NO148747B - ANALOGUE PROCEDURE FOR THE PREPARATION OF N-PHENYL-N- (4-PIPERIDINYL) LOWER ALKYL-TETRAZOLAMIDES - Google Patents
ANALOGUE PROCEDURE FOR THE PREPARATION OF N-PHENYL-N- (4-PIPERIDINYL) LOWER ALKYL-TETRAZOLAMIDES Download PDFInfo
- Publication number
- NO148747B NO148747B NO781559A NO781559A NO148747B NO 148747 B NO148747 B NO 148747B NO 781559 A NO781559 A NO 781559A NO 781559 A NO781559 A NO 781559A NO 148747 B NO148747 B NO 148747B
- Authority
- NO
- Norway
- Prior art keywords
- formula
- parts
- residue
- lower alkyl
- dihydro
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 31
- 238000002360 preparation method Methods 0.000 title claims description 28
- -1 4-PIPERIDINYL Chemical class 0.000 title claims description 15
- 150000001875 compounds Chemical class 0.000 claims description 53
- 239000000203 mixture Substances 0.000 claims description 41
- 229910052739 hydrogen Inorganic materials 0.000 claims description 23
- 239000001257 hydrogen Substances 0.000 claims description 23
- 150000003839 salts Chemical class 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 18
- 239000002253 acid Substances 0.000 claims description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 150000002431 hydrogen Chemical group 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 150000002148 esters Chemical group 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 230000006181 N-acylation Effects 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 238000006264 debenzylation reaction Methods 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- KMJZFJMFHOPFPJ-UHFFFAOYSA-N n-phenylpiperidin-1-amine Chemical compound C1CCCCN1NC1=CC=CC=C1 KMJZFJMFHOPFPJ-UHFFFAOYSA-N 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- 239000003480 eluent Substances 0.000 description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 21
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 20
- 238000002844 melting Methods 0.000 description 20
- 230000008018 melting Effects 0.000 description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 18
- 239000011541 reaction mixture Substances 0.000 description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 16
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 15
- 229960001701 chloroform Drugs 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 239000000741 silica gel Substances 0.000 description 12
- 229910002027 silica gel Inorganic materials 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 229910000029 sodium carbonate Inorganic materials 0.000 description 10
- 239000007858 starting material Substances 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- MUBZPKHOEPUJKR-UHFFFAOYSA-L Oxalate Chemical compound [O-]C(=O)C([O-])=O MUBZPKHOEPUJKR-UHFFFAOYSA-L 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 9
- UFUASNAHBMBJIX-UHFFFAOYSA-N propan-1-one Chemical group CC[C]=O UFUASNAHBMBJIX-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 7
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 6
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 239000000284 extract Substances 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- YVVZUMUVGRLSRZ-UHFFFAOYSA-N 1-ethyl-2h-tetrazol-5-one Chemical compound CCN1NN=NC1=O YVVZUMUVGRLSRZ-UHFFFAOYSA-N 0.000 description 5
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 5
- 238000007126 N-alkylation reaction Methods 0.000 description 5
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical class OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 5
- 230000000202 analgesic effect Effects 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- 239000000730 antalgic agent Substances 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- PDZXSAYPYXZTPZ-UHFFFAOYSA-N n-[1-(2-chloropropyl)-4-(methoxymethyl)piperidin-4-yl]-n-phenylpropanamide;hydrochloride Chemical compound Cl.C1CN(CC(C)Cl)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 PDZXSAYPYXZTPZ-UHFFFAOYSA-N 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- CKOJGMKAXXTOLV-UHFFFAOYSA-N 1-(2-chloroethyl)-4-ethyltetrazol-5-one Chemical compound CCN1N=NN(CCCl)C1=O CKOJGMKAXXTOLV-UHFFFAOYSA-N 0.000 description 3
- WLGREALAOVWKDB-UHFFFAOYSA-N 1-(2-iodoethyl)-4-methyltetrazol-5-one Chemical compound CN1N=NN(CCI)C1=O WLGREALAOVWKDB-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 150000001263 acyl chlorides Chemical class 0.000 description 3
- 238000005917 acylation reaction Methods 0.000 description 3
- 229940035676 analgesics Drugs 0.000 description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 230000036407 pain Effects 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- BCIIMDOZSUCSEN-UHFFFAOYSA-N piperidin-4-amine Chemical compound NC1CCNCC1 BCIIMDOZSUCSEN-UHFFFAOYSA-N 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 3
- PHVQENBNTDWRJW-UHFFFAOYSA-N 1-(2-chloroethyl)-2h-tetrazol-5-one Chemical compound ClCCN1N=NNC1=O PHVQENBNTDWRJW-UHFFFAOYSA-N 0.000 description 2
- IBYHHJPAARCAIE-UHFFFAOYSA-N 1-bromo-2-chloroethane Chemical compound ClCCBr IBYHHJPAARCAIE-UHFFFAOYSA-N 0.000 description 2
- JXBKZAYVMSNKHA-UHFFFAOYSA-N 1h-tetrazol-1-ium-5-olate Chemical class OC=1N=NNN=1 JXBKZAYVMSNKHA-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- ULOZGJWEIWAWML-UHFFFAOYSA-N Noralfentanil Chemical compound C1CNCCC1(COC)N(C(=O)CC)C1=CC=CC=C1 ULOZGJWEIWAWML-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-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
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical compound [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- WBYWAXJHAXSJNI-UHFFFAOYSA-N cinnamic acid Chemical compound OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 2
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- IVLIEQUZEPVOHH-UHFFFAOYSA-N n-[1-(2-hydroxypropyl)-4-(methoxymethyl)piperidin-4-yl]-n-phenylpropanamide;hydrochloride Chemical compound Cl.C1CN(CC(C)O)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 IVLIEQUZEPVOHH-UHFFFAOYSA-N 0.000 description 2
- LKRMTUUCKBQGFO-UHFFFAOYSA-N n-phenylpiperidin-4-amine Chemical compound C1CNCCC1NC1=CC=CC=C1 LKRMTUUCKBQGFO-UHFFFAOYSA-N 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 150000003053 piperidines Chemical class 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 238000010956 selective crystallization Methods 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- IWYDHOAUDWTVEP-ZETCQYMHSA-N (S)-mandelic acid Chemical compound OC(=O)[C@@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-ZETCQYMHSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- OGFAWKRXZLGJSK-UHFFFAOYSA-N 1-(2,4-dihydroxyphenyl)-2-(4-nitrophenyl)ethanone Chemical compound OC1=CC(O)=CC=C1C(=O)CC1=CC=C([N+]([O-])=O)C=C1 OGFAWKRXZLGJSK-UHFFFAOYSA-N 0.000 description 1
- PTXFNAITKCOVFP-UHFFFAOYSA-N 1-(2-chloroethyl)-4-(2-phenylethyl)tetrazol-5-one Chemical compound O=C1N(CCCl)N=NN1CCC1=CC=CC=C1 PTXFNAITKCOVFP-UHFFFAOYSA-N 0.000 description 1
- KZKDCNCAYYURGH-UHFFFAOYSA-N 1-(2-chloroethyl)-4-(2-thiophen-2-ylethyl)tetrazol-5-one Chemical compound O=C1N(CCCl)N=NN1CCC1=CC=CS1 KZKDCNCAYYURGH-UHFFFAOYSA-N 0.000 description 1
- JZRPAQBFQSCPAO-UHFFFAOYSA-N 1-(2-chloroethyl)-4-cyclohexyltetrazol-5-one Chemical compound O=C1N(CCCl)N=NN1C1CCCCC1 JZRPAQBFQSCPAO-UHFFFAOYSA-N 0.000 description 1
- ISLWBWXRZMZCFI-UHFFFAOYSA-N 1-(2-chloroethyl)-4-cyclopropyltetrazol-5-one Chemical compound O=C1N(CCCl)N=NN1C1CC1 ISLWBWXRZMZCFI-UHFFFAOYSA-N 0.000 description 1
- FASCPSHHKFDZKX-UHFFFAOYSA-N 1-(2-chloroethyl)-4-pentyltetrazol-5-one Chemical compound CCCCCN1N=NN(CCCl)C1=O FASCPSHHKFDZKX-UHFFFAOYSA-N 0.000 description 1
- RTUHTRUUYHGXID-UHFFFAOYSA-N 1-(2-chloroethyl)-4-propan-2-yltetrazol-5-one Chemical compound CC(C)N1N=NN(CCCl)C1=O RTUHTRUUYHGXID-UHFFFAOYSA-N 0.000 description 1
- RTGOBOQFBFJTJZ-UHFFFAOYSA-N 1-(2-chloroethyl)-4-propyltetrazol-5-one Chemical compound CCCN1N=NN(CCCl)C1=O RTGOBOQFBFJTJZ-UHFFFAOYSA-N 0.000 description 1
- HAFBIGUYBLKUCD-UHFFFAOYSA-N 1-(2-phenylethyl)-2h-tetrazol-5-one Chemical compound O=C1NN=NN1CCC1=CC=CC=C1 HAFBIGUYBLKUCD-UHFFFAOYSA-N 0.000 description 1
- UJCZVKBDDPDWBN-UHFFFAOYSA-N 1-(3-chloropropyl)-4-ethyltetrazol-5-one Chemical compound CCN1N=NN(CCCCl)C1=O UJCZVKBDDPDWBN-UHFFFAOYSA-N 0.000 description 1
- SXRYBEHIRMBNAF-UHFFFAOYSA-N 1-benzyl-2h-tetrazol-5-one Chemical compound O=C1NN=NN1CC1=CC=CC=C1 SXRYBEHIRMBNAF-UHFFFAOYSA-N 0.000 description 1
- RFGMNHVXOIHQPZ-UHFFFAOYSA-N 1-cyclohexyl-2h-tetrazol-5-one Chemical compound O=C1NN=NN1C1CCCCC1 RFGMNHVXOIHQPZ-UHFFFAOYSA-N 0.000 description 1
- QKFGKKCHXFAAKF-UHFFFAOYSA-N 1-pentyl-2h-tetrazol-5-one Chemical compound CCCCCN1N=NNC1=O QKFGKKCHXFAAKF-UHFFFAOYSA-N 0.000 description 1
- FYYACQQSYSDVJB-UHFFFAOYSA-N 1-phenyl-2h-tetrazol-5-one Chemical compound OC1=NN=NN1C1=CC=CC=C1 FYYACQQSYSDVJB-UHFFFAOYSA-N 0.000 description 1
- VWLKWKCGYOWRMJ-UHFFFAOYSA-N 1-propan-2-yl-2h-tetrazol-5-one Chemical compound CC(C)N1N=NNC1=O VWLKWKCGYOWRMJ-UHFFFAOYSA-N 0.000 description 1
- WBWJLLBFGAVACI-UHFFFAOYSA-N 1-propyl-2h-tetrazol-5-one Chemical compound CCCN1N=NNC1=O WBWJLLBFGAVACI-UHFFFAOYSA-N 0.000 description 1
- RFTHNPDGSJBHMR-UHFFFAOYSA-N 1-tert-butyl-2h-tetrazol-5-one Chemical compound CC(C)(C)N1N=NNC1=O RFTHNPDGSJBHMR-UHFFFAOYSA-N 0.000 description 1
- HLPRKWVEMYDPAU-UHFFFAOYSA-N 2-thiophen-2-ylethyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OCCC1=CC=CS1 HLPRKWVEMYDPAU-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-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
- WRFYIYOXJWKONR-UHFFFAOYSA-N 4-bromo-2-methoxyaniline Chemical compound COC1=CC(Br)=CC=C1N WRFYIYOXJWKONR-UHFFFAOYSA-N 0.000 description 1
- KBIWNQVZKHSHTI-UHFFFAOYSA-N 4-n,4-n-dimethylbenzene-1,4-diamine;oxalic acid Chemical compound OC(=O)C(O)=O.CN(C)C1=CC=C(N)C=C1 KBIWNQVZKHSHTI-UHFFFAOYSA-N 0.000 description 1
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- QFOCKLXLYKLACU-UHFFFAOYSA-N OC(=O)C(O)=O.O=C1N(CCC)N=NN1CCN1CCC(COC)(N(C(=O)CC)C=2C=CC=CC=2)CC1 Chemical compound OC(=O)C(O)=O.O=C1N(CCC)N=NN1CCN1CCC(COC)(N(C(=O)CC)C=2C=CC=CC=2)CC1 QFOCKLXLYKLACU-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 150000001266 acyl halides Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910001516 alkali metal iodide Inorganic materials 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- IUKQLMGVFMDQDP-UHFFFAOYSA-N azane;piperidine Chemical compound N.C1CCNCC1 IUKQLMGVFMDQDP-UHFFFAOYSA-N 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- DVECBJCOGJRVPX-UHFFFAOYSA-N butyryl chloride Chemical compound CCCC(Cl)=O DVECBJCOGJRVPX-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 125000004965 chloroalkyl group Chemical group 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229920001577 copolymer Chemical compound 0.000 description 1
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 1
- ZOOSILUVXHVRJE-UHFFFAOYSA-N cyclopropanecarbonyl chloride Chemical compound ClC(=O)C1CC1 ZOOSILUVXHVRJE-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 description 1
- 229960004275 glycolic acid Drugs 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 1
- 150000004694 iodide salts Chemical group 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- BPCWCZCOOFUXGQ-UHFFFAOYSA-N isocyanoethane Chemical compound CC[N+]#[C-] BPCWCZCOOFUXGQ-UHFFFAOYSA-N 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- BZNIAPRVZVNOLZ-UHFFFAOYSA-N methyl 1-[2-(4-tert-butyl-5-oxotetrazol-1-yl)ethyl]-4-(N-propanoylanilino)piperidine-4-carboxylate oxalic acid Chemical compound OC(=O)C(O)=O.C1CN(CCN2C(N(N=N2)C(C)(C)C)=O)CCC1(C(=O)OC)N(C(=O)CC)C1=CC=CC=C1 BZNIAPRVZVNOLZ-UHFFFAOYSA-N 0.000 description 1
