NO783243L - LASALOCID DERIVATIVES. - Google Patents
LASALOCID DERIVATIVES.Info
- Publication number
- NO783243L NO783243L NO783243A NO783243A NO783243L NO 783243 L NO783243 L NO 783243L NO 783243 A NO783243 A NO 783243A NO 783243 A NO783243 A NO 783243A NO 783243 L NO783243 L NO 783243L
- Authority
- NO
- Norway
- Prior art keywords
- lower alkyl
- formula
- aryl
- compound
- compounds
- Prior art date
Links
- BBMULGJBVDDDNI-OWKLGTHSSA-N lasalocid Chemical class C([C@@H]1[C@@]2(CC)O[C@@H]([C@H](C2)C)[C@@H](CC)C(=O)[C@@H](C)[C@@H](O)[C@H](C)CCC=2C(=C(O)C(C)=CC=2)C(O)=O)C[C@](O)(CC)[C@H](C)O1 BBMULGJBVDDDNI-OWKLGTHSSA-N 0.000 title description 11
- -1 alkoxyalkyl1 Chemical group 0.000 claims description 28
- 150000001875 compounds Chemical class 0.000 claims description 26
- 125000000217 alkyl group Chemical group 0.000 claims description 25
- 125000003118 aryl group Chemical group 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- 125000003107 substituted aryl group Chemical group 0.000 claims description 7
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
- 125000004429 atom Chemical group 0.000 claims description 3
- 125000000068 chlorophenyl group Chemical group 0.000 claims description 3
- 125000005842 heteroatom Chemical group 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims 2
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims 2
- 150000002431 hydrogen Chemical class 0.000 claims 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 1
- 239000000969 carrier Substances 0.000 claims 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims 1
- 231100000252 nontoxic Toxicity 0.000 claims 1
- 230000003000 nontoxic effect Effects 0.000 claims 1
- 125000004001 thioalkyl group Chemical group 0.000 claims 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 18
- 238000010992 reflux Methods 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 11
- 239000000047 product Substances 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 238000001704 evaporation Methods 0.000 description 9
- 230000008020 evaporation Effects 0.000 description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 9
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 9
- 239000002585 base Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 229930182504 Lasalocid Natural products 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 229960000320 lasalocid Drugs 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 239000008259 solid foam Substances 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 238000000855 fermentation Methods 0.000 description 5
- 230000004151 fermentation Effects 0.000 description 5
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 230000003276 anti-hypertensive effect Effects 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Substances O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 description 4
- VZXOZSQDJJNBRC-UHFFFAOYSA-N 4-chlorobenzenethiol Chemical compound SC1=CC=C(Cl)C=C1 VZXOZSQDJJNBRC-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- UENWRTRMUIOCKN-UHFFFAOYSA-N benzyl thiol Chemical compound SCC1=CC=CC=C1 UENWRTRMUIOCKN-UHFFFAOYSA-N 0.000 description 3
- 230000003115 biocidal effect Effects 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- CMKBCTPCXZNQKX-UHFFFAOYSA-N cyclohexanethiol Chemical compound SC1CCCCC1 CMKBCTPCXZNQKX-UHFFFAOYSA-N 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 235000013312 flour Nutrition 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 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 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 description 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 241000187747 Streptomyces Species 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- HHFAWKCIHAUFRX-UHFFFAOYSA-N ethoxide Chemical compound CC[O-] HHFAWKCIHAUFRX-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000006260 foam Substances 0.000 description 2
- 238000000227 grinding Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 description 1
- ZFFTZDQKIXPDAF-UHFFFAOYSA-N 2-Furanmethanethiol Chemical compound SCC1=CC=CO1 ZFFTZDQKIXPDAF-UHFFFAOYSA-N 0.000 description 1
- ZYHQGITXIJDDKC-UHFFFAOYSA-N 2-[2-(2-aminophenyl)ethyl]aniline Chemical group NC1=CC=CC=C1CCC1=CC=CC=C1N ZYHQGITXIJDDKC-UHFFFAOYSA-N 0.000 description 1
- 125000000143 2-carboxyethyl group Chemical group [H]OC(=O)C([H])([H])C([H])([H])* 0.000 description 1
- PWOBDMNCYMQTCE-UHFFFAOYSA-N 2-chlorobenzenethiol Chemical compound SC1=CC=CC=C1Cl PWOBDMNCYMQTCE-UHFFFAOYSA-N 0.000 description 1
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 1
- 125000004398 2-methyl-2-butyl group Chemical group CC(C)(CC)* 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 1
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 1
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010022562 Intermittent claudication Diseases 0.000 description 1
- 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 1
- 238000006683 Mannich reaction Methods 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 241000364057 Peoria Species 0.000 description 1
- 244000046052 Phaseolus vulgaris Species 0.000 description 1
- 235000010627 Phaseolus vulgaris Nutrition 0.000 description 1
- 235000019764 Soybean Meal Nutrition 0.000 description 1
- YBZRLMLGUBIIDN-UHFFFAOYSA-N Spicamycin Chemical compound O1C(C(O)CO)C(NC(=O)CNC(=O)CCCCCCCCCCCCC(C)C)C(O)C(O)C1NC1=NC=NC2=C1NC=N2 YBZRLMLGUBIIDN-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000016383 Zea mays subsp huehuetenangensis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 238000009530 blood pressure measurement Methods 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 208000024980 claudication Diseases 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 description 1
- 125000005265 dialkylamine group Chemical group 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000005555 hypertensive agent Substances 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000002054 inoculum Substances 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 239000011147 inorganic material Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000009973 maize Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 235000013379 molasses Nutrition 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen(.) Chemical compound [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- KPYMODXRSSIYIB-UHFFFAOYSA-N ortho-quinone methide Chemical compound CC(=O)C1=C(O)C(=C)C(=O)C(C)=C1 KPYMODXRSSIYIB-UHFFFAOYSA-N 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 239000003973 paint Substances 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 235000011182 sodium carbonates Nutrition 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 239000004455 soybean meal Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Foreliggende oppfinnelse vedrører lasalocid-derivater med formelen The present invention relates to lasalocid derivatives with the formula
hvor R betyr aryl, substituert aryl, hetroaryl, aralkyl, cykloalkyl, lavere alkyl, lavere alkenyl, karbalkoksy-lavere-alkyl, aminoalkyl, lavere alkylaminoalky1, di-(lavere-alkyl)-aminoalkyl, hydroksyalky1, alkoksyalky1, tioalkoksyalkyl, karboksy-lavere-alky1 eller hydrogen. where R means aryl, substituted aryl, heteroaryl, aralkyl, cycloalkyl, lower alkyl, lower alkenyl, caralkyloxy-lower alkyl, aminoalkyl, lower alkylaminoalkyl1, di-(lower alkyl)aminoalkyl, hydroxyalkyl1, alkoxyalkyl1, thioalkylalkyl, carboxy-lower -alkyl or hydrogen.
