CH672787A5 - - Google Patents

Description

DESCRIPTION Disubstituted 1,4-piperazinyl derivatives.

The invention relates to disubstituted 1,4-piperazinyl derivatives, processes for their preparation, pharmaceutical compositions containing these compounds and the use of these compounds.

In the 1,4-disubstituted piperazine derivatives according to the invention, a substituent is a bicyclic, heterocyclic, condensed ring system. These include furo, pyrro-lo, cyclopentadieno and thieno-pyridine ring systems. The other substituent is an alkylene chain, preferably a butylene chain, bearing a cyclic imide ring or a benzylic carbinol moiety at its end. The following can be mentioned as examples of such terminal units:

means either X or Y is CH2, O, S or NR7 and the other X or Y must then be = CH-;

R1 and R7 independently represent a hydrogen atom or a lower alkyl radical; and

R2 represents a hydrogen or halogen atom or a lower rigalkyl, lower alkoxy, lower alkylthio or hydroxy radical, and the pharmaceutically acceptable acid addition salts thereof, characterized in that (a) a compound of the formula Ild

35

40

45

coy3-q

(IH)

50

with an intermediate compound of formula IIIc to a compound of general formula If

«Azaspiroalkandion unit»

«Dialkylglutarimide unit»

«Thiazolidinedione unit»

55

1

0 0

r!

(If) 60

65

implements

(b) the compound If in acidic medium to a compound of the general formula Ig

"Succinimide unit"

«Morpholindione unit» (V can stand for O or S)

7

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N-

U

«Phthalimide unit»

(U can stand for C = 0 or S02)

Œ

•O*

«Benzylcarbinol unit»

10th

The compounds according to the invention are antipsychotics and serotonin antagonists. As an example of a typical compound with a selective antipsychotic activity, 4- [4- [4- (4-furo [3,2-c] pyridinyl) -1-pipe-15 call razinyl] -butyl] -3,5-morpholinedione.

Numerous publications dealing with similar connections have appeared in the past 15 years.

The relevant state of the art deals with compounds that act on the central nervous system. These known compounds generally have the following general formula (1)

25th

N-alk-N N-B 0 ^^

(1)

30th

wherein alk represents an alkylene chain which connects the piperazine ring with the cyclic imide group, and B represents a heterocyclic ring which is substituted if desired.

Various azaspiro [4.5] decanedions are described in US Pat. Nos. 3,717,634 and 3,907,801 to Wu et al 35 and in a corresponding publication by Wu et al, J. Med. Chem. 15, 447-479 (1972) described that have psychotropic properties. In these compounds, B denotes various monocyclic heterocycles, such as pyridine, pyrimidine or triazine, which, if desired, can have substituents.

Temple, Yevich and Lobeck in U.S. Patent 4,305,944 describe tranquilizing azaspiro [4.5] decanedione compounds in which B represents a 3-cyanopyridin-2-yl or 3-methoxypyridin-2-yl unit.

Temple, Yevich and Lobeck, in US Pat. No. 4,361,565, report tranquilizing dialkylglutarimide compounds in which B is a 3-cyano-pyridin-2-yl ring which, if desired, can have a second substituent.

Temple and Yeager in U.S. Patents 4,367,335 and 4,456,756 describe antipsychotic thiazolodinediones and spirothiazolidinediones in which B represents a 2-pyridinyl ring which is either unsubstituted or has a 55 cyano substituent.

In U.S. Patent Nos. 4,411,901 and 4,452,799, Temple and Yevich describe antipsychotic compounds which have a variety of cyclic imide and benzyl carbinol units in which B represents either benzisothia, 60 or benzisoxazole ring systems.

Reference is also made to the following registrations.

In U.S. application Ser. No. 531,519, filed on September 12, 1983 and now issued, New and Yevich describe 65 psychotropically effective succinimide and phthalimide compounds in which B denotes a 2-pyrimidinyl ring. These compounds show anxiolytic activity.

Various antipsychotic 1-fluorophenyl-carbonyl-carbinol, -ketal and propyl-4- (2-pyrimidinyl) p-perazines are from Yevich and Lobeck in the US application Ser. No. 583,309, filed December 18, 1984.

Finally, New, Yevich, and Lobeck in US application Ser. No. 691 952, filed on January 16, 1985, various antipsychotically active compounds which have a large number of cyclic imide units and in which B denotes a mono- or disubstituted pyridine ring system.

Although the psychotropic compounds listed above are related to the compounds according to the invention, they nevertheless differ from them in structural terms with regard to unit B of structural formula (1).

In the prior art compounds, B usually means a monocyclic heteroaryl ring. The only examples of bicyclic systems are condensed benzo ring heterocycles, i.e. Benzisothiazole or benzisoxazole ring systems. This distinguishes these compounds from the compounds according to the invention in which B denotes different classes of condensed heterocyclic rings, i.e. Furo, pyrrole, cyclopentadieno or thienopyridine ring systems. The compounds according to the invention differ pharmacologically on the basis of the psychotropic properties and the side effect profiles from the compounds of the prior art. The compounds according to the invention thus have a selective antipsychotic (neuroleptic) activity, which is accompanied by a serotonin antagonism. The affinity of the compounds according to the invention for dopamine receptors is surprisingly very low. This is in contrast to the prior art antipsychotic agents described above. Pharmacologically, the compounds according to the invention seem to resemble the atypical standard neuroleptic clozapine (2), compare: The Merck Index, 10th edition 1983, page 344 and the literature references listed there.

(2)

As can be seen, clozapine belongs to the dibenzodiazepine class of psychotropic agents which are structurally not very similar to the compounds according to the invention. In addition, the compounds according to the invention do not appear to tend to produce an adverse extrapyramidal symptomatology which is associated with the chronic administration of the antipsychotic agents currently used. Furthermore, animal models have shown that certain compounds according to the invention have the ability to reverse the catalepsy resulting from the administration of trifluoperazine, a standard neuroleptic.

The invention thus relates to piperazinyl derivatives with neuroleptic (anti-psychotic) properties of the general formula (I) and to the pharmaceutically acceptable acid addition salts thereof.

672787

8th

(I)

In formula (I), Z represents the following radicals:

0

/ —K

w w 0

(c)

/ OH

'"O-" 8'

(d)

(e)

In the radical (a), R3 and R4 independently of one another denote a hydrogen atom or a Q4-alkyl radical or together represent a C3 to C6 alkylene chain. In radical (b), R5 and R6 independently of one another denote a hydrogen atom, a C 1-4 alkyl radical or a phenyl radical substituted by A, where A represents a hydrogen and halogen atom. R5 and R6 can also together form a butylene chain. The radical W can represent a sulfur atom or represent CH2 (methylene group). In the rest (c), V represents an oxygen or sulfur atom. In radical (d), G represents a hydrogen atom, a Q 4-alkyl radical, a C 1-4 alkoxy radical or a halogen radical; m stands for 1-4 and U for C = 0 or S02. Furthermore, n in the formula (I) is 2-4, with the proviso that if Z is a radical (s), n is 3. R1 is a hydrogen atom or a Q 4 alkyl radical. One of the radicals X or Y stands for CH2, O, S or NR7, the other radical X or Y then having to stand for = CH-. R2 represents a hydrogen atom, a C 1-4 alkyl radical, a C 1 -C 4 -alkoxy radical, a C1_4-alkylthio radical, a halogen atom or a hydroxyl radical. R7 represents a hydrogen atom or a Q 4 alkyl radical. The term "Q 4" is synonymous with the expression "low".

