DK164551B - Analogifremgangsmaade til fremstilling af cyclohexylthienyleddikesyreamider eller fysiologisk taalelige syreadditionssalte deraf - Google Patents
Analogifremgangsmaade til fremstilling af cyclohexylthienyleddikesyreamider eller fysiologisk taalelige syreadditionssalte deraf Download PDFInfo
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- DK164551B DK164551B DK540283A DK540283A DK164551B DK 164551 B DK164551 B DK 164551B DK 540283 A DK540283 A DK 540283A DK 540283 A DK540283 A DK 540283A DK 164551 B DK164551 B DK 164551B
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- 239000002253 acid Substances 0.000 title claims description 12
- 150000003839 salts Chemical class 0.000 title claims description 10
- 238000000034 method Methods 0.000 title claims description 7
- 238000002360 preparation method Methods 0.000 title claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 22
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 3
- SSJXIUAHEKJCMH-PHDIDXHHSA-N (1r,2r)-cyclohexane-1,2-diamine Chemical compound N[C@@H]1CCCC[C@H]1N SSJXIUAHEKJCMH-PHDIDXHHSA-N 0.000 claims description 2
- ZFHHWBGMOJTMJE-UHFFFAOYSA-N 2-cyclohexyl-2-thiophen-2-ylacetamide Chemical class C=1C=CSC=1C(C(=O)N)C1CCCCC1 ZFHHWBGMOJTMJE-UHFFFAOYSA-N 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- 125000003386 piperidinyl group Chemical group 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 230000000202 analgesic effect Effects 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- -1 thienyl acetic acid halides Chemical class 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- SMXNAOMXZBNZEW-UHFFFAOYSA-N 2-(4,5-dichlorothiophen-2-yl)acetyl chloride Chemical compound ClC(=O)CC1=CC(Cl)=C(Cl)S1 SMXNAOMXZBNZEW-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 238000006243 chemical reaction Methods 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
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- MFOLKXSQEXMDIR-GHMZBOCLSA-N (1r,2r)-n-methyl-2-pyrrolidin-1-ylcyclohexan-1-amine Chemical compound CN[C@@H]1CCCC[C@H]1N1CCCC1 MFOLKXSQEXMDIR-GHMZBOCLSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ZUFILLMSKFKEIJ-DTPOWOMPSA-N 2-(2,5-dichlorothiophen-3-yl)-n-methyl-n-[(1r,2r)-2-pyrrolidin-1-ylcyclohexyl]acetamide;hydrochloride Chemical compound Cl.N1([C@@H]2CCCC[C@H]2N(C)C(=O)CC2=C(SC(Cl)=C2)Cl)CCCC1 ZUFILLMSKFKEIJ-DTPOWOMPSA-N 0.000 description 1
- SZEPILCUVAREGH-CTHHTMFSSA-N 2-(4,5-dichlorothiophen-2-yl)-n-methyl-n-[(1r,2r)-2-pyrrolidin-1-ylcyclohexyl]acetamide;hydrochloride Chemical compound Cl.N1([C@@H]2CCCC[C@H]2N(C)C(=O)CC=2SC(Cl)=C(Cl)C=2)CCCC1 SZEPILCUVAREGH-CTHHTMFSSA-N 0.000 description 1
- DMOVDEYAPGHEDZ-UHFFFAOYSA-N 2-(4,5-dichlorothiophen-2-yl)acetic acid Chemical compound OC(=O)CC1=CC(Cl)=C(Cl)S1 DMOVDEYAPGHEDZ-UHFFFAOYSA-N 0.000 description 1
- CPQYTHDVUNKJHX-CTHHTMFSSA-N 2-(5-chlorothiophen-2-yl)-n-methyl-n-[(1r,2r)-2-pyrrolidin-1-ylcyclohexyl]acetamide;hydrochloride Chemical compound Cl.N1([C@@H]2CCCC[C@H]2N(C)C(=O)CC=2SC(Cl)=CC=2)CCCC1 CPQYTHDVUNKJHX-CTHHTMFSSA-N 0.000 description 1
- VRBZTHJEGQLBPJ-UHFFFAOYSA-N 2-(5-chlorothiophen-2-yl)acetyl chloride Chemical compound ClC(=O)CC1=CC=C(Cl)S1 VRBZTHJEGQLBPJ-UHFFFAOYSA-N 0.000 description 1
- PXRKCOCTEMYUEG-UHFFFAOYSA-N 5-aminoisoindole-1,3-dione Chemical compound NC1=CC=C2C(=O)NC(=O)C2=C1 PXRKCOCTEMYUEG-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229910010082 LiAlH Inorganic materials 0.000 description 1
- 206010026749 Mania Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical class O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 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
