DK166022B - BIS (piperazinyl or homopiperazinyl) alkanes AND ACID ADDITION SALTS THEREOF, METHOD FOR THEIR PREPARATION, PHARMACEUTICAL PREPARATIONS CONTAINING THE COMPOUNDS, METHOD FOR PRODUCTION OF SUCH PRODUCTS AND USE OF COMPOUNDS FOR THE PREPARATION OF A pharmaceutical composition ANTI-ALLERGIC AND antiinflammatory action - Google Patents
BIS (piperazinyl or homopiperazinyl) alkanes AND ACID ADDITION SALTS THEREOF, METHOD FOR THEIR PREPARATION, PHARMACEUTICAL PREPARATIONS CONTAINING THE COMPOUNDS, METHOD FOR PRODUCTION OF SUCH PRODUCTS AND USE OF COMPOUNDS FOR THE PREPARATION OF A pharmaceutical composition ANTI-ALLERGIC AND antiinflammatory action Download PDFInfo
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- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
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- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
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- C07D295/092—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings with aromatic radicals attached to the chain
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- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
- C07D295/104—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/108—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
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Abstract
Description
DK 166022BDK 166022B
Opfindelsen angår hidtil ukendte bis-(piperazinyl-eller homopiperazinyl)-alkaner og syreadditionssalte deraf, fremgangsmåde til deres fremstilling, farmaceutiske præparater indeholdende forbindelserne, fremgangs-5 måde til fremstilling af sådanne præparater og anvendelse af forbindelserne til fremstilling af et farmaceutisk præparat med antiallergisk og antiinflammatorisk virkning.The invention relates to novel bis (piperazinyl or homopiperazinyl) alkanes and acid addition salts thereof, process for their preparation, pharmaceutical compositions containing the compounds, process for the preparation of such compositions and use of the compounds for the preparation of a pharmaceutical composition with antiallergic and anti-inflammatory effect.
10 Teknikkens stade10 State of the art
Forbindelser med formlen: cH2N0,‘<cH2>n"N0icH2_ hvor n er tallet 2, 6, 8, 9 eller 10, er beskrevet af S.Chiavarelli, P.Mazzeo, F.Costa og A.M.Russo i Faraaco, Ed.Sci.20y 229 (1965). De har en curare-lignende virk-20 ning.Compounds of the formula: cH2N0, "<cH2> n" NO2H2_ where n is the number 2, 6, 8, 9 or 10 are described by S.Chiavarelli, P.Mazzeo, F.Costa and AMRusso in Faraaco, Ed.Sci 20y 229 (1965) They have a curare-like effect.
J.van Alpen beskriver i Rec.Trav.Chim.55, 835 (1936) syntesen af polyaminer med formlerne:J. van Alpen describes in Rec.Trav.Chim.55, 835 (1936) the synthesis of polyamines of the formulas:
ά VCH2-M1^2-OT2-NH-CH2-CH2-CH2-NH-CH2-CH2-NH-CH2-^ J 25 ' ' Wά VCH2-M1 ^ 2-OT2-NH-CH2-CH2-CH2-NH-CH2-CH2-NH-CH2- ^ J 25 '' W
ogand
30 O O30 O O
uden henvisning til en biologisk virkning.without reference to a biological effect.
Arbejdet ifølge C.B.Pollard, W.M.Lauter og N.O.Worked according to C.B.Pollard, W.M.Lauter and N.O.
Nuessle i J.0rg.Chem.24, 764 (1959) angår fremstilling 35 af forbindelser med formlen:Nuessle in J. Chem. 244, 764 (1959) relates to the preparation of compounds of the formula:
RO'N0~CH2'CH2'CH2‘H0O"RRO'N0 ~ CH2'CH2'CH2'H0O "R
DK 166022BDK 166022B
2 hvor R er hydrogen, alkyl eller halogen. Heller ikke her findes nogen angivelse om virkning.2 wherein R is hydrogen, alkyl or halogen. There is no indication of effect here either.
Belgisk patentskrift 633.453 angår forbindelser med formlen: f\n / N' W_^J-CH2-CH2-CH2-N_ 10 hvor R er halogen eller alkoxy, med antimalaria-virkning, anthelmintisk og amøbicid virkning.Belgian Patent Specification 633,453 relates to compounds of the formula: wherein R is halogen or alkoxy, having antimalarial, anthelmintic and amoebicidal activity.
U.S. patentskrift nr. 3.901.889 beskriver 1,2-bis(4-phenyl-1-piperazinyl)ethanderivater med formlen:U.S. U.S. Patent No. 3,901,889 discloses 1,2-bis (4-phenyl-1-piperazinyl) ethane derivatives of the formula:
Cj> O - cn2 "eH*" O “(j) R._ RbCj> O - cn2 "eH *" O “(j) R._ Rb
AA
hvor R^ og Rg uafhængigt kan være halogen, trifluorme-20 thyl eller lavere alkyl, med hypolipæmiinducerende, analgetiske og antiinflammatorisk aktivitet.wherein R 1 and R 9 may independently be halogen, trifluoromethyl or lower alkyl, with hypolipemia-inducing, analgesic and anti-inflammatory activity.
Endelig beskriver M.J.Dorokhova, V.A.Chernow, S.M. Minakova, O. Y.Tikhonova og A.N.Zamskaya, Khim.-Farm. Zh., 10, 36 (1976) , (C.A.j^S, 78079) forbindelser med formlen: 25 f=\l ΓΛ , /~\ »/=\ \J- c-»wN- <ce2) i^-y 30 hvor i er tallet 2, 3, 6 eller 10. Disse forbindelser tjener som udgangsstoffer for forbindelserne med den almene formel VI.Finally, M.J.Dorokhova, V.A.Chernow, S.M. Minakova, O. Y.Tikhonova, and A.N.Zamskaya, Khim.-Farm. Zh., 10, 36 (1976), (CA 2 S, 78079) compounds of the formula: 25 f = \ l ΓΛ, / ~ \ »/ = \ \ J- c-» wN- <ce2) i ^ -y 30 where i is the number 2, 3, 6 or 10. These compounds serve as starting substances for the compounds of general formula VI.
Opfindelsen 35 Det er nu blevet fundet, at visse hidtil ukendte bis-(piperazinyl- eller homopiperazinyl)-alkaner foruden en antiinflammatorisk virkning også besidder en anti-allergisk virkning.Invention It has now been found that, in addition to certain anti-inflammatory action, certain novel bis (piperazinyl or homopiperazinyl) alkanes also possess an anti-allergic effect.
33
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Sådanne forbindelser er ejendommelige ved, at de har den almene formel I: «J^ f7 A-vf11 I8 JL. 4 b5 ^9.^12 r14 *Ί0 % hvor:Such compounds are peculiar in that they have the general formula I: «J ^ f7 A-vf11 I8 JL. 4 b5 ^ 9. ^ 12 r14 * Ί0% where:
Ri, R2, R3 og R4 er ens eller forskellige og er hydrogen, en (C^-C^)alkylgruppe, en hydroxygruppe, en 10 (C^-C^)alkoxygruppe, en (C^-C^)acyloxygruppe, halogen, trihalogenmethyl, di-(C^-C^)alkyl-amino, (C1~C4)alko-xy-carbonyl, nitro, cyano eller (C^-C^lacyl, R5 og Rø er ens eller forskellige og er hydrogen, methyl, hydroxy, carboxy, (C1~c4)alkoxy-carbonyl/ hydroxyme-15 thyl, phenyl eller p-chiorphenyl, R7 og Rø er hydrogen eller methyl, j og k er heltal på 0-3, men tilsammen højst 4, m og n er heltal på 0-3, men tilsammen højst 4, A er -CH2“ eller -CH2-CH2~, eller 20 r og R- tilsammen eller R^ og R„ tilsammen er oxo med den 5 73 7 6 8 betingelse, at k eller m er forskellige fra 0, eller Rø og Ry tilsammen og R^ og Rg tilsammen er oxo med den betingelse, at k og m er forskellige fra 0,R 1, R 2, R 3 and R 4 are the same or different and are hydrogen, a (C 1 -C 4) alkyl group, a hydroxy group, a 10 (C 1 -C 2) alkoxy group, a (C 1 -C 2) acyloxy group, halogen , trihalogenmethyl, di- (C 1 -C 4) alkyl-amino, (C 1 -C 4) alkoxy-carbonyl, nitro, cyano or (C 1 -C 4 lacyl, R 5 and R 9 are the same or different and are hydrogen, methyl, hydroxy, carboxy, (C 1 -C 4) alkoxy-carbonyl / hydroxymethyl, phenyl or p-chiorphenyl, R 7 and R 8 are hydrogen or methyl, j and k are integers of 0-3, but together not more than 4, m and n is integers of 0-3, but together not more than 4, A is -CH 2 "or -CH 2 -CH 2 -, or 20 r and R- together or R 2 and R" together are oxo under the condition k or m are different from 0, or R0 and Ry together and R1 and Rg together are oxo provided that k and m are different from 0,
Rg og R1q er ens eller forskellige og er hydrogen eller 25 én til fire methylsubstituenter på carbonatomerne af en piperazinring (A = -CH2~), R11' R12' R13 °9 R14 er ens eller forskellige og er hydrogen eller methyl, eller R.j 1 og R.J2 tilsammen og/eller R^ og R^4 tilsammen er 30 oxo, og X er en (C.j-C2)alkylenkæde, der eventuelt er substitueret med hydroxy, idet dog, når A er -CH2~, R^-R^4 er hydrogen, og j, k, m og n er 0, kan X ikke være 1,2-ethyléndiol, 35 eller er fysiologisk acceptable syreadditionssalte deraf.Rg and R1q are the same or different and are hydrogen or one to four methyl substituents on the carbon atoms of a piperazine ring (A = -CH2 ~), R11 'R12' R13 ° 9 R14 are the same or different and are hydrogen or methyl, or Rj 1 and R 2 together and / or R 2 and R 4 together are oxo and X is a (C 1 -C 2) alkylene chain optionally substituted by hydroxy, however, when A is -CH 2 R 4 is hydrogen, and j, k, m and n are 0, X cannot be 1,2-ethylenediol, or are physiologically acceptable acid addition salts thereof.
44
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En foretrukket undergruppe danner forbindelser med den almene formel (II): ?·7 ?11f3 %A preferred subgroup forms compounds of the general formula (II):? 7? 11f3%
R5 · ?Ί2 r14 Rg (IDR5 ·? Ί2 r14 Rg (ID
hvor: jk? ,ια» og n1 hver er 0, 1 eller 2, 10 R2' °9 R4*er hydrogen, chlor, methyl eller C.j-C4 alkoxy, r Rg t R*y / Rg samt ^, R^ 2 * R-j g , R-j 4 og X or som defineret ovenfor, og fysiologisk acceptable syreadditionssalte deraf.where: jk? , ια »and n1 are each 0, 1 or 2, 10 R2 '° 9 R4 * is hydrogen, chloro, methyl or C1-C4 alkoxy, R Rg t R * y / Rg as well as R, 2 ^ R R 4 and X or as defined above, and physiologically acceptable acid addition salts thereof.
Særligt foretrukne er forbindelser med den almene 15 formel (III): r-11,r15 r13' _Particularly preferred are compounds of the general formula (III): r-11, r15 r13 '-
Cl-Ø- (CH2) a-00—ch—c —ØJ’ (CH2) b-<Q-'Cl R12‘ R«' (IH, 20 hvor: RØ og RØ er hydrogen eller tilsammen oxo, R^g er hydrogen eller hydroxy, RØ og RØ er hydrogen eller tilsammen oxo, og a og b er 1, 2, 3 eller 4, 25 og fysiologisk acceptable syreadditionssalte deraf.C1- (CH2) a-00-ch-c-EY '(CH2) b- <Q -'Cl R12' R '' (1H, 20 where: R0 and R0 are hydrogen or together oxo, R is hydrogen or hydroxy, R0 and R0 are hydrogen or oxo together, and a and b are 1, 2, 3 or 4, 25 and physiologically acceptable acid addition salts thereof.
Fremgangsmåden til fremstilling af de omhandlede forbindelser er ejendommelig ved, at a} til fremstilling af symmetriske forbindelser med den almene formel I, en forbindelse med den almene 30 formel IV: R.11 R1 3 Y-C-X-C-Z (IV)The process for preparing the subject compounds is characterized in that a} for the preparation of symmetrical compounds of general formula I, a compound of general formula IV: R.11 R1 3 Y-C-X-C-Z (IV)
I II I
R12 Ri 4 35 hvor: R11/ R.12» R-13# R-14 og X er som defineret i krav 1, og Y og Z er reaktive grupper, omsættes med en forbindelse med den almene formel V: 5R 12 R 4 where: R 11 / R 12 »R-13 # R-14 and X are as defined in claim 1, and Y and Z are reactive groups, reacted with a compound of general formula V: 5
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R, i1 R7 2'^^3r"icH2,3’c"icH2)k"N\ {v)R, 1 R7 2 '^^ 3r "icH2,3'c" icH2) k "N \ {v)
*5 T* 5 T
5 hvor R1# R2, R5, P7, R9 , j, k og A er som defineret i krav 1, eller b) en forbindelse med den almene formel VI': 10 ^ ^ ^13 (VI) ^-(CH2)rc-(CH2>k-«IN - C - X - c - r (VI) R5 ΓΓ R12 R14 r9 hvor R^t R21 R5f Ry» Rg » R11f R12# R13/ r14* j, k og A er som ovenfor defineret i krav 1, og Y er defineret som i formel IV ovenfor, omsættes med en forbindelse med den almene formel VII:5 wherein R 1 # R 2, R 5, P 7, R 9, j, k and A are as defined in claim 1, or b) a compound of the general formula VI ': 10 - (CH2> k- «IN - C - X - c - r (VI) R5 ΓΓ R12 R14 r9 where R ^ t R21 R5f Ry» Rg »R11f R12 # R13 / r14 * j, k and A are as defined above in claim 1, and Y is defined as in formula IV above, reacted with a compound of general formula VII:
Ro 20 R4^_jr f® ' ^_/(CH2>n - C - <CH2)n - νΓ^Η (VII) R m hvor R3, R4, R6z Rq/ r10, m, n og A er som ovenfor 25 defineret, eller c) til fremstilling af sådanne slutprodukter med den almene formel I, der er symmetriske med hensyn til den centrale gruppe X, en forbindelse med den almene formel VIII: 30Ro 20 R4 ^ _jr f® '^ _ / (CH2> n - C - <CH2) n - νΓ ^ Η (VII) R m where R3, R4, R6z Rq / r10, m, n and A are as above 25 or (c) for the preparation of such final products of the general formula I which are symmetrical with respect to the central group X, a compound of the general formula VIII: 30
Ril R13 /Α-Λ l11 I13 /A-\ HN N-C-X-C-ΪΓ ;NH (VIII) ·Ril R13 / Α-Λ 1111 I13 / A- \ HN N-C-X-C-ΪΓ; NH (VIII) ·
V R R VV R R V
J K12 K14 JJ K12 K14 J
R9 R10 hvor Rg , Riq/ Ri 1, r12' rij# r14' X °9 A er som defineret i krav 1, omsættes med en forbindelse med den almene formel IX : 35 6R9 R10 wherein Rg, Riq / Ri 1, r12 'rij # r14' X ° 9A is as defined in claim 1, is reacted with a compound of general formula IX: 35 6
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Rl RRl R
^ ~^y^~^"(CH2) j ~ | “ iCH2Jk ‘ Y ίΙΧ) 5 hvor R1# R2/ R5, R?, j og k er som defineret i krav 1, og Y er defineret som i formel IV ovenfor, eller d) til fremstilling af sådanne slutprodukter med den almene formel I, hvor X er en carbinolgruppe, en forbindelse med den almene formel χ: 10 f11 °\ S*13 Y - c - c - c ' '-H ' R12 R14.^ (^ y ^ ~ ^ "(CH2) j ~ |" iCH2Jk 'Y ίΙΧ) wherein R1 # R2 / R5, R ?, j and k are as defined in claim 1 and Y is defined as in Formula IV above or d) for the preparation of such final products of the general formula I, wherein X is a carbinol group, a compound of the general formula χ: 10 f11 ° \ S * 13 Y - c - c - c '' -H 'R12 R14 .
