@H]1O KCIDZIIHRGYJAE-YGFYJFDDSA-L 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 4
- ILPIQJLAIDENHN-UHFFFAOYSA-N ethyl 2-butyl-4-methylsulfanyl-1h-imidazole-5-carboxylate Chemical compound CCCCC1=NC(SC)=C(C(=O)OCC)N1 ILPIQJLAIDENHN-UHFFFAOYSA-N 0.000 description 4
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- JKHHRSIUFVAEOY-UHFFFAOYSA-N 2-iodobenzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1I JKHHRSIUFVAEOY-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 101100448366 Arabidopsis thaliana GH3.12 gene Proteins 0.000 description 3
- 101100129007 Arabidopsis thaliana LTD gene Proteins 0.000 description 3
- 101100505385 Mus musculus Gpd1 gene Proteins 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 125000005115 alkyl carbamoyl group Chemical group 0.000 description 3
- 125000005621 boronate group Chemical class 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000032050 esterification Effects 0.000 description 3
- 238000005886 esterification reaction Methods 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 238000001819 mass spectrum Methods 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000007127 saponification reaction Methods 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-bis(diphenylphosphino)propane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- OQURWGJAWSLGQG-UHFFFAOYSA-N 1-isocyanatopropane Chemical compound CCCN=C=O OQURWGJAWSLGQG-UHFFFAOYSA-N 0.000 description 2
- NKWCGTOZTHZDHB-UHFFFAOYSA-N 1h-imidazol-1-ium-4-carboxylate Chemical compound OC(=O)C1=CNC=N1 NKWCGTOZTHZDHB-UHFFFAOYSA-N 0.000 description 2
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- LULAYUGMBFYYEX-UHFFFAOYSA-N 3-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 2
- ZIYGZFBRRWHRNR-UHFFFAOYSA-N 3-methylsulfanylimidazole-4-carboxylic acid Chemical compound CSN1C=NC=C1C(=O)O ZIYGZFBRRWHRNR-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- 108010064733 Angiotensins Proteins 0.000 description 2
- 102000015427 Angiotensins Human genes 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
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- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- RCTYPNKXASFOBE-UHFFFAOYSA-M chloromercury Chemical compound [Hg]Cl RCTYPNKXASFOBE-UHFFFAOYSA-M 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 125000000068 chlorophenyl group Chemical group 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 229940127271 compound 49 Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229920001577 copolymer Chemical class 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- 125000005366 cycloalkylthio group Chemical group 0.000 description 1
- AAFFTDXPYADISO-UHFFFAOYSA-N cyclohexyne Chemical compound C1CCC#CC1 AAFFTDXPYADISO-UHFFFAOYSA-N 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 229960002887 deanol Drugs 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 239000012972 dimethylethanolamine Substances 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- KLWYPRNPRNPORS-UHFFFAOYSA-N ethyl 1h-imidazole-5-carboxylate Chemical compound CCOC(=O)C1=CN=CN1 KLWYPRNPRNPORS-UHFFFAOYSA-N 0.000 description 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 1
- 125000006125 ethylsulfonyl group Chemical group 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000019256 formaldehyde Nutrition 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Substances OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 1
- 125000003838 furazanyl group Chemical group 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 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 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- BICAGYDGRXJYGD-UHFFFAOYSA-N hydrobromide;hydrochloride Chemical compound Cl.Br BICAGYDGRXJYGD-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- OPUAWDUYWRUIIL-UHFFFAOYSA-N methanedisulfonic acid Chemical compound OS(=O)(=O)CS(O)(=O)=O OPUAWDUYWRUIIL-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- CRVGTESFCCXCTH-UHFFFAOYSA-N methyl diethanolamine Chemical compound OCCN(C)CCO CRVGTESFCCXCTH-UHFFFAOYSA-N 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- SLCVBVWXLSEKPL-UHFFFAOYSA-N neopentyl glycol Chemical compound OCC(C)(C)CO SLCVBVWXLSEKPL-UHFFFAOYSA-N 0.000 description 1
- 125000002560 nitrile group Chemical group 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000002687 nonaqueous vehicle Substances 0.000 description 1
- RQFLGKYCYMMRMC-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O RQFLGKYCYMMRMC-UHFFFAOYSA-N 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 150000002940 palladium Chemical class 0.000 description 1
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- DUCKXCGALKOSJF-UHFFFAOYSA-N pentanoyl pentanoate Chemical compound CCCCC(=O)OC(=O)CCCC DUCKXCGALKOSJF-UHFFFAOYSA-N 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 125000005544 phthalimido group Chemical group 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 150000003057 platinum Chemical class 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920000166 polytrimethylene carbonate Polymers 0.000 description 1
- ZDHURYWHEBEGHO-UHFFFAOYSA-N potassiopotassium Chemical compound [K].[K] ZDHURYWHEBEGHO-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
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- AAZYNPCMLRQUHI-UHFFFAOYSA-N propan-2-one;2-propan-2-yloxypropane Chemical compound CC(C)=O.CC(C)OC(C)C AAZYNPCMLRQUHI-UHFFFAOYSA-N 0.000 description 1
- ULWHHBHJGPPBCO-UHFFFAOYSA-N propane-1,1-diol Chemical compound CCC(O)O ULWHHBHJGPPBCO-UHFFFAOYSA-N 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- CSMWJXBSXGUPGY-UHFFFAOYSA-L sodium dithionate Chemical compound [Na+].[Na+].[O-]S(=O)(=O)S([O-])(=O)=O CSMWJXBSXGUPGY-UHFFFAOYSA-L 0.000 description 1
- 229940075931 sodium dithionate Drugs 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 125000005017 substituted alkenyl group Chemical group 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- 125000005555 sulfoximide group Chemical group 0.000 description 1
- 125000004354 sulfur functional group Chemical group 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- IWVMCIAPBOORJL-UHFFFAOYSA-N thieno[2,3-b]furan Chemical compound C1=CSC2=C1C=CO2 IWVMCIAPBOORJL-UHFFFAOYSA-N 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000004360 trifluorophenyl group Chemical group 0.000 description 1
- 239000013638 trimer Substances 0.000 description 1
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 230000001228 trophic effect Effects 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 230000003639 vasoconstrictive effect Effects 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/91—Nitro radicals
- C07D233/92—Nitro radicals attached in position 4 or 5
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D233/58—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Epoxy Resins (AREA)
- Cephalosporin Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Description
Oblast technikyTechnical field
Vynález sa týka nového spôsobu prípravy sírnych derivátov imidazolu a získaných nových medziproduktov.The present invention relates to a novel process for the preparation of sulfur imidazole derivatives and to novel intermediates obtained.
Podstata vynálezuSUMMARY OF THE INVENTION
Predmetom vynálezu je nový spôsob prípravy produktov vzorca IThe present invention provides a novel process for the preparation of the products of formula I
kdewhere
R predstavuje alkylový, alkenylový, alkinylový zvyšok alebo' alkyltioskupinu, pričom každý z týchto zvyškov je lineárny alebo rozvetvený a obsahuje až 10 atómov uhlíka alebo cykloalkylový zvyšok s 3 až 7 atómami uhlíka, pričom všetky tieto zvyšky sú prípadne, substituované .R represents an alkyl, alkenyl, alkynyl or alkylthio radical, each of which is linear or branched and contains up to 10 carbon atoms or a cycloalkyl radical of 3 to 7 carbon atoms, all of which are optionally substituted.
R9 a R^, rovnaké alebo rôzne, sú vybrané zo súboru zahŕňajúceho a/ atóm vodíka, atómy halogénu, zvySky hydroxylový, merkapto, íormylový, acylový, karboxy voľný, vo forme soli alebo esterifikovaný, nitro, kyano a -PO^ÍR^» predstavuje atóm vodíka alebo prípadne substituovaný alkylový alebo fenylový zvyšok.R 9 and R 9 , the same or different, are selected from the group consisting of a / hydrogen, halogen atoms, hydroxyl, mercapto, methyl, acyl, carboxy free, in salt or esterified, nitro, cyano and -PO 4 R 6 »Represents a hydrogen atom or an optionally substituted alkyl or phenyl radical.
b/ zvyšok “(^Η2)πίη rS(0?m2-X-R1 q, kde predstavuje celé číslo 0 až 4, ^2 Predstavuje celé číslo 0 až 2 a X predstavuje jednoduchú väzbu alebo zvyšky -NH-,b / the remainder "(^ Η 2 ) πίη rS (0? m 2-XR 1 q, where it represents an integer from 0 to 4, ^ 2 Represents an integer from 0 to 2 and X represents a single bond or -NH-,
-NH-CO-, -NH-CO-O-, -N=CH-N-R13, -NH-CO-NH- a θ a R^3> rovnaké alebo rôzne, predstavujú atóm vodíka, lineárny alebo rozvetvený alkylový alebo alkenylový zvyšok až sa 6 atómami uhlíka, cykloalkyl s 3 až 6 atómami uhlíka, prípadne substituovaný fenyl alebo benzyl, dalej pyridyl, nitropyridyl, pyrimidyl, tetrazolyl, diazolyl, piperi.dinyl, alkylpiperidinyl, tiazolyl, alkyltiazolyl, tetrahydrofuranyl, metyltetrahydrofuranyL, c/ alkylový, aleknylový zvyšok, alkoxy alebo alkyltioskupinu, kde atóm síry je prípadne mono- alebo dioxidovaný, pričom každý z týchto zvyškov, lineárnych alebo rozvetvených a až so 6 atómami uhlíka, je prípadne prerušený jedným alebo niekolkými heteroatómami, vybranými zo súboru zahŕňajúceho atómy síry, kyslíka alebo dusíka, a prípadne substituovaný,-NH-CO-, -NH-CO-O-, -N = CH-NR 13 , -NH-CO-NH- and θ and R 3, same or different, represent a hydrogen atom, a linear or branched alkyl or alkenyl C 1 -C 6 -cycloalkyl, optionally substituted phenyl or benzyl, further pyridyl, nitropyridyl, pyrimidyl, tetrazolyl, diazolyl, piperidinyl, alkylpiperidinyl, thiazolyl, alkylthiazolyl, tetrahydrofuranyl, methyltetrahydrofuranyl, C 1-6 alkyl, an alkenyl, alkoxy or alkylthio group, wherein the sulfur atom is optionally mono- or dioxidated, each of which linear or branched and having up to 6 carbon atoms is optionally interrupted by one or more heteroatoms selected from the group consisting of sulfur, oxygen or nitrogen, and optionally substituted,
d./ fenylový, benzylový zvyšok a fenyltioskupinu, kde atóm síry je prípadne mono- alebo dioxidovaný, zvyšky, ktoré sú prípadne substituované,d.) a phenyl, benzyl radical and a phenylthio group, wherein the sulfur atom is optionally mono- or dioxidated, radicals which are optionally substituted,
Rg > Rg e/ zvyšky -CO-N < ' a -N < z r7 ' r9 z kde bucl Rg. 3 Ry alebo Rg a RQ, rovnaké alebo rôzne, sú vybrané zo súboru zahŕňajúcehoR> R e g / radicals -CO-N <'and N <7 from y' R 9 wherein the R Bucl. 3 R y or R g and R Q, same or different, are selected from
- atóm vodíka.,- a hydrogen atom,
- aminokyseliny,- amino acids,
- alkylový a alkenylový zvyšok .až so 6 atómami uhlíka, prípadne substituovaný,- alkyl and alkenyl radical having up to 6 carbon atoms, optionally substituted,
- fenylový, benzylový a fenetylový zvyšok, prípadne substituovaný,- phenyl, benzyl and phenethyl, optionally substituted,
- zvyšok -fCH27ml s^0^m2”X R10’ definovaný vyššie, alebo Rg a R^. alebo . Rg a R^ tvorí vždy s atómom dusíka, ku ktorému sú viazané, monocyklický zvyšok s 5-, 6 alebo 7 atómami v kruhu alebo zvyšok tvorený rovnakými alebo rôznymi kondenzovanými kruhmi s 8 až 14 atómami v kruhu obsahujúcimi prípadne jeden alebo niekolko Óalších heteroatómov, vybraných z atómov kyslíka, dusíka a síry, ktoré sú prípadne substituované jedným alebo niekolkými zvyškami, vybranými zo súboru zahŕňajúceho atómy halogénu, hydroxyl, nitro, alkyl a alkoxy až so 6 atómami uhlíka, amínoskupinu, prípadne substituovanú jedným ale bo dvoma rovnakými alebo rôznymi alkylovými zvyškami až so 6 atómami uhlíka a fenyl, alebo Rg a R^, rovnaké alebo rôzne, predstavujú acylový zvyšok alebo jeden zo substituentov Rg a R^ predstavuje karbamoylový, alkoxykarbonylový alebo benzyloxykarbonylový zvyšok alebo Rg a R^ tvoria spoločne s atómom dusíka, ku ktorému sú viazané, zvyšok ftalamido alebo sukcinimido, f/ zvyšok -S-S-R12> kde Rj 2 ma význam, uvedený pre R2 aleb R-j v odstavcooh a/ až e/ okrem zvyškov amíno a alkoxy, za podmienky, že aspoň jeden zo substituentov R2 a R^ pred stavuje- prípadne substituovanú alkoxyskupinu alebo zvyšok -(CH2)ml -S-(O )m2”x”Ri o s vyšäie definovaným významom.the residue -fCH 2 7 ml with 0 0 m2 2 m 2 X 10 R 10 ' as defined above, or R 8 and R 8. or. R g and R each forming with the nitrogen atom to which they are attached, a monocyclic radical containing 5, 6 or 7 ring atoms or a residue of the same or different fused rings with 8-14 ring atoms optionally containing one or more further pharmaceutical heteroatoms selected from oxygen, nitrogen and sulfur atoms optionally substituted by one or more radicals selected from halogen, hydroxyl, nitro, alkyl and alkoxy of up to 6 carbon atoms, amino optionally substituted by one or two of the same or different alkyl radicals having up to 6 carbon atoms and phenyl, or R g and R, identical or different, represent an acyl radical, or one of R g and R is carbamoyl, alkoxycarbonyl or benzyloxycarbonyl radical, or R g and R ^ taken together with the atom the nitrogen to which they are attached, the phthalamido or succinimido moiety, f / the residue -SSR 12 > where R 2 is as defined for R 2 or R 3 in para and a to e) except for amino and alkoxy, provided that at least one of R 2 and R 2 is an optionally substituted alkoxy or - (CH 2 ) ml -S (O) m 2 "x" R io st s SAIET defined meaning.
R^. je vybrané zo súboru zahŕňajúceho zvyšok ”^^^m1 ~S 0 s vyšsie definovaným významom, atómy halogénu* zvyšok nitro, zvyšky -(CH?)ml-COOR1 4,Rf. is selected from the residue "^^^ m1 ~ 0 In light zwitterionized defined meaning, halogen atoms, nitro * radical, radicals - (CH?) m -COOR 1 4,
-(CH2)' ^-sCONHR^ 4, -CN, kde m1 má vyššie uvedený význam, -SO2“NH-SO2.-R1 4, -NK-SO2-R1 4, -PO^R^,- (CH 2 ) 1 -sCONHR 4 , -CN, wherein m 1 is as defined above, -SO 2 NH-SO 2 , -R 14 , -NK-SO 2 -R 14 , -PO 2 R,
-NHsSCy-CF^ a -SO2“N=C(R^)-N (0¾) 2, -(0¾) m1-SO^ 4,-NHsSCy-CF 2 -SO ^, and "N = C (R ^) - N (0¾) 2, - (0¾) m1 -SO-4,
-CO-NH-OR14, -C0-NH-NH-S02“CF , -CO-NK-SC^-Rj 4 -ch2so2nhco-r14, -ch2conh-so2r1 4, -nhso2nhco-r*4 -CO-NH-OR 14 , -CO-NH-NH-SO 2 CF, -CO-NK-SC-R 4 -ch 2 so 2 nhco-r 14 , -ch 2 conh-so 2 r 1 4 , -nhso 2 nhco-r * 4
-NKC0NHS027R14, -CONHSO2NR14R15, -SO2NHCONR14R15, -SO2N(Ru)OR15, -SO2NHSO2R14, -SO2NHPOfR14)2, -C0NHP0(R14)2, SO2NHCN, -SO2NHCOR14, -SO2NHSO2NR14R1 r -SO2NHSO2NfGH2CH2)2Y, -NHSC^NHSO^ 4, -NHSC^NHPO^ j 2 , -NSSO2R14, “NRi4COGO2H, -S02NHG02R^4, kde R^.má vyáäie uvedený význam a R^ 4 a R^, rovnaké aleboírôzne, predstavujú atóm vodíka, alkylový zvyšok až so 6 atómami uhlíka alebo cykloalkylový zvyšok s 3 až 6 atómami uhlíka, prípadne substituovaný, a Y predstavuje atóm kyslíka alebo síry, pričom všetky zvyšky alkylové, alkenylové, cykloalkylové, alkyltio', fenyltio., alkoxy, fenylové, benzylové sú prípadne v-NKC0NHS0 2 7 R 14, -CONHSO 2 NR 14 R 15, -SO 2 NHCONR 14 R 15, -SO 2 N (R u) OR 15, -SO 2 NHSO 2 R 14, -SO 2 NHPOfR 14) 2, - C0NHP0 (R 14 ) 2 , SO 2 NHCN, -SO 2 NHCOR 14 , -SO 2 NHSO 2 NR 14 R 1 -SO 2 NHSO 2 NfGH 2 CH 2 ) 2 Y, -NHSC 4 NHSO 4 , -NHSC 4 NHPO 2 ^ j, -NSSO 2 R 14, 'DB i4 COGO 2 H, -S0 2 NHG0 2 R 4, wherein R .has higher above and R 4 and R, the same aleboírôzne, are H, an alkyl radical of up to 6 carbon atoms or a cycloalkyl radical of 3 to 6 carbon atoms optionally substituted, and Y represents an oxygen or sulfur atom, wherein all alkyl, alkenyl, cycloalkyl, alkylthio, phenylthio, alkoxy, phenyl, benzyl radicals are optionally in
disubtituované; jedným alebo niekolkými .zvyškami, vybratými zo súboru zahŕňajúceho atómy halogénu, hydroxyl, nitro, alkyl, alkenyl a alkoxy až so 4 atómami uhlíka, trifluormetyl, kyano, vdisubtituované; one or more radicals selected from the group consisting of halogen atoms, hydroxyl, nitro, alkyl, alkenyl and alkoxy of up to 4 carbon atoms, trifluoromethyl, cyano;
amŕno, mono a dialkylamíno, karboxyskupinu, volnú, vo forme soli alebo esterifikovanú, haloalkyl, alkyltio, haloalkyltio, haloalkoxy, fenyl, pyridyl, benzyl, fenetyl, benzoyl, fenoxy, benzyloxy, fenyltio, karbamoyl, acyl, acyloxy a tetrazolyl, a pričom všetky produkty vzorca I sú vo všetkých možných izomérnych racemických, enantiomérnych a diastereomérnych formách, rovnako ako adičných solí produktov vzorca I s minerálnymi a organickými kyselinami alebo s minerálnymi a anorganickými bázami, spočívajúce v tom, že so zlúčeninou vzorca IIamine, mono and dialkylamino, carboxy, free, in salt or esterified, haloalkyl, alkylthio, haloalkythio, haloalkoxy, phenyl, pyridyl, benzyl, phenethyl, benzoyl, phenoxy, benzyloxy, phenythio, carbamoyl, acyl, acyloxy and tetrazolyl, all products of formula I are in all possible isomeric racemic, enantiomeric and diastereomeric forms, as well as addition salts of the products of formula I with mineral and organic acids or with mineral and inorganic bases, consisting of the compound of formula II
// (II) kde R*1 , R*2 a ^*3 majú význam, uvedený vyššie pre R1 , resp. R^, resp. Rj, a kde sú prípadne reaktívne skupiny prípadne chránené, nechá reagovať so zlúčeninou vzorca III// (II) wherein R * 1 , R * 2 and R * 3 are as defined above for R 1 and R 2 , respectively. R ^, resp. R 1, and where optionally reactive groups are optionally protected, is reacted with a compound of formula III
Xi \Xi \
X2 (III) kde Hal predstavuje atóm halogénu, B predstavuje atóm boru a X1, X2 sú také, že buä X1 a X2, rovnaké alebo rôzne, predstavujú hydroxylový alkylový alebo alkoxyzvyšok až so 6 atómami uhlíka, fenyl alebo fenoxy, alebo X- s X~ tvoria s atómom boru, ku ktorému sú viazané / v cyklus vybraný zo súboru zahŕňajúcehoX 2 (III) wherein Hal represents a halogen atom, B represents a boron atom and X 1 , X 2 are such that either X 1 and X 2 , the same or different, represent a hydroxyl alkyl or alkoxy radical of up to 6 carbon atoms, phenyl or phenoxy, or X - with X - form with the boron atom to which they are bound / in a cycle selected from the group consisting of:
kde X3 predstavuje atóm vodíka alebo až so 4 atómami uhlíka, za vzniku produktu vzorca IV alkylový zvyšokwherein X 3 represents a hydrogen atom or up to 4 carbon atoms, to give the product of formula IV an alkyl radical
(IV) kde R*1 , R*2» r#3> X1 » X2 a E ma^ú vyššie potom sa produkt vzorca IV nechá reagovaí vzorca V uvedený význam, s produktom(IV) wherein R 1, R 2 »R # 3> X 1» E X 2 and m ^ u reens wherein the product of formula IV is reacted in the formula above, the product
R'4 (V) kde X. predstavuje atóm halogénu, alkoxy, triflát alebo -O-SC^F a R 4. má význam, uvedený vyššie pre kde prípadné funkčné skupiny sú prípadne chránené., za vzniku produktu vzorca IR '4 (V) wherein X 1 represents a halogen atom, alkoxy, triflate or -O-SO 4 F and R 4 has the meaning given above for which optional functional groups are optionally protected, to give the product of formula I
ktorý sa, ak je to žiadúce a nutné, podrobí jednej alebo n ekolkým nasledujúcim reakciám v akomkolvek poradí :which, if desired and necessary, undergoes one or more of the following reactions in any order:
a/ odstránenie chrániacich skupín, ktoré môžu niesí chránené reaktívne skupiny, b/ prevedenie na sol minerálnou alebo organickou kyselinou alebo bázou, c/ esterifikácia; funkčnej skupiny kyseliny, d/ zmydelnenie esterovej skupiny, e/ premena kyanoskupiny na funkčné skupiny kyseliny, f/ redukcia karboxyskupiny na alkoholickú skupinu, g/ premena alkoxyskupiny na hydroxylovú skupinu, h/ oxidácia skupiny, obsahujúcej atóm síry, na zodpovedajúcu .sulfoxidovú alebo sulfónovú skupinu, i/ premena sulfoxidovej alebo sulfónovej skupiny na zodpovedajúcu sulfoximínovú skupinu,a) removing protecting groups that may carry protected reactive groups, b) converting to a salt with a mineral or organic acid or base, c) esterification; d) saponification of the ester group, e / conversion of the cyano group to acid functionality, f / reduction of the carboxy group to an alcohol group, g / conversion of the alkoxy group to a hydroxyl group, h / oxidation of the sulfur-containing group to the corresponding sulfoxide or sulfonic acid groups i) converting a sulfoxide or sulfone group to the corresponding sulfoximine group,
j./ premena nítrilového zvyšku na tetrazol, k/ rozštiepenie racemických foriem na jednotlivé produkty,j) / conversion of the nitrile residue to tetrazole, k / resolution of racemic forms into individual products,
1/ premena karboxylového zvyšku na karbamoylový zvyšok, m/ premena karbamoylového zvyšku na nitrilový zvyšok, pričom takto získané produkty vzorca I sú vo všetkých možných izomérnych racemických, enantiomérnych a diastereo márnych formách.1) conversion of the carboxyl radical to a carbamoyl radical, m / conversion of the carbamoyl radical to a nitrile radical, the products of the formula I thus obtained being in all possible isomeric racemic, enantiomeric and diastereomeric forms.
