JPS6334152B2 - - Google Patents

Description

[Detailed description of the invention]

FIELD OF THE INVENTION This invention relates generally to heterocyclic carbon compounds with drug and bioactive properties and methods of use thereof.
In particular, the present invention provides pyrimidin-2-yl in which one substituent is substituted with halogen in the 5-position; the other substituent is 1, 4-Disubstituted piperazine derivatives. The terminal carbon is also attached to an oxygen atom providing a carbonyl, carbinol or ketal functionality. Additionally, the terminal carbon can carry a substituent such as an alkyl group or a second 4-fluorophenyl ring. The related technology is the following general structural formula (1): (In the formula, Ar is a phenyl ring, X is a carbonyl or carbinol group, Alk is an alkylene chain, and B is a heterocycle.) Generally, these compounds can be classified as related to antipsychotic butyrophenone compounds and carbinol derivatives. In this connection, the state of the art is
Burgere's Medical Chemintry, 4th edition, Part, edited by ME Wolff, John, Wiley, &
Sands, New York (1981) pp. 917-918, No. 56
It is commented on in the chapter. However, the most closely related technology is 1-butyl-4-
Related to Heteroaryl Piperazine Compounds
It appears to be part of a series of three patents issued to Janusen. U.S. Patent No. issued April 1, 1961
In No. 2979508, Ar is substituted phenyl; X is carbonyl or carbinol; alk is C ₁ ~
A series of compounds were disclosed which are C ₆ alkylene; B can be 2-pyrimidinyl or 2-pyrinidyl. Compounds 1a and 1b were specifically disclosed. (1b): Also known as azaperone and used clinically as an antipsychotic. It does not disclose a halogen substituent on the pyrimidinyl ring, nor does it specifically disclose a fluorophenylbutanol chain attached to a pyrimidinylpiperazine moiety. US Patent No. issued May 23, 1961
No. 2985657 discloses a series of butylophenones in which Ar is halophenyl, X is carbonyl, alk is _C1 - _C4 alkylene, and B is pyrimidinyl and chloropyridazinyl among various heterocycles. It was done. Specifically disclosed were the following two compounds, designated as 1c and 1d. Compound 1c is also published in German Publication No. DE2053759,
It was disclosed on May 27, 1971. Again, no halogenated pyridinyl rings were disclosed or claimed. U.S. Patent No. issued February 28, 1961
No. 2973360 describes a series of CNS depressant compounds in which Ar is 2-thienyl; X is carbonyl or carbinol; alk is _C2 and _C3 alkylene; and B is 2-pyrimidinyl or 2-pyridyl. Disclosed. The most related compound specifically illustrated and claimed in this patent has structure (1e): is shown as Although the following documents are relevant, they are even less relevant to the novel compounds disclosed in this application. US Pat. No. 3,299,067 to Regnier et al., issued January 17, 1967, discloses compounds containing a benzyl-type moiety attached to a 2-pyrimidinylpiperazine. A specific example of this family said to be useful as peripheral vasodilators, analgesics, and anti-inflammatory agents is shown as structure (2). US Pat. No. 3,808,210, issued to Regnier et al. in April 1974, is directed to a series of aryloxypropanolamine antihypertensive compounds having a pyrimidinylpiperazine moiety such as structure (3). However, these compounds are not butyrophenones or derivatives thereof. US Patent No. 4,316,899, issued to Markwell on February 23, 1982, relates to another series of aryloxypropanolamine antihypertensive compounds containing pyrimidinylpiperazines as exemplified by structure (4). In its broadest aspects, the invention relates to the formula: [In the formula, X is

[Formula] (carbonyl), or

[Formula] (carbinol), (wherein R is C _1-4 alkyl, hydrogen or fluorophenyl), and Y is halogen] or a pharmaceutically acceptable acid addition salt thereof The present invention relates to piperazinylbutylophenone derivatives having neuroleptic (antipsychotic) properties. It is to be understood that halogen, as used herein, represents chlorine, bromine, iodine and, preferably, fluorine. Preferred compounds are those in which X is carbinol with R=H and Y is fluorine. In the most preferred compound, X is

