NO144214B - Analogifremgangsmaate for fremstilling av terapeutiak aktive fenyl-imidazoliner - Google Patents
Analogifremgangsmaate for fremstilling av terapeutiak aktive fenyl-imidazoliner Download PDFInfo
- Publication number
- NO144214B NO144214B NO761970A NO761970A NO144214B NO 144214 B NO144214 B NO 144214B NO 761970 A NO761970 A NO 761970A NO 761970 A NO761970 A NO 761970A NO 144214 B NO144214 B NO 144214B
- Authority
- NO
- Norway
- Prior art keywords
- acid
- methyl
- ethyl
- formula
- hydrogen
- 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 7
- -1 PHENYL IMIDAZOLINES Chemical class 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims description 19
- 239000002253 acid Substances 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical group CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 2
- JAJGDBVYNSOVEB-UHFFFAOYSA-N 5-phenyl-4,5-dihydro-1h-imidazole Chemical class C1N=CNC1C1=CC=CC=C1 JAJGDBVYNSOVEB-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims 1
- 125000004433 nitrogen atom Chemical group N* 0.000 claims 1
- 239000007858 starting material Substances 0.000 claims 1
- 230000006378 damage Effects 0.000 description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 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
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-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
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 208000027418 Wounds and injury Diseases 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
- 208000014674 injury Diseases 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-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
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-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
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-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
- 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 2
- 150000007513 acids Chemical class 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-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
- 238000002474 experimental method 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
- 238000001802 infusion Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- OCIDXARMXNJACB-UHFFFAOYSA-N n'-phenylethane-1,2-diamine Chemical class NCCNC1=CC=CC=C1 OCIDXARMXNJACB-UHFFFAOYSA-N 0.000 description 2
- 230000017074 necrotic cell death Effects 0.000 description 2
- 235000006408 oxalic acid Nutrition 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
- 230000002265 prevention Effects 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 230000009528 severe injury Effects 0.000 description 2
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 230000000451 tissue damage Effects 0.000 description 2
- 231100000827 tissue damage Toxicity 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
- 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
- RTBFRGCFXZNCOE-UHFFFAOYSA-N 1-methylsulfonylpiperidin-4-one Chemical compound CS(=O)(=O)N1CCC(=O)CC1 RTBFRGCFXZNCOE-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
- RAXJZPIFBLTJKS-UHFFFAOYSA-N 4-(5-chloro-2-methylphenyl)-2-methyl-1-sulfanyl-4,5-dihydroimidazole;hydrochloride Chemical compound Cl.C1N(S)C(C)=NC1C1=CC(Cl)=CC=C1C RAXJZPIFBLTJKS-UHFFFAOYSA-N 0.000 description 1
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 description 1
- NCLHXQRFHAELKE-UHFFFAOYSA-N 5-(2,6-dichlorophenyl)-2-methylsulfanyl-4,5-dihydro-1h-imidazole;hydrochloride Chemical compound Cl.C1NC(SC)=NC1C1=C(Cl)C=CC=C1Cl NCLHXQRFHAELKE-UHFFFAOYSA-N 0.000 description 1
- GEPMAHVDJHFBJI-UHFFFAOYSA-N 7-[2-hydroxy-3-[2-hydroxyethyl(methyl)amino]propyl]-1,3-dimethylpurine-2,6-dione;pyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC=CN=C1.CN1C(=O)N(C)C(=O)C2=C1N=CN2CC(O)CN(CCO)C GEPMAHVDJHFBJI-UHFFFAOYSA-N 0.000 description 1
- YIUIVFFUEVPRIU-UHFFFAOYSA-N 8-chlorotheophylline Chemical compound O=C1N(C)C(=O)N(C)C2=NC(Cl)=N[C]21 YIUIVFFUEVPRIU-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 239000005632 Capric acid (CAS 334-48-5) 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
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 206010033799 Paralysis Diseases 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
- IUJDSEJGGMCXSG-UHFFFAOYSA-N Thiopental Chemical compound CCCC(C)C1(CC)C(=O)NC(=S)NC1=O IUJDSEJGGMCXSG-UHFFFAOYSA-N 0.000 description 1
- 235000013832 Valeriana officinalis Nutrition 0.000 description 1
- 244000126014 Valeriana officinalis Species 0.000 description 1
