NO138565B - Analogifremgangsmaate ved fremstilling av terapeutisk aktive piperazinyl-propyl-1,2,4-triazolinonderivater - Google Patents
Analogifremgangsmaate ved fremstilling av terapeutisk aktive piperazinyl-propyl-1,2,4-triazolinonderivater Download PDFInfo
- Publication number
- NO138565B NO138565B NO3987/73A NO398773A NO138565B NO 138565 B NO138565 B NO 138565B NO 3987/73 A NO3987/73 A NO 3987/73A NO 398773 A NO398773 A NO 398773A NO 138565 B NO138565 B NO 138565B
- Authority
- NO
- Norway
- Prior art keywords
- triazolin
- diethyl
- treated
- acid
- propyl
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 7
- -1 PIPERAZINYL-PROPYL-1,2,4-TRIAZOLINON DERIVATIVES Chemical class 0.000 title 1
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 7
- VHFVKMTVMIZMIK-UHFFFAOYSA-N 1-(3-chlorophenyl)piperazine Chemical compound ClC1=CC=CC(N2CCNCC2)=C1 VHFVKMTVMIZMIK-UHFFFAOYSA-N 0.000 claims description 6
- PNPCRKVUWYDDST-UHFFFAOYSA-N 3-chloroaniline Chemical compound NC1=CC=CC(Cl)=C1 PNPCRKVUWYDDST-UHFFFAOYSA-N 0.000 claims description 4
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims description 4
- 239000012442 inert solvent Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 2
- ZHZYGIQVBQWOJJ-UHFFFAOYSA-N 3,4-dihydro-1,2,4-triazol-5-one Chemical compound O=C1NCN=N1 ZHZYGIQVBQWOJJ-UHFFFAOYSA-N 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- 241000699670 Mus sp. Species 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 241000700159 Rattus Species 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 7
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 230000000202 analgesic effect Effects 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- MFESCIUQSIBMSM-UHFFFAOYSA-N I-BCP Chemical compound ClCCCBr MFESCIUQSIBMSM-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 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
- 239000002253 acid Substances 0.000 description 3
- 238000009835 boiling Methods 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
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- RLQZIECDMISZHS-UHFFFAOYSA-N 2-phenylcyclohexa-2,5-diene-1,4-dione Chemical compound O=C1C=CC(=O)C(C=2C=CC=CC=2)=C1 RLQZIECDMISZHS-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 206010063659 Aversion Diseases 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-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
- 238000004821 distillation Methods 0.000 description 2
- LBAQSKZHMLAFHH-UHFFFAOYSA-N ethoxyethane;hydron;chloride Chemical compound Cl.CCOCC LBAQSKZHMLAFHH-UHFFFAOYSA-N 0.000 description 2
- 230000001077 hypotensive effect Effects 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 230000037023 motor activity Effects 0.000 description 2
- 239000012053 oil suspension Substances 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 230000001624 sedative effect Effects 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 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
- XHOCKWIJWIXZQZ-UHFFFAOYSA-N 1,4-bis(3-chlorophenyl)piperazine Chemical compound ClC1=CC=CC(N2CCN(CC2)C=2C=C(Cl)C=CC=2)=C1 XHOCKWIJWIXZQZ-UHFFFAOYSA-N 0.000 description 1
- RTBFRGCFXZNCOE-UHFFFAOYSA-N 1-methylsulfonylpiperidin-4-one Chemical compound CS(=O)(=O)N1CCC(=O)CC1 RTBFRGCFXZNCOE-UHFFFAOYSA-N 0.000 description 1
- WBJWXIQDBDZMAW-UHFFFAOYSA-N 2-hydroxynaphthalene-1-carbonyl chloride Chemical compound C1=CC=CC2=C(C(Cl)=O)C(O)=CC=C21 WBJWXIQDBDZMAW-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
- 229910018072 Al 2 O 3 Inorganic materials 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 241000282472 Canis lupus familiaris Species 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
- 241000282326 Felis catus Species 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 208000007101 Muscle Cramp Diseases 0.000 description 1
