LU86421A1 - 1,4-DISUBSTITUTED PIPERAZINE DERIVATIVES, PHARMACEUTICAL COMPOSITION CONTAINING THEM, AND PROCESS FOR OBTAINING THE SAME - Google Patents

Description

t 1 J,

The present invention generally relates to heterocyclic carbon compounds having therapeutic and biological properties, as well as their preparation and use. In particular, the subject of the invention is derivatives of piperazine disubstituted in positions 1 and 4 where a substituent is a condensed bicyclic heterocyclic system comprising systems with a furo-, pyrrolo-, cyclopentadieno-, and thieno-pyridine nucleus; and the other substituent is an alkylidene chain, preferably a butylidene chain carrying a cyclic imide ring or a benzyl carbinol part at its end. Examples of categories of such terminal portions are given below; / 0 & ηΛ X N- ,, 1: ype azaspiro alcanedione "

V- / H

2 ° alkyl _ "dialkoylglutarimide type" alkyl '^> "thiazolidinedione type" 0: 1 "* i 2

-H

/ "succinimide type" r \ „v" morpholinedione type "N — 2 (V may be 0 or S) 10 S <'() i | ._" phthalimide type "(U may be C = 0 or SO2)

0H

F — jV — ÔH- "benzyl carbinol type" 20 '- /

A considerable quantity of documents relating to this technical field has been generated during the last fifteen years, most of these documents coming from the research group of the Bristol-Myers Company.

The state of the art approaching the invention comprising compounds with CNS activity can be illustrated in the light of the following general structural formula (1) / \

(N-alc-N ^ _ÿ-B

** (1) 3 I 1 * in which aie represents an alkylidene chain linking the piperazine ring to the cyclic imide group and B is a heterocyclic ring optionally bearing substituents.

US Patents 3,717,634 and 3,907,801 to WU, et al, as well as the corresponding publication in _J. Med. Chem., 15, 447-479 (1972) describe various psychotropic 4,5-azaspiro-decanedione compounds where B represents various monocyclic heterocycles such as pyridine, pyrimidine, or triazine, each optionally carrying substituents.

Temple, Yevich and Lobeck disclose in US Pat. No. 4,305,944 tranquilizing compounds of azaspiro [4.ôj-decanedione where B is a cyanopyridin-3-oyl-2 or methoxypyridin-3-oyl-2 part.

Temple, Yevich and Lobeck describe in US Pat. No. 4,361,565 tranquilizing compounds of dialkoyl-glutarimide in which B is a cyanopyridin-3-oyl-2 ring optionally carrying a second substituent.

20 Temple and Yeager Reveal in US Patents

4,367,335 and 4,456,756 of the antipsychotic thiazolidinediones and spiro-thiazolidinediones where B is a pyridinyl-2 nucleus, unsubstituted or carrying a cyano substituent.

* Temple and Yevich in US patents 4 411 901 and 4 452 799 disclose antipsychotic compounds comprising a variety of cyclic imide and benzyl carbinol portions where B is a benzisothiazole or benzisoxazole ring system.

30 The following applications are also to be noted.

In application US 531 519, filed September 12, 1983, having just been granted, New and Yevich reveal and claim psychotropic compounds of the succinimide and phthalimide type where B is a pyrimidinyl -2 nucleus. These compounds exhibit anti-anxiety activity.

1 * * * 4

A series of antipsychotic compounds 1-fluoro-phenylcarbonyl-, -carbinol-, -cétal-, propyl-4- (2-pyrimidinyl) pipérazines is disclosed by Yevich and Lobeck in the application US 583 309 filed December 18, 1984.

Finally, New, Yevich and Lobeck in application US 691 952 filed on January 16, 1985, disclose and claim a series of antipsychotic compounds comprising a variety of cyclic imide portions where B is a mono or disubstituted pyridine ring system.

^ - * 0 Although the psychotropic compounds given above are generally close to the compounds of the present invention, they nevertheless differ structurally therefrom relative to the portion B of the structure of formula 1. Essentially, in the compounds of the prior art, B is usually a hetero-aryl monocyclic ring with only examples of bicyclic systems of heterocycles with a fused benzo ring, that is to say systems with a benzoisothiazole or benzoisoxazole ring. This distinguishes these compounds from the compounds of the present invention in which B is chosen from different classes of condensed heterocyclic nuclei, that is to say systems with a furo-, pyrrolo-, cyclo-pentadieno- or thieno-pyridine nucleus. The compounds of the present invention also differ from the compounds of the prior art from the pharmacological point of view with regard to the psychotropic properties and the types of side effect. In this aspect, the compounds of the present invention possess selective antipsychotic (neuroleptic) activity with antagonism to serotonin, and, surprisingly, they have a low affinity for dopamine receptors which is contrary to the antipsychotic agents. the prior art, described in supra. In this regard, the present compounds show from a pharmacological point of view certain resemblances to the atypical neuroleptic agent, clozapine (2) (see The Merck Index, 10th edition (1983), page 344, and 5 i ·.

and references cited therein).

A-3 ή (2) -10

As can be seen, clozapine belongs to the dibenzodiazepine class of psychotropic substances structurally very close to the series of compounds of the present invention. In addition, the present compounds appear to have lost the potential to cause reverse extrapyramidal symptomatology associated with chronic administration of commonly used antipsychotic agents. In addition, compounds selected from the series of compounds of the invention have demonstrated in animal models the ability to reverse catalepsy resulting from the administration of trifluoroperazine, a typical neuroleptic agent.

In its broadest aspect, the present invention relates to piperazine derivatives having neuroleptic (antipsychotic) properties characterized by a compound of formula I or its pharmaceutically acceptable acid addition salts.

R2 30, * TO 6

In formula I, Z represents the following radicals: r5 - K ^

A H H

(a) (b) (c) v 10 (d) (e) 3 4

In the radical (a), R and R are independently chosen from hydrogen, alkyl in or R3 and R4 are chosen together as alkyl chain in 0o to Ce.

5 6 ο o 20 In the radical (b) R3 and R ° are independently chosen from hydrogen, C 6 alkyl. , and phenyl · * ** 5 6

A-substituted, A being hydrogen or halogen or R and R

are chosen to form together a butylidene chain; and W can be S (a sulfur atom) or CH2 (a methylene group). In the radical (c) V is an oxygen atom or a sulfur atom. In the radical (d) G is chosen w from hydrogen, alkyl, C 4 -C 4 alkoxy or halogen, m is an integer from 1 to 4, and U is C = 0 or SO 2 · In addition, in formula I: n is an integer from 30 2 to 4 with the proviso that when Z is (e), n is 3;

R is selected from hydrogen or C 1-4 alkyl; X or Y

is independently selected from CH ", 0, S, or NR ^ on the ^ 2 provided that the other of X or Y is always = C H-; R is selected from hydrogen, 4-alkyl, C 4 -C 4 alkoxy, 4-alkylthio> halogen, and hydroxyl; and R ^ is hydrogen or C1-alkyl. The designation C ^ _4 7 can also be defined by the term "lower".

