NO144296B - Analogifremgangsmaate ved fremstilling av terapeutisk aktive 10-(omega-(benzoylpiperidinyl)-alkyl)-fenothiaziner - Google Patents
Analogifremgangsmaate ved fremstilling av terapeutisk aktive 10-(omega-(benzoylpiperidinyl)-alkyl)-fenothiaziner Download PDFInfo
- Publication number
- NO144296B NO144296B NO762184A NO762184A NO144296B NO 144296 B NO144296 B NO 144296B NO 762184 A NO762184 A NO 762184A NO 762184 A NO762184 A NO 762184A NO 144296 B NO144296 B NO 144296B
- Authority
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- Norway
- Prior art keywords
- fluorobenzoyl
- mol
- piperidine
- phenothiazines
- benzoylpiperidinyl
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 15
- 238000002360 preparation method Methods 0.000 title claims description 3
- -1 BENZOYLPIPERIDINYL Chemical class 0.000 title description 3
- 230000001225 therapeutic effect Effects 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 12
- 239000002253 acid Chemical group 0.000 claims description 10
- 229950000688 phenothiazine Drugs 0.000 claims description 8
- WJFKNYWRSNBZNX-UHFFFAOYSA-N 10H-phenothiazine Chemical compound C1=CC=C2NC3=CC=CC=C3SC2=C1 WJFKNYWRSNBZNX-UHFFFAOYSA-N 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims description 2
- 239000000460 chlorine Chemical group 0.000 claims description 2
- 229910052801 chlorine Chemical group 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims 1
- 150000002367 halogens Chemical group 0.000 claims 1
- 150000002431 hydrogen Chemical group 0.000 claims 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- QCPLFZQQQQDDEW-UHFFFAOYSA-N [1-(3-chloropropyl)piperidin-4-yl]-(4-fluorophenyl)methanone Chemical class C1=CC(F)=CC=C1C(=O)C1CCN(CCCCl)CC1 QCPLFZQQQQDDEW-UHFFFAOYSA-N 0.000 description 10
- 239000000203 mixture Substances 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- 239000012458 free base Substances 0.000 description 4
- 239000001530 fumaric acid Substances 0.000 description 4
- 235000011087 fumaric acid Nutrition 0.000 description 4
- 239000008188 pellet Substances 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- AKXHPNYPANDETL-UHFFFAOYSA-N (4-fluorophenyl)-[1-(3-hydroxypropyl)piperidin-4-yl]methanone Chemical compound C1CN(CCCO)CCC1C(=O)C1=CC=C(F)C=C1 AKXHPNYPANDETL-UHFFFAOYSA-N 0.000 description 3
- LAMUXTNQCICZQX-UHFFFAOYSA-N 3-chloropropan-1-ol Chemical compound OCCCCl LAMUXTNQCICZQX-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-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
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000004587 chromatography analysis 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
- 239000000706 filtrate Substances 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- ABERUOJGWHYBJL-UHFFFAOYSA-N (4-fluorophenyl)-piperidin-4-ylmethanone Chemical compound C1=CC(F)=CC=C1C(=O)C1CCNCC1 ABERUOJGWHYBJL-UHFFFAOYSA-N 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- HCWCAKKEBCNQJP-UHFFFAOYSA-N magnesium orthosilicate Chemical compound [Mg+2].[Mg+2].[O-][Si]([O-])([O-])[O-] HCWCAKKEBCNQJP-UHFFFAOYSA-N 0.000 description 2
- 239000000391 magnesium silicate Substances 0.000 description 2
- 229910052919 magnesium silicate Inorganic materials 0.000 description 2
- 235000019792 magnesium silicate Nutrition 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
