HU195509B - Process for producing pyridinyl-piperazine derivatives and pharmaceutical compositions containing them as active agents - Google Patents

Description

The present invention relates to novel pyridinylpiperazine derivatives and to pharmaceutical compositions containing them. The compounds have antipsychotic and serotonin antagonistic effects.

More particularly, the present invention relates to the preparation of 1,4-disubstituted piperazine derivatives wherein one of the substituents is a bicyclic fused ring heterocyclic system, namely a furo-, purrolo- or thienopyridine ring system, and the other substituent is an alkylene chain, preferably an located. The following are examples of some types of these terminal groups.

- a dialkylglutarimide type of formula (h);

- thiazolidinedione type j;

- a type of morpholine dione of formula (k) wherein V is oxygen or sulfur, or a piperidine dione optionally substituted in the 4-position by alkyl, or - of formula (I) wherein U is > C = O or> SO ₂ .

Compounds with similar chemical structures have been the subject of considerable attention over the past fifteen years, and a significant proportion of these research work comes from the Bristol-Myers Company research team. Relevant literature on compounds with central nervous system activity may be reviewed in accordance with formula XI wherein alk is an alkylene chain linking the piperazine ring to the cyclic imide group, B is an optionally substituted heterocyclic ring.

Wu et al., U.S. Patent Nos. 3,717,634 and 3,907,801. U.S. Pat. J. Med. Chem., 75, 447-479 (1972)] describes various azaspiro [4.5] decanedione compounds wherein B is a monocyclic heterocyclic group such as pyridine, pyrimidine or triazine optionally substituted. These known compounds are psychotropic.

Temple, Ycvích and Lobeck [4,305,944]. U.S. Pat. No. 4,198,198 to Jan Henderson describes a sedative azaspiro [4.5] decanedione compound wherein B is 3-cyanopyridin-2-yl or 3-methoxypyridin-2-yl.

Temple, Yevich and Lobeck [4,361,565]. U.S. Pat. No. 4,198,115 to Jan Hewsley discloses a soothing dialkylglutarimide derivative, wherein B is 3-cyanopyridin-2-yl optionally substituted with another substituent.

Temple and Yeager [4,367,335 and 4,456,756. U.S. Pat. No. 4,198,198 discloses thiazolidinediones and spirothiazolidinediones having antipsychotic activity, wherein B is 2-pyridinyl, which is either unsubstituted or substituted with a cyano group.

Temple and Yevich, U.S. Patent Nos. 4,411,901 and 4,452,799. U.S. Pat. No. 4,198,195 to Hewlett, discloses antipsychotic compounds containing various cyclic imide groups and benzylcarbinol groups, wherein B is a benzisothiazole or benzisoxazole ring system.

We also mention the following patent applications:

No. 531,519, filed December 9, 1983 and recently authorized. US and US Patent No. 5,124,123 to New and Yevich disclose succinimide and phthalimide compounds of the psychotropic action, wherein B is 2-pyrimidinyl. These 2 compounds can be used to reduce anxiety.

A series of antipsychotic 1- (fluorophenylcarbonyl, carbinol, ketal, propyl) -4- (2-pyrimidinyl) piperazine are described by Yebich and Lobeck in Dec. 583,309, filed December 18, 1984. . in U.S. Patent Application Ser.

Finally, New, Yevich and Lobeck, filed Dec. 691,952, filed January 16, 1985. U.S. Pat. No. 4,198,119 discloses a series of compounds having antipsychotic activity. These compounds contain various cyclic imide groups and B is a mono- or disubstituted pyridine ring system.

Although the above-described psychotropic compounds generally resemble the compounds of the present invention, they are different in the meaning of substituent B in formula (XI). For known compounds, B is usually a monocyclic heteroaryl. In the case where B is a bicyclic system, it may be a heterocyclic group containing only a fused bcuzole ring, i.e.. benzisothiazole or benzisoxazole. Accordingly, the known compounds differ from the compounds of the present invention, wherein B may be a different fused heterocyclic group, i.e., a furo-, pyrrolo or thienopyridine ring system.

The compounds of the present invention differ from the known compounds in pharmacological terms in terms of their psychotropic properties and side effects. In this regard, the compounds of the present invention possess selective antipsychotic (neuroleptic) activity in addition to serotonin antagonism and surprisingly low affinity for dopamine receptors. This is different from the properties of the known antipsychotic compounds discussed above. In this regard, the novel compounds resemble to some extent clozapine of Formula XII, which is not a typical standard neuroleptic, cf. The Merck Index, 10th Edition, 1983, p. 344 and references therein.

As can be seen, clozapine belongs to the dibenzodiazepine group of psychotropic compounds and has little chemical similarity to the new compounds. In addition, the new compounds do not cause the adverse extrapyramidal symptoms observed with prolonged use of current antipsychotic drugs. In addition, in animal studies, some selected new compounds have been shown to be able to reverse the catalepsy induced by the administration of trifluoperazine, a commonly used neuroleptic.