Preferred classes of the compounds include the compounds of formula I where Z may be the radicals 5 6 (a); (b) with R and R ° chosen to form together a butylidene chain and where W is a sulfur atom; and (c) where V is an oxygen atom; summer) . For these preferred classes Y is either an oxygen atom or a sulfur atom and X is methinyl (= CH—); n is 4, except 2 when Z is (e) in which case n is 3; and R is i hydrogen.

There are two classes of particularly preferred compounds. For the class of compounds where Y is an oxygen atom, Z is either (a) or (c) provided that V is an oxygen atom, or (e). For the class of compounds where Y is a sulfur atom, Z is either (a), or (b), or (e).

The pharmaceutically acceptable acid addition salts of the invention are those in which the anion does not contribute significantly to the toxicity or pharmacological activity of the salt and, as such, they are the pharmacological equivalents of bases of the compounds of formula I. They are generally preferred for medical use. In some cases, they have physical properties which make them more desirable in pharmaceutical compositions. Such properties may be solubility, lack of hygroscopicity, compressibility relative to the tablet compositions and compatibility with other ingredients with which the substance can be used for pharmaceutical purposes. The salts are made in the usual way by mixing a base of formula I with a selected acid, preferably by bringing solutions into contact using an excess of the inert solvents usually used such as ether, benzene, ethanol, ethyl acetate , acetonitrile, and water. The salt form can also be prepared by any other standard 1 ί4 8 process described in the literature and available to any practitioner specializing in this field. Some examples of useful organic acids are carboxylic acids such as maleic acid, acetic acid, tartaric acid, propionic acid, fumaric acid, isethionic acid, succinic acid, pamoic acid, cyclamic acid, pivalic acid, and the like; a useful inorganic acid can be a hydrohalogenated acid such as HCl, HBr, HI; sulfuric acids; phosphoric acids; * · 10 and their analogs.

It will also be understood that the present invention includes all stereoisomers which can result when, for example, Z contains an asymmetric carbon, which is the case for (e) or possible for (b). The separation of the stereoisomers in individual form can be carried out by the application of various methods which are well known to those skilled in the art.

The compounds of the present invention are useful pharmacological agents for their psychotropic properties. In this regard, they exhibit selective activity on the central nervous system at non-toxic doses and are of particular interest as antipsychotic (neuroleptic) agents. As with other known antipsychotic agents, the compounds of formula I elicit certain responses when studied in standard in vivo and in vitro pharmacological test systems which are known to correspond well with the pattern of symptoms of acute and chronic psychosis in humans.

The sub-classification of the central nervous system receptor in vitro of the prior art is used for a sub-classification of the psychotropic specificity and activity of the compounds of the present invention. Certain compounds (commonly referred to as ligands) have been identified, which preferentially bind to specific sites with high affinity in brain tissue regarding psychotropic activities or the potential for side effects. Inhibition of identified ligand binding to such specific sites with high affinity is considered a measure of the possibility for a compound to perform a corresponding function of the central nervous system or to cause side effects in vivo.

This principle is used in tests, such as, for example, by measuring the inhibition of the binding of the £ 10 spiperone £ 3H ~ \ which indicates the significant activity of binding to the dopamine receptor (cf: Burt, et al , Holecular Pharmacology, 12, 800 (1976); Science, 196, 326 (1977); Crease, et al, Science, 192, 481 (1976)).

Some of the most important link tests used are listed below in Table 1.

Table 1

Receptor binding tests

Ligand Binding Agent 2Q test No. Putative receptor site used specific 252A Dopamine / spiperone / 2 -, D (+) - neuroleptic ^ HjSpiperone Butaclamol 252B Alpha-1 [3h] wB-4101 Phentolamine

252E Serotonin Type 1 (5 - H T ^) ^ 3H ^ 5-HT

2521 Serotonin Type 2 (5 - HT2) t3F0spiperone D-Lysergine References: ~ 252A - given above.

252Β - Crews, et al, Science, 202: 322, 1978

Rosenblatt, et al, Brain Res. , 160: 186, 1979. U'Prichard, et al, Science, 199: 197, 1978; Molec.

30 Pharmacol., 13: 454, 1977.

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

The data derived from the above binding tests demonstrate that the family of compounds of the present invention has a modest to low affinity for dopaminergic receptors, but greater affinities for the serotonin and S2 · sites. These binding properties distinguish the compounds of the invention cited compounds of the prior art as well as clinically useful antipsychotic agents currently used. In this regard, the compounds of the present invention have certain pharmacological properties in common with the atypical standard neuroleptic agent *, clozapine, a dibenzodiazepine compound. The lack of dopaminergic binding affinities of the compounds of the invention seems to relate to the reduced ability to induce unwanted extra-pyramidal side effects common to the most commonly used antipsychotic agents.

The alpha-1 receptor binding activity (Test 252B) indicates that the compounds of the present invention have a calming component of activity which is often desirable in the treatment of subgroups of psychotic patients.

The following in vivo test systems are conventionally used to classify and differentiate a psychotropic agent from a non-specific CNS depressant and to determine the potential side effect suitability such as cataleptic activity.

Table 2

In vivo tests used to assess compounds of formula I

1. Conditioned Leak Response (CAR) - measurement of the tranquilizing activity of a drug determined by its attenuation of response to an electric shock on attached farmed rats (cf. Albert, Pharmacist, 4 , 152 (1962); Wu, et al, J_. Med. Chem., 12, 876-881 (1979)).

2. Inhibition of apomorphine-induced stereotyping (APO) - a distribution of the blockade of dopaminergic activity in rats measured by the attenuation of the behavior syndrome caused by the dopamine agonist, 11 apomorphine. (cf: Jansen, et al, Arzneimitell. Forsch., 17, 841 (1966)).

3. Catalepsy - drug-induced in rats helps predict potential extrapyramidal symptoms (EPS) in humans (see Costall, et al, Psychopharmacologia, 34, 233-241 (1974); Berkson, J. Amer Statist. Assoc., 48, 565-599 (1953)).

£ - 4. Catalepsy reversal - a measure of the ability of a drug to reverse neuroleptic-induced catalepsy in rats.

