CH484094A - Process for the production of new benzofuran derivatives and their salts - Google Patents
Process for the production of new benzofuran derivatives and their saltsInfo
- Publication number
- CH484094A CH484094A CH1806969A CH1806969A CH484094A CH 484094 A CH484094 A CH 484094A CH 1806969 A CH1806969 A CH 1806969A CH 1806969 A CH1806969 A CH 1806969A CH 484094 A CH484094 A CH 484094A
- Authority
- CH
- Switzerland
- Prior art keywords
- formula
- salts
- hydrogen
- production
- benzofuran derivatives
- Prior art date
Links
- 150000003839 salts Chemical class 0.000 title claims description 7
- 238000000034 method Methods 0.000 title claims description 4
- 150000001907 coumarones Chemical class 0.000 title claims description 3
- 238000004519 manufacturing process Methods 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 150000007529 inorganic bases Chemical class 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- 125000004429 atom Chemical group 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 239000007795 chemical reaction product Substances 0.000 claims 1
- -1 heterocyclic carboxylic acids Chemical class 0.000 description 8
- 239000004480 active ingredient Substances 0.000 description 7
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Substances [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 108010010803 Gelatin Proteins 0.000 description 5
- 239000008273 gelatin Substances 0.000 description 5
- 229920000159 gelatin Polymers 0.000 description 5
- 235000019322 gelatine Nutrition 0.000 description 5
- 235000011852 gelatine desserts Nutrition 0.000 description 5
- 239000000454 talc Substances 0.000 description 5
- 229910052623 talc Inorganic materials 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- OFFSPAZVIVZPHU-UHFFFAOYSA-N 1-benzofuran-2-carboxylic acid Chemical compound C1=CC=C2OC(C(=O)O)=CC2=C1 OFFSPAZVIVZPHU-UHFFFAOYSA-N 0.000 description 3
- DXASAURXULABHM-UHFFFAOYSA-N 5-[2-bromo-2-(bromomethyl)butanoyl]-6-methyl-1-benzofuran-2-carboxylic acid Chemical compound BrC(C(=O)C=1C(=CC2=C(C=C(O2)C(=O)O)C1)C)(CC)CBr DXASAURXULABHM-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 3
- 230000029142 excretion Effects 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 229920001592 potato starch Polymers 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 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 2
- 244000215068 Acacia senegal Species 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 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
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 239000000205 acacia gum Substances 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000000975 dye Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical class C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 1
- RYPIRYIQTPHBCI-UHFFFAOYSA-N 4,6-dimethyl-1-benzofuran-2-carboxylic acid Chemical compound CC1=CC(C)=C2C=C(C(O)=O)OC2=C1 RYPIRYIQTPHBCI-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 229920000945 Amylopectin Polymers 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000207199 Citrus Species 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 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 1
- 241001466453 Laminaria Species 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 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
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 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
- 238000004587 chromatography analysis Methods 0.000 description 1
- 235000020971 citrus fruits Nutrition 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 150000004679 hydroxides 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
- 239000007788 liquid Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000003973 paint Substances 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000000894 saliuretic effect Effects 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 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
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 239000004296 sodium metabisulphite Substances 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
-
- 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
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Furan Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Verfahren zur Herstellung von neuen Benzofuranderivaten und ihren Salzen
Die vorliegende Erfindung betrifft ein Verfahren zur Herstellung neuer heterocyclischer Carbonsäuren, welche Benzolfuranderivat darstellen, mit wertvollen pharmakologischen Eigenschaften.
Heterocyclische Carbonsäuren der Formel
EMI1.1
in welcher Q ein Chlor- oder Bromatom, R Wasserstoff oder eine niedere Alkylgruppe, Y Wasserstoff oder die Methylgruppe und Z1 sowie Z, Wasserstoff oder eine niedere Alkyl- oder Alkoxygruppe oder ein Halogenatom bis Atomnummer 35 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 neuen Verbindungen vermögen am Hund und am Kaninchen sowohl die Harnausscheidung wie auch die Ausscheidung von Natrium- und Chlorionen beträchtlich zu erhöhen.
In den heterocyclischen Carbonsäuren der Formel I bedeuten R, Z1 und Z. als niedere Alkylgruppen beispielsweise die Methyl-, Athyl-, Propyl-, Isopropyl-, Butyl- oder die tert. Butylgruppe. Z1 und Ze bedeuten als niedere Alkoxygruppen die Methoxy-, Athoxy-, Propoxy-, Isopropoxy-, Butoxy- oder sek. Butoxygruppe.