- PDVPLLNUWRQQMB-UHFFFAOYSA-N [Na].C(C)C1(C(NC(N(C1=O)CCCC)=S)=O)C Chemical compound [Na].C(C)C1(C(NC(N(C1=O)CCCC)=S)=O)C PDVPLLNUWRQQMB-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 150000001298 alcohols Chemical class 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
- 229910021529 ammonia Inorganic materials 0.000 description 1
- ICAIHGOJRDCMHE-UHFFFAOYSA-O ammonium cyanide Chemical compound [NH4+].N#[C-] ICAIHGOJRDCMHE-UHFFFAOYSA-O 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-N anhydrous glutaric acid Natural products OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
- 238000010171 animal model Methods 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
- 229940125717 barbiturate Drugs 0.000 description 1
- HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 description 1
- 150000003935 benzaldehydes Chemical class 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000017531 blood circulation 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
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- HWJHWSBFPPPIPD-UHFFFAOYSA-N ethoxyethane;propan-2-one Chemical compound CC(C)=O.CCOCC HWJHWSBFPPPIPD-UHFFFAOYSA-N 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 210000003141 lower extremity Anatomy 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
- 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
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 238000009519 pharmacological trial Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 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
- 229960004889 salicylic acid Drugs 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000002048 spasmolytic effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229960003279 thiopental Drugs 0.000 description 1
- 230000009424 thromboembolic effect Effects 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
- 235000016788 valerian Nutrition 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 229940075420 xanthine Drugs 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
- C07D233/48—Nitrogen atoms not forming part of a nitro radical with acyclic hydrocarbon or substituted acyclic hydrocarbon radicals, attached to said nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Description
Denne oppfinnelse angår fremstilling av substituerte 4-fenyl-imidazoliner med den generelle formel
og deres fysiologisk forlikelige syreaddisjonssalter med verdifulle terapeutiske egenskaper. I formel I betyr R^ klor, brom, fluor eller metyl, R2hydrogen, klor eller metyl, R, hydrogen eller metyl og R. hydrogen, metyl eller etyl. R^ og Rg, som kan være like eller forskjellige, betyr metyl, etyl eller etoksyetyl, eller danner sammen en 5-, 6- eller 7-leddet ring som ikke inneholder noen ytterligere heteroatomer,
en morfolin- eller 4-metylpiperazinring.
Forbindelsene med formel I representerer cykliske guanidiner som kan opptre i tautomere former. Forbindelsene med formel I inneholder et asymmetrisk karbonatom og kan derfor foreligge både som racemater og som optiske antipoder.
Forbindelsene med formel I fremstilles ved at et imidazolin med formelen
hvor R^til R^har den ovenfor angitte betydning, omsettes med et amin med formelen
hvor R4, R,, og Rg har den ovenfor angitte betydning.
Omsetningen utføres fortrinnsvis ved oppvarmning av reaksjonskomponentene, men kan også foretas i nærvær av et oppløsningsmiddel, f.eks. dimetylsulfoksyd, dimetylformamid, alkoholer eller etere.
Forbindelser med formel II kan f.eks. fremstilles ved omsetning av substituerte fenyletylendiaminer med formel IV
med karbondisulfid og påfølgende métylering av det dannede fenyletylentiourinstoff med metylhalogenider eller organiske estere, så som dimetylsulfat.
Fenyletylendiaminer med formel IV kan f.eks. fremstilles fra de tilsvarende substituerte benzaldehyder ved omsetning med ammoniumcyanid og hydrogénering av de derved dannede a-cyano-benzylaminer.
De nye forbindelser med den generelle formel I kan på vanlig måte overføres til sine fysiologisk forlikelige syre-addis jonssalter . Syrer som er egnet for saltdannelse, er f.eks. mineralsyrer så som saltsyre, bromhydrogensyre, jod-hydrogensyre, fluorhydrogensyre, svovelsyre, fosforsyre, salpetersyre, eller organiske syrer så som eddiksyre, propionsyre, smørsyre, valeriansyre, kapronsyre, kaprinsyre, oksalsyre, malonsyre, ravsyre, glutarsyre, maleinsyre, fumarsyre, melkesyre, vinsyre, sitronsyre, eplesyre, glukonsyre, benzoesyre, p-hydroksybenzoesyre, ftalsyre, kanelsyre, salicylsyre,
askorbinsyre, 8-klorteofyllin, metansulfonsyre og lignende.
