IE57136B1 - Bis-(piperazinyl or homopiperazinyl)alkanes - Google Patents
Bis-(piperazinyl or homopiperazinyl)alkanesInfo
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- IE57136B1 IE57136B1 IE682/84A IE68284A IE57136B1 IE 57136 B1 IE57136 B1 IE 57136B1 IE 682/84 A IE682/84 A IE 682/84A IE 68284 A IE68284 A IE 68284A IE 57136 B1 IE57136 B1 IE 57136B1
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- piperazinyl
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- C07D403/02—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
- 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
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
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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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- C07D295/04—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
- C07D295/06—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 halogen atoms or nitro radicals
- C07D295/073—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 halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents 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
- C07D295/08—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
- C07D295/084—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
- C07D295/088—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 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
- C07D295/08—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
- C07D295/084—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
- 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
1. Bis-(piperazinyl- or homopiperazinyl) alkanes of the general formula I see diagramm : EP0122488,P21,F1 wherein R1 , R2 , R3 and R4 which may be identical to or different from each other, are each hydrogen, alkyl having 1 to 4 carbon atoms, hydroxyl, alkoxy having 1 to 4 carbon atoms, alkanoyloxy having up to 4 carbon atoms, halogen, trihalomethyl, di-C1-4 alkylamino, C1-4 alkoxycarbonyl, nitro, cyano or acyl having 1 to 3 carbon atoms ; R5 and R6 , which may be identical to or different from each other, are each hydrogen, methyl, hydroxyl, carboxyl, C1-4 alkoxycarbonyl, hydroxymethyl, phenyl or p-chlorophenyl, R7 and R8 are each hydrogen or methyl ; j and k are integers from 0 to 3, their sum being no more than 4 ; m and n are integers from 0 to 3, their sum being no more than 4 ; A is -CH2 - or -CH2 CH2 - ; or R5 and R7 together or R6 and R8 together are oxo, provided k or m is other than O ; or R5 and R7 together and R6 and R8 together are oxo, provided k or m are other than O ; R9 and R10 , which may be the same or different, represent hydrogen or from one to four methyl substituents on the carbon atoms of the piperazine ring (A = -CH2 -) ; R11 , R12 , R13 and R14 , which may be identical to or different from each other, are each hydrogen or methyl ; or R11 and R12 together and/or R13 and R14 together are oxo ; and X is alkylene of 1 to 2 carbon atoms, optionally hydroxy-substituted with the proviso that when A = -CH2 -, R1 to R14 are hydrogen and j, k, m and n are each zero, then X cannot be 1,2-ethylenediol, and physiologically acceptable acid addition salts thereof.
Description
Price 90p i .ib This invention relates to novel bis(piperazinyl or homoplperezinyl) alkane:» and non-toxic acid addition salts thereof, to methods of preparing these compounds and to Pharmaceutical compositions containing them . The above-mentioned compounds may be used as antiallergics and anti-inflammatories· Compounds of the formula wherein n is 2, $, 8, 9 or 10 are described by S. Chiavarelli* P. Mazzeo, F. Costa and A. M. Russo in Farmaco, Ed. Sci. 20, 229 (1965) as having a curare-like activity.
J. van Alpen in Rec. Trav. Chia. 55, 835 (1936) discloses the synthesis of polyamines of the formulae without ascribing a biological activity to them. -2In J. Org. Chem· 24, 764 (1959) C.B. Pollard, W.M. Lauter and M. 0· Nuessle describe the preparation of compounds of the formula r\ /—\ /= -ch2-ch2-ch2-N\_n R wherein It is H, alkyl or halo. No biological properties are ascribed to them· Belgian Patent No. 633,453 discloses compounds of the formula wherein R is halo or alkoxy having antimalarial, anthelmintic and amebicidal properties.
Finally,. M. J. Dorokhova, V. A. Chemow, S. M. Minakova, Ο. Y. Tikhonova and A. N. Zamskaya, Khim.-Farm· Zh., 10, 36 (1976), abstracted in C.A. 85, 78079, describe compounds of the formula wherein n is 2, 3, 6 or 10, as precursors of compounds of the formula VIII below. -3In one aspect, the present Invention provides bi$(piperazinyl or > hoffioptperazinyl) alkanes of formula I Rl (I) wherein Rp Rg, R-j and R4 which may be identical to or different from each other, are each hydrogen, alkyl having 1 to 4 carbon atoms, hydroxyl·, alkoxy having 1 to 4 carbon atoms, alkanoyloxy having up to 4 carbon atoms, halogen, trihalomethyl, di-C^ alkylamino, Cj_4 alkoxycarbonyl, nitro, cyano or acyl having 1 to 3 carbon atoms; Rjj and Rg, which may be identical to or different from each other, are each hydrogen, methyl, hydroxyl, carboxyl, C^4 alkoxycarbonyl, hydroxymethyl, phenyl or p-chlorophenyl; R7 and Rg are each hydrogen or methyl; j and k are integers from 0 to 3, their sum being no more than 4; m and n are integers from 0 to 3, their sum being no more than 4; A is -CH2- or -CH2CH2-; or Rg and Ry together or Rg and Rg together are oxo, provided k or m is other than 0; or Rg and Ry together and Rg and Rg together are oxo, provided k or n is other than 0; Rg and R10, which may be the same or different, represent hydrogen or from one to four methyl substituents on the carbon atoms of the piperazine ring (A » -CH2-); Rp,R12, R13 and R14, which may be identical to or different from each other, are each hydrogen or methyl; or Rjj and R^2 together and/or Rjj and R^4 together are oxo; and X is alkylene of 1 to 2 carbon atoms, optionally hydroxy-substituted with the proviso that when A » -CH2-, Rj to R14 are hydrogen and j, k, a and n are each zero, then X cannot be 1,2-ethylenediol, and physiologically acceptable acid addition, salts thereof. -4Preferred compounds of formula I include those of formula II f7 f—\ N f13 r~\ F8 «12 «14 wherein j, k, m and n are each 0, 1 or 2; R2 and R^ are -H, -Cl, -CH^ or C1-4 alkoxy; Rg, Rg, Rj, Rg as well as R^, R12, R*g, R^ and X are as previously described and physiologically acceptable acid addition salts thereof.
Especially preferred compounds of formula I Include compounds of formula III (ch2> ^11 ?15 F" 2)b (III) wherein Rjj and R^2 are H, or together are oxo; R15 15 H or θ**' R^ and R^ are H, or together are oxo; and a and b are each 1, 2, 3 or 4 and physiologically acceptable acid addition salts thereof. -5but other salts may be useful In the preparation of the free base or of pharmacologically acceptable salts and so are included within the scope of the present invention. Examples of non-toxic, pharma5 cologically acceptable acid addition salts include those formed with a hydrohalic acid, especially hydrochloric or hydrobromic acid, nitric acid, « sulfuric acid, o-phosphoric acid, citric acid, maleic acid, fumaric acid, propionic acid, butyric acid, acetic acid, succinic acid, methanesulfonic * acid, benzenesulfonlc acid, p-toluenesulfonlc acid, or the like.
The process for the preparation of the compound comprises at least one of the following steps: PROCESS A —-— -- Reacting a compound of formula IV ?13 C— I *14 (IV) (wherein Rp , ’ ^3 ^4 snd x are as defined above and Y and Z are groups reactive with amine groups to form a carbon-nitrogen bond, e.g. chloro, bromo, iodo, activated ester, hydroxyl, sulfuric ester, sulfonic ester or the like) with a compound of formula V 1 A~A (V, (CH2)..-C-(CH ,,V-N NH \=/2 \ M-/ 5 5 *a wherein R^, r2. Rg r Ry » Rg » j, k and A ace as defined above : 10 PROCESS B reacting a compound of formula VI (V) CC82):j-C-(CH2,k Λ\ ΐ*3 -Ν Ν—C—X—C—’ Μ-7 I I *12 *14· (VI, wherein R*^, Rj* R^ r R^r Rg, X, j, k and A ,with Λ * * /λ compound of formula are as VII *11' *,2 ' ®I3 ' ®I4 defined above and Y is a reactive group R, . >3 A"\ (CKj^-C-iC^, ϊ-ψ™ *10 (VII) *6 wherein , R^, R^< Rg, R^q, m, u# and A are as defined above ? PROCESS C to prepare compounds of formula I, which is symmetrical about central group X» -7reacting a compound of formula VIII (VIII) wherein Rg , R-jθ tr ^12 * ^13 9 ^14 and A are as defined above with a compound of formula IX (XX) wherein R|, r2, Rg, R?» Y, j, and k are as defined above ; PROCESS 0 to prepare compounds of formula 1 wherein X is a carbinol moiety reacting a compound of' formula X c—c *12 H (X) wherein R^ , R^ , K13 * ^4 are aa defied above, and y has the sare meaning *s in formula IV with a compound of formula VII (as defined above); and Optionally /converting a compound of formula I produced by one of the processes a) to 0) into a physiologically acceptable salt thereof in a manner known per se.
The condensation reactions described in processes (A) to (D) may be performed in the presence or absence of a solvent. Aqueous or organic inert solvents, depending on the nature of the reactants, may be employed. Such solvents include dimethylsulfoxide, dimethylformamide, dioxane, ethoxyethanol and alkanols containing up to five carbon atoms, with or without the addition of water. Aromatic hydrocarbons may also be employed. It is preferred, but not essential, to perform the reaction iri the presence of an acidbinding agent such as triethylamine, and an alkali metal carbonate or an alkali metal hydroxide.