15 w hvor: R11, R12, r13 og R14 er som-defineret i ovenfor, og Y har samme betydning som.i formel IV, omsættes med en forbindelse med den almene formel VII 2Q og at, om ønsket, et ved en af fremgangsmåderne a-d fremstillet slutprodukt med den almene formel I på i og for sig kendt måde overføres i et fysiologisk acceptabelt syreadditionssalt deraf.15 w where: R11, R12, r13 and R14 are as defined above and Y has the same meaning as in Formula IV, reacted with a compound of general formula VII 2Q and, if desired, one of the processes The final product of general formula I prepared in a manner known per se is transferred into a physiologically acceptable acid addition salt thereof.
De reaktive grupper Y og Z i forbindelse med 25 fremgangsmåden trin a) er reaktive grupper, der reagerer med en amin under dannelse af carbon-nitrogen-binding, såsom chlor, brom, iod, aktiveret ester, hydroxy, svovlsyreester, sulfonsyreester og lignende.The reactive groups Y and Z in the process of step a) are reactive groups that react with an amine to form carbon-nitrogen bond such as chlorine, bromine, iodine, activated ester, hydroxy, sulfuric acid ester, sulfonic acid ester and the like.
Ved fremgangsmåden trin b) kan der vindes både 30 symmetriske og usymmetriske forbindelser med den almene formel I.In step b), both symmetric and asymmetric compounds of general formula I can be obtained.
De under fremgangsmådetrinnene a) til d) beskrevne kondensationsreaktioner kan gennemføres i nærværelse eller fraværelse af et opløsningsmiddel. Der kan anvendes vandi-35 9e eller organiske indifferente opløsningsmidler, hvorhos valget af opløsningsmiddel afhænger af arten af reaktionskomponenterne. Eksempler på sådanne opløsningsmidler er dimethylsulfoxid, dimethylformamid, dioxan, ethoxy-The condensation reactions described during process steps a) to d) can be carried out in the presence or absence of a solvent. Vandal or organic inert solvents may be used, the choice of solvent depending on the nature of the reaction components. Examples of such solvents are dimethyl sulfoxide, dimethylformamide, dioxane, ethoxy
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7 ethanol og alkanoler med op til 5 C-atomer, med eller uden tilsætning af vand. Der kan også anvendes aromatiske carbonhydrider. Reaktionen gennemføres fortrinsvis i nærværelse af et syrebindende middel, såsom triethylamin, 5 et alkalimetalcarbonat eller et alkalimetalhydroxid.7 ethanol and alkanols with up to 5 C atoms, with or without the addition of water. Aromatic hydrocarbons can also be used. The reaction is preferably carried out in the presence of an acid-binding agent such as triethylamine, an alkali metal carbonate or an alkali metal hydroxide.
Reaktionstemperaturen afhænger af udgangsforbindelserne og af det til reaktionen anvendte opløsningsmiddel og ligger mellem stuetemperatur og tilbagesvalingstemperaturen for reaktionsblandingen. Reaktionstiden er tem-10 peraturafhængig og ligger fra nogle minutter til flere timer.The reaction temperature depends on the starting compounds and the solvent used for the reaction and lies between room temperature and the reflux temperature of the reaction mixture. The reaction time is temperature dependent and ranges from a few minutes to several hours.
Et slutprodukt med den almene formel I, hvor og/ eller Rg er hydroxy, kan vindes ved hydrogenering af en forbindelse, hvor R^ og R^ og/eller Rg og 1¾ tilsammen 15 er oxo, med sædvanlige hydrogeneringsmidler, såsom natri-umborhydrid, på i og for sig kendt måde. Der vindes herved den tilsvarende hydroxyforbindelse.A final product of general formula I wherein and / or R 9 is hydroxy may be obtained by hydrogenation of a compound wherein R 1 and R 2 and / or R 9 and 1 ox together are oxo, with conventional hydrogenating agents such as sodium borohydride. in a manner known per se. The corresponding hydroxy compound is thereby obtained.
Forbindelserne med den almene formel I er basiske og danner derfor additionssalte med uorganiske eller or-20 ganiske syrer. Eksempler på ikke-toxiske, fysiologisk acceptable syreadditionssalte er sådanne, der vindes ved omsætning med en hydrogenhalogenidsyre, fortrinsvis saltsyre eller hydrogenbromidsyre, med salpetersyre, svovlsyre, o-phosphorsyre, citronsyre, maleinsyre, fumarsyre, 25 propionsyre, smørsyre, eddikesyre, ravsyre, methansulfon-syre, benzensulfonsyre, p-toluensulfonsyre eller lignende.The compounds of general formula I are basic and therefore form addition salts with inorganic or organic acids. Examples of non-toxic, physiologically acceptable acid addition salts are those obtained by reaction with a hydrogen halide acid, preferably hydrochloric or hydrobromic acid, with nitric acid, sulfuric acid, o-phosphoric acid, citric acid, maleic acid, fumaric acid, propionic acid, butyric acid, acetic acid, acetic acid, acetic acid acid, benzenesulfonic acid, p-toluenesulfonic acid or the like.
Udgangsforbindelserne til fremgangsmådetrinene a) til d) er kendte forbindelser, eller de kan fremstil-30 les ved i og for sig kendte metoder.The starting compounds for process steps a) to d) are known compounds, or they can be prepared by methods known per se.
For eksempel er forbindelser med den almene formel III beskrevet i britisk patentskrift 480.358 og i j.Am. Chem.Soc., 66I, 263 (1944).For example, compounds of the general formula III are described in British Patent Specification 480,358 and in J. Am. Chem.Soc., 66I, 263 (1944).
Syntesen af forbindelser med den almene formel VI 35 kendes fra talrige publikationer, for eksempel fra Helv. Chim.Acta 41, 1072 (1958) eller Monatshefte 87, 701 (1956).The synthesis of compounds of general formula VI 35 is known from numerous publications, for example from Helv. Chim.Acta 41, 1072 (1958) or Monatshefte 87, 701 (1956).
Forbindelser med den almene formel VI er beskrevet i britisk patentskrift 480.358 og Khim.-Farm.Zh. 10, 36Compounds of general formula VI are described in British Patent Specification 480,358 and Khim.-Farm.Zh. 10, 36
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8 (1976), refereret i C.A.85, 78079.8 (1976), cited in C.A.85, 78079.
De nedenfor anførte forbindelser med den almene formel I samt deres syreadditionssalte kan fremstilles ved de ovenfor beskrevne fremgangsmåder.The compounds of general formula I and their acid addition salts listed below can be prepared by the methods described above.
5 1,3-Bis- [4- (hydroxybenzyl) - 1-piperazinyl ]-propan- tetra hydrochlorid, 1.3- Bis- [4-(4-chlorbenzyl)-l-piperaz:Lriyl]-propan-tetra- hydrochlord, 1.3- Bis- [4- ( 4- chlorbenzyl)-1-piperazinyl ]-2-hydroxy- 1 o propan, 1.4- Bis- [4- ( 4- chlorbenzyl)-1-piperazinyl ]- butan-hemihydrat, 1.3- Bis- (4-benzyl-l-piperazinyl)-propan- tetrabydrochlorid, 1.3- Bis-[4-(4-fluorbenzyl)-l-piperazinyl]-propan-tetra- hydrochlorid, 1 g 1,3-Bis- [4- (4-chlorbenzyl)-l-piperazinyl j-l-oxopropan-trihydrochlorid, 1.3- Bis- [4- (4-chlorbenzyl)-l-piperazinyi]-l-methylpropan- tetrahydrochlorid-hemihydrat, 1,3“ Bis- [4- (4-chlorbenzhydryl)-l-piperazinyl]-propan-• dihydro chlorid- dibydrat, 20 r 1- [4- ( 4- chlorbenzyl)- 1-piperazinyl ]- 3- [4~ ( 2- ethoxycarbonyl-2-phenylethyl )-l-piperazinyl ]-propan- tetrahydro-chlorid-monohydrat, 1- [4- (4-chlorbenzyl-1-piperazinyl]-3- (4-phenacyl-l- piperazinyl)-propan-tetrahydrochlorid-monohydrat, 25 3- Bis- (4-phenacyi-l-piperazinyl)-propan-tetrahydrochlorid- monohydrat, 1.3- Bis- [4- (2-phenyl-2-hydroxyethyl)-l-piperazinyl]- propan- tetrahydrochlorid, 1.3- Bis- (4- phenethyl- 1-piperazinyl )-propan-dihydrochlorid- 30 dihydrat, 1- [4- (4-chlorbenzyl)-l-piperazinyl]-3- [4- (2-hydroxy-2- phenylethyl)-l-piperazinyl]-propan-tetrahydrochlorid, 1.3- Bis- [4- (4-chlorbenzyl)-l-piperazinyl]-l, 3- ϋ-oxopropan- dihydrochlorid-monohydrat j 35 1,3-Bis- [4- (4-chlorphenethyl)-l-piperazinyl]-propan, 1.3- Bis-[4-(l-phenylethyl)-l-piperazinyl]-propan-tetra- hy^rochlorid, 1.3- 3is-[4-(4-chlorbenzyl-2,5-dimethyl-1-piperazinyl ]- propan-tetrahydrochlorid-dihydrat, 91,3-Bis- [4- (hydroxybenzyl) -1-piperazinyl] -propane-tetrahydrochloride, 1,3-Bis- [4- (4-chlorobenzyl) -1-piperaz: Lriyl] -propane-tetrahydrochloride, 1,3- Bis- [4- (4-chlorobenzyl) -1-piperazinyl] -2-hydroxy-propane, 1,4-Bis- [4- (4-chlorobenzyl) -1-piperazinyl] -butane hemihydrate, 1.3- Bis- (4-benzyl-1-piperazinyl) -propane-tetrahydrochloride, 1,3-Bis- [4- (4-fluorobenzyl) -1-piperazinyl] -propane-tetrahydrochloride, 1 g of 1,3-Bis- [4 - (4-chlorobenzyl) -1-piperazinyl] -1-oxopropane trihydrochloride, 1,3-Bis- [4- (4-chlorobenzyl) -1-piperazinyl] -1-methylpropane-tetrahydrochloride hemihydrate, 1.3 ”Bis- [4 - (4-Chlorobenzhydryl) -1-piperazinyl] propane dihydro chloride dibydrate, 1- [4- (4-chlorobenzyl) -1-piperazinyl] -3- [4- (2-ethoxycarbonyl-2 phenylethyl) -1-piperazinyl] propane tetrahydrochloride monohydrate, 1- [4- (4-chlorobenzyl-1-piperazinyl] -3- (4-phenacyl-1-piperazinyl) propane tetrahydrochloride monohydrate, 25 3- Bis- (4-phenacyl-1-piperazinyl) -propane-tetrahydrochloride monohydric 1.3-Bis- [4- (2-phenyl-2-hydroxyethyl) -1-piperazinyl] propane tetrahydrochloride, 1.3- Bis- (4-phenethyl-1-piperazinyl) propane dihydrochloride dihydrate, 1 - [4- (4-chlorobenzyl) -1-piperazinyl] -3- [4- (2-hydroxy-2-phenylethyl) -1-piperazinyl] -propane tetrahydrochloride, 1,3-Bis- [4- (4-chlorobenzyl) ) -1-piperazinyl] -1,3-ethyl-oxopropane dihydrochloride monohydrate 1,3-Bis- [4- (4-chlorophenethyl) -1-piperazinyl] -propane, 1,3-Bis- [4- ( 1-phenylethyl) -1-piperazinyl] -propane-tetrahydrochloride, 1,3-3-[4- (4-chlorobenzyl-2,5-dimethyl-1-piperazinyl] -propane-tetrahydrochloride dihydrate, 9
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1.3- Bis-[4-(4-methoxybenzyl)-1-p ip erazinyl]- propan, 1.3- Bis- [4- ( 3,4-dichlorben.zyl- l-piperazinyl ]-propan- tetrahydrochlorid, 1.3- Bis- [4- ( 2- chlorbenzyl)-l-pip erazinyl ]-propan- tetrahydrochlorid, 1.3- Bis-[4-(4-methylbenzyl)-l-piperazinyl]-propan- tetrahydrochlorid, 1.3- Bis-[4-(3-chlo rbenzyl)-1-pip erazinyl]-propan- dihydro chlo ri d- monohy dra t, 1.3- Bis- [4- (3- £V chlorphenyl)· - propyl)- l-piperazinyl }-propan- ^ tetrahydrochlorid-monohydrat, 1.3- Bis- [4- (4-butoxybenzyl)-l-piperazinyl-propan, 1.3- Bis-[4- (4-acetoxybenzyl)-l-piperazinyl]-propan- tetrahydrochlorid, 1.3- 3is- [4- (4-brombenzyl)-l-piperazinyl]-propan, 1 5 1,3-3is- [4- ( 4- chlor- 3- trifluornethylbenzyl)-l-piperazinyl ]- propan-tetrahydrochlorid; 1.3- Bis-C^ ·£»- (4-chlorbenzyl 3-2,3,5,6-tetrametbylTj· -l- piperazinyl j-propan, 1.3- Bis-[4- £4- (4-chlorphenylbutyl)^ -l-piperazinyl]-propan, 2q 1” [4- (4- chlorbenzyl)-l-piperazinyl}- 3- [4- (2-carboxy-2- phenylethyl)-l-piperazinyl j-propan-1etraiiydrochlorid, 1.3- Bis- [4- (4-chlorbenzyl )-l-homopiperazinyl]-propan- tetrahydrochlorid, 1.3- Bis-[4-(3- {V chlorphenyl} -propyl)-l-homopiperazinyl]- propan- tetrahydrochlorid, 25 1.3- 3is- [ 4- (4- chlo rb enzyl) -1- homop ip erazinyl ]-1,3~ dl oxo- propan.1,3-Bis- [4- (4-methoxybenzyl) -1-piperazinyl] propane, 1,3-Bis- [4- (3,4-dichlorobenzyl-1-piperazinyl] propane tetrahydrochloride, 1.3-Bis - [4- (2-chlorobenzyl) -1-piperazinyl] -propane-tetrahydrochloride, 1,3-Bis- [4- (4-methylbenzyl) -1-piperazinyl] -propane-tetrahydrochloride, 1.3-Bis- [4- ( 3-Chlorobenzyl) -1-piperazinyl] -propan-dihydro-chloro-di-monohydric, 1,3-Bis- [4- (3-Chlorophenyl) -propyl) -1-piperazinyl} -propane-2 tetrahydrochloride monohydrate, 1,3-Bis- [4- (4-butoxybenzyl) -1-piperazinyl-propane, 1,3-Bis- [4- (4-acetoxybenzyl) -1-piperazinyl] -propane tetrahydrochloride, 1.3-3is- [ 4- (4-bromobenzyl) -1-piperazinyl] -propane, 1,3-3is- [4- (4-chloro-3-trifluoromethylbenzyl) -1-piperazinyl] -propane tetrahydrochloride; 1,3-Bis-C ^ · £ (4-Chlorobenzyl 3-2,3,5,6-tetramethylbutyl) -1-piperazinyl-propane, 1,3-Bis- [4- [4- (4-chlorophenylbutyl) -1-piperazinyl] -propane, 2q 1 ”[4- (4-chlorobenzyl) -1-piperazinyl} - 3- [4- (2-carboxy-2-phenylethyl) -1-piperazinyl] -propane-1-ethanol hydrochloride, 1.3 - Bis- [4- (4-chlorobenzyl) -1-homopiperazinyl] propane tetrahydrochloride, 1.3- Bis- [4- (3- {V chlorophenyl} propyl) -1-homopiperazinyl] propane tetrahydrochloride, 1.3 - 3is- [4- (4-chlorobenzyl) -1-homop ip erazinyl] -1,3 ~ dl oxopropane.
