IE861193L - 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. [GB2174703A]

Description

59201 This invention generally pertains to heterocyclic carbon compounds having drug and bio-affecting properties and to their preparation and use. In particulart, the invention is concerned with 14-disubstiruted piper a sine derivatives wherein one substituent is a hicyclic fussd-ring heterocyclic system comprising furo-1, pyrrolo- L, eyelo-pentadieno- L, and thieno-pvridine ring systems; and the other is an alkylene chain, preferably a butylene chain,, bearing a 5" t*5l cyclic iinide ring or "a benzvlic carbinol moiety at its terminus. Examples of types of these terminal moities a depicted below; [CH«] 'asaspiro alkanedione type 0 alkyl^ ,—.// alky! XJ ™dialkylglutarimide type" : o 3—^ 0 'thiasolidinsdion® type® / 'saecinimids typem 0 r~K V p- W 0 ®morpholine<3ione type6 (V can be 0 or Si "phthalimide type" (U can be C=0 or 30^) "bensylic 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 the following general structural formula (1) 10 in which alk is an alkylene chain connnecting the piperazine ring with the cyclic laid© group and B is a heterocyclic ring %?ith optional substituents„ (1) 4 Wuf et al.f U.S. Patents 3,717,634 and 3,907,801 as well as a corresponding Wu, et alM publication — J„ Med. Chem„, 15, 447-479 (1972) ■— describe various azaspiro-[4.5]-decanedione psychotropic compounds wherein B repre-5 sents various monocylic heterocycles such as pyridine, pyrimidine, or triasinsall with optional substituents.

Templer Yevich and Lobeck in U.S. Patent 4r305,944 disclose azaspiro[4.5]decanedione tranquilissing compounds wherein B is a 3-eyanopyridin-2«»yl or 3-methoxypyridin~2-yl 10 moiety., Temple e, Yevich and Lobeck report dialkyi-glutarimide trenqai1izing compounds in U.S. 4,361e565 in which B is a 3-cyanopyridin-2-yl ring which may bear a second optional substituents 15 Temple and Yeager in 0*8„ Patents 4 j, 367 j, 335 and 4,456,756 disclose antipsychotic thiasolidinediones and spirothiazolidinediones wherein B is a 2-pyridinyI ringf, either unsubstituted or containing a cyano substituent.

Temple and Yevich in U.S. Patents 4,411,901? and 20 4 r 452 ^ 799 disclosed antipsychotic compounds with a variety of cyclic imide and bensylic carbinol moieties wherein B was either bensisothiaaole or ben^isoacazole ring systems,, Attention is also called to the following pending applications„ 25 In U„S„ Serial Ho„ 531,519, filed 9/12/83 and now allowed New and Yevich disclose and claim psychotropic swccinimid® and phthalimide-type compounds wherein B is a 5 2-pyrimidinyl ring. These compounds demonstrate antianxiety activity.

A series of antipsychotic 1-fluorophenylcarbonyl-1. -carbinol-, ~ketal~» propyl-4-(2- pyrimidinyl)piperazines 5 are disclosed by Yevich and Lobeck in U.S. Serial Ho„ 583 f 309 P filed 12/18/84.

Finally,, New, Yevich and Lobeck in U.S. Serial Mo. §91 £,952, filed 1/16/85,*, disclose and claim a series of antipsychotic compounds which contain a variety of cyclic 10 imide moieties and ■wherein B 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 15 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 Sbicyclic systems being fused beniso ring heterocyclics, i.e. benzisothiazole or benzisoxazole ring systems., This distinguishes these 20 compounds from the compounds of the present invention in which B is comprised of different classes of fused heterocyclic rings? i.e. furo-, pyrrolo-, eyclopentadieno-1„ or thieno- pyridine ring systems. The present compounds may also be distinguished pharmacologically on the basis of 25 psychotropic properties and side effect profiles from the art compounds,, In this regard, the compounds of the present invention possess selective antipsychotic'fneuroleptic) activity with serotonin antagonism,* and? surprisingly, have 8 low affinities for dopamine receptors which is in contrast to the prior art antipsychotic agents described? supra. In this regardt, the present compounds pharmacologically bear some semblance to th« atypical standard neuroleptic agent* clozapine (2), cf % The Merck Indexr 10th Edition (1983), page 344, and references therein™ (2) As can be seent> closapine belongs to the dibensodiasepine class of psychotropics which bear little structural relationship to the present series of compounds,. Addi-10 tionally, the present compounds appear to lack the potential for causing the adverse extrapyramidal symptomatology associated with the chronic administration of currently used antipsychotic agents. Further? selected compounds from the present series Slave demonstrated in animal models? the 15 ability to reverse catalepsy resulting from administration of trifluoperazine? a standard neuroleptic agent.

