DK146939B - Analogifremgangsmaade til fremstilling af substituerede 2-phenylamino-imidazolin-(2)-er eller syreadditionssalte deraf - Google Patents
Analogifremgangsmaade til fremstilling af substituerede 2-phenylamino-imidazolin-(2)-er eller syreadditionssalte deraf Download PDFInfo
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- DK146939B DK146939B DK302679AA DK302679A DK146939B DK 146939 B DK146939 B DK 146939B DK 302679A A DK302679A A DK 302679AA DK 302679 A DK302679 A DK 302679A DK 146939 B DK146939 B DK 146939B
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- Prior art keywords
- acid
- imidazoline
- phenylamino
- addition salts
- acid addition
- Prior art date
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- 150000003839 salts Chemical class 0.000 title claims abstract description 11
- 239000002253 acid Substances 0.000 title claims abstract description 10
- JCOPITWIWLFFPC-UHFFFAOYSA-N n-phenyl-4,5-dihydro-1h-imidazol-2-amine Chemical class N1CCN=C1NC1=CC=CC=C1 JCOPITWIWLFFPC-UHFFFAOYSA-N 0.000 title claims description 11
- 238000000034 method Methods 0.000 title claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 5
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 claims abstract description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims abstract description 3
- 239000001257 hydrogen Substances 0.000 claims abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 3
- 239000000460 chlorine Substances 0.000 claims description 22
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 150000004820 halides Chemical class 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 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
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- DZFYBHIZICGHFY-UHFFFAOYSA-N 2-phenyl-4H-imidazol-5-amine Chemical compound C1(=CC=CC=C1)C=1NCC(N=1)=N DZFYBHIZICGHFY-UHFFFAOYSA-N 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 15
- 230000000059 bradycardiac effect Effects 0.000 abstract description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 abstract 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 abstract 1
- 231100000252 nontoxic Toxicity 0.000 abstract 1
- 230000003000 nontoxic effect Effects 0.000 abstract 1
- 150000003254 radicals Chemical group 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-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
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000012259 ether extract Substances 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- SSOLNOMRVKKSON-UHFFFAOYSA-N proguanil Chemical compound CC(C)\N=C(/N)N=C(N)NC1=CC=C(Cl)C=C1 SSOLNOMRVKKSON-UHFFFAOYSA-N 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-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
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 230000000202 analgesic effect Effects 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
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 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
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 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
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- -1 2,6-dichlorophenyl Chemical group 0.000 description 1
- MELXJRCHYMECIY-UHFFFAOYSA-N 2-hydroxybenzoic acid;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound OC(=O)C1=CC=CC=C1O.OC(=O)CC(O)(C(O)=O)CC(O)=O MELXJRCHYMECIY-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
- 241000282461 Canis lupus Species 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
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 238000005684 Liebig rearrangement reaction Methods 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 241000699670 Mus sp. Species 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
- 208000002193 Pain 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
- 150000007513 acids Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229960004050 aminobenzoic acid Drugs 0.000 description 1
- 239000011230 binding agent Substances 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
- 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
- 229960002896 clonidine Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229910000043 hydrogen iodide Inorganic materials 0.000 description 1
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 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
- 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
- 206010027599 migraine Diseases 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- LLDKCOYIVPKCTE-UHFFFAOYSA-N n-(2,6-dichlorophenyl)-n-(3-methylbut-3-enyl)-4,5-dihydro-1h-imidazol-2-amine Chemical compound ClC=1C=CC=C(Cl)C=1N(CCC(=C)C)C1=NCCN1 LLDKCOYIVPKCTE-UHFFFAOYSA-N 0.000 description 1
- WQOPCVWJVVQTFI-UHFFFAOYSA-N n-(cyclopropylmethoxy)-n-(2,6-dichlorophenyl)-4,5-dihydro-1h-imidazol-2-amine;hydrobromide Chemical compound Br.ClC1=CC=CC(Cl)=C1N(C=1NCCN=1)OCC1CC1 WQOPCVWJVVQTFI-UHFFFAOYSA-N 0.000 description 1
- 230000003533 narcotic effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 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
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 150000003138 primary alcohols Chemical class 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 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
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000002904 solvent 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
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229940005605 valeric acid 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
- C07D233/50—Nitrogen atoms not forming part of a nitro radical with carbocyclic radicals directly attached to said nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Cardiology (AREA)
- Vascular Medicine (AREA)
- Heart & Thoracic Surgery (AREA)
- Life Sciences & Earth Sciences (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)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
i 146939
Opfindelsen angår en analogifremgangsmåde til fremstilling af hidtil ukendte substituerede 2-phenyl-amino-imidazolin-(2)-er med den almene formel I (se krav 1), eller syreadditionssalte deraf med værdi-5 fulde terapeutiske egenskaber, hvilken fremgangsmåde er ejendommelig ved det i krav l's kendetegnende del angivne.