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 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
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 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
- 235000011054 acetic acid Nutrition 0.000 description 1
- 239000001361 adipic acid Substances 0.000 description 1
- 235000011037 adipic acid Nutrition 0.000 description 1
- 230000016571 aggressive behavior Effects 0.000 description 1
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- PYHXGXCGESYPCW-UHFFFAOYSA-N alpha-phenylbenzeneacetic acid Natural products C=1C=CC=CC=1C(C(=O)O)C1=CC=CC=C1 PYHXGXCGESYPCW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-N anhydrous glutaric acid Natural products OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
- 159000000032 aromatic acids Chemical class 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- UKXSKSHDVLQNKG-UHFFFAOYSA-N benzilic acid Chemical compound C=1C=CC=CC=1C(O)(C(=O)O)C1=CC=CC=C1 UKXSKSHDVLQNKG-UHFFFAOYSA-N 0.000 description 1
- 235000010233 benzoic acid Nutrition 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
- 230000001914 calming effect Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- MAEBCGDGGATMSC-OSHGGGOQSA-N cyclamine Chemical compound O([C@H]1CO[C@H]([C@@H]([C@H]1O[C@@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O[C@@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)O[C@H]1CC[C@]2(C)[C@H]3CCC45OCC6([C@@H](C[C@@]4(C)[C@]3(C)CCC2C1(C)C)O)CC[C@@](C[C@@H]65)(C)C=O)[C@@H]1OC[C@@H](O)[C@H](O)[C@H]1O MAEBCGDGGATMSC-OSHGGGOQSA-N 0.000 description 1
- 230000008918 emotional behaviour Effects 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 239000005555 hypertensive agent Substances 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 208000021822 hypotensive Diseases 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 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
- 230000000144 pharmacologic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid group Chemical class S(N)(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 231100000901 systemic toxic effect Toxicity 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
- 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
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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
- C07D249/12—Oxygen or sulfur atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- 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
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Anesthesiology (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Description
Foreliggende oppfinnelse angår en fremgangsmåte ved frem-
stilling av 1-[3-(4-m-klorfenyl-l-piperazinyl)-propyl]-3,4-diethyl-^2-l,2,4-triazolin-5-on av strukturformel (I):
og farmasøytisk godtagbare salter av denne.
Den nye forbindelse som kan anvendes som et salt av uor-
ganiske syrer, f .eks. saltsyre, svovelsyre., fosforsyre etc, el-
ler med mono- eller flerbasiske alifatiske carboxylsyrer slik som maursyre, eddiksyre, melkesyre, ravsyre, malonsyre, glutarsyre,
adipinsyre, vinsyre, sitronsyre, maleinsyre, fumarsyre, eller méd aromatiske syrer slik som benzoesyre, salicylsyre, påmoinsyre etc, eller med mandelsyre, difenyleddiksyre, benzylsyre etc,
eller med sulfonsyrer slik som methansulfonsyre, benzensulfonsyre, toluensulfonsyrer etc, eller med sulfaminsyrer slik som cyclamin-
syre etc, utviser interessante farmakologiske egenskaper. For det første utviser forbindelsene en adferdspåvirkende aktivitet som er typisk for beroligende midler, med en sedativ effekt, en.
lav reaktivitet til eksperimentatoren, og som virker nedsettende på den motoriske aktivitet. Ennvidere utviser forbindelsene en ' c hypotensiv og analgesisk aktivitet, den første som vist enten•
hos normale rotter eller hos eksperimentelt hypertensive, den an-
nen ved fenylkinontesten eller halepirringstesten.
