DE1595863B2 - 4-PIPERIDINOACETYL-3,4-DIHYDRO (2H) -1,4-BENZOXAZINE AND THE METHOD FOR PREPARING IT - Google Patents
4-PIPERIDINOACETYL-3,4-DIHYDRO (2H) -1,4-BENZOXAZINE AND THE METHOD FOR PREPARING ITInfo
- Publication number
- DE1595863B2 DE1595863B2 DE1966K0060001 DEK0060001A DE1595863B2 DE 1595863 B2 DE1595863 B2 DE 1595863B2 DE 1966K0060001 DE1966K0060001 DE 1966K0060001 DE K0060001 A DEK0060001 A DE K0060001A DE 1595863 B2 DE1595863 B2 DE 1595863B2
- Authority
- DE
- Germany
- Prior art keywords
- dihydro
- benzoxazine
- piperidinoacetyl
- preparing
- new compound
- 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.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims description 7
- OEFADKPKXPNUFW-UHFFFAOYSA-N 1-(2,3-dihydro-1,4-benzoxazin-4-yl)-2-piperidin-1-ylethanone Chemical compound C1COC2=CC=CC=C2N1C(=O)CN1CCCCC1 OEFADKPKXPNUFW-UHFFFAOYSA-N 0.000 title claims 2
- QRAOZQGIUIDZQZ-UHFFFAOYSA-N 4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1,4-benzoxazine Chemical compound C=1C=C2N(C)CCOC2=CC=1B1OC(C)(C)C(C)(C)O1 QRAOZQGIUIDZQZ-UHFFFAOYSA-N 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 7
- YRLORWPBJZEGBX-UHFFFAOYSA-N 3,4-dihydro-2h-1,4-benzoxazine Chemical compound C1=CC=C2NCCOC2=C1 YRLORWPBJZEGBX-UHFFFAOYSA-N 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 8
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 6
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 6
- 230000000954 anitussive effect Effects 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 206010011224 Cough Diseases 0.000 description 4
- 230000009471 action Effects 0.000 description 4
- 241000700198 Cavia Species 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000000202 analgesic effect Effects 0.000 description 3
- 229940124584 antitussives Drugs 0.000 description 3
- MAFMQEKGGFWBAB-UHFFFAOYSA-N benzonatate Chemical compound CCCCNC1=CC=C(C(=O)OCCOCCOCCOCCOCCOCCOCCOCCOCCOC)C=C1 MAFMQEKGGFWBAB-UHFFFAOYSA-N 0.000 description 3
- 229960003789 benzonatate Drugs 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
- 229960004126 codeine Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000002848 endoanesthetic effect Effects 0.000 description 3
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 description 3
- 229960005181 morphine Drugs 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- RLFWWDJHLFCNIJ-UHFFFAOYSA-N Aminoantipyrine Natural products CN1C(C)=C(N)C(=O)N1C1=CC=CC=C1 RLFWWDJHLFCNIJ-UHFFFAOYSA-N 0.000 description 2
- RMMXTBMQSGEXHJ-UHFFFAOYSA-N Aminophenazone Chemical compound O=C1C(N(C)C)=C(C)N(C)N1C1=CC=CC=C1 RMMXTBMQSGEXHJ-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 229960000212 aminophenazone Drugs 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- PCHPORCSPXIHLZ-UHFFFAOYSA-N diphenhydramine hydrochloride Chemical compound [Cl-].C=1C=CC=CC=1C(OCC[NH+](C)C)C1=CC=CC=C1 PCHPORCSPXIHLZ-UHFFFAOYSA-N 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 229910000039 hydrogen halide Inorganic materials 0.000 description 2
- 239000012433 hydrogen halide Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- DKSZLDSPXIWGFO-BLOJGBSASA-N (4r,4ar,7s,7ar,12bs)-9-methoxy-3-methyl-2,4,4a,7,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-ol;phosphoric acid;hydrate Chemical compound O.OP(O)(O)=O.OP(O)(O)=O.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC DKSZLDSPXIWGFO-BLOJGBSASA-N 0.000 description 1
- PYFPGQMTFQFISA-UHFFFAOYSA-N 1-(3,4-dihydro-2h-1,4-benzoxazin-2-yl)ethanone Chemical compound C1=CC=C2OC(C(=O)C)CNC2=C1 PYFPGQMTFQFISA-UHFFFAOYSA-N 0.000 description 1
- DPXJXQYTQBUEMC-UHFFFAOYSA-N 2-chloro-1-(2,3-dihydro-1,4-benzoxazin-4-yl)ethanone Chemical compound C1=CC=C2N(C(=O)CCl)CCOC2=C1 DPXJXQYTQBUEMC-UHFFFAOYSA-N 0.000 description 1
