CA1218652A - Bis-(piperazinyl or homopiperazinyl)-alkanes - Google Patents

Abstract

ABSTRACT

Bis(piperazinyl or homopiperazinyl) alkanes Compounds of formula I

(I) wherein R1, R2, R3, R4, R5 and R6, which may be identical to or different from each other, are each hydrogen, alkyl of 1 to 4 carbon atoms, hydroxyl, alkoxy of 1 to 4 carbon atoms, alkanoyloxy of upto 4 carbon atoms, halogen, trihalomethyl, di(lower alkyl of 1 to 4 carbon atoms)-amino, (alkoxy of 1 to 4 carbon atoms)-carbonyl, nitro, cyano or alkanoyl of upto 3 carbon atoms;
R7 and R8, which may be identical to or different from each other, are each hydrogen, methyl, hydroxyl, carboxyl, (alkoxy of 1 to 4 carbon atoms)-carbonyl, hydroxymethyl, phenyl or p-chlorophenyl;
R9 and R10 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 R7 and R9 together or R8 and R10 together are oxo, provided k or m is other than 0; or R7 and R9 together and R8 and R10 together are oxo, provided k and m are other than 0;
R11 and R12, which may be the same or different, represent hydrogen or, when A represents a group -CH2-, each represents from one to four methyl substituents on the carbon atoms of the piperazine ring;
R13, R14, R15 and R16, which may be identical to or different from each other, are each hydrogen or methyl, or R13 and R14 together and/or R15 and R16 together are oxo; and X is alkylene of 1 to 2 carbon atoms, optionally hydroxy-substituted) and acid addition salts thereof. The compounds as well as their pharmacologically acceptable salts are useful as antiallergics and anti-inflammatories.

Description

This invention re]ates to novel bis~pi.perazinyl or homopipera-zinyl~alkanes and non--toxi.c acid addition salts thereof useful as anti-allergics and anti-inflammatories, and to methods of prepari.ng these com-pounds.
Compounds of the formula ~ C~l2N~ /-(C~l2)n~N\---/Nc 2 wherein n is 2, 6, 8, 9 or 10 are described by S chiavarelli, P. Mazzeo, F. Costa and A. M. Russo in :Earmaco, Ed. Sci. 20, 229 (1965) as having a curare-like activity.
J. van Alpen in Rec. Trav~ Chim. 55, 835 (1936) di.scloses the synthesis of polyamines o:E the formulae ~ 2 2 C~2-NH-CH2-CH2-CH2-NH-CH2_CH -NH CH

and ~ r--~I r-~
~ 2 N ~ N-cH2-cll2-cll2-N N-C~I

w.ithout ascri.bing a biological activity to them.

i.i''~ - 1 -- -2~ 6S~

In J. OrgO Chem. 24, 754 (1959) C.B~ Pollard, W~M. Laute~ and N. 0. Nuessle describe tne preparation of compounds OL the formula R ~ ~ J N C12 CH2 C~2 N N ~ R

wherein R i5 H, alkyl or halo. No biological pr~perties are ascribed to them.
Belgian Patent No. 633,453 discloses compour.ds of the formula Y ~ N N CX2-CX2-C~

li wh~rein ~ is halo or alkoxy having antimalar al, anthelm~n~ic and amebicidal proper~ies.
Finally,~M. J. Dorokhova, V. A. Chernow, S. M.
Minakova, O. Y. Tikhonova and A. N. Zamskaya, Khim.-Farm.
Zh~, 10, 36 (1976?, abstracte~ in C.A. 85, 78079, describe compounds o~ the formula ~ I~\N- (CH2) n~N~I~--c~

.~ wherein n is 2, 3, 6 or 10, ~5 as precur30rs of compounds of the formula VIII below.

s~

In one aspect, the present invention provides bi,s(piperazinyl or homopiperaziny])alkanes of formula I

2 ~ (CH2)j-C-(cH2)k-u~ ~-C- X- C- N~ ~-(CH2) -C-(CH

Rll 12 (I) wherein Rl, R2, R4 and R5, which may be identical to or different from each other, are each hydrogen, alkyl of 1 to 4 carbon atoms, hydroxyl, alkoxy of 1 to 4 carbon atoms, alkanoyloxy of up to 4 carbon atoms, halogen, trihalomethyl, di(lower alkyl of 1 to 4 earbon atoms)amino, (alkoxy of 1 to 4 carbon atoms)carbonyl, nitro, eyano or alkanoyl of up to 3 carbon atoms;
R7 and R8, which may be identical to or different from each other, are each hydrogen, methyl, hydroxyl, carboxyl, (alkoxy of 1 to 4 carbon atoms)carbonyl, hydroxymethyl, phenyl or p-chlorophenyl;
R9 and Rlo 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 R7 and Rg together or R8 and Rlo together are oxo, provided k or m is other than 0; or R7 and Rg together and R8 and Rlo together are oxo, provided k and m are o-ther than O;
Rll and R12, which may be the same or different, represent hydrogen or, when ~ represents a group -CH2-, each represents from one to four methyl substituents on the carbon atoms of the piperazine ring;
R13, R14, R15 and R16, which may be identical to or different from each other, are each hydrogen or methyl; or R13 and Rl4 together and/or Rl5 and Rl6 together are oxo; and X is alkylene of l to 2 carbon atoms, which is unsubstituted or is substituted by hydroxy, with the proviso that when Rl, R2, R4, R5~ R7~ R8~ Rg~ Rlo~ Rll~ Rl2' 13' 14 Rl5 and Rl6 are each hydrogen, A is -CH2- and j, k, m and n are each 0, X cannot be 1,2 ethylene diol; and pharmaceutically acceptable acid addition salts thereof.
Preferred compounds of formula I include those of formula II

19 ~ Rl3 Rl5 RllO

2 ~ ~CH2)j-C-(C~I2)k_ ~ N~C--X--Ci N~ N (CH2)m IC (C 2 ~ R5 (wherein jl k, m and n are each 0, 1 or 2;

8~

R2 and R5 are -H, -Cl, -CH3 or lower alkoxy, e.g.
methoxy;
R7 and Rg are both hydrogen, or when k is other than O
one is hydrogen and the other is hydroxyl, or when j and k are O
one is hydrogen and the other is phenyl or p-chlorophenyl or when k is other than O together they are oxo;
13' R14, R15 and R16, which may be the same or different, are each -H or - 4a --CH3, or R~3 and Rl~ together and/or Rl5 and R16 together are oxo;
R8 and Rlo are both hydrogen, or when m is o-ther than 0 one is hydrogen ~md the other is hydroxyl, or one is hydrogen and the other is phenyl, p-chlorophenyl or -COO(alkyl of 1 to 4 carbon atoms), or when m is other than O together they are oxo; and X is alkylene of 1 to 2 carbon atoms, optionally hydroxy-sub-stituted) and pharmaceutically acceptable acid addition salts thereof.
Especi.ally preferred compounds of formula I include compounds :l0 of formula III

Cl ~ (CH2) -N N - f _ Cil~ N N-~CH2)b- ~ Cl R14 R16 (III) (wherein R13 and Rl4 are H, or together are oxo;
R17 is H or OH;
R15 and R16 are H, or together are oxo; and a and b are each 1, 2, 3 or ~) and acid addition salts thereof.
The compounds of formulae I, II and III may possess asymmetric carbon atoms and thus may exist in a number of stereoisomeric forms; all such forms and mixtures thereof are deemed to fall within the scope of the 2 n present invention.
The compounds of formulae I, II and III are basi.c and therefore form addition salts with inorganic or organic acids. Of such salts, non-toxic, pharmaceutically acceptable salts are of course intended as the final product of the inven-tion but other salts may be useful in the preparation of the free base or of pharmacologically acceptable salts.
Examples of noi~-toxic, pharmaceutically acceptable acid addition salts in-clude those formed with a hydrohalic acid, especially hydrochloric or hydro-bromic acid, nitric acid, su].furic acid, o-phosphoric acid, citric acid, maleic acid, fumaric acid, propionic acid, butyric acid, acetic acid, suc-cinic acid, methanesulfonic acid, benzenesulfonic acid,p -toluenesulfonic acid, or the like.
In a further aspect, the invention provides a process for the preparation of compounds of formula I and pharmaceutically acceptable acid addi.tion salts thereof, the process comprising:
(A) (to prepare compounds of formula I wherein Rl, R2, ~9 j, R7, R9, k and Rll are the same as R4, R5, ~, n9 R~, Rlo, m and R12, respectively) reacting a compound of formula IV

R R

Y C - X-- C - Z (IV) (wherein R13, Rl~, R~5, R16 and X are as defined above and Y and Z are groups reactive with amine groups to form a carbon-ni-trogen bond, e.g.
chloro, bromog iodo, activated ester, hydroxyl, sulfuric ester, sulfonic ester or the li~e) with a compound of formula V

~8~

2 ~ (CH2)j-C-(cH2)k~ NH (V) R7 Rll (wherein Rl, R2, R7, Rg, Rll, j, k and A are as defined above);
(B) reacting a compound of formula VI
R]

2 ~ (CH2)j-C-(cH2)k-N ~ C- X - f -y (VI) R7 Rll 14 16 (wherein Rl, R2, R7~ Rg, Rll~ R13~ R14~ R15~ 16' A are as defined above) wlth a compound of formula VII

1 IRlO A
~ (CH2~n - f -(CH2)m (VII) (wherein R4, R5, R8, Rlor R12, m, n, and A are as defined above);
(C) (to prepare compounds of formula I wherein Rl, R2, j, R7, Rg and k are the same as R~, R5, n, R8, Rlo and m, respectively) reacting a compound of formula VIII

H~ ~N- C -X--C- N NH (VIII) ~J I I ~
¦ 14 16 R

~, - 7 -6~

n Rll' R12' R13, R14, R15, R16, X and A are as defined above) with a compound of formula IX

2 ~ (CE12)~ (CH2)k (IX) (wherein R1, R2, R7, Rg, Y, j and k are as defined above);
(D) (to prepare compounds of formula I wherein X is a carbinol moiety) reacting a compound of formula X

