NO116271B

NO116271B -

Info

Publication number: NO116271B
Application number: NO15397964A
Authority: NO
Inventors: A Haighton; E Meyer
Original assignee: Unilever Nv
Priority date: 1963-07-12
Filing date: 1964-07-10
Publication date: 1969-02-24
Also published as: GB1046516A; AT250150B; NL6407833A; ES301939A1; BE650420A; CH453867A; DE1492951A1; FI43521B; DK123272B

Description

Fremgangsmåte for fremstilling av fentiazinforbindelser. Process for the preparation of phenthiazine compounds.

Nærværende oppfinnelse angår en fremgangsmåte for fremstilling av fentia-zinderivater som er verdifulle som terapeu-tiske midler og som mellomprodukter for fremstilling av slike midler. The present invention relates to a process for the production of phenthiazine derivatives which are valuable as therapeutic agents and as intermediates for the production of such agents.

De forbindelser som omfattes av nærværende oppfinnelse er de som inneholder strukturen: The compounds covered by the present invention are those containing the structure:

og omfatter ikke bare basene overensstem-mende med denne formel, men også tilsvarende sure addisjons- og kvaternære am-moniumsalter ag addisjonsforbindelser (f. eks. de som dannes mellom basene og 8-klyorteofyllin). I foregående formel betyr A et toverdig mettet, alifatisk kullvann-stof f radikal med rett eller forgrenet kjede inneholdende fra 2 til 6 kullstoff atomer, Ri betyr et vannstoffatom eller en lavere alkyl- eller en aryl- eller aralifatisk gruppe, Y og Yi er henholdsvis et vannstoff- eller halogenatom eller en lavere alkyl-, alkoksy-eller aryl- eller aryloksy-gruppe, fortrinsvis (i tilfelle Y) i 1- eller 3-stilling, og fentiazinringen kan inneholde substituenter i tillegg til Y og Yi, og et eller flere av kullstoffatomene i piperazinringen kan bære en substituent i form av en metylgruppe. Det skal bemerkes at betegnelsen «lavere alkyl», når anvendt i denne beskrivelse og etterfølgende påstander, betyr en alkylgruppe inneholdende ikke mer enn 6 og fortrinsvis ikke mere enn 4 kullstoffatomer. Ifølge nærværende oppfinnelse fremstilles disse forbindelser ved at en fentiazinforbindelse med formelen and includes not only the bases corresponding to this formula, but also corresponding acid addition and quaternary ammonium salts and addition compounds (e.g. those formed between the bases and 8-chlorotheophylline). In the preceding formula, A means a divalent saturated, aliphatic hydrocarbon f radical with a straight or branched chain containing from 2 to 6 carbon atoms, Ri means a hydrogen atom or a lower alkyl or an aryl or araliphatic group, Y and Yi are respectively a hydrogen or halogen atom or a lower alkyl, alkoxy or aryl or aryloxy group, preferably (in the case of Y) in the 1- or 3-position, and the phenthiazine ring may contain substituents in addition to Y and Yi, and a or several of the carbon atoms in the piperazine ring may carry a substituent in the form of a methyl group. It should be noted that the term "lower alkyl", when used in this specification and subsequent claims, means an alkyl group containing no more than 6 and preferably no more than 4 carbon atoms. According to the present invention, these compounds are prepared by a phenthiazine compound with the formula

i hvilken fentiazinringen kan inneholde substituenter i tillegg til Y og/eller Yi, rea-geres med en forbindelse Q, og gruppen P og forbindelsen Q er slik at Q vil reagere med forbindelsen med nevnte formel for å innføre eller danne i 10-stilling av rin-gen en substituentgruppe med strukturen: in which the phenthiazine ring may contain substituents in addition to Y and/or Yi, is reacted with a compound Q, and the group P and the compound Q are such that Q will react with the compound of said formula to introduce or form in the 10-position of ring-gen a substituent group with the structure:

i in

i hvilken en eller flere av kullstoffatomene i piperazinringen kan inneholde en substituent i form av en metylgruppe, Ai betyr et toverdig, mettet, alifatisk kullvannstoffradikal med rett eller forgrenet kjede inneholdende 2 til 6 kullstoffatomer eller en toverdig gruppe som kan omdannes til dette ved reduksjon, R» betyr et hydrogenatom eller en lavere alkyl-, aryl- eller aralifatisk gruppe eller en gruppe som kan omdannes til disse og Y og Yi hver er som in which one or more of the carbon atoms in the piperazine ring may contain a substituent in the form of a methyl group, Ai means a divalent, saturated, aliphatic carbon hydrogen radical with a straight or branched chain containing 2 to 6 carbon atoms or a divalent group which can be converted into this by reduction, R» means a hydrogen atom or a lower alkyl, aryl or araliphatic group or a group which can be converted into these and Y and Yi are each as

foran definert og, hvor enten en eller' begge av nevnte utgangsmaterialer inneholder en eller flere «konvertible» grupper som foran angitt, omdannelse av den konvertible gruppe eller grupper til det ønskede ende-lige atom og/eller gruppe. defined above and, where either one or both of said starting materials contain one or more "convertible" groups as indicated above, conversion of the convertible group or groups into the desired final atom and/or group.

Spesielle utførelsesformer for den ge-neriske fremgangsmåte angitt i sist foregående avsnitt er følgende: (1) innvirkning av et fentiazin med den generelle formel: med et piperazinderivat med den generelle formel: X betyr residiet av en reaksjonsdyktig ester (f. eks. et halogenatom eller et svovelsyre eller sulfonsyreesterradikal som et p-to-luensulfonradikal) og de andre variabler er som angitt foran, (2) innvirkning av et fentiazin med den generelle formel: med et piperazinderivat med den generelle formel: i hvilken de angitte variable er som foran definert, (3) i tilfelle av fremstilling av forbindelser i hvilke piperazinringen inneholder ingen substituent på et kullstoffatom, innvirkning av en forbindelse med den generelle formel: Special embodiments of the generic method indicated in the last preceding paragraph are the following: (1) action of a phenthiazine with the general formula: with a piperazine derivative of the general formula: X denotes the residue of a reactive ester (e.g. a halogen atom or a sulfuric acid or sulfonic acid ester radical such as a p-toluenesulfonic radical) and the other variables are as indicated above, (2) influence of a phenthiazine with the general formula: with a piperazine derivative of the general formula: in which the indicated variables are as defined above, (3) in the case of the preparation of compounds in which the piperazine ring contains no substituent on a carbon atom, action of a compound of the general formula:

med et amin av formelen R2NH2, hvor de angitte variabler er som foran definert. with an amine of the formula R2NH2, where the stated variables are as defined above.

De forannevnte prosesser kan utføres ved oppvarming av reaksjonsdeltagerne i nærvær eller fravær av et organisk fortyn-ningsmiddel og, hvis ønsket, i nærvær av et alkalisk kondenseringsmiddel, f. eks. et al-kalimetall eller derivat av dette som hydr-oksydene, hydridene, amidene eller alkoho-latene, og mere spesielt natriumhydroksyd eller natriumamid. The aforementioned processes can be carried out by heating the reaction participants in the presence or absence of an organic diluent and, if desired, in the presence of an alkaline condensing agent, e.g. an alkali metal or derivative thereof such as the hydroxides, hydrides, amides or alcohols, and more particularly sodium hydroxide or sodium amide.

For å illustrere bruken av grupper som kan omdannes til en gruppe Ri (hvor Ri er forskjellig fra et vannstoffatom) kan de følgende arter mellomprodukter fremstilles ved forannevnte prosesser og omdannes som angitt i det følgende: som kan omdannes ved alkylering til tilsvarende forbindelser i hvilke Ri betyr en alkylgruppe og: To illustrate the use of groups which can be converted into a group Ri (where Ri is different from a hydrogen atom) the following species of intermediates can be prepared by the aforementioned processes and converted as indicated below: which can be converted by alkylation into corresponding compounds in which Ri means an alkyl group and:

hvor R» er en alkyl-, aralkyl- eller aryl-gruppe), som omdannes ved reduksjon til tilsvarende forbindelser inneholdende som gruppe R en alkyl- eller aralkylgruppe. where R» is an alkyl, aralkyl or aryl group), which are converted by reduction to corresponding compounds containing as group R an alkyl or aralkyl group.

For å beskrive bruken av gruppene som kan omdannes til et radikal Ri hvor Ri betyr et vannstoffatom, kan mellomprodukter fremstilles etter forannevnte prosesser inneholdende de følgende grupper og derpå omdannes som angitt i det følgende: (a) forbindelse inneholdende strukturen: som omdannes ved reduksjon (debenzyle-ring) (b) Forbindelser inneholdende strukturen: som omdannes ved nitrosering og spalt-ing, (c) forbindelser inneholdende strukturen : hvor R4 betyr en kullvannstoffgruppe, som kan omdannes ved hydrolyse, (d) forbindelser inneholdende strukturen: To describe the use of the groups that can be converted into a radical Ri where Ri means a hydrogen atom, intermediates can be prepared by the aforementioned processes containing the following groups and then converted as indicated below: (a) compound containing the structure: which is converted by reduction (debenzylation) (b) Compounds containing the structure: which are converted by nitrosation and cleavage, (c) compounds containing the structure : where R4 means a carbon hydrogen group, which can be converted by hydrolysis, (d) compounds containing the structure:

hvor Rn betyr ethvert egnet radikal som kullvannstoffgruppe, som kan omdannes ved hydrolyse. where Rn means any suitable radical such as carbon hydrogen group, which can be converted by hydrolysis.

For å illustrere bruken av toverdige grupper som kan omdannes til gruppen A, med eller uten grupper som kan omdannes til en Ri substituent, kan der fremstilles amidmellomprodukter av følgende arter: hvor gruppen A2 er et alifatisk kullvannstoffradikal inneholdende fra 1 til 5 kullstoffatomer, og de andre variabler er som foran definert, og omdannelsen utføres ved kjente reduksjonsmetoder, f. eks. ved bruk av litium-aluminium-hydrid. To illustrate the use of divalent groups that can be converted to the group A, with or without groups that can be converted to a Ri substituent, amide intermediates of the following species can be prepared: where the group A2 is an aliphatic carbon hydrogen radical containing from 1 to 5 carbon atoms, and the other variables are defined as before, and the transformation is carried out by known reduction methods, e.g. using lithium aluminum hydride.

Forbindelsen etter nærværende oppfinnelse inneholdende en struktur tilsvarende formel I besitter interessante farmo-kodynamiske egenskaper; særlig er de fun-net å være meget aktiv anti-epileptiske og anti-emetiske midler. Som følge herav fin-ner de anvendelse i medisinen eller veteri-nærmedisinen. The compound according to the present invention containing a structure corresponding to formula I possesses interesting pharmacodynamic properties; in particular, they are fun-net to be very active anti-epileptic and anti-emetic agents. As a result, they find use in medicine or veterinary medicine.

Spesielt fremragende brukbarhet som anti-emetiske midler inneholdes i de av nevnte forbindelser i hvilke Y er et vannstoff eller kloratom i 3-stilling, Yt betyr et vannstoffatom, A betyr -(CHj):)-, Ri betyr et vannstoffatom eller en metyl eller etyl-gruppe, og piperazinringen er enten usub-stituert eller er substituert med en metylgruppe. Particularly outstanding utility as antiemetic agents is contained in those of said compounds in which Y is a hydrogen atom or chlorine atom in the 3-position, Yt means a hydrogen atom, A means -(CHj):)-, Ri means a hydrogen atom or a methyl or ethyl group, and the piperazine ring is either unsubstituted or is substituted with a methyl group.

Oppfinnelsen illustreres ved følgende eksempler: Eksempel 1: 10-(2-kloretyl)fentiazin (87.5 g), vannfri piperazin (76 g) og metanol (75 cm<3>) oppvarmes i fire timer under tilbakeløp. Blandingen behandles derpå med destillert vann (100 cm<3>) og kloroform (2 X 100 cm<3>). Den dekanterte kloroform vaskes med vann The invention is illustrated by the following examples: Example 1: 10-(2-chloroethyl)phenthiazine (87.5 g), anhydrous piperazine (76 g) and methanol (75 cm<3>) are heated for four hours under reflux. The mixture is then treated with distilled water (100 cm<3>) and chloroform (2 X 100 cm<3>). The decanted chloroform is washed with water

(2 X 50 cm<3>) og rystes med 2N saltsyre (150 cm<3>). Et bunnfall (10.5 g) dannes som (2 X 50 cm<3>) and shaken with 2N hydrochloric acid (150 cm<3>). A precipitate (10.5 g) forms as

filtreres fra og omkrystalliseres fra buta-nol (1 g pr. 60 cm<3>) for å gi 1 : 4-di(10-fen-tiazinyletyl) piperazin-dihydroklorid, som smelter ved 220° C (inst.). filtered off and recrystallized from butanol (1 g per 60 cm<3>) to give 1 : 4-di(10-phenthiazinylethyl) piperazine dihydrochloride, which melts at 220° C. (inst.).