Vo vyššie definovanom zvyšku -ÍCHg) -S θ v prípade, že m je rôzne od ú, má (CH2)m1 význam alkylénového zvyšku, ako je napríklad metylén, etylén, n-propylén alebo n-butylén, a predovšetkým v prípade, ked m..j predstavuje hodnotu 0., 1 alebo 2, predstavuje zvyšok (CHg) jednoduchú väzbu, resp. metylénový zvyšok, resp, etylénový zvyšok.In the above-defined residue -ÍCHg) S θ where m is different from the L, a (CH 2) m1 defined alkylene radical such as methylene, ethylene, n-propylene or n-butylene, and in particular when when m = 0, 1 or 2, the residue (CHg) represents a single bond, respectively. a methylene residue and an ethylene residue, respectively.
Medzi významy -SÍO^-X-I^ θ je možné ako nie vyčerpávajúce príklady uviest zvyšky -S0o-NH2, -SC^-NH-CK^,The values of ^ -S ^ θ-XI that can not exhaustive examples of the mentioned radicals -S0 2 -NH-, -S-C-NH-CK ^.
-3Ο2-ΝΗ-Ο?3,-3Ο 2 -ΝΗ-Ο? 3 ,
-S0o-NH-GHo-G,H 2 2 o-S0 of the GH-NH-G, H 2 O 2
-CHo-SOo-NHCHO-Soo-NH
-CH9-SO2-NH-C6H5, -5O9-NK-CO-NH-CH3, ,-NK-CO-NK-v -SÓo-NH-CO-NH-CK. ,-CrK-CH 9 -SO 2 -NH-C 6 H 5 , -5O 9 -NK-CO-NH-CH 3 , -NK-CO-NK-v -So-NH-CO-NH-CK. , C r C
-SO^-NH-CO-NH-G^,-SO-NH-CO-NH-G ^,
-Sd.-NH-CO-NH-D,-Sd.-NH-CO-NH-D,
-S0o-NK-C0-NK-CF., .-S0 the -NK-C0-NL-CF.,.
J 2 2 c j ’ 2 kde D predstavuje fenylový, pyridínový alebo pyrimidínovýJ 2 2 c j '2 wherein D represents phenyl, pyridine or pyrimidine
zvyšok, -3O2-MH-G0-NH-CH2-((JV-VSO2-íÍS-=GO-ÍÍH-OH2-CH2-CH3,the remainder, -3O 2 -MH-G0-NH-CH 2 - ((JV-VSO 2 -isS- = GO-1H-OH 2 -CH 2 -CH 3 ,
-S02-NK-C0-NH-CH=GH-GH,, -S02-xNH-C0-NH-CH2-C=CH, kde A a B, A 3 rovnaké alebo rôzne, sú vybrané zo súboru zahŕňajúceho atóm vodíka, fenylový, pyridylový a pyrimidylový zvyšok,-SO 2 -NK-CO-NH-CH = GH-GH, -SO 2 -xNH-CO-NH-CH 2 -C = CH, wherein A and B, A 3 are the same or different are selected from the group consisting of a hydrogen atom, a phenyl, pyridyl and pyrimidyl radical,
-S 09-NK-C 0-NH-GHy-GK? -S 0 9 -NK-C 0-NH-GH y -GK ?
-so2-nh-co-nh-ce2-ξ-so 2 -nh-co-nh-ce 2 -ξ
N· •M i'# _N · • M '# _
-SO--NK-GO-NH- GH2 n-<^ y X N=/ , kde n = 1 alebo 2-SO-NK-GO-NH-GH 2 n - > X N = /, where n = 1 or 2
V produktoch vzorca 1 a v nasledujúcom texteIn the products of Formula 1 and in the following
- výraz lineárny alebo rozvetvený alkylový zvyšok označuje prednostne metyl, etyl, propyl, izopropyl, butyl, izobutyl, sek. butyl a terc. butyl, avšak môže rovnako znamenat pentyl, alebo· hexyl a predovšetkým isopentyl a izohexyl,the term linear or branched alkyl radical denotes preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. butyl and tert. butyl, but may also be pentyl or hexyl, and in particular isopentyl and isohexyl,
- výraz lineárny alebo rozvetvený alkenylový zvyšok označuje prednostne vinyl, allyl, 1-propenyl, butenyl a predovšetkým 1-outenyl alebo pentenyl,- the term linear or branched alkenyl radical denotes preferably vinyl, allyl, 1-propenyl, butenyl and especially 1-outenyl or pentenyl,
- výraz lineárny alebo rozvetvený alkinylový zvyšok označuje prednostne lineárny alebo rozvetvený etinyi, propinyl, butynil,- the term linear or branched alkynyl radical denotes preferably linear or branched ethynyl, propynyl, butynil,
- ako príklady alkylových zvyškov, prerušených jedným alebo niekolkými heteroatómami, je možné uviest metoxymetyl, metoxyetoxymetyl, propyitiopropyl, propyloxypropyl, propyltioetyl, metyltiometyl,examples of alkyl radicals interrupted by one or more heteroatoms include methoxymethyl, methoxyethoxymethyl, propythiopropyl, propyloxypropyl, propylthioethyl, methylthiomethyl,
- výraz atóm halogénu označuje prednostne atóm chlóru alebo brómu, ale môže tiež znamenat atóm fluóru alebo jódu,- the term halogen atom preferably denotes a chlorine or bromine atom, but may also be a fluorine or iodine atom,
- výraz lineárna alebo rozvetvená slkoxyskupina označuje prednostne zvyšky metoxy, etoxy, propoxy alebo izopropoxy, ale môže tiež znamenat lineárnu, sekundárnu alebo terciárnu but cxyskupinu,- the term linear or branched alkoxy preferably denotes methoxy, ethoxy, propoxy or isopropoxy, but may also mean linear, secondary or tertiary butoxy,
- výraz acylový zvyšok označuje prednostne zvyšok s 1 až 6 atómami uhlíka, ako je napríklad formyl, acetyl, propionyl, butyryl alebo benzoyi, ale rovnako pentanoyl, hexynoyl, akryloyi, krotonoyl alebo karbamoyl,the term acyl radical denotes preferably a radical having 1 to 6 carbon atoms, such as formyl, acetyl, propionyl, butyryl or benzoyl, but also pentanoyl, hexynoyl, acryloyi, crotonoyl or carbamoyl,
- výraz amínoskupina, substituovaná jedným alebo dvoma alkylovými zvyškami, označuje prednostne zvyšky,v ktorých je alkylový zvyšok alebo zvyšky vybrané zo zvyškov, definovaných vyššie,, ako je napríklad pre monoalkyiamíno zvyšok metylamínoalebo- etyiamíno alebo napríklad pre dialkylamíno,dimetylamínc alebo ďalej setyletylamino,the term amino substituted by one or two alkyl radicals refers preferably to radicals in which the alkyl radical or radicals are selected from the radicals as defined above, such as, for example, for a monoalkylamino radical methylamino or ethylamino or for dialkylamino, dimethylamino or further setylethylamino,
- výraz acyloxyskupina označuje zvyšok, v ktorom má acylový zvyšok vyššie uvedený význam, a prednostne znamená formyloxy, acetyloxy, propionyloxy, butyryloxy alebo benzyloxy,- acyloxy refers to a radical in which the acyl radical is as defined above, and preferably means formyloxy, acetyloxy, propionyloxy, butyryloxy or benzyloxy,
- výraz cykloaikylový zvyšok označuje prednostne cykiopropyl, cyklo'outyi, cyklopentyl alebo cyklohexyl,- the term cycloalkyl radical preferably denotes cycliopropyl, cycloethyl, cyclopentyl or cyclohexyl,
- výraz monocyklický zvyšok a zvyšok, tvorený kondenzovanými kruhmi označujú nasýtené alebo nenasýtené zvyšky,- the term monocyclic residue and the residue formed by fused rings refer to saturated or unsaturated residues,
- výraz monocyklický zvyšok označuje nasýtené zvyšky, napríklad pyrrolidinyl, ímidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl, morfolinyl, tiomorfolinyl, azepinyl, alebo nenasýtené zvyšky, napríklad pyranyl, pyrrolyl·, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tiazolyl·, tiadiazolyl, oxazolyi, ŕurazanyl, pyrrolinyl, ako je delta-2-pyrrolinyl, imidazolinyl, ako je delta-2—inri azolinyl, pyrazolinyl, ako je delta-j-pyrazolinyl, rovnako ako izoméry v polohe heteroatómu ale&o heteroatómov, ktoré môžu tieto zvyšky obsahoval, ako je napríklad izotiazolyl alebo izoxazolyl,- monocyclic radical denotes saturated radicals, for example pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, azepinyl, or unsaturated radicals, for example pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridimidinyl, pyridimidinyl, pyridimidinyl, pyridimidinyl thiadiazolyl, oxazolyl, furazanyl, pyrrolinyl, such as delta-2-pyrrolinyl, imidazolinyl, such as delta-2-indiazolinyl, pyrazolinyl, such as delta-β-pyrazolinyl, as well as isomers at the heteroatom position but heteroatoms which may have these residues contained, such as isothiazolyl or isoxazolyl,
- výraz zvyšok tvorený kondenzovanými kruhmi označuje nasýtené zvyšky, napríklad 1-oxaspiro[4,5] decyl, tetrahydrooyran-2-spiroeyklohexyl, cyklohexanspiro-2 '-(tezrshydrofuran) alebo- I, : O-daazaanth-4-yl, alebo nenasýtené zvyšky, napríklad bensotienyl, nafto£2,3-bJtienyl, indenyl, indolizinyl, izoindolyl, 3H-indolyl, indolyi, indazolyl, purinyl, chinolizinyl, benzopyrroiyl, benzimidasolyl, izochinolyl, chinolyl, ítalazinyi, naftyridinyl, chinoxalunyi, chinazolinyl, cinnolinyl, pteridinyl, kar’oazolyl, /-karboiinyl, akridinyl, í*enazinyl, indolinyl, izoindolinyi, alebo ďalej kondenzované poly cyklické systémy, tvorené heterocyklickými monocyklami, ktoré sú definované vyššie, ako je napríklad furoi[2,3-bJpyrrol ale bo ti eno [2,3 -b] f urán,the term fused-ring radical denotes saturated residues, for example 1-oxaspiro [4,5] decyl, tetrahydrooyran-2-spiroeyklohexyl, cyclohexanspiro-2 '- (tetrishydrofuran) or -1,10-daazaanth-4-yl, or unsaturated residues such as bensothienyl, naphtho [2,3-b] thienyl, indenyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, quinolizinyl, benzopyrrolidyl, benzimidasolyl, isoquinolyl, quinolyl, thiazolinyl, naphthyridinyl, quinolazolinyl ester, quinolazolinyl , carazolazolyl, t -carbinyl, acridinyl, isoeninyl, indolinyl, isoindolinyl, or further fused polycyclic systems consisting of heterocyclic monocycles as defined above, such as furo [2,3-b] pyrrole or thieno [ 2,3-b] furan,
- výraz haloalkyiový zvyšok označuje prednostne zvyšky, v ktorých má alkylový zvyšok vyššie uvedený význam a je substituovaný jedným alebo niekolkými atómami halogénu s vyššie uvedeným významom, napríklad brómetyl, triílucrmetyí, trifluóre.tyl, alebo ďalej pentafluóretyl,the term haloalkyl radical preferably denotes radicals in which the alkyl radical is as defined above and is substituted by one or more halogen atoms as defined above, for example bromomethyl, trifluoromethyl, trifluoromethyl or further pentafluoroethyl,
- výraz alkyltioskupina označuje prednostne zvyšky, v ktorých má alkylový zvyšok vyššie uvedený význam, napríklad· metyltio alebo etyltio,- the term alkylthio preferably denotes radicals in which the alkyl radical is as defined above, for example methylthio or ethylthio,
- výraz haloalkyltioskupina označuje prednostne zvyšky, v ktorých má alkylový zvyšok vyššie uvedený význam a je šube tituovaný jedným alebo viacerými atómami halogénu s vyššie uvedeným významom, napríklad brómetyltio, trifluórmetyltio, trifluoretyltio alebo dalej pentafluóretyltio,- the haloalkylthio group preferably denotes radicals in which the alkyl radical is as defined above and is substituted by one or more halogen atoms as defined above, for example bromomethylthio, trifluoromethylthio, trifluoroethylthio or other pentafluoroethylthio,
- výraz haloalkoxyskupina označuje prednostne zvyšky, v ktorých má alkoxyskupina vyššie uvedený význam a je substituovaná jedným alebo viacerými atómami halogénu s vyššie uvedeným významom, napríklad brómetoxy, trifluórmetoxy, trifluóretoxy alebo .ďalej pentafluóretoxy,- haloalkoxy preferably denotes radicals in which the alkoxy group is as defined above and is substituted by one or more halogen atoms as defined above, for example bromoethoxy, trifluoromethoxy, trifluoroethoxy or still pentafluoroethoxy,
- výraz karbamoylový zvyšok označuje tiež karbamoylové zvyšky, N-monosubstituované nižšou alkylovou skupinou, ako je: N-metylkarbamoyl, N-etylkarbamoyl, skupinu N,N-di(nižšiu) alkyikarbamoylovú, ako je Ν,Ν-dimetylkarbamoyl, N, N-di e tylkarbamoyl, skupinu N-(nižšiu, hydroxyalkyl)karbanoyiovú, ako je N-( hydroxymetyl)karbamoyl, N-(hydroxyetyl)karbamoyl, karbamoyl(nižší) a 1kyL, ako je karbamoylmetyl, karbamoyletyl,the term carbamoyl radical also denotes carbamoyl radicals, N-monosubstituted by lower alkyl, such as : N-methylcarbamoyl, N-ethylcarbamoyl, N, N-di (lower) alkylcarbamoyl, such as Ν, Ν-dimethylcarbamoyl, N, N- diethylcarbamoyl, an N- (lower, hydroxyalkyl) carbanoyl group such as N- (hydroxymethyl) carbamoyl, N- (hydroxyethyl) carbamoyl, carbamoyl (lower) and 1 alkyl such as carbamoylmethyl, carbamoylethyl,
- výraz fenylový zvyšok, substituovaný aikyltioskupinou, predstavuje napríklad henzyltioskupinu.the phenyl radical substituted with an alkylthio group represents, for example, a henzylthio group.
V produktoch vzorca Tav nasledujúcom texte môžu alkyiové, alkenylové, cykloalylové a fenyiové zvyšky, ktoré môžu predstavoval alebo ni.esl R^ , Rp, P. a R^, mal významy, vyššie uvedené pre tieto zvyšky a môžu byt nesubstituované alebo substituované jedným alebo niekoíkými rovnakými alebo rôznymi substituentami s vyššie uvedeným významom. P9 a R^ môžu napríklad predstavoval alkyltio, fenyltio, alkylsui.finyl, fenylsuiíinyl, alkylsulfonyl alebo arylsuifonyl, ale aj .cykloalkyitio skupinu, ako je napríklad cyklohexyltio,In the products of formula Tav below, the alkyl, alkenyl, cycloalyl and phenyl radicals which may be or are R 1, R p, P and R 3 may have the meanings given above for these radicals and may be unsubstituted or substituted by one or more radicals. several identical or different substituents as defined above. P 9 and R 6 may, for example, represent an alkylthio, phenylthio, alkylsulfinyl, phenylsulfinyl, alkylsulfonyl or arylsulfonyl group, but also a cycloalkylthio group such as cyclohexylthio,
- výrazy alkyltio, alkylsulíinyl a alkylsulfonyl označujú zvyšky, v ktorých lineárny alebo rozvetvený alkylový zvyšok môže mat. napríklad význam, uvedený vyššie pre s lkylové zvyšky : tieto zvyšky potom prednostne predstavujú metyltio, hydroxymetyltio, etyitio, amínoetyltio, metylsulfinyl, etylsulfinyl, metylsulfonyl, etylsulfonyl, ale môžu rovnako· znamenať propyltio, izopropyltio, butyltio, sek.butyltio, terc. butyltio, izopentyltio alebo izohexyltio alebo rovnaké zvyšky, v ktorých je tioskupina oxidovaná na sul fínylový alebo sulfonylový zvyšok,the terms alkylthio, alkylsulphinyl and alkylsulfonyl refer to radicals in which a linear or branched alkyl radical may have. for example, the meaning given above for alkyl radicals: these radicals then preferably represent methylthio, hydroxymethylthio, ethylthio, aminoethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, but may also be propylthio, isopropylthio, butylthio, tert-butylthio, tert-butyl. butylthio, isopentylthio or isohexylthio or the same radicals in which the thio group is oxidized to a sulphinyl or sulphonyl radical,
Podlá významu m^, a - (CH, “S (0) πι2-^^1 0 ”2 zvyšky : fenyltio, pyridyltio lyltio, N-metylímidazolyltio, je tioskupina oxidovaná na sul „ vo zvyšku U a R^ tiež predstavoval tieto alebo· pyrimidyltio, imidazorovnako ako zvyšky, v ktorých finyiovú alebo suifonylovú skupinu, ako- je napríklad fenyls inyl alebo fenylsulfonyl.According to the meaning of m ^, and - (CH, “S (O) π2 - ^ ^ 1 0” 2 residues: phenylthio, pyridylthiolylthio, N-methylimidazolylthio, the thio group oxidized to the salt in the residue U and R ^ also represents these or Pyrimidylthio, imidazole as well as residues in which a finyl or suiphonyl group, such as phenylsinyl or phenylsulfonyl.
Ako on.-'ľlaay sudslí a^kyxovýcnzvyškov je možne uviest zvyšky substituované jedn mi zvyškami, napríklad benzyl, d a zvyšky substituované pyridylov dylmetyľ, pričom samozrejme v uv ým alebo niekoľkými fenylový ifenylmetyl, trifenyimetyl, ým zvyškom, napríklad pyriedenom nevyčerpávajúcom vyratúvaní propyl ai zvyškov môže alkylový zvyšok ebo butyl, ako napríklad vo rovnako znamenať etyl, fenetykovovom zvyšku.Examples of such compounds are those substituted with one residue, for example benzyl, and those substituted by pyridyl dylmethyl, with, of course, some or more phenyl ifenylmethyl, triphenyimethyl, and those, e.g. an alkyl or butyl radical, such as in the same meaning ethyl, may be a phenethylene radical.
Ako príklady substituovaných alkenylových možné uviest zvyšky substituované jedným, alebo fenylovými alebo pyridylovými zvyškami, ako je šie, pričom alkylový zvyšok je nahradený aikeny kom., napríklad fenyivinyl alebo fenyLallyl.Examples of substituted alkenyl include radicals substituted with one or phenyl or pyridyl radicals, such as the above, wherein the alkyl radical is replaced by aikenes com, e.g. phenyivinyl or phenylallyl.
zvyškov je niekolkými uvedené vyšiovým zvýš13 vyšáie uvedené karbamoylové zvyšky a amínoskupiny s hlavne.· zvyškyThe above-mentioned carbamoyl residues and amino groups are mainly mentioned.
aand
znamenajú zvyšky, v ktorých sú na atóm dusíka viazané dva zvyšky, rovnaké alebo rôzne, zvolené zo súboru zahŕňajúceho atóm vodíka za vzniku amínoskupiny, alkylové zvyšky s vyššie uvedeným významom za vzniku monoalkyl- alebo dialkyiamínoskupiny, v ktorých lineárne. alebo rozvetvené alkylové zvyšky obsahujú 1 až 6 atómov uhlíka, predovšetkým metyl, etyl, izopropyl, metoxymetyl, metoxyetyl a fenyl, benzyl alebo fenetyl, prípadne substituované za vzniku napríklad fenylamínoskupiny alebo benzylamía^oskupiny.means radicals in which two radicals, identical or different, are selected from the group consisting of hydrogen to form amino, alkyl radicals as defined above to form a monoalkyl or dialkylamino group in which they are linear. or branched alkyl radicals contain 1 to 6 carbon atoms, in particular methyl, ethyl, isopropyl, methoxymethyl, methoxyethyl and phenyl, benzyl or phenethyl, optionally substituted to form, for example, phenylamino or benzylamino.
Medzi substituovanými karbamoyiovými zvyškami je možné ako substituovaný karbamoylový zvyšok uviesl N-mono(nižšiuJ alkyl-karbamoylovú skupinu, napríklad M-metylkarbamoyl, N-etylkarbamoyl, N,N-di(nižšiu)alkylkarbamoyiovú skupinu, napríklad Μ,Ν-dimetylkarbamoyl, :I,K-dietylkarbamoyl, N-(nižší hydroxyalkyl)karbamoyl, napríklad M-(hydroxymetyi)karbamoyi, N-(hydroxyetyl)karbamoyl, nižšiu karbamoylalkylovú skupinu, napríklad karbaaoylmetyi, karbamoyletyl, fenylkarbamoyl, pyridylkarbamyol, M-mety1-N-fenylkarbamoyl, pyridylmetylkarbamoyl.Among the substituted carbamoyl radicals, N-mono (lower alkylcarbamoyl, e.g., N-methylcarbamoyl, N-ethylcarbamoyl, N, N-di (lower) alkylcarbamoyl, e.g., Μ, Ν-dimethylcarbamoyl) may be mentioned as substituted carbamoyl. N- (hydroxymethyl) carbamoyl, N- (hydroxyethyl) carbamoyl, lower carbamoylalkyl, e.g. carbamoylmethyl, carbamoylethyl, phenylcarbamoyl, pyridylcarbamoyl, N-methylmethyl-N-phenyl, .