De nye forbindelser med den generelle formel I og deres syreaddisjonssalter har verdifulle terapeutiske egenskaper. Særlig skal fremheves den gjennomblødningsfremmende og blodplateaggregasjonshemmende virkning. Særlig hemmer de ved en konsentrasjon på ca. 10 — 5 mol/l in vitro blodplate-aggregas jonen ved metoden ifølge Born. Forbindelsene er således egnet til forebyggelse og behandling av tromboemboliske lidelser. Dessuten medfører de en forbedring av den perifere kargjennomblødning.
Farmakologiske forsøksresultater
De følgende resultater ble oppnådd ved forsøk hvor innvirkningen av gjennomblødningsforbedrende midler på vev-skader på en rottepote kan måles.
Metodikk
Som forsøksdyr anvendes FW-49 hannrotter med vekt mellom 400 og 450 g. Vevskadene fremkalles ved injeksjon av 0,2 ml av en 5%ig oppløsning av 5-etyl-5-metylbutyl-2-tiobarbitursyre-natriumsalt (tiopental) i Art. epigastrica. Administreringen av barbituratet skjer i form av en infusjon som varer i 30sekunder, ved hjelp av en elektrisk infusjonspumpe. Som følge av injeksjonen oppstår en mer eller mindre sterkt utpreget skade i bakekstremiteten. Bedømmelsen foretas daglig i løpet av en uke efter følgende skjema:
Skadegrad 1 = liten skade
Skadegrad 2 = sterkere skade (lamhet)
Skadegrad 3 = sterk skade (begynnende nekrose) Skadegrad 4 = meget sterk skade (vidtgående nekrose).
En forsøksgruppe omfatter 8 dyr.
Efter utløpet av observasjonstiden beregnes for hvert enkelt dyr og den samlede gruppe den midlere skadegrad. Forskjellen i midlere skadegrad mellom behandlet og ubehandlet gruppe uttrykkes relativt i prosent.
Innvirkningen på skadene av prøveforbindelsene bestemmes som følger under anvendelse av den ovenfor beskrevne metodikk:
Optimal skadehemning.
PrøveforbindeIsene administreres oralt ved hjelp av svelgsonde 60 minutter før fremkalling av skaden, hvorved fullstendig gastrointestinal resorpsjon er garantert.
Forskjellen i midlere skadegrad mellom den behandlede og den ubehandlede gruppe uttrykkes i prosent og er et mål for den terapeutiske virkning av den undersøkte forbindelse.
Terapeutisk virkning
For forbindelsen 2-(1,3-bis-dietylamino-isopropyl)-4-(2,6-diklorfenyl)-imidazolin-(2)-hydroklorid ble dessuten den terapeutiske virkning i forhold til xantinolnikotinat bestemt som følger:
Forbindelsen ble efter fremkalling av skaden injisert intravenøst i halevenen. Som i det ovenstående forsøk er også her forskjellen i midlere skadegrad mellom behandlet og ubehandlet gruppe et mål for den terapeutiske virkning av prøveforbindelsene.
De nye forbindelser viser alle ved oral administrering av en dose på 10 mg/kg en tydelig skadehemning, mens derimot xantinol-nikotinat, et anerkjent handelspreparat, først frem-kaller en liten skadehemning ved meget høyere dosering. De samme forhold opptrer ved intravenøs administrering.
Forbindelsene med den generelle formel I og deres syreaddisjonssalter kan anvendes enteralt eller også parenteralt. Doseringen for oral anvendelse ligger ved ca. 0,05 - 80, fortrinnsvis 0,1 - 20 mg. Forbindelsene med formel I og deres syreaddisjonssalter kan også anvendes sammen med andre typer aktive stoffer, f.eks. spasmolytika, sedativer og beroligende midler. Egnede galeniske tilberedelsesformer er f.eks. tabletter, kapsler, stikkpiller, oppløsninger, emulsjoner eller pulvere. For fremstilling av disse kan man anvende de vanlig anvendte galeniske hjelpestoffer, bærestoffer, sprengmidler eller smøremidler eller stoffer som medfører en depotvirkning.Fremstilling av slike galeniske tilberedelsesformer skjer på vanlig måte.
Forbindelsen ifølge eksempel 1 har totalt sett den
gunstigste virkningsprofil og er derfor særlig foretrukket.
De følgende eksempler skal tjene til å illustrere opp-^finnelsen ytterligere.
