DE3615180C2 - Disubstituted 1,4-piperazinyl derivatives, processes for their preparation and pharmaceutical compositions containing these compounds - Google Patents

Description

The invention relates to disubstituted 1,4-piperazinyl derivatives, processes for their preparation and these ver pharmaceutical compositions containing bonds.

In the 1,4-disubstituted piperazine according to the invention derivatives is a substituent a bicyclic hetero cyclic, condensed ring system. These include Furo, pyrrolo, cyclopentadieno and thienopyridine ring systems. The other substituent is an alkylene chain, preferably a butylene chain containing a cyclic imide ring or a benzylic carbinol unit at its end wearing. As examples of such terminal units to call the following:

The compounds according to the invention are antipsychotics and serotonin antagonists. As an example of a typical Association with selective antipsychotic activity one can use 4- [4- [4- (4-Furo [3,2-c] pyridinyl) -1-piperazinyl] name butyl] -3,5-morpholine dione.

There have been numerous publications in the past 15 years appeared that deal with similar connections.  

The relevant prior art deals with ver bonds that affect the central nervous system.

These known compounds generally have the following general formula (1)

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

U.S. Patent Nos. 3,717,634 and 3,907,801 to Wu et al in a corresponding publication by Wu et-al, J.Med.Chem. 15, 447-479 (1972) are various azaspiro [4.5] -decandione described the psychotropic properties have. For these compounds, B means different monocyclic heterocycles such as pyridine, pyrimidine or Triazine, which have substituents if desired can.

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

Temple, Yevich and Lobeck report in U.S. Patent 4,361,565 via tranquilizing dialkylglutarimide compounds which B represents a 3-cyano-pyridin-2-yl ring, the ge if desired, can have a second substituent.  

Temple and Yeager in U.S. Patent 4,367,335 and 4,456,756 antipsychotic thiazolidinediones and Spirothiazolidinediones, where B is a 2-pyridinyl ring means either unsubstituted or one Has cyano substituents.

U.S. Patent 4,411,901 and 4,452,799 describe Temple and Yevich antipsychotic compounds that have a Numerous cyclic imide and benzyl carbinol units have, in which B either for benzisothiazole or Benzisoxazole ring systems stands.

Reference is also made to the following registrations.

In U.S. application Ser. No. 531,519, filed on 12.9.1983 and now issued, describe New and Yevich psychotropic succinimide and phthalimide converters bonds in which B represents a 2-pyrimidinyl ring. These compounds show anxiolytic activity.

Various antipsyotic 1-fluorophenylcarbonyl carbinol, ketal and propyl 4- (2-pyrimidinyl) piperazines are by Yevich and Lobeck in U.S. Application Ser.No. 5,583,309, filed December 18, 1984.

Finally, New, Yevich and Lobeck describe in the U.S. application, Ser.No. 691,952, filed on January 16, 1985, various antipsychotic compounds that have a large number of cyclic imide units and where B is a mono- or disubstituted pyridine ring system means.

Although having the psychotropic compounds listed above are related to the compounds of the invention, under nevertheless differ from them in structural terms  view of unit B of structural formula (1). In the prior art compounds, B means usually a monocyclic heteroaryl ring. The only ones Examples of bicyclic systems are condensed Benzo ring heterocycles, i.e. Benzisothiazole or benzisoxazole ring systems. This is how these connections differ of the compounds of the invention in which B ver different classes of condensed heterocyclic rings indicates, i.e. Furo-, pyrrole-, cyclopentadieno- or thieno pyridine ring systems. The compounds of the invention under differ pharmacologically based on the psychotropic Properties and side effect profiles of the ver Prior art bonds. So he own it Compounds according to the invention a selective antipsychotic (neuroleptic) activity accompanied by one Serotonin antagonism. The affinity of the invention Compounds for dopamine receptors are surprisingly very low. This is in contrast to the above written antipsychotic means of the state of the art Technology. Pharmacologically, the invention seem Connections to the atypical standard neuroleptic clozapine (2) to be similar, compare: The Merck Index, 10th edition 1983, page 344 and the literature references listed there.

