NO792334L - Analogifremgangsmaate for fremstilling av terapeutisk aktive fenylamino-imidazol-derivater - Google Patents
Analogifremgangsmaate for fremstilling av terapeutisk aktive fenylamino-imidazol-derivaterInfo
- Publication number
- NO792334L NO792334L NO792334A NO792334A NO792334L NO 792334 L NO792334 L NO 792334L NO 792334 A NO792334 A NO 792334A NO 792334 A NO792334 A NO 792334A NO 792334 L NO792334 L NO 792334L
- Authority
- NO
- Norway
- Prior art keywords
- acid
- general formula
- phenylamino
- bromo
- preparation
- 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 3
- YCAXQAUEKMQYQH-UHFFFAOYSA-N n-phenyl-1h-imidazol-2-amine Chemical class C=1C=CC=CC=1NC1=NC=CN1 YCAXQAUEKMQYQH-UHFFFAOYSA-N 0.000 title 1
- 239000002253 acid Substances 0.000 claims description 13
- 150000001875 compounds Chemical class 0.000 claims description 12
- -1 2,4,6-tribromophenyl Chemical group 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 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
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 claims description 2
- 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
- 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
- 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
- 239000000460 chlorine Substances 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 2
- UBEPBFYKYSULAI-UHFFFAOYSA-N 2-phenyl-2,5-dihydro-1H-imidazol-4-amine Chemical compound N1C(=N)CNC1C1=CC=CC=C1 UBEPBFYKYSULAI-UHFFFAOYSA-N 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 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
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000015572 biosynthetic process Effects 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
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 150000003585 thioureas Chemical class 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
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-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
- 235000013877 carbamide Nutrition 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
- 239000002904 solvent Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000126 substance 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
- 230000007306 turnover Effects 0.000 description 2
- 150000003672 ureas Chemical class 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-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
- 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
- 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
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 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
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical class NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 235000013832 Valeriana officinalis Nutrition 0.000 description 1
- 244000126014 Valeriana officinalis Species 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
- 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
- 239000000969 carrier Substances 0.000 description 1
- ZVTQWXCKQTUVPY-UHFFFAOYSA-N chloromethylcyclopropane Chemical compound ClCC1CC1 ZVTQWXCKQTUVPY-UHFFFAOYSA-N 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
- 239000013078 crystal Substances 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
- 239000002360 explosive Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- QFWPJPIVLCBXFJ-UHFFFAOYSA-N glymidine Chemical compound N1=CC(OCCOC)=CN=C1NS(=O)(=O)C1=CC=CC=C1 QFWPJPIVLCBXFJ-UHFFFAOYSA-N 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
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 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
- 238000004519 manufacturing process Methods 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
- 239000000203 mixture Substances 0.000 description 1
- VEWWJKYODRUASI-UHFFFAOYSA-N n-(2-bromo-6-chlorophenyl)-4,5-dihydro-1h-imidazol-2-amine Chemical compound ClC1=CC=CC(Br)=C1N=C1NCCN1 VEWWJKYODRUASI-UHFFFAOYSA-N 0.000 description 1
- AEVDCVQMCTUJJP-UHFFFAOYSA-N n-(2-bromo-6-chlorophenyl)-n-(cyclopropylmethyl)-4,5-dihydro-1h-imidazol-2-amine Chemical compound ClC1=CC=CC(Br)=C1N(C=1NCCN=1)CC1CC1 AEVDCVQMCTUJJP-UHFFFAOYSA-N 0.000 description 1
- JCOPITWIWLFFPC-UHFFFAOYSA-N n-phenyl-4,5-dihydro-1h-imidazol-2-amine Chemical compound N1CCN=C1NC1=CC=CC=C1 JCOPITWIWLFFPC-UHFFFAOYSA-N 0.000 description 1
- SACAEVOKRBNXPN-UHFFFAOYSA-N n-phenyl-4,5-dihydroimidazol-1-amine Chemical class C1=NCCN1NC1=CC=CC=C1 SACAEVOKRBNXPN-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229940083254 peripheral vasodilators imidazoline derivative Drugs 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 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
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 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
- 210000002700 urine Anatomy 0.000 description 1
- 235000016788 valerian Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/44—Nitrogen atoms not forming part of a nitro radical
- C07D233/50—Nitrogen atoms not forming part of a nitro radical with carbocyclic radicals directly attached to said nitrogen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
"Analogi fremgangsmåte for fremstilling av terapeutisk
aktive fenylamino- imidazolin- derivater"
Denne oppfinnelse angår fremstilling av nye, substituerte 2-feny lamino-rimidazolin- (2 ) -forbindelser med den
■ generelle formel
og fysiologisk forlikelige syreaddisjonssalter derav, med verdifulle terapeutiske egenskaper.
