DK147197B - Analogifremgangsmaade til fremstilling af 2-hydrazonopropionsyrederivater - Google Patents
Analogifremgangsmaade til fremstilling af 2-hydrazonopropionsyrederivater Download PDFInfo
- Publication number
- DK147197B DK147197B DK373478AA DK373478A DK147197B DK 147197 B DK147197 B DK 147197B DK 373478A A DK373478A A DK 373478AA DK 373478 A DK373478 A DK 373478A DK 147197 B DK147197 B DK 147197B
- Authority
- DK
- Denmark
- Prior art keywords
- propionic acid
- hydrochloride
- melting point
- hydrazine
- sodium
- Prior art date
Links
- 238000000034 method Methods 0.000 title description 6
- 239000002253 acid Substances 0.000 title description 2
- -1 3,3-dimethylbutyl Chemical group 0.000 description 22
- 238000002844 melting Methods 0.000 description 17
- 230000008018 melting Effects 0.000 description 17
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- NHTMVDHEPJAVLT-UHFFFAOYSA-N Isooctane Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 12
- 238000000354 decomposition reaction Methods 0.000 description 12
- JVSWJIKNEAIKJW-UHFFFAOYSA-N dimethyl-hexane Natural products CCCCCC(C)C JVSWJIKNEAIKJW-UHFFFAOYSA-N 0.000 description 12
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 150000003839 salts Chemical class 0.000 description 9
- 239000008280 blood Substances 0.000 description 8
- 210000004369 blood Anatomy 0.000 description 8
- 229940107700 pyruvic acid Drugs 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- 150000002429 hydrazines Chemical class 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 102000010909 Monoamine Oxidase Human genes 0.000 description 4
- 108010062431 Monoamine oxidase Proteins 0.000 description 4
- RMUCZJUITONUFY-UHFFFAOYSA-N Phenelzine Chemical compound NNCCC1=CC=CC=C1 RMUCZJUITONUFY-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000002899 monoamine oxidase inhibitor Substances 0.000 description 4
- 229960000964 phenelzine Drugs 0.000 description 4
- 159000000000 sodium salts Chemical class 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 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 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000001735 carboxylic acids Chemical class 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 150000007857 hydrazones Chemical class 0.000 description 3
- HHRZAEJMHSGZNP-UHFFFAOYSA-N mebanazine Chemical compound NNC(C)C1=CC=CC=C1 HHRZAEJMHSGZNP-UHFFFAOYSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 235000019260 propionic acid Nutrition 0.000 description 3
- 150000005599 propionic acid derivatives Chemical class 0.000 description 3
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- XLVSIZGEIKTDKG-UHFFFAOYSA-N 2-cyclohexylethylhydrazine;sulfuric acid Chemical compound OS(O)(=O)=O.NNCCC1CCCCC1 XLVSIZGEIKTDKG-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 241000700198 Cavia Species 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 229940123685 Monoamine oxidase inhibitor Drugs 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000002837 carbocyclic group Chemical group 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 230000002218 hypoglycaemic effect Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 229950006217 mebanazine Drugs 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000005245 sintering Methods 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- KHIQJCVGWNEQMI-DJWKRKHSSA-N (2z)-2-hydrazinylidenepropanoic acid Chemical class N/N=C(/C)C(O)=O KHIQJCVGWNEQMI-DJWKRKHSSA-N 0.000 description 1
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- ZCRXJCODBRQIKD-UHFFFAOYSA-N 1-(3-cyclohexylprop-1-enyl)-1-methylhydrazine;hydrochloride Chemical compound Cl.CN(N)C=CCC1CCCCC1 ZCRXJCODBRQIKD-UHFFFAOYSA-N 0.000 description 1
- PMDFEGLHKZBZBB-UHFFFAOYSA-N 2-(2-cycloheptylethylhydrazinylidene)propanoic acid Chemical compound OC(=O)C(C)=NNCCC1CCCCCC1 PMDFEGLHKZBZBB-UHFFFAOYSA-N 0.000 description 1
- SAVMSLHOOJTVJR-UHFFFAOYSA-N 2-(2-cyclohex-3-en-1-ylethylhydrazinylidene)propanoic acid Chemical compound OC(=O)C(C)=NNCCC1CCC=CC1 SAVMSLHOOJTVJR-UHFFFAOYSA-N 0.000 description 1
- IPGKROMWTLUUOT-UHFFFAOYSA-N 2-(2-cyclohexylethylhydrazinylidene)propanoic acid Chemical compound OC(=O)C(C)=NNCCC1CCCCC1 IPGKROMWTLUUOT-UHFFFAOYSA-N 0.000 description 1
