NO843171L - PROCEDURE FOR THE PREPARATION OF NEW ACYLATED HYDRAZINE COMPOUNDS - Google Patents
PROCEDURE FOR THE PREPARATION OF NEW ACYLATED HYDRAZINE COMPOUNDSInfo
- Publication number
- NO843171L NO843171L NO843171A NO843171A NO843171L NO 843171 L NO843171 L NO 843171L NO 843171 A NO843171 A NO 843171A NO 843171 A NO843171 A NO 843171A NO 843171 L NO843171 L NO 843171L
- Authority
- NO
- Norway
- Prior art keywords
- formula
- lower alkyl
- compound
- acid
- group
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 43
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical class NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 title description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 156
- 150000003839 salts Chemical class 0.000 claims abstract description 58
- 125000002252 acyl group Chemical group 0.000 claims abstract description 30
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 claims abstract description 5
- 150000002429 hydrazines Chemical class 0.000 claims abstract description 5
- 230000008569 process Effects 0.000 claims abstract description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 191
- 239000000203 mixture Substances 0.000 claims description 44
- 229910052739 hydrogen Inorganic materials 0.000 claims description 34
- 239000001257 hydrogen Substances 0.000 claims description 34
- 125000001424 substituent group Chemical group 0.000 claims description 29
- 125000006239 protecting group Chemical group 0.000 claims description 26
- 125000004432 carbon atom Chemical group C* 0.000 claims description 21
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 17
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 17
- 125000002950 monocyclic group Chemical group 0.000 claims description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 16
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 15
- 125000000524 functional group Chemical group 0.000 claims description 12
- 230000003287 optical effect Effects 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 9
- 125000002619 bicyclic group Chemical group 0.000 claims description 9
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 8
- 125000003277 amino group Chemical group 0.000 claims description 7
- 125000001072 heteroaryl group Chemical group 0.000 claims description 5
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 2
- 125000002029 aromatic hydrocarbon group Chemical class 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 8
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 8
- 150000004945 aromatic hydrocarbons Chemical class 0.000 abstract description 5
- 239000008194 pharmaceutical composition Substances 0.000 abstract 1
- -1 1,2,3,4-tetrahydro-5-naphthyl Chemical group 0.000 description 214
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 168
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 81
- 238000006243 chemical reaction Methods 0.000 description 74
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 65
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 50
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 48
- 239000002253 acid Substances 0.000 description 47
- 239000000243 solution Substances 0.000 description 44
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 43
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 40
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 39
- 229910052736 halogen Inorganic materials 0.000 description 37
- 239000002904 solvent Substances 0.000 description 37
- 125000003545 alkoxy group Chemical group 0.000 description 36
- 150000002367 halogens Chemical class 0.000 description 34
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 34
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 33
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 33
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 30
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 30
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 30
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 29
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 29
- 239000000741 silica gel Substances 0.000 description 29
- 229910002027 silica gel Inorganic materials 0.000 description 29
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
- 125000003282 alkyl amino group Chemical group 0.000 description 26
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- 229910052757 nitrogen Inorganic materials 0.000 description 24
- 239000002585 base Substances 0.000 description 22
- 239000003054 catalyst Substances 0.000 description 22
- 238000001704 evaporation Methods 0.000 description 22
- 239000003795 chemical substances by application Substances 0.000 description 21
- 239000000126 substance Substances 0.000 description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 19
- 150000002148 esters Chemical class 0.000 description 19
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 18
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 18
- 235000011114 ammonium hydroxide Nutrition 0.000 description 18
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 17
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 17
- 125000005115 alkyl carbamoyl group Chemical group 0.000 description 17
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 17
- 239000007858 starting material Substances 0.000 description 17
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- 125000005236 alkanoylamino group Chemical group 0.000 description 16
- 229910021529 ammonia Inorganic materials 0.000 description 16
- 125000003118 aryl group Chemical group 0.000 description 16
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 16
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 16
- 239000013543 active substance Substances 0.000 description 15
- 239000000908 ammonium hydroxide Substances 0.000 description 15
- 238000004587 chromatography analysis Methods 0.000 description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 15
- 238000010626 work up procedure Methods 0.000 description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 14
- 230000008020 evaporation Effects 0.000 description 14
- 230000009467 reduction Effects 0.000 description 14
- 150000007513 acids Chemical class 0.000 description 13
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 13
- 230000002378 acidificating effect Effects 0.000 description 12
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 12
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 12
- 125000004076 pyridyl group Chemical group 0.000 description 12
- 230000036772 blood pressure Effects 0.000 description 11
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 11
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 11
- 125000004414 alkyl thio group Chemical group 0.000 description 10
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 description 10
- 235000011121 sodium hydroxide Nutrition 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- 125000003396 thiol group Chemical class [H]S* 0.000 description 10
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 9
- 229920002472 Starch Polymers 0.000 description 9
- 239000011230 binding agent Substances 0.000 description 9
- 239000000460 chlorine Substances 0.000 description 9
- 229910052801 chlorine Inorganic materials 0.000 description 9
- 238000001816 cooling Methods 0.000 description 9
- 229910052500 inorganic mineral Inorganic materials 0.000 description 9
- 235000010755 mineral Nutrition 0.000 description 9
- 239000011707 mineral Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 8
- 241000700159 Rattus Species 0.000 description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 8
- 238000006640 acetylation reaction Methods 0.000 description 8
- 125000003342 alkenyl group Chemical group 0.000 description 8
- 239000012298 atmosphere Substances 0.000 description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 8
- 229910052794 bromium Inorganic materials 0.000 description 8
- 150000001735 carboxylic acids Chemical class 0.000 description 8
- 239000013078 crystal Substances 0.000 description 8
- 230000007062 hydrolysis Effects 0.000 description 8
- 238000006460 hydrolysis reaction Methods 0.000 description 8
- GSYSFVSGPABNNL-UHFFFAOYSA-N methyl 2-dimethoxyphosphoryl-2-(phenylmethoxycarbonylamino)acetate Chemical group COC(=O)C(P(=O)(OC)OC)NC(=O)OCC1=CC=CC=C1 GSYSFVSGPABNNL-UHFFFAOYSA-N 0.000 description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 8
- 229910052760 oxygen Inorganic materials 0.000 description 8
- 239000001301 oxygen Substances 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 229910052717 sulfur Inorganic materials 0.000 description 8
- 239000011593 sulfur Substances 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- FZCBSLLNILCXEW-UHFFFAOYSA-N (5-butylpyridin-2-yl)hydrazine Chemical compound CCCCC1=CC=C(NN)N=C1 FZCBSLLNILCXEW-UHFFFAOYSA-N 0.000 description 7
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 7
- 150000001340 alkali metals Chemical class 0.000 description 7
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 description 7
- 238000006264 debenzylation reaction Methods 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 239000012458 free base Substances 0.000 description 7
- 150000004820 halides Chemical class 0.000 description 7
- 150000002431 hydrogen Chemical group 0.000 description 7
- 150000007529 inorganic bases Chemical class 0.000 description 7
- 231100000252 nontoxic Toxicity 0.000 description 7
- 230000003000 nontoxic effect Effects 0.000 description 7
- 238000001953 recrystallisation Methods 0.000 description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 7
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-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
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 125000001931 aliphatic group Chemical group 0.000 description 6
- 229910052783 alkali metal Inorganic materials 0.000 description 6
- 125000000304 alkynyl group Chemical group 0.000 description 6
- 150000003863 ammonium salts Chemical class 0.000 description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 6
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 6
- 125000004093 cyano group Chemical group *C#N 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 125000002883 imidazolyl group Chemical group 0.000 description 6
- 238000007912 intraperitoneal administration Methods 0.000 description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 description 6
- 238000012545 processing Methods 0.000 description 6
- 229940100445 wheat starch Drugs 0.000 description 6
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 5
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 5
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 5
- 229960000583 acetic acid Drugs 0.000 description 5
- 125000003302 alkenyloxy group Chemical group 0.000 description 5
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 description 5
- 125000005237 alkyleneamino group Chemical group 0.000 description 5
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 5
- 125000002837 carbocyclic group Chemical group 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000011261 inert gas Substances 0.000 description 5
- 239000012442 inert solvent Substances 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 229910052751 metal Inorganic materials 0.000 description 5
- 239000002184 metal Substances 0.000 description 5
- 150000007530 organic bases Chemical class 0.000 description 5
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Inorganic materials [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- 239000011877 solvent mixture Substances 0.000 description 5
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 4
- FPZWZCWUIYYYBU-UHFFFAOYSA-N 2-(2-ethoxyethoxy)ethyl acetate Chemical group CCOCCOCCOC(C)=O FPZWZCWUIYYYBU-UHFFFAOYSA-N 0.000 description 4
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- RFMMMVDNIPUKGG-YFKPBYRVSA-N N-acetyl-L-glutamic acid Chemical compound CC(=O)N[C@H](C(O)=O)CCC(O)=O RFMMMVDNIPUKGG-YFKPBYRVSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 150000008065 acid anhydrides Chemical class 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 4
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 4
- 125000001118 alkylidene group Chemical group 0.000 description 4
- 125000005133 alkynyloxy group Chemical group 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 description 4
- 150000001718 carbodiimides Chemical class 0.000 description 4
- 150000001721 carbon Chemical group 0.000 description 4
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 4
- 125000002843 carboxylic acid group Chemical group 0.000 description 4
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 229940093915 gynecological organic acid Drugs 0.000 description 4
- 238000007327 hydrogenolysis reaction Methods 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 229910052740 iodine Inorganic materials 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 4
- 125000001624 naphthyl group Chemical group 0.000 description 4
- 150000002829 nitrogen Chemical class 0.000 description 4
- 150000007524 organic acids Chemical class 0.000 description 4
- 235000005985 organic acids Nutrition 0.000 description 4
- 125000004043 oxo group Chemical group O=* 0.000 description 4
- 239000004033 plastic Substances 0.000 description 4
- 229920003023 plastic Polymers 0.000 description 4
- 230000001681 protective effect Effects 0.000 description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 238000003797 solvolysis reaction Methods 0.000 description 4
- 239000000454 talc Substances 0.000 description 4
- 229910052623 talc Inorganic materials 0.000 description 4
- 235000012222 talc Nutrition 0.000 description 4
- 238000005809 transesterification reaction Methods 0.000 description 4
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 4
- 230000024883 vasodilation Effects 0.000 description 4
- NOGFHTGYPKWWRX-UHFFFAOYSA-N 2,2,6,6-tetramethyloxan-4-one Chemical compound CC1(C)CC(=O)CC(C)(C)O1 NOGFHTGYPKWWRX-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 206010047141 Vasodilatation Diseases 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 230000021736 acetylation Effects 0.000 description 3
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 3
- 125000002947 alkylene group Chemical group 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 150000008064 anhydrides Chemical class 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 125000004104 aryloxy group Chemical group 0.000 description 3
- 125000005605 benzo group Chemical group 0.000 description 3
- 150000001649 bromium compounds Chemical class 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 150000001805 chlorine compounds Chemical class 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 150000002463 imidates Chemical class 0.000 description 3
- 238000011065 in-situ storage Methods 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- DWKPPFQULDPWHX-VKHMYHEASA-N l-alanyl ester Chemical compound COC(=O)[C@H](C)N DWKPPFQULDPWHX-VKHMYHEASA-N 0.000 description 3
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 3
- 239000001095 magnesium carbonate Substances 0.000 description 3
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 3
- 150000002825 nitriles Chemical class 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 150000003335 secondary amines Chemical class 0.000 description 3
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- 238000006386 neutralization reaction Methods 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 125000001477 organic nitrogen group Chemical group 0.000 description 1
- 150000003901 oxalic acid esters Chemical class 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical class OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- 230000036513 peripheral conductance Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 150000003012 phosphoric acid amides Chemical class 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229940114930 potassium stearate Drugs 0.000 description 1
- ANBFRLKBEIFNQU-UHFFFAOYSA-M potassium;octadecanoate Chemical compound [K+].CCCCCCCCCCCCCCCCCC([O-])=O ANBFRLKBEIFNQU-UHFFFAOYSA-M 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 229910052952 pyrrhotite Inorganic materials 0.000 description 1
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000008327 renal blood flow Effects 0.000 description 1
- 230000015330 renal sodium excretion Effects 0.000 description 1
- 229940124550 renal vasodilator Drugs 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 239000011833 salt mixture Substances 0.000 description 1
- 238000009738 saturating Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- UQDJGEHQDNVPGU-UHFFFAOYSA-N serine phosphoethanolamine Chemical compound [NH3+]CCOP([O-])(=O)OCC([NH3+])C([O-])=O UQDJGEHQDNVPGU-UHFFFAOYSA-N 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000004289 sodium hydrogen sulphite Substances 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000011699 spontaneously hypertensive rat Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000004299 tetrazol-5-yl group Chemical group [H]N1N=NC(*)=N1 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000005505 thiomorpholino group Chemical group 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- NLVXSWCKKBEXTG-UHFFFAOYSA-N vinylsulfonic acid Chemical compound OS(=O)(=O)C=C NLVXSWCKKBEXTG-UHFFFAOYSA-N 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 150000003953 γ-lactams Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/72—Nitrogen atoms
- C07D213/76—Nitrogen atoms to which a second hetero atom is attached
- C07D213/77—Hydrazine radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/86—Hydrazides; Thio or imino analogues thereof
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
ppfinnelsen gjelder farmasøytiske preparater som inneholder acylerte hydrazinforbindelser med formelen. hvor R betyr en eventuelt substituert alifatisk eller aromatisk hydrokarbonrest og Ac en acylrest og n er et helt tall fra 1-4, eller deres salter, så vel som nye forbindelser av dette slag, eller deres salter, fremgangsmåte for fremstilling av slike forbindelser, farmasøytiske preparater som inneholder slike nye forbindelser og deres anvendelse for fremstilling av farmasøytiske preparater.Så vel de farmasøytiske preparatene som også de nye forbindelsene bevirker en selektiv renal vasodilatasjon og er overensstemmende med det egnet for anvendelse som renale vasodilatorer og antihypertensiva.The invention relates to pharmaceutical compositions containing acylated hydrazine compounds of the formula. wherein R represents an optionally substituted aliphatic or aromatic hydrocarbon residue and Ac an acyl residue and n is an integer from 1-4, or their salts, as well as novel compounds of this kind, or their salts, process for the preparation of such compounds, pharmaceutical preparations containing such novel compounds and their use in the manufacture of pharmaceutical preparations.
Description
Gjenstand for oppfinnelsen er en fremgangsmåte for fremstilling av nye acylerte hydrazinforbindelser med formelen: The object of the invention is a method for the production of new acylated hydrazine compounds with the formula:
hvor R betyr en eventuelt substituert alifatisk eller aromatisk hydrokarbonrest og Ac en acylrest, og n er et helt tall fra 1-4, hvorved, dersom n betyr en verdi fra 2-4, kan restene R være like eller forskjellige og bundet i hver av de mulige stillingene i pyridinringen, under den forutsetning, at R som laverealkyl som er bundet i 3-stilling har 2-7 karbonatomer, og n har verdien 1, når Ac betyr en acyl-gruppe, og med den ytterligere forutsetning at R som laverealkyl som er bundet i 3-, 4-, 5- eller 6-stilling har 2-7 karbonatomer, når Ac betyr benzoylgruppen, som racematblandinger, racemater, optiske antipoder eller deres salter. where R means an optionally substituted aliphatic or aromatic hydrocarbon residue and Ac an acyl residue, and n is an integer from 1-4, whereby, if n means a value from 2-4, the residues R can be the same or different and bound in each of the possible positions in the pyridine ring, under the condition that R as lower alkyl which is bound in the 3-position has 2-7 carbon atoms, and n has the value 1, when Ac means an acyl group, and with the further condition that R as lower alkyl which are bonded in the 3-, 4-, 5- or 6-position have 2-7 carbon atoms, when Ac means the benzoyl group, such as racemate mixtures, racemates, optical antipodes or their salts.
En eventuelt substituert alifatisk hydrokarbonrest R erAn optionally substituted aliphatic hydrocarbon residue R is
f.eks. eventuelt substituert laverealkyl, f.eks. laverealkyl, eventuelt foretret eller forestret hydroksylaverealkyl, e.g. optionally substituted lower alkyl, e.g. lower alkyl, optionally etherified or esterified hydroxyl lower alkyl,
som hydroksylaverealkyl, laverealkoksylaverealkyl eller halogenlaverealkyl, eller eventuelt substituert, som laverealkylert eller acylert aminolaverealkyl, som aminolaverealkyl, N-laverealkylaminolaverealkyl eller N,N-dilaverealkylamino-laverealkyl , laverealkanoylaminolaverealkyl eller laverealkoksykarbonylaminolaverealkyl, laverealkyl som eventuelt er substituert med forestret eller amidert karboksy, som karboksy, laverealkoksykarbonyl eller eventuelt substituert karbamoyl, som karbamoyl, N-laverealkylkarbamoyl ellerN,N-dilaverealkylkarbamoyl eller også laverealkyl som er substituert med en oksogruppe, som karboksylaverealkyl, laverealkoksykarbonyllaverealkyl, karbamoyllaverealkyl, N-laverealkylkarbamoyllaverealkyl ellerN,N-dilaverealkyl-karbamoyl laverealkyl eller også okso-laverealkyl, videre as hydroxyl lower alkyl, lower hydroxy lower alkyl or halogen lower alkyl, or optionally substituted, as lower alkylated or acylated amino lower alkyl, as amino lower alkyl, N-lower alkyl amino lower alkyl or N,N-di lower alkyl amino lower alkyl, lower alkanoylamino lower alkyl or lower alkoxycarbonyl amino lower alkyl, lower alkyl which is optionally substituted with esterified or amidated carboxy, as carboxy, lower alkoxycarbonyl or optionally substituted carbamoyl, such as carbamoyl, N-lower alkylcarbamoyl or N,N-dilower alkylcarbamoyl or also lower alkyl which is substituted with an oxo group, such as carboxy lower alkyl, lower alkoxycarbonyl lower alkyl, carbamoyl lower alkyl, N-lower alkyl carbamoyl lower alkyl or N,N-di lower alkyl-carbamoyl lower alkyl or also oxo lower alkyl , further
cyanlaverealkyl, eventuelt substituert aryllaverealkyl,Cyan lower alkyl, optionally substituted aryl lower alkyl,
hvor aryl er en monocyklisk, aromatisk hydrokarbonrest,where aryl is a monocyclic aromatic hydrocarbon residue,
f.eks. fenyl, eller en bicyklisk aromatisk hydrokarbonrest, som 1- eller 2-naftyl eller delvis mettet naftyl, som 1,2,3,4-tetrahydro-5-naftyl, hvori substituentene kan være laverealkyl, hydroksy og/eller halogen, eventuelt foretret eller forestret hydroksylaverealkyl, f.eks. som angitt, muligens laverealkoksylaverealkyl eller halogenlaverealkyl, laverealkoksy eventuelt foretret eller forestret hydroksylaverealkoksy, som laverealkoksylaverealkoksy eller halogenlaverealkoksy, laverealkenyloksy, laverealkinyloksy, eller eventuelt substituert, som laverealkylert eller acylert aminolaverealkyl, f.eks. som ovenfor angitt, f.eks. mono- eller dilavere-alkylaminoalkyl eller laverealkanoylaminolaverealkyl, eventuelt forestret karboksy, som karboksy eller laverealkoksykarbonyl, amidert karboksy, f.eks. eventuelt substituert karbamoyl, som karbamoyl, N-laverealkylkarbamoyl eller N,N-dilaverealkylkarbamoyl, cyan, nitro eller eventuelt substituert, som acylert amino, f.eks. amino, laverealkanoyl-'amino, laverealkoksykarbonylamino, videre laverealkylamino eller dilaverealkylamino, hvorved slike substituenter er like eller forskjellige og enkle eller mangfoldige, spesielt 1- 3 ganger. e.g. phenyl, or a bicyclic aromatic hydrocarbon residue, such as 1- or 2-naphthyl or partially saturated naphthyl, such as 1,2,3,4-tetrahydro-5-naphthyl, in which the substituents may be lower alkyl, hydroxy and/or halogen, optionally etherified or esterified hydroxy lower alkyl, e.g. as indicated, possibly lower alkyl lower alkyl or halogen lower alkyl, lower alkoxy optionally etherified or esterified hydroxyl lower alkyl, such as lower alkoxy lower alkyl or halogen lower alkyl, lower alkenyloxy, lower alkynyloxy, or optionally substituted, such as lower alkylated or acylated amino lower alkyl, e.g. as stated above, e.g. mono- or dilower alkylaminoalkyl or lower alkanoylaminolower alkyl, optionally esterified carboxy, such as carboxy or lower alkoxycarbonyl, amidated carboxy, e.g. optionally substituted carbamoyl, such as carbamoyl, N-lower alkylcarbamoyl or N,N-dilower alkylcarbamoyl, cyan, nitro or optionally substituted, such as acylated amino, e.g. amino, lower alkanoyl-amino, lower alkoxycarbonylamino, further lower alkylamino or dilower alkylamino, whereby such substituents are the same or different and single or multiple, especially 1-3 times.
En eventuelt substituert aromatisk hydrokarbonrest R erAn optionally substituted aromatic hydrocarbon residue R is
en mono- eller bicyklisk, karbocyklisk eller heterocyklisk aromatisk hydrokarbonrest, f.eks. fenyl, 1- eller 2-naftyl eller delvis mettet naftyl, som 1,2,3,4-tetrahydro-5-naftyl. Som mono- eller bicyklisk heteroaryl er R en rest, fortrinnsvis med 5 eller 6 ringledd som inneholder et oksygen-, svovel- eller nitrogenatom og eventuelt 1-3 ytterligere nitrogenatomer som ringledd som er forbundet med pyridinresten over et ringkarbonatom, som minst delvis kan være hydrert og i dette tilfellet substituert med okso, hvorved den andre ringen i en bicyklisk heterocyklisk rest kan være en ankondensert benzoring, og betyr spesielt pyridyl, f.eks. 2- , 3- eller 4-pyridyl, eller dihydro-okso-pyridinyl, f.eks. a mono- or bicyclic, carbocyclic or heterocyclic aromatic hydrocarbon residue, e.g. phenyl, 1- or 2-naphthyl or partially saturated naphthyl, such as 1,2,3,4-tetrahydro-5-naphthyl. As mono- or bicyclic heteroaryl, R is a residue, preferably with 5 or 6 ring members containing an oxygen, sulfur or nitrogen atom and optionally 1-3 further nitrogen atoms as ring members which are connected to the pyridine residue via a ring carbon atom, which can at least partially be hydrogenated and in this case substituted with oxo, whereby the second ring in a bicyclic heterocyclic residue may be an unfused benzo ring, and means especially pyridyl, e.g. 2-, 3- or 4-pyridyl, or dihydro-oxo-pyridinyl, e.g.
1,6-dihydro-6-okso-2-pyridinyl, pyridazinyl, f.eks. 3-pyridazinyl, pyrazinyl, f.eks. 2-pyrazinyl, pyrimidinyl, f.eks. 2-, 4- eller 5- pyrimidinyl, eller dihydro-okso-pyrimidinyl, f.eks. 3,4-dihydro-4-okso-2-pyrimidinyl, furyl f.eks. 2-eller 3-furyl, pyrryl, f.eks. 2- eller 3-pyrryl, tienyl f.eks. 2- eller 3-tienyl, oksazolyl f.eks. 2- eller 4-oksazolyl, tiazolyl f.eks. 2-, 4- eller 5-tiazolyl, tiadiazolyl f.eks. 1,2,4-triadiazol-3- eller -5-yl eller 1,2,5-tiadiazol-3- yl, imidazolyl, f.eks. imidazol-2- eller -4-yl, pyrazolyl, f.eks. 3- eller 4-pyrazolyl, triazolyl, f.eks. 1,2,3-triazol-4- yl eller 1,2,4-triazol-3-yl, tetrazolyl samt tetrazol-5-yl, videre indolyl, f.eks. indol-4-yl, kinolinyl, f.eks. 2-kinolinyl, isokinolinyl, f.eks. 1-isokinolinyl, benzimidazolyl, f.eks. 2-benzimidazolyl, benzofuranyl, f.eks. 4- eller 5-benzofuranyl, benzotienyl, f.eks. 4- eller 5-benzotienyl eller naftyridinyl, f.eks. 1,8-naftyridin-2-yl. 1,6-dihydro-6-oxo-2-pyridinyl, pyridazinyl, e.g. 3-pyridazinyl, pyrazinyl, e.g. 2-pyrazinyl, pyrimidinyl, e.g. 2-, 4- or 5-pyrimidinyl, or dihydro-oxo-pyrimidinyl, e.g. 3,4-dihydro-4-oxo-2-pyrimidinyl, furyl e.g. 2-or 3-furyl, pyrryl, e.g. 2- or 3-pyrryl, thienyl e.g. 2- or 3-thienyl, oxazolyl e.g. 2- or 4-oxazolyl, thiazolyl e.g. 2-, 4- or 5-thiazolyl, thiadiazolyl e.g. 1,2,4-triadiazol-3- or -5-yl or 1,2,5-thiadiazol-3-yl, imidazolyl, e.g. imidazol-2- or -4-yl, pyrazolyl, e.g. 3- or 4-pyrazolyl, triazolyl, e.g. 1,2,3-triazol-4-yl or 1,2,4-triazol-3-yl, tetrazolyl and tetrazolyl-5-yl, further indolyl, e.g. indol-4-yl, quinolinyl, e.g. 2-quinolinyl, isoquinolinyl, e.g. 1-isoquinolinyl, benzimidazolyl, e.g. 2-benzimidazolyl, benzofuranyl, e.g. 4- or 5-benzofuranyl, benzothienyl, e.g. 4- or 5-benzothienyl or naphthyridinyl, e.g. 1,8-naphthyridin-2-yl.
Substituenter i en mono- eller bicyklisk, karbocyklisk eller heterocyklisk arylrest R, hvorved i sistnevnte tilfelle i første rekke et ringkarbonatom, men også et sekundært ringnitrogenatom kan være substituert, og slike substituenter kan være tilstede en- eller flere ganger, fortrinnsvis høyst fire ganger, er f.eks. eventuelt substituert laverealkyl, f.eks. laverealkyl, eventuelt foretret eller forestret hydroksy-laverealkyl, som hydroksylaverealkyl, laverealkoksylaverealkyl eller halogenlaverealkyl, eller eventuelt substituert, som acylert aminolaverealkyl, som laverealkanoylaminolaverealkyl eller laverealkoksykarbonylaminolaverealkyl, eller laverealkenyl eller laverealkinyl, eventuelt foretret eller forestret hydroksy eller merkapto, som hydroksy, laverealkoksy, fenyllaverealkoksy, halogen, merkapto, laverealkyltio, laverealkoksy som eventuelt er substituert med foretret eller forestret hydroksy eller merkapto eller med acyl, f.eks. laverealkoksy, fenyllaverealkoksy, hydroksylaverealkoksy, laverealkoksylaverealkoksy, laverealkyltiolaverealkoksy, halogenlaverealkoksy eller laverealkanoyllaverealkoksy eller laverealkenyloksy, laverealkinyloksy, acyl, f.eks. laverealkanoyl, eventuelt forestret karboksy, som karboksy eller laverealkoksykarbonyl, amidert karboksy, f.eks. eventuelt substituert karbamoyl, som karbamoyl, N-laverealkylkarbamoyl eller N,N-dilaverealkylkarbamoyl, cyan, nitro eller eventuelt substituert, som acylert amino, f.eks. laverealkanoylamino, laverealkoksykarbonylamino, laverealkylsulfonyl, sulfamoyl, eventuelt substituert ureido, videre amino, N-laverealkylamino eller N,N-dilaverealkylamino. Substituents in a mono- or bicyclic, carbocyclic or heterocyclic aryl residue R, whereby in the latter case primarily a ring carbon atom, but also a secondary ring nitrogen atom may be substituted, and such substituents may be present one or more times, preferably at most four times, is e.g. optionally substituted lower alkyl, e.g. lower alkyl, optionally etherified or esterified hydroxy-lower alkyl, such as hydroxy lower alkyl, lower alkoxy lower alkyl or halogen lower alkyl, or optionally substituted, such as acylated amino lower alkyl, such as lower alkanoylamino lower alkyl or lower alkoxycarbonylamino lower alkyl, or lower alkenyl or lower alkynyl, optionally etherified or esterified hydroxy or mercapto, such as hydroxy, lower alkoxy, phenyl lower alkyl, halogen, mercapto, lower alkylthio, lower alkoxy which is optionally substituted with etherified or esterified hydroxy or mercapto or with acyl, e.g. lower alkoxy, phenyl lower aryl oxy, hydroxy lower rel oxy, lower alkoxy lower rel oxy, lower alkylthio lower rel oxy, halogen lower rel oxy or lower alkanoyl lower rel oxy or lower alkenyloxy, lower alkynyloxy, acyl, e.g. lower alkanoyl, optionally esterified carboxy, such as carboxy or lower alkoxycarbonyl, amidated carboxy, e.g. optionally substituted carbamoyl, such as carbamoyl, N-lower alkylcarbamoyl or N,N-dilower alkylcarbamoyl, cyan, nitro or optionally substituted, such as acylated amino, e.g. lower alkanoylamino, lower alkoxycarbonylamino, lower alkylsulfonyl, sulfamoyl, optionally substituted ureido, further amino, N-lower alkylamino or N,N-dilower alkylamino.
En acyl Ac tilsvarer f.eks. formelen -C(=0)-R^, hvor R.^An acyl Ac corresponds to e.g. the formula -C(=0)-R^, where R.^
betyr en eventuelt substituert alifatisk, cykloalifatisk, aromatisk eller aralifatisk hydrokarbonrest, som eventuelt substituert laverealkyl, laverealkenyl eller laverealkinyl, eventuelt substituert fenyllaverealkyl, fenyllaverealkenyl eller fenyllaverealkinyl, eventuelt substituert mono- eller polycyklisk cykloalkyl, eller som aromatisk rest står for en eventuelt substituert mono- eller bicyklisk, karbocyklisk eller heterocyklisk arylrest, f.eks. som definert ovenfor means an optionally substituted aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon residue, as optionally substituted lower alkyl, lower alkenyl or lower alkynyl, optionally substituted phenyl lower alkyl, phenyl lower alkyl or phenyl lower alkyl, optionally substituted mono- or polycyclic cycloalkyl, or as an aromatic residue stands for an optionally substituted mono- or bicyclic, carbocyclic or heterocyclic aryl radical, e.g. as defined above
for gruppen R, og tilsvarende dette eksempelvis står for fenyl eller pyridyl. for the group R, and corresponding to this, for example, stands for phenyl or pyridyl.
Substituenter av laverealkyl, laverealkenyl eller laverealkinyl så vel som fenyllaverealkyl, fenyllaverealkenyl eller fenyllaverealkinyl så vel som mono- eller polycyklisk cykloalkyl, f.eks. cykloalkyl, er f.eks. eventuelt foretret eller forestret hydroksy, som hydroksy, laverealkoksy og/eller halogen, eventuelt substituert som laverealkylert eller acylert amino, som amino, N-laverealkylamino ellerN,N-dilaverealkylamino, laverealkanoylamino og/eller eventuelt funksjonelt omdannet karboksy, som karboksy, forestret karboksy, f.eks. laverealkoksykarbonyl, eventuelt substituert karbamoyl, cyan eller nitro, hvorved substituerte rester kan oppvise en eller flere, spesielt opptil tre substituenter, som kan være like eller forskjellige i hvilke som helst stillinger som er egnet for substitusjon. Substituents of lower alkyl, lower alkenyl or lower alkynyl as well as phenyl lower alkyl, phenyl lower alkenyl or phenyl lower alkynyl as well as mono- or polycyclic cycloalkyl, e.g. cycloalkyl, is e.g. optionally etherified or esterified hydroxy, such as hydroxy, lower alkoxy and/or halogen, optionally substituted as lower alkylated or acylated amino, such as amino, N-lower alkylamino or N,N-dilower alkylamino, lower alkanoylamino and/or optionally functionally converted carboxy, such as carboxy, esterified carboxy, e.g. lower alkoxycarbonyl, optionally substituted carbamoyl, cyan or nitro, whereby substituted residues may have one or more, especially up to three substituents, which may be the same or different in any positions suitable for substitution.
Substituenter i en mono- eller bicyklisk, karbocyklisk eller heterocyklisk arylrest tilsvarer de substituenter som er angitt for gruppen R, eksempelvis eventuelt substituerte alifatiske hydrokarbonrester, som eventuelt substituert laverealkyl. Substituents in a mono- or bicyclic, carbocyclic or heterocyclic aryl residue correspond to the substituents indicated for the group R, for example optionally substituted aliphatic hydrocarbon residues, such as optionally substituted lower alkyl.