The reaction temperature depends on the starting conpounds and on the solvent which is used for the reaction and lies between ambient temperature and the reflux temperature of the reaction mixture.
The reaction time is temperature-dependent and may be several minutes to many hours.
A compound of formula I in which R§ and/or Rg are hydroxyl is desired, a compound of formula I wherein Rg and R? and/or Rg and Rg -9together are oxo may be hydrogenated with conventional hydrogenating agents, such as sodium borohydride, in a manner known per se to obtain the desired hydroxy-substituted compound. j The starting compounds for process steps (A) to (D) are known compounds or may be prepared by known methods.
Thus, compounds of formula V are described . in British Patent No. 480,358 and J. Am. Chem.Soc., 66, 263 (1944).
The synthesis of compounds of the formula VI is known from numerous publications, such as Helv.Chim.Acta 41, 1072 (1958) or Monatshefte 87, 701 (1956).
Compounds of the formula VIII are disclosed in British Patent No. 480,358 and Khim.-Parm.Zh. , 36 (1976), abstracted in C.A. 85, 78079.
The following compounds are examples of end products of the formula I and their salts which may be prepared by the methods described above: -101.3- BisJ 4- (4-hydroxybenzyl) -1-piperaziny 11 propane tetrahydrochloride, 1.3- Bie{4- (4-chlorobenzyl)-1-piperazinyl) propane tetrahydrochloride/ 1.3- Bis«( 4- (4-chlorobenzyl) -1-piperazinyl] -2-hydroxypropane , 1.4- Bis-i 4 (4-chlorobenzyl) -1-piperazinyl Pbutane hemihydrate, 1.3- Bis- (4-benzy 1-1-piperaziny l>propane tetrahydrochloride, 1.3- BiH4- (4-f luorobenzyl)-1-piperazinyl J-propane-tetrahydrochlor ide , 1.3- Bis4 4- (4-chlorobenzyl) -l-piperazinyl]-l-oxopropane trihydrochloride, 1.3- Bie-{4- (4-chlorobenzyl) -1-piperazinyl]-1-methylpropane tetrahydrochloride hemihydrate, 1.3- Bis-{4- (4-chlorobenzhydryl) -l-piperazinyl)propane dihydrochloride dihydrate, 1- (4- (4-chlorobenzyl)-1-piperazinyl]-3- [4- (2-ethoxycarbonyl2-phenylethyl)-1-piperazinylh>ropane tetrahydro- j I chloride monohydrate, 1- [4- (4-chlorobenzyl) -1-piperazinyl]-3- (4-phenacyl-lpiperazinylFpropane tetrahydrochloride-monohydrate, 1.3- Bi9(4-phenacyl-l-piperazinyl>propane tetrahydrochloride - ! i I monohydrate, i 1.3- Bis44- (2-phenyl-2-hydroxyethyl) -1-piperazinyll - ! i propane tetrahydrochloride, 1.3- Bis44-phenethyl-l-piperazinyl}propane dihydrochloride dihydrate, 1- (4- (4-chlorobenzyl)-1-piperazinyl 1-3-( 4-(2-hydroxy-2- · phenyle thy 1) -1-piperazinyl ^propane-tetrahydrochloride, 1.3- Bis4 4- (4-chlorobenzyl) -1-piperazinyll-l, 3-dioxopropane j dihydrochloride monohydrate, -111.3- Bi®44- (4-chlarophenethyl)-1-piperazinyl] propane» 1.3- BI&44- (l-phenylethyl)-l-piperazinyl}propane tetrahydrochloride, 1.3- Bis44- (4-chlorobenzyl)-2,5-dimethyl-l-piperazinyL]5 propane tetrahydrochloride dihydrate, 1.3- Bis-[4- (4-raethoxybenzyD-l-piperazinyllpropane, 1.3- Bis<4- (3,4-dichloroben«yl) -1-pipefazinyl] propane tetrahydrochloride, 1.3- Bis{4- (2-chlorobenzyl)-1-piperazinyiypropane tetrahydrochloride, 1.3- Bisi 4- (4-aethylhenzyl) -1-piperaziay lVpropane tetrahydrochloride, 1.3- Bia*{4- (3-chlorobenzyl) -l-piperazinyl]pcopane dihydrochloride monohydrate, 1,3-Bis<4- (3-{4-chloxophenyl}propyl) -l-piperazinyllpropane tetrahydrochloride monohydrate, 1.3- Bis-(4- (4-butoxybenzyl)-1-piperazinylVpropane, 1.3- Bie<4- (4-acetoxybenzyl) -l-piperazinyljpropane tetrahydrochloride, 1,3-Bia»{4- (4-bromobenzyl) -l-piperazinyl}?ropane, 1.3- Bis-(4- (4-chloro-3-trif luorome thy lbenzyD-l-piperaainyl]propane tetrahydrochloride 1.3- Bis-[{4- (4-chlorobenzyl) -2,3,5,6-tetramethyl}-lpiperazinyl]propane, 1,3-Bie<4-{4- (4-chlorophenylbutyl) }-l-piperazinyl]propane, 1- [4- (4-chlorobenzyl) -1-piperazinyl] -3-14- (2-carboxy-2phenylethyl)-1-piperazinylJ-propane tetrahydrochloride. -123-Bis-{4- (4-chlorobenzyl) -1-homopiperasinyl{-propane . tetrahydrochloride, 1,3-BiH4- (3-{4-chlorQphenyl}-'propyl)-l-liOTaopiperazinyl] propane tetrahydrochloride, and 1, 3-Bis-l4- (4-chlorobenzyl)-l-homopiperazInyl]-1,3-dioxopropane.
The following examples illustrate the present invention and will enable others skilled in the art to understand it more completely. It should be understood, however, that the invention is not limited solely to the particular examples given below· Example 1 1,3-Sis«(4- (4-chlorobenzyl)—l-piperazinyl|propane tetrahydrochloride A mixture of 10.5 g of 1-(4-chlorobenzy 1)piperazine, 9.5 g of l-bromo-3-chlorppropane, and 100 ml of reagent ethanol was refluxed for 17 hours. The solvent was then removed by rotary evaporation. The resulting oil was mixed with 200 ml of 1M dibasic potassium phosphate. Solid tribasic sodium phosphate was slowly added until the pH rose above 9. This mixture was extracted 5 times with 50 ml portions of ether. The ether was evaporated, and the residue was acidified with 100 ml of 2M phosphoric acid and filtered. The aqueous filtrate was then made basic with 2N sodium hydroxide, again extracted into ether (250 ml) and dried over magnesium sulfate. The product was precipitated with gaseous hydrogen chloride and recrystallized from reagent ethanol/water to give 5.8 g (399 of theory) of -141,3-bis [4- (4-chlorobenzyl)-1-piperazinyl]propane tetrahydrochloride as a white crystalline solid (m.p. 261-274®C, with decomp.).
Example 2 4 1,3-Bis-f 4-(4-chlorobenzyl)-1-piperazinyl)-2- hydroxypropane . ·* A mixture of 4.4 g of epichlorohydrin, 20.1 g of 1-(4-chlorobenzyl)piperazine, 6.0 g of triethylamine and 10 50 g of reagent ethanol was refluxed for 3 days. The solvent was removed from the reaction, mixture by rotary evaporation, and the residue was then made basic with 2N sodium hydroxide 15 r and extracted with ether (5 x 100 ml). The ether extract was dried over magnesium sulfate and evaporated, leaving an oil which solidified on standing. Recrystallization from heptane resulted in the isolation of 18.6 g (82% of theory) of 1,3-bis [4- (4-chlorobenzyl) -1-piperazinyl]-2-hydroxy- propane as a colorless crystalline solid (m.p. 85-86.5°C). 20 Example 3 1,4-B1&J4-(4-chlorobenzyl)-1-piperazinyl^butane hemihydrate A mixture of 2.2 g of 1,4-dibromobutane, 4.2 g of 25 * • 1-( 4-chlorobenzyl) piper azine, 2.8 g of anhydrous potassium carbonate and 20 ml of reagent ethanol was refluxed for 18 hours. The solvent was evaporated under reduced pressure, and the residual oil was heated for 16 hours at 160*C. The product was dissolved in 50 ml of hot water and extracted with ether (3 x 80 ml). The ether extract was -15concentrated to an oil which was chromatographed on a silica column, the eluant being CH2Cl2/CK3OH/amiDonium hydroxide (45:5:1). The resulting brown solid was dissolved in acetone and precipitated with water to give 0.8 g (354 of theory) of 1,4-bis [4-(4-chlorobenzyl)—l-piperazinyl] butane hemihydrate as a white crystalline solid (m.p. 101-103eC).
Example 4 1,3-Bis44-benzyl-l-piperazinylteropane tetrahydrochloride A mixture of 7.0 g of 1—benzylpiperazine, 3.2 g of l-bromo-3-chloropropane, 4.0 g of triethylamine and 100 ml of reagent ethanol was refluxed for 2 ’/ί hours. The reaction mixture was then poured into 1 liter of ether, and the precipitated triethylamine salt was filtered off. The filtrate was evaporated to leave a yellow oil, which was dissolved in 100 ml of heptane and filtered. The solvent was removed by rotary evaporation, and the residue was redissolved in 150 ml of ether. Addition of excess anhydrous hydrogen chloride precipitated 8.8 g (824 of theory) of 1,3-bis (4-benzyl-l-piperazinyl)propane tetrahydrochloride as a white crystalline solid (m.p. 250-265*0.
