DK158515B - 2-PIPERAZINYL- OR -HOMOPIPERAZINYL-QUINAZOLINE DERIVATIVES AND PHARMACEUTICAL PREPARATIONS CONTAINING THESE - Google Patents

Description

DK 158515B

The present invention relates to novel piperazinyl or homopiperazinyl quinazines and acid addition salts thereof, and to pharmaceutical compositions containing them, which are characterized in that they have the general formula I

R2 lCH2> n T

R3 where

R 1 is hydrogen, C 1-6 alkyl, 3-7 cycloalkyl or phenyl, the phenyl ring being optionally monosubstituted with halogen, C 1-4 alkyl or C 1-4 alkoxy, R 2 representing hydrogen, halogen or C 2. g is alkyl, n is 1 or 2, R 3 is hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 acyl or trifluoromethyl, and X represents -CHOH-, and m represents 2 or 3, or X is -CO- or a protected -CO group, and m is 1, 2 or 3, or X is -O- and m is 2 or 3, or

20 X represents a group of general formula II

-CH- LJ) in R5 "6 wherein R5 and Rg are independently hydrogen, halogen, 254-4 alkyl, C1-4 alkoxy or trifluoromethyl, and m is 3, with the proviso that when X represents - CO- or -O-, then R 2 is different from hydrogen, C 1-6 alkyl or phenyl, and acid addition salts thereof.

2

DK 158515 B

An optional alkyl radical of 1-6 carbon atoms preferably has 1-4 carbon atoms, especially 1-2 carbon atoms. An optional alkyl or alkoxy radical having 1-4 carbon atoms preferably has 1-3 carbon atoms, especially 1 or 2 carbon atoms. Halogen represents fluorine, chlorine, bromine or iodine, especially fluorine or chlorine. Acyl refers in particular to acetyl. A suitable -CO protecting group is, for example, a dialkyl ketal group such as dimethyl or diethyl ketal or an alkylene ketal group such as ethylene or n-propylene ketal.

Preferably, R3 sits in the para position relative to the X portion. R 3 preferably represents halogen, especially fluorine. Preferably, R5 sits in the para position relative to the -CH moiety. R5 is suitably halogen, especially fluorine. X is suitably -O-, but especially -C0-.

Particularly suitable values for m are 2 or 3, preferably 3. A preferred value for n is 1.

US Patent No. 3,585,193 discloses 1- (quinazolin-2-yl) -4- (3 ", 4" -methylenedioxybenzyl) piperazines which exhibit vasodilatory and bronchodilatory effects.

From U.S. Patent No. 3,435,036 and J. Med. Ghem., 1972, Vols 15, 295-301, respectively, are known di- and triphenylpropylpiperazines, which on the piperazine nitrogen are substituted with 2-quinazolinyl, and which exhibit antihypertensive, analgesic and vasodilatory effects.

The compounds prepared by the process of the invention differ from the known compounds in that they exhibit neuroleptic effects.

Danish Patent Application No. 5142/83 discloses certain of the 2-piperazinyl-quinazolines different in the method of the present invention with neuroleptic and antihypertensive effect.

A compound of general formula I as set forth above may be prepared by a process wherein a compound of general formula III

3

DK 158515B

|] L / jL, in * 2

where and R 2 is as defined above and Y represents a leaving group, reacting with a compound of general formula IV

wherein R3, X, m and n are as defined above and the compound of general formula I is isolated in the form of the free base or an acid addition salt thereof.

The procedure may be carried out in the usual manner for analogous reactions.

The reaction of a quinazoline with a leaving group in the 2-position, in particular a compound of general formula III, wherein the leaving group Y represents, for example, C 1-4 alkoxy or C 1-6 alkylthio, p-nitrobenzylthio or preferably halogen, especially chlorine, is conveniently carried out in an inert organic solvent such as isopropanol, toluene, dimethylformamide or dimethyl sulfoxide at a temperature in the range 50-200 ° C, preferably 80-140 ° C. The reaction is conveniently carried out in the presence of an acid-binding agent, e.g., potassium carbonate, pyridine or triethylamine. An acid binding agent may also be used in excess of a compound of the general formula IV.

For the preparation of a compound of general formula I wherein X 25 represents -CO-, it may be convenient to protect the -CO group in

DK 158515B

4 the starting material. Examples of such protecting groups are listed above. The removal of such a group can be performed in known manner.