- RHMQNXNXUZLEIY-UHFFFAOYSA-N methanol;2-propan-2-yloxypropane Chemical compound OC.CC(C)OC(C)C RHMQNXNXUZLEIY-UHFFFAOYSA-N 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- GPKDBZQZPNOBGM-UHFFFAOYSA-N (4-fluorophenyl)-piperidin-4-ylmethanone;hydron;chloride Chemical compound [Cl-].C1=CC(F)=CC=C1C(=O)C1CC[NH2+]CC1 GPKDBZQZPNOBGM-UHFFFAOYSA-N 0.000 description 1
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 description 1
- YETRXLVOWPGIHR-WLHGVMLRSA-N (e)-but-2-enedioic acid;(4-fluorophenyl)-[1-[3-[2-(trifluoromethyl)phenothiazin-10-yl]propyl]piperidin-4-yl]methanone Chemical compound OC(=O)\C=C\C(O)=O.C1=CC(F)=CC=C1C(=O)C1CCN(CCCN2C3=CC(=CC=C3SC3=CC=CC=C32)C(F)(F)F)CC1 YETRXLVOWPGIHR-WLHGVMLRSA-N 0.000 description 1
- HAFWELDDNUXLCK-TYYBGVCCSA-N (e)-but-2-enedioic acid;hydrate Chemical compound O.OC(=O)\C=C\C(O)=O HAFWELDDNUXLCK-TYYBGVCCSA-N 0.000 description 1
- JWGBOHJGWOPYCL-UHFFFAOYSA-N 1-(10H-phenothiazin-2-yl)ethanone Chemical compound C1=CC=C2NC3=CC(C(=O)C)=CC=C3SC2=C1 JWGBOHJGWOPYCL-UHFFFAOYSA-N 0.000 description 1
- RKGYJVASTMCSHZ-UHFFFAOYSA-N 2-(trifluoromethyl)-10H-phenothiazine Chemical compound C1=CC=C2NC3=CC(C(F)(F)F)=CC=C3SC2=C1 RKGYJVASTMCSHZ-UHFFFAOYSA-N 0.000 description 1
- POAOYUHQDCAZBD-UHFFFAOYSA-N 2-butoxyethanol Chemical compound CCCCOCCO POAOYUHQDCAZBD-UHFFFAOYSA-N 0.000 description 1
- KFZGLJSYQXZIGP-UHFFFAOYSA-N 2-chloro-10h-phenothiazine Chemical compound C1=CC=C2NC3=CC(Cl)=CC=C3SC2=C1 KFZGLJSYQXZIGP-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
- NHTMVDHEPJAVLT-UHFFFAOYSA-N Isooctane Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-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
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- UWQIEDGNGUIPKS-UHFFFAOYSA-N benzene 2,2,4-trimethylpentane Chemical compound C1=CC=CC=C1.CC(C)CC(C)(C)C UWQIEDGNGUIPKS-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- JOYVJYNWIUYLLE-UHFFFAOYSA-N chloroform;2-propan-2-yloxypropane Chemical compound ClC(Cl)Cl.CC(C)OC(C)C JOYVJYNWIUYLLE-UHFFFAOYSA-N 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229960000632 dexamfetamine Drugs 0.000 description 1
- JVSWJIKNEAIKJW-UHFFFAOYSA-N dimethyl-hexane Natural products CCCCCC(C)C JVSWJIKNEAIKJW-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 239000011147 inorganic material Substances 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000000199 molecular distillation Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 238000010183 spectrum analysis Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
- C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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
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- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Neurosurgery (AREA)
- Life Sciences & Earth Sciences (AREA)
- Neurology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Biomedical Technology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Anesthesiology (AREA)
- Pain & Pain Management (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Foreliggende oppfinnelse angår en analogifremgangsmåte ved fremstilling av terapeutisk aktive 10- {.3-[4- (p-f luorbenzoyl) - piperidinyl]propyl}-fenothiaziner med den generelle formel:
hvor R er hydrogen, klor, trifluormethyl eller acetyl, og syreaddisjonssalter derav.
