NO151200B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE, NEW DERIVATIVES OF 4- (3- (4-CHINOLYL) PROPYL) -PIPERIDINE - Google Patents
ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE, NEW DERIVATIVES OF 4- (3- (4-CHINOLYL) PROPYL) -PIPERIDINE Download PDFInfo
- Publication number
- NO151200B NO151200B NO792550A NO792550A NO151200B NO 151200 B NO151200 B NO 151200B NO 792550 A NO792550 A NO 792550A NO 792550 A NO792550 A NO 792550A NO 151200 B NO151200 B NO 151200B
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- Norway
- Prior art keywords
- formula
- propyl
- vinyl
- piperidine
- group
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 8
- 238000002360 preparation method Methods 0.000 title claims description 4
- AJDSLCRMHNPMOM-UHFFFAOYSA-N 4-(3-piperidin-4-ylpropyl)quinoline Chemical class C=1C=NC2=CC=CC=C2C=1CCCC1CCNCC1 AJDSLCRMHNPMOM-UHFFFAOYSA-N 0.000 title claims description 3
- 230000001225 therapeutic effect Effects 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 33
- 229910052799 carbon Inorganic materials 0.000 claims description 11
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 8
- 125000003386 piperidinyl group Chemical group 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 229920002554 vinyl polymer Polymers 0.000 claims description 5
- 230000002378 acidificating effect Effects 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 239000012458 free base Substances 0.000 claims description 3
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 2
- 230000009466 transformation Effects 0.000 claims 1
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 28
- 229940076279 serotonin Drugs 0.000 description 14
- 239000000243 solution Substances 0.000 description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 210000001772 blood platelet Anatomy 0.000 description 6
- 150000001721 carbon Chemical group 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 210000002569 neuron Anatomy 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- -1 3-(4-quinolyl)-propyl group Chemical group 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 208000019695 Migraine disease Diseases 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 230000002490 cerebral effect Effects 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 239000012259 ether extract Substances 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- WWPITPSIWMXDPE-UHFFFAOYSA-N para-chloroamphetamine Chemical compound CC(N)CC1=CC=C(Cl)C=C1 WWPITPSIWMXDPE-UHFFFAOYSA-N 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229910001220 stainless steel Inorganic materials 0.000 description 2
- 239000010935 stainless steel Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- DKRSEIPLAZTSFD-HUUCEWRRSA-N 3-[(3s,4r)-3-ethenylpiperidin-4-yl]-1-(6-methoxyquinolin-4-yl)propan-1-one Chemical compound C12=CC(OC)=CC=C2N=CC=C1C(=O)CC[C@@H]1CCNC[C@H]1C=C DKRSEIPLAZTSFD-HUUCEWRRSA-N 0.000 description 1
- JSJXVCMOTJREEM-FXUMYAARSA-N 3-[(3s,4r)-3-ethenylpiperidin-4-yl]-1-(6-methoxyquinolin-4-yl)propan-1-one;dihydrochloride Chemical compound Cl.Cl.C12=CC(OC)=CC=C2N=CC=C1C(=O)CC[C@@H]1CCNC[C@H]1C=C JSJXVCMOTJREEM-FXUMYAARSA-N 0.000 description 1
- 208000020401 Depressive disease Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 241000112708 Vates Species 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 239000002269 analeptic agent Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000010779 crude oil Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- BCGWQEUPMDMJNV-UHFFFAOYSA-N imipramine Chemical compound C1CC2=CC=CC=C2N(CCCN(C)C)C2=CC=CC=C21 BCGWQEUPMDMJNV-UHFFFAOYSA-N 0.000 description 1
- 229960004801 imipramine Drugs 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000008517 inhibition of serotonin uptake Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000004089 psychotropic agent Substances 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 230000013275 serotonin uptake Effects 0.000 description 1
- 230000002295 serotoninergic effect Effects 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 231100000563 toxic property Toxicity 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- DKRSEIPLAZTSFD-LSDHHAIUSA-N viquidil Chemical compound C12=CC(OC)=CC=C2N=CC=C1C(=O)CC[C@@H]1CCNC[C@@H]1C=C DKRSEIPLAZTSFD-LSDHHAIUSA-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
-
- 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
-
- 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
- A61P25/06—Antimigraine agents
-
- 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
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Description
I FR-PS 2.354.771 beskrives medikamenter som som aktiv bestanddel inneholder en forbindelse tilsvarende den generelle formel: FR-PS 2,354,771 describes medicines which as active ingredient contain a compound corresponding to the general formula:
der X og R er hydrogenatomer eller R er en vinyl- eller etylgruppe og X er et hydrogenatom eller en metoksygruppe i 6-stilling, idet karbonatomene i piperidinringen som bærer R-gruppen og 3-(4-kinolyl)-propylgruppen begge har rectus (R) konfigurasjon. where X and R are hydrogen atoms or R is a vinyl or ethyl group and X is a hydrogen atom or a methoxy group in the 6-position, the carbon atoms in the piperidine ring bearing the R group and the 3-(4-quinolyl)-propyl group both having rectus ( R) configuration.
