CH449635A - Process for the preparation of diaza-cycloalkane compounds - Google Patents
Process for the preparation of diaza-cycloalkane compoundsInfo
- Publication number
- CH449635A CH449635A CH449367A CH449367A CH449635A CH 449635 A CH449635 A CH 449635A CH 449367 A CH449367 A CH 449367A CH 449367 A CH449367 A CH 449367A CH 449635 A CH449635 A CH 449635A
- Authority
- CH
- Switzerland
- Prior art keywords
- piperazine
- ethanol
- recrystallization
- melts
- dihydrochloride
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 17
- 238000002360 preparation method Methods 0.000 title claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 64
- -1 4- (2-chloro-phenyl) -1- [4- (4-methyl-phenoxy) -butyl] - piperazine Chemical compound 0.000 claims description 47
- 238000001953 recrystallisation Methods 0.000 claims description 31
- 239000000155 melt Substances 0.000 claims description 30
- 125000004432 carbon atom Chemical group C* 0.000 claims description 26
- 150000001875 compounds Chemical class 0.000 claims description 25
- 150000003839 salts Chemical class 0.000 claims description 16
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical class [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- ANHBXSYGJDPUAZ-UHFFFAOYSA-N CC1=C(C=CC=C1)N1CCN(CC1)CCCCOC1=CC=CC=C1 Chemical compound CC1=C(C=CC=C1)N1CCN(CC1)CCCCOC1=CC=CC=C1 ANHBXSYGJDPUAZ-UHFFFAOYSA-N 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- UGRMITBWUVWUEB-UHFFFAOYSA-N 1-$l^{1}-oxidanyl-3-methylbenzene Chemical group CC1=CC=CC([O])=C1 UGRMITBWUVWUEB-UHFFFAOYSA-N 0.000 claims description 2
- 150000005690 diesters Chemical class 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 230000001419 dependent effect Effects 0.000 claims 2
- 150000002431 hydrogen Chemical group 0.000 claims 2
- MPSURKFQWWLYES-UHFFFAOYSA-N 1-(3-methoxyphenyl)-4-(3-phenoxypropyl)piperazine Chemical compound COC1=CC=CC(N2CCN(CCCOC=3C=CC=CC=3)CC2)=C1 MPSURKFQWWLYES-UHFFFAOYSA-N 0.000 claims 1
- GLWZKTMLXFYYHY-UHFFFAOYSA-N 1-[4-(3-methylphenoxy)butyl]-4-phenylpiperazine Chemical compound CC=1C=C(C=CC1)OCCCCN1CCN(CC1)C1=CC=CC=C1 GLWZKTMLXFYYHY-UHFFFAOYSA-N 0.000 claims 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 125000002947 alkylene group Chemical group 0.000 claims 1
- PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-UHFFFAOYSA-N 0.000 claims 1
- 238000002844 melting Methods 0.000 claims 1
- 230000008018 melting Effects 0.000 claims 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 2
- FIVULIJQBBGFFF-UHFFFAOYSA-N 1-(2-methylphenyl)-4-(3-phenoxypropyl)piperazine Chemical compound CC1=CC=CC=C1N1CCN(CCCOC=2C=CC=CC=2)CC1 FIVULIJQBBGFFF-UHFFFAOYSA-N 0.000 description 2
- XPBZPBYLLWQREU-UHFFFAOYSA-N 1-[4-(2-methylphenoxy)butyl]-4-phenylpiperazine Chemical compound CC1=CC=CC=C1OCCCCN1CCN(C=2C=CC=CC=2)CC1 XPBZPBYLLWQREU-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000000739 antihistaminic agent Substances 0.000 description 2
- 239000002220 antihypertensive agent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 229960002748 norepinephrine Drugs 0.000 description 2
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 230000002936 tranquilizing effect Effects 0.000 description 2
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 1
- 229930182837 (R)-adrenaline Natural products 0.000 description 1
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 1
- XHIUHIDIRNZTAW-UHFFFAOYSA-N 1-(3-phenoxypropyl)-4-phenylpiperazine Chemical compound C1CN(C=2C=CC=CC=2)CCN1CCCOC1=CC=CC=C1 XHIUHIDIRNZTAW-UHFFFAOYSA-N 0.000 description 1
- QXQAPNSHUJORMC-UHFFFAOYSA-N 1-chloro-4-propylbenzene Chemical compound CCCC1=CC=C(Cl)C=C1 QXQAPNSHUJORMC-UHFFFAOYSA-N 0.000 description 1
- FZKCAHQKNJXICB-UHFFFAOYSA-N 2,1-benzoxazole Chemical compound C1=CC=CC2=CON=C21 FZKCAHQKNJXICB-UHFFFAOYSA-N 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 1
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 1
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 206010003658 Atrial Fibrillation Diseases 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 208000001387 Causalgia Diseases 0.000 description 1
- 244000248349 Citrus limon Species 0.000 description 1
- 235000005979 Citrus limon Nutrition 0.000 description 1
- 208000023890 Complex Regional Pain Syndromes Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 235000011430 Malus pumila Nutrition 0.000 description 1
- 235000015103 Malus silvestris Nutrition 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 208000018262 Peripheral vascular disease Diseases 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- AYLIEDQYYJIGDP-UHFFFAOYSA-N [C]1=CC=CS1 Chemical compound [C]1=CC=CS1 AYLIEDQYYJIGDP-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000001919 adrenal effect Effects 0.000 description 1
