1-CINNAMYL-4-LOWER ALKYLCARBONYL-or 4-PHENYLCARBONYL PIPERIZINES

Abstract

Compounds of the formula ##SPC1## Wherein R.sub.1 is lower alkylcarbonyl or phenylcarbonyl (benzoyl) and R.sub.2 is H or Cl are very useful analgesics, as well as antiphlogistics because of their antiserotonic action, and are nonaddictive.

Description

The present invention relates to novel therapeutically useful compounds of the formula

wherein R.sub.1 is an acyl radical (lower alkyl carbonyl, wherein the lower alkyl moiety contains from one to six carbon atoms inclusive, or benzoyl) and R.sub.2 is H or halogen, e.g., Cl.

These new compounds are very useful as analgesics, as well as antiphlogistics because of their antiserotonic action.

The following table (table 1) sets forth analgesic activities of representative compounds of the invention.

Fifty percent effective dose (ED.sub.50) was calculated in mice from the oral doses which are needed to cause insensitivity to the pain stimuli applied to the tail roots by 100 mm. Hg of pressure. Fifty percent Lethal dose (LD.sub.50) was determined in ##SPC2## mice from dose which causes death of 50 percent of the animals in 24 hours after oral administration of the drugs. Safety range presents the ratio of LD.sub.50 to ED.sub.50.

Further, the substances of the present invention, being nontolerance analgesics, are of great advantage also in this point.

The compounds of the present invention can be prepared in accordance with the following reaction schema: ##SPC3##

In which R.sub.1 and R.sub.2 are of the same meaning as aforestated.

Further, the acid halide (R.sub.1 Cl) in the above scheme may be replaced by a reactive derivative such as acid anhydride and acid ester of the corresponding acid.

FIG. 1 of the accompanying figures of drawing illustrates the results of investigation of the presence of tolerance, which were obtained with mice continuously dosed with 1-cinnamyl-4-n-butyrylpiperazine hydrochloride and by pursuing the change in analgesic effect detected by pressure stimuli method. (Ordinate: pain threshold mm. Hg pressure; abscissa: the number of days.) In this test, morphine hydrochloride was used as control drug, there being employed as test animal ICR mice of which each group consisted of 10 animals. Each test drug being dosed one time a day, the drug of the invention was orally dosed in an amount of 100 mg./kg. in each dosage while the morphine hydrochloride was subcutaneously injected at 4 mg./kg. The analgesic effect was examined by applying the pressure stimuli method to the tail root of each test animal after 30 minutes since the dosage.

In FIG. 1, represents the morphine hydrochloride curve; represents the test compound of the invention.

FIG. 2 is a graph showing effects of repeated administration of morphine hydrochloride and 1-cinnamyl-4-butyryl-piperazine hydrochloride (AP-237) and cross-administration of these drugs and Levallorphan on body weight of white (albino) rats.

In FIG. 2, the various curves are identified as follows: ##SPC4##

As clearly seen from this graph, (FIG. 2) the morphine administered group show physical dependence or addiction; when the administration is stopped, the group shows remarkable decrease in body weight one day after the stoppage and shows clear addiction. In sharp contrast, the compounds of the present invention do not show these effects and are completely nonaddictive.

The compounds of the present application are useful in the treatment of pain or inflammation in mammals (human and animal, e.g., dogs, etc.) in situations wherein conventional analgesics or anti-inflammatory agents, such as aminopyrine or the like, are usually administered. Administration is advantageously oral, the dosage rate being 20-40 mg. (20-40.times. 3) per day for adult man, and correspondingly adjusted in the adult animal. Nonaddiction is of course a great advantage.

Following are representative but nonlimitative exemplary embodiments of the invention:

EXAMPLE 1

1-Cinnamyl-4-propionyl piperazine hydrochloride

A solution of propionyl chloride (4.9 g.) in chloroform is added, with stirring, to a mixture of 1-cinnamylpiperazine (10.7 g.) and sodium bicarbonate (4.5 g.) in chloroform (100 ml.). After completing the addition, stirring is continued for a while. The resultant solution is then washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a syrup which is distilled under diminished pressure to yield 1-cinnamyl-4-propionyl piperazine as a colorless viscous liquid having a boiling point of 196.degree.-201.degree. C. (0.5 mm. Hg).

