NO115944B - - Google Patents
Info
- Publication number
- NO115944B NO115944B NO152816A NO15281664A NO115944B NO 115944 B NO115944 B NO 115944B NO 152816 A NO152816 A NO 152816A NO 15281664 A NO15281664 A NO 15281664A NO 115944 B NO115944 B NO 115944B
- Authority
- NO
- Norway
- Prior art keywords
- phenthiazine
- reaction
- temperature
- formula
- general formula
- Prior art date
Links
- 239000000047 product Substances 0.000 claims description 35
- WJFKNYWRSNBZNX-UHFFFAOYSA-N 10H-phenothiazine Chemical group C1=CC=C2NC3=CC=CC=C3SC2=C1 WJFKNYWRSNBZNX-UHFFFAOYSA-N 0.000 claims description 32
- 150000001768 cations Chemical class 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 13
- 239000011541 reaction mixture Substances 0.000 claims description 9
- 150000001412 amines Chemical class 0.000 claims description 8
- 150000001450 anions Chemical class 0.000 claims description 7
- 239000002798 polar solvent Substances 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- 239000007795 chemical reaction product Substances 0.000 claims description 2
- 239000012442 inert solvent Substances 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 230000004048 modification Effects 0.000 claims 1
- 238000012986 modification Methods 0.000 claims 1
- 108090000623 proteins and genes Proteins 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 26
- 239000000203 mixture Substances 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 15
- 150000003839 salts Chemical class 0.000 description 15
- 239000000460 chlorine Substances 0.000 description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000000243 solution Substances 0.000 description 11
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000000306 component Substances 0.000 description 8
- 238000002844 melting Methods 0.000 description 8
- 230000008018 melting Effects 0.000 description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 7
- 239000000155 melt Substances 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 229910052801 chlorine Inorganic materials 0.000 description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-O hydron piperazine Chemical compound [H+].C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-O 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 229940075930 picrate Drugs 0.000 description 5
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- 229910052717 sulfur Inorganic materials 0.000 description 5
- KPZGRMZPZLOPBS-UHFFFAOYSA-N 1,3-dichloro-2,2-bis(chloromethyl)propane Chemical compound ClCC(CCl)(CCl)CCl KPZGRMZPZLOPBS-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- 150000001805 chlorine compounds Chemical class 0.000 description 4
- 238000003776 cleavage reaction Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- XPSAAFFCAJIBSC-UHFFFAOYSA-M lithium;2,4,6-trinitrophenolate Chemical compound [Li+].[O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O XPSAAFFCAJIBSC-UHFFFAOYSA-M 0.000 description 4
- 230000007017 scission Effects 0.000 description 4
- 235000011121 sodium hydroxide Nutrition 0.000 description 4
- OZXIZRZFGJZWBF-UHFFFAOYSA-N 1,3,5-trimethyl-2-(2,4,6-trimethylphenoxy)benzene Chemical compound CC1=CC(C)=CC(C)=C1OC1=C(C)C=C(C)C=C1C OZXIZRZFGJZWBF-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- SHOJXDKTYKFBRD-UHFFFAOYSA-N mesityl oxide Natural products CC(C)=CC(C)=O SHOJXDKTYKFBRD-UHFFFAOYSA-N 0.000 description 3
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- AYJRCSIUFZENHW-UHFFFAOYSA-L barium carbonate Chemical compound [Ba+2].[O-]C([O-])=O AYJRCSIUFZENHW-UHFFFAOYSA-L 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- VYXHNENQFJOOJC-UHFFFAOYSA-N piperazin-1-ium tetrachloride Chemical compound [Cl-].[Cl-].[Cl-].[Cl-].[NH2+]1CCNCC1.[NH2+]1CCNCC1.[NH2+]1CCNCC1.[NH2+]1CCNCC1 VYXHNENQFJOOJC-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 235000009518 sodium iodide Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- FRPHFZCDPYBUAU-UHFFFAOYSA-N Bromocresolgreen Chemical compound CC1=C(Br)C(O)=C(Br)C=C1C1(C=2C(=C(Br)C(O)=C(Br)C=2)C)C2=CC=CC=C2S(=O)(=O)O1 FRPHFZCDPYBUAU-UHFFFAOYSA-N 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- GHVZOJONCUEWAV-UHFFFAOYSA-N [K].CCO Chemical compound [K].CCO GHVZOJONCUEWAV-UHFFFAOYSA-N 0.000 description 1
- ZVQOOHYFBIDMTQ-UHFFFAOYSA-N [methyl(oxido){1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-lambda(6)-sulfanylidene]cyanamide Chemical compound N#CN=S(C)(=O)C(C)C1=CC=C(C(F)(F)F)N=C1 ZVQOOHYFBIDMTQ-UHFFFAOYSA-N 0.000 description 1
- CUXSAAMWQXNZQW-UHFFFAOYSA-N acetic acid;butan-1-ol Chemical compound CC(O)=O.CCCCO CUXSAAMWQXNZQW-UHFFFAOYSA-N 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- WDIHJSXYQDMJHN-UHFFFAOYSA-L barium chloride Chemical compound [Cl-].[Cl-].[Ba+2] WDIHJSXYQDMJHN-UHFFFAOYSA-L 0.000 description 1
- 229910001626 barium chloride Inorganic materials 0.000 description 1
- 159000000009 barium salts Chemical class 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- UDSAIICHUKSCKT-UHFFFAOYSA-N bromophenol blue Chemical compound C1=C(Br)C(O)=C(Br)C=C1C1(C=2C=C(Br)C(O)=C(Br)C=2)C2=CC=CC=C2S(=O)(=O)O1 UDSAIICHUKSCKT-UHFFFAOYSA-N 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000004816 paper chromatography Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 238000005185 salting out Methods 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 230000002048 spasmolytic effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
Classifications
-
- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F16—ENGINEERING ELEMENTS AND UNITS; GENERAL MEASURES FOR PRODUCING AND MAINTAINING EFFECTIVE FUNCTIONING OF MACHINES OR INSTALLATIONS; THERMAL INSULATION IN GENERAL
- F16H—GEARING
- F16H1/00—Toothed gearings for conveying rotary motion
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B63—SHIPS OR OTHER WATERBORNE VESSELS; RELATED EQUIPMENT
- B63H—MARINE PROPULSION OR STEERING
- B63H23/00—Transmitting power from propulsion power plant to propulsive elements
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B63—SHIPS OR OTHER WATERBORNE VESSELS; RELATED EQUIPMENT
- B63H—MARINE PROPULSION OR STEERING
- B63H23/00—Transmitting power from propulsion power plant to propulsive elements
- B63H23/02—Transmitting power from propulsion power plant to propulsive elements with mechanical gearing
- B63H23/10—Transmitting power from propulsion power plant to propulsive elements with mechanical gearing for transmitting drive from more than one propulsion power unit
-
- B63B2757/00—
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T74/00—Machine element or mechanism
- Y10T74/19—Gearing
- Y10T74/19023—Plural power paths to and/or from gearing
- Y10T74/19051—Single driven plural drives
- Y10T74/19056—Parallel
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T74/00—Machine element or mechanism
- Y10T74/19—Gearing
- Y10T74/19628—Pressure distributing
Landscapes
- Engineering & Computer Science (AREA)
- Mechanical Engineering (AREA)
- General Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Combustion & Propulsion (AREA)
- Ocean & Marine Engineering (AREA)
- Gear Transmission (AREA)
- Retarders (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Fremgangsmåte for fremstilling av fentiazinderivater. Process for the preparation of phenthiazine derivatives.