Fremgangsmåteforbindelsene med formel I oppviser psykosedativ aktivitet.
Den psykosedative aktivitet av fremgangsmåteforbindelsene av formel I ble påvist ved deres evne til å blokere den letha-le virkning av d-amfetamin i aggregerte mus når de ble prøvet i henhold til en modifisert fremgangsmåte av Burn og Hoobs, Arch. Intern. Pharmacodyn. 113: 290 (1958). Når f.eks. 2-klor-10- i[3-[4- (p-f luorbenzoyl) -piperidinyl] -propylj>-f enothiazin ble admini-strert intraperitonalt i rotter, hadde forbindelsen en ED^Q på
0,72 mg/kg efter 16 timer, hvilket viser at forbindelsen hadde effektive og langvarige psykosedative egenskaper. ED^-verdiene av foregående forbindelse og andre forbindelser er angitt i tabell 1.
De akutte toksisiteter (LD5Q) av forbindelsene fra eksemp-ler 1, 2, 3 og 4 ble bestemt i mus og er angitt i tabell 2.
Fremgangsmåteforbindelsene kan anvendes i form av syreaddisjonssalter som har forbedret vannoppløselighet sammenlignet med den frie base. Passende syreaddisjonssalter er de som avledes av uorganiske syrer som saltsyre, hydrogenbromid, svovelsyre og fosforsyre, og organiske syrer som eddiksyre, sitronsyre, melkesy-re, maleinsyre, oxalsyre, fumarsyre og vinsyre. De foretrukne ad-disjonssalter er hydrokloridet, maleatet og fumaratet. Syreaddi-sjonssaltene fremstilles ved å omsette de basiske forbindelser med den valgte syre, hvorav én eller begge kan være i form av ether-alkohol- eller acetonoppløsninger.
Forbindelsene som anvendes ved fremstilling av de nye forbindelser ved foreliggende fremgangsmåte er fenothiazin og 2-substituerte fenothiaziner som er kommersielt tilgjengelige eller som kan fremstilles ved kjente fremgangsmåter beskrevet i littera-turen og 1-(3-klorpropyl)-4-(p-fluorbenzoyl)-piperidiner. Sist-nevnte forbindelser fremstilles ved å omsette 4-(p-fluorbenzoyl)-piperidin med 3-klorpropanol i et lavere alkanoloppløsningsmiddel som n-butanol, med en syreakseptor for å få 1-(3-hydroxypropyl)-4-(p-fluorbenzoyl)-piperidin som ved omsetning med et reagens som thionylklorid, gir 1-(3-klorpropyl)-4-(p-fluorbenzoyl)-piperidin.
4-(p-fluorbenzoyl)-piperidin kan fremstilles som angitt i US patent 3.576.810.
Fremgangsmåteforbindelsene fremstilles ved å omsette 1-(3-klorpropyl)-4-(p-fluorbenzoyl)-piperidin med formelen: med et fenothiazin med formelen: hvor R er som ovenfor angitt. Reaksjonen utføres fortrinsvis i nærvær av et passende oppløsningsmiddel som f.eks. benzen, toluen eller xylen, og i nærvær av en syreakseptor som en sterk uorganisk base. Reaksjonen utføres fortrinsvis ved forhøyet temperatur som f.eks. tilbakeløpstemperaturen. Ved en variasjon av foregående fremgangsmåte metalliseres fenothiazinet i et passende oppløsnings-middel som benzen, toluen eller dimethylformamid, under anvendelse av et konvensjonelt metalliseringsmiddel som f.eks. natriumhydrid eller n-butyllithium, og ved forhøyet temperatur, f.eks. 80 - 110°C, og 1-(3-klorpropyl)-4-(p-fluorbenzoyl)-piperidinet omsettes med det metalliserte fenothiazin.