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical class OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 206010042618 Surgical procedure repeated Diseases 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 238000010640 amide synthesis reaction Methods 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 150000001559 benzoic acids Chemical class 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000006742 locomotor activity Effects 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 229940127240 opiate Drugs 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical class OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- QERYCTSHXKAMIS-UHFFFAOYSA-N thiophene-2-carboxylic acid Chemical class OC(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-N 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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
- C07D333/28—Halogen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Pain & Pain Management (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
Description
DK 164551 B
i
Opfindelsen angår en analogifremgangsmåde til fremstilling af hidtil ukendte terapeutisk værdifulde cyclohexyl-thienyleddikesyreamider med den i krav 1 angivne almene formel I, hvori R betegner alkyl med 1-3 carbonatomer, 5 og R2 betegner sammen med det nitrogenatom, hvortil de er bundet, en pyrrolidin- eller piperidinring, og X og Y betegner uafhængigt af hinanden hydrogen, chlor eller brom, eller farmaceutisk acceptable syreadditionssalte deraf.
10 De hidtil ukendte forbindelser med formlen I udviser i forskellige dyreforsøg stærke analgetiske egenskaber uden at forårsage fysisk afhængighed (mani). De egner sig derfor fremragende til langtidsbehandling af forskellige smertetilstande.
15
Fra DE-A-2 749 950 og J. Med. Chem. Bind 25, nr. 10, side 1125-1126 kendes forbindelser med lignende struktur og med analgetisk virkning, hvilke forbindelser dog har en phenylring i stedet for en thienylring. Det har nu over-20 raskende vist sig, at man ved erstatning af phenylringen med en thienylring opnår forbindelser, som har en lavere toxicitet og samtidig en kraftigere analgetisk virkning, og at disse forbindelser ikke fører til afhængighed ved længere tids indtagelse.
25
Fremgangsmåden ifølge opfindelsen er kendetegnet ved, at man omsætter en forbindelse med den i krav 1 angivne almene formel II, hvori X og Y har den i det foregående angivne betydning, og Z betegner chlor eller brom, med en 30 trans-cyclohexan-l,2-diamin med den i krav 1 angivne almene formel III, hvori R, R^ og R£ har den tidligere angivne betydning og eventuelt overfører opnåede forbindelser med formlen I i farmaceutisk acceptable syreadditionssalte deraf.
Syreamiddannelsen udføres på sædvanlig måde i et reaktionsinert opløsningsmiddel, som f.eks. chloroform, me- 35
DK 164551 B
2 thylenchlorid, ether eller dioxan. Man går således bedst frem ved, at man tager aminen med formlen III, fortrinsvis sammen med mindst ækvimolære mængder af et let flygtigt, stærkt basisk syreopfangende stof, som f.eks. tri-5 ethylamin, og tildrypper syrechloridet med formlen II, fortyndet med det anvendte opløsningsmiddel, i ækvimolære mængder, eller fortrinsvis i et ringe overskud ved en temperatur på ca. 20 °C. Reaktionen er ved denne temperatur forlængst fuldstændig efter 18 timers forløb.
10
Til oparbejdning rystes reaktionsblandingen med mættet natriumbicarbonatopløsning, den organiske fase fraskilles, tørres og inddampes. Ved ekstraktion af resten med kogende ether og filtrering over aktivt carbon opnår man 15 den rå, olieagtige base med formlen I, som man til yderligere rensning kan søjlechromatografere (f.eks. på sili-cagel med benzen/triethylamin 9:1 som elueringsmiddel) eller kan overføre i krystallinske, farmaceutisk tålelige syreadditionssalte, f.eks. hydrochlorider, som derpå kan 20 renses ved omkrystallisering.