Nærværende oppfinnelse angår en fremgangsmåte for fremstillingen av terapeutisk verdifulle fentiazinderivater. The present invention relates to a process for the production of therapeutically valuable phenthiazine derivatives.
Ifølge nærværende oppfinnelse fremstilles terapeutisk verdifulle fentiazinderivater ved å kondensere ét di((3-substituert-etyl)amin av arten (X-CH2-CH2)2N-R' med fentiazin-derivater av den generelle formel: According to the present invention, therapeutically valuable phenthiazine derivatives are prepared by condensing a di((3-substituted-ethyl)amine of the type (X-CH2-CH2)2N-R' with phenthiazine derivatives of the general formula:
i hvilken A betyr en mettet toverdig alifatisk kullvannstoffgruppe med rett eller for-grenet kjede og inneholdende 2 eller 3 kullstoffatomer, substituentene R betyr metyl-eller etylradikaler, R' et vannstoffatom in which A means a saturated divalent aliphatic carbon hydrogen group with a straight or branched chain and containing 2 or 3 carbon atoms, the substituents R means methyl or ethyl radicals, R' a hydrogen atom
eller et lavere alkylradikal inneholdende 1 or a lower alkyl radical containing 1
til 4 kullstoffatomer eller en benzyl- eller acylgruppe, Y er i 1- eller 3-stilling (Beil-stein nomenklatur) og betyr et vannstoff eller halogenatom eller en metyl-, metoksy-eller fenoksygruppe, og fentiazinringen kan være ytterligere substituert, og X betyr resten av en reaksjonsdyktig ester, f. ek. et halogenatom, og, fortrinsvis et klor-eller bromatom. to 4 carbon atoms or a benzyl or acyl group, Y is in the 1- or 3-position (Beil-stein nomenclature) and means a hydrogen or halogen atom or a methyl, methoxy or phenoxy group, and the phenthiazine ring may be further substituted, and X means the residue of a reactive ester, e.g. a halogen atom, and, preferably, a chlorine or bromine atom.
Forskning og eksperimenter har vist at forannevnte kondensasjonsreaksjon kan forløpe i forskjellige retninger alt etter som de utvalgte spesielle reaksjonsbetin-gelser er. Mere spesielt er det blitt funnet at reaksjonen kan ledes slik at den gir, vanligvis i form av blandinger, en eller flere av tre forskjellige typer fentiazin-derivater, av hvilke alle har interessante terapeutiske egenskaper. Disse tre typer av fentiazinderivater består av saltene hvis kationer overenstemmer med en eller annen av de generelle formler II, III og IV: Research and experiments have shown that the aforementioned condensation reaction can proceed in different directions depending on the selected special reaction conditions. More particularly, it has been found that the reaction can be directed to give, usually in the form of mixtures, one or more of three different types of phenthiazine derivatives, all of which have interesting therapeutic properties. These three types of phenthiazine derivatives consist of the salts whose cations correspond to one or other of the general formulas II, III and IV:
i hvilke de variable er som foran definert, og Y er i 1- eller 3-stilling og fentiazinringen kan være ytterligere substituert. in which the variables are as defined above, and Y is in the 1- or 3-position and the phenthiazine ring may be further substituted.
Når fremstilt etter forannevnte fremgangsmåte, inneholder disse forskjellige typer av kvaternære salter vanligvis som anion radikalet X, f. eks. radikalet av en reaksjonsdyktig ester, slik et halogenatom. Radikalet X kan, imidlertid, være erstattet av et annet fysiologisk eller farmakolog-isk brukbart anion som resten av en kar-bonsyre eller en hydroksylgruppe, og oppfinnelsen inkluderer også denne mulighet innenfor sin ramme. På grunn av nær-været av et piperazinradikal kan produktene som inneholder kationer overensstem-mende med.formel IV eksistere i to stereo-isomere former, nemlig cis og trans- iovm-ene (jfr. W. E. Hanby og H. N. Rydon J. C. S. 1945, 833). When prepared by the aforementioned method, these various types of quaternary salts usually contain as anion the radical X, e.g. the radical of a reactive ester, such as a halogen atom. The radical X can, however, be replaced by another physiologically or pharmacologically usable anion such as the residue of a carboxylic acid or a hydroxyl group, and the invention also includes this possibility within its scope. Owing to the presence of a piperazine radical, the products containing cations corresponding to formula IV can exist in two stereoisomeric forms, namely the cis and trans iovms (cf. W. E. Hanby and H. N. Rydon J. C. S. 1945, 833) .
Forbindelsene etter nærværende oppfinnelse, nemlig de kvaternære salter hvis kationer tilsvarer de generelle formler II, III og IV (og blandinger av disse) har interessante farmakologiske egenskaper (spasmoly tiske, lokal anestetiske, etc). Særlig er noen av forbindelsene av typene III og IV blitt funnet å være blodtrykk-senkende og aktive både ad oral og paren-teral vei. Vanligvis er cis-isomerer hvis kationer tilsvarer den generelle formel IV mindre aktive enn de tilsvarende trans-isomerer. Dessuten er vedkommende trans-isomerer henholdsvis mindre aktive enn rå blandinger inneholdende ikke bare trans-isomerene av typen IV, men også en tilsvarende forbindelse av typen III, hvorav det fremgår at sistnevnte har en synergi-stisk effekt med hensyn til den rene trans-forbindelse. The compounds according to the present invention, namely the quaternary salts whose cations correspond to the general formulas II, III and IV (and mixtures thereof) have interesting pharmacological properties (spasmolytic, local anaesthetic, etc). In particular, some of the compounds of types III and IV have been found to be blood pressure-lowering and active both orally and parenterally. Generally, cis isomers whose cations correspond to the general formula IV are less active than the corresponding trans isomers. Moreover, the trans-isomers in question are respectively less active than raw mixtures containing not only the trans-isomers of type IV, but also a corresponding compound of type III, from which it appears that the latter has a synergistic effect with respect to the pure trans compound .
