CA2004199A1 - Benzenesulphonamide derivatives and processes for their preparation - Google Patents
Benzenesulphonamide derivatives and processes for their preparationInfo
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- CA2004199A1 CA2004199A1 CA002004199A CA2004199A CA2004199A1 CA 2004199 A1 CA2004199 A1 CA 2004199A1 CA 002004199 A CA002004199 A CA 002004199A CA 2004199 A CA2004199 A CA 2004199A CA 2004199 A1 CA2004199 A1 CA 2004199A1
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- 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
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Abstract of the disclosure Benzenesulphonamide derivatives and processes for their preparation Compounds I
I, have a diuretic, saluretic and hypolipidemic action.
They are obtained from II
II, by reaction with an amine III
R1 - NH2 III.
I, have a diuretic, saluretic and hypolipidemic action.
They are obtained from II
II, by reaction with an amine III
R1 - NH2 III.
Description
9~
HO~CHST ~XTIENG~SELLSCHAET EIOE 88/F 335 Dr.v.~./fe De~crip~ion Benzene~ulphonamide derivative~ and proces~e~ for their preparation 5 It i~ known that the benzenesulphonamide dexivative chlorthalidone H2N-~2 ~
posses~es a ~trong diuxetic ~nd ~aluretic action.
In the cour6e of the long-standing therapeutic use of the compound a~ a diuretic and anti-hyperten3ive, ~n un-favo.rable influence on the composition of the serumlipid~ came to light in addition to other phanmaceutical~
caused side effects. It iB known that changes of this type in favor of the atherogenic lipids of the ~DL
fraction increase the risk of atherosclerotic veasel damage.
The in~ention of diuretic~ having a favorabl~ eff~ct on the ~erum lipid çomposition i8 da~cribed in a rec~ntly ~ppearing patent publ ication (~P 0,288,028). However, in thi~ citation there i8 no indication of compounds which contain an isoindolinone ~y~em.
The invention has the ob~ect o~ making available benzene-sulphonamide derivati~es ha~ing further Lmproved propertie~.
Thi~ has been achieved with benz~nesulphonsmide derivative~ of the formula I
HO~J ~
9~
in which R1 denotè~ hydrogen or methyl R2 denotes hydrogen or an alkyl radical having 1 - 6 carbon atom6 R3 denote~ an alkyl radical ha~ing 3 to 5 carbon atoms, and the open-chain tautomeric form~ corre6pQnding to I of the formula Ia ~ 10~ ~NHR
in which R1 to R3 have the meaning indicated.
Preferxed compounds of the formula I are those in whi~h ~1 denote~ hydrogen, R2 denotes methyl, i~opropyl or tert.butyl ancl R3 denotes isopropyl or ~ert.butyl.
The di-t~rt.butyl deri~ative 3-[4~chlor-3-(3~5-di-tert. butyl-4 -hydroxyphenyl-sulfamoyl)-phenyl]-3-hydroxy-l-isoinldolinon2 may be particularly pref~rnbly mentioned as an outstanding individual compound.
~he invention furthermore relates to ~ proces6 for the preparation of the compounds of the formula I which compri~e~
r~acting compounds of the formula II
R3 ~C ~ N ~ C C~ C ~C 11 C ~ 2 ~ CO-X
~ 12 with ~n amine of the formula III
Rl - NH2 III
in which Rl to R3 have ths meaning ~ndi~ted.
The compounds I can be in e~uilibrium with the compounds of the fonmula Ia by mean6 of tautomerism- I , Ia.
Which of the two form~ I or Ia of a compound a~cording to the invention i~ present in ~he eguilibrium to a predo-minant extent depend on the solvent, the tQmp~rature andon the 6ub6tituent Rl. The cyclic tautomer form I i~
preferred.
The compounds of the formula I according to the invention can additionally be present in their pos~ible ~eometrical 0 i80mer forms.
The alkyl radicals of the subs~ituent~ R2 and R3 can b~
both straight-chain and branched.
The proce~ i8 ~dva~tageously carried out in ~uch a way that, for example, compound~ of the formula II, in which R2 and R3 have the ~eaning indicatQd and X i8 the O-(C1-C6)-acyl radical of a mixed anhydride, are made to react with amine~ of the formula III. ~he I~ixed anhydrides are advantageously generated in ~itu by a proce6s in which compounds of the fonmula II, in which X stands ~or -O~
and M denote~ hydrogen, ~re converted u~ing an equivalant of a ~uitable base, for example ~n alkali metal hydroxide or alkaline earth metal hydroxide ~uch a gOH, NaOH, Ca~OH~z, an al~ali ~etal carbonate or hydrogen car~onate ~uch as ~a2C03, ~2CO3, or using a preferably tertiary amine ~uch as trimsth~lamine, triethylamine, tripropylamine, tributylamine or dicyclohexylet~ylamine, into the corre6-ponding car~oxylic acid 8alt8 of the ~ormula II, in which deno~e~ ~ and ~ ~taDd~ f~r ~, R, Ca or a trialkyla~-~onium cation, ~uch as ~HN(ethyl)33', which are then converted to a mi~ed anhydride u~ing 1 to 2.5 mols, preferably usin~ 1 to l.S mols, of an a~tivated ~cid derivative.
The activat~d acid derivati~e used i8 ad~antageou~ly, for example, ~n alkyl shloroforma~e, prefarably ethyl chlorofonmate or methyl chloroformate, ~ c~rb~oyl Z~ L9~
chloride (such as N,N dimethylcarbamoyl chloride or N,N-diethylcarbamoyl chloride) or the acid chloride or an ~liphatic or aromatic ~ulphonic acid, for ex~mple methane, ethane, benzene or p-toluene sl~lphonyl chloride.
