DE1283241B - N- (ªÏ-phenoxyalkyl) -4-alkoxy-4-phenyl-piperidines, their acid addition salts and processes for their preparation - Google Patents
N- (ªÏ-phenoxyalkyl) -4-alkoxy-4-phenyl-piperidines, their acid addition salts and processes for their preparationInfo
- Publication number
- DE1283241B DE1283241B DEN21349A DEN0021349A DE1283241B DE 1283241 B DE1283241 B DE 1283241B DE N21349 A DEN21349 A DE N21349A DE N0021349 A DEN0021349 A DE N0021349A DE 1283241 B DE1283241 B DE 1283241B
- Authority
- DE
- Germany
- Prior art keywords
- parts
- general formula
- phenylpiperidine
- hydrochloride
- mixture
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000002253 acid Substances 0.000 title claims description 7
- 150000003839 salts Chemical class 0.000 title claims description 7
- 238000000034 method Methods 0.000 title claims description 5
- 238000002360 preparation method Methods 0.000 title claims description 4
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 27
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 17
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- 239000000706 filtrate Substances 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- 239000011541 reaction mixture Substances 0.000 claims description 8
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 7
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 7
- 230000008018 melting Effects 0.000 claims description 7
- 238000002844 melting Methods 0.000 claims description 7
- 239000002244 precipitate Substances 0.000 claims description 7
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 6
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- 239000007789 gas Substances 0.000 claims description 5
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 4
- GMBVQDPSOSICDP-UHFFFAOYSA-N 4-ethoxy-4-phenylpiperidine Chemical compound C=1C=CC=CC=1C1(OCC)CCNCC1 GMBVQDPSOSICDP-UHFFFAOYSA-N 0.000 claims description 3
- ODLGSHHBBCINCC-UHFFFAOYSA-N 4-phenyl-4-propoxypiperidine Chemical compound C=1C=CC=CC=1C1(OCCC)CCNCC1 ODLGSHHBBCINCC-UHFFFAOYSA-N 0.000 claims description 3
- OCBFFGCSTGGPSQ-UHFFFAOYSA-N [CH2]CC Chemical group [CH2]CC OCBFFGCSTGGPSQ-UHFFFAOYSA-N 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 1
- 229910052736 halogen Inorganic materials 0.000 claims 1
- 238000010992 reflux Methods 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 11
- 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 4
- 241000699670 Mus sp. Species 0.000 description 4
- CWRVKFFCRWGWCS-UHFFFAOYSA-N Pentrazole Chemical compound C1CCCCC2=NN=NN21 CWRVKFFCRWGWCS-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- JJFOBACUIRKUPN-UHFFFAOYSA-N 2-bromoethoxybenzene Chemical compound BrCCOC1=CC=CC=C1 JJFOBACUIRKUPN-UHFFFAOYSA-N 0.000 description 3
- AZXLOLRTEJEZHJ-UHFFFAOYSA-N 3-chloropropoxybenzene Chemical compound ClCCCOC1=CC=CC=C1 AZXLOLRTEJEZHJ-UHFFFAOYSA-N 0.000 description 3
- PPXQKVKQJDWZFN-UHFFFAOYSA-N 4-methoxy-4-phenylpiperidin-1-ium;chloride Chemical compound Cl.C=1C=CC=CC=1C1(OC)CCNCC1 PPXQKVKQJDWZFN-UHFFFAOYSA-N 0.000 description 3
- 206010010904 Convulsion Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 3
- -1 1- (γ-phenoxypropyl) -4-propoxy-4-phenylpiperidine hydrochloride Chemical compound 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 230000001773 anti-convulsant effect Effects 0.000 description 2
- 239000001961 anticonvulsive agent Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- GEVPUGOOGXGPIO-UHFFFAOYSA-N oxalic acid;dihydrate Chemical compound O.O.OC(=O)C(O)=O GEVPUGOOGXGPIO-UHFFFAOYSA-N 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- JKXCPAVECBFBOC-UHFFFAOYSA-N 4-chlorobutoxybenzene Chemical compound ClCCCCOC1=CC=CC=C1 JKXCPAVECBFBOC-UHFFFAOYSA-N 0.000 description 1
- JLVUUXKHLHNXJM-UHFFFAOYSA-N 4-ethoxy-4-phenylpiperidin-1-ium;chloride Chemical compound [Cl-].C=1C=CC=CC=1C1(OCC)CC[NH2+]CC1 JLVUUXKHLHNXJM-UHFFFAOYSA-N 0.000 description 1