This liquid is dissolved in 100 ml. of dry benzene, and dry hydrogen chloride is introduced into the solution to yield a crystalline precipitate. The precipitate is collected by filtration and recrystallized from ethanol-ether to give 1-cinnamyl-4-propionyl piperazine hydrochloride as colorless needles, m.p. 184.degree.-187.degree. C. Yield is 11.5 g. (73.8 percent).

Analysis Calcd. for C.sub.16 H.sub.23 N.sub.2 OCl: C, 65.18; H, 7.86; N, 9.50 Found: C, 64.73; H, 7.78; N, 9.33%.

in this and in the following examples, "g." stands for grams and "ml." for milliliters.

EXAMPLE 2

1-Cinnamyl-4-n-butyrylpiperazine hydrochloride

A solution of n-butyryl chloride (3.4 g.) in chloroform is added drop by drop to a mixture of 1-cinnamylpiperazine (6.5 g.) and sodium bicarbonate (2.7 g.) in chloroform (100 ml.). The mixture is allowed to stand at room temperature for several hours, while being stirred. The chloroform solution is washed with water, dried over anhydrous sodium sulfate, and a brown oil is obtained by concentration of the solution under reduced pressure. The oily product is distilled under a nitrogen stream to give 1-cinnamyl-4-n-butyrylpiperazine, b.p. 203.degree.-207.degree. C. (0.6 mm. Hg).

This liquid is dissolved in 100 ml. of dry benzene, and dry hydrogen chloride is introduced into the solution to yield a crystalline precipitate. By recrystallizing the product from acetonitrile-ether, 7.1 g. of colorless needles is obtained which have a melting point of 202.degree.-204.degree. C.

yield: 72% Anal. Calcd. for C.sub.17 H.sub.25 N.sub.2 OCl : C, 66.10; H, 8.15; N, 9.07 Found: C, 65.80; H, 8.10; N, 9.15%

example 3

1-cinnamyl-4-acetylpiperazine hydrochloride

A solution of acetyl chloride (3.1 g.) in chloroform is added, with stirring, to a mixture of 1-cinnamylpiperazine (7.1 g.) and sodium bicarbonate (3.4 g.) in chloroform (100 ml.). After completing the addition, stirring is continued for a while. The resultant solution is then washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a syrup which is distilled under diminished pressure to yield 1-cinnamyl-4-acetylpiperazine as a colorless viscous liquid having a boiling point of 182.degree.-185.degree. C. (0.6 mm. Hg). This liquid is dissolved in 100 ml. of dry benzene, and dry hydrogen chloride is introduced into the solution to yield a crystalline precipitate. The precipitate is collected by filtration and recrystallized from acetonitrile-ether to give 1-cinnamyl-4-acetylpiperazine hydrochloride as colorless needles, m.p. 205.degree.-206.degree. C.

yield is 6.3 g. (64.1%). Anal. Calcd. for C.sub.15 H.sub.21 ON.sub.2 Cl: C, 64.16; H, 7.54; N, 9.98 Found: C, 64.04; H, 7.71; N, 9.92%.

example 4

1-cinnamyl-4-isobutyrylpiperazine hydrochloride

A solution of isobutyryl chloride (4.0 g.) in benzene is added drop by drop under cooling, to a mixture of 1-cinnamylpiperazine (7.7 g.) and sodium bicarbonate (3.5 g.) in benzene (100 ml.). After completing the addition, stirring is continued for a while. The benzene solution is washed with water and then dried. Dry hydrogen chloride is passed into the solution, and the precipitate is recrystallized from acetonitrile. There is obtained 6.7 g. (67.3 percent yield) of colorless scaly crystal with m.p. 214.degree.-217.degree. C.

anal. Calcd. for C.sub.17 H.sub.25 N.sub.2 OCl: C, 66.11; H, 8.16; N, 9.07 Found: C, 65.89; H, 8.04; N, 9.06%.