Den vandige klorvannstoffsure oppløs-ning behandles med vandig natrium-hydr-oksyd ( d = 1.33 100 cm<3>) og kloroform The aqueous hydrochloric acid solution is treated with aqueous sodium hydroxide (d = 1.33 100 cm<3>) and chloroform

(4 X 50 cm<3>). Kloroformen tørkes derpå og konsentreres i vakuum for å gi 10-(2-l'-piperazinyletyl) fentiazin (74 g). Denne ba-se gir når behandlet med alkohol og eterisk (4 X 50 cm<3>). The chloroform is then dried and concentrated in vacuo to give 10-(2-1'-piperazinylethyl)phenthiazine (74 g). This ba-se gives when treated with alcohol and ethereal

klorvannstoff dihydroklorid, som når om-krystallisert fra 90 pst. etanol (1 g pr. 25 cm<3>) smelter ved 260° C (inst.). hydrogen chloride dihydrochloride, which when recrystallized from 90 per cent ethanol (1 g per 25 cm<3>) melts at 260° C (inst.).

Eksempel 2: Example 2:

Fentiazin (10 g) omdannes til natriumderivat ved behandling med natriumderivat ved behandling med natriumamid (2.25 g) i xylol (75 cm<3>), og produktet kondenseres med en oppløsning i xylol av l-(2-kloretyl-4-benzyloksykarbonylpiperazin oppnådd fra det tilsvarende hydroklorid (16 g.). Phenthiazine (10 g) is converted to the sodium derivative by treatment with sodium derivative by treatment with sodium amide (2.25 g) in xylol (75 cm<3>), and the product is condensed with a solution in xylol of l-(2-chloroethyl-4-benzyloxycarbonylpiperazine) obtained from the corresponding hydrochloride (16 g.).

Ved behandling av oppløsningen med vann (100 cm<3>), ekstraksjon med 2N saltsyre (2 X 50 cm<3>), behandling med vandig natriumhydroksyd, ekstraksjon med kloroform og fremstilling av hydrokloridet, oppnås der direkte det samme dihydroklorid av 10-(2-l'-piperazinyletyl)-fentiazin som beskrevet i eksempel 1. By treating the solution with water (100 cm<3>), extraction with 2N hydrochloric acid (2 X 50 cm<3>), treatment with aqueous sodium hydroxide, extraction with chloroform and preparation of the hydrochloride, the same dihydrochloride of 10- (2-1'-piperazinylethyl)-phenthiazine as described in Example 1.

1- (2-kloretyl) -4-benzyloksykarbonylpiperazin hydroklorid, smeltepunkt 130— 132° C (inst.), oppnåes ved innvirkning av tionylklorid på l-(2-hydroksyetyl)-4-benzyloksykarbonylpiperazin-hydroklorid i ben sol. 1- (2-hydroksyetyl) -4-benzyloksykarbonylpiperazin, kokepunkt 286—288° C/ 1 mm Hg. oppnås ved å kondensere etylen-oksyd med 1-benzyloksykarbonylpiperazin i metanol. 1-(2-chloroethyl)-4-benzyloxycarbonylpiperazine hydrochloride, melting point 130—132° C (inst.), is obtained by the action of thionyl chloride on 1-(2-hydroxyethyl)-4-benzyloxycarbonylpiperazine hydrochloride in ben sol. 1-(2-hydroxyethyl)-4-benzyloxycarbonylpiperazine, boiling point 286—288° C/ 1 mm Hg. is obtained by condensing ethylene oxide with 1-benzyloxycarbonylpiperazine in methanol.

Eksempel 3: 10-(2-kloretyl)fentiazin (10.5 g) oppvarmes i 4—5 timer ved 180° C med 1-etylpiperazin (22.8 g). Etter avkjøling tilsettes vann (25 cm<3>), og blandingen ekstrahere-med eter (2 X 25 cm<3>). Den eteriske opp-løsning rystes med en normal oppløsning av saltsyre (60 cm<3>), og det sure lag dekanteres og behandles med konsentrert natri-umhydroksydoppløsning (15 cm<3>). Basen ekstraheres med eter (2 X 20 cm<3>), og ekstrakten tørres over natriumsulfat. Konsentrering i vakuum gir 10-(2-4'-etyl-l'-pipe-razinyletyl)fentiazin (11.4 g), smeltepunkt (inst.) 72° C. Pikratet av denne base smelter ved 260° C) inst.). Example 3: 10-(2-chloroethyl)phenthiazine (10.5 g) is heated for 4-5 hours at 180° C. with 1-ethylpiperazine (22.8 g). After cooling, water (25 cm<3>) is added, and the mixture is extracted with ether (2 X 25 cm<3>). The ethereal solution is shaken with a normal solution of hydrochloric acid (60 cm<3>), and the acidic layer is decanted and treated with concentrated sodium hydroxide solution (15 cm<3>). The base is extracted with ether (2 X 20 cm<3>), and the extract is dried over sodium sulfate. Concentration in vacuo gives 10-(2-4'-ethyl-1'-pipe-razinylethyl)phenthiazine (11.4 g), melting point (inst.) 72° C. The picrate of this base melts at 260° C) inst.).

10-(2-4'-etyl-l'-piperazinetyl) fentiazin (2 g) oppvarmes i to timer under tilbake-løp med metyljodid (10 cm<3>). Det oversky-tende metyljodid destilleres fra, og har-piksresiduet oppløses i vann (10 cm<3>). Opp-løsningen behandles med trekull, filtreres og fordampes i vakuum ved 20° C. Resten omkrystalliseres fra 90 pst. etanol (50 cm<3>) for å gi 10-(2-4'-etyl-l'-piperazinyletyl)fentiazin-dimetjodid (2.8 g), som smelter ved 240° C (inst.). 10-(2-4'-ethyl-1'-piperazineethyl)phenthiazine (2 g) is heated for two hours under reflux with methyl iodide (10 cm<3>). The excess methyl iodide is distilled off, and the resin residue is dissolved in water (10 cm<3>). The solution is treated with charcoal, filtered and evaporated in vacuo at 20° C. The residue is recrystallized from 90% ethanol (50 cm<3>) to give 10-(2-4'-ethyl-1'-piperazinylethyl)phenthiazine -dimethiodide (2.8 g), which melts at 240° C (inst.).

Eksempel 4: Example 4:

Ved å gå frem som i eksempel III, men ved å gå ut fra 10-(2-kloretyl)-fentiazin (5.25 g) og 1-metylpiperazin (10 g), oppnås 10- (2-4'-metyl-l'-piperazinyletyl) fentiazin By proceeding as in Example III, but starting from 10-(2-chloroethyl)-phenthiazine (5.25 g) and 1-methylpiperazine (10 g), 10-(2-4'-methyl-1' -piperazinylethyl) phenthiazine

(5.6 g) i form av en viskøs harpiks. Pikratet av denne base smelter ved 265° C (inst.). (5.6 g) in the form of a viscous resin. The picrate of this base melts at 265° C (inst.).

Eksempel 5: Example 5:

Ved å begynne med 10-(2-kloretyl) fentiazin (5.25 g) og 1-benzylpiperazin Starting with 10-(2-chloroethyl) phenthiazine (5.25 g) and 1-benzylpiperazine

(15.5 g) oppnås 10-(2-4'-benzyl-l'-pipera-zinyl-etyl)fentiazin (8 g), som derpå behandles med etanol og eterisk klorvannstoff for å gi dihydrokloridet som, etter omkrystallisering fra vann (1 g pr. 7 cm<3>), smelter ved 230° C (inst.). (15.5 g) yields 10-(2-4'-benzyl-1'-piperazinyl-ethyl)phenthiazine (8 g), which is then treated with ethanol and ethereal hydrogen chloride to give the dihydrochloride which, after recrystallization from water (1 g per 7 cm<3>), melts at 230° C (inst.).

Eksempel 6: Example 6:

(16.2 g) oppnås et monohydroklorid (6.5 g) 3om derpå omkrystalliseres fra en blanding iv dimetylformamid og vann (1 g pr. 20 :m<3> dimetylformamid og 10 cm<3> vann). 10-(2-4'-fenyl-l'-piperazinyl-etyl)fentiazin-monohydroklorid oppnådd slik smelter ved 245° C (inst.). (16.2 g), a monohydrochloride (6.5 g) is obtained, which is then recrystallized from a mixture of dimethylformamide and water (1 g per 20 ml of dimethylformamide and 10 cm of water). 10-(2-4'-phenyl-1'-piperazinyl-ethyl)phenthiazine monohydrochloride thus obtained melts at 245° C. (inst.).

Eksempel 7: Example 7:

Ved å gå frem som i eksempel 3, men ved å gå ut fra 10-(2-kloretyl)-fentiazin (5.25 g) og 1:2:3:5: 6-pentametylpipe-razin (15.6 g) oppnås 10-(2-l' : 2' : 3' : 5' : 6'- pentametyl-4'-piperazinyletyl)-fentiazin (5.2 g) som en viskøs harpiks. Pikratet av denne base smelter ved 228° C (inst.). By proceeding as in example 3, but starting from 10-(2-chloroethyl)-phenthiazine (5.25 g) and 1:2:3:5: 6-pentamethylpiperazine (15.6 g), 10-( 2-l' : 2' : 3' : 5' : 6'- pentamethyl-4'-piperazinylethyl)-phenthiazine (5.2 g) as a viscous resin. The picrate of this base melts at 228° C (inst.).

Eksempel 8: Example 8:

Ved å gå frem som i eksempel 3, men ved å gå ut fra 10-(3-klorpropyl)-fentiazin (11 g) og 1-etylpiperazin (22.8 g), oppnås 10-(3-4'-etyl-l'-piperazinylpropyl)-fentiazin, smeltepunkt (innst.) 52° C. Pikratet av denne base smelter ved 258° C (inst.). By proceeding as in example 3, but starting from 10-(3-chloropropyl)-phenthiazine (11 g) and 1-ethylpiperazine (22.8 g), 10-(3-4'-ethyl-1' is obtained -piperazinylpropyl)-phenthiazine, melting point (est.) 52° C. The picrate of this base melts at 258° C. (est.).

Eksempel 9: Example 9:

Ved å gå frem som i eksempel 3, men ved å gå ut fra 10-(3-klorpropyl<*>)-fentiazin By proceeding as in example 3, but starting from 10-(3-chloropropyl<*>)-phenthiazine

(5.5 g) og l-etyl-2 : 3 : 5 : 6-tetra-metylpiperazin (5.1 g), oppnås 10-(3-l'-etyl-2' :3' :-5' : 6'tetrametyl-4'-piperazinylpropyl)-fentiazin (3 g) som en viskøs harpiks. Pikratet av denne base smelter ved 158° C (inst.). (5.5 g) and 1-ethyl-2 : 3 : 5 : 6-tetramethylpiperazine (5.1 g), 10-(3-1'-ethyl-2' :3' :-5' : 6'tetramethyl- 4'-piperazinylpropyl)-phenthiazine (3 g) as a viscous resin. The picrate of this base melts at 158° C (inst.).

Eksempel 10: Example 10:

Ved å gå frem som i eksempel 1, men ved å gå ut fra 10-(2-klorpropyl)-fentiazin (11 g) og 1-etylpiperazin (21 g), oppnås 10-(2-4'-etyl-l'-piperazinylpropyl)-fentiazin (7.5 g), smeltepunkt (inst.) 68° C. Pikratet av denne base smelter ved 250° C (inst.). Eksempel 11: 10-(2-klorpropyl)-fentiazin (5.5 g) oppvarmes i 5 timer ved 200° C med 1-fenyl-piperazin (16.2 g). Blandingen behandles med vann (50 cm'1) og med eter (50 cm3 fulgt av 20 cm<3>). De eteriske oppløsninger røres om med 7 pst. saltsyre (50 cm<3>), og et svakt oppløselig hydroklorid (4.5 g) oppnås som omkrystalliseres fra en 70 pst. vandig oppløsning av dimetylformamid (50 cm<3>). 10-(2-4'-fenyl-l'-piperazinylpropyl)-fentiazin-monohydroklorid (3.5 g) oppnås, smeltepunkt 245° C (inst.). Proceeding as in example 1, but starting from 10-(2-chloropropyl)-phenthiazine (11 g) and 1-ethylpiperazine (21 g), 10-(2-4'-ethyl-1' is obtained -piperazinylpropyl)-phenthiazine (7.5 g), melting point (inst.) 68° C. The picrate of this base melts at 250° C. (inst.). Example 11: 10-(2-chloropropyl)-phenthiazine (5.5 g) is heated for 5 hours at 200° C. with 1-phenyl-piperazine (16.2 g). The mixture is treated with water (50 cm'1) and with ether (50 cm3 followed by 20 cm<3>). The ethereal solutions are stirred with 7% hydrochloric acid (50 cm<3>), and a slightly soluble hydrochloride (4.5 g) is obtained which is recrystallized from a 70% aqueous solution of dimethylformamide (50 cm<3>). 10-(2-4'-phenyl-1'-piperazinylpropyl)-phenthiazine monohydrochloride (3.5 g) is obtained, melting point 245° C. (inst.).

Eksempel 12: 3-klorfentiazin (9.3 g) omdannes til et natriumderivat med natriumamid (2 g) i xylol (75 cm<3>). Produktet kondenseres med 1-(2-kloretyl)-4-metylpiperazin (8 g) i opp-løsning (45 cm<3>) i xylol ved kokning i 5 timer. 3-klor-10- (2-4'-metyl-l'-piperazinyl-etyl)-fentiazin-dihydroklorid (14.5 g) oppnås derpå ved den vanlige behandling og kan omkrystalliseres fra absolutt etanol (1 g pr. 10 cm<3>). Dihydrokloridet smelter ved 253—255° C (inst.). Example 12: 3-chlorophenthiazine (9.3 g) is converted to a sodium derivative with sodium amide (2 g) in xylol (75 cm<3>). The product is condensed with 1-(2-chloroethyl)-4-methylpiperazine (8 g) in solution (45 cm<3>) in xylol by boiling for 5 hours. 3-Chloro-10-(2-4'-methyl-1'-piperazinyl-ethyl)-phenthiazine dihydrochloride (14.5 g) is then obtained by the usual work-up and can be recrystallized from absolute ethanol (1 g per 10 cm<3 >). The dihydrochloride melts at 253-255° C (inst.).