Oppfinnelsen vedrører videre en fremgangsmåte ved fremstilling av forbindelsene I og farmasøytiske komposisjoner på basis av forbindelsene I. The invention further relates to a method for the production of the compounds I and pharmaceutical compositions based on the compounds I.
Det her anvendte uttrykk "alkyl" betegner alene eller i forbindelse med andre rester en rettlinjet eller forgrenet hydrokarbongruppe med 1-16 C-atomer. Foretrukne alkylgrupper er lavere alkylgrupper. Uttrykket "lavere" betegner grupper med 1-7 C-atomer. Eksempler på lavere alkylgrupper er metyl, etyl, isopropyl og tertiær butyl. The term "alkyl" used here denotes, alone or in connection with other residues, a linear or branched hydrocarbon group with 1-16 C atoms. Preferred alkyl groups are lower alkyl groups. The term "lower" denotes groups with 1-7 C atoms. Examples of lower alkyl groups are methyl, ethyl, isopropyl and tertiary butyl.
Uttrykket "aryl" betegner en usubstituert monokarbocyklisk aromatisk rest, som fenyl. The term "aryl" denotes an unsubstituted monocarbocyclic aromatic residue, such as phenyl.
i I in I
!_ I !_ I
I l ! Eksempler på "substituert aryl" er alkyl-, karboksy-, halogen-,! alkoksy- eller nitro-substituert fenyl, som tolyl. I l! Examples of "substituted aryl" are alkyl-, carboxy-, halogen-,! alkoxy- or nitro-substituted phenyl, such as tolyl.
Uttrykket "halogen" eller "halo" omfatter klor, brom, fluor og jod. The term "halogen" or "halo" includes chlorine, bromine, fluorine and iodine.
En cykloalkylre.st inneholder fortrinnsvis 4-7 C-atomer.. som cykloheksyl. A cycloalkyl residue preferably contains 4-7 C atoms, such as cyclohexyl.
Uttrykket "heteroaryl" betegner en usubstituert mono-heterocyklisk aromatisk rest slik som pyridyl eller furyl. The term "heteroaryl" denotes an unsubstituted mono-heterocyclic aromatic radical such as pyridyl or furyl.
Uttrykket "aralkyl" betegner en rettlinjet eller forgrenet alkyl-gruppe som er substituert ved en mono-karbo-cyklisk rest, som benzyl. The term "aralkyl" denotes a straight or branched alkyl group which is substituted by a mono-carbocyclic residue, such as benzyl.
Uttrykket "lavere alkenyl" betegner en rettlinjet eller forgrenet hydrokarbongruppe som har en olefinisk dobbeltbinding og 2 - 7 C-atomer. The term "lower alkenyl" denotes a straight or branched hydrocarbon group having an olefinic double bond and 2-7 carbon atoms.
En foretrukket gruppe av forbindelser med formel I er de hvori R<1>er aryl, substituert aryl, aralkyl, cykloalkyl, alvere alkyl, karboksy-lavere-alkyl eller hydrogen. Særlig foretrukket er forbindelser med formel I hvori R<1>er fenyl, klorfenyl, cykloheksyl, benzyl eller karboksymetyl. Sterkest foretrukket er forbindelsene med formel I hvori R<1>er fenyl, dvs. forbindelsen 1-(fenyltiometyl)-1-dekarboksylasalocid. A preferred group of compounds of formula I are those in which R<1> is aryl, substituted aryl, aralkyl, cycloalkyl, lower alkyl, carboxy-lower alkyl or hydrogen. Particularly preferred are compounds of formula I in which R<1> is phenyl, chlorophenyl, cyclohexyl, benzyl or carboxymethyl. Most preferred are the compounds of formula I in which R<1> is phenyl, i.e. the compound 1-(phenylthiomethyl)-1-decarboxylasaloside.
Forbindelsene med formel I erholdes ifølge oppfinnelsen ved at man omsetter en forbindelse med formel The compounds of formula I are obtained according to the invention by reacting a compound of formula
2 3 hvor R og R er lavere alkyl eller sammen med nitrogen- 2 3 where R and R are lower alkyl or together with nitrogen-
atomet en 5- til 6-leddet heterocyklisk ring som kan inneholde et ytterligere he.teroatom, the atom a 5- to 6-membered heterocyclic ring which may contain a further heteroatom,
med en forbindelse med formel R^SH, hvor R"^ har ovennevnte be-tydning, i nærvær av en svak base. with a compound of formula R^SH, where R"^ has the above meaning, in the presence of a weak base.