example 5

1-cinnamyl-4-n-valerylpiperazine hydrochloride

A solution of n-valeryl chloride (3.6 g.) in benzene is added drop by drop under cooling to a mixture of 1-cinnamylpiperazine (5.1 g.) and sodium bicarbonate (2.5 g.) in benzene (100 ml.). After completing the addition, stirring is continued for a while. The benzene solution is washed with water and then dried. Dry hydrogen chloride is passed into the solution, and the precipitate is recrystallized from acetonitrile. There is obtained 5.4 g. (67.0 percent yield) of colorless scaly crystals with m.p. 209.degree.-212.degree. C.

anal. Calcd. for C.sub.18 H.sub.27 ON.sub.2 Cl: C, 66.95; H, 8.43; N, 8.68 Found: C, 66.43; H, 8.21; N, 8.76%.

example 6

1cinnamyl-4-n-hexanoylpiperazine hydrochloride

A solution of n-hexanoyl chloride (5.4 g.) in benzene is added drop by drop under cooling to a mixture of 1-cinnamylpiperazine (7.1 g.) and sodium bicarbonate (3.4 g.) in benzene (100 ml.). After completing the addition, stirring is continued for a while. The benzene solution is washed with water and then dried. Dry hydrogen chloride is passed into the solution, and the precipitate is recrystallized from acetonitrile. There is obtained 8.4 g. (71.2 percent yield) of colorless scaly crystal with m.p. 198.degree.-200.degree. C.

anal. Calcd. for C.sub.19 H.sub.29 ON.sub.2 Cl: C, 67.73; H, 8.68; N, 8.38 Found: C, 67.64; H, 8.61; N, 8.38%.

example 7

1-cinnamyl-4-heptanoylpiperazine hydrochloride

A solution of heptanoyl chloride (6.0 g.) in benzene is added drop by drop under cooling to a mixture of 1-cinnamylpiperazine (7.1 g.) and sodium bicarbonate (3.4 g.) in benzene (100 ml.). After completing the addition, stirring is continued for a while. The benzene solution is washed with water and then dried. Dry hydrogen chloride is passed into the solution, and the precipitate is recrystallized from acetonitrile. There is obtained 9.3 g. (75.9 percent yield) of colorless prismatic crystal with m.p. 195.degree.-198.degree. C.

anal. Calcd. for C.sub.20 H.sub.31 ON.sub.2 Cl: C, 68.45; H, 8.90; N, 7.98 Found: C, 68.09; H, 8.62; N, 8.08%.

example 8

1-(2-chlorocinnamyl)-4-n-butyrylpiperazine hydrochloride

A solution of n-butyryl chloride (2.5 g.) in benzene is added drop by drop under cooling, to a mixture of 1-(2-chlorocinnamyl)-piperazine (5.1 g; b.p. 170.degree.-180.degree. C., 7 mm. Hg) and sodium bicarbonate (2.0 g.) in benzene (100 ml.). After completing the addition, stirring is continued for a while. The benzene solution is washed with water and then dried. Dry hydrogen chloride is passed into the solution, and the precipitate is recrystallized from acetonitrile. There is obtained 5.2 g. (70.6 percent yield) of colorless prismatic crystal with m.p. 193.degree.-195.degree. C.

anal. Calcd. for C.sub.17 H.sub.24 ON.sub.2 Cl: C, 59.48; H, 7.05; N, 8.16 Found: C, 59.07; H, 6.88; N, 8.08%.

example 9

1-cinnamyl-4-isovalerylpiperazine hydrochloride

A solution of isolaleryl chloride (4.8 g.) in benzene is added drop by drop under cooling, to a mixture of 1-cinnamylpiperazine (7.1 g.) and sodium bicarbonate (3.4 g.) in benzene (100 ml.). After completing the addition, stirring is continued for a while. The benzene solution is washed with water and then dried. Dry hydrogen chloride is passed into the solution, and the precipitate is recrystallized from acetonitrile. There is obtained 7.0 g. (61.9 percent yield) of colorless crystal leaflets with m.p. 221.degree.-223.degree. C.

