WO1987005022A2 - PHARMACOLOGICALLY ACTIVE OCTAHYDRO-PYRIDO(1,2-a) PYRAZINES - Google Patents
PHARMACOLOGICALLY ACTIVE OCTAHYDRO-PYRIDO(1,2-a) PYRAZINES Download PDFInfo
- Publication number
- WO1987005022A2 WO1987005022A2 PCT/EP1987/000070 EP8700070W WO8705022A2 WO 1987005022 A2 WO1987005022 A2 WO 1987005022A2 EP 8700070 W EP8700070 W EP 8700070W WO 8705022 A2 WO8705022 A2 WO 8705022A2
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- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 65
- 239000002253 acid Substances 0.000 claims abstract description 20
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- 238000004519 manufacturing process Methods 0.000 claims abstract 3
- 238000000034 method Methods 0.000 claims description 17
- 230000008569 process Effects 0.000 claims description 15
- 238000002329 infrared spectrum Methods 0.000 claims description 9
- 230000002908 adrenolytic effect Effects 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- VIUDTWATMPPKEL-UHFFFAOYSA-N 3-(trifluoromethyl)aniline Chemical compound NC1=CC=CC(C(F)(F)F)=C1 VIUDTWATMPPKEL-UHFFFAOYSA-N 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 230000004044 response Effects 0.000 claims description 4
- YYGAHWWIADNRJG-UHFFFAOYSA-N 2-(bromomethyl)piperidine;hydrobromide Chemical compound Br.BrCC1CCCCN1 YYGAHWWIADNRJG-UHFFFAOYSA-N 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 claims description 3
- 229940124531 pharmaceutical excipient Drugs 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- 150000007513 acids Chemical class 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Chemical group 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 238000007599 discharging Methods 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 230000005764 inhibitory process Effects 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 238000004587 chromatography analysis Methods 0.000 claims 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 7
- PHLBKPHSAVXXEF-UHFFFAOYSA-N trazodone Chemical compound ClC1=CC=CC(N2CCN(CCCN3C(N4C=CC=CC4=N3)=O)CC2)=C1 PHLBKPHSAVXXEF-UHFFFAOYSA-N 0.000 description 7
- 229960003991 trazodone Drugs 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 230000000144 pharmacologic effect Effects 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 229940093499 ethyl acetate Drugs 0.000 description 4
- 235000019439 ethyl acetate Nutrition 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- CSBUPKXPDSKABE-UHFFFAOYSA-N 1,2,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-3-one Chemical class C1CCCC2CNC(=O)CN21 CSBUPKXPDSKABE-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- 230000001430 anti-depressive effect Effects 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 206010044565 Tremor Diseases 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- -1 hydrochloric Chemical class 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000000932 sedative agent Substances 0.000 description 2
- 230000001624 sedative effect Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- RLQZIECDMISZHS-UHFFFAOYSA-N 2-phenylcyclohexa-2,5-diene-1,4-dione Chemical compound O=C1C=CC(=O)C(C=2C=CC=CC=2)=C1 RLQZIECDMISZHS-UHFFFAOYSA-N 0.000 description 1
- OAAGDVLVOKMRCQ-UHFFFAOYSA-N 5-piperidin-4-yl-3-pyridin-4-yl-1,2,4-oxadiazole Chemical compound C1CNCCC1C1=NC(C=2C=CN=CC=2)=NO1 OAAGDVLVOKMRCQ-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- PKGNSCXWGXQRRK-UHFFFAOYSA-N CC1N(CCCC2)C2CN(C(CCC2)CC2C(F)(F)F)C1=O Chemical compound CC1N(CCCC2)C2CN(C(CCC2)CC2C(F)(F)F)C1=O PKGNSCXWGXQRRK-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 208000001089 Multiple system atrophy Diseases 0.000 description 1
- 206010031127 Orthostatic hypotension Diseases 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 230000001800 adrenalinergic effect Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229960002896 clonidine Drugs 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000003001 depressive effect Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 201000011264 priapism Diseases 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 230000009291 secondary effect Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- HSFQBFMEWSTNOW-UHFFFAOYSA-N sodium;carbanide Chemical group [CH3-].[Na+] HSFQBFMEWSTNOW-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012439 solid excipient Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- 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
- C07D211/08—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/26—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
Definitions
- This invention relates to a new pharmacologically active compound and to the pharmaceutically acceptable acid addition salts thereof, the pharmaceutical compositions containing same, the process for preparation thereof and a new intermediate useful in said process.