Ifølge et trekk ved nærværende oppfinnelse fremstilles fentiazinderivatene inneholdende kationer representert av de generelle formler II, III' og IV, inklusive blandinger åv slike forbindelser, ved å kondensere et di(|3-substituert-etyl)-amin av typen (X-CH2-CH2)2N-R' med et fentiazinderivat av den generelle formel I ved hjelp av en av de følgende forskrifter for reaksjonsbetingelsene: (1) Mellom ca. 25° C og 50° C i et polart oppløsningsmiddel. I dette tilfelle, likegyldig hvilke forhold som brukes på reaksjonskomponentene, oppnås en reak-sjonsblanding inneholdende, av reaksjons-produktene foran spesifisert, nesten ute-lukkende et derivat av kationet som representeres av formelen III, og de beste resultater oppnås når ekvimolekylare forhold brukes for reaksjonskomponentene. (2) Ved temperatur .mellom 50° og 110° C i et polart oppløsningsmiddel, fortrinsvis i kokende etanol. Hvis ekvimolekylare forhold for reaksjonskomponentene brukes, oppnås en blanding bestående nesten helt av forbindelser av typene II og IV, fra hvilke det kan isoleres et salt hvis kation representeres av formelen IV. Hvis, på den annen side, to eller flere molekyler fentiazin brukes på et molekyl amin reaksjonskomponent, oppnås nesten uteluk-kende salter hvis kationer tilsvarer den generelle formel II. Når mellom 1 og 2 molekyler fentiazin brukes for hvert molekyl amin reaksjonskomponent, oppnås en blanding av salter hvis kationer tilsvarer formelene II, III og IV, og sammensetnin-gen av denne blanding varierer overens-stemmende med anvendte forhold, slik at større overskudd av fentiazin gir høyere forhold av forbindelsen av type II. (3) Ved en temperatur mellom 110° C og 250° C, fortrinsvis mellom 120° C og 140°C . Under disse betingelser, likegyldig hvilket forhold av reaksjonskomponenter som anvendes, oppnås der en blanding av forbindelsene av typene III og IV med eller uten en mengde av forbindelsen av type II. According to a feature of the present invention, the phenthiazine derivatives containing cations represented by the general formulas II, III' and IV, including mixtures of such compounds, are prepared by condensing a di(|3-substituted-ethyl)-amine of the type (X-CH2- CH2)2N-R' with a phenthiazine derivative of the general formula I by means of one of the following prescriptions for the reaction conditions: (1) Between approx. 25° C and 50° C in a polar solvent. In this case, no matter what conditions are used on the reaction components, a reaction mixture is obtained containing, of the reaction products specified above, almost exclusively a derivative of the cation represented by formula III, and the best results are obtained when equimolecular conditions are used for the reaction components. (2) At a temperature between 50° and 110° C. in a polar solvent, preferably in boiling ethanol. If equimolecular ratios of the reaction components are used, a mixture consisting almost entirely of compounds of types II and IV is obtained, from which a salt whose cation is represented by the formula IV can be isolated. If, on the other hand, two or more molecules of phenthiazine are used on one molecule of amine reaction component, almost exclusively salts whose cations correspond to the general formula II are obtained. When between 1 and 2 molecules of phenthiazine are used for each molecule of amine reaction component, a mixture of salts whose cations correspond to formulas II, III and IV is obtained, and the composition of this mixture varies in accordance with the conditions used, so that greater excess of phenthiazine gives higher ratios of the type II compound. (3) At a temperature between 110° C and 250° C, preferably between 120° C and 140° C. Under these conditions, regardless of the ratio of reaction components used, a mixture of the compounds of types III and IV with or without an amount of the compound of type II is obtained.
Denne kondensasjon kan utføres uten et oppløsningsmiddel, men i så tilfelle kan reaksjonen være sterkt eksoterm. Den kan lett kontrolleres ved å tilsette et lite kvan-tum av et inert oppløsningsmiddel som et aromatisk kullvannstoff som koker over 150° C (f. eks. toluol i en mengde på 5—20 pst. av reaksjonsblandingen). Et polart oppløsningsmiddel kan også brukes slik som mesityloksyd, benzonitril eller dimetyl-formarhid. This condensation can be carried out without a solvent, but in that case the reaction can be highly exothermic. It can be easily controlled by adding a small quantity of an inert solvent such as an aromatic hydrocarbon boiling above 150°C (e.g. toluene in an amount of 5-20 percent of the reaction mixture). A polar solvent can also be used such as mesityl oxide, benzonitrile or dimethylformaldehyde.
De samme rå reaksjonsblandinger kan opnås ved å oppvarme til 110°—250° C med eller uten et oppløsningsmiddel, ett eller annet av produktene oppnådd ved å utføre kondensasjonen ved en lavere temperatur. Således kan f. eks. produktene fremstilt etter (1) eller (2) brukes. Fra den rå blanding oppnådd på en eller annen av de foran nevnte måter kan der isoleres et vel-definert produkt representert av formelen IV (antatt å være en trans-form), og de beste resultater oppnås når ekvimolekylare forhold for fentiazin og amin-reaksjonskom-ponenten anvendes. Produktene (rå eller renset) oppnådd under disse temperatur-betingelser (110° C—250° C) er de fore-trukne produkter etter oppfinnelsen. The same crude reaction mixtures can be obtained by heating to 110°—250° C. with or without a solvent, one or other of the products obtained by carrying out the condensation at a lower temperature. Thus, e.g. the products produced according to (1) or (2) are used. From the crude mixture obtained in one or other of the aforementioned ways, a well-defined product represented by the formula IV (assumed to be a trans form) can be isolated, and the best results are obtained when equimolecular ratios of phenthiazine and amine reaction com -ponent is used. The products (raw or purified) obtained under these temperature conditions (110° C—250° C) are the preferred products according to the invention.
Når der arbeides under betingelsene (2) og (3) fremstilles meget lite av produktene av type III. When working under conditions (2) and (3) very little of the products of type III is produced.
Papir-kromatografi av de således oppnådde rå produkter, særlig når de er opp-løst i vann og utviklet med butanol-eddik-syre, viser i noen grad den komplekse natur av disse produkter. Ved å bruke Bromo-fenol Blått eller Bromokresol Grønt som fremkaller oppnås der en serie av punkter, hvilke hver for seg tilsvarer et bestemt stoff. Paper chromatography of the crude products thus obtained, especially when they are dissolved in water and developed with butanol-acetic acid, shows to some extent the complex nature of these products. By using Bromophenol Blue or Bromocresol Green as a developer, a series of points is obtained, each of which corresponds to a specific substance.
