JPS6175A - Antipsychotic 1-fluorophenylbutyl-4-(2-pyrimidinyl) piperazine derivative - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention generally relates to heterocyclic carbon compounds with drug and bioactive properties, and methods of making and using the same. In particular, the invention provides that one substituent is pyrimidin-2-yl, preferably pyrimidin-2-yl substituted in the 5-position by a halogen; the other substituent is pyrimidin-2-yl with a 4-fluorophenyl ring terminal It relates to 1,4-disubstituted piperazine derivatives which are carbon alkylene chains. The terminal carbon is also attached to an oxygen atom providing a carbonyl, carbinol or Kecoul functionality. Additionally, the terminal carbon can have a substituent such as an alkyl group or a second 4-fluorophenyl ring.

The related art is the following general structural formula (1): (wherein A is a phenyl ring, X is a carbonyl or carbinol group, alk is an alkylene chain, and B is a heterocycle) In general, these compounds can be classified as related to antipsychotic butyrophenone compounds and carbinol derivatives. In this context, the state of the art is Burg
are's Medical Chemintry
, 4th edition, par) II [, M, E, Wolff
) John, Wiley, & Zands, Newkoke (1981) pp. 917-918, chapter 56.

The most closely related technology, however, is contained in a series of three patents issued to J. It appears to be.

U.S. Patent No. 2.979 issued April 1, 1961
, 508 discloses a series of compounds in which Ar is substituted phenyl; X is carbonyl or carbinol; ark is C0-C6 alkylene; B can be 2-pyrimidinyl or 2-pyridinyl. Ta.

Compounds (1a) and (1b) were specifically disclosed.

M.

(Ia) (lb): Also known as azaperone and used clinically as an antipsychotic.

There is no disclosure of a halokene substitution on the pyrimidinyl ring (nor is there any specific disclosure of a fluorophenylbutanol chain attached to the pyrimidinylpiperazine moiety).

U.S. Patent No. 2.98 issued May 23, 1961
In No. 5,657, Ar is halophenyl, X is carbonyl, alk is C1-C4 alkylene,
A series of butyrophenones were disclosed in which B is pyrimidinyl and chloropyridazinyl among various heterocycles. Specifically disclosed were the following two compounds designated as (1c) and (1d).

(Ie) Compound (1c) was also published in German Publication, DE2, 053.
No. 759, May 27, 197). Again, no halogenated pyridinyl rings were disclosed or claimed.

U.S. Patent No. 2.97, issued February 280, 1961.
No. 3,360, Ar is 2-chenyl; X is carbonyl or carbinol; alk is C2 and C3 alkylene; B is 2-pyrimidinyl or 2
A series of CNS depressant compounds that are -pyridyls are disclosed. The most related compound specifically illustrated and claimed in this patent is shown as structure (le): (Is).

Although the following documents are relevant, they are even less relevant to the novel compounds disclosed in this application.

U.S. Pat. No. 3,299, ('167) to Regnier et al., issued January 17, 1967, discloses compounds containing a Henschel-type moiety linked to 2-pyrimidinylpiperazine. Peripheral vasodilator, analgesic. A particular example of this family said to be useful as a drug and anti-inflammatory agent 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 aryloxypropaturamine antihypertensive compounds having a pyrimidinylpiperazine moiety such as structure (3). However, these compounds are not butyrophenones or derivatives thereof.

U.S. Pat. No. 4,316,899, issued to Marktvell on February 23, 1982, discloses a series of other pyrimidinyl-piperazine antihypertensive amines, including pyrimidinyl-piperazine, as exemplified by structure (4). Regarding compounds.

In its broadest aspects, the present invention relates to formula I: ■ [wherein ) and Y
is hydrogen or a halogen, but when X is a carbonyl component, Y is only a halogen] or a pharmaceutically acceptable acid addition salt thereof. This invention relates to radinylbutyrophenone derivatives.

It is to be understood that halogen, as used herein, represents chlorine, bromine, iodine and, preferably, fluorine. A preferred compound is a carbinol in which X has R=H;
A compound in which Y is fluorine. It is to be understood that in the most preferred compounds body as a result of the structural asymmetry within. Separation of individual isomers is accomplished by application of various methods familiar to those skilled in the art.

For medical use, preferred are pharmaceutically acceptable acid addition salts, salts in which the anion does not significantly contribute to the toxicity or the pharmacological activity of the organic cation. Obtained by reaction with an inorganic acid, preferably by contact in solution, or by any standard described in the literature available to the person skilled in the art (V drag method). Examples of useful organic acids are maleic acid, acetic acid. , tartaric acid, propionic acid, fumaric acid, isethionic acid, succinic acid, bamic acid, siframic acid, pivalic acid, etc., and useful inorganic acids are hydrohalic acids such as HCI, HBr, t
ll; 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 antipsychotics, the compounds of Formula I have shown consistent results when used in standard in vitro and in vitro pharmacological test systems that are known to correlate well with alleviation of symptoms of acute and chronic psychosis in humans. provoke a reaction.

The next in-vivo test system tests psychotropic drugs in a non-specific CN S 1r
Figure 1 is an illustration of a common test used to classify and differentiate fl from antidrugs and to determine potential side effects such as cataleptic activity.

