GB2169892A - Piperazine derivatives - Google Patents
Piperazine derivatives Download PDFInfo
- 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
- Authority
- 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
Links
- 150000004885 piperazines Chemical class 0.000 title claims description 5
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 9
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 12
- 231100000252 nontoxic Toxicity 0.000 claims description 4
- 230000003000 nontoxic effect Effects 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Chemical group 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 238000000034 method Methods 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims 2
- 239000002253 acid Substances 0.000 claims 1
- 150000007513 acids Chemical class 0.000 claims 1
- 239000002671 adjuvant Substances 0.000 claims 1
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 238000001914 filtration Methods 0.000 claims 1
- 238000000746 purification Methods 0.000 claims 1
- 238000001953 recrystallisation Methods 0.000 claims 1
- 239000002904 solvent Substances 0.000 claims 1
- 239000000739 antihistaminic agent Substances 0.000 abstract description 3
- 229940125715 antihistaminic agent Drugs 0.000 abstract 1
- 229940125692 cardiovascular agent Drugs 0.000 abstract 1
- 239000002327 cardiovascular agent Substances 0.000 abstract 1
- IMCGHZIGRANKHV-AJNGGQMLSA-N tert-butyl (3s,5s)-2-oxo-5-[(2s,4s)-5-oxo-4-propan-2-yloxolan-2-yl]-3-propan-2-ylpyrrolidine-1-carboxylate Chemical compound O1C(=O)[C@H](C(C)C)C[C@H]1[C@H]1N(C(=O)OC(C)(C)C)C(=O)[C@H](C(C)C)C1 IMCGHZIGRANKHV-AJNGGQMLSA-N 0.000 abstract 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- TTXIFFYPVGWLSE-UHFFFAOYSA-N 1-[bis(4-fluorophenyl)methyl]piperazine Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)N1CCNCC1 TTXIFFYPVGWLSE-UHFFFAOYSA-N 0.000 description 3
- 230000001387 anti-histamine Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 2
- DERZBLKQOCDDDZ-JLHYYAGUSA-N cinnarizine Chemical compound C1CN(C(C=2C=CC=CC=2)C=2C=CC=CC=2)CCN1C\C=C\C1=CC=CC=C1 DERZBLKQOCDDDZ-JLHYYAGUSA-N 0.000 description 2
- 229960000876 cinnarizine Drugs 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 125000001153 fluoro group Chemical class F* 0.000 description 2
- CAQZTSCRGMRSHX-ODZAUARKSA-N (z)-but-2-enedioic acid;ethanol Chemical compound CCO.OC(=O)\C=C/C(O)=O CAQZTSCRGMRSHX-ODZAUARKSA-N 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
- 239000003416 antiarrhythmic agent Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000003750 conditioning effect Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- SMANXXCATUTDDT-QPJJXVBHSA-N flunarizine Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)N1CCN(C\C=C\C=2C=CC=CC=2)CC1 SMANXXCATUTDDT-QPJJXVBHSA-N 0.000 description 1
- 229960000326 flunarizine Drugs 0.000 description 1
- 210000003405 ileum Anatomy 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000002227 vasoactive effect Effects 0.000 description 1
Classifications
-
- 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
Landscapes
- 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.
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 |
Family
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)
| Country | Link |
|---|---|
| GB (1) | GB2169892B (en) |
Cited By (1)
| 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 |
-
1985
- 1985-01-23 GB GB08501625A patent/GB2169892B/en not_active Expired
Cited By (2)
| 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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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19970123 |