De oppnådde rå produkter kan separeres i enkeltbestanddelene ved hjelp av van-lige måter innen den organiske kjemi. F. eks. kromatografi kan brukes, fortrinsvis på aluminium. Videre kan med fordel anvendes den vesentlige forskjell i oppløse-lighet av saltene som har det samme anion. F. eks. er det mulig å skille produktene av type IV (transform) fra produktene av typene II og IV (cis-form) ved hjelp av den forskjellige oppløselighet i vann av kloridene og spesielt sulfatene. I tilfelle sulfa-ter er det mulig å arbeide med' fraksjonert bunnfelling, og i tilfelle klorider ved å salte ut ved hjelp av kloridioner (f. eks. ved tilsetning av natriumklorid). På samme måte kan produktene av typen II og IV (cis-form) også skilles fra hverandre ved å gjøre bruk av forskjellen i oppløselighet av kloridene i alkohol, idet kloridene av type IV (cis-form) er meget uoppløselige i alkohol. Produktene som skal skilles kan også separeres ved å bunnfelle dem som svakt oppløselige salter (f. eks. som metylen bis-fi-hydroksynaftol-syre-salter) og derpå spalte disse salter med en sterk syre, f. eks. svovelsyre. De oppnådde produkter kan omkrystalliseres fra organiske oppløsnings-midler, f. eks. etanol, zsopropanol eller metanol. The crude products obtained can be separated into the individual components using usual methods in organic chemistry. For example chromatography can be used, preferably on aluminium. Furthermore, the significant difference in solubility of the salts which have the same anion can be used with advantage. For example is it possible to distinguish the products of type IV (transform) from the products of types II and IV (cis-form) by means of the different solubility in water of the chlorides and especially the sulfates. In the case of sulphates, it is possible to work with fractional sedimentation, and in the case of chlorides by salting out with the help of chloride ions (e.g. by adding sodium chloride). In the same way, the products of type II and IV (cis-form) can also be separated from each other by making use of the difference in solubility of the chlorides in alcohol, the chlorides of type IV (cis-form) being very insoluble in alcohol. The products to be separated can also be separated by precipitating them as slightly soluble salts (e.g. as methylene bis-fi-hydroxynaphthol acid salts) and then cleaving these salts with a strong acid, e.g. sulfuric acid. The products obtained can be recrystallized from organic solvents, e.g. ethanol, isopropanol or methanol.
De følgende eksempler, som ikke be-grenser oppfinnelsen, viser hvordan oppfinnelsen kan utføres i praksis. The following examples, which do not limit the invention, show how the invention can be carried out in practice.
Eksempel 1: Example 1:
En blanding av 3-klor-10-(2'-dimetylaminoetyl)fentiazin (20 g) og N:N-di-(2-kloretyl)metylamin (10.2 g) oppvarmes i 16 timer i et bad som holdes på 125—135° C. Den harpiksaktige masse som oppnås vaskes med vann (100 cm»), og den vandige oppløsning ekstraheres med eter, behandles med trekull og frysetørkes derpå. Et beige pulverprodukt oppnås som gir føl-gende analyse basert på det tørre materiale : % N, 9.14; % S, 6.72; %ionisert Cl, 12.8; A mixture of 3-chloro-10-(2'-dimethylaminoethyl)phenthiazine (20 g) and N:N-di-(2-chloroethyl)methylamine (10.2 g) is heated for 16 hours in a bath maintained at 125-135 ° C. The resinous mass obtained is washed with water (100 cm"), and the aqueous solution is extracted with ether, treated with charcoal and then freeze-dried. A beige powder product is obtained which gives the following analysis based on the dry material: % N, 9.14; %S, 6.72; % ionized Cl, 12.8;
% ionisert Cl etter behandling på vannbad med 2N NaOH, 14.4; total % Cl, 21.0. % ionized Cl after treatment in a water bath with 2N NaOH, 14.4; total % Cl, 21.0.
Eksempel 2: Example 2:
En blanding 3-klor-10-(2'-dimetyl-aminetyl)fentiazin (50.6 g) og N:N-di-(2-kloretyl)metylamin (6.5 g) oppvarmes til 130° C i 16 timer. Den oppnådde masse finmales under vandig eter og separeres derpå og vaskes med eter. Der oppnås en blanding av produktene (25 g) som er opp-løselig i vann og gir følgende analyse: % N, 8.90; % ionisert Cl, 10.25; total % Cl, 19.8; % S, 7.71. A mixture of 3-chloro-10-(2'-dimethylamineethyl)phenthiazine (50.6 g) and N:N-di-(2-chloroethyl)methylamine (6.5 g) is heated to 130° C. for 16 hours. The mass obtained is finely ground under aqueous ether and then separated and washed with ether. A mixture of the products (25 g) is obtained which is soluble in water and gives the following analysis: % N, 8.90; % ionized Cl, 10.25; total %Cl, 19.8; % S, 7.71.
