Classifications

• • 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
  • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
  • C07D307/80—Radicals substituted by oxygen atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/10—Antioedematous agents; Diuretics
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
  • C07D209/12—Radicals substituted by oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
  • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
  • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
  • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
  • C07D333/56—Radicals substituted by oxygen atoms

Definitions

• the invention relates to compounds of general formula I. in which R 1 is hydrogen, halogen, alkyl having 1 to 3 C atoms, methoxy or ethoxy, R 2 and R 3 can be identical or different and is hydrogen or alkyl having 1 to 4 C atoms, X is a halogen atom, methyl or trifluoromethyl and Y is oxygen, sulfur or NR 4 , where R 4 is hydrogen or alkyl having 1 to 4 carbon atoms.
• the alkyl radicals for R 1 to R 4 can be straight-chain or branched.
• halogen-substituted benzene derivatives such as fluoro-, difluoro-, chloro- or dichlorobenzene, among others, have proven to be particularly suitable.
• Aluminum chloride, tin and titanium tetrachloride are preferably used as Friedel-Krafts catalysts, which include both Lewis acids and protonic acids, although other catalysts, such as HF, BF 3 , ZnCl 2 , GaCl 3 , J 2 , are also used can.
• HF, HClO 4 or polyphosphoric acid are suitable as protonic acids.
• A is hydroxy, aluminum chloride, zinc chloride, boron trifluoride, but also hydrogen fluoride and perchloric acid, and also polyphosphoric acid or phosphorus oxychloride are preferably used as catalysts, while POCl 3 is used as a catalyzing Lewis acid, especially when reacting III with the acid amide derivatives of the formula II , both-.
• NEN Y stands for -NR 2 , advantageously used.
• Polar solvents such as water, lower alcohols with 1 to 5 carbon atoms, dioxane, tetrahydrofuran, dimethylacetamide, mono-, di- or triethylene glycol dimethyl ether have proven to be particularly suitable as reaction media, the reaction being between 0 and 100 ° C. , preferably between 10 and 50 ° C.
• the reaction time is between 1/2 and 70 hours, preferably 4 to 14 hours.
• the sulfochlorides of the formula IV can be obtained in various ways in a manner known per se. They are preferably obtained from the amino derivatives of the formula X by the Meerwein reaction (Chem. Ber. 90, 841 (1957)) wherein the substituents have the meaning given.
• the compounds of formula X are, for example, compounds XI in which X and A have the meaning given, by a reaction analogous to procedure a) with compounds III and subsequent reduction of the nitro compound XII shown.
• compounds of the general formula VI are converted into the compounds of the formula I using an oxidizing agent.
• organic and inorganic oxidizing agents such as salts and complex compounds of Fe +3 , nickel peroxide, potassium permanganate, chromium-VI compounds, copper-II salts, halogen, nitrogen oxides such as N 2 0 3 in situ or N0 2 , ENT are suitable 3 , oxygen, inorganic and organic peroxo compounds such as H 2 0 2 , Behzoper- and m-chlorobenzoperic acid, N-chloro- and N-bromosuccinimide, dimethyl sulfoxide, aliphatic nitro compounds, ketones in the presence of an aluminum alcoholate in the sinus of an Oppenauer oxidation.
• active manganese IV oxide has proven to be a mild and particularly suitable oxidizing agent (cf., for example, AJ Fatiadi, Synthesis 1976 , 65; DE-OS 2 436 263), the solvent used preferably being acetonitrile or halogenated hydrocarbons, such as methylene chloride, chloroform, tetrachloroethane, and the reaction at temperatures between 0 ° and 40 ° C., preferably between 20 ° and 30 ° C. , over a period of 6 to 60 hours.
• oxidizing agent cf., for example, AJ Fatiadi, Synthesis 1976 , 65; DE-OS 2 436 263
• the solvent used preferably being acetonitrile or halogenated hydrocarbons, such as methylene chloride, chloroform, tetrachloroethane, and the reaction at temperatures between 0 ° and 40 ° C., preferably between 20 ° and 30 ° C. , over a
• ketimines of the formula VII which can also be present in the form of their acid addition salts, are hydrolyzed.
• the nitriles of the formula XIV are brought with the compounds of formula III in the sense of a Houben-Hoesch reaction for the reaction, cf. Organic Reactions 5, 387 (1949).
