DK146763B - ANALOGY PROCEDURE FOR THE PREPARATION OF 1-SUBSTITUTED 4- (1,2-DIPHENYLETHYL) PIPERAZINE DERIVATIVES - Google Patents

Description

(19) DANMARK (®)(19) DENMARK (®)

§<12) FREMLÆGGELSESSKRIFT ud 146763 B§ <12) SUBMISSION WRITING out 146763 B

DIREKTORATET FOR PATENT- OG VAREMÆRKEVÆSENETDIRECTORATE OF THE PATENT AND TRADEMARKET SYSTEM

(21) Patentansøgning nr.: 3802/76 (51) lnt.CI.3: C 07 D 295/08 (22) Indleveringsdag: 24 aug 1976 (41) Aim. tilgængelig: 25 feb 1978 (44) Fremlagt: 27 dec 1983 (86) International ansøgning nr.: - (30) Prioritet:- (71) Ansøger: ‘DAINIPPON PHARMACEUTICAL CO. LTD.; Osaka-shi, JP.(21) Patent Application No: 3802/76 (51) Lnt.CI.3: C 07 D 295/08 (22) Filing Date: 24 Aug 1976 (41) Aim. available: 25 Feb 1978 (44) Submitted: 27 Dec 1983 (86) International Application No: - (30) Priority: - (71) Applicant: 'DAINIPPON PHARMACEUTICAL CO. LTD .; Osaka-shi, JP.

(72) Opfinder: Haruki ‘Nishlmura; JP, Hitoshi *Uno; JP, Kagayakl ’Natsuka; JP, Norlaki ’Shlmokawa; JP,(72) Inventor: Haruki 'Nishlmura; JP, Hitoshi * Uno; JP, Kagayakl 'Natsuka; JP, Norlaki 'Shlmokawa; JP,

Masanao ’Shimizu; JP, Hideo ’Nakamura; JP.Masanao 'Shimizu; JP, Hideo 'Nakamura; JP.

(74) Fuldmægtig; Plougmann & Vingtoft Patentbureau (54) Analogifremgangsmåde til fremstilling af 1-sub-stituerede 4—(1,2-dipheny lethyl)piperazinderi- vater(74) Plenipotentiary; Plougmann & Vingtoft Patent Bureau (54) Analogous Process for Preparation of 1-Substituted 4- (1,2-Diphenylethyl) Piperazine Derivatives

Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af hidtil ukendte, farmaceutisk aktive 1-substitueredeThe present invention relates to an analogous process for the preparation of novel, pharmaceutically active 1-substituted

4-(1,2-diphenylethyl)piperazinderivater med den almene formel I4- (1,2-diphenylethyl) piperazine derivatives of the general formula I

OISLAND

® \—ch-ch-e/ Vr i o \=/ 2 \_/ (O x S ox® \ —ch-ch-e / Vr i o \ = / 2 \ _ / (O x S ox

<D<D

T“ * o 2 U6763 hvor X betegner hydrogen, methyl eller alkanoyl med 2-5 car-bonatomer, og R betegner allyl, 3-hydroxyisoamyl, 3-methyl-2-bu-tenyl, 3-methyl-3-butenyl, propyl, usubstitueret monocycloalkyl med 6-8 carbonatomer, 2-chlorphenyl eller phenyl, som er substitueret med hydroxy eller methoxy, med det forbehold, at når X betegner methyl, betegner R 3-methyl-2-butenyl, 3-methyl-3-bute-nyl eller 2-methoxyphenyl, eller farmaceutisk tolerable syreadditionssalte deraf, hvilken fremgangsmåde er ejendommelig ved det i krav l's kendetegnende del angivne.Wherein X represents hydrogen, methyl or alkanoyl having 2 to 5 carbon atoms and R represents allyl, 3-hydroxyisoamyl, 3-methyl-2-butenyl, 3-methyl-3-butenyl, propyl , unsubstituted monocycloalkyl having 6-8 carbon atoms, 2-chlorophenyl or phenyl substituted with hydroxy or methoxy, with the proviso that when X represents methyl, R represents 3-methyl-2-butenyl, 3-methyl-3-butane -nyl or 2-methoxyphenyl, or pharmaceutically tolerable acid addition salts thereof, which is characterized by the characterizing part of claim 1.

De ner omnanaxeae foroindelser har et asymmetrisk carbonaLom i molekylet, og der kan derfor optræde optiske isomere. Den foreliggende opfindelse omfatter fremstillingen af alle disse optisk aktive isomere og racemiske forbindelser deraf.The omnanaxial compounds have an asymmetric carbon atom in the molecule and therefore optical isomers can occur. The present invention encompasses the preparation of all these optically active isomers and racemic compounds thereof.

Der kendes nogle forbindelser, som har en struktur, der er analog med de her omhandlede forbindelsers struktur. F.eks. beskrives det i japansk patentpublikation nr. 6304/1972 (Chem. Abstr., bind 77,Some compounds are known which have a structure analogous to the structure of the compounds of the present invention. Eg. is disclosed in Japanese Patent Publication No. 6304/1972 (Chem. Abstr., Vol. 77,

5521, 1972), at forbindelserne med formlen X5521, 1972) that the compounds of formula X

/Γλ T t \ <t\)-CH2-CH-K^_ Ν’-R ’ x Ύ' hvor R' betegner hydrogen, alkyl, aralkyl, aryl, alkenyl, cycloalkyl, hydroxyalkyl eller N-dialkylaminoalkyl, og Y og Y' har ens eller forskellig betydning og hver betegner hydrogen eller halogen, har en ikke nærmere angivet fremragende farmakologisk aktivitet./ Γλ T t (<t \) - CH 2 -CH-K 2 Ν'-R 'x Ύ' wherein R 'represents hydrogen, alkyl, aralkyl, aryl, alkenyl, cycloalkyl, hydroxyalkyl or N-dialkylaminoalkyl, and Y and Y 'has the same or different meaning and each represents hydrogen or halogen, has an unspecified excellent pharmacological activity.

Desuden beskrives i japansk patentpublikation nr. 188/1974 (Chem. Abstr., bind 81, 37579, 1974) en optisk opspaltning af dl-1-(1,2-diphenylethyl)-4-cyclohexylpiperazin med formlen XIIn addition, Japanese Patent Publication No. 188/1974 (Chem. Abstr., Vol. 81, 37579, 1974) discloses an optical cleavage of dl-1- (1,2-diphenylethyl) -4-cyclohexylpiperazine of formula XI

3 1467633 146763

OISLAND

<^ch2-ch-/>^ XI<^ ch2-ch - /> ^ XI

som et eksempel på en forbindelse med den ovenstående formel X. Det beskrives også i The Japanese Journal of Pharmacology, supplementsbind til bind 22, side 88 (27. april 1972), at forbindelsen XI har en morphinlignende analgetisk aktivitet, og dens (S)-optiske isomer viser 20 - 35 gange stærkere analgetisk aktivitet end dens (R)-optiske isomer.as an example of a compound of formula X above. It is also disclosed in The Japanese Journal of Pharmacology, Supplementary Volume 22, page 88 (April 27, 1972), that compound XI has a morphine-like analgesic activity and its (S) -optic isomer shows 20 - 35 times stronger analgesic activity than its (R) -optic isomer.

Endvidere beskrives i J. Med. Chem., bind 18, side 1240 (1975) dl-1-(3-methyl-2-butenyl)- og dl-l-cyclooctyl-4-(1,2-diphenylethyl)-piperazin og lignende forbindelser, der er andre forbindelser med formlen X, og det beskrives på dette litteratursted, at nogle forbindelser, som indeholder en cyclohexyl-, cycloheptyl- eller cyclo-octylgruppe, har en udtalt analgetisk aktivitet.Furthermore, J. Med. Chem., Vol. 18, page 1240 (1975) dl-1- (3-methyl-2-butenyl) - and dl-1-cyclooctyl-4- (1,2-diphenylethyl) -piperazine and similar compounds which are other compounds of formula X, and it is described in this literature that some compounds which contain a cyclohexyl, cycloheptyl or cyclooctyl group have a pronounced analgesic activity.

Det beskrives i USA-patentskrift nr. 3,957,788, at forbindelserne med formlen XIIUS Patent No. 3,957,788 discloses that the compounds of formula XII

__

γ··-^λ_0Η2-0Η-1^_^N-ft" XIIγ ·· - ^ λ_0Η2-0Η-1 ^ _ ^ N-ft „XII

hvor Y" betegner hydroxy, methoxy, methyl eller trifluormethyl, og R" betegner en usubstitueret monocycloalkylgruppe med 6-8 carbonatomer eller 2-methoxyphenyl, med det forbehold, at når Y" betegner hydroxy, betegner R" cyclohexyl, og når Y" betegner trifluormethyl, betegner R" 2-methoxyphenyl, har farmakologisk aktivitet såsom analgetisk, antitussiv og antiinflammatorisk aktivitet .wherein Y "represents hydroxy, methoxy, methyl or trifluoromethyl, and R" represents an unsubstituted monocycloalkyl group of 6-8 carbon atoms or 2-methoxyphenyl, with the proviso that when Y "represents hydroxy, R" represents cyclohexyl and when Y "represents trifluoromethyl, designated R "2-methoxyphenyl, has pharmacological activity such as analgesic, antitussive and anti-inflammatory activity.

Ved omfattende undersøgelser har det nu vist sig, at når en hydroxy-, methoxy- eller alkanoyloxygruppe indføres i 3-stillingen i den phenylgruppe, der er bundet i ethylgruppens 2-stilling i visse 1-substituerede 4-(1,2-diphenylethyl)piperazinderivater, udviser forbindelserne bemærkelsesværdig fremragende analgetisk aktivitet, og 4 146763 det har vist sig, at de hidtil ukendte piperazinderivater med den almene formel I og farmaceutisk tolerable syreadditionssalte deraf udviser kraftigere analgetisk aktivitet end de ovenfor anførte kendte forbindelser. &—Isomere af disse forbindelser er særlig foretrukne, idet de ikke har morphinlignende fysisk "dependence-liability" . Endvidere udviser nogle af de ί,-isomere også en narkotisk antagonistisk aktivitet. Eksempler på sådanne er Jl-isomere af forbindelser med den almene formel I, hvor R betegner 3-methyl- 2-butenyl eller allyl, eller hvor X betegner hydrogen, og R betegner cyclohexyl. De her omhandlede forbindelser er således anvendelige som et analgetisk middel.Extensive studies have now shown that when a hydroxy, methoxy, or alkanoyloxy group is introduced into the 3-position of the phenyl group attached to the 2-position of the ethyl group in certain 1-substituted 4- (1,2-diphenylethyl) piperazine derivatives, the compounds exhibit remarkably excellent analgesic activity, and it has been found that the novel piperazine derivatives of the general formula I and pharmaceutically tolerable acid addition salts thereof exhibit stronger analgesic activity than the above known compounds. & - Some of these compounds are particularly preferred in that they do not have morphine-like physical dependence liability. In addition, some of the isomers also exhibit narcotic antagonistic activity. Examples of such are J1 isomers of compounds of the general formula I wherein R represents 3-methyl-2-butenyl or allyl or where X represents hydrogen and R represents cyclohexyl. Thus, the compounds of the present invention are useful as an analgesic agent.

Særlig egnede forbindelser af de her omhandlede forbindelser er følgende: (3-methyl-2-butenyl)-4-[2-(3-hydroxyphenyl)-1-phenylethyl]pipe-razin, i-1“i 3-methyl-2-butehyl)-4-[2-(3-methoxyphenyl)-1-phenylethyl]pipera-zin, l-cyclohexyl-4-[2-(3-hydroxyphenyl)-1-phenylethyl]piperazin, og farmaceutisk tolerable syreadditionssalte deraf.Particularly suitable compounds of the present compounds are the following: (3-methyl-2-butenyl) -4- [2- (3-hydroxyphenyl) -1-phenylethyl] piperazine, i-1 ”in 3-methyl-2 -butyl) -4- [2- (3-methoxyphenyl) -1-phenylethyl] piperazine, 1-cyclohexyl-4- [2- (3-hydroxyphenyl) -1-phenylethyl] piperazine, and pharmaceutically tolerable acid addition salts thereof.

De her omhandlede forbindelsers aktiviteter belyses ved følgende forsøg: 1) Analgetisk aktivitet: i) D'Amour-Smith's metode (jævnfør F.E.D'Amour og D.L.Smith, J. Pharmacol. Exp. Ther., bind 72, side 74, 1941).The activities of the compounds of this invention are illustrated by the following experiments: 1) Analgesic activity: (i) D'Amour-Smith's method (cf. FED'Amour and DLSmith, J. Pharmacol. Exp. Ther., Vol. 72, pages 74, 1941) .

Termisk smerte induceres ved at rette varmestråler mod den med sort blæk sværtede hale af hanmus af stammen ddN, hvilke mus vejer 9 - 12 g, under anvendelse af D1 Amour-Smith's modificerede apparatur. Den analgetiske ED5Q-værdi (mg/kg) beregnes ud fra det antal dyr, som positivt viser en respons-forlængeIse på mere end 100% sammenlignet med de foregående værdier.Thermal pain is induced by directing heat rays to the tail of black ink of male ddN strain, which weighs 9 - 12 g, using D1 Amour-Smith's modified apparatus. The analgesic ED5Q value (mg / kg) is calculated from the number of animals that positively show a response elongation of more than 100% compared to the previous values.

ii) Haffner-metoden (jævnfør F.Haffner, Deut. Med. Wochschr., bind 55, side 731, 1929).ii) The Haffner method (cf. F. Haffner, Deut. Med. Weekly, vol. 55, pages 731, 1929).

5 1467635 146763

Mekanisk smerte induceres ved at presse halen hos hanrotter af Wistar-stammen og med en vægt på 90 - 110 g under anvendelse af Haffner's modificerede apparatur. Den analgetiske EDc„-værdi (mg/kg) beregnes ud fra det antal dyr, som positivt viser en smertetærskel på 40 mm eller derover (normalværdien er ca. 20 mm).Mechanical pain is induced by squeezing the tail of male rats of the Wistar strain and weighing 90 - 110 g using Haffner's modified apparatus. The analgesic EDc "value (mg / kg) is calculated from the number of animals that positively show a pain threshold of 40 mm or more (the normal value is about 20 mm).

iii) Phenylquinonmetoden (jævnfør E.Siegmund, R.Cadmus og G.Lu,(iii) the phenylquinone method (cf. E.Siegmund, R. Cadmus and G.Lu,

Proc. Soc. Exptl. Biol. Med., bind 95, side 729, 1957).Proc. Soc. Exp. Biol. Med., Vol. 95, pages 729, 1957).

