DE1944419A1 - Antiphlogistic 2-methyl-indole derivs - Google Patents
Antiphlogistic 2-methyl-indole derivsInfo
- Publication number
- DE1944419A1 DE1944419A1 DE19691944419 DE1944419A DE1944419A1 DE 1944419 A1 DE1944419 A1 DE 1944419A1 DE 19691944419 DE19691944419 DE 19691944419 DE 1944419 A DE1944419 A DE 1944419A DE 1944419 A1 DE1944419 A1 DE 1944419A1
- Authority
- DE
- Germany
- Prior art keywords
- methyl
- benzyl
- indolyl
- compounds
- methoxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- BHNHHSOHWZKFOX-UHFFFAOYSA-N 2-methyl-1H-indole Chemical compound C1=CC=C2NC(C)=CC2=C1 BHNHHSOHWZKFOX-UHFFFAOYSA-N 0.000 title abstract description 5
- 239000002260 anti-inflammatory agent Substances 0.000 title abstract description 3
- 230000001741 anti-phlogistic effect Effects 0.000 title abstract 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 18
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims abstract description 10
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 8
- 125000003118 aryl group Chemical group 0.000 claims abstract description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 4
- -1 rhodanines Chemical class 0.000 claims description 54
- 150000001875 compounds Chemical class 0.000 claims description 23
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 150000001412 amines Chemical class 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 14
- 150000001299 aldehydes Chemical class 0.000 claims description 11
- 239000000047 product Substances 0.000 claims description 11
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 claims description 10
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 claims description 10
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- 230000029936 alkylation Effects 0.000 claims description 7
- 238000005804 alkylation reaction Methods 0.000 claims description 7
- 229940051880 analgesics and antipyretics pyrazolones Drugs 0.000 claims description 7
- 150000007656 barbituric acids Chemical class 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 7
- JEXVQSWXXUJEMA-UHFFFAOYSA-N pyrazol-3-one Chemical class O=C1C=CN=N1 JEXVQSWXXUJEMA-UHFFFAOYSA-N 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 6
- 229960000583 acetic acid Drugs 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 239000007859 condensation product Substances 0.000 claims description 6
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical class OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 5
- SUSQOBVLVYHIEX-UHFFFAOYSA-N phenylacetonitrile Chemical compound N#CCC1=CC=CC=C1 SUSQOBVLVYHIEX-UHFFFAOYSA-N 0.000 claims description 5
- DNTVKOMHCDKATN-UHFFFAOYSA-N pyrazolidine-3,5-dione Chemical class O=C1CC(=O)NN1 DNTVKOMHCDKATN-UHFFFAOYSA-N 0.000 claims description 5
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- WDJHALXBUFZDSR-UHFFFAOYSA-N acetoacetic acid Chemical class CC(=O)CC(O)=O WDJHALXBUFZDSR-UHFFFAOYSA-N 0.000 claims description 4
- 150000001408 amides Chemical class 0.000 claims description 4
- 230000003110 anti-inflammatory effect Effects 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 239000012362 glacial acetic acid Substances 0.000 claims description 4
- OCDGBSUVYYVKQZ-UHFFFAOYSA-N gramine Chemical class C1=CC=C2C(CN(C)C)=CNC2=C1 OCDGBSUVYYVKQZ-UHFFFAOYSA-N 0.000 claims description 4
- 150000001469 hydantoins Chemical class 0.000 claims description 4
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 4
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 4
- 230000004048 modification Effects 0.000 claims description 4
- 238000012986 modification Methods 0.000 claims description 4
- 150000002825 nitriles Chemical class 0.000 claims description 4
- 239000012312 sodium hydride Substances 0.000 claims description 4
- JVVRJMXHNUAPHW-UHFFFAOYSA-N 1h-pyrazol-5-amine Chemical class NC=1C=CNN=1 JVVRJMXHNUAPHW-UHFFFAOYSA-N 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 3
- CKRZKMFTZCFYGB-UHFFFAOYSA-N N-phenylhydroxylamine Chemical compound ONC1=CC=CC=C1 CKRZKMFTZCFYGB-UHFFFAOYSA-N 0.000 claims description 3
- 150000003927 aminopyridines Chemical class 0.000 claims description 3
- 150000005005 aminopyrimidines Chemical class 0.000 claims description 3
- 150000001448 anilines Chemical class 0.000 claims description 3
- MLIREBYILWEBDM-UHFFFAOYSA-N cyanoacetic acid Chemical class OC(=O)CC#N MLIREBYILWEBDM-UHFFFAOYSA-N 0.000 claims description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 3
- 150000002475 indoles Chemical class 0.000 claims description 3
- RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical class NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 229940054051 antipsychotic indole derivative Drugs 0.000 claims description 2
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical class ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 claims description 2
- 150000005524 benzylchlorides Chemical class 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 2
- ZIUSEGSNTOUIPT-UHFFFAOYSA-N ethyl 2-cyanoacetate Chemical compound CCOC(=O)CC#N ZIUSEGSNTOUIPT-UHFFFAOYSA-N 0.000 claims description 2
- 230000003647 oxidation Effects 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 claims description 2
