CH540902A - Acryloyl-heterocyclic carboxylic acids - with diuretic and saluretic activity - Google Patents
Acryloyl-heterocyclic carboxylic acids - with diuretic and saluretic activityInfo
- Publication number
- CH540902A CH540902A CH1718270A CH1718270A CH540902A CH 540902 A CH540902 A CH 540902A CH 1718270 A CH1718270 A CH 1718270A CH 1718270 A CH1718270 A CH 1718270A CH 540902 A CH540902 A CH 540902A
- Authority
- CH
- Switzerland
- Prior art keywords
- formula
- carboxylic acid
- benzofuran
- methyl
- carboxylic acids
- Prior art date
Links
- 239000002934 diuretic Substances 0.000 title description 2
- 230000001882 diuretic effect Effects 0.000 title description 2
- 230000000894 saliuretic effect Effects 0.000 title description 2
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 6
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 5
- 125000005843 halogen group Chemical group 0.000 claims abstract description 5
- 239000012433 hydrogen halide Substances 0.000 claims abstract description 5
- 229910000039 hydrogen halide Inorganic materials 0.000 claims abstract description 5
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 4
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 3
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 11
- -1 heterocyclic carboxylic acids Chemical class 0.000 claims description 9
- 150000007530 organic bases Chemical class 0.000 claims description 6
- 150000007529 inorganic bases Chemical class 0.000 claims description 5
- 150000002367 halogens Chemical group 0.000 claims description 4
- 150000002431 hydrogen Chemical group 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 239000007795 chemical reaction product Substances 0.000 claims description 2
- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 239000011593 sulfur Substances 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 abstract description 5
- 229910052801 chlorine Inorganic materials 0.000 abstract description 5
- 229910052731 fluorine Inorganic materials 0.000 abstract 2
- 239000002253 acid Substances 0.000 abstract 1
- 150000007513 acids Chemical class 0.000 abstract 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 6
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- FUHWOXRDZFAXPI-UHFFFAOYSA-N 5-(2-bromo-2-methylpropanoyl)-6-methyl-1-benzofuran-2-carboxylic acid Chemical compound CC1=CC2=C(C=C(O2)C(=O)O)C=C1C(C(C)(C)Br)=O FUHWOXRDZFAXPI-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 230000029142 excretion Effects 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- NRQCYWFYNWDXDP-UHFFFAOYSA-N 6-methoxy-5-(2-methylidenebutanoyl)-1-benzofuran-2-carboxylic acid Chemical compound C1=C(OC)C(C(=O)C(=C)CC)=CC2=C1OC(C(O)=O)=C2 NRQCYWFYNWDXDP-UHFFFAOYSA-N 0.000 description 2
- DLCASBFCJDKEJT-UHFFFAOYSA-N 6-methyl-5-(2-methylprop-2-enoyl)-1-benzofuran-2-carboxylic acid Chemical compound C1=C(C)C(C(=O)C(=C)C)=CC2=C1OC(C(O)=O)=C2 DLCASBFCJDKEJT-UHFFFAOYSA-N 0.000 description 2
- OVKDHPPBTOWMFD-UHFFFAOYSA-N 6-methyl-5-(2-methylpropanoyl)-1-benzofuran-2-carboxylic acid Chemical compound CC1=CC2=C(C=C(O2)C(=O)O)C=C1C(C(C)C)=O OVKDHPPBTOWMFD-UHFFFAOYSA-N 0.000 description 2
