IE59201B1 - Pyridinylpiperazine derivatives - Google Patents

Abstract

Disubstituted 1,4-piperazinyl derivatives are disclosed wherein one substituent is a bicyclic fused-ring furo-, pyrrolo-, cyclopentadieno-, or thieno-pyridine heterocyclic system and the second substituent is an alkylene chain attached to cyclic imide heterocycles, such as azospiro[4.5]decanediones, dialkylglutarimides, thiazolidinediones, succinimides, and morpholine-2,6-diones; or a fluorobenzylic carbinol moiety. These compounds have potent antipsychotic and serotonin antagonist activities. 4-[4-[4- (4-Furo[3,2-c]pyridinyl]-1-piperazinyl]-butyl]-3,5-morpholinedione is an example of a typical embodiment having selective antipsychotic activity.

Description

This invention generally pertains to heterocyclic carbon compounds having drug and bio-affecting properties and to their preparation and use. In particular, the invention is concerned with 1„4-disubstituted piperazine derivatives wherein one substituent is a bicyclic fused-ring heterocyclic system comprising furo-, pvrrolo-, cyclopentadieno-„ and thieno-pyridine ring systemsj and the other is an alkylene chain, preferably a butylene chain, bearing a cyclic imide ring or a benzvlic carbinol snoietv at its terminus. Examples of types of these terminal moities are depicted below; ’dialkylglutarimide type" e3thiazolidinedione type15* succinimide type"3 morpholinedione type® V can be 0 or S? phthalimide type (U can be C=0 or SO^) —d'l··' CH "bensylie carbinol type® A considerable amount of related art has been 5 generated over the past fifteen years, much of which has arisen from the research group of the Bristol-Myers Company,. The pertinent related art comprising compounds with CNS activity may be viewed in light of th® following general structural formula (1) (1) in which alk is an alkylene chain connnecting the piperazine ring with the cyclic imide group and B is a heterocyclic ring with optional substituents.

Wu, et al. , U.S. Patents 3,717,634 and 3,907,801 as well as a corresponding Wu, et a 1. , publication — J.

Med„ Chem., 15, 447-479 (1972) — describe various azaspiro[4...5]-decanedione psychotropic compounds wherein B represents various monoeylic heterocycles such as pyridine, pyrimidine, or triazina, all with optional substituents.

Temple, Yevich and Lobeek in U.S. Patent 4,305,944 disclose azaspiro[4.5]decanedione tranquilizing compounds wherein 3 is a 3-cyanopyridin-2-yl or S-methoxypyridin-^-yl moiety.

Temple, Yevich and Lobeek report dialkylglutarimide tranquilizing compounds in U.S. 4,361,565 in which 3 is a 3-cyanopyridin-2-yl ring which may bear a second optional substituent.

Temple and Yeager in U.S. Patents 4,367,335 and 4,456,756 disclose antipsychotic thiazolidinedionee and spirothiazolidinediones wherein 3 is a 2-pyridinyI ring, either unsubstituted or containing a cyano substituent.

Temple and- Yevich in U.S. Patents 4,411,901, and 4,452,799 disclosed antipsychotic compounds with a variety of cyclic imide and henzylic carbinol moieties wherein Θ was either benzisothiazole or benzisoxazole ring systems.

Attention is also called to the following pending applications.

In U.S. Serial No. 531,519, filed 9/12/83 and now allowed, New and Yevich disclose and claim psychotropic succinimide and phthalimide-type compounds wherein B is a 2-pyrimidinyl ring. These compounds demonstrate antianxiety activity.

A series of antipsychotic X"fluorophenylcarbonyl-, -carbinol-, -ketal-, propyl-4-(2- pyrimidinyl)piperazines are disclosed by Yevich and Lobeck in U.S. Serial No. 583,309, filed 12/18/84.

Finally, New, Yevich and Lobeck in U.S. Serial No. 691,952, filed 1/16/85, disclose and claim a series of antipsychotic compounds which contain a variety of cyclic imide moieties and wherein 3 is a mono- or di-substituted pyridine ring system.

While the psychotropic compounds listed above are generally related to the compounds of the present invention, they are nonetheless distinguishable thereof structurally on the basis of the B moiety of structural formula 1. Essentially, in the art compounds, B is usually a monocyclic heteroaryl ring with the only examples of bicyclic systems being fused benzo ring heterocyclics, i.e. benzisothiasole or benzisoxazole ring systems. This distinguishes these compounds from the compounds of the present invention in which B is comprised of different classes of fused heterocyclic rings, i.e. furo-, pyrrol©-, eyclopentadieno-, or thieno- pyridine ring systems. The present compounds may also be distinguished pharmacologically on. the basis of psychotropic properties and side effect profiles from the art compounds. In this regard, the compounds of the present invention possess selective antipsychotic'(neuroleptic) activity with serotonin antagonism, and, surprisingly, have β low affinities for dopamine receptors which is in contrast to the prior art antipsychotic agents described, supra. In this regard, the present compounds pharmacologically bear some semblance to the atypical standard neuroleptic agent, clozapine (2), cf: The Merck Index, 10th Edition (1983), page 344, and references therein.

As can be seen, clozapine belongs to the dibenzodiasepine class of psychotropics which bear little structural relationship to the present series of compounds. Addi10 tionally, the present compounds appear to lack the potential for causing the adverse extrapysramidal symptomatology associated with the chronic administration of currently used antipsychotic agents. Further, selected compounds from the present series have demonstrated in animal models, the ability to reverse catalepsy resulting from administration of trifluoperazine, a standard neuroleptic agent.

In its broadest aspect, the present invention is concerned with piperazinyl derivatives having neuroleptic (antipsychotic) properties characterised by a compound of Formula Ϊ and its pharmaceutically acceptable acid addition salts.

In Formula I, Z represents the following radicals: In radical (a) R^ and SC are independently chosen from hydrogen, alkyl or and R" are taken together as g g a Cj to Cg alkylene chain» In radical (b) R and R are independently chosen from hydrogen, alkyl, and •Ά-substituted phenyl with A being hydrogen or halogen, or R and R^ are taken together as a butylene chain? and W can b@ » S (s sulfur atom) or CH^ (a methylene groupί. In radical (c) V is an oxygen or sulfur atom» In radical (d) G is selected from hydrogen, ^„4 alkyl, alkoxy or halogen. m is 1-4,and U is C-0 or SO2. Additionally, in Formula Is n is 2-4 with the proviso that when 2 is (e) , n is 3? R is selected from hydrogen or alkyl; either X or Y is independently selected from CH,, 0, S, or NR with the proviso that the other of X or Y must always be "CH-; R" is selected from hydrogen, alkyl, alkoxy, alkylthio, halogen, and hydroxyl? and R is hydrogen or C^^alkyl. The designation may also be defined by the term lower'5.