- 230000026030 halogenation Effects 0.000 claims 2
- 238000005658 halogenation reaction Methods 0.000 claims 2
- CUONGYYJJVDODC-UHFFFAOYSA-N malononitrile Chemical compound N#CCC#N CUONGYYJJVDODC-UHFFFAOYSA-N 0.000 claims 2
- 239000002253 acid Substances 0.000 claims 1
- 150000003863 ammonium salts Chemical class 0.000 claims 1
- 125000001041 indolyl group Chemical group 0.000 claims 1
- 150000002576 ketones Chemical class 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000009835 boiling Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- XDPKQGKEOCYMQC-UHFFFAOYSA-N 1,2-diphenylpyrazolidine-3,5-dione Chemical compound O=C1CC(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 XDPKQGKEOCYMQC-UHFFFAOYSA-N 0.000 description 2
- ARWOBOIBOJPEGY-UHFFFAOYSA-N 1-[(4-chlorophenyl)methyl]-5-methoxy-2-methylindole Chemical compound CC1=CC2=CC(OC)=CC=C2N1CC1=CC=C(Cl)C=C1 ARWOBOIBOJPEGY-UHFFFAOYSA-N 0.000 description 2
- RLFWWDJHLFCNIJ-UHFFFAOYSA-N 4-aminoantipyrine Chemical compound CN1C(C)=C(N)C(=O)N1C1=CC=CC=C1 RLFWWDJHLFCNIJ-UHFFFAOYSA-N 0.000 description 2
- KDXXXECBTWLZSQ-UHFFFAOYSA-N 5-methoxy-2-methyl-1h-indole-3-carbaldehyde Chemical compound COC1=CC=C2NC(C)=C(C=O)C2=C1 KDXXXECBTWLZSQ-UHFFFAOYSA-N 0.000 description 2
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- FMCAFXHLMUOIGG-IWFBPKFRSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2r)-2-formamido-3-sulfanylpropanoyl]amino]-3-methylbutanoyl]amino]-3-(4-hydroxy-2,5-dimethylphenyl)propanoyl]amino]-4-methylsulfanylbutanoic acid Chemical compound O=CN[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCSC)C(O)=O)CC1=CC(C)=C(O)C=C1C FMCAFXHLMUOIGG-IWFBPKFRSA-N 0.000 description 1
- PVRSIFAEUCUJPK-UHFFFAOYSA-N (4-methoxyphenyl)hydrazine Chemical compound COC1=CC=C(NN)C=C1 PVRSIFAEUCUJPK-UHFFFAOYSA-N 0.000 description 1
- VVSASNKOFCZVES-UHFFFAOYSA-N 1,3-dimethyl-1,3-diazinane-2,4,6-trione Chemical compound CN1C(=O)CC(=O)N(C)C1=O VVSASNKOFCZVES-UHFFFAOYSA-N 0.000 description 1
- HBBCKARIXVLLRZ-UHFFFAOYSA-N 1-(1h-indol-2-yl)-n,n-dimethylmethanamine Chemical class C1=CC=C2NC(CN(C)C)=CC2=C1 HBBCKARIXVLLRZ-UHFFFAOYSA-N 0.000 description 1
- JKGRTCOFRZQKPZ-UHFFFAOYSA-N 1-chloro-4-(iodomethyl)benzene Chemical compound ClC1=CC=C(CI)C=C1 JKGRTCOFRZQKPZ-UHFFFAOYSA-N 0.000 description 1
- IURNVVIQOMTXSM-UHFFFAOYSA-N 4-chloro-n-(4-methoxyphenyl)benzohydrazide Chemical compound C1=CC(OC)=CC=C1N(N)C(=O)C1=CC=C(Cl)C=C1 IURNVVIQOMTXSM-UHFFFAOYSA-N 0.000 description 1
- RKIDDEGICSMIJA-UHFFFAOYSA-N 4-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(Cl)C=C1 RKIDDEGICSMIJA-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 229910019213 POCl3 Inorganic materials 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 125000004989 dicarbonyl group Chemical group 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 238000002845 discoloration Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- QUPDWYMUPZLYJZ-UHFFFAOYSA-N ethyl Chemical compound C[CH2] QUPDWYMUPZLYJZ-UHFFFAOYSA-N 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 125000005059 halophenyl group Chemical group 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229960000194 kebuzone Drugs 0.000 description 1
- 150000002690 malonic acid derivatives Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 238000001256 steam distillation Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/12—Radicals substituted by oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Antiphlogistisch wirkende 1-11-, Benzyl- und 1 -Benzoyl-2-methyl-5-alkoxy-skatyl-Derivate von 1,3-Dicarbonyl-Verbindungen und Aminen sowie Verfahren zu ihrer Herstellung.1-11-, benzyl- and 1-benzyl-2-methyl-5-alkoxyskatyl derivatives with anti-inflammatory effects of 1,3-dicarbonyl compounds and amines and processes for their preparation.
Die Erfindung betrifft neuartige Skatyl-Derivate von 1,3-Dicarbonyl-Verbindungen und Aminen sowie Verfahren zur Herstellung derselben.The invention relates to novel skatyl derivatives of 1,3-dicarbonyl compounds and amines and methods of making the same.
Erfindungsgemässe antiphlogistisch wirkende Skatyl-Derivate sind in ihrer einfachsten Form das 2-Methyl-5-alkoxy-skatyl-Derivat von 1,3-Dicarbonyl-Verbindungen der allgemeinen Formel XII: worin R eine Alkylgruppe vorzugsweise mit 1 - 4 C-Atomen oder eine Benzylgruppe, R'einH, eine gf. halogenierte Benzyl- oder Benzoylgruppe sein kann und die - HC(y -Gruppe den Rest einer y CH-aciden Verbindung darstellt, wobei unter einer CH-aciden Verbindung z.B. Acetessigester, Malonsäurester, Cyanessigester, Malondinitril, Barbitursäuren, Dioxopyrazolidine, Pyrazolone und ähnliche zu verstehen sind.Anti-inflammatory skatyl derivatives according to the invention are in their simplest form the 2-methyl-5-alkoxyskatyl derivative of 1,3-dicarbonyl compounds of the general formula XII: where R is an alkyl group, preferably with 1-4 carbon atoms or a benzyl group, R'einH, an optionally halogenated benzyl or benzoyl group and the - HC (y group is the remainder of a y CH-acidic compound, with a CH-acidic compound, for example acetoacetic ester, malonic acid ester, cyanoacetic ester, malondinitrile, barbituric acids, dioxopyrazolidines, pyrazolones and the like are to be understood.