- this invention relates to a compound having an IR spectrum (CCl 4 ) showing a band near 1675 cm -1 , which is obtained reacting a compound of formula
- the compound of formula (II) is also new and therefore is a further object of this invention together with its preparation method which comprises reacting a 2-halomethyl-piperidine or an acid addition salt thereof with m-trifluoromethyl-aniline.
- the product obtained reacting compound (I) with compound (II) consists mainly of a compound the physico-chemical and spectrophotometric characteristics of which are in favour of the following formula
- formula (III) above is not representative of the arrangement of the molecule in space as far as geometric isomerism, stereoi someri sm and configuration are concerned, this invention relates to all the compounds of formula (III) whether pure or in admixture one another.
- the compounds obtained reacting (II) with (I) may be divided in two groups: the compounds which have an IR spectrum in CCl 4 showing a broad band near 1655 cm -1 and the compounds showing in the same solvent a band near 1675 cm -1 .
- the second group exhibits the most interesting pharmacological properties.
- the physico-chemical and spectrophotometric properties taken together lead to impute formula (III) to the compounds of the second group.
- the preparation of the compounds of this invention may be carried out reacting a compound of formula (I) with a compound of formula (II), discharging the compounds extractable by means of solvents from the acid solutions which have an IR spectrum (CCl 4 ) showing a broad band near 1655 cm -1 , collecting the compounds which have an IR spectrum (CCl 4 ) showing a band near 1675 cm -1 and, when desired, preparing a pharmaceutically acceptable acid addition salt thereof.
- Preferred meanings of X in formula (I) are chlorine and bromine; preferred meanings of R' are methyl, ethyl and propyl.
- the reaction of compound (I) with compound (II) is preferably carried out at at least 150°C, still more preferably at
- the preferred ratio of compound (I) to compound (II) is of one mole to from 1 to 3 moles.
- reaction of compound (I) with compound (II) may last from
- reaction mixture contains also some 4-oxo
- composition i somer of the compounds of this invention; they have an IR spectrum (CCl 4 ) showing a broad band near 1655 cm -1 and are insoluble in acids.
- each component of the mixture has an IR spectrum (CCl 4 ) showing a band near 1675 cm -1 .
- reaction of a 2-halomethyl piperidine or an acid addition salt thereof with m-trifluoromethyl-aniline to afford the compound of formula (II) is preferably carried out at at least 150°C and without adding diluents.
- Preferred piperidine derivative is 2-bromomethyl piperidine hydrobromide.
- reaction time is of from 1 to 12 hours.
- Compound C shows a pharmacological profile very close to the profile of trazodone as regards sedative and mi ore laxi ng effects when assayed according to the Irwin test (Animal and Clinical Pharmacological Techniques in Drug Evaluation, Eds: J.H. Nodine and P.E. Siegler, Chicago, 237-240, 1959) and as regards analgesic activity when assayed according to the phenylquinone test (Hendershot L.C. and Forsaith J.J. Pharmacol. Exp. Ther. 125, 237-240, 1959).