Preferred classes of compounds are comprised of compounds of Formula ϊ wherein 2 can be the radicals (a) ? s β (b) with R and R being · taken together as a butylene chain and with W being a sulfur atom? and (c) wherein V is an oxygen atom? and Ce). For these preferred classes Y is either an oxygen or sulfur atom and X is methynyl l-CE-l y n 2 is 4, except when 2 is (&) at which time n is 3? and R is hydrogen.

There ar© two classes of most preferred compounds. For the class of compounds wherein Y is an oxygen atom, 2 is either (a), ic) with V being an oxygen atom, and (ei. For the class of compounds wherein Y is a sulfur atom, 2 is either (si , (bi , or (e).

The pharmaceutically acceptable acid addition salts of the invention are those in which the anion does not contribute significantly to the toxicity or pharmacological activity of the salt and, as such, they are the pharmacological equivalents of the bases of the Formula I compounds. They are generally preferred for medical usage. In some instances, they have physical properties which make them more desirable for pharmaceutical formulation» Such properties ean be solubility, lack of hygroscopicity, compressibility with respect to tablet formation and compatibility with other ingredients with which the substance may be used for pharmaceutical purposes. The salts are routinely made by admixture of a Formula I base with a selected acid, preferably by contacting solutions employing an excess of commonly used inert solvents such as ether, benzene, ethanol, ethyl acetate, acetonitrile, and water. The salt form may also be prepared by any of the other standard methods detailed in the literature and available to any practitioner skilled in the art. Some examples of useful organic acids are the carboxylic acids such as maleic acid, acetic acid, tartaric acid, propionic acid, fumaric acid, isethionie acid, succinic acid, pamoic acid, cyclamic acid and pivalic acid; useful inorganic acid may be hydrohalide acids such as ,· for example, HCl, HBr, HI; sulfuric acids; and phosphoric acids.

It is also to be understood that the present invention is considered to include any stereoisomers which may result when, for example, Z contains an asymmetric carbon; as in (e) and is possible in (b). Separation of the individual stereoisomers may be accomplished by application of various methods which are well known to practitioners in the art.

The compounds of th© present invention are useful pharmacological agents with psychotropic properties, ϊη this regard, they exhibit selective central nervous system activity at non-toxic doses and are of particular interest as antipsychotic (neuroleptic) agents. As with other known antipsychotics, the compounds of Formula 1 evoke certain responses when studied in standard in vivo and in vitro pharmacological test systems which are known to correlate well with the relief of symptoms of acute and chronic psychosis in man.

For subclassification of the psychotropic activity 10 and specificity of the present compounds, state of the art in vitro central nervous system receptor binding methodology is employed. Certain compounds (commonly referred to as ligands) have been identified which preferentially bind to specific high affinity sites in brain tissue dealing with psychotropic activities or potential for side effects.

Inhibition of radiolabeled ligand binding to such specific high affinity sites is considered a measure of a compound's ability to effect corresponding central nervous system function or to cause side effects in vivo. This principle is employed in tests, such as, for example, measuring inhibition of [ B]spiperone binding which indicates significant dopamine receptor binding activity (cf; 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 employed are listed below in Table 1.

Table 1 Receptor Binding Tests Test Specific ’. Putative Receptor Site Ligand Used Bincine Agent 25 2A Dcpamine/spiperone/ neuroleptic 3 [ H]Spiperone D(+)-Eutaclamol 2523 Alpha-1 i3H)WB-4101 Fhentelamine 25 2E Serotonin Type 1 (5-HT^J [3HJ5-HT 5-HT 2521 Serotonin Type 2 (5-HT^) [3H3 Spiperone D~Lysergi.de References: 252A 252B - given supra. - Crews, et al.. Science, 202:322, 1978,., Rosenblatt, et al., Brain Res., 160:186, 1979» U’Prichard, et ai., Sciencet, 199:197, 1978? Holes. Pharmacol., 13:454, 1977,., ’ · 252Ξ - Bennett and Snyder, Molec. Pharmacol.„ 12: 373, 1976» 252X - Peroutka and Snyder/ Molec. Pharmacol., 16s 687, 1979.

Data derived from the above binding tests demonstrate that th® family of compounds of the present invention has modest to low affinity for dopaminergic receptors but much greater affinities for both serotonin S1 and So sites. These binding properties distinguish the present compounds from the cited prior art compounds as well as most of the clinically useful antipsychotic agents now being used. In this regard, the present compounds have some pharmacological properties in common with the atypical standard neuroleptic agent, clozapine, a dibenzodiazepine compound. The lack of dopaminergic binding affinities of the subject compounds is felt to relate to reduced liability to induce the unwanted extrapyrai^.idal side effects common to most currently used antipsychotic agents.

Binding activity at the alpha-1 receptor (Test 2523) indicates that the compounds of the present invention will probably possess a sedating component of activity which is often desirable in the treatment of subgroups of psychotic patients.

The following in vivo test systems are conventionally used to classify and differentiate a psychotropic agent from a non-specific CNS depressant and to determine potential side-effect liabilities such as cataleptic activity. 3 Table 2 In Vivo Tests Used to Evaluate Formula I Compounds 1. Conditioned Avoidance Response (CAR) — measure of a drug's tranguilising activity as determined by its attenuation of avoidance response to electrical shock in trained fasted rats, cf: Albert, Pharmacologist, 4, 152 (1962)? Wu, et al., J. Med. Chero., 12, 876-881 (1969). 2. Inhibition of Apomorphine-Indueed (APO) Stereotypy — an assessment of blockade of dopaminergic activity in rats as measured by attenuation of the behavioral syndrome caused by the dopamine agonist, apomorphine. cf: Janssen, et al., Arsneimittel. Forsch., _17, 841 (1966) . 3. Catalepsy <— drug-induced catalepsy In rats is predictive of potential extrapyramxdal symptoms (EPS) in man. cf: Costall, et al., Psychopharmaeologia, 341- 233-241 (1974)? Berkson, J. Amer. Statist. Assoc., 48, 565-599 (1953). 4. Catalepsy Reversal — measure of a drug’s ability to reverse neuroleptic-induced catalepsy in the rat.