1- (2-kloretyl) -4-metylpiperazin-dihydroklorid, smeltepunkt 265° C (inst.) oppnås ved innvirkning av tionylklorid på l-(2 hydroksyetyl)-4-metylpiperazin i kloroform. 1-(2-chloroethyl)-4-methylpiperazine dihydrochloride, melting point 265° C (inst.) is obtained by the action of thionyl chloride on 1-(2-hydroxyethyl)-4-methylpiperazine in chloroform.

Eksempel 13: 3-klor-10-(3-klorpropyl)-fentiazin (27 g) oppvarmes under tilbakeløp på vannbad i 5 timer med vannfri piperazin (22.4 g) og metanol (25 cm<3>). Blandingen behandles derpå med vann (100 cm3) og kloroform (100 cm<3>). Kloroformoppløsningen rystes med N saltsyre (100 cm<3>), og den sure opp-løsning gjøres alkalisk med natriumhydroksyd (d = 1.33, 50 cm<3>)). Ved ekstraksjor med kloroform (2 X 50 cm<3>) oppnås basen (15.2 g) og behandles med maleinsyre (10 g' og etylacetat. Maleatet omkrystalliseres fra etanol (750 cm<3>), og 3-klor-10-(3-l'-pipera-zinylpropyl)-fentiazin di-acid maleat (18 g) oppnås, smeltepunkt 186° C (inst.). Example 13: 3-chloro-10-(3-chloropropyl)-phenthiazine (27 g) is heated under reflux on a water bath for 5 hours with anhydrous piperazine (22.4 g) and methanol (25 cm<3>). The mixture is then treated with water (100 cm3) and chloroform (100 cm<3>). The chloroform solution is shaken with N hydrochloric acid (100 cm<3>), and the acidic solution is made alkaline with sodium hydroxide (d = 1.33, 50 cm<3>)). By extraction with chloroform (2 X 50 cm<3>), the base (15.2 g) is obtained and treated with maleic acid (10 g' and ethyl acetate. The maleate is recrystallized from ethanol (750 cm<3>), and 3-chloro-10-( 3-1'-piperazinylpropyl)-phenthiazine di-acid maleate (18 g) is obtained, m.p. 186° C. (inst.).

Eksempel 14: 3-(3-klor-10-fentiazinyl)propyl p-to'u-olsulfonat (20 g) oppvarmes under tilbake-løp i 5 timer med vannfri piperazin (11.6 g) og metanol (35 cm<3>). Blandingen behandles med vann (35 cm<3>) og kloroform (70 cm<3>), og kloroformoppløsningen røres med 10 pst. saltsyre (50 cm<3>). Den sure oppløs-ning gjøres alkalisk med natriumhydroksyd (d = 1.33, 50 cm<3>), og basen ekstraheres med kloroform (50 cm<3>). Basen (6.5 g) be handles med maleinsyre (5 g) og etylacetat (100 cm<3>). 3-klor-10-(3-l'-piperazinylpro-pyl)-fentiazin-dimaleat (8 g) oppnås som, etter krystallisering fra etanol, smelter ved 186° C. Example 14: 3-(3-chloro-10-phenthiazinyl)propyl p-to'u-olsulfonate (20 g) is heated under reflux for 5 hours with anhydrous piperazine (11.6 g) and methanol (35 cm<3>) . The mixture is treated with water (35 cm<3>) and chloroform (70 cm<3>), and the chloroform solution is stirred with 10% hydrochloric acid (50 cm<3>). The acidic solution is made alkaline with sodium hydroxide (d = 1.33, 50 cm<3>), and the base is extracted with chloroform (50 cm<3>). The base (6.5 g) please is treated with maleic acid (5 g) and ethyl acetate (100 cm<3>). 3-Chloro-10-(3-1'-piperazinylpropyl)-phenthiazine-dimaleate (8 g) is obtained which, after crystallization from ethanol, melts at 186°C.

3-(3-klor-10-fentiazinyl)propyl p- to-luensulfonat (20 g) fremstilles ved å behandle 3- (3-klor- 10-f entiazinyl) propanol (14.6 g) i vannfri pyridin (73 g) med p-toluensulfonylklorid (10.5 g) tilsatt i løpet av 1 time ved en temperatur i nærheten av 5° C. Blandingen får henstå ved 0° i 48 timer og vaskes derpå i nærvær av eter med isvann, fortynnet saltsyre og en 5 pst.s vandig oppløsning i natriumbikarbonat. Den konsentreres derpå ved 20° C. 3-(3-chloro-10-phenthiazinyl)propyl p-toluenesulfonate (20 g) is prepared by treating 3-(3-chloro-10-phenthiazinyl)propanol (14.6 g) in anhydrous pyridine (73 g) with p-toluenesulfonyl chloride (10.5 g) added over 1 hour at a temperature in the vicinity of 5° C. The mixture is allowed to stand at 0° for 48 hours and is then washed in the presence of ether with ice water, dilute hydrochloric acid and a 5 p.s. aqueous solution in sodium bicarbonate. It is then concentrated at 20°C.

Eksempel 15: Example 15:

Ved å gå frem som i eksempel III, men ved å gå ut fra 3-klor-10-(3-klorpropyl)-fentiazin (19 g) og 1-metylpiperazin (15 g) oppnås der 3-klor-10-(3-4'-metyl-l'-pipe-razinylpropyl) fentiazin (15 g), hvis dihydroklorid smelter ved 195° C (inst.). Pikratet av basen smelter ved 250° C (inst.). By proceeding as in Example III, but by starting from 3-chloro-10-(3-chloropropyl)-phenthiazine (19 g) and 1-methylpiperazine (15 g), 3-chloro-10-(3 -4'-methyl-1'-pipe-razinylpropyl) phenthiazine (15 g), the dihydrochloride of which melts at 195° C. (inst.). The picrate of the base melts at 250° C (inst.).

3-klor-10-(3-4'-metyl-r-piperazinyl-propyl)fentiazin (2 g) oppvarmes i 1 time under tilbakeløp med metyljodid (10 cm<3>). Blandingen konsentreres, oppløses i vann, filtreres og tørres i vakuum, og etter om-krystallisasjon fra metanol oppnås 3-klor-10-(3-4'- metyl-l'-piperazinylpropyl) fentiazin dimetjodid (2 g), smeltepunkt 266° C (inst.). 3-Chloro-10-(3-4'-methyl-r-piperazinyl-propyl)phenthiazine (2 g) is heated for 1 hour under reflux with methyl iodide (10 cm<3>). The mixture is concentrated, dissolved in water, filtered and dried in vacuo, and after recrystallization from methanol, 3-chloro-10-(3-4'-methyl-1'-piperazinylpropyl)phenthiazine dimethiodide (2 g), melting point 266° is obtained C (inst.).

3-klor-10-(3,4'-metyl-l'-piperazinyl-propyl) fentiazin (1.6 g), 8-klorteofyllin (0.8 g) og metanol (2.5 cm<3>) oppvarmes i 1 time under tilbakeløp. Metanol (5 cm<3>) 3-Chloro-10-(3,4'-methyl-1'-piperazinyl-propyl) phenthiazine (1.6 g), 8-chlorotheophylline (0.8 g) and methanol (2.5 cm<3>) are heated for 1 hour under reflux. Methanol (5 cm<3>)

og vann (1 cm<3>) tilsettes derpå, og blandingen kokes i en halv time og filtreres derpå varm for å fjerne uoppløselige be-standdeler. and water (1 cm<3>) is then added, and the mixture is boiled for half an hour and then filtered hot to remove insoluble constituents.

Den alkoholiske oppløsning krystalli-serer ved kjøling og krystallene filtreres fra, vaskes med etanol og tørres i vakuum og gir 3-klor-10-(3,4'-metyl-l'-piperazinyl-propyl) fentiazin 8-klorteofyllinat som smelter ved 175° C (inst.). The alcoholic solution crystallizes on cooling and the crystals are filtered off, washed with ethanol and dried in vacuo to give 3-chloro-10-(3,4'-methyl-1'-piperazinyl-propyl) phenthiazine 8-chlorotheophylline which melts at 175° C (inst.).

Eksempel 16: Example 16:

Ved å behandle 3-(3-klor-10-fentiazin.yl)propyl p-toluolsulfonat (20 g) med 1-metylpiperazin (13.5 g) på en måte lig-nende den beskrevet i eksempel 14 oppnås 3-klor-10-(3-4'-metyl-l'-piperazinylpropyl) fentiazin dimaleat (16 g), smeltepunkt 228° C. By treating 3-(3-chloro-10-phenthiazinyl)propyl p-toluenesulfonate (20 g) with 1-methylpiperazine (13.5 g) in a manner similar to that described in example 14, 3-chloro-10- (3-4'-methyl-1'-piperazinylpropyl) phenthiazine dimaleate (16 g), m.p. 228°C.

Ved å gå frem som i eksempel 15, men ved å bruke etyljodid istedenfor metyljodid oppnås 3-klor-10-(3,4'-metyl-l'-piperazin-ylpropyl) fentiazin dietjodid, smeltepunkt 268° C (inst.). By proceeding as in example 15, but using ethyl iodide instead of methyl iodide, 3-chloro-10-(3,4'-methyl-1'-piperazin-ylpropyl)phenthiazine diiodide is obtained, melting point 268° C. (inst.).

Eksempel 17: Example 17:

Ved å gå frem som i eksempel 3, men ved å gå ut fra 3-klor-10-(3-klorpropyl)-fentiazin (11.7 g) og 1-etylpiperazin (20 g) oppnås 3-klor-10-3-4'-etyl'-piperazinylpro-pyl) fentiazin (10.6 g) i form av en viskøs harpiks. Pikratet av denne base smelter ved 265° (inst.). By proceeding as in example 3, but starting from 3-chloro-10-(3-chloropropyl)-phenthiazine (11.7 g) and 1-ethylpiperazine (20 g), 3-chloro-10-3-4 is obtained ('-ethyl'-piperazinylpropyl) phenthiazine (10.6 g) in the form of a viscous resin. The picrate of this base melts at 265° (inst.).

Basen når behandlet med etanol og eterisk klorvannstoff gir dihydroklorid som omkrystalliseres fra absolutt etanol (1 g pr. 25 cm<:l>). Dihydrokloridet smelter ved 220° C (inst.). The base when treated with ethanol and ethereal hydrogen chloride gives the dihydrochloride which is recrystallized from absolute ethanol (1 g per 25 cm<:l>). The dihydrochloride melts at 220° C (inst.).

3-klor-10-(3-4'-etyl-l'-piperazinylpro-pyl) fentiazin (1.2 g) oppvarmes med etyljodid (10 cm<3>) i to timer under tilbakeløp. Blandingen konsentreres på vannbad, og den oppnådde harpiks oppløses i vann (10 cm<3>). Ved kjøling oppnås et krystallinsk produkt (1.5 g), som derpå omkrystalliseres fra 80 pst. etanol (25 cm<3>) og gir 3-klor-10-(3-4'-etyl-l'-piperazinylpropyl) fentiazin dietjodid (0.8 g), smeltepunkt 260° C (inst.). 3-Chloro-10-(3-4'-ethyl-1'-piperazinylpropyl)phenthiazine (1.2 g) is heated with ethyl iodide (10 cm<3>) for two hours under reflux. The mixture is concentrated on a water bath, and the resin obtained is dissolved in water (10 cm<3>). On cooling, a crystalline product (1.5 g) is obtained, which is then recrystallized from 80% ethanol (25 cm<3>) and gives 3-chloro-10-(3-4'-ethyl-1'-piperazinylpropyl) phenthiazine diiodide ( 0.8 g), melting point 260° C (inst.).

Ved å behandle 3-klor-10-(3-4'-etyl-l'-piperazinylpropyl)fentiazin (3.4 g) med teofyllin-eddiksyre (4 g) og etanol (15 cm<3>) oppnås 3-klor-10-(3-4'-etyl-l'-piperazinyl-propyl)fentiazin di-teofyllin acetat (7.4 g). som er vannoppløselig og smelter ved 100° C (inst.) (ikke skarp). By treating 3-chloro-10-(3-4'-ethyl-1'-piperazinylpropyl)phenthiazine (3.4 g) with theophylline-acetic acid (4 g) and ethanol (15 cm<3>) 3-chloro-10 is obtained -(3-4'-ethyl-1'-piperazinyl-propyl)phenthiazine ditheophylline acetate (7.4 g). which is water-soluble and melts at 100° C (inst.) (not sharp).

3-klor-10-(3-4'-etyl-l'-piperazinylpro-pyl)fentiazin (2 g) oppvarmes i to timer under tilbakeløp med 8-klorteofyllin (1.6 g) i metyletylketon (9 cm<3>) og vann (1 cm<3>). Oppløsningen konsentreres og behandles derpå med etanol (10 cm<3>). Oppløsningen krystalliseres langsomt, og 3-klor-10-(3-4'-etyl-l'-piperazinylpropyl) fentiazin di-8-klorteofyllinat (2.3 g) oppnås, smeltepunkt 185° C (inst.). 3-chloro-10-(3-4'-ethyl-1'-piperazinylpropyl)phenthiazine (2 g) is heated for two hours under reflux with 8-chlorotheophylline (1.6 g) in methyl ethyl ketone (9 cm<3>) and water (1 cm<3>). The solution is concentrated and then treated with ethanol (10 cm<3>). The solution is crystallized slowly, and 3-chloro-10-(3-4'-ethyl-1'-piperazinylpropyl)phenthiazine di-8-chlorotheophylline (2.3 g) is obtained, melting point 185° C. (inst.).