As you can see, clozapine belongs to the dibenzodiazepine class of psychotropic agents that the inventive Structurally, connections are not very similar. In addition, the compounds of the invention are not seem to tend to be an adverse extrapyramidal To induce symptomatology with the chronic Administration of the currently used antipsyotic Agents is associated. Furthermore, based on Animal models are found to be certain inventive appropriate connections have the ability by the administration of trifluoperazine, a standard neuroleptic to reverse resulting catalepsy.

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

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

In the radical (a), R³ and R⁴ independently of one another denote a hydrogen atom or a C _1-4 alkyl radical or together represent a C³ to C₆ alkylene chain. in the remainder (b), R⁶ and R eine together represent a butylene chain and the remainder W a sulfur atom. In the rest (c), V represents an oxygen or sulfur atom. In the rest (d), U stands for C = O or SO₂. Furthermore, n in 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 C _1-4 alkyl group. One of the radicals X or Y is CH₂, O, S or NR⁷, the other radical X or Y then having to be = CH-. R² represents a hydrogen atom, a C _1-4 alkyl radical, or a halogen atom.

R⁷ represents a hydrogen atom or a C _1-4 alkyl radical.

Preferred compounds of the general formula (I) are those in which Z represents residues (a); (b); (c) wherein V represents an oxygen atom;  and (e). In these preferred compounds, Y is ent neither an oxygen or sulfur atom, while X Means methynyl (= CH-); n stands for 4, however, if Z is the radical (e), n is 3; R² stands for a hydrogen atom.

There are two classes of the most preferred Links. With one class of connections, with where Y represents an oxygen atom, Z represents either (a), (c), where V represents an oxygen atom, or (e). For the class of connections where Y is a Represents sulfur atom, Z represents either (a), (b) or (e).

The pharmaceutically acceptable acid addition salts of Compounds according to the invention are those in which the anion is not significant for toxicity or contributes pharmacological activity of the salts. These Salts are therefore pharmacological equivalents of the bases of the compounds of the general formula (I). For these salts are preferably used for medical purposes. In some cases, they have physical properties, due to which they are used for pharmaceutical formulations are more suitable. These properties include the Solubility, the lack of hygroscopicity, the Compressibility in tablet manufacturing and the Compatibility with other components with which the Compounds according to the invention together for pharmaceutical Purposes. The salts are placed on the usual ones Manner by using a base of the general formula (I) mixed with a selected acid, preferably by bringing solutions of it in contact, whereby one an excess of an inert one usually used Solvent used. To these inert solvents  count ether, benzene, ethanol, ethyl acetate, acetonitrile and water. You can also use the salts after each other Establish the usual procedure described in the literature is described and known to the expert. As examples useful organic acids can be called: carboxylic acids, such as malein, vinegar, wine, propion, fumar, isethione, Succinic, pamo-, oyclaminic and pivalic acid. Useful inorganic acids are: hydrohalic acids, such as HCl, HBr, Hl, sulfuric acids and phosphoric acids.

According to the invention, all stereoisomers are also included can occur if the rest Z is, for example contains asymmetric carbon atom. This is an example wisely with the rest (e). This is also possible with Remainder (b). The individual stereoisomers can be used in the usual way Way on separate. The procedures used are well known to those skilled in the art.

The compounds of the invention are useful pharmacological agents with psychotropic properties. They are selective at non-toxic doses Central nervous system activity and are of particular interest as antipsychotics (neuroleptics).

Like other well-known antipsychotics, it works Compounds of the general formula (I) according to the invention in standard pharmacological tests in vivo and in vitro certain reactions. Of these test systems, be knows that the results achieved with the Relief of symptoms of acute and chronic psychoses to correct in people.

For subclassification of psychotropic activity and specificity of the compounds of the invention the well-known in vitro central nervous system receptor  Binding methodology used. Certain ver found bonds that are generally ligands are drawn, which are mainly intended for certain Make high affinity bind in brain tissue, which for the psychotropic effectiveness or the possible occurrence of Side effects play a role. The inhibition of Binding of a radiolabelled ligand to such specific sites of high affinity are considered to be Benchmark for the ability of a connection that ent to influence the speaking function of the central nervous system flow or cause side effects in vivo. This The principle applies to tests where, for example inhibition of [3 H] spiperone binding is measured. this means for significant dopamine receptor binding activity (compare Burt et al, Molecular Pharmacology, 12, 800 (1976); Science, 196, 326 (1977), Crease et al., Science, 192, 481 (1976).