Example 5 1,3-Bla44-(4-fluorobenzyl)-l-piperazinyltpropane tetrahydrochloride (a) A solution of 29 g of p-fluorobenzyl chloride in 50 g of reagent ethanol was added dropwise tc a stirred solution of 34.5 g of piperazine in 150 g of reagent ethanol. A cold water bath was used to maintain the -16reaction temperature at 20°C during the addition. The reaction mixture was stirred for an additional 1 l/a hours and then added to 2 liters of ether. Precipitated piperazine hydrochloride was filtered off. The filtrate was concentrated to an oil, which was chromatographed on a silica column, the eluant being a mixture of CHjCl^/nethanol/ammonium hydroxide in the ratio of 45:5:1. After concentration of appropriate fractions, 21.7 g of 1-(4-fluorobenzyl)piperazine were isolated as a colorless liquid (561 of theory). (b) A mixture of 5.8 g of 1-(4-fluorobenzyl)piperazine, 3.2 g of l-bromo-3-chloropropane, 4.0 g of trietbylamine and 50 ml of reagent ethanol was refluxed for hours and then poured into 1 liter of ether. The precipitate was filtered off, and the filtrate was evaporated to an oil. This oil was dissolved in 100 ml of ether and precipitated with excess anhydrous hydrogen chloride. Recrystallization from ethanol/water gave 3.3 g (291 of theory) of l,3-bis[4-(4-flnorobenzyl)20 1-piperazinyl]propane tetrahydrochloride as a white crystalline solid (m.p. 228-237°C, with deccrap.).
Example 6 1,3-Bjs-{4- (4-chlord-bensyl)-1-piperazinyl1-125 oxo-propane trlhydroch loride A mixture of 2.0 g of 1-(4—chlorobenzyl)piperazine, 1.0 g of triethylamine, 20 g of xylene and C.8 g of 3bromopropionyl chloride was refluxed fcr 18 hours. The reaction mixture was filtered, and the filtrate was mixed with excess hydrogen chloride-saturated ether until the -17* mixture tested acidic to litmus* The resulting precipitate was filtered off and recrystallized from ethanol/water to yield 1.2 g (45% of theory) of 1,3-bis (4-(4-chlorobenzyl)1-piperazinyll-V-oxopropane trihydrochloride as a white crystalline solid (m.p. 222-250*C, with decomp.)· Example 7 1,3-BisA4-(4-chlorobenzyl)-1-piperazinyl-lmethylpropane tetrahydrochioride hemihydrate A mixture of 7.3 g of 1-(4-chlorobenzyl)piperazine, 2.8 g of 1,3-dibrosaobutane, 11.0 g of triethylamine and 50 ml of reagent ethanol was refluxed for 48 hours. The solvent was removed by rotary evaporation. The residue was mixed with 100 ml of toluene and then refluxed for 24 hours.
The mixture was then poured into 1 liter of ether and filtered. The filtrate was evaporated to an oil, which was chromatographed on silica with C^C^/CH^OH/ammonium hydroxide (45:5:1) as the eluant. The resulting oil was dissolved in 100 ml of ether and precipitated with excess anhydrous hydrogen chloride. This product was dissolved in water and precipitated by addition of acetone to give 1.2 g (11% of theory) of 1,3-bis(4-(4-chlorobenzy1,-1piperazinyl)-l-methylpropane tetrahydrochloride hemihydrate as a white crystalline product (m.p. 228-232*0.
' Example 8 1,3-Bis44-(4-chlorobenzhydryi)-1-piperazinyl]propane dihydrochlpride dihydrate A mixture of 7.4 g of N-(p-chlorobenzhydryl)30 piperazine, 2.0 g of l-bromo-3-chloropropane, 1.6 g of -18triethylamine and 25 g of reagent ethanol were refluxed for 18 hours· The reaction mixture was made basic with 5N sodium hydroxide and extracted with methylene chloride (5 x 50 ml) · The extract was dried over magnesium sulfate, and hydrogen chloride-saturated ether was added until the mixture tested acid to litmus. The precipitated crude 1,3-bis [4-(4chlorobenzhydryl)—1-piperaziny 1 ] propane dihydrochloride dihydrate (2.5 g, 27% of theory) was filtered off. Purification by dissolution in methylene chloride followed by pre10 cipitation by addition of ether resulted in a white crystalline product (m.p. 163-196°C, with decomp.).
Example 9 1-[4-(4-Chlorcbenzyl)—l-piperazinyl]-3-[4-(215 ethoxycarbonyl-2-phenylethyl)—1-piperaziny 11 propane tetrahydrochloride monohydrate (a) A mixture of 1.8 g of ethyl atropate and 0.9 g of piperazine was stirred in a round-bottom flask. When the exothermic reaction abated, the mixture was heated 20 to 80°C and stirred for an additional 20 minutes.
The reaction mixture was then allowed to stand overnight at ambient: temperature^ The resulting solid was chromatographed on a silica column using ether as the eluant, followed by CH^Cl^/CH^OH/ammonium hydroxide 25 (45:5:1). The 1-(2-ethoxycarbonyl-2-phenylethyl)piperazine product (0.75 g, 29% of theory) came off the column with the second eluant and was used in the following step without further purification. -19(b) A mixture of 3.0 g of l-chloro-3- [4-(4-chlorobenzyl)1-piperazinyl)propane, 3.5 g of triethylamine, 3.7 g of l-(2-ethoxycarbonyl-2-phenylethyl) piperazine and 50 ml of reagent ethanol was refluxed for 2 hours and was then poured into 1 liter of ether· The resulting mixture was filtered, and the filtrate was evaporated to an oil. This oil was purified by chromatography on a silica column, the eluant being CH2C12/CH3OH/ammonium hydroxide (45:5:1), to yield 3.0 g of an oil. This oil was dissolved in 150 ml of ether and precipitated with excess anhydrous hydrogen chloride to give 3.4 g of a solid. This product was re-chromatographed on silica using ether as the first eluant, then switching to the above methylene chloride mixture. The resulting product was converted into its hydrochloride as above, dissolved in water and precipitated by addition of acetone, to yield 1.1 g (154 of theory) of 1-[4-(4-chlorobenzyl)l-piperazinyl) -3-14- (2-ethoxycarbonyl-2-phenylethyl) l-piperazinyl]propane tetrahydrochloride monohydrate as a white crystalline product (m.p. 198-2-l°C)· Example 10 1-(4-(4-Chlorobenzyl)-l-piperazinyl)-3-(4-phenacyl1-piperazinyl)propane tetrahydrochloride monohydrate a mixture of 4.1 g of 1-phenacylpiperazine, 5.7 g of l-chloro-3-[4-(4-chlorobenzyl)-l-piperazinyl]propane, 2.6 g of triethylamine and 35 ml of reagent ethanol was refluxed for 5 hours. The solvent was removed by rotary evaporation, 150 ml of water were added, and the mixture was extracted with ether (3 x 150 ml). The ether solution -20was evaporated to an oil, which was chromatographed on a silica column, the eluant being CHgC^/CH^OH/ammonium . hydroxide (45:5:1), to yield crude 1-[4-(4-chlorobenzyl)1-piperazinyl]-3-(4-phenacyl-l-piperazinyl)propane (7.0 g, 50% of theory). This oil was dissolved in 200 ml of ether and precipitated with excess anhydrous hydrogen chloride. The precipitate was then dissolved in water and reprecipitated by addition of acetone to give 1-[4-(4-chlorobenzyl)1-piperazinyl J -3- (4-phenacyl-l-piperazinyl)propane tetra10 hydrochloride monohydrate as a white crystalline product (m.p. 211-218eC).
Example 11 1-14- (4-Chlorobenzyl)—*1-piperazinyl]-3- [4- (2-hydroxy-215 phenylethyl)—1-piperazinyl]propane tetrahydrochloride A solution of 3.0 g of 1-(4-chlorcbenzyl)-lpiperazinyl]-3-(4-phenacyl-l-piperazinyl)propane in 50 ml of reagent ethanol was mixed with 3.0 g of 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 solvents were removed under vacuum, and 50 ml of water were added. The mixture was extracted with ether (3 x 250 ml). The extract was evaporated to an oil, which was chromatographed on a silica column, the eluant being CHgC^/CHgOH/ammonium hydroxide (45:5:1). The fractions containing the desired product were combined and evaporated to an oil, which was dissolved in 100 ml cf ether and precipitated by addition of excess anhydrous hydrogen chloride. The resulting solid was dissolved in water and precipitated with acetone to give 0.65 g (16% of theory) of 1-(4-(4-chlorobenzyl)— 1-piperazinyl] -3- (4- (2-hydroxy-2-phenylethyl)—1-piperazinyl]-21propane tetrahydrochloride as a white crystalline product (m.p. 240-248*C, with decomp.)· Example 12 5 * ’3-Bis^ 4-phenacy 1-1-piperazinyl) propane tetrahydrochloride-monohydrate A mixture of 6.1 g of 1-phenacylpiperazine, 2.4 g of l-bromo-3-chloropropane, 3.1 g of triethylamine and 50 ml of reagent ethanol was refluxed for 3 hours and then evaporated to an oil. Water (250 ml) was added, and the I mixture was extracted with ether (3 x 150 ml). After ; evaporation of the ether, the residual oil was chromato- ’ » graphed on silica, the eluant being CSjClj/CH^OH/ammonium ! hydroxide (45:5:1). The high purity fractions were combined > I and evaporated to an oil, which was dissolved in 150 ml of I ether and precipitated with excess anhydrous hydrogen j j chloride. This solid was dissolved in water and precipitated ί i by addition of acetone to give 1.3 g (14* of theory) of 1,3-bis-(4-phenacy 1-1-piperazinyl)propane tetrahydrochloride monohydrate as a white crystalline product (m.p. 194-204*C).
