HU198461B - Process for producing thiadiazole derivatives and pharmaceutical compositions comprising same as active ingredient - Google Patents

Abstract

(1) 1,3,4-Thiadiazole-2-cyanamide and derivs. of formula (I) and their salts are new. In (I), R1 = H; R2 = CN; or R1+R2 = =C(SR6)NH2 or =C(NH2)2; R6 = 1-4C alkyl, cyano-(1-4C)alkyl or pyridyl-(1-4C)alkyl. (2) In vitro antiviral method for protecting mammalian cells in culture comprises adding to the culture a cpd. (I) in which either (A) R1 = H; R2 = CN or =CH-NHR3; or R1+R2 = =C(NH2)2 or =CR5-NHR3(1); R3 = COOR4; R3(1) = H or COOR4; R4 = 1-10C alkyl, 2-10C alkenyl or Ph, each opt. substd.; R5 = H or SR6; R6 = 1-4C alkyl, cyano-(1-4C)alkyl or pyridyl-(1-4C)alkyl; or (B) as defined for (A) except that R1+R2 = =CR5NHR31 only; and R3, R31 = H or COOR4.

Description

The number of diseases caused by viruses is alarming. Sexually transmitted and transfused viral infections have been the focus of intensive research in the last few years. Less serious diseases caused by viruses include 5 common colds.

Few truly effective antivirals have been developed to date, and in many cases the only possible treatment is the administration of antimicrobials; not to fight the virus, but rather to fight the bacterial infection of the weakened biological system. Research will continue to test effective antiviral agents for the treatment and control of simple diseases such as influenza and rhinitis or various strains of the herpes virus, as well as more serious viral infections such as. to prevent AIDS (Acquired Immune Deficiency Syndrome).

The present invention is based on the discovery that certain 2-amino-1,3,4-thiadiazole derivatives are effective in the treatment of viral infections. Thiadiazoles are generally well known in the literature, some of which have been used in medicine. For example, Naik et al. Describe the antimicrobial activity of several thiadiazolyl-thiazolidinones [J. Indian Chem. Soc., Vol. LX / 1983. 25 Jul.) 674-678. Grant et al

J.Med.Chem.Vol. 15, No. 10, (1972), 1082-1084. 1, 2, 3, 4, 5, 6, 8, 9, 11, 13, 13, 13, 13, 13, to 16 to 21 to certain amine-substituted derivatives of 2-amino-1,3,4-thiazole. N-acylated derivatives of 2-amino-1,3,4-thiadiazole according to U.S. Patent No. 3,307,712,316 are effective as fungicides. Russo et al., Farmaco. Ed. Sci., Vol. 30, No. 12 (1975), 1031-1038. 4, 5, 9, 9, 9, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 13, 15, 13, 13, 13, 15, 13, 15, 15, 15, 158 to 1540, and thiourea derivatives of 1,3,4-thiadiazole and their antibacterial activity. Malinoski et al., Virology,

110, 281-291. (1981) describe some antiviral activity of 2-amino-1,3,4-thiazoles.

SUMMARY OF THE INVENTION The present invention relates to a process for the manufacture of a medicament for the prevention, treatment and control of viral infections comprising as active ingredient a compound of formula (I):

R 1 is hydrogen;

R 1 is cyano, or

R1 and Ra taken together are = C (NH1) 1 or = C (NH1) (SR6), wherein R1 is C1-C6 alkyl, cyano-C1-C4 alkyl or pyridyl-50 (C1-C4) alkyl.

The compounds of formula (I) may also be used in the treatment of animals suffering from or susceptible to viral infection. The novel compounds represented by the general formulas (V) and (VI) and (VII) are most suitable for this purpose. In particular, the compounds represented by the formulas (V) and (VI) are potent antiviral agents. The compound of formula (VII) is highly active in vitro.

