WO2000034259A1

WO2000034259A1 - Biologically active 2-r-5-amino-1,3,4-thiadiazole derivatives

Info

Publication number: WO2000034259A1
Application number: PCT/RU1998/000406
Authority: WO
Inventors: Rimma Iliinichna Ashkinazi; Viktor Iosifovich Krutikov
Original assignee: Rimma Iliinichna Ashkinazi; Viktor Iosifovich Krutikov
Priority date: 1998-12-04
Filing date: 1998-12-04
Publication date: 2000-06-15
Also published as: AU3632099A

Abstract

The present invention pertains to the field of medicine, more precisely to that of pharmacology, and essentially relates to biologically active synthetic diazoles that consist of 2-R-5-amino-1,3,4-thiadiazole derivatives. These substances are mainly intended for use in medical practice for treating chlamydiae-mediated viral diseases as well as diseases resulting in immunodeficiency, including malignant tumours. The purpose of the present invention is to create new chemical compounds which have a high antiviral and an anti-microbial (anti-chlamydia) activity, which stimulate the production of endogenous interferons in the organism and which also have anti-aggregating, analgesic and psycho-depressive actions. This invention involves synthesising a new group of substances that consist of 2-R-5-amino-1,3,4-thiadiazole derivatives of general formula (1) where R1 is selected from the group comprising alkyl, aryl and -CH2-CH2C(0)NH-N=CH-Z, provided that Z is aryl or piperonyl, while R2 is selected from the group comprising H and (a), provided that Y is aryl or heteroaryl. This invention further relates to general methods for producing these substances, to 4 examples of the synthesis of said substances, to the identification results of each of the 42 synthesised substances as well as to data concerning the experimental verification of the substance biological activity relative to known preparations used for the same purposes.

Description

\ УΟ 00/34259 ΡСΤ Κϋ98 / 00406

ΜΚand 6 Α 61Κ 31/505, 31/54, 45/04. C 07B 513/12

ΡΟΡΟΒΟΒΟΗΗΕ 2-Κ-5-ΑΜИΗΟ- 1, 3,4-ΤИΑДИΑЗΟЛΑ, ΟTHE BLENDING Ο BIΒΗΟLΟGICΕΕΑΚΤΑΚΤΑΚΤΑΚΤΤΤΤΤ

iοlasτ τeχniκi 0 Izοbρeτenie οτnοsiτsya κ medicine τοchnee - κ φaρmaκοlοgii, κοnκρeτnο - κ sinτeτichesκim biοlοgichesκi aκτivnym diazοlam προizvοdnym 2-Κ-5-aminο-1,3,4-τiadiazοla inventive veschesτva imeyuτ znachiτelnuyu προτivοviρusnuyu aκτivnοsτ πο οτnοsheniyu κ viρusam προsτοgο geρπesa, anτimiκροbnuyu - In relation to chlamydia and 5 drugs, as well as interfering, anti-aggresive, analgesic and psychoactive activity

The substances are mainly intended for use in medical practice, for the treatment of viral diseases caused by chlamydia, as well as diseases that are related to malignant

Level of technology

Χοροshο izvesτnο, chτο προizvοdnye diazοlοv οbladayuτ ρaznοοbρaznοy 5 biοlοgichesκοy aκτivnοsτyu, mnοgie of κοτορyχ izvesτny κaκ leκaρsτvennye πρeπaρaτy [1] Pοsτοyannο προdοlzhaeτsya ποisκ nοvyχ τiadiazοlοv [2 - 4] Seρeznuyu προblemu for sοvρemennοy medicine πρedsτavlyayuτ viρusnye zabοlevaniya Κaκ πρavilο, viρusnye inφeκtsii, naπρimeρ caused viρusami Herpes groups are, at times, poorly treated for treatment, which is associated with an inadequate effect on the drug, and is also susceptible to rapid changes. of resistant drugs [5,6] Of the synthetic drugs for the treatment of diseases caused by the viruses of the herbal group, they have an

There is a problem in the treatment of diseases caused by chlamydia, including widespread genital infections [7], which are internal to the disease. κροme τοgο, ρasπροsτρanivshayasya 0 usτοychivοsτ κ κ ποslednim πρivela ποyavleniyu bοlshοgο number χροnichesκiχ φορm zabοlevaniya For treatment χlamidiynyχ inφeκtsy isποlzuyuτ οδychnο πρeπaρaτy τeτρatsiκlinοvοgο ρyada, and maκροlidy φτορχinοlοny, naπρimeρ tsiπροφlοκsatsin [7] ν θ 00/34259

Chasτο zabοlevaniya viρusnοy and baκτeρialnοy πρiροdy προτeκayuτ on φοne reduce aκτivnοsτi immunnοy sisτemy ορganizma, ποeτοmu προblema sοzdaniya eφφeκτivnyχ πρeπaρaτοv to treat immunοdeφitsiτnyχ sοsτοyany ρazlichnοgο προisχοzhdeniya τaκzhe yavlyaeτsya οdnοy of aκτualneyshiχ. In addition, stimulation of the activity of the immune system contributes to the overthrow of the body by accelerating the use of drugs while it is observed that By taxes of the claimed compounds for chemical purposes and purpose, there may be etazole, diacarb and butazolamide.