~ - 8 -R13 /\ ~R15 y - c - c~c l~ 18 Rl6 (wherein Rl3, Rl~, Rl5, Rl6 and Y are as defined above, and Rl8 is hydrogen or lower alkyl, e.g. Cl 4 alkyl) with a compound of formula VII (as defined above);
(E) to prepare a compound of formula I wherein R7 and/or R8 are hydroxyl, hydrogenating a compound of formula I wherein R7 and R9 together and/or R8 and Rlo together are oxo; and, if required, converting a salt of a compound of formula I into the free base or converting the compound of formula I into a pharmaceutically accep-table salt.
The condensation reactions described in steps (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, ethoxy-ethanol 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 reac-tion in the presence of an acid-binding agent such as triethylamine, and an alkali metal carbonate or an alkali metal hydroxide.
The reaction temperature depends on the starting compounds and ~0 on -the solvent which is used for the reaction and lies between ambient temperature and the reflux temperature of the reaction mixture. The reac-tion time is temperature-dependent and may be several minutes to many hours.
In cases where a compound of formula I or II in which R7 and/or R8 are hydroxyl is desired, a compound of formula I wherein R7 and R9 and/or R8 and Rlo 9 _ , 8~

together 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. The free hydroxyl group may subsequently be alkylated or acylated by conventional methods if desired.
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 (194~).
The synthesis of compounds of the formula VI is known from numerous publications, such as 15 Helv.Chim.Acta 41, 1072 ~1958) or Monatshefte 37, 701 (19~6).
Compounds of the formula VIII are disclosed in British Patent No. 480,358 and Khim.-Farm.~h.
10, 36 (1976), abstracted in C.A. 85, 78079.
The following compounds are examples of end products of the formula I and their sal~s which may be prepared by the methods described above:

1,3-Bi~[4-(4-hydroxyben~yl~ piperazinyl3propane te~ra-hydrochloride, 1,3-~is~4-(4-chlorobenzyl)-1 piperazinyl.]propane tetra-hydrochloride, 1~3~Bis~4-(4-chlorobenzyl)~l piperazinyl]~-hydrox~-propane, 1,4-Bis~4-(4- hlorobenzyl)-l-piperazinyl~butane hemihydra~e, 1,3-Bis~4-benzyl~l-piperazinyl~pxopane tet-ahydrochloride, 1,3-Bis{~-~4-1uo.oben~yl~ pip~raz~nyl~propane t2tra 1 n hydrochloride, 1,3-Bis~4-~4-chlorobenzyl)-1-piperazinyl3-1-oY~opropane trihydrochloxide, 1,3-Bis~4-(4-chlorobenzyl)-1-piperazinyl3-1-methylpropan~ -.etrahydroch~oride h ~ihydrate, 1~3-Bi~-~4-~4-chlorobenzhydry~ oipex~2inyl~propane dihydrochlor de dihydrate, 1-[4-~4-chlorobenzyl)-1-piperazinyl~-,-[4-(~-e-~hoxycarbonyl-2-phenylethyl)-1 piperazinyl}propane te~rahydro-chloride monohydrate, 1-~4-(4-chlorobenzyl)-l-pipera2inyl]-3-(4-pnenacyl~
pipPrazinyl~propane tetrahydrochloride-monohydrate, 1,3-Bi~(4 phenacyl-l-piperazin~l~propane tetrahydrochlorids -monohydratQ~ i 1,3~ 4-(2-phenyl-7-hydroxye hyl) l-~iperazinyl]-~5 propane tetrahydrochloride, , L,3-Bi~(4-ph~nethyl-1-piperazin~l~propane dihvdrochloride dihydrate, 1-[4-(4-chlorobenzyl)-1-piperazinyl~ 3-E4-~2-hYdroxY~
phenylethyl)-i-piperazinyl~ropane ~etrahydrochloride, 1,3-Bi~E4-(4-chlorobenz 1)-1-pipera~in~1]-1,3 dio~opropane dihydrochloride monohydra~e, 1,3~Bi s~E4- (4- chlorophenetnyl~ piperazinyllpropane, 1~3-Bis~4~ phenyle~hy~ -piperazi~yl}propane tetra-hydrochlori~e, l,3-Bis~4-(4-chloro~enzyl3-2,S-dimethyl-l-pipera2inyl3-S propane tetrahydrochloride dihydra~e, l,3~Bis-~4-(4-methoxyhenzyl~ pipera3inyl~p~opa~e, 1,3-Bis-L4-~3,4-dichlorobenzyl)-1 piperazinyl~propane tetrahydrochlcride, 1,3-Bis-~4-~2-chlor~benzyl) ~ ipera7i~yl~pr~pane 1~ te~rahydrochloride, 1,3-Bi~E~-(4-.methylbenzvl)-1 piperazinvl~propane tetrahydro~hloride, 1,3-B.~{4~3-chloro~enzyl)-1-piperazin~lLpropane dihydrochloride monohydrate, 1,3-Bis-r4-~3-~4-chlorophenyl~propyl)-7-piperazinyl}propane tetrahydrochloride monohydrate, l,3-Bi~[4-(4-~utoxybenzyl~ pipera2inylrpropane, 1,3-Bi~4-(4-acetoxybenzyl~ l-p~perazinyl}propane tetrahydrochlorid?, 1,3-Bi~4~(4-bromobenzyl)-1-piperazinyl~ropane, 1,3-Bis-[4-(4-chloro-3-trifluoro~ethylbenzyl)-1-piperazinyl~-propane tetrahydrochloride 1,3-Bis~{~-(4-chlorobenzyl)-~,3,~5-'e'-~methyl} 1-pipera2inyl~propane, 1~3-Bi3-~4-~4-(4-chlorophenylbutyl)}-l-piperazinyi,prcpane, 1-[4-(4-chlorobenzyl~-1-pipeLazinyl~-3-~4-~2-carboxy~2-phenylethyl)-l-pipe_azinvl,Lpropane ~etrahydrochloxide, -13- ~2~

1,3-~is~4-~4-chlorobenzyl)-l-homopiperazinyl}pro~ane tetrahydrochlori~e, 1,3-Bi~4-(3-~4-chloropnen~l}-proDyl~ homopiperaz~yl]
propane tetrahydrochloride, and l/3-Bis~4-(4-chlorobenzyl)-l homopipera~inyl3-1,3-dioxo-propane.

5~

Particularly preferred compounds of the invention include:
(a) 1,3-bis[4-(4-chlorobenzyl)-1-piperazinyl]propane;
(b) 1,3-bis[4-~4-chlorobenzyl)-1-piperazinyl]-2-hydroxy-propane;
(c) 1,3_bis14-(4-chlorobenzyl)-1-piperazinyl]-1,3-dioxo-propane;
(d) 1,3-bis[4-(4-chlorophenethyl)-1-piperazinyl]propane;
(e) 1,3-bis[4-(3-[4-chlorophenyl]propyl) l-piperazinyl]-propane; andacid addition salts, especially non-toxic pharmaco-logically acceptable salts, thereofO
Compounds of the present invention, that ;s 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, parent-erally, rectally or by the respiratory route as active ingredien~s in customary pharmaceutical compositions, that is, compositions comprising an inert pharmaceutical carrier or excipient and an effective amount of the active ingrediPnt.
Thus in another aspect, the invention provides pharmaceutical composi~ions comprising a compound of formula I or a pharmacologically acceptable ~ z~- 15 -acid additi~on salt thereof together with at least one pharmaceutical carrier or excipient.
Compounds of formula I (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 oarriers are various starche~, lactose, glucos~, 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 f~avoring or coloring a~ents to form syrups.
The compounds of this inven~ion may also be adminis tered by other than the oral route. I~ accordance with 2S routine pharmaceutical procedure, the compositions may be formulated, for example, for rectal administration as a suppository or for presentation in an injectable form in an a~ueous or non-aqueous solution, suspension or emulsior 5~

in a pharmaceutically acceptable liquid, ~uch as sterile pyrogen free water or a ~arenterally acceptable oil or a mixture of liquids, whic~l may contain bacteriostatic agents, antioxidants, preser~atives, buffers, or o~hex solutes to render the solu~ion isO~QniC with ~he blood, thickening agen~s, suspending agents. or other pharmaceut~cally acc pt~
able addi~ivesO Such forms may be presented iTl unit dose ~orms such as ampules or disposable injection devices ur in mu-lti-dose vials such as a bot~le from which the appropriate dose may be wi~hdrawn, or in solid form or concentra~e which can be used te prepare an injectable formul~tion.
Compounds of this invention may also be suitably presented for administr~tion to the respiratory trac~ as an aerosol or solu.ion for a nebulizer, or as a microfine powder for insufflation, alone or in combination wi h an inert ca~--er such as lactose. ~n such a cas~ the particles of active compounds suitably have diameters of less than ~0 microns, preferably less than 10 microns. Where approp-riate, small amounts of other anti-alle~gics, anti-as~hmatics and bronchoailators, for example, sympathomimetic amines such as isoprenaline, isoetharine, metaproterenol, salbutamol, phenylephrine, ~enoterol and ephedrine; xan~hine derivati~es such as theophylline and aminophylline; cor~icoste~oids such as prednisolone and adrenal sti~.ulants such as ACT~
may be included.
Co~pounds o 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 o~ this inver.tion, suitabl~ bufers, toxicity adjusters, micro~ial preservatives, a1ltioxidants and viscosity-impairing agents in an aqueous vehicle~
Examples of agen~s used ~o increase viscosity are polyvinyl alcohol, cellulose derivatives, pol~vinylpyrrolidone, polysorba~es or glycerin. Micr~bial preservatives added may include benzalkonium chloride, thimerosal, chloro-butar.ol or phenylethyl alcohol. Topical preparations for the eye may also be presented as ointments in a suitable inert base consisting of mineral oil, pe~rolatum9 poly-ethylene glycols or lanolin deriva~i~es 9 along with microbial preservati~es.
In any of the foregoing formulations, a suitab~e dosage unit may contain fxom 0~005 to 500 mg of active ingredien~. The effective dose of compounds of this lS invention depends on the particular compound employed, the condi,ion of the patient and on the frequer.cy and route of administration, but in general it is in the range of from O.OOOl mg/kg to lO mg/kg body weight~
As is common practice, the composi~ions will usually be accompanied by written or printed directions for use in the medical tr~atment concerned, in this case as an anti-allergic agent for the prophylaxis and treatment of ~or example, asthma, hay-fever, rhinitis or allergic eczema.
For the preparation of pharmaceutical compositionsr 2~ the compounds of formula I or salts thereof are mixed in the usual way with appropriate pharmaceutical carrier substances and aroma, flavoring and coloring materials and formed t for example, into tablets or capsules or, with the addition of appropriate adjuvants, suspended or dissolved in water or in an oil, for example corn oil.

