LT4726B

LT4726B - Methyl esters of 5-substituted arylalkyloxybenzimidazole-2-yl-carbamine acids with antihelmintic acitivity

Info

Publication number: LT4726B
Application number: LT98-200A
Authority: LT
Inventors: Jonas Šarlauskas; Narimantas Čėnas
Original assignee: Biochemijos Institutas
Priority date: 1998-12-29
Filing date: 1998-12-29
Publication date: 2000-11-27
Also published as: LT98200A

Abstract

The invention refers to synthetic organic chemistry, i.e. it is related to 5-modified arylalkyloxybenzimidazole-2-yl-carbamic acid methyl esters.The compounds defined with joint formula (I) may be used in medicine and veterinary medicine for curing animal, bird and human parasitic diseases.In order to explore anti-helminthic activity of present class agents, new compounds were synthesized. The compounds were extracted by condensing respective modified 1,2-fenyldiamines with N-monomethoxycarbonyl - or N,N'-di(methoxycarbonyl)-S-methylisothiocarbamide or with N-monomethoxycarbonylcyanamide in organic solvent medium.

Description

Junginiai pasižymi antihelmintiniu aktyvumu, ir gali būti panaudoti medicinoje ir veterinarijoje parazitinėms ligoms gydyti.The compounds have an anthelmintic activity and can be used in medicine and veterinary medicine for the treatment of parasitic diseases.

Yra žinomi panašios struktūros benzimidazol-2-ilkarbamatai, pasižymintys antihelmintiniu aktyvumu, pavyzdžiui, benzimidazol-2-ilkarbamino rūgšties metilo esteris (II) (BMK, medaminas, karbendazinas) /CbepeųKOBCKan H.H. n xtp. HobuIi coBeTCKMii aHTrejibMHHTHK Meaa.vtHH: pesy.TbTaTbi KJiHHmiecKHX HcnbrraHHft npn KiiineuHbix He.\taToao3ax- Meų. napa3HTon., 1986, No 5, C. 7 - 10/.Benzimidazol-2-ylcarbamates of similar structure with anthelmintic activity are known, such as benzimidazol-2-ylcarbamic acid methyl ester (II) (BMC, medamine, carbendazine) / CbepeuKOBCKan H.H. n xtp. HobuIi coBeTCKMii aHTrejibMHHTHK Meaa.vtHH: pesy.TbTaTbi KJiHHmiecKHX HcnbrraHHft npn KiiineuHbix He. \ TaToao3ax- Meu. napa3HTon., 1986, No. 5, C. 7-10 /.

O .□L (II) bei l-fenoksiacetil-benzimidazol-2-ilkarbamino rūgšties metilo esteris (benacilas)O □ L (II) and 1-Phenoxyacetyl-benzimidazol-2-ylcarbamic acid methyl ester (benacyl)

Minėtų junginiu pagrindinis trūkumas yra per aukštos jų terapinės dozės kai kurių rūšių gyvuliams / TSRS autor. liud. Nr.660683 (1973)/.The main disadvantage of the mentioned compounds is their therapeutic doses in some animal species / author of the USSR. witness No. 660683 (1973)).

Artimiausias siūlomiems paraiškoje junginiams pagal stuktūrą yra antihelmintikas mebendazolas (mebenvetas) - 5-benzoil-benzimidazol-2-ilkarbamino rūgšties metilo esteris, kurio struktūrinė formulė (IV) pateikiama žemiau:The closest structured compounds proposed in the application are mebendazole (mebenvet), a 5-benzoyl-benzimidazol-2-ylcarbamic acid methyl ester having the structural formula (IV) below:

H HH H

Junginys (IV), pasirinktas prototipu, pasižymi nemažu toksiškumu ir žemu aktyvumu prieš kai kurių rūšių apvaliąsias parazitines kirmėles, nematodas- Ascciridia gaili bei Ascaris suum. / H B HeMiųtOB ''AHTrejiBMHHTHKH b BeTepHHapnH” M., Konoc”, 1982, c.289-296. ‘7Compound (IV), selected as a prototype, exhibits considerable toxicity and low activity against roundworm worm of some species, the nematode Ascciridia gaili and Ascaris suum. / H B HeMiutOB '' AHTrejiBMHHTHKH b BeTepHHapnH 'M., Konoc', 1982, c.289-296. '7