Ved denne reaksjonen er en svak base en sådan som er tilstrek-kelig til å danne ortokinon-metid og den konjugerte base av det foreliggende merkaptan, dvs. R^S uten å bevirke en retro-aldolspaltning av lasalocidmolekylet. Egnede baser er alkali-metall, f.eks. natrium-eller kaliumkarbonater og bikarbonater, trialkylaminer eller pyridin. Egnede løsningsmidler for denne reaksjonen er alkoholer f.eks. metanol eller etanol, høytkok-ende etere, dioksan eller tetrahydrofuran og etylacetat. Reaksjonstemperaturen kan ligge mellom romtemperatur og tilbake-løpstemperatur, hvorved det anvendte løsningsmiddels tilbake-løpstemperatur er foretrukket. Foretrukne reaksjonspartnere er tiofenol, p-klortiofenol, cykloheksylmerkaptan, benzylmerkaptan og merkaptoeddiksyre, idet man får forbindelse med formel I hvori R"<*>" er f enyl, p-klorfenyl, cykloheksyl, benzyl hhv. karboksymetyl. ;Utgangsmaterialet med formel II kan fremstilles fra lasalocid, en forbindelse med formel ; ; ved hjelp av en Mannich-reaksjon, nærmere bestemt ved hjelp av en blanding av et dialkylamin eller et cyklisk amin som morfo-lin, piperidin eller pyrrolidin og p-formaldehyd eller vandig formaldehyd. Egnede løsningsmidler for denne reaksjonen er C^-C^alkoholer, toluen, benzen, klorerte hydrokarboner og etere i som dioksan eller tetrahydrofuran. Reaksjonstemperaturen kan ;'variere fra 60°C til det avendte løsningsmiddels tilbakeløps-temperatur hvorved tilbakeløpstemperatur'er foretrukket. ;Forbindelsen med formel III, lasalocid, også kjent som "antibiotikum X-537 A", er et krystallinsk antibiotikum som produ-seres av en streptomycin-organisme fra en jordprøve samlet i Hyde Park, Massachusetts. Lyofiliserte prøver av kulturen som har laboratoriebetegnelsen-X-537, ble deponert-i United States Department of Agriculture, Agriculture Research Service, Northern Utilization Research and Development Division, Peoria, Illinois. Kulturen, som fikk identifikasjonsnummer NRRL 3382 av Agricultural Research Service, ble gjort offentlig tilgjengelig gjennom NRRL. En erstatningskultur som er en nær beslektet stamme av den opprinnelige deponerte kultur NRRL 3382, dvs. har både felles avstamnings- og morfologiske karakteristika, ble deponert hos NRRL under nummeret NRRL 3382R.. Denne kultur er i likhet med den opprinnelige deponerte kultur NRRL 3382 offentlig tilgjengelig. ;Lasalocid (antibiotikum X-537 A) fremstilles ved dyrkning av Streptomyces-organismen i en luftgjennomblåst neddykknings-kultur hvis pH er omtrent nøytral, dvs. ca. 6,5 til 7,5. Mediet får en nitrogenkilde som gjær, et gjærderivat, maismel, bønnemel ol., hvorved soyabønnemel er spesielt foretrukket, ;og en kullhydratkilde som sukker, melasse ol., hvorved råsukker er særlig foretrukket. Fermenteringen utføres ved litt høyere temperaturer, dvs. mellom 25°C og 3 5°C, særlig foretrukket er en inkubasjonstemperatur på ca. 28°C. Etter 4- til 6-dagers inkubering frafiltreres fermenteringsgrøten og antibiotikumet erholdes gjennom ekstraksjon. ;Forbindelsen med formel I har antihypertensiv aktivitet. ;Under anvendelse av en standard som kontroll for sammenlign-ingsformål ble 1-(fenyltio-metyl)-1-dekarboksylasalocid under-søkt med hensyn på antihypertensiv aktivitet. Forsøkene ble gjennomført med enkeltvis orale doser på DOCA-Na-rotte over et tidsrom på 5 dager. Etter 5-dagers perioden ble preparatet jstanset. Blodtrykksmålinger ble utført under 5-dagers periodenj I og deretter daglig etter opphør av preparatet inntil blodtrykk-*i et hadde innstilt seg på utgangsverdien før medikamenteringen. Den daglige dosering var 10 mg/kg. De følgende resultater ble oppnådd: In this reaction, a weak base is one that is sufficient to form the orthoquinone methide and the conjugate base of the present mercaptan, i.e. R 2 S without causing a retro-aldol cleavage of the lasalocid molecule. Suitable bases are alkali metal, e.g. sodium or potassium carbonates and bicarbonates, trialkylamines or pyridine. Suitable solvents for this reaction are alcohols, e.g. methanol or ethanol, high-boiling ethers, dioxane or tetrahydrofuran and ethyl acetate. The reaction temperature can lie between room temperature and reflux temperature, whereby the reflux temperature of the solvent used is preferred. Preferred reaction partners are thiophenol, p-chlorothiophenol, cyclohexyl mercaptan, benzyl mercaptan and mercaptoacetic acid, whereby a compound of formula I is obtained in which R"<*>" is phenyl, p-chlorophenyl, cyclohexyl, benzyl respectively. carboxymethyl. The starting material of formula II can be prepared from lasalocid, a compound of formula; ; by means of a Mannich reaction, more specifically by means of a mixture of a dialkylamine or a cyclic amine such as morpholine, piperidine or pyrrolidine and p-formaldehyde or aqueous formaldehyde. Suitable solvents for this reaction are C₁-C₂ alcohols, toluene, benzene, chlorinated hydrocarbons and ethers such as dioxane or tetrahydrofuran. The reaction temperature can vary from 60°C to the reflux temperature of the solvent used, whereby reflux temperature is preferred. The compound of formula III, lasalocid, also known as "antibiotic X-537 A", is a crystalline antibiotic produced by a streptomycin organism from a soil sample collected in Hyde Park, Massachusetts. Lyophilized samples of the culture bearing the laboratory designation-X-537 were deposited-in the United States Department of Agriculture, Agriculture Research Service, Northern Utilization Research and Development Division, Peoria, Illinois. The cultivar, given the identification number NRRL 3382 by the Agricultural Research Service, was made publicly available through NRRL. A replacement culture which is a closely related strain of the original deposited culture NRRL 3382, i.e. has both common lineage and morphological characteristics, was deposited with NRRL under the number NRRL 3382R.. This culture, like the original deposited culture NRRL 3382, is in the public domain available. ;Lasalocid (antibiotic X-537 A) is produced by growing the Streptomyces organism in an air-blown immersion culture whose pH is approximately neutral, i.e. approx. 