[Formula], and Y is fluorine. It is to be understood that the present invention includes mixtures of stereoisomers as well as optical isomers, such as enantiomers, as well as individual enantiomers and diastereomers, and it is understood that the structural asymmetry in this series of carbinol compounds results. Separation of individual isomers is accomplished by application of various methods familiar to those skilled in the art. For medical use, pharmaceutically acceptable acid addition salts, salts in which the anion does not significantly contribute to the toxicity or pharmacological activity of the organic cation, are preferred. Acid addition salts are formed by the reaction of a structural organic base with an organic or inorganic acid.
Preferably obtained by contacting in solution or by any standard method described in the literature available to the person skilled in the art. Examples of useful organic acids are carboxylic acids such as maleic, acetic, tartaric, propionic, fumaric, isethionic, succinic, pamic, cyclamic, pivalic, etc., and useful inorganic acids are halogenated Hydrogen acids such as HCl, HBr,
HI: Sulfuric acid, phosphoric acid, etc. The compounds of the invention are useful pharmacological drugs with psychoactive properties. In this context, they exhibit selective central nervous system activity at non-toxic doses and are of particular importance as neuroleptic (antipsychotic) agents. Like other known antipsychotic drugs, the compound of the formula did have a certain response when tested in standard in vitro and in vitro pharmacological test systems known to correlate well with alleviation of symptoms of acute and chronic psychosis in humans. cause For example, piperazine similar to the compounds of the present invention, ie 1-phenyl-4-
Compared to [4-(4-methyl-2-pyrimidyl)piperazine]-1-butanol, the piperazine of the present invention exhibits more than twice the persistence in conditioned avoidance response (CAR) and apomorphine-induced stereotypic response (APO). have. Furthermore, the effect of conventional piperazine on catalepsy reversal with respect to the dose changes in an inverted U-shape, with the reversal rate peaking at 50% at most, and once this peak is exceeded, the reversal rate decreases again. Thus, the piperazine of the present invention increases its reversal rate linearly with dose, providing a catalepsy reversal rate of about 90% at the peak-effect dose. The next in-vivo test system tests psychotropic drugs in the non-specific CNS
It is illustrative of common tests used to classify and differentiate from depressants and to determine potential side effects such as cataleptic activity. Table 1 In Vivo Tests Used to Evaluate Compounds of Formula 1 Conditioned Avoidance Response (CAR) Measurement of the tranquilizing activity of a drug as determined by the dilution of its avoidance response to electric shock in trained fasted rats. Albert,
Pharmacologist, 4 , 152 (1962); Wu et al., J.
See Med.Chem., 12 , 876-881 (1969). 2 Suppression of Apomorphine-Induced (APO) Stereotypy Evaluation of blockade of dopaminergic activity in rats as measured by dilution of behavioral syndromes induced by the dopamine agonist, apomorphine.
Janssen et al., Arzenimittel Forsch., 17 , 841
(1966). 3 Catalepsy Drug-induced catalepsy in rats is predictive of subclinical extrapyramidal syndrome (EPS) in humans.
Costall et al., Psychopharmacologia, 34 ,
233Statist.Assoc., 48 , 565-599 (1953). 4 Catalepsy Reversal Measurement of the ability of a drug to reverse neuroleptic-induced catalepsy in rats. 5 Suppression of norepinephrine lethality Drug suppression of the lethality of the norepinephrine agonist, norepinephrine, indicates α ₁ -adrenergic blockade. 6 Sidman Avoidance Test Predicts antipsychotic activity when an animal's avoidance behavior is disrupted without affecting its escape behavior. Hill
and Tedeschi, “Introduction to Psychopharmacology”, Reck and
Moore (ed.), Raven Press, New York.
1971 276 pages. Butyrophenones, such as haloperidol, and many derivatives useful in the treatment of schizophrenia, are also strong dopaminergic antagonists. However, the therapeutic efficacy of these drugs is accompanied by serious side effects, especially movement disorders. Short-term use of butyrophenones often results in parkinsonian-like extrapyramidal side effects (EPS), while their long-term administration results in severe and often irreversible symptoms of tardive dyskinesia. Although compounds of the formulas of the invention generally exhibit significant antipsychotic activity at dose levels far below those capable of inducing catalepsy, certain representatives of this series also demonstrate that these compounds are free from EPS side effects. This shows a predictable catalepsy dilution effect. As a further indication of the psychoactive activity and specificity of these compounds, state-of-the-art in vitro central nervous system receptor binding techniques can be used. Certain compounds (usually designated as ligands) have been identified that preferentially bind to specific high-affinity sites in brain cells, dealing with the potential for psychoactive activity or side effects.
Inhibition of radiolabeled ligand binding to such specific affinity sites is considered a measure of the compound's ability to affect corresponding central nervous system functions or cause in vivo side effects. This principle is used in the following test as an example. Table 2 In vitro radioreceptor binding assay for evaluating compounds of formula Receptor binding assay Literature Dobamine Burt et al., Molec.
Pharmacol., 12 , 800
(1976);Science, 196,
326 (1977); Greese et al.
Science, 192 , 481 (1976). Cholinergic Yamamura et al., Proc. Natn.
Acad.Sci., USA 71 , 1725
(1974). α-receptor Crews et al., Science, 202 :
322 (1978); Rosenblatt
et al., Brain Res., 160 :
186 (1979); U′Prichard
et al., Science, 199 :197
(1978); U′Prichard et al.
Molec. Pharmacol., 13 :
454 (1977). Serotonin type 2 Peroutka and Synder,
Molec. Pharmacol., 16 :
687 (1979) According to the pharmacological aspects established by all the above-mentioned tests, compounds of this formula show that they are relatively potent in the standard conditioned avoidance test, the Sidman avoidance test and the suppression test of apomorphine stereotypy. and in these three studies ≦100mg/Kg-
It has promising neuroleptic potential in that it has an oral ED ₅₀ value of body weight. Activity in these tests appears to be predictive of neuroleptic potential in humans. Regarding side effects, this compound has >100
Inactive in catalepsy production or alpha blockade with an oral ED ₅₀ of mg/Kg. Even more importantly, preferred compounds of the invention exhibit the ability to reverse catalepsy with ED ₅₀ values of <20 mg/Kg given orally. Surprisingly, preferred compounds of the invention exhibit very low activity in inhibiting [ ^3H ]spiperone binding by having _IC50 values of >1000 nM. The lack of potency in dopaminergic binding of these compounds in striatal tissues suggests that these compounds are atypical neuroleptics, with significant potency in the conditioned avoidance test and inhibition of apomorphine stereotypy. suggests something. The most preferred compounds of the invention (X=-CHOH
-, Y=F; also known as MJ14802) is essentially inactive at serotonergic, α ₂ -adrenergic, cholinergic, GABA and opiate binding sites. The duration of action of MJ14802 in suppressing CAR and apomorphine stereotypy was observed to be over 7 and 4 hours, respectively. In contrast, the desfluoro analogue of MJ14802 (Y
The CAR activity of =H) is lost after 3 hours. Table 3 shows a comparison of the biological aspects of MJ14802 and those of the standard control drugs thioridazine and clozapine. Based on test data for inhibition of conditioned avoidance responses and apomorphine stereotypy, it is anticipated that this compound will be used as a neuroleptic similar to the reference drug clozapine.

