DE3008693A1 - 6-ARYL-PYRIMIDINE COMPOUNDS - Google Patents

Description

The preparation and use of 2-amino-5-halo-6-alkyl-4-pyrimidinols as antiviral agents is known (see US Pat. No. 3,956,502 and Nicols, Weed and Underwood, Antimicrobial Agents, Chemo.Ther. 9 Kyp , 1976). The preparation of 2-amino-5-bromo-6-phenyl-4-pyrimidriol (compound V, where X, bromine and X _{1 are} phenyl) was described by Brown and Stevens, JCS Perkin I, 1023, 1975. » described, but without any indication of usability. The GB-PS

1,223,686 describes a number of 5,6-disubstituted 2-amino-4-pyrimidinols such as 2-dimethylamino-5-bromo-6-methyl-4-pyrite-bi3einol, but no antiviral properties are found. Various 5-position unsubstituted 2-amino-6-arylpyrimidinole are known (see, for example Shirahawa, Yakuyaku Passhi 50, 1562, i960 (CA 55 '10651b); Kulkarui et al, J.Sei and Ind Res.... Ihdil. 19C, 6, 19öOj US-PS 2,776,283. The diuretic and heart-regulating properties of various 2-amino- and 2- (substituted-amino) -5-aminomethyl- and -S-aryl-ö-aryl - ^ - pyrimidinols are in the US PSS

2,704,285, 2,723,777 and 2,776,285. Here too antivirus properties are not reported.

The 2-amino-5-bromo-6-methyl-4-pyrimidinol (see US Pat. No. 3,956,302) Although it shows antiviral and interferon-inducing effects, it has been found that the therapeutic application this compound is limited to smaller doses because the material in the urine and kidney is of high therapeutic value Can-receiving animals crystallized.

The novel 5-substituted 2-amino-6-arylpyrimidinols according to the invention show antiviral activity, improved therapeutic index and fewer side effects and are useful for the prevention and treatment of viral infections. The antiviral effect of numerous compounds according to the invention is with linked to increased interferon production. Other inventive

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bulk compounds show antiviral activity, but yield no increased interferon production.

The invention relates to new 6 -aryl -pyrim id inve rbindungen and a broader group of such compounds which can be used for treatment and preventing virus infections and inducing interferon production and altering the i% nunoregulatory system eig_xien.

The compounds according to the invention are made from β-ketoesters manufactured. The ß-keto esters used as starting material are obtained as follows:

a four step process begins with a connection of the Formula Ia, in which Z is an alkyl radical having 1 to 5 carbon atoms, including isomeric forms, or a residue

the formula

^R io;

S.
I.
R ₁₂

-Si-R ₁₁

represents in which R _1Q , R ₁₁ and R ₁₂ , which can be the same or different, denote alkyl radicals having 1 to 5 carbon atoms, including isomeric forms, or the phenyl radical. X and X ₁ have the meaning given above.

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'Sti

ο Il

CH ₂ -C

- OZ Ia

Step 1

L i -B a s e

H O I Il

• _c _c_ c — oz

Li Li

Level 2

0
X ₁

0 II -C- halogen

H 0

I Il

C-C-OZ

C = O

0-Li

level 3

(-) CO ₂

Li

c Λ Λ -oz Ib

Ic

Id

step

Il
C-CH ₂ -C -OZ

π O) level * <2)

H Q

O ^ II ^ CCC-

/ I

X, X

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For the sake of clarity, the reaction sequence is given as four stages, but from the chemist's point of view it is "one-stage", because it takes place in a single reaction vessel and no separation and purification operations after each reaction required are.

In step 1, the starting material, a monoalkyl malonate, and preferably the monoethyl malonate, Ia (Z = CgH ₁ -) is reacted in a dry solvent with 2 equivalents of a lithium base at a reduced temperature. Suitable dry solvents are, for example, tetrahydrofuran, diglyme, glyme, dioxane, hexamethylphosphoric acid triamide or dimethylformamide. A lithium base is understood to mean compounds of the formula Ro-Li, where R _Q den

^ö s- ^ö η-butyl, methyl, phenyl, t-butyl or butyl radical, or of the formula (R ") pj in which R_ represents the isopropyl, cyclohexyl or trimethylsilyl radical or a corresponding combination. n-Butyllithium is preferred.

Under reduced temperature is meant a temperature of O to -80 ⁰ C, being preferred as a starting temperature of about -70 ⁰ C.

After the addition of the lithium base and simultaneous temperature rose the reaction mixture is cooled again to about -65 ⁰ C abge, followed by an acid halide of the formula X · ¹ CDHalogen is added (Step 2). The acid halide can be added neat or in a dry solvent. Preferably, the acid halide in dry solvent is added dropwise at about -65 ⁰ C.

The optimal ratio of malonate to acid halide to achieve the highest yields is 1.7 (or more). The Acylie

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(Stage 2) and decarboxylation (stage 3), which the compound Id results is accelerated if the reaction mixture is allowed to slowly warm to room temperature.

In the work-up stage 4 (1), the reaction is only stopped at the appropriate time with dilute acid ,, then is extracted with ether. The organic phase is with B £ ~ Washed carbonate solution, dried and concentrated, the desired β-ketoester II (1) being obtained.

In alternative stage 4 (2) (X is not hydrogen) at least 1 equivalent of X is chloride, bromide or iodide (preferably X-bromide or X-iodide) added at room temperature, whereupon the reaction mixture is left to stand until the Alkylation is complete. If desired, the mixture can be heated to accelerate the alkylation. Then that will Mixture treated with dilute acid, extracted with ether and the ether phase is washed and concentrated, as in step 4 (1) described. This gives the desired njU-substituted β-keto ester II (2). If desired, connection 11 (2) can be further purified in a conventional manner, for example by chromatography, distillation and the like.

example 1
Isobutyrylacetic acid ethyl ester

19 * 8 g (14-7 millimoles) of monoethyl malonate, 350 ml of dried tetrahydrofuran and 2 mg of bispyridyl are poured into a 1 liter three-necked flask equipped with a nitrogen inlet, thermometer and stirrer. The solution is ^{cooled to -70 0} C, then a 1.6 molar solution of

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n-Buty! lithium in hexane (Poote Chemicals Co. or Aldrich Chemical Co.) is added dropwise at -70 to -5 ° C until a pink color persists. The temperature is allowed to rise slowly to -5 ° C during the addition of the butyllithium, whereby the ros => coloration that has arisen disappears. After the pink coloring 5 min at -5 ° C consist büefc (addition of about 10 ml of butyllithium solution), the mixture is cooled to -65 ⁰ C, then 7.9 ml (7.98 g, 75 Millimo] isobutyryl chloride at -60 to -65 ° C. The solution is stirred vigorously at -60 to -65 ° C. for 5 minutes and poured into 50 ml of iodine plus 300 ml of ice-cold 1N hydrochloric acid. After shaking, the phases are separated and the organic phase is mixed with twice 150 ml of saturated aqueous sodium bicarbonate solution each and washed once with 150 ml of water and dried over anhydrous sodium sulfate. The ethereal solution is then filtered, the solids are washed with ether and the combined filtrates are concentrated to dryness. This gives 11.7 g (98%). 4 %) ethyl isobutyrylacetate with a molecular weight of 158.19.NMR (CDCL ·,):

S 4.38-4 (q, 2H, P 1 -C H ₂ -CH ₅ ), 3.5

(s, 2H, COCHp CO), 2.96-2.41 (m, 1H, CH (CH, ) ₂ ) _f 1.46-1 (m, 9H, CH,) '.

GLPC (gas / liquid distribution chromatography) RT = 3.2 (τ = 90 °, y, 3 % ov 17)

GC / MS M ⁺ m / e 159 ( $ 27), H6 (100 %)

Example 2 '. ^!

n-Butyrylacetic acid ethyl ester

If the process for the preparation of ethyl isobutyrylacetate is repeated, but using 7 * 98 g

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~ Z1-

(75 millimoles) of n-butyryl chloride in 50 ml of dry tetrahydrofuran instead of the 7.9 ml of isobutyryl chloride, 11.4 6 (96.6 %) of the title compound with a molecular weight of 158.19 are obtained.

NMR (CDCl,):

"5 * from 4.38 to 4.0 (q, 2H, OCH), 3.43 (s, 2H, COCH ₂ CO), (m, 2 H COCH ₂ CH _2), 1-91-0,78

(m, 1OH, ^ ₅ CH ₂ CH ₂ C, CH, CH ₂ O)

GLPC RT- = 3.1 min (T = 90 °, 3 ¹ , 3 % OV 17)

Example 3
Ethyl propionylacetate

If the process for the preparation of ethyl isobutyrylacetate is repeated, but using 71 g of monoethylmalonate (0.613 mol), 1300 ml of tetrahydrofuran and 58 »1 g of propionyl chloride (0.305 mol) in 300 ml of tetrahydrofuran (added dropwise), 42.0 is obtained g (95 * 2 %) of the Ti te! compound as an oil (molecular weight 144.17).

NMR (CDCl,):

(T 4.36-4 (q, 2H, O-OT ₂ -CH ₃ ), 3.41

(s, 2H, CO-CH ₂ -CO), 2.75-2.38 (q, 2H, COCH ₂ ), 1.5-0.86 (m, 5H, CH ₃ ).

GLPC RT = 5.6 min (90 °, 6 ', 3 # OV 17) GC / MS M ⁺ m / e (76.5 %)> 115 (100 ^)

Example 4
Ethyl phenylacetylacetate

If the procedure is repeated: / of ethyl isoDutyryatissigsaureester, but using 10.0 ml (11.69 S * 75 millimoles)

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Phenylacetyl chloride (Aldrich Chem. Co) instead of the 7.9 ml Isobutyryl chloride, 15.4 g (98.8 #) of the title compound are obtained of molecular weight 206.23.

NMR (CDCl,):

<f 7.38-7.13 (m, 5H, Ar), 4.31-3.95 (q * 2H, OCH ₂ ), 3.78 (s, 2H, CH ₂ ), 3.38 (s , 2H, COCH ₂ ), 1.33-1.11 (t, 3H, CH ₃ ).

Example 5
/ Ethyl benzoylacetate

Repeating the procedure for preparing ethyl isobutyrylate, but using 6.06 g of monoethyl malonate (45 millimoles), 250 ml of tetrahydrofuran and 2.64 ml of benzoyl chloride (3.15 g, about 2.55 millimoles), gives when the reaction mixture is stirred at -65 ° C. for 60 minutes, 4.18 g (97 $) ethyl benzoyl acetate as an oil, molecular weight 192.21. This product was isolated as a ^{mixture of tautomers (H 1} -NMR).

NMR (CdCl ₃ ): H OH

S 8.06-7.25 (m, 5H, Ar), 5.66 (s, 0.2H, CfC), "4.43-3.96 ^ (m, 3.9H, OCH ₂ CH ₃ , COOIpCO), 1.45-1.11 (m, 3H, CH ₃ ). GLPC RT- = 3.1 min (85, 60 cm, UCW-98-2) GC / MS M ⁺ m / e 192 (6.8 %), I05 (100 %).

Example 6
Toluylacetic acid ethyl ester

Repeat the process for the preparation of benzoyl acetic acid ethyl ester, but using 15.5 g of monoethyl malonate (115 millimoles), 500 ml tetrahydrofuran and 11.1 g

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(78.1 millimoles) of toluyl chloride, 13.44 g (90.8 %) of ethyl toluene acetate are obtained as an oil. The H 'NMR spectrum indicates the product is a mixture of tautomers, molecular weight 206.23.
NMR (CDCl ₃ ):

6 8.05-7.61 (m, 2H, 2,6-ArH), 7.41-7.13 (a, 2H, 3,5-ArH), 5.63 (2, 0.15H, C = C), 4.41-4.03

H OH

(m, 2H, CH ₂ CH _3), 3.95 (s, 1.6 H, COCHgCO), 2.4 (s, 3H, ArCH _3), 1.43 to 1.11 (m, 3H, CH ₂ CH ₃ ).