- BOHVIWUFHXRQHD-UHFFFAOYSA-N 2-(2-cyclopentylethylhydrazinylidene)propanoic acid Chemical compound OC(=O)C(C)=NNCCC1CCCC1 BOHVIWUFHXRQHD-UHFFFAOYSA-N 0.000 description 1
- APULSDJLVFGJHG-UHFFFAOYSA-N 2-(2-ethylbutylhydrazinylidene)propanoic acid Chemical compound CCC(CC)CNN=C(C)C(O)=O APULSDJLVFGJHG-UHFFFAOYSA-N 0.000 description 1
- LUNXTKMYBXHPSU-UHFFFAOYSA-N 2-(2-ethylhexylhydrazinylidene)propanoic acid Chemical compound CCCCC(CC)CNN=C(C)C(O)=O LUNXTKMYBXHPSU-UHFFFAOYSA-N 0.000 description 1
- XCKUNPKWWVMURZ-UHFFFAOYSA-N 2-(2-methylpropylhydrazinylidene)propanoic acid Chemical compound CC(C)CNN=C(C)C(O)=O XCKUNPKWWVMURZ-UHFFFAOYSA-N 0.000 description 1
- LZTTXWHJWGFZRC-UHFFFAOYSA-N 2-(3,3-dimethylbutylhydrazinylidene)propanoic acid Chemical compound OC(=O)C(C)=NNCCC(C)(C)C LZTTXWHJWGFZRC-UHFFFAOYSA-N 0.000 description 1
- NTSMBVBKRTVSFJ-UHFFFAOYSA-N 2-(3-cyclopentylpropylhydrazinylidene)propanoic acid Chemical compound OC(=O)C(C)=NNCCCC1CCCC1 NTSMBVBKRTVSFJ-UHFFFAOYSA-N 0.000 description 1
- YEAMDJSQTCOJTI-UHFFFAOYSA-N 2-(3-methylbutylhydrazinylidene)propanoic acid Chemical compound CC(C)CCNN=C(C)C(O)=O YEAMDJSQTCOJTI-UHFFFAOYSA-N 0.000 description 1
- QVRJSUUYYFZCFZ-UHFFFAOYSA-N 2-(4-methylhexylhydrazinylidene)propanoic acid Chemical compound CCC(C)CCCNN=C(C)C(O)=O QVRJSUUYYFZCFZ-UHFFFAOYSA-N 0.000 description 1
- YFSHRWXCGAQHPZ-UHFFFAOYSA-N 2-(4-methylpentylhydrazinylidene)propanoic acid Chemical compound CC(C)CCCNN=C(C)C(O)=O YFSHRWXCGAQHPZ-UHFFFAOYSA-N 0.000 description 1
- NDEFYBJKCSDMFJ-UHFFFAOYSA-N 2-(5-methylhexylhydrazinylidene)propanoic acid Chemical compound CC(C)CCCCNN=C(C)C(O)=O NDEFYBJKCSDMFJ-UHFFFAOYSA-N 0.000 description 1
- QLSFQXOVODLAHV-UHFFFAOYSA-N 2-(cyclohexylhydrazinylidene)propanoic acid Chemical compound OC(=O)C(C)=NNC1CCCCC1 QLSFQXOVODLAHV-UHFFFAOYSA-N 0.000 description 1
- BWPBYHRJHWYWRY-UHFFFAOYSA-N 2-(dec-9-enylhydrazinylidene)propanoic acid Chemical compound OC(=O)C(C)=NNCCCCCCCCC=C BWPBYHRJHWYWRY-UHFFFAOYSA-N 0.000 description 1
- BDWGVKUAMYSKQW-UHFFFAOYSA-N 2-(decylhydrazinylidene)propanamide Chemical compound CCCCCCCCCCNN=C(C)C(N)=O BDWGVKUAMYSKQW-UHFFFAOYSA-N 0.000 description 1
- VPWLXKNCZAMGDH-UHFFFAOYSA-N 2-(decylhydrazinylidene)propanoic acid Chemical compound CCCCCCCCCCNN=C(C)C(O)=O VPWLXKNCZAMGDH-UHFFFAOYSA-N 0.000 description 1
- QZHWESTUQGGHJL-UHFFFAOYSA-N 2-(dodecylhydrazinylidene)propanoic acid Chemical compound CCCCCCCCCCCCNN=C(C)C(O)=O QZHWESTUQGGHJL-UHFFFAOYSA-N 0.000 description 1
- MRNGTPYCVLTQEK-UHFFFAOYSA-N 2-(heptan-2-ylhydrazinylidene)propanoic acid Chemical compound CCCCCC(C)NN=C(C)C(O)=O MRNGTPYCVLTQEK-UHFFFAOYSA-N 0.000 description 1
- RLBVXEJQICRODO-UHFFFAOYSA-N 2-(hex-1-enylhydrazinylidene)propanoic acid Chemical compound CCCCC=CNN=C(C)C(O)=O RLBVXEJQICRODO-UHFFFAOYSA-N 0.000 description 1
- FRHFHOUXONAWCG-UHFFFAOYSA-N 2-(hex-3-enylhydrazinylidene)propanoic acid Chemical compound CCC=CCCNN=C(C)C(O)=O FRHFHOUXONAWCG-UHFFFAOYSA-N 0.000 description 1
- KHTXCMBZBJTRBZ-UHFFFAOYSA-N 2-(hex-4-enylhydrazinylidene)propanoic acid Chemical compound CC=CCCCNN=C(C)C(O)=O KHTXCMBZBJTRBZ-UHFFFAOYSA-N 0.000 description 1
- IDHDJZAAXWYJSA-UHFFFAOYSA-N 2-(hex-5-enylhydrazinylidene)propanoic acid Chemical compound OC(=O)C(C)=NNCCCCC=C IDHDJZAAXWYJSA-UHFFFAOYSA-N 0.000 description 1
- KUSQXACIGUDUMF-UHFFFAOYSA-N 2-(octadecylhydrazinylidene)propanoic acid Chemical compound CCCCCCCCCCCCCCCCCCNN=C(C)C(O)=O KUSQXACIGUDUMF-UHFFFAOYSA-N 0.000 description 1
- NETWAMWHZFFNDL-UHFFFAOYSA-N 2-cycloheptylethylhydrazine;hydrochloride Chemical compound Cl.NNCCC1CCCCCC1 NETWAMWHZFFNDL-UHFFFAOYSA-N 0.000 description 1
- YKONFNRNHKTUDJ-UHFFFAOYSA-N 2-cyclohex-3-en-1-ylethylhydrazine;hydrochloride Chemical compound Cl.NNCCC1CCC=CC1 YKONFNRNHKTUDJ-UHFFFAOYSA-N 0.000 description 1
- HKIVTJOODWTEBW-UHFFFAOYSA-N 2-cyclohexylethylhydrazine Chemical compound NNCCC1CCCCC1 HKIVTJOODWTEBW-UHFFFAOYSA-N 0.000 description 1
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- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- SUFNSZIJMAMLCJ-UHFFFAOYSA-N 2-ethylhexylhydrazine Chemical compound CCCCC(CC)CNN SUFNSZIJMAMLCJ-UHFFFAOYSA-N 0.000 description 1
