NO176180B - Analogifremgangsmåte for fremstilling av nye terapeutisk aktive 2-karbonyl-substituerte N,N-di(trimetoksybenzoyl) piperanziner - Google Patents
Analogifremgangsmåte for fremstilling av nye terapeutisk aktive 2-karbonyl-substituerte N,N-di(trimetoksybenzoyl) piperanziner Download PDFInfo
- Publication number
- NO176180B NO176180B NO894038A NO894038A NO176180B NO 176180 B NO176180 B NO 176180B NO 894038 A NO894038 A NO 894038A NO 894038 A NO894038 A NO 894038A NO 176180 B NO176180 B NO 176180B
- Authority
- NO
- Norway
- Prior art keywords
- formula
- trimethoxybenzoyl
- preparation
- carbon atoms
- piperazine
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 6
- 238000002360 preparation method Methods 0.000 title claims description 6
- -1 trimethoxybenzoyl Chemical group 0.000 title claims description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 150000004885 piperazines Chemical class 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- BUHYMJLFRZAFBF-UHFFFAOYSA-N 3,4,5-trimethoxybenzoyl chloride Chemical compound COC1=CC(C(Cl)=O)=CC(OC)=C1OC BUHYMJLFRZAFBF-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 claims description 3
- 239000003610 charcoal Substances 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 claims description 3
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 2
- 239000000010 aprotic solvent Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- 230000001476 alcoholic effect Effects 0.000 claims 1
- 125000004429 atom Chemical group 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- 238000007327 hydrogenolysis reaction Methods 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- GGMSKCDVFZFTEQ-UHFFFAOYSA-N hexyl 2,3-dibromopropanoate Chemical compound CCCCCCOC(=O)C(Br)CBr GGMSKCDVFZFTEQ-UHFFFAOYSA-N 0.000 description 3
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical compound [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 241000283977 Oryctolagus Species 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- XBEQXYIHPVWOBO-UHFFFAOYSA-N hexyl 1,4-bis(3,4,5-trimethoxybenzoyl)piperazine-2-carboxylate Chemical compound CCCCCCOC(=O)C1CN(C(=O)C=2C=C(OC)C(OC)=C(OC)C=2)CCN1C(=O)C1=CC(OC)=C(OC)C(OC)=C1 XBEQXYIHPVWOBO-UHFFFAOYSA-N 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- CLWISFKUJSYGNP-UHFFFAOYSA-N (5-methyl-2-propan-2-ylcyclohexyl) 1,4-bis(3,4,5-trimethoxybenzoyl)piperazine-2-carboxylate Chemical compound COC1=C(OC)C(OC)=CC(C(=O)N2CC(N(CC2)C(=O)C=2C=C(OC)C(OC)=C(OC)C=2)C(=O)OC2C(CCC(C)C2)C(C)C)=C1 CLWISFKUJSYGNP-UHFFFAOYSA-N 0.000 description 1
- CYGUDRFVYPQFMG-UHFFFAOYSA-N 2,3-dibromo-n-hexylpropanamide Chemical compound CCCCCCNC(=O)C(Br)CBr CYGUDRFVYPQFMG-UHFFFAOYSA-N 0.000 description 1
- HVAUUPRFYPCOCA-AREMUKBSSA-N 2-O-acetyl-1-O-hexadecyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCOC[C@@H](OC(C)=O)COP([O-])(=O)OCC[N+](C)(C)C HVAUUPRFYPCOCA-AREMUKBSSA-N 0.000 description 1
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 1
- YZXBAPSDXZZRGB-DOFZRALJSA-M Arachidonate Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC([O-])=O YZXBAPSDXZZRGB-DOFZRALJSA-M 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 108010003541 Platelet Activating Factor Proteins 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 229940114078 arachidonate Drugs 0.000 description 1
