US2891063A - Piperazine derivatives and process of - Google Patents
Piperazine derivatives and process of Download PDFInfo
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- US2891063A US2891063A US2891063DA US2891063A US 2891063 A US2891063 A US 2891063A US 2891063D A US2891063D A US 2891063DA US 2891063 A US2891063 A US 2891063A
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- Prior art keywords
- piperazine
- benzene
- mixture
- analysis
- methoxyphenyl
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- 238000000034 method Methods 0.000 title description 6
- 150000004885 piperazines Chemical class 0.000 title description 6
- 229940066771 systemic antihistamines Piperazine derivatives Drugs 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims description 24
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 136
- 238000004458 analytical method Methods 0.000 description 70
- 239000000203 mixture Substances 0.000 description 58
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 54
- 239000000047 product Substances 0.000 description 50
- 229910052739 hydrogen Inorganic materials 0.000 description 42
- 229910052799 carbon Inorganic materials 0.000 description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 38
- 239000000243 solution Substances 0.000 description 30
- 150000003839 salts Chemical class 0.000 description 28
- 239000011780 sodium chloride Substances 0.000 description 28
- 229910052757 nitrogen Inorganic materials 0.000 description 26
- 239000002585 base Substances 0.000 description 24
- 238000010992 reflux Methods 0.000 description 24
- 239000000284 extract Substances 0.000 description 20
- ODUCDPQEXGNKDN-UHFFFAOYSA-N Nitroxyl Chemical compound O=N ODUCDPQEXGNKDN-UHFFFAOYSA-N 0.000 description 18
- 238000009835 boiling Methods 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- -1 alkoxyalkyl halide Chemical class 0.000 description 16
- 229960005141 piperazine Drugs 0.000 description 16
- 125000000217 alkyl group Chemical group 0.000 description 14
- 230000036772 blood pressure Effects 0.000 description 14
- 239000003921 oil Substances 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- 239000000126 substance Substances 0.000 description 14
- 239000003814 drug Substances 0.000 description 12
- 229940079593 drugs Drugs 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 239000002253 acid Substances 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- JOXIMZWYDAKGHI-UHFFFAOYSA-N P-Toluenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 8
- 125000004432 carbon atoms Chemical group C* 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 8
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- VNZLQLYBRIOLFZ-UHFFFAOYSA-N 1-(2-methoxyphenyl)piperazine Chemical compound COC1=CC=CC=C1N1CCNCC1 VNZLQLYBRIOLFZ-UHFFFAOYSA-N 0.000 description 6
- 206010020772 Hypertension Diseases 0.000 description 6
- 238000004821 distillation Methods 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 239000000155 melt Substances 0.000 description 6
- HISPATBMMMNTSD-UHFFFAOYSA-N 3-methoxybutyl 4-methylbenzenesulfonate Chemical compound COC(C)CCOS(=O)(=O)C1=CC=C(C)C=C1 HISPATBMMMNTSD-UHFFFAOYSA-N 0.000 description 4
- FAXDZWQIWUSWJH-UHFFFAOYSA-N 3-methoxypropan-1-amine Chemical compound COCCCN FAXDZWQIWUSWJH-UHFFFAOYSA-N 0.000 description 4
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-Toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- WPKRYYKTIVRCTE-UHFFFAOYSA-N C(C)OC1=C(C=CC=C1)N1CCN(CC1)CCCOC Chemical compound C(C)OC1=C(C=CC=C1)N1CCN(CC1)CCCOC WPKRYYKTIVRCTE-UHFFFAOYSA-N 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N Phosphoryl chloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- OXNIZHLAWKMVMX-UHFFFAOYSA-N Picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 4
- 238000007792 addition Methods 0.000 description 4
- 230000001476 alcoholic Effects 0.000 description 4
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 4
- 125000005036 alkoxyphenyl group Chemical group 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 239000000727 fraction Substances 0.000 description 4
- 230000001631 hypertensive Effects 0.000 description 4
- 230000000147 hypnotic Effects 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 4
- 229910052753 mercury Inorganic materials 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N o-xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 4
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical class [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 4
- 229940114148 picric acid Drugs 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 230000002035 prolonged Effects 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000001187 sodium carbonate Substances 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 229950002929 trinitrophenol Drugs 0.000 description 4
- 238000005292 vacuum distillation Methods 0.000 description 4
- 230000002792 vascular Effects 0.000 description 4
- 239000008096 xylene Substances 0.000 description 4
- UVZLJHOUUPMNMV-UHFFFAOYSA-N 1-(6-methoxyhexyl)piperazine Chemical compound COCCCCCCN1CCNCC1 UVZLJHOUUPMNMV-UHFFFAOYSA-N 0.000 description 2
- OGWXTWGOYZGJTH-UHFFFAOYSA-N 1-bromo-9-methoxynonane Chemical compound COCCCCCCCCCBr OGWXTWGOYZGJTH-UHFFFAOYSA-N 0.000 description 2