- ROLMZTIHUMKEAI-UHFFFAOYSA-N 4,5-difluoro-2-hydroxybenzonitrile Chemical compound OC1=CC(F)=C(F)C=C1C#N ROLMZTIHUMKEAI-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- 241000251730 Chondrichthyes Species 0.000 description 1
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 1
- 206010038678 Respiratory depression Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 239000003434 antitussive agent Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229960004415 codeine phosphate Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- -1 haloacetyl halides Chemical class 0.000 description 1
- 230000004217 heart function Effects 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 210000003801 laryngeal nerve Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 210000000412 mechanoreceptor Anatomy 0.000 description 1
- 229940126601 medicinal product Drugs 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 108091008709 muscle spindles Proteins 0.000 description 1
- 230000003836 peripheral circulation Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 210000003504 pulmonary stretch receptor Anatomy 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 201000002932 second-degree atrioventricular block Diseases 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
- C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Description
(H)(H)
in welcher Hal ein Halogenatom bedeutet, in an sich bekannter Weise mit Piperidin in An- oder Abwesenheit halogenwasserstoffbindender Mittel umsetzt und, falls erwünscht, anschließend mit einer Säure in ein Salz überführt.in which Hal denotes a halogen atom, in a manner known per se with piperidine in an or Reacts the absence of hydrogen halide binding agent and, if desired, then with a Acid converted into a salt.
3. Arzneimittel, bestehend aus 4-Piperidinoacetyl-3,4-dihydro-(2 H)-l,4-benzoxazin oder dessen Salzen, in Verbindung mit üblichen Hilfs- und Trägerstoffen.3. Medicinal product consisting of 4-piperidinoacetyl-3,4-dihydro- (2 H) -l, 4-benzoxazine or its salts, in conjunction with the usual auxiliary and Carriers.
Gegenstand der Erfindung ist das 4-Piperidinoacetyl-3,4-dihydro-(2 H)-l,4-benzoxazin der Formel IThe invention relates to 4-piperidinoacetyl-3,4-dihydro- (2 H) -l, 4-benzoxazine of the formula I
(I)(I)
bzw. dessen Salze.or its salts.
Die neue Verbindung wird hergestellt, indem man am Stickstoffatom halogenacetyliertes 3,4-Dihydro-(2 H)-1,4-benzoxazin der allgemeinen Formel IIThe new compound is prepared by adding halogen-acetylated 3,4-dihydro- (2 H) -1,4-benzoxazine on the nitrogen atom of the general formula II
(H)(H)
in welcher Hai ein Halogenatom bedeutet, in an sich bekannter Weise mit Piperidin in An- oder Abwesenheit halogenwasserstoffbindender Mittel umsetzt und, falls erwünscht, anschließend mit einer Säure in ein Salz überführt. Vorzugsweise bedeutet Hai ein Chlor- oder Bromatom.in which Hai means a halogen atom, in a manner known per se with piperidine in the presence or absence Reacts hydrogen halide binding agent and, if desired, then with an acid into a salt convicted. Preferably shark means a chlorine or bromine atom.
Vorzugsweise wird ein Überschuß des eingesetzten Piperidins verwendet. Die Reaktion wird zweckmäßig in inerten Lösungsmitteln, vorzugsweise in Kohlenwasserstoffen wie Benzol oder Toluol, durchgeführt. Die Umsetzung erfolgt zwischen Raumtemperatur und Siedepunkt des verwendeten Lösungsmittels.An excess of the piperidine used is preferably used. The reaction becomes convenient carried out in inert solvents, preferably in hydrocarbons such as benzene or toluene. the The reaction takes place between room temperature and the boiling point of the solvent used.