Table 1. Evaluation of the compound of formula I. Conditioned avoidance response (CAR). Conditioned avoidance response (CAR). 4+S. A]ber1. , Pharmacolo
gisL.

↓, 152 (1962); Wu et al., J.M.
r: d, Chem, + upper master, 876-881 (
(1969).

21) Evaluation of the blockade of dopaminergic activity in 1- as measured by the dilution of the behavioral syndrome induced by the dopamine agonist, apomorphine, which inhibits apomorphine-induced (APO) cyclothymia.

Janssen (also, 8rzenimittel)
Forsch,, I 7-.

841 (1966).

3. Prediction of subclinical extrapyramidal symptoms (EPS) in 64 drug-induced catalepsy rats.

Co5tall et al., Psychopharmacol
ogia+ 34, 233StatisL, 85s
oc,, 4 8. 5 6 5 ~5 9 9
(1953).

4. Catalepsy Reversal Measurement of the ability of drugs to reverse neuroleptic-induced catalepsy in Lano I~.

5. Suppression of norepinephrine lethality Drug suppression of the lethality of norepinephrine, a noratornaline agonist, shows α, -7 trenaline agonist blockade.

5.5idman avoidance test predicts antipsychotic activity when an animal's avoidance behavior is disrupted without affecting its escape behavior. l1illand
Tedcschi, Introduction to Psychopharmacology J, Re
Ek and Moore C, eds.), Reichen Press, New York.

197). 276 pages.

Butyrophenones, such as heroperidol, and many derivatives useful in the treatment of schizophrenia, are also strong [-paminergic 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 Parkinnon syndrome-like extrapyramidal side effects (EPS), while their long-term total administration results in severe and often irreversible symptoms of tardive dyskinesia. Although the compounds of Formula I of the present invention generally exhibit significant antipsychotic activity at dose levels much lower than those capable of inducing catalepsy, certain representatives of this series also indicate that these compounds may cause EPS side effects. It shows a catalepsy dilution effect that can be expected to be completely eliminated.

As an indicator 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 Procedure for evaluating compounds of formula I Dopamine Our L and others, Mo1ec.

Pharmacol, +12'.

800 (1976); 5science, Danhong 326 (
(1977); Greese et al.

5science, ■2. 48H1976).

Cholinergic Yamamura et al., Proc, Natn
.

Acad, Sci, ll5A 7 1 1i725
(1974).

α-receptor Crews (lb, 5cien
ce, 202:322 (197B) HRosenb
Latt et al.

Brain Res, 160: 186 (197
9) ;11' Pr1chard et al.

5science, 19 Flood 197 (1978); U'P
r1chard et al., Mo1ec.

Pharmacol, 13: 454 (1977)
.

Serotonin type 2 Peroutka and 5y
nder.

Molec, PharmacoJ, 16:6
B? (1979) According to the pharmacological aspects established by all of the above tests, this second compound shows that they are relatively potent in the standard conditioned avoidance test, the Sidman avoidance test and the suppression test of apomorphine-induced psychosis. Yes, in these three studies ≦100 ■/kg single body weight oral ET) so
It has potential as a promising antipsychotic drug. Activity in these tests appears to be predictive of antipsychotic potential in humans. Regarding side effects, the present compound is inactive in catalev 5z-), L formation or α blockade with a DE'D5° of >100 μ/kg. Even more importantly, preferred compounds of the invention are
EDS of 20■/kg can be obtained by J5. The value represents the ability to reverse katalebuu/-. Surprisingly, preferred compounds of the invention exhibit very low activity in inhibiting [3-former spiberone binding] by having IC1° values of >1000 nH. The lack of potency in dopaminergic binding of these compounds in striatal tissues suggests that these compounds are atypical antipsychotics, with significant potency in the conditioned avoidance test and inhibition of apomorphine syndrome. The most preferred compound of the present invention (X
= -Cll011-2Y=F, also M J 14
802) is essentially inactive at serotonergic, α2-adrenergic, cholinergic, GABA and opiate binding sites. The duration of action of M J 14802 in suppressing CAR and apomorphine syndrome was found to be over 7 and 4 hours, respectively. In contrast, the CAR activity of the desfluoro analogue (Y=H) of M J 14802 is lost after 3 hours.

Table 3 shows a comparison of the biological aspects of M J 14802 and those of the standard reference drugs thioridazine and clozapine. Based on test data for inhibition of conditioned avoidance responses and apomorphine syndrome, it is anticipated that this compound will be used as an antipsychotic similar to the reference drug clozapine.

As seen in the table, M J 14802 appears to be a potential atypical antipsychotic. 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.

Furthermore, M J 14802 has anticholinergic and α,
- one of these activities, lacking adrenergic activity
One or both are side effects of almost all commercially available and experimental antipsychotic drugs.

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 present invention relates to a method of ameliorating a psychotic condition in a mammal in need of treatment comprising systemic administration to the mammal of an effective dose of a compound of Formula I, or a pharmaceutically acceptable acid addition salt thereof. It is expected that the administration and dosing schedule of compound 2 should be similar to the reference compound, clozabine.
index.