- ASUDFOJKTJLAIK-UHFFFAOYSA-N 2-methoxyethanamine Chemical compound COCCN ASUDFOJKTJLAIK-UHFFFAOYSA-N 0.000 description 2
- ZRJOUVOXPWNFOF-UHFFFAOYSA-N 3-dodecoxypropan-1-amine Chemical compound CCCCCCCCCCCCOCCCN ZRJOUVOXPWNFOF-UHFFFAOYSA-N 0.000 description 2
- SOYBEXQHNURCGE-UHFFFAOYSA-N 3-ethoxypropan-1-amine Chemical compound CCOCCCN SOYBEXQHNURCGE-UHFFFAOYSA-N 0.000 description 2
- JSGVZVOGOQILFM-UHFFFAOYSA-N 3-methoxybutan-1-ol Chemical compound COC(C)CCO JSGVZVOGOQILFM-UHFFFAOYSA-N 0.000 description 2
- YUUFAJOXLZUDJG-UHFFFAOYSA-N 4-methoxybutan-1-amine Chemical compound COCCCCN YUUFAJOXLZUDJG-UHFFFAOYSA-N 0.000 description 2
- UVOBODVSFRKUQX-UHFFFAOYSA-N 6-methoxyhexan-1-amine Chemical compound COCCCCCCN UVOBODVSFRKUQX-UHFFFAOYSA-N 0.000 description 2
- PEVHLEAAXLKMSZ-UHFFFAOYSA-N 7-methoxyheptan-1-amine Chemical compound COCCCCCCCN PEVHLEAAXLKMSZ-UHFFFAOYSA-N 0.000 description 2
- 241000409326 Armiger Species 0.000 description 2
- JEGQXPZCMWTJHJ-UHFFFAOYSA-N C(CCCCCCCCCCC)OCCCN1CCNCC1 Chemical compound C(CCCCCCCCCCC)OCCCN1CCNCC1 JEGQXPZCMWTJHJ-UHFFFAOYSA-N 0.000 description 2
- 101700030855 CESS Proteins 0.000 description 2
- PHLYRTUTMPFUSD-UHFFFAOYSA-N COC(CCCCC#N)C Chemical compound COC(CCCCC#N)C PHLYRTUTMPFUSD-UHFFFAOYSA-N 0.000 description 2
- MZIIWNUYCOWMAK-UHFFFAOYSA-N COC1=C(C=CC=C1)N1CCN(CC1)CCCCCCCCCOC Chemical compound COC1=C(C=CC=C1)N1CCN(CC1)CCCCCCCCCOC MZIIWNUYCOWMAK-UHFFFAOYSA-N 0.000 description 2
- QXYOORBSYFYMHE-UHFFFAOYSA-N COC1=C(C=CC=C1)N1CCN(CC1)CCCCCCCCOC Chemical compound COC1=C(C=CC=C1)N1CCN(CC1)CCCCCCCCOC QXYOORBSYFYMHE-UHFFFAOYSA-N 0.000 description 2
- VXAIDFHQSRYIAJ-UHFFFAOYSA-N COC1=C(C=CC=C1)N1CCN(CC1)CCCCCCCOC Chemical compound COC1=C(C=CC=C1)N1CCN(CC1)CCCCCCCOC VXAIDFHQSRYIAJ-UHFFFAOYSA-N 0.000 description 2
- YUCFCZPAQKSIET-UHFFFAOYSA-N COCCCCCCCCCCCN1CCNCC1 Chemical compound COCCCCCCCCCCCN1CCNCC1 YUCFCZPAQKSIET-UHFFFAOYSA-N 0.000 description 2
- 206010011703 Cyanosis Diseases 0.000 description 2
- RCJVRSBWZCNNQT-UHFFFAOYSA-N Dichlorine monoxide Chemical compound ClOCl RCJVRSBWZCNNQT-UHFFFAOYSA-N 0.000 description 2
- 210000002027 Muscle, Skeletal Anatomy 0.000 description 2
- VMPITZXILSNTON-UHFFFAOYSA-N O-Anisidine Chemical compound COC1=CC=CC=C1N VMPITZXILSNTON-UHFFFAOYSA-N 0.000 description 2
- BHAAPTBBJKJZER-UHFFFAOYSA-N P-Anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 description 2
- 229960001954 Piperazine phosphate Drugs 0.000 description 2
- 229910000564 Raney nickel Inorganic materials 0.000 description 2
- 240000000754 Rauvolfia serpentina Species 0.000 description 2
- 208000003782 Raynaud Disease Diseases 0.000 description 2
- 206010037912 Raynaud's phenomenon Diseases 0.000 description 2
- 206010039710 Scleroderma Diseases 0.000 description 2
- 206010039897 Sedation Diseases 0.000 description 2
- 206010041349 Somnolence Diseases 0.000 description 2
- 206010047141 Vasodilatation Diseases 0.000 description 2
- 230000032683 aging Effects 0.000 description 2
- 125000006231 alkoxy propyl group Chemical group 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 150000008107 benzenesulfonic acids Chemical class 0.000 description 2
- 230000002490 cerebral Effects 0.000 description 2
- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000002934 diuretic Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 125000006232 ethoxy propyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 239000003457 ganglion blocking agent Substances 0.000 description 2
- 150000008131 glucosides Chemical class 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 201000009939 hypertensive encephalopathy Diseases 0.000 description 2
- 201000002053 hypertensive heart disease Diseases 0.000 description 2
- 239000003326 hypnotic agent Substances 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 230000003000 nontoxic Effects 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- NQQWFVUVBGSGQN-UHFFFAOYSA-N phosphoric acid;piperazine Chemical compound OP(O)(O)=O.C1CNCCN1 NQQWFVUVBGSGQN-UHFFFAOYSA-N 0.000 description 2
- PMGABIJVFLPSLS-UHFFFAOYSA-N piperazine phosphate Chemical compound O.OP(O)(O)=O.C1CNCCN1 PMGABIJVFLPSLS-UHFFFAOYSA-N 0.000 description 2
- 239000001184 potassium carbonate Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000000750 progressive Effects 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 230000036280 sedation Effects 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 230000001225 therapeutic Effects 0.000 description 2
- 230000024883 vasodilation Effects 0.000 description 2
Classifications
-
- 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
- C07D295/04—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
Definitions
- the compounds of the present invention which have been found to satisfy the foregoing requirements and which have a therapeutic activity when administered in the range of 25 mg. oral dose for an average man, preferably every four hours or at greater intervals if administered in a prolonged release dosage form and according to a doctors prescription, have thefollowing general formula:
- R is a lower alkyl group having from 1 to 6 carbon atoms, R is an alkyl group having from 1 to 12, 1
- R,R' and n have the above-specified values.
