DK160553B - Analogy process for preparing benzisothiazole- and benzisoxazolepiperazine derivatives - Google Patents

Description

in

DK 160553 B

The present invention relates to an analogue and method for the preparation of novel benzisothioazole and benzisoxazole piperazine derivatives having anti-psychotic or neuroleptic activity.

Wu, U.S. Patent No. 3,398,151, Wu, et al., U.S. Patent No. 5,717,634, and correspondingly Wu, et al. Publications - J. Med.Chem., 12, 876-881 (1969), 15, 477-479 (1972) - variously describe psychotropic azaspiro [4.5] decandionic and dialkylglutarimide compounds corresponding to formula (1) 10

X N-carbide - N N-B

/ W wo 15 (1) 1 2 wherein R and R are all cooled or joined to form - (CH 2) 5 - or - (CH 2) 5-, and B inter alia represents phenyl plus various heterocyclic groups (all with optional substituents ): 20

-O -O O

25

Casten, et al., U.S. Patent No. 4,182,763 discloses the anxiolytic use of compound (2), which in biological literature 30 is referred to as buspirone.

o // ___ - \ / - \ 'N- \ X N- (OIL) .- N \ —J \ / v / 24 \ _y \ - ^

35 Vv lN

ISLAND

(2) 2

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Buspirone is closely related to the compounds of the invention and has very weak and short-term neuroleptic activity (see GL Sathananthan, MD, DPM, I. Sanghvi, PH.D., N. Phillips, MD, and S. Gershon, MD. DPM., Therapeutic Research, Vol. 18, pages 5 701-705, (1975)).

Benica, et al., J. Am. Pharmaceutical Association, 451-456 (1950) 1 2 discloses 3,3-dialkylglutarimides wherein R is Cj_ al alkyl and R is hydrogen or alkyl as shown by formula (3) and it is stated that the compounds lack significant physiological activity.

10, o x> 15 R \ (o)

Thiazolidinediones are known. Eg. Jones et al., J. Chem.

20 Soc., London, 91-92 (1946) to 5,5-dialkyl-2,4-thiazolidinedione barbituric acid analogs, and it is stated that a 5-spirocyclohexyl-2,4-thiazolidinedione (4) induces anesthesia and analgesia in mice.

25

S .NH

II

30 0 (4)

Various types of 1,4-substituted piperazine derivatives are also known per se as shown in the following references.

GB-A-2,023,594A discloses 1 (R-alkyl) -4- (3-trifluoro-methylthiophenyl) piperazines useful for the treatment of nervousness and depression, of the general formula (5) 3

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R- (CH2) n-1 / ^ to O-SCF3 5 (5) wherein n is 1-3 and R inter alia represents heterocyclic groups such as 10 WiC / - Å ~ in 0 wherein m is 0 or 1, and X is -S-, -O-, imino, alkyl-imino or methyl one.

Rojsner, et al., Collect. Czech. Chem. Commun., 40 (4) 1218-1230 (1975) discloses inter alia butyrophenone derivatives of formula (6) as part of a psychotropic structure-activity relationship study.

20, __ n / - '° / \ _ "Η j> -C- <cH2> 3- ^ 25 (6)

On the basis of the references cited above, it was not expected that the 1,2-benzisothiazole or 1,2-benzisoxazole-piperazine derivatives provided by the present invention possess potent neuroleptic or antipsychotic activity.

The process of the invention provides piperazinyl derivatives having neuroleptic (anti-psychotic) properties which are characterized by having formula (I) 35 R-Γλ-ι-wl Jx / Lz

wherein R represents the group T

Wherein Y represents oxygen or sulfur and Z, represents hydrogen or halogen, or a pharmaceutically acceptable non-toxic acid addition salt thereof.

It is to be understood that the term halogen as used herein means fluorine, iodine, and preferably chlorine and bromine.

