GB2048250A - 2-amino-6-aryl-4-pyrimidinols and their pharmaceutical uses - Google Patents

Abstract

Compounds of the formula <IMAGE> wherein X3 is halogen, mono-, di- or tri-halomethyl, mono-, di- or tri- fluoroethyl, perfluoropropyl, C1-3 alkyl, 2-propenyl or 2-propynyl; and X1 is phenyl; o-substituted phenyl in which the substituent is C1-8 alkyl, C1-8 alkoxy, halogen or nitro; m- substituted phenyl in which the substituent is halogen, nitro, CF3, C1-8 alkoxy, (C1-5 alkoxy)ethoxy or NR5R6 in which either R5 and R6 are the same or different and are each C1-8 alkyl or benzyl or NR5R6 is a C3-6 saturated heterocyclic ring optionally substituted by two C1-3 alkyl groups; p-substituted phenyl in which the substituent is halogen or C1-3 alkyl; disubstituted phenyl in which the substituents are independently selected from halogen, C1-8 alkyl, C1-8 alkoxy, nitro and CF3; trihalophenyl; optionally substituted ???-naphthyl in which any substituent is C1-8 alkyl, C1-8 alkoxy, halogen or nitro; 2-furyl; 2-pyridyl; 3-pyridyl or 2-pyrazyl; many of which are novel, have been found or are believed to have pharmaceutical utility which can include the induction of interferon production, the prevention of skin graft rejection or the treatment or prevention of virus infections, acquired or congenital hypergammaglobulinemia, cancer, bacterial infections, parasitic infections or aplastic anaemia.

Description

SPECIFICATION 6-Arylpyrimldines and their pharmaceutical uses This invention relates to 2-amino-5.6-disubstituted -4-pyrimidinols of formula V

wherein X1 is aryl.

U.S. Patent Specification No. 3,956.302 and Nicols et a/, Antimicrobial Agents Chemother. 9 (1978) 433, disclose 2-amlno-5-halo-8-alkyl-4-pyrimldlnois as antiviral agents. 2-Amino-5-bromo-6phenyl-4-pyrimidinol (V, X3 = Br and X1 = phenyl) has been reported by Brown and Stevens, JCS Perkin 1(1975) 1023, but no utility has been described for this material. British Patent Specification No.

1,223,686 discloses a variety of 5,6-dlsubstituated 2-amino-4-pyrimidinols, such as 2-dimethylamino5-bromo-8-methyl-4-pyrimidlnol, as fungicidal agents. -Unsubstituted -2-amino-6-arylpyrimidinols have been disclosed by Shirahawa, Yakuyaku Fasshi 50(1960)1562 and CA 55, 10651 b: Kalkarui et el. J. Sci. and Ind. Res. Indil. 19C (1960) 6; and U.S. Patent Specification No. 2,776,283. Diuretic and cardioregulatory properties are described for various 2-amino and 2-substituted-amino-5-aminomethyl and 5-anyl-6-aryl-4-pyrimidlnols in lJ.S. Patent Specifications Nos. 2,704,285; 2,723,977 and 2.776,283.

The compound 2-amlno-5-bromo-8-methyl-4-pyrlmidinol disclosed in U.S. Patent Specification No. 3,956,302 exhibits useful antlvlral and irterferon inducing properties. However, we have found that its therapeutic appilcation is limited to moderate doses since the material may crystallise in the urine and kidney of animals receiving large doses.

The compounds of the present invention are of formula V wherein X3 is halogen, mono-, di- or trihelomethyl, mono-, di- or tri-fluoroethyl, perfloropropyl, C1-3 alkyl, 2-propenyl or 2-propynyl ; and X1 is phenyl; o-substituted phenyl in which the substituent is C1-8 alkyl.C1-3 alkoxy, halogen or nitro; m-substituted phenyl in which the substituent is halogen. nitro, CF3, C1-B alkoxy (C1-5 alkoxy)ethoxy or NR6R3 in which either F and R3 are the same or different and are each C1-3 alkyl or benzyl or NR8R6 is a C3-8 saturated heterocyclic ring optionally substituted by two C1-8 alkyl groups; psubstituted phenyl n which the substltuent : is halogen or C1-3 alkyl; disubstituted phenyl in which the substituents are independenfly selected frcm halogen, C1-3 alkyl, C1-8 alkoxy, nitro and CF3; trihalophenyl; optionally substituted &alpha;-naphthyl in which any substituent is C1-8 alkyl, Cats alkoxy, halogen or nitro; 2-furyl: 2-pyrldyl ; 3-pyridyl or 2-pyrazyl; and include the salts thereof.

The compounds of the invention can I-ta'-' pharmaceutical and particularly antiviral activity, with or without the property of Inducing interferon production The compounds of the invention can exist in various tautomerla forms but for convenience, are represented in the manner shown by formula V. They carl be named 2-amino-6-aryl-5-substituted-4pyrimldinols or as isocytosines.For example, 2-amino-5-bromo-6-m-fluorophenyl-4-pyrlmidinol can aiso be named 5-bromo-8-m-fluorophenyilsocytosine The compounds of formula V in which X is halogen may be prepared by reacting a compound of formuls lli X1OC-CH2-COO2 lli wherein X1 is as defined above and Z is C1-5 alkyl or SiR10R11R12 in which R10 R11 and R12 are independently selected from C1-6 alkyl and phenyl, with guanldlne to obrsin a 5-unsubstitutedpyrimidinol corresponding to the desireu pradout, and halogenatlng the 5-unsubstituted compound, The ccmpounds of formula V in which X3 is other than halogen may be prepared by reacting a compound or formula llii X.OC-CHX-COOZ lili wherein X, and Z are as defined above and X's X, as defined above but is not halogen, wlth guanidine.

The. corpounds of formula Ili ana i:!i miv b?. be prepared by a reaction sequence which will be describes as .~ou.- steps, for clarity, alth@@@ '- ms athemist's point-of-view the reaction is "one-step" in that the saquence can he conducted i? a single re, -ion vesse; without the need for separation and ourlfication aiter eachs step.

In step 1, a monoalkyl malonate, preferably monoethyl malonate, of formula 1 a HOOC-CH2-COOZ wherein Z is as defined above, is treated in a dry solvent with two equivalents of lithium base at O to -800C to form a compound of formula Ib LIO0C-CHLi-COOZ Suitable dry solvents include tetrahydrofuran, diglyme, glyme, dioxane, hexamethylphosphoric triamide and dimethylformamide. Examples of lithium bases are compounds of the formula R8Li wherein R8 is n-butyl, methyl, phenyl, t-butyl, s-butyl or LiN(Rg)2 wherein the Rg's are isopropyl, cyclohexyl or trimethylsilyl, or a combination thereof. n-Butyllithium is preferred. A starting temperature of about -700C is preferred.

In step 2,following the addition of the lithium base, with a concomitant rise in temperature, the reaction mixture is recooled to about -650C whereupon an acid halide of the formula X1COhal, X1 being as defined above, is added. The acid halide can be added either neat or diluted with dry solvent.

Dropwise addition of acid halide in dry solvent at about -650C is preferred.

The optimum ratio of malonate to acid halide is 1.7:1 (or greater) for highest yields. This acylation yields a compound of formula Ic LiOOC-CH(COX1)-COOZ Ic and decarboxylation (step 3) affords Id X1OC-CHLi-CO0Z Id The decarboxylation is hastened by allowing the reaction temperature to warm slowly to room temperature.

Step 4, a work-up procedure, may simply involve quenching the reaction at the appropriate time with dilute acid followed by extraction with ether. The organic phase is washed with bicarbonate, dried, and concentrated to yield the desired ,d-ketoesterofformula Ili.

Alternatively, to obtain a compound of formula llii, at least one equivalent a chloride or, preferably, bromide or iodide of X is added at room temperature and the reaction mixture allowed to stand until the alkylation is complete. If desired, the mixture may be warmed to hasten the alkylation. The mixture is then quenched with dilute acid, extracted with ether and the ether phase washed and concentrated, as described above. If desired, ilii may be further purified by conventional methods such a chromatography and distillation.

The following Examples 1 to 10 illustrate the preparation of formula Il compounds.

EXAMPLE 1 Ethylisobutyryl Acetate To a 1 liter, 3-necked round--bottom flask, fitted with a nitrogen inlet thermometer, and an overhead stirrer is added 19.8 g. (147 mM) of monoethyl malonate, 350 ml. of dried THF and 2 mg. of bipyridyl. The solution is cooled to 70CC. and a 1.6 M solution of n-butyllithium in hexane (Foote Chemicals Co. or Aldrich Chemical Co.) is added, dropwise at -700C to -50C. until a pink color persisted. The temperature is allowed to slowly rise to C., throughout the butyllithium addition, during which time the pink color formed will dissipate.After the pink color remains for five minutes at 5 (approx. 210 ml. of butyllithium has been added), the mixture is cooled to -650C. and 7.9 ml.

(7.98 g. 75 mM) of isobutyryl chloride is added dropwise at -600C. to --65"C. The solution is stirred vigorously at -600C. to -650C., for 5 minutes and poured into 500 ml. of ether + 300 mi. of ice-cold 1 N hydrochloric acid. After shaking, the layers are separated and the organic layer is washed 2 x 150 ml. saturated aqueous sodium bicarbonate 1 x 150 ml. water and dried over sodium sulfate (anhyd.).

The ethereal solution is filtered, the solids washed with ether and the combined filtrates evaporated to dryness to yield 11.7 g. (98.4%) of ethylisobutyryl acetate, m.w. 158.19.

GLPC R.T. = 3.2 min (T = 90 , 3', 3% OV 17) GC/MS M+ m/e 159 (27%), 1 16 (100%).

EXAMPLE 2 Ethyl-n-butyryl Acetate Following the procedure for the preparation of ethylisobutyryl acetate but substituting 7.98 g. (75 mM) of n-butyryl chloride in 50 ml. of dried THF for the 7.9 ml. of isobutyryl chloride, 1 1.4 g. (96.6%) of ethyl n-butyryl acetate is isolated, m.w. 158.19.

GLPC R.T. = 3.1 min (T= 90 ,3', 3% OV 17) EXAMPLE 3 Ethylpropionyl Acetate Following the procedure for the preparation of ethylisobutyryl acetate but substituting 71. g. of monoethylmalonate (0.61 3M), 1300 ml. of THF and 28.1 g. of propionyl chloride (0.305 M) in 300 ml.

THF (added dropwise) to yield 42.0 g. (95.2%) of ethylpropionyl acetate as an oil, m.w. 144.17.

GLPC R.T. = 5.6 min (900, 6', 3% OV 17) GC/MS M+ m/e (76,5%), 115(100%) EXAMPLE 4 Ethylphenylacetyl Acetate Following the procedure for the preparation of ethylisobutyryl acetate but substituting 10.0 ml.

(11.69 g. 75 mM) of phenylacetylchloride (Aldrich Chem. Co.) for the 7.9 ml. of isobutyryl chloride gave 1 5.4 9. (98.9%) of ethyl phenylacetyl acetate, m.w. 206.23.

