NO150118B - Analogifremgangsmaate for fremstilling av et terapeutisk aktivt imidazolidin-derivat. - Google Patents
Analogifremgangsmaate for fremstilling av et terapeutisk aktivt imidazolidin-derivat. Download PDFInfo
- Publication number
- NO150118B NO150118B NO811156A NO811156A NO150118B NO 150118 B NO150118 B NO 150118B NO 811156 A NO811156 A NO 811156A NO 811156 A NO811156 A NO 811156A NO 150118 B NO150118 B NO 150118B
- Authority
- NO
- Norway
- Prior art keywords
- acid
- formula
- imidazolidine
- chloro
- compound
- Prior art date
Links
- 230000001225 therapeutic effect Effects 0.000 title description 2
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 title 1
- 239000002253 acid Substances 0.000 claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 14
- 150000003839 salts Chemical class 0.000 claims abstract description 10
- NJGRRCIKURPQPP-UHFFFAOYSA-N n-(2-chloro-4-cyclopropylphenyl)-4,5-dihydro-1h-imidazol-2-amine Chemical compound ClC1=CC(C2CC2)=CC=C1NC1=NCCN1 NJGRRCIKURPQPP-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000002360 preparation method Methods 0.000 claims abstract description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 5
- 125000002252 acyl group Chemical group 0.000 claims description 5
- 125000004414 alkyl thio group Chemical group 0.000 claims description 5
- -1 aliphatic alcohols Chemical class 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 150000007513 acids Chemical class 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 125000001931 aliphatic group Chemical group 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 2
- 239000007795 chemical reaction product Substances 0.000 claims 1
- 229910052500 inorganic mineral Chemical class 0.000 claims 1
- 239000011707 mineral Chemical class 0.000 claims 1
- 230000000059 bradycardiac effect Effects 0.000 abstract description 2
- 238000006243 chemical reaction Methods 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical class NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 5
- AXRUBPOKONMDEQ-UHFFFAOYSA-N 2-chloro-4-cyclopropylaniline Chemical compound C1=C(Cl)C(N)=CC=C1C1CC1 AXRUBPOKONMDEQ-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical class NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 4
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 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
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 235000013877 carbamide Nutrition 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- RLAROPIDCNCRNR-UHFFFAOYSA-N Cl.Cl.[C-]#N Chemical compound Cl.Cl.[C-]#N RLAROPIDCNCRNR-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
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- JCOPITWIWLFFPC-UHFFFAOYSA-N n-phenyl-4,5-dihydro-1h-imidazol-2-amine Chemical class N1CCN=C1NC1=CC=CC=C1 JCOPITWIWLFFPC-UHFFFAOYSA-N 0.000 description 2
- 239000012454 non-polar solvent Substances 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-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
- 239000003880 polar aprotic solvent Substances 0.000 description 2
- 239000003586 protic polar solvent Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 150000003585 thioureas Chemical class 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 150000003672 ureas Chemical class 0.000 description 2
- TURSKPMQGOBOIZ-UHFFFAOYSA-N (2-chloro-4-cyclopropylphenyl)cyanamide Chemical compound C1=C(NC#N)C(Cl)=CC(C2CC2)=C1 TURSKPMQGOBOIZ-UHFFFAOYSA-N 0.000 description 1
- MGMZLTVZPMJFRL-UHFFFAOYSA-N (2-chloro-4-cyclopropylphenyl)thiourea Chemical compound C1=C(Cl)C(NC(=S)N)=CC=C1C1CC1 MGMZLTVZPMJFRL-UHFFFAOYSA-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
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- RTAGQMIEWAAKMO-UHFFFAOYSA-N 1-(2-cyclopropylphenoxy)-3-(propan-2-ylamino)propan-2-ol Chemical compound CC(C)NCC(O)COC1=CC=CC=C1C1CC1 RTAGQMIEWAAKMO-UHFFFAOYSA-N 0.000 description 1
- NYHHYPOSSHHUSO-UHFFFAOYSA-N 2-(2-chloro-4-cyclopropylphenyl)guanidine Chemical compound C1=C(Cl)C(NC(=N)N)=CC=C1C1CC1 NYHHYPOSSHHUSO-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
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 229940090248 4-hydroxybenzoic acid Drugs 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
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Natural products OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- 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