In its broadest aspect,, the present invention is concerned with piperasinyl derivatives having neuroleptic {antipsychotic! properties characterised by a compound of 20 Formula 1 and its pharmaceutically acceptable acid addition salts. 7 IT 1 X^Y z- \_/ In Formula % represents the following radicalss R. // v~i .■M (a) R- N- rV 0 0 (c) OH 0 CH- (d) (e) In radical (a) R and H" are independently chosen 5 from hydrogen, alkyl or and K" are taken together as 5 Q a to Cg alkylene chain,. In radical (b) R and R are independently chosen from hydrogen, ci_4 alkyl, and ■^-substituted phenyl with K being hydrogen or halogen, or R® end are taken together as a butylene chain? and W can be i. 10 S fa sulfur atom) or CH^ (a methylene group!. In radical (c) ¥ is an oxygen or sulfur atom,. In radical (d) G is selected from hydrogen, alkyl, C1_^ alkoxy or halogen,. 8 m is 1-4,and U is C~0 or SO^. Additionallyr in Formula Is n 1 is 2-4 with the proviso that when Z is (@), n is 3? R~ is selected from hydrogen or C.,_4 alkyl; either X or Y is 7 independently selected from CH,, 0? S, or NR with the 5 proviso that the other of X or Y must always be ~GH»; r" is selected from hydrogen„ C. A alkyl, C, A alkojtv^ C« A A,""1® J. """a: "* J."'® 7 alkylthiOj, halogen, and frydroxyl; and E is hydrogen or C^^alkyl. The designation C.,^ may also be defined by the term "lower"- 10 Preferred classes ox compounds are comprised of compounds of Formula 1 wherein 2 can be the radicals (aj ? S 6 (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 (el» ?or these preferred classes Y is 15 either an oseygen or sulfur atom and X is m&thynyl y n 2 is 4f except when % is (e) at which time n is 3? and R is hydrogen.

There are two classes of most preferred compounds. For the class of compounds wherein Y is an oseygen atom, 2 is • 20 either fa) , (c) with V being an o&ygen atemtf and (e) . For the class of compounds wherein Y is a sulfur atomB, Z is either (a!, (b), or ?e).

The pharmaceutically acceptable acid addition salts of the invention are those in which the anion does not 25 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 X compounds.

They are generally preferred for medical usage. In sons 9 instances, they have physical properties which make them more desirable for pharmaceutical formulation™ Such properties can be solubility, lack of hygroscopicity, compressibility with respect to tablet formation and 5 compatibility with other ingredients with which the substance may be used for pharmaceutical purposes. The 6. 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 10 ether , ben sen® t, ethanol,, ethyl acetate £, acetonitrilef 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 15 such as maleic acid, acetic acid, tartaric acid, propionic acid, fumaric acid,, isethionic acid, succinic acid, pasnoic acid, cyclamic acid and pivalic acid; useful inorganic acid may be hydrohalide acids such as for example, HC1„ HBr, HI; sulfuric acids; and phosphoric acids. 20 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 (ej and is possible in (b). Separation of the individual stereoisomers may be accomplished by application 25 of various methods which are well known to practitioners in the art.

The compounds of the present invention are useful * pharmacological agents with psychotropic properties. In 10 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 I evoke certain 5 responses when studied in standard in vivo and in vitro pharmacological test systems which are known to correlate veil with the relief of symptoms of acute and chronic psychosis in mean.

For subclassification of the psychotropic activity 10 and specificity of the present compounds, state of tha 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 15 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 20 is employed in tests, such as, for example, measuring inhibition of [ H]spiperone binding which indicates significant dopamine receptor binding activity (cf: Burt* et al., Molecular Pharmacology, 12, 800 (1976); Science, 196, 32S (1977); Crease, et al.. Science, 192, 481 (1976)). 25 Some of the more important binding tests employed are listed below in Table 1.

Table 1 Receptor Binding Tests Test Specific No. Putative 'Receptor Sits Ligand Used Binding Agent 3 5 25 2A Dopamine/spiperone/ [ H] Spiperone D (+) -Eutaclan-.ol neuroleptic 252B Alpha-! l3H]WB-4101 Phertolamine 252E Serotonin Type 1 (5-HT^ [3H]5-HT 5-HT * 2521 Serotonin Type 2 (5-HT?) [3H]Spiperone D-Lysergide 10 References s 252A - given supra. 2523 - Crews, et al., Science, 202?322, 1978» Rosenblatt,? et al. , Brain Res., ISO: 186, 1979. U'Prichard, et al., Science, 199x197^ 1978? Molee. 15 Pharmacol.f 13:454, 1977. r • 252E ~ Bennett and Snyder, Molec. Pharmacol.„ 12s 373, 1976„ 2521 ™ Peroutka and Snyder," Molec. Pharmacol*, 16s 687, 1979.