The present invention provides piperazinyl derivatives of formula (I) and pharmaceutically acceptable acid addition salts thereof, wherein:

Z is a group of formula (1), (3), (4), (5) or (8) or (2), wherein in formula (2) R ³ and R ⁴ are hydrogen or C4-C4 alkyl; ii = 2, 3 or 4;

R ² is hydrogen, halogen, or C 1-4 alkyl;

R ¹ is hydrogen;

One of X and Y is = CH-, the other is oxygen or sulfur or> NR ⁷ and in the latter R ⁷ is C 1 -C 4 alkyl.

195,509

X can only be = CH- or S;

one of the two bonds marked with a dotted line represents a simple bond and the other a double bond.

In the remainder of this specification, the term "C 1 -C 4" is optionally referred to as "low carbon".

Among the compounds of formula (I) as defined above, those having Z in the group of formula (2) or (1) or (8) are preferred. In these preferred compounds of Formula I, Y is oxygen or sulfur and X is methynyl (= CH-), n is 4.

Particularly preferred are two groups of compounds of formula (I). In one group, Y is O, Z is 2 or 8. In the other group of compounds, Y is sulfur, Z is 2 or 1.

The pharmaceutically acceptable acid addition salts of the compounds of formula (I) are salts in which the anion does not contribute significantly to the toxicity or pharmacological activity of the salt, and thus the pharmacological activity of the acid addition salts corresponds to that of the compounds of formula (I). Pharmaceutically acceptable acid addition salts are generally preferred for therapeutic use. In some cases, they have physical properties that make them more favorable for the preparation of a pharmaceutical composition. Such properties include, for example, solubility, lack of hygroscopicity, compressibility for tablet formulation, and compatibility with other ingredients of the pharmaceutical composition.

The acid addition salts are routinely prepared by reacting a base of formula (I) with an acid. Preferably, the solutions of each of the reaction components are combined using conventional inert solvents such as ether, benzene, ethanol, ethyl acetate, acetonitrile or water. The acid addition salts may be prepared by any of the methods detailed in the literature and known to those skilled in the art.

Organic acids for the salt formation include, for example, carboxylic acids such as maleic acid, acetic acid, tartaric acid, propionic acid, fumaric acid, isethionic acid, succinic acid, pamoic acid, cyclamic acid, pivalic acid, etc., and inorganic acids such as hydrogen halide such as hydrochloric acid, hydrobromic acid; sulfuric acid; phosphoric acid, etc. can be used.

The compounds of formula I are useful in medicine for their psychotropic properties. The compounds exhibit selective central nervous system activity at non-toxic doses and are particularly important as active ingredients in pharmaceutical compositions having antipsychotic (neuroleptic) activity. As with other known antipsychotics, the compounds of formula I provide definitive results in standard in vivo and in vivo pharmacological tests that are associated with the alleviation of symptoms of acute and chronic psychosis in humans.

The known in vitro central nervous system receptor binding methods are used to classify the psychotropic activity and specificity of the compounds of formula (I). Some compounds, commonly referred to as ligands, preferentially bind to specific high affinity sites in brain tissue that are associated with psychotropic activity or possible side effects. When a compound inhibits the binding of a radioactive isotope-labeled ligand to such high affinity specific sites, it is believed that the compound is capable of inducing appropriate central nervous system effects or side effects in vivo. This principle is used in assays, e.g., inhibition of ( ³ H) spiperone binding and indicates significant dopamine receptor binding activity [cf. Búrt et al., Molecular Pharinacology, 12, 800 (1976); Science, 1967, 326 (1977); Crease et al., Science, 192, 481 (1976)].

Some of the more important binding assays we used are listed in Table 1.

Table I

Receptor Binding Assays

examination see number Presumed receptor site ligand specifically, absorbed from material 25 2A dopamine (spiperone) neuroleptics ( ³ H) spiperone D (+) - butaclamol 25 2B Alpha-1 ( ³ H) WB-4101 phentolamine 25E serotonin type 1 (5-HT,) ^(3H) 5-HT 5-HT 2521 serotonin type 2 (5-HT ₂ ) ( ³ H) spiperone D lizergid

References:

252A - already given above.

252B - Crews et al., Science, 202, 322 (1978);

Rosenblatt et al., 1979, Brain Res 160, 186;

U'Prichard et al., Science, 199, 197 (1978); Molec. Pharmacol., 13, 454 (1977).

252E - Bennett and Snyder, Molec. Pharmacol., 12, 373 (1976).

2521 - Pcroutka and Snyder, Molec. Pharmacol., 16,

687 (1979).

