NO154054B - Analogifremgangsmaate for fremstilling av terapeutisk aktive hydroksypyrimidinderivater. - Google Patents
Analogifremgangsmaate for fremstilling av terapeutisk aktive hydroksypyrimidinderivater. Download PDFInfo
- Publication number
- NO154054B NO154054B NO800664A NO800664A NO154054B NO 154054 B NO154054 B NO 154054B NO 800664 A NO800664 A NO 800664A NO 800664 A NO800664 A NO 800664A NO 154054 B NO154054 B NO 154054B
- Authority
- NO
- Norway
- Prior art keywords
- methyl
- residue
- acid
- piperidyl
- citrate
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 8
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical class OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 title 1
- 230000001225 therapeutic effect Effects 0.000 title 1
- 239000002253 acid Substances 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 150000007522 mineralic acids Chemical class 0.000 claims description 4
- 150000007524 organic acids Chemical class 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 150000008064 anhydrides Chemical class 0.000 claims description 3
- CCGKOQOJPYTBIH-UHFFFAOYSA-N ethenone Chemical compound C=C=O CCGKOQOJPYTBIH-UHFFFAOYSA-N 0.000 claims description 3
- 150000004820 halides Chemical class 0.000 claims description 3
- 150000002440 hydroxy compounds Chemical class 0.000 claims description 3
- 235000005985 organic acids Nutrition 0.000 claims description 3
- 150000003053 piperidines Chemical class 0.000 claims description 3
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 2
- 125000001589 carboacyl group Chemical group 0.000 claims 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 20
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- -1 alkyl radical Chemical class 0.000 description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229960001138 acetylsalicylic acid Drugs 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 230000000202 analgesic effect Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 229940035676 analgesics Drugs 0.000 description 2
- 239000000730 antalgic agent Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229960004106 citric acid Drugs 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- 230000007794 irritation Effects 0.000 description 2
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- NIQQIJXGUZVEBB-UHFFFAOYSA-N methanol;propan-2-one Chemical compound OC.CC(C)=O NIQQIJXGUZVEBB-UHFFFAOYSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 229940095574 propionic acid Drugs 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000007858 starting material Substances 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
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical group O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- HUUPVABNAQUEJW-UHFFFAOYSA-N 1-methylpiperidin-4-one Chemical compound CN1CCC(=O)CC1 HUUPVABNAQUEJW-UHFFFAOYSA-N 0.000 description 1
- XYHKNCXZYYTLRG-UHFFFAOYSA-N 1h-imidazole-2-carbaldehyde Chemical compound O=CC1=NC=CN1 XYHKNCXZYYTLRG-UHFFFAOYSA-N 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-M 3-Methylbutanoic acid Natural products CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 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
- 244000215068 Acacia senegal Species 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-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
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 244000126014 Valeriana officinalis Species 0.000 description 1
- 235000013832 Valeriana officinalis Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000000954 anitussive effect Effects 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N beta-methyl-butyric acid Natural products CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229960002598 fumaric acid Drugs 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229960000448 lactic acid Drugs 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
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 150000007530 organic bases Chemical group 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000002445 parasympatholytic effect Effects 0.000 description 1
- 230000001499 parasympathomimetic effect Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 229960003424 phenylacetic acid Drugs 0.000 description 1
- 239000003279 phenylacetic acid Substances 0.000 description 1
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical class O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 235000016788 valerian Nutrition 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Fremgangsmåte til fremstilling av hittil ukjente terapeutisk virksomme piperidinderivater.
Nærværende oppfinnelse vedrører
fremgangsmåte til fremstilling av hittil
ukjente terapeutisk virksomme piperindin-derivater med verdifulle farmakologiske
egenskaper.
Det er overraskende funnet ut at
piperidinderivater med den generelle formel I,
hvor R, betyr en lavere alkylrest,
R2 hydrogen eller methylresten og
R;l en alkylrest med i høyden 4 karbonatomer eller sammen med R, en eventuelt methylsubstituert trimethylen-til hexamethylenrest, R, hydrogen eller
methylresten og
R5-CO- en alkanoylrest med i høyden
5 fortrinnsvis 2—3 karbonatomer,
og deres salter med uorganiske og organiske syrer, innehar verdifulle farmakologiske egenskaper i særdeleshet en utmerket
analgetisk virkning ved oral som parenteral administrasjon og sterk antitussiv virkning. I motsetning til andre analgetikå innehar de ingen parasympatikolytiske egenskaper, men virker snarere parasym^ patikomimetisk. De er samtidig relativt lite toksiske og egner seg derfor til lindring og opphevelse av smerter av forskjellig opprinnelse og også ved hosteirritasjon.