Foreliggende oppfinnelse angår fremstilling av nye deri- The present invention relates to the production of new deri-
vater av 4-[3-(4-kinolyl)propyl]-piperidin med terapeutisk akti-vitet. vates of 4-[3-(4-quinolyl)propyl]-piperidine with therapeutic activity.
Disse nye derivater tilsvarer formelen: These new derivatives correspond to the formula:
hvori X' er et hydrogenatom eller en metoksygruppe, R' er en vinyl-eller etylgruppe, idet karbonatomet som bærer R'-gruppen in which X' is a hydrogen atom or a methoxy group, R' is a vinyl or ethyl group, the carbon atom bearing the R' group
har (S)-konfigurasjon og karbonatomet bærer 3-(4-kinolyl)propyl-gruppen, dvs. karbonatomet i 4-stilling på piperidinringen, has (S) configuration and the carbon atom carries the 3-(4-quinolyl)propyl group, i.e. the carbon atom in the 4-position on the piperidine ring,
har (R)-konfigurasjon, samt syreaddisjonssalter derav. have (R) configuration, as well as acid addition salts thereof.
Forbindelsene med formel (II) kan fremstilles ved reduk-sjon, spesielt ved hjelp av hydrazinhydrat, i nærvær av et alkalimetallhydroksyd og et oppløsningsmiddel, slik som en alkohol, av forbindelser med formelen: The compounds of formula (II) can be prepared by reduction, in particular by means of hydrazine hydrate, in the presence of an alkali metal hydroxide and a solvent, such as an alcohol, of compounds of the formula:
der X' og R' har den samme betydning som formel (II), og karbonet som bærer R'-gruppen har (S)-konfigurasjon og karbonatomet i 4-stilling i piperidinringen har (R)-konfigurasjon. where X' and R' have the same meaning as formula (II), and the carbon carrying the R' group has (S) configuration and the carbon atom in the 4-position of the piperidine ring has (R) configuration.
Forbindelsene med formel (III) der R<1>er en vinylgruppe kan i seg selv fremstilles ved å oppvarme i et surt medium en forbindelse med formelen: The compounds of formula (III) where R<1> is a vinyl group can themselves be prepared by heating in an acidic medium a compound of the formula:
hvori R<1>er en vinylgruppe og karbonatomet som bærer gruppen R' wherein R<1>is a vinyl group and the carbon atom bearing the group R'
og det i 4-stilling i piperidinringen begge har (R)-konfigurasjon . and that in the 4-position of the piperidine ring both have (R) configuration.
Forbindelsene med formel (II) der R' er en etylgruppe The compounds of formula (II) where R' is an ethyl group
kan også fremstilles ved katalytisk hydrogenering av tilsvarende forbindelser med formel (II), der R' er en vinylgruppe. Denne hydrogenering kan f.eks. gjennomføres ved omgivelsestemperatur, under et hydrogentrykk tilsvarende det atmosfæriske trykk, i et inert oppløsningmiddel, slik som en alkohol (f.eks. metanol eller etanol) eller en syre (f.eks. eddiksyre), i nærvær av en katalysator slik som palladium, nikkel, rhodium, ruthenium eller platina. can also be prepared by catalytic hydrogenation of corresponding compounds of formula (II), where R' is a vinyl group. This hydrogenation can e.g. is carried out at ambient temperature, under a hydrogen pressure corresponding to the atmospheric pressure, in an inert solvent, such as an alcohol (e.g. methanol or ethanol) or an acid (e.g. acetic acid), in the presence of a catalyst such as palladium, nickel, rhodium, ruthenium or platinum.
Til slutt kan forbindelser med formel (II) der R' er en vinylgruppe også fremstilles ved oppvarming i et surt medium av forbindelser med formelen: Finally, compounds of formula (II) where R' is a vinyl group can also be prepared by heating in an acidic medium compounds of the formula:
hvori karbonatomet som bærer vinylgruppen og det i 4-stilling i piperidinringen, har (R)-konfigurasjon. in which the carbon atom bearing the vinyl group and that in the 4-position of the piperidine ring has (R) configuration.