See 10th edition (1983), page 344 and its references. Based on animal studies, the effective oral dose is approximately 2-50 ■/k
g, and effective parenteral doses could be expected to be lower (in the range of about 0.05 to 1 kg/kg body weight).

Although dosing and administration regimens should be carefully adjusted in each individual case using sound professional judgment, taking into account the age, weight and condition of the recipient, the route of administration and the nature and severity of the disease;- - Generally, the daily dose is about 0.05 to about 10 mg/kg when administered parenterally, preferably 0.1 to 2 mg/kg, and about 1 to about 50 mg/kg when administered intravenously. kg, preferably 2-30■/kg
Will. In some cases a sufficient therapeutic effect may be obtained with lower doses, while in other cases higher doses may be necessary.

The term systemic administration is used to refer to oral, rectal, and parenteral (ie, intramuscular, intravenous and subcutaneous) routes. 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 levels that will 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 r, or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable carrier. Pharmaceutical compositions for carrying out such therapy contain large or small amounts, e.g. 95-0.5%, of at least one compound of the invention in combination with a pharmaceutical carrier;
Carriers include one or more non-toxic, inert and pharmaceutically acceptable solid, semi-solid or liquid diluents, fillers and formulation aids. 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. The dosage unit is 1,2. 3.4
or more single dose or single dose '/2. '／
, or l/.

can include. A single dose is preferably an amount sufficient to produce the desired therapeutic effect when administered in one application of 1 or more dosage units according to the scheduled dosage regimen, usually once per day.
This includes the whole, half, 18, or 18 daily doses administered once, twice, three times, or four times. Other therapeutic agents may also be present.

Pharmaceutical compositions providing from about 1 to 500 grams 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 and contain binders such as syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone, fillers (
lubricants (e.g. magnesium stearate, talc, polyethylene glycol or silica), disintegrants (e.g. starch) and lubricants (e.g. sodium lauryl sulfate). excipients. Solutions or suspensions of compounds of formula I with conventional pharmaceutical vehicles are employed in parenteral compositions, such as aqueous solutions for intravenous injection or oily or suspensions for intramuscular administration. Such compositions having the desired clarity, stability, and suitability for parenteral use may 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 It is obtained by dissolving it in a vehicle consisting of a mixture thereof. Polyethylene glycols are soluble in water and organic liquids and consist of a mixture of non-volatile, normally liquid polyethylene glycols with a molecular weight of about 200-1,500.

The general preparation of compounds of Formula 1 is outlined in Scheme 1.

As shown in Scheme 1, 5-Y-substituted I-pyrimidine-
2-yl-piperazine (I+) was alkylated with γ-chloroquecur (prepared from Illillionally available ketone 1v) in the presence of KzCOz and acidified to produce the ketone product, Ia; produces carbonyl.

When la is treated with N a B Hs in ethanol, 5
Secondary carbinol Ia; X-carbinol is produced in 0-70% yield. 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. Thus, compounds of Ia can be prepared by combining the appropriate intermediates, ■ and ■, in an inert reaction medium in the presence of a base suitable for use as an acid binding agent.
It is obtained by reacting at a temperature of C. Inorganic and organic acid-binding bases that can be used include tertiary amines, alkali and alkaline earth metal carbonates, bicarbonates, or hydrides, with thorium carbonate and potassium carbonate being particularly preferred. The term "inert reaction medium" as used throughout the specification refers to a propynic or aprotic solvent that does not participate to a substantial extent in the reaction. In this connection, aceInitrile 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 generation 1a can be prepared by crystallization methods from standard solvent media such as acetonitrile, isopropanol, methanol, ethanol, etc. and by chromatography using a silica gel column with a mixture of chloroform and alkanols such as methanol and ethanol as eluent. It can be purified by other conventional methods such as. It will be clear to those skilled in chemistry that intermediate (1) has a getal 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, gentle treatment with dilute acid, preferably HCI, rapidly cleaves the ketal protecting group to provide the desired functionality.

Reduction of Ta is accomplished using an alcoholic slurry of boron hydride, preferably with ethanol as the alkanol reaction liquid to produce a secondary carbinol product.
produces b. The tertiary carbinol product IC is conveniently prepared from a carbonyl compound [a] by reaction of an alkyl or aryl halide with a magnesium foil in dry ether, preferably tetrahydrofuran, with a suitable Grignard reagent prepared in a conventional manner. Ru. 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 is shown in Scheme 2
It can be manufactured by several steps as shown in .

<
The bacterial 5-fluoro derivative (I[a) was obtained from the intermediate compound, 2-chloro-5-fluoro-4-methylthiopyrimidine (■), by treatment with N-calhetoxypiperazine (■), followed by Raney nickel desulfurization. (2) and acid-catalyzed removal of the carhethoxy group to give Ila. Intermediates that are Y or chloro, bromo or iodo■
Although can be obtained by direct halogenation of 1-pyrimidin-2-ylpiperazine itself as in procedure B, in the case of Y-chloro, better yields are obtained with N-calhetoxyl-pyrimidine-2- This is achieved by chlorinating the ylpiperazine (X) and then cleaving the carhethoxy group of XI to give the desired 5-chloro-pyrimidinylpiperazine Ila.

Certain intermediate compounds used in the above preparation procedures, such as compounds 1, 2, 2, are commercially available and there is no need to provide examples or explanations of their preparation.