I det følgende gjengis forsøksresultater av den analgetiske virkning ved visse forbindelser ifølge oppfinnelsen i sammenlig-ning med acetylsalicylsyre.
a) Prøvede forbindelser.
I 2-(l'-methyl-4'-propionoxy-4'-piperidyl)-cyklohexanon (citrat)
II l-(l'-methyl-4'-propionoxy-4'-piperidyl)-2-butanon (citrat)
III Acetylsalicylsyre
b) Forsøk ifølge Friebel.
Den analgetiske virkning bestemmes
efter metode av Gross, hvorved halene på hvite mus irriteres med apparatet av Friebel og Reichle (Heiv. Physicol. u. Pharma-kol. Acta 5 C 31 (1947)) ved thermisk be-stråling.
Den ifølge Gross definerte reaksjonstid ved den ovenfor nevnte irritasjon bestemmes på forskjellige grupper av 10—20 dyr av hvilke hvert veier 18—25 g, 30 og 15 minutter før administrasjonen av prøve-substansene. Derefter administreres alle dyregruppene en suspensjon av prøvesub-stansene med gummi arabicum i vann i aksjonstid efter 30, 45 og 60 minutter på doser på 200, resp. 400 mg/kg p. o. I løpet den ene side og den gjennomsnittlige reak-av den første time efter administrasjonen sjonstid før administrasjonen av prøve-av prøvesubstansene bestemmes hver kvar- substansene på den annen side, uttrykt i ter den gjennomsnittlige reaksjonstid for prosent av de sistnevnte,
hver dyregruppe og derpå fastslås diffe-
ransen mellom den gjennomsnittlige re- c) Resultater.
d) Konklusjon.
De ifølge oppfinnelsen fremstillbare
forbindelser ifølge nærværende patent-skrift viser, som milde analgetika, overfor acetylsalicylsyre en stor overlegenhet.
I forbindelse med den generelle formel
I og de tilhørende, videre nedenfor nevnte utgangsstoffer betyr R, f. eks. som lavere alkylrester, methyl-, ethyl-, n-propyl-, isopropyl-, n-butyl-, isobutyl- eller sek. butylresten.
R3 er alene f. eks. methyl-, ethyl-, n-propyi-, isopropyl-, n-butyl-, eller tert. butylresten.
R., danner videre sammen med R« f. eks. en trimethylen-, tetramethylen-," 1-methyl-tetramethylen-, pentamethylen-eller hexamethylenrest.
Den lavere alkanoylrest R--CO- er f. eks. acylresten av eddiksyre, propionsyre, smørsyre, isosmørsyre, valeriansyre eller isovaleriansyre.
Til fremstilling av forbindelser med den generelle formel I omsetter man en hydroxyforbindelse med den generelle formel II,
hvor R,, R2, R:i og R, har ovenfor an-gitte betydning,
med et halogenid eller anhydrid av en lavere alkansyre eller med et tilsvarende keten.
Som reaksjonsmedium tjener fortrinnsvis et overskudd av det anvendte anhydrid eller halogenid; andre acylerings-midler anvendes i inerte organiske oppløs-ningsmidler som f. eks. diethylether, tetra-hydrofuran eller benzol. Et syrebindende middel f. eks. en tertiær organisk base som pyridin eller triethylamin kan hvis ønsket tilsettes, men er for en fullstendig omset-ning ikke nødvendig.
Viktig for oppnåelsen av omsetningen efter oppfinnelsen er punktlig overholdelse av lavere reaksjonstemperaturer og i høy-den ca. 60°, fortrinnsvis fra 0° til værelsetemperatur, da det ved utgangsstoffet med den generelle formel II dreier seg om terti-ære hydroxyforbindelser som lett reagerer med acyleringsmidlene ved høyere tempe-raturer under vannavspaltning.
For fremstillingen av utgangsstoffer med den generelle formel II står forskjellige fremgangsmåter til disposisjon f. eks. idet man omsetter et tilsvarende substitu-ert piperidon med et keton, som beskrevet i patent nr. 111 402.
Med uorganiske og organiske syrer som saltsyre, bromhydrogensyre, svovel-syre, salpetersyre, fosforsyre, methansul-fonsyre, ethandisulfonsyre, |3-hydroxy-ethansulfonsyre, eddiksyre, propionsyre, maleinsyre, fumarsyre, melkesyre, eplesyre, vinsyre, citronsyre, benzoesyre, salicylsyre, fenyleddiksyre og mandelsyre danner forbindelser med den generelle formel I salter, som er delvis godt vannoppløselige.