Dertil opløser man den rå base med formlen I i et egnet opløsningsmiddel, f.eks. en lavere alkohol eller vand, tilsætter et ækvivalent protonsyre, afdamper opløsnings-25 midlet i vakuum og krystalliserer resten af methanol, eventuelt under tilsætning af ether, eller man opløser den rå frie base med formlen I i ether eller benzen, udfælder syreadditionssaltene ved tilsætning af den tilsvarende protonsyre og omkrystalliserer som angivet i det 30 foregående. Egnede eksempler på sådanne farmaceutisk tålelige salte er foruden saltet af saltsyre saltet af svovlsyre, saltet af salpetersyre, saltet af phosphorsy-re, salte af sulfonsyrer, saltet åf benzoesyre, saltet af ravsyre, saltet af maleinsyre, saltet af vinsyre og sal-35 tet af citronsyre.
3
DK 164551 B
De ved fremgangsmåden ifølge opfindelsen fremstillede syreadditionssalte har en lige så stor analgetisk virkning som de tilsvarende frie baser med formel I.
5 Forbindelserne med formlen III er kendt i litteraturen. Thienyleddikesyrehalogeniderne med formlen II kan man, såfremt de ikke er kendt i litteraturen, opnå ud fra de tilsvarende thienyleddikesyrer med formlen X på en for fagmanden nærliggende måde, f.eks. ved opvarmning i over-10 skud af thionylchlorid eller -bromid.
For så vidt thienyleddikesyrerne ikke er kendt i litteraturen, kan man fremstille dem ud fra i litteraturen kendte thiophencarboxylsyrer med formlen IV på følgende for 15 fagmanden indlysende syntesemåde: x i.sxi2 x li--1 2.æ3OH r—j—j| LiAlH, r——n
Y—-j — C00H->Y—j- -jpC00CH3-»Y jf- -Jr^OH
20 >s^ (IV) CV) (VI) I HBr X X φ
X
li--Π 1.i£l/CH30H-- KCN π-1—u (IX) / (VIII) (VII)
/ NaOH
r —a SOZo 30 y—J- 1 4-CH2-OOOH----> (n) (X) 35
DK 164551 B
4
Her har X og Y og Z den i det foregående angivne betydning.
Det efterfølgende eksempel forklarer opfindelsen nærmere.
5
EKSEMPEL
Trans-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-4,5-di-chlor-2-thienyleddikesyreamid-hydrochlorid 10 (Formel I, R = CH3, -NR^ = N^),X=4-C1, Y-5-C1) [LG-83-8-01]
En opløsning af 1,61 g (7,01 mmol) 4,5-dichlor-2-thienyl-15 eddikesyrechlorid (formel II, X = 4-C1, Y = 5-C1, Z = Cl) i 15 ml absolut chloroform dryppes i løbet af 15 minutter til en opløsning af 1,24 g (6,80 mmol) trans-N-methyl-2-(1-pyrrolidinyl)-cyclohexylamin (formel III, R = methyl, 20 -Nrir2 = -O ) og 0,69 g (6,80 mmol) triethylamin i 60 ml absolut chloroform ved stuetemperatur, hvorpå der -yderligere omrøres 18 timer ved stuetemperatur. Derpå ud-rystes reaktionsblandingen med mættet natriumhydrogencar-bonatopløsning, den organiske fase vaskes med vand, 25 tørres over natriumsulfat og inddampes. Den olieagtige rest, der består af den rå base med formlen I og en smule etheruopløseligt biprodukt, optages i 30 ml ether, filtreres over aktivt carbon, og i opløsningen indledes HC1-gas. Det krystallinske hydrochlorid, der udfælder, frasu-30 ges, opløses i 4 ml methanol, udfældes med 50 ml fugtig ether, frasuges, og proceduren gentages endnu en gang. De farveløse krystaller tørres ved 13,3 Pa og stuetemperatur i 5 timer. På denne måde opnår man det ikke-hygroskopiske hemihydrat af hydrochloridet. Udbytte: 57%, Kp. 216-218 35 °C. Den forbindelse, der er fri for krystalvand, som man opnår ved tørring i vakuum ved 13,3 Pa og 140 °C, er hygroskopisk.