Example 7
Anisoylesslgsäureethylester

If the procedure for the preparation of ethyl benzoyl acetate is repeated, but using 15.5 S monoethyl malonate (115 millimoles), 400 ml of tetrahydrofuran and 12.24 g (71.8 millimoles) of anisoyl chloride, 14.45 g (90 %) are obtained Anisoylesslgsäureethylester as an oil with a molecular weight of 222.23.
NMR (CDCl ₃ ):

£ 8.03-7.86 (m, 2H, 2,6-ArH), 7.08-6.86 (m, 2H, 3,5-ArH), 4.38-3.85 (m, 7H , OCH ₃ , COCH ₂ CO, OCJI ₂ CH ₃ ), 1.36-1.13 (t, 3H, CH ₂ CJ ₃ ).

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Example 8
ethyl p-chlorobenzoyl acetate

If the procedure for the preparation of ethyl benzoyl acetate is repeated, However, using 15 * 5 g of monoethyl malonate (115 millimoles), 400 ml of tetrahydrofuran and 1.5 g (71.5 millimoles) of p-chlorobenzoyl chloride is obtained 15.56 g (95.6 #) of p-chlorobenzoyl acetic acid ethyl ester as Pestilence. When an analytical sample is recrystallized from methanol, the solid p-chlorobenzoyl acetic acid becomes ethyl ester obtained as a tautomer mixture, molecular weight 226.65

NMR (CDCl,):

cT 7.95-7.21 (m, 4H-ArH), 5.61 (s, 0.27H, C = C), 4.4l-4

H OH

(m, 2H, CH ₂ CH ^), 3.9 (s, 1.36 H, COCH ₂ CO), 1.43-1.1 (m, 3H, CH ₀ CH,). ■

Analysis:

calculated for: ^c ii ^H in ^cl0 3 ^:

C: 58.28, H: 4.89, Cl: 15.64, found:. C: 58, ^, H: 5.13, Cl: 15.32.

Example 9

3,4-dichlorobenzoyl acetic acid ethyl ester

Repeating the procedure for making Benzoylessij acid ethyl ester, but using 15.5 g (115 Mii: mol) monoethyl malonate, 400 ml of tetrahydrofuran and 12.0 g

j (57.5 millimoles) 3,4-dichlorobenzoyl chloride, 14, | are obtained

(97 %) 3, ^ -Dlchlorobenzoyl acetic acid ethyl ester. This material *

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crystallized on standing at -12 ⁰ C slowly and was isolated as a mixture of tautomers, molecular weight 261.1.

NMR (CDCl ₃ ):

cf 8.06-7.5 (m, 3H, ArH), 5.63 (s, 0.3H, H OH

fc = C), 4.4-4.03

(m, 2H, CH ₂ CH ₃ ), 3.93 (s, 1.42 H, COCH ₂ CO), 1.46-1.13 (m, 3H, CH ₂ CH ₃ ).

Analysis; ·

calculated for: ^c n ^H io ^C1 2 ° 3 ^:

C: 50.59, H: 3.86.
Found: C: 50.21, H: 4.79.

Example 10
oi-ethylbenzoyl acetic acid ethyl ester

300 ml of tetrahydrofuran and 5 mg of 5 $ pyrE 3yl are added to 13.2 g of monoethyl malonate. At -70 to -10 ⁰ C butyllithium is added until a pink color persists. The reaction mixture is again cooled to -70 ⁰ C and treated with 6.4 ml of benzoyl chloride (0.06 mol). After stirring for one hour at -60 ° C., 28.2 g (0.182 mol) of ethyl iodide are added and the reaction mixture is stirred at room temperature for 18 hours. The mixture is then ^{heated to 50 °} C. and kept at this temperature for 90 hours. The mixture is then poured into 500 ml of methyl ether plus 300 ml of In hydrochloric acid, the layers are separated and the organic phase is washed once with In hydrochloric acid, once with saturated aqueous sodium bicarbonate solution and once with water. After drying over anhydrous sodium sulfate, filtering and concentrating, 13.6 g of ethylbenzoyl acetic acid ethyl ester are obtained as an oil.

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NMR:

8.11-7.91 (m, 2H, 0), 7.66-7.30 (m, 3H, 0), 4.35-3.96 (m, 3H, COCHCO, OCHpCH,), 2, 30-1.80 (m, 2H, CH ₀ CH,), 1.43-0.76 (m, 6H,

The novel compounds according to the invention correspond to formula

The compounds can be in tautoral form as follows;

N'H

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The pyrimidine compounds can also be referred to as isocyanates and so you can, for example, the 2-amino-5-bromo-6-fluorophenyl-4-pyrimidinol also S-bromo-o-m-fluorophenylisocytosine to name.

The new pyrimidines (V) can in the following way from the

ß-ketoesters described above are produced:

NH '' ι

11 (2) + · Il OH

H ₂ N

NH,

III

11 (1) ⁺ ΙΠ

OH

IV

V (X ₃ »X or.

V (X ₃ - X ₄ )

The condensation of the ß-ketoester 11 (2) with guanidine (III) can in polar solvents such as ethanol, isopropanol, 1-butanol, Dimethylformamide or the like, with ethanol being preferred, in the presence of a base such as one Carbonate (for example sodium carbonate or guanidine carbonate) or an alkoxide (such as sodium ethylate) and the like, in

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usually under reflux. The product V (where X ^ X, or X, - means) is isolated by neutralizing, of the reaction mixture after the end of the condensation (by thin-layer chromatography determined) with acid or carbon dioxide, filtration or chromatography, proceeding in a conventional manner.

The preparation of compound V (where X-, the same Meaning like Xj, has) is based on the corresponding ß-Ketoester 11 (1) and guanidine (III), whereby one in above proceeds as described and the compound IV is obtained. The subsequent halogenation of the compound IV, for example by treatment with N-chlorosuccinimide in acetic acid to form the compound V, where X -, = Xk = C1, or for example by treatment with bromine in acetic acid to form a compound V wherein X-J = X ^ = Br, or for Example by treatment with one equivalent of ln sodium hydroxide and then with iodine in chloroform, whereby one a connection V with Χ, = Χ ^ = Ι can be carried out for the formation of new pyrimidines V, where X ^ = Xj, means. Further" Halogenation procedures are described below. The final pyrimidines can be isolated by concentration in vacuo, triturating the residue with water and filtering off the solid.

Example 11

General procedure for making pyrimidine of formula

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H
O

N '

The compounds obtained in this way are summarized in the table.

Procedure 1:

Condensation to form a compound IV or V = X or X ₅ ).

120 ml of absolute ethanol and 20 ml of toluene are added to 20 millimoles of powdered!] Guanidine carbonate in a nitrogen atmosphere. The reaction mixture is refluxed and 50 ml of solvent are distilled off. The mixture is then ^{cooled to 45 °} C. and 40 millimoles of the β-keto ester (II) or 11 (2) are added. The mixture is refluxed with stirring, ^bi | _e ^ ^e reaction according to the thin-layer chromatogram appears to / appears to have ended. Then 50 ml of water are added and the mixture is refluxed for a further 30 minutes, then the reaction mixture is ^{cooled to 20 °} C. and neutralized with dry carbon dioxide or 1N aqueous hydrochloric acid. The mixture is cooled for 18 hrs. At 5 ⁰ C and filtered, the resulting precipitate is washed thoroughly with water und'dann with diethyl ether. The pesticides are dried at 60 C under vacuum, the desired lyrimidine is obtained as a white solid. If the crude product is not analytically pure, it can be recrystallized from suitable solvents, for example from dimethylformamide, aqueous ethanol and the like.

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r20-

Method 2;
condensation

The reaction is carried out as described under process 1, but after neutralization (addition of carbon dioxide or 1N hydrochloric acid) the aqueous mixture is concentrated to dryness in vacuo, then 10O ml of water and 100 ml of ethyl ether are added. The mixture is poured and ^{left to stand at 5 °} C. for 18 hours. It is then filtered and the solid is washed well with water and then with ethyl ether. Drying and crystallization are carried out as in method 1, the analytically pure lyrimidine being obtained. ,

Method 3:
Bromination (X ^

80 ml of glacial acetic acid are added to 15 millimoles of the corresponding pyrisslidine. The reaction mixture is heated to 50 ⁰ C, to cause the solution (if present at 22 ° C Peststoffe in the solution must be heated), then 0.8l ml of bromine are added. The solution is stirred at room temperature / 3 hours, then the reaction mixture is in vacuo

concentrated to dryness and the resulting pest is mixed with 150 ml of hot water. The slurry is refluxed and cooled to 22 ° C. The pests are filtered and washed well with water. They are then pulverized and reheated with 150 ml of water as described. This procedure is repeated. The pyrimidine is dried in Vakuumt ro ckens ore ank at 60 ⁰ C, to yield the analytically pure material. If necessary, recrystallization can be carried out from water and dimethylformamide

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taking dimethylformamide slowly with stirring to a Slurry the compound in 150 ml of boiling water admits until solution occurs. By cooling down and then The analytically pure material is obtained by filtering.

procedure

Bromination (X-S = Br)

80 ml of water and 0.66 g (16.5 millimoles) of sodium hydroxide are added to 15 millimoles of the corresponding pyrimidine. The solution is stirred at room temperature for 30 minutes, then 0.9 ml of bromine (22.62 g _; 16.5 millimoles) in 50 ml of chloroform is added. The reaction mixture is stirred vigorously for 2 hours and then filtered. The solid is washed well with water and then with ether and dried at 60 ° C. in a vacuum drying cabinet for 18 hours. When recrystallizing from water and dimethylformamide, as described in process 3, the analytically pure material is obtained.

Procedure 5:
Coding (XZ = I)

50 ml v / water and 0.80 g (20 millimoles) sodium hydroxide are added to 15 millimoles of the corresponding pyrimidine. The mixture is ^{heated to 50 °} C. with stirring until solution occurs. A slurry of 3.79 g of powdered iodine (15 millimoles) in 100 ml of chloroform is then added. Remaining iodine is washed into the reaction vessel with a further 30 ml of chloroform. The mixture is stirred vigorously at room temperature for 4 hours.

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Then the pest is filtered off, washed well with water (until the water is neutral to pH paper), then washed with acetone or ethyl acetate until the organic wax solution is colorless. It is often a good idea to pulverize the pesticide before washing. It is then ^{dried at 60 ° C.} in a vacuum drying cabinet. If the material is not analytically pure, it can be recrystallized from water and dimethylformamide by slowly adding dimethylformamide to a vigorously stirred suspension of the ityriäidin in 150 ml of boiling water until it dissolves. While cooling, filter
Material.

Filtering and drying at βθ C gives the analytical grade

Procedure 6:
Iodination (X ₃ = I)

25.0 ml of glacial acetic acid and 4 J4 mg (2 millimoles) of N-iodosuccinimide are added to 1.95 millimoles of the corresponding pyrimidine. The reaction mixture is stirred for 5 days at room temperature, then concentrated to dryness in vacuo at 50.degree. The solid is purified by refluxing it with 50 ml of absolute ethanol and cooling it to room temperature. After filtering and washing with absolute ethanol, pure 5-iodopyrimidine is obtained.

Procedure ¹ J:
Chlorination

To 0.1 mol of a 6-arylpyrimidine 500 ml of glacial acetic acid and 1 ^ 16 g (0.11 mol) of N-chlorosuccinimide were added. The reaction mixture is heated on the steam bath for 1 1/2 hours, then to 22

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cooled, concentrated to 200 ml and filtered. The thus obtained The solid is washed with glacial acetic acid and then with ethyl ether and dried at 60 ° C. in a vacuum drying cabinet. If the solid is not analytically pure, it can be recrystallized from water and dimethylformamide by Add dimethylformamide to a boiling slurry of the fyrimidine in 500 ml of water until it dissolves. At the Cooling and filtering off gives the analytically pure 5-chloro-6-arylpyrimidine.

Procedure8:
Fluorination (X, = F)

The introduction of fluorine in the 5 position of the yrimldine ring takes place by fluorine & ung the compound IV with trlfluoromethyl hypofluorite followed by treatment with base by the method of M. J. Robbins and S.R. Naik, J. Am. Chem. Soo. 93, 5277 (1971). You can also, if desired, the compound IV fluorine directly with the fluorine / ityridine complex to form a compound V wherein X, = F, following the procedure Von H. Meinert and D. Cech, Z. Chem. 12, 292 (1972).

Procedure 9?