Kemisk smerte induceres ved intraperitoneal injektion af 0,1 ml/ 10 g legemsvægt af 0,03% phenylquinon i 5%'s vandigt ethanol til hunmus med en vægt på 18 - 22 g og af stammen ddN. Medikamenterne indgives 30 minutter før doseringen med phenylquinon.Chemical pain is induced by intraperitoneal injection of 0.1 ml / 10 g body weight of 0.03% phenylquinone in 5% aqueous ethanol for female mice weighing 18-22 g and of the strain ddN. The drugs are administered 30 minutes before dosing with phenylquinone.

Forsøgsresultaterne er anført i nedenstående tabel I - III.The test results are listed in Tables I - III below.

Tabel I.Table I.

Forsøgs- Analgetisk aktivitet ED5Q-værdi (mg/kg) forbin- D'Amour-Smith-metode Phenylquinonmetode delse x (subcutant) (peroralt) 1 2 3 4 5 6 7 8 9 0,40 0,20 2 25,1 13,6 3 0,038 0,28 4 8,64 3,62 5 1,87 6 ca. 0,5 7 14,0 0,94 8 ca. 40 18,8 9 1,57 5,99 146763 6Experimental Analgesic Activity ED5Q Value (mg / kg) Combined D'Amour-Smith Method Phenylquinone Method x (Subcutaneous) (Oral) 1 2 3 4 5 6 7 8 9 0.40 0.20 2 25.1 13 , 6 3 0.038 0.28 4 8.64 3.62 5 1.87 6 approx. 0.5 7 14.0 0.94 8 approx. 40 18.8 9 1.57 5.99 146763 6

Sammenligningsforbindelse A >160 (inaktiv) B Έ70 ^100 (toxisk dosis) C >160 D 12/7 ca. 26 K 2,39 4,20Comparative Compound A> 160 (inactive) B Έ70 ^ 100 (toxic dose) C> 160 D 12/7 approx. 26 K 2.39 4.20

Forsøgsforbindelserne er følgende: 1: dJt-l- (3-rMethyl-2-buteny 1) -4- [2- (3-hydroxyphenyl) -1-phenylethyl] -piperazin. 2HC1 2: )1-1-(3-Methyl-2-butenyl)-4-[2-(3-hydroxyphenyl)-1-phenylethyl]-piperazin. 2HC1The test compounds are as follows: 1: dJt-1- (3-methyl-2-butenyl) -4- [2- (3-hydroxyphenyl) -1-phenylethyl] -piperazine. 2HCl2:) 1-1- (3-Methyl-2-butenyl) -4- [2- (3-hydroxyphenyl) -1-phenylethyl] -piperazine. 2HC1

3: d£-l-(3-Methy1-3-buteny1)-4-[2-(3-hydroxyphenyl)-1-phenylethyl]-piperazin. 2HC1. 1/2 E^O3- [1- (3-Methyl-3-butenyl) -4- [2- (3-hydroxyphenyl) -1-phenylethyl] -piperazine. 2HC1. 1/2 E ^ O

4: dJl-1-Ally 1-4- [ 2- (3-hydroxyphenyl) -1-phenylethyl] piperazin.4: dJl-1-Ally 1-4- [2- (3-hydroxyphenyl) -1-phenylethyl] piperazine.

2HC1. C2H5OH2HC1. C2H5OH

5: d£-l-Propyl-4-(2-(3-hydroxyphenyl)-1-phenylethyl]piperazin.5: dβ-1-Propyl-4- (2- (3-hydroxyphenyl) -1-phenylethyl] piperazine.

2HC1. 1/2 Η,Ο2HC1. 1/2 Η, Ο

6: dA-1-(3-Hydroxyisoamyl)-4-[2-(3-hydroxyphenyl)-1-phenylethyl]-piperazin. 2HC1. 1 1/2 E^O6: dA-1- (3-Hydroxyisoamyl) -4- [2- (3-hydroxyphenyl) -1-phenylethyl] -piperazine. 2HC1. 1 1/2 E ^ O

7: d£-l-(3-Methyl-2-butenyl)-4-[2-(3-methoxyphenyl)-1-phenylethyl]-piperazin. 2HC1 8: λ—1—(3-Methyl-2-butenyl)-4-[2-(3-methoxyphenyl)-1-phenylethyl]-piperazin. 2HC17: dβ-1- (3-Methyl-2-butenyl) -4- [2- (3-methoxyphenyl) -1-phenylethyl] -piperazine. 2HC18: λ-1- (3-Methyl-2-butenyl) -4- [2- (3-methoxyphenyl) -1-phenylethyl] -piperazine. 2HC1

9: d£-l-(3-Methyl-3-butenyl)-4-[2-(3-methoxyphenyl)-1-phenylethyl]-piperazin. 2HC1. 1/2 I^O9: dβ-1- (3-Methyl-3-butenyl) -4- [2- (3-methoxyphenyl) -1-phenylethyl] -piperazine. 2HC1. 1/2 I ^ O

A: d2--l-Ally 1-4- (1,2-diphenylethyl) piperazin. 2HC1 (beskrevet i Chem. Abstr., bind 77, 5521, 1972) 7 146763 B: di.-1-Isobuty 1-4-(1,2-diphenylethyl) piperazin. 2HC1 (beskrevet i Chem. Abstr., bind 77, 5521, 1972) C: d£-l-Allyl-4-[2-(3-chlorphenyl)-l~phenylethyl]piperazin. 2HC1 D: dJl-1- (3-Methyl-2-butenyl)-4-(1,2-diphenylethyl)piperazin. 2HC1 (beskrevet i J. Med. Chem., bind 18, side 1240, 1975) E: Morphin-hydrochloridA: d2-1-Ally 1-4- (1,2-diphenylethyl) piperazine. 2HCl (described in Chem. Abstr., Vol. 77, 5521, 1972) B: di-1-Isobuty 1-4- (1,2-diphenylethyl) piperazine. 2HCl (described in Chem. Abstr., Vol. 77, 5521, 1972) C: d -1-Allyl-4- [2- (3-chlorophenyl) -1-phenylethyl] piperazine. 2HC1 D: dYl-1- (3-Methyl-2-butenyl) -4- (1,2-diphenylethyl) piperazine. 2HCl (described in J. Med. Chem., Vol. 18, page 1240, 1975) E: Morphine hydrochloride

Tabel II.Table II.

Forsøgsfor- Analgetisk aktivitet ED-g-værdi (mg/kg) bindelse D'Amour-Smith-metode (subcutant) 10 0,065 11 0,028 12 ca. 0,07 13 0,47 14 uopløselig [ca. 2,1 (intraperitonealt)] 15 ca. 0,8 16 ca. 16,0 17 1,41 18 1,40Experimental Analgesic Activity ED-g Value (mg / kg) Binding D'Amour-Smith Method (Subcutaneous) 10 0.065 11 0.028 12 ca. 0.07 13 0.47 14 insoluble [ca. 2.1 (intraperitoneally)] approx. 0.8 16 approx. 16.0 17 1.41 18 1.40

Sammenlignings- forbindelse F >160 G 15,4 H uopløselig [>80 (intraperitonealt)] I 2 30 E 2,39 K Sammenligningsforbindelsen E er som defineret i tabel I, og de andre sammenligningsforbindelser og forsøgsforbindelser er: 10: d£-l-(2-Methoxyphenyl)-4-[2-(3-hydroxyphenyl)-1-phenylethyl]-piperazin. 2HC1. 1/2 H20 8 146763 11: d-1-(2-Methoxyphenyl)-4-[2-(3-hydroxyphenyl)-1-phenylethyl]-piperazin. 2HC1. 1/2 H20 12: d£-l-(2-Hydroxyphenyl)-4-[2-(3-hydroxyphenyl)-1-phenylethyl]-piperazin. 2HBr 13: d£-l-(3-Methoxyphenyl)-4-[2-(3-hydroxyphenyl)-1-phenylethyl]-piperazin. 2HC1 14: d£-l-(3-Hydroxyphenyl)-4-[2-(3-hydroxyphenyl)-1-phenylethyl]-piperazin. 2HC1 15: d£-l-(4-Methoxyphenyl)-4-[2-(3-hydroxyphenyl)-1-phenylethyl]-piperazin. 2HC1 16: £-1-(2-Methoxyphenyl)-4-(2-(3-methoxyphenyl)-1-phenylethyl]-piperazin. 2HC1. 1/2 H20Comparative Compound F> 160 G 15.4 H Insoluble [> 80 (intraperitoneal)] I 2 30 E 2.39 K Comparative Compound E is as defined in Table I, and the other Comparative Compounds and Test Compounds are: 10: d - (2-methoxyphenyl) -4- [2- (3-hydroxyphenyl) -1-phenylethyl] piperazine. 2HC1. 1/2 H 2 O: d-1- (2-Methoxyphenyl) -4- [2- (3-hydroxyphenyl) -1-phenylethyl] -piperazine. 2HC1. 1/2 H 2 O 12: d 6 - 1- (2-Hydroxyphenyl) -4- [2- (3-hydroxyphenyl) -1-phenylethyl] -piperazine. 2HBr 13: dβ-1- (3-Methoxyphenyl) -4- [2- (3-hydroxyphenyl) -1-phenylethyl] -piperazine. 2HCl: 14: 1- [1- (3-Hydroxyphenyl) -4- [2- (3-hydroxyphenyl) -1-phenylethyl] -piperazine. 2HCl: 15 - [1- (4-Methoxyphenyl) -4- [2- (3-hydroxyphenyl) -1-phenylethyl] -piperazine. 2HC1 16: 1- (2-Methoxyphenyl) -4- (2- (3-methoxyphenyl) -1-phenylethyl] -piperazine. 2HC1. 1/2 H2 O

17: d£-l-(2-Chlorphenyl)-4-[2-(3-hydroxyphenyl)-1-phenylethyl]-piperazin. HC1. 1/2 E^O17: d β-1- (2-Chlorophenyl) -4- [2- (3-hydroxyphenyl) -1-phenylethyl] -piperazine. HC1. 1/2 E ^ O

18: d£-l-(2-Methoxyphenyl)-4-[2-(3-methoxyphenyl)-1-phenylethyl]-piperazin. 2HC1. 1/2 H20 F: d£-l-Phenyl-4-(1,2-diphenylethyl)piperazin. 2HC1 (beskrevet i Chem. Abstr., bind 77, 5521, 1972) G: d£-l-(2-Methoxyphenyl)-4-(1,2-diphenylethyl)piperazin. 2HC1.18: d β-1- (2-Methoxyphenyl) -4- [2- (3-methoxyphenyl) -1-phenylethyl] -piperazine. 2HC1. 1/2 H 2 O F: d 6 -L-Phenyl-4- (1,2-diphenylethyl) piperazine. 2HCl (described in Chem. Abstr., Vol. 77, 5521, 1972) G: d - 1- (2-Methoxyphenyl) -4- (1,2-diphenylethyl) piperazine. 2HC1.

1/2 H20 (beskrevet i Chem. Abstr., bind 77, 5521, 1972) H: d£-l-(2-Methoxyphenyl)-4-[2-(3-chlorphenyl)-1-phenylethyl]-piperazin. 2HC1 I: d£-l-(2-Methoxyphenyl)-4-[2-(4-methoxyphenyl)-1-phenylethyl]-piperazin. 2HC1.H20 (beskrevet i USA-patentskrift nr. 3,957,788) 9 1467631/2 H2 O (described in Chem. Abstr., Vol. 77, 5521, 1972) H: d - 1- (2-Methoxyphenyl) -4- [2- (3-chlorophenyl) -1-phenylethyl] -piperazine. 2HCl: 1- [1- (2-Methoxyphenyl) -4- [2- (4-methoxyphenyl) -1-phenylethyl] -piperazine. 2HC1.H2O (disclosed in U.S. Patent No. 3,957,788) to 9,66763

Tabel III.Table III.

Forsøgsfor- Analgetisk aktivitet ED5Q-værdi (mg/kg) (subcutant) bindeIse K D'Amour-Smith-metode Haffner-metode 19 0,14 0,06 20 0,056 21 3,12 0,26 22 0,11 <0,04 23 0,18Experimental Analgesic Activity ED5Q value (mg / kg) (subcutaneously) binding K D'Amour-Smith method Haffner method 19 0.14 0.06 20 0.056 21 3.12 0.26 22 0.11 <0, 04 23 0.18

Tabel III fortsat.Table III continued.

24 0,2124 0.21

Sammenlignings- forbindelse J 3,09 0,73 K 1,92 0,73 L 50,7 M =160 N 3,45 0 13,1 6'95 p >160 E 2,39 1,17 K Forbindelsen E er som defineret i tabel I, og de øvrige sammenligningsforbindelser og forsøgsforbindelser er: 19: d£-l-Cyclohexyl-4-[2-(3-hydroxyphenyl)-1-phenylethyl]pipera-zin. 2HBr 20: d-l-Cyclohexyl-4-[2-(3-hydroxyphenyl)-1-phenylethyl]pipera-zin. 2HC1 21: £-l-Cyclohexyl-4-[2-(3-hydroxyphenyl)-1-phenylethyl]pipera-zin. 2HC1 146763 10 22: d£-l-Cycloheptyl-4- [2-(3-hydroxyphenyl) -1-phenylethyl] piperazin. 2HBr 23: d£-l-Cyclooctyl-4-[2-(3-hydroxyphenyl)-1-phenylethyl]pipe-razin. 2HBr 24: dÆ,-1-Cyclohexyl-4- [1-pheny 1-2- (3-propionyloxyphenyl) ethyl] -piperazin. 2HC1 J: d£-l-Cyclohexyl-4-(l,2-diphenylethyl)piperazin. 2HC1 (beskrevet i Chem. Abstr., bind 77, 5521, 1972) K: d-l-Cyclohexyl-4-(l,2-diphenylethyl)piperazin. 2HC1 (beskrevet i Chem. Abstr., bind 81, 37579, 1974) L: S,-l-Cyclohexyl-4-(l,2-diphenylethyl) piperazin. 2HC1 (beskrevet i Chem. Abstr., bind 81, 37579, 1974) M: d5.-l-Cyclohexyl-4- [2-(3-chlorphenyl) -1-phenylethyl] piperazin.Comparative Compound J 3.09 0.73 K 1.92 0.73 L 50.7 M = 160 N 3.45 0 13.1 6'95 p> 160 E 2.39 1.17 K Compound E is as defined in Table I, and the other comparative compounds and test compounds are: 19: dβ-1-Cyclohexyl-4- [2- (3-hydroxyphenyl) -1-phenylethyl] piperazine. 2HBr 20: d-1-Cyclohexyl-4- [2- (3-hydroxyphenyl) -1-phenylethyl] piperazine. 2HC1 21: β-1-Cyclohexyl-4- [2- (3-hydroxyphenyl) -1-phenylethyl] piperazine. 2HC1 22: dβ-1-Cycloheptyl-4- [2- (3-hydroxyphenyl) -1-phenylethyl] piperazine. 2HBr 23: dβ-1-Cyclooctyl-4- [2- (3-hydroxyphenyl) -1-phenylethyl] piperazine. 2HBr 24: dα, -1-Cyclohexyl-4- [1-phenyl-1-2- (3-propionyloxyphenyl) ethyl] -piperazine. 2HC1J: dβ-1-Cyclohexyl-4- (1,2-diphenylethyl) piperazine. 2HC1 (described in Chem. Abstr., Vol. 77, 5521, 1972) K: d-1-Cyclohexyl-4- (1,2-diphenylethyl) piperazine. 2HC1 (described in Chem. Abstr., Vol. 81, 37579, 1974) L: S, -1-Cyclohexyl-4- (1,2-diphenylethyl) piperazine. 2HCl (described in Chem. Abstr., Vol. 81, 37579, 1974) M: d5.-1-Cyclohexyl-4- [2- (3-chlorophenyl) -1-phenylethyl] piperazine.