The data from the above binding assays show that the compounds of the present invention have moderate or low affinity for dopaminergic receptors, but significantly higher affinity for serotonin St and S ₂ sites. In these binding properties, the compounds of formula (I) differ from both the known compounds listed and most of the currently used clinically valuable antipsychotics. In this regard, the compounds of the invention exhibit some of the pharmacological properties of clozapine, a dibenzodiazepine derivative, and an atypical standard neuroleptic. It is believed that the lack of affinity of the compounds of formula (1) for dopaminergic binding is due to their lesser induction of unwanted extrapyramidal side effects.

-3,195,509, which can be found in recent antipsychotics.

The mcg binding activity at the alpha-1 receptor (assay 252B) shows that the compound of formula (I) has the following activity: compounds are also likely to have a sedative effect and are often desirable in the treatment of certain groups of psychotic patients.

The following in vivo assay systems are commonly used to classify and distinguish a psychotropic agent from a nonspecific CNS depressant and to identify potential side effects, such as cataleptic activity.

Table 2

In vivo studies used to evaluate compounds of formula (I)

1. Conditional Avoidance Reaction (CAR) - A measure of the 'tranquillizing effect of a drug, as determined by attenuation of the avoidance response to an electric shock in trained and fasted rats. Albert, Pharntacologist, 4, 152 (1962); Wu et al., J. Med. Chem., 12, 876-881 (1969).

2. Inhibition of Apomorphine-Induced Stereotype (APO) - Evaluation of blockade of dopaminergic activity in rats, as measured by reduction of the dopamine antagonist apomorphine-induced behavioral syndrome. Cf .: Janssen et al., Arzneimittel. Forsch., 17, 841 (1966).

3. Catalepsy - drug-induced catalepsy in the rat; it can be used to infer extrapyramidal symptoms (EPS) that may occur in humans. Cf. Costall et al., Psychopharmacologia, 34, 233-242 (1974); Berkson, J. Amer. Assoc., 45, 565-599 (1953).

4. Reversal of Catalepsy - This is the degree to which a therapeutic vc compound is able to reverse neuroleptically induced catalepsy in a rat.

According to the pharmacological profile determined by the in vivo assays listed in Table 2, the compounds of formula I are promising antipsychotics when relatively effective in the CAR assay and have an oral ED _{50 of} less than 100 mg / kg body weight. Furthermore, the compounds effectively inhibit apomorphine-induced stereotyping. This inhibition of the apomorphine-induced stereotype may exhibit dopamine antagonistic activity and is specific enough for neuroleptic activity. The compounds of formula (I) may be said to possess selective antipsychotic activity, and this antipsychotic activity is expressed at doses that do not induce catalepsy. Not only are the compounds of formula (I) relatively inactive in the production of catalepsy, but more importantly, the preferred compounds of the invention are capable of reversing neuroleptic-induced catalepsy with oral ED ₅₀ values below 20 mg / kg.

The effect of the compounds of formula I on inducing and reversing catalepsy can be further appreciated when one considers that antipsychotic drugs are generally known to induce extrapyramidal reactions. These unwanted extrapyramidal reactions are a serious risk during treatment and may include acute torsional dystonia, akathesis, Parkinson's disease and delayed dyskinesia. Some characteristic in vivo biological data are shown in Table 6 (see later in this specification).

In conclusion, the compounds of formula (I) have psychotropic properties which make them particularly suitable for use as selective antipsychotic (neuroleptic) agents, with little risk of side effects associated with movement disorders. Therefore, according to the invention, the psychotic state of a mammal in need of such treatment may be improved by systemically administering to said mammal an effective dose of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof.

The mode of administration and dose range of the compounds of formula I are similar to those of the reference substance clozapine, cf. The Merck Index, 10th Edition (1983), 344, and references therein. Although the dosage should be carefully adjusted in each case, taking into account the age, weight and condition of the subject being treated, the route of administration, the nature and severity of the disease, the daily dose will generally be 0.05-10 mg / kg, preferably 0.1- 2 mg / kg for parenteral administration, and 1-50 mg / kg, preferably 2-30 mg / kg for oral administration. In some cases, satisfactory doses may be achieved with lower doses, while other doses may be required. The term "systemic administration" as used herein refers to oral, rectal and parenteral, i.e., intranasal, intravenous and subcutaneous administration.

In general, it has been found that when a compound of formula (I) is administered orally, which is otherwise the preferred mode of administration, a greater amount of the active ingredient is required to achieve the same effect as parenteral administration. In accordance with good clinical practice, the compounds of formula I are administered in such concentrations as to provide a favorable antipsychotic (neuroleptic) effect without causing deleterious or deleterious side effects.

To achieve a therapeutic effect, the compounds of Formula I are usually administered in the form of a pharmaceutical composition comprising a psychotically effective amount of a compound of Formula I, or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable carrier. The pharmaceutical compositions used for the treatment contain, to a greater or lesser extent, at least one compound of the present invention, for example 95-0.5%, in combination with a pharmaceutically acceptable carrier. The carrier may be one or more solid, semi-solid or liquid diluents, excipients and adjuvants which are non-toxic, inert and pharmaceutically acceptable.