4-HalogenacetyI-3,4-dihydro-(2 H)-l,4-benzoxazine der allgemeinen Formel II sind erhältlich durch Umsetzung von 3,4-Dihydro-(2 H)-l,4-benzoxazin mit Halogenacetylhalogeniden.4-HaloacetyI-3,4-dihydro- (2 H) -1, 4-benzoxazines of the general formula II can be obtained from Reaction of 3,4-dihydro- (2 H) -l, 4-benzoxazine with haloacetyl halides.
Durch Umsetzung mit Säuren kann das Verfahrensprodukt schBeßlich in die betreffenden Salze übergeführt werden.The process product can finally be converted into the relevant salts by reaction with acids will.
ίο Die neue Verbindung besitzt wertvolle pharmakologische
Eigenschaften, insbesondere ausgeprägte analgetische sowie antitussive Wirksamkeit, und soll als
Arzneimittel Verwendung finden.
Die analgetische Wirkung wurde nach der Methode von Chen und Beckmann, Science 113 (1951),
S.631 (Hot-Plate-Methode), und nach Luckner und
M a g u η, Z. f. exp. Med. 117 (1951), S. 133 (Elektroreiz),
ermittelt. Es sind jeweils die Dosen in der Tabelle angegeben, nach deren Verabfolgung eine analgetische
Wirkung gerade nachweisbar ist. Die LD50 wurde nach L i t c h f i e 1 d und W i 1 c ο χ ο η, J. Pharmacol, exp.
Ther. 96 (1949), S. 99-113, bestimmt.ίο The new compound has valuable pharmacological properties, in particular pronounced analgesic and antitussive effectiveness, and is intended to be used as a medicament.
The analgesic effect was determined by the method of Chen and Beckmann, Science 113 (1951), p.631 (hot plate method), and according to Luckner and Magu η, Z. f. Exp. Med. 117 (1951), p. 133 (Elektroreiz). In each case the doses are given in the table, after the administration of which an analgesic effect can just be demonstrated. The LD50 was determined according to L itchfie 1 d and W i 1 c ο χ ο η, J. Pharmacol, exp. Ther. 96 (1949), pp. 99-113.
I III II
LD50 Hots.c. Plate
s.c.LD 50 Hots.c. Plate
sc
mg/kg mg/kgmg / kg mg / kg
I/III / II
III I/IIIIII I / III
Elektroreiz s.c.Elektroreiz s.c.
mg/kgmg / kg
4-Piperidino- 150 15
acetyl-3,4-dihydro-(2H)-1,4-benzoxazin
4-piperidino 150 15
acetyl-3,4-dihydro- (2H) -1,4-benzoxazine
Aminophenazon 350 60Aminophenazone 350 60
1010
5,5 275.5 27
6060
Wie sich aus der Tabelle ergibt, besitzt die neue Verbindung eine bessere therapeutische Breite als die bekannte Verbindung Aminophenazon.As can be seen from the table, the new compound has a better therapeutic index than that known compound aminophenazone.
Außerdem besitzt das 4-Piperidinoacetyl-3,4-dihydro-(2 H)-l,4-benzoxazin auffallend starke hustenhemmende Eigenschaften. So wurde mit Hilfe der Methode von G ö s s w a 1 d, Arzneimittel-Forschung 8 (1958), S. 550, und Friebel, Arch. exp. Path. Pharmak. 243 (1962), S. 162, nachgewiesen, daß die antitussive Wirkung der neuen Substanz am Meerschweinchen, bei dem der Husten durch ein Citronensäure-Aerosol ausgelöst wird, nach oraler Gabe die des Codeins übertrifft (vgl. Tabelle 2).In addition, the 4-piperidinoacetyl-3,4-dihydro- (2 H) -l, 4-benzoxazine strikingly strong antitussive properties. So with the help of the method of G ö s s w a 1 d, Arzneimittel -forschung 8 (1958), p. 550, and Friebel, Arch. exp. Path. Pharmac. 243 (1962), S. 162, demonstrated that the antitussive effect of the new substance on guinea pigs in which the Cough caused by a citric acid aerosol exceeds that of codeine after oral administration (see table 2).