EKSEMPEL 1
2-(1,3-bis-dietylamino-isopropylamino)-4-(2,6-diklorfenyl)-imidazolin-( 2)- hydroklorid
6,5 g (0,022 mol) 4- (2,6-diklorfenyl)-2-metylmerkapto-imidazolin-hydroklorid og 10,65 g (0,053 mol) 1,3-bis-dietylamino-isopro-pylamin røres sammen og oppvarmes langsomt til 100°C. Det skjer en sterk metylmerkaptanutvikling og selvoppvarmning til 130°C. Denne temperatur holdes i ytterligere 30 minutter, og blandingen avkjøles derefter til 40°C og tilsettes 15 ml aceton. 2-(1,3-bis-dietylamino-iroprppylamino)-4-(2,6-diklorfenyl)-imidazolin-(2)-monohydroklorid utkrystalliserer og vaskes med aceton-eter (1:1). Man får 4,2 g slutt-produkt som omkrystalliseres fra vann og som har et sm.p. på 192°C.
EKSEMPEL 2
2-(1,3-bis-dietylamino-isopropylamino)-4-(2-metyl-5-klorfenyl)-imidazolin-( 2)- tritartrat
2,77 g (0,01 mol) 4-(2-metyl-5-klor-fenyl)-2-metyl-merkapto-imidazolin-hydroklorid omrøres sammen med 2,0 g (0,01 mol) 1,3-bis-dietylamino-isopropylamin og 70 ml vannfritt dimetylsulfoksyd og oppvarmes langsomt til 130°C. Efter-4 timer avkjøler man og tilsetter 600 ml vann. Medøkende mengder av tilsatt natronlut utristes frak-sjonert med eter, og oppløsningene inneholdende forbindelsen tørres og inndampes. Man får 1,7 g rått 2-(1,3-bis-dietylamino-isopropyl-amino)-4-(2-metyl-5-klorfenyl)-imidazolin-(2) som renses over en sil-ikagelkolonne (elueringsmiddel aceton:benzen:metanol:konsentrert am-moniakk=10:10:8:2). De ønskede fraksjoner inndampes, opptaes i eter og tilsettes vinsyre oppløst i alkohol. Det først amorft utfelte bunnfall felles på ny fra alkohol-eter og smeltes da fra 85°C under spaltning.
I de følgende eksempler ble det arbeidet efter metodene ifølge eksemplene 1 og 2, idet oksalatene ble utfelt fra basene opp-løst i eter under tilsetning av eterisk oksalsyre og omkrystallisert fra etanol.
Claims (2)
- I- Analogifremgangsmåte for fremstilling av terapeutisk aktive 4-fenyl-imidazoliner med den generelle formelhvor betyr klor, brom, fluor eller metyl, R2 betyr hydrogen, klor eller metyl, R^ betyr hydrogen eller metyl, og R^ betyr hydrogen, metyl'eller etyl, R,, og Rg, som kan være like eller forskjellige, betyr metyl, etyl, etoksyetyl eller sammen med nitrogenatornet en 5-, 6-eller 7-leddet ring som ikke inneholder noen ytterligere heteroatomer, en morfolin- eller 4-metylpiperazinring, og syreaddisjonssalter derav, karakterisert vedat et imidazolin med formelenhvor R^til R^har den ovenfor angitte betydning, omsettes med et amin med formelenhvor R4, R,, og Rg har den ovenfor angitte betydning, og eventuelt omdannes den erholdte forbindelse til et syre-addisjonssalt derav.
