DK146258B - Analogifremgangsmaade til fremstilling af 10-(3-(4-(p-fluorbenzoyl)piperidinyl)propyl)phenothiaziner eller syreadditionssalte deraf - Google Patents
Analogifremgangsmaade til fremstilling af 10-(3-(4-(p-fluorbenzoyl)piperidinyl)propyl)phenothiaziner eller syreadditionssalte deraf Download PDFInfo
- Publication number
- DK146258B DK146258B DK274076AA DK274076A DK146258B DK 146258 B DK146258 B DK 146258B DK 274076A A DK274076A A DK 274076AA DK 274076 A DK274076 A DK 274076A DK 146258 B DK146258 B DK 146258B
- Authority
- DK
- Denmark
- Prior art keywords
- fluorobenzoyl
- propyl
- piperidinyl
- piperidine
- acid addition
- Prior art date
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- 150000003839 salts Chemical class 0.000 title description 13
- 239000002253 acid Substances 0.000 title description 11
- -1 PIPERIDINYL Chemical class 0.000 title description 10
- 238000000034 method Methods 0.000 title description 8
- 238000002360 preparation method Methods 0.000 title description 4
- 150000002990 phenothiazines Chemical class 0.000 title description 3
- OCBFFGCSTGGPSQ-UHFFFAOYSA-N [CH2]CC Chemical class [CH2]CC OCBFFGCSTGGPSQ-UHFFFAOYSA-N 0.000 title 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- 150000001875 compounds Chemical class 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- QCPLFZQQQQDDEW-UHFFFAOYSA-N [1-(3-chloropropyl)piperidin-4-yl]-(4-fluorophenyl)methanone Chemical compound C1=CC(F)=CC=C1C(=O)C1CCN(CCCCl)CC1 QCPLFZQQQQDDEW-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 229950000688 phenothiazine Drugs 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-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
- 239000012043 crude product Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- WJFKNYWRSNBZNX-UHFFFAOYSA-N 10H-phenothiazine Chemical compound C1=CC=C2NC3=CC=CC=C3SC2=C1 WJFKNYWRSNBZNX-UHFFFAOYSA-N 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 230000001624 sedative effect Effects 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- 239000011324 bead Substances 0.000 description 4
- 125000003386 piperidinyl group Chemical group 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
- 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
- 230000000694 effects Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- 239000001530 fumaric acid Substances 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000004809 thin layer chromatography Methods 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
- ABERUOJGWHYBJL-UHFFFAOYSA-N (4-fluorophenyl)-piperidin-4-ylmethanone Chemical compound C1=CC(F)=CC=C1C(=O)C1CCNCC1 ABERUOJGWHYBJL-UHFFFAOYSA-N 0.000 description 2
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-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
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000003474 anti-emetic effect Effects 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 229960000632 dexamfetamine Drugs 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
- 238000000199 molecular distillation Methods 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 239000000932 sedative agent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- GPQBOGVFIZEKTG-UHFFFAOYSA-N (4-fluorophenyl)-[1-(3-phenothiazin-10-ylpropyl)piperidin-4-yl]methanone Chemical class C1=CC(F)=CC=C1C(=O)C1CCN(CCCN2C3=CC=CC=C3SC3=CC=CC=C32)CC1 GPQBOGVFIZEKTG-UHFFFAOYSA-N 0.000 description 1
- 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
- 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
- WGPBQPGEOAOGES-UHFFFAOYSA-N 1-[10-[3-[4-(4-fluorobenzoyl)piperidin-1-yl]propyl]phenothiazin-2-yl]ethanone Chemical compound C12=CC(C(=O)C)=CC=C2SC2=CC=CC=C2N1CCCN(CC1)CCC1C(=O)C1=CC=C(F)C=C1 WGPBQPGEOAOGES-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
- KFZGLJSYQXZIGP-UHFFFAOYSA-N 2-chloro-10h-phenothiazine Chemical compound C1=CC=C2NC3=CC(Cl)=CC=C3SC2=C1 KFZGLJSYQXZIGP-UHFFFAOYSA-N 0.000 description 1
- WCIBOXFOUGQLFC-UHFFFAOYSA-N 4-[4-(4-fluorobenzoyl)piperidin-1-yl]-1-(4-fluorophenyl)butan-1-one Chemical compound C1=CC(F)=CC=C1C(=O)CCCN1CCC(C(=O)C=2C=CC(F)=CC=2)CC1 WCIBOXFOUGQLFC-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- NHTMVDHEPJAVLT-UHFFFAOYSA-N Isooctane Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 241000287433 Turdus Species 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 239000002111 antiemetic agent Substances 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
- 239000000460 chlorine Chemical group 0.000 description 1
- 229910052801 chlorine Chemical group 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000010908 decantation Methods 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
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical group 0.000 description 1
- 239000001257 hydrogen Substances 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
- 230000001665 lethal effect Effects 0.000 description 1
- 231100000225 lethality Toxicity 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000003176 neuroleptic agent Substances 0.000 description 1
- 230000000701 neuroleptic effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000000746 purification Methods 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
- 239000007858 starting material Substances 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
1 & (19) DANMARK \fig/
f(,2) FREMLÆGGELSESSKRIFT , 146258 B
DIREKTORATET FOR PATENT- OG VAREMÆRKEVÆSENET
(21) Patentansøgning nr.: 274076 (51) Int.CI.3: C 07 D 417/06 ' (22) Indleveringsdag: 18 |un 1976 (41) Aim. tilgængelig: 28 dec 1976 (44) Fremlagt: 15 aug 1983 (86) International ansøgning nr.:-(30) Prioritet: 27 ]un 1975 US 591216 (71) Ansøger: A.H. ‘ROBINS COMPANY INCORPORATED; Richmond, US.