- WVYWICLMDOOCFB-UHFFFAOYSA-N 4-methyl-2-pentanol Chemical compound CC(C)CC(C)O WVYWICLMDOOCFB-UHFFFAOYSA-N 0.000 description 1
- 101100356682 Caenorhabditis elegans rho-1 gene Proteins 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 244000223760 Cinnamomum zeylanicum Species 0.000 description 1
- 235000005979 Citrus limon Nutrition 0.000 description 1
- 244000131522 Citrus pyriformis Species 0.000 description 1
- 150000000996 L-ascorbic acids Chemical class 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000007101 Muscle Cramp Diseases 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000000573 anti-seizure effect Effects 0.000 description 1
- 229940125681 anticonvulsant agent Drugs 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 235000017803 cinnamon Nutrition 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229910000043 hydrogen iodide Inorganic materials 0.000 description 1
- UPZJLQCUYUTZIE-UHFFFAOYSA-N hydron;4-phenylpiperidine;chloride Chemical compound Cl.C1CNCCC1C1=CC=CC=C1 UPZJLQCUYUTZIE-UHFFFAOYSA-N 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 229960002695 phenobarbital Drugs 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000005303 weighing Methods 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
- C07D211/20—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 singly bound oxygen or sulphur atoms
- C07D211/22—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 singly bound oxygen or sulphur atoms by oxygen atoms
-
- 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
-
- 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
- C07D211/36—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 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
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
-
- 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
- C07D211/36—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 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
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
Description
DEUTSCHESGERMAN
PATENTAMTPATENT OFFICE
AUSLEGESCHRIFTEDITORIAL
Int. Cl.:Int. Cl .:
Deutsche Kl.:German class:
Nummer:
Aktenzeichen:
Anmeldetag:
Auslegetag:Number:
File number:
Registration date:
Display day:
C07dC07d
AOIk ·AOIk
12 ρ-1/01
30 h-2/3612 ρ -1/01
30 h-2/36
P 12 83 241.6-44 (N 21349)P 12 83 241.6-44 (N 21349)
20. März 1962March 20, 1962
21. November 1968November 21, 1968
Gegenstand der Erfindung sind N-(r»-Phenoxyalkyl)-4-alkoxy-4-phenylpiperidine der allgemeinen Formel IThe invention relates to N- (r »-phenoxyalkyl) -4-alkoxy-4-phenylpiperidines of the general formula I.
in der R einen Methyl-, Äthyl- oder Propylrest und (0 // eine der Zahlen 2, 3 oder 4 bedeutet, deren Säureadditionssalze sowie ein Verfahren zu ihrer Herstellung. in which R is a methyl, ethyl or propyl radical and (0 // is one of the numbers 2, 3 or 4, their acid addition salts and a process for their preparation.
Diese Verbindungen sind wirksame Hemmstoffe für durch Pentamethylentetrazol hervorgerufene ,5 Krämpfe. Diese Wirksamkeit ist unerwartet, da die entsprechenden Alkohole, nämlich die N-(fj-Phenoxyalkyl)-4-phenylpiperidin-4-ole, diese Antikrampfwirksamkeit nicht besitzen.These compounds are potent inhibitors of induced pentamethylenetetrazole, 5 cramps. This activity is unexpected because the corresponding alcohols, namely the N- (fj-phenoxyalkyl) -4-phenylpiperidin-4-ols, do not have this anti-seizure activity.
Gegenüberstellung der therapeutischen Eigenschäften der erfindungsgemäßen Verbindungen der allgemeinen Formel IComparison of the therapeutic properties of the compounds of the general formula I according to the invention
O-(CH2),,O- (CH 2 ) ,,
mit der Vergleichssubstanz 5-Phenyl-5-äthylbarbitursäure. with the comparison substance 5-phenyl-5-ethylbarbituric acid.