Establishing a connection V

A compound V in which X, = CF- ,, can be prepared starting from a compound V, in which X, = I, through Exchange procedure according to the regulation of D.Cech, R. Wohlfeil and G. Efzold, Nucleic Acids Research 2, 2183 (1975) and Y. Kobayashi, I. Kumadaki and F. Yamamato J.C.S. Chem. Comm. (1977) using trifluoromethyl iodide and copper bronze.

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The 5-perfluoroalkylpyrimidines (V, X, = perfluoroalkyl) using perfluoroalkyl iodides getting produced.

Furthermore, if desired, the trifluoromethyl or Introduce perfluoroalkyl group in an earlier stage and the resulting trifluoromethyl or perfluoroalkyl-ß-ketoester then condense with the guanidine according to method 1 or 2, whereby, one the compound V (X, = CF or perfluoroalkyl) receives. A trifluoromethyl or perfluoromethyl-β-keto ester can be prepared by known methods are executed. For example, condensation provides a compound of the formula

0
X ₁ CF

with vinyl fluoride in the presence of antimony pentafluoride a Compound of the formula ~

X .. CCHgCF.,,

and carry out the carbalkoxylation under standard conditions to connection 0

X ₁ CCH (CF ₃ ) CO ₂ C ₂ H

Procedure 10:

Preparation of a compound V (X ₅ = CH ₂ -X ^)

A compound V in which X ^ = CHpXh can be prepared in a known manner from the corresponding hydroxymethyl compound (V, X, = CH ₂ OH) under standard conditions. This intermediate product is made from a compound under standard conditions

0 300 40/0 63 9

and formaldehyde or from an appropriately protected β-keto ester, for example ArCOCH (CH ₂ OCH ₂ ^) CO ₂ Et .., which in turn is formed from a compound I in which X = -CH. The hydrogenolytic or protolytic removal of the benzyl group leads to the compound V, where X, = CH ^ OH, after condensation of the β-ketoester with guanidine according to method 1. The resulting 5-hydroxymethylpyrimidine is converted into the corresponding 5-halomethylpyrimidine in a known manner, either by displacement reaction with the corresponding 5-tosyloxymethyl derivative (formed with toluenesulfonyl chloride in pyridine) with alkali or alkaline earth metal halides, or directly by the known method with phosphine / Tetrahalocarbon.

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X ₁ Author
^x no.
a - 36- H N P 3008693 - 0 7 Table 1 - calculated: C. 3.63 18.95 - Cl Br Cl found. : 3.75 19.15 ■ - - - 0 3 54.19 15.99 - - calculated: 54.64 3.03 15.79 - 15.38 - Br found. : 3.00 15.66 - - - _ 0 5 45.13 30.03 - - calculated: 45.20 2.57 13.42 - 29.92 I. found. : 2.57 13.28 - 44, -27 0 1 38.36 43.36 calculated: 38.46 5.51 20.88 - CH, found, : 5.38 20.86 - - r, 0 1 65.65 calculated: 65.52 6.08 19.52 - CH CH found. : 5.94 19.63 - 4-CH,
0-HBi 3 66.95 calculated: 66.63 2.79 11.63 - Br found. : 3.18 12.01 - 4-CH, 0 5 36.59 calculated: 37.48 3.08 12.84 - I. found, : 3.19 12.93 - 40.38 40.32

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Table 1 (port setting)

^X 3 X ₁ Author
No. C. H N P. 93
84 Cl Br ' I. Br 4-Cl 0 3 68
74 Cl calculated:
found, :
3-P 0 7 39.96
39.92 2.34
2.38 13.98
* 14.12 - 74
59 11.79
10.65 26.59
27.87 - Br calculated:
found, :
3-P 0 3 50.12
50.16 ro ro
VO VO
O Ui 17.53
17.43 7,
7, 14.80
14.40 - - I. calculated:
found, :
3-P 0 5 42.27
42.24 2.48
2.47 14.79
14.73 6,
6, - 28.13
28.15 - Br calculated:
found ^:
3-Br 0 3 36.27
36.30 2.13
2.18 12.64
12.65 5,
5, - 38.73
38.10 I. calculated:
found ^:
3-Br 0 5 34.8l
34.78 2.04
1.78 12.18
12.15 - - 46.32
45.72 - G
Cl calculated:
found, ;
3-1 0 7 30.64
30.95 1.80
1.89 1Q72
11.05 - - 20.38
20.54
I. 32.07
32.06 calculated:
found, : 34.56.
34.55 2.03
1.94 12.09
11.77 - 10.20
10.54 - 36.51
36.2

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Cable 1 (port setting)

, X ₁ author.

¹ No. CHNP Cl Br 1

et

Br 3-1 0 3

calculated: l 30.64, 80 10.72 - - 20.39 I

found _Fe : 30.86 1.94 10.90 - - 20.10 I.

3-1 0

calculated: 27.33 1.60 9, 57 - - - found,: 27.58 1.77 9, 62 - - - Cl 3-CH, 0 0 7 calculated: 52.58 3.98 16 .73 - 13th .94 - found, : 52.22 3.95 16 .65 - 13th .91 - Br 3-CH, 0 0 3

calculated: 44.59 3.40 14.19-26.99
found ^: 44.22 3.62 14.11 - - 26.59

3-CH ^ O 0 5

calculated: 38.51 2.94 12.25 -. -. - 3

found ^: 38.78 3.03 12.16 - - - 3

Br 3-NO ^ 0 3

calculated: 38.6l 2.27 l8.01 - - 25.68 -

found _b : 38.71 2.23 18.23 - - 25.75 -

calculated: 33.54 1.97 15.65 - - - 3 found _b : 31.97 1.91 14.96 - - - 3

030040/0639

Table 1 (Ports.)

X ₁ Author

^x No. C HN P Cl Br

Br, 3-CF, 0.3

calculated: 39.54 2.11 12.57 17.06 - 2 ^, 92 found _b : 39.79 2.02 12.8θ 17.04 - 24.11

calculated: 34.66 1.85 11.02 14.95 - - 33.30

found _b : 34.65 1.47 11.22 14.87 - - 33.39

H nl-naphthyl 1

calculated: 70.87 4.67 17.71 -

found _b : 70.76 4.76 17.49 -

Br nL-naphthyl 3

calculated: 53.18 3.19 13.29 -

found _b : 53.05 3.24 12.71 -

Cl 2-yuryl 7

calculated: 4-5.40 2.85 19.86 -

found _b : 4-5.53 2.87 19.56 -

Br 2-furyl 4

calculated: 37.52 2.35 l6.4l - - 31.20

found ^ · 36.66 2.41 16.10 - - 32.39

2-furyl 5

- , 75 25, 27 - , 33 25, 23 16 _ 17th -

calculated: 31.70 2.00 13.87 found _b : 33.10 1.94 14.40

$ 630040/063

Table 1 (cont.)

X ₁ Author

No. C H N F. Cl Br. I.

calculated: 46.30 2.77 11.57 -

found _b : 46.54 2.90 ll, 4l -

CH, ct-naphthyl 1 71.69 5.21 16.72 -

70.91 5.34 16.75 -

I 4-Cl 0 5

calculated: 34.56 2.03 12.09

found _b : 35.00 2.29 12.46

Br 3,4-Cl ₂ 0 3

calculated: 28.87 1.45 10.10

found: 29.68 1.77 10.86

3,4-Cl ₂ 0 5

calculated: 31.44 1.58 11.00

found _b : 31.27 1.65 10.99

(. Br 3,5-Cl ₂ 0 3

calculated: 35.85 1.80 12.54

found _b : 36.07 1.82 12.69

I 3,5-Cl ₂ 0 5

calculated: 31.44 1.58 11.00

found _b : 31.12 1.50 10.75

10, 20th - 43 36 10, 64 - 28 35 17, 05 38, 16, 64 38, - 18 56 . 85 33 17, 07 85 35 21 17th 23, 20, 18th 25, - 18 56 33 19 20th _ 28

030040/0639

X ₁ Author
No. _a Table 1 (Ports.) HNP Cl 3008693 2,5-OU0 7 C. Br I Cl calculated:
found. : 2.08 14.46 -
2.18 14.63 - 36,
36, 41.33 61 -
50 -

P. 260 to 280 C (decomposition)

Br 2,5-Cl ₂ 0 calculated:

found. : P. 255 to 275 ⁰ C (decomposition)

2,5-Cl ₂ 0

calculated: 31.44 1.58 11.00 -

found ^ 31.54 1.62 10.98 - -. P. 180-181 ° C

Cl 3-Cl 0 7

calculated: 46.90 2.75 l6.4l - 27.69 -

found _fe : 46.95 2.67 16.54 - 27.91 -

Br 3-Cl 0 3

calculated: 39.96 2.34 13.98 - 11.79 26.59 -

found _b : 40.33 2.40 14.00 - 11.62 26.90 -

3-Cl 0 5 calculated: 34.56 2.03 12.09-10.20-36.52 found _b : 34.80 2.12 12.12-9.93-36.46

Br 2-pyridyl. HBr 3

calculated: 31.06 2.32 16.10 - - 45.93 -

found _b : 30.47 3.00 16.09 - - 45.51 -

030040/0639

* COPY - ¹

Table 1 (Ports.)

X, Ed.

No. C H N F Cl Br

I. 2-pyridyl 5 34.41 3 40.47 5 34.41 2.25 17.84 - - ■ - _ 4c calculated: 34.49 3?, 8p 34.83 2.39 18.06 - - - 4C found, : Br 3-pyridyl 46.90 2.64 20.99 - 27 _ _ calculated: 46.75 2.66. 21.85 - 27 - - found. : I. 3-pyridyl 4o, oo 2.24 17.84 - 11 - 4c calculated: 49.90 2.22 18.23 - 11 - 4c found. : Cl 2-Cl0 7 2.75 16.41 - 69 - - calculated: 2.74 16.23 - 64 - found, : Br 2-Cl 0 3 2.35 13.98 - 80 26.69 - calculated: 2.29 14.10 - 05 28.07 _ found, :

2-Cl 0. 5

calculated: 34.56 2.03 12.09-10.20-35

found ^ 34.36 2.09 12.16-10.75-34

Cl g-CH, 0 7

calculated: 56.05 4.27 17.83 - - 15.04 -

found _b : 55.95 4.03 17.64 - - 15.01 -

030040/0639

Table 1 (Ports.)

Author

a C H N P Cl Br

Br 2-CH ₃ 0 3 47.16 3.59 15.00 -

47.04 3.77 14.81 -

I 2-ca, 0 5

calculated: 40.38 5.08 12.84 - found ^: 40.10 5.04 12.75 - Cl 2-CH ₃ O 0 7 calculated: 52.49 4.01 16.70 - - found, : 52.56 4.27 16.69 - Br 2-CH ₃ O 0 3 calculated: 44.61 5.40 14.19 - - found,: 44.91 5.58 14.59 P. 288-289 ° c Br 2-P 0 3 calculated: 42.27 2.48 14.79 - found, : 42.86 2.76 14.47 - I. 2-P 0 5 calculated: 56.27 2.15 12.69 5.73 - found, t 56.54 2.14 12.85 5.65 - Cl 2-P 0 7 calculated: 50.12 1.94 17.52 14.79 found ^: 49.82 5, oo 17.15 14.48 I. 4-F 0 5 calculated: 56.27 2.15 12.69 5.73 - found ^: 56.11 2.15 12.55 5.63 -

28.64 - 79 29.09 - 05 58 mm 59, 14.09 15.11 - 26.90 26.64

38.33

38.04

58.55 38.03

030040/0639

Table 1 (cont.)

Ä, X ₁ author.

^x No. CH NF Cl Br

Br 4-F 0 3 42.47 2.48 14.79 6.68 -

41.81 2.53 1 *, * 7 6.43 -

Cl 4-F 0 7

calculated: 50.12 2.94 17.53 - 1 *. 79 -

found _b : 50.27 3.15 17, * 9 - 14.77 -

C ₂ H ^ 4-F 0 2

calculated: 61.79 5.18 18.01 8.14 -

found ^ 60.37 5.16 18.03 8.07 -

C ₂ H ₅ 2-F 0 2 61.79 5.18 18.01 8.14 -

61.59 5.12 17.85 7.9 * -

Cl -3, * - Cl ₂ 0 7

calculated: * 1.33 2.07 1 *, * 6 - 36.31 -

found _b : * 1.79 2.21 14.5 - 32.59 -

/ Cl 3-NO ₂ 0 7 .

