NO802099L - Dihydronikotinsyre-derivater og deres fremstilling - Google Patents
Dihydronikotinsyre-derivater og deres fremstillingInfo
- Publication number
- NO802099L NO802099L NO802099A NO802099A NO802099L NO 802099 L NO802099 L NO 802099L NO 802099 A NO802099 A NO 802099A NO 802099 A NO802099 A NO 802099A NO 802099 L NO802099 L NO 802099L
- Authority
- NO
- Norway
- Prior art keywords
- naphthyl
- acid
- ethyl
- formula
- oxo
- Prior art date
Links
- 239000002253 acid Substances 0.000 title claims description 6
- 238000002360 preparation method Methods 0.000 title claims 2
- 150000001875 compounds Chemical class 0.000 claims description 9
- 150000002148 esters Chemical class 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 239000007858 starting material Substances 0.000 claims description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- 150000001340 alkali metals Chemical group 0.000 claims description 4
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 4
- 150000001342 alkaline earth metals Chemical group 0.000 claims description 4
- 150000003863 ammonium salts Chemical class 0.000 claims description 4
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 4
- IBRPASKYXURDBT-UHFFFAOYSA-N methyl 1-ethyl-6-naphthalen-2-yl-4-oxopyridine-3-carboxylate Chemical compound CCN1C=C(C(=O)OC)C(=O)C=C1C1=CC=C(C=CC=C2)C2=C1 IBRPASKYXURDBT-UHFFFAOYSA-N 0.000 claims description 3
- SSHRVPMSFQLCAG-UHFFFAOYSA-N 1,2,3,4-tetrahydropyridine-5-carboxylic acid Chemical compound OC(=O)C1=CNCCC1 SSHRVPMSFQLCAG-UHFFFAOYSA-N 0.000 claims description 2
- FHDQRDHNKMTDLF-UHFFFAOYSA-N 1-ethyl-6-naphthalen-2-yl-4-oxopyridine-3-carboxylic acid Chemical compound CCN1C=C(C(O)=O)C(=O)C=C1C1=CC=C(C=CC=C2)C2=C1 FHDQRDHNKMTDLF-UHFFFAOYSA-N 0.000 claims description 2
- 150000004702 methyl esters Chemical class 0.000 claims description 2
- HVXLOOZTCQBPFZ-UHFFFAOYSA-N methyl 1-ethyl-2-naphthalen-2-yl-4-oxo-2,3-dihydropyridine-5-carboxylate Chemical compound CCN1C=C(C(=O)OC)C(=O)CC1C1=CC=C(C=CC=C2)C2=C1 HVXLOOZTCQBPFZ-UHFFFAOYSA-N 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 239000013078 crystal Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 239000003921 oil Substances 0.000 description 4
- 235000019198 oils Nutrition 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- UGNWTBMOAKPKBL-UHFFFAOYSA-N tetrachloro-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(Cl)=C(Cl)C1=O UGNWTBMOAKPKBL-UHFFFAOYSA-N 0.000 description 3
- 150000004057 1,4-benzoquinones Chemical class 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Chemical compound 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
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000012876 carrier material Substances 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 235000011121 sodium hydroxide Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 description 1
- OPSXYAFWJPPHQK-UHFFFAOYSA-N 1,2,3,6-tetrahydropyridine-3-carboxylic acid Chemical class OC(=O)C1CNCC=C1 OPSXYAFWJPPHQK-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- SQAINHDHICKHLX-UHFFFAOYSA-N 1-naphthaldehyde Chemical compound C1=CC=C2C(C=O)=CC=CC2=C1 SQAINHDHICKHLX-UHFFFAOYSA-N 0.000 description 1