2HC1 N: dil- l-Cyclooctyl-4- (1,2-diphenylethyl) piperazin. 2HC1 (beskrevet i J. Med. Chem., bind 18, side 1240, 1975) 0: d&-1-Cyclohexyl-4-[2-(4-hydroxyphenyl)-1-phenylethyl]piperazin.2HC1 N: dil-1-Cyclooctyl-4- (1,2-diphenylethyl) piperazine. 2HCl (described in J. Med. Chem., Vol. 18, p. 1240, 1975) 0: d &lt; 1 &gt; -Cyclohexyl-4- [2- (4-hydroxyphenyl) -1-phenylethyl] piperazine.

2HBr (beskrevet i USA-patentskrift nr. 3,957,788) P: d&-l-Cyclooctyl-4-[2-(4-methoxyphenyl)-1-phenylethyl]piperazin.2HBr (described in U.S. Patent No. 3,957,788) P: d & l-Cyclooctyl-4- [2- (4-methoxyphenyl) -1-phenylethyl] piperazine.

2HC1 (beskrevet i USA-patentskrift nr. 3,957,788)2HC1 (disclosed in U.S. Patent No. 3,957,788)

Det fremgår klart af dataene i tabellerne I, II og III, at dl-isomererne af de her omhandlede forbindelser udviser fremragende analgetisk aktivitet af samme størrelsesorden eller større end aktiviteten hos morphin og langt større end aktiviteten hos dl-isomererne af de kendte analoge forbindelser. Desuden udviser d-eller 1-isomerer af de her omhandlede forbindelser langt større analgetisk aktivitet end aktiviteten hos d- eller 1-isomererne af de kendte forbindelser.It is clear from the data in Tables I, II and III that the dl isomers of the compounds of this invention exhibit excellent analgesic activity of the same order or greater than the activity of morphine and far greater than the activity of the dl isomers of the known analogous compounds. Furthermore, the d or 1 isomers of the compounds of the present invention exhibit much greater analgesic activity than the activity of the d or 1 isomers of the known compounds.

2) Narkotisk antagonist-aktivitet (jævnfør L.S. Harris og A.K.2) Narcotic antagonist activity (cf. L.S. Harris and A.K.

Pierson, J. Pharmacol. Exp. Ther., bind 143, side 141, 1964): 146763 11Pierson, J. Pharmacol. Exp. Ther., Vol. 143, pages 141, 1964): 146763 11

Antagonist-aktiviteten af forbindelsen nr. 2 undersøges ved dens evne til at blokere den typiske forsinkede respons-tid på en termisk stimulering vist på hanmus af stammen ddN og med en vægt på 9 - 12 g behandlet med morfin-hydrochlorid.The antagonist activity of compound # 2 is investigated by its ability to block the typical delayed response time to a thermal stimulation shown in male mice of the strain ddN and weighing 9-12 g treated with morphine hydrochloride.

Den ovenfor beskrevne D'Amour-Smith-metode anvendes med en 15 sekunders cut-off tid. Graduerede doser af forbindelsen nr. 2 administreres subcutant til mus 15 minutter før subcutaninjektion af morfin-hydrochlorid (5 mg/kg). De valgte standarddoser af morfin--hydrochlorid svarer til doser, som fremkalder analgesi hos 80 -100% af ikke i forvejen med medicin behandlede dyr. Når respons--tiden målt 30 minutter efter injektion af morfin-hydrochloridet er mindre end 10 sekunder, bedømmes den antagonistiske effekt til at være signifikant.The D'Amour-Smith method described above is used with a 15 second cut-off time. Graduated doses of compound # 2 are administered subcutaneously to mice 15 minutes prior to subcutaneous injection of morphine hydrochloride (5 mg / kg). The standard doses of morphine hydrochloride selected correspond to doses that induce analgesia in 80-100% of non-medicated animals. When the response time measured 30 minutes after injection of the morphine hydrochloride is less than 10 seconds, the antagonistic effect is judged to be significant.

Den 50%'s antagonistdosis (ED^q) beregnes ud fra de effektive værdier efter Litchfield-Wilcoxon-metode. Aktiviteten af forbindelsen nr. 2 er anført i tabel IV sammen med aktiviteten af pentazo-cin, et ikke-narkotisk analgetikum.The 50% antagonist dose (ED ^ q) is calculated from the effective values by Litchfield-Wilcoxon method. The activity of compound # 2 is listed in Table IV together with the activity of pentazocin, a non-narcotic analgesic.

Tabel IV.Table IV.

Fors øgs forbindelse* Antagonistaktivitet EDj-g-værdi (mg/kg, subcutant) 2 3,54Increase compound * Antagonist activity EDj-g value (mg / kg, subcutaneously) 2 3.54

SammenligningsforbindelseComparator

Pentazocin 3,79 * Forbindelsen nr. 2 er som defineret i forbindelse med tabel I.Pentazocin 3.79 * Compound # 2 is as defined for Table I.

3) Tilbøjelighed til fysisk afhængighed:3) Tendency to physical dependence:

Substitutionsforsøg på morfinafhængige rotter (jævnfør O.J. Lo-renzetti og L.F. Sancilio, Arch. int. Pharmacodyn., bind 183, side 391, 1970; S. Nurimoto, Japan. J. Pharmacol., bind 23, side 401, 1973; og H. Nakamura et al., Folia Pharmacol. Japonica, bind 71, side 105P, 1975).Substitution experiments on morphine-dependent rats (cf. OJ Lo-renzetti and LF Sancilio, Arch. Int. Pharmacodyn., Vol. 183, pp. 391, 1970; S. Nurimoto, Japan. J. Pharmacol., Vol. 23, pp. 401, 1973; and H. Nakamura et al., Folia Pharmacol. Japonica, Vol. 71, p. 105P, 1975).

146763 12146763 12

Hanrotter af Wistar-stammen med en vægt på 200 - 250 g fik mor-fin-hydrochlorid subcutant 2 gange daglig. Den indledende dosis på 20 mg/kg forøges en gang ugentligt med 20 mg/kg, indtil der er opnået en vedholdende værdi på 100 mg/kg x 2/dag. Til dyrene blev givet tb subcutane eller orale administrationer af en forsøgsforbindelse i stedet for morfin-hydrochlorid. iÆ»stinens-symptomerne blev bestemt, og den procentvise reduktion af hvert abstinens-symptom blev beregnet ud fra værdierne for forsøgsforbindelsen og kontrolgruppen med opløsningsmiddel.Male rats of the Wistar strain weighing 200 - 250 g received morphine hydrochloride subcutaneously twice daily. The initial dose of 20 mg / kg is increased once weekly by 20 mg / kg until a sustained value of 100 mg / kg x 2 / day is achieved. The animals were given subcutaneous or oral administrations of a test compound in place of morphine hydrochloride. The symptoms of withdrawal were determined and the percent reduction of each withdrawal symptom was calculated from the values of the test compound and the control group with solvent.

Resultaterne viste, at forbindelserne 2, 8, 16 og 21.The results showed that compounds 2, 8, 16 and 21.

ikke viste undertrykkelse af abstinens-symptomerne, det vil sige den morfinlignende fysiske afhængighed.did not show suppression of withdrawal symptoms, that is, morphine-like physical dependence.

Forbindelserne med formlen I og de farmaceutisk tolerable syreadditionssalte deraf skal anvendes som lægemidler, f.eks. i form af farmaceutiske præparater indeholdende forbindelsen sammen med et organisk eller uorganisk, fast eller flydende farmaceutisk adju-vans, der er egnet til oral eller parenteral administration. De farmaceutiske præparater kan, f.eks., være pulvere, tabletter, suppositorier eller kapsler eller i flydende form som opløsninger, suspensioner eller emulsioner. Når forbindelserne administreres som væsker, kan sædvanlige flydende bærestoffer såsom sirup, jordnøddeolie, olivenolie eller vand anvendes. Til intravenøs, intramuskulær eller subcutan injektion anvendes forbindelserne i syreadditions-saltform efter opløsning i vand, om nødvendigt, efterfulgt af pufring eller indstilling på isotonisk værdi med glucose eller saltopløsning. Disse præparater kan yderligere indeholde andre terapeutisk værdifulde stoffer. Præparaterne fremstilles på sædvanlig måde.The compounds of formula I and the pharmaceutically tolerable acid addition salts thereof should be used as drugs, e.g. in the form of pharmaceutical compositions containing the compound together with an organic or inorganic, solid or liquid pharmaceutical adjuvant suitable for oral or parenteral administration. The pharmaceutical compositions may, for example, be powders, tablets, suppositories or capsules or in liquid form as solutions, suspensions or emulsions. When the compounds are administered as liquids, conventional liquid carriers such as syrup, peanut oil, olive oil or water may be used. For intravenous, intramuscular or subcutaneous injection, the compounds are used in acid addition salt form after dissolving in water, if necessary, followed by buffering or adjusting to isotonic value with glucose or saline solution. These compositions may further contain other therapeutically valuable substances. The preparations are prepared in the usual manner.

En klinisk dosis af forbindelsen med formlen I eller et farmaceutisk tolerabelt syreadditionssalt deraf afhænger af legemsvægten, alderen og administrationsvejen, men ligger i almindelighed i området mellem 0,1 og 200 mg/dag, fortrinsvis mellem 0,5 og 100 mg/ dag.A clinical dose of the compound of formula I or a pharmaceutically tolerable acid addition salt thereof depends on body weight, age and route of administration, but is generally in the range of 0.1 to 200 mg / day, preferably between 0.5 and 100 mg / day.

Forbindelserne med formlen X og de farmaceutisk tolerable syreadditionssalte deraf fremstilles ved nedenstående fremgangsmådevarianter a - c.The compounds of formula X and the pharmaceutically tolerable acid addition salts thereof are prepared by the following process variants a - c.

U6763 13U6763 13

Fremgangsmådevariant a:Process variant a:

Forbindelserne kan fremstilles ved omsætning af en forbindelse med den almene formel IIThe compounds can be prepared by reacting a compound of general formula II

_o $ y- ch2-ch-nh2 11 ox_o $ y- ch2-ch-nh2 11 ox

hvor X har den ovenfor anførte betydning, og en reaktionsdygtig diester af en alkohol med den almene formel IIIwherein X is as defined above and a reactive diester of an alcohol of the general formula III

hoch2ch2 xhoch2ch2 x

N-R IIIN-R III

/ HOCH2CH2 hvor R har den ovenfor anførte betydning, eller et salt deraf med en syre. Eksempler på en reaktionsdygtig diester af en alkohol med den almene formel III omfatter diesterne af alkoholen III med hy-drogenhalogensyre (f.eks. saltsyre eller brombrintesyre), en aryl-sulfonsyre (f.eks. p-toluensulfonsyre eller benzensulfonsyre) og en alkylsulfonsyre (f.eks. methansulfonsyre)./ HOCH2CH2 where R has the meaning given above, or a salt thereof with an acid. Examples of a reactive diester of an alcohol of the general formula III include the diesters of the alcohol III with hydrogen halogenic acid (e.g. hydrochloric or hydrobromic acid), an aryl sulfonic acid (e.g. p-toluenesulfonic acid or benzenesulfonic acid) and an alkyl sulfonic acid (e.g., methanesulfonic acid).

Fremgangsmådevariant a kan udføres ved opvarmning af en blanding af forbindelsen med formlen III og en ækvimolær mængde eller en overskydende mængde af forbindelsen med formlen II i nærværelse eller fraværelse af et opløsningsmiddel, f.eks. en aliphatisk alkohol (f.eks. vandigt eller vandfrit ethanol eller isopropanol), et aromatisk carbonhydrid (f.eks. toluen eller xylen), en ether (f.eks. dioxan), dimethylformamid eller dimethylsulfoxid. Egnede reaktionstemperaturer kan ligge mellem 60 og 170°C, og reaktionen kan sædvanligvis udføres ved tilbagesvalingstemperatur.Process variant a can be performed by heating a mixture of the compound of formula III and an equimolar amount or an excess amount of the compound of formula II in the presence or absence of a solvent, e.g. an aliphatic alcohol (e.g., aqueous or anhydrous ethanol or isopropanol), an aromatic hydrocarbon (e.g., toluene or xylene), an ether (e.g., dioxane), dimethylformamide, or dimethylsulfoxide. Suitable reaction temperatures can be between 60 and 170 ° C, and the reaction can usually be carried out at reflux temperature.

Reaktionen kan også udføres i nærværelse af et basisk materiale, f.eks. et alkalimetalhydrogencarbonat (f.eks. natriumhydrogencar-bonat eller kaliumhydrogencarbonat), et alkalimetalcarbonat (f.eks. natriumcarbonat eller kaliumcarbonat) eller en organisk base (f.eks. triethylamin). Reaktanterne med formlen II kan også anvendes som det basiske materiale ved at blive anvendt i overskydende mængde.The reaction may also be carried out in the presence of a basic material, e.g. an alkali metal hydrogen carbonate (e.g., sodium hydrogen carbonate or potassium hydrogen carbonate), an alkali metal carbonate (e.g., sodium carbonate or potassium carbonate), or an organic base (e.g., triethylamine). The reactants of formula II can also be used as the basic material by being used in excess.

1yi 146763 141yi 146763 14

Udgangsmaterialet med formlen XX i fremgangsmådevariant a kan fremstilles på lignende måde som beskrevet i Archiv der Pharmazie, bind 274, side 153, 1936 og britisk patentskrift nr. 1.300.428 (1972).The starting material of formula XX in process variant a can be prepared in a similar manner as described in Archiv der Pharmazie, Vol. 274, pages 153, 1936 and British Patent Specification No. 1,300,428 (1972).