The present invention also relates to the preparation of the pharmaceutically acceptable salts of the compounds of formula (VI) 60 with bases and of the compounds (V) and (VII) with acids. According to the invention

a) for the preparation of compounds of formula I wherein R 1 and R a together are 65 2 = C (NHa) (SR 6) wherein R 6 is as defined above (1,3,4-thiadiazol-2-yl) - reacting thiourea with an alkylating agent of the formula R x wherein R is as defined above and X is a leaving group and optionally

i) for the preparation of a compound of formula I wherein R1 is hydrogen and R1 is -CN, a compound of formula I wherein R1 and R1 together are = C (NHa) (SR6) and R1 is reacting the above with an oxidizing agent, or ii) preparing a compound of formula (I) wherein R 1 is hydrogen and R 1 is -CN or R 1 and R 2 together are = C (NH 1) i; wherein R1 and R2 are taken together = C (NH1) (SR6) and R6 is as defined above, is reacted with ammonia and the two compounds are separated, or

b) debenzylating 3- (phenylmethyl) -1,3,4-thiadiazol-2 (3H) -ylidenecyanamide to produce (1,3,4-thiadiazol-2-yl) cyanamide and optionally The resulting compound of formula I is reacted with a suitable organic or inorganic base or acid to form a pharmaceutically acceptable salt.

Most of the foregoing compounds are prepared by reaction of (1,3,4-thiadiazol-2-yl) thiourea with the formula R x (where R e is as defined above and X is any alkyl leaving group). , bromide, iodide and sulfonic acid ester groups such as tosylate and mesylate, so suitable alkylating agents include alkyl halides such as methyl bromide or substituted alkyl halides such as cyanomethyl bromide or Pyridylmethyl iodide Reactions are generally accomplished by mixing approximately equimolar amounts of (2-thiadiazolyl) thiourea with an alkylating agent in an inorganic organic solvent such as dimethylformamide or acetonitrile in the presence of a base such as sodium carbonate. hours at 20 ° C to 50 ° C energy required is removed, vacuum distillation. The product can be purified by routine methods, including recrystallization, e.g., ethanol, ethyl acetate, hexane or chromatography, using silica or the like as a solid phase.

A particularly preferred group of compounds of the present invention is (1,3,4-thiadiazol-2-yl) cyanamide and pharmaceutically acceptable salts thereof. The compound is prepared according to process a) by reaction of an S-alkyl isothio with an oxidizing agent of urea (e.g., metachloroperbenzoic acid, peracetic acid, sodium peroxide, hydrogen peroxide, ozone, chlorine, etc.).

The present invention relates to a protected 2-aminothiadiazole derivative of (1,3,4-thiadiazol-2-yl) cyanamide, namely 2-imino-3- (phenylmethyl) -1,3,4-thiadiazole and cyanobromide, wherein the deprotection of the 3-position can be accomplished by debenzylation with a Lewis acid such as aluminum chloride. An organic solvent for debenzylation is, for example, n methylene chloride, toluene or benzene. Preferably, at least 2 equivalents, and more preferably 4-8 equivalents, of Lewis acid is preferred. Temperature-21

GB 198461 Life is not critical, debenzylation is effected, for example, at 0'C to 90'C, room temperature is recommended.

A cyanamide derivative is also formed when S-alkylisourea is reacted with ammonia as in Example 8.

The cyanamide derivative is reacted with organic and inorganic bases such as sodium acetate, calcium acetate, calcium carbonate, sodium hydroxide, etc. to form pharmaceutically acceptable salts. The other compounds form acid addition salts.

The compounds of the invention may exist in various tautomeric forms, all of which are encompassed by the invention. For example, the preferred (1,3,4-thiadiazol-2-yl) cyanamide may exist in the following forms:

Q) --► (2) --► (3)

Another present invention? compounds in several tautomeric forms can be represented by the following formulas:

(4) '_. (5)

The invention thus encompasses all possible tautomeric forms.

The following detailed examples illustrate the preparation of thiadiazoles as antiviral agents according to the invention.

Starting example 1

Ethyl N - [(1,3,4-thiadiazol-2-ylamino) -thioxonethyl] -carbamic acid

To a solution of 19.2 g (190 mM) of 2-amino-1,3,4-thiadiazole in 200 ml of acetonitrile was added 25 g (190 mM) of ethoxycarbonyl isothiocyanate in one portion, followed by further stirring at 24 ° C. Stir for 16 hours. The precipitate was collected by filtration, washed three times with ethyl acetate, and dried to give 35 g (80% yield) of the title compound. Analysis: Calculated for C 6 H 8 N 4 O 2 S 2: C, 31.02; H, 3.47; N:

Found: C, 31.32; H, 3.27; N, 24.40.