- HXIPLHBIHBQWGY-UHFFFAOYSA-N 2,3-dihydropyridine-3-carboxylic acid Chemical compound OC(=O)C1CN=CC=C1 HXIPLHBIHBQWGY-UHFFFAOYSA-N 0.000 description 1
- PJKVFARRVXDXAD-UHFFFAOYSA-N 2-naphthaldehyde Chemical compound C1=CC=CC2=CC(C=O)=CC=C21 PJKVFARRVXDXAD-UHFFFAOYSA-N 0.000 description 1
- KHWGRLRCZSYJNT-UHFFFAOYSA-N 2-oxo-3h-pyridine-3-carboxylic acid Chemical compound OC(=O)C1C=CC=NC1=O KHWGRLRCZSYJNT-UHFFFAOYSA-N 0.000 description 1
- RNKGDBXXIBUOTR-UHFFFAOYSA-N 3,6-dioxocyclohexa-1,4-diene-1-carbonitrile Chemical compound O=C1C=CC(=O)C(C#N)=C1 RNKGDBXXIBUOTR-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 1
- 241000978776 Senegalia senegal Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 230000002378 acidificating effect Effects 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
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 229960000632 dexamfetamine Drugs 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 235000019439 ethyl acetate Nutrition 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors 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
- 239000000543 intermediate Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- MIBDLWXWTGGZCY-UHFFFAOYSA-N methyl 3-methoxy-5-naphthalen-2-ylpenta-2,4-dienoate Chemical compound C1=CC=CC2=CC(C=CC(OC)=CC(=O)OC)=CC=C21 MIBDLWXWTGGZCY-UHFFFAOYSA-N 0.000 description 1
- WGASDMQEZHXQJP-UHFFFAOYSA-N methyl 5-naphthalen-2-yl-3-oxopent-4-enoate Chemical compound C1=CC=CC2=CC(C=CC(=O)CC(=O)OC)=CC=C21 WGASDMQEZHXQJP-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- XXPANQJNYNUNES-UHFFFAOYSA-N nomifensine Chemical compound C12=CC=CC(N)=C2CN(C)CC1C1=CC=CC=C1 XXPANQJNYNUNES-UHFFFAOYSA-N 0.000 description 1
- 229960001073 nomifensine Drugs 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 229950000193 oteracil Drugs 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/08—Preparation by ring-closure
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
-
- 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, ***e
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Neurosurgery (AREA)
- Life Sciences & Earth Sciences (AREA)
- Neurology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Psychiatry (AREA)
- Pharmacology & Pharmacy (AREA)
- Biomedical Technology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Hydrogenated Pyridines (AREA)
Description
Foreliggende oppfinnelse vedrører dihydronikotinsyre-
<1>i lerivater, spesielt den nye 1-etyl-l, 4-dihydro-6-(2-naf tyl) -
i i i i-oxonikcrtinsyre og estere derav med formel j I j
hvori R er hydrogen eller C^_g-alkyl, hhv. alkalimetall-, jordalkalimetall- og (evt. substituerte) ammoniumsalter derav og en fremgangsmåte til fremstilling og anvendelse derav.
Som C-^_g-alkylrester kommer rettkjedede eller forgrenede rester så som metyl, etyl, propyl, isopropyl eller tert.-!butyl på tale.
;Forbindelsen ifølge oppfinnelsen kan fremstilles ved at man
.dehydrogenerer den tilsvarende 1,4,5,6-tetrahydronikotin-'syre, hhv. ester derav med formel '. I L
I
i ,hvori R har den ovenfor angitte betydning, i 5,6-stilling
og om ønsket overfører den erholdte syre i et alkalimetall, jordalkalimetall eller (evt. substituert) ammoniumsalt eller i for estere med C, , alkanol, hhv. forsåper den erholdte i l i I • ..