- 210000004100 adrenal gland Anatomy 0.000 description 1
- 239000000674 adrenergic antagonist Substances 0.000 description 1
- 230000002908 adrenolytic effect Effects 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229960004909 aminosalicylic acid Drugs 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000003440 anti-fibrillation Effects 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000003416 antiarrhythmic agent Substances 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- WXBLLCUINBKULX-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1 WXBLLCUINBKULX-UHFFFAOYSA-N 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 230000001269 cardiogenic effect Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 208000014439 complex regional pain syndrome type 2 Diseases 0.000 description 1
- 229940039227 diagnostic agent Drugs 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 208000021822 hypotensive Diseases 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 125000005948 methanesulfonyloxy group Chemical group 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical class C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 230000001272 neurogenic effect Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical class OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 208000003663 ventricular fibrillation Diseases 0.000 description 1
- NLVXSWCKKBEXTG-UHFFFAOYSA-N vinylsulfonic acid Chemical compound OS(=O)(=O)C=C NLVXSWCKKBEXTG-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 235000014101 wine Nutrition 0.000 description 1
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
-
- 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
-
- 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
- C07D295/092—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 with aromatic radicals attached to the chain
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Verfahren zur Herstellung von Diaza-cycloalkanverbindungen
Gegenstand der vorliegendenErfindung ist ein Verfahren zur Herstellung von N-Ar-N'- (Ph-Oxy-al- kyl)-diaza-cycloalkanen, worin Ar einen gogebenenfalls substituierten Phenylrest oder einen monocyclisch-hete- rocyclischen Rest aromatischen Charakters bedeutet, Ph für einen gegebenenfalls substituierten Phenylrest steht und worin der Alkylrest 3-7 Kohlenstoffatome aufweist und das Sauerstoff-vom Stickstoffatom durch 3-5 Kohlenstoffatome und die zwei Stickstoffatome des Diaza-cycloalkanringes durch je 2 oder 3 Kohlenstoffatome getrennt sind, oder ihren Säureadditionssal- zen,
insbesondere von Verbindungen der Formel
EMI1.1
worin Ph und Ar die vorher angegebene Bedeutung haben, die Gruppe der Formel-(CnH2n)-für einen Alkylenrest mit 3-7 Kohlenstoffatomen steht, welcher das Sauerstoff-vom Stickstoffatom durch 3-5 Kohlenstoffatome trennt, jede der Gruppen Zl und Z2 einen Alkylenrest mit 2-7 Kohlenstoffatomen bedeutet, welcher die zwei Stickstoffatome durch 2 oder 3 Kohlenstoffatome trennt, oder ihren Säureadditionssalzen.
Das Symbol Ph steht für einen unsubstituierten Phenylrest oder einen substituierten Phenylrest mit einem oder mehreren, gleichen oder verschiedenen Substituenten. Die Substituenten sind z. B. Niederalkyl, wie Methyl, Äthyl, n-Propyl, Isopropyl, n-Butyl, Isobutyl oder tert.-Butyl, Niederalkoxy, wie Methoxy, Äthoxy, n-Propyloxy, Isopropyloxy oder n-Butyloxy, Halogen, z. B. Fluor, Chlor oder Brom, oder Trifluormethyl. Die Gruppe Ph steht insbesondere für Phenyl, tNiederalkyl)-phenyl, (ntederaLkoxy)-phenyl, Haloge4- phenyl oder (Trifluormethyl)-phenyl.
Der Alkylrest des Ph-Oxy-alkyl-Substituenten, worin Ph die vorher angegebene Bedeutung hat, d. h. die Gruppe- (C"H2")- in der oben angegebenen Formel, ist ein Alkylenrest mit 3-7 Kohlenstoffatomen, welcher das Sauerstoff-vom Stickstoffatom durch 3-5 Kohlenstoffatome trennt. Diese Alkylenradikale sind vorzugsweisegeradkettig, d. h. 1, 3-Propylen, 1, 4-Butylen oder 1, 5-Pentylen, sie können aber auch verzweigt sein, z. B. 1, 3-Butylen, 1-Methyl-1, 3-butylen, 1, 4-Pentylen, 2, 4-Pentylen, 1, 3-Pentylen, 1, 5-Hexylen, 1, 5-Heptylen oder 2, 6-Heptylen.
Jede der Gruppen Zt und Z2 bedeutet einen Alky- lenrest mit 2-7, vorzugsweise 2 oder 3 Kohlenstoffato- men, welcher die zwei Stickstoffatome durch 2 oder 3 Kohlenstoffatome trennt. Diese Alkylenradikale sind vor allem 1, 2-Äthylen, auch 1, 2-Propylen oder 1, 3-Propylen, aber auch 1, 2-Butylen, 2, 3-Butylen, 1, 2-Isobutylen, 1, 2-Pentylen, 2, 3-Pentylen, 1, 2-Isopentylen, 1, 2-Hexylen, 3, 4-Hexylen, 3-Methyl-1, 2-isopentylen oder 1, 2-Heptylen.