NMR (CDCI3):ô 7.38-7.13 (m, 5H, Ar), 4.31-3.85 (q, 2H, OCH2), 3.78 (s, 2H. CH2),

EXAMPLE 5 Ethylbenzoyl Acetate Following the procedure for the preparation of ethyl-isobutyryl acetate but substituting 6.06 g. of monoethylmalonate (45 mM), 250 ml. THF and 2.64 ml. of benzoylchloride (3.15 g. # 2.55 mM) and stirring the reaction mixture at-86 for 60 minutes gave 4.18 g. (97%) of ethylbenzoyl acetate as an oil, m.w. 192.21. This material was isolated as a mixture of tautomers (H'-NMR).

GLPC R.T. = 3.1 min (850, 60.cm, UCW-98-2) GC/MS M+ m/e 192 (6.8%), 105 (100%).

EXAMPLE 6 Ethyltoluoyl Acetate Following the procedure for the preparation of ethylbenzoyl acetate but substituting 1 5.5 g. of monoethylmalonate (11 5 mM), 500 ml. THF and 11.1 g. (71.8 mM) of toluoyl chloride gave 13.44 g.

(90.8%) of ethyl toluoyl acetate as an oil. H'-NMR indicates the desired product is a mixture of tautomers, m.w. 206.23.

NMR (CDCI3):S 8.05-7.61 (m, 2H, 2,6-ArH), 7.41-7.13 (m, 2H, 3,5-ArH) 5.63

EXAMPLE 7 Ethylanisoyl Acetate Following the procedure for the preparation of ethylbenzoyl acetate but substituting 16.5 g. of monoethyl malonate (11 5 mM), 400 ml. of THF and 12.24 g. (71.8 mM) of anisoyl chloride gave 14.45 9. (90.3%) of ethylanisoyl acetate as an oil, m.w. 222.23.

NMR(CDCl3) : # 8.03-7.86 (m, 2H, 2,6-ArH), 7.08-6.86 (m, 2H, 3,5-ArH), 4.38-3.85 (m, 7H, OCH3, COCH2CO, OCH,CH,), 1.36--1.13 (t, 3H, CH2CH30.

EXAMPLE 8 Ethyl-p-Chlorobenzoyl Acetate Following the procedure for the preparation of ethylbenzoyl acetate but substituting 1 5.5 g. of monoethylmalonate (115 mM), 400 ml. THF and 12.5 g. (71.5 mM) of p-chiorbenzoyl chloride gave 15.56 g. (95.6%) of ethyl p-chlorobenzoyl acetate as a solid. Recrystallization of an analytical sample from methanol gave solid ethyl-p-chlorobenzoyl acetate as a mixture of tautomers, m.w. 226.65.

3.9 (s, 1,36H, COCH2CO). 1.43-1 1(m. 3H, CH2CH3).

Analysis: Calc'd. for C11H11ClO3 ; C, 58.28; H, 4.89: Cl, 15.64.

Found: C, 58.34; H, 5.13; Cl,15.32 EXAMPLE 9 Ethyl 3,4-Dichlorobenzoyl Acetate Following the procedure for the preparation of ethylbenzoyl acetate but substituting 15.5 9.

(115 mM) of monoethylmalonate, 400 ml. of THF, and 12.0 9. (57.5 mM) 3,4-dichlorobenzoyl chloride gave 14.56 g. (97%) of ethyl 3.4-dichlorobenzoyl acetate. This material slowly crystallized on standing at-12 C and was isolated as 3 mixture of tautomers, m.w. 261.1.

3.93 (s, 1.42H, COCH2CO), 1.46-1.13 (m, 3H, CH2CH3).

Analysis : Calc'd. for C11H10Cl2O3 : C, 50.59; H. 3.86.

Found: C, 50.21. H, 4.79.

EXAMPLE 10 Ethyl-iu-ethyl-benzoylacetate To 13.2 g. of monoethylmalonate was added 300 ml. THF and 5 mg. of bipyridyl. Butyl lithium was added at-70 C. to -1 00C. until a pink color persisted. The reaction mixture was recooled to -70 C. and 6.4 ml. of benzoyl chloride (0.06 M) was added. After stirring at-60 C. for 60 minutes, 28.2 g. (0.182 M) of ethyl idodide was added and the reaction mixture allowed to stir, at ambient temperature, for 18 hours. The mixture was then warmed to 50 C. and kept at 500C. for 90 hours. At this time the entire mixture was poured into 500 ml. diethyl ether + 300 ml. 1 N hydrochloric acid, the layers separated, and the organic layer washed one time 1 N hydrochloric acid, once in saturated aqueous sodium bicarbonate and once with water.Drying over sodium sulfate (anhyd.), filtering and evaporating yielded 13.8 g. of ethyl cz-ethyl-benzoyl-acetate as an oil.

NMR : 8.11-7.91 (m, 2H, #), 7.66-7.30 (m, 3H #], 4.36-3.96 (m, 3H, COCHCO, OCH2CH3), 2.30-1.80 (m, 2H, CH2CH3), 1.43-0.76 (m, 6H, CH3), The condensation of the appropriate ss-ketoester Ilii with guanidine can be carried out in a polar solvent such as ethanol, isopropanol, 1 -butanol or dimethylformamide (ethanol is preferred) in the presence of a base such as a carbonate (for example, sodium carbonate or guanidium carbonate itself) or an alkoxide (such as sodium ethoxide) under reflux in conventional manner.The product V (wherein X3 is not halogen) is isolated by neutralisation with acid or carbon dioxide of the reaction mixture when condensation is complete, as determined by TLC, and filtration or chromatography in conventional manner.

The preparation cf V (wherein X3 is halogen) is carried out from an appropriate ss-letoester Ili and guanidine as described above to yield the 5-unsubstituted compound in a manner parallel to that described above. Subsequent halogenatlon is achieved, for example, by treatment with Nchlorosuccinlmide in acetic acid to yield V wherein X3 = Cl, by treatment with bromine in acetic acid to yield V wherein X3 = Br, or for example by treatment with an equivalent of 1 N sodium hydroxide followed by iodine in chloroform to yield V wherein X3 = l. Alternative methods of halogenation are illustrated in the following Example.The final pyramidines can be isolated by concentration in vacuo and aqueous trituration of the residue followed by filtration of the resultant solid.

EXAMPLE 11 The compounds prepared and procedure used in each specific case are shown in Table I.

Procedure 1 Condansation to V(X3 = X) or 5-unsubstituted precursor Te 20 mM of powdered guanidine carbonate were added, under nitrogen, 120 m! of absolute ethanol and 20 ml of toluene. The reaction mixture was heated to reflux and 50 ml of solvent was distilled off. The mixture was cooled to 450C and 40mM of of ss-ketoester (Ili or llii) added. This mixture was heated to refiux, with stirring, until the reaction appeared complete by TLC. Water (50 ml) was added and the refluxing continued for an additional 30 minutes at which time the reaction mixture was cooled to 200C and neutralised by addition of dry carbon dioxide or 1 N aqueous hydrochloric acid.The mixture was allowed to cool at 6 C for 18 hours, filtered and the resulting precipitate washed well with water followed by diethyl ether. The solids were dried at 600C under vacuum to yield the desired pyrimidine as a white solid. If the crude solids were not analytically pure they could be recrystallised from appropriate solvents, such as aqueous DMF or aqueous ethanol.

Procedure 2 Condensation The reaction was carried out exactly as described in Procedure 1, except, after neutralization addition oi carbon dioxide or 1 N hydrochloric acid! the aqueous mixture was evaporated to dryness under vacuum and 100 ml. of water and 100 ml. ethyl ehter were added. The mlxture was shaken and ellowed to sit ct 5 C. for 1 8 hours. The mixture was filtered and solids washed weii with water followed cv ethyl ether. Drying and crystallization as described in Procedure 1 gave analytically pure pyrimidine.

vocedure 3 Bromination (wherein X3=Br) lo 1E mM of the appropriate pyrimidine was added 80 ml. of glacial acetic acid. The reaction ni'A".dre was into med to 500C to affect solution tif solids were in solution at 22 C., then it was not @@assary to warml and 0.81 ml. of Br2 was added. The solution was allowed to stir at ambient temperature f'."- hours The reaction was evaporated to dryness, under vacuum, and, to the resulting sollds was @dded 150 ml. of hot water. The slotry wasteated to relfoux and allowed to cool to 22 C. The so! ds were @@@@ and washed well with water. The solids were pulverized and reheated with 150 ml.

Of water as described previously. This procedure was repeated. The pyrimidine was dried in a vacuum oven at ' C-.. n active analytically pure materlal. If deslred. it ca be recrystallized from watom DMF by addine DMF slow'y to a stirring slurry of compound in 150 ml. of boiling water until stlution occurs.

Cooling and filteringyielded analytically poure material, Procedure 4 Bromination (wherein X2 = Br) To 15 mM of the appropriate pyrimidine was added 50 ml. of water and 0.66 g. of NaOH (16.5 mM). The solution was allowed to stir at ambient temperature for 30 minutes and 0.9 ml. of Br2 (22.62 g.

16.5 mM) in 50 ml. of chloroform was added. The reaction mixture was stirred, vigorously, for 2 hours and filtered. Solids were washed well with water, followed by water and dried at 600C. in a vacuum oven for 1 8 hours. Recrystallisation from water:DMF as per Procedure 3 gave analytically pure material.

Procedure 5 lodination (wherein X2 = 1) To 1 5 mM of the appropriate pyrimidine was added 50 ml. of water and 0.80 g. (20 mM) of sodium hydroxide. The mixture was stirred and heated to 500C. until solution occurred. A slurry of 3.79 g. of powdered 12 (15 mM) in 100 ml. of chloroform was added. The excess 12 was washed into the reaction vessel with an additional 30 ml. of chloroform. The mixture was allowed to stir, vigorously, at ambient temperature for four hours.

The solids were filtered, washed well with water (until water was neutral to pH paper) followed by either acetone or ethyl acetate until the organic wash was colorless. It is often desirable to pulverize the solids before washing. The solids were dried at 600 C. in a vacuum oven. If material is not analytically pure it may be recrystallized from water:DMF by adding DMF slowly to a vigorously stirring slurry of the pyrimidine in 1 50 ml. of boiling water until solution occurs. Cooling, filtering and drying at 600 C. gives analytically pure material.

Procedure 6 lodination (X2 = I) To 1.95 mM of the appropriate pyrimidine was added 25.0 ml. of glacial acetic acid and 434 mg.

(2 mM) of N-iodosuccinimide. The reaction mixture was allowed to stir at ambient temperature for 5 days. The mixture was allowed to stir at ambient temperature for 5 days. The mixture was evaporated to dryness under vacuum at 500C. The solids were purified by heating with 50 ml. of absolute ethanol at reflux and cooling to room temperature. Filtering and washing with absolute ethanol gave the pure 5iodo-pyrimidine.

Procedure 7 Chlorination (X3 = Cl) To 0.1 M of a 6-arylpyrimidine was added 500 ml. of glacial acetic acid and 14.6 g. of Nchlorosuccinimide (0.1 1 M). The reaction mixture was heated on a steam bath for 1 1/2 hours. The reaction mixture was cooled to 220C., evaporated to a volume of 200 ml. and filtered. The solids thus obtained were washed with glacial acetic acid followed by ethyl ether and dried at 600C. in a vacuum oven. If the solids are not analytically pure, they can be recrystallized from water:DMF by adding DMF to a boiling slurry of the pyrimidine in 500 ml. water until solution occurred. Cooling and filtering gives an analytically pure 5-chloro-6-arylpyrimidine.