According to the pharmacological profile established by these vivo tests, the compounds of the present invention of formula I have promised an antipsychotic potential since they are powerful in the CAR test, have oral ED ^ -g values of less than 100 mg / kg of bodyweight, and effectively block apomorphine-induced stereotyping. This blocking of apomorphine-induced stereotypy reflects the activity of dopamine antagonist and is considered to be a good specific screen for neuroleptic activity. The family of compounds of the invention can be considered to have selective antipsychotic activity since antipsychotic activity can be seen at doses which do not produce catalepsy. Not only are these compounds relatively inactive with respect to the production of catalepsy, but more significantly, the preferred compounds of this invention have the ability to reverse neuroleptic-induced catalepsy with ED ^ g values below 30 mg / kg, by oral administration. The significant aspect of the effects of the compounds of the present invention on the induction and reversal of catalepsy are better appreciated when it is considered that the antipsychotic agents as such are known to produce extrapyramidal reactions. These unwanted reactions represent a serious responsibility for treatment • D Λ 12 and include acute torsional dystonia, akathesis, parkinsonism, and tardive dyskinesia. Some representative iji vivo biological data are summarized in Table 6.

In summary, the compounds of the present invention have psychotropic properties which are particularly suitable for their use as selective anti-psychotic (neuroleptic) agents with little potential for side effects leading to disease. Thus, another aspect of the present invention relates to a method for ameliorating a psychotic state in a mammal in need of such treatment which comprises the systematic administration to such a mammal of an effective amount of a compound of formula I or a pharmaceutically acceptable acid addition salt thereof.

The administration and dosage regime for the compounds of formula I is considered to be carried out in the same way as for the reference compound clozapine 20 (see The Merck Index, 10th edition, (1983), page 344, and their references) . Although the dosage and dosage regimen should be carefully adjusted in each case, using professional judgment and considering the age, weight and condition of the recipient, the route of administration and the nature and severity of the disease, in general the daily dose will be approximately * 0.05 to approximately 10 mg / kg, preferably 0.1 to 2 mg / kg, when the administration is carried out parenterally; and from about 1 to about 50 mg / kg, preferably 2 to 30 mg / kg, 30 when the administration is oral. In some cases, a sufficient therapeutic effect can be obtained at lower doses while in other cases, higher doses are necessary. The term "routine administration" used herein refers to the oral, rectal, and parenteral routes, for example, intramuscular, intravenous, and subcutaneous. Generally, we will discover

', 4D

13 that when a compound of the present invention is administered orally, which is the preferred route, a larger amount of active agent is required to produce the same effect as a lesser amount administered parenterally. In accordance with clinical practice, it is preferred to administer the compounds of the present invention at a level of concentration which will produce effective antipsychotic (neuroleptic) effects without causing side effects - harmful or irreversible.

Therapeutically, the present compounds are generally administered in the form of pharmaceutical compositions comprising an effective antipsychotic amount of a compound of formula I or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier. Pharmaceutical compositions for carrying out such treatments will contain a major or minor amount, for example 95 to 0.5% of at least one compound of the present invention in combination with a pharmaceutically acceptable vehicle vehicle comprising one or more solid , semi-solid, or liquid diluent, filler, and adjuvant of composition which is not toxic, inert and pharmaceutically acceptable. Such pharmaceutical compositions are preferably in the form of dosage units; that is, physically discrete units containing a predetermined amount of drug corresponding to a fraction or a multiple of the dose which is calculated to produce the desired therapeutic response. Dosage units 30 can contain one, two, three, four or more single doses; or alternatively a half, a third, or a quarter of a single dose. A single dose preferably contains an amount sufficient to produce the desired therapeutic effect by administering an application of one or more dosage units according to the predetermined dosage regimen, usually one, a half, a *, 'ί 14 thirds or a quarter of a daily dose given once, twice, three or four times a day. Other therapeutic agents may also be present. Pharmaceutical compositions which provide from about 1 to 500 mg of active ingredient per unit dose are preferred and are prepared in the conventional manner in the form of tablets, lozenges, capsules, powders, aqueous or oily suspensions, syrups, elixirs, and aqueous solutions. Preferred oral compositions are in the form of tablets or capsules and may contain conventional excipients such as binding agents (e.g. syrup, acacia, gelatin, sorbitol, adraganthe, or polyvinylpyrrolidone), supplements (e.g. lactose, sugar , corn starch, calcium phosphate, sorbitol or glycine), lubricants (e.g. magnesium stearate, talc, polyethylene glycol or silica), disintegrants (e.g. starch) and wetting agents (e.g. sodium lauryl sulfate ).

Solutions or suspensions of a compound of formula I with conventional pharmaceutical vehicles are used for parenteral compositions such as an aqueous solution for intravenous injection or an oily suspension for intramuscular injection. Such compositions having the desired purity, stability and adaptability for parenteral use are obtained by dissolving from 0.1% to 10% by weight of the active compound in water or a vehicle consisting of aliphatic alcohol polyhydric such as glycerin, propylene glycol, and polyethylene glycols or their mixtures.

Polyethylene glycols consist of a mixture of non-volatile polyethylene glycols, usually liquids, which are soluble in both water and organic liquids and which have molecular weights of about 200 to 1,500.

The compounds of formula I where Z is one of the radicals (ae) of the present invention are obtained by processes involving the alkylation of piperazinyl or "imide" intermediates analogous to the methods described by Wu, et al, Patents, supra, or Temple, et al, patents, supra. These methods can be incorporated into a unit process which is used for the preparation of the compounds of formula I. The methods can be adapted to produce other compounds embracing this invention but not specifically disclosed. In addition, variations of these methods for producing the same compounds in a somewhat different manner are of course within the reach of those of skill in the art. Some examples will be given for a specific illustration. Unit process R2 R1 A

D-E + J-N N- (Π \ - ^ I

2o v ^ y (II) (III) 1 2

In this diagram, R, R, X and Y have the same meaning as previously given in formula I. The symbol D represents either the bivalent structures relative to the radicals (ad) as shown below in partial structures {a * - d *) or the radical (e ') also given below.

Rw — rS - (- f ° γΛ ”Λ K u (ε) ΗΌΙ ^ F - \ J / 2> r (d ·) (e ') 16

In the radicals ta * -e ') all the symbols have the same meaning as that given above. The symbol "E" in the previous diagram can be 0; N-H; or N- (CH2) n-Q. The symbol "n" is as defined above and "Q" represents any suitable displacement group such as chloride, bromide, iodide, sulfate, phosphate, tosylate, or mesylate. The symbol "J" can be H2N- (CH2) n-; Q- (CH2) n-; Q Θ; or H-.