- DUOCBNIILWGWQK-UHFFFAOYSA-N methyl 1-[2-(5-oxo-4-pentyltetrazol-1-yl)ethyl]-4-(N-propanoylanilino)piperidine-4-carboxylate oxalic acid Chemical compound C(C(=O)O)(=O)O.O=C1N(N=NN1CCN1CCC(CC1)(C(=O)OC)N(C1=CC=CC=C1)C(CC)=O)CCCCC DUOCBNIILWGWQK-UHFFFAOYSA-N 0.000 description 1
- OHAKVFPGXHKSME-UHFFFAOYSA-N methyl 4-(n-propanoylanilino)piperidine-4-carboxylate;hydrochloride Chemical compound Cl.C1CNCCC1(C(=O)OC)N(C(=O)CC)C1=CC=CC=C1 OHAKVFPGXHKSME-UHFFFAOYSA-N 0.000 description 1
- ARBRDZRQUWKCLC-UHFFFAOYSA-N methyl 4-[n-(cyclopropanecarbonyl)anilino]-1-[2-(4-ethyl-5-oxotetrazol-1-yl)ethyl]piperidine-4-carboxylate;oxalic acid Chemical compound OC(=O)C(O)=O.O=C1N(CC)N=NN1CCN1CCC(C(=O)OC)(N(C(=O)C2CC2)C=2C=CC=CC=2)CC1 ARBRDZRQUWKCLC-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- AJFDBNQQDYLMJN-UHFFFAOYSA-N n,n-diethylacetamide Chemical compound CCN(CC)C(C)=O AJFDBNQQDYLMJN-UHFFFAOYSA-N 0.000 description 1
- NTEHWJBQADMGCG-UHFFFAOYSA-N n,n-dimethylformamide;nitrobenzene Chemical compound CN(C)C=O.[O-][N+](=O)C1=CC=CC=C1 NTEHWJBQADMGCG-UHFFFAOYSA-N 0.000 description 1
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 1
- BLIBIIGBEHUUAK-UHFFFAOYSA-N n-[1-(2-chloro-2-phenylethyl)-4-(methoxymethyl)piperidin-4-yl]-n-phenylpropanamide Chemical compound C1CN(CC(Cl)C=2C=CC=CC=2)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 BLIBIIGBEHUUAK-UHFFFAOYSA-N 0.000 description 1
- HQKQJRHPRICRFY-UHFFFAOYSA-N n-[1-(2-chloro-2-phenylethyl)-4-(methoxymethyl)piperidin-4-yl]-n-phenylpropanamide;hydrochloride Chemical compound Cl.C1CN(CC(Cl)C=2C=CC=CC=2)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 HQKQJRHPRICRFY-UHFFFAOYSA-N 0.000 description 1
- FLGJQVIXZNBCJZ-UHFFFAOYSA-N n-[1-(2-chloropropyl)-4-(methoxymethyl)piperidin-4-yl]-n-phenylpropanamide Chemical compound C1CN(CC(C)Cl)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 FLGJQVIXZNBCJZ-UHFFFAOYSA-N 0.000 description 1
- CKGXIGKMYMSTRC-UHFFFAOYSA-N n-[1-(2-hydroxy-2-phenylethyl)-4-(methoxymethyl)piperidin-4-yl]-n-phenylpropanamide;hydrochloride Chemical compound Cl.C1CN(CC(O)C=2C=CC=CC=2)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 CKGXIGKMYMSTRC-UHFFFAOYSA-N 0.000 description 1
- AHXPNJLXGBAUKQ-UHFFFAOYSA-N n-[1-[3-(4-ethyl-5-oxotetrazol-1-yl)propyl]-4-(methoxymethyl)piperidin-4-yl]-n-phenylpropanamide;hydrochloride Chemical compound Cl.C1CN(CCCN2C(N(CC)N=N2)=O)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 AHXPNJLXGBAUKQ-UHFFFAOYSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- RFCOXZQIPPZKDK-UHFFFAOYSA-N n-[4-(methoxymethyl)-1-[1-(5-oxo-4-phenyltetrazol-1-yl)propan-2-yl]piperidin-4-yl]-n-phenylpropanamide;nitric acid Chemical compound O[N+]([O-])=O.C1CN(C(C)CN2C(N(C=3C=CC=CC=3)N=N2)=O)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 RFCOXZQIPPZKDK-UHFFFAOYSA-N 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- FGHSTPNOXKDLKU-UHFFFAOYSA-N nitric acid;hydrate Chemical compound O.O[N+]([O-])=O FGHSTPNOXKDLKU-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000002924 oxiranes Chemical class 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 229960005137 succinic acid Drugs 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 125000001273 sulfonato group Chemical class [O-]S(*)(=O)=O 0.000 description 1
- 150000003461 sulfonyl halides Chemical class 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000000375 suspending agent 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
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pain & Pain Management (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biomedical Technology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Description
Foreliggende oppfinnelse angår fremstilling av nye forbindelser i serien N-fenyl-N-(4-piperidinyl)alkyl-tetra-zolamider med en (4,5-dihydro-4-R-5-okso-lH-tetrazol-l-yl)-alkylgruppe i 1-stilling i piperidinkjernen, hvilke forbindelser er brukbare som analgetiske midler.- The present invention relates to the preparation of new compounds in the series of N-phenyl-N-(4-piperidinyl)alkyl-tetrazolamides with a (4,5-dihydro-4-R-5-oxo-1H-tetrazol-1-yl) -alkyl group in the 1-position in the piperidine nucleus, which compounds are usable as analgesic agents.-
Som nevnt angår oppfinnelsen nye N-fenyl-N-(4-piperi-dinyl )alkyl-tetrazolamider som kan representeres ved følgende formel: As mentioned, the invention relates to new N-phenyl-N-(4-piperidinyl)alkyl-tetrazolamides which can be represented by the following formula:
samt farmasøytisk akseptable syreaddisjonssalter derav, hvori: R er valgt blant hydrogen, lavere alkyl, cykloalkyl med 3-6 C-atomer, 2-(2-tienyl)-etyl, fenyl og fenyl-lavere alkyl; as well as pharmaceutically acceptable acid addition salts thereof, wherein: R is selected from hydrogen, lower alkyl, cycloalkyl with 3-6 C atoms, 2-(2-thienyl)-ethyl, phenyl and phenyl-lower alkyl;
R ier valgt blant hydrogen, lavere alkyl og fenyl: R is selected from hydrogen, lower alkyl and phenyl:
R 2er valgt blant hydrogen og lavere alkyl; R 2 is selected from hydrogen and lower alkyl;
R 3 er valgt blant lavere alkyloksykarbonyl eller lavere alkyloksymetyl; R 3 is selected from lower alkyloxycarbonyl or lower alkyloxymethyl;
R 4er valgt blant lavere alkyl, cyklopropyl og lavere alkyl-oksy; og R 4 is selected from lower alkyl, cyclopropyl and lower alkyloxy; and
n er 0 eller 1. n is 0 or 1.
Forbindelsen med formelen I kan generelt fremstilles ved omsetning av 4,5-dihydro-lH-tetrazol-5-on-derivater med formelen: The compound of formula I can generally be prepared by reacting 4,5-dihydro-1H-tetrazol-5-one derivatives with the formula:
med et N-fenyl-N-(4-pipéridinyl)amid med formelen: med et N-fenyl-N-(4-piperidinyl)amid med formelen: 3 4 1 hvori R, R og R er som angitt ovenfor og X enten er hydrogen og X en rest med formelen: eller X er hydrogen og X<1> er en rest med formelen: with an N-phenyl-N-(4-piperidinyl)amide of the formula: with an N-phenyl-N-(4-piperidinyl)amide of the formula: 3 4 1 wherein R, R and R are as defined above and X is either is hydrogen and X is a residue with the formula: or X is hydrogen and X<1> is a residue with the formula:
I de ovenfor angitte formler IV og V har R 1 , R ? og In the formulas IV and V indicated above, R 1 , R ? and
n den tidligere angitte betydning og Y er en reaktiv esterrest, slik som f.eks. halogen, mer spesielt klor, brom eller jod, eller en sulfonyloksygruppe, slik som f.eks. metylsulfonyloksy eller 4-metylfenylsulfonyloksy. n has the previously stated meaning and Y is a reactive ester residue, such as e.g. halogen, more particularly chlorine, bromine or iodine, or a sulfonyloxy group, such as e.g. methylsulfonyloxy or 4-methylphenylsulfonyloxy.
Reaksjonen mellom II og III kan gjennomføres ved å følge standard N-alkyleringsprosedyrer, som generelt kjent i teknikkens stand. Nevnte reaksjon gjennomføres fordelaktig i et egnet reaksjonsinert organisk oppløsningsmiddel, slik som f.eks. et aromatisk hydrokarbon, f.eks. benzen, metylbenzen, dimetylbenzen o.l.; en lavere alkanol, f.eks. metanol, etanol, 2-propanol, 1-butanol o.l.; et keton, f.eks. 4-metyl-2-penta-non o.l.; en enter, f.eks. 1,4-dioksan, 1,1'-oksybisetan o.l.; N,N-dimetylformamid; nitrobenzen o.l. The reaction between II and III can be carried out by following standard N-alkylation procedures, as generally known in the art. Said reaction is advantageously carried out in a suitable reaction-inert organic solvent, such as e.g. an aromatic hydrocarbon, e.g. benzene, methylbenzene, dimethylbenzene, etc.; a lower alkanol, e.g. methanol, ethanol, 2-propanol, 1-butanol and the like; a ketone, e.g. 4-methyl-2-penta-none and the like; an enter, e.g. 1,4-dioxane, 1,1'-oxybisethane and the like; N,N-dimethylformamide; nitrobenzene etc.
Tilsetningen til reaksjonsblandingen av en egnet base, slik som f.eks. et alkalimetallkarbonat eller -hydrogenkarbonat, eller en organisk base, slik som f.eks. N,N-dietyl-etanamin eller N-(1-metyletyl)-2-propanamin kan benyttes for å fange opp den syre som frigjøres under reaksjonen. I enkelte tilfelle er tilsetningen av et jodidsalt, fortrinnsvis et alkalimetalljodid, hensiktsmessig. Noe forhøyede tempera-turer benyttes fordelaktig for å øke reaksjonshastigheten. Under visse omstendigheter, spesielt når én av substituent-1 2 The addition to the reaction mixture of a suitable base, such as e.g. an alkali metal carbonate or hydrogen carbonate, or an organic base, such as e.g. N,N-diethyl ethanamine or N-(1-methylethyl)-2-propanamine can be used to capture the acid released during the reaction. In some cases, the addition of an iodide salt, preferably an alkali metal iodide, is appropriate. Somewhat elevated temperatures are advantageously used to increase the reaction rate. Under certain circumstances, especially when one of substituent-1 2
ene R og R er metyl og den andre er hydrogen, kan en par-tiell ombytting inntre under reaksjonen, noe som gir en blanding av isomerer der hhv. R 1 er metyl og R 2 er hydrogen og omvendt R1l - er hydrogen og R 2 er metyl. Slike stillingsisomerer kan lett separeres fra hverandre ved kjente isolasjonsteknik-ker, slik som f.eks. selektiv krystallisasjon fra egnede opp-løsningsmiddelsystemer eller kolonnekromatografi. one R and R is methyl and the other is hydrogen, a partial exchange can occur during the reaction, which gives a mixture of isomers where respectively R 1 is methyl and R 2 is hydrogen and conversely R 11 - is hydrogen and R 2 is methyl. Such positional isomers can be easily separated from each other by known isolation techniques, such as e.g. selective crystallization from suitable solvent systems or column chromatography.
Forbindelsene med formelen I kan også fremstilles ved acylering av et egnet 4-piperidinamin med formelen: The compounds with the formula I can also be prepared by acylation of a suitable 4-piperidinamine with the formula:
Nevnte acyleringsreaksjoner gjennomføres hensiktsmessig i henhold til kjente N-acyleringsprosedyrer, f.eks. ved å omsette VI med et egnet acylhalogenid, R<4->CO-halogen, representerende hhv. et lavere alkylkarbonylhalogenid, et cykloalkylkarbonylhalogenid, et arylacetylhalogenid eller et lavere alkylkarbonhalogenat, ved å følge kjente metoder. Når R<4> angir lavere alkyl eller cykloalkyl, kan acyleringen gjen-nomføres med et anhydrid som stammer fra syren R^COOH. Said acylation reactions are conveniently carried out according to known N-acylation procedures, e.g. by reacting VI with a suitable acyl halide, R<4->CO halogen, representing respectively a lower alkylcarbonyl halide, a cycloalkylcarbonyl halide, an arylacetyl halide or a lower alkylcarbonyl halide, following known methods. When R<4> denotes lower alkyl or cycloalkyl, the acylation can be carried out with an anhydride originating from the acid R^COOH.
Forbindelsene med formel I hvori R angir hydrogen, avledes fortrinnsvis fra den tilsvarende forbindelse I der R angir fenylmetyl ved debenzylering av sistnevnte på vanlig måte, f.eks. ved katalytisk hydrogenering ved bruk av egnet The compounds of formula I in which R denotes hydrogen are preferably derived from the corresponding compound I in which R denotes phenylmethyl by debenzylation of the latter in the usual way, e.g. by catalytic hydrogenation using suitable
katalysator, slik som palladium-på-trekull. catalyst, such as palladium-on-charcoal.