Forbindelsene fremstillet ved ovenstående fremgangsmåte isoleres fra reaksjonsblandingen ved å anvende passende metoder,
som f.eks. destillasjon, kromatografi, krystallisasjon eller ved overføring til et passende syreaddisjonssalt.
Metode 1
4-( p- fluorbenzoyl)- 1-( 3- hydroxypropyl)- piperidin En blanding av 24,3 g (0,1 mol) 4-(p-fluorbenzoyl)-piperidin-hydroklorid, 12,5 g (0,125 mol) 3-klorpropanol og 42,0 g (0,5 mol) natriumbicarbonat i 500 ml n-butanol omrøres under til-bakeløp i 15 timer. Ytterligere 3,0 g (0,025 mol) 3-klorpropanol ble tilsatt efter at tynnskiktskromatografi viste ufullstendig omsetning, og reaksjonen ble fortsatt i 3 timer. Den avkjølte reaksjonsblanding ble filtrert, filtratet ble inndampet under nedsatt trykk, og den gjenværende olje krystallisert ved triturering i isopropylether. Det lærbrune faste stoff veiet 23 g (87 %) og smeltet ved 107 - 109°C. Omkrystallisering fra benzen-isooctan ga 17,7 g materiale som smeltet ved 111 - 112°C.
Metode 2
4-( p- fluorbenzoyl)- 1-( 3- klorpropyl)- piperidin 38,7 g (0,376 mol) thionylklorid ble tilsatt dråpevis til en omrørt oppløsning av 43,1 g, (0,163 mol) 4-(p-fluorbenzoyl)-1-(3-hydroxypropyl)-piperidin i 400 ml kloroform ved værelsetemperatur. Efter at tilsetningen var avsluttet, ble reaksjonsblandingen omrørt ved værelsetemperatur i ytterligere 16 timer. Blandin-gen ble så avkjølt, og 125 ml 6N natriumhydroxydoppløsning ble tilsatt dråpevis. Kloroformoppløsningen ble fraskilt, vasket med vann og tørret over magnesiumsulfat. Fjernelse av oppløsningsmidlet ga 42,7 g råprodukt (92 % utbytte) som krystalliserte ved avkjøling. Omkrystallisasjon fra isooctan ga 25,3 g rent produkt med smeltepunkt 6 6,5 - 68,5°C.
Analyse: Beregnet for C^H^NOFCl: • C 63 , 49 ; H 6,75; N 4,94
Funnet: C 63,49; H 6,86; N 4,81.
5
Eksempel 1
10-{ 3-[ 4-( p- fluorbenzoyl)- piperidin]- propyl} - fenothiazin Fumarat- hydrat ( 1:4)
En blanding av 4,9 g (0,025 mol) fenothiazin, 7,5 g (0,0265 mol) 1-(3-klorpropyl)-4-(p-fluorbenzoyl)-piperidin og 8,4 g (,15 mol) knuste kaliumhydroxyd-pellets ble omrørt i 200 ml tørt toluen under tilbakeløp i 20 timer. Den avkjølte reaksjonsblanding ble filtrert og filtratet inndampet under nedsatt trykk. Restoljen ble vist å være en blanding av produktet og reaktanter ved tynnskiktskromatografisk analyse. Delvis rensning ble oppnådd ved å oppløse oljen i ether og behandle med etherisk hydrogenklorid-oppløsning for å danne hydrokloridsaltet. Saltet ville imidlertid ikke omkrystallisere, og ble overført til den frie base. Den frie base (4,5 g, 40,5 % utbytte) ble behandlet med én ekvivalent fumarsyre for å danne fumaratsaltet. Omkrystallisasjon fra methanol-isopropylether ga 4,7 g lærfarvet fast stoff med smeltepunkt 190 - 192°C.