- Other aryl sulfonic acid esters may be used instead of the p-toluene sulfonic acid ester, such as benzene sulfonic acid esters.
- Chemical analysis calculated for C H N O Theory 69.03% C; 9.41% H; 10.06% N; as .compared with the found analysis of 69.05% C; 9.33% H and 9.44%
- the dihydrochloride salt of the above base has a M.P. of 174-175" C.
- N-(o-methoxyphenyl) N (11-methoxyundecyl)- piperazine is prepared by refluxing for about 12 hours a mixture of ll-bromoundecylmethylether (0.1 mole) and N-(o-methoxyphenyl)-piperazine (0.1
- N-(o-methoxyphenyl) -N'-(8-methoxyoctyl)-piperazine is prepared by refluxing a mixture of S-bromooctylmethylether (0.1 mole) and N-(o-methoxyphenyD-piperazine (0.1 mole) as in Example 11 and N-(o-methoxyphenyl)-N'-(9-methoxynonyl) piperazine is prepared by refluxing a mixture of 9-bromononylmethylether (0.1 mole) and N-(o-methoxyphenyl)-piperazine (0.1 mole) as in Example .11.
- the combined benzene fractions are heated to remove the benzene and the residue is subjected to a vacuum distillation.
- the crude picrate salt of the said product has a melting point of 127-429 C. and after recrystallization from methanol has a M.P. of 131131.5 C. Chemical analysis of the said picrate salt shows 52.22% C; 6.15% H; 29.23% 0 and 12.66% N; compared with a theoretical analysis of 52.05% C; 5.98% H; 29.20% 0 and 12.78% N.
- N ,N-bis- (fi-chlomethyl roeethoxyaniline) is prepared by..adding .154 g. '0f,N,N,bis ( ⁇ 8:hydroxyethyl)-o-ethoxyaniline to.2 1.6 g. of phosphorus oxychloride during a period of one hour, and, heating the ture on -a steam bath forone additional hour. To the mixture is added 1.5; liters of water in one portion. After the exothermic r-eactionwis completed,- shake the mixture :with 400 mL.
- the monohydrochloride salt is prepared by dissolving the free base product in isopropanol and adding one equivalent of hydrogen chloride per mole of base.
- the compounds of the present invention appear to have a two-fold action in that they act peripherally to lower the vascular resistance and thus the effective vascular blood pressure and also have a marked central action which reduces the causative factors operating centrally to increase the blood pressure of the patient who suffers from hyertension.
- the compounds are therefore particularlysuitable for treating patients with progressive hypertension and also those 'afi'licted with hypertensive encephalopathy.
- the compounds off-the present invention also'produce somnolence or sedation, depending on the dose ad-
- the compounds moreover, reduce excitement of the patient, thus having a transquilizing action, and also tend to relax the skeletal muscles of the patent.
- a 25 mg. dose of N- o-methoxyphenyl) -N- 3-methoxylpropyl) piperazine phosphate is administered to an average patient on retiring, there occurs in addition to a rapid drop in blood pressure, a sound peaceful sleep from which the patient readily awakens and returns to a normal state.
- the foregoing piperazine phosphate salt having a hypnotic effect of shorter duration than the barbiturates, is therefore also suited for hypertensive patients who desire to take a nap during the middle of the day or otherwise relax in the middle of the stress which he experiences during the day.
- the piperazine compounds of the present invention arecompatible with other drugs commonly used to treat the hypertensive state, they can, if desired, be combined with these other drugs, such as the hypnotics and sedativesincluding the barbiturates, where a prolonged sornnolence is desired, the rauwolfia alkaolids and glucosides,;diuretic agents, ganglionic blocking agents and with-combinations'of the drugs commonly employed
- the present application is a continuation application .of the inventors co pending application Serial No.
- R is a lower alkyl group
- R is an alkyl group having between 1 and 12 inclusive carbon atoms in the alkyl chain
- n is an integer between 2 and 12 inclusive, and the acid addition salts thereof.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
United Sttes Patent PIPERAZINE DERIVATIVES AND Pl IO CESS OF PREPARING Armiger H. Sommers, Lake Forest, 11]., assignor to 4bbott Laboratories, North Chicago, 111., a corporation oflllinois.
No Drawing. Application December 31, 1958 Serial No. 784,096 1 Claims. (Cl. 260-268) particularly desirable thata drug be substantially nontoxic, effective orally, and able to produce a significant reduction in blood pressure. It is also highly desirable that the patients blood pressure be lowered an amount which is proportional to the dosage of the drug administered and that the recumbent blood pressure of the patient as well as the blood pressure of the patient when standing be lowered by the drug.