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

The data obtained from the above binding tests show that the compounds of the invention have a low to low affinity for dopaminergic receptors, however much larger affinities for both serotonin S₁ as well as S₂ positions. These binding properties distinguish the compounds of the invention from the compounds of the prior art mentioned and of most of the clinically useful, currently on put antipsychptics. In this regard, the fiction according to some pharmacological properties with the atypical standard neurolepic, clozapine, one Dibenzodiazepine derivative, together. The lack of dopaminergic binding affinities in the Invention connections seem to reduce the tendency to induce undesirable extrapyramidal side effects, by most of the currently used anti psychotics are caused.

Binding activity with respect to the α 1 receptor (Test 252B) indicates that the compounds of the invention have sedative component, what in the treatment often desired by subgroups of psychotic patients is worth.

The following in vivo test systems are common test methods drive to classify a psychotropic agent be used. Based on these tests, a psychotropic agent from a nonspecific CNS Depressive (CNS = central nervous system) differentiated will. With these tests, possible inclinations can also be determined side effects, for example cataleptic activity, be determined.  

Table 2 To evaluate the compounds of the invention general formula (I) used in vivo tests 1. Addressing the conditional escape reflex (CAR)

Ability 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 Pharmacologist, 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 "apomorphine".
Literature: Janssen et al, Arzneimittel Forsch. 17, 841 (1966).

3. Catalepsy

Drug-induced catalepsy in rats can be used to predict possible extrapyramidal symptoms (EPS) in humans.
Literature: Costall et al, Psychopharmacologia 34, 233-241 (1974); Berkson J.Amer.Statist.Assoc. 48, 565-599 (1953).

4. Reversal of catalepsy

Ability of a drug by a Neuroleptic induced catalepsy in rats to sweep.

According to the pharmacological profile, which with the help of the above tests he developed Compounds of the general formula (I) according to the invention a promising antipsychotic potential, because they are relatively effective in the CAR test, with ED₅₀ values <100 mg / kg body weight, and since it is the stereotype induced by apomorphine block effectively. This blockage of through Apomorphine-induced stereotype can dopamine Antagonist activity reflect and is ver relatively specific "screen" for a neuro viewed leptic activity. It can therefore assume be gone that the compounds of the invention have selective antipsychotic activity because they lead to antipsychotic activity at doses, that don't cause catalepsy. The invention Connections are not just about catalepsy Production relatively inactive. Rather, what even even more significant are preferred fiction moderate connections the ability to be a neuroleptic reverse induced catalepsy, taking the ED₅₀ values <20 mg / kg are administered orally. The Significanz der Effects of these compounds of the invention on Catalepsy induction and reversal is even greater if you consider that antipsychotic Agents known as extrapyramidal class Cause reactions. This unwanted extra pyramidal reactions are great for treatment disadvantageous. These include acute torsional dystonia,  Akathesis, Parkinsonism and tärdive dyskinesia. Some representative biological in vivo data are in the Table 6 summarized below.

In summary, it can be said that the invention connections according to psychotropic properties ver due to which they are used in particular as selective antipsychotics (neuroleptics) are suitable. The Compounds according to the invention also lead only too much low side effects of movement disorders. Subject of Invention is thus the use of the invention Relief to relieve a psychotic condition a mammal (human and animal) that one Treatment is needed. To do this, systemically administered one effective dose of a compound of general formula (I) or a pharmaceutically acceptable acid addition salt thereof to such a mammal.

The compounds of the general formula according to the invention (I) are administered and dosed in the same way, like the reference compound clozapine, compare Merck Index, 10th edition, (1983), page 344 and those there references listed. Although the dosage and the dosing schedule in any case carefully under Her attraction of the specialist knowledge of the treating physician ge would have to be chosen, the age, the weight, the Condition of the patient, route of administration and type and severity of the disease must be taken into account the daily dose is generally about 0.05 to about 10 mg / kg, preferably 0.1 to 2 mg / kg for parenteral Administration. When administered orally, the ent speaking dose about 1 to about 50 mg / kg, preferably 2 to 30 mg / kg. In some cases you can get one out sufficient therapeutic effect at lower doses  achieve, while in other cases it is necessary to choose larger cans. The expression used here "Systemic administration" means oral, rectal and parenteral (i.e. intramuscular, intravenous and subcutaneous) routes of administration. If you administer a he Oral compound according to the invention (preferred administration art), then there is generally a larger amount of active ingredient required to produce the same effect as with a smaller but parenterally administered amount. In It is in accordance with good clinical practice preferred, the compounds of the invention in one Concentrate to be administered that is effective anti psychotic (neuroleptic) effects results without doing so cause harmful or undesirable effects.