- 125000006040 2-hexenyl group Chemical group 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- GHRBRHSMUPEADI-UHFFFAOYSA-N 3,3-dimethylbutylhydrazine;hydrochloride Chemical compound Cl.CC(C)(C)CCNN GHRBRHSMUPEADI-UHFFFAOYSA-N 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- WHWIJTYMEOCDFT-UHFFFAOYSA-N 3-cyclohexylprop-1-enylhydrazine;hydrochloride Chemical compound Cl.NNC=CCC1CCCCC1 WHWIJTYMEOCDFT-UHFFFAOYSA-N 0.000 description 1
- SZKZAWOWHNTOOQ-UHFFFAOYSA-N 3-cyclohexylpropylhydrazine;hydrochloride Chemical compound Cl.NNCCCC1CCCCC1 SZKZAWOWHNTOOQ-UHFFFAOYSA-N 0.000 description 1
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- ZGISDJPJIHAFON-UHFFFAOYSA-N 3-methylbutylhydrazine;hydrochloride Chemical compound Cl.CC(C)CCNN ZGISDJPJIHAFON-UHFFFAOYSA-N 0.000 description 1
- 125000006042 4-hexenyl group Chemical group 0.000 description 1
- CAGACUWDXQTGKT-UHFFFAOYSA-N 4-methylhexylhydrazine;dihydrochloride Chemical compound Cl.Cl.CCC(C)CCCNN CAGACUWDXQTGKT-UHFFFAOYSA-N 0.000 description 1
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- 125000006043 5-hexenyl group Chemical group 0.000 description 1
- IZQGLYQLXCYWGO-UHFFFAOYSA-N 5-methylhexylhydrazine;hydrochloride Chemical compound Cl.CC(C)CCCCNN IZQGLYQLXCYWGO-UHFFFAOYSA-N 0.000 description 1
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- OQBRYWWNIWXQBK-UHFFFAOYSA-N dec-9-enylhydrazine;hydrochloride Chemical compound Cl.NNCCCCCCCCC=C OQBRYWWNIWXQBK-UHFFFAOYSA-N 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- ZMKZXUXIGOMQBQ-UHFFFAOYSA-N decylhydrazine;dihydrochloride Chemical compound Cl.Cl.CCCCCCCCCCNN ZMKZXUXIGOMQBQ-UHFFFAOYSA-N 0.000 description 1
- YDSDREDXERGPTR-UHFFFAOYSA-N decylhydrazine;hydrochloride Chemical compound Cl.CCCCCCCCCCNN YDSDREDXERGPTR-UHFFFAOYSA-N 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- HTYLRISWZCEJAD-UHFFFAOYSA-N dodecylhydrazine;dihydrochloride Chemical compound Cl.Cl.CCCCCCCCCCCCNN HTYLRISWZCEJAD-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 230000004153 glucose metabolism Effects 0.000 description 1
- 230000002641 glycemic effect Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- NOFDKWCBBPHCDM-UHFFFAOYSA-N heptan-2-ylhydrazine;oxalic acid Chemical compound OC(=O)C(O)=O.CCCCCC(C)NN NOFDKWCBBPHCDM-UHFFFAOYSA-N 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- OVQNWGCPHIRNNB-UHFFFAOYSA-N heptylhydrazine 2-(heptylhydrazinylidene)propanoic acid hydrochloride Chemical compound C(CCCCCC)NN=C(C(=O)O)C.Cl.C(CCCCCC)NN OVQNWGCPHIRNNB-UHFFFAOYSA-N 0.000 description 1
- ZMGCUVWCWNBFMI-UHFFFAOYSA-N hex-1-enylhydrazine;oxalic acid Chemical compound OC(=O)C(O)=O.CCCCC=CNN ZMGCUVWCWNBFMI-UHFFFAOYSA-N 0.000 description 1
- SHSMYNVEUSCXLV-UHFFFAOYSA-N hex-3-enylhydrazine;hydrochloride Chemical compound Cl.CCC=CCCNN SHSMYNVEUSCXLV-UHFFFAOYSA-N 0.000 description 1
- CJXNGKPHBHRQEU-UHFFFAOYSA-N hex-4-enylhydrazine;hydrochloride Chemical compound Cl.CC=CCCCNN CJXNGKPHBHRQEU-UHFFFAOYSA-N 0.000 description 1
- JTGNZHGIMFPLQF-UHFFFAOYSA-N hex-5-enylhydrazine;hydrochloride Chemical compound Cl.NNCCCCC=C JTGNZHGIMFPLQF-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- RRIJZRZUKBIERI-UHFFFAOYSA-N hexylhydrazine;hydrochloride Chemical compound Cl.CCCCCCNN RRIJZRZUKBIERI-UHFFFAOYSA-N 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 208000021822 hypotensive Diseases 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005394 methallyl group Chemical group 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- LEPFDJZATUOEPP-UHFFFAOYSA-N nonylhydrazine;hydrochloride Chemical compound Cl.CCCCCCCCCNN LEPFDJZATUOEPP-UHFFFAOYSA-N 0.000 description 1
- WUQYDWGNDDKVNA-UHFFFAOYSA-N octadecylhydrazine;dihydrochloride Chemical compound Cl.Cl.CCCCCCCCCCCCCCCCCCNN WUQYDWGNDDKVNA-UHFFFAOYSA-N 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- QAIUKOKJKLIFAP-UHFFFAOYSA-N octylhydrazine;hydrochloride Chemical compound Cl.CCCCCCCCNN QAIUKOKJKLIFAP-UHFFFAOYSA-N 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- ZTILHLWDFSMCLZ-UHFFFAOYSA-N prop-2-enylhydrazine Chemical compound NNCC=C ZTILHLWDFSMCLZ-UHFFFAOYSA-N 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- WKPUPFFUKBBFCK-UHFFFAOYSA-N propan-2-ylhydrazine 2-(propan-2-ylhydrazinylidene)propanoic acid hydrochloride Chemical compound C(C)(C)NN=C(C(=O)O)C.Cl.C(C)(C)NN WKPUPFFUKBBFCK-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- FPOLWERNILTNDK-UHFFFAOYSA-N pyruvamide Chemical compound CC(=O)C(N)=O FPOLWERNILTNDK-UHFFFAOYSA-N 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate 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