According to the pharmacological profile established by these in vivo tests, th® present compounds of Formula I have promising antipsychotic potential in that they are relatively potent in the CAR test, having oral values <100 mg/kg body weight, and they, effectively block apomorphine-induced stereotypy. This blockade of apomorphine-induced stereotypy may reflect dopamine antagonist activity and is accepted as a fairly specific screen for neuroleptic activity. The present family of compounds may be considered to have selective antipsychotic activity inasmuch as antipsychotic activity is seen at doses which do not produce catalepsy. Not only are the present compounds relatively inactive in catalepsy production but, even more significantly, preferred compounds of the invention demonstrate the ability to reverse neurolepticinduced catalepsy with ΕΟ,-θ va^ues *20 mg/kg, given orally. The significance of the effects of these compounds of the present, invention on catalepsy induction and reversal are better appreciated when one considers that antipsychotic agents as & class are known to produce extrapyramidal reactions. These unwanted extrapyramidal reactions represent a serious treatment liability and comprise acute torsion dystonia# akathesia, Parkinsonism, and tardive dyskinesia. Some representative in vivo biological data is tabulated in Table 6 (see further!.

In summary of the foregoing discussion, the present compounds have psychotropic properties particularly suited to their use as selective antipsychotic (neuroleptic) agents with little potential for movement disorder side effects» Thus, the invention includes compounds (and salts) and pharmaceutical compositions according to the invention» and more particularly medication comprising an effective antipsychotic amount of a compound according to the invention, for use in a method for ameliorating an undesirable psychotic state in a mammal.

The administration and dosage regimen of compounds of Formula I is considered to be done in the same manner as for the reference compound clozapine, cfs The Merck Index, 10th Edition, (1983), page 344, and references therein. Although the dosage and dosage regimen must in each case be carefully adjusted, utilizing sound professional judgment and considering the age, weight and condition of the X recipient, th® rout® of administration and the nature and gravity of the illness, generally the daily dose will be from about 0.05 to about 10 mg/kg, preferably, 0.1 to· 2 mg/kg, when administered parenterally? and frosa about 1 to about 50 mg/kg, preferably 2 to 30 mg/kg, when administered orally. In some instances, a sufficient therapeutic affect can be obtained at lower doses while in others, larger doses will be required. The term systemic administration® as used herein refers to oral, rectal, and parenteral, i.e., intramuscular, intravenous, and subcutaneous routes. Generally, it will be found that when a compound of the present invention is administered orally, whieh is the preferred route,. a larger quantity of the active agent is required to produce the same effect as a smaller quantity when given parenterally. In accordance with good clinical practice, it is preferred to administer the present compounds at a concentration level that will produce effective antipsychotic (neuroleptic) effects without causing any harmful or untoward side effects.

Therapeutically, the present compounds are generally given as pharmaceutical compositions comprised of'an effective antipsychotic amount of a compound of Formula X or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier. Pharmaceutical compositions for effecting such treatment will contain a major or minor amount, e.g. from 95 to 0.5S of at least one compound of the present invention in combination with a pharmaceutical carrier, th® carrier comprising one or more solids, semi-solid, or liquid diluent, filler, and formulation adjuvant which is non-toxic, inert and pharmaceutically acceptable. Such pharmaceutical compositions are preferably in dosage unit forms; i.e., physically discrete units containing a pre-determined amount of the drug corresponding to a fraction or multiple of the dose which is calculated to produce the desired therapeutic response. The dosage units ean contain one, two, three, four or more single doses; or alternatively, one-half, one-third, or one-fourth of a single dose. A single dose preferably contains an amount sufficient to produce the desired therapeutic effect upon administration at one application of one or more dosage units according to th® pre-determined dosage regimen, usually a whole, half, third, or quarter of a daily dosage administered once, twice, three or four times a day. Other therapeutic agents can also be present. Pharmaceutical compositions which provide from about 1 to 500 mg of the active ingredient per unit dose are preferred and are conventionally prepared as tablets, loaenges, capsules, powders, aqueous or oily suspensions, syrups, elixirs, and aqueous solutions. Preferred oral compositions are in the form of tablets or capsules and may contain conventional excipients such as binding agents (e.g. syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone), fillers (e.g. lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine), lubricants (e.g. magnesium stearate, talc, polyethylene glycol or silica), disintegrants (e.g. starch), and wetting agents (e.g. sodium lauryl sulfate) ., Solutions or suspensions of a Formula I compound with conventional pharmaceutical vehicles are employed for parenteral compositions such as an aqueous solution for intravenous injection or an oily suspension for intramuscular injection. Such compositions having the desired clarity, stability and adaptability for parenteral use are obtained by dissolving from 0.1¾ to 10% by weight of the active compound in water or a vehicle consisting of a polyhydric aliphatic alcohol such as glycerine, propylene glycol, and polyethylene glycols or mixtures thereof. The polyethylene glycols consist of a mixture of non-volatile, usually liquid, polyethylene glycols which ar® soluble in both water and organic liquids and which have molecular weights of from about 200 to 1500.

The compounds of Formula I wherein 2 is comprised of the radicals (a-e) of the present invention are obtained by procedures involving alkylation of piperazinyl or 63imideM intermediates analogous to methods described by Wu, et al,, patents, supra., or Temple, et al., patents, supra. These methods may be incorporated into a unitary process which is employed 8 fcr preparation of the compounds of Formula I. The methods may be adapted to variation in order to produce other compounds embraced by this invention but not specifically disclosed. Further, variations of the methods to produce the same compounds in somewhat different fashion vzill also be e-vident to one skilled in the art. Certain examples will be given for specific illustration,., D"E + (II) Unitary Process i ? In this scheme, R , R', X and Y have the same 10 meanings as previously assigned to them in Formula I. The symbol D is either the. divalent structures related to radicals (a-d? as shown below In partial structures (a'-d’! ’ or D is the radical (eaS also shown below.

