DE1620419C - 1,4 substituted piperazines and processes for their production - Google Patents
1,4 substituted piperazines and processes for their productionInfo
- Publication number
- DE1620419C DE1620419C DE19661620419 DE1620419A DE1620419C DE 1620419 C DE1620419 C DE 1620419C DE 19661620419 DE19661620419 DE 19661620419 DE 1620419 A DE1620419 A DE 1620419A DE 1620419 C DE1620419 C DE 1620419C
- Authority
- DE
- Germany
- Prior art keywords
- piperazine
- propyl
- pyrimidyl
- triphenyl
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 150000004885 piperazines Chemical class 0.000 title claims description 3
- -1 2-quinazolyl Chemical group 0.000 description 27
- 238000002844 melting Methods 0.000 description 11
- 239000000155 melt Substances 0.000 description 9
- 239000002253 acid Substances 0.000 description 8
- 150000007513 acids Chemical class 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 238000000354 decomposition reaction Methods 0.000 description 5
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- LSVAHJRFSZHOBF-UHFFFAOYSA-N 2-[4-(3,3,3-triphenylpropyl)piperazin-1-yl]pyrimidine Chemical compound C1CN(C=2N=CC=CN=2)CCN1CCC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 LSVAHJRFSZHOBF-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 230000000202 analgesic Effects 0.000 description 3
- 230000003110 anti-inflammatory Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 150000002366 halogen compounds Chemical class 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-N propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- DKSZLDSPXIWGFO-BLOJGBSASA-N (4R,4aR,7S,7aR,12bS)-9-methoxy-3-methyl-2,4,4a,7,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-7-ol;phosphoric acid;hydrate Chemical compound O.OP(O)(O)=O.OP(O)(O)=O.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC DKSZLDSPXIWGFO-BLOJGBSASA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N (E)-but-2-enedioate;hydron Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- WMVRLRVVLUHMSQ-UHFFFAOYSA-N 2-[4-(3,3,3-triphenylpropyl)piperazin-1-yl]-1H-pyrimidin-6-one Chemical compound N1C(=O)C=CN=C1N1CCN(CCC(C=2C=CC=CC=2)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 WMVRLRVVLUHMSQ-UHFFFAOYSA-N 0.000 description 2
- SSHUEVNEGPWTJB-UHFFFAOYSA-N 2-[4-(3,3,3-triphenylpropyl)piperazin-1-yl]pyrimidin-4-amine Chemical compound NC1=CC=NC(N2CCN(CCC(C=3C=CC=CC=3)(C=3C=CC=CC=3)C=3C=CC=CC=3)CC2)=N1 SSHUEVNEGPWTJB-UHFFFAOYSA-N 0.000 description 2
- 125000006325 2-propenyl amino group Chemical group [H]C([H])=C([H])C([H])([H])N([H])* 0.000 description 2
- XGOABVFJUBZOCN-UHFFFAOYSA-N 4,5-dimethyl-2-[4-(3,3,3-triphenylpropyl)piperazin-1-yl]pyrimidine Chemical compound N1=C(C)C(C)=CN=C1N1CCN(CCC(C=2C=CC=CC=2)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 XGOABVFJUBZOCN-UHFFFAOYSA-N 0.000 description 2
- VGCJPZYRZQLIGU-UHFFFAOYSA-N 4-methoxy-2-[4-(3,3,3-triphenylpropyl)piperazin-1-yl]pyrimidine Chemical compound COC1=CC=NC(N2CCN(CCC(C=3C=CC=CC=3)(C=3C=CC=CC=3)C=3C=CC=CC=3)CC2)=N1 VGCJPZYRZQLIGU-UHFFFAOYSA-N 0.000 description 2
- XFJFIWCXGAQABP-UHFFFAOYSA-N 4-methyl-2-[4-(3,3,3-triphenylpropyl)piperazin-1-yl]pyrimidine Chemical compound CC1=CC=NC(N2CCN(CCC(C=3C=CC=CC=3)(C=3C=CC=CC=3)C=3C=CC=CC=3)CC2)=N1 XFJFIWCXGAQABP-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 229960004415 Codeine Phosphate Drugs 0.000 description 2
- 210000002683 Foot Anatomy 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 229960002895 Phenylbutazone Drugs 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000007792 addition Methods 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N n-butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 239000001184 potassium carbonate Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 2