1 2 I formel I angiver R og R , der kan være ens eller forskellige, et hydrogenatom, et chloratom eller'en 1 2 10 methylgruppe, herved kan R og R ikke samtidigt være hydrogen.
R angiver gruppen -(CH2)2-C(CH3)=CH2, -(CH2)2-CH= ch2, -o-ch2-ch=ch2, -o-(ch2)2-ch=ch2, -o-ch2-c{ch3)= 15 CH2, -0-CH2-CH= CH-CH3, -0-CH2-<^j, -CH^CgHg, -CH2“CH= CH-C6H5, -ca2-(o) , -CH2-(^, -ch2-/o) eller °H 3 ^
Fremstillingen af forbindelserne med formlen I sker ved; a) Omsætning af en 2-phenylimino-imidazolidin med 1 2 den almene formel II (se krav 1), hvori R og R har den ovennævnte betydning,med et halogenid med den alme-25 ne formel III (se krav 1), hvori Hal er §t chlor-, bromeller jodatom, og R har den ovennævnte betydning, eller b) Med henblik på fremstilling af 2-[N-(subst.- phenyl)-N-(subst.-methoxy)amino]-imidazolin-(2)-er med 1 2 den almene formel V (se krav 1), hvori R og R har den 30 ovennævnte betydning, og R' har delformlen -CH2-CH=CH2, -ch2-c(ch3)=ch2, -(ch2)2-ch=ch2, -ch2-ch=ch-ch3 eller -CH2-<^J , omsættes en 2-[N-(subst. phenyl)-N-hydroxy- amino]-imidazolin-(2) med den almene formel VI (se 35 12 krav l), hvori R og R er defineret som ovenfor,med et halogenid med den almene formel VII (se krav 1), hvori Hal og R' har de ovennævnte betydninger.
2 146939
Ved alkyleringen af 2-arylimino-imidazolidiner med formlen II ifølge fremgangsmåde, å) sker substitutionen udelukkende ved brodannende nitrogenatomer.
Ved omsætningen ifølge fremgangsmåde b).er slut-.
5 forbindelsernes konstitution fastlagt ved syntesen. Substituenternes stilling kan udover ved syntesen også bestemmes ved NMR-spektroskopi. (Sammenlign H. Stahle og K.-H. Pook/ Liebigs Ann. Chem. 751/ 159 ff (1971)).
Omsætningen ifølge fremgangsmåde a) og b) sker 10 hensigtsmæssigt ved opvarmning af reaktanterne - fortrinsvis i nærværelse af et polært eller upolært organisk opløsningsmiddel - ved temperaturer på ca. 50-150°C.
Særlige reaktionsbetingelser er i høj grad afhængig af reaktanternes reaktivitet. Det anbefales ved alkylerin-15 gen at anvende halogenidet i overskud og gennemføre omsætningen i nærværelse af et syrebindende middel.
Udgangsmaterialer med formlen II er beskrevet i f. eks. de belgiske patenter nr. 623.305, 687.657 og 705.944.