In radicals (a~e) all symbols have the same meanings as previously assigned hereinabove. The symbol !,E" in the above scheme can be 0; N-H? or N-(CH?)The symbol n is as previously defined and Q81 refers to a suitable displacement group such as chloride, bromide, iodide, sulfate, phosphate, tosylate, or mesylate. The symbol J can be (CH?) R-y ? relationship between E and J is Method No. A B c when E is: b (Ila) )ϊΗ (lib) (CH?)^-0 (11c) Then J is: V-(C»2»n- X-(CHJ - or .Θ i n Q, H- (Ilia) c (Ille) (Illb) (Illb'I Method A Δ dry solvent Ίζο Ila Ilia Method Β ί<^» V* ;!. iiia is a special case wherein n is fixed at 4) IIIc The condensation in Method A is carried out hy refluxing the reactants in a dry, inert reaction medium-such as pyridine or xylene. For Methods 3 and C the process is carried out under reaction conditions suitable for the preparation of tertiary amines by alkylation of secondary amines. The reactants ar® heated in a suitable organic liquid at temperatures of about 60° to about 100°C in the presence of an acid binding agent. Bensene# dimethylformamide, ethanol# acetonitrile# toluene and n-butyl XO aleohol are preferred examples of the organic liquid reaction media. The preferred acid binding agent is potassium carbonate, but other inorganic and tertiary organic bases may be employed including other alkali and alkaline earth metal carbonates, bicarbonates, or hydrides, and the tertiary amines. All three methods have been adequately described in the patent references referred to hereinabove. For the compounds of the present invention, Method C is the preferred synthetic process. The required lie intermediates were synthesized according to methods given in the reference patents.

For preparation of the Formula I products wherein Z is (e), the following adaptation of Method C is employed. 1) alkvlacioa As an example of a method variation to produce the compounds of Formula ϊ somewhat differently a Z-substitutefi alkyl piperazine (IV) can be reacted with an appropriate fused bicyelic pyridine system (V) to yield a. product of Formula I, e.g. B1 s2 Λ Z+\ Ζ-ζω^-^Ι-Η + _, IV To summarize the foregoing, there is described a process for the preparation of a compound of Formula I , 23 this process comprises selection of a process from the group of processes consisting of (a) reacting an intermediate of Formula Ila D^O wherein the symbol D* is the divalent structure of Formulae a’-d’ with an intermediate of Formula Ilia Ilia 4 2 wherein R , R", η, X and Y are as previously defined, to give a product of Formula I; (b) reacting a compound of Formula lib Xlb with an intermediate compound of Formula Illb wherein Q is a suitable displacement group such as chloride, bromide, iodide, sulfate, phosphate, 7 tosylate, or mesylate, and D, R , R", η, X and Y are as previously defined, to give a product of Formula I? (c) reacting a compound of Formula lib with an intermediate compound of Formula Illb’ R2 Illb9 2 wherein Q, R „. R , X and Y are as previously defined, to yield a product of Formula I wherein n is fixed at the integer 4; (d) reacting a compound of Formula IJc o D N-(CHJ-Q He j « wherein D, n, Q# R", R , X, and Y are as previously defined, to yield a product of Formula I? (e{ reacting a compound of Formula IV iv an intermediate compound of Formula V r2 Y V 9 wherein Z, n, R , R", Q, X, and Y are as previously defined to give a product of Formula I? and if) (1) reacting a compound of Formula lid with an intermediate compound of Formula UIc to give a compound of Formula If? (2) hydrolyzing If in acidic media to provide a 2? (3) reducing the compound of Formula Ig with sodium borohydride to give the product le.

The intermediate compounds of Formulae II or Iv 5 are adequately described in the above-cited patent references and references therein? as well as several Formula II compounds being commercially available„ The bicyclic pyridinylpiperaaine intermediate compounds of Formula III, as well as the starting bicyclic heterocycles (V) themselves, are either eommerieally available, found In the chemical literature, or described herein. Methods used for th© synthesis of Formula III intermediates are illustrated in Scheme I.

Scheme I Synthesis of the Bicyclic Intermediates III. ®2(co2h) piperidine catalvst pyridine solvent 90° SOC1? DMFe CHC1 Γί Η In Scheme I, synthesis of the furo-, pyrrole-, cvclcpentadieno-, or thieno-pyridine ring systems is accomplished starting with a carboxaldehyde intermediate of Formula X. The 2-carboxaldehyde intermediate is shown in Scheme I and ultimately gives rise to the intermediate IIIc as shown in Scheme I. If the 3-carboxaldehyde intermediate X5 is used in Scheme 1, the resultant product is the. "reversee’ isomer IIIc.

ZJ CHO Schema 1 X CX’) Generic structure III (wherein J-H) of the unitary process, supra, generally depicts the structures of both intermediate IIIc and IIIc'.

In Scheme I, the requisite starting carboxaldehyde can either be obtained commercially or by simple synthesis, e.g. Vilsmeier-Haack Formylation of an N-alkylpyrrole, utilizing methods readily available In the chemical literature and familiar to one skilled in the chemical arts. Condensation of intermediate X with malonic acid at 100°C usually in pyridine as a solvent with piperidine as a catalyst, for approximately 12 hours, followed by a short reflux period to enhance decarboxylation, yields the corresponding acrylic acid intermediates of struetux-e IX.

Chlorinetion of the Formula IX acids with thionyl chloride · in chloroform and a catalytic amount of dimethyl forxnamide affords the acid chloride derivatives of structure VllI, vzhieh are net purified but may be used in crude ferm in the preparation of the acid azides of Formula VII. These acid azides are prepared either in a biphasic mixture of acetone in water at 5° through th© agency of sodium azide or with trimethylsilylazide in refluxing benzene. Unpurified' preparations of the acid azides of Formula VII in methylene chloride solutions are added in portions to either diphenyl ether or diphenylmethane and heated to 230° facilitating the Curtius-type rearrangement via isocyanates which. immediately cyclize to the fused 6-5 bicyelic intermediates of Formula VI. Chlorination of VI is achieved using phosphorous oxychloride or a phosphorus pentachloridephosphorus oxychloride mixture to generate the chloro. substituted heterocyclic of Formula V. Reaction of V with an excess of an appropriate piperazine In a bomb at 120-140°C for varying periods of time affords the desired piperazine intermediate IIIc. This general synthesis of intermediates of Formula IIIc has been reported previously (cfs Eloy, et al., Bull. Soc. Chim. Beiges., 79, 301 (1976)? J. Heterocyclic* Chem., No. 8, 57 (1971)? Kelv. Chim. Acta., 53, 645 (1970)). Introduction of the substituent R may be done either by its incorporation in the starting compound X or by introduction later in the scheme, e.g. metalation of V (X-S, r2»h) with t^-butyl lithium and subsequent reaction with dimethyldisulfide to give an intermediate of Formula V wherein r2=sch3.

Utilization of the intermediate compounds of Formula HI in the unitary process described above and employing Methods A-C, preferably Method C„ results in svnthesis of the antipsychotic compounds of Formula I.