Example 13 1,3-Bis-t4- (2-phenyl-2-hydroxyethyl)-l- · piperazinyD-propane tetrahydrochloride » I * a solution of 2.5 g of 1,3-bis(4-phenacy1-1piperazinyDpropane in 50 ml of reagent ethanol was mixed ί with 2.5 g of sodium borohydride and stirred for 4 hours. { I Residual sodium borohydride was destroyed by the addition of ! ί ml of acetone, and then the solvents were removed by ι rotary evaporation. Water (SO ml) was added, and the mixture . i s -22was extracted with ether (3 x 150 ml). After evaporation of the ether, the product was chromatographed on silica, the eluant being CI^Cl^/CH^OH/ammonium hydroxide (45:5:1). The resulting oil was dissolved in 100 ml of ether and precipitated by addition of excess anhydrous hydrogen chloride to yield 0.75 g (22* of theory) of 1,3-bis(4-(2phenyl-2-hydroxyethyl)-1-piperazinyl]propane tetrahydrochloride as a white crystalline product (m.p. 233-240®C).
Example 14 1.3- Bi9-(4-phenethy I-1-piperazinyl ^propane dihydrochloride dihydrate A mixture of 5.7 g of 1-phenethylpiperazine, 2.4 g of l-bromo-3-chloropropane, 4.1 g of triethylamine and 30 ml of reagent ethanol was refluxed for 3 hours. 50 ml of water were then added, and the mixture was concentrated to about 40 ml by rotary evaporation. The resulting mixture was extracted with ether (3 x 150 ml), and the extract was evaporated to a brown oil. This oil was dissolved in 150 ml of ether and was precipitated by addition of excess anhydrous hydrogen chloride. The precipitate was dissolved in water and reprecipitated by the addition of acetone to give 3.1 g (37* of theory) of l,3-bis(4-phenethyl-lpiperazinyl)propane dihydrochloride dihydrate as a white crystalline product (m.p. 210-225eC).
Example 15 1.3- Bis-[4-(4-chlorobenzyl)-1-piperazinyl]-1,3dioxopropane dlhydrochloride monohydrate A mixture of 4.2 g of l-(4-chlorobenzyl)piperazine, 1.4 g of malonyl dichloride, 10 g of methylene chloride and -232.0 g of triethylamine was stirred for 60 hours. The reaction mixture was made basic with 2n sodium hydroxide.
The organic layer was separated, and the aqueous phase was extracted with three 50 ml portions of ether, followed by three 50 ml portions of methylene chloride. The organic phases were combined and mixed with 100 ml of 2M hydrochloric acid. The aqueous phase was separated and made basic with 2N sodium hydroxide solution· The resulting oil was collected and chromatographed on silica, the eluant being CHjClj/C^OH/annnonium hydroxide (200:5:1). The appropriate fractions were combined, evaporated to an oil, dissolved in 100 ml of ether and precipitated with excess anhydrous hydrogen chloride. The precipitate was recrystallized from reagent ethanol to yield 1.3 g (22% of theory) of 1,3-bis [4- (4—chlorobenzyl)-1-piperazinyl)-lz 3dioxopropane dihydrochloride monohydrate as a very slightly yellow crystalline solid (m.p. 199-206*0.
Example 16 1,3-Bis-{4- (4—"Chlorophenethyl)-l-piperazinyllpropane A mixture of 6.7 g of 1-(4- chlorophenethyl) piperazine, 2.4 g of l-bromo-3-chloropropane, 3.1 9 of triethylamine and 20 ml of reagent ethanol was refluxed for 3 hours. The reaction mixture was diluted with 50 ml of water and then concentrated to about 50 ml by rotary * evaporation. The resulting mixture was extracted with ether (3 x 150 ml), and the extract was evaporated to give a colorless solid which was recrystallized from heptane to yield 3.3 g (45% of theory) of 1,3-bis(4-(4-chlorophen30 ethyl)-l-piperazinyljpropane as a white crystalline product (m.p. 87-88*0. -24Example 17 1,3-Bis-(4- (1-phenylethyl)—1-plperazinyl ]propane tetrahydrochloride A mixture of 7.6 g of 1-(1-phenylethyl)piperazine, 3.2 g of l-bromo-3-chloxopropane and 50 ml of reagent ethanol was refluxed for 5 hours. The solvent was then removed under vacuum, 75 ml of water were added, and the mixture was extracted with ether (3 x 150 ml).jThe ether extract was evaporated to an oil and chromatographed on silica, the eluant being CHgC^/C^OH/ammonium hydroxide (45:5:1). The resulting yellow oil was dissolved in 150 ml of ether and precipitated with excess anhydrous hydrogen chloride to yield 6.1 g (51% of theory) of 1,3-bis[4-(1phenylethyl) -1-piperazinyl]propane tetrahydrochloride.
The product was recrystallized from ethanol/water to yield a white crystalline solid (m.p. 236-246eC, with decomp.).
Example 18 1,3-Bis[4-(4—chlorobenzy1)-2,5-dimethy1-120 piperazinyll-propane tetrahydrochloride dihydrate (a) A solution of 16 g of p-chlorobenzyl chloride in 75 ml of reagent ethanol was added dropwise to a solution of 25 g of 2,5-dimethylpiperazine in 75 ml of reagent ethanol. The mixture was stirred overnight and then filtered. The solvent was removed from the filtrate by vacuum. The residue was extracted with ether (3 x 350 ml), and the extract was evaporated to an oil and chromatographed on silica, the eluant being C^C^/CH^OH/amraonium hydroxide (45:5:1). This yielded 9.1 g (38% of theory) of 1-(4-chlorobenzyl)-2,5-25 dimethylpiperazine as a colorless liquid which was used in the following step. (b) A mixture of 6.0 g of 1-(4-chlorobenzy1)-2,5-dimethy1piperazine, 2.0 g of l-bromo-3-chloropropane, 3.2 g of triethylamine and 50 ml of reagent ethanol was refluxed for 6 hours. The solvent was then removed under vacuum, 50 ml of water were added, and the mixture was extracted with ether (3 x 150 ml) . The extract was then evaporated to an oil and chromatographed on silica, the eluant being CHjClj/CH^OH/ ammonium hydroxide (45:5:1). The product was dissolved in 150 ml of ether and precipitated with excess anhydrous hydrogen chloride. The precipitate was dissolved in water and reprecipitated by addition of acetone to give 0.7 g of l,3-bis[4-(4-chlorobenzyl)2,5-dimethy1-1-piperazinyl ] propane tetrahydrochloride dihydrate as a white crystalline product (m.p. 204214*C).
Example 19 1,3-Bis-[4- (4-methoxyben2yl)-l-piperazinyll propane A mixture of 4.1 g of 1-(p-methoxybenzyl)piperazine, 1.6 g of l-bromo-3-chloropropane, 25 ml of reagent ethanol and 2.5 ml of triethylamine was refluxed for 5 hours. The resulting mixture was evaporated under vacuum, and the residue was mixed with 25 ml of water and extracted with ether. The extract was evaporated to a yellow oil which solidified on standing. Recrystallization twice from heptane resulted in 2.3 g (51% of theory) of l,3-bis(4-(4-methoxybenzyl)-l-piperazinyl]propane as a white crystalline solid (m.p. 86-87*0. -26Example 20 1,3-Bis-(4-(3,4—dichlorobenzyl)-1-piperazinyl) propane tetrahydrochioride A mixture of 5.2 g of 1-(3,4-d±chlorobenzyl)~ piperazine, 2.2 g of 1-bromo-3-chloropropane, 3.0 g of triethylamine and 20 g of reagent ethanol was refluxed.
After 1 hour an additional 0.06 g of 1-brorao-3-chloropropane was added, and after another hour another 0.06 g of the dihalide was added. The mixture was refluxed over10 night and then evaporated under vacuum to yield a gummy solid which was mixed with 150 ml of ether and filtered.
The filtrate was dried over magnesium sulfate. Hydrogen chloride-saturated ether was added to the filtrate until the mixture remained acidic when tested with litmus.
The resulting precipitate was dissolved in a minimum amount of water. Concentrated hydrochloric acid was then added dropwise, forming a heavy precipitate. Addition was continued until no further precipitation occurred. Filtration and drying under vacuum resulted in 4,5 g (444 of theory) of l,3-bis[4-(3,4—dichlorobenzyl)-1-piperazinyl]propane tetrahydrochioride as white needles (m.p. 245-251’C, with decomp.).
Example 21 25 1,3-Bis 14- (2—chlorobenzyl)-l-piperazinyl)propane tetrahydrochioride 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 reagent ethanol was refluxed overnight. The solvent was evaporated under vacuum, and the residue was -27mixed with 150 ml of ether and filtered. The filtrate was dried over magnesium sulfate. Hydrogen chloride-saturated ether was then slowly added to the dry filtrate until the resulting mixture tested acidic to litmus. The resulting precipitate was filtered off, dried and weighed. This yielded. 6.1 g (50% of theory) of crude 1,3-bis[4-(2-chlorobenzyl)1-piperazinyl]propane tetrahydrochloride. Recrystallization from ethanol/water yielded a white crystalline solid (m.p. 251-255°C)· Example 22 1,3-Bis-[4- (4—methylbenzyD-l-piperazinyl]propane tetrahydrochloride A mixture of 5.7 g of l-(4-methylbenzyl)piperazine, 2.4 g of l-bromo-3-chloropropane, 25 ml of reagent ethanol and 3.0 g of triethylamine was refluxed for 5 hours. The solvent was removed under vacuum, and the residue was mixed with 40 ml of water. The resulting aqueous mixture was extracted with ether (3 x 150 ml). Evaporation of the ether resulted in a light yellow oil which solidified on standing. This product was dissolved in 50 ml of ether, and hydrogen chloride-saturated ether was added until the mixture tested acidic to litmus. The resulting precipitate was dissolved in 20 ml of water, and acetone was added until product ceased coming out of solution. This yielded 5.8 g (68% of theory) of l,3-bis[4-(4—methylbenzyl)-l-piperazinyl]propane tetrahydrochloride as a white crystalline product (m.p. 245-252*C, with decomp.). -28-.