Etazol - 2- (4-Mineral-8-benzene sulfamide) -5-ethyl-1,3,4-thiadiazole. It has antibacterial activity in relation to illnesses, pneumonia, meningitis, atherosclerosis, and atherosclerosis. Described, for example, diacarb - acetylamine-1,3,4-thiadiazole-5-sulfamide. It is used in the form of a medicinal product, and also for the treatment of glaucoma. It is written, in particular, in operation [1].

Butazolamide - 2-Butyrilamine-1,3,4-thiadiazole-5-sulfamide has the following structural formula

Butazolamide - only known as an anti-bacterial agent. It was written in [10]. The closest to the claimed substances for chemical purposes and purpose is butazolamide. It was chosen by us as a quality.

Butazolamide is a very good antibiotic, but, unfortunately, it is not very active in the treatment of viruses, chlamydia, and it does not always affect the body.

OBJECT OF THE INVENTION

The object izοbρeτeniya yavlyaeτsya ποluchenie nοvyχ χimichesκiχ sοedineny, οbladayuschiχ vysοκοy προτivοviρusnοy and προτivοmiκροbnοy (anτiχlamidiynοy) aκτivnοsτyami, sτimuliρuyuschiχ vyρabοτκu endοgennyχ inτeρφeροnοv in ορganizme and τaκzhe imeyuschiχ analgeziρuyuschee, and anτiagρegatsiοnnοe πsiχοdeπρessivnοe deysτviya. In other words, the task of the invention is reduced to the chemical synthesis of biologically active substances. Possessing beneficial, immunocompromising, immunostimulating, antiaggregating, analgesic and psychoactive actions. ΡСΤ / ΚΙΙ98 / 00406

The present invention

The posed problem is solved by the synthesis of a new group of substances of 2-Κ-5-amine-1,3,4-thiadiazole) general formula (1)

where Κι is selected from the group alkyl, aryl, -C- ₂ -CΗ ₂ С (0) ΝΗ-Ν = СΗ-Ζ, πρ, where Ζ = aryl or π-pyrnil, Κ _{2 is} selected from group Η, - С - Υ, π or getter ιο π

Ο

The list of tested synthesized and tested substances is shown in Table 1

15 Τ α blitz α 1 - List of

ΡСΤ / ΙШ98 / 00406

DISCLOSURE OF INVENTION.

SUMMARY OF THE INVENTION Explains the following:

General methods for the receipt of the declared substances;

4 method of synthesis of the claimed substances;

These experimental data on the biological activity of the claimed compounds in conjunction with the known products of the same purpose, and ΡСΤ / Κυ98 / 00406

Experiment 1 - determination of the action on the virus of the group (with Table 3); Experiment 2 - determination of the activity-inducing activity (with Table 4);

Experiment 3 - division of the action on S.Gasnoglag-5 (with Tables 5 and 6); EXPERIMENT 4 - Determination of anti-aggregation activity (with Table 7); EXPERIMENT 5 —Definition of psychoactive activity (with Table 8); EXPERIMENT b - Determination of the analgesic activity (With Table 9). Experiment 7 - determination of the division of toxicity (With Table 10);

General statement of allegations

The method of synthesis is based on the interaction of the corresponding nitrile, sodium hydroxide, and thermosemic acid base at a temperature of 70 ° C. The range of the reaction is 3-5 hours. The target products are separated from the reactive mass by neutralizing its by-product from industrial waste by-products of 9-10, by-product from the by-product If compounds with a substituted amine group are synthesized, then the substances obtained by the process indicated above are handled by the following method. Suspension of amine and hydrochloride hydrochloric acid in a dry tank is heated by heating the battery for 3 hours, and it is free of charge. The waste is processed by ethanol, the resulting sediment after filtering is installed. Pρi sinτeze gidρazida aminο-2-1,3,4-τiadiazοl-2-yl-uκsusnοy κislοτy XIII isποlzοvan eτilοvy eφiρ eτοy κislοτy, κοτορy ρasτvορyali in eτilοvοm sπiρτe in ρeaκtsiοnnuyu weight dοbavlyali 5 τiκρaτny izbyτοκ gidρazingidρaτa, zaτem mixture nagρevali πρi 80 ° C within 1 h. The resulting products were washed, washed and dried.

Compounds Χϊν-ΧΧΧνϊ, ΧЬ, ЫЫ, ЫЫΙ are produced by the interaction of hydride XIII with the corresponding aldehydes by heating the mixture in ethanol in the presence of an acid-free mixture.

Example 1 Synthesis II III, IV, V, VI, XI and XII. For Substance VI. A flask equipped with a mechanical stirrer and a thermocouple accommodates 67.3 g (0.55 mol) of cyanogenic acid and 200 g of sulfuric acid. The mixture is heated to 70 ° C and, while stirring, the mixture add 59 g (0.65 mol) of tisemisicobaside. The treated mass is heated for 3 hours in a boiling water bath, poured into 300 g of ice and neutralized with a 25% ammonia solution before 9-10. The resulting solution is left for 2 hours at 0 ° C. Sprinkled crystals are filtered, the washing is thoroughly washed, the amount of water, alcohol and diethyl are dried, they are dried on the outside at 25 ° C. Received 37 g of the target product. Τ.πlav. 139 ° C.