Analyse: Beregnet for C^H^I^OFS ,C4H404 .1/4 H20:
C 65,65; H 5,60; N 4,94 Funnet: C 65,82; H 5,60; N 4,93
Eksempel 2
2-trifluormethyl-l0-{3-[4-(p-fluorbenzoyl)-piperidinyl]-propyl)-fenothiazin- fumarat
En blanding av 8,6 g (0,032 mol) 2-trifluormethylfeno-thiazin, 10,0 g (0,035 mol) 1-(3-klorpropyl)-4-(p-fluorbenzoyl)-piperidin og 11,2 g (0,2 mol) knuste kaliumhydroxyd-pellets ble om-rørt i 300 ml tørt toluen under tilbakeløp i 20 timer. Den avkjølte reaksjonsblanding ble filtrert, filtratet ble vasket med vann, tør-ret over magnesiumsulfat og inndampet, hvorved man fikk 14,2 g råprodukt (88 % utbytte). Råproduktet ble behandlet med overskudd av fumarsyre i methanol-isopropylether, hvorved man fikk 20,5 g fumaratsalt. Omkrystallisasjon fra isopropanol-isopropylether ga 12,2 g fumaratsalt med smeltepunkt 158,5 - 161°C.
Analyse: Beregnet for C32H3Q<N>2<0>5<S>F4: C 60,94; H 4,80; N 4,44
Funnet: C 60,77; H 4,88; N 4,37
D
Eksempel 3
2-acetyl-lO-[3-(4-p-fluorbenzoylpiperidinyl)-propyl]-fenothiazin-difumarat- seskvihydrat
En blanding av 7,7 g (0,032 mol) 2-acetylfenothiazin, 10,0 g (O,o353 mol) 1-(3-klorpropyl)-4-(p-fluorbenzoyl)-piperidin og 14,0 g (0,25 mol) knuste kaliumhydroxyd-pellets ble omrørt i 300 ml tørt toluen under tilbakeløp i 24 timer. Tynnskiktskromatografi viste ufullstendig reaksjon. Ytterligere 10,0 g (0,0353 mol) 1-(3-klorpropyl)-4-(p-fluorbenzoyl)-piperidin i 75 ml tørt toluen ble tilsatt til reaksjonsblandingen,og tilbakeløpskokningen ble fortsatt i ytterligere 24 timer. Den avkjølte reaksjonsblanding ble vasket med vann, tørret over magnesiumsulfat og inndampet, hvorved man fikk 23,2 g råprodukt. Kromatografi på 400 g magnesium-silikat ga 6 g urent produkt. Forurensningene ble fjernet ved mo-lekylærdes tillasjon, hvilket ga produktet som residuum. Residuet veiet 4,0 g (24,5 % utbytte). Den frie base ble behandlet med to ekvivalenter fumarsyre i methanol. Methanolen ble fordampet, og det faste residuum ble omkrystallisert fra aceton-petrolether
(30 - 60°C), og hadde smeltepunkt 146 - 149°C.
Analyse: Beregnet for c74Hs0<N>4<0>23<S>2<F>2: C 59'43> H 5/39? N 3'75
Funnet: C 59,57; H 5,06; N 3,39
Eksempel 4
2-klor-10-i3-[4-(p-fluorbenzoyl)-piperidinyl]-propyl} -fenothiazin-hydroklorid- hydrat ( 1:4)
En blanding av 9,4 g (0,04 mol) 2-klorfenothiazin,
12,0 g (0,0425 mol) 4-(p-fluorbenzoyl)-1-(3-klorpropyl)-piperidin og 14,0 g (0,25 mol) knuste kaliumhydroxyd-pellets i 300 ml tørt toluen ble omrørt og kokt under tilbakeløp i 36 timer. Efter av-kjøling ble toluenoppløsningen dekantert fra det uorganiske materiale og inndampet, hvorved man fikk 17,5 g råprodukt. Dette ble kromatografert på en 250 g magnesiumsilicatkolonne, hvorved man fikk 12,0 g av et temmelig rent produkt (63 % utbytte). Molekylær-destillasjon ved 250°C ga 6,7 g gult glass. Oljen ble oppløst i ether og behandlet med etherisk hydrogenklorid, hvilket ga et hyg-
roskopisk hydrokloridsalt. Saltet ble triturert med kokende isopropylether og ble omkrystallisert fra isopropylether-kloroform. Saltet ble ved kjernemagnetisk resonans og massespektral analyse vist å være solvatisert, og ble tørret ved 120°C i en vakuumovn. Saltet,med smeltepunkt 204 - 206°C, var ifølge analyse et 1/4-hydrat.