[Table] As seen in the table, MJ14802 appears to be a potential atypical neuroleptic drug. In this context, it exhibits potency and duration of action in in vivo tests that predict antipsychotic efficacy. Unique aspects of this compound include its very weak dopamine receptor binding and the fact that it not only does not cause catalepsy, but also reverses neuroleptic-induced catalepsy. moreover
MJ14802 lacks anticholinergic and α ₁ -adrenergic activities, one or both of which are side effects of almost all commercially available and tested antipsychotics. To summarize the above discussion, the present compounds have psychotropic properties that make them particularly suitable for use as neuroleptic (antipsychotic) agents. Accordingly, another aspect of the invention relates to a method of ameliorating a psychotic state in a mammal in need of treatment comprising systemic administration to the mammal of an effective dose of a compound of formula or a pharmaceutically acceptable acid addition salt thereof. . It is expected that the administration and dosing regimen of the compound of formula should be similar to the reference compound, clozapine. The Merk Index
See 10th edition (1983), page 344 and its references. Based on animal studies, an effective oral dose could be expected to be about 2-50 mg/Kg, and an effective parenteral dose would be lower, in the range of about 0.05-1 mg/Kg body weight. Although dosing and administration regimens should be carefully adjusted in each individual case using sound professional judgment and taking into account the age, weight and condition of the recipient, the route of administration and the nature and severity of the disease, in general The daily dose when administered parenterally is about 0.05 to about
10 mg/Kg, preferably 0.1 to 2 mg/Kg, about 1 to about 50 mg/Kg, preferably 2 to 2 mg/Kg when administered orally
It would be 30mg/Kg. In some cases a sufficient therapeutic effect may be obtained with lower doses, while in other cases higher doses may be necessary. The terms systemic administration used include oral, rectal, and parenteral (i.e., intramuscular, intravenous, and subcutaneous).
Show the route. It will generally be appreciated that when the compounds of this invention are administered orally, which is the preferred route, larger amounts of active drug are required to produce effects similar to lower doses given parenterally. Based on good clinical experience, it is preferred that the compounds be administered at concentration levels that produce effective psychotic-relaxing (antipsychotic) effects without causing harmful or undesirable side effects. For treatment, the compounds are generally presented as a pharmaceutical composition consisting of an effective antipsychotic amount of a compound of formula or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier. Pharmaceutical compositions for carrying out such therapy contain a large or small amount, e.g. 95-0.5%, of at least one compound of the invention in combination with a pharmaceutical carrier, the carrier being non-toxic, inert and non-toxic. One or more pharmaceutically acceptable solid, semisolid or liquid diluents, fillers and formulation aids are included. Such pharmaceutical compositions are preferably in dosage unit form, i.e. physically separated units containing a predetermined amount of drug corresponding to a fraction or multiple of the dose calculated to produce the desired therapeutic response. The unit is. A dosage unit can contain 1, 2, 3, 4 or more single doses or 1/2, 1/3 or 1/4 of a single dose. A single dose is preferably an amount sufficient to produce the desired therapeutic effect when administered in one application of one or more dosage units according to a scheduled dosage regimen, usually once, twice, three or four times a day. Dispense the entire amount, half, 1/3, or 1/4 of the daily dose to be administered. Other therapeutic agents may also be present. Pharmaceutical compositions providing from about 1 to 500 mg of active ingredient per unit dose are preferred and are conveniently prepared as tablets, lozenges, capsules, powders, aqueous or oily suspensions, syrups, elixirs and aqueous solutions.
Preferred oral compositions are in the form of tablets or capsules, containing binders such as syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone, fillers such as lartose, sugar, corn starch, calcium phosphate, sorbitol or glycerin. ,
Conventional excipients can be included, such as lubricants (eg magnesium stearate, talc, polyethylene glycol or silica), disintegrants (eg starch) and lubricants (eg sodium lauryl sulfate). Solutions or suspensions of a compound of the formula in conventional pharmaceutical vehicles are employed in parenteral preparations, such as aqueous solutions for intravenous injection or oily suspensions for intramuscular injection. Such compositions having the desired clarity, stability and suitability for parenteral use contain from 0.1 to 10% by weight of the active ingredient in water, or polyhydric aliphatic alcohols such as glycerin, propylene glycol and polyethylene glycol or mixtures thereof. It is obtained by dissolving it in a vehicle consisting of: Polyethylene glycol is soluble in water and organic liquids and has approximately 200 to
Consists of a mixture of non-volatile, normally liquid polyethylene glycols with a molecular weight of 1500. The general preparation of compounds of formula is shown schematically in Scheme 1. As shown in Scheme 1, 5-Y-substituted 1-pyrimidin-2-yl-piperazine () can be converted to K ₂ CO ₃
Alkylation with a γ-chloroketal (made from commercially available ketones) in the presence of and acidic work-up yields the ketone product, Ia; X=carbonyl. Ia NaBH ₄ in ethanol
Secondary carbinol in 50-70% yield when treated with