The compounds which constitute this invention and their methods of preparation will appear more fully from a consideration of the following examples which are given for the purpose of illustration only and are not to ba construed as limiting the invention in sphere or scope. All temperatures are understood to be in degrees C when not specified. The nuclear magnetic resonance (NMR) spectral characteristics refer to chemical shifts (6) expressed in parts per million (ppm) versus tetramethylsilane (TMS) as reference standard. The relative area reported for the various shifts in the proton (PMR) spectral data corresponds to the number of hydrogen atoms of a particular functional type in the molecule. The nature of the shift as to multiplicity is reported as broad singlet (bs), singlet (s), multiples (m), doublet id), doublet of doublets (dd), triplet (t), or quartet (q). Abbreviations employed are DMSO-dg (perdeuterodimethylsulfoxide), CDCl^ (deuterochloroform) and are otherwise conventional. The infrared (IR) spectral descriptions include only absorption wave numbers (cm"b having functional, group identification value.

The IR determinations were employed using potassium bromide (KBr) as diluent. All compounds gave satisfactory elemental analysis.

The following representative examples of chemical intermediates of Formulas V-X illustrate synthesis of the key intermediate IIIc, which ean he further converted using known reactions as in the cited patents, into other synthetic intermediates such as Ilia or Illb.

· EXAMPLE 1 N-Methylpyrrole-2-carboxaldehyde (X) A stirred mixture of N-methyIpyrrole (10 g, 0.12 mole) in dichloroethane (80 ml'4 and dimethylformamide (11.3 g, 0„15 mole) was treated dropwise at 5° with phosphorus oxychloride (23»S g, 0.15 mole) which led to an exothermic reaction with formation of a precipitate.

Stirring was continued for an additional 15 minutes and the precipitate was collected by filtration, suspended in 3 N NaOH solution (300 ml.) and extracted with chloroform (3 x 100 mL). The chloroform portions were combined, dried (MgSOg), filtered, and concentrated in vacuo affording 6.1 g (49%) of a dark oil, b.p. 87-90° at 22 Torr., whose NMR was consistent with the assigned structure. This intermediate was generally used unpurified in the next step of Scheme 1.

EXAMPLE 2 3-(2-Thieno)acrylic Acid (IX) A mixture of 2-thiophenecarboxaldehyde (100 g, 0.89 mole); naIonic acid (182.5 gf 1.70 nola)j pyridine (446 mL); and piperidine (8.9 mL) was heated at 100° for 12 hours. The reaction solution was then refluxed for 20 minutes and allowed to cpol, whereupon it was poured into water (1000 mL) and the resulting aqueous mixture was ' acidified with cone. HC1. The resulting off-white precipitate was collected by filtration and recrystallised from ethanol-water (Isl) yielding 109 g (80¾) of product, m.p. 145-148®.

EXAMPLE 3 3-(2-Thieno?acryloyl Chloride (VIII) A stirr’ed suspension of 3-(2-thieno)acrylic acid (118.9 g, 0.77 mole) and dimethylformamide (12 mL) in chloroform (600 mL), was treated dropwise with thionyl chloride (110.1 g, 0.13 mole) at room temperature. The reaction was then refluxed for 2 hours, cooled and concentrated in vacuo to a brown oil which solidified upon further standing to 131 g (991) of a low melting solid, which was ' used without further purification.

EXAMPLE 4 4-Oxo-4,5~dihydrothieno[3,2-c]pyridine (VI) A stirred suspension of sodium azide (168.6 g, 2.6 mole) in a mixture of p-dioxane (400 mL) and water (400 mL) was treated dropwise with a solution of 3-(2-thieno)acryloyl chloride (223.9 g, 1.3 mole) in dioxane at 5°. The dioxane layer' resulting from this biphasic mixture was isolated, concentrated in vacuo, dissolved in methylene chloride (500 ml,) , dried (MgSO^) , and filtered. This methylene chloride filtrate was added dropwise to refluxing diphenylether (400 mL) in a 3-neck flask equipped with two.air condensers. The solution was refluxed an additional hour, cooled, and concentrated in vacuo to a dark syrup which was crystallized in acetonitrile to afford a brown solid which was collected by filtration., Recrystallization of the solid from water (650 mL) yielded 106 g (54%) of a pale yellow solid, m.p. 213-214°.

EXAMPLE 5 4-Chlorothieno [3,, 2-c)pyridine (V) Finely divided 4-oxo-4,5-dihydrothienoi3„2-c)pyridine (105.6 g, 0.65 mole) was stirred while being treated dropwise with phosphorus oxychloride (321.5 g, 2.1 mole) at 0°. The reaction mixture was then refluxed for 2.5 hours, cooled, and cautiously poured onto crushed ice (1000 mL). The resulting solution was stirred for 30 minutes and extracted with dichloromethane (3 x 400 mL).

The organic portions were combined, dried (KgSOg), filtered, and concentrated in vacuo to a solid which was recrystal3 5 lized from acetonitrile (400 mL) affording 101 g (85%) of light yellow solid, m.p. 91°.

EXAMPLE 6 4-(1-Piperazinyl)thieno[3,2-c]pyridine (IIIc) A mixture of 4-chlorofchier.o [3,2-c]pyridine (22,,7 g, 0.13 mole) and piperazine (57.7 g, 0.67 mole) were heated in a bomb with a minimum amount of ethanol (50 mL) at 120° for 24 hours. The reaction was cooled, partitioned between dichloromethane and water, and the organic layer was isolated, dried (MgSO^), filtered, and concentrated in vacuo to an oil. Flash chromatography (methylene chloride-10% methanol-1% ammonium hydroxide) of this material gave 16 g (54%) of a golden oil. Treatment of an ethanol solution of the oil with ethanolic HCl followed by recrystallization from ethanol gave the hydrochloride salt as off-white crystals, m.p. 275-283®.

EXAMPLE 7 Synthesis of 7-(l^Piperazinyl)thieno[2,3-c]pyridine (IIIc8) The synthesis of this compound was accomplished with the same sequence of reactions as used to prepare IIIc, except that the starting material (X) is 3-thiophenecarboxaldehvde. The multiple step preparation of the positional isomer 111c8 was complicated, however, in that th® Curtius-type rearrangement reaction (Example 4) gave the desired VI intermediate compound in low yield as the major product of this reaction was a sym-triasine by-product which resulted from trimerization of the isocyanate intermediate. 6 Nonetheless# application of the reactions outlined in Scheme 1 resulted in production of the Ulc’ product, whieh was a brown gum and was used without further purification.