Procedure 8 Fluorination (X3 = F) The introduction of fluorine into the 5-position of the pyrimidine ring is effected by fluorination of IV with trifluoromethylhypofluorite followed by base according to the procedure of M. J. Robbins and S.

R. Naik, J. Am. Chem. Soc. 93, 5277 (1971). Alternatively, if desired, IV may be fluorinated directly with fluorine-pyridine complex to product V where X3 = F by the procedure described by H. Meinert and D.

Cech, Z. Chem. 12, 292 (1972).

Procedure 9 Preparation of V (X3 = CF2) Preparation of V wherein X3 = CF3 may be achieved starting with V wherein X3 = I by the exchange procedures described by D. Cech, R. Wohifeil and G. Efzold, Nucleic Acids Research 2, 2183 (1975) and by Y. Kobayashi, I. Kumadaki and F. Yamamato J.C.S. Chem. Comm. 535 (1977) using trifluoromethyliodide and copper-bronze. In like manner, 5-perfluoroalkylpyrimidines (V, X3 = perfluoroalkyl) may be prepared using perfluoroalkyl iodides.

Alternatively, if desired, the trifluoromethyl or perfluoroalkyl group can be introduced earlier at the XB-ketoester stage and the resulting trifiuoromethyl or perfluoroalkyl /3-ketoester condensed with guanidine as in Procedures 1 or 2 to produce V (X3 = CF3 or perfluoroalkyl). Preparation of a trifluoromethyi or perfluoromethyl, 'S-ketoester may be achieved by methods known in the art.For example, condensation of

andCH2=CF2 in the presence of SbF5 affords

and carboalkoxylation under standard conditions yields

Procedure 10 Preparation of V (X3 = CH2-X4) Preparation of V wherein X3 = CH2X4 can be accomplished under standard conditions known in the art from the corresponding hydroxymethyl (V, wherein X3 = CH2OH) intermediates.These intermediates can be prepared under standard conditions from IV and formaldehyde or alternatively from a suitable protected p-ketoester, for example ArCOCH(CH2OCH2#)CO2E# itself prepared from I by the previously described chemistry where in X is -CH20CH2. Hydrogenylitic or protolytic removal of the benzyl group will yield V wherein X3 = CH2OH, after condensation of the ss-ketoester with guanidine as described in Procedure 1.The resulting 5-hydroxymethylpyrimidine is transformed into the corresponding 5-halomethylpyrimidine by standard procedures known in the art, either via displacement reactions on the corresponding 5-tosyloxymethyl derivative (formed with toluensulfonyl chloride in pyridine) with alkali or alkaline earth halogen salts, or directly with the known phosphinecarbon tetrahalide methodology.