20 Udgangsmaterialer med formlen III og vil frem stilles ved halogenering af de til grund liggende primære alkoholer.
Udgangsmaterialer med formlen VI opnås ved oxidation af forbindelser med den almene formel II med per-25 syrer ifølge tysk offentliggørelsesskrift 24 57 979.
De omhandlede 2-phenylamino-imidazolin-(2)-er med den almene formel I kan på kendt vis omdannes til deres fysiologisk forenelige syreadditionssalte. Syrer, der er egnede til saltdannelsen er f.eks. saltsyre, 30 hydrogenbromidsyre, hydrogeniodidsyre, flussyre, svovlsyre, phosphorsyre, salpetersyre, eddikesyre, propion-syre, smørsyre, capronsyre, valeriansyre, oxalsyre, ma-lonsyre, ravsyre, maleinsyre, fumarsyre, mælkesyre, vinsyre, citronsyre, æblesyre, benzoesyre, p-hydroxybenzoe-35 syre, p-aminobenzoesyre, Phthalsyre, kanelsyre, salicylsyre, aseorbinsyre, methansulfonsyre og 8-chlortheophyl-lin 3 146939
De hidtil ukendte forbindelser samt disses svread-ditionssalte har værdifulde analgetiske egenskaber og kan derfor finde anvendelse ved de forskellige udtryksformer for smertetilstande, såsom f.eks. migræne. De 5 omhandlede forbindelsers analgetiske virkning blev afprøvet på mus, efter "Writhing"-prøven (Blumberg,
Wolf og Dayton, Proc. Soc. Exp. Biol. Med. 118 (1965) 763) og "Hot-Plate"-prøven (Woolfe og MacDonald, J.
Pharmacol. Exp. Ther. 80 (1944) 300), hvorved det viste 10 sig, at de hidtil ukendte 2-phenylamino-imidazoliner har en indtil 100-gange kraftigere virkning end morfin.
I sammenligning med de i tysk offentliggørelsesskrift 1 958 201 beskrevne N-allyl-2-phenylamino-imidazolin-(2) -er fandtes ligeledes en virkningsforøgelse på ca. 100 15 gange ved de hidtil ukendte forbindelser.
De hidtil ukendte forbindelser med den almene formel I, især sådanne der indeholder en cyclopropyl-methyl- eller cyclobutylmethylgruppe samt disses syreadditionssalte, har derudover en meget kraftig brady-20 card virkning og er derfor egnede til behandling af koronarlidelser. Indvirkningen på hjertefrekvensen undersøgtes på kaniner og spinalrotter samt på intakte narkotiserede rotter.
Farmakologisk sammenligningsforsøg.
25 For de nedenfor anførte forbindelser fandtes den dosis, der på spinalrotter (5 dyr pr. forbindelse) ved kumulativ intravenøs indgift sænker hjertefrekvensen med 150 slag/minut (D 150).
30 R1 · —Cf—i <p
*5 R H
4 146939
Forbindelser R1 R2 R3 R D 150 mg/kg 5 A. Forbindelser fremstillet ved fremgangsmåden ifølge opfindelsen.
ci h ci -(ch2)2-ch=ch2 1,4 ci h ci -o-ch2-ch=ch2 1,1
Cl H ' Cl -(CH2)2-C(CH3)=CH2 0,28 10 Cl H CH3 -(CH2)2-C(CH3)=CH2 0,95 ci h ci -o-ch2-c(ch3)=ch2 1,1
Cl H Cl -0-CH2-CH=CH-CH3 0,65 B, Kendte forbindelser 15 Cl H Cl -CH2-CH=CH 2,5 ci η ci -ch2-ch=ch-ch3 1,7
Cl . H Cl -CH2-CH=C(CH3)2 8,1
Cl H Cl -CH2-C(CH3)=CH2 7,0
Cl H CH3 -CH2-C(CH3)=CH2 4,3 20 De følgende eksempler belyser fremgangsmåden ifølge opfindelsen.