6~

The compounds of this inv2ntion can be administer~d orally and paren~erally in liquid or solid formO As injection medi~m, it is preferred to use water which contains the stabilizing agents, solubilizing agents and/~r ~uffers conventionally used ~or injec~lon solutions. Addi~ives 5 of this type include, for example, tartra~e~ citr~te an~
acetate buffers, ethanol, propylene glycol r polyethylene glycoly complex formers (such as EDTA~, antioxidants (such as sodium bisulfite, sodium metabisulfite or ascorbic acidj, high-mol~-ular-weight polymers 5such as li~uid 10 polyethylene oxides) for v.scosit~ regulation, and poly-ethyler.e derivativQs of sor~itol anhydrides.
Preservati~es may also be added, if necessary, such as ben~oic ac~d ! methyl or propyl paraben, benzalkonium chloride or other ~uaternary a~monium compounds.
Solid carrier materials wnich can be used include, for example, starch, lactose, mannitol, methyl cellulose, microcrystalline cellulose, talcum, ailica, dicalcium phosphate, and high-molecular-wei~ht polymers ~such as polyethy~ene glycol).
>O Compositions suitable for orai administration can, i ~esired, contain flavorinq and~or sweetenin~ agents.
For topical adminis~ration, the compounds of ~he pxes2n~
invention can also be used in the form of solu~ions, ipowders, or ointments, for which purpose they are mixed 25 with, for e~ample, physiologically compatible diluents or conventional ointment bases.

~z~

In a yet further aspect, the invention provides a method of supressing allergic reactions or inflammation in a warm blooced animal which method comprises administering to said animal an effective anti-allergic or anti-inflammatory amount of a compound of formula I or a pharmacologically acceptable acid a~dition salt thereof.
I

The following exampl23 illustrate ~e present invention and will enable others skilled in the ar~ to understand it more completely. It should be understood, how2ver, that t'ne inven,ion is not limi~d solel~ to ~e particular examples given below.

Example 1 15 . 1,3-~is-~4-(4-chlorobenzyl)~ ipexaziny~l~ro~ane ~etra-hydrochloride A mi~ture o 10 . 5 g of 1- ( 4-chloro~enzyl)-piperazine, 9.5 g o~ 1 ~romo-3-chloropropane, and 150 ml of reagent ethanol was reflu~ed for 17 hours~ The solvent was then removed by rotary evapora~ion. The resulting oil was mi~;ed with 200 ml of lM di~asic potassium phospha~e. Solid tri~asic sodi~m phosphate was 5 lowly added until the pH
rose above 9. This mi~tur~ was extr_ct~d 5 ~imes with 50 m~
portions of ether. The ether was ev~porated, ~nd .he residue was acidi'ied with 100 ml of 2~ phosphoric acid a~.d filtered. The aqueous filtrate was then made basic with 2N sodium hydroxide, again ex~racted int~ ether (250 ml) and dried over magnesium sulfate. The product was precipit-ated ~ith gaseous hydrogen cnloride and recry~tallized from ~0 reagent ethano~/water to gi~Je 5.8 g (39~ o~ _heory) of -20~

173-bis[4~(4-chlorobenzyl)-l-piperazi~yl]p~opane te~ra-hydrochloride as a white crystalline solid (m.p. 261-274~C, with decomp.).

_~ ~
1,3-Bis~4-(4-chloro~enzyl)-1-piperaziny~]-2-hydroxyproF2ne ~ mixture of 4.4 ~ of epichlo~onydrin, 20~1 g of 1~(4-chlorobenzyl~piper~zine, 6.0 g of triethylamine znd 50 g of reager.t ethano' was reflu.~ed for 3 days. ~he soivent was removed from the reaction.mi~ture by ro~a~y evaporation, a~d the residue was t~en made basic w~th 2~ sodium h-dr3xide and extracted with ether (5 x 100 ml)~ The e~her e:~tract was dried over masnesium sulFate and evapora~ed, leavir!g a~
oil wh~ch solidified on stan~ing. Recrystallization ,rom heptane resulted in the isolation of 18.6 g ~82~ of theory) o~ 1,3-bis[4-t4 chlorobenzyi)-l pipera7inyl]-2-hydroxy-propane as a colorless crystalline solid (m.p. 85 86.5C).

Example 3 1~ 4 -Ris~ 4 ~ ( 4-chlorobenzyl)-l-pipera2inyl~butane emihydrate A mixture of 2.2 g of 1,4-dibro~obu~ane, 4.2 g o~
1-~4-chloxobenzyl)piperazine, 2.8 g o~ anhydrous potassi~m carbonate and 20 ml of reasent ethanol was ~e~luxed fo~
18 hours. The solven_ ~las evapor~ted under reduced ~ress~r2, and the residuaL oil was heated for 16 hours at 160C.
The product was dissol~Jed in 50 ~1 of hot wa~er and e~-tracted with ether (3 x 80 ml). The ether extract ~aS

` 21- ~2~5~

concentra~ed to an oil which was cnrom~ograph~d on a silica column~ the eluant being CH2C12~CH3OH/ammonium hydroxide (45:5:1). The resulting brown solid was disso]ved in ac~tone and precipitated with wa~er to give 0.8 g ~35 of theory~) of 1,4-bis~4-(4-chlorobenzyl) ~ l-plperaziny butane hemihydrate as a whi~e crystalline solid (m.p 5 101-103C).

Example 4 1,3-Bis~4-be~zyl-1-piperazinyl)~ropane tetrahydrochloride A mixture of 7~0 g of 1- oen~ylpiperazine, 3.2 g o~ l-bromo-3-chloropropane, 4.0 g of triethylamine and 100 ml of reagent ethanol was refluxed fo-r 21/~ hours. The reaction ~.ixture was then poured in~o 1 liter of ether, a~d the pxecipitated triethylamlne salt was filt~re~ o . T~e filtrate was evapoxated to leave a yellow oil, which ~as dissolved in 100 ml of heptane and filtered. The sol~ent was re~oved by rotary e~-apora~ion, and the residue was re-dissoived in 150 ml of ether. Addition of excess anhy~rous hydrogen chloride precipitated B.8 g (82g~ of ~heory) of 1,3-bis(4-benzyl-1-piperazinyl)propane tetrahyd-ochloride as a white crystalline so.id (m.p. 250~255C).

E:~ample 5 ?5 1 3-~is~ 4-1luorobenzyl)-l-~iperazin~l}~rcpane tetrahydroc~loride (a3 ~ solution of 29 g of p~fluorobenzyl chloride in 50 g of reager.t ethanol was addea dropwise tc a stirred solution of 34.5 g of piperzzine in L50 g of reagent e~nanol. A cold water Dath was used to maintain the -22- ~ 6 ~ ~

reaction temperature at 20C during the addi~ion. The r~action mixtu~e was stirred for an addi~ional 1 l/2 hou~s and the~ ~dded to ~ ers of e~her~ Rrec~pitated piperazine hydrochloride was filtered o~. The ~iltrate was concentrated to an o.il, which was chromatograph~a on a silica column~ the eluant being a mix~ure of C12/me~hanol/zmmoni~m hydroxide in theratio OI
45:5:1. Ater concentration o~ appro~ria~e ractions, 21.7 g of 1-(4-~luoro~e~zyl3piperazine were isola~ed as a colorless li~uid (56% of ~h~orv~.
~b) A mixture of 5.8 ~ of l~ f1uorobe~.~yl)~iperaz ne,

3.2 g o~ l-bromo-~-ch'oropropane, 4.0 ~ of triethyl-amine and 50 ml of reagent ethanol was reflu:~ed for 3 hours and then poured into 1 l~ter o~ e~hex. The lS precipitate was îiltered off, and the filtrat2 was evaporated to an oil. This oil was dissclv~d i~ '~00 ml of ether and precipitated with excess a~hydrous hydrogen chloride. Recrystal ization from ethanol~water 02ve 3.3 g (29~ of thecry) of 1,3-bis[4-~4-fluoroben7yl)-l-piperazinyl]propane ~etrahydrochloride as ~ white crys.alline solid (m.p. 278-237C, with deccmp.).

Exam~le 6 1,3-Bis~4-(4-c;nlor~-ben~yl)-i-piperazi~vll-1-..
~S xo-pro~ne trihydrocnlori~e mixture of 200 g of l-(a- chloroben~ piperazine~
l.a g of t_iethylamine, ~0 g o~ xylene ancl C.8 g or 3 bromopropionyl onlo-ide was re lu~ed fcr 18 hours. The reaction mi~ture was fil,e~ed, and the fi trate ~as m~ed with excess hydrogen chloride-saturated ether un.il the mixture tested acidic to litmus. The res~ ing precipitate was ~iltered off and recrystallized from ethanol/water to yield 1.2 g ~45% of theory) of 1,3-bis[4-(4-chloro~enzyl)-l-piperazinyl]-l-oxopropane trihydrochloriae as a white crystalline so~id ~m.p. ~22-~50C, ~th deccmp.j.

1,3-Bis-E4-~4-chlorobenzyl?-1-p~'pera~ yl-1-.. . ,. _._ , _ , _ methylpropane tetrahvdrochloride hemihydrate .. . _ . _ . . . . . _ A mixture of 7.3 g of 1-~4~chlorobe~zyi)pi~erazine, 2.3 g of 1,3-dibro~obutane, 11.~ y Ol trie'hylamine and 50 ml of reagent ethanol -~as refluxed for 48 hours~ ~he solven~ was removed by rotary evaporation~ The residue was mixed t.~ith 100 ml of toluene an~ ~hen reflux2d for 24 hours.
The mixture was then poured into 1 liter of ether an~
filtered. The f~ltrate was evaporated to an oii, which was chromatographed on silica wi~h CH2C12/C~3O~ammcnium hydroxide (45:5:1~ as the eluant. The resultlng oil was dissolved in 100 ml of ether and precipita~ed wifh excess anhyd~ous ~ydrogen chloride. This produc~ was dissol~ed in water and precipitated by addition of acetone to gi~e 1.2 g (11% o~ theory) or 1,3-~is~4-(4-chlorobenzyl~
piperazinyl]-l-methylprop2ne tetrahydrochloride hemihyd~ate as a white crystalline product (m.p. 228-232C).
Exam~le 8 1,3-Bis~4-(4-chlorobenzh~dryl)-1-piperazinvl~-~ . . _ , , , prop~ne dihydrochloride dih~drate ~ mixture of 7.4 g of N-(p-chlorobenzhydryl)-pi?erazine, 2.0 ~ o- 1-b.romo-3-cnioro?ropane, 1.6 g of trie~hylamine and 25 g of rea~ent ethanol were r~luxed ~or 18 hours. The reaction mixture was made basic with 5N sodium hydroxide and extracte~ with methylene chloride ~5 x 50 ml)O
The extract was dried over magnesium sulfa~e, and hydrogen chloride-sa~urated ether was added un~il the mixture ~est~d acid to litmus. The precipi~a~ed crude 1,3-~is[4-(4-chlorobenzhydryl) - l-piperazinyl]propane dihydrochloride dihydrate t2.5 g, 27~ of theory) was ~il.ered o7. ~urifica-tion b~ dissolution in methylene chloride followed by pre-cipitation by addition of e~her resulied in a white crystall~ne product ~m.p. 163-196C, wit~ decomp.?~

EXample 9 1-~4-(4-Chloro,benzyl~ l~piperazinyl]-3-~4-(2-e~ho~ycarbonyl-2-phenylethyl)- 1 piperazinyl]-propane tetrahydrochloride monohydrate (a) A mixture of 1.8 g of ethyl atropa~e and 0.9 g o p perazine was stirred in a round-bottom flask. When the exothermic reaction abated, the mix~ure was heated to 80C and stirred for an additional 20 minutes.
The reaction mixture was then allowed to stand o~e~night at ambien~ temperature.~ The resulting solid was chromatographed on a silica column using ether as the ~ ~luant/ followed by C'~rI2C12/CH30E~/ammonium hydroxide (45:5:1). The 1-~2-etr.oxycar~onyl-2-pr7envlethyl)~
piperazine product (C.75 g, 29~ or theory) came orf the column with the second e7uant an~ was used in the following step without urther purificatiGn.