1010
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Foretrukne forbindelser ifølge opfindelsen opregnes i krav 4.Preferred compounds of the invention are listed in claim 4.
De farmaceutiske præparater ifølge opfindelsen er ejendommelige ved det ikrav6's kendetegnende del 5 angivne, foretrukket som i krav 7. Fremgangsmåderne ifølge opfindelsen til fremstilling af sådanne farmaceutiske præparater er ejendommelige ved det i hhv. krav 8 og 9's kendetegnende del angivne, og anvendelsen ifølge opfindelsen af de omhandlede forbindelser er 10 ejendommelig ved det i krav 10 angivne.The pharmaceutical compositions of the invention are characterized by the characterizing part 5 of claim 6, preferably as in claim 7. The methods of the invention for the preparation of such pharmaceutical compositions are characterized by those of the present invention, respectively. The characterizing part of claims 8 and 9, and the use according to the invention of the compounds of the invention is characterized by that of claim 10.
Opfindelsen beskrives nærmere gennem følgende eksempler.The invention is further described by the following examples.
15 Eksempel 1 1,3-Bis- [4-(4-chlorbenzyl) -1-piperazinyl] -propan-tetra-hydrochlorid.Example 1 1,3-Bis- [4- (4-chlorobenzyl) -1-piperazinyl] propane-tetrahydrochloride.
En blanding af 10,5 g 1-(4-chlorbenzyl)-piperazin, 9,5 g l-brom-3-chlorpropan og 100 ml ethanol blev opvar-20 met 17 timer under tilbagesvaling. Derefter blev opløsningsmidlet fjernet ved rotationsfordampning, og den tilbageværende olie blev blandet med 200 ml 1M dibasisk kaliumphosphat. Fast tribasisk natriumphosphat blev tilsat, indtil der var opnået en pH-værdi på over 9. Denne 25 blanding blev ekstraheret 5 gange med 50 ml ether, ethe-ren blev fordampet, inddampningsresten blev syrnet med 100 ml 2M phosphorsyre og filtreret. Det vandige filtrat blev gjort basisk med 2N natriumhydroxidopløsning, igen ekstraheret med 250 ml ether og tørret over magnesium-30 sulfat. Efter indføring af luftformigt hydrogenchlorid og omkrystallisation af ethanol/vand vandtes 5,8 g (39% 11A mixture of 10.5 g of 1- (4-chlorobenzyl) -piperazine, 9.5 g of 1-bromo-3-chloropropane and 100 ml of ethanol was heated at reflux for 17 hours. Then, the solvent was removed by rotary evaporation and the residual oil was mixed with 200 ml of 1M dibasic potassium phosphate. Solid tribasic sodium phosphate was added until a pH greater than 9. This mixture was extracted 5 times with 50 ml of ether, the ether was evaporated, the residue was acidified with 100 ml of 2M phosphoric acid and filtered. The aqueous filtrate was basified with 2N sodium hydroxide solution, again extracted with 250 ml of ether and dried over magnesium sulfate. After introduction of gaseous hydrogen chloride and recrystallization of ethanol / water, 5.8 g (39% 11
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af det teoretiske) af titelforbindelsen i fom af hvide krystaller med smp. 261-274°C (dek.).of the theoretical) of the title compound in white crystals, m.p. 261-274 ° C (dec.).
Eksempel 2 5 l,3-Bis-[4-(4-chlorbenzyl)-1-piperazinyl]-2-hydroxypro- pan.Example 2 1,3-Bis- [4- (4-chlorobenzyl) -1-piperazinyl] -2-hydroxypropane.
En blanding af 4,4 g epichlorhydrin, 20,1 g l-(4-chlorbenzyl)-piperazin, 6,0 g triethylamin og 50 g ethanol blev opvarmet 3 dage under tilbagesvaling. Opløs-10 ningsmidlet blev fjernet fra reaktionsblandingen ved rotationsfordampning, og inddampningsresten blev gjort basisk med 2N natriumhydroxidopløsning og ekstraheret med 5 gange 100 ml ether. Efter tørring af etherekstrakten over magnesiumsulfat og fordampning af opløsningsmidlet 15 vandtes en olie, der størknede ved henstand. Efter omkrystallisation af heptan vandtes 18,6 g (82% af det teor.) 1,3-bis-[4-(4-chlorbenzyl)-1-piperazinyl]-2-hy-droxypropan i form af farveløse krystaller med smp. 85-86,5°C.A mixture of 4.4 g of epichlorohydrin, 20.1 g of 1- (4-chlorobenzyl) -piperazine, 6.0 g of triethylamine and 50 g of ethanol was heated at reflux for 3 days. The solvent was removed from the reaction mixture by rotary evaporation and the residue was basified with 2N sodium hydroxide solution and extracted with 5 times 100 ml of ether. After drying the ether extract over magnesium sulfate and evaporation of solvent 15, an oil solidified upon standing was obtained. After recrystallization from heptane, 18.6 g (82% of theory) of 1,3-bis- [4- (4-chlorobenzyl) -1-piperazinyl] -2-hydroxypropane were obtained in the form of colorless crystals, m.p. 85 to 86.5 ° C.
2020
Eksempel 3 1,3—Bis-[4-(4-chlorbenzyl)-1-piperazinyl]-butan-hemi-hydrat.Example 3 1,3-Bis- [4- (4-chlorobenzyl) -1-piperazinyl] -butane hemihydrate.
En blanding af 2,2 g 1,4-dibrombutan, 4,2 g l-(4-25 chlorbenzyl)-piperazin, 2,8 g vandfrit kaliumcarbonat og 20 ml ethanol blev opvarmet 18 timer under tilbagesvaling. Opløsningsmidlet blev derefter fjernet ved reduceret tryk, og den som inddampningsrest vundne olie blev opvarmet 16 timer ved 160°C. Derefter blev olien opløst 3 0 i 50 ml varmt vand og ekstraheret med 3 gange 80 ml ether. Etherekstrakten blev inddampet, og den som inddampningsrest vundne olie blev chromatograferet på en silicagel-søjle (elueringsmiddel methylenchlorid/methanol/ammoni-umhydroxid 45:5:1). Den vundne brunfarvede faste masse 35 blev opløst i acetone, og titelforbindelsen blev fældet med vand i form af hvide krystaller, smp. 101-103°C.A mixture of 2.2 g of 1,4-dibromobutane, 4.2 g of 1- (4-25 chlorobenzyl) -piperazine, 2.8 g of anhydrous potassium carbonate and 20 ml of ethanol was heated at reflux for 18 hours. The solvent was then removed at reduced pressure and the oil recovered as evaporation residue was heated at 160 ° C for 16 hours. Then, the oil was dissolved in 50 ml of hot water and extracted with 3 x 80 ml of ether. The ether extract was evaporated and the oil recovered as evaporation residue was chromatographed on a silica gel column (eluent methylene chloride / methanol / ammonium hydroxide 45: 5: 1). The brownish solid solid obtained 35 was dissolved in acetone and the title compound precipitated with water in the form of white crystals, m.p. 101-103 ° C.
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1212
Eksempel 4 1.3- Bis-(4-benzyl-l-piperazinyl)-propan-tetrahydrochlor-id.Example 4 1.3- Bis- (4-benzyl-1-piperazinyl) -propane-tetrahydrochloride.
5 En blanding af 7,0 g 1-benzylpiperazin, 3,2 g 1- brom-3-chlorpropan, 4,0 g triethylamin og 100 ml ethanol blev opvarmet 2^ time under tilbagesvaling. Derefter blev reaktionsblandingen hældt i 1 liter ether, og det udfældede triethylaminsalt blev frafiltreret. Filtratet 10 blev inddampet, og den tilbageværende olie blev opløst i 100 ml heptan og filtreret. Opløsningsmidlet blev fjernet ved rotationsfordampning, og inddampningsresten blev igen opløst i 150 ml ether. Ved tilsætning af et overskud af vandfri saltsyre vandtes 8,8 g (82% af det teor.) 15 af titelforbindelsen i form af hvide krystaller med smp. 250-265°C.A mixture of 7.0 g of 1-benzylpiperazine, 3.2 g of 1-bromo-3-chloropropane, 4.0 g of triethylamine and 100 ml of ethanol was heated at reflux for 2 hours. Then, the reaction mixture was poured into 1 liter of ether and the precipitated triethylamine salt was filtered off. The filtrate 10 was evaporated and the residual oil was dissolved in 100 ml of heptane and filtered. The solvent was removed by rotary evaporation and the residue was again dissolved in 150 ml of ether. With the addition of an excess of anhydrous hydrochloric acid, 8.8 g (82% of theory) of the title compound were obtained in the form of white crystals, m.p. 250-265 ° C.
Eksempel 5 1.3- Bis-[4-(4-fluorbenzyl)-1-piperazinyl]-propan-tetra-2 0 hydrochlorid.Example 5 1.3-Bis- [4- (4-fluorobenzyl) -1-piperazinyl] -propane-tetra-2-hydrochloride.
a) En opløsning af 29 g p-fluorbenzylchlorid i 50 g ethanol blev dråbevis sat til en omrørt opløsning af 34,4 g piperazin i 150 g ethanol. Ved hjælp af et koldt vandbad holdtes reaktionstemperaturen ved 20°C.a) A solution of 29 g of p-fluorobenzyl chloride in 50 g of ethanol was added dropwise to a stirred solution of 34.4 g of piperazine in 150 g of ethanol. By means of a cold water bath, the reaction temperature was maintained at 20 ° C.
25 Reaktionsblandingen blev omrørt i yderligere l| time og derefter hældt i 2 liter ether. Der blev filtreret fra udfældet piperazin-hydrochlorid, og filtratet blev inddampet til en olieagtig inddampningsrest, der blev chromatograferet på silicagel (elueringsmiddel methyl-30 enchlorid/methanol/ammoniumhydroxid 45:5:1). Efter oparbejdning af de passende fraktioner vandtes 21,7 g (56% af det teor.) 1-(4-fluorbenzyl)-piperazin i form af en farveløs væske.The reaction mixture was stirred for a further 1 hour and then poured into 2 liters of ether. Filtered from precipitated piperazine hydrochloride and the filtrate was evaporated to an oily residue which was chromatographed on silica gel (eluent methylene chloride / methanol / ammonium hydroxide 45: 5: 1). After working up the appropriate fractions, 21.7 g (56% of theory) of 1- (4-fluorobenzyl) -piperazine was obtained as a colorless liquid.
b) En blanding af 5,8 g 1-(4-fluorbenzyl).-piperazin, 3,2 35 g l-brom-3-chlorpropan, 4,0 g triethylamin og 50 ml ethanol blev opvarmet 3 timer under tilbagesvaling og derefter hældt i 1 liter ether. Bundfald blev frafilb) A mixture of 5.8 g of 1- (4-fluorobenzyl) piperazine, 3.2 g of 1-bromo-3-chloropropane, 4.0 g of triethylamine and 50 ml of ethanol was heated at reflux and then refluxed. poured into 1 liter of ether. Precipitation was removed
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13 treret, og filtratet blev inddampet til en olie. Denne olie blev opløst i 100 ml ether, og tetrahydro-chloridet blev udfældet med overskud af vandfri saltsyre og vandtes, efter omkrystallisation af ethanol/ 5 vand, i et udbytte på 3,3 g (29% af det teor.) i form af hvide krystaller med smp. 228-237°C (dek.).13, and the filtrate was evaporated to an oil. This oil was dissolved in 100 ml of ether and the tetrahydrochloride was precipitated with excess anhydrous hydrochloric acid and, after recrystallization of ethanol / 5 water, was obtained in a yield of 3.3 g (29% of theory). white crystals with m.p. 228-237 ° C (dec.).
Eksempel 6 1.3- Bis-[4-(4-chlorbenzyl)-1-piperazinyl]-1-oxo-propan-10 trihydrochlorid.Example 6 1.3-Bis- [4- (4-chlorobenzyl) -1-piperazinyl] -1-oxo-propane trihydrochloride.
En blanding af 2,0 g 1-(4-chlorbenzyl)-piperazin, 1,0 g triethylamin, 20 g xylen og 0,8 g 3-brompropionyl-chlorid blev opvarmet 18 timer under tilbagesvaling, reaktionsblandingen blev filtreret, og til filtratet blev 15 der sat et overskud af saltsyre-mættet ether indtil sur reaktion over for lakmus. Det dannede bundfald blev frafiltreret og omkrystalliseret af ethanol/vand. Der vandtes 1,2 g (45% af det teor.) af titelforbindelsen i form af hvide krystaller med smp. 222-250°C (dek.).A mixture of 2.0 g of 1- (4-chlorobenzyl) -piperazine, 1.0 g of triethylamine, 20 g of xylene and 0.8 g of 3-bromopropionyl chloride was heated at reflux, the reaction mixture was filtered and to the filtrate. an excess of hydrochloric acid-saturated ether was added until acidic reaction to litmus. The resulting precipitate was filtered off and recrystallized from ethanol / water. 1.2 g (45% of theory) of the title compound were obtained in the form of white crystals, m.p. 222-250 ° C (dec.).
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Eksempel 7 1.3- Bis-[4-(4-chlorbenzyl)-1-piperazinyl]-1-methylpropan-tetrahydrochlorid-hemihydrat.Example 7 1.3-Bis- [4- (4-chlorobenzyl) -1-piperazinyl] -1-methylpropane tetrahydrochloride hemihydrate.
En blanding af 7,3 g 1-(4-chlorbenzyl)-piperazin, 25 2,8 g 1,3-dibrombutan, 11,0 g triethylamin og 50 ml ethar nol blev opvarmet 48 timer under tilbagesvaling. Opløsningsmidlet blev fjernet ved rotationsfordampning, ind-dampningsresten blev blandet med 100 ml toluen og opvarmet 24 timer under tilbagesvaling. Derefter blev blandin-30 gen hældt i 1 liter ether og filtreret. Filtratet blev inddampet til en olie, og denne blev chromatograferet på silicagel (elueringsmiddel methylenchlorid/methanol/ammo-niumhydroxid 45:5:1). Den vundne olie blev opløst i 100 ml ether, og der blev fældet med overskud af vandfri 35 saltsyre. Bundfaldet blev opløst i vand og påny fældet ved tilsætning af acetone. Der vandtes 1,2 g (11% af det teor.) af titelforbindelsen i form af hvide krystaller, smp. 228-232°C.A mixture of 7.3 g of 1- (4-chlorobenzyl) -piperazine, 2.8 g of 1,3-dibromobutane, 11.0 g of triethylamine and 50 ml of ethanol was heated at reflux for 48 hours. The solvent was removed by rotary evaporation, the residue was mixed with 100 ml of toluene and heated at reflux for 24 hours. Then the mixture was poured into 1 liter of ether and filtered. The filtrate was evaporated to an oil and chromatographed on silica gel (eluent methylene chloride / methanol / ammonium hydroxide 45: 5: 1). The oil obtained was dissolved in 100 ml of ether and the excess anhydrous hydrochloric acid was precipitated. The precipitate was dissolved in water and precipitated again by the addition of acetone. 1.2 g (11% of theory) of the title compound were obtained in the form of white crystals, m.p. 228-232 ° C.