The pharmaceutical compositions preferably contain unit dosage forms, that is, units which are physically discrete and in which a predetermined amount of the active ingredient is present. This amount corresponds to a fraction or multiple of the dose where the dose is calculated to produce the desired therapeutic effect.

195,509 created. Dosage units may contain one, two, three, four or more individual doses, or the head, one third or one quarter of the individual dose. Preferably, the individual dose is an amount of active ingredient sufficient to produce the desired therapeutic effect by administering one or more dosage units, within a predetermined dosage range. The daily dose is usually administered in one or two, three or four divided doses.

Other therapeutic agents may also be present in the pharmaceutical composition. Preferred are pharmaceutical compositions containing from 1 to 500 mg of active ingredient per dosage unit, and generally in the form of tablets, troches, capsules, powders, aqueous or oily suspensions, syrups, elixirs or aqueous solutions.

Preferred pharmaceutical compositions for oral administration are tablets or capsules and contain customary excipients such as sugar syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone; fillers such as lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; lubricants such as magnesium stearate, talc, polyethylene glycol or silica; disintegrants such as starch and wetting agents such as sodium lauryl sulfate.

Solutions or suspensions containing the compound of formula (I) formulated with pharmaceutical carriers are intended for parenteral administration. Thus, the aqueous solution is used for intravenous injection and the oily suspension for intramuscular injection. Formulations for parenteral administration of the desired purity and stability are prepared by dissolving 0.1 to 10% by weight of the active ingredient in water or a medium consisting of a polybasic aliphatic alcohol such as glycerol, propylene glycol, polyethylene glycols or mixtures thereof. Polyethylene glycols are a non-volatile, usually liquid, polyethylene glycol mixture that is soluble in both water and organic liquids and has a molecular weight of 200 to 1500.

Compounds of formula (I) wherein Z is a group of formulas (1), (3), (4), (5) or (8) or (2) are prepared by alkylation of piperazinyl intermediates by analogous methods. such as those described by Wu et al. or Temple et al., see the patents listed above. These methods can be integrated into a single process used to prepare compounds of formula (1). For the preparation of other compounds encompassed by the general formula (1) but not disclosed herein, it is possible to adapt these methods appropriately. It will also be apparent to one skilled in the art that it is possible to modify the methods in order to obtain the same compound in slightly different ways. Some examples will illustrate this.

Compounds of formula (I) may be prepared by the reaction of Scheme A with a compound of formula (II) and compound of formula (III). In the formulas, n, R ¹ , R ² , X and Y are as defined above for formula (I), D is a divalent group of formula (a), (b), (c) or (d), in accordance with (1). ), Q is a suitable leaving group, for example chloride, bromide, iodide, alk 11, sulfate, tosylate or mesylate.

Scheme A illustrates the preparation process. Accordingly, a compound of formula (II) is reacted with a compound of formula (III).

The process is carried out under reaction conditions which are suitable for the preparation of tertiary amines by alkylation of secondary amines. The reaction components are heated in a suitable organic liquid at a temperature of about 60-100 ° C in the presence of an acid binder. Preferably, the organic liquid used as the reaction medium is benzene, dimethylformamide, ethanol, acetonitrile, toluene and n-butyl alcohol. Potassium carbonate is the preferred acid scavenger, but other inorganic bases or organic tertiary amines may also be used, including other alkali and alkaline earth metal carbonates, bicarbonates or hydrides or tertiary amines.

In summary, the compounds of formula (I) are prepared according to the invention by reacting a compound of formula (II) wherein D is a group of formula (a), (b), (c) or (d)

R ³ and R ⁴ are each hydrogen or C 1-4 alkyl,

R ^s or R ⁶ is 1,4-butylene,

V is oxygen or sulfur,

U represents> C = O or> SO ₂ ,

W is S;

Q is a suitable leaving group, preferably chloride, bromide, iodide, alkylsulfate, tosylate or mesylate;

n = 2, 3 or 4, with a compound of formula (III) wherein R ¹ , R ² , X and Y are as defined herein;

and optionally converting the resulting compound of formula I to an acid addition salt with an inorganic or organic acid

The intermediates of formula (II) are well described in the patents listed above and in the literature references therein. In addition, several compounds of formula II are commercially available. The bicyclic pyridinylpiperazinyl derivates of formula (III) and the starting bicyclic heterocyclic compounds of formula (V) for their synthesis are partly commercially available, partly in the literature or described herein. Methods for the preparation of compounds of formula (III) are summarized in Scheme G.