Zur erfindungsgemässen Herstellung von Verbindungen der Formel I wird an eine Verbindung der Formel
EMI1.2
in welcher Y, Z1 und Z. die unter Formel I angegebene Bedeutung haben, nach Friedel Crafts mit einem Carbonsäurechlorid der Formel
EMI1.3
in welcher R und Q die unter der Formel I angegebene Bedeutung haben, in 5-Stellung acyliert.
Verbindungen der Formel III sind in der Literatur beschrieben, z. B. die Benzofuran-2-carbonsäure [vgl.
R. Fittig et al., Ann. Chem. 216, 162 (1883)1, die 6-Methyl-benzofuran-2-carbonsäure [vgl. K. von Auwers, Ann. Chem. 408, 255 (1915)1 und die 4,6 Dimethyl-benzofuran-2-carbonsäure (vgl. F. M. Dean et al., J. Chem. Soc. 1953, 1250).
Die neuen Wirkstoffe oder pharmazeutisch annehmbaren Salze derselben werden vorzugsweise peroral verabreicht. Zur Salzbildung können anorganische oder organische Basen, wie beispielsweise Alkali- oder Erdalkaligydroxide, Carbonate oder Bicarbonate, Triäthanolamin 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 bis 500 mg eines erfindungsgemässen Wirkstoffes, und zwar 20-80 % einer Verbindung der Formel I. Zu ihrer Her stellung kombiniert man den Wirkstoff z.
B. mit festen pulverförmigen Trägerstoffen, wie Lactose, Saccharose, Sorbit, Mannit; Stärken, wie Kartoffel-, Maisstärke oder Amylopektin, ferner Laminariapulver oder Citruspulpenpulver; Cellulosederivaten oder Gelatine, gegebenenfalls unter Zusatz von Gleitmitteln, wie Magnesium- oder Calciumstearat oder Polyäthylenglykolen, zu Tabletten oder zu DrageeKernen. Letztere überzieht man beispielsweise mit konzentrierten Zuckerlösungen, welche z. B. noch arabischen Gummi, Talk und/oder Titandioxid enthalten können, oder mit einem in leichtflüchtigen organischen Lösungsmitteln oder Lösungsmit telgemischen gelösten Lack. Diesen Überzügen können Farbstoffe zugefügt werden, z. B. zur Kennzeichnung verschiedener Wirkstoffdosen.
Als weitere orale Doseneinheitsformen eignen sich Steckkapseln aus Gelatine sowie weiche, geschlossene Kapseln aus Gelatine und einem Weichmacher, wie Glycerin. Die Steckkapseln enthalten den Wirkstoff vorzugsweise als Granulat, z. B.. in Mischung mit Füllstoffen, wie Maisstärke, und/oder Gleitmitteln, wie Talk oder Magnesiumstearat, und gegebenenfalls Stabilisatoren, wie Natriummetabisulfit (NaOS2O) oder Ascorbinsäure. In weichen Kapseln ist der Wirkstoff vorzugsweise in geeigneten Flüssigkeiten, wobei ebenfalls Stabilisatoren zugefügt sein können.
Die folgenden Vorschriften sollen die Herstellung von Tabletten und Dragees näher erläutern: a) 1000 g 5-(2-Brom-2-brommethyl-butyryl)-6-me- thyl-benzofuran-2-carbonsäure werden mit 500 g Lactose und 270 g Kartoffelstärke vermischt, die Mischung mit einer wässrigen Lösung von 8 g Gelatine befeuchtet und durch ein Sieb granuliert.
Nach dem Trocknen mischt man 60 g Kartoffelstärke, 60 g Talk, 10 g Magnesiumstearat und 20 g kolloidales Siliciumdioxid zu und presst die Mischung zu 10000 Tabletten von je 200 mg Gewicht und 100 mg Wirkstoffgehalt, die gewünschtenfalls mit Teilkerben zur feineren Anpassung der Dosierung versehen sein können. b) Aus 1000 g 5-(2-Brom-2-brommethyl-butyryl)-6- methyl-benzofuran-2-carbonsäure, 345 g Lactose und der wässrigen Lösung von 6 g Gelatine stellt man ein Granulat her, das man nach dem Trocknen mit 10 g kolloidalem Siliciumdioxid, 40 g Talk, 40 g Kartoffelstärke und 5 g Magnesiumstearat mischt und zu 10 000 Dragee-Kernen presst. Diese werden anschliessend mit einem konzentrierten Sirup aus 533 g krist. Saccharose, 20 g Schellack, 75 g arabischem Gummi, 250 g Talk, 20 g kolloidalem Siliciumdioxid und 1,5 g Farbstoff überzogen und getrocknet.