.14 ,.14,
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Eksempel 8 1, 3—Bis-[4-(4-chlorbenzhydryl)-1-piperazinyl]-propan-dihydrochlorid-dihydrat.Example 8 1,3-Bis- [4- (4-chlorobenzhydryl) -1-piperazinyl] propane dihydrochloride dihydrate.
En blanding af 7,4 g N-(p-chlorbenzhydryl)-pipera-5 zin, 2,0 g l-brom-3-chlorpropan, 1,6 g triethylamin og 25 g ethanol blev opvarmet 15 timer under tilbagesvaling. Reaktionsblandingen blev indstillet alkalisk med 5N natriumhydroxid og ekstraheret med 5 gange 50 ml methylen-chlorid. Ekstrakten blev tørret over magnesiumsulfat, og 10 der blev tilsat hydrogenchlorid-mættet ether indtil sur reaktion over for lakmus. Bundfaldet af råproduktet (2,5 g = 27% af det teor.) blev frafiltreret og renset ved opløsning i methylenchlorid og efterfølgende udfældning ved ethertilsætning. Der vandtes hvide krystaller af ti-15 telforbindelsen med smp. 163-196°C (dek.).A mixture of 7.4 g of N- (p-chlorobenzhydryl) -piperazine, 2.0 g of 1-bromo-3-chloropropane, 1.6 g of triethylamine and 25 g of ethanol was heated at reflux. The reaction mixture was adjusted alkaline with 5N sodium hydroxide and extracted with 5 times 50 ml of methylene chloride. The extract was dried over magnesium sulfate and hydrogen chloride-saturated ether was added until acidic to the litmus. The precipitate of the crude product (2.5 g = 27% of theory) was filtered off and purified by dissolving in methylene chloride and subsequently precipitated by ether addition. White crystals of the title compound were obtained with m.p. 163-196 ° C (dec.).
Eksempel 9 1-[4-(4-Chlorbenzyl)-1-piperazinyl]-3-[4-(2-ethoxycarbo-nyl-2-phenylethyl)-1-piperazinyl]-propan-tetrahydrochlo-20 rid-monohydrat.Example 9 1- [4- (4-Chlorobenzyl) -1-piperazinyl] -3- [4- (2-ethoxycarbonyl-2-phenylethyl) -1-piperazinyl] propane tetrahydrochloride monohydrate.
a) En blanding af 1,8 g atropasyreethylester og 0,9 g piperazin blev omrørt i en rundkolbe. Efter at den eksoterme reaktion var aftaget, blev blandingen opvarmet til 80°C og omrørt i yderligere 20 minutter. Der- 25 efter blev reaktionsblandingen henstillet natten over ved stuetemperatur. Den vundne faste masse blev chro-matograferet på silicagel, idet der som elueringsmid-del først anvendtes ether og derefter methylenchlorid/ methanol/ammoniumhydroxid i forholdet 45:5:1. 1—(2— 30 Ethoxycarbonyl-2-phenylethyl)-piperazinen (0,75 g = 29% af det teor.) kom fra kolonnen med det andet elue-ringsmiddel og anvendtes uden yderligere rensning til den følgende reaktion.a) A mixture of 1.8 g of atropic acid ethyl ester and 0.9 g of piperazine was stirred in a round bottom flask. After the exothermic reaction subsided, the mixture was heated to 80 ° C and stirred for a further 20 minutes. Then, the reaction mixture was allowed to stand overnight at room temperature. The solid solid obtained was chromatographed on silica gel, using ether as the eluent first and then methylene chloride / methanol / ammonium hydroxide in a 45: 5: 1 ratio. The 1- (2-30 Ethoxycarbonyl-2-phenylethyl) -piperazine (0.75 g = 29% of theory) came from the column with the second eluent and was used without further purification for the following reaction.
b) En blanding af 3,0 g l-chlor-3-[4-(4-chlorbenzyl)-1-35 piperazinyl]-propan, 3,5 g triethylamin, 3,7 g 1-(2^ ethoxycarbonyl-2-phenylethyl)-piperazin og 50 ml ethanol blev opvarmet 2 timer under tilbagesvaling og der- 15.b) A mixture of 3.0 g of 1-chloro-3- [4- (4-chlorobenzyl) -1- 35 piperazinyl] propane, 3.5 g of triethylamine, 3.7 g of 1- (2'-ethoxycarbonyl-2) -phenylethyl) -piperazine and 50 mL of ethanol were heated at reflux for 2 hours.
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efter hældt i 1 liter ether. Blandingen blev filtreret, og filtratet blev inddampet. Den som inddampningsrest vundne olie blev renset ved chromatografi på silicagel (elueringsmiddel methylenchlorid/methanol/ammoniumhydro-5 xid 45:5:1). Der vandtes 3,0 g af en olie, der blev opløst i 150 ml ether. Ved tilsætning af et overskud af vandfri saltsyre vandtes 3,4 g af en fast masse. Denne blev igen chromatograferet på silicagel, idet der som første elueringsmiddel anvendtes ether og som andet en 10 blanding af methylenchlorid/methanol/ammoniumhydroxid i forholdet 45:5:1. Det vundne produkt blev overført i hydrochloridet som ovenfor beskrevet og opløst i vand, og titelforbindelsen blev udfældet som hvide krystaller ved tilsætning af acetone, udbytte 1,1 g (15% af det 15 teor.), smp. 198-201°C.after poured into 1 liter of ether. The mixture was filtered and the filtrate was evaporated. The oil recovered as evaporation residue was purified by chromatography on silica gel (eluent methylene chloride / methanol / ammonium hydroxide 45: 5: 1). 3.0 g of an oil were dissolved, dissolved in 150 ml of ether. By adding an excess of anhydrous hydrochloric acid 3.4 g of a solid mass were obtained. This was again chromatographed on silica gel using ether as the first eluent and secondly a mixture of methylene chloride / methanol / ammonium hydroxide in a 45: 5: 1 ratio. The product obtained was transferred into the hydrochloride as described above and dissolved in water and the title compound precipitated as white crystals by the addition of acetone, yield 1.1 g (15% of theory), m.p. 198-201 ° C.
Eksempel 10 1-[4-(4-Chlorbenzyl)-1-piperazinyl]-3-(4-phenacyl-l-piperazinyl)-propan-tetrahydrochlorid-monohydrat.Example 10 1- [4- (4-Chlorobenzyl) -1-piperazinyl] -3- (4-phenacyl-1-piperazinyl) propane tetrahydrochloride monohydrate.
20 En blanding af 4,1 g 1-phenacylpiperazin, 5,7 g l-chlor-3-[4-(4-chlorbenzyl)-1-piperazinyl]-propan, 2,6 g triethylamin og 35 ml ethanol blev opvarmet 5 timer under tilbagesvaling. Opløsningsmidlet blev fjernet på rotationsfordamper, til inddampningsresten blev der sat 25 150 ml vand, og blandingen blev ekstraheret 3 gange med 150 ml ether. Etheropløsningen blev inddampet, og den tilbageværende olie blev chromatograferet på silicagel med som elueringsmiddel methylenchlorid/methanol/ammoni-umhydroxid (45:5:1). Der vandtes 7,0 g (50% af det teor.) 30 rå 1-[4-(4-chlorbenzyl)-1-piperazinyl]-3-(4-phenacyl-l-piperazinyl-propan i form af en olie. Denne olie blev opløst i 200 ml ether, og hydrochloridet blev fældet med overskud af vandfri saltsyre, bundfaldet blev opløst i vand, og titelforbindelsen blev udfældet ved tilsætning 35 af acetone, smp. 211-218°C.A mixture of 4.1 g of 1-phenacylpiperazine, 5.7 g of 1-chloro-3- [4- (4-chlorobenzyl) -1-piperazinyl] propane, 2.6 g of triethylamine and 35 ml of ethanol was heated. hours under reflux. The solvent was removed on a rotary evaporator, to the evaporation residue was added 150 ml of water and the mixture was extracted 3 times with 150 ml of ether. The ether solution was evaporated and the residual oil was chromatographed on silica gel using as eluent methylene chloride / methanol / ammonium hydroxide (45: 5: 1). 7.0 g (50% of theory) of crude 1- [4- (4-chlorobenzyl) -1-piperazinyl] -3- (4-phenacyl-1-piperazinyl-propane) as an oil were obtained. This oil was dissolved in 200 ml of ether and the hydrochloride was precipitated with excess anhydrous hydrochloric acid, the precipitate was dissolved in water and the title compound precipitated by addition of acetone, mp 211-218 ° C.
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Eksempel 11 1-[4-(4-Chlorbenzyl)-1-piperazinyl]-3-[4-(2-hydroxy-2-phenylethyl) -1-piperazinyl] -propan-tetrahydrochlorid.Example 11 1- [4- (4-Chlorobenzyl) -1-piperazinyl] -3- [4- (2-hydroxy-2-phenylethyl) -1-piperazinyl] propane tetrahydrochloride.
En opløsning af 3,0 g 1-[4-(4-chlorbenzyl)-1-pipe-5 razinyl]-3-(4-phenacyl-l-piperazinyl)-propan i 50 ml ethanol blev blandet med 3,0 g natriumborhydrid. Blandingen blev omrørt i 4 timer, og derefter blev det ikke-om-satte natriumborhydrid destrueret ved tilsætning af 25 mL acetone. Opløsningsmidlet blev fjernet i vakuum, og til 10 inddampningsresten blev der sat 50 ml vand. Blandingen blev ekstraheret med 3 gange 250 ml ether, opløsningsmidlet blev fordampet, og den som inddampningsrest vundne olie blev chromatograferet på silicagel med som elue-ringsmiddel methylenchlorid/methanol/ammoniumhydroxid 15 (45:5:1). De fraktioner, der indeholdt slutproduktet, blev samlet, opløsningsmidlet blev fordampet, den som inddampningsrest vundne olie blev opløst i 100 ml ether, og hydrochloridet blev udfældet ved tilsætning af overskud af vandfri saltsyre. Efter opløsning i vand og ud-20 fældning med acetone vandtes slutproduktet i et udbytte på 0,65 g (16% af det teor.) i form af hvide krystaller, smp. 240-248°C (dek.).A solution of 3.0 g of 1- [4- (4-chlorobenzyl) -1-piperazinyl] -3- (4-phenacyl-1-piperazinyl) propane in 50 ml of ethanol was mixed with 3.0 g sodium borohydride. The mixture was stirred for 4 hours and then the unreacted sodium borohydride was destroyed by the addition of 25 mL of acetone. The solvent was removed in vacuo and to the evaporation residue 50 ml of water was added. The mixture was extracted with 3x 250 ml of ether, the solvent was evaporated and the oil recovered as evaporation residue was chromatographed on silica gel with eluant methylene chloride / methanol / ammonium hydroxide 15 (45: 5: 1). The fractions containing the final product were combined, the solvent was evaporated, the residual oil was dissolved in 100 ml of ether and the hydrochloride precipitated by addition of excess anhydrous hydrochloric acid. After dissolving in water and precipitating with acetone, the final product was obtained in a yield of 0.65 g (16% of theory) in the form of white crystals, m.p. 240-248 ° C (dec.).
Eksempel 12 25 1,3—Bis—(4-phenacyl-l-piperazinyl)-propan-tetrahydro- chlorid-monohydrat.Example 12 1,3-Bis- (4-phenacyl-1-piperazinyl) -propane-tetrahydrochloride monohydrate.
En blanding af 6,1 g 1-phenacylpiperazin, 2,4 g l-brom-3-chlorpropan, 3,1 g triethylamin og 50 ml ethanol blev opvarmet 3 timer under tilbagesvaling. Opløsnings-30 midlet blev fordampet, og til inddampningsresten blev der sat 250 ml vand, og blandingen blev ekstraheret 3 gange med 150 ml ether. Efter fordampning af etheren blev den som inddampningsrest vundne olie chromatograferet på silicagel med som elueringsmiddel methylenchlorid/metha-35 nol/ammoniumhydroxid (45:5:1). Fraktionerne med høj renhed blev samlet, opløsningsmidlet blev fordampet, og den som inddampningsrest vundne olie blev opløst i 150 mlA mixture of 6.1 g of 1-phenacylpiperazine, 2.4 g of 1-bromo-3-chloropropane, 3.1 g of triethylamine and 50 ml of ethanol was heated at reflux for 3 hours. The solvent was evaporated and to the evaporation residue was added 250 ml of water and the mixture was extracted 3 times with 150 ml of ether. After evaporation of the ether, the oil recovered as evaporation residue was chromatographed on silica gel using as eluent methylene chloride / methanol / ammonium hydroxide (45: 5: 1). The high purity fractions were collected, the solvent was evaporated and the oil recovered as evaporation residue was dissolved in 150 ml.
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*7 ether og fældet med et overskud af vandfri saltsyre. Efter opløsning i vand og fældning ved tilsætning af acetone vandtes 1,3 g (14% af det teor.) af titelforbindelsen, smp. 194-204°C, i form af hvide krystaller.* 7 ether and precipitated with an excess of anhydrous hydrochloric acid. After dissolving in water and precipitating with the addition of acetone, 1.3 g (14% of theory) of the title compound, m.p. 194-204 ° C, in the form of white crystals.
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Eksempel 13 1,3-Bis-[4-(2-phenyl-2-hydroxyethyl)-1-piperazinyl]-pro-pan-tetrahydrochlorid.Example 13 1,3-Bis- [4- (2-phenyl-2-hydroxyethyl) -1-piperazinyl] propane tetrahydrochloride.
En opløsning af 2,5 g 1,3-bis-(4-phenacyl-l-pipe-10 razinyl)-propan i 50 ml ethanol blev blandet med 2,5 g natriumborhydrid og omrørt 4 timer. Overskud af natrium-borhydrid blev destrueret ved tilsætning af 25 ml acetone, og opløsningsmidlet blev fjernet ved rotationsfordampning. Til inddampningsresten blev der sat 50 ml vand, 15 og blandingen blev ekstraheret med 3 gange 150 ml ether.A solution of 2.5 g of 1,3-bis (4-phenacyl-1-pipe-razinyl) propane in 50 ml of ethanol was mixed with 2.5 g of sodium borohydride and stirred for 4 hours. Excess sodium borohydride was destroyed by the addition of 25 ml of acetone and the solvent was removed by rotary evaporation. To the residue was added 50 ml of water, 15 and the mixture was extracted with 3 times 150 ml of ether.
Efter fordampning af etheren blev det tilbageværende produkt chromatograferet på silicagel med som elueringsmid-del methylenchlorid/methanol/ammoniumhydroxid (45:5:1).After evaporation of the ether, the remaining product was chromatographed on silica gel with eluent methylene chloride / methanol / ammonium hydroxide (45: 5: 1).
Den vundne olie blev opløst i 100 ml ether, og ved til-20 sætning af overskud af vandfri saltsyre blev titelforbindelsen udfældet i et udbytte på 0,75 g (22% af det teor.), smp. 233-240°C, i form af hvide krystaller.The oil obtained was dissolved in 100 ml of ether and, by adding excess anhydrous hydrochloric acid, the title compound precipitated in a yield of 0.75 g (22% of theory), m.p. 233-240 ° C, in the form of white crystals.