The starting materials can be prepared in known manner.

Insofar as the preparation of starting materials is not specifically described, these compounds are known or can be prepared analogously to known compounds or analogously to a process described herein.

The compounds of the invention can be converted into acid addition salts thereof in the usual manner and vice versa. Suitable acids include, for example, 10 hydrochloric acid, hydrobromic acid, succinic acid, maleic acid and fumaric acid.

In the examples below, all temperatures are uncorrected.

Description of procedure: Example 1

Preparation of 4 * [4- (Quinazolin-2-yl) -2-piperazinyl] -1- (4-fluorophenyl) -1-butanone (known from Danish Patent Application No. 5142/83).

2.25 g of 2-chloroquinazoline, 4.2 g of 1- (3- [2- (4-fluorophenyl) -1,3-dioxolan-2-yl] propyl) piperazine and 2 ml of triethylamine in 8 ml of isopropanol are stirred and heated for 2.5 hours at 80 ° C. The solvent is then evaporated in vacuo and the residue taken up in hexane. The hexane solution is treated with charcoal, filtered and concentrated to crystallize the ketal of the title compound. The resulting precipitate is dissolved in 40 ml of aqueous 1N hydrochloric acid. After 1 hour, the acidic solution is made basic with aqueous ammonia. The resulting precipitate is filtered off and recrystallized from ethyl acetate to give the title compound, mp 129-131 ° C.

DK 158515 B

5

Description of procedure: EXAMPLE 2

Preparation of 2- {4- [3- (4-Fluorophenoxy) propyl] -1-piperazinyl) quinazoline (known from Danish Patent Application No. 5142/83).

2.5 g of 2-chloroquinazoline, 3.8 g of 1- [3- (4-fluorophenoxy) propyl] piperazine and 2.5 ml of triethylamine in 15 ml of isopropanol are stirred under reflux for 5 hours. The solvent is then evaporated in vacuo and the residue partitioned between water and methylene chloride. The organic phase is dried and evaporated. The residue is recrystallized from ethanol to give the title compound, mp 126-128 ° C.

EXAMPLE 3

By analogy to the method described in Example 1 or 2, the following compounds of the general formula I are prepared, where n is 1 and m is 3.

Ex. R-1 R2 X B-3 Melting point ° C

a cyclohexyl H CO 4 -F 93-95 b p-chlorophenyl H CO 4-F 103.5-105.5 cp - fluorophenyl H CO 4-F 102-105 d p-tolyl H CO 4-F 91- 94 e p-methoxy-H CO 4-F 99.5-103.5 phenyl f-chlorophenyl 6-Cl CO 4-F 102-112 g p-chlorophenyl 7-C1 CO. 4-F 165-168 25h phenyl H CH 4-F 142-144 Φ

F

in phenyl H CH 4-F> 153 (decomposition) OH dihydrochloride

DK 158515B

έ

The compounds of the invention have pharmacological activity and are therefore indicated for use as pharmaceuticals, eg for therapy. In particular, the compounds have neuroleptic activity as shown in standard tests, e.g., by inhibiting movement in mice. In this test, groups of 3 male mice (18-24 g, OF-1, Sandoz, Basel) received 3.2, 10, 32, 100 and 320 mg of test compound orally. One hour after drug administration, the mice were examined separately and their movements were compared with those of control animals.

ISLAND

Furthermore, the compounds of the invention bind to H-spiperone-10 binding sites in the brain (modified method of J. Leysen et al., Biochem. Pharmac., 27, 1978, p. 307). The test was performed as follows: freshly striated calf brain tissue was homogenized in 25 times as much tris buffer (pH 7.4, 50 mM, 120 mM sodium chloride) and centrifuged. The pellets were suspended in a 22x volume but trifluorescent buffer, incubated for 15 minutes at 37 ° C, and centrifuged.

The pellets were suspended in a 3 times the volume of tris buffer. The composition of the assay mixtures was as follows: 45 mM tris buffer, pH 7.7, 108 mM sodium chloride, membranes corresponding to 6 mg of original tissue weight, 0.1 nM ^ H-spiperone, 5 x 10-½ cinanserin 20 to eliminate the contribution of 5-HT2 receptors and 1 μια unlabeled spi-peron in determining non-specific binding. To determine the inhibition of the specific binding of% -spiperone, test compound sequences were added so as to obtain from 5 to 9 different concentrations between 1 nM and 10 μη, each in duplicate. After incubation for 25 minutes at room temperature, the assay mixtures were rapidly filtered through Whatman GF / B filter and the filters were washed twice with 5 ml of ice-cold tricuffer and scintillation gel.