Proce- C A L C U L A T E O dure X3 X1 NO.a C H N F C-I Br I C1 f 7 54.19 3.63 18.95 15.99 F 0 U N D - m.p., otherb C H N F C1 Br I 54.64 3.75 19.15 15.38 CALCULATED C H N F C1 Br I Br f 3 45.13 3.03 15.79 30.03 F O U N D - m.p., otherb C H N F C1 Br I 45.20 3.00 15.66 29.92 CALCULATED C H N F C1 Br I I # 5 38.36 2.57 13.42 40.53 Proce- F 0 U N D - m.p., otherb dure X3 X1 No.a C H N F Cl Br I] 38.46 2.57 13.28 39.74 CALCULATED C H N F Cl Br CH3 # 1 65.65 5.51 20.88 F 0 U N D- m.p., otherb C H N F Cl Br 65.52 5.38 20.86 CALCULATED C H N F Cl Br CH3CH2 f 1 66.95 6.08 19.52 F 0 U N D- m.p., otherb C H N F Cl Br 66.63 5.94 19.63 C A L C U L A T E D C H N F Cl Br Br 4-CH3 f HBr 3 36.59 2.79 11.63 44.27 F 0 U N D - m.p., otherb C H N F Cl Br I 37.48 3.18 12.01 43.36 C A L C U L A T E D C H N F C Br I 4-CH3 # 5 40.38 3.08 12.84 38.80 F 0 U N D - m.p., otherb C H N F Cl Br . I 40.32 3.19 12.93 38.14 C A L C U L A T E D C H N F Cl Br i Br 4-C1 # 3 39.96 2.34 13.98 11.79 26.59 Proce dure No 0 U N D - m.p., otherb A3 A1 NO.C H N F Cl Br 39.92 2.38 14.12 10.65 27.87 CALCULATED C H N F Cl Br Cl 3-F 7 50.12 2.95 17.53 7.93 14.80 F 0 U N D - m.p., otherb C H N F C1 Br 50.16 2.90 17.43 7.84 14.40 CALCULATED C H N F Cl Br Br 3-F # 3 42.27 2.48 14.79 6.68 28.13 F 0 U N D - m.p., otherb C H N F Cl Br 42.24 2.47 14.73 6.74 28.15 CALCULATED C H N F Cl Br I 3-F f 5 36.27 2.13 12.64 5.74 38.73 F 0 U N D - m.p., otherb C H N F Cl Br 36.30 2.18 12.65 5.59 38.10 CALCULATED C H N F Cl Br Br 3-Br # 3 34.81 2.04 12.18 46.32 F O U N D - m.p., otherb C H N F Cl Br 34.78 1.78 12.15 45.72 CALCULATED C H N F Cl Br I 3-Br # 5 30.64 1.80 10.72 20.38 32.07 Proce- F 0 U N D - m.p., otherb dure X3 X7 No.a. C H N F Cl Br 30.95 1.89 11.05 20.54 32.06 CALCULATED C H N F Cl Br I Cl 3-I # 7 34.56 2.03 12.09 10.20 36.51 F 0 U N D - m.p., otherb C H N F Cl Br I 34.55 1.94 11.77 10.54 36.2 CALCULATED C H N F Cl Br I Br 3-I # 3 30.64 1.80 10.72 20.39 32.37 F O U N D - m.p., otherb C H N F Cl Br I 30.86 1.94 10.90 20.10 32.08 C A L C U L A T E D C H N F Cl Br I I 3-1 f 5 27.33 1.60 9.57 57.82 F 0 U N D - m.p., otherb C H N F Cl Br I 27.58 1.77 9.62 56.22 CALCULATED C H N F Cl Br I Cl 3-CH30 # 7 52.58 3.98 16.73 13.94 F 0 U N O - m.p., otherb C H N F Cl Br I 52.22 3.95 16.65 13.91 CALCULATED C H N F Cl Br I Br 3-CH30 3 44.59 3.40 14.19 26.99 Proce- F O U N D - m.p., otherb dure X3 X7 No.a C H N F Cl Br 44.22 3.62 14.11 26.59 CALCULATED C H N F Cl Br I I 3-CH3O f 5 38.51 2.94 12.25 36.98 F 0 U N D - m.p., otherb C H N F Cl Br I 38.78 3.03 12.16 36.85 CALCULATED C H N F Cl Br ~ I Br 3-NO2 # 3 38.61 2.27 18.01 25.68 F 0 U N D - m.p., otherb C H N F Cl Br 1 38.71 2.23 18.23 25.75 CALCULATED C H N F Cl Br I I 3-N02 # 5 33.54 1.97 15.65 35.44 F 0 U N D - m.p., otherb C H N F Cl Br- I 31.97 1.91 14.96 32.57 CALCULATED C H N F Cl Br I Br 3-CF3 (p 3 39.54 2.11 12.57 17.06 23.92 F 0 U N D - m.p., otherb C H N F Cl Br I 39.79 2.02 12.80 17.04 24.11 CALCULATED C H N F I Br I 3-CF3 # 5 34.66 1.85 11.02 14.95 33.30 Proce- F 0 U N D - m.p., otherb dure X3 X1 No.a C H N F Cl- Br 34.65 1.47 11.22 14.87 33.39 CALCULATED C H N F C1 Br H a-naphthyl 1 70.87 4.67 17.71 F O U N D - m.p., otherb C H N F C1 Br 70.76 4.76 17.49 CALCULATED C H N F Cl Br 53.18 3.19 13.29 25.27 F 0 U N D - m.p., otherb C H N F Cl Br Br a-naphthyl 3 53.05 3.24 12.71 25.23 F 0 U N D - m.p., otherb C H N F Cl Br 45.53 2.87 19.56 17.33 CALCULATED C H N F Cl Br Br 2-furyl 4 37.52 2.35 16.41 31.20 F O U N D - m.p., otherb C H N F Cl Br 36.66 2.41 16.10 32.39 CALCULATED C H N F Cl Br 2-furyl 5 31.70 2.00 13.87 F 0 U N D - m.p., otherb C H N F Cl Br 33.10 1.94 14.40 Proce- C A L C U L A 1 E D dure X3 X1 No.a C H N F Cl Br I I a-naphthyl 5 46.30. 2.77 11.57 34.95 F 0 U N D - m.p., otherb C H N F Cl Br I 46.54 2.90 11.41 34.86 CALCULATED C H N F Cl Br I CH3&alpha;;-naphthyl 1 71.69 5.21 16.72 F O U N D - m.p., otherb C H N F Cl Br I 70.91 5.34 16.75 CALCULATED C C H N F Cl Br I Cl 2-furyl 7 45.40 2.85 19.86 16.75 C A L C U L A T E D C H N F Cl Br I I 4-C1 # 5 34.56 2.03 12.09 10.20 36.52 F 0 U N D - m.p., otherb C H N F Cl Br I 35.00 2.29 12.46 10.64 35.02 CALCULATED C H N F Cl Br I Br3,4-Cl2# HBr 3 28.87 1.45 10.10 17.05 38.43 F 0 U N D - m,p., otherb C H N F Cl Br I 29.68 1.77 10.86 16.64 38.28 CALCULATED C H N F Cl Br I 3,4-Cl2 # 5 31.44 1.58 11.00 18.56 33.22 Proce- F 0 U N D- m.p., otherb dure X3 No.a C H N F Cl Br 31.27 1.65 10.99 17.07 35.43 CALCULATED C H N F Cl Br I Br 3,5-Cl2 # 3 35.85 1.80 12.54 21.17 23.85 F 0 UN D- m.p., otherb C H N F Cl Br I 36.07 1.82 12.69 20.18 25.85 CALCULATED C H N F Cl Br I I 3,5-C12 # 5 31.44 1.58 11.00 18.56 33.22 F O U N D - m.p., otherb C H N F Cl Br I 31.12 1.50 10.75 19.20 28.11 CALCULATED C H N F Cl Br I Cl 2,5-Cl2 f 7 41.33 2.08 14.46 36.61 F 0 U N D- m.p., otherb - 260-280d C H N F Cl Br I 41.54 0.18 14.63 36.50 CALCULATED C H N F Cl Br I Br 2,5-Cl2 # 3 F 0 U N D - m.p., otherb - 255-275d C H N F Cl Br I CALCULATED C C H N F Cl Br I I 2,5-Cl2 f 5 31.44 1.58 11.00 Proce dure F O U N D - m.p., otherb - 180-181 X3 X1 No.a C H N F Cl Br 31.54 1.62 10.98 CALCULATED C H N F Cl Br Cl 3-C1 # 7 46.90 2.75 16.41 27.69 F 0 U N D - m.p., otherb C H N F Cl Br 46.95 2.67 16.54 27.91 CALCULATED C H N F Cl Br Br 3-C1 f 3 39.96 2.34 13.98 11.79 26.59 F 0 U N D - m.p., otherb C H N F Cl Br 40.33 2.40 14.00 11.62 26.99 C A L C U L A T E D C H N F Cl Br I 3-Cl 5 34.56 2.03 12.09 10.20 36.52 F 0 U N D - m.p., otherb C H N F # Br 34.80 2.12 12.12 9.93 36.46 CALCULATED C H N F Cl Br Br 2-pyridyl 3 31.06 2.32 16.10 45.93 HBr F 0 U N D - m.p., otherb C H N F Cl Br 30.47 3.00 16.09 45.51 CALCULATED C H N F Cl Br I 2-pyridyl 5 34.41 2.25 17.84 40.40 Proce dure F O U N D - m.p., othrb X3 X1 No.a C H N F Cl Br I 34.49 2.39 18.06 40.25 CALCULATED C H N F Cl Br I Br 3-pyridyl 3 40.47 2.64 20.99 FOUND - m.p., otherb C H N F cl Br I 39.89 2.66 21.85 CALCULATED C H N F Cl Br i I3-pyridyl 5 34.41 2.24 17.84 40.40 F O U N D - m.p., otherb C H N F Cl Br I 34.83 2.22 18.23 40.47 C A L C U L A T E D C H N F Cl Br Cl 2-C1 # 7 46.90 2.75 16.41 27.69 F 0 U N D- m.p., otherb C H N F Cl Br I 46.75 2.74 16.23 27.64 CALCULATED C H N F Cl Br I Br 2-C1 # 3 40.00 2.35 13.98 11.80 26.69 F O U N D - m.p., otherb C H N F Cl Br I 49.-90 2.29 14.10 11.05 28.07 CALCULATED C H N F Cl Br I I 2-C1 # 5 34.56 2.03 12.09 10.20 35.52 Proce- F 0 U N D - tn.p., otherb dure X1 No.a C H N F Cl Br I 34.36 2.09 12.16 10.75 34.75 C A L C U L A T E D C H N F C1 Br I Cl 2-CH3 # 7 56.05 4.27 17.83 15.04 F O U N D - m.p., otherb C H N F Cl Br I 55.95 4.03 17.64 15.01 CALCULATED C H N F Cl Br I Br 2-CH3 # 3 47.16 3.59 15.00 28.64 F 0 U N D - m.p., otherb C H N F Cl Br I 47.04 3.77 14.81 29.09 C A L C U L A T E D C H N F Cl Br I 2-CH3 # 5 40.38 3.08 12.84 38.79 F O U N D - m.p., otherb C H N F Cl Br I 40.10 3.04 12.73 39.05 CALCULATED C H N F Cl Br I Cl 2-CH30 # 7 52.49 4.01 16.70 14.09 F O U N D - m.p., otherb C H N F Cl Br I 52.56 4.27 16.69 13.11 CALCULATED C H N F Cl Br 1 Br 2-CH3O # 3 44.61 3.40 14.19 26.99 Proce dure F O U N D - m.p., otherb - 288-289 X3 X1 No. a C H N F Cl Br I 44.91 3.38 14.39 26.64 CALCULATED C H N F Cl Br I Br 2-F # 3 42.27 2.48 14.79 F 0 U N D - m.p., otherb C H N F Cl Br I 42.86 2.76 14.47 CALCULATED C H N F Cl Br I I 2-F f 5 36.27 2.13 12.69 5.73 38.33 F 0 U N D - m.p., otherb C H N F Cl Br I 36.54 2.14 12.83 5.65 38.04 CALCULATED C H N F Cl Br I Cl 2-F f 7 50.12 1.94 17.52 14.79 F 0 U N D- m.p., otherb C H N F Cl Br I 49.82 3.00 17.13 14.48 CALCULATED C H N F Cl .Br I I 4-F # 5 36.27 2.13 12.69 5.73 38.33 F 0 U N D - m.p., otherb C H N F Cl Br I 36.11 2.15 12.53 5.63 38.03 CALCULATED C H N F Cl Br I Br 4-F f 3 42.47 2.48 14.79 6.68 Proce- FOUN D - nip., other dure X3 X1 No.a C H N F Cl Br Cl 4-F # 7 41.81 2.53 14.47 6.43 CALCULATED C H N F Cl Br 50.12 2.94 17.53 14.79 F O U N D - m.p., otherb C H N F Cl Br 50.27 3.15 17.49 14.77 CALCULATED C H N F Cl Br C2H5 4-F # 2 61.79 5.18 18.01 8.14 F 0 U N D - m.p., otherb C -H N F Cl Br 60.37 5.16 18.03 8.07 C A L C U L A T E D C H N F Cl Br C2H5 2-F f 2 61.79 5.18 18.01 8.14 F 0 U N D - m.p., otherb C H N F Cl Br 61.59 5.12 17.85 7.94 CALCULATED C H N F Cl Br Cl 3,4-Cl2 # 7 41.33 2.07 14.46 36.31 F O U N D - m.p., otherb C H N F Cl Br I 41.79 2.21 14.5 32.59 CALCULATED C H N F Cl Br Cl 3-N02 f 7 45.04 2.64 21.01 Proce dure F O U N D - m.p., otherb X3 X1 No.a C H N F Cl Br 45.11 2.50 20.67 CALCULATED C H N F Cl Br Cl a-naphthyl 7 61.88 3.71 15.46 13.04 F O U N D - m.p., otherb C H N F Cl Br 61.08 3.76 15.18 12.73 CALCULATED C H N F Cl Br CH2 # # 1 73.62 5.45 15.15 F O U N D - m.p., otherb C H N F Cl Br 73.34 5.45 15.17 CALCULATED C H N F Cl Br CH2CH2CH2- # 1 68.09 6.59 18.33 F 0 U N D - m.p., otherb C H N F Cl Br 67.84 6.49 18.33 CALCULATED C H N F Cl Br CH2=CHCH2- + 1 68.70 5.76 18.49 FOUN D - m.p., otherb C H N F Cl Br 68.34 5.78 18.39 C A L C U L A -T E D C H N F Cl Br Br 2-pyrazine 3 35.84 2.26 26.13 29.81 Proce dure F O U N D - m.p., otherb X3 X1 No.a C H N F C1 Br I 35.24 2.33 26.18 29.09 CALCULATED C H N F Cl Br I I 2-pyrazine 5 30.49 1.92 22.23 40.28 F 0 U N D - m.p., otherb C H N F Cl Br I 30.67 2.13 22.34 40.39 CALCULATED C H N F Cl Br I Cl; 2-pyrazine 7 42.96 2.70 31.32 15.86 F O U N D - m.p., otherb C H N F Cl Br I 43.10 2.90 31.41 15.89 CALCULATED C H N F Cl Br I I2-CH3O f 5 38.50 2.94 12.25 36.98 FOUND - ni.p., otherb - 280-281 C H N F Cl Br I 39.09 3.77 12.81 33.64 CALCULATED C H N F Cl Br I Cl 3,5-(CH3O)2# 7 51.16 4.29 14.91 12.58 F O U N D - m.p., otherb C H N F Cl Br I 51.35 4.18 14.78 12.84 CALCULATED C H N F Cl Br I Br3,5- (CH3O)2# 3 3 44.18. 3.90 12.88 24.50 Proce- F O U N D - m.p., otherb - 0.78% H20 dure ~ X3 X1 No.a C H N F C1 Br I 43.81 3.74 13.08 24.57 CALCULATED C H N F Cl Br I I 3,5-(CH3O)2# 5 38.62 3.24 11.26 34.01 F O U N D - m.p., otherb - 0.485 H2O C H N F Cl Br I 37.26 3.15 11.15 34.74 CALCULATED C H N F Cl Br I 3-C2H5O # 5 40.35 3.38 11.76 35.53 F O U N D O - m.p., otherb C H N F Cl Br I 40.31 3.23 12.04 32.22 CALCULATED C H N F Cl Br I Cl 3-C2H50 f 7 54.24 4.55 15.81 13.34 F O U N D - m.p., otherb - 7.57% 1120 C H N F Cl Br I 49.77 4.65 14.52 12.38 CALCULATED C H N F Cl Br I Br 3-n-C3H7O# 3 48.16 4.35 -12.96 24.65 F 0 U N D - m.p., otherb C H N F Cl Br I 47.86 4.30 12.87 25.33 CALCULATED C H N F Cl Br I -n-C2H7O# 5 42.06 3.80 11.32 34.19 Proce dure F O U N D - m.p., otherb X3 X1 No.a C H N F Cl Br I 42.41 3.75 11.85 33.50 C A L C U L A T E D Cl 3-n-C2H79# 7 C H N F Cl Br 55.82 5.04 15.02 12.68 F O U N D - m.p., otherb C H N F Cl Br 55.89 5.22 14.99 12.64 C A L C U L A T E D C H N F Cl Br 1 3-C2H5OC2H4O# 5 41.90 4.02 10.47 F O U N D - m.p., otherb C H N F Cl Br 40.58 3.96 10.73 a In all of the examples where X3 is halogen, the procedure number listed refers only to the appropriate halogenation procedure and presumes Procedure 1 or 2 has already bA majority of the products exhibit melting points that are not necessarily a distinguishing characteristic of the compound either because of decomposition or greater than 200 and are therefore not listed.

EXAMPLE 12 2-Amino-6-(2-furyl)-4-pyrimidinol To a 3-neck, 500 ml. flask fitted with a paddle stirrer, Dean-Stark trap, and a reflux condenser is added 5.76 g. of powdered guanidine carbonate (31.9 mM), 200 ml. absolute C2HsOH and 20 ml.

toluene. The solution is removed azeotropically. The reaction mixture is allowed to cool to 50"C., the Dean-Stark trap removed, and 10.4 g. (64 mM) of ethyl-2-furyl-acetate (57.07 mM) is added. The reaction mixture is heated at reflux for 1 8 hours; 50 ml. of water is added and heating is continued for 30 minutes. The reaction is allowed to cool to 250C. Chips of carbon dioxide are added until the mixture is neutral and the flask is placed in the refrigerator at 50C. under vacuum to yield 5.6 g. (49%) of pure 2 amino-6-(2-furyl)-4-pyrimidinol.

EXAMPLE 13 2-Amino-6-(m-chlorophenyl)-4-pyrimidinol To a 3-neck, 500 ml. RB flask fitted with an overhead stirrer, condenser, and Dean-Stark trap under nitrogen is added 5.76 g. (32 mmole) of powdered guanidine carbonate, 200 ml. of absolute ethanol and 20 ml. of toluene. By heating to reflux 100 ml. of solvent is removed via the trap following which the solution is cooled to approximately 500C. and trap removed. Ethyl-m-chlorobenzoyl acetate (14.8 g., 65 mmole) is introduced into the vessel and the reaction is stirred at reflux for 17 hours.

Approximately 30 ml. of water is added and heating continued for 30 minutes. The mixture is then cooled in a refrigerator for 1 8 hours. The precipitate is filtered and washed with ethanol followed by ether and dried at 600 C. under vacuum to yield 10.6 g. (74%) of 2-amino-6-(m-chlorophenyl)-4 pyrimidinol.