Eksempel 14 25 1,3—Bis—(4-phenethyl-l-piperazinyl)-propan-dihydrochlo- rid-dihydrat.Example 14 1,3-Bis- (4-phenethyl-1-piperazinyl) -propane dihydrochloride dihydrate.
En blanding af 5,7 g 1-phenethylpiperazin, 2,4 g l-brom-3-chlorpropan, 4,1 g triethylamin og 30 ml ethanol blev opvarmet 3 timer under tilbagesvaling. Derefter blev 30 der tilsat 50 ml vand, blandingen blev ved rotationsfordampning inddampet til ca. 40 ml, og denne blanding blev ekstraheret med 3 gange 150 ml ether. De samlede ekstrakter blev inddampet, den som inddampningsrest vundne brune olie blev opløst i 150 ml ether, og ved tilsætning af 35 overskud af vandfri saltsyre blev hydrochloridet udfældet. Det blev opløst i vand, og ved tilsætning af acetone vandtes 3,1 g (37% af det teor.) af titelforbindelsen, smp. 210-225°C, som hvide krystaller.A mixture of 5.7 g of 1-phenethylpiperazine, 2.4 g of 1-bromo-3-chloropropane, 4.1 g of triethylamine and 30 ml of ethanol was heated at reflux for 3 hours. Then, 50 ml of water was added. The mixture was evaporated by rotary evaporation to ca. 40 ml and this mixture was extracted with 3x 150 ml of ether. The combined extracts were evaporated, the brown oil recovered as evaporation residue was dissolved in 150 ml of ether, and by the addition of an excess of anhydrous hydrochloric acid the hydrochloride was precipitated. It was dissolved in water and upon addition of acetone 3.1 g (37% of theory) of the title compound, m.p. 210-225 ° C, as white crystals.
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Eksempel 15 1.3- Bis-[4-(4-chlorbenzyl)-1-piperazinyl]-1,3-dioxo-propan-dihydrochlorid-monohydrat.Example 15 1.3-Bis- [4- (4-chlorobenzyl) -1-piperazinyl] -1,3-dioxo-propane dihydrochloride monohydrate.
En blanding af 4,2 g 1-(4-chlorbenzyl)piperazin, 5 1,4 g malonsyre-dichlorid, 10 g methylenchlorid og 2,0 g triethylamin blev omrørt 60 timer. Reaktionsblandingen blev indstillet alkalisk med 2N natriumhydroxid, det or-, ganiske lag blev fraskilt, og den vandige fase blev ekstraheret med 3 gange 50 ml ether, og derefter med 3 gange-10 50 ml methylenchlorid. De organiske faser blev samlet og blandet med 100 ml 2N saltsyre. Den vandige fase blev fraskilt og indstillet basisk med 2N natriumhydroxid.A mixture of 4.2 g of 1- (4-chlorobenzyl) piperazine, 1.4 g of malonic acid dichloride, 10 g of methylene chloride and 2.0 g of triethylamine was stirred for 60 hours. The reaction mixture was adjusted alkaline with 2N sodium hydroxide, the organic layer was separated, and the aqueous phase was extracted with 3 times 50 ml of ether, and then with 3 times-50 ml of methylene chloride. The organic phases were combined and mixed with 100 ml of 2N hydrochloric acid. The aqueous phase was separated and basified with 2N sodium hydroxide.
Den tilbageværende olie blev samlet og chromatograferet på silicagel med som elueringsmiddel methylenchlorid/ 15 methanol/ammoniumhydroxid (200:5:1). De egnede fraktioner blev samlet, opløsningsmidlet blev fordampet, og den som inddampningsrest vundne olie blev opløst i 100 ml ether og fældet med et overskud af vandfri saltsyre. Bundfaldet blev omkrystalliseret af ethanol, og der vaml· 20 tes 1,3 g (22% af det teor.) af titelforbindelsen,· smp. 199-206°C, i form af let gullige krystaller.The residual oil was collected and chromatographed on silica gel eluting with methylene chloride / methanol / ammonium hydroxide (200: 5: 1). The appropriate fractions were combined, the solvent was evaporated and the oil recovered as evaporation residue was dissolved in 100 ml of ether and precipitated with an excess of anhydrous hydrochloric acid. The precipitate was recrystallized from ethanol and 1.3 g (22% of theory) of the title compound was collected, m.p. 199-206 ° C, in the form of slightly yellowish crystals.
Eksempel 16 1.3— Bis—[4-(4-chlorphenethyl)-1-piperazinyl]-propan.Example 16 1.3-Bis- [4- (4-chlorophenethyl) -1-piperazinyl] propane.
25 En blanding af 6,7 g 1-(4-chlorphenethyl)piperazin, 2,4 g l-brom-3-chlorpropan, 3,1 g triethylamin og 20 ml ethanol blev opvarmet 3 timer under tilbagesvaling. Reaktionsblandingen blev fortyndet med 50 ml vand og ved rotationsfordampning inddampet til ca. 50 ml. Den tilbage-30 værende blanding blev ekstraheret med 3 gange 150 ml ether, og ekstrakten blev inddampet. Den tilbageværende farveløse faste masse blev omkrystalliseret af heptan, og der vandtes 3,3 g (45% af det teor.) af titelforbindelsen, smp. 87-88°C, i fom af hvide krystaller.A mixture of 6.7 g of 1- (4-chlorophenethyl) piperazine, 2.4 g of 1-bromo-3-chloropropane, 3.1 g of triethylamine and 20 ml of ethanol was heated at reflux for 3 hours. The reaction mixture was diluted with 50 ml of water and evaporated by rotary evaporation to ca. 50 ml. The remaining mixture was extracted with 3x 150 ml of ether and the extract was evaporated. The remaining colorless solid was recrystallized from heptane, and 3.3 g (45% of theory) of the title compound, m.p. 87-88 ° C, in white crystals.
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Eksempel 17 1.3- Bis-[4-(1-phenylethyl)-1-piperazinyl]-propan-tetra-hydrochlorid.Example 17 1.3-Bis- [4- (1-phenylethyl) -1-piperazinyl] propane tetrahydrochloride.
En blanding af 7,6 g 1-(l-phenylethyl)piperazin, 5 3,2 g l-brom-3-chlorpropan og 50 ml ethanol blev opvarmet 5 timer under tilbagesvaling. Derefter blev · opløsningsmidlet fjernet i vakuum, der blev tilsat 50 ml vand, og blandingen blev ekstraheret med 3 gange 150 ml ether. Etheropløsningsmidlet blev fordampet, og den tilbagevæ-10 rende olie blev chromatograferet på silicagel (eluerings-middel methylenchlorid/methanol/ammoniumhydroxid 45:5:1).A mixture of 7.6 g of 1- (1-phenylethyl) piperazine, 3.2 g of 1-bromo-3-chloropropane and 50 ml of ethanol was heated at reflux for 5 hours. Then, the solvent was removed in vacuo, 50 ml of water was added and the mixture was extracted with 3x 150 ml of ether. The ether solvent was evaporated and the residual oil was chromatographed on silica gel (eluent methylene chloride / methanol / ammonium hydroxide 45: 5: 1).
Den herved vundne gule olie blev opløst i 150 ml ether, og med overskud af vandfrit hydrogenchlorid blev der fældet 6,1 g (51% af det teor.) af titelforbindelsen.The resulting yellow oil was dissolved in 150 ml of ether and with excess anhydrous hydrogen chloride 6.1 g (51% of theory) of the title compound was precipitated.
15 Efter omkrystallisation af ethanol/vand vandtes hvide krystaller, smp. 236-246°C (dek.).After recrystallization from ethanol / water, white crystals were obtained, m.p. 236-246 ° C (dec.).
Eksempel 18 1.3- Bis-[4-(4-chlorbenzyl)-2,5-dimethyl-l-piperazinyl] -20 propan-tetrahydrochlorid-dihydrat.Example 18 1.3-Bis- [4- (4-chlorobenzyl) -2,5-dimethyl-1-piperazinyl] -propane tetrahydrochloride dihydrate.
a) En opløsning af 16 g p-chlorbenzylchlorid i 75 ml ethanol blev dråbevis sat til en opløsning af 25 g 2,5-dimethylpiperazin i 75 ml ethanol, og blandingen blev omrørt natten over og derefter filtreret. Opløsningsmid- 25 let blev fjernet ved vakuumdestillation, inddampningsre-sten blev ekstraheret 3 gange med 350 ml ether, opløsningsmidlet blev fordampet, og den tilbageværende olie blev chromatograferet på silicagel (elueringsmiddel methylenchlorid/methanol/ammoniumhydroxid 45:5:1). Der 30 vandtes herved 9,1 g (38% af det teor.) 1-(4-chlorbenzy]) -2,5-dimethylpiperazin som farveløs væske. Den anvendtes uden yderligere rensning til den følgende omsætning.a) A solution of 16 g of p-chlorobenzyl chloride in 75 ml of ethanol was added dropwise to a solution of 25 g of 2,5-dimethylpiperazine in 75 ml of ethanol and the mixture was stirred overnight and then filtered. The solvent was removed by vacuum distillation, the residue was extracted 3 times with 350 ml of ether, the solvent was evaporated and the residual oil was chromatographed on silica gel (eluent methylene chloride / methanol / ammonium hydroxide 45: 5: 1). There was thus obtained 9.1 g (38% of theory) of 1- (4-chlorobenzyl) -2,5-dimethylpiperazine as a colorless liquid. It was used without further purification for the following reaction.
b) En blanding af 6,0 g 1-(4-chlorbenzyl)-2,5-dime-thylpiperazin, 2,0 g l-brom-3-chlorpropan, 3,2 g tri- 35 ethylamin og 50 ml ethanol blev opvarmet 6 timer under tilbagesvaling. Opløsningsmidlet blev fjernet i vakuum,b) A mixture of 6.0 g of 1- (4-chlorobenzyl) -2,5-dimethylpiperazine, 2.0 g of 1-bromo-3-chloropropane, 3.2 g of triethylamine and 50 ml of ethanol was obtained. heated 6 hours at reflux. The solvent was removed in vacuo,
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20 til inddampningsresten blev der sat 50 ml vand, og blandingen blev ekstraheret 3 gange med 150 ml ether. Opløsningsmidlet blev fordampet, og den tilbageværende olie blev chromatograferet på silicagel (elueringsmiddel me-5 thylenchlorid/methanol/ammoniumhydroxid 45:5:1). Det vundne produkt blev opløst i 150 ml ether og fældet med overskud af vandfri saltsyre. Bundfaldet blev opløst i vand, og ved tilsætning af acetone vandtes 0,7 g af titelforbindelsen i form af hvide krystaller, smp. 204-10 214°C.To the residue, 20 ml of water was added and the mixture was extracted 3 times with 150 ml of ether. The solvent was evaporated and the residual oil was chromatographed on silica gel (eluent methylene chloride / methanol / ammonium hydroxide 45: 5: 1). The obtained product was dissolved in 150 ml of ether and precipitated with excess anhydrous hydrochloric acid. The precipitate was dissolved in water and by the addition of acetone 0.7 g of the title compound was obtained in the form of white crystals, m.p. 204-10 214 ° C.
Eksempel 19 l,3-Bis-[4-(4-methoxybenzyl)-1-piperazinyl]-propan.Example 19 1,3-Bis- [4- (4-methoxybenzyl) -1-piperazinyl] propane.
En blanding af 4,1 g 2-(p-methoxybenzyl)piperazin, 15 1,6 g l-brom-3-chlorpropan, 25 ml ethanol og 2,5 ml tri- ethylamin blev opvarmet 5 timer under tilbagesvaling. Opløsningsmidlet blev fjernet i vakuum, og inddampningsresten blev blandet med 25 ml vand og ekstraheret med ether Efter fordampning af opløsningsmidlet vandtes en gul olie, 20 der størknede ved henstand.- Efter to omkrystallisationer af heptan vandtes 2,3 g (51% af det teor.) af titelforbindelsen i form af hvide krystaller, smp. 86-87°C.A mixture of 4.1 g of 2- (p-methoxybenzyl) piperazine, 1.6 g of 1-bromo-3-chloropropane, 25 ml of ethanol and 2.5 ml of triethylamine was heated at reflux. The solvent was removed in vacuo and the residue was mixed with 25 ml of water and extracted with ether. After evaporation of the solvent, a yellow oil, 20 which was solidified on standing, was obtained. After two recrystallizations of heptane, 2.3 g (51% of the theory) were obtained. .) of the title compound in the form of white crystals, m.p. 86-87 ° C.
Eksempel 20 25 1,3-Bis-[4-(3,4-dichlorbenzyl)-1-piperazinylJ-propan- tetrahydrochlorid.Example 20 1,3-Bis- [4- (3,4-dichlorobenzyl) -1-piperazinyl] propane tetrahydrochloride.
En blanding af 5,2 g 1-(3,4-dichlorbenzyl)-piperazin, 2,2 g l-brom-3-chlorpropan, 3,0 g triethylamin og 20 g ethanol blev opvarmet under tilbagesvaling. Efter 30 en time blev der tilsat yderligere 0,06 g l-brom-3-chlor-propan og efter endnu en time yderligere 0,06 g. Blandingen blev opvarmet natten over under tilbagesvaling, og derefter blev opløsningsmidlet fjernet i vakuum. Der vandtes en gummiagtig fast masse, der blev blandet med 35 ether og filtreret. Filtratet blev tørret over magnesiumsulfat, og derefter blev der tilsat hydrogenchlorid-mæt-tet ether, indtil blandingen reagerede surt over for lak·^A mixture of 5.2 g of 1- (3,4-dichlorobenzyl) -piperazine, 2.2 g of 1-bromo-3-chloropropane, 3.0 g of triethylamine and 20 g of ethanol was heated at reflux. After 30 one hour, an additional 0.06 g of 1-bromo-3-chloro-propane was added and after another hour another 0.06 g. The mixture was heated overnight under reflux, and then the solvent was removed in vacuo. A rubbery solid mass was obtained which was mixed with 35 ether and filtered. The filtrate was dried over magnesium sulfate and then hydrogen chloride-saturated ether was added until the mixture reacted acidically with lacquer.
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21 mus. Det vundne bundfald blev opløst i lidt vand, og der blev dråbevis tilsat koncentreret saltsyre indtil dannelse af et bundfald. Tilsætningen af saltsyre blev fortsat, indtil der ikke dannedes mere bundfald. Efter filtrering 5 og tørring i vakuum vandtes 4,5 g (44% af det teor.) af titelforbindelsen i form af hvide nåle, snip. 245-251°C (dek.).21 mice. The resulting precipitate was dissolved in a little water and concentrated hydrochloric acid was added dropwise to form a precipitate. The addition of hydrochloric acid was continued until no more precipitate formed. After filtration 5 and drying in vacuo, 4.5 g (44% of theory) of the title compound in the form of white needles were sniped. 245-251 ° C (dec.).
Eksempel 21 10 1,3—Bis-[4-(2-chlorbenzyl)-1-piperazinyl]-propan-tetra- hydrochlorid.Example 21 1,3-Bis- [4- (2-chlorobenzyl) -1-piperazinyl] propane tetrahydrochloride.
En blanding af 8,4 g 1-(2-chlorbenzyl)piperazin, 3,2 g l-brom-3-chlorpropan, 4,0 g triethylamin og 30 g ethanol blev opvarmet natten over under tilbagesvaling.A mixture of 8.4 g of 1- (2-chlorobenzyl) piperazine, 3.2 g of 1-bromo-3-chloropropane, 4.0 g of triethylamine and 30 g of ethanol was heated at reflux overnight.