For therapeutic purposes, the Ver bonds in general in the form of pharmaceutical agents administered. These contain an effective antipsychotic Amount of a compound of general formula (I) or of a pharmaceutically acceptable acid addition salt thereof and, where appropriate, a pharmaceutically acceptable one Carrier. Pharmaceutical means to carry out a such treatment contain a major or minor stock part, e.g. B. from 95 to 0.5%, at least one invention modern compound in combination with a pharmaceutical Carrier. The carrier can be one or more Fat, semi-solid or liquid diluent, Fillers and formulation adjuvants don't act are toxic, inert and pharmaceutically acceptable. The Like pharmaceutical agents are preferably in the form of dosage units before, d. H. it is a matter of physically discrete units that are a predetermined Amount of the drug included, which is a part or corresponds to a multiple of the dose from which be  was calculated to be the desired therapeutic Addressing leads. The dosage units can be one contain two, three, four or more individual cans.

Alternatively, they can be 1/2, 1/3, or 1/4 one single dose included. Contains a single dose preferably an amount sufficient to achieve the desired to achieve therapeutic effect and after administration sufficient when using one or more doses units according to the predetermined dosing schedule, ge usually a 1/1, 1/2, 1/3 or 1/4 of a daily Dosage administered 1x, 2x, 3x or 4x daily becomes. Other therapeutic agents may also be used be there. Pharmaceutical agents, which are about 1 to 500 provide mg of the active substance per single dose, be prefers. The pharmaceutical agents are common in the form of tablets, lozenges, capsules, powders, aqueous or oily suspensions, syrups, elixirs and aqueous solutions are provided. Preferred oral Means are in the form of tablets or capsules and can contain conventional excipients. These include bandages medium (e.g. syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone), fillers (e.g. lactose, Sugar, corn starch, calcium phosphate, sorbitol or Glycine), lubricants (e.g. magnesium stearate, talc, poly ethylene glycol or silica), disintegrating agents (e.g. Starch), and wetting agents (e.g. sodium lauryl sulfate).

Solutions or suspensions of the compounds of the general my formula (I) along with usual pharmaceutical Carriers are used for parenteral means, for example as an aqueous solution for intravenous injection or an oily suspension for intramuscular injection.

Such means that the desired clarity, Stability and suitability for parenteral use indicate, is obtained by 0.1 to 10 wt .-% of the active ingredient  dissolves in water or a carrier. The carrier exists from an aliphatic polyalcohol, for example Glycerin, propylene glycol or polyethylene glycols or Mixtures of these. The polyethylene glycols consist of a mixture of non-volatile, generally liquid Polyethylene glycols, both in water and in organic liquids are soluble and their molecular weight is about 200 to 1500.

The compounds of the general formula according to the invention (I), in which Z represents the radicals (a) to (e), is obtained by processes in which piperazinyl or "imide" Intermediates are alkylated. This procedure correspond to those described by Wu et al. in the above Patents or by Temple et al. in the above ge called patents are described on the here Reference is made. These procedures can become one Standard procedures are summarized, the Her position of the compounds of the general my formula (I) is applied. The procedures can can be varied to include other Ver to obtain bonds that are not specifically disclosed. Changes to these procedures that lead to the same ver Having ties in a slightly different way is for obvious to the expert. There are certain examples explained in more detail below.

Standard procedure

In this scheme, R¹, R², X and Y have the previously in Connection with the meanings given by the formula (I). The symbol D either represents the divalent structures residues (a) to (d) as shown in the following Substructures (a ') to (d') is reproduced, or for the rest also shown below (e ′).