Data derived froxa the above binding tests demonstrate that the family of compounds of the present 20 invention has modest to low affinity for dopaminergic receptors but much greater affinities for both serotonin S1 and S, sites. These binding properties distinguish the present compounds froia the cited prior art compounds as well as most of the clinically useful antipsychotic agents now 25 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 30 to induce the unwanted extrapyramidal side effects common to &> most currently used antipsychotic agents. 12 Binding activity at the alpha-1 receptor (Test 252B) 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 5 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-affeet liabilities such as cataleptic 10 activity. 13 Table 2 In Vivo Tests Used to Evaluate Formula- I Compounds 1„ Conditioned Avoidance Response (CAE) ■— measure of a drug's tranquilising activity as determined by its 5 attenuation of avoidance response to electrical shock in trained fasted rats, cfs Albert, Pharmacologist„ 4_, 152 (1962); Wu, et al., J. Med. Ghent., 12, 876-881 (1969). 2. Inhibition of Apoitiorphing-Induced (A?0) Stereotypy ■— 10 an assessment of blockade of dopaminergic activity in rats as measured by attenuation of the behavioral syndrome caused by the dopamine agonists apomorphin®, cfs J&nssen? et al., Araneimittel. Forsch., 17g 841 (1966) . 15 3. Catalepsy — drug-induced catalepsy in rats is predictive of potential extrapyramidal symptoms (EPSl in man. c£s Costall E, et al., Psychopharmacoloqia, 34, 233-241 11974) According to the pharmacological profile established by these in vivo tests e, the present compounds of Formula X have promising antipsychotic potential in that 25 they are relatively potent in the CAR test,, having oral values <100 mg/kg body weighty and they, effectively block apomorphine-induced stereotypy. This blockade of apomorphine-induced stereotypy way reflect dopamine 1 4 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 bute even more significantly, preferred compounds of the invention demonstrate the ability to reverse neuroleptic-induced catalepsy with va*ues mf/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 a class ere 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 discussion9 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, cf: The Merck Index, 10th Edition, (1983) , page 344e, and references therein. 5 Although the dosage and dosage regimen must in each case be carefully adjustedt> utilising sound professional judgment and considering the age, weight and condition of the ✓ recipient,, the route of administration and the nature and gravity of the illness, generally the daily dose will be 10 from about 0„05 to about 10 mg/kgiB preferablyf, 0.1 to- 2 mg/kg, when administered parenterally; and from about 1 to about 50 mg/kg, preferably 2 to 30 mg/kg, when administered orally. In some instances, a sufficient therapeutic effect can be obtained at lower doses while in others, larger doses 15 will he 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 %?hen a compound of the present invention is administered orally, which is the 20 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 25 effective antipsychotic Cneuroleptic) effects without causing any harmful or untoward side effects.

Therapeutically, the present compounds are generally given as pharmaceutical compositions comprised of an 16 effective antipsychotic amount of a compound of Formula I or a pharmaceutical^ acceptable acid addition salt thereof and a pharmaceutical^ acceptable carrier. Pharmaceutical compositions for effecting such treatment will contain a 5 major or minor amount, e.g. from 95 to 0„5§ of at least one compound of the present invention in combination with a pharmaceutical carrier, the carrier comprising one or more solids, semi-solidj, or liquid diluent, filler, and formulation adjuvant which is non-to^ic, inert and pharmaceutically 10 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 15 can contain one* two, three, four or more single doses; or alternatively, on@-»hal£, 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 20 units according to the predetermined 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 25 active ingredient per unit dose are preferred and are conventionally prepared as tablets, loaengas, capsules, powders, aqueous or oily suspensions, syrups, elixirs, and aqueous solutions,, Preferred oral compositions are in the 17 form of tablets or capsules and may contain conventional excipients such as binding agents (e.g. syrup, acaciat gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone)„ fillers (e.g. lactose, sugar, maixe-starch, calcium phos-5 phate, sorbitol or glycine), lubricants (e.g. magnesium stearate, talc, polyethylene glycol or silica), * disintegrants (e.g. starch), and wetting agents (e„g„ sodium lauryl sulfateJ - Solutions or suspensions of a Formula 1 compound with conventional pharmaceutical vehicles are 10 employed for parenteral compositions sueh 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 0.1% to 10% by weight of 15 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 liquidt polyethylene glycols %?hich are soluble in 20 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 piperaainyl or Bimid®?!l 25 intermediates analogous to methods described by Wu, et al.,,,, . patents,,, supra. ff or Temple,, et al., patents, supra. These methods nay be incorporated into a unitary process which is er.ployed 1 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* Furthert, variations of the methods to produce 5 the same compounds in somewhat different fashion will also be evident to one skilled in the art. Certain examples will be given for specific illustration,., 2 Unitary Process R 10 meanings as previously assigned to them in Formula I. The symbol D is either the. divalent structures related to radicals (a-fi) as shown below in partial structures (a"-d*J * or D is the radical (e'D also shown below,, I (II) (III) In this scheme „ R^P, 1 and Y have the same B' 6 0 (a') (b9) (c9) 0 (d9) (e®) 1 9 In radicals (a9-e9) all symbols have the same meanings as previously assigned hereinabove„ The symbol "E" in the above scheme can be 0? N-H; or N-(CHp)n~Q« The symbol "p." is as previously defined and "Q" refers to a suitable 5 displacement group such as chloride, bromidet iodide, sulfate, phosphate, tosylate, or mesylate„ The symbol "J" can be H,N-(CH2)n-; Q"(CH2^n"? C relationship between E and J is Method No„ A B C 10 when E is: / (Ub) >-(CH2)n-Q (lie) Then J is: H2N-(CH,)„- X-(CH,)W- or (Ilia) (Illb) (ZZXb1) Method A dry solvent I Ila Ilia 20 Method B 1) 1) N-H + w ♦^00 lib nib 2) Q ® R1 xA' lib + 111b1 (Illb1 is a special case wherein n is fixed at 4) Method C (the preferred method) 0-«w lie IIIc 21 The condensation in Hathod A is carried out by refluxing the reactants 'in a dry, inert reaction medium-such as pyridine or xylene. For Methods B and C the process is carried out und^r reaction conditions suitable for the 5 preparation of tertiary amines by alkylation of secondary amines. The reactants are heated in a suitable organic liquid et temperatures of about 60° to about 100°C in the presence of an acid binding agent. Bensene^ dimethyl- formamidel? ethanol, acetonitrile* toluene and n-butyl 10 alcohol are preferred examples of the organic liquid reaction media. The preferred acid binding agent is potassium carbonate e, but other inorganic and tertiary organic bases may be employed including other alkali and alkaline earth metal carbonates,, bicarbonates, or hydrides, 15 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 20 given in the reference patents.