- this compound is devoid of adreno lyt i c effects both in vitro, when assayed according to the isolated deferent test (Patil P.N., Lapidus J.B., Tye A.J. Pharmacol. Exp. Ther. 155, 1-12, 1967 Metodiche sperimentali di Fisiologia e Farmacologia in vivo Tamburini Ed. Milano 1974, pag. 71-74), and in vivo when assayed according to the pressure response to noradrenaline in the rat and clonidine adrenergic tremor in the mouse (Silvestrini 8. e Lisciani R. Curr. Ther. Res. 20, 716, 1976) up to doses substantially higher than those which are active in case of trazodone, as summarized in Table 1.
- Compound C is thus endowed with pharmaceutical and therapeutical properties similar to those of trazodone and has the advantage of being free of the adrenolytic action which is responsible for some side effects of trazodone. Preliminary tests in man have confirmed the favourable properties of "Compound C”.
- the compound according to this invention and the pharmaceutically acceptable acid addition salts thereof will be preferably administered in pharmaceutical formulations.
- Said pharmaceutical forms will be preferably administered by oral or injectable route. Therefore, they will be preferably solid such as tablets, sugar coated pills, powders and capsules, or liquid such as solutions or suspensions. They may also be slow release preparations.
- the compound of formula (III) or a pharmaceutically acceptable acid addition salt thereof will be dosed in the formulation as such or microincapsulated.
- suitable solid excipients are lactose, saccarose, talc, gelatin, agar, terra alba, pectin, acacia, magnesium stearate, stearic acid, potato starch and the like.
- the amount of the excipients will change substantially but each tablet or capsule will not preferably exceed 1 gram.
- suitable liquid excipient are water, olive oil, syrups and the like.
- said pharmaceutical forms may contain other active ingredients, preserving agents, stabilizers, dyes, sweetening agents, emulsifiers, surfactants or flavouring agents, and will be prepared by ordinary operations such as granulation, compression, dissolution and sterilization.
- the active ingredient will be dosed in each dosage unit in such an amount as to exert the desi red therapeutic action.
- the posology of the compound of formula (III) and of the pharmaceutically acceptable acid addition salts thereof will change in accordance with the formulation, the chosen administration route, the kind and severity of the illness to be treated and the general conditions of the patient, according to parameters which are well known to prescribers. In view of the analogy with trazodone, the skilled man will not have any difficulty in determining the posology of the compound of formula (III) and of the pharmaceutically acceptable acid addition salts thereof.
- each dosage unit will contain an amount of from 25 to 250 mg, as base, of a compound of formula (III) or of a pharmaceutically acceptable acid addition salt thereof, and each dosage unit will be administered from one to six times a day.
- the hot reaction mixture is poured into water (1 I), 160 ml of 2N sodium hydroxide (0.32 mol) are added, the organic layer is extracted with ethyl ether, the solvent is removed and the oily residue is distilled, collecting the fraction which boils at 138-142°C at 1 mmHg.
- the solution thus obtained is extracted 4 times with 100 ml of 1N hydrochloric acid.
- the organic phase which contains two (4-oxo) position isomers (A and B) of the compounds of formula (III) is separated and discharged.
- the aqueous layer is made alkaline with 2N sodium hydroxide (120 ml) and the separated oil is extracted with ethyl acetate.
- the solvent is removed, the residue thus obtained (30 g) is chromatographed on a silica column (900 g), eluting with: hexane/ethyl acetate 1:4.
Abstract
Pharmacologically active compound of formula (III), and pharmaceutically acceptable acid addition salts thereof. The process for preparing the compound (III) involves the use as a new intermediate of 2-(N-3-trifluoromethylphenylaminomethyl)-piperidine (II). Pharmaceutical formulations containing the compound of formula (III) or an acid addition salt thereof.
Description
PHARMACOLOGICALLY ACTIVE OCTAHYDRO-PYRIDO (1,2-a) PYRAZINES
* * * * * This invention relates to a new pharmacologically active compound and to the pharmaceutically acceptable acid addition salts thereof, the pharmaceutical compositions containing same, the process for preparation thereof and a new intermediate useful in said process.