Forbindelsen som fremstilles ifølge foreliggende analogifremgangsmåte utviser følgende terapeutiske aktivitet:
1. Beroligende aktivitet:
(a) Sedativ virkning ved følgende doser:
6 mg/kg (os), 3 mg/kg i.p., 1,5 mg/kg i.v. hos mus; 3 mg/kg (os), 1,5 mg/kg i.p. hos rotter; (b) Reduksjon av reaktivitet, eksploratorisk aktivitet og emosjonell adferd ved doser på 1-5-10 mg/kg i.p hos rotter . (c) Reduksjon av den spontane motoriske aktivitet ved doser på 2,5-5-10 mg/kg (os) hos mus. 2. Dekondisjoneringsaktivitet. DD50 hos rotter er 15,50 (8,50-26,80 er referansegrenser).
DD50 = dekondisjoneringsdosen 50 = bedømt under anvendelse av sluttpunktet for antall rotter i hver forsøksgruppe som reduserer deres avvergereaksjon med 50 % i en Shuttle boks, og hvor avvergereaksjonen under hvert forsøk er 80 - 90 %. 3. Antiaggresjonsaktivitet. I isolerte mus er AD50 11,2 (7,2 - 18,4 er referansegrenser (mg/kg os.
AD50 = antiaggresjonsdosen 50 = bedømmes som sluttpunktet for for antall mus i hver gruppe som ikke utviser aggre-sjon i løpet av en 5 minutters periode.
4. Analgesisk aktivitet.
I fenylkinon-vridningssyndromet hos mus er AD50 lik 22 (13 - 36 er referansegrenser) i mg/kg os.
AD50 = analgesisk dose 50 = bedømt ved sluttpunktet for antall mus i hver forsøksgruppe som ikke utviser spasmer i løpet av en 5 minutters periode.
Ved varmplatetesten hos mus er AD50 lik 7 (3,4 - 14,5 referansegrense) mg/kg os.
AD50 = analgesisk dose 50 = bedømt ved sluttpunktet for antall mus i hver forsøksgruppe som øket hovedre-aksjonstiden for kontrollgruppen med 2SD (Standard Deviation).
Hypotensiv aktivitet.
Ved målinger på katter efter en enkelt administrering på 300 - 600 - 1200 mcg/kg i.v. ble der målt et blodtrykksfall på 20 - 30 - 50 mg Hg.
Forbindelsen utviser en relativt lav toksisitet. LD50 er 518 mg/kg oralt, 140 mg/kg i.p., og 72 mg/kg i.v. hos mus, 868 mg/kg oralt, 120 mg/kg i.p., 68 mg/kg i.v. og 525 mg/kg s.c. hos rotter.
På rotter kan en daglig dosering på 15 - 50 - 150 mg/kg administreres oralt 6 måneder uten å gi noen systemisk toksisk effekt.
Hos hunder kan en daglig dose på 5 - 15 - 25 mg/kg gies oralt 6 måneder uten å frembringe noen bemerkelsesverdige toksis-ke virkninger.
Oppfinnelsen angår følgelig en analogifremgangsmåte ved fremstilling av terapeutisk aktivt 1-[3-(4-m-klorfenyl-l-pipera-zinyl)-propyl]-3,4-diethyl-A2-l,2,4-triazolin-5-on med strukturformelen
og farmasøytisk godtagbare salter av denne, hvilken fremgangsmåte er kjennetegnet ved ved at a) 3,4-diethyl-A2~l,2,4-triazolin-5-on behandles med 1-m-klorfenyl-4-(3-halogenpropyl)-piperazin i et inert oppløsnings-middel; eller b) 3,4-diethyl-A2~lf2,4-triazolin-5-on behandles med l-brom-3-klorpropan, hvorefter det erholdte produkt behandles med N-m-klprfenyl-piperazin i et inert oppløsningsmiddel; eller c) 1-(3-klorpropyl)-3,4-diethyl-A2~l,2,4-triazolin-5-on oppvarmes med diethanolaminoverskudd, hvorefter det erholdte produkt først behandles med thionylklorid, og derefter med m-kloranilin, hvorefter saltene, om ønsket, fremstilles på i og for seg kjent måte.