En acylrest Ac er videre resten fra en monoester ellerAn acyl residue Ac is further the residue from a monoester or
et monoamid av karbonsyre, som usubstituert eller substituert, f.eks. fri eller foretret hydroksy, som laverealkoksy, a monoamide of carboxylic acid, as unsubstituted or substituted, e.g. free or etherified hydroxy, such as lower alkoxy,
eller usubstituert eller substituert amino, som amino, laverealkylamino, og i første rekke disubstituert amino, or unsubstituted or substituted amino, such as amino, lower alkylamino, and primarily disubstituted amino,
som dilaverealkylamino, N-laverealkyl-N-fenyllaverealkyl-amino eller laverealkylenamino som eventuelt er avbrutt av oksygen, svovel eller usubstituert eller, f.eks. med laverealkyl, substituert nitrogen eller laverealkoksykarbonyl som inneholder usubstituert eller, f.eks. med laverealkyl, laverealkoksy og/eller halogen substituert fenyl, videre N-usubstituert eller N-mono- eller N,N-disubstituert karbamoyl, som N-laverealkylkarbamoyl,N,N-dilaverealkylkarbamoyl, eller N,N-laverealkylen-karbamoyl som eventuelt er avbrutt i laverealkylendelen med oksygen, svovel eller usubstituert eller, f.eks. med laverealkyl, substituert nitrogen. such as diloweralkylamino, N-loweralkyl-N-phenylloweralkylamino or loweralkyleneamino optionally interrupted by oxygen, sulfur or unsubstituted or, e.g. with lower alkyl, substituted nitrogen or lower alkoxycarbonyl containing unsubstituted or, e.g. with lower alkyl, lower alkoxy and/or halogen substituted phenyl, further N-unsubstituted or N-mono- or N,N-disubstituted carbamoyl, such as N-lower alkylcarbamoyl, N,N-dilower alkylcarbamoyl, or N,N-lower alkylene-carbamoyl which is optionally interrupted in the lower alkylene moiety by oxygen, sulfur or unsubstituted or, e.g. with lower alkyl substituted nitrogen.
De rester og forbindelser som i foreliggende beskrivelseThe residues and compounds as in the present description
er betegnet med "lavere", inneholder fortrinnsvis opptil 7 og i første rekke opptil 4 karbonatomer. is denoted by "lower", preferably contains up to 7 and primarily up to 4 carbon atoms.
Laverealkyl er f.eks. metyl, etyl, n-propyl, isopropyl, n-butyl, isobutyl eller tert-butyl. Tilsvarende dette er laverealkyl med 2-7 karbonatomer f.eks. etyl, n-propyl eller n-butyl. Substituert laverealkyl er spesielt tilsvarende metyl eller 1- eller 2-etyl. Lower alkyl is e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. Corresponding to this is lower alkyl with 2-7 carbon atoms, e.g. ethyl, n-propyl or n-butyl. Substituted lower alkyl is particularly equivalent to methyl or 1- or 2-ethyl.
Laverealkenyl er f.eks. vinyl, allyl, 2- eller 3-metallyl eller 3,3-dimetylallyl. Lower range alkenyl is e.g. vinyl, allyl, 2- or 3-methallyl or 3,3-dimethylallyl.
Laverealkinyl er spesielt propargyl.Low real akinyl is especially propargyl.
Laverealkoksy er f.eks. metoksy, etoksy, n-propyloksy, isopropyloksy, n-butyloksy eller isobutyloksy, mens fenyllaverealkoksy f.eks. er benzyloksy eller 1- eller 2-fenyl-etoksy, laverealkenyloksy f.eks. er allyloksy, 2- eller 3-metallyloksy eller 3,3-dimetylallyloksy og laverealkinyloksy spesielt er propargyloksy. Low-area coke is e.g. methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy or isobutyloxy, while phenyl lower alkyloxy e.g. is benzyloxy or 1- or 2-phenylethoxy, lower alkenyloxy e.g. is allyloxy, 2- or 3-methylallyloxy or 3,3-dimethylallyloxy and lower alkynyloxy in particular is propargyloxy.
Laverealkyltio er f.eks. metyltio, etyltio, n-propyltioLower alkylthio is e.g. methylthio, ethylthio, n-propylthio
eller isopropyltio.or isopropylthio.
Laverealkylsulfonyl er f.eks. metylsulfonyl eller etylsulfonyl. Lower alkyl sulfonyl is e.g. methylsulfonyl or ethylsulfonyl.
Halogen er fortrinnsvis halogen med atomnummer opptil 35,Halogen is preferably halogen with atomic number up to 35,
dvs. fluor, klor eller brom.i.e. fluorine, chlorine or bromine.
Laverealkanoyl er f.eks. acetyl, propionyl eller butyryl. Lowerealkanoyl is e.g. acetyl, propionyl or butyryl.
Eventuelt substituert laverealkoksykarbonyl er f.eks. laverealkoksykarbonyl som eventuelt er substituert med acyl som er bundet over et oksygenatom, f.eks. laverealkanoyl som acetyl eller pivaloyl, laverealkoksykarbonyl, som metoksy-eller etoksykarbonyl eller aroyl som benzen, og er f.eks. metoksykarbonyl, etoksykarbonyl, 1- eller 2-(acetyloksy)-etoksykarbonyl, pivaloyloksymetoksykarbonyl, 1- eller 2-(metoksykarbonyloksy)-etoksykarbonyl eller 1- eller 2-(benzoyl-oksy)-etoksykarbonyl. Optionally substituted lower alkoxycarbonyl is e.g. lower alkoxycarbonyl which is optionally substituted with acyl which is bonded over an oxygen atom, e.g. lower alkanoyl such as acetyl or pivaloyl, lower alkoxycarbonyl such as methoxy or ethoxycarbonyl or aroyl such as benzene, and are e.g. methoxycarbonyl, ethoxycarbonyl, 1- or 2-(acetyloxy)-ethoxycarbonyl, pivaloyloxymethoxycarbonyl, 1- or 2-(methoxycarbonyloxy)-ethoxycarbonyl or 1- or 2-(benzoyloxy)-ethoxycarbonyl.
Eventuelt substituert karbamoyl er f.eks. karbamoyl, eller N-laverealkyl- ellerN,N-dilaverealkylkarbamoyl som N-metyl-karbamoyl, N,N-dimetylkarbamoyl, N-etylkarbamoyl eller N,N-dietylkarbamoyl. Optionally substituted carbamoyl is e.g. carbamoyl, or N-lower alkyl or N,N-dilower alkylcarbamoyl such as N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-ethylcarbamoyl or N,N-diethylcarbamoyl.
Aminolaverealkyl er f.eks. aminometyl eller 2-aminoetyl. Amino lower alkyl is e.g. aminomethyl or 2-aminoethyl.
Oksy-laverealkyl er f.eks. 2-okso-n-butyl.Oxy-lower alkyl is e.g. 2-oxo-n-butyl.
Laverealkanoylamino er f.eks. acetylamino eller propionylamino. Lower alkanoylamino is e.g. acetylamino or propionylamino.
Laverealkoksykarbonylamino er f.eks. metoksykarbonylamino eller etoksykarbonylamino. Lower oxycarbonylamino is e.g. methoxycarbonylamino or ethoxycarbonylamino.
Eventuelt substituert ureido er f.eks. ureido eller 3-laverealkyl- eller 3-cykloalkyl-ureido, hvori cykloalkyl f.eks. inneholder 5-7 ringledd, f.eks. 3-metylureido, 3-etylureido eller 3-cykloheksylureido. Optionally substituted ureido is e.g. ureido or 3-lower alkyl- or 3-cycloalkyl-ureido, in which cycloalkyl e.g. contains 5-7 ring joints, e.g. 3-methylureido, 3-ethylureido or 3-cyclohexylureido.
N-laverealkylamino og N,N-dilaverealkylamino er f.eks. metylamino, etylamino, dimetylamino eller dietylamino. N-lower alkylamino and N,N-dilower alkylamino are e.g. methylamino, ethylamino, dimethylamino or diethylamino.
Hydroksylaverealkyl er fortrinnsvis hydroksymetyl ellerHydroxyl lower alkyl is preferably hydroxymethyl or
1- og i første rekke 2-hydroksyetyl.1- and primarily 2-hydroxyethyl.
Laverealkoksylaverealkyl er fortrinnsvis laverealkoksymetyl eller 1- og i første rekke 2-laverealkoksyetyl, f.eks. metoksymetyl, etoksymetyl, 2-metoksy-etyl eller 2-etoksy- Lower alkyl lower alkyl is preferably lower alkoxymethyl or 1- and primarily 2-lower oxyethyl, e.g. methoxymethyl, ethoxymethyl, 2-methoxy-ethyl or 2-ethoxy-
etyl.ethyl.
Halogenlaverealkyl er fortrinnsvis halogenmetyl, f.eks. trifluormetyl. Halogen-lower alkyl is preferably halomethyl, e.g. trifluoromethyl.
Hydroksylaverealkoksy er f.eks. hydroksymetoksy eller 2- hydroksyetoksy. Hydroxylavereal oxy is e.g. hydroxymethoxy or 2-hydroxyethoxy.
Laverealkoksylaverealkoksy er f.eks. 2-metoksyetoksy eller 2-etoksyetoksy. Low-real oxylave-real oxy is e.g. 2-methoxyethoxy or 2-ethoxyethoxy.
Laverealkanoylaminolaverealkyl er spesielt laverealkanoyl-aminometyl eller 1- og i første rekke 2-laverealkanoylamino-etyl, f.eks. acetylaminometyl, 2-acetylamino-etyl eller 2-propionylamino-etyl. Lower alkanoylaminolower alkyl is especially lower alkanoyl-aminomethyl or 1- and primarily 2-lower alkanoylamino-ethyl, e.g. acetylaminomethyl, 2-acetylamino-ethyl or 2-propionylamino-ethyl.
Laverealkoksykarbonylaminolaverealkyl er spesielt laverealkoksy-karbonylaminometyl, eller 1- og i første rekke 2-laverealkoksykarbonylamino-etyl, f.eks. metoksykarbonylaminometyl, 2-metoksykarbonylamino-etyl eller 2-etoksykarbonylamino-etyl. Lower oxycarbonylaminolower alkyl is especially lower alkoxycarbonylaminomethyl, or 1- and primarily 2-lower oxycarbonylaminoethyl, e.g. methoxycarbonylaminomethyl, 2-methoxycarbonylaminoethyl or 2-ethoxycarbonylaminoethyl.
Karboksylaverealkyl er f.eks. 2-karboksyetyl. Carboxyl lower alkyl is e.g. 2-carboxyethyl.
Laverealkoksykarbonyllaverealkyl er f.eks. metoksykarbonyl-metyl eller 2-etoksykarbonyletyl. Lower oxycarbonyl lower alkyl is e.g. methoxycarbonylmethyl or 2-ethoxycarbonylethyl.
Cyanlaverealkyl er f.eks. cyanmetyl.Cyanolower alkyl is e.g. cyanomethyl.
Laverealkoksylaverealkoksy er bl.a. laverealkoksymetoksy eller 1- og spesielt 2-laverealkoksy-etoksy, f.eks. metoksy-metoksy, 2-metoksy-etoksy eller 2-etoksy-etoksy. Lavereal oxylavereal oxy is i.a. lower alkoxy methoxy or 1- and especially 2-lower methoxy ethoxy, e.g. methoxy-methoxy, 2-methoxy-ethoxy or 2-ethoxy-ethoxy.
Laverealkyltiolaverealkoksy er spesielt laverealkyltio-metoksy eller 1- og i første rekke 2-laverealkyltioetoksy, f.eks. 2-metyltio-etoksy eller 2-etyltio-etoksy. Lower alkyl thiolavereal oxy is in particular lower alkyl thiomethoxy or 1- and primarily 2-lower alkyl thioethoxy, e.g. 2-methylthio-ethoxy or 2-ethylthio-ethoxy.
Halogenlaverealkoksy er spesielt 2-halogenetoksy, f.eks. 2-kloretoksy. Halogen-lower oxy is especially 2-haloethoxy, e.g. 2-chloroethoxy.
Laverealkanoyllaverealkoksy er f.eks. laverealkanoylmetoksy eller 1- eller 2-laverealkanoyletoksy, f.eks. acetylmetoksy. Fenyllaverealkyl er f.eks. benzyl eller 2-fenyletyl. Lowerealkanoyllaverealcoxy is e.g. lower alkanoylmethoxy or 1- or 2-lower alkanoylmethoxy, e.g. acetylmethoxy. Phenyl lower alkyl is e.g. benzyl or 2-phenylethyl.
N-laverealkyl-N-fenyllaverealkyl-amino er f.eks. N-metyl-N-benzylamino eller N-metyl-N-(2-fenyletyl)-amino. N-lower alkyl-N-phenyl lower alkyl-amino is e.g. N-methyl-N-benzylamino or N-methyl-N-(2-phenylethyl)-amino.
Fenyllaverealkenyl er f.eks. fenylvinyl eller l-fenyl-2-propenyl. Fenyllaverealkinyl er f.eks. 1-fenyl-2-propinyl. Phenylvarealalkenyl is e.g. phenylvinyl or 1-phenyl-2-propenyl. Phenylaveralkynyl is e.g. 1-phenyl-2-propynyl.
Laverealkylenamino inneholder fortrinnsvis 4-6 ringkarbon-atomer og er f.eks. pyrrolidino eller piperidino, mens laverealkylenamino som er avbrutt av oksygen er f.eks. morfolino som 4-morfolino, laverealkylenamino som er avbrutt av svovel er f.eks. tiomorfolino, som 4-tiomorfolino, og laverealkylenamino som er avbrutt av nitrogen som eventuelt er substituert med laverealkyl, er f.eks. piperazino eller 4-metyliperazino. Lower alkyleneamino preferably contains 4-6 ring carbon atoms and is e.g. pyrrolidino or piperidino, while lower alkyleneamino interrupted by oxygen is e.g. morpholino such as 4-morpholino, lower alkyleneamino which is interrupted by sulfur is e.g. thiomorpholino, such as 4-thiomorpholino, and lower alkylene amino which is interrupted by nitrogen optionally substituted with lower alkyl, are e.g. piperazino or 4-methyliperazino.
N,N-laverealkylen-karbamoyl er f.eks. pyrrolidinokarbonyl eller piperidinokarbonyl, hvorved tilsvarende rester i hvilke laverealkylendelen er avbrutt av oksygen, svovel eller usubstituert eller substituert nitrogen, betyr f.eks. 4-morfolino-karbonyl, 4-tiomorfolino-karbonyl, 1-piperazino-karbonyl eller 4-metyl-l-piperazino-karbonyl. N,N-lower alkylene-carbamoyl is e.g. pyrrolidinocarbonyl or piperidinocarbonyl, whereby corresponding residues in which the lower alkylene part is interrupted by oxygen, sulfur or unsubstituted or substituted nitrogen, means e.g. 4-morpholinocarbonyl, 4-thiomorpholinocarbonyl, 1-piperazinocarbonyl or 4-methyl-1-piperazinocarbonyl.
Monocyklisk cykloalkyl medregnet polycyklisk cykloalkyl inneholder fortrinnsvis 3-10 karbonatomer og er f.eks. cyklopropyl, cyklopentyl eller cykloheksyl, mens polycyklisk cykloalkyl f.eks. er bicyklo[2,2,1]heptyl (norbornyl), bicyklo[2,2,2]oktyl eller adamantyl, som 1-adamantyl. Monocyclic cycloalkyl including polycyclic cycloalkyl preferably contains 3-10 carbon atoms and is e.g. cyclopropyl, cyclopentyl or cyclohexyl, while polycyclic cycloalkyl e.g. is bicyclo[2,2,1]heptyl (norbornyl), bicyclo[2,2,2]octyl or adamantyl, such as 1-adamantyl.
De nye forbindelsene kan foreligge i form av deres salter, som deres syreaddisjonssalter og i første rekke deres farma-søytisk anvendbare, ikke-toksiske syreaddisjonssalter. The new compounds may exist in the form of their salts, such as their acid addition salts and primarily their pharmaceutically usable, non-toxic acid addition salts.
Egnede salter er f.eks. slike med uorganiske syrer, som halogenhydrogensyrer, f.eks. klorhydrogensyre eller brom-hydrogensyre, svovelsyre eller fosforsyre, eller med organiske syrer, som alifatiske, cykloalifatiske, aromatiske eller heterocykliske karboksyl- eller sulfonsyrer, f.eks. maur-, eddik-, propion-, rav-, glykol-, melke-, Suitable salts are e.g. those with inorganic acids, such as halogen hydrogen acids, e.g. hydrochloric acid or hydrobromic acid, sulfuric acid or phosphoric acid, or with organic acids, such as aliphatic, cycloaliphatic, aromatic or heterocyclic carboxylic or sulphonic acids, e.g. ant-, vinegar-, propion-, amber-, glycol-, milk-,
eple-, vin-, sitron-, malein-, hydroksymalein-, pyrodrue-, fumar-, benzo-, 4-aminobenzo-, antranil-, 4-hydroksybenzo-, salicyl-, embon-, metansulfon-, etansulfon-, 2-hydroksy-etansulfon-, etylensulfon-, toluensulfon-, naftalinsulfon-eller sulfanilsyre, eller med andre sure organiske stoffer, som askorbinsyre. Salter er videre slike som er dannet med baser, spesielt farmasøytisk anvendbare, ikke-toksiske baser og sure grupper, f.eks. forbindelser med formel I apple, wine, lemon, maleic, hydroxymaleic, pyrrhotite, fumaric, benzo, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic, embonic, methanesulfonic, ethanesulfonic, 2 -hydroxyethanesulfonic, ethylenesulfonic, toluenesulfonic, naphthalenesulfonic or sulfanilic acid, or with other acidic organic substances, such as ascorbic acid. Salts are further those formed with bases, especially pharmaceutically usable, non-toxic bases and acidic groups, e.g. compounds of formula I
som inneholder karboksygrupper. Egnede baser er f.eks.containing carboxyl groups. Suitable bases are e.g.
slike av uorganisk natur, som karbonatene eller hydroksydene av alkalimetaller eller jordalkalimetaller, f.eks. karbonater eller hydroksyder av natrium, kalium, magnesium eller kalsium, videre ammoniakk, eller organiske baser, f.eks. egnede nitrogenbaser, som egnede amider, som eventuelt substituerte, f.eks. med hydroksy substituerte primære, sekundære eller tertiære, alifatiske eller cykliske aminer, so f.eks. trietylamin, N-etylpiperidin, di- eller trietanolamin, pyrrolidin, N-(2-hydroksyetyl)-pyrrolidin, piperazin, N-(2-hydroksyetyl)-piperazin, og videre N-metylglukosamin. those of an inorganic nature, such as the carbonates or hydroxides of alkali metals or alkaline earth metals, e.g. carbonates or hydroxides of sodium, potassium, magnesium or calcium, further ammonia, or organic bases, e.g. suitable nitrogen bases, such as suitable amides, which optionally substituted, e.g. with hydroxy substituted primary, secondary or tertiary, aliphatic or cyclic amines, such as e.g. triethylamine, N-ethylpiperidine, di- or triethanolamine, pyrrolidine, N-(2-hydroxyethyl)-pyrrolidine, piperazine, N-(2-hydroxyethyl)-piperazine, and further N-methylglucosamine.
De farmasøytiske preparatene ifølge oppfinnelsen som inneholder acylerte hydrazinforbindelser med formel I som også The pharmaceutical preparations according to the invention which contain acylated hydrazine compounds of formula I which also
de nye forbindelsene med formel I har verdifulle farmako-logiske egenskaper. Spesielt virker de på spesifikk måte the new compounds of formula I have valuable pharmacological properties. In particular, they work in a specific way
på nyregjennomblødningen og natriumutskillelsen. således bevirker de en selektiv renal vasodilatasjon, som det kan vises ved hemodynamiske målinger på rotter, således kan på narkotiserte rotter, hvis blodtrykk og nyregjennomblødning måles kontinuerlig (elektromagnetisk strømningsmåler), etter intravenøs tilførsel av ca. 3 mg/kg til ca. 15 mg/kg av slike substanser, spesielt slike forbindelser med formel I, hvor Ac betyr Y-glutamylresten, observeres en renal vasodilatasjon uten blodtrykkssenkning, mens det etter applikasjon av meget høyere doser, av ca. 70 mg/kg intravenøs opptrer en blodtrykkssenkning på ca. -20 mm Hg. På rotter hos hvilke samtidig hjerteminuttvolumet (termodilusjon), gjennomblødningen av nyren, mesenterialområdet og den bakre ekstremiteten (elektromagnetisk strømningsmåler) måles, fører den intravenøse tilførsel av en dose på 4 mg/kg av slike forbindelser til en ca. 25 %-ig minskning av den renale tarmmotstanden, mens den mesenteriale, femorale og den totale perifere karmotstanden forblir uforandret. on renal blood flow and sodium excretion. thus they cause a selective renal vasodilatation, which can be shown by hemodynamic measurements on rats, thus on anesthetized rats, whose blood pressure and renal perfusion are measured continuously (electromagnetic flow meter), after intravenous administration of approx. 3 mg/kg to approx. 15 mg/kg of such substances, especially such compounds of formula I, where Ac means the Y-glutamyl residue, a renal vasodilatation is observed without blood pressure lowering, while after application of much higher doses, of approx. 70 mg/kg intravenously causes a blood pressure reduction of approx. -20 mm Hg. In rats in which the cardiac output (thermodilution), the perfusion of the kidney, the mesenteric area and the hind limb (electromagnetic flow meter) are simultaneously measured, the intravenous administration of a dose of 4 mg/kg of such compounds leads to an approx. 25% reduction in renal intestinal resistance, while mesenteric, femoral and total peripheral vascular resistance remains unchanged.
I lignende forsøk på voksne, spontant hypertensive rotter med kronisk implanterte Doppler-ultralyd-strømmålingshoder kan det likeledes vises, at slike forbindelser i et doseområde fra ca. 3 mg/kg til ca. 10 mg/kg intravenøst senker den renale karmotstanden, mens karmotstanden i mesenterialområdet og i bakekstremiteten ikke blir påvirket. Først tydelig høyere doser, (ca. 30 mg/kg intravenøst) fører til et blodtrykksfall og en vasodilatasjon i alle tre undersøkte kar-områder. Først høyere doser bevirker etter intravenøst applikasjon av ca. 30 mg/kg eller pr. oral tilførsel av 60 mg/kg på våkne rotter et blodtrykksfall på ca. -25 mm Hg som holder seg i minst 4 timer. Etter intravenøs tilførsel av doser i området av 15 mg/kg til rotter fører disse forbindelser til en økning av natriumutskillelsen som varer In similar experiments on adult, spontaneously hypertensive rats with chronically implanted Doppler ultrasound flow measuring heads, it can likewise be shown that such compounds in a dose range from approx. 3 mg/kg to approx. 10 mg/kg intravenously lowers the renal vascular resistance, while the vascular resistance in the mesenteric area and in the hind limb is not affected. First, clearly higher doses (approx. 30 mg/kg intravenously) lead to a drop in blood pressure and a vasodilatation in all three vascular areas examined. Only higher doses cause, after intravenous application of approx. 30 mg/kg or per oral administration of 60 mg/kg in awake rats a drop in blood pressure of approx. -25 mm Hg that lasts for at least 4 hours. After intravenous administration of doses in the range of 15 mg/kg to rats, these compounds lead to an increase in sodium excretion that lasts
i 3 timer. I forsøk på narkotiserte rotter kan det vises, at spesielt slike forbindelser med formel I, hvor Ac betyr en y-glutamylrest, i en dose på 10 mg/kg intravenøst fører til en økning av den glomerulære filtrasjonshastigheten for 3 hours. In experiments on anesthetized rats, it can be shown that especially such compounds of formula I, where Ac means a y-glutamyl residue, in a dose of 10 mg/kg intravenously leads to an increase in the glomerular filtration rate
(målt som "inulin-clearance") på ca. 50%. Av dette kan (measured as "inulin clearance") of approx. 50%. Of this can
det utledes at slike forbindelser bevirker en overveiende preglomerulær vasodilasjon. Den kroniske perorale tilførsel av slike forbindelser i en dose på 10 mg/kg to ganger daglig i tre uker fører hos rotter med spontan hypertoni til en vedholdende blodtrykkssenkning på ca. -20 til —25 mm Hg, hvorved hjertefrekvensen forblir upåvirket. Lignende virkninger kan observeres under behandling med 10 mg/kg i.v. it is inferred that such compounds cause a predominantly preglomerular vasodilation. The chronic oral administration of such compounds in a dose of 10 mg/kg twice a day for three weeks leads to a sustained blood pressure reduction of approx. -20 to -25 mm Hg, whereby the heart rate remains unaffected. Similar effects can be observed during treatment with 10 mg/kg i.v.
pr. dag, tilført over osmotiske minipumper i en uke. Forbindelser med formel I hvor Ac betyr en Y-L-glutamyl-rest spaltes i nyren av Y-glutamyl-trans-peptidase. Utover dette kan det fastslås utpreget blodtrykkssenkende virkninger, spesielt av slike forbindelser med formel I, hvor Ac betyr resten av en monoester av karbonsyre. Spesielt forbindelser av denne art bevirker en utpreget blodtrykkssenkning på renale hypertensive hannrotter (Goldblatt-metode), som på indirekte måte beregnes på ikke-anestiserte rotter etter metoden til Gerold et al. (Heiv. Physiol. Acta 24, 58 (1966)). Således kan det etter daglig peroral tilførsel av slike forbindelser i fire dager, hvorved målet på blodtrykks-senkningen bestemmes den fjerde dagen, to timer etter tilførsel av den siste dosen, fastslås ved en dagsdose på 3 mg/kg en blodtrykkssenkning på -27 mm Hg, ved en dagsdose på 10 mg/kg en blodtrykkssenkning på -81 mm Hg og ved en dagsdose på 100 mg/kg en blodtrykkssenkning på -108 mm Hg. per day, supplied via osmotic mini-pumps for a week. Compounds of formula I where Ac means a Y-L-glutamyl residue are cleaved in the kidney by Y-glutamyl-trans-peptidase. In addition to this, distinct blood pressure-lowering effects can be determined, especially of such compounds of formula I, where Ac means the residue of a monoester of carbonic acid. Compounds of this kind in particular cause a marked lowering of blood pressure in renal hypertensive male rats (Goldblatt method), which is indirectly calculated in non-anesthetized rats according to the method of Gerold et al. (Heiv. Physiol. Acta 24, 58 (1966)). Thus, after daily oral administration of such compounds for four days, whereby the measure of blood pressure reduction is determined on the fourth day, two hours after administration of the last dose, a blood pressure reduction of -27 mm Hg can be determined at a daily dose of 3 mg/kg , at a daily dose of 10 mg/kg a blood pressure reduction of -81 mm Hg and at a daily dose of 100 mg/kg a blood pressure reduction of -108 mm Hg.
På grunn av disse egenskaper viser de farmasøytiske preparatene som inneholder forbindelser med formel I eller de nye forbindelsene med formel I seg egnet for anvendelse som renale vasodilatorer og som antihypertensiva. Because of these properties, the pharmaceutical preparations containing compounds of formula I or the new compounds of formula I prove suitable for use as renal vasodilators and as antihypertensives.
Forbindelser med formel I hvor Ac betyr pyridylkarbonylresten, har dessuten antileukemisk virksomhet, som det eksempelvis kan vises på mus med leukemi P 388 som er forårsaket ved intraperitoneal transplantasjon, idet kvotienten T/C oppgår 129% etter intraperitoneal tilførsel av 100 mg/kg av slike forbindelser i fem på hverandre følgende dager en gang daglig, henholdsvis oppgår kvotienten T/C til 125% etter gjennomført intraperitoneal tilførsel av 50 mg/kg av slike forbindelser en gang daglig i fem på hverandre følgende dager. På leukemi L 1210 som er forårsaket av intraperitoneal transplantasjon på mus, kan det fastslås en verdi på kvotienten T/C på 151% etter gjennomført intraperitoneal tilførsel av 100 mg/kg av slike forbindelser en gang daglig i ni på hverandre følgende dager, henholdsvis til 123% etter intraperitoneal tilførsel av 60 mg/kg av slike forbindelser på samme måte og varighet. Disse funn ble oppnådd på oppdrag av søkeren i testmodeller som Developmental Therapeutics Program, Division of Cancer Treatment, National Cencer Institute, Bethesda, Maryland (USA). På grunn av disse egenskaper synes forbindelser med formel I, hvor Ac betyr pyridylkarbonylresten, å være egnet til behandling av leukemi. Compounds of formula I where Ac means the pyridylcarbonyl residue also have antileukemic activity, as can be shown, for example, in mice with leukemia P 388 which is caused by intraperitoneal transplantation, with the quotient T/C amounting to 129% after intraperitoneal administration of 100 mg/kg of such compounds for five consecutive days once a day, respectively the quotient T/C amounts to 125% after intraperitoneal administration of 50 mg/kg of such compounds once a day for five consecutive days. On leukemia L 1210 which is caused by intraperitoneal transplantation in mice, a value for the quotient T/C of 151% can be determined after intraperitoneal administration of 100 mg/kg of such compounds once a day for nine consecutive days, respectively to 123% after intraperitoneal administration of 60 mg/kg of such compounds in the same manner and duration. These findings were obtained at the behest of the applicant in test models such as the Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute, Bethesda, Maryland (USA). Because of these properties, compounds of formula I, where Ac means the pyridylcarbonyl residue, appear to be suitable for the treatment of leukemia.
De nye' forbindelsene med formel I kan også anvendes som verdifulle mellomprodukter for fremstilling av andre verdifulle, spesielt farmasøytisk virksomme forbindelser. The new compounds of formula I can also be used as valuable intermediates for the production of other valuable, particularly pharmaceutically active compounds.
Oppfinnelsen gjelder spesielt fremgangsmåte for fremstilling av nye forbindelser med formel I, hvor n er et helt tall fra 1-4 og R betyr eventuelt substituert laverealkyl, laverealkenyl eller laverealkinyl, eller en mono- eller bicyklisk, karbocyklisk eller heterocyklisk, aromatisk hydrokarbonrest, Ac betyr en rest med formelen -C(=0)-R^, hvor R-^betyr en eventuelt substituert" alifatisk, cykloalifatisk, aromatisk eller aralifatisk hydrokarbonrest, eller resten av en monoester eller et monoamid av kullsyre, under den forutsetning at R som laverealkyl som er bundet i 3-stilling, har 2-7 karbonatomer, når Ac betyr acetylgruppen, og med den ytterligere forutsetning at R som bundet laverealkyl i 3-, 4-, 5- eller 6-stilling har 2-7 karbonatomer, når Ac betyr benzoylgruppen, som racematblandinger, racemater, optiske antipoder eller deres salter. The invention relates in particular to methods for the preparation of new compounds of formula I, where n is an integer from 1-4 and R means optionally substituted lower alkyl, lower alkenyl or lower alkynyl, or a mono- or bicyclic, carbocyclic or heterocyclic, aromatic hydrocarbon residue, Ac means a residue of the formula -C(=O)-R^, where R-^ means an optionally substituted" aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon residue, or the residue of a monoester or a monoamide of carbonic acid, on the condition that R as lower alkyl which is bound in the 3-position, has 2-7 carbon atoms, when Ac means the acetyl group, and with the additional proviso that R as bound lower alkyl in the 3-, 4-, 5- or 6-position has 2-7 carbon atoms, when Ac means the benzoyl group, such as racemate mixtures, racemates, optical antipodes or their salts.