Example 23 1.3- Bis (4- (3-chlorobenzyl) -l-piperazinyl ] propane dihydrochloride -monohydrate A mixture of 6.3 g of 1-(3-chlorobenzyl)piperazine, 2.4 g of l-bromo-3-chloropropane, 50 ml of reagent ethanol and 3.0 g of triethylamine was refluxed for 4 hours. Water (70 ml) was added, and the mixture was concentrated under vacuum to about 70 ml. The resulting aqueous mixture was extracted with ether (3 x 150 ml), and the extract was concentrated under vacuum to give a reddish-yellow oil.
Chromatography of this oil on a silica column, the eluant being C^C^/CH^OH/ammonium hydroxide (45:5:1), resulted in an oil which was dissolved in 50 ml of ethanol. Hydrogen chloride-saturated ether was added to this solution until the mixture tested acidic to litmus. The resulting precipitate was filtered off, dried and weighed to yield 5.6 g (68* of theory) of 1,3-bis[4-(3-chlorobenzyl)-l-piperazinyl] propane dihydrochloride monohydrate. Recrystallization from water gave a white crystalline solid (m.p. 248-257°C, with deconrp·).
Example 24 1.3- Bis[4-(3-{4-chlorophenyl)propyl)~l-piperazinyl] propane tetrahydrochloride monohydrate (a) A mixture of 40.6 g of 3-(4-chlorophenyl)propyl chloride, 130.0 g of anhydrous piperazine and 550 ml of reagent ethanol was refluxed for 2 hours. Solvent was removed under vacuum and the residue was chromatographed on silica with the eluant being CUgClz/CHjOH/ammonium hydroxide (45:5:1). Appropriate , -2930 fractions were combined, concentrated to an oil, mixed with 1400 ml IN HCl and filtered· The filtrate was brought to pH 10 with concentrated aqueous NaOH and then extracted with ether (4 x 200 ml). The extract was dried over MgSO* and stripped to an oil which solidified on standing. The resulting 1-(3-(4chlorophenyl)propyl]piperazine (m.p. 54-62*C) was used without further purification (b) A mixture of 7.2 g of 1-(3-(4-chlorophenyl)propyl] piperazine, 2.4 g of l-hromo-3-chloropropane, 3.5 g of triethylamine and 30 ml of reagent ethanol was refluxed for 6 hours. The solvent was then evaporated under vacuum, and the residue was mixed with 40 ml of water and extracted with ether (3 x 150 ml). The extract was then evaporated to a yellow oil which was chromatographed on a silica column, the eluant being CH2Cl2/CH3OH/ammonium hydroxide (45:5:1). This resulted in 4.6 g (59% of theory) of 1,3-bisI4-(3-{4-chlorophenyl Ipropyl) -1-piperazinyl] propane as a colorless oil. Part of this oil (3.0 g) was dissolved in 100 ml of ether, and hydrogen chloride-saturated ether was added to this solution until the resulting mixture tested acidic to litmus. The resulting precipitate was dissolved in 25 ml of water, and acetone was added until precipitation appeared complete. This resulted in 2.7 g (41% of theory) of 1,3-bis (4-(3-(4-chlorophenyl }propyl) -1-piperazinyl]propane tetrahydrochloride monohydrate as a white crystalline solid (m.p. 245246°C, with decomp.). *30* Example 25 β 3-Bis-t 4-(4—chloro-3-trlfluororoethylbenzyl) 1-piperazinyl ^propane tetrahydrochioride A mixture of 11.5 g of 3-chloro~4-trifluoromethyl5 benzyl chloride, 5.3 g of 1,3-bis (1-piperazinyl)propane, g of reagent ethanol and 7.0 g of triethylamine was refluxed for 16 hours. The reaction mixture was evaporated under reduced pressure, and the residue was mixed with 150 ml of water. The resulting mixture was extracted with ether (5 x 100 ml). The combined extracts were washed with 1M sodium carbonate solution (3 x 100 ml). The resulting ether solution was dried over magnesium sulfate, filtered and evaporated to a yellow oil (6.8 g). This oil was dissolved in 100 ml of hexane and filtered. The filtrate was extracted three times with 20 ml of aqueous 2% acetic acid each. The product was found by TLC to be localized in the second and third extracts. These were combined, made strongly basic with 2N NaOH and extracted with 100 ml ether/hexane (1:1). The extract was dried over anhydrous potassium carbonate and then evaporated. The residual oil (2.6 g) in 10 ml of methanol, upon treatment with 30 ml of hydrogen chloride saturated ether, yielded a white precipitate. An additional 50 ml of ether was added and the precipitate was filtered off and recrystallized from methanol to yield colorless crystalline 1,3-bis(4- (4chloro-3-trifluoromethylbenzyl)-1-piperazinyl]propane tetrahydrochioride (m.p. 265-268°C, with decomp. >250eC). -31Example 26 1,3-Pis44-(4-hydroxybenzyl)-l-piperazinylTpropane A mixture of 4.5 g of 1,3-bis[4~(4-methoxybenzyl)~lpiperazinyl]propane from Example 19 and 125 ml of 49* hydro5 bromic acid was refluxed for 2 hours and was then cooled and diluted with 125 ml of water. After filtration the aqueous solution was neutralized with 2N sodium hydroxide to adjust the pH to 8. The resulting mixture was extracted three times each with 150 ml of ethanol. The alcohol was then removed by rotary evaporation and the residue was chromatographed on silica with the eluant being methylene chloride containing 1* ammonium hydroxide and 10* methanol to obtain 1.3 g (31* of theory) of 1,3-bisI4-(4-hydroxybenzyl)-l-piperazinyl]propane as a white crystalline product, melting at 197-201*C. t Example 27 1,3-Bis44-(4-bromobenzy 1)-l-piperazinyl^propane tetrahydrochloride A mixture of 3.8 g of 1-(4-bromobenzyl)piperazine, g of ethanol, 1.2 g of l-bromo-3-chloropropane and 1.6 g of triethylamine was refluxed for 18 hours. The solvent was then removed by rotary evaporation and the residue was mixed with 50 ml of water and sufficient 2N sodium hydroxide to bring the pH above 10. The resulting mixture was extracted twice with ether (75 + 25 ml) and the combined extract was then washed twice with 25 ml of water, dried over MgSO4 and filtered. To this solution was then added HCl-saturated ether until the mixture remained acidic and the resulting precipitate was filtered off and was mixed with 100 ml of -32ethanol. The mixture was brought to reflux and water was added dropwise to the refluxing mixture until a solution was formed. Cooling resulted in the crystallization of the product and filtration yielded 4.2 g (81% of theory) of 1,3-bis(4-(4-broroobenzyl)-1-piperazinyl]propane tetrahydrochloride as- a white crystalline product melting at 237-243eC.
Example 28 1,3-Bis^4-(4-οΗ1οη#>6ηζγ1)-1-Ηοπιορ1ρβΧΒζΐην11ρχορΒηβ tetrahydrochloride A mixture of 4.5 g of 1-(4-chlorobenzyl)homopiperazine, 1,6 g of l-bromo-3-chloropropane and 20 g of ethanol was refluxed for 18 hours. The solvent was removed under vacuum and the mixture was extracted three times with ether (75 ml each) and the extract was evaporated to an oil. This oil was chromatographed on a silica column with the eluant boing methylene chloride containing 0.5% concentrated ammonia hydroxide and 2.5% methanol. The fractions containing the product were combined, evaporated to an oil, dissolved in ether and filtered. The resulting ether solution was mixed with hydrogen chloride-saturated ether until the mixture tested acidic to litmus. The resulting precipitate was dried to obtain 1.4 g.(22% of theory) of product which after crystallization from aqueous ethanol resulted in 1,3-bis[4-(4-chlorobenzyl)-1-homopiperazinyl] propane tetrahydrochloride as a white crystalline product, melting at 218-224qc {decomp.). -33Example 29 1,3-Bis-[4- (4-f4-chlorophenYl)butyl)-l-piperazinyllpropane tetrahydrochloride (a) A mixture of 26.4 9 of 4-(4-chlorophenyl)butyl chloride, 86.1 9 of anhydrous piperazine and 250 ml of reagent ethanol was refluxed overnight. Solvent was evaporated from the product and the residue was chromatographed twice on silica with the eluant being CH2Cl2/CH3OH/annnoniuni hydroxide (45:5:1). The first chromatography removed the bulk of the excess piperazine, the second provided 15.2 g of 1-[4-(4chlorophenyl)butyl]piperazine as a colorless oil which solidified on standing (m.p. 139-145*0 15 (b) A mixture of 1.5 g of l-[4-(4-chlorophenyl)butyl] piperazine, 0.5 g of l-bromo-3-chlor©propane, 0.7 g of triethylamine and 10 g of reagent ethanol was refluxed overnight. After addition of 3.5 ml of 2N NaOH, solvent was removed under vacuum. The residue was extracted with methylene chloride and the extract was chromatographed on silica with the eluant being CHjClj/CH^OH/ammoniura hydroxide (90:10:1). The product fractions were concentrated to an oil and dissolved in ether. HCl-saturated ether was added precipitating 0.7 g (31%) of 1,3-bis[4-(4-{4<-chlorophenyllbutyl)-1-piperazinyl]propane tetrahydrochloride as a light tan solid. Recrystallization from ethanol/water gave a white crystalline solid (m.p. 213-217°C decomp.). -34Example 30 1,3-Bis-H- (4-ace toxyben zy 1)-1-piperazinyl ]-propane A mixture of 2.0 g of 1,3-bis [4-(4-hydro^benzyl)1-piperazinyl] propane (Example 26), 1.0 g of pyridine and 50 g of acetic anhydride was stirred overnight et ambient temperature. The product mixture was concentrated under vacuum to an amber oil which was mixed with 100 ml of pH 8 phosphate buffer and extracted with ether (3 x 100 ml).