By appropriate modification of the Scheme 1 5 reaction sequence and the various synthetic reactions exemplified above# additional IIIc compounds may be synthesized. Some additional representative IIIc compounds are shown in Table 3.

Table 3 Additional Formula IIIc Compounds Example R* X V 8 H H CH N-i 9 ' H H CH O 10 n T«a CH 11 Π P? M-CH3 p»«ar 12 w H 0 CH 13 3 H CH S 14 Πu 3 CH N-i 15 CF aa och3 0 16 H SCH^ CH s 17 CHg Ci V* tet» O CH 18 IT? a>A § CH 19 OH C®3 VrSA CO 20 0 C*1 P? u2~5 CH s 21 O® n ww A® S CH 22 H SCHj CH S m.p.i°CI >250 203-205 Synthesis of Formula I Compounds EXAMPLE 23 General Synthesis Synthesis of the product compounds of Formula I was accomplished hy alkylation of appropriate halo-substituted imide derivatives (lie), where D is (ae-d8) and K is N-(CH^) -0 with Q being halide? or the fluorophenylbutyrophenone derivative (lid) with an appropriate IIIc intermediate compound in refluxing acetonitrile, with three equivalents of potassium carbonate present. The carbinol derivatives were generated by sodium borohydride reduction of the corresponding butvrophenone. Reaction times for the alkylation varied from 5 to 72 hours and th© resulting products were usually subjected to flash chromatography In an ethanol-chloroform mixture for purification. The Formula I products were usually formulated as the hydrochloride salt for testing.

EXAMPLE 24 4,4-Dimethy1-1-[4-(4 (thieno ί3,2-c Jpyridin-4-yl)l-piperazinyllbutyl)-2,6-piperidinedione A mixture of 4-(1-piperazinyl)thieno(3,2-c)pyridine (IIIc; 2.79 g, 0.012 mole), H-4-bromobutyl)-3dimethylglutarimide (3.3 g, 0.012 mole) and potassium carbonate (3.3 g, 0.024 mole) was refluxed In acetonitrile (150 mL) for 24 hour. The reaction mixture was- filtered, concentrated in vacuo and partitioned between dichloromethane and water. Th© organic layer was isolated, dried (MgSO^) and concentrated in vacuo to a gold oil which was flash chromatographed (5% ethanol-chloroform). The chromatographed material was dissolved in acetonitrile and treated with ethanolic HCl to yield 1„3 g (24% yield) of the hydrochloride salt, m.p. 195-197°.

Anal. Calcd. for C22H30N4°2S.HCl: C, 58.59; H, 6.93; N, 12.42. Found: C, 58.64; H, 7.02; N, 12.72.

PMR (DMSO-dg); 1.08 (6,8)? 1.71 (4,m)? 2.60 (4,s) ; 3.40 (10,m)s 4.00 (2,m) ; 7.65 (2,m)? 7.87 (X,m); 8.08 (l,d [5.0 Hz])? 11.75 (l,bs).

IB (KBr): 715, 965, 1425, 1535, 1670, 1720, 2580, 2960 cm1.

EXAMPLE 25 4-[4-(4-(4-Furo[3,2-c]pyridinyl)1-piperazinyl]butyl]-3,5-morpholinedlone 15 A mixture of 4-(1-piperasinyl)furo[3,2-c]pyridine (4.5 g, 0.022 mole), 4-(4-bromohutyl)-3,5-morphelinedione (5.5 g, 0.022 mole), and potassium carbonate (9.1 g, 0.066 mole) was refluxed in acetonitrile for 24 hour. The reaction mixture was filtered, concentrated in yacuo, and partitioned beteen dichloromethane and water. Th© organic layer was isolated, dried (MgSO^), and concentrated in vacuo to a yellow oil which was flash chromatographed. The appropriate chromatographic fractions were combined, concentrated in vacuo, and crystallized from isopropanol yielding 6,2 g (69%) of the free base, m.p. 109-110°.

Anal. Calcd. for C~;eH2^4°42 C, 61.28; H, 6.50? N, 15.04. Found: C, 60.98? H, 6.60? M, 15.19.

PKR (CDClg, s 1.60 (4,m)? 2.40 (2,m); 2.57 (4,m)? 3.74 (S-rnb 4.31 (4,s); '6.78 (l,d [2.0 Hz)); 5.89 (l,d (5.8 Hz))? 7.49 (l,d [2.0 Hz)); 8.01 (l,d [5.8 Hz)).

IR (KBr): 760, 780, 1250, 1285, 1440, 1460, 1570 5 1595, 1690, 1735, 2830 cnT1. using the methodology referred to above, or alternate synthetic methods disclosed in the referenced patents, a wide assortment of Formula I products may be provided. Tables 4 and 5 contain a listing of additional representative Formula I products. Table 6 contains in vivo biological data for representative compounds of Formula I.

Ex.

No. (h) ie) 31 (e) Tame -4 n R* R X Y Formula a) H CH S C„«H^oN.0o0„ &· & S " -¾ <=* Η H CH S C21H24FN3OS m.p. v-C) 180—182 115-118 Br CH S 203-205 27 422 Br CH S C9,H,qBx-N4O-S :hci; 0.5 b,,o 216-219 CH 3 CH S C23H30^4°2S’ 195-X97 CH S C.eH,^N.O9S7 186-188 :Ϊ„lC7Hg03Se0.5H2O 2 Table 4' - Continued £,X„ Ko. .2 n a R X Y Formula' m„o„(°C) (d) (d) 0-tfi V •*h( (b) (b) JO xz> w- ·» H CH S C?2H24N^O3S2 .HCl 229-230 CH S C93H94NaO2§ .HCl 226-227 ,0.5 H2O CB C,,9,aN40,§, zHCi 1 S « tioeVe* Ii) Θ CB O C,,B,ftN.O^S . ® <£»Si Vj J> ω otoS W 2 H CB 0 C,,H,nN.O, 3P^'? 3 Β H CH 0 H CH, CH 0 C, gfj II.

N.OgS i 20-"« it 250 205-207 176-177 Table 4 - Continued Ex.

No.