Ia; produces X=carbinol. Reaction of Ia with Grignard reagent yields tertiary carbinol Ic. In the above formula, R and Y are as described above. Procedures for preparing compounds of structure Ia include reaction conditions commonly used for the preparation of tertiary amines by alkylation of secondary amines. Compounds of Ia can thus be obtained by reacting a suitable intermediate with in an inert reaction medium in the presence of a base suitable for use as an acid binding agent at temperatures of from about 50 to about 200°C. . Inorganic and organic acid-binding bases that can be used include tertiary amines, alkali and alkaline earth metal carbonates, bicarbonates, or hydrides, with sodium carbonate and potassium carbonate being particularly preferred. The term "inert reaction medium" as used throughout the specification refers to a protic or aprotic solution that does not participate in the reaction to any substantial extent. In this connection, acetonitrile is a particularly preferred solvent and the reaction is conveniently carried out at reflux temperature. Good yields of the present compounds are obtained with reaction times ranging from about 2 to about 24 hours. The product of formula Ia can be prepared by crystallization methods from standard solvent media such as acetonitrile, isopropanol, methanol, ethanol, etc., and by chromatography using silica gel columns with mixtures of chloroform and alkanols such as methanol and ethanol as eluent. It can be purified by other conventional methods. It will be apparent to those skilled in chemistry that the intermediate has a ketal functionality on the carbon atom attached to the para-fluorophenyl residue. The ketal functionality acts in this example as a protecting group for the initial carbonyl moiety. After the alkylation step, dilute acid,
Upon gentle treatment, preferably with HCl, the ketal protecting group is rapidly cleaved to provide the desired functionality. Reduction of Ia is accomplished using an alcoholic slurry of sodium borohydride, preferably with ethanol, as the alkanol reaction liquid to yield the secondary carbinol product Ib. The tertiary carbinol product Ic is conveniently prepared from the carbonyl compound Ia by reaction with a suitable Grignard reagent prepared in a conventional manner from an alkyl or aryl halide and a magnesium foil in dry ether, preferably tetrahydrofuran. . Alternatively, similar chemical conversions can be achieved using other suitable organometallic reagents. Alternative methods and modifications of these methods will be apparent to those skilled in the chemical arts. The 5-halogenated pyrimidinylpiperazine intermediate can be prepared by several procedures as shown in Scheme 2. 5-fluoro derivative (a) is an intermediate compound,
From 2-chloro-5-fluoro-4-methylthiopyrimidine (), treatment with N-carbethoxypiperazine () followed by Raney nickel desulfurization gives V
and acid-catalyzed removal of the carbetoxy group to give a. Intermediates in which Y is chloro, bromo or iodo can be obtained by direct halogenation of 1-pyrimidin-2-ylpiperazine itself as in procedure B,
=chloro, a better yield is obtained by chlorinating N-carbethoxy-1-pyrimidin-2-ylpiperazine () and then cleaving the carbethoxy group of XI to give the desired 5-chloro-pyrimidinylpiperazine a. It is realized by giving. Certain intermediate compounds, such as compounds, used in the above preparation procedures are commercially available, and therefore there is no need to provide examples or descriptions of their preparation. DESCRIPTION OF SPECIFIC EMBODIMENTS The compounds constituting the invention and their method of preparation will become more fully apparent from a consideration of the following examples, which are given by way of illustration only and do not limit the invention in scope or scope. Then it should not be understood. All temperatures are in °C unless otherwise specified. Nuclear magnetic resonance (NMR) spectral characteristics are expressed as chemical shifts (δ) expressed in parts per million (ppm) relative to a reference standard of tetramethylsilane (TMS). The relative areas reported for various shifts in the proton NMR spectral data correspond to the number of hydrogen atoms of a particular functional type in the molecule. The nature of the shift with respect to multiplicity is broad singlet (bs), singlet (s), multiplet (m), doublet (d), doublet of doublets (dd) or quartet (q). Reported as. The abbreviations used are DMSO-d ₆ (deuterodimethyl sulfoxide) and CDCl ₃ (deuuterochloroform), and other commonly used abbreviations are used. In the description of the infrared (IR) spectrum, only absorption wavenumbers (cm ^-1 ) with functional group identification values are shown. IR measurements used potassium bromide (KBr) as a diluent. Elemental analysis is given as weight %. Production Example of Intermediates 1 γ-Chloro-p-fluorobutylphenone ethylene ketal () γ-chloro-p-fluorobutylphenone (50
A solution of ethylene glycol (50 ml); p-toluenesulfonic acid (0.1 g) in 300 ml of benzene was refluxed for 18 hours, and the water of reaction was removed by a Dean Stark water trap. do. After cooling to room temperature, the reaction mixture was washed with dilute sodium bicarbonate, dried (MgSO ₄ ) and
Filter and remove the benzene in vacuo in a conventional manner.
The residual oil was distilled to yield 57.7 g (93%) of product, boiling point 106-112°/0.1 torr. Example 2 5-fluoro-2-(1-piperazinyl)pyrimidine (a) (1) Ethyl 4-(5-fluoro-4-methylthio-2-pyrimidinyl)-1-piperazinecarboxylate () 2-chloro-5 -Fluoro-4-methylthiopyridine (28.3 g, 0.16 mol), N-carbethoxypiperazine (25.26 g, 0.16 mol),
Stir a mixture of anhydrous K ₂ CO ₃ (66.0 g) and a catalytic amount of KI in acetonitrile (400 ml);
Heated under reflux for 18 hours. The hot reaction mixture was filtered, concentrated in vacuo, and the residue was crystallized from ethanol to yield 29.8 g (62%) of product. (2) Ethyl 4-(5-fluoro-2-pyrimidinyl)-1-piperazinecarboxylate ()
Ethyl 4-(5-fluoro-4-methylthio-
2-pyrimidinyl)-1-piperazinecarboxylate (29.8 g, 0.1 mol) and Raney-nickel catalyst (15 tsp) in ethanol (550
ml) was stirred and heated under reflux for 48 hours. The reaction mixture was filtered and concentrated in vacuo;
The residue was recrystallized twice from ethanol to give the product,
11.2 g (45%) was obtained, melting point 104-107°. 6N− of this intermediate (, 11.2 g, 0.04 mol)
The solution in HCl (100ml) was stirred and heated under reflux overnight. Cooled reaction mixture to 50%
Made alkaline by addition of NaOH, extracted with ether, and dried the extract (MgSO ₄ ).
Concentration in vacuo yielded 7.23 g (100%) of the product as a viscous oil, which was treated with ethanolic HCl in ethanol to give the hydrochloride salt, mp 250~
252°. Elemental analysis, calculated values for C ₈ H ₁₁ FN ₄・HCl:
C, 43.95; H, 5.54; N, 25.63. Measured value: C,
44.23; H, 5.57; N, 25.38. The above example is useful for illustrating Step A in Scheme 2. Example 3 5-Bromo-2-(1-piperazinyl)pyrimidine (c) This example is useful in illustrating Procedure B of Scheme 2. Bromine (15.98 g, 0.1 mol) was added dropwise to an ice-cold solution of 1-(2-pyridinyl)piperazine (16.4 g, 0.1 mol) in 1N HCl (100 ml). 0.5 at 0°
Stir the mixture for an hour until the red color disappears.
It was heated to 100°. Filter the mixture, cool and reduce to 50%
The mixture was made alkaline with NaOH and extracted with ether. The dried (MgSO ₄ ) extract was concentrated in vacuo to yield 14.5 g (62%) of product, mp 73-75°. By appropriate modification of this procedure, 5-chloro intermediate b, and 5-iodo intermediate d can be prepared. Example 4 5-Chloro-2-(1-piperazinyl)pyrimidine (b) This example is illustrative of Procedure C of Scheme 2.
Ethyl 4-(2-pyrimidinyl)-1-piperazinecarboxylate (31.4
g, 0.133 mol) was passed through chlorine gas for 15 hours. The reaction mixture was cooled in ice and the solid product was collected by filtration and dried to yield the 5-chloro-N-carbetoxy intermediate compound, mp 80-83°, 19.3 g.
(54%) occurred. This intermediate was converted into 5 in Example 2.
- Hydrolyzed under acidic conditions as described for fluoro analogues. N-carbethoxy intermediate compound
b, 10.7 (77%) was obtained from 19.3 g (0.07 mol). Example 5 5-iodo-2-(1-piperazinyl)pyrimidine (d) The preparation of this reaction intermediate was described by JPEnglish et al.
Some 2 described in JACS, 68, 1039 (1946)
This can be achieved by modification of the process given for the synthesis of -amino-5-iodopyrimidine. 1-(2-pyrimidinyl)piperazine (5.0g,
A refluxing mixture of mercuric acetate (19.2 g, 0.06 mol) and mercuric acetate (19.2 g, 0.06 mol) in 90 ml of glacial acetic acid was mixed with iodine (9.4
g, 0.037 mol). After 15 minutes, the reaction mixture is then added to a solution of potassium iodide (21 g) and sodium sulphite (4.5 g) in 125 ml of water.
The resulting mixture is filtered, the filtrate is neutralized with 50% NaOH solution and extracted with methylene chloride. The methylene chloride extract was washed successively with potassium iodide solution and sodium sulfite solution, dried (MgSO ₄ ),
Concentrate the dry product in vacuo. Product Preparation Example 6 1-(4-fluorophenyl)-4-[4-(5-
Fluoro-2-pyrimidinyl)-1-piperazinyl]butanone hydrochloride (a) 5-fluoro-2-(1-piperazinyl)pyrimidine (a, 7.3 g, 0.04 mol), γ-chloro-
A mixture of p-fluorobutylphenone ethylene ketal (14.5 g, 0.06 mol), anhydrous K ₂ CO ₃ (24.8 g) and a catalytic amount of KI in acetonitrile (100 ml) was stirred and heated under reflux for 36 hours. The hot mixture was filtered, concentrated in vacuo, and the residue was diluted with 3N−
Treated with 20ml HCl and 100ml ethanol. After cooling in ice the product was collected by filtration and dried to yield 7.6 g (50%) of the product as a white solid, mp 234~
Obtained as 236°. Elemental analysis _, calculated values _{for C18H20F2N4O.HCl} : C, 56.48; H, 55.3; _N , 14.64. measured value:
C, 56.27; H, 5.52; N, 14, 27. NMR (DMSO-d ₆ ): 2.10 (2, m); 3.20 (6,
m); 3.54 (4, m); 4.58 (2, m); 7.34
(2, m); 8.08 (2, m); 8.55 (2, s);
11.60 (1, bs). IR (KBr): 960, 1235, 1245, 1365, 1510,
1560, 1600, 1680, 2550 and 2920 cm ^-1 . Example 7 4-[4-[5-fluoro-2-pyriminidyl]
-1-piperazinyl]-1-(4-fluorophenyl)butanol hydrochloride (1b, MJ14802-1) Compound a produced in Example 6 (7.6 g, 0.02
mol) and sodium borohydride (2.3 g,
(0.06 mol) in ethanol (650 ml) was stirred overnight. The mixture was treated with ethanolic HCl, stirred at room temperature for 1.5 hours, then heated to reflux. The solvent was removed in vacuo and the residue was diluted with 1N−
NaOH and methylene chloride were added. The organic layer was separated, dried (MgSO ₄ ) and concentrated in vacuo.
This residue was dissolved in ethanol (treated with ethanolic HCl and cooled). The hydrochloride salt is collected by filtration and dried to produce a product, melting point 236-238°, 6.2
g (81%) was produced. Elemental analysis, calculated _{for C18H22F2N4O.HCl} : C, 56.18; _H , 6.03; _N , 14.56. measured value:
C, 55.98; H, 6.06; N, 14.23. NMR (DMSO-d ₆ ): 1.71 (2, m); 3.10 (4,
m) 3.47 (4, m) 4.59 (3, m); 5.30 (1,
bs); 7.11 (2, m); 7.40 (2, m); 8.53
(2, s); 11.50 (1, bs). IR (KBr): 955, 1220, 1235, 1370, 1440,
1455, 1480, 1510, 1560, 1605, 2600, and 2920 cm ^-1 . Example 8 4-[4-5-fluoro-2-pyrimidinyl)-
1-Piperazinyl]-1,1-bis(4-fluorophenyl)butanol hydrochloride (Ic) 4-bromofluorobenzene (6.3 g, 0.03 mol) and magnesium foil (0.73 g, 0.03 mol) in dry tetrahydrofuran (40 ml). A solution of compound a prepared in Example 5 (7.87 g, 0.023 mol) in tetrahydrofuran (40 ml) was added to Grignard reagent prepared in a conventional manner from mol). Stir the mixture, heat under reflux for 18 hours, cool,
Treated with NaCl solution. The decanted tetrahydrofuran solution was concentrated in vacuo to remove the solvent and the oily residue was extracted with 3:7 hexane-ethyl acetate.
Flash chromatography was performed on silica gel using as eluent. The single component fractions (Rf 0.43 in hexane-ethyl acetate 3:7) were combined and concentrated in vacuo to give 5.2 g of a viscous oil. The latter ethanol solution was treated with ethanolic HCl,
The ethanol was then removed in vacuo and the residue was azeotropically distilled in 100 ml of benzene. The resulting solution was concentrated to half its volume at atmospheric pressure and a solid separated. The solid product is collected by filtration and dried to yield the tertiary carbinol product, mp 153-155°, 1.9 g (17%).
was gotten. Elemental analysis _, calculated values _{for C24H25F3N4O.HCl} : C, 60.19; H, 5.47; _N , 11.70. measured value:
C, 60.30; H, 5.36; N, 11.78. NMR (DMSO-d ₆ ): 1.66 (2, m); 2.34 (2,
m); 3.08 (4, m); 3.42 (4, m); 4.50
(2, m); 5.82 (I, bs); 7.07 (4, m);
7.46 (4, m); 8.50 (2, s); 11.30 (1,
bs). IR (KBr): 835, 950, 1220, 1235, 1365,
1450, 1490, 1510, 1560, 1605, 2590 and 2930 cm ^-1 . Using the appropriate starting compounds, additional examples of formula products can be prepared using substantially the same procedures as described above. Some additional products of the formula that can be prepared are shown in Table 4.