Starting Example 2 (13,4-Thiadiazol-2-yl) -thiourea

10 g of the ethyl ester of N - ((1,3,4-thiadiazol-2-ylamino) -thioxymethyl] -carbamic acid prepared in Preparation 1 is refluxed for 90 minutes in 150 ml of 1N sodium hydroxide. The precipitate was filtered off and dissolved in water (20 mL), acidified with aqueous hydrochloric acid (200 mL), filtered, recrystallized from 200, Ν-dimethylformamide to give 5 g of the title compound. 253C Calculated for C3H4N4S2: C, 22.49; H, 2.52; N, 34.97; S, 40.02. Found: C, 22.73; H, 2; 33, N: 34.74, S: 40.26%.

Example 1

3- (1,3,4-Thiadiazol-2-yl) -2-methyl-ozothiourea

A mixture of 4.8 g of (1,3,4-thiadiazole-2-Η) thiourea (9) prepared as described above was treated with 45 ml of IN sodium hydroxide, 15 ml of ethanol and 4 ml of methyl iodide for 10 min. Heat at C. The mixture was acidified by addition of 50 ml of IN hydrochloric acid and then concentrated by vacuum distillation. The precipitate was filtered off to give 3.02 g of the title compound. 116-117'C. Elemental analysis for C4H6N4S2:

Calculated: C, 27.57; H, 3.47; N, 32.15.

S, 36.80;

Found: C, 27.78; H, 3.55; N, 31.92; S, 36.54. 1 H NMR Spectrum (300 MHz) (DMSO 2 / Si (CH 3) 4): delta: 2.42 (s 3H, -S-CH ₃ ), 8.90 (bs, 2H.-NH 2), δ , 08 (s, 1H, ring H), FD (knee desorption) mass spectrum: molecular ion M ⁺ 174.

Example 2

3- (1,3,4-thiadiazol-2-yl) -2-ethylisothiourea of formula (6):

3.2 g (20 mM) of (1,3,4-thiadiazol-2-yl) thiourea

A solution of 1.6 ml (20 mM) of ethyl iodide and 2.12 g (20 mM) of sodium carbonate in 100 ml of N, N-dimethylformamide was stirred at 24 ° C for 24 hours. The reaction mixture was filtered and the filtrate was evaporated in vacuo to give an oil which was chromatographed on a Waters preparative 500 column using 75% ethyl acetate / hexane (v / v). The appropriate fractions were collected, evaporated to dryness and the solid residue was recrystallized from diethyl ether and hexane.

2.08 g of 3- (1,3,4-thiadiazol-2-yl) -2-ethylisothiourea are obtained. Analysis: Calculated for C 5 H 8 N 4 S 2: C, 31.90; H, 4.28; N, 29.76; S, 34.06; Found: C, 32.18; H, 4.18; N, 29.59; S, 34.08; 1 H NMR (300 MHz) (DMSODe / Si (CH 3) 4): delta (t , 3H, -CH ₃ ), 3.02 (q, 2H.-CH 2 -),

8.88 (broad s, 1.06 2H, -NH 2), 9.08 (s, 1H, ring H).

IR spectrum (KBr), cm -1: 3259.9, 3089.2, 1624.2, 1510.4, 1416.8, 1377.3, 1347.4, 1247.1, 1209.5, 718.5. FD mass spectrum: M ⁺ 188.

3-5. example

The following thiadiazolylisothioureas were prepared by reaction of (1,3,4-thiadiazol-2-yl) thiourea with an alkyl halide according to Examples 1 and 2.

3- (1,3,4-thiadioazol-2-yl) -2- (n-butyl) -isothiourea; Yield: 1.68 g, m.p. 40'C.