I formel I betyr Ar resten 2,4,6-tribromfeny1, 2-brom-6-fluorfenyl, 2-bromfenyl, 2-brom-6-klorfeny1, 2,6-difluorfenyl eller 2-brom-3-klorfenyl.
Forbindelsene med formel I fremstilles ved
a) omsetning av et 2-fenylimino-imidazolidin med den generelle formel
hvor Ar har de ovenfor angitte betydninger, med et halogenid med den generelle formel
hvor Hal betyr et klor-, brom- eller jodatom; eller
b) omsetning av en forbindelse med den generelle formel
hvor Ar 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, 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. 50-150°C. De spesielle reaksjonsbetingelser er i sterk grad avhengig av reaktiviteten av reaksjonskomponentene. Det anbefales å anvende halogenidet i overskudd ved alkyleringen og gjennomføre 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. syreaddisjonssalter derav, anvendes i overskudd.
Utgangsforbindelsene med formel II er f.eks. beskrevet
i de belgiske patenter 623.305, 687.657 og 705.944.
Utgangsforbindelser med formel III kan fremstilles ved halogenering av de tilsvarende primære alkoholer.
Forbindelser med formel IV får man ved å gå ut fra aniliner, ved omsetning med forbindelser med formel III og på-følgende omsetning av de derved dannede sekundære aminer med cyanater eller tiocyanater, hvorved det dannes henholdsvis urinstoffer eller tiourinstoffer. Urinstoffer og tiourinstoffer kan derefter overføres videre med alkyleringsmidler til.henholdsvis tilsvarende isouroniumsalter eller isotiouroniumsalter. Fra disse syreaddisjons forbindelser kan man med baser utvinne de tilsvarende henholdsvis isourinstoffer eller isotiourinstoffer. Ved vannavspaltning 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, jod-hydrogensyre, fluorhydrogensyre, svovelsyre, fosforsyre, salpetersyre, eddiksyre, propionsyre, smørsyre, kapronsyre, valeriansyre, oksalsyre, malonsyre, ravsyre, maleinsyre, fumarsyre, melkesyre, vinsyre, sitronsyre, eplesyre, benzoesyre, p-hydroksy-benzoesyre, p-aminobenzoesyre, ftalsyre, kanelsyre, salicylsyre, askorbinsyre, metansulfonsyre , 8-klorteofy 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. Innvirkningen på hjertefrekvensen ble undersøkt på kaniner og på spinalbedøvede rotter såvel som intakte, narkotiserte rotter. Doseringen ligger ved 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. For fremstilling av .slike preparater kan man anvende de vanlig anvendte galeniske hjelpestoffer, bæremidler, sprengmidler eller smøremidler eller stoffer som gir en depotvirkning.
De følgende eksempler skal tjene til å illustrere opp-finnelsen ytterligere.
Eksempel 1
2-[ N-( 2- brom- 6- klorfenyl)- N-( cyklopropylmetyl)- amino]- 2- imidazolin
4,3 g (0,0157 mol) 2-(2-brom-6-klorfenylimino)-imidazolidin oppvarmes sammen med 1,6 g (110%) klormetyl-cyklopropan i 50 ml etanol i 24 timer under omrøring ved tilbakeløps-temperatur. Derefter avdrives i vakuum både oppløsningsmidlet og flyktige bestanddeler, residuet oppløses i en blanding (1:1)
av fortynnet saltsyre (2N) og vann, og oppløsningen ekstraheres to ganger med eter (eterekstraktene kastes). Den saltsure oppløsning ekstraheres derefter fraksjonert med eter ved stigende pH-verdier (trinnvis alkalisering med 2N .natronlut) . De tynnskikt-kromatografisk enhetlige eterekstrakter samles, tørres over MgSO^, filtreres over aktivt kull, og filtratet inndampes i
vakuum. Herved faller det nye imidazolin ut som hvite krystaller. Utbytte: 1,2 g (23,3% av det teoretiske). Smeltepunkt: 136-137°C. Rf: 0,2. System: benzen 50, dioksan 40, etanol 5, kons. NH^OH 5; bærer: silikagel G + lyspigment; detektor: UV og kaliumjod-platinat.
C13H15BrlC1lN3 <328'64)
Beregnet: C 47,51%, H 4,60%, Hal 35,10%, N 12,79%
Funnet: C 47,61%, H 4,48%, Hal 34,93%, N 12,73%.
I henhold til det foregående eksempel ble de følgende forbindelser fremstilt. Smeltepunktene gjelder for basene med formel I.