EXAMPLE 14 2-Amino-6-(o-methoxyphenyl)-4-pyrimidinol Following the procedure of Example 12 but substituting 5.67 g. (31.5 mM) of guanidine carbonate, 200 ml. of absolute ethanol, 20 ml. of toluene, 14.15 g. of ethyl-o-methoxybenzoyl acetate, and 1 50 hours of reflux gives 7.91 g. (57.8%) of 2-amino-6-(o-methoxyphenyl)-4-pyrimidinol as a white solid (m.p. 283.5-284.50C.) EXAMPLE 15 2-Amino-5-bromo-6-(m-chlorophenyl)-4-pyrimidinol To 3.13 g. (1 5 mM) of 2-amino-6-(m-chlorophenyl)-4-pyrimidinol is added 80 ml. of glacial acetic acid. The solution is heated to 800C. and 0.81 ml. of Br2 is added. The mixture is allowed to stir at 800C.

for 1 5 minutes and cooled to 250C. The mixture is evaporated to dryness under vacuum at 400 C. and the resulting solids heated at reflux with 1 50 ml. of water. The reaction mixture is cooled and filtered, and the solids washed very well with cold water. The solids are dried at 600 C. in a vacuum oven and pulverized when dry. The boiling water tritration is repeated. 3.90 G. (86.9) of title compound is recovered. Recrystallization of the solids from water:DMF by adding DMF slowly to a stirring slurry of 3.9 g. of compound in 1 50 ml. boiling water until solution occurs, cooling and filtering yields analytically pure material (80% recovery).

EXAMPLE 1 6 2-Amino-6-(m-chlorophenyl)-5-iodo-4-pyrimidinol To 3.13 g. (15 mM) of 2-amino-6-(m-chlorophenyl)-4-pyrimidinol is added 50 ml. water + 0.80 g.

sodium hydroxide (20 mM). The mixture is heated to dissolve the pyrimidinol and filtered if necessary. It is cooled to 250C. and 3.79 g. of 12 (powdered) is added in 100 ml. chloroform. The excess 12 is washed in with 30 ml. chloroform. The reaction mixture is allowed to stir vigorously with paddle stirrer at 250C.

for 4 hours.

The reaction is filtered and the solids washed very well with water until the aqueous wash is neutral to litmus. The solids are then washed with acetone until the acetone wash is colorless. (It is desirable to pulverize the solids before washing with acetone). Drying the solids at 600C. yields 3.50 g.

(67%) of 2-amino-6-(m-chlorophenyl)-4-pyrimidinol.

EXAMPLE 17 2-Amino-5-iodo-6-(2-furyl)-4-pyrimdinol To 2.65 g. (15 mM) of 2-amino-6-(2-furyl)-4-pyrimdinol is added 50 ml. water adn 0.72 g. sodium hydroxide. The reaction mixture is heated to 750C. to effect solution and then cooled to 250C. A slurry of 4.0 g. (1 5.8 mM) of powdered iodine in 100 ml. chloroform is added, with vigorous stirring, and the reaction mixture is allowed to stir for 2 hours at ambient temperature. The reaction mixture is filtered.

The solids are washed.well with water (until wash is neutral to litmus) followed by acetone (until the acetone wash is colorless), and dried in a vacuum oven to give 3.95 g. (87%) of 2-amino-5-iodo-6-(2furyl)-4-pyrmidinol.

EXAMPLE 18 2-Amino-5-bromo-6-(2-furyl)-4-pyrimidinoi To 2.65 g. (15 mM) of 2-amino-6-(2-furyl)-4-pyrimidinol is added 50.0 ml. of water and 0.66 sodium hydroxide (16.5 mM). A cloudy solution results. The solution is allowed to stir for 30 minutes and 0.9 ml. Br2 (2.62 g., 16.5 mM) in 20 ml. chloroform is added. The solution is allowed to stir vigorously for 2 hours and is filtered. The solids are washed well with water (until neutral to litmus) followed by acetone (until acetone is colorless) and dried at 600C. to give 3.3 g. of 2-amino-5-bromo-6 (2-furyl)-4-pyrimidinol (86%).

EXAMPLE 19 2-Amino-5-chloro-6-phenyl-4-pyrimidinol To 1.87 g. (10 mM) of 2-amino-6-phenyl-4-pyrimidinol is added 50 ml. of glacial acetic acid and 1.46 g. (11 mM) of N-chlorosuccinimide. The mixture is heated with magnetic stirring under nitrogen at 90"C. for 2 hours (solution was complete in less than 20 minutes). The heat is removed and the amber solution is allowed to cool to room temperature. The solution is evaporated to a volume of 10 ml. under vacuum, cooled to 200 C. and filtered. The resulting solids are washed successively with CH3COOH (5 ml.), water (50 ml.), acetone (100 ml.) and diethyl ether (100 ml.). The solids are dried at 600C. in a vacuum oven to yield 1.40 g. (63%) of title compound.The solids can be recrystallized from ethanol:DMF by adding DMF to a hot, ethanol slurry of the pyrimidine until solution is complete. Cooling the solution at 50C. for 18 hours filtering and drying gives analytically pure 2-amino-5-chloro-6-phenyl4-pyrimidinol.

EXAMPLE 20 2-Amino-5-iodo-6-phenyl-4-pyrimdinol Following the procedure of Example 16 but substituting 21.4 g. (0.113 M) of 2-amino-6-phenyl 4-pyrimidinol, 200 ml. water, 500 ml. chloroform,5.6 g. sodium hydroxide and 28.8 g. 12 a yield of 29.0 9. (78%) of 2-amino-5-iodo-6-phrnyl-4-pyrimidinol is obtained.

EXAMPLE 21 2-Arnino-5-iodo-6-phenyl-4-pyrimidinol, zinc salt To 1.56 g. (5 mmole) of 2-amino-5-iodo-6-phenyl-4-pyrimidinol in 1 5 ml. of methanol under nitrogen with stirring at room temperature is added 1.1 ml. of a 25% NaOCHWCH3OH solution. After five minutes 340 mg. (2.5 mmole) of anhydrous zinc chloride (ZnCl2)) was added. After one hour the heterogeneous solution is concentrated to dryness, washed with 2 x 50 ml. water, filtered, and dried in vacuo at 600C. for 18 hours. The product is white solid with m.p. at 2850C.

This invention further relates to new pharmaceutical compositions and a method of preventing or treating viral infections and inducing interferon production in vivo and in vitro (tissue cuiture).

The present invention comprises the compositions and the method of inducing interferon production and/or preventing or treating viral infections, therapeutically and prophylactically by administration of a compound selected from the group consisting of compounds having the formula:

wherein X3 and X1 are as previously defined, referred generically as 6-aryl-pyrimidines and hereafter termed "active ingredients", or the pharmacologically acceptable acid addition salts thereof; in association with a pharmaceutical carrier.

Suitable pharmacologically acceptable acid addition salts are for example the hydrochloride, sulfate, phosphate, nitrate, and the like. These salts can be used in the same manner as the base compounds.

According to the present invention, a viral infection is treated or prevented and interferon production is increased in vivo by administering the active ingredients to a suitable host. By "host" is meant interferon producing animals, i.e., intact viable animals which are capable of interferon production. The host may be warm-blooded animals such as mammals, e.g., mice, rats, rabbits, bovine.

pigs, hamsters, dogs, cats; guinea pigs, horses, goats, sheep, monkeys, man; and birds, e.g., chickens, ducks, turkeys, pigeons, parakeets, and canaries. The mode of adminstration can be parenterally such as subcutaneously, intramuscularly, intradermally, intraperitoneally, intrathecally, intravenously or locally, preferably on a mucous mernbrane such as intranasally, pharyngolarnygeally, bronchially, broncholially, intravaginally, rectally or ocularly. The mode of adminstration can also be by implantation. Alternatively or concurrently, administration can be by the oral route, a preferred mode of adminstration for an interferon inducer. Practically, it is advanageous to administer the active ingredient to the host orally.

intranasally, topically, locally, subcutaneously or intramuscularly.

The induction of interferon by adminstration of an active ingredient is demonstrated by established interferon assay methods such as plaque-reduction, see Finter, Inteiferons and Interferon induces, (1973). The interferon induced by the adminstration of an active ingredient can also be demonstrated by the protection of the host animals as well as tissue cultures against virus challenge.

The adminstration of the active ingredients are also useful prophylactically and therapeutically for preventing and treating viral infections. For example, pharmaceutical compositions containing the active ingredients are useful in prophylactic or therapeutic treatment of humans and animals infected or likeiy to be infected with viruses, e.g., hepatitis virus, rubella, rubeolla, influenza, encephalitis viruses (i.e.

arboviruses such as western or eastern equine encephalitis virus, Semliki Forest virus), herpes viruses (types 1 or 2 herpes simplex virus, cytamogalovirus, varicella-zoster and infectious bovine rhinotracheitis virus), rabies, enteroviruses (picornaviruses, echoviruses, coxsackie viruses), parainfluenza viruses, respiratory syncytial virus, sendai virus, poliomyelitis viruses, yellow fever, Epstein Barr virus (infectious mononucleosis), small pox, Dengue virus, common cold virus (rhinoviruses, coronaviruses, etc.), adenoviruses, polyomaviruses, papovaviruses, RNA-tumor viruses (e.g., Feline leukemia virus, Avian ieukosis virus, Avian sarcoma viruses), B virus, Aleutians disease of mink, karena viruses, blue tongue virus of sheep, bovine viral diarrhea-mucosal disease virus, canine distemper virus, canine hepatitis virus, canine herpesvirus, equine abortion virus, infectious equine anemia virus, fowl pox virus, hog cholera virus Marek's disease, mink enteritis virus, Newcastle disease virus, porcine enterovirus, pseudorabies virus, foot and mouth disease virus, reoviruses, and all other viruses or diseases or viral origin (for example, slowly progressing diseases that may be of viral origin such as multiplesclerosis) that are sensitive to the antiviral action of interferon or the pyrimidine antiviral agents disclosed in this patent.