Výraz aminokyselina označuje prednostne zvyšok odvodený od. jednej z prírodných aminokyselín, ako je glyc.ín, alanín, valín, leucín, izoleucín, íenylalalnín a predovšetkým prolín. alebo jednej z uaiších prírodných aminokyselín, známych odborníkom.The term amino acid preferably denotes a residue derived from. one of the natural amino acids such as glycine, alanine, valine, leucine, isoleucine, phenylalanine and especially proline. or one of the other natural amino acids known to those skilled in the art.
Medzi zvyšky -(CH2 )jnl -X-?1 Q, ktorá môžu predstavoval R<,Among the residues - (CH 2 ) n -X-? 1 Q , which may represent R <,
Ηγ, Rg alebo Rg, je možne uviest predovšetkým zvyšky -NH-SC^-CH^, -nh-so2-c6h , -nh-so2-gf3, -nh-ch2-so2-nh-g6h5^Ηγ, R g and R g, which may be mentioned in particular, radicals -NH-SC-CH ^ -NH-SO 2 -C 6 H -NH-SO2 -GF 3, -NH-CH 2 -SO 2 -NH -g 6 h 5
-Π-Π
O-NK-SO?-C2H5, -co-nk-so2-ch3, -co-nk-so2-ch9-c5h5 O-NK-SO 2 -C 2 H 5 , -co-nk-so 2 -ch 3 , -co-nk-so 2 -ch 9 -c 5 h 5
Heterocyklus, ktorý môžu tvoril Rg a R? alebo Rg a RQ, je prednostne nasýtený.Heterocycle that may be formed by Rg and R? or R 8 and R 8 , is preferably saturated.
Môže byt prípadne substituovaný vyššie uvedenými substitue.ntami, predovšetkým jedným alebo niekoľkými zvýšt v z z kami, vybranými so súboru, zahŕňajúceho atómy chlóru a fluóru, metyl, etyl, izopropyl, terc.butyl, metoxy, etoxy, propoxy, benzoyl, metoxykarbonyl, etoxykarbonyl : je. možné uvies* napríklad metylpiperazinyl, etylpiperazinyl, propylpiperasinyl, fenylpiperazinyl alebo benzylpiperazinyl : v týchto posledných dvoch zvyškoch môže byt fenyl a benzyl substituovaný vyššie uvedeným spôsobom, napríklad ako chlórfenyl alebo trifluórfenyl.It may be optionally substituted by the abovementioned substituents, in particular by one or more substituents selected from the group consisting of chlorine and fluorine atoms, methyl, ethyl, isopropyl, tert-butyl, methoxy, ethoxy, propoxy, benzoyl, methoxycarbonyl, ethoxycarbonyl: is a. for example methylpiperazinyl, ethylpiperazinyl, propylpiperasinyl, phenylpiperazinyl or benzylpiperazinyl: in the latter two residues, phenyl and benzyl may be substituted as described above, for example as chlorophenyl or trifluorophenyl.
Acy^ové svysxy, kcore môžu by- predovšetkým zvolené môžu oredstavoval Rc a R„,The acyloxy moieties which may be selected, in particular, may be R c and R c ,
S acetylového, propionylového, butyrylového, pentancylového a karbamoylového zvyšku.With an acetyl, propionyl, butyryl, pentancyl and carbamoyl radical.
Ak oredstavuje Rc alebo R„ alkoxykarbonylový zvyšok, je c v týmto zvyškom prednostne terc. butyloxykarbonyl.When R c or R c is an alkoxycarbonyl radical, c is preferably tert. butyloxycarbonyl.
Karboxylové zvyšky produktov vzorca I môžu byt vo forme soli alebo esterifikované rôznymi skupinami, známymi odborníkovi, medzi ktorými je možné napríklad uviest :The carboxyl residues of the products of formula (I) may be in the form of a salt or esterified with various groups known to those skilled in the art, including, for example:
- ako zlúčeniny, tvoriace soli, minerálne bá^-', ako je napríklad sodná, draselná, lítna, vápenatá, horečnatá alebo amónna soľ, alebo organické bázy , ako je napríklad me tylamín, propylamín, trimetylamín, dietylamín, trietylamín, Ν,Ν-dimatyletanolamín, tris(hydroxymetyl)amínoneoan, etanolamín, pyridín, pikolín, dicyklohexamín, morfolín, benzylamín, prokaín, lyzín, arginín, histidín, N-metylglukamín.- as salt-forming compounds, mineral bases such as sodium, potassium, lithium, calcium, magnesium or ammonium salt, or organic bases such as methylamine, propylamine, trimethylamine, diethylamine, triethylamine, Ν, Ν dimethylethanolamine, tris (hydroxymethyl) aminooneoane, ethanolamine, pyridine, picoline, dicyclohexamine, morpholine, benzylamine, procaine, lysine, arginine, histidine, N-methylglucamine.
- ako esterifikačné zlúčeniny alkylové zvyšky za vzniku aikoxykarbonylových skupín, ako je napríklad ne toxykartóny 1, etoxykarbonyl, terc.butoxykarbonyl alebo benzyloxykarbonyl, pričom tieto alkylové zvyšky nožu byt substituované zvyšky, zvolené napríklad z atómov halogénu, hydroxylu, skupín alkoxy, acyl, acyloxy, alkyltio·, amíno- alebo aryl, ako napríklad v skupinách chlórmetyl, hydroxypropyl, metoxymetyl, propionyloxymetyl, metyltiometyl, dimetylamínoetyl, benzyl alebo fenetyl.as esterifying compounds, alkyl radicals to form alkoxycarbonyl groups such as nontoxycartones 1, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl, these knife radicals being substituted by radicals selected from, for example, halogen, hydroxyl, alkoxy, acyl, acyloxy, alkylthio, amino or aryl such as in the groups chloromethyl, hydroxypropyl, methoxymethyl, propionyloxymethyl, methylthiomethyl, dimethylaminoethyl, benzyl or phenethyl.
Adičné soli produktov vzorca I s minerálnymi alebo organickými kyselinami môžu byt napríklad soli, vytvorené s kyselinou chlorovodíkovou, oromovodíkovou, jodovodíkovou, dusičnou, sírovou, fosforečnou, propionovcu, octovou, mravčou, benzoovou, maleínovou, fumarovou, jantárovou, vínnou, citrónovou, štavelovou, glyoxylovou, asparágovou, askorbovou, s 'kyselinami alkylmonosuifónovými, ako napríklad kyselina metansulfónová, kyselina etansulfónová, kyselina prooansulfonová, s kyselinami slkyidisulfónovými, ako je naprík' lad kyselina metandisulfónová, kyselina -etandisulfónová, s kyselinami aryimonosuifonovými, ako je kyselina benzénsulfónová a s kyselinami aryldisuifónovými.The mineral or organic acid addition salts of the products of formula (I) may be, for example, salts formed with hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, propionic, acetic, formic, benzoic, maleic, fumaric, succinic, tartaric, citric, glyoxyl, aspartic, ascorbic, with alkylmonosuifonic acids, such as methanesulfonic acid, ethanesulfonic acid, prooansulfonic acid, with slkyidisulfonic acids, such as methanedisulfonic acid, ethanedisulfonic acid, aryimonosuifonic acids, and aryimonosuifonic acids, such as methionosulfonic acid, such as benzenesulfonic acid.
Ak oba zvyšky a ? predstavujú sírnu skupinu aikyltio· alebo fenyltio, prípadne oxidovanú, pričom Ro a 3, sú rovnaké alebo rôzne, sú výhodnými :p>j£ftdttktaini... podlá vynálezu predovšetkým produkty vzorca 1, v ktorom majú tieto sírne skupiny ovnaký oxidačný stupeň u oredovsetedsn zo zvyškov Rn a R predscs—If both residues and? represent a sulfur or a group aikyltio · phenylthio optionally oxidized, and wherein the R 3, the same or different, are preferred: p> £ j ... ftdttktaini invention in particular the products of formula 1, in which the sulfur of the oxidation state of the same co lor oredovsetedsn from residues R n and R predscs—
Jedzi výhodnými produktami podlá vynálezi , kde .j<= kým produkty vzorca ľ vuje vyššie uvedenú sírnu skupinu, prípadne oxiuovsnú, a druhý so zvyškov R? a Rj predstavuje prednostne alkyl, alkoxy, karboxyskupinu volnú, vo forme soli alebo esteri_ikovanú alebo fenyl, prípadne substituovaný jedným alebo niekolkými substituentami, ako je definované vyššie.One preferred product of the present invention wherein the products of formula I 'is the above-mentioned sulfur group, optionally oxoic acid, and the other one of the radicals R @ 1. and R 1 is preferably alkyl, alkoxy, carboxy, free, in the form of a salt or esterified or phenyl, optionally substituted with one or more substituents as defined above.
Medzi vhodnými produktsmi podľa vynálezu sa konkrétne nachádzajú produkty vzorca 1, kde R2 predstavuje sírny zvyšok.Among the suitable products according to the invention are, in particular, products of formula 1, wherein R 2 represents a sulfur residue.
I?2 a/alebo R^ môže predovšetkým predstavoval zvyšky alkyltio albo alkenyltio, prípadne substituované jedným alebo niekoľkými zvyškami, vybranými zo skupiny zahŕňajúcej formyl, hydroxyl, alkoxy, acyloxy, karboxyskupinu voľnú, vo forme soli alebo esterifikovanú, amíno, substituovanú amínoskupinou, karbamoyl, substituovaný karbamoyl, alkyltio, fenyltio, pyridinyl, pyrimidinyL, fenyl.In particular, R 2 and / or R 6 may represent alkylthio or alkenylthio radicals, optionally substituted with one or more radicals selected from the group consisting of formyl, hydroxyl, alkoxy, acyloxy, carboxy, free, in salt form or esterified, amino substituted with amino, carbamoyl , substituted carbamoyl, alkylthio, phenylthio, pyridinyl, pyrimidinesL, phenyl.
Medzi substituentami, ktoré môžu niest zvyšky R9 a R<, môžu predovšetkým amínoskupina a karbamoyl byt substituované jedným alebo dvoma zvyškami a vyššie uvedenými aminokyselinami.Among the substituents which may be carried by the radicals R 9 and R 8, in particular the amino group and the carbamoyl may be substituted by one or two residues and the above-mentioned amino acids.
Substituované aaínoskupiny a karbamoylové zvyšky, ktoré môžu niest zvyšky R^ a R?, môžu rovnako tvoril hezeroeyklus, napríklad vyššie popísaného typu.Substituted amino groups and carbamoyl radicals which can carry R R and R a radicals . , may also formed hezeroeyklus, for example of the type described above.
Ro a R, môžu dalej predovšetkým predstavoval alkyltioskupiny, substituované jedným alebo niexoikými atómami naxogénu, ako je chlór a fluór. -Je možné uviest napríklad zvyš.ty — S—O-d « — o— «« — s—uŕí R a and R, it may in particular further represented alkylthio substituted by one or niexoikými naxogénu atoms such as chlorine and fluorine. It is possible to mention, for example, the remainder - S - From - - - -
vyšky Ro a R^, môžu t3kto oredstavovat nasledujúc^ zvyšky, kde n, n^ a n^, rovnaké alebo rôzne, môžu mat hodnotu 0 až 2 : -S-C-uH^, -SO^ií, -o-uH·^, *S-f ~S ”^4» the heights r and R, may t3kto oredstavovat following the ^ radicals wherein n ^ n ^ n, identical or different, may have a value of 0 to 2: -SO-uH ^, -SO ^ ii, o-^ · mH , * Sf ~ S ”^ 4»
-S-(CH2)n-X4, -S-(CH2)n1-MH-ÍCH2)n2-X4, -S-CH=CH-(CH2)n-X4,-S- (CH 2) n -X 4, -S- (CH 2) n 1 -NH-ICH 2) n 2 -X 4, -S-CH = CH- (CH 2) n -X 4,
-S-(CH2?pl-CH=CH-fCH2) 9-X4, kde X predstavuje H, OH, cyklohexyl, pyridyl, fenyí, OHO, GOOH, NH2 alebo-S- (CH 2? CH = CH full-FCH 2) 4 -X 9 wherein X is H, OH, cyclohexyl, pyridyl, phenyl, ERO, COOH, NH 2 or
V'IN'
N íN í
Rrrr
Zvyšky R^. a R^ môžu tiež predstavoval predovšetkým nasledujúce zvyšky : -GOOH, -GOjX^j ”SX^, -NH2,Residues R ^. and R 6 may also represent, in particular, the following radicals: -GOOH, -GO 1, X 1, X 2, -NH 2 ,
-OMe, OEt, -GH=GH-COOH, tetrazolyl,-OMe, OEt, -GH = GH-COOH, tetrazolyl,
-C=CCCH3>-CH2I-C CCCH3> -CH 2 I.
COOMeCOOMe
COOH COOIICOOH COOII
C - CHz -C - CH 2 -
vo všetkých izomérnych formách, izoméry cis-transin all isomeric forms, cis-trans isomers
-CH-NH-C-CH-NH-C
II
COOHCOOH
\\
0X50x5
-NH-CHz-COO-Xfe,NH-CH-COO-Xfe,
-NH-COO-X5, kde Χς predstavuje alkylový alebo arylový zvyšok,-NH-COO-X5, where Χς represents an alkyl or aryl radical,
Zvyšky R2: a R^ môžu predovšetkým predstavoval zvyšokRadicals R2 and R can be in particular a radical
-CO-NHΝ'-CO-NHΝ '
Produkty vzorca I teda predstavujú predovšetkým produkty, v ktorých 3 ^3 majú vyššie uvedený význam, a zvlášt produkty, v ktorých R^ Predstavuje vyššie definovanú aikyitioskupinu, prípadne substituovanú alebo alkoxyskupinu, ako je napríklad metoxy, a predstavuje karboxyskupinu vo vodnej forme, vo forme soli, esteru alebo amidu, ako je predovšetkým -GOOH, -COO-metyl, -COo-etyl, -CONH2 al.eboThe products of formula I, therefore, are in particular those wherein the 3 R 3 are as defined, and especially products in which R represents the above defined aikyitioskupinu, optionally substituted, or alkoxy, such as methoxy, a is carboxyl in aqueous form, in the form of a salt, ester or amide such as, in particular, -GOOH, -COO-methyl, -COo-ethyl, -CONH 2, or
N'-N h \x N'-N h \ x
-CO-NII-v/ N-CO-NII-v / N
NN
II
HH
Medzi prednostnými všetkým skupinu kyano, definovaným významom a významami R4 je možné menovat p skupinu -tCH?)ail-SOp-X-R1 θ s vyš zvlášt'· zvyšky -S02-NK-C0-NH~CHo redošieThe preferred all of cyano, and a defined meaning of R 4 is a group, may be mentioned p -tCH? ) Ail -SOp-XR 1 with t θ separately · radicals -S0 2 -NK-C0-NH -CH the Redos
:í-CO-NE-GH2-GHy 1-CO-NE-GH 2 -GH y
Predmetom vynálezu je predovšetkým vyššie uvedený pre prípravu produktov vzorca I, zodpovedajúcich vzorcuIn particular, the invention relates to the above for the preparation of products of the formula I corresponding to the formula
SD^SObSD ^ SOB
fla>fla>
kde.where.
R, predstavuje lineárny alebo rozvetvený alkylový alebo alkenylový zvyšok až so 4 atómami uhlíka, R2a a K3a rovnaka alebo rôzne, sú vybrané zo súboru zahŕňajúceho a/ atóm vodíka, merkapto, formyl, karboxyskupinu volnú vo forme soli alebo esterifikovanú, atómy halogénu, hydroxyl, kyano, nitro, acyl, b/ alkyl, alkenyl, alkoxy, alkyltio, kde atóm síry je prípadne mono- alebo dioxidovaný, pričom tieto zvyšky sú lineárne alebo rozvetvené a obsahujú až 6 atómov uhlíka, fenyl, benzoyl, fenyltio, kde atóm síry je prípadne mono- alebo dioxidovaný, pričom všetky · tieto zvyšky sú prípadne substituovaná jedným alebo niekolkými rovnakými alebo rôznymi zvyškami, vybranými zo súboru zahŕňajúceho atómy halogénu, hydroxyl, trifluormetyl, kyano, nitro, formyl, alkyl a alkoxyR 1 represents a linear or branched alkyl or alkenyl radical having up to 4 carbon atoms, R 2a and K 3a equally or differently are selected from the group consisting of a / hydrogen, mercapto, formyl, carboxy free in salt or esterified, halogen atoms, hydroxyl, cyano, nitro, acyl, b / alkyl, alkenyl, alkoxy, alkylthio, wherein the sulfur atom is optionally mono- or dioxidized, these radicals being linear or branched and containing up to 6 carbon atoms, phenyl, benzoyl, phenylthio, where the atom the sulfur is optionally mono- or dioxidated, all of which are optionally substituted with one or more of the same or different radicals selected from the group consisting of halogen atoms, hydroxyl, trifluoromethyl, cyano, nitro, formyl, alkyl and alkoxy
..... až so 4 atómami uhlíka, fenyl a karboxyskupinou νοϊnou vo forme soli alebo esterifikovanou^ c/ zvyšky -CO-N <... with up to 4 carbon atoms, phenyl and carboxy group in salt form or esterified with (-CO-N) residues
a -N <and -N <
8a8a
R,R
7a kde bud Rga, R^a, Rga a R^a, rovnaké alebo rôzne, sú vybrané zo súboru zahŕňajúceho atóm vodíka, amíno21 formách a tiež ich adičných solí s minerálnymi a organickými kyselinami alebo· minerálnymi a organickými bázami, spočívajúce v tom, že sa pre vyššie popísanú prípravu použijú produkty vzorcov II, III a IV, v ktorých R*1, R*2-> a R*4 majú významy,, uvedené vyššie pre R^a, resp. R2a> resp. R^, v ktorých sú reaktívne funkčné skupiny prípadne chránené.7 wherein one of R a, R a, R a and R a, the same or different, are selected from H, amíno21 forms, and also their addition salts with mineral and organic acids or · mineral and organic bases consisting of in that the products of formulas II, III and IV in which R * 1 , R * 2 → R and R * 4 have the meanings given above for R @ 1 and R @ 2 are respectively used for the preparation described above. R2 and > R 6 in which the reactive functional groups are optionally protected.
Predmetom vynálezu je zvlášl vyššie uvedený sposob pre prípravu produktov vzorca I, zodpovedajúcich vzorcu I&In particular, the present invention relates to the above process for the preparation of products of formula I corresponding to formula I &
kdewhere
R, k1bR, k 1b
3b3b
R,R
2b predstavuje alkylový zvyšok až so 4 atómami uhlíka, predstavuje atóm vodíka, formyl, acyloxy, prípadne substituovaný alkyl alebo aikoxy alebo karboxyskupinu volnú, vo forme soli alebo esterifikovanú alkylovým zvyškom, predstavuje fenyltio, fenylsulfonyl, fenylsulfinyl, alkyltio, alkyisulfonyl alebo alkylsulŕinyl, prípadne substituovaný, takže,/vo všetkých zvyškoch, ktoré môžu predstavoval R^ a R^b, obsahujú alkylová -zvyšky a alkoxyskupiny až 6 atomov uhlíka a fenyiové zvyšky sú prípadne substituované jedným2b represents an alkyl radical of up to 4 carbon atoms, represents a hydrogen atom, formyl, acyloxy, optionally substituted alkyl or alkoxy or carboxy, free, in salt form or esterified with an alkyl radical, represents phenylthio, phenylsulfonyl, phenylsulfinyl, alkylthio, alkyisulfonyl or alkylsulphinyl optionally such that, in all the radicals which R @ 1 and R @ 2 b may represent, the alkyl radicals and alkoxy groups contain up to 6 carbon atoms and the phenyl radicals are optionally substituted by one
V vV v
- alebo- niekolkými- zvyškami vybranými zo súboru zahrnujúceho atómy halogénu, hydroxyl, trifluormetyl, acyloxy, karboxyskupinu volnú, vo forme soli alebo esterifikovanú, fenyl, pyridyl, tetrazolyl, alkyl a aikoxy až so 4 atómami uhlíka a prípadne, substituované alkoxyskupinou až so 4 atómami uhlíka,- or by several radicals selected from the group consisting of halogen atoms, hydroxyl, trifluoromethyl, acyloxy, carboxy, free, in salt or esterified form, phenyl, pyridyl, tetrazolyl, alkyl and alkoxy of up to 4 carbon atoms and optionally substituted with alkoxy of up to 4 carbon atoms,
R^b predstavuje kyano, karboxyskupinu volnú, vo forme soli alebo esterifikovanú, zvyšok -SO2“Xb“R^ob’ k kde predstavuje, zvyšky -NH-, -NH-CO-, -NH-CO-O-, -N=CH-N-R1 -jb> -NH-CO-NH- alebo jednoduchú väzbu a R1 Ob a b* rovnaka alebo rôzne, predstavujú atóm vodíka, metyl, etyl, propyl, vinyl, allyl, pyridyl, fenyl, benzyl, nitropyridyl, pyrimidyl, tetrazolyl, diazolyl, piperidinyl, alkylpiperidinyl, tiazolyl, alkyltiazolyl, tetrahydrofuranyl, metyltetrahydrofuranyl, pričom uvedené produkty vzorca sú vo vštkých možných izomérnych racemických, enantiomerných a diastereoizomérnych formách a tiež.ich adičných solí a minerálnymi a organickými kyselinami alebo s minerálnymi alebo organickými bázami, spočívajúce v tom, že sa pre ich prípravu vyššie uvedeným spôsobom použijú produkty vzorcov II, III a IV, v ktorých R*1 , R*2, ^*3 a ^*4 maďú významy, uvedené vyššie ^4.b’ v ktorých reak resp. R^b> resp pre R1b resp. R2b, tívne funkčné skupiny prípadne chránené.R b is cyano, carboxy, a free, salified or esterified, radical -SO 2 "X b" R ob 'of which is, radicals -NH-, -NH-CO-, -NH-CO-O-, -N = CH-NR 1 -j b > -NH-CO-NH- or a single bond and R 10b and b * equally or differently represent hydrogen, methyl, ethyl, propyl, vinyl, allyl, pyridyl, phenyl, benzyl, nitropyridyl, pyrimidyl, tetrazolyl, diazolyl, piperidinyl, alkylpiperidinyl, thiazolyl, alkylthiazolyl, tetrahydrofuranyl, methyltetrahydrofuranyl, wherein said products of the formula are in all possible isomeric racemic, enantiomeric and diastereoisomeric salts, and also organic isomers, and also isichloroisomeric salts. mineral or organic bases, consisting in the fact that for their preparation as described above are used the products of formulas II, III and IV wherein R 1, R 2, ^ * 3 N * 4 mA TI values, the above ^ 4.b ' in which reactions resp. R ^ b > respectively for R 1b resp. R 2b , active groups optionally protected.