Das Symbol Ar bedeutet in erster Linie einen unsubstituierten Phenylrest oder einen substituierten Phenylrest mit einem oder mehreren, gleichen oder verschiedenen Substituenten. Die Substituenten sind z. B. die gleichen wie oben, wie Niederalkyl, Niederalkoxy, Halogen oder Trifluormethyl. Die Gruppe Ar steht in erster Linie für Phenyl, (Niederalkyl)-phenyl, (Niederalkoxy)-phenyl, (Halogen)-phenyl oder (Trifluormethyl)-phenyl. Das Symbol Ar steht auch für einen einkernigen, heterocyclischen Rest aromatischen Charakters, insbesondere für einen Pyridylrest, z. B. den 2-Pyridyl-, 3-Pyridyl-oder 4-Pyridylrest, oder einen (Niederalkyl)-pyridylrest, oder einen Furyl-, z. B.
2-Furyl-, oder Thienyl-, z. B. 2-Thienylrest.
Die Verbindungen der vorliegenden Erfindung weisen antiinflammatorische, antihypertensive, tranquili- sierende und sedative Wirkungen auf, besitzen aber auch adrenolytische, antihistaminische oder antifibrilla- torische Eigenschaften und könnenentsprechend als antiinflammatorische Mittel oder als hypotensive Mittel oder als tranquilisierende oder sedative Mittel, oder als gefässerweitemde Mittel bei peripheren Gefässkrank- heiten, wie Reynaud'sche Krankheit oder Causalgia, verwendet werden. Die neuen Substanzen sind auch Antagonisten von Verbindungen, welche einen starken Effekt auf das Gewebe ausüben, wie z.
B. das Norepinephrin. Ferner können sie als diagnostische Mittel zur Kontrolle der Nebennierenfunktion verwendet werden, da sie bei den normal funktionierenden Nebennieren die Ausscheidung von blutdrucksteigernden Substanzen, wie Epinephrin oder Norepinephrin, unterdrük- ken, oder als antihistaminische Mittel eingesetzt werden. Die neuen Verbindungen können überdies als antifibrillatorische Mittel zur Behandlung von neuroge- nen oder cardiogenen Auricular-oder Ventricular-Fi- brillationen verwendet werden.
Besonders wertvolle Verbindungen sind diejenigen der Formel
EMI2.1
worin m 3 oder 4 bedeutet, das Radikal Rut fur Wasserstoff oder Methyl steht und jede der Gruppen Ra und R,, Wasserstoff, Niederalkyl, Niederalkoxy, Halogen oder Trifluormethyl bedeutet, oder ihre Säureaddi- tionssalze.
Besonders wertvoll, insbesondere als hypotensive und adrenolytische Mittel, sind die Verbindungen der Formel
EMI2.2
worin m die vorher angegebene Bedeutung hat und jede der Gruppen Ra und Ri, Wasserstoff, Niederalkyl, insbesondere Methyl, Niederalkoxy, insbesondere Methoxy oder Halogen, vorzugsweise Chlor bedeutet, insbesondere das 4- (2-Methyl-phenyl)-1- (4-phenoxy-butyl)-piperazin, 1- [4- (2-Methyl-phenoxy)-butyl]-4-phenyl-piperazin, 1- [4- (3-Methyl-phenoxy)-butyl]-4-phen, yl-piperazin, 1- [3- (4-Methoxy-phenoxy)-propyl]-4- (3-methy-l-phenyl)- piperazin, 1- [4- (4-Methyl-phenoxy)-butyl]-4-phenyl-piperazin, )-piperazin, l- [3- (4-Methoxy-phenoxy)-propyl]-4- (2-methyl-phenyl) piperazin, 4- (2-Methyl-phenyl)-1- (3-phenoxy-propyl)-piperazin,
4- (4-Methoxy-phenyl)-1- (3-phenoxy-propyl)-piperazin, 4- (4-Chlor-phenyl)-1- (4-phenoxy-butyl)-piperazin, 4- (2-Chlor-phenyl)-1- [3- (4-methoxy-phenoxy)-propyl]- piperazin und das 1- [3- (3-Methoxy-phenoxy)-propyll-4- (4-methyl-phenyl)- piperazin, oder ihre Säureadditionssalze.