The reaction iB advanta~eously carried out in an an-hydrous p~lar organic solvent~ for example in acetone, methyl ethyl ketone, an alkyl (Cl-C6)-alkanoate such a~
methyl acetate ~r ethyl acetate, an alkanoic acid amine, for example dimethylformamide, dimethylacetamide, in dLmethyl ~ulphoxide, in acetonitrile, in a lower aliphat-ic alcohol, for example in methanol, ethanol or i~o-propanol, prefer~bly in a ~yclic or open-chain ether or polyether/ ~uch a~ tetrahydrofuran, dioxane, ethylene glycol dimethyl ether and diethylen glycol dimethyl ether. The duration of the reaction for a 0.1 molar batch is 1 minute to 5 hour~, the mixture prefer~bly beinq ~tirred over a period of S to 60 minutes. The reaction c~n be carried out in a t~nperature range from -50~C to 100C, advantageously working between -30C and +30C, preferably between -lQC and ~15C.
Although the mixed ~nhydrides can be isolated, for oxample, by ~vaporating the ~olv~lnt at t~mperatures between -5C and +lBC and extracting with a ~uitable solvent, ~uch as ethyl acetate, from the re~idue, a procedure i~ advanta~eously u~ed in which the isolation of the mixed anhydride i~ a~oided and the amine of the formula III i~ added to the reacticn mixture. The amine can be added both undiluted and in the form of a solution where, as the so1vent~ that of the reaction ~ixture or one of the ~olvent~ indicated th~refor ~nd ~queous ~olution~ of the ~ine or of ~nia can ~dvant~geously be u~ed. In this ca~e J relati~e to the co~po~d o~ the formula II, at l~a~t 1 mol, ~u~ frequen~ly ~d~ant~eou~ly a claar molar exce~s o~ amin~ ~10 ~old and m~xe) 1~ u~ed.
The reaction is carried out in a t~mperature range ~etwcen -30C and ~lOO~C, ~referably between +5~C and ~40C. ~h~ reaction time i8 betw~en 10 minutes and S
HO~CHST ~XTIENG~SELLSCHAET EIOE 88/F 335 Dr.v.~./fe De~crip~ion Benzene~ulphonamide derivative~ and proces~e~ for their preparation 5 It i~ known that the benzenesulphonamide dexivative chlorthalidone H2N-~2 ~
posses~es a ~trong diuxetic ~nd ~aluretic action.
In the cour6e of the long-standing therapeutic use of the compound a~ a diuretic and anti-hyperten3ive, ~n un-favo.rable influence on the composition of the serumlipid~ came to light in addition to other phanmaceutical~
caused side effects. It iB known that changes of this type in favor of the atherogenic lipids of the ~DL
fraction increase the risk of atherosclerotic veasel damage.
The in~ention of diuretic~ having a favorabl~ eff~ct on the ~erum lipid çomposition i8 da~cribed in a rec~ntly ~ppearing patent publ ication (~P 0,288,028). However, in thi~ citation there i8 no indication of compounds which contain an isoindolinone ~y~em.
The invention has the ob~ect o~ making available benzene-sulphonamide derivati~es ha~ing further Lmproved propertie~.
Thi~ has been achieved with benz~nesulphonsmide derivative~ of the formula I
HO~J ~
9~
in which R1 denotè~ hydrogen or methyl R2 denotes hydrogen or an alkyl radical having 1 - 6 carbon atom6 R3 denote~ an alkyl radical ha~ing 3 to 5 carbon atoms, and the open-chain tautomeric form~ corre6pQnding to I of the formula Ia ~ 10~ ~NHR
in which R1 to R3 have the meaning indicated.
Preferxed compounds of the formula I are those in whi~h ~1 denote~ hydrogen, R2 denotes methyl, i~opropyl or tert.butyl ancl R3 denotes isopropyl or ~ert.butyl.
The di-t~rt.butyl deri~ative 3-[4~chlor-3-(3~5-di-tert. butyl-4 -hydroxyphenyl-sulfamoyl)-phenyl]-3-hydroxy-l-isoinldolinon2 may be particularly pref~rnbly mentioned as an outstanding individual compound.
~he invention furthermore relates to ~ proces6 for the preparation of the compounds of the formula I which compri~e~
r~acting compounds of the formula II
R3 ~C ~ N ~ C C~ C ~C 11 C ~ 2 ~ CO-X
~ 12 with ~n amine of the formula III
Rl - NH2 III
in which Rl to R3 have ths meaning ~ndi~ted.
The compounds I can be in e~uilibrium with the compounds of the fonmula Ia by mean6 of tautomerism- I , Ia.
Which of the two form~ I or Ia of a compound a~cording to the invention i~ present in ~he eguilibrium to a predo-minant extent depend on the solvent, the tQmp~rature andon the 6ub6tituent Rl. The cyclic tautomer form I i~
preferred.
The compounds of the formula I according to the invention can additionally be present in their pos~ible ~eometrical 0 i80mer forms.
The alkyl radicals of the subs~ituent~ R2 and R3 can b~
both straight-chain and branched.
The proce~ i8 ~dva~tageously carried out in ~uch a way that, for example, compound~ of the formula II, in which R2 and R3 have the ~eaning indicatQd and X i8 the O-(C1-C6)-acyl radical of a mixed anhydride, are made to react with amine~ of the formula III. ~he I~ixed anhydrides are advantageously generated in ~itu by a proce6s in which compounds of the fonmula II, in which X stands ~or -O~
and M denote~ hydrogen, ~re converted u~ing an equivalant of a ~uitable base, for example ~n alkali metal hydroxide or alkaline earth metal hydroxide ~uch a gOH, NaOH, Ca~OH~z, an al~ali ~etal carbonate or hydrogen car~onate ~uch as ~a2C03, ~2CO3, or using a preferably tertiary amine ~uch as trimsth~lamine, triethylamine, tripropylamine, tributylamine or dicyclohexylet~ylamine, into the corre6-ponding car~oxylic acid 8alt8 of the ~ormula II, in which deno~e~ ~ and ~ ~taDd~ f~r ~, R, Ca or a trialkyla~-~onium cation, ~uch as ~HN(ethyl)33', which are then converted to a mi~ed anhydride u~ing 1 to 2.5 mols, preferably usin~ 1 to l.S mols, of an a~tivated ~cid derivative.