More particularly, this invention relates to a compound having an IR spectrum (CCl4) showing a band near 1675 cm-1, which is obtained reacting a compound of formula
CH3-CHX-COOR' (I) wherein X is a leaving group selected from halogen and O-SO2-R where R is methyl, phenyl, p-methylphenyl or triphenylmethyl; and R' is 1-6 C alkyl; with a compound of the formula
The compound of formula (II) is also new and therefore is a further object of this invention together with its preparation method which comprises reacting a 2-halomethyl-piperidine or an acid addition salt thereof with m-trifluoromethyl-aniline.
The product obtained reacting compound (I) with compound (II) consists mainly of a compound the physico-chemical and spectrophotometric characteristics of which are in favour of the
following formula
Although formula (III) above is not representative of the arrangement of the molecule in space as far as geometric isomerism, stereoi someri sm and configuration are concerned, this invention relates to all the compounds of formula (III) whether pure or in admixture one another.
3-oxo-octahydro-pyrido(1,2-a)pyrazines are not very known.
Concerning numbering of substituents, reference is made to "The Ring Index", Am. Chem. Soc, page 208, No. 1612). The only precedent is an article of 1972 (J. Chem. Soc. Perkin, 2, 1972, 1374) which relates to their stereochemistry. None of the three 3-oxo-octahydro-pyrido(1,2-a)pyrazines described by said article anticipate the compound of formula (III).
It does not appear that the preparation of other 3-oxo-octahydro-pyrido(1,2-a)pyrazines or the pharmacological properties of the known ones have been described subsequently.
The compounds obtained reacting (II) with (I) may be divided in two groups: the compounds which have an IR spectrum in CCl4 showing a broad band near 1655 cm-1 and the compounds showing in the same solvent a band near 1675 cm-1. The second group exhibits the most interesting pharmacological properties. The physico-chemical and spectrophotometric properties taken together lead to impute formula (III) to the compounds of the second group.
Among them, the product which exhibits the most interesting pharmacological properties is the one the NMR (CCl4) of which
shows a centered quartet at 2.81 + 0.05 p.p.m. ( ). For the sake of brevity it will be referred to hereinafter as "Compound C".
For correct interpretation of the pharmacological properties of "Compound C" express reference is made to the entire literature originated by the Applicant regarding another compound: trazodone. This drug exhibits three basic properties. They are a well proved antidepressive and anxio lyti c-anti depressive effect in man, adrenolytic activity either in the experimental animal or in man, and the ability to inhibit response to unpleasant stimuli in the experimental animal (Physician s Desk Reference, 38th Ed., 1202, 1984).
This profile agrees well with the assumption that depression is related to a painful mental condition (SiIvestrini, B. Activ. Nerv. Super. 21, 301-303, 1979). In contrast, the adreno lyti c activity of trazodone is not related to antidepressive effects but to secondary effects such as orthostatic hypotension and priapism. This is why a compound which inhibits the response to unpleasant stimuli in the experimental animal without possessing adrenolytic effects and which therefore maintains the antidepressive activity of trazadone without exhibiting its peculiar side effects would be useful.
The preparation of the compounds of this invention may be carried out reacting a compound of formula (I) with a compound of formula (II), discharging the compounds extractable by means of solvents from the acid solutions which have an IR spectrum (CCl4) showing a broad band near 1655 cm-1, collecting the compounds which have an IR spectrum (CCl4) showing a band near 1675 cm-1 and, when desired, preparing a pharmaceutically acceptable acid addition salt thereof. Preferred meanings of X in formula (I) are chlorine and
bromine; preferred meanings of R' are methyl, ethyl and propyl. The reaction of compound (I) with compound (II) is preferably carried out at at least 150°C, still more preferably at
170°-180°C and in the absence of diluents. The preferred ratio of compound (I) to compound (II) is of one mole to from 1 to 3 moles.