- 210000001367 artery Anatomy 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
- 239000007979 citrate buffer Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- BPZOLCZBCCYTOD-UHFFFAOYSA-N ethyl 1,4-bis(3,4,5-trimethoxybenzoyl)piperazine-2-carboxylate Chemical compound CCOC(=O)C1CN(C(=O)C=2C=C(OC)C(OC)=C(OC)C=2)CCN1C(=O)C1=CC(OC)=C(OC)C(OC)=C1 BPZOLCZBCCYTOD-UHFFFAOYSA-N 0.000 description 1
- OENICUBCLXKLJQ-UHFFFAOYSA-N ethyl 2,3-dibromopropanoate Chemical compound CCOC(=O)C(Br)CBr OENICUBCLXKLJQ-UHFFFAOYSA-N 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- HXYBBZKXOQADOY-UHFFFAOYSA-N hexyl 1,4-dibenzylpiperazine-2-carboxylate Chemical compound C1CN(CC=2C=CC=CC=2)C(C(=O)OCCCCCC)CN1CC1=CC=CC=C1 HXYBBZKXOQADOY-UHFFFAOYSA-N 0.000 description 1
- ZXBPCTDCLHDBHE-UHFFFAOYSA-N hexyl piperazine-2-carboxylate Chemical compound CCCCCCOC(=O)C1CNCCN1 ZXBPCTDCLHDBHE-UHFFFAOYSA-N 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 210000004623 platelet-rich plasma Anatomy 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
Denne oppfinnelse angår en fremgangsmåte for fremstilling av piperazin-derivater med den generelle formel I:
hvor Z utgjør
enten en substituent OA, hvori A utgjør en rett eller for-grenet alkylkjede med fra 1 til 8 karbonatomer; en cykloalkyl-gruppe med fra 6 til 9 karbonatomer, eller en substituent
-NH-Ai hvor Ax er en rett alkylkjede med fra 1 til 8 karbonatomer, eller en gruppe med formelen
hvor n er null eller 1 og Ri er et hydrogen-, klor- eller bromatom.
Fremgangsmåten i henhold til oppfinnelsen omfatter omsetning av en forbindelse med formel II: hvor Z er som definert ovenfor, med en ekvimolar mengde N, N' - dibenzyletylendiamin. Omsetningen utføres hensiktsmessig i et aprotisk oppløsningsmiddel (så som benzen eller toluen) ved 80°C i nærvær av trietylamin. Det oppnådde trisubstituerte piperazin med formel III:
hydrogenolyseres deretter i nærvær av Pd/kull i et oppløsningsmiddel, så som etanol ved 4 0°C under trykk, hvorpå det oppnådde tilsvarende monosubstituerte piperazin med formel
IV:
disubstitueres ved behandling med 3,4,5-trimetoksybenzoylklorid i et oppløsningsmiddel, så som benzen og i nærvær av trietylamin, ved romtemperatur.
Utgangsmaterialet med den generelle formel II kan frem-stilles ved å behandle den korresponderende etylenforbindelse med den generelle formel V:
med brom.
Eksempel 1
N,N'-di-(3',4',5'-trimetoksybenzoyl)-2-n-heksyloksykarbonyl piperazin
Z = 0-(CH2)5-CH3
Trinn A
Fremstilling av N,N'-dibenzyl 2-n-heksyloksykarbonyl-piperazin (III, Z = 0(CH2)5CH3).
En oppløsning av 48,5 g (154 mmol) n-heksyl-2,3-dibrompropionat (II, Z = 0(CH2)5CH3) i 100 ml tørr benzen omrørt ved 40°C, ble dråpevis tilsatt til en varm oppløsning (80°C) av 37 g (154 mmol) N,N'-dibenzyletylendiamin og 55 ml trietylamin i 100 ml benzen. Blandingen ble omrørt ved 80°C i 3 timer. Etter avkjøling og frafiltrering av trietylammoniumklorid, ble oppløsningen inndampet og det rå residuum behandlet med dietyleter og vasket med vann. Det organiske lag ble tørket (MgSOJ , inndampet og krornatografert på en silikagelkolonne ved bruk av dietyleter/petroleter (10:90, volumdeler) som eluent, hvilket ga 52,5 g (86,5%) av tittelforbindelsen som en olje. IR (film): 3080, 3060, 3030 (Aromatisk C-H), 2940, 2800 (C-H), 1740 (C = 0) , 1600 (Aromatisk C = C) , 1145 (C-0) cm"<1>.