The relation between E and J is: 10

Process N ° A B C

___ χ v When E is: (Ha) ^ NH (Ilb) / N- (CH2) n-Q

_____(Isle)

Then J is: H2N- (CH2) n- X- (CH2) n ~ or q © (I lia) (IIIc) (Illb) (Illb ·) 20

Method A

R2 i Λ

X ‘VY

! —V) —- l Δ w lia IIIc

30 Method B

R2 13 1

R1 XAY

dQn-H ^ * 1

Ilb IIIb 17 R2

21 Q ® R1 A

iib + R \! Ro) —-1 - (\ - / N — t

Illb '(Illb' is a special case where n is 10 fixed equal to è 4)

Method C (preferred method) R2 R · ^ x ^ y

Qi- (CH2) n-Q ♦ H'Nv_y ~ ^) -

Island IIIc 20

The condensation in process A is carried out by reflux of the reactants in a dry, inert reaction medium, such as pyridine or xylene. For processes B and C, the process is carried out under suitable reaction conditions for the preparation of tertiary amines by alkylation of secondary amines. The reagents are heated in a suitable organic liquid at temperatures of about 60 ° C to about 100 ° C in the presence of an acid binding agent. Preferred examples of organic liquid reaction media are benzene, dimethylformamide, ethanol, acetonitrile, toluene and n-butyl alcohol. preferred acid bond is potassium carbonate, but other tertiary and inorganic organic bases can be used like other carbonates of alkali or alkaline earth metals, 18, 1 ί bicarbonates, or hydrides, and tertiary amines. have been sufficiently described in the patents cited in the introductory part of the present application.For the compounds of the present invention, method C is the preferred synthesis method.

The required Ile intermediates were synthesized according to methods given in the cited patents of the prior art.

For the preparation of the products of formula I where 10 Z is (e), process C must be adapted as follows: t— \ _ ^ \ χ 1) alkylation F - (OV \ rH vn TTT 2) hydrolysis of / (CHgJg-Q + IIIc ketal HO®

Ild 3) sodium borohydride

20 I

R1 X * i I (e) By way of example of a variant of the process for obtaining the compounds of formula I, a Z-substituted alkylated piperazine (IV) can be reacted with a bicyclic pyridine system suitable condensate (V) to yield the product of formula I.

R2 19 wire À / Ιλ n Z ’(CH2) n-Ns_ + -4,1 IV v

In summary, a method has been described for obtaining a compound of formula I, this method comprising the selection of a method from the group of methods consisting in: (a) reacting an intermediate of formula IIa dC3

Ha where the symbol "D" represents the bivalent structures of the formulas a'-d "" y- ^ r-Ç R4 '- ^ w ^ lob (a') (b ') (c1), n · 30 (d ') with an intermediate of formula IIIc ** *' * 20 B2 - "r1 ar ~ \ b = k H2N- (CH2) n -N ^ / ^ U / IIIc 1 2 where R, R, η, X and Y are as defined above, to give a product of formula I; (b) the reaction of a compound of formula Ilb

Ilb with an intermediate compound of formula Illb .. α i R χ * Ά Q-'CH2> n

Illb where Q is a suitable displacement group such as chloride, bromide, iodide, sulfate, Λ phosphate, tosylate, or mesylate, and D, R, 2 30 R, η, X and Y are as defined above, to give a product of formula I; (c) reacting a compound of formula Ilb with an intermediate compound of formula Illb '21 R2

O R1 xA> Y

qJ L \ _i Ν- (θ) - / \ —f N— /

Illb '12 "where Q, R, R, X and Y are as defined above, to lead to a compound of formula I where n is an integer equal to 4; (d) the reaction of a compound of formula Ile

(3- (CH2) n-Q

Ile with an intermediate compound of formula IIIc R2 F1 "w-p IIIc 1 2 where D, n, Q, R, R, X and Y are as defined above, to yield the product of formula I;

(e) the reaction of a compound of formula IV

30 Ζ- (0Η2) η-Ν ^ Ν-Η

IV

22 ♦ ** with an intermediate compound of formula V R2 Λ

V

1 2 ν 'or Z, n, R, R, Q, X and Y are as defined above to lead to the product of formula I; and (f) (1) the reaction of a compound of formula Ild ΓΛ F _ ’^ Ç) ^ 'CH2> 3-0

Ild 20 with an intermediate compound of formula IIIc to give a compound of formula If; R2

/ - ^ R1 X · * · Y

F ~~ ^ 0 / tCH2 ’3'n ^ 7 ^ vU) '' \ - / _ /

If 30 (2) hydrolysis of If in an acid medium to yield the compound of formula Ig; and 23 I ** R2 ο j * χΑ f ~~ ^ AA ^ CH2> 3 "\ N- '\ -f N— /: ig (3) reduction of the compound of formula Ig 10 with sodium borohydride to give the product the R2 1 Λ R χίΑγ F - <gHH- (CH2) 3-N6- ^) the

20 The intermediate compounds of formulas II or IV

are sufficiently described in the literature of the cited prior art, certain compounds of formula II being commercially available. The pyridinylpiperazine bicyclic intermediate compounds of formula III, and the starting bicyclic heterocycles (V), are either commercially available or described in the chemical literature. Methods used for the synthesis of intermediates of formula III are illustrated in scheme I.

24

Diagram I

Synthesis of bicyclic intermediates III

r ~ \, r, —λ co2h / C piperidine (catalyst) Jj \\ j R2 x CHO pyridine (solvent) p2 ÇqO λ.

x IX

S0C12 DMF, CHC13

, jOJ -s- 2XlX

I ^ O-acé tone j> 2 / \

VII

VIII

diphenyl 240 ° ether o C1 —KH P0C1,

jri) -1— / P

r2 / ^ X ^ Ri VI H-ifSî-H / v d2 's— T> ^ 20 h. at 120 ° K1 ^ Nî ^ IIIc 25

In scheme I, the synthesis of systems with a furo-, pyrrolo-, cyclopentadieno- or thieno-pyridine nucleus is carried out starting from a carboxaldehyde intermediate of formula X. The carbox-aldehyde-2 intermediate is represented in the scheme I and finally gives rise to intermediate IIIc as shown in scheme I. If the intermediate carboxaldehyde-3 X 'is used in scheme I, the resulting product is the "reverse" isomer IIIc'.

ΐ 10 R2 R1

.-r-CHO y - \ / TVV

It ^ -► Diagram 1 - * H _ ^ _ n - \ C3 /

r2 X

(X ') (IIIC) The general structure III (where J = H) of the unit process, supra. generally describes the structures of intermediates IIIc and IIIc '.

Without scheme I, the required starting carboxaldehyde can be obtained either commercially or by simple synthesis, for example Vilsmeier formylation.

Haack of an N-alkylpyrrole, using methods readily available in the chemical literature and familiar to those skilled in the art in this field. Condensation of intermediate X with malonic acid at 100 ° C usually in pyridine as solvent with piperidine as catalyst, for approximately 12 hours, followed by a short period of reflux to promote decarboxylation, leads to intermediates corresponding acrylic acids of formula IX.