Mūsų išradimo tikslas yra surasti naujas medžiagas, pasižyminčias padidintu antihelmintiniu aktyvumu ir žemu toksiškumu, o taip pat išplėsti antihelmintinių priemonių arsenalą, nes seniems preparatams parazitai įgyja rezistentiškumą ir pastarųjų terapinis poveikis susilpnėja./ Biochemistry of benzimidazole resistance./Lacey E, Gili JH. //Actą Trop 1994 Mar Vol.56,Nr.2-3,P.245-62 ./The object of the present invention is to find new substances having increased anthelmintic activity and low toxicity, as well as to expand the arsenal of anthelmintic agents, as the parasites acquire resistance to the old preparations and the therapeutic effect of the latter is reduced. // Act Trop 1994 Mar Vol.56, no.2-3, P.245-62 ./

Siame išradime pateikiamos naujos cheminės struktūros medžiagos - 5-pakeisti benziloksibenzimidazol-2-ilkarbamino rūgščiu metilo esteriai, kurių bendra formulė (I):The present invention provides novel chemical structures of the 5-substituted benzyloxybenzimidazol-2-ylcarbamic acid methyl esters of the general formula (I):

CH (I) kurioje a) kai R=Y= H,CH (I) where a) when R = Y = H,

1) X,= 2-F;X₂=X₃-H;1) X 1 = 2-F; X ₂ = X ₃ -H;

2) X,=X₃ = -H; X₂ = 3-F;2) X 1 = X ₃ = -H; X ₂ = 3-F;

3) X,=X₂= -H;X₃ = 4-F;3) X 1 = X ₂ = -H; X ₃ = 4-F;

4) X,= 2-C1; X₂=X₃ - H;4) X1 = 2-C1; X ₂ = X ₃ - H;

5) X,=X₃=-H ; X₂= 3-C1;5) X 1 = X ₃ = -H; X ₂ = 3-C1;

6) Χ[=χ₂= -H; X₃= 4-C1;6) Χ [= χ ₂ = -H; X ₃ = 4-C1;

7) X,= 2-Br; X₂=X₃ - H;7) X 1 = 2-Br; X ₂ = X ₃ - H;

S)X,=X₃= -H ; X₂= 3-Br;S) X 1 = X ₃ = -H; X ₂ = 3-Br;

9) X,=X₂= -H;X₃= 4-Br;9) X 1 = X ₂ = -H; X ₃ = 4-Br;

10) 1) X,= 2-I;X₂=X₃-H;10) 1) X 1 = 2-I; X ₂ = X ₃ -H;

11) Xi=X₃= -H ; X₂= 3-1;11) X ₁ = X ₃ = -H; X ₂ = 3-1;

12) Xį =X₂=-H ; X₃= 4-1;12) X = X ₂ = -H; X ₃ = 4-1;

13) X,= 2-C1; X₂ = H, X₃=4-C1;13) X1 = 2-C1; X ₂ = H, X ₃ = 4-C1;

14) Xi=H, X₂=3-C1; X₃= 4-C1;14) X ₁ = H, X ₂ = 3-C 1; X ₃ = 4-C1;

15) )X,= 2-CH₃; X₂=X₃ - H;15)) X 1 = 2 -CH ₃ ; X ₂ = X ₃ - H;

16) X,=X₃ = -H ; X₂= 3-CH₃;16) X 1 = X ₃ = -H; X ₂ = 3-CH ₃ ;

17) X)=X₂= -H;X₃=4-CH₃;17) X) = X ₂ = -H; X ₃ = 4-CH ₃ ;

18) Xi = H, X₂=3-CH₃; X₃=5-CH₃;18) X ₁ = H, X ₂ = 3-CH ₃ ; X ₃ = 5-CH ₃ ;

19) Xi=2-CH₃, X₂=4-CH₃; X₃=6-CH₃;19) X 1 = 2-CH ₃ , X ₂ = 4-CH ₃ ; X ₃ = 6-CH ₃ ;

b) kai R=C_fiH_?- ir Y=H,b) when R = C _fi H _? - and Y = H,

20) X,=X₂=X₃=H;20) X 1 = X ₂ = X ₃ = H;

c) kaiR=CH₃irY=H,c) when R = CH _{3 and} Y = H,

21) Xi=X₂=X₃=H;21) X ₁ = X ₂ = X ₃ = H;

d) kai R=H ir Y=CH₃,d) when R = H and Y = CH ₃ ,

22) X,= X₂=X₃=H;22) X 1 = X ₂ = X ₃ = H;

e) kaiR=HirY=H,e) when R = HirY = H,

23) X,=H, X₂=3-OCH₃, X₃=4-OCH₃;23) X 1 = H, X ₂ = 3-OCH ₃ , X ₃ = 4-OCH ₃ ;

24) X-=H, X₂=3-OCH₂O-4;24) X- = H, X ₂ = 3-OCH ₂ O-4;

25) X,=H, X₂=3-OCH₂CH₂O-4;25) X 1 = H, X ₂ = 3-OCH ₂ CH ₂ O-4;