Das erfindungsgemässe Verfahren zur Herstellung der neuen Verbindungen ist dadurch gekennzeichnet, dass man ein N-Ar-N'-(Ph-Oxy-alkyl)-alkylendiamin, worin Ar, Alkyl und Ph die vorher angegebene Bedeutung haben, das Sauerstoff-vom Stickstoffatom durch 3-5 Kohlenstoffatome getrennt ist und die zwei Stickstoffatome durch 2 oder 3 Kohlenstoffatome getrennt sind, insbesondere eine Verbindung der Formel
EMI2.3
worin Z, und die Gruppe der Formel-(CnH2n)-die vorher angegebene Bedeutung haben, mit einem reak tionsfähigen Diester eines Alkandiols, worin die zwei Hydroxylgruppen durch zwei oder drei Kohlenstoffatome getrennt sind,
insbesondere mit einer Verbindung der Formel Y-Z2-Y worin Z2 die vorher angegebene Bedeutung hat, und Y eine reaktionsfähige veresterte Hydroxygruppe bedeutet, umsetzt.
In der oben angegebenen Formel bedeutet Y in erster Linie ein Halogenatom, insbesondere ein Chloratom oder Bromatom, ferner eine Sulfonyloxygruppe, z. B. Methansulfonyloxy-oder p-Toluol-sulfonyloxy- gruppe.
Dieses Verfahren wird in an sich bekannter Weise durchgeführt. Man arbeitet vorzugsweise in Gegenwart eines basischen Mittels, z. B. eines Überschusses am N-Ar-N'-(Ph-Oxy-alkyl)-alkylendiamin, worin Ar, Alkyl und Ph die vorher angegebenen Bedeutung haben.
Die letztgenannten Ausgangsstoffe können durch Umsetzung von überschüssigem N-Ar-Alkylendiamin, worin die zwei Stickstoffatome durch 2 oder 3 Kohlenstoffatome getrennt sind, mit einem Mol eines reak tionsfähigen Esters eines entsprechenden Ph-Oxy-alkanols hergestellt werden.
Je nach den Verfahrensbedingungen und Ausgangsstoffen kann der Endstoff in freier Form oder in der ebenfalls in der Erfindung inbegriffenen Form seiner Säureadditionssalze erhalten werden. So können bei- spielsweise basische, neutrale, saure oder gemischte Salze, gegebenenfalls auch Hemi-, Mono-, Sesqui-oder Polyhydrate davon, erhalten werden, Die Säureaddi- tionssalze der neuen Verbindungen können in an sich bekannber Weise in die freie Verbindung übergeführt werden, z. B. mit basischen Mitteln, wie Alkalien oder Ionenaustauscher. Anderseits kann die erhaltene freie Base mit organischen oder anorganischen Säuren Salze bilden.
Zur Herstellung von Säureadditionssalzen kön- nen insbesondere therapeutisch verwendbare Säuren verwendet werden, y. B. Halogenwasserstoffsäuren, Schwefelsäure, Phosphorsäuren, Salpetersäure, Per chlorsäure ; aliphatische, alicyclische, aromatische oder heterocyclische Carbon-oder Sulfonsäuren, wie Amei- sen-, Essig-, Propion-, Bernstein-, Glykol-, Milch-, Apfel-, Wein-, Zitronen-, Ascorbin-, Malein-, Hydroxymalein-oder Brenztraubensäure ;
Phenylessig-, Benzoe-, p-Amino-benzoe-, Anthranil-, p-Hydroxy-ben zoe-, Salicyl-oder p-Amino-salicylsäure. Embonsäure, Methansulfon-, Athansulfon-, Hydroxyäthansulfon-, Äthylensulfonsäure ; Halogenbenzolsulfon-, Toluolsulfon-, Naphthalinsulfonsäuren oder Sulfanilsäure ; Meth- ionin, Tryptophan, Lysin oder Arginin.
Diese oder andere Salze der neuen Verbindung, wie z. B. die Pikrate, können auch zur Reinigung der erhaltenen freien Verbindung dienen, indem man die freie Verbindung in Salze überführt, diese abtrennt und aus den Salzen wiederum die freie Verbindung freimacht.
Infolge der engen Beziehung zwischen der neuen Verbindung in freier Form und in Form ihrer Säuread- ditionssalze sind im Vorausgegangenen und nachfol- gend unter der freien Verbindung sinn-und zweckmäs- sig gegebenenfalls auch die entsprechenden Säureadditionssalze zu verstehen.
Die neuen Verbindungen können als Racemate oder Racematgemische vorliegen, welche nach an sich bekannten Methoden aufgetrennt werden können.
Beim Verfahren der vorliegenden Erfindung werden vorzugsweise solche Ausgangsstoffe verwendet, welche zu den eingangs als besonders wertvoll geschil- derten Verbindungen führen.
Die neuen Verbindungen können als Heilmittel, z. B. in Form von pharmazeutischen Präparaten, verwendet werden, welche diese Verbindungen zusammen mit pharmazeutischen, organischen oder anorgani- schen, festen, halbfesten oder flussigen Trägerstoffen, die für enterale, z. B. orale, oder parenterale Gabe geeignet sind, enthalten.
Die Temperaturen sind im folgenden Beispiel in Celsiusgraden angegeben.