Außerdem vermag die neue Verbindung — wie auch Codein — den durch elektrische Reizung des N. laryngeus der Katze nach Domenjoz, Arch. exp. Path. Pharmak. 215 (1952), S. 19, ausgelösten Husten zu bekämpfen.In addition, the new compound - like codeine - is able to generate electrical stimulation of the laryngeal nerve the cat after Domenjoz, Arch. exp. Path. Pharmac. 215 (1952), p. 19, induced cough fight.
Im Unterschied zu den Morphinkörpern zeigt die neue Verbindung nach intraduodenaler Applikation am Meerschweinchen starke endoanästhetische Wirkungen auf die Dehnungsrezeptoren der Lunge (Methode nach Bein und Bucher, HeIv. Physiol. Acta 15 [1957], S. 55), die wesentlich für die antitussive Eigenschaft sind (Bucher, Schweiz. Med. Wschr. 86 [1956], S.94). In dieser Wirkqualität ist das 4-Piperidinoacetyl-3,4-dihydro-(2 H)-l,4-benzoxazin dem ebenfalls nicht zu den Morphinkörpern zählenden synthetischen Hustenhemmer Benzonatate pharmakologisch vergleichbar. Bezüglich der Wirkdauer ist das 4-Piperidinoacetyl-3,4-dihydro-(2 H)-l,4-benzoxazin dem Benzonatate um mehr als das 8fache überlegen (vgl. Tabelle 3).In contrast to the morphine bodies, the new compound shows am after intraduodenal administration Guinea pigs have strong endo-anesthetic effects on the stretch receptors of the lungs (method according to Bein and Bucher, HeIv. Physiol. Acta 15 [1957], p. 55), which are essential for the antitussive property (Bucher, Switzerland. Med. Wschr. 86 [1956], p.94). In 4-Piperidinoacetyl-3,4-dihydro- (2 H) -l, 4-benzoxazine is also not one of this quality of action Synthetic cough suppressant benzonatate, which counts to morphine bodies, is pharmacologically comparable. In terms of the duration of action is the 4-piperidinoacetyl-3,4-dihydro- (2 H) -l, 4-benzoxazine the benzonatate by more than 8 times superior (see Table 3).
Ver
suchs
tierenumber of
Ver
search
animals
mg/kg
Wirkungdose
mg / kg
effect
male
dauer*)Maxi
times
duration*)
wirk-HaIb-
effective
denalintraduo-
denal
MeerschweinchensEndo anesthesia of the pulmonary stretch receptors
Guinea pig
tyl-3,4-dihydro-
(2H)-l,4-benz-
oxazin4-piperidinoace-
tyl-3,4-dihydro-
(2H) -l, 4-benz-
oxazine
*) Die Halbwirkdauer ist die Zeit für die Abnahme der Wirkung vom Maximum auf die Hälfte.*) The half-action period is the time for the effect to decrease from the maximum to half.
Die endoanästhetische Wirkung von 4-Piperidinoacetyl-3,4-dihydro-(2 H)-l,4-benzoxazin ist bereits 10 Minuten nach intraduodenaler Gabe statistisch signifikant nachweisbar. Ein derartig schneller Wirkungseintritt bei langer Dauer nach enteraler Applikation ist für die therapeutische Anwendung als außerordentlich günstig anzusehen.The endo-anesthetic effect of 4-piperidinoacetyl-3,4-dihydro- (2 H) -l, 4-benzoxazine is already statistically significant 10 minutes after intraduodenal administration verifiable. Such a rapid onset of action with a long duration after enteral application is for the therapeutic application to be regarded as extraordinarily favorable.
Für das Codein konnten selbst in sehr hohen Dosen (10 mg/kg i.v.) keine derartigen endoanästhetischen Eigenschaften nachgewiesen werden.For codeine, even in very high doses (10 mg / kg i.v.), no such endo-anesthetic was found Properties can be demonstrated.