26) X,=H, X₂=3-OCH₂CH₂CH₂O-4;26) X 1 = H, X ₂ = 3-OCH ₂ CH ₂ CH ₂ O-4;

27) X,=H, X₂=3-OCH(CH3)CH₂-4;27) X 1 = H, X ₂ = 3-OCH (CH 3) CH ₂ -4;

Išradime siūlomi junginiai keletą kartų mažiau toksiški už prototipą mebendazolą (IV). Jie nesukelia neigiamų reiškinių >4000 mg/kg dozėse, o tai keturis kartus viršija mebendazolo letalinę dozę LD 50 (1280 mg/kg). Nauji junginiai turi antihelmintinio veikimo spektrą. Jie pasižymi aukštu aktyvumu prieš Nyppostrongylus braziliensis helmintus, avių strongiliatozę. Preparatai parodė aukštą intens-efektyvumą vištų askaridiozės atveju, naudojant 100 mg/kg dozę,tuo tarpu, kai žinomas prototipas - mebendazolas aukštu aktyvumu pasižymi tik 10 kartų didesniai dozei (1000 mg/kg). Šių medžiagų sintezę vykdo kondensuojant atitinkamus pakeistus 1,2-fenilendiaminus su N-monometoksikarbonil- arba N,N’-di(metoksikarbonil)-S-metilizotiokarbamidu, arba su N-monometoksikarbonilcianamidu organinio tirpiklio terpėje.The compounds of the invention are several times less toxic than the prototype mebendazole (IV). They do not cause adverse effects at doses> 4000 mg / kg, which is four times the lethal dose of mebendazole LD 50 (1280 mg / kg). The novel compounds have an anthelmintic action spectrum. They exhibit high activity against Nyppostrongylus braziliensis helminths, strong sheep of the sheep. The formulations showed high intensity in case of chicken ascaridiosis at a dose of 100 mg / kg, whereas the prototype mebendazole exhibits high activity only 10 times the dose (1000 mg / kg). The synthesis of these materials is accomplished by condensation of the corresponding substituted 1,2-phenylenediamines with N-monomethoxycarbonyl or N, N'-di (methoxycarbonyl) -S-methylisothiourea or with N-monomethoxycarbonyl cyanamide in an organic solvent medium.

I. SINTEZĖI. SYNTHESIS

Pavyzdys. S-D’-fluorobenziloksil-lH-benzimidazol-ž-ilkarbamino rūgšties metilo esteris (VBŠ-67).An example. S-D'-Fluorobenzyloxy-1H-benzimidazole-2-ylcarbamic acid methyl ester (VBS-67).

2,3 g (0,01 M) 4-(3’-fluorobenziloksi)-l,2-fenilendiamino, 2,27 g (0,011 M) N,N- dimetoksikarbonil-S-metil-izotiokarbamido, 0,03 g (0,00016 M) parametilbenzeno sulfoninės rūgšties ir 50 ml 2-propanolio mišinį virina 4 vai., atšaldo iki 15 - 20° C, filtruoja susidariusias smulkiakristalines nuosėdas, praplauna 2-propanoliu, vandeniu ir džiovina. Gauna 2,86 g miltelių su lyd. temp. 237 - 238° C (sk.). Išeiga 84,5 % nuo teorinės.2.3 g (0.01 M) of 4- (3'-fluorobenzyloxy) -1,2-phenylenediamine, 2.27 g (0.011 M) of N, N-dimethoxycarbonyl-S-methyl-isothiourea, 0.03 g ( 0.00016 M) is stirred at room temperature for 15 hours, cooled to 15-20 [deg.] C., filtered to give a fine crystalline precipitate, washed with 2-propanol, water and dried. 2.86 g of a powder are obtained with a melt. temp. 237-238 ° C (dec.). Yield 84.5% of theory.

Pavyzdys. 5-(2^,-chlorobenziloksi)-lH-benzimidazoI-2-iIkarbamino rūgšties metilo esteris (VBŠ-39).An example. 5- (2 ^, -Chlorobenzyloxy) -1H-benzimidazol-2-ylcarbamic acid methyl ester (VBS-39).

4,95 g (0,02 M) 4-(2’- chlorobenziloksi)-l,2-fenilendiamino, 3,11 g (0,021 M) N-monometoksikarbonil-S-metil-izotiokarbamido, 1,5 g (0,025 M) acto rūgšties bei 100 ml etanolio virina 6 vai. ir palieka stovėti kambario temperatūroje 20 val.Iškritusias kristalines nuosėdas filtruoja, perplauna ant filtro šiltu etanoliu (30-40° C), vandeniu ir džiovina. Gauna 4,1 g smulkiakristalinių miltelių su lyd temp. 242-243° C (sk.). Išeiga - 61,8 %.4.95 g (0.02 M) of 4- (2'-chlorobenzyloxy) -1,2-phenylenediamine, 3.11 g (0.021 M) of N-monomethoxycarbonyl-S-methyl-isothiourea, 1.5 g (0.025 M). ) of acetic acid and 100 ml of ethanol are boiled for 6 hours. and leave to stand at room temperature for 20 hours. The precipitated crystalline precipitate is filtered off, washed on the filter with warm ethanol (30-40 ° C), water and dried. 4.1 g of a fine crystalline powder with a melting point of m.p. 242-243 ° C (dec.). Yield 61.8%.