Preferred compounds of the general formula (I) are those in which Z represents the radicals (a); (b) wherein R5 and R6 together represent a butylene chain and W represents a sulfur atom; (c) wherein V represents an oxygen atom; and (e). In these preferred compounds, Y is either an oxygen or sulfur atom, while X is methynyl (= CH-); n is 4, but if Z is (e), n is 3; R2 stands for a hydrogen atom.

There are two classes of most preferred compounds. In the one class of compounds in which Y represents an oxygen atom, Z represents either (a), (c), where V represents an oxygen atom, or (e). In the class of compounds in which Y represents a sulfur atom, Z represents either (a), (b) or (e).

The pharmaceutically acceptable acid addition salts of the compounds according to the invention are those in which the anion does not make a significant contribution to the toxicity or pharmacological activity of the salts. These salts are thus pharmacological equivalents of the bases of the compounds of the general formula (I). These salts are preferably used for medical purposes. In some cases, they have physical properties that make them more suitable for pharmaceutical formulations. These properties include the solubility, the lack of hygroscopicity, the compressibility in tablet production and the compatibility with other constituents with which the compounds according to the invention are used together for pharmaceutical purposes. The salts are prepared in a customary manner by mixing a base of the general formula (I) with a selected acid 15, preferably by contacting solutions thereof, using an excess of an inert solvent usually used. These inert solvents include ether, benzene, ethanol, ethyl acetate, acetonitrile and water. The salts 20 can also be prepared by any other conventional procedure which is described in the literature and is known to the person skilled in the art. Examples of useful organic acids include: carboxylic acids such as maleic, vinegar, tartaric, propionic, fumaric, isethione, succinic, pamic, cyclamine-25 and pivalic acid. Useful inorganic acids are: hydrohalic acids such as HCl, HBr, HI, sulfuric acids and phosphoric acids.

According to the invention, all stereoisomers are also included which can occur if the radical Z contains, for example, an asymmetric carbon atom. This is the case, for example, with the rest (e). This is also possible with the rest (b). The individual stereoisomers can be separated in the usual way. The methods used are well known to the person skilled in the art.

35 The compounds according to the invention are useful pharmacological agents with psychotropic properties. At non-toxic doses, they have a selective activity with regard to the central nervous system and are of particular interest as antipsychotics (neuroleptics). 40 Like other known antipsychotics, the compounds of the general formula (I) according to the invention bring about specific reactions in pharmacological in vivo and in vitro standard tests. These test systems are known to correlate well with the relief of symptoms of acute and chronic psychosis in humans.

The known in vitro central nervous system receptor binding methodology was used for the subclassification of the psychotropic activity and specificity of the compounds according to the invention. Certain compounds have been found, commonly referred to as ligands, that bind primarily to certain high affinity sites in brain tissue that play a role in the psychotropic activity or possible occurrence of 55 side effects. The inhibition of the binding of a radiolabeled ligand to such specific high affinity sites is considered a measure of a compound's ability to affect the corresponding function of the central nervous system or to cause side effects in 60 vivo. This principle is used in tests in which, for example, the inhibition of [3H] spiperone binding is measured. This indicates significant dopamine receptor binding activity (see Burt et al, Molecular Pharmacology, 12, 65,800 (1976); Science, 196, 326 (1977), Crease et al, Science, 192,481 (1976).

Some of the more important binding tests used are listed in Table 1 below.

9

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Table 1

Receptor binding tests

Test Possible receptor sites specific ligand used

No binding agent

252A dopamine / spiperon / [3H] spiperon D (+) - butaclamol neuroleptic

252B ct-1 [3H] WB-4101 phentolamine

252E serotonin type 1 (5-HT,) [3H] 5-HT 5-HT

2521 Serotonin Type 2 (5-HT2) [3H] Spiperon D-Lysergide

Literature:

252A - see above

252B - Crews et al, Science, 202: 322, 1978, Rosenblatt et al, Brain Res., 160: 186, 1979; U'Prichard et al., Science 199: 197,

1978; Molec. Pharmacol., 13: 454, 1977.

252E - Bennet and Snyder, Molec. Pharmacol., 12: 373, 1976 2521 - Peroutka and Snyder, Molec. Pharmacol., 16: 687, 1979.

The data obtained from the above binding tests show that the compounds according to the invention have a low to low affinity for dopaminergic receptors, but have significantly higher affinities for both serotonin Sj and S2 sites. These binding properties distinguish the compounds according to the invention from the compounds of the cited prior art and from most of the clinically useful antipsychotics currently used. In this regard, the compounds according to the invention have some pharmacological properties in common with the atypical standard neuroleptic, clozapine, a dibenzodiazepine derivative. The lack of dop aminergic binding affinities in the compounds according to the invention appears to reduce the tendency to induce undesirable extrapyramidal side effects which are caused by most of the antipsychotics currently used.

The binding activity with respect to the ar receptor (test 252B) indicates that the compounds according to the invention have a sedative component, which is often desirable when treating subgroups of psychotic patients.

The following in vivo test systems are common test procedures that are used to classify a psychotropic agent. These tests can be used to differentiate a psychotropic agent from a non-specific CNS depressive (CNS = central nervous system). These tests can also be used to determine possible tendencies towards side effects, for example cataleptic activity.

Table 2

In vivo tests used to evaluate the compounds of the general formula (I) according to the invention

1. Addressing the conditional escape reflex (CAR):

Maturity of a drug to have a tranquilizing effect. This is determined by the drug-induced suppression of the response of the conditional escape reflex to an electrical shock in trained rats that had to fast. Literature: Albert Pharma-cologist, 4,152 (1962); WU et al, J. Med. Chem., 12,

876-881 (1969).

2. Inhibition of Apomorphine-Induced (APO) Stereotype:

Evaluation of a blockage of dopaminergic activity in rats, determined by suppression of the behavioral syndrome caused by the dopamine agonist «Apomorphin».

Literature: Janssen et al, Arzneimittel Forsch. 17, 841 (1966).

3. Catalepsy:

30 Drug-induced catalepsy in rats can be used to predict possible extrapyramidal symptoms (EPS) in humans.

Literature: Costali et al, Psychopharmacologia 34, 233-241 (1974); Berkson J. Amer. Extra. Assoc. 48, 35 '565-599 (1953).

4. Reversal of catalepsy:

Ability of a drug to reverse catalepsy induced by neuroleptic in rats.