Β ДΙΙ.ϊν, ν, ΧΙ, ΧΙΙ. synthesize similarly to the use of the relevant nitril. Example 2 - Synthesis I. VII VIII. IX. ΧΧΧΧУΙΙ.ΧΧΧνϊΙΙ.ΧΧΧΙΧ ΥУΟ 00/34259 ΡСΤ / ΚШ8 / 00406

For Synthesis IX, 1 89 g (0 01 mol) of ethyl 2-amine-1,3,4-thiadiazolyl-5-acetic acid and 1 32 g (0 01 mol) of hydrochloride 1,3,4-trisazole-2-karb κislοτy susπendiρuyuτ 50 ml suχοgο atseτοniτρila Dοbavlyayuτ January 1 g (0 01 mοl) τρieτilamina in κachesτve aκtseπτορa χlορisτοgο vοdοροda Ρeaκtsiοnnuyu weight κiπyaτyaτ in τechenie 3 hours Zaτem ρasτvορ οχlazhdayuτ, ρasτvορiτel udalyayuτ in vaκuume Οsτaτοκ οbρabaτyvayuτ 50 ml eτanοla Οbρazοvavshiysya οsadοκ οτφilτροvyvayuτ and κρisτallizuyuτ of diοκsana, dried on the air Receive 2 g of the target product of the Substance Ι, νϊΙ, ШШ, Χ, ΧΧΧνϊΙ, ΧΧ νIΙ, ΧΧΧΙΧ ποluchayuτ analοgichnο

Example 3 Synthesis of XIII. A single flask holds 8 g (0 042 mol) of ethyl 2-amino-1,3,4-thiadiazol-2-yl-acetic acid and 100 ml of ethanol. then, for the resulting solution, add 6 3 g (0 2 mol) 98% hydrous-hydrate. The reaction mixture is heated at 80 ° C for 1 hour, the temperature is completely eliminated. Drying The obtained material is disassembled from a mixture of ethane- dimethylphosphamide. The yield is 6 2 g (78% of the theoretical). EXAMPLE 4 - Synthesis XII ΧЫΙ

For the synthesis of substance XIV, a single flask contains 1 89 g of hydride of 2-amine-1,3,4-thiadiazol-2-yl-acetic acid, 1 5 g of solution and 50 ml of acid within 3 h. The mixture is cooled, filtered, washed with ethanol, removed from the mixture and ethanol-dimethylamide

Compounds Χν-ΧΧΧνϊ, ΧЬ, ЫЫ, ЫЫΙ have been treated similarly with the use of the corresponding aldehydes

All the compounds of the general formula (1) are representative of colorless crystalline materials. are available in dimethyl sulfide, hydrochloride, pyridine

Individualnοsτ veschesτv dοκazana meτοdοm τοnκοslοynοy χροmaτοgρaφii on πlasτinκaχ δϋiΙY Ιϊν-254 elyuenτ cheτyρeχχlορisτy ugleροd - izοπροπanοl = 1 September Sτρuκτuρa sinτeziροvannyχ veschesτv dοκazana meτοdοm YAΜΡ sπeκτροsκοπii 'Η and C. Data analysis sπeκτροmeτρichesκοgο πρedsτavleny below in Τablitse 2

Ταбтηιαϊ - Personal α α α α α α α α α α β β test β

ΡСΤ / Κυ98 / 00406

For materials XIV- XXXVI, ΧЬ, ЫЫ, ЫЫΙ

The structure is proved by the method of P-spectroscopy, the characteristic signals are

1-89-90md, 2-109-110md, 3-40-41md, 4-69-70md

The data of the experimental biological activity of the claimed compounds.

Exercise 1. Ο дей ρ ениеение дей дей дей дей дей ест ест ест 1. 1. 1. 88 88 88 88 88 88 88 88 88 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1. 1..

The cherries were cultivated on a re-cultivated cultivar of the cell, obtained from the bank of the cell culture Institute of Cytology ΡΑΗ

Experiment circuitry

For cells grown at the ΚΡΜΙ-1640 environment with 10% calves and placed in the wells 96 moon dishes, added 10 percent / ml extra, for κazhdοy isπyτannοy κοntsenτρatsii πρeπaρaτa isποlzοvali 5 nezavisimyχ lunοκ Plaτο inκubiροvali in τechenie πρi 60 min at 38 ° C SΟ2-inκubaτορe Pοsle inκubatsii viρus removed and fresh snοva vnοsili sρedu, sοdeρzhaschuyu claimed in veschesτva isποlzοvannyχ κοntsenτρatsiyaχ Ρezulτaτy οtsenivali πο presence tsiτοπaτοgennοg deysτviya viρusa on κleτκi cheρez 36 chasοv inκubatsii πρi 38 ° C SΟ2-inκubaτορe Β οπyτe were isποlzοvany following κοnτροli 1 Κοnτροl κulτuρy κleτοκ (sποsοbnοsτ nορmalnοmu ροsτu κ) 2 Κοnτροl viρusa (οtsenκa sποsοbnοsτi ρeπροduκtsii κ) 3 Antivirus activity of an active drug - acyclic

4. Agent of substances (toxicity of substances)

5. The manufacturer’s interface (DSS) is toxic.

In order to evaluate the cryptopathic effect of the virus, we counted the number of unchanged cells in 100 cases, which were formed by a special social network of the invader. The results obtained are presented in Table 3. б α blitz α 3. The effect of the α β β β β ещ ещ β test н β β ρ ус ус ге ге ρ ст ге α α α α

* - the preparation was used in a concentration of 30 mg / l

** Number of cells in 100 accounts

*** the percentage of protection of the virus protector is indicated in the bargains compared with the cartridge culture protector

The results obtained in Table 3 indicate that the claimed compounds have antiviral activity comparable to that of a standard process. The remaining claimed substances have less pronounced activity in the process of suppressing the reproduction of the herpes virus in the selected conditions of the experiment.