Predmetom vynálezu je äalej zvláší spôsob pre prípravu produktov vzorca I, zodpovedajúcich vzorcu 1^Another object of the invention is a particular process for the preparation of products of formula I corresponding to formula I
(Iu>(Iu>
kde predstavuje, alkylový zvyšok až so 4 atómami uhlíka, Rjd predstavuje karboxyskupinu volnú, vo forme soli alebo esterifikovanú. lineárnym alebo rozvetveným alkylovým zvyškom až so 4 atómami uhlíka, formyl, acyloxy, alkyl až so 4 atómami uhlíka, prípadne substituovaný hydroxylom.where it represents, an alkyl radical of up to 4 carbon atoms, R 1d represents a carboxy group free, in salt form or esterified. a linear or branched alkyl radical having up to 4 carbon atoms, formyl, acyloxy, an alkyl having up to 4 carbon atoms, optionally substituted by hydroxyl.
predstavuje fenyltio, fenylsulfonyl, fenylsulfinyl, alkyltio, alkylsulfonyl, alebo alkylsulfinyl, kde alkylový zvyšok obsahuje až 4 atómy uhlíka,represents phenylthio, phenylsulfonyl, phenylsulfinyl, alkylthio, alkylsulfonyl, or alkylsulfinyl, wherein the alkyl moiety contains up to 4 carbon atoms,
R^d predstavuje zvyšok -SC^-NHg , -SO^-NH-CO-O-R^R d is a radical -SO -NHg, -SO-NH-CO-OR ^
-SOq-N=CH-NR1 ,. alebo ^S0o-NH-C0-NH-R.n,, kde R. n, a 2 13d 2 lOď t 1 Od ^13ď Γ0νη3^θ alebo rôzne, sú vybrané z atomov vodíka, metylu, etylu, n-propylu a propenylu, pričom uvedené produkty vzorca Id sú vo všetkých možných izomérnych racemických, enantiomerných a diasteroizomérnych formách a tiež ich adičných solí s minerálnymi a organickými kyselinami alebo s minerálnymi a organickými bázami, spočívajúcimi v tom, že sa pre ich prípravu vyššie uvedeným sposobom použijú produkty vzorcov II, III a IV, v ktorých R*, R*2> 3 majú významy, uvedené vyššie pre Rld, resp. Rg^, resp. R^, resp. R^, a v ktorých sú reaktívne funkčné skupiny prípadne chránené.-SO q -N = CH-NR 1. ^ S0 or a NH-C0-NH-R. n wherein R ,, n, 2 and 13 d 2 from the ship T ^ 1 ^ θ 13d Γ0νη3 or different, are selected from hydrogen, methyl, ethyl, n-propyl and propenyl, the said products of formula I, d being in all possible isomeric racemic, enantiomeric and diasteroisomeric forms, as well as their addition salts with mineral and organic acids or with mineral and organic bases, characterized in that products of formulas II, III and IV in which R *, R * 2> 3 have the meanings given above for R 1d and R 1d , respectively. Rg ^, respectively. R ^, resp. In which the reactive functional groups are optionally protected.
predmetom vynálezu je Šalej zvlášt vyššie uvedený spôsob, spočívajúci v tom, že sa ako východiskový produkt použije produkt vzorca II, kde R*^ predstavuje alkylový zvyšok až so 4 atómami uhlíka, R*^ predstavuje karboxyskupinu volnú, vo forme soli alebo esterifikovanú lineárnym alebo rozvetveným alkylovým zvyškom až so 4 atómami Uhlíka, forr myl, acyloxy, alkyl až so 4 atómami uhlíka, prípadne substituované hydroxylovým zvyškom, B.'? predstavuje fenyltio, fenylsulf onyl, fenylsulf inyl, alkyi.tiom, alkylsulfonyl alebo alkylsulfinyl, kde alkylový zvyšok obsahuje, až. 4 atómy uhlíka a reaktívne funkčné skupiny sú prípadne chránené a produkt vzorca V, kde R*^ predstavuje zvyšok -SC^-NI^-, -SO2-NH-CO-O-R1Qd, -S02-N=GH-NR1 alebo -SO^-NH-CO-NH-R^od, kde R1 a R^ rovnaké alebo rôzne: z.sú vybrané z atómu vodíka, metylu, etylu, n-propylu a propenylu, kde reaktívne . funkčné skupiny sú prípadne chránené.Another object of the present invention is the above-mentioned process, wherein the starting product is a product of formula II wherein R @ 1 represents an alkyl radical of up to 4 carbon atoms, R @ 3 represents a carboxy group, free, in salt or esterified by linear or branched alkyl of up to 4 carbon atoms, formyl, acyloxy, alkyl of up to 4 carbon atoms, optionally substituted with hydroxyl, B. represents phenylthio, phenylsulfonyl, phenylsulfinyl, alkylthio, alkylsulfonyl or alkylsulfinyl, wherein the alkyl moiety contains, up to. 4 carbon atoms, and the reactive functions are optionally protected and a product of formula V, wherein R ^ is a radical -SO -NH ^ -, -SO 2 -NH-CO-1QD, -S0 2 -N = NR 1-GH or -SO-NH-CO-NH-R to which R 1 and R the same or different: for .SU selected from hydrogen, methyl, ethyl, n-propyl and propenyl, in which reactive. the functional groups are optionally protected.
Predmetom vynálezu je Šalej zvlášl vyššie uvedený spôsob, spočívajúci v tom, že sa ako východiskový produkt použije produkt vzorca II, kde R*^ predstavuje alkoxyskupinu alebo karboxyskupinu voínú, vo forme soli alebo' es« terifikovanú a R*2 predstavuje alkyltio alebo fenyltio, prípadne oxidované vo forme sulfoxidu alebo sulfónu,pri• čom, tieto zvyšky alkoxy, alkyltio a fenyltio: sú prípadne substituované jedným alebo niekolkými zvyškami, vybranými zo súboru, zahrňujúceho' atómy, halogénu, alkyl alebo alkQtyskupinu až so 4 atómami uhlíka, trifluórmetyl, amíno, mono- alebo dialkylamíno, kyano, acyl, acyloxy alebo fenyl.The present invention furthermore relates to a process according to the above-mentioned process, wherein the starting product is a product of formula II wherein R @ 1 is alkoxy or carboxy in the form of a salt or esterified and R @ 2 is alkylthio or phenylthio; optionally oxidized in the form of a sulfoxide or sulfone, wherein the alkoxy, alkylthio and phenylthio radicals are optionally substituted by one or more radicals selected from the group consisting of atoms, halogen, alkyl or alkyl of up to 4 carbon atoms, trifluoromethyl, amino , mono- or dialkylamino, cyano, acyl, acyloxy or phenyl.
Predmetom vynálezu je ďalej hlavne vyŠŠie uvedený spôsob prípravy produktov vzorca I, zodpovedajúcich týmto vzorcom:In particular, the present invention further relates to the above process for the preparation of products of formula I corresponding to the following formulas:
- kyselina 2-butyl-1 — LĽ2 *-karboxy(1,1 ‘’-bifenyl) -4-ylJ.metylJ-4-(fenyltio)-1H-imidazol-5-karboxylová,- 2-butyl-1-L, 2 * -carboxy (1,1'-biphenyl) -4-yl] methyl] -4- (phenylthio) -1H-imidazole-5-carboxylic acid,
- kyselina 2-butyl-l - [[2 *-karboxy-(1 ,1 *-bifenyl) -4 -yUmetyl]-4- (metylticr)-l H-imidazo'l.-5-karboxylová,- 2-butyl-1 - [[2'-carboxy- (1,1'-biphenyl) -4-ylmethyl] -4- (methylthyrr) -1H-imidazole-5-carboxylic acid,
- kyselina 4*-C[2-butyl-4-(etyltio)-5“íhydroxymetyl)-1H-imidazol.-1 -ylľjmetylj- (1 ,1 *-bifenyi)-2-karboxylová,- 4 * -C [2-butyl-4- (ethylthio) -5'-hydroxymethyl) -1H-imidazol-1-yl] methyl} - (1,1'-biphenyl) -2-carboxylic acid,
-kyselina 2-butyl-1 -[[2 '-karboxy-(l , 1 '-bifenyl}-4-yiJmetyl] -4-(etýlsulfonyl)-1 H-imidazoi-5-karboxylová,- 2-butyl-1 - [[2'-carboxy- (1,1'-biphenyl} -4-ylmethyl) -4- (ethylsulfonyl) -1H-imidazole-5-carboxylic acid,
- kyselina 2-buty 1-1 — [[2 '-karboxy-( 1,1 *-bifenyl)-4-ylJ- . m'etyl] -4-(etýlsulf inyl) -1 H-imidazol-5-karboxylová,2-butyl-1 - [[2'-carboxy- (1,1'-biphenyl) -4-yl] -. methyl] -4- (ethylsulfinyl) -1H-imidazole-5-carboxylic acid,
- kyselina 2-butyL-1 - [t2 '-karboxy- (1,1 *-bif enyl) “4-y lj metyl]-4- (etyltio)-1H-imidazol-5-karboxylová,- 2-butyl-1- [12'-carboxy- (1,1'-biphenyl) -4-yl] methyl] -4- (ethylthio) -1H-imidazole-5-carboxylic acid,
- kyselina 2-butjrl-1 - C[2 *-karboxy-(i., 1 #-bifenyl)-4-yl7metyl] -4- (fenylsulfonyl) -1 H-imidazol-5-karboxylová,- 2-butjrl acid-1 - C [2-carboxy-* (i., 1 # -biphenyl) -4-yl7metyl] -4- (phenylsulfonyl) -1H-imidazole-5-carboxylic acid,
- kyselina 2-butyl-1- [[2 *-karboxy-(l ,1 *-bifenyl)-4-ylJmetylj -4- (fenylsulfinyl)-1 H-imidazol-5-karboxylová,- 2-butyl-1 - [[2'-carboxy- (1,1'-biphenyl) -4-yl] methyl] -4- (phenylsulfinyl) -1H-imidazole-5-carboxylic acid,
- kyselina 2-butyl-1 [[2 '-tetrazolyl- (1 ,1 '-bifenyl) -4-ylJmetylj -4-(metyltio)-1H-imidazol-5-karboxylová,- 2-butyl-1 [[2'-tetrazolyl- (1,1'-biphenyl) -4-yl] methyl] -4- (methylthio) -1H-imidazole-5-carboxylic acid,
- etyl-2-butyl-4-(metyltio)-1-[£2#- ff((propylamínojkarbonyl)amíno)sulfonyl) -(1,1 '-bifenyl)-4-ylj mety 1J-1H-imidazoL-5-karboxylát,- ethyl 2-butyl 4- (methylthio) -1- [# £ 2 - ff ((propylamínojkarbonyl) amino) sulfonyl) - (1,1'-biphenyl) -4-methyl-YLJ 1J-1 H-imidazol-5 carboxylate,
- kyselina 2-butyl-4-(metyltio>)-1 - ££2 *-(((( propylamíno) karbonyl) amíno)sulfonyl)- (Ί , 1 *-bifenyl) -4-y Ij metylj-1 H-imidazol-5-karboxylová,- 2-Butyl-4- (methylthio>) -1 - ££ * 2 - ((((propylamino) carbonyl) amino) sulfonyl) - (Ί, 1 ' -biphenyl) -4-yl Ij methyliodide 1H imidazole-5-carboxylic acid,
- didraselná soí kyseliny 2-butyl-4- (metyltio)-l - [{2 '- (Y(.(propylamíno)karbonyl) amíno) sulfonyl )-(1 ,1 *-bifenyl)-4-ylJmetylJ-1 H-imidazol-5-karboxylov ej.2-butyl-4- (methylthio) -1 - [{2 '- (Y (. (propylamino) carbonyl) amino) sulfonyl) - (1,1'-biphenyl) -4-yl] methyl] -1H-dipotassium salt -imidazole-5-carboxylic acid.
Predmetom vynálezu je ďalej zvlášť vyššie uvedený, sposob .prípravy produktov vzorca I,. zodpovedajúcich týmto vzorcom :The invention furthermore relates in particular to the above-mentioned process for the preparation of the products of the formula I. corresponding to the following formulas:
- etyl-2-butyl-4-(metyltio)-1-£[2 *- ((((propylamíno)karbonyl) amíno) sulfonyl.)- (1 ,1 *-bifenyl) -4-ylJmetylJ-1H-imid.a z ol-5-karboxy 1 át,- ethyl-2-butyl-4- (methylthio) -1- [2 * - ((((propylamino) carbonyl) amino) sulfonyl)) - (1,1'-biphenyl) -4-yl] methyl] -1H-imide az-5-carboxylate,
- kyselina 2-butyl-4-(metyltio)-1-EĽ2*-(((( propylamíno)karbonyl) amíno) sulfonyl) -(i ,1 *-bifenyl)-4-ylJmetylJ-1H-imidazol-5“karboxylová,'- 2-butyl-4- (methylthio) -1-E2 * - ((((propylamino) carbonyl) amino) sulfonyl) - (1,1'-biphenyl) -4-ylmethyl] -1H-imidazole-5-carboxylic acid , '
- didraselná soí kyseliny 2-buty1-4-(metyltio)-1 -[[2- dipotassium salt of 2-butyl-4- (methylthio) -1 - [[2
- (((( propylamíno)karbonyl) amínojsulf onyl)- (1 ,1 *-bifenyl)-4.-y Ij metylj-1 R-imidazol-5-karboxylovej.- ((((propylamino) carbonyl) amino) sulfonyl) - (1,1'-biphenyl) -4-yl] methyl] -1H-imidazole-5-carboxylic acid.
2a výhodných podmienok realizácie vynálezu je produkt vzorca III taký,’ že Hal predstavuje prednostne atóm brómu,, ale môže tiež predstavovat atóm c&oru alebo jódu.In preferred conditions for carrying out the invention, the product of formula III is such that Hal is preferably a bromine atom, but may also be a sulfur or iodine atom.
Reakcia produktu vzorca III s produktom vzorca II môže byť realizovaná v rozpúšťadle, ako je napríklad dimetylformamid, tetrahydrofuran, acetón, acetonitril, dimetylpropylmočovina, dimetoxyetan alebo dimetylsulfoxid, pri refluxe rozpúšťadla alebo pri teplote miestnosti, prednostne za miešania : reakcia sa realizuje v prítomnosti bázy, ako je napríkLad hydrid sodný alebo draselný, metylát, etylát. alebo terc.butylát sodný alebo draselný, alebo prednostne uhličitan sodný, draselný alebo cézný.The reaction of the product of formula III with the product of formula II can be carried out in a solvent such as dimethylformamide, tetrahydrofuran, acetone, acetonitrile, dimethylpropylurea, dimethoxyethane or dimethylsulfoxide, at reflux of the solvent or at room temperature, preferably with stirring: such as sodium or potassium hydride, methylate, ethylate. or sodium or potassium tert-butylate, or preferably sodium, potassium or cesium carbonate.
Reakcia takto získaného produktu vzorca IV s vyššie definovanou zlúčeninou vzorca V, kde predstavuje prednostne. atóm brómu, jódu alebo chlóru, môže byt realizovaná v rozpúšťadle, ako je napríklad zmes toluénu a etanolu,alebo ďalej v dimetylformamide v prítomnosti slabej, bázy, ako je napríklad hydrogénuhličitan sodný, draselný alebo cézny, prednostne v prítomnosti katalyzátora, ako je napríklad tetrakistrifenylf osfín paládia alebo zmes trifenylfosfínu a diacetátu paládia alebo ďalej tetrakistrifenylfosfín niklu.Reaction of the thus obtained product of formula IV with a compound of formula V as defined above, wherein it represents preferably. the bromine, iodine or chlorine atom may be carried out in a solvent such as a mixture of toluene and ethanol, or further in dimethylformamide in the presence of a weak base such as sodium, potassium or cesium bicarbonate, preferably in the presence of a catalyst such as tetrakistriphenyl palladium osphine or a mixture of triphenylphosphine and palladium diacetate or tetrakistriphenylphosphine nickel.
Ako ďalšie katalyzátory je možné uviesť napríklad komplexy niklu, paládia, ruténia alebo platiny a prednostne kom plexy paládia : bis (dibenzylidenacetón)Pd v prítomnosti PPh-, tris(dibenzylidenaceton)Pd, trans-benzyl(chlór? bis ftrifenylf osfín) paládLum, Pd^OAc^-trisfurylfosfín, Pd(0Ac)2 -trifenyl fosfín, tetrakis (trifenylfosfín) paládium, 1,4-bis(difenylfosfíno) bután Pd, CL, Sr alebo OAc, 1 ,3-bis(difenylfosfíno)propán Pd, Cl, Br alebo OAc, 1 ,2-bis(difenylfosfíno)etan Pd, Cl, Br alebo OAc, 1,1-bis(difenylfosfíno)ferroceň Pd, Cl, Br alebo OAc.Other catalysts include, for example, nickel, palladium, ruthenium or platinum complexes and preferably palladium complexes: bis (dibenzylideneacetone) Pd in the presence of PPh-, tris (dibenzylideneacetone) Pd, trans-benzyl (chloro-bis-triphenylphosphine) palladium, Pd OA OAc--trisfurylphosphine, Pd (OAc) 2 -triphenyl phosphine, tetrakis (triphenylphosphine) palladium, 1,4-bis (diphenylphosphino) butane Pd, CL, Sr or OAc, 1,3-bis (diphenylphosphino) propane Pd, Cl , Br or OAc, 1,2-bis (diphenylphosphino) ethane Pd, Cl, Br or OAc, 1,1-bis (diphenylphosphino) ferrocene Pd, Cl, Br or OAc.
Pri reakcii produktu vzorca IV s produktom vzorca V sú použité. rozpúšťadlá. východne vopred odplynené, napríklad prebublávaním argónu.In the reaction of the product of formula IV with the product of formula V, they are used. solvents. pre-degassed, for example by bubbling argon.
Rôzne reaktívne funkčné skupiny, ktoré môžu niesť niektoré'vyŠsie uvedené reakčné zložky, môžu byť, ak je to nutné chránené : jedná sa napríklad o hydroxylové, acylové, voíné karboxylové zvyšky a nalej amíno a monoalkylamíno, ktoré mozu Dy:t chranene príslušnými cnramacimi skupinami.The various reactive functional groups which may carry some of the above-mentioned reactants may, if necessary, be protected: for example, hydroxyl, acyl, free carboxyl residues and poured amine and monoalkylamino, which may be protected by the respective protecting groups. .
Výpočet rôznych použitelných chrániacich skupín je mo; né nájst napríklad v patente 3F 2 499 995.Calculation of the various protecting groups available is possible; can be found, for example, in Patent 3F 2,499,995.
Tu je možné uviest nevyčerpávajúce príklady ochrany reaktívnych funkčných skupín :The following are non-exhaustive examples of the protection of reactive functional groups:
- hydroxylové skupiny je. možné chránil napríklad alkyiovými zvyškami, ako je terc.butyl, trimetylsilyi, terc.butyldimetylsilyL, metoxymetyl, tetrahydropyranyl, benzyl alebo acetyl,the hydroxyl group is. can be protected, for example, with alkyl radicals such as tert-butyl, trimethylsilyl, tert-butyldimethylsilyl, methoxymethyl, tetrahydropyranyl, benzyl or acetyl,
- amínoskupiny je možné chránil napríklad acetylovým trityiovým,benzylovým,terc.butoxykarbonylovým zvyškom, ftaiimidoskupinou alebo inými zvyškami, známymi v chémii peptidov,- amino groups can be protected, for example, with acetyl trityl, benzyl, tert-butoxycarbonyl, phthalimido or other residues known in peptide chemistry,
- acylové skupiny, ako je formyl, je možné chránil nanríklsd vo forme cyklických alebo acyklických ketalov, ako je dimetyl-alebo dietylketal alebo etyléndioxyketal,- acyl groups such as formyl can be protected with n-butyls in the form of cyclic or acyclic ketals such as dimethyl or diethyl ketal or ethylenedioxyketal,
- kyslé funkcie vyššie uvedených produktov je možné, ak ;acidic functions of the above products are possible if;
s.with.
to žiaduce, amidifikovat primárnym alebo sekundárnym amínom, naoríklad v metylénci'iíoride. v orítomnoszi naoríklad hydro— chloridu 1-etyl-J- dimetylamínopropyl. karbodiimidu pri teplote miestnosti,if desired, amidify with a primary or secondary amine, for example in methylene chloride. in the presence of, for example, 1-ethyl-N-dimethylaminopropyl hydrochloride. carbodiimide at room temperature,
Λ- kyslé funkcie môžu byt dalej chránené napríklad voThe acid functions can be further protected, for example, in
V V forme esterov, tvorených sa lahko odštiepitelnymi esterami,axo je benzylester alebo terc.butylester, známymi v chémii peptidov,In the form of esters formed by readily cleavable esters, axo is the benzyl ester or the tert-butyl ester known in peptide chemistry,
Získaná produkty vzorca I .aeubvV „v 1 , Λ p, Λ -s &The obtained products of formula I .aeubvV 'v 1, Λ p, Λ -s &
produkty vzorca I.products of formula I.
v zavisiosii na vyznáme suo5otom bua tvoria alebo netvoriain accordance with the well-known feature, they either form or do not form
Ak produkty vzorca 1 nepredstavujú produkty vzorca I, nožu byl, ak je to nutné alebo žiadúce, podrobené lalej uvedeným reakciám za vzniku produktov vzorca I.If the products of Formula 1 do not represent the products of Formula I, the knife was, if necessary or desirable, subjected to the abovementioned reactions to give the products of Formula I.
