FI85484B - FOERFARANDE FOER FRAMSTAELLNING AV ANTIPSYKOTISKA PYRIDINYLPIPERAZINDERIVAT SOM INNEHAOLLER EN KONDENSERAD RING. - Google Patents

Description

1 85484

This invention relates to a process for the preparation of novel heterocyclic compounds having pharmaceutical and biologically active properties. In particular, the invention relates to a process for the preparation of 1,4-disubstituted piperazine derivatives in which one substituent is a heterocyclic furo, pyrrolo, cyclopentadieno or thienopyridine system containing two fused rings and the other is an alkylene chain, preferably a butylene chain containing a terminal ethylene chain. an imide group or a benzylcarbinol group, as further defined below.

Over the past fifteen years, a considerable amount of information has been accumulated in the field, much of which has been produced by a research team at the Bristol-Myers Company. Relevant information in the art, compounds acting on the central nervous system, can be viewed in the light of the following general structural formula (1): CN-alkV Vb ^ 0 \ - / wherein alk is an alkylene chain connecting a piperazine ring to a cyclic imide group, and B is a heterocyclic ring , optionally containing substituents.

U.S. Patent Nos. 3,717,634 and 3,907,801 (Wu et al.) And the corresponding Wun et al. in J. Med. Chem. 15 (1972) 447-476 - discloses various psychotropic azaspiro [4.5] decanedione compounds in which B is one of various monocyclic heterocyclic groups, such as a pyridine, pyrimidine or triazine ring, all of which may contain substituents.

In U.S. Patent No. 4,305,944, Temple, Yevich, and Lobeck disclose the sedative azaspiro [4.5] decanedione-5 compounds wherein B is a 3-cyanopyridin-2-yl or 3-methoxypyridin-2-yl group.

In U.S. Patent 4,361,565, Temple, Yevich and Lobeck disclose sedative dialkylglutarimide compounds wherein B is a 3-cyanopyridin-2-yl group which may contain another substituent.

In U.S. Patent Nos. 4,367,335 and 4,456,756, Temple and Yeager disclose antipsychotic thiazolidinediones and spirothiazolidinediones in which B is a 2-pyridinyl group which is either unsubstituted or contains 15 cyano substituents.

U.S. Patent Nos. 4,411,901 and 4,452,799

Temple and Yevich disclose antipsychotic compounds containing a variety of cyclic imide and benzyl carbinol groups and wherein B is either a benzisothiazole or a benzisoceazole ring system.

Attention is also drawn to the following open patent applications.

U.S. Patent Application No. 531,519, filed September 12, 1983 (patent now granted), New Yevich. 25 describe psychotropic succinimide and f or imide type compounds wherein B is a 2-pyrimidinyl group, and; claim them. These compounds have an anxiolytic effect.

In U.S. Patent Application No. 583,309, filed December 18, 1984, Yevich and Lobeck disclose a series of antipsychotic 1-fluorophenylcarbonyl, carbinol, and ketal propyl-4- (2-pyrimidinyl) piperidines.

··, ··: In U.S. Patent Application No. 691,952, filed January 16, 1985, New, Yevich, and Lobeck describe a further 35 sets of antipsychotic compounds containing various cyclic imide groups of 3,85,484 and wherein B is mono- or di- substituted pyridine ring, and claim them.

Although the psychotropic compounds 5 listed above are generally close to the compounds prepared according to the present invention, they are nevertheless structurally distinguishable from the compounds according to the invention on the basis of group B of structural formula (1). Essentially, the known compounds B usually have a monocyclic hetero-roaryl ring, the only examples of bicyclic systems being heterocyclic rings fused to a benzene ring, i. benzisothiazole and benzisoxazole ring systems. This distinguishes these compounds from those prepared according to the invention in which B consists of 15 different groups of fused heterocyclic rings, i.e. furo-, pyrrolo, cyclopentadieno or thienopyridine ring systems. A pharmacological distinction can also be made between the compounds of this invention and the known compounds on the basis of psychotropic effects and side effect profiles. With respect to this difference, the compounds of the invention have a selective antipsychotic (neuroleptic) effect associated with serotonin antagonism and, surprisingly, a low affinity for dopamine receptors, in contrast to the hitherto known antipsychotics described above. In this respect, the compounds according to the invention pharmacologically resemble somewhat aberrant basic neuroleptic, clozapine (2); see The Merck Index, 10th Edition, 30 1983, p. 344 and references therein.

Aa: “‘ teo

B

·: ·: (2) 4 85484

As can be seen, clozapine belongs to the group of psychotropic substances dibenzodiazepines, which group has little structural similarity to the group of compounds according to the invention. In addition, the compounds of the present invention appear to lack the ability to cause adverse extrapyramidal symptoms associated with the long-term administration of currently used antipsychotic agents. In addition, certain compounds of the invention have been shown in animal models to have the ability to reverse cataples resulting from the administration of trifluoperazine, a basic neuroleptic.

