GB2139217A - Antipsychotic 5-fluoro-pyrimidin-2-yl piperazine compound - Google Patents

Antipsychotic 5-fluoro-pyrimidin-2-yl piperazine compound Download PDF

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GB2139217A
GB2139217A GB08403102A GB8403102A GB2139217A GB 2139217 A GB2139217 A GB 2139217A GB 08403102 A GB08403102 A GB 08403102A GB 8403102 A GB8403102 A GB 8403102A GB 2139217 A GB2139217 A GB 2139217A
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Davis L Temple
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Bristol Myers Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/20—Spiro-condensed ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/56—One oxygen atom and one sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

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Abstract

8- [4-[-(5-Fluoro-pyrimidin-2-yl)-1-piperazinyl]butyl] -8-azaspiro[4.5]decane-7,9-dione and its pharmaceutically acceptable salts demonstrate antipsychotic activity. Methods of preparation of this compound are also given.

Description

SPECIFICATION Antipsychotic 5 - fluoro - pyrimidin - 2 - yl piperazine compound This invention involves drug, bio-affecting, and body-treating compositions and methods employing a heterocyclic organic compound ofthe pyrimidine series as active ingredient.
Related art may be viewed in light ofthe following strncturaiformula (1):
in which n is 4or 5 andW and Yare different, one being CH and the other being N; R1 and R2 are independently selected from a group ofsubstituents consisting of, among other moieties, hydrogen and halogen.
Wu, et al., discloses tranquilizing compounds of this structural type in J. Med Chem.,15/5,477479 (1972) and in U.S. Patent No.3,717,634 patented Feb.
20,1973. Additionally, three 5-substituted pyrimidinyl derivatives were disclosed. These correspond to the above structural formula wherein W is N and Y is C-NO2, C-NHSO2C4Hg and C-OH. No 5 - halogenopyrimidines were specificallydisclosed orclaimed.
Thefollowing group of references represent re- lated but less pertinent art.
Wu, etal., U.S. Patent No. 3,907,801, issued Sept.
23,1975, is a divisional oftheabovecited '634Wu patent. U.S. 3,907,801 claimsthe pyridinyl compound subject matter te.g. W andYare both CH}.
Wu, et al., U.S. Patent No.3,976,776, issued Aug.
24,1976, is also a divisionalwhich claimsthe use of these compounds inatranquilizing process.
Casten, etal., U.S. Patent No.4,182,763, issued Jan.
8,1980, discloses ancf clairnsthe use of buspirone (2), a specific compound ofthe above series, fortreating anxiety.
Wu, U.S. Patent No. 3,398,151, issuedAug. 20, 1968, discloses and claims related compounds wherein the pyrimidine ring has been replaced by a phenyl moiety,,unsubstituted or substituted (e.g., halogen).
Wu, eta!., JournaiMedidna! Chemistry, 1214, 876-881 (1969) also reports work done with these phenyl analogs. No fluoro substituted phenyl derivatives are listed as examples or in any ofthe tables.
Finally, attention is calledto pending application 06/334, 688 filed December 28,1981. This application discloses and claims a series of 1 - [4(4,4- dialkyl - 2, 6 - piperidinedion - 1 - yl)butyl]piperazineswith 2 pyrimidinyl substituents in the 4- position which demonstrate useful anxiolytic properties. The pyrimidine ring in this series of compounds may either be unsubstituted or monosubstituted bearing a fluoro, chloro, hydroxyl, ortrifluoromethyl substituent.
The present invention involves the discovery that the previously unsynthesized compound 8 - 14 - [4 - 85 -fluoro- pyrimidin -2-yl) - 1 - piperazinyllbutyll -8 - azaspiro[4.5]decane - 7,9 - - dione possesses long acting antipsychotic activity. This pharmacological activity sets the instant invention apartfrom related pyrimidinyl compounds of the above references.
These reference compounds mainly act as anxiolytics, with only minor antipsychotic action and that of short duration.
8-[4-[4-(5-Fluoro- pyrimidin-2-yl)-l- piperazinyllbutyl] - 8 - azaspiro[4.5]decane - 7,9 dione (I), hereinafter referred to as MJ 14594, and its pharmaceutically acceptable salts have been demonstrated to possess useful a ntipsychoticactivity with a good duration of action. This compound has the following structural formula:
A unitary process comprehending several method embodiments (A, B and C) may be employed for preparation ofthe Formula I compound, MJ 14594.
Variations of the methods to produce the same compounds in somewhatdifferentfashion will be evidentto one skilled in the art. Examples will be given for specific illustration ofthe preferred embodiment.
Unitary Process
In the above scheme, the symbol "W" can be
The symbol "Y" can be H2N - (CH2)4-; X -(CH2)4 - (OH2)4-;
or H -. The relationship between Wand Y Is: Formulae in the printed specification were reproduced from drawings submitted afterthe date of filing, in accordance with Rule 20(14) of the Patents Rules 1982.