The reaction of compound (I) with compound (II) may last from
1-2 hrs to 3-4 days; preferably the reaction time is of about 24 hrs. The thus obtained reaction mixture contains also some 4-oxo
(position) i somer of the compounds of this invention; they have an IR spectrum (CCl4) showing a broad band near 1655 cm-1 and are insoluble in acids.
After separation of the 4-oxo, (position)isomers, it is obtained a mixture of compounds of this invention; i.e. each component of the mixture has an IR spectrum (CCl4) showing a band near 1675 cm-1.
Further separation by column chromatography, affords two fractions. One of the fractions has an NMR spectrum (CCl4) showing a centered quartet at 2.81 ± 0.05 p.p.m. (δ) (Compound C).
Also the reaction of a 2-halomethyl piperidine or an acid addition salt thereof with m-trifluoromethyl-aniline to afford the compound of formula (II) is preferably carried out at at least 150°C and without adding diluents.
Preferred piperidine derivative is 2-bromomethyl piperidine hydrobromide.
Preferably the reaction time is of from 1 to 12 hours.
"Compound C", shows a pharmacological profile very close to the profile of trazodone as regards sedative and mi ore laxi ng
effects when assayed according to the Irwin test (Animal and Clinical Pharmacological Techniques in Drug Evaluation, Eds: J.H. Nodine and P.E. Siegler, Chicago, 237-240, 1959) and as regards analgesic activity when assayed according to the phenylquinone test (Hendershot L.C. and Forsaith J.J. Pharmacol. Exp. Ther. 125, 237-240, 1959).
In contrast, this compound is devoid of adreno lyt i c effects both in vitro, when assayed according to the isolated deferent test (Patil P.N., Lapidus J.B., Tye A.J. Pharmacol. Exp. Ther. 155, 1-12, 1967 Metodiche sperimentali di Fisiologia e Farmacologia in vivo Tamburini Ed. Milano 1974, pag. 71-74), and in vivo when assayed according to the pressure response to noradrenaline in the rat and clonidine adrenergic tremor in the mouse (Silvestrini 8. e Lisciani R. Curr. Ther. Res. 20, 716, 1976) up to doses substantially higher than those which are active in case of trazodone, as summarized in Table 1.
The results shown in the Table prove that "Compound C" exhibits sedative, tranquillizing and analgesic action while it is free of adrenolytic effects both centrally and peripherally.
"Compound C" is thus endowed with pharmaceutical and therapeutical properties similar to those of trazodone and has the advantage of being free of the adrenolytic action which is responsible for some side effects of trazodone. Preliminary tests in man have confirmed the favourable properties of "Compound C".
It is another object of this invention to provide the acid addition salts of the compound of formula (III) with pharmaceutically acceptable organic and inorganic acids such as hydrochloric, sulfuric, succinic, malic, pyruvic, tartaric, mandelic acid and the like.
For pharmaceutical use the compound according to this invention and the pharmaceutically acceptable acid addition salts thereof will be preferably administered in pharmaceutical formulations.
Therefore, further objects of this invention are the pharmaceutical formulations containing a compound of formula (III) or a pharmaceutically acceptable acid addition salt thereof together with one or more suitable pharmaceutical excipients as well as a method for treating depression by administering said pharmaceutical forms.
Said pharmaceutical forms will be preferably administered by oral or injectable route. Therefore, they will be preferably solid such as tablets, sugar coated pills, powders and capsules, or liquid such as solutions or suspensions. They may also be slow
release preparations.
The compound of formula (III) or a pharmaceutically acceptable acid addition salt thereof will be dosed in the formulation as such or microincapsulated. Examples of suitable solid excipients are lactose, saccarose, talc, gelatin, agar, terra alba, pectin, acacia, magnesium stearate, stearic acid, potato starch and the like. The amount of the excipients will change substantially but each tablet or capsule will not preferably exceed 1 gram. Examples of suitable liquid excipient are water, olive oil, syrups and the like.