Oppfinnelsen gjelder spesielt fremgangsmåte for fremstilling av forbindelser med formel I, hvori n er et helt tall fra 1-4 og R betyr laverealkyl, eventuelt foretret eller forestret hydroksylaverealkyl, som hydroksylaverealkyl, laverealkoksylaverealkyl eller halogenlaverealkyl eller eventuelt substituert, som laverealkylert eller acylert aminolaverealkyl, som aminolaverealkyl, N-laverealkylaminolaverealkyl ellerN,N-dilaverealkylaminolaverealkyl, laverealkanoylaminolaverealkyl eller laverealkoksykarbonylaminolaverealkyl, laverealkyl som eventuelt er substituert med forestret eller amidert karboksy, som karboksy, etoksykarbonyl eller eventuelt substituert karbamoyl, som karbamoyl, som karboksylaverealkyl, laverealkoksykarbonyllaverealkyl, karbamoyllaverealkyl, okso-laverealkyl, videre cyanlaverealkyl, eventuelt substituert aryllaverealkyl, hvori aryl er en monocyklisk, aromatisk hydrokarbonrest, f.eks. fenyl, eller en bicyklisk aromatisk hydrokarbonrest, som 1- eller 2-naftyl, eller delvis mettet naftyl, som 1,2,3,4-tetrahydro-5-naftyl, hvorved substituentene er laverealkyl, hydroksy og/eller halogen, hydroksylaverealkyl, laverealkoksylaverealkyl, halogenlaverealkyl, laverealkoksy, laverealkenyloksy eller eventuelt laverealkylert eller acylert aminolaverealkyl, f.eks. mono- eller dilaverealkyl-aminolaverealkyl eller laverealkanoylaminolaverealkyl, eventuelt forestret karboksy, som karboksy eller laverealkoksykarbonyl, amidert karboksy, f.eks. eventuelt substituert karbamoyl, som karbamoyl, N-laverealkylkarbamoyl eller N,N-dilaverealkylkarbamoyl, cyan, nitro eller eventuelt acylert amino, f.eks. amino, laverealkylamino, laverealkoksykarbonylamino, laverealkylamino eller dilaverealkylamino og slike substituenter kan være like eller forskjellige og være tilstede 1-3 ganger, eller R og R-, som inneholdes i gruppen Ac hver står for aryl, som fenyl, 1- eller 2-naftyl eller delvis mettet naftyl, som 1,2,3,4-tetra-hydro-5-naftyl eller en rest fortrinnsvis med 5 eller 6 ringledd som inneholder et oksygen-, svovel- eller nitrogenatom og eventuelt 1-3 ytterligere nitrogenatomer som ring ledd som er forbundet med pyridinresten over et ringkarbonatom, som minst delvis kan være hydrert og i dette tilfellet substituert med okso, hvorved den andre ringen i en bicyklisk, heterocyklisk rest kan være en tilkondensert benzoring, og spesielt betyr pyridyl, f.eks. 2-, 3- eller 4-pyridyl eller dihydro-okso-pyridyl, f.eks. 1,6-dihydro-6-okso-2-pyridinyl, pyridazinyl, f.eks. 3-pyridazinyl, pyrazinyl, f.eks. 2-pyrazinyl, pyrimidinyl, f.eks. 2-, The invention relates in particular to methods for the preparation of compounds of formula I, in which n is an integer from 1-4 and R means lower alkyl, optionally etherified or esterified hydroxyl lower alkyl, such as hydroxyl lower alkyl, lower hydroxy lower alkyl or halogen lower alkyl or optionally substituted, such as lower alkylated or acylated amino lower alkyl, which amino lower alkyl, N-lower alkyl amino lower alkyl or N,N-di lower alkyl amino lower alkyl, lower alkanoylamino lower alkyl or lower alkoxycarbonylamino lower alkyl, lower alkyl optionally substituted with esterified or amidated carboxy, such as carboxy, ethoxycarbonyl or optionally substituted carbamoyl, such as carbamoyl, such as carboxy lower alkyl, lower alkoxycarbonyl lower alkyl, carbamoyl lower alkyl, oxo-lower alkyl, further Cyan lower alkyl, optionally substituted aryl lower alkyl, in which aryl is a monocyclic, aromatic hydrocarbon residue, e.g. phenyl, or a bicyclic aromatic hydrocarbon residue, such as 1- or 2-naphthyl, or partially saturated naphthyl, such as 1,2,3,4-tetrahydro-5-naphthyl, whereby the substituents are lower alkyl, hydroxy and/or halogen, hydroxy lower alkyl, lower hydroxy lower alkyl , halolower alkyl, lower alkoxy, lower alkenyloxy or optionally lower alkylated or acylated amino lower alkyl, e.g. mono- or dilower alkyl-aminolower alkyl or lower alkanoylamino lower alkyl, optionally esterified carboxy, such as carboxy or lower alkoxycarbonyl, amidated carboxy, e.g. optionally substituted carbamoyl, such as carbamoyl, N-lower alkylcarbamoyl or N,N-dilower alkylcarbamoyl, cyan, nitro or optionally acylated amino, e.g. amino, lower alkylamino, lower alkoxycarbonylamino, lower alkylamino or dilower alkylamino and such substituents may be the same or different and be present 1-3 times, or R and R-, which are contained in the group Ac each stand for aryl, such as phenyl, 1- or 2-naphthyl or partially saturated naphthyl, such as 1,2,3,4-tetra-hydro-5-naphthyl or a residue preferably with 5 or 6 ring members containing an oxygen, sulfur or nitrogen atom and optionally 1-3 further nitrogen atoms as ring members which is connected to the pyridine residue via a ring carbon atom, which may be at least partially hydrogenated and in this case substituted with oxo, whereby the second ring in a bicyclic, heterocyclic residue may be a fused benzo ring, and in particular means pyridyl, e.g. 2-, 3- or 4-pyridyl or dihydro-oxo-pyridyl, e.g. 1,6-dihydro-6-oxo-2-pyridinyl, pyridazinyl, e.g. 3-pyridazinyl, pyrazinyl, e.g. 2-pyrazinyl, pyrimidinyl, e.g. 2-,
4- eller 5-pyrimidinyl, eller dihydro-okso-pyrimidinyl, f.eks. 3,4-dihydro-4-okso-2-pyrimidinyl, furyl, f.eks. 2-eller 3-furyl, pyrryl, f.eks. 2- eller 3-pyrryl, tienyl, f.eks. 2- eller 3-tienyl, oksazolyl, f.eks. 2- eller 4-oksazolyl, tiazolyl, f.eks. 2-, 4- eller 5-tiazolyl, tiadiazolyl, f.eks. 1,2,4-tiadiazol-3- eller 5-yl eller 1,2,5-tiadiazol-3- yl, imidazolyl, f.eks. imidazol-2- eller -4-yl, pyrazolyl. f.eks. 3- eller 4-pyrazolyl, triazolyl, f.eks. 1,2,3-triazol-4- yl eller 1,2,4-triazol-3-yl, tetrazolyl som tetrazol-5-yl, videre indolyl, f.eks. inol-4-yl, kinolinyl, f.eks. 2-kinolinyl, isokinolinyl, f.eks. 1-isokinolinyl, benzimidazolyl, f.eks. 2-benzimidazolyl, benzofuranyl, f.eks. 4-eller 5-benzofuranyl, benzotienyl, f.eks. 4- eller 5-benzotienyl, eller naftyridinyl f.eks. 1,8-naftyridin-2-yl, hvorved slike arylrester i første rekke står til et ringkarbonatom, men også til et sekundært ringnitrogenatom og kan være substituert en eller flere ganger, fortrinnsvis høyst fire ganger, med eventuelt substituert laverealkyl, f.eks. laverealkyl, eventuelt foretret eller forestret hydroksy-laverealkyl, som hydroksylaverealkyl, laverealkoksylaverealkyl eller halogenlaverealkyl, eller eventuelt substituert, som laverealkylert eller acylert aminolaverealkyl som aminolaverealkyl, N-laverealkylaminolaverealkyl, N,N-dilaverealkylaminolaverealkyl, laverealkanoylaminolaverealkyl eller laverealkoksykarbonylaminolaverealkyl, eller laverealkenyl eller laverealkinyl, eventuelt foretret eller forestret hydroksy eller merkapto, som hydroksy, laverealkoksy, fenyllaverealkoksy, halogen, merkapto, laverealkyltio, fenyllaverealkyltio, laverealkoksy som eventuelt er 4- or 5-pyrimidinyl, or dihydro-oxo-pyrimidinyl, e.g. 3,4-dihydro-4-oxo-2-pyrimidinyl, furyl, e.g. 2-or 3-furyl, pyrryl, e.g. 2- or 3-pyrryl, thienyl, e.g. 2- or 3-thienyl, oxazolyl, e.g. 2- or 4-oxazolyl, thiazolyl, e.g. 2-, 4- or 5-thiazolyl, thiadiazolyl, e.g. 1,2,4-thiadiazol-3- or 5-yl or 1,2,5-thiadiazol-3-yl, imidazolyl, e.g. imidazol-2- or -4-yl, pyrazolyl. e.g. 3- or 4-pyrazolyl, triazolyl, e.g. 1,2,3-triazol-4-yl or 1,2,4-triazol-3-yl, tetrazolyl such as tetrazol-5-yl, further indolyl, e.g. inol-4-yl, quinolinyl, e.g. 2-quinolinyl, isoquinolinyl, e.g. 1-isoquinolinyl, benzimidazolyl, e.g. 2-benzimidazolyl, benzofuranyl, e.g. 4-or 5-benzofuranyl, benzothienyl, e.g. 4- or 5-benzothienyl, or naphthyridinyl e.g. 1,8-naphthyridin-2-yl, whereby such aryl residues primarily stand for a ring carbon atom, but also for a secondary ring nitrogen atom and may be substituted one or more times, preferably at most four times, with optionally substituted lower alkyl, e.g. lower alkyl, optionally etherified or esterified hydroxy-lower alkyl, such as hydroxyl lower alkyl, lower hydroxy lower alkyl or halogen lower alkyl, or optionally substituted, as lower alkylated or acylated amino lower alkyl such as amino lower alkyl, N-lower alkyl amino lower alkyl, N,N-di lower alkyl amino lower alkyl, lower alkanoylamino lower alkyl or lower alkoxycarbonylamino lower alkyl, or lower alkenyl or lower alkynyl, optionally etherified or esterified hydroxy or mercapto, such as hydroxy, lower alkoxy, phenyl lower alkyl, halogen, mercapto, lower alkylthio, phenyl lower alkylthio, lower alkoxy which is optionally
substituert med foretret eller forestret merkapto eller med acyl, f.eks. laverealkoksy, fenyllaverealkoksy, hydroksylaverealkoksy, laverealkoksylaverealkoksy, laverealkyltiolaverealkoksy, halogenlaverealkoksy eller laverealkanoyllaverealkoksy, eller laverealkenyloksy, laverealkinyloksy, laverealkyltio, acyl, f.eks. laverealkanoyl, eventuelt forestret karboksy, som karboksy eller laverealkoksykarbonyl, amidert karboksy, f.eks. eventuelt substituert karbamoyl, som karbamoyl, N-laverealkylkarbamoyl eller N,N-di-laverealkylkarbamoyl, cyan, nitro eller eventuelt substituert, som acylert amino, f.eks. laverealkanoylamino, laverealkoksykarbonylamino, laverealkylsulfonyl, sulfamoyl, eventuelt substituert ureido, videre amino, N-laverealkylamino eller N,N-dilaverealkylamino, som i en gruppe Ac som inneholder R-^ dessuten betyr laverealkyl, laverealkenyl, laverealkinyl, fenyllaverealkyl, fenyllaverealkenyl, fenyllaverealkinyl, mono- eller polycyklisk cykloalkyl, f.eks. cykloalkyl, som eventuelt er substituert med eventuelt foretret eller forestret hydroksy, som hydroksy, laverealkoksy og/ eller halogen, eventuelt substituert som laverealkylert eller acylert amino, som amino, N-laverealkylamino eller N,N-dilaverealkylamino, laverealkanoylamino og/eller eventuelt funksjonelt omdannet karboksy, som karboksy, forestret karboksy, f.eks. eventuelt substituert laverealkoksykarbonyl, eventuelt substituert karbamoyl, eller cyan, hvorved substituerte rester kan oppvise en eller flere substituenter som kan være like eller forskjellige og være tilstede 1-3 ganger, i hvilke som helst stillinger som er egnet for substitusjon, eller Ac dessuten er usubstituert eller substituert, f.eks. fri eller forestret hydroksy, som laverealkoksy, eller usubstituert eller substituert amino, som amino, laverealkylamino, og i første rekke disubstituert amino, som dilaverealkylamino, N-laverealkyl-N-fenyllavere-alkylamino, eller laverealkylenamino som eventuelt er avbrutt av oksygen, svovel eller usubstituert eller substituert nitrogen, f.eks. med laverealkyl, eller laverealkoksykarbonyl som inneholder fenyl som er usubstituert eller substituert f.eks. med alverealkyl, laverealkoksy og/eller halogen, videre N-usubstituert eller N-mono- eller N,N-disubstituert karbamoyl, som laverealkylkarbamoyl, dilavere-alkylkarbamoyl, ellerN,N-laverealkylenkarbamoyl som i laverealkylendelen er avbrutt av oksygen, svovel eller nitrogen som er usubstituert eller substituert, f.eks. substituted with etherified or esterified mercapto or with acyl, e.g. lower alkoxy, phenyl lower aryl oxy, hydroxy lower aryl oxy, lower alkoxy lower rel oxy, lower alkylthio lower rel oxy, halogen lower rel oxy or lower alkanoyl lower rel oxy, or lower alkenyloxy, lower alkynyloxy, lower alkylthio, acyl, e.g. lower alkanoyl, optionally esterified carboxy, such as carboxy or lower alkoxycarbonyl, amidated carboxy, e.g. optionally substituted carbamoyl, such as carbamoyl, N-lower alkylcarbamoyl or N,N-di-lower alkylcarbamoyl, cyan, nitro or optionally substituted, such as acylated amino, e.g. loweralkanoylamino, loweralkylcarbonylamino, loweralkylsulfonyl, sulfamoyl, optionally substituted ureido, further amino, N-loweralkylamino or N,N-diloweralkylamino, which in a group Ac containing R-^ also means loweralkyl, loweralkenyl, loweralkynyl, phenylloweralkyl, phenylloweralkenyl, phenylloweralkynyl, mono - or polycyclic cycloalkyl, e.g. cycloalkyl, which is optionally substituted with optionally etherified or esterified hydroxy, such as hydroxy, lower alkoxy and/or halogen, optionally substituted as lower alkylated or acylated amino, such as amino, N-lower alkylamino or N,N-dilower alkylamino, lower alkanoylamino and/or optionally functionally converted carboxy, such as carboxy, esterified carboxy, e.g. optionally substituted lower alkoxycarbonyl, optionally substituted carbamoyl, or cyan, whereby substituted residues may have one or more substituents which may be the same or different and be present 1-3 times, in any positions suitable for substitution, or Ac is also unsubstituted or substituted, e.g. free or esterified hydroxy, such as lower alkoxy, or unsubstituted or substituted amino, such as amino, lower alkylamino, and primarily disubstituted amino, such as dilower alkylamino, N-lower alkyl-N-phenyl lower alkylamino, or lower alkylene amino which is optionally interrupted by oxygen, sulfur or unsubstituted or substituted nitrogen, e.g. with lower alkyl, or lower alkoxycarbonyl containing phenyl which is unsubstituted or substituted e.g. with lower alkyl, lower alkoxy and/or halogen, further N-unsubstituted or N-mono- or N,N-disubstituted carbamoyl, such as lower alkylcarbamoyl, dilower alkylcarbamoyl, or N,N-lower alkylenecarbamoyl which in the lower alkylene part is interrupted by oxygen, sulfur or nitrogen which is unsubstituted or substituted, e.g.
med laverealkyl, med den forutsetning, at R som i 3-stilling bundet laverealkyl har 2-7 karbonatomer og f.eks. er etyl, n-propyl eller n-butyl, når Ac er acetylgruppen, og med den ytterligere forutsetning at R som i 3-, 4-, 5- with lower alkyl, with the proviso that R as lower alkyl bound in the 3-position has 2-7 carbon atoms and e.g. is ethyl, n-propyl or n-butyl, when Ac is the acetyl group, and with the further proviso that R as in 3-, 4-, 5-
eller 6-stilling bundet laverealkyl har 2-7 karbonatomer,or 6-position bonded lower alkyl has 2-7 carbon atoms,
og f.eks. betyr forannevnte etyl, n-propyl eller n-butyl, når Ac er benzoylgruppen, som racematblandinger, racemater, optiske antipoder eller deres salter. and e.g. means the aforementioned ethyl, n-propyl or n-butyl, when Ac is the benzoyl group, as racemate mixtures, racemates, optical antipodes or their salts.
Oppfinnelsen gjelder spesielt fremgangsmåte for fremstilling av nye forbindelser med formel I, hvor n står for 1 eller 2 og R betyr laverealkyl, f.eks. metyl, laverealkoksylaverealkyl, f.eks. 2-metoksyetyl, halogenlaverealkyl, f.eks. trifluormetyl, laverealkanoylaminolaverealkyl, f.eks. acetylaminometyl, og R^i gruppen Ac betyr fenyl eller pyridyl som eventuelt er substituert med laverealkyl, f.eks. The invention relates in particular to methods for the preparation of new compounds of formula I, where n stands for 1 or 2 and R means lower alkyl, e.g. methyl, lower alkyl lower alkyl, e.g. 2-methoxyethyl, halolower alkyl, e.g. trifluoromethyl, lower alkanoylaminolower alkyl, e.g. acetylaminomethyl, and R^ in the group Ac means phenyl or pyridyl which is optionally substituted with lower alkyl, e.g.
metyl, laverealkoksylaverealkyl, f.eks. 2-metoksyetyl, halogenlaverealkyl, f.eks. trifluormetyl, laverealkanoylaminolaverealkyl, f.eks. 2-acetylaminoetyl, hydroksy, laverealkoksy, f.eks. metoksy, laverealkoksylaverealkoksy, f.eks. 2-etoksyetoksy, halogen, laverealkoksykarbonyl, methyl, lower alkyl lower alkyl, e.g. 2-methoxyethyl, halolower alkyl, e.g. trifluoromethyl, lower alkanoylaminolower alkyl, e.g. 2-acetylaminoethyl, hydroxy, lower alkoxy, e.g. methoxy, lower alkyl lower alkyl, e.g. 2-Ethoxyethoxy, Halogen, Lower Alkoxycarbonyl,
f.eks. etoksykarbonyl, karbamoyl, cyano, amino eller laverealkanoylamino, f.eks. acetylamino, eller sulfamoyl, videre laverealkyl som eventuelt er substituert med laverealkoksy, f.eks. metoksy, amino, laverealkanoylamino, f.eks. acetylamino, karboksy, eventuelt substituert laverealkoksykarbonyl, f.eks. etoksykarbonyl eller 2- eller 1-(laverealkylkarbonyl-oksy)-laverealkoksykarbonyl eller karbamoyl, f.eks. etyl eller n-propyl, eller Ac dessuten betyr laverealkoksykarbonyl som er usubstituert eller substituert med laverealkoksy, som metoksy, eller amino, som etoksykarbonyl, eller karbamoyl, e.g. ethoxycarbonyl, carbamoyl, cyano, amino or lower alkanoylamino, e.g. acetylamino, or sulphamoyl, further lower alkyl which is optionally substituted with lower alkoxy, e.g. methoxy, amino, lower alkanoylamino, e.g. acetylamino, carboxy, optionally substituted lower alkoxycarbonyl, e.g. ethoxycarbonyl or 2- or 1-(lower alkylcarbonyloxy)-lower oxycarbonyl or carbamoyl, e.g. ethyl or n-propyl, or Ac also means lower alkoxycarbonyl which is unsubstituted or substituted with lower alkoxy, such as methoxy, or amino, such as ethoxycarbonyl, or carbamoyl,
under den forutsetning, at R som i 3-stilling bundet laverealkyl har 2-7 karbonatomer, og f.eks. betyr etyl, n-propyl eller n-butyl, når Ac er acetylgruppen, og med den ytterligere forutsetning at R som i 3-, 4-, 5- eller 6-stilling bundet laverealkyl har 2-7 karbonatomer, og betyr f.eks. forannevnte etyl, n-propyl eller n-butyl, dersom Ac er benzoylgruppen, som racematblandinger, race-' mater, optiske antipoder eller deres salter. under the condition that R as lower alkyl bound in the 3-position has 2-7 carbon atoms, and e.g. means ethyl, n-propyl or n-butyl, when Ac is the acetyl group, and with the further proviso that R as a 3-, 4-, 5- or 6-position bonded lower alkyl has 2-7 carbon atoms, and means e.g. . aforesaid ethyl, n-propyl or n-butyl, if Ac is the benzoyl group, as racemate mixtures, racemates, optical antipodes or their salts.
Oppfinnelsen gjelder spesielt fremgangsmåte for fremstilling av nye forbindelser med formel I, hvor n står for 1, og R er laverealkyl, f.eks. metyl, laverealkoksylaverealkyl, f.eks. 2-metoksyetyl, halogenlaverealkyl, f.eks. trifluormetyl, R^i gruppen Ac er fenyl eller pyridyl som eventuelt er substituert med laverealkyl, f.eks. metyl, laverealkoksylaverealkyl, f.eks. 2-metoksyetyl, halogenlaverealkyl, f.eks. trifluormetyl, hydroksy, laverealkoksy, f.eks. metoksy, laverealkoksylaverealkoksy, fe.ks. 2-etoksyetoksy, halogen, laverealkoksykarbonyl, fe.ks. etoksykarbonyl, karbamoyl, cyano, amino eller sulfamoyl, videre lavere-alkanoyllaverealkyl som eventuelt er substituert med laverealkoksy, f.eks. metoksy, amino, f.eks. 2-metoksyetyl, R^The invention relates in particular to methods for the preparation of new compounds of formula I, where n stands for 1, and R is lower alkyl, e.g. methyl, lower alkyl lower alkyl, e.g. 2-methoxyethyl, halolower alkyl, e.g. trifluoromethyl, R^ in the group Ac is phenyl or pyridyl which is optionally substituted with lower alkyl, e.g. methyl, lower alkyl lower alkyl, e.g. 2-methoxyethyl, halolower alkyl, e.g. trifluoromethyl, hydroxy, lower alkoxy, e.g. methoxy, lower alkoxy lower real oxy, fe.ks. 2-ethoxyethoxy, halogen, lower alkoxycarbonyl, e.g. ethoxycarbonyl, carbamoyl, cyano, amino or sulfamoyl, further lower alkanoyl lower alkyl which is optionally substituted with lower alkoxy, e.g. methoxy, amino, e.g. 2-Methoxyethyl, R^
i gruppen Ac er fenyl som eventuelt er substituert med laverealkyl, f.eks. metyl, halogenlaverealkyl, f.eks. trifluormetyl, hydroksy, laverealkoksy, f.eks. metoksy, halogen, karbamoyl, cyano og/eller sulfamoyl, videre laverealkyl som eventuelt er substituert med amino, laverealkanoylamino, f.eks. acetylamino, og karboksy eller eventuelt substituert laverealkoksykarbonyl, som laverealkoksykarbonyl, f.eks. etoksykarbonyl eller 2- eller fortrinnsvis l-(lavere-alkylkarbonyloksy)-laverealkoksykarbonyl, f. eks. etyl., n-propyl eller n-butyl, eller Ac dessuten betyr laverealkoksykarbonyl, som etoksykarbonyl, under den forutsetning at R som i 3-stilling bundet laverealkyl har 2-7 karbonatomer, og betyr f.eks. etyl, .n-propyl eller n-butyl, når Ac betyr acetylgruppen, og med den ytterligere forutsetning at R som i 3-, 4-, 5- eller 6-stilling bundet laverealkyl har 2-7 in the group Ac is phenyl which is optionally substituted with lower alkyl, e.g. methyl, halolower alkyl, e.g. trifluoromethyl, hydroxy, lower alkoxy, e.g. methoxy, halogen, carbamoyl, cyano and/or sulfamoyl, further lower alkyl which is optionally substituted with amino, lower alkanoylamino, e.g. acetylamino, and carboxy or optionally substituted lower alkoxycarbonyl, such as lower alkoxycarbonyl, e.g. ethoxycarbonyl or 2- or preferably 1-(lower alkylcarbonyloxy)-lower oxycarbonyl, e.g. ethyl., n-propyl or n-butyl, or Ac also means lower alkoxycarbonyl, such as ethoxycarbonyl, under the condition that R as lower alkyl bound in the 3-position has 2-7 carbon atoms, and means e.g. ethyl, .n-propyl or n-butyl, when Ac means the acetyl group, and with the further proviso that R as a 3-, 4-, 5- or 6-position bonded lower alkyl has 2-7
karbonatomer, og f.eks. betyr forannevnte etyl, n-propyl eller n-butyl, dersom Ac er benzoylgruppen, som racematblandinger, racemater, optiske antipoder eller deres salter. carbon atoms, and e.g. means the aforementioned ethyl, n-propyl or n-butyl, if Ac is the benzoyl group, as racemate mixtures, racemates, optical antipodes or their salts.
Oppfinnelsen gjelder spesielt fremgangsmåte for fremstilling av nye forbindelser med formel I, hvor n står for 1, og R betyr laverealkyl, f.eks. metyl, laverealkoksylaverealkyl, f.eks. 2-metoksyetyl, R^i gruppen Ac er fenyl som eventuelt er substituert med laverealkyl, f.eks. metyl, halogenlaverealkyl, f.eks. trifluormetyl, hydroksy, laverealkoksy, f.eks. metoksy, halogen, karbamoyl, cyano og/eller sulfamoyl, videre laverealkyl som eventuelt er substituert med amino, laverealkanoylamino, f.eks. acetylamino, og karboksy eller eventuelt substituert laverealkoksykarbonyl, som laverealkoksykarbonyl, f.eks. etoksykarbonyl eller 2- eller fortrinnsvis 1-(laverealkylkarbonyloksy)-laverealkoksykarbonyl, f.eks. etyl, n-propyl eller n-butyl, eller Ac dessuten er laverealkoksykarbonyl, som etoksykarbonyl, under den forutsetning at R som i 3-stilling bundet laverealkyl har 2-7 karbonatomer, og f.eks. betyr etyl, n-propyl eller n-butyl, når Ac betyr acetylgruppen, og med den ytterligere forutsetning at R som i 3-, 4-, 5- eller 6-stilling bundet laverealkyl har 2-7 karbonatomer og f.eks. betyr forannevnte etyl, n-propyl eller n-butyl, dersom Ac er benzoylgruppen, som racematblandinger, racemater, optiske antipoder eller deres salter. The invention relates in particular to methods for the preparation of new compounds of formula I, where n stands for 1, and R means lower alkyl, e.g. methyl, lower alkyl lower alkyl, e.g. 2-methoxyethyl, R^ in the group Ac is phenyl which is optionally substituted with lower alkyl, e.g. methyl, halolower alkyl, e.g. trifluoromethyl, hydroxy, lower alkoxy, e.g. methoxy, halogen, carbamoyl, cyano and/or sulfamoyl, further lower alkyl which is optionally substituted with amino, lower alkanoylamino, e.g. acetylamino, and carboxy or optionally substituted lower alkoxycarbonyl, such as lower alkoxycarbonyl, e.g. ethoxycarbonyl or 2- or preferably 1-(lower alkylcarbonyloxy)-lower oxycarbonyl, e.g. ethyl, n-propyl or n-butyl, or Ac is also lower alkoxycarbonyl, such as ethoxycarbonyl, under the condition that R as lower alkyl bound in the 3-position has 2-7 carbon atoms, and e.g. means ethyl, n-propyl or n-butyl, when Ac means the acetyl group, and with the additional proviso that R as a lower alkyl bound in the 3-, 4-, 5- or 6-position has 2-7 carbon atoms and e.g. means the aforementioned ethyl, n-propyl or n-butyl, if Ac is the benzoyl group, as racemate mixtures, racemates, optical antipodes or their salts.
Oppfinnelsen gjelder spesielt fremgangsmåte for fremstilling av nye forbindelser med formel I, hvor n står for 1 og R The invention relates in particular to methods for the preparation of new compounds of formula I, where n stands for 1 and R
er laverealkyl, f.eks. n-butyl, videre laverealkoksylaverealkyl, f.eks. 3-metoksy-n-propyl og R^ i gruppen Ac betyr laverealkyl som fortrinnsvis er substituert i w-stilling med karboksy, eller laverealkoksykarbonyl, f.eks. etoksykarbonyl, videre 2- eller fortrinnsvis 1-(laverealkylkarbo-nyloksy ) -laverealkoksykarbonyl , f.eks. pivalyl-karbonyloksy-metoksykarbonyl, eller karbamoyl, f.eks. etyl eller n-propyl, som racematblandinger, racemater, optiske antipoder, eller is lower alkyl, e.g. n-butyl, further lower alkyl lower alkyl, e.g. 3-methoxy-n-propyl and R^ in the group Ac means lower alkyl which is preferably substituted in the w-position with carboxy, or lower alkoxycarbonyl, e.g. ethoxycarbonyl, further 2- or preferably 1-(lower alkylcarbonyloxy)-lower oxycarbonyl, e.g. pivalyl-carbonyloxy-methoxycarbonyl, or carbamoyl, e.g. ethyl or n-propyl, as racemate mixtures, racemates, optical antipodes, or
deres salter, spesielt deres farmasøytisk anvendbare salter . their salts, especially their pharmaceutically acceptable salts.
Oppfinnelsen gjelder spesielt fremgangsmåte for fremstilling av nye forbindelser med formel I, hvor n står for 1 The invention relates in particular to methods for the production of new compounds of formula I, where n stands for 1
og R er i 5-stilling bundet laverealkyl, f.eks. n-butyl, videre laverealkoksylaverealkyl, f.eks. 3-metoksy-n-propyl, og R^i gruppen Ac er n-propyl som er substituert i to-stilling med amino eller i første rekke med laverealkanoylamino, f.eks. acetylamino, og med karboksy eller laverealkoksykarbonyl, f.eks. etoksykarbonyl, videre 1-(laverealkylkarbonyl-oksy)-laverealkoksykarbonyl, f.eks. pivalyl-karbonyloksy-metoksykarbonyl, hvorved en forbindelse med en gruppe R^and R is in the 5-position bonded lower alkyl, e.g. n-butyl, further lower alkyl lower alkyl, e.g. 3-methoxy-n-propyl, and R^ in the group Ac is n-propyl which is substituted in the two position with amino or primarily with lower alkanoylamino, e.g. acetylamino, and with carboxy or lower alkoxycarbonyl, e.g. ethoxycarbonyl, further 1-(lower alkylcarbonyloxy)-lower oxycarbonyl, e.g. pivalyl-carbonyloxy-methoxycarbonyl, whereby a compound with a group R 1
som er definert på denne måten, fortrinnsvis foreligger i optisk aktiv form, spesielt i L-formen, eller deres salter, spesielt deres farmasøytisk anvendbare salter. which are defined in this way, preferably present in optically active form, especially in the L-form, or their salts, especially their pharmaceutically usable salts.
Oppfinnelsen gjelder spesielt fremgangsmåte for fremstilling av de nye forbindelsene med formel I som er beskrevet i eksemplene. The invention relates in particular to methods for the preparation of the new compounds of formula I which are described in the examples.
De nye forbindelsene med formel I fremstilles på i og for seg kjent måte. De kan oppnås ved at en forbindelse med formelen The new compounds of formula I are prepared in a manner known per se. They can be obtained by a compound with the formula
omsettes med en forbindelse med formelen is reacted with a compound with the formula
eller et reaksjonsdyktig derivat av en slik karboksylsyre, eller med et reaksjonsdyktig derivat av en monoester eller et monoamid av karbonsyre (IV), og om ønsket omdannes en således oppnådd forbindelse med formel I til en annen for- or a reactive derivative of such a carboxylic acid, or with a reactive derivative of a monoester or a monoamide of carboxylic acid (IV), and if desired, a thus obtained compound of formula I is converted into another form
bindelse med formel I, og/eller om ønsket, oppdeles en oppnådd racematblanding i racematene, eller et oppnådd racemat i de optiske antipodene, og/eller om ønsket, over-føres en oppnådd fri forbindelse med formel I til et salt eller et oppnådd salt til en fri forbindelse eller et annet salt. bond with formula I, and/or if desired, an obtained racemate mixture is split into the racemates, or an obtained racemate into the optical antipodes, and/or if desired, an obtained free compound with formula I is transferred to a salt or an obtained salt to a free compound or another salt.