^ calculated: 45.04 2.64 21.01 - - -

found ^: 45.11 2.50 20.67 -

Cl u (-naphthyl 7

calculated 6l. 88 3.71 15.46 - 13.04 -

found _b : 6l, o8 3.76 15, l8 - 12.73 -

Cfa U0 0

calculated: 73.62 5.45 15.15 found _b : 73.3 * 5, * 5 15.17

030040/0639

Table 1 (Ports.)

X, X ₁ avail.

- * No. C HN P Cl Br

0 ^ 1

y ■ »-

calculated: 68.09 6.59 18.33 found _b : 67.84 6.49 18.33

CH ₂ = CHCH ₂ 0 1

Calculated: 68.70 5.76 l8.49 found ^ 68.34 5.78 18.39

Br 2-ffyrazine

calculated : 35.84 2.26 26.13 - 29.81 - 40, 15.86 - • 36, 28 found. : 35.24 2.33 26.18 - 29, 09 40, 15.89 - - · 33, 39 I. 2-iyrazine '5 calculated : 30.49 1.92 22.23 - found _b : 30.67 2.13 22.34 - Cl 2-pyrazine 7th calculated : 42.96 2.70 31.32 - 98 found. : 43.10 2.90 31.41 - 64 I. 2-CH, 0 JZi 5 calculated : 38 ^ 50 2.94 12.25 - found _b : 39.09 3.77 12.81 - F. 280-281 ⁰ C.

calculated 51.16 4.29 14.91 - 12.58

found _b : 51.35 4.18 14.78-12.84

030040/0639

Table 1 (cont.)

X ₁ Author

No. C HN P Cl Br I

et

calculated: ^ 44.18 3.90 12.88 - - 24.50

found ^: 43.8l 3.7 ^ 13.08 - - 24.57

calculated: 38.62 3.24 11.26 - - _ 3Y

_b found: 37.26 3.15 11.15 3 ^J

3-C ₂ H ₅ O 0 5

calculated: 40.35 3.38 11.76 - - 3;

found _b : 40.31 3.23 12.04 - - - 3;

Cl 3 -C ₂ H ₅ O 0. 7th

calculated: 5 ^, 24 4.55 15.8l - 13.34 -

found ^ 49.77 4.65 14.52 - 12.38 -

Br 3-nC, H ₇ 0 0 3

calculated: 48.16 4.35 12.96 - - 24.65 -

found ^ "47.86 4.30 12.87 - 25.33. -

3-HC ₅ -H ₇ O 0 5

calculated: 42.06 3.80 11.32 - -

found _b : 42.4l 3.75 11.85 - 33.50 -

Cl 3 ^ -C ₃ H ₇ O 0- 7

calculated: 55.82 5.04 15.02 - 12.68 -

found _b : 55.89 5.22 14.99 - 12.64 -

030040/0639

Table 1 {Ports.-) -

_Author

No. C HN P Cl Br I

9.

calculated: 41.90 4.02 10.47 - 31.63

found _b : 40.58 3.96 10.73-32.69

a: In all examples where X denotes halogen the specified procedural mimmer applies only to the respective person Halogenation procedure provided that procedure 1 or 2 has already been performed.

b: Most products show melting points that are not necessary represent a distinguishing feature of the compound, since decomposition occurs or the melting point is above 200 ° C and was therefore not mentioned »

Example 12

2-amino ~ 6- (2-furyl) -4-pyrimidinol

5.76 g of powdery guajiidine carbonate (51.9 millimoles), 200 ml of absolute ethanol and 20 ml of toluene are poured into a 500 ml three-necked flask equipped with a paddle stirrer, Dean-Stark trap and reflux condenser. The solution is dried azeotropically. The reaction mixture is ^{cooled to 50 °} C., then the Dean-Stark trap is removed and 10.4 g (64 millimoles) of ethyl 2-furyl acetate are added. The reaction mixture is refluxed for 18 hours, then 50 ml of water are added and the mixture is heated for a further JO min. The reaction mixture is then cooled to 25 ° C., after which pieces of carbon dioxide are added until the mixture is neutral. The flask is placed in a vacuum refrigerator at 5 ° C., 5.6 g (49 %) of pure 2-amino-6- (2-furyl) -4-pyrimidinol are obtained.

example

2-amino-6- (m-chlorophenyl) -4-pyrimidinol

5.76 g (52 millimoles) of powdered guanidine carbonate, 200 ml of absolute ethanol and 20 ml of toluene are introduced under nitrogen into a 500 ml RB flask equipped with a stirrer, condenser and Dean-Stark trap. 100 ml of solvent are introduced by refluxing removed via the trap, and the solution is cooled to 50 C and the trap is released. Thereafter, 14.8 g (65 millimoles) of m-benzoylacetate were added and the mixture is stirred for I7 h. under reflux. Anschlies be about JO ml V Water is added and the mixture is heated for a further JQ min. The mixture is then cooled for 18 hours in the refrigerator. The precipitate is filtered off, washed with ethanol and ether and dried at 60 ° C. in vacuo, 10.6 g (74 %) 2-Amino-6- (m-chlorophenyl) -4-pyrimidinol is obtained.

030040/0639 COPY

MI / MLl Λ Ι

Example 14

2-amino-6- (o-methoxyphenyl) -4-pyrimidinol

The procedure of Example 12 is followed using 5.67 g (31.5 millimoles) of guanidine carbonate, 200 ml of absolute ethanol, 20 ml of toluene and 14.15 g of ethyl o-methoxybenzoyl acetate. In 150stündigem heating under reflux to obtain 7.91 g (57.8 #) 2-Amino-6- (o-methoxyphenyl) -4-pyrimidinol as a white Peststoff, mp 283.5 to 284.5 ⁰ C

Example 15

2-amino-5-bromo-6- (m-chlorophenyl) -4-pyrimidinol

To 3 * 13 g (15 millimoles) of 2-amino-6- (m-chlorophenyl) -4-pyrimidinol are added 80 ml of glacial acetic acid, the solution is heated to 80 ⁰ C and treated with Ό, 8l ml of bromine. The mixture is ^{stirred at 80 °} C. for 15 min and then ^{cooled to 25 °} C., then concentrated to dryness at 40 ° C. in vacuo. The resulting solid is refluxed with 150 ml of water,. the reaction mixture is cooled and filtered and the pesticide is washed very well with cold water. It is then dried at 60 ° C. in a vacuum drying cabinet, whereupon the product is pulverized dry. It is then triturated again with boiling water, and finally 3 × 90 g (86.9 %) of the title compound are obtained. By recrystallizing the solid from water and dimethylformamide, slowly stirring the dimethylformamide into a. Slurry of 3 * 9 g of the compound in 150 ml of boiling water is added until solution occurs, cooling and filtering give the analytically pure material (yield 80 %).

030 ^ 0/0 63
COPY

Example 16
2-amino-6- (m-chlorophenyl) -5-iodo-4-pyrimidinol

To 3.13 g (15 millimoles) of 2-amino-6- (m-chlorophenyl) -4-pyrimidinol are added 50 ml of water and 0.8O g of sodium hydroxide (20 millimoles). The mixture is heated until the pyrimidinol is dissolved and, if necessary, filtered. The mixture is then cooled to 25 ° C. and 3.79 g of iodine powder in 100 ml of chloroform are added. Remaining iodine is washed in with 30 ml of chloroform. The reaction mixture is then vigorously stirred ^{at 25 °} C. for 4 hours with a paddle stirrer.

Then the mixture is filtered, the solid is washed very well with water until the washing solution is neutral to litmus. Then it is washed with acetone until the acetone filtrate is colorless (it is advisable to pulverize the product with acetone before washing). During drying of the Peststoffs at 60 ⁰ C is obtained 3.50 g (67%) of 2-amino-6- (m-chlorophenyl) -4-pyrimidinol.

Example 17

2-Amino-5-iodo-6- (2-furyl) -4-pyrimidinol

To 2.65 g (15 millimoles) of 2-amino-6- (2-furyl> 4-pyrimidinol are added 50 ml of water and 0.72 g of sodium hydroxide. The reaction mixture is warmed to 75 ° C to effect solution and then cooled to 25 ⁰ C. then a slurry of 4.0 g (15.8 millimoles) Jodpulver in chloroform with vigorous stirring is added and the reaction mixture is stirred 2 hrs. at room temperature. then the mixture is filtered, the solid is washed with Wash water well (until the wash water is neutral to litmus), then acetone is used

30040/0639

wash (until the washing solution is colorless) and dried in a vacuum drying cabinet, giving 5 * 95 g (87 %) of the Tite compound.

Example l8
2-Amino-5-bromo-6- (2-furyl -) - 4-pyrimidinol

50.0 ml of water and 0.66 g of sodium hydroxide (16.5 millimoles) are added to 2.65 g (15 millimoles) of 2-amino-6- (2-furyl) -4-pyrimidinol, a cloudy solution resulting . The solution is stirred for JO min, then 0.9 nil of bromine (2.62 g, 16.5 millimoles) in 20 ml of chloroform is added. It is then stirred vigorously for 2 hours and then filtered, the pest is washed well with water (until neutral to litmus) _} then with acetone (until the acetone remains colorless) and ^{dried at 60 °} C., 3 * 3 g of the titre ! Connection (86 %) received.

Example 1-9
2-amino-5-chloro-6-phenyl-4-pyrimidinol

To 1.87 g (10 millimoles) of 2-amino-6-phenyl-4-pyrimidinol 50 ml of glacial acetic acid and 1.46 g (11 millimoles) of N-chlorosuccinimide were added .. The mixture with a magnetic stirrer under nitrogen at 90 ⁰ C Stirred for 2 hours (complete solution occurred after less than 20 minutes). The heat source is then removed and the amber-colored solution is allowed to cool to room temperature and finally concentrated in vacuo to a volume of 10 ml, cooled to 20 ° C. and filtered. The resulting solid is washed successively with 5 rol of acetic acid, 50 ml of water, 100 ml of acetone and 100 ml of diethyl ether

030040/0639

and dried at βθ ° C. in a vacuum drying cabinet, 1.40 g (63 %) of the Tite compound being obtained. The solid can be recrystallized from ethanol and dimethylformamide, the dimethylformamide being added to a hot slurry of the pyrimidine in ethanol until solution has occurred. After cooling the solution to 5 ° C. for 18 hours, filtering off and drying, the analytically pure 2-amino-5-chloro-6-phenyl-4-pyrimidinol is obtained.

Example 20
2-amino-5-iodo-6-phenyl-4-pyrimidinol

If the procedure of Example 16 is repeated, but with 21.4 (0.113 mol) of 2-amino-6-phenyl-4-pyrimidinol, 200 ml of water, 50% chloroform, 5.6 g of sodium hydroxide and 28.8 g of iodine, so obtained m. 29.0 g (78 %) of 2-amino-5-iodo-6-phenyl-4-pyrimidinol.

Example 21
2-Amino-5-iodo-6-phenyl-4-pyrimidinol, zinc salt

To 1.56 g (5 millimoles) of 2-amino-5-iodo-6-phenyl-4-pyrimidinol / in 15 ml of methanol are stirred in a nitrogen atmosphere

1.1 ml of a 25% solution of sodium methylate in methanol were added at room temperature. After 5 minutes, 340 mg (2.5 millimoles) of anhydrous zinc chloride are added and after 1 hour the heterogeneous solution is concentrated to dryness, washed twice with 50 ml of water each time and filtered. The residue is l8 hours under vacuum at 60 ⁰ C. Dried. The product obtained is a white plague from P. 285 ⁰ C.

OSOOAO / 0639 COPY

The invention also relates to new pharmaceutical preparations and a method for prevention or treatment of viral infections and to induce interferon production in vivo and in vitro (tissue cultures).

The invention relates to preparations and the method for inducing interferon production and / or for prevention or treating viral infections by administering a compound of the formula

wherein X, and X, have the meanings given above and which are referred to here as 6-arylpyrimidines or in the following description as "active ingredients", or their pharmacologically acceptable acid addition salts in conjunction with a pharmaceutically acceptable carrier.

