NO152171B - Analogifremgangsmaate ved fremstilling av terapeutisk virksomme imidazolinderivater - Google Patents
Analogifremgangsmaate ved fremstilling av terapeutisk virksomme imidazolinderivater Download PDFInfo
- Publication number
- NO152171B NO152171B NO794047A NO794047A NO152171B NO 152171 B NO152171 B NO 152171B NO 794047 A NO794047 A NO 794047A NO 794047 A NO794047 A NO 794047A NO 152171 B NO152171 B NO 152171B
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- Prior art keywords
- acid
- preparation
- therapeutically effective
- formula
- compound
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- 238000000034 method Methods 0.000 title claims description 3
- 238000002360 preparation method Methods 0.000 title claims description 3
- 150000002462 imidazolines Chemical class 0.000 title 1
- 229940083254 peripheral vasodilators imidazoline derivative Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 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
- 159000000000 sodium salts Chemical class 0.000 claims description 2
- 239000003495 polar organic solvent Substances 0.000 claims 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 9
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 229960002896 clonidine Drugs 0.000 description 5
- 230000001077 hypotensive effect Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 241000700159 Rattus Species 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 208000001953 Hypotension Diseases 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 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
- 230000001882 diuretic effect Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 208000021822 hypotensive Diseases 0.000 description 3
- 241000282472 Canis lupus familiaris Species 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
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010020772 Hypertension Diseases 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
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000004872 arterial blood pressure Effects 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
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- 230000001631 hypertensive effect Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-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
- 208000024891 symptom Diseases 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
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N (e)-2-hydroxybut-2-enedioic acid Chemical compound OC(=O)\C=C(\O)C(O)=O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- QRECIVPUECYDDM-UHFFFAOYSA-N 2-chlorooxane Chemical compound ClC1CCCCO1 QRECIVPUECYDDM-UHFFFAOYSA-N 0.000 description 1
- PKRSYEPBQPFNRB-UHFFFAOYSA-N 2-phenoxybenzoic acid Chemical compound OC(=O)C1=CC=CC=C1OC1=CC=CC=C1 PKRSYEPBQPFNRB-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
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 description 1
- LLKFNPUXQZHIAE-UHFFFAOYSA-N 5-(3-aminopropyl)-8-bromo-3-methyl-2h-pyrazolo[4,3-c]quinolin-4-one Chemical compound O=C1N(CCCN)C2=CC=C(Br)C=C2C2=C1C(C)=NN2 LLKFNPUXQZHIAE-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 208000005156 Dehydration Diseases 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
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- 208000001431 Psychomotor Agitation Diseases 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 206010038743 Restlessness Diseases 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
- 206010044565 Tremor Diseases 0.000 description 1
- 102000004305 alpha Adrenergic Receptors Human genes 0.000 description 1
- 108090000861 alpha Adrenergic Receptors Proteins 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
- 229960004909 aminosalicylic acid Drugs 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004365 benzoic acid Drugs 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
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000007788 liquid 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
- 229960002510 mandelic acid Drugs 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012454 non-polar solvent 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
- 230000001734 parasympathetic effect Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000002243 precursor 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
- 230000001624 sedative effect Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members 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
- C07D307/22—Nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members 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
- C07D309/14—Nitrogen atoms not forming part of a nitro radical
-
- 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
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
Foreliggende oppfinnelse vedrører fremstilling av en serie substituerte 2-fenylamino-imidazoler-(2) med den generelle formel (I)
samt deres farmasøytisk akseptable salter.
I formel(I) betyr R gruppen
hvori n betyr 3 eller 4, R1 og R2 som kan være like eller forskjellige betyr hver hydrogen, fluor, klor eller brom eller en lavere alkylgruppe med 1-4 karbonatomer.
Forbindelsene som fremstilles utviser hypotensive, bradykardiserende og diuretisk aktivitet.
Forbindelsen med formel (I) kan erholdes ved å omsette 2-fenylimino-imidazolidin med formelen (II) eller dens natriumsalt med en forbindelse med formel (III)
hvori n har den ovenfor angitte betydning og X betyr et halogenatom (klor eller brom),
Forbindelsen (III) kan anvendes i ren tilstand eller fremstilles in situ i henhold til velkjente fremgangsmåter (Reel. Trav. Chim. Pays-Bas 98, 371-380, 1979).