- 239000002904 solvent Substances 0.000 description 1
- 125000001424 substituent group Chemical group 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
- DDPWVABNMBRBFI-UHFFFAOYSA-N tert-butylhydrazine;hydron;chloride Chemical compound Cl.CC(C)(C)NN DDPWVABNMBRBFI-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000002889 tridecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C251/72—Hydrazones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Diabetes (AREA)
- General Chemical & Material Sciences (AREA)
- Emergency Medicine (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Endocrinology (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (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)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
147197
Det er kendt, at nogle monoaminoxidasehæmmere, f.eks. phenelzin (2-phenylethylhydrazin) eller mebanazin (1-phenylethylhydrazin) i høj dosering kan være hypoglykæmisk virksomme (Adnitt, P.I.: Hypoglyce-mic action of monoamino oxidase inhibitors, Diabetes 17: 628-633 (1968), Wickstrom, L., Petterson, K.: Treatment of diabetics with monoamino oxidase inhibitors, Lancet 2: 995-997 (1964), Cooper, A.J., Keddie, K.M.G.: Hypotensive collapse and hypoglycaemia after mebanazin - a monoamin-oxidase inhibitor, Lancet 1: 1133-1135 (1964)).
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Hovedvirkningen er dog monoaminoxidasens (MAO) inhibitorvirkning, således at disse forbindelser ganske vist har fået anvendelse i terapien af psykiske sygdomme (Van Praag, H.M.: Leijnse, B.: The influence of some antidepressives of the hydrazin type on the glucose metabolism in depressed patients, Clin. Chim. Acta 8: 466-475 (1963)), men ikke kunne anvendes som blodsukkersænkende medikamenter.
Det var derfor en opgave at finde forbindelser, som udviser en hypo= glykæmisk virkning i et dosisområde, hvori MAO-hæmningen ikke optræder eller kun optræder uvæsentligt.
Overraskende har det vist sig, at hydrazoner af pyrodruesyre med en fra phenelzin afvigende hydrazinkomponent udviser en betydeligt forstærket hypoglykæmisk virkning sammenlignet med de tilsvarende hydraziner, medens den MAO-hæmmende virkning er trængt næsten helt tilbage. Den foreliggende opfindelse angår derfor en analogifremgangsmåde til fremstilling af hidtil ukendte 2-hydrazonopropionsyrederivater med den almene formel 1 /CH3 R-X-NH-N=C (I)
^COOH
hvor R er en ligekædet, mættet alkylrest med 1-18 carbonatomer, en forgrenet, mættet alkylrest med 1-9 carbonatomer eller en ligekædet eller forgrenet alkenylrest med 1-10 carbonatomer, og X er en valensstreg, eller R er en eventuelt umættet cykloalkylrest med
3-8 carbonatomer, og X er en ligekædet eller forgrenet, mættet eller umættet alkylengruppe med 1-4 carbonatomer, eller deres fysiologisk uskadelige salte, G^c.j-alkylestere eller amider, hvilken fremgangsmåde 'er ejendommelig ved, at man omsætter en hydrazin med den almene formel II
r-x-nh-nh2 (II)
hvor R og X har den ovennævnte betydning, med et propionsyrederivat af formlen III
CH3-C (Y,Y') - COR' (III) hvor Y og Y1 er halogen eller C^-C^ alkoxy,eller tilsammen er et oxygen- 3 147197 atom, og R' er hydroxy, en C^-C^ alkoxy- eller en aminogruppe, og derpå om nødvendigt frigør syren og/eller omdanner den til et farmaceutisk acceptabelt salt, en ester eller et amid som ovenfor defineret.
Forbindelsen 2-(cyklohexylhydrazono)-propionsyre, som ikke er omfattet af kravet, er kendt fra litteraturen (Chem. Zen-tral Bl 1911, II, 362).
Farmakologiske undersøgelser viste dog, at dette stof er uvirksomt sammenlignet med forbindelserne fremstillet ifølge opfindelsen.
Som ligekædede, mættede alkylrester kan f.eks. anvendes methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl og tetradecyl. Foretrukne forgrenede, mættede alkylrester er isopropyl-, isobutyl-, sek.-butyl-, tert.-butyl-, isopentyl-, isohexyl-, 2-ethylbutyl-, 3,3-dimethylbutyl-, 1-methylhexyl-, 4-methylhexyl-, 5-methylhexyl-, 2-ethylhexyl-, 3,5-dimethylhexyl- og 3-methyloctylresterne.
Ligekædede eller forgrenede, umættede alkylrester er fortrinsvis allyl-, 3-butenyl-, 3-pentenyl-, 2-, 3-, 4- eller 5-hexenyl-, 9-dece= nyl-, 2-methylallyl-, 3,7-dimethyl-6-octenylresterne.