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

According to the invention, infection is preventative or treated curatively and increased interferon production in vivo by placing the active ingredients in a suitable host administered. "Host" is understood to mean interferon-producing animals, that is to say viable animals that are capable of

030040/0639

Interferon production are capable. The host animal can
be warm-blooded like mammals, for example mice,
Councilors, rabbits, cattle, pigs, hamsters, dogs, cats,
Guinea pigs, horses, goats, sheep, monkeys and humans, furthermore it can be birds like chickens, ducks,
Turkeys, pigeons, budgies and canaries. the
Administration can be parenteral, such as
subcutaneously, intramuscularly, intradermally, intraperitoneally, intravaginally, intravenously or locally, preferably on a mucous membrane such as intranasal, pharyngolaryngeal, bronchial, broncholial, intravaginal, rectal or ocular. Administration can also be carried out by implantation. Alternatively or simultaneously, the active ingredient can be administered orally
Route be given which is a preferred mode of administration for interferon production. In practice, it is advisable to give the active ingredient orally, intranasally, topically, locally, subcutaneously or intramuscularly.

The induction of interferon production by administration of an active substance is proven by recognized Interferon test methods such as plaque containment, see Pinter, Interferons and Interferon Inducers, (1973). The durc Administration of an active ingredient formed interferon can also be detected by the shelter, the host animal or tissue cultures purchase against virus attack.

The administration of the active ingredients is also useful prophylactically and therapeutically for the prevention and treatment of Vin infections. For example, pharmaceutical preparations that contain the active ingredients are suitable for the prophylaxis or treatment of people and animals that are infected by viruses or threaten to be infected, for example by
Hepatitis virus, rubella virus, flu or encephalitis virus (i.e. arboviruses such as equine encephalitis virus, semliki
Forest virus), herpes viruses (type 1 or 2 of herpes simplex

030040/0639

Virus, cytomagalovirus, varieella zoster and virus of infectious khinotracheitis in cattle}, rabies viruses, enteroviruses (pieornavirus, echovirus, coxsackie virus) Parainflue ¹ .z viruses, viruses in respiratory syncytium, Sendai virus, viruses of polio, Epstein-Barr virus (infectious mononucleosis), smallpox virus, dengue virus, common cold viruses (rhinovirus, coronavirus and the like), adenovirus, polyomavirus, papovavirus, RNA tumor viruses (for example, leukemia virus in cats, leukemia virus and sarcoma virus in birds) , B virus, Aleutian ¹ see mink disease, arena virus, bluetongue virus in sheep, diarrheal gastric mucosal disease virus, canine distemper virus, hepatitis virus and herpes virus, horse abortion virus, virus infectious anemia in horses, smallpox virus in chickens, choleravirus in pigs, Marök's disease, enteritis virus in mink, Newcastle disease virus, enterovirus in pigs, pseudo rabies virus, viruses of puss and mouth diseases, reovirus and all other viruses or diseases caused by viruses (for example slowly progressing diseases, which can be caused by viruses such as multiple sclerosis), which affect the antiviral action of interferon or the antiviral agents according to the invention speak to.

Preferred connections are:

2-amino-5-iodo-6- (3-bromophenyl) -4-pyrimidinol, 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,

030040/0639

2-Amino-5-iodo-6- (2-methoxyphenyl) -4-pyrimidinol, ■ 2-amino-5-bromo-6- (3-chlorophenyl) -4-pyrim'idinol, 2-amino-5-iodo-6- (3-chlorophenyl) -4-pyrimidinol,

-O- (3-chlorophenyl) -4-pyrimidinol, -ö- (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 _ί . 2-Amino-5-'bromo-6-phenyl-4-pyrimidinol, 2AIShI-O - (^ - methoxyphenyl) -4-pyrimidinol,

2-amino-5-bromo-6- (5-methoxyphenyl) -4-pyrimidinol, 2-amino-5-iodo-6- (3-methoxyphenyl) -4-pyriraidinol, 2-amino-5-bromo-6- (2-pyridyl) -4-pyrimidinol, 2-amino-5-iodo-6- (3, ² l-dichlorophenyl) -4-pyrimidinol, 2-amino-5-bromo-6- (1-4 -naphthyl) -4 -pyrimidinol, 2-amino-5-chloro-6- (3-nitrophenyl) -4-pyrimidinol, -O- (3-nitrophenyl) -4-pyrimidinal, -O- (3-trifluoromethylphenyl) -4-pyrimidinol, 2 -Amino-5-ethyl-6-phenyl-4-pyrimidinol, 2-amino-5-bromo-6- (3,5-dimethoxyphenyl) -4-pyrimidinol, -O- (3-propyloxyphenyl) -4-pyrimidinol

or their pharmaceutically acceptable acid addition salts or Alkali metal or alkaline earth metal salts.

In addition to the described antivirus effect and effect on the Interferon production, the compounds according to the invention have an immunoregulatory effect; the connections For example, increase antibody production and reduce postponed hypersensitivity; they are useful for the treatment of parasitic diseases, in rejection

030040/0639

of organ transplants and skin transplants and in the case of immune defects, including those that are a side effect of cytotoxic therapy or radiation appear.

The dose to be administered depends on the desired amount of interferon, the virus infection, the animal to be treated, its age, state of health, weight, the species at the same time further treatments, the frequency of administration, the therapeutic index and tolerability away.

In the dosage regimen for the prevention of various diseases, caused by viruses, care must be taken. ' Since the mechanism of the antivirus effect of the invention Pyrimidine goes beyond interferon production and other effects, for example direct antiviral effects or Immune modulation, the type of disease being treated, the patient's condition and need to be considered the nature of the cause (sensitive to the antiviral effects of interferon). The route of administration of the active ingredient depends on such criteria. For example, infection of the respiratory tract is most effectively treated by intranasal Administration, while systemic infections are more effectively controlled by systemic injection.

The time at which the active substance is administered can also be important when exercising an anti-virus effect. It is enough demonstrated (Stringfellow, DA., Antimicrobial Agents and Chemotherapy, 11: 934-992 (I977)) that the ability Interferon production in animals is impaired in response to agents that stimulate interferon synthesis,

030040/0639

if these remedies are given in frequent (daily) doses. In contrast, with less frequent administration (once a week), animals remain responsive to each injection of the stimulant (Stringfellow, DA and SD Weed, Am. J Vet. Research, 38: 1963-1967 (1977) · Since interferon is an intracellular antivirus Conveyed a condition that persists for several days after the interferon is out of circulation, such treatment (for example, once a week) should be appropriate for treating infections caused by interferon-responsive viruses, but some viruses are responsive less sensitive to interferon, but the pyrimidines according to the invention have an antivin effect which is separate from the ability to induce the production of infeferon, and dosage regimens that maintain the appropriate amount of active ingredient in the body or tissue would be used in the treatment and prevention of such Infections more suitable. For example, the herpes simplex virus (HSV-I) type 1 does not respond s o sensitive to interferon like other viruses, for example Semliki forest virus (SFV). Nevertheless, infections by both viruses HSV-I and SFV can be successfully suppressed in mice by administration of 2-amino-5-iodo-6-phenyl ~ ^{^} ^ -pyrimidinol. To effectively combat HSV-I, however, the active ingredient must be administered twice a day for three consecutive days, while an effect against SFV is achieved with a single injection once a week. The dosage must therefore be carried out carefully, taking into account the condition of the patient, the nature of the disease process and the pharmacological properties of the host substance used.

The administration of the compounds according to the invention also serves to change the immunoregulatory system of a person

030040/0 63

■ S3-

Host animal. Administration of an active ingredient increases antibody production and can be used for treatment of acquired or congenital. ^ Hypo-ip-globulinemia, for Propagation of natural killer cells and for the treatment of various forms of cancer, for activating macrophages and for the treatment or prevention of intracellular or extracellular infections caused by parasites, including Bacteria and protozoa, for the reproduction of haematopoietic ones Stem cells in bone marrow and spleen and used to treat or prevent aplastic anemia, and can also be used to generate Allospecific killer cells are diminished and the compounds can be used to prevent rejection to prevent organ and skin transplants.

The doses of active ingredients to be administered can be:

intravenous 0.1 to about 50 mg / kgj

intraperitoneally 0.1 to about 200 mg / kg; subcutaneously 0.1 to about 150 mg / kg;

intramuscularly 0.1 to about 150 mg / kg; orally 0.1 to about 400 mg / kg $

and preferably about 1 to 200 mg / kg, by intranasal introduction 0.1 to about 50 mg / kg and in aerosols 0.1 to about 50 mg / kg body weight.

Based on the concentration, an active ingredient can be used in pharmaceutical preparations according to the invention for local application to the skin, intranasally, pharyn, golaryngeal, bronchial, broncholial, intravaginal, rectal or in the eye in an amount of about 0.1 to about 50 % ( Weight / weight) of the agent, preferably from about 1 to about 20 % , in the case of parenteral use in a concentration of about 0.5 to 50 % (weight / volume) and preferably from about 5 to about 20 %.

030040/0639

-GO-

The agents according to the invention are preferably used for administration offered to humans and animals in dose units, for example as tablets, capsules, pills, powders, granules Suppositories, sterile parenteral solutions or suspensions, sterile non-parenteral solutions or suspensions, oral Solutions or suspensions and the like containing suitable amounts of an active ingredient.

Solid or liquid dosage units can be used for oral administration be prepared.

Powders are easily made by grinding the active ingredient to a sufficiently fine size and using a similar one crushed diluent mixed together. The diluent can be an edible carbohydrate material such as lactose or be strength. A sweetener or sugar and a flavoring oil are expediently added.

Capsules are produced by, as described above, prepared a powder mixture and filled it with gelatin. A lubricant is used as an aid during filling such as talc, magnesium stearate, calcium stearate or the like, which is added to the powder mixture before filling the capsules.

Soft gelatin capsules are mechanically encapsulated a suspension of the active ingredient with a suitable vegetable oil, liquid petrolatum or another inert oil or made of a triglyceride.

Tablets are obtained by preparing a powder mixture, this is granulated, a lubricant is added and pressed into tablets. The powder mixture is prepared inde the appropriately comminuted active ingredient with a diluent or base material such as starch, lactose, kaolin, Dicalcium phosphate or the like mixed. The powder

Maxssii Mix can be granulated by using a binder like

030040/0639

Gelatin solution, methyl cellulose solution, or gum jacacia wetted and the mixture brushes through a sieve. Instead of granulating, you can make the powder mixture lumpy, that is, run through the tablet machine and put the resulting imperfect looking tablets in Break pieces. These pieces can be provided with lubricant so that they stick to the tablets to avoid using stearic acid, a stearic acid salt, talc or mineral oil for this purpose. The lubricated mixture is then compressed into tablets.

The tablets are advantageously provided with a protective coating, which consists of a sealing layer or essential Layer of Schell ack, a coating of sugar and methyl cellulose and a glossy coating of carnauba wax consists.

Liquid dosage units for oral administration such as syrups, Elixirs and suspensions can be prepared in which one teaspoon contains a predetermined amount of the active ingredient contains. The water soluble forms can be in an aqueous vehicle along with sugar, flavorings and preservatives can be combined into a syrup. An elixir is made using an aqueous-alcoholic carrier and suitable sweeteners and flavors. Suspensions are taken from the insoluble forms with a suitable carrier With the aid of a suspending agent such as gum acacia, tragacanth, methyl cellulose and the like.

For parenteral administration, liquid dosage units are produced using an active ingredient and a sterile vehicle, with water being preferred. The active ingredient can, depending on the form and concentration, in the carrier

030040/0639

to be suspended or dissolved - For the preparation of solutions the water-soluble active ingredient is dissolved in water for injection purposes and before filling into suitable ampoules sterilized by filtration. Aids such as local anesthetics, preservatives and buffers are useful solved in the carrier. Parenteral suspensions are prepared in practically the same way / with the active ingredient in the carrier is not dissolved, but suspended and sterilization cannot be carried out by filtration. The active substance can be sterilized by exposure to ethylene oxide prior to suspension in the sterile vehicle. Becomes expedient (. A surface-active agent or wetting agent added to the mixture in order to ensure even distribution of the active ingredient facilitate.

In addition to oral and parenteral administration, it can also be administered rectally and administered vaginally. An active ingredient can be delivered through suppositories. A product can be used as a carrier used that have a melting point around body temperature possesses or is easily soluble. For example, cocoa butter or various polyethylene glycols can be used (Carbow axis) serve as a carrier.