1 H-Nuclear Magnetic Resonance Spectrum (300 MHz) (DMSOD 6 / Si (CH 3) 4): delta: 0.90 (t, 3H, -CH _{3 -} ), 1.38 (sextet, 2H, -CH 2 -), 1.60 (pentet, 2H, -CH 2 -), 3.04 (triplet, 2H, -CH 2 -), 8.90 (bs, 2H, -NH ₂ ), 9.09 (s, 1H, ring H).

FD mass spectrum: M ⁺ 216.

3- (1,3,4-Thiadiazol-2-yl) -2- (2-pyridylmethyl) -isothiourea. HCl; Yield: 3.72 g.

1 H NMR Spectrum (300 MHz) (DMSOD 6 / Si (CH ₃ ) 4): delta: 4.64 (s, 2H, -CH ₂ ), 7.82 (t, 1Hm pyridine-H), 7.98 (d, 1H, pyridine-H), 8.40 (t, H, pyridine-H), 8.79 (d, 1H, pyridine-H), 9.11 (s, 1H, ring H). FD mass spectrum: M ⁺ 251.

3- (1,3,4-thiadiazol-2-yl) -2- (cyanomethyl) -isothiourea; Yield: 1.04 g.

1 H NMR Spectrum (300 MHz) (DMSOD 6 / Si (CH 3) 4): delta: 4.14 (s, 2H, -CH ₂ -), 9.09 (bs, 2H, -NH 2), 9, 15 (s, 1H, ring H), FD mass spectrum: M ⁺ 199.

Example 6 (13,4-Thiadiazol-2-yl) cyanamide

3.48 g (20 mM, prepared as in Example 1)

3- (1,3,4-Thiadiazol-2-yl) -2-methylisothiourea 4 g 3

HU 198461 Β (based on 85% purity 20mM) in methylene chloride (200ml) was stirred at 24 ° C for two hours. The mixture was filtered and the precipitate was further stirred with 40 ml of water for 2 hours. The solid precipitate was filtered off and dried, yielding 1.7 g of the title compound. FD mass spectrum: M ⁺ 126. Elemental analysis for C3H2N4S:

Calculated: C, 28.57; H, 1.60; N, 44.42.

S, 25.42;

Found: C, 28.95; H, 1.80; N, 43.60; S, 24.87.

Example 7 (1,3,4-Thiadiazol-2-yl) -diananide Sodium Salt

To a solution of 1.38 g of (1,3,4-thiadiazol-2-yl) cyanamide in 10.5 ml of 1N sodium hydroxide is added 100 ml of ethanol. The mixture was filtered and the filtrate evaporated to give an oil which was crystallized from a mixture of methanol (20 ml) and isopropyl alcohol (100 ml) by slow distillation of methanol in a vacuum oven. 980 mg of the title compound are obtained.

1 HNMR (300 MHz) (D 6 DMSO / Me 4 Si) d: 8.68 (s, 1H, ring H); FD mass spectrum: 126. Elemental analysis for C3HN4SNa:

Calculated: C, 24.33; H, 0.68; N, 37.83.

S, 21.65%;

Found: C, 24.59; H, 0.87; N, 38.06; S, 21.90.

Example 8 (13,4-Thiadiazol-2-yl) guanidine

A mixture of 5.0 g of 3- (1,3,4-thiadiazol-2-yl) -2-methylisothiourea, prepared according to Example 1, in 50 ml of ammonia and 100 ml of ethanol was heated in a bomb at 140 ° C for 14 hours. TLC on silica gel plates (66%

CHCl3, 26% MeOH, 8% HOAc) two new spots were separated, one of which ran at the same site as (1,3,4-thiadiazol-2-yl) cyanamide (Example 6). The solvent was evaporated and the crude product was stirred with 200 mL of IN hydrochloric acid and filtered to remove insoluble cyanamide. The hydrochloric acid solution was evaporated to dryness and the residue was purified by reverse phase HPLC (90% MeOH / H 2 O) as eluent. 1.5 g of the title compound are obtained.

1 H NMR Spectrum (300 MHz) (DMSOD 2 / Si (CH 3) 4): delta 8.37 (bs, 4H, -NH ₂ ), 9.27 (s, 1H, ring H). FD mass spectrum: M ⁺ 144.