In addition, said pharmaceutical forms may contain other active ingredients, preserving agents, stabilizers, dyes, sweetening agents, emulsifiers, surfactants or flavouring agents, and will be prepared by ordinary operations such as granulation, compression, dissolution and sterilization.
The active ingredient will be dosed in each dosage unit in such an amount as to exert the desi red therapeutic action.
The posology of the compound of formula (III) and of the pharmaceutically acceptable acid addition salts thereof will change in accordance with the formulation, the chosen administration route, the kind and severity of the illness to be treated and the general conditions of the patient, according to parameters which are well known to prescribers. In view of the analogy with trazodone, the skilled man will not have any difficulty in determining the posology of the compound of formula (III) and of the pharmaceutically acceptable acid addition salts thereof.
Preferably, each dosage unit will contain an amount of from 25 to 250 mg, as base, of a compound of formula (III) or of a
pharmaceutically acceptable acid addition salt thereof, and each dosage unit will be administered from one to six times a day.
The following examples are intended to illustrate this invention without limiting it. EXAMPLE 1 a) A mixture of 2-bromomethylpiperidine hydrobromide (80 g; 0.309 mol) and m-trifluoromethylani line (149.4 g; 0.927 mol) is heated at 160-170°C for four hrs.
The hot reaction mixture is poured into water (1 I), 160 ml of 2N sodium hydroxide (0.32 mol) are added, the organic layer is extracted with ethyl ether, the solvent is removed and the oily residue is distilled, collecting the fraction which boils at 138-142°C at 1 mmHg.
53 g of 2-(N-3-trif luoromethylphenylaminomethyl)-piperidine, viscous and colourless oil are thus obtained.
Analysis Found % C:60.10 H:6.77 N:10.98 for C13H17F N2 Calcd % C:60.45 H:6.63 N:10.85 3 b) A mixture of the above product (45.5 g; 0.176 mol) and of ethyl 2-chloropropionate (41 g; 0.3 mol) is heated at 170-180°C for 24 hrs. The hot mixture is poured into a 10% sodium carbonate solution (600 ml).
After cooling, the organic layer is extracted with chloroform. The volatile portion is removed at 20 mmHg and 150°C, and the residue thus obtained (59 g) is dissolved in ethyl ether (300 ml).
The solution thus obtained is extracted 4 times with 100 ml of 1N hydrochloric acid. The organic phase which contains two (4-oxo) position isomers (A and B) of the compounds of formula (III) is separated and discharged. The aqueous layer is made alkaline with 2N sodium hydroxide
(120 ml) and the separated oil is extracted with ethyl acetate. The solvent is removed, the residue thus obtained (30 g) is chromatographed on a silica column (900 g), eluting with: hexane/ethyl acetate 1:4. 13.5 g of the product which has been named "Compound C" are thus obtained while, eluting again with ethyl acetate/methyl alcohol 4:1 (800 ml) there are eluted 4.5 g of another crude compound (D) which is embraced by formula (III).
"Compound C" solidifies spontaneously. After ricrystallization from hexane, it melts at 75-77°C.
Analysis Found % C: 61.45 H: 6.16 N: 8.86 for C16H19F3N2O Calcd % 61.53 6.13 8.97
IR (CCl4) vC=0 1674 cm- 1
NMR (CCl4) 1.35 (d,J=6cps),3H 1.10-2.60 (non resolved multiplets), 8H
2.81 ± 0.05 p. p.m. (δ) (q,J=6cps), 1H
3.00-3.80 (multiplet), 3H
7.47 (s), 3H
7.61 (m), 1H Hydrochloride, m.p. 231-3°C (from ethyl alcohol/ethylacetate)
Analysis Found % C:55.00 H:5.82 N:7.91 Cl:10.05 for C16H19F3N2O.HCI Calcd % 55.10 5.78 8.03 10.16
IR (KBr) vC=0 1680 cm-1; vN-H 2310 cm-1 (broad). The characteristics of the fractions prepared and separated according to the process described in Example 1 b) are shown in Table 2.