Ved denne omsetning omdannes først 3,4-diethyl-A2_l»2,4-triazolin-5-on til salt med alkali alkoholat eller natriumamid eller natriumhydrid, og oppvarmes derefter i dioxan, benzen, alkohol, tetralin, dimethylsulfoxyd, dimethylformamid i flere timer. De efterfølgende fremgangsmåter kan altså betraktes som alternati-ve, og som deler av et enkelt generelt reaksjonsskjema, da forbindelse (III) ikke anvendes som sådan, men spaltes:
I reaksjonsskjema A) erholdes N-m-klorfenyl-N'-halogen-propyl-piperazinet fra N-m-klorfenylpiperazin ved tilsetning av l-brom-3-klorpropan, derefter behandles et alkalisalt av 3,4-diethyl-/^2-l, 2, 4-triazolin-5-on med l-brom-3-klorpropan i et egnet oppløsningsmiddel slik som en alkohol. 1-(3-klorpropyl)-3,4-diethyl-^-l / 2,4-triazolin-5-on oppvarmes suksessivt flere timer med N-m-klorfenylpiperazin i et inert oppløsningsmiddel og i nær-vær av en HCl-akseptor.
I reaksjonsskjema B) konstrueres n-m-klorfenyl-piperazin-propylkjeden på 3,4-diethyl-A2~l,2,4-triazolin-5-on i tre trinn. I det første trinn fremstilles i likhet med skjema A 1-(3-klorpro-pyl) -3,4-diethyl-A2_l/2,4-triazolin-5-on. Derefter oppvarmes det-te produkt med et overskudd diethanolamin, og 1-(3-bis-hydroxy-ethylaminopropyl)-3,4-diethyl-A2-l» 2,4-triazolin-5-on oppsamles. Endelig konstrueres på denne forbindelse m-klorfenyl-piperazin-ringen først med thionylklorid, og derefter, altså uten isolering av reaksjonsproduktet, med m-kloranilin.
De følgende eksempler illustrerer oppfinnelsen:
Eksempel 1
62 g 3,4-diethyl-A2-l,2,4-triazolin-5-on ble oppløst i ca. 500 ml vannfri dioxan. 21 g NaH i 50 % <p>ljesuspensjon ble tilsatt, og blandingen ble kokt under tilbakeløp 30 minutter, hvorefter 119 g N-m-klorfenyl-N'-(3-klorfenyl)-piperazin ble tilsatt under omrøring. Blandingen ble kokt under tilbakeløp 20 timer. Oppløsningsmidlet ble fordampet under vakuum, og residuet ble oppsamlet med 2N HCl-oppløsning.
Oppløsningen ble vasket med ethylether for å fjerne hyd-rid oljesuspensjonen og gjort alkalisk med 50 % I^CO^-oppløsning. Produktet ble ekstrahert med ethylether.
Etheroppløsningen ble tørket, fordampet til tørrhet og
produktet destillert under vakuum.
Der ble erholdt 115 g produkt med kokepunkt 230°C (0,5 mm Hg); hydrokloridet fra isopropylalkohol hadde et smeltepunkt på 197 - 198°C, Sulfatet et smeltepunkt på,178 - 180°C, fosfatet et smeltepunkt på 164 - 166°C, maleatet et smeltepunkt på 122 - 123°C, benzylatet et smeltepunkt på 132 - 133°C, og p-toluensul-fohatet et smeltepunkt på 127 - 129°C.
Eksempel 2
a) 6 g 3,4-diethyl-A2-l,2,4-triazolin-5-on og 6,6 g 3-brom-klorpropan ble tilsatt til 0,98 g Na i 20 ml methylalkoholoppløs-ning.
Blandingen ble kokt under tilbakeløp til nøytral pH, og derefter oppløst i vann, ekstrahert med ethylether, hvorefter opp-løsningsmidlet ble fordampet, og det oljeaktige residuum ble destillert. Kokepunktet til 1-(3-klorpropyl)-3,4-diethyl-A2-l,2,4-triazolin-5-on var 121°C ved 0,05 mm Hg.
b) lg 1-(3-klorpropyl)-3,4-diethyl-A2-l,2,4-triazolin-5-on, 0,9 g m-klorfenyl-piperazin og 0,46 g triethylamin i 25 ml
toluen ble kokt under tilbakeløp 12 timer.