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 230000031709 bromination Effects 0.000 description 2
- 238000005893 bromination reaction Methods 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- DLTWLXUYSLIIQN-UHFFFAOYSA-N furacrinic acid Chemical compound C1=C(C)C(C(=O)C(=C)CC)=CC2=C1OC(C(O)=O)=C2 DLTWLXUYSLIIQN-UHFFFAOYSA-N 0.000 description 2
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- CQLFBEKRDQMJLZ-UHFFFAOYSA-M silver acetate Chemical compound [Ag+].CC([O-])=O CQLFBEKRDQMJLZ-UHFFFAOYSA-M 0.000 description 2
- 229940071536 silver acetate Drugs 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- IKMJGHPYOYVETB-UHFFFAOYSA-N 1,4-dioxane;ethyl acetate Chemical compound CCOC(C)=O.C1COCCO1 IKMJGHPYOYVETB-UHFFFAOYSA-N 0.000 description 1
- DGMOBVGABMBZSB-UHFFFAOYSA-N 2-methylpropanoyl chloride Chemical compound CC(C)C(Cl)=O DGMOBVGABMBZSB-UHFFFAOYSA-N 0.000 description 1
- CYTFMBZVPUBGMY-UHFFFAOYSA-N 3,6-dimethyl-5-(2-methylidenebutanoyl)-1-benzofuran-2-carboxylic acid Chemical compound CC1=C(OC2=C1C=C(C(=C2)C)C(C(CC)=C)=O)C(=O)O CYTFMBZVPUBGMY-UHFFFAOYSA-N 0.000 description 1
- YVEZTZZKJXJOEF-UHFFFAOYSA-N 4,6-dimethyl-5-(2-methylidenebutanoyl)-1-benzofuran-2-carboxylic acid Chemical compound CC1=C(C(=CC2=C1C=C(O2)C(=O)O)C)C(C(CC)=C)=O YVEZTZZKJXJOEF-UHFFFAOYSA-N 0.000 description 1
- UPUYXAOCRSQHJL-UHFFFAOYSA-N 4-chloro-5-(2-methylidenebutanoyl)-1-benzofuran-2-carboxylic acid Chemical compound ClC1=C(C=CC2=C1C=C(O2)C(=O)O)C(C(CC)=C)=O UPUYXAOCRSQHJL-UHFFFAOYSA-N 0.000 description 1
- FDOKRIDWESVKTM-UHFFFAOYSA-N 4-chloro-5-(2-methylidenebutanoyl)-1H-indole-2-carboxylic acid Chemical compound ClC1=C2C=C(NC2=CC=C1C(C(CC)=C)=O)C(=O)O FDOKRIDWESVKTM-UHFFFAOYSA-N 0.000 description 1
- IPBNJWPJVRBOCK-UHFFFAOYSA-N 4-methyl-5-(2-methylidenebutanoyl)-1-benzofuran-2-carboxylic acid Chemical compound CC1=C(C=CC2=C1C=C(O2)C(=O)O)C(C(CC)=C)=O IPBNJWPJVRBOCK-UHFFFAOYSA-N 0.000 description 1
- UWWHJLKVWYOXKR-UHFFFAOYSA-N 5-(2-methylidenebutanoyl)-1-benzofuran-2-carboxylic acid Chemical compound C=C(C(=O)C=1C=CC2=C(C=C(O2)C(=O)O)C1)CC UWWHJLKVWYOXKR-UHFFFAOYSA-N 0.000 description 1
- FTWKTEYMZJWOSZ-UHFFFAOYSA-N 6-chloro-5-(2-methylidenebutanoyl)-1-benzofuran-2-carboxylic acid Chemical compound C=C(C(=O)C=1C(=CC2=C(C=C(O2)C(=O)O)C1)Cl)CC FTWKTEYMZJWOSZ-UHFFFAOYSA-N 0.000 description 1
- FRPJVIKXPDPKEW-UHFFFAOYSA-N 6-ethoxy-5-(2-methylidenebutanoyl)-1-benzofuran-2-carboxylic acid Chemical compound C(C)OC1=CC2=C(C=C(O2)C(=O)O)C=C1C(C(CC)=C)=O FRPJVIKXPDPKEW-UHFFFAOYSA-N 0.000 description 1
- JYVZRRLDAFCFJH-UHFFFAOYSA-N 6-ethyl-5-(2-methylidenebutanoyl)-1-benzofuran-2-carboxylic acid Chemical compound C(C)C1=CC2=C(C=C(O2)C(=O)O)C=C1C(C(CC)=C)=O JYVZRRLDAFCFJH-UHFFFAOYSA-N 0.000 description 1
- PSBUPVYEUWGKHS-UHFFFAOYSA-N 6-methoxy-5-(2-methylprop-2-enoyl)-1-benzofuran-2-carboxylic acid Chemical compound COC1=CC2=C(C=C(O2)C(=O)O)C=C1C(C(C)=C)=O PSBUPVYEUWGKHS-UHFFFAOYSA-N 0.000 description 1
- STGSJLZWQHRTGE-UHFFFAOYSA-N 6-methyl-1-benzofuran-2-carboxylic acid Chemical compound CC1=CC=C2C=C(C(O)=O)OC2=C1 STGSJLZWQHRTGE-UHFFFAOYSA-N 0.000 description 1
- UKNLZJGUUXBXPU-UHFFFAOYSA-N 6-methyl-5-(2-methylidenepentanoyl)-1-benzofuran-2-carboxylic acid Chemical compound CC1=CC2=C(C=C(O2)C(=O)O)C=C1C(C(CCC)=C)=O UKNLZJGUUXBXPU-UHFFFAOYSA-N 0.000 description 1