Pavyzdys. 5-(3’,5’-dimetiIbenziloksi)-lH-benzimidazol-2-ilkarbamino rūgšties metilo esteris (VBŠ-126).An example. 5- (3 ', 5'-Dimethylbenzyloxy) -1H-benzimidazol-2-ylcarbamic acid methyl ester (VBS-126).

Sumaišo 10 g (0,lM) techninio kalcio cianamido (— 77 % ), 2,2 g kalcio oksido (0.04 M) ir 85 ml vandens. 35-40° C temperatūroje pridedama lašais 6 ml (0,078 M) chloroskruzdžių rūgšties metilo esterio. Pamaišius 1 valandą 40 °C temperatūroje, mišinys atšaldomas iki 5 -10 °C, atsargiai neutralizuojamas druskos rūgštimi iki pH - 5 ir filtruoja. Gautą vandenini N-metoksikarbonilkarbamino rūgšties nitrilo (V) tirpalą sumaišo su 15,7 g (0,065 M) 4-(3’,5’-dimetilbenziloksi)-l,2fenilendiamino tirpalu lOOml10 g (0.1M) of technical calcium cyanamide (-77%), 2.2 g of calcium oxide (0.04 M) and 85 ml of water were mixed. At 35-40 ° C, 6 ml (0.078 M) of chloroformic acid methyl ester was added dropwise. After stirring for 1 hour at 40 ° C, the mixture is cooled to 5 to 10 ° C, carefully neutralized with hydrochloric acid to pH 5 and filtered. The resulting aqueous solution of N-methoxycarbonylcarbamic acid nitrile (V) was mixed with a solution of 15.7 g (0.065 M) of 4- (3 ', 5'-dimethylbenzyloxy) -1,2-phenylenediamine in 100 ml.

2-propanolio, ir prideda 10 ml acto rūgšties. Mišinį virina 8 valandas. Iškritusias šviesiai pilkas nuosėdas praplauna 2-propanoliu, vandeniu ir džiovina iki pastovaus svorio 60 °C temperatūroje. Gauna baltos spalvos kristalinį produktą, kurio l.t. 224 225 °C ( su skilimu). Išeiga - 18, 3 g ( 86 %).2-propanol, and add 10 ml of acetic acid. The mixture is boiled for 8 hours. The resulting light gray precipitate is washed with 2-propanol, water and dried to constant weight at 60 ° C. This gives a white crystalline product with a l.t. 224 225 ° C (with decomposition). Yield: 18.3 g (86%).

Sintezių duomenys, fizikines-cheminės savybės, IR ir PMR spektrų charakteristikos, bei elementinės analizės duomenys siūlomiems junginiams pateikti 1, 2,3 ir 4 lentelėse.Synthesis data, physico-chemical properties, IR and PMR spectral characteristics, and elemental analysis data for the proposed compounds are shown in Tables 1, 2,3 and 4.

Lentelė. Preparatų fizikinių charakteristikų ir išeigų duomenysTable. Data on physical properties and yields of preparations