(72) Opfinder: William John ‘Welstead Jr.; US, Robert Frederick ‘Boswell Jr.,- US.
(74) Fuldmægtig: Ingeniørfirmaet Budde, Schou & Co_ (54) Analogifremgangsmåde til fremstilling af 10-(3-(4-(p-fluorbenzoyl)piperidinyl)propyl)pheno-thiaziner eller syreadditionssalte deraf
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af hidtil ukendte 10- ^3-[4-(p--fluorbenzoyl)piperidinyl]propylJ phenothiaziner med den almene formel \ txxj' hvor R betyder hydrogen, trifluormethyl, acetyl eller chlor, eller syreadditionssalte deraf.
2 146258
Fra beskrivelsen til dansk patent nr. 91.121 kendes visse substituerede carbamoyl-piperidinoalkyl-phenthiazinforbindelser (f.eks. 2-acetyl-10-(3-4'-carbamoyl-piperidin-propyl)-phenthiazin) med beroligende virkning, antiemetisk virkning og analgetisk virkning. Fra beskrivelsen til dansk patent nr. 124.551 kendes endvidere visse substituerede alkyloxycarbonyloxyethyl-(piperazino-eller piperidino-propyl)-phenthiazinforbindelser med beroligende virkning, neuroleptisk virkning og antiemetisk virkning. Endvidere kendes fra tysk offentliggørelsesskrift nr. 1.930.818 visse 1-sub-stituerede 3- eller 4-aroylpiperidinforbindelser, f.eks. 1-(3-(p--acetyl-O-methoxyphenoxy)-propyl]- og 1-[3-(p-fluorbenzoyl)-propyl] -4-(p-fluorbenzoyl)-piperidin, med beroligende virkning.
De omhandlede forbindelser har beroligende virkning. Den beroligende virkning ved de omhandlede forbindelser er påvist ved deres evne til at blokere lethale virkninger af d-amphetamin i sammenhobede mus ved afprøvning i overensstemmelse med den modificerede fremgangsmåde ifølge Burn og Hobbs, Arch. Intern. Pharmaco-dyn. 113:290 (1958). Når eksempelvis 2-chlor-lO- ^3-[4-(p-fluorbenzoyl) piperidinyl]propyl} -phenothiazin indgives intraperitonealt til mus, har forbindelsen en ED^-værdi på 0,72 mg/kg efter 16 timer, hvilket indicerer, at forbindelsen har effektiv og langvarig beroligende virkning. ED^q-værdien for førnævnte forbindelse samt andre af de omhandlede forbindelser er anført i nedenstående tabel I.
Tabel I
Virkningerne af forskellige præbehandlingstidsintervaller _på d-amphetaminlethaliteten hos mus_
Protektiv EDgQ (95% konfidensgrænser) mg/kg i.p.
1 time 4 timer 8 timer 16 timer 4 0,17 (0,1-14) 0,53 (0,2-1,1) 0,19 (0,1-0,5) 0,72 (0,4-1,3) 3 0,14 (0,06-0,3) 0,10 (0,05-0,22) 0,06 (0,03-0,13) 0,76 (0,6-1,1) 1 0,94 (0,4-1,9) 0,35 (0,1-1,2) 0,27 (0,7-2,1) 12,1 (8-18) 2 1,44 (0,6-3,3) 3,5 (1,1-10,8) 1,4 (0,8-2,2) 1,89 (1,2-2,8)
Den akutte toksicitet (LD50~værdien) af de ifølge eksempel 1, 2, 3 og 4 fremstillede forbindelser er bestemt på mus. Værdierne anføres i nedenstående tabel II.