40

According to the pharmacological profile which was developed with the aid of the tests mentioned above, the compounds of the general formula (I) according to the invention have a promising antipsychotic potential since they are relatively effective in the CAR test, with ED50 values <100 mg / kg body weight, and because they effectively block the apomorphine-induced stereotype. This blockage of the apomorphine-induced stereotype can reflect the dopamine antagonist activity and is regarded as a relatively specific “screen” for neuroleptic activity. It can thus be assumed that the compounds according to the invention have selective antipsychotic activity since they lead to antipsychotic activity at doses 55 which do not cause catalepsy. The compounds according to the invention are not only relatively inactive with regard to the production of catalepsy. Rather, even more significant, preferred compounds of the invention have the ability to orally reverse neuroleptically-induced catalepsy, with ED50 values <20 mg / kg. The significance of the effects of these compounds according to the invention on catalepsy induction and reversal is even greater when one considers that antipsychotic agents, as a class, are known to cause extrapyramidal reactions. These undesirable extrapyramidal reactions are very disadvantageous for treatment. These include acute torsional dystonia, akathesis, Parkinsonis

672 787

mus and tärdive dyskinesia. Some representative biological in vivo data are summarized in Table 6 below.

In summary, it can be stated that the compounds according to the invention have psychotropic properties on the basis of which they are particularly suitable for use as selective antipsychotics (neuroleptics). The compounds according to the invention also only lead to very low side effects of movement disorders.

The compounds of the general formula (I) according to the invention are administered and metered in the same way as the reference compound clozapine, see Merck Index, 10th edition, (1983), page 344 and the references cited therein. Although the dosage and regimen should in each case be carefully selected using the specialist knowledge of the therapist, taking into account the age, weight, condition of the patient, route of administration and the type and severity of the disease, the daily dose is generally about 0.05 to about 10 mg / kg, preferably 0.1 to 2 mg / k when administered parenterally. When administered orally, the corresponding dose is about 1 to about 50 mg / kg, preferably 2 to 30 mg / kg. In some cases a sufficient therapeutic effect can be achieved at lower doses, while in other cases it is necessary to choose larger doses. The term "systemic administration" used here refers to oral, rectal and parenteral (i.e. intramuscular, intravenous and subcutaneous) routes of administration. If a compound according to the invention is administered orally (preferred mode of administration), a larger amount of active ingredient is generally required in order to produce the same effect as with a smaller, but parenterally administered amount. In accordance with good clinical practice, it is preferred to administer the compounds of the invention in a concentration which leads to effective antipsychotic (neuroleptic) effects without causing harmful or undesirable effects.

For therapeutic purposes, the compounds according to the invention are generally administered in the form of pharmaceutical agents. These contain an effective antipsychotic amount of a compound of general formula (I) or a pharmaceutically acceptable acid addition salt thereof and optionally a pharmaceutically acceptable carrier. Pharmaceutical agents for performing such treatment contain a major or minor ingredient, e.g. from 95 to 0.5%, at least one compound according to the invention in combination with a pharmaceutical carrier. The carrier can be one or more solids, semi-solids or liquid diluents, fillers and formulation adjuvants that are non-toxic, inert and pharmaceutically acceptable. Such pharmaceutical agents are preferably in the form of dosage units, i.e. they are physically discrete units that contain a predetermined amount of the drug, which corresponds to a part or a multiple of the dose that was calculated to lead to the desired therapeutic response. The dosage units can contain one, two, three, four or more individual doses. Alternatively, they can contain '/ 2, V3 or' / 4 of a single dose. A single dose preferably contains an amount sufficient to achieve the desired therapeutic effect after administration with the application of one or more dosage units according to the predetermined dosage schedule, usually a '/ i, lh, xh or' / 4 of a daily dose,

which is administered once, twice, three times or four times a day. Other therapeutic agents can also be present. Pharmaceutical agents which provide about 1 to 500 mg of the active ingredient per single dose are preferred. The pharmaceutical agents are usually provided in the form of tablets, troches, capsules, powders, aqueous or oily suspensions, syrups, elixirs and aqueous solutions. Preferred oral agents are in the form of tablets or capsules and can contain conventional excipients! "These include binders (eg syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone), fillers (eg lactose, sugar, corn starch, calcium phosphate, sorbitol or Glycine), lubricants (for example magnesium stearate, talc, polyethylene glycol or silica), disintegrating agents (for example 5 starch) and wetting agents (for example sodium lauryl sulfate). Solutions or suspensions of the compounds of the general formula (I) together with customary pharmaceutical carriers are used for parenteral agents, such as an aqueous solution for intravenous injection 20 or an oily suspension for intramuscular injection, such agents having the desired clarity, stability and suitability for parenteral use can be obtained by 0.1 to 10 wt % of the active ingredient dissolves in water or a carrier, which consists of an aliphatic n polyalcohol, for example glycerol, propylene glycol or polyethylene glycols or mixtures thereof. The polyethylene glycols consist of a mixture of non-volatile, generally liquid polyethylene glycols which are soluble in both water and organic liquids and whose molecular weight is approximately 200 to 1500.

The compounds of the general formula (I) according to the invention in which Z represents the radicals (a) to (e) are obtained by processes in which piperazinyl or “imide” intermediate compounds are alkylated. These procedures correspond to those described by Wu et al. in the above-mentioned patents or by Tempie et al. are described in the above-mentioned patents, to which reference is made here. These processes can be combined into one unit process which is used to prepare the compounds of the general formula (I) according to the invention. The methods can be varied to obtain other compounds encompassed by the invention that are not specifically disclosed. Modifications 45 to these methods which lead to the same compounds in somewhat different ways are also obvious to the person skilled in the art. Certain examples are explained in more detail below.

50 standard procedures

In this scheme, R ', R2, X and Y have the meanings given above in connection with the formula (I). The symbol D either represents the divalent structures of the radicals (a) to (d), as shown in the following substructures (a ') to (d') is shown, or for the rest (e ') also shown below.

11

672 787

W— ^ 0

(b ')

CCH2) 3-

<d ')

(e ')

In the residues (a ') to (e') all symbols have the previously mid, iodide, sulfate, phosphate, tosylate or mesylate. That assigned meanings. The symbol «E» in the above 20 symbol <(J >> can be for h2N_ (CH?) Q_ (CH2) n-; f "0"; scheme can stand for O; NH; or N- (CH2) nQ . ^

Symbol «n» has the meanings given above. Q ° of standing. The relationship between E and J is as designated a suitable leaving group, such as chloride, Bro- follows:

Method No.

If E stands for:

)> (Ha)

^ TH (IIb)

W (CH2) n-Q (Ile)

Darai means J:

H2N- (CH2) rìdila)

X- (CH_) -or _ ©

c

• (Illb) (Illb1)

H- (IIIc)

Method A

D Ò + H2N- (CH2) n-N

IIa

Method B 1)

D N-H

+ N

Illb

A

dry solvent j -1 ^ 0

2)

IIb +

R.

R1

+ N

No\

\ _V

Illb '

(Illb 'is a special case where n is fixed to 4)

672787

12

Method C (preferred method)

K

1

- + I

Ile

IIIc

In method A, the condensation is carried out by refluxing the reactants in a dry, inert reaction medium, for example pyridine or xylene. In methods B and C, the reaction is carried out under reaction conditions which are suitable for the preparation of tertiary amines via the alkylation of secondary amines. The reactants are heated in a suitable organic liquid to temperatures from about 60 ° to about 100 ° C in the presence of an acid binding agent. Benzene, dimethylformamide, ethanol, acetonitrile, toluene and n-butyl alcohol are preferred examples of such liquid organic reaction media. Potassium carbonate is preferably used as the acid-binding agent, but other inorganic and tertiary organic bases can also be used. These include a further 15 alkali and alkaline earth metal carbonates, bicarbonates or hydrides and the tertiary amines. All three methods are described in more detail in the above-mentioned patents, to which reference is hereby made. Method C represents the preferred synthetic process for the preparation of the compounds according to the invention. The required intermediate compounds Ile are prepared by methods which are described in more detail in the patents to which reference has been made.