For preparation of the Formula I products wherein Z is (e), the following adaptation of Method C is employed. 3 2 1) alleviation (Ci2)3-0 + 1X1 c lid 2) ketal hvdrolysis k3O ® 3) sodlun borohvdride \ ! 1(e) As an example of a method variation to produce the compounds of Formula I somewhat differently a Z-substituted alkyl piperazine {IV) can be reacted with an appropriate fused bicyclic pyridine system {V) to yield a product of Formula If e.g.

/"K f - rv To summarize the foregoing, there is described a process for the preparation of a compound of Formula 2 , 23 this process comprises selection of a process from the group of processes consisting of (a) reacting an intermediate of Formula Ila D™0 Ila wherein the symbol mDm is the divalent structure of Formulas a8~d* R R' (as) CbO 0 (c<) (G), 0 m W) with an intermediate of Formula Ilia V-CVif v_y Ilia 24 1 ? wherein R , R~, n, X and Y are as previously defined, to give a product of Formula I? (b) reacting a compound of Formula lib lib with an i n t ermed i at a compound of Formula IXIb ,2 n CHOO -H « " \ / Illb 10 wherein Q is a suitable displacement group such as chloride, bromide, iodide, sulfate, phosphate, 1 *> tosylate, or mesylate, and D, R , R~, n„ X and Y are as previously definedr to give a product of Formula I? (e) reacting a compound of Formula lib with an intermediate compound of Formula Xllb * 'R* ,0 R © Illb' 25 1 2 wherein Q, R „. R , X and Y are as previously definedp to yield a product of Formula I wherein is fixed at the integer 4? reacting a compound of Formula XIc /^\ lie with an intermediate compound of Formula IXIe IIIc wherein D„ n, Q, R"% X, and ¥ are as previously defined, to yield a product oi Formula I? reacting a compound of Formula IV 1 . w- I /"•A Z- (CH^)^-13 )l-H " V / IV with an intermediate compound of Formula V 2 6 r2 N 1 "> wherein Z, n? R , R", X, and Y are as previously defined to giv*e a product of Formula I; and (£) (1) reacting a compound of Formula lid n.

(OH^-Q lid 10 with an intermediate compound of Formula Ilia to give a compound of Formula Ifs ,2 (2) hydrolyzing If in acidic media to provide a compound of Formula Jgy and '> -O^ 1 n~\ 2>r\J X--' N 21 (3) reducing the compound of Formula Ig with sodium borohvdride to give the product le, le The intermediate compounds of Formulae XI or IV 5 are adequately described in the above-cited patent references and references therein? as well as several Formula IX compounds being commercially available- The bicyclic pyridinylpiper&aine intermediate compounds of Formula IIIj. as &ell as the starting bicyclic heterocycles 10 (v) themselves, are either commerieally availablef found in the chemical literature, or described herein. Methods used for the synthesis of Formula III intermediates are illustrated in Scheme I„ S8 Schasne 1 Synthesis of the Bicyclic Intermediates III.

R l' \x X ffl2(OD2H) piperidine catalvst: CKO pyridine solvent ' 90° jj ' V "pf f R" X' • i SOC1, £>MF„ CHC1 3 diphenyl ether 240 mil . R H-K - R 20 hrs. In 120° bomb ic I gs In Scheme le synthesis of the ffuro-c, pyrrolo-0 cyclcpentadiano-f or th i e n o-pyr i d ine ring systems is accomplished starting with a carboxaldehyde intermediate of Formula X. The 2-carboxaldehyde intermediate is shown in Scheme 1 and ultimately gives rise to the intermediate JIlc as shown in Scheme If the 3-earboxaldehyde intermediate X® is used in Scheme I, phe resultant product is the. "reverse8' isomer IJIeu» 2 a (Xs) ClIIc") Generic structure III (wherein J-H) of the unitary process„ supra- generally depicts the structures of both intermediate XIIc 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 on© skilled in the chemical arts. Condensation of intermediate X with malonie 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 decarboxylations yields the corresponding acrylic acid intermediates of structure IX. 30 Chlorinetion of the Formula IX acids with t'hionyl chloride -in chloroform and a catalytic amount of dimethylformaraide affords the acid chloride derivatives of structure VI11, which are r.ct purified but may be used in crude form in the 5 preparation of the acid asides of Formula VII„ These acid azides are prepared either in a biphasic mixture of acetone in water at 5° through the agency of sodium azides or with trimethylsilylazide in refluxing benzene. Unpurified• preparations of the acid abides of Formula VII in methylene 10 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 cyclise to the rased 6-5 bicyclic intermediates of Formula VI. Chlorination of VI is achieved using 15 phosphorous oxychloride or a phosphorus pentachloride-phosphorus oxychloride mixture to generate the chloro. substituted heterocyclic of Formula V. Reaction of ¥ with an excess of an appropriate piperazine in a bomb at 120-1<40°C for varying periods of time affords the desired 20 piperazine Intermediate IIXc. This general synthesis of . intermediates of Formula IIIc has been reported previously (cfs Eloy The following representative examples of chemical intermediates of Formulas V-X illustrate synthesis of the key intermediate IXIce which can be further converted using known reactions as xn the cited patents, into other synthetic intermediates such aa Ilia or Illb„ EXAMPLE 1 N-Methylpyrrole-2-carboaealdehyde (X) A stirred mixture of N-methylpyrrole (10 gP 0„12 mole) in dichloroethane J80 and dims thy 1formamida (11.3 gf 0-15 mole) was treated dropwise at 5° with phosphorus oxychloride (23.6 g, 0«15 mole) which led to an exothermic reaction with formation of a precipitate.