Die erhaltenen Dragees wiegen je 240 mg und enthalten je 100 mg Wirkstoff.
Das nachfolgende Beispiel erläutert die Herstellung der neuen Verbindungen der Formel I näher.
Die Temperaturen sind in Celsiusgraden angegeben.
Beispiel
8,0 g 6-Methyl-benzofuran-2-carbonsäure [K. von Auwers, Ann. Chem. 408, 255 (1915)1 werden in 40 ml Nitrobenzol aufgeschlämmt. Diese Suspension wird abgekühlt und zwischen 0 und +100 während 30 Minuten portionenweise mit 28 g Aluminiumchlorid (wasserfrei) versetzt. Nachher werden bei der gleichen Temperatur während 30 Minuten 20 g 2-Brom-2-bromethyl-buttersäurechlorid [Merck & Co., Neth. Appl. 6 411 330 (CA 63 9872 (1965)] ins Reaktionsgemisch getropft, dann langsam erwärmt, 48 Stunden bei 200 und 5 Stunden bei 500 gerührt. Nachher giesst man das Gemisch vorsichtig auf 500 g Eis und extrahiert den entstandenen Brei zweimal mit je 250 ml Essigsäure äthylester. Diese organischen Lösungen werden nach Waschen mit 100 ml Wasser zweimal mit je 100 ml konz.
Natriumhydrogencarbonatlösung ausgeschüttelt, die so erhaltenen wässrig alkalischen Lösungen mit 4n Salzsäure auf pH 3-4 angesäuert. Die erhaltene Suspension kristallisiert nach Rühren. Dann wird die Kristallmasse abgenutscht und im Vakuum bei 200 getrocknet.
Nach chromatographischer Reinigung auf Silicagel schmilzt die erhaltene 5-(2-Bromo-2-bromomethylbutyryl)-6-methyl-benzofuran-2-carbonsäure bei 193 bis 1950.
In analoger Weise wird die
5 (2-Brom-2-brommethyl-propionyl)-6 methyl-benzofuran-2-oarbonsäure, Smp. 210-2110 Zersetzung (aus Essigester), hergestellt.
Process for the production of new benzofuran derivatives and their salts
The present invention relates to a process for the preparation of new heterocyclic carboxylic acids, which are benzolfuran derivatives, with valuable pharmacological properties.
Heterocyclic carboxylic acids of the formula
EMI1.1
in which Q is a chlorine or bromine atom, R is hydrogen or a lower alkyl group, Y is hydrogen or the methyl group and Z1 and Z are hydrogen or a lower alkyl or alkoxy group or a halogen atom up to atom number 35, 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 new compounds are able to increase the urine excretion as well as the excretion of sodium and chlorine ions in dogs and rabbits.
In the heterocyclic carboxylic acids of the formula I, R, Z1 and Z. as lower alkyl groups are, for example, methyl, ethyl, propyl, isopropyl, butyl or tert. Butyl group. Z1 and Ze, as lower alkoxy groups, denote methoxy, ethoxy, propoxy, isopropoxy, butoxy or sec. Butoxy group.
For the preparation according to the invention of compounds of the formula I, a compound of the formula
EMI1.2
in which Y, Z1 and Z. have the meaning given under formula I, according to Friedel Crafts with a carboxylic acid chloride of the formula
EMI1.3
in which R and Q have the meaning given under formula I, acylated in the 5-position.
Compounds of formula III are described in the literature, e.g. B. the benzofuran-2-carboxylic acid [cf.
R. Fittig et al., Ann. Chem. 216, 162 (1883) 1, 6-methyl-benzofuran-2-carboxylic acid [cf. K. von Auwers, Ann. Chem. 408, 255 (1915) 1 and 4,6 dimethyl-benzofuran-2-carboxylic acid (cf. F. M. Dean et al., J. Chem. Soc. 1953, 1250).
The new active ingredients or pharmaceutically acceptable salts thereof are preferably administered orally. Inorganic or organic bases, such as alkali or alkaline earth hydroxides, carbonates or bicarbonates, triethanolamine 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 coated tablets, tablets, preferably contain 25 to 500 mg of an active ingredient according to the invention, namely 20-80% of a compound of the formula I. To prepare it, the active ingredient is combined, for.
