GB2169892A - Piperazine derivatives - Google Patents

Piperazine derivatives Download PDF

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Publication number
GB2169892A
GB2169892A GB08501625A GB8501625A GB2169892A GB 2169892 A GB2169892 A GB 2169892A GB 08501625 A GB08501625 A GB 08501625A GB 8501625 A GB8501625 A GB 8501625A GB 2169892 A GB2169892 A GB 2169892A
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GB
United Kingdom
Prior art keywords
piperazine
ethanol
addition salts
alkanol
dioxolane
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
GB08501625A
Other versions
GB8501625D0 (en
GB2169892B (en
Inventor
Rafael Foguet
Santiago Gubert
Manuel Raga
Aurelio Sacristan
Jose A Ortiz
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ferrer Internacional SA
Original Assignee
Ferrer Internacional SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ferrer Internacional SA filed Critical Ferrer Internacional SA
Priority to GB08501625A priority Critical patent/GB2169892B/en
Publication of GB8501625D0 publication Critical patent/GB8501625D0/en
Publication of GB2169892A publication Critical patent/GB2169892A/en
Application granted granted Critical
Publication of GB2169892B publication Critical patent/GB2169892B/en
Expired legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/28—Radicals substituted by nitrogen atoms

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The compound of the formula <IMAGE> and its salts are cardiovascular agents and antihistamines.r

Description

SPECIFICATION A piperazine derivative, a process for preparing it and pharmaceutical composition The present invention relates to a piperazine derivative of the formula (I):
and the non-toxic addition salts thereof.
The compound of the present invention may be prepared according to the following scheme:
wherein X, in the starting coompound of the general formula (III), is chlorine or bromine.
The reaction between N-mono-(4,4'-difluorobenzhydryl)piperazine (II) and 2-(3-halopropyl)-2-phenyl-1,3-dioxolane (III) is conveniently carried out in a medium constituted by an alkanol having from 1 to 4 carbon atoms, preferably ethanol, and in the presence of a base selected from an alkaline/alkaline earth carbonate or bicarbonate, preferably sodium bicarbonate, under reflux.
The compound of the present invention like its non fluorine analogue, which was described in Spanish Patent No. 514 340, has strong properties on blood stream and thus it is a useful vaso-active, antiarrhythmic and hypotensor agent. Furthermore, the compound of the present invention has proved to possess an additional antihistamic effect higher than that of its non fluorine analogue. In Table 1 the parameter of anti-histamine activity expressed as EDso (mol/liter) is comparatively tabulated for the compound of formula (I) as well as its analogue (Spanish Patent No. 514 340) versus Cinnarizine and Flunarizine.
TABLE 1
Compound t-- f- ED50 (mol/liter) Example 1 - R = F 1.5 x Spanish Pat. 514340 R = H 3.5 x Cinnarizine -- 1.7 x Flurarizine -- 2.7 x The anti-histamine activity was tested in an isolate of guinea-pig ileum suspended in a Tyrode bath at 32-35"C according to a protocol described by R.A. Turner (Screening Methods in Pharmacology. Academic Press, 1965, pp. 43).
The compound of the present invention and the non-toxic addition salts thereof mixed with pharmaceutically acceptable carriers can be administered by the oral route in the form of tablets, capsules, syrup, solution, etc., by injectable route and by rectal route, at daily doses ranging from 50 to 500 mg.
EXAMPLE 1:1 -(4,4'-Difluorobenzhydryl)-4-(2-phenyl- 1 ,3-dioxolane-2-propyl)piperazine 14 g of N-mono-(4,4'-difluorobenzhydryl)piperazine (0.049 mol) are dissolved in 200 ml of absolute ethanol in the presence of 5.88 g of sodium bicarbonate (0.07 mol). The resulting mixture is gently treated with 13.3 g solution 2-(3-chloropropyl)-2-phenyl-1,3,-dioxolane (0.059 mol) in 50 ml of absolute ethanol, and then refluxed for 24 hours. After conditioning the reaction mass, it is filtered off and the ethanol is removed by distillation at vacuum. The residue, dissolved in n-hexane, is subjected to solicagel column chromatography (1-hour activation at 120"C) and a mixture of n-hexane and acetone is used as eluent.The eluate is concentrated up to dryness and the obtained oil crystallizes from n-hexane, yielding 9.2 g of crystals of 1-(4,4' difluorobenzyhydryl)-4-(2-phenyl- 1 ,3-dioxolane-2-propyl)piperazine. Yield 39%. M.p. 76-78"C (d).
IR (KBr), cm l: 3000-2800, 1600, 1500, 1230, 1010, 840-830, 780, 710.
EXAMPLE 2:1 -(4,4'-Difluorobenzyhydryl)-4-(2-phenyl- 1 ,3-dioxolane-2-propyl)piperazine maleate 11 g of 1-(4,4'-difluorobenzhydryl)-4-(2-phenyl-1 ,3-dioxolane-2-propyl)piperazine are dissolved in 250 ml of absolute ethanol and then treated with 1M maleic acid ethanol solution up to pH=4.0. The mixture is left to crystallize in refrigerator, yielding 8.3 g of crystals of 1-(4,4' difluorobenzhydryl)-4-(2-phenyl- 1 ,3-dioxolane-2-propyl)piperazine. Yield 61%. M.p. 190-193"C.
IR(KBr), cm 1: 3000-2400, 1700, 1600, 1575, 1350, 1220, 870, 830, 700.