The pharmaceutically acceptable acid addition salts of the invention are those in which the anion does not significantly contribute to the toxicity or pharmacological activity of the salt and as such are the pharmacological equivalents to the bases of formula (I). They are generally preferred for medical use. In some cases, the physical properties which make them more desirable for pharmaceutical formulation such as solubility, lack of hygroscopicity, compressibility with respect to tablet formation, and compatibility with other ingredients with which the substance can be used for pharmaceutical use, have. The salts are routinely prepared by mixing a base of formula (I) with the selected acid, preferably by contact in solution, using an excess of commonly used inert solvents such as water, ether, benzene, ethanol, ethyl acetate, and preferably acetonitrile. They can also be prepared by metathesis or treatment with an ion exchange resin under conditions where the anion of one salt of a compound of formula (I) is replaced by another anion under conditions which allow separation of the desired compounds, such as by precipitation from solution or extraction. in a solvent or elution from or retention on an ion exchange resin. Pharmaceutically acceptable acids for salt formation of the compounds of formula (I) include sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, hydrogen iodide acid, citric acid, acetic acid, benzoic acid, cinnamic acid, almond acid, phosphoric acid, nitric acid, mucic acid, isethionic acid, palmic acid and heptic acid. others.

Compounds of formula (I) wherein R is the group "e" or "f" are obtained by a process involving the alkylation of a piperazinyl intermediate of formula (III)

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HN \] —.- VJ {I 1 (III)

5 \ γ / χΛ Z

wherein Y is oxygen or sulfur and Z is hydrogen or halogen, with a compound of formula (X) 10 - <o F \ y ^^ ici, 2h-x. wherein X has the meaning given above, and most preferably chlorine or bromine, in a solvent inert for the reaction to provide the compounds of formula (Ie). 25 (d) is reduced to the formation of the corresponding compounds of formula (If) / = \ OH yy

Piperazinyl benzisothiazole and benzisoxazole intermediates of formula (III) are obtained by reaction of 3-chloro-6-Z-1,2-benzisothiazole or 3-chloro-6-Z-1,2-benzisoxazole with excess piperazine at elevated temperature. Eg. the starting material 3-chloro-1,2-benzisothiazole is prepared by treating 1,2-benzisothiazol-3 (2H) one with phosphorus pentachloride at 100-140 ° C for 4 hours. A corresponding conversion of 1,2-benzisoxazole-6

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3-one to 3-chloro-1,2-benzisoxazole is carried out with phosphorus oxychloride / triethylamine according to the procedure of H. Boshagen, Ber. 100, 3326 (1967).

The compounds of this invention are valuable pharmacological agents 5 with psychotropic properties. In this regard, they exhibit selective central nervous system activity at non-toxic doses and are of particular interest as neuroleptic (anti-psychotic) agents. As with other known antipsychotics, the compounds of formula (I) induce certain reactions in standard in vivo and in vitro pharmacological test systems which are known to correlate well with anxiety release and symptoms of acute and chronic psychosis in humans. The following systems are illustrative of such conventional in vivo test systems used to classify and differentiate a psychotropic agent from a non-specific CNS depressant and to determine potential risks of adverse events (e.g., cataleptic activity). In relation to the latter, antipsychotic agents are a group known to induce sedation and extrapyramidal reactions such as acute torsional dystonia, akathiasia, parkinsonism, tardive dyskinesia and autonomic nervous system effects.

20 Behavior Test Reference

Suppression of Condi- Albert, Pharmacologist, 4, 152 (1962); tional avoidance reaction Wu, et al., J. Hed. Chem., 12, (CAR) 876-881 (1969).

25

Catalepsy Costal1, et al., Psychopharmacology, 34, 233-241 (1974); Berkson, J. Amer. Statist. Assoc., 48, 565-599 (1953).

Fighting mice Tedeschi, et al., J. Pharmacol.

Expt. Therap., 125, 28 (1959) "Rotarod" Kinnard, et al., J. Pharmacol. Expt.

35 Therap., 121, 354 (1957).

Apomorphine stereotypy Janssen, et al., Drug.

Research, 17, 841 (1966).

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As further indication of psychotropic activity and specificity of the compounds of the invention, known in vitro central nervous system receptor binding methodology may be used. Certain compounds (commonly referred to as ligands) have been identified that preferentially bind to specific high-affinity points in brain tissue that have to do with psychotropic activity or potential for side effects. Inhibition of radiolabeled ligand binding to such specific high affinity points is considered a measure of a compound's ability to affect corresponding central nervous system function or to cause adverse effects in vivo. This principle is used in the following examples, for example.