Det andet udgangsmateriale med formlen III kan fremstilles på lignende måde som beskrevet i Journal of American Chemical Society, bind 73, side 3635, 1951; Journal of Chemical Society, side 183, 1949; og Journal of Medicinal Chemistry, bind 6, side 822, 1963, f.eks. ved omsætning af N-cyclohexyldiethanolamin eller et salt deraf og et sædvanligt halogeneringsmiddel, f.eks. thionyl-chlorid eller thionylbromid, eller med et sædvanligt sulfoneringsmiddel, f.eks. p-toluensulfonylchlorid, benzensulfonylchlorid eller methansulfonylchlorid.The second starting material of formula III may be prepared in a similar manner as described in the Journal of the American Chemical Society, Vol. 73, pages 3635, 1951; Journal of Chemical Society, pages 183, 1949; and Journal of Medicinal Chemistry, Vol. 6, pages 822, 1963, e.g. by reaction of N-cyclohexyldiethanolamine or a salt thereof and a conventional halogenating agent, e.g. thionyl chloride or thionyl bromide, or with a usual sulfonating agent, e.g. p-toluenesulfonyl chloride, benzenesulfonyl chloride or methanesulfonyl chloride.

Fremgangsmådevariant b:Method variant b:

Forbindelserne med formlen I og de farmaceutisk tolerable syreadditionssalte deraf kan fremstilles ved omsætning af en reaktions-dygtig diester af en alkohol med den almene formel IVThe compounds of formula I and the pharmaceutically tolerable acid addition salts thereof can be prepared by reacting a reactive diester of an alcohol of the general formula IV

OISLAND

O ch%,/CWH -O ch%, / CWH -

Ns'CH2CH2DHNs'CH2CH2DH

oxox

hvor X har den ovenfor anførte betydning, eller et salt deraf med en syre med en forbindelse med den almene formel Vwherein X is as defined above, or a salt thereof with an acid having a compound of the general formula V

h2n-r Vh2n-r V

hvor R har den ovenfor anførte betydning. Eksempler på en reaktiv diester af en alkohol med den almene formel IV omfatter diesterne af alkoholen IV med en hydrogenhalogensyre (fx saltsyre eller brombrin-tesyre), en arylsulfonsyre (fx p-toluensulfonsyre eller benzensulfon-syre) og en alkylsulfonsyre (fx methansulfonsyre).where R has the meaning given above. Examples of a reactive diester of an alcohol of the general formula IV include the diesters of the alcohol IV with a hydrogen halogenic acid (e.g., hydrochloric or hydrobromic acid), an arylsulfonic acid (e.g. p-toluenesulfonic acid or benzenesulfonic acid) and an alkylsulfonic acid (e.g. methanesulfonic acid).

15 146763146763

Fremgangsmådevariant b kan udføres ved opvarmning af en blanding af forbindelsen med formlen IV med en ækvimolær mængde eller en overskydende mængde af forbindelsen med formlen V i nærværelse eller fraværelse af et opløsningsmiddel på lignende måde som beskrevet for fremgangsmådevariant a.Process variant b can be performed by heating a mixture of the compound of formula IV with an equimolar amount or an excess amount of the compound of formula V in the presence or absence of a solvent in a similar manner as described for process variant a.

Udgangsmaterialet med formlen IV til fremgangsmådevariant b kan f.eks. fremstilles på den nedenfor beskrevne måde:The starting material of formula IV for process variant b can e.g. prepared in the manner described below:

3-(2-Hydroxyethyl)-2-phenyloxazolidin omsættes med en forbindelse med den almene formel VI3- (2-Hydroxyethyl) -2-phenyloxazolidine is reacted with a compound of general formula VI

O CH^MgCl VIO CH 2 MgCl VI

y* dCH3y * dCH3

i et inert opløsningsmiddel til dannelse af en forbindelse med den almene formel viIin an inert solvent to form a compound of the general formula vii

OISLAND

f\ chX/cwh V=/ \ch2ch2oh 0CH3 eller et salt deraf.f \ chX / cwh V = / \ ch2ch2oh 0CH3 or a salt thereof.

Derpå omsættes den således vundne forbindelse med formlen VII eller et salt deraf med et sædvanligt halogenerings- eller sulfoneringsmiddel som beskrevet under fremgangsmådevariant a til dannelse af den ønskede forbindelse med formlen IV, hvor X er methyl. Når den således vundne forbindelse med formlen IV (X er methyl) underkastes spaltning af etherbindingen ved behandling med et spaltningsmiddel til spaltning af ethere, fås der den ønskede forbindelse med formlen IV, hvor X er hydrogen. Eksempler på sådanne spaltningsmidler til spaltning af ethere er f.eks. Lewis-syrer (f.eks. aluminiumchlorid, aluminiumbromid eller bortribromid) og hydrogenhalogenidsyrer (f.eks. brombrintesyre, iodbrintesyre eller saltsyre). Når forbindelsen med formlen IV, hvor X er hydrogen, endvidere omsættes med et alkano-yleringsmiddel på sædvanlig måde, fås der den ønskede forbindelse med formlen IV, hvor X er alkanoyl med 2-5 carbonatomer.Then, the compound of formula VII thus obtained or a salt thereof is reacted with a conventional halogenating or sulfonating agent as described under process variant a to give the desired compound of formula IV wherein X is methyl. When the compound of formula IV thus obtained (X is methyl) is subjected to cleavage of the ether bond by treatment with a cleavage agent for cleavage of ethers, the desired compound of formula IV wherein X is hydrogen is obtained. Examples of such cleavage agents for cleavage of ethers are e.g. Lewis acids (e.g. aluminum chloride, aluminum bromide or boron tribromide) and hydrogen halide acids (e.g. hydrobromic acid, iodohydric acid or hydrochloric acid). Furthermore, when the compound of formula IV wherein X is hydrogen is reacted with an alkanoylating agent in the usual manner, the desired compound of formula IV wherein X is alkanoyl having 2-5 carbon atoms is obtained.

16 14676316 146763

Forbindelsen med formlen IV kan også fremstilles ved omsætning af forbindelsen med formlen II og ethylenoxid efterfulgt af omsætningen med et halogenerings- eller sulfoneringsmiddel som anført ovenfor .The compound of formula IV may also be prepared by reaction of the compound of formula II and ethylene oxide followed by the reaction with a halogenating or sulfonating agent as set forth above.

Fremgangsmådevariant c:Process variant c:

Forbindelsen med den almene formel VIIIThe compound of general formula VIII

OISLAND

/~\ 1 v 3/ ~ \ 1 v 3

^ CH2-CH-N^_N-R VIII^ CH2-CH-N ^ _N-R VIII

O-alkanoyl 3O-alkanoyl 3

hvor alkanoyloxygruppen indeholder 2-5 carbonatomer, og R har den samme betydning som defineret ovenfor for R, bortset fra hydroxy-phenyl og 3-hydroxyisoamyl, eller et farmaceutisk tolerabelt syreadditionssalt deraf fremstilles ved omsætning af en forbindelse med den almene formel IXwherein the alkanoyloxy group contains 2-5 carbon atoms and R has the same meaning as defined above for R except hydroxy-phenyl and 3-hydroxyisoamyl, or a pharmaceutically tolerable acid addition salt thereof is prepared by reaction of a compound of general formula IX

f y— CH„-CH-N N-R IXf y— CH 2 -CH-N N-R IX

)=/ 2) = / 2

OHOH

3 hvor R har den ovenfor anførte betydning, eller et salt deraf med et alkanoyleringsmiddel med 2-5 carbonatomer i alkanoyIdelen.3 wherein R has the meaning given above, or a salt thereof with an alkanoylating agent having 2-5 carbon atoms in the alkanoyl moiety.

Alkanoyleringen af forbindelsen med formlen IX til dannelse af forbindelsen med formlen VIII udføres på sædvanlig måde og fortrinsvis ved omsætning af forbindelsen med formlen IX med en carboxylsyre eller et reaktivt derivat deraf, f.eks. et syrehalogenid eller et syreanhydrid i nærværelse eller fraværelse af et opløsningsmiddel. Egnede eksempler på carboxylsyrer er eddikesyre, pro-pionsyre, smørsyre og isosmørsyre. Som opløsningsmiddel kan anvendes et hvilket som helst opløsningsmiddel, som ikke har uønsket 17 146763 virkning på reaktionen, f.eks. et inert opløsningsmiddel såsom py-ridin, benzen, toluen eller dioxan. Egnede reaktionstemperaturer ligger mellem 0 og 150°C, og reaktionen udføres sædvanligvis ved tilbagesvalingstemperatur.The alkanoylation of the compound of formula IX to form the compound of formula VIII is carried out in the usual manner and preferably by reacting the compound of formula IX with a carboxylic acid or a reactive derivative thereof, e.g. an acid halide or acid anhydride in the presence or absence of a solvent. Suitable examples of carboxylic acids are acetic acid, propionic acid, butyric acid and isobutyric acid. As a solvent can be used any solvent which has no undesirable effect on the reaction, e.g. an inert solvent such as pyridine, benzene, toluene or dioxane. Suitable reaction temperatures are between 0 and 150 ° C and the reaction is usually carried out at reflux temperature.

Ved de ovenfor beskrevne fremgangsmåder til fremstilling af de omhandlede forbindelser kan udgangsmaterialerne og mellemprodukterne enten foreligge i racemisk form eller i optisk aktiv form, når de indeholder et asymmetrisk carbonatom i molekylet. Når den racemi-ske forbindelse anvendes som udgangsmateriale eller mellemprodukt, fås slutforbindelsen med formlen I også i form af en racemisk forbindelse. Når en optisk aktiv forbindelse anvendes som udgangsmateriale eller mellemprodukt, fås den endelige forbindelse med formlen I også i form af den optisk aktive forbindelse. Den optisk aktive forbindelse med formlen I kan også fremstilles ved opspaltning af en racemisk forbindelse med formlen I med et optisk opspaltningsmiddel, f.eks. optisk aktiv vinsyre-monoanilid (f.eks. 2'-ni-trotartranilinsyre) eller diaroylvinsyrer (f.eks. dibenzoylvinsyre).In the methods described above for preparing the subject compounds, the starting materials and intermediates may be either in racemic form or in optically active form when they contain an asymmetric carbon atom in the molecule. When the racemic compound is used as a starting material or intermediate, the final compound of formula I is also obtained in the form of a racemic compound. When an optically active compound is used as the starting material or intermediate, the final compound of formula I is also obtained in the form of the optically active compound. The optically active compound of formula I can also be prepared by cleavage of a racemic compound of formula I with an optical cleavage agent, e.g. optically active tartaric acid monoanilide (e.g., 2'-nitrotartranilic acid) or diaroyltartaric acids (e.g., dibenzoyltartaric acid).

Ved fremgangsmåden ifølge den foreliggende opfindelse kan de ønskede forbindelser med formlen I fremstilles i form af frie baser eller salte, alt afhængigt af udgangsmaterialernes art og reaktionsbetingelserne. Når de fås i form af en fri base, kan de omdannes til de farmaceutisk tolerable salte af forskellige uorganiske eller organiske syrer. Egnede syrer omfatter uorganiske syrer (f.eks. saltsyre, brombrintesyre, iodbrintesyre, svovlsyre eller phosphorsyre) og organiske syrer (f.eks. citronsyre, maleinsyre, fumarsyre, vinsyre, dibenzoylvinsyre, eddikesyre, benzoesyre, mælkesyre, methansulfon-syre, 2-naphthalensulfonsyre, salicylsyre eller acetylsalicylsyre).In the process of the present invention, the desired compounds of formula I can be prepared in the form of free bases or salts, depending on the nature of the starting materials and the reaction conditions. When obtained in the form of a free base, they can be converted into the pharmaceutically tolerable salts of various inorganic or organic acids. Suitable acids include inorganic acids (e.g. hydrochloric, hydrobromic, iodobaric, sulfuric or phosphoric) and organic acids (e.g., citric, maleic, fumaric, tartaric, dibenzoyltartaric, acetic, benzoic, lactic, methanesulfonic), naphthalenesulfonic acid, salicylic acid or acetylsalicylic acid).

Det foretrækkes, at der under anvendelse af fremgangsmåde c fremstilles en forbindelse med den almene formel I, hvor X er alkanoyl med 2-5 carbonatomer, og R er som ovenfor defineret, dog forskellig fra hydroxyphenyl og 3-hydroxyisoamyl.It is preferred that, using process c, a compound of general formula I be prepared in which X is alkanoyl of 2-5 carbon atoms and R is as defined above, however different from hydroxyphenyl and 3-hydroxyisoamyl.

Ved fremgangsmåden ifølge opfindelsen fremstilles især forbindelser med den almene formel I, hvor X er hydrogen, og R er 3-methyl-2-bute-nyl; X er methyl, og R er 3-methyl-2-butenyl; X er hydrogen, og R er cyclohexyl; X er methyl, og R er 2-methoxyphenylj og X er hydrogen, og R er 4-methoxyphenyl.In particular, the process of the invention produces compounds of the general formula I wherein X is hydrogen and R is 3-methyl-2-butenyl; X is methyl and R is 3-methyl-2-butenyl; X is hydrogen and R is cyclohexyl; X is methyl and R is 2-methoxyphenyl and X is hydrogen and R is 4-methoxyphenyl.

18 14676318 146763

Fremgangsmåde ifølge opfindelsen illustreres nærmere ved nedenstående eksempler, i hvilke de procentvise angivelser er beregnet på vægt, hvis intet andet er anført, mens referenceeksemplerne illustrerer fremstilling af udgangsmaterialer:The process according to the invention is further illustrated by the following examples in which the percentages are by weight, unless otherwise stated, while the reference examples illustrate the preparation of starting materials:

Eksempel 1.Example 1.

d£-l-Cyclohexyl-4-[2-(3-hydroxyphenyl)-l-phenylethyl]piperazin.d £ -L-cyclohexyl-4- [2- (3-hydroxyphenyl) -l-phenylethyl] piperazine.