AlkylLower
Alkyl
tetrazohest:
ED51, in
mg kg s. c.Pcntamothylene
tetrazohest:
ED 51 , in
mg kg sc
bei MäusenToxicity
in mice
sches
VerhältnisTherapeuti
sches
relationship
5-phenyl-
barbitursäure
(Phenobarbital)5-ethyl
5-phenyl-
barbituric acid
(Phenobarbital)
N-(w-Phenoxyalkyl)-4-alkoxy-4-phenylpiperidine,
ihre Säureadditionssalze sowie
Verfahren zu ihrer HerstellungN- (w-phenoxyalkyl) -4-alkoxy-4-phenylpiperidines, their acid addition salts and
Process for their manufacture
Anmelder:Applicant:
Janssen Pharmaceutica,Janssen Pharmaceutica,
Naamlozevennootschap, Beerse (Belgien)Naamlozevennootschap, Beerse (Belgium)
Vertreter:Representative:
Dipl.-Chem. Dr. Arthur UllrichDipl.-Chem. Dr. Arthur Ullrich
und Dipl.-Chem. Dr. Thurmod Ullrich,and Dipl.-Chem. Dr. Thurmod Ullrich,
Patentanwälte, 6900 HeidelbergPatent Attorneys, 6900 Heidelberg
Als Erfinder benannt:Named as inventor:
Paul Adriaan Jan Janssen, Vosselaar, TurnhoutPaul Adriaan Jan Janssen, Vosselaar, Turnhout
(Belgien)(Belgium)
Beanspruchte Priorität:Claimed priority:
V. St. v. Amerika vom 22. März 1961 (97 424) -V. St. v. America March 22, 1961 (97 424) -
*l Höchste getestete Dosis ohne tödliche Wirkung.* l Highest dose tested with no lethal effect.
TestbeschreibungTest description
(Durch Pentamethylentetrazol erzeugte
Anfälle bei Mäusen)(Generated by pentamethylenetetrazole
Seizures in mice)
Es wurden erwachsene Albinomäuse von- 18 bis g Körpergewicht verwendet, um die krampfhemmende Wirkung der erfindungsgemäßen Verbindungen zu erproben.Adult albino mice weighing -18 to g. Body weight were used to give the anticonvulsant To test the effect of the compounds according to the invention.
Die krampfartigen Anfälle wurden durch intravenöse Einspritzung einer 5°/oigen wäßrigen Lösung von Pentamethylentetrazol bei einer Geschwindigkeit von 0,0625 ml je 10 Sekunden durch die Schwanzvene ausgelöst.The seizures were cured by intravenous injection of a 5% aqueous solution of pentamethylenetetrazole at a rate of 0.0625 ml per 10 seconds through the tail vein triggered.
Die zu prüfende erfindungsgemäße Verbindung wurde auf subkutanem Wege (0,1 ml einer wäßrigen Lösung auf 10 g Körpergewicht) 1 Stunde vor der Verabfolgung des krampfauslösenden Mittels an die Mäuse verabreicht.The compound according to the invention to be tested was administered subcutaneously (0.1 ml of an aqueous Solution to 10 g body weight) 1 hour before the administration of the anticonvulsant agent to the Administered to mice.
Die krampfhemmende Wirkung jeder Verbindung wurde statistisch (P <0,05) unter Anwendung des »Kolmogorov-Smirnov-Zweiprobentests« (Siegel, S., Nonparametric Statistics for the Behavioural Sciences, 1956, S. 127) zusammengestellt. Die ED.50-Werte geben die Dosen (in mg/kg) an, die 50% der Tiere gegen die durch Pentamethylentetrazol erzeugten Anfälle schützen. (Literatur: Chen, G. and Bohner, B., J. Pharmacol., 117, 142 [1956].)The anticonvulsant effect of each compound was statistically (P <0.05) using the "Kolmogorov-Smirnov two-sample tests" (seal, S., Nonparametric Statistics for the Behavioral Sciences, 1956, p. 127). The ED.50 values indicate the doses (in mg / kg) produced by 50% of the animals against those produced by pentamethylenetetrazole Protecting seizures. (Literature: Chen, G. and Bohner, B., J. Pharmacol., 117, 142 [1956].)