The compounds of the present invention which have been found to satisfy the foregoing requirements and which have a therapeutic activity when administered in the range of 25 mg. oral dose for an average man, preferably every four hours or at greater intervals if administered in a prolonged release dosage form and according to a doctors prescription, have thefollowing general formula:
wherein R is a lower alkyl group having from 1 to 6 carbon atoms, R is an alkyl group having from 1 to 12, 1
carbon atoms, and n is an integer from 2 to 12 inclusive. Compounds having the foregoing general formula can be prepared in the following manner:
(1) By reacting an N,N-bis-(B-haloethyl)-arylamine with the appropriate alkoxyalkylamine, preferably in an inert organic solvent, such as 95% ethanol, in accordance with the following general equation:
(IZtR zine with the appropriate alkoxyalkyl halide according to the following general equation:
wherein R,R, n and X have the above-specified values.
2,891,063 Patented June 16, 1959 (3) By the reaction in a suitable solvent of an N-(oalkoxyphenyl)-piperazine with the p-toluene sulfonic acid ester of the appropriate alkoxy carbinol according to the following general equation: 1
wherein R,R' and n have the above-specified values. Other aryl sulfonic acid esters may be used instead of the p-toluene sulfonic acid ester, such as benzene sulfonic acid esters.
The following specific examples are for the purpose of illustrating the present invention and should not be construed to limit the invention to the specific proportions and compounds used and prepared. 1
EXAMPLE I N (o-methoxyphevtyl) -N (3-meth0xypr0pyl -piperazine of N,N-bis-(fl-chloroethyl)-o-anisidine, 134 g. (1.5 moles) of 3-methoxypropylamine, and 550 ml. of ethanol. The mixture is heated at reflux for about three hours or until reaction is complete and then is concentrated on a steam bath to remove most of the solvent. The residue is treated with 500 ml. of water and 200 mlQof benzene and shakenwell. The aqueous layer is separated and again shaken with 200 ml. of benzene. The combined benzene solutions are shaken once with ml. of water, separated, and concentrated. Distillation of the residual oil gives 116 g. of product, N-(o-methoxyphenyl -N-(3- methoxypropyl)-piperazine, a colorless oil boiling at about 138 C. at 0.1 mm. pressure and n =l.5369. Chemical analysis calculated for C H N O Theory 68.14% Cl; 9.15% H and 10.60% 'N; as compared with the found analysis of 68.35% C; 9.43% H and10.63% N.
Following the same procedure used in Example 1, it is possible to obtain the said product by using a mole to mole ratio of N,N-bis-(B-chloroethyl)o-anisidine and 3-methoxypropylamine together with one: mole of sodium carbonate which neutralizes the hydrogen chloride formed in the reaction. Similarly, two moles of triethylamine can be used instead of the sodium carbonate as the acid acceptor. i
. Several salts of the above base products can be prepared by treating a solution of the said base in ethanol with an ethanolic solution of the appropriate acid in suitable molar amounts, cooling the reaction solution, filtering the precipitated salt and drying. Thus, the mono hydrochloride salt of the said base was found to melt at l55-158 C. and the dihydrochloride salt was found to have a M.P. of 205-206 C. The furrnarate salt.of the said base was found to have a M.P. of 143 C. and the phosphate salt of the said base was found to have a M.P. of 143-144 C. i 1
EXAMPLE II N- (o-methoxyphenyl) -N'- (3- nezhoxypr0pyl) -piperazine A mixture of 8.2 g. 0.042s mole) of N-(o-methoxyphenyD-piperazine, 6.5 g. (0.0425 mole) of ii-broom} propyl methyl ether, and 4.3 g. (0.0425 mole) of triethylamine is placed in a 100 ml. 3,-necked flask along with 50 ml. of xylene. The mixture is heated for hours at reflux, then cooled, extracted 'with three 30 ml. portions of 3NHC1. The acid solution is extracted with three 50 ml. portions of benzene, and is then saturated with potassium carbonate and extracted again with three 50 portions of benzene. The benzene extracts are washed free of base with water, and distilled to remove solvent. the product boiling at 135-137 C. at 0.15 mm. pressure.
EXAMPLE III N-(o-methoxyphenyl) -N-(3-meth0xypr0pyl) -piperazine To 39 g. of N-(o-methoxyphenyl)-piperazine is slowly added, with stirring, 25 g. of 3-methoxypropyl-p-to1uenesulfo'nate The mixture is heated for two hours on the steam bath and is then cooled and treated with 200 ml. of aqueous sodium hydroxide solution. The mixture The residue is distilled under vacuum to give is extracted with 200 ml. ofbenzene and the organic N-(o-ethoxyphenyl)-N'-(3-methoxypropyl) -piperazine A mixture of 13.1 g. of N,N-bis-( 3-ch1oroethyl)- o-ethoxyaniline, 13.4 g. of S-methoxypropylamine and 75 ml. of 95% ethanol is heated at reflux for 12 hours. After evaporation of the solvent, 250 ml. of water is added to the residue which is then shaken with 100 ml. and 50 ml. portions of benzene. The combined organic extracts are shaken with 100 ml. of water, separated and distilled. This gives 11.6 g. of product, N-(o-ethoxyphenyl)-N'-(3-methoxypropyl)-piperazine, a colorless oil which boils at 131-135 C. at 0.1 mm. pressure, and n =1.5270. Analysis calculated for C H N O Theory 69.03% C; 9.41% H and 10.06% N; as compared with the found analysis of 69.04% C; 9.50% H and 10.14% N.