The process of the present invention provides piperazinyl derivatives having neuroleptic (antipsychotic) properties and of formula (I) R2

R1 x ^ V

wherein Z is one of the following groups: "& wherein R 3 and R 4 are each independently hydrogen or lower; an alkyl group or R 3 and R 4 together form a C 3-6 alkylene chain; R 6 R 0 R 5 - <S- (b)» « - (5 85484 wherein R 5 and R 6 are each independently hydrogen, a lower alkyl group or an A-substituted phenyl group when A is hydrogen or halogen or R 5 and R 6 together form a butylene chain and W is S or CH 2; where V is O or S, where G is hydrogen, a lower alkyl or alkoxyl group or halogen, m is an integer from 1 to 4 and U is C = O or SO 2, and F - ^ - ^ H- (β) n is an integer from 2 to 4 with the proviso that when Zsn is (e) n is 3, either X or Y is independently CH 2 / O, S or NR 7 provided that one of them is always = CH-, each of R 1 and R 7 is independently hydrogen or a lower alkyl group, and R 2 is hydrogen, a lower alkyl, lower alkoxyl, lower alkylthio or hydroxyl group or halogen, and a pharmacist thereof acceptable acid addition salts.

The term "lower" used in the definition of radicals means that the relevant. the radical has 1 to 4 carbon atoms.

Preferred groups of compounds are those compounds of formula (I) wherein Z is group (a); group (b) R5 and R6 6 85484 together form a butylene chain and W is a sulfur atom? group (c) when V is an oxygen atom; and group (e). In the case of these preferred groups, Y is either an oxygen or sulfur atom and X is a methynyl group (= CH-); n is 4 pairs-5 si with Z being (e), wherein n is 3; and R 2 is hydrogen.

There are two groups of highly preferred compounds. In the case of a group of compounds in which Y is an oxygen atom, Z is either (a), (c) V being an oxygen atom or (e). In the case of a group of compounds in which Y is a sulfur atom, Z is either 10 (a), (b) or (e).

Compounds of formula (I) are prepared according to the invention such that (a) a compound of formula (He) 15 / '"λ D N- (C10 -Q Ile v, ___ / 2 n wherein n is as defined above, Q is a suitable displaceable group-20 such as chloride, bromide, iodide, sulphate, phosphate, phosphate or mesylate, and D is a divalent radical of formula

SH H H

(a *) Cb ’) (O (d <) 30 is reacted with an intermediate compound of formula (IIIc)

: T- K1 A

7 85484 wherein R 1, R 2, X and Y are as defined above to give a product of formula (I); or (b) (1) reacting a compound of formula (IIId) wherein N is as defined above with an intermediate compound of formula (IIIc) to give a compound of formula (If) R 2 JTk R 1 yAy 20 ( 2) hydrolyzing a compound of formula (If) in an acidic medium to give a compound of formula (Ig) 25 and (3) reducing a compound of formula (Ig) with sodium borohydride to give a product of formula formula (Ie) 8 85484 R2 R1 x ^ »y wherein R1, R2, X and Y are as defined above.

Process a) is carried out under conditions suitable for the preparation of tertiary amines by alkylation of secondary amines. The reactants are heated in a suitable organic solvent at about 60 to 1000 ° C in the presence of an acid scavenger. Preferred Examples of organic liquid media are benzene, dimethylformamide, ethanol, acetonitrile, toluene and n-butanol. The preferred acid scavenger is potassium carbonate, but other inorganic and tertiary bases may be used, including other alkali and alkaline earth metal carbonates, bicarbonates and hydrides, and tertiary amines. All three methods are described in detail in the above-mentioned patent reference, which is incorporated herein by reference in its entirety. Process a) is the preferred synthetic process for the preparation of compounds of formula (I). Needed. The following intermediates (Ile) were prepared according to the methods set forth in the referenced patent publications.

Method b) can be represented by the following reaction; ; . 30 thio diagram: 35 «♦ ·· *» • · * · * · · a * »* m * · 9 85484 Π> 1) alkylation 2) ketal hydro- 5 '(CH?), - 0 + IIIc lysis H30 ® ^ J 3) sodium borohydride R2 10 1'-O- ^ 03 · 15 Ke)

Intermediate compounds of formulas (He) and (IId) are described in the above-referenced patents and references cited therein; a few compounds of formula 20 (II) are also commercially available. The bicyclic pyridinylpiperazine intermediates of formula (IIIc) are either commercially available or can be found in the chemical literature and described therein. Methods for synthesizing intermediates of formula (IIIc) are described in Scheme I.