^ Liquid dosage units are used for infectious introduction made using an active ingredient and a suitable pharmaceutical carrier, wherein water intranasal introduction is also preferred Snuff can be made.

The active ingredient can also be added to animal feed. The active ingredients are expediently prepared in the form of a feed premix. The feed premix can contain the active ingredient along with an edible pharmaceutical diluent

030040/0639

such as starch, oat flour, wheat flour, calcium carbonate, talc, Contain fish meal or similar non-toxic, orally acceptable pharmaceutical diluents. The premix then becomes the normal. Feed added.

When used in aerosols, the active ingredient is in a pressurized aerosol container filled, along with a gaseous or liquefied propellant such as Dichlorodifluoromethane, carbon dioxide, nitrogen, propane and the like, together with common auxiliaries such as co-solvents and wetting agents, as required.

In the ^{present description and the claims, “dose unit 1} ” is understood to mean physically discrete units which are suitable as a dose for human or animal patients, each unit containing a predetermined amount of active ingredient calculated for the desired therapeutic effect, together with the required amount pharmaceutical diluents or carriers. The regulations for the novel dose units according to the invention are dictated by and are directly dependent on (a) the unique properties of the active ingredients and the therapeutic effect to be achieved in each case and (b) the limitations imposed by galenics on the formulation of such Active ingredient for therapeutic use in humans Examples of suitable dosage units according to the invention are tablets, capsules, lozenges, suppositories, powder packets, amounts of teaspoons, amounts of tablespoons, drops, ampoules, multiples of these units and others described herein flat shapes.

Used for interferon production and as an antiviral agent too using active ingredients according to the invention can easily

030040/0639

be formulated in dosage units using pharmaceutical Accompanying substances that are known and are produced using known methods. The following preparations are exemplary for the production of dose units according to the invention, but should not be regarded as a limitation.

Example 22

Hard gelatin capsules

1000 two-part hard gelatin capsules for oral use, each containing 100 mg of 2-amino-5-bromo-6-m-fluorophenyl ~ ² J-pyrimidino, are made from the following ingredients:

2-Amino-5-bromo-6-m-fluorophenyl-pyrimidin.ol, 100 g micronized.

Lactose 100 g

Corn starch 20 g

Talc 20 g

Magnesium stearate · · 2g.

The 2-amino-5-bromo-6-m-fluorophenyl-4-pyrimidinol, finely ground with the aid of a micronizer is added to the other fine powder ingredients, then carefully mixed and in usually filled into the capsules.

These capsules are useful for preventing or treating viral infections and for inducing interferon production by oral administration of one or two capsules one to four times a day.

The capsules are also useful for the prevention or treatment of skin graft rejection, using 1 or Capsules administered one to four times a day.

030040/0639

3Ö08693

In the above manner, capsules can also be produced which contain the 2-amino-5-bromo-6-m-fluorophenyl-4-pyrimidinol in quantities of 50, 250 and 500 mg, with the above specified 100 mg of active ingredient replaced by 50, 250 or 500g.

Example 23

Soft gelatin capsules

One-piece soft gelatin capsules for oral use, each containing 250 mg of 2-amino-5-bromo-6-m-fluorophenyl-4-pyrimidinol (finely chopped up with the help of an air micronizer) are prepared by first putting the active ingredient in Suspended 0.5 ml of corn oil and then capsules in the above manner processed.

The capsules are suitable for the prevention or treatment of Viral infections and to induce interferon production with oral administration of 1 to 2 capsules one to four times a day.

The capsules are also suitable for the prevention or treatment of bacterial infections, in particular intracellular bacterial infections, with oral administration of 1 or 2 capsules one to four times a day.

Example 24
Tablets

1000 tablets, each containing 500 mg of 2-amino-5-bromo-6-m-fluorophenyl- ² ! -Pyrimidinol, are produced using the following ingredients:

300A0 / 0 639

2-Amino-5-bromo-6-m-fluorophenyl- ⁱ J ~ pyrimidinol 500 g

Lactose 75 g

Corn starch 50 g

Magnesium stearate 4 g

Liquid petrolatum, micronized 5 S

The 2-amino-5-bromo-6-m-fluorophenyl-4-pyrimidinol, finely comminuted with the aid of an air micronizer, is mixed with the other ingredients carefully mixed and made into pieces. The pieces are crushed by adding the mixture pushes through a sieve with a mesh size of 0.99 mm. the The resulting pieces are then compressed into tablets, each tablet 500 mg of 2-amino-5-bromo-6-m-fluorophenyl-4-pyrimidinol contains.

These tablets are suitable for the prevention or treatment of viral infections and for inducing the formation of interferon, with 1 or 2 tablets administered orally one to four times a day. Tablets are also suitable for Treatment of hypoglobulinemia when administered orally from 1 to 2 tablets one to four times a day.

Tablets containing 250 and 100 mg of 2-amino-5-bromo-6-m-fluorophenyl-5-pyrimidinol be prepared inde one the above used 500 g by 250 or 100 g Replaced 2-amino-5-bromo-6-m-fluorophenyl-4-pyriraidinol.

Example 25

Suspension for oral administration

100 ml of an aqueous suspension for oral use, wovo 1 teaspoon (5 ml) 500 mg 2-amino ~ 5-bromo-6-m-fluorophenyl ~ ⁱ l-

030040/0639

3Ö08693

containing pyrimidinol are made from the following components:

2-Amino-5-bromo-6-m-fluorophenyl ~ ⁱ l ~ pyrimidinol,

micronized 100 g

Citric acid 2 g

Benzoic acid 1 g

Cane sugar 700 g

Tragacanth 5 g

Lemon oil 2 g

deionized water to 1 000 ml

Citric acid, benzoic acid, cane sugar, tragacanth and lemon oil are dispersed in enough water for 850 ml of suspension. The 2-amino-5-bromo-6-m-fluorophenyl-4-pyrimidinol, which has been split up with the aid of an air micronizer is stirred into the syrup until it is evenly distributed. With water becomes made up to 1000 ml.

The mixture obtained in this way is suitable for prophylaxis or contraception of viral infections and to induce interferon production at a dose of 1 tablespoon (15 ml) three times a day. The mixture is also suitable for treating the aplastic anemia, where a dose of 1 tablespoon (15 ml) is given three times a day.

Example 26

A sterile aqueous suspension for parenteral injection consisting of 1 ml of 300 mg of 2-amino-5-bromo-6-m-fluorophenyl-4-pyrimidinol contains, is made from the following substances:

030040/0639

2-Amino-5-bromo-6-m-fluorophenyl-4-pyrimidinol,

micronized x 300 g

Polysorbate 80 5 g

Methyl paraben 2.5 g

Propyl paraben 0.17 g water for injections per 1,000 ml

All components, with the exception of the 2-amino-5-bromo-6-mfluorophenyl-4-pyrimidinol, are dissolved in the water and the
Solution is sterilized by filtration. The sterilized 2-amino-5-bromo-6-m-fluorophenyl-4-pyrimidinol is added to the sterile solution, which is then removed with the aid of an air micronizer
was finely ground. The finished suspension is filled into sterile ampoules and these are sealed.

The preparation is suitable for the prevention and prevention of viral infections and for the initiation of interferon production when used in a dose of 1 ml three times a day. the
The formulation is also suitable for the treatment of hypo- ^ f-globilinaemia when used in an amount of 1 ml three times a day

Example 27

Rectal and vaginal suppositories

1,000 suppositories weighing 2.5 g each containing 150 mg
2-Amino-5-bromo-6-m-fluorophenyl-4-pyrimidinol are made from
the following components:

2-amino-5-bromo-6-m-fluorophenyl-4-pyrimidinyl,

micronized 150 g

Propylene glycol 150 g

Polyethylene glycol 4000 to 2,500 g

030040/0639

The 2-amino-5-bromo-6-m-fluorophenyl-4-pyrimidinol is finely ground with an air micronizer and added to the propylene glycol and the mixture is homogenized in a colloid mill. The polyethylene glycol 4,000 is melted and the propylene glycol dispersion is slowly added with stirring. The suspension is poured with 4θ ⁰ C in uncooled forms. The mixture is allowed to cool and solidify and then removed from the mold, each suppository being wrapped in foil.

The suppositories are inserted rectally or vaginally to prevent or treat viral infections and to induce interferon formation. You can too used rectally or vaginally to treat bacterial infections.

Example 28
Intranasal suspension

1000 ml of a sterile aqueous suspension for intranasal use containing 150 mg of 2-amino-5-bromo- «6-m-fluorophenyl-4-pyrimidinol per milliliter contains, is made from the following components:

2-amino-5-bromo-6-m-fluorophenyl-4-pyrimidinol,

micronized 150 g

Polysorbate 80 5g

Methyl paraben 2.5 g

Propyl paraben 0.17 g deionized water per 1,000 ml.

030040/0639

3Ö08693

All components, with the exception of 2-amino-5-bromo-6-mfluorophenyl-4-pyrimidinol, are dissolved in water and the solution is sterilized by filtration. To the sterile The solution is the sterilized 2-amino-5-chromium-6-m-fluorophenyl-4-pyrimidinol added, which has been finely ground with the help of an air micronisatc. The suspension becomes aseptic filled in sterile containers.

The preparation obtained in this way is suitable for the prevention and treatment of viral infections and to initiate the formation of inter- , feron by intranasal introduction of 0.2 to 0.5 ml one to four times a day. The preparation is also suitable for the treatment of intracellular bacterial infections, 0.2 to 0.5 ml being introduced one to four times a day.

Example 29
Animal feed

1000 g of a putter premix are made up of the following ingredients manufactured:

2-Amino-5-bromo-6-m-fluorophenyl-4-pyrimidinol 20 g

Soybean meal 400 g

Fish meal 400 g

Wheat germ oil 50 g

Sorghum molasses 130 g

The ingredients are mixed and pressed into pellets.

The premix can be fed directly to laboratory animals, i.e. rats and mice, for prevention or treatment

030040/0639

of viral infections and induction of interferon formation and for the prevention or treatment of intracellular parasite infections.

In the case of large animals, the premix can be added to the usual putter be added in a calculated manner so that you get the desired dose of 2-amino-5-bromo-6-m-fluorophenyl-4-pyrimidinol achieved. For example, 1 part Vorgetnisch is added to 2.5 parts of ordinary cat food, the desired dose of 200 mg / kg / day achieved in a cat weighing 2.5 kg.

Examples JfO to 33 show that the active ingredient can also be present in undiluted, pure form with local use on the skin, with intranasal, pharyngolaryngeal, bronchial, broncholial or oral administration.

Example 30
powder

500 g of 2-amino-5-bromo-6-m-fluorophenyl - ^ - pyrimidinol are with finely crushed with an air micronizer, the powder is poured into a hopper.

The above preparation is suitable for the prevention or treatment of viral infections and for inducing the formation of interferon by local application one to four times a day. The powder is also useful for preventing or treating infection by protozo ^ fi by oral administration of 1 or 2 Powder amounts in a glass of water one to four times a day.

030040/0638

3Ö08693

Example 31

Powder for oral use

1000 g of 2-amino-5-bromo-6-m-fluorophenyl-4-pyrimidinol become finely chopped with a • Luf.t micronizer, then the total amount is packed in portions of 250 mg.

These powders are suitable for the prevention or treatment of viral infections and for inducing the formation of interferon with oral administration of 1 or 2 powder packets in one Glass of water one to four times a day. The powder is also suitable for the prevention or treatment of metastases to the breast amputation, with 1 to 2 packets given one to four times a day.

Example 32

Administration by rhinitis

1000 g of 2-amino-5-bromo-6-m-fluorophenyl-4-pyrimidinol become finely chopped with an air micronizer.

This product is suitable for the prevention or treatment of viral infections and f initiation of Interferon-formation on inhalation of 30 to 75 mg one to four times daily.

Example 33

Hard gelatin capsules

1000 g two-part hard gelatin capsules for oral use, each with 100 mg 2-amino-5-bromo-6-m-fluorophenyl-4- * pyrimidine are made from 100 g of 2-amino-5-bromo-6-m-fluorophenyl-4-pyrimidinol.

030040/0639

The 2-amino-5-bromo-6-m-fluorophenyl-4-pyrimidinol is with finely chopped in an air micronizer and filled into the capsules in the usual way.