The activat~d acid derivati~e used i8 ad~antageou~ly, for example, ~n alkyl shloroforma~e, prefarably ethyl chlorofonmate or methyl chloroformate, ~ c~rb~oyl Z~ L9~
chloride (such as N,N dimethylcarbamoyl chloride or N,N-diethylcarbamoyl chloride) or the acid chloride or an ~liphatic or aromatic ~ulphonic acid, for ex~mple methane, ethane, benzene or p-toluene sl~lphonyl chloride.
The reaction iB advanta~eously carried out in an an-hydrous p~lar organic solvent~ for example in acetone, methyl ethyl ketone, an alkyl (Cl-C6)-alkanoate such a~
methyl acetate ~r ethyl acetate, an alkanoic acid amine, for example dimethylformamide, dimethylacetamide, in dLmethyl ~ulphoxide, in acetonitrile, in a lower aliphat-ic alcohol, for example in methanol, ethanol or i~o-propanol, prefer~bly in a ~yclic or open-chain ether or polyether/ ~uch a~ tetrahydrofuran, dioxane, ethylene glycol dimethyl ether and diethylen glycol dimethyl ether. The duration of the reaction for a 0.1 molar batch is 1 minute to 5 hour~, the mixture prefer~bly beinq ~tirred over a period of S to 60 minutes. The reaction c~n be carried out in a t~nperature range from -50~C to 100C, advantageously working between -30C and +30C, preferably between -lQC and ~15C.
Although the mixed ~nhydrides can be isolated, for oxample, by ~vaporating the ~olv~lnt at t~mperatures between -5C and +lBC and extracting with a ~uitable solvent, ~uch as ethyl acetate, from the re~idue, a procedure i~ advanta~eously u~ed in which the isolation of the mixed anhydride i~ a~oided and the amine of the formula III i~ added to the reacticn mixture. The amine can be added both undiluted and in the form of a solution where, as the so1vent~ that of the reaction ~ixture or one of the ~olvent~ indicated th~refor ~nd ~queous ~olution~ of the ~ine or of ~nia can ~dvant~geously be u~ed. In this ca~e J relati~e to the co~po~d o~ the formula II, at l~a~t 1 mol, ~u~ frequen~ly ~d~ant~eou~ly a claar molar exce~s o~ amin~ ~10 ~old and m~xe) 1~ u~ed.
The reaction is carried out in a t~mperature range ~etwcen -30C and ~lOO~C, ~referably between +5~C and ~40C. ~h~ reaction time i8 betw~en 10 minutes and S
2~ 9'9 day , it being po~ible to follow the progre~ of the reaction by thin layer chromatography, advantageou~ly on silica gel.
The acid chloride~ of the formula II, in whi~h ~ ~tand~
for chlorine, which can be prepared from compound~ of $he formula II, ~ith X having the meaning of OH~ u~ing COCl2, oxalylchloride, POCl3, SOCl2, PCl3 or PCl5 are in principle reacted a~ the mixed anhydrides in the manner de~cribed above.
A likewi6e advantageous variant of procedure a) con~i6~s in the reaction of the carbo~ylic acids of the forMula II, with ~ having the meaning of OH, with 1 mol of carbonyldiimidazole, the activated carboxylic acid imidazolide of the formula II with Xel-~midazolyl being ~ormed in an inert polar ~olvent under the mild reaction condition~ indicated, which carboxylic acid imidazolide can then be converted into the compounds of the formula I accordin~ to the invention using an amine of the fonmula III under analogous conditions as for the ~ixed acid anhydride described abo~e.
A further advantageous variant of process variant a) con~ in the reaction of co~pound~ of the formula II, in which Rl to ~3 have the m~aning indicated and X denotes a l~wer alk~xy ~roup having 1 to 6 cax~on atoms in the alkyl moiety, preferably methoxy and ethoxy, or a phenyl-o~y radical optionally sub~tituted by F, Cl or Br, with an amine of the formula III. The reaction i~ ~dvantage-ously c~rried ou~ in water or a polar organi~ solvent which i~ inert to ~mine~, for e~ample in a low~r alkanoic acid amide, such as di~thylform~mide, dimethylacetamide~
dimethyl sulpho~ide, in a ~yclic or open ~ha~n ethar or polyether, such ~ tetr~hydrofuran, dioxane, ethylene ~lycol dimethyl ether, but pr~fer~bly in ~ lo~er alcohol~
~uch a~ meth~nol, ethanol, propanDl, ~opropanol or in a 3S pure undilut~d amine of the formula III without the u~e of a ~olvent. ~he r~act:ion i~ preferably carried out in Z~ 99 a tempPrature r~nge from 10 to 60C, particul~rly preferably at 15 to 30C. The end of the reaction i8 advantageously determined by thin layer chromatography on ~ilica ~el. Depending on ~he reaction te~pernture and amino component u~d, the duration of the reaction i~
usually ~etween 1 hour and 14 days, ~or example between 5 snd 72 hour~ at room temperature. The carboxylic acid e~ters of the formula II and the amines of the formula III are preferably reacte~ in a molar ratio of 1:1 to 1:3, where, however, the amine can also be used in an up to 10-fold molar excess. The compound of the formula II, in which R1 to R3 have th~ abovementioned meaning and X
stands for -O-(C1-C6)-alkyl, i8 obtained by protonic catalysi~ in a manner known per ~e, for example in the presence of an organic os inorganic acid chloride, by th~
action of a lower alkanol having 1 to 6 carbon atoms, preferably methanol, ethanol, propanol, isopropsnol and butanol .
In an identical manner, the corresponding activated ester6 of the formula II with X=CN, N3 or -O-CH2CN can likewi~e be made to react with an amine of the formula III.