I 60 ml ethanol opløses 3,0 g dA-2-(3-hydroxyphenyl)-l-phenylethyl-amin og 2,6 g N,N-bis(2-chlorethyl)cyclohexylamin-hydrochlorid, og hertil sættes 2,8 g natriumhydrogencarbonat. Blandingen koges under tilbagesvaling under omrøring i 24 timer. Efter reaktionen afdestilleres opløsningsmidlet under reduceret tryk. Til remanensen sættes 20 ml 10%'s saltsyreopløsning, og blandingen lades afkøle. Det resulterende bundfald isoleres ved filtrering, vaskes med en ringe mængde koldt vand og derefter med acetone og omkrystalliseres af methanol, hvorved der fås 2,6 g af den ønskede forbindelse i form af dihydrochloridet, smeltepunkt 264 - 270°C (sønderdeling) .In 60 ml of ethanol dissolve 3.0 g of dA-2- (3-hydroxyphenyl) -1-phenylethylamine and 2.6 g of N, N-bis (2-chloroethyl) cyclohexylamine hydrochloride, to which 2.8 g sodium bicarbonate. The mixture is refluxed under stirring for 24 hours. After the reaction, the solvent is distilled off under reduced pressure. To the residue is added 20 ml of 10% hydrochloric acid solution and the mixture is allowed to cool. The resulting precipitate is isolated by filtration, washed with a small amount of cold water and then with acetone and recrystallized from methanol to give 2.6 g of the desired compound in the form of the dihydrochloride, mp 264-270 ° C (dec.).

Til det således vundne dihydrochlorid sættes fortyndet vandig ka-liumcarbonatopløsning, og den basiske opløsning ekstraheres med ether. Ekstrakten inddampes, og remanensen omkrystalliseres af benzen, hvorved der fås den frie base i form af farveløse nåle, smeltepunkt 140 - 141°C.To the thus obtained dihydrochloride is added dilute aqueous potassium carbonate solution and the basic solution extracted with ether. The extract is evaporated and the residue is recrystallized from benzene to give the free base in the form of colorless needles, mp 140-141 ° C.

Den på den ovenfor beskrevne måde vundne frie base opløses i en ringe mængde methanol, og opløsningen indstilles på sur reaktion med en 25%'s brombrintesyre-eddikesyreopløsning. Det resulterende bundfald omkrystalliseres af methanol, hvorved der fås dihydrobro-midet af den ønskede forbindelse, smeltepunkt 268 - 270°C.The free base obtained in the manner described above is dissolved in a small amount of methanol and the solution is adjusted to acidic reaction with a 25% hydrobromic acid acetic acid solution. The resulting precipitate is recrystallized from methanol to give the dihydrobromide of the desired compound, mp 268-270 ° C.

Eksempel 2.Example 2.

t-l-Cyclohexyl-4-[2-(3-hydroxyphenyl)-l-phenylethyl]piperazin.t-l-cyclohexyl-4- [2- (3-hydroxyphenyl) -l-phenylethyl] piperazine.

19 U67G3 I 30 ml ethanol opløses 1,2 g £-2-(3-hydroxyphenyl)-1-phenyl-ethylamin og 1,3 g Ν,Ν-bis(2-chlorethyl)cyclohexylamin-hydrochlo-rid, og der tilsættes 1,4 g natriumhydrogencarbonat. Blandingen koges under tilbagesvaling under omrøring i 18 timer. Efter reaktionen afdestilleres opløsningsmidlet under reduceret tryk. Til remanensen sættes fortyndet vandig kaliumcarbonatopløsning, og blandingen ekstraheres med ethylacetat. Ethylacetatfasen vaskes med vand og tørres over vandfrit natriumsulfat, hvorefter opløsningsmidlet afdestilleres. Remanensen (den frie base) behandles med methanolisk saltsyre til dannelse af dihydrochloridet, som omkrystalliseres af methanol, hvorved der fås 0,9 g af den ønskede forbindelse i form af dihydrochloridet, farveløse nåle, smeltepunkt 275 - 280°C (sønderdeling), [a]^9 = -48,8° (c = 0,5 i methanol) .19 U67G3 In 30 ml of ethanol, dissolve 1.2 g of 2- (3-hydroxyphenyl) -1-phenyl-ethylamine and 1.3 g of-, Ν-bis (2-chloroethyl) cyclohexylamine hydrochloride and add 1.4 g of sodium bicarbonate. The mixture is refluxed under stirring for 18 hours. After the reaction, the solvent is distilled off under reduced pressure. To the residue is added dilute aqueous potassium carbonate solution and the mixture is extracted with ethyl acetate. The ethyl acetate phase is washed with water and dried over anhydrous sodium sulfate, after which the solvent is distilled off. The residue (the free base) is treated with methanolic hydrochloric acid to form the dihydrochloride, which is recrystallized from methanol to give 0.9 g of the desired compound in the form of the dihydrochloride, colorless needles, mp 275-280 ° C (decomp.), [ α] 9 = -48.8 ° (c = 0.5 in methanol).

Eksempel 3.Example 3

d-l-Cyclohexyl-4-[2-(3-hydroxyphenyl)-l-phenylethyl]piperazin.d-l-cyclohexyl-4- [2- (3-hydroxyphenyl) -l-phenylethyl] piperazine.

Der gås frem som beskrevet i eksempel 2, idet der anvendes 1,1 g d-2-(3-hydroxyphenyl)-1-phenylethylamin, 1,3 g N,N-bis(2-chlorethyl) cyclohexylamin-hydrochlorid og 1,4 g natriumhydrogencarbonat til dannelse af den ønskede forbindelse, hvorved der fås 0,8 g af dihydrochloridet, farveløse nåle, smeltepunkt 275 - 280°C (sønderdeling) . [α]^° = +48,6° (c = 0,5 i methanol).Proceed as described in Example 2 using 1.1 g of d-2- (3-hydroxyphenyl) -1-phenylethylamine, 1.3 g of N, N-bis (2-chloroethyl) cyclohexylamine hydrochloride and 1, 4 g of sodium bicarbonate to give the desired compound to give 0.8 g of the dihydrochloride, colorless needles, mp 275-280 ° C (decomposition). = + 48.6 ° (c = 0.5 in methanol).

Eksempel 4.Example 4

d£-l-(2-Methoxypheny1)-4-[2-(3-methoxyphenyl)-1-phenylethyl]pipe-razin.d £ -L- (2-Methoxypheny1) -4- [2- (3-methoxyphenyl) -1-phenylethyl] pipe Razin.

I 40 ml dimethylformamid opløses 2,3 g d£-2-(3-methoxyphenyl)-1--phenylethylamin og 2,8 g Ν,Ν-bis(2-chlorethyl)-o-anisidin-hydrochlo-rid, og hertil sættes 2,7 g natriumhydrogencarbonat. Blandingen koges under tilbagesvaling med omrøring i 10 timer. Efter afkøling filtreres de uorganiske forbindelser fra reaktionsblandingen. Opløsningsmidlet afdestilleres fra filtratet. Til remanensen sættes en koncentreret vandig ammoniakopløsning, og blandingen ekstraheres .In 40 ml of dimethylformamide dissolve 2.3 gd of 2 -2- (3-methoxyphenyl) -1-phenylethylamine and 2.8 g of Ν, Ν-bis (2-chloroethyl) -o-anisidine hydrochloride and add 2.7 g of sodium bicarbonate. The mixture is refluxed with stirring for 10 hours. After cooling, the inorganic compounds are filtered from the reaction mixture. The solvent is distilled off from the filtrate. To the residue is added a concentrated aqueous ammonia solution and the mixture is extracted.

20 146763 med ether. Den etheriske fase tørres over vandfrit natriumsulfat, og opløsningsmidlet afdestilleres. Remanensen behandles med etha-nolisk saltsyre til dannelse af hydrochloridet, som omkrystalliseres af ethanol, hvorved fås 2,2 g af den ønskede forbindelse i form af et dihydrochlorid-hemihydratet, smeltepunkt 225 - 228 C.Ether. The etheric phase is dried over anhydrous sodium sulfate and the solvent is distilled off. The residue is treated with ethanolic hydrochloric acid to form the hydrochloride, which is recrystallized from ethanol to give 2.2 g of the desired compound in the form of the dihydrochloride hemihydrate, mp 225-222 ° C.

Den frie base svarende hertil har smeltepunkt 97 - 99°C efter omkrystallisation af ethanol.The free base corresponding thereto has melting point 97 - 99 ° C after recrystallization of ethanol.

Eksempel 5.Example 5

£"1"(3-Methyl-2-butenyl)-4-[2-(3-hydroxyphenyl)-1-phenylethyl]pipe-razin.£ "1" (3-methyl-2-butenyl) -4- [2- (3-hydroxyphenyl) -1-phenylethyl] pipe Razin.

I 30 ml ethanol opløses 1,3 g 1-2-(3-hydroxyphenyl)-1-phenylethyl-amin og 1,2 g N,N-bis(2-chlorethyl)-3-methyl-2-butenylamin-hydro-chlorid, og hertil sættes 1,4 g natriumhydrogencarbonat. Blandingen koges under tilbagesvaling under omrøring i 18 timer. Efter omsætningen afdestilleres opløsningsmidlet under reduceret tryk. Til remanensen sættes en fortyndet vandig kaliumcarbonatopløsning, og blandingen ekstraheres med ethylacetat. Ethylacetatfasen vaskes med vand og tørres over vandfrit natriumsulfat, og opløsningsmidlet afdestilleres. Remanensen (den frie base) behandles med ethano-lisk saltsyre til dannelse af dihydrochloridet, som omkrystalliseres af ethanol, hvorved der fås 1,1 g af den ønskede forbindelse i form af dihydrochloridet, smeltepunkt 221 - 224°C. [a]^ = -56,2° (c = 1,00 i methanol).In 30 ml of ethanol dissolve 1.3 g of 1-2- (3-hydroxyphenyl) -1-phenylethylamine and 1.2 g of N, N-bis (2-chloroethyl) -3-methyl-2-butenylamine hydrochloride. chloride, and to this is added 1.4 g of sodium bicarbonate. The mixture is refluxed under stirring for 18 hours. After the reaction, the solvent is distilled off under reduced pressure. To the residue is added a dilute aqueous potassium carbonate solution and the mixture is extracted with ethyl acetate. The ethyl acetate phase is washed with water and dried over anhydrous sodium sulfate and the solvent is distilled off. The residue (the free base) is treated with ethanolic hydrochloric acid to give the dihydrochloride which is recrystallized from ethanol to give 1.1 g of the desired compound in the form of the dihydrochloride, mp 221 - 224 ° C. [α] D = -56.2 ° (c = 1.00 in methanol).

Eksempel 6.Example 6

De nedenfor anførte forbindelser fremstilles på samme måde som beskrevet i ovenstående eksempler: dfe-l-Cyclohepty1-4-[2-(3-hydroxyphenyl)-1-phenylethyl]piperazin- -dihydrobromid, smeltepunkt 279 - 281°C, d£-l-Gycloocty1-4-[2-(3-hydroxyphenyl)-1-phenylethyl]piperazin--dihydrobromid, smeltepunkt 274 - 276°C, 21 146763 λ-l-(2-Methoxyphenyl)-4-[2-(3-methoxyphenyl)-1-phenylethylJpipera-zin-dihydrochlorid-hemihydrat, smeltepunkt 229 - 234°C, di-1-(3-Methyl-3-butenyl)-4-[2-(3-methoxyphenyl)-1-phenylethyl]-piperazin-dihydrochlorid-hemihydrat, smeltepunkt 212 - 215°C, di-1-(3-Methyl-2-butenyl)-4-[2-(3-methoxyphenyl)-1-phenylethyl]-piperazin-dihydrochlorid, smeltepunkt 205 - 209°C, d£-l-(2-Methoxyphenyl)-4-(2-(3-hydroxyphenyl)-1-phenylethyl]pipe-razin-dihydrochlorid-hemihydrat, smeltepunkt 185 - 188°C, d-1-(2-Methoxyphenyl)-4-[2-(3-hydroxyphenyl)-1-phenylethyl]pipera-zin-dihydrochlorid-hemihydrat, smeltepunkt 181 - 184°C, d£-l- (3-Methyl-2-butenyl)-4-[2-(3-hydroxyphenyl)-1-phenylethyl]pi-perazin-dihydrochlorid-monohydrat, smeltepunkt 222 - 224°C, d-1-(3-Methyl-2-butenyl)-4-[2-(3-hydroxyphenyl)-1-phenylethyl)piperazin-dihydrochlorid, smeltepunkt 221 - 224°C, dil-1-(3-Methyl-3-butenyl)-4-[2-(3-hydroxyphenyl)-1-phenylethyl]-piperazin-dihydrochlorid-hemihydrat, smeltepunkt 209 - 212°C, i-1-(3-Methyl-2-butenyl)-4-[2-(3-methoxyphenyl)-1-phenylethyl]piperazin-dihydrochlorid, smeltepunkt 215 - 217°C, di-1-(2-Hydroxyphenyl)-4-[2-(3-hydroxyphenyl)-1-phenylethyl]pipe-razin-dihydrobromid, smeltepunkt 219 - 224°C, diL-1- (3-Methoxyphenyl) -4- [2- (3-hydroxyphenyl) -1-phenylethyl] piperazin-dihydrochlorid, smeltepunkt 190 - 195°C, dJL-1- (3-Hydroxyphenyl) -4- [2- (3-hydroxyphenyl) -1-phenylethyl] piperazin-dihydrochlorid, smeltepunkt 196 - 203°C, l-1-(4-Methoxypheny1)-4-[2-(3-hydroxyphenyl)-1-phenylethyl]piperazin-dihydrochlorid, smeltepunkt 193 - 198°C, d£-l-(4-Methoxyphenyl)-4-[2-(3-hydroxyphenyl)-1-phenylethyl]piperazin-dihydrochlorid, smeltepunkt 187 - 191°C, 22 146763 d£-l-(2-Chlorphenyl)-4-[2-(3-hydroxyphenyl)-1-phenylethyl]pipe-razin-dihydrochlorid-hemihydrat, smeltepunkt 202 - 205°C, λ-1-Ally1-4-[2-(3-hydroxypheny1)-1-phenylethyl]piperazin-dihydro-chlorid-monoethanolat, smeltepunkt 197 - 204°C og dfc-l-Propyl-4-[2-(3-hydroxyphenyl)-1-phenylethyl]piperazin-dihy-drochlorid-hemihydrat, smeltepunkt 212 - 214°C.The compounds listed below are prepared in the same manner as described in the above examples: dfe-1-Cycloheptyl-4- [2- (3-hydroxyphenyl) -1-phenylethyl] piperazine dihydrobromide, m.p. 279-281 ° C, d 1-Gyclooctyl-4- [2- (3-hydroxyphenyl) -1-phenylethyl] piperazine dihydrobromide, m.p. 274 - 276 ° C, λ-1- (2-Methoxyphenyl) -4- [2- (3 -methoxyphenyl) -1-phenylethylpiperazine dihydrochloride hemihydrate, mp 229 - 234 ° C, di-1- (3-methyl-3-butenyl) -4- [2- (3-methoxyphenyl) -1-phenylethyl] -piperazine dihydrochloride hemihydrate, m.p. 212 - 215 ° C, di-1- (3-methyl-2-butenyl) -4- [2- (3-methoxyphenyl) -1-phenylethyl] -piperazine dihydrochloride, m.p. 205 - 209 ° C, d-1- (2-Methoxyphenyl) -4- (2- (3-hydroxyphenyl) -1-phenylethyl] piperazine dihydrochloride hemihydrate, m.p. 185-188 ° C, d-1- (2-Methoxyphenyl) -4- [2- (3-hydroxyphenyl) -1-phenylethyl] piperazine dihydrochloride hemihydrate, mp 181 - 184 ° C, d-1- (3-Methyl-2-butenyl) 4- [2- (3-hydroxyphenyl) -1-phenylethyl] pi perazi n-dihydrochloride monohydrate, m.p. 222 - 224 ° C, d-1- (3-Methyl-2-butenyl) -4- [2- (3-hydroxyphenyl) -1-phenylethyl) piperazine dihydrochloride, m.p. 221 - 224 ° C, dil-1- (3-Methyl-3-butenyl) -4- [2- (3-hydroxyphenyl) -1-phenylethyl] -piperazine dihydrochloride hemihydrate, mp 209 - 212 ° C, 1- (3-Methyl-2-butenyl) -4- [2- (3-methoxyphenyl) -1-phenylethyl] piperazine dihydrochloride, m.p. 215 - 217 ° C, di-1- (2-Hydroxyphenyl) -4- [2 - (3-hydroxyphenyl) -1-phenylethyl] piperazine dihydrobromide, mp 219 - 224 ° C, diL-1- (3-Methoxyphenyl) -4- [2- (3-hydroxyphenyl) -1-phenylethyl] piperazine dihydrochloride, m.p. 190-195 ° C, dJL-1- (3-Hydroxyphenyl) -4- [2- (3-hydroxyphenyl) -1-phenylethyl] piperazine dihydrochloride, mp 196-203 ° C, 1- (4-Methoxyphenyl) -4- [2- (3-hydroxyphenyl) -1-phenylethyl] piperazine dihydrochloride, m.p. 193 - 198 ° C, d-1- (4-Methoxyphenyl) -4- [2- (3 -hydroxyphenyl) -1-phenylethyl] piperazine dihydrochloride, m.p. 187 DEG-191 DEG C. 22 DEG-1- (2-Chlorophenyl) enyl) -4- [2- (3-hydroxyphenyl) -1-phenylethyl] piperazine dihydrochloride hemihydrate, mp 202-205 ° C 1-phenylethyl] piperazine dihydrochloride monoethanolate, m.p. 197-204 ° C and dfc-1-Propyl-4- [2- (3-hydroxyphenyl) -1-phenylethyl] piperazine dihydrochloride hemihydrate, m.p. 212 - 214 ° C.