- VMQDSECUDLRTDK-UHFFFAOYSA-N 6-methyl-5-(3-methyl-2-methylidenebutanoyl)-1-benzofuran-2-carboxylic acid Chemical compound CC1=CC2=C(C=C(O2)C(=O)O)C=C1C(C(C(C)C)=C)=O VMQDSECUDLRTDK-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- GVBRVJZOXXPFLR-UHFFFAOYSA-N CC(C(C(C=CC1=C2C=C(C(O)=O)S1)=C2Cl)=O)=C Chemical compound CC(C(C(C=CC1=C2C=C(C(O)=O)S1)=C2Cl)=O)=C GVBRVJZOXXPFLR-UHFFFAOYSA-N 0.000 description 1
- GJVQPEVJKAYSFZ-UHFFFAOYSA-N CCC(C(C(C=CC1=C2C(Cl)=C(C(O)=O)O1)=C2Cl)=O)=C Chemical compound CCC(C(C(C=CC1=C2C(Cl)=C(C(O)=O)O1)=C2Cl)=O)=C GJVQPEVJKAYSFZ-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229910021607 Silver chloride Inorganic materials 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 229910052808 lithium carbonate Inorganic materials 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000005920 sec-butoxy group Chemical group 0.000 description 1
- ADZWSOLPGZMUMY-UHFFFAOYSA-M silver bromide Chemical compound [Ag]Br ADZWSOLPGZMUMY-UHFFFAOYSA-M 0.000 description 1
- HKZLPVFGJNLROG-UHFFFAOYSA-M silver monochloride Chemical compound [Cl-].[Ag+] HKZLPVFGJNLROG-UHFFFAOYSA-M 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 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
- 210000002700 urine Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
- C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D307/85—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Title acids of formula (I) (where R is lower alkyl; X is O, S, NH or NHC3; Y is H, F, Cl, Br or CH3; and Z1 and Z2 are H, F, Cl, Br, lower alkyl or alkoxy), and their salts with org. and inorg. bases, are prepd. by eliminating hydrogen halide from a cpd. of formula I (where R-C(=CH2)- is R-C(CH3(Q)-; Q is halogen), and opt. converting the reaction prod. into a salt with an org. or inorg. base.
Description
Die vorliegende Erfindung betrifft ein Verfahren zur Herstellung von neuen heterocyclischen Carbonsäuren.
Heterocyclische Carbonsäuren der Formel I,
EMI1.1
in welcher
R eine niedere Alkylgruppe,
X Sauerstoff, Schwefel, die Iminogruppe oder die Methyliminogruppe,
Y Wasserstoff, Halogen bis Atomnummer 35 oder die Methylgruppe und
Z1 sowie Z2 Wasserstoff, Halogen bis Atomnummer 35, eine niedere Alkyl- oder Alkoxygruppe bedeuten, sowie ihre Salze mit anorganischen oder organischen Basen sind bisher nicht bekanntgeworden.
Wie nun gefunden wurde, besitzen die neuen Verbindungen wertvolle pharmakologische Eigenschaften. Sie zeigen diuretische und saluretische Wirkung. Diese Eigenschaften kennzeichnen diese Verbindungen als geeignet zur Behandlung von Störungen, welche durch mangelhafte Ausscheidung von Elektrolyten, insbesondere von Natriumchlorid, bedingt sind. Solche Störungen sind die Ursache von Ödemen und Hypertonien. Diese Verbindungen, z. B. die 4-Chlor-5-(2 methylen-butvryl)-indol-2-carbonsäure, die 6-Methoxy-5 (2-methylen-butyryl)-b enzofuran-2-carbonsäure und die 6-Methyl-5-(2-methylen-butyryl)-benzofuran-2-carbonsäure vermögen am Hund und am Kaninchen bei einer Dosierung von 10 mg/kg p.o. die Harnausscheidung sowie die Ausscheidung der Natriumionen und der Chlorionen beträchtlich zu erhöhen.