10 85484

Scheme I

Synthesis of bicyclic intermediates (IIIc)

f \ ΓΛ Cj ° 2H

r2 / \ X ^ CHO> p2 Λ χ / V1 piperidine catalyst pyridine χχ * solvent 90 ° soci2 DMF, CHCl3 ^

Yjj H2O-acetone mi difen- 240 ° yyii-ether 'f C1 / NH POCU / 7 ^ Π \

* jrfj - ', / P

RZ * R1

": VI V

--.:0 γ2 '· · * oi * n, \ f 20 h at 120 ° C Γ.-Λ-Η * ·: ··: IIIc * · 11 85484

In Scheme I, the synthesis of furo, pyrrolo, cyclopentadieno or thienopyridine ring systems is carried out using the carboxaldehyde intermediate of formula (X) as starting material. The 2-carboxaldehyde intermediate is shown in Scheme I and ultimately leads to intermediate (IIIc) as shown in Scheme I. If the 3-carboxaldehyde intermediate (X ') is used in Scheme I, the resulting product is the "reverse" isomer (IIIc'). 2 10 r1 C-? -> diagram 1-► H - ^ "^ -

R2 X

15 (X '> (IIIc1)

The carboxaldehyde starting material required in Scheme I can either be obtained commercially or prepared in a simple manner, for example by Vilsmeier-20 Haack formylation of N-alkylpyrrole, using methods readily available in the chemical literature and known to those skilled in the art. Condensation of intermediate (X) with malonic acid at 100 ° C, usually in a pyridine solvent using piperidine as catalyst, with a reaction time of about 12 hours followed by a short reflux period to improve decarboxylation leads to: Y: corresponding acrylic acid intermediates with structural formula (IX). Chlorination of acids of formula (IX) with thionyl chloride in chloroform and a catalytic amount of di-methylformamide gives acid chloride derivatives of structural formula (VIII) which are not purified but can be used crude in the preparation of acid azides of formula (VII). These acid azides are prepared in either a biphasic acetone-water mixture at 5 ° C using sodium azide 85434 or trimethylsilyl azide as refluxing benzene. The crude acid azides of formula (VII) prepared are added in small portions to methylene chloride dissolved in diphenyl ethers or diphenylmethane and heated to 230 ° C to give 6-5 bisisates of Curtius-type rearrangements of isocyanates which immediately cyclize. of formula (VI). Chlorination of compound (VI) is carried out using phosphorus-10 oxychloride or a phosphorus pentachloride-phosphorus oxychloride mixture to form a chlorine-substituted heterocyclic compound of formula (V). Reaction of compound (V) with the appropriate piperazine used in excess in a bomb at 120-140 ° C affords the desired piperazine intermediate (IIIc). This general synthesis of intermediates of formula (IIIc) has been reported previously (see Eloy et al., Bull. Soc. Chim. Beiges. 79 (1976) 301; J. Heterocyclic Chem. 8 (1971) 57; Helv. Chim. Acta 53 (1970) 645). The introduction of the substituent R2 into the molecule 20 can be done either by coupling it to the starting compound (X) or at a later stage in the reaction sequence, for example by metallizing compound (V) (X = S, R2 = H) with t-butyllithium and then reacting the product with dimethyl disulfide. to give an intermediate of formula (V) wherein R 2 is SCH 3.

The pharmaceutically acceptable acid addition salts prepared according to the invention are those in which the anion does not significantly contribute to the toxicity or pharmacological activity of the salt and which are in themselves pharmacologically equivalent to the base form of the compounds of formula (I). They are generally inexpensive for medical use. In some cases, they have physical properties that make them more desirable for drug formulation. Such properties may include solubility, lack of hygroscopicity, compressibility in tablet formulation, and compatibility with other ingredients with which the substance may be used for pharmaceutical purposes. The salts are usually prepared by mixing the base of formula (I) with the desired acid, preferably by contacting solutions in excess of conventional inert solvents such as ether, benzene, ethanol, ethyl acetate, acetonitrile or water. The salt form may also be prepared by any other conventional method, as described in detail in the literature, and may be used by any person skilled in the art. Some examples of useful organic acids include 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; and inorganic acids such as HCl, HBr, HI, sulfuric acids, phosphoric acids and the like.

It should also be noted that the above definition of compounds of formula (I) is considered to include all stereoisomers which may be formed, for example, when Z contains an asymmetric carbon atom, such as in (e) or optionally (b). The various stereoisomers can be separated by a variety of methods known to those skilled in the art.

The compounds of the invention are useful as pharmacological agents having psychotropic properties. In terms of these properties, the compounds have a selective action on the central nervous system and are of particular interest as antipsychotic (neuroleptic) agents. Like other known antipsychotic agents, the compounds of formula (I) elicit certain responses when tested using standard pharmacological in vivo and in vitro test models known to correlate well with the relief of symptoms of acute and chronic psychosis in humans.

Subdivision of the compounds of the invention on the basis of psychotropic activity and specificity uses a method known in the art for studying binding to central nervous system receptors in vitro. Some compounds (commonly referred to as ligands) have been identified that bind primarily to specific, high-affinity sites in brain tissue that are associated with psychotropic activity or potential side effects. Inhibition of the binding of radiolabeled ligands to such specific, high-affinity sites is considered a measure of the ability of a compound to affect the corresponding central nervous system function or to cause side effects in vivo. This principle is used in assays, for example, to measure inhibition of [3H] -spiperone binding, which is indicative of significant binding activity at dopamine receptors (see Burt et al., Molecular Pharmacology 12 (1976) 800; Science 196 (1977) 326; Crease et al., Science 192 (1976) 481).