Z n R1 B2 X Y Formula al ϊϊι.Οο (°) 43 (e) z-t <€) K CH, CH 0 C,,H,,N,O, 321-233 ?Ll£cf .8.5B,O B .0 CH 0 Ο,βΗ,^Ν.Ο.δ 245-250 . 2 C. r. 0 ® 5 (e) 3 S CH3 CH 0 C2^H9.gFN3O2 · 121-122 Q. (c) /° <7 (a)° (a) CH S ClgH24N4O3S ,Ι.Κ^ΗθΟ^.Ο.δΗ O a a ca s εηΗ2Λο2® ®HCl k- 4 H CK 5 ’ cj>oB2S^A§ ®HC1 114-115 173-175 199-201 CH NMe C23H31N5O9S.2HC1 148-150 to X ω 4 Table 4 - Continued Formula*5m.p. (°, C20H27N5°3 144-146 .2.3HC1.0.9H2O SjnCl 2.6H2O 192-194 a) C, H, and M elemental analyses were all with +0.4% of theoretical values for the formulae given.

Table 5 Table 5 - Continued 7 Table 6 Repr esentative In Vivo Biological Data (mg/kg,p.o.) Example CAR APO Catalepsy Catalepsy Number —50 —50 Induction ED„O Reversal EDe^ 5 24 6 40 >24 25 i i 34 >46 2 26 12 A 6* 3» - IA 27 10 9 >40 IA 28 >100 >100 _b) 'ϊ s 10 29 /* I·» ob - IA 30 35 - >142 IA 31 32 >128 IA 36 43 ' 47 - XA 37 Q of 18 23 IA 15 38 4 »9 I 13 IA 39 3 5 11 ή| 40 28 Al I - 41 14 OO &* am 40 ik 42 3s, 63 - 1 & 20 43 □ η <&> - Λ 7 . 60 rf® ffl 0 X IA 48 >100 >100 - IA 49 67 >100 - IA a) IA means inactive and is used if 1 the ED 25 is >20 mg/kg. □ u b) - means that data not available. 8

Claims (49)

1.CLAIMS: 1„ A compound of Formula 1 or a pharma* ceutically acceptable acid addition salt thereof wherein is selected from among the following radicals:

2.R /AΛ-/ (a) 1 A where R and R are independently chosen from hydrogen, lower alkyl or may be taken together as a Cg-Cg alkylene chain? (b) s s in which R and R are independently chosen from hydrogen, lower alkyl, and A-substituted phenyl with A being hydrogen or halogen, or R and R are taken together as a butylene chain, and if can be S or CH,; Γ\ \\ ο (c) in which G is selected from hydrogen, lower alkyl, lower alkoxy, or halogen, m is the integer 1-4, and ϋ is C=0 or SO^; and n is the integer 2-4 with th® proviso that when Z is ie) , n is 3; either

3.X or ¥ is independently selected from CH 9 , 0, S, or 7

4.NR with the proviso that the other X or Y must always be =CH-j 1 7

5.R and R are independently selected from hydrogen or lower alkyl; and

6.R is selected from hydrogen, lower alkyl, lower alkoxy, lower alkylthio, halogen, and hydroxyl. radical 2. (a) . The compound of claim 1 wherein Z is the radical 3. (b) . The compound of claim 1 wherein Z is the radical 4. (c) . The compound of claim 1 wherein 2 is the radical 5. (d) . The compound of claim 1 wherein Z is the radical S. (e). The compound of claim X wherein Z is the I

7. The compound of claim 1 wherein Y is an oxygen atom.

8. The compound of.claim 1 wherein Y is a sulfur atom.

9. The £ compound of claim 3 therein IT ’ and R® are taken together as a butylene chain and W is sulfur. 91

10. The compound of claim 4 wherein V is an oxygen atom.

11. The compound of claim 7 wherein 2 is the radical (a)„ (c) or (e). 5 1

12. The compound of claim 8 wherein 3 is the radical (a), (b), or (e).

13. The compound of claim 2·, I-[4-[4-(furo[3,2-c]pyridin-4-yl)-1-piperazinyl]butyl]-4,4-dime thy 1--2,65 piperidinedione.

14. The compound of claim 2, 4,4-dimethyl-l-[4[4-(2-methylfuro[3,2-e]pyridin -4=yl) -l-piperazinyl]butyl]2 s δ-piperidinedione.

15. The compound of claim 2, 4,4-dimethyl-l-[4-[41Q (thieno[3,2-cJpyridin-4-yl)-1-piperasinyl]butyl)-2,6piperidinedione„

16. The compound of claim 2, 4,4-dimethyl-l-[4-[4~ (1-methyl-XH-pyrrolo[3,2-c]pyridxn-4-yli-l-piperazinyl)butyl]-2,6~piperidinedione. 15

17. The compound of claim 2, 4,4-dimethyl-l-[4-[4(2-bromothieno(3,2-c]pyridin-4-yl)-1-piperazinyl]butyl)-2,6piperidinedione.

18. The compound of claim 2, l”[4-i4-(thleno[3,2-c]pyridin-4-yl) -1-piperaz inyl]butyl]1,©-piperidinedione. 5 2

19. The compound of claim 2# 4-methyl-l-(4-[4“ (thieno (3# 2-c]pyr.idin-4-yX) -l-piperasinyllbutyl]-X # Spiperidinedione.

20. The compound of claim 3# 3-[4-[4-(furo[3,2-c]pyridin-4-yl)-X-piperazinyl]butyl]-l-thia-3-azaspiro[4.4]nonane-2,4-dione.

21. The compound of claim 3# 3-[4-[4-iZ-methylfuro[3#2-e]pyridin-4-yl)-1-piperazinyl]butyl]-l-thia-3-azaspiro[4.4}nonane-2#4-dione.

22. The compound of claim 3# 3-(4-[4-(thieno[3 #2-e]pyridin-4-yl]-X-piperazinylj butyl]-l-thia-3-asaspiro[4.4]nonane-2#4-dione.

23. The compound of claim 3# 3-(4-(4-(1-methylpyrrolo[3 # 2-e]pyridin-4-yl)-1-piperasinyl)butyl]-l-thia-3asaspiro (4.4] nonan-2 # 4-dione ...

24. The compound of claim 3# 3-[4-(4-(2-bromothieno(3 #2»c]pyridin-4-yl)-1-piperaxinyX]butyl]-l-thia-3azaspiro[4.4]nonane-2#4-dione. *

25. The compound of claim 3# 3-(4-(4-(2-methyXthieno(3 # 2-c]pyridxn-4-yl]-1-piperazinyl]butyl]-l-thia-3asaspiro(4.4]nonane-2 # 4-dione„ S3

26. The compound of claim 1, 3-(4-[4-(thieno[2,3-c]pyridin-7-yl)-1-piperazinyl]butyl]-i-thla-3-azaspiro[4.4]nonane-2,4-dione.