Omsetningen utføres i polare eller ikke-polare oppløsnings-midler, ved en temperatur i området fra -50°C til romtemperatur .
Salter kan fremstilles fra forbindelsene med den generelle formel (I) med farmasøytisk akseptable uorganiske syrer eksempelvis saltsyre, hydrobromsyre, salpetersyre, svovel-syre eller fosforsyre, eller med organiske' karboksylsyrer så som eddiksyre, propionsyre, glykolsyre, malonsyre, rav-syre, maleinsyre, hydroksymaleinsyre, fumarsyre, eplesyre, vinsyre, sitronsyre, glukoronsyre, benzosyre, mandelsyre, salisylsyre, 4-aminosalisylsyre, 2-fenoksybenzosyre, palme-tinsyre, nikotinsyre, isonikotinsyre eller organiske sul-fonsyrer så som metansulfonsyre, etansulfonsyre, 2-hydroksy-etansulfonsyre, etan-1,2-disulfonsyre, paratoluensulfonsyre eller naftalen 2-sulfonsyre.
Forbindelsene med den generelle formel (I) og deres syreaddisjonssalter er stabile ved 37°C både i simulert mavesaft og i tarmsaft.
De nye forbindelser, samt deres syreaddisjonssalter utmer-ker seg med en bemerkelsesverdig hypotensiv, bradykardiserende og diuretisk aktivitet. Doser som kan administreres oralt ligger i området 0,3 - 100 mg.
De nye forbindelser utviser visse fordeler sammenlignet med deres respektive forløpere (forbindelser med den generelle formel (I) hvori R=H), særlig utviser 2-[N-2,6-diklorfenyl-N-(2-tetrahydropyranyl)amino]-imidazolin-(2) og 2-[N-(2,6-diklorfenyl)-N-(2-tetrahydrofuranyl)amino]-imidazolin-(2) flere fordelaktige trekk sammenlignet med 2-(2,6-diklor-anilino)- /\<2->imidazolin ("Clonidin").
Selv ved doser større enn de som er indikert i de etterføl-gende tabeller, vil de ikke forandre et dyrs oppførsel og ytterligere mangler de både stimulerende og inhiberende egenskaper for a-adrenergiske reseptorer og det parasympatiske system.
Forbindelsen nr. 1 utviser ved dyreforsøk en mere effektiv
og vedvarende hypotensiv aktivitet enn "Clonidin" og ytterligere en mere fordelaktig oppførsel i de forsøk som viser
mulige sideeffekter.
Av tabell I fremgår det at "Clonidin" ved oral administrasjon til en rotte forårsaker en initial trykkstigning og således en periferisk a-adrenergisk aktivitet, som er en egenskap som er ansett for uønsket innen den kliniske lite-ratur (HUNYOR S.N. et al. Brit .Med. ,_4 , 23 (1975) WING L.M.H.
et al.Brit.Med.,1 136(1977)), i motsetning til dette er denne hypertensive fase fraværende etter en tilsvarende dosering av forbindelsen nr. 1.
Ytterligere vil administrasjon av 5 uM/kg "Clonidin" til
en våken hund indusere, etter en initial arterietrykksenk-ning som varer 90 min. oppsto det en bemerkelsesverdig stig-ning i arterietrykket med symptomer på urolighet og skjel-ving, symptomer som kan sammenlignes med "rebound" hyper-tensivkriser som kan oppserveres hos mennesker (LESLEY
MATIER W. og COMER W.T., Annual Reports in Medicinal Chemistry, 13 (1978) Chapter 8 - Antihypertensive agents, sidene 71
og 72), den samme dose av forbindelsen nr. 1 utviser derimot kun vedvarende hypotensiv aktivitet.
Sluttligen er forbindelsen nr. 1 henholdsvis 40 og 800 ganger mindre aktiv enn "Clonidin" med hensyn til å nedsette spon-tan motilitet hos rotter og i mus (tabell IV) og utviste således en helt ubetydelig sedativ aktivitet, en aktivitet som er uønsket (LESLEY MATIER W. og COMER W.T. 1978).
Forbindelsene i henhold til oppfinnelsen kan administreres oralt ved injeksjon eller rektalt under anvendelse av egnede farmasøytiske blandinger i fast, flytende eller suspendert form (tabletter, kapsler, ampuller, siruper, suppositorer etc.)