Eksempel 1 2-[N- (2,6-dichlorphenyl)-N- (cyclopropylmethyloxy)-ami-25 no]-2-imidazolin-hydrobromid
N
30 (O/—“-(j XB“ ^C1 ° CH- Δ 35 6,0 g (0,021 Mol) 2-[N(2,6-dichlorphenyl)-N-hydroxyami-no]-2-imidazolin-hydrochlorid sættes til en opløsning af 0,93 g natrium i 95 ml absolut ethanol. Derpå dryppes under god omrøring 2,2 g (117%) chlormethylcyclo- 146939 5 propan til opløsningen og opvarmes i yderligere 30 minutter under tilbacesvaling. Det udskilte kogesalt suges af og remanensen inddampes i vakuum til tørhed. Den 1 resten tilbageblivende brunfarvede olie opløses koldt 5 i fortyndet svovlsyre (1 N) ,og opløsningen behandles flere gange med ether (etherekstrakterne bortkastes). Efter behandling med aktivt kul alkaliseres den saltsure opløsning med 2N natriumhydroxid,og det udskilte hvide stof suges af. Der er her tale om den tyndlagskromato-10 grafisk rene hidtil ukendte imidazolinbase. Denne opløses i en smule methanol og omdannes ved tilsætning af koncentreret hydrogenbromidsyre til dens hydrobro-mid. Dette udskilles ved tilsætning af ether i krystallinsk fonn. Efter afsugning og tørring opnås et udbyt-15 fe på 1,1 g svarende til 14,6% af det teoretiske. Smeltepunkt: 215-216°C.
Eksempel 2 2-[N-(2,6-dichlorphenyl)-N-(2-methyl-l-buten-4-yl)-ami-20 no]-2-imidazolin N CH, a 25 Λ
Kril £ i-CH3
II
ch2 6,9 g (0,03 mol) clonidin opvarmes sammen med 5,6 g 30 4-brom-2-methyl-buten-(1) og 5 ml triethylamin i 25 ml toluen i 24 timer i et rør. Efter afkøling afdekanteres opløsningsmidlet, og den tilbageblivende rest opløses i 1 N saltsyre. Efter gentagen behandling med ether (etherékstrakteme bortkastes) ekstraheres der frak- 35 tionerende ved stigende pH-værdier (alkaliseret med 2 N natriumhydroxidopløsning). De tyndtlagskromatogra- ‘ fisk ensartede etherekstrakter samles, tørres over MgS04 og -etheren fjernes i vakuum. Udbytte 1,8 g (19,6% af det teoretiske). Smeltepunkt: 117-119°C.
6 146939
De følgende forbindelser fremstilles analogt med de foregående eksempler. Smeltepunkterne henviser til baserne med formelen I. Såfremt andet er tilfældet er saltformen angivet.
5 Udbytte af det
Eks. , 0 Smp. teore- nr. R1 R R_[°C] tiske [%3 (3) H Cl -(CH2)2-CH«CH2 133-135 39,6 (4) h Cl -0-CH2-CH»CH2 153-154 61,6 (5) H Cl -0-CH2-C(CH3)=CH2 112-113 18,4 (6) H Cl -0-(CH2)2-CH»CH2 108-109 39,6 (7) H Cl -0-CH2-CH«CH-CH3 135-138 47,6 (8) H CHj -(CH2)2-C(CH3)»CH2 109-111 19,3 (9) H Cl 261 90,4 '—^0H (Hydrobromid) (10) H Cl -®i<0^0CH 118/5-119,5 63,6 P 3 dl) CH, Cl 225-227 32,6 * p^—\ p (Hydrochlorid)
F F
(12) H Cl -CH2\0/“F 228-231 43,3 p / \ p (Hydrochlorid)
F F
(13) Cl H -CM0)—F 181-184 27,4 S—\ F (Hydrochlorid) (14) h 99-101 45,3 146933 7
J
Udbytte af det
Eks. , „ Smp. teore- nr. R R R_[°C] tiske 5 (15) H Cl -CH2-CH*CH-C6H5 114-116 56,8 α6) H Cl -CH2-C6H5 103-105 12,8 (17) H CH3 -CH2-.CH*CH-C6H5 109-111 17,4
Claims (4)
146939 PATENTKUV