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 235000013832 Valeriana officinalis Nutrition 0.000 description 1
- 244000126014 Valeriana officinalis Species 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229960004050 aminobenzoic acid Drugs 0.000 description 1
- SOIFLUNRINLCBN-UHFFFAOYSA-N ammonium thiocyanate Chemical compound [NH4+].[S-]C#N SOIFLUNRINLCBN-UHFFFAOYSA-N 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 150000001913 cyanates Chemical class 0.000 description 1
- BNJBUDJCJPWKRQ-UHFFFAOYSA-H dipotassium;hexaiodoplatinum(2-) Chemical compound [K+].[K+].[I-].[I-].[I-].[I-].[I-].[I-].[Pt+4] BNJBUDJCJPWKRQ-UHFFFAOYSA-H 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- DYDNPESBYVVLBO-UHFFFAOYSA-N formanilide Chemical compound O=CNC1=CC=CC=C1 DYDNPESBYVVLBO-UHFFFAOYSA-N 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- TYQCGQRIZGCHNB-JLAZNSOCSA-N l-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(O)=C(O)C1=O TYQCGQRIZGCHNB-JLAZNSOCSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate 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
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 150000002730 mercury Chemical class 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- RRLNUWRVTRDWIX-UHFFFAOYSA-N n-(4-cyclopropylphenyl)acetamide Chemical compound C1=CC(NC(=O)C)=CC=C1C1CC1 RRLNUWRVTRDWIX-UHFFFAOYSA-N 0.000 description 1
- GTPHHSDNEHXLJQ-UHFFFAOYSA-N n-(4-methylphenyl)-4,5-dihydro-1h-imidazol-2-amine Chemical compound C1=CC(C)=CC=C1N=C1NCCN1 GTPHHSDNEHXLJQ-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229950003591 procinolol Drugs 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 238000000746 purification Methods 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
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003567 thiocyanates Chemical class 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 235000016788 valerian Nutrition 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C335/30—Isothioureas
- C07C335/32—Isothioureas having sulfur atoms of isothiourea groups bound to acyclic carbon atoms
-
- 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Seasonings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Description
Fra J. Med. Chem. 19 (1976) s. 1049-1054 er det kjent en
rekke fenylimino-imidazolidiner, som i sin fenyldel er modifisert med forskjellige typer substituenter, f.eks. halogen-, alkoksy-eller alkylrester. Blandt disse har 2,6-diklorfenylimino-imidazolidin, 2-klor-4-metylfenyl- resp. 4-metylfenylimino-imidazolidin fått betydning som midler til å senke blodtrykket og/eller hjerte-frekvensen .
Legemidler som inneholder en cyklopropylfenylrest i sin kjemiske struktur er likeledes kjent, f.eks. procinolol i M. Negwer: Org. Chem. Arzneimittel, Berlin (1978), s. 518, nr. 2889.
Denne oppfinnelse angår fremstilling av 2-(2-klor-4-cyklopropyl-fenyl-imino)-imidazolidin med formelen
og fysiologisk forlikelige syreaddisjonssalter derav med verdifulle terapeutiske egenskaper.
Forbindelsene med formel I fremstilles ved
a) Omsetning av en forbindelse med den generelle formel
hvor A betyr en cyanogruppe eller resten
hvor
Y betyr en alkoksy- eller alkyltiogruppe med opptil 4 C-atomer eller en sulfhydryl- eller aminogruppe, med etylendiamin eller syreaddisjonssalter derav.
Omsetningen skjer ved temperaturer mellom 100 og 250°C. Som oppløsningsmidler kan anvendes polare protiske, polare aprotiske eller upolare. Omsetningen kan imidlertid også fore-tas uten anvendelse av oppløsningsmidler ved forhøyet temperatur. Reaksjonstiden varierer mellom noen minutter og flere timer.
b) Omsetning av en forbindelse med formelen
hvor X og Z, som kan være like eller forskjellige, betyr
et halogenatom eller en alkoksy- eller alkyltiogruppe med opptil 4 C-atomer, med etylendiamin.
Når X og Z betyr et halogenatom, fortrinnsvis et kloratom, skjer omsetningen ved temperaturer mellom 0°C og romtemperatur. Som oppløsningsmidler kan anvendes inerte oppløsningsmidler
så som etere, ketoner, estere eller alifatiske eller aromatiske hydrokarboner.
Når X og Z betyr alkoksy- eller alkyltiogrupper, forløper omsetningen ved forhøyet temperatur, fortrinnsvis tilbakeløps-temperatur. Som oppløsningsmidler kan anvendes polare protiske, polare aprotiske eller upolare.
c) Avspaltning av acylresten fra en forbindelse med formelen
hvor Acyl betyr en alifatisk eller aromatisk acylgruppe, ved hjelp av alifatiske alkoholer eller fortynnede syrer.