Eil. Nr. Yesterday No. X. X. X: X: X-, X-, R R Y Y Preparat o šifras Preparat o cipher Preparato bruto formulė Preparation gross formula Gavi mo sche ma Gavi mo sche ma Išeiga (%) Yield (%) L.t.', c L.t. ', c 1 1 2-F 2-F H H H H H H H H VBŠ-57 VBŠ-57 C_1SH₁₄N;,O;FC _{1 S} H ₁₄ N _;, O, F 1 1 82,3 82.3 223-224 223-224 2 2 H H 3-F 3-F H H H H H H VBŠ-67 VBŠ-67 C₁₆H₁₄N;0;FC ₁₆ H ₁₄ N; 0; F 1 1 84,5 84.5 237-238 237-238 3 3 H H H H 4-F 4-F H H H H VBŠ-14 VBŠ-14 C₁₆H_l4N;,O;FC ₁₆ H ₁₄ N ;, O; F 1 1 86 86 238-239 238-239 4 4 2-C1 2-C1 H H H H H H H H VBŠ-39 VBŠ-39 C₁₆H_l4N-,O-,ClC ₁₆ H ₁₄ N-, O-, Cl 2 2 61,8 61.8 242-243 242-243 5 5 H H 3-C1 3-C1 H H H H H H VBŠ-13 VBŠ-13 C₁₆H₁₄N;,O;,C1C ₁₆ H ₁₄ N;, O;, C 1 1 1 67,8 67.8 215-217 215-217 6 6th H H H H 4-CI 4-CI H H H H VBŠ-61 VBŠ-61 C₁₆H₁₄N;O;C1C ₁₆ H ₁₄ N; O; C 1 2 2 68,7 68.7 228-230 228-230 7 7th 2-Br 2-Br H H H H H H H H VBŠ-102 VBŠ-102 C_loH₁₄N.;O;,BrC _lo H ₁₄ N.; O ;, Br 1 1 85,4 85.4 240-241 240-241 8 8th H H 3-Br 3-Br H H H H H H VBŠ-70 VBŠ-70 C_InH₁₄N;O.;BrC _In H ₁₄ N; O.; Br 1 1 80,6 80.6 217-219 217-219 9 9th H H H H 4-Br 4-Br H H H H VBŠ-69 VBŠ-69 Ci₆H₁₄N;O;BrCi ₆ H ₁₄ N; O; Br 1 1 79,2 79.2 231-233 231-233 10 10th 2-1 2-1 H H H H H H H H VBŠ-123 VBŠ-123 C₁₆H_l4N;O;lC ₁₆ H ₁₄ N; O; l Ω Ω 59,8 59.8 230-231 230-231 11 11th H H 3-1 3-1 H H H H H H VBŠ-124 VBŠ-124 C,₆H₁₄N;O;IC, ₆ H ₁₄ N; O; 2 2 63 63 233-234 233-234 12 12th H H H H 4-1 4-1 H H H H VBŠ-125 VBŠ-125 C₁₆H₁₄N;O;IC ₁₆ H ₁₄ N; O; I Ί Ί 65,4 65.4 235-237 235-237 13 13th 2-C1 2-C1 H H 4-CI 4-CI H H H H VBŠ-62 VBŠ-62 C₁₆H₁₄N;0;CbC ₁₆ H ₁₄ N; 0; Cb 2 2 68,7 68.7 238-240 238-240 14 14th H H 3-C1 3-C1 4-CI 4-CI H H H H VBŠ-107 VBŠ-107 C₁₆H₁₄N;O;C1₂ C ₁₆ H ₁₄ N ₂ O ₂ Cl ₂ Ί Ί 70,1 70.1 241-242 241-242 15 15th 2-CH; 2-CH; H H H H H H H H VBŠ-101 VBŠ-101 C[₇H_l7N;0;C ₇ H ₁₇ N 0; 3 3 83,1 83.1 207-209 207-209 16 16th H H 3-CH- 3-CH- H H H H H H VBŠ-58 VBŠ-58 C_rH_l7N-,O;C _r H ₁₇ N-, O; 3 3 80,9 80.9 198-200 198-200 17 17th H H H H 4-CH; 4-CH; H H H H VBŠ-82 VBŠ-82 C₁₇H_i7N;O;C ₁₇ H _i7 N; O; -> -> 66,7 66.7 213-215 213-215 1S 1S H H 3-CH; 3-CH; 5-CH, 5-CH, H H H H VBŠ-126 VBŠ-126 C_1SH₁₉N;O;C ₁ H ₁₉ N; O; 1 1 82,5 82.5 224-225 224-225 19 19th 2-CH; 2-CH; 4-CH; 4-CH; 6-CH-, 6-CH-, H H H H VBŠ-127 VBŠ-127 C₁₉H₂|Nj0;C ₁₉ H ₂ | Nj0; Ί Ί 67,9 67.9 238-240 238-240 20 20th H H H H H H CčH; CCH; H H VBŠ-163 VBŠ-163 C-H₁₉N;O;CH ₁₉ N, O; 1 1 80,2 80.2 275-277 275-277 21 21st H H H H H H CH; CH; H H VBŠ-164 VBŠ-164 C|₇H₁₇N;O;C | ₇ H ₁₇ N, O; 77 77 241-243 241-243 22 22nd H H H H H H H H CH; CH; VBŠ-166 VBŠ-166 C₁₇H₁₇N;O;C ₁₇ H ₁₇ N, O; 1 1 83,3 83.3 273-275 273-275 23 23rd H H OCH; OCH; OCH, OCH, H H H H VBŠ-322 VBŠ-322 C]fįH[₉N;O;C] 6H [ ₉ N, O; 2 2 71,5 71.5 210-211 210-211 24 24th H H -OCH₂O--OCH ₂ O- H H H H VBŠ-310 VBŠ-310 CkHh-N-.Oj CkHh-N-.Oj T T 80,7 80.7 246-248 246-248 25 25th H H -OCH: CHO- -OCH: CHO- H H H H VBŠ-165 VBŠ-165 C,sH₁₇N;OjC, s ₁₇ N; 0 0 69,4 69.4 203-207 203-207 26 26th H H -O(ČH₂)-,'O--O (CH ₂ ) -, 'O- H H H H VBŠ-312 VBŠ-312 C[₉Hi₉N;OjC [ ₉ Hi ₉ N; Oj 2 2 88,6 88.6 213-216 213-216 27 27th H H -CTL-CHO- 1 CH;, -CTL-CHO- 1 CH ;, H H H H VBŠ-244 VBŠ-244 C₁₇H₁₇x\;O;C ₁₇ H ₁₇ x; O; 2 2 84,2 84.2 215-218 215-218