De efterfølgende eksempler redegjør for gjennomføringen av fremgangsmåten efter oppfinnelsen. Temperaturene er an-gitt i Celsiusgrader.
Eksempel 1.
17,1 g l-(l'-methyl-4'-hydroxy-4'-piperidyl)-2-propanon (fremstilt ved om-setning av l-methyl-4-piperidon og aceton i alkalisk miljø) forkjøles under røring til 0°, derefter tilsettes 10,2 g acetanhydrid, iskjølningen fjernes og blandingen røres videre i 15 minutter. Derefter tilsettes den under iskjølning 200 .ml aceton. Uten yt-terligere kjølning feller man ut ved tilsetning av en mettet citronsyreoppløsning i aceton inntil sur reaksjon l-(l'-methyl-4'-acetoxy-4'-piperidyl) -2-propanon-citrat,
filtrerer det fra og omkrystalliserer det fra aceton-methanol. Smeltepunkt 153°.
På analog måte under anvendelse av de tilsvarende 4'-hydroxyforbindelser fremstilles: l-(r-methyl-4'-acetoxy-4'-piperidyl)-2-butanon, citrat smp. 139°; l-(l'-methyl-4'-acetoxy-4'-piperidyl)-2-pentanon, citrat smp. 164°; l-(l'-methyl-4'-acetoxy-4'-piperidyl)-2-hexanon;
1- (l'-methyl-4'-acetoxy-4'-piperidyl)-3-methyl-2-butanon, citrat smp. 157°; 2- (l'-methyl-4'-acetoxy-4'-piperidyl)-cyklohexanon, citrat smp. 162—163°; 2-(l'-methyl-4'-acetoxy-4'-piperidyl)-cyklopentanon, citrat smp. 158°; 2-(l'-methyl-4'-acetoxy-4'-piperidyl)-6-methyl-cyklohexanon; 2-(l'-methyl-4'-acetoxy-4'-piperidyl)-3-pentanon, citrat smp. 182—184°; 1- (l',3'-dimethyl-4'-acetoxy-4'-piperidyl)-2- propanon, citrat smp. 127—129°.
Eksempel 2.
Anvender man i fremgangsmåten efter eksempel 1 istedetfor acetanhydrid 13 g propionsyreanhydrid og rører iy2 til 2 ti-mer, så oppnår man l-(l'-methyl-4'-propi-onoxy-4'-piperidyl)-2-propanon-citratet
med smeltepunkt 129—130°.
På analog måte fremstilles:
1 - (1 '-methyl-4'-propionoxy-4'-piperidyl) 2-butanon, citrat smp. 162°; 1- (r-methyl-4'-propionoxy-4'-piperidyl)-2- pentanon, citrat smp. 156°; l-(l'-methyl-4'-propionoxy-4'-piperidyl)-3- methyl-2-butanon, citrat smp. 146— 148°;
2-(r-methyl-4'-propionoxy-4'-piperidyl)-cyklohexanon, citrat smp. 150—152°;
2-(l'-methyl-4'-propionoxy-4'-piperidyl) cyklopentanon, citrat smp. 146°;
2- (r-methyl-4'-propionoxy-4'-piperidyl)-3- pentanon, citrat smp. 162—163°.
Eksempel 3.
1-( l'- methyl- 4'- acetoxy- 4'- piperidyl)-2- butanon.
2,1 g acetylklorid helles under god kjølning langsomt i 5 ml pyridin, det opp-ståtte krystalline bunnfall pulveriseres med en glasstav og tilsettes porsjonsvis til 1-(l'-methyl-4'-hydroxy-4'-piperidyl)-2-butanonet, oppløst i 5 ml pyridin, under kjølning. Derefter røres blandingen ved værelsetemperatur iy2 time (f. eks. med magnetrører) hvorved den farver seg mørk og.bunnfallet forsvinner. Derefter avdam-pes pyridinet i høy vakuum på rotasjons-fordamper ved 20°, resten tilsettes is, innstilles alkalisk med konsentrert natron-lut og trekkes ut med kloroform. Kloroform-oppløsningen tørkes og inndampes. Resten oppløses i aceton og ved tilsetning av acetonisk sitronsyreoppløsning utfelles og avfiltreres citratet av basen. Efter om-krystallisasjon fra methanol-aceton smel-ter 1 - (1 '-methyl-4'-acetoxy-4'-piperidyl) - 2-butanon-citratet ved 139°, (sammenlign eksempel 1).