Analyse: Beregnet for C27H2<gN>2OFCl2S • 1/4 H20:
C 62,13; H 5,31; N 5,37
Funnet: C 62,04; H 5,23; N 5,40
Claims (1)
- Analogifremgangsmåte ved fremstilling av terapeutisk aktive 10-[u>-(benzoylpiperidinyl)-alkyl]-fenothiaziner med formelen:hvor R er hydrogen, trifluormethyl, acetyl eller klor, og syreaddisjonssalter derav, karakterisert ved at et 1-(3-halogen-propyl)-4-(p-fluorbenzoyl)-piperidin med formelen: hvor X er halogen, omsettes med fenothiazin med formelen: hvor R er som ovenfor angitt, og at den således erholdte forbindelse, om ønskes, overføres til et syreaddisjonssalt derav.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US59121675A | 1975-06-27 | 1975-06-27 | |
| US05/678,575 US4021552A (en) | 1975-06-27 | 1976-04-20 | 10-[ω-(BENZOYLPIPERIDINYL)ALKYL]PHENOTHIAZINES |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO762184L NO762184L (no) | 1976-12-28 |
| NO144296B true NO144296B (no) | 1981-04-27 |
| NO144296C NO144296C (no) | 1981-08-05 |
Family
ID=27081083
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO762184A NO144296C (no) | 1975-06-27 | 1976-06-24 | Analogifremgangsmaate ved fremstilling av terapeutisk aktive 10-(omega-(benzoylpiperidinyl)-alkyl)-fenothiaziner |
Country Status (14)
| Country | Link |
|---|---|
| US (1) | US4021552A (no) |
| JP (1) | JPS6036436B2 (no) |
| CA (1) | CA1079277A (no) |
| CH (1) | CH599187A5 (no) |
| DE (1) | DE2628570A1 (no) |
| ES (1) | ES449196A1 (no) |
| FR (1) | FR2316955A1 (no) |
| GB (1) | GB1548284A (no) |
| IL (1) | IL49758A (no) |
| NL (1) | NL7606966A (no) |
| NO (1) | NO144296C (no) |
| PH (1) | PH12436A (no) |
| PT (1) | PT65274B (no) |
| SE (1) | SE409712B (no) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AT335570B (de) * | 1973-11-14 | 1977-03-25 | Danfoss As | Hochbelastbarer ptc-widerstand und verfahren zu seiner herstellung |
| US4225641A (en) * | 1977-03-18 | 1980-09-30 | Motohiro Yokomizo | Picture-making device |
| JPS57115697U (no) * | 1981-01-06 | 1982-07-17 | ||
| JPH06237B2 (ja) * | 1986-12-26 | 1994-01-05 | 佐内 藤田 | 廃水処理方法及びその装置 |
| US4812456A (en) * | 1987-05-13 | 1989-03-14 | Hoechst-Roussel Pharmaceuticals Inc. | 1-(N-(2-alkylthio-10H-phenothiazin-10-yl)alkyl)-4-benzoylpiperidines and pharmaceutical use |
| US4822796A (en) * | 1987-06-01 | 1989-04-18 | Helsley Grover C | 1-((Phenothiazin-10-yl)alkyl)-alpha-phenyl-4-piperidinemethanols and pharmaceutical use |
| JPH0737355B2 (ja) * | 1989-02-21 | 1995-04-26 | 株式会社新潟鐵工所 | 血液の乾燥処理法 |
| JPH0325635U (no) * | 1989-07-21 | 1991-03-15 | ||
| US5225412A (en) * | 1991-04-29 | 1993-07-06 | Hoechst-Roussel Pharmaceuticals Incorporated | Benzoisothiazole-and benzisoxazole-3-carboxamides |