Visos medžiagos lydosi skildamosAll materials melt when decomposed

Lentelė. Elementinės analizės duomenysTable. Elemental analysis data

Eil. Nr. Yesterday No. Preparato šifras Preparation cipher Preparato bruto formulė Preparation gross formula Rasta /Apskaičiuota,% % Found / estimated C C H H N N Hal Hal 1 X 1 X VBŠ-57 VBŠ-57 c₁₆h_ufnac ₁₆ h _u fna 60,77/60,95 60.77 / 60.95 4,51/4,48 4.51 / 4.48 13,42/13,33 13.42 / 13.33 F 6,08/ F 6.02 F 6.08 / F, 6.02 VBŠ-67 VBŠ-67 C_lf)H₁₄FN-,O₃ C _lf) H ₁₄ FN-, O ₃ 60,91/60,95 60.91 / 60.95 4,5S/4,48 4.5S / 4.48 13,60/13,33 13.60 / 13.33 F 6,11/ F 6,02 F 6.11 / F, 6.02 J J VBŠ-14 VBŠ-14 C₁₆H₁₄FN₅O₅ C ₁₆ H ₁₄ FN ₅ O ₅ 61,13/60,95 61.13 / 60.95 4,45/4,48 4.45 / 4.48 13,51/13,33 13.51 / 13.33 F 5,96/ F 6,02 F 5.96 / F, 6.02 4 4 VBŠ-39 VBŠ-39 CinHuCINjO.; CinHuCINjO .; 57,90/57,93 57.90 / 57.93 4,41/4,25 4.41 / 4.25 12,85/12,67 12.85 / 12.67 Cl 10,39/ Cl 10,68 Cl, 10.39 / Cl, 10.68 5 5 VBŠ-13 VBŠ-13 C₁₆H₁₄CIN-,O.-,C ₁₆ H ₁₄ CIN-, O.-, 58,22/57,93 58.22 / 57.93 4,20/4,25 4.20 / 4.25 12,81/12,67 12.81 / 12.67 Cl 10,39/ Cl 10,68 Cl, 10.39 / Cl, 10.68 6 6th VBŠ-61 VBŠ-61 C|fįH|₄BrN;O.·,C | f | H | ₄ BrN; O. ·, 57,99/57,93 57.99 / 57.93 4,18/4,25 4.18 / 4.25 12,60/12,67 12.60 / 12.67 Cl 10,50/ Cl 10, 68 i Cl, 10.50 / Cl 10, 68 i 7 7th VBŠ-102 VBŠ-102 C₁₆H₁₄BrN-,O_;,C ₁₆ H ₁₄ BrN, O _; , 50,89/51,08 50.89 / 51.08 3,84/3,75 3.84 / 3.75 11,28/11,17 11.28 / 11.17 Br 21,45/ Br 21,24 Br 21.45 / Br, 21.24 8 8th VBŠ-70 VBŠ-70 C,₆H₁₄BrN;O.;C ₆ H ₁₄ BrN O; 50,94/51,08 50.94 / 51.08 3,70/3,75 3.70 / 3.75 11,22/11,17 11.22 / 11.17 Br 21,50/ Br 21,24 Br 21.50 / Br, 21.24 9 9th VBŠ-69 VBŠ-69 CioHiųBrN^O;, C10H6BrN2O ;, 51,35/51,08 51.35 / 51.08 3,81/3,75 3.81 / 3.75 11,04/11,17 11.04 / 11.17 Br 20,90/ Br 21,24 Br 20.90 / Br, 21.24 10 10th VBŠ-123 VBŠ-123 C_1oH₁₄IN.;O;,C _{1 o} H ₁₄ IN. O ;, 45,16/45,41 45.16 / 45.41 3,59/3,33 3.59 / 3.33 9,91/9,93 9.91 / 9.93 I 29,86/ I 29,98 I 29.86 / I 29.98 11 11th VBŠ-124 VBŠ-124 c₁₆h₁₄in_?o₃ c ₁₆ h ₁₄ in _? o ₃ 45,21/45,41 45.21 / 45.41 3,67/3,33 3.67 / 3.33 9,74/9,93 9.74 / 9.93 1 29,86/ 1 1 29,98 Į 1 29.86 / 1 1 29.98 In 12 12th VBŠ-125 VBŠ-125 c₁₆h₁₄in_;o₅ c ₁₆ h ₁₄ in _; o ₅ 45,38/45,41 45.38 / 45.41 3,62/3,33 3.62 / 3.33 9,90/9,93 9.90 / 9.93 130,12/ j 1 29,98 j 130.12 / j 1 29.98 j 13 13th VBŠ-62 VBŠ-62 ε,όΗ,.,α,Ν,ο, ε, όΗ,., α, Ν, ο, 52,40/52,48 52.40 / 52.48 3,64/3,58 3.64 / 3.58 11,39/11,47 11.39 / 11.47 Cl 19,10/ Cl 19,36 Cl, 19.10 / Cl, 19.36 14 14th VBŠ-107 VBŠ-107 ε,₆Η₁₅α₂Ν.