25th

The modified method C described below is used to prepare the compounds of the general formula (I) in which Z is the radical (s).

An example of a modified method for the preparation of the compounds of the general formula (I) according to the invention is explained in a somewhat different way below, using an alkylpiperazine-4 substituted with Z.

/ ■ n

Z- (CH ") -N N-H +

w

IV

The invention thus also relates to a process for the preparation of the compounds of the general formula

50 with a suitable condensed bicyclic pyridine system 5 to give a compound of general formula (I), e.g.

R2

V

(I), which is characterized in that (a) an intermediate compound of the formula IIa

13

672 787

D 0

(IIa)

where the symbol "D" means a divalent structure of the formulas a'-d '

(Illb ')

Ca ')

S

Cb '>

10th

wherein Q, R1, R2, X and Y have the meanings given above, to give a compound of the general formula I, in which n is the integer 4; or (d) a compound of formula Ile

15

(C)

N- (CH2) n-Q

(Hey)

(G).

m

20th

with an intermediate compound of formula IIIc u-

CD')

with an intermediate compound of the formula purple

Ï

u

./*vK

25th

30th

Î

R1 X / "', Y

(IIIc)

wherein D, n, Q, R1, R2, X and Y have the meanings given above, to give a compound of the general (purple) formula I; or

35 (e) a compound of formula IV

lynciyn-

wherein R1, R2, n, X and Y have the meanings given above, are converted into a compound of the formula I;

or

(b) a compound of the formula

A- \

Z-CCH ^ -N N-H

(IV)

D N-H

with an intermediate compound of the formula Illb

(IIb)

45 with an intermediate compound of formula V.

K2 t

X '"** Y

Margin

50

55

(V)

(Illb) wherein Z, n, R1, R2, Q, X and Y has the meanings given above, to give a compound of the general formula I; or

(f) (i) a compound of formula Ild

60

O 0

(Ild)

wherein Q is a suitable leaving group, for example chloride, bromide, iodide, sulfate, phosphate, tosylate or mesylate,

and D, R1, R2, n, X and Y have the meanings given above, are converted into a compound of the general formula I; or

(c) a compound of the formula IIb with an intermediate compound with an intermediate compound of the formula IIIc to give a compound of the formula IIIb 'compound of the general formula If

(CH ^ -Q

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14

/ 1

0 0

-O*

f

R1 x .. «.. y

(If)

R

k

X * '-Y

(le)

converts, (ii) the compound If in acidic medium to a compound of the general formula Ig

^ Ca) 2) 3-H

10 reduced.

The intermediate compounds of the formulas (II) or (IV) are described in a suitable manner in the abovementioned patents and the literature citations mentioned therein, to which reference has been made. Various compounds 15 of formula (II) are also commercially available. The bicyclic pyridinylpiperazine intermediates of the formula (Ig) (III) and the bicyclic heterocycles (V) used as starting compounds are either commercially available, described in the chemical literature or explained in more detail in the 20 documents available. The methods used for the synthesis of the intermediate compounds of the formula (III) are explained in more detail in scheme I.

hydrolyzes and (iii) the compound of formula Ig with Na scheme I.

triumborohydride to a compound of formula Ie 25 Synthesis of bicyclic intermediates III:

CH2 (C02H)

Piperidine catalyst

* r \ i

CO "H

R * ^ CHO pyridine solvent _2

90 °

X

X) J '.

VII

Biphenyl ether

240

, zv>

VI

NaN.

I ^ O-Acetcm

P0C1.

IX

SOCI,

DMF, CHC1.

YYY

0

If

Ç-C1

R2 '

VIII

• R '

20 h in 120 ° baroe

15

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Thieno-pyridine ring systems according to Scheme I are based on the carboxaldehyde intermediate compound of the formula (X). The 2-carboxyaldehyde intermediate is shown in Scheme I and leads directly to the intermediate 111-c 5 compound (IIIc), also shown in Scheme I. If the 3-carboxaldehyde intermediate (X ') is used according to Scheme I, the product obtained is the “reverse” isomer (IIIc').

For the synthesis of furo-, pyrrolo-, cyclopentadieno- or io

YY

CHO

Scheme 1

aK

H = N Tî

v_y

(X ')

(IIIC)

The general structure (III) (where J = H) of the unit procedure explained above generally reflects the structures of the two intermediates (IIIc) and (IIIc ').

The carboxyaldehyde required as starting compound shown in Scheme I can either be obtained commercially or can be prepared in a simple manner, e.g. by Vils-Meier-Haack formylation of an n-alkylpyrrole, using methods which are described in the chemical literature and are well known to the person skilled in the chemical art. The condensation of the intermediate compound (X) with malonic acid at 100 ° C. is usually carried out in pyridine as a solvent, using piperidine as a catalyst. The reaction is generally carried out for 12 hours and then refluxed for a short time in order to promote decarboxylation. The corresponding acrylic acid intermediate compounds of the formula (IX) are obtained.

The acids of the formula IX are chlorinated with thionyl chloride in chloroform and a catalytic amount of dimethylformamide to give the acid chloride derivatives of the formula VIII, which are not purified, but are used in crude form for the preparation of the acid azides of the formula VII. These acid azides are prepared either in a two-phase mixture of acetone in water at 5 ° using sodium azide or with trimethylsilyl azide in refluxing benzene. The unpurified preparations of the acid azides of the formula VII in methylene chloride solutions are added in portions to either diphenyl ether or diphenylmethane and heated to 230 °, which facilitates the Curtius rearrangement via isocyanates, which immediately cyclize to the condensed 6-5 bicyclic intermediates of the formula VI . The compound VI is chlorinated by using phosphorus oxychloride or a phosphorus pentachloride-phosphorus oxychloride mixture to produce the chlorine-substituted heterocycle of the formula V. The reaction of V with an excess of a suitable piperazine in a bomb at 120-140 ° C. with reaction times of different lengths leads to the desired piperazine intermediates IIIc. This general synthesis for the preparation of the intermediate compounds of the formula IIIc has already been described, see Eloy, et al., Bull. Soc. Chim. Beiges., 79, 301 (1976); J. Heterocyclic Chem., No. 8: 57 (1971); Helv. Chim. Acta., 53, 645 (1970)). The R2 substituent can then be introduced

25 either by incorporating it into the starting compound X or later introducing it into the reaction, e.g. by methylation of V (X = S, R2 = H) with t-butyllithium and subsequent reaction with diethyl disulfide, giving an intermediate compound of the formula V, in which 30 R2 = SCH3.

The. Use of the intermediate compounds of the general formula III in the unit process described above and the use of methods A-C, preferably C, leads to the antipsychotic compounds of the general formula I.

