US3846428A

US3846428A - Nitrofurylpyrimidines

Info

Publication number: US3846428A
Application number: US00235426A
Authority: US
Inventors: E Schroder; R Albrecht; H Kessler
Original assignee: Schering AG
Current assignee: Bayer Pharma AG
Priority date: 1971-03-17
Filing date: 1972-03-16
Publication date: 1974-11-05
Anticipated expiration: 1991-11-05
Also published as: AU463550B2; AU3976972A; PL83278B1; FR2130327A1; FR2130327B1; HU163178B; AT312589B; NL7203650A; IL38962A0; DD96950A5; SU458130A3; CA945557A; GB1391933A; DE2113529B2; ES400560A1; IL38962A; CH575943A5; DK126999B; DE2113529C3; BE780879A

Abstract

Compounds of the formula WHEREIN R is saturated or unsaturated, straight-chain or branched hydrocarbon aliphatic group of 1-6 carbon atoms or cyclic alkyl of 3-7 carbon atoms, alkyl of 1-6 carbon atoms wherein 1-2 carbon atoms are substituted by hydroxy or by acyloxy of 1-6 carbon atoms or one carbon atom thereof is substituted by alkoxy of 1-6 carbon atoms, by dialkylamino wherein each alkyl group contains 1-6 carbon atoms, by tetrahydrofuryl or phenyl and R'' is hydrogen or acyl of 1-6 carbon atoms possess systemic antibacterial activity in addition to activity against Trichomonas vaginalis.

Description

Nov. 5, 1974 NITROFURYLPYRIMIDINES Inventors: Rudolf Albrecht; Hans-Joachim Kessler; Eberhard Schriider, all of Berlin, Germany Schering Aktiengesellschaft, Berlin & Bergkamen, Germany Filed: Mar. 16, 1972 Appl. No.: 235,426

Assignee:

Foreign Application Priority Data Mar. 17 19 71 Germany 2113529 US. CL... 260/256.4 C, 260/2471 A, 260/2475 R, 260/251, 424/248, 424/251 lnt. Cl C07d 51/36 Field of Search 260/2564 C References Cited UNITED STATES PATENTS 12/1972 Gutsche et a1. 260/2564 C Primary Examiner-Raymond V. Rush Attorney, Agent, or FirmMillen, Raptcs & White [57] ABSTRACT Compounds of the formula I I N /R 0 wherein R is saturated or unsaturated, straight-chain or branched hydrocarbon aliphatic group of 1-6 carbon atoms or cyclic alkyl of 3-7 carbon atoms, alkyl Fa ho 19 1 einl $199! om are substituted by hydroxy or by acyloxy of l-6 carbon atoms or one carbon atom thereof is substituted by alkoxy of l-6 carbon atoms, by dialkylamino wherein each alkyl group contains l-6 carbon atoms, by tetrahydrofuryl or phenyl and R is hydrogen or acyl of l-6 carbon atoms possess systemic anti-bacterial activity in addition to activity against Trichomonas vaginalis.

28 Claims, N0 Drawings BACKGROUND OF THE INVENTION This invention relates to novel nitrofurylpyrimidines. U.S. application Ser. No. 55,601, filed July, 16, 1.970, now US. Pat. No. 3,707,485, relates to compounds of the formula SUMMARY OF THE INVENTION The compounds of this invention are nitrofurylpyrimidines of the general Formula I wherein R is saturated or unsaturated, straight-chain or branched aliphatic hydrocarbon, e.g., alkyl, or l-6 carbon atoms or cyclic alkyl of 3-7 carbon atoms, alkyl of l-6 carbon atoms wherein 1-2 carbon atoms are substituted by hydroxy or acyloxy of l-6 carbon atoms or one carbon atom thereof is substituted by alkoxy of l-6 carbon atoms or by dialkylamino wherein each alkyl group contains l-6 carbon atoms, or by tetrahydrofuryl or phenyl and R is hydrogen or acyl of l-6 carbon atoms.

DETAILED DISCUSSION As used herein, alkyl and acyl in each instance contain l-6 carbon atoms and cyclic alkyl preferably contains 3-7 carbon atoms.

Examples of various classes of compounds of this invention are those of Formula I wherein:

a. R is H or acetyl;

b/R is alkyl of l-6 carbon'atoms, preferably l-4, in-

cluding methyl, ethyl, propyl, isopropyl, n-butyl & 2- butyl, e.g., those of(a), and, in addition to alkyl of l-6 carbon atoms, R can also be a corresponding unsaturated group, e.g., allyl and ethynyl;

c. R is alkyl as defined in (b) substituted with l-2 of a hydroxy and acyloxy, e.g.,.acetoxy, preferably in the l or 2 position, e;g., those of (a);

d. R is alkyl as defined in (b) substituted with dialkylamino, e.g., dimet'hylamino, methylethylamino, dicthylamino, preferably in the 2 position, e.g., those of (a);

e. the compound is in the form of an acid addition salt, e.g., hemisulfate of hydrochloride including those of (a), (b), (c) and (d). Examples of cycloalkyl are cyclopropyl, cyclopentyl and cyclohexyl.

2 Examples of acyloxy are formyloxy, acetoxy, propionyloxy, butyryloxy and other alkanoyloxy.

Examples of alkoxy are methoxy, ethoxy, propoxy, i-propoxy and n-butoxy. The tetrahydrofuryl substituent is preferably at the 1 -position and preferably attached by the 2-carbon atom thereof. The phenyl group is preferably at the 1-position.

The compounds of this invention which are sufficiently basic to form acid addition salts can be in-the form of physiologically acceptable acid addition salts. Thus, this invention embraces compounds of Formula I both in free base form and in the form of an acid addition salt with a physiologically compatible acid. Examples of physiologically acceptable acids are hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, propionic acid, lactic acid, succinic acid, tartaric acid, citric acid, benzoic acid, salicylic acid, nicotinic acid and heptagluconic acid.

