AU463550B2 - Nitrofurylpyrimidine derivatives - Google Patents

Description

39,769/72 The present invention is concerned with new

nitrofuryl-pyrimidine derivatives and with their

manufacture and use.

German Offenlegungsschrift No. 1,937,629 has

described inter alia compounds of the general formula

02- "N OCH2 CH 2 -R

in which R represents, for example, a dialkylamino group

containing 1 to 5 carbon atoms in each alkyl group, or a

pyrrolidino, piperidino, hexamethyleneimino, piperazino

or morpholino group. These compounds are active against

Trichomonas vaginalis and Candida albicans.

It has now been found that structurally

similar compounds are more valuable pharmaceuticals than

the aforesaid compounds, because they couple an

equally good action against Trichomonas vaginalis with

a good activity against Gram-positive and Gram-negative

bacteria.

The present invention accordingly provides

such compounds, namely compounds of the general formula I

2- 4635.50

39.7 69 /72

o- ocCHgg- (1)

linear, in which R represents a saturated or unsaturated, may branched or cyclic aliphatic hydrocarbon group which by one or be substituted by one or two hydroxyl groups,

two acyloxy groups or by an alkoxy, dialkylamino, a tetrahydrofuryl or phenyl group and R' represents

hydrogen atom or an acyl group. The afore-mentioned aliphatic hydrocarbon and atoms. acyl groups are those containing up to 6 carbon

Cyclic aliphatic hydrocarbon groups should preferably

contain 3 to 7 carbon atoms. As the compounds of the general formula I are also capable of forming salts, the present invention acid provides corresponding physiologically tolerable

addition salts thereof. As physiologically tolerable

acids there may be mentioned, for example, hydrochloric,

sulphuric, phosphoric, acetic, propionic, lactic, nicotinic succinic, tartaric, citric, benzoic, salicylic,

and heptagluconic acids. The present invention also provides a process general for the manufacture of the compounds of the a formula I and their acid addition salts, wherein

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39,769/72 compound of the general formula II

ROCH 2 CH -Z (II)

nitro group in which R" represents a hydrogen atom or a acid or and Z represents an acyloxy group of a sulphonic a primary a bromine or chlorine atom, is reacted with

amine of the general formula III

R-NH 2

a resulting in which R has the meaning given above, and in the compound not containing a nitro group the compound of of the furan ring (that is when R"=H in if desired, in the general formula II) is nitrated and, any hydroxyl the resulting compound any -NH-group and/or and/or any group is/are acylated or any acylamino group if desired, a acyloxy group is/are hydrolysed and/or, formula I is resulting free compound of the general with an converted into an acid addition salt thereof acid organic or inorganic acid and/or a resulting free addition salt is converted into the corresponding the aforesaid compound by means of a.base, each of

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39,769/72 optional steps being carried cut before or after the

nit rat ion.

Depending on the reaction conditions the

compounds of the general formula I are obtained in the

free form or in the form of their acid addition salts.

The salts of the compounds of the general formula I may

be manufactured by directly isolating them from the

reactions carried out in an acidic medium (for example nitration and acid hydrolysis) in the form of, for

example, hydrochlorides or acid or neutral sulphates,

or by preparing the salts from the basic compounds by

means of a subsequent treatment with an acid. It is

possible, alternatively, to liberate a free compound of

the general formula I from a previously isolated salt by treatment with a base.

The reaction of the furylpyrimidine of the .general formula II with an amine of the general formula

III may be carried out by dissolving the furylpyrimidine

in any desired solvent, but preferably in dioxan, ethanol

or hexamethylphosphoryl triamide, and then reacting it

with the amine at an elevated temperature, in general 0 within the range of from 500 to i00oC.

To nitrate the compounds not containing a nitro

group in the 5-position of the furan ring they are

dissolved in concentrated sulphuric acid or acetic

anhydride and mixed with concentrated nitric acid or a

mixture of concentrated nitric acid and concentrated

sulphuric acid, in general at a temperature within the 0 range of from -200 to +40 C.

4635,50

39,769 172 The acylations are carried out by treating the compounds to be acylated with an acid anhydride or by reacting them with an acid halide in a basic medium, espzciaJly pyridine. An acylamino -rcup or an acyloxy group, respectively, is hydrolysed in a known manner. The new compounds have a good activity against bacteria and against Trichomonas vaginalis. The values of the minimum inhibiting concentration (liIC) against some 1athogens are shown in Table I below, in which they are compared with the L;IC-values of commercial nitrofurantoin established under identical conditions. Table I XIC(pg/ml) C o m p o u n d E.coli Prot Kiebs. Trich. vulg. pneum. vag.

Nitrofurantoin 3.1 50 25 12.5

2-(5-nitro-2-furyl-5-(2-(2- 0.8 12.5 12.5 6.3 hydroxyethylamino) -ethoxy)- pyrinidine hydrochloride

2-(5-nitro-2-furyl)-5-(2-(2- 1.6 12.5 12.5 3.1 diethylaminoethylamino)- ethoxy) -pyrimid ine dihydrochioride

2-(5-nitro-2-furyl)-5-(2-(l- 1.6 12.5 12.5 0.8 hydroxy-2-n-butylamino ethoxy)-pyrimidine

2-(5-nitro-2-uuryl)-5-(2-(- 0.8 50 25 0.2 acctyl-methylamino)-ethoxy)- pyrimidine

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-39.7 69/72 In contrast to nitrofurantoin, which after

oral administration can be identified in a microbiologic-

ally active form only in the urine but not in the-blood,

the above-mentioned conpounds can alse be identified in

the blood. As a result, these compounds display a

systemic activity also in model infections, for example

with staphylococci as is shown in Table II below; such a

systemic activity is not found with nitrofurantoin.

Tab 1 e II

Microbiologically active level after oral adminis- tration of 100 mg/g g)aph. blood urine aureus

Nitrofurantoin over 200

2-(5-Nitro-2-furyl)- 20.1 5-(2-(2-hydroxyethyl-

amino)-ethoxy)-pyrimidine hydrochloride

The new compounds may be used in the conventional pharmaceutical forms. The present invention accordingly further provides a pharmaceutical preparation which comprises a compound of the general formula I or a physiologically tolerable acid addition salt of such a compound, in admixture or conjunction with a pharmaceutically suitable carrier. The present invention further provides a pharmaceutical preparation which comprises two or more compounds selected from compounds of the general formula I and

physiologically tolerable acid addition salts of such

4635,50 7"-

397 69/72 compounds. For oral administration there are especially

suitable tablets, dragees, capsules, pills and suspcnsions. cablets conain, for cxample, 0.0 to 0.50 g of active

substance and 0.1 to 5 g of a pharmacologically inert

carrier. Carriers suitable for use in tabe ts are, for

example, lactose, starches, talcum, gelatin and magnesium

stearate.

The new active compounds should be administered

in a quantity of from 0.1 to 4.0 g per patient per day. The following Examples illustrate the

invention:

Example 1

2-(2-Furyl) -5-(2-methylamino-ethoxy)-pyrimidine

5.4 g of 2-(2-furyl)-5-(2-2-toluenesulphony-

loxy-ethoxy)-

pyrimidine in 75 ml of ethanol and 50 ml of an aqueous methylamine solution were refluxed

for 18 hours. Then another 25 ml of methylamine solution were added and boiling was continued for 6 hours. The reaction mixture was then concentrated, mixed with water, rendered alkaline with 2N-sodium hydroxide and the product was extracted by agitation with ethyl acetate. The

ethyl acetate solution was dried and evaporated and the residue was recrystallized from diisopropyl

ether.

Yield: 2.2 g. Melting point: 105 0 C.

2-(5-Nitro-2-furyl)-5-(2-methylamino-ethoxy)-

46355 0

39,769 /2 pyrimidine hydrochloride 2 A solution of 1.0 g of 2-(2-furyl)-5-(

methylamino-ethoxy)-pyrimidine in 7 ml of 0 C and concentrated sulphuric acid was cooled to 0

a mixture of 0.4 ml of concentrated nitric acid concentrated (specific gravity 1.52) and 0.4 ml of

sulphuric acid was added. The mixture was stirred

for 1 hour at 0°C and then for 2 hours at room neutralized temperature, then poured into ice water,

with sodium hydroxide, saturated with sodium

chloride and the product was extracted by agitation was with ethyl acetate. The ethyl acetate solution and dried, mixed with ethanolic HC1 and evaporated the residue was recrystallized from methanol/ ethanol 1 1. Yield: 0.1 g. Melting point: 23500 with

decomposition. Example 2

2-(2-Puryl)-5-(2- n-propylamino-ethoxy)-pyrimidine 18.0 g of 2-(2-furyl)-5-(2-p-toluenesulphonyloxy- in 200 ethoxy)-pyrimidine and 41 ml of n-propylamine

ml of ethanol were refluxed for 30 hours, then alkaline evaporated, mixed with water and rendered extracted with 2N-sodium hydroxide. The product was ethyl by agitation with ethyl acetate and the evaporated acetate solution was washed, dried and

and the residue was recrystallized from diisopropyl

ether.

Yield: 9.3 g. Melting point: 740C.

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39,769/72 2-(5-Nitro-2-furyl).-5-(2-n-propylamino-ethoxy)- pyrimidine hydrochloride

This compound was prepared as described in

Example l(b) from 2.47 g of 2-(2-furyl)-5-(2-n-

propylamino-ethoxy)-pyrimidine. The product was

recrystallized from ethanol.

Yield: 1.7 g. Melting point: 2170C.

Example 3

2-(2-Euryl)-5-(2-(N-acetyl-2-acetoxy-ethylamino)- ethoxy)-pyrimidine

36.0 g of 2-(2-furyl)-5-(2-p-toluenesulphonyloxy-

ethoxy)-pyrimidine and 30.6 g of ethanolamine in 400

ml of ethanol were refluxed for 30 hours. The

solution was then evaporated and mixed with water

and sodium hydroxide and the product was extracted

by agitation with ethyl acetate. The ethyl acetate

solution was dried, concentrated, mixed with 150 ml

of acetic anhydride and a few drops of concentrated 0 sulphuric acid and heated for 2 hours at 100 C. The

solution was then evaporated under vacuum and the

residue recrystallized from toluene.

Yield: 12.9 g. Melting point: 100 0 C.

2-(5-Nitro-2-furyl)-5-(2-(2-hydroxyethylamino)-ethoxy)-

pyrimidine hydrochloride

A solution of 12.9 g of 2-(2-furyl)-5-(2-(N-acetyl-

2-acetoxy-ethylamino)-ethoxy)-pyrimidine in 80 ml of

acetic anhydride was mixed at 0°C with a mixture of

4.15 ml of concentrated nitric acid (specific

gravity 1.52) and 4.15 ml of concentrated sulphuric

acid, stirred for 1 hour at 000, and then poured into

39,7 69/72 ice water; the precipitate was filtered off and

refluxed for 1 hour with 100 ml of

acid, then evaporated under vacuum and the residue

was recrystallized from methanol.

Yield: 7.1 g. Melting point: 214 0 0.

2-(5-Nitro-2-furyl)-5-(2-(2-hydroxyethylamino-ethoxy)- pyrimidine hydrochloride

0.40 g of 2-(5-nitro-2-furyl)-5-(2-p-toluene-

sulphonyloxy-ethoxy)-pyrimidine and 0.24 g of

ethanolamine in 1 ml of hexamethylphosphoryl triamide 0 were stirred for 1 hour at 60 C, then mixed with

water and some N-sodium hydroxide and the product was

extracted by agitation with ethyl acetate. The ethyl

acetate solution was mixed with ethanolic hydrochloric

acid and evaporated and the residue was recrystallized

from methanol.

Yield: 0.9 g.

Example 4

2-(5-Nitro-2-furyl)-5-(2-(N-acetyl-2-acetoxy-ethylamino)-

ethoxy)-pyrimidine

While cooling a solution of 1.25 g of 2-(2-furyl)

2-(2-N-acetyl-2-acetoxy-ethylamino)-ethoxy)-pyrimidine

in 8 ml of acetic anhydride with ice,. 0.9 ml of concentrated

sulphuric acid and 0.45 ml of concentrated nitric acid

(specific gravity 1.48) were slowly added dropwise and the

whole was stirred for 1 hour with further cooling, then

poured out over ice, neutralized with sodium hydroxide

and the solid product was filtered off and recrystallized

from ethanol.

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39.7 69 /720 yield: 0.9 g. M~elting point: 139 141 C.

Exam-ole 2-2Prl--2(:-ctll-ctx,2-i-'lmn) etho-xy) -P--imid- "nc 36.0 g of 2-2frl-- .ptleeupoy

loxy-ethoxy)-pyrimidile and 44.5 g of 2-amino- (l-n)-butanol were reacted together as described in Example The non-crystallizable oily crude

-product (60 g) was further processed in the form that it was obtained. 2-5Nto2 frl--2(lhdoy2nbtlmn) ethoxy) -pyrimidine hydrochloride 49.0 g of 2-2frl--2(-ctx--ctl

2--btlm~)ehx)prmdn were reacted as

described in Example 3(b) and the product was recrystallized from ethanol. 0 Yield: 19.0 g. Melting point 147 C.

2-5Nto2frl-.(-l-yrx---uyaio- ethoxy) -pyrimidine An aqueous soluti on of 19.0 g of 2-(5-nitro-2- furyl) 2-(l yrxy2nbtyaio-ethoxy)

pyrimidine hydrochloride was mixed with sodium bicarbonate, stirred for hour, and then the solid

product was, filItered off and recrystallized from ethanol. Yield: 2.7 g. Melting 'point: 11400C. Example 6 5-Nitro-2 -furyl) 2- (N-ac etyl-l-ac etoxy-2-n-but ylamino)

ethoxy) -pyrimidine 49.0 g of 2 -(2-furyl)-5-(2(NTaOctyllacetoxy-

4635.50

39 769ra reacted as 2-n-butyl-amino)-ethoxy)-pyrimidine were was recrystallized described in Example 4. The product from methanol. Yield: 21.0 g. .eltin. point: 720C.

Exsmle 7

2-(5-Nitro-2-furyl)-5-(2-(2-methoxy-ethylamino)-ethoxy)- pyrimidine hydrochloride 10.0 g of 2 -(5-nitro-2-furyl)-5-(2-1-toluene- g of 2-methoxyethyl- sulphonyloxy-ethoxy)-pyrimidine and 5.6 5 hours, then amine in 80 ml of dioxan were refluxed for alkaline with evaporated, mixed with water, rendered extracted by agitation sodium hydroxide and the product was solution was dried, with ethyl acetate. The ethyl acetate and the residue was mixed with ethanolic HC1 and evaporated recrystallized from methanol. Yield: 1.8 g. Melting point: 190 0 C.

Example 8

2-(5-Nitro-2-furyl)-5-(2-(3-methoxy-.n-propylamino)-ethoxy)- pyrimidine hydrochloride g of 2 5 -nitro-2-furyl)-5-(2--toluene- 2.7 g of 3-methoxy-n- sulphonyloxy-ethoxy)-pyrimidine and refluxed for 6 hours, propylamine in 20 ml of dioxan were with sodium then mixed with water, rendered alkaline by agitation with hydroxide and the product was extracted and ethyl acetate. The ethyl acetate solution was dried g) was chromatographed evaporated and the residue (aout 4 1 1. on 80 g of silica gel with methanol/chloroform (thin-layer The fractions having an Rf-value of 0.37 system) were chromatography on silica gel, sanme eluent

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39,7 69 /n and the combined, mixed with ethanolic HC1 and evaporated residue was recrystallized from isopropanol. Yield: 0.3 g. !4elting point: 1860C.

Zxamle 9

2-(2-Furyl)-5-(2-(N-actyl-2-dimethylamino-ethlapino)- ethoxy) -pyrimidine 18.0 g of 2-(2-furyl)-5-(2-g-toluenesulphonyloxy- ethoxy)-pyrimidine and 33.0 g of.-2-dinethylamino- refluxed for -ethylamine in 150 ml of ethanol were 48 hours, then poured into water, rendered alkaline, taken up in ethyl acetate and evaporated. The residue was dissolved in 50 ml of acetic anhydride, mixed with a few drops of.concentrated sulphuric 0 evaporated acid, heated for 15 minutes at 100 C and under vacuum. The residue was crystallized from toluene. Yield: 14.9 g. Melting point: 1120C.

2-(5-Nitro-2-furyl)-5-(2-(2-dimethylamino-ethylamino)- ethoxy)-pyrimidine dihydrochloride 5.1 g of 2-(2-furyl)-5-(2-(N-acetyl-2-dimethyl- nitrated amino-ethylamino)-ethoxy)-pyrimidine were as described in Example 3(b) and then hydrolysed. The product was recrystallized from methanol. Yield: 0.9 g. Melting point: 210 21800 with

decomposition Example 2-(5-Nitro-2-furyl)-5-(2-(N-acetyl-2-dimethylamino-

ethylamino)-ethozy)-pyrimidine hydrOgensulphate 5.9 g of 2-(2-furyl)-5-(2-(Ii-acetyl-2-

4635.50

39,769 /72 dimcthylamino-ethlaino)-ethoxy)-pyrimidine in 40 ml of 0 acetic acid were mixed at 0 C with 2.1 ml of concentrated nitric acid (specific gravity 1.48) and 2.1 ml of concentrated sulphuric acid, then stirred for a further 1 hour, poured into ice water and neutralised with sodium hydroxide. The product, which crystallized out on cooling with ice, was filtered off and recrystallized from methanol in the presence of 2.0 ml of sulphuric acid. Yield: 2.6g. Melting point: 170 0C with decomposition. ExanDle 11 2-(2-Furyl)--(2-(N-acetyl-2-diethylamino-ethyl- amino)-ethioxy)-pyrimidine This product was manufactured as described in Example 9(a) from 3.6 g of 2-(2-furyl)-5- (2-2-toluenesulphonyloxy-ethoxy)-pyrimidine and

5.8 g of 2-diethylamino-ethylamine. The

non-crystallizable crude product (2.9 g) was further processed in the form that it was obtained. 2-(5-itro-2-furyl)-5-(2-(N-acetyl-2-diethyl- amino-ethylamino)-ethoxy)-pyrimidine This product was manufactured as described in Example 10 from 2.9 g of 2-(2-furyl)-5-(2-(N- acetyl-2-diethylamino-ethyiamino)-ethoxy)- pyrimidine,.but the crude product was recry- stallized from ethanol without adding sulphuric acid. Yield: 1.9 g. Melting point: 141 1430 C.

Example 12 2-(5-Nitro-2-furyl)-5-(2-(2-diethylamino)-

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39,769/72 ethoxy)-pyrlmidine dihydrochloride 1.9 g of 2-(5-nitro-2-firyl)-5-(2-(N-acetyl- 2-diethylamino-ethylamino) -ethoxy) -pyrimidine in rl of 5-hYochloic alcid re-fluxed for l- hours, then completely evaporated under vacuum aid the residue was recrystallized from ethanol. Yield: 0.98 g. Melting point: 186 1870C.

2-(5-litro-2-furyl)-5-(2-(2-diethylan-thl amino) -ethoxy) -pyrimidine dihydrochioride 12.2 g of 2-(5-nitro-2-furyl)-5-(2--toluene- sulphonyloxy-ethoxy)-pyrilidine and 7.0 g of 2-diethylaninoethylamine in 60 ml of dioxan were refluxed for 4 hours, then mixed with water and taken up in ethyl acetate; the ethyl acetate solution was dried, mixed with ethanolic HUl and evaporated and the residue was recrystallized from ethanol. Yield: 2.6 g.

Exam-Dle 13 2-(5-Nitro-2-furyl)-5- (2-(tetrahydro-2-furylmethylm ino)- ethoxy)-pyrimidine hydrochloride 0.81 g of 2-(5-nitro-2-furyl)-5-(2-.n-toluene- sulphonyloxy-ethoxy)-pyrimidine and 0.4 g of tetrahydrofur- furylamine in 20 ml of dioxan were refluxed for 4 hours, then evaporated'and taken up in water, and the product was extracted by agitation with ethyl acetate. The ethyl

acetate solution was dried, mixed with ethanolic HICland evaporated and the residue was recrystallized from ethanol. Yield: 0.30 g. Melting point: 23200.

16

39,769/72 Example 14 2-(5-Nitro-2-furyl)-5-(2-(N-acetyl-methylamino)-ethoxy)- pyrimidine

g of 2-(2-furyl)-5-(2-methylamino-ethoxy)-

pyrimidine in 50 ml of acetic anhydride were heated for 0 j hour at 100 C, then cooled to 0-50C and 1.65 ml of

concentrated nitric acid (specific gravity 1.52) and 1.65

ml of concentrated sulphuric acid were added. The mixture

was then stirred for another hour while cooling, poured

into ice water and the product was filtered off and re-

crystallized from ethanol.

Yield: 1.9 g. Melting point: 1530C.

Example 2-(2-Puryl)-5-(2-(N-acetyl-ethylamino)-ethoxy)- pyrimidine 5.4 g of 2-(2-furyl)-5-(2-,-

toluenesulphonyloxy-ethoxy)-pyrimidine and

ml of ethylamine in 70 ml of ethanol were

refluxed for 20 hours, then evaporated and mixed

with water, rendered alkaline with 2N-sodium

hydroxide and the product was extracted by

agitation with ethyl acetate. The ethyl

acetate solution was washed, dried and

evaporated. The residue was mixed with 40 ml

of acetic anhydride and 2 drops of concentrated 0 sulphuric acid and heated for 1 hour at 100 C, then evaporated under vacuum; the residue was

mixed with water, rendered alkaline with 2N-

sodium hydroxide, and extracted by agitation with

ethyl acetate and the ethyl acetate solution was

evaporated and the residue recrystallized from

4635.50

39,769 /72 1. diisoproPYl ether/tetrahydro-furan 2 0 Yield: 3.3 g. Melting point: 133 C. 2-(5-Nitro-2-furyl)-5-(2-(N-acetyl-ethylamino)- ethoxy)-pyrimidine A solution of 3.3 g of 2-(2-furyl)-5-(2-(N- in 20 ml of acetyl-ethylamino)-ethoxy)-pyrimidine 0 C with acetic anhydride was mixed dropwise at 0-5 a mixture of 1.3 il of concentrated nitric acid

1.48) and 1.3 ml of concentrated (specific gravity

sulphuric acid. The mixture was then stirred for into 1 hour while being cooled with ice, poured ice water and the product was extracted by ethyl acetate agitation with ethyl acetate. The evaporated and the solution was washed, dried and residue was recrystallized from ethanol. 0 Yieldi 2.0 g. Melting point: 142 C.

Exanmple 16' 2-(2-Puryl)-5-(2-(N-acetyl-n-propylamin)-ethoxy)- pyrimidine in This product was manufactured as described Example 15 from 10.8 g of 2-(2-furyl)-5- and 2 -p-toluenesulphonyloxy-ethoxy)-pyrimidine from 17.7 g of n-propylamine and recrystallized 1: 2. ethyl acetate/diisopropyl ether Yield: 6.2 g. Melting point: 1160C.

2-(5-Nitro-2-furyl)-5-(2-(-acetyl--propylamino)- ethoxy)-pyrimidine in This product was manufactured as described 2 Example 15(b) from 6.2 g of 2-(2-furyl)-5-( and (N-acetyl-B-propylamino)-ethoxy)-pyrimidine

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39,769/72 recrystallized from ethanol. Yield: 2.9 g. Melting point: 128 0C. Examile 17 2-(2-Furyi)-5-(2-(N-acetyl-isopropylamino)- ethoxy) -pyrimid ine This product was manufactured as described in Example 15(a) from 5.4 g of 2-(2-furyl)-5-(2-2- toluenesulphonyloxy-ethoxy)-pyrimidine and 4.43 g of isopropylamine and recrystallized from diisopropyl ether. Yield: 2.9 g. Melting point: 1000 C. 2-(5-Nitro-2-furyl)-5-(2-(-acetyl-isopropylamino)- ethoxy) -pyrimid ine This product was manufactured as described in Example 15(b) from 2.9 g of 2-(2-furyl)-5-(2-(IT- acetyl-isopropylamino)-ethoxy)-pyrimidine and re- crystallized from ethanol.

Yield: 2.0 g. Melting point: 16600. Example 18 2-(2-Furyl)-5-(2-(N-acetyl-n-butylamino)-ethoxy)- pyrimidine This product was manufactured as described in Example 15(a) from 2.5 g of 2-(2-furyl)-5-( toluenesulphonyloxy-ethoxy)-pyrimidine and 2.6 g of n-butylamine and further processed in the crude form. Yield: 1.05 g. Melting point: 113 1140 C.

2-(5-Nitro-2-furyl) N-acetyl--butylamino) ethoxy) -pyrimidine The product was manufactured as described in

19' 4635,50

39769/72 E1xample 15(b) from 1.b5 g of 2-(2-furyl)-5- N-ac etyl--butylaino) -ethoxy) -pyrimid ine and recrystallized from ethanol. ield: 0.45 I1+in ppoint: 124 1250 C.

Example 19 2-(2-Furyl) W-acetyl-2-butylmio)-ethoxy)- pyrimidine This product was manufactured as described Example 15(a) from 3.60 g of 2-(2-furyl)-5- in

(2-,ptoluensuphonylxy-ethoxy) -pyrinidine and 3.65 g of 2-butylamine and recrystallized from toluene. Yield: 2.1 g. Melting point: 100 -1010C.

2-(5-Nitro-2-furyl) -5-(2-(N-acety1-2-butlamino)-- ethoxy) -pyrimidiine This product was manufactured as described in Example 15(b) from 2.1 g of 2-(2-furyl)-5-(2-(N- acetyl--butylamino0) -ethoxy)-pyrimidine and re- crystallized from ethanol. Yield: 1.5 g. Melting point: 137 -13800.

Example 2-(2-FPuryl)-5-(2-(N-acetyl-cyclopentylamino)- ethoxy) -pyrimidine This product was manufactured as described in Example 15(a) from 3.6 g of 2-(2-furyl)-5- (2-.R-toluenesulphonyloxyethoxy) -pyrimidine and 4.25 g of cyclopentylamine and recrystallized from toluene. Yield: '2.73 g. Melting point: 110 1110C.

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39,769 P2 2-(5-Nitro-2-furyl)-5-(2-(N-acetyl-cyclopentylamino)-

ethoxy) -pyrimid ine

This product was manufactured as described in

Example 15(t) from 2.45 of 2- (Ni-ac-etyl-cyclopentylamino) -ethoxy)-pyrinid ine and

recrystallized from ethanol.

Yield: 0.82 g. Melting point:. 139 0 C. Example 21

2-(2-Furyl)-5-(2-(N-acetyl-cyclohexylamino)-

ethoxy) -pyrimid ine

This product was manufactured as described in

Example 15(a) from 3.6 g of 2-(2-furyl)-5-(2-j-.

toluenesulphonyloxy-ethoxy)-pyrimidie and 9.9 g of cyclohexylamine and recrystallized from toluene. Yield: 2.1 g. Melting point: 136* 137 0 0. 2-C 5-Nitro-2-furyl) N-acetyl-cyclohexyamino)

ethoxy) -pyrimid ins

This.product was manufactured as described, in

Example 15(b) from 2.05 g of 2-(2-furyl)-5-

N-ac etyl-cyclohexylamino) -ethoxy) -pyrimid ins

and recrystallized from ethanol.

Yield: 1.25 g. Melting point: 143 144 0 C. Example 22

2-(2-Furyl)-5-(2-(N-acetyl-2-methoxyethylamino)-

ethoxy) -pyrimid ine

This product was manufactured as described in

Example 15(a) from 27.0 g of 2-(2-furyl)-5-(2-.-

toluenesulphonyloxy-ethoxy)-pyrimidine and 28.2 g

of 2-methoxyethylamine and recrystallized from

S- 21 4635.50

39,769 /72 diisopropyl ether/tetrahydrofuran 2 1.

Yield: 15.2 g. Melting point: 11300.

2-(5-Nitro-2-furyl)-5-(2-(N-acetyl-2-

This product was manufactured as described in Example 15(b) from 15.2 g of 2-(2-furyl)-5- (2-(N-ac etyl-2 -methoxyethylmino)-ethoxy) pyrimidine and recrystallized from ethanol. Yield: 8.8 g. Melting point: 11800.

Examle 23 2-(2-Furyl) -5-(2-(N-acetyl-benzylamino) -ethoxy) pyrimidine This .product was manufactured as described in Example 15(a) from 2.52 g of 2-(2-furyl)-5-(2-2- toluenesulphonyloxy-ethoxy)-pyrimidine and 3.75 g

of benzylamine and further processed in the crude form. Yield: 1.30 g. Melting point: 107 1090.

2-(5-Nitro-2-furyl) 1-acetyl-benzylamino)

ethoxy) -pyrimid ine This product was manufactured as described in 2 Example 15(b) from 1.20 g of 2-(2-furyl)-5-( (N-acetyl-benzylamino)-ethoxy)-pyrimidine and

recrystallized from isopropanol. Yield: 0.36 g. Melting point: 131 1340C.

Example 24 2-(2-Furyl)-5-( N-formyl-2--propyla no-ethoxy)- pyrimid ine A solution of 2.47 g of 2-(2-furyl)-5- (2-n-propylamino-ethoxy) -pyrimidine in 20 ml

4635.50

39.769/72 of formic acid and 6 ml of acetic anhydride was

allowed to stand overnight, then completely

evaporated under vacuum, and the residue was

recrystallized from diisopropyl ether.

Yield: 1.70 g. Melting point: 980 C.

2-(5-Nitro-2-furyl)-5-(N-formyl-2-n-propylamino- ethoxy)-pyrimidine

A solution of 0.27 g of 2-(2-furyl)-5-

(N-formyl-2-n-propylamino-ethoxy)-pyrimidine

in 5 ml of acetic anhydride was mixed with 0.1

ml of concentrated sulphuric acid and 0.1 ml of 0 concentrated nitric acid at 0 C and stirred

for a further hour at this temperature, then

poured into ice water, and the solid product was

recrystallized from isopropanol.

Yield: 0.1 Melting point: 13200. Example 2-(2-Puryl)-5-(2-(N-n-butyryl-_-propylamino)- ethoxy)-pyrimidine

A solution of 1.20 g of 2-(2-furyl)-5-

(2-n-propylamino-ethoxy)-pyrimidine in 20 ml of

pyridine was mixed with 0.51 ml of n-butyryl

chloride and stirred for 1 hour at room

temperature, then poured into water and acidified

with hydrochloric acid and the product was

extracted by agitation with ethyl acetate. The

ethyl acetate solution was dried, evaporated and

recrystallized.from ethanol.

Yield: 0.50 g. LMelting point: 1100 C.

2-(5-Nitro-2-furyl)-5-(2-(N-n-butyryl-n-propylamino)-

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39,769/72 ethoxy) -pyrimidine This product was manufactured as-described in Example 24(b) from.0.3 g of 2-(2-furyl)'-5-(2- -ii-ut yryl--propylamf3 noo) -ethoxy)--pyTrimid -1 and recrystallized from isopropanol. Yield: 0.15 g. Melting point: 900C.

ExamnDle 26 2-(5-llitro-2-furyl)-5-(2-(N-acetyl-2-hydroxy-ethylamifo)- ethoxy) -pyrinidine 3.78 g of 2-(5-nitro-2-furyl)-5-(2-( -acetyl- 2

acetoxy-ethylamino)-ethoxy)-pyrimidie in 200 ml of N- 0 hydrochloric acid were stirred for 12 hours at 40 C, then completely evaporated under vacuum and the residue was recrystallized from methanol. Yield: 1.1 g. Melting point:. 17900. Example 27 2-(5-Nitro-2-furyl) 2-cyclohexylaminoethoxy) -pyrimidine hydrochloride A-mixture of 2.0 g of 2-(5-nitro-2-furyl)-5- (2-Ltoluene-sulphonylox-ethoxy) -pyrimidine, 5 ml of hexamethylphosphoryl triamide and 1.7 g of cyclohexylamine was stirred for 2 hours at 6090, then mixed with water, the solidprecipitate was filtered off, washed with water, dissolved in ethanolic hydrochloric acid, heated for a short time, evaporated to dryness and the residue was recrystallized from methanol. Yield: 1.0 g. Melting point: 25000 with decomposition.

Example 28 2-(5-Nitro-2-furyl)-5-(2-cyclopentylaminethoxy) -pyrimidine hydrochloride

24 4635.50

39,769/72 This product was manufactured as described in Example 27 using cyclopentylamine instead of cyclohexil- amine. Yield: 0.3 o. ielting point: 23800 With decomposition. Example 29 2 2 -Furyl)-5-(2-(2-hydroxy-propylamino)-ethoxy)- pyrimidine A mixture of 18.2 g of 2-(2-furyl)-5-(2-p- toluenesulphonyloxy-ethoxy)-pyrimidine, 18.8 g of 2-hydroxypropylamine and 200 ml of ethanol was refluxed for 20 hours, then evaporated and mixed with water and N-sodium hydroxide, and the product was extracted by agitation with ethyl acetate and the ethyl acetate solution was evaporated. The residue was recrystallized from diisopropyl ether. Yield: 9.3 g. Melting point: 1000 C. 2 2 -uryl)-5-(2-(N-acetyl-2-acetoxy-propylamino)- ethoxy)-pyrimidine 1 drop oftconcentrated sulphuric acid was added to a solution of 9.3 g of 2-(2-furyl)-5- (2-(2-hydroxy-propylamino)-ethoxy)-pyrimidine in 100 ml of acetic anhydride. The whole was allowed to stand for 12 hours at room temperature, then heated for 1 hour on a steam bath and evaporated; the product was purified by chromatography on 300 g of silica gel in methylene chloride/acetone 1 1 and then recrystallized from ethyl acetate. Yield: 6.7 g. Melting point: 121 0 C. 2-(5-itro-2-furyl)-5-(2-(N-acetyl-2-acetoxy- propylamino)-ethoxy)-pyrimidine

4634.50

3 9,769 /72 2 A solution of 5.8 g of 2-(2-furyl)-5-( 2 (N-acetyl- -acetoxy-propylamino)-ethoxy)-pyrimidine 00 C with in 80 ml of acetic anhydride was mixed at of concentrated nitric acid (specific gravity 2.6 acid. 1.52) and 1.75 ml of concentrated sulphuric 0 poured The mixture was stirred for 1 hour at 0oC, 4.5 with into ice water, adjusted to a pH value of filtered sodium hydroxide and the precipitate was Soff and recrystallized from ethanol. Yield: 3.9 g. Melting point: 123 0 C.

Examule 2-(5-Nitro-2-furyl)-5-(2-(2-hydroxy-propylamino)-ethoxy)- pyrimidine hydrochloride 1.96 g of 2-(5-nitro-2-furyl)-5-(2-(N-acetyl-2- in 20 ml of acetoxy-propylamino)-ethoxy)-pyrimidine hour, then completely hydrochloric acid were refluxed for 1 from methanol. evaporated and the residue was recrystallized Yield: 1.3 g. Melting point: 20800. Example 31 2 2-(2-Furyl)-5-(2-( ,3-dihydroxy-propylamino)- ethoxy)-pyrimidine 51.0 g of -furyl)-5-(2--toluenesulphony- 2 2 of 1-amino- .1oxy-ethoxy)-pyrimidine and 77.9 g were refluxed 2,3-propanediol in 500 ml of ethanol with water for 7 hours, then evaporated and mixed extracted and sodium hydroxide-and the product was by agitation with ethyl acetate. The ethyl the residue acetate solution was evaporated and with chromatographed on 300 g of silica gel

46345 0

3 9 ,7 69 P2 methanol/chloroform 1 1 and then recrystallized

from ethyl acetate. Yield: 6.8 g. Melting point: 94 0 C.

0-(2-=uryl -)-5-(2-(H-ece'Lyl-,3-diacetoxy-pro'01l- amino)-ethoxy)-pyrimidine 2 A mixture of 6.8 g of 2-(2-furyl)-5-(2-( ,3- and 1 dihydroxy-propylamino)-ethoxy)-pyrimidine in 120 ml of drop of concentrated sulphuric acid was heated for 2 hours on a acetic anhydride

and the steam bath, then completely evaporated gel residue was chromatographed on 250 g of silica with methanol/chloroform 1 2 and then recrystall-

ized.from methanol. 0 Yield: 3.9'g. Melting point:- 108 C.

2 (5-Nitro-2-furyl)-5-(2-(N-acetyl-2,3-diacetoxy- propylamino)-ethoxy)-pyrimidine A mixture of 0.41 ml of concentrated nitric ml of acid (specific gravity 1.52) and 0.41 at concentrated sulphuric acid was added dropwise 2 0 0 to a solution of 1.5 g of 2-(2-furyl)-5-( 2 (N-acetyl- 3-diacetoxy-propyl-amino)-ethoxy)- pyrimidine in 20 ml of acetic anhydride. The 000, reaction mixture was stirred for 1 hour at with then poured into ice water and neutralized extracted sodium hydroxide, and the product was ethyl. by agitation with ethyl acetate. The residue acetate extract was evaporated and the was recrystallized from ethanol. Yield: 0.8 g. Melting point: 9200.

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X. -pe3 39,769/72 2 2 2-(5-Nitro-2fury)5( ,3dihydroxypropylami11O)-ethoxy)-

pyrimidine hydrochloride

in 20 ml of 211- dictx-rplmn)-toy-yiiii for 1 hour, then evaporated hydrochloric acid were refluxed recrystallized from etha.nol. to dryness and the residue was 192 C. Yield: 1.1 g. M~elting point:

463.550

39,769 /72 The Claims defining the inve ntion are as follows:-

1. A compound of the general formula I

0 NOCH C H 2 NR

in which R represents a saturated or unrsaturated, linear, branched or cyclic aliphatic hydrocarbon group which may be substituted by one or two hydroxyl groups, by one or two acyloxy groups where the acyl is derived from an organic acid or by an alkoxy, dialkylamilo, tetrahydro- furyl or phenyl group and RI represents a hydrogen atom or an'-acyl group where the acyl is derived from an orga- nic acid and both'the aliphatic hydrocarbon and acyl groups have 1 to 6 carbon atom s..

2. A physiologically tolerable acid addition salt of a compound as claimed in claim 1. 3. 5-Nitro-2-furyl) 2-methylaxnino-ethoxy)

pyrimidine hydrochloride. 4. 2-(5-1Ilitro-2-furyl) 2-.n-propylamino-ethoxy) pyrimidine hydrochloride. 2-5Nto;-frl--(2(-yrxehlmn) ethoxy) -pyrimidime hydrochloride. 2-(5-lNitro-2-fluryl)-5-(2-( N-acetyl-2-acetoxy- iethylamino) -ethoxy) -pyrimidine. 7. 2-(5-Ni'tro-2-furyl) l-hydroxy-2-fl-

but ylamino) -thoxy) -pyrimid ie hydrochloride.

aTnino) -ethoxy) -pyrimidine.-

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39,.7 6V~ /72 9. 2-5Nto2frl '-2(r-ctllaeoy

2-n--butylanfo) -ethoxy) -pyrimidine. 2-.t5.Nitro-2-furyl) (2 -(2-methoxy-ethyaiino)

gyri.~idine h~ydrochloride.

11. 2 -(5S'iitro-2fuyl)5(2(3metoy-.apropyanUio)- ethox,-j-plyrimidile hydrochloride. 12.* 2- (5-Nitro-2-uryl) 2-dimethylamfiflo-

ethylamilo)-thoxy) -:.yrimidine dihydrochioride.

ethylaniino) -ethoxy) -pyrimid The hydrogensuiphate. 14. 5-I'itro-2-fury1) N-acetyl-2-dieuhylamino-

ethylamnfo)-ethO2y) -pyrixuidine. 16. 2-5Nto2frl--2(-dityaioehlmn) ethoxy) -pyrimidifle dihydrochloride. 16. 2-(5-N1itro-2-ful) 2-.(tetrahydro-2-f1Xrylmethyl-

amino)-ethoxy) -pyrimidine hydrochloride. 17. 2-5Nto2frl--2(-ctlmtyamn) ethoxy) -pyriiuidine. 18.* 2-C 5-Nitro-2-furyl) N-acety1-ethylamiO)

ethoxy) -5riuid The. 19. 2 to frl--2(I-ctl,-rplnn) ethoxy) -pyrimid The. 2-5Nto2frl--2(I-ctliorplmn) ethoxy-pyrimIfid Te.. 21. 2 -(5-Nitro 2 fury)-5(2(Nacetyl1B-utyaaino)

ethoxy) -pyrimi-difle. 22. 2-5Ntb2frl--2(Naey--uyamn) ethoxy) -pyr inid Thie., 23. 2 -(5-"itro-2fury)(2(NcetYl-cyclop~-yl,-i

-so- 4635,

39769 /72 etlioxy) -pyrimidime. 24. 2-(5-i-litro-2-fuLryl) -5-(2-(N-acetyl-cyclohexylamflo)- ethoxy) -pyrimidine'.

ainino)-ethoxy)-pyrimidinle. 26. 2-(5-Nitro-2-furyl) N-acetyl-bcnzylamino) ethoxy)-pyrinidinfe. 27.* 2- -I17itro-2 -fixryl) (N-tf ormyl-2-n-propylamino- ethoxy) -pyrimidine.

ethoxy) -pyrimidine.' 29. 2-(5-Nitro-2-furyl) -5-(2-(N-acetyl-2-hydroxyethyl- amino) -ethoxy) -pyrimidine. 2-5Nto2frl)5(2c oeyaiotoy-

pyrimidime hydrochloride. 31. '2-C 5-Nitro-2-fur-yl) -5-4 2-cyclopentylamiloethoxy) pyrixnidine hydrochloride. 32. 2-5Nto2frl--2-Naey- aeoy

propylamino)-ethoxy) -pyrimid±iie. 33.* 2-(.5-Nitro-2-furyl) 2-hydroxypropylamino)

ethoxy) -pyrimidine hydrochloride. 34o. 2-(.5-Njitro-2-f Uryl) N-acet yl-2, 3-d iacetoxy-

piropylamino)-ethoxy)-pyrmidine. 2 2-(5-Nitro-2-furyJ.)-5-(2-( ,3-dihydroxypropylamino)- ethoxy)-pyrifidile hydrochloride. .36. A process for the manufactur'e of a compound as claimed in claim 1 or an acid addition salt thereof, wherein a compound of the general formula II

31 4635.

39,769/72

1 OCH 2CH2 -z (I) S

in which represents a hydrogen atom or a nitro group acid or and Z represents an acyloxy group of a sulphonic a primary a bromine or chlorine atom, is reacted with

amine of the general formula III

m

and a resulting in which R has the meaning given above, the compound not containing a nitro group in desired, in the of the furan ring is nitrated and, if any hydroxyl resulting compound any -1H-group and/or group and/or/any group is/are acylated or any acylamino if desired, a acyloxy group is/are hydrolysed and/or, formula I resulting free compound of the general salt thereof with an is converted into an acid addition resulting acid organic or inorganic acid and/or a corresponding free addition salt is converted into the of the aforesaid compound by means of a base, each or after the optional steps being carried out before

nitration.

32 4635.50

Claims (1)

1. 39,769/72 the 37. A process as claimed in claim 36, wherein or hexamethyl- reaction is carried out in dioxan, ethanol phosphoryl triamide. herein the 3C3. A. process a. claimed in claim 56 or within the range reaction is carried out at a temperature

   of from 50° to 100°C. to 38, 39. A process as claimed in any one of claims 36 in concen- wherein the compound being nitrated is dissolved and the nitration trated sulphuric acid or acetic anhydride acid or a mixture is carried out with concentrated nitric sulphuric acid. of concentrated nitric acid and concentrated the nitra- A process as claimed in claim 39, wherein the range of tion is carried out at a temperature within from -20° to +4000. of the 41. A process for the manufacture of a compound conducted sub- general formula I, as defined in claim I, 1 to stantially as described in any one of Examples herein. compound of the 42. A process for'the manufacture of a I, conducted sub- general formula I, as defined in claim Examples 26 to 32 stantially as described in any one of

   herein. a 43. A pharmaceutical preparation which comprises compound as claimed .in claim 1, in admixture or con- carrier. junction with a pharmaceutically suitable a 44. A .pharmaceutical preparation which comprises as claimed physiologically tolerable acid addition salt a in claim 2, in admixture or conjunction with pharmaceutically suitable carrier.

   4635.50

   39,769/72 A pharmaceutical preparation which comprises two the general or more compounds selected from compounds of

   formula I, as defined in claim I, and physiologically -tolerable acid addition salts of 5uch compounds. the 46. A pharmaceutical preparation which comprises 28, in admixture compound claimed in any one of claims 3 to carrier. or conjunction with a pharmaceutically suitable the 47. A pharmaceutical preparation which comprises to 35, in admixture compound claimed in any one of claims 29 suitable carrier. or conjunction with a pharmaceutically in any one 48. A pharmaceutical preparation as claimed of a tablet, of claims 43 to 47, which is in the form

   dragee, capsule, pill or suspension. in claim 48, 49. A pharmaceutical preparation as claimed 0.50 g of the active wherein the tablet contains 0.05 to substance.

   7th day of March, 1972 DATED this

   SCh ING AKTIENGESELLSCHAFT

   By its Patent Attorneys,

   ARTHUR S. CAVE CO.

   0 34 4635.50