By dissolving the 'abovebase in isopropyl alcohol and adding two equivalents of hydrogen chloride per mole of the base, one obtains the, dihydrochloride salt thereof as white crystals having a M.P. of 170 C. Analysis calculated for C H Cl N O Theory 7.97% N, as compared with the found analysis of 7.87% N.
EXAMPLE V N-(o-m'ethoxyphenyl) -N'-(Z-methoxyethyl)-piperazine A solution of 25 g. of N,N-bis-( 6-chloroethy1)-oanisidine and 23 g. of 2-methoxyethylamine in 100 ml. of 95 ethanol is heated at reflux for six hours. The solvent is evaporated on a steam bath and the residue is treated with 200 ml. of water. The mixture is shaken with 150 ml. of benzene, and the benzene extract is distilled to give the product, N-o-methoxyphenyl-N'-(2- methoxyethyD-piperazine having a B.P. of 134 C. at 0.1 mm. pressure and n =1.5423. Chemical analysis calculated for C H N O Theory 67.16% C; 8.86% H; 11.19% N and 12.78% 0; as compared with the found analysis of 67.08% C; 8.86% H; 11.13% N and 13.01% 0. The phosphate salt of the above base has a M.P. of 158-159 C.
EXAMPLE VI ';Ihe solvent is removed on a steam bath and the residue is treated with 250 ml. of water. 'The mixture shaken with 150 ml. of benzene and the benzene extract is separated and distilled to obtain the product,
4 N-(o-methoxyphenyl) .N (3-isopropoxyp1'opy1) piperazine, having a B.P. of 15.3-155 C. at 0.2 mm. pressure and n =1.5245. Chemical analysis calculated for C H N O Theory 69.82% C; 9.65% H; 9.58% and 10.94% 0; as compared with the found analysis of 69.93% C; 9.80% H; 9.63% N and 11.25% 0. The dihydrochloride salt of the above base has a M.P. of 175-180 C.
EXAMPLE VII N-(o-methoxyphenyl)-N'-(3-eth0xypr0pyl)-piperazine A solution of 25 vg. of N,N bis-(fl-chloroethyl)-oanisidine and 31 g. of 3-ethoxypropylamine in 75 ml. of ethanol is heated at reflux for three hours. The alcohol is removed by evaporation ona steam bath and the residue is treated with 200 m1. of water. The mixture isshaken with 150 ml. of benzene and the benzene extract is separated and distilled to obtain the product, N (.owmethoxyphenyl) -N-.(3 ethoxypropyl) -piperazine, having a B.P. of 13.9-141 C. at a pressure of 0.1 mm. and a refractive index .of n '4 =1.5294. Chemical analysis calculated for C H N O Theory 69.03% C; 9.41% H; 10.06% N; as .compared with the found analysis of 69.05% C; 9.33% H and 9.44% The dihydrochloride salt of the above base has a M.P. of 174-175" C.
EXAMPLE VIII N -'(o-me=tihoxyph'enyl -N (4-metho'xy-n-butyl -pip erazine N N-(C H,). -0 0113 .A solution of 25 'g. (0.1 mole) of N,N-bis-(2-chloroethyl )'-o-anisidine and 31 g. (0.3 mole) of 4-methoxybutylamine in cc. of 95% ethanol is heated at reflux for three hours and is then concentrated on a steam bath under vacuum. To the residue is added ml. of water, and the mixture is shaken with 150 ml. and 100 ml. portions of benzene. The combined benzene extracts are concentrated and distilled giving 24 g. of product, a light oil which boils at 136-140" at 0.1 mm., n =1.5318. Analysis: Calculated for C H N O C, 69.0%; H, 9.41%; N, 10.1%; 0, 11.5%. Found: C, 69.0%; H, 9.39%; N, 10.2%; 0, 11.4%.
The product reacts with picric acid in alcohol solvent to form a dipicrate salt, M.P. 158-159. Analysis: Calculated for C28H32N3016; N, 15.2%. Found: N, 15.2%.
EXAMPLE IX N (0 methoxyphenyl) N' (3 methoxybutyD- piperazine (and dihydrochloride salt) N N-cnz-on -t zrpoorn A mixture of 11.5 g. (0.06 mole) of l-(o-methoxyphenyl)-piperazine and 7.5 g. (0.03 mole) of 3-methoxybutyl-p-toluene sulfonate is heated with steam for 14 hours. The resulting oil is taken up in 300 cc. of water and the mixture is shaken with three 75 cc. portions "of benzene. Distillation gives 6.5 'g. (78%) of product boiling at 140 at 0.3 rnm., n =1.53l7. Analysis: Calculated for C H N O C, 69.0%; H, 9.4%; N, 10.1%. Found: C, 69.1%; H, 9.6%; N, 10.2%.
The dihydrochloride salt prepared in isopropanol melts at 160-162". Analysis: Calculated for C H Cl N O C, 54.7%; H, 8.0%. Found: C, 54.8%; H, 8.3%.
EXAMPLE X N o-methoxyphenyl -N '-(5-methoxypentyl -piperazine oorr. Q-H- QHm-O on.