I de foregående1, og etterfølgende fremstillinger blir reaksjonsproduktene isolert fra reaksjonsblandingen og, hvis nødvendig, renset ytterligere ved anvendelse av konven-sjonelle isolasjons- og renseprosedyrer, slik som generelt kjent. In the foregoing1 and subsequent preparations, the reaction products are isolated from the reaction mixture and, if necessary, further purified using conventional isolation and purification procedures, as is generally known.
Et antall av forbindelsene innen rammen av formel A number of compounds within the framework of formula
I har ett eller flere asymmetriske karbonatomer i strukturen og foreligger som følge derav i forskjellige stereokjemisk isomere former. Mer spesielt er, når R 1 eller R 2 er forskjellig fra hydrogen, karbonatomet hvortil disse er bundet asymmetrisk, mens ytterligere asymmetriske karbonatomer kan I has one or more asymmetric carbon atoms in the structure and consequently exists in different stereochemically isomeric forms. More particularly, when R 1 or R 2 is different from hydrogen, the carbon atom to which these are bonded is asymmetrical, while additional asymmetric carbon atoms may
3 4 3 4
være tilstede i de lavere alkylgrupper i R, R og R . be present in the lower alkyl groups in R, R and R .
Mens man ved de ovenfor angitte fremstillinger oppnår i det vesentlige blandinger, inkludert racemiske blandinger, av slike stereokjemiske isomerer, kan slike blandinger generelt gjenoppløses i de: stereok jemisk rene isomere former ved anvendelse av kjente teknikker, f.eks. saltdannelse med optiske isomerer av asymmetriske syrer og selektiv krystallisasjon av de således oppnådde salter. De stereokjemisk isomere former av forbindelser med formelen I ligger innenfor rammen av formel I. While in the above preparations essentially mixtures, including racemic mixtures, of such stereochemical isomers are obtained, such mixtures can generally be redissolved in the: stereochemically pure isomeric forms using known techniques, e.g. salt formation with optical isomers of asymmetric acids and selective crystallization of the salts thus obtained. The stereochemically isomeric forms of compounds of formula I lie within the scope of formula I.
Som et resultat av de basiske egenskaper, kan forbindelsene med formelen I omdannes til terapeutisk aktive ikke-toksiske syreaddisjonssalter ved behandling med en egnet syre, f.eks. en uorganisk syre som hydrogenhalogensyre, f.eks. saltsyre, hydrobromsyre o.l., samt svovelsyre, salpetersyre, fosforsyre o.l.; eller en organisk syre slik som f.eks. eddik-syre, propansyre, hydroksyeddiksyre, 2-hydroksypropansyre, 2-oksopropansyre, propandionsyre, butandionsyre, (Z)-2-buten-dionsyre, (E)-2-butendionsyre, 2-hydroksybutandionsyre, 2,3-dihydroksybutandionsyre, 2-hydroksy-l,2,3-propantrikarboksyl-syre, benzosyre, 3-fenyl-2-propensyre, a-hydroksybenzeneddik-syre, metansulfonsyre, etansulfonsyre, benzensulfonsyre, 4-metylbenzensulfonsyre, cykloheksansulfaminsyre, a-hydroksy-benzosyre, 4-amino-2-hydroksybenzosyre og lignende syrer. Omvendt kan saltformen omdannes til fri base ved behandling As a result of the basic properties, the compounds of formula I can be converted into therapeutically active non-toxic acid addition salts by treatment with a suitable acid, e.g. an inorganic acid such as hydrohalic acid, e.g. hydrochloric acid, hydrobromic acid, etc., as well as sulfuric acid, nitric acid, phosphoric acid, etc.; or an organic acid such as e.g. acetic acid, propanoic acid, hydroxyacetic acid, 2-hydroxypropanoic acid, 2-oxopropanoic acid, propanedioic acid, butanedioic acid, (Z)-2-butenedioic acid, (E)-2-butenedioic acid, 2-hydroxybutanedioic acid, 2,3-dihydroxybutanedioic acid, 2- hydroxy-1,2,3-propanetricarboxylic acid, benzoic acid, 3-phenyl-2-propenoic acid, a-hydroxybenzeneacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, cyclohexanesulfamic acid, a-hydroxybenzoic acid, 4-amino- 2-hydroxybenzoic acid and similar acids. Conversely, the salt form can be converted into a free base by treatment
med alkali. with alkali.
Utgangsstoffene med formelen II hvori X er hydrogen, II-a, kan lett fremstilles ved omsetning av et egnet The starting substances with the formula II in which X is hydrogen, II-a, can be easily prepared by reacting a suitable
isocyanat med formelen VII eller et acylklorid med formelen VIII med natriumazid i nærvær av aluminiumklorid i et egnet organisk oppløsningsmiddel, fortrinnsvis en eter, slik som tetrahydrofuran (THF). isocyanate of the formula VII or an acyl chloride of the formula VIII with sodium azide in the presence of aluminum chloride in a suitable organic solvent, preferably an ether, such as tetrahydrofuran (THF).
R=N=C=0 R=N=C=0
Reaksjonen gjennomføres hensiktsmessig ved omrør-ing og oppvarming av reaktantene sammen i oppløsningsmidlet i flere timer. Når et acylklorid med formelen VII benyttes som en reaktant, må minst 2 molekvivalenter av azidet benyttes, og bruken av et ytterligere overskudd er vanligvis hensiktsmessig . The reaction is conveniently carried out by stirring and heating the reactants together in the solvent for several hours. When an acyl chloride of formula VII is used as a reactant, at least 2 molar equivalents of the azide must be used, and the use of a further excess is usually appropriate.
Utgangsstoffer med formelen II hvori X er en rest med formelen IV, II-b, kan oppnås ved å innføre nevnte rest i den tilsvarende forbindelse II-a ved kjente metoder. Starting substances of the formula II in which X is a residue of the formula IV, II-b, can be obtained by introducing said residue into the corresponding compound II-a by known methods.
Generelt kan utgangsstoffene II-b fremstilles ved å gjennomføre følgende trinn: 1) omsetning av det egnede II-a med et halogenalkanol-derivat med formelen: ved å følge generelt N-alkyleringsprosedyrer, slik som beskrevet tidligere, for å oppnå et mellomprodukt med formelen: og; 2) etterfølgende omdanning av hydroksygruppen i den således oppnådde forbindelse IX til en reaktiv estergruppe ved å følge kjente prosedyrer for fremstilling av reaktive estere ved å gå ut fra de; tilsvarende alkoholer: In general, the starting substances II-b can be prepared by carrying out the following steps: 1) reaction of the suitable II-a with a haloalkanol derivative of the formula: by generally following N-alkylation procedures, as described previously, to obtain an intermediate of the formula: and; 2) subsequent conversion of the hydroxy group in the thus obtained compound IX into a reactive ester group by following known procedures for the preparation of reactive esters starting from them; corresponding alcohols:
Halogenider oppnås hensiktesmessig ved omsetning Halides are conveniently obtained by reaction
av IX med et egnet halogeneringsmiddel, slik som f.eks. sulfinylklorid, sulfurylklorid, fosforpentaklorid, fosforpenta-bromid, fosforylklorid o.l. Når den reaktive ester er et jodid, avledes den fortrinnsvis fra det tilsvarende klorid eller bromid ved erstatning av det angjeldende halogenatom med jod. Reaktive sulfonatestere, slik som metansulfonater og 4-metylbenzensulfonater, fremstilles hensiktsmessig ved omsetning av alkoholen med et egnet sulfonylhalogenid, slik som f.eks. metansulfonylklorid og 4-metylbenzensulfonyl-klorid. of IX with a suitable halogenating agent, such as e.g. sulfinyl chloride, sulfuryl chloride, phosphorus pentachloride, phosphorus pentabromide, phosphoryl chloride, etc. When the reactive ester is an iodide, it is preferably derived from the corresponding chloride or bromide by replacing the relevant halogen atom with iodine. Reactive sulfonate esters, such as methanesulfonates and 4-methylbenzenesulfonates, are conveniently prepared by reacting the alcohol with a suitable sulfonyl halide, such as e.g. methanesulfonyl chloride and 4-methylbenzenesulfonyl chloride.
Når Y i II-b er klor, II-b-1, kan innføringen av kloralkylkjeden også gjennomføres ved omsetning av en egnet II-a med et egnet bromkloralkanderivat med formelen X ved å følge standard N-alkyleringsprosedyrer for å oppnå den tilsvarende forbindelse II-b-1: When Y in II-b is chlorine, II-b-1, the introduction of the chloroalkyl chain can also be accomplished by reacting a suitable II-a with a suitable bromochloroalkane derivative of the formula X by following standard N-alkylation procedures to obtain the corresponding compound II -b-1:
Alternativt kan utgangsstoffene II-b-1 der R er forskjellig fra hydrogen eller fenyl, oppnås ved å innføre R-substituenten i en forløper med formelen: Alternatively, the starting substances II-b-1 where R is different from hydrogen or phenyl can be obtained by introducing the R substituent into a precursor with the formula:
Nevnte innføring av R gjennomføres hensiktsmessig ved omsetning av XI med en egnet reaktiv ester RY, hvori R er som angitt ovenfor, men forskjellig fra hydrogen eller fenyl, ved å følge standard N-alkyleringsprosedyrer som beskrevet ovenfor. Det skal bemerkes at når Y i RY er jod, kan klorsub-stituenten i XI erstattes under reaksjonen med jod, spesielt når det benyttes et overskudd av alkyleringsjodid. Said introduction of R is conveniently carried out by reacting XI with a suitable reactive ester RY, wherein R is as indicated above, but different from hydrogen or phenyl, by following standard N-alkylation procedures as described above. It should be noted that when Y in RY is iodine, the chlorine substituent in XI may be replaced during the reaction with iodine, especially when an excess of alkylating iodide is used.
Forløperforbindelsen med formelen XI kan fremstilles ved å følge de fremgangsmåter som er beskrevet i "Tetra-hedron", 31, 765 (1975) hvori forbindelsen med formelen XI, The precursor compound of formula XI can be prepared by following the procedures described in "Tetra-hedron", 31, 765 (1975) in which the compound of formula XI,
1 2 1 2
der R og R begge er hydrogen og n er 1, spesielt er beskrevet. where R and R are both hydrogen and n is 1, are particularly described.
Utgangsforbindelsen med formel III hvori X"<*>" er hydrogen, III-a, kan fremstilles ifølge de fremgangsmåter som er beskrevet i US-PS 3.998.834, der et antall slike utgangsstoffer og deres fremstilling er beskrevet. The starting compound of formula III in which X"<*>" is hydrogen, III-a, can be prepared according to the methods described in US-PS 3,998,834, where a number of such starting substances and their preparation are described.
Utgangsforbindelsene med formel III hvori X"<*>" er en The starting compounds of formula III wherein X"<*>" is one
rest med formelen V, III-b, kan fremstilles ved en N-alkyler-ing av et piperidinderivat med formelen III-a med et halogen-alkanol med formelen XII på vanlig måte for å oppnå et mellom- residue of the formula V, III-b, can be prepared by an N-alkylation of a piperidine derivative of the formula III-a with a haloalkanol of the formula XII in the usual way to obtain an intermediate
produkt med formelen XIII og deretter å omdanne hydroksygruppen i dey sistnevnte til en reaktiv estergruppe som beskrevet tidligere: product of the formula XIII and then converting the hydroxy group in the latter to a reactive ester group as described earlier:
Mellomprodukter med formelen XIII hvori n er lik 0, kan også oppnås ved omsetning av III-a med et egnet substi-tuert oksiran med formelen: Intermediates with the formula XIII in which n is equal to 0, can also be obtained by reaction of III-a with a suitable substituted oxirane with the formula:
Det skal bemerkes at når i formel XIV én av restene R 1 og R<2 >er metyl, og den andre er hydrogen, oppnås det i det vesentlige et mellomprodukt XIII hvori metylsubstituenten befinner seg i 3-stilling med henblikk på piperidinnitrogenet. Mellomprodukter med formelen XIII hvori R"<*>" er fenyl og n er lik 0 og fremgangsmåter for fremstilling av disse er også beskrevet i US-PS nr. 3.998.834. It should be noted that when in formula XIV one of the residues R 1 and R<2> is methyl, and the other is hydrogen, an intermediate XIII is essentially obtained in which the methyl substituent is in the 3-position with respect to the piperidine nitrogen. Intermediate products of the formula XIII in which R"<*>" is phenyl and n is equal to 0 and methods for preparing these are also described in US-PS No. 3,998,834.
Reaksjonen mellom XIV og III-a gjennomføres hensiktsmessig ved å omrøre og oppvarme reaktantene sammen i et egnet organisk oppløsningsmiddel, slik som f.eks. et aromatisk hydrokarbon, f.eks. benzen, metylbenzen, dimetylbenzen o.l.; et halogenert hydrokarbon, f.eks. diklormetan og triklormetan; eller en lavere alkanol, f.eks. metanol, etanol, 2-propanol o.l.; og fortrinnsvis i en blanding av et aromatisk hydrokarbon og en lavere alkanol. Reaksjonen kan frem-mes ved tilsetning av en egnet base, slik som f.eks. et alkalimetallkarbonat eller -hydrogenkarbonat. The reaction between XIV and III-a is conveniently carried out by stirring and heating the reactants together in a suitable organic solvent, such as e.g. an aromatic hydrocarbon, e.g. benzene, methylbenzene, dimethylbenzene, etc.; a halogenated hydrocarbon, e.g. dichloromethane and trichloromethane; or a lower alkanol, e.g. methanol, ethanol, 2-propanol etc.; and preferably in a mixture of an aromatic hydrocarbon and a lower alkanol. The reaction can be promoted by adding a suitable base, such as e.g. an alkali metal carbonate or hydrogen carbonate.