In the residues (a ′) to (e ′), all symbols have the meanings previously assigned. The symbol "E" in the diagram above can be used for O; NH; or N- (CH₂) _n -Q are. The symbol "n" has the meanings given above. Q denotes a suitable leaving group, such as chloride, bromide, iodide, sulfate, phosphate, tosylate or mesylate. The symbol "J" can be used for

or H- stand. The relationship between E and J is as follows:

Method A

Method B

(IIIb ′ is a special case where n is fixed to 4)  

Method C (preferred method)

With method A, the condensation is carried out, by inerting the reactants in a dryer Reaction medium, for example pyridine or xylene, on Reflux heated. With methods B and C one leads the implementation at reaction conditions for the Production of tertiary amines via alkylation secondary amines are suitable. The reactants are heated one in a suitable organic liquid Temperatures from about 60 ° to about 100 ° C in the presence an acid binding agent. Benzene, dimethylformamide, Ethanol, acetonitrile, toluene and n-butyl alcohol are be preferred examples of such liquid organic Reaction media. The acid-binding agent is used preferably potassium carbonate, but you can also other inorganic and tertiary organic bases ver turn. These include other alkali and alkaline earths metal carbonates, bicarbonates or hydrides and the tertiary amines. All three methods are in the above mentioned patents described in more detail on the hereby Reference is made. Method C is the preferred one Synthesis process for the preparation of the invention Connections. The required interconnections IIc is produced by methods described in the patent specifications  are described in detail, to which reference has been made.

To prepare the compounds of the general formula (I), where Z represents the rest (e), one sets the following described, modified method C.

Below is an example of a modified one Method for producing the ver bonds of the general formula (I) to something explained another way, one with Z substituted alkylpiperazin-4 with a suitable one condensed bicyclic pyridine system 5 to a ver binds the general formula (I), z. B.

The invention thus also relates to a method for Preparation of the compounds of the general formula (I), which is characterized in that one is known per se wise

• a) an intermediate compound of formula IIa wherein the symbol "D" means a divalent structure of the formulas a'-d ' with an intermediate compound of formula IIIa wherein R¹, R², n, X and Y have the meanings given above, to give a compound of formula I; or
• b) a compound of the formula with an intermediate compound of formula IIIb in which Q has a suitable leaving group, for example chloride, bromide, iodide, sulfate, phosphate, tosylate or mesylate, and D, R 1, R 2, n, X and Y have the meanings given above, to give a compound of the general formula I; or
• c) a compound of formula IIb with an intermediate compound of formula IIIb ' in which 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 IIc with an intermediate compound of formula IIIc wherein D, n, Q, R¹, R², X and Y have the meanings given above, to a connec tion of the general formula I; or
• e) a compound of formula IV with an intermediate compound of formula V wherein Z, n. R¹, R², Q, X and Y has the meanings given above, to a connec tion of the general formula I; or
• f) (i) a compound of formula IId with an intermediate compound of formula IIIc to a compound of general formula If implements
• ii) the compound If in acidic medium to a compound of the general formula Ig hydrolyzed and
• iii) the compound of the formula Ig with sodium borohydride to a compound of the formula Ie

reduced.

The intermediate compounds of formulas (II) or (IV) are in the above-mentioned patents and ge named citations to which reference was made, described in a suitable manner. Various ver Compounds of formula (II) are also commercially available. The bicyclic pyridinylpiperazine intermediates of the formula (III) and those as starting compounds set bicyclic heterocycles (V) are either in Commercially available, be in the chemical literature wrote or detailed in the available documents purifies. The for the synthesis of the intermediates of Formula (III) methods used are in Scheme I explained in more detail.

Scheme I

Synthesis of bicyclic intermediates III:  

For the synthesis of furo-, pyrrolo-, cyclopentadieno- or Thieno-pyridine ring systems according to Scheme I are assumed the carboxaldehyde intermediate of formula (X). The 2-carboxyaldehyde intermediate is in Scheme I. shown and leads directly to the interconnection (IIIc), also shown in Scheme I. If you put that  3-carboxaldehyde intermediate (X ′) according to Scheme I then the product obtained is the "reverse" isomer (IIIc ′).

The general structure (III) (where J = H) of the above he refined standard procedures generally give the Structures of the two interconnections (IIIc) and (IIIc ′) again.