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

.. 25 Table 1

Receptor

Assay Receptor Used Ligand Specific No. Binding Substance 302A Dopamine / spipero- [3H] spiperone (D) -butaclan / neuroleptic mole. . 252B Alpha-1 [3H] -WB-4101 Phentolamine

252E Serotonin- [3H] -5-HT 5-HT

type 1 (5-HTO

35 2521 Serotonin- [3H] -spiperone D-lysergide type 2 (5-HT2) li 8 8 4 8 4

Literature references: 252A - cited above 252B - Crews et al., Science 202 (1978) 322

Rosenblatt et al., Brain Res. 160 (1979) 186 5 U'Prichard et al., Science 199 (1978) 197

Molec. Pharmacol. 12 (1977) 454 252E - Bennett and Snyder, Molec. Pharmacol. 12 (1976) 373 2521 - Peroutka and Snyder, Molec. Pharmacol. 16 (1979) 687 10 The results obtained from the above binding assays show that the compounds of the invention have a moderate to moderate affinity for dopaminergic receptors but a much higher affinity for both serotonin Si 15 and S 2 sites. These binding properties distinguish the compounds of the invention from said known compounds as well as most of the clinically useful antipsychotic agents currently in use. In this regard, the compounds of the invention according to the invention share some pharmacological properties with said aberrant basic neuroleptic, clozapine, a dibenzodiazepine compound. The lack of dopaminergic binding affinity of the compounds of the invention is thought to be associated with a reduced tendency to cause undesirable extrapyramidal side effects common to most currently used antipsychotic agents.

The binding affinity for alpha-1 receptors (Test 252B) indicates that the compounds of the invention are likely to have a sedative partial effect that is often desirable in the treatment of certain subgroups of psychotic patients.

The following in vivo test models are conventionally used to classify and differentiate psychotropic substances from non-specific CNS depressants and to determine potential side effects such as cataleptic effects.

Table 2 5 In Vivo Tests Used to Test Compounds of Formula (I) 1. Conditioned Avoidance Response (CAR) A measure of the sedative effect of a drug, as determined by the attenuation of a drug-induced electric shock avoidance response in trained, fasted rats. Pharmacologist 4 (1962) 152, Wu et al., J. Med. Chem. 12 (1969) 876-881.

2. Inhibition of Apomorphine-Induced (APO) Stereotype - Evaluation of Blockade of Dopaminergic Effect in Rats by Dopamine Agonist, Apomorphine-Induced Behavioral Syndrome. See Janssen et al., Arz-Neimittel. Forsch. 17 (1966) 841.

3. Catalepsy - 20 drug-induced catalepsy in rats is predictive of possible extrapyramidal symptoms (EPS) in humans. See Costall et al., Psychopharmacology 34 (1974) 233-241; Berkson, J. Amer. Statist. Assoc. 48 (1953) 565-599.

25 4. Catalepsy Cancellation - measures the ability of a drug to reverse neuroleptic-induced catalepsy in a rat.

According to the pharmacological profile demonstrated in these in vivo experiments, the compounds of formula (I) according to the invention have a promising antipsychotic potential in that they are relatively effective in the CAR test and have oral ED values when administered. less than 100 mg / kg body weight and that they effectively prevent apomorphine-induced ste-35 rheotype. This inhibition of apomorphine-induced stereotype i7 85 484 may be indicative of a dopamine antagonist effect, and this test is recognized as a rather specific mode of study for neuroleptic effect. The group of compounds of formula I can be considered to have a selective anti-5 psychotic effect, as the antipsychotic effect is detectable at doses which do not cause catalepsy. In addition to the fact that the compounds of formula I hardly cause catalepsy, it is even more significant that the preferred compounds of formula I are able to reverse neuroleptic catalepsy with ED50 values below 20 mg / kg when administered orally. The significance of the effect of these compounds of formula I on the induction of catalepsy is better understood in view of the fact that, as a group, antipsychotic agents are known to cause extrapyramidal reactions.

The tendency to these undesirable extrapyramidal reactions is a serious aspect of treatment, and such reactions include acute torsional dystonia, akathisia, parkinsomy, and slow motility. Some descriptive in vivo bio-20 vo data are presented in Table 3 below.

is 6 5 4 84

Table 3

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

For example, CAR APO ED5q cat- ED50 in the induction of catalepsy No. * ^ 50 ^ 50 in the reversal of lepsy_ 11 6 40> 24 lAa) 12 11 34> 46 2

13 12 35 IA

14 10 9> 40 IA

15> 100> 100 -b) 16

16 65 - IA

17 35 -> 142 IA

18 32 -> 128 IA

21 43 47 - IA

22 9 18 23 IA

23 4 7 13 IA

24 3 5 11 IA

25 28 41 -

26 14 22 40 IA

• V; 27 36 63 - IA

:: 28 23 - IA

* · ·

32 60 61 IA

• * «» · · • ·

33> 100> 100 - IA

·: · *: 34 67> 100 - IA

♦ ·· (a) IA stands for inactive and is used when the ED, -n is ____: less than 20 mg / kg ____; (b) - means that the data were not available i9 6 5484

In summary, these compounds of formula I have psychotropic properties which make them particularly suitable for use as selective antipsychotics (neuroleptics) with only a low potential for side effects. Thus, these compounds can be used in a method of ameliorating a psychotic condition in need of treatment comprising administering to such a mammal a systemically effective dose of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof.