Utgangsstoffer med formelen III-b hvori Y er klor, III-b-1, kan også fremstilles direkte ved omsetning av III-a med et bromkloralkan med formelen XV ved å følge fremgangsmåter lik de som er beskrevet tidligere for fremstilling av utgangsstoffene II-b-1 ut fra II-a: Starting substances with the formula III-b in which Y is chlorine, III-b-1, can also be prepared directly by reacting III-a with a bromochloroalkane of the formula XV by following procedures similar to those described earlier for the preparation of the starting substances II-b -1 from II-a:
Utgangsstoffene med formelen VI kan generelt fremstilles ved omsetning av en reaktiv ester med formelen II hvori R angir en rest med. formelen IV med et 4-piperidinamin med formelen: The starting materials with the formula VI can generally be prepared by reacting a reactive ester with the formula II in which R denotes a residue with. the formula IV with a 4-piperidinamine of the formula:
ved å følge fremgangsmåter lik de som er beskrevet tidligere for fremstilling av forbindelsene I-a ut fra II og III. by following procedures similar to those described earlier for the preparation of the compounds I-a from II and III.
4-piperidinaminene med formelen XVI som benyttes som utgangsstoffer, kan også fremstilles ved å følge de fremgangsmåter som er beskrevet i US-PS 3.998.834 der et antall slike forbindelser spesielt er beskrevet. The 4-piperidinamines of the formula XVI which are used as starting materials can also be prepared by following the methods described in US-PS 3,998,834 where a number of such compounds are specifically described.
De første utgangsstoffer i hver av de ovenfor angitte fremgangsmåter er generelt kjent, og de kan alle fremstilles ved å følge kjente, prosedyrer slik disse er beskrevet i litteraturen. The first starting materials in each of the above-mentioned methods are generally known, and they can all be prepared by following known procedures as described in the literature.
Forbindelsene med formelen I og de farmasøytisk akseptable syreaddisjonssalter har meget interessante farma-kologiske egenskaper. Mer spesielt er de virksomme morfin-lignende analgetika og som sådanne kan de benyttes for å undertrykke smerte hos varmblodige dyr. The compounds of formula I and the pharmaceutically acceptable acid addition salts have very interesting pharmacological properties. More specifically, they are effective morphine-like analgesics and as such they can be used to suppress pain in warm-blooded animals.
De brukbare analgetiske egenskaper for forbindelsene med formel I og syreaddisjonssaltene derav, påvises tydelig ved de resultater som er oppnådd i den såkalte "rat tail withdrawal test", beskrevet i "Arzneimittel-Forschung", 13, 502 (1963) og 21, 862 (1971). The useful analgesic properties of the compounds of formula I and their acid addition salts are clearly demonstrated by the results obtained in the so-called "rat tail withdrawal test", described in "Arzneimittel-Forschung", 13, 502 (1963) and 21, 862 ( 1971).
Resultatene i tabellen nedenfor viser LED, dvs. den laveste 100%-ig effektive dose i mg/kg ved intravenøs inngivelse, og varigheten (uttrykt i minutter) for denne virkning ved den angitte dose. The results in the table below show the LED, i.e. the lowest 100% effective dose in mg/kg by intravenous administration, and the duration (expressed in minutes) of this effect at the indicated dose.
En foretrukket gruppe forbindelser innenfor rammen av formelen A preferred group of compounds within the scope of the formula
I er vist ved de der R er en lavere-alkylrest. Således er disse foretrukne forbindelser meget virksomme analgetika med kort virkningsvarighet. Analgetika med en slik kort virkningsvarighet er meget ønskelige under omstendigheter der akutt alvorlig smerte må elimineres i løpet av et kort tidsrom, f.eks. ved bedøvelse. I is shown by those where R is a lower alkyl residue. Thus, these preferred compounds are highly effective analgesics with a short duration of action. Analgesics with such a short duration of action are highly desirable in circumstances where acute severe pain must be eliminated within a short period of time, e.g. by anesthesia.
I lys av den analgetiske virkning kan foreliggende forbindelser formuleres til forskjellige farmasøytiske former for inngivelsesformål. For å fremstille farmasøytiske preparater ifølge oppfinnelen, blir en effektiv analgetisk mengde av den angjeldende forbindelse i baseform eller i form av et syre-addis jonssalt, som aktiv bestandel grundig blandet med en farma-søytisk akseptabel bærer valgt blant et stort antall former avhengig av hvilken inngivelsesform som er ønskelig. Disse farmasøytiske preparater foreligger fortrinnsvis i enhetsdoser egent fortrinnsvis for oral, rektal eller parenteral inngivelse. Ved fremstilling av preparater i oral doseringsform, kan man f.eks. benytte et hvilket som helst av de vanlige farmasøytiske media, slik som f.eks. vann, glykoler, oljer, alkoholer o.l., når det gjelder orale flytende preparater, slik som suspensjoner, siruper, eleksirer og oppløsninger; eller faste bærere, slik som stivelser, sukkere, kaolin, smøremidler, bindemidler, disinteg-reringsmidler o.l., når det gjelder pulvere, piller, kapsler og tabletter. På grunn av inngivelseslettheten representerer tabletter og kapsler den mest fordelaktige orale enhetsdoseform i hvilket tilfelle det selvfølgelig benyttes faste farmasøy-tiske bærere. For parenterale preparater omfatter bæreren vanligvis sterilt vann, i det minste hovedsakelig, selv om andre bestanddeler kan innarbeides f.eks. for å lette oppløseligheten. Injiserbare oppløsninger, f.eks., kan fremstilles hvori bæreren omfatter saltoppløsning, glukoseoppløsning eller en blanding av salt- og glukoseoppløsning. injiserbare suspensjoner kan også fremstilles hvori det benyttes egnede væskebærere, suspensjons-midler eller lignende. Syreaddisjonssalter av I er selvfølgelig mer hensiktsmessige ved fremstilling av vandige preparater på grunn av den økede vannoppløselighet i forhold til den tilsvarende baseform. In light of the analgesic effect, the present compounds can be formulated into various pharmaceutical forms for administration purposes. In order to prepare pharmaceutical preparations according to the invention, an effective analgesic amount of the compound in question in base form or in the form of an acid addition salt, as active ingredient is thoroughly mixed with a pharmaceutically acceptable carrier selected from among a large number of forms depending on which submission form that is desirable. These pharmaceutical preparations are preferably available in unit doses specifically for oral, rectal or parenteral administration. When preparing preparations in oral dosage form, one can e.g. use any of the usual pharmaceutical media, such as e.g. water, glycols, oils, alcohols, etc., in the case of oral liquid preparations, such as suspensions, syrups, elixirs and solutions; or solid carriers, such as starches, sugars, kaolin, lubricants, binders, disintegrants and the like, in the case of powders, pills, capsules and tablets. Due to the ease of administration, tablets and capsules represent the most advantageous oral unit dosage form, in which case solid pharmaceutical carriers are of course used. For parenteral preparations, the carrier usually comprises sterile water, at least mainly, although other ingredients may be incorporated, e.g. to facilitate solubility. Injectable solutions, for example, can be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. injectable suspensions can also be prepared in which suitable liquid carriers, suspending agents or the like are used. Acid addition salts of I are of course more suitable for the preparation of aqueous preparations due to the increased water solubility compared to the corresponding base form.
Det er spesielt fordelaktig å formulere de ovenfor nevnte farmasøytiske preparater i enhetsdoseform på grunn av inngivelsesletthet og doseringsenhetlighet. Enhetsdoseformen slik den benyttes i beskrivelse og krav, angir fysikalsk dis-krete enheter egnet som enhetsdoser, der hver enhet inneholder en på forhånd bestemt mengde av aktiv bestanddel beregnet for å gi den ønskede terapeutiske virkning i forbindelse med den nødvendige farmasøytiske bærer. Eksempler på slike enhets-doseformer er tabletter, kapsler, piller, pulverpakker, injiserbare oppløsninger eller suspensjoner. It is particularly advantageous to formulate the above-mentioned pharmaceutical preparations in unit dose form due to ease of administration and uniformity of dosage. The unit dosage form as used in the description and claims indicates physically discrete units suitable as unit doses, where each unit contains a predetermined amount of active ingredient calculated to provide the desired therapeutic effect in connection with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets, capsules, pills, powder packets, injectable solutions or suspensions.
I lys av den analgetiske virkning for angjeldende forbindelser er det åpenbart at foreliggende oppfinnelse til-byr en fremgangsmåte for forhindring eller bekjempelse av smerte i varmblodige dyr ved systemisk inngivelse av en effektiv analgetisk mengde av forbindelsen med formelen I eller et farmasøytisk akseptabelt syreaddisjonssalt derav i blanding med en farmasøytisk bærer. In light of the analgesic effect of the compounds in question, it is obvious that the present invention provides a method for preventing or combating pain in warm-blooded animals by systemically administering an effective analgesic amount of the compound of formula I or a pharmaceutically acceptable acid addition salt thereof in mixture with a pharmaceutical carrier.
Selv om mengden av aktiv bestanddel som inngis kan variere innenfor heller vide grenser, avhengig av de spesielle omstendigheter i hvert enkelt tilfelle, er doser fra 0,01 mg/ kg til ca. 1 mg/kg, inngitt en eller flere ganger, vanligvis funnet effektive. Although the amount of active ingredient administered can vary within rather wide limits, depending on the special circumstances in each individual case, doses are from 0.01 mg/kg to approx. 1 mg/kg, given once or more, usually found effective.
De følgende eksempler er ment å illustrere oppfinnelsen. Hvis ikke annet er angitt, er alle deler på vektbasis. The following examples are intended to illustrate the invention. Unless otherwise stated, all parts are by weight.
Fremstilling av mellomprodukter: Production of intermediate products:
Eksempel I Example I
Til en omrørt blanding av 14,2 deler isocyantetan, 2 9,2 deler natriumazid og 135 deler tørr tetrahydrofuran tilsettes en oppløsning av 39 deler aluminiumklorid i 225 deler tørr tetrahydrofuran. Omrøringen fortsettes over natt ved tilbakeløpstemperatur. Reaksjonsblandingen avkjøles og sur-gjøres med en 6N saltsyreoppløsning. Det hele fordampes til tørr tilstand, og produktet ekstraheres fire ganger med 2-propan. De kombinerte ekstrakter tørkes, filtreres og fordampes. Resten tørkes over natt, og man oppnår 18 deler 65% 1-etyl-l,4-dihydro-5H-tetrazol-5-on som ble benyttet for A solution of 39 parts of aluminum chloride in 225 parts of dry tetrahydrofuran is added to a stirred mixture of 14.2 parts of isocyanethane, 29.2 parts of sodium azide and 135 parts of dry tetrahydrofuran. Stirring is continued overnight at reflux temperature. The reaction mixture is cooled and acidified with a 6N hydrochloric acid solution. The whole is evaporated to dryness, and the product is extracted four times with 2-propane. The combined extracts are dried, filtered and evaporated. The residue is dried overnight, and 18 parts of 65% 1-ethyl-1,4-dihydro-5H-tetrazol-5-one are obtained, which was used for
fremstilling av forbindelsen ifølge eksempel V. preparation of the compound according to Example V.
Eksempel II Example II
Ved å følge fremgangsmåten i eks. I, men ved å benytte en ekvivalent mengde av hhv. isocyanatcykloheksan og 2-isocyanatpropan som utgangsstoff, oppnås: 1) 1-cykloheksyl-l,4-dihydro-5H-tetrazol-5-on, som ble benyttet for fremstilling av forbindelsen i eks. VI,-, 2) 1,4-dihydro-l-(1-metyletyl)-5H-tetrazol-5-on som en rest, og som ble benyttet for fremstilling av forbindelsen i eks. VI2. By following the procedure in ex. I, but by using an equivalent amount of isocyanatecyclohexane and 2-isocyanatepropane as starting material, the following is obtained: 1) 1-cyclohexyl-1,4-dihydro-5H-tetrazol-5-one, which was used for the preparation of the compound in ex. VI,-, 2) 1,4-dihydro-1-(1-methylethyl)-5H-tetrazol-5-one as a residue, and which was used for the preparation of the compound in ex. VI2.