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Tabel II
72 timers LD5Q-værdi hos mus pjVg nr * LD50 konfidensgrænser) mg/kg i.p.
4 248 (211-290) 3 287 (227-361) 1 330 (268-405) 2 317 (251-399)
De omhandlede forbindelser kan anvendes i form af syreadditionssalte, som har bedre vandopløselighed end de fri baser. Egnede syreadditionssalte er afledt af uorganiske syrer såsom saltsyre, hy-drogenbromidsyre, svovlsyre og phosphorsyre og organiske syrer såsom eddikesyre, citronsyre, mælkesyre, maleinsyre, oxalsyre, fumarsyre og vinsyre. De foretrukne syreadditionssalte er hydrochloriderne, maleaterne og fumaraterne. Syreadditionssaltene fremstilles ved at omsætte .baseforbindelserne med den pågældende syre, idet den ene eller begge reaktanter kan anvendes i form af en opløsning i ether, alkohol eller acetone.
Forbindelserne, som anvendes til fremstilling af de omhandlede forbindelser er phenothiazin eller 2-substituerede phenothiaziner, der er kommercielt tilgængelige, eller som kan fremstilles på kendt måde, samt l-(3-chlorpropyl)-4-(4-fluorbenzoyl)piperidin. Denne forbindelse fremstilles ved at omsætte 4-(p-fluorbenzoyl)piperidin med 3-chlorpropanol i et lavere alkanolopløsningsmiddel såsom n-butanol med en syreacceptor til dannelse af 1-(3-hydroxypropyl)-4-(p-fluor-benzoyl)piperidin, som ved omsætning med et reagens såsom thionyl-chlorid giver l-(3-chlorpropyl)-4-(p-fluorbenzoyl)piperidin.
4-(p-Fluorbenzoyl)piperidin kan fremstilles ved den i DSA patentskrift nr. 3.576.810 beskrevne fremgangsmåde.
Fremgangsmåden ifølge opfindelsen er ejendommelig ved, at 1-(3-halogenpropyl)-4-(p-fluorbenzoyl)piperidin med formlen 4 146258 k>’ o
CH2CH2CH2X
hvor X betyder halogen, omsættes med en phenothiazin med formlen
H
crixr hvor R har den ovenfor anførte betydning, eller et metalsalt deraf. Reaktionen gennemføres fortrinsvis i nærværelse af et egnet opløsningsmiddel, f.eks. benzen, toluen eller xylen, samt i nærværelse af en syreacceptor såsom en stærk uorganisk base. Omsætningen gennemføres fortrinsvis ved forhøjet temperatur, f.eks. ved tilbagesvalingstemperaturen. Ved en udførelsesform for denne fremgangsmåde metalliseres phenothiazinet i et egnet opløsningsmiddel såsom benzen, toluen eller dimethylformamid under anvendelse af et konventionelt metalliseringsmiddel, f.eks. natriumhydrid eller n-butyllithium ved forhøjet temperatur, f.eks. 80-110°C, og l-(3--halogenpropyl)-4-(p-fluorbenzoyl)piperidinen omsættes med den metalliserede phenothiazin.
Forbindelserne fremstillet som angivet ovenfor isoleres fra reaktionsblandingen på passende måde, f.eks. ved destillation, chromatografering, krystallisation eller ved omdannelse til et egnet syreadditionssalt.
Fremgangsmåden ifølge opfindelsen illustreres nærmere i de følgende eksempler, hvor eksempel A belyser fremstillingen af en udgangsforbindelse med formlen (II), som anvendes i de efterfølgende eksempler 1-4.
Eksempel A
4-(p-Fluorbenzoyl)-1-(3-hydroxypropyl)piperidin
En blanding af 24,3 g (0,1 mol) 4-(p-fluorbenzoyl)piperidin--hydrochlorid, 12,5 g (0,125 mol) 3-chlorpropanol og 42,0 g (0,5 mol) natriumhydrogencarbonat i 500 ml n-butanol omrøres under tilbagesvaling i 15 timer. Ved hjælp af tyndtlagschromatografi konstateres ufuldstændig omsætning, og der tilsættes yderligere 3,0 g (0,025 mol) 3-chlorpropanol, hvorefter omsætningen fortsættes i 3 timer. Reak- 146258 5 tionsblandingen afkøles og filtreres, filtratet koncentreres ved formindsket tryk, og remanensolien krystalliseres ved triturering i iso-propylether. Der fås 23 g (87%) gulbrunt fast stof med smp. 107-109°C.