Ferner fallen unter die erfindungsgemässen antiphlogistischen Skatyl-Derivate die Amine XIII der allgemeinen Formel: worin R" eine Arylgruppe oder eine heterocyclische Gruppe darstellen kann; und die der Verbindung XII entsprechenden Amide der allgemeinen Formel:XI: Auch die Alkylierungsprodukte aus XII und'XIII stellen wertvolle antiphlogistische Stoffe dar: Die Darstellung dieser neuen Verbindungen verläuft erfindungsgemäss wie folgt: Das 2-Methyl-5-alkoxy-indol der Formel I wird durch Behandeln mit Cyanwasserstoff und Chlorwasserstoff in den 2-Methyl-5-alkoxy-indol-3-Aldehyd II überführt: Diese Aldehyde II werden mit CH-aciden Verbindungen der allge-#x meinen Formel CH2 oder mit Aminen zu Indolyl-methyliden-#y bzw. Indolyl-methyliden-amino-Verbindungen der Formeln III und IX kondensiert: Rtt = Aryl, Heterocycl.The anti-inflammatory skatyl derivatives according to the invention also include the amines XIII of the general formula: in which R "can represent an aryl group or a heterocyclic group; and the amides corresponding to compound XII of the general formula: XI: The alkylation products from XII and XIII are also valuable anti-inflammatory substances: According to the invention, these new compounds are prepared as follows: The 2-methyl-5-alkoxy-indole of the formula I. is converted into 2-methyl-5-alkoxy-indole-3-aldehyde II by treatment with hydrogen cyanide and hydrogen chloride: These aldehydes II are condensed with CH-acidic compounds of the general formula CH2 or with amines to give indolyl-methylidene- # y or indolyl-methylidene-amino compounds of the formulas III and IX: Rtt = aryl, heterocycl.
Diese Verbindungen werden durch katalytische Hydrierung in die gewünschten Skatyl-Derivate der Formeln XII und XIII überführt, die sich mühelos durch Behandlung mit einem Alkylierungsmittel in Gegenwart einer Base zu den Alkylierungsprodukten XIV und XV umsetzen lassen.These compounds are converted into the desired ones by catalytic hydrogenation Skatyl derivatives of the formulas XII and XIII, which can be easily converted by treatment with an alkylating agent in the presence of a base to give the alkylation products Have XIV and XV implemented.
Die Verbindungen II sind auch auf folgendem Wege zugänglich, wie am Beispiel der Herstellung des 2-Methyl-5-methoxy-indol-5-aldehyd gezeigt werden soll: Das )-Dialkyl-aminomethyl-indol oder sein quartäres Ammoniumsalz der allgemeinen Formeln: wird mit N-Phenyl-hydroxylamin zum N-Skatyl-N-phenylhydroxylamin und dieses durch anschliessende Oxydation und Alkalibehandlung zum Aldehyd II umgesetzt: Wie eingangs erwähnt, kann R' ein H, eine gf. halogenierte (F, C1, Br, J) Benzyl- oder gfs. halogenierte Benzoylgruppe bedeuten. Es ist jedoch nicht erforderlich, dass die Benzyl-und Benzoyl-Gruppen bereits am Ausgangsindol substituiert sind.The compounds II are also accessible in the following way, as is to be shown using the example of the preparation of 2-methyl-5-methoxy-indole-5-aldehyde: The) -dialkyl-aminomethyl-indole or its quaternary ammonium salt of the general formulas: is converted with N-phenyl-hydroxylamine to N-skatyl-N-phenylhydroxylamine and this is converted to aldehyde II by subsequent oxidation and alkali treatment: As mentioned at the outset, R 'can be an H, an optionally halogenated (F, C1, Br, J) benzyl or optionally mean halogenated benzoyl group. However, it is not necessary that the benzyl and benzoyl groups are already substituted on the starting indole.
Es kann in der Verbindung II der Wasserstoff = R' (II a) nachträglich durch Umsetzen mit Natriumhydrid in Dioxan und gfs.In compound II, the hydrogen = R '(II a) can subsequently be added by reacting with sodium hydride in dioxane and gfs.
halogeniertem Benzylchlorid oder gfs. halogeniertem Benzoylchlorid unter Bildung der analogen Verbindungen II b und II c substituiert werden: Diese Aldehyde lassen sich mühelos mit den eingangs erwähnten CH-aciden Verbindungen (Acetessigester, Malonsäure-Derivaten, Barbitursäuren, Dioxyprazolidinen, Pyrazolonen) und Aminen (z.B. Amino-antipyrin) zu den Verbindungen III bzw. des Typs VI, VII, VIII und den Aminen IX kondensieren. Das nachfolgende Formelbild veranschaulicht diese Reaktionen: R" in den Verbindungen VI, VII und VIII: H, CH3, C2H5, Phenyl, Hydroxy- und Methoxyphenyl sowie Halogenphenyl.halogenated benzyl chloride or gfs. halogenated benzoyl chloride to form the analogous compounds II b and II c: These aldehydes can easily be combined with the aforementioned CH-acidic compounds (acetoacetic esters, malonic acid derivatives, barbituric acids, dioxyprazolidines, pyrazolones) and amines (e.g. amino antipyrine) to form compounds III or of type VI, VII, VIII and the amines IX condense. The following formula illustrates these reactions: R ″ in the compounds VI, VII and VIII: H, CH3, C2H5, phenyl, hydroxy and methoxyphenyl and halophenyl.
Die Kondensation der Verbindungen II mit Aminen verläuft wie folgt: R'1 = Aryl Heterocycl.The condensation of the compounds II with amines proceeds as follows: R'1 = aryl heterocyclic.
Als CH-acide Verbindungen kommen für die Kondensation zu den Verbindungen VI, VII,und VIII insbesondere die folgenden in Frage: Dicarbonylverbindungen, wie Acetessigsäureester, Malonsäureester, Cyanessigsäureester, Malondinitril, Benzylcyanid, Acetylaceton, Hydantoine, Pyrazolone, Dioxo-pyrazolidine, Rhodanine, Barbitursäuren.The compounds are used as CH-acidic compounds for the condensation VI, VII, and VIII in particular the following in question: Dicarbonyl compounds, such as Acetoacetic acid ester, malonic acid ester, cyanoacetic acid ester, malondinitrile, benzyl cyanide, Acetylacetone, hydantoins, pyrazolones, dioxo-pyrazolidines, rhodanines, barbituric acids.