Oppløsningen ble behandlet med 5 N NaOH-oppløsning og ekstrahert med ethylether og destillert i dampstrøm. Residuet fra destillasjonen ble ekstrahert med ethylether, etheroppløsnin-gen ble behandlet med saltsyre-etheroppløsning. Det erholdte hyd-rokloridbunnfall krystllisert fra isopropylalkohol var eksakt det samme som ble syntetisert i eksempel 1.
Eksempel 3
1,5 g 1-(3-klorpropyl)-3,4-diethyl-A2-l,2,4-triazolin-5-on og 1,5 g diethanolamin ble oppvarmet til 100°C i 15 timer. 10 ml CHCl^ ble tilsatt, og den organiske oppløsning behandlet med 0,5 Al203 (II/III). Blandingen ble filtrert, oppløsningsmidlet fordampet, og det oljeaktige residuum destillert. Der ble erholdt 1,4 g l-(3-bis hydroxy-ethylamino-propyl)-3,4-diethyl-^2-l,2,4-triazolin-5-on med kokepunkt 205 - 210°C ved 0,1 mm Hg.
1,3 g 1-(3-bis hydroxy-ethylarnino-<p>rop<y>l)-3,4-dieth<y>l-A2-l,2,4-triazolin-5-on ble behandlet med 1,3 ml thionylklorid 30 minutter ved 75°C.
Overskudd thionylklorid ble fjernet under vakuum, og residuet ble oppløst i 30 ml amylalkohol.
0,57 g m-kloranilin ble tilsatt, og blandingen ble kokt under en nitrogenstrøm ved 150°C i 8 timer.
Den basiske del ble ekstrahert og destillert i en damp-strøm. Residuet fra destillasjonen, ble ekstrahert med ethylether og behandlet med saltsyre-etheroppløsning. Det erholdte hydroklo-rid (siti.p. 197 - 198°C fra isopropylalkohol) var eksakt lik det som ble syntetisert i eksempel 1.
Claims (1)
- Analogifremgangsmåte ved fremstilling av terapeutisk aktivt 1-L3- [4-m-klorfenyl-l- piperazinyl)-propyl ] -3 , 4-diethyl-A2~ 1,2,4-triazolin-5-on med strukturformelenog farmasøytisk godtagbare salter av denne, karakterisert ved at a) 3,4-diethyl-^2~l/2,4-triazolin-5-on behandles med l-m klorfenyl-4-(3-halogenpropyl)-piperazin i et inert oppløsnings-middel, eller b) 3,4-diethyl-A2~l,2,4-triazolin-5-on behandles med l-brom-3-klorpropan, hvorefter det erholdte produkt behandles med N-m-klorfenyl-piperazin i et inert oppløsningsmiddel, eller c) 1-(3-klorpropyl)-3 , 4-diethyl--^2-l, 2, 4-triazolin-5-on oppvarmes med diethanolaminoverskudd, hvorefter det erholdte produkt først behandles med thionylklorid, og derefter med m-kloranilin, hvorefter saltene, om ønsket, fremstilles på i og for seg kjent måte.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT53380/72A IT1052119B (it) | 1972-10-16 | 1972-10-16 | Derivati del triazolinone e procedimento per la loro preparazione |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NO138565B true NO138565B (no) | 1978-06-19 |
| NO138565C NO138565C (no) | 1978-09-27 |
Family
ID=11282276
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO3987/73A NO138565C (no) | 1972-10-16 | 1973-10-15 | Analogifremgangsmaate ved fremstilling av terapeutisk aktive piperazinyl-propyl-1,2,4-triazolinonderivater |
Country Status (19)
| Country | Link |
|---|---|
| US (1) | US3857845A (no) |
| JP (1) | JPS5550948B2 (no) |
| AR (1) | AR204086A1 (no) |
| AT (1) | AT336021B (no) |