Mættede og umættede cykliske alkylrester som substituenten R er carbo= cykliske grupper med 3-8 carbonatomer. Som mættede carbocykliske grupper kan der fortrinsvis være tale om cyklopentyl-, cyklohexyl- og cykloheptylresten og som umættede carbocykliske grupper 1-, 2- eller 3-cyklohexen-l-yl-resten.
Opfindelsen angår endvidere fremstilling af samtlige stereoisomere former af en forbindelse med den almene formel I, som kan optræde på grund af de i mange forbindelser værende asymmetriske carbonatomer eller dobbeltbindinger (C=C; C=N).
Halogen som resterne Y og Y' i formlen III betyder fluor, chlor, brom og jod, men fortrinsvis chlor og brom. Alkoxygrupper som resterne Y, Y' og R' er fortrinsvis methoxy- og ethoxygrupper.
4 147197
Ved fremgangsmåden bliver der til den substituerede hydrazin II
eller et tilsvarende salt i et egnet polært opløsningsmiddel (f.eks. vand, en lavere alkohol eller eddikesyre) sat et propionsyrederivat III eller fortrinsvis dettes salte, og eventuelt indstilles der ved hjælp af en stødpude, f.eks. natriumacetat,på et svagt surt pH-område. Reaktionen forløber ved stuetemperatur, men kan også udføres under opvarmning. Hydrazonerne I kan filtreres fra reaktionsmediet som tungt-opløselige forbindelser eller ekstraheres med egnede opløsningsmidler, f.eks. upolære opløsningsmidler.
Eventuelt kan den substituerede hydrazin II også fremstilles udfra den tilsvarende amin, med hydroxylamin-O-sulfonsyre, og den ønskede hydrazon udfældes i samme beholder efter tilsætning af propionsyre-derivatet III.
De substituerede hydraziner eller deres salte er til dels hidtil ukendte forbindelser. En renfremstilling er i almindelighed ikke nødvendig, således at de fremkomne råprodukter kan benyttes. Hydrazinerne kan fremstilles på i og for sig kendte måder, f.eks. ved omsætning af hydrazin med tilsvarende alkylhalogenider.
Som fysiologisk uskadelige salte kan der især være tale om alkalime= talsalte, jordalkalimetalsalte eller ammoniumsalte (samt eventuelt salte med ligeledes blodsukkersænkende biguanider). Fremstillingen af disse salte sker på i og for sig kendt måde, f.eks. ved omsætning med de tilsvarende frie baser, carbonater eller alkoholater.
De ved den ovenfor anførte fremgangsmåde som mellemprodukter optrædende estere kan isoleres eller eventuelt forsæbes direkte til de tilsvarende carboxylsyrer. Omvendt kan de fremkomne carboxylsyrer igen omsættes på i og for sig kendte måder til de ønskede estere. Forsæbningerne af esterne udføres fortrinsvis i alkalisk medium.
Som estere af carboxylsyrerne med den almene formel I kan nævnes estere af methanol, ethanol, propanol eller isopropanol.
5 147197
Opfindelsen belyses nærmere i følgende eksempler.
Eksempel 1.
2U (2-cyklohexyl-ethylhydrazono) -propionsyre.
2,7 g (2-cyklohexylethyl)-hydrazinsulfat (smeltepunkt 185-187°C under dekomponering) opløses i 50 ml vand, og under omrøring ved stuetemperatur tilsættes en opløsning af 1,1 g pyrodruesyre og 3,0 g natrium= acetat (trihydrat) i 10 ml vand. Derved udskilles først en olie, som snart krystalliserer. Stoffet frasuges, opløses i vand under tilsætning af 6 ml 2 N natronlud og syrnes langsomt med 2 N saltsyre. Den først fremkomne mængde indeholder forureninger, frasuges og ka's'seres'
Den ved yderligere syrning udfældede hovedmængde er ren og tørres i ekssikkator over calciumchlorid.
Udbytte 1,6 g (67% af det teoretiske), smeltepunkt 47°C.