Receptor Binding Test Reference

Dopamine Burt, et al., Holec. Pharmacol., 12, 800 (1976); Science, 196, 326 (1977); Creese, et al.,

Science, 1921, 481 (1976).

Cholinergic Yamamura, et al., Proc. Natn.

20 Acad. Sci. U.S.A. 71, 1725 (1974).

α-receptor Crews, et al., Science 202: 322 (1978); Rosenblatt, et al.,

Brain Res. lf> 0: 186 (1979); U'Prichard, et al., Science 199: 197 (1978); U'Prichard, et al., Molec. Pharmacol. 13: 454 (1977) Serotonin type 2 Peroutka and Snyder, Molec.

Pharmacol. 16: 687 (1979).

According to the pharmacological profile established by the aforementioned tests, the compounds of formula (I) have promising anti-psychotic potential, being relatively potent in the CAR test with oral ED5Q values <100 mg / kg body weight and IC Q values of <1000 nanomolar in the ^ H-spi-peron-dopamine receptor binding assay. Activity in the CAR test and the spipe ron test is considered predictive of antipsychotic potential in humans.

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happens. With regard to selective antipsychotic activity, preferred compounds have significant dopamine receptor binding activity and they suppress CAR in rats during cataleptic doses.

The term systemic administration as used herein refers to 5 oral, rectal and parenteral (i.e., intramuscular, intravenous and subcutaneous) routes. In general, when one of the subject compounds is administered, it will be found that the preferred route is that a greater amount of the active ingredient is required to produce the same effect as a smaller amount administered parenterally. In accordance with good clinical practice, it is preferred to administer the subject compounds at a concentration level that will produce effective neuroleptic (anti-psychotic) effects without causing any harmful or undesirable side effects.

Therapeutically, the compounds of the invention are generally administered as 15 pharmaceutical compositions consisting of an effective antipsychotic amount of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier. Pharmaceutical compositions which provide from ca. 1 to 500 mg of the active ingredient per day. unit dose, are preferred and are conventionally prepared as tablets, lozenges, capsules, powders, aqueous or oily suspensions, syrups, elixirs and aqueous solutions.

Preferred oral preparations are in the form of tablets or capsules and may contain conventional excipients such as binders (e.g., syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone), fillers (e.g., lactose, sugar , corn starch, calcium phosphate, sorbitol or glycine), lubricants (e.g., magnesium stearate, talc, polyethylene glycol or silica), disintegrating agents (e.g., starch), and wetting agents (e.g., sodium lauryl sulfate). Solutions or suspensions of a compound of formula (I) 30 with conventional pharmaceutical vehicles are used for parenteral preparations such as an aqueous solution for intravenous injection or an oily suspension for intramuscular injection. Such preparations having the desired clarity, stability and suitability for parenteral use are obtained by dissolving from 0.1 to 10% by weight of the active ingredient in water or a vehicle consisting of a polyhydric aliphatic alcohol such as glycerine, propylene glycol and polyethylene glycols or mixtures thereof. The polyethylene glycols consist of a mixture of non-volatile, normally liquid polyethylene glycols, which are soluble in both water and organic liquids.

9 DK 160553 B

and having molecular weights from ca. 200 to 1500.

TABLE

5 The compounds listed below were tested for activity in the tests described on pages 6 and 7. The data given below relate to suppression of conditioned avoidance reaction (CAR) (test A) and catalepsy (test B) page 6 and dopamine receptor binding test (test C) on page 7. All doses are per day. grams, unless otherwise indicated for in vivo assays.

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Compound Example _ Name of Compound E E 4- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl-1- (4-fluorophenyl) -1-butanone hydrochloride 6 2 α- [3- [4 - (1,2-Benzisothiazol-3-yl) -1-piperazinyl] propyl] -4-fluorobenzene-methanol hydrochloride L 3 4- [4- (1,2-Benzisoxazol-3-yl) -1-piperazinyl ] -1- (4-fluorophenyl) -1-butanone hydrochloride, M 4 α- [3- [4- (1,2-Benzisoxazol-3-yl) -1-piperazinyl] propyl] -4-fluorobenzene methanol

Connect Test Results_ 30 E A ED 50 = 7.4mg / kg.