3-klor-10-(3-4'-etyl-l'-piperazinylpro-pyl)fentiazin (2 g) oppvarmes i iy2 time under tilbakeløp med metyljodid (3 g) og aceton (10 cm<3>). Blandingen konsentreres, oppløses i vann, filtreres og tørres i vakuum ved 20° C, og produktet omkrystalliseres fra metanol (10 cm<3>). 3-klor-10-(3-4'-etyl-l'-piperazinylpropyl) fentiazin dimetjodid (0.6 g) oppnås, smeltepunkt 260 3-Chloro-10-(3-4'-ethyl-1'-piperazinylpropyl)phenthiazine (2 g) is heated for 1/2 hour under reflux with methyl iodide (3 g) and acetone (10 cm<3>). The mixture is concentrated, dissolved in water, filtered and dried in vacuo at 20° C., and the product is recrystallized from methanol (10 cm<3>). 3-chloro-10-(3-4'-ethyl-1'-piperazinylpropyl)phenthiazine dimethiodide (0.6 g) is obtained, m.p. 260

—265° C (inst.). -265° C (inst.).

Eksempel 18. Example 18.

Ved å gå frem som i eksempel 3, men ved å gå ut fra 3-klor-10-(2-klorpropyl)-fentiazin (12.4 g) og 1-etylpiperazin (22.8 By proceeding as in example 3, but starting from 3-chloro-10-(2-chloropropyl)-phenthiazine (12.4 g) and 1-ethylpiperazine (22.8

g) oppnås 3-klor-10-(2-4'-etyl-l'-pipera- g) 3-chloro-10-(2-4'-ethyl-1'-pipera-

zinylpropyl) fentiazin (8.3 g) i form av en zinylpropyl) phenthiazine (8.3 g) in the form of a

viskøs harpiks. Pikratet av denne base smelter ved 254° C (inst.). viscous resin. The picrate of this base melts at 254° C (inst.).

Eksempel 19. Example 19.

Ved å gå frem som i eksempel 11, men ved å gå ut fra 3-klor-10-(2-klorpropyl)-fentiazin (6.2 g) oppnås 3-klor-10-(2-4'-f enyl -1' -piperazinylpropyl) -fentiazin monohydroklorid (3.4 g), smeltepunkt 225° C. By proceeding as in example 11, but starting from 3-chloro-10-(2-chloropropyl)-phenthiazine (6.2 g), 3-chloro-10-(2-4'-phenyl-1') is obtained -piperazinylpropyl)-phenthiazine monohydrochloride (3.4 g), melting point 225° C.

Eksempel 20. Example 20.

En blanding av fentiazin (6.65 g), 85 pst. natriumamid (2 g) og zylol (40 cm<3>) oppvarmes i 1 time under tilbakeløp. Under fortsatt tilbakeløpsbehandling tilsettes 1 - (2 -f enylallyl) -4- (3 -klorpropyl) piperazin (11 g) og oppvarmingen fortsettes i 4 timer. Blandingen behandles med vann (80 cm<3>), og xylolet dekanteres fra. Xylollaget behandles med N saltsyre (90 cm<3>), og 10-[3-4'- (2- f enylallyl) -1 '-piperazinylpropyl] - fentiazin hydroklorid bunnfeller som en olje. Den omdannes til basen ved å tilsette natriumhydroksyd ( d = 1.33, 10 cm<3>) og etanol (25 cm<3>), og basen ekstraheres med eter. (2 X 80 cm<3>). Den eteriske ekstrakt tørres over natriumsulfat og eteren fjernes på vannbad. 10-[3-4'-(2-f enylallyl) - l'-piperazinylpropyl]-fentiazin (14 g) oppnås slik og renses ved omdannelse til oksa-latet i aceton. Hydrokloridet av den rene base smelter ved 200—202° C. 1 - (2 -f enylallyl) -4 - (3 -klorpropyl) piperazin som tjener som utgangsmateriale fremstilles ved innvirkning av l-klor-3-brompropan på l-2'-fenylallylpiperazin i eter. A mixture of phenthiazine (6.65 g), 85% sodium amide (2 g) and xylol (40 cm<3>) is heated for 1 hour under reflux. During continued reflux treatment, 1-(2-phenylallyl)-4-(3-chloropropyl)piperazine (11 g) is added and heating is continued for 4 hours. The mixture is treated with water (80 cm<3>), and the xylol is decanted from it. The xylene layer is treated with N hydrochloric acid (90 cm<3>), and 10-[3-4'-(2-phenylallyl)-1'-piperazinylpropyl]-phenthiazine hydrochloride settles as an oil. It is converted to the base by adding sodium hydroxide (d = 1.33, 10 cm<3>) and ethanol (25 cm<3>), and the base is extracted with ether. (2 X 80 cm<3>). The ethereal extract is dried over sodium sulphate and the ether is removed on a water bath. 10-[3-4'-(2-phenylallyl)-1'-piperazinylpropyl]-phenthiazine (14 g) is thus obtained and purified by conversion to the oxalate in acetone. The hydrochloride of the pure base melts at 200-202° C. 1-(2-phenylallyl)-4-(3-chloropropyl)piperazine which serves as starting material is prepared by the action of 1-chloro-3-bromopropane on 1-2' -phenylallylpiperazine in ether.

Eksempel 21. Example 21.

En blanding av fentiazin (7.6 g), 85 pst. natriumamid (4.5 g) og vannfri xylol A mixture of phenthiazine (7.6 g), 85% sodium amide (4.5 g) and anhydrous xylol

(150 cm<3>) oppvarmes i 2 timer under til-bakeløp. Blandingen kjøles til 30° C, 1-(4-brombutyl) -4-etylpiperazin monohydro-bromid (15 g) tilsettes, blandingen opp-hetes igjen gradvis inntil tilbakeløp be-gynner, og tilbakeløpsbehandlingen fortsettes i 8 timer. Overskuddet av natriumamid smeltes, etter kjøling, med vann (20 cm<3>) og xyllollaget ekstraheres med N saltsyre (2 X 50 cm<3>). Den saltsure ekstrakt gjøres alkalisk med kaustisk soda ( d = 1.33, 15 cm<3>), og den oljeaktige base som skilles ut ekstraheres med eter (3 X 100 cm<3>). Etter tørring over natriumsulfat fjernes eteren under normalt trykk, og residuet destilleres i vakuum. 10-(4-4'-etyl-l'-piperazinylbutyl)fentiazin (5.5 g), koke- (150 cm<3>) is heated for 2 hours under reflux. The mixture is cooled to 30° C., 1-(4-bromobutyl)-4-ethylpiperazine monohydrobromide (15 g) is added, the mixture is heated again gradually until reflux begins, and the reflux treatment is continued for 8 hours. The excess of sodium amide is melted, after cooling, with water (20 cm<3>) and the xyllol layer is extracted with N hydrochloric acid (2 X 50 cm<3>). The hydrochloric acid extract is made alkaline with caustic soda (d = 1.33, 15 cm<3>), and the oily base that separates out is extracted with ether (3 X 100 cm<3>). After drying over sodium sulphate, the ether is removed under normal pressure, and the residue is distilled in vacuum. 10-(4-4'-ethyl-1'-piperazinylbutyl)phenthiazine (5.5 g), boiling

punkt 210—215° C/0.4 mm Hg, oppnås slik. Dets dihydroklorid smelter ved 218—220° C. point 210—215° C/0.4 mm Hg, is thus achieved. Its dihydrochloride melts at 218-220°C.

1- (4-brombutyl) -4-etylpiperazin mono-hydrobromidet, som tjener som utgangsmateriale i den foranstående fremstilling, oppnås ved brominering med tionylbromid i kloroform av l-(4-hydroksybutyl)-4-etylpiperazin, k.p. 110—115° C/10.3 mm Hg, som selv fremstilles ved oppvarming av 1 mol 4-klorbutanol med 2 mol etylpiperazin ved oppvarming i 10 timer ved 100° C. The 1-(4-bromobutyl)-4-ethylpiperazine mono-hydrobromide, which serves as starting material in the preceding preparation, is obtained by bromination with thionyl bromide in chloroform of 1-(4-hydroxybutyl)-4-ethylpiperazine, b.p. 110—115° C/10.3 mm Hg, which itself is produced by heating 1 mol of 4-chlorobutanol with 2 mol of ethyl piperazine by heating for 10 hours at 100° C.

Eksempel 22. Example 22.

Ved å gå frem som i eksempel 12, men ved å begynne med 3-klorfentiazin og 1-(2-kloretyl)-4-etylpiperazin, oppnås 3-klor-10-(2-4'-etyl-l'-piperazinyletyl) fentiazin dihydroklorid, som smelter ved 228— 230° C (inst.). Proceeding as in Example 12, but starting with 3-chlorophenthiazine and 1-(2-chloroethyl)-4-ethylpiperazine, 3-chloro-10-(2-4'-ethyl-1'-piperazinylethyl) is obtained phenthiazine dihydrochloride, which melts at 228— 230° C (inst.).

3-klor-10-(2-4'-etyl-l'-piperazinyletyl)-fentiazin (1.7 g) og metyljodid (10 cm<8>) oppvarmes i 4 timer under tilbakeløp. Overskuddet av metyljodid destilleres fra, og den således oppnådde harpiks oppløses i vann (20 cm<3>). Oppløsningen behandles med trekull, filtreres og konsentreres i vakuum ved 20° C, og produktet omkrystalliseres fra 80 pst. etanol (12 cm<3>) for å gi 3-klor-10-(2,4'-etyl-l'-piperazinyletyl) fentiazin dimetjodid, som smelter ved 262° C (inst.). 3-Chloro-10-(2-4'-ethyl-1'-piperazinylethyl)-phenthiazine (1.7 g) and methyl iodide (10 cm<8>) are heated for 4 hours under reflux. The excess of methyl iodide is distilled off, and the resin thus obtained is dissolved in water (20 cm<3>). The solution is treated with charcoal, filtered and concentrated in vacuo at 20° C., and the product recrystallized from 80% ethanol (12 cm<3>) to give 3-chloro-10-(2,4'-ethyl-1'- piperazinylethyl) phenthiazine dimethiodide, which melts at 262° C (inst.).

Eksempel 23. Example 23.

3-klorfentiazin (7 g) omdannes til natriumderivat med natriumamid (1.4 g) i xylol (50 cm<3>). 1-(2-kloretyl)-4-butyl-piperazin (7 g) i xylol (30 cm<3>) tilsettes derpå i løpet av 10 minutter, og blandingen oppvarmes i 2 timer under tilbakeløp. Den vanlige behandling gir 3-klor-10-(2-4'-butyl-l'-piperazinyletyl)fentiazin dihydroklorid (11.9 g), sm.p. 208° C (inst.). l-(2-kloretyl)-4-butylpiperazin dihydroklorid, sm.p. 245° C (inst.) oppnås ved innvirkning av tionylklorid på hydroksy-forbindelsen i kloroform. 3-Chlorophenthiazine (7 g) is converted to the sodium derivative with sodium amide (1.4 g) in xylol (50 cm<3>). 1-(2-Chloroethyl)-4-butyl-piperazine (7 g) in xylol (30 cm<3>) is then added over 10 minutes, and the mixture is heated for 2 hours under reflux. The usual work-up gives 3-chloro-10-(2-4'-butyl-1'-piperazinylethyl)phenthiazine dihydrochloride (11.9 g), m.p. 208° C (inst.). 1-(2-chloroethyl)-4-butylpiperazine dihydrochloride, m.p. 245° C (inst.) is obtained by the action of thionyl chloride on the hydroxy compound in chloroform.

1- (2-hydroksyetyl) -4-butylpiperazin, k.p. 98—100° C/mm Hg., oppnås ved oppvarming av 1-(2-hydroksyetyl) piperazin med 7i-butyl p-toluolsulfonat i 2 timer på vannbad, og behandling av blandingen med vandig natriumhydroksyd og kloroform og derpå destillering. 1-(2-hydroxyethyl)-4-butylpiperazine, m.p. 98-100° C/mm Hg., is obtained by heating 1-(2-hydroxyethyl)piperazine with 7i-butyl p-toluenesulfonate for 2 hours on a water bath, and treating the mixture with aqueous sodium hydroxide and chloroform and then distilling.

Eksempel 24. Example 24.