På analog måde får man ved omsætning af pyrodruesyre a) med isobutylhydrazinsulfat (smeltepunkt 127°C under dekomponering) 2-(isobutylhydrazono)-propionsyre smeltepunkt 88°C (af isooctan) b) med methylallylhydrazinoxalat (smeltepunkt 160-161°C under dekomponering) 2-(methylallylhydrazono)-propionsyre smeltepunkt 68-69°C (af isooctan + toluen) c) med propylhydrazinoxalat 2-(propylhydrazono)-propionsyre smeltepunkt 56-58°C (af ligroin + toluen) d) med isopentylhydrazinhydrochlorid (smeltepunkt 128-130°C under dekomponering) 6 147197 2-(isopentylhydrazono)-propionsyre smeltepunkt 48-50°C (af isooctan) e) med octylhydrazinhydrochlorid
2- (octylhydrazono)-propionsyre smeltepunkt 37-38°C
f) med (cyklohexylmethyl)-hydrazinhydrochlorid 2- (cyklohexylmethyl-hydrazono)-propionsyre smeltepunkt 81-82°C (af isooctan + toluen) g) med isopropylhydrazinhydrochlorid 2-(isopropylhydrazono)-propionsyre smeltepunkt 83-84°C (af ligroin) h) med allylhydrazinhydrochlorid 2-(allylhydrazono)-propionsyre smeltepunkt 47-48°C (af methylenchlorid) i) med butylhydrazinsulfat 2- (butylhydrazono)-propionsyre smeltepunkt 56-57°C (af cyklohexan) j) med sekundær butylhydrazinsulfat 2- (sek.-butylhydrazono)-propionsyre smeltepunkt 67-68°C (udfældet med soda og omkrystalliseret af HC1) k) med tert.-butylhydrazinhydrochlorid 2-(tert.-butylhydrazono)-propionsyre smeltepunkt 99-100°C (isopropanol + vand) l) med hexylhydrazinhydrochlorid η 147197 2-(hexylhydrazono)-propionsyre smeltepunkt 44°C (opløst med soda og udkrystalliseret med HC1) m) med 4-methylpentylhydrazinhydrochlorid (råprodukt) 2-(4-methylpentylhydrazono)-propionsyre olieagtig n) med 2-ethylbutylhydrazinhydrochlorid (smeltepunkt 118-125°C, råprodukt) 2-(2-ethylbutylhydrazono)-propionsyre smeltepunkt 83-86°C (af isopropanol + vand) o) med 5-hexenylhydrazinhydrochlorid (smeltepunkt 130-135°C, råprodukt) 2-(5-hexenylhydrazono)-propionsyre olieagtig p) med heptylhydrazinhydrochlorid 2- (heptylhydrazono)-propionsyre smeltepunkt 48-49°C (af ligroin) q) med cyklopentylhydrazin 2-(cyklopentylhydrazono)-propionsyre smeltepunkt 87-88°C (isooctan + toluen) q) med (2-cyklopentylethyl)-hydrazinhydrochlorid (smeltepunkt 160°C, råprodukt) 2-(2-cyklopentylethylhydrazono)-propionsyre smeltepunkt 64-65°C (af ether + ligroin) r) med 2-(3-cyklohexen-l-yl)-ethylhydrazinhydrochlorid (smeltepunkt 98-138°C, råprodukt) 8 147197 2- [2-(3-cyklohexen-l-yl)-ethylhydrazono]-propionsyre smeltepunkt 67-68°C (af isopropanol + vand) s) med 2-cykloheptylethylhydrazinhydrochlorid (smeltepunkt 132-145°C, råprodukt) 2-(2-cykloheptylethylhydrazono)-propionsyre ; smeltepunkt 59-61°C (af cyklohexan) t) med decylhydrazinhydrochlorid (smeltepunkt 94°C under dekomponering) 2-(decylhydrazono)-propionsyre smeltepunkt 48-49°C (af isooctan) u) med nonylhydrazinhydrochlorid (smeltepunkt 115°C under dekomponering) 2- (nonylhydrazono)-propionsyre smeltepunkt 46-47°C (af isooctan)
Eksempel 2.
Natrium-2-(pentylhydrazono)-propionat.
2,3 g pentylhydrazinhydrochlorid opløses i 10 ml vand og blandes med en opløsning af 1,5 g pyrodruesyre og 2,2 g natriumacetat i 5 ml vand.
Der danner sig en olie. Man omrører i ca. 1 time, ekstraherer olien med methylenchlorid, vasker opløsningen med vand, tørrer den med na= triumsulfat og afdamper methylenchloridet. Den olieagtige remanens opløser man i 8 ml ethanol og tilsætter under omrøring 3,0 ml af en 30% natriummethylatopløsning. Natrium-2-(pentylhydrazono)-propionatet udskiller sig, frasuges og vaskes først med lidt ethanol og derpå med ether.
Udbytte 1,9 g (59% af det teoretiske), smeltepunkt 225-228°C under dekomponering.
9 147197 På analog måde får man ved omsætning af pyrodruesyre a) med (2-cyklohexylethyl)-hydrazinsulfat og påfølgende fremstilling af natriumsaltet
Natrium-2-(2-cyklohexylethylhydrazono)-propionat smeltepunkt 230-233°C under dekomponering b) med (3-cyklohexylpropyl)-hydrazinhydrochlorid (smeltepunkt 220-225°C) og påfølgende fremstilling af natriumsaltet
Natrium-2-(3-cyklohexylpropylhydrazono)-propionat Smeltepunkt 224-226°C under dekomponering.
Eksempel 3.
På analog måde som beskrevet i eksempel 1 får man ved omsætning af pyrodruesyre a) med 9-decenylhydrazinhydrochlorid (råprodukt) 2-(9-decenylhydrazono)-propionsyre smeltepunkt 39-41°C (hexan) b) med 2-hexenylhydrazinoxalat (smeltepunkt 166-167°C) 2-(2-hexenylhydrazono)-propionsyre olieagtig c) med methylhydrazinsulfat 2-(methylhydrazono)-propionsyre smeltepunkt 89-91°C (isopropanol + isooctan) d) med 5-methylhexylhydrazinhydrochlorid (smeltepunkt 184-188°C, råprodukt) 2-(5-methylhexylhydrazono)-propionsyre olieagtig.
10 147197
Eksempel 4 2- (decylhydrazono)-propionsyreainid.
6,5 g decylhydrazindihydrochlorid opløses i 30 ml vand, og der tilsættes en opløsning af 2,3 g pyrodruesyreamid i 40 ml vand. Ved tilsætning af fortyndet natronlud indstilles pH-værdien på ca. 3, og opløsningen henstilles i køleskab i 16 timer. Derved udkrystalliserer det ønskede stof, som frasuges og omkrystalliseres af isooctan.
Udbytte 3,3 g (51,6% af det teoretiske), smeltepunkt 64°C under de-komponering.
Eksempel 5 .
Pa analog måde som beskrevet i eksempel 1 får man ved omsætning af pyrodruesyre a) med 4-hexenylhydrazinhydrochlorid, fri forbindelse kogepunkt^ 82-89°C, HCl-salt hygroskopisk 2-(4-hexenylhydrazono)-propionsyre olieagtig.
