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Publication numberUS3625965 A
Publication typeGrant
Publication dateDec 7, 1971
Filing dateDec 27, 1967
Priority dateDec 28, 1966
Publication numberUS 3625965 A, US 3625965A, US-A-3625965, US3625965 A, US3625965A
InventorsNoriko Ichinoseki, Tsutomu Irikura, Masatoshi Ito, Kuniyasu Masuzawa, Keigo Nishino, Hideo Okubo, Hiroaki Uchida
Original AssigneeKyorin Seiyaku Kk
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
1-CINNAMYL-4-LOWER ALKYLCARBONYL-or 4-PHENYLCARBONYL PIPERIZINES
US 3625965 A
Abstract  available in
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Description  (OCR text may contain errors)

United States Patent Tsutomu lrikura;

Kuniyasu Masuzawa; lifieigo Nishino; Hiroaki Uchida; Masaioshi 110, all oi? Tokyo; Noriko lchinoseki, Saltama; lilideo Inventors l-ClNNAMYL-4-LOWER ALKYLCARBONYlL-OR 4- PIHENYLCARBONYL PIPERIZINES 10 Claims, 2 Drawing Figs.

ILLS. Cll 260/240 1K, 424/250 Int. Cl C07d 51/70 Field of Search 260/240, 240 D, 240 K [56] References Cited UNITED STATES PATENTS 3,318,876 5/1967 Cignarella et al 260/240 FOREIGN PATENTS 809,760 3/1959 Great Britain 260/240 Primary Examiner-Henry R. .liles Assistant Examiner-G. Thomas Todd At!orney--Wenderoth, Lind & Ponack Compounds of the formula wherein R is lower alkylcarbonyl or phenylcarbonyl (benzoyl) and R is H or Cl are very useful analgesics, as well as antiphlogistics because of their antiserotonic action, and are nonaddictive.

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l-ClNNAMYL-4-LOWER ALKYLCARBONYlL-OR 4- PHENYLCARBONYL PIPERIZINES The present invention relates to novel therapeutically useful 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 lcinnamyl- 4-n-butyrylpiperazine hydrochloride and by pursuing the compounds of the formula 5 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 CH:CHCH2N. used as control drug, there being employed as test animal ICR mice of which each group consisted of animals Each test R1 10 drug being closed one time a day, the drug of the invention was mm W orally dosed in an amount of I00 mg/kg in each dosage while the morphine hydrochloride was subcutaneously injected at 4 wherein R, is an acyl radical (lower alkyl carbonyl, wherein mgJkg. The analgesic effect was examined by applying the the lower alkyl moiety contains from one to six carbon atoms pressure stimuli method to the tail root of each test animal inclusive, or benzoyl) and R is H or halogen, e.g., Cl. after minutes since the dosage.

These new compounds are very useful as analgesics, as well in lFlG. l,- represents the morphine hydrochloride as antiphlogistics because of their antiserotonic action. curve; A A represents the test compound of the invention. The following table (table 1) sets forth analgesic activities FIG. 2 is a graph showing effects of repeated administration of representative compounds of the invention. of morphine hydrochloride and Lcinnamyl-4-butyryl- Fifty percent effective dose (ED was calculated in mice 20 piperazine hydrochloride (AP237) and cross-administration from the oral doses which are needed to cause insensitivity to of these drugs and Levallorphan on body weight of white (althe pain stimuli applied to the tail roots by 100 mm. Hg of bino) rats. pressure. Fifty percent Lethal dose (LD was determined in in FIG. 2, the various curves are identified as follows:

TABLE 1 Analgesic Safety ED (100 range mm. Hg), LD o, (LDsO/ Structure of the compound tested mg./kg. mg-l so) E 200 1, 000 Z CH=CH-CH2-I\{ NCOCHa-HCI 3 2s. 9 715 24. 7 CH=CH-CHZN NCOCHzCHa-HO1 3a 5 s32 22. 7 CH=CH-CH2N\ NCOCHz-CHz-CHa-HCI 117. 0 790 0. 7 0H=0H-0&N Noocm-om-cm-crn-flci 200 CH=CH-CHg-N NCOC5Hn-HCl CH=CH-CH2N NCOCoHwHCl CH3 79. 5 G93 8. 7 HC=CHCH:N\ NCOCH-HC1 57. 7 1, s00 27 c11=oH-cm1-r NCO crncmcmfiol Aminopyrine (aminophenazone) 16 120 8 X X Control roup.