anal. Calcd. for C.sub.18 H.sub.27 ON.sub.2 Cl: C, 66.95; H, 8.43; N, 8.68 Found: C, 66.70; H, 8.42; N, 8.79%.

example 10

1-cinnamyl-4-pivaloylpiperazine hydrochloride

A solution of pivaloyl chloride (4,8 g.) in benzene is added drop by drop under cooling, to a mixture of 1-cinnamylpiperazine (7.1 g.) and sodium bicarbonate (3.4 g.) in benzene (100 ml.). After completing the addition, stirring is continued for a while. The benzene solution is washed with water and then dried. Dry hydrogen chloride is passed into the solution, and the precipitate is recrystallized from acetonitrile. There is obtained 8.2 g. (72.6 percent yield) of white powder with m.p. 252.degree.-254.degree. C.

anal. Calcd. for C.sub.18 H.sub.27 ON.sub.2 Cl: C, 66.9; H, 8.43; N, 8.68 Found: C, 66.68; H, 8.37; N, 8.52%.

example 11

1-(3-chlorocinnamyl)-4-n-butyrylpiperazine hydrochloride

A solution of n-butyryl chloride (3.4 g.) in benzene is added drop by drop under cooling, to a mixture of 1-(3-chlorocinnamyl) piperazine (b.p. 182.degree.-184.degree. C.- 4 mm. Hg) (5.0 g.) and sodium bicarbonate (2.7 g.) in benzene (100 ml.). After completing the addition, stirring is continued for a while. The benzene solution is washed with water and then dried. Dry hydrogen chloride is passed into the solution, and the precipitate is recrystallized from acetonitrile. There is obtained 5.8 g. (80.2 percent yield) of colorless crystal needles with m.p. 202.degree.-204.degree. C.

anal. Calcd. for C.sub.17 H.sub.24 ON.sub.2 Cl: C, 59.48; H, 7.05; N, 8.16 Found: C, 59.07; H, 6.85; N, 8.17%.

example 12

1-cinnamyl-4-benzoylpiperazine hydrochloride

Benzoyl chloride (b.0 g.) is added, drop by drop, to a mixture of 1 -cinnamylpiperazine (7.0 g.) and sodium bicarbonate (3.3 g.) in benzene (100 ml.). The mixture is kept at room temperature for several hours, while being stirred. The benzene solution is washed with water and dried over anhydrous sodium sulfate. Dry hydrogen chloride is introduced into the solution to yield a crystalline precipitate. By recrystallizing the product from acetronitrile, 9.5 g. of colorless needles are obtained, which have a melting point of 240.degree.-242.degree. C.

yield: 78 % Analysis: C.sub.20 H.sub.23 N.sub.2 OCl Calculated: C% 70.66 H% 6.76 N% 8.17 Determined: 69.95 6.87 8.29

Claims

Having thus disclosed the invention, what is claimed is:

1. A compound selected from the group consisting of a compound of the formula

and pharmaceutically acceptable acid addition salts thereof, wherein R.sub.1 is lower alkylcarbonyl or phenylcarbonyl and R.sub.2 is H or chlorine.

2. 1-cinnamyl-4-acyl-piperazine of the formula:

wherein R is a linear or branched chain C.sub.1 -C.sub.6 alkyl radical and X stands for a hydrogen or a chlorine atom.

3. A compound according to claim 1, namely, 1-cinnamyl-4-acetylpiperazine.

4. A compound according to claim 1, namely, 1-cinnamyl-4-propionylpiperazine hydrochloride.

5. A compound according to claim 1, namely, 1-cinnamyl-4-n-butyrylpiperazine hydrochloride.

6. A compound according to claim 1, namely 1-cinnamyl-4-isobutyrylpiperazine.

7. A compound according to claim 1, namely, 1-cinnamyl-4-n-valerylpiperazine.

8. A compound according to claim 1, namely, 1-cinnamyl-4-n-hexanoylpiperazine.

9. A compound according to claim 1, namely, 1-cinnamyl-4-n-heptanoylpiperazine.

10. A compound according to claim 1, namely, 1-(2-chlorocinnamyl)-4-n-butyrylpiperazine.