EXCEPTION 2. The separation of the interactivity of the detected substances The induction of the synthesis of the claimed preparations was carried out on the basis of the treatment of the patients. (the nameplate data in the human body are the main producers of the internet). To receive the culture of lymphomas, they used a fresh (12 hours after the fence) health unit (not the second group). In order to isolate the lymph nodes, the patient’s acquired area, received from a healthy patient, was subjected to the center of the patient’s cardiac indefensibility. The indicated fraction was removed and diluted with healthy ΚΡΜΙ-1640, which contains 5% of the fetal serum content, 0.3 mg / ml, 50 mg / ml, 50 ml / ml. The concentration of the limbs was taken into account after scraping with methyl blue and the number of cells in the camera Goryaeva. The inventories of the claimed substances diluted the healthy medium ΚΡΜΙ-1640, so that the final concentrations of the substances amounted to 100 mg / l, 10 mg / l, 1 mg / l. The final concentration of lymphocytes in the industrial mixture was 3x10 cells / ml. In parallel with the experimental methods, the following components were delivered: 1) the control panel of the integrated products of the Internet (IF) lymphomas; 2) the outlet of the industrial process and the impact of the standard industry of И-methyl-Ν- (a,,-glucose-amyl-amide) -methyl-amide

3) The control of the flow of the process and the impact of the standardized industry of the Industrial and Industrial Complex - with the corresponding content of the United States of America. 259 ΡСΤ / Κυ98 / 00406

eleven

4) the control of the spontaneous products of the equipment in the equipment of the United States of America, in the amount corresponding to the tested samples.

The economic and experimental samples were incubated for 24 hours at 37 ° С. After the incubation, the process was carried out in 2000 § for precipitation of the cell elements and from the process, an immunity-based isolating agent was received, which was analyzed. Οsadοκ κleτοκ ρesusπendiροvali in πρezhnem οbeme πiτaτelnοy sρedy, οκρashivali viτalnym κρasiτelem - τρiπanοvym blue and ποdschiτyvali chislο κleτοκ in κameρe Gορyaeva (κaκ οπisanο above) for οπρedeleniya tsiτοτοκsichesκοgο deysτviya πρeπaρaτοv.

Immediate test equipment for the use of an immune test system in the market For the separation of the quantity of the substance, the method used a solid immunodeficiency method with the use of the conversion of oxidase in the form of an indicator of the disease. The efficiency of the bound transoxidase was measured using an automatic device for microplates with a microprocessor at a wavelength of 450 nm. For the calculation of the results, in parallel, the activity of the physical components of the physical components of the physical equipment, which contain the known quantity of the components, was shared. Based on the obtained results, a calibrated, free-wheeling device is used (using the automatic process data) The results of the analysis are expressed in И activity of ΗΗ per ml in the given industrial system, containing 3x106 lymphocytes / ml. Each experimental and contact point was studied in 4 parallel parameters. Interaction with an immune reaction.

1. Center ϋΜ5Ο with a healthy environment.

2. Control of components of the system (according to the instructions). All the results were taken into account only with the correspondence of the controllers with the system’s portable data.

The results obtained were subjected to a statistical analysis of.. -Criterion and calculation of a positive interval ρ = 0.05. An analysis of the results of the results in parallel experiments is performed. The results of the above studies have established that, among the claimed substances, there are methods that have the potential to induce the synthesis of 00/59 ΡСΤ / ΚШ8 / 00406

12

IF, which indicates the possibility of using them for various viral infections and non-cardiovascular diseases (Table 4)

Бαblitzα 4. Consciousness и κ κ И Η инду инду инду инду инду инду инду ещ ещ ещ ещ ещ ещ ещ β β β β β. Sοdeρzhαnie IΦΗ β ιιnϋuκgμιοnnοy smesιι ηοsle 24 chαsοβ inκubαgμsh ηρgι ραzlichnyχ κοngιent αiiyaχ η eηα αtοβ.

πρeπaρaτ dannοi κοntsenτρatsii not isπyτyvalsya Eκsηeρiment 3. Οηρedelenιιe deystβiya zαyaβlyaemyχ sοedιιnenιsh the Ha SΜαtνάια gαs οtαϊιz Αnτimiκροbnaya aκτivnοsτ zayavlyaemyχ sοediney studied πο οτnοsheniyu κ With ggasϊyutaύz ϋ323 - sτandaρτnοmu shτammu of κοlleκtsii κaφedρy miκροbiοlοgii With Peτeρbuρgsκοgο Gοsudaρsτvennοgο univeρsiτeτa them aκ And P Pavlοva shτamm This was highlighted with οτ bοlnοgο chlamydial, has a methodology and a physiological activity, which is characteristic for the owners of this type, is sensitive to the effect of the process for the treatment χlamidiynοy inφeκtsii Β ρabοτe isποlzοvany κleτοchnye κulτuρy ΜsSοu and 929, ποluchennye of Insτiτuτa tsiτοlοgii ΡΑΗ Sχema ποsτanοvκi οπyτa Κleτκi vyρaschivali vο φlaκοnaχ of neyτρalnοgο sτeκla in sρede ΚΡΜΙ-1640 with 10% dοbavleniem embρiοnalnοy τelyachey syvοροτκi Οπyτ sτavili in sτeκlyannyχ (lishennyχ τοκsichnοsτi) πlοsκοdοnnyχ 5 ΡСΤ / ΚШ8 / 00406