-,ο₅ ε, ₆ Η ₁₅ α ₂ Ν .-, ο ₅ 52,53/52,48 52.53 / 52.48 3,61/3,58 3.61 / 3.58 11,52/11,47 11.52 / 11.47 CI 19,40/ Cl 19,36 i CI 19.40 / Cl, 19.36 i 15 15th VBŠ-101 VBŠ-101 C_rH_|7CI₂NAC _r H _{| 7} CI ₂ NA 65,57/65,58 65.57 / 65.58 5,53/5,50 5.53 / 5.50 13,54/13,50 13.54 / 13.50 - - 16 16th VBŠ-58 VBŠ-58 C_i7H₁₇N.;O; _I7 C H ₁₇ N; O; 65,60/65,58 65.60 / 65.58 5,48/5,50 5.48 / 5.50 13,60/13,50 13.60 / 13.50 - - 17 17th VBŠ-82 VBŠ-82 C_i7H₁₇NO, _I7 C H ₁₇ NO 65,42/65,58 65.42 / 65.58 5,61/5,50 5.61 / 5.50 13,59/13,50 13.59 / 13.50 1 1 18 18th VBŠ-126 VBŠ-126 C1SHI9N5O3 C1SHI9N5O3 66,60/66,60 66.60 / 66.60 5,79/5,88 5.79 / 5.88 12,68/12,91 12.68 / 12.91 - - 19 19th VBŠ-127 VBŠ-127 C_iqH_:iN.;O.·,C _iq H _{: i} N.; O. ·, 67,11/67,24 67.11 / 67.24 6,32/6,24 6.32 / 6.24 12,30/12,38 12.30 / 12.38 - - 20 20th VBŠ-163 VBŠ-163 (ΜΗ^Ν,Ο; {ΜΗ ^ Ν, Ο; 70,93/70,76 70.93 / 70.76 5,28/5,13 5.28 / 5.13 11,43/11,25 11.43 / 11.25 1 1 21 21st VBŠ-164 VBŠ-164 C,-H₁₇N₅O.-,C, -H ₁₇ N ₅ O.-, 65,66/65,58 65.66 / 65.58 5,47/5,50 5.47 / 5.50 13,59/13,50 13.59 / 13.50 1 1 -n -n VBŠ-166 VBŠ-166 C_rH₁₇N₃O₇.C _r H ₁₇ N ₃ O ₇ . 65,60/65,58 65.60 / 65.58 5,61/5,50 5.61 / 5.50 13,42/13,50 13.42 / 13.50 i i 23 23rd VBŠ-322 VBŠ-322 CisH^NtO, CisH ^ NtO, 60,27/60,50 60.27 / 60.50 5,40/5,36 5.40 / 5.36 12,01/11,76 12.01 / 11.76 ! ! 24 24th VBŠ-310 VBŠ-310 Cį7H^N₃OsC7 H ^ N ₃ Os 59,98/59,85 59.98 / 59.85 4,32/4,43 4.32 / 4.43 12,25/12,31 12.25 / 12.31 - - 25 25th VBŠ-165 VBŠ-165 C_1SH₁₇N,O₅ C _{1 S} H ₁₇ N, O ₅ 60,73/60,84 60.73 / 60.84 4,86/4,82 4.86 / 4.82 11,70/11,82 11.70 / 11.82 - - 26 26th VBŠ-312 VBŠ-312 c₁₉H_lqN;05c ₁₉ H _lq N; 05 62,11/61,78 62.11 / 61.78 5,09/5,18 5.09 / 5.18 11,20/11,38 11.20 / 11.38 - - 27 27th VBŠ-244 VBŠ-244 C[mH[uN₇O₄ C [m H [uN ₇ O _4] 64,83/64,58 64.83 / 64.58 5,31/5,42 5.31 / 5.42 11,77/11,89 11.77 / 11.89 į to