Beispiel
Ein Gemisch von 9, 4 g N- (4-Phenoxy-butyl)- N'-phenyl-äthyldiamin, 5, 9 g Äthylenbromid, 70 ml n-Butanol, welches eine Spur Wasser enthält, und 10 g Natriumcarbonat wird 17 Stunden unter Rühren unter Rückfluss gekocht. Das heisse Reaktionsgemisch wird filtriert, das Filtrat unter vermindertem Druck eingedampft, der Rückstand destilliert und das. 1-(4-PhenW oxy-butyl)-4-phenyl-piperazin bei 176-176 /0, 05 mm Hg gesammelt. Das Produkt wird in sein Dihydrochlo r, id durch Umsetzung der äthanolischen Lösung der freien Base mit Chlorwasserstoff in Äthanol und Ver dünnung des Reaktionsgemisches mit Äther hergestellt.
Der erhaltene Niederschlag wird abfiltriert und aus Äthanol umkristallisiert. F. 206 .
Die folgenden Verbindungen werden gemäss dem oben beschriebenen Verfahren hergestellt : 4-(2-Methyl-phenyl)-1-(4-phenoxy-butyl)-piperazin, dessen Dihydrochlorid, nach Umkristallisation aus Äthanol, bei 183 schmilzt ; 4-(3-Chlor-phenyl)-l-(4-phonoxy-butyl)-pipe]'azin, dessen Dihydrochlordi, nach Umkristallisation aus Äthanol, bei 178-180 schmilzt ; 4-(3-Methoxy-phenyl)-1-(4-phenoxy-butyl)-pipera- zin, dessen Dihydrochlorid, nach Umkristallisation aus Äthanol, bei 192-193 schmilzt ;
4-Phenyl-1-(3-phenoxy-propyl)-piperazin, dessen Dihydrochlorid, nach Umkristallisation aus Äthanol, bei 206-208 schmilzt ; l- [3- (2-Chlor-phenoxy)-propyl]-4- (3-methyI-phe- nyl)-piperazin, dessen dihydrochlorid, nach Umkristallisation aus Äthanol, bei 178-180 schmilzt ;
1-[3-(4-Methoxy-phenoxy)-propyl]-4-(3-methyl phenyl)-piperazin, dessen Dihydrochlorid, nach Umkristallisation aus Äthanol, bei 190-191'schmilzt ; 1- [4- (2-Methyl-phenoxy)-butyl]-4-phenyl-piperazin, dessen Dihydrochlorid, nach Umkristallisation aus Äthanol, bei 205-08 , schmilzt ;
1- [4- (4-Methyl-phenoxy) butyl]-4-phenyl-piperazin, dessen Dihydrochlorid, nach Umkristallisation aus Äthanol, bei 210-212 schmilzt ;
4- (4-Methyl-phenyl)-1- (4-phenoxy-butyl)-piperazin, dessen Dihydrochlorid, nach Umkristallisation aus Äthanol, bei 219-220 schmilzt ;
4- (2-Methyl-phenyl)-1- (3-phenoxy-prpyl)-piperazin, dessen Hydrochlorid, nach Umkristallisation aus Athanol, bei 210-213 schmilzt ; 4-(2-Methyl-phenyl)-l-[4-(2-methyl-phenoxy)-bu- tyl]-piperazin, dessen Dihydrochlorid, nach Umkristallisation aus Äthanol, bei 167-168 schmilzt ;
Process for the preparation of diaza-cycloalkane compounds
The present invention relates to a process for the preparation of N-Ar-N'- (Ph-oxy-alkyl) -diaza-cycloalkanes, where Ar is an optionally substituted phenyl radical or a monocyclic-heterocyclic radical of aromatic character, Ph for an optionally substituted phenyl radical and in which the alkyl radical has 3-7 carbon atoms and the oxygen atom is separated from the nitrogen atom by 3-5 carbon atoms and the two nitrogen atoms of the diaza-cycloalkane ring are separated by 2 or 3 carbon atoms each, or their acid addition salts,
in particular of compounds of the formula
EMI1.1
wherein Ph and Ar have the meaning given above, the group of the formula - (CnH2n) - stands for an alkylene radical with 3-7 carbon atoms, which separates the oxygen from the nitrogen atom by 3-5 carbon atoms, each of the groups Zl and Z2 is an alkylene radical with 2-7 carbon atoms, which separates the two nitrogen atoms by 2 or 3 carbon atoms, or their acid addition salts.
The symbol Ph stands for an unsubstituted phenyl radical or a substituted phenyl radical with one or more, identical or different substituents. The substituents are e.g. B. lower alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, lower alkoxy such as methoxy, ethoxy, n-propyloxy, isopropyloxy or n-butyloxy, halogen, e.g. B. fluorine, chlorine or bromine, or trifluoromethyl. The group Ph stands in particular for phenyl, t-lower alkyl) -phenyl, (ntederaLkoxy) -phenyl, haloge4-phenyl or (trifluoromethyl) -phenyl.