Example 9 (13,4-Thiadiazol-2-yl) cyanamide

A) Benzylation of 2-amino-1,3,4-thiadiazole A mixture of 101 g of 2-amino-1,3,4-thiadiazole, 650 ml of n-propanol and 140 ml of benzyl bromide was heated in a 2 liter flask. When the temperature reached 88'C, the 2-amino-1,3,4-thiadiazole was completely dissolved. At 98'Con, the solution began to reflux and the flask, except the heating jacket, was placed in a water bath to control the efflux. To maintain the liquid state, an additional 250 mL of n-propanol was added and the temperature was heated to 86'C with heating if necessary, and then cooled to 3'C. The product 2-imino-3- (phenylmethyl) -2,3-dihydro-1,3,4-thiadiazole hydrobromide formed was filtered off, washed with n-propanol and air dried. Yield: 190 g (70%). M.p. 200-202C.

B) Reaction with bromocyanide

To a stirred mixture of 146 g of the product obtained in A), 1 L of water and 1 L of ethyl acetate, 44 ml of a 50% aqueous solution of sodium hydroxide were added to make the starting thiadiazole derivative. The aqueous phase was then separated and discarded. To the remaining ethyl acetate solution was added 800 ml of water containing 84 g of sodium bicarbonate, and 56.3 g of bromelane dissolved in 150 ml of ethyl acetate were added dropwise over 25 minutes. The mixture was stirred for an additional 30 minutes. The aqueous layer was separated and discarded, and the remaining ethyl acetate layer was washed with 200 mL of water. Saturated brine was added to expedite the phases, and the aqueous phase was separated and discarded again. The ethyl acetate solution was evaporated to one third of its volume and 100 ml of toluene were added. This solution was concentrated again to one third of the original volume, and another 10 µl of toluene was added. This concentration was repeated several times to give the desired [3-phenylmethyl) -1,3,4-thiadiazol-2 (3H) -ylidene] cyanamide as a precipitate which was filtered off, washed with toluene and dried 57.7 g of product is obtained

In 50.6% yield.

C) Debenzylation Six equivalents (7.4 g) of finely powdered aluminum chloride was added to 50 ml of [3- (phenylmethyl) -1,3,4-thiadiazole-2 (3H) -ylidene] cyanamide in methylene chloride. After stirring for 2 hours, tetrahydrofuran (50 mL) was added and the reaction mixture was poured into cold water (50 mL). After stirring for 10 minutes, the insolubles were filtered off. To better separate the phases, about 5 g of sodium chloride was added and the THF phase was separated. An additional 2 g of salt was added to the aqueous phase and the extractions were repeated twice with 25 mL portions of THF. The tetrahydrofuran layers were combined, dried over magnesium sulfate and evaporated to dryness. To the solid product was added methylene chloride (25 mL), and the precipitate was collected and dried to give 0.91 g (1,3,4-thiadiazol-2-yl) cyanamide (78% yield), which was determined by HPLC (HPLC). analysis) was 96.7% pure.

The thiadiazoles described above exhibit antiviral activity in standard test systems and can thus be used to treat and prevent diseases caused by various viruses. For example, thiadiazoles are effective against the following typical viral strains: all influenza A and B viruses tested, including, for example, A-Ann Arbor, A-Hong Kong, B-Great Lakes, B-Taiwan, B-Singapore, AB-Brazil, A- Texas, A-Fukushina, B-Maryland and other strains of virus. Other viruses that can be overcome by the invention include parainfluenza respiratory syncytial viruses, various Herpes I and II strains, Echo and Vaccinia viruses, measles Semliki Forcst 'and AIDS-causing viruses.

The thiadiazole-type antiviral agents of the present invention exert their effects both in vitro and in vivo. For example, it's called A-Ann Arbor

HU 198461 Β The in vivo activity against the influenza virus is particularly well characterized.

In in vivo test experiments, groups of 18 CD-I mice were examined after challenge with predetermined amounts of A-Ann Arbor influenza culture. Thiadiazole was also given at a fixed dose and served as a vehicle-only control.