809 638/1707809 638/1707
Die erfindungsgemäßen basischen Verbindungen bilden nichttoxische Säureadditionssalze mit einer Anzahl organischer und anorganischer Säuren, wie Schwefel-, Phosphor-, Chlorwasserstoff-, Bromwasserstoff-, Jodwasserstoff-, Sulfamin-, Citronen-, Milch-, Malein-, Äpfel-, Bernstein-, Wein-, Zimt-,', Essig-, Benzoe-, Glukon- und Ascorbinsäure.The basic compounds of the invention form non-toxic acid addition salts with a Number of organic and inorganic acids, such as sulfur, phosphorus, hydrogen chloride, hydrogen bromide, Hydrogen iodide, sulfamine, lemon, milk, male, apple, amber, wine, cinnamon, ', Acetic, benzoic, gluconic and ascorbic acids.
Die erfindungsgemäßen Verbindungen können durch Kondensation des entsprechenden w-Phenoxyalkylhalogenids mit einem 4-Alkoxy-4-phenylpiperidin hergestellt werden. Die Reaktion wird in einem geeigneten inerten Lösungsmittel, wie z. B. 4-Methyl-2-pentanol oder Toluol, ausgeführt. Die Reaktion kann durch Erhitzen der Mischung bei atmosphärischem Druck oder in zugeschmolzenem Rohr beschleunigt werden.The compounds according to the invention can be prepared by condensation of the corresponding w-phenoxyalkyl halide with a 4-alkoxy-4-phenylpiperidine. The response is in a suitable inert solvent, such as. B. 4-methyl-2-pentanol or toluene performed. the Reaction can be carried out by heating the mixture at atmospheric pressure or in sealed Tube to be accelerated.
Die Herstellung der neuen Verbindungen wird an folgenden Beispielen erläutert.The preparation of the new compounds is illustrated by the following examples.
Eine wäßrige Lösung von 6,83 Teilen 4-Methoxy-4-phenylpiperidin-hydrochlorid wird alkalisch gemacht und mit Benzol extrahiert. Nach dem Abdampfen des Lösungsmittels wird der Rückstand in 120 Teilen 4 - Methyl - 2 - pentanon zusammen mit 8,4 Teilen l-Brom-2-phenoxyäthan, 9,5 Teilen Natriumcarbonat und 0,1 Teil Kaliumiodid gelöst. Die Mischung wird 40 Stunden unter Rückfluß gehalten und heiß filtriert. Das Lösungsmittel wird aus dem Filtrat abgedampft und der ölige Rückstand in 400 Teilen wasserfreiem Diisopropyläther gelöst. Durch Einleiten von Chlorwasserstoffgas in die ätherische Lösung wird das Hydrochlorid niedergeschlagen, das abfiltriert und aus 2-Propanol umkristallisiert wird. Man erhält so das l-(^-Phenoxyäthyl) - 4 - methoxy -A- phenylpiperidin - hydrochlorid. Schmelzpunkt 207,5 bis 208,20C. Die freie Base dieser Verbindung hat die FormelAn aqueous solution of 6.83 parts of 4-methoxy-4-phenylpiperidine hydrochloride is made alkaline and extracted with benzene. After evaporation of the solvent, the residue is dissolved in 120 parts of 4 - methyl - 2 - pentanone together with 8.4 parts of 1-bromo-2-phenoxyethane, 9.5 parts of sodium carbonate and 0.1 part of potassium iodide. The mixture is refluxed for 40 hours and filtered hot. The solvent is evaporated from the filtrate and the oily residue is dissolved in 400 parts of anhydrous diisopropyl ether. By introducing hydrogen chloride gas into the ethereal solution, the hydrochloride is precipitated, which is filtered off and recrystallized from 2-propanol. Is obtained as the l - (^ - phenoxyethyl) - 4 - methoxy -A- phenylpiperidin - hydrochloride. Melting point 207.5 to 208.2 0 C. The free base of this compound has the formula
4-Methyl-2-pentanon wird gerührt und 50 Stunden unter Rückfluß gehalten. Die heiße Reaktionsmischung wird filtriert und das Lösungsmittel aus dem Filtrat abgedampft. Eine Lösung des Rückstands in 2-Propanol wird mit einer Lösung von 2,1 Teilen Oxalsäure-dihydrat in 300 Teilen 2-Propanol gemischt. Der sich bildende Niederschlag besteht aus l-(/?-Phenoxyäthyl)-4-propoxy-4-phenylpiperidin-oxalat, Schmelzpunkt 174 bis 176,4° C.4-methyl-2-pentanone is stirred and refluxed for 50 hours. The hot reaction mixture is filtered and the solvent is removed evaporated from the filtrate. A solution of the residue in 2-propanol is mixed with a solution of 2.1 parts of oxalic acid dihydrate mixed in 300 parts of 2-propanol. The precipitate that forms consists of l - (/? - phenoxyethyl) -4-propoxy-4-phenylpiperidine oxalate, Melting point 174 to 176.4 ° C.