Stirring %?as 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 C3 x 100 mL). The chloroform portions were combined, dried (MgSO^P, filteredr and concentrated in vacuo affording 6.1 g (49%) of a dark oil,, b.p. 87-90° at 22 Torr,„P whose HMR was consistent with the assigned structure. This intermediate was generally used unpurified in the next step of Scheme 1. 33 EXAMPLE 2 3-(2-Thieno)acrylic &eid (IX) A mixture of 2~thiephenecarboxaldehyde (100 g, 0.89 mole) ? naIonic acid (182.5 g, 1.70 mole) ; pyridine 5 (4 46 nL); end piperidina (8.9 mL) was heated at 100° for 12 hours. The reaction solution was then refluxed for 20 minutes and allowed t© cpoli9 thereupon it was poured into v&ter (1000 mL) and the resulting aqueous mixture was * acidified, with Gone. HC1. The resulting off-white preci-X0 pitate was collected by filtration and reerystalliasd from sthanol-water (lslj yielding 109 g (804) of product, sn.p. 145-148°® EXAMPLE 3 3-(2-Thieno)acrylovl Chloride lIVIIH XS A stirred suspension of 3-(2-thieno)acrylic acid (118.9 g, 0,77 mole) and dimethy1formamide (12 raLj in chloroform (600 mL!f was treated dropwise with thionyl chlorid© (110.1 g, 0.13 snole! at room temperature- Th® reaction was then refluxed for 2 hours, cooled and concen-20 trated in vacuo to a brown oil which solidified upon further standing to 131 g (9§t) of a low melting solid, ^?hieh was ' used without further purification.. 3 4 EXAMPLE 4 4-0XO-4,S-dihydrothieno[3,2-dpyridine (VI) A stirred suspension of sodium azide (1686 g, 2.6 mole) in a mixture of p-dioxane (400 mL) and water (400 mL) 5 was treated dropwise with a solution of 3-(2-thiano)acryloyl chloride (223.9 g, 1.3 mole) in dioxane at 5°. The dioxane layer resulting from this biphasie mixture was isolated,, concentrated in vacuoe dissolved in methylene chloride (500 ml.) , dried (MgSG^D , and filtered. This methylene 10 chloride filtrate was added dropwise to refluxing diphenyl-ether (400 mL) in a 3-neek flask equipped with two .air condensers™ The solution was refluxed an additional hour„ cooled, and concentrated in vacuo to a dark syrup which was crystallised in aeetonitrile to afford a brown solid which 15 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-cIpyridine (V) 20 Finely divided 4-03Co-4,5-dihydrothienoI3#2-cJ- pyridine (105.6 g, O.Sf 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 25 (3,000 mL) . The resulting solution was stirred for 30 minutes and extracted with dichloromethane {3 x 400 mL) -The organic portions were combined,, dried CHgSO^I, filtered, and concentrated in vacuo to a solid which was recrystal— 3 5 1ized from acetonitrile (400 mL) affording 101 g (85%) of light yellow solid, sn„p„ 91°„ EXAMPLE 6 4-(l°Piperasinyl)thieno T3,2-c]pyridine (IIIc) A mixture of 4~chlorothier.o [3P2-c]pyridine (22„7 gr 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 coolede 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~l% 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 reerystalligation from ethanol gave the hydrochloride salt as off-white crystals,, m.p. 275-283°.

EXAMPLE 7 Synthesis of 7-(l-Piperaginyl)thieno[2,3~c]pyridine (IIIc8 The synthesis of this compound was accomplished with the same sequence of reactions as used to prepare llIcF except that the starting material (X) is 3-thiophen@« carboxaldehyde, The multiple step preparation of the positional isomer 111cs was complicated, however, in that the Curtius=type rearrangement reaction (Example 4^ gave the desired vT intermediate compound in low yield as the major product of this reaction was a syra-triazine by-product which resulted from trimerisation of the isocyanate intermediate„ 3 6 Nonethelesse application of the reactions outlined in Scheme 1 resulted in production of the IIIc* products, which was a brown gum and was used without further purification.