The test lasted 10 days. In each group, the number of animals killed on each day was monitored. The animal, which reached the end of day 10, was considered to be surviving. We used the survival index method to analyze the data as follows:

From the control group data, a survival index '(ΤΙχ, κιρ) was assigned to each day (X) from the day on which the first death occurred in the control group (typically X = 4) until day 10. On the day of the first death, the survival index 'is defined as zero. The values for the remaining days can be calculated using the following formula:

Tiksuup = (X-l) Total number of control animals killed on day X.ΊΙΙηΐηΚ- situation + TI (day X.n.

For example, if the first day on which a control animal dies is exactly X = Day 4, and on Day 5 an additional 3 of the 18 control animals die, because

TU.nap = zero, Τβ, ηαρ = (5-1) - + 0 = γτ 0.66 lo lo

For survivors, ”T.I. survivors' index can also be calculated from control group data using the following formula:

Overage Time = 10 X Number of Control Animals Killed on 10 Nanon Total Number of Control Animals + TI 10 days

The indices so calculated can then be used to determine the mean survival values for both the control group and the groups of test animals using the following procedure: it can be calculated by multiplying each ΤΙχ _η3 ρ by the number of control animals killed on that day, and by multiplying the TI survivors by the number of survivors, if any, by the total number of control animals. The mean survival value for the treated group is CTJkczcit ") is calculated by multiplying each value of ΤΙχηαρ by the number of treated animals that died on that day, and the value of TI overdoses by the number of treated animals surviving, and summing these values by number.

Using the following formula, where P is:% of maximum, a comparison with the results of the control group can be calculated

P ⁼ TlktzclL- ThnmrnlÍ X 100

Fluorescents - Tlürontroll

If the mean survival value for the treated animals is less than or equal to the mean survival value for the control animals, then P = 0% based on this formula. If the mean survival value for treated animals is equal to the survival index, then P = 100%.

This P value is then given by a so-called. relative activity index (RA) as follows:

P RA

20% or less = 20-40% 40-60% 60-80% 80-100% 1 (threshold) 2 (slightly active) 3 (Moderately active) 4 (good activity) 5 (very active) Table I shows the RA values for representative compounds of the invention: TABLE I Compounds of Formula IV Rs R3 RA -S-CH2CH3 H 5 SCH3 H 5 -S-CH2CH2CH2CH3 H 5 _-S-CH2-CN H 2.5 -S-CH2-2-pyridyl H 2.5

Methods for the quantitative determination of inhibition of viral replication in tissue cell culture systems in vitro are stain reduction assays.

In this assay, the sensitized MDCK cells were grown in 25 cnP Falcon dishes at 37'C in Medium 199 in the presence of 5% inactivated fetal oxide serum (FBS), penicillin (300 units / ml) and streptomycin (300 pg / ml). After the formation of a continuous monolayer, the medium was removed and 0.3 ml of appropriately diluted virus was added to each flask. After adsorption for 1 hour at room temperature, the infected cell layer was covered in equal proportions with 1% agarose and 2x Medium 199,

2.5% FBS, penicillin and streptomycin embedded in different concentrations of test compounds in the agar cover.

The compounds were dissolved in dimethyl sulfoxide (DMSO) at a concentration of 10,000 pg / ml and an aliquot diluted to the desired concentration with agar. The flasks were incubated until the control vessels showed an optimal stain size (2-10 mm). A solution containing 10% formalin and 2% sodium acetate was added to each flask to inactivate the virus and bind the cell layer to the plastic surface. The stains were counted after staining the surrounding cell areas with crystal violet. At each concentration, the results obtained for duplicate flasks were averaged and compared with the control flasks. The inhibition of plaque formation at 50% (I50) was estimated by plotting the results for 1090% inhibition. Our results for three influenza strains are presented in Table III. spreadsheet.

When used in vitro, the compounds are added to tissue culture to suppress viral growth.

The preferred administration of the compounds may be in vivo, when the compounds are administered parenterally, topically, orally, or by inhalation through the nose in a patient suffering from or susceptible to a viral infection.