The invention is explained in more detail below with the aid of the examples. All temperature data refer to degrees Celsius, unless stated otherwise. The NMR spectral data denote the chemical shifts (5), which are expressed as parts per million (ppm) compared to tetramethylsilane (TMS) as the standard. The relative area given for the various shifts in the 'H-NMR spectrum corresponds to the number of hydrogen atoms of a certain functional type in the mole-45 kIl. The type of multiplicity shifts is given as follows: Broad singlet = bs, singlet = s, multiple «= m, doublet = d, doublet of doublets = dd, triplet = t, quartet = q. The following abbreviations are used: DMSO-d6 = perdeuterodimethyl sulfoxide, CDC13 50 = deuterochloroform. Otherwise, usual abbreviations are used. Of the IR spectra, only the wave numbers (cm-1) of those absorptions are given which are important for the identification of functional groups. IR images were taken using potassium 55 bromide (KBr) as a diluent. All compounds gave satisfactory elemental analysis. The following representative examples of the chemical intermediates of the formulas VX illustrate the synthesis of the key intermediary IIIc, which can be converted into other synthetic intermediates, such as lilac or Illb, using known reactions, as described, for example, in the patents mentioned .

65 Example 1

N-methylpyrrole-2-carboxaldehyde (X)

A stirred mixture of N-methylpyrrole (10 g; 0.12 mol) in dichloroethane (80 ml) and dimethylformamide

672 787

16

(11.3 g; 0.15 mol) is replaced dropwise at 5 ° with phosphorus oxychloride (23.6 g; 0.15 mol). This leads to an exothermic reaction in which a precipitate forms. The mixture is stirred for a further 15 minutes and the precipitate is filtered off, suspended in 300 ml of 3N NaOH solution and extracted with 3 × 100 ml of chloroform. The chloroform portions are combined, dried over MgSO4, filtered and concentrated in vacuo to give 6.1 g (49%) of a dark oil, boiling point 87-90 ° at 22 torr. The NMR spectrum agrees with the assigned structure. This intermediate was generally used unpurified in the next step of Scheme 1.

Example 2 3- (2-Thieno) acrylic acid (IX)

A mixture of 2-thiophene carboxaldehyde (100 g; 0.89 mol); Malonic acid (182.5 g; 1.70 mol); Pyridine (446 ml) and piperidine (8.9 ml) are heated at 100 ° for 12 hours. The reaction solution is heated under reflux for 20 minutes, allowed to cool, poured into 1000 ml of water and the resulting aqueous mixture is acidified with conc. HCL on. The gray-white precipitate obtained is filtered off and crystallized from ethanol-water (1: 1), giving 109 g (80%) of the product, melting point 145-148 °.

Example 3

3- (2-thieno) acryloyl chloride (VIII)

A stirred suspension of 3- (2-thieno) acrylic acid (118.9 g; 0.77 mol) and 12 ml of dimethylformamide in 600 ml of chloroform is added dropwise at room temperature with thionyl chloride (110.1 g; 0.93 mol). The reaction mixture is then heated under reflux for 2 hours, cooled and concentrated in vacuo to a brown oil which solidifies on standing. This gives 131 g (99%) of a low-melting solid which is used without further purification.

Example 4

4-oxo-4,5-dihydrothieno [3,2-c] pyridine (VI)

A stirred suspension of sodium azide (168.6 g; 2.6 mol) in a mixture of 400 ml of p-dioxane and 400 ml of water is added dropwise with a solution of 3- (2-thieno) acryloyl chloride (223.9 g ; 1.3 mol) in dioxane at 5 °. The dioxane layer obtained from this two-phase mixture is isolated, concentrated in vacuo, dissolved in 500 ml of methylene chloride, dried and filtered. The methylene chloride filtrate is added dropwise to diphenyl ether (400 ml) boiling under reflux, which is located in a triple flask equipped with two air coolers. The solution is refluxed for an additional hour, cooled and concentrated in vacuo to a dark syrup which is crystallized from acetonitrile to give a brown solid which is filtered off. After recrystallization of the solid from 650 ml of water, 106 g (54%) of a pale yellow solid, melting point 213-214 °.

Example 5 4-chlorothieno [3,2-c] pyridine (V)

Finely ground 4-oxo-4,5-dihydrothieno [3,2-c] pyridine (105.6 g; 0.69 mol) is stirred, giving phosphorus oxychloride (321.5 g; 2.1 mol) dripped at 0 °. The reaction mixture is then heated under reflux for 2.5 hours, cooled and carefully poured onto 1000 ml of crushed ice. The solution obtained is stirred for 30 minutes and extracted with 3 x 400 ml dichloromethane. The organic components are combined, dried over MgSO4, filtered and concentrated in vacuo to a solid which is recrystallized from 400 ml of acetonitrile, giving 101 g (85%) of a light yellow solid, melting point 91 ° C.

Example 6

5 4- (l-piperazinyl) thieno [3,2-c] pyridine (IIIc)

A mixture of 4-chlorothieno [3,2-c] pyridine (22.7 g; 0.13 mol) and piperazine (57.7 g; 0.67 mol) is heated in a bomb with a minimal amount of ethanol (50 ml) 24 hours at 120 ° C. The reaction is cooled, dichloromethane and water are divided between two, and the organic layer is isolated, which is dried over MgSO4, filtered and concentrated in vacuo to an oil. Flash chromatography (methylene chloride-10% methanol-1% ammonium hydroxide) of this material gives 16 g (54%) of a gold-colored oil. After treating an ethanol solution of this oil with ethanolic HCl and subsequent recrystallization from ethanol, the hydrochloride salt is obtained in the form of gray-white crystals, melting point 275-283 ° C.

20 Example 7

Preparation of 7- (l-piperazinyl) thieno [2,3-c] pyridine (IIIc ') This compound is prepared by carrying out the same reaction steps as in the preparation of compound IIIc, but using 25 X 3 as the starting compound -Thiophencarboxaldehyd uses. However, the multistep preparation of the positional isomer IIIc 'is complicated because the Curtius rearrangement (Example 4) only provides the desired intermediate VI in low yield. The main product of this reaction is a sym-triazine by-product which results from the trimerization of the isocyanate intermediate.

Nevertheless, the use of the reactions shown in Scheme 1 leads to the preparation of product IIIc ', which is a brown rubber-like material that is used without further purification.

Suitable compounds IIIc can be synthesized by suitable modifications of the reaction steps shown in Scheme 1 and the various synthesis reactions explained above. Some other representative compounds IIIc are listed in Table 3.

Table 3

Other compounds of formula IIIc

IIIc

60

65

At

game

R1

R2

x

Y

8th

H

H

CH

N-CH3

9

H

H

CH

O

10th

H

H

CH

CH,

11

H

H

N-CH

, CH

12

H

H

O

CH

13

CH3

H

CH

s

14

H

ch3

CH

N-CH,

15

ch3

och3

CH

O

16

H

sch3

CH

s

Mp 0 C

> 250

203-205 (.Hcl.H20)

17th

672 787

table

3 (continued)

Analysis.