B eisp iel 4Example 4
Aus' einer wäßrigen Lösung von 11,5 Teilen 4-Methoxy-4-phenylpiperidin-hydrochlorid wird die Base durch Alkalischmachen mit Natriumhydroxyd in Freiheit gesetzt. Die erhaltene Mischung wird mit Toluol extrahiert, das Lösungsmittel aus der Toluollösung abgedampft und der Rückstand in einem zugeschmolzenen Rohr mit 4,3 Teilen 1-Chlor-3-phenoxypropan und 0,1 Teil Kaliumiodid in 120 Teilen wasserfreiem Toluol 88 Stunden auf 1500C erhitzt. Die gekühlte Reaktionsmischung wird mit Wasser gewaschen und über Magnesiumsulfat getrocknet. Nach dem Abdampfen des Lösungsmittels wird der Rückstand in 32 Teilen Petroläther gelöst und 50 Teile 1 : 1 verdünnter Chlorwasserstoffsäure zugesetzt. Der sich bildende Niederschlag wird abfiltriert, aus Wasser umkristallisiert und stellt l-(y-Phenöxypropyl)-4-methoxy-4-phenylpiperidin-hydrochlorid vom Schmelzpunkt 219 bis 22O0C dar. Die freie Base dieses Produkts hat die FormelThe base is liberated from an aqueous solution of 11.5 parts of 4-methoxy-4-phenylpiperidine hydrochloride by making it alkaline with sodium hydroxide. The mixture obtained is extracted with toluene, the solvent from the toluene solution evaporated and the residue in a sealed tube with 4.3 parts of 1-chloro-3-phenoxypropane and 0.1 part of potassium iodide in 120 parts of anhydrous toluene, 88 hours at 150 0 C. heated. The cooled reaction mixture is washed with water and dried over magnesium sulfate. After evaporation of the solvent, the residue is dissolved in 32 parts of petroleum ether and 50 parts of 1: 1 dilute hydrochloric acid are added. The precipitate which forms is filtered off, recrystallised from water and provides l- (y-Phenöxypropyl) -4-methoxy-4-phenylpiperidine hydrochloride of melting point 219 to 22O 0 C. The free base of this product has the formula
OCH,OCH,
OCH, CH, CH, — NOCH, CH, CH, - N
OCH,OCH,
OCH2CH2 OCH 2 CH 2
Eine Mischung aus 8,04 Teilen l-Brom-2-phenoxyäthan, 7,2"Teilen 4-Äthoxy-4-phenylpiperidin, isoliert aus dem Hydrochlorid durch Verdampfen des Lösungsmittels aus der benzolischen Lösung einer wäßrigen alkalischen Lösung des Salzes, 10,6 Teilen Natriumcarbonat und 0,1 Teil Kaliumjodid in 280 Teilen 4-Methyl-2-pentanon wird gerührt und etwa 100 Stunden unter Rückfluß gehalten. Die Reaktionsmischüng wird heiß filtriert und das Lösungsmittel aus dem Filtrat abgedampft. Der ölige Rückstand wird in 560 Teilen Diisopropyläther gelöst und Chlorwasserstoffgas in diese Lösung eingeleitet. Das niedergeschlagene Hydrochlorid wird abfiltriert, aus Äthylacetat umkristallis'iert und stellt l-(ß- Phenoxyäthyl) - 4 - äthoxy - 4 - phenylpiperidinhydrochlorid vom Schmelzpunkt 147 bis 148 0C dar.A mixture of 8.04 parts of 1-bromo-2-phenoxyethane, 7.2 "parts of 4-ethoxy-4-phenylpiperidine, isolated from the hydrochloride by evaporation of the solvent from the benzene solution of an aqueous alkaline solution of the salt, 10.6 Parts of sodium carbonate and 0.1 part of potassium iodide in 280 parts of 4-methyl-2-pentanone are stirred and refluxed for about 100 hours. The reaction mixture is filtered hot and the solvent is evaporated from the filtrate. The oily residue is dissolved in 560 parts of diisopropyl ether and hydrogen chloride gas is introduced into this solution, the precipitated hydrochloride is filtered off, umkristallis'iert of ethyl acetate and is l- (.beta.-phenoxyethyl) -. 4 - ethoxy - 4 - phenylpiperidine hydrochloride of melting point 147-148 0 C represents.