The chlorination of the acids of formula IX with thionyl chloride in chloroform and a catalytic amount of 26 I ** of dimethylformamide makes it possible to use the acid chloride derivatives of structure VIII, which are not purified, but in the form crude in the preparation of the acid azides of formula VII. These acid azides are prepared either in a two-phase mixture of acetone in water at 5 ° by the action of a sodium azide or with trimethylsilylazide in benzene - under reflux. Unpurified preparations of the acid azides of the formula VII in methylene chloride solutions are added in parts either in diphenyl ether or in diphenylmethane and heated to 230 ° C to facilitate rearrangement of the Curtius type by isocyanates which immediately cyclize to condensed 6-5 bicyclic intermediates of formula VI. The chlorination of VI is carried out using phosphorus oxychloride or a mixture of phosphorus pentachloride-phosphorus oxychloride to form the substituted chloro hetero cycle of formula V. Reaction of V with an excess of an appropriate piperazine in a bomb 20 to 120-140 ° C for various periods of time allows the desired piperazine intermediate IIIc to be obtained. This general synthesis of the intermediates of formula IIIc has been reported previously (cf.: Eloy, et al, Bull. Soc. Chim. Belges., 79, 301 (1976); J_. Heterocyclic chem., N ° 8, 57 (1971) ; Helv. Chim. Acta., 53, 645 (1970)). The introduction of the substituent R 2 can be carried out either by its incorporation into the starting compound X or by its subsequent introduction into the scheme, for example 2 metalation of V (X = S, R = H) with t- butyllithium and the subsequent reaction with methyldisulfide to give an intermediate of formula V where R = 601 ^.

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

27 * ** The invention will be better understood, and other objects, details and advantages thereof will appear more clearly on reading the explanatory description which will follow made with reference to several specific embodiments of the invention given only by way of nonlimiting examples.

The spectral characteristics of nuclear magnetic resonance (NMR) relate to the chemical shift (S) expressed in parts per million (ppm) relative to tetramethylsilane (TMS) as a reference.

The relative area reported for the various displacements in the proton spectral data (RMP) corresponds to the number of hydrogen atoms of a particular functional type in the molecule. The nature of the displacement as well as the multiplicity is reported as large singleton (bs), singleton (s), multiplet (m), doublet (d), doublet of doublets (dd), triplet (t), or quartet (q).

The abbreviations used are DMSO-dg (perdeutero-dimethyl sulfoxide) CDClg (deuterochloroform) and are otherwise conventional. Infrared spectrum (IR) descriptions include only absorption wave numbers (cm) having a functional group identification value. Infrared determinations were used using potassium bromide (KBr) as the diluent. All of the compounds show satisfactory elemental analysis.

Synthesis of intermediates of formula IIIc The following representative examples of chemical intermediates of formulas VX illustrate the synthesis 39 of the key intermediate IIIc, which can be subsequently converted, using known reactions, into other synthetic intermediates such as Ilia. or Illb.

EXAMPLE 1 N-methylpyrrole-2-carboxaldehyde (X)

A stirred mixture of N-methylpyrolle (10 g, 0.12 mole) in dichloroethane (80 ml) and dimethylformamide 28 (11.3 g, 0.15 mole) was treated dropwise at 5 ° C with phosphorus oxychloride (23.6 g, 0.15 mole) to give an exothermic reaction with the formation of a precipitate. Stirring was continued for an additional 15 minutes and the precipitate was collected by filtration, suspended in NaOH (3N) solution (300 ml) and then extracted with chloroform (3 x 100 ml). The chloroform parts were combined, dried over magnesium sulfate, filtered, and 10 vacuo concentrates to give 6.1 g (49%) of a dark oil, melting point 87-90 ° C at 22 torr, of which NMR data corresponded to the title structure. This intermediate was used in unpurified form in the next step of scheme I.

EXAMPLE 2

3- (2-thieno) acrylic acid (IX)

A mixture of 2-thiophenecarboxyaldehyde (100 g, 0.89 mole); malonic acid (182.5 g, 1.7 moles); pyridine (446 ml); and piperidine (8.9 ml) was heated at 100 ° C for 12 hours, the reaction solution was refluxed for 20 minutes and cooled, then poured into water (1000 ml) and the The resulting aqueous mixture was acidified with concentrated hydrochloric acid. The resulting white precipitate was collected by filtration and recrystallized from an ethanol / water mixture (1: 1) leading to 109 g (80%) of product, with a melting point of 145-148 ° C.

EXAMPLE 3

3- (2-thieno) acryloyl chloride (VIII) 30 A stirred suspension of 3- (2-thieno) acrylic acid (118.9 g, 0.77 mole) and dimethylformamide (12 ml) in chloroform ( 600 ml) was treated dropwise with thionyl chloride (110.1 g, 0.93 mole) at room temperature. The reaction was refluxed for 2 hours, cooled and concentrated in vacuo to form a brown oil which solidified on standing to give 131 g (99%) 1 * ** 29 of a low melting solid, which was used without further purification.

EXAMPLE 4 4-OXO-4,5-dihydrothieno ^ .3,2-c3pyridine (VI)

A stirred suspension of sodium azide (168.6 g, 2.6 moles) in a mixture of p-dioxane (400 ml) and water (400 ml) was treated dropwise with a solution. 3- (2-thieno) acryloyl chloride (223.9 g, 1.3 moles) in dioxane at 5 ° C. The resulting dioxane phase of this two-phase mixture was isolated, concentrated in vacuo, dissolved in methylene chloride (500 ml), dried over MgSO 4, and filtered. The methylene chloride filtrate was added dropwise to the diphenyl ether at reflux (400 ml), in a three-necked flask equipped with two condensers. The solution was refluxed for an additional hour, cooled, and concentrated in vacuo to a dark syrup which was crystallized from acetonitrile to yield a brown solid which was collected by filtration. Recrystallization of the solid from water (650 ml) resulted in 106 g (54%) of a pale yellow solid with a melting point of 213-214 ° C.

EXAMPLE 5 4-chlorothieno Ç 3,2-c3 pyridine (V)

105.6 g (0.69 mole) of finely divided 4-oxo-4,5-dihydrothieno L3,2-c ^ pyridine were stirred while adding phosphorus oxychloride (321.5 g, dropwise) 2.1 moles) at 0 ° C. The reaction mixture was then refluxed for 2.5 hours, cooled, and poured carefully into crushed ice (1,000 ml).

The resulting solution was stirred for 30 minutes and extracted with dichloromethane (3 x 400 ml). The organic parts were combined, dried over MgSO4, filtered and concentrated in vacuo to a solid which was recrystallized from acetonitrile (400 ml) leading to 101 g (85%) of a light yellow solid with a melting point equal to 91 ° C.

EXAMPLE 6 4- (1-piperazinyl) thieno L3,2-cH pyridine (IIIc)

A mixture of 4-chlorothieno \ _3,2-c ^ pyridine (22.7 g, 0.13 mole) and piperazine (57.7 g, 0.67 mole) was heated in a bomb with a minimum amount of ethanol (50 ml) at 120 ° C for 24 hours. The reaction was cooled, divided into the dichloromethane and aqueous phase, and the organic phase was isolated, dried over magnesium sulfate, filtered, and concentrated in vacuo to give an oil. Flash chromatography (methylene chloride-10% methanol-1% ammonium hydroxide) of this material resulted in 16 g (54%) of a gold-colored oil.