Wegen der verschiedenartigen Wirkmechanismen bzw. Angriffspunkte ist für die neue Verbindung eine hohe Erfolgsquote und damit therapeutische Sicherheit bei der Behandlung von Hustenanfällen unterschiedlicher Genese zu erwarten. Die neue Verbindung unterscheidet sich somit von den bisher zur Behandlung von Hustenanfällen bekannten Stoffen.Because of the different mechanisms of action or points of attack, a high success rate and therefore therapeutic safety in the treatment of coughing attacks of various kinds Genesis to be expected. The new compound thus differs from the previous treatment substances known from coughing fits.
Die therapeutische Breite der neuen Substanz ist als günstig anzusehen. Im Vergleich zu Benzonatate zeigt sich das am Fehlen von AV-Blocks zweiten Grades bei hoher Dosierung am Meerschweinchen. Außerdem ergibt die eingehende Prüfung auf Nebenwirkungen an der Katze, daß das 4-Piperidinoacetyl-3,4-dihydro-(2 H)-l,4-benzoxazin die Herzfunktionen und den peripheren Kreislauf selbst nach intravenöser Zufuhr hoher Dosen nicht beeinträchtigt. Weiterhin führt die neue Verbindung nicht zu Atemdepression, die von hustenhemmenden Morphinkörpern bekannt ist.The therapeutic range of the new substance can be regarded as favorable. When compared to Benzonatate shows This is due to the lack of second-degree AV blocks at high doses in guinea pigs. aside from that A detailed test for side effects in cats shows that the 4-piperidinoacetyl-3,4-dihydro- (2 H) -l, 4-benzoxazine the cardiac functions and the peripheral circulation even after intravenous administration high doses not affected. Furthermore, the new compound does not lead to respiratory depression caused by antitussive morphine bodies.
4- Piperidinoacetyl-S^-dihydro-(2 H)-l,4-benzoxazin4- piperidinoacetyl-S ^ -dihydro- (2 H) -1,4-benzoxazine
21,2 g4-Chloracetyl-3,4-dihydro-(2 H)-l,4-benzoxazin (Fp. = 108-109° C, aus Alkohol), hergestellt durch Umsetzung von 3,4-Dihydro-(2 H)-l,4-benzoxazin mit Chloracetylchlorid, werden mit einer Lösung von 19 g Piperidin in 100 ecm Benzol zwei Stunden unter Rückfluß am Sieden gehalten. Nach dem Abkühlen wird die benzolische Lösung vom ausgeschiedenen Piperidinhydrochlorid abgesaugt und der Rückstand mehrmals mit verdünnter Salzsäure extrahiert. Aus den sauren Auszügen wird die Base durch Zugabe verdünnter Natronlauge ausgefällt und in Äther aufgenommen. Nach Trocknen über Kaliumcarbonat wird das Lösungsmittel abdestilliert. Man erhält 23 g Base (89% der Theorie) Kp.o.otmm 138-1400C; Fp. = 68-70°C; Hydrochlorid Fp. 216° C (aus Äthanol).21.2 g of 4-chloroacetyl-3,4-dihydro- (2 H) -1, 4-benzoxazine (melting point = 108-109 ° C., from alcohol), prepared by reacting 3,4-dihydro- (2 H ) -1, 4-benzoxazine with chloroacetyl chloride are kept at the boil for two hours under reflux with a solution of 19 g of piperidine in 100 ecm of benzene. After cooling, the benzene solution is filtered off with suction from the precipitated piperidine hydrochloride and the residue is extracted several times with dilute hydrochloric acid. The base is precipitated from the acidic extracts by adding dilute sodium hydroxide solution and taken up in ether. After drying over potassium carbonate, the solvent is distilled off. This gives 23 g base (89% of theory) Kp.o.otmm 138-140 0 C; Mp = 68-70 ° C; Hydrochloride m.p. 216 ° C (from ethanol).