These capsules are suitable for the prevention or prevention of viral infections and for inducing the formation of inferons with oral administration of 1 or 2 capsules one to four times a day.

Further capsules containing 50, 250 or 500 mg of 2-amino-5-bromo-6-m-fluorophenyl-4-pyrimidinol are produced in the above manner contain, whereby the 100 g of 2-amino-5-bromo-6-m-fluorophenyl-4-pyrimidinol used above by 50, 250 or 500 g of the substance.

Example 34

Following the procedure of Examples 22-33, formulations prepared by replacing the free base used in these examples with equivalent amounts of pharmaceutically acceptable Acid addition salts of 2-amino-5-bromo-6-m-fluorophenyl-4-pyrimidinol replaced.

Example 35

Following the procedures of Examples 22 to 34 are pharmaceutical Preparations produced by replacing the active ingredients used there with equivalent amounts of the compounds

2-amino-5-iodo-6- (3-bromophenyl) -4-pyrimidinol, 2-amino-5-bromo-6- (3-fluorophenyl) -4-pyrimidinol, 2-amino-5-bromo-6- (3-ethoxyethy! Phenyl) -4-pyrimidinol,

030040/0639.

2-Amino-5-bromo-6- (2-methoxyphenyl) -4-pyrimidinol, 2-AmInO-S-ChIOr-O- (2-methoxyphenyl) -4-pyrimidinol, 2-amino-5-iodo-6- (2-methoxyphenyl) -4-pyrimidinol, ■ 2-amino-5-bromo-6- (3-chlorophesiyl) -4-pyrididinol, 2-AmInO-S-JOd-O - (? - chlorophenyl) -4-pyrimidinol , 2-Amino-5-chloro-6- (3-chlorophenyl) -4-pyrimidinol, 2-amino-5-chloro-6- (2-fluorophenyl) -4-pyrimidinol _i 2-AmInO-S-Chlor-O - (j5-Fluorophenyl) -4-pyrimidinol, 2r-amino-5-bromo-6- (2-fluorophenyl) -4-pyrimidinol, 2-amino-5-iodo-6- (3-i "luophenyl) -4-pyrimidinol , 2-Amino-5-iodo-6-phenyl-4-pyriIπidinol _J

^ 2-Amino-5-chloro-0-phenyl-4-pyrimidinol, 2-amino-5-bromo-6-phenyl-4-pyrimidinol ₃ 2-amino-5-chloro-0- (3-methoxyphenyl) -4 -pyrimidinol, 2-amino-5-bromo-6- (3-jiiethoxyphenyl) -4-pyrimidinol, 2-amino-5-iodo-6- (5-methoxyphenyl) -4-pyrimidinol, 2-amino-5- bromo-6- (2-pyridyl) -4-pyrimidinol _i 2-amino-5-bromo-β- (o (-naphthyl) -4-pyrimidinol / 2-AmInO-S-JOd ^ -O- (3i4-dichlorophenyl ) -4-pyrimidinol j 2-amino-5-chloro-6- (3-nitrophenyl) -4-pyrimidinol, 2-amino-5-iodo-6- (3-nitrophenyl) -4-pyrimidinol j 2-amino-5 -iodo-6- (3-trifluoromethylphenyl) -4-pyrimidinol, 2-amino-5-ethyl-6-phenyl-4-pyrimidinol,

f 2-amino-5-bromo-6- (3j5-dimethoxyphenyl) -4-pyrimidinol,

-O- (3-propyloxyphenyl) -4-pyrimidinol,

or their pharmaceutically acceptable acid addition salts or the alkali metal or alkaline earth metal salts. These preparations are suitable for the prevention and prevention of viral infections and causing interferon production when administered in the manner described in Examples 22-4.

030040/0639

Example 36
Interferon formation in cats

The cats received the compound 2-amino-5-bromo-6-phenyl-4-pyrimidinol orally. The active ingredient was suspended in carboxymethyl cellulose in amounts of 50 * 100 or 200 mg / ml and 1 ml was administered per kg of body weight. The cats were periodically bled after drug administration, the serum was collected and tested on kidney cells for feline interferon using a plaque reduction test (see Stringfellow and Weed, Am.J.Vet.Res.m Vol. 30, pp. 1963-1967 (1977). As can be seen from the following table 2, the active ingredient caused high interferon levels in the serum, indicating that it is an effective antiviral agent for cats.

Table 2

Interferon level in serum (units per milliliter) oral administration of 2-amino-5-bromo-6-phenyl-4-pyrimidinol

dose
(mg / kg)

Cat,

Hours after drug administration 0 3.: -6 12.

200
100
50
Placebo"

A B A B A B A B

10 200 r-f 300 320 5 100 2 600 1,300 640 320 80 20th 500 10 200 ND ⁺⁺⁺ 640 32O 80 1 280 80 80

0300A0 / 0639

+ means 1 liter with less than 50 units / ml ++ animals treated with placebo received the vehicle (1 ml /]

without active ingredient
+++ ND = not determined

Example 37

Treatment and prevention of respiratory tract infection in cattle.

Calves received the compound 2-amino-5-bromo-6-phenyl- ^i- pyrimidinol in an amount of 1 g per calf once daily for β days in a row, starting either 12 hours before or 6 hours after intranasal infection by infectious rhinotracheitis (IBR) virus. Nasal swabs were collected daily to determine the amount of virus, and 3 weeks after infection, all calves were slaughtered and autopsied. The extent of the pneumonia was determined by gross examination. With a rating system from 0 to 5, each lobe of the lung was examined for the extent of the pneumonia. A rating of O was given if each lung lobe showed no pneumomy damage, and a rating of 5 was given when the flap was completely solidified. Each lung has 7 lobes, resulting in a maximum rating per lung of 35. The values contained in Table 3 show that the active ingredient reduces the severity of the infection both when used therapeutically (6 hours after infection) and when used prophylactically (12 hours before infection). The amount of virus in the nose would correspond to the development of pneumonia.

030040/0639

-ψΓ-

Table 3

treatment

Calves / group

Lung damage (points)

12 hours before infection
6 hours after infection

2.0 5.0

Placebo given starting 12 hours before infection 4

14.0

Example 38

Analogously to Examples 36 to 37, preparations according to Examples 2.2 to 35 prevent virus infections or cured and interferon production brought about.

For The Upjohn Company, Kalamazoo, Mich., V.St.A.

Dr. H (/ J. Wolff Lawyer

03004070639

Our no. 22 824

D / wl

The Upjohn Company
Kalamazoo, Mich., V.St.A.

6-aryl-pyrimidine compounds

Summary:

New compounds of the formula

H ₀ N

wherein X, the same meaning as X, "wherein X is
Alkyl radical with 1 to J5 carbon atoms, the 2-propynyl or 2-propenyl radical or an alkyloxyacyl radical with an alkyl portion with 1 to 3 carbon atoms, and X-, furthermore d: the same meaning as X ^ or X ₅ has ¹ ^ JHeS. X ^ Pluori Cti. Bromine or iodine and X ₁ - a mono-, di- or trihalomethyl, mono-, di- or trifluoroethyl radical or perfluoropropyl radical, and X,

a) the phenyl radical, but not if L bromine or X be indicates

0300A0 / 0639

b) a monosubstituted phenyl radical of the formula

wherein one of the radicals R, R ₁ , Rg, R_ and Rj, is not a hydrogen and R or R ₁ , an alkyl radical with 1 to 8 carbon atoms, including isomeric forms, alkoxy radical with 1 to 8 carbon atoms, including isomeric forms, fluorine , Chlorine, bromine, iodine or the nitro group, R or R, fluorine, chlorine, bromine, iodine, the nitro or trifluoromethyl group or an alkoxy radical with 1 to 8 carbon atoms, including isomeric forms, an alkoxyethyloxy radical with an alkoxy portion with 1 to 5 carbon atoms , including isomeric forms, or a radical of the formula R-

wherein R ₁ - and Rg, which can be identical or different, alkyl radicals with 1 to 8 carbon atoms, the benzyl radical or together with -N ^ a saturated cycloalkylamino radical -N ^ 3c _n t, where n ^{1 is} the number j5, 4, 5 or 6 denotes, or a dialkyl-substituted cycloalkylamino radical, in which each alkyl radical has 1 to 5 carbon atoms, and R _{2 represents} chlorine, fluorine, bromine, iodine or an alkyl radical having 1 to 8 carbon atoms,

c) a disubstituted phenyl radical of the formula

030040/0639

wherein two of the radicals R, R ₁ , Rg, R, and R ^ kei denote hydrogen, are identical or different and are fluorine, chlorine, bromine, iodine, alkyl radicals with 1 to 8 carbon

/ Atoms of matter, including isomeric forms, alkoxyr

with 1 to 8 carbon atoms, including isomeric Forms representing nitro or trifluoromethyl group

d) a trihalogen-substituted phenyl radical in which the halogen is chlorine, bromine, iodine or fluorine,

e) a c6-naphthyl radical of the formula

v- wherein the substituent R “is on one of the two rings

and consists of hydrogen, an alkyl radical with 1 to carbon atoms, including isomeric forms, Alkoxy radical with 1 to 8 carbon atoms, including borrowed isomeric forms, fluorine, chlorine, iodine, bromine or the nitro group exists,

f) the 2-furyl radical,

g) the 3-pyridyl radical,

h) the 2-yridyl radical or

i) represents the 2-iyrazyl radical, or a salt thereof.

030040/0639

These compounds are used to treat viral infections or induction of interferon production in humans and animals.

030040/0639

Claims (1)