The administration and dosing instructions for the compounds of formula (I) are considered to be similar to those of the reference compound clozapine; see The Merck Index, 10. 15th ed., 1983, p. 344 and references therein. Although the dosage and dosing instructions in each case must be carefully determined using sound professional judgment and taking into account the patient's age, weight and condition, route of administration and the nature and severity of the disease, the general daily dose is about 0.05 to 10 mg / kg, preferably 0.1 -2 mg / kg, parenterally and about 1-50 mg / kg, preferably 2-30 mg / kg, orally. In some cases, a sufficient therapeutic effect can be achieved at lower doses, while in other cases higher doses are required. As used herein, the term "systemic administration" means oral, rectal and parenteral, i.e., intramuscular, intravenous and subcutaneous administration. In general, when a compound of formula I is administered orally, which is the preferred route of administration, a greater amount of the active ingredient is required than to achieve the same effect by parenteral administration. In accordance with good clinical practice, it is preferred that these compounds of formula I *: * "be administered at concentrations that produce an effective antipsychotic (neuroleptic) effect without causing adverse or undesirable side effects.

Therapeutically, the compounds of the invention are generally administered as pharmaceutical compositions comprising an antipsychotically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Pharmaceutical compositions for achieving such treatment contain less or more, e.g. 0.5 to 95%, of at least one compound prepared according to the invention in association with a pharmaceutical carrier, the carrier consisting of one or more solid, semi-solid or liquid diluents, excipients or excipients. which is non-toxic, inert and pharmaceutically acceptable. Such pharmaceutical compositions are preferably in unit dosage form, i. as physically discrete units containing a predetermined quantity of drug which is a fraction or multiple of the calculated dose to produce the desired therapeutic response. Dosage units may contain one, two, three, four or more single doses or, alternatively, half, one-third or one-quarter of a single dose. A single dose preferably contains an amount of the compound sufficient to produce the desired therapeutic effect when the compound is administered in one or more dosage units in accordance with predetermined dosage regimens, usually administered as a full daily dose or half, a third or a quarter thereof once, twice, three times or four times a day. 30 Other therapeutic agents may be included. Pharmaceutical compositions containing from about 1 to about 500 mg of active ingredient per dose are preferred and are conventionally prepared in the form of tablets, lozenges, capsules, powders, aqueous or oily suspensions, syrups, tinctures or aqueous solutions. Preferred 2 8 8 4 84 oral compositions are in the form of tablets or capsules and may contain conventional excipients such as binders (e.g. syrup, acacia, gelatin, sorbitol, gum tragacanth or polyvinylpyrrolidone), excipients (e.g. lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine), lubricants (e.g. magnesium stearate, polyethylene glycol or silica), disintegrants (e.g. starch) and wetting agents (e.g. sodium) for lauryl enteral sulphate (e.g. aqueous solutions for intramuscular injection, and for intramuscular injection For oily suspensions, the compounds of formula (I) are used in combination with conventional pharmaceutical media. Compositions having the desired brightness, stability and suitability for parenteral administration are obtained by dissolving 0.1 to 10% by weight of the active compound in water or a medium containing a polyhydric aliphatic alcohol such as glycerol, propylene glycol, ethylene glycol or a mixture thereof. . Polyethylene glycols consist of a mixture of non-volatile, usually liquid, polyethylene glycols that are soluble in both water and organic solvents and have a molecular weight of about 200 to 1500.

Compounds of formula (I) are prepared according to the invention in such a way that (a) a compound of formula (Ile) 11c

: D N- (CL) -Q

Wherein n is as defined above, Q is a suitable displaceable group such as chloride, bromide, iodide, sulfate, phosphate, phosphate or mesylate, and D is a divalent radical of formula 22 8 5 4 8 4

3 O. f O J O

, x; (q - -oc (a ') Cb') (c ') Cd') is reacted with an intermediate compound of formula (IIIc) R 2 R 1

"AH

15 ”wherein R 1, R 2, X and Y are as defined above to give a product of formula (I); or (b) (1) reacting a compound of formula (IIId) n, -O * 25 wherein Q is as defined above with an intermediate compound of formula (IIIc) to give a compound of formula (If) 'v' 30 R2 f ~ i J1 xAc -ÖX I £ 35 * 23 8 5484 (2) a compound of formula (If) is hydrolyzed in an acidic medium to give a compound of formula (Ig)

, X

And (3) the compound of formula (Ig) is reduced with sodium borohydride to give the product of formula (Ie) R 2 R 1 fV OH rU p == i Ie ? ~ 0 "wherein R 1, R 2, X and Y are as defined above.