Natriumamid (8.2 g) tilsettes til en oppløsning av 3-klorfentiazin (44 g) i toluol (250 cm<3>) holdt ved ca. 120° C, og 1-(3-klorpropyl)-4-metylpiperazin (37 g) tilsettes derpå gradvis i løpet av 40 minutter. Etter oppheting i ytterligere 40 minutter under tilbakeløp kjøles blandingen, behandles med vann (200 cm<3>), og surgjøres med saltsyre ( d = 1.19, 40 cm<3>). Det organiske lag separeres fra, og det vandige lag vaskes med eter (200 cm<3>), gjøres alkalisk med vandig natriumhydroksyd ( d = 1.33, 50 cm<3>), og ekstraheres med eter (300 cm<3>). Den eteriske ekstrakten tørres over natriumsulfat, eteren fordampes, og residuet destilleres og gir 3-klor-10-(3-4'-metyl-l'-piperazinylpropyl)fentiazin (57 g) k.p.260—275° C/2 mm Hg, hvis hydroklorid smelter ved 200—210° C. Sodium amide (8.2 g) is added to a solution of 3-chlorophenthiazine (44 g) in toluene (250 cm<3>) kept at approx. 120° C., and 1-(3-chloropropyl)-4-methylpiperazine (37 g) is then added gradually over 40 minutes. After heating for a further 40 minutes under reflux, the mixture is cooled, treated with water (200 cm<3>), and acidified with hydrochloric acid (d = 1.19, 40 cm<3>). The organic layer is separated, and the aqueous layer is washed with ether (200 cm<3>), made alkaline with aqueous sodium hydroxide (d = 1.33, 50 cm<3>), and extracted with ether (300 cm<3>). The ethereal extract is dried over sodium sulfate, the ether is evaporated, and the residue is distilled to give 3-chloro-10-(3-4'-methyl-1'-piperazinylpropyl)phenthiazine (57 g) b.p. 260-275° C/2 mm Hg, whose hydrochloride melts at 200-210° C.

3-klor-10-(3-4'-metyl-l'-piperazinyl-propyl)fentiazin (6.9 g) oppvarmes under tilbakeløp med teobromin eddiksyre (8.75 g) og etanol (20 cm<3>). Alkoholen destilleres fra i vakuum, og residuet tørres i vakuum i nærvær av svovelsyre. 3-klor-10-(3-4'-metyl-l'-piperazinylpropyl) fentiazin di-teobromin acetat (15.5 g) oppnås, hvil-ket er oppløselig i vann og smelter ved ca. 130° C (inst.). 3-Chloro-10-(3-4'-methyl-1'-piperazinyl-propyl)phenthiazine (6.9 g) is heated under reflux with theobromine acetic acid (8.75 g) and ethanol (20 cm<3>). The alcohol is distilled off in a vacuum, and the residue is dried in a vacuum in the presence of sulfuric acid. 3-Chloro-10-(3-4'-methyl-1'-piperazinylpropyl) phenthiazine ditheobromine acetate (15.5 g) is obtained, which is soluble in water and melts at approx. 130° C (inst.).

1- (3-klorpropyl) -4-metylpiperazin, k.p. 82—83° C/3 mm Hg, kan fremstilles ved innvirkning av l-klor-3-brompropan på 1-metylpiperazin. 1-(3-chloropropyl)-4-methylpiperazine, m.p. 82-83° C/3 mm Hg, can be prepared by the action of 1-chloro-3-bromopropane on 1-methylpiperazine.

Eksempel 25. Example 25.

Natriumamid (12.9 g) tilsettes til en oppløsning av 3-klorfentiazin (23.4 g) i toluol (300 cm<3>) holdt ved 80° C. Blandingen oppvarmes til i nærheten av dens kokepunkt (110° C), og 1-(3-klorpropyl) - 4-metyl-piperazin dihydroklorid (27.5 g) tilsettes gradvis i løpet av 1 time. Etter at tilsetningen er fullført fortsetter oppvarmingen i ytterligere 3 timer. Etter avkjø-ling behandles blandingen med vann (250 cm<3>) og gjøres sur til Kongorød med saltsyre ( d = 1.19, 30 cm<3>). Toluollaget skilles Sodium amide (12.9 g) is added to a solution of 3-chlorophenthiazine (23.4 g) in toluene (300 cm<3>) maintained at 80° C. The mixture is heated to near its boiling point (110° C), and 1-( 3-chloropropyl)-4-methyl-piperazine dihydrochloride (27.5 g) is added gradually over 1 hour. After the addition is complete, heating continues for a further 3 hours. After cooling, the mixture is treated with water (250 cm<3>) and acidified to Congo red with hydrochloric acid (d = 1.19, 30 cm<3>). The toluene layer is separated

fra, og det vandige lag vaskes med eter from, and the aqueous layer is washed with ether

(250 cm<3>) og gjøres derpå alkalisk overfor fenolftalein med natriumhydroksyd ( d = 1.33, 35 cm<3>). Basen som skilles fra ekstraheres med eter. Eteren fordampes, og residuet destilleres. 3-klor-10-(3-4'-metyl-l'-piperazinylpropyl)fentiazin (27.3 g) oppnås på denne måte, og dets dihydroklorid smelter ved ca. 195° C. (250 cm<3>) and then made alkaline over phenolphthalein with sodium hydroxide ( d = 1.33, 35 cm<3>). The base which separates is extracted with ether. The ether is evaporated, and the residue is distilled. 3-Chloro-10-(3-4'-methyl-1'-piperazinylpropyl)phenthiazine (27.3 g) is obtained in this way, and its dihydrochloride melts at approx. 195°C.

Ved å behandle 3-klor-10-(3-4'-metyl-l'-piperazinylpropyl)-fentiazin (5 g) med teofyllin eddiksyre (6.3 g) og etanol (20 cm<3>) som beskrevet i eksempel 24, oppnås 3-klor-10-(3-4'-metyl-l'-piperazinylpropyl) fentiazin diteofyllin acetat (11.2 g), som er vannoppløselig og smelter ved 100° C (inst.) (ikke skarpt). By treating 3-chloro-10-(3-4'-methyl-1'-piperazinylpropyl)-phenthiazine (5 g) with theophylline acetic acid (6.3 g) and ethanol (20 cm<3>) as described in Example 24, 3-chloro-10-(3-4'-methyl-1'-piperazinylpropyl) phenthiazine ditheophylline acetate (11.2 g) is obtained, which is water-soluble and melts at 100° C (inst.) (not sharp).

Eksempel 26. Example 26.

3-klorfentiazin (8 g), vannfri xylol (35 cm<3>) og 95 pst. natriumamid (1.52 g) oppvarmes under tilbakeløp i y2 time. En opp-løsning av 1-(3-klorpropyl)-4-butylpipera-zin (9 g) i vannfri xylol (18 cm<3>) tilsettes gradvis i løpet av 15 minutter til den kokende suspensjon av natriumderivat av 3-klorfentiazin oppnådd på denne måte, og oppvarmingen under tilbakeløp fortsettes i 2<!>/2 time. 3-Chlorophenthiazine (8 g), anhydrous xylol (35 cm<3>) and 95% sodium amide (1.52 g) are heated under reflux for y2 hours. A solution of 1-(3-chloropropyl)-4-butylpiperazine (9 g) in anhydrous xylol (18 cm<3>) is added gradually over 15 minutes to the boiling suspension of sodium derivative of 3-chlorophenthiazine obtained in this way, and the heating under reflux is continued for 2<!>/2 hours.

Overskuddet av natriumamid spaltes med vann. (30 cm<3>), det vandige lag dekanteres, og xylollaget ekstraheres med til-nærmet normal saltsyre (2 X 50 cm<3>). Saltsyreekstraktene gjøres alkaliske med natriumhydroksyd (d = 1.33, 15 cm<3>), og den oljeaktige base som skiller seg ut ekstraheres med eter (3 X 80 cm<8>). Etter tør-ring av natriumsulfat fjernes eteren under normalt trykk, og resten destilleres. 3-klor-10-(3-4'-butyl-l'-piperazinylpropyl) fentiazin (9.45 g), k.p. 237—246° C/0.6 mm Hg, oppnås slik, og dihydrokloridet smelter ved 232—234° C (inst.). The excess of sodium amide is decomposed with water. (30 cm<3>), the aqueous layer is decanted, and the xylene layer is extracted with approximately normal hydrochloric acid (2 X 50 cm<3>). The hydrochloric acid extracts are made alkaline with sodium hydroxide (d = 1.33, 15 cm<3>), and the oily base which separates out is extracted with ether (3 X 80 cm<8>). After drying the sodium sulphate, the ether is removed under normal pressure, and the residue is distilled. 3-Chloro-10-(3-4'-butyl-1'-piperazinylpropyl)phenthiazine (9.45 g), b.p. 237—246° C/0.6 mm Hg, is thus obtained, and the dihydrochloride melts at 232—234° C (inst.).

1- (3-klorpropyl) -4-butylpiperazin som tjener som utgangsmateriale ved foranstående fremstilling oppnås ved innvirkning av l-klor-3-brompropan på 1-butylpipera-zin i eter under tilbakeløp. Det koker ved 85—87° C/0.8 mm Hg. 1-(3-Chloropropyl)-4-butylpiperazine, which serves as starting material in the above preparation, is obtained by the action of 1-chloro-3-bromopropane on 1-butylpiperazine in ether under reflux. It boils at 85-87° C/0.8 mm Hg.

Eksempel 27. Example 27.

Ved å gå frem som i eksempel 12, men ved å begynne med 1-klorfentiazin og 1-(2-kloretyl)-4-etylpiperazin, oppnås der 1-klor-10-(2-4'-etyl-l'-piperazinyletyl) fentiazin dihydroklorid, som smelter ved 238— 240° C (inst.). By proceeding as in example 12, but starting with 1-chlorophenthiazine and 1-(2-chloroethyl)-4-ethylpiperazine, 1-chloro-10-(2-4'-ethyl-1'-piperazinylethyl) is obtained ) phenthiazine dihydrochloride, which melts at 238— 240° C (inst.).

Eksempel 28. Example 28.

Ved å gå frem som i eksempel 26, men ved å gå ut fra 1-klorfentiazin og l-(3-klorpropyl) -4-etylpiperazin, oppnås 1-klor-10-(3-4'-etyl-l'-piperazinylpropyl) fentiazin k.p. 213—230° C/0.25 mm Hg, med 55 pst. utbytte. Dets dihydroklorid smelter ved 200—202° C. By proceeding as in example 26, but starting from 1-chlorophenthiazine and 1-(3-chloropropyl)-4-ethylpiperazine, 1-chloro-10-(3-4'-ethyl-1'-piperazinylpropyl) is obtained ) phenthiazine c.p. 213—230° C/0.25 mm Hg, with 55 percent yield. Its dihydrochloride melts at 200-202°C.

Eksempel 29. Example 29.

Ved å gå frem som i eksempel 26, men ved å begynne med 1-klorfentiazin, oppnås l-klor-10-(3,4'-butyl-l'-piperazinylpropyl) fentiazin (k.p. 236—245° C/0.4 mm Hg) i 71 pst. utbytte. Dets dihydroklorid smelter ved 255—256° C. By proceeding as in Example 26, but starting with 1-chlorophenthiazine, 1-chloro-10-(3,4'-butyl-1'-piperazinylpropyl)phenthiazine is obtained (b.p. 236-245° C/0.4 mm Hg ) in 71 per cent dividend. Its dihydrochloride melts at 255-256°C.

Eksempel 30. Example 30.

Ved å gå frem som i eksempel 21, men ved å begynne med 1-klorfentiazin, oppnås l-klor-10-(4-4'-etyl-l'-piperazinylbutyl)-fentiazin (k.p. 180—210° C/0.3 mm Hg) i 40 pst. utbytte. Dets dihydroklorid smelter ved 225—230° C. Proceeding as in Example 21, but starting with 1-chlorophenthiazine, 1-chloro-10-(4-4'-ethyl-1'-piperazinylbutyl)-phenthiazine is obtained (b.p. 180—210° C/0.3 mm Hg) in 40 per cent dividend. Its dihydrochloride melts at 225-230°C.

Eksempel 31. Example 31.

Ved å gå frem som i eksempel 27, men ved å begynne med 3-metylfentiazin (27 g), oppnås 3-metyl-10-(3-4'-metyl-l'-pipera-zinylpropyl) fentiazin (40 g), k.p. 230— 245° C/0.9 mm Hg, og dihydrokloridet smelter ved ca. 200° C. By proceeding as in Example 27, but starting with 3-methylphenthiazine (27 g), 3-methyl-10-(3-4'-methyl-1'-piperazinylpropyl)phenthiazine (40 g) is obtained, k.p. 230— 245° C/0.9 mm Hg, and the dihydrochloride melts at approx. 200°C.

Eksempel 32. Example 32.

3-metylfentiazin (21.3 g) omdannes til natriumderivat med natriumamid (4.5 g) i kokende xylol 180 cm<3>), og produktet kondenseres med 1-(3-klorpropyl)-4-etylpiperazin (22.9 g) ved oppvarming under til-bakeløp i 3 timer. Blandingen behandles med vann, xylollaget ekstraheres med 2N saltsyre, og det vandige lag gjøres alkalisk og ekstraheres med eter. Eterekstrakten tørres, eteren fordampes, og residuet destilleres for å gi 3-metyl-10-(3,4'-etyl-l'-piperazinylpropyl)fentiazin (30 g), k.p. 233 —235° C/0.2 mm Hg, hvis dihydroklorid smelter ved 242—244° C. 3-Methylphenthiazine (21.3 g) is converted to the sodium derivative with sodium amide (4.5 g) in boiling xylol 180 cm<3>), and the product is condensed with 1-(3-chloropropyl)-4-ethylpiperazine (22.9 g) by heating under to- back race for 3 hours. The mixture is treated with water, the xylene layer is extracted with 2N hydrochloric acid, and the aqueous layer is made alkaline and extracted with ether. The ether extract is dried, the ether evaporated, and the residue distilled to give 3-methyl-10-(3,4'-ethyl-1'-piperazinylpropyl)phenthiazine (30 g), m.p. 233 —235° C/0.2 mm Hg, whose dihydrochloride melts at 242—244° C.