-5IIU 198461 Β

III. SPREADSHEET

In vitro activity against influenza viruses l50 (MCG / ML)

Compound NWS-A A-Ann Arbor B-Great Lake Example 1 18.6 18.0 Example 2 9.8 9.5 Example 3 21.3 25.0 Example 6 0.85 Example 7 0.58 0.70 0.32 Example 8 0.04 0.3

mammalian body. For parenteral administration, e.g. for intraperitoneal administration, the compound is dissolved or suspended in water containing 2% surfactant, mainly emulph (polyhydroxy fatty acid). Oral administration is, of course, most preferred. In this case, the compound defined herein may be formulated with one or more standard pharmaceutically acceptable substances such as starch, sucrose, lactose, calcium carbonate, and the like. and mixing the mixture into empty, push-in gelatin capsules such that each of the 25 capsules contains the compound in an amount effective to suppress the growth of influenza or other viruses, whether present or present. In other words, these compounds are both prophylactic (prophylactic) and curative. Similarly, the active ingredient may be mixed with any carrier such as starch, lubricants, wetting agents, and the like. such as stearic acid, magnesium stearate and the like, and the mixture can be compressed into tablets, each containing the amount necessary to stop and suppress an attack caused by influenza or other viruses. For children, half or a quarter of the dosage of these tablets is suitable, but may also be administered in the form of a solution or suspension.

The use of the antiviral method of the invention simply means that an appropriate amount of an antiviral of thiadiazole antiviral is applied to the tissue to be treated or orally in a subject suffering from or susceptible to a viral infection. Ideally, the compounds are formulated in combination with pharmaceutically acceptable carriers suitable for convenient administration and can be administered orally, topically or parenterally for prophylactic or therapeutic purposes. The formulations may contain from 1% to 95% by weight of the active thiadiazole antiviral.

For oral (oral) administration, the compounds may be combined with customary diluents and carriers, such as sucrose, starch, microcrystalline cellulose, acacia, etc., to form tablets or pills, filled into gelatin capsules, or as a solution, we can do more. For topical application, the compositions are prepared by admixing 60 of the thiadiazole antiviral agent with a variety of carriers such as beeswax, lanolin, oil and so on ointments, herbs, creams, tinctures, cosmetic solutions. For major viral infections, intravenous or intramuscular administration is appropriate. These compositions contain from 1 to 50% of the active ingredient. For intravenous infusion, the compounds are dissolved in common diluents such as isotonic saline or dextrose solution;

in the case of intravenous or intramuscular injection, the active component is dissolved in aliphatic polyhydroxy alcohols, such as propylene glycol or polyethylene glycol.

The pharmaceutically acceptable salts of the acidic or basic compounds of the above formula may be prepared by reaction with common organic or inorganic acids or bases, such as hydrochloric acid, succinic acid or sodium hydroxide. Pharmaceutically acceptable salts generally have better solubility than the parent compounds and are therefore more suitable for liquid or emulsion formulations.

The above-described thiadiazole antiviral agents are effective over a wide dosage range. Although each dose to be used will be determined by the nature and severity of the viral infection to be treated or prevented, and the dosage and other conditions will be determined by the physician, the usual doses will be in the range of 0.1-100 mg / kg and most commonly 0.5-25 mg / kg. fall.

In a preferred application of the treatment, thiadiazole-type compounds are administered to mammals susceptible to influenza virus infection, such as horses, mice, pigs, and humans. In the case of humans, prophylactic treatment was given especially to the elderly, infants, nurses, doctors and other hospital and healthcare staff, where an imminent influenza epidemic could be expected. The compounds can be administered to anyone exposed to the risk of infection by an influenza person. A particular advantage of the curative effect described in the present invention is that the compounds can be administered for prophylactic or curative purposes without first determining that the influenza virus belongs to strain A or B, since these compounds are effective against both strains.

The following examples illustrate some representative formulations of the compounds of formula (I).

Example 10

Preparation of tablets

The compound prepared in Example 1 was 100 mg

Lactose 200 mg

Corn starch 300 mg

Corn starch germ 50 mg

HU 198461 Β

Calcium stearate 5 mg

Dicalcium phosphate 45 mg

The active ingredient is uniformly mixed with starch, lactose and dicalcium phosphate. The corn starch germ, a 10% aqueous paste, is also blended evenly into the mixture, and then calcium stearate is added and tablets are then compressed.