6.5 to 7.5. The medium receives a nitrogen source such as yeast, a yeast derivative, maize flour, bean flour etc., whereby soybean flour is particularly preferred, and a carbohydrate source such as sugar, molasses etc., whereby raw sugar is particularly preferred. The fermentation is carried out at slightly higher temperatures, i.e. between 25°C and 35°C, an incubation temperature of approx. 28°C. After a 4- to 6-day incubation, the fermentation mash is filtered off and the antibiotic is obtained through extraction. The compound of formula I has antihypertensive activity. Using a standard as a control for comparison purposes, 1-(phenylthiomethyl)-1-decarboxylasalocid was examined for antihypertensive activity. The experiments were carried out with individual oral doses on DOCA-Na rats over a period of 5 days. After the 5-day period, the preparation was discontinued. Blood pressure measurements were carried out during the 5-day periodj I and then daily after cessation of the preparation until the blood pressure-*i et had adjusted to the starting value before the medication. The daily dosage was 10 mg/kg. The following results were obtained:
1-[(karboksymetyl)tiometyl]-1-dekarboksylasalocid, 1-(p-klor-fenyltiometyl)-1-dekarboksylasalocid, 1-(benzyltiomety1)-1-de-karboksylasalocid og 1-(cykloheksyltiometyl)-1-dekarboksylasa-locid ble likeledes undersøkt. 1-[(carboxymethyl)thiomethyl]-1-decarboxylasaloside, 1-(p-chloro-phenylthiomethyl)-1-decarboxylasaloside, 1-(benzylthiomethyl)-1-decarboxylasaloside and 1-(cyclohexylthiomethyl)-1-decarboxylasaloside was also investigated.
Resultatene er gjengitt i den etterfølgende tabell. Av resultatene fremgår at under påbegynnelse og varighet av antihyper-tensive virkninger består forskjeller, men at de ovenfor nevnte forbindelser har en antihypertensiv aktivitet når man sammen-ligner blodtrykket 1. dag med 5. dag etter opphør av medikament-et. The results are reproduced in the following table. The results show that there are differences in the onset and duration of antihypertensive effects, but that the above-mentioned compounds have an antihypertensive activity when blood pressure is compared on the 1st day with the 5th day after discontinuation of the drug.
Eksempel A I Example A I
Kapsler kan inneholde følgende bestanddeler: Capsules may contain the following ingredients:
Fremgangsmåte: Approach:
1. Bestanddelene 1, 3 og 5 blandes. 1. The components 1, 3 and 5 are mixed.
2. Bestanddelene-2 og 5 løses i destillert vann og/eller alkohol, granuleres til den riktige konsistens og males. 2. Components-2 and 5 are dissolved in distilled water and/or alcohol, granulated to the correct consistency and ground.
3. Tørking i ovn. 3. Drying in oven.
4. Maling og blanding med talkum og magnesiumstearat i 2 min. 4. Grinding and mixing with talc and magnesium stearate for 2 min.
5. Forkapsling. 5. Encapsulation.
Eksemne1 B Example 1 B
& &
Tabletter kan følgende sammensetning: Tablets can have the following composition:
Fremgangsmåte: I Procedure: I
1. Blanding av bestanddelene 1 - 4 i et egnet apparat. 1. Mixing the components 1 - 4 in a suitable device.
2. Granulering med destillert vann til passende konsistens. 2. Granulation with distilled water to a suitable consistency.
3. Maling. 3. Paint.
3. Tørking i ovn. 3. Drying in oven.
4. Maling av blanding med magnesiumstearat i 3 minutter. 4. Grinding mixture with magnesium stearate for 3 minutes.
5. Pressing til tabletter. 5. Pressing into tablets.
Til anvendelse som hypertensive midler kan forbindelsen med formel I bringes i form av farmasøytiske preparater med inerte far-masøytiske hjelpemidler i egnet doseringsform for oral administrering. Andre doseringsformer, f.eks. den parenterale, er også mulig. Eksempler på orale doseringsformer er tabletter, kapsler, drageer, suspensjoner og løsninger. Som hjelpemidler kan uorganiske eller organiske stoffer som f.eks. gelatin, al-bumin, laktose, stivelse, magnesiumstearat, konserveringsmidler (stabilisatorer), glidemidler, emulgatorer, salter for endring For use as hypertensive agents, the compound of formula I can be brought in the form of pharmaceutical preparations with inert pharmaceutical aids in a suitable dosage form for oral administration. Other dosage forms, e.g. the parenteral, is also possible. Examples of oral dosage forms are tablets, capsules, dragees, suspensions and solutions. As aids, inorganic or organic substances such as e.g. gelatin, albumin, lactose, starch, magnesium stearate, preservatives (stabilizers), lubricants, emulsifiers, salts for modification
av det osmotiske trykk og puffer anvendes som er vanlig i slike preparater. of the osmotic pressure and buffers are used which are common in such preparations.