The one shown in Scheme I is required as the starting compound Liche carboxyaldehyde can either be obtained commercially or produce in a simple manner, e.g. B. by Vilsmeier- Haack formylation of an n-alkyl pyrrole using methods applies, which are described in the chemical literature and are well known to the chemical artisan. The Condensation of the intermediate compound (X) with malonic acid at 100 ° C usually in pyridine as a solvent by using piperidine as a catalyst. Man generally reacts for 12 h and then heats for a short time to reflux to promote decarboxylation. Man receives the corresponding acrylic acid intermediates of formula (IX).  

The acids of formula IX are chlorinated with thionyl chloride in chloroform and a catalytic amount of dimethyl formamide to the acid chloride derivatives of the formula VIII, which you do not clean, but in raw form for production uses the acid azides of the formula VII. These acid azides is made either in a two-phase mixture of Acetone in water at 5 ° with hilde of sodium azide or with trimethylsilyl azide in refluxing benzene forth. The unpurified preparations of acid azides Formula VII in methylene chloride solutions is added in portions as either diphenyl ether or diphenyl methane and heated to 230 °, causing the Curtius rearrangement to over Isocyanates is facilitated, which immediately leads to the condensed 6-5 bicyclic intermediates of Cyclize Formula VI. The compound VI is chlorinated, by using phosphorus oxychloride or a phosphorus penta chloride-phosphorus oxychloride mixture to produce the chlorine-substituted heterocycle of the formula V starts. The implementation of V with an excess of one suitable piperazine in a bomb at 120-140 ° C reaction times of different lengths lead to the ge wish piperazine intermediates IIIc. This general my synthesis to make the interconnects Formula IIIc has been described earlier, see Eloy, et al., Bull. Soc. Chim. Belges., 79: 301 (1976); J. Heterocyclic Chem., No. 8: 57 (1971); Helv. Chim. Acta., 53, 645 (1970)). The substituents R² can then be introduced by either using the Starting compound X incorporated or later in the reaction introduces workflow, e.g. B. by methylation of V (X = S, with t-butyllithium and subsequent implementation with dimethyl disulfide, whereby an intermediate compound of Formula V obtained, wherein R² = SCH₃.  

The use of interconnections of the general Formula III in the standard procedure described above and the use of methods A-C, preferably C, leads to the antipsychotic compounds of the general my formula I.

The invention is explained in more detail below with the aid of the examples. Unless otherwise stated, all temperature data refer to degrees Celsius. The NMR spectral data denote the chemical shifts (δ), 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 1 H-NMR spectrum corresponds to the number of hydrogen atoms of a certain functional type in the molecule. The type of shifts in terms of multiplicity is given as follows: Broad singlet = bs, singlet = s, multiplet = m, doublet = d, doublet of dublets = dd, triplet = t, quartet = q. The following abbreviations are used: DMSO-d₆ = perdeuterodimethyl sulfoxide, CDCl₃ = 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 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 intermediate IIIc, which can be converted into other synthetic intermediates such as IIIa or IIIb using known reactions, as described, for example, in the cited patents .

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

A stirred mixture of N-methylpyrrole (10 g; 0.12 mol) in dichloroethane (80 ml) and dimethylformamide (11.3 g; 0.15 mol) are added dropwise at 5 ° with phosphoroxy chloride (23.6 g; 0.15 mol). This leads to an exothermic Reaction in which a precipitate forms. You stir another 15 minutes and the precipitate is filtered off, sus pendulum in 300 ml of 3 N NaOH solution and extracted with 3 x 100 ml chloroform. The chloroform portions combined one dries 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 is correct with the assigned structure. This intermediate compound was generally unpurified in the next level of scheme 1 used.

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

A mixture of 2-thiophene carboxaldehyde (100 g; 0.89 Mole); Malonic acid (182.5 g; 1.70 mol); Pyridine (446 ml) and piperidine (8.9 ml) is heated at 100 ° for 12 hours. The reaction solution is refluxed for 20 minutes, let cool, pour it into 1000 ml of water and acidify the aqueous mixture obtained with conc. HCL on. You fil the gray-white precipitate obtained and it crystallizes from ethanol-water (1: 1), whereby 109 g (80%) of the product obtained, melting point 145-148 °.  