| BE (1) | BE806146A (no) |
| CA (1) | CA1013746A (no) |
| CH (1) | CH589643A5 (no) |
| DE (1) | DE2351739C3 (no) |
| DK (1) | DK141750B (no) |
| ES (1) | ES419687A1 (no) |
| FI (1) | FI58495C (no) |
| FR (1) | FR2202702B1 (no) |
| GB (1) | GB1438337A (no) |
| IT (1) | IT1052119B (no) |
| KE (1) | KE2823A (no) |
| NL (1) | NL184782C (no) |
| NO (1) | NO138565C (no) |
| SE (1) | SE390819B (no) |
| YU (1) | YU39914B (no) |
Families Citing this family (23)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1047702B (it) * | 1975-07-24 | 1980-10-20 | Acraf | Nuova sintesi degli psicofarmaci denominati trazodone ed eteroperidone |
| US4162318A (en) * | 1976-05-05 | 1979-07-24 | Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A. | Use of trazodone and etoperidone in Parkinsonism and in other extrapyramidal syndromes characterized by tremors |
| IT1073639B (it) * | 1976-05-05 | 1985-04-17 | Acraf | Impiego del trazodone e etoperidone nel morbo di parikinson ed in altre sindromi extrapiramidali caratterizzate da tremori |
| US4465683A (en) * | 1979-09-14 | 1984-08-14 | Mead Johnson & Company | Anti-psychotic agents |
| US4254124A (en) * | 1979-09-24 | 1981-03-03 | Mead Johnson & Company | Antidepressant agent |
| US4338317A (en) * | 1981-03-16 | 1982-07-06 | Mead Johnson & Company | Phenoxyethyl-1,2,4,-triazol-3-one antidepressants |
| US4487773A (en) * | 1981-03-16 | 1984-12-11 | Mead Johnson & Company | 1,2,4-Triazol-3-one antidepressants |
| US4367335A (en) * | 1981-08-03 | 1983-01-04 | Mead Johnson & Company | Thiazolidinylalkylene piperazine derivatives |
| US4386091A (en) * | 1982-02-24 | 1983-05-31 | Mead Johnson & Company | 2-Phenoxyalkyl-1,2,4-triazol-3-one antidepressants |
| US4575555A (en) * | 1983-06-29 | 1986-03-11 | Mead Johnson & Company | 4-(3-Chlorophenyl)-1,2,3,6-tetrahydropyridine derivative |
| US4613600A (en) * | 1983-09-30 | 1986-09-23 | Mead Johnson & Company | Antidepressant 1,2,4-triazolone compounds |
| US4784998A (en) * | 1987-04-06 | 1988-11-15 | Bristol-Myers Company | 1,3,4-oxadiazole pyschotropic compounds |
| US4931445A (en) * | 1988-10-06 | 1990-06-05 | Irwin Goldstein | Agents for treatment of male impotence |
| US5229406A (en) * | 1990-09-19 | 1993-07-20 | G. D. Searle & Co. | 1,3,5-trisubstituted-1,2,4-triazole compounds for treatment of circulatory disorders |
| US5140036A (en) * | 1990-09-19 | 1992-08-18 | G. D. Searle & Co. | 1,3,5-trisubstituted-1,2,4-triazole compounds for treatment of circulatory disorders |
| US5087634A (en) * | 1990-10-31 | 1992-02-11 | G. D. Searle & Co. | N-substituted imidazol-2-one compounds for treatment of circulatory disorders |
| US5238952A (en) * | 1990-10-31 | 1993-08-24 | G. D. Searle & Co. | N-substituted imidazol-2-one compounds for treatment of circulatory disorders |
| US5196537A (en) * | 1991-03-21 | 1993-03-23 | G. D. Searle & Co. | 5-apylheteroarylalkyl-1,3,5-trisubstituted-1,2,4-triazole compounds for treatment of circulatory disorders |