S metylester. , i i •
i ' •
i Dehydrogeneringen av en forbindelse II ifølge oppfinnelsen i kan skje ved i og for seg kjente metoder, hensiktsmessig, med et substitiuert benzokinon, så som 2,3-diklor-5,6-di-I cyan-1,4-benzokinon (DDQ) eller tetraklor-1,4 benzokinonj I (kloranil) i et inert organisk løsningsmiddel så som mety-j lenklorid, benzen eller dioksan, og innenfor et temperatur- . I område fra romtemperatur til reaksjonsblandingens tilbake-, løpstemperatur. I alminnelighet tildrypper mån løsningen 1 av tetrahydronikotinsyrederivat en løsning av det substitu- : erte benzokinon idet man passer på at ekvimolare mengder;-. .'omsettes. Ved ufarget utgangsmateriale er slutten av I reaksjonen lett å se p.g.a. fargingen av reaksjonsblandihgen ' som opptrer. Reaksjonsproduktet kan isoleres på vanlig måte i ifra blandingen og f.eks. renses ved omkrystallisering eller. I kromatografiske metoder.
i
I
Både foresteringen av en forbindelse I med R = hydrogen og overføringen derav i saltene h.h.v. forsåpningen av en :forbindelse I med R = metyl til syre skjer på i og for seg
i kjent måte. •Utgangsforbindelsen med formel II kan fremstilles etter det følgende reaksjonsskjema fra 2-naftylaldehyd.
i
'Mellomproduktene med den generelle formel II og III er som jlikeledes nye forbindelser gjenstand for foreliggende opp-j f inne Ise'.
iFbrbindelsere med formel I er farmakologisk aktive.
De har særlig en stimulerende virkning på sentralnerve- 1 systemet idet de utmerker seg ved lav akutt toksisitet, :Således er f.eks. 1-etyl-l,4-dihydro-6-(2-naftyl)—4- '<1>oxonikotinsyre ved omtrent samme ld5q/virkningsmessig vesentlig bedre enn nomi-fensin, mens den adskiller seg for-I delaktig ved omtrent like sterk virkning ved d-amfetamin' ij gjennom den vesentlig lavere IA^q (se tabell I) . De ifølge forbindelsen fremstilte forbindelser med formel ; I kan derfor anvendes til å stimulere sentralnervesystemet , i form av farmasøytiske preparater med direkte eller for-! sinket frigjøring av virkestoffet i blanding med et jorganisk eller uorganisk inert bæremateriale som er egnet ;for'oral eller parenteral applikasjon, f.eks., vann, !,gelatin, gummi arabicum, melkesukker, stivelse, magnesium-stearat, talkum, planteholdige oljer, polyalkylenglykoler, ! vaseliner osv. De farmasøytiske preparatene kan foreligge
i fast form, f. eks. som tabletter, drageer, suppositorer, kapsler; i halvfast form, f.eks. som salver eller i flyt-ende form; f.eks. som . løsninger, suspensjoner eller emul-: sjoner.Eventuelt er de sterilisert og hhv./eller inneholder<1>jytterligere hjelpestoffer så som konserverings-, stabili-
sering, fukte- eller emulgeringsmidler, midler for smaksfor-bedring, ..salter for forandring av det osmotiske trykk eller puffersubstanser.
I
Fremstillingen av de farmasøytiske preparater kan gjøres
på enhver vanlig måte for en fagmann, nemlig ved at man < blander den virksomme substans med et égnet ikke-toksint-inert bæremateriale for terapeutisk administrering og bringer den erholdte blanding i .den egnede galeniske form.
i Som doseringsretningslinje kan man for forbindelsen ifølge oppfinnelsen sette en mengde på 100 ug-10 mg/kg kroppsvekt pr. dag.
EKSEMPLER
i
Eksempel 1
1 ■ !
I 1
! 12 g (38,8 mMol) metyl-2-[(etylamino)-metylen]-5-(2-naftyl)- il3-oxo-4-pentenoat ble oppløst i 100 ml dimetylformamid
;og rørt 4 timer ved 150°C. Etter fordampning av løsningsmid-delet under høyvakuum ved 60°C fikk man 12 g av en mørkerød seig olje som ble løst i 60 ml toluen. Mån oppvarmet ved ! tilbakeløp og lot en oppslemming av 10,6 g (42,6 mMol)
kloranil i 5.0 ml toluen langsomt dryppe til. Den erholdte reaksjonsblanding ble tilsatt eddikester og rystet ut 3 g
med iskald 3N saltsyre. De sure ekstraktene ble under kjøling bragt til pH 6 med 4N natronlut og ekstrahert 3 g med metylenklorid. De organiske ekstraktene ble vasket med mettet koksaltløsning, tørket over natriumsulfat og inndampet.