1. Analogifremgangsmåde til fremstilling af substituerede 2-phenylamino-imidazolin-(2)-er med den almene formel I /1 5 -_/ N_ V R H 1 2 hvori R og R , der kan være ens eller forskellige, er 10 et hydrogenatom, et chloratom eller en methylgruppe, 1 2 hvorved R og R ikke samtidigt kan være hydrogen, og R er gruppen -(CH2)2“C(CH3)=CH2, "(CH2)2“CH=CH2, -0-CH2-CH=CH2, -o-(CH2)2-CH=CH2, -0-CH2-C(CH3)=CH2, 15 -0-CH2-CH=CH-CH3, -0-CH2-<^j, -CH^CgHj, -CH2-CH=CH-C6H5, -2-^0} ' ~CH2~^0 ^ ' ~CH2~^ 0 ^ eller ΌΗ ^0£:Η3 pX
20. F -°Η2-{όΎ—Γ F ^F 25 eller syreadditionssalte deraf, kendetegnet ved, at man a) omsætter en 2-phenyl-iminoimidazolin med den almene formel XX
30 P1 H KqV'-O V 1 2 35 hvori R og R har den ovennævnte betydning med et halogenid med den almene formel III Hal-R III hvori Hal er et chlor-, brom- eller jodatom, og R har den ovennævnte betydning eller
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19782831671 DE2831671A1 (de) | 1978-07-19 | 1978-07-19 | Neue substituierte 2-phenylamino-imidazoline-(2), deren saeureadditionssalze, diese enthaltende arzneimittel und verfahren zur herstellung derselben |
| DE2831671 | 1978-07-19 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK302679A DK302679A (da) | 1980-01-20 |
| DK146939B true DK146939B (da) | 1984-02-20 |
| DK146939C DK146939C (da) | 1984-07-30 |
Family
ID=6044762
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK302679A DK146939C (da) | 1978-07-19 | 1979-07-18 | Analogifremgangsmaade til fremstilling af substituerede 2-phenylamino-imidazolin-(2)-er eller syreadditionssalte deraf |
Country Status (17)
| Country | Link |
|---|---|
| US (1) | US4277487A (da) |
| EP (1) | EP0007438B1 (da) |
| JP (1) | JPS5515466A (da) |
| AT (1) | ATE1503T1 (da) |
| AU (1) | AU524192B2 (da) |
| CA (1) | CA1121824A (da) |
| DE (2) | DE2831671A1 (da) |
| DK (1) | DK146939C (da) |
| ES (1) | ES482581A1 (da) |
| FI (1) | FI69067C (da) |
| GR (1) | GR69931B (da) |
| IE (1) | IE48452B1 (da) |
| IL (1) | IL57834A (da) |
| NO (1) | NO150435C (da) |
| NZ (1) | NZ191052A (da) |
| PT (1) | PT69934A (da) |
| ZA (1) | ZA793636B (da) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| DE2950345A1 (de) * | 1979-12-14 | 1981-07-02 | C.H. Boehringer Sohn, 6507 Ingelheim | Neue substituierte 2-phenylaminoimidazoline-(2), deren saeureadditionssalze, diese enthaltende arzneimittel und verfahren zur herstellung derselben |
| FR2499991A1 (fr) * | 1981-02-19 | 1982-08-20 | Sandoz Sa | Nouveaux 2,1,3-benzothiadiazoles et 2,1,3-benzoxadiazoles, leur preparation et leur application comme medicaments |
| US4393077A (en) * | 1981-07-02 | 1983-07-12 | William H. Rorer, Inc. | 1-Methylene-1-phenylguanidine compounds |
| IT1211138B (it) * | 1981-12-01 | 1989-09-29 | Ausonia Farma Srl | Composto antiipertensivo procedimento per la sua preparazione e relative composizioni farmaceutiche. |