The alkyl radical of the Ph-oxy-alkyl substituent in which Ph has the meaning given above, d. H. the group - (C "H2") - in the formula given above, is an alkylene radical with 3-7 carbon atoms, which separates the oxygen from the nitrogen atom by 3-5 carbon atoms. These alkylene radicals are preferably straight chain; H. 1, 3-propylene, 1, 4-butylene or 1, 5-pentylene, but they can also be branched, e.g. B. 1,3-butylene, 1-methyl-1,3-butylene, 1,4-pentylene, 2,4-pentylene, 1,3-pentylene, 1,5-hexylene, 1,5-heptylene or 2, 6-heptylene.
Each of the groups Zt and Z2 denotes an alkylene radical having 2-7, preferably 2 or 3 carbon atoms, which separates the two nitrogen atoms by 2 or 3 carbon atoms. These alkylene radicals are primarily 1,2-ethylene, also 1,2-propylene or 1,3-propylene, but also 1,2-butylene, 2,3-butylene, 1,2-isobutylene, 1,2-pentylene, 2,3-pentylene, 1,2-isopentylene, 1,2-hexylene, 3,4-hexylene, 3-methyl-1,2-isopentylene or 1,2-heptylene.
The symbol Ar means primarily an unsubstituted phenyl radical or a substituted phenyl radical with one or more, identical or different substituents. The substituents are e.g. B. the same as above, such as lower alkyl, lower alkoxy, halogen or trifluoromethyl. The group Ar stands primarily for phenyl, (lower alkyl) phenyl, (lower alkoxy) phenyl, (halogen) phenyl or (trifluoromethyl) phenyl. The symbol Ar also stands for a mononuclear, heterocyclic radical of aromatic character, in particular for a pyridyl radical, e.g. B. the 2-pyridyl, 3-pyridyl or 4-pyridyl radical, or a (lower alkyl) pyridyl radical, or a furyl, z. B.
2-furyl, or thienyl, e.g. B. 2-thienyl radical.
The compounds of the present invention have antiinflammatory, antihypertensive, tranquilizing and sedative effects, but also have adrenolytic, antihistaminic or antifibrillation properties and can accordingly be used as antiinflammatory agents or as hypotensive agents or as tranquilizing or sedative agents, or as vasodilating agents peripheral vascular diseases, such as Reynaud's disease or causalgia, can be used. The new substances are also antagonists of compounds which have a strong effect on the tissue, such as e.g.
B. the norepinephrine. Furthermore, they can be used as diagnostic agents for controlling the adrenal function, since they suppress the excretion of substances that increase blood pressure, such as epinephrine or norepinephrine, in the normally functioning adrenal glands, or are used as antihistaminic agents. The new compounds can also be used as antifibrillatory agents for the treatment of neurogenic or cardiogenic auricular or ventricular fibrillation.
Particularly valuable compounds are those of the formula
EMI2.1
where m is 3 or 4, the radical rut is hydrogen or methyl and each of the groups Ra and R 1 is hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl, or their acid addition salts.
The compounds of the formula are particularly valuable, especially as hypotensive and adrenolytic agents
EMI2.2
wherein m has the meaning given above and each of the groups Ra and Ri, hydrogen, lower alkyl, in particular methyl, lower alkoxy, in particular methoxy or halogen, preferably chlorine, in particular 4- (2-methylphenyl) -1- (4- phenoxy-butyl) -piperazine, 1- [4- (2-methyl-phenoxy) -butyl] -4-phenyl-piperazine, 1- [4- (3-methyl-phenoxy) -butyl] -4-phen, yl -piperazine, 1- [3- (4-methoxyphenoxy) propyl] -4- (3-methy-1-phenyl) -piperazine, 1- [4- (4-methyl-phenoxy) -butyl] -4 -phenyl-piperazine,) -piperazine, 1- [3- (4-methoxyphenoxy) -propyl] -4- (2-methyl-phenyl) piperazine, 4- (2-methyl-phenyl) -1- (3 -phenoxy-propyl) -piperazine,
4- (4-methoxyphenyl) -1- (3-phenoxypropyl) -piperazine, 4- (4-chloro-phenyl) -1- (4-phenox-butyl) -piperazine, 4- (2-chloro -phenyl) -1- [3- (4-methoxyphenoxy) -propyl] - piperazine and 1- [3- (3-methoxyphenoxy) propyll-4- (4-methyl-phenyl) piperazine, or their acid addition salts.
The process according to the invention for the preparation of the new compounds is characterized in that an N-Ar-N '- (Ph-oxy-alkyl) -alkylenediamine, in which Ar, alkyl and Ph have the meanings given above, the oxygen atom from the nitrogen atom 3-5 carbon atoms separated and the two nitrogen atoms separated by 2 or 3 carbon atoms, especially a compound of the formula
EMI2.3
wherein Z, and the group of the formula - (CnH2n) - have the meaning given above, with a reactive diester of an alkanediol, in which the two hydroxyl groups are separated by two or three carbon atoms,
in particular with a compound of the formula Y-Z2-Y in which Z2 has the meaning given above and Y is a reactive esterified hydroxyl group.
In the formula given above, Y is primarily a halogen atom, in particular a chlorine atom or bromine atom, also a sulfonyloxy group, e.g. B. methanesulfonyloxy or p-toluene-sulfonyloxy group.