Preferred compounds are: 2-amino-5-iodo-6-(3-bromophenyl)-4-pyrimidinoí; 2-amino-5-bromo-6-(3-fluorophenyl)-4-pyrimidinol; 2-amino-5-bromo-6-(3-ethoxyethylphenyl)-4-pyrimidinol; 2-amino-5-bromo-6-(2-methoxyphenyl)-4-pyrimidinol; 2-amino-5-chloro-6-(2-methoxyphenyl)-4-pyrimidinol; 2-amino-5-iodo-6-(3-chlorophenyl)-4-pyrimidinol; 2-amino-5-bromo-6-(3-chlorophenyl)-4-pyrimidinol; 2-amino-5-iodo-6-(3-chlorophenyl)-4-pyrimidinol; 2-amino-5-chloro-6-(3-chlorophenyl)-4-pyrimidinol; 2-amino-5-chloro-6-(2-fluorophenyl)-4-pyrimidinol; 2-amino-5-chloro-6-(3-fluorophenyl)-4-pyrimidinol; 2-amino-5-bromo-6-(2-fluorophenyl)-4-pyrimidinol; 2-amino-5-iodo-6-(3-fluorophenyl)-4-pyrimidinol; 2-amino-5-iodo-6-phenyl-4-pyrimidinol; 2-amino-5-chloro-6-phenyl-4-pyrimidinol;; 2-amino-5-bromo-6-phenyl-4-pyrimidinol; 2-amino-5-chloro-6-(3-methoxyphenyl)-4-pyrimidinol; 2-amino-5-bromo-6-(3-methoxyphenyl)-4-pyrimidinol; 2-amino-5-iodo-6-(3-methoxyphenyl)-4-pyrimidinol; 2-amino-5-bromo-6-(2-pyridyl)-4-pyrimidinol; 2-amino-5-iodo-6-(3,4-dichlorophenyl)-4-pyrimidinol; 2-amino-5-bromo-6-(a-naphthyl)-4-pyrimidinol; 2-amino-5-chloro-6-(3-nitrophenyl)-4-pyrimidinol; 2-amino-5-iodo-6-(3-nitrophenyl)-4-pyrimidinol; 2-amino-5-iodo-6-(3-trifluoromethylphenyl)-4-pyrimidinol; 2-amino-5-ethyl-6-phenyl-4-pyrimidinol; 2-amino-5-bromo-6-(3,5-dimethoxyphenyl)-4-pyrimidinol; 2-amino-5-chloro-6-(3-propyloxyphenyl)-4-pyrimidinol; or the pharmaceutically acceptable acid addition salts or alkali metal or alkaline earth metal salts thereof.

In addition to the anti-viral and interferon production activity disclosed, the compounds have immunoregulatory activity; for example the compounds increased antibody formation and decreased delayed hypersensitivity and are useful in the treatment of parasitic diseases, organ transplants and skin graft rejections, and immune deficiencies including those caused as a side effect of therapy with cytotoxic agents and radiation.

The dosage adminstered will be dependent upon the level of interferon desired, the identity of the virarinfection, the type of animal involved, its age, health, weight, kind of concurrent treatment, if any, frequency of treatment, therapeutic ratio, and tolerance.

Care must be taken in choosing dosage regimens to be used in preventing various diseases of viral origin. Since the mechanism of antiviral action of the pyrimidines is mediated through interferon and other actions, such as direct antiviral activity of the compounds or immune modulation, consideration must be given to the type of disease being treated, the condition of the host and the nature of the causative agent (is it sensitive to the antiviral action of interferon). The route of adminstration of the drug will depend upon such criteria. For example, an upper respiratory tract infection may be most effectively treated by intranasal administration of the drug while systemic infections would more effectively be treated by systemic injection of the drug.

Also, the timing of drug adminstration can be important in maintenance of antiviral activity. It is well documented [Stringfellow, D. A., AntimicrobialAgents and Chemotherapy, 11:934-992 (1977)1 that the ability of animals to produce interferon in response to agents that stimulate interferon synthesis is impaired if such agents are administered in frequent (daily) dosage regimens. In contrast, when given less frequently (once a week) animals remained responsive to each injection of inducer [Stringfellow, D.

A., and S. D. Weed, Am. J. Vet. Research, 38:1963-1967 (1 977)j. Since interferon mediates an intracellular antiviral state that can persist for several days after interferon is cleared from the circulation, such a treatment regimen (e.g., once a week) would be suitable for treatment of infections caused by interferon sensitive viruses. Some viruses, however, are less sensitive to interferon but the pyrimidines have antiviral activity separable from the ability to induce interferon and treatment regimens that maintain appropriate levels of circulating or tissue associated drug would be more suitable for treating or preventing such infections. For example, type 1 Herpes simplex virus (HSV-1) is not as sensitive to the antiviral action of interferon as are other viruses such as Semliki forest virus (SFV).Yet, both HSV-1 and SFV infections in mice can be effectively prevented by adminstration of 2amino-5-iodo-6-phenyl-4-pyrimidinol. However, for effective prevention of HSV-1, drug must be given twice a day for three consecutive days while activity against SFV is achieved with a single injection being given once a week. Therefore, care must be taken in selecting proper treatment regimens and must consider the condition of the host, the nature of the disease process and the pharmacological properties of the agent being used.

Additionally, a method of the present invention is for alteration of the immunoregulatory system of .the host animal. The administration of the active compounds increases antibody formation and can be used to treat acquired or congenital hypogammaglobulinemia; increases natural killer cells and can be used to treat various forms of cancer; activates macrophages and can be used to treat or prevent intracellular or extracellular parasitic infections, including bacterial and protozoal; increases hematopoietic stem cells in bone marrow and spleen and can be used to treat or prevent aplastic ariemia; and decreases generation of allospecific keller cells and can be used to prevent rejection of organ and skin grafts.

Illustratively, dosage levels of the administered active ingredients can be: intravenous, 0.1 to about 50 mg./kg.; intraperitoneal, 0.1 to about 200 mg./kg.; subcutaneous, 0.1 to about 150 mg./kg.; intramuscular, 0.'1 to about 150 mg./kg.; orally, 0.1 to about 400 mg./kg, and preferably about 1 to 200 mg./kg.; intranasal instillation, 0.1 to about 50 mg./kg.; and aerosol, 0.1 to about 50 mg./kg. of animal (body) weight.

Expressed in terms of concentration, an active ingredient can be present in the compositions of the present invention for rocalised use about the cutis, intranasally, pharyngolaryngeally, bronchially, broncholially, intravaginally, rectally, or ocularly in a concentration of from about 0.1 to about 50% w/w of the composition; preferably about 1 to about 20% w/w of the composition; and for parenteral use in a concentration of from about 0.5 to about 50% w/v of the composition and preferably from about 5 to about 20% w/v.

The compositions of the present invention are preferably oresented for adminstration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, suppositories, sterile parenteral solutions or suspensions, sterile non-parenteral solutions or suspensions, and oral solutions or suspensions and the like, containing suitable quantities of an active ingredient.

For oral adminstration either solid or fluid unit dosage forms can be prepared.

Powders are prepared quite simply by comminuting the active ingredient to a suitably fine size and mixing with a similarly comminuted diluent. The diluent can be an edible carbohydrate material such as lactose or starch. Advantageously, a sweetening agent or sugar is present as well as a flavoring oil.

Capsules are produced by preparing a powder mixture as hereinbefore described and filling into formed gelatin sheaths. Advantageously, as an adjuvant to the filling operation, a lubricant such as talc, magnesium stearate, calcium stearate and the like is added.to the powder mixture before the filling operation.

Soft gelatin capsules are prepared by machine encapsulation of a slurry of active ingredients with an acceptable vegetable oil, light liquid petrolatum or other inert oil or triglyceride.

Tablets are made by preparing a powder mixture, granulating or slugging, adding a lubricant and pressing into tablets. The powder mixture is prepared by mixing an active ingredient, suitably comminuted, with a diluent or base such as starch, Lactose, kaolin, dicalcium phosphate and the like.

The powder mixture can be granulated by wetting with a binder such as corn syrup, gelating solution, methylcellulose solution or acacia mucilage and forcing through a screen. As an alternative to granulating, the powder mixture can be slugged, i.e., run through the tablet machine and the resulting imperfectly formed tablets broken into pieces (slugs). The slugs can be lubricated to prevent sticking to the tablet-forming dies by means of the addition of stearic acid, a stearic salt, talc or mineral oil. The lubricated mixture is then compressed into tablets.

Advantageously the tablet can be provided with a protective coating consisting of a sealing coat or enteric coat of sheliac, a coating of sugar and methylcellulose and a polish coating of carnauba wax.

Fluid unit dosage forms for oral adminstration such as syrups, elixirs and suspensions can be prepared wherein each teaspoonful of composition contains a predetermined amount of active ingredient for administration. The water-soluble forms can be dissolved in an aqueous vehicle together with sugar, flavoring agents and preservatives to form a syrup. An elixir is prepared by using a hydroalcoholic vehicle with suitable sweeteners together with a flavoring agent. Suspensions can be prepared of the insoluble forms with a suitable vehicle with the aid of a suspending agent such as acacia, tragacanth, metylcellulose and the like. For parenteral administration, fluid unit dosage forms are prepared utilizing an active ingredient and a sterile vehicle, water being preferred.The active ingredient, depending on the form and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the water-soluble active ingredient can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampule and sealing. Advantageously, adjuvants such as a local anesthetic, preservative and buffering agents can be dissolved in the vehicle. Parenteral suspensions are prepared in substantially the same manner except that an active ingredient is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration. The active ingredient can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the active ingredient.

In addition to oral and parenteral administration, the rectal and vaginal routes can be utilized. An active ingredient can be administered by means of a suppository. A vehicle which has a melting point at about body temperature or one that is readily soluble can be utilized. For example, cocoa butter and various polyethylene glycols (Carbowaxes) can serve as the vehicle.

For intranasal instillation, fluid unit dosage forms are prepared utiiizing an active ingredient and a suitable pharmaceutical vehicle, water being preferred or by dry povvder for insulflation.

The active ingredients can also be admixed in animal feed. The active ingredients can conveniently be prepared in the form of a food premix. The food premix can comprise an active ingredient in admixture with an edible pharmaceutical diluent such as starch, oatmeal, flour, calcium carbonate, talc, dried fish meal and the like non-toxic, orally acceptable pharmaceutical diluents. The prepared premix is then conveniently added to the regular feed.

For use as aerosols the active ingredients can be packaged in a pressurized aerosol container together with a gaseous or liquefied propellant, for example, dichloro-difluoromethane, carbon dioxide, nitrogen, propane, and the like, with the usual adjuvants such as co-solvents and wetting agents, as may be necessary or desirable.

The term "unit dosage form" as used in the specification and claims refers to physically discrete units suitable as unitary dosages for human and animal subjects, each unit containing a predetermined quantity of active material calcualted to produce the desired therapeutic effect in association with the required pharmaceutical diluent, carrier or vehicle. The specifications for the novel unit dosage forms of this invention are dictated by and are directly dependent on (a) the unique characteristics of the active material and the particular therapeutic effect to be achieved, and (b) the limitation inherent in the art of compounding such an active material for therapeutic use in humans, as disclosed in this specification, these being features of the present invention.Examples of suitable unit dosage forms in accord with this invention are tablets, capsules, troches, suppositories, powder packets, wafers, cachets teaspoonfuls, tablespoonfuls, dropperfuls, ampuls, vials, segregated multiples of any of the foregoing, and other forms as herein described.

The active ingredients to be employed as interferon inducers and as anti-viral agents can be easily prepared in unit dosage form with the employment of pharmaceutical materials which themselves are available in the art and can be prepared by established procedures. The following preparations are illustrative of the preparation of the unit dosage forms of the present invention, but are not intended to be limiting.

EXAMPLE 22 Hard-Gelatin Capsules One thousand two-piece hard gelatin capsules for oral use, each capsule containing 100 mg. of 2 amino-5-bromo-6-m-fluorophenyl-4-pydmidinol, are prepared from the following types and amounts of ingredients; 2-Amino-5-bromo-6-m-fluoro- phenylpyrimidinol, micronized 100 gm.

Lactose 100 gm.

Corn starch 20 gm.

Talc 20 gm.

Magnesium stearate 2 gm.