- 2. Fremgangsmåte som angitt i krav 1 for fremstilling av 2-(1,3-bis-dietylamino-isopropylamino)-4-(2,6-diklorfenyl)-imidazolin- (2),karakterisert vedat det anvendes utgangsmaterialer hvor R^er 2-klor,R2er 6-klor, R^er hydrogen, R^er hydrogen, R,, er etyl og Rg er etyl.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2525725A DE2525725C3 (de) | 1975-06-10 | 1975-06-10 | Basisch substituierte 2-AIkylamino-4-phenyl-imidazoline, deren Säureadditionssalze, Verfahren zu ihrer Herstellung und deren Verwendung |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO761970L NO761970L (no) | 1976-12-13 |
| NO144214B true NO144214B (no) | 1981-04-06 |
| NO144214C NO144214C (no) | 1981-07-15 |
Family
ID=5948681
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO761970A NO144214C (no) | 1975-06-10 | 1976-06-09 | Analogifremgangsmaate for fremstilling av terapeutiak aktive fenyl-imidazoliner |
Country Status (23)
| Country | Link |
|---|---|
| US (1) | US4058616A (no) |
| JP (1) | JPS603066B2 (no) |
| AT (1) | AT351020B (no) |
| AU (1) | AU498253B2 (no) |
| BE (1) | BE842768A (no) |
| CA (1) | CA1069514A (no) |
| CH (1) | CH622785A5 (no) |
| DE (1) | DE2525725C3 (no) |
| DK (1) | DK142172C (no) |
| ES (1) | ES448696A1 (no) |
| FI (1) | FI62069C (no) |
| FR (1) | FR2313926A1 (no) |
| GB (1) | GB1481948A (no) |
| GR (1) | GR60041B (no) |
| IE (1) | IE43793B1 (no) |
| IL (1) | IL49747A (no) |
| LU (1) | LU75114A1 (no) |
| MX (1) | MX3153E (no) |
| NL (1) | NL7606266A (no) |
| NO (1) | NO144214C (no) |
| PT (1) | PT65201B (no) |
| SE (1) | SE422936B (no) |
| ZA (1) | ZA763422B (no) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4105765A (en) * | 1975-06-10 | 1978-08-08 | Boehringer Ingelheim Gmbh | 2-(N-(1,3-diamino-isopropyl)-amino)-4-phenyl-2-imidazolines and salts thereof |
| US4288447A (en) * | 1979-02-06 | 1981-09-08 | A. H. Robins Company, Inc. | Antihyperglycemic 4-substituted 2-iminoimidazolidine compositions |
| US4288591A (en) * | 1979-02-06 | 1981-09-08 | A. H. Robins Company, Inc. | 4-Substituted 2-iminoimidazolidine compounds |
| US4647557A (en) * | 1982-12-28 | 1987-03-03 | Gerard Moinet | Novel heterocyclic derivatives bearing an amino radical, processes for their production and the pharmaceutical compositions containing them |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2586844A (en) * | 1947-10-21 | 1952-02-26 | Ayerst Mckenna & Harrison | Preparation of delta2-1, 3-diazacycloalkenes |
| FR2081571B1 (no) * | 1970-03-12 | 1973-04-06 | Synthelabo |
-
1975
- 1975-06-10 DE DE2525725A patent/DE2525725C3/de not_active Expired
-
1976
- 1976-05-20 AT AT366676A patent/AT351020B/de not_active IP Right Cessation
- 1976-05-20 FI FI761423A patent/FI62069C/fi not_active IP Right Cessation
- 1976-05-27 GR GR50828A patent/GR60041B/el unknown
- 1976-06-03 US US05/692,325 patent/US4058616A/en not_active Expired - Lifetime
- 1976-06-08 LU LU75114A patent/LU75114A1/xx unknown
- 1976-06-08 PT PT65201A patent/PT65201B/pt unknown
- 1976-06-08 CH CH719176A patent/CH622785A5/de not_active IP Right Cessation
- 1976-06-09 BE BE167776A patent/BE842768A/xx not_active IP Right Cessation
- 1976-06-09 IL IL49747A patent/IL49747A/xx unknown
- 1976-06-09 AU AU14770/76A patent/AU498253B2/en not_active Expired
- 1976-06-09 ZA ZA00763422A patent/ZA763422B/xx unknown
- 1976-06-09 ES ES448696A patent/ES448696A1/es not_active Expired
- 1976-06-09 DK DK255976A patent/DK142172C/da not_active IP Right Cessation
- 1976-06-09 GB GB23913/76A patent/GB1481948A/en not_active Expired
- 1976-06-09 NO NO761970A patent/NO144214C/no unknown
- 1976-06-09 SE SE7606497A patent/SE422936B/xx not_active IP Right Cessation
- 1976-06-09 CA CA254,445A patent/CA1069514A/en not_active Expired
- 1976-06-09 JP JP51067548A patent/JPS603066B2/ja not_active Expired
- 1976-06-10 MX MX000300U patent/MX3153E/es unknown
- 1976-06-10 FR FR7617539A patent/FR2313926A1/fr active Granted
- 1976-06-10 IE IE1256/76A patent/IE43793B1/en unknown
- 1976-06-10 NL NL7606266A patent/NL7606266A/xx unknown
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