Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
  • C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
  • C07C205/57—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
  • C07C205/59—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
  • C07C205/60—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms in ortho-position to the carboxyl group, e.g. nitro-salicylic acids
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
  • C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
  • C07C205/57—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
  • C07C205/58—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton the carbon skeleton being further substituted by halogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups

Definitions

• X is selected from the group consisting of O, S, and NH-;
• R is selected from the group consisting of hydrogen and aliphatic radicals with from one to four carbon atoms;
• R is selected from the group consisting of hydrogen, saturated and unsaturated, straight and branched aliphatic radicals with from one to six carbon atoms, and aryland heterocyclic-substituted aliphatic radicals with from one to four carbon atoms;
• R is selected from the group consisting of saturated and unsaturated, straight and branched aliphatic radicals with from one to six carbon atoms, and aryland heterocyclic-substituted aliphatic radicals with from one to four carbon atoms, and
• R is selected from the group consisting of unsubstituted and substituted phenyl radicals; to salts and esters of these compounds and to methods for their preparation.
• the present 5-aminoisophthalic acid derivatives have pronounced diuretic and saluretic activity with rapid onset of effect and high electrolyte excretion level.
• a straight or branched, saturated or unsaturated, aliphatic radical means e.g., a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert. butyl radical, or one of the different isomeric pentyl or hexyl radicals, an alkenyl or alkynyl radical, e.g., a vinyl, allyl or propargyl radical.
• the aromatic part of the radical can be a monoor bicyclic aryl radical, e.g., a phenyl or naphthyl radical
• the heterocyclic part of the radical can be a monoor bicyclic radical containing one or more oxygen, sulphur and nitrogen atoms as ring members, e.g., 2-, 3- or 4-pyridyl, 2- or 3-furyl or -thienyl, thiazolyl, imidazolyl, benzimidazolyl, and the corresponding hydrogenated ringsystems
• the aliphatic part of the radicals can contain 1 to 4 carbon atoms.
• Illustrative examples of such aromatically or heterocyclically substituted aliphatic radicals are benzyl, lor 2-phenethyl, 1- or Z-naphthylmethyl, furylmethyl and the corresponding ethyl, propyl and butyl radicals.
• the salts of the compounds are pharmaceutically acceptable salts, such as alkali metal salts, alkaline earth metal salts, the ammonium salt or organic amine salts, e.g., mono-, di-, or trialkylamine salts, mono-, di-, or trialkanolamine salts, or cyclic amine salts.
• esters of the compounds of formula I are particularly esters with lower alkanols, e.g., methanol or ethanol the different isomers of propanols and butanols, and substituted alkanols, e.g., cyanomethanol, or aryllower alkanols, e.g., benzylalcohol or phenylethanol.
• lower alkanols e.g., methanol or ethanol the different isomers of propanols and butanols
• substituted alkanols e.g., cyanomethanol
• aryllower alkanols e.g., benzylalcohol or phenylethanol.
• radicals R, to R4 can be further substituted with hydroxy, alkyl, or alkoxy groups with from one to four carbon atoms, with halogen atoms,
• haloalkyl groups e.g., a trifluoromethyl group.
• the present compounds are effective after oral, enteral or parenteral administration, and are preferably prescribed in the form oftablets, pills, dragees, or capsules containing the free acid or salts thereof with atoxic bases, or the esters or amides thereof, mixed with carriers and/or auxiliary agents.
• compositions containing the present compounds can be used to make up compositions containing the present compounds.
• Gelatine, lactose, starch, magnesium stearate, talc, vegetable and animal fats and oils, gum, polyalkylene glycol, or other known carriers for medicaments are all suitable as carriers.
• compositions may further contain other therapeutic compounds applied in the treatment of, for example oedemas and hypertension, besides the well known auxiliary agents.
• Such other compounds may be, for instance, Veratrumor Rauwolfia alkaloids, e.g., reserpine, rescinnamine or protoveratrine or synthetic hypotensive compounds, e.g., hydralazine, or other diuretics and saluretics, such as the well-known benzothiadiazines, e.g., hydroflumethiazide, bendroflumethiazide, and the like. Potassium-sparing diuretics, e.g., triamterene, may also be used in the preparation of the compositions. For some purposes it may be desirable to add small amounts of carboanhydrase inhibitors or aldosterone antagonists, e.g., spironolactone.