Treatment of an ethanolic oil solution with ethanolic hydrochloric acid followed by recrystallization from ethanol gave the hydrochloride salt as white crystals with melting point 275-283 ° C.

EXAMPLE 7

Synthesis of 7- (1-piperazinyl) thieno ^ 2,3-c pyridine (IIIc ') The synthesis of this compound was carried out by the same reaction sequences as those used to prepare compound IIIc, except that the starting material (X) is 3-thiophene-carboxaldehyde. The multi-step preparation of the IIIc 'isomer was complicated, however, due to the fact that the Curtius-type rearrangement reaction (Example 4) led to the desired intermediate compound VI in low yield, the major product of this reaction being a sym-triazine by-product resulting from the trimerization of the isocyanate intermediate. Nevertheless, the application of the reactions outlined in Scheme I led to the production of product IIIc ', which was a brown gum and which was used without further purification.

By appropriate modifications of the Scheme I reaction sequences and various synthetic reactions given above, additional compounds IIIc can be synthesized. Some complementary representative compounds IIIc are given in Table 3.

»32

Table 3

Complementary compounds of formula tttr R2

R1 XÎ ^ Y

111c

Example R1 R2 X Y P.F. (° q 8 H H CH N-CH3 9 H H CH O> 250 10 H H CH CH2 11 H H n ~ CH3 ch

12 H H O CH

13 CH3 H CH S

2 p.m. CH3 CH N-CH3

15 CH3 OCH3 CH O

4 PM SCH. CH S 203-205 (.hci, h2o)

17 CH3 Cl O CH

6 PM Br S CH

19 H OH CH CH2

8 PM C2H5 CH S

9:00 p.m. CH

10 PM SCH3 CH S

. <4 33

Synthesis of the compounds of formula I EXAMPLE 23 General synthesis

The synthesis of the compounds of formula I was carried out by alkylation of suitable halo-substituted imide derivatives (Ile), where D is (a'-d ') and E is N-ÎCHg) -Q, Q being halide; or the fluorophenyl-butyro-phenone derivative (Ild) with a suitable intermediate compound IIIc in acetonitrile under reflux, with three equivalents of potassium carbonate present. The carbinol derivatives were generated by reduction by the sodium borohydride of the corresponding butyrophenone. The reaction time for the alkylation ranges from 5 to 72 hours and the resulting products were customarily subjected to flash chromatography in an ethanol / chloroform mixture for purification. The products of formula I were put into composition in the form of hydrochloride salt for the tests.

EXAMPLE 24 4,4-dimethyl-1- £ 4- (thieno t.3,2-c 1 pyridin-4- oyl) -l-piperazinyl ^ l butyl ^ -2,6-piperidinedione A mixture of 4- ( 1-piperazinyl) thieno ^ 3,2-c ^ \ -pyridine (IIIc; 2.79 g, 0.012 mole), N-4-bromobutyl) -3-dimethylglutarimide (3.3 g, 0.012 mole) and potassium carbonate (3.3 g, 0.024 mole) was refluxed in acetonitrile (150 ml) for 24 hours). The reaction mixture was filtered, concentrated in vacuo and divided into chloromethane and aqueous phases. The organic phase was isolated, dried over magnesium sulfate and concentrated in vacuo to a golden oil which was subjected to flash chromatography (5% ethanol-chloroform). The chromatographed material was dissolved in acetonitrile and treated with ethanolic HCl to yield 1.3 g (yield: 24%) of the hydrochloride salt, m.p. 195-197 ° vs.

34

Analysis Calculated for ^ 22 ^ 30 ^ 4 ^ 2 ^^ 1: C: 58.59; H: 6.93; N: 12.42. Found: C: 58.64; H: 7.02; N: 12.72.

RMP (DMS0-d6): 1.08 (6, s); 1.71 (4, m); 2.60 (4, s); 3.40 (10, m); 4.00 (2, m); 7.65 (2, m); 7.87 (b, m); 8.08 (l, d [5.0 Hz]); 11.75 (b, bs).

IR (KBr): 715, 965, 1425, 1535, 1670, 1720, 2580, 2960 cm'1.

EXAMPLE 25 10 4-L 4- [4- (4-furo [3,2-c] pyridinyl) - 1-piperazinyl] butyl] -3,5-morpholinedione

A mixture of 4- (1-piperazinyl) furo [3,2-cl -pyridine (4.5 g, 0.022 mole), 4- (4-bromobutyl) -3.5-morpholinedione (5.5 g, 0.022 mole ) and potassium carbonate (9.1 g, 0.066 mole) was refluxed in acetonitrile for 24 hours. The reaction mixture was filtered, concentrated in vacuo, and distributed into a dichloromethane phase and an aqueous phase. The organic phase was isolated, dried over magnesium sulfate, and concentrated in vacuo to form a yellow oil which was chromatographed. The appropriate chromatographic fractions were combined, concentrated in vacuo, and crystallized from isopropanol to form 6.2 g (69%) of the free base, m.p. 109-110 ° C.

Analysis Calculated for cigH24N4 ^ 4: C: 61.28; H: 6.50; N: 15.04. Found: C: 60.98; H: 6.60; N: 15.19.

RMP (CDClg): 1.60 (4, m); 2.40 (2, m); 2.57 (4, m); 3.74 (6, m); 4.31 (4, s); 6.78 (l, d [2.0 Hz]); 6.89 (b, d 30 [5.8 Hz]); 7.49 (l, d [2.0 Hz]); 8.01 (l, d [5.8 Hz]).

IR (KBr): 760, 780, 1250, 1285, 1440, 1460, 1570, 1595, 1690, 1735, 2830 cm'1.

Using the methodology described above, or alternative synthetic methods disclosed in the documents cited in the introductory part, a wide variety of compounds of formula I can be obtained. Tables 4 and 5 contain a list of additional representative products of formula I. Table 6 contains In vivo biological data for representative compounds of formula I.

* 36

Table 4

Formula I products

R2

he fS

Z- (CH2> n-0 ~ ©

Ex- 1 P n N ° £ R R X Y Formulas3j P.F. (° C) 26 4 HH CH S C22H22N40202. 180-182 N- 1,4HC1 (b) 27 (e) 3 H H CH S c2iH24FN30S 115-118

A / P

28 ^ 4 H Br CH S C22H27BrN402S2. 203-205 3-λ 'HCl (b> 29 V N- 4 H Br CH S C22H2gBrN402S 216-219 .HCl. 0,5 H20 (a) <Cu ° 30 w- 4 H CH3 CH S C23H30N4 ° 2S2 195- 197 -HCl (b) 31 4 HH CH S CigH24N4 ° 2S2 186-188 1,1C7HR0 „S.