B. with solid powdery carriers such as lactose, sucrose, sorbitol, mannitol; Starches, such as potato, corn starch or amylopectin, also laminaria powder or citrus pulp powder; Cellulose derivatives or gelatin, optionally with the addition of lubricants such as magnesium or calcium stearate or polyethylene glycols, to tablets or to coated tablets. The latter is coated, for example, with concentrated sugar solutions, which z. B. can contain gum arabic, talc and / or titanium dioxide, or with a paint dissolved in volatile organic solvents or solvents. Dyes can be added to these coatings, e.g. B. to identify different drug doses.
Push-fit capsules made of gelatin and soft, closed capsules made of gelatin and a plasticizer, such as glycerine, are suitable as further oral unit forms. The push-fit capsules contain the active ingredient preferably as granules, e.g. B. mixed with fillers, such as corn starch, and / or lubricants, such as talc or magnesium stearate, and optionally stabilizers, such as sodium metabisulphite (NaOS2O) or ascorbic acid. In soft capsules, the active ingredient is preferably in suitable liquids, it also being possible for stabilizers to be added.
The following instructions are intended to explain the production of tablets and coated tablets in more detail: a) 1000 g of 5- (2-bromo-2-bromomethyl-butyryl) -6-methylbenzofuran-2-carboxylic acid are mixed with 500 g of lactose and 270 g Potato starch mixed, the mixture moistened with an aqueous solution of 8 g gelatin and granulated through a sieve.
After drying, 60 g of potato starch, 60 g of talc, 10 g of magnesium stearate and 20 g of colloidal silicon dioxide are mixed in and the mixture is pressed into 10,000 tablets, each weighing 200 mg and containing 100 mg of active ingredient, which, if desired, can be provided with partial notches for fine adjustment of the dosage can. b) From 1000 g of 5- (2-bromo-2-bromomethyl-butyryl) -6-methyl-benzofuran-2-carboxylic acid, 345 g of lactose and the aqueous solution of 6 g of gelatin, granules are produced which are then after Drying with 10 g of colloidal silicon dioxide, 40 g of talc, 40 g of potato starch and 5 g of magnesium stearate, mixed and pressed to form 10,000 coated tablets. These are then crystallized with a concentrated syrup of 533 g. Sucrose, 20 g of shellac, 75 g of gum arabic, 250 g of talc, 20 g of colloidal silicon dioxide and 1.5 g of dye coated and dried.
The coated tablets each weigh 240 mg and each contain 100 mg of active ingredient.
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
8.0 g of 6-methyl-benzofuran-2-carboxylic acid [K. from Auwers, Ann. Chem. 408, 255 (1915) 1 are suspended in 40 ml of nitrobenzene. This suspension is cooled and 28 g of aluminum chloride (anhydrous) are added in portions between 0 and +100 for 30 minutes. Afterwards, 20 g of 2-bromo-2-bromoethyl-butyric acid chloride [Merck & Co., Neth. Appl. 6 411 330 (CA 63 9872 (1965)] was added dropwise to the reaction mixture, then slowly heated, stirred for 48 hours at 200 and 5 hours at 500. The mixture is then carefully poured onto 500 g of ice and the resulting paste is extracted twice with 250 ml each time Ethyl acetate These organic solutions are washed with 100 ml of water twice with 100 ml of conc.
Shaken out sodium hydrogen carbonate solution, acidified the resulting aqueous alkaline solutions with 4N hydrochloric acid to pH 3-4. The suspension obtained crystallizes after stirring. The crystal mass is then suction filtered and dried at 200 in a vacuum.
After purification by chromatography on silica gel, the 5- (2-bromo-2-bromomethylbutyryl) -6-methyl-benzofuran-2-carboxylic acid obtained melts between 193 and 1950.
In an analogous way, the
5 (2-Bromo-2-bromomethyl-propionyl) -6 methyl-benzofuran-2-carboxylic acid, m.p. 210-2110 decomposition (from ethyl acetate).