Det har vist seg at den subakutte orale administrering for behandling av høyt trykk hos varmblodige vesener f.eks. DOCA-Na-hypertensiv rotte, dvs. en dosering opp til 5 dager med derpå følgende opphør av preparatet er mest. virksomt, når doserings-området ligger mellom ca. 5 mg/kg og 100 mg/kg, spesielt mellom 5 mg/kg og 10 mg/kg. Den kroniske orale administrering, dvs. It has been shown that the subacute oral administration for the treatment of high pressure in warm-blooded beings e.g. DOCA-Na hypertensive rat, i.e. a dosage of up to 5 days followed by cessation of the preparation is the most. effectively, when the dosage range is between approx. 5 mg/kg and 100 mg/kg, especially between 5 mg/kg and 10 mg/kg. The chronic oral administration, i.e.
en dosering utover 5 dager, er mest virksom når et lavt doserings-nivå anvendes, dvs. lavere enn 0,1 mg/kg daglig, f.eks. 0,01 mg/kg til ca. 5 mg/kg pr. dag. De forannevnte beskrevne, doserings-planer kan også anvendes ved behandling av andre kardiovaskulære a dosage beyond 5 days is most effective when a low dosage level is used, i.e. lower than 0.1 mg/kg daily, e.g. 0.01 mg/kg to approx. 5 mg/kg per day. The dosage plans described above can also be used in the treatment of other cardiovascular diseases
symptomer som Angina pectoris, Claudicatio og nedsatt blodgjennom-strømning i hjernen. Ved doseringen er doseringsskjemaet for den kroniske administrering særlig foretrukket, dvs. en dosering fra mindre enn 0,1 mg/kg pr. dag opp til ca. 5 mg/kg pr. dag. symptoms such as Angina pectoris, Claudication and reduced blood flow in the brain. For the dosage, the dosage form for the chronic administration is particularly preferred, i.e. a dosage from less than 0.1 mg/kg per day up to approx. 5 mg/kg per day.
EKSEMPEL 1 EXAMPLE 1
Streptomycesstammen NRRL 3382 R ble dyrket i beluftet dypkultur i rystekolber. Substratet ble ved tilsetning av kalilut innstilt på pH 6,5 - 7,5 og deretter sterilisert. I en fermenter-ingstank ble substratet som inneholdt 2% soyabønnemel, 2% råsukker, 0,5% maissvellevann og 0,1% K^IPO^ podet med 5 - 10% The Streptomyces strain NRRL 3382 R was grown in aerated deep culture in shake flasks. The substrate was adjusted to pH 6.5 - 7.5 by the addition of potassium hydroxide and then sterilized. In a fermentation tank, the substrate containing 2% soybean meal, 2% raw sugar, 0.5% corn-swell water and 0.1% K^IPO^ was inoculated with 5 - 10%
av et inokulum fra en 3 dager gammel dypkultur. Fermenteringen ble utført ved 28° under positivt lufttrykk hvorunder pr. min-utt og pr. 150 - 300 1 væske en luftstrøm på 140-280 1 opprett-holdt. Kulturen ble høstet etter 4 til 6 dagers fermentering, filtrert og antibiotikumet utskilt ved ekstraksjon som følger: 204 1 kulturløsning ble filtrert og den fuktige filterkaken ble oppslemmet i 100 1 butylacetat og rørt natten over ved romtemperatur. Blandingen ble så filtrert og det vandige skiktet ad-skilt og kastet. Butylacetatløsningen som hadde 30 millioner Bazillus E-enheter, ble konsentrert under redusert trykk til 3 1, vasket med 10%-ig natriumkarbonatløsning og tørket over natriumsulfat. of an inoculum from a 3-day-old deep culture. The fermentation was carried out at 28° under positive air pressure during which per min-out and per 150 - 300 1 liquid an air flow of 140-280 1 maintained. The culture was harvested after 4 to 6 days of fermentation, filtered and the antibiotic separated by extraction as follows: 204 L of culture solution was filtered and the moist filter cake was slurried in 100 L of butyl acetate and stirred overnight at room temperature. The mixture was then filtered and the aqueous layer separated and discarded. The butyl acetate solution having 30 million Bazillus E units was concentrated under reduced pressure to 3 L, washed with 10% sodium carbonate solution and dried over sodium sulfate.
Etter ytterligere inndampning til 300 ml og fortynning med 350 ml petroleter (kokepunkt 50 - 60°) ble 41 g fast stoff med et innhold på 25 millioner;.Bazillus E-enheter isolert. Dette faste stoffet ble så ekstrahert i et Soxhletapparat 40 timer med 4 1 petroleter (kokepunkt 50 - 60°). Ekstraktet ble bragt til tørr-het under redusert trykk, den krystallinske resten oppslemmet i petroleter og filtrert og ga 24,49 g av en blanding av 3-metyl-6-[7-etyl-4-hydroksy-3,5-dimetyl-6-okso-7-Z5-etyl-3-metyl-5-(5-etyl-5-hydroksy-6-metyl-2-tetrahydropyranyl)-2-tetrahydrofuryl7~heptyl]salicylsyre(Lasalocid) og saltet derav. Moderluten ga ytterligere 5,73 g av antibiotikumet. After further evaporation to 300 ml and dilution with 350 ml of petroleum ether (boiling point 50-60°), 41 g of solid containing 25 million Bazillus E units were isolated. This solid was then extracted in a Soxhlet apparatus for 40 hours with 4 l of petroleum ether (boiling point 50 - 60°). The extract was brought to dryness under reduced pressure, the crystalline residue slurried in petroleum ether and filtered to give 24.49 g of a mixture of 3-methyl-6-[7-ethyl-4-hydroxy-3,5-dimethyl- 6-oxo-7-Z5-ethyl-3-methyl-5-(5-ethyl-5-hydroxy-6-methyl-2-tetrahydropyranyl)-2-tetrahydrofuryl7~heptyl]salicylic acid (Lasalocid) and its salt. The mother liquor gave an additional 5.73 g of the antibiotic.