A compound of the formula is prepared using the procedure given in Example 6.

The compound of the formula [Formula] is shown in Example 7. can be manufactured using the given procedure,

[Formula] Some can be made according to Example 8.

[Table] The CAR values of the compounds produced in Examples 9, 10, 13, 14, and 16 are approximately 100, approximately 100, 87.1, and 87.1, respectively.
They were 50.0 and 48.5. These values demonstrate that the compounds of these Examples are effective as neuroleptics. Further Detailed Description of the Invention Some additional compounds similar to the above compounds defined by the formula also have antipsychotic properties.
For example, they are active in conditioned avoidance responses at non-catalepsy producing doses of less than 100 mg/Kg, and have been shown to have no inhibition of [ ^3H ]spiperone binding by having _IC50 values of >1000 nM. The significance of these findings in relation to their antipsychotic potential has already been adequately discussed for compounds of formula. Formula XXI (below) extends the scope of the invention to include all of these additional materials having the structure given as Formula ', as illustrated in Examples 19 and 20. These additions are expressed as the expression ′, In the formula, X is

[Formula] or -CHOH-, Y is halogen, and Z is alkyl or hydrogen) or pharmaceutically acceptable acid additions and/or solvates thereof. Therefore, the redefined invention is represented by formula XXI, [In the formula, X is

[Formula] (carbonyl),

[Formula] (ketal), or

(Carbinol) where R is C _1-4 alkyl, hydrogen or fluorophenyl, Y is halogen, and Z is alkoxy or hydrogen. or pharmaceutically acceptable acid addition salts and/or solvates thereof. As stated above, formula XXI encompasses both compounds of formula and formula '. A preferred solvated form of the compound of formula XXI is a hydrate, ie a complex with water or a hydrated compound. Compounds of formula ' can be obtained by the methods set out above for compounds of formula or by obvious modifications of the procedures shown in Schemes 1 and 2. X is