Reaksjonsdyktige derivater av de karboksylsyrer som er definert med formel III, er f.eks. syreanhydrider, eksempelvis syreanhydrider som er dannet ved intramolekylær ringslutning av dikarboksylsyrer som omfattes av formel III, f.eks. tilsvarende substituert glutarsyreanhydrid, videre blandede syreanhydrider, f.eks. slike med halogenhydrogensyrer, som kloridene eller bromidene, eller med f.eks. laverealkankarboksylsyrer, som eddiksyre eller propionsyre, lavere-alkoksyalkankarboksylsyrer, som 2-metoksyeddiksyre, videre azidene, cyanidene eller amidene av slike karboksylsyrer. Reaksjonsdyktige derivater av karboksylsyrer med formel III er spesielt estere, f.eks. laverealkyl-, som metyl- eller tert-butylestere, videre aktiverte estere, f.eks. med cyan-metanol, N-hydroksysuccinimid eller N-hydroksybenztriazol, videre estere som er dannet med aryllaverealkanoler, f.eks. benzylalkohol som eventuelt er substituert med laverealkyl, f.eks. metyl eller laverealkoksy, f.eks. metoksy, eller fenoler, som eventuelt er aktivert med egnede substanser, f.eks. med halogen, f.eks. 4-halogen, som 4-klor, laverealkoksy, f.eks. 4-laverealkoksy som 4-metoksy, 4-nitro-eller 2,4-dinitro, som f.eks. 4-klorfenol, 2,3,4,5,6-penta-klorfenol, 4-metoksyfenol, 4-nitro- eller 2,4-dinitrofenol, videre estere som dannes med cykloalkanoler, som f.eks. cyklopentanol eller.cykloheksanol, som eventuelt kan være substituert med laverealkyl, f.eks. metyl. Reaksjonsdyktige derivater av monoestere eller monoamider av karbonsyren er f.eks. halogenidene, f.eks. kloridene eller bromidene derav. Omsetningen gjennomføres på i og for seg kjent måte i fravær eller nærvær av et løsningsmiddel eller løsningsmiddelblan-ding og, om nødvendig, under avkjøling eller oppvarming, i et åpent eller lukket kar og/eller i en inert gassatmosfære, f.eks. under nitrogen. Omsetningen mellom frie karboksylsyrer med formel III og forbindelser med formel II foregår om nødvendig i nærvær av en sur, vannavspaltende katalysator, som en protonsyre, f.eks. klorhydrogen-, bromhydrogen-, svovel-, fosfor- eller borsyre, benzensulfon- eller toluensulfonsyre, eller en Lewis-syre, f.eks. bortrifluorid-eterat, om nødvendig under destillativ, f.eks. azeotrop, fjerning av det vann som frigjøres ved reaksjonen. Videre kan omsetningen også gjennomføres i nærvær av vannbindende kondensasjonsmidler, som egnet substituerte karbodiimider, f.eks. N,N'-dietyl-, N,N'-dicykloheksyl- eller N-etyl-N'-(3-dimetylaminopropyl)-karbodiimid, i inerte organiske løsningsmidler. Blandede anhydrider, spesielt syrehaloge-nider, omsettes eksempelvis i nærvær av syrebindende midler, f.eks. organiske, spesielt tertiære nitrogenbaser, som trietylamin, etyldiisopropylamin eller pyridin, eller alko-holater, f.eks. alkalimetall-laverealkanolater, f.eks. natriummetylat, eller også uorganiske baser, f.eks. alkalimetall- eller jordalkalimetallhydroksyder eller -karbonater, som natrium-, kalium- eller kalsiumhydroksyd henholdsvis--karbonat. Reactive derivatives of the carboxylic acids defined by formula III are e.g. acid anhydrides, for example acid anhydrides which are formed by intramolecular ring closure of dicarboxylic acids which are covered by formula III, e.g. similarly substituted glutaric anhydride, further mixed acid anhydrides, e.g. those with hydrohalic acids, such as the chlorides or bromides, or with e.g. lower alkane carboxylic acids, such as acetic or propionic acid, lower alkoxyalkane carboxylic acids, such as 2-methoxyacetic acid, further the azides, cyanides or amides of such carboxylic acids. Reactive derivatives of carboxylic acids of formula III are especially esters, e.g. lower alkyl, such as methyl or tert-butyl esters, further activated esters, e.g. with cyano-methanol, N-hydroxysuccinimide or N-hydroxybenztriazole, further esters formed with aryl lower alkanols, e.g. benzyl alcohol which is optionally substituted with lower alkyl, e.g. methyl or lower alkoxy, e.g. methoxy, or phenols, which are optionally activated with suitable substances, e.g. with halogen, e.g. 4-halogen, such as 4-chloro, lower alkoxy, e.g. 4-lower oxy such as 4-methoxy, 4-nitro or 2,4-dinitro, such as e.g. 4-chlorophenol, 2,3,4,5,6-penta-chlorophenol, 4-methoxyphenol, 4-nitro- or 2,4-dinitrophenol, further esters which are formed with cycloalkanols, such as e.g. cyclopentanol or cyclohexanol, which may optionally be substituted with lower alkyl, e.g. methyl. Reactive derivatives of monoesters or monoamides of the carbonic acid are e.g. the halides, e.g. the chlorides or bromides thereof. The reaction is carried out in a manner known per se in the absence or presence of a solvent or solvent mixture and, if necessary, during cooling or heating, in an open or closed vessel and/or in an inert gas atmosphere, e.g. under nitrogen. The reaction between free carboxylic acids of formula III and compounds of formula II takes place if necessary in the presence of an acidic, water-splitting catalyst, such as a protonic acid, e.g. hydrochloric, hydrobromic, sulphurous, phosphoric or boric acid, benzenesulphonic or toluenesulphonic acid, or a Lewis acid, e.g. boron trifluoride etherate, if necessary under distillate, e.g. azeotrope, removal of the water released by the reaction. Furthermore, the reaction can also be carried out in the presence of water-binding condensation agents, such as suitably substituted carbodiimides, e.g. N,N'-diethyl-, N,N'-dicyclohexyl- or N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide, in inert organic solvents. Mixed anhydrides, especially acid halides, react for example in the presence of acid binding agents, e.g. organic, especially tertiary nitrogen bases, such as triethylamine, ethyldiisopropylamine or pyridine, or alcohols, e.g. alkali metal lower-area anolates, e.g. sodium methylate, or also inorganic bases, e.g. alkali metal or alkaline earth metal hydroxides or carbonates, such as sodium, potassium or calcium hydroxide respectively--carbonate.
Omsetningene med estere, f.eks. slike av nevnt art, eller med reaksjonsdyktige estere, f.eks. cyanmetyl- eller penta-klorfenyl- eller N-hydroksysuccinimidestere, gjennomføres eksempelvis i et løsningsmiddel som er inert overfor reak-deltagerne ved forhøyet eller senket temperatur. The reactions with esters, e.g. those of the aforementioned kind, or with reactive esters, e.g. cyanomethyl or penta-chlorophenyl or N-hydroxysuccinimide esters are carried out, for example, in a solvent which is inert towards the reactants at elevated or lowered temperatures.
Omsetningene med reaksjonsdyktige derivater av monoestere eller monoamider av.karbonsyre, f.eks. halogenidene, foregår vanligvis i et løsningsmiddel som ikke deltar i reaksjonen, under avkjøling eller oppvarming, eventuelt i nærvær av et syrebindende middel, f.eks. en organisk base, f.eks. en nitrogenbase, som trietylamin, eller et overskudd av utgangsmateriale med formel II, eller i nærvær av en uorganisk base, som et alkalimetall- eller jordalkalimetallkarbonat eller The reactions with reactive derivatives of monoesters or monoamides of carbonic acid, e.g. the halides, usually takes place in a solvent that does not participate in the reaction, during cooling or heating, possibly in the presence of an acid-binding agent, e.g. an organic base, e.g. a nitrogen base, such as triethylamine, or an excess of starting material of formula II, or in the presence of an inorganic base, such as an alkali metal or alkaline earth metal carbonate or
-hydroksyd, som natrium- eller magnesiumkarbonat eller -hydroksyd. Disse reaksjoner foretas på vanlig måte. Utgangsstoffer med formel II er kjente eller kan fremstilles på i og for seg kjent måte. således kan disse forbindelser oppnås ved at f.eks. en forbindelse med formelen -hydroxide, such as sodium or magnesium carbonate or -hydroxide. These reactions are carried out in the usual way. Starting substances with formula II are known or can be prepared in a manner known per se. thus, these compounds can be obtained by e.g. a connection with the formula
hvor X betyr en egnet avgangsgruppe, f.eks. eventuelt reaksjonsdyktig forestret hydroksy, som halogen, f.eks. klor eller brom, eller en hydroksygruppe som er forestret med en organisk sulfonsyre, f.eks. en alifatisk eller aromatisk, som en laverealkylsulfonsyre, f.eks. metansulfonsyre eller en aromatisk, som en eventuelt substituert, som laverealkylert, og/eller halogenert arylsulfonsyre, f.eks. benzosyre, eller laverealkoksy som metoksy, eventuelt foretret merkapto, som merkapto eller laverealkyltio, laverealkylsulfinyl, where X means a suitable departure group, e.g. optionally reactive esterified hydroxy, such as halogen, e.g. chlorine or bromine, or a hydroxy group which is esterified with an organic sulphonic acid, e.g. an aliphatic or aromatic, such as a lower alkyl sulphonic acid, e.g. methanesulfonic acid or an aromatic, as an optionally substituted, as lower alkylated, and/or halogenated arylsulfonic acid, e.g. benzoic acid, or lower alkoxy such as methoxy, optionally etherified mercapto, such as mercapto or lower alkylthio, lower alkylsulfinyl,
som metylsulfinyl, laverealkylsulfonyl, som metylsulfonyl eller resten -SO^H eller gruppen -NH-NC^, omsettes med vannfritt hydrazin eller dets hydrat eller med hydrazin som har opptil tre beskyttelsesgrupper som substituenter, as methylsulfonyl, lower alkylsulfonyl, as methylsulfonyl or the residue -SO^H or the group -NH-NC^, is reacted with anhydrous hydrazine or its hydrate or with hydrazine having up to three protecting groups as substituents,
og deretter avspaltes eventuelt tilstedeværende beskyttelsesgrupper og erstattes med hydrogen. and then any protective groups present are split off and replaced with hydrogen.
Beskyttelsesgrupper er f.eks. slike som avspalter og erstattes med hydrogen, ved hjelp av reduksjon innbefattet hydrogenolyse, eller ved hjelp av solvolyse, f.eks. hydrolyse, f.eks. aryl-laverealkylgrupper som en fenyllaverealkylgruppe, f.eks. benzyl, som i den aromatiske delen eventuelt er substituert med laverealkyl, som metyl, halogen, som klor, laverealkoksy, som metoksy, og/eller nitro. Omsetningen med hydrazin eller dets hydrat så vel som avspaltningen av eventuelt tilstedeværende beskyttelsesgrupper foregår på vanlig måte ved for-høyet eller senket temperatur, i nær- eller fravær av et ytterligere syrebindende middel, f.eks. en organisk eller uorganisk base, vanligvis dog ved hjelp av et overskudd av hydrazinforbindelser, eventuelt i nærvær av et løsnings-middel, f.eks. etanol, i åpent eller lukket kar og/eller i en beskyttelsesgassatmosfære, f.eks. nitrogen. Foreligger gruppen X i en forbindelse med formel Ila som fri hydroksygruppe, så foregår omsetningen med en hydrazinforbindelse udner skjerpede reaksjonsbetingelser, f.eks. ved forhøyet temperatur. På den annen side kan nærvær av et middel som begunstiger vannavspaltningen, f.eks. et karbodiimid, som N,N-dicykloheksylkarbodiimid være fordelaktig. Protection groups are e.g. such as split off and replaced with hydrogen, by means of reduction including hydrogenolysis, or by means of solvolysis, e.g. hydrolysis, e.g. aryl lower alkyl groups such as a phenyl lower alkyl group, e.g. benzyl, which in the aromatic part is optionally substituted with lower alkyl, such as methyl, halogen, such as chlorine, lower alkoxy, such as methoxy, and/or nitro. The reaction with hydrazine or its hydrate as well as the cleavage of any protective groups present takes place in the usual way at an elevated or lowered temperature, in the presence or absence of a further acid-binding agent, e.g. an organic or inorganic base, usually using an excess of hydrazine compounds, possibly in the presence of a solvent, e.g. ethanol, in an open or closed vessel and/or in a protective gas atmosphere, e.g. nitrogen. If the group X is present in a compound of formula IIa as a free hydroxy group, then the reaction with a hydrazine compound takes place under stricter reaction conditions, e.g. at elevated temperature. On the other hand, the presence of an agent which favors the splitting off of water, e.g. a carbodiimide, such as N,N-dicyclohexylcarbodiimide would be advantageous.
Utgangsstoffer med formelen II kan videre oppnås ved atStarting substances with the formula II can further be obtained by
en forbindelse med formelena connection with the formula
omsettes med hydroksylamin-O-sulfonsyre (Ile). Omsetningen foregår på vanlig måte, ved normal eller forhøyet temperatur, i fra- eller nærvær av et løsningsmiddel, f.eks. vann, hensiktsmessig i en beskyttelsesgassatmofære, f.eks. under nitrogen.Utgangsstoffer med formel II kan dessuten oppnås ved at nitrogruppen i en forbindelse med formelen is reacted with hydroxylamine-O-sulfonic acid (Ile). The reaction takes place in the usual way, at normal or elevated temperature, in the absence or presence of a solvent, e.g. water, suitably in a protective gas atmosphere, e.g. under nitrogen. Starting substances with formula II can also be obtained by the nitro group in a compound with the formula
reduseres til aminogruppe, reduksjonen foregår på vanlig måte, f.eks. ved hjelp av et egnet metall i surt medium, f.eks. i nærvær av en vandig mineralsyre, som svovelsyre, is reduced to an amino group, the reduction takes place in the usual way, e.g. using a suitable metal in an acidic medium, e.g. in the presence of an aqueous mineral acid, such as sulfuric acid,
men spesielt i alkalisk medium, f.eks. i en vandig løsning av en base, som en uorganisk base, f.eks. natriumhydroksyd. but especially in alkaline medium, e.g. in an aqueous solution of a base, such as an inorganic base, e.g. sodium hydroxide.
Utgangsstoffer med formel lic kan i sin tur oppnås fra forbindelser med den forannevnte formel Ilb ved nitrering, på vanlig måte, f.eks. ved hjelp av salpetersyre i nærvær av konsentrert svovelsyre. Starting materials of formula 11c can in turn be obtained from compounds of the aforementioned formula Ilb by nitration, in the usual way, e.g. by means of nitric acid in the presence of concentrated sulfuric acid.
Utgangsstoffer med formelen Ila, hvor R betyr en mono-eller bicyklisk heteroarylgruppe R dannes som beskrevet i det etterfølgende ved forbindelser med formel VI, i en forbindelse med formelen Starting substances of the formula IIa, where R means a mono- or bicyclic heteroaryl group R is formed as described below by compounds of the formula VI, in a compound of the formula
hvor R_ angir en substituent som er i stand til dannelse av en mono- eller bicyklisk heteroarylrest R, og eventuelt tilstedeværende beskyttelsesgrupper avspaltes og erstattes med hydrogen. Således kan eksempelvis en forbindelse med formel Ild hvor R^er en formylgruppe, omsettes med en 1,2-dikarbonylforbindelse med formelen Via og ammoniakk til en forbindelse med formel Ild på den måte som er beskrevet der, hvori en imidazolylrest står istedenfor gruppen R£, som er knyttet i sin 2-stilling til pyridinringen. where R_ denotes a substituent capable of forming a mono- or bicyclic heteroaryl residue R, and any protective groups present are removed and replaced with hydrogen. Thus, for example, a compound of formula Ild where R^ is a formyl group can be reacted with a 1,2-dicarbonyl compound of formula Via and ammonia to a compound of formula Ild in the manner described there, in which an imidazolyl residue stands in place of the group R£ , which is linked in its 2-position to the pyridine ring.
Reaksjonsdyktige derivater av utgangsstoffer med formel III kan oppnås på vanlig måte. Således gir omsetningen Reactive derivatives of starting substances of formula III can be obtained in the usual way. Thus the turnover gives
med et middel som virker halogenerende på egnet måte, f.eks. tionylklorid, det tilsvarende karboksylsyreklorid, mens forestringen med en alkohol, f.eks. en usubstituert eller substituert laverealkanol, eller med N-hydroksysuccinimid eller N-hydroksybenztriazol eller omsetningen med egnede diazoforbindelser, som usubstituerte eller substituerte diazoalkaner, fører til tilsvarende karboksylsyreestere med formel III. with an agent that has a halogenating effect in a suitable way, e.g. thionyl chloride, the corresponding carboxylic acid chloride, while the esterification with an alcohol, e.g. an unsubstituted or substituted lower alkanol, or with N-hydroxysuccinimide or N-hydroxybenztriazole or the reaction with suitable diazo compounds, such as unsubstituted or substituted diazoalkanes, leads to corresponding carboxylic acid esters of formula III.
Slike forbindelser kan likeledes oppnås, når det som utgangsstoffer anvendes salter, spesielt alkalimetall- eller jord-alkalimetallsalter av frie karboksylsyrer og disse behandles med reaksjonsdyktige estere av alkoholer, som usubstituerte eller substituerte laverealkanoler, som tislvarende haloge-nider f.eks. klorider, bromider eller jodider, eller organiske sulfonsyreestere, f.eks. laverealkansulfonsyre- eller arensulfonsyreestere, som metansulfonsyre- hhv. p-toluen-sulfonsyreestere, eller når tilsvarende hydrolyserbare iminoestere, som tilsvarende iminolaverealkylestere hydrolyseres til esterne. Such compounds can also be obtained when salts are used as starting materials, especially alkali metal or alkaline earth metal salts of free carboxylic acids and these are treated with reactive esters of alcohols, such as unsubstituted or substituted lower alkanols, such as reducing halides, e.g. chlorides, bromides or iodides, or organic sulphonic acid esters, e.g. lower alkanesulphonic acid or arenesulphonic acid esters, such as methanesulphonic acid or p-toluene sulfonic acid esters, or when corresponding hydrolyzable imino esters, such as corresponding imino lower alkyl esters are hydrolyzed to the esters.
Karboksylsyreazider eller -cyanider med formel III kan oppnås på vanlig måte ved omsetning av et karboksylsyre-halogenid, f.eks. kloridet med et salt av nitrogenhydrogen-syre eller cyanhydrogensyfe, f.eks. natriumsaltet, hensiktsmessig i nærvær av et inert løsningsmiddel, som benzen. Carboxylic acid azides or cyanides of formula III can be obtained in the usual way by reacting a carboxylic acid halide, e.g. the chloride with a salt of nitrous acid or hydrocyanic acid, e.g. the sodium salt, conveniently in the presence of an inert solvent, such as benzene.
De nye forbindelsene med formel I kan likeledes oppnåsThe new compounds of formula I can also be obtained
ved at i en forbindelse med formelenin that in a connection with the formula
hvor X-^ og X2hver betyr hydrogen eller en substituent som kan erstattes med hydrogen eller X-^eller X2sammen betyr en toverdig rest som kan erstattes med to hydrogenatomer, og/eller funksjonelle grupper som er tilstede i gruppene R og Ac eventuelt foreligger i beskyttet form under den forutsetning at minst en av restene X-^ ogX2 where X-^ and X 2 each means hydrogen or a substituent that can be replaced by hydrogen or X-^ or X 2 together means a divalent residue that can be replaced by two hydrogen atoms, and/or functional groups that are present in the groups R and Ac are optionally present in protected form under the condition that at least one of the residues X-^ and X2
er forskjellig fra hydrogen, eller minst X^og X2sammen utgjør en toverdig rest som kan erstattes med to hydrogenatomer, eller minst tilstedeværende funksjonelle grupper i gruppen R og/eller Ac foreligger i beskyttet form, eller is different from hydrogen, or at least X^ and X2 together constitute a divalent residue that can be replaced by two hydrogen atoms, or at least the present functional groups in the group R and/or Ac are in protected form, or
i et salt derav, erstattes de grupper X-^, X2eller X^og X2sammen som er forskjellige fra hydrogen, med hydrogenatomer, og/eller i en gruppe R og/eller Ac avspaltes de beskyttelsesgrupper som er bundet til en eller flere funksjonelle grupper og erstattes med hydrogen, og om ønsket gjennomføres de ytterligere fremgangsmåtetrinn som er beskrevet i anslutning til den første fremgangsmåten. in a salt thereof, the groups X-^, X2 or X^ and X2 together which are different from hydrogen are replaced by hydrogen atoms, and/or in a group R and/or Ac the protective groups attached to one or more functional groups are removed and is replaced with hydrogen, and if desired, the further method steps described in connection with the first method are carried out.
Beskyttede funksjonelle grupper i en rest R og/eller AcProtected functional groups in a residue R and/or Ac
er f.eks. beskyttede hydroksy-, amino-, merkapto- eller karboksylsyregrupper, hvorved de sistnevnte foreligger som estere eller imidoestere, hvis imidogrupper kan erstattes med et oksygenatom ved hjelp av hydrolyse og estergrup-pen kan spaltes til karboksylsyregruppen. Avspaltningen av. gruppene X-^ og X2eller X-^og X2sammen så vel som beskyttelsesgrupper som står i en rest R og/eller Ac til funksjonelle grupper, -f.eks. til hydroksy- og/eller amino-eller karboksylsyregrupper, foretas ved hjelp av solvolyse, som hydrolyse, alkoholyse eller acidolyse, eller ved hjelp av reduksjon innbefattet hydrogenolyse. is e.g. protected hydroxy, amino, mercapto or carboxylic acid groups, whereby the latter are present as esters or imidoesters, whose imido groups can be replaced with an oxygen atom by means of hydrolysis and the ester group can be cleaved to the carboxylic acid group. The spin-off of. the groups X-^ and X2 or X-^ and X2 together as well as protective groups standing in a residue R and/or Ac to functional groups, -e.g. to hydroxy and/or amino or carboxylic acid groups, is carried out by means of solvolysis, such as hydrolysis, alcoholysis or acidolysis, or by means of reduction including hydrogenolysis.
En særlig egnet, avspaltbar gruppe X^eller X2, eller en hydroksy-, merkapto- eller amino-beskyttelsesgruppe i en rest R og/eller Ac er i første rekke en hydrogenolytisk avspaltbar a-aryl-laverealkylgruppe, som en eventuelt substituert 1-polyfenyl-laverealkyl- eller 1-fenyllaverealkylgruppe, f.eks. benzhydryl eller trityl, hvori substituenter, særlig i fenyldélen, f.eks. kan være laverealkyl, som metyl, eller laverealkoksy som metoksy, og i første rekke benzyl. En gruppe X^og X2så vel som hydroksy-, merkapto- og/eller amino-beskyttelsesgrupper i en rest R og/eller Ac kan også være en solvolytisk, som hydrolytisk eller acidolytisk, videre en' reduktiv, innbefattet hydrogenolytisk, avspaltbar rest, særlig en tilsvarende acylrest, som acylresten fra en organisk karboksylsyre, f.eks. laverealkanoyl, som acetyl, eller aroyl, som benzoyl, videre acylresten fra en halvester av karbonsyre, som laverealkoksykarbonyl, f.eks. metoksykarbonyl, etoksykarbonyl eller tert-butyloksykarbo-nyl, 2-halogenlaverealkoksykarbonyl, f.eks. 2,2,2-triklor-etoksykarbonyl eller 2-jod-etoksykarbonyl, eventuelt substituert 1-fenyllaverealkoksykarbonyl, f.eks. benzyloksy-karbonyl eller difenylmetoksykarbonyl, eller aroylmetoksy-karbonyl, f.eks. fenacyloksykarbonyl, videre en eventuelt substituert 1-polyfenyl-lavérealkylgruppe, f.eks. som ovenfor angitt, og i første rekke trityl. A particularly suitable, cleavable group X₂ or X₂, or a hydroxy, mercapto or amino protecting group in a residue R and/or Ac is primarily a hydrogenolytically cleavable α-aryl-lower alkyl group, such as an optionally substituted 1-polyphenyl -lower alkyl or 1-phenyl lower alkyl group, e.g. benzhydryl or trityl, in which substituents, especially in the phenyl part, e.g. can be lower alkyl, such as methyl, or lower alkoxy such as methoxy, and primarily benzyl. A group X^ and X 2 as well as hydroxy, mercapto and/or amino protecting groups in a residue R and/or Ac can also be a solvolytic, such as hydrolytic or acidolytic, further a' reductive, including hydrogenolytic, cleavable residue, in particular a corresponding acyl residue, such as the acyl residue from an organic carboxylic acid, e.g. lower alkanoyl, such as acetyl, or aroyl, such as benzoyl, further the acyl residue from a half-ester of carboxylic acid, such as lower alkoxycarbonyl, e.g. methoxycarbonyl, ethoxycarbonyl or tert-butyloxycarbonyl, 2-halolower oxycarbonyl, e.g. 2,2,2-trichloro-ethoxycarbonyl or 2-iodo-ethoxycarbonyl, optionally substituted 1-phenyl lower oxycarbonyl, e.g. benzyloxycarbonyl or diphenylmethoxycarbonyl, or aroylmethoxycarbonyl, e.g. phenacyloxycarbonyl, further an optionally substituted 1-polyphenyl-lower alkyl group, e.g. as stated above, and primarily trityl.
En avspaltbar rest som er dannet av X-^og X~sammen, erA cleavable residue formed by X-^and X~ together is
i første rekke en hydrogenolytisk avspaltbar gruppe, som eventuelt substituert 1-fenyl-laverealkyliden, hvori substituenter, særlig i fenyldelen, f.eks. kan være laverealkyl eller laverealkoksy, og spesielt benzyliden, eller cykloalkyliden, f.eks. cyklopentyliden eller cykloheksyliden. primarily a hydrogenolytically cleavable group, such as optionally substituted 1-phenyl-lower alkylidene, in which substituents, particularly in the phenyl part, e.g. can be lower alkyl or lower alkoxy, and especially benzylidene, or cycloalkylidene, e.g. cyclopentylidene or cyclohexylidene.
Beskyttede karboksylsyregrupper som foreligger som estere-eller imidoestere, er spesielt slike, som spaltes ved hjelp av de ovenfor beskrevne metoder, spesielt ved hjelp av reduksjon innbefattet hydrogenolyse i den grunnleggende karboksylsyren og den tilsvarende alkoholen. Som ester-bestanddeler i de dertil svarende egnede beskyttelsesgrup-pene, kommer f.eks. i betraktning hydrogenolytisk avspaltbare a-aryllaverealkoksygrupper, som en eventuelt substituert 1-polyfenyllaverealkyl eller 1-fenyllaverealkylgruppe, f.eks. benzhydryl eller trityl, hvori substituenter, særlig i fenyldelen f.eks. kan være laverealkyl, som metyl, laverealkoksy, f.eks. metoksy, og/eller halogen, og i første rekke benzyl. Protected carboxylic acid groups that exist as esters or imidoesters are especially those that are cleaved using the methods described above, especially by means of reduction including hydrogenolysis in the basic carboxylic acid and the corresponding alcohol. As ester components in the correspondingly suitable protective groups, e.g. in consideration hydrogenolytically cleavable α-aryl lower alkyl groups, such as an optionally substituted 1-polyphenyl lower alkyl or 1-phenyl lower alkyl group, e.g. benzhydryl or trityl, in which substituents, especially in the phenyl part, e.g. can be lower alkyl, such as methyl, lower alkoxy, e.g. methoxy, and/or halogen, and primarily benzyl.
Anvendbare utgangsstoffer i form av salter anvendes i første rekke i form av syreaddisjonssalter, f.eks. med mineralsyrer, så vel som med organiske syrer. Usable starting materials in the form of salts are primarily used in the form of acid addition salts, e.g. with mineral acids, as well as with organic acids.
Hydrogenolytisk avspaltbare rester X-^eller X2, spesielt eventuelt substituerte 1-fenyllaverealkylgrupper, videre også egnede acylgrupper, som eventuelt substituert 1-fenyl laverealkoksykarbonyl, så vel som eventuelt substituerte 1-fenyl-laverealkylidengrupper som er dannet sammen med gruppene X-^ og X£, så vel som hydroksy-, merkapto- og/eller amino-beskyttelsesgrupper av denne art som foreligger i en gruppe R og/eller Ac, videre a-aryllaverealkyl som foreligger i karboksylsyreestere eller -imidoestere som avspaltbar gruppe, kan avspaltes ved behandling med katalytisk aktivert hydrogen, f.eks. med hydrogen i nærvær av en katalysator, som en egnet edelmetallkatalysator, f.eks. palladium eller platina. Hydrogenolytically cleavable residues X-^ or X2, especially optionally substituted 1-phenyl lower alkyl groups, further also suitable acyl groups, such as optionally substituted 1-phenyl lower alkoxycarbonyl, as well as optionally substituted 1-phenyl-lower alkylidene groups which are formed together with the groups X-^ and X £, as well as hydroxy, mercapto and/or amino protecting groups of this type present in a group R and/or Ac, further α-aryl lower alkyl present in carboxylic acid esters or -imido esters as a cleavable group, can be cleaved by treatment with catalytically activated hydrogen, e.g. with hydrogen in the presence of a catalyst, such as a suitable noble metal catalyst, e.g. palladium or platinum.
Hydrolytisk avspaltbare grupper X-^og X2 / som acylresterHydrolytically cleavable groups X-^ and X2 / as acyl residues
av organiske karboksylsyrer, f.eks. laverealkanoyl, og av halvestere av karbonsyre, f.eks. laverealkoksykarbonyl, videre f.eks. tritylrester, så vel som laverealkyliden-, 1-fenyl-laverealkyliden- eller cykloalkylidengrupper som er dannet sammen med restene X^og X2, så vel som beskyttelsesgrupper av denne art som i en rest R og/eller Ac står til funksjonelle grupper, som til hydroksy-, merkapto- og/eller aminogrupper, kan avhengig av arten av slike rester avspaltes ved behandling med vann under sure eller basiske betingelser, f.eks. i nærvær av en mineralsyre, som klorhydrogen- eller svovelsyre, eller et alkalimetall- eller jord-alkalimetallhydroksyd eller -karbonat eller et amin, som isopropylamin. of organic carboxylic acids, e.g. lower alkanoyl, and of half-esters of carboxylic acid, e.g. lower alkoxycarbonyl, further e.g. trityl residues, as well as lower alkylidene, 1-phenyl-lower alkylidene or cycloalkylidene groups which are formed together with the residues X^ and X 2 , as well as protective groups of this kind which in a residue R and/or Ac stand for functional groups, such as hydroxy, mercapto and/or amino groups, depending on the nature of such residues, can be split off by treatment with water under acidic or basic conditions, e.g. in the presence of a mineral acid, such as hydrochloric or sulfuric acid, or an alkali metal or alkaline earth metal hydroxide or carbonate, or an amine, such as isopropylamine.
Hydrolysen av iminoestergrupper eksempelvis til tilsvarende rester av monoestere eller monoamider av karbonsyre foregår eksempelvis ved hjelp av vannholdige mineralsyrer, som saltsyre eller svovelsyre, hvorved de imidoester-saltet, f.eks. -hydroklorider, som f.eks. oppnås ved tilsetning av klorhydrogen til nitrilet og omsetning med vannfrie alkoholer, spesielt usubstituerte eller substituerte laverealkanoler, kan hydrolyseres etter tilsetning av vann direkte til de tilsvarende estere. The hydrolysis of iminoester groups, for example, to corresponding residues of monoesters or monoamides of carbonic acid takes place, for example, with the aid of hydrous mineral acids, such as hydrochloric or sulfuric acid, whereby the imidoester salt, e.g. -hydrochlorides, such as obtained by addition of hydrogen chloride to the nitrile and reaction with anhydrous alcohols, especially unsubstituted or substituted lower alkanols, can be hydrolyzed after addition of water directly to the corresponding esters.
Acidolytisk avspaltbare rester X-^og X2 og/eller til funksjonelle grupper, f.eks. de nevnte, f.eks. til hydroksy, merkapto og/eller amin stående beskyttelsesgrupper i en rest R og/eller Ac, er spesielt visse acylrester av halvestere av karbonsyre som f.eks. tert-laverealkoksykarbonyl eller eventuelt substituerte difenylmetoksykarbonylrester, videre også en tert-laerealkylrest. Slike rester kan avspaltes f.eks. ved behandling med egnede sterke, organiske karboksylsyrer, som laverealkankarboksylsyrer som eventuelt er substituert med halogen, særlig fluor, i første rekke med trifluoreddiksyre (om nødvendig, i nærvær av et akti-verende middel, som anisol), så vel som med maursyre. Acidolytically cleavable residues X-^ and X2 and/or to functional groups, e.g. the aforementioned, e.g. to hydroxy, mercapto and/or amine standing protective groups in a residue R and/or Ac, are especially certain acyl residues of half-esters of carboxylic acid such as e.g. tert-lower oxycarbonyl or optionally substituted diphenylmethoxycarbonyl residues, further also a tert-lower alkyl residue. Such residues can be split off, e.g. by treatment with suitable strong, organic carboxylic acids, such as lower alkane carboxylic acids optionally substituted with halogen, especially fluorine, primarily with trifluoroacetic acid (if necessary, in the presence of an activating agent, such as anisole), as well as with formic acid.