A further advantageou~ ~ariant of procedure a) consist~
in the reac~ion c>f compound~ o$ the fosmula II, in which 25 R2 and R3 have the meaning indicated and X ~enote6 a 1-benzotriazolyloxy radical, with ~n æmine of the f~rmula III. These activated carboxylic acid l-benzotriazolyloxy e~ters are obtained in a manner ~nown per se by reaction of the carboxylic a~i~s of the ~ormula II, with X having the meani~g of OH, with l-hydro~yb~n~otriazole in the presence of dicyclohexylcarbodiimide, advanta~eously working between 0C and 60DC in a polar org~nic ~ol~ent, such a~ in dimethylfonma~ide or dimethylac~t~ide.
The earboxylic acid~ of the for~ula II, ~ith X h~vi~g th0 meaning of OH, are obtained by reaction of the sulpho chloride of ~he formula IV which i~ known from ~he ~ 7 --literature with an aniline derivative of the formula V
~ 3 R3~ e~r~y( 3C"~3~?
C125 HO--~ 2 HC' COOI I R2 ' ( X=O~
lY V
in which R2 ~nd ~3 h~v~ ~he ~e~ning indic~t~d, in the presence of a suitable inorg~nic or organic ba~e.
Bases used advantageously are alkali metal carbonate~ or hydrogen carbonates, or organic bases, 3uch as triethyl-amine, pyridine or dimethylaminopyridine. The r~action i~ advantageously carried out in a polAr protic or aprotic ~olvent, for exampl~ in methanol, ethanol, i~opropanol, ethyl acetate, tetrahydrofuran, dLmethoxy~
ethane, dLmethyl sulphoxide, dimethylform2mide or dimeth-ylacetamide, in a preferred temp0rature range bet~ween 20 and 80C. The preferred work-up after the reaotion i6 carried out by partially or completely evsporatin~ the solvent under reduced pre~sure and subsequently adding hydrochloric acid or sulphuric acid, which leadæ to precipitation of the carboxylic acid.
According to the invention, for ex~lple, in addition to the benzene~ulphonamids~ de~cribed in the e~emplary e~bodiment~, the ~oll~wing compoundæ of the structure I
csn also be prepared:
The acid chloride~ of the formula II, in whi~h ~ ~tand~
for chlorine, which can be prepared from compound~ of $he formula II, ~ith X having the meaning of OH~ u~ing COCl2, oxalylchloride, POCl3, SOCl2, PCl3 or PCl5 are in principle reacted a~ the mixed anhydrides in the manner de~cribed above.
A likewi6e advantageous variant of procedure a) con~i6~s in the reaction of the carbo~ylic acids of the forMula II, with ~ having the meaning of OH, with 1 mol of carbonyldiimidazole, the activated carboxylic acid imidazolide of the formula II with Xel-~midazolyl being ~ormed in an inert polar ~olvent under the mild reaction condition~ indicated, which carboxylic acid imidazolide can then be converted into the compounds of the formula I accordin~ to the invention using an amine of the fonmula III under analogous conditions as for the ~ixed acid anhydride described abo~e.
A further advantageous variant of process variant a) con~ in the reaction of co~pound~ of the formula II, in which Rl to ~3 have the m~aning indicated and X denotes a l~wer alk~xy ~roup having 1 to 6 cax~on atoms in the alkyl moiety, preferably methoxy and ethoxy, or a phenyl-o~y radical optionally sub~tituted by F, Cl or Br, with an amine of the formula III. The reaction i~ ~dvantage-ously c~rried ou~ in water or a polar organi~ solvent which i~ inert to ~mine~, for e~ample in a low~r alkanoic acid amide, such as di~thylform~mide, dimethylacetamide~
dimethyl sulpho~ide, in a ~yclic or open ~ha~n ethar or polyether, such ~ tetr~hydrofuran, dioxane, ethylene ~lycol dimethyl ether, but pr~fer~bly in ~ lo~er alcohol~
~uch a~ meth~nol, ethanol, propanDl, ~opropanol or in a 3S pure undilut~d amine of the formula III without the u~e of a ~olvent. ~he r~act:ion i~ preferably carried out in Z~ 99 a tempPrature r~nge from 10 to 60C, particul~rly preferably at 15 to 30C. The end of the reaction i8 advantageously determined by thin layer chromatography on ~ilica ~el. Depending on ~he reaction te~pernture and amino component u~d, the duration of the reaction i~
usually ~etween 1 hour and 14 days, ~or example between 5 snd 72 hour~ at room temperature. The carboxylic acid e~ters of the formula II and the amines of the formula III are preferably reacte~ in a molar ratio of 1:1 to 1:3, where, however, the amine can also be used in an up to 10-fold molar excess. The compound of the formula II, in which R1 to R3 have th~ abovementioned meaning and X
stands for -O-(C1-C6)-alkyl, i8 obtained by protonic catalysi~ in a manner known per ~e, for example in the presence of an organic os inorganic acid chloride, by th~
action of a lower alkanol having 1 to 6 carbon atoms, preferably methanol, ethanol, propanol, isopropsnol and butanol .
In an identical manner, the corresponding activated ester6 of the formula II with X=CN, N3 or -O-CH2CN can likewi~e be made to react with an amine of the formula III.
A further advantageou~ ~ariant of procedure a) consist~
in the reac~ion c>f compound~ o$ the fosmula II, in which 25 R2 and R3 have the meaning indicated and X ~enote6 a 1-benzotriazolyloxy radical, with ~n æmine of the f~rmula III. These activated carboxylic acid l-benzotriazolyloxy e~ters are obtained in a manner ~nown per se by reaction of the carboxylic a~i~s of the ~ormula II, with X having the meani~g of OH, with l-hydro~yb~n~otriazole in the presence of dicyclohexylcarbodiimide, advanta~eously working between 0C and 60DC in a polar org~nic ~ol~ent, such a~ in dimethylfonma~ide or dimethylac~t~ide.
The earboxylic acid~ of the for~ula II, ~ith X h~vi~g th0 meaning of OH, are obtained by reaction of the sulpho chloride of ~he formula IV which i~ known from ~he ~ 7 --literature with an aniline derivative of the formula V
~ 3 R3~ e~r~y( 3C"~3~?