The extract was dried over MgSO4 and stripped to a white solid. Recrystallization from heptane yielded 1.9 g (78%) of 1,3-bis [4-(4-acetoxybenzyl)-l-piperazinyl]propane as a white crystalline solid m.p. 102-105*C.
Example 31 1,3-Bis«t4- (4-butoxybenzyl)-1-piperazinyl Tpropane tetrahydrochioride A mixture of 1.0 g of l,3-bis[4-(4-hydroxybenzyl)1-piperazinyl]propane (from example 26), 10 ml of 2H NaOH, 0.2 g of tetrabutylammonium hydroxide (40% in water) and 5.0 g of 1-bromobutane was heated on a steam bath for 3 hours. The mixture was then extracted with ether (3 x 75 ml), dried over MgSO4 and evaporated to a colorless oil which solidified on standing. This product was dissolved in 100 ml of ether and HCl-saturated ether was added until precipitation was complete'. Filtration resulted in 1.4 g (91% of theory) of 1,3-bis(4-(4-butoxybenzyl)-1-piperazinyl]propane tetrahydrochioride as a white solid. Recrystallization from reagent ethanol/water resulted in a white crystalline product (m.p. 207-218*0. -35Example 32 1,3-B1&44-(4-chlorobenzyl-2r3,5,e-tatraaethyl-lpiperazinyl)propane tetrahydrochloride A mixture of 1-(4-chlorobenzyl)-2,3,5,6-tetramethyl piperazine, 1 g of l-bromo-3-chloropropane, and 1 g of triethylamine is heated under reflux in 20 ml of ethanol for 24 hours and the reaction mixture is evaporated under reduced pressure to an oil. The residue is dissolved in water and extracted with ether. The ether extract is washed with water and dried over magnesium sulfate. The product is precipitated from the ether solution by precipitation with excess ethereal hydrogen chloride and crystallization from ethanol to provide 1,3-bis[4-(4chlorobenzyl )-2,3,5,6-tetraxnethyl-l-piperazinyl ] propane tetrahydrochloride as a white crystalline solid.
Example 33 1- [ 4- (4-chlorobenzyl) -1-piperazinyl j - 3- [ 4- (2-carboxy2- phenylethyl)-1-piperazinyl] propane tetrahydrochloride A suspension of 340 mg of 1-[4-(4-chlorobenzyl)-1piperazinyl]-3- [4- (2-ethoxycarbonyl-2-phenylethyl) -1piperazinyl] propane tetrahydrochloride in 10 ml of ethanol was treated with 1 ml of aqueous 5M sodium hydroxide and heated under reflux for 1 hour. The reaction mixture was evaporated to dryness under reduced pressure. The residue was mixed with IN hydrochloric acid (3 ml) and the resulting mixture extracted with ether (2 x 10 ml). The extract was discarded and the pH of aqueous phase adjusted to 5.5 with IN hydrochloric acid. Aqueous saturated sodium chloride solution (10 ml) was added and the mixture extracted with -36butanol (2 x 10 ml). The butanol extract was filtered and treated with excess ethereal hydrogen chloride. The white precipitate was collected and recrystallized from aqueous ethanol to yield 1- [4- (4-chloxobenzyl)-1-piperaziny1]-35 14- (2-carboxy-2-phenylethyl)-l-piperazinyl]propane tetrahydrochloride (140 mg, 40% yield) as a white crystalline solid (m.p. 230-245*C decomp.)· Example 34 1,3-BiaH 4- (3-{4-chlorophenyl }propy11 -l-hamopiperazinyl]propane tetrahydrochloride A mixture of 3.8 g of l-(3-(4-chlorophenyl)propyl] homQpiperazine, 1.2 g of l-bramo-3-chloropropane, 1.8 g of triethylamine is heated under reflux in 10 ml of ethanol for 18 hours and the reaction mixture evaporated to dryness under reduced pressure. The residue is mixed with water and extracted with ether. The ether extract is evaporated and the residue chromatographed on silica gel [CH2C12/CH3OH/NH4OH (35:5:1)1. The resulting oil is dissolved in ether and the product precipitated with excess ethereal hydrogen chloride. Crystallization from ethanol provides 1,3-bis (4-(3-{4-chlorophenylJpropyl)1-homopiperazinyl] propane tetrahydrochloride as a crystalline solid. -37Exainple 35 lf 3—Bis-{4— (4-chlorobenzyl)-1-homopiperazinyl ]1,3-dioxopropane dihydrochloride 0.7 g of malonyl dichloride is added at once to a solution of 2.2 g of l-(4-chlorobenzyl)homopiperazlne and g of triethylamine in 10 ml of methylene chloride at room temperature and the reaction mixture heated under reflux for one hour and then evaporated under reduced , pressure. The residue is triturated with water and the crude product extracted with methylene chloride and purified by chromatography on silica [C^C^/CH^OH/N^OH (200:5:1)). The appropriate fractions are evaporated, dissolved in ether and treated with excess ethereal hydrogen chloride to obtain 1,3-bis [4-(4-chlorobenzyl)15 1-homopiperazinyl]-1,3-dioxopropane dihydrochloride as a crystalline solid. -38As mentioned above, mediator release from meat cells and basophils has been Implicated in many allergic and inflammatory disorders. The activity of compounds in inhibiting the noncytotoxic exocytosis of such mediators can be evaluated in in vitro models such as the inhibition of mediator release from isolated cellular systems induced by antigen-antibody interaction. The following table shows data obtained in examples of such models to illustrate the biological activity of the compounds of the present invention and the broad scope of their effect.
The cellular systems cited therein are as follows: RPMC: Rat peritoneal mast cell preparation; GPBL: Guinea pig basophil-enriched leukocytes; HBL: Human basophil-enriched leukocytes.
A comparison with the activities of the clinical standards, theophylline and disodium cromoglycate (DSCG) in these systems is also provided. -39» reaction mixture to inhibit 50% of the release of the pharmacological mediators from the target cells.
NT = not tested.
Compounds of the present invention, that is compounds of formula I above and non-toxic, pharmacologically acceptable acid addition salts thereof, have been found to exhibit useful pharmacodynamic properties. More particularly, by virtue of their potent inhibition of mediator release in numerous cell systems they exhibit anti-inflammatory and anti-allergic activities in warm-blooded animals such as rats, and may therefore be useful for the treatment of allergic diseases such as allergic asthma, rhinitis, conjunctivitis, hay fever, urticaria, food allergies and the like. Mediator release from mast cells and basophils has been implicated in many allergic and inflammatory disorders.
For pharmaceutical purposes the compounds according to the present invention may be administered to warm-blooded animals topically, perorally, parent30 erally, rectally or by the respiratory route as active ingredients in customary pharmaceutical compositions, that is, compositions comprising an inert pharmaceutical carrier or excipient and an effective amount of the active ingredient. -41Compounds of formula 1 (and salts thereof) which are active when given by the oral route, may be formulated in the form of syrups, tablets, capsules, pills and the like. Preferably, the compositions are in unit dosage form, or in a form in which the patient can administer to himself a single dose. When the composition is in the form of a tablet, powder or lozenge, any pharmaceutical carrier suitable for formulating solid compositions may be used. Examples of such carriers are various starches, lactose, glucose, sucrose, cellulose, dicalcium phosphate, and chalk. The composition may also be in the form of an ingestible capsule (for example of gelatin) containing the compound; or in the form of a syrup, a liquid solution or a suspension. Suitable liquid pharmaceutical carriers Include ethyl alcohol, glycerin, saline, water, propylene glycol or sorbitol solution, which may be compounded with flavoring or coloring agents to form syrups.
The compounds of this invention may also be adminis tered by other than the oral route. In accordance with routine pharmaceutical procedure, the compositions stay be formulated, for example, for rectal administration as a. suppository or for presentation in an Injectable form in an aqueous or non-aqueous solution, suspension or emulsior in a pharmaceutically acceptable liquid, such as sterile pyrogen-free water or a parenterally acceptable oil or a mixture of liquids, which may contain bacteriostatic agents, antioxidants, preservatives, buffers, or other solutes to render the solution isotonic with the blood, thickening agents, suspending agents.or other pharmaceutically acceptable additives. Such forms may be presented in unit dose forms such as ampules or disposable injection devices or in multi-dose vials such as a bottle from which the appropriate dose' may be withdrawn, or in solid form or concentrate which can be used to prepare an injectable formulation.