Description of specific embodiments Compounds constituting the present invention and methods for producing them are as follows:
It will become more fully clear from the discussion of the following examples, which are given by way of example only and are not to be construed as limiting the invention in scope or scope. All temperatures are in °C unless otherwise specified.

Nuclear magnetic resonance (NMR) spectral characteristics are expressed as percentages (%) with respect to tetramethylsilane (TMS) as a reference standard.
The chemical shifts (δ) are expressed as ppm). The relative areas reported for the various shifts in the proton NMR spectra correspond to the number of hydrogen atoms of a particular functional type in the molecule. The properties of the shifts regarding multiplicity are broad-multiplet (bs), -multiplet (S), multiplet (m),
Double line (d), double line double line (dd) or quartet line (
reported as q). The abbreviation used is DMSO-d6
(Shuuterodimethyl sulfoxide), CDI! ,l
(xuuterochloroform), and other commonly used ones are used. In the description of the infrared (IR) spectrum, only absorption wavenumbers (cm-') with functional group identification values are shown. Potassium bromide (K
Br) was used. Elemental analysis is given as weight %.

Preparation of intermediate Example 1, γ-Chloro p-fluorobutyrophenone ethylene kecool (III) γ-chloro p-fluorobutyrophenone (50 g),
0.25 mol, commercially available); ethylene glycol (50 ml); p-1-luenesulfonic acid (0,1
g) Hensen 300mA! The solution is refluxed for 18 hours and the water of reaction is removed with a Dean-Stark water trap. After cooling to room temperature, the reaction mixture is washed with dilute sodium bicarbonate, dried (MgSO4), filtered and the Hensens removed in vacuo in a conventional manner. The residual oil was distilled to give a product, boiling point 1 (16-112°10.1) liters, 57.7 g (
93%).

Example 2 5-Fluoro-2-(1-piperazinyl)pyrimidine (Ila) (ll) Ethyl 4-(5-fluoro-4-methylthio-2-pyrimidinyl)-1-piperazine lupooxylate (Vl) 2-lysyl 10 -5-Fluoro-4-methylthiopyridine (■, 28.3 g, 0.16 mol), N-calhetoxopiperazine (■, 25.26 g).

0.16 mol), anhydrous 2CO:l (66,0 g)
and a catalytic amount of KI acetonyl-1-lyl (400 mn>
The mixture was stirred and 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 (V) Ethyl 4
-(5-Fluoro-4-methylthio-2-pyrimidinyl)7)-piperazine lupooxylate (■, 29.8
g, 0.1 mol) and Raney nickel catalyst (15ts
A mixture of p) in ethanol (550 mn) was stirred and heated under reflux for 48 hours. The reaction mixture was filtered, concentrated in vacuo, and the residue was recrystallized twice from ethanol to yield 11.2 g (45%) of product, mp 104-107°.

6 of this intermediate (■, 11.2 g, 0.04 mol)
The solution in 1'OOmj of N-HCI was stirred and heated under reflux overnight. The cooled reaction mixture was diluted with 50% Na
Made alkaline by addition of OH, extracted with ether, dried (MgSO, ) and concentrated the extract in vacuo to give 7.23 g (100%) of the product as a viscous oil, which was ethanolic in ethanol. treated with HCI,
The hydrochloride salt, melting point 250-252°, can be produced.

Elemental analysis, C, a H++ F Ns ・Calculated value for HCI: C, 43,95; H, 5,: 54; N+
25.63° Measured value: C, 44, 23; H, 5, 57;
N.

25, 3 B.

The above example is useful for illustrating Step A in Scheme 2.

Example 3 5-Bromo-2-(1-piperazinyl)pyrimidine (Ilc) This example is useful in illustrating Step 3 of Scheme 2. I
Bromine (15.98 g, 0.1 mol) was added dropwise to a water-cooled solution of 1-(2-pyridinyl)piperazine (16.4 g, 0.1 mol) in N-11cI (100 m#). After stirring for 0.5 h at 0°, the mixture was heated to 100° until the red color disappeared. The mixture is filtered and marked,
The mixture was made alkaline with 50% NaOH and extracted with ether. The dried (MgSOa) extract was concentrated in vacuo to yield 14.5 g (62%) of product, mp 73-75°.

By appropriate modification of this procedure, the 5-chloro intermediate nb,
and the 5-iodo intermediate rld.

Example 4 5-chloro-2-(1-piperazini ) pyrimidine (I[b) This example is an illustration of procedure C in Scheme 2.

Chlorine gas was passed through a solution of ethyl 4-(2-pyrimidinyl)-1-piperazinecarboxylate (31.4 g, 0.133 mol) in 150 ml of I N -flcI for 15 h. The reaction mixture was cooled in water. The solid product is collected by filtration and dried to give 5-chloro-N
- carhethoxy intermediate compound, melting point 80-83°, 19
．． 3g (54%) was produced. This intermediate was hydrolyzed under acidic conditions as described for the 5-fluoro analog in Example 2. N-carbethoxy intermediate compound 19.3 g
(0.07 mol) yielded 10.7 g (77%) of nb.