A solution of 6.4 g. of N,N-bis-(2-chloroethyl)-o- C, 71.2%; H, 10.1%; N, 8.74%.
d anisidine and 9 g. of S-methoxypentylamine in 75 m1. of 95% ethanol is heated at reflux overnight. It is then concentrated and the residue is treated with 100 ml. of water. The mixture is shaken with 100 ml. and 50 ml. portions of benzene and the combined benzene extract is concentrated and distilled. There is obtained g. of product, a light oil boiling at 146149 at 0.1 mm., n =1.5287. Analysis: Calculated for C H N O C, 69.8%; H, 9.65%; N, 9.58%. Found: C, 69.5%; H, 9.37%; N, 9.58%.
The product reacts with alcoholic picric acid to yield a dipicrate salt, M.P. 149-150. Analysis: Calculated for C29H34N3O15Z N, 14.9%. Found: N, 14.8%.
EXAMPLE )G N (o-methoxyphenyl -N 6-methoxyhexyl -piperazine CCH;
-N N- 0H OCH Q :)oa A solution of 8.2 g. of N,N-bis-(;3-chloroethyl)-oanisidine and 13.1 g. of 6-methoxyhexylamine in 75 cc. of 95 ethanol is heated at reflux for four hours and is then concentrated. To the semi-solid residue is added 150 ml. of water and 100 ml. of benzene and the mixture is shaken Well. The organic layer is separated and distilled. There is obtained 8 g. of product, a light oil which boils at l55-l60 at 0.1 mm., n =1.5252. Analysis: Calculated for C H N O C, 70.6%; H, 9.87%;
N, 9.14%. Found: C, 70.3%; H, 9.64%; N, 9.10%.
The base reacts in isopropyl alcohol with hydrogen chloride to yield a dihydrochloride salt, M.P. 172-176". Analysis: Calculated for C H Cl N O C, 57.0%; H, 8.50%; N, 7.38%. Found: C, 56.7%; H, 8.06%; N,
EXAMPLE XII N-(o-methoxyphenyl)-N'-(7-methoxyheptyl)-piperazine A solution of 7.5 g. of N,N-bis-(2-chloroethyl)-oanisidine and 13 g. of 7-methoxyheptylarnine in 100 ml. of 95% ethanol is heated at reflux for 17 hours and then concentrated to an oil which is treated with 100 ml. of water. The mixture is shaken with 100 ml. of benzene and the benzene layer is concentrated and distilled yielding 6.6 g. of product, an oil boiling at 157-160 at 0.2 mm., n =1.5219. Analysis: calculated for C H N O Found: C, 71.4%; H, 10.2%; N, 8.76%.
The product reacts in alcoholic solution with anhydrous hydrogen chloride to form a dihydrochloride salt which melts at 178 Analysis: Calculated for C H Cl N 0 C, 58.0%; H, 8.71%; N, 7.12%. Found: C, 58.2%; H, 8.61%; N, 7.12%.
(a) 7 -METHOXYHEPTYLAMINE A mixture of 15 g. of 6-methoxyenanthonitrile, 15 ml. of liquid ammonia, 7 g. of Raney nickel catalyst and 500 cc. of methanol is shaken at 100 under 1500 lb. per square inch pressure of hydrogen for 20 minutes, when hydrogenation is complete. The mixture is filtered and distilled to obtain 13 g. of product, B.P. 106/25 mm, n =1.4338. Analysis: Calculated for C H NO: C, 66.2%; H, 13.2%; N, 9.64%. Found: C, 66.1%; H, 13.1%; N, 9.79%.
Other higher alkoxyalkyl derivatives of o-alkoxyphenyl piperazines coming within the scope of the present invention can be made by any of the foregoing methods. ThusN-(o-methoxyphenyl) N (11-methoxyundecyl)- piperazine, for example, is prepared by refluxing for about 12 hours a mixture of ll-bromoundecylmethylether (0.1 mole) and N-(o-methoxyphenyl)-piperazine (0.1
mole) with an inert solvent, such as xylene, which contains triethylamine as an acid acceptor in accordance with the procedure of Example 11 described herein. In the same manner, N-(o-methoxyphenyl) -N'-(8-methoxyoctyl)-piperazine is prepared by refluxing a mixture of S-bromooctylmethylether (0.1 mole) and N-(o-methoxyphenyD-piperazine (0.1 mole) as in Example 11 and N-(o-methoxyphenyl)-N'-(9-methoxynonyl) piperazine is prepared by refluxing a mixture of 9-bromononylmethylether (0.1 mole) and N-(o-methoxyphenyl)-piperazine (0.1 mole) as in Example .11.
EXAMPLE XIII N-(o-methoxyphenyl) -N'-(3-n-hexyioxypropyl)- piperazine A mixture of 12 g. (0.05 mole) of N,N-bis-(fi-chloroethyl)-o-anisidine, 25 g. (0.15 mole) of 3nhexyloxypropylamine, and 50 ml. of ethanol is refluxed for about 12 hours on a steam bath. The reaction mixture is then cooled, diluted with 75 ml. of water, and extracted first with 50 ml. of benzene and then with four 25-30 ml. portions of benzene. The combined benzene frac tions are heated to remove the benzene and the residue is subjected to a vacuum distillation. A yield of 11.3 g. of the product N-(o-methoxyphenyl)-N-(3-n-hexylpropyl)-piperazine is obtained having a boiling point of C. at a pressure of 0.6 mm. of mercury and a refractive index of n =1.5 153. Chemical analysis of the said product shows 71.22% C; 10.59% H; 9.28% O and 8.32% N; as compared with a theoretical analysis of 71.81% C; 10.25% H; 9.57% O and 8.38% N.