Compounds of this invention may also be suitably presented for administration to the respiratory tract as an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an , inert carrier such as lactose. In such a case the particles of active compounds suitably have diameters of less than 20 microns, preferably less than 10 microns. Where appropriate, small amounts of other anti-allergies, anti-asthmatics and bronchodilators, for example, sympathomimetic amines such as isoprenaline, isoetharine, metaproterenol, salbutamol, phenylephrine, fenoterol and ephedrine; xanthine derivatives such as theophylline and aminophylline; corticosteroids such as prednisolone and adrenal stimulants such as ACTH may be included.
Compounds of this invention may also be presented as an ointment, cream, lotion, gel, aerosol or solution for topical application to the skin, nose, or eye. Topical solutions for the nose and the eye may contain, in addition to the compounds of this invention, suitable buffers, -43• 1 toxicity adjusters, microbial preservatives, antioxidants and viscosity-inqpairing agents in an aqueous vehicle.
Examples of agents used to increase viscosity are polyvinyl alcohol, cellulose derivatives, polyvinylpyrrolidone, polysorbates or glycerin. Microbial preservatives added may include benzalkonium chloride, thimerosal,' chlorobutanol or phenylethyl alcohol. Topical preparations for the eye may also be presented as ointments in a suitable inert base consisting of mineral oil, petrolatum, poly10 ethylene glycols or lanolin derivatives, along with j microbial preservatives.
Xn any of the foregoing formulations, a suitable dosage unit may contain from 0.005 to 500 mg of active ingredient. The effective dose of compounds of this invention depends on the particular compound employed, the condition of the patient and on the frequency and route of | administration, but in general it is in the range of from 0.0001 mg/kg to 10 ugAg body weight.
As is common practice, the compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned, in this case as an anti-allergic agent for the prophylaxis and treatment of for example, asthma, hay-fever, rhinitis or allergic eczema.
For the preparation of pharmaceutical compositions, the compounds of formula X or salts thereof are mixed In the usual way with appropriate pharmaceutical « carrier substances and aroma, flavoring and coloring materials and formed, for example, into tablets or * i capsules or, with the addition of appropriate adjuvants, suspended or dissolved in water or in an oil, for example corn oil. -44The compounds of this invention can be administered , orally and parenterally in liquid or solid form. As injection medium, it is preferred to use water which contains the stabilizing agents, solubilizing agents and/or buffers conventionally used for injection solutions. Additives of this type include, for example, tartrate, citrate and acetate buffers, ethanol, propylene glycol, polyethylene glycol, complex formers (such as EDTA), antioxidants (such as sodium bisulfite, sodium metabisulfite or ascorbic acid), high-molecular-weight polymers (such as liquid polyethylene oxides) for viscosity regulation, and polyethylene derivatives of sorbitol anhydrides.
Preservatives may also be added, if necessary, such as benzoic acid, methyl or propyl paraben, benzalkonium chloride or other quaternary ammonium compounds.
Solid carrier materials which can be used include, for example, starch, lactose, mannitol, methyl cellulose, microcrystalline cellulose, talcum, silica, dicalcium phosphate, and high-molecular-weight polymers (such as polyethylene glycol).
Compositions suitable for oral administration can, if desired, contain flavoring and/or sweetening agents.
For topical administration, the compounds of the present invention can also be used in the form of solutions, i powders, or ointments, for which purpose they are mixed with, for example, physiologically compatible diluents or conventional ointment bases. -45The following examples illustrate a few pharmacuetical dosage unit compositions comprising a compound of the present invention as an active -46Example 36 Tablets Tablets The tablet composition is compounded from the following ingredients: 1,3-3is[4-(4-chlorobenzyl)-lpiperazinyl]propane tetrahydrochloride 0.010 parts Stearic acid 0.010 " Dextrose 1.890 ** Total 1.910 parts Preparation: The ingredients are admixed in conventional manner, and the mixture is compressed into 1.91 gm-tablets, each of which is an oral dosage unit composition containing 10 mg of the active ingredient.
Example 37 Ointment The ointment composition is compounded from the following ingredients: 1,3-Bis(4-(4-chlorobenzyl)-1piperazinylI-2-hydroxypropane Fuming hydrochloric acid Sodium pyrosulfite Mixture (1:1) of cetyl alcohol and stearyl alcohol White Vaseline Synthetic bergamot oil 2.000 parts 0.011 0.050 .000 .000 0.075 Distilled water q.s.ad 100.000 -47Preparation: The ingredients are uniformly blended in conventional manner into an ointment, 100 mg of which contain 2.0 mg of the active ingredient.
Example 38 Inhalation aerosol The aerosol composition is compounded from the following ingredients: 1,3-Bis [4-(4-chlorobenzyl)-1piperazinyl] -1,3-dioxopropane dihydrochloride monohydrate 1.00 parts Soybean lecithin 0.20 Propellant gas mixture 15 (Freon 11, 12 and 14) q.s.ad 100.00 Preparation: The ingredients are compounded in conventional manner, and the composition is filled into aerosol containers with a metering valve which releases 0.5 to 2.0 mg of active ingredient per actuation of the valve.
Example 39 Hypodermic solution The solution is compounded from the following 25 ingredients: 1,3—Bis(4—(4—chlorophenethyl)—1— piperazinyl]propane dihydrochloride 5.0 parts Sodium pyrosulfite 1.0 a Sodium salt of EDTA 0.5 a Sodium chloride 8.5 a Double-distilled water q.s.ad 100Q.0 a -48Preparation: The individual ingredients are dissolved in a sufficient amount of double-distilled water, the solution is diluted to the indicated concentration with additional double-distilled water, the resulting solution is filtered until free from suspended particles, and the filtrate is filled under aseptic conditions into 1 ml-ampules which are subsequently sterilized and sealed. Each ampule contains 5 mg of the active ingredient.
Example 40 Topical solution (ophthalmic or nasal) The solution composition is compounded from the following ingredients: 1,3-Bis(4-(4-chlorobenzyl)-1piperaziny1]-2-hydroxypropane tetrahydrochloride 0.020 parts Disodium hydrogen phosphate 0.758 * Dihydrogen sodium phosphate 0.184 R Sodium chloride 0.365 1» Polyvinyl alcohol 3.500 W ’ Benzalkonium chloride 0,010 N Distilled water q.s.ad 100.000 w Preparation: * The ingredients are dissolved in the conventional manner to form an aqueous solution. The solution is appropriately filtered, with the ophthalmic solution requiring sterile filtration. Each ml of the solution contains 0.2 mg of the active ingredient. -49Any one of the other compounds embraced by formula X or a non-toxic, pharmacologically acceptable acid addition salt thereof may be substituted for the particular active ingredient in Examples 36 -to 40. Likewise, the amount of active ingredient in these illustrative examples may be varied to achieve the dosage unit range set forth above, and the amounts and nature of the inert pharmaceutical ' carrier ingredient may be varied to meet particular require-
Claims (18)
1. Bis-(piperaziny1- or homopiperazinyl) alkanes of the general formula I Rp R 2 , Rg and R 4 which may be Identical to or different from each other, are each hydrogen, alkyl having 1 to 4 carbon atoms, hydroxyl, alkoxy having 1 to 4 carbon atoms, alkanoyloxy having up to 4 carbon atoms, halogen, trihalomethyl, di-Cj_ 4 alkylamino, C^ 4 alkoxycarbonyl, nitro, cyano or acyl having 1 to 3 carbon atoms; Rg and Rg, which may be identical to or different from each other, are each hydrogen, methyl, hydroxyl, carboxyl, Cj_ 4 alkoxycarbonyl, hydroxymethyl, phenyl or p-chlorophenyl; Rj and Rg are each hydrogen or methyl; j and k are integers from 0 to 3, their sum being no more than 4; m and n are integers from 0 to 3, their sum being no more than 4; A is -CH 2 - or -CH 2 CH 2 -; or Rg and R? together or Rg and Rg together are oxo, provided k or m is other than 0; or Rg and R? together and Rg and Rg together are oxo, provided k or m is other than 0; Rg and R 10 , which may be the same or different, represent hydrogen or from one to four methyl substituents on the carbon atoms of the piperazine ring (A - -CH 2 -); ft ll ,R 12' R 13 and R 14' *hich may be identical to or different from each other, are each hydrogen or methyl; or R n and R 12 together and/or R 13 and R 14 together are oxo; and -51X Is alkylene of 1 to 2 carbon atoms, optionally hydroxy-substituted with the proviso that when A » -CH^-, Ry to R 14 are hydrogen and j, k, m and n are each zero, then X cannot be 1,2-ethylenediol, and physiologically acceptable acid addition salts thereof.
2. A compound according to claim 1 of formula II ? 7 fn ?13 f8 wherein j, k, a and π are each 0, 1 or 2; R 2 and R^ are -H, -Cl, -CH^ or C|_ 4 alkoxy; Rg, Rg, Ry* Rq as well as R^, R^ 2 , *14 X are as set forth In claim 1, and physiologically acceptable acid addition salts thereof.
3. A compound according to claim 1 of formula 111 *14 (III) wherein R n and R| 2 are H, or together are oxo; R|g Is K or OH; R 13 and R 14 are Η, or together are oxo; and a and b are each 1, 2, 3 or 4, and phylologlcally acceptable acid addition salts thereof. <
4. l,3-bis[4-(4-chlorobenzy1)-l-piperaz1nyl] propane and the physiologically acceptable acid addition salts thereof. -52•A
5.. l,3-bis[4-(4-cblorobenzy1)-l-p1perazinyl]-2-hydroxy-propane and the physiologically acceptable acid addition salts thereof.
6. l,3-bis[4-(4-chlorobenzyl)-l-piperazinyl]~l,3-d1oxo-propane and 5 the physiologically acceptable acid addition salts thereof.