The preparation of compound (d) of formula ' is shown in Scheme 3. This compound is designated as d for consistency of sign of the compounds of related products of all inventions. In this step, γ-chloroketal (,
(prepared from a commercially available ketone) with piperazine in the presence of potassium carbonate results in a compound that is then converted to XII by a nucleophilic aromatic substitution reaction on the pyrimidine intermediate. Desulfurization by the standard Ranu-nickel procedure yields the ketal structure . Compounds of formula ' where Z is alkoxy are represented by scheme 4
It can be manufactured as shown in . The procedure in Scheme 4 is mainly a modification of Scheme 1. Starting with the ketal thiomethyl intermediate compound XII, a selected alkoxy group is used to replace the methylthio moiety to yield the desired (Z=OR) formula 'd product.
This compound can be converted to other desired ' _a-c products in which the structure of X is altered using the reactions shown. In the above schemes 3 and 4, R, Y and Z
are all as specified above. The preparation of compounds of formula can be accomplished by the following unitary process. R and Y in the above scheme are as defined above. Another observation of the present invention relates to stereoisomers of preferred compounds of formula. This compound, also known as BMY14802, has a chiral center, as indicated by the star, and therefore exists as (-) and (+) enantiomers. To resolve racemic BMY14802 into its enantiomers, the racemic free base is converted to S-(-)- to generate a mixture of diastereomeric carbamates.
Or treated with R-(+)-α-methylbenzyl isocyanate. (-) and (+) of BMY14802
S-(-) and R- to produce enantiomers
The pure crystalline diastereomer obtained by reaction with (+) isocyanate was cleaved with trichlorosilane. These isocyanate resolving agents are commercially available and the use of such reagents in the resolution of racemic alcohols and amines has already been described in the literature. Theme enantiomeric resolution was accomplished using the procedure outlined in Scheme 5. In theory, two diastereomers should be obtained from the reaction of racemic BMY14802 regardless of the isocyanate used. However, in each case one crystalline diastereomer was obtained by filtration and no further crystalline material could be obtained from the filtrate. Attempts to separate and isolate the second diastereomer from the filtrate using chromatography were unsuccessful. In fact, treatment of racemic carbinol with S-(-)isocyanate gives only one diastereomer in crystalline form, which can be isolated and cleaved with trichlorosilane.
The pure (-)-enantiomer of BMY14802 was produced. Similarly, R-(+) isocyanate gave a pure crystalline diastereomer that could be cleaved to generate the (+)-enantiomer of BMY14802. Evaluation of the biological activity of the enantiomer showed that the (-)-enantiomer was more potent than the racemic substance in suppressing apomorphine stereotypy in rats, but was less effective in reversing neuroleptic-induced catalepsy. It was shown that there are few. (+)- of BMY14802
The mirror image was exactly the opposite. This led to the conclusion that there is no significant advantage in pharmacological aspects as a potential antipsychotic for any of the enantiomers compared to the racemic mixture. Example 19 5-Fluoro-2-[4-[3-[2-(4-fluorophenyl)-1,3-dioxolane-2-
yl]-propyl]-1-piperazinyl]-pyrimidine hydrochloride (') γ-chloroketal (, 27.49 g, 0.112 mol); piperazine (48.24 g, 0.56 mol); potassium carbonate (46.43 g, 0.33 mol); catalyst A mixture of all the amounts of potassium iodide in 358 ml of acetonitrile was refluxed for 18 hours. The hot reaction mixture was filtered, the filtrate concentrated in vacuo and the residue partitioned between water (250ml) and ether. The aqueous layer was further extracted with ether and the ether extracts were combined and dried (MgSO ₄ ).
and concentrated in vacuo to yield 28.5 g of 1-[3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]ropyl]piperazine (). piperazine intermediate (7.8 g, 0.026 mol); 2-chloro-5-fluoro-4-methylthio-2-pyrimidine (4.73 g, 0.026 mol); potassium carbonate powder (11.05 g); and a catalytic amount of potassium iodide. was refluxed in 80 ml of acetonitrile for 18 hours. The hot reaction mixture was filtered and the filtrate was concentrated in vacuo to yield 11.1 g of a residue which was subjected to flash chromatography (3% methanol/methylene chloride). Combine appropriate fractions, dissolve in 10 ml of ethanol, cool and ethanolic
HCl and then 5-fluoro-2-[4
-[3-[2-(4-fluorophenyl]-1,3-
1.5 g of dioxolan-2-yl[propyl]-1-piperazinyl]-4-(methylthio)pyrimidine hydrochloride (), melting point 233-235°, were obtained. Elemental analysis, calculated _{for C21H26F2N4O2S.HCl} : _C , 53.33; _H , 5.75; _N , 11.85. Measured values: C, 53.53; H, 5.81; N, 12.03. 5-Fluoro-2-[4-[3-[2-(4-fluorophenyl]-1,3-dioxolan-2-yl]propyl]-1-piperazinyl]-4-(methylthio]pyrimidine (, 7.45 g, 0.017 mol); triethylamine (3.05 g, 0.034 mol);
Two teaspoons of Raney-nickel in water were mixed in ethanol (125 ml) and refluxed for 18 hours. The hot reaction mixture was filtered and the filtrate was concentrated in vacuo to approximately 1/5 volume.
A crude crystalline product is obtained by filtration, which is recrystallized in 20-25 ml of ethanol to give a solid, mp 220~
222°, 1.6 g was produced. This solid was converted to the hydrochloride salt using ethanolic HCl in ethanol. Filter and dry product, melting point 242-244°, 1.6 g
occurred. Elemental analysis, calculated _{for C20H24F2N4O2.HCl : C} , 56.27; H, 5.90; _N , 13.12. measured value:
C, 56.12; H, 6.06; 12.90. Example 20 4-[4-5-fluoro-4-methoxy-2-
pyrimidinyl)-1-piperazinyl]-1-(4
-Fluorophenyl)butanol hydrochloride. Following the procedures given in Examples 6-8, but with 2
-Carbinol intermediate compound, 4-[4-(5-fluoro-4-methylthio-2-pyrimidinyl)-1-piperazinyl]-1 using chloro-5-fluoro-4-methylthiopyrimidine as starting material
-(4-fluorophenyl)butanol can be produced. 3.77g (0.01 mol) of this intermediate
A portion was mixed with KOH (7.54g) in methanol (75ml) and refluxed for 18 hours. The methanol was removed in vacuo and the extract was dissolved in water. The aqueous solution was extracted with ethyl ether, the ether extracts were combined and dried,
Concentrate in vacuo to a residue of 2.2 g, which is subjected to flash chromatography (ethyl acetate). Combining the appropriate fractions gave 1.6 g of an oily product, which was converted to the hydrochloride salt with ethanolic HCl to yield 1.5 g of the 'd product, mp 235-237°. _Elemental analysis, calculated _{for C19H24F2N4O2.HCl} : _C , 55.01; H, 6.07; _N , 13.50. measured value:
C, 55.02; H, 6.22; N, 13.28. Example 21 Isolation of (−)-4-[4-(5-fluoro-2-pyrimidinyl)-1-piperazinyl]-1-(4-fluorophenyl)butanol hydrate in 400 ml of benzene. 4-(5-fluoro-
2-pyrimidinyl)-1-piperazinyl]-1-
A mixture of (4-fluorophenyl)butanol (BMY14802; 9.47 g, 0.027 mol) was stirred and heated under reflux for 4 hours with a Dean Stark trap for azeotropic removal of water of hydration. After cooling to room temperature, S-(-)-α-methylbenzylisocyanate was added and the mixture was stirred under _N2 for 18-20 hours. After 60 hours at room temperature, the mixture was freed of solvent in vacuo and the residue was flash chromatographed on silica gel using ethyl acetate as eluent. Removing the solvent in vacuo produces an oil
13.07 g resulted, which was dissolved in 5-7 ml of ethanol and refrigerated. The resulting crystalline precipitate was collected by filtration and dried in vacuo at 70° to yield 5.13 g of carbamate derivative, melting point 117-119°. proton
NMR showed the material to be a single enantiomer. In 60 ml of benzene, the carbamate obtained above (4.75 g, 0.0096 mol) and triethylamine (1.17 g, 0.0116 mol) were stirred under an atmosphere of _N2 . Trichlorosilane (1.44 g, 0.0106 mol) in 30 ml of benzene was added dropwise over about 20 minutes.
The mixture was stirred at room temperature for 20 hours and heated under reflux for 1 hour. The reaction mixture was extracted with 2 x 100 ml of saturated ammonium chloride solution. The aqueous extract was made basic with sodium carbonate and extracted with methylene chloride.
After drying (MgSO ₄ ), the methylene chloride extract was concentrated in vacuo and the residue was flash chromatographed on silica gel using methylene chloride:methanol (19:1) as eluent. Rf0.44
(methylene chloride/methanol, 19:1) were combined and the solvent was removed in vacuo to give 2.04 g of a solid, which was recrystallized from ethanol to form the (-)-enantiomer of BMY14802, mp 123~
125°, [α] ²⁵ _D = −15.2° (0.5% by weight in methanol
concentration), 1.3 g was produced. The yield of the (-)-enantiomer based on the racemic material was 27.3%. Elemental analysis, C ₁₈ H ₂₂ F ₂ N ₄ O・0.25H ₂ O (MW=
Calculated values for 352.9): C, 61.26; H, 6.43;
N, 15.88; _H2O , 1.28. Measured value: C, 61.29; H,
6.46; N, 15.85; _H2O , 1.33. Example 22 Isolation of (+)-4-[4-5-fluoro-2-pyrimidinyl)-1-piperazinyl]-1-(4-fluorophenyl)butanol hydrate The procedure was as described in Example 21. It was the same. Racemic BMY14802 free base (9.47 g, 0.027 mol) and R-(+)-α-methylbenzylisocyanate (4.0 g, 0.027 mol) in 400 ml of benzene.
After chromatography and recrystallization, 5.3 g of carbamate, melting point 117-119°, were obtained. Proton NMR confirmed that this substance is a single enantiomer. Continuing the procedure of Example 21, carbamate (5.29
g, 0.0107 mol) was treated with trichlorosilane (1.59 g, 0.0117 mol) in the presence of triethylamine (1.29 g, 0.0127 mol) in benzene (90 ml). After chromatography and recrystallization
(+)-enantiomer of BMY14802, melting point 123-125°,
[α] ²⁵ _D = +15.4° (concentration of 0.5% by weight in methanol)
,
2.2g was obtained. The yield was 44.5% based on racemic material. Elemental analysis, C ₁₈ H ₂₂ F ₂ N ₄ O・0.25H ₂ O (MW=
Calculated value for 352.9); C, 61.26; H, 6.43;
N, 15.88; _H2O , 1.28. Measured value; C, 61.27; H,
6.50; N, 16.14; _H2O , 1.31.