The invention is further illustrated by the following examples. All temperatures should be reported in degrees Celsius when not mentioned. Characteristic data obtained by nuclear magnetic resonance spectroscopy (NMR) refer to chemical shifts (delta) in parts per million (ppm) relative to tetramethylsilane (TMS) used as a common reference. The relative areas reported in the proton spectral data (PMR) for the different transition peaks correspond to the number of hydrogen atoms in each functionality type of the molecule. The nature of the transition in terms of the number of peaks is reported as follows: broad Singlet-35 ti (bs), singlet (s), multiplet (m), doublet (d), 24 8 5 484 double doublet (dd), triplet (t), quartet (q). The abbreviations used are DMSO-d6 (perdeuterodimethyl sulfoxide) and CDCl 3 (deuterochloroform), and are otherwise conventional. The infrared spectral data (IR) contain only the wavenumber (cm-1) of the absorbances that have a value for functional group identification. Potassium bromide (KBr) was used as a diluent in the IR assays. Elemental analysis results for all compounds were satisfactory.

10 Manufacture of filled intermediates of formula

The following typical examples of chemical intermediates of formulas (V) - (X) illustrate the synthesis of the avan intermediate (IIIc).

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

To a stirred mixture of N-methylpyrrole (10 g, 0.12 mol) in dichloroethane (80 ml) and dimethylformamide (11.3 g, 0.15 mol) at 5 ° C was added phosphorus oxychloride (23 , 6 g, 0.15 mol), which led to an exothermic reaction and the formation of a precipitate. Stirring was continued for an additional 15 minutes, the precipitate was collected by filtration and suspended in 3N NaOH solution (300 mL), and the suspension was extracted with chloroform (3 x 100 mL). The chloroform portions were combined, dried (MgSO 4), filtered and evaporated under reduced pressure to give

6.1 g (49%) of a dark oil, m.p. 87-90 ° C, were obtained

At a pressure of 22 torr, the NMR spectrum of the oil corresponding to the desired structure. This intermediate was generally used crude in the next step of Scheme I.

Example 2 3- (2-Thienyl) acrylic acid (IX) A mixture of 2-thiophenecarboxaldehyde '**' (100 g, 0.89 mol), malonic acid (182.5 g, 1.70 mol), pyr - ·: **: 35 dine (446 ml) and piperidine (8.9 ml) were heated at ... ·: 100 ° C for 12 hours. The reaction solution was then refluxed for 20 minutes and allowed to cool, after which it was poured into water (1000 ml) and the resulting aqueous mixture was acidified with concentrated HCl. The resulting off-white precipitate was collected by filtration and recrystallized from ethanol-water (1: 1) to give 109 g (80%) of product, m.p. 145-148 ° C.

Example 3 3- (2-Thienyl) acryloyl chloride (VIII) To a suspension of 3- (2-thienyl) acrylic acid (118.9 g, 0.77 mol) and dimethylformamide (12 mL) in chloroform (600 mL). and stirred, thionyl chloride (110.1 g, 0.93 mol) was added dropwise at room temperature. The reaction mixture was then refluxed for 2 hours and cooled and evaporated under reduced pressure to a brown oil which solidified on standing to give 131 g (99%) of a low melting solid which was used without further purification.

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

To a stirred suspension of sodium azide (168.6 g, 2.6 mol) in a mixture of p-dioxane (400 ml) and water (400 ml) at 5 ° C was added a solution of 3- (2- thienyl) acryloyl chloride 25 (223.9 g, 1.3 mol) in dioxane. The dioxane layer of this biphasic mixture was separated, concentrated in vacuo,; dissolved in methylene chloride (500 mL), dried (MgSO 4) and filtered. This methylene chloride filtrate was added dropwise to a boiling diphenyl ether (400 mL) in a 3-necked flask equipped with two air coolers. The solution was refluxed for an additional 1 hour and concentrated in vacuo to a dark syrupy substance which was crystallized from acetonitrile to give a brown; solid which was collected by filtration. Recrystallization of this solid from water (650 mL) gave 106 g (54%) of a pale yellow solid 26 85484, m.p. 213-214 ° C.

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

Fine 4-oxo-4,5-thieno [3,2-c] pyridine 5 (105.6 g, 0.69 mol) was stirred while phosphorus oxychloride (321 g, 2.1 mol) was added dropwise at 0 ° C. The reaction mixture was then refluxed for 2.5 hours and cooled and carefully poured onto crushed ice (1000 ml). The resulting solution was stirred for 30 mL to 10 minutes and extracted with dichloromethane (3 x 300 mL). The organic portions were combined, dried (MgSO 4), filtered and evaporated under reduced pressure to give a solid which was recrystallised from acetonitrile (400 ml) to give 101 g (85%) of a pale yellow solid, m.p. 91 ° C.

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

A mixture of 4-chlorothieno [3,2-c] pyridine (22.7 g, 0.13 mol) and piperazine (57.7 g, 0.67 mol) was heated in a bomb at 120 ° C for 24 hours. with a minimum amount (50 ml) of ethanol. The reaction mixture was cooled, partitioned between dichloromethane and water, and the organic layer separated, dried (MgSO 4), filtered and concentrated in vacuo to an oil. Flash chromatography of this material (methylene chloride containing 10% methanol and 1% ammonium hydroxide) afforded 16 g (54%) of a golden oil, treatment of the oil with ethanol in HCl and subsequent recrystallization from ethanol afforded resulting in 1 to 30 hydrochloride salts as off-white crystals, m.p. 275-283 ° C.