C125 HO--~ 2 HC' COOI I R2 ' ( X=O~
lY V
in which R2 ~nd ~3 h~v~ ~he ~e~ning indic~t~d, in the presence of a suitable inorg~nic or organic ba~e.
Bases used advantageously are alkali metal carbonate~ or hydrogen carbonates, or organic bases, 3uch as triethyl-amine, pyridine or dimethylaminopyridine. The r~action i~ advantageously carried out in a polAr protic or aprotic ~olvent, for exampl~ in methanol, ethanol, i~opropanol, ethyl acetate, tetrahydrofuran, dLmethoxy~
ethane, dLmethyl sulphoxide, dimethylform2mide or dimeth-ylacetamide, in a preferred temp0rature range bet~ween 20 and 80C. The preferred work-up after the reaotion i6 carried out by partially or completely evsporatin~ the solvent under reduced pre~sure and subsequently adding hydrochloric acid or sulphuric acid, which leadæ to precipitation of the carboxylic acid.
According to the invention, for ex~lple, in addition to the benzene~ulphonamids~ de~cribed in the e~emplary e~bodiment~, the ~oll~wing compoundæ of the structure I
csn also be prepared:
3-~4~chloro-3-(3,5~dii~opropyl-4-hydroxyphenyl-sulfa-moyl~-phenyl)-3-h~ro~y-l-ifioindolinone~
3-~4-chloro-3-(3-tert.butyl-5-methyl-4-hydroxyphenyl-sul~amoyl)-phenyl]-3-hydroxy~ oindolinone.
The process product~ are u~eful pharmaceutical~ ~nd are distingui~hed by a large n~ber of v~ry favor~ble thera-peutically u~ilizable propexti~s, in par~icul~r ~y the cQmbination of their very goed diuretic ~nd saluretic action~ with pronoun~ed ~nti-ath~r~sclerotic properties.
aL.3t,lLYY
This is therPfore in p~rticular of considerable thera-peu ic intere~t since the saluretics commercially ~vailable up to now either do not decreaRe or even increase those lipid componentR (VLDL and LDL fractions) of the blood which are held responsible for inducing or advancing atherosclero~is ~o that, n particulAr in the last ca6e, active compounds of this type posses6 a certain atherogeneric potential.
Even today, because of their numerous favorable proper-ties and their relatively good tolerability, diuretics still belong to the basis therapeutics in the treatment of high blood pre~ure. Since high blood pres~ure in old age to a ~ubstantial extent i~ a consequence and initiator of ath~ro~clerotic vessel change~, which in turn increase the high blood pressure, saluretic active compounds, wit:h a r~duction of the atherosclerotic risk by lowering, in particular, the atherogeneric LDL frac-tion of the cholesterol in the blood, are of particular therapeutic ~ignificance.
It was surprising that the compounds of the formula I, which differ from chlorthalidonQ by the introduction of a substituted phenyl radical on the sulphonamide group, p~8~S an action lowering the ~erum l~v~l ~ the athero-generic lipid fraction6 in addition to the diuretic and ~alure~ic ac~ion. Such a profile of action signifies a therapeutic advance in the treatment of hyper~onia of old people.
Fro~ numerou~ public~tion~ in recent y~ars, it amerges that the formation of athero~clerotic plaques proceed in~uries to the ~es~el endothelium. ~ndoth~ l inJurie~
of this tyFe can be caused by fatty acid psroxides, ~o that a reducti~n of the Atherogenic ri~k i~ inev~t~bly connected with a reduction in these lipid p~ro~ides, which are ~entially tr~n~ported in the hDL fraction.
35 The compounds ~c~ording to the invention are able to ~uppr~ th~ format~on of malondi~ldehyde, ~hich i8 a 2~ 9gl g measure of lipid peroxida~ion. The antioxidative activP
c~mponant can b~ ~raced back to the hydro~yphenylamino nubstituent on the sulphonyl group of ths ccmpound~ I.
The compound6 ~ccording to the invention do not only reduce the advance of athero~clerosis by reducing the atherogenic cholesterol fraction and by reducing the increased blood pressure, but moreover act preventatively again~t a xenewal of the atherosclerotic plaque~ through the destruction of the lipid peroxide6.
~he co~pounds I according to the in~ention ~how a fialur-etic action comparable to that o hydrochloro~hiozide and chlorthalidone in animal esperLment~ (rat). Moreov~r, the ~ompounds I are distinguished by a long-la~ting duration of action. The compound~ I according to the invention are therefore al80 suitable for the treatment of hypertonic ætates where, as generslly customary today, they are optionally combined with anot:her antihypertonic.
The compound~ I are used in do~es of at least 0.5 mg/kg ~nd day, preferably 1 mg/k~ and day ko at most 10 mg/kg/-day, preferably up to 5 mg/kg/day, based on ~n adulthuman of about 75 k~ body wei~ht.
5uitab1e therapeutic preparations oX the new compound~
are, ahove all, table~6, coated tablets, capsules and ~uppositories and al~o ampoule~ for parenteral adminis-tration (i.v., ~.c. and i.~.). The t~er2peutic unit dosei8 between 0.5 and 500 mg, preferably between 10 and 300 m~ per tablet.
In addition to the customary filler~ and ~cipientæ, the~e preparation~ may additionally contain ~n a~tihyper-tensive, especially in t~e treatmenk of h~gh bloodpre~ure, ~uch a~, for example, re~erpine, ~sala~ine, guanethidine, ~-methyldopa, clonidine~ a ~-~y~patholytic active compound, ~uch a~ propanolol, ox an A~E inhibitor, ~uch a~ ~aptopril, enAlapril or ramipril~
Z~ 99 In addition, therapeutic combination preparation~ with pot~ssium-retaining compounds, su~h a~ aldosterone antagonist6, for e~ample ~pironolactone or p~eudo-aldosterone antagoni~t~, such as triamterine or ~milor-ide, are of interest. Furthermore, potaQsium ~ubstitu-tion in variou~ use form5, for example coated tablets, tablet~, efferve~cent tablet6, ~yrup~ etc. i8 pos~ible.