<X>H NMR (80 MHz, CDC13, HMDS) S ppm: 7,25 (stor s, 10H, ArH) , 4,17 (t, 2H, CH20C = 0), 4,01-3,41 (m, 4H, CH2ø) , 3,37-2,12 (m, 7H, piperazinyl), 1,5 (m, 2H, CH2-C-OC = O), 1,2 (stor s, 6H, (CH2)3) , 0,80 (t, 3H, CH3) .
Trinn B
Fremstilling av 2-n-heksyloksykarbonyl piperazin
(IV, Z = 0(CH2)5CH3)
En oppløsning av 25 g (63,5 mmol) av forbindelsen fremstillet i Trinn A og 200 mg Pd(10%)/kull i 200 ml etanol ble behandlet med H2 ved et trykk på 2,8 bar under omrøring ved 4 0°C over natten. Etter filtrering ble etanolen inndampet under redusert trykk og det rå residuum renset på en silikagelkolonne ved bruk av MeOH/CHCl3 (5:95, volumdeler) som eluent, hvilket førte til 12,5 g (92%) av tittelforbindelsen som en sterkt hygroskopisk forbindelse.
IR (film): 3195 (N-H) , 2930, 2850 (C-H), 1735 (C = O) cm"<1>.
<X>H NMR (80 MHz, CDC13, HMDS) S ppm: 4,2 (t, 2H, CH2OC = O) , 3,53-3,23 (m, 1H, CH-C = O) , 3,17-2,65 (m, 6H, CH2 piperazin), 1,90 (s, 2H, NH), 1,5 (m, 2H, CH2-C-0C = O), 1,22 (stor s, 6H, (CH2)3) , 0,85 (t, 3H, CH3) .
Trinn C
Fremstilling av N,N'-di-(3',4',5'-trimetoksybenzoyl)-2-n-heksyloksykarbonyl piperazin
(I, Z = 0(CH2)5CH3)
En oppløsning av 10 g (47 mmol) av forbindelsen fremstillet i Trinn B i 150 ml tørr benzen og 25 ml trietylamin, ble dråpevis tilsatt til en oppløsning av 22,7 g (99 mmol) 3,4,5-trimetoksybenzoylklorid i 50 ml tørr benzen. Blandingen ble holdt ved romtemperatur under omrøring over natten. Overskudd av acylklorid ble deretter fjernet ved tilsetning av 5 ml EtOH. Etter fordampning av oppløsningsmidlene under redusert trykk, ble residuet behandlet med CHC13, vasket med H20, fortynnet NaHC03, deretter med HzO. Etter tørking (MgS0A) og fordampning av kloroformen, ble produktet renset på en silikagelkolonne ved bruk av MeOH/CHCl3 (0,5:99,5, volumdeler), hvilket førte til 25 g (88%) av en sirup som krystalliserte i dietyleter; Smp. = 142,2°C.
IR (film): 3010 (ArC-H), 2940, 2860 (C-H), 1740 (C = O ester), 1645 (C = O amid) , 1590 (ArC = C) cm"<1>.
<X>H NMR (80 MHz, CDC13, HMDS): S ppm: 6,65 (s, 4H, ArH), 4,85 (m, 1H, CHC =0), 4,12 (m, 4H, CH20C = 0 og
0 = C-NCH2-C-C = O) , 3,82 (s, 18H, CH30) , 3,62-3,05 (m, 4H,
0 = C-N-CH2) , 1,58 (m, 2H, CH2-C-C = O) , 1,21 (stor s, 6H, (CH2)3) , 0,81 (t, 3H, CH3) .
Eksempel 2
N, N'-di-(3',4',5'-trimetoksybenzoyl)-2-etoksykarbonyl piperazin
Tittelforbindelsen ble oppnådd som beskrevet i Eksempel 1, Trinn A, B, C ved å gå ut fra etyl 2,3-dibrompropionat i stedet for n-heksyl 2,3-dibrompropionat; hvite krystaller, smp. 129,5°C.
IR (film): 3010 (ArC-H), 2940, 2830 (C-H), 1735 (C = O ester), 1635 (C = O amid) , 1580 (ArC = C) cm"<1>.