ISethod lSo. C when W i5: IP (IIa) 9 (IIb) jU-(C112)4-X (IIe) then Y is: | H2N-(CE2)4- X-(C112)4or g h (IIIc) (IIIa) (IIb) (I1Ib') The symbol "X" refers to a suitable displacement group such as chloride, bromide, iodide, sulfate, phosphate, tosylate, ormesylate. In practice, in termediate compound Illb readily converts to Illb', the only species which can be isolated. For use as intermediates, the two compounds are equivalent.
MethodA
Method B
Method
The condensation process in Method A is carried out by refluxing the reactants in a dry, inert reaction medium such as pyridine or xylene. For Methods B and Cthe process is carried out under reaction conditions suitableforthe preparation of tertiary amines by alkylation of secondary amines. The reactants are heated in a suitable organic liquid at temperatures of about 60"C to about 150 C in the presence ofan acid binding agent. Benzene, dimethylformamide, ethanol, acetonitrile, toluene, and n - butyl alcohol are preferred examples ofthe 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 alkyleneearth metal carbonates, bicarbonates, or hydrides, and the terti- ary amines. Allthree methods have been adequately described byWu, etalin the cited patents and articles listed above and these are hereby incorporated in entirety by reference.
As an example of a method variation to producethe same compounds somewhat differently, an N substituted [4- (1 - piperazinyl) - butyl]azaspirode- canedione (V) can be reacted with an appropriate pyrimidine system to yield the product of Formula I, e.g.
From this variation is derived the currently preferred method, described hereinafter, for preparation of I.
The intermediate spiro glutaric acid anhydrides or imides of Formula II are either commercially available, found in the above references, or described herein.
Pyrimidinylpiperazine intermediates (III) are described in the aforementioned Wu, petal patents and certain references cited therein. Although these procedures are applicable to the preparation of 5 fluoropyrimidinyl piperazine intermediates not specifically disclosed therein butwhich are required as intermediates for the present invention, a representative synthesis of Illc is given as a working example for further exemplification. Intermediates Illa and Illb are readilyobtainablefrom lllc using the standard methods shown byWu, etal.
Model Synthesis of (Ilic)
This synthetic scheme begins with 5 - fluorouracil and proceeds by known reactions to the desired piperazine intermediate. Although the route via carbethoxypiperazine is more involved, the higher yield of Illcwithout by-products makes it somewhat superior.
In practice, itwasfound preferableto prepare Ifrom IV and V as shown in the following scheme.
The distinguishing psychotropic profile displayed by NJ 14594 was determined by results of the following screening tests. MJ 14594 is approximately three times more potentthan buspirone in the conditioned avoidance response test according to method described in the Wu, etal patents and publications, supra.
This test method utilizes orally treated fasted rats and generally reflects tranquilizing activity of a compound without necessarily differentiating anx iolytic from antipsychotic compounds. Of even grea- ter interest was the finding that MJ 14594, given at 35 mglkg p.o. had an approximatelythree-fold increase in duration compared with buspirone given at 100 mg/kg, p.o.
A more definitive test for anti psychotic efficacy is the apomorphine stereotype behaviourtest in non- fasted rats. This test determines the ability of centrally active compounds to blockapomorphine induced stereotyped behavior. This preclinical test is a useful indicator of potential anti psychotic efficacy (Janssen, etaj,Arzneimittel-Forsch., 17:841(1966)).
While MJ 14594 was roughlyequipotentwith buspirone in this reversal of apormorphine stereotopy test, its activity was maintained for over 6 hours versus a 1 to 2 hour duration for buspirone in this test.
Anti psychotic drugs are believed to control the symptomatoiogy of psychosis by acting as post synapticdopamine receptorantagonists. Sincethe stereotopy reversal test is reflective of dopamine antiagonist activity, comparison of duration of action forth two drugsindicatesthattheantagonist component (anti psychotic action) of MJ 14594 perseveres while that of buspirone is rapidly diminished.
Additional supportfor classifying MJ 14594 as an anti-psychotic agent is obtained from radioreceptor binding studies. Radioreceptor binding assays which measure the inhibition of binding of various neuro nallyactive molecules are used to more specifically definetranquilizing activity. Although MJ 14594 has only 10-20% of the binding affinity of buspirone for dopaminergic receptors, it appears to be much more antagonist-like in nature. The binding affinity of buspirone at [H3]spiperone - labeled receptors decreases in the presence of SuM guanine triphosphate (GTP) whilethat of MJ 14594 is essentially unchanged. Such a GTP-induced shift in binding indi catesagonistactivitywhereasthe lack of a shift is associated with antagonist action.Additional background associated with dopamine receptor binding assays and their reflections of antipsychotic activity may be found in the following references: Burt, Creese, and Snyder, Molecular Pharmacology, 12:800(1976); Burt, Creese, and Snyder, Science, 196:326(1977); Creese, Burt, and Snyder, Science, 192:481 (1976); Creese, Prosser, and Snyder, Life Science, 23:495(1978); Creese and Snyder, European Journal of Pharmacology, 50:459(1978); Creese, Usdin, and Snyder, Nature, 278:577(1979).