Example 7 Synthesis of 7- (1-piperazinyl) thieno [2,3-c] pyridine (IIIc '): ____: 35 The synthesis of this compound was carried out using the same reaction procedure as for the preparation of compound (IIIc). *.

27 8 5 4 8 4 with the exception that the starting material (X) was 3-thiophenecarboxaldehyde. However, the multi-step preparation of the site isomer (IIIc ') was complicated in that the Curtius-type rearrangement reaction (Example 4) afforded 5 desired intermediates (VI) in low yield, with the major product of this reaction being the symtriazine by-product resulting from the trimerization of the isocyanate intermediate. Nevertheless, application of the reactions shown in Scheme I resulted in the product of formula (IIIc '), which was a brown gum and was used without further purification.

Other compounds of formula (IIIc) can be prepared by appropriate modification of the reaction sequence of Scheme I and the various synthetic reactions exemplified above. Some typical other compounds of formula (IIIc) are shown in Table 4.

Table 4

Other compounds of formula (IIIc) R2 R1 »-ÖiÖ> IIIc. . 30 Eg R1 R2 X Y m.p. (° C) 8 H H CH O> 250. 9 H SCH3 CH S 203-205 (.HCl1.H2O) 35 28 Ö54S4

Preparation of compounds of formula (I)

Example 10

general synthesis

The synthesis of the products of formula (I) was carried out by alkylation of the appropriate halogen-substituted imide derivatives (Ile) in which D is (a ') - (d') and E is N- (CH2) nQ Q being a halide, or fluorophenylbutyl. -phenophenone derivatives (IIId) with a suitable intermediate compound (IIIc) in refluxing acetonitrile-10 in the presence of three equivalents of potassium carbonate. Carbinol derivatives were formed by reduction of the corresponding butyrophenones with sodium borohydride. Reaction times in alkylation ranged from 5 hours to 72 hours, and the resulting products were usually purified by flash chromatography (ethanol-chloroform mixture). Hydrochloride salts were usually formed from the products of formula (I) for testing.

Example 11 4,4-Dimethyl-1- [4 - [(thieno [3,2-c] pyridin-4-yl) -1-20 piperazinyl] butyl] -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) were refluxed in acetonitrile (150 ml) for 24 hours. The reaction mixture was filtered and concentrated under reduced pressure, and partitioned between dichloromethane and water. The organic layer was separated, dried (MgSO 4) and concentrated in vacuo to a golden oil which was subjected to flash chromatography (5% ethanol in chloroform). The chromatographed material was dissolved in acetonitrile and treated with ethanolic HCl to give 1.3 g (24% yield) of the hydrochloride salt, mp 195-197 ° C. Initial: Analysis for C 22 H 30 N 4 O 2 S.HCl s 35 Calculated: C 58.59, H 6.93, N 12.42 Found: C 58.64, H 7.02, N 12.72 29 8 5 484 PMR (DMSO- 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 (1, m); 8.08 (1, d [5.0 Hz]; 11.75 (1, bs) IR (KBr); 715, 9.65, 1425, 1535, 1670, 1720, 2580, δ 2960 cm-1

Example 12 4- [4- (4-furo [3,2-c] pyridinyl) -1-piperazinyl] -butyl] -3,5-morpholinedione

A solution of 4- (1-piperazinyl) furo-10 [3,2-c] pyridine (4.5 g, 0.022 mol), 4- (4-bromobutyl) -3,5-morpholinedione (5.5 g , 0.022 mol) and potassium carbonate (9.1 g, 0.066 mol) were refluxed in acetonitrile for 24 hours. The reaction mixture was filtered and concentrated in vacuo and partitioned between dichloromethane and water. The organic layer was separated, dried (MgSO 4) and concentrated in vacuo to a yellow oil which was subjected to flash chromatography. The appropriate chromatography fractions were combined and evaporated under reduced pressure, and the residue was crystallized from isopropanol to give 6.2 g (69%) of the free base, m.p. 109-110 ° C.

Elemental analysis for C19H24N4O4:

Calculated: C 61.28, H 6.50, N 15.04 Found: C 60.98, H 6.60, N 15.19 PMR (CDCl 3): 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 30 A wide variety of products of formula (I) can be obtained using the method discussed above or the alternative synthetic methods disclosed in the referenced patent publications. 5 Si-V contain a list of other typical ____: 35 products of formula (I) Table 3 contains in vivo bio-____: biological data for typical compounds of formula (I).