Combin2tionQ of the compounds according to the invention with an active antihyperuricemic and/or urico~emic agent which avoids stron~ increases in blood uric acid either by an inhibition of xanthine oxidase or by increasing the renal uric acid excretion may likewise be of therapeutic interest.
In the following example, melting point and decompo6ition point~ are not corrected.
~ample 1:
3-t4-~hloro-3--(3,5-di-tert.butyl-4-llydro~yphenyl-sulfa-~oyl)-phe~yl]-3-hydro~y~ oLndolinone a) 4'-chloro-3'-~3,5-di-tert.butyl-4-hydroxyphenyl-sulfamoyl)-benzophenone-2 carboxylic acid A mixture of 8.6 g of 4-amino-2,6-di-t~rt.butyl-phenol, 80 ml of ethyl acetate and 6 ml of triethylamine are ~dded to a ~olution of 14.3 g of 4'-chloro 3~-chloro~ul-phonylbenzophenone-2-carbo~ylic acid in 70 ml of ethyl 2~ aceta~e. ~fter ~h~ exothermic reaction has ~ubsidided, the mixt~re is warmed to 55C for two hour~, 300 ~1 of water are then added at room temperature and the aqueous pha~e i~ ad~u~ted to pH 1 using 2 ~ hy~r~hloric acid.
The organic pha~e i~ separated off and w~shed once wîth water. After dryi~g over m~gneYium ~ulphate, the ~olvent i~ di~tilled off and the vi ~COU8 re~idue i8 made to crystalli~e by addition of 50 ml of isopropanol and 250 2~
ml of N-h~xane. After allowing to stand for ~everal day6, the cry~tals are filtered off and dissolved and allowed to crystallize ~everal time~ from i~opropanol/N-hexans .
S Colorless to pinkish colore~ crystal~, .p. 150-152~.
b) 3-[4-chloro-(3,5-di-tert.butyl-4-hydxoxyphenyl-sulfamoyl)-phenyl]-3-hydroxy-1-i~oindolinone A ~olution of 3.3 g of dicyclohexyl carbodiimide in 50 ml of anhydrou~ dLmethylformamidP i~ added dropwise with the exclu~ion of moisture ~nd with magnetic ~tirring at room temperature to a solution of 8.7 g of 4'-chloro-3~-~3,5-di-tert.butyl-4-hydroxyphenyl-~ulf~moyl)-benzophenone-2-carboxylic acid and 2.38 g of l-hydroxybenzotriazole in 50 ml of anhyc~ous dimethylformamide. After th~ weakly exo hermic reaction ha6 subsided, the reaction i6 ~tirred for 3 hours at room temperature alnd the mixture i~
:Eiltered o~f from the dicyclohexyl urea precipitate.
After adding dropwise to a 25~ ~trength agueous ammonia ~olution, the mixture i~ ~ubsequently stirred for 30 min.
at room ~emperature, ad~usted t~ pH }-2 with 2 N HCl ~nd extracted with ethyl acetate. The organic phase i~ dried over m~gne6ium ulp~ate, the solvent i~ di3tilled o$f, the amorphou~ residue i~ made to cry~talli~e under 50 ~1 of warm dii~opropyl ether and the product i~ purified by column chr~matography on 150 g of silica sel (O.063-0.200~ u~in~ eth~l acetate~toluene = 1:3 to 1:1.
Colorle~s cry6tals, b~p. 145~C~148C (dec.).
3-~4-chloro-3-(3-tert.butyl-5-methyl-4-hydroxyphenyl-sul~amoyl)-phenyl]-3-hydroxy~ oindolinone.
The process product~ are u~eful pharmaceutical~ ~nd are distingui~hed by a large n~ber of v~ry favor~ble thera-peutically u~ilizable propexti~s, in par~icul~r ~y the cQmbination of their very goed diuretic ~nd saluretic action~ with pronoun~ed ~nti-ath~r~sclerotic properties.
aL.3t,lLYY
This is therPfore in p~rticular of considerable thera-peu ic intere~t since the saluretics commercially ~vailable up to now either do not decreaRe or even increase those lipid componentR (VLDL and LDL fractions) of the blood which are held responsible for inducing or advancing atherosclero~is ~o that, n particulAr in the last ca6e, active compounds of this type posses6 a certain atherogeneric potential.
Even today, because of their numerous favorable proper-ties and their relatively good tolerability, diuretics still belong to the basis therapeutics in the treatment of high blood pre~ure. Since high blood pres~ure in old age to a ~ubstantial extent i~ a consequence and initiator of ath~ro~clerotic vessel change~, which in turn increase the high blood pressure, saluretic active compounds, wit:h a r~duction of the atherosclerotic risk by lowering, in particular, the atherogeneric LDL frac-tion of the cholesterol in the blood, are of particular therapeutic ~ignificance.
It was surprising that the compounds of the formula I, which differ from chlorthalidonQ by the introduction of a substituted phenyl radical on the sulphonamide group, p~8~S an action lowering the ~erum l~v~l ~ the athero-generic lipid fraction6 in addition to the diuretic and ~alure~ic ac~ion. Such a profile of action signifies a therapeutic advance in the treatment of hyper~onia of old people.
Fro~ numerou~ public~tion~ in recent y~ars, it amerges that the formation of athero~clerotic plaques proceed in~uries to the ~es~el endothelium. ~ndoth~ l inJurie~
of this tyFe can be caused by fatty acid psroxides, ~o that a reducti~n of the Atherogenic ri~k i~ inev~t~bly connected with a reduction in these lipid p~ro~ides, which are ~entially tr~n~ported in the hDL fraction.