Odstránenie chrániacich skupín, ako sú napríklad vyššie uvedené skupiny, je možné realizovat za podmienok, známych odborníkovi, predovšetkým kyslou hydrolýzou s použitím kyseliny, ako je kyselina chlorovodíková, benzénsulfónová alebo vRemoval of protecting groups, such as those mentioned above, may be accomplished under conditions known to those skilled in the art, in particular by acid hydrolysis using an acid such as hydrochloric, benzenesulfonic
p-toLuénsulfonová, mravčia alebo trifluoroctová alebo dalej katalytickou hydrogenáciou.p-toluenesulfonate, formic or trifluoroacetic acid, or else by catalytic hydrogenation.
Ftalamidoskupina môže byt odštiepená hydrazínom.The phthalamido group may be cleaved with hydrazine.
Vyššie uvedené produkty môžu byt, ak js to žiaduce, podrobená reakciám, vedúcim k tvorbe solí, napríklad s minerálnou alebo organickou kyselinou, obvyklými metódami, známymi odborníkovi.If desired, the above products may be subjected to salt-forming reactions, for example with a mineral or organic acid, by conventional methods known to those skilled in the art.
Vyššie uvedené produkt;/ môžu byt, ak je to žiadúce, na prípadnej karboxyskupine podrobené reakcii tvorby solí s minerálnou alebo organickou bázou alebo esterifikáciou : tieto· reakcie je možné realizovat obvyklými metódami, odborníkovi známymi.The above product may, if desired, be subjected to a salt formation reaction with a mineral or organic base or esterification, if desired, to a carboxy group: these reactions may be carried out by conventional methods known to the person skilled in the art.
Prípadné premeny esterovej funkcie na kyslú funkciu u vyššie uvedených produktov môžu byí, ak je to žiaduce, realizované pri obvyklých podmienkach, odborníkovi známych, predovšetkým kyslou alebo alkalickou hydrolýzou, napríklad hydroxiaom sodným alebo draselným v prostredí alkoholu, napríklad metanolu alebo kyselinou chlorovodíkovou alebo sírovou.The possible conversion of the ester function to the acid function of the above products may, if desired, be carried out under conventional conditions known to the person skilled in the art, in particular by acid or alkaline hydrolysis, for example sodium or potassium hydroxide in an alcohol such as methanol or hydrochloric or sulfuric acid.
rW prípadné kyanoskupiny vyššie uvedených produktov môžu by ak je to žiadúce, premenené na kyslú funkciu pri obvyklých podmienkach, odborníkovi známych, napríklad dvojitou hydrolýzou realizovanou v kyslom prostredí, ako napríklad v zmesi kyseliny sírovej, ľadovej kyseliny octovej a vody, prednostne pri29 tomných v rovnakých dieloch alebo v zmesi hydroxidu sodného, etanolu a vody za refluxu.If desired, the cyano groups of the above products may, if desired, be converted to acidic function under conventional conditions known to the person skilled in the art, for example by double hydrolysis carried out in an acid medium such as a mixture of sulfuric acid, glacial acetic acid and water. parts or in a mixture of sodium hydroxide, ethanol and water at reflux.
Prípadné volné alebo esterifikované karboxyskupiny vo vyššie uvedených produktoch môžu byt, ak je to žiadúce, redukované metódami, odborníkovi známymi, na alkoholickú funkciu : v prípade esterifikovaných karboxyskupín je možné použit predovšetkým hydrid lítny a hlinitý v rozpúštadie, ako je napríklad tetrahydrofuran alebo nalej dioxan alebo etyláter.The optional free or esterified carboxy groups in the above products may, if desired, be reduced by methods known to those skilled in the art to alcoholic function: in the case of esterified carboxy groups, lithium and aluminum hydride may be used in a solvent such as tetrahydrofuran or poured dioxane; etyláter.
v v v v
Pre volné karboxyskupiny je možne použit predovšetkým· hydrid boru.In particular, boron hydride may be used for the free carboxy groups.
prípadné alkoxyskupiny, vyššie uvedených produktoch, vedené na hydroxylovú skupinu níkovi známych, napríklad bro je napríklad metylénchlorid, dom pyridínu alebo ďalej kyse ako je predovšetkým metoxy, môžu byt, ak je to žiadúce, vo pre rovodíkovou vo vode aiebc kyselinou octovo za obvyklých podmienok, odbormidom boritým v rozpúštadie, ak hydrobromidom alebo hydrochiori linou bromovodíkovou alebo chio refxuxu.optional alkoxy groups of the above products, led to the hydroxyl group known to one another, for example bro is, for example, methylene chloride, pyridine house or further an acid such as, in particular, methoxy, can be, if desired, hydrogenated in water or acetic acid under usual conditions, borohydride in the solvent, and hydrobromide or hydrochloride hydrobromide or chio refxux.
Prípadné skupiny, obsahujúce atóm síry, vo vyššie uvedených produktoch môžu byt, ak je to žiadúce, premenené :na zodpovedajúce sulfoxidové alebo suifónovéskupiny za obvyklýc podmienok, odborníkovi známych, napríklad pomocou perkyseiín ako je napríklad kyselina peroctová alebo kyselina m-chlórpe benzoová, alebo' ozónom, oxónom, jodistanom sodným v rozpúšťadle.,. ako je napríklad metylénchlorid alebo dioxan, pri tep lote miestnosti.Optional sulfur-containing groups in the above products can, if desired, be converted into the corresponding sulfoxide or suiphone groups under conventional conditions known to the person skilled in the art, for example with perkysines such as peracetic acid or m-chloro benzoic acid, or ozone, oxone, sodium periodate in solvent. such as methylene chloride or dioxane at room temperature.
Sulfoxidovú funkciu je možné získaš ekvimolárnym zmieša ním produktu, obsahujúceho alkyltio alebo aryltioskupinu a činidlá, ako je predovšetkým perkyseiina.The sulfoxide function can be obtained by equimolar mixing of a product containing an alkylthio or arylthio group and reagents such as, in particular, peracid.
- 30 Sulfónovú funkciu je možné získat zmiešaním produktu, obsahujúceho alkyítioskupinu alebo aryltioskupinu, s prebytkom činidla, ako- je predovšetkým perkyselina.The sulfone function can be obtained by mixing a product containing an alkylthio or arylthio group with an excess of a reagent such as, in particular, a peracid.
Prípadné alkoholické skupiny vyššie popísaných produktov môžu byl, ak je to žiaduce, premenené na aldehydlckú alebo kyslú funkciu oxidáciou pri obvyklých podmienkach, odborníkovi známych, ako je napríklad pôsobenie oxidu manganatého, za vzniku aldehydov alebo Jonesovho činidla, vedúceho ku kyselinám.The optional alcohol groups of the above-described products can, if desired, be converted to an aldehyde or acid function by oxidation under conventional conditions known to those skilled in the art, such as manganese oxide treatment, to form aldehydes or an acid-leading Jones reagent.
Prípadné nitrilo^ej funkcie vyššie popísaných produktov môžu byl, ak je to žiaduce, premenené na tetrazol pri ovbyk lých pdomienkach, známych odborníkovi, ako napríklad cykloadíciou kovového azidu, ako je napríklad tMalkyícínasid, zostupe, popísanom na nitrilovú skupinu, ako- 53 uveasní v článku v J. Orgsnometallic Chemistry 33, 337 >971 , ľúozima, Ξ. a d.The optional nitrile function of the above-described products may, if desired, be converted to tetrazole in common conditions known to those skilled in the art, such as cycloaddition of a metal azide, such as a alkyl alkynide, of the descent described to the nitrile group, as disclosed. article in J. Orgsnometallic Chemistry 33, 337> 971, lozozima, Ξ. and d.
Prípadne opticky aktívne axupiny v pr oduktoch vzorca I môžu byt pripravené štiepením recemických zmesí obvyklými metódami, odborníkovi známymi.Optionally, the optically active axupins in the products of formula I may be prepared by cleavage of the recemic mixtures by conventional methods known to those skilled in the art.
Produkty vzorca I sú známe a sú popísané predovšetkým v európskych patentových prihláškach č. 0 465 3-63 a 0 pC3 162.The products of formula I are known and are described in particular in European patent applications no. 0 465 3-63 and 0 pC3 162.
Produkty vzorca 1 pripravené vyššie uvedeným spôsobom, rovnako ako ich adičné soli 3 kyselinami , majú zaujímavé farmakologické vlastnosti.The products of formula 1 prepared by the above process, as well as their acid addition salts 3, have interesting pharmacological properties.
t Produkty sú obdarené, antagonistickými vlastnosťami voči receptoru angiotensínu II 2 sú teda hlavne inhibítor mi účinkov angiotensínu II, zvlášt vasokonstrikčného účinku a tiež trofického účinku na úrovni myocytov.Thus, the products are endowed with angiotensin II receptor 2 antagonist properties, in particular, being inhibitors of the effects of angiotensin II, especially vasoconstrictive effect, and also a trophic effect at the level of myocytes.
Tieto vlastnosti oprávňujú použitie produktov vzorca I pripravených vyššie uvedeným spôsobom, v terapii ako liečiv, pričom uvedené produkty vzorca I sú vo všetkých možných izomérnych racemických alebo opticky aktívnych formách, alebo adičných solí produktov vzorca I s farmaceuticky prijatelnými minerálnymi alebo organickými kyselinami,These properties justify the use of the products of formula I prepared as described above in therapy as medicaments, said products of formula I being in all possible isomeric racemic or optically active forms, or addition salts of the products of formula I with pharmaceutically acceptable mineral or organic acids,
Produkty vzorca I, pripravené vyššie uvedeným spôsobom, rovnako ako ich adičné soli s farmaceutický prijateínými minerálnymi alebo organickými kyselinami, môžu byt používané predovšetkým ako liečivá pri liečbe arteriálnej hypertenzie, srdečných nedostatočností , .ľ’enálnych nedostatočností a pri prevencii post-angioplastických restenôz.The products of formula (I) prepared as described above, as well as their addition salts with pharmaceutically acceptable mineral or organic acids, can be used primarily as medicaments in the treatment of arterial hypertension, cardiac insufficiency, endocrine deficiency and prevention of post-angioplastic restenosis.
Z,lôšu byt používané tiež pri liečbe niektorých gastrointestináinych a gynekologických porúch a predovšetkým pre relaxačný účinok na úrovni delohy vo· forme farmaceutických prostriedkov, obsahujúcich ako účinnú látku aspoň jedno vyššie definované liečivo.It can also be used in the treatment of certain gastrointestinal and gynecological disorders, and in particular for the relaxing effect at the delohy level in the form of pharmaceutical compositions containing, as an active ingredient, at least one medicament as defined above.
Tieto farmaceutické prostriedky môžu byt podávané bukáinou, re.ktáinou, parenteráínou alebo lokálnou cestou pri topickej aplikácii na kožu alebo na sliznice.These pharmaceutical compositions may be administered by either the buccal, rectal, parenteral or topical routes for topical application to the skin or mucous membranes.
Tieto prostriedky môžu byt tuhé alebo kvapalné a môžu sa nachádzal vo všetkých farmaceutických formách, používaných bežne v humánnej medicíne, ako sú napríklad oinjek;These compositions can be solid or liquid and can be found in all pharmaceutical forms commonly used in human medicine, such as ointments;
á pré'* byčajné tabletky(alebo drsžé, kapsle, čipky, paráty, masti, krémy, gély a aerosólové prípravky : priora vujú sa obvyklými metódami. Účinná látka môže byt formulovaná v nosičoch, používaných obvykle v týchto farmaceutických prostriedkoch ako je talek, arabská guma, laktóza, škrob, stearát horečnatý, kakaové maslo, vodné alebo ne.vodné vehikula, tukové základy živočíšneho .alebo rastlinného pôvodu, paraŕinické deriváty, glykoly, rôzne nanáčadlá, dispergátory alebo eaiulgátory, konzervačné prostriedky.And for the "* byčajné tablet (or drsžé, capsules, suppositories, talons, ointments, creams, gels and aerosol preparations: prior of vujú the usual methods. The active ingredient may be formulated in carriers conventionally used in these pharmaceutical compositions such as talc, gum gum, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty bases of animal or vegetable origin, para-derivative derivatives, glycols, various coating agents, dispersing or emulsifying agents, preservatives.
Obvyklé dávkovanie, meniace sa podlá použitého produktu liečeného subjektu a typu napadnutia, môže byt napríklad 1 až 1 00 mg denne u dospelého orálnou cestou.The usual dosage, varying according to the product to be treated and the type of attack, may be, for example, 1 to 100 mg per day in an adult by oral route.
Niektoré východiskové produkty vzorca II sú známe a môžu byô pripravené napríklad podlá európskeho ostentu EF 158 950.Some of the starting products of formula II are known and can be prepared, for example, according to European ostent EF 158 950.
Východiskový produkty vzorca II môžu byt predovs-e tkým pripravované sposooom, spočívajúcim v tom, vzorca Ila •a ziucenimIn particular, the starting products of formula (II) may be prepared by a sposoo consisting of formula (IIa) and reduction.
HO——C =N (Π J kd.e R*2 má vyššie uvedený význam, podrobí pôsobeniu redukc néhc činidla za vzniku zodpovedajúceho aminu vzorca II.HO - C = N (R 1, where R * 2 is as defined above) is treated with a reducing agent to give the corresponding amine of formula II.
kde H má vyššie uvedený význam, ktorý sa podrobí pôsobeniu zlúčeniny vzorca II.,wherein H is as defined above which is treated with a compound of formula II.
R , _ C _Hal ( ) ' II- L ~R, -C (Hal) II- L-
O kde má vyššie uvedený význam, za vzniku produktu vzorca 1¾O is as defined above to give the product of formula (I ')
- 33 .0 = N- 33 .0 = N
G — NHGH'G - NHGH '
R kde R^ s H j majú vyššie uvedený význam, ktorý sa nechá reagovat so zlúčeninami vzorca IIWherein R 1 and H 2 are as defined above, which are reacted with compounds of formula II
R 3-YH < T-Te >R @ 3 -YH < T - T e>
kde R * má vyššie uvedený význam a Y predstavuje- atóm síry alebo kyslíka, za vzniku produktu vzorca IIwherein R * is as defined above and Y represents a sulfur or oxygen atom to give the product of formula II
NH, mne onroo:NH, me onroo:
(11J(11J
R , a Y majú vyššie uvedený význam, ktorý sa 'yklizacnej reaxcii za vzniku produš .t,x,.R 1 and Y have the same meaning as above, which is followed by elimination reaction to produce t, x, y.
vzorca n, kt;of formula n, kt;
’ý sa potom pourooi, ak je niekoľkým nasledujúcim reakciám v f· .auuce a nutné, jednej slečo uoov oinom ooraci :Then, if several of the following responses are needed in the academic class, it is necessary to have one or more ooros:
a/ odštiepenie chrániacich « nené reaktívne funkčné skupiny, skupín, ktoré môžu niest chrácz reakcia s minerálnou aieco organickou kyselinou alebo bázou za vzniku zodpovedajúcej soli, c/ esterifikácia kyslej funkcie, d/ -zmydeinenie esterovej funkcie na kyslú funkciu, premena kyanoskupiny na kyslú funkciu, redukcia karboxyskupiny na alkoholickú funkciu, g/ reakcia premeny aikoxyskupiny na hjdroxylovú funkciu, h/ oxidácia skupiny obsahujúcej atóm síry na zodpovedajúcu sulfoxidovú alebo sulfónovú funkciu, i/ oxidačné alkoholické funkcie .na aldehydickú alebo e z f/ kyslú funkciu, j/ premena nitrilovej funkcie ns tetrasolovú funkciu, k/ štiepenie, racemických foriem na jednotlivá izoméry, 1/ premena karboxyskupiny na karbamoylový zvyšok, m/ premena karbamoylového zvyšku na nitrikový zvyšok, pričom takto získané produkty vzorca II sú vo všetkých možných izomérnych,racemických, enantiomérnych a diastereoizomérnych formách.a) cleavage of the unreacted reactive functional groups, groups which can be protected by reaction with a mineral or some organic acid or base to form the corresponding salt, c) esterification of the acid function, d) saponification of the ester function to an acid function, conversion of the cyano group to an acid function g / reaction of conversion of an alkoxy group to a hydroxyl function, h / oxidation of a group containing a sulfur atom to the corresponding sulfoxide or sulfone function, i) oxidative alcohol functions to an aldehyde or esph / acid function, j / conversion of the nitrile function ns tetrasol function, k (resolution), racemic forms to the individual isomers, 1 / conversion of the carboxy group to a carbamoyl residue, m / conversion of the carbamoyl residue to a nitric residue, the products of formula II thus obtained are in all possible isomeric, racemic, enantiomeric and diastereoisomeric forms.
Za prednostných podmienok realizácie vynálezu je vyššie uvedený spôsob robený týmto spôsobom :Under preferred conditions for carrying out the invention, the above process is carried out in the following manner:
- redukcia vzorca ΖΖΛ za vzniku zlúčeniny vzorca 3 ,- reduction of formula ΖΖ Λ to give a compound of formula 3 ,
II môže byt realizovaná obvyklými metódami, odborníkovi známymi, ako je napríklad amalgám hliníka, pripravený za obvyklých podmienok, ako je napríklad pôsobenie chloridu ortuti na hliník; reakcia sa robí v rozpúšmadle, ako je naprík lad tetrahydrofurán alebo toluén, prednostne pri teplote as ?0° G;II can be carried out by conventional methods known to those skilled in the art, such as, for example, aluminum amalgam, prepared under conventional conditions, such as the action of mercury chloride on aluminum; the reaction is carried out in a solvent such as, for example, ice-cold tetrahydrofuran or toluene, preferably at a temperature of? 0 ° C;
- adícia produktu vzorca IZ„, kde W predstavuje atóm brómu alebo prednostne atóm chlóru, na amín vzorca ZZ^ môže byt realizovaná metódami, odborníkovi známymi, napríklad v prítomnosti bázy, ako je pyridín áLebo trietyiamín; reakci sa robí prednostne: pri teplote asi P G. Je možne tiež získa* zlúčeninu vzorca ZZ.^ podrobením zlúčeniny vzorca ZZ re axn o;- the addition of the product of formula IZ ', wherein W represents a bromine atom or preferably a chlorine atom, to the amine of formula ZZ ^ may be carried out by methods known to the person skilled in the art, for example in the presence of a base such as pyridine or triethylamine; the reaction is preferably carried out: at a temperature of about P G. It is also possible to obtain a compound of formula ZZ by subjecting the compound of formula ZZ to axially;
lukcii a acylácii v prítomnosti anhydridu, akc naoríklac acetanhydrid, anhydrid kyseliny maslovej aiebo Valérovej, hydrogenáciou v prítomnosti naladia aiebo zinku alebo daLej ditionátu sodného.and the acylation in the presence of anhydride, such as acetic anhydride, butyric acid or valeric anhydride, by hydrogenation in the presence of tune or zinc or other sodium dithionate.
- adícia sírneho derivátu vzorca ZZ na amid vzorca ZZ- addition of a sulfur derivative of formula ZZ to an amide of formula ZZ
O sa robí napríklad rozpustením amidu vzorca ZZH v rozpúšťal.Á le, napríklad v alkohole, ako je etanol alebo metanoi, a po tom. postupným prídavkom bázy, ako je trietyiamín a zlúčenín, vzorca ZZ prednostne za miešania a pri teplote miestnosti, e - ··O is accomplished, for example, by dissolving the amide of formula ZZ H in a solvent, e.g., in an alcohol such as ethanol or methanol, and thereafter. by sequential addition of a base such as triethylamine and compounds of formula ZZ preferably with stirring and at room temperature, e - ··
- reakcia cyklizácie zlúčeniny vzorca 11^ sa môže robiť v rozpúšťadle, ako je napríklad diehiórmetan, dichlóretan alebo chloroform; reakcia môže byť robená napríklad v prítomnosti chloridu fosforečného, vopred rozpusteného v dichlórmetane, pri teplote asi -75° G v prítomnosti bázy, ako je.· napríklad pyridín alebo dimetylamínopyridín; reakcia môže byť robená za miešania pri teplote miestnosti.the cyclization reaction of the compound of formula 11 may be carried out in a solvent such as, for example, dichloromethane, dichloroethane or chloroform; the reaction may be carried out, for example, in the presence of phosphorus pentachloride, previously dissolved in dichloromethane, at a temperature of about -75 ° C in the presence of a base such as pyridine or dimethylaminopyridine; the reaction can be carried out with stirring at room temperature.
Takt.o získaný produkt vzorca II môže byť podrobený jednej alebo niekoíkým reakciám, ktoré je možné robit za rovnakých podmienok, aké sú uvedené vyššie pre produkty vzor ca I.The product of formula II thus obtained may be subjected to one or more reactions which may be carried out under the same conditions as those described above for the products of formula ca I.
Zlúčeninou vzorca II môže byť naoríklad etylizonitroa zokyanoacetát, ktorý sa môže nachádzať napríklad vo forme ko merčného produktu fy LANCASTSR pod označením S93C.The compound of formula II may be, for example, ethyl isonitrone and cyanoacetate, which may be present, for example, in the form of a commercial product of LANCASTSR under the designation S93C.
Zlúčeninu vzorca III, ako je definovaná vyššie, je možné získať reakciou zlúčeniny v rovnováhe s jej trimérnou for mou vzorca 71The compound of formula III as defined above may be obtained by reacting the compound in equilibrium with its trimeric form of formula 71
B C OH >2B C OH> 2
t.ol-St.ol-S
I oI o
S-tolTable
I oI o
(71) kde(71) where
B má vyššie uvedený význam a tol predstavuje toíyíový zvyšok s príslušným alkoholom, ako je napríklad meíanol,etanol, alebo butanoi, alebo s dmolom, ako je napríklad propandiol, etylénglykoi alebo dimei^Xpropandioi, za vzniku zlúčeniny vzorca ViliB is as defined above and tol represents a tertiary moiety with an appropriate alcohol, such as methanol, ethanol, or butanol, or with a mole such as propanediol, ethylene glycol or dimethylpropanedio, to give a compound of formula VIIa.
\ / fVIII) kde 3, Xj a X9 majú vyššie uvedený význam, ktorá sa nechá reagovať s haiogenačným činidlom za vzniku produktu vzorca III.(III) wherein 3, X 1 and X 9 are as defined above, which are reacted with a halogenating agent to give the product of formula III.
Je možné Hale j uviesť spôsob prípravy produktu vyššie uvedeného vzorca I, spočívajúceho v tom, že sa získa produkt vzorca IV reakciou zlúčeniny vyššie uvedeného vzorca VI s haiogenačným činidlom, uvedeným v H, H. SNYDER a d.,A process for the preparation of the product of formula (I) above is obtained by obtaining a product of formula (IV) by reacting a compound of formula (VI) with a halogenating agent mentioned in H, H. SNYDER et al.