5
DK 164551 B
Analogt fremstilledes: trans-N-methyl-N-[2-(1-pyrrolidiny1)-cyclohexyl ]-5-chlor- 2-thienyleddikesyreamid-hydrochlorid, formel I, R = CH^, 5 -NR1R2 = -NØ , X = Η, Y = 5-C1), kp. (methanol/ether): 175-178 °C (60%), krystalvandfri forbindelse, farveløse krystaller, ikke hygroskopisk.
10 trans-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-2,5-di- chlor-3-thienyleddikesyreamid-hydrochlorid (formel I) R = CH3, -NR1R2 = -NØ , X = 2-Cl, Y = 5-C1, [LG-83-8-02], kp. (methanol/ether): 252-254 °C (55%), krysitalvandfri forbindelse, farveløse krystaller, ikke hygroskopisk.
15
Udgangsmaterialet kan fremstilles som følger:
4,5-dichlor-2-thienyleddikesyrechlorid (formel II
» gg X = 4-C1, Y = 5-C1, Z = Cl).
1,48 g (7,01 mmol) 4,5-dichlor-2-thienyleddikesyre oplø-25 ses i 15 ml thionylchlorid og opvarmes under tilbagesvaling i 2 timer. Derpå afdestilleres overskuddet af thionylchlorid i vakuum, og det tilbageblivende syrechlorid anvendes i næste trin uden videre rensning. Råudbytte: Næsten kvantitativt.
30
Analogt fremstilles: 5-chlor-2-thienyleddikesyrechlorid og 2,5-chlor-3-thienyleddikesyrechlorid.
Det fremgår af den farmakologiske undersøgelse af to af 35 de ved fremgangsmåden ifølge opfindelsen fremstillede forbindelser, nemlig LG83-8-01 og LG83-8-02, at de omhandlede forbindelser er K-specifikke analgetika: 6
DK 164551 B
Begge forbindelser udviser efter oral indgift ved brand-stråle-analgesitest på mus en ED5Q-værdi på 0,48 mg/kg legemsvægt ved en LD^q-værdi på ca. 50 mg/kg, hvorved de typiske u-receptoragonistiske egenskaber, som de forefin-5 des ved opiaterne, nemlig det Straub'ske halefænomen, de bukkede rygge og en forøget lokomotorisk aktivitet, ikke var at iagttage.
De omhandlede forbindelser kan indgives oralt i form af 10 tabletter eller kapsler, som indeholder en enhedsdosis af forbindelserne sammen med fortyndingsmidler, såsom majsstivelse, calciumcarbonat, dicalciumphosphat, alginsyre, lactose, magnesiumstearat, primogel eller talkum. Tabletterne fremstilles på sædvanlig måde ved granulering af 15 indholdsstofferne og slåning, kapslerne ved ifyldning i hårde gelatinekapsler af egnet størrelse.
De omhandlede forbindelser kan også indgives parenteralt, f.eks. ved intramuskulær, intravenøs eller subcutan in-20 jektion. Til den parenterale indgift anvendes de bedst i form af en steril vandig opløsning, som kan indeholde andre opløste stoffer, såsom toniske midler og midler til indstilling af pH-værdien. Forbindelserne kan sættes til destilleret vand, og pH-værdien kan indstilles under an-25 vendelse af en syre, såsom citronsyre, mælkesyre eller saltsyre, på 3-6. Tilstrækkeligt opløste stoffer, såsom dextrose eller saltopløsning, kan tilsættes, for at gøre opløsningen isotonisk. Den opnåede opløsning kan da steriliseres og fyldes i sterile ampuller af egnet størrel-30 se, således at man opnår det ønskede opløsningsvolumen.