Claims (1)

[Claims] 1 Formula XXI, [ _wherein , hydrogen] and its pharmaceutically acceptable acid addition salts and/or hydrates thereof. 2. The compound according to claim 1, wherein X is [Formula] and Y is halogen. 3 1-(4-fluorophenyl)-4-[4-(5
-fluoro-2-pyrimidinyl)-1-piperazinyl]butanone hydrochloride. 4. The compound according to claim 1, wherein X is [Formula] and Y is halogen. 5 5-Fluoro-2-[4-[3-[2-(4-fluorophenyl)-1,3-dioxolane-2-
5. The compound according to claim 4, which is yl]propyl]-1-piperazinyl]pyrimidine hydrochloride. 6. The compound according to claim 1, wherein X is -CHOH-. 7 4-[4-(5-bromo-2-pyrimidinyl)
-1-piperazinyl]-1-(4-fluorophenyl)butanol hydrochloride, the compound according to claim 6. 8 4-[4-(5-chloro-2-pyrimidinyl)
-1-piperazinyl]-1-(4-fluorophenyl)butanol hydrochloride, the compound according to claim 6. 9 4-[4-(5-fluoro-4-methoxy-2
-pyrimidinyl)-1-piperazinyl]-1-(4
- fluorophenyl)butanol hydrochloride,
A compound according to claim 6. 10 Claim 1, wherein Y is fluoro
Compounds described in Section. 11 Claim 6, in which Y is fluoro
Compounds described in Section. 12 is an anhydride or hydrate of 4-[4-[5-fluoro-2-pyrimidinyl]-1-piperazinyl]-1-(4-fluorophenyl)butanol,
A compound according to claim 11. 13 The compound according to claim 11, which is 4-[4-[5-fluoro-2-pyrimidinyl]-1-piperazinyl]-1-(4-fluorophenyl]butanol hydrochloride. 14 (- )-4-[4-(5-fluoro-2-pyrimidinyl)-1-piperazinyl]butanol hydrate. 15 (+)-4-[4-5 -fluoro-2-pyrimidinyl)-1-piperazinyl]butanol hydrate. 16 Formula XXI, [ _wherein , A neuroleptic drug comprising an effective amount of the compound and its pharmaceutically acceptable acid addition salt and/or hydrate thereof. 17 The compound of formula XXI is 4-[4-[5-fluoro-2-pyrimidinyl]-1-piperazinyl]-1
The neuroleptic drug according to claim 16, which is -(4-fluorophenyl)-butanol or a pharmaceutically acceptable acid addition salt thereof. 18. The neuroleptic drug of claim 16, comprising a formulation carrier and about 1 to 500 mg of a compound of formula XXI, in a dosage unit form suitable for systemic administration.