1- (3-klorpropyl) -4-etylpiperazin, k.p. 83—84° C/l mm Hg, kan fremstilles ved innvirkning av 1 klor-3-brompropan på 1-etylpiperazin. 1-(3-chloropropyl)-4-ethylpiperazine, m.p. 83—84° C/l mm Hg, can be produced by the action of 1-chloro-3-bromopropane on 1-ethylpiperazine.

Eksempel 33. Example 33.

Ved å gå frem som i eksempel 27, men ved å begynne med 3-metoksyfentiazin (23.4 g), oppnås 3-metoksy-10-(3-4'-metyl-l'-piperazinylpropyl)-fentiazin (28 g), k.p. 245—255° C/l mm Hg, hvis dihydroklorid smelter ved ca. 225° C. By proceeding as in Example 27, but starting with 3-methoxyphentyazine (23.4 g), 3-methoxy-10-(3-4'-methyl-1'-piperazinylpropyl)-phenthiazine (28 g) is obtained, b.p. 245—255° C/l mm Hg, whose dihydrochloride melts at approx. 225°C.

Eksempel 34. Example 34.

Ved å gå frem som i eksempel 26, men ved å begynne med 3-metoksyfentiazin (12 g) og 1-(3-klorpropyl)-4-etylpiperazin (11.5 g), oppnås 3-metoksy-10-(3,4'-etyl-l'-pipe-razinylpropyl) fentiazin (12.5 g), k.p. 238— Proceeding as in Example 26, but starting with 3-methoxyphentazine (12 g) and 1-(3-chloropropyl)-4-ethylpiperazine (11.5 g), 3-methoxy-10-(3,4') is obtained -ethyl-1'-piperazinylpropyl) phenthiazine (12.5 g), b.p. 238—

243° C/0.7 mm Hg, hvis dihydroklorid smelter ved 229° C. 243° C/0.7 mm Hg, whose dihydrochloride melts at 229° C.

Eksempel 35. Example 35.

Ved å gå frem som i eksempel 26, men ved å begynne med 3-metoksyfentiazin, oppnås 3-metoksy-10-(3-4'-butyl-l'-pipera-zinylpropyl)fentiazin, k.p. 230—243° C/0.35 mm Hg, i 56 pst. utbytte. Dets hydroklorid smelter ved 252—254° C. Proceeding as in Example 26, but starting with 3-methoxyphentyazine, 3-methoxy-10-(3-4'-butyl-1'-piperazinylpropyl)phenthiazine is obtained, m.p. 230—243° C/0.35 mm Hg, in 56 percent yield. Its hydrochloride melts at 252-254°C.

Eksempel 36. Example 36.

Ved å gå frem som i eksempel 27, men ved å begynne med 3-fenylfentiazin (20 g), xylol (200 cm<3>), natriumamid (3.1 g) og 1-(3-klorpropyl)-4-metylpiperazin (14 g), oppnås 3-fenyl-10- (3-<4>'met<y>l-<l>'-ierazm-ylpropyl)-fentiazin (25 g), k.p. 275—285° C/0.9 mm Hg, hvis dihydroklorid smelter ved 220° C. Proceeding as in Example 27, but starting with 3-phenylphenthiazine (20 g), xylol (200 cm<3>), sodium amide (3.1 g) and 1-(3-chloropropyl)-4-methylpiperazine (14 g), 3-phenyl-10-(3-<4>'meth<y>l-<l>'-ierazm-ylpropyl)-phenthiazine (25 g) is obtained, b.p. 275—285° C/0.9 mm Hg, whose dihydrochloride melts at 220° C.

Eksempel 37. Example 37.

Natriumamid (0.9 g) tilsettes til en oppløsning av 1-fenylfentiazin (5.5 g) i xylol (55 cm<3>) opphetet til 100° C. Blandingen oppvarmes derpå til i nærheten av dens kokepunkt (120—130° C), og en opp-løsning av 1-(3-klorpropyl)-4-metylpiperazin (3.9 g) i xylol (8 cm<3>) tilsettes langsomt. Etter at tilsetningen er fullført, fortsettes oppvarmingen i iy2 time. Etter kjø-ling behandles blandingen med vann (5£ cm<3>) og gjøres derpå sur til Kongorød med saltsyre ( d = 1.19, 6 cm<3>). Det organiske lag skilles fra, og den vandige oppløsning vaskes med eter (50 cm<3>) og gjøres derpå alkalisk til fenolftalein med natriumhydroksyd ( d = 1.33, 6.5 cm<3>). Sodium amide (0.9 g) is added to a solution of 1-phenylphenthiazine (5.5 g) in xylol (55 cm<3>) heated to 100° C. The mixture is then heated to near its boiling point (120-130° C), and a solution of 1-(3-chloropropyl)-4-methylpiperazine (3.9 g) in xylol (8 cm<3>) is added slowly. After the addition is complete, heating is continued for iy2 hours. After cooling, the mixture is treated with water (5£ cm<3>) and then acidified to Congo red with hydrochloric acid (d = 1.19, 6 cm<3>). The organic layer is separated, and the aqueous solution is washed with ether (50 cm<3>) and then made alkaline to phenolphthalein with sodium hydroxide (d = 1.33, 6.5 cm<3>).

Basen som skilles ut ekstraheres med eter (3 X 150 cm<3>), eteren fordampes, og residuet destilleres i vakuum, l-fenyl-10-(3-4'-metyl-l'-piperazinylpropyl) fentiazin (5.2 g), k.p. 275—285° C/l mm Hg, oppnå-slik, og dihydrokloridet smelter ved ca. 210° C. The base which separates is extracted with ether (3 X 150 cm<3>), the ether is evaporated, and the residue is distilled in vacuo, l-phenyl-10-(3-4'-methyl-l'-piperazinylpropyl) phenthiazine (5.2 g) , k.p. 275—285° C/l mm Hg, obtain-thus, and the dihydrochloride melts at approx. 210°C.

Eksempel 38. Example 38.

Ved å gå frem som i eksempel 26, mer ved å begynne med 2 : 3-dimetylfentiazir (22.7 g), 85 pst. natriumamid (5 g), xylol (210 cm<3>) og 1-(3-klorpropyl)-4-metylpiperazin (19.4 g) i xylol (50 cm<3>), oppnå: 2 : 3-dimetyl-10-(3-4'-metyl-l'-piperazi-nyl)fentiazin (24.75 g), k.p. 215—225° C/ 0.2 mm Hg, hvis dihydroklorid smelter ved 238° C. 2 : 3-dimetylfentiazin (sm.p. 204° C), som tjener som utgangsmateriale, fremstilles ved innvirkning av svovel på 3:4-dimetyldifenylamin i nærvær av jod. Proceeding as in Example 26, more starting with 2 : 3-dimethylphenthiazire (22.7 g), 85% sodium amide (5 g), xylol (210 cm<3>) and 1-(3-chloropropyl)- 4-methylpiperazine (19.4 g) in xylol (50 cm<3>), obtain: 2 : 3-dimethyl-10-(3-4'-methyl-1'-piperazinyl)phenthiazine (24.75 g), b.p. 215—225° C/ 0.2 mm Hg, the dihydrochloride of which melts at 238° C. 2 : 3-dimethylphenthiazine (m.p. 204° C), which serves as starting material, is prepared by the action of sulfur on 3:4-dimethyldiphenylamine in presence of iodine.

Eksempel 39. Example 39.

10-(2-1'- piperazinetyl) fentiazin (9.3 g) oppvarmes under omrøring og tilbake-løp med n-propyl p-toluolsulfonat (9.6 g), 10-(2-1'- piperazineethyl) phenthiazine (9.3 g) is heated with stirring and refluxed with n-propyl p-toluenesulfonate (9.6 g),

vannfri natriumkarbonat (2.4 g) og absolutt etanol (15 cm<3>). Etter 6 timers oppvarming destilleres alkoholen fra, og residuet behandles med N natriumhydroksyd (45 cm<3>) og eter (100 cm<3>). Eterlaget dekanteres, det vandige lag vaskes med eter (60 cm<3>), og de kombinerte eteroppløsnin-ger behandles med N saltsyre (50 cm<3>). Den sure oppløsning rystes med natriumhydroksyd ( d = 1.33, 20 cm<3>) og derpå med eter (2 X 50 cm3).anhydrous sodium carbonate (2.4 g) and absolute ethanol (15 cm<3>). After 6 hours of heating, the alcohol is distilled off, and the residue is treated with N sodium hydroxide (45 cm<3>) and ether (100 cm<3>). The ether layer is decanted, the aqueous layer is washed with ether (60 cm<3>), and the combined ether solutions are treated with N hydrochloric acid (50 cm<3>). The acidic solution is shaken with sodium hydroxide (d = 1.33, 20 cm<3>) and then with ether (2 X 50 cm3).

Etter tørring og konsentrering oppnås basen (6 g). Hydrokloridet' fremstilles i alkohol-eter, og 10-(2-4'-propyl-l'-pipera-zinyletyl)fentiazin dihydroklorid (7.7 g) oppnås, som smelter ved 240° C (inst.) etter krystallisering fra etanol (5 deler). After drying and concentration, the base (6 g) is obtained. The hydrochloride' is prepared in alcohol-ether, and 10-(2-4'-propyl-1'-piperazinylethyl)phenthiazine dihydrochloride (7.7 g) is obtained, which melts at 240° C. (inst.) after crystallization from ethanol (5 parts).

Eksempel 40. Example 40.

10-(2-l'-piperazinetyl)fentiazin (6.2 g) 7i-butyl p-toluolsulfonat (6.9 g)„ vannfritt natriumkarbonat (1.6 g) og etanol (10 cm<3>) oppvarmes i 5 timer under tilbakeløp. Blandingen behandles med N natriumhydroksyd (30 cm<3>) og eter (2 X 50 cm<3>), og eteroppløsningen ekstraheres med N saltsyre (2 X 20 cm<3>). Det sure lag behandles derpå med vandig natriumhydroksyd ( d = 1.33, 10 cm<3>) og ekstraheres med eter (2 X 50 cm<3>). Etter konsentrering behandles 10-(2-1'-piperazineethyl)phenthiazine (6.2 g), 7i-butyl p-toluenesulfonate (6.9 g), anhydrous sodium carbonate (1.6 g) and ethanol (10 cm<3>) are heated for 5 hours under reflux. The mixture is treated with N sodium hydroxide (30 cm<3>) and ether (2 X 50 cm<3>), and the ether solution is extracted with N hydrochloric acid (2 X 20 cm<3>). The acidic layer is then treated with aqueous sodium hydroxide (d = 1.33, 10 cm<3>) and extracted with ether (2 X 50 cm<3>). After concentration is processed

basen med alkohol og eterisk klorvannstoff for å gi 10-(2-4'-butyl-l'-piperazinyletyl)-fentiazin dihydroklorid (4.5 g), som smelter ved 226° C (inst.). the base with alcohol and ethereal hydrogen chloride to give 10-(2-4'-butyl-1'-piperazinylethyl)-phenthiazine dihydrochloride (4.5 g), melting at 226° C. (inst.).

Eksempel 41. Example 41.

3-klor-10-(3-r-pierazin<y>lroyl) fentiazin (0.4 g) hydreres i 1 time ved normalt trykk og ved 20° C med 30 pst. formal-dehyd (0.3 g) og eddikksyre (10 cm<3>) i nærvær av for-redusert Adams' platinakataly-sator (0.2 g). 3-chloro-10-(3-r-pyrerazin<y>lroyl) phenthiazine (0.4 g) is hydrated for 1 hour at normal pressure and at 20° C with 30 per cent. formaldehyde (0.3 g) and acetic acid (10 cm<3>) in the presence of pre-reduced Adams' platinum catalyst (0.2 g).

Blandingen filtreres og, etter vasking av det faste stoff med vann (4 X 10 cm<3>), Tjøres alkalisk med natriumhydroksyd ( d = 1.33) og ekstraheres suksessivt med eter (3 X 25 cm<3>) og kloroform. Etter tørring destilleres oppløsningsmidlene fra og, etter behandling med eterisk klorvannstoff, oppnås 3-klor-10-(3-4'-metyl-l'-piperazinyl-propyl)-fentiazin dihydroklorid, sm.p. 195— 200° C (inst.). The mixture is filtered and, after washing the solid with water (4 X 10 cm<3>), made alkaline with sodium hydroxide ( d = 1.33) and extracted successively with ether (3 X 25 cm<3>) and chloroform. After drying, the solvents are distilled from and, after treatment with ethereal hydrogen chloride, 3-chloro-10-(3-4'-methyl-1'-piperazinyl-propyl)-phenthiazine dihydrochloride is obtained, m.p. 195— 200° C (inst.).

Eksempel 42: Example 42:

En oppløsning på 10-(2-4'-propionyl-l'-piperazinyletyl)-fentiazin (1.5 g) i tetrahydrofuran (8 cm<3>) tilsettes i løpet av 15 minutter til en 2 pst. eterisk oppløsning av litium aluminium hydrid (10 cm<3>). A solution of 10-(2-4'-propionyl-1'-piperazinylethyl)-phenthiazine (1.5 g) in tetrahydrofuran (8 cm<3>) is added over 15 minutes to a 2% ethereal solution of lithium aluminum hydride (10 cm<3>).