• the two reactants are preferably reacted in a molar ratio of 1: 1 in an inert polar and, as far as possible, water-free organic solvent, such as diethyl ether, diisopropyl ether, tetrahydrofuran, glacial acetic acid, dioxane, a halogenobenzene, preferably chlorobenzene, advantageously using mono- , Dier triethylene glycol dimethyl or diethyl ether as a solvent.
• the reaction mixture is passed over a period of 2 to 20 hours a dry stream of HCI gas until saturation, at temperatures between -30 ° and + 40 ° C, advantageously between -5 ° and + 15 ° C. Subsequently, the mixture is advantageously left at -5 ° to + for 1 to 3 days Stand at 15 ° C. It is also possible to work in the presence of an additional Lewis acid, such as, in particular, anhydrous zinc or aluminum chloride.
• ketimine hydrochlorides of the formula VII are obtained by adding a less polar solvent by precipitation, in particular by means of diisopropyl ether, ether, but also lower alkyl acetate, acetone and mixtures of the stated solvents with petroleum ether or cyclohexane.
• the hydrolysis of the ketimine hydrochloride can be carried out either in an alkaline or acidic medium, the compounds VII being heated in water or ethanol / water mixtures, if appropriate in the presence of small amounts of ammonia, sodium hydroxide solution, calcium carbonate, dilute hydrochloric acid or sulfuric acid, and the resulting mixture Filtered ketone or isolated after extraction with an organic solvent, preferably with ethyl acetate.
• the ketimines of the formula VII can also be obtained by reacting compounds of the formula VIII with the nitriles of the formula XIV by the method of Blaise, cf. Houben-Weyl, 4th edition, volume 7/2 a, page 603 (1973) become.
• the solvents used are the inert and anhydrous solvents customary for organometallic reactions, preferably ethers such as diethyl ether, dibutyl ether, but particularly advantageously tetrahydrofuran or mono-, di-, tri- ethylene glycol dimethyl or diethyl ether.
• Inert aromatic hydrocarbons such as toluene or xylene can be used.
• the process is preferably carried out between 30 ° and 130 ° C., between 3 and 50 hours; the reaction mixture is usually worked up by stirring with water for 10 to 24 hours.
• the imines obtained are converted into the compounds of formula I by hydrolysis in an acidic or basic medium.
• reaction is carried out in an inert and anhydrous solvent customary for organometallic reactions, preferably in ether, tetrahydrofuran, dioxane or in a mono-, di- or triethylene glycol dimethyl or -diethyl ether, preferably at temperatures between -0100 ° and + 100 ° C.
• the reaction products are hydrolyzed in a customary manner, for example by introducing the reaction mixture into an aqueous saturated ammonium chloride solution at temperatures between -5 ° and + 20 ° C. while maintaining a pH range from 6 to 11.
• the starting materials of the formula IX are obtained by reacting a halogen ketone of the formula XV where Hal is preferably bromine or iodine, with compounds of the formula XVI known from the literature wherein Z is preferably S or O.
• the process is carried out using the bases described in the cyclocondensation in the solvents mentioned there, advantageously under milder temperature conditions between -10 ° and + 60 ° C, but preferably between + 10 ° and + 40 ° C.
• the preparation of IX and whose cyclocondensation to I can proceed without isolation of the compounds IX in a one-pot reaction.
• R 3 denotes lower alkyl
• R 3 -X conventional alkylating agents of the formula R 3 -X are used, in which X is, for example, bromine, iodine, chlorine, -O-SO 2 CH 3 , -O-SO 2 OR 3 or stands..
• the alkylation is carried out in water, but preferably in polar organic solvents such as a lower alcohol having 1 to 4 carbon atoms, in dioxane, tetrahydrofuran, dimethylformamide, dimethylacetamide or a mono-, di-, triethylene glycol mono- or dimethyl- or -ethyl ether at temperatures. between -20 ° and + 50 ° C, preferably between + 15 ° and + 35 ° C, being left to regress for a period of 5 to 72 hours.
• a base for Acid binding is preferably carried out using carbonates, alcoholates or hydroxides of sodium or potassium.
• the most important compounds according to the invention are those of the general formula I in which the substituent X is bromine or chlorine, preferably chlorine, R 3 is hydrogen, methyl or ethyl, preferably hydrogen, R 2 is hydrogen, methyl or ethyl, R1 is hydrogen , Chlorine, methyl or methoxy in position 4 or 5 of the heterocycle, but is preferably hydrogen and Y is oxygen or sulfur.