- ARTJAHOMQQCUFB-UHFFFAOYSA-N 1-(3,3,3-triphenylpropyl)piperazine Chemical compound C1CNCCN1CCC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 ARTJAHOMQQCUFB-UHFFFAOYSA-N 0.000 description 1
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-Aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 1
- UNCQVRBWJWWJBF-UHFFFAOYSA-N 2-chloropyrimidine Chemical compound ClC1=NC=CC=N1 UNCQVRBWJWWJBF-UHFFFAOYSA-N 0.000 description 1
- JOYIPEFATCKVPI-UHFFFAOYSA-N 3,3,3-triphenylpropyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OCCC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 JOYIPEFATCKVPI-UHFFFAOYSA-N 0.000 description 1
- 229940116904 ANTIINFLAMMATORY THERAPEUTIC RADIOPHARMACEUTICALS Drugs 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 229960003563 Calcium Carbonate Drugs 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N Carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N DMA Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N Dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 229940045996 Isethionic Acid Drugs 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N Isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- PHTQWCKDNZKARW-UHFFFAOYSA-N Isoamyl alcohol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- AXVBJXVSFUOBFI-UHFFFAOYSA-N N,N-dimethyl-2-[4-(3,3,3-triphenylpropyl)piperazin-1-yl]pyrimidin-4-amine Chemical compound CN(C)C1=CC=NC(N2CCN(CCC(C=3C=CC=CC=3)(C=3C=CC=CC=3)C=3C=CC=CC=3)CC2)=N1 AXVBJXVSFUOBFI-UHFFFAOYSA-N 0.000 description 1
- ZDJJYFKGWFWSON-UHFFFAOYSA-N N-methyl-2-[4-(3,3,3-triphenylpropyl)piperazin-1-yl]pyrimidin-4-amine Chemical compound CNC1=CC=NC(N2CCN(CCC(C=3C=CC=CC=3)(C=3C=CC=CC=3)C=3C=CC=CC=3)CC2)=N1 ZDJJYFKGWFWSON-UHFFFAOYSA-N 0.000 description 1
- 229940074726 OPHTHALMOLOGIC ANTIINFLAMMATORY AGENTS Drugs 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 229960004838 Phosphoric acid Drugs 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-N Sulfamic acid Chemical compound NS(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
- 229940032330 Sulfuric acid Drugs 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000005712 crystallization Effects 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drugs Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical group 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 201000008125 pain agnosia Diseases 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229940094025 potassium bicarbonate Drugs 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229940093956 potassium carbonate Drugs 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 239000001187 sodium carbonate Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 230000001225 therapeutic Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Description
2020th
in der R ein Wasserstoffatom und Het einen 2-Chinazolyl-, 2-Methyl-4-chinazolyl- und einen durch ein Chloratom oder einen Methoxy-, Methylamino oder einen oder zwei Methylreste substituierten 2-Pyrimidylrest oder R einen Phenylrest und Het einen 2-Methyl-4-chinazolyl-, 2-Amino-4-pyrimidyl- und einen gegebenenfalls durch einen Methoxy-, Hydroxy-, Amino-, Methylamino-, Dimethylamino-, Allylamino- oder einen oder zwei Methylreste substituierten 2-Pyrimidylrest bedeutet, sowie deren Additionssalze mit Säuren. 'in which R is a hydrogen atom and Het is a 2-quinazolyl, 2-methyl-4-quinazolyl and a substituted by a chlorine atom or a methoxy, methylamino or one or two methyl radicals 2-pyrimidyl radical or R a phenyl radical and Het a 2-methyl-4-quinazolyl-, 2-amino-4-pyrimidyl- and a methoxy, hydroxy, amino, methylamino, dimethylamino, Allylamino or one or two methyl radicals substituted 2-pyrimidyl radical, and their addition salts with acids. '
2. 1 - (3,3 - Diphenyl -1 - propyl) - 4 - (4,6 - dimethyl-2-pyrimidyl)-piperazin. 2. 1 - (3,3 - Diphenyl -1 - propyl) - 4 - (4,6 - dimethyl-2-pyrimidyl) piperazine.