~b) A mix~ure of 3.0 g of 1-chloro-3-[4-(4-chlorobenzyl)-l-pipera~inyl)propane, 3 a 5 g Of ~riethylam~ne, 3.7 a o ^~
1-~2-ethoxycarbonyl-2-pheny7ethyl)piperazine and 50 ml o~ reagent e~hanol was refluxed for 2 hou~s and was then poured into 1 liter of ether. The resulting mixture was filtered, and ~he ~i~tra~e was evaporated to an oil. This oil was purified by chromatography on a silica column, ~he eluant being CH2C12/CE3O~am~oni~m hydroxide (45:5:1), to yield 3O0 g of an o~l. mhis oil wa~ dissolved in 150 ml of ether and precipitated hi~h excess anhydrous hy~rogen chl~ride to ~ive 3.4 g or a solidO ~his product was re-chromatographed o~ silic~
usins ether as the first eluant, ~hen switchin~ to the abo~e methylene c~lo-ide mixtureO Tne resul~ing product was converted into its hydrochloride as above, dissol-~ed in water and precipitated by addition of aceton , .o yield 1.1 g (15% of theory) of 1-[4-(4-chlorobenzyl)-l-piperazinyl]-3-~4-(2-ethoxycarbonyl-2-phenylethyl)-l-pipera2inyl]propane tetrahydrochloride monohydrate ~s a white crystalline product (m.p. 198-2-1C).

Example 10 ~- E~l- ( 4-chlorobenzyl)-l-pi~erazinvl]-3-(4-phenacyl-l-piperazlnyl ? propane tetrahy~rcchlor de monohydrate A mi~ture of 4.1 g of l-phenacylpipèrazine, 5.7 g o~ l-chloro-3- [A- (4-chloroDenzyl)-l-piperazinyl~propane~
2.6 g of triethylamine and 35 ml of reagen. e~anol W2S
refluxec for 5 hours. ~he solvent was removed by rotary evaporation, 150 ml cf water were added, and the mixtu~e was ex~racted with ether (3 ~ lS0 ml~. rhe ether solution was evaporated to an oil, wnich was chroma~ographed on a silica column, the eluant bei.ng CH2C12/C~3O~/a~monium hydroxide ~45 5:1), to yield crude 1-[4-54-chlorobenzyl7-l-piperazinylJ-3-(4~phe~acyl-1-pipe~azi~yl)~ro~ane ~7~0 g, 50~ of theory~O This oil was dissolYed in ~G0 ~1 of e~her and pxecipita~ed wi~h exces~ anhydrous hydrogen chloriae.
T~e precipitate was then dissolved in wa~er and reprecipit~
ated by addition o' acetone to give 1- L4- (4-chlorobenzyl)--l-piperazinyl]-3~ phenac~l~l-piperazinyl)propane ~etra-.10 hydrochloride monohydrate as a whi~ crys~311ine pro~uct ~m.p. 211-213C).

Ex~mple_ll 1-[4-(4-Chlorobenzyl) l-pi~erazinyl]-3- r4- (2-hydro~
phenylethyl)~ 1-~iperazinYl~ropane tetrahy~rochl3ride A solution o~ 3.0 g of 1-~4-chlorcbenzyl)-1-piperazinyl]-3-~4-phenacyl-1-piperazinyl)p~opane in _0 m' o~ reagent ethanol was mixed with 3~Q g of sodium boro~
hydride. The mixture was stir~ed for 4 hours, and then the unreacted sodium borohydride was destroyed bv the addition of 25 ml of acetone. The solven-~s ~exe r~moved under vacuum, and 50 ml of water were added. The mixture was extracted ~ith ether (3 x 250 ml). The e:ctract ~as evaporated to an oil, which was chromatographed on a silica column, the eluant being CH2C12/C~3OH/ammonium hyd~o~ide (45:5:1). The fractions containing ~he desired product were com~ined and evaporated ~o an oil, which was dissolved in 100 ml cf ether and precipitated Dy addition or excess anhydrous hydro~en chloride. The resultins solid ~as dissolved in ~ater and precipitated ~.~itn acetone to yive C.6~ g (16~ of tne~ry) of 1-[4-~4~cnlorobenzy~ piper-azinyl)~3-la-(2-hydroxy-2-phenylethyl)- l-p;perazinyl.~--- 2 7~
propane ~etrahydr~chloride as a whi te crystalline product ~m.p. 240-248C, with decomp.).

A mi~ure o 6.1 g o~ l-phenac~lpiperazine, 2-4 g o~ l-bromo-3-chloropropane, 3.1 g OL triethylamine and 50 ml o~ reagent ethanol wais refluxed for 3 hours and ~hen ev2porated to an oil . Water ~ 250 ml~ was adde~, and the mixture was eixtracted with ether ~3 x 1~0 ~.1). A~e~
evaporation of the ether, the re~idual oil was chrsmato-graphed on silica, the eluan~ beiny C~2C12/C~3OHfammoT~- u~.
hydroxide (45:5:1~. The high puri~y fractions were co;r~ined lS and evapora~ed ~o an oil, which wzs disso1~ed in lS0 ml of e~her and precipitated wi~h excess anhydrous hydrogen chloride~ ~his solid was dissolved in water and precipita_ed by addition o~ aicetone to gi~e 1.3 g (14% or theory) o' 1,3-bis-(4-phenacyl-1-piperazir,yl)propane tetrahydrocnloride ~l monohydrate as a white crystalline product (m.p. 194-204C).

Example 13 1,3~Bis-~4-(2-phenyl-2-hydroxyeihyl)-1-piperazinyl3-propane tetrahydrochloride ... . , ___ ;
, A solution of 2.5 g of 1,3-bis(4 phenac~
piperazinyl)propane in 50 ml of reagent ethanol was mii~ed with 2.5 g of sodium borohydrid~ and stirred for 4 hours.
Residual sodiumi borohydride was destroyed by the add~tion of 25 ml of acetone, and then the solvents were removed by ~0 rotary evaporation. ~ater (50 ml) was added, and the mi~:ture -2~
was extracted wi~h ether (3 x 150 ml). A~ter evaporation of the ether~ the product was chromatographed on silica, the eluant being CH2C12/C~3O~/ammonium hy~roxide (45:5 The resultin~ oil was dissolved in 100 ml of ekhe.r ana precipitated by addition o~ excess anhydrous hyd~ogen chloride to yield 0.75 g ~22% o~ ~heory3 of 1,3-bis~4-(2-phenyl-2-hydroxyethyl~ piperazinyl]propane tetrahydro-chloride as a whi~e crystalline product (m.p. 233-240C)~

Example ~4 1,3-Bis-(4-phenethyl-1-piperaz yl)-p~opane dihyarochlo i~ dihvdrate A mixture of 5.7 g of l-phenethylpi~erazine, 2.4 g of l-bromo-3-chloropropane, 4.1 g of triethy,amine and 30 ml o~ reagent ethanol was reflwted for 3 hours. 50 ml of water were then added, and the mixture wa~ concentrated to about 40 ml by ro-tary e~aporation. The resulting mix~ure 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 addit~on oS 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) o 1,3-~is~4-phenethyl-1-piperazinyl)propane dihydrochloride dihydra~e as a white crystalline product (m.p. 210-225C~.

~xamPle 15 -1~3-Bis-E4-(4-c~lorobenzyl?-l~piperaziny~ 3 dioxoproPane dihydrochloride monohvdrate A mixture of ~.2 g of 1-(4-chlorobenz-~l)piperazine, 1.4 g of malonyl dichloride, lC ~ of methylene chloride and 29~
2.0 g of triethylamine was stirred for 60 hours. The reaction mixture was made basic Wl th 2N sodi~ hydroxide.
The organic layer was separa~ed, and the aqueous phase was extracted with three 50 ml portions of et~,er, followea ~y three 50 ml poxtions of methylene chloride~ The organic phases were combined and mixed with 100 ml of 2N hydro-chloric ac~d, T~.~ aqueous phase was separated and made basic with 2N sodium hydroxide solution. The resulting oi' was co11ectea and chromatographed on silica, ~:he el~ant being CH2C12/CH2O~fammonium hy~roxi~e ~200:5:1~. The approp-riate fractions were co~bined, evaporated to an oil, d~s-solved in 100 ml o~ ether and ~recipita~ed ~ith excess anhydr~us hydrogen chloride. The precipitate was re-crystallized from reagent ~thanol to yield 1.3 ~ (22% of theory) ol 1,3-bis[4~ chlorobenzyl)-1-piperazinyl]-i,3-dio~opropane dihydrochloride monohvdrate as a very siightly yellow crystalline solid (m.p. 199-206C).

Example 16 1,3-Bis-E~-(4- chlorophenethy~ piperaziny77propane A mixture of 6.7 g of 1-(4- chlorophenethyl) piperazine, 2.4 g of 1-bromo-3-chloropropane, 3,1 g or triethvlamine and 20 ml of reagent ethanol was re~luxed for 3 hours. The reaction mix~ure was diluked with 50 ml of water and then concentrated to about S0 ml by rotary evaporation. The resulting mi~.x~ure was extracted with ether (3 x 150 ml), and the extract was evaporated to gi~Je a colorless solid which was recrystallized from hep~ane to vield 3.3 g (45~ of theory) of 1,3-bis[4-(4-chlorcpher.-e~hyl)-l piperazinyl3propane as a white crystalline produc~
(~.p. ~7~88C).