Testing of MJ 14594 in the ratVogel model, an anxiolytic behavioural paradigm, demonstrates that the compound lacks activity at doses below 5 mg/kb whereas buspirone is active at a level of 1.0 mg/kg in this anxiolytic screening test. The ratvogel model is a modification of the Vogel Conflicttestwhich is a reliable conflict procedure for testing antianxiety agents (Vogel, Beer, and Clody, Psychopharmacolo gia(Berl.)21, 1-7(1971)).
Additional data have been obtained from compara tivetesting in other CNS screening methods. MJ 14594 exhibits no catalepsy at doses up to 70 mg/kg (higher dose levels cause toxicity) but unlike buspir one does not reversetrifluoperazine - induced catelepsy. Tested against standard anti psychotic agents in a recently developed monkey model (model described in Kavacic, Domino, J. Clin. Psychophar macol, 2:305-307,1982), MJ 14594 appeared to lack the potential for development of clinical side effects, such as extrapyramidal symptoms. Accordingly, MJ 14594 would offer a significanttherapeutic advantage over most other established antipsychotic agents. MJ 14594 displays a cat cortical electroencephalogram pattern similarto but indicative of greater potency than buspirone.
In summary,the in vivo potency, long duration of action and antagonist-like binding profile of MJ 14594 clearly showthatthe pharmacological activity ofthis antipsychoticcompound differs from buspirone and related compounds.
According to the pharmacological profile estab lished bythe aforementioned tests, this compound of Formula (I) has promising potential as an antipsycho tic agent. Thus, another aspect of the instant inven tion concerns a process for ameliorating a psychotic state in a mammal in need of such treatment which comprises systemic administration to said mammal of an effective dose of about 0.01 to 40 mg/kg body weight of a formula (I) compound or a pharmaceuti cally acceptable acid addition salt thereof.
The term systemic administration as used herein refersto oral, rectal, and parenteral (i.e., intramuscu lar, intravenous, and subcutaneous) routes. General ly, itwill befoundthatwhenthe compoundofthe present invention is administered orally, which is the preferred route, a larger quantity oftheactive agent is required to produce the same effect as a smaller quantity given parenterally. In accordance with good clinical practice, it is preferred to administerthe instant compound ata concentratfon level thatwill praduce effective anti psychotic effects without cauls ing any harmful or untoward side effects.
Therapeutically, the instant compound can-be generally given as pharmaceutical compositibrw comprised of an effective antipsychotic a mounf of MS 14594 ora pharmaceutically acceptable acid addition saltthereofand a pharmaceutically acceptable ca-rw rier. Pharmaceutical compositions which providefrom about 1 to 500 mg ofthe active ingredient per unit dose are preferred and are conventionally prepared astablets, lozenges, capsules, powders, aqueous or oily suspensions, syrups, elixirs and aqueous solutions.
Preferred oral compositions are in the form of tablets or capsu les and may contain conventional excipients such as binding agents (e.g. syrup, acacia, gelatin, sorbitol, tragecanth, or polyvinyl pyrrolidone), fillers (e.g. lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine), lubricants (e.g.
magnesium stearate, talc, polyethyleneglycol or sili- ca), disintegrants (e.g. starch), and wetting agents (e.g. sodium lauryl sulfate). Solutions or suspension of MJ 14594 with conventional pharmaceutical vehicles may be 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 0.1 % to 10% by weight of the active compound in water or a vehicle consisting of a polyhydric aliphatic alcohol such as glycerine, propyleneglycol, and polyethyleneglycols or mixtures thereof. The polyethyleneglycols consist of a mixture of non-volatile, normally liquid, polyethyleneglycols which aresoluble in bothwaterand organic liquids and which have molecularweightsfrom about200lo 1500.
The compounds which constitute this invention and their methods of preparation will appear morefullyfrom a consideration ofthefollowing examples which are given for the purpose of illustration only and are notto be construed as limiting the invention in sphere or scope. All temperatures are understood to be in "C when not specified.