Other pharmaceutically acceptable acid addition salts, i.e., of acids which do not materially increase the toxicity of the compounds of this v invention, include salts of other mineral acids, such as, forexample, hydriodic, hydrobromic, metaphospho'ric and .nitric as well as salts of organic acids, such as, for example, malic, glycolic, gluconic and arylsulfonic, e.g., p-toluenesulfonic acids. H I f The acid addition salts of this invention are not limited to those formed with pharmaceutically acceptable acids. Other acids, e.g., those formed with perchloric and other toxic and/or unstable acids are useful for isolation, characterization and purification of the free base. These acid addition salts can, if desired, thereafter be converted back to the free base and acid addition salts of pharmeceutically acceptable acids, employing conventional procedures. 1 v

This invention relates both to single compounds of Formula I and to mixtures of one or more thereof.

The compounds of Formula I are produced by reacting a compound of the general Formula II 'ocrr CH-Z o N 2 2 wherein R" is hydrogen or nitro, and Z is a sulfonic acid ester group, a bromine or chlorine, with a primary amine of the general Formula R-NH (Ill) wherein R has the values given above; and subsequently hitrating the thus-obtained compounds wherein R" H and, optionally, prior to or after thenitration, acylating the amino group and/or any hydroxy groups present and/or saponifying the acylamino group and/or any acyloxy groups present; and optionally isolating the amino compounds of general Formula I from the reaction product in the form of the acid addition salts thereof; or optionally converting the free amino compounds of general Formula I, with organic or inorganic acids, into the acid addition salts thereof orliberating the free amino compounds of Formula I fromthe acid addition salts with bases.

The compounds according to Formula I can be produced in acid addition salt form by isolating them directly from the reactions conducted in an acidic medium, e.g., nitration, acidic saponification, for example, in the form of the hydrochlorides, acid sulfates, or'neutral sulfates, or by preparing them from the free base by subsequent treatment with an acid. Compounds acpounds in concentrated sulfuric acid or acetic anhydride and mixing with concentrated nitric acid or a mixture of concentrated nitric acid and concentrated sulfuric acid. In general, this reaction is conducted at a temperature from C. to +40 C.

The acylations are conducted by treating the secondary amino compounds with an acid anhydride, or reacting same in a basic medium, e.g., pyridine, with an acid halogenide. The saponification of the acylamino group and/or of the acyloxy group is conducted in a conventional manner. v

The novel compounds possess anti-bacteria activity as well as activity against Trichomonas vaginalis. The minimum inhibitory concentrations (MIC) of several compounds of Formula I against several pathogenic germs are set forth in Table I. For purposes of comparison, the MIC values of the commercially available nitrofurantoin, determined under identical conditions are ethoxy ]-pyrimidine In contrast to nitrofurantoin which, after oral administration, is detectable in microbiologicallyactive form only in the urine, the above-mentioned compounds of this invention can also be detected in the bloodstream. Consequently, these compoundsexhibit a systemic effect, not shown by nitrofurantoin, even in case of model infections, e.g., staphylococci, as shown in Table II.

TABLE II The compounds of this invention can be employed in the treatment of trichomoniasis and in bacterial infections, e.g., staph. infections. They can be administered in forms customarily employed in pharmaceuticals. For oral administration, especially suitable are tablets, dragees, capsules, pills, suspensions and solutions. Suitable excipients for tablets are, for example, lactose, amylose, talc, gelatin, magnesium stearate, etc.

For topical administration, suitable are powders, solutions, suspensions, aerosols, and vaginal suppositories. For parenteral application, aqueous and oily solutions or suspensions can be employed.

The compounds of this invention are formulated so as to provide, for example, 005 0.5 g. of the effective agent in admixture with 0,1 to 5 g. of a pharmacologically indifferent excipient, e.g., a pharmaceutically acceptable carrier, per unit dosage, e.g., per tablet.

The novel effective agents are usually administered in amountsof between 0.1 and 4.0 g. per patient per day.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description,

utilize the present invention to its fullest extent. The

following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not li'mitative of the remainder of the disclosure in any way whatsoever;

EXAMPLE 1 a. 2-(2-Furyl)-5-(2-methylaminoethoxy)-pyrimidine 5.4 g. of 2-(2-furyl)-5-(2-toluenesulfonyloxyethoxy)-pyrimidine is refluxed for 18 hours in ml. of ethanol and 50 ml. of aqueous methylamine solution (35 percent strength). Then, 25 ml. of methylamine solution is again added, and the refluxing continued for 6 hours. Thereafter, the reaction mixture is concentrated, mixed with water, made alkaline with 2N NaOH, and the product is extracted with ethyl acetate. The'ethyl acetate solution is dried, evaporated, and the residue is recrystallized from diisopropyl ether. Yield: 2.2 g. Melting point: C. b. 2-(5-Nitro- 2-furyl)-5-(2-methylaminoethoxy)- pyrimidine Hydrochloride 1.0 g. of 2-(2-furyl)-5-(2-methylaminoethoxy)- pyramidine is dissolved in 7 ml. of concentrated sulfuric acid, cooled to 0 C., and a mixture of 0.4 ml. of concentrated nitric acid (s.g. 1.52) and 0.4 ml. of concentrated sulfuric acid is added thereto. The mixture is agitated for 1 hour at 0 C. and then for 2 hours at room temperature. Then, the mixture is poured into ice water, neutralized with NaOH, saturated with NaCl, and the product is extracted with ethyl acetate. The ethyl acetate solution is dried, mixed with ethanolic HCl,

Mic robiologically Active ED (mg/kg.)

Level after Application Staph.aur. of I00 mg./kg. p.o.

Blood Urine Nitrofurantoin 200 2-(5-Nitro-2-furyl)- 5-[2-(2-hydroxyethyl' amino)-ethoxy]- 20.1

p rimidine hydrochloride evaporated, and the residue is recrystallized from methanol/ethanol 1:1. Yield: 0.1 g., m.p. 235C. (decomposition).

EXAMPLE 2 a. 2-(2-Furyl)-5-(2-n-propylaminoethoxy)-pyrimidine 18.0 g. of 2-(2-furyl)-5-(Z-p-toluenesulfonyloxyethoxy)-pyrimidine and 41 ml. of n-propylamine are refluxed in 200 ml. of ethanol for 30 hours. Then, the mixture is concentrated, mixed with water, made alkaline with 2N NaOH; the product is extracted with ethyl acetate, the ethyl acetate solution is washed, dried, evaporated, and the residue is recrystallized from diisopropyl ether. Yield: 9.3 g., m.p. 74 C.

. b. 2-(5-Nitro-2-furyl)-5-(2-n-propylaminoethoxy)- pyrimidine Hydrochloride This compound is produced analogously to Example 1(b) from 2.47 g. of 2-(2-furyl)-5-(2-n-propylaminoethoxy)-pyrimidine. The product is recrystallized from ethanol. Yield: 1.7 g., m.p. 217 C.

EXAMPLE 3 ethoxy]-pyrimidine Hydrochloride 12.9 g. of 2-( 2-furyl)-5-[ 2-(N-acetyl-2- acetoxyethylamino)-ethoxy]-pyrimidine is dissolved in 80 ml. of acetic anhydride; at C., a mixture of 4.15 ml. of concentrated nitric acid (s.g. 1.52) and 4.15 ml. of concentratedsulfuric acid is added thereto. The reaction mixture is agitated at 0 C. for 1 hour, poured into ice water, the precipitate is filtered off and refluxed for 1 hour with 100 ml. of 5N hydrochloric acid. Thereafter, the mixture is evaporated under vacuum, and the residue is recrystallized from methanol; yield: 7.1 g., m.p. 214 C.

c. 2-(5-Nitro-2 -furyl)-5-[2-(2-hydroxyethylamino)- ethoxy]-pyrimidine Hydrochloride 0.40 of 2-(5-nitro-2- furyl)-5-(2-p-toluenesulfonyloxyethoxy)-pyrimidine and 0.24 g. of ethanolamine are stirred in 1 ml. of hexamethylphosphoric triamide for 1 hour at 60 C. The mixture is mixed with water and a small amount of 1N NaOH and extracted with ethyl acetate. The ethyl acetate solution is mixed withethanolic hydrochloric acid, evaporated, and the residue is recrystallized from methanol. Yield: 0.9 g.

EXAMPLE 4 2-(5-Nitro-2-furyl)-5[2-(N-acetyl- 2acetoxyethylamino)-ethoxy]-pyrimidine 1.25 g, of 2-(2-furyl)-5-[2-(N-acetyl-2- acetoxyethylamino)-ethoxy]-pyrimidine is dissolved in 8 ml. of acetic anhydride; under ice cooling, 0.9 ml. of concentrated sulfuric acid and 0.45 ml. of concentrated nitric acid (s.g. 1.48) is gradually added dropwise and the mixture is stirred for 1 hour under continued cooling. The reaction mixture is poured on ice, neutralized with NaOH, and the solid product is filtered off and recrystallized from ethanol. Yield: 0.9 g., m.p. 139-141 C.

EXAMPLE 5 a. 2-(2-Furyl)-5-[2-(N-acetyl-l-acetoxy- 2-n-butylamino)-ethoxy]-pyrimidine 36.0 g. of 2-(2-furyl)-5-(2-p-toluenesulfonyloxyethoxy)-pyrimidine and 44.5 g. of 2-amino-l-n-butanol are reacted analogously toExample 3(a). The uncrystallized oily crude product (60 g.) is further processed as such. b. 2-(5-Nitro-2-furyl)-5-[ 2-( l-hydroxy- 2-n-butylamino)-ethoxy]-pyrimidine Hydrochloride 49.0 g. of 2-(2-furyl)-5-[2-( l-acetoxy-N-acetyl- Z-n-butylamino)-ethoxy]-pyrimidine is reacted analogously to Example 3(b). The product is recrystallized from ethanol. Yield: 19.0 g., m.p. 147 C. c. 2-(5-Nitro-2-furyl)-5-[2-(1-hydroxy-2-nbutylamino)-ethoxy]-pyrimidine 19.0 g. of 2-(5-nitro-2-furyl)-5-[2-(1- hydroxy-2-n-butylamino)-ethoxy]-pyrimidine hydrochloride is dissolved in water; NaHCO is added thereto and the mixture is agitated for one-half hour; then, the solid product is filtered off and recrystallized from ethanol. Yield: 2.7 g., m.p. 114 C.

EXAMPLE 6 2-(5-Nitro-2-furyl)-5-[2-N-acetyl-1-acetoxy-2-nbutylamino)-ethoxy]-pyramidine 49.0 g. of 2-(2-furyl)-5-[2-(N-acetyl-.l-acetoxy- 2-n-butylamino)-ethoxy]-pyrimidine is reacted analogously to Example 4. The product is recrystallized from methanol. Yield: 21.0 g., m.p. 72 C.

EXAMPLE 7 2-(5-Nitro-2-furyl)-5-[2-(2-methoxyethylamino)- ethoxy]-pyrimidine Hydrochloride 10.0 g. of 2-(5-nitro-2-furyl)-5-(2-ptoluenesulfonyloxyethoxy)-pyrimidine is refluxed with 5.6 g. of 2-methoxyethylamine in '80 ml. of dioxanefor 5 hours, then concentrated, mixed with water, made alkaline with NaOH, and extracted with ethyl acetate. The ethyl acetate solution is dried, mixed with ethanolic HCl, concentrated by evaporation, and the residue is recrystallized from methanol. Yield: 1.8 g., m.p. 190 C.

EXAMPLE 8 2-( 5-Nitro-2-fury1)-5- 2-( 3 methoxy-n-propylamino ethoxy]-pyrimidine Hydrochloride 4.0 g. of 2-(5-nitro-2-furyl)-5-(2-ptoluenesulfonyloxyethoxy)-pyrimidine is refluxed with 2.7 g. of 3-methoxy-n-propylamine in 20 ml. of dioxane for 6 hours. The mixture is mixed with water, made alkaline with NaOH, and extracted with ethyl acetate. The ethyl acetate solution is dried, evaporated, and the residue (about 4 g.) is chromatographed on g. of silica gel with methanol/chloroform 1:1. The fractions with R; 0.37 (thin-layer chromatography on silica gel, same mobile phase system) are combined, mixed with ethanolic HCl, evaporated, and the residue is recrystallized from isopropanol. Yield: 0.3 g., m.p. 186 C.

EXAMPLE 9 a. 2-(2-Furyl)-5-[2-(N-acetyl-Z-dimethylaminoethylamino)-ethoxy]-pyrimidine 18.0 g. of 2-(2-furyl)-5-(2-p-toluenesulfonyloxyethoxy)-pyrimidine and 33.0 g. of 2-dimethylaminoethylamine are refluxed in 150 ml. of ethanol for 48 hours. The mixture is then poured into water, made alkaline, taken up in ethyl acetate, and evaporated. The residue is dissolved in 50 ml. of acetic anhydride, mixed with several drops of concentrated H SO heated for 15 minutes to 100 C., and evaporated under vacuum. The residue is recrystallized from toluene. Yield: 14.9 g., m.p. 112 C. b. 2-(5-Nitro-2-furyl)-5-[2-(2- dimethylaminoethylamino)-ethoxy]-pyrimidine Dihydrochloride 5.1 g. of 2-(2-furyl)-5-[2-N-acetyl-2-dimethylaminoethylamino)-ethoxy]-pyrimidine is nitrated and saponified analogously to Example 3(b). The product is recrystallized from methanol. Yield: 0.9 g., m.p. 2 l-2l 8 C. (decomposition).

EXAMPLE l0 2-(5-Nitro-2-furyl)-5-[2-(N-acetyl-2-dimethylaminoethylamino)-ethoxy]-pyrimidine Hydrogen Sulfate 5.9 g. of 2-(2-furyl)-5-[2-(N-acetyl-2- dimethylaminoethylamino)-ethoxy]'-pyrimidine is mixed in 40 ml. of acetic anhydride with 2.1 ml. of concentrated nitric acid (s.g. 1.48) and 2.1 ml. of concen: trated sulfuric acid at 0 C.; the mixture is agitated for 1 hour, poured into ice water, and neutralized with NaOH. The product which crystallizes upon ice cooling is filtered off and recrystallized from ethanol in the presence of 2.0 ml. of sulfuric acid. Yield: 2.6 g., m.p. 170 C. (decomposition).

EXAMPLE 1 l a. 2-(2-Furyl)-5-[2-(N-acetyl-2- diethylaminoethylamino)-ethoxy]-pyrimidine The compound is produced analogously to Example 9(a) from 3.6 g. of 2-(2-furyl)-5-(2-ptoluenesulfonyloxyethoxy)-pyrimidine and 5.8 g. of 2-diethylaminoethylamine. The uncrystallizable crude product (2.9 g.) is further processed as such. b. 2-(5-Nitro-2-furyl)-5-[2-(N-acetyl-2-diethylaminoethylamino)-ethoxy]-pyrimidine The compound is prepared analogously to Example 10 from 2.9 g. of 2-(2-furyl)-5-[2-(N-acetyl-2-diethylaminoethylamino)-ethoxy]-pyrimidine, but the crude product is recrystallized from ethanol without adding sulfuric acid. Yield: 1.9 g., m.p. l4ll43 C.

EXAMPLE 12 a. 2-(5-Nitro-2-furyl)-5-[2-(2-diethylaminoethylamino)-ethoxy]-pyrimidine Dihydrochloride 1.9 g. of 2-(5-nitro-2-furyl)-5-[2-(N-acetyl-2- diethylaminoethylamino)-ethoxy]-pyrimidine is refluxed in ml. of 5N l-lCl for l 178 hours. The reaction mixture is completely evaporated under vacuum, and the residue is recrystallized from ethanol. Yield: 0.98 g., m.p. l86187 C. b. 2-(5-Nitro-2-furyl)-5-[2-(2-diethylaminoethylamino)-ethoxy]-pyrimidine Dihydrochloride 12.2 of 2-( 5-Nitro-2-furyl)-5-(2-ptoluenesulfonyloxyethoxy)-pyrimidineand 7.0 g. of Z-diethylaminoethylamine are refluxed in 60 ml. of dioxane for 4 hours. Then, the mixture is mixed with water, taken up in ethyl acetate, and the ethyl acetate solution is dried, mixed withethanolic HCl, evaporated and the residue recrystallized from ethanol. Yield: 2.6

EXAMPLE 13 2-(5-Nitro-2-furyl)-5-[2-(tetrahydro-2- furylmethylamino)-ethoxy]-pyrimidine Hydrochloride 0.81 g. of 2-( 5-nitro-2-furyl)-5-( 2-ptoluenesulfonyloxyethoxy)-pyrimidine and 0.4 g. of tetrahydrofurfurylamine are refluxed in 20 ml. of dioxane for 4 hours. Thereafter, the reaction mixture is concentrated, taken up in water, extracted with ethyl acetate, the ethyl acetate solution is dried, mixed with ethanolic HCl, evaporated, and the residue recrystallized from ethanol. Yield: 0.30 g., m.p. 232 C.

EXAMPLE l4 2-(5-Nitro-2-furyl)-5-[2-(N-acetyl-methylamino)- ethoxy]-pyrimidine 3.5 g. of 2-(2-furyl)-5-(2-methylaminoethoxy)- pyrimidine is heated to 100 C. for one-half hour in 50 ml. of acetic anhydride; then, the mixture is cooled to 05 C. and 1.65 ml. of concentrated nitric acid (s.g. 1.52) and 1.65 ml. of concentrated sulfuric acid are I added thereto. The reaction mixture is agitated for anpyrimidine 5.4 g. of 2-(2-furyl)-5-(2-p-toluenesulfonyloxyethoxy)-pyrimidine and 15 ml. of ethylamine are refluxed in ml. of ethanol for 20 hours. Then, the mixture is concentrated, mixed with water, made alkaline ith 2N NaOl-l, the product is extracted with ethyl acetate, the ethyl acetate solution is washed, dried, and evaporated. The residue is mixed with 40 ml. of aetic anhydride and 2 drops of concentrated sulfuric acid, and then heated for 1 hour to C. The mixture is then evaporated under vacuum, the residue mixed with water, made alkaline with 2N NaOH, extracted with ethyl acetate, the ethyl acetate solution is evaporated, the residue is recrystallized from diisopropyl ether/tetrahydrofuran 2:1. Yield: 3.3 g., m.p. 133 C.

b. 2-(5-Nitro-2-furyl) 5-[Z-(N-acetyl-ethylamino)- ethoxy]-pyrimidine 3,3 g. of 2-(2-furyl)-5-[2-(N-acetyl-ethylamino)- ethoxy]-pyrimidine is dissolved in 20 ml. of acetic anhydride and, at 05 C., a mixture of 1.3 ml. of concentrated nitric acid (s.g. 1.48) and 1.3 ml. of concentrated sulfuric acid is added dropwise thereto. Then, the mixture is agitated under ice cooling for 1 hour, poured into ice water, the product extracted with ethyl acetate, and the ethyl acetate solution is washed, dried, evaporated, and the residue recrystallized from ethanol. Yield: 2.0 g., m.p. 142 C.

EXAMPLE 16 a. 2-(2-Fury1)-5-[2-(N-acetyl-n-propylamino)-ethoxy]- pyrimidine This compound is produced analogously to Example 15(a) from 10.8 g. of 2-(2-furyl)-5-(2-ptoluenesulfonyloxyethoxy)-pyrimidine and 17.7 g. of n-propylamine. The product is recrystallized from ethyl acetate/diisopropyl ether 1:2. Yield: 6.2 g., m.p. 116 C b. 2-(5-Nitro-2-furyl)-5-[2-(N-acetyl-n-propylamino)- ethoxy]-pyrimidine The compound is prepared in analogy to Example 15(b) from 6.2 g. of 2-(2-furyl)-5-(N-acetyl-npropylamino)-ethoxy]-pyrimidine. The product is recrystallized from ethanol. Yield: 2.9 g., m.p. 128 C.

EXAMPLE 17 a. 2-(2-Furyl)-5-[2-(N-acetyl-isopropylamino)- ethoxy]-pyrimidine This compound is prepared analogously to Example 15(a) from 5.4 g. of 2-(2-furyl)-5-(2-ptoluenesulfonyloxyethoxy)-pyrimidine and 4.43 g. of isopropylamine. The product is recrystallized from diisopropyl ether. Yield: 2.9 g., m.p. 100 C.

b. 2-(5-Nitro-2-furyl)-5-[2-(N-acetyl-isopropylamino)- ethoxyl-pyrimidine The compound is produced analogously to Example 15(b) from 2.9 g. of 2-(2-furyl)-5-[2-(N-acetylisopropylamino)-ethoxy]-pyrimidine. The product is recrystallized from ethanol. Yield: 2.0 g., m.p. 166 C.

EXAMPLE 18 EXAMPLE 10 a. 2-(2-Furyl)-5-[2-(N-acetyl-Z-butylamino)-ethoxy]- pyrimidine 19 This compound is prepared in analogy to Example 15(a) from 3.60 g. of 2-(2-furyl)-5,-(2-ptoluenesulfonyloxyethoxy)-pyrimidine and 3.65 g. of 2-butylamine. The product is recrystallized from toluene. Yield: 2.1 g., m.p. 100-101 C. b. 2-(5-Nitro-2 -furyl)--[2-(N-acetyl-2-butylamino)- ethoxy]-pyrimidine This compound is prepared analogously to Example 15(b) from 2.1 g. of 2-(2-furyl)-5-[2-(N-acetyl-2- butylamino)-ethoxy]-pyrimidine. The product is re crystallized from ethanol. Yield: 1.5 g., m.p. 137-l39 C.

EXAMPLE 20 a. 2-(2-Furyl)-5-[2-(N-acetyl-cyclopentylamino)- ethoxyI-pyrimidine The compound is prepared analogously to Example 15(a) from 3.6 g. of 2-(2-furyl) 5-(2-ptoluenesulfonyloxyethoxy)-pyrimidine and 4.25 g. of cyclopentylamine. The product is recrystallized from toluene. Yield: 2.73 g., m.p. ll0-1 1 1 C.

b. 2-(5-Nitro-2-furyl)-5-[Z-(N-acetylcyclopentylamino) -ethoxy]-pyrimidine The compound is prepared in analogy to Example 7 (b) from 2.45 g. of 2-(2-fury1)-5-[2-(N-acety1- 15(b) ,from 1.20 g.

cyclopentylamino)-ethoxy]-pyrimidine. The product is recrystallized from ethanol. Yield: 0.82 g., m.p. 139 C.

EXAMPLE 21 a. 2-(2-Furyl)-5-[2-(N-acetyl-cyclohexylamino)- ethoxyl-pyrimidine This compound is produced according to Example 15(a) from 3.6 g. of 2-(2-furyl)-5-(2-ptoluenesulfonyloxyethoxy)-pyrimidine and 9.9 g. of cyclohexylamine. The product is recrystallized from toluene. Yield: 2.1 g., m.p. 136137 C.

b. 2-(5-Nitro-2-furyl)-5-(N-acetyl-cyclohexylamino)- ethoxy]-pyrimidine The compound is prepared analogously to Example 15(b) from 2.05 g. of 2-(2-furyl)-5-[2-(N-acetylcyclohexylamino)- ethoxy[-pyrimidine. The product is recrystallized from ethanol. Yield: 1.25 g., m.p. 143144 C.

EXAMPLE 22 b. 2-(2-Furyl)-5-[2-(N-acetyl-2-methoxyethylamino)- ethoxyl-pyrimidine This compound is prepared analogously to Example 15(a) from 27.0 g. of 2-(2-furyl)-5-(2-ptoluenesulfonyloxyethoxy)-pyrimidine and 28.2 g. of 2-methoxyethylamine. The product is recrystallized from diisopropyl ether/tetrahydrofuran. 2:1. Yield: 15.2 g., m.p. 113 C. b. 2-(5-Nitro-2-furyl)-5-[2-(N-acetyl-2- methoxyethylamino)-ethoxy]-pyrimidine This compound is produced analogously to Example 15(b) from 15.2 g. of 2-(2-furyl)-5-[2-(N-acetyl-2- methoxyethylamino)-ethoxy]-pyrimidine. The product is recrystallized from ethanol. Yield: 8.8 g., m.p. 1 18C.

EXAMPLE 23 a. 2-(2-Furyl)-5-[2-(N-acetyl-benzylamino)-ethoxy]- pyrimidine This compound is prepared analogously to Example 15(a) from 2.52 g. of 2-(2-furyl)-5-(2-ptoluenesulfonyloxyethoxy)-pyrimidine and 3.75 g. of benzylamine. The product is further processed as the crude product. Yield: 1.30 g., m.p. 107-109 C. 2-(5-Nitro-2furyl)-5-[Z-(N-acetyl-benzylamino)- ethoxy]-pyrimidine The compound is prepared in analogy to Example of 2-(2-furyl)-5-(N-acetylbenzylamino)-ethoxy]-pyrimidine. The product is recrystallized from isopropanol. Yield: 0.36 g., m.p. 131-134 C.

EXAMPLE 24 a. 2-(2-Furyl)-5-(N-formyl-2-n-propylaminoethoxy)- pyrimidine 2.47 g. of 2-(2-furyl)-5-(2-n-propylaminoethoxy)- pyrimidine is dissolved in 20 ml. of formic acid and 6 ml. of acetic anhydride and allowed to stand overnight. The reaction mixture is completely evaporated under vacuum, and the residue is recrystallized from diisopropyl ether. Yield: 1.70 g., m.p. 98 C.

b. 2-(5-Nitro-2-furyl)-5-(N-formyl-2-n-propylaminoethoxy)-pyrimidine 0.27 g. of 2-(2-furyl)-5-(N-formyl-2-n-propylaminoethoxy)-pyrimidine is dissolved in 5 ml. of acetic anhydride, mixed at C. with 0.1 ml. of concentrated sulfuric acid and 0.1 ml. of concentrated nitric acid, agitated at this temperature for 1 hour, poured into ice water, and the solid product isrecrystallized from isopropanol.

Yield: 0.1 g., m.p. 132 C.

EXAMPLE 25 a. 2-(2-Furyl)-5-[2-(N-n-butyryl-n-propylamino)- ethoxy]-pyrimidine 1.20 g. of 2-(2-furyl)-5-(2-n-propylaminoethoxy)- pyrimidine is dissolved in 20 ml. of pyridine; 0.51 ml. of n-butyryl chloride is added and the mixture is agitated at room temperature for 1 hour, then poured into water, acidified with hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate solution is dried, concentrated, and recrystallized from ethanol.

Yield: 0.50 g., m.p. 110 C. I b. 2-(5-Nitro-2-furyl)-5-[2-(N-n-butyryl-npropylamino)-ethoxy]-pyrimidine The compound is prepared analogously to Example 24(b) from 0.3 g. of 2-(2-furyl)-5-[Z-(N-n-butyryl-npropylamino)-ethoxy]-pyrimidine. The product is recrystallized from isopropanol. Yield: 0.15 g., m.p. 90 C.

EXAMPLE 26 2-(5-Nitro-2-furyl)-5-[2-(N-acetyl-2- hydroxyethylamino)-ethoxy]-pyrimidine 3.78 g. of 2-(5-nitro-2-furyl)-5-[2-(N-acetyl-2- acetoxyethylamino)-ethoxy]-pyrimidine is agitated in 200 ml. of 1N HCl for 12 hours at 40 C.; then, the reaction mixture is completely evaporated under vacuum and the residue recrystallized from methanol. Yield: 1.1 g., m.p. 179 C.

EXAMPLE 27 2-(5-Nitro-2-furyl)-5-(2-cyclohexylaminoethoxy)- pyrimidine Hydrochloride 2.0 of 2-(5-nitro-2-furyl)-5-('2-ptoluenesulfonyloxyethoxy)-pyrimidine is agitated in ml. of hcxamethylphosphoric triumide with 1.7 g. of cyclohexylamine for 2 hours at 60 C. The reaction mixture is mixed with water, the thus-precipitated solid product is filtered off, washed with water, dissolved in ethanolic hydrochloric acid, briefly heated, evaporated to dryness, and the residue is recrystallized from methanol. Yield: 1.0 g., m.p. 250 C. (decomposition).

EXAMPLE 28 2-(5-Nitro-2-furyl)-5-(2-cyclopentylaminoethoxy)- pyrimidine Hydrochloride This compound is produced analogously to Example 27 with cyclopentylamine. Yield: 0.3 g., m.p. 238 C. (decomposition).

EXAMPLE 29 a. 2-(2-Furyl)-5-[2-(2-hydroxypropylamino)-ethoxy]- pyrimidine 18.2 g. of 2-(2-furyl)-5-(2-p-toluenesulfonyloxyethoxy)-pyrimidine is refluxed with 18.8 g. of 2- hydroxypropylamine in 200 ml. of ethanol for hours. The mixture is concentrated, mixed with .water and 1N NaOH, extracted with ethyl acetate, and the ethyl acetate solution is evaporated. The residue is recrystallized from diisopropyl ether. Yield: 9.3 g., m.p. 100 C. b. 2-(2-Furyl)-5-[2-(N-acetyl-Z-acetoxypropylamino)- ethoxy]-pyrimidine 9.3 g. of 2(2-furyl)-5-[2-(2-hydroxypropylamino)- ethoxy]-pyrimidine is dissolved in 100 ml. of acetic anhydride and mixed with 1 drop of concentrated sulfuric acid. The mixture is allowed to stand for 12 hours at room temperature and then heated for 1 hour on a steam bath, whereafter it is concentrated, and the product is purified by chromatographing on 300 g. of silica gel in methylene chloride/acetone 1:1 and then recrystallized from ethyl acetate. Yield: 6.7 g., m.p. 121 C.

c. 2-(5-Nitro-2-furyl)-5-[2-(N-acetyl-2 acetoxypropylamino)-ethoxy]-pyrimidine 5.8 g. of 2-(2-furyl)-5-[2-(N-acetyl-2- acetoxypropylamino)-ethoxy]-pyrimidine is dissolved in 80 ml. of acetic anhydride and mixed, at 0 C., with 2.6 g. of concentrated nitric acid (s.g. 1.52) and 1.75 ml. of concentrated sulfuric acid. The mixture is agitated for 1 hour at 0 C., poured into ice water, brought to a pH of 4.5- with NaOH, and the thus-precipitated material is filtered off and recrystallized from ethanol. Yield: 3.9 g., m.p. 123 C.

EXAMPLE 30 2-(5-Nitr0-2-furyl)-5-[2-(2-hydroxypropylamino)- ethoxy]-pyrimidine Hydrochloride 1.96 g. of 2-(5-nitro-2-furyl)-5-[2-(N-acetyl-2- acetoxypropylamino)-ethoxy]-pyrimidine is refluxed in 20 ml. of 5N HCl for 1 hour. The mixture is completely evaporated, and the residue is recrystallized from methanol. Yield: 1.3 g., m.p. 208 C.

EXAMPLE 31 a. 2-(2-Furyl)-5-[2-(2,3-dihydroxypropylamino)- ethoxy]-pyrimidine 51.0 g. of 2-(2-furyl)-5-(2-p-toluenesulfonyloxyethoxy)-pyrimidine is refluxed with 77.9 g. of l-amino- 2,3-propanediol in 500 ml. of ethanol for 7 hours. The mixture is concentrated, mixed with water and NaOH, and extracted with ethyl acetate. The ethyl acetate solution is evaporated and the residue chromatographed on 300 g. of silica gel with methanol/chloroform 1:1 and thereafter recrystallized from ethyl acetate. Yield: 6.8 g., m.p. 94 C. b. 2-(2-Furyl)-5-[2-(N-acetyl-2,3- diacetoxypropylamino)-ethoxy]-pyrimidine 6 g. of 2-(2-furyl)-5-[2-(2,3-dihydroxypropylamino)-ethoxy]-pyrimidine is heated on a steam bath for 2 hours in 120 ml. of acetic anhydride in the presence of 1 drop of concentrated H SO Then, the mixture is completely evaporated, and the residue is chromatographed on 250 g. of silica gel with methanol/chloroform 1:2, and the product is thereafter recrystallized from methanol. Yield: 3.9 g., m.p. 108 C. c. 2-(5-Nitro-2-furyl)-5-[2-(N-acetyl-2,3- diacetoxypropylamino)-ethoxy]-pyrimidine 1. v g. of 2-(2-furyl)-5-[2-(N-acetyl-2,3- diacetoxypropylamino)-ethoxy]-pyrimidine is dissolved in 20 ml. of acetic anhydride and, at 0 C., a mixture of 0.41 ml. of concentrated HNO (s.g. 1.52) and 0.41 ml. of concentrated H is added dropwise thereto. The mixture is agitated at 0 C. for 1 hour,

EXAMPLE 32 2-(5-Nitro-2-furyl)-5-[2-(2,3-dihydroxypropylamino)- ethoxy.]-pyrimidine Hydrochloride 1.8 g. of 2-(5-nitro-2-furyl)-5-[2-(N-acetyl-2,3- diacctoxypropylamino)-cthoxyl-pyrimidine is refluxed in 20 ml. of 2N HCI for 1 hour. The mixture is evaporated to dryness and the residue recrystallized from ethanol. Yield: 1.1 g., m.p. 192 C.

The preceding examples can be repeated with similar success by substituting the generically and specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.

From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.

What is claimed is:

l. A compound of the formula wherein R is alkyl of 1 -6 carbon atoms, cycloalkyl of 3-7 carbon atoms, alkyl of 1-6 carbon atoms wherein 1-2 carbon atoms thereof are substituted by hydroxy or by alkanoyloxy of l-6 carbon atoms or 1 carbon atom thereof is substituted by alkoxy of l-6 carbon atoms or by dialkylamino wherein each alkyl group contains 1-6 carbon atoms or by tetrahydrofuryl or phenyl, and R is alkanoyl of l-6 carbon atoms and the physiologically acceptable acid addition salts thereof.

2. A compound of claim 1, 2-(5-nitro-2-furyl)-5-[2- (N-acetyl-2-acetoxyethylamino)-ethoxy]-pyrimidine.

3. A compound of claim 1, 2-(5-nitro-2-furyl)-5-[2- -acetyll acemy: ir butyi am'm'a enian 7 pyrimidine.

4. A compound of claim 1, 2-(5-nitro-2-furyl)=5-[2- (N-acetyl-2-dimethylaminoethyl-amino )-ethoxy pyrimidine hydrogen sulfate.

5. A compound of claim 1, 2-(5-nitro-2-furyl)-5-[2- (N-acetyl-Z-diethylaminoethylamino)-ethoxy]- pyrimidine.

6. A compound of claim 1, 2-(5-nitro-2-furyl)-5-[2- (N-acetyl-methylamino)-ethoxy]-pyrirnidine.

7. A compound of claim 1, 2-(5-nitro-2-furyl)-5-[2- (N-acetyl-ethylamino)-ethoxy]-pyrimidine.

8. A compound of claim 1, 2-(5-nitro-2-furyl) -[2- (N-acetyl-n-propylamino)-ethoxy]-pyrimidine.

9. A compound of claim 1, 2-(5-nitro-2-furyl)-5-[2- (N-acetyl-isopropylamino)-ethoxy]-pyrimidine.

10. A compound of claim 1, 2-(5-nitro-2-furyl)-5 [2- (N-acetyl-n-butylamino)-ethoxy]-pyrimidine.

11. A compound of claim 1, 2-(5-nitro-2-furyl)-5-[2- (N-acetyl-Z-butylamino)-ethoxyl-pyrimidine.

12. A compound of claim 1, 2-(5-nitro-2-furyl)-5-[2- (N-acetyl-cyclopentylamino)-ethoxy]-pyrimidine.

13. A compound of claim 1, 2-(5-nitro-2-furyl)-5-[2- (N-acetyl-cyclohexylamino )-ethoxy]-pyrimidine.

14. A compound of claim 1, 2-(5-nitro-2-furyl)-5-[2- (N-acetyl-2-methoxyethylamino)-ethoxy]-pyrimidine.

15. A compound of claim 1, 2-(5-nitro-2-furyl)-5-[2- (N-acetyl-benzylamino)-ethoxy]-pyrimidine.

16. A compound of claim 1, 2-(5-nitro-2-furyl)-5-(nformyl-2-n-propylaminoethoxy)-pyrimidine.

17. A compound of claim 1, 2-(5-nitro-2-furyl)-5-[2- (N-n-butyrl-n-ropylamino)-ethoxy]-pyrimidine.

18. A compound of claim 1, 2-(5-nitro-2-furyl)-5-[2- (N-acetyl-2-hydroxy-ethylamino)-ethoxy]-pyrimidine.

19. A compound of claim 21, 2-(5-nitro-2-furyl)-5- [2-(N-acetyl-2-acetoxy-propylamino)-ethoxyl-pyrimidine.

20. A compound of claim 1, 2-(5-nitro-2-furyl)-5-[2- (N-acetyl-2,3-diacetoxy-propylamino)-ethoxy]- pyrimidine.

21. A compound of the formula wherein R is cycloalkyl of 3-7 carbon atoms and the physiologically acceptable acid addition salts thereof.

22. A compound of claim 21, 2-(5-nitro-2-furyI)-5- (2-cyclohexylaminoethoxy)-pyrimidine hydrochloride.

23. A compound of claim 21, 2-(5-nitro-2-furyl)-5- (2-cyclopentylaminoethoxy)-pyrimidine hydrochloride.

24. A compound of the formula wherein R is alkyl of 1-6 carbon atoms substituted by tetrahydrofuryl and the physiologically acceptable acid addition salts thereof.

28. A compound of claim 27, 2-(5-nitro-2-furyll-5- :[2 (tetrahydro 2- furylmethylamino) -ethoxy]-pyrimidis? hy o hl

Claims

1. A COMPOUND OF THE FORMULA

2. A compound of claim 1, 2-(5-nitro-2-furyl)-5-(2-(N-acetyl-2-acetoxyethylamino)-ethoxy)-pyrimidine.

3. A compound of claim 1, 2-(5-nitro-2-furyL)-5-(2-(N-acetyl-1-acetoxy-2-n-butyl-amino)-ethoxy) -pyrimidine.

4. A compound of claim 1, 2-(5-nitro-2-furyl)-5-(2-(N-acetyl-2-dimethylaminoethyl-amino)-ethoxy) -pyrimidine hydrogen sulfate.

5. A compound of claim 1, 2-(5-nitro-2-furyl)-5-(2-(N-acetyl-2-diethylaminoethylamino)-ethoxy) -pyrimidine.

6. A compound of claim 1, 2-(5-nitro-2-furyl)-5-(2-(N-acetyl-methylamino)-ethoxy)-pyrimidine.

7. A compound of claim 1, 2-(5-nitro-2-furyl)-5-(2-(N-acetyl-ethylamino)-ethoxy)-pyrimidine.

8. A compound of claim 1, 2-(5-nitro-2-furyl)-5-(2-(N-acetyl-n-propylamino)-ethoxy)-pyrimidine.

9. A compound of claim 1, 2-(5-nitro-2-furyl)-5-(2-(N-acetyl-isopropylamino)-ethoxy)-pyrimidine.

10. A compound of claim 1, 2-(5-nitro-2-furyl)-5-(2-(N-acetyl-n-butylamino)-ethoxy)-pyrimidine.

11. A compound of claim 1, 2-(5-nitro-2-furyl)-5-(2-(N-acetyl-2-butylamino)-ethoxy)-pyrimidine.

12. A compound of claim 1, 2-(5-nitro-2-furyl)-5-(2-(N-acetyl-cyclopentylamino)-ethoxy)-pyrimidine.

13. A compound of claim 1, 2-(5-nitro-2-furyl)-5-(2-(N-acetyl-cyclohexylamino )-ethoxy)-pyrimidine.

14. A compound of claim 1, 2-(5-nitro-2-furyl)-5-(2-(N-acetyl-2-methoxyethylamino)-ethoxy)-pyrimidine.

15. A compound of claim 1, 2-(5-nitro-2-furyl)-5-(2-(N-acetyl-benzylamino)-ethoxy)-pyrimidine.

16. A compound of claim 1, 2-(5-nitro-2-furyl)-5-(n-formyl-2-n-propylaminoethoxy)-pyrimidine.

17. A compound of claim 1, 2-(5-nitro-2-furyl)-5-(2-(N-n-butyrl-n-ropylamino)-ethoxy)-pyrimidine.

18. A compound of claim 1, 2-(5-nitro-2-furyl)-5-(2-(N-acetyl-2-hydroxy-ethylamino)-ethoxy)-pyrimidine.

19. A compound of claim 11, 2-(5-nitro-2-furyl)-5-(2-(N-acetyl-2-acetoxy-propylamino)-ethoxy) -pyrimidine.

20. A compound of claim 1, 2-(5-nitro-2-furyl)-5-(2-(N-acetyl-2, 3-diacetoxy-propylamino)-ethoxy)-pyrimidine.

21. A compound of the formula

22. A compound of claim 21, 2-(5-nitro-2-furyl)-5-(2-cyclohexylaminoethoxy)-pyrimidine hydrochloride.

23. A compound of claim 21, 2-(5-nitro-2-furyl)-5-(2-cyclopentylaminoethoxy)-pyrimidine hydrochloride.

24. A compound of the formula

25. A compound of claim 24, 2-(5-nitro-2-furyl)-5-(2-(2-dimethylaminoethylamino)-ethoxy)-pyrimidine dihydrochloride.

26. A compound of claim 24, 2-(5-nitro-2-furyl)-5-(2-(2-diethylaminoethylamino)-ethoxy)-pyrimidine dihydrochloride.

27. A compound of the formula

28. A compound of claim 27, 2-(5-nitro-2-furyl)-5-(2-(tetrahydro-2-furylmethylamino)-ethoxy)-pyrimidine hydrochloride.