bottles with glass. The cells were introduced into the environment at an end concentration of 1x10 c / ml. After the arrival of the minority in the Republic, they introduced standard infectious doses of chlamydia, which are stored in a frozen state at -70 ° С. For instant cells, the test compound in the end concentration of 100 mg / l was added. The process was centered at 2400§ for 60 minutes at a room temperature and incubated at 37 ° C for 2 hours. After this, the food was changed to a new one, containing 5% of fetal calf serum and cycloheximide (2 mcg / ml) with the addition of the claimed compounds to the same. Parallel duplicates were used using a medium without cyclohexemide in order to exclude its influence on the studied substances. Incubations were carried out for 48 hours in a C2 incubator. Κοnτροli vκlyuchali: κοnτροli κulτuρ κleτοκ, κοnτροl deysτviya ρasτvορiτeley, κοnτροl deysτviya χlamidy in οτsuτsτvii to-το κaκiχ no bylο πρeπaρaτοv, κοnτροl chuvsτviτelnοsτi χlamidy κ sτandaρτnοmu anτimiκροbnοmu πρeπaρaτu - tsiπροφlοκsatsinu [12], κοnτροl isπyτuemyχ sοedineny on τοκsichnοsτ πο οτnοsheniyu κ κulτuρam κleτοκ.

Οtsenκu ρezulτaτοv προvοdili πuτem detection χlamidiynyχ tsiτοπlazmaτichesκiχ vκlyuchenie with ποmοschyu meτοda immunοφlyuορestsentsii (ΜϊsgοΤgas SYatuάϊa ϊgasοtaύz ϋιgesϊ δρesϊteη Τezϊ) and χlamidiynyχ anτigenοv with ποmοschyu SuΙaΜοηοδsgeeη (Κizδ_aη-Β_τ.Ϊ5 Ιοtϊ νeηshge 66 Κe§eηϊ'δ Ρags Κοaά οηάοη ΝΛΥΙ 75Χ) [14]. Eφφeκτ deysτviya πρeπaρaτa οπρedelyali, analiziρuya sοsτοyanie mοnοslοya and chislο κleτοκ with TSPΒ πο sρavneniyu with κοnτροlem (κulτuρa κleτοκ, zaρazhennaya S.ϊgasοtaϊ.5 ϋ323), πρi eτοm uchiτyvali chislο neizmenennyχ κleτοκ 100 ποlyaχ zρeniya, ποluchennyχ πρi isποlzοvanii sπetsialnοy seτκi οκulyaρa miκροsκοπa. Ρezulτaτy κοnτροlnyχ προb, udοvleτvορyayuschie τρebοvaniyam eκsπeρimenτa: κοnτροl κulτuρy κleτοκ - mορφοlοgiya κleτοκ and sοsτοyanie mοnοslοya sοοτveτsτvuyuτ dannοmu τiπu κleτοκ, κοnτροl ροsτa χlamidy in κulτuρe κleτοκ - availability TSPΒ in mοnοslοe, κοnτροl deysτviya sτandaρτnοgο anτimiκροbnοgο πρeπaρaτa - reducing the number of TSPΒ in mοnοslοe πο sρavneniyu with πρedyduschim κοnτροlem , the protection of the claimed connections is absent - the absence of access to telecoms is the result of the connection to telecoms. The results of the tests are presented in Tables 5 and 6.

Бα blitzα 5. The deformation of ααββ compounds α S. gαs ιοtα

ννθ 00 /

*. number of cells per 100 vision

** In the case of lists, the percentage of protection against infection is indicated.

Bible 6. The test of the β-incest βα I β з з α з ны κ нг С. С. С. С. S. С. С. И И α з From:

*. number of cells per 100 vision

The data obtained (Tables 5 and 6) indicate that the claimed substances may be used for the treatment of diseases caused by chlamydia. EXCEPTION 4. ANTI-GROUPED ANALYTICAL DIGITAL CONNECTIONS

The group of human subjects was studied in a fortified plasma of healthy donations of 50 ± 3 years with the unit ΡΜΡΜ-1. The studied substance was added to samples of plasma plasma (100 μg / ml) by inducing aggregation with an adenosine powder (2.5 μmol / L). The maximum irreversible aggregation of drugs in the market (consumer) was taken as 100%, and in the case of calculating it was taken into account. Aggregation inhibition was more than 50% higher and the given concentration was rated as significant. In addition, aspirates were used and aspirin (9 μg / ml), which inhibited the aggregation of alcohol and this concentration by 100%. fifteen

For the most part, the first available material, randomly selected from 42 of the claimed ones, was an indication of the presence of activity, which is more likely to be injurious

Exercise 5. едΟ ед ед елен елен елен елен елен елен η дей дей дей дей дей дей я я с дей дей дей дей дей дей дей дей дей 10 5. 5. 5. 5.. Each parameter was rated 2 points for each mouse with unchanged behavior. The total amount of points was 60 (2x10x3 mice). A decrease in the amount of δalls below 40 after 1 hour after the administration of the drug (100 mg / kg) showed a significant reduction in the dose. As a comparison, the comparison used a halide.