Eksempel 3: Example 3:
En blanding av 3-klor-10-(2'-dimetylaminoetyl)fentiazin (121.8 g), N:N-di-(2-kloretyl)metylamin (62.4 g) og toluol (10 cm.3) oppvarmes til 110—115° C. Den ekso-terme reaksjon som oppstår hemmes ved tilbakeløp av toluolen og temperaturen overstiger ikke 125° C. Temperaturen opp-rettholdes for ytterligere 16 timer ved 115— 125° C. En brun harpiks oppnås som behandles med vann (800 cm») på vannbad inntil oppløsningen er fullstendig, pH for den oppnådde oppløsning, som er ca. 3.5—5, justeres til pH 7 ved tilsetning av N kaustisk soda (ca. 25—50 cm<3>). Den nøytrali-serte oppløsning ekstraheres med eter (4 x 125 cm3), 4n svovelsyre (400 cm«) tilsettes derpå under svak omrøring, og krystallisa-sjon igangsettes. Et uoppløselig bunnfall dannes, og bunnfellingen fullføres ved tilsetning av 18 n svovelsyre (100 cm?»). Bunnfallet skilles fra og vaskes med 4 n svovelsyre (500 cm3), og til dette tilsettes gradvis bariumkarbonat (500 g) og derpå en vandig oppløsning av bariumklorid (40 g) i vann (150 cm3). pH justeres til 7 ved tilsetning av litt kaustisk soda, og de bunnfelte bariumsalter skilles fra ved sentri-fugering. Bunnfallet vaskes med vann (200 cm.3), og filtratet inndampes til tørrhet under forminsket trykk. Resten behandles med etanol (200 ems), saltene filtreres fra, benzol (200 cm») tilsettes, og oppløsningen destilleres, først under ordinært trykk og derpå under forminsket trykk. Resten behandles med vandig propanol (300 cm3), og restsaltene skilles, og propanolen fordampes i vakuum. Et svakt beige amorft produkt (57 g) oppnås som behandles med etanol (125 ems) på vannbad. Etter å være overlatt til krystallisering ved smitting separeres produktet , vaskes med isopropyl alkohol og derpå med eter, og et hygroskopisk hvitt krystallinsk produkt med smeltepunkt 287° C (Maquenne blokk) oppnås. Ved omkrystallisering av dette produkt fra vandig metanol (30 cm») oppnås et produkt med smeltepunkt 303° C (Maquenne blokk), hvilket smeltepunkt ikke endrer seg etter ytterligere omkrystallisa--sjon. Produktet er l:4-dimetyl-l:4-di[5'-(3"-klor-10"-fentiazinyl)-3':3'-dimetyl-3'-azanium-l'-pentyl]piperazinium tetraklor-■ id, som antas å være av transform. Den føl-gende analyse oppnås: A mixture of 3-chloro-10-(2'-dimethylaminoethyl)phenthiazine (121.8 g), N:N-di-(2-chloroethyl)methylamine (62.4 g) and toluene (10 cm.3) is heated to 110-115 ° C. The exothermic reaction that occurs is inhibited by reflux of the toluene and the temperature does not exceed 125° C. The temperature is maintained for a further 16 hours at 115-125° C. A brown resin is obtained which is treated with water (800 cm» ) on a water bath until the solution is complete, the pH of the solution obtained, which is approx. 3.5—5, adjusted to pH 7 by adding N caustic soda (approx. 25—50 cm<3>). The neutralized solution is extracted with ether (4 x 125 cm3), 4N sulfuric acid (400 cm3) is then added with gentle stirring, and crystallization is initiated. An insoluble precipitate forms, and the precipitation is completed by the addition of 18 N sulfuric acid (100 cm?). The precipitate is separated and washed with 4 N sulfuric acid (500 cm3), and to this is gradually added barium carbonate (500 g) and then an aqueous solution of barium chloride (40 g) in water (150 cm3). The pH is adjusted to 7 by adding a little caustic soda, and the settled barium salts are separated by centrifugation. The precipitate is washed with water (200 cm.3), and the filtrate is evaporated to dryness under reduced pressure. The residue is treated with ethanol (200 ems), the salts are filtered off, benzene (200 cm») is added, and the solution is distilled, first under ordinary pressure and then under reduced pressure. The residue is treated with aqueous propanol (300 cm3), and the residual salts are separated, and the propanol is evaporated in vacuo. A faint beige amorphous product (57 g) is obtained which is treated with ethanol (125 ems) on a water bath. After being left to crystallize by contamination, the product is separated, washed with isopropyl alcohol and then with ether, and a hygroscopic white crystalline product with a melting point of 287° C (Maquenne block) is obtained. By recrystallization of this product from aqueous methanol (30 cm"), a product with a melting point of 303° C (Maquenne block) is obtained, which melting point does not change after further recrystallization. The product is 1:4-dimethyl-1:4-di[5'-(3"-chloro-10"-phenthiazinyl)-3':3'-dimethyl-3'-azanium-1'-pentyl]piperazinium tetrachloro- ■ id, which is assumed to be of transform. The following analysis is achieved:
% N, 8.85; % ionisert Cl, 15.47; total % Cl, 23.4. %N, 8.85; % ionized Cl, 15.47; total % Cl, 23.4.
Teoretiske verdier for C42H5(iN(iS2Cl2,Cl4: % N, 9.12; % ionisert Cl, 15.42; total % Cl, 23.1. Theoretical values for C42H5(iN(iS2Cl2,Cl4: % N, 9.12; % ionized Cl, 15.42; total % Cl, 23.1.
Dette produkt er hygroskopisk og usedvan-lig lett oppløselig i vann. This product is hygroscopic and unusually easily soluble in water.
Pikratet, som oppnås ved dobbelt-. spalting med litiumpikrat, smelter ved-273—274° C (Maquenne blokk). Jodidet som oppnås ved dobbelt-spalting med natrium-jodid i vandig medium smelter ved 212—215° C. The picrate, which is obtained by double-. cleavage with lithium picrate, melting at -273—274° C (Maquenne block). The iodide obtained by double cleavage with sodium iodide in an aqueous medium melts at 212-215° C.
Eksempel 4: Example 4:
En blanding av 3-klor-10-(2'-dimetylaminoetyl)fentiazin (30.5 g), N:N-di(2-kloretyl)metylamin (14.9 g) og mesityl oksyd (45 cm.3) oppvarmes i 16 timer til 130° C. Blandingen behandles derpå med vann (250 erna), blandingen av mesityl oksyd og vann destilleres fra under 24 mm/Hg., og volumet bringes til 300 cm» ved tilsetning av vann, og den vandige oppløsning behandles på en måte lik den i eksempel 3. A mixture of 3-chloro-10-(2'-dimethylaminoethyl)phenthiazine (30.5 g), N:N-di(2-chloroethyl)methylamine (14.9 g) and mesityl oxide (45 cm.3) is heated for 16 hours to 130° C. The mixture is then treated with water (250 erna), the mixture of mesityl oxide and water is distilled from below 24 mm/Hg., and the volume is brought to 300 cm" by the addition of water, and the aqueous solution is treated in a manner similar to the one in example 3.