Under reduktivt avspaltbare rester X^og X^og/eller beskyttelsesgrupper som står til funksjonelle grupper, f.eks. Under reductively cleavable residues X^ and X^ and/or protective groups that stand for functional groups, e.g.
de nevnte, f.eks. til hydroksy, merkapto og/eller amino,the aforementioned, e.g. to hydroxy, mercapto and/or amino,
i en rest R og/eller Ac, forstås også slike grupper, som kan avspaltes ved behandling med et kjemisk reduksjonsmiddel (spesielt med et reduserende metall eller en reduserende metallforbindelse). Slike rester er spesielt 2-halogenlaverealkoksykarbonyl eller arylmetoksykarbonyl, som kan avspaltes f.eks. ved behandling med et reduserende tung-metall, som sink eller med et reduserende tungmetallsalt, som et krom(II)salt, f.eks. -klorid eller -acetat, vanligvis i nærvær av en organisk karboksylsyre som maursyre eller eddiksyre, og av vann. in a residue R and/or Ac, such groups are also understood which can be split off by treatment with a chemical reducing agent (especially with a reducing metal or a reducing metal compound). Such residues are especially 2-halogen lower oxycarbonyl or arylmethoxycarbonyl, which can be cleaved off e.g. by treatment with a reducing heavy metal, such as zinc or with a reducing heavy metal salt, such as a chromium (II) salt, e.g. -chloride or -acetate, usually in the presence of an organic carboxylic acid such as formic or acetic acid, and of water.
Beskyttelsesgrupper, som står til funksjonelle grupper, f.eks. hydroksy-, merkapto- og/eller aminogrupper som er tilstede i en rest R og/eller Ac, tilsvarer de forannevnte grupper som er avspaltbare og kan erstattes med hydrogen, ved hjelp av de beskrevne metoder, hvorved slike grupper i løpet av den beskrevne fremgangsmåte avspaltes med andre grupper eller senere i en adskilt fremgangsmåteforholds-regel. Protecting groups, which stand for functional groups, e.g. hydroxy, mercapto and/or amino groups present in a residue R and/or Ac correspond to the aforementioned groups which are cleavable and can be replaced by hydrogen, using the described methods, whereby such groups during the described method split off with other groups or later in a separate method ratio rule.
De ovenstående reaksjoner gjennomføres vanligvis i nærvær av et løsningsmiddel, eller en løsningsmiddelblanding, hvorved egnede reaksjonsdeltagere samtidig også kan funksjo- nere som slike, og om nødvendig, under avkjøling eller oppvarming, f.eks. i et åpent eller lukket kar og/eller i en inert gassatmosfære, f.eks. nitrogen. The above reactions are usually carried out in the presence of a solvent, or a solvent mixture, whereby suitable reaction participants can also function as such, and if necessary, during cooling or heating, e.g. in an open or closed vessel and/or in an inert gas atmosphere, e.g. nitrogen.
Utgangsstoffer med formel IV kan oppnås på vanlig måte, idet en forbindelse med den forannevnte formel Ila omsettes med en forbindelse med formelen Starting substances with formula IV can be obtained in the usual way, as a compound of the aforementioned formula IIa is reacted with a compound of the formula
hvor X^, X2og Ac har de ovennevnte betydninger. Hensiktsmessig arbeides i nærvær av et kondensasjonsmiddel, eksempelvis for det tilfellet at X er en reaksjonsdyktig forestret hydroksygruppe, i nærvær av et syrebindende, f.eks. et alkalisk kondensasjonsmiddel, f.eks. en organisk base, som trietylamin, eller en uorganisk base, som et alkalikar-bonat eller -bikarbonat, som natriumkarbonat eller -bikarbonat. Dersom X i en forbindelse med formelen Ila er en fri hydroksygruppe, kan omsetningen med en forbindelse med formel IVb foregå i nærvær av et vannbindende middel, f.eks. et karbodiimid, som N,N'-dicykloheksylkarbodiimid eller N-etyl-N'-(3-dimetylaminopropyl)karbodiimid i et inert løsningsmiddel, f.eks. tetrahydrofuran. Det kan også arbeides slik at det for den beskrevne omsetning istedenfor en forbindelse med formel IVb anvendes en forbindelse med formelen where X^, X2 and Ac have the above meanings. It is expedient to work in the presence of a condensing agent, for example in the case that X is a reactive esterified hydroxy group, in the presence of an acid binder, e.g. an alkaline condensing agent, e.g. an organic base, such as triethylamine, or an inorganic base, such as an alkali carbonate or bicarbonate, such as sodium carbonate or bicarbonate. If X in a compound of formula IIa is a free hydroxy group, the reaction with a compound of formula IVb can take place in the presence of a water-binding agent, e.g. a carbodiimide, such as N,N'-dicyclohexylcarbodiimide or N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide in an inert solvent, e.g. tetrahydrofuran. It can also be worked out so that for the described reaction instead of a compound of formula IVb a compound of the formula is used
og i den oppnådde forbindelse med formel IV, som har et hydrogenatom istedenfor en gruppe Ac, innføres gruppen and in the obtained compound of formula IV, which has a hydrogen atom instead of a group Ac, the group is introduced
Ac, f.eks. under anvendelse av en tilsvarende karboksylsyre, som eventuelt foreligger som reaksjonsdyktig derivat, som halogenid eller anhydrid, eller som reaksjonsdyktig ester. Disse omsetninger foregår på vanlig måte i nærvær av et egnet inert løsningsmiddel i nær- eller fravær av et kondensasjonsmiddel-ved forhøyet eller senket temperatur og om nødvendig under en beskyttelsesgassatmosfære, som nitrogen. Ac, e.g. using a corresponding carboxylic acid, which is optionally present as a reactive derivative, as a halide or anhydride, or as a reactive ester. These reactions usually take place in the presence of a suitable inert solvent in the presence or absence of a condensing agent at elevated or lowered temperature and if necessary under a protective gas atmosphere, such as nitrogen.
De nye forbindelsene med formel I kan likeledes oppnås ved at en forbindelse med formelen The new compounds of formula I can likewise be obtained by a compound of the formula
hvor X er en egnet avgangsgruppe og R har den ovenstående betydning, omsettes med en forbindelse med formelen where X is a suitable leaving group and R has the above meaning, is reacted with a compound of the formula
hvor Ac har ovenstående betydning, og om ønsket gjennomføres de ytterligere fremgangsmåtetrinn som er beskrevet i tilslutning til den første fremgangsmåten. En egnet gruppe X er f.eks. eventuelt reaksjonsdyktig forestret hydroksy, som hydroksy, eller halogen, som klor eller brom, eller en hydroksygruppe som er forestret med en organisk sulfonsyre, f.eks. en alifatisk sulfonsyre, som en laverealkansulfonsyre, som metansulfonsyre, eller en aromatisk, som en eventuelt substituert, som laverealkylert og/eller halogenert arylsulfonsyre, f.eks. benzosyre, videre laverealkoksy, f.eks. metoksy, eventuelt foretret merkapto, som merkapto eller laverealkyltio, som metyltio, laverealkylsulfinyl, som metylsulfinyl, laverealkylsulfonyl som metylsulfonyl, nitro, resten -SO^H eller gruppen -NH-NC>2 . where Ac has the above meaning, and if desired, the further method steps described in connection with the first method are carried out. A suitable group X is e.g. optionally reactive esterified hydroxy, such as hydroxy, or halogen, such as chlorine or bromine, or a hydroxy group which is esterified with an organic sulphonic acid, e.g. an aliphatic sulfonic acid, such as a lower alkanesulfonic acid, such as methanesulfonic acid, or an aromatic, such as an optionally substituted, such as lower alkylated and/or halogenated arylsulfonic acid, e.g. benzoic acid, further lower alkoxy, e.g. methoxy, optionally preferred mercapto, such as mercapto or lower alkylthio, such as methylthio, lower alkylsulfinyl, such as methylsulfinyl, lower alkylsulfonyl such as methylsulfonyl, nitro, the residue -SO^H or the group -NH-NC>2 .
Omsetningen gjennomføres på i og for seg kjent måte, hensiktsmessig i et egnet løsningsmiddel i fra- eller nærvær av et kondensasjonsmiddel, eksempelvis, når X er en reak sjonsdyktig forestret hydroksygruppe, et syrebindende middel, som en base, f.eks. en organisk nitrogenbase, som trietylamin, eller et metallalkoholat, som et metall-laverealkanolat, f.eks. natriummetylat eller en uorganisk base, som et alkalimetall- eller jordalkalimetallkarbonat eller -hydroksyd, som natrium- eller magnesiumkarbonat. Løsningsmidler kan herved tjene som kondensasjonsmidler, dvs. akselerere omsetningen. Som løsningsmiddel av denne art som eventuelt anvendes i blanding med andre løsnings-midler, f.eks. slike av upolar karakter, kommer i første rekke slike av polar karakter i betraktning, f.eks. laverealkanoler, som metanol eller etanol, videre amider av laverealkankarboksylsyrer, f.eks. dimetylformamid, N-metyl-acetamid, N,N-dimetylacetamid, videre fosforsyreamider, The reaction is carried out in a manner known per se, suitably in a suitable solvent in the absence or presence of a condensing agent, for example, when X is a reactive esterified hydroxy group, an acid binding agent, such as a base, e.g. an organic nitrogen base, such as triethylamine, or a metal alkoxide, such as a metal lowereal alkoxide, e.g. sodium methylate or an inorganic base, such as an alkali metal or alkaline earth metal carbonate or hydroxide, such as sodium or magnesium carbonate. Solvents can thereby serve as condensation agents, i.e. accelerate turnover. As a solvent of this kind which is possibly used in a mixture with other solvents, e.g. those of a non-polar character, primarily those of a polar character come into consideration, e.g. lower alkanols, such as methanol or ethanol, further amides of lower alkane carboxylic acids, e.g. dimethylformamide, N-methyl-acetamide, N,N-dimethylacetamide, further phosphoric acid amides,
som f.eks. heksametylfosforsyretriamid, så vel som poly-metylerte urinstoffer som N,N,N<1>,N<1->tetrametylurea, så like for example. hexamethylphosphoric acid triamide, as well as poly-methylated ureas such as N,N,N<1>,N<1->tetramethylurea, so
vel som sulfolan, dessuten eventuelt laverealkylert, som N-metylert 2-pyrrolidon, videre dimetylsulfoksyd, så vel som blandinger av slike stoffer. Dersom X i en forbindelse med formel Ila står for hydroksy, gjennomføres omsetningen om nødvendig i nærvær av et middel som begunstiger vann-avspaltning. Som slike kommer f.eks. i betraktning surt reagerende stoffer, som f.eks. mineralsyrer, som klorhydrogen eller svovelsyre, videre organiske syrer, spesielt sulfonsyrer, f.eks. benzen- eller p-toluensulfonsyre, som i nærvær av et egnet, inert løsningsmiddel, f.eks. butanol, eller en aromatisk forbindelse, som benzen eller toluen, akselererer den destillative, f.eks. azeotrope, fjerning av det dannede reaksjonsvann. Kondensasjonen ifølge fremgangsmåten under binding av det dannede vannet kan dog også foregå ved hjelp av et karbondiimid, f.eks. N,N-dietyl-eller N,N-dicykloheksylkarbodiimid i et inert løsnings-middel . as well as sulfolane, also optionally lower alkylated, such as N-methylated 2-pyrrolidone, further dimethylsulfoxide, as well as mixtures of such substances. If X in a compound of formula IIa stands for hydroxy, the reaction is carried out, if necessary, in the presence of an agent which favors the elimination of water. As such, e.g. in consideration of acid-reactive substances, such as e.g. mineral acids, such as hydrogen chloride or sulfuric acid, further organic acids, especially sulphonic acids, e.g. benzene or p-toluenesulfonic acid, which in the presence of a suitable, inert solvent, e.g. butanol, or an aromatic compound, such as benzene or toluene, accelerates the distillative, e.g. azeotrope, removal of the water of reaction formed. However, the condensation according to the method during binding of the formed water can also take place with the help of a carbon diimide, e.g. N,N-diethyl or N,N-dicyclohexylcarbodiimide in an inert solvent.
Disse omsetninger gjennomføres på vanlig måte ved forhøyet eller senket temperatur i åpne eller lukkede kar, om nød-vendig under en beskyttelsesgass som nitrogen. Utgangsstoffene er kjente eller kan dersom de er nye, fremstilles ifølge vanlige metoder. Således oppnås utgangsstoffer med formel V ved omsetning av hydrazin som eventuelt inneholder beskyttelsesgrupper, eller dets hydrat, som er avspaltbare og kan erstattes med hydrogen, f.eks. ved hjelp av reduksjon og hydrogenolyse, eller ved hjelp av solvolyse, som hydrolyse, eksempelvis a-aryllaverealkyl-grupper som benzyl, eller acylgrupper, f.eks. laverealkanoyl, som acetyl, med en forbindelse som tillater innføring av en acylrest Ac, f.eks. en tilsvarende karboksylsyre eller et reaksjonsdyktig derivat derav, f.eks. som ovenfor beskrevet, og etterfølgende avspaltning av eventuelt foreliggende beskyttelsesgrupper og deres erstatning med hydrogen. These reactions are carried out in the usual way at elevated or lowered temperatures in open or closed vessels, if necessary under a protective gas such as nitrogen. The starting materials are known or, if they are new, can be prepared according to usual methods. Thus, starting substances of formula V are obtained by reacting hydrazine which optionally contains protective groups, or its hydrate, which are cleavable and can be replaced with hydrogen, e.g. by means of reduction and hydrogenolysis, or by means of solvolysis, such as hydrolysis, for example α-aryl lower alkyl groups such as benzyl, or acyl groups, e.g. lower alkanoyl, such as acetyl, with a compound which allows the introduction of an acyl residue Ac, e.g. a corresponding carboxylic acid or a reactive derivative thereof, e.g. as described above, and subsequent removal of any protective groups present and their replacement with hydrogen.
De nye forbindelsene med formel I, hvor n står for 1 ogThe new compounds of formula I, where n stands for 1 and
R er en mono- eller bicyklisk heteroarylrest, kan likeledes oppnås ved at i en forbindelse med formelen R is a mono- or bicyclic heteroaryl radical, can likewise be obtained by that in a compound with the formula
hvor hydroksy- og/eller aminogrupper er beskyttet med beskyttelsesgrupper, og R2er en substituent som er i stand til å danne en mono- eller bicyklisk heteroarylrest R, den mono- eller bicykliske heteroarylgruppen R dannes, eventuelt tilstedeværende beskyttelsesgrupper samtidig eller deretter avspaltes og erstattes med hydrogen, og om ønsket, gjennomføres, de ytterligere fremgangsmåtetrinn som er beskrevet i tilslutning til den første fremgansmåten. Beskyttelsesgrupper er f.eks. acyl, som laverealkanoyl, f.eks. acetyl som avspaltes under de fremgangsmåtebetingel-ser som anvendes for dannelse av heteroarylresten R og erstattes med hydrogen. Således kan for fremstilling av en forbindelse med formel I, hvor R betyr en imidazolylrest, som f.eks. er knyttet til den substituerte pyridylgruppen i 2-stilling, en forbindelse med formel VI, hvor R2er formylgruppen, på vanlig måte omsettes med en 1,2-dikarbonylforbindelse med formelen where hydroxy and/or amino groups are protected with protective groups, and R2 is a substituent capable of forming a mono- or bicyclic heteroaryl residue R, the mono- or bicyclic heteroaryl group R is formed, any protective groups present simultaneously or subsequently are cleaved off and replaced with hydrogen, and if desired, the further method steps described in connection with the first method are carried out. Protection groups are e.g. acyl, such as lower alkanoyl, e.g. acetyl which is cleaved off under the process conditions used to form the heteroaryl radical R and replaced with hydrogen. Thus, for the preparation of a compound of formula I, where R means an imidazolyl residue, such as e.g. is attached to the substituted pyridyl group in the 2-position, a compound of formula VI, where R 2 is the formyl group, is reacted in the usual way with a 1,2-dicarbonyl compound of the formula
hvor R^og/eller R^hver betyr hydrogen eller en rest som substituerer heteroarylgruppen, f.eks. som ovenfor beskrevet, i nærvær av ammoniakk eller med en monooksimino-forbindelse som tilsvarer formel Via. Avhengig av arten av restene R^og/eller R^kan forbindelsen med formel Via anvendes som sådan eller den kan dannes in situ i reaksjonsblandingen fra et egnet forstadium. Hertil egnede forstadier er f.eks. derivater av hydroksyaceton og er f.eks. 1,1-dihalogen-, som f.eks. 1,1-dibromaceton, som eventuelt er substituert i 1- og/eller 3-stilling med gruppen R^og/eller R^. Andre forstadier er slike i hvilke dikarbo-nylforbindelsen med formel Via foreligger i omdannet form, f.eks. som acetal, som dimetylacetal, som hydrat eller som bisulfittaddisjonsforbindelser. Fra sliek forstadier kan når det gjelder 1,1-dihalogenacetonderivater ved behandling med hydrolyserende midler, fortrinnsvis svake alkalier, f.eks. natriumacetat, eller når det gjelder acetaler eller bisulfittaddisjonsforbindelser med vandige syrer, oppnås forbindelsen med formel Via in situ. På denne måte oppnås forbindelser med formel I, hvor den substituerte pyridyl-rest substituerer en 2-stilling, en gruppe R^og/eller R^hver 4- hhv. 5-stillingen i den dannede imidazolrest. where R^ and/or R^ each means hydrogen or a residue which substitutes the heteroaryl group, e.g. as described above, in the presence of ammonia or with a monooximino compound corresponding to formula Via. Depending on the nature of the radicals R^ and/or R^, the compound of formula Via can be used as such or it can be formed in situ in the reaction mixture from a suitable precursor. Precursors suitable for this are e.g. derivatives of hydroxyacetone and are e.g. 1,1-dihalo-, such as e.g. 1,1-dibromoacetone, which is optionally substituted in the 1- and/or 3-position with the group R^ and/or R^. Other precursors are those in which the dicarbonyl compound of formula Via is present in a converted form, e.g. as acetal, as dimethyl acetal, as hydrate or as bisulphite addition compounds. In the case of 1,1-dihaloacetone derivatives, treatment with hydrolysing agents, preferably weak alkalis, e.g. sodium acetate, or in the case of acetals or bisulphite addition compounds with aqueous acids, the compound of formula Via is obtained in situ. In this way, compounds of formula I are obtained, where the substituted pyridyl residue substitutes a 2-position, a group R^ and/or R^ each 4- or The 5-position in the formed imidazole residue.
For fremstilling av forbindelser med formel I, hvori en imidazolrest R f.eks. er substituert i 4-stilling med den substituerte pyridylresten, kan man f.eks. ved omsetning av en forbindelse med formel VI, hvor R2er gruppen med en forbindelse med formel For the preparation of compounds of formula I, in which an imidazole residue R e.g. is substituted in the 4-position with the substituted pyridyl residue, one can e.g. by reacting a compound of formula VI, where R 2 is the group with a compound of formula
og oppnår ammoniakk. Herved kan gruppene and obtains ammonia. In this way, the groups can
med formel VIb eller VIc også foreligge i funksjonelt omdannet form, f.eks. som acetaler, som dimetylacetaler, with formula VIb or VIc also exist in functionally converted form, e.g. as acetals, as dimethyl acetals,
som hydrater eller som bisulfittaddisjonsforbindelser,as hydrates or as bisulphite addition compounds,
fra hvilke de frie forbindelser dannes in situ ved behandling med vandige syrer, og deretter omsettes videre i samme reaksjonsblanding. Disse omsetninger gjennomføres på vanlig måte, f.eks. i nærvær av et løsningsmiddel eller en løsningsmiddelblanding, og om nødvendig, under avkjøling og oppvarming, om nødvendig i et lukket kar og/eller i en inert gassatmosfære, f.eks. under nitrogen. from which the free compounds are formed in situ by treatment with aqueous acids, and are then reacted further in the same reaction mixture. These transactions are carried out in the usual way, e.g. in the presence of a solvent or solvent mixture, and if necessary, during cooling and heating, if necessary in a closed vessel and/or in an inert gas atmosphere, e.g. under nitrogen.
Utgangsstoffene kan fremstilles på i og for seg kjent måte. The starting materials can be produced in a manner known per se.
Således kan det fremstilles forbindelser med formel VI, hvor R ? er formylgruppen eller gruppen med formel VIb, Thus, compounds of formula VI can be prepared, where R ? is the formyl group or the group of formula VIb,
ved omsetning av en forbindelse med formelen P^-Py-OH (Vid), hvor formylgruppen eller gruppen med formel VIb som tilsvarer resten P^, fortrinnsvis foreligger i beskyttet form, f.eks. som acetal, som dimetylacetal, som hydrat eller som bisulfittaddisjonsforbindelse, f.eks. den som er dannet med natriumsulfitt, og hydroksygruppen også foreligger i reaksjonsdyktig, forestret form, f.eks. som halogen, som klor eller brom, eller som en hydroksygruppe som er forestret med en sulfonsyre, som metan- eller en aryl-, som benzensulfonsyre, med en forbindelse av den ovenfor angitte formel IVb eller V på den der beskrevne måte, f.eks. i nærvær av et karbodiimid, som N,N-dicykloheksylkarbodiimid, eller dersom hydroksygruppen er reaksjonsdyktig forestret, i nærvær av et basisk kondensasjonsmiddel, og avspaltning av tilstedeværende beskyttelsesgrupper, f.eks. som beskrevet. by reacting a compound with the formula P^-Py-OH (Vid), where the formyl group or the group with formula VIb corresponding to the residue P^, is preferably present in protected form, e.g. as acetal, as dimethyl acetal, as hydrate or as bisulphite addition compound, e.g. the one formed with sodium sulphite, and the hydroxy group is also present in a reactive, esterified form, e.g. as halogen, as chlorine or bromine, or as a hydroxy group which is esterified with a sulfonic acid, such as methane- or an aryl-, such as benzenesulfonic acid, with a compound of the above formula IVb or V in the manner described there, e.g. . in the presence of a carbodiimide, such as N,N-dicyclohexylcarbodiimide, or if the hydroxy group is reactively esterified, in the presence of a basic condensing agent, and removal of protecting groups present, e.g. as described.
En forbindelse med formel I, hvor R betyr tiazolylresten, som f.eks. er substituert i 2-stilling med den substituerte pyridylgruppen, kan oppnås ved at en forbindelse med formel VI, hvor R2er gruppen med formelen A compound of formula I, where R means the thiazolyl radical, which e.g. is substituted in the 2-position with the substituted pyridyl group, can be obtained by a compound of formula VI, where R 2 is the group of the formula
omsettes med en forbindelse med formelen hvor Hal står for halogen, f.eks. for klor og spesielt for brom, og R^og/eller R^hver betyr hydrogen eller en rest som substituerer heteroarylgruppen, f.eks. som ovenfor beskrevet. Avhengig av arten av resten R^og/eller R^kan det anvendes en forbindelse med formel VIf i form av dens derivater, f.eks. acetalene, som dietylacetalene. For fremstilling av forbindelser med formel I, hvor R er en tiazolylrest som er substituert i 4- eller 5-stilling med den substituerte pyridylgruppen, kan f.eks. en forbindelse med formel VI, hvorR2er gruppen med formelen eller formelen og karbonylgruppen eventuelt foreligger i beskyttet, f.eks. acetalform, hvor Hal hver står for halogen, f.eks. for klor eller brom, og R^og R^har de ovenstående betydninger, omsettes med en forbindelse med formelen is reacted with a compound with the formula where Hal stands for halogen, e.g. for chlorine and especially for bromine, and R^ and/or R^ each means hydrogen or a residue substituting the heteroaryl group, e.g. as described above. Depending on the nature of the radical R^ and/or R^, a compound of formula VIf can be used in the form of its derivatives, e.g. the acetals, such as the diethyl acetals. For the preparation of compounds of formula I, where R is a thiazolyl residue which is substituted in the 4- or 5-position with the substituted pyridyl group, e.g. a compound of formula VI, where R 2 is the group with the formula or the formula and the carbonyl group is optionally present in protected, e.g. acetal form, where Hal each stands for halogen, e.g. for chlorine or bromine, and R^ and R^ have the above meanings, is reacted with a compound of the formula
Disse reaksjoner gjennomføres på i og for seg kjent måte, f.eks. i nærvær av et egnet løsningsmiddel, f.eks. en laverealkanol som etanol, eller en eteraktig væske, som dioksan, eventuelt ved forhøyet temperatur og eventuelt i nærvær av et basisk middel, f.eks. et metall-, som alkali- eller jordalkalisalt av en svak syre, som karbonsyre eller eddiksyre, f.eks. magnesiumkarbonat eller natriumacetat, og om nødvendig, i et lukket kar og/eller i en inert gassatmosfære, f.eks. under nitrogen. These reactions are carried out in a manner known per se, e.g. in the presence of a suitable solvent, e.g. a lower alkanol such as ethanol, or an ethereal liquid, such as dioxane, optionally at elevated temperature and optionally in the presence of a basic agent, e.g. a metal, such as alkali or alkaline earth salt of a weak acid, such as carbonic acid or acetic acid, e.g. magnesium carbonate or sodium acetate, and if necessary, in a closed vessel and/or in an inert gas atmosphere, e.g. under nitrogen.
Utgangsstoffene kan fremstilles ved hjelp av kjente frem-gangsmåter. Således kan det oppnås en forbindelse med formel VI med gruppen Vie som R2, idet i en forbindelse med formelen The starting materials can be produced using known methods. Thus, a compound of formula VI can be obtained with the group Vie as R2, being in a compound of the formula
gruppen N=C- omdannes til gruppen Vie ved omsetning med svovelhydrogen i et egnet, f.eks. et basisk organisk løs-ningsmiddel, som f.eks. pyridin eller trietylamin eller blandinger derav. Utgangsstoffer med formel Vik kan på sin side oppnås ved at en forbindelse med formelen the group N=C- is converted to the group Vie by reaction with hydrogen sulphide in a suitable, e.g. a basic organic solvent, such as e.g. pyridine or triethylamine or mixtures thereof. Starting substances with the formula Vik can, in turn, be obtained by a compound with the formula
hvor hydroksygruppen eventuelt foreligger i reaksjonsdyktig where the hydroxy group is possibly present in reactive
forestret form, f.eks. som halogen eller en sulfonyloksy-gruppe, f.eks. som ovenfor beskrevet, omsettes med en forbindelse med formelen IVb eller V, f.eks. som beskrevet der, og eventuelt tilstedeværende beskyttelsesgrupper avspaltes og erstattes med hydrogen. esterified form, e.g. such as halogen or a sulfonyloxy group, e.g. as described above, is reacted with a compound of the formula IVb or V, e.g. as described there, and any protective groups present are cleaved off and replaced with hydrogen.
Utgangsstoffer med formelen VI, hvor R^står for en gruppe med formelen Vlh eller VIi, kan f.eks. oppnås ved at en forbindelse med formelen Starting substances with the formula VI, where R^ stands for a group with the formula Vlh or VIi, can e.g. is achieved by a compound with the formula
eller formelen or the formula
hvor Hal står for halogen, f.eks. klor eller brom, og hydroksygruppen også kan foreligge i reaksjonsdyktig form, f.eks. som beskrevet, som halogen, som klor eller brom, omsettes med en forbindelse med formel IVb eller V, f.eks. som beskrevet, og eventuelt tilstedeværende beskyttelsesgrupper avspaltes og erstattes med hydrogen. where Hal stands for halogen, e.g. chlorine or bromine, and the hydroxy group can also be present in a reactive form, e.g. as described, as halogen, as chlorine or bromine, is reacted with a compound of formula IVb or V, e.g. as described, and any protective groups present are split off and replaced with hydrogen.
En forbindelse med formel I, hvor R betyr en pyrimidinylrest som er knyttet til den substituerte pyridylgruppen i 4(6)-stilling, kan oppnås vedat f.eks. en forbindelse med formel VI, hvor R2er gruppen med formelen A compound of formula I, where R means a pyrimidinyl residue which is linked to the substituted pyridyl group in the 4(6) position, can be obtained by e.g. a compound of formula VI, where R 2 is the group of the formula
hvor karbonylgruppen (karbonylgruppene) eventuelt foreligger i beskyttet, f.eks. acetalisert form, f.eks. som dimetylacetal, eller som bisulfittaddisjonsforbindelse, f.eks. med natriumbisulfitt, omsettes med en forbindelse med formelen where the carbonyl group(s) may be present in a protected form, e.g. acetalized form, e.g. as dimethyl acetal, or as bisulphite addition compound, e.g. with sodium bisulphite, is reacted with a compound of the formula
hvor R. og har de ovennevnte betydninger. where R. and have the above meanings.
Denne reaksjon foretas på vanlig måte og fortrinnsvis under sure betingelser, f.eks. i nærvær av et surt reagerende middel, som f.eks. ammoniumklorid. This reaction is carried out in the usual way and preferably under acidic conditions, e.g. in the presence of an acidic reacting agent, such as ammonium chloride.
Utgangsstoffene kan fremstilles på i og for seg kjent måte. The starting materials can be produced in a manner known per se.
Således kan f.eks. et utgangsmateriale med formelen VIThus, e.g. a starting material of the formula VI
med gruppen VIo som R^fremstilles, ved at en forbindelse med formelen with the group VIo as R^ is prepared by a compound of the formula
med fortrinnsvis beskyttet, f.eks. som beskrevet, f.eks. acetalisert karboksaldehydgrupper omsettes med en forbindelse med formel IVb eller V, f.eks. som beskrevet og eventuelt tilstedeværende beskyttelsesgrupper avspaltes. with preferably protected, e.g. as described, e.g. acetalised carboxaldehyde groups are reacted with a compound of formula IVb or V, e.g. as described and any protective groups present are cleaved off.
For fremstilling av forbindelser med formel I, hvor R betyr en pyrimidinylrest, som f.eks. er knyttet til den substituerte pyridylgruppen i 2-stilling, kan f.eks. en forbindelse med formel VI, hvor R^er gruppen med formelen omsettes med en forbindelse med formelen For the preparation of compounds of formula I, where R means a pyrimidinyl residue, such as e.g. is linked to the substituted pyridyl group in the 2-position, can e.g. a compound of formula VI, where R^ is the group of the formula is reacted with a compound of the formula
hvor karbonylgruppen (karbonylgruppene) eventuelt foreligger i beskyttet, f.eks. acetalisert form, f.eks. som dimetylacetaler, og og R^har de angitte betydninger. Denne omsetning foretas på i og for seg kjent måte, f.eks. under sure betingelser, f.eks. som beskrevet, f.eks. i nærvær av ammoniumklorid. where the carbonyl group(s) may be present in a protected form, e.g. acetalized form, e.g. as dimethyl acetals, and and R^ have the indicated meanings. This turnover is carried out in a manner known per se, e.g. under acidic conditions, e.g. as described, e.g. in the presence of ammonium chloride.
Utgangsstoffene kan fremstilles på i og for seg kjent måte. Således kan en forbindelse med formel VI med gruppen Vir som R2oppnås ved at en forbindelse med den ovenfor angitte formel (Vik) omdannes til den tilsvarende iminoester, f.eks. ved metning av en absolutt-etanolisk løsning av en slik forbindelse med klorhydrogen, og herfra oppnås ved omsetning med vannfri ammoniakk en forbindelse med formel VI The starting materials can be produced in a manner known per se. Thus, a compound of formula VI with the group Vir as R2 can be obtained by converting a compound of the above-mentioned formula (Vik) into the corresponding iminoester, e.g. by saturating an absolute ethanolic solution of such a compound with hydrogen chloride, and from this a compound of formula VI is obtained by reaction with anhydrous ammonia
som inneholder gruppen (Vir) som R2, fortrinnsvis i form-containing the group (Vir) as R2, preferably in the form
av et salt, f.eks. med en sterk syre, f.eks. som hydro-klorid, og eventuelt fjernes tilstedeværende beskyttelsesgrupper samtidig eller senere og erstattes med hydrogen. of a salt, e.g. with a strong acid, e.g. as hydrochloride, and optionally present protective groups are removed at the same time or later and replaced with hydrogen.
Ved utvalg av den egnede ovenstående fremgangsmåte for fremstilling av forbindelser med formel I må det passes på, at tilstedeværende substituenter ikke omdannes eller avspaltes, dersom slike omdannelser henholdsvis avspalt-ninger ikke er ønsket. Således kan spesielt funksjonelt omdannede karboksylgrupper, som forestrede eller amiderte karboksylgrupper, så vel som cyangrupper, delta i reaksjonen og omdannes under solvolyse, spesielt hydrolyse, videre også ved reduksjoner. På den annen side kan det være ønsket med samtidige omdannelser av substituenter, f.eks. kan umettede substituenter, som laverealkenyl, under betingelsene ved en reduksjonsfremgangsmåte som anvendes ifølge oppfinnelsen, f.eks. reduseres til laverealkyl. When selecting the suitable above method for preparing compounds of formula I, care must be taken that the substituents present are not converted or split off, if such conversions or splits off are not desired. Thus, especially functionally converted carboxyl groups, such as esterified or amidated carboxyl groups, as well as cyano groups, can participate in the reaction and be converted during solvolysis, especially hydrolysis, further also by reductions. On the other hand, it may be desired with simultaneous conversions of substituents, e.g. can unsaturated substituents, such as lower alkenyl, under the conditions of a reduction method used according to the invention, e.g. is reduced to lower alkyl.