In Scheme G, a carboxaldehyde of formula (X) is used to prepare the furo-, pyrrolo, or thieno pyridine ring systems. The carboxaldehyde X is finally obtained as intermediate IIIa. In the case where the G by the method of Scheme A, but starting with (X ^r) carboxaldehyde of formula, it is finally obtained in the "reverse" isomer of formula (IIIa '). In the uniform procedure depicted in Scheme A, the structure of Formula (III), both of Formula (IIIa) and (IIIa), is generally encompassed.

The starting carboxaldehyde of Scheme G is either commercially available or is readily prepared, for example, by Vilsmeier-Haackformylation of an N-alkylpyrrole. The accomplishment of this reaction is known to those skilled in the art.

-5195 509

The carboxaldehyde X is condensed at 100 ° C with malonic acid, usually in pyridine as solvent, in the presence of piperidine as catalyst, for about 12 hours. Subsequently, a short nerve reflux is used to promote decarboxylation. The corresponding acrylic acid intermediate IX is obtained. The acrylic acid of formula (IX) is chlorinated with thionyl chloride in chloroform in the presence of a catalytic amount of dimethylformamide and the acid chloride of formula (VIII) formed is not purified but used crude to produce the acid azide of formula (VII). The acid azide is prepared either with sodium azide in a biphasic mixture of acetone and water at 5 ° C, or with trimethylsilyl azide in benzene under reflux. The acid azide of formula (VII) is dissolved in dichloromethane without purification, added in portions to diphenyl ether or diphenylmethane, and the reaction mixture is heated to 230 ° C, thereby promoting Curtius-type rearrangement via isocyanates, which are immediately are cyclized to a fused bicyclic intermediate. The compound of formula (VI) is chlorinated with phosphorus oxychloride or a mixture of phosphorus pentachloride and phosphorus oxychloride, and the resulting chlorinated heterocyclic compound of formula (V) is reacted with the corresponding excess piperazine at a temperature of 120140 ° C for a period of time. In this way, the desired piperazine intermediate (IIIa) is obtained. This general procedure for the preparation of compounds of formula (IIIa) has already been described [cf. Eloy et al., Bull. Soc. Chim. Belges, 79, 301 (1976); J. Heterocyclic Chem., No. 8. 57 (1971); Helv. Chim. Acta, 53, 645 (1970)].

Preparation of compounds having the R ² substituent from a compound of formula X which already contains this substituent, or may be introduced at a later stage in the synthesis. For example, a compound of formula (V) wherein Y is sulfur and R ^z is hydrogen is converted to a metal derivative with tertiary butyllithium and then reacted with dimethyl sulfide. This gives an intermediate of formula (V) wherein R ² is methylthio.

The invention is illustrated in detail by the following examples. The Nuclear Magnetic Resonance Spectrum (NMR) characteristics given in the examples refer to chemical shifts (delta, dimension per million, ppm) relative to tetramethylsilane (TMS) as an internal standard. In the PMR spectral data, the values for shifts correspond to the number of hydrogen atoms present in a functional group of the molecule. The shift property for multiplicity is given by: broad singlet (bs), singlet (s), multiplet (m), doublet (d), doublet of doublets (dd), triplet (t) or quartet (q)). The usual abbreviations are DMSO-d ₆ (deuterodimethylsulfoxide) and CDCl ₃ (deuterochlorophorin).

In the description of the infrared spectra, only the absorption wavelength values which identify the functional groups are given. Potassium bromide (KBr) is used as a diluent for infrared absorption. All compounds were found to have a satisfactory elemental analysis.

Preparation of intermediates of formula (purple)

Representative examples of the preparation of intermediates of formulas V to X illustrate the synthesis of key intermediates of formula IIIa.

Example 1

N-Methylpyrrole-2-carboxaldehyde - A mixture of compound of formula X in g (0.12 mol) of N-methylpyrrole, 80 ml of dichloroethane and 11.3 g (0.15 mol) of dimethylformamide at 5 ° C

Phosphorous oxychloride (23.6 g, 0.15 mol) was added dropwise. An Fxothermic reaction occurred and a precipitate formed. The reaction mixture was stirred for an additional 15 minutes, the precipitate was filtered, suspended in 300 ml of 3N sodium hydroxide solution and extracted with 3 x 100 ml of chloroform. The chloroform solutions were combined, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. 6.1 g (49%) of a dark oil are obtained, boiling at 89-90 ° C at 22 torr. The MMR spectrum was consistent with the structure attributed to the title compound. The resulting compound was generally used without purification for the next step in Scheme G.

Example 2

3- (2-Thienyl) acrylic acid - Compound of Formula IX

A mixture of 100 g (0.89 mol) of 2-thiophenecarboxaldehyde, 182.5 g (1.7 mol) of malonic acid, 446 ml of pyridine and 8.9 ml of piperidine was heated at 100 ° C for 12 hours. The reaction mixture was refluxed for 20 minutes, allowed to cool, poured into water (1000 mL) and acidified with concentrated hydrochloric acid. The resulting off-white precipitate was collected by filtration and recrystallized from ethanol / water (1: 1). 109 g (80%) of the title compound are obtained, m.p. 145-148 ° C.