De etterfølgende, ikke-begrensede tabeller angir summarisk
de farmakologiske egenskaper for forbindelse nr. 1, som er 2-[N-(2,6-diklorfenyl)-N-(2-tetrahydropyranyl)amino]-imida-zolin- (2), og forbindelse nr. 2 som er 2-[N-(2,6-diklor-fenyl)-N-(tetrahydrofuranyl)amino]-imidazolin-(2).
De hypo.tensive og bradikardiserende aktiviteter ble under-søkt for våkne rotter og hunder ved hjelp av kontinuerlig injisering i henholdsvis karotid og safena arterien og med kontinuerlig registrering ved hjelp av trandusere.
Den diuretiske aktivitet er undersøkt for våkne rotter under vannbelastning (oralt administrert fysiologisk oppløsning 2 5 ml/kg).
De følgende eksempler illustrerer oppfinnelsen.
Smeltepunktene er ikke korrekte. Forbindelsenes identitet og renhet ble bestemt ved hjelp av elementæranalyse for C,H,N og Cl, samt infrarødt, N.M.R. og U.V.-spektra.
EKSEMPEL 1
2-[N-(2,6-diklorfenyl)-N-(2-tetrahydropyranyl)amino]-imida-zolin-( 2)
Til en oppløsning av 2,46 g (10,2 mmol) 2-(2,6-diklorfenyl-imino)-imidazolidin i 60 ml vannfritt metylenklorid ble lang-somt under omrøring ved romtemperatur tilsatt 0,28 g (12,24 mmol) NaH. Etter tilsetning ble oppløsningen ytterligere omrørt i 60 min. og deretter avkjølt til -40°C og en opp-løsning av 1,6 g (13,2 6 mmol) 2-klor-tetrahydropyran i 2 ml vannfritt metylenklorid tilsatt dråpevis. Etter tilsetning ble kjølebadet fjernet og temperaturen fikk stige til romtemperatur. Etter filtrering ble oppløsningen vasket med fortynnet NH^OH, og deretter tørket over Na2S04 og inndam-pet til tørrhet under nedsatt trykk.
Smp. = 122 - 123°C (fra heksan).
På samme måte ble fremstilt: 2-[N-(2,6-diklorfenyl)-N-(2-tetrahydrofuranyl)amino]-imida-zolin- (2), smp. = 71 - 72°C (fra diisopropyleter).
2-[N-(2-klor-4-metylfenyl)-N-(2-tetrahydropyranyl)amino]-imidazolin-(2), smp. = 135 - 137°C (fra heksan).
2-[N-(2-metyl-5-fluorfenyl)-N-(2-tetrahydropyranyl)amino]-imidazolin-(2), smp. = 125 - 127°C (fra heksan).
2-[N-(2,6-dietylfenyl)-N-(2-tetrahydropyranyl)amino]-imida-zolin- (2), smp. = 135 - 140°C (fra heksan).
Claims (1)
1. Analogifremgangsmåte ved fremstilling av en terapeutisk virksom forbindelse med den generelle formel (I)
samt farmasøytisk akseptable salter derav hvor R har betydningen
hvori n er 3 eller 4 og R^^ og R2 som er like eller forskjellige er hver hydrogen, fluor, klor eller brom eller en alkylgruppe med 1-4 karbonatomer, karakterisert ved at et 2-fenyliminoimidazolin med formelen (II)
eller natriumsalt derav omsettes med en forbindelse med formelen (III)
hvori ri har den ovenfor angitte betydning og X betyr et halogenatom, såsom klor eller brom, ved en temperatur i området -50°C til romtemperatur i et polart eller ikke-polart organisk oppløsningsmiddel, og, om ønsket, fremstilles saltene på kjent måte.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT30738/78A IT1101727B (it) | 1978-12-12 | 1978-12-12 | Nuove 2-fenilammino-imidazoline-(2) sostituite, dotate di particolari proprieta' terapeutiche, loro processo di sintesi e composizioni farmaceutiche |
| IT27202/79A IT1127215B (it) | 1979-11-12 | 1979-11-12 | Nuove 2-fenilammino-imidazoline-(2)sostitutite,dotate di particolari proprieta' terapeutiche,loro processo di sintesi e composizioni farmaceutiche |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO794047L NO794047L (no) | 1980-06-13 |