Blandingen oppvarmes under omrøring og tilbakeløp i 6 timer og, etter henstand over natt, behandles den suksessivt med vann (0.25 cm<3>), 15 pst. natriumhydroksyd (0.25 cm<3>), vann (7 cm<3>) og kloroform (20 cm<3>). Bunnfallet filtreres fra og vaskes med kloroform (5X5 cm<3>). Væskene tør-res over natriumsulfat og konsentreres, og etter tilsetning av eterisk klorvannstoff fås 10-(2-4'-propyl-l'-piperazinyletyl)-fentiazin dihydroklorid (1.5 g), som smelter ved 240° C (inst.) som i eksempel 39. The mixture is heated with stirring and reflux for 6 hours and, after standing overnight, is treated successively with water (0.25 cm<3>), 15% sodium hydroxide (0.25 cm<3>), water (7 cm<3>) and chloroform (20 cm<3>). The precipitate is filtered off and washed with chloroform (5X5 cm<3>). The liquids are dried over sodium sulfate and concentrated, and after addition of ethereal hydrogen chloride, 10-(2-4'-propyl-1'-piperazinylethyl)-phenthiazine dihydrochloride (1.5 g) is obtained, which melts at 240° C. (inst.) as in example 39.

10-(2-4'-propionyl-l'-piperazinyletyl)-fentiazin hydroklorid, sm.p. 165° C (inst.), oppnås ved innvirkning av propionylklorid på 10-(2-l'-piperazinyletyl)-fentiazin i nærvær av pyridin. 10-(2-4'-propionyl-1'-piperazinylethyl)-phenthiazine hydrochloride, m.p. 165° C (inst.), is obtained by the action of propionyl chloride on 10-(2-1'-piperazinylethyl)-phenthiazine in the presence of pyridine.

Ekseempel 43: Example 43:

En oppløsnnig av 3-klor-10- (3-4'-acetyl l'-piperazinyl-propyl)-fentiazin (0.6 g) i tetrahydrofuran (8 cm<3>) tilsettes i løpet av y2 time til en 2 pst. eteroppløsning av li-tiumaluminiumhydrid (10 cm<3>), og blandingen oppvarmes i 7 timer under tilbake-løp med omrøring. Den vanlige behandling gir 3-klor-10- (3-4'-etyl-l'-piperazinylpro-pyl)-fentiazin dihydroklorid, sm.p. 220— 225° C (inst.). A solution of 3-chloro-10-(3-4'-acetyl 1'-piperazinyl-propyl)-phenthiazine (0.6 g) in tetrahydrofuran (8 cm<3>) is added over y2 hours to a 2% ether solution of lithium aluminum hydride (10 cm<3>), and the mixture is heated for 7 hours under reflux with stirring. The usual treatment gives 3-chloro-10-(3-4'-ethyl-1'-piperazinylpropyl)-phenthiazine dihydrochloride, m.p. 220— 225° C (inst.).

3-klor-10-(3-4'-acetyl-l'-piperazinyl-propyl)-fentiazin hydroklorid, sm.p. 215° C (inst.), oppnås ved innvirkning av acetyl-klorid og pyridin på 3-klor-10-(3-l'-pipera-zinylpropyl) fentiazin. 3-chloro-10-(3-4'-acetyl-1'-piperazinyl-propyl)-phenthiazine hydrochloride, m.p. 215° C (inst.), is obtained by the action of acetyl chloride and pyridine on 3-chloro-10-(3-1'-piperazinylpropyl) phenthiazine.

Eksempel 44: 3-klor-10-[3-(di-N-2-kloretyl)amino-propyl]-fentiazin hydroklorid (1.8 g) oppvarmes i forseglet rør i 4 timer ved 140° C med en 290 g/l. vandig oppløsnnig (9 cm<3>) av monometylamin. Innholdet av røret behandles med kloroform (40 cm3). Det vandige lag dekanteres, og kloroformlaget rystes med N saltsyre (15 cm<3> fulgt av 2 cm<3>). Den vandige oppløsning behandles med natriumhydroksyd ( d = 1.33, 10 cm<3>) og kloroform (20 cm<3>). Etter fordampning av oppløsningsmidlet oppnås basen (1.5 g). En oppløsning av maleinsyre (lg) i etanol (5 cm<3>) tilsettes, og etter omkrystallisering fra vann oppnås 3-klor-10-(3-4'-metyl-l'-piperazinylpropyl)-fentiazin dimaleat, sm.p. 228° C. (inst.). Example 44: 3-chloro-10-[3-(di-N-2-chloroethyl)amino-propyl]-phenthiazine hydrochloride (1.8 g) is heated in a sealed tube for 4 hours at 140° C. with a 290 g/l. aqueous soluble (9 cm<3>) of monomethylamine. The contents of the tube are treated with chloroform (40 cm3). The aqueous layer is decanted, and the chloroform layer is shaken with N hydrochloric acid (15 cm<3> followed by 2 cm<3>). The aqueous solution is treated with sodium hydroxide (d = 1.33, 10 cm<3>) and chloroform (20 cm<3>). After evaporation of the solvent, the base (1.5 g) is obtained. A solution of maleic acid (lg) in ethanol (5 cm<3>) is added, and after recrystallization from water, 3-chloro-10-(3-4'-methyl-1'-piperazinylpropyl)-phenthiazine dimaleate is obtained, m.p. . 228° C. (inst.).

Eksempel 45: 10-(2-4'-benzyl-l'-piperazinyletyl)-fentiazin dihydroklorid (0.4 g) hydreres i eddiksyre (7 cm<3>) med palladisert trekull (0.5 g, 10 pst. palladium) ved 20° C og atmosfæ-risk trykk. Hydreringen er fullført etter 2 timer. Etter filtrering og vasking med vann ' gjøres alkalisk med konsentrert, vandig natriumhydroksyd, og den slik oppnådde base ekstraheres med eter (4 X 10 cm<3>). Behandling av basen med eter-klorvannstoff gir 10-(2-l'-piperazinyletyl)-fentiazin dihydroklorid (0.2 g), som etter omkrystallisering fra absolutt etanol, smelter ved 260° C (inst.). Example 45: 10-(2-4'-benzyl-1'-piperazinylethyl)-phenthiazine dihydrochloride (0.4 g) is hydrated in acetic acid (7 cm<3>) with palladium charcoal (0.5 g, 10% palladium) at 20° C and atmospheric pressure. Hydration is complete after 2 hours. After filtering and washing with water ' is made alkaline with concentrated aqueous sodium hydroxide, and the base thus obtained is extracted with ether (4 X 10 cm<3>). Treatment of the base with ether-hydrogen chloride gives 10-(2-1'-piperazinylethyl)-phenthiazine dihydrochloride (0.2 g), which, after recrystallization from absolute ethanol, melts at 260° C. (inst.).

Eksempel 46: 10-(2-4'-fenyl-l'-piperazinyletyl)-fentiazin hydroklorid (1.15 g), omrørt med dimetylformamid (20 cm<3>) og saltsyre ( d = 1.19, 2 cm<3>), behandles med en oppløsning av natrium-nitrit (0.2 g) i vann (2 cm<3>), og temperaturen holdes under 0° C. Etter 1 time tilsettes natrium bisulfit ( d —- 1.33, 3 cm<3>), og etter henstand over natt behandles blandingen med natriumhydroksyd ( d = 1.33, 6 cm<3>) og vann (20 cm<3>). Den rystes derpå med kloroform (2 X 25 cm3) og, etter tilsetning av eterklorvannstoff, oppnås 10-(2-l'-piperazinyletyl)-fentiazin dihydroklorid (0.9 g), sm.p. 260° C (inst.). Example 46: 10-(2-4'-phenyl-1'-piperazinylethyl)-phenthiazine hydrochloride (1.15 g), stirred with dimethylformamide (20 cm<3>) and hydrochloric acid (d = 1.19, 2 cm<3>), treated with a solution of sodium nitrite (0.2 g) in water (2 cm<3>), and the temperature is kept below 0° C. After 1 hour, sodium bisulphite ( d —- 1.33, 3 cm<3>) is added, and after standing overnight, the mixture is treated with sodium hydroxide (d = 1.33, 6 cm<3>) and water (20 cm<3>). It is then shaken with chloroform (2 X 25 cm 3 ) and, after addition of ether hydrogen chloride, 10-(2-1'-piperazinylethyl)-phenthiazine dihydrochloride (0.9 g) is obtained, m.p. 260° C (inst.).

Eksempel 47: 10-(2-4'-etoksykarbonyl-r-piperaz'inyl-etyl)-fentiazin (1 g) oppvarmes i 24 timer under tilbakeløp med alkoholisk kalium-hydroksyd (250 g pr. liter, 15 cm<3>). Oppløs-ningen konsentreres og behandles med vann (5 cm<3>) og eter (4 X 10 cm<3>). Tilsetningen av eter-klorvannstoff gir 10-(2-1'-piperazinyletyl) -fentiazin dihydroklorid (0.7 g), som, etter omkrystallisering fra etanol, smelter ved 260° C (inst.). Example 47: 10-(2-4'-ethoxycarbonyl-r-piperazinyl-ethyl)-phenthiazine (1 g) is heated for 24 hours under reflux with alcoholic potassium hydroxide (250 g per liter, 15 cm<3> ). The solution is concentrated and treated with water (5 cm<3>) and ether (4 X 10 cm<3>). The addition of ether-hydrogen chloride gives 10-(2-1'-piperazinylethyl)-phenthiazine dihydrochloride (0.7 g), which, after recrystallization from ethanol, melts at 260° C. (inst.).

10-(2-4'-etoksykarbonyl-l'-piperazinyl-etyl-)-fentiazin kan oppnås ved å oppvar-me 10-(2-kloretyl)-fentiazin (10.5 g) med 1-etoksykarbonylpiperazin (31.6 g) i 4 timer ved 195° C og derpå behandle blandingen med vann (30 cm<3>) og eter (2 X 20 cm<3>). Eteroppløsningen rystes med 10 pst. saltsyre (35 cm<3>), og behandling med natriumhydroksyd og eter gir 10-(2-4'-etoksykarbo-nyl-l'-piperazinyletyl)-fentiazin (16.5 g), sm.p. 95° C (inst.). 10-(2-4'-ethoxycarbonyl-1'-piperazinyl-ethyl-)-phenthiazine can be obtained by heating 10-(2-chloroethyl)-phenthiazine (10.5 g) with 1-ethoxycarbonylpiperazine (31.6 g) in 4 hours at 195° C and then treat the mixture with water (30 cm<3>) and ether (2 X 20 cm<3>). The ether solution is shaken with 10% hydrochloric acid (35 cm<3>), and treatment with sodium hydroxide and ether gives 10-(2-4'-ethoxycarbonyl-1'-piperazinylethyl)-phenthiazine (16.5 g), m.p. 95° C (inst.).

Eksempel 48: 10-(2-4'-dietylkarbamyl-l'-piperazinyl-etyl)-fentiazin hydroklorid (0.3 g) oppvarmes i 30 timer under tilbakeløp med saltsyre ( d = 1.19, 7 cm<3>). Vann (20 cm<3>) tilsettes så, en liten mengde av uoppløselige stoffer filtreres fra, og den vandige oppløs-ning behandles med natriumhydroksyd-oppløsning ( d = 1.55, 8 cm<3>). Ekstraksjon med kloroform (2 X 20 cm<3>), tørring over natriumsulfat, konsentrering og behandling med eter-klorvannstoff gir 10-(2-l'-pipera-zinyletyl)-fentiazin dihydroklorid (0.15 g), som, etter omkrystallisering fra etanol, smelter ved 260° C (inst.). Example 48: 10-(2-4'-diethylcarbamyl-1'-piperazinyl-ethyl)-phenthiazine hydrochloride (0.3 g) is heated for 30 hours under reflux with hydrochloric acid (d = 1.19, 7 cm<3>). Water (20 cm<3>) is then added, a small amount of insoluble substances is filtered off, and the aqueous solution is treated with sodium hydroxide solution (d = 1.55, 8 cm<3>). Extraction with chloroform (2 X 20 cm<3>), drying over sodium sulfate, concentration and treatment with ether-hydrogen chloride gives 10-(2-1'-piperazinylethyl)-phenthiazine dihydrochloride (0.15 g), which, after recrystallization from ethanol, melts at 260° C (inst.).

10-(2-4'-dietylkarbamyl-l'-piperazinyl-etyl)-fentiazin kan oppnås ved oppvarming av 10-(2-kloretyl)-fentiazin (5.2 g) med 1-dietylkarbamylpiperazin (18.5 g) i 5 timer ved 200° C. Den vanlige behandling gir 10-(2-4'-dietyl-karbamyl-l'-piperazinyletyl)-fentiazin hydroklorid (6 g), sm.p. 128—184° C (inst.). 10-(2-4'-diethylcarbamyl-1'-piperazinyl-ethyl)-phenthiazine can be obtained by heating 10-(2-chloroethyl)-phenthiazine (5.2 g) with 1-diethylcarbamylpiperazine (18.5 g) for 5 hours at 200 ° C. The usual treatment gives 10-(2-4'-diethyl-carbamyl-1'-piperazinylethyl)-phenthiazine hydrochloride (6 g), m.p. 128—184° C (inst.).

De følgende derivater kan også bli behandlet på samme måte: 10- (2-4'-dimetylkarbamyl-1 '-piperazi-nyletyl-)fentiazin hydroklorid, sm.p. 215° C (inst.). The following derivatives can also be treated in the same way: 10-(2-4'-dimethylcarbamyl-1'-piperazi-nylethyl-)phenthiazine hydrochloride, m.p. 215° C (inst.).

10-(2-4'-fenylkarbamyl-l'-piperazinyl-etyl)-fentiazin, sm.p. 160° C (inst.). 10-(2-4'-phenylcarbamyl-1'-piperazinyl-ethyl)-phenthiazine, m.p. 160° C (inst.).