3o 85484

Table 5

Products of formula (I)

, X

R1 X 'y

Ex.z_n R1 R2 X Y Formula a) S .o. (2ci No. · - - nTV 4 H »CH s C? 2H N4020j. 180-182 (b) 14 (e) 3 H H CH S C21H24FN3OS 115-118

Cu 15 | g_ ^ ~ 4 H Br CH S C22H2? BrN402S2.HCl 203-205 (b) ^ 16) Q- «H Br CH S C H BrN 0SS 216-21, o 2 ·· * ·; (a) =. =: = Cu 17 L / '4 H CH3 CH S C2 ^ | 0N4 ° 2S2 195'197 (b) ° * · · *: *: i «$ V 4 H H CH S C H N 02S? 186-188 8: i.fc7fi863s.o.5H2o: <c> • · - »·" 0 *

Table 5 - continued 3i 8 5 484

Esiir. 2 n R1 R2 XY Formula a) S p. (° c) 19 Oi "4 HH CH S C22H24N4 ° 3S2 * KCl 229-230 (d) 20 O ) 0- * ° 21 V 4 HHS CH C.-H.pN.OS- 120-122 's- / Untl.il Lo 22 V- 4 HH CH O C-, H, RN.OS 251-253: 2hci .c2h6o '0 (b) .0 23 X> 4 HH CH O C2 | H ^ NJ ° 3> 25 ° ...' \>

. . O

00 24 ie) 3 H H CH O C ^ H ^ FN ^ 205-207 25 Lr 4 "CH3 ch 0 c; jH2 ^ i ° 3s I76-177 o (b)»

Table 5 - continued 32 85484 Z n R1 R2 X Y Formula P.o. (°)

Ex. ~ Q ~ ~ —-- 26) Q- 4 K CH 3 CH ° C ^ H ^ ci ° 3.5H 2 O 321'233 (a) 27 4 HH CH 0 C} 2HaiHÄO 3 S 245-250 3 H CH 3 CH 0 C ^ H ^ FN · ^ 121-122 0 29 4 HH CH S ri "/ 31 Is- 4 HH CH S C20H26N4 ° 2S 199-201 o (a)

Table 5 - continued 33 85484

Esin :. 2 n R1 R2 X I Formula a) Sp. (°) No. 1 "£ 33 4 HH CH NMe 144-146 M) (c) XV 4 HH CH NMe C ,, H ,, N, 0- 192-194 34 '> -Z Z2.IHCl 2.6H, 0 0 1 (a) (a) The analytical results for elements C, H and N were all within + 0.4% of the theoretical values calculated for the given formulas.

«

Claims (12)

A process for the preparation of an antipsychotic compound of formula (I) wherein R 2 and R 4 are any of the following groups: and wherein both R 3 and R 4 are independently hydrogen or a lower alkyl group or R 3 and R 4 together form a C 3-6 alkylene chain α; R 9 is R5 - {T (b) - 25 - wherein both R 5 and R 6 are independently hydrogen, a lower alkyl group or an A-substituted phenyl group, wherein A is hydrogen or halogen, or R 5 and R 6 together form a butylene chain and N is S or CH 2; 0: 0 35 40 8 5 484 where V is 0 or S; (C) + - 0V- <a> where G is hydrogen, a lower alkyl or alkoxyl group or halogen, m is an integer of 1-4 and U is C = O or SO2; and <RTI ID = 0.0> 0H P </RTI> QY-CH- (e) n is an integer 2-4 provided that Z is (e), n is 3; either X or Y is independently CH 2, 0, S or NR 7, provided that one of them is always = CH-; each group R 1 and R 7 is independently hydrogen or a lower alkyl group; and R 2 is hydrogen, a lower alkyl, lower alkoxyl, lower alkylthio or hydroxyl group or halogen; and its pharmaceutically acceptable acid addition salts, characterized in that (a) a compound of formula (Ile) Ile; wherein n is as defined above, phosphate, tosylate or mesylate, and D is a cross-linked radical of formula (I) (a) (b ') (b) (C) W) 85484 an intermediate compound of formula (IIIc) rt Wherein R 1, R 2, X and Y are as defined above to give a product of formula (I); or (b) (1) a compound of formula (Ild) n in which Q is as defined above is reacted with an intermediate compound of formula (IIIc) to give a compound of formula (If) f (2) the compound of formula (If) is hydrolyzed in an acidic medium to give a compound of formula (Ig) 42 8 5 484 and (3) the compound of formula (Ig) is reduced by sodium borohydride, whereby a product of formula (Ie) is obtained R2 R 1 / -λ CH y - pv Ie f ~ \ Cy Where R1, R2, X and Y are as defined above. 2. A process according to claim 1, characterized in that compounds of formula (I) are prepared, wherein Z is group (a). A process according to claim 1, characterized in that compounds of the formula (I) are prepared, wherein Z is group (b). 4. A process according to claim 1, characterized in that compounds of formula (I) are prepared, wherein Z is group (c). 5. A process according to claim 1, characterized in that compounds of formula (I) are prepared, wherein Z is group (d). 6. A method according to claim 1, characterized in. The compound of formula (I), wherein Z is group (e). 43 85484 7. A process according to claim 1, characterized in that compounds of formula (I) are prepared, wherein Y is an oxygen atom. 8. A process according to claim 1, characterized in that compounds of formula (I) are prepared, wherein Y is a sulfur atom. 9. A process according to claim 1, characterized in that compounds of formula (I) are prepared, wherein R5 and R6 together form a butylene chain and W is sulfur. Process according to claim 1, characterized in that compounds of formula (I) are prepared, wherein V is an oxygen atom. 11. A process according to claim 1, characterized in that compounds of formula (I) are prepared, wherein Z is group (a), (c) or (e). Process according to claim 1, characterized in that compounds of formula (I) are prepared, wherein Z is group (a), (b) or (e).