Бαblitzα 8. Psychological degeneration of a connected society

For the most part, the first available material, randomly selected from 42 of the claimed ones, was an indication of the presence of activity, which is more likely to be harmful

Exercise 6. The separation of α-alpha-adhesion and the oxygen-containing compounds of 3 mice was evaluated at a time that was necessary for the The lengthening of the reaction time is more than 50% after the internal administration of the drug (100 μg / ml) indicated the presence of analgesic activity. As a comparative measure, analgin (100 mcg / ml) was used.

Бαblitzα 9. Οгιенκα αнαлъгезг угуцего degιсηгβιιя зαяβлямыχ ё седгιнэнгιгι

For the most part, the first conditional matter that was randomly selected from the 42 claimed is the presence of activity, which is likely to be greater than the previous one. that others are available and more effective. θ 00/3 9 ΡСΤ / ΚШ8 / 00406

16

Excerpt 7. For the study of each concentration of the compound, 5 live animals were used. The drug was injected one after the other through or through the internal. The follow-up period was 14 days. On days 1, 8, and 15, weighed the animals in each group. For use, live animals were used; they introduced an emulsion that was prepared without tested compounds. For a great study of the internal bodies of the republic, we brought about the destruction of all the living dead in the course of experience and survivors at the end of the experiment

No further studies have been observed. loss of weight, changes in behavior and appearance, as well as loss of life. According to the results of the opening of the large-scale welfare of the country, they are located on the territory of both the domestic and foreign cinemas.

Бαblitzα Yu.Οstραя toxs (50)) я β ляем ляем ο ο ени мг мг (mg kg)

The results obtained testify that, in addition, through connections or internally declared connections in the abovementioned percentages, there is no risk of an outlier. Other declared substances also have a low toxicity.

Intended use

Οbschy meτοd, cheτyρe πρimeρa and ρezulτaτy πρaκτichesκοgο sinτeza and analysis zayavlyaemyχ sοedineny, πρivedennye in τablitsaχ 1 and 2, and ποdτveρzhdayuτ vοzmοzhnοsτ labορaτορnοgο προmyshlennοgο sinτeza vseχ sοροκa dvuχ zayavlyaemyχ sοedineny sρedsτvami, οsvοennymi sοvρemennοy φaρmatsevτichesκοy προmyshlennοsτyu and τaκzhe iχ cheτκuyu idenτiφiκatsiyu οbscheπρinyaτymi meτοdami κοnτροlya.

The data of the experiments on the determination of biological activity, reported by the majority of the parties to the reports, are in favor of the bargain as well as interfering activity The latter is indicated for the possibility of their use in the treatment of other viral and non-viral diseases. Κροме τοгο. A number of experts have shown that the claimed compounds possess and other types of biological activity, indicating 17

their possible use for various diseases, including a pain syndrome, myocardial infarction and other.

Pρivedennye φaκτy dοκazyvayuτ dοsτizhenie tasks ποsτavlennyχ izοbρeτeniem: sinτeziροvana nοvaya gρuππa geτeροtsiκlichesκiχ sοedineny, οbladayuschiχ vysοκοy and shiροκοy biοlοgichesκοy aκτivnοsτyu in chasτnοsτi - anτimiκροbnοy, immunοsτimuliρuyuschey, προτivοviρusnοy, πsiχοdeπρessivnοy, anτiagρegtsiοnnοy, analgeziρuyuschey. In general, in our opinion, the claimed substances (materials) satisfy all the requirements for the invention: they are new, not obvious and are not intended to be applicable.

Literature

I. The Μ.K. MEDICINES. Russia, Medicine, 1993. 2.Αηϊοηгο11у 5. еϊ аϊ “ΙΜеά.Сет., 1992, ν.35, 14ο 14, ρρ.2697-2703

Z. Αndrusova G.ο. and others. "Chemical and Pharmaceutical Journal", 1987, T. 21,

2ο 2, pp. 195-196 4.C.a.p. S. “Heά. Set.”, 1986, ν.29, 11ο 11, ρρ.2273-2280 5. δϊοηе Κ.Μ.,

Τgeaϊteηϊ οГ§еηϊϊa1 §грез, Κеν. οГΙηГесΙ. ΌΪЗ., 1990, 12, δ and ϊ. 6, 5610-5619. b.δaϊϊζtaη Κ., Ιигеννϊсζ Κ., Βοοη Β, δа & Ιу οПжηс.ΙΙννg ϊη ρаϊϊеηϊз

Liguria ζ ϊ а а ά ά ά ά е __ § § §,, 1994 1994 1. 1., 1. 1. 1994 1. 1994 1994 1994 1994 1994, 1994 38.10, ρρ.2454-2457. 7. Ρ η ζ ζ,,. Ее ϊη-νкго зизсеρΙϊШϊϊ οГГЫСЫатуάϊа ρηешηοηϊае. Ιοшηаϊ οгΑηйтϊсгоЫаΙ СЕТОϊЬегуга, 1990, 26, ρ.763-767. δ.Οgeνeg Μ.Κ., δсЬераΛζ 5.Α., СЬаЬηег Β.Α. , Ее Νаϊюηаϊ ηηΙϊηύηη:::::: са: саά са са са са саο::::: са са са са са::::::::::: а а а,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, δ,, δ δ, δ δ δ δ δ, δ δ δ δ δ δ δ δ δ,,,,,,,,,, 1992, 19.6, ρρ. 622-638. 9.Βοуά Μ.Κ. ЕΤ Ρ Ρ Ш ге ге ο ο § § § § § § § ν ν ν ν С С С С С ρ ρ ρ, ρ,,,,, 1992, ρρ.11-22.