Etter ferdig reaksjon, behandles reaksjonsblandingen som oppnås ved de ovenfor angitte prosésser i henhold til konvensjo-nelle metoder, fysikalske (fordamping, oppløsningsmiddelekstrak-sjon, destillasjon, krystallisasjon, kromatografi osv.) eller kjemiske (dannelse av salt og regenerering av basen, osv.), for å isolere produktene ved formel (II) i ren tilstand, enten som fri base eller som et salt derav med en syre. After completion of the reaction, the reaction mixture obtained by the above-mentioned processes is treated according to conventional methods, physical (evaporation, solvent extraction, distillation, crystallization, chromatography, etc.) or chemical (formation of salt and regeneration of the base, etc. ), to isolate the products of formula (II) in their pure state, either as a free base or as a salt thereof with an acid.
Forbindelsene med formel (II) i form av den frie base kan, hvis ønsket, omdannes til syreaddisjonssalter med en mineral-syre eller en organsik syre ved påvirkning av en slik syre i et egnet oppløsningsmiddel. The compounds of formula (II) in the form of the free base can, if desired, be converted into acid addition salts with a mineral acid or an organic acid by the action of such an acid in a suitable solvent.
Slik det er antydet i den innledningsvis nevnte franske publikasjon, er forbindelsene med formel (I) brukbare ved behandling av patologiske tilstander forårsaket av en forstyrrelse i virkningen av de serotoninergiske systemer og spesielt finner forbindelsene anvendelse som psykotropiske midler, mere spesielt som antidepresjonsmidler. Disse anvendelser står i forbindelse med kapasiteten for forbindelsene med formel (I) for å inhibere opptaket av serotonin av membranene i cerebral neuronene. As indicated in the initially mentioned French publication, the compounds of formula (I) are useful in the treatment of pathological conditions caused by a disturbance in the action of the serotoninergic systems and in particular the compounds find use as psychotropic agents, more particularly as antidepressants. These uses are related to the capacity of the compounds of formula (I) to inhibit the uptake of serotonin by the membranes of the cerebral neurons.
Forbindelsene med formel (I) har også egenskaper som forårsaker frigjøring av serotonin, inneholdt enten i neuronene éller i blodplatene. The compounds of formula (I) also have properties that cause the release of serotonin, contained either in the neurons or in the blood platelets.
Forbindelsene med formel (II) har de to for forbindelser med formel (I) nevnte egenskaper. For forbindelsene med formel (II) er imidlertid egenskapen som forårsaker frigjøring av serotonin, betraktelig mer markert enn den for inhibering av opptak av dette amin. Dette kunne resultere terapeutisk i en meget hurtig virkning under behandlingen av depresjonen ( i dette tilfelle virker produket på serotoninet i cerebral neuronene) The compounds of formula (II) have the two properties mentioned for compounds of formula (I). For the compounds of formula (II), however, the property of causing the release of serotonin is considerably more marked than that of inhibiting the uptake of this amine. This could therapeutically result in a very rapid effect during the treatment of depression (in this case the product acts on the serotonin in the cerebral neurons)
og under behandling av migrene (i dette tilfelle virker pro-duketet på serotoninet i blodplater). and during the treatment of migraine (in this case the product acts on the serotonin in blood platelets).
De følgende eksempler illustrerer oppfinnelsen uten å begrense den. The following examples illustrate the invention without limiting it.
Eksempel 1 Example 1
4-^R)^-^3-^6-metoksY-4-kino<l>Y<l>).<gro>2Yilz21§ilYiSYlEiESEi§iS4-^R)^-^3-^6-methoxyY-4-kino<l>Y<l>).<gro>2Yilz21§ilYiSYlEiESEi§iS
0,31 g kaliumhydroksyd tilsettes til en suspensjon av 0.31 g of potassium hydroxide is added to a suspension of
1,1 g 1-(6-metoksy-4-kinolyl)-3-[3(S)-vinyl-4(R)-piperidyl]-1-propanondihydroklorid i 3,5 ml dietylenglykol og 0,18 ml av en 85%-ig vandig oppløsning av hydrazinhydrat. Blandingen oppvarmes langsomt til 150°C og avkjøles til 100°C, og 0,47 g kaliumhydroksyd tilføres. Reaksjonsblandingen oppvarmes til 150°C og holdes ved denne temperatur i 5 timer. 1.1 g of 1-(6-methoxy-4-quinolyl)-3-[3(S)-vinyl-4(R)-piperidyl]-1-propanone dihydrochloride in 3.5 ml of diethylene glycol and 0.18 ml of a 85% aqueous solution of hydrazine hydrate. The mixture is slowly heated to 150°C and cooled to 100°C, and 0.47 g of potassium hydroxide is added. The reaction mixture is heated to 150°C and kept at this temperature for 5 hours.