• Salts which are soluble in water, may with advantage be administered by injection.
• the pharmaceutical preparations are useful in the treatment of oedematous conditions, e.g., cardiac, hepatic, renal, lung and brain oedema, or oedematous conditions during pregnancy, and of pathological conditions which produce an abnormal retension of the electrolytes of the body, and in the treatment of hypertension.
• the parenteral preparations are in particular useful in the treatment of conditions in which a quick dehydration is desirable, e.g., in the intensive therapy in the case of oedemas in the lung.
• the tablets or capsules may be the appropriate form of pharmaceutical preparation owing to the prolonged effect obtained when the drug is given orally, in particular inthe form of sustained-release tablets.
• Such tablets may advantageously contain other active components, as specified hereinbefore.
• This alkylation can be performed by a reaction with an alkylating agent of the formula R X, in which R is as defined above and X stands for halogen, preferably chlorine or bromine, or a hydroxy group, a hydroxysulfonyloxy group, an R -oxysulfonyloxy group, or an alkylor arylsulfonyloxy group.
• R is as defined above and X stands for halogen, preferably chlorine or bromine, or a hydroxy group, a hydroxysulfonyloxy group, an R -oxysulfonyloxy group, or an alkylor arylsulfonyloxy group.
• the reaction can be performed in an alcoholic solvent in which case the corresponding ester of the compound of formula I can be formed simultaneously. If desired, the esters can be hydrolyzed to the corresponding free acids and vice versa in known manner.
• the R substituent can also be introduced by a well-known reductive alkylation process by means of the appropriate aldehyde.
• rim-R 11 x I J III YOC/ X coon or an ester thereof in which R R and X are as defined before and -COY is a reactive derivative ofa carboxylic group, preferably a lower alkyl ester group, with an amine R R NH in which R and R are as defined above.
• the starting materials of formula II are new compounds. ln one method for the preparation of these new compounds 4-chloroisophthalic acid is used as starting material. By nitration of this compound a nitro group is introduced in the 5-position. After esterification of the two free carboxylic acid groups and treatment with R X-H, in which R4 and X are as defined, the R X radical replaces the chlorine atom in the 4-position, forming an alkyl 4-R.,X-S-nitroisophthalate.
• the R X radical can in the same manner be introduced in the corresponding free acids as well, whereafter an esterification is performed, if desired.
• R and X are as defined above and the -COOE group is an ester group, preferably an alkyl ester group.
• an alkyl 4-R X-5-nitroisophthalate prepared as described above can be subjected to a partial saponification process with for instance the calculated amount of an alkali hydroxide, whereby an alkyl 4- R4X-5-carboxy-3-nitrobenzoate is obtained.
• This compound can be converted into the corresponding acid chloride by treatment with e.g., thionyl chloride, the acid chloride afterwards being reacted with an amine NHR R whereby a compound of the formula V:
• the starting compounds of formula III are obtained from a 4-R X-5-amino-isophthalic acid or esters thereof prepared as described above, by alkylation processes similar to those as described above, esterification and/or saponification processes which can be performed in arbitrary order. If desired, a free carboxylic group in the 3-position is converted to the COY group as the last step by known procedures.
• the crude potassium salt is dissolved in boiling water (2100 ml) and after filtration the acid is precipitated by the addition of acetic acid (150 ml). The acid is collected by suction, washed with water and dried. The melting point is: 273274C. (decomp.).
• Ethyl 4-anilino-5-chlorocarbonyl-3-nitrobenzoate (24 g) is added in portions to an ice-cooled and vigorously stirred 25 percent aqueous ammonia solution (200 ml). The stirring is continued for l-2 hours.
• Example 1 F By substituting 35 percent aqueous methylamine solution for 25 percent aqueous ammonia solution in Example 1 F., the compound is obtained with a melting point of 161.5-163C. (decomp.) after recrystallization from ethanol.
• Example 1 G. By substituting ethyl 4-anilino-5-methylcarbamyl- 3-nitrobenzoate for ethyl 4-anilino-5-carbamyl-3- nitrobenzoate in Example 1 G., and reducing the refluxing time to 45 minutes, the compound is obtained with a melting point of 164-166C., (decomp.) when recrystallized from ethanol/water. The compound crys' tallizes with one mole of water.