Eksempel 5: Example 5:
En blanding av 3-klor-10-(2'-dimetylaminoetyl) fentiazin (30.5 g), N:N-di-(2-kloretyl)metylamin (15.6 g) og dimetyl-formamid (100 cm«) oppvarmes i 16 timer til 130° C. Størstedelen av dimetylform-amid destilleres av under redusert trykk, og restmassen behandles derpå med vann (1.5 liter). Etter ekstraksjon med eter hel-les den vandige oppløsning i en omrørt oppløsning av natrium metylen bis-[3-hydr-oksynaftoat (850 em<s>) inneholdende 45 g metylen bis-(3-hydroksynaftolsyre pr. liter. Bunnfallet skilles fra, suspenderes i etanol (400 cm3) og vann (30 cm»), oppvarmes under tilbakeløp og omrøres, og 4 n salt-syre (65 cm.3) tilsettes fort. Etter avkjøling fraskilles metylen bis-p-hydroksynaftolsy-ren, filtratet fortynnes med vann (1.6 liter) og den annen andel syre som bunnfaller skilles også fra. pH justeres til 7 med N kaustisk soda, og blandingen fordampes til tørrhet under redusert trykk. Resten behandles med etanol (330 cm«), de uoppløse-lige salter fjernes, benzol (200 cm») tilsettes til filtratet og oppløsningsmidlene destilleres fra, først under vanlig trykk og derpå under redusert trykk. Resten behandles med vandig propanol (150 cm3), uoppløselige salter filtreres fra, og opp-løsningen fordampes til slutt til tørrhet under 0.2 mm/Hg. Et fast beige produkt (24 g) oppnås slik som gir følgende analyse basert på tørt materiale: % N, 9.12; % S, 7.17; % ionisert Cl, 11; A mixture of 3-chloro-10-(2'-dimethylaminoethyl)phenthiazine (30.5 g), N:N-di-(2-chloroethyl)methylamine (15.6 g) and dimethylformamide (100 cm«) is heated for 16 hours to 130° C. Most of the dimethylformamide is distilled off under reduced pressure, and the residue is then treated with water (1.5 litres). After extraction with ether, the aqueous solution is poured into a stirred solution of sodium methylene bis-[3-hydroxynaphthoate (850 em<s>) containing 45 g methylene bis-(3-hydroxynaphtholic acid) per liter. The precipitate is separated, suspended in ethanol (400 cm 3 ) and water (30 cm 3 ), heated under reflux and stirred, and 4 N hydrochloric acid (65 cm 3 ) quickly added. After cooling, the methylene bis-p-hydroxynaphtholic acid is separated, the filtrate is diluted with water (1.6 liters) and the other portion of acid that precipitates is also separated. The pH is adjusted to 7 with N caustic soda, and the mixture is evaporated to dryness under reduced pressure. The residue is treated with ethanol (330 cm«), the insoluble salts is removed, benzene (200 cm") is added to the filtrate and the solvents are distilled off, first under normal pressure and then under reduced pressure. The residue is treated with aqueous propanol (150 cm3), insoluble salts are filtered off, and the solution is finally evaporated to dryness below 0.2 mm/Hg A solid beige product (24 g) op obtained as giving the following analysis based on dry material: % N, 9.12; % S, 7.17; % ionized Cl, 11;
total % Cl, 20.1. total % Cl, 20.1.
Eksempel 6: Example 6:
En blanding av 3-klor-10-(2'-dimetylaminoetyl) fentiazin (62.2 g), N:N-di-(2-kloretylamin (31.2 g) og absolutt etanol (100 cm3) får henstå i 48 timer ved vanlig temperatur. En liten mengde av uoppløselig stoff filtreres fra, og oppløsningen konsentreres under redusert trykk (maksimum badetemperatur, 40° C). Absolutt eter (70.0 cm») tilføyes til den viskøse rest, og etter henstand 2 dager ved ordinær temperatur har massen atter krystallisert ut. Det rives med eter, separeres, vaskes med eter og tørres i en vakuum desikator. Kloridet av 3:3:6-trimetyl-8-klor-6-aza-3-azanium (3' A mixture of 3-chloro-10-(2'-dimethylaminoethyl)phenthiazine (62.2 g), N:N-di-(2-chloroethylamine (31.2 g) and absolute ethanol (100 cm3) is allowed to stand for 48 hours at room temperature . A small amount of insoluble material is filtered off, and the solution is concentrated under reduced pressure (maximum bath temperature, 40° C). Absolute ether (70.0 cm") is added to the viscous residue, and after standing for 2 days at ordinary temperature, the mass has crystallized again out. It is triturated with ether, separated, washed with ether and dried in a vacuum desiccator. The chloride of 3:3:6-trimethyl-8-chloro-6-aza-3-azanium (3'
-klor-10'-fentiazinyl)oktan (66 g) oppnås. -chloro-10'-phenthiazinyl)octane (66 g) is obtained.
Dette produkt er hygroskopisk og spal-ter på Koflerblokken mellom 150—160° C. Det er ustabilt i vandig oppløsning. This product is hygroscopic and splits on the Kofler block between 150-160° C. It is unstable in aqueous solution.
Eksempel 7: Example 7:
En blanding av 3-klor-10-(2'-dimetylaminoetyl)-fentiazin (92,7 g), N:N-di-(2-kloretyl)metylamin (46.8 g) og absolutt etanol (225 cm») oppvarmes under tilbake-løp i 18 timer. Et hvitt produkt krystalliserer som skilles fra etter avkjøling. Etter vasking og tørring oppnås et produkt (18 g) som omkrystalliseres to, ganger fra vann (150 cm» og 85 cm» henholdsvis). Et produkt (13 g) oppnås som smelter ved 296° C (Maquenne blokk) og som er omtrent 1 pst. oppløselig i vann ved ordinær temperatur. Dette er 1:4-dimetyl-l:4-di[5'-(3"-klor-10"-fentiazinyl)3-:3'-dimetyl-3' azanium-1 '-pentyl]piper-azinium tetraklorid, og som antas å være cisform. Det gir følgende analyse: A mixture of 3-chloro-10-(2'-dimethylaminoethyl)-phenthiazine (92.7 g), N:N-di-(2-chloroethyl)methylamine (46.8 g) and absolute ethanol (225 cm») is heated under return run for 18 hours. A white product crystallizes which separates after cooling. After washing and drying, a product (18 g) is obtained which is recrystallized twice from water (150 cm" and 85 cm" respectively). A product (13 g) is obtained which melts at 296° C (Maquenne block) and which is approximately 1% soluble in water at ordinary temperature. This is 1:4-dimethyl-1:4-di[5'-(3"-chloro-10"-phenthiazinyl)3-:3'-dimethyl-3' azanium-1'-pentyl]piperazinium tetrachloride, and which is believed to be the cis form. It provides the following analysis:
% H20 Fischer, 4.9. % H 2 O Fischer, 4.9.
På tørt materiale: % N, 9.15; % ionisert On dry material: % N, 9.15; % ionized
Cl, 15.4; % S, 7.20. Cl, 15.4; % S, 7.20.
Teoretiske verdier for C42Hr,(jN(.S2Cl4 : Theoretical values for C42Hr,(jN(.S2Cl4 :
% N, 9.12; % ionisert Cl, 15.42; % S, 6.95. % N, 9.12; % ionized Cl, 15.42; % S, 6.95.
Pikratet fremstilt ved dobbelt spalting med en oppløsning av litium pikrat smelter ved 296° C — 300° C. The picrate produced by double cleavage with a solution of lithium picrate melts at 296° C — 300° C.