Eksempel 4.
3,5 g l-(l'-methyl-4'-hydroxy-4'-piper-idyl)-2-propanon og 250 ml p-toluolsulfon-syre oppløses i 150 ml kloroform. Gjennom denne oppløsning ledes friskt fra aceton fremstilt keten (apparatur ifølge Quad-beck, Angew. Chemie 68, 369 (1956)). Det videre reaksjonsforløp følges med tynn-skiktskromatografi. Efter 15—20 minutter kan intet utgangsmaterial mer fastslås. I løpet av reaksjonen forandrer oppløsnin-gen farge til gul og temperaturen holdes ved kjøling på 20°. Oppløsningen tørkes og konsentreres i vakuum. Den sure opp-løsning innstilles alkalisk med soda, det utfelte produkt ekstraheres 3 ganger, hver gang med 100 ml ether, og tørkes med vannfritt natriumsulfat og inndampes. Det olj eaktige 1- (1 '-methyl-4'-acetoxy-4'-pi-peridyl)-2-propanon overføres til citratet, smp. 153°.
Claims (1)
- Fremgangsmåte til fremstilling av hittil ukjente terapeutisk virksomme piperidinderivater med den generelle formel I, hvor R, betyr en lavere alkylrest, R2 hydrogen eller methylresten, og R„ en alkylrest med i høyden 4 karbonatomer eller sammen med R„ -en eventuelt methylsubstituert trimethylen- til hexamethylenrest, R4 hydrogen eller methylresten, og R5-CO- en alkanoylrest med i høyden 5, fortrinnsvis 2—3 karbonatomer, og deres salter med uorganiske og organiskesyrer, karakterisert ved at man ved høyst 60°C, fortrinnsvis fra 0°C til værelsetemperatur, omsetter en hydroxy-forbindelse med den generelle formel II,hvor R,, R2, R., og R,, har ovenfor an-gitte betydning,med et halogenid eller anhydrid av en lavere alkansyre eller med et tilsvarende keten, og hvis ønsket overfører den erholdte forbindelse med den generelle formel I til et salt med en uorganisk eller organisk syre.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB7908494 | 1979-03-10 | ||
| GB7914987 | 1979-04-30 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO800664L NO800664L (no) | 1980-09-11 |
| NO154054B true NO154054B (no) | 1986-04-01 |
| NO154054C NO154054C (no) | 1986-07-09 |
Family
ID=26270867
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO800664A NO154054C (no) | 1979-03-10 | 1980-03-07 | Analogifremgangsmaate for fremstilling av terapeutisk aktive hydroksypyrimidinderivater. |
Country Status (24)
| Country | Link |
|---|---|
| JP (1) | JPS55122768A (no) |
| AR (1) | AR222691A1 (no) |
| AU (1) | AU533547B2 (no) |
| BE (1) | BE881752A (no) |
| CA (1) | CA1132561A (no) |
| CH (1) | CH644368A5 (no) |
| DE (3) | DE3009071C2 (no) |
| EG (1) | EG14282A (no) |
| FI (1) | FI66357C (no) |
| FR (2) | FR2451191A1 (no) |
| GB (1) | GB2045756B (no) |
| HK (1) | HK55383A (no) |
| IE (1) | IE49547B1 (no) |
| IN (1) | IN153791B (no) |
| LU (1) | LU82185A1 (no) |
| MX (1) | MX6218E (no) |
| MY (1) | MY8400200A (no) |
| NL (1) | NL184833C (no) |
| NO (1) | NO154054C (no) |
| NZ (1) | NZ192927A (no) |
| OA (1) | OA06484A (no) |
| PT (1) | PT70882A (no) |
| SE (1) | SE435180B (no) |
| SG (1) | SG22683G (no) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE894517A (fr) * | 1981-10-16 | 1983-01-17 | Sod Conseils Rech Applic | Nouveau derive de l'isopropylamino pyrimidine, sa preparation et composition therapeutiques a base de ses composes |
| US4673677A (en) * | 1983-10-03 | 1987-06-16 | Pfizer Inc. | Method for treatment of gastrointestinal disorders |
| US4554276A (en) * | 1983-10-03 | 1985-11-19 | Pfizer Inc. | 2-Amino-5-hydroxy-4-methylpyrimidine derivatives |
| US4711888A (en) | 1985-07-24 | 1987-12-08 | Pfizer Inc. | Hydroxy and alkoxy pyrimidines |