Claims (2)
Priority Applications (9)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE1966K0060001 DE1595863C3 (en) | 1966-08-11 | 1966-08-11 | 4-Piperidinoacetyl-3,4-dihydro- (2H) -1, 4-benioxazine and process for its preparation |
| GB3576167A GB1137796A (en) | 1966-08-11 | 1967-08-03 | New substituted benzo-1,4-oxazines products, their use and methods of manufacture |
| CH1949669A CH501658A (en) | 1966-08-11 | 1967-08-03 | Process for the preparation of N-aminoacyl-3,4-dihydro- (2H) -1,4-benzoxazines |
| CH1949769A CH501659A (en) | 1966-08-11 | 1967-08-03 | Process for the preparation of N-aminoacyl-3,4-dihydro- (2H) -1,4-benzoxazines |
| CH1092867A CH502367A (en) | 1966-08-11 | 1967-08-03 | Process for the preparation of N-aminoacyl-3,4-dihydro- (2H) -1,4-benzoxazines |
| BE702360D BE702360A (en) | 1966-08-11 | 1967-08-07 | |
| US659302A US3547915A (en) | 1966-08-11 | 1967-08-09 | Substituted benzo-1,4-oxazines |
| FR117801A FR6572M (en) | 1966-08-11 | 1967-08-11 | |
| NL6711108A NL6711108A (en) | 1966-08-11 | 1967-08-11 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE1966K0060001 DE1595863C3 (en) | 1966-08-11 | 1966-08-11 | 4-Piperidinoacetyl-3,4-dihydro- (2H) -1, 4-benioxazine and process for its preparation |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DE1595863A1 DE1595863A1 (en) | 1970-02-12 |
| DE1595863B2 true DE1595863B2 (en) | 1977-07-14 |
| DE1595863C3 DE1595863C3 (en) | 1978-03-02 |
Family
ID=7229402
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE1966K0060001 Expired DE1595863C3 (en) | 1966-08-11 | 1966-08-11 | 4-Piperidinoacetyl-3,4-dihydro- (2H) -1, 4-benioxazine and process for its preparation |
Country Status (4)
| Country | Link |
|---|---|
| BE (1) | BE702360A (en) |
| DE (1) | DE1595863C3 (en) |
| GB (1) | GB1137796A (en) |
| NL (1) | NL6711108A (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4030906A (en) | 1974-09-27 | 1977-06-21 | Chevron Research Company | Herbicidal N-haloacetyl-1,2-dihydro-4H-3,1-benzoxazine |
| MX159669A (en) * | 1983-12-12 | 1989-08-02 | Ciba Geigy Ag | PROCEDURE FOR THE PREPARATION OF ACILAMIDE DERIVATIVES |
| JPS61215381A (en) * | 1985-03-22 | 1986-09-25 | Ube Ind Ltd | Benzoxazine derivatives and herbicides |
| DK0450097T3 (en) * | 1989-10-20 | 1996-05-20 | Otsuka Pharma Co Ltd | Benzoheterocyclic Compounds |
| US5420126A (en) * | 1989-11-08 | 1995-05-30 | Yamanouchi Pharmaceutical Co., Ltd. | 3,4-dihydro-2H-1,4-benzoxazine derivatives and pharmaceutical compositions containing the same |
| TW224941B (en) * | 1989-11-08 | 1994-06-11 | Yamanouchi Pharma Co Ltd | |
| US5496815A (en) * | 1990-02-08 | 1996-03-05 | Tanabe Seiyaku Co., Ltd. | Thiazine (or oxazine) derivatives and preparation thereof |
| US10087151B2 (en) | 2014-01-09 | 2018-10-02 | The J. David Gladstone Institutes, A Testimentary Trust Established Under The Will Of J. David Gladstone | Substituted benzoxazine and related compounds |
| EP4232161A1 (en) * | 2020-10-23 | 2023-08-30 | Dana-Farber Cancer Institute, Inc. | Covalent inhibitors of creatine kinase (ck) and uses thereof for treating and preventing cancer |
-
1966
- 1966-08-11 DE DE1966K0060001 patent/DE1595863C3/en not_active Expired
-
1967
- 1967-08-03 GB GB3576167A patent/GB1137796A/en not_active Expired
- 1967-08-07 BE BE702360D patent/BE702360A/xx unknown
- 1967-08-11 NL NL6711108A patent/NL6711108A/xx unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NL6711108A (en) | 1968-02-12 |
| BE702360A (en) | 1968-02-07 |
| GB1137796A (en) | 1968-12-27 |
| DE1595863C3 (en) | 1978-03-02 |
| DE1595863A1 (en) | 1970-02-12 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C3 | Grant after two publication steps (3rd publication) | ||
| EHJ | Ceased/non-payment of the annual fee |