Example 3

3- (2-Thienyl) acryloyl chloride - Compound VIII

118.9 g (0.77 mole) of 3- (2-thienyl) acrylic acid was suspended in 12 ml of dimethylformamide and 600 ml of chloroform and 110.1 g (0.93 mole) of thionyl chloride was added dropwise at room temperature with stirring. The reaction mixture was refluxed for 2 hours, cooled and concentrated in vacuo. The residual brown oil solidified on standing to give the title compound (131 g, 99%) as a low melting solid. The product was used without further purification.

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Example 4

4-Oxo-4,5-diyldiO-thieno [3,2-c] pyridine Compound (VI)

Sodium azide (168.6 g, 2.6 mol) was suspended in a mixture of p-dioxane (400 ml) and water (400 ml) and 3- (2-thienyl) acryloyl chloride (223.9 g, 1.3 mol) was added dropwise with stirring. solution of dioxane at 5 ° C. The dioxane phase was separated from the biphasic mixture, concentrated in vacuo, dissolved in 500 mL of dichloromethane, dried over anhydrous magnesium sulfate and filtered. The dichloromethane filtrate thus obtained was added dropwise to a three-necked flask fitted with two air coolers and boiled in 400 ml of boiling diphenyl ether. The solution was refluxed for an additional hour, fixed, and concentrated in vacuo. The remaining dark syrup was crystallized from acetonitrile. The precipitated brown solid was filtered and recrystallized from 650 mL of water. This gave 106 g (54%) of a pale yellow solid, m.p. 213-214 ° C.

Example 5

4-Chloro-thieno [3,2-c] pyridine - Compound (V)

To a fine distribution of 105.6 g (0.69 mole) of 4-oxo-4,5-dihydrothieno [3,2-c] pyridine at 0 ° C was added 321.5 g (2.1 mole) of phosphorus oxychloride. The reaction mixture was refluxed for 2.5 hours, cooled and carefully poured onto 1000 ml of crushed ice. The resulting solution was stirred for 30 minutes and then extracted with dichloromethane (3 x 400 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The precipitated solid was recrystallized from 400 ml of acetonitrile. This gave 101 g (85%) of the title compound as a light yellow solid, mp 91 ° C.

Example 6

4- (1-Piperazinyl) -thienol-3,2-c] pyridine - Compound (IIIa)

A mixture of 22.7 g (0.13 mole) of 4-chlorothieno [3,2-c] pyridine and 57.7 g (0.67 mole) of piperazine was added with a minimum amount of ethanol (50 mL) in a closed tube (bomb). and heated at 120 ° C for 1 hour. The reaction mixture was cooled, partitioned between dichloromethane and water, then the organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residual oil was subjected to flash chromatography (dichloromethane containing 10% methanol and 1% ammonium hydroxide). This gave 16 g (54%) of a golden oil. The ethanol solution of the oil was treated with ethanolic hydrochloric acid and the precipitated salt was recrystallized from ethanol. This gave the hydrochloride of the title compound as off-white crystals, mp 275-283 ° C.

Example 7

Synthesis of 7 (1-pipiprazinyl) thieno [2,3-c] pyridine Compound of Formula IIa '

This compound was synthesized using the same reaction sequence as in the preparation of the compound of formula IIa except that the starting material was 3-thiophenecarboxaldehyde. However, the multi-step preparation of the isomer of Formula IIa 'was complicated when the Curtius rearrangement reaction (Example 4) provided poor yield of the desired intermediate of Formula VI, since the main product of the steam reaction was a symmetric triazone compound. , formed by the tr merization of the isocyanate intermediate. However, using the reactions shown in Scheme G, the compound of formula (Pia ') was obtained which was a brown gum and was further purified; without using it.

Suitable modifications of the reaction scheme depicted in Scheme G and the various synthetic reactions described above in the Examples may provide additional compounds of Formula II. Some other representative compounds of formula (111) are shown in Table 3.

Table 3

Other compounds of formula III

Example In formula (III), the number is R * R ¹ XY

8 H H CH n-ch ₃ 9 H H CH SHE > 250 10 H H CH ch ₂ 11 H H n-ch ₃ CH 12 H H 0 CH 13 ch ₃ H CH s 14 11 Cll ₃ CH N CIIj 15 ch ₃ ocii ₃ CH 0 16 H sch ₃ CH s 203-5 (HClHjO) 17 ch ₃ cl SHE CH 18 H Br S CH 19 H OH CH CII ₂ 20 H C ₂ H ₅ CH s 21 H H S CH 22 H sch ₃ CH s

Synthesis of compounds of formula (I)

Example 23

General Procedure The compounds of formula (I) were prepared by reacting the corresponding halide substituted imide of formula (II) wherein D is a compound of formula (a),

-7,195,509 (b), (c) or (d), Q is halogen, was used to prepare a suitable compound of formula (III). The reaction component was refluxed in acetonitrile in the presence of three molar equivalents of potassium carbonate. The carbinol derivatives were obtained by reduction of the corresponding butyrophenone with sodium borohydride. The reaction time for alkylation was 5 to 72 hours and the product obtained was usually subjected to flash chromatography using a mixture of ethanol and chloroform for purification. The compounds of formula (I) are usually tested in their hydrochloride form.