B ED 50 = 16.4 mg / kg.

C IC 50 = 10.2nM

G A ED 50 = 2.4mg / kg.

B ED 50 = 5.0mg / kg.

C IC5Q = 2.03nM

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10 L A EDgQ = 5.8mg / kg.

B ED 50 = 39.9mg / kg.

C IC 50 = 73.4 nm

5 Μ A ED 50 = lmg / kg.

B ED 50 = 2.2mg / kg.

C IC 50 = 29.5nM

The invention is illustrated in more detail in the following examples.

Example 1 4- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] -1- (4-fluorophenyl) -1-butanone

'- \> - wvrOrTO

(A) 2- (3-Chloropropyl) -2- (4-fluorophenyl) -1,3-dioxane - As stated in Chem. Abs. 63, 9959b (1965), a mixture of 4-chloro-4, fluorobutyrophenone (20 g), ethylene glycol (6.9 g) and p-toluenesulfonic acid (0.05 g) is refluxed in 50 ml of benzene for 30 minutes. hours, with the resulting water being collected. Concentration of the reaction mixture under vacuum gives 2- (3-chloropropyl) -2- (4-fluorophenyl) -1,3-dioxane.

(b) Title product, hydrochloride - A mixture of 2- (3-chloropropyl) - 2- (4-fluorophenyl) -1,3-dioxane (4.31 g, 0.0176 mol), 3- (1- piperazinyl) - 1,2-benzisothiazole (3.86 g, 0.0176 mol), powdered potassium carbonate (2.43 g, 0.0176 mol) and potassium iodide (0.88 g, 0.0053 mol) in 180 ml dry acetonitrile is refluxed for 20 hours. The reaction mixture is filtered, concentrated in vacuo, and the residual oil is dissolved in chloroform and filtered. Concentration of the filtrate gives an oily residue which is taken up in 100 ml of ethanol containing 10 ml of 3 N hydrochloric acid and refluxed for 15 minutes. Acetonitrile is added to the cooled mixture and the resulting solid is collected, 3.3 g, m.p. 248-250 ° C. Crystallization of this material from ethanol gives analytically pure

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H

4- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] -1- (4-fluorophenyl) -1-butanone, hydrochloricyl, m.p. 251-254eC.

Analysis calculated for m.p. FNgOS'HCl: C, 60.06; H, 5.52; N, 10.01.

Found: C, 59.70; H, 5.47; N, 9.78.

NMR (DMSO-d 6): 2.12 (2H, m); 3.25 (6H, m); 3.56 (4H, m); 4.06 (2H, d, 12.0 Hz); 7.41 (4H, m); 8.08 (4H, m); 11.60 (1H, bs).

Example 2 tt- [3- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] propyn-4-fluorobenzene methanol

/ = \ OH 'y V

Sodium borohydride (1.0 g, 0.026 mol) is added portionwise to a stirred suspension of 4- [4- (1,2-benzisothiazol-3-yl) -1 -piperazinyl] -1- (4-fluorophenyl) -1-butanone hydrochloride (3.34 g, 0.008 mol) in 150 ml of absolute ethanol. The mixture is stirred for 20 hours, acidified with ethanol in so-called hydrogen chloride, stirred for another 2 hours and concentrated under vacuum.

The remaining material is partitioned between chloroform and 1N aqueous sodium hydroxide, and the chloroform phase is dried over magnesium sulfate and concentrated in vacuo to give 2.31 g (69% yield) of the title compound as the free base. The free base is converted to the hydrochloride in ethanol with ethanolic hydrogen chloride to give at- [3- [4- (1,2-benz-30 in sothiazol-3-yl) -1-piperazinyl] propyl] -4-fluorobenzene methanol »hydrochloride -rid, m.p. 200-202eC.

Analysis calculated for C 21 H 24 FN 3 S * HCl: C, 59.78; H, 5.97; N, 9.96.

Found: C, 59.34; H, 5.95; N, 9.82.