| WO1989000423A1 (en) * | 1987-07-09 | 1989-01-26 | Pfizer Inc. | 2-amino-5-hydroxy-4-pyrimidones |
| US4910204A (en) * | 1988-06-28 | 1990-03-20 | Pfizer Inc. | 2-amino-5-hydroxy-4-pyrimidones |
| HU206337B (en) * | 1988-12-29 | 1992-10-28 | Mitsui Petrochemical Ind | Process for producing pyrimidine derivatives and pharmaceutical compositions |
| US5264435A (en) * | 1988-12-29 | 1993-11-23 | Mitsui Petrochemical Industries, Ltd. | Pyrimidines and their pharmaceutical acceptable salts, and their use as medicines |
| US4940712A (en) * | 1989-05-26 | 1990-07-10 | Pfizer Inc. | Derivatives of hydroxyprimidines as leukotriene synthesis inhibitors |
| US5270319A (en) * | 1991-09-09 | 1993-12-14 | Warner-Lambert Company | 5-hydroxy-2-pyrimidinylmethylene derivatives useful as antiinflammatory agents |
| US5220025A (en) * | 1992-02-24 | 1993-06-15 | Warner-Lambert Company | 2-substituted amino-4, 6-di-tertiary-butyl-5-hydroxy-1, 3-pyrimidines as antiinflammatory agents |
| US5196431A (en) * | 1992-02-24 | 1993-03-23 | Warner-Lambert Company | 2-substituted amino-4, 6-di-tertiary-buthyl-5-hydroxy-1, 3-pyrimidines as antiinflammatory agents |
| US9133212B1 (en) * | 2005-06-15 | 2015-09-15 | Vanderbilt University | Inhibitors of hemeprotein-catalyzed lipid peroxidation |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB741667A (en) * | 1952-12-05 | 1955-12-07 | Ici Ltd | New pyrimidine derivatives |
| GB756189A (en) * | 1954-02-01 | 1956-08-29 | Ici Ltd | New pyrimidine derivatives |
| ZA711152B (en) * | 1970-03-02 | 1971-11-24 | Ici Ltd | Manufacture of pyrimidines |
| GB1525995A (en) * | 1976-02-18 | 1978-09-27 | Soc D Etudes Prod Chimique | Aminopyrimidine salt |
-
1980
- 1980-02-12 IN IN103/DEL/80A patent/IN153791B/en unknown
- 1980-02-15 BE BE0/199421A patent/BE881752A/fr not_active IP Right Cessation
- 1980-02-20 NZ NZ192927A patent/NZ192927A/xx unknown
- 1980-02-20 LU LU82185A patent/LU82185A1/fr unknown
- 1980-02-26 FI FI800566A patent/FI66357C/fi not_active IP Right Cessation
- 1980-02-27 AR AR280106A patent/AR222691A1/es active
- 1980-02-29 PT PT70882A patent/PT70882A/pt unknown
- 1980-03-03 CH CH165080A patent/CH644368A5/fr not_active IP Right Cessation
- 1980-03-04 CA CA346,981A patent/CA1132561A/en not_active Expired
- 1980-03-04 NL NLAANVRAGE8001289,A patent/NL184833C/xx not_active IP Right Cessation
- 1980-03-07 GB GB8007908A patent/GB2045756B/en not_active Expired
- 1980-03-07 NO NO800664A patent/NO154054C/no unknown
- 1980-03-07 IE IE477/80A patent/IE49547B1/en unknown
- 1980-03-07 AU AU56248/80A patent/AU533547B2/en not_active Ceased
- 1980-03-07 SE SE8001812A patent/SE435180B/sv not_active IP Right Cessation
- 1980-03-09 EG EG131/80A patent/EG14282A/xx active
- 1980-03-10 FR FR8005277A patent/FR2451191A1/fr active Granted
- 1980-03-10 MX MX808702U patent/MX6218E/es unknown
- 1980-03-10 OA OA57049A patent/OA06484A/xx unknown
- 1980-03-10 FR FR8005278A patent/FR2451370A1/fr active Granted
- 1980-03-10 DE DE3009071A patent/DE3009071C2/de not_active Expired
- 1980-03-10 DE DE3050999A patent/DE3050999C2/de not_active Expired
- 1980-03-10 JP JP2931280A patent/JPS55122768A/ja active Granted
- 1980-04-30 DE DE19803016752 patent/DE3016752A1/de active Granted
-
1983
- 1983-04-28 SG SG226/83A patent/SG22683G/en unknown
- 1983-11-17 HK HK553/83A patent/HK55383A/xx unknown
-
1984
- 1984-12-30 MY MY200/84A patent/MY8400200A/xx unknown
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