Claims (1)
- Analogi fremgangsmåte for fremstilling av terapeutisk aktive, substituerte 2-fenylamino-imidazolin-(2)-forbindelser med den generelle formelhvor Ar betyr resten 2,4,6-tribromfenyl, 2-brom-6-fluorfenyl, 2-bromfenyl, 2-brom-6-klorfenyl, 2,6-difluorfenyl eller 2-brom-3-klorfenyl, og syreaddisjonssalter derav, kar, akterisert ved at a) et 2-fenyl-iminoimidazolidin med den generelle formelhvor Ar har den ovenfor angitte betydning, omsettes med et halogenid med den generelle formelhvor Hal betyr et klor-, brom- eller jodatom, eller b) en forbindelse med den generelle formelhvor Ar er som ovenfor angitt, og A betyr en cyanogruppe eller restenidet Y representerer en alkoksy- eller alkyltio gruppe med opptil 4 karbonatomer eller en sulfhydryl- eller aminogruppe, omsettes med etylendiamin eller syreaddisjonssalter derav, og en forbindelse, fremstilt som angitt ovenfor, overføres eventuelt til et syreaddisjonssalt derav.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19782831234 DE2831234A1 (de) | 1978-07-15 | 1978-07-15 | Neue substituierte 2-phenylamino-imidazoline-(2) deren saeureadditionssalze, diese enthaltende arzneimittel und verfahren zur herstellung derselben |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO792334L true NO792334L (no) | 1980-01-16 |
Family
ID=6044530
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO792334A NO792334L (no) | 1978-07-15 | 1979-07-13 | Analogifremgangsmaate for fremstilling av terapeutisk aktive fenylamino-imidazol-derivater |
Country Status (11)
| Country | Link |
|---|---|
| EP (1) | EP0007422A1 (no) |
| JP (1) | JPS5515469A (no) |
| AU (1) | AU4894679A (no) |
| DE (1) | DE2831234A1 (no) |
| DK (1) | DK296879A (no) |
| ES (1) | ES482469A1 (no) |
| FI (1) | FI792205A (no) |
| IL (1) | IL57793A0 (no) |
| NO (1) | NO792334L (no) |
| PT (1) | PT69921A (no) |
| ZA (1) | ZA793541B (no) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2933930A1 (de) * | 1979-08-22 | 1981-03-12 | C.H. Boehringer Sohn, 6507 Ingelheim | 2-(2-chlor-4-cyclopropyl-phenylimino)-imidazolidin, dessen saeureadditionssalze, diese enthaltende arzneimittel und verfahren zur herstellung derselben. |
| DE2947563A1 (de) * | 1979-11-26 | 1981-06-04 | C.H. Boehringer Sohn, 6507 Ingelheim | Neue substituierte 2-phenylamino-imidazoline-(2), deren saeureadditionssalze, diese enthaltende arzneimittel und verfahren zur herstellung derselben |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2636732A1 (de) * | 1976-08-14 | 1978-02-16 | Boehringer Sohn Ingelheim | Neue substituierte 2-phenylamino- imidazoline- (2), deren saeureadditionssalze, diese enthaltende arzneimittel und verfahren zur herstellung derselben |
-
1978
- 1978-07-15 DE DE19782831234 patent/DE2831234A1/de active Pending
-
1979
- 1979-06-15 EP EP79101949A patent/EP0007422A1/de not_active Withdrawn
- 1979-07-12 JP JP8754579A patent/JPS5515469A/ja active Pending
- 1979-07-13 ES ES482469A patent/ES482469A1/es not_active Expired
- 1979-07-13 NO NO792334A patent/NO792334L/no unknown
- 1979-07-13 FI FI792205A patent/FI792205A/fi not_active Application Discontinuation
- 1979-07-13 ZA ZA00793541A patent/ZA793541B/xx unknown
- 1979-07-13 PT PT69921A patent/PT69921A/pt unknown
- 1979-07-13 IL IL57793A patent/IL57793A0/xx unknown
- 1979-07-13 DK DK296879A patent/DK296879A/da unknown
- 1979-07-16 AU AU48946/79A patent/AU4894679A/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5515469A (en) | 1980-02-02 |
| DE2831234A1 (de) | 1980-01-31 |
| FI792205A (fi) | 1980-01-16 |
| EP0007422A1 (de) | 1980-02-06 |
| PT69921A (de) | 1979-08-01 |
| ES482469A1 (es) | 1980-04-01 |
| AU4894679A (en) | 1980-01-24 |
| IL57793A0 (en) | 1979-11-30 |
| DK296879A (da) | 1980-01-16 |
| ZA793541B (en) | 1981-03-25 |
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