Etter avkjøling blir reaksjonsblandingen behandlet med After cooling, the reaction mixture is treated with
15 ml vann. Oljen som separeres ut ekstraheres med etylacetat. Den organiske fase dekanteres, vaskes, tørkes over magnesiumsulfat og fordampes deretter. Råoljen som oppnås fikseres på en kolonne inneholdende 45 g silisiumdioksyd og elueres deretter med en blanding inneholdende 90% kloroform og 10% dietylamin. 15 ml of water. The oil that separates out is extracted with ethyl acetate. The organic phase is decanted, washed, dried over magnesium sulphate and then evaporated. The crude oil obtained is fixed on a column containing 45 g of silicon dioxide and then eluted with a mixture containing 90% chloroform and 10% diethylamine.
Det rensede produkt som således er isolert oppløses i aceton og omdannes til hydrokloridet ved tilsetning av en opp-løsning av saltsyre i eter. Man oppnår 0,24 g 4(R)-[3-(6-metoksy-4-kinolyl)propyl]-3(S)-vinylpiperidinhydroklorid med sme1tepunkt 151°C. The purified product thus isolated is dissolved in acetone and converted to the hydrochloride by adding a solution of hydrochloric acid in ether. 0.24 g of 4(R)-[3-(6-methoxy-4-quinolyl)propyl]-3(S)-vinylpiperidine hydrochloride with a melting point of 151°C is obtained.
Utgangsketonet ble fremstilt som følger: The starting ketone was prepared as follows:
Ved 20 ml destillert vann ble tilsatt til 2,1 g l-(6-metoksy-4-kinolyl)-3-[3(R) -vinyl-4(R)-piperidyl]-1-propanon (kinisin) og pH-verdien ble brakt til 3,5 ved tilsetning av en lN-oppløsning av svovelsyre. Blandingen ble tilført til en 225 ml autoklav av rustfritt stål og oppvarmet i 48 timer til 140°C. Oppløsningen ble deretter gjort alkalisk ved tilsetning av en 2N-oppløsning av natriumhydroksyd og ekstrahert med eter. Eterekstraktene ble vasket med vann, tørket over vandig natriumsulfat og fordampet til tørr tilstand. At 20 ml of distilled water was added to 2.1 g of 1-(6-methoxy-4-quinolyl)-3-[3(R)-vinyl-4(R)-piperidyl]-1-propanone (quinisine) and pH -value was brought to 3.5 by adding a 1N solution of sulfuric acid. The mixture was added to a 225 ml stainless steel autoclave and heated for 48 hours at 140°C. The solution was then made alkaline by the addition of a 2N solution of sodium hydroxide and extracted with ether. The ether extracts were washed with water, dried over aqueous sodium sulfate and evaporated to dryness.
Den oppnådde resten i en mengde på 1,7 g ble oppløst i The obtained residue in an amount of 1.7 g was dissolved in
■ w ■ w V w en liten mengde 9:1 toluen:dietylamin og fiksert på en kolonne inneholdende 500 g silisiumdioksyd. Eluering skjedde med en 9:1 toluen:dietylaminblanding under et trykk på 4 bar. Man isolerte således 0,51 g av utgangsproduktet (kinicin), og 1,08 ■ w ■ w V w a small amount of 9:1 toluene:diethylamine and fixed on a column containing 500 g of silica. Elution took place with a 9:1 toluene:diethylamine mixture under a pressure of 4 bar. 0.51 g of the starting product (kinicin) was thus isolated, and 1.08
g 1-(6-metoksy-4-kinolyl)-3-[3(S)-vinyl-4(R)-piperidyl]-1-propanon. Den sistnevnte forbindelse ble oppløst i metanol og omdannet til hydrokloridet ved tilsetning av en 8N-oppløsning av saltsyre i metanol. g 1-(6-Methoxy-4-quinolyl)-3-[3(S)-vinyl-4(R)-piperidyl]-1-propanone. The latter compound was dissolved in methanol and converted to the hydrochloride by addition of an 8N solution of hydrochloric acid in methanol.