Forbindelsen indeholder 0,6 mol vand
b) med octadecylhydrazindihydrochlorid, smeltepunkt 264°C under de-komponering efter sintring fra 88°C
2-(octadecylhydrazono)-propionsyre smeltepunkt 80°C (af isooctan)
c) med 3,3-dimethylbutylhydrazinhydrochlorid, smeltepunkt 213-214°C
2-(3,3-dimethylbutylhydrazono)-propionsyre smeltepunkt 95°C (af isooctan) cL) med 3-cyklohexyl-2-propenylhydrazinhydrochlorid, smeltepunkt 165°C under dekomponering 2- (3-cyklohexyl-2-propenylhydrazono)-propionsyre olieagtig
e) med dodecylhydrazindihydrochlorid, smeltepunkt 210°C under dekomponering efter sintring fra 80°C
2-(dodecylhydrazono)-propionsyre smeltepunkt 60-61°C (med isooctan) 11 147197 f) med 4-methylhexylhydrazindihydrochlorid (hygroskopisk, fri base,
Kp13 86-88°C) 2-(4-methylhexylhydrazono)-propionsyre olieagtig
g) med 1-methylhexylhydrazinoxalat, smeltepunkt 95°C
2-(1-methylhexylhydrazono)-propionsyre olieagtig h) med (2-ethylhexyl)-hydrazin (fri base, Kpg ^ 56-60°C) 2-(2-ethylhexylhydrazono)-propionsyre olieagtig
i) med (3-hexenyl)-hydrazinhydrochlorid, smeltepunkt 166-167°C
2-(3-hexenylhydrazono)-propionsyre olieagtig
k) med (3-cyklopentylpropyl)-hydrazinhydrochlorid, smeltepunkt 197-202°C
2-(3-cvklopentvlpropvlhvdrazono)-propionsyre olieagtig
Eksempel 6 .
På analog måde som i eksempel 2 får man ved omsætning af pyrodruesyre a) med 3-cyklohexyl-2-methyl-2-propenylhydrazinhydrochlorid (olieagtig) og påfølgende fremstilling af natriumsaltet
Natrium-2-(3-cyklohexyl-2-methyl-2-propenyihydrazono)-propionat smeltepunkt 266-268°C under dekomponering (af ethanol).
For at illustrere de farmakologiske egenskaber af forbindelserne fremstillet ifølge opfindelsen blev den blodsukkersænkende virkning bestemt og sammenlignet med nogle tilsvarende hydraziner. De hidtil ukendte forbindelser sænker blodsukkeret i en lavere koncentration end de tilsvarende hydraziner, således at de er egnede som antidiabetika.
12 147197
Udførelse af blodsukkerprøverne.
Metabolisk sunde krydsede fastende marsvin fik injiceret stofferne som vandige opløsninger af deres natriumsalte i.p. En kontrolgruppe modtager ækvivalente mængder af en isotonisk NaCl opløsning. Direkte før og med en times mellemrum op til den fjerde time efter injektionen udtages 10μ1 blod fra en ørevene, og blodglucosen bestemmes ved hjælp af den ubesværede og specifikke hexokinaseteknik. Den dosås betragtes som tærskelværdi, som kendeligt nedsætter koncentrationen af blodglueose sammenlignet med kontrolgruppen.
Tabel
Eks. Nr. Tærskelværdi i marsvin, mq/kg 1 15 I c 25 ld 25 le 5 li 25 II 10 1 m 25 lo 10 (flere dyr) lp 10 1 q 10-25 lr 25 2 10 (flere dyr) 2 b 25 3b 15-25 3 d 20 5 a 10 5 d 25 5 f 10 5 g 15 - 20 5 h 30 5 i 10 5 k 15-20
Cyklohexylethylhydrazin 50
Phenelzin > 50
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE2739380 | 1977-09-01 | ||
DE19772739380 DE2739380A1 (de) | 1977-09-01 | 1977-09-01 | N-substituierte 2-hydrazono-propionsaeure-derivate, verfahren zur herstellung derselben und arzneimittel, die diese enthalten |
Publications (3)
Publication Number | Publication Date |
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DK373478A DK373478A (da) | 1979-03-02 |
DK147197B true DK147197B (da) | 1984-05-14 |
DK147197C DK147197C (da) | 1984-10-29 |
Family
ID=6017861
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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DK373478A DK147197C (da) | 1977-09-01 | 1978-08-24 | Analogifremgangsmaade til fremstilling af 2-hydrazonopropionsyrederivater |
Country Status (22)
Country | Link |
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US (1) | US4206231A (da) |
EP (1) | EP0001144B1 (da) |
JP (1) | JPS5452028A (da) |
AR (1) | AR216531A1 (da) |
AT (1) | AT363454B (da) |
AU (1) | AU516223B2 (da) |
CA (1) | CA1109077A (da) |
CS (1) | CS199744B2 (da) |
DD (1) | DD138652A5 (da) |
DE (2) | DE2739380A1 (da) |
DK (1) | DK147197C (da) |
ES (1) | ES472749A1 (da) |
FI (1) | FI66843C (da) |
HU (1) | HU177956B (da) |
IE (1) | IE47260B1 (da) |
IL (1) | IL55427A (da) |
IT (1) | IT1098384B (da) |
PL (1) | PL111073B1 (da) |
PT (1) | PT68483A (da) |
SU (1) | SU725555A1 (da) |
YU (1) | YU204778A (da) |
ZA (1) | ZA784969B (da) |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3031842A1 (de) * | 1980-08-23 | 1982-04-08 | Boehringer Mannheim Gmbh, 6800 Mannheim | N-substituierte brenztraubensaeurehydrazone, verfahren zu ihrer herstellung und arzneimittel, die diese verbindungen enthalten |