NMR (DMSO-d 6): 1.70 (4H, m); 3.40 (8H, m); 4.05 (2H, d, 12.0 Hz); 4.59 (1H, m); 5.30 (1H, bs); 7.35 (6H, m); 8.10 (2H, m); 11.20 (1H, bs).

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Example 3 4- [4- (1,2-Benzisoxazol-3-yl) -1-piperazinyl] -1- (4-fluorophenyl) yl-1-butanone 5β, 2β, β-β 10

Reaction of 2- (3-chloropropyl) -2- (4-fluorophenyl) -1,3-dioxane with 3- (1-piperazinyl) -1,2-benzisoxazole by the procedure of Example 1 and conversion of the free base to the hydrochloride salt gives a 25% yield of 4- [4- (1,2-benzisoxazol-3-yl) -1-piperazinyl] -1- (4-fluorophenyl) -1-butanone, hydrochloride, m.p. 260-262 ° C, from methanol (25% yield).

Calcd for C21 ** 223 * V +: C, 62.46; H, 5.75; N, 10.1.

Found: C, 62.18; H, 5.59; N, 10.50.

NMR (DMSO-d 6): 2.11 (2H, m); 2.56 (2H, m); 3.40 (8H, m); 4.12 (2H, m); 7.33 (5H, m); 7.60 (1H, m): 8.06 (2H, m); 11.20 (1H, bs).

Example 4 α- [3- [4- (1,2-Benzoxazol-3-yl) -1-piperazinyl] propyl] -4-fluoro-benzene methanol F (CH

Reduction of 4- [4- (1,2-benzoxazol-3-yl) -1-piperazinyl] - (4-fluoro-phenyl-1-butane, hydrochloride (2.0 g, 0.005 mol) with Sodium borohydride 35 (0.57 g, 0.015 mole) in 200 ml of absolute ethanol is made according to the procedure of Example 2. Residual material after concentration of the acidified mixture is basified with sodium hydroxide and extracted with chloroform.

Claims (5)

Analysis calculated for C 21 H 24 FN 3 ° 2 C, 68.28; H, 6.55; N, 11.38. Found: C, 68.13; H, 6.56; N, 11.43. NMR (CDCl 3): 1.79 (4H, m); 2.60 (6H, m); 3.64 (4H, m); 4.68 (1H, m); 7.22 (8H, m). 10 An analogue and process for the preparation of benzisothioazole or benzisoxazole piperazine derivatives of formula (I), wherein R represents the group "e" or "f" / " VS / "\? H 25 \ _ / _ c '(CH2) r F \ _ / CIMCVr (e) (f) wherein Y represents oxygen or sulfur and Z, represents hydrogen or halogen, FEATURED by alkylating a piperazinyl intermediate of formula (III) / ~ Y / s HH No; - "f η \ / * 35 v Y in (III) DK 160553 B wherein Y and Z have the above meanings, with a compound of formula (X) 10 wherein X represents the acid residue of a reactive ester group, in a reaction inert solvent to provide the compounds of formula (Ie), wherein Y and Z have the meanings given above, wherein (Ie), if desired, is reduced to the formation of the corresponding compounds of formula (If) wherein Y and Z have the above meanings and / or, if desired, the resulting compound (I) is converted to a pharmaceutically acceptable, non-toxic acid addition salt thereof. 2. A process according to claim 1, characterized in that 4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] -1- (4-fluorophenyl) -1 is prepared from the corresponding starting materials. -butanone or a pharmaceutically acceptable acid addition salt thereof. 3. A process according to claim 1, characterized in that 4 - [- (1,2-benzisoxazol-3-yl) -1-piperazinyl] -1- (4-fluorophenyl) -1 is prepared from corresponding starting materials. -butanone or a pharmaceutically acceptable acid addition salt thereof. 4. A process according to claim 1, characterized in that a- [3- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] propyl] -4-fluorobenzene methanol or a pharmaceutically acceptable acid addition salt thereof. 5. A process according to claim 1, characterized in that a- [3- [4- (1,2-benzisoxazol-3-yl) -1-piperazinyl] propyl] -4-fluorobenzene methanol or a pharmaceutically acceptable acid addition salt thereof.