Etter omkrystallisering fr.a. eter-petroleter ble det natriumhold-ige materialet løst i eter og vasket med fortynnet svovelsyre for å overføre det i den frie syren. Fjerning av eteren ga en oljeaktig rest som krystalliserte fra etanol og ga rent Lasalocid-etanolåt. Flere omkrystalliseringer fra etanol endret ikke smeltepunktet som forble uskarpt ved 100-109°C. After recrystallization from ether-petroleum ether, the sodium-containing material was dissolved in ether and washed with dilute sulfuric acid to transfer it into the free acid. Removal of the ether gave an oily residue which crystallized from ethanol to give pure Lasalocid ethanolate. Several recrystallizations from ethanol did not change the melting point which remained indistinct at 100-109°C.
i I in I
Eksempel2I En blanding av 5 g Lasalocid-etanolat, 2,5 g paraformaldehyd og 2,5 g dietylamin i 200 ml toluen ble oppvarmet 90 minutter under røring ved tilbakeløp. Under tilbakeløpsoppvarmingen ble vann-et samlet i en felle. Den erholdte løsningen ble fortynnet med eter, vasket med vann og med sterkt fortynnet (ca. 0,05 N) saltsyre. Det organiske skiktet ble tørket, filtrert og løsnings-midlet fjernet under redusert trykk, hvorved en lysegul (mange ganger fargeløs harpiks) ble tilbake. Denne rå Mannich-basen, 1-(dietylaminometyl)-1-dekarboksylasalocid, inneholdt toluen, men ble anvendt direkte i det neste trinn. Example 2I A mixture of 5 g of Lasalocid ethanolate, 2.5 g of paraformaldehyde and 2.5 g of diethylamine in 200 ml of toluene was heated for 90 minutes with stirring at reflux. During reflux heating, the water was collected in a trap. The solution obtained was diluted with ether, washed with water and with highly diluted (approx. 0.05 N) hydrochloric acid. The organic layer was dried, filtered and the solvent removed under reduced pressure, whereby a pale yellow (many times colorless resin) remained. This crude Mannich base, 1-(diethylaminomethyl)-1-decarboxylasaloside, contained toluene but was used directly in the next step.
Eksempel 3 Example 3
En løsning av 9,7 g av den i eksempel 2 fremstilte Mannich-base, 4,5 ml tiofenol og 4 mg trietylamin i 125 ml etanol ble oppvarmet 18 timer ved tilbakeløp. Løsningsmidlet ble avdampet under redusert trykk og resten tatt opp i'metylenklorid. Etter vask-ing med vann og fortynnet natriumkarbonatløsning ble løsningen tørket og løsningsmidlet avdampet. Råproduktet ble renset ved kromatografi på 200 g kiselgel. Med heksan/etylacetat (8:1) ble tiofenol og med heksan/etylacetat (6:1) produktet, 1-(fenyl-tio-metyl)-1-dekarboksylasalocid eluert. Avdampning av løsningsmid-let, til slutt under redusert trykk, ga et fargeløst skum. A solution of 9.7 g of the Mannich base prepared in example 2, 4.5 ml of thiophenol and 4 mg of triethylamine in 125 ml of ethanol was heated for 18 hours at reflux. The solvent was evaporated under reduced pressure and the residue taken up in methylene chloride. After washing with water and dilute sodium carbonate solution, the solution was dried and the solvent was evaporated. The crude product was purified by chromatography on 200 g of silica gel. With hexane/ethyl acetate (8:1) thiophenol and with hexane/ethyl acetate (6:1) the product, 1-(phenyl-thio-methyl)-1-decarboxylasaloside, were eluted. Evaporation of the solvent, finally under reduced pressure, gave a colorless foam.
Eksempel 4 Example 4
En løsning av 1,4 g 1-(dietylaminometyl)-1-dekarboksylasalocid, A solution of 1.4 g of 1-(diethylaminomethyl)-1-decarboxylasaloside,
2 g p-klortiofenol og 2 ml trietylamin i 50 ml etanol ble oppvarmet 18 timer ved tilbakeløp. Da reaksjonen ikke var full-stendig (tynnskiktkromatogram) ble ytterligere 2 g p-klortiofenol og 2 ml trietylamin tilsatt og tilbakeløpsoppvarmingen fort-satte i 24 timer. Etter avkjøling ble løsningsmidlet aminet avdampet under redusert trykk og resten tatt opp i metylenklorid. Denne løsningen ble vasket .med vandig natriumkarbonatløsning, tørket over natriumsulfat og inndampet. 2 g of p-chlorothiophenol and 2 ml of triethylamine in 50 ml of ethanol were heated for 18 hours at reflux. When the reaction was not complete (thin-layer chromatogram), a further 2 g of p-chlorothiophenol and 2 ml of triethylamine were added and reflux heating continued for 24 hours. After cooling, the solvent amine was evaporated under reduced pressure and the residue taken up in methylene chloride. This solution was washed with aqueous sodium carbonate solution, dried over sodium sulfate and evaporated.
Resten var en blanding, hovedsaklig av p<->klortiofenol og den ønskede tioeter, 1-(p-klorfenyltiometyl)-1-dekarboksylasalocid, som ble kromatografert med benzen/etylacetat (2:1) som eluerings-middel. Fraksjonene som inneholdt produktet (tynnskiktkromato-J grafi) ble slått sammen og ga ved inndampning et fargeløst fast skum som ble flytende ved 42-46°C. The residue was a mixture, mainly of p<->chlorothiophenol and the desired thioether, 1-(p-chlorophenylthiomethyl)-1-decarboxylasaloside, which was chromatographed with benzene/ethyl acetate (2:1) as eluent. The fractions containing the product (thin layer chromatography) were combined and, on evaporation, gave a colorless solid foam which liquefied at 42-46°C.
Eksempel 5 Example 5
1,4 g 1-(dietylaminometyl)-1-dekarboksylasalocid, 2 ml cykloheksylmerkaptan og 2 ml trietylamin ble oppvarmet i 50 ml etanol ved tilbakeløp. Ved hjelp av den i eksempel 4 beskrevne fremgangsmåte' innbefattende tilsetning av ytterligere cykloheksylmerkaptan og trietylamin etter 18 timer ble produktet, 1-(cykloheksyl-tiometyl)-1-dekarboksylasalocid, erholdt som fargeløst fast skum etter rensning på en kiselgelkolonne. 1.4 g of 1-(diethylaminomethyl)-1-decarboxylasaloside, 2 ml of cyclohexyl mercaptan and 2 ml of triethylamine were heated in 50 ml of ethanol at reflux. By means of the method described in example 4, including the addition of further cyclohexyl mercaptan and triethylamine after 18 hours, the product, 1-(cyclohexyl-thiomethyl)-1-decarboxylasalocid, was obtained as a colorless solid foam after purification on a silica gel column.
Eksempel 6 Example 6
4v5 g 1-(dietylaminometyl)-1-dekarboksylasalocid, 5 ml benzylmerkaptan og 5 ml trietylamin ble oppvarmet under tilbakeløp natten over i 100 ml etanol. Etter kjøling og avdampning av løsnings-midlet under redusert trykk ble resten kromatografert på kis.el-gel med heksan/etylacetat (5:1). Fraksjonene som inneholdt produktet ble forenet og inndampet. Det herved erholdte produkt var forurenset av små mengder benzylmerkaptan og ble renset ved preparativ skiktkromatografi på 6 20 x 20 cm kiselgelplater med heksan/etylacetat (4:1). Det rene produkt, 1-(benzyltiomety1-1-dekarboksylasalocid, ble erholdt som fargeløst fast skum. 4v5 g of 1-(diethylaminomethyl)-1-decarboxylasaloside, 5 ml of benzyl mercaptan and 5 ml of triethylamine were heated under reflux overnight in 100 ml of ethanol. After cooling and evaporation of the solvent under reduced pressure, the residue was chromatographed on silica gel with hexane/ethyl acetate (5:1). The fractions containing the product were combined and evaporated. The product thus obtained was contaminated by small amounts of benzyl mercaptan and was purified by preparative layer chromatography on 6 20 x 20 cm silica gel plates with hexane/ethyl acetate (4:1). The pure product, 1-(benzylthiomethyl-1-decarboxylasaloside), was obtained as a colorless solid foam.
Eksempel 7 Example 7
En løsning av 3 g av den ifølge eksempel 2 fremstilte Mannichbase, 3 ml merkaptoeddiksyre og 3 ml trietylamin i 100 ml etanol ble A solution of 3 g of the Mannich base prepared according to example 2, 3 ml of mercaptoacetic acid and 3 ml of triethylamine in 100 ml of ethanol was
oppvarmet 36 timer ved tilbakeløp. Etanolet ble så fjernet under redusert trykk og resten i metylenkloridløsning vasket med fortynnet vandig natriumkarbonatløsning, vann, 0,5N saltsyre og vann. Etter tørkning og inndampning ble råproduktet kromatografert på kiselgel med 4% metanol i kloroform. Da det viste seg at produktet absorberte natriumioner fra uorganisk materiale, ble eluatet som inneholdt produktet vasket før inndampning med sterkt fortynnet saltsyre. 1-[(karboksymety1)tiometyl]-1-dekarboksylasalocid ble således erholdt som fargeløst skum. heated 36 hours at reflux. The ethanol was then removed under reduced pressure and the residue in methylene chloride solution washed with dilute aqueous sodium carbonate solution, water, 0.5N hydrochloric acid and water. After drying and evaporation, the crude product was chromatographed on silica gel with 4% methanol in chloroform. As the product was found to absorb sodium ions from inorganic material, the eluate containing the product was washed before evaporation with highly dilute hydrochloric acid. 1-[(carboxymethyl)thiomethyl]-1-decarboxylasaloside was thus obtained as a colorless foam.
Eksempel 8 Example 8
En løsning av 1,85 g 1-(dietylaminometyl)-1-dekarboksylasalocid | og 2 ral trietylamin i 50 ml etanol ble oppvarmet 32 timer ved tilbakeløp mens en langsom strøm av hydrogensulfid ble ledet gjennom løsningen. Etter avdampning av løsningsmidlet under 'redusert trykk ble resten kromatografert på preparative skiktplat-er ( 20 x 20 cm, kiselgel) . Produktet, 1-merkaptometyl-l-dekarboksy-lasalocid, ble erholdt som fargeløst fast skum. A solution of 1.85 g of 1-(diethylaminomethyl)-1-decarboxylasaloside | and 2 ral of triethylamine in 50 ml of ethanol were heated for 32 hours at reflux while a slow stream of hydrogen sulphide was passed through the solution. After evaporation of the solvent under reduced pressure, the residue was chromatographed on preparative layer plates (20 x 20 cm, silica gel). The product, 1-mercaptomethyl-1-decarboxylasaloside, was obtained as a colorless solid foam.
Eksempel 9 Example 9
~En løsning av 1 g 1-(dietylaminometyl)-1-dekarboksylasalocid og ~A solution of 1 g of 1-(diethylaminomethyl)-1-decarboxylasalocid and
2 ml trietylamin i 50 ml etanol ble oppvarmet 8 timer ved tilbake-løp hvorved gassformig metylmerkaptan ble innledet. Etter inndampning og rensning ved preparativ skiktkromatografi ble 300 mg 1-(metyltiometyl)-1-dekarboksylasalocid erholdt som fargeløst fast skum. 2 ml of triethylamine in 50 ml of ethanol were heated for 8 hours at reflux whereby gaseous methyl mercaptan was introduced. After evaporation and purification by preparative layer chromatography, 300 mg of 1-(methylthiomethyl)-1-decarboxylasalocid was obtained as a colorless solid foam.
Eksempel 10 Example 10
En løsning av 1,4 g 1-(dietylaminometyl)-1-dekarboksylasalocid, A solution of 1.4 g of 1-(diethylaminomethyl)-1-decarboxylasaloside,
2 ml furfurylmerkaptan og 2 ml dietylamin i 50 ml etanol ble oppvarmet 42 timer ved tilbakeløp hvorved 2 ml ytterligere base og 2 ml merkaptan ble tilsatt etter 18 timer. Etter inndampning.og 2 ml of furfuryl mercaptan and 2 ml of diethylamine in 50 ml of ethanol were heated for 42 hours at reflux whereby 2 ml of additional base and 2 ml of mercaptan were added after 18 hours. After evaporation.and
rensning ved preparativ skiktkromatografi erholdtes produktet, 1-(furylmetyltiometyl)-1-dekarboksylasalocid,som fargeløst fast skum. purification by preparative layer chromatography yielded the product, 1-(furylmethylthiomethyl)-1-decarboxylasalocid, as a colorless solid foam.
Eksempel 11 Example 11
Ved den overfor beskrevne fremgangsmåte og under anvendelse av det passende tiol kan forbindelsen med formel I fremstilles hvori R er allyl, 2-aminofenyl, 4-aminofenyl, 4-brom-3-metylfenyl, 4-bromfenyL lt-butyl, 2-butyl, tert.butyl, isobutyl, karboetoksy-metyl, karbometoksymetyl, 2-karboksyetyl, o-karboksyfenyl, 4-klor-benzyl, 2-n-decylaminoetyl, 2,5-diklorfenyl, 3,4-diklorfeny1, 2-dietylaminoetyl, 2-diisopropylaminoetyl, 1-dodecyl, etyl, 4-fluor-fenyl, n-heptyl, n-heksadecy1, 2-hydroksyety1, 2-etoksyetyl, 2-etyltioetyl, 1-mety1-2-imidazolyl, 2,3-dihydroksypropyl, 2-pyridyl, 4-pyridyl, 3-hydroksy-2-pyridy1, 2-tiazolyl, 2-metoksyfenyl, 3-metoksyfenyl, 4-metoksyfeny1, 2-metyl-2-butyl, 3-metyl-l-buty1, 4-nitrofenyl, 1-nonyl, 1-octyl, pentaklorfeny1, pentafluorfeny1, 1-pentyl, 3-fenyl-l-propyl, 1-propyl, 2-propyl, 2-kinolyl, 2 , 3 ,5 ,6-tetraf luorf enyl, p-tolyl, 2 , 4 , 5-triklorf enyl, 7-trifluorj- By the process described above and using the appropriate thiol, the compound of formula I can be prepared in which R is allyl, 2-aminophenyl, 4-aminophenyl, 4-bromo-3-methylphenyl, 4-bromophenyl, t-butyl, 2-butyl, tert.butyl, isobutyl, carboethoxy-methyl, carbomethoxymethyl, 2-carboxyethyl, o-carboxyphenyl, 4-chloro-benzyl, 2-n-decylaminoethyl, 2,5-dichlorophenyl, 3,4-dichloropheny1, 2-diethylaminoethyl, 2- diisopropylaminoethyl, 1-dodecyl, ethyl, 4-fluoro-phenyl, n-heptyl, n-hexadecy1, 2-hydroxyethyl1, 2-ethoxyethyl, 2-ethylthioethyl, 1-methyl1-2-imidazolyl, 2,3-dihydroxypropyl, 2- pyridyl, 4-pyridyl, 3-hydroxy-2-pyridy1, 2-thiazolyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxypheny1, 2-methyl-2-butyl, 3-methyl-l-buty1, 4-nitrophenyl, 1-nonyl, 1-octyl, pentachlorophenyl1, pentafluorophenyl1, 1-pentyl, 3-phenyl-1-propyl, 1-propyl, 2-propyl, 2-quinolyl, 2 , 3 ,5 ,6-tetrafluorophenyl, p- tolyl, 2, 4, 5-trichlorophenyl, 7-trifluoro-
Claims (13)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US83635077A | 1977-09-26 | 1977-09-26 | |
| US05/921,645 US4193928A (en) | 1977-09-26 | 1978-07-03 | Lasalocid derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO783243L true NO783243L (en) | 1979-03-27 |
Family
ID=27125862
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO783243A NO783243L (en) | 1977-09-26 | 1978-09-25 | LASALOCID DERIVATIVES. |
Country Status (12)
| Country | Link |
|---|---|
| AR (1) | AR222312A1 (en) |
| DE (1) | DE2861018D1 (en) |
| DK (1) | DK425278A (en) |
| ES (1) | ES473636A1 (en) |
| FI (1) | FI782934A (en) |
| GR (1) | GR72000B (en) |
| IL (1) | IL55619A0 (en) |
| IT (1) | IT1099191B (en) |
| MC (1) | MC1209A1 (en) |
| NO (1) | NO783243L (en) |
| NZ (1) | NZ188484A (en) |
| PT (1) | PT68588A (en) |
-
1978
- 1978-09-22 IL IL7855619A patent/IL55619A0/en unknown
- 1978-09-22 NZ NZ18848478A patent/NZ188484A/en unknown
- 1978-09-22 MC MC781327A patent/MC1209A1/en unknown
- 1978-09-25 AR AR27383178A patent/AR222312A1/en active
- 1978-09-25 NO NO783243A patent/NO783243L/en unknown
- 1978-09-25 GR GR57296A patent/GR72000B/el unknown
- 1978-09-25 ES ES473636A patent/ES473636A1/en not_active Expired
- 1978-09-25 DK DK425278A patent/DK425278A/en unknown
- 1978-09-25 PT PT6858878A patent/PT68588A/en unknown
- 1978-09-26 DE DE7878100991T patent/DE2861018D1/en not_active Expired
- 1978-09-26 IT IT2810978A patent/IT1099191B/en active
- 1978-09-26 FI FI782934A patent/FI782934A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| AR222312A1 (en) | 1981-05-15 |
| GR72000B (en) | 1983-08-26 |
| IL55619A0 (en) | 1978-12-17 |
| DK425278A (en) | 1979-03-27 |
| FI782934A (en) | 1979-03-27 |
| IT1099191B (en) | 1985-09-18 |
| NZ188484A (en) | 1981-05-01 |
| DE2861018D1 (en) | 1981-11-26 |
| MC1209A1 (en) | 1979-05-18 |
| PT68588A (en) | 1978-10-01 |
| ES473636A1 (en) | 1979-04-16 |
| IT7828109A0 (en) | 1978-09-26 |
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