2) 4-(p-Fluorbenzoyl)-1-(3-chlorpropyl)piperidin 38,7 g (CV376 mol) thionylchlorid sættes dråbevis til en omrørt opløsning af 43,1 g (0,163 mol) 4-(p-fluorbenzoyl)-1-(3-hydroxypropyl)-piperidin i 400 ml chloroform ved stuetemperatur. Efter endt tilsætning omrøres reaktionsblandingen ved stuetemperatur i yderligere 16 timer. Dérpå afkøles blandingen, og der tilsættes dråbevis 125 ml 6 N natriumhydroxidopløsning. Chloroformopløsningen isoleres, vaskes med vand og tørres over magnesiumsulfat. Ved fjernelse af opløsningsmidlet fås 42,7 g råprodukt (92%'s udbytte), der krystalliserer ved afkøling. Ved omkrystallisation af isooctan fås 25,3 g rent stof med smp. 66,5-68,5°C.
Analyse for C^H^gNOFCl: C% H% N%
Beregnet 63,49 6,75 4,94
Fundet 63,49 6,86 4,81
Eksempel 1 10—[3-[4-(p-Fluorbenzoy1)piperidiny1]propyl} phenothiazin-fumarat-hydrat-_(1:4)_
En blanding af 4,9 g (0,025 mol) phenothiazin, 7,5 g (0,0265 mol) 1-(3-chlorpropyl)-4-(p-fluorbenzoyl)piperidin og 8,4 g (0,15 mol) knuste kaliumhydroxidperler omrøres i 200 ml tør toluen under tilbagesvaling i 20 timer. Den afkølede reaktionsblanding filtreres, og filtratet koncentreres under formindsket tryk. Remanensolien underkastes tyndtlagschromatografi og viser sig at være en blanding af produktet og reaktanterne. Delvis rensning opnås ved at opløse olien i ether, hvorefter der tilsættes etherisk saltsyre til dannelse af hydrochlo-ridsaltet. Saltet krystalliserer imidlertid ikke og omdannes til den fri base. Den fri base (4,5 g,40,5% udbytte) behandles med 1 ækvivalent fumarsyre til dannelse af fumaratsaltet. Ved omkrystallisation af en blanding af methanol og isopropylether fås 4,7 g gulbrunt fast stof med smp. 190-192°C.
Analyse for C29H39N20FS.C4H404.l/4 H20: C% H% N%
Beregnet 65,65 5,60 4,94
Fundet 65,82 5,60 4,93 6 146258
Eksempel 2 2-Trifluormethyl-10- {3-[4-(p-fluorbenzoyl)piperidinyl]propyl}phenothia-_ zin-fumarat_._~
En blanding af 8,6 g (0,032 mol) 2-trifluormethylphenothiazin, 10,0 g (0,035 mol) 1-(3-chlorpropyl)-4-(p-fluorbenzoyl)piperidin og 11,2 g (0,2 mol) knuste kaliumhydroxidperler omrøres i 300 ml tør toluen under tilbagesvaling i 20 timer. Den afkølede reaktionsblanding filtreres, filtratet vaskes med vand, tørres over magnesiumsulfat og koncentreres, hvorved fås 14,2 g råprodukt (88% udbytte). Råproduktet behandles ved overskud af fumarsyre i en blanding af methanol og isopropylether, hvorved fås 20,5 g af fumaratsaltet. Ved omkrystallisation af en blanding af isopropanol og isopropylether fås 12,2 g fumaratsalt med smp. 158,5-161°C.
Analyse for C32H3oN2®5SF4: C% H% N%
Beregnet 60,94 4,80 4,44
Fundet 60,77 4,88 4,37
Eksempel 3 2-Acetyl-10-[3-(4-p-fluorbenzoylpiperidinyl)propyl]phenothiazin-difuma-_rat-sesquihydrat_
En blanding af 7,7 g (0,032 mol) 2-acetylphenothiazin, 10,0 g (0,0353 mol) 1-(3-chlorpropyl)-4-(p-fluorbenzoyl)piperidin og 14,0 g (0,25 mol) knuste kaliumhydroxidperler omrøres i 300 ml tør toluen under tilbagesvaling i 24 timer. Tyndtlagschromatografi viser ufuldstændig reaktion. Til reaktionsblandingen sættes yderligere 10,0 g (0,0353 mol) 1-(3-chlorpropyl)-4-(p-fluorbenzoyl)piperidin i 75 ml tør toluen, og der tilbagesvales i yderligere 24 timer. Den afkølede reaktionsblanding vaskes med vand, tørres over magnesiumsulfat og koncentreres, hvorved fås 23,2 g råprodukt. Ved chromatografering på 400 g magnesiumsilicat fås 6 g urent produkt. Urenhederne fjernes ved molekulardestillation, hvorved produktet fås som remanens. Remanensen vejer 4,0 g (24,5% udbytte). Den fri base behandles med to ækvivalenter fumarsyre i methanol. Methanolen fordampes, og den faste remanens omkrystalliseres af en blanding af acetone og petroleumsether (30-60°C), smp. 146-149°C.