The 2-amino-5 bromo-6-m-fluorophenyl-4-pyrimidinol, finely divided by means of an air micronizer, is added to the other finely powdered ingredients, mixed thoroughly and then encapsulated in the usual manner.

The foregoing capsules are useful for preventing or treating viral infection and for inducing interferon formation by the oral administration of one or two capsules one to four times a day.

The foregoing capsules are useful for preventing or treating skin graft rejection by the oral administration of one or two capsules one or four times a day.

Using the procedure above, capsules are similarly prepared containing 2-amino-5-bromo-6-mfluorophenyl-4-pyrimidinol in 50, 25-0 and 500 mg. amounts by substituting 50 gm., 250 gm. and 500 gm. of 2-amino-5-bromo-6-m-fluorophenyl-5-pyrimidinol for the 100 gm. used above.

EXAMPLE 23 Soft Gelatin Capsules One-piece soft gelatin capsules for oral use, each containing 250 mg. of 2-amino-5-bromo-6-mfluorophenyl-4-pyrimidinol (finely divided by means of an air micronizer), are prepared by first suspending the compound in 0.5 ml. of corn oil to render the material capsulatable and then capsulating in the above manner.

The foregoing capsules are useful for preventing or treating viral infection and for inducing interferon formation by the oral administration of one or two capsules one to four times a day.

The foregoing capsules are useful for preventing or treating bacterial infection particularly intracellular bacterial infection by the oral administration of one or two capsules one to four times a day.

EXAMPLE 24 Tablets One thousand tablets, each containing 500 mg. of 2-amino-5-bromo-6-m-fluorophenyl-4pyrimidinol, are prepared from the following types and amounts of ingredients: 2-Amino-5-bromo-6-m-fluoro- phenyl-4-pyrimidinol 500 gm.

Lactose . 75 gm.

Corn starch 50 gm.

Magnesium stearate 4 gm.

Light liquid petrolatum micronized 5 gm.

The 2-amino-5-bromo-6-m-fluorophenyl-4-pyrimidinol, finely divided by means of an air micronizer, is added to the other ingredients and then thoroughly mixed and slugged. The slugs are broken down by forcing through a Number Sixteen screen. The resulting granules are then compressed into tablets, each tablet containing 500 mg. of 2-amino-5-bromo-6-m-fluorophenyl-4-pyrimidinol.

The foregoing tablets are useful for preventing or treating viral infection and for inducing interferon formation by the oral administration- of one or two tablets one to four times a day.

The foregoing tablets are useful for treating hypogammaglobulinemia by the oral administration of one or two tablets one to four times a day.

Using the procedure above, tablets are similarly prepared containing 2-amino-5-bromo-6-mfluorophenyl-5-pyrimidinol in 250 mg. and 100 mg. amounts by substituting 250 gm. and 10 gm. of 2 amino-5-bromo-6-m-fluorophenyl-4-pyrimidinol for the 500 gm. used above.

EXAMPLE 25 Oral Suspension One thousand ml. of an aqueous suspension for oral use, containing in each teaspoonful (5 ml.) dose, 500 mg. of 2-amino-5-bromo-6-m-fluorophenyl-4-pyrimidinoi, is prepared from the following types and amounts of ingredients: 2-Amino-5-bromo-6-m-fluoro phenyl-4-pyrimidinol, micronized 100 gm.

Citric acid 2 gm.

Benzoic acid 1 gm.

Sucrose 700 gm.

Tragacanth 5 gm.

Lemon oil 2 gm.

Deionized water, q.s. 1000 ml The citric acid, benzoic acid, sucrose, tragacanth and lemon oil are dispersed in sufficient water to make 850 ml. of suspension. The 2-amino-5-bromo-6-m-fluorophenyl-4-pyrimidinol, finely divided by means of an air micronizer, is stirred into the syrup until uniformly distributed. Sufficient water is added to make 1000 ml.

The composition so prepared is useful for preventing or treating viral infection and for inducing interferon formation at a dose of 1 tablespoonful (15 ml.) three times a day.

The composition so prepared is useful for treating aplastic anemia at a dose of 1 tablespoonful (15 ml.) three times a day.

EXAMPLE 26 A sterile aqueous suspension for parenteral injection, containing in 1 ml. 300 mg. of 2-amino-5 bromo-6-m-fluorophenyl-4-pyrimidinol, is prepared from the following types and amounts of ingredients: 2-Amino-5-bromo-6-m-fluoro phenyl-4-pyrimidinol, micronized 300 gm.

Polysorbate 80 5 gm.

Methylparaben 2.5 gm.

Propylparaben 0.17 gm.

Water for injection, q.s. 1 000 ml.

All the ingredients, except the 2-amino-5-bromo-6-m-fluorophenyl-4-pyrimidinol, are dissolved in the water and the solution sterilized by filtration. To the sterile solution is added the sterilized 2-amino 5-bromo;61-m-fluprophenyl-4-pyrimidinol, finely divided by means of an air micronizer, and the final suspension is filled into sterile vials and the vials sealed.

The composition so prepared is useful for preventing or treating viral infection and for inducing interferon formation at a dose of 1 milliliter (1 M) three times a day.

The composition so prepared is useful for treating agammaglobuiinemia at a dose of 1 milliliter (1 M) three times a day.

EXAMPLE 27 Suppository, Rectal and Vaginal One thousand suppositories, each weighing 2.5 gm. and containing 1 50 mg. of 2-amino-S- bromo-6-m-fluorophenyl-4-pyrimidinol are prepared from the following types and amounts of ingredients: 2-Amino-5-bromo-6-m-fluoro phenyl-4-pyrimidinol, micronized 1 50 gm.

Propylene glycol 150 gm.

Polyethylene glycol, 4000 q.s. 2,500 gm.

The 2-amino-5-bromo-6-m-fluorophenyi-4-pyrimidinol is finely divided by means of an air micronizer and added to the propylene glycol and the mixture passed through a colloid mill until uniformly dispersed. The polyethylene glycol 40000 is melted and the propylene glycol dispersion added slowly with stirring. The suspension is poured into unchilled molds at 40"C. The composition is allowed to cool and solidify and then removed from the mold and each suppository foil wrapped.

The foregoing suppositories are inserted rectally or vaginally for preventing or treating viral infection and for inducing interferon formation.

The foregoing suppositories are inserted rectally or vaginally for treating bacterial infection.

EXAMPLE 28 Intranasal Suspension One thousand ml. of a sterile aqueous suspension for intranasal instillation, containing in each ml.

1 50 mg. of 2-amino-5-bromo-6-m-fluorophenyl-4-pyrimidinol, is separated from the following types and amounts of ingredients: 2-Amino-5-bromo-6-m-fluoro phenyl-4-pyrimidinol, micronized 1 50 gm.

Polysorbate 80 - 5 gm.

Methylparaben 2.5 gm.

Propylparaben 0.17gm.

Deionized water, q.s. 1000 ml.

All the ingredients, except the 2-amino-5-bromo-6-m-fluorophenyl-4-pyrimidinol, are dissolved in the water and the solution sterilized by filtration. To the sterile solution is added the sterilized 2-amino5-bromo-m-fluorophenyl-4-pyrimidinol, finely divided by means of an air micronizer, and the final suspension is aseptically filled into sterile containers.

The composition so prepared is useful for preventing or treating viral infection and for inducing interferon formation by intranasal instillation of 0.2 to 0.5 ml. given one to four times per day.

The composition so prepared is useful for treating intracellular bacterial infection by intranasal instillation of 0.2 to 0.5 ml. given one to four times per day.

EXAMPLE 29 Animal Feed One thousand grams of feed premix is prepared from the following types and amounts of ingredients: Z-Amino-5-bromo-6-m-fluoro- phenyl-4-pyrimidinol 20 gm.

Soybean meal 400 gm.

Fish meal 400 gm.

Wheat germ oil 50 gm.

Sorghum molasses 130 gm.

The ingredients are mixed together and pressed into pellets.

The premix can be fed to laboratory animals directly, i.e., rats and mice, for preventing or treating viral infection and for induction of interferon formation and for preventing or treating intracellular parasitic infection.

For large animals the premix can be added to the animal's regular feed in an amount calculated to give the desired dose of 2-amino-5-bromo-6-m-fluorophenyl-4-pyrimidinol. For example, one part of premix is added to 2.5 parts of a cat's regular feed to provide the desired dose of 200 mg./kg./day for a cat of 2.5 kg.

An active ingredient can also be present, as shown in Examples 30--33 in the undiluted pure form for use locally about the cutis, intranasally, pharyngolaryngeally, bronchially, broncholially or orally.

EXAMPLE 30 Powder Five hundred gramms of 2-amino-5-bromo-6-m-fluorophenyl-4-pyrimidinol in bulk form is finely divided by means of an air micronizer. The micronized powder is piaced in a shaker-type container.

The foregoing composition is useful for preventing or treating viral infection and for inducing interferon formation at localized sites by applying the powder one to four-times per day.

The foregoing powders are useful for preventing or treating protozoal infection by the oral administration of one or two powders suspended in a glass of water, one to four times per day.

EXAMPLE 31 Oral Powder One thousand grams of 2-amino-5-bromo-6-m-fluorophenyl-4-pyrimidinol in bulk form is finely divided by means of an air micronizer. The micronized powder is divided into individual doses of 250 mg. and packaged.

The foregoing powders are useful for preventing or treating viral infection and for inducing interferon formation by the oral administration of one or two powders suspended in a glass of water, one to four times per day.

The foregoing capsules are useful for preventing or treating metastasis following mastectomy by the oral administration of one or two capsules one to four times a day.

EXAMPLE 32 Insufflation One thousand grams of 2-amino-5-bromo-6-m-fluorophenyl-4-pyrimidinol in bulkform is finely divided by means of an air micronizer.

The foregoing composition is useful for preventing or treating viral infection and for inducing interferon formation by the inhalation of 30 to 75 mg. one to four times per day.

EXAMPLE 33 Hard Gelatin Capsules One thousand two-piece hard gelatin capsules for oral use, each capsule containing 100 mg. of 2 amino-5-bromo-6-m-fluorophenyl-4-pyrimidinol. are prepared from 100 grams of 2-amino-5-bromo- methyl-4-pyrimidinol.

The 2-amino-5-bromo-6-methyl-4-pyrimidinol is finely divided by means of an air micronizer and encapsulated in the usual manner The foregoing capsules are useful for preventing or treating viral infection and for inducing interferon formation by the oral adminstration of one or two capsules one to four times a day.

Using the procedure above, capsules are similarly prepared containing 2-amino-5-bromo-6-mfluorophenyl-4-pyrimidinol in 50, 250 and 500 mg. amounts by substituting 50 gm., 250 gm. and 500 gm. of 2-amino-5-bromo-6-m-fluorophenyl-4-pyrimidinol for the 100 gm. used above.

EXAMPLE 34 Following the procedure of the preceding Examples 22 through 33, inclusive, compositions are prepared substituting equivalent amounts of the pharmaceutically acceptable acid addition salts of 2amino-5-bromo-6-m-fluorophenyl-4-pyrimidinol for the free base of the examples.