1953 za vzniku zlúčeniny v rov:P, o1953 to give a compound of formula: P, o
u. Ann. Jnem. boe, nováhe. so svojou trimérnou formou vzorcau. Ann. Jnem. boe, neha. with its trimeric form of the formula
Hal lialHal lial
Lol-S' ILol-S'I
OABOUT
S-tol-HalTol-S-Hal
II
OABOUT
I t-ol II t-ol I
Ha l kde S a toi majú vyššie uvedený význam 2 Hal predstavuje, atóm halogénu, prednostne atóm brómu,táto zlúčenina vzorca VI*sa nechá reagovať so zlúčeninou vzorca II za vzniku produktu vzorca IV, potom sa pokračuje v syntéze vyššie uve42Ha 1 where S and toi are as defined above 2 Hal represents, a halogen atom, preferably a bromine atom, this compound of formula VI * is reacted with a compound of formula II to give a product of formula IV, then the synthesis is continued
co2vco 2 v
SCH·SCH ·
SCH-SCH
co2v spôsobom sa vzniku produktu vzorca Io co 2 in the process to form the product of formula I o
Tieto reakcie je možné realizovat pri vyššie uvedených podmienkach a tak, ako je uvedené v príkladoch realizácie.These reactions can be carried out under the above conditions and as described in the Examples.
Ako je uvedené vyššie, je možné spôsob prípravy produktov vzorca I realizovat reakciou produktu vzorca IIAs mentioned above, the process for preparing the products of formula I can be carried out by reacting the product of formula II
kde P.*1 , R*o a R*ma.jú vyššie uvedený význam, dukt vzorca ITT zodpovedá vzorcu IIIa or o·where P. * 1 , R * o and R * are as defined above, the duct of formula ITT corresponds to formula III and or o ·
HalHal
kde Kal a b majú vyššie uvedený význam, za vzniku oroduktu vzorca 17, zodpovedájúceho vzorcu IVwherein Kal and b are as defined above to form an oroduct of formula 17 corresponding to formula IV
kde H'., H'j, r'j sa produkt vzorca a B majú vyššie uvedený význam, potom IVo nechá reagoval so zlúčeninou vzorca Vwhere H ', H'j, r'j the product of formula and B are as defined above, then IV o is reacted with a compound of formula V
HalHal
R'-» (vj kde Hal a Rmajú vyššie uvedený význam.R 1 - (wherein J 1 and R 2 are as defined above).
príklad takejto prípravy produktu vyššie uvedeného vzorca I je uvedený v príklade 1.an example of such a preparation of the product of formula (I) above is given in Example 1.
Vo vyššie uvedenom postupe je možné nechal reagoval produkt vyššie uvedeného vzorca 11 s produktom vzorca 111, zodpovedajúcom vzorca III.In the above process, it is possible to react the product of formula (11) with a product of formula (III) corresponding to formula (III).
kde Kal a rto majú vyššie uvedený význam, za vzniku produktu vzorca IV, zodpovedajúceho vzorewherein Kal and rto are as defined above to give the product of formula IV corresponding to the pattern
R'2R2 '
R'3R '3
(IV J axeoo nrodu e R , R 9, R a o majú vysaie uvedený vyznám, potom sa odukt vzorca IV, alebo IV*, nechá reagovať s vyššie uvedeným produktom vzorca V(IV J axes of products R, R 9 , R 8 are as described above, then the product of formula IV or IV * is reacted with the above product of formula V
Príklad takejto prípravy produktu vyššie uvedeného vzorca 1 je uvedený v príklade 2.An example of such a preparation of the product of formula (1) above is given in Example 2.
Takýto produkt vzorca I môže byt podrobený, ak .je to nutné a ak je to žiadúce, rôznym reakciám pri vzniku Ôalších produktov vzorca I, uvedeným vyššie, predovšetkým zmydelnenie.· Tak isto produkty vzorca IV a napríklad produkty vzorca IVg, IV& alebo IV*^ môžu byt tiež podrobené rôznym reakciám za vzniku ôalších produktov vzorca IV.Such a product of formula I may, if necessary and if desired, be subjected to various reactions to form the other products of formula I mentioned above, in particular saponification. Also, products of formula IV and, for example, products of formula IV g , IV & They can also be subjected to various reactions to form other products of formula IV.
Predmetom vynálezu sú äalej ako nové priemyslové produkty a predovšetkým ako medziprodukty, nevyhnutné k príprave produktov vzorca I, z účeniny vyššie uvedených vzorcov IV a V.The invention furthermore relates to novel industrial products and, in particular, to intermediates necessary for the preparation of the products of the formula I, for the benefit of the above formulas IV and V.
Niektoré produkty vzorca III sú tiež nové a tvoria z toho titulu predmet vynálezu.Some of the products of formula III are also novel and therefore form the subject of the invention.
Predmetom vynálezu sú zvlášt, ako nové priemyslové produkty, tie.to produkty :In particular, as new industrial products, the invention relates to the following products:
· 2-jódbenzénsulfonamid2-iodobenzenesulfonamide
2. 2-jód-N- [(propyiamíno) karbonyij benzénsulfonamid2. 2-Iodo-N - [(propylamino) carbonyl] benzenesulfonamide
4.a 2-[4-(brómmetyl>fenyl3-5,5-dimetyl-1 ,3,2-dioxaborolan4.a 2- [4- (Bromomethyl> phenyl) -5,5-dimethyl-1,3,2-dioxaborolan
4b 2-[4-(brómmetyl) fenyl]-1 ,3,2-dioxaborolan etyl-1- [(4-boronofenyl)metyl]-2-buty1-4-(metyltio)-1K-imidazoT-5-karboxylát4b 2- [4- (Bromomethyl) phenyl] -1,3,2-dioxaborolane ethyl 1 - [(4-boronophenyl) methyl] -2-butyl-4- (methylthio) -1K-imidazole-5-carboxylate
6a e.tyl-2-butyl-1 -£4-( 5,5“dimetyl-1 ,3,2-dioxaborolan-2-yl)ŕenylmetyl]-4-(metylt.io)-1 H-imidazol-5-karboxylát 6b etyl-2-butyl-1 - [4-(l ,3,2-dioxaborolan-2-yl.)fenylmetyl.J-(metyltio)-lH-imidazol-5-karboxylát · (7-4) ((4-((2-butyl-4-(hietyltiO')-5'-(etoxykarbonyl)-lHimidazol-1 -yl-(( metyl) fenyl)-((2 ,2 *-(metylimíno)-bis(etanolato)) (2-)-N,0,0*-bor6a Ethyl-2-butyl-1- [4- (5,5-dimethyl-1,3,2-dioxaborolan-2-yl) phenylmethyl] -4- (methylthio) -1H-imidazole-5 6b Ethyl 2-butyl-1- [4- (1,3,2-dioxaborolan-2-yl) phenylmethyl] - (methylthio) -1H-imidazole-5-carboxylate (7-4) ( (4 - ((2-butyl-4- (hiethylthio) ') - 5' - (ethoxycarbonyl) -1H-imidazol-1-yl - ((methyl) phenyl) - ((2,2 '- (methylimino) -bis (ethanolato) () - (2 -) - N, 0,0 * -bor
8 etyl-2-butyl-1-((4-(l,3,2-benzodioxaborol 2-yl)fenyJJmetyl)-4-(metyltio?-1H-imidazol-5-karboxylát 9a etyl-2-butyl-1 - ((4-(4,4,5,5-1etrámetyl-1,3,2-dioxolaborolan-2-ylJfenyl)metyl)-4-(metyltio)-1 H-imidazol-5-karboxylát8-Ethyl 2-butyl-1 - ((4- (1,3,2-benzodioxaborol-2-yl) phenyl) methyl) -4- (methylthio-1H-imidazole-5-carboxylate) 9a Ethyl 2-butyl-1- ((4- (4,4,5,5-1-trimethyl-1,3,2-dioxolaborolan-2-yl) phenyl) methyl) -4- (methylthio) -1H-imidazole-5-carboxylate
9b etyl-2-buty-1 - ((4- (1,3,2-dioxolaboŕolan-2-yl )fenylj metyl)-4-(metyltio)-1H-imidazol-5“karboxyláť.9b Ethyl 2-butyl-1 - ((4- (1,3,2-dioxolaborolan-2-yl) phenyl) methyl) -4- (methylthio) -1H-imidazole-5-carboxylate.
Tieto produkty zodpovedajú nasledujúcim vzorcom 1 až 9 :These products correspond to the following formulas 1 to 9:
vin
SCHco2vSCHco 2 v
5CH3 5CH 3
Bu—\BU \
B co2vB co 2 v
«άώαύΟΒώ&αΛββίααι «ΆώαύΟΒώ & αΛββίααι
kde. Z a W, rovnaké alebo rôzne, predstavujú atóm vodíka alebo1 alkylový zvyšok, predovšetkým metyl alebo etyl, a vyššie uvedené. produkty 4, 6 a 9 sú označené 4a, 6a a 9a, ak predstavuje Z mety Lovy zvyšok a 4b, 6b a 9b, ak predstavuje Z atóm vodíka .where. Z and W, identical or different, represent a hydrogen atom or one alkyl radical, in particular methyl or ethyl, and the above-mentioned. products 4, 6 and 9 are designated 4a, 6a and 9a when Z is methyl and 4b, 6b and 9b when Z is hydrogen.
- 44 Spôsoby prípravy vyššie uvedených zlúčenín a niektorých, ich homológov sú uvedené v experimentálnej časti.Methods for preparing the above compounds and some of their homologues are set forth in the experimental section.
Príklad?/ realizácie vynálezuAn example of an embodiment of the invention
Príklady prípravy produktov vzorca I sú uvedené pre osvetlenie vynálezu, ale neobmedzujú jeho rozsah.Examples of preparation of the products of formula I are given for the purpose of illustrating the invention but do not limit its scope.
CJCJ
Príprava 1 : 2-jodbenzénsulfonamid (produkt 1)Preparation 1: 2-Iodobenzenesulfonamide (Product 1)
Na 60° G sa zahrieva j,5 g χ-amínobenzénsuíz'onamidu a 25 ml kyseliny sírovej, koncentrácie 36 ?í. Pridá sa 20 g iadu a pri 0 až 5° G sa pridá roztok 1,45 g dusitanu sodného v 4 ml vody. Zmes sa mieša 3 hod. pri teplote nižšej ako 10' G, potom sa pri 5 až i 0° G pridá roztok 3,75 g did.u draselného v 25 ml vody.60 g of χ-aminobenzenesulphonamide and 25 ml of sulfuric acid (36 µl) were heated to 60 ° C. 20 g of ice are added and a solution of 1.45 g of sodium nitrite in 4 ml of water is added at 0-5 ° C. The mixture was stirred for 3 hours. at a temperature lower than 10 ° C, then a solution of 3.75 g of potassium potassium in 25 ml of water is added at 5 to 0 ° C.
Zmes sa mieša 1.9 hodín a pridá sa 50 ml vody, urobí sa filtrácia a premytie vodou, potom sa zvyšok vyjae do 50 mi etylacetätu, premyje 0,2N roztokom tiosíranu sodného, potom vodou, zahustí sa a získajú sa 4 g očakávaného oroduktu.The mixture is stirred for 1.9 hours and 50 ml of water are added, filtered and washed with water, then the residue is taken up in 50 ml of ethyl acetate, washed with 0.2N sodium thiosulfate solution, then with water, concentrated to give 4 g of the expected oroduct.
Analytické výsledky :Analytical results:
Teplota topenia 197-196Melting point 197-196
IP fnujoi;IP fnujoi;
3367, 3255, 1562 cm“1 3367, 3255, 1562 cm -1
4*4 *
Hmotnostné spektrum 11 NMP : GDGí { 11 NMP Mass Spectrum: GDGi {
5,17 fbs,NHp) , 7,23 a 7,52 (td, arornáty, 2H), 6,08 (iď, aromáty, 2H).5.17 fbs, NHp), 7.23 and 7.52 (td, aromatic salts, 2H), 6.08 (i, aromatics, 2H).
s 3,20with 3.20
263 «—MWMÍMBS263 «—MWMIMBS
- 45 Príprava 2 t 2-jód-N- [(propylamíno)karbonyy benzénsuif onamid (produkt 2)- 45 Preparation of 2 t 2-Iodo-N - [(propylamino) carbonyl benzenesulfonamide (Product 2)
Zmieša sa 4 g jodbenzénsuiŕonamidu a 40 ml acetónu. Pridá sa 3,92 g uhličitanu draselného. Zmes sa privedie k reŕluxu, pridá sa 1,46 ml n-propylizokyanátu a zmes sa udržuje 2 hod. na reŕiuxe. Zahustí sa, pridá sa 200 ml vody, potom sa za chladenia reakčnou zmesou na asi 0 až 5° C pridá 2N roztok kyseliny chlorovodíkovej, do pH 3. Prekryštaiizovaním zo zmesi acetôn-izopropyléter sa získa 4,9 g očakávaného produktu.4 g of iodobenzenesulfonamide and 40 ml of acetone are mixed. 3.92 g of potassium carbonate are added. The mixture is brought to reflux, 1.46 ml of n-propyl isocyanate is added and the mixture is maintained for 2 hours. na reŕiuxe. It is concentrated, 200 ml of water are added, then 2N hydrochloric acid solution is added to the pH of 3 with cooling of the reaction mixture to about 0 to 5 ° C. Recrystallization from acetone-isopropyl ether gives 4.9 g of the expected product.
Analytické výsledky :Analytical results:
Teplota topenia 2·1-212 ~ C TP (nujol) β 1Melting point 2 · 1-212 ~ C TP (nujol) β 1
3^06, 3366, 1715, 1565, 1539 cm3.066, 3366, 1715, 1565, 1539 cm
4Hmtnostné spektrum M 366 JblH . --J4H-mass spectrum M 366 JblH. --J
0,82 (t J - Ί,ϊ, CH-j t 3H), 1 ,4p (m. CH? , 2H), 3,14 (m. CH,, 2H), 6,39 (t, C ONE, 1H ), 7,29 ( dt, J=1 ľ ô, arornáty J, 7,54 (td, J=S,15, srornáty), 8,13 (m, arornáty) , 7,59 (s, SC?HH, 1H).0.82 (t J - ϊ, ϊ, CH - 1 t 3 H), 1.4p (m, CH 2, 2H), 3.14 (m, CH 3, 2H), 6.39 (t, C ONE) , 1H), 7.29 (dt, J = 11'6, boronates J, 7.54 (td, J = S, 15, boronates), 8.13 (m, boronates), 7.59 (s, SC (1H, 1H).
Príprava produktov 5a, 6'o, 7, 5, 9a a 9b, popísaných vPreparation of the products 5a, 6'o, 7, 5, 9a and 9b described in U.S. Pat
v experimentálnej časti, je možné schematicky znázornit takto :in the experimental part, it can be schematically represented as follows:
fiiiÉfnhťWťťťifirŕŕi fiiiÉfnhťWťťťifirŕŕi
tn otn o
H ’YH 'Y
<30<30
CDCD
O o λλO o λλ
(0 (J* vi * y^ \_y v^O-O * cz>(0 (J * vi * y ^ \ _y in ^ O-O * cz>
HH
ΎΎ
inand
S 3= o o uS3 = o o u
Vi O y=^ vh>O ‘Vi O y = ^ vh> O ‘
SCHÉMASCHEME
33 o o33 o o
Vivi
HH
ΎΎ
(0(0
UDUD
II
OJ sOJ p
o o (Λ Uo o (. U
H 2 ·* YH 2 · * Y
οΥΆ oooeeiiafiadttEäfe^.οΥΆ oooeeiiafiadttEäfe ^.
- 47 Príprava J etyl-1- ((4-boronof ehyi) metylj ~2-butyl-4-(metyltio)-1 H-imidazol-p-karboxylát (produkt 5)- 47 Preparation J Ethyl 1 - ((4-boronophenyl) methyl) -2-butyl-4- (methylthio) -1H-imidazole-p-carboxylate (Product 5)
Metoda 1 :Method 1:
Ku zmesi 0,434 g etyl-2-butyl-4-(metyltio)-1H-imidazol-5-karboxylátu, 5 ml dimetylformamidu a 0,552 g uhličitanu draselného sa pridá 0,423 g kyselinyTo a mixture of 0.434 g of ethyl 2-butyl-4- (methylthio) -1H-imidazole-5-carboxylate, 5 ml of dimethylformamide and 0.552 g of potassium carbonate is added 0.423 g of acid
4-brómmetylfenylboronovej (pripravenej metódou podía Snydera a d., JACS 30, 335 (1955)). Po 43 hod. miešania pri teplote miestnosti sa reakčná zmes naleje do íadovej vody. Mieša sa 15 minút, zmes sa prefiltruje, premyje vodou a prekryátalizuje zo zmesi cyklohexaru a isopropyléteru a získa sa 0,450 g očakávaného produktu.4-bromomethylphenylboronic acid (prepared by the method of Snyder et al., JACS 30, 335 (1955)). After 43 hrs. After stirring at room temperature, the reaction mixture was poured into ice water. After stirring for 15 minutes, the mixture is filtered, washed with water and recrystallized from a mixture of cyclohexar and isopropyl ether to give 0.450 g of the expected product.
Metoda 2 :Method 2:
Do zmesi 9,44 g etyl-2-butyl-4-(metyltio)-!H-imidazol-5-karboxylátu, 62 ml bezvodeho dimetyiformamidu a 10,75 g uhličitanu draselného sa pridá roztok 11 g 2'-(4-(brómmetyi)fenyl)-1,3>2-dioxabcrolanu v 56 mi dimetylformamidu. Po 43 hodinách miešania ori teoiote miestnosti sa reakčná zmes vleje do ladovej vedy a okyslí sa na pH 2 '27 kyselinou ohlo— dt1! I ‘r*’!- — ?---— — .--‘o - , emyje vogou, a vysusi a získa síTo a mixture of 9.44 g of ethyl 2-butyl-4- (methylthio) -1H-imidazole-5-carboxylate, 62 ml of anhydrous dimethyiformamide and 10.75 g of potassium carbonate is added a solution of 11 g of 2 '- (4- ( bromomethylphenyl) -1,3,2-dioxabrocrolan in 56 ml dimethylformamide. After 43 hours of stirring, the ori teoiote temperature the reaction mixture was poured into ice science and acidified to pH 2 with hydrochloric ohlo- dt '27 1! I 'r *'! - -? ---— - .-- 'o -, washes through the water, and dries and gets the net
10,45 .g očakávaného produktu.10.45 .g of expected product.
Teplota topenia 159-170° GM.p. 159-170 ° C
IR (aujol) _ 1 £C < 1 0 1 'S - C 1 J rvm • “-D f i t V j í > „· ✓ f · ,· · J- w JaIR (aujol) _ 1 £ C <1 0 1 'S - C 1 J rvm • “-D f i t V i>„ · ✓ f ·, · · J- w Ja
Hmotnostná spektrum 1074 (trimérna forma)Mass spectrum 1074 (trimeric form)
NMR : 3DC1< NMR: 3DCl ?
Zmes moneméru a zdvojenie triméru - 3/4-1/4 signálov 0,37 a 0.,36 (t GHp JH), 1,32 (m, GH2, 2H), 1,30 (t, 502CH9CHjh), 1,64 (m, GH2, 2H), 2,6.0 (m, GH2, 2H), 2,Ó1 a 2,5j (s, SCH , 3H), 4,25 (zdvojený q. GO^GH^GH-^. 2H), 5,5 a 5,60 (s, Monemer mixture and trimer doubling - 3 / 4-1 / 4 signals 0.37 and 0., 36 (t GHp JH), 1.32 (m, GH 2 , 2H), 1.30 (t, 50 2 CH 9) CHjh), 1.64 (m, GH 2, 2H), 2,6.0 (m, GH 2, 2H), 2, and O1 2,5j (s, SCH, 3H), 4.25 (q doubled. GO (2H, 2H, 2H, 2H), 5.5 and 5.60 (s,
Anotácia PVAnnotation PV
Názov vynálezuTitle of the invention
Nov?/ soosob prípravy sírnych derivátov imidazolu a nové medziproduktyA novel process for the preparation of sulfur derivatives of imidazole and novel intermediates
Produkty vzorca I, kde R,, Rp, R^ a R4 majú význam, uvedený v patentových nárokoch, sa pripravujú reakciou zlúčeniny vzorca II, kde R*1 , R*2-a R*^ majú význam, .uvedený v patentových nárokoch, so . * z kde Hal je atóm halogénu s X, aProducts of formula I wherein R 1, R 1, R 1 and R 4 are as defined in the claims are prepared by reacting a compound of formula II wherein R * 1 , R * 2 and R * are as defined in the claims. claims, so. * z wherein Hal is a halogen atom with X, and
I v patentových nárokoch, za vzni kde R tových vzorcaAlso in the claims, where R is of the formulas
T3 P 7 , u p, - 3» A] nárokoch, ktorsT3 P 7, up, - 3 » A ] Claims, which
V.IN.
k p Ucí j u sa nechá zlúčeninou vzorca III, majú význam uvedený ku zlúčeniny vzorca IV, význam uvedený v pstenreagovať so zlúčeninouThe compound of formula III has the meaning given to the compound of formula IV, the meaning given in the reaction with the compound
Produkty majú ·: toru angiotenzínu Iľ účinkov angiotenzínu a tiež tropického ú>'The products have: angiotensin activity and angiotensin activity
lastnosti voči ovšeokým inhibí okonstrikčného myocytov.inhibition of ovarian constriction myocytes.
receptory účinku ^í^tUMUSxiS.receptors of action.
- 76 Vzorce pre anotaciu C I,- 76 Formulas for annotation C I,
IIII
III, IV, V)III, IV, V)
Xz /Xz /
CIII) <V>CIII) <V>
μβμβββ.μβμβββ.
- 43 N-Cí^-Ph, 2H) , 7,00 a 7,63 (bd, aromáty, 2H.), 7,1 1 a 8,12 (bd, aromáty, 2H), 4,93. (m, široký - 0,2H, mobilný).43 N-Cl 2 -Ph, 2H), 7.00 and 7.63 (bd, aromatics, 2H), 7.1 L and 8.12 (bd, aromatics, 2H), 4.93. (m, broad - 0.2H, mobile).
