United States Patent t19
`Seydel et al.
`
`[m Patent Number: 4,912,112
`[451 Date of Patent: Mar. 27, 1990
`
`[54] SUBSTITUTED
`2,4-DIAMINO-S-BENZYLPYRIMIDINES,
`THEIR PREPARATION AND THEIR USE AS
`MEDICAMENTS WITH AN
`A_NTIMICROBIAL ACTIVITY
`
`[75]
`
`Inventors: Joachim Seydel, Borstel; Rolf Hailer;,
`Manfred gan~y, both of Kiel; Gerd
`Hachtel, Raisdorf, all of Fed. Rep. of
`Germany
`
`[73] Assignee: Saarstickstoff-Fatol GmbH
`Chem.-Pharm. Fabrik, Schiffweiler,
`Fed. Rep. of Germany
`
`[21] Appl. No.: 11,957
`
`Feb. 6, 1987
`
`[22] Filed:
`Foreign Application Priority Data
`[30]
`Feb. 6, 1986 [DE] Fed. Rep. of Germany ....... 3603577
`[51] Int. CI.+ .................. C07D 239/49; A61K 31/505
`[52] U.S. CI ...................................... 514/275; 544/325
`
`[56]
`
`[58] Field of Search ......................... 544/325; 514/275
`References Cited
`U.S. PATENT DOCUMENTS
`4,115,650 9/1978 Manchand ........................... 544/325
`4,143,227 3/1979 Rosen .................................. 544/325
`4,515,948 5/1985 Kompis et al ....................... 544/325
`Primary Examiner--John M. Ford
`Attorney, Agent, or Firm--Cushman, Darby & Cushman
`
`ABSTRACT
`[57]
`Novel substituted 2,4-diamino-5-benzyl pyrimidines are
`described. The novel substances have antimicrobial
`activity and are particularly suitable for inhibiting the
`growth of mycobacteria. Combined with inhibitors
`such as diaminodiphenylsulphones, ring-substituted
`4-aminodiphenylsulphones or ring and/or nitrogen-sub-
`stituted diaminodiphenylsulphones, they have a marked
`synergistic activity.
`
`21 Claims, 2 Drawing Sheets
`
`1 of 13
`
`Almirall EXHIBIT 2009
`Amneal v. Almirall
`IPR2018-00608
`
`

`

`U.S. Patent Mar. 27, 1990
`S
`7.,2m
`tm
`
`0991
`
`Sheet 1 of 2 4,912,112
`\ 4,912,112
`
`1w.
`
`
`
`
`
`
`
`a;Duo.#0.XtCSOn—Eoo,3:.._2_E\m:m0
`
` 2
`
`M#0.
`
`rmfl
`
`$0
`
`A
`I--
`e-
`
`25OON0900.On0
`
`0—
`
`+no.
`
`2 of 13
`20f13
`
`

`

`Mar. 27, 1990
`U.S. Patent Mar. 27,1990
`US. Patent
`
`Sheet 2 of2
`4,912,112 1
`Sheet 2 of 2 4,912,112
`
`.521no0
`
`EEK2‘4EEK0..o
`
`EEKONAN
`
`EEKOND
`
`00m
`
`15
`
`OmN
`
`OON
`
`09
`
`0
`00.
`
`Om
`
`3:..2
`
`on.x.2:858
`
`NGE
`
`_E\m:mo
`
`3 of 13
`30f13
`
`
`

`

`SUBSTITUTED
`2,4-DIAMINO-5-BENZYLPYRIMIDINES, THEIR
`PREPARATION AND THEIR USE AS
`MEDICAMENTS WITH AN ANTIMICROBIAL
`ACTIVITY
`
`4,912,112
`1 2
`(4-heptyloxy-3-methoxybenzyl)-pyrimidine; 2,4-
`diamino-5-(4-octyloxy-3,5-dimethoxybenzyl)-pyrimi-
`dine; 2,4-diamino-5-(4-nonyloxy-3,5-dimethoxybenzyl)-
`pyrimidine; 2,4-diamino-5-(4-decyloxy-3-methoxyben-
`5 zyl)-pyrimidine; 2,4-diamino-5-[3,5-dimethoxy-4-(4’-
`nitrophenyl-4-sulphonylphenyl)-methoxybenzyl]-
`pyrimidine; 2,4-diamino-5-(3,5-dimethoxy-4-[3-(4’-
`The invention relates to novel substituted 2,4-
`nitrophenyl-4-sulphonylphenylamino)propoxy]benzyl)-
`diamino-5-benzylpyrimidines, their preparation and
`2,4-diamino-5-(4-methoxy-3-[2-(4’-
`pyrimidine;
`their use as medicaments for the treatment of microbial 10 nitrophenyl-4-sulphonylphenylamino)ethoxy]benzyl)-
`and in particular mycobacterial infections,
`2,4-diamino-5-(4-methoxy-3-[3-(4’-
`pyrimidine;
`The antibacterial activity of compounds of the ben-
`nitrophenyl-4sulphonylphenylamino)propoxy]benzyl)-
`zylpyrimidinetype is known. Such compounds, such as
`2,4-diamino-5 [4-(4’-aminophenyl-4-sul-
`pyrimidine;
`e.g. the known products trimethoprim, brodimoprim phonylphenylmethoxy)-3,5-dimethoxybenzyl]-pyrimi-
`and tetroxoprim exert theft activity by inhibiting dihy- 15 dine; 2,4-diamino-5-(4-[3-(4’-aminophenyl-4-sulphonyl-
`drofolic acid reductase (DHFR) in the case or Gram
`phenylamino)-propoxy]-3,5-dimethoxybenzyl)-pyrimi-
`negative and Gram positive bacteria. However, it has
`dine; 2,4-diamino-5-[3-(4’-aminophenyl-4-sulphonyl-
`been found that these compounds have only an ex-
`phenylmethoxy)-4-methoxybenzyl] -pyrimidine; 2,4-
`tremely limited activity with respect to mycobacteria,
`diamino-5-(3-[2-(4’-aminophenyl-4-sulphonyl-
`With these agents the concentrations necessary for in- 20
`phenylamino)-ethoxy]-4-methoxybenzyl)-pyrimidine;
`hibiting mycobacterial growth are so high, that they
`2,4-diamino-5-(4-[3-(4-aminophenyl-4-sulphonyl-
`cannot be attained in vivo or are not acceptable.