15 Derefter blev opløsningsmidlet fjernet i vakuum, og ind-dampningsresten blev blandet med 150 ml ether og filtreret. Filtratet blev tørret over magnesiumsulfat, og derefter blev der langsomt tilsat hydrogenchlorid-mættet ether indtil sur reaktion over for lakmus. Det dannede 20 bundfald blev frafiltreret, tørret og vejet. Der vandtes 6,1 g (50% af det teor.) af titelforbindelsen, der efter omkrystallisation af ethanol/vand forelå som hvidt krystaller, smp. 251-255°C.Then, the solvent was removed in vacuo and the residue was mixed with 150 ml of ether and filtered. The filtrate was dried over magnesium sulfate and then slowly added hydrochloride-saturated ether until acidic reaction to litmus. The resulting 20 precipitate was filtered off, dried and weighed. 6.1 g (50% of theory) of the title compound were obtained which, after recrystallization of ethanol / water, were obtained as white crystals, m.p. 251-255 ° C.
25 Eksempel 22 1,3-Bis-[4-(4-methylbenzyl)-1-piperazinyl]-propan-tetra-hydrochlorid.Example 22 1,3-Bis- [4- (4-methylbenzyl) -1-piperazinyl] propane tetrahydrochloride.
En blanding af 5,7 g 1-(4-methylbenzyl)piperazin, 2,4 g l-brom-3-chlorpropan, 25 ml ethanol og 3,0 g tri-30 ethylamin blev opvarmet 5 timer under tilbagesvaling. Opløsningsmidlet blev fjernet i vakuum, og inddampningsre-’ sten blev blandet med 40 ml vand. Den vandige blanding blev ekstraheret 3 gange med 150 ml ether, og efter fordampning af etheren vandtes en let gullig olie, der 35 størknede ved henstand. Dette produkt blev opløst i 50 ml ether, og der blev tilsat hydrogenchlorid-mættet ether indtil sur reaktion over for lakmus. Det dannede bundfaldA mixture of 5.7 g of 1- (4-methylbenzyl) piperazine, 2.4 g of 1-bromo-3-chloropropane, 25 ml of ethanol and 3.0 g of triethylamine was heated at reflux. The solvent was removed in vacuo and the residue was mixed with 40 ml of water. The aqueous mixture was extracted 3 times with 150 ml of ether and, after evaporation of the ether, a slightly yellowish oil was obtained, which solidified on standing. This product was dissolved in 50 ml of ether and hydrogen chloride-saturated ether was added until acidic to the litmus. It formed precipitate
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22 blev opløst i 20 ml vand, og ved tilsætning af acetone udfældede titelforbindelsen' i et udbytte på 5,8 g (68% af det teor.) i form af hvidt krystaller, smp. 245-252°C (dek.).22 was dissolved in 20 ml of water, and by the addition of acetone the title compound precipitated in a yield of 5.8 g (68% of theory) in the form of white crystals, m.p. 245-252 ° C (dec.).
55
Eksempel 23 1.3- Bis-[4-(3-chlorbenzyl)-1-piperazinyl]-propan-dihydro-chlorid-monohydrat.Example 23 1.3- Bis- [4- (3-chlorobenzyl) -1-piperazinyl] -propane dihydrochloride monohydrate.
En blanding af 6,3 g 1-(3-chlorbenzyl)piperazin, 10 2,4 g l-brom-3-chlorpropan, 50 ml ethanol og 3,0 g tri- ethylamin blev opvarmet 4 timer under tilbagesvaling.A mixture of 6.3 g of 1- (3-chlorobenzyl) piperazine, 2.4 g of 1-bromo-3-chloropropane, 50 ml of ethanol and 3.0 g of triethylamine was heated at reflux.
Derefter blev der tilsat 70 ml vand, blandingen blev inddampet i vakuum til ca. 70 ml, og den herved vundne vandige blanding blev ekstraheret med 3 gange 150 ml ether.Then 70 ml of water was added, the mixture evaporated in vacuo to ca. 70 ml, and the resulting aqueous mixture was extracted with 3x 150 ml of ether.
15 Efter inddampning af ekstrakten i vakuum vandtes en rødliggul olie, der blev chromatograferet på silicagel (elueringsmiddel methylenchlorid/methanol/ammoniumhydroxid 45:5:1). Den herved vundne olie blev opløst i 50 ml ethanol, og der blev tilsat hydrogenchlorid-mættet ether ind-20 til sur reaktion over for lakmus. Bundfaldet blev frafiltreret, tørret og omkrystalliseret af vand. Der vandtes 5,6 g (68% af det teor.) af titelforbindelsen i form af hvide krystaller, smp. 248-257°C (dek.).After evaporation of the extract in vacuo, a reddish-yellow oil was obtained which was chromatographed on silica gel (eluent methylene chloride / methanol / ammonium hydroxide 45: 5: 1). The oil thus obtained was dissolved in 50 ml of ethanol and hydrogen chloride-saturated ether was added to acidic reaction to litmus. The precipitate was filtered off, dried and recrystallized from water. 5.6 g (68% of theory) of the title compound were obtained in the form of white crystals, m.p. 248-257 ° C (dec.).
25 Eksempel 24 1.3- Bis-[4-(3-{4-chlorphenyl}-propyl)-1-piperazinyl]-propan-tetrahydrochlorid-monohydrat.Example 24 1.3- Bis- [4- (3- {4-chlorophenyl} propyl) -1-piperazinyl] propane tetrahydrochloride monohydrate.
a) En blanding af 40,6 g 3-(4-chlorphenyl)propylchlo-rid, 130,0 g vandfri piperazin og 550 ml ethanol blev op-30 varmet 2 timer under tilbagesvaling. Opløsningsmidlet blev fjernet i vakuum, og inddampningsresten blev chromatograferet på silicagel (elueringsmiddel methylenchlo-rid/methanol/ammoniumhydroxid 45:5:1). De passende fraktioner blev samlet og inddampet til en olie, der blev 35 blandet med 1400 ml IN saltsyre og derefter filtreret. Filtratet blev med koncentreret vandigt natriumhydroxid bragt til pH 10 og derefter ekstrateret med 4 gange 200 ml ether. Ekstrakten blev tørret over magnesiumsulfat og .23a) A mixture of 40.6 g of 3- (4-chlorophenyl) propyl chloride, 130.0 g of anhydrous piperazine and 550 ml of ethanol was heated at reflux for 2 hours. The solvent was removed in vacuo and the residue was chromatographed on silica gel (eluent methylene chloride / methanol / ammonium hydroxide 45: 5: 1). The appropriate fractions were combined and evaporated to an oil which was mixed with 1400 ml of 1N hydrochloric acid and then filtered. The filtrate was brought to pH 10 with concentrated aqueous sodium hydroxide and then extracted with 4 times 200 ml of ether. The extract was dried over magnesium sulfate and .23
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inddampet til en olie, der størknede ved henstand. Den herved vundne 1-[3-(4-chlorphenyl)propyl]piperazin med smp. 54-62°C anvendtes uden yderligere rensning til det næste trin.evaporated to an oil which solidified on standing. The resulting 1- [3- (4-chlorophenyl) propyl] piperazine with m.p. 54-62 ° C was used without further purification for the next step.
5 b) En blanding af 7,2 g 1-[3-(4-chlorphenyl)propyl]-piperazin, 2,4 g l-brom-3-chlorpropan, 3,5 g triethylamin og 30 ml ethanol blev opvarmet 6 timer under tilbagesvaling. Derefter blev opløsningsmidlet fjernet i vakuum, og inddampningsresten blev blandet med 40 ml vand og eks-10 traheret med 3 gange 150 ml ether. Ekstrakten blev inddampet til en gul olie, der blev chromatograferet på si-licagel (elueringsmiddel methylenchlorid/methanol/ammoni-umhydroxid 45:5:1). Der vandtes 4,6 g (59% af det teor.) 1.3- bis-{4-(3-{4-chlorphenyl}-propyl)-1-piperazinyl]- 15 propan som farveløs olie. Af denne olie blev 3,0 g opløst i 100 ml ether, og der blev tilsat hydrogenchlorid-mættet ether indtil sur reaktion over for lakmus. Det dannede bundfald blev opløst i 25 ml vand, og der blev tilsat acetone indtil endt udfældning. Der vandtes 2,7 g (41% 20 af det teor.) af titelforbindelsen, smp. 245-246°C (dek.), i form af hvide krystaller.B) A mixture of 7.2 g of 1- [3- (4-chlorophenyl) propyl] -piperazine, 2.4 g of 1-bromo-3-chloropropane, 3.5 g of triethylamine and 30 ml of ethanol was heated for 6 hours. under reflux. Then, the solvent was removed in vacuo and the residue was mixed with 40 ml of water and extracted with 3x 150 ml of ether. The extract was evaporated to a yellow oil which was chromatographed on silica gel (eluent methylene chloride / methanol / ammonium hydroxide 45: 5: 1). 4.6 g (59% of theory) of 1.3-bis- {4- (3- {4-chlorophenyl} -propyl) -1-piperazinyl] -propane was obtained as colorless oil. Of this oil, 3.0 g was dissolved in 100 ml of ether and hydrogen chloride-saturated ether was added until acidic to the litmus. The resulting precipitate was dissolved in 25 ml of water and acetone was added until the precipitation was completed. 2.7 g (41% of theory) of the title compound were obtained, m.p. 245-246 ° C (dec.), In the form of white crystals.
Eksempel 25 1.3- Bis-[4-(4-chlor-3-trifluormethylbenzyl)-1-piperazin-25 yl]-propan-tetrahydrochlorid.Example 25 1.3-Bis- [4- (4-chloro-3-trifluoromethylbenzyl) -1-piperazin-25-yl] -propane tetrahydrochloride.
En blanding af 11,5 g 3-chlor-4-trifluormethylbenz-ylchlorid, 5,3 g 1,3-bis-(1-piperazinyl)propan, 50 g ethanol og 70 g triethylamin blev opvarmet 16 timer under tilbagesvaling. Derefter blev reaktionsblandingen inddam-30 pet i vakuum, inddampningsresten blev blandet med 150 ml vand, og blandingen blev ekstraheret med 5. gange 100 ml ether. De samlede etherekstrakter blev vasket med 3 gange 100 ml 1M natriumcarbonatopløsning, tørret over magnesiumsulfat, filtreret og inddampet til 6,8 g af en gul olie.A mixture of 11.5 g of 3-chloro-4-trifluoromethylbenzyl chloride, 5.3 g of 1,3-bis (1-piperazinyl) propane, 50 g of ethanol and 70 g of triethylamine was heated at reflux for 16 hours. Then, the reaction mixture was evaporated in vacuo, the residue was mixed with 150 ml of water and the mixture was extracted with 5x 100 ml of ether. The combined ether extracts were washed with 3 times 100 ml of 1 M sodium carbonate solution, dried over magnesium sulfate, filtered and evaporated to 6.8 g of a yellow oil.
35 Denne olie blev opløst i 100 ml hexan og filtreret. Filtratet blev ekstraheret med 3 gange 20 ml 2%'s vandig eddikesyre, hvorved det ønskede produkt forelå i 2, og 3. ekstrakt (prøve ved tyndtlagschromatografi). Disse eks-This oil was dissolved in 100 ml of hexane and filtered. The filtrate was extracted with 3 x 20 ml of 2% aqueous acetic acid to give the desired product in 2, and 3. extract (sample by thin layer chromatography). These ex-
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24 trakter blev samlet, indstillet stærkt alkalisk med 2N natriumhydroxid og ekstraheret med 100 ml ether/hexan (1:1). Ekstrakten blev tørret over vandfrit kaliumcarbo-nat, og derefter blev opløsningsmidlet fordampet. Den 5 tilbageværende olie (2,6 g) blev opløst i 10 ml methanol, og efter tilsætning af 30 ml hydrogenchlorid-mættet ether vandtes et hvidt bundfald. Yderligere 50 ml ether blev tilsat, og bundfaldet blev frafiltreret og cmkrystalliseret af methanol. Der vandtes titelforbindelsen i form af farvelø-10 se krystaller, smp. 265-268°C (dek.> 250°C).Twenty-four funnels were combined, adjusted strongly alkaline with 2N sodium hydroxide and extracted with 100 ml of ether / hexane (1: 1). The extract was dried over anhydrous potassium carbonate and then the solvent was evaporated. The remaining oil (2.6 g) was dissolved in 10 ml of methanol and after the addition of 30 ml of hydrogen chloride-saturated ether a white precipitate was obtained. An additional 50 ml of ether was added and the precipitate was filtered off and crystallized by methanol. The title compound was obtained in the form of colorless crystals, m.p. 265-268 ° C (dec.> 250 ° C).
Eksempel 26 1.3- Bis-[4-(4-hydroxybenzyl)-1-piperazinyl]-propan.Example 26 1.3- Bis- [4- (4-hydroxybenzyl) -1-piperazinyl] propane.
En blanding af 4,5 g l,3-bis-[4-(4-methoxybenzyl)-15 1-piperazinyl]propan (se Eksempel 19) og 250 ml 49%'s hydrogenbromidsyre blev opvarmet 2 timer under tilbagesvaling, derefter afkølet og fortyndet med 125 ml vand.A mixture of 4.5 µl, 3-bis- [4- (4-methoxybenzyl) -1-piperazinyl] propane (see Example 19) and 250 ml of 49% hydrogen bromide acid was heated at reflux, then cooled and cooled. diluted with 125 ml of water.
Den vandige opløsning blev filtreret og bragt til pH 8 med 2N natriumhydroxid. Denne blanding blev ekstraheret 20 med 3 gange 150 ml ethanol, alkoholen blev fjernet ved rotationsfordampning, og inddampningsresten blev chroma-tograferet på silicagel (elueringsmiddel methylenchlorid med 1% ammoniumhydroxid og 10% methanol). Der vandtes 1,3 g (31% af det teor.) af titelforbindelsen, smp. 197-25 201°C, i form af hvide krystaller.The aqueous solution was filtered and brought to pH 8 with 2N sodium hydroxide. This mixture was extracted with 3x 150 ml of ethanol, the alcohol removed by rotary evaporation, and the residue was chromatographed on silica gel (eluent methylene chloride with 1% ammonium hydroxide and 10% methanol). 1.3 g (31% of theory) of the title compound, m.p. 197-25 201 ° C, in the form of white crystals.
Eksempel 27 1.3- Bis-[4-(4-brombenzyl)-1-piperazinyl]-propan-tetra-hydrochlorid.Example 27 1.3- Bis- [4- (4-bromobenzyl) -1-piperazinyl] propane tetrahydrochloride.
30 En blanding af 3,8 g 1-(4-brombenzyl)piperazin, 7 g ethanol, 1,2 g 1-brom-3-chlorpropan og 1,6 g tri-ethylamin blev opvarmet 18 timer under tilbagesvaling. Opløsningsmidlet blev fjernet ved rotationsfordampning, inddampningsresten blev blandet med 50 ml vand og bragt 35 til pH 10 med 2N natriumhydroxid. Denne blanding blev ekstraheret 2 gange med ether (75 + 25 ml), de samlede ekstrakter blev vasket med 2 gange 25 ml vand, tørretA mixture of 3.8 g of 1- (4-bromobenzyl) piperazine, 7 g of ethanol, 1.2 g of 1-bromo-3-chloropropane and 1.6 g of triethylamine was heated at reflux for 18 hours. The solvent was removed by rotary evaporation, the residue was mixed with 50 ml of water and brought to pH 10 with 2N sodium hydroxide. This mixture was extracted 2 times with ether (75 + 25 ml), the combined extracts washed with 2 times 25 ml of water, dried
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25 over magnesiumsulfat og filtreret. Til denne opløsning blev der sat hydrogenchlorid-mættet ether indtil sur reaktion, og det dannede bundfald blev frafiltreret og blandet med 100 ml ethanol. Blandingen blev bragt til 5 tilbagesvalingstemperatur, og der blev dråbevis tilsat vand, indtil bundfaldet var bragt i opløsning. Ved afkøling udkrystalliserede slutproduktet, der blev frafiltreret. Der vandtes 4,2 g (81% af det teor.) af titelforbindelsen, smp. 237-243°C, i form af hvide krystaller.25 over magnesium sulfate and filtered. To this solution was added hydrogen chloride-saturated ether until acidic reaction and the resulting precipitate was filtered off and mixed with 100 ml of ethanol. The mixture was brought to 5 reflux temperature and water was added dropwise until the precipitate was dissolved. Upon cooling, the final product crystallized and filtered off. 4.2 g (81% of theory) of the title compound were obtained, m.p. 237-243 ° C, in the form of white crystals.