| DE3514351A1 (de) * | 1985-04-20 | 1986-11-06 | Boehringer Ingelheim KG, 6507 Ingelheim | Neue substituierte 2-(n-alkinyl-n-phenyl)amino)-imidazolinderivate, deren saeureadditionssalze, diese enthaltende arzneimittel und verfahren zu deren herstellung |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE759125A (fr) * | 1969-11-19 | 1971-05-18 | Boehringer Sohn Ingelheim | Nouvelles n-allyl-2-arylamino-imidazolines-(2) substituees et procedes pour les fabriquer |
| DE2102733A1 (en) * | 1971-01-21 | 1972-08-03 | CH. Boehringer Sohn, 6507 Ingelheim | 2-arylamino-2-imidazolines |
| US3850926A (en) * | 1971-01-21 | 1974-11-26 | Boehringer Sohn Ingelheim | 2-(n-substituted-phenylamino)-imidazolines-(2) |
| DD95843A5 (da) * | 1971-01-21 | 1973-02-20 |
-
1978
- 1978-07-19 DE DE19782831671 patent/DE2831671A1/de not_active Withdrawn
-
1979
- 1979-06-21 DE DE7979102052T patent/DE2963605D1/de not_active Expired
- 1979-06-21 EP EP79102052A patent/EP0007438B1/de not_active Expired
- 1979-06-21 AT AT79102052T patent/ATE1503T1/de not_active IP Right Cessation
- 1979-07-09 JP JP8600679A patent/JPS5515466A/ja active Pending
- 1979-07-13 GR GR59597A patent/GR69931B/el unknown
- 1979-07-17 US US06/058,165 patent/US4277487A/en not_active Expired - Lifetime
- 1979-07-18 DK DK302679A patent/DK146939C/da not_active IP Right Cessation
- 1979-07-18 NO NO792389A patent/NO150435C/no unknown
- 1979-07-18 IL IL57834A patent/IL57834A/xx unknown
- 1979-07-18 ZA ZA00793636A patent/ZA793636B/xx unknown
- 1979-07-18 FI FI792251A patent/FI69067C/fi not_active IP Right Cessation
- 1979-07-18 PT PT69934A patent/PT69934A/pt unknown
- 1979-07-18 CA CA000332040A patent/CA1121824A/en not_active Expired
- 1979-07-18 NZ NZ191052A patent/NZ191052A/xx unknown
- 1979-07-18 ES ES482581A patent/ES482581A1/es not_active Expired
- 1979-07-18 AU AU49022/79A patent/AU524192B2/en not_active Ceased
- 1979-08-08 IE IE1356/79A patent/IE48452B1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5515466A (en) | 1980-02-02 |
| ES482581A1 (es) | 1980-04-01 |
| IE791356L (en) | 1980-01-19 |
| NO150435C (no) | 1984-10-17 |
| PT69934A (de) | 1979-08-01 |
| IL57834A0 (en) | 1979-11-30 |
| AU524192B2 (en) | 1982-09-02 |
| DK146939C (da) | 1984-07-30 |
| GR69931B (da) | 1982-07-21 |
| US4277487A (en) | 1981-07-07 |
| EP0007438A1 (de) | 1980-02-06 |
| NO792389L (no) | 1980-01-22 |
| DE2831671A1 (de) | 1980-02-07 |
| AU4902279A (en) | 1980-01-24 |
| CA1121824A (en) | 1982-04-13 |
| FI69067B (fi) | 1985-08-30 |
| IL57834A (en) | 1983-03-31 |
| FI792251A7 (fi) | 1980-01-20 |
| DK302679A (da) | 1980-01-20 |
| FI69067C (fi) | 1985-12-10 |
| NZ191052A (en) | 1981-02-11 |
| DE2963605D1 (en) | 1982-10-28 |
| NO150435B (no) | 1984-07-09 |
| ZA793636B (en) | 1981-03-25 |
| ATE1503T1 (de) | 1982-09-15 |
| EP0007438B1 (de) | 1982-09-01 |
| IE48452B1 (en) | 1985-01-23 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PBP | Patent lapsed |