Eksempel 2 Example 2
13zi6-metoksy- 4-kinolyl iEE°.EZiIl ^S^yinylgigeridin 13zi6-Methoxy- 4-quinolyl iEE°.EZiIl ^S^yinyl gigeridine
2,1 g 4(R)-[3-(6-metoksy-4-kinolyl)propyl)-3(R)-vinyl-piperidin ble oppløst i 20 ml destillert vann og pH-verdien ble justert til 2 ved tilsetning av 5N-oppløsning av svovelsyre. Blandingen ble tilført til en 225 ml autoklav av rustfritt stål og oppvarmet til 140°C i 48 timer. Deretter ble oppløsningen gjort alkalisk ved tilsetning av en 2N-oppløsning av natriumhydroksyd og ekstrahert med eter. Eterekstraktene ble vasket med vann, tørket over vannfri natriumsulfat og fordampet til tørr tilstand. Den oppnådde rest i en mengde på l,9g, ble oppløst i en liten mengde 9:1 toluen:dietylamin og fiksert på en kolonne inneholdende 500 g silisiumdioksyd. Etter eluering med 9:1 toluen:dietylamin under et trykk på 4 bar, oppnådde man 0,71 g utgangsprodukt og 0,68 g 4(R)-[3-(6-metoksy-4-kinolyl)propyl]-3(S)-vinylpiperidin i form av en olje. 2.1 g of 4(R)-[3-(6-methoxy-4-quinolyl)propyl)-3(R)-vinyl-piperidine was dissolved in 20 ml of distilled water and the pH was adjusted to 2 by adding 5N solution of sulfuric acid. The mixture was added to a 225 ml stainless steel autoclave and heated to 140°C for 48 hours. The solution was then made alkaline by the addition of a 2N solution of sodium hydroxide and extracted with ether. The ether extracts were washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The obtained residue in an amount of 1.9 g was dissolved in a small amount of 9:1 toluene:diethylamine and fixed on a column containing 500 g of silica. After elution with 9:1 toluene:diethylamine under a pressure of 4 bar, 0.71 g of starting product and 0.68 g of 4(R)-[3-(6-methoxy-4-quinolyl)propyl]-3( S)-vinyl piperidine in the form of an oil.
Den sistnevnte forbindelse ble oppløst i metanol og omdannet til hydrokloridet ved tilsetning av en oppløsning av saltsyre i metanol. The latter compound was dissolved in methanol and converted to the hydrochloride by addition of a solution of hydrochloric acid in methanol.
Karakteristika for 4(R)-[3-(6-metoksy-4-kinolyl)propyl]-3(S)-vinylpiperidinhydroklorid: Characteristics of 4(R)-[3-(6-methoxy-4-quinolyl)propyl]-3(S)-vinylpiperidine hydrochloride:
Smeltepunkt 151°C Melting point 151°C
Optisk dreining (målt i vann ved 25°C): Optical rotation (measured in water at 25°C):
r i 25 -> t o r in 25 -> t o
[a]D = -31 [a]D = -31
NMR-spektrum (oppløsningsmiddel: deuterokloroform; referanse: tetrametylsilan): Den kjemiske skifting 6 for hydrogenatomene 10, 11 og 11' i formel (V) nedenfor er: NMR spectrum (solvent: deuterochloroform; reference: tetramethylsilane): The chemical shift 6 for the hydrogen atoms 10, 11 and 11' in formula (V) below is:
tS10= 5,4 ppm tS10= 5.4 ppm
511 X1<i><=><5><ppm> 511 X1<i><=><5><ppm>
Fremstillingen av 4(R)-[3-(6-metoksy-4-kinolyl)propyl]-3(R)-vinylpiperidin som ble brukt som utgangsstoff er beskrevet i fransk publikasjon nr. 2.354.771. The preparation of 4(R)-[3-(6-methoxy-4-quinolyl)propyl]-3(R)-vinylpiperidine which was used as starting material is described in French publication No. 2,354,771.
Eksempel 3 Example 3
4 1.3- i6_-metoksy_-iilsi22lziiEE2EYill2i§lz§tYl2igeridin 4 1.3- i6_-methoxy_-iilsi22lziiEE2EYill2i§lz§tYl2igeridine
En godt omrørt suspensjon inneholdende 2g 10% palladium-behandlet karbon og 6,8 g 4(R)-[3-(6-metoksy-4-kinolyl)propyl]-3(S)-vinylpiperidinmonohydroklorid i oppløsning i 100 ml absolutt etanol ble holdt ved omgivelsestemperatur under et hydrogentrykk tilsvarende et overtrykk på 50 mm vannsøyle i forhold til det atmosfæriske inntil absorpsjonen av hydrogen var stanset. A well-stirred suspension containing 2 g of 10% palladium-treated carbon and 6.8 g of 4(R)-[3-(6-methoxy-4-quinolyl)propyl]-3(S)-vinylpiperidine monohydrochloride dissolved in 100 ml of absolute ethanol was kept at ambient temperature under a hydrogen pressure corresponding to an overpressure of 50 mm water column relative to atmospheric until the absorption of hydrogen had stopped.