C22H30N4O2S HCl: C% H% N%

At

calculated: 58.59 6.93 12.42

game

R1

R2 X

Y

Mp 0 ° C

found: 58.64 7.02 12.72

5

17th

ch3

Cl O

CH

'H NMR:

18th

H

Br S

CH

1.08 (6, s); 1.71 (4.m); 2.60 (4, s); 3.40 (10, m); 4.00 (2.m);

19th

H

OH CH

ch2

7.65 (2, m); 7.87 (1, m); 8.08 (1, d [5.0 Hz]); 11.75 (1, bs).

20th

H

C2H5 CH

S

21st

H

H S

CH

10 IR (KBr):

22

H

SCH3 CH

S

715, 965, 1425, 1535, 1670, 1720, 2580, 2960 cm "1.

The preparation of the compounds of the general formula I is described below.

Example 23

General synthesis

The compounds of general formula I are synthesized by alkylating imide derivatives (Ile) substituted by suitable halogen substituents, in which D is (a'-d ') and E is N- (CH2) nQ, where Q is a halide . The fluorophenylbutrophenone derivative (Ild) can also be reacted with a suitable intermediate IIIc in refluxing acetonitrile, three equivalents of calcium carbonate being present. The carbinol derivatives are produced by reducing the corresponding butyrophenone with sodium borohydride. The reaction times for the alkylation are between 5 and 72 hours. The products obtained are generally purified using flash chromatography in an ethanol-chloroform mixture. The compounds of general formula I were generally converted into the hydrochloride salts for test purposes.

Example 24

4,4-dimethyl-l- [4- [4 (thieno [3,2-c] pyridine -4-yl) -1-pipe-razinyl] butyl] -2,6-piperidinedione

A mixture of 4- (l-piperazinyl) thieno [3,2-c] pyridine (IIIc; 2.79 g, 0.012 mol), N-4-bromobutyl) -3-dimethylglutamide (3.3 g, 0.012 Mol) and potassium carbonate (3.3 g, 0.024 mol) are heated under reflux in 150 ml of acetonitrile for 24 hours. The reaction mixture is filtered, concentrated in vacuo and partitioned between dichloromethane and water. The organic layer is isolated, dried over MgSO4 and concentrated in vacuo to a golden oil which is flash chromatographed (5% ethanol-chloroform). The chromatographed material is dissolved in acetonitrile and treated with ethanolic HCl, giving 1.3 g (24% yield) of the hydrochloride salt, melting point 195-197 ° C.

Example 25

4- [4- [4- (4-Furo [3,2-c] pyridinyl) -1-piperazinyl] butyl] -3,5-morpholine dione

A mixture of 4- (l-piperazinyl) furo [3,2-c] pyridine (4.5 g; 0.022 mol), 4- (4-bromobutyl) -3,5-morpholinedione (5.5 g; 0.022 mol ) and potassium carbonate (9.1 g; 0.066 mol) are heated under reflux for 24 hours. The reaction mixture is filtered, concentrated in vacuo and partitioned between dichloromethane and water. The organic layer is isolated, dried over MgSO4 and concentrated in vacuo to a yellow oil which is flash chromatographed. The appropriate chromatographic fractions are combined, concentrated in vacuo and crystallized from isopropanol, giving 6.2 g (69%) of the free base, melting point 109-110 °.

Analysis for CI9H24N404; C% H% N% calculated: 61.28 6.50 15.04

found: 60.98 6.60 15.19

> H NMR (CDC13):

1.60 (4.m); 2.40 (2, m); 2.57 (4. m); 3.74 (6, m); 4.31 (4, s); 6.78 (1, d [2.0 Hz]); 6.89 (1, d [5.8 Hz]); 7.49 (1, d [2.0 Hz]); 8.01 (1, d [5.8 Hz]).

IR (KBr):

760, 780, 1250, 1285, 1440, 1460, 1570, 1595, 1690, 1735, 2830 cm "1.

Further compounds of the general formula I can be obtained by the procedure described above or by alternative synthetic processes which are disclosed in the abovementioned patents. Tables 4 and 5 below list further representative compounds of the general formula I. In Table 6, biological in vivo data for representative compounds of the general formula I are compiled.

20th

25th

30th

35

40

45

Table 4

Compounds of the general formula I

Z-tCH 1 -N £ n

Ile 4

E.g.

No.

26

27th

28

29

30th

31

32

34

36

37

^ K

H

(b)

(a) °

S-4o

(b)

r ~ $

S fl-

y \\

0

<c)

0

2nd

<d)

18th

R1 R2 X Y Formula3 '

4 H H CH S C22H22N4O2O2.

S- ^ 1.4 HCl

(b)

(e) 3 H H CH S C21H24FN3OS

H Br CH S C22H27BrN402S2HCl

N_ 4 H Br CH S C2, H, 9BrN402S

• HCl-0.5 H20

H CH, CH S C23H30N4O2S2-HCl

H H CH S Ci9H24N402S,

• 1, 1C7H803S-0.5H20

H H CH S C22H24N403S2HC1

0

4 H H CH S C23H24N402S * HC1

w%

4 H H S CH C22H, 8N402S2 I yj_ -2HCH, 8H, 0

H

(b) °

cu °

N- 4 H H CH O C22H28N403S

S J -2 HC1C2H60 O

(b)

19th

672 787

Table 4 (continued) Z

38

Example No.

x>

39

40

41

42

44

45

46

47

49

*

(a)

(e)

. (b)

jr-

<»>

rJ

s K-

w

(c) °

43 (e)

r \

S K-

\\

(O

(»)

(•)

<^ K

1 N

.H

0 N

M>

(c)

N-

(*)

R1 R1 X Y Formula3 '

H H CH O C22H3ON403

• 1.4 HCl

Mp (° C)> 250

H H CH O C21H24FN302-HC1 205-207

H CH3 CH O C23H30N4O3S-1, 2 HCl 176-177

H CH3 CH O C23H32N403

1.2 HCl-0.5 H20

H H CH O

CI9H24N403S • 2HC10.5 H20

H CH3 CH O C22H26FN302HC1

H H CH S C19H24N403S

H H CH S C21H28N402S

H H CH S C20H26N4O2S

4 H H CH

NMe C23H3IN502S-2 HCl ■ 1.6 H20

H H CH NMe C20H27N5O3

H H CH NMe C23H33N502

• 2.1 HCl-2.6 H20

321-233

245-250

121-122 114-115

173-175

199-201

148-150

144-146

192-194

a) The elementary analyzes for C, H and N were all within ± 0.4% of the theoretical values for the given formulas.

672 787

20th

Table 5

Other compounds of general formula I.

R1 xA,

aK

Z-tCH,] -H N

w

E.g.

No. Z

33

35

DQ

»Xj

* ^

51

52

'-Q-

Hey

fi V

lî-

53

54

55

° -Q $

ö

56

57

<-

n R1 R2 X Y 4 H H CH S

4 CH3 H CH S

4 CHj OH CH N-CH3

4 H SCH, CH S

4 H H CH O

4 H H CH O

4 H OMe S CH

N- 4 H OH CH S

SO"

4 H SCH3 CH S

4 H SCH, CH S

21st

Table 6

Representative biological in vivo data (mg / kg, p.o.)