EXAMPLE XIV N -(o-methoxyphenyl -N (3-n-dodecyloxypropyl piperazine A mixture of 7 g. (0.028 mole) of N,N-bis-(/8-chloroethyD-o-anisidine, 21 g. (0.086 mole) of 3-dodecyloxypropylamine and 50 ml. of 95% ethanol is refluxed for about 12 hours on a steam bath. The reaction mixture is then cooled, diluted with 75 ml. of water, and extracted first with 50 ml. of benzene and then with four 25 ml. portions of benzene. The combined benzene fractions are heated to remove the benzene and the residue is subjected to a vacuum distillation. The product, N-(o-methoxyphenyl) -N'-(S-n-dodecyloxypropyl) -pipera- Zine has a boiling point of 232234 C. at a pressure of 0.5 mm. mercury and a refractive index of n =1.5030. The crude picrate salt of the said product has a melting point of 127-429 C. and after recrystallization from methanol has a M.P. of 131131.5 C. Chemical analysis of the said picrate salt shows 52.22% C; 6.15% H; 29.23% 0 and 12.66% N; compared with a theoretical analysis of 52.05% C; 5.98% H; 29.20% 0 and 12.78% N.
EXAMPLE XV pressure and n =1.550O. Chemical analysis calculated .for C H NO Theory 62.53% C; 8.11% H; as compared withthe found analysis of 62.40% C and 8.58%
OCH;
To 31g. ofphosphorus oxychloride is added inportions, with shaking, 21 g. of N,N-bis-(,B-hydroxyethyl)- o-anisidine. The mixture is thetnheated on a steam bath for one hour and diluted with 200 cc. of Water and allow to stand for three hours to complete the reaction. Theresulting solution is shaken with two 100 :cc. portions of benzene. The combined benzene extracts are distilled to give 16 g. of product which boils at l46150 C. at 1 mm. pressure and, n =1.5477. Analysis calculated for C I-1 01 110: Theory 53.24% C and 6.09% H; as compared with the found analysis of 53.48% C and 5.88%,H.
EXAMPLE XVII @nnom-ormorn,
N ,N-bis- (fi-chlomethyl roeethoxyaniline The intermediate, N,N-bis-(fl-chloro.ethyl)-o-ethoxyaniline, is prepared by..adding .154 g. '0f,N,N,bis (}8:hydroxyethyl)-o-ethoxyaniline to.2 1.6 g. of phosphorus oxychloride during a period of one hour, and, heating the ture on -a steam bath forone additional hour. To the mixture is added 1.5; liters of water in one portion. After the exothermic r-eactionwis completed,- shake the mixture :with 400 mL. of benzene, separate the benzene layer and distill to obtain,125 g. of the intermediate which has a B.P. ,of 141 C. at0.41mrn. .pressurerand a refractive index of 11 115381.
- (1)011 1Q N'-'0Hs A mixture of 17 3 parts by weight of N,N-bis'-'(B chloroethyl)-o-anisidine and 29 parts of 30% aqueous methylamine in 50 parts ethanolisheated in a closed vessel at 125 C. for eighthours. The alcohol is then removed by distillation and 150 parts of water is added to the residue which is made strongly alkaline with 25 parts of sodium hydroxide. The mixture is then shaken with two 100 cc. portions of benzene and the combined extracts are distilled to give 11 gcf product boiling at 100 -l0l C. at 0.3 mm. pressure, 11 =1.5483. Analysis 'caleulated'for C I-1 F1 0; Theory 69.86% 'C;; 8.79% H;-
as compared with,thefoundanalysis of 70.07% C. and
' The monohydrochloride salt is prepared by dissolving the free base product in isopropanol and adding one equivalent of hydrogen chloride per mole of base. On
,in the treatment of hypertensive heart disease.
ministered and the condition of the patent.
addition of two volumes of dry ether, N-(o-methoxyphenyl)-N-methylpiperazine .monohydrochloride precipitates as a while crystalline solid which is collected and dried. It melts at'200=20l-=C. Analysis calculated for C H gClN 'Oz Theory 59.37% iC.; 7.89% H; as compared with the found analysis of 59.29% C. and 7.63%
EXAMPLE XX 3-methoxybutyl-p-toluene sulfonate To a solution of 26 g. (0.25 mole) of 3methoxybutanol in 200 ml. ofpyridine cooled to -l0 C., add54 g. 0.28 mole) of p-toluene sulfonyl chloride. The mixture is stirred at 0 C. for 20 hours, and is then treated with 220 cc. of Water, in portions. The aqueous solution is extracted with ether, and the extract is dried and distilled. This gives g. (37%) of product, a liquid boiling at 162 at '1.5 mm., n =1.4996. Analysis: Calculated for Co 50 C, 55.8%; H, 7.0%. Found: C, 56.2%;H, 7.1%.