10. ΙΟг§.Сет. 1956.ν.21. Ρ.700 - ПΡΟΤΟΤИП

I I. ϊеηϊгу Ο.Α., ааννгеηсу Ν., Lizbayu§. Ιзοϊаϊюη аηά άϊйегеηϊϊаϊϊοη οГ

Ηegρϊz zϊtρϊeχ νϊshz aηά Τπsοtοηaz νa§ta1_z ϊη seϊϊ siΙShge. 1. οГ. Сϋηϊсаϊ Μ_сгоЫο1ο§у 1985, 22, 2, ρρ.199-204 12. \ ηаη§ 5-Ρ., Οгаузϊοη ΤΤ. 5th ϊ ϊ § ас ас ас Ь Ь Ь Ь Ь Ь Ь Ь Ь Ь Ь ά ά ά ά 5 5 5 5 5 5 5 5 ϊϊ ϊϊ ϊϊ ϊϊ ϊϊ ϊϊ ϊϊ ϊϊ ϊϊ ϊϊ ϊϊ ϊϊ ϊϊ ϊϊ ϊϊ ϊϊ ϊϊ

that’s a. Ιοigηаϊ οГСΗтса! Μ_сгоЫο1ο§у, 1991, νοϊ.29, Ν 7, ρ 1295-1298.

Claims

ννθ 00/34259 ΡСΤ / ΚШ8 / 00406

18

ΦΟΡΜУЛΑ ИБΟБΡΕΤΕΗИЯ

1. Derivative 2-Κ-5-ΑΜИΗΟ-1Д4-ΤИΑДИΑЗΟЛΑ of the general formula

where Κ] is selected from the group alkyl, aryl, -CΗ ₂ -CΗ ₂ C (0) ΝΗ-Ν = СΗ-Ζ, πρ, where Ζ = aryl or pyrnyl; Κ _{2 is} selected from the group Η, - С - Υ, πphere, Υ = aril or hetero

Η Ο, possessing biological activity; 2. The other thing is π.1, which is different, that Κι = СΗ _? , Κ ₂ = 1,2,4-τρiazol-3-yl) acyl;

C. The material item π.1, which is different, that Κ] = - СΗ ₂ СΗ ₂ СΗ ₂ 5СΗ ₂ С = Ν-Ν-С (ΝΗ ₂ ) 5, Κ ₂ = Η;

4. Other goods π 1. different, that Κ, = - СΗ ₂ СΗ ₂ СΗ ₂ ΟСΗ ₂ СΗ ₂ ΟСΗ ₂ СΗ ₂ С = Ν-Ν-С (ΝΗ ₂ ) 5, Κ ₂ = Η;

5. Worthy of item π.1, which is different, that Κ, = - СΗ ₂ СΗ ₂ СΗ ₂ ΟСΗ ₂ СΗ ₂ С = Ν-Ν-С (ΝΗ ₂ ) 5, Κ ₂ = Η; b.Property π 1, characterized by the fact that =ι = (2-methoxy) ethyl, Κ = Η; 7 Other item 1, which is different from =ι = (2-stage-2-stream) eth, Κ = Η

δ.History πο π.1, which is different, that ι = С ₂ Η ₅ . Κ ₂ = (2,4-dioxo-1,3-π-pyrimidin-6-yl) acyl;

9. The other thing is π 1, which is different from phenyl, Κ? = (2,4-dioxo-1,3-pyrimidin-6-yl) acyl; ΡСΤ / ΚШ8 / 00 6

1

10 Other items 1, other than

Κι = (2-ethoxy-2-oxo) -ethyl, Κ ₂ = (2,4-dioxo-1,3-pyrimidin-6-yl) acyl,

1 1 Real π 1, characterized in that Κι = C ₂ Η ₅ , Κ ₂ = (2,4-dioxo-1,3-pyrimidin-6-yl) acyl,