Als Amine kommen insbesondere die folgenden in Betracht: Anilin-Derivate, heterocyclische Amine, wie z.B.: Aminopyridine, Aminopyrimidine, Aminopyrazole, Aminothiazole. Die Verbindungen VI, VII und VIII lassen sich auch direkt durch Reaktion entsprechender Indol-Derivate mit den Hydroxy-Methylen-Abkömmlingen der CH-aciden Verbindungen in Eisessig darstellen: Die Amide XI lassen sich aus den Kondensationsprodukten III bzw. VI, VII und VIII dadurch herstellen, dass diese mit Cyanwasserstoff oder Alkalicyanid in Nitrile der Verbindung X überführt werden: Diese Nitrile können mühelos z.B. mittels Schwefelsäure zu den gewünschten Amid-en XI hydrolysiert werden: Die Hydrierung der Verbindungen III bzw. VI, VII, VIII und des Amin IX verläuft glatt unter den üblichen Bedingungen. Als Hydrierungskatalysatoren kommen insbesondere Edelmetalle, wie Platinoder R ium auf Kohlenstoff oder Raney-Nickel in Frage.Particularly suitable amines are the following: aniline derivatives, heterocyclic amines, such as, for example: aminopyridines, aminopyrimidines, aminopyrazoles, aminothiazoles. The compounds VI, VII and VIII can also be prepared directly in glacial acetic acid by reacting corresponding indole derivatives with the hydroxy-methylene derivatives of the CH-acidic compounds: The amides XI can be prepared from the condensation products III or VI, VII and VIII by converting them into nitriles of the compound X with hydrogen cyanide or alkali metal cyanide: These nitriles can easily be hydrolyzed, for example using sulfuric acid, to the desired amide-s XI: The hydrogenation of the compounds III or VI, VII, VIII and the amine IX proceeds smoothly under the usual conditions. Particularly suitable hydrogenation catalysts are noble metals, such as platinum or rum on carbon or Raney nickel.
Die erfindungsgemässe Herstellung der Verbindungen XII und XIII ist auch dadurch möglich, dass man die CH-aciden Verbindungen bzw. Amine mit dem entsprechenden Gramin-Derivat oder dessen Methojodid in Gegenwart einer Base, z.B. Natriumhydroxid oder Natriumhydrid, umsetzt. Diese Abänderung des Verfahrens setzt allerdings voraus, dass die erforderlichen Dimethyl-aminomethyl-indole wohlfeil zur Verfügung stehen. Diese Reaktion verläuft nach folgender allgemeiner Formel: Die Darstellung der Alkylverbindungen XIV und XV ist nicht nur durch direkte Alkylierung der Verbindungen XII und XIII möglich, man kann vielmehr auch die vorstehend erwähnte, vom Gramin-Derivat oder dessen Methojodid ausgehende Reaktion-dazu benutzen, unmittelbar zu den Alkylierungsprodukten XIV und XV zu gelangen, indem man von bereits alkylierten CH-aciden Verbindungen oder Aminen ausgeht. Der formelmäßige Ablauf der Reaktion wäre demnach der folgende: Das erfindungsgemäße Verfahren läßt sich weiterhin zur Herstellung der Verbindungen XII, XIII, XIV und XV in der Weise abändern, daß in Anwendung der von E. Wischer angegebenen Indolsynthese das p-Alkoxyphenylhydrazin oder dessen N-Benzyl oder Benzoyl-Derivat mit entsprechenden Retonen umgesetzt wird. Den Verlauf dieser Reaktion zeigt das nachfolgende Formelbild: Auch der erste Schritt des erfindungsgemäßen Verfahrens läßt sich bezüglich der -Herstellung des Halogeno-Benzyl-Derivats der Verbindung II dadurch abändern, daß 1 Halogeno-benzyl-2-methyl-5-alkoxy-indol nach dem Vilsmeier-Verfahren in den entsprechenden. Aldehyd II. überführt wird. Diese Reaktion wird durch die nachfolgende Formel veranschaulicht: Ausführungsbeispiele: 2-Methyl-5-methoxyindol-3-aldehyd. Schmp. 198°C (IIa) und 1-p-Chlorbenzyl-2-methyl-5-methoxyindol-3-aldehyd. Schmp.The preparation according to the invention of the compounds XII and XIII is also possible by reacting the CH-acidic compounds or amines with the corresponding gramin derivative or its methiodide in the presence of a base, for example sodium hydroxide or sodium hydride. However, this modification of the process presupposes that the required dimethyl-aminomethyl-indoles are cheaply available. This reaction proceeds according to the following general formula: The preparation of the alkyl compounds XIV and XV is not only possible by direct alkylation of the compounds XII and XIII, but the above-mentioned reaction starting from the gramin derivative or its methoiodide can also be used to obtain the alkylation products XIV and XV directly by starting from already alkylated CH-acidic compounds or amines. The formulaic course of the reaction would be as follows: The process according to the invention can furthermore be modified for the preparation of the compounds XII, XIII, XIV and XV in such a way that the p-alkoxyphenylhydrazine or its N-benzyl or benzoyl derivative is reacted with corresponding retons using the indole synthesis given by E. Wischer . The following formula shows the course of this reaction: The first step of the process according to the invention can also be modified with regard to the preparation of the halogeno-benzyl derivative of the compound II by converting 1 halogeno-benzyl-2-methyl-5-alkoxy-indole into the corresponding. Aldehyde II. Is converted. This reaction is illustrated by the formula below: Working examples: 2-methyl-5-methoxyindole-3-aldehyde. Mp. 198 ° C (IIa) and 1-p-chlorobenzyl-2-methyl-5-methoxyindole-3-aldehyde. M.p.