Example 5 5-iodo-2-(1-piperazinyl)pyrimidine (Ild) The preparation of this reaction intermediate was described by J. P. Englis.
h et al.

It can be achieved by modifying the production method given for the synthesis of some 2-amino-5-iodopyriminone described in JAC 3,68,1039 (1946).

1-(2-pyrimidinyl)piperazine (5.0 g, 0.
0.03 mol) and mercuric acetate (19.2 g, 0.(1
A refluxing mixture of iodine (6 mol) in 90 mn of glacial acetic acid was dissolved in iodine (9
, 4 g, (1,037 mol).

After 15 minutes, the reaction mixture was then dissolved in potassium iodide (21 g,) and sodium sulfite (4,5
Add to the solution of g). The resulting mixture was filtered and the filtrate was
Neutralize with 0% NaOH solution and extract with methylene chloride. The methylene chloride extract was washed sequentially with potassium iodide solution and sodium sulfite solution and dried (MgS04).
Then, concentrate the dry product in vacuo.

■Product production example 6 l-(4-fluorophenyl)-4-,,(4-(5-fluoro-2-pyrimidinyl)-1
-Piperazinyl]butanone hydrochloride (I a) 5-Fluoro-2-(1-piperazinyl)pyrimidine (
II a, 7.3 g, 0.04 mol), T-chloro-p-fluorobutylphenone ethylene kecool (I
II, 14.5 g, 0. (16 mo/I/), anhydrous z CO:+ (24,8 g), # and a catalytic amount of Kl in acetonitrile (100 mn) were stirred;
Heated under reflux for 36 hours. The hot mixture was filtered, concentrated in vacuo and the residue was dissolved in 3N-It(:I 20rnff
and 100m7 of ethanol! Processed with. After cooling in water, the product is collected by filtration and dried to yield product 7.
Obtained 6 g (50%) as a white solid, melting point 234-236°.

Elemental analysis, C+eH□. Calculated values for F2 N, O HCI: C, 56, 48, H, 5, 5, 3, N.

14, 64° Measured value: C, 55, 27; H, 5, 52;
N, 14.27°NMR (DMSO-db): 2.10 (
2, m); 3.20 (6, m); 3.54 (
4, m); 4.58 (21) m); 7.34 (
2, m) ; 8.08 (2, m) ; 8.55
(2,s); 11.60 (1,bs).

IR (KBr): 960, 1235, 1245°136
5.1510,1560,1600°1680.255
0 and 2920cffI-'.

Example 7 4-(47(5-fluoro-2-pyrimidinyl)-1-piperazinyl)-1-(4-fluorophenyl)butanol hydrochloride Hh, MJ The la compound produced in Example 6 (7.6 g, 0 0.02 mol) and sodium borohydride (2.3 g, 0.02 mol) and sodium borohydride (2.3 g, 0.02 mol).
(16 mol) in ethanol (650 m'z) was stirred overnight. The mixture was treated with ethanolic 11C1, stirred at room temperature for 1.5 hours, then heated to reflux. The solvent was removed in vacuo and 1N-NaOH and methylene chloride were added to the residue.

The organic layer was separated, dried (Mgso4) and concentrated in vacuo. This residue was dissolved in ethanol (treated with ethanolic 11cI and cooled). The hydrochloride salt was collected by filtration and dried to give the product, mp 236-238°, 6.2
g (81%) was produced.

Elemental analysis, Cln H2°F 2 Na 0. 11C
Calculated value for 1: C, 56, 18; I=I, -
6,0,3;N.

1 4, 5 6. Measurement direct: C, 55, 98
; H, 6, (16; N, 14.23° NMR (DMSOdb): 1.7) (2, m)
;3.10 (4,m);3.47 (4,m);4
．． 59 (3, m); 5.30 (1, br
,) ;7.1 1 (2゜m);7.40 (
2, m); 8.53 (2, s); 11.5
0 (], bs).

IR (KBr): 955. 1220. 1235
゜1370, 144.0. 1455. 1480°151.0, 1560, 1605.2600. and 2
920cm-'.

Example 8 4-(4-5-Fluoro-2-pyrimidinyl)-1-piperazinyl]-1,1-bis(4-fluorophenyl)butanol hydrochloride (Ic) 4-bromofluorochloride in dry tetrahydrofuran (40 mρ) Grignard reagent prepared in a conventional manner from benzene (6.3 g, 0.03 mol) and magnesilla 1, foil (0.73 g, 0.03 mol) was added with I prepared in Example 5.
Compound a (7.87 g, 0.023 mol) in tetrahydrofuran (40 mff)? M? (Added 1.

The mixture was stirred and heated under reflux for 18 hours, cooled and
Treated with NaCl solution. Decantation person 2 te 1
- Rahi l' +:+1 volume t of furan (9) was concentrated in vacuo to remove the solvent and the oily residue was dissolved in hexane-ethyl acetate 3
The mixture was subjected to flash chroma 1 to chroma using C as an eluent and Sorikakel as an eluent. Fraction containing a single component (Rf0.4 in 4-'IJ-convex ethyl 1-acid 3nia)
3) were combined and concentrated in vacuo to obtain 5.2 g of a viscous oil. Seven volumes of the latter ethanol were treated with ethanolic HCI, the ethanol was then removed in vacuo, and the residue was azeotropically distilled in a 100 mn Hengaf. The resulting solution was concentrated to half its volume at atmospheric pressure, and a solid was separated. The solid product is collected by filtration and dried to produce the tertiary carbinol product,
1.9 g (17%) was obtained, melting point 153-155°.