Bv appropriate modification of the Scheme 1 reaction sequence and the various synthetic reactions exemplified above? additional IIIc compounds may be synthesized„ Some additional representative IIIc compounds are sho°©?n in Table 3. 37 Table 3 Additional Formula IIIc Compounds Example R1 IT X ' Y ' m.p. ?°Cl 8 B H CH H-CH- 3 5 9 H H CH O >250 10 e H CH CH2 11 H B N-CH3 CH 12 B B O CH 1 -a r?? n ch «5 A A A* M 3 14 H CH, CH N-CH- J 3 15 CH3 OCH3 CH 0 IS H SCH. CH B 203-205 J (.HCl.Bo0) 10 15 17 CH3 CI O CH 18 H Br S CH 19 H OH CH CH, 20 B C,Br CH S 2 5 21 EES CB 22 'B SCB„ CH S 33 Synthesis of Formula 1 Compounds EXAMPLE 23 General Synthesis Synthesis of the product compounds of Formula I 5 was accomplished by alkyiation of appropriate halo-substituted imide derivatives (lie), where D is (ae-d8) and E is 8?-(CH^J^-0 with Q being halide? or the fluorophenyl-butyrophenone derivative (IId$ with an appropriate IIIc intermediate compound in reflating &eetonitril@t» with three 10 equivalents of potassium carbonate present. The carbinol derivatives ware generated by sodium borohydride reduction of the corresponding butvrophenone. Reaction times for the alkyiation varied from 5 to 72 hours and the resulting products were usually subjected to flash chromatography in 15 an ethanol-chloroform mixture for purification,. The Formula I products were usually formulated as the hydrochloride salt for testing.

EIM4PLE 24 4,4-Dimethyl-1~[4 - [ 4 (thien© f3,2-c]pyridin-4-yl)- 20 l-piperaasinyl] butyl] -2,6-piperidinedione A mixture of 4-(l-piperazinylJthieno(3#2-c]- pyridine {Ixlcy 2„79 g, 0*012 mole'J , N-4-bromobutyl5-3-dimethylgiutarimide (3-3 g, 0„, 012 mole) and potassium carbonate (3.3 gf> 0„024 mole) was refluxed in acetonitrile 25 (150 mL) for 24 hour* The reaction mixture was- filteredr concentrated in vacuo and partitioned between dichloro-methane and water. The organic layer was isolated, dried (MgSOj) and concentrated in vacuo to a gold oil which was 3 9 flash chromatographed (5% ethanol^chloroform) . The chromatography material was dissolved in acetonitrile and treated with ethanolic HCl to yield 1„3 g (24% yield) of the hydrochloride salt4, m9p. 195-197°,, Anal. Calcd. for C^H^N^C^S-HCl: C, 58„59; H, 6.93? N, 12 „ 42„ Found". Cf 58„64y H, 7„02? N , 12.72.

PMR (DMSO-dg) : 1.08 (6,s); 1.71 (4,m); 2.60 (4,s); 3 o 40 (10,m); 4.00 (2,m) ; 7.65 (2,m); 7.87 IR (KBr!: 715, 965, 1425, 1535, 1670, 1720, 2580, 2960 cm"1.

EXAMPLE 25 4- [4- [4- (4-Furo [3 ,2-cJpyridinyl) - l~piperazinyl]butyl]-3 , S-morpholinedione A mixture of 4~(1-piperaz iny1)furo[3,2-c]pyridine (4.5 g, 0.022 molej 4- (4-broraobutyl) ~3,5~morphelinedione (5.5 g, 0.022 moleI, and potassium carbonate (9,1 g, 0.066 mole) was refluxed in acetonitrile for 24 hour. The reaction mixture filtered„ concentrated in vacuo, and partitioned beteen dichloromethane and water. The 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 crystallised from isopropanol yielding 6.2 g (69%! of the free base,, m.p. 109-110°.

Anal. Calcd. for C, : C, 61.28; H, 6.50,? J. Sr A *3 "SI », 15.04. Found: C, 60.98? H, 6.60; N, 15.19. 40 PF-R (CDClg) s 1*60 (4,m); 2.40 (2f,m); 2.57 (4rn); 3.74 (6,m); 4.31 (4,s); '6.78 (l,d [2.0 Hz])y 6.89 (lPd [5.8 Hz]); 7.49 (l,a [2.0 Hz]); 8.01 (l,d [5.8 Hz]).