Eksempel III Example III
Til 990 deler tetrahydrofuran, avkjølt i et isbad, tilsettes porsjonsvis 156 deler aluminiumklorid, og det hele omrøres heftig inntil alle faststoffer er gått i oppløsning. Denne oppløsning tilsettes hurtig til en omrørt suspensjon av 208 deler natriumazid i 225 deler tetrahydrofuran, og omrør-ingen fortsettes i 1 time under tilbakeløpstemperatur. Etter avkjøling til romtemperatur tilsettes dråpevis en oppløsning av 54 deler butanoylklorid i 225 deler tetrahydrofuran ved en temperatur under 30°C. Det hele oppvarmes langsomt til til-bakeløpstemperatur, og omrøringen fortsettes over natt under denne temperatur. Under avkjølingen blir reaksjonsblandingen surgjort med 800 deler 6N saltsyreoppløsning, og oppløsnings-midlet fordampes. Resten omrøres i en natriumhydrogenkarbo- 1 i nat-oppløsning og triklormetan tilsettes, og sjiktene separeres. Den vandige fase surgjøres med konsentrert saltsyre, og oppløsningsmidlet fordampes. Resten omrøres i 2-propanon. Bunnfallet filtreres av, og filtratet fordampes, og man oppnår 32 deler i 1,4-dihydro-l-propyl-5H-tetrazol-5-on som en rest, og som ble benyttet for fremstilling av forbindelsen i eksempel VI^. To 990 parts of tetrahydrofuran, cooled in an ice bath, 156 parts of aluminum chloride are added in portions, and the whole is stirred vigorously until all solids have dissolved. This solution is added rapidly to a stirred suspension of 208 parts of sodium azide in 225 parts of tetrahydrofuran, and stirring is continued for 1 hour at reflux temperature. After cooling to room temperature, a solution of 54 parts butanoyl chloride in 225 parts tetrahydrofuran is added dropwise at a temperature below 30°C. The whole is slowly heated to reflux temperature, and stirring is continued overnight below this temperature. During cooling, the reaction mixture is acidified with 800 parts of 6N hydrochloric acid solution, and the solvent is evaporated. The residue is stirred in a sodium bicarbonate solution and trichloromethane is added, and the layers are separated. The aqueous phase is acidified with concentrated hydrochloric acid, and the solvent is evaporated. The residue is stirred in 2-propanone. The precipitate is filtered off, and the filtrate is evaporated, and 32 parts of 1,4-dihydro-1-propyl-5H-tetrazol-5-one are obtained as a residue, which was used for the preparation of the compound in Example VI^.
Eksempel IV Example IV
Ved å følge fremgangsmåten i eks. III og ved å benytte en ekvivalent mengde av et egnet acylklorid som utgangsstoff, oppnås følgende forbindelser: 1) 1-(1,1-dimetyletyl)-1,4-dihydro-5H-tetrazol-5-on som en rest og som ble benyttet for fremstilling av forbindelsen By following the procedure in ex. III and by using an equivalent amount of a suitable acyl chloride as starting material, the following compounds are obtained: 1) 1-(1,1-dimethylethyl)-1,4-dihydro-5H-tetrazol-5-one as a residue and which was used for the preparation of the compound
i eksempel VI^, in Example VI^,
2) 1,4-dihydro-l-pentyl-5H-tetrazol-5-on som ble benyttet for fremstilling av forbindelsen i eksempel VI^, 3) 1,4-dihydro-l-(2-fenyletyl)-5H-tetrazol-5-on som en fast rest som ble benyttet for fremstilling av forbindelsen 2) 1,4-dihydro-1-pentyl-5H-tetrazol-5-one which was used for the preparation of the compound in example VI^, 3) 1,4-dihydro-1-(2-phenylethyl)-5H-tetrazol -5-one as a solid residue which was used for the preparation of the compound
i eksempel VI^, in Example VI^,
4) 1,4-dihydro-l-(fenylmetyl)-5H-tetrazol-5-on med smeltepunkt 152°C og som ble benyttet for fremstilling av forbindelsen i eksempel Vig/ og 5) 1-cyklopropyl-l ,'4-dihydro-5H-tetrazol-5-on med smeltepunkt 128°C, som ble benyttet for fremstilling av forbindelsen i eksempel VI^. 4) 1,4-dihydro-1-(phenylmethyl)-5H-tetrazol-5-one with a melting point of 152°C and which was used for the preparation of the compound in example Vig/ and 5) 1-cyclopropyl-1,'4- dihydro-5H-tetrazol-5-one with a melting point of 128°C, which was used for the preparation of the compound in example VI^.
Eksempel V Example V
En blanding av 22 deler 1-etyl-l,4-dihydro-5H-tetrazol-5-on, 45 deler l-brom-2-kloretan, 26 deler natriumkarbonat, 0,3 deler kaliumjodid og 240 deler 4-metyl-2-penta-non omrøres og kokes under tilbakeløp over natt med vannseparator. Reaksjonsblandingen avkjøles, vann tilsettes og sjiktene separeres. Den vandige fase ekstraheres tre ganger med diklormetan. De kombinerte, organiske faser tørkes, filtreres og fordampes. Resten renses ved kolonnekromatografi over silikagel ved bruk av triklormetan som elueringsmidde1. De rene fraksjoner samles, elueringsmidlet fordampes, og man oppnår således 28,4 deler eller 80% 1-(2-kloretyl)-4-etyl-1,4-dihydro-5H-tetrazol-5-on som en rest som ble benyttet for fremstilling av forbindelsen i eksempel 1. A mixture of 22 parts of 1-ethyl-1,4-dihydro-5H-tetrazol-5-one, 45 parts of 1-bromo-2-chloroethane, 26 parts of sodium carbonate, 0.3 parts of potassium iodide and 240 parts of 4-methyl-2 -penta-none is stirred and boiled under reflux overnight with a water separator. The reaction mixture is cooled, water is added and the layers are separated. The aqueous phase is extracted three times with dichloromethane. The combined organic phases are dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using trichloromethane as eluent1. The pure fractions are collected, the eluent is evaporated, and thus 28.4 parts or 80% of 1-(2-chloroethyl)-4-ethyl-1,4-dihydro-5H-tetrazol-5-one are obtained as a residue which was used for the preparation of the compound in Example 1.
Eksempel VI Example VI
Ved å følge fremgangsmåten i eksempel V og ved å benytte ekvivalente mengder av et egnet l,4-dihydro-5H-tetrazol-5-on og et egnet bromkloralkan som utgangsstoff, oppnås følgende 1-(kloralkyl)-1,4-dihydro-5H-tetrazol-5-oner: 1) 1-(2-kloretyl)-1,4-dihydro-4-propyl-5H-tetrazol-5-on som en rest som ble benyttet for fremstilling av forbindelsen i eksempel 4, By following the procedure in example V and by using equivalent amounts of a suitable 1,4-dihydro-5H-tetrazol-5-one and a suitable bromochloroalkane as starting material, the following 1-(chloroalkyl)-1,4-dihydro- 5H-tetrazol-5-ones: 1) 1-(2-chloroethyl)-1,4-dihydro-4-propyl-5H-tetrazol-5-one as a residue that was used to prepare the compound in example 4,
2) 1-(2-kloretyl)-1,4-dihydro-4-(l-metyletyl)-5H-tetrazol-5-on som en rest, som ble benyttet for fremstilling av forbindelsen i eksempel 2^, 3) 1-(2-kloretyl)-4-(1,1-dimetyletyl)-1,4-dihydro-5H-tetra-zol-5-on som en rest, som ble benyttet for fremstilling av forbindelsen i eksempel 4^, 4) 1-(2-kloretyl)-1,4-dihydro-4-pentyl-5H-tetrazol-5-on som en rest som ble benyttet for fremstilling av forbindelsen i eks. 4^, 5) 1-(2-kloretyl)-4-cykloheksyl-l,4-dihydro-5H-tetrazol-5-on som en rest, som ble benyttet for fremstilling av forbindelsen i eksempel 4^ 6) 1-(2-kloretyl)-1,4-dihydro-4-(2-fenyletyl)-5H-tetrazol-5-on som en rest, som ble benyttet for fremstilling av forbindelsen i eksempel 4^, 7) 1-(3-klorpropyl)-4-etyl-l,4-dihydro-5H-tetrazol-5-on som en rest, som ble benyttet for fremstilling av forbindelsen i eksempel 2^, 8) 1-(2-kloretyl)-1,4-dihydro-4-(fenylmetylj-5H-tetrazol-5-on som en rest, som ble benyttet for fremstilling av forbindelsen i eksempel 2^, og 9) 1-(2-kloretyl)-4-cyklopropyl-l,4-dihydro-5H-tetrazol-5-on som en rest, som ble benyttet for fremstilling av forbindelsen i eksempel 4g. 2) 1-(2-chloroethyl)-1,4-dihydro-4-(1-methylethyl)-5H-tetrazol-5-one as a residue, which was used for the preparation of the compound in example 2^, 3) 1 -(2-chloroethyl)-4-(1,1-dimethylethyl)-1,4-dihydro-5H-tetra-zol-5-one as a residue, which was used to prepare the compound in example 4^, 4) 1-(2-Chloroethyl)-1,4-dihydro-4-pentyl-5H-tetrazol-5-one as a residue which was used to prepare the compound in ex. 4^, 5) 1-(2-chloroethyl)-4-cyclohexyl-1,4-dihydro-5H-tetrazol-5-one as a residue, which was used for the preparation of the compound in example 4^ 6) 1-( 2-chloroethyl)-1,4-dihydro-4-(2-phenylethyl)-5H-tetrazol-5-one as a residue, which was used to prepare the compound in Example 4^, 7) 1-(3-chloropropyl )-4-ethyl-1,4-dihydro-5H-tetrazol-5-one as a residue, which was used to prepare the compound in example 2^, 8) 1-(2-chloroethyl)-1,4-dihydro -4-(phenylmethylj-5H-tetrazol-5-one as a residue, which was used to prepare the compound in example 2^, and 9) 1-(2-chloroethyl)-4-cyclopropyl-1,4-dihydro- 5H-tetrazol-5-one as a residue, which was used to prepare the compound in example 4g.
Eksempel VII Example VII
En blanding^av 49 deler jodmetan, 10,5 deler l-(2-kloretyl)-1,4-dihydro-5H-tetrazol-5-on, 15 deler natriumkarbonat, 0,2 deler kaliumjodid og 240 deler 4-metyl-2-pentanon om-røres og kokes under tilbakeløp over natt med vannseparator. Reaksjonsblandingen avkjøles, og det tilsettes 100 deler vann, og sjiktet separeres. Den vandige fase ekstraheres med diklormetan. De kombinerte organiske faser tørkes, filtreres og fordampes. Resten renses ved kolonnekromatografi over silikagel ved bruk av triklormetan som elueringsmiddel. De rene fraksjoner samles, og elueringsmidlet fordampes, og man oppnår således 15 deler eller 85% 1,4-dihydro-l-(2-jodetyl)-4-metyl-5H-tetrazol-5-on som en rest, som ble benyttet for fremstilling A mixture of 49 parts of iodomethane, 10.5 parts of 1-(2-chloroethyl)-1,4-dihydro-5H-tetrazol-5-one, 15 parts of sodium carbonate, 0.2 parts of potassium iodide and 240 parts of 4-methyl- 2-pentanone is stirred and boiled under reflux overnight with a water separator. The reaction mixture is cooled, and 100 parts of water are added, and the layer is separated. The aqueous phase is extracted with dichloromethane. The combined organic phases are dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using trichloromethane as eluent. The pure fractions are collected and the eluent is evaporated, thus obtaining 15 parts or 85% of 1,4-dihydro-1-(2-iodoethyl)-4-methyl-5H-tetrazol-5-one as a residue, which was used for manufacturing
av forbindelsen i eksemplene 5 og 6. of the compound in Examples 5 and 6.
Eksempel VIII Example VIII
En blanding av 19,6 deler [2-(2-tienyl)etyl]-4-metylbenzensulfonat, 10 deler 1-(2-kloretyl)-1,4-dihydro-5H-tetrazol-5-on, 10 deler natriumkarbonat og 90 deler N,N-dime-tylformamid omrøres og oppvarmes over natt ved 70°C. Reaksjonsblandingen avkjøles, og det tilsettes 100 deler vann, hvoretter produktet ekstraheres tre ganger med metylbenzen. De kombinerte ekstrakter tørkes, filtreres og fordampes. Resten renses ved kromatografi over silicagel ved bruk av en blanding av triklormetån og petroleumeter (70:30 på volumbasis) som elueringsmiddel. De rene fraksjoner samles, og elueringsmidlet fordampes, og man oppnår således 15 deler eller 46,5% 1-(2-kloretyl)-1,4-dihydro-4-[2-(2-tienyl)etyl]-5H-tetrazol-5-on som en rest, som ble benyttet for fremstilling av forbindelsen i eksempel 2^. A mixture of 19.6 parts [2-(2-thienyl)ethyl]-4-methylbenzenesulfonate, 10 parts 1-(2-chloroethyl)-1,4-dihydro-5H-tetrazol-5-one, 10 parts sodium carbonate and 90 parts of N,N-dimethylformamide are stirred and heated overnight at 70°C. The reaction mixture is cooled, and 100 parts of water are added, after which the product is extracted three times with methylbenzene. The combined extracts are dried, filtered and evaporated. The residue is purified by chromatography over silica gel using a mixture of trichloromethane and petroleum ether (70:30 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, thus obtaining 15 parts or 46.5% of 1-(2-chloroethyl)-1,4-dihydro-4-[2-(2-thienyl)ethyl]-5H-tetrazole -5-one as a residue, which was used to prepare the compound in example 2^.