Example 24

4,4-Dimethyl-1- [4 - [- (thieno [3,2-c] pyridin-4-yl) -1-piperazinyl] butyl] -2,6-piperidin-dione

2.79 g (0.012 mol) of 4- (1-piperazinyl) thieno [3,2-c] pyridine - (111) - 3.3 g (0.012 mol) of N- (4-bromobutyl) A mixture of -3,3-dimethylglutarimide, 3.3 g (0.024 mol) of potassium carbonate and 150 ml of acetonitrile was heated at reflux for 24 hours. The reaction mixture was filtered, concentrated in vacuo and partitioned between dichloromethane and water. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residual golden oil was subjected to flash chromatography using 5% ethanol in chloroform. The chromatographed material was dissolved in acetonitrile and treated with hydrochloric ethanol. This gave 1.3 g (24%) of the title compound as the hydrochloride, m.p. 195-197 ° C.

Analysis calculated for C ₂₂ H ₃₀ N ₄ O ₂ S · HCl: C, 58.59; H, 6.93; N, 12.42. Found: C, 58.64; H, 7.02; N, 12.72.

PMR spectrum (d ₆ -dimethylsulfoxide) δ 1.08 (6, singlet), 1.71 (4, multiplet), 2.60 (4, singlet), 3.40 (10, multiplet), 4, 00 (2, multiplet), 7.65 (2, multiplet), 7.87 (1, multiplet), 8.08 (1, doublet, 5 Hz), 11.75 (1, broad singlet).

infrared (potassium bromide pellet): 715, 965, 1425, 1535, 1670, 1720, 2580 and 2960 cm ^-1 .

Example 25

4- {4- [4- (4-Furo [3,2-c] pyridinyl) -1-piperazinyl] butyl} -3,5-morpholinone

4.5 g (0.022 mol) of 4- (1-piperazinyl) -furo [3,2-c] pyridine, 5.5 g (0.022 mol) of 4- (4-bromobutyl) -3,5-morpholine- dion, 9.1 g (0.066 mol) of potassium carbonate and acetonitrile was heated at reflux for 24 hours. The reaction mixture was filtered, evaporated in vacuo and partitioned between dichlormentane and water. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residual yellow oil was subjected to flash chromatography. The appropriate fractions were cleaved, evaporated in vacuo and crystallized from isopropanol. This gave 6.2 g (69%) of the free base, which was the title compound. Melting point 109-110 ° C.

Analysis for C ₁₉ H ₂₄ N ₄ Ö ₄ :

Calculated: C 61.28%, H6.50%, N 15.04%; Found: C, 60.98; H, 6.60; N, 15.19.

PMR spectrum (deuterochloroform) delta: 1.60 (4, multiplet), 2.40 (2, multiplet), 2.57 (4, multiplet), 3.74 (6, multiplet), 4, 31 (4, singlet), 6.78 (1, doublet) 2.0 Hz; 6.89 (1, doublet, 5.8 Hz), 7.49 (1, doublet, 2.0 Hz), 8.01 (1, doublet, 5.8 Hz).

Infrared (potassium bromide pastilles): 760, 730, 1250, 1285, 1440, 1460, 1570, 1595, 1690, 1735,

2830 cm ^-1 .

A variety of compounds of formula (I) can be prepared using the above methods or the known methods referred to. Tables 4 and 5 list further representative compounds of Formula I. Table 6 shows in vivo biological data for representative compounds of formula (1).

Table 4 Compounds of formula (I)

Example number Z In the general formula (I) n is R ¹ R ² X Y formula ⁸ M.p. 26 (1) 4 H H CH S C ₂₂ H ₂₂ N ₄ O ₂ S ₂ · 1,4HCl 180-2 28 (1) 4 H Br CH s C 21 H 27 BrN 4 O 2 S 2 · HCl 203-5 29 (2) 4 H Br CH s C ₂₂ H ₂₉ BrN ₄ 0 ₂ S · HCl · 0.5 H ₂ O 216-9

(R ³ , R ⁴ = CH ₃ )