• Example 1 H By substituting 4-ani1ino-5-methylcarbamyl-3- nitrobenzoic acid for 4-anilino-5-carbamyl-3- nitrobenzoic acid in Example 1 H., the compound is obtained with a melting point of 250-250,5C. (decomp.) after recrystallization from ethanol (99.9 percent) and drying in high vacuo at 80C. for 16 hours.
• Example 5 A By substituting 3-amino-4-anilino-5-methylcarbamylbenzoic acid for 3-amino-4-ani1ino-5-carbamylbenzoic acid in Example 5 A., the compound is obtained with a melting point of 140.5142C. after recrystallization from aqueous ethanol.
• Example 6 B By substituting ethyl 4-anilino-3-benzylamino-5- methylcarbamylbenzoate for n-butyl 4-anilino3-nbutylamino-5-carbamylbenzoate in Example 6 B. and extending the refluxing time to 1 hour, the compound is obtained with a melting point of 279-281C. (decomp.) after recrystallization from acetic acid/water.
• EXAMPLE 8 4-Anilino-3-benzylamino-S-dimethylcarbamylbenzoic acid A. Ethyl 4-anilino-3-benzylamino-5-dimethylcarbamylbenzoate.
• Example 5 A By substituting 3-amino-4-anilino-S-dimethylcarbamylbenzoic acid for 3-amino-4-anilino5- carbamylbenzoic acid in Example 5 A., the compound is obtained with a melting point of l62163C. after recrystallization from aqueous ethanol.
• a mixture of 5-amino-4-phenylthioisophthalic acid (15 g), benzyl bromide (25 g) and dry ethanol (300 ml) is refluxed, while stirring. Refluxing is continued for 2 days while after 6, 30, and 36 hours additional benzyl bromide (7.5 ml each time) is added. Thereafter the reaction mixture is evaporated in vacuo, and the resi due is triturated with diethyl ether (1 l) precipitating crude diethyl S-benzylamino-4-phenylthioisophthalate hydrobromide. The salt is collected by suction and washed with diethyl ether.
• a solution of 3-benzylamino-5-carbethoxy-4- phenylthiobenzoic acid (0.6 g) in aqueous ammonia ml containing percent NH is left for 15 days at room temperature.
• the precipitated ammonium salt of 3-benzylamino-5-carbamyl-4-phenylthiobenzoic acid is collected by filtration and washed with aqueous ammonia.
• the salt is dissolved in hot water (65 ml) and the acid liberated by the addition of 1 N hydrochloric acid until pH 2.
• the compound has a melting point of 229-230C.
• the sodium salt is redissolved in hot water and the 3-benzylamino- 5-carbethoxy-4-(p-chlorophenylthio)-benzoic acid precipitated by the addition of 1 N hydrochloric acid until pH 2.
• the compound is obtained with a melting point of l82l83C.
• 3-benzylamin0-5- carbethoxy-4-phenylthiobenzoic acid With 3- benzylamino-5-carbethoxy-4-p-chlorophenylthiobenzoic acid, 3-benzylamino-5-carbamyl-4-p-chlorophenylthiobenzoic acid is obtained with a melting point of 253 254C.
• Diethyl 5-nitro-4-phenoxyisophthalate (36 g) is suspended in 99.9 percent ethanol (1500 ml) and hydrogenated after addition of a palladium-on-carbon catalyst (3 g catalyst, containing 10 percent Pd).
• a palladium-on-carbon catalyst (3 g catalyst, containing 10 percent Pd).
• the catalyst is removed by filtration and the diethyl 5-amino-4- phenoxyisophthalate is precipitated from the filtrate by the addition of water.
• the compound After crystallizing in a refrigerator, the compound is collected by suction, washed with 50 percent aqueous ethanol and recrystallized from 60 percent aqueous ethanol. It has a melting point of 73.575C.
• 3-benzylamino-5- carbethoxy-4-phenylthiobenzoic acid with 3- benzylamino-5-carbethoxy-4-phenoxybenzoic acid (0.6 g)
• 3-benzylamino-S-carbamyl-4-phenoxybenzoic acid is obtained with a melting point of 245-247C after drying in vacuo.