Eksempel IX Example IX
Til 4,5 deler sulfinylklorid tilsettes dråpevis en blanding av 13 deler N-[1-(2-hydroksy-2-fenyletyl)-4-(metoksy-metyl) -4-piperidinyl] -N-f enylpropanamidhydroklor id og 260 deler diklormetan. Etter ferdig tilsetning omrøres det hele under tilbakeløp i noen timer. Reaksjonsblandingen avkjøles, og oppløsningsmidlet fordampes. Resten has opp i 2-propanon. Blandingen filtreres, og filtratet behandles med aktivert trekull. Det sistnevnte filtreres av, og filtratet fordampes. Resten krystalliseres fra en blanding av 2-propanon og 2,2'-oksybispropan. Produktet filtreres av og tørkes, og man oppnår således 9,2 deler eller 61,7% N-[1-(2-klor-2-fenyletyl)-4-(metoksymetyl)-4-piperidinyl]-N-fenylpropanamidmonohydroklorid med smeltepunkt 145,3°C, som ble benyttet for fremstilling av forbindelsen i eksempel 10. To 4.5 parts of sulfinyl chloride is added dropwise a mixture of 13 parts of N-[1-(2-hydroxy-2-phenylethyl)-4-(methoxy-methyl)-4-piperidinyl]-N-phenylpropanamide hydrochloride and 260 parts of dichloromethane. After the addition is complete, the whole thing is stirred under reflux for a few hours. The reaction mixture is cooled and the solvent is evaporated. The rest is taken up in 2-propanone. The mixture is filtered, and the filtrate is treated with activated charcoal. The latter is filtered off, and the filtrate is evaporated. The residue is crystallized from a mixture of 2-propanone and 2,2'-oxybispropane. The product is filtered off and dried, and thus 9.2 parts or 61.7% of N-[1-(2-chloro-2-phenylethyl)-4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide monohydrochloride with m.p. 145.3°C, which was used to prepare the compound in example 10.
Eksempel X Example X
a) En blanding av 35 deler 2-metyloksiran, 83 deler N-[4-(metoksymetyl)-4-piperidinyl]-N-fenylpropanamid, 25 deler a) A mixture of 35 parts 2-methyloxirane, 83 parts N-[4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide, 25 parts
natriumhydrogenkarbonat, 450 deler benzen og 80 deler metanol sodium bicarbonate, 450 parts benzene and 80 parts methanol
omrøres og kokes under tilbakeløp over natt. Reaksjonsblandingen fordampes, og resten tas opp i vann. Produktet ekstraheres med triklormetan. Ekstraktet tørkes, filtreres og fordampes. Resten omdannes til hydrokloridsaltet i 2-propanol. Saltet filtreres av og krystalliseres fra en blanding av 2,2'-oksybispropan og 2-propanol, og man oppnår 41,5 deler eller 37% N-(l-(2-hydroksypropyl)-4-(metoksymetyl)-4-piperidinyl]-N-fenylpro-panamidmonohydroklorid. Denne forbindelse ble benyttet i trinn b). b) 14 deler sulfinylklorid omrøres, og det tilsettes dråpevis en oppløsning av 37 deler N-[1-(2-hydroksypropyl)-4-(metoksymetyl)-4-piperidinyl]-N-fenylpropanamidmonohydroklorid, fra trinn a), i 360 deler diklormetan. Ved ferdig tilsetning fortsettes omrøringen over natt under tilbakeløpstemperatur. Reaksjonsblandingen fordampes, og resten suspenderes i 2-propanon. Produktet filtreres av og tørkes, og man oppnår 31,5 deler eller 85% N-[1-(2-klor-propyl)-4-(metoksymetyl)-4-piperidinyl]-N-fenylpropanamidmonohydroklorid. stir and boil under reflux overnight. The reaction mixture is evaporated, and the residue is taken up in water. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is converted to the hydrochloride salt in 2-propanol. The salt is filtered off and crystallized from a mixture of 2,2'-oxybispropane and 2-propanol, and one obtains 41.5 parts or 37% of N-(1-(2-hydroxypropyl)-4-(methoxymethyl)-4-piperidinyl ]-N-phenylpropanamide monohydrochloride This compound was used in step b). b) 14 parts of sulfinyl chloride are stirred, and a solution of 37 parts of N-[1-(2-hydroxypropyl)-4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide monohydrochloride, from step a), in 360 parts is added dropwise dichloromethane. When addition is complete, stirring is continued overnight at reflux temperature. The reaction mixture is evaporated, and the residue is suspended in 2-propanone. The product is filtered off and dried, and 31.5 parts or 85% of N-[1-(2-chloro-propyl)-4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide monohydrochloride are obtained.
Fremstilling av sluttprodukter: Manufacture of end products:
Eksempel 1. Example 1.
En blanding av 1,8 deler 1-(2-kloretyl)-4-etyl-1,4-dihydro-5H-tetrazol-5-on, 3,45 deler N-4-(metoksymetyl)-4-piperidinyl-N-fenylpropanamid, 5 deler natriumkarbonat, 0,2 deler kaliumjodid og 24 0 deler 4-metyl-2-pentanon omrøres og kokes under tilbakeløp over natt med vannseparator. Reaksjonsblandingen helles i vann, og sjiktene separeres. Den organiske fase tørkes, filtreres og fordampes. Resten renses ved kolonnekromatografi over silikagel ved bruk av en blanding av triklormetan og metanol (97:3 på volumbasis) som elueringsmiddel. De rene fraksjoner samles, og elueringsmidlet fordampes. Resten omdannes til hydrokloridsaltet i 2-propanon. Saltet filtreres av og krystalliseres fra 2-propanon, og man oppnår 1,5 deler eller 33,3% N-£l-[2-(4-etyl-4,5-dihydro-5-okso-lH-tetrazol-l-yl)-etyl]-4-(metoksymetyl)-4-piperidinyl)-N-fenylpropanamidmonohydrokloridmonohydrat med smeltepunkt 14 0,8°. A mixture of 1.8 parts 1-(2-chloroethyl)-4-ethyl-1,4-dihydro-5H-tetrazol-5-one, 3.45 parts N-4-(methoxymethyl)-4-piperidinyl-N -phenylpropanamide, 5 parts sodium carbonate, 0.2 parts potassium iodide and 240 parts 4-methyl-2-pentanone are stirred and refluxed overnight with a water separator. The reaction mixture is poured into water, and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The pure fractions are collected, and the eluent is evaporated. The remainder is converted to the hydrochloride salt in 2-propanone. The salt is filtered off and crystallized from 2-propanone, and one obtains 1.5 parts or 33.3% of N-£1-[2-(4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1 -yl)-ethyl]-4-(methoxymethyl)-4-piperidinyl)-N-phenylpropanamide monohydrochloride monohydrate with melting point 14 0.8°.
Eksempel 2. Example 2.
Ved å følge fremgangsmåten i eksempel 1 og ved å bruke ekvivalente mengder av egnede utgangsstoffer, oppnås følgende forbindelser som syreaddisjonssalter etter behandling av den frie base med en egnet syre By following the procedure in Example 1 and using equivalent amounts of suitable starting materials, the following compounds are obtained as acid addition salts after treatment of the free base with a suitable acid
1) N-{l-[2-(4,5-dihydro-5-okso-4-propyl-lH-tetrazol-l-yl)-etyl]-4-(metoksymetyl)-4-piperidinyl} -N-fenylpropanamidetan-dioat (1:2)-monohydrat med smeltepunkt 103,8°C; 2) [N-{1- 2-[4,5-dihydro-4-(1-metyletyl)-5-okso-lH-tetrazol-1- yl] -etyl) -4-(metoksymetyl) -4-piperidinyl] -N-fenylpropanamid-mononitrat-monohydrat med smeltepunkt 104,5°C; 3) metyl-l-[2-{4,5-dihydro-5-okso-4-[2-(2-eitnyl)etyl]-1H-tetrazol-l-yl}etyl}-4-](1-oksopropyl)fenylamino]-4-piperidin-karboksylatetandioat (1:1) med smeltepunkt 162,9°; 4) N-{1-[3-(4-etyl-4,5-dihydro-5-okso-lH-tetrazol-l-yl)pro-pyl]-4-(metoksymetyl)-4-piperidinyl}-N-fenylpropanamidhydro-klorid-hemihydrat med smeltepunkt 182°C; og 5) N- [l-{2-(4,5-dihydro-5-okso-4-(fenylmetyl)-lH-tetrazol-1-yl]-etyl}-4-(metoksymetyl)-4-piperidinyl] -N-fenylpropanamid-etandioat med smeltepunkt 16 6,4°C. 1) N-{1-[2-(4,5-dihydro-5-oxo-4-propyl-1H-tetrazol-1-yl)-ethyl]-4-(methoxymethyl)-4-piperidinyl} -N- phenylpropanamide ethanedioate (1:2) monohydrate, m.p. 103.8°C; 2) [N-{1-2-[4,5-dihydro-4-(1-methylethyl)-5-oxo-1H-tetrazol-1-yl]-ethyl)-4-(methoxymethyl)-4-piperidinyl ] -N-phenylpropanamide mononitrate monohydrate of melting point 104.5°C; 3) methyl-1-[2-{4,5-dihydro-5-oxo-4-[2-(2-ethylnyl)ethyl]-1H-tetrazol-1-yl}ethyl}-4-](1- oxopropyl)phenylamino]-4-piperidine carboxylate ethanedioate (1:1) m.p. 162.9°; 4) N-{1-[3-(4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)propyl]-4-(methoxymethyl)-4-piperidinyl}-N -phenylpropanamide hydrochloride hemihydrate with melting point 182°C; and 5) N-[1-{2-(4,5-dihydro-5-oxo-4-(phenylmethyl)-1H-tetrazol-1-yl]-ethyl}-4-(methoxymethyl)-4-piperidinyl] -N-phenylpropanamide ethanedioate with melting point 16 6.4°C.
Eksempel 3. Example 3.
En blanding av 3,6 deler 1-(2-kloretyl)-4-etyl-l,4-dihydro-5H-tetrazol-5-on, 6,4 deler metyl-4-[N-(1-oksopro-pyl) -N-fenylamino] -4-piperidinkarboksylathydroklorid, 4 deler natriumkarbonat, 0,1 deler kaliumjodid og 240 deler 4-metyl-2- pentanon omrøres og kokes under tilbakeløp over natt med A mixture of 3.6 parts 1-(2-chloroethyl)-4-ethyl-1,4-dihydro-5H-tetrazol-5-one, 6.4 parts methyl-4-[N-(1-oxopropyl ) -N-phenylamino]-4-piperidinecarboxylate hydrochloride, 4 parts sodium carbonate, 0.1 part potassium iodide and 240 parts 4-methyl-2-pentanone are stirred and refluxed overnight with
vannseparator. Reaksjonsblandingen avkjøles og helles i vann. Den organiske fase separeres, tørkes, filtreres og fordampes. Resten renses ved kolonnekromatografi over silikagel ved bruk av en blanding av triklormetan og metanol (97:3 på volumbasis) som elueringsmiddel. De rene fraksjoner samles, og elueringsmidlet fordampes. Resten omdannes til etandioatsaltet i 2-propanon. Saltet filtreres av og tørkes, og man oppnår 1,5 deler eller 13% metyl-1-[2-(4-etyl-4,5-dihydro-5-okso-lH-tetrazol-l-yl)etyl]-1-[(1-oksopropyl)fenylamino]-4-piperidin-karboksylatetandioat (2:3) med smeltepunkt 158,9°C. water separator. The reaction mixture is cooled and poured into water. The organic phase is separated, dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The pure fractions are collected, and the eluent is evaporated. The residue is converted to the ethanedioate salt in 2-propanone. The salt is filtered off and dried, and 1.5 parts or 13% of methyl-1-[2-(4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)ethyl]-1 is obtained -[(1-oxopropyl)phenylamino]-4-piperidine carboxylate ethanedioate (2:3) with melting point 158.9°C.