Man fikk 10 g av en brunaktig olje som krystalliserte fra eter/metanol og ga 8,7 g (73%) 1-etyl-l,4-dihydro-6-(2-naftyl) -4-oxonikotinsyremetylester, F. 138-139°C (fargeløs krystall).
3,8 g 1-etyl-l,4-dihydro-6-(2-naftyl)-4-oxonikotinsyremetyl-ester ble løst i 10 ml metanol og blandet med 20 ml- IN. natronlut. Etter 15 min. røring ved romtemperatur ble reaksjonsblandingen ekstrahert to ganger med eddikkester og den vandige fase nøytralisert under kjøling med IN saltsyre. Den derved dan-, nede frie syre ble frafiltrert, vasket med vann og eter og omkrystallisert fra etanol/metylenklorid. Man fikk 3,1 g (85,5%) 1-etyl-l,4-dihydro-6-(2-naftyl)-4-oxonikotinsyre.
i form fargeløs krystall, F. 209-210°C.
i ' ■
Utgangsmaterialene ble fremstilt på følgende måte:
Til en løsning av 25 g (0,16 Mol) 1-naf'tyl-aldehyd og
78. g (0,165 Mol) 2-metoxy-3-(metoxy-carbonyl)-allyltrifenyl-fosfoniumbromid i 300 ml metylenklorid dryppet man under røring ved romtemperatur 84 ml 50%ig natronlut. Etter 3'timers røring ved romtemperatur og 1.times føring ved 40° C ble fasen adskilt. Den vandige fasen ble ekstrahert to ganger'med i ! metylenklorid og de samlede organiske faser ble vasket ■ .i.
1 nøytrale med vann. Etter tørking over natriumsulfat ved ! i inndampn~ing av, løsningsmiddelet fikk man en viskoseaktig, i lys gul olje, som.delvis krystalliserte. Blandingen ble ; revet med eter/eddikkester, inndampet og omkrystallisert<;>: fra metanol. Man fikk 29,4 g (68,5%) metyl-3-metoxy-5-(2-I naftyl)-2,4-pentadienoat i form fargeløs krystall, F.94-'
;En løsning av 23,5 g (87,7 mMol) metyl-3-metoxy-5-(2-naftyl)-2,4-pentadienoat i 500 ml metanol ble blandet med 50 ml konsentrert saltsyre. Etter ca. 3 min. røring ved rom-!temperatur falt et hvitt, krystallinsk produkt ut, som ble
.filtrert fra, vasket med kaldt vann og løst i metylenklorid. Den organiske fasen ble rystet ut 2 ganger med iskaldt, ' mettet natriumbikarbonat-løsning, tørket over natriumsulfat . ,og inndampet. Etter omkrystallisering av'den krystallinske
rest fra metanol, fikk man 20,8 g(93%) metyl-5-(2-naftyl)-'-3-oxo-4-pentenoat i form fargeløse krystaller, F. 86-87°C.
i 9 g (35,4 mMol) metyl-5-(2-naftyl)-3-oxo-4-pentenoat og
.4,7 g (39 mMol) . dimetylformamid-dimetylacetal ble løst i
100 ml toluen og rørt 22 timer ved 60°C. Etter avkjøling ble reaksjonsblandingen inndampet. Man fikk ca. 10 g av en
• mørkerød, seig olje, som ble blandet med en løsning av 100 g etylamin ill toluen. Reaksjonsblandingen ble rørt .20 timer ved romtemperatur, inndampet og råproduktet renset ■ved søylekromatografi [kieselgel, metylenklorid/metanol i(19:1, v/v)]. Etter omkrystallisering fra eter/pentan
■fikk man 6,0 g (55 %) metyl-2-[(etylamino)-metylen]-5-1(2-naftyl)-3-oxo-4-pentenoat i form av lett gulaktig krystall, F. 80-82°). Eksempel 2
Tabletter ble fremstilt på 120 mg hhv. 500 mg på i og for
: seg kjent måte, inneholdende: i
Claims (5)
1. Fremgangsmåte ved fremstilling av 1-etyl-l,4-di-' hydro-6-(2-naftyl)-4-oxonikotinsyre og estere derav , med formel
hvori R er hydrogen eller C^ _g-alkyl, hhv. alkalimetal-, jordalkalimetall- og (evt. substituerte)■ammoniumsalter derav, karakterisert ved at man dehydrogenerer den tilsvarende 1,4,5,6-tetrahydronikotinsyre, hhv. ester derav med formel
hvori R har den ovenfor angitte betydning, i 5 ,.6-stilling, og om ønsket overfører den erholdte forbindelse i ét alkalimetall,. jordalkalimetall eller (evt. substituert) ammoniumsalt eller for estere med en C-L_g-alkanol, hhv. forsåper
en erholdt metylester.
2. Fremgangsmåte ifølge krav 1 ved fremstilling av i 1-etyl-l,4-dihydro-6-(2-naftyl)-4-oxonikotinsyre k.a r a k-
terisertved at man velger tilsvarende substituert utgangsmateriale..
i
3. Fremgangsmåte ifølge krav 1 ved fremstilling av 1-etyl-l,4-dihydro-6-(2-naftyl)-4-oxonikotinsyremetyl-ester karakterisert ved at man velger til- . svarende substituerte utgangsmate.rialer.
4. Fremgangsmåte ved fremstilling av farmasøytiske [ preparater, karakterisert ved at man på i og for seg kjent måte bringer en forbindelse med formel
hvor R er hydrogen eller C^ _g-alkyl i en galenisk admini-streringsform.
5. l-e ty 1-6 - (2-naf tyl) -4-oxo-l, 4 , 5 , 6-rtetrahydronikotin-syre og estere derav med formel
■ karakterisert ved at R er hydrogen eller C^ g-alkyl.
,6. l-etyl-6-(2-naftyl)-4-oxo-l,4,5,6-tetrahydronikotin-! syre. j
!
■ 7. l-etyl-6-(2-haftyl)-4-oxo-l,4,5,6-tetrahydroniko-: tinsyremetylester.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH655579 | 1979-07-13 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO802099L true NO802099L (no) | 1981-01-14 |
Family
ID=4311435
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO802099A NO802099L (no) | 1979-07-13 | 1980-07-11 | Dihydronikotinsyre-derivater og deres fremstilling |
Country Status (21)
| Country | Link |
|---|---|
| US (1) | US4278798A (no) |
| EP (1) | EP0023593B1 (no) |
| JP (1) | JPS5615269A (no) |
| KR (1) | KR840001034B1 (no) |
| AR (1) | AR225447A1 (no) |
| AT (1) | ATE2520T1 (no) |
| AU (1) | AU537900B2 (no) |
| CA (1) | CA1125762A (no) |
| DE (1) | DE3062022D1 (no) |
| DK (1) | DK148082B (no) |
| ES (1) | ES8105712A1 (no) |
| FI (1) | FI802097A (no) |
| GR (1) | GR69304B (no) |
| HU (1) | HU180589B (no) |
| IL (1) | IL60513A (no) |
| MC (1) | MC1335A1 (no) |
| NO (1) | NO802099L (no) |
| NZ (1) | NZ194258A (no) |
| PH (1) | PH16046A (no) |
| PT (1) | PT71542B (no) |