10- (2-4'-karbamyl-l'-piperazinyletyl) - fentiazin hydroklorid, sm.p. 180° C (inst.). 10-(2-4'-carbamyl-1'-piperazinylethyl)-phenthiazine hydrochloride, m.p. 180° C (inst.).

Eksempel 49: 3-klor-10-(2-kloretyl)-fentiazin (29.6 g) oppvarmes i 6 timer under tilbakeløp med vannfri piperazin (26 g) og metanol (30 cm<3>). Blandingen behandles derpå med kloroform (100 cm<3>) og vann (100 cm<3>) og filtreres, og kloroformlaget omrøres med 10 pst. saltsyre (100 cm<3>). Det vandige lag behandles med vandig natriumhydroksyd (d= 1 33, 40 cm<3>), og basen ekstraheres med kloroform (2 X 50 em<s>). Etter at kloroform er fordampet, oppnås den rå base (27.7 g), til hvilken tilsettes etylacetat (200 cm<3>) og en varm oppløsning av maleinsyre (20.8 g) i etylacetat (600 cm<3>). Et maleat oppnås som omkrystalliseres fra etanol (1.200 cm<3>) for å gi 3-klor-10-(2-l'-piperazinyletyl)-fentiazin dimaleat (34.8 g), sm.p. 195° C. Example 49: 3-chloro-10-(2-chloroethyl)-phenthiazine (29.6 g) is heated for 6 hours under reflux with anhydrous piperazine (26 g) and methanol (30 cm<3>). The mixture is then treated with chloroform (100 cm<3>) and water (100 cm<3>) and filtered, and the chloroform layer is stirred with 10% hydrochloric acid (100 cm<3>). The aqueous layer is treated with aqueous sodium hydroxide (d= 1 33.40 cm<3>), and the base is extracted with chloroform (2 X 50 em<s>). After the chloroform is evaporated, the crude base (27.7 g) is obtained, to which are added ethyl acetate (200 cm<3>) and a hot solution of maleic acid (20.8 g) in ethyl acetate (600 cm<3>). A maleate is obtained which is recrystallized from ethanol (1,200 cm<3>) to give 3-chloro-10-(2-1'-piperazinylethyl)-phenthiazine dimaleate (34.8 g), m.p. 195°C.

Eksempel 50: 3-etylfentiazin (5.7 g) oppvarmes i 1 time under tilbakeløp med natriumamid (3.6 g) i xylol (150 cm<3>), l-metyl-4-(3-klorpropyl) -piperazin dihydroklorid (7.5 g) tilsettes i løpet av y4 time, og oppvarming under tilbakeløp fortsettes i 6 timer. Vann (100 cm<3>) tilsettes derpå og xylollaget røres med 7 pst. saltsyre (50 cm<3> fulgt av 25 cm<3>). Det vandige lag behandles med vandig natriumhydroksyd (d = 1.33, 25 cm<3>), og basen ekstraheres med eter (2 X 25 cm<3>). Etter fordampning av eteren oppnås den rå base (9 g), som rives med en varm opp-løsning av maleinsyre (5.8 g) i etylacetat (150 cm<3>) for å gi 3-etyl-10-(3-4'-metyl-l'-piperazinylpropyl)fentiazin dimaleat (12 g), sm.p. 200° C, som kan omkrystalliseres fra vann. Example 50: 3-ethylphenthiazine (5.7 g) is heated for 1 hour under reflux with sodium amide (3.6 g) in xylol (150 cm<3>), 1-methyl-4-(3-chloropropyl)-piperazine dihydrochloride (7.5 g) is added during y4 hours, and heating under reflux is continued for 6 hours. Water (100 cm<3>) is then added and the xylene layer is stirred with 7% hydrochloric acid (50 cm<3> followed by 25 cm<3>). The aqueous layer is treated with aqueous sodium hydroxide (d = 1.33, 25 cm<3>), and the base is extracted with ether (2 X 25 cm<3>). After evaporation of the ether, the crude base (9 g) is obtained, which is triturated with a hot solution of maleic acid (5.8 g) in ethyl acetate (150 cm<3>) to give 3-ethyl-10-(3-4' -methyl-1'-piperazinylpropyl)phenthiazine dimaleate (12 g), m.p. 200° C, which can be recrystallized from water.

Eksempel 51. Example 51.

2 : 5-dimetylpiperazin (6.9) g) oppvarmes i 7 timer under tilbakeløp med 3-klor-10-(3-hydroksypropyl)fentiazin p-toluolsulfonat (8.9 g) og metanol (10 cm<3>). Blandingen behandles med kloroform (100 cm<3>) og vann (100 cm<3>), og kloroformlaget røres med 10 pst. saltsyre (25 cm<3>). Det vandige lag filtreres, som vandig natriumhydroksyd ( d = 1.33, 10 cm<3>) tilsettes. Basen ekstraheres med kloroform (3 X 25 2 : 5-dimethylpiperazine (6.9) g) is heated for 7 hours under reflux with 3-chloro-10-(3-hydroxypropyl)phenthiazine p-toluenesulfonate (8.9 g) and methanol (10 cm<3>). The mixture is treated with chloroform (100 cm<3>) and water (100 cm<3>), and the chloroform layer is stirred with 10% hydrochloric acid (25 cm<3>). The aqueous layer is filtered, to which aqueous sodium hydroxide ( d = 1.33, 10 cm<3>) is added. The base is extracted with chloroform (3 X 25

cm<3>), og etter fordampning av kloroform oppnås den rå base (4 g), som behandles med eterklorvannstoff for å gi 3-klor-10-(3-2' : 5'-dimetyl-l'-piperazinylpropyl)-fentiazin dihydroklorid (2.7 g), sm.p. 195°C. cm<3>), and after evaporation of chloroform the crude base (4 g) is obtained, which is treated with ether hydrogen chloride to give 3-chloro-10-(3-2' : 5'-dimethyl-1'-piperazinylpropyl)- phenthiazine dihydrochloride (2.7 g), m.p. 195°C.

Eksempel 52. Example 52.

En blanding av 10-(2-klorpropyl)fentiazin (13.8 g) og vannfri piperazin (13 g) smeltes sammen ved oppvarming i et olje-bad i 7 timer ved 160° C. Blandingen behandles derpå med vann (40 cm<3>) og kloroform (60 cm<3>), og kloroformlaget røres med 10 pst. saltsyre (40 cm3), og det vandige lag A mixture of 10-(2-chloropropyl)phenthiazine (13.8 g) and anhydrous piperazine (13 g) is fused together by heating in an oil bath for 7 hours at 160° C. The mixture is then treated with water (40 cm<3> ) and chloroform (60 cm<3>), and the chloroform layer is stirred with 10% hydrochloric acid (40 cm3), and the aqueous layer

filtreres derpå og behandles med vandig natriumhydroksyd ( d = 1.33, 30 cm<3>). Basen ekstraheres med kloroform (2 X 20 cm<3>), og etter fordampning av kloroformen isoleres den rå base (5.9 g) og behandles med maleinsyre (4.2 g) i etylacetat (50 cm<3>) for å gi 10-(2-l'-piperazinylpropyl)-fentiazin dimaleat (8.1 g), sm.p. 160° C, som kan omkrystalliseres fra etanol. is then filtered and treated with aqueous sodium hydroxide ( d = 1.33, 30 cm<3>). The base is extracted with chloroform (2 X 20 cm<3>), and after evaporation of the chloroform, the crude base (5.9 g) is isolated and treated with maleic acid (4.2 g) in ethyl acetate (50 cm<3>) to give 10-( 2-1'-piperazinylpropyl)-phenthiazine dimaleate (8.1 g), m.p. 160° C, which can be recrystallized from ethanol.

Eksempel 53. Example 53.

10-(3-klorpropyl)fentiazin (7.5 g) oppvarmes i 5V2 time under tilbakeløp med vannfri piperazin (7 g) og metanol (10 cm<3>). Vann (30 cm<3>) og kloroform (2 X 20 cm<3>) tilsettes derpå, og kloroformlaget 10-(3-Chloropropyl)phenthiazine (7.5 g) is heated for 5V2 hours under reflux with anhydrous piperazine (7 g) and methanol (10 cm<3>). Water (30 cm<3>) and chloroform (2 X 20 cm<3>) are then added, and the chloroform layer

røres med 9 pst. saltsyre (20 cm<3>). Det vandige sure lag gjøres alkalisk med natriumhydroksyd ( d = 1.33, 10 cm<3>), og basen ekstraheres med kloroform (2 X 20 cm3). stirred with 9 per cent hydrochloric acid (20 cm<3>). The aqueous acid layer is made alkaline with sodium hydroxide (d = 1.33, 10 cm<3>), and the base is extracted with chloroform (2 X 20 cm3).

Etter konsentrering isoleres basen (6.7 g) og behandles med maleinsyre (6 g) og etylacetat (150 cm<3>) for å gi 10-(3-1'-piperazinylpropyl)fentiazin dimaleat (7.7 After concentration, the base (6.7 g) is isolated and treated with maleic acid (6 g) and ethyl acetate (150 cm<3>) to give 10-(3-1'-piperazinylpropyl)phenthiazine dimaleate (7.7

g), sm.p. 185° C. g), sm.p. 185°C.

Eksempel 54. Example 54.

Fentiazin (8 g) oppvarmes i en time under tilbakeløp med natriumamid (1.8 g) og xylol (100 cm<3>), og en oppløsning av 1-(3-klorpropyl)-4-metylpiperazin (8.5 g) i xylol (20 cm<3>) tilsettes derpå dråpevis i løpet av 2 timer. Blandingen oppvarmes under tilbakeløp i 5 timer og behandles derpå med vann (100 cm<3>) og med eter (100 cm<3>). Eter-xylollaget røres med 7 pst. saltsyre (60 cm3 fulgt av 2 X 20 cm<3>), det vandige sure lag gjøres alkalisk med natriumhydroksyd ( d = 1.33, 40 cm<3>), og basen ekstraheres med eter (3 X 50 cm<3>). Phenthiazine (8 g) is heated for one hour under reflux with sodium amide (1.8 g) and xylol (100 cm<3>), and a solution of 1-(3-chloropropyl)-4-methylpiperazine (8.5 g) in xylol (20 cm<3>) is then added dropwise over the course of 2 hours. The mixture is heated under reflux for 5 hours and then treated with water (100 cm<3>) and with ether (100 cm<3>). The ether-xylene layer is stirred with 7% hydrochloric acid (60 cm3 followed by 2 X 20 cm<3>), the aqueous acid layer is made alkaline with sodium hydroxide ( d = 1.33, 40 cm<3>), and the base is extracted with ether (3 X 50 cm<3>).

Etter konsentrering isoleres basen (13 After concentration, the base is isolated (13

g)' og behandles med maleinsyre (9 g) og etylacetat (230 cm<3>). Det rå maleat omkrystalliseres fra kokende vann (750 cm<3>), og 10- (3-4'-metyl-l'-piperazinylpropyl) - fentiazin dimaleat (15 g) oppnås, sm.p. 210° C. g)' and treated with maleic acid (9 g) and ethyl acetate (230 cm<3>). The crude maleate is recrystallized from boiling water (750 cm<3>), and 10-(3-4'-methyl-1'-piperazinylpropyl)-phenthiazine dimaleate (15 g) is obtained, m.p. 210°C.

Det skal bemerkes at i foranstående beskrivelse og etterfølgende påstander er systemet for nummereringen av substitu-entene i fentiazinringen ifølge Beilstein. It should be noted that in the preceding description and subsequent claims, the system for numbering the substituents in the phenthiazine ring is according to Beilstein.

Claims

1. Process for the preparation of phenthiazine compounds of the formula

in which A means a divalent, saturated straight or branched chain aliphatic carbon hydrogen radical containing from 2 to 6 carbon atoms, Ri means a hydrogen atom or a lower alkyl or an aryl or araliphatic group, Y and Yi are respectively a hydrogen or halogen atom or a lower alkyl, alkoxy or aryl or aryloxy group, and where the phenthiazine ring may contain substituents in addition to Y and Yi, and one or more carbon atoms in the piperazine ring may be a substituent in the form of a methyl group, characterized in that a phenthiazine compound with the formula in which the phenthiazine ring may contain substituents in addition to Y and/or Yi, is reacted with a compound Q, and the group P and the compound Q are such that Q will react with the compound of said formula to introduce or form in the 10-position of ring-gen a substituent group with the structure: in which one or more of the carbon atoms in the piperazine ring may contain a substituent in the form of a methyl group, Ai means a divalent, saturated, straight or branched chain aliphatic carbon hydrogen radical containing 2 to 6 carbon atoms or a divalent group which can be converted thereto by reduction, R" means a hydrogen atom or a lower alkyl, aryl or aliphatic group or a group which can are converted into these and Y and Yi are each as defined above and, where either one or both of said starting materials contain one or more "convertible" groups as indicated above, conversion of the convertible group or groups into the desired finite atom and/ or group.

2. Method as stated in claim 1, characterized by the action of a phenothiazine with the general formula: on a piperazine derivative of the general formula: where X means the residue of a reactive ester.

3. Method as stated in claim 1, characterized by the action of a phenothiazine with the general formula: on a piperazine derivative of the general formula: where X means the residue of a reactive ester.

4. Process as set forth in claim 1, characterized by, in the case of the preparation of compounds in which the piperazine ring does not contain any substituent on a carbon atom, the action of a compound of the general formula: on an amine of the general formula R2NH2, where X means the residue of a reactive ester.