IR (KBr): 750, 780, 1250, 1285, 1440, 1460, 1570tf 5 1595, 1690, 1735j, 2830 cm"1. 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 10 of additional representative Formula I products. TabIs 6 contains in vivo biological data for representative compounds of Formula I. 41 Taaie 4 Formula I Products X R 1 y Z-ICHJ -N N- 2n \_/ ^ Ex. No„ 25 00 27 Ce) n R1 H2 x Y Formula®* h ce s H MOO 1 *!2,4U2U2" CH S C21H24F^3OS in.p. C—C) 180-182 115-118 28 29 (b) $ v.! 0 (a) :22H,?BrM4O^S2„HCl 203-205 B Br CH S 216-219 reci; o.5 h«,o 30 (b) CH3 CH S C--H 4°2S2 195-197 .0 r~\ 0 (c) CH S C.qH,^H40„S^ 186-188 :i„iC7h863s.o.5h2o 4 2 S f 0 Ut~9lt SSO&M0eHSc3 0 HD (q) 0 Of? OT IQZ-502 Z0€!U*cH^23 • 0 {a) 6£ QSZ« "• T 81 eoW*D 0 HD H 0N se gc;y=.rcg Cp a) W fi) fvi w a z THEJT' ■ S 0 H H 3 0 H3 H E f (<0 4C ' OH B'l'ipHZl EEI-0e"S &St0l'MBCEfe6D HD OH S"0* LZZ~9ZZ T3H° t8f% P o. (<0 B ft A o*X> (p) °v \\ 9E ft (P) 0E2-622 TDH* ZSC0*M*ZHZcD S HD zz (D0) *a-"ui (« sqnui-xoj A 3C _H « •oa p^nux^uoD - .Br 0|qaj Table 4 - Continued Ex No. z n H1 B2 X * Forimalaa' m.g>„ (°) 41 v/~~* K CH3 CH 0 C2|H||^°g 5H 0 321-233 =,iv (e) /"Y 42 4 H .S CH D C.^.K.O^S 245-250 flnei J Je.o (c) 2 . 43 |e) 3 3 CH3 CH 0 C^HygFl^Og • 121-122 4 3 B CH S CipH24M4°3S 114-115 (c) 0 .1»1C7H803S„0.5H20 <5 o (a) 0 4 H 1 CS S C2iH28M4°2S 173-175 .HCl 46 ^3" 4 H H CH S ' C™H'«H*0'S 199-201 (a) 20 26 4 2" .HCl O-^ 47 [^„v 4 H S CB NMe C^H^N^S^HCl 148-150 4 4 Table 4 - Continued Ex. n E1 R™ X Y Formula^ m.p„ (°) J> 4B 6 V 4 H H CH NHe C20H27N5°3 144-146 .2.3HC1.0.9H20 (c) 5 49 4 B B CH KMe C,,H,,N-0, 192-194 ^a.IHCI 2.6H20 C, Hr and N elemental analyses were all with +0.4% of theoretical valises for the formulae given. N>) 57 A r 4 H SCH3 CH 4 7 Table 6 Peor esentati vs In Vi vo Biological Data (mg/kq,p,e.) Example Number CAR —50 APO -—50 Catalepsy Induction ED„fi Catalepsy Reversal EDP„ D U _ so 5 24 • 6 40 >24 ,. a) 25 11 A Sa 34 ' >46 2 26 12 35 _ 1A 27 10 9 >40 1A 28 >100 >100 b) 1 £ <£» U 10 ' 29 _ 1A 30 35 _ >142 1A 31 32 _ >128 1A 36 43 ' 47 - 1A 37 o 18 23 1A 15 38 4 "9 / 13 1A 39 3 5 11 40 28 41 sTf as, « - 41 14 ">'5 »-» am 40 1 IK 42 3t> 63 20 43 ■51} _ - K 47 60 100 >100 1A 49 67 >100 _ 1A a) 1A means inactive and is used if the EDrQ 25 is >20 mg/kg. 0 b) - means that data not available.

Claims (1)