| NO152171B true NO152171B (no) | 1985-05-06 |
| NO152171C NO152171C (no) | 1985-08-14 |
Family
ID=26328719
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO794047A NO152171C (no) | 1978-12-12 | 1979-12-11 | Analogifremgangsmaate ved fremstilling av terapeutisk virksomme imidazolinderivater |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US4262006A (no) |
| CA (1) | CA1137090A (no) |
| CH (1) | CH645358A5 (no) |
| DE (1) | DE2949971C2 (no) |
| DK (1) | DK159317C (no) |
| ES (1) | ES8102565A1 (no) |
| FI (1) | FI65428C (no) |
| FR (1) | FR2444036A1 (no) |
| GB (1) | GB2041355B (no) |
| NL (1) | NL183139C (no) |
| NO (1) | NO152171C (no) |
| PT (1) | PT70584A (no) |
| SE (1) | SE430503B (no) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4398028A (en) * | 1977-01-14 | 1983-08-09 | Sandoz Ltd. | Bicyclic heterocyclic amino derivatives |
| KR101881115B1 (ko) * | 2015-06-25 | 2018-08-20 | 가천대학교 산학협력단 | 신규 2-치환된 테트라하이드로피란 또는 2-치환된 테트라하이드로퓨란 유도체 화합물, 이의 제조방법 및 이의 용도 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DD95843A5 (no) * | 1971-01-21 | 1973-02-20 | ||
| US3850926A (en) * | 1971-01-21 | 1974-11-26 | Boehringer Sohn Ingelheim | 2-(n-substituted-phenylamino)-imidazolines-(2) |
-
1979
- 1979-11-28 FI FI793727A patent/FI65428C/fi not_active IP Right Cessation
- 1979-11-29 CH CH1061279A patent/CH645358A5/it not_active IP Right Cessation
- 1979-11-29 CA CA000340891A patent/CA1137090A/en not_active Expired
- 1979-12-03 DK DK512479A patent/DK159317C/da not_active IP Right Cessation
- 1979-12-04 GB GB7941802A patent/GB2041355B/en not_active Expired
- 1979-12-06 US US06/100,833 patent/US4262006A/en not_active Expired - Lifetime
- 1979-12-07 NL NLAANVRAGE7908853,A patent/NL183139C/xx not_active IP Right Cessation
- 1979-12-10 SE SE7910157A patent/SE430503B/sv not_active IP Right Cessation
- 1979-12-11 NO NO794047A patent/NO152171C/no unknown
- 1979-12-11 ES ES487167A patent/ES8102565A1/es not_active Expired
- 1979-12-11 FR FR7930361A patent/FR2444036A1/fr active Granted
- 1979-12-12 DE DE2949971A patent/DE2949971C2/de not_active Expired
- 1979-12-12 PT PT70584A patent/PT70584A/pt unknown
Also Published As
| Publication number | Publication date |
|---|---|
| US4262006A (en) | 1981-04-14 |
| FR2444036A1 (fr) | 1980-07-11 |
| ES487167A0 (es) | 1980-12-16 |
| NL183139B (nl) | 1988-03-01 |
| CH645358A5 (it) | 1984-09-28 |
| SE430503B (sv) | 1983-11-21 |
| FR2444036B1 (no) | 1985-03-15 |
| GB2041355A (en) | 1980-09-10 |
| NO152171C (no) | 1985-08-14 |
| DK159317B (da) | 1990-10-01 |
| DE2949971C2 (de) | 1983-11-24 |
| NL183139C (nl) | 1988-08-01 |
| CA1137090A (en) | 1982-12-07 |
| ES8102565A1 (es) | 1980-12-16 |
| FI793727A7 (fi) | 1980-06-13 |
| DK159317C (da) | 1991-02-25 |
| SE7910157L (sv) | 1980-06-13 |
| DK512479A (da) | 1980-06-13 |
| DE2949971A1 (de) | 1980-07-03 |
| FI65428C (fi) | 1984-05-10 |
| NO794047L (no) | 1980-06-13 |
| PT70584A (en) | 1980-01-01 |
| FI65428B (fi) | 1984-01-31 |
| NL7908853A (nl) | 1980-06-16 |
| GB2041355B (en) | 1983-02-16 |
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