`phenylamino)propoxy]-3,5-dimethoxybenzyl)-pyrimi-
`The problem of the present invention is therefore to
`2,4-diamino-5-(4’-aminophenyl-4-sulphonyl-
`dine;
`provide compounds, which in low physiologically ac-
`2,4-
`ceptable concentrations constitute effective inhibitors 25 phenylmethoxy)-3-methoxybenzyl]pyrimidine;
`diamino-5-(4-[3-(4’-methylphenyl-4-sulphonyl-
`of microbial growth and particularly mycobacterial
`phenylamino) -propoxy]-3,5 -dimethoxybenzyl)-pyrimi-
`growth,
`dine; 2,4-diamino-5-(4-[2-(4’-aminophenyl-4-sulphonyl-
`According to the invention this problem is solved by
`the novel substituted 2,4-diamino-5-benzylpyrimidines
`phenylamino)ethoxy]-3,5-dimethoxybenzyl)-pyrimi-
`of general formula I
`
`~
`
`I
`
`30 dine; 2,4-diamino-5-(4-[2-(2’-methyl-4’-aminophenyl-4-
`snlphonylphenylamino)ethoxy)-3,5-dimethoxybenzyl)-
`pyrimidine.
`.According to the invention, it has surprisingly been
`found that the introduction of substituents according to
`
`NH2
`
`N
`
`.. H2N
`
`~CH2.~,~R I
`~_~N!
`
`~
`[
`
`.
`
`[1
`
`~p,2
`
`¯
`
`35 formula I into compound of the benzylpyrimidine type
`leads to a dramatic increase in the activity of these
`compounds as mycobacterial growth inhibitors (of.
`table 1).
`The inventive substituted 2,4-diamino-5-benzyl-
`
`in which one-~ the substituents Rl to R3
`(i) is an alkoxy or alkylthio group with more than 4 40 pyrimidines can be prepared in that for obtaining corn-
`pounds according to formula I (i)
`carbon atoms and advantageously 4 to 10 carbon atoms,
`(aa) a compound of general formula II
`a phenylalkoxy, phenylalkylthio, phenoxyalkoxy, phe-
`noxyalkylthio, phenylaminoalkoxy, phenylaminoal-
`kylthio group with 3 to 6 C atoms in the alkyl chain or
`a, cyoloalkoxy, cycloalkylthio, cycloalkylalkylthio or 45
`cycloalkylalkoxy group wherein the cyclic radical as
`
`R1
`
`II
`
`o
`N,N
`
`tivelyWell aSorthe alkyl chain have 3 to 6 carbon atoms respec-
`~"-R2~.~
`H/C--~
`
`R3
`
`(ii) a 2’,4’-substituted phenyl-4-sulphonylphenyl ami-
`noalkoxy, phenyl-4-sulphonylphenyl-aminoalkylthio, 50
`phenyl-4-sulphonylphenylalkoxy or phenyl-4-sul-
`in which one or the substituents R1 to R3 is a hydroxyl
`phonylphenylakylthio group, in which the substituents
`or a mereapto group and the two other of the substitu-
`in the 2’,4’-position are the same or different and are
`ents Rito R3 are the same or different and are hydrogen,
`hydrogen, amino, alkylamino, dialkylamino, alkoxy,
`alkyl, nitro, alkylthio and/or acetamino groups wherein 55 alkoxy, alkylthio and/or alkylamino groups is etherified
`with a halide suitable for forming an alkoxy, alkylthio,
`the alkyl radical has 1 to 6 C-atoms in the chain and the
`phenylalkoxy, phenylalkylthio, phenylalkoxy, phe-
`two others of the substituents R1 to R3 are the same or
`noxyalkylthio, phenylaminoalkoxy, phenylaminoal-
`different and are hydrogen, alkoxy, alkylthio and/or
`kylthio, cycloalkoxy, cycloalkylthio, cycloalkylal-
`alkylaminogroups,
`The alkyl radical of the two other substituents R1 to 60 kylthio or cyeloalkylalkoxy group,
`(ab) the compound obtained in stage aa) is condensed
`R3 preferably has 1 to 3 C-atoms and in particular 1
`with a/3-morpholinopropionitrile,
`C-atom.