The nuclear magnetic resonance (NMR) spectral characteristics referto chemical shifts (o) expressed as parts per million (ppm) versustetramethylsilane (TMS) as reference standard. The relative area reportedforthevariousshiftsinthe proton NMR spectral data corresponds to the number of hydrogen atoms of a particularfunctional type in the molecule.
The nature ofthe shifts as to multiplicity is reported as broad singlet (bs), singlet(s), multiplet (m), or doublet (d). Abbreviations employed are DMSO-d6 (deuter odimethylsulfoxide), CDCI3 (deuterochloroform), and are otherwise conventional. The infrared (IR) spectral descriptions include only absorption wave numbers (cm~1) having functional group identification value.
The IR determinations were employed using potassium bromide (KBr) as diluant. The elemental analyses are reported as percent by weight.
Synthesis of Intermediates EXAMPLE 1 2 - Chloro - 5 - fluoro - 4 - methylthiopyrimidin - 2 - one (IVJ 5- Fluoro -4- thiouracil.-A mixture of 5 fluorouracil (26g,0.12 mole) and phosphorus pentasulfide (45 g, 0.2 mole) in 500 mL dioxane was heated under refluxfor 3 hr. The hot reaction mixture was filtered and concentrated in vacuo. The residue was dissolved in 650 mLwater, heated with 5 g charcoal and filtered. The solid which crystallized on cooling was collected by filtration to yield 25.4 9 (88%) of 5 fluoro - 4 - thiou racil, m.p.269-272 C.
5 - Fluoro - 4 - methylthiopyrimidin - 2 - one.- To a solution of -fluoro - 4 -thiouracil (25.49, 0.174 mole) in 350 mL 0.15N NaOH was added dropwise methyl iodide (59.4 g, 0.348 mole). The mixture was stirred at room temperaturefor 2 hr, cooled in ice and filtered.
The collected solid was triturated with hot methanol to afford 18.5 g (66%) ofthe product, m.p.205-207)C.
A mixture of 5 - fluoro - 4 - methylthiopyrimidin - 2 one (21.1 g, 0.132 mole) phosphorusoxychloride (126.4 9,0.824 mole) and N, N -dimethylaniline (27.0 g, 0.224 mole) was heated at refluxfor 2 hr. The mixture was cooled in ice bath while ice was added to the reaction mixturefollowed by extraction with ether.Theetheroxtractwasdried (MgSO4) and evaporated to a residue which was taken up in two 100 mL portions of hot Skelly B. The Skelly B supernatantwas decanted from insoluble material, treated with charcoal, filtered and concentrated to provide 20.8 9 (88%) of IV.
EXAMPLE 2 8 - [4 - (Piperazinyl)butyl]-8-azaspiro[4.5]decane -7, 9- dione (V) A mixture of 3,3 -tetramethyleneglutarimide (50.2 g, 0.3 mole), 1,4 - dibromobutane (130 g, 0.6 mole) and anhydrous K2CO3 (06.7 9, 0.7 mole) in 500 mL toluene was heated at refluxfor20 hr, filtered and concentrated in vacuo.The residue was distil led (165-170 C/0.01 mM)to give 64.1 g of8- [4- (1 bromo)butylj .8.azaspiro[4.Sjdecane-7,9-dione which was combined with piperazine (90.4 g, 1.05 mole) and K2CO3 (145.5 9, 1.05 mole) in 900 mL toluene and heated at refluxfor 18 hr, filtered and concentrated in vacuo. The residue was distilled (180-200 C/0.01 mM) to yield 52.7 g (82% ) of V.
EXAMPLE 3 8 - [4 - [4 - (5-F!uoro-2-pyrimidinyl)- 1 - piperazinelbuty!] - 8 - azaspiro 4.5 decane - 7, 9 - dione Hydrated (I, MJ 14594-3) A mixture of IV (4.47 g, 0.025 mole), V (7.7 g, 0.025 mole), K2CO3(10.37 g, 0.07 mole) and KI (catalytic amount) in 100 mL acetonitrile was heated at reflux for 18 hr. The mixture was filtered, concentrated in vacuo and the residue chromatographed on 230 g silica gel using 2% ethanol - chloroform as eluant.
Solvent removal gave 9.0 g (80%) of 8 - [4 - [4 - [5 fluoro-4-(methylthio)-2-pyrimidinyl]-1 piperazinylibutyl] - 8 - azaspiro[4.5]decane -7,9 dione.
A 3.5 g portion (0.008 mole) and moist Raney Nickel catalyst (1.5tsp.) in 70 mL ethanol was heated at refluxfor3 hr, filtered and the solvent evaporated.
The residue was heated in acetonitrile, filtered and concentrated in vacuo. This residuewasthen heated on a steam bath with Skew liy B, the supernatant decanted from insoluble material and cooled to afford 1.8g (59%) of I in hydrated form, m.p. 83-85 C.
Anal. Calcd. for C21 H30FN502-0.1 H2O: C, 62.23; H, 7.51; N, 17.28. Found: C, 62.17; H, 7.46; N, 16.88.
EXAMPLE 4 The Hydrochloride Salt of MJ 14594 The hydrochloride salt of I was obtained following a modification of the above procedure in which 8 - [4 [4- [5-fluoro-4- (methylthio)-2-pyrimidinyl]-1- piperazinylibutyll - 8 - azaspiro[4.5]decane - 7,9 dione (9.0 g, 0.02 mole) and Raney Nickel (10-15 g) in 200 mL ethanol was heated at reflux 6 hr, filtered and concentrated. Water (50 mL) was added, the mixture basified with 50% NaOH and extracted with ether.
The dried (MgSO4) extract was evaporated, the residue dissolved in 20 mL ethanol and treated with 2.15 mL7N ethanolic HCI to give 5.6 (64%) of MJ 14594 hydrochloride, m.p. 224-226 C.
AnaL.Calcd.for C21H30FN5O2.HCl: C, 57.34; H, 7.12; N,15.92.Found:C,57,42; H,7,15;N,15.66.
NMR (DMSO-d6): 1.50(12,m); 2.61(4,s); 3.02 (4,m); 3.50 (4,m); 3.64 (2,t [6.9 Hz]); 4.54 (2,m); 8.51 (2,s); 11.70 (1,bs).
IR (KBr): 790,11 10,1250,1350,1490,1560, 1670, 1750,2600,2935 and 2950 cm".