• 3-benzylamino-5- carbethoxy-4-phenylthiobenzoic acid By replacing in example I l, 3-benzylamino-5- carbethoxy-4-phenylthiobenzoic acid with 3- benzylamino-5-carbethoxy-4-phenoxybenzoic acid, 3- benzylamino-5-methylcarbamyl-4phenoxybenzoic acid is obtained with a melting point of 252-254C.
• EXAMPLE 22 3-Amino-5-carbamyl-4-phenoxybenzoic acid. A. 3-Amino-5-carbethoxy-4-phenoxybenzoic acid.
• Diethyl amino-4-phenoxyisophthalate g) is dissolved in 99.9 percent ethanol (75 ml) by warming and a solution of 88 percent potassium hydroxide (2 g) in 99.9 percent ethanol (25 ml) is added during half an hour by vigorous stirring. Then the reaction mixture is refluxed for 1.5 hours, while stirring. After cooling, excess of starting material is precipitated by the addition of water and is removed by filtration after standing in a refrigerator. The filtrate is adjusted to pH 3 by the addition of acetic acid, and the precipitated 3-amino-5- carbethoxy-4-phenoxybenzoic acid is collected by suction and washed with water. After recrystallization from aqueous ethanol the compound has a melting point of l7l.5-l72.5C.
• a solution of 3-amino-5-carbethoxy-4- phenoxybenzoic acid (3 g) in 25 percent aqueous ammonia solution (50 ml) is kept dark at room temperature for 8 days.
• the reaction mixture is evaporated to dryness in vacuo and the residue dissolved in acetic acid (50 ml).
• the 3-amino-5-carbamyl-4- phenoxybenzoic acid crystallizes by the addition of water (50 ml) to the solution on cooling. After collection by suction and recrystallization from 50 percent aqueous ethanol the compound has a melting point of 249250C. (decomp.).
• diethyl 5-nitro-4-phenoxyisophthalate in ethanol with a solution of diethyl 5nitro-4-p-toloxyisophthalate (37.3 g) in acetic acid (250 ml).
• diethyl 5-amino-4-ptoloxyisophthalate is obtained with a melting point of 8082C.
• a suspension of 3amino-4-methylcarbamyl-4-ptoloxybenzoic acid (0.45 g) in water 15 ml) is adjusted to a pH of 7.5 by the addition of 2 N sodium hydroxide.
• benzyl bromide (0.26 g) is added and, while stirring the pH is kept at 7.5 by automatic titration with sodium hydroxide.
• 1 N hydrochloric acid is added until pH 2 to precipitate 3-benzylamino- 5methylcarbamyl4-p-toloxybenzoic acid.
• the compound is obtained with a melting point of 26l263C.
• R is selected from the group consisting of hydrogen and aliphatic hydrocarbon radicals with from one to four carbon atoms; R is selected from the group consisting of hydrogen, saturated and unsaturated, straight and branched aliphatic hydrocarbon radicals with from one to six carbon atoms; R;, is selected from the group consisting of saturated and unsaturated, straight and branched aliphatichydrocarbon radicals with from one to six carbon atoms, and aryl.
• R and R are hydrogen, R is benzyl, R4 is phenyl, and X is sulphur, and pharmaceutically acceptable salts and esters thereof.
• R. is hydrogen, R is methyl, R is benzyl, R is phenyl. and X is sulphur, and pharmaceutically acceptable salts and esters thereof.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Furan Compounds (AREA)

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  • BE BE789679D patent/BE789679A/xx unknown
• 1971
  • 1971-10-05 GB GB4629171A patent/GB1380065A/en not_active Expired
• 1972
  • 1972-09-12 IE IE1238/72A patent/IE37392B1/xx unknown
  • 1972-09-26 CA CA152,555A patent/CA1002964A/en not_active Expired
  • 1972-09-27 NL NL7213059A patent/NL7213059A/xx not_active Application Discontinuation
  • 1972-09-27 US US292525A patent/US3864385A/en not_active Expired - Lifetime
  • 1972-10-03 LU LU66227A patent/LU66227A1/xx unknown
  • 1972-10-04 FR FR7235179A patent/FR2158208B1/fr not_active Expired
  • 1972-10-04 SE SE7212799A patent/SE400551B/xx unknown
  • 1972-10-04 JP JP47099744A patent/JPS4844229A/ja active Pending
  • 1972-10-04 DE DE19722248596 patent/DE2248596A1/de active Pending

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