35 The compounds ~c~ording to the invention are able to ~uppr~ th~ format~on of malondi~ldehyde, ~hich i8 a 2~ 9gl g measure of lipid peroxida~ion. The antioxidative activP
c~mponant can b~ ~raced back to the hydro~yphenylamino nubstituent on the sulphonyl group of ths ccmpound~ I.
The compound6 ~ccording to the invention do not only reduce the advance of athero~clerosis by reducing the atherogenic cholesterol fraction and by reducing the increased blood pressure, but moreover act preventatively again~t a xenewal of the atherosclerotic plaque~ through the destruction of the lipid peroxide6.
~he co~pounds I according to the in~ention ~how a fialur-etic action comparable to that o hydrochloro~hiozide and chlorthalidone in animal esperLment~ (rat). Moreov~r, the ~ompounds I are distinguished by a long-la~ting duration of action. The compound~ I according to the invention are therefore al80 suitable for the treatment of hypertonic ætates where, as generslly customary today, they are optionally combined with anot:her antihypertonic.
The compound~ I are used in do~es of at least 0.5 mg/kg ~nd day, preferably 1 mg/k~ and day ko at most 10 mg/kg/-day, preferably up to 5 mg/kg/day, based on ~n adulthuman of about 75 k~ body wei~ht.
5uitab1e therapeutic preparations oX the new compound~
are, ahove all, table~6, coated tablets, capsules and ~uppositories and al~o ampoule~ for parenteral adminis-tration (i.v., ~.c. and i.~.). The t~er2peutic unit dosei8 between 0.5 and 500 mg, preferably between 10 and 300 m~ per tablet.
In addition to the customary filler~ and ~cipientæ, the~e preparation~ may additionally contain ~n a~tihyper-tensive, especially in t~e treatmenk of h~gh bloodpre~ure, ~uch a~, for example, re~erpine, ~sala~ine, guanethidine, ~-methyldopa, clonidine~ a ~-~y~patholytic active compound, ~uch a~ propanolol, ox an A~E inhibitor, ~uch a~ ~aptopril, enAlapril or ramipril~
Z~ 99 In addition, therapeutic combination preparation~ with pot~ssium-retaining compounds, su~h a~ aldosterone antagonist6, for e~ample ~pironolactone or p~eudo-aldosterone antagoni~t~, such as triamterine or ~milor-ide, are of interest. Furthermore, potaQsium ~ubstitu-tion in variou~ use form5, for example coated tablets, tablet~, efferve~cent tablet6, ~yrup~ etc. i8 pos~ible.
Combin2tionQ of the compounds according to the invention with an active antihyperuricemic and/or urico~emic agent which avoids stron~ increases in blood uric acid either by an inhibition of xanthine oxidase or by increasing the renal uric acid excretion may likewise be of therapeutic interest.
In the following example, melting point and decompo6ition point~ are not corrected.
~ample 1:
3-t4-~hloro-3--(3,5-di-tert.butyl-4-llydro~yphenyl-sulfa-~oyl)-phe~yl]-3-hydro~y~ oLndolinone a) 4'-chloro-3'-~3,5-di-tert.butyl-4-hydroxyphenyl-sulfamoyl)-benzophenone-2 carboxylic acid A mixture of 8.6 g of 4-amino-2,6-di-t~rt.butyl-phenol, 80 ml of ethyl acetate and 6 ml of triethylamine are ~dded to a ~olution of 14.3 g of 4'-chloro 3~-chloro~ul-phonylbenzophenone-2-carbo~ylic acid in 70 ml of ethyl 2~ aceta~e. ~fter ~h~ exothermic reaction has ~ubsidided, the mixt~re is warmed to 55C for two hour~, 300 ~1 of water are then added at room temperature and the aqueous pha~e i~ ad~u~ted to pH 1 using 2 ~ hy~r~hloric acid.
The organic pha~e i~ separated off and w~shed once wîth water. After dryi~g over m~gneYium ~ulphate, the ~olvent i~ di~tilled off and the vi ~COU8 re~idue i8 made to crystalli~e by addition of 50 ml of isopropanol and 250 2~
ml of N-h~xane. After allowing to stand for ~everal day6, the cry~tals are filtered off and dissolved and allowed to crystallize ~everal time~ from i~opropanol/N-hexans .
S Colorless to pinkish colore~ crystal~, .p. 150-152~.
b) 3-[4-chloro-(3,5-di-tert.butyl-4-hydxoxyphenyl-sulfamoyl)-phenyl]-3-hydroxy-1-i~oindolinone A ~olution of 3.3 g of dicyclohexyl carbodiimide in 50 ml of anhydrou~ dLmethylformamidP i~ added dropwise with the exclu~ion of moisture ~nd with magnetic ~tirring at room temperature to a solution of 8.7 g of 4'-chloro-3~-~3,5-di-tert.butyl-4-hydroxyphenyl-~ulf~moyl)-benzophenone-2-carboxylic acid and 2.38 g of l-hydroxybenzotriazole in 50 ml of anhyc~ous dimethylformamide. After th~ weakly exo hermic reaction ha6 subsided, the reaction i6 ~tirred for 3 hours at room temperature alnd the mixture i~
:Eiltered o~f from the dicyclohexyl urea precipitate.
After adding dropwise to a 25~ ~trength agueous ammonia ~olution, the mixture i~ ~ubsequently stirred for 30 min.
at room ~emperature, ad~usted t~ pH }-2 with 2 N HCl ~nd extracted with ethyl acetate. The organic phase i~ dried over m~gne6ium ulp~ate, the solvent i~ di3tilled o$f, the amorphou~ residue i~ made to cry~talli~e under 50 ~1 of warm dii~opropyl ether and the product i~ purified by column chr~matography on 150 g of silica sel (O.063-0.200~ u~in~ eth~l acetate~toluene = 1:3 to 1:1.
Colorle~s cry6tals, b~p. 145~C~148C (dec.).
Claims (7)
1. A compound of the formula I
I, in which R1 denotes hydrogen or methyl R2 denotes hydrogen or an alkyl radical having 1 - 6 carbon atoms R3 denotes an alkyl radical having 3 to 5 carbon atoms, and the open-chain tautomeric forms corresponding to I of the formula Ia Ic), in which R1 to R2 have the meaning indicated.