27. The compound of claim 4, 4-[4-[4-(4-furo[3,2-c ]pyridinyl)-1-piperazinyl]butyl]-3,5-morphoXinedione.

28.» The compound of claim 4, 4-[4-[4-(1-methyl-lHpyrrolo[3,2-c]pyridin-4-yl)=1-piperazinyl]butyl]3,5-morpholinedione.

29.,., The compound of claim 4, 4-(4-[4-(4-thieno(3,2-c]pyridinyl)-1-piperazinyl3 butyl]-3,5-thiomorpholinedione.

30. The compound of claim 4, 4-[4-[4-(4-thieno[3,2-c]pyridinyl)-1-piperazinyl)butyl]-3,S-morpholinedione.

31. The compound of claim 5, 2-[4-[4-(thieno(3,2-c] pyridin-4-yl)-l.-piperazinyl ] butyl] -lS-isoindole-1,3« (2H)-dione.

32. The compound of claim 5, 2-[4- [4-(thieno• [3,2-cJpyridxn~4-yl)-l-piperazinyl]butyl)-l,2-benzisothiazol-3(2H)-on© 1,l-dioxide.

33.» The compound of claim 6, o-(4-fluorophenyl)4-(furo{3,2-c)pyrifixn-4-yl)-1-piperazinebutanol»

34. The compound of claim 6, c -(4-fluorophenyl)4- i2-methylfuroi3 r 2-cJpyridxn-4-yl)-l-piperazinebutanol.

35. The compound of claim 6, c-(4-fluorophenyl)~ 4-(thienoί3,2-c)pyridin-4-yl)-l-piperazinebutanol.

36.«, Medication comprising an effective antipsychotic amount of a compound claimed in claim 1, for use in a method for ameliorating an undesirable psychotic state in a mammal.

37. The medication of claim 36 wherein the said compound is that claimed in claim 15.

38. The medication of claim 36 wherein the said compound is that claimed in claim 23.

39. A pharmaceutical composition in dosage unit form suitable for systemic administration to a mammalian host comprising a pharmaceutical carrier and from about 1-500 mg. of an active compound selected from the compounds claimed in claims 1 to 35.

40. The pharmaceutical composition of claim 39 wherein the active compound is the compound claimed in claim 15.

41. The pharmaceutical composition of claim 39 wherein the active compound is the compound claimed in claim 23. 5 5

42. A process for preparing a compound of Formula I R* z-[ch,3„-k n« V_y R z - *Y or a pharmaceutically acceptable acid addition salt thereof wherein 2 is selected from among the following radicals : (a) where R J and R are independently chosen from hydrogen, lower alkyl or may be taken together as a Cg-Cg alkylene chain; R. ί (o) in which R 5 and R® are independently chosen from hydrogen, lower alkyl, and A-substituted phenyl with A being hydrogen or halogen, or R 5 and R® are taken together as a butylene chain, and w can be S or CH 9 j 5 6 (c) in which G is selected frora hydrogen, loweralkyl, lower alkoxy, or halogen, m is the integer 1-4, and U is C-0 or S0 9 ; and (a) n is the integer 2-4 with the proviso that when Z is (e), n is 3? 10 either S or X Is independently selected from CH 9 , O, S, or NR^ with the proviso that the other X or '? must always he -CS-; R 1 and R* are independently selected from hydrogen or 15 lower alkyl? and R~ is selected from hydrogen, lower alkyl, lower alkoxy, lower alkylthio, halogen, and hydroxyl; S7 this process comprises selection of a process from the group of processes consisting of (a) reacting an intermediate of Formula Ila iO Ila 5 wherein the symbol “D® is the divalent structure of Formulae a'-d’ *s 0 \/^‘ B?— ,6 1 Q _A 0 r\ a 4 M ί 0 V o (a e ) s ) (e’) (G) Z E _j^A Uv (d’) with Ilia Ilia 1 2 wherein R , R , η, X and Y are as previously defined, to give a product of Formula I? (hl reacting a compound of Formula lib Ρ» Ilh 5 with an intermediate compound of Formula Illb wherein Q is a suitable displacement group such as chloride, bromide, iodide, sulfate, phosphate, 1 2 tosylate, or mesylate, and D, Κ,Μ,η, X and Y 10 are as previously defined, to give a product of Formula ϊ; (c) reacting a compound of Formula lib with an Intermediate compound of Formula Illb’ 5 9 1 “> wherein Q, R , R“, X and Y are as previously defined, to yield a product of Formula I wherein n is fixed at the integer 4? (d) reacting a compound of Formula lie djhq^-q He with an intermediate compound of Formula IIIc j 2 wherein D, s, 0, R~, R , X» and Y are as previously defined, to yield a product of Formula I; (eS reacting a compound of Formula IV xv with an intermediate compound of Formula V $ 0 R 2 V 1 7 wherein I, n, R“, R“, Q, X, and Y are as previously defined to give a product of Formula I? and (£) ¢1) reacting a compound of Formula IId with an intermediate compound of Formula IIIc to give a compound of Formula If? 2. (2) hydrolyzing If in acidic media to provide a compound of Formula Ig? and 9 ST (CH 2>3‘ xg 6l Π) reducing the compound of Formula Ig with sodium borohydride to give the product le.

43. A process as claimed in claim 42, substantially as described in respect of any of the foregoing Examples.

44. A compound (or salt) as claimed in claim 1, prepared by a process as claimed in claim 42 or 43.

45. A pharmaceutical composition comprising a compound (or salt) as claimed in any of claims 1 to 35, or claim 44, and a pharmaceutically acceptable carrier.

46. A compound (or salt) as claimed in any of claims 2 to 14, 16 to 22, and 24 to 35, or claim 44, or pharmaceutical composition as claimed in claim 39, 40, 41 or 45, for use in a method of ameliorating an undesirable psychotic state in a mammal.

47. Use of a compound (or salt) as claimed in any of claims 1 to 35, or claim 44, in the preparation of a medicament for treatment of undesirable psychotic states in mammals.

48. Use of a compound (of salt) according to any one of claims 1-35 or claim 44, a medication according to any one of claims 36-38 or a pharmaceutical composition according to any one of claims 39-41 or 45 for ameliorating an undesirable psychotic state in a mammal.

49. A pharmaceutical composition according to claim 45, substantially as hereinbefore described. F. R. KELLY & CO., AGENTS FOR THE APPLICANTS.