7. l,3-bis[4-(4-chlorophenethyl)-l-piperazinyl]propane and the physiologically acceptable acid addition salts thereof. 10
8. l,3-b1s[4-(3-[4-chloropheny1]propyy1)-l-piperazinyl]propane and the physiologically acceptable acid addition salts thereof.
9. A process for the preparation of b1s-(piperazinyl- or homopiperazinyl) alkanes of general formula I according to claim 1, wherein a) to prepare symmetric compounds of formula I a compound of general formula IV ?n ^13 y—c—x—c— (IV) *14 wherein R 12 » R^, R 14 and X are as defined in claim 1 and Y and Z are reactive groups is reacted with a compound of formula V «7 I A~\ (CK*)NK 2 3 I 2 * V| / Ri «3wherein Rp R 2 , R^, R?, Rg, j, k and A are as defined in claim 1; b) reacting a compound of formula VI «5 T 12 »a fn p3 N—C—X—C—Y I *14 (V) (VI) -53wherein R p R k and A are compound of 2* Rg. R 7 . Rg. R U . R 12 , R 13· R14. X. j. as defined in claim 1 and Y is a reactive group with a formula VII wherein Rp R 4 , Rg, Rg, R^, m, n and A are as defined in claim 1. c) (to prepare compounds of fonnula I, which is symmetrical about central group X) reacting a compound of formula VIII R-π Λλ Ι υ Γ χ Λλ KN N—C—X—C—N NH I Vl7 (VIII) 12 V *10 wherein Rg, R 1Q , Rp, Rp, ^13^14» end A are as defined in claim 1 with a compound of formula IX (IX) Ri wherein Rp R^, Rg, Rp Y, j and k are as defined in claim 1 or d) (to prepare compounds of formula I wherein X is a carbinol moiety) reacting a compound of formula X •4 IiZv’' 13 I “I I *12 H R h (X) wherein R n»»i2 r Rjg and Rj 4 are as defined in clain 1 and Y has the same meaning as in formula IV, with a compound of formula VII and optionally converting a compound of formula I produced by one of the processes a) to d) into a physiologically acceptable acid addition salt thereof in a manner known per se.
10. A pharmaceutical preparation, containing as active Ingredient a compound of the general formula ft . JU *13 . [· Rj Rg R12 «14 »10 in which Rp R 2 , R3 and R 4 can be the same or different and are hydrogen, an alkyl group containing 1 to 4 carbon atoms, hydroxy, an alkoxy group containing 1 to 4 carbon atoms, an acyloxy group containing 1 to 4 carbon atoms, halogen, trihalomethyl, di-(Cj_ 4 alkyl) amino, Cj_ 4 a1koxycarboriyl, nitro, cyano or acyl containing 1 to 3 carbon atoms, Rg and Rg can be the same or different and are hydrogen, methyl, hydroxy, carboxy, Cj_ 4 alkoxycarbonyl, hydroxymethyl, phenyl or p-chlorophenyl; Ry and Rg are hydrogen or methyl; j and k are integers from 0 to 3, their sum being no more than 4; m and n are integers from 0 to 3, their sum being not more than 4; A is -CH 2 - or -CH 2 CH 2 -; or Rg and Ry together or Rg and Rg together are oxo, with the proviso that k or m is not zero or Rg and Ry together and Rg and Rg together are oxo provided that k and m are other than 0; Rg and Rjg are the same or different, and are hydrogen, or one or more methyl substituents on thecarbon atoms of a piperazinyl ring (A -CH 2 -); - 55 Rjp R 12 > R n an d R i4 are the saee or different, are hydrogen or Rjj and Rj2 together and/or R 13 and R J4 together are oxo and 5 X is an alkyl chain with 1 to 2 carbon atoms optionally substituted by hydroxy, or a physiologically acceptable acid addition salt thereof, in combination with a conventional carrier or excipient. 10
11. A pharmaceutical preparation containing as an active ingredient a compound according to claim 10, in combination with a further pharmacologically active substance and a conventional carrier or excipient. 15
12. A process for the preparation of a pharmaceutical preparation according to claim 10, wherein a compound according to claim 10 and a conventional galenic carrier or excipient are worked into a conventional pharmaceutical form. 20
13. A process for the preparation of a pharmaceutical preparation according to claim 11, wherein a compound according to claim 10 in combination with another pharmacologically active substance,and a conventional carrier or excipient, are worked into a conventional pharmaceutical form.
14. The use of a compound according to claim 10, in the production of a pharmaceutical preparation for the treatment of allergic reactions and inflammations in warm-blooded animals. * 1 30
15. A process for the preparation of (bis-piperazinyl- or homopiperazinyl) alkanes of general formula I substantially as hereinbefore described with reference to any of Examples 1 to 35.
16. . Bis-(p1peraziny1- or homopiperazinyl) alkanes of general formula 35 I whenever prepared by a process as claimed in claim 9 or claim 16. -5617.
17.A process for the preparation of a pharmaceutical preparation containing as active ingredient a compound of the general formula I substantially as hereinbefore described with reference to any of Examples 36 to 40.
18. A pharmaceutical preparation containing as active ingredient a compound of general formula 1 whenever prepared by a process as claimed l in any of claims 12, 13 or 17.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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US47700883A | 1983-03-21 | 1983-03-21 |
Publications (2)
Publication Number | Publication Date |
---|---|
IE840682L IE840682L (en) | 1984-09-21 |
IE57136B1 true IE57136B1 (en) | 1992-05-06 |
Family
ID=23894132
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IE682/84A IE57136B1 (en) | 1983-03-21 | 1984-03-20 | Bis-(piperazinyl or homopiperazinyl)alkanes |
Country Status (24)
Country | Link |
---|---|
EP (1) | EP0122488B1 (en) |
JP (1) | JPS59176265A (en) |
KR (1) | KR890000487B1 (en) |
AT (1) | ATE43843T1 (en) |
AU (1) | AU568122B2 (en) |
CA (1) | CA1218652A (en) |
CS (1) | CS254971B2 (en) |
DD (1) | DD219642A5 (en) |
DE (1) | DE3478601D1 (en) |
DK (1) | DK166022C (en) |
ES (4) | ES530762A0 (en) |
FI (1) | FI80269C (en) |
GR (1) | GR81827B (en) |
HU (1) | HU191599B (en) |
IE (1) | IE57136B1 (en) |
IL (1) | IL71291A (en) |
NO (1) | NO162907C (en) |
NZ (1) | NZ207554A (en) |
PH (1) | PH25216A (en) |
PL (2) | PL252632A1 (en) |
PT (1) | PT78278B (en) |
SU (2) | SU1574174A3 (en) |
YU (2) | YU45598B (en) |
ZA (1) | ZA842037B (en) |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4692448A (en) * | 1984-11-20 | 1987-09-08 | Boehringer Ingelheim Pharmaceuticals, Inc. | Bis(arylpiperazinyl)sulfur compounds |
JPS645287Y2 (en) * | 1984-11-20 | 1989-02-09 | ||
CA2180190A1 (en) * | 1995-07-10 | 1997-01-11 | Kazumi Ogata | Benzylpiperazine derivatives |
EP1057815B1 (en) * | 1998-02-19 | 2007-09-05 | Kowa Co., Ltd. | Cyclic amide compounds |
US6897305B2 (en) * | 1998-06-08 | 2005-05-24 | Theravance, Inc. | Calcium channel drugs and uses |
US7101909B2 (en) | 1998-10-12 | 2006-09-05 | Theravance, Inc. | Calcium channel drugs and uses |
DK1179341T3 (en) | 1999-05-18 | 2006-03-27 | Teijin Ltd | Medicines or preventive agents for diseases associated with chemokines |
CN1192773C (en) * | 1999-08-04 | 2005-03-16 | 帝人株式会社 | Cyclic amine CCR3 antagonisis |
US6849621B2 (en) * | 2001-03-13 | 2005-02-01 | Schering Corporation | Piperidine compounds |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 YU YU48284A patent/YU45598B/en unknown
- 1984-03-19 FI FI841081A patent/FI80269C/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 HU HU841102A patent/HU191599B/en not_active IP Right Cessation
- 1984-03-20 PH PH30420A patent/PH25216A/en unknown
- 1984-03-20 CA CA000450025A patent/CA1218652A/en not_active Expired
- 1984-03-20 ES ES530762A patent/ES530762A0/en active Granted
- 1984-03-20 ZA ZA842037A patent/ZA842037B/en unknown
- 1984-03-20 IL IL71291A patent/IL71291A/en not_active IP Right Cessation
- 1984-03-20 PT PT78278A patent/PT78278B/en unknown
- 1984-03-20 AU AU25891/84A patent/AU568122B2/en not_active Ceased
- 1984-03-20 CS CS841960A patent/CS254971B2/en unknown
- 1984-03-20 NZ NZ207554A patent/NZ207554A/en unknown
- 1984-03-20 DK DK160184A patent/DK166022C/en not_active IP Right Cessation
- 1984-03-20 PL PL1984246774A patent/PL141127B1/en unknown
- 1984-03-20 DD DD84261058A patent/DD219642A5/en not_active IP Right Cessation
- 1984-03-21 KR KR1019840001447A patent/KR890000487B1/en not_active IP Right Cessation
- 1984-03-21 JP JP59054152A patent/JPS59176265A/en active Pending
- 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 SU864027087A patent/SU1574174A3/en active
- 1986-03-12 SU SU864027076A patent/SU1568887A3/en active
- 1986-06-19 YU YU01072/86A patent/YU107286A/en unknown
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
MM4A | Patent lapsed |