Eksempel 8: Example 8:
Ved å gå frem som i eksempel III, men å begynne med 10-(2'-dimetylaminoetyl) fentiazin (61.6 g) og N:N-di-(2-kloretyl) metylamin (35.6 g), oppnås der, etter sul-fatbunnfelling, et amorft produkt (34 g), fra hvilket der oppnås ved gjentatt krystal-lisasjon i vandig etanol et hvitt krystallinsk produkt som smelter ved 254° C (Maquenne blokk), og som er l:4-dimetyl-l:4-di[5'-(10"-fentiazinyl)-3':3'-dimetyl-3'-azanium-l'-pentyl]piperazinium tetraklorid, og antas å være transform, og hvis pikrat, oppnådd ved dobbelt spalting med en oppløsning av litium pikrat, smelter ved 257° C — 258° C (Maquenne blokk). By proceeding as in Example III, but starting with 10-(2'-dimethylaminoethyl) phenthiazine (61.6 g) and N:N-di-(2-chloroethyl) methylamine (35.6 g), there is obtained, after sul- barrel bottom precipitation, an amorphous product (34 g), from which is obtained by repeated crystallization in aqueous ethanol a white crystalline product which melts at 254° C (Maquenne block), and which is 1:4-dimethyl-1:4- di[5'-(10"-phenthiazinyl)-3':3'-dimethyl-3'-azanium-1'-pentyl]piperazinium tetrachloride, and is believed to be transform, and if picrate, obtained by double cleavage with a soln. of lithium picrate, melting at 257° C — 258° C (Maquenne block).
Eksempel 9: Example 9:
Ved å gå frem som beskrevet i eksem pel 3, men ved å gå ut fra 3-metyl-10-(2'- dimetylaminoetyl) fentiazin og N:N-di-(2-kloretyl) metylamin, oppnås trans l:4-di-metyl-1:4-di[5'-3"-metyl-10"-fentiazinyl) -3' :3'-dimetyl-3'-azanium-l '-pentyl] piper-azinium tetraklorid, smeltepunkt 265 —268° C. (inst.) Maquenne blokk). By proceeding as described in eczema column 3, but starting from 3-methyl-10-(2'- dimethylaminoethyl) phenthiazine and N:N-di-(2-chloroethyl) methylamine, trans 1:4-dimethyl-1:4-di[5'-3"-methyl-10"-phenthiazinyl)-3' is obtained: 3'-dimethyl-3'-azanium-1 '-pentyl] piper-azinium tetrachloride, melting point 265 —268° C. (inst.) Maquenne block).
Eksempel 10: 3-klor-10-(2'-dimetylaminoetyl) fentiazin (1320 g) oppløses i absolutt etanol (2.31 liter), og en 18 pst. etanolisk oppløs-ning av kaliumetylat (2 lit.) tilsettes. Den oppnådde oppløsning kjøles til 10° C, og N:N-di- (2-kloretyl) metylamin hydroklorid (835 g) tilsettes langsomt. Etter 40 timers omrøring ved værelsestemperatur filtreres det bunnfelte kaliumklorid fra og vaskes med etanol. Filtratet konsentreres ved fordampning under redusert trykk ved lav temperatur inntil en tykk viskøs masse er oppnådd. Denne tas opp i benzonitril (5.5 liter), og restetanolen fjernes ved å des-tillere av litt benzonitril under redusert trykk, og blandingen oppvarmes derpå i 24 timer ved 130° C under omrøring. Produktet som krystalliserer fra den varme blanding skilles fra den varme blanding ved filtrering og vaskes med varm bensonitril. Det faste stoff tas opp i vann (5 liter), og rést-bensonitrilen fjernes ved fordampning til tørrhet under redusert trykk. Resten de-hydreres ved å løse den opp i metanol, tilsetning av bensol og fordampning inntil en tykk masse oppnås. Denne tas opp i metanol (3.6 liter) ved værelsestemperatur, uoppløselige salter fjernes ved filtrering, og oppløsningen konsentreres ved å destil-lere av 2.8 liter metanol under redusert trykk. Ved kjøling med is krystalliserer et produkt som filtreres fra og vaskes med etanol og eter for å gi et råprodukt (314 Example 10: 3-chloro-10-(2'-dimethylaminoethyl)phenthiazine (1320 g) is dissolved in absolute ethanol (2.31 litres), and an 18% ethanolic solution of potassium ethylate (2 litres) is added. The resulting solution is cooled to 10° C. and N:N-di-(2-chloroethyl) methylamine hydrochloride (835 g) is slowly added. After stirring for 40 hours at room temperature, the precipitated potassium chloride is filtered off and washed with ethanol. The filtrate is concentrated by evaporation under reduced pressure at low temperature until a thick viscous mass is obtained. This is taken up in benzonitrile (5.5 litres), and the residual ethanol is removed by distilling off a little benzonitrile under reduced pressure, and the mixture is then heated for 24 hours at 130° C with stirring. The product which crystallizes from the hot mixture is separated from the hot mixture by filtration and washed with hot benzonitrile. The solid is taken up in water (5 litres), and the residual benzonitrile is removed by evaporation to dryness under reduced pressure. The residue is dehydrated by dissolving it in methanol, adding benzol and evaporating until a thick mass is obtained. This is taken up in methanol (3.6 liters) at room temperature, insoluble salts are removed by filtration, and the solution is concentrated by distilling 2.8 liters of methanol under reduced pressure. On cooling with ice, a product crystallizes which is filtered off and washed with ethanol and ether to give a crude product (314
g) som derpå renses ved omkrystallisasjon' fra absolutt metanol. Det således oppnådde g) which is then purified by recrystallization from absolute methanol. It thus achieved
produkt er trans 1:4-dimetyl-l:4-di[5'-3"-klor-10"-fentiazinyl)-3': 3'-dimetyl-3'-azanium-l'-pentil]piperazinium tetraklorid. product is trans 1:4-dimethyl-1:4-di[5'-3"-chloro-10"-phenthiazinyl)-3':3'-dimethyl-3'-azanium-1'-pentyl]piperazinium tetrachloride.
Pikratet oppnådd ved behandling av kloridet med en vandig oppløsning av litium pikrat smelter ved 275° C (inst.) (Maquenne blokk). The picrate obtained by treating the chloride with an aqueous solution of lithium picrate melts at 275° C (inst.) (Maquenne block).
Eksempel 11: Example 11:
Ved å gå frem som beskrevet i eksempel 10, men ved å gå ut fra 10-(3'-dimetyl-aminopropyl) fentiazin, oppnås et klorid som ikke kan krystalliseres, men som ved behandling med natrium jodid i vandig oppløsning gir trans 1:4-dimetyl-l:4-di[6'- By proceeding as described in example 10, but starting from 10-(3'-dimethylaminopropyl)phenthiazine, a chloride is obtained which cannot be crystallized, but which, on treatment with sodium iodide in aqueous solution, gives trans 1: 4-dimethyl-1:4-di[6'-
(3"-klor-10"-fentiazinyl)-3':3'-dimetyl-3'-azanium-rheksyl]piperazinium tetra-jodid, smeltepunkt 224—226° C (inst.) (3"-chloro-10"-phenthiazinyl)-3':3'-dimethyl-3'-azanium-rhexyl]piperazinium tetra-iodide, melting point 224-226° C (inst.)