Claims (14)

1. The compound 8 - [4- [4-(5 -fluoro - 2 pyrimidinyl) - 1 - piperazinelbutyl] - azaspiro[4.5]decane - 7,9 - dione, and pharmaceutically acceptable acid addition salts thereof.
2. Aprocessforeliciting an antipsychotic effect in a psychotic mammal comprising administering to said mammal a non-toxic but effective anti psychotic dose of the compound of Claim 1 or of a pharmaceutically acceptable acid addition salt thereof.
3. A process according to Claim 2, wherein said dose is a dose within the rangefrom about 0.01 to about40 mg of the compound of Formula (I)orofa pharmaceutically acceptable acid addition saltthere- of per kg body weight of said mammal.
4. A pharmaceutical composition in unit dosage form suitable for systemic administration comprising a pharmaceutical carrier and an amountoftho compound of Formula (I) orofa pharmaceutically acceptable acid addition saltthereof which is non toxic but which is sufficient to provide an effective antipsychotic dose.
5. Acomposition according to Claim 4, wherein said dose is a dose within the range from about 0.01 to about 40 mg ofthe compound of Formula (I) or of a pharmaceutically acceptable acid addition salt there of per kg body weight.
6. Aprocessforpreparing the compound of Formula I
or a pharmaceutically acceptable salt thereof, said process comprising contacting (1) contacting a com- pound of Formula II
with a compound of Formula Ill
under reaction conditions suitable so as to form the compound of Formula I, using one of the following alternatives:: (a) Wherein when W is O, then Y is H2N-(CH2)4- and compounds II and Ill react in a condensation process and lose water; (b) WhereinwhenWis NH,
and compounds Il and Ill react under conditions suitable for the preparation of tertiary am ines by alkylation ofsecondaryamines; (c) Wherein when W is N-(CH2)4-C, then Y is H and compounds li and Ill react under conditions suitable for the preparation oftertiary amines by alkylation of secondary amines; and wherein X recited above in (b) and (c) isasuitabledisplacementgroup; (2) and then optionallyformingthesaltoftho compound of Formula I by known methods.
7. A process according to Claim 6, wherein alternative (a) is used and wherein compounds II and Ill are refluxed in a dry, inert reaction medium such as pyridine orxylene.
8. A process according to Claim 6,wherein alternative (b) or (c) is used and wherein compounds II and Ill are heated in a suitable organic liquid at temperature(s) within the range from about 60"C to about 150"C in the presence of an acid binding agent.
9. A process for preparing the compound of Formula I,
said process comprising contacing compound IV
with compound V
under conditions so as to form compound (X)
- compound (X) and thereaftertreating compound (X) with Raney nickel in ethyl alcohol so asto form compound I.
10. A process as claimed in claim 9, substantially as described in the foregoing Example 3.
11. The compound of Formula "(1)" prepared by a process as claimed in claim 6,7,8,9 or 10.
12. A pharmaceutical composition comprising a compound as claimed in claim 1 or 11 and a pharmaceutically acceptable carrier.
13. Acomposition as claimed in claim 12 in unit dosage form, providing 1 to 500 mg of the compound of Formula "(1)" per unit dose.
14. For use in a method of eliciting an anti psychotic effect in a psychotic mammal, a compound or composition as claimed in claim 1,4,5,11, 1 2or 13.
GB08403102A 1983-02-07 1984-02-06 Antipsychotic 5-fluoro-pyrimidin-2-yl piperazine compound Expired GB2139217B (en)