140° (IIb) 0.022 Mol 2-ìV§ethyl-5-methoxyindol bzw. l-p-Chlorbenzyl-2-methyl-5-methoxyindol werden in wasserfreiem Äther gelöst und mit-4 ml wasserfreier Blausäure versetzt. Unter Kühlung wird 3 Std. lang trockenes HC1 eingeleitet. Das ausgefallene Ketimin-hydrochlorid wird abfiltriert, in Wasser gelöst und auf dem Wasserbad erwärmt. Nach dem Abkühlen wird der Aldehyd (II a bzw. II b) abgenutscht. Ausbeute 85%.140 ° (IIb) 0.022 mol of 2-ìV§ethyl-5-methoxyindole or 1-p-chlorobenzyl-2-methyl-5-methoxyindole are dissolved in anhydrous ether and treated with -4 ml of anhydrous hydrocyanic acid. Dry HCl is introduced for 3 hours with cooling. The precipitated ketimine hydrochloride is filtered off, dissolved in water and warmed on a water bath. After cooling down the aldehyde (II a or II b) is sucked off. Yield 85%.
0.01 Mol des Methojodids der Indol-Mannichbase (z. B. 2-Methyl-5-methoxy-3-piperidinomethyl-indol)werden in 20 ml Methanol gelöst und 1.2 g Phenylhydroxylamin hinzugegeben. Die Lösung wird mit 20 ml 2n-Natronlauge versetzt und einige Zeit gerührt, dann gibt man 4 ml Nitrobenzol hinzu und erwärmt 1 Std. unter Rückfluß. Nach Zugabe von 80 ml 2n-NaOH wird wasserdampfdestilliert. Die im Destillationskolben verbliebene Lösung wird mit Essigsäure neutralisiert. Nach einigem Stehen kann der Aldehyd (Ilabzw. IIb) abgesaugt werden. Ausbeute 90?/o.0.01 mol of the methoiodide of the indole Mannich base (e.g. 2-methyl-5-methoxy-3-piperidinomethyl-indole) dissolved in 20 ml of methanol and added 1.2 g of phenylhydroxylamine. The solution will be 20 ml of 2N sodium hydroxide solution are added and the mixture is stirred for some time, then 4 ml of nitrobenzene are added added and heated under reflux for 1 hour. After adding 80 ml of 2N NaOH, steam distillation is carried out. The solution remaining in the distillation flask is neutralized with acetic acid. After standing for a while, the aldehyde (IIab or IIb) can be suctioned off. Yield 90? / O.
l-p-Chlorbenzyl-2-methyl-5-methoxyindol-3-aldehyd (IIb) Zu 60 ml eisgekühltem wasserfreien DRiFA werden unter Rühren tropfenweise 16.5 g POCl3 hinzugefügt. Die erhaltene Lösung wird mit 0.1 Mol l-p-Chlorbenzyl-2-methyl-5-methoxyindol in 50 ml DMFA versetzt. Nach einiger Zeit wird das Eisbad entfernt und auf 35-40°C erwärmt, nach 1.5 Std. werden 150 g zerkleinertes Eis zugegeben und dann mit einer Lösung von 75 g WaOH in 200 ml Wasser versetzt. Darauf wird zum Sieden erhitzt und mit Wasser verdünnt. Ausbeute 95%.l-p-Chlorobenzyl-2-methyl-5-methoxyindole-3-aldehyde (IIb) To 60 ml ice-cold anhydrous DRiFA are added dropwise 16.5 g of POCl3 with stirring. the solution obtained is with 0.1 mol of 1-p-chlorobenzyl-2-methyl-5-methoxyindole in 50 ml DMFA added. After a while the ice bath is removed and warmed to 35-40 ° C, After 1.5 hours, 150 g of crushed ice are added and then with a solution of 75 g of WaOH in 200 ml of water are added. It is then heated to the boil and with Water diluted. Yield 95%.
l-p-Chlorbenzoyl-2-methyl-5-methoxyindol-3-alGeLyd. Schmp 15500 JIc) 1-p-Chlorbenzyl-2-methyl-5-methoxyindol-3-aldehyd (IIb) 0.01 Mol 2-Methyl-5-methoxyindol-3-aldehyd wird in abs.Dioxan gelöst und zu einer Suspension von 0.011 ol NaH in trockenem Dioxan gegoben. Nach einstündigem Rühren bei Zimirtertemperatur, und in der Siedehitze tropft man unter Eiskühlung langsam 0.011 Mol p-Chlorbenzyljodid oder p-Chlorbenzoylchlorid hinzu.1-p-Chlorobenzoyl-2-methyl-5-methoxyindole-3-alGeLyd. M.p. 15500 JIc) 1-p-Chlorobenzyl-2-methyl-5-methoxyindole-3-aldehyde (IIb) 0.01 mole of 2-methyl-5-methoxyindole-3-aldehyde is dissolved in absolute dioxane and added to a suspension of 0.011 ol NaH in dry Dioxane given. After stirring for one hour at room temperature and at the boiling point 0.011 mol of p-chlorobenzyl iodide or p-chlorobenzoyl chloride is slowly added dropwise while cooling with ice added.
Nach längerem Rühren bei Zimmertemperatur wird kurz zum Sieden erhitzt und schließlich das Reaktionsgemisch heiß filtriert.After prolonged stirring at room temperature, the mixture is briefly heated to boiling and finally the reaction mixture is filtered hot.
Das Filtrat wird mit Wasser versetzt. Der auftretende Niederschlag wird abgenutscht und aus Ligroin bzw. ethanol umkristallisiert. Ausbeuten 40-60%.The filtrate is mixed with water. The occurring precipitation is suction filtered and recrystallized from ligroin or ethanol. Yields 40-60%.