`(ac) the compound obtained in stage ab) is reacted
`Representative examples of compounds of the invert-
`with aniline and
`tion include 2,4-diamino-5-(4-propoxyphenyl-benzyl)-
`2,4-diamino-5-(4-propoxyphenyl-3- 65 (ad) the compound obtained in stage ac) is cyclized
`pyrimidine;
`with guanidine.
`methoxy-benzyl)-pyrimidine; 2,4-diamino-5-(4-pent-
`For the preparation of compounds according to for-
`loxy-3-methoxybenzyl)-pyrimidine; 2,4-diamino-5-(4-
`mula I (ii) it is possible to either
`hexyloxy-3-methoxybenzyl)-pyrimidine; 2,4-diamino-5-
`
`4 of 13
`
`

`

`NH2
`
`N
`
`H2N|~
`
`N
`
`III
`
`.R1
`
`R3
`
`4,912,112
`3 4
`(ba) a compound of general formula III
`two other of the substituents R1 to R3 are the same or
`different and are hydrogen, alkoxy, alkylthio and/or
`alkylamino groups.
`Reduction is appropriately carried out in per se
`5 known manner in solvents such as water, methanol,
`ethanol, glacialacetic acid, ethylaeetate, dimethylform-
`amide, water/ethanol, water/dioxan, water tetrahydro-
`furan, ethyleneglycol monomethylester and further
`alkyl and aryl ethers of ethylene glycol, diethylenegly-
`in which one of the substituents Rl to R3 is a hydroxyl 10 col and mixtures thereof in the presence of a hydroge-
`nating catalyst such as Raney nickel, platinum or pal-
`or a mercapto group and the two other of the substitu-
`ladium/charcoal. Reduction can take place with metals
`ents R1 to R3 are the same or different and are hydro-
`such as iron, tin or zinc in the presence of an acid such
`gen, alkoxy, alkylthio and/or alkylamino groups is eth-
`as hydrochloric or acetic acid, with salts such as ferrous
`erified with a compound of general formula IV
`15 sulphate, stannous chloride/hydrochloric acid or so-
`dium dithionide in the presence of a base such as sodium
`IV hydroxide solution, pyridine or hydrazine and Raney
`
`R6x
`
`or formula V
`
`R4~(CH2)nwNH
`
`R6
`
`25
`
`v
`
`R5
`
`II
`
`. o ~
`
`,~ N"~
`H2N
`
`5 of 13
`
`~i~
`
`nickel, the temperatures being between 0° and 100° C.,
`ii°
`R4--(CH2)n--{/ \~-’S--q//\\’)mRS 20 but preferably 50° C.
`It has proved to be particularly advantageous to
`~/ IoI ~_J
`carry out the reduction in ethyleneglycol monomethyl-
`ether, methanol or mixtures thereof at 500 C, 1 to 6 bar
`and in the presence of Raney nickel W2 (produced in
`accordance with Org. Synth. Coil. 3, 181, 1955) or
`palladium/charcoal.
`The effectiveness of the compounds according to the
`invention as growth inhibitors for in particular myco-
`bacteria was proved on bacterial cell cultures by deter-
`30 mining the minimum inhibiting concentrations and the
`concentrations necessary for half maximum growth
`inhibition (150) when using typical representatives of the
`in which R4 is a halogen radical and R5 and R6 are the
`inventive compounds.
`same or different and are hydrogen, amino, alk.ylamino,
`There was surprisingly found to be an up to 300 times
`dialkylamino, alkoxy, alkyl, nitro, alkylthio and/or
`acetamino groups.
`35 increased activity of the inventive compounds com-
`Etherification appropriately takes place in per se
`pared with commercially available products, such as
`known manner in solvents such a water, methanol,
`e.g. pyrimethamine. There was also found to be a syner-
`ethanol, n-propanol; isoproaanol, butanol, dimethyl-
`gistic effect of combinations of the claimed compounds
`formamide, dimethylsulphoxide, acetone, methylethyl-
`and inhibitors ofdihydropteroic acid synthetase, such as
`ketone and monoalkylated and dialkylated ethers of 40 e.g. with diaminodiphenylsulphone (DDS).
`ethyleneglycol and diethyleneglycol and mixtures
`The inventive compounds can therefore be used as
`thereof, accompanied by the addition or a base such as
`active ingredients in medicaments for the treatment of
`sodium, sodium ethoxide, sodium or potassium hydrox-
`microbial infections and in particular mycobacterioses
`ide, potassium or sodium carbonate at a temperature
`either alone or combined with inhibitors such as
`between -20* C. and the boiling point of the solvent
`ring-substituted
`4-
`45 diaminodiphenylsulphones,
`used, but preferably at ambient temperature,
`aminodiphenylsulphones or ring and/or nitrogen-sub-
`According to a preferred embodiment of the inven-
`stituted diaminodiphenylsulphones and/or antibacteri-
`tion, etherification is carried out in ethyleneglycol
`ally acting sulphonamides. Their importance lies inter
`monomethylether as the solvent and the sodium alkox-
`alia in the possibility of treating both partially DDS and
`ide of the ethyleneglycol monomethylether.