Forbindelser som oppnås ifølge oppfinnelsen kan i rammen for definisjonen av forbindelsene med formel I på vanlig måte overføres til andre sluttstoffer, f.eks. ved at egnede substituenter omdannes, innføres eller avspaltes. Compounds obtained according to the invention can, within the framework of the definition of the compounds of formula I, be transferred in the usual way to other end substances, e.g. in that suitable substituents are converted, introduced or cleaved off.
Frie karboksylgrupper kan forestres på vanlig måte, eksempelvis ved omsetning med en tilsvarende alkohol, fordelaktig i nærvær av en syre, som en mineralsyre, f.eks. svovelsyre eller klorhydrogensyre, eller i nærvær av et vannbindende middel, som dicykloheksylkarbodiimid, eller ved omsetning med en tilsvarende diazoforbindelse, f.eks. diazometan. Forestringen kan også gjennomføres ved omsetning av et Free carboxyl groups can be esterified in the usual way, for example by reaction with a corresponding alcohol, advantageously in the presence of an acid, such as a mineral acid, e.g. sulfuric acid or hydrochloric acid, or in the presence of a water-binding agent, such as dicyclohexylcarbodiimide, or by reaction with a corresponding diazo compound, e.g. diazomethane. The esterification can also be carried out by converting a
salt, fortrinnsvis et alkalimetallsalt av syren med en reaksjonsdyktig forestret alkohol, f.eks. et tilsvarende halogenid, som klorid. salt, preferably an alkali metal salt of the acid with a reactive esterified alcohol, e.g. a corresponding halide, such as chloride.
Fri karboksylgrupper kan på vanlig måte amideres eksempelvis ved omsetning med ammoniakk, eller med et primært eller sekundært amin, fordelaktig i nærvær av et vannbindende middel, som dicykloheksylkarbodiimid, eller ved overføring av karboksylgruppen til en halogenkarbonyl-, f.eks. klor-karbonylgruppe og påfølgende omsetning med ammoniakk eller med et primært eller sekundært amin. Free carboxyl groups can be amidated in the usual way, for example by reaction with ammonia, or with a primary or secondary amine, advantageously in the presence of a water-binding agent, such as dicyclohexylcarbodiimide, or by transferring the carboxyl group to a halocarbonyl, e.g. chloro-carbonyl group and subsequent reaction with ammonia or with a primary or secondary amine.
I forbindelser som inneholder en forestret karboksylgruppe, kan denne på vanlig måte, f.eks. ved hydrolyse, fortrinnsvis i nærvær av sterke baser, som et alkalimetallhydroksyd, f.eks. natrium- eller kaliumhydroksyd, eller sterke syrer, f.eks. en sterk mineralsyre, som en halogenhydrogensyre, f.eks. klorhydrogensyre eller svovelsyre, overføres til en fri karboksylgruppe. In compounds containing an esterified carboxyl group, this can be in the usual way, e.g. by hydrolysis, preferably in the presence of strong bases, such as an alkali metal hydroxide, e.g. sodium or potassium hydroxide, or strong acids, e.g. a strong mineral acid, such as a hydrohalic acid, e.g. hydrochloric acid or sulfuric acid, is transferred to a free carboxyl group.
I forbindelser som inneholder en forestret karboksylgruppe, kan denne i nærvær av en annen alkohol, fortrinnsvis i overskudd, omdannes til en karboksylgruppe som inneholder den andre alkoholen som esterbestanddel, f.eks. i nærvær av en basisk katalysator, f.eks. en alkalimetallforbindelse av den alkohol som anvendes for omestringen, eller en egnet In compounds containing an esterified carboxyl group, this can, in the presence of another alcohol, preferably in excess, be converted into a carboxyl group containing the other alcohol as an ester component, e.g. in the presence of a basic catalyst, e.g. an alkali metal compound of the alcohol used for the transesterification, or a suitable
katalysator, f.eks. en edelmetallkatalysator, som f.eks.catalyst, e.g. a noble metal catalyst, such as
en palladium-på-kull-katalysator.a palladium-on-charcoal catalyst.
I forbindelser med en forestret karboksylgruppe som substituent kan denne på vanlig måte, f.eks. ved ammonolyse eller aminolyse med ammoniakk eller et primært eller sekundært amin overføres til den tilsvarende karbamoylgruppe. In compounds with an esterified carboxyl group as a substituent, this can be used in the usual way, e.g. by ammonolysis or aminolysis with ammonia or a primary or secondary amine is transferred to the corresponding carbamoyl group.
Forbindelser med en usubstituert karbamoylgruppe kan på vanlig måte, f.eks. ved innvirkning av vannuttrekkende midler, som fosforpentoksyd, fosforoksyklorid eller tri-fluoreddiksyreanhydrid, fortrinnsvis ved høyere temperaturer, dehydratiseres til de tilsvarende cyanforbindelser. Compounds with an unsubstituted carbamoyl group can in the usual way, e.g. by the action of water-extracting agents, such as phosphorus pentoxide, phosphorus oxychloride or trifluoroacetic anhydride, preferably at higher temperatures, are dehydrated to the corresponding cyan compounds.
I forbindelser med en forestret karboksylgruppe som substituent kan den forestrede karboksylgruppen på vanlig måte, f.eks. ved innvirkning av en organisk, f.eks. en dilavere-alkyl-aluminiumamid-forbindelse, f.eks. dietylaluminiumamid, omdannes til en cyanogruppe. In compounds with an esterified carboxyl group as a substituent, the esterified carboxyl group can be used in the usual way, e.g. by impact of an organic, e.g. a dilave alkyl aluminum amide compound, e.g. diethylaluminium amide, is converted to a cyano group.
Forbindelser som inneholder en cyansubstituent, kan på vanlig måte, f.eks. i nærvær av konsentrerte vandige mineralsyrer eller alkalimetallhydroksyder, hydrolyseres til de tilsvarende karbamoyl- eller direkte til karboksylforbindel-sene. Compounds containing a cyano substituent can be conventionally, e.g. in the presence of concentrated aqueous mineral acids or alkali metal hydroxides, are hydrolysed to the corresponding carbamoyl or directly to carboxyl compounds.
Forbindelser med en cyangruppe som substituent kan på vanlig måte, f.eks. ved tilsetning av alkoholer i nærvær av en vannfri syre, som klorhydrogen, og påfølgende hydrolyse av den oppnådde imidoester alkoholiseres til de tilsvarende forbindelser med forestrede karboksylgrupper. Compounds with a cyano group as a substituent can in the usual way, e.g. by addition of alcohols in the presence of an anhydrous acid, such as hydrogen chloride, and subsequent hydrolysis of the obtained imido ester is alcoholized to the corresponding compounds with esterified carboxyl groups.
Forbindelser, som inneholder en aminogruppe som substituent, kan på vanlig måte, omdannes til tilsvarende acylaminofor-bindelser, som f.eks. laverealkanoylaminoforbindelser, Compounds which contain an amino group as a substituent can, in the usual way, be converted into corresponding acylamino compounds, such as e.g. lower alkanoylamino compounds,
f.eks. ved omsetning av en tilsvarende karboksylsyre, som en laverealkankarboksylsyre eller et reaksjonsdyktig derivat e.g. by reacting a corresponding carboxylic acid, such as a lower alkane carboxylic acid or a reactive derivative
derav, som et halogenid, eller et anhydrid eller en ester, som laverealkylester. thereof, as a halide, or an anhydride or an ester, such as a lower alkyl ester.
Forbindelser, som inneholder en aminogruppe som substituent, kan på vanlig måte omdannes til tilsvarende laverealkylamino- hhv. dilaverealkylaminoforbindelser, eksempelvis ved omsetning med et laverealkylhalogenid, som et bromid eller et jodid derav. Compounds, which contain an amino group as a substituent, can be converted in the usual way to the corresponding lower alkylamino or dilower alkylamino compounds, for example by reaction with a lower alkyl halide, such as a bromide or an iodide thereof.
Forbindelser som har en laverealkyltio-, f.eks. metyltio-gruppe i en aromatisk ring, kan f.eks. ved egnede midler som virker desulfurerende, f.eks. Raney-nikkel, i et egnet løsningsmiddel, f.eks. dioksan, omdannes til de svovelfrie forbindelsene. Compounds having a lower alkylthio-, e.g. methylthio group in an aromatic ring, can e.g. by suitable agents that have a desulfurizing effect, e.g. Raney nickel, in a suitable solvent, e.g. dioxane, is converted to the sulphur-free compounds.
Som ved fremstillingsfremgangsmåtene må det også ved gjennom-føring av tilleggsskrittene passes på, at uønskede bireak-sjoner, som kan ha tilfølge omdannelsen av ytterligere grupperinger, ikke inntrer. As with the production methods, care must also be taken when carrying out the additional steps that unwanted side-reactions, which may result in the transformation of further groupings, do not occur.
De ovenfor beskrevne reaksjoner kan eventuelt gjennomføres samtidig eller etter hverandre, videre i tilfeldig rekke-følge . The reactions described above can optionally be carried out simultaneously or one after the other, further in random order.
Dersom det er nødvendig foregår de i nærvær av fortynningsmidler, kondensasjonsmidler og/eller midler som virker katalyserende ved senket eller forhøyet temperatur, i lukket kar under trykk og/eller i en inert gassatmosfære. If necessary, they take place in the presence of diluents, condensing agents and/or agents that act as catalysts at a lowered or elevated temperature, in a closed vessel under pressure and/or in an inert gas atmosphere.
Avhengig av fremgangsmåtebetingelsene og utgangsstoffene oppnås de nye forbindelsene i fri form eller i form av deres salter som likeledes omfattes av oppfinnelsen, hvorved de nye forbindelsene eller saltene derav også kan foreligge som hemi-, mono-, seskvi- eller polyhydrater derav. Syreaddisjonssalter av de nye forbindelsene kan på i og Depending on the process conditions and starting materials, the new compounds are obtained in free form or in the form of their salts, which are likewise covered by the invention, whereby the new compounds or their salts can also be present as hemi-, mono-, sesqui- or polyhydrates thereof. Acid addition salts of the new compounds can on i and
for seg kjent måte, f.eks. ved behandling med basiske midler, som alkalimetallhydroksyder, -karbonater eller -hydrogen- known manner, e.g. when treated with basic agents, such as alkali metal hydroxides, -carbonates or -hydrogen-
karbonater eller ionevekslere, overføres til den frie forbindelsen. På den annen side kan oppnådde frie baser danne syreaddisjonssalter, f.eks. med de nevnte syrer, hvorved det for deres fremstilling spesielt anvendes slike syrer, som egner seg til dannelse av farmasøytisk godtagbare, ikke-toksiske salter. Salter av de nye forbindelser med baser kan på i og for seg kjent måte, f.eks. ved behandling med sure midler, som fortynnede mineralsyrer, som saltsyre eller svovelsyre, eller med organiske syrer, som eddiksyre, eller med sure ionevekslere overføres til de frie karboksylsyrene. Disse kan igjen danne tilsvarende salter ved omsetning med baser, f.eks. uorganiske eller organiske baser, hvorved det spesielt anvendes farmasøy-tisk godtagbare, ikke-toksiske baser, eksempelvis de nevnte. carbonates or ion exchangers, are transferred to the free compound. On the other hand, free bases obtained can form acid addition salts, e.g. with the aforementioned acids, whereby for their preparation such acids are particularly used, which are suitable for the formation of pharmaceutically acceptable, non-toxic salts. Salts of the new compounds with bases can in a manner known per se, e.g. by treatment with acidic agents, such as dilute mineral acids, such as hydrochloric or sulfuric acid, or with organic acids, such as acetic acid, or with acidic ion exchangers are transferred to the free carboxylic acids. These can in turn form corresponding salts by reaction with bases, e.g. inorganic or organic bases, whereby pharmaceutically acceptable, non-toxic bases are particularly used, for example those mentioned.
Disse eller andre salter, spesielt syreaddisjonssalterThese or other salts, especially acid addition salts
av de nye forbindelsene, som f.eks. oksalater eller per-klorater, kan også tjene til rensing av de oppnådde frie basene, idet de frie basene overføres til salter, disse fraskilles og renses, og fra saltene frigjøres igjen basene. of the new connections, such as oxalates or perchlorates, can also serve to purify the free bases obtained, as the free bases are transferred to salts, these are separated and purified, and the bases are released from the salts again.
De nye forbindelsene kan avhengig av valg av utgangsstoffer og arbeidsmåte, foreligge som optiske antipoder eller racemater, eller dersom de inneholder to asymmetriske karbonatomer, også som racematblandinger. Utgangsstoffene kan også anvendes som bestemte optiske antipoder. Depending on the choice of starting materials and method of working, the new compounds can exist as optical antipodes or racemates, or if they contain two asymmetric carbon atoms, also as racemate mixtures. The starting materials can also be used as specific optical antipodes.
Oppnådde racematblandinger kan på grunn av de fysikalisk-kjemiske forskjeller på diastereoisomerene på kjent måte, f.eks. ved kromatografi og/eller fraksjonert krystallisa-sjon, oppdeles i de to stereoisomere (diastereomere) racemater . Obtained racemate mixtures can, due to the physico-chemical differences in the diastereoisomers, in a known manner, e.g. by chromatography and/or fractional crystallization, are divided into the two stereoisomeric (diastereomeric) racemates.
Oppnådde racemater kan på i og for seg kjent måte oppdelesObtained racemates can be divided in a manner known per se
i antipodene, f.eks. ved omkrystallisering fra et optisk aktivt løsningsmiddel, ved behandling med egnede mikroorga-nismer eller ved omsetning med en optisk aktiv substans som danner salter med den racemiske forbindelsen, som syrer in the antipodes, e.g. by recrystallization from an optically active solvent, by treatment with suitable microorganisms or by reaction with an optically active substance that forms salts with the racemic compound, which acids
eller baser, og adskillelse av den saltblanding som oppnås på denne måten, f.eks. på grunn av forskjellige løselig-heter, i de diastereomere,saltene, fra hvilke de frie antipodene kan frigjøres ved innvirkning av egnede midler. Særlig brukbare optisk aktive syrer er f.eks. D- og L-formen av vinsyre, di-0,0'-(p-toluoyl)-vinsyre, eplesyre, mandelsyre, kamfersulfonsyre, glutaminsyre, asparaginsyre eller kinasyre. Spesielt brukbare optisk aktive baser er f.eks. optisk aktive aminer, som optisk aktive amino-syreestere, (-)-brucin, (+)-kinidin, (-)-kinin, (+)-kin-konin, (+)-dehydroabietylamin, (+)- eller (-)-efedrin. Fordelaktig isoleres den mest virksomme av de to antipodene. or bases, and separation of the salt mixture obtained in this way, e.g. due to different solubilities, in the diastereomeric salts, from which the free antipodes can be liberated by the action of suitable agents. Particularly usable optically active acids are e.g. The D and L form of tartaric acid, di-0,0'-(p-toluoyl)-tartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid. Especially usable optically active bases are e.g. optically active amines, such as optically active amino acid esters, (-)-brucine, (+)-quinidine, (-)-quinine, (+)-quin-conine, (+)-dehydroabiethylamine, (+)- or (- )-ephedrine. Advantageously, the most effective of the two antipodes is isolated.
Oppfinnelsen gjelder også de utførelsesformer av fremgangsmåten, ifølge hvilket det startes fra en forbindelse som oppnås som mellomprodukt på et hvilket som helst trinn i fremgangsmåten, og de manglende fremgangsmåtetrinn ut-føres, eller fremgangsmåten avbrytes på et hvilket som helst trinn, eller ved hvilke det under reaksjonsbetingelsene dannes et utgangsstoff, eller ved hvilke en reaksjonsbestand-del eventuelt foreligger i form av dens salt. The invention also applies to those embodiments of the method, according to which it is started from a compound obtained as an intermediate product at any step in the method, and the missing method steps are carried out, or the method is interrupted at any step, or in which under the reaction conditions, a starting substance is formed, or in which a reaction component is possibly present in the form of its salt.
Hensiktsmessig anvendes ved gjennomføring av reaksjonene ifølge oppfinnelsen slike utgangsstoffer, som fører til de innledningsvis særlig nevnte grupper av sluttstoffer og særlig til de spesielt beskrevne eller fremhevede sluttstoffer. Expediently, when carrying out the reactions according to the invention, such starting substances are used, which lead to the groups of end substances mentioned in particular at the beginning and in particular to the particularly described or highlighted end substances.
Utgangsstoffene er kjente eller kan dersom de er nye, oppnås ved hjelp av i og for seg kjente metoder, som beskrevet ovenfor, f.eks. analogt med eksemplene. Nye utgangsstoffer, spesielt slike med den forannevnte formel II, hvor R og n har de betydninger som er angitt under formel I, n spesielt står for 1 og R står \ 3- eller 6-stilling, men spesielt i 5-stilling, og betyr laverealkoksylaverealkyl, The starting materials are known or, if they are new, can be obtained using methods known per se, as described above, e.g. analogous to the examples. New starting substances, especially those with the above-mentioned formula II, where R and n have the meanings given under formula I, n in particular stands for 1 and R stands for \ 3- or 6-position, but especially in the 5-position, and means lower alkoxy lower alkyl,
f.eks. 2-metoksyetyl, eller fenyllaverealkyl, f.eks. benzyl, eller dersom n er 1, er laverealkyl med 2-7 karbonatomer e.g. 2-methoxyethyl, or phenyl lower alkyl, e.g. benzyl, or if n is 1, is lower alkyl of 2-7 carbon atoms
som etyl, n-propyl eller n-butyl og med den ytterligere forutsetning at R som laverealkyl i 4-stilling har 3-7 karbonatomer og eksempelvis betyr n-propyl eller n-butyl, når n er 1, eller deres salter, spesielt farmasøytisk anvendbare ikke-toksiske syreaddisjonssalter, så vel som fremgangsmåten for fremstilling av dem danner likeledes en gjenstand for oppfinnelsen. Oppfinnelsen gjelder også nye mellomprodukter som kan oppnås ved hjelp av fremgangsmåten, så vel som fremgangsmåten for fremstilling av dem. as ethyl, n-propyl or n-butyl and with the further proviso that R as lower alkyl in the 4-position has 3-7 carbon atoms and for example means n-propyl or n-butyl, when n is 1, or their salts, especially pharmaceutical applicable non-toxic acid addition salts, as well as the process for their preparation, likewise form an object of the invention. The invention also relates to new intermediates that can be obtained by means of the method, as well as to the method for their production.
Oppfinnelsen gjelder likeledes anvendelsen av forbindelsene med formel I eller av farmasøytisk anvendbare salter av slike forbindelser, spesielt som farmakologisk aktive forbindelser, spesielt i renalt og kardiovaskulært område. Derved kan man anvende dem, fortrinnsvis i form av farma-søytiske preparater, i en fremgangsmåte for profylaktisk og/eller terapeutisk behandling av hypertoni. Doseringen av det aktive stoffer, som tilføres alene eller sammen med de vanlige bærer- og hjelpematerialer, avhenger av den art som skal behandles, dens alder og individuelle tilstand, så vel som tilførselsmåten. Den daglige total-dose av de antihypertensivt virkende forbindelsene som skal tilføres i en eller flere, fortrinnsvis høyst fire enkeltdoser, ligger for pattedyr med en kroppsvekt på ca. 70 kg, avhengig av arten av sykdom, individuell tilstand og alder, fortrinnsvis mellom 150 og 750 mg. The invention likewise relates to the use of the compounds of formula I or of pharmaceutically usable salts of such compounds, especially as pharmacologically active compounds, especially in the renal and cardiovascular area. Thereby, they can be used, preferably in the form of pharmaceutical preparations, in a method for prophylactic and/or therapeutic treatment of hypertension. The dosage of the active substances, which are supplied alone or together with the usual carrier and auxiliary materials, depends on the species to be treated, its age and individual condition, as well as the method of administration. The total daily dose of the antihypertensive compounds to be administered in one or more, preferably no more than four single doses, is for mammals with a body weight of approx. 70 kg, depending on the nature of the disease, individual condition and age, preferably between 150 and 750 mg.
Oppfinnelsen gjelder videre farmasøytiske preparater, som inneholder en farmakologisk virksom mengde av den aktive substans, eventuelt sammen med farmasøytisk anvendbare bærestoffer, som egner seg for enteral, f.eks. oral, eller parenteral tilførsel, og kan være uorganisk eller organisk, fast eller flytende. Således anvendes tabletter eller gelatinkapsler, som inneholder det aktive stoffet sammen med fortynningsmidler, f.eks. laktose, dekstrose, sukrose, mannitol, sorbitol, cellulose og/eller glyserol, og/eller smøremidler, f.eks. kieseljord, talk, stearinsyre eller salter derav, som magnesium- eller kaliumstearat, og/eller polyetylenglykol. Tabletter kan likeledes inneholde binde-midler, f.eks. magnesium-aluminiumsilikat, stivelser som mais-, hvete-, ris- eller pilrotstivelse, gelatin, tragant, metylcellulose, natriumkarboksymetylcellulose og/eller polyvinylpyrrolidon, og om ønsket, sprengmidler, som f.eks. stivelse, agar, alginsyre eller et salt derav, som natrium-alginat, og/eller oppbrusningsblandinger, eller adsorpsjons-midler, fargestoffer, smaksstoffer og søtningsmidler. The invention further relates to pharmaceutical preparations, which contain a pharmacologically effective amount of the active substance, optionally together with pharmaceutically usable carriers, which are suitable for enteral administration, e.g. oral, or parenteral administration, and can be inorganic or organic, solid or liquid. Thus, tablets or gelatin capsules are used, which contain the active substance together with diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycerol, and/or lubricants, e.g. diatomaceous earth, talc, stearic acid or salts thereof, such as magnesium or potassium stearate, and/or polyethylene glycol. Tablets can also contain binders, e.g. magnesium aluminum silicate, starches such as corn, wheat, rice or arrowroot starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and if desired, explosives, such as e.g. starch, agar, alginic acid or a salt thereof, such as sodium alginate, and/or effervescent mixtures, or adsorbents, colourings, flavorings and sweeteners.
Videre kan de nye farmakologisk virksomme forbindelser anvendes i form av preparater som kan tilføres parenteralt eller i form av infusjonsløsninger. Slike løsninger er fortrinnsvis isotoniske, vandige løsninger eller suspen-sjoner, hvorved disse f.eks. ved lyofiliserte preparater, som inneholder den aktive substansen alene eller sammen med et bærermateriale, f.eks. mannitol, kan fremstilles før bruken. De farmasøytiske preparatene kan være sterili-sert og/eller inneholde hjelpestoffer, f.eks. konserverings-, stabiliserings-, fornetnings- og/eller emulgeringsmidler, løselighetsformidlere, salter for regulering av det osmotiske trykket og/eller buffere. Foreliggende farmasøytiske preparater som om ønsket kan inneholder andre farmakologisk virksomme stoffer, fremstilles på i og for seg kjent måte f.eks. ved hjelp av konvensjonelle blande-, granu-lerings-, drageerings-, løsnings- eller lyofiliserings-fremgangsmåter, og inneholder fra ca. 0,1 til 100%, spesielt fra ca. 1% til ca. 50%, lyofilisater opptil 100% av det aktive stoffet. Furthermore, the new pharmacologically active compounds can be used in the form of preparations that can be administered parenterally or in the form of infusion solutions. Such solutions are preferably isotonic, aqueous solutions or suspensions, whereby these e.g. in the case of lyophilized preparations, which contain the active substance alone or together with a carrier material, e.g. mannitol, can be prepared before use. The pharmaceutical preparations may be sterilized and/or contain excipients, e.g. preservatives, stabilisers, cross-linking and/or emulsifiers, solubility mediators, salts for regulating the osmotic pressure and/or buffers. Present pharmaceutical preparations which, if desired, can contain other pharmacologically active substances, are prepared in a manner known per se, e.g. by means of conventional mixing, granulation, coating, solution or lyophilization methods, and contains from approx. 0.1 to 100%, especially from approx. 1% to approx. 50%, lyophilisates up to 100% of the active substance.
Følgende eksempler tjener til illustrasjon av oppfinnelsen. Temperaturer angis i Celsius-grader. The following examples serve to illustrate the invention. Temperatures are given in degrees Celsius.
Eksempel 1Example 1
En løsning av 15,1 g N-(benzyloksykarbonyl)-L-glutaminsyre-5-[N<2->(5-n-butyl-2-pyridyl)-hydrazid]-1-benzylester i 150 A solution of 15.1 g of N-(benzyloxycarbonyl)-L-glutamic acid-5-[N<2->(5-n-butyl-2-pyridyl)-hydrazide]-1-benzyl ester in 150
ml metanol hydreres etter tilsetning av 1,5 g palladium-på-kull-katalysator (5%) under normalbetingelser til avsluttet hydrogenopptak. Suspensjonen fortynnes med metanol, ml of methanol is hydrogenated after adding 1.5 g of palladium-on-charcoal catalyst (5%) under normal conditions until hydrogen absorption is complete. The suspension is diluted with methanol,
oppvarmes og filtreres gjennom et filterhjelpemiddel. Filtratet inndampes til et lite volum på en rotasjonsfordamper, utrøres med isopropanol og filtreres deretter. is heated and filtered through a filter aid. The filtrate is evaporated to a small volume on a rotary evaporator, stirred with isopropanol and then filtered.
Ved omkrystallisasjon av resten fra metanol og tørkingBy recrystallization of the residue from methanol and drying
i høyvakuum oppnås L-glutaminsyre-5-[N<2->(5-n-butyl-2-pyridyl)-hydrazid ]-hemihydrat med smeltepunkt 155-157°, [a]p°: + 27° ±1° (c = 0,5 - 1% i metanol). in high vacuum, L-glutamic acid-5-[N<2->(5-n-butyl-2-pyridyl)-hydrazide]-hemihydrate is obtained with melting point 155-157°, [a]p°: + 27° ±1° (c = 0.5 - 1% in methanol).
Utgangsmaterialet kan fremstilles som følger:The starting material can be prepared as follows:
En løsning av 6,9 g 2-hydrazino-5-n-butyl-pyridin i 175A solution of 6.9 g of 2-hydrazino-5-n-butyl-pyridine in 175
ml tørt tetrahydrofuran avkjøles i isbad, tilsettes porsjons-vis under omrøring 19,6 g N-(benzyloksykarbonyl)-L-glutaminsyre-l-benzylester-5-(N-hydroksysuccinimid)-ester, og om-røres deretter ennå i 2 timer ved 0°. Etter fjerning av løsningsmidlet på en rotasjonsfordamper og kromatografering av resten over silikagel under anvendelse av eddiksyreetylester som elueringsmiddel oppnås fra hovedfraksjonen N-(benzyloksykarbonyl)-L-glutaminsyre-5-[N<2->(5-n-butyl-2-pyridyl)-hydrazid]-1-benzylester som olje, som videre forarbeides som sådan. ml of dry tetrahydrofuran is cooled in an ice bath, 19.6 g of N-(benzyloxycarbonyl)-L-glutamic acid-1-benzyl ester-5-(N-hydroxysuccinimide)-ester are added in portions while stirring, and then stirred for a further 2 hours at 0°. After removal of the solvent on a rotary evaporator and chromatography of the residue over silica gel using ethyl acetate as eluent, N-(benzyloxycarbonyl)-L-glutamic acid-5-[N<2->(5-n-butyl-2-pyridyl )-hydrazide]-1-benzyl ester as oil, which is further processed as such.
Eksempel 2Example 2
Til en suspensjon av 1,47 g L-glutaminsyre-5-[N<2->5-n-butyl-2-pyridyl)-hydrazid og 1,33 g vannfritt natriumkarbonat i 20 ml dimetylformamid tildryppes under omrøring ved romtemperatur en løsning av 0,53 g eddiksyreanhydrid i 5 ml dimetylformamid i løpet av 15 minutter. Det omrøres ytterligere i 15 timer ved romtemperatur, filtreres deretter gjennom et filterhjelpemiddel og filtratet befris for løs-ningsmiddel på en rotasjonsfordamper. Det gjenværende gulaktige skum kromatograferes på silikagel med en løsnings-middelblanding kloroform/metanol/ammoniakk 5:3:1. Hovedfraksjonene forenes og befris for løsningsmiddel på en rotasjonsfordamper. For fremstilling av ammoniumsaltet oppløses resten i et overskudd av metanolisk ammoniakk, løsningen inndampes og produktet omkrystalliseres fra isopropanol, hvorved det oppnås ammoniumsaltet av N-acetyl-L-glutaminsyre-5-[N<2->(5-n-butyl-2-pyridyl)-hydrazid], smp. 147-149°; [a]£ 7 o: +29° ± 1°, (c = 0,5-1% i metanol); Rf-verdi i systemet metylenklorid/metanol/NH^OH kons. To a suspension of 1.47 g of L-glutamic acid-5-[N<2->5-n-butyl-2-pyridyl)-hydrazide and 1.33 g of anhydrous sodium carbonate in 20 ml of dimethylformamide, while stirring at room temperature, a of 0.53 g of acetic anhydride in 5 ml of dimethylformamide during 15 minutes. It is stirred for a further 15 hours at room temperature, then filtered through a filter aid and the filtrate is freed of solvent on a rotary evaporator. The remaining yellowish foam is chromatographed on silica gel with a solvent mixture of chloroform/methanol/ammonia 5:3:1. The main fractions are combined and freed from solvent on a rotary evaporator. To prepare the ammonium salt, the residue is dissolved in an excess of methanolic ammonia, the solution is evaporated and the product is recrystallized from isopropanol, whereby the ammonium salt of N-acetyl-L-glutamic acid-5-[N<2->(5-n-butyl-2 -pyridyl)-hydrazide], m.p. 147-149°; [a]£ 7 o: +29° ± 1°, (c = 0.5-1% in methanol); Rf value in the system methylene chloride/methanol/NH^OH conc.
(5:3:1) 0,76. (5:3:1) 0.76.
Eksempel 3Example 3
En løsning av 2,7 g N-acetyl-L-glutaminsyre-5-[N<2->(5-n-butyl-2-pyridyl)-hydrazid]-1-benzylester i 50 ml metanol hydreres etter tilsetning av 0,5 g palladium-på-kull-katalysator (5%) under normalbetingelser til avsluttet hydrogenopptak. A solution of 2.7 g of N-acetyl-L-glutamic acid-5-[N<2->(5-n-butyl-2-pyridyl)-hydrazide]-1-benzyl ester in 50 ml of methanol is hydrated after adding 0 .5 g of palladium-on-charcoal catalyst (5%) under normal conditions until hydrogen absorption is complete.
Katalysatoren frafiltreres og filtratet befris for løsnings-middel på en rotasjonsfordamper. Resten kromatograferes på silikagel med en løsningsmiddelblanding kloroform/metanol/ ammoniakk 5:3:1. Hovedfraksjonene forenes og befris for løsningsmiddel. For fremstilling av ammoniumsaltet oppløses resten i et overskudd av metanolisk ammoniakk, løsningen inndampes på nytt og produktet omkrystalliseres fra isopropanol, hvorved det oppnås ammoniumsaltet av N-acetyl-L-glutaminsyre-5- [ N2 -(5-n-butyl-2-pyridyl)-hydrazid]; The catalyst is filtered off and the filtrate is freed of solvent on a rotary evaporator. The residue is chromatographed on silica gel with a solvent mixture of chloroform/methanol/ammonia 5:3:1. The main fractions are combined and freed from solvent. To prepare the ammonium salt, the residue is dissolved in an excess of methanolic ammonia, the solution is evaporated again and the product is recrystallized from isopropanol, whereby the ammonium salt of N-acetyl-L-glutamic acid-5- [ N2 -(5-n-butyl-2- pyridyl)-hydrazide];
smp. 147-149°, [a]£ ? n: +29° ± 1°, (c = 0,5-1% i metanol). m.p. 147-149°, [a]£ ? n: +29° ± 1°, (c = 0.5-1% in methanol).