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Eksempel 28 1,3—Bis—[4-(4-chlorbenzyl)-1-homopiperazinyl]-propan-tetrahydrochlorid.Example 28 1,3-Bis- [4- (4-chlorobenzyl) -1-homopiperazinyl] propane tetrahydrochloride.
En blanding af 4,5 g 1-(4-chlorbenzyl)-homopipera-15 zin, 1,6 g l-brom-3-chlorpropan og 20 g ethanol blev opvarmet 18 timer under tilbagesvaling. Opløsningsmidlet blev fjernet i vakuum, og den tilbageværende blanding blev ekstraheret med 3 gange 75 ml ether. Efter fordampning af etheren vandtes en olie, der blev chromatografe-20 ret på silicagel (elueringsmiddel methylenchlorid indeholdende 0,5% koncentreret ammoniumhydroxid og 2,5% methanol) . De fraktioner, der indeholdt slutproduktet, blev samlet, opløsningsmidlet blev fordampet, og den tilbageværende olie blev opløst i ether, og opløsningen blev 25 filtreret. Den tilbageværende etheropløsning blev med hydrogenchlorid-mættet ether bragt til sur reaktion over for lakmus. Det dannede bundfald blev tørret, og der vandtes 1,4 g (22% af det teor.) af titelforbindelsen i form af hvide krystaller, der efter omkrystallisation af 30 vandig ethanol havde smp. 218-224°C (dek.).A mixture of 4.5 g of 1- (4-chlorobenzyl) homeopiperazine, 1.6 g of 1-bromo-3-chloropropane and 20 g of ethanol was heated at reflux for 18 hours. The solvent was removed in vacuo and the remaining mixture was extracted with 3 times 75 ml of ether. After evaporation of the ether, an oil was chromatographed on silica gel (eluent methylene chloride containing 0.5% concentrated ammonium hydroxide and 2.5% methanol). The fractions containing the final product were combined, the solvent was evaporated and the residual oil was dissolved in ether and the solution was filtered. The remaining ether solution was brought to acidic reaction with litmus with hydrogen chloride-saturated ether. The resulting precipitate was dried and 1.4 g (22% of theory) of the title compound was obtained in the form of white crystals which, after recrystallization from 30 aqueous ethanol, m.p. 218-224 ° C (dec.).
Eksempel 29 1,3—Bis—[4-(4-{4-chlorphenyl}-butyl)-1-piperazinyl]-propan-tetrahydrochlorid.Example 29 1,3-Bis- [4- (4- {4-chlorophenyl} -butyl) -1-piperazinyl] -propane tetrahydrochloride.
35 a) En blanding af 26,4 g 4-(4-chlorphenyl)butylchlo-rid, 86,1 g vandfri piperazin og 250 ml ethanol blev opvarmet natten over under tilbagesvaling. OpløsningsmidletA) A mixture of 26.4 g of 4- (4-chlorophenyl) butyl chloride, 86.1 g of anhydrous piperazine and 250 ml of ethanol was heated at reflux overnight. The solvent
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26 blev fordampet, og inddampningsresten blev chromatogra-feret 2 gange på silicagel (elueringsmiddel methylenchlo-rid/methanol/ammoniumhydroxid 45:5:1). Den første fraktion indeholdt hovedsageligt overskud af piperazin, den 5 anden indeholdt 15,2 g 1-[4-(4-chlorphenyl)-butyl]-piperazin som farveløs olie, der størknede ved henstand (smp. 139-145°C). Dette råprodukt anvendtes uden yderligere rensning til det næste trin.26 was evaporated and the residue was chromatographed twice on silica gel (eluent methylene chloride / methanol / ammonium hydroxide 45: 5: 1). The first fraction mainly contained excess piperazine, the second contained 15.2 g of 1- [4- (4-chlorophenyl) -butyl] -piperazine as a colorless oil which solidified on standing (mp 139-145 ° C). This crude product was used without further purification for the next step.
b) En blanding af 1,5 g 1-[4-(4-chlorphenyl)butyl]-10 piperazin, 0,5 g l-brom-3-chlorpropan, 0,7 g triethyl-amin og 10 g ethanol blev opvarmet under tilbagesvaling natten over. Efter tilsætning af 3,5 ml 2N natriumhydroxid blev opløsningsmidlet fjernet i vakuum. Inddampningsresten blev ekstraheret med methylenchlorid, og ekstrak-15 ten blev chromatograferet på silicagel (elueringsmiddel methylenchlorid/methanol/ammoniumhydroxid 90:10:1). De fraktioner, der indeholdt det ønskede produkt, blev inddampet til en olie, og denne blev opløst i ether. Efter tilsætning af hydrogenchlorid-mættet ether vandtes et 20 bundfald af 0,7 g (31% af det teor.) af titelforbindelsen som en lysebrun fast masse, der ved omkrystallisation af ethanol/vand blev omdannet til hvide krystaller, smp. 213-217°C (dek.).b) A mixture of 1.5 g of 1- [4- (4-chlorophenyl) butyl] -10 piperazine, 0.5 g of 1-bromo-3-chloropropane, 0.7 g of triethylamine and 10 g of ethanol was heated. under reflux overnight. After the addition of 3.5 ml of 2N sodium hydroxide, the solvent was removed in vacuo. The residue was extracted with methylene chloride and the extract was chromatographed on silica gel (eluent methylene chloride / methanol / ammonium hydroxide 90: 10: 1). The fractions containing the desired product were evaporated to an oil and dissolved in ether. After addition of hydrogen chloride-saturated ether, a precipitate of 0.7 g (31% of theory) of the title compound was obtained as a light brown solid which was converted to white crystals by crystallization of ethanol / water, m.p. 213-217 ° C (dec.).
25 Eksempel 30 1,3-Bis-[4-(4-acetoxybenzyl)-1-piperazinyl]-propan.Example 30 1,3-Bis- [4- (4-acetoxybenzyl) -1-piperazinyl] propane.
En blanding af 2,0 g 1,3-bis-[4-(4-hydroxybenzyll- 1-piperazinyl]-propan (se Eksempel 26}., 1,0 g pyridin og 50 g eddikesyreanhydrid blev omrørt natten over ved 30 stuetemperatur. Blandingen blev inddampet i vakuum til en ravfarvet olie, der blev blandet med 100 ml phosphat-puffer (pH 8) og ekstraheret med 3 gange 100 ml ether. Ekstrakten blev tørret over magnesiumsulfat og inddampet til en hvid fast masse. Efter omkrystallisation af hep-35 tan vandtes 1,9 g (78% af det teor.). af titelforbindelsen i form af hvide krystaller, smp, 102-105°C.A mixture of 2.0 g of 1,3-bis- [4- (4-hydroxybenzyl-1-piperazinyl] propane (see Example 26), 1.0 g of pyridine and 50 g of acetic anhydride was stirred overnight at room temperature. The mixture was evaporated in vacuo to an amber oil which was mixed with 100 ml of phosphate buffer (pH 8) and extracted with 3 times 100 ml of ether. The extract was dried over magnesium sulfate and evaporated to a white solid. -35 tan was obtained 1.9 g (78% of theory) of the title compound as white crystals, mp 102-105 ° C.
.270.27
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Eksempel 31 1.3- Bis-[4-(4-butoxybenzyl)-1-piperazinyl]-propan-tetra-hydrochlorid.Example 31 1.3-Bis- [4- (4-butoxybenzyl) -1-piperazinyl] propane tetrahydrochloride.
En blanding af 1,0 g 1,3-bis-[4-(4-hydroxybenzyl)-5 1-piperazinyl]-propan (se Eksempel 26), 10 ml 2N natriumhydroxid, 0,2 g tetrabutylammoniumhydroxid (40% i vand) og 5,0 g 1-brombutan blev opvarmet 3 timer på dampbad. Blandingen blev derefter ekstraheret med 3 gange 75 ml ether, tørret over magnesiumsulfat og inddampet til en 10 farveløs olie, der størknede ved henstand. Dette produkt blev opløst i 100 ml ether, og der blev tilsat hydrogen-mættet ether indtil endt udfældning. Efter filtrering vandtes 1,4 g (91% af det teor.) af titelforbindelsen, der efter omkrystallisation af ethanol/vand forelå som 15 hvide krystaller, smp. 207-218°C.A mixture of 1.0 g of 1,3-bis- [4- (4-hydroxybenzyl) -5-piperazinyl] propane (see Example 26), 10 ml of 2N sodium hydroxide, 0.2 g of tetrabutylammonium hydroxide (40% in water) ) and 5.0 g of 1-bromobutane were heated for 3 hours on a steam bath. The mixture was then extracted with 75 ml of ether, dried over magnesium sulfate and evaporated to a colorless oil which solidified on standing. This product was dissolved in 100 ml of ether and hydrogen-saturated ether was added until precipitation ended. After filtration, 1.4 g (91% of theory) of the title compound, which after recrystallization of ethanol / water, was obtained as 15 white crystals, m.p. 207-218 ° C.
Eksempel 32 1.3- Bis-[4-(4-chlorbenzyl-2,3,5,6-tetramethyl-l-pipera-ziny1]-propan-tetrahydrochlorid.Example 32 1,3-Bis- [4- (4-chlorobenzyl-2,3,5,6-tetramethyl-1-piperazinyl] -propane-tetrahydrochloride).
20 En blanding af 3 g 1- (4-chlorbenz.yl) -2,3,5,6-tetra- methylpiperazin, 1 g l-brom-3-chlorpropan og 1 g tri-ethylamin blev opvarmet 24 timer i 20 ml ethanol under tilbagesvaling. Derefter blev opløsningsmidlet fjernet i vakuum, den tilbageværende olie blev opløst i vand og 25 ekstraheret med ether. Etherekstrakten blev vasket med vand og tørret over magnesiumsulfat. Titelforbindelsen vandtes som hvide krystaller fra etheropløsningen ved fældning med et overskud af etherisk saltsyre og omkrystallisation af ethanol.A mixture of 3 g of 1- (4-chlorobenzyl) -2,3,5,6-tetramethylpiperazine, 1 g of 1-bromo-3-chloropropane and 1 g of triethylamine was heated for 24 hours in 20 ml. ethanol under reflux. Then, the solvent was removed in vacuo, the residual oil was dissolved in water and extracted with ether. The ether extract was washed with water and dried over magnesium sulfate. The title compound was obtained as white crystals from the ether solution by precipitation with an excess of ethereal hydrochloric acid and recrystallization from ethanol.
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Eksempel 33 1- [4-(4-Chlorbenzyl) -1-piperazinyl] ^-3- [4- (2r-carboxy-2-phenylethyl)-1-piperazinyl]-propan-tetrahydrochlorid.Example 33 1- [4- (4-Chlorobenzyl) -1-piperazinyl] -3- [4- (2R-carboxy-2-phenylethyl) -1-piperazinyl] propane tetrahydrochloride.
Til en suspension af 340 mg 1-[4-(4-chlorbenzyl)- 35 1-piperazinyl]-3-[4-(2-ethoxycarbonyl-2-phenylethyl)-1-piperazinyl]-propan-tetrahydrochlorid i 10 ml ethanol blev der sat 1 ml vandig 5M natriumhydroxid, og der blevTo a suspension of 340 mg of 1- [4- (4-chlorobenzyl) - 1-piperazinyl] -3- [4- (2-ethoxycarbonyl-2-phenylethyl) -1-piperazinyl] propane tetrahydrochloride in 10 ml of ethanol 1 ml of aqueous 5M sodium hydroxide was added and there was
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28 opvarmet en time under tilbagesvaling. Derefter blev reaktionsblandingen inddampet til tørhed ved reduceret tryk. Inddampningsresten blev blandet med IN saltsyre (3 ml), og denne blanding blev ekstraheret med 2 gange 5 IQ ml ether. Ekstrakten blev bortkastet, og pH-værdien af den vandige fase blev indstillet på 5,5 med IN saltsyre. Derefter blev der tilsat 10 ml mættet kogsaltopløsning, og blandingen blev ekstraheret med 2 gange 10 ml butanol. Butanolekstrakten blev filtreret, og der blev 10 tilsat overskud af etherisk saltsyre. Det hvide bundfald blev opsamlet og omkrystalliseret af vandig ethanol. Der vandtes 140 ml (40% af det teor.) af titelforbindelsen i form af hvide krystaller, smp. 230-245°C (dek.).28 heated for 1 hour under reflux. Then, the reaction mixture was evaporated to dryness at reduced pressure. The residue was mixed with 1N hydrochloric acid (3 ml) and this mixture was extracted with 2 times 5 IQ ml of ether. The extract was discarded and the pH of the aqueous phase was adjusted to 5.5 with 1N hydrochloric acid. Then 10 ml of saturated brine was added and the mixture was extracted with 2x 10 ml of butanol. The butanol extract was filtered and excess ethereal hydrochloric acid was added. The white precipitate was collected and recrystallized from aqueous ethanol. 140 ml (40% of theory) of the title compound were obtained in the form of white crystals, m.p. 230-245 ° C (dec).
15 Eksempel 34 1.3- Bis-[4-(3-{4-chlorphenyl}-propyl)-1-homopiperazinyl]-propan-tetrahydrochlorid.Example 34 1.3- Bis- [4- (3- {4-chlorophenyl} propyl) -1-homopiperazinyl] propane tetrahydrochloride.
En blanding af 3,8 g l-[3-(4-chlorphenyl)propyl]-homopiperazin, 1,2 g l-brom-3-chlorpropan og 1,8 g tri-20 ethylamin blev i 10 ml ethanol opvarmet 18 timer under tilbagesvaling. Reaktionsblandingen blev inddampet ved reduceret tryk, inddampningsresten blev blandet med vand og ekstraheret med ether. Etheren blev fordampet, og inddampningsresten blev chromatograferet på silicagel 25 (elueringsmiddel methylenchlorid/methanol/ammoniumhydro- xid 35:5:1). Den vundne olie blev opløst i ether, og titelforbindelsen blev udfældet med overskud af etherisk saltsyre. Efter omkrystallisation af ethanol vandtes 1.3- bis-[4-(3-{4-chlorphenyl}-propyl)-1-homopiperazinyl]-30 propan-tetrahydrochlorid i krystallinsk form.A mixture of 3.8 g of 1- [3- (4-chlorophenyl) propyl] homopiperazine, 1.2 g of 1-bromo-3-chloropropane and 1.8 g of triethylamine was heated in 10 ml of ethanol for 18 hours. under reflux. The reaction mixture was evaporated under reduced pressure, the residue was mixed with water and extracted with ether. The ether was evaporated and the residue was chromatographed on silica gel 25 (eluent methylene chloride / methanol / ammonium hydroxide 35: 5: 1). The oil obtained was dissolved in ether and the title compound precipitated with excess ethereal hydrochloric acid. After recrystallization from ethanol, 1,3-bis- [4- (3- {4-chlorophenyl} propyl) -1-homopiperazinyl] -propane tetrahydrochloride was obtained in crystalline form.