Eksempel 4 Example 4
Ved å følge fremgangsmåten i eksempel 3 og ved å bruke ekvivalente mengder av egnede utgangsstoffer, oppnår følgende etandioatsalter: 1) metyl-1-[2-(4,5-dihydro-5-okso-4-propyl-lH-tetrazol-l-yl)-etyl]-4-](1-oksopropyl)fenylamino]-4-piperidinkarboksylatetan-dioat(l:l) med smeltepunkt 168,4°C; 2) metyl-l-{2-[4,5-dihydro-4-(1-metyletyl)-5-okso-lH-tetra-zol-l-yl]-etyl}-4-[(1-oksopropyl)fenylamino]-4-piperidinkar-boksylatetandioat(1:1) med smeltepunkt 184,2°C; 3) metyl-1-(2-[4-(1,1-dimetyletyl)-4,5-dihydro-5-okso-lH-tetrazol-l-yl]etyl}-4-[(1-oksopropyl)fenylamino]-4-piperidin-karboksylatetandioat(1:1) med smeltepunkt 168,1°C; 4) metyl-1-[2-(4,5-dihydro-5-okso-4-pentyl-lH-tetrazol-l-yl)etyl]-4-[(1-oksopropyl)fenylamino]-4-piperidinkarboksylat-etandioat(1:1) med smeltepunkt 153,5°C; 5) metyl-1-[2-(4-cykloheksyl-4,5-dihydro-5-okso-lH-tetrazol-1-yl)-etyl]-4-[(1-oksopropyl)fenylamino]-4-piperidinkarboksy-latetandioat(1:1) med smeltepunkt 17 3°C; 6) metyl-l-£2-[4,5-dihydro-5-okso-4-(2-fenyletyl)-lH-tetrazol-1-yl]-etyl}-4[(1-oksopropyl)fenylamino]-4-piperidinkarbosylat-etandioat(2:3) med smeltepunkt 162,2°C; ' 7) metyl-l-f2-[4,5-dihydro-5-okso-4-(fenylmetyl)-lH-tetrazol-1-yl]-etyl}-4-[(1-oksopropyl)fenylamino(-4-piperidinkarboksy-latetandioat(1:1) med smeltepunkt 191,7°C; 8) metyl-1-[2-(4-cyklopropyl)-4,5-dihydro-5-okso-lH-tetrazol-1-yl)-etyl]-4 -[(1-oksopropyl)fenylamino]-4-piperidinkarboksy-latetandioat(2:3)hemihydrat med smeltepunkt 155,9°C; og 9) metyl-1-[2-(4-etyl-4,5-dihydro-5-okso-lH-tetrazol-l-yl)-etyl]-4-fenylamino)-4-piperidinkarboksylatetandioat(2:3) med smeltepunkt 172°C. By following the procedure in Example 3 and using equivalent amounts of suitable starting materials, the following ethanedioate salts are obtained: 1) methyl-1-[2-(4,5-dihydro-5-oxo-4-propyl-1H-tetrazol-1) -yl)-ethyl]-4-](1-oxopropyl)phenylamino]-4-piperidinecarboxylate ethanedioate (1:1) m.p. 168.4°C; 2) methyl-1-{2-[4,5-dihydro-4-(1-methylethyl)-5-oxo-1H-tetra-zol-1-yl]-ethyl}-4-[(1-oxopropyl) phenylamino]-4-piperidinecarboxylate ethanedioate (1:1) m.p. 184.2°C; 3) methyl-1-(2-[4-(1,1-dimethylethyl)-4,5-dihydro-5-oxo-1H-tetrazol-1-yl]ethyl}-4-[(1-oxopropyl)phenylamino ]-4-piperidine carboxylate ethanedioate (1:1) with melting point 168.1°C; 4) methyl-1-[2-(4,5-dihydro-5-oxo-4-pentyl-1H-tetrazol-1- yl)ethyl]-4-[(1-oxopropyl)phenylamino]-4-piperidine carboxylate ethanedioate (1:1) m.p. 153.5°C; 5) methyl-1-[2-(4-cyclohexyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)-ethyl]-4-[(1-oxopropyl)phenylamino]-4-piperidinecarboxy -late tandioate (1:1) with melting point 17 3°C; 6) methyl-1-£2-[4,5-dihydro-5-oxo-4-(2-phenylethyl)-1H-tetrazol-1-yl]-ethyl}-4[(1-oxopropyl)phenylamino]- 4-piperidine carboxylate ethanedioate (2:3) m.p. 162.2°C; ' 7) methyl-1-f2-[4,5-dihydro-5-oxo-4-(phenylmethyl)-1H-tetrazol-1-yl]-ethyl}-4-[(1-oxopropyl)phenylamino(-4 -piperidine carboxylate ethanedioate (1:1) with melting point 191.7°C; 8) methyl-1-[2-(4-cyclopropyl)-4,5-dihydro-5-oxo-1H-tetrazol-1-yl) -ethyl]-4-[(1-oxopropyl)phenylamino]-4-piperidine carboxylate tanedioate (2:3) hemihydrate, m.p. 155.9°C; and 9) methyl 1-[2-(4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)-ethyl]-4-phenylamino)-4-piperidinecarboxylate ethanedioate (2:3) with melting point 172°C.
Eksempel 5. Example 5.
En blanding av 2,55 deler 1,4-dihydro-l-(2-jodetyl)-4-metyl-5H-tetrazol-5-on, 3,45 deler N-[4-(metoksymetyl)-4-piperidinyl]-N-fenylpropanamid, 2 deler natriumkarbonat, 0,2 deler kaliumjodid og 160 deler 4-metyl-2-pentanon omrøres og kokes under tilbakeløp over natt ved vannseparator. Reaksjonsblandingen avkjøles, 100 deler vann tilsettes og sjiktene separeres. Den vandige fase ekstraheres med diklormetan. De kombinerte organiske faser tørkes, filtreres og fordampes. Resten renses ved kolonnekromatografi over silikagel ved A mixture of 2.55 parts of 1,4-dihydro-1-(2-iodoethyl)-4-methyl-5H-tetrazol-5-one, 3.45 parts of N-[4-(methoxymethyl)-4-piperidinyl] -N-phenylpropanamide, 2 parts sodium carbonate, 0.2 parts potassium iodide and 160 parts 4-methyl-2-pentanone are stirred and refluxed overnight in a water separator. The reaction mixture is cooled, 100 parts of water are added and the layers are separated. The aqueous phase is extracted with dichloromethane. The combined organic phases are dried, filtered and evaporated. The residue is purified by column chromatography over silica gel at
bruk av en blanding av triklormetan og metanol (97:3 på volumbasis) som elueringsmiddel. De rene fraksjoner samles og elueringsmidlet fordampes. Resten omdannes til etandioatsaltet i 2-propanon. Saltet filtreres av og krystalliseres fra 2-propanon. og man oppnår 2,1 deler eller 42% N-£l-[2-(4,5-dihydro-4-metyl-5-okso-lH-tetrazol-l-yl)etyl]-4-(metoksymetyl)-4-piperidinyl3-N-fenyl-propanamidetandioat(1:1) med smeltepunkt 155,9°C. using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is converted to the ethanedioate salt in 2-propanone. The salt is filtered off and crystallized from 2-propanone. and one obtains 2.1 parts or 42% of N-£1-[2-(4,5-dihydro-4-methyl-5-oxo-1H-tetrazol-1-yl)ethyl]-4-(methoxymethyl)- 4-piperidinyl 3-N-phenyl-propanamide ethanedioate (1:1) with melting point 155.9°C.
Eksempel 6. Example 6.
Ved å følge fremgangsmåten i eksempel 5 fremstilles metyl-1-[2-(4,5-dihydro-4-metyl-5-okso-lH-tetrazol-l-yl)etyl]-4-[(1-oksopropyl)fenylamino]-4-piperidinkarboksylatetandioat (1:1) med smeltepunkt 18 5,9°C ved omsetning av 1,4-dihydro-l-(2-jodetyl)-4-metyl-5H-tetrazol-5-on med 4-[(1-eksopropyl)-fenylamino]-4-piperidinkarboksylat. By following the procedure in example 5, methyl-1-[2-(4,5-dihydro-4-methyl-5-oxo-1H-tetrazol-1-yl)ethyl]-4-[(1-oxopropyl)phenylamino is prepared ]-4-piperidinecarboxylate ethanedioate (1:1) with melting point 18 5.9°C by reaction of 1,4-dihydro-1-(2-iodoethyl)-4-methyl-5H-tetrazol-5-one with 4-[ (1-Exopropyl)-phenylamino]-4-piperidine carboxylate.
Eksempel 7. Example 7.
En blanding av 3 deler 1-etyl-l,4-dihydro-5H-tetra-, zol-5-on, 9,4 deler N-[1-(2-klorpropyl)-4-(metoksymetyl)-4-piperidinyl]-N-fenylpropanamid, 2,5 deler natriumkarbonat, A mixture of 3 parts 1-ethyl-1,4-dihydro-5H-tetra-, zol-5-one, 9.4 parts N-[1-(2-chloropropyl)-4-(methoxymethyl)-4-piperidinyl ]-N-phenylpropanamide, 2.5 parts sodium carbonate,
2,5 deler N,N-dietyletanamid og 90 deler N,N-dimetylformamid omrøres og oppvarmes over natt til 7 0°C. Reaksjonsblandingen avkjøles, 100 deler vann tilsettes og produktet ekstraheres i tre ganger med metylbenzen. De kombinerte ekstrakter tørkes, filtreres og fordampes. Resten renses to ganger ved kolonnekromatografi over silikagel ved å bruke først en blanding av triklormetan og metanol (97:3 på volumbasis) og deretter en blanding av etylacetat og etanol (99:1 på volumbasis) som l elueringsmiddel. De rene fraksjoner samles, og elueringsmidlet fordampes. Resten omdannes til hydrokloridsaltet i 2-propanon og 2,2'-oksybispropan. Saltet filtreres av og tørkes, og man oppnår 2,1 deler eller 18% N-{l-[2-(4-etyl-4,5-dihyro- 2.5 parts of N,N-diethylethanamide and 90 parts of N,N-dimethylformamide are stirred and heated overnight to 70°C. The reaction mixture is cooled, 100 parts of water are added and the product is extracted three times with methylbenzene. The combined extracts are dried, filtered and evaporated. The residue is purified twice by column chromatography over silica gel using first a mixture of trichloromethane and methanol (97:3 by volume) and then a mixture of ethyl acetate and ethanol (99:1 by volume) as eluent. The pure fractions are collected, and the eluent is evaporated. The residue is converted to the hydrochloride salt of 2-propanone and 2,2'-oxybispropane. The salt is filtered off and dried, and 2.1 parts or 18% of N-{1-[2-(4-ethyl-4,5-dihydro-
5-okso-lH-tetrazol-l-yl)-1-metyletyl]-4-(metoksymetyl)-4-piperidinyl)-N-fenylpropanamidmonohydroklorid med smeltepunkt 185,4°C. 5-oxo-1H-tetrazol-1-yl)-1-methylethyl]-4-(methoxymethyl)-4-piperidinyl)-N-phenylpropanamide monohydrochloride with melting point 185.4°C.
Eksempel 8 Example 8
En blanding av 1,2 deler 1-etyl-l,4-dihydro-5H-tetrazol-5-on, 3,9 deler N-[1-(2-klorpropyl)-4-(metoksymetyl)-4-piperidinyl]-N-fenylpropanamidmonohydroklorid, 2 deler natriumkarbonat, 0,1 deler kaliumjodid og 120 deler 4-metyl-2-pentanon omrøres og kokes under tilbakeløp over natt med vannseparator. Reaksjonsblandingen avkjøles, helles i vann A mixture of 1.2 parts 1-ethyl-1,4-dihydro-5H-tetrazol-5-one, 3.9 parts N-[1-(2-chloropropyl)-4-(methoxymethyl)-4-piperidinyl] -N-phenylpropanamide monohydrochloride, 2 parts sodium carbonate, 0.1 parts potassium iodide and 120 parts 4-methyl-2-pentanone are stirred and refluxed overnight with a water separator. The reaction mixture is cooled, poured into water
og sjiktene separeres. Den organiske fase tørkes, filtreres og fordampes. Resten renses ved kolonnekromatografi over silikagel ved bruk av en blanding av triklormetan og metanol i et volumforhold på 99:1 som elueringsmiddel. De rene fraksjoner samles, og elueringsmidlet fordampes. Resten omdannes til nitratsaltet i 2-propanon. Saltet filtreres av og krystalliseres to ganger, først fra en blanding av 2,2'-oksybispropan og 2-propanon og deretter fra 2-propanon, og man oppnår således 1,5 deler eller 30% N-fl-[2-(4-etyl-4,5-dihydro-5-okso-lH-tetrazol-l-yl)-1-metyletyl]-4-(metoksymetyl)-4-piper-idinyl}-N-f enylpropanamidmononitrat med smeltepunkt 14 6,6°C. and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol in a volume ratio of 99:1 as eluent. The pure fractions are collected, and the eluent is evaporated. The remainder is converted to the nitrate salt in 2-propanone. The salt is filtered off and crystallized twice, first from a mixture of 2,2'-oxybispropane and 2-propanone and then from 2-propanone, and one thus obtains 1.5 parts or 30% of N-fl-[2-(4 -ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)-1-methylethyl]-4-(methoxymethyl)-4-piperidinyl}-N-phenylpropanamide mononitrate with melting point 14 6.6°C .
Eksempel 9. Example 9.
Ved å følge fremgangsmåten i eksempel 8 fremstilles N-[l-(2-(4,5-dihydro-5-okso-4-fenyl-lH-tetrazol-l-yl)-1-metyl-etyl} -4 -(metoksymetyl)-4-piperidinyl]-N-fenylpropanamidmono-nitrat med smeltepunkt 151,2°C ved omsetning av 1,4-dihydro-l-fenyl-5H-tetrazol-5-on med N-[1-(2-klorpropyl)-4-(metoksymetyl)-4-piperidinyl]-N-fenylpropanamidmonohydroklorid. By following the procedure in example 8, N-[1-(2-(4,5-dihydro-5-oxo-4-phenyl-1H-tetrazol-1-yl)-1-methyl-ethyl}-4 -( methoxymethyl)-4-piperidinyl]-N-phenylpropanamide mono-nitrate with melting point 151.2°C by reaction of 1,4-dihydro-1-phenyl-5H-tetrazol-5-one with N-[1-(2-chloropropyl )-4-(Methoxymethyl)-4-piperidinyl]-N-phenylpropanamide monohydrochloride.
Eksempel 10. Example 10.
En blanding av 3 deler 1-etyl-l,4-dihydro-5H-tetra-zol-5-on, 8 deler N-[1-(2-klor-2-fenyletyl)-4-(metoksymetyl)-4-piperidinyl]-N-fenylpropanamid, 0,2 deler kaliumjodid, 5 deler natriumkarbonat og 135 deler N,N-dimetylformamid om-røres og oppvarmes over natt ved 7 0°C. Reaksjonsblandingen avkjøles til romtemperatur, og det tilsettes 150 deler vann. Produktet ekstraheres tre ganger med metylbenzen. De kombinerte ekstrakter tørkes, filtreres og fordampes. Den faste rest renses ved kolonnekromatografi over silikagel ved bruk av en blanding av triklormetan og metanol i et volumforhold på 97:3 som elueringsmiddel. De rene fraksjoner samles og elu-er ing smidlet fordampes. Resten krystalliseres fra en blanding av petroleumeter og 2,2<1->oksybispropan. Produktet filtreres av og tørkes, og man oppnår 5,7 deler eller 65% N-{l-[2-(4-etyl-4,5-dihydro-5-okso-lH-tetrazol-l-yl)-2-fenyletyl]-4-(metoksymetyl)-4-(metoksymetyl)-4-piperidinyl}-N-fenylpropan-amid med smeltepunkt 12 5,7°C. A mixture of 3 parts 1-ethyl-1,4-dihydro-5H-tetra-zol-5-one, 8 parts N-[1-(2-chloro-2-phenylethyl)-4-(methoxymethyl)-4- piperidinyl]-N-phenylpropanamide, 0.2 parts of potassium iodide, 5 parts of sodium carbonate and 135 parts of N,N-dimethylformamide are stirred and heated overnight at 70°C. The reaction mixture is cooled to room temperature, and 150 parts of water are added. The product is extracted three times with methylbenzene. The combined extracts are dried, filtered and evaporated. The solid residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol in a volume ratio of 97:3 as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of petroleum ether and 2,2<1->oxybispropane. The product is filtered off and dried, and 5.7 parts or 65% of N-{1-[2-(4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)-2- phenylethyl]-4-(methoxymethyl)-4-(methoxymethyl)-4-piperidinyl}-N-phenylpropane-amide with melting point 12 5.7°C.