This process is carried out in a manner known per se. It is preferably carried out in the presence of a basic agent, e.g. B. an excess of N-Ar-N '- (Ph-oxy-alkyl) -alkylenediamine, wherein Ar, alkyl and Ph have the meanings given above.
The last-mentioned starting materials can be prepared by reacting excess N-Ar-alkylenediamine, in which the two nitrogen atoms are separated by 2 or 3 carbon atoms, with one mole of a reactive ester of a corresponding Ph-oxyalkanol.
Depending on the process conditions and starting materials, the end product can be obtained in free form or in the form of its acid addition salts, which is also included in the invention. For example, basic, neutral, acidic or mixed salts, optionally also hemi-, mono-, sesqui- or polyhydrates thereof, can be obtained. The acid addition salts of the new compounds can be converted into the free compound in a manner known per se , e.g. B. with basic agents such as alkalis or ion exchangers. On the other hand, the free base obtained can form salts with organic or inorganic acids.
For the preparation of acid addition salts, therapeutically useful acids in particular can be used, y. B. hydrohalic acids, sulfuric acid, phosphoric acids, nitric acid, perchloric acid; aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic, acetic, propionic, amber, glycol, milk, apple, wine, lemon, ascorbic, maleic, hydroxymaleinic or pyruvic acid;
Phenylacetic, benzoic, p-amino-benzoic, anthranil, p-hydroxy-benzoic, salicylic or p-amino-salicylic acid. Emboxylic acid, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, ethylene sulfonic acid; Halobenzenesulfonic, toluenesulfonic, naphthalenesulfonic acids or sulfanilic acid; Methionine, tryptophan, lysine or arginine.
These or other salts of the new compound, such as. B. the picrates, can also be used to purify the free compound obtained by converting the free compound into salts, separating them and in turn liberating the free compound from the salts.
As a result of the close relationship between the new compound in free form and in the form of its acid addition salts, in the preceding and in the following the free compound is to be understood meaningfully and expediently, if appropriate, also to mean the corresponding acid addition salts.
The new compounds can be present as racemates or mixtures of racemates, which can be resolved by methods known per se.
In the process of the present invention it is preferred to use those starting materials which lead to the compounds described at the beginning as being particularly valuable.
The new compounds can be used as remedies, e.g. B. in the form of pharmaceutical preparations can be used, which these compounds together with pharmaceutical, organic or inorganic, solid, semi-solid or liquid carrier substances which are used for enteral, z. B. oral or parenteral administration are suitable.
In the following example, the temperatures are given in degrees Celsius.
example
A mixture of 9.4 g of N- (4-phenoxy-butyl) - N'-phenyl-ethyl diamine, 5.9 g of ethylene bromide, 70 ml of n-butanol, which contains a trace of water, and 10 g of sodium carbonate is added for 17 hours Stir refluxed. The hot reaction mixture is filtered, the filtrate is evaporated under reduced pressure, the residue is distilled and the 1- (4-PhenW oxy-butyl) -4-phenyl-piperazine is collected at 176-176 / 0.05 mm Hg. The product is produced in its dihydrochloride by reacting the ethanolic solution of the free base with hydrogen chloride in ethanol and diluting the reaction mixture with ether.
The precipitate obtained is filtered off and recrystallized from ethanol. F. 206.
The following compounds are prepared according to the method described above: 4- (2-methyl-phenyl) -1- (4-phenoxy-butyl) piperazine, the dihydrochloride of which, after recrystallization from ethanol, melts at 183; 4- (3-chloro-phenyl) -l- (4-phonoxy-butyl) -pipe] 'azine, the dihydrochloride of which, after recrystallization from ethanol, melts at 178-180; 4- (3-Methoxy-phenyl) -1- (4-phenoxy-butyl) -piperazine, the dihydrochloride of which, after recrystallization from ethanol, melts at 192-193;
4-phenyl-1- (3-phenoxypropyl) piperazine, the dihydrochloride of which, after recrystallization from ethanol, melts at 206-208; 1- [3- (2-chloro-phenoxy) -propyl] -4- (3-methyl-phenyl) -piperazine, the dihydrochloride of which, after recrystallization from ethanol, melts at 178-180;
1- [3- (4-Methoxyphenoxy) propyl] -4- (3-methylphenyl) piperazine, the dihydrochloride of which, after recrystallization from ethanol, melts at 190-191 '; 1- [4- (2-methyl-phenoxy) -butyl] -4-phenyl-piperazine, the dihydrochloride of which, after recrystallization from ethanol, melts at 205-08;