4-(2-Methyl-5-methoxy-3-indolyl)-methyliden-1.2-diphenyl-3.5-dioxopyrazolidin. Schmp. 2300C (VIIa) 4-(2-Ifethyl-5-methoxy-3-indolyl)-methyliden-1-phenyl-3-methyl-pyrazolon-5. Schmp. 2200C (Zers.) (VIIIa) 5-(2-Methyl-5-methoxy-3-indolyl)-methyliden-1.3-dimethylbarbitursäure. Schmp. 2700C (Zers.) (VIa) 5-(2-Methyl-5-methoxy-3-indolyl)-methyliden-1.3-diphenylbarbitursäure. Schmp. 315°C (Zers.) (VIa) 5-(2-Methyl-5-methoxy-3-indolyl)-methyliien-1 .3-diphenylthiobarbitursäure. Zersp. bei 2300C (VIa) 4-( 1-p-Ohlorbenzoyl-2-methyl-5-methbxy-3-indolyl ) -methyliden-1.2-diphenyl-3.5-dioxopyrazolidin. Schmp. 2150 C (VIIc) 4-( 1-p-Ohlorbenzyl-2-methyl-5-methoxy-3-indolyl) -methyliden-1.2-diphenyl-3.5-dioxopyrazolidin. Schmp. 2500 C (VIIb) 4-( 1-p-Ohlorbenzyl-2-methyl-5-methoxy-3-indolyl) -methylidenl-phenyl-3-methyl-pyrazolon (5). Schmp. 2100 C (VIlIb) 5-(1-p-Chlorbenzoyl-2-methyl-5-methoxy-3-indolyl)-methyliden-1.3-dimethylbarbitursäure. Schmp. 205°C (VIc) 4-(2-Methyl-5-methoxy-3-indolyl)methylidenamino-l-phenyl-2.3-dimethyl-pyrazolon (5). Schmp. 3150 C (IXa) 4-(1-p-Chlorbenzoyl-2-methyl-5-methoxy-4-indolyl)-methylidenamino-1-phenyl-2.3-dimethyl-pyrazolon (5). Schmp.4- (2-methyl-5-methoxy-3-indolyl) -methylidene-1,2-diphenyl-3,5-dioxopyrazolidine. M.p. 2300C (VIIa) 4- (2-Ifethyl-5-methoxy-3-indolyl) -methylidene-1-phenyl-3-methyl-pyrazolone-5. M.p. 2200C (decomp.) (VIIIa) 5- (2-Methyl-5-methoxy-3-indolyl) -methylidene-1,3-dimethylbarbituric acid. M.p. 2700C (decomp.) (VIa) 5- (2-Methyl-5-methoxy-3-indolyl) -methylidene-1,3-diphenylbarbituric acid. Mp. 315 ° C (decomp.) (VIa) 5- (2-Methyl-5-methoxy-3-indolyl) -methyliien-1,3-diphenylthiobarbituric acid. Chopped at 2300C (VIa) 4- (1-p-chlorobenzoyl-2-methyl-5-methoxy-3-indolyl) -methylidene-1,2-diphenyl-3,5-dioxopyrazolidine. M.p. 2150 C (VIIc) 4- (1-p-chlorobenzyl-2-methyl-5-methoxy-3-indolyl) -methylidene-1,2-diphenyl-3,5-dioxopyrazolidine. M.p. 2500 C (VIIb) 4- (1-p-chlorobenzyl-2-methyl-5-methoxy-3-indolyl) -methyliden-phenyl-3-methyl-pyrazolone (5). M.p. 2100 C (VIlIb) 5- (1-p-chlorobenzoyl-2-methyl-5-methoxy-3-indolyl) -methylidene-1,3-dimethylbarbituric acid. Mp. 205 ° C (VIc) 4- (2-methyl-5-methoxy-3-indolyl) methylideneamino-1-phenyl-2,3-dimethyl-pyrazolone (5). M.p. 3150 C (IXa) 4- (1-p-chlorobenzoyl-2-methyl-5-methoxy-4-indolyl) -methylideneamino-1-phenyl-2,3-dimethyl-pyrazolone (5). M.p.
250°C (IXc) 2-(2-Methyl-5-methoxy-3-indolyl)-methylidenamino-4-methylthiazol-5-essigsäureäthylester. Schmp. 1950 C (IXa) Darstellungsmethode für VI, VII, VIII: a. Aldehyd und die CH-acide bzw. Amin-Komponente werden im molaren Verhältnis 1;1 gelöst und mehrere Minuten bis Stunden unter Rückfluß gekocht, die ausfallenden Kondensationsprodukte nach dem Abnutschen umkristallisiert. Als Lösungsmittel können Alkohole, Eisessig, Acetanhydrid, Pyridin, Piperidin oder Benzol verwendet werden. Ausbeute nahezu quantitativ.250 ° C (IXc) 2- (2-methyl-5-methoxy-3-indolyl) -methylidenamino-4-methylthiazole-5-acetic acid ethyl ester. 1950 C (IXa) Representation method for VI, VII, VIII: a. Aldehyde and the CH-acidic or amine component are im molar ratio 1; 1 dissolved and Boiled under reflux for several minutes to hours, the precipitating condensation products recrystallized after suction filtration. Alcohols, glacial acetic acid, Acetic anhydride, pyridine, piperidine or benzene can be used. Almost quantitative yield.
b. Äquimolare Mengen des 3-unsubstituierten Indol-Derivates und des Hydroxymethylen-Derivates einer CH-aciden Verbindung werden etwa 10 Min. in Eisessig erhitzt. Das beim Erkalten sich ausscheidende Produkt wird durch Umkristallisieren gereinigt. Ausbeute 80-9G%.b. Equimolar amounts of the 3-unsubstituted indole derivative and the Hydroxymethylene derivatives of a CH-acidic compound are in glacial acetic acid for about 10 minutes heated. The product that separates out when it cools is recrystallized cleaned. Yield 80-9% by weight.