Claims (5)

1. Piperazine derivative having the formula (I):
and the non-toxic addition salts thereof.
2. A process for preparing the compound according to claim 1, characterized by reacting Nmono-(4,4'-difluorobenzyhydryl)piperazine with a 2-(3-halopropyl)-2-phenyl-1 ,3-dioxolane of the general formula (III):
wherein X is chlorine or bromine, in a medium constituted by an alkanol having from 1 to 4 carbon atoms, preferably ethanol, and in the presence of a base selected from an alkaline/alkaline earth carbonate or bicarbonate, preferably sodium bicarbonate, under reflux, followed by purification under filtration, removal of solvent at vacuum and recrystallization, and if desired, the non-toxic addition salts are obtained by treating respective acids, preferably dissolved in an alkanol having from 1 to 4 carbon atoms, preferably methanol, ethanol or isopropanol.
3. Pharmaceutical composition comprising the compound according to claim 1, optionally in combination with pharmaceutically acceptable carriers and adjuvants.
4. A piperazine derivative as claimed in claim 1, substantially as hereinbefore described.
5. A process as claimed in claim 2, substantially as hereinbefore described.
GB08501625A 1985-01-23 1985-01-23 Piperazine derivatives Expired GB2169892B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
GB08501625A GB2169892B (en) 1985-01-23 1985-01-23 Piperazine derivatives

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB08501625A GB2169892B (en) 1985-01-23 1985-01-23 Piperazine derivatives

Publications (3)

Publication Number Publication Date
GB8501625D0 GB8501625D0 (en) 1985-02-27
GB2169892A true GB2169892A (en) 1986-07-23
GB2169892B GB2169892B (en) 1988-02-03

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ID=10573263

Family Applications (1)

Application Number Title Priority Date Filing Date
GB08501625A Expired GB2169892B (en) 1985-01-23 1985-01-23 Piperazine derivatives

Country Status (1)

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GB (1) GB2169892B (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0397031A1 (en) * 1989-05-12 1990-11-14 Ono Pharmaceutical Co., Ltd. Novel esters of phenylalkanoic acid

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0397031A1 (en) * 1989-05-12 1990-11-14 Ono Pharmaceutical Co., Ltd. Novel esters of phenylalkanoic acid
US5013734A (en) * 1989-05-12 1991-05-07 Ono Pharmaceutical Co., Ltd. Novel esters of phenylalkanoic acid

Also Published As

Publication number Publication date
GB8501625D0 (en) 1985-02-27
GB2169892B (en) 1988-02-03

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PCNP Patent ceased through non-payment of renewal fee

Effective date: 19970123