B eispiel 3Example 3
Eine Mischung aus' 8,05 Teilen l-Brom-2-phenoxyäthan, 7,66 Teilen 4-Propoxy-4-phenylpiperidin, isoliert aus dem Hydrochlorid, 10,6 Teilen Natriumcarbonat und 0,1 Teil Kaliumiodid in 280 Teilen Eine Mischung aus 3,3 Teilen l-Chlor-3-phenoxypropan, 3,6 Teilen 4-Äthoxy-4-phenylpiperidin, isoliert aus dem Hydrochlorid, 5,3 Teilen Natriumcarbonat und 0,1 Teil Kaliumiodid in 280 Teilen 4-Methyl-2-pentanon wird gerührt und 50 Stunden unter Rückfluß gehalten. Die gekühlte Reaktionsmischung wird filtriert und das Lösungsmittel aus dem Filtrat abgedampft. Der Rückstand wird in 400 Teilen Diisopropyläther gelöst. Durch Einleiten von Chlorwasserstoffgas in die ätherische Lösung fällt das Hydrochlorid aus, das abfiltriert und aus Äthylacetat umkristallisiert wird. Man erhält so 1 - (y- Phenoxypropyl) - 4 - äthoxy - 4 - phenylpiperidinhydrochlorid, Schmelzpunkt 173 bis 174,50C.A mixture of 8.05 parts of 1-bromo-2-phenoxyethane, 7.66 parts of 4-propoxy-4-phenylpiperidine, isolated from the hydrochloride, 10.6 parts of sodium carbonate and 0.1 part of potassium iodide in 280 parts 3.3 parts of 1-chloro-3-phenoxypropane, 3.6 parts of 4-ethoxy-4-phenylpiperidine, isolated from the hydrochloride, 5.3 parts of sodium carbonate and 0.1 part of potassium iodide in 280 parts of 4-methyl-2-pentanone is stirred and refluxed for 50 hours. The cooled reaction mixture is filtered and the solvent is evaporated from the filtrate. The residue is dissolved in 400 parts of diisopropyl ether. By introducing hydrogen chloride gas into the ethereal solution, the hydrochloride precipitates, which is filtered off and recrystallized from ethyl acetate. One obtains 1 - (y-phenoxypropyl) - 4 - ethoxy - 4 - phenylpiperidine, mp 173 to 174.5 0 C.
B e i s ρ i e 1 6B e i s ρ i e 1 6
Eine Mischung aus 6,6 Teilen l-Chlor-3-phenoxypropan, 7,66 Teilen 4-Propoxy-4-phenylpiperidin, isoliert aus dem Hydrochlorid, 10,6 Teilen Natriumcarbonat und 0,1 Teil Kaliumiodid in 280 Teilen 4-Methyl-2-pentanon wird gerührt und 50-Stunden unter Rückfluß gehalten. Die Reaktionsmischung wird abfiltriert und das Lösungsmittel aus dem Filtrat abgedampft: Chlorwasserstoffgas wirdiri die ätherische Lösung des Rückstandes eingeleitet. Beim Stehenlassen fällt l-(y-Phenoxypropyl)-4-propoxy-4-phenylpiperidin-hydrochlorid aus der ätherischen Lösung aus. Das Produkt schmilzt bei 168,5 bis 169,50C.A mixture of 6.6 parts of 1-chloro-3-phenoxypropane, 7.66 parts of 4-propoxy-4-phenylpiperidine, isolated from the hydrochloride, 10.6 parts of sodium carbonate and 0.1 part of potassium iodide in 280 parts of 4-methyl 2-pentanone is stirred and refluxed for 50 hours. The reaction mixture is filtered off and the solvent is evaporated from the filtrate: hydrogen chloride gas is introduced into the ethereal solution of the residue. When left to stand, 1- (γ-phenoxypropyl) -4-propoxy-4-phenylpiperidine hydrochloride precipitates from the ethereal solution. The product melts at 168.5 to 169.5 0 C.