Example 3 3- (2-thieno) acpyloyl 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 Chloroform is added dropwise at room temperature with thionyl chloride (110.1 g; 0.93 mol). You heat the The reaction mixture was then refluxed for 2 hours, cooled and evaporates in vacuo to a brown oil that solidified when standing. This gives 131 g (99%) of one low melting solid, which one without further Cleaning used.

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 p-dioxane and 400 ml water a solution of 3- (2-thieno) is added dropwise acryloyl chloride (223.9 g; 1.3 mol) in dioxane at 5 °. Man isolates the one obtained from this two-phase mixture Dioxane layer, concentrated in vacuo, dissolves in 500 ml Methylene chloride, dries and filtered. The methylene Chloride filtrate is added dropwise to those boiling on the return flight Diphenyl ether (400 ml), which is in a triple flask is located, which is equipped with two air coolers. The solution is refluxed for a further hour, cools and constricts in a vacuum to a dark syrup, the one crystallizes from acetonitrile, whereby one brown solid is obtained, which is filtered off. After order crystallization of the solid obtained 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)

Fine 4-oxo-4,5-dihydrothieno (3,2-c] pyridine (105.6 g; 0.69 mol) is stirred to give phosphorus oxy chloride (321.5 g; 2.1 mol) was added dropwise at 0 °. One heats up the reaction mixture was then refluxed for 2.5 hours, cools and pour carefully onto 1000 ml of crushed ice. The solution obtained is stirred for 30 minutes and extracted with 3 × 400 ml dichloromethane. One unites the organi portions, dries over MgSO₄, filtered and concentrated in vacuo to a solid which is made from 400 ml Acetonitrile recrystallized, 101 g (85%) of one pale yellow solid obtained, melting point 91 ° C.

Example 6 4- (1-piperazinyl) thieno [3,2-c] pyridine (IIIc)

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

Example 7 Production of 7- (1-piperazinyl) thieno [2,3-c] pyridine (IIIc ′)

This connection is made by using the same Carries out reaction steps as in the production of compound IIIc, but starting from compound X uses 3-thiophenecarboxaldehyde. The more stage preparation of the positional isomer IIIc 'is however complicated because the Curtius rearrangement (example 4) the desired intermediate VI only in lower Yield yields. The main product of this implementation is a sym-triazine by-product resulting from trimerization of the isocyanate intermediate results.

Nevertheless, the application of the in scheme 1 shown implementations for the manufacture of the product IIIc ′, which is a brown rubbery Material that one without further cleaning puts.

By suitable modifications to those shown in Scheme 1 Reaction steps and the different, explained above Synthesis reactions can be further compounds IIIc synthesize. Some other representative connections gen IIIc are listed in Table 3.  

Table 3

Other compounds of formula IIIc

Below is the preparation of the compounds of the general formula I described.

Example 19 General synthesis

The compounds of general formula I are synthesized by alkylating imide derivatives (IIc) substituted by suitable halogen substituents, in which D is (a′-d ′) and E is N- (CH₂) _n -Q, where Q means a halide. The fluorophenyl butyrophenone derivative (IId) can also be reacted with a suitable intermediate compound IIIc in refluxing acetonitrile, three equivalents of potassium 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 20 4,4-dimethyl-1- [4- [4- (thieno [3,2-c] pyridin-4-yl) - 1-piperazinyl] buty] -2,6-piperidinedione

A mixture of 4- (1-piperazinyl) thieno [3,2-c] pyridine (IIIc; 2.79 g, 0.012 mol), N- (4-bromobutyl) -3- dimethylglutarimide (3.3 g, 0.012 mol) and potassium carbonate (3.3 g, 0.024 mol) is heated in 150 ml for 24 hours Acetonitrile on the return flight. The reaction is filtered  mixture, concentrates in a vacuum and distributes between Dichloromethane and water. The organic is isolated Layer, dries over MgSO₄ and constricts it in vacuo to a golden oil that flash chromatographs mar (5% ethanol-chloroform). The chromatographed Material is dissolved in acetonitrile and treated with ethanolic HCl, 1.3 g (24% yield) of the hydrochloride salt obtained, melting point 195-197 ° C.