30 (1) 4 H CH ₃ CH S C ₂₃ H ₃₀ N ₄ O ₂ S ₂ HCl 195-7 31 (3) 4 H H CH S C ₁₉ H ₂₄ N ₄ O ₂ S ₂ · 1,1C ₇ H ₈ O ₃ S · 0,5H ₂ O 186-8 32 (4) 4 H H CH S C ₂₂ H ₂₄ N ₄ O ₃ S ₂ · HCl 229-230 34 (5) 4 H H CH S C ₂₃ H ₂₄ N ₄ O ₂ S · HCl 226-227 36 (1) 4 H H S CH C ₂₂ H ₂₈ N ₄ O ₂ S ₂ · 2HC 1 1.8H ₂ O 120-122 37 (1) 4 H H CII SHE * C ₂₂ H ₂₈ N ₄ O ₃ S 2110 · C ₂ ll ₆ O 251-3 38 (2) 4 H H CH SHE C ₂₂ H ₃₀ N ₄ O ₃ · 1,4HCl > 250

(R ³ , R ⁴ = CH ₃ )

40 (1) 4 H ch ₃ CH SHE C ₂₃ H _3o N ₄ O ₃ S · 1.2HC1 176-7 41 (2) 4 H (R ³ , R ⁴ = CH ₃ ) ch ₃ CH SHE C ₂₃ H ₃₂ N ₄ O ₃ · 1.2HC1 · 0.5 H ₂ O 231-3

195,509

Table 4 (continued)

Example number Z In the general formula (I) n is R ¹ R ² X Y formula ⁸ M.p. 42 (3) 4 H H CH 0 C _I9 H ₂₄ N ₄ O, S · 2I1C1 · 0.5 HjO 245-250 44 (3) 4 H H CH S Ci ₉ H ₂₄ N ₄ O ₃ S 114-115 45 (6) 4 H H CH s ChH ₂₈ N ₄ O ₂ S 173-175 46 (7) 4 H H CH s C _2o H ₂₆ N ₄ O ₂ S 199-201 47 (1) 4 H H CH NMe C ₂₃ H ₃₁ N _s 0 ₂ S · 2HC1 · 1.6H ₂ O 148-150 48 (8) 4 H H CH NMe L ₂ oH ₂₇ N _s O ₃ 144-146 49 (2) (R ³ , R ⁴ = 4 ch ₃ ) H CH C11 NMe C ₂₃ H ₃₃ N ₅ O ₂ · 2.1IICI 2,611 ₂ O 192-194

⁸ The values measured for elemental analysis (C, Η, N) were within ± 0.4% of those calculated for the given formula.

Table 6

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

Compound (example number) ' CAR ed ₅₀ APÓ ed ₅₀ Catalepsy Induction ED _S0 Catalepsy Reversal ED _S0 24 6 40 24 1A ⁸ 25 11 34 46 2 26 12 35 _b 1A 28 100 100 - 16 29 65 -r-. 1A 30 35 - 142 1A 31 32 - 128 1A 36 43 47 - 1A 37 9 18 23 1A 38 4 7 13 1A 40 28 41 - - 41 14 22 40 1A 42 36 63 - 1A 47 60 61 - 1A 48 100 100 - 1A 49 67 100 - 1A

'IA is inactive and is used when ED _S0 45 is _greater than 20 mg / kg.

^{b —} meaning: data not available.

Explanation for Table 6:

CAR = conditional avoidance reaction,

APO = inhibition of apomorphine-induced stereotype.

Claims (2)

A process for the preparation of compounds of formula I in this formula Z is selected from the group consisting of (1), (3), (4), (5) or (8) or (2), wherein R ³ and R ⁴ are hydrogen or C 1-4 alkyl; n = 2, 3 or 4; R ¹ is hydrogen; R ² is hydrogen, halogen, or C 1-4 alkyl; One of X and Y is = CH, the other is oxygen or sulfur, or> N-R ⁷ , wherein R ⁷ is C 1 -C 4 alkyl, while X is only = CH or sulfur and pharmaceutically acceptable acid addition salts thereof, characterized in that a compound of formula II wherein D is a group of formula (a), (b), (c) or (d) R ³ and R ⁴ are hydrogen or C 1-4 alkyl, R ⁵ and R ⁶ is 1,4-butylene, V is oxygen or sulfur, U is> C = O or> SOI, W is S; Q is a suitable leaving group, preferably chloride, bromide, iodide, alkyl sulfate, tosylate or mesylate; n = 2, 3 or 4, with a compound of formula (III): wherein R ', R ² , X and Y are as defined herein; and optionally converting the resulting compound of formula (I) to an acid addition salt with an inorganic or organic acid. A process for the preparation of medicaments having a predominantly antipsychotic and scroton antagonist activity, wherein a compound of the formula I as claimed in claim ¹ , wherein R ¹ , R ² , X, Y, Z and n have the same meanings as defined in claim 1 Or a pharmaceutically acceptable salt thereof, in admixture with a carrier and / or other excipient in the preparation of a medicament, to form a pharmaceutical composition.