• the process products are valuable medicinal products and cause a very good effect, which lowers the uric acid level of the blood, which is caused in particular by a uricosuric effect.
• the compounds according to the invention are distinguished by a desired good diuretic and saluretic activity, and are therefore superior to the previously known uricosuric agents.
• the uricosuric effect of the new process products was determined on the oxonate-treated rat in a unit dose of 50 mg / kg per os. They show the antiuricopathic efficacy of known commercial preparations of the probencid type and the benzbromarone type.
• the salidiuretic activity of the compounds according to the invention was determined on the rat in a unit dose of 50 mg / kg per os. You will achieve the salidiuretic activity of well-known commercial products like that of chlorothalidone.
• the new process products are characterized by a long-lasting effect, which means that the preparations are also suitable for the treatment of hypertensive conditions in humans. You can combine them with an antihypertensive.
• Tablets, dragees, capsules, suppositories and ampoules for parenteral administration are particularly suitable as therapeutic preparations for the new compounds.
• the therapeutic unit dose is between 5 and 1000 mg, preferably 10 to 500 mg per tablet.
• these preparations can also contain an antihypertensive, such as, for example, reserpine, hydralazine, guanethidine, ⁇ -methyldopa, a ⁇ -sympathicolytic or chloridine.
• an antihypertensive such as, for example, reserpine, hydralazine, guanethidine, ⁇ -methyldopa, a ⁇ -sympathicolytic or chloridine.
• potassium-retaining compounds such as aldosterone antagonists, for example spironolactone, or pseudoaldosterol antagonists, such as triamterene or amiloride
• aldosterone antagonists for example spironolactone
• pseudoaldosterol antagonists such as triamterene or amiloride
• K + substitution can also be used in various forms of application, for example coated tablets, tablets, effervescent tablets, juices and others.
• Combinations of the compounds according to the invention with another antihyperuricemic active agent can also be of therapeutic interest, which agent leads to an increase in the antiuricopathic effects, particularly by inhibiting xanthine oxidase.
• Any desired desired enhancement of the salidiuretic activity can be achieved by combining the compounds according to the invention with a salidiuretic.
• Example 10 a is obtained analogously to the procedure given in Example 10 a) from 2.68 g of 4-chloro-3-methylsulfamoylbenzoyl chloride and 1.3 g of 2-methylindole in the presence of 2.7 g of aluminum chloride in dichloroethane. Colorless crystals, mp 246 ° C.
• Example 10 a is obtained analogously to the procedure given in Example 10 a) from 10 g of 4-chloro-3-sulfamoylbenzoyl chloride and 7.8 g of 2,5-dimethylindole in dichloroethane in the presence of 12 g of aluminum chloride. Mp 248 ° - 250 ° C.
• Example 10 a is obtained analogously to the procedure given in Example 10 a) from 10 g of 4-chloro-3-sulfamoylbenzoyl chloride and 6.53 g of 1,2-dimethylindole in dichloroethane in the presence of 12 g of aluminum chloride. After treatment with isopropanol, crystals with a melting point of 247 ° -249 ° C. are obtained.
• Example 2 is obtained analogously to the procedure given in Example 1 from 2.5 g of 4-chloro-3-sulfamoylbenzoyl chloride, 1.6 g of 3-methyl-benzo [b] thiophene and 3 g of aluminum chloride in 50 ml of chlorobenzene. Colorless crystals, mp 210 ° C.
• Example 10 a is obtained analogously to the procedure given in Example 10 a) from 10.0 g of 4-chloro-3-sulfamoylbenzoyl chloride, 5.1 g of 3-methylindole in the presence of 10.4 g of aluminum chloride. Colorless crystals of isopropanol, mp. 205 ° C.
• Example 10 a is obtained analogously to the procedure given in Example 10 a) from 4-chloro-3-sulfamoylbenzoyl chloride and 2-methylbenzo [b] thiophene in dichloroethane in the presence of aluminum chloride.

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• 1977
  • 1977-06-21 DE DE19772727802 patent/DE2727802A1/de not_active Withdrawn
• 1978
  • 1978-06-08 EP EP78100118A patent/EP0000128A1/fr not_active Withdrawn
  • 1978-06-19 IT IT24695/78A patent/IT1096492B/it active
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