In den heterocyclischen Carbonsäuren der Formel I nimmt Z1 die 4- oder 6-Stellung und Z2 die 6- oder 7-Stellung ein.
R, Z1 und Z2 bedeuten als niedere Alkylgruppen beispielsweise die Methyl-, Äthyl-, Propyl-, Isopropyl-, Butyl- oder die tert.-Butylgruppe und Z1 sowie Z2 als niedere Alkoxygruppen beispielsweise die Methoxy-, Äthoxy-, Propoxy-, Isopropoxy-, Butoxy- oder die sek.-Butoxygruppe.
Nach dem erfindungsgemässen Verfahren stellt man die Verbindungen der Formel I her, indem man von einer Verbindung der Formel II
EMI1.2
in welcher R, X, Y, Z1 und Z2 die unter der Formel I angegebene Bedeutung haben und Q ein Halogenatom bedeutet, Halogenwasserstoff abspaltet und gewünschtenfalls das erhaltene Reaktionsprodukt mit einer anorganischen oder organischen Base in ein Salz überführt.
Als Halogenatom ist Q vorzugsweise Chlor oder Brom.
Die Abspaltung des Halogenwasserstoffes geschieht z. B. durch Kochen in einer organischen Base, wie Kollidin oder Dimethylformamid. Man kann den Halogenwasserstoff jedoch auch abspalten, indem man die Verbindung der Formel II in einem organischen Lösungsmittel wie Benzol oder Toluol in Gegenwart von Silberacetat oder in Dimethylformamid in Gegenwart von Lithiumbromid und Lithiumcarbonat kocht.
Die Ausgangsstoffe der Formel II erhält man z. B. ausgehend von Carbonsäuren der Formel III
EMI1.3
in welcher X, Y, Zl und Z2 die unter Formel I angegebene Bedeutung haben.
Diese Carbonsäuren können z. B. nach Friedel-Crafts mit Hilfe von Aluminiumchlorid in Nitrobenzol mit Carbonsäurechlorid der Formel IV,
EMI1.4
in welcher R die unter Formel I angegebene Bedeutung hat und Q ein Halogenatom bedeutet, in 5-Stellung acyliert werden. Sie können aber auch hergestellt werden durch Bromieren oder Chlorieren einer gesättigten 5-Alkanoylverbindung der Formel V.
EMI1.5
in welcher R, X, Y, Z1 und Z2 die unter Formel I angegebene Bedeutung haben und deren Herstellung ebenfalls nach Friedel-Crafts, durch Umsetzung einer Carbonsäure der Formel III mit einem Carbonsäurechlorid der Formel VI,
R-CH2-COCI(VI) in welcher R die unter Formel I angegebene Bedeutung hat, erfolgen kann. Diese Chlorierung oder Bromierung wird z. B.
durch Zugabe der äquimolaren Menge Chlor oder Brom zur Lösung einer Verbindung der Formel V in einem geeigneten Lösungsmittel wie Eisessig, Nitrobenzol oder einem halogenierten Kohlenwasserstoff erreicht.
Die neuen Wirkstoffe oder die pharmazeutisch annehmbaren Salze derselben werden vorzugsweise peroral verabreicht. Zur Salzbildung können anorganische oder organische Basen, wie beispielsweise Alkali- oder Erdalkalihydroxide, Carbonate oder Bicarbonate, Träthanolamin oder Cholin, verwendet werden. Die täglichen Dosen bewegen sich zwischen 50 und 1000 mg für erwachsene Patienten.
Geeignete Doseneinheitsformen, wie Dragees, Tabletten, enthalten vorzugsweise 25-SW mg eines erfindungsgemassen Wirkstoffes, und zwar 20-80 % einer Verbindung der Formel.
Das nachfolgende Beispiel erläutert die Herstellung der neuen Verbindungen der Formel I näher. Die Temperaturen sind in Celsiusgraden angegeben.
Beispiel a) Man rührt 1,2 g 6-Methyl-5-(2-brom-2-methyl-propionyl)-benzofuran-2-carbonsäure in 80 ml absolutem Benzol mit 1,8 g Silberacetat während 4 Stunden unter Rückfluss.