-30~
Example 1.7 _ 1,3-Bis-[4~ phen~lethyl)- l~piperazinyl]-A mixture of 7O6 g of l~ phenylethyl)piper~Æine, 3.2 g of 1-bromo-3-chloropropane and 50 ml of rea~ent ethanGl was refluxed for 5 hours. The solvent was then removed under vacuum, 75 ml of water wexe added, and the mixture was ex~racted with ether ~3 x 150 ml~.lThe ether extract was evaporated ~o an oil and ch~oma~ographed on silica, the eluant being C~2C12/C~3OH/ammoniwm hydroxide ~45:3:1). The resulting yellcw oil was dissolved in 150 ml of ether and precipitatea with e~cess anhyd~ous hydrogen chlo-ide to yield 6.1 g (51% of theory) of 1,3-bis[4 (1-~henylethyl) -l-pipe-a~inyl]propane ~etrahydrochloride.
The product was recrystallized from eth2nol~ater to yield a white crystalline solid (m.p. 236-246C, wiLh decom~.).

Exampl~ 18 1,3-Bis~4-(4 -chlorobenzyl?-2,5~di~ethyl~1-piperazinyl]-pro~________ ydrochloride dihydrate ~a) A solution of 16 g of p-chlorobenzyl chloride in 75 ml of reagent ethanol was added dropwice to a solution of 25 g of 2,5-dimethylpiperazine in 75 ml of reagert 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 CH2C12/CH3OH~ammonium hydroxide (45:5:1~. This yielded 9.1 g (38~ of theory) of 1-(4-chloro~enzyl)-2,5-s~

dimethylpipera2ine as a colorless liquid which was used in the follcwing step.
(b) A mixture of 6.0 g o 1 ~4-chlorohenzyl)-2,5-dimethyl-piperazine, 2.0 g o~ 1-bromo-3-chloropropane, 3 n 2 g of ~riethylamine and 50 ml o~ reagent ethanol was refluxed for 6 hours. The solvent was then removed under vacuum, 50 ml o~ water were added, ~nd the mixture was extxacted with ether (3 ~ 150 ml). The extract was then evaporated to an oil and chromato-graphed on silica, ~he eluant being CH2C12/CH3OH/
ammonium hydroxide (45:5:1). The produc~ was dissolved in 150 ml of ether and precipitated with excess anhydrous hydrogen chloride. The precipitate was dissolved in water and reprecipitated by addition oS
acetone to give 0.7 g of 1,3-bis~4-S4-chlorobenz~
2,5-dimethyl-1-piperazinyl~propane tetrahydrochloride dihydrate as a whi~e c~ys~alline product (m p. 204-214C~.

Example 19 1,3-Bis-~ 4-A t4-methoxYbenzyl)-l-piperazinyllpropane A mixtuxe of 4.1 g o~ p-methoxybenzy~)piperazine, 1.6 g of 1-bromo-3-chloropropane, 25 ml of reagent ethanol and 2.5 ml of -triethylamine was refluxea for 5 hours. The resulting mixture was evaporated under vacuum, and the residue was mixed with 25 ml of water and ex~racted with ether. The e~tract was evaporated to a yellow oil which solidified on standing. Recrystalllzation twice from he2tane resulted in 2.3 g (51~ of theor~r) of 1,3-bis~4-~4-methoxy-benzyl)-l-piperazinyl]propane as a white crystalline solid (m.p. 86 87C).

5~
-~32-Example 20 1,3-Bis-l4-(3,4 - dichlorobenzyl)-l-piperazin~
propane tetrahydrochloride A mixture of 5.2 g of 1 (3,4-dichlorobenzyl)-piperazine, 2.2 g of l-bromo- 3-chloro~ropane, 3.0 y o~
triethylamine and ~0 g of reasent ethanol was refluxed~
Ater l hour an additional 0.06 g of l-bromo-3-chloro-propane was added, and a~ter another hour another 0.06 g of the dihalide was added~ The mixture was reEluxed over-night and then evaporated under vacuum to yield a gummy solid which was mixed wi~h 150 ml of ether and filtered.
The filtrate was dried over ma~nesium sulfate~ Hya~ogen chloride-saturated ether was added to the liltrate until the mixture remained acidic when tested with litmus.
The resultin~ pxecipita~e W25 dissolved in a minimum amount of water. Concentrated hydrochloric acid was then added dropwise, formung a heavy precipitate. Addition was con~
tinued until no further precipitation occurred. Filtration and drying under vacuum resulted in 4,5 g (44% of theory) of 1,3-bis[4-(3,4~ dichlorobenzyl3-l-piperazinyl]propane tetranydrochloride as white needles (m.p. 245 251C, with decomp.~.

EXample 21 1,3-Bis[4-(2- chloroben7.yl) l-piperazinyl}propa~e tetrahydrochloride ~ mixture of 8.4 g of l- (2-chlorobenzyl)piperazine, 3.2 g of l-~romo-3-chloropropane, 4.0 g of triethylamine and 30 g of reagent ethanol was reEluxed overnight. The solvent ~as evaporated under vacuum, and the residue was mixed with 150 ml of ether and filtered. The filtrate was dried vver magnesium sulfate. }~ydrogen chloride-sa~tlrated ether was then slowly added to ~he dry :Eiltrate unt~ 1 the resulting mixture tes~ed acidic to litmus. The resulting pxecipitate was filtered o~f, dried and weighed. ~rhiS yielded Ç.l g (50~ of theory) Oc cxude 1,3-bis14-~2 chlorobenzyl)-1 pipera~inylJpropane tetrahydrochloride. Recrystallization from ethanol/water yielded a white crystalline solid (m.p. 251-255C)~
- Example 22 1,3-Bis-E4-{4~ methylbenzyl~ piperazinyl]-propane tetrahydrochloride ___ ~ mlxture of 5.7 g of 1-(4-methylbenzyl)piperazine, 2.4 g of 1-bromo-3-chloropropane, 25 ml o~ reagent ethanol ard 3.0 g of triethylamine was refluxed for 5 hours. The sol~ont was removed under vacuum, and the residue was mixed with 40 ml of water. ~he resulting aqueous mi~ture was ex-tracted with ether ~3 x 150 ml). Evaporation of the ether x~sulted in a light yellow oil which solidified on standing.
This product was dissol~ed in 50 ml of ether, and hydrogen chloride-saturated ether was added until ~he mixture tested acidic to litmus. The resulting precipitate was dissolved in 20 ml of water, and acetone was added un~il product ceased coming out o~ solution. This yielde~ 5.8 g (68~ of theory) o 1,3-bis[4-(4- methylb~nzyl)-1-piperazinyl3propane tetrahydrochloride as a white crystalline product (m.p.
245-252C, with decomp.).

-3~
Example 23 Bis E4- (3-chlorobenzyl)-1-piperazinyl~-nohydrate A mixture of 6.3 g of 1-~3-chlorobenzyl)piperazine, 2.4 g of 1-bromo-3-chlQropropane, 50 ml of reagent ethanol ana 3.0 g of triethylamine was refluxed for 4 hours. Water (70 ml) was added, and the mixture was concentrated under vacuum to a~out 70 ml. The resulting aqueous mix~ure was extracted with ether ~3 x 150 ml), and the extrac~ was concentrated ~nder vacu~m to give a r~oddish-yellow oil.
Chromatography of this oil on a s~lica column, ~he eluant ~eing CH2Cl~C~130H/ammonium hydroxide ~45:5:1), resulted in an oil which was dissolved in 50 ml of ethanoln Hydrogen chloride-saturated ether was added to this solu~ion until the mixture tested acidic to lit~us. The resulting precip-itate was filtered off, dried and weighed ~o yield 5.6 g (68% of theory) of 1,3~his[4-~3 chlorobenzy~)-l-pipera~inyl]
propane dihydrochloride monohydrate. Recrystallization rrom water gave a white crystalline solid (m.p. 248-257C, with decomp.).

Example 24 1~3~ E~;r (3-{4-chlorophenyl~propyl)-1-pipe ~inyl~-pro~ane_tetrahydrochloride ~onohydr2te ~5 (a) A ~ixture of 40.6 g of 3-(4-chlorophenyl)propy chloride, 130.0 g of anhydrous pipera~ine and 550 ml of reagent ethanol was re.~lu~ed for 2 hours. Solvent was removed under vacuum and the resi.due was chromatographed on silica with the eluan~ bei.ng C~12C12/CH30H~ammonium hydroxide (45:5:1). Appropriate ~23~.~36~
fractions were combined, concentrated to an oil, mixed with 1400 ml lN HCl and filtered. The filtrate was brought to pH 10 wit~ concen-~xated aqueous NaOH
and then extracte~ with ether ~4 x 200 ml~. The extract was dried over MgS04 and strippe~ to an oil which solidified on standing. The resulkins 1-~3-~4-chlorophenyl)propyl~piperazine (m.p. 54-62C) was used without further purification ~b) A mixture of 7.2 ~ of 1-[3-t4-cnlorophenyl)propyl]
piperazine, 2.4 ~ of 1-bromo-3-chloroprop~r~e, 3.5 ~ of triethylamine and 3~ ml of re~gent e~hanol was refluxed for 6 hours. The solvent was then evapora~ed under ~acuum, and the residue was mixed with 40 ml o~ wat~r and extracted with ether (3 x 150 ml). ~he extract was ~hen evaporated to z yellow oil which was chroma~o-graphed on a silica colu~n, the eluant being CH2C12/CH30H/ammonlum hydroxide (45:5:1). This resulted in 4.6 g (59% of ~heory) of 1,3-bis~4-(3-~4-chloro-phenyl}propyl)-l-piperazinyl]propane as a colorless oil. Part of this oil (3.0 g) was dissolved n 100 ml of e~her, and hydxogen chloride-saturated ether was added to this solution until the resulting mixture kested acidic to litmus. The resulting precipita-te was dissolved in 25 ml of water, and acetone was added until precipitation appeared complete. This resul~ed in 2.7 g ~41% of theory) of 1~3~bis~4-(3-{4-chloro-phenyl}propyl)-l-piperazinyl~propane tetrahydrochloride monohydrate as a white crystalline solid (m.p. 245-246C, with decomp.).