3. 1 - (3,3 - Diphenyl -1 - propyl) - 4 - (4 - methylamino-2-pyrimidyl)-piperazin. 3. 1 - (3,3 - Diphenyl -1 - propyl) - 4 - (4 - methylamino-2-pyrimidyl) piperazine.
4. 1 - (3,3 - Diphenyl -1 - propyl) - 4 - (2 - chinazolyl)-piperazdn. 4.1 - (3,3 - Diphenyl -1 - propyl) - 4 - (2 - quinazolyl) piperazdn.
5. 1 - (3,3,3 - Triphenyl -1 - propyl) - 4 - (2 - pyrimidyl)-piperazin. 5. 1 - (3,3,3 - triphenyl -1 - propyl) - 4 - (2 - pyrimidyl) piperazine.
6. 1 - (3,3,3 - Triphenyl -1 - propyl) - 4 - (4 - hydroxy-2-pyrimidyl)-piperazin. 6. 1 - (3,3,3 - triphenyl -1 - propyl) - 4 - (4 - hydroxy-2-pyrimidyl) piperazine.
7. 1 - (3,3,3 - Triphenyl -1 - propyl) - 4 - (4 - methyl-2-pyrimidyl)-piperazin. 7. 1 - (3,3,3 - triphenyl -1 - propyl) - 4 - (4 - methyl-2-pyrimidyl) piperazine.
8. 1 - (3,3,3 - Triphenyl -1 - propyl) - 4 - (4,5 - dimethyl-2-pyrimidyl)-piperazin. 8. 1 - (3,3,3 - triphenyl -1 - propyl) - 4 - (4,5 - dimethyl-2-pyrimidyl) piperazine.
9. 1 -(3,3,3- Triphenyl -1 - propyl) - 4 - (4 - methoxy-2-pyrimidyl)-piperazin. 9. 1 - (3,3,3-Triphenyl -1-propyl) -4 - (4-methoxy-2-pyrimidyl) -piperazine.
10. l-(3,3,3-Triphenyl-l-propyl)-4-(4-amino-2-pyrimidyl)-piperazin. 10. 1- (3,3,3-Triphenyl-1-propyl) -4- (4-amino-2-pyrimidyl) piperazine.
11. 1 - (3,3,3 - Triphenyl -1 - propyl) - 4 - (2 - methyl-4-chinazolyl)-piperazin. 11. 1 - (3,3,3 - triphenyl -1 - propyl) - 4 - (2 - methyl-4-quinazolyl) piperazine.
12. Verfahren zur Herstellung von Verbindungen nach Anspruch 1, dadurch gekennzeichnet, daß man eine Halogenverbindung der allgemeinen Formel Het — Z, in der Z ein Chlor- oder-Bromatom ist, mit einem N-mono-substituierten Piperazin der allgemeinen Formel12. A method for the preparation of compounds according to claim 1, characterized in that that a halogen compound of the general formula Het - Z, in which Z is a chlorine or bromine atom is, with an N-mono-substituted piperazine of the general formula
HN N—(CH2)2—C—RHN N- (CH 2 ) 2 -C-R
wobei Het und R die gleiche Bedeutung besitzen wie im Anspruch 1, gegebenenfalls in einem polaren Lösungsmittel und in Gegenwart einer Base in an sich bekannter Weise umsetzt.where Het and R have the same meaning as in claim 1, optionally in a polar one Reacts solvent and in the presence of a base in a manner known per se.
1,4-substituierte Piperazine der allgemeinen Formel I1,4-substituted piperazines of the general formula I.
R—C—(CH2)2—N N—Het (I)R — C— (CH 2 ) 2 —NN — Het (I)
in der R ein Wasserstoffatom und Het einen 2-Chinazolyl-, 2-Methyl-4-chinazolyl- und einen durch ein Chloratom oder einen Methoxy-, Methylamino- oder einen oder zwei Methylreste substituierten 2-Pyrimidylrest oder R einen Phenylrest und Het einen 2-Methyl-4-chinazolyl-, 2-Amino-4-pyrimidyl- und einen gegebenenfalls durch einen Methoxy-, Hydroxy-, Amino-, Methylamino-, Dimethylamino-, Allylamino- oder einen oder zwei Methylreste substituierten 2-Pyrimidylrest bedeutet, sowie der Additionssalze mit Mineralsäuren oder organischen Säuren^ können alsin which R is a hydrogen atom and Het is a 2-quinazolyl-, 2-methyl-4-quinazolyl- and one by one Chlorine atom or a methoxy, methylamino or one or two methyl radicals substituted 2-pyrimidyl radical or R is phenyl and Het is 2-methyl-4-quinazolyl, 2-amino-4-pyrimidyl and an optionally by a methoxy, hydroxy, Amino, methylamino, dimethylamino, allylamino or one or two methyl radicals substituted 2-pyrimidyl radical means, as well as the addition salts with mineral acids or organic acids ^ can as
schmerzstillende oder als entzündungshemmende Mittel verwendet werden.used as pain relievers or as anti-inflammatory agents.