TABLE 2 m.p. IR (C=0),CCI4 NMRCCCl4) (significant peaks) (ºC) (cm-1) 4-5 (δ) 7-8(δ) 2,6-3(δ)
C 75-7 1674 - 7.47 2.81+0.05 p.p.m.
(q,J=6cps)
D oil 1673 7.47
A 110-13 1654-8 4.2-4.8(m,2H) 7.2
B 100-03 1654-7 4.2-4.8(m,2H) 7.2 EXAMPLE 2 a) 25 mg vials "Compound C" 25 mg Sorbitol 115 mg
Water for injection q.s. to 2.5 ml b) 50 mg Capsules "Compound C" 50 mg Starch 33.5 mg Lactose 35 mg
Magnesium Stearate 1 mg Precipitated Sylica 0.5 mg c) Tablets "Compound C" 100 mg 250 mg
Microgranulated Cellulose 59 mg 147.5 mg Starch 20 mg 50 mg
Polyvinylpyrrolidone 9 mg 22.5 mg Sodium Methyl Starch 0.75 mg 1.875 mg Magnesium Stearate 1.25 mg 3.125 mg d) 2.5% Drops 100 ml contain 2.5 g "Compound C" 0.1 g Sodium Saccharinate 4 g 95% Alcohol 4 g Glycerol 60 ml
Purified water q.s. to 100 ml
Claims
1. A compound of formula
2. A compound according to claim 1 above which has an NMR spectrum (CCl4) showing a centered quartet at 2.81 ± 0.05 p.p.m.
(δ).
3. A compound according to anyone of claims 1 and 2 above which exhibits inhibition to an animal including humans, in response to unpleasant stimuli without possessing adrenolytic effects.
4. A pharmaceutical compositions containing an effective amount of a compound according to anyone of claim from 1 to 3 above and a pharmaceutical excipient.
5. A pharmaceutical composition according to claim 4 above, wherein each dosage unit contains from 25 to 250 mg of a compound according to anyone of claim from 1 to 3, calculated as base.
6. A compound of formula
7. A process for preparing a compound of formula
CH3-CHX-COOR' (I) where X is a leaving group selected from halogen and O-SO2-R where R is methyl, phenyl, p-methylphenyl and triphenylmethyl; and
R' is 1-6 C alkyl, with a compound of formula
discharging the compounds insoluble in acids which have an IR spectrum (CCl4) showing a broad band near 1655 cm-1, collecting the compounds which have an IR spectrum (CCl4) showing a band near 1675 cm-1 and, when desired, preparing a pharmaceutically acceptable acid addition salt thereof.
8. A process according to claim 7 above, wherein a compound of formula (I) is used where X is chlorine or bromine, and R, is methyl, ethyl or propyl.
9. A process according to anyone of claims 7 and 8 above, wherein the reaction of compound (I) with compound (II) is
carried out at at least 150°C.
10. A process according to anyone of claims from 7 to 9 above, wherein the reaction of compound (I) with compound (II) is carried out in the absence of diluents.
11. A process according to anyone of claims from 7 to 10 above, wherein the reaction of compound (I) with compound (II) is carried out for a time ranging from 1 to 4 days.
12. A process according to claim 11, wherein the reaction
Lasts 24 hours.
13. A process according to anyone of claims from 7 to 12 above, wherein the compounds which have an IR spectrum (CCl4) showing a band near 1675 cm-1 are separated to afford a compound which has an NMR spectrum (CCl4) showing a centered quartet at
2.81+0.05 p.p.m. (δ).
14. A process according to claim 13 above, wherein the separation is carried out via chromatography.
15. A process according to anyone of claims from 7 to 12 above, wherein compound (II) is prepared reacting a 2-halomethyl piperidine or an acid addition salt thereof with m-trifluoromethylaniline.