In these experiments, for a number of the compounds prepared in the Examples, the results set forth in the table below were obtained compared to the known neuroleptic compound, Clozapine.

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TABLE

Receptor binding IC50 nM

Example No. H-spiperone 5 _ 3a 150 3d 690 3e 618 3f 565 10 Clozapine 990

Furthermore, by administering 2-20 mg / kg orally to rats, the compounds increase sleep phase II and decrease the paradoxical sleep / wake cycle performed in accordance with those of H. Kleinlogel 15 et al., European J. Pharmacol., 33, 1975, pp. 159-163, principles described. Furthermore, the resulting sleep phase II exhibits atypical qualitative characteristics.

The compounds are therefore indicated for use as neuroleptic agents. For this use, an indicated daily dose of approx.

25 - approx. 600 mg of the compounds conveniently administered in divided doses 2-4 times daily in unit dosage form containing ca.

6 - approx. 300 mg or in retard form.

Furthermore, the compounds of the invention are useful as antihypertensive agents, as demonstrated in standard tests, for example, in the% -Prazosin binding assay for α-receptors (modified method of Greengrass P. et al., Fur. J. Pharmac. 55, 1979 , pp. 323-326). The test was performed as follows: Fresh cerebral cortex tissue is homogenized in a 20-fold volume of tris-HCl buffer (50 µM, pH 7.7) using a polytron PT 20 and centrifuged at 30,000 x g for 25 minutes.

The pellets are resuspended in a 13-fold volume of the same buffer, incubated for 15 minutes at 37 ° C and centrifuged again at 50,000 x g for 11 minutes. Pellets from this centrifugation are frozen at -20 ° C and resuspended in a 60-fold volume of the same buffer as used above before use in the binding experiment. The compound -35 composition of the assay mixtures (total volume 2 ml) is as follows: 50 millimoles of tris-HCl buffer, pH 7.7, membranes corresponding to 30 mg of the original tissue weight and 0.3 nM% -razosin. Assays for

Claims (4)

The compounds are therefore indicated for use as an antihypertensive drug. For this use, an indicated daily dose of approx. 5 - approx. 100 mg of the compounds conveniently administered in divided doses 2-4 times daily in unit dosage form containing ca. 1 - approx. 50 mg or in retard form. The compounds of the invention may be administered in the form of pharmaceutically acceptable acid addition salts thereof. Such acid addition salts have the same efficiency as the free base forms. The pharmaceutical compositions of the invention are characterized in that they contain a compound of the general formula X or a pharmaceutically acceptable acid addition salt thereof together with a pharmaceutical carrier or diluent. Such preparations may, for example, be in the form of a solution or tablet. The neuroleptic effect is the preferred indication for the compounds of the invention. 25 PATENT REQUIREMENTS 1. Quinazoline derivatives, characterized in that they have the general formula I DK 158515B R2 (¾ T R3 where Represents hydrogen, C1-6 alkyl, C3-6 cycloalkyl 1 or pheyl, the phenyl ring being optionally monosubstituted with halogen, O1-4 alkyl or C1-4 alkoxy, Ry represents hydrogen, halogen or C 1-6 alkyl, n is 1 or 2, R 3 represents hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 acyl or trifluoromethyl, and X represents -CHOH-, and m represents 2 or 3, or X represents -CO- or a protected - CO group, and m is 1, 2, or 3, or 15. represents -O-, and m is 2 or 3, or X represents a group of the general formula II -CH- ^ oj | Wherein R5 and Rg independently represent hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy or trifluoromethyl, and m is 3, with the proviso that when X represents -CO- or -O- , then R 1 is different from hydrogen, - g -alkyl or phenyl, or pharmaceutically tolerable acid addition salts thereof. A compound according to claim 1 for use as a medicament. A compound according to claim 1 for use as a neuroleptic or antihypertensive agent. DK 158515B Pharmaceutical composition, characterized in that it contains a compound according to claim 1 together with a pharmaceutical carrier or diluent.