1- [4- (4-methyl-phenoxy) butyl] -4-phenyl-piperazine, the dihydrochloride of which, after recrystallization from ethanol, melts at 210-212;
4- (4-methyl-phenyl) -1- (4-phenoxy-butyl) -piperazine, the dihydrochloride of which, after recrystallization from ethanol, melts at 219-220;
4- (2-methyl-phenyl) -1- (3-phenoxy-propyl) -piperazine, the hydrochloride of which, after recrystallization from ethanol, melts at 210-213; 4- (2-methylphenyl) -1- [4- (2-methylphenoxy) butyl] piperazine, the dihydrochloride of which, after recrystallization from ethanol, melts at 167-168;
Claims (1)
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US25104763A | 1963-01-14 | 1963-01-14 | |
| US25778463A | 1963-02-11 | 1963-02-11 | |
| US25778363A | 1963-02-11 | 1963-02-11 | |
| US27189063A | 1963-04-10 | 1963-04-10 | |
| US32133463A | 1963-11-04 | 1963-11-04 | |
| US32134263A | 1963-11-04 | 1963-11-04 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH449635A true CH449635A (en) | 1968-01-15 |
Family
ID=27559375
Family Applications (5)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH449167A CH449633A (en) | 1963-01-14 | 1964-01-09 | Process for the preparation of diaza-cycloalkane compounds |
| CH449367A CH449635A (en) | 1963-01-14 | 1964-01-09 | Process for the preparation of diaza-cycloalkane compounds |
| CH449467A CH449636A (en) | 1963-01-14 | 1964-01-09 | Process for the preparation of diaza-cycloalkane compounds |
| CH449267A CH449634A (en) | 1963-01-14 | 1964-01-09 | Process for the preparation of diaza-cycloalkane compounds |
| CH22764A CH449030A (en) | 1963-01-14 | 1964-01-09 | Process for the preparation of diaza-cycloalkane compounds |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH449167A CH449633A (en) | 1963-01-14 | 1964-01-09 | Process for the preparation of diaza-cycloalkane compounds |
Family Applications After (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH449467A CH449636A (en) | 1963-01-14 | 1964-01-09 | Process for the preparation of diaza-cycloalkane compounds |
| CH449267A CH449634A (en) | 1963-01-14 | 1964-01-09 | Process for the preparation of diaza-cycloalkane compounds |
| CH22764A CH449030A (en) | 1963-01-14 | 1964-01-09 | Process for the preparation of diaza-cycloalkane compounds |
Country Status (5)
| Country | Link |
|---|---|
| BE (3) | BE642427A (en) |
| CH (5) | CH449633A (en) |
| DE (1) | DE1232587B (en) |
| FR (1) | FR3734M (en) |
| GB (2) | GB1061571A (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5513209A (en) * | 1978-07-11 | 1980-01-30 | Synthelabo | Antidepressive made of piperazine derivative |
| JPS56115769A (en) * | 1980-02-18 | 1981-09-11 | Tanabe Seiyaku Co Ltd | Piperazine derivative and its preparation |
| FR2568878B1 (en) * | 1984-08-07 | 1986-11-21 | Cortial | NOVEL (PHENYLPIPERAZINYLETHYLAMINE ETHOXY) -4 PHENOL DERIVATIVES, THEIR PREPARATION METHOD AND THEIR THERAPEUTIC APPLICATION |
| DE3715763A1 (en) * | 1987-05-12 | 1988-11-24 | Hoechst Ag | DIARYLALKYL-SUBSTITUTED ALKYLAMINE, METHOD FOR THE PRODUCTION THEREOF, THEIR USE AND MEDICINAL PRODUCTS CONTAINING THE SAME |
| US6528529B1 (en) | 1998-03-31 | 2003-03-04 | Acadia Pharmaceuticals Inc. | Compounds with activity on muscarinic receptors |
| BR9909277A (en) * | 1998-03-31 | 2001-10-16 | Acadia Pharm Inc | Compounds with activity at muscarinic receptors |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1197461B (en) | 1962-02-23 | 1965-07-29 | Abbott Lab | Process for the preparation of 1,4-diazine derivatives |
-
0
- GB GB1053301D patent/GB1053301A/en active Active
-
1964
- 1964-01-09 CH CH449167A patent/CH449633A/en unknown
- 1964-01-09 CH CH449367A patent/CH449635A/en unknown
- 1964-01-09 CH CH449467A patent/CH449636A/en unknown
- 1964-01-09 CH CH449267A patent/CH449634A/en unknown
- 1964-01-09 CH CH22764A patent/CH449030A/en unknown
- 1964-01-10 DE DEC31848A patent/DE1232587B/en active Pending
- 1964-01-13 BE BE642427A patent/BE642427A/xx unknown
- 1964-01-13 BE BE642429A patent/BE642429A/xx unknown
- 1964-01-13 BE BE642428A patent/BE642428A/xx unknown
- 1964-01-14 GB GB170264A patent/GB1061571A/en not_active Expired
- 1964-04-07 FR FR969932A patent/FR3734M/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| GB1053301A (en) | |
| CH449634A (en) | 1968-01-15 |
| DE1232587B (en) | 1967-01-19 |
| CH449633A (en) | 1968-01-15 |
| BE642427A (en) | 1964-07-13 |
| CH449030A (en) | 1967-12-31 |
| BE642428A (en) | 1964-07-13 |
| FR3734M (en) | 1965-12-06 |
| GB1061571A (en) | 1967-03-15 |
| BE642429A (en) | 1964-07-13 |
| CH449636A (en) | 1968-01-15 |
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