`The compounds according to formula I (ii) can also 50 TMP-resistant mycobacterioses and avoiding the devel-
`opment of resistance in the case of DDS or TMP
`be prepared in that
`monotherapy.
`(bb) a compound of general formula VI
`The inventive medicaments contain the active sub-
`stances of the invention or active substance combina-
`VI 55 tions together with a pharmaceutically acceptable car-
`tier. The latter can be an organic or inorganic carrier
`material suitable for enteral, percutaneous or parenteral
`administration, such as e.g. water, gum Arabic, lactose,
`starch, magnesium stearate, tallow, vegetable oils, po-
`60 lyalkyleneglycols, vaseline and the like. The products
`R3
`can also contain other pharmaceutically active sub-
`is reduced, in which one of the substituents R1 to R3 is
`stances, such as antipyrific agents, pain relieving agents,
`a 2’,4’ substituted phenyl-4-sulphonylphenylaminoalk-
`anti-inflammatory agents and the like. The pharmaceu-
`oxy, phenyl-4-sulphonylphenylaminoalkylthio, phenyl-
`tical products can be administered orally, e.g. in the
`4-sulphonylphenylalkoxy or phenyl-4-sulphonylal-
`kylthio group with a terminal nitro group, the substitu- 65 form of tablets, capsules, pills, powders, granules, solu-
`ents in the 2 ’4’-position being the same or different and
`tions, syrups, suspensions, elixirs and the like. However,
`hydrogen, amino, alkylamino, dialkylamino, alkoxy,
`administration can also by effected parenterally, e.g. in
`alkyl, nitro, alkylthio and/or acetamino groups and the
`the form or sterile solutions, suspensions or emulsions or
`
`NH2
`
`% CH2~,
`
`N
`
`

`

`EXAMPLE 2
`
`EXAMPLE 1
`
`4,912,112
`5 6
`2,4-diamino-5-(4-nonyloxy-3,5-dimethoxybenzyl)-
`locally in the form of suspensions, ointments, powders,
`pyrimidine, GH 309, melting point 128" C.
`aerosols and the like.
`The pharmaceutical products can also be sterilized
`and/or contained constituents such as preservatives,
`stabilizers, wetting agents, emulsifiers, salts and buffer 5 Preparation of 2,4-diamino-5-[3,5-dimethoxy-4-(4’-
`substances,
`nitrophenyl-4-sulphonylphenyl)-methoxybenzyl]-
`The invention is illustrated hereinafter by means of
`pyrimidine (K 95) 2.76.g (0.01 mole) of 2,4-diamino-5-
`examples.
`(4-hydroxy-3,5-dimethoxybenzyl)-pyrimidine (J. Med.
`Chem., 14, 58, 1971) were dissolved by stirring in a
`.10 solution of 0.23 g (0.01 mole) of sodium in 45 ml or
`ethyleneglycol monomethylether. This was followed
`Preparation of 2,4-diamino-5-(4-decyloxy-3-methox-
`ybenzyl)-pyrimidine (GH 310)
`by the addition of 3.92 g (0.011 mole) of 4-bromometh-
`(a) 4-decyloxy-3-methoxybenzaldehyde:
`yl-4’-nitrodiphenylsulphone (J. Chem. Soc., 22, 1508,
`30.4 g (0.2 mole) of vanillin and 48.7 g (0.22 mole) of
`1957) and stirring took place for 17 hours at ambient
`1 bromodecane ar dissolved, accompanied by stirring, 15 temperature.
`in a solution of 5.75 g (0.25 mole) of sodium in 300 ml of
`The end product was precipitated by introducing
`ethyleneglycol monomethylether. The solution was
`HC1 gas, followed by suction filtering and dissolving in
`heated to boiling or 18 hours, mixed with 200 ml of
`a mixture of 30 ml of ethylene glycol monomethylether
`water and cooled. The crystallized substance was re-
`and 10 ml of acetone, accompanied by heatingand the
`moved by suction and recrystallized from methanol. 20 addition or concentrated ammonia and a little water.
`White crystals with a melting point of 51" C. were ob-
`Until the first permanent turbidity occurred, mixing
`mined,
`slowly took place with water in the boiling heat, follow-
`3-morpholino-2-(4-decyloxy-3-methoxybenzyl)-
`(b)
`ing by cooling to room temperature and the filtering off
`acrylonitrile (E/Z mixture):
`of the precipitated crystals. The crude product was
`29.2 g (0.1 mole) of 4-decyloxy-3-methoxybenzalde- 25 recrystaUized from ethyleneglycol monomethylether/-
`hyde and 14.5 g (0.11 mole) of/3-morpholinopropioni-
`water (see above). Yellow crystals with a melting point
`trile were heated to 65° C. in 150 ml of dimethylsutph-
`of 225 ° to 229* C. were obtained (accompanied by
`oxide. Accompanied by vigorous stirring, 1.6 g (0.02
`decomposition).
`mole) of sodium methoxide were introduced, the tem-
`perature r4sing to approximately 75" C. After 30 rain- 30
`utes, 200 ml of water were added and the product ex-
`tracted with diehloromethane. A yellow-brown oil was
`obtained as the crude product,
`(c) 3-anilino-2-(4-decyloxy-3-methoxybenzyl)-acryloni-
`35 (a) 4,[N-(2-bromomethyl)-N-tosylamino]-4’-nitrodiphe-
`trile (E/Z mixture):
`nylsulphide (Anand et al, J. Sci. Industr. Res., 13B,
`20.7 g (0.05_mole) of l-morpbolino-2-(4-decyloxy-3-
`pp.260-269, 1954).
`metho:~ybenzyl~crylonitrile, 4.7 g (0.05 mole) of ani-
`40.05 g (0.1 mole) of 4-tosylamino-4’-nitrodiphenyl-
`line and 4.1 ml Of concentrated hydrochloric acid were
`sulphide (Baker et al, J. Org. Chem., 15, 400, 1950) and
`heated to borg for 1 hour in 70 ml of 2-propanol.
`After cooling to 4* C, the precipitated substance was 40 376 g (2.0 mole) of 1,2-dibromomethane were heated to
`boiling for a total of 24 hours in 540 ml of ethanol and
`removed by suction and recrystallized from methanol,
`following the addition of 100 mg of Cu(I)J and a solu-
`White crystals with a melting point of 80° to 99* C.
`tion of 8 g of potassium hydroxide in water. After 12
`¯ were obtained,
`hours, again 8 g of potassium hydroxide in 20 ml of
`2,4-diamino-5-(4-decyloxy-3-methoxybenzyl)-
`(d)
`pyrimidine:
`45 water were added and further heating to boiling took
`place. The mixture was rotated to approximately 150
`16.8 g (0.04 mole) of 1-aniline-2-(4-decyloxy-3me-
`ml, the precipitated substance was filtered off, washed
`thoxybenzyl)acrylonitrile, 5.7 g (0.06 mole) of guani-
`with water and dried. For purification purposes, the
`dine hydrochloride and 4.9 g (0.09 mole) of sodium
`product was dissolved in methylene chloride and puri-
`methoxide were heated to boiling for 24 hours, accom-
`panied by vigorous stirring, in 60 ml of absolute ethanol. 50 fled with activated carbon or recrystallized from ethy-
`lacetate. In both cases, white-yellowish crystals were
`Following cooling, the resulting substance was re-
`obtained with a melting point of 133 to 135" C.
`moved by suction, washed with water and methanol
`(b) 4-[N-(2-bromomethyl)-N-tosylamino]-4’-nitrodiphe-
`and reerystallized from methanol. White crystals with a
`nylsulphone (Anand et al see above).
`melting point of 138° C. were obtained,
`The following compounds were prepared in the same 55 40.5 g (0.08 mole) of 4-N-(2-bromomethyl)-N-
`tosylamino-4’-nitrodiphenylsulphide were stored for 4
`way as in the processes according to (a) to (d):
`hours on the water bath at 65* .C in a mixture of 94 ml
`2,4-diamino-5-(4-propoxyphenyl-benzyl)-pyrimidine,
`of concentrated hydrogen peroxide solution and 500 ml
`GH 003, melting point 169° C.
`of glacial acetic acid. By diluting with 1000 ml of water
`2,4-diamino-5-(4-propoxyphenyl-3-methoxy-benzyl)-
`60 and cooling in the icebath, the end product was com-
`pyrimidine, GH 103, melting point 139" C.
`pletely precipitated, filtered off, washed with water and
`2,4-diamir~o-5-(4-pentyloxy-3-methoxybenzyl)-pyrimi-
`well dried. White crystals with a melting point of 182"
`dine, GH 305, melting point 157" C.
`2,4-diamino-5-(4-hexyloxy-3-methoxybenzyl)-pyrimi-
`to 184* C. were obtained.
`dine, GH 306, melting point t47° C.
`(c) 4-[N-(2-bromomethyl)-amino]-4’-nitrodiphenylsul-
`2,4-diamino-5-(4-heptyloxy-3-methoxybenzyl)-pyrimi-
`phone (Anand et al, see above)
`16.2 g (0.03 mole) of dried 4-[N-(2-bromomethyl)-N-
`dine, GH 307, melting point 145" C.
`2,4-diamino-5-(4-octyloxy-3,5-dimethoxybenzyl)-
`tosylamino]-4’-nitrodiphenylsulphone were mixed with
`32.5 ml of concentrated sulphuric acid and stirred for
`pyrimidiee, GH 308, melting point 152° C.
`
`EXAMPLE 3
`Preparation of
`2,4-diamino-5-(3,5-dimethoxy-4-[2-(4’-nitrophenyl-4-
`sulphonylphenylamino)ethoxy]-benzyl)-pyrirnidine (K
`
`65
`
`6 of 13
`
`

`

`4,912,112
`7 8
`precisely 1 hour at room temperature. Then, accompa-
`glacial acetic acid. The solution was diluted with 900 ml
`nied by stirring, the mixture was poured onto 300 ml of
`of water as in example 3 b) and the end product com-
`ice and 200 ml of water were added. The precipitated
`pletely precipitated by cooling in the icebath. Recrys-
`yellow product was filtered off and washed with water,
`tallization took place in methanol, accompanied by the
`The substance was then dissolved in 250 ml of acetone, 5 addition of a little methylene chloride. White crystals of
`accompanied by stirring and then adjusted to pH 9 with
`melting point 153 to 155° C. were obtained.
`dilute ammonia. The solution was rotated in vacuo to
`(c) 4-[N-(3-bromopropyl)-amino]-4’-nitrodiphenylsul-
`100 ml, again poured on to 500 ml of ice and the preeipi-
`phone:
`tated substance was filtered off. Recrystallization then
`10 g (0.018 mole) of 4-[N-bromopropyl)-N-
`took place from ethylacetate or acetone/water. Yellow 10 tosylamino]-4’-nitrodiphenylsulphone were mixed with
`crystals with a melting point or 164° to 167" C. were
`20 ml of concentrated sulphuric acid and stirred for
`obtained,
`precisely 60 minutes at ambient temperature. Accompa-
`(d) 2,4-diamino-5-(3,5-dimethoxy-4-[2-(4’-nitrophenyl-
`nied by stirring, the mixture was then poured on to 500
`4-sulphonylphenyl-amino)-ethoxy]-benzyl)-pyrimi-
`ml of ice, filtered off, washed with water and dissolved
`dine.
`15 in 150 to 200 ml of acetone, accompanied by heating.
`An alkoxide solution was prepared from 0.3 g (0.013
`The solution was then adjusted with concentrated am-
`mole) of sodium and 200 ml of ethyleneglycol mono-
`monia to pH 9, filtered, completely concentrated by
`methylether. 3.5 g (0.0126 mole) of 2,4-diamino-5-(4-
`evaporation in vacuo and cooled. Recrystallization then
`hydroxy-3,5-dimethoxybenzyl)-pyrimidine according
`took place in methanol, accompanied by the addition of
`to example 2 were added and the solution stirred until 20 a little methylene chloride. Yellow crystals of melting
`the phenol has completely dissolved giving a red col-
`point 130° to 132° C. were obtained.
`our. 0.1 g of NaJ and 4.9 g (0.0127 mole) of 4-[N-
`(d) 2,4-diamino-5-(3,5-dimethoxy-4-[3-(4’-nitrophenyl-
`(bromeethylamino)] -4’-nitrodiphenylsulphone were
`4-suphonylphenylamino)-propoxy]-benzyl)-pyrimi-
`added and the solution was stirred for 4 days at room
`dine:
`temperature. The mixture was poured on to 400 ml of 25
`0.35 g (0.015 mole) of sodium were dissolved in 100 ’
`ice, the precipitated substance was filtered off, dried
`ml of ethyleneglycol monomethylether, 4.2 g (0.015
`and dissolved whilst heating in 250 ml of acetone. The
`mole) of 2,4-diamino-5-(4-hydroxy-3,5-dimethoxyben-
`solution was filtered, rotated to approximately 5 ml in
`zyl)-pyrimidine (cf. example 2) were added and stirred
`vacuo and purified over a column, diameter 6.5 cm, until the phenol had completely dissolved. The solution"
`length 30 cm, silica gel (particle size corresponding to 30
`was then mixed with 0.1 g of Na.l and 6.2 g (0.155 mole)
`an internal mesh size of 0.21 to 0.063 mm, 300 g) with a
`of 4-[N-(3-bromopropyl)-amino]-4’-nitrodiphenylsul-
`mobile solvent mixture of 80 parts methylene chloride,
`phone and stirred for 3 days at ambient temperature.
`20 parts n-p.ropanol and 1 part of concentrated ammo-
`The mixture was mixed with 500 ml of ice, filtered,
`nia: The pure substance fractions were combined and
`rotated to 20 ml giving a yellow substance, which was 35 washed with water, dissolved in 300 to 400 ml of ace-
`tone accompanied by heating, filtered again and rotated
`filtered off after cooling overnight. Yellow crystals
`in vacuo to 75 to 100 ml. This solution was kept over-
`with a melting point or 235* to 238° C. were obtained
`night at 5* C. and the precipitated crystals filtered off.
`(accompanied b3r-decomposition),
`This was followed by reerystallization in methanol,
`accompanied by the addition of a little methylene chlo-
`40 ride. Yellow crystals with a melting point of 210° to
`
`-~--
`
`o
`
`EXAMPLE 4
`Preparation of
`2,4-diamino-5-(3,5-dimethoxy-4-[3-(4’-nitrophenyl-4-
`sulphonylphenylamino)-propoxy]-benzyl)-pyrimidine
`(K 122)
`
`213" C. were obtained.
`
`EXAMPLE 5
`
`Preparation of
`(a) 4-[N[(3-bromopropyl)-H-tosylamino]-4’-nitrodiphe- 45 2,-diamino-5-[4-methoxy-3-(4’-nitrophenyl-4-sulphonyl-
`nylsulphide:
`phenyl)-methoxybenzyl]-pyrimidine (K 127)
`40.05 g (0.1 mole) of 4-tosylamino-4’-nitrodiphenyl-
`(a) 3-benzyloxy-4-methoxybenzaldehyde:
`sulphide according to example 3 (a) and 150 ml (1.5
`A phenotate solution was prepared from 21.6 g (0.4
`mole) of 1,3-dibromopropane in 500 ml of ethanol were
`heated to boiling after adding 01 g ofCu(I)3. A solution 50 mole) of sodiummethoxide and 60.9 g (0.4 mole) of
`3-hydroxy-4-methoxybenzaldehyde in 350 ml of ethyl-
`or 14 g of potassium hydroxide in 30 ml of water was
`eneglycol monometylether. The solution was heated to
`slowly added dropwise to the boiling solution within 8
`100° C, 51 g (0.4 mole) of benzylchloride were added
`hours and boiling took place for a further 2 hours. The
`ethanol was removed under reduced pressure and ex-
`and stirring took place for 2 hours at this temperature.
`tess dibromopropane by means of steam distillation. 55 The mixture was cooled to ambient temperature, mixed
`The remaining residue was cooled, dissolved aecompa-
`with 600 ml of water and placed cool. The crude prod-
`uct was filtered off, recrystallized from methanol, dried
`nied by heating in 300 ml of ethylacetate, mixed with 4
`g of activated carbon and filtered. The solution was
`and further processed. White crystals of melting point
`mixed with 200 ml of ethanol, rotated to approximately
`62° to 63* C. were obtained.
`half, placed cool, the precipitated crystals were filtered 60 (b)
`3-benzyloxy-4-methoxy-morpholinome-
`off and then recrystallized in ethylacetate. Crystals of
`thylidenedihydrocinnamicnitrile:
`melting point 112" to 114" C. were obtained.
`Accompanied by heating to 65* C, 89.6 (0.37 mole) of
`(b) 4-[N,(3-bromopropyl)-N-tosylamino]-4’-nitrodiphe-
`3-benzyloxy-4-methoxybenzaldehyde were dissolved in
`nylsulphone:
`500 ml of dimethylsulphoxide. Successively 57 g (0.4
`36.5 g (0.07 mole) of 4-[N-(3-bromopropyl)-N- 65 mole) of 3-morpholinopropionionitrile and 4.5 g (0.083
`tosylamino]-4’-nitrodiphenylsulphide were stirred for 4
`mole) of sodiummethoxide were added, the temperature
`hours at 65° C. accompanied by the addition of 80 ml of
`rising to over 70° C. Stirring took place for a further 15
`concentrated hydrogen peroxide solution in 400 ml of
`minutes at 65* C., followed by cooling to room tempera-
`
`7 of 13
`
`

`

`EXAMPLE 7
`
`EXAMPLE 8
`
`Preparation of
`2,4-diamino-5-[3-methoxy-4-(4’-nitrophenyl-4-sul-
`phonylphenyl)-methoxybenzyl]-pyrimidine (K 116)
`
`4,912,112
`9 10
`ture, mixing the solution with a mixture of 750 ml of
`solved in 15 ml of ethyleneglycol monomethylether,
`isoproponol/water (1:10) and cooling overnight a 5* C.
`accompanied by the addition of 0.66 g (0.0122 mole) of
`The crude product was extracted with methylene chlo-
`sodium methoxide and were added dropwise within 8
`ride, the combined methylene chloride phases were
`hours to a suspension of 4.7 g (0.0122 mole) of 4-N-(2-
`well dried over sodium sulphate and evaporated to 5 bromomethyl)-amino-4’-nitrodiphenylsulphone (cf. ex,
`dryness in vacuo. The viscous crude product was di-
`ample 3c) in 20 ml of ethyleneglycol monomethylether,
`rectly further processed,
`followed by stirring for a further 3 days at ambient
`(c) Anilinomethyliene-3-benzyloxy-4-methoxy-dihy-
`temperature. The further preparation was as in example
`drocinnamicnitrile:
`5 (0- Reerystallization took place from ethyleneglycol
`72.9 (0.2 mole) .of 3-benzyloxy-4-methoxymor-10
`monomethylether and yellow crystals with a melting
`pholinomethylidene-dihydrocinnamicnitrile in 250 ml
`point of 178" to 182’ C. were obtained. According to
`of isopropanol were mixed with 22.3 g (0.24 mole) of
`the elementary analysis, the substance crystallizes with
`aniline and 27 ml of concentrated hydrochloric acid and
`0.5 mole of H20.
`heated to boiling for 1 hour. The mixture was allowed
`to cool to room temperature, the precipitated substance 15
`was filtered off and washed with water and die-
`thylether. Recrystallization then took place from is.-
`2,4-diamino-5-(4-methoxy-3-[3-(4’-nitrophenyl-4-sul-
`propanol. White crystals with a melting point of 148" to
`phonylphenylamino)-propoxy]-benzyl)-pyrimidine (K
`151" C. were obtained.