EXAMPLE 35 Following the procedure of the preceding Examples 22 through 34, inclusive, compositions are prepared substituting equivalent amounts of 2-amino-5-iodo-6-(3-brnmophenyl)-4-pynmidinol; 2-amino-5-bromo-6-(3-fluorophenyl)-4-pyrimidinol; 2-amino-5-bromo-6-(3-ethoxyethylphenyl)-4-pyrimidinol; 2-amino-5-bromo-6-(2-methoxyphenyl)-4-pyrimidinol; 2-amino-5-chloro-6-(2-methoxyphenyl)-4-pyrimidinol; 2-amino-5-iodo-6-(methoxyphenyl)-4-pyrimidinol; 2-amino-5-bromo-6-(3-chlornphenyl)-4-pyrimidinol; 2-amino-5-iodo-6-(3-chlorophenyl)-4-pyrimidinol; 2-amino-5-chloro-6-(3-chlorophenyl)-4-pyrimidinol; 2-amino-5-chloro-6-(2-fluorophenyl)-4-pyrimidinol; 2-amino-5-chloro-6-(3-fluorophenyl)-4-pyrimidinol; 2-amino-5-bromo-6-(2-fluorophenyl)-4-pyrimidinol;; 2-amino-5-iodo-6-(3-fluorophenyl)-4-pyrimidinol; 2-amino-5-iodo-6-phenyl-4-pyrimidinol; 2-amino-5-chloro-6-phenyl-4-pyrimidinol; 2-amino-5-bromo-6-phenyl-4-pyrimidinol; 2-amino-5-chloro-6-(3-methoxyphenyl)-4-pyrimidinol; 2-amino-5-bromo-6-(3-methoxyphenyl)-4-pyrimidinol; 2-amino-5-iodo-6-(3-methoxyphenyl)-4-pyrimidinol; 2-amino-5-bromo-6-(2-pyridyl)-4-pyrimidinol; 2-amino-5-iodo-6-(3,4-dichlorophenyl)-4-pyrimldinol : 2-amino-5-bromo-6-(&alpha;-naphthyl)-4-pyrlmidinol : 2-amino-5-chloro-6-(3-nitrophenyl)-4-pyrimidinol; 2-a mino-5-iodo-6-(3-nitrophenyl)-4-pyrimidinol; 2-amino-5-iodo-6-(3-trifluoromethylphenyl)-4-pyrimidinol; 2-amino-5-ethyl-6-phenyl-4-pyrimidinol:: 2-amino-5-bromo-6-(3,5-dimethoxyphenyl)-4-pyrimidinol 2-amino-5-chloro-6-(3-propyloxyphenyl)-4-pyrimidinol; or the pharmaceutically acceptable acid addition salts or alkali metal or alkaline earth metal salts of each of the foregoing compounds for 2amino-5-bromo-6-m-fluorophenyl-4-pyrlmldinol of each of the examples. Those compositions are useful for preventing and treating viral infection and for inducing interferon production where administered as - described above and in Examples 22 through 34, inclusive.

EXAMPLE 36 Interferon induction in cats Cats were given 2-amino-5-bromo-6-phenyl-4-pyrimidinol orally. The drug was suspended in carboxymethyl cellulose at 50, 1 00 or 200 mg./ml. and 1 ml. was administered orally per kg. of body weight. Cats were bled periodically after drug administration and serum was collected and assayed for feline interferon on kitten kidney cells using a plaque reduction assay as previously described (Stringfellow and Weed, Am. J. Vet. Res., vol. 30, page 1963-1967 (1977). As indicated below, in Table 1, the drug effectively induced high levels of serum interferon indicating that it will be an effective antiviral agent in cats.

TABLE1 Serum interferon levels (units/ml.) after oral administration of 2-amino-5-bromo-6-pheny-4-pyrimidinol Dose (mg./kg.) Cat &num; Hours post drug administration 0 3 6 12 200 A * 10.200 1,300 320 B - 5,100 2,600 1,300 100 A - 640 320 80 B - 20,500 10,200 ND*** 50 A - 640 320 80 B - 1,280 80 80 Placebo** A - - - B - - - * - indicates a liter of less than 50 units/ml.

** placebo treated animals received vehicle (1 ml./kg.) without drug.

ND ND = Not done EXAMPLE 37 Effective treatment and prevention of a respiratory tract infection in bovines Calves were given 2-amino-5-bromo-6-phenyl4-pyrimidinol (1 gm/calf/day) intranasally once a day for 6 consecutive days beginning either 12 hours before or 6 hours after intranasal infection with infectious bovine rhinotracheitis (IBR) virus. Nasal swabs were collected daily for measurement of virus levels and three weeks after infection all calves were sacrificed and autopsied. The level of pneumonia was determined by gross examination. Using a scoring system of O to 5 each lobe of each lung was scored for degree of pneumonia. A score of 0 was given to each lobe with no pneumonia lesions, a score of 5 was complete lobe consolidation. Each lung had 7 lobes giving a maximum total score/lung of 35. The results presented in Table 2 indicate that the drug effectively reduced the severity of infection when given either therapeutically (6 hours after infection) or prophylacticaily (12 hours before infection).

Nasal virus titers correspond to development of pneumonia.

TABLE 2 Treatment No. calves/group Lung lesion score 12 hr. before infection 4 2.0 6 hr. after infection 4 5.0 Placebo given beginning 12 hr. before infection 4 14.0 EXAMPLE 38 Following the procedure of Examples 36-37 but substituting for 2-amino-5-bromo-6-phenyl-4- pyrimidinol the compositions described in Examples 22 through 35, inclusive, virus infection is prevented or treated and interferon production is induced.

Claims (39)

1. A compound for pharmaceutical use of the formula

wherein X3 is halogen, mono-, di- or tri- halomethyl, mono-, di- or tri-fluoroethyl, perfluoropropyl, C13 alkyl, 2-propenyl or 2-propynyl; and X1 is phenyl; o-substituted phenyl in which the substituent is C1-8 alkyl. C18 alkoxy, halogen or nitro; m-substituted phenyl in which the substituent is halogen, nitro, CF3, C C1~8 alkoxy (C15 alkoxy)ethoxy or NR5R6 in which either R5 and R6 are the same or different and are each C1B alkyl or benzyl or NR6R8 is a C36 saturated heterocyclic ring optionally substituted by two C1-3 alkyl groups; psubstituted phenyl in which the substituent is halogen or C13 alkyl; disubstituted phenyl in which the substituents are independently selected from halogen, C18 alkyl, C18 alkoxy, nitro and CF3; trihalophenyl; optionally substituted a-naphthyl in which any substituent is C18 alkyl, C18 alkoxy.

halogen or nitro; 2-furyl; 2-pyridyl; 3-pyridyl or 2-pyrazyl; with the proviso that X1 is not dimethoxyphenyl when X3:Is C1-3alkyl ; or a salt thereof.

2. A compound as claimed in claim 1 with any part or all of the additional provisos (1) that X1 is not methoxyphenyl or dimethoxyphenyl when X3 is C13 alkyl or 2-propenyl; (2) that X1 is not alkoxyphenyl or dialkoxyphenyl when X3 is C13 alkyl or 2-propenyl; (3) that X1 is not phenyl when X3 is C1 alkyl.

3. A compound as claimed in claim 2 for the induction of interferon production, the prevention of skin graft rejection or the treatment or prevention of virus infections, acquired or congenital hype;gammaglobulinemia, cancer, bacterial infections, parasitic infections or aplastic anaemia.

4. A compound of the formula defined in claim 1, optionally with any or all of the provisos of claim 2, with any part or all of the additional provisos that (1) X1 is not phenyl when X3 is halogen, C13 alkyl, 2-propenyl or 2-propynyl and (2) X, is not a-naphthyl. 2-furyl, 3-pyridyl, 2-pyridyl or 2-pyrazyl when X3 is C13 alkyl, 2-propenyl or 2-propynyl.

5. A compound as claimed in any preceding claim wherein X3 is halogen.

6. A compound as claimed in any of claims 1 to 4 wherein X3 is C1-3 alkyl.

7. A compound as claimed in claim 5 wherein X1 is phenyl.

8. A compound as claimed in 5 wherein X1 is as defined in claim 1 but is not phenyl.

9. 2-Amino-Bromo-6-phenyl-4-pyrimidinol, or a salt thereof, for pharmaceutical use.

10. 2-Amino-5-bromo-6-phenyl-4-pyrimidinol. or a salt thereof, for the induction of interferon production, the prevention skin graft rejection or the treatment or prevention of virus infection, acquired or congenital hypergammaglobulinemia, cancer, bacterial infections, parasitic infections or aplastic anaemia.

11.2-Amino-5-iodo-6-(3-bromophenyl)-4-pyrimidinol.

12. 2-Amino-5-bromo-6-(3-fluorophenyl)-4-pyrimidinol.

13.2-Amino-5-bromo-6-(3-ethoxyethylphenyl)-4-pyrimidinol.

14. 2-Amino-5-bromo-6-(2-methoxyphenyl)-4-pyrimidinol.

15.2-Amino-5-chloro-6-(2-methoxyphenyl)-4-pyrimidinol.

16. 2-Amino-5-iodo-6-(2-methoxyphenyl)-4-pyrimidinol.

17. 2-Amino-5-bromo-6-(3-chlorophenyl)-4-pyrimidinol.

18. 2-Amino-5-iodo-6-(3-chlorophenyl)-4-pyrimidinol.

19. 2-Amino-5-chloro-6-(3-chlorophenyl)-4-pyrimidinol.

20. 2-Amino-5-chloro-6-(2-fluorophenyl)-4-pyrimidinol.

21. 2-Amino-5-chloro-6-(3-fluorophenyl)-4-pyrimidinol.

22. 2-Amino-5-bromo-6-(2-fluorophenyl)-4-pyrimidinol.

23. 2-Amino-S-iodo-6-(3-fluorophenyl)-4-pyrimidinol.

24. 2-Amino-5-iodo-6-phenyl-4-pyrimidinol.

25.2-Amino-5-chloro-6-phenyl-4-pyrimidinol.

26. 2-Amino-5-iodo-6-(24luorophenyl)-4-pyrimidinol.

27. 2-Amino-5-chloro-6-(3-methoxyphenyl)-4-pyrimidinol.

28.2-Amino-5-bromo-6-(3-methoxyphenyl)-4-pyrimidinol.

29. 2-Amino-5-iodo-6-(3-methoxyphenyl)-4-pyrimidinol.

30. 2-Amino-5-bromo-6-(2-pyridyl)-4-pyrimidinol.

31.2-Amino-5-iodo-6-(3,4-dichlorophenyl)-4-pyrimidinol.

32. 2-Amino-5-bromo-6-(a-naphthyl)-4-pyrimidinol.

33. 2-Amino-5-chloro-6-(3-nitrophenyl)-4-pyrimidinol.

34.2-Amino-5-iodo-(3-nitrophenyl)-4-pyrimidinol.

35. 2-Aminb-S-ioclo-6-(3-trifluoromethylphenyl)-4-pyrimidinol.

36. 2-Amino-5-bromo-6-(44luorophenyl)-4-pyrimidinol.

37.2-Amino-5-bromo-6-(3,5-dimethoxyphenyl)-4-pyrimidinol.

38. 2-Amino-5-chloro-6-(3-propyloxyphenyl)-4-pyrimidinol.

39. A pharmaceutical composition comprising a compound as claimed in any preceding claim in association with a physiologically acceptable excipient.