--36~
Example 25 1,3-Bi~[4-(g-chloro-3-trifluoromethylber~æyl)-l-piperaz nyl}propane tetrahydxocnloride ~ mixtur~ o~ S g of 3-chloro-4 tri~luoromethyl-benzyl chloride, 5.3 g of 1,3 bis(l-piperazi~l)propane, 50 g of reagen~ ekhanol and 7.~ g of trie~hylamine was refluxed for 16 hours. The reactio~ mixture was evaporated under red~ced pressure, and the residue was mixed with 150 ml of water. The resulting mix~ure was extracted with ether (5 x 100 ml~. The comblned extracts were washed wlth 1~ sodium carbonate solution (3 x 100 ml). The resulting ether solution was dried over magnesium sulfa~e, filtered and evaporated to a yellow oil (6.8 g). This oil was dissol~ed in 100 ml of hexane and filtered. The Ii ltrate was ext_acted 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 ~trongly basic with 2N NaOH and extracted with 10~ 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 o hydrogen chloride saturated ether, yielded a white precipitate. An additional 50 ml o~ ether was added and the precipitate was riltered o~f and recrystallized fro~
~5 methanol to yield colorless crystalline 1,3-bis~-(4-chloro-3-trifluoromethylbenzy~ -piperazinyl]propane tetrahydrochloride (mOp. 265-268C, with deco~p. >250C).

- ~ 2 ~ J
Example 26 1,3-Bis{4-(4-hydroxybenzyl3-1-piperazinylhpropane A mixtura of 4.5 g of 1,3-bisE4~ methoxy~enzylj-1-piperazinyl]propane from Exam~le 19 and 125 ml of 49% hydro-bromic acid was refluxed for 2 hours 2nd was then cooled and diluted with 125 ml of water~ After filtration the aqueous solution was neutralized wi~h 2N sodium hydroxide to adjust the pH to 8. The resulting mixture was extract-ea three times each with 150 ml o~ ethanol. ~he alcohol was O then removed by ro~ary evaporation and the residu~ was chromatographed on silica wi~h the eluant being me~hylene chloride containing 1% ammonium hydroxide and 10% methanol to obtain 1.3 g ~31~ of theory~ of 1,3-bis[4-(4-hydroxy-benzyl)-l-piperazinyl]propane as a white crystalline produt, melting at 197 201C~

Example 27 1,3-~is~4 (4-bromobenzyl)-1-pioerazinyl}pro~ane tetrahydrochloride .0 A mixture of 3.8 g of 1-(4-bromobenzyl3piperazine, 7 g of ethanol, lr 2 g of 1-bromo-3-chloropropane and 1.6 g of triethylamin~ 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, dri.ed over MgSO4 and filtered. To this solution was then added E~Cl-saturated ether until the mixture remained acidic and the resulting orecipitate was filtered orf and was mixed with 10~ ml of ethanol. The mi~ture was brought to reflux and water was added d~opwise to the refluxing mixture un~il a solution was formedO Cooling xesulted in the crystalliza~ion of the product and filtration yielded 4.2 g (81~ o~ theory) of 1 ~ 3-hi s 1 4 - ( 4 -bromobenzyl)~l-piperazinyl~propane te~rahydro-chloride as a white crystalline product mel~ing a~ 237-243C.

Exam~le 28 1,3~~is-~4~t4-chlorobenzyl)-1=homopiperazinyl}propane -etrahydrochloride A mixture of 4.5 g of 1-(4-chlorobenzyl~homopipe--azine, 1.6 5 of 1-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 lS ether (75 ml each) and the extract was evaporated to an r oil. This oil was chromatographed on a silica column with tne eluant being methylene chloride containing 0.5% con-centrated ammonia hydroxide and 2.5% me~hanol. The fractions containin~ the product were combined, evaporated to an ~0 oil, dissolved in ether ar.d filtered. T~e resulting ether solution was mixed with hydrogen chloride-saturated e~ner until the mixture tested acidic to litmus. The resulting precipitate was dried to obtain 1.4 ~.(22~ of theory) of produc~ which alter crystallization from a~ueous ethanol resulted in 1~3-bis~4-(4-chlorobenzyl)-l-homopiperazinyl3 propane tetrahydrochloride as a white crystalline product, melting at 218-224C tdecomP.).

~39~ 5'~
Example 29 1!3-Bl~[4-(4-{4~chlorophenyl~utyl)-1-piperazinyl]-pro~ane tetrah~drochloride (a) A mi~ture of 26~4 g of 4-~4~chlorophenyl~butyl chlori~e, 86.1 g of anhydrous piperazine and 250 ml Q~ re gent ethanol was refluxed ov0rnigh~. Solvent was evaporated ~rom th~ product a~d ~he residue was chromatographed twice on silica wi~h the eluant baing CH2C12/C~3OH/ammor.ium hydroxide (45:5:1). The ~irst c~romatography removed the bulk o~ the e~cess piperazine, ~he second provided 15.2 g of 1-~4 (4-chlorophenyl)butyl3piperazine as a colorless oil which solidified on standing (m~p. 139-145C).

(b~ A mix~ure of loS g Of 1- E4~(4-chlorophenyl)butyl]
piperazine, 0.5 g of 1-bromo-3-chloropropane~ 0.7 g of triethylamine and 10 g of reagent ethanol was refluxed overnight. After addition vf 3.5 ml of 2N
~aOH, solvent was remo~ed under vacuum. The residue was extracted with me~hylene chloride and the extract was chromatographed on silica with the eluant being CH2C12~CH3OH/ammonium 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-his~4-t4-{4-chloro-phenyl}butyl)-l-piperazinyl~propane tetrahydrochloride as a light tan solid. Recrystallization lrom ethanol/water gave a white crystalline solid (m.p. 213-217C decomp.).

~o ~ 6~

Example 30 1,3-Bis~4-(4-~cetoxybenz~ piperazin~lkpropane _ _ .
A mixture of 2.0 g of 1,3-bis[4-~4-hydroxy~en~yl)-l-piperaz~nyl]propar~e (Example 26), 1.0 g of ~yridine and -5 50 g of acetic anhydride was stirred overnight a~ ambient temperature~ The product mixture was concen~rated under vacuum to an amber oil which was mixed with 100 ml of p~ 8 pnosphate buffer and extracted with ether 13 x 100 ml).
The eætract was dried over MgSO4 and s-tripped to a white solid. Recrystallization from heptane yielded 1.9 g (78%) of 1,3-bis[4-(4-acetoxybenzyl)-1-~iperaz~nyl]propane as a white crystalline sol ia m.p. 102-105C.

Example 31 1,3-Bis~4-~4-butoxybenzyl)-1-piperazinyl~propane -~etrahydrochloride . . _ .
A mix~ure of ~.0 g of 1,3-bis~4-(!l-hydroxybenzyl)-l-piperazinyl~propane ~from example ~6), 10 ml of 2N NaOH, 0~2 g o~ tetrabutylammon~um hydroxide ~40~ in water~ and 5.0 g of l-bromobutane was heated on a steam bath for 3 hours. The mixture was then ex~racted with ether ~3 x 75 ml), dri.ed over ~1gSO4 and evaporated to a color-less oil which~ solidified on standing. This product was dissolved in 100 ml o ether and HCl-saturatea ether was added until precipitation was complete`. Filtration resulted in 1.4 g (91% of theory) of 1,3-bis~4-(4-bu.oxy-benzyl)-l-piperazinyl]propane ~etrahydrochloride as a white solid. Recrystallization from reagent ethanol/water resulted in a white crystalline product (m.p. 207-218C).

- 4 1 -Example 32 1,3-Bls{4-~4-c ~ thyl-l-ipera~inyl3propane tetrahydrochlorlde A mixture of 1-~4 chlorobenzylJ-2,305,6-tetramethyl piperazine, 1 g of 1-bromo-3-chloropropane, and 1 g or triethylamine is heated under reflux in 20 ml o e~hanol fGr 24 hours and the reaction mix~ure is evapora~ed under reduced pressure to an Oilr ~he residue ls dissol~Jed in water a~d extracted with ether. The etner extract is washed with water a~d dried over magnesium sul~ate. The product is precipitated ~rom the ether solution ~y precipitation with excess ethereal hydrogen chloride and crystallization from ethanol to provide 1,3-bis~4-(4-chloro~enzyl)-2,3,5,6-tetramethyl-1-piperazinyl]propane tetrahydrochloride as a white crystalline solid.

Example 33 1-[4-(4-chlorobenzyl)-1-p,iperazinyl~-3-[4-(2-car~oxy-2-phenylethyl)-1-piperazinyl,lpropane tetrahydrochloride ~0 A suspension o-E 340 mg of 1-[4-(4-chloroben~yl)-1-piperazinyl]-3-~4~ ethoxycaxbonyl-2-phenylethyl) 1-piperazinyllpropane tetrahydrochloride in 10 ml o~ ethanol was treated with 1 ml of aqueous SM sodium hydroxide and h~ated under re lux or 1 hour. The reaction mixture was ~5 evaporated to dryness under reduced pressure. The residue was mixed with lN hydrochloric acid (3 ~1) and the resulting mixture extracted with etner (~ x 10 ml). Tl~e extract was discarded and the pH of aqueous phase adjusted ~o 5.5 wi~h 1~ hydrochloric acid. Aqueous saturaied sodium chloride solution (10 ml) was added and th~ mixture extracted witn -~2~

butanol (2 x 10 ml). The butanol extract was filterea and treated with excess ethereal hydrogen rhloride. ThP white precipitate was collected a~d recrystalliz~d ~rom a~ueous ethanol to yield 1- r~- 14-chlorobenzyl)-1-piperazinyl]-3-~4-(2-carboxy-2-phenylethyl)-1-piperazinyl3propane tetra-hydrochloride ~140 mg, 40~ yiel~) as a white crys~alline solid (m.p. 230-245C decomp.~.

~x~pl~ 34 1,3-Bis{4-(3 {4-chlorophenyl}~ropyl]-1-homo-piperazinyl]pxopane tetrahydrochloride A mix.ure of 3.8 g of 1-~3-(4-chlorophenyl)propyl]
~omopiperazine, 1.2 g of 1-bromo-3-chloropropane, 1.~ 5 o triethylamine is heated unde- reflu~ in 10 ml of ethanol for 18 hours and the reaction mix~ure evaporated ~o dry-ness und~r reduced pressure. The residue is mixed with water and extracted with ether. The ether extract is evaporated and the residue chromatographed on silica gel [CH2Cl~/CH3OH/NH4O~ ~35:5~ . The resulting oil is 2~ dissolved in ether and ~he product precipitated with excess ethereal hydrogen chloride. Crystallization from ethanol provides 1,3-~1s[4-(3-{4-chlorophenyl}propyl)-l-homopiperazinyl~propane tetrahydrochloride as a crystalline solid.