Den palladiserte karbon ble deretter separert ved filtrering og den alkoholiske oppløsning ble konsentrert. Resten ble deretter oppløst i 50 ml vann og oppløsningen ble brakt til pH 10 ved å tilsette en oppløsning av natriumhydroksyd. The palladiumized carbon was then separated by filtration and the alcoholic solution was concentrated. The residue was then dissolved in 50 ml of water and the solution was brought to pH 10 by adding a solution of sodium hydroxide.
Oljen som saltet ut ble ekstrahert med kloroform og ekstrakten vasket med vann, deretter tørket over magnesiumsulfat. Etter fordamping av kloroform, ble restoljen på 5,6 g omdannet til fumaratet ved oppløsning i etanol og tilsetning av 2,1 g fumarsyre. The oil that salted out was extracted with chloroform and the extract washed with water, then dried over magnesium sulfate. After evaporation of chloroform, the residual oil of 5.6 g was converted to the fumarate by dissolution in ethanol and addition of 2.1 g of fumaric acid.
Man oppnådde 5,5 g av det sure fumarat 4(R)-[3-(6-metoksy-4-kinolyl)propyl]-3 (S)-etylpiperidin og denne forbindelse hadde et smeltepunkt på 180°C. 5.5 g of the acidic fumarate 4(R)-[3-(6-methoxy-4-quinolyl)propyl]-3(S)-ethylpiperidine were obtained and this compound had a melting point of 180°C.
Analyse for C„nHooNo0, C.H.O. Analysis for C„nHooNo0, C.H.O.
220 28 2 4 4 4 220 28 2 4 4 4
Beregnet: % N = 6,54 Calculated: % N = 6.54
Funnet: % N = 6,4 7 Found: % N = 6.4 7
Eksempel 4 Example 4
ålBizI^zil-kinolYlipropYlll^S^-yinYlpiper ålBizI^zil-quinolYlipropYlll^S^-yinYlpiper
Ved å arbeide som i eksempel 2, men ved å erstatte de 2,1 g 4(R)-[3-(6-metoksy-4-kinolyl)propyl]-3(R)-vinylpiperidin med 1,3 g 4 (R) -[3-(4-kinolyl)propyl]-3(R)-vinylpiperidin ble det oppnådd 0,8 g 4(R)-[3-(4-kinolyl)propyl)-3(S)-vinylpiperidin i form av en olje. By working as in Example 2, but by replacing the 2.1 g of 4(R)-[3-(6-methoxy-4-quinolyl)propyl]-3(R)-vinylpiperidine with 1.3 g of 4 ( R)-[3-(4-quinolyl)propyl]-3(R)-vinylpiperidine, 0.8 g of 4(R)-[3-(4-quinolyl)propyl)-3(S)-vinylpiperidine were obtained in form of an oil.
Karakteristika for 4(R)-[3-(4-kinolyl)propyl]-3(S)-vinyl-piperidin : Characteristics of 4(R)-[3-(4-quinolyl)propyl]-3(S)-vinyl-piperidine :
NMR-spektrum: NMR spectrum:
De kjemiske skift 6 for hydrogenatomene 10, 11 og 11' i formel (V) er: The chemical shifts 6 for the hydrogen atoms 10, 11 and 11' in formula (V) are:
fi10 = 5/5 ppm fi10 = 5/5 ppm
ii'= 5,05 ppm ii' = 5.05 ppm
Fremstillingen av 4(R)-[3-(4-kinolyl)propyl]-3(R)-vinylpiperidin som ble benyttet som utgangsstoff er beskrevet i fransk publikasjon nr. 2.354.771. The preparation of 4(R)-[3-(4-quinolyl)propyl]-3(R)-vinylpiperidine, which was used as starting material, is described in French publication No. 2,354,771.
Farmakologiske egenskaper Pharmacological properties
Det er kjent at opptaket av serotonin i blodplatene er en god modell for opptaket av dette amin i neuroner (se J. Tuomisto, J. Pharm., Pharmac, 26^, 92 (1974)). Når den anvendes på under-søkelsen av medikamenter, er en metode som bringer blodplatene inn i bildet av stor interesse fordi denne metode gjør det mulig å benytte humanceller, noe som muliggjør å oppnå en god anti-cipering av virkningen av produktene på mennekser. It is known that the uptake of serotonin in blood platelets is a good model for the uptake of this amine in neurons (see J. Tuomisto, J. Pharm., Pharmac, 26^, 92 (1974)). When applied to the investigation of drugs, a method that brings platelets into the picture is of great interest because this method makes it possible to use human cells, which makes it possible to achieve a good anticipation of the effect of the products on humans.