Príprava 4 : etyl-2-butyl-1-f4-(l,3,2-dioxaborolsn-2-yl)f enylmetyl]-4-(metyltio)-1H-imidazol-5“ -karboxylát. (produkt 6b)Preparation 4: Ethyl 2-butyl-1- [4- (1,3,2-dioxaborolsn-2-yl) phenylmethyl] -4- (methylthio) -1H-imidazole-5'-carboxylate. (Product 6b)
Po dobu 4 hod. sa pri refluxe za odstraňovania vznikajúcej vody mieša zmes 1,292 g etyl-1 - Ĺ(4-boroncŕenyl)metylJ-2For 4 hours A mixture of 1,292 g of ethyl-1 - Ĺ (4-boronophenyl) methyl] -2-ethyl acetate is stirred at reflux to remove the water formed.
-butyl·-4“ (metyltio)-1H-imidazol-5karboxylátu, získaného v ' 3 j, podlá prípravy 3, 25 cm toluénu a 0,710 cm^ 1,3-propandiolu. Zmes sa odparí za zníženého tlaku, zvyšok sa vykryštalizuje pôsobením tepla a chladu z heptanu, prefiltruje, premyje a získa sa 1,12 g hľadaného produktu.-butyl-4 '(methylthio) -1H-imidazole-5-carboxylate, obtained in 3', according to Preparation 3, 25 cm @ 3 of toluene and 0.710 cm @ 3 of 1,3-propanediol. The mixture is evaporated under reduced pressure, the residue is crystallized by treatment with heat and cold from heptane, filtered, washed to give 1.12 g of the desired product.
NIvIR : CDC13 (250 MHz) ppmNIvIR: CDCl 3 (250 MHz) ppm
0,36 (t, 3K): 0H3 nBu, 1,30 (m, 23)-1,60 (m, 2H)-2,5S (t, 2H):. CH? nBu, 1,23 (t, 3H)-4,23 ( Q, 2H): -OOOEt, 2,01 (m, 2H): 0-ČH2-eH7-CH7-0, 4,14 (t, 4KJ: -0-CH2-CHo-CH9-0-, 2,55 (s, 3K):’SCH3, 5?52 (s, 2H): Ar-CK^-imidizol“ 6,94 a 7,63 (22, 4H): aromáty.0.36 (t, 3K): 1H 3 nBu, 1.30 (m, 23) -1.60 (m, 2H) -2.5S (t, 2H); CH? nBu; 1.23 (t, 3H) -4.23 (q, 2H): -OOOEt, 2.01 (m, 2H): 0-CH2-CH -eh 7 7 -0, 4.14 (t , 4kJ: -0-CH2-CH-CH 9 of -0-, 2.55 (s, 3H): 'SCH 3, 5? 52 (s, 2H): Ar-CK ^ -imidizol "6.94 and 7.63 (22, 4H): aromatics.
Príorsva 5 etyl-2-butyl-1-£4-(5,5-dimetyl-1,3,2-d Lan-2-yl) fenylmeeylj -4-(metylt.io)-1 H-i -5-karboxylát (produkt 6a) aoxa o or o211US 2 Οχ”Example 5 Ethyl 2-butyl-1- [4- (5,5-dimethyl-1,3,2-dan-2-yl) phenylmethyl] -4- (methylthio) -1H-5-carboxylate ( 6a) aoxa o or o211US 2 Οχ ”
Postupujeme podie prípravy 4 s· použitím 2?0 mg etyl-·- L( 4-boronofenyl) metyl) -2-butyl. l-(me tyltio)-i H-imidazol- 5-karboxylátu a 70 mg 2,2*-dimetyl-‘,3-propsnlioiu a získa sa 200 mg hladeného produktu.Proceed to Preparation 4 using 2 - 0 mg ethyl-L - (4-boronophenyl) methyl) -2-butyl. 1- (methylthio) -1H-imidazole-5-carboxylate and 70 mg of 2,2 ' -dimethyl-β, 3-propanol are obtained to give 200 mg of a fasted product.
Príprava ( T-4) - (( 4- (( 2-butyl-4-(metyltio)-5-( ezoxyKarbonyl) -1 H-imidazol-1 -yl)metyl) fenyl) -((2,2 -(metylimino) -bis (etanolato)- (2-) -N,0,0^-bor (produkt 7)Preparation of (T-4) - ((4 - ((2-Butyl-4- (methylthio) -5- (eshoxycarbonyl) -1H-imidazol-1-yl) methyl) phenyl) -) ((2,2 - ( methylimino) -bis (ethanolato) - (2-) -N, 0,04-bor (product 7)
AäÄíi£síifiSíiiiáaižaátasaiSíÄi£iiÄ5iidiidÍii5ŕa^ŕiÄíiaŕití£áÄäciÄíto^^AAAI síifiSíiiiáaižaátasaiSíÄi £ £ £ ŕiÄíiaŕití iiÄ5iidiidÍii5ŕa ^ ^^ áÄäciÄíto
Postupuje sa podlá prípravy 4 s použitím 2 g etyl-1- f(4-boronofenyl)metyl]-2-buty1-4-(metyltio)-1 H-imidazolj jProceed according to Preparation 4 using 2 g of ethyl 1- [f (4-boronophenyl) methyl] -2-butyl-4- (methylthio) -1H-imidazole.
-5-karboxylátu, 30 cnľ' cyklohexynu a 1 0 cm etylacetatu a po rozpustení za tepla 0,611 cm^ N-metyldietanolamínu. Po zahustení sa získa 2,17 g hľadaného produktu.5-carboxylate, 30 cm @ 3 of cyclohexyne and 10 cm @ 3 of ethyl acetate, and 0.61 cm @ 3 of N-methyldiethanolamine, when dissolved hot. After concentration, 2.17 g of the desired product is obtained.
NMR : CĽCl^ (250MHz? ppmNMR: CH 2 Cl 2 (250MHz? Ppm)
0,35 (t, 3H): CH< nBu, 1,3 (t, 3H?: CH^ z -COOEt, 1,3 (m, 2H)-1,62 (q, 2H?: CK2 v polohe J a CH2 v polohe 2 nBu, 2,30 (s, 3H?, -N+-CHj, 2,60 (s, 2H a T, 2H?: S-CH^ a CH2 v polohe 1 nBu, 2,98 a J,20(m, 4H) : 4,15 (m, 4 H) .CH2-3ť.0.35 (t, 3H): CH <nBu; 1.3 (t, 3H of CH ?: COOEt, 1.3 (m, 2H) -1.62 (q, 2H ?: CK at position 2 J and CH 2 at position 2 nBu, 2.30 (s, 3 H 2, -N + -CH 3, 2.60 (s, 2H and T, 2H 2: S-CH 2 and CH 2 at position 1 nBu, 2 , and J 98, 20 (m, 4 H) 4.15 (m, 4 H) .CH 2 -3T.
4,27 (q, 2H}, CH^ z COOEt, 5,50 ( s, 2H): Ár-CH2-imidazol,.4.27 (q, 2H), CH 2 of COOEt, 5.50 (s, 2H): N-CH 2 -imidazole.
6,9 a 7,5 (2d, 4H) aromáty.6.9 and 7.5 (2d, 4H) aromatics.
Príprava 7 : etyl-2-butyl-l - ((4-(l , 3,2-beinzodicosborol-2-yi)· fenyl) me ty l) - 4- (me ty 1 ti o) -1 H- imid a z ol- 5-karboxvlát (orodukt 3)Preparation 7: ethyl-2-butyl-1 - ((4- (1,3,2-beinzodicosborol-2-yl) phenyl) methyl) -4- (methylthio) -1H-imide az-5-carboxylate (oroduct 3)
Postupuje sa pódia prípravy 4 s použitím 1 g etyl-1-1(4-boron.oŕenyl) metyl) -2-’outyi-4- (metyltio)-1 H-imidazol-5-karboxylátu a 0,233 g kszecholu. Získa sa i,16 g hľadaného. produktu.Preparation 4 was carried out using 1 g of ethyl 1-1 (4-boronophenyl) methyl) -2-methyl-4- (methylthio) -1H-imidazole-5-carboxylate and 0.233 g of cechechol. 16 g of the sought-after product are obtained. product.
2ÍMR : CDC13 (200 MHz ) ppm 0,37 (t, 3H): CH-, nBu, 1,35 (m, 2H): 2¾ ( m, 2K) y I λ í- a O 2 O 7 “5 v .„-J·.-.- jolone 3 n cu,2 DIR: CDCl 3 (200 MHz) ppm 0.37 (t, 3H): CH-, nBu, 1.35 (m, 2H): 2¾ (m, 2K) γ-α and O 2 O 7 5 5 v. '- J ·.-.- jolone 3 n cu,
OO· ( í. , ir.) ;OO · (i., Ir.);
LoheLohe
-. · ) r> /í- '-j·^ . .-»tt .-t9 τρσι λ qc ii_u, . (-> u--/· -1--' -^2-ι-, p, 2H '“9 polohe ľ. nBu, 1,jC· Lt, 3E), CE^ v C02-£t, 4,25 (q, 2H): CE, v •vOpit, 2,&3 (s, j,-); p,c (·=, 2u): oenz.yl, 7,1 a 3,05 (2d):- aromáty, 7, 15 a 7,3 : katechol.-. ·). .- »tt.-T 9 τρσι λ qc ii_u,. (-> u - / - - 1 - '- ^ 2 -ι-, p, 2H''9 position 1' nBu, 1, J · L t, 3E), CE 2 in CO 2 - £ t, 4.25 (q, 2H): CE, [nu] OH, 2, & 3 (s, j, -); p, c (· =, 2u): oenzyl, 7.1 and 3.05 (2d): aromatics, 7, 15 and 7.3: catechol.
Príprava 8 : etyl-2-butyl-l - ((4- (4,4,5 ,p-tetrametyl-1 ,3,2-di oxa bor o len-2-y i) fenyl) metyl.)-4-( metyl tio ) aaeúB&eS£&äS£.Preparation 8: Ethyl-2-butyl-1 - ((4- (4,4,5, p-tetramethyl-1,3,2-dioxa-borol-2-yl) phenyl) methyl) -4- (methylthio) a < B >
·· .·.; ?··ζ^^··. · .; ? · · Ζ ^^
- 50 -1H-imidazol-5-karboxylat (produkt '9a)- 50-1H-imidazole-5-carboxylate (product '9a)
Postupuje sa podlá prípravy 4 : vychádza sa z 0,5 g etyl-1 -£( 4-boronofenyl) metylj -2-butyl-4- (metyitio)-l H-imidazol-5-karboxylátu s použitím 0,189 g pinakolu. Získa sa 0,511 g hladaného produktu.Preparation 4 proceeds: starting with 0.5 g of ethyl 1- (4-boronophenyl) methyl] -2-butyl-4- (methylthio) -1H-imidazole-5-carboxylate using 0.189 g of pinacol. 0.511 g of the product sought is obtained.
Príprava 9 : etyl-2-butyl-((4-(1,3,2-dioxabcrol2n-2-yl) fenyl)metyl)-4-(metyltio )-1H-imidazol·---karboxyiát (produkt 9b)Preparation 9: Ethyl 2-butyl - ((4- (1,3,2-dioxabrolol-2-yl) phenyl) methyl) -4- (methylthio) -1H-imidazole-7-carboxylate (Product 9b)
Postupuje sa pódia prípravy 4 : vychádza sa z 0,2 g etyl-' -[(4-boronofenyl)mexyl] -2-butyl-4- (metyltio)-l H-imidazol.-5-karboxylátu s použitím 39 mg eiyiéngiykolu. Získa oroduktu.Preparation 4 proceeds: starting with 0.2 g of ethyl 1 - [(4-boronophenyl) mexyl] -2-butyl-4- (methylthio) -1H-imidazole-5-carboxylate using 39 mg of ethylene glycol . Obtains an oroduct.
sa 0,2' g očakávanéhoto 0.2 'g of the expected
NMR : GDC1-, (2 50 MKz ) ppmNMR: GDC1-, (250MHz) ppm
0,9 (t, 3?/): GH nSu, 1 ,35 (m, 2H): GE9 v polohe 3 nBu, ,65 (m, 2H): GH9 v polohe 2 nBu, 2,6 j”(t, 2H): 7E9 v polohe 1 nEu, 1,3θ'(ΐ. jH): GC92t, 4,25 (q, 2H): G09Žt, 2,5J (s, 3H): 3-GHj, 5,60 (s, 2H): Ar-GH9-imidazoi, 4,45 (s, 4H): 2CH,-O, 7,92 9 7,S (2 i): woaéty.0.9 (t, 3?): GH nSu, 1.35 (m, 2H): GE 9 at 3 nBu position, 65 (m, 2H): GH 9 at 2 nBu position, 2.6 j " (t, 2H): 7E 9 at position 1 nEu, 1.3θ '(ΐ. JH): GC 9 2t, 4.25 (q, 2H): G0 9 Zt, 2.5J (s, 3H): 3 -GHj, 5.60 (s, 2H): Ar-GH 9 -imidazole, 4.45 (s, 4 H): CH2, O, 7.92 9 7, s (2 i) woaéty.
’ioraví'ioraví
2-brom-N- [(propylamíno) karbonyľ] benzá; amid2-bromo-N - [(propylamino) carbonyl] benzo; amide
X rsfluxu sa zahrieva i 5 g 2-brombenzánsuifonsmidu v 150 car acetónu, pridá sa 17,5 g uhličitanu draselného a potom 6,6 cnP N-propylizokyanátu, zmes sa mieša 2,5 hod.5 g of 2-bromobenzanesulfonamide in 150 car acetone are heated to reflux, 17.5 g of potassium carbonate are added, followed by 6.6 cnP of N-propylisocyanate, and the mixture is stirred for 2.5 hours.
- 51 za refluxu, ochladí na ú3 C a okyslí na pH 5. Získa sa 18,35 g očakávaného produktu (teplota topenia 218-219° G), NMR : GDC1 ppm- 51 to reflux, cooled to 3 C and D adjusted to pH 5 to give 18.35 g of the expected product (m.p. 218-219 DEG C.) NMR: ppm GDC1
0,84 (t, 3H): CK3, 1,45 (m, 2Hj, 3,07 (q, 2K), GH2, 6,08, (1, 1H): NH, 7,5 (m, 2H), 7,71 fdd, 1H), 8,25 (dá, 1H>: aromáty, 10,00 (L, 1H): NH.0.84 (t, 3H): CK 3 , 1.45 (m, 2H, 3.07 (q, 2K), GH 2 , 6.08, (1, 1H): NH, 7.5 (m, 2H), 7.71 (fdd, 1H), 8.25 (d, 1H): aromatics, 10.00 (L, 1H): NH.
Príklad 1Example 1
Didraselná soí kyseliny 2-buryi-4H-(metyitio)-1-[£2'- ŕ(((. propylaaíno) karbonyl) amíno)sulfonyl)-1 ,1 #-bifenyl-4-ylj· metylj-lH-imidazol-5-karboxylovej itupen A : 2- C(4-brommetyi)f enylJ-5,5-dimetyl-i, 3,2-díoxaborolan hod. sa zahrieva k refluxu za odstraňovania vznikajúcej vody j,4 g kyseliny 4-metylfenylboronovej alebo jejDipotassium salt of 2-Bury-4H- (methylthio) -1- [2 '£ t (((. Propylaaíno) carbonyl) amino) sulfonyl) -1, 1 # -biphenyl-4-methyliodide YLJ · H-imidazole -5-carboxylic acid itupene A: 2- C (4-bromomethyl) phenyl] -5,5-dimethyl-1,3,2-dioxaborolane hr. is heated to reflux to remove the resulting water j. 4 g of 4-methylphenylboronic acid or its
Λ trimérnej formy a 2,6 g 2,2-dimetyIpropan-l,3-diolu v 50 cm° cyklohexanu. Pridá sa 4,45 g M-brómsukcinimidu a 1 00 mg azobisizoOutyronitriiu. Zmes sa udržuje 4 hod. na rez luxe, chladí sa, prefiltruje, premyje cykĺohexanom a v o dlabaného oroduktu, Teciota točenia 1 i 0' G.Of the trimeric form and 2.6 g of 2,2-dimethylpropane-1,3-diol in 50 cm @ 3 of cyclohexane. 4.45 g of M-bromosuccinimide and 100 mg of azobisoisoutyronitrile are added. The mixture is maintained for 4 hours. Luxe cut, cooled, filtered, washed with cyclohexane and a mortar oroduct, Teciota rotating 1 and 0 < 0 > G.
;nsma sa; nsma se
NľvIH : GDG1 :omNH: GDG1: om
1,01 (s, 6H): OH, ?-G, 3,75 (s, 4H): GH^-C-H, 4,52 (s, 2H) : OH03r, 6,95 (d, 2E\ 7,72 (d, 2H) aromáty.1.01 (s, 6 H): OH? -G, 3.75 (s, 4 H): GH-CH, 4.52 (s, 2H): 0 3 r OH, 6.95 (d, 2 E \ 7.72 (d, 2H) aromatics.
tupeň S : etyl-2-butyi-l-£4- (5,5-dimetyi-S , 3,2-dioxaborolan-2-yí )fenyimetyij -4-(mezyltio)-í H-im: dazoi-ô-karboxylát min. sa mieša zmes etyl-2-butyi-4-(metyltio)-1Himidazol-5-karboxyiátu, 65 cm^ dimetylformamidu a 3,75 g step S: ethyl-2-butyl-1- [4- (5,5-dimethyl-S, 3,2-dioxaborolan-2-yl) phenylmethyl] -4- (mesylthio) -1H-imidazole-6-one; carboxylate min. A mixture of ethyl 2-butyl-4- (methylthio) -1H-imidazole-5-carboxylate, 65 cm @ 3 of dimethylformamide and 3.75 g is stirred.
«gaggwtp«gaggwtp
-.^ij^aBS uhličitanu draselného, potom sa pridá 3 g produktu, pripraveného v stupni A, v roztoku v 32 cm^ dimetylformamidu. Zmes sa mieša 48 hodín pri teplote miestnosti. Vleje sa. do vody, extrahuje aetylacetátom, vysuší a odparí pri zníženom tlaku do sučhaQPo rozotrení so zmesou cyklohexan-etylacetát(8:2) sa získa 5,67 g hladaného produktu (teplota topenia 145-146° G?.potassium carbonate, then 3 g of the product prepared in Step A in solution in 32 cm @ 3 of dimethylformamide are added. The mixture was stirred at room temperature for 48 hours. It flows. Q. After trituration with cyclohexane-ethyl acetate (8: 2), 5.67 g of the desired product is obtained (m.p. 145-146 ° C).
NMR : GDCl-j ppmNMR: GDCl-1 ppm
0,86 (t, 3H): GH^ nBu, 1,29 (t, 3H): GH3 v GO2St, 1,34 fm, 2H), 1,62 (m, 2H?, 2,60 (d, 2H): GH2 v nBu, 2,61 (s, 3H): S-GHp 4,23 (q, 2H?: CK2 v GO2Et, 5,52 (s, 2H>: QR? benzyl,· 6,36 (d, 2H? a 7,71 (d, 2H): aromáty.0.86 (t, 3H): GH 3 nBu, 1.29 (t, 3H): GH 3 in G 2 O 2 , 1.34 fm, 2H), 1.62 (m, 2H 2, 2.60 ( d, 2H): GH 2 in nBu, 2.61 (s, 3H): S-GHp 4.23 (q, 2H ?: CK 2 in G 2 Et, 5.52 (s, 2H): QR? benzyl 6.36 (d, 2H) and 7.71 (d, 2H): aromatics.
Stupeň G : etyl-2-butyl-4K- (metyltio)-1 - [[2 (((( propylamíno) karbony i? amíno ^sulf onyi) -1 ,1 *-( bifenyl) -4-ylj metylJ-iH-imidszol-5-karboxylát hod. sa k refluxu zahrieva zmes 62 mg 2-bróm-IJ-f f propylaaíno)karbonyi]bensénsulľonamidu, získaného nocia oríoravy 10, 4 ca* toluénu, 0,193 cm' 2N roztoku uh_ičitanu sodnénc vo vode, 7 mg tezrakis(trifenyfosfín)paládia, 1,5 cm' etanolu, 55,5 mg produktu, získaného v stupni 3, a 0,4 cmJ toluénu.Step G: ethyl-2-butyl-4K- (methylthio) -1 - [[2 (((((propylamino) carbonylamino) sulfonyl) -1,11- (biphenyl) -4-yl) methyl) -1H -imideszole-5-carboxylate was heated at reflux for 1 hour with a mixture of 62 mg of 2-bromo-1 H- (propylamino) carbonyl] -benzenesulfonamide, obtained overnight at 10.4 cm @ 3 of toluene, 0.193 cm @ 2 of 2N sodium carbonate solution in water. tezrakis mg (triphenyl phosphine) palladium, 1.5 cm @ of ethanol, 55.5 mg of the product of step 3, and 0.4 cc of toluene.
Pridá sa malé množstvo toluénu -a zmes sa okyslí na p3 2,-2K kyselinou chlorovodíkovou. Extrahuje sa metylénchloridom, premyje vodou, vysuší,odparí do sucha a získa sa í 65 mg produktu, ktorý sa c-iromatografuje na siiikagele s slúciou zmesou toluén-dioxan-kyselina octová (95:4:1 )j získa sa tak 75 mg Laného produktu (teplota topenia '32° G).A small amount of toluene was added and the mixture was acidified to β2.2K with hydrochloric acid. It is extracted with methylene chloride, washed with water, dried, evaporated to dryness to give 65 mg of product which is c-iromatographed on silica gel with toluene-dioxane-acetic acid (95: 4: 1) to give 75 mg of lane. product (m.p. '32 ° C).
T.T.
i — J'UČi - JUU
NMR : GDG1, ppmNMR: GDG1, ppm
0,72 (t, 3H): GH-, nBu, 1,67 (m, 2H): GH?, 5,03 (q, 2H?:0.72 (t, 3H): GH-, nBu; 1.67 (m, 2H): GH? , 5.03 (q, 2H ?:
-Q | -'I W « \ ,-Q | -'I W «,
7,64 f t), 7,53 (t), 8,12 (d): aromáty.7.64 (t), 7.53 (t), 8.12 (d): aromatics.