At

CAR

APO

Catalepsy-

Catalepsy-

game edjo ed50

induction

Reversal ed50

number

ed50

24th

6

40

> 24

lAa)

25th

11

34

> 46

2nd

26

12

35

-

1A

27th

10th

9

> 40

1A

28

> 100

> 100

_b)

16

29

65

-

-

1A

30th

35

-

> 142

1A

31

32

-

> 128

1A

36

43

47

-

1A

37

9

18th

23

1A

38

4th

7

13

1A

39

3rd

5

11

1A

40

28

41

-

-

41

14

22

40.

1A

42

36

63

-

1A

43

23

-

-

1A

47

60

61

-

1A

48

> 100

> 100

-

1A

49

67

> 100

-

1A

a) 1A means inactive and is used if the ED50 value is> 20 mg / kg.

b) The indent means that the corresponding value is not available.

Claims (17)

672 787 PATENT CLAIMS 1. Disubstituted 1,4-piperazinyl derivatives of the general formula I Z- [CH2] n ~ N (I) V_ / wherein Z represents one of the following radicals: (a) wherein R3 and R4 independently of one another represent a hydrogen atom or a lower alkyl radical or together represent a C3-C6-alkylene chain: (b) N- W - ^ wherein R5 and R6 independently of one another represent a hydrogen atom, a lower alkyl radical or an A-substituted phenyl radical, where A represents a hydrogen or halogen atom, or R5 and R6 together represent a butylene chain, and W represents S or CH2 is; (c) wherein V is O or S; (d) rA \ _J \\ 0 <G). 10th 15 20th 25th N- wherein G represents a hydrogen atom, a lower alkyl radical, a lower alkoxy radical or a halogen atom, m represents an integer from 1 to 4 and U represents C = 0 or S02; and (e) -O-* n is an integer from 2 to 4, where if Z is (e), n is 3; either X or Y is CH2, O, S or NR7 and the other X or Y must then be = CH-; R1 and R7 independently represent a hydrogen atom or a lower alkyl radical; and R2 represents a hydrogen or halogen atom or a lower alkyl, lower alkoxy, lower alkylthio or hydroxy radical, and the pharmaceutically acceptable acid addition salts thereof. 2. Compounds according to claim 1, wherein Z represents the radical (b) and R5 and R6 together represent a butylene chain and W represents a sulfur atom. 3. Compounds according to claim 1, wherein Z represents the radical (c) and V represents an oxygen atom. 4. Compounds according to claim 1, wherein Z represents the radical (a), (c) or (e) and Y represents an oxygen atom. 5. Compounds according to claim 1, wherein Z represents the radical (a), (b) or (e) and Y represents a sulfur atom. 6. l- [4- [4- (Furo [3,2-c] pyridin-4-yl) -1-piperazinyl] -bu-tyl] -4,4-dimethyl -2,6-piperidinedione, 4,4-dimethyl-1- [4- [4- (2-methylfuro [3,2-c] pyridine -4-yl) -1-piperazinyl] butyl] -2,6-piperidinedione, 4,4-dimethyl-l- [4- [4 - (thieno [3,2-c) pyridin-4-yl) -1-piperazinyl] butyl] -2,6-piperidinedione, 4,4-Dimethyl-l- [4- [4- (1-methyl-1H-pyrrolo [3,2-c] pyridin-4-yl) -1-piperazinyl] butyl] -2,6- piperidinedione, 4,4-dimethyl-l- [4- [4- (2-bromothieno [3,2-c] pyridine -4-yl) -1-piperazinyl] butyl] -2,6-piperidinedione, 1- [4- [4- (Thieno [3,2-c] pyridine -4-yl -1-piperazinyl] -bu-30 tyl] -1,6-piperidinedione or 4-Methyl-l- [4- [4- (thieno [3,2-c] pyridin-4-yl) -1-piperazinyl] butyl] -1,6-piperidinedione, as a compound according to claim 1, wherein Z the rest (a) means. 7. 3- [4- [4- (Furo [3,2-c] pyridin-4-yl) -1-piperazinyl] -bu-35 tyl] -1-thia -3-azaspiro [4.4] nonane -2 4 dion 3- [4- [4- (2-Methylfuro [3,2-c] pyridine -4-yl) -1-piperazinyl] butyl] -1-thia -3-azaspiro [4.4] nonane -2,4- dion, 3- [4- [4- (Thieno [3,2-c] pyridine -4-yl) -1-piperazinyl] -bu-tyl] -l-thia -3-azaspiro [4.4] nonane 2,4-dione or 3- [4- [4- (l-methylpyrrolo [3,2-c] pyridine -4-yl) -1-piperazinyl] butyl] -1-thia -3-azaspiro [4.4] nonan-2, 4-dion, 3- [4- [4- (2-Bromothieno [3,2-c] pyridine -4-yl) -1-piperazinyl] butyl] -1-thia -3-azaspiro [4.4] nonane-2,4- dion, 3- [4- [4- (2-Methylthieno [3,2-c] pyridine -4-yl) -1-piperazinyl] butyl] -1-thia -3-azaspiro [4.4] nonane-2,4- dion, 3- [4- [4- (Thieno [2,3-cpyridin -7-yl) -1-piperazinyl] -bu-tyl] -1-thia -3-azaspiro [4.4] nonane -2,4-dione, as a compound according to claim 1, wherein Z represents the radical (b). 4- [4- [4- (4-Furo [3,2-c] pyridinyl) -1-piperazinyl] butyl] 50 -3,5-morpholine dione, 4- [4- [4- (1-methyl-1H-pyrrolo [3,2-c] pyridine -4-yl) -1-piperazinyl] butyl] -3,5-morpholinedione, 4- [4- [4- (4-Thieno [3,2-c] pyridinyl) -1-piperazinyl] butyl] -3,5-thiomorpholinedione or 4- [4- [4- (4-Thieno [3,2-c] pyridinyl) -1-piperazinyl] butyl] -3,5-morpholinedione, as a compound according to claim 1, in which Z represents the radical (c) . 9. 2- [4- [4- (Thieno [3,2-c] pyridin-4-yl -1-piperazinyl] butyl] -1H isoindole -1, 3- (2H) dione or 2- [4- [4- (Thieno [3,2-c] pyridine -4-yl) -1-piperazinyl] butyl] -1,2-benzisothiazole -3 (2H) -one -1,1-dioxide as a compound according to claim 1, wherein Z represents the radical (a). 10. a- (4-fluorophenyl) -4- (furo [3,2-c] pyridine -4-yl) -1-pi-perazinbutanol, 65 a- (4-fluorophenyl) -4- (2-methylfuro [3,2-c] pyridine -4-yl) -1-piperazinbutanol or a- (4-fluorophenyl) -4- (thieno [3,2- c] pyridine -4-yl) -1-pipe- 40 45 55 60 3rd 672 787 razinbutanol as a compound according to claim 1, wherein Z represents the radical (s). 11. A compound according to claim 1 as a means of alleviating an undesirable psychotic condition in a mammal. 12. A pharmaceutical composition in the form of a dosage unit suitable for systemic administration to a mammal, which contains a pharmaceutical carrier and 1-500 mg of an active compound according to claim 1. 