Elemental analysis, old calculation for C24H2SF3 N4O-HCI: C, 60, 19; H, 5, 47, N.

11.70° Measured value: C, 60, 30; H, 5, 36;
N, 11.78°NMR (DMSOdb): 1.66 (2, m); 2
．． 34 (2, m); 3.08 (4, m)
; 3.42 (4, m) ; 4.50 (2, m
); 5.82 (1, bs); 7.07 (4
, m) ;7.46 <4. m) ;8.50(
2,s); 1'1.30 (1,bs)
.

IR (KBr): 835. 950. 1220°1235, 1365. 1450. 1490°15
10.1560.1605.2590 and 2930c
m-'.

Using the appropriate starting compounds, additional examples of Formula 1 products can be prepared using substantially the same procedures as described above. Some additional products of formula (v) that can be prepared are shown in Table 4. )(=-C-) is prepared using the procedure given in Example 6.

H can be prepared using the procedure described above, and those in which X=-CR- can be prepared according to Example 8.

FURTHER DETAILED DESCRIPTION OF THE INVENTION Some additional compounds similar to the compounds defined by formula I also have antipsychotic properties.

For example, they are active in conditioned avoidance responses at non-catalepsy producing doses of less than 100 kg/kg and >11
It has an IC5o value of 000n, indicating that it does not inhibit [3H]spiverone binding at all. The significance of these findings in relation to their antipsychotic potential has already been adequately discussed for compounds of Formula 1.

Formula XXI (below) defines the scope of the invention in Examples 19 and 2.
0 to include all of these additional substances having the structure given as formula ■'. These additions include compounds of formula 1', or pharmaceutically acceptable acid additions and/or solvates thereof. Therefore, the present invention as redefined is 2XXI, hydrogen, and Z is alkoxy or hydrogen. However, when X is carbonyl and Z is hydrogen, Y is only a halogen] or a pharmaceutically acceptable acid addition salt thereof;
or) includes solvates. As already mentioned, the formula XX
I encompasses both compounds of formula I and formula I'. Formula X
A preferred solvated form of the compound of XI is a hydrate, ie a complex with water or a hydrated compound.

The preparation of the compound of formula I' (I d) is shown in Scheme 3, where the compound of formula I' is shown above for the compound of formula I. This compound is designated as Id for consistency of sign of the compounds of related products of all inventions.

JII XX ■ In this process, T-ri II + moss turf 1 no (■
, prepared from the commercially available ketone ■) with piperazine in the presence of potassium carbonate yields x, which is then converted to xxn by an aromatic nucleophilic substitution reaction on the pyrimidine intermediate ■. Transform.

Desulfurization by standard Raney nickel procedures yields the ketal structure of I'.

Compounds of formula 1' where Z is alkoxy can be prepared as shown in Scheme 4.

The procedure in Scheme 4 is mainly a modification of Scheme I. Starting with the ketal thiomethyl intermediate compound x
A product of formula I'd is formed.

This compound can be converted to other desired I' products in which the structure of X is altered by using the reactions shown.IL+C. In Schemes 3 and 4 above, R, X, Y and Z are all as defined above.

The preparation of the compound of formula XXI is as follows: This can be achieved by

4.4.4 R and Y in the above scheme are as defined above.

Other observations of the present invention relate to stereoisomers of preferred compounds of formula xxn. This compound, also known as BMY14802, has a chiral center, as indicated by the asterisk, and thus exists as (-) and (+) enantiomers.

To resolve racemic BMY 14802 into its enantiomers, the racemic free base can be converted to 5-(-)- or R-(
+)-α-methylhensyl isocyanate.

The pure crystalline diastereomers obtained by reaction with 5-(-) and R-(+) isocyanates were cleaved with trichlorosilane to generate the (-) and (+) enantiomers of BMY14802. 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.

ω m Theoretically 2
Two diastereomers should result 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. Indeed, treatment of racemic carbinol with 5-(-) isocyanate gave only one diastereomer in crystalline form, which, when isolated and cleaved with trichlorosilane, yielded the pure (-)-enantiomer of BMY14802. . Similarly, R-(+) isocyanate gives a pure crystalline diastereomer, which can be cleaved to give BMY148
The (+)-enantiomer of 02 could be produced.

Evaluation of the biological activity of the enantiomer showed that the (-)-enantiomer was more potent than the racemic substance in suppressing apomorphine cyclothymia in rats, but less effective in reversing neuroleptic-induced catalepsy. It was shown that B
The (+)-enantiomer of MY14802 was just 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- (1-(4-fluorophenyl)= 1.3-dioxolan-2-yl] -propyl]-1-piperazinyl] -Birimidine hydrochloride 4') γ-chloroquecur (■, 27.49 g.