(c) 0 0.5H20 0 J

"J <37

Table 4 - Continuation Ex N ° Z n R1 R2 XY Formulas8 ^ PF (° C) 32 4 HH CH S C22H24N4 ° 3S2 '229-230 ° 2 HCl · 0.5 Ho9 ^ (d) 4 34 (Qlj- 4 HH CH S C23H24N4 ° 2S 226-227 (d) ^ -HC1 <2uo 36 I N- 4 HHS CH 120-122 S ^ .2HC1.1.8 H20 (b) 37 y 4 HH CH 0 C22H28N4 ° 3S 251-253 .2HCl .C2Hg0 38 YV 4 HH CH 0 C22H30N4 ° 3> 250 1.4HC1 0 (a) 39 (e) 3 HH CH 0 C21H24FN3 ° 2 205-207 .HCl 40 J N_ 4 H CH3 CH 0 C23H30N4 ° 3S 176-177 S1 , 2HC1 0 1 38

Table 4 - Continuation E x N ° 'Z n R1 R2 XY Formulasa) PF (° C) 41 \ / 4 H CH3 CH 0 C23H32N4 ° 3 221-233 A — 4 1,2HC1.0,5H20 (a) ^ \ ° 42 s N- 4 HH CH 0 ci9H24N403S 245-250. 2HC1. 0.5H20 (c) 43 (e) 3 H CH3 CH 0 C22H26FN3 ° 2 121-122 .HCl Λ 44 S N- 4 HH CH S C. QH „.N.0_S 114-115 v / 19 24 4 3 N - ^ .0.5 H „0 0 z (c) / -1 ° 45 _ / N- 4 HH CH S C21H28N4 ° 2S 174-175 '—4 .HCl 0 (a) 46 (N- 4 HH CH S C20H26N4 ° 2S 199-201 '.HCl (a) 47 fl- 4 Η H CH NMe c23H3iN5 ° 2S148-150 S- ^ 2HC1.1,6H20 39 _.

Table 4 - Ex Suite.

N ° zn R1 R2 XY Formulas a) PF (° C) 48 0 / N 4 HH CH NMe C20H27N5 ° 3 144-146 ^ 2.3 HCl 0,9 H „0 \ Q l (c) yf ° 49 A / 4 HH CH NMe C23H33N502 192-194 '\ g 2.1HC1 2.6H20 (a) a) The elementary analyzes of C, H and N were all _ + 0.4% of the theoretical values for the given formulas.

! * * 1 40

Table 5

Complementary products of formula I

AÂ ^ î a è i1 * *

33 OQ- «« H CH S

O

35 OQ- 4 CH3 H CH S

50 *) 0 4 CB3 08 CB "'CH3

O

51 DCf 4 H SCH3 CH S

52 T ~ © ~ hV 4 B H CH O

4 H H CH O

O

54 C1 ~ 0C ^ · 4 H OH * S CH

Λ 41

Table 5 - Continued-

Ex 12

No z n R R X X

55 0 ^ - 4 H OH CH S

56 4 "SCH3 CH S

57 V) * - 4 H SCH3 CH S

/ K ~ S> * * t 42

Table 6

Representative in-vivo biological data (mq / kq, p.o.) CAR N ° APO Catalepsy of eata_

Example ED-- ED-- Induction ED.ft lepsie ED, "- —5 q —3 U —-3 0 -5 0 24 6 40> 24 lAa * 25 11 34> 46 2

26 12 35 IA

27 10 9> 40 IA

28> 100> 100 -1 16

29 65 - IA

30 35 -> 142 IA

31 32 -> 128 IA

36 43 47 - IA

37 9 18 23 IA

38 4 7 13 IA

39 3 5 11 IA

40 28 41 -

41 14 22 40 IA

- 42 36 63 - IA

43 23 - IA

47 60 61 - IA

48> 100> 100. - IA

49 67> 100 - AI

a) IA indicates inactivity and is used if ED50 is> 20 mg / kg.

- indicates that this data is not available.

Claims (17)