Eksempel 11. Example 11.
En blanding av 3 deler 1-etyl-l,4-dihydro-5H-tetra-zol-5-on, 9,4 deler N-[1-(2-klorpropyl)-4-(metoksymetyl)-4-piperidinyl]-N-fenylpropanamidmonohydroklorid, 2,5 deler N,N-dietyletanamin, 2,5 deler natriumkarbonat og 90 deler N,N-dimetylformamid omrøres og oppvarmes over natt ved 70°C. Reaksjonsblandingen avkjøles og 100 deler vann tilsettes. Produktet ekstraheres tre ganger med metylbenzen. De kombinerte ekstrakter tørkes, filtreres og fordampes. Resten renses to ganger ved kolonnekromatografi over silikagel ved først å benytte en blanding av triklormetan og metanol i et volumforhold på 97:3 og deretter en blanding av etylacetat og etanol i et volumforhold på 99:1 som elueringsmiddel. De rene fraksjoner samles, og elueringsmidlet fordampes. Resten omdannes til hydrokloridsaltet i 2-propanon og 2,2<1->oksybispropan. Saltet filtreres av og tørkes, og man oppnår 3,9 deler eller 33,4% N-[1-[2-(4-etyl-4,5-dihydro-5-okso-lH-tetrazol-1-yl)propyl]-4-(metoksymetyl)-4-piperidinyl}-N-fenylpropan-amidmonohydroklorid med smeltepunkt 192,7°C. A mixture of 3 parts 1-ethyl-1,4-dihydro-5H-tetra-zol-5-one, 9.4 parts N-[1-(2-chloropropyl)-4-(methoxymethyl)-4-piperidinyl] -N-phenylpropanamide monohydrochloride, 2.5 parts of N,N-diethylethanamine, 2.5 parts of sodium carbonate and 90 parts of N,N-dimethylformamide are stirred and heated overnight at 70°C. The reaction mixture is cooled and 100 parts of water are added. The product is extracted three times with methylbenzene. The combined extracts are dried, filtered and evaporated. The residue is purified twice by column chromatography over silica gel by first using a mixture of trichloromethane and methanol in a volume ratio of 97:3 and then a mixture of ethyl acetate and ethanol in a volume ratio of 99:1 as eluent. The pure fractions are collected, and the eluent is evaporated. The residue is converted to the hydrochloride salt in 2-propanone and 2,2<1->oxybispropane. The salt is filtered off and dried, and 3.9 parts or 33.4% of N-[1-[2-(4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)propyl are obtained ]-4-(methoxymethyl)-4-piperidinyl}-N-phenylpropanamide monohydrochloride with melting point 192.7°C.
Eksempel 12. Example 12.
En blanding av 5,7 deler metyl-1-[2-(4-etyl-4,5-dihydro-5-okso-lH-tetrazol-l-yl)etyl]-4-(fenylamino)-4-piperi-dinkarboksylat, 1,9 deler cyklopropankarbonylklorid, 2,7 deler N,N-dietyletanamin og 68 deler metylbenzen omrøres og kokes under tilbakeløp over natt. Reaksjonsblandingen avkjø-les, 100 deler vann tilsettes og sjiktene separeres. Den organiske fase tørkes, filtreres og fordampes. Resten renses ved kolonnekromatografi over silicagel ved bruk av en blanding av triklormetan og metanol i et volumforhold på 98:2 som elueringsmiddel. De rene fraksjoner samles og behandles med 1 del etandionsyre. Det dannede etandioatsalt filtreres av og krystalliseres fra en blanding av 2-propanon og 2,2<1->oksybispropan, hvorved man oppnår en 1,5 deler eller 17,5% metyl-4-[(cyklo-propylkarbonyl)fenylamino]-1-[2-(4-etyl-4,5-dihydro-5-okso-lH-tetrazol-l-yl)etyl]-4-piperidinkarboksylat-etandioat(2:3) med smeltepunkt 181,5°C. A mixture of 5.7 parts of methyl-1-[2-(4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)ethyl]-4-(phenylamino)-4-piperi- diene carboxylate, 1.9 parts of cyclopropane carbonyl chloride, 2.7 parts of N,N-diethylethanamine and 68 parts of methylbenzene are stirred and refluxed overnight. The reaction mixture is cooled, 100 parts of water are added and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol in a volume ratio of 98:2 as eluent. The pure fractions are collected and treated with 1 part ethanedioic acid. The formed ethanedioate salt is filtered off and crystallized from a mixture of 2-propanone and 2,2<1->oxybispropane, whereby 1.5 parts or 17.5% of methyl-4-[(cyclo-propylcarbonyl)phenylamino]- 1-[2-(4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)ethyl]-4-piperidinecarboxylate ethanedioate (2:3) with melting point 181.5°C.
Eksempel 13. Example 13.
En blanding av 5 deler N-[1--[2-[4 , 5-dihydro-5-okso-4-(fenylmetyl)-lH-tetrazol-l-yl]etyl]-4-(metoksymetyl)-4-piperidinyl]-N-fenylpropanamid og 120 deler metanol hydro-generes ved vanlig trykk og ved romtemperatur med 2 deler 10%-ig palladium-på-trekull som katalysator. Etter at den beregnede mengde hydrogen er tatt opp, filtreres katalysa-toren av og filtratet fordampes. Resten renses ved kolonnekromatografi over silikagel ved bruk av en blanding av triklormetan og metanol i et volumforhold på 95:5 som elueringsmiddel. De rene fraksjoner samles og elueringsmidlet fordampes. Resten omdannes til hydrokloridsaltet: i 2-propanol. Det hele fordampes og resten krystalliseres fra 2-prop'anon. Etter avkjøling til romtemperatur filtreres produktet av og omkrystalliseres fra en blanding av 2-propanon, 2-propanol og metanol. Produktet filtreres av og tørkes i vakuum ved 50°C og man oppnår 2,1 deler N- [ 1- [ 2 - (4 ,5-dihydro-5-ok so-1 li-te tr azo 1-1-yl )etyl]-4-(metoksymetyl)-4-piperidinyl]-N-fenyl-propanamid -monohydroklorid med smeltepunkt 235,6°C. A mixture of 5 parts N-[1-[2-[4,5-dihydro-5-oxo-4-(phenylmethyl)-1H-tetrazol-1-yl]ethyl]-4-(methoxymethyl)-4- piperidinyl]-N-phenylpropanamide and 120 parts of methanol are hydrogenated at ordinary pressure and at room temperature with 2 parts of 10% palladium-on-charcoal as catalyst. After the calculated amount of hydrogen has been taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol in a volume ratio of 95:5 as eluent. The pure fractions are collected and the eluent is evaporated. The residue is converted to the hydrochloride salt: in 2-propanol. It is all evaporated and the residue crystallized from 2-prop'anone. After cooling to room temperature, the product is filtered off and recrystallized from a mixture of 2-propanone, 2-propanol and methanol. The product is filtered off and dried in a vacuum at 50°C and 2.1 parts of N- [ 1- [ 2 - (4,5-dihydro-5-oxo-1 li-te tr azo 1-1-yl) are obtained ethyl]-4-(methoxymethyl)-4-piperidinyl]-N-phenyl-propanamide monohydrochloride with melting point 235.6°C.
Claims (1)
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Application Number | Priority Date | Filing Date | Title |
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US79381477A | 1977-05-05 | 1977-05-05 | |
US88618878A | 1978-03-13 | 1978-03-13 |
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Publication Number | Publication Date |
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NO781559L NO781559L (en) | 1978-11-07 |
NO148747B true NO148747B (en) | 1983-08-29 |
NO148747C NO148747C (en) | 1983-12-07 |
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Application Number | Title | Priority Date | Filing Date |
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NO781559A NO148747C (en) | 1977-05-05 | 1978-05-03 | ANALOGUE PROCEDURE FOR THE PREPARATION OF N-PHENYL-N- (4-PIPERIDINYL) LOWER ALKYL-TETRAZOLAMIDES |
Country Status (26)
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JP (1) | JPS53149980A (en) |
AT (1) | AT368994B (en) |
AU (1) | AU514360B2 (en) |
CA (1) | CA1105464A (en) |
CH (1) | CH635585A5 (en) |
CY (1) | CY1253A (en) |
DE (1) | DE2819873A1 (en) |
DK (1) | DK152211C (en) |
ES (1) | ES469473A1 (en) |
FI (1) | FI64364C (en) |
FR (1) | FR2389622B1 (en) |
GB (1) | GB1598872A (en) |
HK (1) | HK72585A (en) |
HU (1) | HU179204B (en) |
IE (1) | IE46836B1 (en) |
IL (1) | IL54639A (en) |
IT (1) | IT1105288B (en) |
KE (1) | KE3429A (en) |
LU (1) | LU79575A1 (en) |
NL (1) | NL186861C (en) |
NO (1) | NO148747C (en) |
NZ (1) | NZ187164A (en) |
PH (1) | PH12831A (en) |
SE (1) | SE437516B (en) |
SU (1) | SU867304A3 (en) |
YU (1) | YU40703B (en) |
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JPS6144294A (en) * | 1984-08-07 | 1986-03-03 | Nippon Denso Co Ltd | Heat exchanger |
US5053411A (en) * | 1989-04-20 | 1991-10-01 | Anaquest, Inc. | N-aryl-N-[4-(1-heterocyclicalkyl)piperidinyl]amides and pharmaceutical compositions and methods employing such compounds |
USRE34201E (en) * | 1989-04-20 | 1993-03-23 | Anaquest, Inc. | N-aryl-N-[4-(1-heterocyclicalkyl)piperidinyl]amides and pharmaceutical compositions and methods employing such compounds |
JPH08193074A (en) * | 1994-11-18 | 1996-07-30 | Nippon Bayeragrochem Kk | Herbicidal 1-cyclopropyltetrazolinones |
JP2000327668A (en) | 1999-05-21 | 2000-11-28 | Nippon Bayer Agrochem Co Ltd | Tetrazolinone derivative |
DE60030883T2 (en) | 1999-12-06 | 2007-09-06 | Mallinckrodt, Inc. | PROCESS FOR THE PREPARATION OF ALFENTANIL, SUFENTANIL AND REMIFENTANIL |
EP1795526A4 (en) * | 2004-09-14 | 2010-10-13 | Nippon Chemiphar Co | N-substituted n-(4-piperidinyl)amide derivative |
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US3998834A (en) * | 1975-03-14 | 1976-12-21 | Janssen Pharmaceutica N.V. | N-(4-piperidinyl)-n-phenylamides and -carbamates |
-
1978
- 1978-04-24 FR FR7812084A patent/FR2389622B1/fr not_active Expired
- 1978-04-25 PH PH21055A patent/PH12831A/en unknown
- 1978-04-27 AU AU35522/78A patent/AU514360B2/en not_active Expired
- 1978-05-02 LU LU79575A patent/LU79575A1/en unknown
- 1978-05-03 NO NO781559A patent/NO148747C/en unknown
- 1978-05-03 DK DK193778A patent/DK152211C/en not_active IP Right Cessation
- 1978-05-03 NZ NZ187164A patent/NZ187164A/en unknown
- 1978-05-03 AT AT0322078A patent/AT368994B/en not_active IP Right Cessation
- 1978-05-03 CY CY1253A patent/CY1253A/en unknown
- 1978-05-03 SE SE7805110A patent/SE437516B/en not_active IP Right Cessation
- 1978-05-03 GB GB17566/78A patent/GB1598872A/en not_active Expired
- 1978-05-04 IL IL54639A patent/IL54639A/en unknown
- 1978-05-04 JP JP5287378A patent/JPS53149980A/en active Granted
- 1978-05-04 IE IE901/78A patent/IE46836B1/en not_active IP Right Cessation
- 1978-05-04 CA CA302,616A patent/CA1105464A/en not_active Expired
- 1978-05-04 IT IT49203/78A patent/IT1105288B/en active
- 1978-05-04 ES ES469473A patent/ES469473A1/en not_active Expired
- 1978-05-04 HU HU78JA819A patent/HU179204B/en unknown
- 1978-05-04 FI FI781398A patent/FI64364C/en not_active IP Right Cessation
- 1978-05-05 SU SU782613447A patent/SU867304A3/en active
- 1978-05-05 YU YU1085/78A patent/YU40703B/en unknown
- 1978-05-05 NL NLAANVRAGE7804844,A patent/NL186861C/en not_active IP Right Cessation
- 1978-05-05 CH CH492478A patent/CH635585A5/en not_active IP Right Cessation
- 1978-05-05 DE DE19782819873 patent/DE2819873A1/en active Granted
-
1984
- 1984-07-20 KE KE3429A patent/KE3429A/en unknown
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1985
- 1985-09-26 HK HK725/85A patent/HK72585A/en not_active IP Right Cessation
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