0.112 mol); piperazine (48.24 g, 0.5
A mixture of potassium carbonate (46.43 g, 0.33 mol); catalytic amount of potassium iodide in 358 ml of acetonitrile was refluxed for 18 hours. The hot reaction mixture was filtered, the filtrate was concentrated in vacuo and the residue was dissolved in water (250 m
z) and the ether. The aqueous layer was further extracted with ether, and the ether extract was dried by combining (MgSO
4) When concentrated in vacuo, i -(3-(2-(4-
This yielded 28.5 g of fluorophenyl)-1,3-dioxolan-2-yl]ropyl]piperazine (XTIt).

Piperazine intermediate (Xl, 7.8g, 0.026mol)
;2-chloro-5-furl:l-4-methylthio-2
-Pyrimidine (4.73 g, 0.026 L); potassium carbonate powder (11.05 g); and a catalytic amount of potassium iodide were refluxed in 80 m/m of acetonitrile for 18 hours. The hot reaction mixture was filtered and the filtrate was concentrated in vacuo to leave a residue of 11.1 g, which was subjected to Franche chromatography (3% methanol/methylene chloride). Combine with appropriate fluxin and add ethanol l Qm
j! 5-fluoro-2-[4-(3-(2-(4
-fluorophenyl)-13-dioxolan-2-yl]propyl]-1-piperazinyl)-4-(methylthio)pyrimidine hydrochloride (XXn), melting point 233-235
°, 1.5 g was obtained.

Elemental analysis, Cz+Hz6Fz Calculated for N4025-HCI: C, 53°33; H, 5,75; N.

l 185. N11 Ride+? f: C, 53,
53; l(, 5,81; N, 12.03°5 fluoro-2-[4-(3-(2(4-fluor-1-phenyl)-], , ]3-nooxolan-2-yl)
Propyl-1,-piperazinylcy4-methyldio]virimison (XXn, 7.4'5 g, 0,,Ol 7
mol); triconitylamine 0, 0 3, 1 mol)
; Two cups of Ufuji and Keru in water are mixed with ethanol (1
25m7+) and refluxed for 18 hours. The hot reaction mixture was filtered and the filtrate was concentrated in vacuo to approximately 1 volume. The crude crystalline product was obtained by filtration and dissolved in ethanol 20~
When recrystallized in 25mff, it becomes a solid, melting point 220-22
2°, 1.6 g was produced. This solid was converted to the hydrochloride salt using ethanolic HCI in ethanol. 7If filtered and dried to give product, mp 242-2446, 1.6 g
served.

Elemental analysis, C 20 H 24 F 2 Na ○2
- Calculated value for HCI: C, 56.2 7
;I+. 5,90;N.

1 3, 1 2. Measured value: C, 56.12; H. 6
．． (16 ; 12.90゜Example 20 4- (4-5-fluoroL1-4 me1~xy-2-
pyrimidinyl)-1-piperazinyl)-1-(4-fluorophenyl)butanol hydrochloride.

The carbinol intermediate compound, 4-(4-(
5-Fluoro-4-methylthio-2-pyrimidinyl)-
1-piperazinyl]-1-(4-fluorophenyl)butanol can be produced. This intermediate 3.77
A part of g (0.01 mol) was mixed with KOH (7.54 g) in methanol (75 mn) 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 combined ether extracts were dried and concentrated in vacuo to a residue of 2.2 g, which was subjected to flash chromatography (ethyl acetate). Combining the appropriate fractions yields 1.6 g of oily product.
is obtained, which is converted to the hydrochloride salt with ethanolic TlCl to give I゛(1 product, mp 235-237°, 1.5
g occurred.

Elemental analysis, C, 98□4F2 N-0□ - Calculated values for HCI: C, 55,01; H, 6,07; N.

13, 50° measurement 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 hydrochloride in benzene 400 rr+jl 4-(4-(5-fluoro-2-pyrimidinyl)-1-piperazinyl)-1-
(4-fluorophenyl)butanol (BMY1480
2; 9.47 g, 0.027 mol) was stirred and heated under reflux for 4 hours with a Dean-Stark toranop for azeotropic removal of water of hydration. After cooling to room temperature, 5-(-)
-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. Removal of the solvent in vacuo yielded 13.07 g of oil, which was dissolved in 5-7 mβ of ethanol and refrigerated. The resulting crystalline precipitate was collected by filtration and dried in vacuo at 70°, giving the carbamate derivative, melting point 1
17-119°, 5,13 g was obtained. Pro 1~nNM
+'? showed that this substance is a single enantiomer.

Benzene 60mj! Carbame obtained in the middle, on top) (
4.75 g, 0.0(11) 6 mol) and triethylamine (1.17 g, 0.0116 mol) were stirred under N2 atmosphere. Trichlorosilane (1.44 g, 0.01 (16 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 diluted with saturated ammonium chloride solution 2X100rr
+7! Extracted with. The aqueous extract was made basic with sodium carbonate and extracted with methylene chloride. Drying (MgSOn
), the methylene chloride extract was concentrated in vacuo and the residue was subjected to furanochromatography on silica gel using methylene chloride:methanol (19:1) as eluent. RfO, -44 (methylene chloride/methanol,
19:1) were combined and the solvent was removed in vacuo to yield 2.04 g of a solid, which was recrystallized from ethanol to yield the (-)-enantiomer of BMY14802, mp 123-125°, [α] , = -L5.2° (concentration of 0.5% by weight in methanol), yielding 1.3 g. The yield of the (=)-enantiomer based on the racemic material is 27.3
%0 Elemental analysis, C1118Z□F2N40・0.25H20
Calculated value for (MW=352.9): C261,26
i H,6,4'3;N,15.88;HzO
.