-mlce f dose whlch causes deg"! of 50 percent of Morphin HCl was injected (s.c.) twice a day, and saline animals in 24 hours after oral administration of the drugs. was injected in place f morphine when the cross test Safety range presents the ratio of LB, to ED was carried out.

- M hi HCl was in ected (s.c. twice a day, and Level- Further, the substances of the present invention, being nonfgf gfi 10 mg/kg ,J,, in place f morphine tolerance analgesics, are of great advantage also in this point. I gf f gfigfif gfii ggi ffg gi m a day and M3437 The compounds of the present invention can be prepared 1n u g was administered (p-OJ in placeof morphine accordance with the following reaction schema: whe h cross test Was carried O -O AP-237 was administered (p.0.) twice a day, and saline was injected in place of AP-237 when the cross test was A Ai h a i out d 1m r d (p 0 m a day and Leval Wasam sere \ce OH=CH CHN\ NH R101 A lorphan 10 mgJkg. was injected (s.c.) in place of AP-237 when the cross test was carried out.

El El AP-237 was administered (p.o.) twice a day, and morphine in which R, and R, are of the same meaning as aforestated.

Further, the acid halide (RC 1) in the above scheme may be hydrochloride 40 mgJkg. (s.c.) wasinjccted in place of AP237 when the cross test was earned out.

NOTE.Ordinate: Body weight (grams). Abscissa: Day(s). Cross-test.

As clearly seen from this graph, (FIG, 2) the morphine administered group show physical dependence or addiction;

replaced by a reactive derivative such as acid anhydride and when the administration is stopped, the group shows remarkaacid ester of the corresponding acid.

ble decrease in body weight one day after the stoppage and shows clear addiction. ln 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 s aminopyrine or the like, are usually administered. Administration is advantageously oral, the dosage rate being 2040 mg. (20-40X3 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 I l-Cinnamyl-4-propionyl piperazine hydrochloride A solution of propionyl chloride (4.9 g.) in chloroform is added, with stirring, to a mixture of l-cinnamylpiperazine (107 g.) and sodium bicarbonate (4.5 g.) in chloroform (l 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 l-cinnamyl-4-propionyl piperazine as a colorless viscous liquid having a boiling point of l962l0C. (0.05 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 l-cinnamyl- 4-propionyl piperazine hydrochloride as colorless needles, mp. l84-l87 C. Yield is l 1.5 g. (73.8 percent).

Analysis Calcd. for C H, ,N,OCI: 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 chlorofonn is added drop by drop to a mixture of l-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 l-cinnamyl-4-n-butyrylpiperazine, b.p. 203207C. (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 acetaonitrile-ether, 7.1 g. of colorless needles is obtained which have a melting point of 202204 C.

Yield: 72%

Anal.

Calcd. for c,,n,,N,oci c. 66.10; H, a.|s; N, 9.01

Found: c, 65.80; H, 8.10; N, 9.15%

EXAMPLE 3 l-Cinnamyl-4-acetylpiperazine hydrochloride A solution of acetyl chloride (3.l g.) in chloroform is added, with stirring, to a mixture of l-cinnamylpiperazine 7.1 g.) and sodium bicarbonate (3.4 g.) in chloroform (100 ml.). After completing the addition, stirring is continued for a C. (0.6 mm. Hg). This liquid is dissolved in 100 ml. of dry benzene, and dry hydrogenchloride is introduced into the solution to yield a crystalline precipitate. The precipitate is collected by filtration and recrystallized from acetonitrileether to give l-cinnamyl-4-acetylpiperazine hydrochloride as colorless needles, mp. 205 206 C.

Yield is 6.3 g. (641%). Anal.

Found: C, 64.04; H, 7.71; N, 9.92%.

EXAMPLE 4 l-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 l-cinnamylpiperazine (7.7 g.) and sodium bicarbonate (3.5 g.) in benzene 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. 2 l4-2 1 7 C.

Anal.