- ~I 3-Example 35 ~4-chlorobenzyl) -l-homopiperazinyl]-1, 3-dioxopropane dihydrochloride O ~ 7 g of malonyl dichloride is added at once to a solution of ~.2 g of l~ chlcrobe~zyl)homopiperazine and 1 g of triethylamine in 10 ml of methylene chloride at room te~perature and the reac~io~ mixture hea~ed under reflux for one hour and then evaporated under reduced pressure. The residue is triturated with water and the crude product extracted witn me~hylene chloride and purified by chromatography on silica ECH2C12/CH3OHjNH2OH
(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)-1-homopiperazi~yl]-1,3-dioxopropane dihydrochloride as a crystalline solid.

As mentioned abover mediator release frorn mast cells and basophils has been implicated in many allergic and inflammatory disorders. ~he activity of compounds in inhibiting the noncytotoxic exocytosis of such mediators can be evaluated in n vitro models such as the inhibition of mediator release from isolated cellular systems induced by an~igen-antibody interaction. I~he 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 ~re âS Xollcws:
lS ~P~IC: Ra~ peritoneal mast cell preparation;
GPBL: Guinea pig basophil-enrichea leukocytes;
HBL: Human baso~hil-~nriched leukocvtes.
A com~arison wi~h the aotivit es of the clinical s.andar~s theophylline and disodium c-omoglycate (~SC~) in these systems is also provided.

--~I 5--__ _ _ Compound ~5ediator 3~elease Inhibition ~ f ~
Example IC5~q) *
. . _ _ _ _ _ RPMC GPBL HBL
_ ___ 2 ~30 20 :3 16 NT 10 0 . 7 24 0 5 9 0.7 Theophylline >1000 ~00 400 ¦ DSCG -- -- >1000 .... _ _ * Concentration of the compound required in the celiular reaction mixture to inhibit 50% of ~he rel ease of the pharmacological mediators from the target cells.
- NT = not tested.

~86~'~

The following examples .illustrate a few phar macuetical dosage unit compositions comprising a compound of the present invention as an active ingredient. The parts are parts by weiyht unless otherwise specified.

5~
-~7-~xample 36 Tablets The tablet composition is compounded from the following ingredients:
1,3-~is[4-(4-chlorobenzyl)-1-piperazinyl]propane tetrahyd.ochloride 0.010 parts Stearic acid 0.010 Dextrose 1.890 Total 1.910 par~s Preparation:
The ingredients are admixed in conventional manner, r and the mixture is compressed into 1.91 gm taDlets, each o~
which is an oral dosage unit composition containing 10 mg o the active ingredien~.

Example 37 Ointment The ointment composition is compounded from the following ingredien~s:
1,3-3is~4-(4-chlorobenzyl)~l-~S pi~erazinyl]-2-hydroxypropane 2.000 parts Fuming hydrochloric acid 0.011 Sodium pyrosulfite 0.050 "
Mi~ture (':1) of ceiyl alcohol and stearyl alcohol 20.000 ~7~ite Vaseline 5.000 "
Synthetic bergamot oil 0.075 Distilled water q.s.ad 100.000 "

Preparation The ingredients are uniformly blended in conven-tional manner into an ointme~t, 100 mg of which contain 2.0 mg of th~ active ir,gredient.
Example 3B
Inhala~ion aerosol The aerosol composition is compounded from the following ingredients:
1,3-~is[4-(4~chlorobe~zyl)-1-piperazinyl] 1,3-dioxopropane dihydrochloride monohydratel.G0 parts Soybean lecithin 0.20 "
Propellant gas mixture (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 con~
tainers with a metering valve which releases 0.5 to 2.G mg of active ingredient per actuation of the valve.

Example -39 }Iypodermic solution The solution is compounded ~rom the ~ollowing ~5 ingredients~
1,3-Bis~4-(4-chlorophenethyl) 1-piperazinyl]propane dihydrochloride 5.0 parts Sodium pyrosul ite 1.0 "
Sodium salt or EDTA 0.5 Sodium chloride 8.5 Double-distilled water q.s.ad 1000.0 ~ ~a~ Qr~

Preparation:
The individual ingredients are dissolved in a su~ficient amount o~ double-distilled water, the solution is diluted to the indicated concentration with additional do~ble-distilled water, the resulting solution is filtered until fxee fxom suspended ~articles, and the filtrate is filled un~er aseptic conditions into 1 ml-ampules which are subsequently sterilized and sealed. Each ampule con-tains 5 mg o~ the active ingredient.
Example 40 Topical solution ~opht:~ ~
The solution composi~ion is compounded from the followlng ingredients:
1,3-Bis~4-(4-chlorobenzyl)-1-piperazinyl]-2-hydroxypropane tetrahydrochloride 0.020 parts Disodium hydrogen phosphate 0.758 "
Dihydrogen sodium phosphate 0.184 Sodium chloride 0.365 "
Polyvinyl alcohol 3.500 "
Ben~alkonium chlorideOoO10 "
Distilled water q.s.ad 100.000 "
Preparation:
The lngredients are dissolved in the conventional ~5 m~nne~ 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.

Any one of the other compounds embraced by formula I
or a non-toxic, pharmacologically acceptable acid addition salt thereof may be substitu~ed for t}le particular active ingredient in E~amples 36 .to 40. Likewise~ the amount of active ingredient in ~hese illustrative examples may be varied t-o achieve the dosage unit range set forth above, and the amounts and nature of the inert pharmaceu~ical carrier ingredient may be varied to mee~ par-ticular xequire-ments.

Claims (25)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for producing a compound of formula I

(I) wherein R1, R2, R4 and R5, which may be identical to or different from each other, are each hydrogen, alkyl of 1 to 4 carbon atoms, hydroxyl, alkoxy of 1 to 4 carbon atoms, alkanoyloxy of up to 4 carbon atoms, halogen, trihalomethyl, di(lower alkyl of 1 to 4 carbon atoms)amino, (alkoxy of 1 to 4 carbon atoms)carbonyl, nitro, cyano or alkanoyl of up to 3 carbon atoms;
R7 and R8, which may be identical to or different from each other, are each hydrogen, methyl, hydroxyl, carboxyl, (alkoxy of 1 to 4 carbon atoms)carbonyl, hydroxymethyl, phenyl, chlorophenyl, tolyl or (alkoxy of 1 to 4 carbon atoms)phenyl;
R9 and R10 are each independently hydrogen or methyl;
j and k are each independently integers from 0 to 3, their sum being no more than 4;
m and n are each independently integers from 0 to 3, their sum being no more than 4;
A is -CH2- or -CH2-CH2-; or R7 and R9 together or R8 and R10 together are oxo, provided k or m is other than 0; or R7 and R9 together and R8 and R10 together are oxo, provided k and m are other than 0;
R11 and R12, which may be the same or different, represent hydrogen or, when A represents a group -CH2-, each represents from one to four methyl substituents on the carbon atoms of the piperazine ring;
R13, R14, R15 and R16, which may be identical to or different from each other, are each hydrogen or methyl; or R13 and R14 together and/or R15 and R16 together are oxo; and X is alkylene of 1 to 2 carbon atoms, which is unsubstituted or substituted with hydroxy, with the proviso that when R1, R2, R4, R5, R7, R8, R9, R10, R11, R12, R13, R14, R15 and R16 are each hydrogen, A is -CH2- and j, k, m, and n are each 0, X cannot be 1,2-ethylene diol; or a pharmaceutically acceptable acid addition salt thereof, which said process comprises:
(A) to prepare a compound of formula I wherein R1, R2, j, R7, R9, k and R11 are the same as R4, R5, n, R8, R10, m and R12, respectively, reacting a compound of formula IV

(IV) wherein R13, R14, R15, R16 and X are as defined above, and Y and Z are groups reactive with amine groups to form a carbon-nitrogen bond, with a compound of formula (V) wherein R1, R2, R7, R9, R11, j, k and A are as defined above;
(B) reacting a compound of formula VI

(VI) wherein R1, R2, R7, R9, R11, R13, R14, R15, R16, X, j, k and A
are as defined above and Y is as defined in (A) above, with a compound of formula VII

(VII) wherein R4, R5, R8, R10, R12, m, n and A are as defined above;
(C) to prepare a compound of formula I wherein R1, R2, j, R7, R9 and k are the same as R4, R5, n, R8, R10 and m, respectively, reacting a compound of formula VIII

(VIII) wherein R11, R12, R13, R14, R15, R16, X and A are as defined above, with a compound of formula (IX) wherein R1, R2, R7, R9, j and k are as defined above and Y is as defined in (A) above;
(D) to prepare a compound of formula I wherein X is a carbinol moiety, reacting a compound of formula X

(X) wherein R13, R14, R15 and R16 are as defined above, R18 is hydrogen or lower alkyl, and Y is as defined in (A) above with a compound of formula VII

(VII) wherein R4, R5, R8, R10, m, n and A are as defined above; or (E) to prepare a compound of formula I wherein R7 and/or R8 are hydroxyl, hydrogenating a compound of formula I
wherein R7 and R9 together and/or R8 and R10 together are oxo;
and, if required, converting a salt of a compound of formula I
into the free base or converting the compound of formula I into a pharmaceutically acceptable salt.

2. A compound of formula I

(I) wherein R1, R2, R4 and R5, which may be identical to or different from each other, are each hydrogen, alkyl of 1 to 4 carbon atoms, hydroxyl, alkoxy of 1 to 4 carbon atoms, alkanoyloxy of up to 4 carbon atoms, halogen, trihalomethyl, di(lower alkyl of 1 to 4 carbon atoms)amino, (alkoxy of 1 to 4 carbon atoms)carbonyl, nitro, cyano or alkanoyl of up to 3 carbon atoms;
R7 and R8, which may be identical to or different from each other, are each hydrogen, methyl, hydroxyl, carboxyl, (alkoxy of 1 to 4 carbon atoms)carbonyl, hydroxymethyl, phenyl or chlorophenyl;
R9 and R10 are each independently hydrogen or methyl;
j and k are each independently integers from 0 to 3, their sum being no more than 4;
m and n are each independently integers from 0 to 3, their sum being no more than 4;
A is -CH2- or -CH2-CH2-; or R7 and R9 together or R8 and R10 together are oxo, provided k or m are other than 0; or R7 and R9 together and R8 and R10 together are oxo, provided k and m are other than 0;
R11 and R12, which may be the same or different, represent hydrogen or, when A represents a group -CH2-, each represents from one to four methyl substituents on the carbon atoms of the piperazine ring;
R13, R14, R15 and R16, which may be identical to or different from each other are each hydrogen or methyl; or R13 and R14 together and/or R15 and R16 together are oxo; and X is alkylene of 1 to 2 carbon atoms which is unsubstituted or substituted with hydroxy, with the provisos that:

(a) when R1, R2, R4, R5, R7, R8, R9, R10, R11, R12, R13, R14, R15 and R16 are each hydrogen, A is -CH2- and j, k, m and n are each 0, X cannot be 1,2-ethylene diol; and (b) when R7, R8, R9, R10, R11, R12, R13, R14, R15 and R16 are each hydrogen and j, k, m and n are each 0, and X is an alkylene of 1 or 2 carbon atoms, then each of R1, R2, R4 and R5 cannot be alkoxy, or a pharmaceutically acceptable acid addition salt thereof, whenever prepared or produced by the process of claim 1 or by an obvious chemical equivalent thereof.