1.28° Measured value: C, 61, 29; H, 6, 46; N
, 15.85; II□0.4.33゜Example 22 (+) -4-(4-5-fluoro-2-pyrimidinyl)-1-piperazinyl)-1-(4-fluoroI'1 phenyl) The isolation procedure for butanol hydrate was similar to that described in Example 21.

Racemic RM Y14802 in Hensen 400 mIf
Free base (9.47 g, 0.027 mol) and R-'
(+)-α-methylhensyl isocyanate (4.0g
, 0.027 mol) Karari 177 tograph and after recrystallization Calhame-1, melting point 117-119°, 5
．． 3g was obtained. Plasma NMR confirmed that this material was a single enantiomer.

Continuing the procedure of Example 21, add Calhame-1 (5.29 g
, 0.0107 mol) in the presence of triconitylamine (1.29 g, 0.0127 mol) in Hensen (90 mβ) (1.59 g, 0.011
7 mol). (+)-enantiomer of BMY 14802 after chromadowphy and recrystallization, melting point 1
23-125°, Cα]o = + 15.4° (concentration of 0.5% in methanol), 2.2 g were obtained.

Yield was 44.5% based on racemic material.

Elemental analysis, Cla H2□F2N40・0.25 t+
Calculated value for 2° (MW=352.9): C161,
26;H, 6,43;N, 15.881H2o.

Claims (21)

[Claims] (1) Formula XX I, ▲There are mathematical formulas, chemical formulas, tables, etc.▼ XX I [In the formula, , chemical formulas, tables, etc. ▼ (where R is C_1_~_4 alkyl, hydrogen or fluorophenyl), Y is halogen or hydrogen, but when X is carbonyl and Z is hydrogen, Y is only halogen, and Z is lower alkoxy or hydrogen] and its pharmaceutically acceptable acid addition salts;
or) its hydrate. (2) X is ▲There are mathematical formulas, chemical formulas, tables, etc.▼,
The compound according to claim (1), wherein Y is halogen. (3) 1-(4-fluorophenyl)-4-[4-(5
-fluoro-2-pyrimidinyl)-1-piperazinyl]
The compound according to claim (2), which is butanone hydrochloride. (4) X is ▲There are mathematical formulas, chemical formulas, tables, etc.▼,
The compound according to claim (1), wherein Y is halogen. (5) 5-fluoro-2-[4-[3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]
The compound according to claim (4), which is propyl]-1-piperazinyl]pyrimidine hydrochloride. (6) X is -CHOH- and Y is halogen,
A compound according to claim (1). (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-
The compound according to claim (6), which is (pyrimidinyl)-1-piperazinyl]-1-(4-fluorophenyl)butanol hydrochloride. (10) Claim No. (1), wherein Y is fluoro
Compounds described in Section. (11) Claim No. (6), wherein Y is fluoro
Compounds described in Section. (12) Claim No. 11, which is an anhydride or hydrate of 4-[4-[5-fluoro-2-pyrimidinyl]-1-piperazinyl]-1-(4-fluorophenyl)butanol. Compounds described in Section. (13) Claim No. (11) which is 4-[4-[5-fluoro-2-pyrimidinyl]-1-piperazinyl]-1-(4-fluorophenyl]butanol hydrochloride
Compounds described in Section. (14) The compound according to claim (11), which is (-)-4-[4-(5-fluoro-2-pyrimidinyl)-1-piperazinyl]butanol hydrate. (15) The compound according to claim (11), which is (+)-4-[4-5-fluoro-2-pyrimidinyl)-1-piperazinyl]butanol hydrate. (16) A method of ameliorating an undesirable psychotic state in a mammal, comprising orally administering to the mammal an effective antipsychotic amount of a compound according to claim (1). (17) The compound of formula XX I is 4-[4-[5-fluoro-2-pyrimidinyl]-1-piperazinyl]-1-(
Claim No. (16), which is 4-fluorophenyl)-butanol or a pharmaceutically acceptable acid addition salt thereof.
The method described in section. (18) A method for ameliorating an undesirable psychotic state in a mammal, comprising parenterally administering to the mammal an effective antipsychotic amount of a compound according to claim (1). (19) The compound of formula XX I is 4-[4-[5-fluoro-2-pyrimidinyl]-1-piperazinyl]-1-(
Claim No. (18), which is 4-fluorophenyl)-butanol or a pharmaceutically acceptable acid addition salt thereof.
The method described in section. (20) Pharmaceutical carrier and Claim No. (1)
A pharmaceutical composition in dosage unit form suitable for systemic administration to mammalian receptors containing about 1 to 500 mg of a compound of formula XX I as described above. (21) The compound of formula XX I according to claim (1) is 4-[4-[5-fluoro-2-pyrimidinyl]-1-piperazinyl]-1-(4-fluorophenyl)butanol or The pharmaceutical composition according to claim 20, which is a pharmaceutically acceptable acid addition salt thereof.