Utgangsmaterialet kan fremstilles som følger:The starting material can be prepared as follows:
En suspensjon av 3,17 g 2-hydrazino-5-n-butyl-pyridin-dihydroklorid i 60 ml tørt tetrahydrofuran avkjøles til 5° og tilsettes under røring først 4,2 ml trietylamin og etter 5 minutter 5,0 g N-acetyl-L-glutaminsyre-l-benzyl-ester-5-(N-hydroksysuccinimid)-ester. Deretter omrøres blandingen i 15 timer ved romtemperatur, trietylaminhydroklorid frafiltreres og filtratet befris for løsnings-middel ved en badtemperatur på 30-40°. Den lett grønn-aktige resten kromatograferes på silikagel med en kloroform-metanol-blanding (95:5). A suspension of 3.17 g of 2-hydrazino-5-n-butyl-pyridine dihydrochloride in 60 ml of dry tetrahydrofuran is cooled to 5° and, with stirring, first 4.2 ml of triethylamine and after 5 minutes 5.0 g of N-acetyl are added -L-glutamic acid 1-benzyl ester 5-(N-hydroxysuccinimide) ester. The mixture is then stirred for 15 hours at room temperature, triethylamine hydrochloride is filtered off and the filtrate is freed of solvent at a bath temperature of 30-40°. The slightly greenish residue is chromatographed on silica gel with a chloroform-methanol mixture (95:5).
Den fra hovedfraksjonene i form av et fargeløst skum oppnådde N-acetyl-L-glutaminsyre-5-[N<2->5-n-butyl-2-pyridyl)-hydrazid]-1-benzylester videreforarbeides som sådan, Rf-verdi i systemet metylenklorid/metanol (9:1) på silikagel 0,29. The N-acetyl-L-glutamic acid-5-[N<2->5-n-butyl-2-pyridyl)-hydrazide]-1-benzyl ester obtained from the main fractions in the form of a colorless foam is further processed as such, Rf value in the system methylene chloride/methanol (9:1) on silica gel 0.29.
Eksempel 4Example 4
En løsning av 7,0 g 2-hydrazino-5-n-butyl-pyridin i 210A solution of 7.0 g of 2-hydrazino-5-n-butyl-pyridine in 210
ml tørt tetrahydrofuran tilsettes 5,9 ml trietylamin, tildryppes deretter ved romtemperatur under omrøring i løpet av en time en løsning av 10,8 g 3-sulfamoyl-4-klor-benzoyl-klorid i 12 0 ml tetrahydrofuran og omrøres videre i 2^ time ved denne temperatur. Trietylaminhydroklorid frafiltreres, og filtratet tilsettes under omrøring 300 ml vandig 2N eddiksyre. Det krystallisat som dannes avfil-treres, tørkes og omkrystalliseres to ganger fra eddiksyreetylester, hvorved 2,5 ml iseddik tilsettes til løsnings-midlet ved den siste omkrystallisasjonen. ml of dry tetrahydrofuran is added to 5.9 ml of triethylamine, then a solution of 10.8 g of 3-sulfamoyl-4-chloro-benzoyl chloride in 120 ml of tetrahydrofuran is added dropwise at room temperature with stirring over the course of one hour and further stirred for 2 hour at this temperature. Triethylamine hydrochloride is filtered off, and the filtrate is added with stirring to 300 ml of aqueous 2N acetic acid. The crystallisate that is formed is filtered off, dried and recrystallized twice from acetic acid ethyl ester, whereby 2.5 ml of glacial acetic acid is added to the solvent in the last recrystallization.
Etter avfiltrering og tørking av bunnfallet, oppnås N2 - After filtering off and drying the precipitate, N2 - is obtained
(5-n-butyl-2-pyridyl)-3-sulfamoyl-4-klor-benzosyrehydrazid-acetat med smp. 142-144°. (5-n-butyl-2-pyridyl)-3-sulfamoyl-4-chloro-benzoic acid hydrazide acetate with m.p. 142-144°.
Eksempel 5Example 5
Til en suspensjon av 3,2 g natriumhydrid i 40 ml toluen tilsettes i løpet av 15 minutter en løsning av 10,0 g 2-hydrazino-5-n-butylpyridin i 150 ml toluen og deretter i løpet av 10 minutter en løsning av 9,2 g pikolinsyre-etylester i 20 ml toluen. Deretter oppvarmes forsiktig i løpet av en h time ved 40° (først eksoterm reaksjon), To a suspension of 3.2 g of sodium hydride in 40 ml of toluene, a solution of 10.0 g of 2-hydrazino-5-n-butylpyridine in 150 ml of toluene is added over the course of 15 minutes and then over the course of 10 minutes a solution of 9 .2 g of picolinic acid ethyl ester in 20 ml of toluene. It is then gently heated for one hour at 40° (first exothermic reaction),
så videre i 2h timer til koking under tilbakeløp. Etter avkjøling ekstraheres reaksjonsblandingen med ialt 200 so continue for 2 hours until boiling under reflux. After cooling, the reaction mixture is extracted with a total of 200
ml 2N saltsyre, den vandig-sure fasen vaskes med eter, den vandig-sure fasen gjøres alkalisk ved hjelp av natronlut og ekstraheres uttømmende med eter. Etter tørking av eterløsningen tilsettes denne en 5N løsning av klorhydrogen i eter til sterkt sur reaksjon, bunnfallet frafiltreres og omkrystalliseres fra etanol, hvoretter N2 - ml of 2N hydrochloric acid, the aqueous-acidic phase is washed with ether, the aqueous-acidic phase is made alkaline with caustic soda and extracted exhaustively with ether. After drying the ether solution, a 5N solution of hydrogen chloride in ether is added to this for a strongly acidic reaction, the precipitate is filtered off and recrystallized from ethanol, after which N2 -
(5-n-butyl-2-pyridyl)-pikolinsyre-hydrazid-dihydroklorid oppnås som lett gulstikkende krystaller med smeltepunkt 186-191° (spaltning). (5-n-butyl-2-pyridyl)-picolinic acid hydrazide dihydrochloride is obtained as slightly yellowish crystals with a melting point of 186-191° (decomposition).
Eksempel 6Example 6
Til en løsning av 8,55 g 2-hydrazino-5-n-butylpyridin iTo a solution of 8.55 g of 2-hydrazino-5-n-butylpyridine i
100 ml toluen tilsettes i løpet av 15 minutter en løsning av 6,5 g klormaursyreetylester i 50 ml toluen under av-kjøling, omrøring og gjennomledning av en nitrogenstrøm. Reaksjonsproduktet utskilles i oljeaktig form som nedre sjikt. For å gjøre omsetningen fullstendig oppvarmes blandingen enda i 2 timer under tilbakeløp, inndampes til slutt til tørrhet, den harpiksaktige resten opptas i en blanding av 250 ml vann og 10 ml 4N saltsyre og den uklare løsningen vaskes med 100 ml eter. Fra den vandige fasen frigjøres reaksjonsproduktet som base ved alkalisering med 25 ml 4N sodaløsning, ekstraheres med 100 ml eter og isoleres som råprodukt etter tørking av eterløsningen over natriumsulfat og inndampning til tørrhet. Dette råprodukt løses i en blanding av 100 ml eter og 50 ml vannfri etanol og tilføres 10 ml av en 5N løsning av klorhydrogen i eter, hvoretter N-etoksykarbonyl-N<2->(5-n-butyl-2-pyridyl)-hydrazin oppnås som monohydroklorid som fargeløse krystaller med smeltepunkt 133-135°, (fra etanol-eter). 100 ml of toluene is added in the course of 15 minutes to a solution of 6.5 g of chloroformic acid ethyl ester in 50 ml of toluene while cooling, stirring and passing through a stream of nitrogen. The reaction product is separated in an oily form as a lower layer. To make the reaction complete, the mixture is heated under reflux for a further 2 hours, finally evaporated to dryness, the resinous residue is taken up in a mixture of 250 ml of water and 10 ml of 4N hydrochloric acid and the cloudy solution is washed with 100 ml of ether. From the aqueous phase, the reaction product is released as a base by alkalization with 25 ml of 4N soda solution, extracted with 100 ml of ether and isolated as a crude product after drying the ether solution over sodium sulphate and evaporating to dryness. This crude product is dissolved in a mixture of 100 ml of ether and 50 ml of anhydrous ethanol and 10 ml of a 5N solution of hydrogen chloride in ether is added, after which N-ethoxycarbonyl-N<2->(5-n-butyl-2-pyridyl)- hydrazine is obtained as monohydrochloride as colorless crystals with melting point 133-135°, (from ethanol-ether).
Eksempel 7Example 7
Til en løsning av 4,0 2-hydrazino-5-n-butylpyridin i 40To a solution of 4.0 2-hydrazino-5-n-butylpyridine in 40
ml eter tilsettes i løpet av en h time en løsning av 2,5 g eddiksyreanhydrid i 20 ml eter under avkjøling og kraftig røring. Etter henstand i 3 timer tildryppes under omrøring og avkjøling en løsning av 7,3 ml av en 5N løsning av klorhydrogen i eter, som er fortynnet med 50 ml eter, det utfelte bunnfallet skilles ut og omkrystalliseres fra etanol-eter. Det oppnås N<2->(5-n-butyl-2-pyridyl)-N-eddiksyre-hydrazid som monohydroklorid i form av svakt fargede krystaller med smeltepunkt 211-212°. ml of ether is added over the course of one hour to a solution of 2.5 g of acetic anhydride in 20 ml of ether while cooling and vigorous stirring. After standing for 3 hours, while stirring and cooling, a solution of 7.3 ml of a 5N solution of hydrogen chloride in ether, which is diluted with 50 ml of ether, is added dropwise, the precipitate that has formed is separated and recrystallized from ethanol-ether. N<2->(5-n-butyl-2-pyridyl)-N-acetic acid hydrazide is obtained as monohydrochloride in the form of faintly colored crystals with a melting point of 211-212°.
Eksempel 8Example 8
Til en suspensjon av 3,2 g natriumhydrid i 40 ml toluen tilsettes i løpet av en<J>5time en løsning av 10,0 g 2-hydrazino-5-n-butylpyridin i 150 ml toluen og deretter i løpet av 10 minutter en løsning av 11,7 g fusarinsyre-etylester i 20 ml toluen, blandingen oppvarmes i løpet av en time til 60° og kokes deretter i 2 timer under tilbake-løp. Etter avkjøling ekstraheres reaksjonsblandingen med ialt 200 ml 2N saltsyre, den vandig-sure fasen vaskes med eter, den vandige fasen gjøres alkalisk med konsentrert natronlut, ekstraheres uttømmende med eter, eterløsningen tørkes over natriumsulfat og inndampes til tørrhet. Resten oppløses i 200 ml vannfri eter og løsningen tilsettes 20 To a suspension of 3.2 g of sodium hydride in 40 ml of toluene, a solution of 10.0 g of 2-hydrazino-5-n-butylpyridine in 150 ml of toluene is added over the course of 5 hours and then over the course of 10 minutes a solution of 11.7 g of fusaric acid ethyl ester in 20 ml of toluene, the mixture is heated during one hour to 60° and then boiled for 2 hours under reflux. After cooling, the reaction mixture is extracted with a total of 200 ml of 2N hydrochloric acid, the aqueous-acidic phase is washed with ether, the aqueous phase is made alkaline with concentrated caustic soda, extracted exhaustively with ether, the ether solution is dried over sodium sulfate and evaporated to dryness. The residue is dissolved in 200 ml of anhydrous ether and the solution is added 20
ml av en 5N løsning av klorhydrogen i eter, det utfelte bunnfallet avsuges og dette omkrystalliseres fra etanol. ml of a 5N solution of hydrogen chloride in ether, the precipitate that precipitates is suctioned off and this is recrystallized from ethanol.
Det oppnåsN<2->(5-n-butyl-2-pyridy1)-N-fusarinsyrehydrazid som dihydroklorid i form av lett gulaktige nåler med smeltepunkt 175° (spaltning). N<2->(5-n-butyl-2-pyridyl)-N-fusaric acid hydrazide is obtained as dihydrochloride in the form of slightly yellowish needles with a melting point of 175° (decomposition).
Eksempel 9Example 9
En løsning av 11,5 g av det ifølge eksempel 3 oppnådde N-acetyl-L-glutaminsyre-5-[N<2->(5-n-butyl-2-pyridy1)-hydrazid] -1-benzylester i 120 ml vannfri metanol omrøres i nærvær av 2,3 g palladium-på-kull-katalysator (5%) i 24 timer ved romtemperatur. Etter frafiltrering av katalysatoren inndampes filtratet på en rotasjonsfordamper, og resten kromatograferes over silikagel ("FLUKA" 60) under anvendelse av en kloroform-metanol-blanding (95:5). Herved oppnås N-acetyl-L-glutaminsyre-5-[N<2->(5-n-butyl-2-pyridy1)-hydrazid] -1-metylester, hvis Rf-verdi i systemet metylenklorid/ metanol (9:1) på silikagel er 0,23. A solution of 11.5 g of the N-acetyl-L-glutamic acid 5-[N<2->(5-n-butyl-2-pyridyl)-hydrazide]-1-benzyl ester obtained according to example 3 in 120 ml anhydrous methanol is stirred in the presence of 2.3 g of palladium-on-charcoal catalyst (5%) for 24 hours at room temperature. After filtering off the catalyst, the filtrate is evaporated on a rotary evaporator, and the residue is chromatographed over silica gel ("FLUKA" 60) using a chloroform-methanol mixture (95:5). This results in N-acetyl-L-glutamic acid-5-[N<2->(5-n-butyl-2-pyridy1)-hydrazide]-1-methyl ester, whose Rf value in the system methylene chloride/methanol (9:1 ) on silica gel is 0.23.
Eksempel 10Example 10
Analogt, som forklart i den allmenne beskrivelsen og beskrevet i eksemplene 1-9, kan også følgende forbindelser med formel I eller deres salter fremstilles under anvendelse av egnede utgangsstoffer og reaksjonsbetingelser: a) N-acetyl-L-glutaminsyre-5-[N<2->(5-n-butyl-2-pyridyl)-hydrazid]-1-etylester ved omestring av den ifølge eksempel 3 oppnådde N-acety'l-L-glutaminsyre-5-[ N2-( 5-n-butyl-2-pyridyl)-hydrazid]-1-benzylester med overskudd vannfri etanol i nærvær av en palladium-på-kull-katalysator (5%) ved romtemperatur, opparbeiding og kromatografi av den rest som oppnås etter inndamping av overskudd etanol, over silikagel ("FLUKA" 60) som beskrevet i eksempel 9, Rf-verdi i systemet metylenklorid/metanol (9:1) på silikagel 0,25. b) N-acetyl-L-glutaminsyre-5-[N<2->(5-n-buty1-2-pyridyl)-hydrazid]-1-(2,2-dimetylpropyl)-ester ved omestring av den ifølge eksempel 3 oppnådde N-acetyl-L-glutaminsyre-5-[N2-(5-n-butyl-2-pyridyl)-hydraz in]-1-benzylester med overskudd vannfri 2,2-dimetylpropanol i nærvær av en palladium-på-kull-katalysator (5%), ved romtemperatur, opparbeiding og kromatografi på silikagel ("FLUKA" 60) av den rest som ble oppnådd etter inndampning av overskudd 2,2-dimetylpropanol som beskrevet i eksempel 9. Rf-verdi i systemet metylenklorid/metanol (9:1) på silikagel 0,28. c) N-acetyl-L-glutaminsyre-5-[N<2->(5-n-butyl-2-pyridyl)-hydrazid]-1-n-butylester ved omestring.av den ifølge eksempel 3 oppnådde N-acetyl-L-glutaminsyre-5-[N<2->(5-n-butyl-2-pyridyl)-hydrazid]-1-benzylester med overskudd vannfri n-butanol i nærvær av en palladium-på-kull-katalysator ved en temperatur på 40-50°, avfiltrering av katalysatoren, inndamping av filtratet på en rotasjonsfordamper og kroma-tograf i av resten på silikagel ("FLUKA" 60), som beskrevet i eksempel 9. Rf-verdi i systemet metylenklorid/metanol (9:1) på silikagel 0,27. Analogously, as explained in the general description and described in examples 1-9, the following compounds of formula I or their salts can also be prepared using suitable starting materials and reaction conditions: a) N-acetyl-L-glutamic acid-5-[N< 2->(5-n-butyl-2-pyridyl)-hydrazide]-1-ethyl ester by transesterification of the N-acetyl-L-glutamic acid-5-[N2-(5-n-butyl) obtained according to example 3 -2-pyridyl)-hydrazide]-1-benzyl ester with excess anhydrous ethanol in the presence of a palladium-on-charcoal catalyst (5%) at room temperature, work-up and chromatography of the residue obtained after evaporation of excess ethanol, over silica gel ("FLUKA" 60) as described in example 9, Rf value in the system methylene chloride/methanol (9:1) on silica gel 0.25. b) N-acetyl-L-glutamic acid 5-[N<2->(5-n-butyl1-2-pyridyl)-hydrazide]-1-(2,2-dimethylpropyl)-ester by transesterification of the according to example 3 obtained N-acetyl-L-glutamic acid-5-[N2-(5-n-butyl-2-pyridyl)-hydrazine]-1-benzyl ester with excess anhydrous 2,2-dimethylpropanol in the presence of a palladium-on- charcoal catalyst (5%), at room temperature, work-up and chromatography on silica gel ("FLUKA" 60) of the residue obtained after evaporation of excess 2,2-dimethylpropanol as described in example 9. Rf value in the system methylene chloride/ methanol (9:1) on silica gel 0.28. c) N-acetyl-L-glutamic acid-5-[N<2->(5-n-butyl-2-pyridyl)-hydrazide]-1-n-butyl ester by transesterification of the N-acetyl obtained according to example 3 -L-glutamic acid-5-[N<2->(5-n-butyl-2-pyridyl)-hydrazide]-1-benzyl ester with excess anhydrous n-butanol in the presence of a palladium-on-charcoal catalyst at a temperature of 40-50°, filtering off the catalyst, evaporating the filtrate on a rotary evaporator and chromatographing the residue on silica gel ("FLUKA" 60), as described in example 9. Rf value in the system methylene chloride/methanol (9: 1) on silica gel 0.27.
d) N-acetyl-L-glutaminsyre-5-[N2 7(5-n-butyl-2-pyridyl)-hydrazid]-1-amid ved omsetning av det ifølge eksempel 1 d) N-acetyl-L-glutamic acid-5-[N2 7(5-n-butyl-2-pyridyl)-hydrazide]-1-amide by reacting it according to example 1
oppnådde L-glutaminsyre-5-[N<2->(5-n-butyl-2-pyridyl)-hydrazid] -hemihydrat med overskudd metanol i nærvær av cyklo-heksylkarbodiimid ved romtemperatur til L-glutaminsyre-5-[N<2->(5-n-butyl-2-pyridyl)-hydrazid]-1-metylester, hvis etterfølgende omsetning med overskudd ammoniakk løst i metanol i lukket kar i 5 timer ved romtemperatur og opparbeiding av reaksjonsblandingen til L-glutaminsyre-5- obtained L-glutamic acid-5-[N<2->(5-n-butyl-2-pyridyl)-hydrazide] hemihydrate with excess methanol in the presence of cyclohexylcarbodiimide at room temperature to L-glutamic acid-5-[N< 2->(5-n-butyl-2-pyridyl)-hydrazide]-1-methyl ester, whose subsequent reaction with excess ammonia dissolved in methanol in a closed vessel for 5 hours at room temperature and work-up of the reaction mixture to L-glutamic acid-5-
[N<2->(5-n-buty1-2-pyridyl)-hydrazid]-1-amid og dettes etter-følgende omsetning med eddiksyreanhydrid i dimetylformamid i nærvær av vannfritt natriumkarbonat ved romtemperatur i 15 timer, så vel som opparbeiding og kromatografi av resten som beskrevet i eksempel 2. Rf-verdi i systemet metylenklorid/metanol (9:1) på silikagel 0,15. [N<2->(5-n-buty1-2-pyridyl)-hydrazide]-1-amide and its subsequent reaction with acetic anhydride in dimethylformamide in the presence of anhydrous sodium carbonate at room temperature for 15 hours, as well as working up and chromatography of the residue as described in example 2. Rf value in the system methylene chloride/methanol (9:1) on silica gel 0.15.
e) N-propionyl-L-glutaminsyre-5-[N<2->(5-n-butyl-2-pyridyl)-hydrazid] ved omsetning av det ifølge eksempel 1 oppnådde e) N-propionyl-L-glutamic acid-5-[N<2->(5-n-butyl-2-pyridyl)-hydrazide] by reaction of the obtained according to example 1
L-glutaminsyre-5-[N<2->(5-n-buty1-2-pyridyl)-hydrazid]-hemi-hydrat med propionsyreanhydrid i dimetylformamid i nærvær av vannfritt natriumkarbonat ved romtemperatur i 2 0 timer, opparbeiding og kromatografi av resten på silikagel så L-glutamic acid-5-[N<2->(5-n-buty1-2-pyridyl)-hydrazide]-hemi-hydrate with propionic anhydride in dimethylformamide in the presence of anhydrous sodium carbonate at room temperature for 20 hours, work-up and chromatography of the rest on silica gel then
vel som videreforarbeidelse av hovedfraksjonene som beskrevet i eksempel 2. Rf-verdi i systemet metylenklorid/metanol/ NH4OH konsentrert (5:3:1) 0,78. as well as further processing of the main fractions as described in example 2. Rf value in the system methylene chloride/methanol/NH4OH concentrated (5:3:1) 0.78.
f) N-pivaloyl-L-glutaminsyre-5-[N<2->(5-n-butyl-2-pyridyl)-hydrazid] ved omsetning av det ifølge eksempel 1 oppnådde L-glutaminsyre-5-[N<2->(5-n-buty1-2-pyridyl)-hydrazid]-hemihydrat med pivalinsyreanhydrid i dimetylformamid i nærvær av vannfritt natriumkarbonat ved en temperatur på 40-50° i 20 timer, opparbeiding og kromatografi av resten på silikagel, så vel som videreforarbeidelse av hovedfraksjonene som beskrevet i eksempel 2. Rf-verdi i systemet metylenklorid/metanol/NH4OH kons. (5:3:1) 0,80. f) N-pivaloyl-L-glutamic acid-5-[N<2->(5-n-butyl-2-pyridyl)-hydrazide] by reacting the L-glutamic acid-5-[N<2 obtained according to example 1 ->(5-n-buty1-2-pyridyl)-hydrazide]-hemihydrate with pivalic anhydride in dimethylformamide in the presence of anhydrous sodium carbonate at a temperature of 40-50° for 20 hours, working up and chromatography of the residue on silica gel, as well as further processing of the main fractions as described in example 2. Rf value in the system methylene chloride/methanol/NH4OH conc. (5:3:1) 0.80.
g) N-benzoyl-L-glutaminsyre-5-[N<2->(5-n-buty1-2-pyridyl)-hydrazid] ved omsetning av det ifølge eksempel 1 oppnådde g) N-benzoyl-L-glutamic acid-5-[N<2->(5-n-buty1-2-pyridyl)-hydrazide] by reacting the obtained according to example 1
L-glutaminsyre-5-[N<2->(5-n-buty1-2-pyridyl)-hydrazid]-hemi-hydrat med benzosyreanhydrid i dimetylformamid i nærvær av vannfritt natriumkarbonat ved en temperatur på 40-50° L-glutamic acid-5-[N<2->(5-n-buty1-2-pyridyl)-hydrazide]-hemi-hydrate with benzoic anhydride in dimethylformamide in the presence of anhydrous sodium carbonate at a temperature of 40-50°
i 25 timer, opparbeiding og kromatografi av resten på silikagel så vel som videreforarbeiding av hovedfraksjonene som beskrevet i eksempel 2. Rf-verdi i systemet metylenklorid/metanol/NH4OH kons. (5:3:1) 0,79. for 25 hours, working up and chromatography of the residue on silica gel as well as further processing of the main fractions as described in example 2. Rf value in the system methylene chloride/methanol/NH4OH conc. (5:3:1) 0.79.
h) N-acetyl-L-glutaminsyre-5-[N<2->(5-mety1-2-pyridyl)-hydrazid] ved omsetning av 2-hydrazino-5-metyl-pyridin h) N-acetyl-L-glutamic acid-5-[N<2->(5-methyl-2-pyridyl)-hydrazide] by reaction of 2-hydrazino-5-methyl-pyridine
med N-(benzyloksykarbonyl)-L-glutaminsyre-l-benzylester-5-(N-hydroksysuccinimid)ester i vannfritt tetrahydrofuran i 0° i 2 timer, avdampning av løsningsmidlet og kromatografi av resten på silikagel under anvendelse -av eddiksyreetylester som elueringsmiddel og opparbeiding av hovedfraksjonene til (N-benzyloksykarbonyl)-L-glutaminsyre-5-[N<2->(5-metyl-2-pyridyl)-hydrazid]-1-benzylester, hvis etterfølgende avbenzylering ved hjelp av hydrogen i metanol i nærvær av en palladium-på-kull-katalysator (5%), omkrystallisering fra metanol av L-glutaminsyre-5-[N<2->(5-metyl-2-pyridyl)-hydrazid]som oppnås etter opparbeiding, with N-(benzyloxycarbonyl)-L-glutamic acid-1-benzyl ester-5-(N-hydroxysuccinimide)ester in anhydrous tetrahydrofuran at 0° for 2 hours, evaporation of the solvent and chromatography of the residue on silica gel using -ethyl acetate as eluent and work-up of the main fractions to (N-benzyloxycarbonyl)-L-glutamic acid-5-[N<2->(5-methyl-2-pyridyl)-hydrazide]-1-benzyl ester, whose subsequent debenzylation using hydrogen in methanol in the presence of a palladium-on-charcoal catalyst (5%), recrystallization from methanol of L-glutamic acid-5-[N<2->(5-methyl-2-pyridyl)-hydrazide] which is obtained after work-up,
og dets N-acetylering ved omsetning med eddiksyreanhydrid i dimetylformamid i nærvær av vannfritt natriumkarbonat i 15 timer ved romtemperatur, avdamping av løsningsmidlet og kromatografering av resten på silikagel ved hjelp av en blanding av kloroform/metanol/ammoniakk 5:3:1 og opparbeiding av hovedfraksjonene. Rf-verdi i systemet metylenklorid/metanol/konsentrert ammoniumhydroksyd (5:3:1) 0,70. and its N-acetylation by reaction with acetic anhydride in dimethylformamide in the presence of anhydrous sodium carbonate for 15 hours at room temperature, evaporation of the solvent and chromatography of the residue on silica gel using a mixture of chloroform/methanol/ammonia 5:3:1 and work-up of the main factions. Rf value in the system methylene chloride/methanol/concentrated ammonium hydroxide (5:3:1) 0.70.
i) N-benzoyl-L-glutaminsyre-5-[ N2-(5-mety1-2-pyridyl)-hydrazid] ved omsetning av det ifølge eksempel h) oppnådde L-glutaminsyre-5-[N<2->(5-metyl-2-pyridyl)-hydrazid] med benzosyreanhydrid i dimetylformamid i nærvær av vannfritt natriumkarbonat i 2 0 timer ved romtemperatur, avdamping av løsningsmiddel, kromatografering av resten på silikagel ved hjelp av en blanding av kloroform/metanol/ammoniakk 5:3:1 og opparbeiding av hovedfraksjonene. Rf-verdi i systemet metylenklorid/metanol/konsentrert ammoniumhydroksyd (5:3:1) 0,73. i) N-benzoyl-L-glutamic acid-5-[N2-(5-methyl-2-pyridyl)-hydrazide] by reacting the L-glutamic acid-5-[N<2->(5 -methyl-2-pyridyl)-hydrazide] with benzoic anhydride in dimethylformamide in the presence of anhydrous sodium carbonate for 20 hours at room temperature, evaporation of solvent, chromatography of the residue on silica gel using a mixture of chloroform/methanol/ammonia 5:3: 1 and processing of the main fractions. Rf value in the system methylene chloride/methanol/concentrated ammonium hydroxide (5:3:1) 0.73.
j) N-acetyl-L-glutaminsyre-5-[N<2->(5-benzy1-2-pyridyl)-hydrazid] ved omsetning av 2-hydrazino-5-benzyl-pyridin med N-(benzyloksykarbonyl)-L-glutaminsyre-l-benzylester-5-(N-hydroksysuccinimid)ester i vannfritt tetrahydrofuran j) N-acetyl-L-glutamic acid-5-[N<2->(5-benzyl1-2-pyridyl)-hydrazide] by reaction of 2-hydrazino-5-benzyl-pyridine with N-(benzyloxycarbonyl)-L -glutamic acid-1-benzyl ester-5-(N-hydroxysuccinimide) ester in anhydrous tetrahydrofuran
ved 0° i 2 timer, avdamping av løsningsmidlet og kromatografering av resten på silikagel under anvendelse av eddiksyreetylester som elueringsmiddel og opparbeiding av hovedfraksjonene til (N-benzyloksykarbonyl)-L-glutaminsyre-5- [ N2-(5-benzyl-2-pyridyl)-hydrazid]-1-benzyl-ester, denne etterfølgende avbenzylering ved hjelp av hydrogen i metanol i nærvær av en palladium-på-kull-katalysator (5%), omkrystallisering fra metanol av det L-glutaminsyre-5-[N2-(5-benzyl-2-pyridyl)-hydrazid] som at 0° for 2 hours, evaporating the solvent and chromatographing the residue on silica gel using ethyl acetate as eluent and working up the main fractions to (N-benzyloxycarbonyl)-L-glutamic acid-5-[ N2-(5-benzyl-2-pyridyl )-hydrazide]-1-benzyl ester, this subsequent debenzylation using hydrogen in methanol in the presence of a palladium-on-charcoal catalyst (5%), recrystallization from methanol of the L-glutamic acid-5-[N2- (5-benzyl-2-pyridyl)-hydrazide] as
ble oppnådd etter opparbeidingen, og dettes N-acetylering ved omsetning med eddiksyreanhydrid i dimetylformamid i nærvær av vannfritt natriumkarbonat 15 timer ved romtemperatur, avdamping av løsningsmidlet og kromatografering av resten på silikagel ved hjelp av en blanding av kloroform/metanol/ammoniakk 5:3:1 og opparbeiding av hovedfraksjonene. Rf-verdi i systemet metylenklorid/metanol/konsentrert ammoniumhydroksyd (5:3:1) 0,81. was obtained after the work-up, and its N-acetylation by reaction with acetic anhydride in dimethylformamide in the presence of anhydrous sodium carbonate for 15 hours at room temperature, evaporation of the solvent and chromatography of the residue on silica gel using a mixture of chloroform/methanol/ammonia 5:3: 1 and processing of the main fractions. Rf value in the system methylene chloride/methanol/concentrated ammonium hydroxide (5:3:1) 0.81.
k) N-acetyl-L-glutaminsyre-5-[N<2->(5-fenyl-2-pyridyl)-hydrazid] ved omsetning av 2-hydrazino-5-fenyl-pyridin med N-(benzyloksykarbonyl)-L-glutaminsyre-l-benzylester-5-(N-hydroksysuccinimid)-ester i vannfritt tetrahydrofuran ved 0° i 2 timer, avdamping av løsningsmidlet og kromatografering av resten på silikagel under anvendelse av eddiksyreetylester som elueringsmiddel og opparbeiding av hovedfraksjonene til (N-benzyloksykarbonyl)-L-glutaminsyre-5- [ N2 -(5-feny1-2-pyridyl)-hydrazid]-1-benzylester, dennes etterfølgende avbenzylering ved hjelp av hydrogen i metanol i nærvær av en palladium-på-kull-katalysator (5%), omkrystallisering fra metanol av det L-glutaminsyre-5-[N<2->(5-fenyl-2-pyridyl)-hydrazid] som oppnås etter opparbeiding, og dettes N-acetylering ved omsetning med eddiksyreanhydrid i dimetylformamid i nærvær av vannfritt natriumkarbonat i 15 timer ved romtemperatur, avdamping av løsnings-midlet og kromatografering av resten på silikagel ved k) N-acetyl-L-glutamic acid-5-[N<2->(5-phenyl-2-pyridyl)-hydrazide] by reaction of 2-hydrazino-5-phenyl-pyridine with N-(benzyloxycarbonyl)-L -glutamic acid-1-benzyl ester-5-(N-hydroxysuccinimide)-ester in anhydrous tetrahydrofuran at 0° for 2 hours, evaporation of the solvent and chromatography of the residue on silica gel using ethyl acetate as eluent and work-up of the main fractions to (N-benzyloxycarbonyl )-L-glutamic acid-5- [ N2 -(5-phenyl1-2-pyridyl)-hydrazide]-1-benzyl ester, its subsequent debenzylation using hydrogen in methanol in the presence of a palladium-on-charcoal catalyst (5 %), recrystallization from methanol of the L-glutamic acid-5-[N<2->(5-phenyl-2-pyridyl)-hydrazide] obtained after work-up, and its N-acetylation by reaction with acetic anhydride in the presence of dimethylformamide of anhydrous sodium carbonate for 15 hours at room temperature, evaporation of the solvent and chromatography of the residue on silica gel by
hjelp av en blanding av kloroform/metanol/ammoniakk 5:3:1 og opparbeiding av hovedfraksjonene. Rf-verdi i systemet using a mixture of chloroform/methanol/ammonia 5:3:1 and working up the main fractions. Rf value in the system
metylenklorid/metanol/konsentrert ammoniumhydroksyd (5:3:1) 0,79. methylene chloride/methanol/concentrated ammonium hydroxide (5:3:1) 0.79.