Eksempel 7.Example 7

d£-l-(2-Methoxyphenyl)-4-[2-(3-methoxyphenyl)-1-phenylethyl]pipera-zin.d £ -L- (2-methoxyphenyl) -4- [2- (3-methoxyphenyl) -1-phenylethyl] piperazine Zin.

I 50 ml dimethylformamid opløses 5,6 g d£-N,N-bis(2-chlorethyl)-2--(3-methoxyphenyl)-1-phenylethylamin-hydrochlorid, og til denne opløsning sættes 7,3 g o-anisidin. Blandingen koges under tilbagesvaling under omrøring i 5 timer. Efter omsætningen sidestilleres opløsningsmidlet under reduceret tryk. Til remanensen sættes koncentreret vandig ammoniakopløsning, og den basiske opløsning ek-straheres med ether. Etherfasen vaskes med vand, og tørres over vandfrit natriumsulfat, og opløsningsmidlet afdestilieres. Den olie-agtige remanens destilleres under reduceret tryk til fjernelse af overskydende o-anisidin. Destillationsremanensen opløses i ethanol og behandles med ethanolisk saltsyre, hvorved der fås hydrochlo-ridet, som omkrystalliseres af ethanol, hvorved der fås 2,8 g af den ønskede forbindelse i form af dihydrochiorid-hemihydratet, smeltepunkt 225 - 228°C.Dissolve 5.6 g of d -N, N-bis (2-chloroethyl) -2- (3-methoxyphenyl) -1-phenylethylamine hydrochloride in 50 ml of dimethylformamide and add 7.3 g of o-anisidine to this solution. The mixture is refluxed under stirring for 5 hours. After the reaction, the solvent is equilibrated under reduced pressure. To the residue is added concentrated aqueous ammonia solution and the basic solution is extracted with ether. The ether phase is washed with water and dried over anhydrous sodium sulfate and the solvent is distilled off. The oily residue is distilled under reduced pressure to remove excess o-anisidine. The distillation residue is dissolved in ethanol and treated with ethanolic hydrochloric acid to give the hydrochloride which is recrystallized from ethanol to give 2.8 g of the desired compound in the form of the dihydrochloride hemihydrate, mp 225-222 ° C.

Eksempel 8.Example 8.

dJl-1- (2-Methoxyphenyl) -4- [2- (3-hydroxyphenyl) -1-phenylethyl] pipera-zin.dJl-1- (2-Methoxyphenyl) -4- [2- (3-hydroxyphenyl) -1-phenylethyl] piperazine.

I 70 ml dimethylformamid opløses 5,1 g dJl-N,N-bis (2-bromethyl) -2--(3-hydroxyphenyl)-1-phenylethylamin-hydrobromid, og til denne opløsning sættes 6,5 g o-anisidin. Blandingen koges under tilbagesvaling under omrøring i 5 timer. Efter omsætningen afdestilleres opløsningsmidlet under reduceret tryk. Til remanensen sættes en koncentreret vandig ammoniakopløsning, og den basiske blanding ek- 23 146763 straheres med ether. Etherfasen vaskes med vand og tørres over vandfrit natriumsulfat, og opløsningsmidlet afdestilleres. Den olie-agtige remanens destilleres under reduceret tryk til fjernelse af overskydende o-anisidin. Den krystallinske destillationsremanens (den frie base) opløses i ethanol og behandles med methanolisk saltsyre, hvorved der fås hydrochloridet, som omkrystalliseres af methanol til dannelse af 2,8 g af den ønskede forbindelse i form af dihydrochlorid-hemihydratet, smeltepunkt 185 - 188°C.In 70 ml of dimethylformamide dissolve 5.1 g of dJ1-N, N-bis (2-bromethyl) -2- (3-hydroxyphenyl) -1-phenylethylamine hydrobromide and to this solution 6.5 g of o-anisidine are added. The mixture is refluxed under stirring for 5 hours. After the reaction, the solvent is distilled off under reduced pressure. To the residue is added a concentrated aqueous ammonia solution and the basic mixture is extracted with ether. The ether phase is washed with water and dried over anhydrous sodium sulfate and the solvent is distilled off. The oily residue is distilled under reduced pressure to remove excess o-anisidine. The crystalline distillation residue (free base) is dissolved in ethanol and treated with methanolic hydrochloric acid to give the hydrochloride which is recrystallized from methanol to give 2.8 g of the desired compound as the dihydrochloride hemihydrate, m.p. 185 - 188 ° C .

Eksempel 9.Example 9

d&-l-Cyclohexyl-4-[2-(3-hydroxyphenyl)-1-phenylethyl]-piperazin.d & -l-cyclohexyl-4- [2- (3-hydroxyphenyl) -1-phenylethyl] piperazine.

I 60 ml ethanol opløses 3,7 g d&-N,N-bis(2-chlorethyl)-1-phenyl--2-(3-hydroxyphenyl)ethylamin-hydrochlorid og 1,4 g cyclohexylamin, og til denne opløsning sættes 3,0 g natriumhydrogencarbonat. Blandingen koges under tilbagesvaling under omrøring i 24 timer. Efter reaktionen afdestilleres opløsningsmidlet. Til remanensen sættes en fortyndet vandig natriumcarbonatopløsning, og blandingen ekstra-heres med ethylacetat. Ethylacetatfasen vaskes med vand og tørres over vandfrit natriumsulfat, og opløsningsmidlet afdestilleres. Remanensen (den rå frie base) opløses i en ringe mængde methanol, og blandingen indstilles på sur reaktion med en 25%'s brombrintesyre--eddikesyreopløsning og lades afkøle. De udfældede krystaller vaskes med en blanding af acetone og ether og omkrystalliseres af methanol, hvorved der fås 2,9 g af den ønskede forbindelse i form af dihydrobromidet, smeltepunkt 268 - 270°C.In 60 ml of ethanol are dissolved 3.7 g of d & -N, N-bis (2-chloroethyl) -1-phenyl-2- (3-hydroxyphenyl) ethylamine hydrochloride and 1.4 g of cyclohexylamine, and to this solution is added 3 , 0 g sodium bicarbonate. The mixture is refluxed under stirring for 24 hours. After the reaction, the solvent is distilled off. To the residue is added a dilute aqueous sodium carbonate solution and the mixture is extracted with ethyl acetate. The ethyl acetate phase is washed with water and dried over anhydrous sodium sulfate and the solvent is distilled off. The residue (the crude free base) is dissolved in a small amount of methanol and the mixture is adjusted to acidic reaction with a 25% hydrochloric acid-acetic acid solution and allowed to cool. The precipitated crystals are washed with a mixture of acetone and ether and recrystallized from methanol to give 2.9 g of the desired compound in the form of the dihydrobromide, mp 268-270 ° C.

Det på den ovenfor beskrevne måde vundne dihydrobromid behandles med en fortyndet vandig kaliumcarbonatopløsning på sædvanlig måde, og de vundne krystaller omkrystalliseres af benzen, hvorved der fås den frie base af den ønskede forbindelse i form af farveløse nåle med smeltepunkt 140 - 141°C.The dihydrobromide obtained in the manner described above is treated with a dilute aqueous potassium carbonate solution in the usual manner and the crystals obtained are recrystallized from benzene to give the free base of the desired compound as colorless needles, mp 140-141 ° C.

Den således vundne frie base behandles med methanolisk saltsyre, og de vundne krystaller omkrystalliseres af methanol, hvorved der fås dihydrochloridet af den ønskede forbindelse, smeltepunkt 264 -270°C (sønderdeling).The free base thus obtained is treated with methanolic hydrochloric acid and the crystals obtained are recrystallized from methanol to give the dihydrochloride of the desired compound, mp 264-270 ° C (dec.).

24 14676324 146763

Eksempel 10-Example 10

De nedenfor anførte forbindelser fremstilles på samme måde som beskrevet i eksempel 7-9: d£-l-Cycloheptyl-4- [2- (3-hydroxyphenyl) -1-phenylethyl] piperazin--dihydrobromid, smeltepunkt 279 - 281°C, d£-l-Cyclooctyl-4-[2-(3-hydroxyphenyl)-1-phenylethyl]piperazin-di-hydrobromid, smeltepunkt 274 - 276°C, t-l-Cyclohexyl-4-[2-(3-hydroxyphenyl)-1-phenylethyl]piperazin-di-hydrochlorid, smeltepunkt 275 - 280°C (sønderdeling), d-l-Cyclohexyl-4-[2-(3-hydroxyphenyl)-1-phenylethyl]piperazin-di-hydrochlorid, smeltepunkt 275 - 280°C (sønderdeling), d£-l-(3-Methyl-2-butenyl)-4-[2-(3-methoxyphenyl)-1-phenylethyl]-piperazin-dihydrochlorid, smeltepunkt 205 - 209°C, d£-l-(3-Methyl-3-butenyl)-4-[2-(3-hydroxyphenyl)-1-phenylethyl]-piperazin-dihydrochlorid-hemihydrat, smeltepunkt 209 - 212°C, dA-1-(3-Methyl-2-butenyl)-4-[2-(3-hydroxyphenyl)-1-phenylethyl]-piperazin-dihydrochlorid-monohydrat, smeltepunkt 222 - 22 4°C, di.-l- (3-Hydroxyisoamyl) -4- [2- (3-hydroxyphenyl) -1-phenylethyl] -piperazin-dihydrochlorid-sesquihydrat, smeltepunkt 200 - 202°C, dt-1-(4-Methoxyphenyl)-4-[2-(3-hydroxyphenyl)-1-phenylethyl]piperazin-dihydrochlorid, smeltepunkt 187 - 191°C, d&-l-Allyl-4-[2-(3-hydroxyphenyl)-1-phenylethyl]piperazin-dihy-drochlorid-monoethanolat, smeltepunkt 194 - 197°C, £-1-(3-Methyl-2-buteny1)-4-[2-(3-hydroxyphenyl)-1-phenylethyl]piperazin-dihydrochlorid, smeltepunkt 221 - 224°C, &-1-(3-Methyl-2-butenyl)-4-[2-(3-methoxyphenyl)-1-phenylethyl]piperazin-dihydrochlorid, smeltepunkt 215 - 217°C, 146763 25 λ-l-(2-Methoxyphenyl)-4-[2-(3-methoxyphenyl)-1-phenylethyl]pipera-zin-dihydrochlorid-hemihydrat, smeltepunkt 229 - 234°C.The compounds listed below are prepared in the same manner as described in Examples 7-9: dβ-1-Cycloheptyl-4- [2- (3-hydroxyphenyl) -1-phenylethyl] piperazine dihydrobromide, mp 279-281 ° C. dβ-1-Cyclooctyl-4- [2- (3-hydroxyphenyl) -1-phenylethyl] piperazine dihydrobromide, m.p. 274 - 276 ° C, tl-Cyclohexyl-4- [2- (3-hydroxyphenyl) - 1-phenylethyl] piperazine dihydrochloride, m.p. 275-280 ° C (decomp.), Dl-Cyclohexyl-4- [2- (3-hydroxyphenyl) -1-phenylethyl] piperazine dihydrochloride, m.p. 275-280 ° C (decomposition), dβ-1- (3-Methyl-2-butenyl) -4- [2- (3-methoxyphenyl) -1-phenylethyl] -piperazine dihydrochloride, m.p. 205-209 ° C, d 1- (3-Methyl-3-butenyl) -4- [2- (3-hydroxyphenyl) -1-phenylethyl] -piperazine dihydrochloride hemihydrate, m.p. 209 - 212 ° C, dA-1- (3-methylphenyl) 2-butenyl) -4- [2- (3-hydroxyphenyl) -1-phenylethyl] -piperazine dihydrochloride monohydrate, m.p. 222 - 22 4 ° C, di-1- (3-Hydroxyisoamyl) -4- [2 - (3-hydroxyphenyl) -1-phenylethyl] -piperazine dihydrochlori d-sesquihydrate, m.p. 200-202 ° C, dt-1- (4-Methoxyphenyl) -4- [2- (3-hydroxyphenyl) -1-phenylethyl] piperazine dihydrochloride, m.p. 187-191 ° C, d & l -Allyl 4- [2- (3-hydroxyphenyl) -1-phenylethyl] piperazine dihydrochloride monoethanolate, m.p. 194 - 197 ° C, -1- (3-Methyl-2-butenyl) -4- [ 2- (3-hydroxyphenyl) -1-phenylethyl] piperazine dihydrochloride, m.p. 221 - 224 ° C, & -1- (3-Methyl-2-butenyl) -4- [2- (3-methoxyphenyl) -1- phenylethyl] piperazine dihydrochloride, m.p. 215 - 217 ° C, λ-1- (2-Methoxyphenyl) -4- [2- (3-methoxyphenyl) -1-phenylethyl] piperazine dihydrochloride hemihydrate, m.p. 229 - 234 ° C.