DE3036281A1 (de) | 1980-09-26 | 1982-05-13 | Boehringer Mannheim Gmbh, 6800 Mannheim | 0-substituierte brenztraubensaeureoxime, verfahren zu ihrer herstellung, ihre verwendung sowie arzneimittel, die diese verbindungen enthalten |
HU197668B (en) * | 1984-07-17 | 1989-05-29 | Boehringer Mannheim Gmbh | Process for producing pharmaceutical compositions comprising alpha-ketocarboxylic acid hydrazines and oximes |
WO2005014530A2 (en) * | 2003-08-08 | 2005-02-17 | La Jolla Pharmaceutical Co. | Inhibitors of semicarbazide-sensitive amine oxidase (ssao) and vap-1 mediated adhesion useful for treatment of diseases |
WO2006041922A2 (en) * | 2004-10-08 | 2006-04-20 | Dara Biosciences, Inc. | Agents and methods for administration to the central nervous system |
US20090012067A1 (en) * | 2005-02-14 | 2009-01-08 | Luciano Rossetti | Modulation of Hypothalamic Atp-Sensitive Potassium Channels |
US8242058B2 (en) * | 2006-07-21 | 2012-08-14 | Wisconsin Alumni Research Foundation | Reagents and methods for appending functional groups to proteins |
US9047945B2 (en) | 2012-10-15 | 2015-06-02 | Marvell World Trade Ltd. | Systems and methods for reading resistive random access memory (RRAM) cells |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CA1106389A (en) * | 1976-09-25 | 1981-08-04 | Rainer Haeckel | 2-(phenylalkylhydrazono)-propionic acid derivatives and the preparation thereof |
DE2643303A1 (de) * | 1976-09-25 | 1978-03-30 | Haeckel Rainer | Hypoglykaemisch wirksames arzneimittel |
-
1977
- 1977-09-01 DE DE19772739380 patent/DE2739380A1/de not_active Withdrawn
-
1978
- 1978-08-16 CA CA309,492A patent/CA1109077A/en not_active Expired
- 1978-08-17 US US05/934,291 patent/US4206231A/en not_active Expired - Lifetime
- 1978-08-22 ES ES472749A patent/ES472749A1/es not_active Expired
- 1978-08-23 FI FI782574A patent/FI66843C/fi not_active IP Right Cessation
- 1978-08-24 AU AU39233/78A patent/AU516223B2/en not_active Expired
- 1978-08-24 SU SU2652698A patent/SU725555A1/ru active
- 1978-08-24 DK DK373478A patent/DK147197C/da not_active IP Right Cessation
- 1978-08-24 IL IL55427A patent/IL55427A/xx unknown
- 1978-08-25 AR AR273447A patent/AR216531A1/es active
- 1978-08-25 DD DD78207485A patent/DD138652A5/xx unknown
- 1978-08-28 PL PL1978209256A patent/PL111073B1/pl unknown
- 1978-08-28 IT IT27078/78A patent/IT1098384B/it active
- 1978-08-28 PT PT68483A patent/PT68483A/pt unknown
- 1978-08-29 EP EP78200166A patent/EP0001144B1/de not_active Expired
- 1978-08-29 AT AT0627478A patent/AT363454B/de not_active IP Right Cessation
- 1978-08-29 YU YU02047/78A patent/YU204778A/xx unknown
- 1978-08-29 DE DE7878200166T patent/DE2860777D1/de not_active Expired
- 1978-08-30 HU HU78BO1732A patent/HU177956B/hu unknown
- 1978-08-31 IE IE1756/78A patent/IE47260B1/en unknown
- 1978-08-31 CS CS785653A patent/CS199744B2/cs unknown
- 1978-08-31 ZA ZA00784969A patent/ZA784969B/xx unknown
- 1978-09-01 JP JP10743578A patent/JPS5452028A/ja active Granted
Also Published As
Publication number | Publication date |
---|---|
IT7827078A0 (it) | 1978-08-28 |
DE2739380A1 (de) | 1979-03-08 |
DK147197C (da) | 1984-10-29 |
AR216531A1 (es) | 1979-12-28 |
DE2860777D1 (en) | 1981-09-24 |
PL209256A1 (pl) | 1979-06-04 |
CS199744B2 (en) | 1980-07-31 |
IT1098384B (it) | 1985-09-07 |
AU3923378A (en) | 1980-02-28 |
US4206231A (en) | 1980-06-03 |
EP0001144A1 (de) | 1979-03-21 |
PT68483A (de) | 1978-09-01 |
IL55427A (en) | 1981-12-31 |
AU516223B2 (en) | 1981-05-21 |
FI66843C (fi) | 1984-12-10 |
ES472749A1 (es) | 1979-02-16 |
JPS5452028A (en) | 1979-04-24 |
AT363454B (de) | 1981-08-10 |
DD138652A5 (de) | 1979-11-14 |
IE47260B1 (en) | 1984-02-08 |
ATA627478A (de) | 1981-01-15 |
FI782574A7 (fi) | 1979-03-02 |
EP0001144B1 (de) | 1981-06-17 |
HU177956B (en) | 1982-02-28 |
ZA784969B (en) | 1979-09-26 |
PL111073B1 (en) | 1980-08-30 |
IE781756L (en) | 1979-03-01 |
SU725555A3 (en) | 1980-03-30 |
YU204778A (en) | 1982-10-31 |
DK373478A (da) | 1979-03-02 |
JPS6218545B2 (da) | 1987-04-23 |
CA1109077A (en) | 1981-09-15 |
FI66843B (fi) | 1984-08-31 |
SU725555A1 (ru) | 1980-03-30 |
IL55427A0 (en) | 1978-10-31 |
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