Forbindelser med formel II får man ved å gå ut fra 2-klor-4-cyklopropylanilin ved omsetning med cyanater eller tiocyanater, hvorved det dannes urinstoffer resp. tiourinstoffer. Urinstoffer og tiourinstoffer kan derefter overføres videre
med alkyleringsmidler til de tilsvarende isouroniumsalter resp. isotiouroniumsalter. Fra disse syreaddisjonsforbindelser kan det tilsvarende isourinstoff resp. isotiourinstoff utvinnes med baser. Ved vannavspaltning fra urinstoffet resp. I^S-
avspaltning fra tiourinstoffet med bly- eller kvikksølvsalter får man 2-klor-4-cyklopropylfenylcyanamid, til hvilket ammoniakk kan tilleires under dannelse av 2-klor-4-cyklopropyl-fenylguanidin.
Isocyaniddikloridet med formel III kan fremstilles ved omsetning av 2-klor-4-cyklopropyl-anilin med maursyre og videre omsetning av det dannede formanilid med en blanding av tionyl-klorid og sulfurylklorid.
Ved omsetning av isocyaniddikloridet med alkoholer eller tioalkoholer får man ytterligere utgangsforbindelser med formel III.
Utgangsforbindelser med formel IV kan fremstilles ved omsetning av 2-klor-4-cyklopropyl-anilin med N-acyl-imidazolidinon-(2)-forbindelser i nærvær av fosforoksyklorid.
Det nye 2-fenylimino-imidazolidin med formel I kan på vanlig måte overføres til sine fysiologisk forlikelige syre-addis jonssalter . Syrer som er egnet til saltdannelse, er f.eks. saltsyre, bromhydrogensyre, jodhydrogensyre, fluor-hydrogensyre, svovelsyre, fosforsyre, salpetersyre, eddiksyre, propionsyre, smørsyre, kapronsyre, valeriansyre, oksalsyre, malonsyre, ravsyre, maleinsyre, fumarsyre, melkesyre, vinsyre, sitronsyre, eplesyre, benzoesyre, p-hydroksybenzoesyre, p-amino-benzoesyre, ftalsyre, kanelsyre, salicylsyre, askorbinsyre, metansulfonsyre, 8-klorteofyllin o.l.
Den nye forbindelse med formel I og dens syreaddisjonssalter virker meget sterkt bradykard og er derfor egnet til behandling av coronarlidelser. Innvirkningen på hjerte-frekvensen ble undersøkt på kaniner og på spinalbedøvede rotter og på narkotiserte rotter. Doseringen ligger ved 0,1 til 80 mg, fortrinnsvis 1 til 30 mg.
Forbindelsen med formel I resp. dens syreaddisjonssalter kan også anvendes sammen med andre typer virkestoffer. Egnede galeniske tilberedelsesformer er f.eks. tabletter, kapsler, stikkpiller, oppløsninger eller pulvere} idet man for fremstilling av disse kan anvende de vanlig anvendte galeniske hjelpestoffer, bæremidler, sprengmidler eller smøremidler eller stoffer som medfører en depotvirkning.
De følgende eksempler illustrerer oppfinnelsen:
Eksempel 1 2- ( 2- klor- 4- cyklopropyl- fenyl- imino)- imidazolidin
Mol.vekt: 235,7
Summeformel: C.-H-.C1N.
12 14 3
Sm.p.: 135,5-138,5°C
Elementæranalyse:
a) N-(2-klor-4-cyklopropylfenyl)-S-metyl-isotiouronium-jodid 4-cyklopropylanilin acetyleres til 4-cyklopropylacet-anilid (sm.p. 111-113,5°C) og kloreres og forsepes analogt med forskriften i J. Amer. Chem. Soc. 62 (1940) 2103 til 2-klor-4-cyklopropylanilin. Ved omsetning av anilinet med ammoniumtiocyanat og påfølgende metylering av det erholdte N-(2-klor-4-cyklopropyl-fenyl)-tiourinstoff med metyljodid
får man den ovenstående forbindelse.
b) 2-(2-klor-4-cyklopropylfenyl-imino)-imidazolidin
8,30 g N-(2-klor-4-cyklopropylfenyl)-S-metyl-isotio-uronium- jodid oppvarmes i 25 ml metanol sammen med 2,3 ml (150%) etylendiamin i 15 timer under tilbakeløpskjøling. Derefter inndampes den klare reaksjonsblanding i vakuum, hvorved det blir tilbake et honningaktig residuum. Dette oppløser man i IN HC1 og ekstraherer den saltsure oppløsning to ganger med eter. Den vandige fase bufres derefter med 2N NaOH til pH 6 og ekstraheres (50 ml porsjoner) fraksjonert med eter ved stigende pH-verdier. (fraksjonert alkalisering med 2N NaOH).