The compounds of the present invention appear to have a two-fold action in that they act peripherally to lower the vascular resistance and thus the effective vascular blood pressure and also have a marked central action which reduces the causative factors operating centrally to increase the blood pressure of the patient who suffers from hyertension. The compounds are therefore particularlysuitable for treating patients with progressive hypertension and also those 'afi'licted with hypertensive encephalopathy. 'Because of the vaso-dilatation effect of the compounds disclosed herein, they have additional utility in the treatment of many disease associated with aging, such as coronary insufliciency, cerebral insufiiciency, and arterial insufiiciency, and those diseases in which acrocyanosis is a component, such as Raynauds disease, scleroderma, and the like.
The compounds off-the present invention also'produce somnolence or sedation, depending on the dose ad- The compounds, moreover, reduce excitement of the patient, thus having a transquilizing action, and also tend to relax the skeletal muscles of the patent. When a 25 mg. dose of N- o-methoxyphenyl) -N- 3-methoxylpropyl) piperazine phosphate is administered to an average patient on retiring, there occurs in addition to a rapid drop in blood pressure, a sound peaceful sleep from which the patient readily awakens and returns to a normal state. The foregoing piperazine phosphate salt, having a hypnotic effect of shorter duration than the barbiturates, is therefore also suited for hypertensive patients who desire to take a nap during the middle of the day or otherwise relax in the middle of the stress which he experiences during the day.
Since the piperazine compounds of the present invention arecompatible with other drugs commonly used to treat the hypertensive state, they can, if desired, be combined with these other drugs, such as the hypnotics and sedativesincluding the barbiturates, where a prolonged sornnolence is desired, the rauwolfia alkaolids and glucosides,;diuretic agents, ganglionic blocking agents and with-combinations'of the drugs commonly employed The present application is a continuation application .of the inventors co pending application Serial No.
643,545, filed March 4,1957, now abandoned.
Others may readily adapt the invention for use under various conditions of service, by ernploying oneor more of thenovel features disclosed or equivalents thereof. As .at present'advised- .withrespect to the apparent scope of my invention, I desire to claim the following subject ma t r.
9 I claim: 1. A chemical compound selected from the group consisting of compounds having the general formula:
wherein R is a lower alkyl group, R is an alkyl group having between 1 and 12 inclusive carbon atoms in the alkyl chain, and n is an integer between 2 and 12 inclusive, and the acid addition salts thereof.
2. N-(o-lower alkoxyphenyl) N (w-lower alkoxyalkyl)-piperazine, wherein the alkyl group has between 2 and 11 carbon atoms in the alkyl chain.
3. N-(o-lower alkoxyphenyl) N (3-1ower alkoxypropyl) -piperazine.
4. N-(o-methoxyphenyl) N (3 methoxypropyD- piperazine.
5. N-(o-methoxyphenyl) N (3-isopropoxypropy1)- piperazine.
6. N (o ethoxyphenyl) N (3 methoxypropyD- piperazine.
piperazine.
9. N-(o-methoxyphenyl) N (5 methoxypenty1)- piperazine.
10. N-(o-methoxyphenyl) N (7 methoxyheptynpiperazine.
References Cited in the file of this patent UNITED STATES PATENTS Weston et a1. Nov. 18, 1958
Claims (1)
1. A CHEMICAL COMPOUND SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS HAVING THE GENERAL FORMULA:
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3089819A (en) * | 1961-09-05 | 1963-05-14 | Abbott Lab | Method for the treatment of hypertension |
US3270004A (en) * | 1962-12-26 | 1966-08-30 | Abbott Lab | Disubstituted piperazines useful as schistosomiasis agents |
US3997667A (en) * | 1974-02-23 | 1976-12-14 | Boehringer Mannheim G.M.B.H. | 1-[3-(Naphth-1-yloxy)-propyl]-piperazine compounds and therapeutic compositions |
EP1178972A1 (en) * | 1999-04-19 | 2002-02-13 | Teva Pharmaceutical Industries Ltd. | Novel synthesis of piperazine ring |
WO2005028457A1 (en) * | 2003-09-23 | 2005-03-31 | Fermion Oy | Preparation of quetiapine |
Citations (1)
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US2861072A (en) * | 1952-07-19 | 1958-11-18 | Abbott Lab | Preparation of piperazine derivatives |
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0
- US US2891063D patent/US2891063A/en not_active Expired - Lifetime
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
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US2861072A (en) * | 1952-07-19 | 1958-11-18 | Abbott Lab | Preparation of piperazine derivatives |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3089819A (en) * | 1961-09-05 | 1963-05-14 | Abbott Lab | Method for the treatment of hypertension |
US3270004A (en) * | 1962-12-26 | 1966-08-30 | Abbott Lab | Disubstituted piperazines useful as schistosomiasis agents |
US3997667A (en) * | 1974-02-23 | 1976-12-14 | Boehringer Mannheim G.M.B.H. | 1-[3-(Naphth-1-yloxy)-propyl]-piperazine compounds and therapeutic compositions |
EP1178972A1 (en) * | 1999-04-19 | 2002-02-13 | Teva Pharmaceutical Industries Ltd. | Novel synthesis of piperazine ring |
EP1178972A4 (en) * | 1999-04-19 | 2002-06-12 | Teva Pharma | Novel synthesis of piperazine ring |
US6852855B2 (en) | 1999-04-19 | 2005-02-08 | Teva Pharmaceutical Industries Ltd. | Synthesis of piperazine ring |
WO2005028457A1 (en) * | 2003-09-23 | 2005-03-31 | Fermion Oy | Preparation of quetiapine |
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