4-(2-E1ethyl-5-methoxy-3-indolyl)-cyanmethyl-1.2-diphenyl-3.5-dioxopyrazolidin. Schmp. 19800 (Zers.) (Xa) 4-( l-p-Ohlorbenzyl-2-methyl-5-methoxy-3-indolyl) -cyanmethyl-1.2-diphenyl-3.5-dioxopyrazolidin Schmp. 195°C (Xb) 0.01 Mol VI, VII oder VIII werden für 3 Stunden in einer Lösung von 0.012 Mol KON in 90proz. ethanol gekocht. Nach Ansäuern wird im Vakuum zur Trockne eingeengt und mit Wasser versetzt.4- (2-ethyl-5-methoxy-3-indolyl) -cyanmethyl-1,2-diphenyl-3,5-dioxopyrazolidine. 19800 (decomp.) (Xa) 4- (1-p-chlorobenzyl-2-methyl-5-methoxy-3-indolyl) -cyanmethyl-1,2-diphenyl-3,5-dioxopyrazolidine Mp. 195 ° C (Xb) 0.01 mol VI, VII or VIII are for 3 hours in a solution of 0.012 mol KON in 90% boiled ethanol. After acidification it goes to dryness in vacuo concentrated and mixed with water.
Das unlösliche farblose Produkt wird aus Benzol/Petroläther umkristallisiert. Ausbeute 70%.The insoluble colorless product is recrystallized from benzene / petroleum ether. Yield 70%.
α-(1-p-Chlorbenzyl-2-methyl-5-methoxy-3-indolyl)-α-(1.2-diphenyl-3.5-dioxopyrazolidinyl-4-)-acetamii. Schmp. 22500 (XI) Xb wird bei Zimmertemperatur in 4 SQ gelöst und für 24 Std.α- (1-p-Chlorobenzyl-2-methyl-5-methoxy-3-indolyl) -α- (1,2-diphenyl-3,5-dioxopyrazolidinyl-4 -) - acetamii. Melting point 22500 (XI) Xb is dissolved in 4 SQ at room temperature and heated for 24 hours.
im Kühlschrank aufbewahrt. Dann wird die Losung~auf Eis gegossen, das ausgefallene Produkt abgenutscht und aus Alkohol umkristallisiert.stored in the refrigerator. Then the solution ~ is poured onto ice, the precipitated product is suction filtered and recrystallized from alcohol.
4-(2-Methyl-5-methoxy-skatyl)-1.2-diphenyl-3.5-dioxopyrazolidin. Schmp. 152°C (XIIa) 5-(2-Methyl-5-methoxy-skatyl)-1.3-dimethyl-barbitursäure.4- (2-methyl-5-methoxyskatyl) -1.2-diphenyl-3.5-dioxopyrazolidine. M.p. 152 ° C (XIIa) 5- (2-methyl-5-methoxyskatyl) -1.3-dimethyl-barbituric acid.
Schmp. 143°C (XIIa) (4) bzw. (6) werden in Dioxan suspendiert, mit 10% pdJC versetzt und bis zur vollstandigen Lösung und Entfärbung in einer Wasserstoffatmosphäre (evtl. unter Envarmen) geschüttext. Nach Filtration und Abziehen des Lösungsmittels erhält man ein Ö1, das zur KristallIsation gebracht wird und aus Essigester-Cyclohexan-Petroläther umkristallisiert werden kann. Ausbeute etwa 8/p.Melting point 143 ° C (XIIa) (4) or (6) are suspended in dioxane, with 10% pdJC added and until complete solution and discoloration in a hydrogen atmosphere (possibly under Envarmen) protected text. After filtration and removal of the solvent receives an oil that is brought to crystallization and out Ethyl acetate-cyclohexane-petroleum ether can be recrystallized. Yield about 8 / p.
Darstellung von XII und XIII aus Dimethylaminomethyl-indolen: a. Eine Mischung von 1.3-Dimethylbarbitursäure bzw. 1.2-Diphenyl-dioxopyrazolidin und etwas gepulvertem NaOH wird in Toluol bzw. Xylol mit 2-Methyl-5-methoxy-3-dimethylamino methylindol solange unter gleichzeitigem -Durchleiten von getrocknetem N2 unter Rückfluß gekocht, bis keine Dimethylaminentwicklung mehr nachweisbar ist. Das Lösungsmittel wird abgezogen und der Rückstand zur Kristallisation gebracht.Representation of XII and XIII from dimethylaminomethyl indoles: a. One Mixture of 1,3-dimethylbarbituric acid or 1,2-diphenyl-dioxopyrazolidine and something Powdered NaOH is mixed with 2-methyl-5-methoxy-3-dimethylamino in toluene or xylene methylindole while at the same time passing dried N2 under Boiled under reflux until the evolution of dimethylamine is no longer detectable. The solvent is drawn off and the residue caused to crystallize.
b. Barbitursäure bzw. Diphenyldioxopyrazolidin wird in Dioxan mit einer äquimolaren Menge WaH versetzt und nach beendeter Wasserstoffentwicklung mit dem Methojodid des 2-;.:ethyl-5-methoxy-3-piperidinomethylindols versetzt. Nach einstündigem Rühren bei Zimmertemperatur wird erviärmt und schließlich filtriert und das Lösungsmittel im Vakuum abgezogen. Der Rückstand wird zur Kristallisation gebracht.b. Barbituric acid or Diphenyldioxopyrazolidin is in dioxane with an equimolar amount of WaH is added and, after the evolution of hydrogen has ceased, with the methoiodide of 2 -;.: ethyl-5-methoxy-3-piperidinomethylindole added. To stirring for one hour at room temperature is warmed up and finally filtered and the solvent removed in vacuo. The residue becomes crystallization brought.