;Η9-λΉ, 6,01 (s, 1K): 30qNH, 6,11 (t, 1H): CONH, 7,25 (d), Δ 9 -λΉ, 6.01 (s, 1K): 30 q NH, 6.11 (t, 1H): CONH, 7.25 (d),
^?J<^? J <
Stupeň D : didraselná sol kyseliny 2-butyl-4H- (metyitio)-í - CC2 '-(((( propyiamíno)karbonyl) amíno? sulfonyl) -í, 1 *- (’oif enyl)-4-yijmetylj-lK-imidazol-5-karboxylovejStep D: Dipotassium salt of 2-butyl-4H- (methylthio) -1-CC2 '- ((((propylamino) carbonyl) amino-sulfonyl) -1,11- (' oiphenyl) -4-ylmethyl) -1K imidazole-5-carboxylic acid
K roztoku 2 g produktu, získaného podlá stupňa G v cm^ etanolu sa pridá pri 0° C 2,J cm^ 6N roztoku hydroxidu draselného. Zmes sa nechá ohriaľ na teolotu miestnosti.To a solution of 2 g of the product obtained according to Step G in cm @ 3 of ethanol was added at 0 DEG C., 2 cm @ 3 of a 6N potassium hydroxide solution. The mixture was allowed to warm to room temperature.
“3"3
Po 72 hodinách sa zrazenina odfiltruje a premyje 4 czJ etanolu a potom 4 cnP etylacetátu. Po vysušení sa získa 2,04 g hľadaného produktu :After 72 hours, the precipitate was filtered off and washed with 4 L of ethanol and then with 4 mL of ethyl acetate. After drying, 2.04 g of the product sought is obtained:
teplota topenia>260° Gmp > 260 ° C
Analýza pre C26H3oK2N4°5S2 : vypočítané 50,jC % G, 4,S7 50,5 % C, 4,9 nájdenéAnalysis for C 26 H 30 K 2 N 4 ° 5 S 2 : Calculated : C, 50.5; C, 50.5; C, 4.9 found
H, 9,02 % N, 10,33 H, 9,0 % N, 10,3H, 9.02; N, 10.33; N, 9.0; 10.3
S,WITH,
Príklad 2aExample 2a
Didraselná soľ kyseliny 2-butyl-4H-<metyltio)-1-[[2'- f ((( propylanínojkarbonyl) amíno) sulf onyl) -1, < ŕbifenyl)-4-yij metvlj-1 H-imidaz ol- 5-karboxylove jDipotassium salt of 2-butyl-4H- (methylthio) -1 - [[2'-f (((propylamino-carbonyl) amino) sulfonyl) -1,4-biphenyl) -4-yl] methyl-1H-imidazole-5-yl -carboxylove j
C-*-, tne ň A : 2-£(4-broametyl?fenylJ -1 , 3,2-dioxaborolanC - * -, m.p. A: 2- (4-Broamethylphenyl) -1,3,2-dioxaborolan
Pracuje sa ako v stuoni & oríkiadu 1 ; vycnádza sa z · oIt works as in stucco & oriad 1; barring
21,06 g kyseliny 4-metyifenylborcncvej s použitím 17,i cm trimetylénglykolu, 250 cmJ cyklohexynu, 44o mg azobisizobutyronitrilu a 32,03 g N-oromsukciáimidu.Získa sa jl daného produktu '(teplota topenia 108-109 °G).21.06 g of 4-metyifenylborcncvej using a 17 cm trimethylene and 250 cc of cyclohexyl, 44o mg of azobisisobutyronitrile and 32.03 g of N-oromsukciáimidu.Získa jl is the product '(m.p. 108-109 DEG C.).
.r hľa..r behold.
ΝΜΉ : ( GDG1< ) ppmΝΜΉ: (GDG1 <) ppm
2,05 (m, 2Hb centrálne GHS, i, 14 (t, 4H): 5-0-GH,, 4,49 (s, 2H): GH2-3r, 7,27 (d, 2H) a 7,7* (d, 2K): aromáty.2.05 (m, 2Hb centrally with GH, and 14 (t, 4H) 5-0-GH ,, 4.49 (s, 2H): GH 2 -3R, 7.27 (d, 2H), and 7.7 * (d, 2K): aromatics.
- 54 Stupeň 3' : etyl-2-butyi-1 - £4-( 1 , j, 2-dioxaborolan-2-ylJ fenylmetylj -4-ŕ mety ltio)-1H-imidazoi-5-karboxylát minút sa pri 20 až 22 °G zahrieva zmes 34,5 g etyi-2-butyi-4-(metyitio)-1H-imidazol-5“karboxylátu, 59 h uhličitanu draselného, 3,32 g tetrabutylamóniumbromidu a 312 cnP acetónu-. Potom sa pridá 33,6 g produktu, získaného podlá stupňa A. Zmes sa mieša 24 hod., prefiltruje a zahustí do sucha pri zníženom tlaku. Po kryštalizácii teplom a chladom v 59 cm^ etanolu sa zísxa 20,1 g hladaného produktu fteplota topenia 120-121° G).Step 3 ': Ethyl 2-butyl-1- [4- (1,1,2-dioxaborolan-2-yl) phenylmethyl] -4-methylthio) -1H-imidazole-5-carboxylate for 20 minutes 22 ° C heats a mixture of 34.5 g of ethyl 2-butyl-4- (methylthio) -1H-imidazole-5-carboxylate, 59 h of potassium carbonate, 3.32 g of tetrabutylammonium bromide and 312 cnP of acetone. 33.6 g of the product obtained in Step A are then added. The mixture is stirred for 24 hours, filtered and concentrated to dryness under reduced pressure. After crystallization by heat and cold in 59 cm @ 3 of ethanol, 20.1 g of the desired product (m.p. 120-121 DEG C.) are obtained.
NMR : (GDC1 ) ppmNMR: (GDC1) ppm
0,86 (t, 3K): GH-j, 1,28 ft, 3H): GH v CO,Et, 1,30 (m, 2H) : GH2, 1,60 (m, 2H): GH2, 2,53 (t, 2HJ: CH2-C=N, 2,55 (s, JH): S-GH,, 2,04 (m, 2H): centrálna CH9, 4,11 f t, 4H?: 50-CH?0.86 (t, 3H): GH-J, 1.28 feet, 3H): GH CO, Et, 1.30 (m, 2H): GH 2, 1.60 (m, 2H): GH 2 , 2.53 (t, 2HJ CH 2 -C = N, 2.55 (s, J H) s-GH ,, 2.04 (m, 2H): CH central 9 4.11 feet, 4H? : 50-CH?
4,23 (t, 2HJ: GH2 v C023t, 5,52 (š, 2HJ : GH2-N, ó,94 2H? a 7,63 (d, 2H): aromäty.4.23 (t, 2HJ: GH 2 in CO 2 3t, 5.52 (b, 2HJ: GH 2 -N, δ, 94 2H) and 7.63 (d, 2H): aromatics.
Stupeň G : etyl-2-bu t,yl-4H-(metyítio-)-1 - [f5 '-(((( propyiamíno) karbonyi) amíno) sulfonyl) -1,1 *- (bifenyl) -4-yij-metylj-1H-imidazol-5-karcoxyiát — ν’» o hu zmesi io4 mg procuktu, získaného poa-a cm toluénu, 1 ,C27 cm' •avy 10,Step G: ethyl-2-tert-yl-4H- (methylthio) -1- [t5 '- ((((propylamino) carbonyl) amino) sulfonyl) -1,1 * - (biphenyl) -4-yl - methyl 1-1H-imidazole-5-carboxylate - a mixture of 14 mg of the product obtained after about 1 cm @ 3 of toluene;
2N roztoku uhličitanu sodného,2N sodium carbonate solution,
17,3 mg gaívinoxyiu, miešaná 1517,3 mg gaivinoxyium, mixed 15
12,9 mg trifenylfosfínu a 5,5 mg acetátu paládia. Zmes sa mieša 15 minút a oridá sa roztok 400 mg prôí ' o duktu, pripraveného v stupni 3, v 1,3 cm toluénu e 5,3 cm12.9 mg triphenylphosphine and 5.5 mg palladium acetate. The mixture is stirred for 15 minutes and a solution of 400 mg of the product prepared in step 3 in 1.3 cm of toluene and 5.3 cm is added.
I , ~ m r* í í *· ·:I, ~ m y *: ·:
refiuxe.refiuxe.
irisdení etanolu. zmes sa missa 24 noc.irisdení ethanol. the mixture is missed 24 night.
énorn a okyslení prídavkom 1,47 csJ 2Z1 kyseliny chlorovodíkovej sa zmes extrahuje metylénchloridom, vysuší 3 odparí pri zníženom tlaku do sucha. Zvyšok sa chromotograťuje na siiikagele felúcia zmesou cyklofiexan/n-chlórbutan/iáopropylaikohoi 75:25:5) a získa sa 0,25 g hladaného produktu., identického s produktom, získaným v stupni G príkladu 1.énorn and acidified by the addition of 1.47 j 2Z1 acid, the mixture was extracted with methylene chloride, dried 3 evaporated in vacuo to dryness. The residue is chromatographed on silica gel, eluting with 75: 25: 5 cyclophiexane / n-chlorobutane / iopropylaikohoi) to give 0.25 g of the desired product, identical to the product obtained in Step G of Example 1.
w»«i«i>rii>n<H>aicftiiaiiMaeiiŕ»aeiaaitfŕaagBiiiagä8BBÍŕs^^W »« i «i> rii> n <H> aicftiiaiiMaeiiŕ» aeiaaitfŕaagBiiiagä8BBÍŕs ^^
- 55 Stupeň D : didraselná sol kyseliny 2-outyl-4H-(metylt io)-1 — £ C 2 (((( propylamíno·) karbonyi) amíno) sulfoo yl) -1,1*- 55 Step D: Dipotassium salt of 2-outyl-4H- (methylthio) -1- CC 2 ((((propylamino) carbonyl) amino) sulfooyl) -1,1 *
-( bifenyl) -4-y 1J metylj -1 H-imid3Zol- 5-karboxylovej- (Biphenyl) -4-yl] methyl-1H-imide-3Zole-5-carboxylic acid
Postupuje sa ako v stupni Ľ príkladu 1.The procedure is as in Step 1 of Example 1.
Príklad 2bExample 2b
Didraselná sol. kyseliny 2-butyl-4H-ímetyltio)-1-ff 2 *- (((( propylamíno) karbonyi) amíno)sulf onyl)-1 ,1 - (bif enyl) -4-ylJ metylj-1H-imidazol-5-karboxylovejDipotassium sol. 2-butyl-4H-methylthio) -1-ff 2 * - ((((propylamino) carbonyl) amino) sulfonyl) -1,1- (biphenyl) -4-yl] methyl] -1H-imidazole-5- carboxylic acid
Postupuje sa ako v príklade to 12,9 mg trifenylfos fosfínopropanu. Získa v stupni C príkladu 2s stupni D príkladu 1, íínu použij sa tak 49,č , ktorý sa pri vznikuThe procedure is as follows: 12.9 mg triphenylphosphine phosphinopropane. In step C of Example 2, with step D of Example 1, the compound 49, which is used in the formation, is used
2s ; v stupni d sa namiese I C, 1 mg 1 , j-bisdif enylmg produktu, pripraveného spracuje, ako je uvedené v o č a k ávoného produktu.2s; in step d, 1 mg of 1, 1'-bisdiphenylmg of the product prepared is treated as indicated in the product.
Όν» »* ’/·Ί klad 3Ίν »» * ´ / · Ί example 3
2tyl-2-cutyl.-4H-faetyitdo)-:-[C2 '-(ίΎ f propylamíno)karbonyi) amíno) sulfonyl) -1,1 - (bif eny 1?-4-yIjmety 1J-12-ethyl-2-cutyl-4H-phenylamino) -: - [C2 '- (t-propylamino) carbonyl) amino) sulfonyl) -1,1- (biphenyl-4-ylmethyl) -1J-1
-imidazol-p-karboxylátimidazole-p-carboxylate
PostUDuje sa ako v stuoni C oríkladu í s použitímIt is studied as in Stage C of Example 1 using
0,0524 g 2-jod-ií-propýUaBÍnokarbcnyibenzénsulfonamiôu, získaného podlá prípravy 2, a 109 mg produktu, pripraveného rodia prípravy 4, a získa sa očakávaný produkt.0.0524 g of the 2-iodo-1-propoxycarbonylbenzenesulfonamide obtained according to Preparation 2 and 109 mg of the product prepared by Preparation 4 gave the expected product.
Príklad 4Example 4
Etyl-2-butyL-4H- (mety ltio)-1 -[['é '-(((( propylamíno) - 56 karbonyl) amíno)suifony i?-1,1 -(bifenyl?-4-yijmstylj -1H-inidazol-5-karboxvlá· '«z </.Ethyl-2-butyl-4H- (methylthio) -1 - [['(1') - ((((propylamino) - 56 carbonyl) amino) suifonyl) -1,1- (biphenyl-4-ylmethyl) -1H Inidazole-5-carboxylate.
príklad 2 s oouz;Example 2 with oouz;
Postupuje ss ako v stupni mg 2-jód-N-propylamínokaroonylsulfónamidu a 1,2 g produktu, pripraveného pcdla prípravy 5, a získa sa 905 ag hiadaného produktu.Proceed as in step mg of 2-iodo-N-propylaminocaroonylsulfonamide and 1.2 g of the product prepared in Preparation 5 to give 905 g of the desired product.
Príklad 5Example 5
Etyl-2-butyl-4H-(metyltio)-i-Cf2'-(((( propyiamíno) karbonyl) amíno) sulíonyl) -1 , i - (bifer.yl) -4-ylJmetylJ -1Ethyl-2-butyl-4H- (methylthio) -1-Cl 2 - (((((propylamino) carbonyl) amino) sulfonyl) -1,1- (biphenyl) -4-yl) methyl] -1
-ímidszol-5-karboxvlát • a sko v spupíi;imidazole-5-carboxylate and in the spup;
príkladu 1{ vyohadzaof Example 1
orsprávy o, avv .m a 313:0 53 03 kadministration o, avv.m and 313: 0 53 03 k
Príklad ó ^1-2-ο^γ1-ΐΗ-^β^111ο}-ΐ -fC2 '-(((( propy iamino).· karbonyiJomínoJsuifony J -1,1 -(biienyl) l-yj meoyí] POSPUPUjO sa i n ,·>' vf f ·: --* f X 1· - * w kZEXAMPLE 6-1-2-ο-γ1-ΐΗ-β-β-111ο} -ΐ-fC2 '- (((((propylamino). -Carbonylamino) -sulfones J -1,1- (benyl) 1-yl) meoyl) PROCEDURE in,>> vf f ·: - * f X 1 · - * w kZ
Ου Li x.Liυ Li x.
—' V-» Λ -rn .*> »> · VS”'1 -Ί- 'V - »Λ -r. *>»> · VS ”' 1 -Ί
-.·—j—U. z, v .y η -».»>ο·:ττ ~ o fcX.' -- C· ‘lorsvy-. · J-U. z, v .y η - ».»> ο ·: ττ ~ o fcX. ' - C ‘lorsvy
Ä 7. ΐ 15 > '7 ά · vQUľľ -.U<Ä 7. ΐ 15> '7 QU QU QU ľ--.U <
*íklad 7* Example 7
StyL-2'-butyl-4E-(metyltio )-1 -fí i'-((({. propyiamíno )F7 kar b onvl) amínoJsulf onyl·) -1 , 1 '-(bifenyi) -4-ylJsetylJ-1H-imidazoL-5-karboxylátStyyl-2'-butyl-4E- (methylthio) -1-phenyl - ((((propylamino) F7 carbonyl) amino) sulfonyl) -1,1 '- (biphenyl) -4-yl] ethyl-1H imidazole-5-carboxylate
Postupuje sa ako v príklade o ; vychádza sa s 1 g produktu, získaného pódia prípravy j, a 528 mg 2-jôd-N-C(propyľ amíno) -karbonylj benzénsulfónamidu, pripraveného podlá prípravy 2, a získa sa tak ;71 mg híadaného produktu.The procedure is as in Example o; starting with 1 g of the product obtained in Preparation j and 528 mg of 2-iodo-N-C (propylamino) -carbonyl] benzenesulfonamide prepared according to Preparation 2 to obtain 71 mg of the desired product.
Príklad 8Example 8
Stvl-2-butyl-4H-(metyitioj -1 - CL2 '-(((( propylamino) karbonyi) amíno) suifonyl) -1,1 *-(bif er.yD -4-yIj mety!} -1H-imidazol-p-karboxylátStvl-2-butyl-4H- (methylthio-1-CL2 '- ((((propylamino) carbonyl) amino) sulfonyl) -1,1 * - (biphenyl-4-yl) methyl} -1H-imidazole -p-carboxylate
Postupuje. sa ako v stupni 1 príkladu 2 s použitím namiesto produktu, získaného podlá stupňa B príkladu 2, 432,5 o produktu, pripraveného pódia prípravy 7» s získa sa tak 121 ns očakávaného oroduktu.Progresses. as in Step 1 of Example 2, using instead of the product obtained according to Step B of Example 2, 432.5 o the product prepared in Preparation 7 's, 121 ns of the expected oroduct is obtained.
Styl-2-buty L-4í:-(metyltio)-i -[Γ2 '-(< (Cpropylamíno )karbonyi)amíno)suifonyl·) ,·, '-(.bi-er.yl) -s-ylj ne tyl J - i:Styl-2-butyl L-4 ', :-( methylthio) -1- ['2' - (<(propylamino) carbonyl) amino) sulfonyl} -1 '- (bi-ethyl) -s-yl tulle J - i:
-imidazol-p-karboxylátimidazole-p-carboxylate
Postupuje oa ako v stupni u príkladu 2 s použitím namiesto produktu, získaného podía stupňa B príkladu 2, 387 mg produktu, pripraveného podía prípravy 9, a získa sa tak 22'J,; mg očakávaného produktu.The procedure of Example 2 was followed using, instead of the product obtained in Example 2, Step B, 387 mg of the product prepared in Preparation 9 to give 22 '. mg of expected product.
Styl-2-butyl-d.H- (nemyltioý-l -[Ĺ2 *-(((( propy iamíno)namiesto produktu, získaného podlá stupňa Ξ príkladu 2, 440 mg produktu, pripraveného pódia prípravy 8, a získa sa tak 172 mg očakávaného produktu.Styl-2-butyl-dH- (non-methylthioyl-1- [*2 * - ((((propylamino)) instead of the product obtained according to step Ξ of Example 2, 440 mg of the product prepared in Preparation 8 to give 172 mg of the expected product.
Príklad 1 íExample 1 i
Farmaceutický prostriedokPharmaceutical composition
Boli pripravené tabletky tonoto zloženia : produkt príkladu 1 p? m>:Tablets of the following composition were prepared: Example 1 p? m>:
r* a per p:) + a a — * ň *·.r * a per p :) + and a - * ň * ·.
u L - V.. .A (nosič konkrétne: Laktóza, talek, škrob, stearát uorečn • ;/ λ · · · .n ŕ-. - «-s -* ··» - r»«“ - .3 i — n ** /Λ y» o i * u co n r’,f r» c «** r*· onu L - V .. .A (carrier in particular: Lactose, talc, starch, stearate stearate; --s n s «« «« «« «« « - n ** / Λ y o oi * u co n r ', fr c c «** r * · on
-1Λ.0 -t*- e...-.-J ) - - ..4. ‘ - -·£—Ι.τ ·. -Í λ J T-íZii,/.:* Cyúx •/U'J.-1Λ.0 -t * - e ...-.- J) - - ..4. ‘- - · £ —Ι.τ ·. -Í λ T ii ii ii / Cy Cy ú ú ú
pódia vynálezu, je rečné uvieso pred:vsetkým zlúčeninyAccording to the invention, it is said to precede all compounds
Claims (9)
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FR9311030A FR2711368B1 (en) | 1993-09-16 | 1993-09-16 | New process for the preparation of sulfur derivatives of imidazole and the new intermediates obtained. |
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DE19820064A1 (en) * | 1998-05-06 | 1999-11-11 | Hoechst Marion Roussel De Gmbh | Substituted sulfonylcyanamides, process for their preparation and their use as a medicament |
DE19832428A1 (en) * | 1998-07-18 | 2000-01-20 | Hoechst Marion Roussel De Gmbh | New imidazolylmethyl-biphenyl-sulfonylcyanamides, are sodium-dependent bicarbonate/chloride exchanger inhibitors used e.g. for treating cardiovascular disorders such as cardiac infarction |
DE19832429A1 (en) * | 1998-07-18 | 2000-01-20 | Hoechst Marion Roussel De Gmbh | New imidazolylmethyl-biphenyl-sulfonylcyanamides, are sodium-dependent bicarbonate/chloride exchanger inhibitors used e.g. for treating cardiovascular disorders such as cardiac infarction |
JP3946518B2 (en) | 2001-12-28 | 2007-07-18 | 株式会社リコー | Color toner for image formation, image forming apparatus and toner container |
WO2006125592A2 (en) * | 2005-05-24 | 2006-11-30 | Lek Pharmaceuticals D.D. | Process for the preparation of 2-alkyl-1-((2'-substituted-biphenyl-4-yl)methyl)-imidazole, dihydroimidazole or benzimidazole derivatives |
JP2009530256A (en) * | 2006-03-17 | 2009-08-27 | シプラ・リミテッド | 4- [1- (4-Cyanophenyl) -1- (1,2,4-triazol-1-yl) methyl] benzonitrile and 4- [1- (1H-1,2,4-triazole-1- Yl) methylenebenzonitrile intermediate |
US8034526B2 (en) | 2006-09-07 | 2011-10-11 | Ricoh Company Limited | Method for manufacturing toner and toner |
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US4411690A (en) * | 1981-01-26 | 1983-10-25 | E. I. Du Pont De Nemours & Co. | Fused [1,2,4]oxadiazolylidenebenzenesulfonamides and their use as herbicides and plant growth regulants |
US4537618A (en) * | 1982-05-26 | 1985-08-27 | Ciba Geigy Corporation | N-phenylsulfonyl-N'-pyrimidinylureas |
ATE29260T1 (en) * | 1982-12-27 | 1987-09-15 | Ciba Geigy Ag | PHOSPHORUS-CONTAINING N-PHENYLSULFONYL-N'-PYRIMIDINYL AND TRIAZINYL UREAS. |
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CZ1294A3 (en) | 1995-05-17 |
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ZA9419B (en) | 1995-01-04 |
KR950008486A (en) | 1995-04-17 |
CN1100415A (en) | 1995-03-22 |
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NO940018L (en) | 1995-03-17 |
AU5300394A (en) | 1995-04-13 |
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HUT67958A (en) | 1995-05-29 |
YU82493A (en) | 1996-07-24 |
US5391732A (en) | 1995-02-21 |
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