Example 11

Making cones

The compound prepared in Example 1 was 500 mg

Theobromo oil 1500 mg

The above ingredients were uniformly mixed at 60 ° C and then cooled in a conical form.

Example 12

Preparation of oral suspension

The compound prepared in Example 8 was 500 mg

Sorbitol solution (70% N.F.) 40 mg

Sodium benzoate 150 mg

Lactose 10 mg

Cherry substance 50 mg

Ethanol 100 ml

The above ingredients are mixed so that each ml of syrup contains 5 mg of active ingredient. A daily dose of 5 to 20 ml of syrup protects people from viral infections such as influenza.

Example 13

Nasal Composition The compound prepared in Example 8 was 1.0 wt% Antarox (non-ionic, poxyoxyethylated oil, GAF Corp) 38.5 wt%

Ethanol 10.0% by weight

Freon-11 (trichlorofluoromethane) 25.0% by weight

Freon-12 (dichlorodifluoromethane) 25.0% by weight

Menthol 0.5% by weight

The active ingredient is added to Antarox at 70-80 ° C and stirred until a solution is formed, cooled and diluted with methanolic ethanol. The imaginary solution is placed in an aerosol container, cooled to 0'C, Freon ingredients are added and the aerosol container is fitted with a valve.

Claims (6)

PATENT CLAIMS A process for the preparation of a compound of formula I wherein R 1 is hydrogen and R2 is -CN, or R and R together represent a group = C (NH 2) (SRO) or = C (NH ₂₎ 2, wherein R 6 is C 1 -C 6 alkyl, cyano-C 1 -C 4 alkyl pyridyl (C 1 -C 4) alkyl, and a compound of formula (I) wherein R 1 is hydrogen, R ₂ is -CN and pharmaceutically acceptable salts of the other compounds with acids, a) for the preparation of compounds of formula I wherein R 1 and R 1 together are = C (NH 2) (SR 6), wherein R 6 is as above, 1,3,4-thiadiazol-2-yl-thiourea is reacted with an alkylating agent of formula R X , where R is as defined above and X is a leaving group, if desired (i) for the preparation of a compound of formula (I) wherein R 1 is hydrogen and R ₂ is -CN, the compound of formula (I) obtained above is obtained wherein R 1 and R ₂ together are = C (NH ₂ ) (SR ₆ ). ), and R & are as defined above, with an oxidising agent, or ii) for the preparation of compounds (I) wherein Ri is hydrogen and _R2 is -CN, or Ri and _R2 together form = C (NH ₂ ) 2 groups, reacting a compound of formula (I) obtained above, wherein R 1 and R ₂ together = C (NH 2) (SR 6) and R 5 s are as described above, with ammonia and separating the two compounds, or b) for the preparation of 1,3,4-thiadiazol-2-yl-cyanamide a 3- (Phenylethyl) -1,3,4-thiadiazol-2 (3H) -ylidenecyanam time is debenzylated and optionally a) or b) reacting the compound of formula I formed by process (b) with a suitable organic or inorganic base or acid to form a pharmaceutically acceptable salt. The subsequent step i) of process a) according to claim 1, characterized in that a compound of formula I obtained by process a), wherein R 1 and R ₂ together are = C (NH ₂ ) (SR 6) group and R 1 is as defined in claim 1, with an oxidizing agent. Process (a) or (b) according to claim 1, wherein 1,3,4-thiadiazol-2-yl cyanamide and pharmaceutically acceptable salts thereof, characterized in that it is based on appropriately substituted materials. The subsequent step ii) of process a) according to claim 1 for the preparation of 1,3,4-thiadiazol-2-yl guanidine, characterized in that a compound of formula I obtained by process a), wherein R 1 and R ₂ together = C (NH 2) (SR 6) and R 1 is as defined in claim 1, with ammonia. Process b) according to claim 1, characterized in that the debenzylation is carried out using Lewis acid and aluminum chloride as Lewis acid. 6. A process for the preparation of a pharmaceutical composition, wherein one or more of the active compounds of formula I according to claim 1, wherein R 1 and R _{2 are} as defined in claim 1, or a salt thereof is converted into a conventional dosage form with pharmaceutically acceptable carriers.