`135) 3 g (0.0122 mole) of 2,4-diamino-5-(3-hydroxy-4-
`2,4-diamino-5-(3-benzyloxy-4-methoxybenzyl)- 20 methoxybenzyl)pyrimidine (of. example 5) were dis-
`(d)
`pyrimidine:
`solved in 15 ml of ethyleneglycol monomethylether,
`92.6 g (0.25 mole) of anilinomethylidene-3-ben-
`accompanied by the addition of 0.66 g (0.0122 mole) of
`zyloxy-4methoxydihydrocinnamienitrile were heated
`sodiummethoxide and in accordance with example 5
`to boiling for 22 hours with 38.2 g (0.4 mole) of guani-
`added dropwise to a suspension of 4.9 g of 4-[N-(3-
`dine hydrochloride and 30.25 g (0.56 mole) of sodium- 25 bromopropyl)-amino] -4’-nitrodiphenylsulphone in 20
`methoxide in 600 ml ethanol. The mixture was allowed
`ml of ethyleneglycol monomethylether and stirred for 3
`to cool to ambient temperature, was mixed with 20 ml
`days at ambient temperature. The precipitated sub-
`of concentrated ammonia, the precipitated substance
`stance was filtered off and washed with ethanol and a
`was filtered off and washed with water. White crystals
`with a melting point of 210" to 213" C. were obtained. 30 little acetone. Subsequently recrystallization took place
`2,4-diamino-5-(3-hydroxy-4-methoxybenzyl)-
`from acetone and ethyleneglycol monomethylether.
`(e)
`pyrimidine:
`Yellow crystals with a melting point of 131° to 134" C.
`20.2 g (0.06 mole)of 2,4-diamino-5-(3-benzyloxy-4-
`were obtained.
`methoxybenzyl)-pyrimidine were hydrogenated with 4
`g of palladium/5% charcoal in 250 ml of ethyleneglycol 35
`monomethylether for 45 minutes at 3 bar and 45° C. The
`solution was faltered, poured on to 600 ml of water,
`mixed with 10--ml of concentrated ammonia and the
`precipitated strl~stance was filtered off. For recrystalli-
`zation purposes, the substance was dissolved in boiling 40 (a) 4-benzyloxy-3-methoxybenzaldehyde:
`Starting with 4-hydroxy-3-methoxybenzaldehyde the
`water accompanied by the addition of dilute hydrochlo-
`ric acid. This was followed by filtration, adjusting to pH
`procedure of example 5 (a) was used and white crystals
`8 with concentrated ammonia and slow cooling to ambi-
`with a melting point of 63" to 64* C. were obtained.
`ent temperature. White crystals with a melting point of
`(b) 4-benzyloxy-3-methoxy-morpholinomethylidene
`208° to 210" C. were obtained.
`dihydrocirmamic nitrile:
`(f) 2,4-diamirto-5-[4-methoxy-3-(4’-nitrophenyl-4-sul-
`The procedure of example 5 (b) was adopted and the
`phonylphenyl)-methoxybenzyl]-pyrimidine:
`viscous crude product further processed.
`6.65 g (0.027 mole) of 2,4-diamino-5-(3-hydroxy-4-
`(c) Anilinomethylidene-4-benzyloxy-3-methoxydihy-
`methoxybenzyl)-pyrimidine were dissolved in 30 ml of
`drocinnarnicnitrile:
`ethyleneglycol monomethylether, accompanied by the 50 Reaction took place as in example 5 c) and white
`addition of 1.46 g (0.027 mole) of sodiummethoxide.
`crystals with a melting point of 119" to 121" C. were
`The solution was added dropwise in 5 hours to a suspen-
`sion of 9.64 g (0.027 mole) of 4-bromomethyl-4’- obtained.
`nitrodiphenylsulphone (J. Chem. Sot., 22, 1508, 1957) (d) 2,4-diamino-5-(4-benzyloxy-3-methoxybenzyl)-
`pyrimidine:
`accompanied by stirring and at ambient temperature. 55
`The procedure of example 5 d) was adopted and
`The mixture was allowed to stand overnight, the pre-
`white crystals with a melting point of 161° to 163" C.
`cipitated substanoe was f’fltered off and washed with a
`were obtained.
`little ethanol. It was then recrystallized from ethylene-
`2,4-diamino-5-(4-hydroxy-3-methoxybenzyl)-
`glycol monomethylether. Yellowish crystals with melt-
`(e)
`hag point of 234* to 238* C. were obtained.
`pyrimidine:
`The reaction took place as in example 5 e) and white
`crystals with a melting point of 266° to 267* C. were
`obtained.
`(f) 2,4-diamino-5-[3-methoxy-4-(4’-nitrophenyl-4-sul-
`phonylphenyl)-methoxybenzyl]-pyrimidine:
`The reaction took place as in example 5 f) and yellow
`crystals with a melting point of 210" to 213" C. were
`obtained.
`
`Preparation of
`2,4-diamino-5=(4-methoxy-3-[2-(4’-nitrophenyl-4-sul-
`phonylphenylamino)-ethoxy]-benzyl)-pyrimidine (K
`132)