De omhandlede forbindelser kan også indføres i en vene ved fusion af et parenteralt præparat som beskrevet i det foregående.
35 Til den orale indføring hos mennesker antages, at den daglige doseringsværdi for en af de omhandlede forbindelser ligger i området fa 0,1 til 10 mg pr. kg. pr. dag for
DK 164551B
7 en typisk voksen patient på 70 kg.
Lægen vil dog selvsagt i hvert tilfælde bestemme den pågældende dosering, som er mest egnet for den individuelle 5 patient, hvorved denne kan variere med patientens behov bedømt ud fra alder, vægt og udsagn.
10 15 20 25 30 35
Claims (2)
1. Analogifremgangsmåde til fremstilling af cyclohexyl-5 thienyleddikesyreamider med den almene formel 1' "j~i! - 2 kj ' 15 hvori R betegner alkyl med 1-3 carbonatomer, R1 og R^ betegner sammen med det nitrogenatom, hvortil de er bundet, en pyrrolidin- eller piperidinring, og X og Y betegner uafhængigt af hinanden hydrogen, chlor eller brom, eller farmaceutisk acceptable syreadditionssalte deraf, k e n -20 detegnet ved, at man omsætter en forbindelse med den almene formel X
25 Y-jr- -jj—CK2-CO-Z π ^Sr hvori X og Y har den i det foregående angivne betydning, 30 og Z betyder chlor eller brom, med en trans-cyclohexan-1,2-diamin med den almene formel 35 DK 164551 B
5 N\r2 hvori R, R^, R2 har den tidligere angivne betydning, og eventuelt overfører opnåede forbindelser med formlen I i 10 farmaceutisk acceptable syreadditionssalte deraf.
2. Fremgangsmåde ifølge krav 1, kendetegnet ved, at man overfører en opnået base med formlen I i sy~ rechloridet deraf. 15 20 25 30 35
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AT0430882A AT376669B (de) | 1982-11-26 | 1982-11-26 | Verfahren zur herstellung neuer thienylessigsaeureamid-derivate und pharmazeutisch vertraeglicher saeureadditionssalze davon |
| AT430882 | 1982-11-26 |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| DK540283D0 DK540283D0 (da) | 1983-11-25 |
| DK540283A DK540283A (da) | 1984-05-27 |
| DK164551B true DK164551B (da) | 1992-07-13 |
| DK164551C DK164551C (da) | 1992-11-30 |
Family
ID=3562308
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK540283A DK164551C (da) | 1982-11-26 | 1983-11-25 | Analogifremgangsmaade til fremstilling af cyclohexylthienyleddikesyreamider eller fysiologisk taalelige syreadditionssalte deraf |
Country Status (10)
| Country | Link |
|---|---|
| US (1) | US4499286A (da) |
| EP (1) | EP0110869B1 (da) |
| JP (1) | JPS59106484A (da) |
| AT (1) | AT376669B (da) |
| CA (1) | CA1244438A (da) |
| CS (1) | CS332291A3 (da) |
| DE (1) | DE3370328D1 (da) |
| DK (1) | DK164551C (da) |
| FI (1) | FI73987C (da) |
| PT (1) | PT77745B (da) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0232612B1 (en) * | 1985-12-23 | 1990-04-04 | Dr. Lo. Zambeletti S.p.A. | Azacyclic compounds, processes for their preparation, and their use as pharmaceuticals |
| US5010085A (en) * | 1986-09-10 | 1991-04-23 | E. I. Du Pont De Nemours And Company | Benzo-fused cycloalkane and oxa- and thia-cycloalkane trans-1,2-diamine derivatives |
| GB8801304D0 (en) * | 1988-01-21 | 1988-02-17 | Ici Plc | Diamine compounds |
| US5229414A (en) * | 1988-01-21 | 1993-07-20 | Imperial Chemical Industries Plc | Diamine compounds |