Eksempel 35 1.3- Bis-[4-(4-chlorbenzyl)-1-homopiperazinyl]-1,3-dioxo-propan-dihydrochlorid.Example 35 1.3-Bis- [4- (4-chlorobenzyl) -1-homopiperazinyl] -1,3-dioxopropane dihydrochloride.
35 Til en opløsning af 2,2 g 1-(4-chlorbenzyl)homo- piperazin og 1 g triethylamin i 10 ml methylenchlorid blev der ved stuetemperatur på én gang sat 0,7 g malon-To a solution of 2.2 g of 1- (4-chlorobenzyl) homopiperazine and 1 g of triethylamine in 10 ml of methylene chloride, 0.7 g of malone was added at room temperature at one time.
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s 29 syredichlorid, og reaktionsblandingen blev opvarmet en time under tilbagesvaling. Opløsningsmidlet blev fjernet ved reduceret tryk, inddampningsresten blev revet med vand, og råproduktet blev ekstraheret med methylenchlo-5 rid og renset ved chromatografi på silicagel (eluerings-middel methylenchlorid/methanol/hydroxylamin 200:5:1).s 29 acid dichloride and the reaction mixture was heated at reflux for one hour. The solvent was removed at reduced pressure, the residue evaporated with water and the crude product extracted with methylene chloride and purified by chromatography on silica gel (eluent methylene chloride / methanol / hydroxylamine 200: 5: 1).
De egnede fraktioner blev samlet, opløsningsmidlet blev fordampet, inddampningsresten blev opløst i ether, og der blev tilsat overskud af etherisk saltsyre. Der vand-10 tes titelforbindelsen i krystallinsk form.The appropriate fractions were combined, the solvent was evaporated, the residue was dissolved in ether, and excess ethereal hydrochloric acid was added. The title compound is watered in crystalline form.
Forbindelserne med den almene formel I og deres ikke toxiske, fysiologisk acceptable syreadditionssalte har værdifulde farmakodynamiske egenskaber.The compounds of general formula I and their non-toxic, physiologically acceptable acid addition salts have valuable pharmacodynamic properties.
15 Som følge af deres stærke hæmning af mediator-fri- gøringen i talrige cellesystemer udviser de navnlig inflammationshæmmende og antiallergiske egenskaber hos varmblodede dyr, såsom rotter, og er derfor egnede til bekæmpelse af allergiske sygdomme, såsom allergisk astma, 20 rhinitis, conjunctivitis, høfeber, urticaria, levnedsmiddelallergier og lignende.Because of their strong inhibition of the mediator release in numerous cell systems, they exhibit particularly inflammatory and antiallergic properties in warm-blooded animals, such as rats, and are therefore suitable for the control of allergic diseases such as allergic asthma, rhinitis, conjunctivitis, hay fever. , urticaria, food allergies and the like.
Mediator-frigøring fra mastceller og basofiler forekommer ved mange allergiske sygdomme og inflammationssygdomme. Aktiviteten af forbindelser, der hæmmer den 25 ikke-cytotoxiske exocytose af sådanne mediatorer, kan testes i in vitro-modeller, såsom modellen med hæmning af mediator-frigøringen fra isolerede cellesystemer udløst ved en antigen-antistof-reaktion.Mediator release from mast cells and basophils occurs in many allergic and inflammatory diseases. The activity of compounds that inhibit the 25 non-cytotoxic exocytosis of such mediators can be tested in in vitro models, such as the model of inhibition of the mediator release from isolated cell systems triggered by an antigen-antibody reaction.
I den følgende Tabel I er samlet data, der viser den 30 biologiske virkning af nogle af de omhandlede forbindelser ved forskellige teste. Følgende cellesystemer er opført i tabellen: RPMC: Peritoneale mastcelle-præparationer fra rotte.The following Table I summarizes data showing the biological effect of some of the compounds of this invention in various tests. The following cell systems are listed in the table: RPMC: Peritoneal mast cell preparations from rat.
GPBL: Med basofiler berigede leukocyter fra marsvine-3 5 unger.GPBL: Basophils enriched with guinea pig-3.5 5 leukocytes.
HBL : Med basofiler berigede leukocyter fra mennesker.HBL: Basophiles enriched human leukocytes.
Som kliniske standard-stoffer anvendtes theophyllin og dinatrium-cromoglycat (DSCG).Theophylline and disodium cromoglycate (DSCG) were used as standard clinical agents.
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30 _Tabel I_Table I_
Forbindelse Hæmning af Mediator-frigøringen ifølge ----Connection Inhibition of Mediator release according to ----
Eksempel IC50 *Example IC50 *
RPMC GPBL HBLRPMC GPBL HBL
51 3 40 2 2 80 20 3 15 10 50 3 16 NT 10 0/7 24 0/5 9 0/7 1051 3 40 2 2 80 20 3 15 10 50 3 16 NT 10 0/7 24 0/5 9 0/7 10
Theophyllin >1000 200 400 DSCG - - >1000 * Den forbindelseskoncentration/ der kræves for _ at hæmme frigøringen af farmakologiske media- torer fra de pågældende celler med 50%.Theophylline> 1000 200 400 DSCG - -> 1000 * The compound concentration / required to inhibit the release of pharmacological mediators from the cells concerned by 50%.
NT = ikke testet.NT = not tested.
Den antiallergiske virkning af forbindelserne ifølge opfindelsen kan påvises ved måling af in vitro inhibering af histaminfrigivelse fra humane leukocyter 20 (basofiler) ved følgende fremgangsmåde:The antiallergic effect of the compounds of the invention can be demonstrated by measuring in vitro inhibition of histamine release from human leukocytes 20 (basophils) by the following procedure:
Fraskillelse af leukocyter.Separation of leukocytes.
Man anvendte en modifikation af fremgangsmåden ifølge L. Lichtenstein og A. Osler, J. Exp. Med. 120 25 (1964), 507. Hepariniseret menneskeblod (80-100 ml) blev i propylencentrifugerør blandet med 20 ml 0,2% saltvand indeholdende 0,6 g dextrose og 1,2 g dextran. Efter henstand af blandingen ved stuetemperatur i 60-90 min., hvorved erythrocyterne skilles fra den blodplade-leukocyt-30 rige overstand, fjernedes denne og centrifugeredes i 8 min. ved 100 g i kulden. Leukocytbundfaldet blev vasket to gange med Tris-puffer og til slut udsuspenderet i 150— 180 ml Tris-ACM-puffer med 1-2 x 10^ celler/ml.A modification of the method of L. Lichtenstein and A. Osler, J. Exp. With. 120 25 (1964), 507. Heparinized human blood (80-100 ml) was mixed in propylene centrifuge tubes with 20 ml of 0.2% saline containing 0.6 g of dextrose and 1.2 g of dextran. After standing the mixture at room temperature for 60-90 minutes, separating the erythrocytes from the platelet-leukocyte-rich supernatant, this was removed and centrifuged for 8 minutes. at 100 g in the cold. The leukocyte precipitate was washed twice with Tris buffer and finally suspended in 150-180 ml Tris-ACM buffer at 1-2 x 10 6 cells / ml.
35 Reaktionsblanding.Reaction mixture.
Reaktionen blev gennemført i 12 x 75 mm plastrør iThe reaction was carried out in 12 x 75 mm plastic tubes
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31 et totalrumfang på 1,23 ml. Reaktionsmediet inkluderede 0,05 ml kanin anti-human IgE (antigenet), 0,2 ml prøveforbindelse i vand med koncentrationer på 10-100 M og 0,1 ml af leukocytsuspensionen. Reaktionsblandingen 5 blev under omrystning inkuberet i 60 min i et vandbad ved 37°C. Efter afsluttet reaktion centrifugerede man rørene og udtog supernatanterne, hvorfra protein blev fjernet ved udfældelse med 0,2 ml 8% perchlorsyre.31, a total volume of 1.23 ml. The reaction medium included 0.05 ml of rabbit anti-human IgE (the antigen), 0.2 ml of test compound in water with concentrations of 10-100 M and 0.1 ml of the leukocyte suspension. The reaction mixture 5 was incubated with shaking for 60 minutes in a water bath at 37 ° C. After completion of the reaction, the tubes were centrifuged and the supernatants removed from which protein was removed by precipitation with 0.2 ml of 8% perchloric acid.
10 Histaminassay.Histamine assay.
Histaminfrigivelsen blev målt ved den automatiserede fluorimetriske metode ifølge W. Siraganian og W. Hook, i kapitel 102 i "Manual of Clinical Immunology", ed. R. Rose og H. Friedman, American Society for Micro-15 biology, Washington, D.C., 1980.Histamine release was measured by the automated fluorimetric method according to W. Siraganian and W. Hook, in Chapter 102 of "Manual of Clinical Immunology", ed. R. Rose and H. Friedman, American Society for Micro-15 Biology, Washington, D.C., 1980.
Den procentiske inhibition blev beregnet som; (Kontrol-blankprøve) - (Testprøve-blankprøve) χ (Kontrol-blankprøve) 20 Den koncentration, der medfører en 50% inhibition af histaminfrigivelse (IC^^Jm findes ved interpolation i en afbildning af procentisk inhibition mod logaritmen af koncentrationen af prøveforbindelsen.The percent inhibition was calculated as; (Control Blank) - (Test Blank) Kontr (Control Blank) 20 The concentration that results in a 50% inhibition of histamine release (IC ^^ Jm is found by interpolation in a plot of percent inhibition against the logarithm of the concentration of the test compound.
Resultaterne ses i nedenstående Tabel II.The results are shown in Table II below.
2525
Tabel IITable II
In-vitro-hæmning af histaminfrigivelse (IC^q, M) fra humane leukocyter (basofiler)In vitro inhibition of histamine release (IC (q, M) from human leukocytes (basophils)
Forbindelse IC™ Forbindelse IC^q n fra Eks. nr. fra Eks. nr.Compound IC ™ Compound IC ^ q n from Ex. No. from Ex. no.
JU 1 11 16 3 2 12 17 80 3 24 19 100 4 53 20 3 5 45 21 14 6 12 22 20 7 4 23 14 35 9 10 24 2 10 3 25 6 11 20 27 3 12 800 28 6 14 28 29 2 15 17 31 4YES 1 11 16 3 2 12 17 80 3 24 19 100 4 53 20 3 5 45 21 14 6 12 22 20 7 4 23 14 35 9 10 24 2 10 3 25 6 11 20 27 3 12 800 28 6 14 28 29 2 15 17 31 4
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Til farmaceutisk anvendelse kan de omhandlede forbindelser gives varmblodede dyr topisk, peroralt, paren-teralt, rectalt eller ved inhalation. Forbindelserne foreligger hertil som aktive bestanddele i sædvanlige præ-5 paratformer, f.eks. i kompositioner, der i det væsentlige består af en indifferent farmaceutisk bærer og en effektiv dosis af det virksomme stof.For pharmaceutical use, the subject compounds may be given warm-blooded animals topically, orally, parenterally, rectally or by inhalation. The compounds are present as active ingredients in conventional formulations, e.g. in compositions consisting essentially of an inert pharmaceutical carrier and an effective dose of the active substance.
Forbindelser med den almene formel I, der anvendes oralt, kan foreligge i form af sirupper, tabletter, kaps-10 ler, piller og lignende. Der foretrækkes kompositioner i enhedsdosisform eller i en form, hvormed patienten kan indtage en enkeltdosis. Tabletter, pulvere eller pastiller kan som blandingsmiddel indeholde et hvilket som helst hjælpestof, der er egnet til sammensætning af fa-15 ste farmaceutiske kompositioner. Eksempler på sådanne hjælpestoffer er forskellige stivelsesarter, lactose, glucose, saccharose, cellulose, calciumphosphat og kalk. Kompositionerne kan også foreligge i form af kapsler (f. eks. af gelatine), der indeholder det virksomme stof, el-20 ler i form af en sirup, en opløsning eller en suspension.Compounds of the general formula I used orally may be in the form of syrups, tablets, capsules, pills and the like. Compositions are preferred in unit dosage form or in a form by which the patient can take a single dose. Tablets, powders or lozenges may contain, as a mixing agent, any excipient suitable for the composition of solid pharmaceutical compositions. Examples of such excipients are various starches, lactose, glucose, sucrose, cellulose, calcium phosphate and lime. The compositions may also be in the form of capsules (e.g., gelatin) containing the active ingredient, or in the form of a syrup, solution or suspension.
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|---|---|---|---|---|
| CA675224A (en) * | 1963-12-03 | Gabler Rudolf | Piperazine derivatives | |
| JPS5914032B2 (en) * | 1976-04-09 | 1984-04-02 | 日本新薬株式会社 | Bistrimethoxybenzylpiperazinoalkanes |
| US4692448A (en) * | 1984-11-20 | 1987-09-08 | Boehringer Ingelheim Pharmaceuticals, Inc. | Bis(arylpiperazinyl)sulfur compounds |
-
1984
- 1984-03-16 GR GR74132A patent/GR81827B/el unknown
- 1984-03-17 DE DE8484102979T patent/DE3478601D1/en not_active Expired
- 1984-03-17 EP EP84102979A patent/EP0122488B1/en not_active Expired
- 1984-03-17 AT AT84102979T patent/ATE43843T1/en not_active IP Right Cessation
- 1984-03-19 FI FI841081A patent/FI80269C/en not_active IP Right Cessation
- 1984-03-19 YU YU48284A patent/YU45598B/en unknown
- 1984-03-20 ZA ZA842037A patent/ZA842037B/en unknown
- 1984-03-20 PH PH30420A patent/PH25216A/en unknown
- 1984-03-20 NZ NZ207554A patent/NZ207554A/en unknown
- 1984-03-20 IL IL71291A patent/IL71291A/en not_active IP Right Cessation
- 1984-03-20 NO NO841078A patent/NO162907C/en unknown
- 1984-03-20 PL PL25263284A patent/PL252632A1/en unknown
- 1984-03-20 IE IE682/84A patent/IE57136B1/en not_active IP Right Cessation
- 1984-03-20 DD DD84261058A patent/DD219642A5/en not_active IP Right Cessation
- 1984-03-20 DK DK160184A patent/DK166022C/en not_active IP Right Cessation
- 1984-03-20 CA CA000450025A patent/CA1218652A/en not_active Expired
- 1984-03-20 HU HU841102A patent/HU191599B/en not_active IP Right Cessation
- 1984-03-20 ES ES530762A patent/ES8505992A1/en not_active Expired
- 1984-03-20 PL PL1984246774A patent/PL141127B1/en unknown
- 1984-03-20 CS CS841960A patent/CS254971B2/en unknown
- 1984-03-20 AU AU25891/84A patent/AU568122B2/en not_active Ceased
- 1984-03-20 PT PT78278A patent/PT78278B/en unknown
- 1984-03-21 JP JP59054152A patent/JPS59176265A/en active Pending
- 1984-03-21 KR KR1019840001447A patent/KR890000487B1/en not_active IP Right Cessation
- 1984-08-27 ES ES535439A patent/ES8600229A1/en not_active Expired
- 1984-08-27 ES ES535438A patent/ES8600228A1/en not_active Expired
- 1984-08-27 ES ES535440A patent/ES8600230A1/en not_active Expired
-
1986
- 1986-03-12 SU SU864027076A patent/SU1568887A3/en active
- 1986-03-12 SU SU864027087A patent/SU1574174A3/en active
- 1986-06-19 YU YU01072/86A patent/YU107286A/en unknown
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| PBP | Patent lapsed |