De tilnærmet enhetlige eterfraksjoner samles (ved tynnskiktkromatogram-kontroll), tørres over MgSO^ .og inndampes i vakuum. For videre rensning kromatograferes det rå 2-(2-klor-4-cyklo-propylfenyl-imino)-imidazolidin over silikagel. Eluerings-middel: isopropanol:etylacetat:kons. ammoniakk = 50 : 50 : 1. Utbytte: 1,3 g (svarende til 23,6% av det teoretiske). Sm.p.: 135,5 til 138,5°C.
Tynnskiktkromatogram:
System: isopropanol:etylacetat:kons. ammoniakk (50:50:1). Bærer: silikagel-ferdigplater Merck-Darmstadt Nr. 60 F 254 Detektor: (a) UV, (b) kaliumjodplatinat ifølge Schlittler Rf: 0,3.
Claims (1)
- Analogifremgangsmåte for fremstilling av den terapeutisk aktive forbindelse 2-(2-klor-4-cyklopropylfenyl-imino)-imidazolidin med formelenog syreaddisjonssalter derav,karakterisert ved at a) en forbindelse med den generelle formel II hvor A betyr en cyanogruppe eller resten hvor Y betyr en alkoksy- eller alkyltiogruppe med opptil 4 C-atomer eller en sulfhydryl- eller aminogruppe, omsettes med etylendiamin eller syreaddisjonssalter derav; eller b) en forbindelse med formelen hvor X og Z, som kan være like eller forskjellige, betyr et halogenatom eller en alkoksy- eller alkyltiogruppe med opptil 4 C-atomer, omsettes med etylendiamin; eller c) en forbindelse med formelen ■ hvor Acyl betyr en alifatisk eller aromatisk acylgruppe, omsettes med alifatiske alkoholer eller mineralsyrer, og eventuelt overføres det erholdte sluttprodukt i et syreaddisjonssalt.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19792933930 DE2933930A1 (de) | 1979-08-22 | 1979-08-22 | 2-(2-chlor-4-cyclopropyl-phenylimino)-imidazolidin, dessen saeureadditionssalze, diese enthaltende arzneimittel und verfahren zur herstellung derselben. |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO811156L NO811156L (no) | 1981-04-03 |
| NO150118B true NO150118B (no) | 1984-05-14 |
| NO150118C NO150118C (no) | 1984-08-22 |
Family
ID=6079013
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO811156A NO150118C (no) | 1979-08-22 | 1981-04-03 | Analogifremgangsmaate for fremstilling av et terapeutisk aktivt imidazolidin-derivat |
Country Status (21)
| Country | Link |
|---|---|
| US (1) | US4341788A (no) |
| EP (2) | EP0024673B1 (no) |
| JP (1) | JPS56501087A (no) |
| AT (1) | ATE4204T1 (no) |
| BG (1) | BG33281A3 (no) |
| CS (1) | CS212724B2 (no) |
| DD (1) | DD152783A5 (no) |
| DE (2) | DE2933930A1 (no) |
| DK (1) | DK157381A (no) |
| ES (1) | ES494417A0 (no) |
| FI (1) | FI68815C (no) |
| GR (1) | GR69874B (no) |
| HU (1) | HU181790B (no) |
| IE (1) | IE50114B1 (no) |
| NO (1) | NO150118C (no) |
| PT (1) | PT71725B (no) |
| RO (1) | RO82161A (no) |
| SU (1) | SU1021341A3 (no) |
| WO (1) | WO1981000565A1 (no) |
| YU (1) | YU211180A (no) |
| ZA (1) | ZA805201B (no) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL7711390A (nl) * | 1977-10-18 | 1979-04-20 | Philips Nv | Nieuwe 2-arylimino-hexahydopyrimidinen en - imi- dazolidinen, zouten en complexen daarvan, werk- wijze ter bereiding van de nieuwe verbindingen, alsmede fungicide preparaten op basis van de nieuwe verbindingen. |
| HU192986B (en) * | 1984-05-23 | 1987-08-28 | Egyt Gyogyszervegyeszeti Gyar | Process for production of imidasodiline derivatives |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA462824A (en) * | 1950-01-31 | Frank Short Wallace | Manufacture of heterocyclic amines | |
| BE632578A (no) * | 1963-05-22 | |||
