NO792368L - Analogifremgangsmaate for fremstilling av terapeutisk aktive fenylamino-imidazolin-derivater - Google Patents
Analogifremgangsmaate for fremstilling av terapeutisk aktive fenylamino-imidazolin-derivaterInfo
- Publication number
- NO792368L NO792368L NO792368A NO792368A NO792368L NO 792368 L NO792368 L NO 792368L NO 792368 A NO792368 A NO 792368A NO 792368 A NO792368 A NO 792368A NO 792368 L NO792368 L NO 792368L
- Authority
- NO
- Norway
- Prior art keywords
- acid
- general formula
- phenylamino
- preparation
- acid addition
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 7
- 238000002360 preparation method Methods 0.000 title claims description 6
- 230000001225 therapeutic effect Effects 0.000 title description 2
- SACAEVOKRBNXPN-UHFFFAOYSA-N n-phenyl-4,5-dihydroimidazol-1-amine Chemical class C1=NCCN1NC1=CC=CC=C1 SACAEVOKRBNXPN-UHFFFAOYSA-N 0.000 title 1
- 239000002253 acid Substances 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 10
- -1 2,6-dibromophenyl Chemical group 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 3
- 150000004820 halides Chemical class 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- JCOPITWIWLFFPC-UHFFFAOYSA-N n-phenyl-4,5-dihydro-1h-imidazol-2-amine Chemical compound N1CCN=C1NC1=CC=CC=C1 JCOPITWIWLFFPC-UHFFFAOYSA-N 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 2
- 239000005864 Sulphur Substances 0.000 claims 1
- 239000007795 chemical reaction product Substances 0.000 claims 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical class NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 235000013877 carbamide Nutrition 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 150000003585 thioureas Chemical class 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000012259 ether extract Substances 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 150000003672 ureas Chemical class 0.000 description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- FUOHKPSBGLXIRL-UHFFFAOYSA-N 2-(chloromethyl)thiophene Chemical compound ClCC1=CC=CS1 FUOHKPSBGLXIRL-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 238000005684 Liebig rearrangement reaction Methods 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229960004050 aminobenzoic acid Drugs 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000000059 bradycardiac effect Effects 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 150000001912 cyanamides Chemical class 0.000 description 1
- 150000001913 cyanates Chemical class 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 150000002357 guanidines Chemical class 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 1
- 150000002462 imidazolines Chemical class 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 150000002541 isothioureas Chemical class 0.000 description 1
- 150000002542 isoureas Chemical class 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 150000002730 mercury Chemical class 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- XIVCHYWIEHVAJG-UHFFFAOYSA-N n-(2,6-dibromophenyl)-4,5-dihydro-1h-imidazol-2-amine Chemical compound BrC1=CC=CC(Br)=C1N=C1NCCN1 XIVCHYWIEHVAJG-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 150000003138 primary alcohols Chemical class 0.000 description 1
- 235000019260 propionic acid Nutrition 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
- 230000009257 reactivity Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 125000000467 secondary amino group Chemical class [H]N([*:1])[*:2] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229910052717 sulfur Chemical group 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003567 thiocyanates Chemical class 0.000 description 1
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical class NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Animal Behavior & Ethology (AREA)
- Cardiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
"Analogifremgangsmåte for fremstilling av terapeutisk aktive fenylamino-iinidazolin-derivater"
Denne oppfinnelse angår fremstilling av nye substituerte 2-fenylamino-imidazolin-(2)-forbindelser med den generelle formel
og fysiologisk forlikelige syreaddisjonssalter derav, med verdifulle terapeutiske egenskaper.
I formel I betyr Ar 2,6-dibromfeny1, 2,4-dibromfeny1
eller 3-brom-4-fluorfenyl, og X betyr oksygen eller svovel.