| US5164403A (en) * | 1991-04-05 | 1992-11-17 | G. D. Searle & Co. | N-arylheteroarylalkyl imidazol-2-one compounds for treatment of circulatory disorders |
| IT1256387B (it) * | 1992-11-13 | 1995-12-04 | Acraf | Procedimento per preparare triazoloni |
| CA2182241C (en) * | 1996-07-29 | 2002-09-17 | Bo Lei | Methods for the manufacture of nefazodone |
| ES2152860B1 (es) * | 1998-10-23 | 2001-08-16 | Finaf 92 Sa | Forma cristalina de la nefazodona y procedimiento para su preparacion. |
| WO2012072665A1 (en) | 2010-11-30 | 2012-06-07 | Pharmaneuroboost N.V. | Compositions comprising pipamperone and serotonin antagonist reuptake inhibitors |
-
1972
- 1972-10-16 IT IT53380/72A patent/IT1052119B/it active
-
1973
- 1973-01-01 AR AR250515A patent/AR204086A1/es active
- 1973-10-02 DK DK535473AA patent/DK141750B/da not_active IP Right Cessation
- 1973-10-03 CH CH1412473A patent/CH589643A5/xx not_active IP Right Cessation
- 1973-10-04 SE SE7313538A patent/SE390819B/xx unknown
- 1973-10-05 GB GB4654073A patent/GB1438337A/en not_active Expired
- 1973-10-08 YU YU2634/73A patent/YU39914B/xx unknown
- 1973-10-12 AT AT871173A patent/AT336021B/de not_active IP Right Cessation
- 1973-10-15 DE DE2351739A patent/DE2351739C3/de not_active Expired
- 1973-10-15 FI FI3188/73A patent/FI58495C/fi active
- 1973-10-15 NO NO3987/73A patent/NO138565C/no unknown
- 1973-10-15 US US00406432A patent/US3857845A/en not_active Expired - Lifetime
- 1973-10-15 JP JP11565973A patent/JPS5550948B2/ja not_active Expired
- 1973-10-15 CA CA183,407A patent/CA1013746A/en not_active Expired
- 1973-10-16 NL NLAANVRAGE7314204,A patent/NL184782C/xx not_active IP Right Cessation
- 1973-10-16 ES ES419687A patent/ES419687A1/es not_active Expired
- 1973-10-16 FR FR7336853A patent/FR2202702B1/fr not_active Expired
- 1973-10-16 BE BE136751A patent/BE806146A/xx not_active IP Right Cessation
-
1978
- 1978-03-08 KE KE2823A patent/KE2823A/xx unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DK141750C (no) | 1980-11-03 |
| ATA871173A (de) | 1976-08-15 |
| AT336021B (de) | 1977-04-12 |
| DE2351739C3 (de) | 1980-09-04 |
| NL184782C (nl) | 1989-11-01 |
| FI58495B (fi) | 1980-10-31 |
| NL7314204A (no) | 1974-04-18 |
| AR204086A1 (es) | 1975-11-20 |
| DE2351739B2 (de) | 1980-01-10 |
| SE390819B (sv) | 1977-01-24 |
| IT1052119B (it) | 1981-06-20 |
| BE806146A (fr) | 1974-02-15 |
| NO138565C (no) | 1978-09-27 |
| YU263473A (en) | 1983-02-28 |
| JPS4993381A (no) | 1974-09-05 |
| US3857845A (en) | 1974-12-31 |
| NL184782B (nl) | 1989-06-01 |
| DK141750B (da) | 1980-06-09 |
| YU39914B (en) | 1985-06-30 |
| CA1013746A (en) | 1977-07-12 |
| JPS5550948B2 (no) | 1980-12-20 |
| FR2202702A1 (no) | 1974-05-10 |
| FI58495C (fi) | 1981-02-10 |
| ES419687A1 (es) | 1976-10-16 |
| GB1438337A (no) | 1976-06-03 |
| KE2823A (en) | 1978-03-31 |
| FR2202702B1 (no) | 1976-07-02 |
| DE2351739A1 (de) | 1974-04-18 |
| CH589643A5 (no) | 1977-07-15 |
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