(Kofler. (Kofler.
Eksempler 12: Examples 12:
Ved å gå frem på lignende måte som By proceeding in a similar manner as
beskrevet i eksempel 10, med ved å gå ut described in example 10, with by going out
fra 3-f enoksy-10- (2'-dimetylaminoetyl) - from 3-phenoxy-10-(2'-dimethylaminoethyl)-
fentiazin, oppnås trans l:4-dimetyl-l:4-di-[5'-(3"-fenoksy-10"-fentiazinyl)-3':3'-dimetyl-3'-azanium-l'-pentyl]piperazinium tetraklorid, smeltepunkt 270° C (inst.) phenthiazine, trans 1:4-dimethyl-1:4-di-[5'-(3"-phenoxy-10"-phenthiazinyl)-3':3'-dimethyl-3'-azanium-1'-pentyl] is obtained piperazinium tetrachloride, melting point 270° C (inst.)
(Maquenne blokk). (Maquenne block).
Eksempel 13: Example 13:
Ved å gå frem på lignende måte som By proceeding in a similar manner as
beskrevet i eksempel 11, men ved å begynne described in Example 11, but by starting
med l-klor-10(2'-dimetylaminoetyl) with 1-chloro-10(2'-dimethylaminoethyl)
fentiazin, oppnås et produkt som, etter phenthiazine, a product is obtained which, after
rensning ved bunnfelling med svovelsyre purification by precipitation with sulfuric acid
som beskrevet i eksempel 3, smelter ved as described in example 3, wood melts
284—285° C. (inst.) (Maquenne blokk) og 284—285° C. (inst.) (Maquenne block) and
er trans 1:4-di[5'-(l"-klor-10"-fentiazinyl-3': 3'-dimetyl-3'-azanium-l'-pentyl] piperazinium tetraklorid. Pikratet smelter ved 249—250° C (inst.) (Maquenne blokk). is trans 1:4-di[5'-(1"-chloro-10"-phenthiazinyl-3':3'-dimethyl-3'-azanium-1'-pentyl] piperazinium tetrachloride. The picrate melts at 249-250° C (inst.) (Maquenne block).
Nærværende krav omfatter ikke den fremgangsmåte som er gjenstand for pa-tent nr. 86.034, i hvilket et dialkyl-amino-fentiazin av formelen: oppvarmes til en temperatur på minst 50° C med et amin av formelen: The present claim does not cover the method which is the subject of patent no. 86,034, in which a dialkyl-amino-phenthiazine of the formula: is heated to a temperature of at least 50° C with an amine of the formula:
I eller formelen: In or the formula:
hvor A betyr en mettet toverdig alifatisk kullvannstoffgruppe med rett eller forgre-net kjede omfattende 2 eller 3 kullstoffatomer, n er 2 eller 3, og substituentene R ■betyr metylr eller etylradikaler, R' betyr et vannstoffatom eller et lavere alkylradikal omfattende 1 til 4 kullstoffatomer eller en benzyl- eller acylgruppe, Y betyr et vannstoff- eller halogen atom eller en metyl-, metoksy- eller fenoksygruppe, og Hal betyr et halogenatom, som utskiller fra reaksjonsblandingen et fentiazin inneholdende kationet med den generelle formel: where A means a saturated divalent aliphatic carbon hydrogen group with a straight or branched chain comprising 2 or 3 carbon atoms, n is 2 or 3, and the substituents R ■ means methyl or ethyl radicals, R' means a hydrogen atom or a lower alkyl radical comprising 1 to 4 carbon atoms or a benzyl or acyl group, Y means a hydrogen or halogen atom or a methyl, methoxy or phenoxy group, and Hal means a halogen atom, which separates from the reaction mixture a phenthiazine containing the cation of the general formula:
og anionet er halogen, og fortrinsvis omdannelse av anionet i produktet til et annet and the anion is halogen, and preferably conversion of the anion in the product to another
anion. anion.
Claims (6)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE522963 | 1963-05-13 |
Publications (1)
Publication Number | Publication Date |
---|---|
NO115944B true NO115944B (en) | 1968-12-30 |
Family
ID=20265986
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO152816A NO115944B (en) | 1963-05-13 | 1964-04-14 |
Country Status (5)
Country | Link |
---|---|
US (1) | US3196714A (en) |
DE (1) | DE1914498U (en) |
GB (1) | GB989161A (en) |
NL (1) | NL6404079A (en) |
NO (1) | NO115944B (en) |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SE213154C1 (en) * | 1965-12-15 | 1967-05-23 | ||
US4114468A (en) * | 1973-02-16 | 1978-09-19 | Universal Power Corporation | Drive means for electric generators particularly adapted in floating power plant |
JPS5134061B2 (en) * | 1973-02-23 | 1976-09-24 | ||
US4022083A (en) * | 1973-03-14 | 1977-05-10 | Fa. Zahnraederfabrik Renk Ag | Drive system for connecting two drive shafts to a single output shaft, as in a propeller drive for a watercraft |
DE2347608A1 (en) * | 1973-09-18 | 1975-03-27 | Mannesmann Meer Ag | DEVICE FOR DRIVING A PIVOTING SHAFT |
DE2514029B2 (en) * | 1975-03-29 | 1977-07-21 | ELASTICALLY MOUNTED COUPLING PART | |
GB1597475A (en) * | 1977-09-22 | 1981-09-09 | Vickers Shipbuilding Group Ltd | Reversing gear transmissions |
US4242925A (en) * | 1978-07-17 | 1981-01-06 | Westinghouse Electric Corp. | Reversing apparatus |
US4531429A (en) * | 1983-06-20 | 1985-07-30 | Westech Gear Corporation | Marine transmission |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR930702A (en) * | 1946-07-16 | 1948-02-03 | Const Aeronautiques Du Sudoues | Speed reducer |
US2708416A (en) * | 1951-05-31 | 1955-05-17 | Falk Corp | Marine drive |
-
1964
- 1964-04-01 GB GB133?7/64A patent/GB989161A/en not_active Expired
- 1964-04-03 DE DEST17160U patent/DE1914498U/en not_active Expired
- 1964-04-14 NO NO152816A patent/NO115944B/no unknown
- 1964-04-15 NL NL6404079A patent/NL6404079A/xx unknown
- 1964-05-13 US US366986A patent/US3196714A/en not_active Expired - Lifetime
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US3196714A (en) | 1965-07-27 |
GB989161A (en) | 1965-04-14 |
NL6404079A (en) | 1964-11-16 |
DE1914498U (en) | 1965-04-22 |
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