Forbindelsene med formel I fremstilles ved
a) omsetning av et 2-fenylimino-imidazolidin med den generelle formel
hvor Ar har den ovenfor angitte betydning, med et halogenid med den generelle formel hvor Hal betyr et klor-, brom- eller jodatom, og X har den ovenfor angitte betydning; eller b) omsetning av en forbindelse med den generelle formel hvor Ar og X er som ovenfor angitt, og A betyr en cyanogruppe eller resten
, idet Y representerer en alkoksy- eller
alkyltiogruppe med opptil 4 C-atomer eller en sulfhydryl- eller aminogruppe, omsettes med etylendiamin eller syreaddisjonssalter derav.
Ved alkyleringen av 2-arylimino-imidazolidinene med formel II ved fremgangsmåte a) skjer substitusjonen utelukkende på bro-nitrogenatomet. Ved omsetningen ifølge fremgangsmåte b) er konstitusjonen av sluttforbindelsen fastlagt ved syntesen. Substituentenes stilling kan foruten ved syntesen også fastslås ved NMR-spektroskopi (kfr. H. Stahle og K.H. Pook, Liebigs Ann. Chem. 751, 159 ff (1971).
Omsetningen ifølge fremgangsmåte a) skjer hensiktsmessig ved oppvarmning av reaksjonskomponentene - fortrinnsvis i nærvær av et polart eller upolart organisk oppløsningsmiddel, til temperaturer på ca. 50 til 150°C. De spesielle reaksjons-betingelser er i sterk grad avhengig av reaktiviteten av reaksjonskomponentene. Det anbefales å anvende halogenidet i overskudd ved alkyleringen og utføre omsetningen i nærvær av et syrebindende middel.
Ved fremgangsmåte b) er det nødvendig å arbeide ved forhøyet temperatur, mellom 60 og 180°C. Oppløsningsmidler er ikke nødvendig. Det er hensiktsmessig at det som reaksjons-. komponent anvendte etylendiamin, resp. syreaddisjonssaltet derav, anvendes i overskudd.
Utgangsforbindelsene med formel II er f.eks. beskrevet
i de belgiske patenter 623.305, 687.657 og 705.944.
Utgangsforbindelsene med formel III kan fremstilles
ved halogenering av de tilsvarende primære alkoholer.
Forbindelsene med formel IV får man ved å gå ut fra aniliner, ved omsetning med forbindelser med formel III og påfølgende omsetning av de derved dannede sekundære aminer med cyanater eller tiocyanater, hvorved det dannes henholdsvis urinstoffer eller tiourinstoffer. Urinstoffer og tiourinstoffer kan derefter overføres til henholdsvis tilsvarende isouronium-salter og isotiouroniumsalter med alkyleringsmidler. Fra disse syreaddisjonsforbindelser kan man med baser utvinne de tilsvarende henholdsvis isourinstoffer og isotiourinstoffer. Ved vann-avspaltning fra urinstoffer resp. H^S-avspaltning fra tiourinstoffer ved hjelp av bly- eller kvikksølvsalter får man cyanamider til hvilke ammoniakk kan tilleires under dannelse av guanidiner.
De nye 2-fenylamino-imidazolin-(2)-forbindelser med
den generelle formel I kan på vanlig måte overføres til sine fysiologisk forlikelige syreaddisjonssalter. Syrer som er egnet for saltdannelse, er f.eks. saltsyre, bromhydrogensyre, jodhydrogensyre, fluorhydrogensyre, svovelsyre, fosforsyre, salpetersyre, eddiksyre, propionsyre, smørsyre, kapronsyre, •valeriansyre, oksalsyre, malonsyre, ravsyre, maleinsyre, fumarsyre, melkesyre, vinsyre, sitronsyre, eplesyre, benzoesyre, p-hydroksybenzoesyre, p-aminobenzoesyre, ftalsyre, kanelsyre, salicylsyre, askorbinsyre, metansulfonsyre, 8-klorteof y Hin o.l.
De nye forbindelser med den generelle formel I og
deres syreaddisjonssalter har en sterk bradykard virkning og er derfor egnet til behandling av coronarlidelser. Innvirkning på hjertefrekvensen er undersøkt på kaniner og på spinalbedøvede rotter, foruten intakte, narkotiserte rotter.