Dann wird das Reaktionsgemisch auf eine Mischung von 100 g Eis und 10 ml konz. Salzsäure gegossen, gut durchgerührt und vom ausgefallenen Niederschlag, bestehend aus Silberbromid und Silberchlorid abfiltriert. Man wäscht den Rückstand mit 100 ml Essigsäureäthylester nach. Das Filtrat wird in einen Scheidetrichter gebracht, die organische Schicht wird abgetrennt, mit 50 ml Wasser gewaschen, über Magnesiumsulfat getrocknet und eingedampft. Der Rückstand wird aus Benzol umkristallisiert, und man erhält 6-Methyl-5-(2 methylen-propionyl)-benzofuran-2-carbonsäure vom Smp.
185-186 .
b) Das Ausgangsmaterial, die 6-Methyl-5-(2-brom-2- methyl-propionyl)-benzofuran-2-carbonsäure wird wie folgt hergestellt:
3,0 g 6-Methyl-5-isobutyryl-benzofuran-2-carbonsäure werden in 30 ml Eisessig gelöst, zu dieser Lösung gibt man bei 50 während 15 Minuten tropfenweise 0,7 ml Brom zu.
Man rührt weitere 15 Minuten bei der gleichen Temperatur weiter. Dann wird der Eisessig im Rotationsverdampfer abgedampft und der Rückstand aus Essigester-Dioxan umkristallisiert. Man erhält so 3,65 g 6-Methyl-5-(2-brom-2-methylpropionyl)-benzofuran-2-carbonsäure vom Smp. 231-233" c) Die 6-Methyl-5-isobutyryl-benzofuran-2-carbonsäure wird analog Beispiel lb) aus 6-Methyl-benzofuran-2-carbonsäure (vgl. K. von Auwers, Ann. Chem. 408, [1915] 255) mit Isobutyrylchlorid und Aluminiumchlorid in Nitrobenzol hergestellt. Sie schmilzt bei 174-175" (aus Methyläthylketon).
In analoger Weise zu diesem Beispiel werden die folgenden Verbindungen erhalten:
2. 5-(2-Methylen-butyryl)-benzofuran-2-carbonsäure vomSmp. 128-129 .
3. 3,4-Dichlor-5-(2-methylen-butyryl)-benzofuran-2- carbonsäurevom Smp. 210-211".
4. l-Methyl3 ,4-dichlor-5- (2-methylen-butytyl)-indol- 2-carbonsäurevom Smp. 163-164".
5. 4-Methyl-5-(2-methylen-butyryl)-benzofuran-2-carbonsäure vom Smp. 159-160 .
6. 6-Methyl-5 -(2-methylen-butyryl)-benzofuran-2-carbon- säure vom Smp. 141-142".
7. 4, 6-Dimethyl-5-(2-methylen-butyryl)-b enzofuran-2- carbonsäure vom Smp. 208-210 .
8. 4-Chlor-5-(2-methylen-propionyl)-benzothiophen-2carbonsäure vom Smp. 239-241".
9. 6-Methyl-5-(2-methylen-propionyl)-benzofuran-2carbonsäure vom Smp. 185-186".
10. 6-Methyl-5-(2-methylen-valeroyl)-benzofuran-2carbonsäure vom Smp. 160-162".
11. 6-Methyl-5-(2-methylen-3 -methylbutyryl)-benzo- furan-2-carbonsäure vom Smp. 153-154".
12. 6-Methoxy-5-(2-methylen-propionyl)-benzofuran-2carbonsäure vom Smp. 169-170 .
13. 6-Methoxy-5-(2-methylen-butyryl)-benzofuran-2 carbonsäure vom Smp. 153-156 .
14. 6-Äthoxy-5-(2-methylen-butyryl)-benzofuran-2 carbonsäure vom Smp. 143-144 .
15. 6-Äthyl-5 -(2-methylen-butyryl)-benzofuran-2-carbon- säure vom Smp. 121-122".
16. 6-Chlor-5-(2-methylen-butyryl)-benzofuran-2-carbonsäure vom Smp. 188-189 .
17. 4-Chlor-5-(2-methylen-butyryl)-benzofuran-2-carbonsäure vom Smp. 156-158".
18. 3 ,6-Dimethyl-5-(2-methylen-butyryl)-benzofuran-2- carbonsäure vom Smp. 153-154".
The present invention relates to a process for the preparation of new heterocyclic carboxylic acids.