Analyse for C^H^O^S^s C% H% N%
Beregnet 59,43 5,39 3,75
Fundet 59,57 5,06 3,39 7 1Λ6258
Eksempel 4 2-Chlor-lO^- [4- (p-fluorbenzoyl) piperidiny 1 ]propyl} phenothiazin-hydro-_chlorid-hydrat (1:4)_
En blanding af 9,4 g (0,04 mol) 2-chlorphenothiazin, 12,0 g (0,0425 mol) 4-(p-fluorbenzoyl)-1-(3-chlorpropyl)-piperidin og 14,0 g (0,25 mol) knuste kaliumhydroxidperler i 300 ml tør toluen omrøres og tilbagesvales i 36 timer. Efter afkøling isoleres toluenopløsningen fra det uorganiske materiale ved dekantering, og toluenopløsningen koncentreres, hvorved fås 17,5 g råprodukt. Dette chroma-tograferes på en søjle af 260 g magnesiumsilicat, hvorved fås 12,0 g rimeligt rent produkt (63% udbytte). Ved molekulardestillation ved 250°C fås 6,7 g af et gult glasagtigt stof. Olien opløses i ether og behandles med etherisk saltsyre, hvorved fås et hygroskopisk hydro-chloridsalt. Saltet tritureres i kogende isopropylether og omkrystalliseres af en blanding af isopropylether og chloroform. Ved NMR- og massespektralanalyse viser det sig, at saltet er solvatiseret, og det tørres ved 120°C i en vakuumovn. Saltet med smp. 204-206°C analyseres som 1/4-hydratet.
Analyse for C27H28N2OFC12S · 1/4 1^0: C% H% N%
Beregnet 62,13 5,31 5,37
Fundet 62,04 5,23 5,40
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US59121675A | 1975-06-27 | 1975-06-27 | |
| US59121675 | 1975-06-27 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK274076A DK274076A (da) | 1976-12-28 |
| DK146258B true DK146258B (da) | 1983-08-15 |
| DK146258C DK146258C (da) | 1984-01-23 |
Family
ID=24365576
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK274076A DK146258C (da) | 1975-06-27 | 1976-06-18 | Analogifremgangsmaade til fremstilling af 10-(3-(4-(p-fluorbenzoyl)piperidinyl)propyl)phenothiaziner eller syreadditionssalte deraf |
Country Status (7)
| Country | Link |
|---|---|
| AU (1) | AU503576B2 (da) |
| BE (1) | BE843281A (da) |
| BR (1) | BR7604100A (da) |
| DK (1) | DK146258C (da) |
| IE (1) | IE44487B1 (da) |
| NZ (1) | NZ181291A (da) |
| ZA (1) | ZA763813B (da) |
-
1976
- 1976-06-15 AU AU14890/76A patent/AU503576B2/en not_active Expired
- 1976-06-18 DK DK274076A patent/DK146258C/da not_active IP Right Cessation
- 1976-06-22 IE IE1357/76A patent/IE44487B1/en not_active IP Right Cessation
- 1976-06-23 BE BE168200A patent/BE843281A/fr not_active IP Right Cessation
- 1976-06-24 BR BR7604100A patent/BR7604100A/pt unknown
- 1976-06-25 ZA ZA763813A patent/ZA763813B/xx unknown
- 1976-06-25 NZ NZ181291A patent/NZ181291A/xx unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AU503576B2 (en) | 1979-09-13 |
| BR7604100A (pt) | 1977-07-26 |
| ZA763813B (en) | 1977-05-25 |
| DK146258C (da) | 1984-01-23 |
| IE44487B1 (en) | 1981-12-16 |
| IE44487L (en) | 1976-12-27 |
| BE843281A (fr) | 1976-10-18 |
| AU1489076A (en) | 1977-12-22 |
| DK274076A (da) | 1976-12-28 |
| NZ181291A (en) | 1978-06-20 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PBP | Patent lapsed |