Dabei sind die erfindungsgemäßen Verbindungen hinsichtlich ihrer analgetischen und entzündungshemmenden Eigenschaften unter Berücksichtigung der Toxizität bekannten, handelsüblichen Arzneimitteln gleicher Wirkungsrichtung überlegen, wie die nachstehend beschriebenen Versuche zeigen. Hin-, sichtlich der entzündungshemmenden Eigenschaften wurde hierbei als Vergleichssubstanz Phenylbutazon gewählt, im Hinblick auf die analgetischen Eigenschaften wurden als Vergleichsverbindungen Codeinphosphat und d-Propoxyphenolchlorhydrat verwendet. Die analgetische Wirksamkeit wurde nach der bekannten Methode der erhitzten Platte bestimmt, die entzündungshemmende Wirksamkeit wurde nach der ebenfalls bekannten Carrageenin-Pfotenödem-Mcthodc bestimmt. Die erhaltenen Ergebnisse zeigt die nachstehende Tabelle.The compounds according to the invention are here with regard to their analgesic and anti-inflammatory properties Properties taking into account the toxicity of known, commercially available drugs superior to the same direction of action, as the experiments described below show. There-, In terms of its anti-inflammatory properties, phenylbutazone was used as the comparison substance With regard to the analgesic properties, codeine phosphate were chosen as comparison compounds and d-propoxyphenol chlorohydrate are used. The analgesic effectiveness was according to the known Determined the anti-inflammatory effectiveness was determined according to the method of heated plate also known carrageenin paw edema Mcthodc determined. The results obtained show the table below.
Substanz gemäß
BeispielExamined
Substance according to
example
Maus mg/kgToxicity DL 50
Mouse mg / kg
Maus mg/kgAnalgesia*)
Mouse mg / kg
Ratte mg/kg P. O.Inflammation **)
Rat mg / kg PO
Anal
DL50(LP.)
anal. (I. P.)T
Anal
DL 50 (LP.)
anal. (IP)
gesie Inflam
DL50(P-O.)
anal. (P. O.)therapeutic inde;
Gesie Inflam
DL 50 (PO.)
anal. (PO)
nation
DL50(RO.)
inf. (P.O.) t
nation
DL 50 (RO.)
inf. (PO)
substanz
Codein-
phosphatComparison
substance
Codeine
phosphate
phenol-
chlorhydratd-propoxy
phenol-
chlorohydrate
butazonPhenyl
butazon
Anmerkung zur Tabelle:Note on the table:
*) Prozentuale Erhöhung der Zeit bis zum Lecken der Pfote: + + = 50%, + = 25%.*) Percentage increase in time until the paw is licked: + + = 50%, + = 25%.
**) Prozentuale Hemmung des Odems in bezug auf die Vergleichstiere, 3 Stunden nach Behandlung: + + = 30%, + = 20%.**) Percentage inhibition of the odema in relation to the comparison animals, 3 hours after treatment: + + = 30%, + = 20%.
Diese Verbindungen werden dadurch hergestellt, daß eine Halogenverbindung der allgemeinen Formel Het — Z, in der Z ein Chlor- oder Bromatom darstellt, mit einem N-monosubstituierten Piperazin der allgemeinen FormelThese compounds are prepared by using a halogen compound of the general formula Het - Z, in which Z represents a chlorine or bromine atom, with an N-monosubstituted piperazine of the general formula
HNHN
N—(CH2)2—C—R (IV)N— (CH 2 ) 2 —C — R (IV)
1515th
kondensiert wird, wobei man die Halogenverbindung auf das Piperazin einwirken läßt. Das Piperazin ist dabei in einem polaren Lösungsmittel gelöst, z. B. in einem Alkohol, wie Butanol oder Isopentanol, oder in einem aliphatischen N,N-disubstituierten Amid, wie Dimethylformamid und Dimethylacetamid. Dabei ist es vorteilhaft, bei Temperaturen zwischen 120 und 150° C in Gegenwart einer Base zu arbeiten, welche die im Laufe der Reaktion gebildete Halogenwasserstoffsäure bindet.is condensed, allowing the halogen compound to act on the piperazine. That is piperazine dissolved in a polar solvent, e.g. B. in an alcohol such as butanol or isopentanol, or in an aliphatic N, N-disubstituted amide such as dimethylformamide and dimethylacetamide. It is advantageous to work at temperatures between 120 and 150 ° C in the presence of a base, which binds the hydrohalic acid formed in the course of the reaction.
Zur Bindung der Säure kann ein Überschuß von N-mono-substituiertem Piperazin oder ein Alkalioder Erdalkalisalz der Kohlensäure, wie Natriumoder Kaliumcarbonat oder -bicarbonat oder CaI-ciumcarbonat, sowie eine tertiäre, organische Base, wie Dimethylanilin, Pyridin oder Triäthylamin, eingesetzt werden.To bind the acid, an excess of N-mono-substituted piperazine or an alkali or Alkaline earth salt of carbonic acid, such as sodium or potassium carbonate or bicarbonate or calcium carbonate, and a tertiary organic base, such as dimethylaniline, pyridine or triethylamine, are used will.
Die auf diese Weise erhaltenen neuen Derivate sind schwache Basen und können mit Säuren in Salze übergeführt werden, die durch Einwirkung der Basen auf Säuren, die in geeigneten Lösungsmitteln, wie Wasser oder in mit Wasser mischbaren Alkoholen, gelöst sind, erhalten werden können. Als geeignete Säuren seien die Chlorwasserstoffsäure, Bromwasserstoffsäure, Methansulfonsäure, Isäthionsäure, Schwefelsäure, Phosphorsäure und Sulfaminsäure sowie Essigsäure, Propionsäure, Maleinsäure, Fumarsäure, Weinsäure, Zitronensäure, Oxalsäure und Benzoesäure genannt.The new derivatives obtained in this way are weak bases and can be converted into salts with acids be converted by the action of the bases on acids in suitable solvents, such as Water or in water-miscible alcohols, can be obtained. As suitable Acids are hydrochloric acid, hydrobromic acid, methanesulfonic acid, isethionic acid, sulfuric acid, Phosphoric acid and sulfamic acid as well as acetic acid, propionic acid, maleic acid, fumaric acid, Called tartaric acid, citric acid, oxalic acid and benzoic acid.
Die neuen Verbindungen können z. B. durch Destillation, Kristallisation, Chromatographie und durch Salz-Bildung mit Säuren und Zersetzung der Salze mit Alkali gereinigt werden.The new connections can e.g. B. by distillation, crystallization, chromatography and by Salt formation can be cleaned with acids and decomposition of salts with alkali.
5050
l-(3,3,3-Triphenyl-1 -propyl)-4-(2-pyrimidyl)-piperazin1- (3,3,3-triphenyl-1-propyl) -4- (2-pyrimidyl) piperazine
Man erwärmt 25 g l-(3,3,3-Triphenyl-l-propyl)-piperazin (Kp.,^,,,,,, = 227 bis 228° C) und 8,02 g 2-Chlorpyrimidin in einer Lösung von 400 ml Dimethylformamid in Gegenwart von 19,3 g trockenem Kaliumcarbonat auf 135° C. Nach 5 Stunden erhält man nach Filtration und Eindampfen des Filtrats unter vermindertem Druck 22 g l-(3,3,3-Triphenyll-propyl)-4-(2-pyrimidyl)-piperazin, Schmelzpunkt bei 130° C aus Äthanol.25 g of 1- (3,3,3-triphenyl-1-propyl) piperazine (boiling point, ^ ,,,,,, = 227 to 228 ° C.) and 8.02 g are heated 2-chloropyrimidine in a solution of 400 ml of dimethylformamide in the presence of 19.3 g of dry Potassium carbonate to 135 ° C. After 5 hours, the filtrate is obtained after filtration and evaporation 22 g of 1- (3,3,3-triphenyl-propyl) -4- (2-pyrimidyl) -piperazine under reduced pressure, Melting point at 130 ° C from ethanol.
Das als Ausgangsmaterial verwendete l-(3,3,3-Triphenyl-l-propyl)-piperazin
wird durch Einwirkung von 3,3,3-Triphenyl-l-propanol-tosylat auf einen Überschuß
von wasserfreiem Piperazin bei 140° C hergestellt.
Analog werden folgende Verbindungen erhalten:The l- (3,3,3-triphenyl-l-propyl) piperazine used as starting material is prepared by the action of 3,3,3-triphenyl-l-propanol tosylate on an excess of anhydrous piperazine at 140.degree.
The following connections are obtained analogously:
2. 1 - (3,3 - Diphenyl -1 - propyl) - 4 - (5 - chlor - 2 - pyrimidyl)-piperazin, dessen Methansulfonat bei 251° C schmilzt.2.1 - (3,3 - Diphenyl -1 - propyl) - 4 - (5 - chloro - 2 - pyrimidyl) piperazine, whose methanesulfonate melts at 251 ° C.
3. l-(3,3-Diphenyl-l-propyl)-4-(4-methyl-2-pyrimidyl)-piperazin schmilzt bei 8O0C.3. 1- (3,3-Diphenyl-1-propyl) -4- (4-methyl-2-pyrimidyl) -piperazine melts at 8O 0 C.
4. 1 - (3,3 - Diphenyl -1 - propyl) - 4 - (4,5 - dimethyl-2 - pyrimidyl) - piperazin, dessen Fumarat unter Zersetzung bei 195 bis 205° C schmilzt.4.1 - (3,3 - Diphenyl -1 - propyl) - 4 - (4,5 - dimethyl-2 - pyrimidyl) - piperazine, the fumarate of which melts at 195 to 205 ° C with decomposition.
5. 1 - (3,3 - Diphenyl - 1 - propyl) - 4 - (4,6 - dimethyl-2 - pyrimidyl) - piperazin, Schmelzpunkt bei 103 bis 105° C.5. 1 - (3,3 - Diphenyl - 1 - propyl) - 4 - (4,6 - dimethyl-2 - pyrimidyl) - piperazine, melting point at 103 to 105 ° C.
6. l-(3,3-Diphenyl-l-propyl)-4-(4-methoxy-2-pyrimidyl)-piperazin, Schmelzpunkt bei 88° C.6. l- (3,3-Diphenyl-l-propyl) -4- (4-methoxy-2-pyrimidyl) piperazine, melting point at 88 ° C.
7. 1 - (3,3 - Diphenyl -1 - propyl) - 4 - (4 - methylamino-2 - pyrimidyl) - piperazin, dessen Dichlorhydrat bei 175 bis 178° C schmilzt.7. 1 - (3,3 - Diphenyl -1 - propyl) - 4 - (4 - methylamino-2 - pyrimidyl) - piperazine, the dichlorohydrate of which melts at 175 to 178 ° C.
8. 1 - (3,3 - Diphenyl -1 - propyl) - 4 - (2 - chinazolyl)-piperazin, dessen Dichlorhydrat bei 235 bis 240° C schmilzt.8. 1 - (3,3 - Diphenyl -1 - propyl) - 4 - (2 - quinazolyl) piperazine, the dichlorohydrate of which melts at 235 to 240 ° C.
9. 1 - (3,3 - Diphenyl - 1 - propyl) - 4 - (2 - methyl-4 - chinazolyl) - piperazin, dessen Fumarat-Halbhydrat bei 167 bis 17O0C schmilzt.9. 1 - (3,3 - diphenyl - 1 - propyl) - 4 - (2 - methyl-4 - quinazolyl) - piperazine, its fumarate hemihydrate melting at 167 to 17O 0 C.
10. 1 - (3,3,3 - Triphenyl -1 - propyl) - 4 - (4 - hydroxy-2 - pyrimidyl) - piperazin, dessen Dichlorhydrat unter Zersetzung bei 176 bis 180°C schmilzt.10. 1 - (3,3,3 - triphenyl -1 - propyl) - 4 - (4 - hydroxy-2 - pyrimidyl) - piperazine, the dichlorohydrate of which melts with decomposition at 176 to 180 ° C.
11. 1 - (3,3,3 - Triphenyl - 1 - propyl) - 4 - (4 - methyl-2-pyrimidyl)-piperazin, Schmelzpunkt bei 128° C.11. 1 - (3,3,3 - triphenyl - 1 - propyl) - 4 - (4 - methyl-2-pyrimidyl) piperazine, Melting point at 128 ° C.
12. 1 - (3,3,3 - Triphenyl -1 - propyl) - 4 - (4,5 - dimethyl-2 - pyrimidyl) - piperazin, dessen Fumarat unter Zersetzung bei 190 bis 2000C schmilzt.12. 1 - (3,3,3 - triphenyl -1 - propyl) - 4 - (4,5 - dimethyl-2 - pyrimidyl) - piperazine, its fumarate melts with decomposition at 190 to 200 0 C.
13.1- (3,3,3 - Triphenyl -1 - propyl) - 4 - (4,6 - dimethyl-2-pyrimidyl)-piperazin, Schmelzpunkt bei 1400C.13.1- (3,3,3 - triphenyl -1 - propyl) - 4 - (4,6 - dimethyl-2-pyrimidyl) piperazine, melting at 140 0 C.
14. 1 - (3,3,3 - Triphenyl -1 - propyl) - 4 - (4 - methoxy-2-pyrimidyl)-piperazin, Schmelzpunkt bei 125° C.14. 1 - (3,3,3 - triphenyl -1 - propyl) - 4 - (4 - methoxy-2-pyrimidyl) -piperazine, Melting point at 125 ° C.
15. 1 - (3,3,3 - Triphenyl - 1 - propyl) - 4 - (4 - amino-2-pyrimidyl)-piperazin, dessen Dihydrat bei 132 bis 140° C schmilzt.15. 1 - (3,3,3 - triphenyl - 1 - propyl) - 4 - (4 - amino-2-pyrimidyl) piperazine, its dihydrate melts at 132 to 140 ° C.
16. 1 - (3,3,3 - Triphenyl - 1 - propyl) - 4 - (2 - amino-4 - pyrimidyl) - piperazin, Schmelzpunkt bei 188 bis 190° C.16. 1 - (3,3,3 - triphenyl - 1 - propyl) - 4 - (2 - amino-4 - pyrimidyl) - piperazine, melting point at 188 to 190 ° C.
17. l-(3,3,3-Triphenyl-l-propyl)-4-(4-methylamino-2 - pyrimidyl) - piperazin, Schmelzpunkt bei 150 bis 153° C.17. 1- (3,3,3-Triphenyl-1-propyl) -4- (4-methylamino-2-pyrimidyl) -piperazine, melting point 150 up to 153 ° C.
18. 1 - (3,3,3 - Triphenyl -1 - propyl) - 4 - (4 - dimethylamino - 2 - pyrimidyl) - piperazin, Schmelzpunkt bei 115° C.18. 1 - (3,3,3 - triphenyl -1 - propyl) - 4 - (4 - dimethylamino - 2 - pyrimidyl) - piperazine, melting point at 115 ° C.
19. 1 -(3,3,3-Triphenyl-1 - propyl)-4-(4-allylamino-2 - pyrimidyl) - piperazin, Schmelzpunkt bei 154 bis 158° C.19. 1- (3,3,3-Triphenyl-1-propyl) -4- (4-allylamino-2 - pyrimidyl) - piperazine, melting point at 154 to 158 ° C.
20. 1 - (3,3,3 - Triphenyl - 1 - propyl) - 4 - (2 - methyl-4-chinazolyl)-piperazin, dessen Fumarat unter Zersetzung bei 205 bis 210° C schmilzt.20. 1 - (3,3,3 - triphenyl - 1 - propyl) - 4 - (2 - methyl-4-quinazolyl) piperazine, the fumarate of which melts at 205 to 210 ° C. with decomposition.
Claims (1)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB5347765 | 1965-12-16 | ||
| GB53477/65A GB1148378A (en) | 1965-12-16 | 1965-12-16 | Disubstituted piperazines and process for preparing them |
| DES0106704 | 1966-10-25 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE1620419A1 DE1620419A1 (en) | 1972-03-09 |
| DE1620419C true DE1620419C (en) | 1973-06-28 |
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