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1806969A CH484094A (en) | 1967-07-28 | 1967-07-28 | Process for the production of new benzofuran derivatives and their salts |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1806969A CH484094A (en) | 1967-07-28 | 1967-07-28 | Process for the production of new benzofuran derivatives and their salts |
| CH1076467A CH484092A (en) | 1967-07-28 | 1967-07-28 | Process for the preparation of new heterocyclic carboxylic acids |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH484094A true CH484094A (en) | 1970-01-15 |
Family
ID=4366590
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1807069A CH484095A (en) | 1967-07-28 | 1967-07-28 | Process for the preparation of new heterocyclic carboxylic acids |
| CH1806969A CH484094A (en) | 1967-07-28 | 1967-07-28 | Process for the production of new benzofuran derivatives and their salts |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1807069A CH484095A (en) | 1967-07-28 | 1967-07-28 | Process for the preparation of new heterocyclic carboxylic acids |
Country Status (15)
| Country | Link |
|---|---|
| AT (4) | AT281811B (en) |
| BG (2) | BG15387A3 (en) |
| BR (1) | BR6800997D0 (en) |
| CH (2) | CH484095A (en) |
| CS (2) | CS153467B2 (en) |
| DK (1) | DK121087B (en) |
| FI (2) | FI49415C (en) |
| GT (1) | GT197640170A (en) |
| IE (1) | IE32222B1 (en) |
| IL (1) | IL30442A (en) |
| NO (1) | NO122751B (en) |
| PL (1) | PL69796B1 (en) |
| SE (1) | SE364270B (en) |
| SU (1) | SU393827A3 (en) |
| YU (1) | YU32705B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2467004C2 (en) * | 2010-10-07 | 2012-11-20 | Учреждение Российской Академии Наук Институт Нефтехимии И Катализа Ран | METHOD OF OBTAINING METHYL ESTER OF 2-BENZO[b]FURANCARBOXYLIC ACID |
-
1967
- 1967-07-28 CH CH1807069A patent/CH484095A/en not_active IP Right Cessation
- 1967-07-28 CH CH1806969A patent/CH484094A/en not_active IP Right Cessation
-
1968
- 1968-07-19 FI FI682063A patent/FI49415C/en active
- 1968-07-19 NO NO2865/68A patent/NO122751B/no unknown
- 1968-07-19 SE SE09915/68A patent/SE364270B/xx unknown
- 1968-07-19 FI FI682064A patent/FI49416C/en active
- 1968-07-19 DK DK351368AA patent/DK121087B/en unknown
- 1968-07-25 YU YU1783/68A patent/YU32705B/en unknown
- 1968-07-26 CS CS547268A patent/CS153467B2/cs unknown
- 1968-07-26 AT AT07301/68A patent/AT281811B/en not_active IP Right Cessation
- 1968-07-26 PL PL1968128332A patent/PL69796B1/pl unknown
- 1968-07-26 CS CS719771*1A patent/CS153468B2/cs unknown
- 1968-07-26 BG BG012203A patent/BG15387A3/en unknown
- 1968-07-26 BG BG012202A patent/BG15386A3/en unknown
- 1968-07-26 AT AT729868A patent/AT280272B/en not_active IP Right Cessation
- 1968-07-26 IL IL30442A patent/IL30442A/en unknown
- 1968-07-26 BR BR200997/68A patent/BR6800997D0/en unknown
- 1968-07-26 SU SU1415775A patent/SU393827A3/ru active
- 1968-07-26 IE IE904/68A patent/IE32222B1/en unknown
- 1968-07-26 AT AT446869A patent/AT283346B/en not_active IP Right Cessation
- 1968-07-26 AT AT06940/69A patent/AT285595B/en not_active IP Right Cessation
-
1976
- 1976-02-13 GT GT197640170A patent/GT197640170A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| FI49416B (en) | 1975-02-28 |
| YU178368A (en) | 1974-12-31 |
| YU32705B (en) | 1975-06-30 |
| PL69796B1 (en) | 1973-10-31 |
| CS153467B2 (en) | 1974-02-25 |
| FI49416C (en) | 1975-06-10 |
| BR6800997D0 (en) | 1973-01-02 |
| BG15387A3 (en) | 1976-05-10 |
| AT285595B (en) | 1970-11-10 |
| BG15386A3 (en) | 1976-03-23 |
| CH484095A (en) | 1970-01-15 |
| AT281811B (en) | 1970-06-10 |
| SE364270B (en) | 1974-02-18 |
| FI49415B (en) | 1975-02-28 |
| IL30442A (en) | 1972-01-27 |
| FI49415C (en) | 1975-06-10 |
| IE32222L (en) | 1969-01-28 |
| IL30442A0 (en) | 1968-11-27 |
| DK121087B (en) | 1971-09-06 |
| AT280272B (en) | 1970-04-10 |
| AT283346B (en) | 1970-08-10 |
| GT197640170A (en) | 1977-08-06 |
| NO122751B (en) | 1971-08-09 |
| SU393827A3 (en) | 1973-08-10 |
| IE32222B1 (en) | 1973-05-16 |
| CS153468B2 (en) | 1974-02-25 |
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