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US5484788A (en) * 1993-03-26 1996-01-16 Beth Israel Hospital Association Buspirone as a systemic immunosuppressant
US5631017A (en) * 1993-03-26 1997-05-20 Beth Israel Deaconess Medical Center, Inc. Topical application of buspirone for treatment of pathological conditions associated with immune responses
US5637314A (en) * 1995-06-07 1997-06-10 Beth Israel Deaconess Medical Center, Inc. Topical and systemic application of buspirone or derivatives thereof for treating atopic dermatitis

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BE759371A (en) * 1969-11-24 1971-05-24 Bristol Myers Co HETEROCYCLICAL AZASPIRODECANEDIONES AND METHODS FOR THEIR PREPARATION
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US5631017A (en) * 1993-03-26 1997-05-20 Beth Israel Deaconess Medical Center, Inc. Topical application of buspirone for treatment of pathological conditions associated with immune responses
US5637314A (en) * 1995-06-07 1997-06-10 Beth Israel Deaconess Medical Center, Inc. Topical and systemic application of buspirone or derivatives thereof for treating atopic dermatitis

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JPH0319233B2 (en) 1991-03-14
GB2139217B (en) 1986-07-09
GB8403102D0 (en) 1984-03-07
DE3404193C2 (en) 1987-06-11
FR2540499A1 (en) 1984-08-10
FR2540499B1 (en) 1986-09-26
JPS59148780A (en) 1984-08-25
DE3404193A1 (en) 1984-08-09
MY8800109A (en) 1988-12-31

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