| US5143923B1 (en) * | 1991-04-29 | 1993-11-02 | Hoechst-Roussel Pharmaceuticals Incorporated | Benzoisothiazole-and benzisoxazole-3-carboxamides |
| US6284279B1 (en) | 1999-12-03 | 2001-09-04 | Avecia, Inc. | Phenothiazine in prill form and method for making the same |
| DE10032137B4 (de) * | 2000-07-01 | 2009-04-02 | Allessachemie Gmbh | Verfahren zur Herstellung von Phenothiazin-Granulat mit verbesserten Eigenschaften |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB863243A (en) * | 1958-09-04 | 1961-03-22 | Searle & Co | Improvements in or relating to acylphenothiazines |
| US3225037A (en) * | 1959-03-30 | 1965-12-21 | Sterling Drug Inc | 10-[(amino- and acylamino-1-piperidyl) lower-alkyl]-phenothiazines |
| GB1177525A (en) * | 1967-04-13 | 1970-01-14 | Leo Ab | New Heterocyclic Aminoketones of Therapeutic Interest |
-
1976
- 1976-04-20 US US05/678,575 patent/US4021552A/en not_active Expired - Lifetime
- 1976-06-10 IL IL49758A patent/IL49758A/xx unknown
- 1976-06-16 SE SE7606847A patent/SE409712B/xx not_active IP Right Cessation
- 1976-06-23 PH PH18598A patent/PH12436A/en unknown
- 1976-06-24 GB GB7626360A patent/GB1548284A/en not_active Expired
- 1976-06-24 NO NO762184A patent/NO144296C/no unknown
- 1976-06-24 PT PT65274A patent/PT65274B/pt unknown
- 1976-06-25 NL NL7606966A patent/NL7606966A/xx not_active Application Discontinuation
- 1976-06-25 FR FR7619434A patent/FR2316955A1/fr active Granted
- 1976-06-25 DE DE19762628570 patent/DE2628570A1/de active Granted
- 1976-06-25 CA CA255,762A patent/CA1079277A/en not_active Expired
- 1976-06-25 ES ES449196A patent/ES449196A1/es not_active Expired
- 1976-06-25 CH CH819876A patent/CH599187A5/xx not_active IP Right Cessation
- 1976-06-26 JP JP51075934A patent/JPS6036436B2/ja not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| GB1548284A (en) | 1979-07-11 |
| PT65274B (en) | 1977-12-10 |
| DE2628570B2 (no) | 1980-02-07 |
| JPS6036436B2 (ja) | 1985-08-20 |
| NL7606966A (nl) | 1976-12-29 |
| ES449196A1 (es) | 1977-07-16 |
| FR2316955A1 (fr) | 1977-02-04 |
| US4021552A (en) | 1977-05-03 |
| NO762184L (no) | 1976-12-28 |
| PT65274A (en) | 1976-07-01 |
| JPS525779A (en) | 1977-01-17 |
| FR2316955B1 (no) | 1980-11-07 |
| CH599187A5 (no) | 1978-05-12 |
| PH12436A (en) | 1979-02-22 |
| IL49758A0 (en) | 1976-08-31 |
| SE409712B (sv) | 1979-09-03 |
| NO144296C (no) | 1981-08-05 |
| SE7606847L (sv) | 1976-12-28 |
| DE2628570C3 (no) | 1980-10-02 |
| CA1079277A (en) | 1980-06-10 |
| DE2628570A1 (de) | 1976-12-30 |
| IL49758A (en) | 1978-12-17 |
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