Aus 11,5 Teilen 4 - Methoxy - 4 - phenylpiperidinhydrochlorid wird die Base gemäß Beispiel 4 in Freiheit gesetzt. Die rohe Base wird mit 4,6 Teilen 1 -Chlor-4-phenoxybutan, 0,1 Teil Kaliumiodid und 120 Teilen wasserfreiem Toluol gemischt und in einem zugeschmolzenen Rohr 92 Stunden auf 1500C erhitzt. Die gekühlte Reaktionsmischung wird mit Wasser gewaschen und das organische Lösungsmittel abgedampft. Der Rückstand wird mit 82 Teilen Petroläther behandelt und 50 Teile 1 : 1 verdünnter Chlorwasserstoffsäure zugesetzt. Der ausfallende Niederschlag wird abfiltriert, aus Wasser umkristallisiert und stellt 1 - (<) - Phenoxybutyl) - 4 - methoxy-· 4-phenylpiperidin-hydrochlorid vom Schmelzpunkt 196 bis 1970C dar. Die freie Base dieser Verbindung hat die FormelThe base according to Example 4 is liberated from 11.5 parts of 4 - methoxy - 4 - phenylpiperidine hydrochloride. The crude base is mixed with 4.6 parts of 1-chloro-4-phenoxybutane, 0.1 part of potassium iodide and 120 parts of anhydrous toluene and heated to 150 ° C. for 92 hours in a sealed tube. The cooled reaction mixture is washed with water and the organic solvent is evaporated. The residue is treated with 82 parts of petroleum ether and 50 parts of 1: 1 dilute hydrochloric acid are added. The precipitate is filtered off, recrystallised from water and provides 1 - (<) - phenoxybutyl) - 4 -. Methoxy- · 4-phenylpiperidine hydrochloride of melting point 196-197 0 C represents The free base of this compound has the formula
OCH2CH2CH2CH2 — NOCH 2 CH 2 CH 2 CH 2 -N
carbonat und 0,1 Teil Kaliumjodid in 280 Teilen 4-Methyl-2-pentanon wird gerührt und 50 Stunden unter Rückfluß gehalten. Die heiße Reaktionsmischung wird filtriert und das Lösungsmittel aus dem Filtrat abgedampft. Zu einer Lösung des Rückstandes in 2-Propanol wird eine Lösung von 3,5 Teilen Oxalsäure-dihydrat in 320 Teilen 2-Propanol zugesetzt. Beim Stehen bei Raumtemperatur fällt - (() - Phenoxybutyl) - 4 - propoxy- 4- phenylpiperidinoxalat vom Schmelzpunkt 191,8 bis 192,6°C aus.carbonate and 0.1 part of potassium iodide in 280 parts of 4-methyl-2-pentanone is stirred and refluxed for 50 hours. The hot reaction mixture is filtered and the solvent is evaporated from the filtrate. A solution of 3.5 parts of oxalic acid dihydrate in 320 parts of 2-propanol is added to a solution of the residue in 2-propanol. When standing at room temperature, - ( () - phenoxybutyl) - 4 - propoxy- 4-phenylpiperidine oxalate with a melting point of 191.8 to 192.6 ° C. precipitates.
Claims (3)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US1283241XA | 1961-03-22 | 1961-03-22 |
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| Publication Number | Publication Date |
|---|---|
| DE1283241B true DE1283241B (en) | 1968-11-21 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DEN21349A Pending DE1283241B (en) | 1961-03-22 | 1962-03-20 | N- (ªÏ-phenoxyalkyl) -4-alkoxy-4-phenyl-piperidines, their acid addition salts and processes for their preparation |
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| Country | Link |
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| DE (1) | DE1283241B (en) |
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1962
- 1962-03-20 DE DEN21349A patent/DE1283241B/en active Pending
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