Kapasiteten for produktene for inhibering av opptak av serotonin eller for å forårsake frigjøring av denne forbindelse, er vist på humanblodplater i henhold til J.L. David et al. i "Platelets Function and thrombosis, a review of methods", side 335 (Plenum Press, London, 1972). The capacity of the products to inhibit the uptake of serotonin or to cause the release of this compound has been shown on human platelets according to J.L. David et al. in "Platelets Function and thrombosis, a review of methods", page 335 (Plenum Press, London, 1972).
a) Inhibering av serotoninopptak a) Inhibition of serotonin uptake
Resultatene er uttrykt ved 50%-ig inhiberingsdose, I5QfThe results are expressed at a 50% inhibition dose, I5Qf
som representerer produktdosen i mikromol pr. liter som reduserer opptaket av serotonin ved 50%. which represents the product dose in micromoles per liter which reduces the uptake of serotonin by 50%.
b) Frigjøring av serotonin b) Release of serotonin
Virkningen av produktene på frigjøring av serotonin er The effect of the products on the release of serotonin is
prøvet ved to konsentrasjoner: 5x10 pr. liter og 5x10 pr. liter. tested at two concentrations: 5x10 per liter and 5x10 per litres.
De oppnådde resultater er uttrykt ved en prosentandeløkning av frigjøringen av serotonin sammenlignet med resultater som oppnås med kontroller. The results obtained are expressed by a percentage increase in the release of serotonin compared to results obtained with controls.
Resultatene som ble oppnådd er anført i den følgende tabell. I denne tabell er det også for sammenligningens skyld anført de resultater man oppnådde med to referanseprodukter (imipramin, og p-kloramfetamin). The results obtained are listed in the following table. In this table, for the sake of comparison, the results obtained with two reference products (imipramine and p-chloroamphetamine) are also listed.
Det fremgår av tabellen at forbindelsene ifølge eksemplene 1 og 3 er meget mindre virksomme enn deres epimerer som inhibi-torer for opptak av serotonin (forbindelsen ifølge eksempel 1 er 100 ganger mindre effektiv enn sin epimer og forbindelsen ifølge eksempel 3 er minst 10 ganger mindre effektiv enn sin epimer). It appears from the table that the compounds according to examples 1 and 3 are much less effective than their epimers as inhibitors of serotonin uptake (the compound according to example 1 is 100 times less effective than its epimer and the compound according to example 3 is at least 10 times less effective than its epimer).
Forbindelsene ifølge eksemplene 1 og 3 er kraftige midler for frigjøring av serotonin. De er sogar mer effektive enn p-kloramfetamin. The compounds of Examples 1 and 3 are potent serotonin releasers. They are even more effective than p-chloroamphetamine.
Toksiske egenskaper Toxic properties
Den akutte giftighet for produktene er bestemt på hann- The acute toxicity of the products is determined for male
mus CD^(Charles River) ved oral inngivelse. mouse CD^(Charles River) by oral administration.
LDj-g-dosen ble etter 3 dagers observasjon beregnet ved After 3 days of observation, the LDj-g dose was calculated by
den kumulative metode ifølge J.J. Reed og Coll. (am. J. Hyg., the cumulative method according to J.J. Reed and Coll. (am. J. Hyg.,
1938, 27_, 493) og var 225 mg/kg for forbindelsen ifølge eksempel 1 og ca. 200 mg/kg for forbindelsen ifølge eksempel 3. 1938, 27_, 493) and was 225 mg/kg for the compound according to example 1 and approx. 200 mg/kg for the compound according to example 3.
Forbindelsene ifølge oppfinnelsen er giftige ved 100 mg/ The compounds according to the invention are toxic at 100 mg/
kg og oppfører seg da lik substanser med relativt lav giftighet overfor mus. kg and then behaves like substances with relatively low toxicity towards mice.
Terapeutisk anvendelse Therapeutic application
Forbindelsene ifølge oppfinnelsen og deres farmasøytisk akseptable salter kan benyttes i humanterapien i form av tabletter, kapsler, gelatinbelagte piller, suppositorier, injiserbare opp-løsninger osv, som regulatorer for serotoninavhengig vaskulær tonisitet, spesielt for behandling av migrener, og som tymo-analeptisk medikament med en spesielt hurtig virkning (på grunn av virkningen på frigjøring av serotonin). The compounds according to the invention and their pharmaceutically acceptable salts can be used in human therapy in the form of tablets, capsules, gelatin-coated pills, suppositories, injectable solutions, etc., as regulators of serotonin-dependent vascular tonicity, especially for the treatment of migraines, and as a thymo-analeptic drug with a particularly rapid effect (due to the effect on the release of serotonin).