Doseringen ligger på 0,1 til 80 mg, fortrinnsvis
1 til 30 mg.
Forbindelsene med formel I og deres syreaddisjonssalter kan også anvendes sammen med andre aktive stoffer. Egnede galeniske tilberedelsesformer er f.eks. tabletter, kapsler, stikkpiller, oppløsninger eller pulvere, og for fremstillingen kan man anvende de vanlig anvendte galeniske hjelpestoffer, bæremidler, sprengmidler eller smøremidler eller stoffer som medfører en depotvirkning.
De følgende eksempler skal tjene til å illustrere oppfinnelsen ytterligere.
Eksempel 1
2- [ N- ( 2, 6- dibromfeny1)- N-( 2- tienylmety1) amino]- 2- imidazolin-hydroklorid
63,8 g (0,2 mol) 2-(2,6-dibromfenylimino)imidazolidin oppvarmes sammen med 33,1 g (125%) 2-klormetyltiofen og 30 ml trietylamin i 400 ml absolutt toluen i 6 timer under omrøring ved tilbakeløpstemperatur. Efter denne tid foretas avsugning,
og filter-residuet, som består av det nye imidazolin-derivat, vaskes flere ganger med toluen. Derefter oppløser man det i ca. 3 liter vann under tilsetning av 25 ml 2N HC1. Den saltsure opppløsning ekstraheres to ganger med 300 ml eter hver gang (eterekstraktene kastes) og innstilles på pH 7 ved tilsetning
av 5N NaOH. Efter fornyet ekstrahering av den nøytrale oppløsning med 300 ml eter (eterekstrakten kastes) foretas fraksjonert ekstraksjon med eter ved stigende pH-verdier (trinnvis alkalisering med 2N NaOH, hver gang ca. 3 ml), inntil alle forurensninger er fjernet fra den vandige fase (løpende kontroll ved hjelp av tynnskiktkromatogram). Derefter tilsettes den vandige oppløsning 200 ml 2N NaOH, hvorved imidazolinbasen utskilles i ren form. Utbytte efter avsugning, vasking med vann og tørring: 48,4 g (58,3% av det teoretiske). Smeltepunkt: 106-108°C. Hydrokloridet smelter ved 239-240°C.
C14H13Br2N3S X HC1 (451'62)
Beregnet: C 37,23 , H 3,12, Br 35,39, . Cl 7,85, N 9,30, S 7,10 Funnet: C 37,32, H 3,11, Br 35,22, Cl 8,19, N 9,12, S 6,91 Tynnskiktkromatogram:
Rf: 0,7; utviklingsmidde lsystem: benzen : dioksan : etanol-:
kons. NH^OH: 50:40:5:5, påvisning: jodplatinat.
Analogt med det foregående eksempel ble de følgende forbindelser fremstilt, idet smeltepunktene gjelder for basene med formel I.