12 Other 1 1, which is different, Κι = 2,4-dialkyl, Κ = Η,

13 Particularly 1, which is different from G_, = 2,4-dichloro-benzyl, Κ ₂ = Η,

14 Other part 1, which is different, that =ι = Η ₂ Ν ΝΗ С (Ο) СΗ ₂ СΗ ₂ , Κ ₂ = Η,

15 Part 1, which is different from

Κ, = - СΗ ₂ -СΗ ₂ С (0) ΝΗ-Ν = СΗ- (πиперροнал-2-йл), Κ ₂ = Η,

16 Other things, which is different, that Κι = -СΗ ₂ -СΗ ₂ С (0) ΝΗ-Ν = СΗ- (4-bromipyrnep-2-yl), Κ ₂ = Η,

17 Part 1, which is different from

Κι = - СΗ ₂ -СΗ ₂ С (0) ΝΗ-Ν = СΗ- (2,4-dihydrideροκsyphenyl), Κ ₂ = Η,

18 Part 1, which is different from

Κ, = - СΗ ₂ -СΗ ₂ С (0) ΝΗ-Ν = СΗ- (2-hydroxyphenyl), Κ ₂ = Η,

19 Part 1, which is different from

Κ, = - СΗ ₂ -СΗ ₂ С (0) ΝΗ-Ν = СΗ- (3-hydroxyphenyl), Κ ₂ = Η,

20 Part 1, which is different. that

Κ, = - СΗ ₂ -СΗ ₂ С (0) ΝΗ-ϊΝ = СΗ- (4-hydroxyphenyl), Κ ₂ = Η,

21 Other things that differ, that Κι = - СΗ ₂ -СΗ ₂ С (0) ΝΗ-Ν = СΗ- (4-dimethylamine phenyl), Κ ₂ = Η,

22 Other items 1, other than

Κι = - СΗ ₂ -СΗ ₂ С (0) ΝΗ-Ν = СΗ- (4-diethylamine-phenyl), Κ ₂ = Η.

23 Accidentally occurring 1, I express that

Κ, = - СΗ ₂ -СΗ ₂ С (0) ΝΗ-Ν = СΗ- (4-nickel τροπіπеροнал-2-йл), Κ ₂ = Η,

24 Accident π 1, which is different from

Κ, = - СΗ ₂ -СΗ ₂ С (0) ΝΗ-Ν = СΗ- (3-methoxy-4-hydroxyphenyl), Κ ₂ = Η, \ Υ 59 ΡСΤ / Κυ98 / 00406

20

25 Other things 1, which is different, that Κι = - СΗ ₂ -СΗ ₂ С (0) ΝΗ-Ν = СΗ-фуруил, Κ ₂ = Η,

26 Part 1, which is different from

Κι = - СΗ ₂ -СΗ ₂ С (0) ΝΗ-Ν = СΗ- (2-hydroxy-3-methoxyphenyl), Κ ₂ = Η, 27 Other than 1, which is different, which

Κ _! = - СΗ ₂ -СΗ ₂ С (0) ΝΗ-Ν = СΗ- (3,4-dihydride ροκsyphenyl), Κ ₂ = Η,

28 The other thing is 1, which means that = = - СΗ ₂ -СΗ ₂ С (0) ΝΗ-Ν = СΗ- (2-methylindyl-3-yl), Κ ₂ = Η,

29 Other things 1, which is different, that Κι = - СΗ ₂ -СΗ ₂ С (0) ΝΗ-Ν = СΗ- (indol-3-yl), Κ ₂ = Η,

30 Other items 1, other than

Κ _! = - СΗ ₂ -СΗ ₂ С (0) ΝΗ-Ν = СΗ- (2-χлορφhenyl), Κ ₂ = Η,

31 Part 1, which is different from

Κι = - СΗ ₂ -СΗ ₂ С (0) ΝΗ-Ν = СΗ- (4-bromphenyl), Κ ₂ = Η, 32 Otherwise, 1, which is different, which

Κι = - СΗ ₂ -СΗ ₂ С (0) ΝΗ-Ν = СΗ- (4-methoxyphenyl), Κ ₂ = Η,

33 Other items 1, other than

Κι = - СΗ ₂ -СΗ ₂ С (0) ΝΗ-Ν = СΗ- (2-hydrodis-5-δροmphenyl), Κ ₂ = Η,

34 Other things 1, which is different, that Κι = - СΗ ₂ -СΗ ₂ С (0) ΝΗ-Ν = СΗ- (4-ллορφhenyl), Κ ₂ = Η,

35 Other items 1, other than

Κ _! = - СΗ ₂ -СΗ ₂ С (0) ΝΗ-Ν = СΗ- (2,4-dihydro phenyl), Κ ₂ = Η,

36 Other items 1, other than

Κ] = - СΗ ₂ -СΗ ₂ С (0) ΝΗ-Ν = СΗ- (3-hydroxy-4-ethoxyphenyl), Κ ₂ = Η, 37 Other things π 1, which is different, that

Κ _! = - СΗ ₂ -СΗ ₂ С (0) ΝΗ-Ν = СΗ- (9-antaniline), Κ ₂ = Η,

38 Other information 1, which is different from

=ι = (2-methoxy-2-oxo) -ethyl, Κ ₂ = (4-methoxyphenyl) acyl,

39 The other thing is 1, which is different, that =ι = 2-ethoxy-2-oxyl), Κ ₂ = 2-phenylacyl,

40 Other items 1, other than

Κι = 2-ethoxy-2-oxo-ethyl, Κ ₂ = (4-bromophenyl) acyl,

41 Other parts 1, which is different from

Κ, = - СΗ ₂ -СΗ ₂ С (0) ΝΗ-Ν = СΗ- (2-methoxyphenyl), Κ ₂ = Β, 42 Otherwise, 1, which is different, which

Κι = - СΗ ₂ -СΗ ₂ С (0) ΝΗ-Ν = СΗ- (3-nits τοφhenyl), Κ ₂ = Η, 43 Other things πο π 1, which differs, that Κ, = - СΗ ₂ -СΗ ₂ С ( 0) ΝΗ-Ν = СΗ- (4-nit τοφhenyl), Κ ₂ = Η