43 1.- Compound or pharmaceutically acceptable acid addition salt of this compound, characterized in that it is represented by the formula I R2 r! where Z is chosen from the following radicals: Λ-γ 20 0 3 4 where R and R are independently chosen from hydrogen, lower alkyl or may be chosen - together forming a Cg-Cgj alkyl chain R6 R5 — L ^ ° N- (b) W- / 0 5 6 30 in which Ra and R ° are independently chosen from hydrogen, lower alkyl, and A-substituted phenyl, A being hydrogen or halogen or R g and R are chosen together to form a butylidene chain , and W can be S or CH2; * 4 44 γΛ V N- (c) H in which V is 0 to S; , e, h © i5- ™ 10 in which G is chosen from hydrogen, lower alkyl, lower alkoxy, or halogen, m is an integer from 1 to 4, and U is C = 0 or SC ^; and F - ^ - CH— (e); 20. is an integer from 2 to 4 provided that when Z is (e), n is 3; either X or Y is independently chosen from CH9, 0, S, 7 ά or NR on condition that the other of X or Y is always = CH-; 1 7 R and R are independently selected from hydrogen or lower alkyl; and 2 R is selected from hydrogen, lower alkyl, lower alkoxy, lower alkylthio, halogen, and hydroxyl. 2.- Compound according to claim 1, characterized in that Z is the radical (a), or one of the following compounds: t * 45 1- £ 4- £ 4- (furo £ 3,2-cl pyridin- 4-oyl) -1-piperazinyll butyl "] -4,4-dimethyl-2,6-piperidinedione or 4.4- dimethyl-l- [4- £ 4- (2-methylfuro £ 3,2-c 1 pyridin-4 -oyl) -1-piperazinyl 1 butyll -2,6-piperidinedione or 4.4- dimethyl-l ~ r 4- £ 4- (thieno £ 3,2-c] pyridin-4-oy £ -1-piperazinyll butylJ-2 , 6-piperidinedione or 4.4- dimethyl-l- £ 4- £ 4- (1-methyl-1H-pyrrolo £ 3,2-cl -pyridin-4-oy]) - 1-pipérazinyl 1 butyll -2,6- piperidinedione or 4,4-dimethyl-l- £ 4- £ 4- (2-bromothieno £ 3,2-c1 pyridin- 10 4-oyl) -piperazinyll butyl] -2,6-piperididione or 1- £ 4- £ 4- (thieno £ 3.2-0 ^ pyridin-4-oyl-l-piperazinyl 1 -butyll 1,6-piperidinedione or 4-methyl-l- £ 4- £ 4- (thieno £ 3.2-cl pyridin-4-oy]) - 1-piperazinyl J butyll-1,6-piperidinedione. 3. Compound according to claim 1, characterized in that Z is the radical (b), said compound possibly being one of the following compounds: 3- £ 4-1 4- (furo £ 3,2-c] pyridin- 4-oy]) - 1-piperazinyl *] butyll -l-thia-3-azaspiro £ 4.41 nonane-2,4- ^ dione; 3- £ 4- £ 4- (2-methyl-furo £ 3,2-cl pyridin-4-qyl) -1-pipérazinylbutyll -l-thia-3-azaspiro £ 4.41 nonane-2,4-dione; 3- £ 4- £ 4- (thieno £ 3,2-c 1 pyridin-4-oyl) -1-pipérazinyll butyl 1 -l-thia-3-azaspiro £ 4.4] nonane-2,4-dione; 3- £ 4- £ 4- (1-methyl-pyrrolo [3,2-c] pyridin-4-oyl) - 1- pipérazinyllbutyll -l-thia-3-azaspiro £ 4.4 1 nonane-2,4-dione; 3-L 4- £ 4- (2-bromo-thieno £ 3,2-cl pyridin-4-qyl) - 2- piperazinyl 1 butyl] -l-thia-3-azaspiro £ 4.4} nonane-2,4- dione; 3- £ 4- C4- (2-methyl-thieno £ 3,2-cl pyridin-4-oyl) -l-piperazinyl ^ | butyl 1 -l-thia-3-azaspiro £ 4.41 nonane-2,4- 30 dione 4. Compound according to claim 1, characterized in that Z is the radical (c), said compound possibly being one of the following compounds: 3- £ 4-C4- (thieno £ 2,3-cJ pyridin-7- oy]) - l-piperazinyl ^ butyll ~ l-thia-3-azaspiro- £ 4.4jnonane-2,4-dione; 46 4- ^ 4- ^ 4- {4 — furo £ 3,2-c] pyridinyl) -1-piperazinyl] butyl] - 3,5-morpholinedione; 4- £ 4- £ 4- (1-methyl-1H (pyrrolo £ 3,2-c 3 pyridin-4-oyl) -1-piperazinyl] butyl]] 3,5-morpholinedione, 4- £ 4- £ 4- (4-thieno £ 3,2-c ^ pyridinyl) - 1- pipérazinyl] butylj-3,5-thiomorpholinedione; 4- [4-L 4- (4-thieno [3,2-c] pyridinyl) - 1-piperazinyl] -butyll -3,5-morpholinedione wj 5.- Compound according to claim 1, characterized in that Z is the radical (d), said compound possibly being one of the following compounds: 2- £ 4- C4- (thieno £ 3,2-c] pyridin-4-yl-1-piperazinyl] butyl J-1H-isoindole-1,3, (2H) -dione; 2- 1 4- £ 4- ( thieno £ 3,2-c 3 pyridin-4-oy]) -1-piperazinyl 3 -butyl "] -1,2-benzisothiazol-3 (2H) -one 1,1-dioxide. 6. Compound according to claim 1, characterized in that Z is the radical (e), said compound being one of the following compounds: 0 (- (4-fluorophenyl) -4- (f uro L3,2-c] pyridin-4-oyl) -1-piperazinebutanol; c> (- (4-fluorophenyl) - 4- (2-methylfuro-20 £ 3,2-c ”] pyridin-4-oyl) -l-piperazinebutanol; o ( - (4-fluorophenyl) -4-thieno [3,2-c "] pyridin-4-oyl) -1-piperazinebutanol. 7. Compound according to claim 1, characterized in that Y is an oxygen atom, and in that Z is the radical (a), (c) or (e). 8. Compound according to claim 1, characterized in that Y is a sulfur atom, and in that Z is the radical (a), (b), or (e). 9. Compound according to claim 3, characterized in that R 6 and R 3 are chosen together to form a butylidene chain and in that W is a sulfur atom. 10. Compound according to claim 4, characterized in that V is an oxygen atom. 11. Pharmaceutical composition in the form of a dosage unit suitable for systematic administration to a mammal, characterized in that it comprises a pharmaceutical vehicle and approximately 1 to 500 mg of an active compound chosen from the compounds according to claim 1. 12. Pharmaceutical composition according to claim 11, characterized in that the active compound is a 4,4-dimethyl-l- £ 4-L 4- (thieno Q3,2-cpyridin-4-oyl) -l ~ piperazinyl "] i butyl "} -2,6-piperidinedione or the 3-L 4-L 4- (1-methyl-pyrrolo £ 3,2-c] pyridin-4-oyl) -1-piperazinyl ^ butyl ^ -l-thia-3-azaspiro Q4.4J nonane-2,4 -10 dione. 13. Process for obtaining a compound of formula I R2 1,1 X- ^ Y z- (ch ^ "- n ^ n— 20 or its pharmaceutically acceptable acid addition salt according to claim 1, characterized in what it includes: (a) the reaction of an intermediate of formula IIa D ^^ O Ha where the symbol "D" represents a bivalent structure of formula a'-d '3 ^ - (fiS— {r ~ ^ · Λ H (a ') (b *) (C) 48 (d ·) with an intermediate of formula IIIc R2 1 I 10 F H2N- (CH2) n- IIIc 1 2 where R, R, η, X and Y are as defined above, to give a product of formula I; (b) reacting a compound of formula Ilb 20 Ilb with an intermediate compound of formula Illb R2 X to 30 illb where Q is a suitable displacement group such as chloride, bromide, iodide, sulfate, phosphate, 1 2 tosyilate, or mesylate, and D, R, R, η, X and Y t 49 are as defined above, for give a product of formula I; (c) the reaction of a compound of formula Ilb with an intermediate compound of formula Illb 'R2' P r1 X * -Y ^ _ \ / '~ © V n - (Çy> 10 __ / \ _y Illb' 1 2 where Q, R, R, X and Y are as defined above, to give a compound of formula I where n is a fixed integer equal to 4; (d) reacting a compound of formula Ile D ^ jHCH2) nQ 20 with an intermediate compound of formula IIIc R2 X * '*' - YH - _J - IIIc 1 2 30 where D, n, Q, R, R, X, and Y are as defined above, to lead to a compound of formula I; (e) the reaction of a compound of formula IV * 50 R1 / \ Z- (CH2> n-NwN-H IV ^ with an intermediate compound of formula V v r2 A, 10 \ / a ~ \ 0) N— 'V 1 2 where Z, n, R, R, Q, X, and Y are as defined above to give a product of formula I; and (f) (1) reacting a compound of formula Ild 20 / \ F - (^^ tCH2> 3-Q - Ild with an intermediate compound of formula IIIc to give a compound of formula If; 9 f 30. f Π * wN- <g> If> f 51 (2) hydrolysis of If in an acid medium to produce a compound of formula Ig; and R2 f - (0) ^ <Ch2) 3-n (K- ^ > 10 ig (3) reduction of the compound of formula Ig with a sodium borohydride to give the compound R2 R1 XÂv F- (9) -fcH '(CH2} 3' / N- (Q ^> v