Patent claims: wherein X, has the same meaning as X, X ₂ ^ or X_, where Xu is fluorine, chlorine, bromine or iodine, X ₁ - a mono-, di- or trihalomethyl, mono-, di- or trifluoromethyl or perfluoropropyl radical and X is an alkyl radical m 1 to 3 carbon atoms, including isomeric Fc men, the 2-propynyl or 2-propenyl radical, and X, a) the phenyl radical, but not if X ^, bromine or X means b) a monosubstituted phenyl radical of the formula in which one of the radicals R, R ^, JL ·, R, and R ^, is not hydrogen and R or R ^ is an alkyl radical having 1 to 8 carbon atoms, including isomeric forms, alkoxy radical having 1 to 8 carbon atoms, including isomeric forms Forms, fluorine, chlorine, bromine, iodine or the nitro 030040/0639 -2- '3Ö08693 Group, R ₁ or R, fluorine, chlorine, bromine, iodine or the nitro group, the trifluoromethyl radical or an alkoxy radical having 1 to 8 carbon atoms, including isomeric forms, an alkoxyethyloxy radical having an alkoxy portion having 1 to 5 carbon atoms, including isomeric forms, or a Remainder of the formula s "" wherein R ₁ - and R,;, which are the same or different 5 ο can, alkyl radicals with 1 to 8 carbon atoms, including isomeric forms, the benzyl radical or together with the -Έ a saturated cycloalkyl aminorest -N ^ v ^c _n «'where η' is the number J5, ² I-, 5 or means, or a dialkyl-substituted cycloalkyl amino radical, wherein any alkyl radical. 1 to 3 carbon atoms has, including isomeric forms, and Rg chlorine, fluorine, bromine, iodine or a Represent an alkyl radical with 1 to 3 carbon atoms, c) a disubstituted phenyl radical of the formula J Vp. in which two of the radicals R, R, R ₃ , R and R _{1 are} not hydrogen, can be identical or different, and fluorine, chlorine, bromine, iodine, alkyl radicals 30 040 / 0.639 with 1 to 8 carbon atoms, including isomeric forms, alkoxy radicals with 1 to 8 carbon atoms, including isomeric forms denoting nitro or trifluoromethyl groups, d) a trihalo-substituted rienyl radical, the contains chlorine, bromine, iodine or fluorine as halogen, e) an o6-naphthyl radical of the formula where IL is a substituent on one of the two and consists of hydrogen, an alkyl radical from I to carbon atoms, including isomeric forms, alkoxy radical having 1 to 8 carbon atoms, including isomeric forms, fluorine, chlorine, iodine, bromine or the nitro group, among the Provided that if X denotes X, X is not the o (-naphthyl radical, f) the 2-furyl radical, g) the ^ -! pyridyl residue., h) the 2-pyridyl radical or i) the 2-pyrazyl radical, with the proviso that when X is the 2-propynyl or 2-propenyl radical, X _{1 is} neither the 2-furyl, 3-pyridyl- »2-pyridyl nor the 2-pyrazyl radical is, represents, or a salt thereof. 030040/0639 2. Compound according to claim 1, characterized in that that X-, fluorine j means chlorine, bromine or iodine. Jf. A compound according to claim 1, characterized in that X- denotes an alkyl radical with 1 to J> carbon atoms. K. A compound according to claim 1, characterized in that X denotes the phenyl radical _u with the exclusion of 2-amino-5-bromo-6-phenyl-4-pyrimidinol _> and X denotes fluorine, chlorine, bromine or iodine. 5. Compound according to claim 1, characterized in that that X, a) a monosubstituted phenyl radical of the formula RR ₁ wherein one of the radicals R, R ₁ , R, R-, and Rj, none ^v denotes hydrogen and R or R _{1 is} an alkyl radical with 1 to 8 carbon atoms, including isomeric Forms, alkoxy radical with 1 to 8 carbon atoms «including isomeric forms, fluorine, chlorine, bromine, Iodine or the nitro group, R, or R_ fluorine, chlorine, bromine, iodine, the nitro group, the trifluoromethyl radical or an alkoxy radical having 1 to 8 carbon atoms, an alkoxyethyloxy radical having an alkoxy moiety 1 to 5 carbon atoms, or a remainder of the form 030040/0639 ^R 6 where R_ and Rg, which can be the same or different, alkyl radicals with 1 to 8 carbon atoms, the benzyl radical or together with the -N ^ a saturated cycloalkylamino radical " ^N vv ^c _n " where n ^{1 is} the number 2, 4, 5 or 6 , or a dialkyl-substituted cycloalkylamino radical, in which each alkyl radical has 1 to 3 carbon atoms, and R _{2 represents} chlorine, fluorine, bromine, iodine or an alkyl radical having 1 to J carbon atoms, b) a disubstituted phenyl radical of the formula in which two of the radicals R, R _{1, R 1, R 1 and R 2 are} not hydrogen, can be identical or different and are composed of fluorine, chlorine, bromine, iodine, alkyl radicals with 1 to 8 carbon atoms, alkoxy radicals with 1 to 8 Carbon atoms consisting of nitro or trifluoromethyl group, c) a trihalogen-substituted phenyl radical, in which the halogen consists of chlorine, bromine, iodine or fluorine, d) an oil-naphthyl radical of the formula 0300A0 / 0639 wherein the substituent R ₁₇ can be on one of the two rings and is composed of hydrogen, an alkyl radical having 1 to 8 carbon atoms, including isomeric forms, an alkoxy radical having 1 to 8 carbon atoms, including isomeric forms, fluorine, chlorine, Jo'd, bromine or the nitro group, e) the 2-furyl radical, f) the 3-yridyl radical, g) the 2-Fyridylrest or h) the 2-pyrazyl radical and X · represent fluorine, chlorine, bromine or iodine, or a salt of it. 6. 2-AmInO-S-JOd-O- (3-bromophenyl) -4-pyrimidinol. 7. 2-Amino-5-bromo-6- (3-fluorophenyl) -4-pyrimidinol. 8. 2-Amino-5-bromo-6- (3-ethoxyethylphenyl) - ² t-pyrimidinol. 9 · 2-Amino-5-bromo-6- (2-methoxyphenyl) -4-pyrimidinol. 10. 2-Amino-5-chloro-6- (2-methoxyphenyl) -4-pyrimidinol. 11. 2-Amino-5-iodo-6- (2-methoxyphenyl) -4-pyrimidinol. 12. 2-Amino-5-bromo-6- (3-chlorophenyl) -4-pyrimidinol. 0 30 0 40/063 9 13 · 2-Amino-5-iodo-6- (3-chlorophenyl) ~ 4-pyrimidinol. -O- (3-chlorophenyl) -4.-pyrimidinol .. 15. 2-Amino-5-chloro-6- (2-fluorophenyl) -4-pyrimidinol. 16. 2-Amino-5-chloro-6- (3-fluorophenyl) -4-pyrimidinol. 17. 2-Amino-5-bromo-6- (2-fluorophenyl) -4-pyrimidinol. 18. 2-Amino-5-iodo-6- (3-fluorophenyl) -4-pyrimidinol. 19. 2-Amino-5-iodo-6-phenyl-4-pyrirπidinol. 20. 2-Amino-5-chloro-0-phenyl-4-pyrimidinol. 21. 2-Amino-5- ^ od-6- (2-fluorophenyl) -4-pyrimidinol. 22. 2-Amino-5-chloro-6- (3-methoxyphenyl) -4-pyrimidinol. 23. 2-Amino-5-bromo-6- (3-methoxyphenyl) -4-pyrimidinol. 24. 2-Amino-5-3od ~ 6- (3-methoxyphenyl) ~ 4-pyrimidinol. 25. 2-Amino-5-bromo-6- (2-pyridyl) -4-pyrimidinol. 26. 2-Araino-5-iodo-6- (3,4-dichlorophenyl) -4-pyrimidinol. 27. 2-Amino-5-bromo-6- (cil-naphthyl) -4-pyriniidinol. 28. 2-AmInO-S-Chlor-O- (3-nitrophenyl) -4-pyrimidinol. 030040/0639 VS- 29. 2-Amino-5 ~, iodo-6- (j5-nitrophenyl) -4-pyrimidinol. 30. 2-Araino-5-iodo-6- (3-trifluoromethylphenyl) -4-pyrimidinol, . 2-amino-5-bromo-6- (4-fluorophenyl) -4-pyrimidinol. 32. 2-Amino-5-DrOm-O- (J, 5-dimethoxyphenyl) -4-pyrimidinol.
33-2-Amino-5-chloro-6- (3-propyloxyphenyl) -4-pyrimidinol. 34. Compound of Formula where X, the same meaning as X, X ^ or X_-besltz1 where X ^, fluorine, chlorine, bromine or iodine, X, - a mono-,
Di- or trihalomethyl, mono-, di- or trifluoroethj or perfluoropropyl radical and X is an alkyl radical with 1 to carbon atoms, including isomeric forms, the 2-propynyl or 2-propenyl radical and X, a) the phenyl radical, b) a monosubstituted pienyl radical of the formula 030040/0639 wherein one of the radicals R, R-, Rg, R, and R ₁ ^ none R, and R ₁ ^ Denotes hydrogen and R or R ₁ , an alkyl radical with 1 to 8 carbon atoms, including isomeric forms, alkoxy radical with 1 to 8 carbon atoms, including isomeric forms, fluorine, chlorine, bromine, iodine or the nitro group, R, or R, fluorine, chlorine , Bromine, iodine, the nitro group, the trifluoromethyl radical or an alkoxy radical having 1 to 8 carbon atoms, including isomeric forms, an alkxyethyloxy radical having an alkoxy moiety having 1 to 5 carbon atoms, including isomeric forms, or a radical of the formula Rr -N wherein R- and R ^, which are the same or different 5 ο can, alkyl radicals with 1 to 8 carbon atoms> including isomeric forms, or the benzyl radical or together with -N <^ a saturated cycloalkylamino radical -N C ₍ * where n ^{1 is} the number j5, ² K * 5 or 6, or a dialkyl- substituted cyclo * - alkylamino radical, in which each alkyl radical has 1 to 3 carbon atoms, including isomeric forms, and Rp represents chlorine, fluorine, bromine, iodine or an alkyl radical with 1 to 3 carbon atoms, c) a disubstituted phenyl radical of the formula 030040/0639 C- - 40-. wherein two of the radicals R, R- ,, Rp, R-, and R ^, do not represent hydrogen, can be identical or different and fluorine, chlorine, bromine, iodine, alkyl radicals with 1 to 8 carbon atoms, including isomic forms, alkoxy radicals with 1 to 8 carbon atoms, e finally isomeric forms, which mean nitro or trifluoromethy! group, d) a trihalo-substituted phenyl resin, which halogen contains chlorine, bromine, iodine or fluorine, e) an ssi-naphthyl radical of the formula wherein the substituent R "on one of the two rings can stand and hydrogen, an alkyl radical having 1 to 8 carbon atoms, including isomeric Forms, alkoxy radical with 1 to 8 carbon atoms, including isomeric forms, fluorine, chlorine, iodine, Bromine or the nitro group means 030040/0639 f) the 2-furyl radical, g) the 3-pyridyl radical, h) the 2-pyridyl radical or
i) the 2-pyrazyl radical represents a salt thereof for use in To cause interferon to be produced, to prevent skin graft rejection, or to treat or prevention of the following diseases: viral infections, acquired or congenital hypo - ^ - globulinemia, cancer, bacterial infections, parasitic infections, and aplastic anemia. 55 · 2-Amino-5-bromo-6-phenyl-4-pyrimidine oil or a salt thereof for use in inducing interferon production, in preventing rejection of skin grafts or to treat or prevent the following diseases: viral infections, acquired or congenital Hypo - $ - globulinemia, SJ? Ebs, bacterial infections, parasite infections and aplastic anemia. 36. Pharmaceutical preparation for inducing interferon production, to prevent skin graft rejection, or to treat or prevent the following Diseases: viral infections, acquired or congenital Hype-iT-globulinäaiie, cancer, bacterial infections, Parasitic infections and aplastic anemia characterized by a compound of the formula 030040/0639 where X has the same meaning as X, X ₁ . or X_ where Xji, fluorine, chlorine, bromine or iodine, X ₁ - a mono-, di or trihalomethyl, mono-, di- or trifluorosefehyl or perfluoropropyl radical and X an alkyl radical with 1 to; Carbon atoms, including isomeric forms, denote the 2-propynyl or 2-propenyl radical, and X, a) the phenyl radical, but not if X_ ^ bromine or X means. b) a monosubstituted phenyl radical of the formula R .R, wherein one of the radicals R, R, R and R ^, none Is hydrogen and R or R _{2 is} an alkyl radical with 1 to 8 carbon atoms, including isomers. Forms, alkoxy radical with 1 to 8 carbon atoms, including isomeric forms, fluorine, chlorine, bromine, iodine or the nitro group, R or R., fluorine, chlorine, bromine, iodine or the nitrc group, the trifluoromethyl radical or an alkoxy radical with 1 to 8 Carbon atoms, including isomeric forms, an alkoxyethyloxyresi 0 300 4.0 / 06 39 including isomeric forms, or a remainder of the formula / ^R 5 Xr ₆ wherein R ₁ - and R ^ -, which can be the same or different, alkyl radicals with 1 to 8 carbon atoms, including isomeric forms, the benzyl radical or together with the -N ^ a saturated cycloalkylamino radical - ^N O ^C n " ^{where n} 'is ^the number J5> ^ * 5 or n
or a dialkyl-substituted cycloalkylamino radical in which each alkyl radical has 1 to y carbon atoms, including isomeric forms, and Rp represents chlorine, fluorine, bromine, iodine or an alkyl radical having 1 to 5 carbon atoms, c) a disubstituted phenyl radical of the formula in which two of the radicals R, R ₁ , R, B- and R _{2 are} not hydrogen, can be identical or different, and fluorine, chlorine, bromine, iodine, alkyl radicals with 1 to 8 carbon atoms, including isomeric forms, alkoxy radicals with 1 to 8 carbon *, atoms, including isomeric forms that denote nitro or trifluoromethyl groups, d) a trihalogen-substituted phenyl radical which has chlorine, bromine, iodine or fluorine as halogen, 030040/0639 e) a ^ -naphthyl radical of the formula where PU is a substituent on one of the two rings is and from hydrogen, an alkyl radical with 1 to carbon atoms, including isomeric forms, Alkoxy radical with 1 to 8 carbon atoms, including isomeric forms, fluorine, chlorine, iodine, bromine or the nitro group, provided that if X ^ X means, X is not the oC-naphthyl radical, f) the 2-furyl radical, g) the 3-ryridyl radical, h) the 2-pyridyl radical or i) the 2-pyrazyl radical, provided that, if X denotes the 2-propynyl or 2-propenyl radical, X_ neither the 2-furyl-, 35-pyridyl-, 2-pyridyl- nor the 2-pyrazyl radical, represents, or a salt thereof. 030040/0 639