1. CLAIMS; 1. A compound of Formula I or a pharmaceutical ly acceptable acid addition salt thereof ,2 wherein 2 a Z is selected from among the following radicalss R3 V^S A-/' (a) 0 ^ as where R and R&J are independently chosen from hydrogen, lower alkyl or may be taken together as a C^-Cg alkylene chain? R6 R5 i (b) -C y_ '0 5 £ in which R and R are independently chosen from hydrogen t, lower alkyl, and A-substituted phenyl with A being hydrogen or halogen, or H S R and E are taken together as a butylan® chain, and W can be S or CH,; 4 B 0 ws- (c) w 0 in which V is O or S; -H0C/- (d> in which G is selected from hydrogenP lower alkyl, lo«er aIkoasy„ or halogen, in is the integer 1-4, and u is C=0 or SO^? and ~©-s OH CH™ (a) is the integer 2-4 with the proviso that ferhen % is 's) , n is is independently selected from CH,, 0(, S, or 7 MR with the proviso that the other X or Y must always be =CH-; are independently selected from hydrogen or lower alkyl? and is selected from hydrogen„ lower alkyl, lower alkoseVf lower alkylthios, halogen, and hydroxy1. 5 0 2. The compound of claim 1 wherein Z is the radical (a) . 3„ The compound of claim 1 wherein Z is the radical (b). 4. The compound of claim 1 therein Z is the radical (c)_ 5„ The compound of claim 1 wherein % is the radical (d)„ S„ The compound of claim 1 wherein Z is the radical (e). 7„ The compound of claim 1 wherein Y is aa oxygen atom* 8- The compound of.claim 1 wherein Y is a sulfur atom™ 5 g 9. The compound of claim 3 wherein K and R are taken together as a butylene chain and W is sulfur. 10. The compound of claim 4 wherein v is an oxygen atom. 11. The compound of claim 7 wherein 2 is the radical fa!„ Ce} or (e!. 12, The compound of claim 8 wherein Z is the radical (a)„ (b), or (e). 13. The compound of claim 2> 1-[4-[4-(furo-[ 3, 2-c]pyridin-4-yl) -l-piperasinyl] butyl] -4 ,4-dimethy 1-21.6-piperidinedione. 14- The compound of claim 2f 4,4-dimethyl-l-[4- [4-(2-methylfuro[3e.2-ejpyridin -4=yl) -1-piperasinylJbtatyX]-2,6-piperidinedione. 15- The compound of claim 2L, 4, 4-dimethyl-l- [4-[4 (thieno [3? 2~c*jpyridin-4~yl) -l-piperazinyljbratylJ-2,6-piperidinedione- 16- The compound of claim 2, 4f4-dimethyl-l-[4-[4 (1-methyl-lH-pyrrolo f3,2-c]pyridin-4-ylJ-1-piperazinyl]- butyl]-2 £J 6-piper idinedione™ 17. The compound of claim 2, 4,4-dimethyl-l-[4-[4 (2-bromothieno[3„2-e]pyridin-4-ylJ-1-piperazinyl]butyl]-2»6 piperidinedione. 18. The compound of claim 2, 1-[4-[4™(thieno- C 3 f, 2-c ] pyridir* -4-yl) -l-piperas iny 1 ] butyl ] 1 „ 6-piper idinedione 19. The compound of claim 2t, 4-methyl-l- [4- [ 4« (thieno[3 P2-c]pyridin-4-yl)-l-piperasinyl]butyl]-1,6-piperidinedione„ 20. The compound of claim 3f 3-[4-[4-(furo[3,2-c]-pyridin-4-yl) -1-pipera^inyl] butyl] ~l«~thia=-3«asaspiro [4.4] -nonans-2,4-dione. 21. The compound of claim 3, 3- [4- [4- (2-methyl-furo[312-e]pyridin-4-yl!-X-piperasinyl]butyl]«l-thia-3-aaa» spiro[4.4]nonane-2,4-dione. 22. The compound of claim 3, 3-[4-[4-(thieno- [3 f2-c]pyridin-4-yl)~l~piperasinyl]butyl]-l~thia-3-azaspiro~ (4.4]nonane-2f4-dione. 23. The compound of claim 3„ 3-[4-14-(1-methyl-pyrjfoloC3e,2»c]pyridin-4~yl) -l-piperazinyllbutylJ-l~thia-3-asaspiro [4.4 J nonan-2,4~dione ... 24. The compound of claisa 3, 3- [4- [4- (2-bromo-thieno[3 ff2-c]pyridin-4-yl)-l~piperazinyl]butyl]-l-thia~3- azaspiro[4.4]nonane-2,4-diona. 25. The compound of claim 3* 3~[4-[4-(2-methyl-thienoC 3,2-c1pyr idin-4-y1!-i-piperas inyl]butyl]-l-thia-3-aaaspiro[4.4]nonane-2,4-dione„ 26 . The compound of claim 1e 3~[4-[4-(thieno-[ 2 , 3~e]pyridin=7-yX) -1-piperazinyl] butyl] -1-thia-3-azaspiro-[4.4]nonane-2,4-dione. 27. The compound of claim 4, 4-[4- [4- (4-furo- 5 [3 f 2-c] pyridinyi) -l-pipe'razinyl ] butyl] -3, S-morpholinedione* 28. The compound of claim 4e 4- f4~ [4-(1-methyl-lH-pyrrolo[3 p 2-c]pyridin-4-yl)-1-piperazinyl]butyl]3,5-morpho-linedione. 29. The compound of claim 4, 4~{4-[4-(4-thieno-10 13#2-c]pyridinyi)-1-piperazinyl)butylJ-3,5-thiomorpholine- cSione. 30. The compound of claim 4, 4-[4-[4-(4-thieno-|3,2-c]pyridinyi)-1-piperazinyl]butyl]-3,5-morpholinedione. 31. The compound of claim 5# 2-[4-(4-(thieno- 15 13,2-c] pyridin-4-yl)-l.-piperazinyl]bu.tyl] -lH-isoindole-1 „ 3-(2H)-dione. 32. The compound of claim 5, 2-[4-[4-(thiene-• [3,2-c]pyridin~4-yl)-l-piperazinyl]butyl]-l,2-benz- isothia;zel~3 (2H) -on© 1 , 1-dioxide. 2o 33. The compound of claim 6„ o-(4-fluorophenyl)- 4- (fur© {3,2-c]pyridin-4-yl) -1-piperazinebutanol. 54 34. The compound of claim 6, o—<4—fluoropheaylj-4~ {2-methyl£uro (3„2-c]pyridin—4-yl) -l-piparaEinebut&nol. 35. The compound of claim 6, c-(4-fluorophenyl)-4-(thieno[3e%~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 35 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 a2 i I 2-[CH23^~!? N \_y -© or a pharmaceutically acceptable acid addition salt thereof wherein Z is selected from among the following radicals s « 0 R It X-/ a v> j- (©) o where R and R" are independently chosen from hydrogen E, lower alkyl or may b