Heterocyclic carboxylic acids of the formula I,
EMI1.1
in which
R is a lower alkyl group,
X oxygen, sulfur, the imino group or the methylimino group,
Y is hydrogen, halogen up to atomic number 35 or the methyl group and
Z1 and Z2 denote hydrogen, halogen up to atomic number 35, a lower alkyl or alkoxy group, and their salts with inorganic or organic bases have not yet become known.
As has now been found, the new compounds have valuable pharmacological properties. They show diuretic and saluretic effects. These properties characterize these compounds as being suitable for the treatment of disorders which are caused by inadequate excretion of electrolytes, in particular sodium chloride. Such disorders are the cause of edema and hypertension. These compounds, e.g. B. 4-chloro-5- (2-methylen-butyryl) -indole-2-carboxylic acid, 6-methoxy-5 (2-methylen-butyryl) -benzofuran-2-carboxylic acid and 6-methyl-5- (2-methylen-butyryl) -benzofuran-2-carboxylic acid can be used in dogs and rabbits at a dose of 10 mg / kg po to considerably increase the excretion of urine and the excretion of sodium ions and chlorine ions.
In the heterocyclic carboxylic acids of the formula I, Z1 is in the 4- or 6-position and Z2 is in the 6- or 7-position.
Lower alkyl groups R, Z1 and Z2 are, for example, methyl, ethyl, propyl, isopropyl, butyl or tert-butyl groups, and Z1 and Z2 are lower alkoxy groups, for example methoxy, ethoxy, propoxy and isopropoxy -, butoxy or the sec-butoxy group.
According to the process according to the invention, the compounds of the formula I are prepared by using a compound of the formula II
EMI1.2
in which R, X, Y, Z1 and Z2 have the meaning given under the formula I and Q is a halogen atom, splits off hydrogen halide and, if desired, converts the reaction product obtained into a salt with an inorganic or organic base.
As a halogen atom, Q is preferably chlorine or bromine.
The elimination of the hydrogen halide is done, for. B. by boiling in an organic base such as collidine or dimethylformamide. However, the hydrogen halide can also be split off by boiling the compound of the formula II in an organic solvent such as benzene or toluene in the presence of silver acetate or in dimethylformamide in the presence of lithium bromide and lithium carbonate.
The starting materials of the formula II are obtained, for. B. starting from carboxylic acids of formula III
EMI1.3
in which X, Y, Zl and Z2 have the meaning given under formula I.
These carboxylic acids can, for. B. Friedel-Crafts using aluminum chloride in nitrobenzene with carboxylic acid chloride of the formula IV,
EMI1.4
in which R has the meaning given under formula I and Q is a halogen atom, are acylated in the 5-position. However, they can also be prepared by bromination or chlorination of a saturated 5-alkanoyl compound of the formula V.
EMI1.5
in which R, X, Y, Z1 and Z2 have the meaning given under formula I and their production also according to Friedel-Crafts, by reacting a carboxylic acid of the formula III with a carboxylic acid chloride of the formula VI,
R-CH2-COCI (VI) in which R has the meaning given under formula I, can take place. This chlorination or bromination is z. B.
achieved by adding the equimolar amount of chlorine or bromine to the solution of a compound of formula V in a suitable solvent such as glacial acetic acid, nitrobenzene or a halogenated hydrocarbon.
The new active ingredients or the pharmaceutically acceptable salts thereof are preferably administered orally. Inorganic or organic bases such as alkali or alkaline earth metal hydroxides, carbonates or bicarbonates, trethanolamine or choline can be used for salt formation. The daily doses range between 50 and 1000 mg for adult patients.
Suitable dosage unit forms, such as dragees, tablets, preferably contain 25 SW mg of an active ingredient according to the invention, specifically 20-80% of a compound of the formula.
The following example explains the preparation of the new compounds of the formula I in more detail. The temperatures are given in degrees Celsius.
Example a) 1.2 g of 6-methyl-5- (2-bromo-2-methyl-propionyl) -benzofuran-2-carboxylic acid in 80 ml of absolute benzene with 1.8 g of silver acetate are stirred under reflux for 4 hours.
Then the reaction mixture is concentrated on a mixture of 100 g of ice and 10 ml. Poured hydrochloric acid, stirred well and filtered off from the precipitate, consisting of silver bromide and silver chloride. The residue is washed with 100 ml of ethyl acetate. The filtrate is placed in a separatory funnel, the organic layer is separated, washed with 50 ml of water, dried over magnesium sulfate and evaporated. The residue is recrystallized from benzene, and 6-methyl-5- (2-methylene-propionyl) -benzofuran-2-carboxylic acid is obtained with a mp.