| NL7711390A (nl) * | 1977-10-18 | 1979-04-20 | Philips Nv | Nieuwe 2-arylimino-hexahydopyrimidinen en - imi- dazolidinen, zouten en complexen daarvan, werk- wijze ter bereiding van de nieuwe verbindingen, alsmede fungicide preparaten op basis van de nieuwe verbindingen. |
| DE2831234A1 (de) * | 1978-07-15 | 1980-01-31 | Boehringer Sohn Ingelheim | Neue substituierte 2-phenylamino-imidazoline-(2) deren saeureadditionssalze, diese enthaltende arzneimittel und verfahren zur herstellung derselben |
| DE2854659A1 (de) * | 1978-12-18 | 1980-07-10 | Boehringer Sohn Ingelheim | Neue 3,4-disubstituierte 2-phenylimino-imidazolidine, deren saeureadditionssalze, diese enthaltende arzneimittel und verfahren zu deren herstellung |
| US4290971A (en) * | 1979-01-19 | 1981-09-22 | Dso "Pharmachim" | Method of preparing 2-(phenylamino)-imidazolines-(2) |
-
1979
- 1979-08-22 DE DE19792933930 patent/DE2933930A1/de not_active Withdrawn
-
1980
- 1980-08-19 EP EP80104917A patent/EP0024673B1/de not_active Expired
- 1980-08-20 AT AT80901722T patent/ATE4204T1/de not_active IP Right Cessation
- 1980-08-20 WO PCT/EP1980/000081 patent/WO1981000565A1/de active IP Right Grant
- 1980-08-20 US US06/253,860 patent/US4341788A/en not_active Expired - Fee Related
- 1980-08-20 DE DE8080901722T patent/DE3064276D1/de not_active Expired
- 1980-08-20 RO RO80104087A patent/RO82161A/ro unknown
- 1980-08-20 JP JP50203780A patent/JPS56501087A/ja active Pending
- 1980-08-20 HU HU801056A patent/HU181790B/hu unknown
- 1980-08-21 ES ES494417A patent/ES494417A0/es active Granted
- 1980-08-22 ZA ZA00805201A patent/ZA805201B/xx unknown
- 1980-08-22 PT PT71725A patent/PT71725B/pt unknown
- 1980-08-22 DD DD80223464A patent/DD152783A5/de unknown
- 1980-08-22 BG BG8048913A patent/BG33281A3/xx unknown
- 1980-08-22 GR GR62724A patent/GR69874B/el unknown
- 1980-08-22 IE IE1785/80A patent/IE50114B1/en unknown
- 1980-08-22 FI FI802651A patent/FI68815C/fi not_active IP Right Cessation
- 1980-08-22 CS CS805760A patent/CS212724B2/cs unknown
- 1980-08-25 YU YU02111/80A patent/YU211180A/xx unknown
-
1981
- 1981-03-09 EP EP80901722A patent/EP0034623B1/de not_active Expired
- 1981-04-03 NO NO811156A patent/NO150118C/no unknown
- 1981-04-07 DK DK157381A patent/DK157381A/da not_active IP Right Cessation
- 1981-04-21 SU SU813272152A patent/SU1021341A3/ru active
Also Published As
| Publication number | Publication date |
|---|---|
| GR69874B (no) | 1982-07-20 |
| EP0034623A1 (de) | 1981-09-02 |
| BG33281A3 (en) | 1983-01-14 |
| EP0024673B1 (de) | 1983-07-20 |
| FI68815B (fi) | 1985-07-31 |
| SU1021341A3 (ru) | 1983-05-30 |
| RO82161B (ro) | 1983-06-30 |
| HU181790B (en) | 1983-11-28 |
| DE2933930A1 (de) | 1981-03-12 |
| ATE4204T1 (de) | 1983-08-15 |
| ZA805201B (en) | 1982-07-28 |
| DE3064276D1 (en) | 1983-08-25 |
| ES8107191A1 (es) | 1981-08-16 |
| WO1981000565A1 (en) | 1981-03-05 |
| IE50114B1 (en) | 1986-02-19 |
| CS212724B2 (en) | 1982-03-26 |
| YU211180A (en) | 1983-06-30 |
| DK157381A (da) | 1981-04-07 |
| PT71725B (pt) | 1982-01-26 |
| EP0034623B1 (de) | 1983-07-20 |
| FI68815C (fi) | 1985-11-11 |
| IE801785L (en) | 1981-02-22 |
| FI802651A (fi) | 1981-02-23 |
| JPS56501087A (no) | 1981-08-06 |
| DD152783A5 (de) | 1981-12-09 |
| US4341788A (en) | 1982-07-27 |
| EP0024673A1 (de) | 1981-03-11 |
| ES494417A0 (es) | 1981-08-16 |
| NO811156L (no) | 1981-04-03 |
| PT71725A (de) | 1980-09-01 |
| RO82161A (ro) | 1983-07-07 |
| NO150118C (no) | 1984-08-22 |
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