1) N-acetyl-L-glutaminsyre-5-[N2-(5-(2-okso-n-butyl)-2 - pyridyl)-hydrazid]ved omsetning mellom 2-hydrazino-5-(2-okso-n-butyl)-pyridin og N-(benzyloksykarbony1)-L-glutaminsyre-l-benzylester-5-(N-hydroksysuccinimid)-ester i vannfritt tetrahydrofuran ved 0° i 2 timer, avdamping av løsningsmidlet og kromatografering av resten på silikagel under anvendelse av eddiksyreetylester som elueringsmiddel og opparbeiding av hovedfraksjonene til (N-benzyloksy-karbonyl) -L-glutaminsyre-5-[N2-(5-(2-okso-n-buty1-2-pyridyl ) -hydrazid] -1-benzylester , dennes etterfølgende avbenzylering ved hjelp av hydrogen i metanol i nærvær av en palladium-på-kull-katalysator (5%), omkrystallisering fra en metanol/etanol-blanding av det L-glutaminsyre-5-[N<2->1) N-acetyl-L-glutamic acid-5-[N2-(5-(2-oxo-n-butyl)-2 - pyridyl)-hydrazide] by reaction between 2-hydrazino-5-(2-oxo-n -butyl)-pyridine and N-(benzyloxycarbonyl)-L-glutamic acid-1-benzyl ester-5-(N-hydroxysuccinimide)-ester in anhydrous tetrahydrofuran at 0° for 2 hours, evaporating the solvent and chromatographing the residue on silica gel using of acetic acid ethyl ester as eluent and processing of the main fractions to (N-benzyloxy-carbonyl)-L-glutamic acid-5-[N2-(5-(2-oxo-n-buty1-2-pyridyl)-hydrazide]-1-benzyl ester, its subsequent debenzylation using hydrogen in methanol in the presence of a palladium-on-charcoal catalyst (5%), recrystallization from a methanol/ethanol mixture of the L-glutamic acid-5-[N<2->
(5-(2-okso-n-butyl)-2-pyridyl)-hydrazid]som oppnås etter opparbeidingen, og dettes N-acetylering ved omsetning med eddiksyreanhydrid i dimetylformamid i nærvær av vannfritt natriumkarbonat i 15 timer ved romtemperatur, avdamping av løsningsmidlet og kromatografering av resten på silikagel ved hjelp av en blanding av kloroform/metanol/ammoniakk 5:3:1 og opparbeiding av hovedfraksjonene. Rf-verdi i systemet metylenklorid/metanol/konsentrert ammoniumhydroksyd (5:3:1) 0,71. (5-(2-oxo-n-butyl)-2-pyridyl)-hydrazide] which is obtained after the work-up, and its N-acetylation by reaction with acetic anhydride in dimethylformamide in the presence of anhydrous sodium carbonate for 15 hours at room temperature, evaporation of the solvent and chromatographing the residue on silica gel using a mixture of chloroform/methanol/ammonia 5:3:1 and working up the main fractions. Rf value in the system methylene chloride/methanol/concentrated ammonium hydroxide (5:3:1) 0.71.
m) N-acetyl-L-glutaminsyre-5-[N<2->(5-acetyl-2-pyridyl)-hydrazid]ved omsetning mellom 2-hydrazino-5-acetyl-pyridin og N-(benzyloksykarbonyl)-L-glutaminsyre-l-benzylester-5-(N-hydroksysuccinimid)-ester i vannfritt tetrahydrofuran ved 0° i 2 timer, avdamping av løsningsmidlet og kromatografering av resten på silikagel under anvendelse av eddiksyreetylester som elueringsmiddel og opparbeiding av hovedfraksjonene til (N-benzyloksykarbonyl)-L-glutaminsyre-5-[N<2->(5-acetyl-2-pyridyl)-hydrazid]-1-benzylester, dennes etterfølgende avbenzylering ved hjelp av hydrogen i metanol i nærvær av en palladium-på-kull-katalysator (5%), omkry- m) N-acetyl-L-glutamic acid-5-[N<2->(5-acetyl-2-pyridyl)-hydrazide] by reaction between 2-hydrazino-5-acetyl-pyridine and N-(benzyloxycarbonyl)-L -glutamic acid-1-benzyl ester-5-(N-hydroxysuccinimide)-ester in anhydrous tetrahydrofuran at 0° for 2 hours, evaporation of the solvent and chromatography of the residue on silica gel using ethyl acetate as eluent and work-up of the main fractions to (N-benzyloxycarbonyl )-L-glutamic acid-5-[N<2->(5-acetyl-2-pyridyl)-hydrazide]-1-benzyl ester, its subsequent debenzylation using hydrogen in methanol in the presence of a palladium-on-charcoal catalyst (5%), ambient
stallisering fra metanol av det L-glutaminsyre-5-[N<2->(5-acetyl-2-pyridyl)-hydrazid]som oppnås etter opparbeidingen, og dettes N-acetylering ved omsetning med eddiksyreanhydrid i dimetylformamid i nærvær av vannfritt natriumkarbonat i 15 timer ved romtemperatur, avdamping av løsningsmidlet og kromatografering av resten på silikagel ved hjelp av en blanding av kloroform/metanol/ammoniakk 5:3:1 og opparbeiding av hovedfraksjonene. Rf-verdi i systemet metylenklorid/metanol/konsentrert ammoniumhydroksyd (5:3:1) 0,65. stallation from methanol of the L-glutamic acid-5-[N<2->(5-acetyl-2-pyridyl)-hydrazide] which is obtained after the work-up, and its N-acetylation by reaction with acetic anhydride in dimethylformamide in the presence of anhydrous sodium carbonate for 15 hours at room temperature, evaporating the solvent and chromatographing the residue on silica gel using a mixture of chloroform/methanol/ammonia 5:3:1 and working up the main fractions. Rf value in the system methylene chloride/methanol/concentrated ammonium hydroxide (5:3:1) 0.65.
n) N-acetyl-L-glutaminsyre-5-[N<2->(5-n-buty1-2-pyridyl)-hydrazid]-1-(pivaloyloksymetyl)-ester ved omsetning av det ifølge eksempel 3 som mellomprodukt oppnådde N-acetyl-L-glutaminsyre-5- [ N2-( 5-n-2-pyridyl) -hydraz id], og dettes natriumsalt som har oppnådd ved nøytralisering med natronlut og inndampning til tørrhet, med pivalinsyrejodmetyl-ester i dimetylformamid ved en temperatur på 0-50° og etterfølgende omrøring i 17 timer ved romtempreatur, inndamping av reaksjonsblandingen i høyvakuum, ekstrahering med eddiksyreetylester og Flash-kromatografering av den rest som ble oppnådd etter avdamping av løsningsmidlet, n) N-acetyl-L-glutamic acid-5-[N<2->(5-n-buty1-2-pyridyl)-hydrazide]-1-(pivaloyloxymethyl)-ester by reaction of the intermediate product obtained according to example 3 N-acetyl-L-glutamic acid-5-[N2-(5-n-2-pyridyl)-hydrazide], and its sodium salt obtained by neutralization with caustic soda and evaporation to dryness, with pivalic acid iodomethyl ester in dimethylformamide at a temperature of 0-50° and subsequent stirring for 17 hours at room temperature, evaporation of the reaction mixture under high vacuum, extraction with acetic acid ethyl ester and flash chromatography of the residue obtained after evaporation of the solvent,
med en metylenklorid/metanol-blanding 9:1. Rf-verdi i systemet metylenklorid/metanol (9:1 på silikagel 0,26. with a methylene chloride/methanol mixture 9:1. Rf value in the system methylene chloride/methanol (9:1 on silica gel 0.26.
På analog måte som for fremstillingen av de forbindelser som er angitt under h) - n), kan også følgende forbindelser fremstilles via de tilsvarende mellomstadier: o) N-acetyl-L-glutaminsyre-5-[N<2->(3-n-butyl-2-pyridyl)-hydrazid] fra 2-hydrazino-3-n-butyl-pyridin og det derav ved omsetning med N-(benzyloksykarbonyl)-L-glutaminsyre-1- benzylester-5-(N-hydroksysuccinimid)-ester oppnåelige (N-benzyloksykarbonyl)-L-glutaminsyre-5-[N<2->(3-n-buty1-2- pyridyl)-hydrazid], dettes avbenzylering til L-glutaminsyre-5- [ N2 -( 3 -n-butyl-2-pyridyl ) -hydraz id] og dettes acetylering til den ovenfor nevnte N-acetylforbindelse. In an analogous manner to the preparation of the compounds indicated under h) - n), the following compounds can also be prepared via the corresponding intermediate stages: o) N-acetyl-L-glutamic acid-5-[N<2->(3- n-butyl-2-pyridyl)-hydrazide] from 2-hydrazino-3-n-butyl-pyridine and its derivative by reaction with N-(benzyloxycarbonyl)-L-glutamic acid-1-benzyl ester-5-(N-hydroxysuccinimide) -ester obtainable (N-benzyloxycarbonyl)-L-glutamic acid-5-[N<2->(3-n-buty1-2- pyridyl)-hydrazide], its debenzylation to L-glutamic acid-5- [ N2 -( 3 -n-butyl-2-pyridyl)-hydrazide] and its acetylation to the above-mentioned N-acetyl compound.
Rf-verdi i systemet metylenklorid/metanol/konsentrert Rf value in the system methylene chloride/methanol/concentrate
ammoniumhydroksyd (5:3:1) 0,78.ammonium hydroxide (5:3:1) 0.78.
p) N-acetyl-L-glutaminsyre-5-[N<2->(4-n-butyl-2-pyridyl)-hydrazid] fra 2-hydrazino-4-n-butyl-pyridin, og den derav ved omsetning med N-(benzyloksykarbonyl)-L-glutaminsyre-l-benzylester-5-(N-hydroksysuccinimid)-ester oppnåelige (N-benzyloksykarbonyl)-L-glutaminsyre-L-glutaminsyre-5-[N 2-(4-n-butyl-2-pyridyl)-hydrazid] og dettes acetylering til den ovenfor nevnte N-acetylforbindelse. Rf-verdi i systemet metylenklorid/metanol/konsentrert ammoniumhydroksyd (5:3:1) 0,77. p) N-acetyl-L-glutamic acid-5-[N<2->(4-n-butyl-2-pyridyl)-hydrazide] from 2-hydrazino-4-n-butyl-pyridine, and the derivative by reaction with N-(benzyloxycarbonyl)-L-glutamic acid-l-benzyl ester-5-(N-hydroxysuccinimide)-ester obtainable (N-benzyloxycarbonyl)-L-glutamic acid-L-glutamic acid-5-[N 2-(4-n- butyl-2-pyridyl)-hydrazide] and its acetylation to the above-mentioned N-acetyl compound. Rf value in the system methylene chloride/methanol/concentrated ammonium hydroxide (5:3:1) 0.77.
q) N-acetyl-L-glutaminsyre-5-[N<2->(6-n-butyl-2-pyridyl)-hydrazid] fra 2-hydrazino-6-n-butyl-pyridin, og det derav ved omsetning med N-(benzyloksykarbonyl)-L-glutaminsyre-1- benzylester-5-(N-hydroksysuccinimid)-ester oppnåelige (N-benzyloksykarbonyl)-L-glutaminsyre-5-( N2-(6-n-butyl-2- pyridyl)-hydrazid], dettes avbenzylering til L-glutaminsyre-5- [N2-( 6-n-butyl-2-pyridyl) -hydrazid] og dettes acetylering til den ovenfor nevnte N-acetylforbindelse. Rf-verdi i systemet metylenklorid/metanol/konsentrert ammoniumhydroksyd (5:3:1) 0,77. q) N-acetyl-L-glutamic acid-5-[N<2->(6-n-butyl-2-pyridyl)-hydrazide] from 2-hydrazino-6-n-butyl-pyridine, and that by reaction with N-(benzyloxycarbonyl)-L-glutamic acid-1-benzyl ester-5-(N-hydroxysuccinimide)-ester obtainable (N-benzyloxycarbonyl)-L-glutamic acid-5-( N2-(6-n-butyl-2-pyridyl )-hydrazide], its debenzylation to L-glutamic acid-5-[N2-( 6-n-butyl-2-pyridyl)-hydrazide] and its acetylation to the above-mentioned N-acetyl compound Rf value in the system methylene chloride/methanol /concentrated ammonium hydroxide (5:3:1) 0.77.
r) L-alanyl-[N<2->(5-n-butyl-2-pyridyl)-hydrazid] ved omsetning mellom 2-hydrazino-5-n-butylpyridin og L-alanin-metylester ved 2-timers oppvarming under tilbakeløp i benzen i en nitrogenatmosfære, avdamping av løsningsmidlet, oppløsning av resten i toluen, vasking med vann, og ekstrahering av den organiske fasen med 2N saltsyre, vasking av den vandig-sure løsningen med eter, tilsetning til den vandige løsningen av konsentrert natronlut til sterkt alkalisk reaksjon, og ekstrahering av blandingen med eter, vasking av eterløsningen med vann og tilsetning til eter-løsningen som er tørket ved hjelp av natriumsulfat, av en 5N løsning av klorhydrogen i eter til sterkt sur reaksjon og fraskillelse av det oppnådde L-alanyl-[N<2->(5-n-butyl-2-pyridyl)-hydrazid]-dihydroklorid i form av hvite krystaller. Rf-verdi for den frie basen i systemet r) L-alanyl-[N<2->(5-n-butyl-2-pyridyl)-hydrazide] by reaction between 2-hydrazino-5-n-butylpyridine and L-alanine methyl ester by heating for 2 hours under refluxing in benzene under a nitrogen atmosphere, evaporating the solvent, dissolving the residue in toluene, washing with water, and extracting the organic phase with 2N hydrochloric acid, washing the aqueous-acidic solution with ether, adding to the aqueous solution concentrated sodium hydroxide solution to strongly alkaline reaction, and extracting the mixture with ether, washing the ether solution with water and adding to the ether solution dried with sodium sulfate a 5N solution of hydrogen chloride in ether to strongly acid reaction and separating the obtained L-alanyl -[N<2->(5-n-butyl-2-pyridyl)-hydrazide]-dihydrochloride in the form of white crystals. Rf value of the free base in the system
metylenklorid/metanol/konsentrert ammoniumhydroksyd (5:3:1) 0,92. methylene chloride/methanol/concentrated ammonium hydroxide (5:3:1) 0.92.
s) L-alanyl-[N<2->(6-n-butyl-2-pyridyl)-hydrazid] ved omsetning mellom 2-hydrazino-6-n-butylpyridin og L-alanin-metylester og etterfølgende opparbeiding som beskrevet under r) og fraskilling av det oppnådde L-alanyl-[N<2->(6-n-butyl-2-pyridyl)-hydrazid]-dihydroklorid i form av hvite krystaller. Rf-verdi for den frie basen i systemet metylenklorid/metanol/konsentrert ammoniumhydroksyd (5:3:1) 0,90. s) L-alanyl-[N<2->(6-n-butyl-2-pyridyl)-hydrazide] by reaction between 2-hydrazino-6-n-butylpyridine and L-alanine methyl ester and subsequent work-up as described under r) and separation of the obtained L-alanyl-[N<2->(6-n-butyl-2-pyridyl)-hydrazide]-dihydrochloride in the form of white crystals. Rf value for the free base in the system methylene chloride/methanol/concentrated ammonium hydroxide (5:3:1) 0.90.
t) N-acetyl-L-alanyl-[N<2->(5-n-butyl-2-pyridyl)-hydrazid] ved omsetning av det ifølge q) oppnådde L-alanyl-[N<2->(5-n-butyl-2-pyridyl-hydrazid]-dihydroklorid med konsentrert natronlut og den således oppnådde base med eddiksyreanhydrid i dimetylformamid i nærvær av vannfritt natriumkarbonat ved romtemperatur i 10 timer, avdamping av løsnings-midlet under forminsket trykk, opptak av resten i eter, vasking av eterløsningen med vann, tilsetning til eter-løsningen av en 5N løsning av klorhydrogen til sterkt sur reaksjon og fraskillelse av det oppnådde N-acetyl-L-alany1-[ N2 - ( 5 -n-buty 1-2 -pyridyl) -hydrazid]-hydroklorid i form av hvite krystaller. Rf-verdi for den frie basen i systemet metylenklorid/metanol/konsentrert ammoniumhydroksyd (5:3:1) 0,85. t) N-acetyl-L-alanyl-[N<2->(5-n-butyl-2-pyridyl)-hydrazide] by reacting the L-alanyl-[N<2->(5 -n-butyl-2-pyridyl-hydrazide]-dihydrochloride with concentrated caustic soda and the base thus obtained with acetic anhydride in dimethylformamide in the presence of anhydrous sodium carbonate at room temperature for 10 hours, evaporation of the solvent under reduced pressure, absorption of the residue in ether , washing the ether solution with water, adding to the ether solution a 5N solution of hydrogen chloride for a strongly acidic reaction and separating the obtained N-acetyl-L-alany1-[N2-(5-n-butyl 1-2-pyridyl) -hydrazide] hydrochloride in the form of white crystals Rf value of the free base in the system methylene chloride/methanol/concentrated ammonium hydroxide (5:3:1) 0.85.
u) N-acetyl-L-alany1-[N<2->(6-n-butyl-2-pyridyl)-hydrazid] ved omsetning av det ifølge s) oppnådde L-alany1-[N<2->(6-n-butyl-2-pyridyl)-hydrazidfdihydroklorid med konsentrert natronlut, omsetning av den således oppnådde base med eddiksyreanhydrid analogt som beskrevet under s), opparbeiding av reaksjonsblandingen og fraskillelse av det oppnådde N-acetyl-L-alanyl-[N<2->(6-n-buty1-2-pyridyl)-hydrazid]-hydroklorid i form av hvite krystaller. Rf-verdi for den frie basen i systemet metylenklorid/metanol/ konsentrert ammoniumhydroksyd (5:3:1) 0,83. u) N-acetyl-L-alany1-[N<2->(6-n-butyl-2-pyridyl)-hydrazide] by reacting the L-alany1-[N<2->(6 -n-butyl-2-pyridyl)-hydrazide dihydrochloride with concentrated caustic soda, reaction of the base thus obtained with acetic anhydride analogously to that described under s), work-up of the reaction mixture and separation of the obtained N-acetyl-L-alanyl-[N<2 ->(6-n-butyl1-2-pyridyl)-hydrazide]-hydrochloride in the form of white crystals. Rf value for the free base in the system methylene chloride/methanol/concentrated ammonium hydroxide (5:3:1) 0.83.
v) Fra den frie basen som oppnås ved behandling av det L-alanyl-[N<2->(5-n-buty1-2-pyridyl)-hydrazid]-dihydroklorid som er oppnådd ved behandlingen ifølge r) med konsentrert natronlut, kan ved omsetning med det tilsvarende syre-anhydrid oppnås følgende forbindelse i form av dets hydro-klorid analogt t): N-propionyl-L-alany1-[N<2->(5-n-butyl-2-pyridyl)-hydrazid]. Rf-verdi for den frie basen i systemet metylenklorid/metanol/konsentrert ammoniumhydroksyd (5:3:1) 0,85. v) From the free base obtained by treating the L-alanyl-[N<2->(5-n-buty1-2-pyridyl)-hydrazide]-dihydrochloride obtained by the treatment according to r) with concentrated caustic soda, by reaction with the corresponding acid anhydride, the following compound can be obtained in the form of its hydrochloride analogous to t): N-propionyl-L-alany1-[N<2->(5-n-butyl-2-pyridyl)-hydrazide ]. Rf value for the free base in the system methylene chloride/methanol/concentrated ammonium hydroxide (5:3:1) 0.85.
w) N-benzoy1-L-alanyl-[N<2->(6-metyl-2-pyridyl)-hydrazid] ved omsetning mellom 2-hydrazino-6-metylpyridin og L-ala-ninmetylester ved 3 timers oppvarming under tilbakeløp i benzen i en nitrogenatmosfære, avdamping av løsnings-midlet, løsning av resten i toluen, vasking med vann, og ekstrahering av den organiske fasen med 2N saltsyre, vasking av den vandig-sure løsningen med eter, tilsetning av konsentrert natronlut til den vandige fasen til sterkt alkalisk reaksjon, og ekstraheringen av blandingen med eter, vasking av eterløsningen med vann og tilsetning av en 5N løsning av klorhydrogen i eter til den eterløsingen som er tørket ved hjelp av natriumsulfat, til stert sur reaksjon og fraskillelse av det oppnådde L-alany1-[N<2->(6-metyl-2-pyridyl)-hydrazid]-dihydroklorid i form av hvite krystaller. Behandling av en vandig løsning av det oppnådde dihydroklorid med konsentrert natriumhydroksydløs-ning til sterkt alkalisk reaksjon, utrystingen av den frie basen med eter, vasking av eterløsningen med vann, tørking av natriumsulfat og avdamping av løsningsmidlet, omsetning mellom resten som består av L-alanyl-[N<2->(6-metyl-2-pyridyl) -hydrazid] og benzosyreanhydrid i dimetylformamid i nærvær av vannfritt natriumkarbonat i 24 timer ved romtemperatur og opparbeiding av reaksjonsblandingen til N-benzoyl-L-alanyl-[N<2->(6-metyl-2-pyridyl)-hydrazid]. Rf-verdi i systemet metylenklorid/metanol/konsentrert ammoniumhydroksyd (5:3:1) 0,80. w) N-benzoy1-L-alanyl-[N<2->(6-methyl-2-pyridyl)-hydrazide] by reaction between 2-hydrazino-6-methylpyridine and L-alanine methyl ester by heating under reflux for 3 hours in benzene in a nitrogen atmosphere, evaporating the solvent, dissolving the residue in toluene, washing with water, and extracting the organic phase with 2N hydrochloric acid, washing the aqueous-acidic solution with ether, adding concentrated caustic soda to the aqueous phase to strongly alkaline reaction, and extracting the mixture with ether, washing the ether solution with water and adding a 5N solution of hydrogen chloride in ether to the ether solution dried with sodium sulfate, to strongly acid reaction and separation of the obtained L-alany1 -[N<2->(6-methyl-2-pyridyl)-hydrazide]-dihydrochloride in the form of white crystals. Treatment of an aqueous solution of the obtained dihydrochloride with concentrated sodium hydroxide solution to a strongly alkaline reaction, shaking off the free base with ether, washing the ether solution with water, drying the sodium sulfate and evaporating the solvent, reaction between the residue consisting of L-alanyl -[N<2->(6-methyl-2-pyridyl)-hydrazide] and benzoic anhydride in dimethylformamide in the presence of anhydrous sodium carbonate for 24 hours at room temperature and working up the reaction mixture to N-benzoyl-L-alanyl-[N<2 ->(6-methyl-2-pyridyl)-hydrazide]. Rf value in the system methylene chloride/methanol/concentrated ammonium hydroxide (5:3:1) 0.80.
Eksempel 11Example 11
Tabletter som inneholder 20 mg aktiv substans fremstilles på vanlig måte med følgende sammensetning: Tablets containing 20 mg of active substance are produced in the usual way with the following composition:
Fremstilling Manufacturing
Ammoniumsaltet av N-acetyl-L-glutaminsyre-5-[N<2->(5-n-butyl-2-pyridyl)hydrazidj blandes en del av hvetestivelsen, med melkesukker og kolloidal kiselsyre og blandingen drives gjennom en sikt. En ytterligere del av hvetestivelsen forklistres med den fem ganger så store mengden vann på vannbad og pulverblandingen utgnis med dette klister, til det er oppstått en svakt plastisk masse. The ammonium salt of N-acetyl-L-glutamic acid-5-[N<2->(5-n-butyl-2-pyridyl)hydrazide is mixed with part of the wheat starch, with milk sugar and colloidal silicic acid and the mixture is run through a sieve. A further part of the wheat starch is pasted with five times the amount of water in a water bath and the powder mixture is rubbed out with this paste, until a slightly plastic mass has formed.
Den plastiske massen trykkes gjennom en sikt på ca. 3 mm maskevidde, tørkes og det oppnådde tørre granulatet drives igjen gjennom en sikt. Derpå tilblandes resten av hvetestivelsen, talk og magnesiumstearat og blandingen presses til tabletter med en vekt på 145 mg og med bruddsnitt. The plastic mass is pressed through a sieve of approx. 3 mm mesh size, is dried and the resulting dry granulate is run through a sieve again. Then the rest of the wheat starch, talc and magnesium stearate are mixed in and the mixture is pressed into tablets with a weight of 145 mg and with a break section.
Eksempel 12Example 12
Tabletter som inneholder 1 mg aktiv substans fremstilles på vanlig måte med følgende sammensetning: Tablets containing 1 mg of active substance are produced in the usual way with the following composition:
Sammensetning Fremstilling L-glutaminsyre-5-[N<2->(5-n-buty1-2-pyridyl)-hydrazid]-hemihydrat blandes med en del av hvetestivelsen, med melkesukker og kolloidal kiselsyre og blandingen drives gjennom en sikt. En ytterligere del av hvetestivelsen forklistres med en fem ganger så stor mengde vann på vannbad og pulverblandingen utgnis med dette klister, til det er oppstått en svak plastisk masse. Composition Preparation L-glutamic acid-5-[N<2->(5-n-buty1-2-pyridyl)-hydrazide]-hemihydrate is mixed with part of the wheat starch, with milk sugar and colloidal silicic acid and the mixture is run through a sieve. A further part of the wheat starch is pasted with five times the amount of water in a water bath and the powder mixture is rubbed out with this paste, until a weak plastic mass has formed.
Den plastiske massen trykkes gjennom en sikt med ca. 3 mm maskevidde, tørkes og det oppnådde tørre granulatet drives ennå en gang gjennom en sikt. Derpå tilblandes resten av hvetestivelsen, talk og magnesiumstearat og blandingen presses til tabletter med en vekt av 145 mg og med bruddsnitt. The plastic mass is pressed through a sieve with approx. 3 mm mesh size, is dried and the resulting dry granulate is passed once more through a sieve. Then the rest of the wheat starch, talc and magnesium stearate are mixed in and the mixture is pressed into tablets with a weight of 145 mg and with a break section.
Eksempel 13Example 13
Kapsler som inneholder 10 mg aktiv substans fremstillesCapsules containing 10 mg of active substance are produced
på følgende måte:in the following way:
SammensetningComposition
Fremstilling Manufacturing
Den aktive substansen blandes godt med talk og kolloidal kiselsyre, blandingen drives gjennom en sikt med 0,5 mm maskevidde og denne fylles i porsjoner på hver 11 mg i hårde gelatinkapsler av egnet størrelse. The active substance is mixed well with talc and colloidal silicic acid, the mixture is passed through a sieve with a mesh size of 0.5 mm and this is filled in portions of 11 mg each in hard gelatin capsules of a suitable size.
Eksempel 14Example 14
En steril løsning av 5,0 g ammoniumsalt av N-acetyl-L-glutaminsyre-5- [ N2 -(5-n-butyl-2-pyridyl)-hydrazid] i 5000 ml destillert vann fylles i ampuller på 5 ml, som i 5 ml løsning inneholder 5 mg aktivt stoff. A sterile solution of 5.0 g of the ammonium salt of N-acetyl-L-glutamic acid-5-[ N2 -(5-n-butyl-2-pyridyl)-hydrazide] in 5000 ml of distilled water is filled into ampoules of 5 ml, which 5 ml of solution contains 5 mg of active substance.
Eksempel 15Example 15
3,62 g N<2->(5-n-butyl-2-pyridy1)-3-sulfamoyl-4-klor-benzo-syrehydrazidacetat oppløses i destillert vann til et volum på 18100 ml. Den steriliserte løsning fylles i ampuller a 5,0 ml, i hvilke det inneholdes 1 mg aktivt stoff. 3.62 g of N<2->(5-n-butyl-2-pyridyl)-3-sulfamoyl-4-chloro-benzoic acid hydrazide acetate are dissolved in distilled water to a volume of 18100 ml. The sterilized solution is filled in ampoules of 5.0 ml, which contain 1 mg of active substance.
Eksempel 16Example 16
Istedenfor de forbindelser som ble anvendt som aktiv substans i eksemplene 11 til 15, kan også følgende forbindelser med formel I eller deres farmasøytisk anvendbare, ikke-toksiske syreaddisjonssalter anvendes som aktive stoffer i tabletter, dragéer, kapsler osv.: N2-(5-n-buty1-2-pyridyl)-pikolinsyrehydraz id, N-etoksykarbonyl-N<2->(5-n-buty1-2-pyridyl)-hydrazid,N<2->(5-n-buty1-2-pyridyl)-N-eddiksyrehydrazid ellerN<2->(5-n-buty1-2-pyridyl)-N-fusarinsyrehydrazid, N-acetyl-L-glutaminsyre-5 - [ N2-( 5-n-buty 1-2-pyridyl) hydrazid] - 1-metylester, Instead of the compounds that were used as active substances in examples 11 to 15, the following compounds of formula I or their pharmaceutically usable, non-toxic acid addition salts can also be used as active substances in tablets, dragees, capsules, etc.: N2-(5-n -buty1-2-pyridyl)-picolinic acid hydrazide, N-ethoxycarbonyl-N<2->(5-n-buty1-2-pyridyl)-hydrazide,N<2->(5-n-buty1-2-pyridyl) -N-acetic acid hydrazide or N<2->(5-n-buty1-2-pyridyl)-N-fusaric acid hydrazide, N-acetyl-L-glutamic acid-5 - [ N2-( 5-n-buty 1-2-pyridyl) hydrazide] - 1-methyl ester,
eller de forbindelser med formel I eller deres salter som er beskrevet i eksempel 10, spesielt farmasøytisk anvendbare, ikke-toksiske syreaddisjonssalter. or the compounds of formula I or their salts described in Example 10, especially pharmaceutically usable, non-toxic acid addition salts.
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NO (1) | NO843171L (en) |
PT (1) | PT79024A (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2657610A1 (en) * | 1990-01-29 | 1991-08-02 | Rhone Poulenc Agrochimie | TRIAZOLOPYRIDINES HERBICIDES. |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4071632A (en) * | 1976-12-30 | 1978-01-31 | Morton-Norwich Products, Inc. | Method of alleviating hypertension |
US4260767A (en) * | 1979-12-26 | 1981-04-07 | American Cyanamid Company | 2-Pyridylhydrazides |
-
1984
- 1984-08-03 PT PT79024A patent/PT79024A/en unknown
- 1984-08-06 FI FI843086A patent/FI843086A/en not_active Application Discontinuation
- 1984-08-06 IL IL72596A patent/IL72596A0/en unknown
- 1984-08-06 EP EP84109311A patent/EP0139917A1/en not_active Withdrawn
- 1984-08-07 GR GR80055A patent/GR80055B/en unknown
- 1984-08-07 ES ES534940A patent/ES534940A1/en not_active Expired
- 1984-08-07 DD DD84266047A patent/DD223447A5/en unknown
- 1984-08-08 AU AU31733/84A patent/AU3173384A/en not_active Abandoned
- 1984-08-08 DK DK381784A patent/DK381784A/en not_active Application Discontinuation
- 1984-08-08 HU HU843026A patent/HUT34733A/en unknown
- 1984-08-08 NO NO843171A patent/NO843171L/en unknown
Also Published As
Publication number | Publication date |
---|---|
DK381784D0 (en) | 1984-08-08 |
FI843086A (en) | 1985-02-10 |
IL72596A0 (en) | 1984-11-30 |
DD223447A5 (en) | 1985-06-12 |
EP0139917A1 (en) | 1985-05-08 |
ES534940A1 (en) | 1985-11-01 |
FI843086A0 (en) | 1984-08-06 |
GR80055B (en) | 1984-12-12 |
PT79024A (en) | 1984-09-01 |
HUT34733A (en) | 1985-04-28 |
AU3173384A (en) | 1985-02-14 |
DK381784A (en) | 1985-02-10 |
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