Analysis.
C₂₂H₃₀N₄O₂S · HCl:
calculated: C 58.59; H 6.93; N 12.42%;
found: C 58.64; H 7.02; N 12.72%;
1 H NMR: 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 (1, m); 8.08 (1, d [5.0 Hz]); 11.75 (1, bs).
IR (KBr): 715, 965, 1425, 1535, 1670, 1720, 2580, 2960 cm ^-1 .

Example 21 4- [4- [4- (4-Furo [3,2-c] pyridinyl) - 1-piperazinyl] butyl] 1-3,5-morpholine dione

A mixture of 4- (1-piperazinyl) furo [3,2-c] pyridine (4.5 g; 0.022 mol), 4- (4-bromobutyl) -3,5-morpholine indione (5.5 g; 0.022 mol) and potassium carbonate (9.1 g; 0.066 mol) one heats up 24 hours on the return flight. You filter the  Reaction mixture, concentrated in vacuo and distributed between dichloromethane and water. You isolate them organic layer, dries over MgSO₄ and constricts in Vacuum to a yellow oil that you flash chromato graphed. The appropriate chromatographi are combined fractions, concentrated in vacuo and crystallized from isopropanol, whereby 6.2 g (69%) of the free Base obtained, melting point 109-110 °.

Analysis for C₁₉H₂₄N₄O₄:
calculated: C 61.28; H 6.50; N 15.04%;
found: C 60.98; H 6.60; N 15.19%
1 H NMR (CDCl₃): 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 .

According to the procedure described above or according to alternative synthetic methods mentioned in the above ten patents are disclosed, others Compounds of the general formula I can be obtained. Tables 4 and 5 below are others representative compounds of general formula I. listed. Table 6 shows biological in vivo Data for representative compounds of the general Formula I compiled.  

Table 4

Compounds of the general formula I

Table 5

Other compounds of general formula I.

Table 6

Representative biological in vivo data (m / k, po)

Claims (4)

1. Disubstituted 1,4-piperazinyl derivatives of the general formula I wherein
Z means one of the following radicals: wherein R³ and R⁴ independently represent a hydrogen atom or a C₁-C₄ alkyl radical or together represent a C₃-C₆ alkylene chain: wherein R⁵ and R⁶ together represent a butylene chain and W represents S; where V is O or S; wherein
U represents C = O or SO₂; and n is an integer from 2 to 4, where Z is the radical (e) 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 C₁-C₄ alkyl radical; and R² represents a hydrogen or halogen atom or a C _1-4 alkyl radical,
as well as the pharmaceutically acceptable acid addition salts thereof. 2. Pharmaceutical composition containing at least one A compound according to claim 1, optionally together with a pharmaceutical carrier and / or diluent. 3. Pharmaceutical composition according to claim 2, in the form of a Dosage unit and containing 1-500 mg at least a compound according to claim 1. 4. A process for the preparation of the compounds of general formula I according to claim 1, characterized in that in a manner known per se

• a) an intermediate compound of formula IIa wherein the symbol "D" means a divalent structure of the formulas a'-d ' with an intermediate compound of formula IIIa wherein R¹, R², n, X and Y have the meanings given above, to give a compound of formula I; or
• b) a compound of the formula with an intermediate compound of formula IIIb in which Q has a suitable leaving group, for example chloride, bromide, iodide, sulfate, phosphate, tosylate or mesylate, and D, R 1, R 2, n, X and Y have the meanings given above, to give a compound of the general formula I; or
• c) a compound of formula IIb with an intermediate compound of formula IIIb ' in which Q, R 1, R 2, 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 IIc with an intermediate compound of formula IIIc wherein D, n, Q, R¹, R², X and Y have the meanings given above, to a connec tion of the general formula I; or
• e) a compound of formula IV with an intermediate compound of formula V wherein Z, n, R¹, R², Q, X and Y has the meanings given above, to a connec tion of the general formula I; or
• f) (i) a compound of formula IId with an intermediate compound of formula IIIc to a compound of general formula If implements
• (ii) the compound If in acidic medium to a compound of the general formula Ig hydrolyzed and
• (iii) the compound of the formula Ig with sodium borohydride to a compound of the formula Ie reduced.