Posologien avhenger av de ønskede virkninger og av den benyttede inngivelsesmetode. For eksempel kan den ved oral inngivelse være mellom 15 og 250 mg aktivt stoff pr. dag med enkelt-doser fra 5 til 50 mg. The dosage depends on the desired effects and on the administration method used. For example, when administered orally, it can be between 15 and 250 mg of active substance per day with single doses from 5 to 50 mg.
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR7822968A FR2432518A2 (en) | 1978-08-03 | 1978-08-03 | ((QUINOLYL-4) -3 PROPYL-1) -4 PIPERIDINE DERIVATIVES FOR USE AS MEDICAMENTS |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO792550L NO792550L (en) | 1980-02-05 |
| NO151200B true NO151200B (en) | 1984-11-19 |
| NO151200C NO151200C (en) | 1985-02-27 |
Family
ID=9211557
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO792550A NO151200C (en) | 1978-08-03 | 1979-08-02 | ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE, NEW DERIVATIVES OF 4- (3- (4-CHINOLYL) PROPYL) -PIPERIDINE |
Country Status (15)
| Country | Link |
|---|---|
| EP (1) | EP0008962B1 (en) |
| JP (1) | JPS5522696A (en) |
| AR (1) | AR223493A1 (en) |
| AT (1) | AT375657B (en) |
| AU (1) | AU536054B2 (en) |
| CA (1) | CA1121354A (en) |
| DE (1) | DE2964710D1 (en) |
| DK (1) | DK311579A (en) |
| ES (1) | ES483131A0 (en) |
| FR (1) | FR2432518A2 (en) |
| GR (1) | GR69879B (en) |
| HU (1) | HU182588B (en) |
| MX (1) | MX5519E (en) |
| NO (1) | NO151200C (en) |
| ZA (1) | ZA793969B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL7908031A (en) * | 1979-11-01 | 1981-06-01 | Acf Chemiefarma Nv | NEW QUINOLINE DERIVATIVES AND PHARMACEUTICAL PREPARATIONS CONTAINING SUCH A COMPOUND AND METHOD FOR PREPARING THESE COMPOUNDS. |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2354771A1 (en) * | 1976-06-18 | 1978-01-13 | Mar Pha Etu Expl Marques | ((QUINOLYL-4) -3 PROPYL-1) -4 PIPERIDINES, THEIR PREPARATION AND THEIR USE AS MEDICINAL PRODUCTS |
-
1978
- 1978-08-03 FR FR7822968A patent/FR2432518A2/en active Granted
-
1979
- 1979-07-10 DE DE7979400479T patent/DE2964710D1/en not_active Expired
- 1979-07-10 EP EP79400479A patent/EP0008962B1/en not_active Expired
- 1979-07-11 GR GR59575A patent/GR69879B/el unknown
- 1979-07-24 DK DK311579A patent/DK311579A/en not_active Application Discontinuation
- 1979-08-01 AT AT0527879A patent/AT375657B/en not_active IP Right Cessation
- 1979-08-02 HU HU79PA1358A patent/HU182588B/en unknown
- 1979-08-02 MX MX798298U patent/MX5519E/en unknown
- 1979-08-02 NO NO792550A patent/NO151200C/en unknown
- 1979-08-02 ZA ZA00793969A patent/ZA793969B/en unknown
- 1979-08-02 AU AU49498/79A patent/AU536054B2/en not_active Ceased
- 1979-08-02 JP JP9910479A patent/JPS5522696A/en active Pending
- 1979-08-02 CA CA000333074A patent/CA1121354A/en not_active Expired
- 1979-08-03 AR AR277603A patent/AR223493A1/en active
- 1979-08-03 ES ES483131A patent/ES483131A0/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| AU4949879A (en) | 1980-02-07 |
| HU182588B (en) | 1984-02-28 |
| DE2964710D1 (en) | 1983-03-17 |
| FR2432518A2 (en) | 1980-02-29 |
| DK311579A (en) | 1980-02-04 |
| ZA793969B (en) | 1980-07-30 |
| CA1121354A (en) | 1982-04-06 |
| GR69879B (en) | 1982-07-20 |
| AR223493A1 (en) | 1981-08-31 |
| AU536054B2 (en) | 1984-04-19 |
| JPS5522696A (en) | 1980-02-18 |
| EP0008962B1 (en) | 1983-02-09 |
| EP0008962A1 (en) | 1980-03-19 |
| ES8101066A1 (en) | 1980-12-01 |
| ES483131A0 (en) | 1980-12-01 |
| MX5519E (en) | 1983-09-20 |
| NO151200C (en) | 1985-02-27 |
| ATA527879A (en) | 1984-01-15 |
| NO792550L (en) | 1980-02-05 |
| FR2432518B2 (en) | 1982-02-19 |
| AT375657B (en) | 1984-08-27 |
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