Eksempel 11.Example 11.

d&-l-cyclohexyl~4- [ 1-phenyl-2- (3-propionyloxyphenyl) ethyl] piperazin.d & l-cyclohexyl-4- [1-phenyl-2- (3-propionyloxyphenyl) ethyl] piperazine.

En blanding af 5,2 g d£-l-cyclohexyl-4-[2-(3-hydroxyphenyl)-1-phenyl-ethyl] piperazin-dihydrochlorid, 10,0 g propionsyreanhydrid og 100 ml pyridin koges under tilbagesvaling i 4 timer. Efter omsætningen af-destilleres opløsningsmidlet under reduceret tryk. Til remanensen sættes acetone. De udfældede krystaller isoleres ved filtrering og omkrystalliseres af ethanol, hvorved der fås 4,5 g af den ønskede forbindelse i form af dihydrochloridet, smeltepunkt 219 - 222°C.A mixture of 5.2 g of dl-1-cyclohexyl-4- [2- (3-hydroxyphenyl) -1-phenyl-ethyl] piperazine dihydrochloride, 10.0 g of propionic anhydride and 100 ml of pyridine is refluxed for 4 hours. After the reaction, the solvent is distilled off under reduced pressure. Acetone is added to the residue. The precipitated crystals are isolated by filtration and recrystallized from ethanol to give 4.5 g of the desired compound in the form of the dihydrochloride, mp 219 - 222 ° C.

Eksempel 12.Example 12.

Optisk opspaltning af d£-cyclohexyl-4-[2-(3-hydroxyphenyl)-1-phenyl-ethyl]piperazin.Optical cleavage of dβ-cyclohexyl-4- [2- (3-hydroxyphenyl) -1-phenylethyl] piperazine.

Til en opvarmet opløsning af 13,6 g d£-1-cyclohexy1-4-[2-(3-hydroxyphenyl) -1-phenylethyl]piperazin i 70 ml 95%'s ethanol sættes en opvarmet opløsning af 21,2 g £.-2'-nitrotartranilinsyre i 70 ml 95%'s ethanol. Blandingen lades afkøle. De udfældede krystaller fraskilles ved filtrering og omkrystalliseres fraktioneret af 95%'s ethanol, hvorved der fås 6,7 g Jl-l-cyclohexy 1-4-[2-(3-hydroxyphenyl)-1--phenylethyl]piperazin-di-£-2'-nitrotartranilat, gule prismer med smeltepunkt 157 - 158°C, [a]^9 = -64,0° (c = 2 i methanol).To a heated solution of 13.6 gd of β-1-cyclohexy-4 - [2- (3-hydroxyphenyl) -1-phenylethyl] piperazine in 70 ml of 95% ethanol is added a heated solution of 21.2 g. -2'-nitrotartranilic acid in 70 ml of 95% ethanol. The mixture is allowed to cool. The precipitated crystals are separated by filtration and recrystallized from 95% ethanol to give 6.7 g of J1-1 cyclohexy 1-4- [2- (3-hydroxyphenyl) -1-phenylethyl] piperazine di £ -2'-nitrotartranilate, yellow prisms, m.p. 157 - 158 ° C, [α] 20 = -64.0 ° (c = 2 in methanol).

Til det således vundne salt sættes vand, og blandingen indstilles på alkalisk reaktion med natriumcarbonat og ekstraheres med ethyl-acetat. Ethylacetatfasen vaskes med vand og tørres over vandfrit natriumsulfat, og opløsningsmidlet sidestilleres. Remanensen (den frie base) behandles med methanolisk saltsyre, hvorved der fås dihydrochloridet, som omkrystalliseres af methanol, hvorved der fås JL-1-cyclohexy 1-4- [2- (3-hydroxyphenyl) -1-phenylethyl]piperazin-di-hydrochlorid, smeltepunkt 275 - 280°C (sønderdeling), [a]^9 = -49,1° (c = 0,5 i methanol).To the salt thus obtained is added water and the mixture is adjusted to alkaline reaction with sodium carbonate and extracted with ethyl acetate. The ethyl acetate phase is washed with water and dried over anhydrous sodium sulfate and the solvent is equilibrated. The residue (the free base) is treated with methanolic hydrochloric acid to give the dihydrochloride which is recrystallized from methanol to give JL-1-cyclohexy 1-4- [2- (3-hydroxyphenyl) -1-phenylethyl] piperazine-di hydrochloride, m.p. 275-280 ° C (dec.), [α] 20 = -49.1 ° (c = 0.5 in methanol).

26 14676326 146763

Desuden destilleres moderluden, der fås efter fjernelse af 1-2*--nitrotartranilatet på den ovenfor beskrevne måde, til fjernelse af opløsningsmidlet. Til remanensen sættes en fortyndet vandig na-triumcarbonatopløsning, og den basiske blanding ekstraheres med ethylacetat. Ethylacetatfasen vaskes med vand og tørres over vandfrit natriumsulfat, og opløsningsmidlet afdestilleres. Remanensen (6,0 g rå fri base) opløses i 30 ml 95%'s ethanol, og hertil sættes en opvarmet opløsning af 9,3 g d-2'-nitrotartranilinsyre i 30 ml 95%'s ethanol, og blandingen lades afkøle. De udfældede krystaller fraskilles ved filtrering og omkrystalliseres fraktioneret af 95%'s ethanol, hvorved der fås 4,3 g d-l-cyclohexyl-4-[2-(3-hydroxyphenyl)--1-phenylethyl]piperazin-di-d-2'-nitrotartranilat, smeltepunkt 157 -158°C. [a]^2 = +63,8° (c = 2 i methanol).In addition, the mother liquor obtained after removal of the 1-2 * nitrotartranilate in the manner described above is distilled to remove the solvent. To the residue is added a dilute aqueous sodium carbonate solution and the basic mixture is extracted with ethyl acetate. The ethyl acetate phase is washed with water and dried over anhydrous sodium sulfate and the solvent is distilled off. The residue (6.0 g of crude free base) is dissolved in 30 ml of 95% ethanol, and to this is added a heated solution of 9.3 g of d-2'-nitrotartranilic acid in 30 ml of 95% ethanol and the mixture is allowed to cool . The precipitated crystals are separated by filtration and recrystallized from 95% ethanol to give 4.3 g of dl-cyclohexyl-4- [2- (3-hydroxyphenyl) -1-phenylethyl] piperazine-di-d-2 Nitrotartranilate, mp 157 -158 ° C. [α] 25 = + 63.8 ° (c = 2 in methanol).

Det på den ovenfor beskrevne måde vundne salt behandles med en fortyndet vandig natriumcarbonatopløsning, og den resulterende frie base behandles med methanolisk saltsyre, hvorved der fås dihydro-chloridet, som omkrystalliseres af methanol, hvorved der fås d-1--cyclohexyl-4-[2-(3-hydroxyphenyl)-1-phenylethyl]piperazin-dihydro-chlorid, smeltepunkt 275 - 280°C (sønderdeling). [a]29 = +49,0° (c = 0,5 i methanol).The salt obtained in the manner described above is treated with a dilute aqueous sodium carbonate solution and the resulting free base is treated with methanolic hydrochloric acid to give the dihydrochloride which is recrystallized from methanol to give d-1-cyclohexyl-4- [ 2- (3-hydroxyphenyl) -1-phenylethyl] piperazine dihydrochloride, mp 275-280 ° C (dec.). [α] 29 = + 49.0 ° (c = 0.5 in methanol).

Eksempel 13.Example 13

Optisk opspaltning af dA-1-(3-methyl-2-butenyl)-4-[2-(3-hydroxyphe-nyl)-1-phenylethyl]piperazin.Optical cleavage of dA-1- (3-methyl-2-butenyl) -4- [2- (3-hydroxyphenyl) -1-phenylethyl] piperazine.

Til en opvarmet opløsning af 10,2 g d£-l-(3-methyl-2-butenyl)-4--[2-(3-hydroxyphenyl)-1-phenylethyl]piperazin i 50 ml 95%'s ethanol sættes en opvarmet opløsning af 16,6 g f-2'-nitrotartranilinsyre i 50 ml 95%'s ethanol, og blandingen inddampes til 1/3 rumfang og lades afkøle. De udfældede krystaller isoleres ved filtrering og omkrystalliseres fraktioneret af ethanol, hvorved der fås 7,7 g £-1-(3-methyl-2-butenyl)-4-[2-(3-hydroxyphenyl)-l-phenyl-ethylipiperazin-di-Æ·^ '-nitrotartranilat i form af gule nåle med smeltepunkt 126,5 - 128°C. [a]2® = -64,4° (c = 2,00 i methanol).To a heated solution of 10.2 gd of β-1- (3-methyl-2-butenyl) -4 - [2- (3-hydroxyphenyl) -1-phenylethyl] piperazine in 50 ml of 95% ethanol is added a heated solution of 16.6 g of f-2'-nitrotartranilic acid in 50 ml of 95% ethanol and the mixture is evaporated to 1/3 volume and allowed to cool. The precipitated crystals are isolated by filtration and recrystallized from ethanol to give 7.7 g of 1- (3-methyl-2-butenyl) -4- [2- (3-hydroxyphenyl) -1-phenyl-ethylipiperazine]. di-Æ · n-nitrotartan trianate in the form of yellow needles, m.p. 126.5 - 128 ° C. [α] 2 D = -64.4 ° (c = 2.00 in methanol).

27 14676327 146763

Til det således vundne salt sættes vand, og blandingen indstilles på basisk reaktion med natriumcarbonat og ekstraheres med ethylace-tat. Ethylacetatfasen vaskes med vand og tørres over vandfrit natriumsulfat, og opløsningsmidlet afdestilleres. Remanensen (den frie base) behandles med ethanolisk saltsyre, hvorved der fås di-hydrochloridet, som omkrystalliseres af ethanol, hvorved der fås &-l-(3-methyl-2-butenyl)-4-[2-(3-hydroxyphenyl)-l-phenylethyl]pi-perazin-dihydrochlorid, smeltepunkt 221 - 224°C, [a]^** = -56,2° (c = 1,00 i methanol).To the salt thus obtained is added water and the mixture is adjusted to basic reaction with sodium carbonate and extracted with ethyl acetate. The ethyl acetate phase is washed with water and dried over anhydrous sodium sulfate and the solvent is distilled off. The residue (the free base) is treated with ethanolic hydrochloric acid to give the dihydrochloride which is recrystallized from ethanol to give & 1- (3-methyl-2-butenyl) -4- [2- (3-hydroxyphenyl) -1-phenylethyl] piperazine dihydrochloride, m.p. 221 - 224 ° C, [α] D = -66.2 ° (c = 1.00 in methanol).

Den efter fraskillelse af 1-2'-nitrotartranilatet vundne moderlud afdestilieres til fjernelse af opløsningsmidlet. Til remanensen sættes en fortyndet vandig natriumcarbonatopløsning, og den basiske opløsning ekstraheres med ethylacetat. Ethylacetatfasen vaskes med vand og tørres over vandfrit natriumsulfat, og opløsningsmidlet afdestilleres. Remanensen (den rå frie base) opløses i 20 ml 95%'s ethanol, og hertil sættes en opvarmet opløsning af 8,5 g d-2'-nitrotartranilinsyre i 20 ml 95%'s ethanol, og blandingen inddampes til 1/3 rumfang og lades afkøle. De udfældede krystaller i-soleres ved filtrering og omkrystalliseres fraktioneret af ethanol, hvorved der fås 5,5 g d-l-(3-methyl-2-butenyl)-4-[2-(3-hydroxyphenyl) -1-phenylethyl]piperazin-di-d-2'-nitrotårtranilat, smeltepunkt 126,5 - 128°C. [a]£9 = +64,7° (c = 2,00 i methanol).The mother liquor obtained after separation of the 1-2'-nitrotartranilate is distilled off to remove the solvent. To the residue is added a dilute aqueous sodium carbonate solution and the basic solution extracted with ethyl acetate. The ethyl acetate phase is washed with water and dried over anhydrous sodium sulfate and the solvent is distilled off. The residue (the crude free base) is dissolved in 20 ml of 95% ethanol, and to this is added a heated solution of 8.5 g of d-2'-nitrotartranilic acid in 20 ml of 95% ethanol and the mixture is evaporated to 1/3. volume and let cool. The precipitated crystals were isolated by filtration and recrystallized fractionally by ethanol to give 5.5 g of dl- (3-methyl-2-butenyl) -4- [2- (3-hydroxyphenyl) -1-phenylethyl] piperazine. di-d-2'-nitrotearn tranilate, mp 126.5 - 128 ° C. [.alpha.] @ 9 = + 64.7 ° (c = 2.00 in methanol).

Det således vundne salt behandles med fortyndet vandig natriumcarbonatopløsning til dannelse af en fri base, og den frie base behandles med ethanolisk saltsyre, hvorved der fås dihydrochlori-det, som omkrystalliseres af ethanol, hvorved der fås d-l-(3-methyl--2-butenyl)-4-[2-(3-hydroxyphenyl)-1-phenylethyl]piperazin-dihy-drochlorid, smeltepunkt 221 - 224°C. [a]^® = +56,0° (c = 1,00 i methanol).The salt thus obtained is treated with dilute aqueous sodium carbonate solution to form a free base, and the free base is treated with ethanolic hydrochloric acid to give the dihydrochloride which is recrystallized from ethanol to give dl- (3-methyl-2- butenyl) -4- [2- (3-hydroxyphenyl) -1-phenylethyl] piperazine dihydrochloride, mp 221 - 224 ° C. [α] D = + 56.0 ° (c = 1.00 in methanol).

Eksempel 14.Example 14.

&-1-(2-Methoxyphenyl)-4-[1-pheny1-2-(3-methoxyphenyl) ethyl]piperazin.& -1- (2-Methoxyphenyl) -4- [1-phenyl-2- (3-methoxyphenyl) ethyl] piperazine.

Til en opvarmet opløsning af 22,0 g dA-1-(2-methoxyphenyl)-4-[1--phenyl-2-(3-methoxyphenyl)ethyl]piperazin i 50 ml ethanol sættes 1467S3 en opvarmet opløsning af 16,0 g 5.-2'-nitrotartranilinsyre i 50 ml ethanol, og blandingen lades henstå ved stuetemperatur. De udfældede krystaller isoleres ved filtrering og omkrystalliseres fraktioneret af ethanol, hvorved der fås 6,0 g 5,-1-(2-methoxyphenyl)-4-- [l-phenyl-2- (3-methoxyphenyl) ethyl] piperazin-5,-21 -nitrotartranilat--hemihydrat, smeltepunkt 84 - 86°C. [a]^ = -60° (c = 2,0 i methanol) .To a heated solution of 22.0 g of dA-1- (2-methoxyphenyl) -4- [1- phenyl-2- (3-methoxyphenyl) ethyl] piperazine in 50 ml of ethanol is added a heated solution of 16.0 g of 5-2'-nitrotartranilic acid in 50 ml of ethanol and leave to stand at room temperature. The precipitated crystals are isolated by filtration and recrystallized fractionally by ethanol to give 6.0 g of 5, -1- (2-methoxyphenyl) -4- [1-phenyl-2- (3-methoxyphenyl) ethyl] piperazine-5 , -21-nitrotartranilate - hemihydrate, mp 84 - 86 ° C. [α] D = -60 ° (c = 2.0 in methanol).

Til det således vundne salt sættes vand, og blandingen indstilles på basisk reaktion med natriumcarbonat og ekstraheres med ethylace-tat. Ethylacetatfasen vaskes med vand og tørres over vandfrit natriumsulfat, og opløsningsmidlet afdestilleres. Remanensen (den frie base) behandles med ethanolisk saltsyre, hvorved der fås dihydrochlo-ridet, som omkrystalliseres af ethanol, hvorved der fås den ønskede forbindelse i form af dihydrochlorid«-hemihydratet, smeltepunkt 229 - 234°C.To the salt thus obtained is added water and the mixture is adjusted to basic reaction with sodium carbonate and extracted with ethyl acetate. The ethyl acetate phase is washed with water and dried over anhydrous sodium sulfate and the solvent is distilled off. The residue (the free base) is treated with ethanolic hydrochloric acid to give the dihydrochloride, which is recrystallized from ethanol to give the desired compound in the form of the dihydrochloride 'hemihydrate, mp 229 - 234 ° C.

På analog måde som ovenfor beskrevet fremstilles følgende forbindelse: d-1-(2-Methoxyphenyl)-4-[l-phenyl-2-(3-hydroxyphenyl)ethyl]pipera-zin-dihydrochlorid-hemihydrat, smeltepunkt 181 - 184°C.By analogy as described above, the following compound is prepared: d-1- (2-Methoxyphenyl) -4- [1-phenyl-2- (3-hydroxyphenyl) ethyl] piperazine dihydrochloride hemihydrate, mp 181 - 184 ° C .

Referenceeksempel 1.Reference Example 1.

d5,-2- (3-Hydroxyphenyl) -1-phenylethylamin.d5, -2- (3-Hydroxyphenyl) -1-phenylethylamine.

En blanding af 11,3 g dA-2-(3-methoxyphenyl)-1-phenylethylamin-hy-drochlorid, 100 ml 48%'s brombrintesyre og 30 ml iseddike koges under tilbagesvaling i 4 timer. Efter omsætningen afdestilleres opløsningsmidlet. Til remanensen sættes vand, og blandingen indstilles på basisk reaktion med ammoniak og ekstraheres med chloroform. Chloroformfasen tørres over vandfrit kaliumcarbonat, og opløsningsmidlet afdestilleres. Til remanensen sættes ether. De udfældede krystaller isoleres ved filtrering og omkrystalliseres af ethanol-ethyl-acetat, hvorved der fås 7,3 g af den ønskede forbindelse, smeltepunkt 179 - 181°C.A mixture of 11.3 g of dA-2- (3-methoxyphenyl) -1-phenylethylamine hydrochloride, 100 ml of 48% hydrobromic acid and 30 ml of glacial acetic acid is refluxed for 4 hours. After the reaction, the solvent is distilled off. To the residue is added water and the mixture is adjusted to basic reaction with ammonia and extracted with chloroform. The chloroform phase is dried over anhydrous potassium carbonate and the solvent is distilled off. To the residue is added ether. The precipitated crystals are isolated by filtration and recrystallized from ethanol-ethyl acetate to give 7.3 g of the desired compound, m.p. 179 - 181 ° C.

U6763 29U6763 29

Referenceeksempel 2.Reference Example 2.

d-2-(3-Hydroxyphenyl)-1-phenylethylamin.d-2- (3-hydroxyphenyl) -1-phenylethylamine.

I 5 ml 95%'s ethanol opløses 3,2 g dSL-2- (3-hydroxyphenyl) -1-phenyl-ethylamin og 4,2 g 1-2'-nitrotartranilinsyre under opvarmning. Efter afkøling tilsættes en blanding ethylacetat og ether, og blandingen lades afkøle. De udfældede krystaller isoleres ved filtrering og omkrystalliseres fraktioneret af ethanol, hvorved der fås 1,1 g d-2- (3-hydroxyphenyl) -l-phenylethylamin-i.^' -nitrotartranilat i form af gule nåle med smeltepunkt 159 - 160°C. [a]= +3,3° (c = 1,99 i methanol). Til det således vundne salt sættes vand, og blandingen gøres alkalisk med ammoniak og ekstraheres med chloroform. Chloro-formfasen tørres over vandfri kaliumcarbonat, og opløsningsmidlet destilleres af. Til remanensen sættes ether. De udfældede krystaller skilles fra ved filtrering og omkrystalliseres af ethanol/n-hexan, hvilket giver den ønskede forbindelse (0,44 g), smeltepunkt 130-131°C.In 5 ml of 95% ethanol, 3.2 g of dSL-2- (3-hydroxyphenyl) -1-phenyl-ethylamine and 4.2 g of 1-2'-nitrotartranilic acid are dissolved under heating. After cooling, a mixture of ethyl acetate and ether is added and the mixture is allowed to cool. The precipitated crystals are isolated by filtration and recrystallized fractionally by ethanol to give 1.1 g of d-2- (3-hydroxyphenyl) -1-phenylethylamine-1 H -nitrotartranilate in the form of yellow needles, mp 159-160 ° C. [α] = + 3.3 ° (c = 1.99 in methanol). To the salt thus obtained is added water and the mixture is made alkaline with ammonia and extracted with chloroform. The chloroform phase is dried over anhydrous potassium carbonate and the solvent is distilled off. To the residue is added ether. The precipitated crystals are separated by filtration and recrystallized from ethanol / n-hexane to give the desired compound (0.44 g), mp 130-131 ° C.

Referenceeksempel 3.Reference Example 3.

dÅ-N,N-Bis(2-bromethyl)-2-(3-hydroxyphenyl)-1-phenylethylamin.DAA-N, N-bis (2-bromoethyl) -2- (3-hydroxyphenyl) -1-phenylethylamine.

i) En opløsning af 11,0 g 3-(2-hydroxyethyl)-2-phenyloxazolidin i 30 ml vandfrit ether sættes dråbevis under omrøring til Grignard--reagens, som er fremstillet ud fra 3,3 g magnesiumspåner og 20,7 g m-methoxybenzylchlorid i 150 ml vandfrit ether, og blandingen koges under tilbagesvaling i 3 timer. Efter reaktionen sønderdeles reaktionsblandingen ved tilsætning af vand. Etherfasen fraskilles og ekstraheres med 100 ml 10%'s saltsyreopløsning. Saltsyrefasen indstilles på basisk reaktion med ammoniak og ekstraheres med ether. Etherfasen tørres over vandfrit natriumsulfat, og opløsningsmidlet sidestilleres, hvorved der fås 12,7 g rå d&-N,N-bis(2-hydroxyethyl)--2-(3-methoxyphenyl)-1-phenylethylamin i form af et olieagtigt stof. Når stoffet omkrystalliseres af ethanol, smelter det ved 67 - 69°C.i) A solution of 11.0 g of 3- (2-hydroxyethyl) -2-phenyloxazolidine in 30 ml of anhydrous ether is added dropwise with stirring to Grignard reagent prepared from 3.3 g of magnesium chips and 20.7 g m-methoxybenzyl chloride in 150 ml of anhydrous ether and the mixture is refluxed for 3 hours. After the reaction, the reaction mixture is decomposed by the addition of water. The ether phase is separated and extracted with 100 ml of 10% hydrochloric acid solution. The hydrochloric acid phase is adjusted to basic reaction with ammonia and extracted with ether. The ether phase is dried over anhydrous sodium sulfate and the solvent is equilibrated to give 12.7 g of crude d & -N, N-bis (2-hydroxyethyl) -2- (3-methoxyphenyl) -1-phenylethylamine in the form of an oily substance. When the substance is recrystallized from ethanol, it melts at 67 - 69 ° C.

ii) 12,7 g af den på den ovenfor beskrevne måde vundne d£-N,N-bis-(2-hydroxyethyl)-2-(3-methoxyphenyl)-1-phenylethylamin opløses i 15 ml chloroform, og hertil sættes 2 dråber dimethylformamid, og der tilsættes desuden dråbevis en opløsning af 25 ml thionylbro-mid i 15 ml chloroform, og blandingen koges under tilbagesvaling iii) 12.7 g of the d -N, N-bis- (2-hydroxyethyl) -2- (3-methoxyphenyl) -1-phenylethylamine obtained in the above described manner are dissolved in 15 ml of chloroform and added 2 drops of dimethylformamide and a solution of 25 ml of thionyl bromide in 15 ml of chloroform is added dropwise and the mixture is refluxed

Claims (2)

30 146763 3 timer. Efter omsætningen afdestilleres opløsningsmidlet og overskud af thionylbromid under reduceret tryk. Til den sirupslignende remanens (21 g) sættes 210 ml 47%'s brombrintesyre, og blandingen koges forsigtigt under tilbagesvaling i 1 time. Derpå fraskilles den vandige fase ved dekantering, behandles med aktivkul og destilleres endelig under reduceret tryk til fjernelse af opløsningsmidlet. Til remanensen sættes acetone-benzen, hvorefter opløsningsmidlet afdestilleres, hvorved der fås 13,5 g af den ønskede forbindelse som hydrobromidet i form af en sirup. Patentkrav.30 hours 3 hours. After the reaction, the solvent and excess thionyl bromide are distilled off under reduced pressure. To the syrup-like residue (21 g) is added 210 ml of 47% hydrochloric acid and the mixture is gently boiled under reflux for 1 hour. The aqueous phase is then separated by decantation, treated with activated charcoal and finally distilled under reduced pressure to remove the solvent. To the residue is added acetone-benzene, after which the solvent is distilled off to give 13.5 g of the desired compound as the hydrobromide in the form of a syrup. Claims. 1. Analogifremgangsmåde til fremstilling af 1-substituerede 4-(1,2-diphenylethyl·)piperazinderivater med den almene formel I {/ ch9-ch-/ n-r i ox hvor X betegner hydrogen, methyl eller alkanoyl med 2-5 carbonatomer, og R betegner allyl, 3-hydroxyisoamyl, 3-methyl-2-butenyl, 3-methyl-3-butenyl, propyl, usubstitueret monocycloalkyl med 6-8 carbonatomer, 2-chlorphenyl eller phenyl substitueret med hydroxy eller methoxy, med det forbehold, at R er 3-methyl-2-butenyl, 3-methyl-3-butenyl eller 2-methoxyphenyl, når X er methyl, eller farmaceutisk tolerable syreadditionssalte heraf, kendetegnet ved, at a) en forbindelse med den almene formel _o <Q>-ch2-ch-hh2 ox hvor X har den ovexitui anførte betydning, omsættes med en reaktionsdygtig diester af en alkohol med den almene formel 31 146763 HOCH2CH2-. ^N-R hcch2ch2// hvor R har den ovenfor anførte betydning, eller et salt deraf med en syre, eller b) en reaktionsdygtig diester af en alkohol med den almene formel Q.CH„CH0OH / <' ch2-ch-n / ' ^CH CH^OH ox hvor X har den ovenfor anførte betydning, eller et salt deraf med en syre omsættes med en forbindelse med den almene formel h2n-r hvor R har den ovenfor anførte betydning, eller c) til fremstilling af forbindelser, hvor X betegner alkanoyl med 2-5 carbonatomer, og R har den ovenfor anførte betydning» bortset fra hydroxyphenyl og 3-hydroxyisoamyl, en forbindelse med den almene formel ζ) \~y- ch2~ch~n^ n-r3 OH 3 hvor R har samme betydning som ovenfor defineret for R bortset fra hydroxyphenyl og 3-hydroxyisoamyl, eller et salt deraf med en syre omsættes med et alkanoyleringsmiddel med 2-5 carbonatomer i alkanoyl-delen,An analogous process for the preparation of 1-substituted 4- (1,2-diphenylethyl ·) piperazine derivatives of the general formula I {/ ch9-ch- / nr in ox where X represents hydrogen, methyl or alkanoyl having 2-5 carbon atoms, and R represents allyl, 3-hydroxyisoamyl, 3-methyl-2-butenyl, 3-methyl-3-butenyl, propyl, unsubstituted monocycloalkyl of 6-8 carbon atoms, 2-chlorophenyl or phenyl substituted by hydroxy or methoxy, with the proviso that R is 3-methyl-2-butenyl, 3-methyl-3-butenyl or 2-methoxyphenyl when X is methyl, or pharmaceutically tolerable acid addition salts thereof, characterized in that a) a compound of the general formula _o <Q> - ch 2 -ch-hh 2 ox, where X is as defined above, is reacted with a reactive diester of an alcohol of the general formula 31 CHCH 2 CH 2 -. Wherein R is as defined above, or a salt thereof with an acid, or b) a reactive diester of an alcohol of the general formula Q.CH2 CHOOH / <'ch2-ch-n /' CH CH2 OH ox where X has the meaning given above, or a salt thereof with an acid is reacted with a compound of the general formula h2n-r where R has the meaning given above, or c) to prepare compounds where X represents alkanoyl having 2-5 carbon atoms, and R has the meaning given above 'except for hydroxyphenyl and 3-hydroxyisoamyl, a compound of the general formula ζ) - ~ y - ch 2 ~ ch ~ n - n 3 r 3 OH 3 where R is the same meaning as defined above for R except hydroxyphenyl and 3-hydroxyisoamyl, or a salt thereof with an acid is reacted with an alkanoylating agent having 2-5 carbon atoms in the alkanoyl moiety,