Calcd. for C H,,N,OC I:

Found:

C, 66.] l; H, 8.16; N, 9.07 C, 65.89; H, 8.04; N, 9.06%.

EXAMPLE 5 l-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 l-cinnamylpiperazine (5.l 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. 2092 l 2 C.

Anal.

Calcd. for C,,H,,0N,Cl:

Found:

C, 66.95; H, 8.43; N, 8.68 C, 66.43; H, 8.2l; N, 8.76%.

EXAMPLE 6 l-cinnamyl-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 l-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. (7l .2 percent yield) of colorless scaly crystal with m.p. l98-200 C.

Anal.

Calcd. for C,,H,,0N,Cl:

Found:

C, 67.73; H, 8.68; N, 8.38 C, 67.64; H, 8.6l; N, 8.38%.

EXAMPLE 7 added drop by drop under cooling to a mixture of l-cinnamylpiperazine (7.1 g.) and sodium bicarbonate (3.4 g.) in benzene (I00 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. l95-l98 C.

Anal.

Calcd. for C,,H,,0N,Cl: c, 68.45; H, 3.90; N, 7.93

Found: C, 68.09;!1, 8.62; N, 8.08%.

EXAMPLE 8 l-(2chlorocinnamyl)-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 l-(2-chlorocinnamyl)-piperazine (5.1 g; b.p. l70l80 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. l93l9SC.

Anal. Calcd. for C,,H,,ON,C1: C, 59.48; H, 7.05; N, 8.16

Found: C, 59.07; H, 6.88; N, 8.08%.

EXAMPLE 9 l-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 l-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. 221223 C.

Anal.

Calcd. for C, H,,ON,Cl: c, 66.95; H, 8.43; N, 8.68

Found: C, 66.70; H, 8.42; N, 8.79%.

EXAMPLE l0 l-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 l-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. 252254 C.

Anal.

Calcd. for C H ON CI: C, 66.9 H, 8.43; N, 8.68

Found: C, 66.68; H, 8.37; N, 8.52%.

EXAMPLE I l l-(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 l-(3-chlorocinnamyl) piperazine (b.p. l82-l84 C.-4 mm. Hg) (5.0 g.) and sodium bicarbonate (2.7 g.) in benzene 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. 202-204 C.

Anal. Calcd. for c,,H,,oN,c1: c. 59.48; H, 7.05; N, a. [6

Found: C, 59.07; H, 6.85; N, 8.17%.

EXAMPLE [2 Yield: 78

Calculated: C% 70.66 H% 6.76 N% 8.17 Determined: 69.95 6.87 8.29

Having thus disclosed the invention, what is claimed is: ll. A compound selected from the group consisting of a compound of the formula and pharmaceutically acceptable acid addition salts thereof, wherein R, is lower alkylcarbonyl or phe-nylcarbonyl and R is H or chlorine.

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

CH=CHCHr-N Q U wherein R is a linear or branched chain C -C alkyl radical and X stands for a hydrogen or a chlorine atoms.

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

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

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

6. A compound according to claim 1, namely l-cinnamyl4- isobutyrylpiperazine.

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

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

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

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

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US3318876 *Nov 26, 1963May 9, 1967Lepetit SpaSubstituted piperazines and process for preparing same
GB809760A * Title not available
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US3947411 *Sep 18, 1973Mar 30, 1976Warner-Lambert CompanyNovel 1-aryl-2-arylalkyl-3-or-4-[4'-(substituted-alkyl)piperazino-1']butanols-2-or-butenes-1, and methods of manufacture thereof
US4001223 *Dec 16, 1975Jan 4, 1977Idemitsu Kosan Co., Ltd.Adamantane-piperazine derivatives
US4104383 *Jun 4, 1976Aug 1, 1978C M IndustriesDerivatives of phenylpropenylamine
US4562191 *Nov 2, 1984Dec 31, 1985Euroresearch S.R.L.Methyl-piperazino derivatives with analgesic activity
US4804661 *Jun 9, 1987Feb 14, 1989Ciba-Geigy CorporationDisubstituted piperazines
Classifications
U.S. Classification544/391
International ClassificationC07D295/185
Cooperative ClassificationC07D295/185
European ClassificationC07D295/185