| DE4034785A1 (de) * | 1990-11-02 | 1992-05-07 | Merck Patent Gmbh | 1-(2-arylethyl)-pyrrolidine |
| US4965278A (en) | 1989-04-21 | 1990-10-23 | Warner-Lambert Company | 7-(substituted)amino)-8-((substituted)carbonyl)-methylamino)-1-oxaspiro[4,5]decanes as diuretics antiiflammatory, and cerebrovascular agents |
| US5063242A (en) * | 1989-04-21 | 1991-11-05 | Warner-Lambert Company | 7-((substituted)amino)-8-((substituted)carbonyl)-methylamino-1-oxaspiro[4,5]decanes as diuretics antiinflammatory, and cerebrovascular agents |
| DE4011172A1 (de) * | 1990-04-06 | 1991-10-10 | Degussa | Verbindungen zur bekaempfung von pflanzenkrankheiten |
| IL99320A (en) * | 1990-09-05 | 1995-07-31 | Sanofi Sa | Arylalkylamines, their preparation and pharmaceutical preparations containing them |
| US5317028A (en) * | 1992-09-08 | 1994-05-31 | Warner-Lambert Co. | 7-((substituted)amino)-8((substituted)carbonyl)-methylamino-1-oxaspiro(4,5)decanes useful in Parkinson's disease, dystonia, and other movement disorders |
| WO1999016431A1 (en) * | 1997-09-26 | 1999-04-08 | Nortran Pharmaceuticals Inc. | Mixtures of enantiomers of aminocyclohexylamides to produce simultaneous analgesia with local anaesthesia or antiarrhythmia |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4192885A (en) * | 1976-11-12 | 1980-03-11 | The Upjohn Company | Analgesic N-{2-[N'-(2-furylmethyl and 2-thienyl-methyl)-N'-alkylamino]cycloaliphatic}cyanobenzamides |
| US4145435A (en) * | 1976-11-12 | 1979-03-20 | The Upjohn Company | 2-aminocycloaliphatic amide compounds |
| US4098904A (en) * | 1976-11-12 | 1978-07-04 | The Upjohn Company | Analgesic n-(2-aminocycloaliphatic)benzamides |
-
1982
- 1982-11-26 AT AT0430882A patent/AT376669B/de not_active IP Right Cessation
-
1983
- 1983-11-11 EP EP83890206A patent/EP0110869B1/de not_active Expired
- 1983-11-11 DE DE8383890206T patent/DE3370328D1/de not_active Expired
- 1983-11-15 CA CA000441249A patent/CA1244438A/en not_active Expired
- 1983-11-22 US US06/554,416 patent/US4499286A/en not_active Expired - Lifetime
- 1983-11-24 JP JP58219667A patent/JPS59106484A/ja active Granted
- 1983-11-25 PT PT77745A patent/PT77745B/pt not_active IP Right Cessation
- 1983-11-25 DK DK540283A patent/DK164551C/da not_active IP Right Cessation
- 1983-11-25 FI FI834323A patent/FI73987C/fi not_active IP Right Cessation
-
1991
- 1991-11-01 CS CS913322A patent/CS332291A3/cs unknown
Also Published As
| Publication number | Publication date |
|---|---|
| FI834323A (fi) | 1984-05-27 |
| DK540283D0 (da) | 1983-11-25 |
| PT77745B (de) | 1986-04-16 |
| FI834323A0 (fi) | 1983-11-25 |
| PT77745A (de) | 1983-12-01 |
| EP0110869A1 (de) | 1984-06-13 |
| JPS59106484A (ja) | 1984-06-20 |
| AT376669B (de) | 1984-12-27 |
| JPH0527634B2 (da) | 1993-04-21 |
| DK540283A (da) | 1984-05-27 |
| EP0110869B1 (de) | 1987-03-18 |
| CS332291A3 (en) | 1992-04-15 |
| DE3370328D1 (en) | 1987-04-23 |
| DK164551C (da) | 1992-11-30 |
| ATA430882A (de) | 1984-05-15 |
| US4499286A (en) | 1985-02-12 |
| FI73987C (fi) | 1987-12-10 |
| FI73987B (fi) | 1987-08-31 |
| CA1244438A (en) | 1988-11-08 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| AHB | Application shelved due to non-payment | ||
| PBP | Patent lapsed |