185-186.
b) The starting material, the 6-methyl-5- (2-bromo-2-methyl-propionyl) -benzofuran-2-carboxylic acid, is prepared as follows:
3.0 g of 6-methyl-5-isobutyryl-benzofuran-2-carboxylic acid are dissolved in 30 ml of glacial acetic acid, and 0.7 ml of bromine is added dropwise to this solution at 50 over 15 minutes.
The mixture is stirred for a further 15 minutes at the same temperature. The glacial acetic acid is then evaporated off in a rotary evaporator and the residue is recrystallized from ethyl acetate-dioxane. This gives 3.65 g of 6-methyl-5- (2-bromo-2-methylpropionyl) -benzofuran-2-carboxylic acid of melting point 231-233 "c) The 6-methyl-5-isobutyryl-benzofuran-2- carboxylic acid is prepared analogously to Example 1b) from 6-methylbenzofuran-2-carboxylic acid (cf. K. von Auwers, Ann. Chem. 408, [1915] 255) with isobutyryl chloride and aluminum chloride in nitrobenzene. It melts at 174-175 " (from methyl ethyl ketone).
The following compounds are obtained in a manner analogous to this example:
2. 5- (2-Methylen-butyryl) -benzofuran-2-carboxylic acid from Mp. 128-129.
3. 3,4-Dichloro-5- (2-methylene-butyryl) -benzofuran-2-carboxylic acid of m.p. 210-211 ".
4. 1-Methyl3, 4-dichloro-5- (2-methylen-butytyl) -indole-2-carboxylic acid of m.p. 163-164 ".
5. 4-Methyl-5- (2-methylene-butyryl) -benzofuran-2-carboxylic acid of m.p. 159-160.
6. 6-Methyl-5 - (2-methylene-butyryl) -benzofuran-2-carboxylic acid of m.p. 141-142 ".
7. 4,6-Dimethyl-5- (2-methylene-butyryl) -benzofuran-2-carboxylic acid of m.p. 208-210.
8. 4-Chloro-5- (2-methylene-propionyl) -benzothiophene-2-carboxylic acid of m.p. 239-241 ".
9. 6-Methyl-5- (2-methylene-propionyl) -benzofuran-2-carboxylic acid of m.p. 185-186 ".
10. 6-Methyl-5- (2-methylen-valeroyl) -benzofuran-2-carboxylic acid of m.p. 160-162 ".
11. 6-Methyl-5- (2-methylen-3-methylbutyryl) -benzo-furan-2-carboxylic acid of m.p. 153-154 ".
12. 6-Methoxy-5- (2-methylene-propionyl) -benzofuran-2-carboxylic acid of m.p. 169-170.
13. 6-Methoxy-5- (2-methylene-butyryl) -benzofuran-2-carboxylic acid of m.p. 153-156.
14. 6-Ethoxy-5- (2-methylene-butyryl) -benzofuran-2-carboxylic acid of m.p. 143-144.
15. 6-Ethyl-5 - (2-methylene-butyryl) -benzofuran-2-carboxylic acid of m.p. 121-122 ".
16. 6-Chloro-5- (2-methylen-butyryl) -benzofuran-2-carboxylic acid of m.p. 188-189.
17. 4-Chloro-5- (2-methylen-butyryl) -benzofuran-2-carboxylic acid of m.p. 156-158 ".
18. 3,6-Dimethyl-5- (2-methylene-butyryl) -benzofuran-2-carboxylic acid of m.p. 153-154 ".
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1718270A CH540902A (en) | 1968-07-17 | 1968-07-17 | Acryloyl-heterocyclic carboxylic acids - with diuretic and saluretic activity |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1718270A CH540902A (en) | 1968-07-17 | 1968-07-17 | Acryloyl-heterocyclic carboxylic acids - with diuretic and saluretic activity |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH540902A true CH540902A (en) | 1973-10-15 |
Family
ID=4423406
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1718270A CH540902A (en) | 1968-07-17 | 1968-07-17 | Acryloyl-heterocyclic carboxylic acids - with diuretic and saluretic activity |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH540902A (en) |
-
1968
- 1968-07-17 CH CH1718270A patent/CH540902A/en not_active IP Right Cessation
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