| ZA (1) | ZA804079B (no) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1110234A (en) * | 1978-01-18 | 1981-10-06 | Hoffmann-La Roche Limited | 4-pyridone-3-carboxylic acids and process for the preparation thereof |
| US4649157A (en) * | 1986-03-28 | 1987-03-10 | G. D. Searle & Co. | Pharmaceutical compositions containing 5-phenyl-1,3-dioxoalkenyl compounds |
| US9988373B2 (en) | 2013-12-26 | 2018-06-05 | Shionogi & Co., Ltd. | Nitrogen-containing six-membered cyclic derivatives and pharmaceutical composition comprising the same |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4051142A (en) * | 1976-05-24 | 1977-09-27 | Rohm And Haas Company | 1-Aryl-4-pyridones |
| EP0001041A3 (en) * | 1977-07-27 | 1979-06-27 | Sandoz Ag | Alpha(pyridonecarboxylamino)-alpha substituted acetamido penicillins and -cephalosporins, process for their preparation, their use in pharmaceuticals; pyridones used in the process |
| CA1110234A (en) * | 1978-01-18 | 1981-10-06 | Hoffmann-La Roche Limited | 4-pyridone-3-carboxylic acids and process for the preparation thereof |
-
1980
- 1980-06-09 CA CA353,626A patent/CA1125762A/en not_active Expired
- 1980-06-11 MC MC801452A patent/MC1335A1/xx unknown
- 1980-07-01 FI FI802097A patent/FI802097A/fi not_active Application Discontinuation
- 1980-07-02 DK DK287080AA patent/DK148082B/da unknown
- 1980-07-07 US US06/166,506 patent/US4278798A/en not_active Expired - Lifetime
- 1980-07-07 AU AU60153/80A patent/AU537900B2/en not_active Ceased
- 1980-07-07 NZ NZ194258A patent/NZ194258A/en unknown
- 1980-07-07 IL IL60513A patent/IL60513A/xx unknown
- 1980-07-07 HU HU80801689A patent/HU180589B/hu unknown
- 1980-07-07 AR AR281682A patent/AR225447A1/es active
- 1980-07-07 ZA ZA00804079A patent/ZA804079B/xx unknown
- 1980-07-08 EP EP80103895A patent/EP0023593B1/de not_active Expired
- 1980-07-08 AT AT80103895T patent/ATE2520T1/de not_active IP Right Cessation
- 1980-07-08 DE DE8080103895T patent/DE3062022D1/de not_active Expired
- 1980-07-09 PH PH24260A patent/PH16046A/en unknown
- 1980-07-11 GR GR62435A patent/GR69304B/el unknown
- 1980-07-11 JP JP9410780A patent/JPS5615269A/ja active Pending
- 1980-07-11 NO NO802099A patent/NO802099L/no unknown
- 1980-07-11 PT PT71542A patent/PT71542B/pt unknown
- 1980-07-12 KR KR1019800002785A patent/KR840001034B1/ko active
- 1980-07-12 ES ES493355A patent/ES8105712A1/es not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| DK287080A (da) | 1981-01-14 |
| AU537900B2 (en) | 1984-07-19 |
| EP0023593B1 (de) | 1983-02-16 |
| CA1125762A (en) | 1982-06-15 |
| US4278798A (en) | 1981-07-14 |
| ZA804079B (en) | 1981-07-29 |
| KR830003423A (ko) | 1983-06-20 |
| ES493355A0 (es) | 1981-06-16 |
| HU180589B (en) | 1983-03-28 |
| ATE2520T1 (de) | 1983-03-15 |
| JPS5615269A (en) | 1981-02-14 |
| FI802097A (fi) | 1981-01-14 |
| IL60513A (en) | 1983-10-31 |
| DK148082B (da) | 1985-02-25 |
| PH16046A (en) | 1983-06-02 |
| GR69304B (no) | 1982-05-14 |
| NZ194258A (en) | 1984-07-06 |
| KR840001034B1 (ko) | 1984-07-26 |
| PT71542A (en) | 1980-08-01 |
| DE3062022D1 (en) | 1983-03-24 |
| MC1335A1 (fr) | 1981-04-21 |
| EP0023593A1 (de) | 1981-02-11 |
| AU6015380A (en) | 1981-01-15 |
| ES8105712A1 (es) | 1981-06-16 |
| IL60513A0 (en) | 1980-09-16 |
| AR225447A1 (es) | 1982-03-31 |
| PT71542B (en) | 1981-12-14 |
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