13. A process for the preparation of the disubstituted 1,4-pi-perazinyl derivatives of the general formula I 2- [CH.] -N 2 n 10th 15 (I) wherein G represents a hydrogen atom, a lower alkyl radical, a lower alkoxy radical or a halogen atom, m represents an integer from 1 to 4 and U represents C = 0 or S02; n represents an integer of 2 or 4; either X or Y is CH2, O, S or NR7 and the other X or Y must then be = CH-; R1 and R7 independently represent a hydrogen atom or a lower alkyl radical; and R2 represents a hydrogen or halogen atom or a lower rigalkyl, lower alkoxy, lower alkylthio or hydroxy radical, and the pharmaceutically acceptable acid addition salts thereof, characterized in that an intermediate compound of the formula IIa / ^ \ 20 in which the symbol "D" denotes a divalent structure of the formulas a'-d 'in which Z denotes one of the following radicals: (a) wherein R3 and R4 independently of one another represent a hydrogen atom or a lower alkyl radical or together represent a C3-C6 alkylene chain: 3 0 35 Cb ') r ~ X w: CO (b) 40 -K V- wherein R5 and R6 independently of one another represent a hydrogen atom, a lower alkyl radical or an A-substituted phenyl radical, where A represents a hydrogen or halogen atom or R5 and R6 together represent a butylene chain and W represents S or CH2 ; (c) wherein V is O or S; 0 / K V N- v_ / \\ 0 (d) CD') with an intermediate compound of the formula purple 45 50 /"H X »•" • Y wherein R1, R2, n, X and Y have the meanings given above, is converted to a compound of the formula I, and 55 the compound obtained is optionally converted into a pharmaceutically acceptable acid addition salt. 14. Process for the preparation of the disubstituted 1,4-pi-perazinyl derivatives of the general formula I 60 2- [CH.] -N 2 n (I) 672787 wherein Z represents one of the following radicals; (a) wherein R3 and R4 independently of one another represent a hydrogen atom or a lower alkyl radical or together represent a C3-C6-alkylene chain: (b) v- wherein R5 and R6 independently of one another represent a hydrogen atom, a lower alkyl radical or an A-substituted phenyl radical, where A represents a hydrogen or halogen atom, or R5 and R6 together represent a butylene chain, and W represents S or CH2 ; (c) wherein V is O or S; . 0 r-K V N- v_y w 0 (d) <C) N- R2 8-1 (nib) 10th or 15 20th (HIb ') wherein Q chloride, bromide, iodide, sulfate, phosphate, tosylate or mesylate and D, R1, R2, n, X and Y have the meanings given above, to a compound of the general formula I, and the compound obtained if necessary transferred to a pharmaceutically acceptable acid addition salt. 15. Process for the preparation of the disubstituted 1,4-pi-perazinyl derivatives of the general formula I. 30th 35 Z-tCH,] -N 2 n (I) \ _ / 40 wherein Z represents one of the following radicals; wherein G represents a hydrogen atom, a lower alkyl radical, a lower alkoxy radical or a halogen atom, m represents an integer from 1 to 4 and U represents C = 0 or S02; n represents an integer of 2 or 4, either X or Y represents CH2, O, S or NR7 and the other radical X or Y must then stand for = CH-; R1 and R7 independently represent a hydrogen atom or a lower alkyl radical; and R2 represents a hydrogen or halogen atom or a lower rigalkyl, lower alkoxy, lower alkylthio or hydroxy radical, and the pharmaceutically acceptable acid addition salts thereof, characterized in that a compound of the formula 45 (a) wherein R3 and R4 independently of one another represent a hydrogen atom or a lower alkyl radical or together represent a C3-C6 alkylene chain: 55 (b) J / 60 tf- (Hb) with an intermediate compound of the formula in which R5 and R6 independently of one another represent a hydrogen atom, a lower alkyl radical or an A-substituted phenyl radical, where A represents a hydrogen or halogen atom or R5 and R6 together represent a butylene chain and W is S or CH2; 672 787 (c) wherein V is O or S; r ~ K V N- W • 5 V \ 0 (d) N- (CH-) -Q 2 n with an intermediate compound of the formula IIIc in which R3 and R4 independently of one another denote a hydrogen atom or a lower alkyl radical or together 10 represent a C3-C6-alkylene chain: (b) 15 wherein G represents a hydrogen atom, a lower alkyl radical, a lower alkoxy radical or a halogen atom, m represents an integer from 1 to 4 and U represents C = 0 or S02; n represents an integer of 2 or 4; either X or Y is CH2, O, S or NR7 and the other X or Y must then be = CH-; R1 and R7 independently represent a hydrogen atom or a lower alkyl radical; and R2 represents a hydrogen or halogen atom or a lower rigalkyl, lower alkoxy, lower alkylthio or hydroxy radical, and the pharmaceutically acceptable acid addition salts thereof, characterized in that a compound of the formula Ile K- 20 in which R5 and R6 independently of one another represent a hydrogen atom, a lower alkyl radical or an A-substituted phenyl radical, where A represents a hydrogen or halogen atom or R5 and R6 together represent a butylene chain, and W represents S or CH2 is; 25th 0 (c) 30th \\ 0 wherein V is O or S; (Hey) 35 (d) (G). N- r yy ** Y 40 in which G represents a hydrogen atom, a lower alkyl radical, a lower alkoxy radical or a halogen atom, (IIIc) m represents an integer from 1 to 4 and U represents C = 0 or S02; and 45 Z- [CH,] -N 2 n (e) wherein D, n, R1, R2, X and Y have the meanings given above and Q is chloride, bromide, iodide, sulfate, phosphate, tosylate or mesylate, converted to a compound of general formula I and the compound obtained optionally in a pharmaceutical tolerated acid addition salt transferred. 16. Process for the preparation of the disubstituted 1,4-pi-perazinyl derivatives of the general formula I n is an integer from 2 to 4, where Z is the radical (s) 50 when n is 3; either X or Y is CH2, O, S or NR7 and the other X or Y must then be = CH-; R1 and R7 independently represent a hydrogen atom or a lower alkyl radical; and 55 R2 represents a hydrogen or halogen atom or a lower rigalkyl, lower alkoxy, lower alkylthio or hydroxy radical, and the pharmaceutically acceptable acid addition salts thereof, characterized in that a compound of the formula IV 60 (I) Ä. A 65 Z-COiO-H N-H 7n \ r (IV) wherein Z represents one of the following radicals; with an intermediate compound of formula V 672 787 6 R2 tÀy fj (V) wherein Z, n, R1, R2, X and Y have the meanings given above and Q is chlorine, bromide, iodide, sulfate, phosphate, tosylate or mesylate, is converted into a compound of general formula I, and the compound obtained optionally in one transferred pharmaceutically acceptable acid addition salt. 17. Process for the preparation of the disubstituted 1,4-pi-perazinyl derivatives of the general formula Ie -O ^ (CH2) 3-N 10th 15 hydrolyzed and (c) the compound of the formula Ig is reduced with sodium borohydride to a compound of the formula Ie, and the compound obtained is optionally converted into a pharmaceutically acceptable acid addition salt. 20th 25th (le) where Z 30th