4» ethyl-4-(2-methyl-5-methoxy-skatyl)-1.2-diphenyl-5.5-dioxopyrazolidin. Schmp. 15200 (XIVa) Verbindungen des Typs XII oder XIII werden in abs. Alkohol mit einer äquimolaren Menge Natriumäthylat bei Zimmertemperatur behandelt. Dann wird eine äquimolare Menge KethylJodid zugetropft und 3 Std. bei Zimmertemperatur sowie 1/2 Std. auf dem siedenden Wasserbad erwärmt. Das Lösungsmittel wird abgezogen und der in Wasser und Natronlauge unlösliche Anteil des Rückstandes aus Alkohol-Wasser umkristallsiert, oder: 2.6 g 2-Methyl-5-methoxy-3-piperidinomethylindol werden in 10 ml Benzylalkohol gelöst und mit 1.2 g Dimethylsulfat versetzt. Zu dieser Lösung fügt man 2.7 g 1.2-Diphenyl-4-methyl dioxo-3.5-pyrazolidin. Die erhaltene Lösung gibt man unter Rühren zu einer Lösung von 0.4 g Kalium in 30 ml Benzylalkohol.4 »ethyl-4- (2-methyl-5-methoxyskatyl) -1.2-diphenyl-5.5-dioxopyrazolidine. Melting point 15200 (XIVa) compounds of type XII or XIII are given in abs. Alcohol with treated with an equimolar amount of sodium ethylate at room temperature. Then it will be an equimolar amount of methyl iodide was added dropwise and 3 hours at room temperature as well Heated for 1/2 hour on the boiling water bath. The solvent is drawn off and the portion of the alcohol-water residue that is insoluble in water and sodium hydroxide solution recrystallized, or: 2.6 g of 2-methyl-5-methoxy-3-piperidinomethylindole are in 10 ml of benzyl alcohol dissolved and treated with 1.2 g of dimethyl sulfate. To this solution 2.7 g of 1,2-diphenyl-4-methyl dioxo-3,5-pyrazolidine are added. The solution obtained are added with stirring to a solution of 0.4 g of potassium in 30 ml of benzyl alcohol.
Nach gelindem Erwärmen versetzt man mit Wasser und extrahiert mit CH2C12. Das nach Verdampfen des Lösungsmittels verbleibende Öl wird zur Kristallisation gebracht und umkristallisiert.After gentle warming, water is added and the mixture is extracted with CH2C12. The remaining after evaporation of the solvent oil is brought to crystallization and recrystallized.
Darstellung von XII nach dem Fischer-Verfahren: 4-(1-p-Chlorbenzoyl-2-methyl-5-methoxy-skatyl)-1.2-diphenyl-3.5-dioxopyrazolidin (XIIc) 4-(1-p-Chlorbenzyl-2-methyl-5-methoxy-skatyl)-1.2-diphenyl-3.5-dioxopyrazolidin (XIIb) p-Methoxyphenylhydrazin, N1-p-chlorbenzoyl-p-methoxyphenylhydrazin bzw. N1 -p-Chlorbenzyl-p-mehoxyphenylhydrazin werden in äquimolarem Verhältnis mit γ-Ketophenylbutazon in abs.Representation of XII by the Fischer method: 4- (1-p-chlorobenzoyl-2-methyl-5-methoxyskatyl) -1.2-diphenyl-3.5-dioxopyrazolidine (XIIc) 4- (1-p-Chlorobenzyl-2-methyl-5-methoxyskatyl) -1.2-diphenyl-3.5-dioxopyrazolidine (XIIb) p-methoxyphenyl hydrazine, N1-p-chlorobenzoyl-p-methoxyphenyl hydrazine, and N1, respectively -p-chlorobenzyl-p-mehoxyphenylhydrazine are in equimolar proportions with γ-ketophenylbutazone in abs.
Alkohol unter Zusatz katalytischer Mengen wasserfreien Zn-II-Cl2 oder BortrifluoridS2 Std. zum Sieden erhitzt (als Lösungsmittel können auch Essigsäure und andere-organische Säuren verwendet werden). Das Lösungsmittel wird im Vakuum abgezogen und der in Wasser unlösliche Rückstand durch Umkristallisieren gereinigt.Alcohol with the addition of catalytic amounts of anhydrous Zn-II-Cl2 or Boron trifluoride heated to boiling for 2 hours (acetic acid and other organic acids can be used). The solvent is in vacuo drawn off and the water-insoluble residue purified by recrystallization.
Claims (14)
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| DE19691944419 DE1944419A1 (en) | 1969-09-02 | 1969-09-02 | Antiphlogistic 2-methyl-indole derivs |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2988598A4 (en) * | 2013-04-23 | 2016-11-16 | Univ Arkansas | POLYMERASE, ENDONUCLEASE AND HELICASE INHIBITORS AND METHODS OF USE |
| US9884842B2 (en) | 2013-04-19 | 2018-02-06 | Bioventures, Llc | Combretastatin analogs |
| US9938246B2 (en) | 2014-03-31 | 2018-04-10 | Bioventures, Llc | Disubstituted triazole analogs |
| CN118878546A (en) * | 2024-09-30 | 2024-11-01 | 苏州大学 | A spirocyclic barbituric acid derivative and its preparation method and application |
-
1969
- 1969-09-02 DE DE19691944419 patent/DE1944419A1/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9884842B2 (en) | 2013-04-19 | 2018-02-06 | Bioventures, Llc | Combretastatin analogs |
| US10100029B2 (en) | 2013-04-19 | 2018-10-16 | Bioventures, Llc | Combretastatin analogs |
| EP2988598A4 (en) * | 2013-04-23 | 2016-11-16 | Univ Arkansas | POLYMERASE, ENDONUCLEASE AND HELICASE INHIBITORS AND METHODS OF USE |
| US9938246B2 (en) | 2014-03-31 | 2018-04-10 | Bioventures, Llc | Disubstituted triazole analogs |
| US10239844B2 (en) | 2014-03-31 | 2019-03-26 | Bioventures, Llc | Disubstituted triazole analogs |
| CN118878546A (en) * | 2024-09-30 | 2024-11-01 | 苏州大学 | A spirocyclic barbituric acid derivative and its preparation method and application |
| CN118878546B (en) * | 2024-09-30 | 2025-01-03 | 苏州大学 | Spirobutyric acid derivative and preparation method and application thereof |
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