US3625965A - 1-CINNAMYL-4-LOWER ALKYLCARBONYL-or 4-PHENYLCARBONYL PIPERIZINES - Google Patents

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

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Publication number
US3625965A
US3625965A US693786A US3625965DA US3625965A US 3625965 A US3625965 A US 3625965A US 693786 A US693786 A US 693786A US 3625965D A US3625965D A US 3625965DA US 3625965 A US3625965 A US 3625965A
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Prior art keywords
cinnamyl
solution
benzene
hydrochloride
namely
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US693786A
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English (en)
Inventor
Tsutomu Irikura
Kuniyasu Masuzawa
Keigo Nishino
Hiroaki Uchida
Masatoshi Ito
Noriko Ichinoseki
Hideo Okubo
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Kyorin Pharmaceutical Co Ltd
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Kyorin Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids

Definitions

  • Threshold PATENIED DEC 7 ISYI mmHg SHEET 1 OF 2 Morphine Hydrochloride Inventive Substance MASATOSHI ITO.
  • SHEET 2 BF 2 A u iuzsuvl I a 1 7 2% 0; T mur? o Tddv i o nuavni lou TSLITOMU lRlKURA,
  • 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.
  • morphine hydrochloride was CH:CHCH2N.
  • 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.
  • 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.
  • 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:
  • El 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.
  • 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.
  • the group shows remarkaacid ester of the corresponding acid.
  • 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.
  • 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).
  • 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.
  • dry hydrogen chloride is introduced into the solution to yield a crystalline precipitate.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • R is a linear or branched chain C -C alkyl radical and X stands for a hydrogen or a chlorine atoms.
  • a compound according to claim 1 namely, l-cinnamyl- 4-acetylpiperazine.
  • a compound according to claim l namely, l-cinnamyl- 4-propionylpiperazine hydrochloride.
  • a compound according to claim 1 namely, l-cinnamyl- 4-n-butyrylpiperazine hydrochloride.
  • a compound according to claim 1 namely l-cinnamyl4- isobutyrylpiperazine.
  • a compound according to claim ll namely, l-cinnamyl- 4-n-valerylpiperazine.
  • a compound according to claim ll namely, l-cinnamyl- 4-n-heptanoylpiperazine.
  • a compound according to claim 1 namely, l-(2- chlorocinnamyl)4-n-butyrylpiperazine.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US693786A 1966-12-28 1967-12-27 1-CINNAMYL-4-LOWER ALKYLCARBONYL-or 4-PHENYLCARBONYL PIPERIZINES Expired - Lifetime US3625965A (en)

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JP4266566 1966-12-28

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3947411A (en) * 1972-09-21 1976-03-30 Warner-Lambert Company Novel 1-aryl-2-arylalkyl-3-or-4-[4'-(substituted-alkyl)piperazino-1']butanols-2-or-butenes-1, and methods of manufacture thereof
US4001223A (en) * 1975-01-13 1977-01-04 Idemitsu Kosan Co., Ltd. Adamantane-piperazine derivatives
US4104383A (en) * 1973-11-02 1978-08-01 C M Industries Derivatives of phenylpropenylamine
US4562191A (en) * 1983-11-15 1985-12-31 Euroresearch S.R.L. Methyl-piperazino derivatives with analgesic activity
US4804661A (en) * 1986-06-16 1989-02-14 Ciba-Geigy Corporation Disubstituted piperazines

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB809760A (en) * 1956-04-20 1959-03-04 Lab Pharmaceutica Dr C Janssen Improvements in or relating to pharmacologically active piperazine derivatives and processes for preparing them
US3318876A (en) * 1962-12-11 1967-05-09 Lepetit Spa Substituted piperazines and process for preparing same

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB809760A (en) * 1956-04-20 1959-03-04 Lab Pharmaceutica Dr C Janssen Improvements in or relating to pharmacologically active piperazine derivatives and processes for preparing them
US3318876A (en) * 1962-12-11 1967-05-09 Lepetit Spa Substituted piperazines and process for preparing same

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3947411A (en) * 1972-09-21 1976-03-30 Warner-Lambert Company Novel 1-aryl-2-arylalkyl-3-or-4-[4'-(substituted-alkyl)piperazino-1']butanols-2-or-butenes-1, and methods of manufacture thereof
US4104383A (en) * 1973-11-02 1978-08-01 C M Industries Derivatives of phenylpropenylamine
US4001223A (en) * 1975-01-13 1977-01-04 Idemitsu Kosan Co., Ltd. Adamantane-piperazine derivatives
US4562191A (en) * 1983-11-15 1985-12-31 Euroresearch S.R.L. Methyl-piperazino derivatives with analgesic activity
US4804661A (en) * 1986-06-16 1989-02-14 Ciba-Geigy Corporation Disubstituted piperazines

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