I, in which R1 denotes hydrogen or methyl R2 denotes hydrogen or an alkyl radical having 1 - 6 carbon atoms R3 denotes an alkyl radical having 3 to 5 carbon atoms, and the open-chain tautomeric forms corresponding to I of the formula Ia Ic), in which R1 to R2 have the meaning indicated.
2. A compound I as claimed in claim 1, wherein R1 denotes hydrogen, R2 denotes methyl, isopropyl or tert.-butyl and R3 denotes isopropyl or tert.butyl.
3. A compound as claimed in claim 1, which is 3-[4-chloro-3-(3,5-di-tert.butyl-4-hydroxyphenylsulfamoyl)-phenyl]-3-hydroxy-1-isoindolinone.
4. A process for the preparation of a compound of the formula I as claimed in claim 1 I, in which R1 denotes hydrogen or methyl R2 denotes hydrogen or an alkyl radical having 1 - 6 carbon atoms R3 denotes an alkyl radical having 3 to 5 carbon atoms, and the open-chain tautomeric forms corresponding to I of the formula Ia Ic) in which R1 to R3 have the meaning indicated, which comprises reacting compounds of the formula II
II
with an amine of the formula III
in which R1 to R3 have the meaning indicated and option-ally converting into the salt.
II
with an amine of the formula III
in which R1 to R3 have the meaning indicated and option-ally converting into the salt.
5. A compound I as claimed in claim 1 for use as a blood lipid-lowering medicament.
6. The use of a compound I as claimed in claim 1 for the production of a medicament having a blood lipid-lowering action.
7. The compound as claimed in claim 1, and substantially as described herein.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3840354A DE3840354A1 (en) | 1988-11-30 | 1988-11-30 | BENZOLSULFONAMIDE DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF |
| DEP3840354.4 | 1988-11-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2004199A1 true CA2004199A1 (en) | 1990-05-31 |
Family
ID=6368173
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002004199A Abandoned CA2004199A1 (en) | 1988-11-30 | 1989-11-29 | Benzenesulphonamide derivatives and processes for their preparation |
Country Status (14)
| Country | Link |
|---|---|
| EP (1) | EP0371461A3 (en) |
| JP (1) | JPH02193960A (en) |
| AU (1) | AU621691B2 (en) |
| CA (1) | CA2004199A1 (en) |
| DE (1) | DE3840354A1 (en) |
| DK (1) | DK602389A (en) |
| FI (1) | FI895688A7 (en) |
| HU (1) | HU207294B (en) |
| IL (1) | IL92481A0 (en) |
| NO (1) | NO894763L (en) |
| NZ (1) | NZ231558A (en) |
| PH (1) | PH26579A (en) |
| PT (1) | PT92441A (en) |
| ZA (1) | ZA899100B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9204466D0 (en) * | 1992-03-02 | 1992-04-15 | Sandoz Ltd | Improvements in or relating to organic compounds |
| CN114409964A (en) * | 2021-12-29 | 2022-04-29 | 江苏坤腾包装有限公司 | Modified nano silicon dioxide and application thereof in preparation of PET packing belt |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3055904A (en) * | 1957-11-04 | 1962-09-25 | Geigy Chem Corp | New isoindoline derivatives |
| EP0051217A1 (en) * | 1980-10-31 | 1982-05-12 | Usv Pharmaceutical Corporation | Oxidation process |
| DE3713757A1 (en) * | 1987-04-24 | 1988-11-10 | Hoechst Ag | BENZOLSULPHONAMIDE DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF |
-
1988
- 1988-11-30 DE DE3840354A patent/DE3840354A1/en not_active Withdrawn
-
1989
- 1989-11-28 EP EP19890121940 patent/EP0371461A3/en not_active Withdrawn
- 1989-11-28 PH PH39608A patent/PH26579A/en unknown
- 1989-11-28 HU HU896213A patent/HU207294B/en unknown
- 1989-11-28 FI FI895688A patent/FI895688A7/en not_active Application Discontinuation
- 1989-11-28 NZ NZ231558A patent/NZ231558A/en unknown
- 1989-11-28 IL IL92481A patent/IL92481A0/en unknown
- 1989-11-29 NO NO89894763A patent/NO894763L/en unknown
- 1989-11-29 CA CA002004199A patent/CA2004199A1/en not_active Abandoned
- 1989-11-29 PT PT92441A patent/PT92441A/en not_active Application Discontinuation
- 1989-11-29 DK DK602389A patent/DK602389A/en not_active Application Discontinuation
- 1989-11-29 AU AU45615/89A patent/AU621691B2/en not_active Ceased
- 1989-11-29 ZA ZA899100A patent/ZA899100B/en unknown
- 1989-11-29 JP JP1307845A patent/JPH02193960A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| HU207294B (en) | 1993-03-29 |
| ZA899100B (en) | 1990-08-29 |
| DK602389D0 (en) | 1989-11-29 |
| FI895688A0 (en) | 1989-11-28 |
| AU4561589A (en) | 1990-06-21 |
| HUT53075A (en) | 1990-09-28 |
| EP0371461A2 (en) | 1990-06-06 |
| IL92481A0 (en) | 1990-08-31 |
| PH26579A (en) | 1992-08-19 |
| PT92441A (en) | 1990-05-31 |
| NZ231558A (en) | 1991-08-27 |
| JPH02193960A (en) | 1990-07-31 |
| AU621691B2 (en) | 1992-03-19 |
| NO894763L (en) | 1990-05-31 |
| FI895688A7 (en) | 1990-05-31 |
| DE3840354A1 (en) | 1990-06-07 |
| HU896213D0 (en) | 1990-02-28 |
| EP0371461A3 (en) | 1991-10-23 |
| NO894763D0 (en) | 1989-11-29 |
| DK602389A (en) | 1990-05-31 |
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| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |