United States Patent t101
`Seydel et al.
`
`tll~ Patent Number: 4,829,058
`[451 Date of Patent: May 9, 1989
`
`[54] SUBSTITUTED
`BIS-(4-AMINOPHENYL)-SULFONES
`
`Attorney, Agent, or Firm--D. E. Frankhouser;
`Mary-Ellen M. Timbers; Alan R. Stempel
`
`[75]
`
`Inventors: Joachim K. Seydel, Borstel; Helmut
`Pieper; Gerd Kruger, both of
`Biberach; Klaus Noll, Warthausen;
`Johannes Keck, Biberach; Uwe
`Lechner, Ummendorf, all of Fed.
`Rep. of Germany
`
`[57]
`
`ABSTRACT
`
`Disclosed arc substituted bis(4-aminophenyl)-sulfones
`of general formula
`
`R3
`
`O)
`
`[73] Assignee: Dr. Karl Thomae GmbH, Biberach an
`der Riss, Fed. Rep. of Germany
`
`H2N
`
`so~
`
`[21] Appl. No.: 62,291
`
`[22] Filed:
`
`Jun, 15, 1987
`
`Related U.S. Application Data
`
`[63] Continuation of Ser. No. 732,024, May 8, 1985, aban-
`doned.
`
`[30]
`
`Foreign Application Priority Data
`
`May 22, 1984 [DE] Fed. Rep. of Germany ....... 34191309
`
`[51]
`Int. Cl.4 ............................................ C07C 103/22
`[52] U.S. CI ................................... 514/155; 260/397.6
`[58] Field of Search ...................... 260/397.6; 514/155
`
`[56]
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`2,382,924 8/1945 Tschesche ........................ 260/397.6
`2,454,835 11/1948 Rawlins ............................ 260/397.6
`3,325,521 6/1967 Elslager et al ................... 260/397.6
`3,696,131 10/1972 Matzner et al ................... 260/397.6
`
`FOREIGN PATENT DOCUMENTS
`1164829 9/1969 United Kingdom .
`
`OTHER PUBLICATIONS
`
`Kumar et al., CA 89:123198r.
`Popott et al., J. Med. Chem. 1971, vol. 14, No. 12, pp.
`1166-1169.
`Stacey et al., J.O.C. 24, pp. 1892-1896, 1959.
`
`\R2
`__~ ~r/R’
`R4
`
`wherein
`R1 is hydrogen, alkyl or cycloalkyl; group,
`R2 is hydrogen or CI-C3 alkyl,
`R3 is nitrile, Ct-C3 alkylaminocarbonyl, di CI-C3 al-
`kylaminocarbonyl, C3-C7 N-cycloalkyl-Ci-C3 a1-
`kylaminocarbonyl Ct-C3 alkylamino, Ci-C3, di al-
`kylaminocarbonyl alkoxy, alkylaminosulfonyl, di
`C1-C3 alkylaminono, diCI-C3 alkylaminosulfonyl,
`hydroxy Ct-C3 alkyl, C!-C3 alkylcarbonyl, amino
`CI-C3 alkyl or Ct-C3 alkoxy C1-C3 alkyl group
`or, when Rt and R2 arc each hydrogen, R3 can be hy-
`droxy, hydroxycarbonyl Ca-C3 alkoxy or di Ct-C3
`aminocarbonylalkoxy;
`or, when RI is CI-C3 alkyi or CI-C3 cycloalkyl and R2
`is hydrogen or CI-C3 alkyl, R3 can also be halogen,
`trifluoromethyl, nitro, amino, aminesulfonyl, amino-
`carbonyl, C1-C3 alkyl, carboxy or C1-C3 alkoxycar-
`bonyl; and
`R4 is hydrogen or, when RI and R2 are each hydrogen
`and R3 is halogen or hydroxy, R4 can also be halogen,
`hydroxy or Ct-C3 alkoxy; or a nontoxic, pharmaceu-
`tically acceptable salt thereof. Also disclosed are
`pharmaceutical compositions comprising such com-
`pounds alone and in combination with dihydrofolic
`acid-reductase inhibitors. The compounds and com-
`positions are useful for their inhibiting effect on bac-
`teria, mycobacteria and plasmodia.
`
`Primary Examiner--Jane T. Fan
`
`11 Claims, No Drawings
`
`1 of 15
`
`Almirall EXHIBIT 2008
`Amneal v. Almirall
`IPR2018-00608
`
`

`

`SUBSTITUTED
`BIS-(4-AMINOPHENYL).SULFONES
`
`BACKGROUND OF THE INVENTION
`
`4,829,058
`1 2
`methoxy, or a nontoxic, pharmaceutically acceptable
`salts thereof.
`A further subgeneric aspect includes compounds of
`formula I wherein:
`This is a continuation of application Set. No. 732,024, 5 Rt is hydrogen, CI-C3 alkyl or C4-C7 cycloalkyl;
`filed May 8, 1985 now abandoned.
`R2 is hydrogen or, when R1 is methyl, R2 can also be
`methyl;
`R3 is chlorine, bromine, methyl, trifluoromethyl, hy-
`droxymethyl, hydroxyethyl, methylamino, dimethyl-
`amino, cyano or methylcarbonyl in the 2-position:
`and
`R4 is hydrogen; or a nontoxic, pharmaceutically accept-
`able addition salt thereof.
`The present invention thus relates to the compounds
`15 of formula I above, the addition salts thereof, particu-
`
`1. Field of the Invention
`The present invention relates to the field of corn- 10
`pounds useful for inhibiting bacteria, mycobacteria and
`plasmodia, particularly to sulfone compounds which
`are useful in this regard and in treating animals and
`humans suffering from infections of such organisms.
`2. Brief Information Disclosure Statement
`U.S. Pat. No. 2,385,899 describes the compound bis-
`(4-aminophenyl)-sulfone which has an inhibiting effect
`on the growth of bacteria, mycobacteria and plasmodia,
`
`larly the acid addition salts thereof with pharmaceuti-
`tally acceptable inorganic or organic acids, pharmaceu-
`tical compositions containing these compounds includ-
`SUMMARY OF THE INVENTION ing their addition salts, their preparation and the use
`20
`thereof for inhibiting bacteria, mycobacteria and plas-
`The present invention provides substituted bis-(4-
`modia and for treating animals and humans suffering
`aminophenyl)-sulfones of formula I
`from infections of such organisms.
`This invention further relates to combinations of the
`substituted bis(4-aminophenyl)-sulfones of formula I
`25 including their nontoxic, pharmaceutically acceptable
`
`R3
`
`H2N
`
`SO2
`
`/R~
`N
`
`_@__
`
`_~
`
`\R2
`
`R4
`
`30
`
`addition salts with a dihydrofolic acid-reductase inhibi-
`tor such as pyrimethamine, trimethoprim or trimetho-
`prim derivatives.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`R2 can be hydrogen, methyl, ethyl, n-propyl or iso-
`propyl.
`R3 can be cyano, methylaminocarbonyl,
`
`40 ethylaminocarbonyl, isopropylaminocarbonyl, dime-
`thylaminocarbonyl, diethylaminocarbonyl, di-n-
`propylaminocarbonyl, N-methylethylaminocarbonyl,
`N-methyl-
`N-methyi-cyclopentylaminocarbonyl.
`
`wherein
`Rt is hydrogen, CI-.C7 alkyl or C3-C7 cycioalkyi;
`Examples of groups Rt to’ R4 include the following.
`R2 is hydrogen or CI-C3 alkyl;
`RI can be hydrogen, methyl, ethyl, n-propyl, isopro-
`R3 is nitrile, Ct-C3 alkylaminocarbonyl, di C1-C3 al-
`pyl, n-butyl, isobutyl, n-pentyi, isoamyl, n-hexyl, n-hep-
`kylaminocarbonyl, C3-C7 N-cycloalkyl Cl-C3 al- 35 tyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
`kylaminocarbonyl, Ct-C3 alkylamino, di Ct-C3alkyl-
`amino, di C1-C3 alkylaminocarbonyl, C1-C3 alkoxy,
`CI-C3 alkylaminosulfonyl, di C1-C3 alkylaminosulfo.
`nyl, hydroxy CI-C3 alkyl, Ct-C3 alkylcarbonyi,
`amino CI-C3 alkyl or CI-C3 alkoxy Ct-C3 alkyl
`or, when R1 and R2 are each hydrogen, R3 can be hy-
`droxy or hydroxycarbonyl C1-C3 alkoxy
`or, when Rt is Ci-C3 alkyl or C3-C7 cycloalkyl and Rz
`is hydrogen or CI-C3 alkyl, R3 can also be halogen, cyclohexylaminocarbonyl, N-methyl-cyclohep-
`trifluoromethy!, nitro, amino, aminosu|fonyl, amino- 45 tylaminocarbonyl, N-ethyl-cyclohexylaminocarbonyl,
`methylamino,
`ethylamino, n-propylamino, iso-
`carbonyl, C1-C3 alkyl, carboxy or Cl-C3 alkoxycar-
`propylamino, dimethylamino, diethylamino, diiso-
`bonyl; and
`propylamino,
`N-methyl-ethylamino,
`N-ethyl-n-
`R4 is hydrogen, or when RI and R2 are each hydrogen
`propylamino, dimethylaminocarbonylmethoxy, die-
`and R3 is halogen or hydroxy in the 2-position, [Lccan
`2-dimethylaminocar-
`also be halogen, hydroxy or C1-C3 alkoxy, or a non- 50 thylaminocarbonylmethoxy,
`bonylethoxy, 2-diethylaminocarbonylethoxy, me-
`toxic, pharmaceutically acceptable salt thereof,
`ethylaminosulfonyl,
`thylaminosulfonyl,
`iso-
`One subgeneric aspect includes compounds of for-
`dimethylaminosulfonyl,
`propylaminosulfonyl,
`die-
`mula I wherein:
`thylaminosulfonyi, hydroxymethyl, l-hydroxyethyl,
`Rt is hydrogen, Cl-C7 alkyl or a C4-C7 cycloalkyl;
`55 2-hydroxyethyl, 1-hydroxypropyl, 3-hydroxypropyl,
`Rzis hydrogen or methyl;
`methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, ami-
`R3 is nitrile, methylaminocarbonyl, N-cyclohexyl-
`nomethyl, 2-aminoethyl, 3-aminopropyl, methox-
`methylaminocarbonyl, methylamino, dimethylamino,
`ymethyl, 2-methoxyethyl, ethoxymethyl, 2-ethox-
`dimethylaminocarbonylmethoxy, hydroxymethyl,
`yethyl, n-propoxymethyl, 2-n-propoxyethyl, hydroxy,
`hydroxyethyl, methylcarbonyl, aminocarbonyl or
`60 hydroxycarbonylmethoxy, 2-hydroxycarbonylethoxy,
`methoxymethyl;
`3-hydroxycarbonylpropoxy, 2-dimethylaminoethoxy,
`or when, RI and R2 are each hydrogen, R3 can also be
`2-diethylaminoethoxy, trifluoromethyl, nitro, amino,
`hydroxy or hydroxycarbonylmethoxy
`aminosulfonyl, aminocarbonyi, methyl, ethyl, n-propyl,
`or, when Rl is alkyl or cycloalkyl and R2 is hydrogen or
`methyl, R3 can also be chlorine, bromine, methyl,
`isopropyl, carboxy, methoxycarbonyl, ethoxycarbonyl,
`trifiuoromethyl, nitro, amino or aminoearbonyi; and 65 n-propoxycarbonyl, isopropoxycarbonyl, fluorine,
`R4 is hydrogen or, when R1 and R2 are each hydrogen
`chlorine, bromine or iodine.
`and R3 is hydroxy, chlorine or bromine in the 2-posi-
`R4 can be hydrogen, fluorine, chlorine, bromine,
`tion, R4 can also be chlorine, bromine, hydroxy or
`iodine, hydroxy, methoxy, ethoxy or n-propoxy.
`
`2 of 15
`
`

`

`4,829,058
`3 4
`pionyl; benzoyl, p-toluenesulfonyl, methanesulfonyl or
`According to the invention the compounds of for-
`ethoxycarbonyl, or hydrogenolytically removable
`mula I can be obtained by the following processes,
`groups such as benzyl.
`Method A
`In one method, compounds of formula I are made by
`Any protecting group used is preferably split off by
`5 hydrolysis, e.g. with an acid such as hydrochloric, sul-
`reduction of a compound of formula II
`phuric or phosphoric acid or with a base such as sodium
`hydroxide or potassium hydroxide in a suitable solvent
`or a mixture of solvents such as water, water/methanol
`ethanol, water/ethanol, water/isopropanol or water/di-
`10 oxan at temperatures of --10° to 120" C., preferably
`ambient temperature to the boiling temperature of the
`reaction mixture, or by hydrogenolysis, e.g. with hy-
`drogen in the presence of a hydrogenation catalyst such
`as palladium/charcoal in a suitable solvent such as
`wherein R3 and tG are as previously defined, one of A 15 methanol, ethanol, glacial acetic acid, ethyl acetate.
`and B is nitro and the other is
`
`R3
`
`(II)
`
`A
`
`SO2
`
`B
`
`_@_
`
`_~
`
`P.4
`
`dioxan or dimethylformamide at temperatures of 0° to
`50° C., preferably at ambient temperature.
`Method C
`Compounds of formula I wherein R3 is cyano are
`20 prepared by dehydration of a compound of formula IV
`
`R1
`_N/
`\
`R2
`
`CONH2
`
`(IV)
`
`R)
`
`~
`
`R~
`
`wherein Rl and R2 are as previously defined, or is also
`nitro.
`The reduction is conveniently carried out in a solvent 25 ~
`or mixture of solvents such as water, methanol, ethanol,
`N
`SO2
`H2N
`glacial acetic acid, ethyl acetate, dimethylformamide,
`--@’- x~
`R2
`water/ethanol or water/tetrahydrofuran in the pres-
`ence of a reduction agent, e.g. with hydrogen in the
`presence of an hydrogenation catalyst such as Raney 30
`nickel, platinum or palladium/charcoal, with metals
`wherein RI, R2 and IL¢ are as previously defined.
`such as iron, tin or zinc in the presence of an acid such
`The dehydration is conveniently carried out with a
`as hydrochloric or acetic acid, with salts such as iron-
`dehydrating agent such as phosphorus pentoxide, con-
`(II)suiphate, tin(II)chloride/hydrochloric acid or so-
`cetrated suiphuric acid, p-toluenesulphonic acid, thio-
`dium dithionite in the presence of a base such as sodium 35 nylchloride, phosphorus oxychloride, sulfurylchloride,
`hydroxide solution or pyridine or with hydrazine in the
`phosphoric acid or dicyclohexylcarbodiimide, option-
`presence of Raney nickel, at temperatures of 0* to 50*
`ally in a solvent such as methylene chloride, phyridine
`C., preferably at ambient temperature,
`or chlorobenzene or in an excess of the dehydrating
`Method B
`agent used such as thionyl chloride, phosphorus oxy-
`In another method, one or two protecting groups are 40 chloride, sulfurylchloride, or phosphoric acid at tern-
`cleaved from a compound of formula III
`peratures of 0* to 100’, preferably 20* to 80° C. How-
`ever, the reaction can also be carried out without a
`solvent.
`Method D
`4S Compounds of formula wherein R3 is hydroxycar-
`
`R3
`
`(!II)
`
`G
`soz
`_~
`
`E
`
`@
`R,
`
`bonylalkoxy or dialkylaminocarbonyl-alkoxy can be
`prepared by alkylation of a compound of formula V
`
`50 OH <V)
`
`CI-C7 alkylamino or C3-C7 cycloalkylamino protected
`by a protecting group, or is
`
`H2N
`
`SO2
`
`N
`
`R2
`
`~ x~
`R1 55 R4
`/
`--N
`\
`R2
`
`wherein R1, R2 and IL, are as previously defined with a
`compound of formula VI
`
`wherein
`Rt and R2 are as previously defined; and
`G is an amino group optionally protected by a protect-
`ing group. At least one of E and G must be one of the
`above-mentioned groups protected by a protecting
`group.
`Suitable protecting groups are the protecting groups
`conventionally used for amino groups, e.g. hydrolyti-
`tally removable protecting groups such as acetyl, pro-
`
`6o
`
`X--AIk--CO---R 5
`
`(VI)
`
`wherein
`Alk is a C t-C3 alkylene;
`R5 is hydroxy, CI-C3 alkoxy or di C1-C3alkylamino;
`65 and
`X is a nucleophilically exchangeable group such as
`chlorine or bromine, optionally with subsequent hy-
`drolysis.
`
`3 of 15
`
`

`

`4,829,058
`
`~R~
`
`~t x
`
`~ ~
`N
`H2N
`502
`
`g~
`
`g-.
`
`P-4
`
`6
`The reaction is preferably carried out in a solvent
`tor or by adding a drying agent such as magnesium
`sulphate or molecular sieve.
`such as diethylether, tetrahydrofuran, dioxan, metha-
`In this reaction it can also be advantageous to prepare
`nol, ethanol, pyridine or dimethylformamide, optionally
`an activated derivative of a compound of formula VII
`with a base such as sodium hydride, potassium hydride,
`5 or VIII in the reaction mixture initially and then react
`potassium carbonate or potassium tert.butoxide at tern-
`this derivative with a compound of formula VIII or
`peratures of 0* to 75* C. preferably at ambient tempera-
`VII.
`ture.
`Method F
`The optional subsequent hydrolysis is preferably car-
`Compounds of formula I wherein R3 is hydroxy-
`tied out either with an acid such as hydrochloric, sul-
`phuric, phosphoric or trichloroacetic acid or with a 10 methyl, aminomethyl or l-hydroxyalkyl can be pre-
`pared by reduction of a compound of formula IX
`base such as sodium hydroxide or potassium hydroxide
`in a suitable solvent such as water, water/methanol,
`ethanol, water/ethanol, water/isopropanol or water/di-
`oxan at temperatures of - 10" C. to 120" C., e,g. ambient 15
`temperature to the boiling temperature of the reaction
`mixture.
`Method E
`Compounds of formula I wherein R3 is aminocarbo-
`nyl, alkylamino-carbonyl, diaikylaminocarbonyl or 20
`dialkylaminocarbonylalkoxy can be prepared by reac-
`tion of a compound of formula VII.
`
`R’~
`
`(VU)
`
`_~ ~ N/R~
`
`H2N
`
`$O2
`
`N
`
`R2
`
`x.~
`R4
`
`wherein
`R1 and R2 and R4 are as previously defined; and
`R3" is hydroxycarbonyl, alkoxycarbony!, aminocarbo-
`nyl or C2-C4 alkylcarbonyl.
`25 The reaction is preferably carried out with a metal
`hydride such as sodium borohydride, lithium aluminium
`hydride or diborane in a solvent such as water, metha-
`nol, water/methanol, diethyl ether, tetrahydrofuran or
`dioxan at temperatures of 0* to 80* C., preferably ambi-
`30 ent temperature to 70* C.
`Method O
`-
`wherein
`Compounds of formula I wherein R1 is alkyl or cyclo-
`RI, R2 and Ra are as hereinbefore defined; and
`alkyl and R2 is hydrogen can be prepared by reduction
`R3’ is hydroxyearbonyl, hydroxycarbonyl-alkoxy or a of a compound of formula X
`reactive derivative thereof, with an amine of formula 35
`VIII R3 IX)
`
`HN 40
`
`L SO2 N-~--C
`
`R7
`
`R4
`
`wherein
`
`wherein
`R6 is hydrogen atom or Cl-C3 alkyl; and
`R7 is hydrogen or C1-C3 alkyl, or reactive derivatives 45 R3 and R4 are as previously defined;
`L is amino or nitro; and
`thereof.
`Rs and I(9 together with the carbon atom between them
`The reaction is conveniently carried out in a solvent
`are a Ct-C7 alkylidene or a C3-C7 cycloalkylidene.
`such as methylene chloride, chloroform, carbon tetra-
`The reduction is preferably carried out in a suitable
`chloride, ether, tetrahydrofuran, dioxan, benzene, tolu-
`ene, acetronitrile or dimethylformamide, optionally in 50 solvent such as methanol, ethanol, methanol/water,
`ethyl acetate, tetrahydrofuran or dioxan with nascent or
`the presence of an acid-activating agent or a dehydrat-
`catalytically activated hydrogen or with a hydride such
`ing agent, e.g. in the presence of ethylchloroformate,
`as diborane, sodium borohydride or lithium aluminium
`thionylchloride, phosphorus trichloride, phosphorus
`hydride at temperatures of 0* to 50* C., preferably at
`pentoxide, N,N’-dicyclohexylcarbodiimide, N,N’-dicy- 55 ambient temperature.
`clohexylcarbodiimide/N-hydroxy succinimide, N,N’-
`If L is nitro, the reduction is particularly advanta-
`carbonyldiimidazole or N,N’-thionyldiimidazole or tri-
`geously carded out in a solvent such as methanol or
`phenylphosphineicarbon tetrachloride, or an agent
`ethyl acetate with hydrogen in the presence of a hydro-
`which activates the amino group, e.g. phosphorus tri.
`genation catalyst such as platinum or palladium/char-
`chloride, and optionally in the presence of an inorganic 60 coal and under a hydrogen pressure of 0 to 5 bar or with
`base sucl-t as sodium carbonate or a tertiary organic base
`a complex metal hydride such as lithium aluminium
`such as triethylamine or pyridine, which can simulta-
`hydride or diborane at temperatures of 0° to 50* C.,
`neously serve as solvent, at temperatures of --25* C. to
`preferably at ambient temperature.
`250* C., preferably --10" C. to the boiling temperature
`If L in a compund of formula X is amino, the reduc-
`of the solvent used. The reaction can also be carried out 65 tion is carried out particularly advantageously in a sol-
`without a solvent and furthermore any water formed
`vent such as methanol, methanol/water, tetrahydrofu-
`during the reaction can be removed by azeotropic distil-
`ran or dioxan with a complex metal hydride such as
`lation, e.g. by heating with toluene using a water separa-
`sodium borohydride or lithium aluminium hydride at
`
`4 of 15
`
`

`

`4,829,058
`7 8
`temperatures of 0* to 50° C., preferably at ambient tem-
`perature.
`If a compound of formula I is obtained wherein R3 is
`alkoxycarbonyl or alkoxycarbonylalkoxy, it can be con-
`vetted by hydrolysis into a corresponding compound of 5
`formula I wherein R3 is hydroxycarbonyl or hydrox-
`ycarbonylalkoxy. If a compound of formula I is ob-
`tained hwerein R3 and/or R4 is chlorine or bromine, it
`can be converted by hydrolysis or alcoholysis into a
`corresponding compound of formula I wherein R3 is 10
`
`R
`/
`
`--N\
`R2
`
`wherein, R1 and R2 are as previously defined.
`Moreover a compound of formula XIII
`
`R3
`~,..j SO~Ya
`
`(Xlll)
`
`bromine.hydr°xy or alkoxy in the 2 position and R4 is chlorine or
`
`30 formula XI with a corresponding carbonyl drivative,
`optionally in the presence of titanium(IV) chloride and
`optional subsequent reduction of the nitro group, for
`example with catalytically activated hydrogen.
`As already mentioned hereinbefore, the new com-
`
`35 pounds of formula I including their nontoxic, pharma-
`ceutically acceptable addition salts having an inhibiting
`effect on the growth of bacteria and parasites such as
`plasmodia and mycobacteria which is believed to be due
`to their inhibiting effect on 7,8-dihydropteroic acid-syn-
`
`Itl
`
`R2
`
`R4
`
`This hydrolysis is conveniently carried out either
`with an acid such as hydrochloric or sulphutrc acid or
`with a base such as sodium hydroxide or potassium 15
`hydroxide in a suitable solvent such as water, water/-
`methanol, ethanol, water/ethanol, water/isopropanol
`wherein Rl to R4 are as previously defined and Na is a
`or water/dioxan at temperatures of -- 10" C. to 120" C.,
`e.g. at temperatures of ambient temperature to the boil- 20 sodium ion, can be reacted with a 4-halonitrobenzene to
`form a corresponding diphenylsulfone of formula III.
`ing temperature of the reaction mixture,
`A cycloalkylamino compound of formula II, how-
`The alcoholysis is conveniently carried out in a corre-
`ever, is preferably obtained by reductive amination of a
`sponding alcohol as the solvent such as methanol, etha-
`corresponding amino compound with a cycloalkanone
`nol or propanol, optionally in a pressure vessel, prefera-
`bly with a base such as sodium hydroxide or potassium 25 in the presence of sodium cyanoborohydride or by re-
`duction of the corresponding SchitT’s base with a com-
`hydroxide at temperatures of 20* C. to 200° C., prefera-
`plex metal hydride.
`bly 50* to 180" C.
`A compound of formula X used as starting material is
`The compounds of general formulae II to X used as
`obtained by reacting a corresponding compound of
`starling materials are known from the literature or can
`be obtained by methods known from the literature.
`Thus, for example, a compound of formula II or III
`can be obtained by reacting an alkali metal salt of a
`corresponding acylaminophenyl-sulfinic acid with a
`corresponding p-halonitrobenzene. A compound of
`formula XI
`
`R3 (XI)
`
`_~
`O2N
`SO2
`
`NH2
`
`R4
`
`40 thetase.
`For example, the following compounds
`A = 4-Ethylamino-4’-amino-2-chloro-diphenylsul fone,
`B = 4’-Amino-2-chloro-4-is0Propylamino-diphenylsal-
`fone,
`optionally obtained after splitting offan acyl protecting 45 C=4-Ethylamino-4’-amino-2-methyl-diphenylsulfone,
`group, wherein R3 and R4 are as previously defined, can
`D = 4-Ethylamino-4’-amino-2-trifluoromethyl-diphe-
`subsequently be converted by reductive amination into
`nyl-suifone,
`E=4,4’-Diamino-2-hydroxymethyl-diphenylsulfone,
`a compound of formula II or after tosylation, subse-
`F----4,4’-Diamino-2-(1-hydroxyethyl)-diphenylsulfone,
`quent alkylation and reduction of the nitro group and
`optionally subsequent acylation into a compound of 50 G=4,4’-Diamino-2-(N,N-dimethylamino)-diphenylsul-
`formula IlI.
`lone,
`H=4,4’-Diamino-2-(N-methylamino)-diphenylsulfone,
`Moreover, a compound of formula XII
`I = 4,4’-Diamino-2-cyano-diphenylsulfone,
`
`R3
`
`Cxtt) K = 4,4’-Diamino-2-methylcarbonyl-diphenylsulfone,
`55 L=4’-Amino-2-methyl-4-methylamino-diphenylsulfoneand
`
`N
`H\ _@ ~
`SO2
`N I"I2
`/
`Acyl
`
`R4
`
`(20
`
`M = 4’-Amino-2-methyl-4-propylamino-diphenylsul-
`fone were tested for their biological activity in cell-
`free enzyme extract of Plasmodiumberghei as fol-
`lOWS.
`1. Preparation of the enzyme extract
`prepared by methods known from the literature,
`Plasmodia are isolated from mouse blood infected
`wherein R3 and R4 are as previously defined and Acyl is
`with Plasmodium berghei in accordance with the follow-
`an organic acyl group, can be converted by reductive
`ing reference (Heidrich, H.-G. et al., Z. Parasitenkd. 59:
`amination or by reduction of a Schiff’s base obtained 65 151 (1979). The plasmodia were opened by ultrasound.
`after reaction with a corresponding carbonyl corn-
`Proteins with 7,8-hydropteroic acid synthetase activity
`pound into a compound of formula III wherein D is an
`are concentrated by gel t’dtration.
`aminoacyl group and E is
`2. Biological test system
`
`5 of 15
`
`

`

`4,829,058
`9 10
`The inhibiting effect on 7,8-dihydropteroic acid syn-
`tained is suction filtered, washed with ethanol and then
`thesis of plasmodia is determined as follows:
`dried. This crude product is recrystallised from metha-
`Under optimum reaction conditions, i.e. Vmax for the
`nol.
`reaction which is to be inhibited, the concentration of
`Yellow crystals, m.p. 123"-126" C.,
`inhibitor in the new compounds resulting in a 50% 5
`reduction in the enzyme synthesis performance is deter-
`mined. For this purpose the quantity of 7,8-dihydrop-
`teroic acid synthesised from the enzyme extract is deter-
`mined by means of high performance liquid ehromatog-
`raphy (HPLC) using a UV detector after an incubation 10 (150 ml). Perhydrol (20 ml) is added dropwise to this
`solution with stirring at ambient temperature. After it
`period of 4 hours. It was established that the synthesis of
`has all been added the mixture is refluxed for a further
`7,8-dihydropteroic acid proceeded in a linear manner
`1 ~ hours during which a white substance is precipitated.
`during this period.
`The i50 values obtained by this method for a selection
`After the suspension has cooled the substance is suction
`of the compounds claimed and those of the comparison 15 filtered, washed with ethanol and water and then dried.
`preparations bis (4-aminophenyl)sulfone (Dapsone®,
`Yellow crystals, m.p.: 188"-190" C.
`DDS) and Nl-(5,6-dimethoxy-4-pyrimidinyl)-sulfanila-
`mide (Fanasil (~)) are given in the following Table:
`
`(b) 3-Cyano-4,4’-dinitro-diphenylsulfone
`
`Next, the 3-cyano-4,4’-dinitro-diphenylsulfide (t0 g,
`0.033 tool) is dissolved by heating in glacial acetic acid
`
`(c) 3-Cyano-4,4’-diamino-diphenylsulfone
`
`The 3-cyano-4,4’-dinitro-diphenyl-sulfone (2 g, 0.006
`20 tool) is added in batches, with stirring, at 10" to 20* C.,
`
`tO a mixture of SnCI2X2H20 (8.1 g) and conc. hydro-
`chloric acid (15 ml). After it has all been added, the
`mixture is stirred for a further 4 hours at ambibnt tem-
`
`Substance
`A
`8
`c
`D
`E
`F
`G
`H
`I
`K
`L
`M
`Dapsone ~)
`Fanasil ~)
`
`i50 [~M]
`2.10
`2.67
`2.62
`5.86
`4.90
`10.4o
`12.90
`4.10
`12.48
`12.90
`2.94
`2.44
`12.41
`200
`
`25 perature and then the mixture is stirred into 10N sodium
`hydroxide solution (50 ml) while being intensively
`cooled. The product precipitated is suction filtered and
`dried. The crude product is purified by column chroma-
`tography. For this, the substance is dissolved in ethyl
`30 acetate and chromatographed over silica gel (200 g,
`0.063-0.2 mm), ethyl acetate and methylene chloride 1:1
`being used as eluant. The corresponding fractions are
`combined and evaporated. Colorless crystals, m.p.:
`Moreover, in contrast to Dapsone (~), the new corn- 240"-242" C.
`pounds are well tolerated and in particular show a very 35
`low methemoglobin formulation. For example, when
`substances I and M are administered to cats in a dosage
`of 200 mg/kg by oral route no methemoglobin formula-
`tion is detected.
`On the basis of their biological properties the new 40 At 20* C., with stirring and cooling with ice, a solu-
`compounds and the nontoxic, pharmaceutically accept-
`tion of 2,6-dibromo-4-nitro-aniline (47.2 g) in acetic acid
`able acid addition salts thereof are suitable for the treat-
`(1.6 liters) is slowly poured into a solution of sodium
`merit of bacterial diseases, malaria and leprosy,
`nitrite (12 g) in concentrated sulphuric acid (85 ml).
`In monotherapy the single dosage for adults is from
`Then, the mixture is stirred for 20 minutes at ambient
`100 to 300 rag, preferably 100 to 200 rag, once or twice 45
`temperature. The solution thus prepared is then slowly
`a day. In combined therapy with a dihydrofolic acid-
`added with stirring and cooling with ice to a solution of
`reductase inhibitor the single dose for adults is 50 to 200
`copper (I) bromide (12.8 g) in 63% hydrobromic acid
`rag+5 to 30 mg of pyrimethamine, preferably 50 to 150
`(40 ml)/. After it has all been added the mixture is
`mg+6.25 to 25 mg of pyrimethamine.
`The new compounds and the nontoxic, pharmaceuti- 50 stirred for a further 30 minutes. It is diluted with water,
`the precipitate is filtered off and washed with water.
`eally acceptable acid addition salts thereof optionally
`This crude product is recrystallized from methanol.
`combined with a dihydrofolic acid reductase inhibitor
`Colorless crystals, m.p. 110° C.
`such as pyrimethamine, trimethoprim or a trimethoprim
`derivative, can be made into preparations such as plain
`or coated tablets, capsules or suspensions.
`The following Examples illustrate the invention:
`
`EXAMPLE 2
`
`4,4’-Diamino-2,6-dibromo-diphenylsulfone
`
`(a) 3,4,5-Tribromonitrobenzene
`
`55
`
`(b) 4’-Acetamino-2,6-dibromo-4-nitro-diphenylsulfide
`
`Sodium (2.9 g) is dissolved in absolute ethanol (520
`ml). Then, 4-acetamino-thiophenol (22 g) is dissolved in
`the sodium alkoxide solution this prepared, and 3,4,5-
`3-Cyano-4,4’-diamino-diphenylsulfone tribromonitrobenzene (44.5 g) is added. The mixture is
`60
`
`EXAMPLE 1
`
`(a) 3-Cyano-4,4’-dinitro-dipbenylsulfide
`
`then heated to reflux temperature for 5 hours. After
`cooling it is poured onto water, extracted exhaustively
`(a) First, 4-nitrothiophenoi (10 g, 0.064 tool) is dis-
`with ethyl acetate, the combined ethyl acetate extracts
`solved by stirring in a solution of sodium hydroxide (2.8
`are washed with water, dried over sodium sulfate and
`g) in water (10 ml) and ethanol (100 ml). Then, 5-
`chloro-2-nitrobenzonitrile (I 1.8 g, 0.064 tool) is added in 65 evaporated down to a small volume. The material pre-
`cipitated is suction filtered and recrystallized from
`order to reflux the resulting solution for 1 hour with
`stirring, whereupon a yellow substance is precipitated,
`methanol.
`After the suspension has been cooled the product ob-
`Colorless crystals, m.p.: 208*-209* C.
`
`6 of 15
`
`

`

`(c) 2,6-Dibromo-4,4’-dinitro-diphenylsulfone
`Next, 4’-acetamido-2,6-dibromo-4-nitro-diphenylsul-
`fide (5 g) is dissolved in glacial acetic acid (40 ml) by
`heating. Perhydrol (20 ml) is added dropwise to this
`solution at ambient temperature with stirring. After it
`has all been added the mixture is stirred at reflux tern-
`perature for a further 2 hours. On cooling, yellow crys-
`tals are precipitated which are suction filtered and
`washed first with water and then with methanol.
`M.p.: 170"-175° C.
`
`(d) 4,4’-Diamino-2,6-dibromo-diphenylsulfone
`
`5
`
`(b)
`4’-Acetamino-4-(N-ethyl-N-tosyl-amino)-2-methyl-
`diphenylsulfide
`
`The 4’-acetamino-2-methyl-4-tosylamino-diphenyl-
`10 sulfide (3.5 g), ethyl iodide (2 g) and dry potassium
`
`carbonate (1.5 g) are heated to 95° C. in dimethylform-
`amide (50 ml) with stirring for 17 hours. After cooling
`the mixture is poured onto water. The solids precipi-
`tated are suction filtered and thoroughly washed with
`water and petroleum ether and then dried.
`IR spectrum (methylene chloride): 3420 cm-1 NH,
`1695 cm-1 amide, 1505 era-1 suifonamide.
`
`Tin (II) chloride dihydrate 07 g) is dissolved in con-
`centrated hydrochloric acid (17 ml). Then, 2,6-15
`dibromo-4,4’-dinitro-diphenyisulfone (3.96 g) is added
`to this solution with a spatula, with stirring, and the
`temperature rises to about 50° C. The mixture is stirred
`for a further 2 hours and left to stand for 16 hours at
`(c)
`ambient temperature. Then it is slowly poured into 10N 20 4’-Acetamino-4-(N-ethyl-tosylamino)-2-methyl-diphe-
`sodium hydroxide solution (40 ml) with stirring and
`nylsulfone
`cooling with ice. The precipitate is filtered off and
`washed thoroughly with water and then with isopropa-
`nol. Colorless crystals, m.p.: 168°-170° C. (decomp.).
`
`4,829,058
`11 12
`with water (50 ml). The solids precipitated are suction
`filtered and carefully washed with water and then with
`petroleum ether and dried.
`M.p.: 130°-134° C.
`
`EXAMPLE 3
`
`4,4’-Diamino-2-hydroxy-6-methoxy-diphenylsulfone
`
`The 4’-acetamino-4-(N-ethyl-tosylamino)-2-methyl-
`diphenylsuifide (2.25 g) is heated to 90° C. for 3 hours in
`25 acetic acid (20 ml) and perhydroi (6 ml). After cooling,
`the mixture is diluted with water, the solids precipitated
`are carefully washed with water and petroleum ether
`and dried. This crude product is chromatographed over
`First, 4,4’-diamino-2,6-dibromo-diphenylsulfone (1 g)
`silica gel with a methylene chloride/methanol mixture
`(Example 2) is added to potassium hydroxide (1.12 g) in
`water (0.15 ml) and methanol (25 ml). This mixture is 30 (25:1). Light yellow foamy substance.
`heated to 150° C. under pressure for 14 hours. It is then
`diluted with water, the insoluble matter is filtered off
`and the filtrate is concentrated to dryness in vacuo. The [R spectrum (KBr~: 3420 cm-1 NH
`amide
`1680 cm- I
`solid residue is taken up in a little water. The aqueous
`150o cm-I
`sulfonamide
`solution is acidified with 2N hydrochloric acid up to pH 35
`sulfone
`~ 315. 1150 cm- i
`5 and the colorless precipitate obtained is suction fil-
`tered, washed with water and dried, M.p: 127’ C. (de-
`comp.).
`
`(d) 4-Ethylamino-4’-amino-2-methy!-diphenylsulfone
`
`EXAMPLE 4 40 The 4’-acetamino-4-(N-ethyl-tosylamino)-2-methyl-
`diphenylsulfone (1.05 g) is dissolved in concentrated
`2-Bromo-4,4’-diamino-6-hydroxy-diphenylsulfone
`sulfuric acid (6 ml). This solution is left to stand for 4
`Here, 4,4’-diamino-2,6-dibromo-diphenylsulfone (1 g) hou