Claims (1)
- Analogifremgangsmåte for fremstilling av terapeutisk aktive substituerte 2-fenylamino-imidazolin-(2)-forbindelser med den generelle formelhvor Ar betyr 2,6-dibromfenyl, 2,4-dibromfeny1 eller 3-brom-4-fluorfeny1, og X betyr oksygen eller svovel, og syreaddisjonssalter derav, karakterisert ved ata) et 2-fenylimino-imidazolidin med den generelle formelhvor Ar har de ovenfor angitte betydninger, omsettes med et halogenid med den generelle formelhvor Hal betyr et klor-, brom- eller jodatom, og X har den ovenfor angitte betydning, ellerb) en forbindelse med den generelle formelhvor Ar og X er som ovenfor angitt, og A betyr en cyanogruppe eller restenhvor Y representerer en alkoksy- eller alkyltiogruppe med opptil 4 karbonatomer eller en sulfhydryl-eller aminogruppe,' omsettes med etylendiamin eller syreaddis jons-salter derav, og et således fremstilt sluttprodukt overføres eventuelt til et syreaddisjonssalt.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19782831480 DE2831480A1 (de) | 1978-07-18 | 1978-07-18 | Neue substituierte 2-phenylamino- imidazoline-(2), deren saeureadditionssalze, diese enthaltende arzneimittel und verfahren zur herstellung derselben |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO792368L true NO792368L (no) | 1980-01-21 |
Family
ID=6044662
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO792368A NO792368L (no) | 1978-07-18 | 1979-07-17 | Analogifremgangsmaate for fremstilling av terapeutisk aktive fenylamino-imidazolin-derivater |
Country Status (13)
| Country | Link |
|---|---|
| EP (1) | EP0007428A1 (no) |
| JP (1) | JPS5519264A (no) |
| AU (1) | AU4899379A (no) |
| DE (1) | DE2831480A1 (no) |
| DK (1) | DK299779A (no) |
| ES (1) | ES482540A1 (no) |
| FI (1) | FI792234A (no) |
| GR (1) | GR70254B (no) |
| IL (1) | IL57820A0 (no) |
| NO (1) | NO792368L (no) |
| NZ (1) | NZ191037A (no) |
| PT (1) | PT69926A (no) |
| ZA (1) | ZA793604B (no) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2951601A1 (de) * | 1979-12-21 | 1981-07-02 | C.H. Boehringer Sohn, 6507 Ingelheim | Neue substituierte 2-phenylaminoimidazoline-(2), deren saeureadditionssalze, diese enthaltende arzneimittel und verfahren zur herstellung derselben |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3850926A (en) * | 1971-01-21 | 1974-11-26 | Boehringer Sohn Ingelheim | 2-(n-substituted-phenylamino)-imidazolines-(2) |
| DE2102733A1 (en) * | 1971-01-21 | 1972-08-03 | CH. Boehringer Sohn, 6507 Ingelheim | 2-arylamino-2-imidazolines |
| DE2308883C3 (de) * | 1973-02-23 | 1978-05-24 | C.H. Boehringer Sohn, 6507 Ingelheim | 2-Phenylamino-thienylmethyl-imidazoline-(2), Verfahren zur Herstellung derselben und diese enthaltene Arzneimittel |
-
1978
- 1978-07-18 DE DE19782831480 patent/DE2831480A1/de not_active Withdrawn
-
1979
- 1979-06-18 EP EP79101988A patent/EP0007428A1/de not_active Withdrawn
- 1979-07-16 PT PT69926A patent/PT69926A/pt unknown
- 1979-07-17 NO NO792368A patent/NO792368L/no unknown
- 1979-07-17 FI FI792234A patent/FI792234A/fi not_active Application Discontinuation
- 1979-07-17 ES ES482540A patent/ES482540A1/es not_active Expired
- 1979-07-17 AU AU48993/79A patent/AU4899379A/en not_active Abandoned
- 1979-07-17 ZA ZA00793604A patent/ZA793604B/xx unknown
- 1979-07-17 NZ NZ191037A patent/NZ191037A/xx unknown
- 1979-07-17 DK DK299779A patent/DK299779A/da unknown
- 1979-07-17 JP JP9088979A patent/JPS5519264A/ja active Pending
- 1979-07-17 IL IL57820A patent/IL57820A0/xx unknown
- 1979-07-18 GR GR59625A patent/GR70254B/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP0007428A1 (de) | 1980-02-06 |
| AU4899379A (en) | 1980-01-24 |
| JPS5519264A (en) | 1980-02-09 |
| ES482540A1 (es) | 1980-04-01 |
| PT69926A (de) | 1979-08-01 |
| ZA793604B (en) | 1981-03-25 |
| FI792234A (fi) | 1980-01-19 |
| GR70254B (no) | 1982-09-02 |
| IL57820A0 (en) | 1979-11-30 |
| NZ191037A (en) | 1981-04-24 |
| DE2831480A1 (de) | 1980-01-31 |
| DK299779A (da) | 1980-01-19 |
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