3. A process for producing a compound of formula II

(II) wherein j, k, m and n are each 0, 1 or 2;
R2 and R5 are -H, -Cl, -CH3 or lower alkoxy;
R7 and R9 are both hydrogen, or when k is other than 0 one is hydrogen and the other is hydroxyl, or when j and k are 0 one is hydrogen and the other is phenyl or p-chlorophenyl, or when k is other than 0 together they are oxo;
R13, R14, R15 and R16, which may be the same or different, are each -H or -CH3, or R13 and R14 together and/or R15 and R16 together are oxo;
R8 and R10 are both hydrogen, or when m is other than 0 one is hydrogen and the other is hydroxyl, or one is hydrogen and the other is phenyl, p-chlorophenyl or -COO(alkyl of 1 to 4 carbon atoms), or when m is other than 0 together they are oxo; and X is alkylene of 1 to 2 carbon atoms, optionally hydroxysubsti-tuted or a pharmaceutically acceptable acid addition salt thereof, which process comprises:
(A) to prepare a compound of formula II wherein R2, j, R7, R9 and k are the same as R5, n, R8, R10 and m, respectively, reacting a compound of formula IV

(IV) (wherein R13, R14, R15, R16 and X are as defined above, and Y and Z are groups reactive with amine groups to form a carbon-nitrogen bond) with a compound of the formula (wherein R2, R7, R9, j and k are as defined above);

(B) reacting a compound of the formula (wherein R2, R7, R9, R13, R14, R15,,R16, X, j, k and A are as defined above, and Y is as defined in (A) above) with a compound of the formula (wherein R5, R8, R10, m, n and A are as defined above);
(C) to prepare a compound of formula II wherein R2, j, R7, R9 and k are the same as R5, n, R8, R10 and m, respectively, reacting a compound of the formula (wherein R13, R14, R15, R16, X and A are as defined above)with a compound of the formula (wherein R2, R7, R9, j and k are as defined above, and Y is as defined in (A) above);
(D) to prepare a compound of formula II wherein X is a carbinol moiety, reacting a compound of the formula (wherein R13, R14, R15 and R16 are as defined above, R18 is hydrogen or lower alkyl, and Y is as defined in (A) above) with a compound of the formula (wherein R5, R8, R10, m, n and A are as defined above), (E) to prepare a compound of formula II wherein R7 and/or R8 are hydroxyl, hydrogenating a compound of formula II wherein R7 and R9 together and/or R8 and R10 together are oxo; and (F) if required, converting a salt of a compound of formula II into the free base or converting the compound of formula II into a pharmaceut-ically acceptable salt.

4. A process for producing a compound of formula III

(wherein R13 and R14 are H, or together are oxo; R17 is 11 or OH; R15 and R16 are H, or together are oxo; and a and b are each 1, 2, 3, or 4) or a pharmaceutically acceptable acid addition salt thereof, which process comprises:
(A) to prepare a compound of formula III wherein a and b are the same, reacting a compound of the formula (wherein R13, R14, R15, R16 and R17 are as defined above, and Y and Z are groups reactive with amino groups to form a carbon-nitrogen bond) with a compound of the formula (wherein a is as defined above);
(B) reacting a compound of the formula (wherein R13, R14, R15, R16, R17 and a are as defined above, Y is as defined in (A) above) with a compound of the formula (wherein b is as defined above);
(C) to prepare a compound of formula III wherein a and b are the same, reacting a compound of the formula (wherein R13, R14, R15, R16 and R17 are as defined above) with a compound of the formula (wherein a is as defined above and Y is as defined in (A) above) (D) to prepare a compound of formula III wherein R17 is OH, reacting a compound of the formula (wherein R13, R14, R15 and R16 are as defined above, and Y is as defined in (A) above); with a compound of the formula (wherein a is as defined above); and (F) if required, converting a salt of a compound of formula III into the free base or converting the compound of formula III into a pharmaceut-ically acceptable salt.

5. A process as claimed in claim 1, 3 or 4 wherein one of steps (A) to (D) is performed in the presence of an acid-binding agent.

6. A process according to claim 4, wherein process alternative (A), (B) or (C) is carried out using starting materials in which R13, R14, R15, R16 and R17 are H, and a and b are each 1, thereby obtaining a compound of formula III wherein R13, R14, R15, R16, R17, a and b are as defined above or a pharmaceutically acceptable acid addition salt thereof.

7. A process for producing 1,3-bis[4-(4-chlorobenzyl)-1-piperazinyl]-propane or a pharmaceutically acceptable acid addition salt thereof, which process comprises: reacting 1-(4-chlorobenzyl)piperazine with 1,3-dihalo-propane wherein the halogens are independantly from each other chlorine or bromine; and if required, converting the reaction product to the free base or to a pharmaceutically acceptable salt thereof.

8. A process according to claim 7, wherein the 1,3-dihalopropane is 1-bromo-3-chloropropane.

9. 1,3-Bis[4-(4-chlorobenzyl)-1-piperazinyl]-propane or a pharmaceut-ically acceptable acid addition salt thereof, whenever prepared or produced by the process of claim 6, 7 or 8, or by an obvious chemical equivalent thereof.

10. A process according to claim 4, wherein process alternative (A), (B) or (C) is carried out using starting materials in which R13, R14, R15 and R16 are H, R17 is OH, and a and b are each 1, or process alternative (D) is carried out using starting materials in which R13, R14, R15 and R16 are H
and a is 1, thereby obtaining a compound of formula III wherein R13, R14, R15 and R16 are H, R17 is OH and a and b are each 1 or a pharmaceutically acceptable acid addition salt thereof.

11. A process for producing 1,3-bis[4-(4-chlorobenzyl)-piperazinyl]-2-hydroxy-propane or a pharmaceutically acceptable acid addition salt thereof, which process comprises: reacting 1-(4-chlorobenzyl)piperazine with an epihalohydrin in which the halogen is chlorine or bromine, and if required, converting the reaction product to the free base or to a pharmaceutically acceptable salt thereof.

12, A process according to claim 11, wherein the epihalohydrin is epichlorohydrin.

13. 1,3-Bis[4-(4-chlorobenzyl)-piperazinyl]-2-hydroxy-propane or a pharmaceutically acceptable acid addition salt thereof, whenever prepared or produced by the process of claim 10, 11 or 12, or by an obvious chemical equivalent thereof.

14. A process according to claim 4, wherein process alternative (A), (B) or (C) is carried out using the starting materials in which R13 and R14 together are oxo, R15 and R16 together are oxo, R17 is H and a and b are each 1, thereby obtaining a compound of formula III wherein R13, R14, R15, R16, R17, a and b are as defined above or a pharmaceutically acceptable acid addition salt thereof.

15. A process for producing 1,3-bis[4-(4-chlorobenzyl)-1-piperaziny]-1,3-dioxopropane or a pharmaceutically acceptable acid addition salt thereof, which process comprises: reacting 1-(4-chlorobenzyl)piperazine with a malonic acid dihalide wherein the halogen is chlorine, bromine or iodine, and if desired, converting the reaction product to the free base or to a pharmaceutically acceptable salt thereof.

16, A process according to claim 15, wherein the malonic acid dihalide is malonic dichloride.

17. 1,3-Bis[4-(4-chlorobenzyl)-1-piperazinyl]-1,3-dioxopropane or a pharmaceutically acceptable acid addition salt thereof, whenever prepared or produced by the process of claim 14, 15 or 16, or by an obvious chemical equivalent thereof.

18. A process according to claim 4, wherein process alternative (A), (B) or (C) is carried out using the starting materials in which R13, R14, R15, R16 and R17 are H, a and b are each 2, thereby obtaining a compound of formula III wherein R13, R14, R15, R16, R17, a and b are as defined above or a pharmaceutically acceptable acid addition salt thereof.

19. A process for producing 1,3-bis[4-(4-chlorophenethyl)-1-piperazinyl]-propane or a pharmaceutically acceptable acid addition salt thereof, which process comprises: reacting 1-(4-chlorophenethyl)piperazine with a 1,3-dihalopropane wherein the halogens are independantly from each other chlorine or bromine; and if desired, converting the reaction product to the free base or to a pharmaceutically acceptable salt thereof.

20. A process according to claim 19, wherein the 1,3-dihalopropane is 1-bromo-3-chloropropane.

21. 1,3-Bis[4-(4-chlorophenethyl)-1-piperazinyl]-propaane or a pharma-ceutically acceptable acid addition salt thereof, whenever prepared or pro-duced by the process of claim 18, 19 or 20, or by an obvious chemical equiv-alent thereof.

22. A process according to claim 4, wherein process alternative (A), (B) or (C) using the starting materials in which R13, R14, R15, R16 and R17 are H, a and b are each 3, thereby obtaining a compound of formula III where-in R13, R14, R15, R16, R17, a and b are as defined above or a pharmaceutically acceptable acid addition salt thereof.

23. A process for producing 1,3-bis[4-(3-[4-chlorophenyl]propyl)-1-piperazinyl]-propane or a pharmaceutically acceptable acid addition salt thereof, which process comprises: reacting 1-[3-(4-chlorophenyl)propyl]
piperazine with a 1,3-dihalopropane wherein the halogens are independantly from each other chlorine or bromine; and if desired, converting the reaction product to the free base or to a pharmaceutically acceptable salt thereof.

24. A process according to claim 23, wherein the 1,3-dihalopropane is 1-bromo-3-chloropropane.

25. 1,3-Bis[4-(3-[4-chlorophenyl]propyl)-1-piperazinyl]-propane or a pharmaceutically acceptable acid addition salt thereof, whenever prepared or produced by the process of claim 22, 23 or 24, or by an obvious chemical equivalent thereof.