<X>H NMR (60 MHz, CDCl3, HMDS) S ppm: 6,66 (s, 4H, Aromatisk H) , 4,86 (m, 1H, CHC = O), 4,13 (m, 4H,
CH2OC = O + 0 = CN-CH2-C-C = 0), 3,9 (s, 18H, CH30) , 3,6-2,88 (m, 4H, CH2-NC0) , 0,9 (t, 3H, CH3) .
Eksempel 3
N,N'-di-(3',4',5'-trimetoksybenzoyl)-2-(2'-isopropyl 5'-metyl)-cykloheksyloksykarbonyl piperazin
Tittelforbindelsen ble oppnådd som beskrevet i Eksempel 1, Trinn A, B, C ved å gå ut fra (2'-isopropyl 5'-metyl)-cykloheksyl 2,3-dibrompropionat; hvite krystaller,
smp. = 151,9°C.
IR (Nujol): 1740 (C = 0 ester), 1645 (C = O amid), 1585
(ArC = O) cm"<1>.
<X>H NMR (80 MHz, CDC13, HMDS) S ppm: 6,67 (m, 4H, ArH) , 5,3 (m, 1H, CHOC = 0), 4,87 (m, 1H, CHC = O), 4,15 (m, 2H,
O = CN-CH2-C-C = O) , 3,67-2.75 (m, 4H, CH2NC = O) , 2,17-1,11 (m, 9H, CH2 av cykloheksyl + (CH3)2CH), 0,87 (m, 9H, CH3) .
Eksempel 4
N,N'-di-(3',4',5'-trimetoksybenzoyl)-2-(N-ortoklorfenyl)-amido piperazin
Tittelforbindelsen ble oppnådd som beskrevet i Eksempel 1, Trinn A, B, C ved å gå ut fra 2'-klorfenyl 2,3-dibrom-propionamid i stedet for n-heksyl-2,3-dibrompropionat; hvite krystaller, smp.: 144,2°C.
IR (film): 3280, (N-H), 3070 (ArC-H), 2950, 2840 (C-H), 1710 (0 = CNAr) , 1635 (Ar-C-N) , 1590 (ArC = C) cm"<1>.
0
<X>H NMR (80 MHz, CDC13, HMDS) S ppm: 8,27 (m, 1H, NH) , 7,5-6,9 (m, 4H, ortoklorfenyl), 6,77 (d, 4H, trimetoksybenzoyl ArH), 5,22 (m, 1H, CHCON) , 4,47-4,05 • (m, 2H, (0 = CN-CH2-C-C = O) , 3,87 (s, 18H, CH30) , 3,65-2,95 (m, 4H, CH2NCO) .
Eksempel 5
N,N'-di-(3',4',5'-trimetoksybenzoyl)-2-(N-n-heksyl)-amido piperazin
Tittelforbindelsen ble oppnådd som beskrevet i Eksempel 1, Trinn A, B, C ved å gå ut fra n-heksyl 2,3-dibrompropion-amid; hvite krystaller, smp. = 189,2°C.
IR (film): 3330 (N-H), 3010 (ArC-H), 2940, 2820 (C-H), 1665 (A1NC = 0) , 1635 (ArNC = 0) , . 1590 (ArC = C) cm"<1>.
<4>i NMR (80 MHz, CDCI3, HMDS) S ppm: 6,71 (stor s, 5H,
ArH + NH), 4,8 (m, 1H, CHCON), 4,72-3,97 (m, 2H,
O = CN-CH2-C-C = O) , 3,47-2,97 (m, 6H, CH2C0N + CH2NC0) , 1,70-1,08 (m, 8H, (CH2)*)# 0,82 (t, 3H, CH3) .
Eksempel 6
Ifølge samme fremgangsmåte som beskrevet i Eksempel 1, Trinn A, B, C, ble følgende forbindelse fremstillet (kun endringer av <1>H NMR-spektrene er angitt):
N,N'-di-(3',4',5'-trimetoksybenzoyl)-2-N"-benzylamido piperazin
Voksaktig forbindelse. <X>H NMR S ppm: 7,22 (s, 5H, C6H5) , 4,40 (d, 2H, NCH2ø) .
Toksikologi
Forbindelsene fremstillet i henhold til oppfinnelsen ble gitt til mus per os for bestemmelse av akutt LD50. For samtlige forbindelser var LD50 over 800 mg/kg.
Farmakologi
En bekreftelse på den farmasøytiske betydning av de nye forbindelsene gir det følgende farmasøytiske forsøk: Hemming av blodplateaggregasion hos New Zealand- kaniner
Forsøket ble utført på blodplater med plasma fra New Zealand-kaniner.
Blodprøver ble tatt fra ørearterien og anbragt i citrat-buffer (3,8%; pH 7,4); blodet ble sentrifugert videre i 15 minutter ved 1200 RPM.
Testforbindelsen ble oppløst i DMSO, deretter helt over i blodplaterikt plasma i 1 minutt, hvoretter en dose på 2,5 nM PAF ble tilsatt.
Bestemmelsen ble gjort på et Cronolog Coultronics apparat, som bestemmer den prosentuelle transmisjon ved toppens maksimumshøyde før desaggregasjonen.
Den prosentuelle variasjon av hemmingen med hensyn til den prosentuelle transmisjon, ble beregnet (kontroll: ren
DMSO).
Denne fremgangsmåte er utførlig beskrevet i LABORATORY INVESTIGAT".ONS, Vol. 41, No. 3, p. 275, 1979, Jean-Pierre Cazenave, Jacques Benveniste & J. Fraser Mustard, "Aggregation of rabbits platelets by platelet-activating factor is independent of the release reaction and the arachidonate pathway ånd inhibited by membrane-active drugs".
Resultatene viser at forbindelsene hemmer aggregasjonen indusert av 2,5 nM PAF. Fem forsøk gjort på fem forskjellige kaniner tillot oss å beregne IC50 av de forskjellige forbindelser ved lineær regresjon.
Verdiene for IC50 på blodplate var som følger:
Eksempel 1 : 2,15 IO"<6>
Eksempel 2 : 1,29 . IO"6
Eksempel 3 : 1,6 . IO"5
Eksempel 4 : 3,3 6 .IO"6
Eksempel 5 : 8,84 .IO"<6>
Eksempel 6 : 1,97 . IO"5
Ved human terapeutisk anvendelse utgjør virksomme døgn-doser 1-30 mg/kg ved oral administrasjon (tabletter eller gelatinkapsler inneholdende for eksempel 50 mg eller 100 mg per enhetsdose) eller 0,1 til 5 mg/kg ved i.v. administrasjon (enhetsdoser på 5 til 100 mg i individuelle ampuller).
Claims (1)
- Analogifremgangsmåte for fremstilling av terapeutisk aktive piperazin-derivater med den generelle formel I:hvor Z utgjørenten en substituent OA, hvori A utgjør en rett eller for-grenet alkylkjede med fra 1 til 8 karbonatomer; en cykloalkyl-gruppe med fra 6 til 9 karbonatomer, eller en substituent -NH-Ai hvor Ax er en rett alkylkjede med fra 1 til 8 karbon-atomer, eller en gruppe med formelenhvor n er null eller 1 og Rx er et hydrogen-, klor- eller bromatom,karakterisert vedomsetning av en forbindelse med formel II:hvor Z er som definert ovenfor, med en ekvimolar mengde N,N'-dibenzyletylendiamin i et aprotisk oppløsningsmiddel, fortrinnsvis benzen eller toluen, ved 80°C i nærvær av trietylamin, hydrogenolyse av det oppnådde trisubstituerte piperazin med formel III:i nærvær av Pd/kull i et alkoholisk oppløsningsmiddel ved 40°C under trykk, hvorpå det oppnådde tilsvarende monosubstituerte piperazin med formel IV:behandles med 3,4,5-trimetoksybenzoylklorid i benzen og i nærvær av trietylamin, ved romtemperatur.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB888823775A GB8823775D0 (en) | 1988-10-11 | 1988-10-11 | New 2-carbonyl substituted n n'-di-(trimethoxybenzoyl)piperazines |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| NO894038D0 NO894038D0 (no) | 1989-10-10 |
| NO894038L NO894038L (no) | 1990-04-17 |
| NO176180B true NO176180B (no) | 1994-11-07 |
| NO176180C NO176180C (no) | 1995-02-15 |
Family
ID=10644988
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO894038A NO176180C (no) | 1988-10-11 | 1989-10-10 | Analogifremgangsmåte for fremstilling av nye terapeutisk aktive 2-karbonyl-substituerte N,N-di(trimetoksybenzoyl) piperanziner |
Country Status (33)
| Country | Link |
|---|---|
| US (1) | US4923870A (no) |
| JP (1) | JPH0635452B2 (no) |
| KR (1) | KR970004912B1 (no) |
| AR (1) | AR245110A1 (no) |
| AT (1) | AT395423B (no) |
| AU (1) | AU618220B2 (no) |
| BE (1) | BE1003519A3 (no) |
| CA (1) | CA1320958C (no) |
| CH (1) | CH679859A5 (no) |
| DE (1) | DE3933881C2 (no) |
| DK (1) | DK500389A (no) |
| DZ (1) | DZ1365A1 (no) |
| ES (1) | ES2018403A6 (no) |
| FI (1) | FI96854C (no) |
| FR (2) | FR2637500B1 (no) |
| GB (2) | GB8823775D0 (no) |
| GR (1) | GR1000343B (no) |
| HK (1) | HK47592A (no) |
| IE (1) | IE62011B1 (no) |
| IN (1) | IN173325B (no) |
| IT (1) | IT1237088B (no) |
| LU (1) | LU87604A1 (no) |
| MA (1) | MA21652A1 (no) |
| MY (1) | MY106235A (no) |
| NL (1) | NL8902520A (no) |
| NO (1) | NO176180C (no) |
| NZ (1) | NZ230927A (no) |
| OA (1) | OA09139A (no) |
| PT (1) | PT91941B (no) |
| SE (1) | SE505239C2 (no) |
| SG (1) | SG41292G (no) |
| TN (1) | TNSN89110A1 (no) |
| ZA (1) | ZA897554B (no) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8823776D0 (en) * | 1988-10-11 | 1988-11-16 | Scras | New 2-methoxycarbonyl sustituted n n'-di-(trimethoxybenzoyl)piperazines |
| GB8908587D0 (en) * | 1989-04-15 | 1989-06-01 | Scras Societe De Conseils De R | New 2-substituted n,n'-ditrimethoxybenzoyl piperazines |
| WO1992020661A1 (en) * | 1991-05-22 | 1992-11-26 | Merck & Co., Inc. | N, n-diacylpiperazines |
| US5344830A (en) * | 1992-12-10 | 1994-09-06 | Merck & Co., Inc. | N,N-diacylpiperazine tachykinin antagonists |
| US5348955A (en) * | 1993-06-22 | 1994-09-20 | Merck & Co., Inc. | N,N-diacylpiperazines |
| FR2780649B1 (fr) | 1998-07-06 | 2001-03-09 | Univ Paris Vii Denis Diderot | Derives de la piperazine pour l'inhibition de la replication du virus de l'immunodeficience humaine |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3186993A (en) * | 1962-06-07 | 1965-06-01 | Ethyl Corp | alpha, alpha'-(1, 4-piperazinediyl) bis (3, 5-dialkyl-4-hydroxythiobenzaldehyde) compounds |
| GB1243991A (en) * | 1968-06-10 | 1971-08-25 | Ici Ltd | Piperidine, morpholine and piperazine derivatives |
| FR2209560A1 (en) * | 1972-12-07 | 1974-07-05 | Degussa | N-(Trialkoxyaroyl)-ethylenediamine derivs - useful as cardioactive medicaments, exhibit anti-ischaemic activity comparable to nitroglycerin |
| DE2423847A1 (de) * | 1973-05-28 | 1975-01-02 | Ciba Geigy Ag | Neue sulfamoylbenzoesaeureamide |
| GB8427735D0 (en) * | 1984-11-02 | 1984-12-12 | Fujisawa Pharmaceutical Co | Piperazine compound |
| FR2581993B1 (fr) * | 1985-05-14 | 1988-03-18 | Synthelabo | Derives de (benzoyl-4 piperidino)-2 phenyl-1 alcanols, leur preparation et leur application en therapeutique |
| DE3636278A1 (de) * | 1986-10-24 | 1988-05-05 | Hoechst Ag | Herbizide mittel auf der basis von cyclischen (alpha)-iminocarbon-saeureaniliden sowie neue (alpha)-iminocarbonsaeureanilide und verfahren zu ihrer herstellung |
| IL85700A0 (en) * | 1987-03-24 | 1988-08-31 | Takeda Chemical Industries Ltd | 1,4-disubstituted piperazine compounds,their production and use |
| GB8823776D0 (en) * | 1988-10-11 | 1988-11-16 | Scras | New 2-methoxycarbonyl sustituted n n'-di-(trimethoxybenzoyl)piperazines |
| US4997836A (en) * | 1988-11-11 | 1991-03-05 | Takeda Chemical Industries, Ltd. | Trisubstituted piperazine compounds, their production and use |
-
1988
- 1988-10-11 GB GB888823775A patent/GB8823775D0/en active Pending
-
1989
- 1989-09-29 CA CA000615178A patent/CA1320958C/en not_active Expired - Fee Related
- 1989-10-03 IN IN875DE1989 patent/IN173325B/en unknown
- 1989-10-04 ZA ZA897554A patent/ZA897554B/xx unknown
- 1989-10-06 CH CH3658/89A patent/CH679859A5/fr not_active IP Right Cessation
- 1989-10-06 NZ NZ230927A patent/NZ230927A/xx unknown
- 1989-10-06 US US07/418,114 patent/US4923870A/en not_active Expired - Lifetime
- 1989-10-09 GR GR890100647A patent/GR1000343B/el not_active IP Right Cessation
- 1989-10-09 DZ DZ890157A patent/DZ1365A1/fr active
- 1989-10-09 SE SE8903312A patent/SE505239C2/sv not_active IP Right Cessation
- 1989-10-10 AU AU42688/89A patent/AU618220B2/en not_active Ceased
- 1989-10-10 DK DK500389A patent/DK500389A/da not_active Application Discontinuation
- 1989-10-10 MA MA21904A patent/MA21652A1/fr unknown
- 1989-10-10 KR KR1019890014506A patent/KR970004912B1/ko not_active Expired - Fee Related
- 1989-10-10 NO NO894038A patent/NO176180C/no not_active IP Right Cessation
- 1989-10-10 PT PT91941A patent/PT91941B/pt not_active IP Right Cessation
- 1989-10-10 ES ES8903410A patent/ES2018403A6/es not_active Expired - Lifetime
- 1989-10-10 MY MYPI89001392A patent/MY106235A/en unknown
- 1989-10-10 TN TNTNSN89110A patent/TNSN89110A1/fr unknown
- 1989-10-10 IE IE325889A patent/IE62011B1/en not_active IP Right Cessation
- 1989-10-10 LU LU87604A patent/LU87604A1/fr unknown
- 1989-10-10 BE BE8901089A patent/BE1003519A3/fr not_active IP Right Cessation
- 1989-10-10 AR AR89315126A patent/AR245110A1/es active
- 1989-10-11 FI FI894812A patent/FI96854C/fi not_active IP Right Cessation
- 1989-10-11 GB GB8922870A patent/GB2223753B/en not_active Expired - Lifetime
- 1989-10-11 IT IT02199289A patent/IT1237088B/it active IP Right Grant
- 1989-10-11 AT AT0234689A patent/AT395423B/de not_active IP Right Cessation
- 1989-10-11 FR FR898913261A patent/FR2637500B1/fr not_active Expired - Lifetime
- 1989-10-11 JP JP1263142A patent/JPH0635452B2/ja not_active Expired - Lifetime
- 1989-10-11 DE DE3933881A patent/DE3933881C2/de not_active Expired - Fee Related
- 1989-10-11 NL NL8902520A patent/NL8902520A/nl not_active Application Discontinuation
- 1989-10-11 FR FR898913260A patent/FR2637593B1/fr not_active Expired - Lifetime
- 1989-10-11 OA OA59663A patent/OA09139A/xx unknown
-
1992
- 1992-04-14 SG SG412/92A patent/SG41292G/en unknown
- 1992-07-02 HK HK475/92A patent/HK47592A/xx not_active IP Right Cessation
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