16. A process according to claim 15 above, wherein 2-bromomethyl piperidine hydrobromide is used.
17. A process according to anyone of claims 15 and 16 above, wherein the reaction is carried out at at least 150°C.
18. A process according to anyone of claims from 15 to 17 above, wherein the reaction is carried out in the absence of diluents.
19. A process according to anyone of claims from 15 to 18 above, wherein the reaction time ranges from 1 to 12 hours.
20. A process for preparing a pharmaceutical composition whi c h
comprises mixing an effective amount of a compound prepared according to anyone of claims from 7 to 19 with a pharmaceutical excipient.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT19431/86A IT1204803B (en) | 1986-02-17 | 1986-02-17 | PHARMACOLOGICALLY ACTIVE COMPOUND AND PHARMACEUTICAL COMPOSITIONS CONTAINING IT, PROCEDURE TO PREPARE IT AND INTERMEDIATE USEFUL IN THAT PROCEDURE |
| IT19431A/86 | 1986-02-17 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO1987005022A2 true WO1987005022A2 (en) | 1987-08-27 |
| WO1987005022A3 WO1987005022A3 (en) | 1987-10-22 |
Family
ID=11157870
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP1987/000070 WO1987005022A2 (en) | 1986-02-17 | 1987-02-09 | PHARMACOLOGICALLY ACTIVE OCTAHYDRO-PYRIDO(1,2-a) PYRAZINES |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0257072A1 (en) |
| AU (1) | AU7122387A (en) |
| ES (1) | ES2004255A6 (en) |
| IT (1) | IT1204803B (en) |
| PT (1) | PT84299A (en) |
| WO (1) | WO1987005022A2 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0380217A1 (en) * | 1989-01-23 | 1990-08-01 | Pfizer Inc. | Bis-aza-bicyclic anxiolytic agents and antidepressants |
| US5852031A (en) * | 1994-09-30 | 1998-12-22 | Pfizer Inc. | 2,7-substituted octahydro-1H-pyrido 1,2-a!pyrazine derivatives |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR6363M (en) * | 1966-01-07 | 1968-10-07 | ||
| GB1137410A (en) * | 1965-10-04 | 1968-12-18 | Ciba Ltd | Novel aza-cycloalkano-[1,2-a]-pyrazines and process for preparing same |
-
1986
- 1986-02-17 IT IT19431/86A patent/IT1204803B/en active
-
1987
- 1987-02-09 AU AU71223/87A patent/AU7122387A/en not_active Abandoned
- 1987-02-09 WO PCT/EP1987/000070 patent/WO1987005022A2/en unknown
- 1987-02-09 EP EP87901432A patent/EP0257072A1/en not_active Withdrawn
- 1987-02-16 PT PT84299A patent/PT84299A/en unknown
- 1987-02-17 ES ES8700631A patent/ES2004255A6/en not_active Expired
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1137410A (en) * | 1965-10-04 | 1968-12-18 | Ciba Ltd | Novel aza-cycloalkano-[1,2-a]-pyrazines and process for preparing same |
| FR6363M (en) * | 1966-01-07 | 1968-10-07 |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0380217A1 (en) * | 1989-01-23 | 1990-08-01 | Pfizer Inc. | Bis-aza-bicyclic anxiolytic agents and antidepressants |
| AP128A (en) * | 1989-01-23 | 1991-03-20 | Pfizer | Bis-aza-bicyclic anxiolytic agents. |
| US5852031A (en) * | 1994-09-30 | 1998-12-22 | Pfizer Inc. | 2,7-substituted octahydro-1H-pyrido 1,2-a!pyrazine derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1987005022A3 (en) | 1987-10-22 |
| EP0257072A1 (en) | 1988-03-02 |
| PT84299A (en) | 1987-03-01 |
| AU7122387A (en) | 1987-09-09 |
| ES2004255A6 (en) | 1988-12-16 |
| IT1204803B (en) | 1989-03-10 |
| IT8619431A0 (en) | 1986-02-17 |
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