Lentelė. PMR spektrų duomenysTable. PMR spectra data

Preparato struktūros formulė Preparation structures formula PMR - spektrų duomenys(sausame DMSO-Dfij.m.d. PMR - spectral data (in dry DMSO-Dfij.m.d. -och₃ -och ₃ -ch₂ -ch ₂ Aromatinio benzolo žiedo protonai 4,6,7 padėtyse Protons of aromatic benzene ring at 4,6,7 positions Aromatinio žiedo protonai Aromatic ring protons -ch₃ -ch ₃ VBŠ-57 VBŠ-57 3,74 3.74 5,12 5.12 6,80 dubletas H-6 6.80 doublet H-6 7.13-7,99 7.13-7.99 - - X; =2 -F, X.=X-,=H, Y=R-H X; = 2 -F, X. = X -, = H, Y = R-H singletas singlet singletas singlet J_M= 2,35 %= 8,69 7,08 dubletas H-4 Jv, = 2,11J _M = 2.35% = 8.69 7.08 doublet H-4 Jv, = 2.11 multipletas multiplet VBŠ-67 VBŠ-67 X;=3-F, X = 3-F, 3.74 3.74 5,11 5.11 6,83-7,47 6.83-7.47 6,83-7,47 6.83-7.47 X,=X-,=H, X, = X -, = H, singletas singlet singletas singlet multipletas multiplet multipletas multiplet - - Y=R-H Y = R-H VBŠ-14 VBŠ-14 3,76 3.76 5.06 5.06 6,80 dubletas H-6 6.80 doublet H-6 7,10-7.57 7.10-7.57 X;, = 4-F. X,=X-,=H. Y=R-H X 1 = 4-F. X, = X -, = H. Y = R-H singletas singlet singletas singlet J«= 2,35 J_6T= 8,69 7,06 dubletas H-4 Us = 2,35J «= 2.35 J _6T = 8.69 7.06 doublet H-4 Us = 2.35 multipletas multiplet - - VBŠ-39 VBŠ-39 3,74 3.74 5.14 5.14 6.81 dubletas H-6 6.81 doublet H-6 7.26-7.65 7.26-7.65 X;=2-CI, χ_:=χ,=Η, Y=R-HX; = 2-CI, χ _: = χ, = Η, Y = RH singletas singlet singletas singlet J_M= 2,35 J₅₇= 8,69 7,06 dubletas H-4 ^=2,11J _M = 2.35 J ₅₇ = 8.69 7.06 doublet H-4 ^ = 2.11 multipletas multiplet VBŠ-13 VBŠ-13 3.74 3.74 5,10 5.10 6,81 dubletas H-6 6.81 doublet H-6 7.38-7.51 7.38-7.51 X; = 2-C1. X,=X, = H, Y=R-H X; = 2-C1. X, = X, = H, Y = R-H singletas singlet singletas singlet J_M= 2,35 J₆;= 8,45 7,06 dubletas H-4 Jas = 2,35 7,30 dubletas H-7 J₇₆= 8,45J _M = 2.35 J ₆ ; = 8.45 7.06 doublet H-4 Jas = 2.35 7.30 doublet H-7 J ₇₆ = 8.45 multipletas multiplet - - VBŠ-61 VBŠ-61 3.74 3.74 5,08 5.08 6,80 dubletas H-6 6.80 doublet H-6 7.09-7.75 7.09-7.75 X-,=4-Cl, X;—X' ⁼ H.X -, = 4-Cl, X; —X ' ⁼ H. singletas singlet singletas singlet Js-= 8,45 7,03 dubletas H-4 Js = 8.45 7.03 doublet H-4 multipletas multiplet Y=R-H Y = R-H VBŠ-102 VBŠ-102 3.75 3.75 5,10 5.10 6,81 dubletas H-6 6.81 doublet H-6 7.41-7.72 7.41-7.72 X:=2-Br. X.=X,=H. Y=R-H X: = 2-Br. X. = X, = H. Y = R-H singletas singlet singletas singlet Jm= 2.58 J_f,₇= 8,69 7,08 dubletas H-4 Jis = 2,35 IJm = 2.58 J _f , ₇ = 8.69 7.08 doublet H-4 He = 2.35 I multipletas multiplet - - VBŠ-70 VBŠ-70 3,74 3.74 5,10 5.10 1 6,81 dubletas H-6 1 6.81 doublet H-6 7.28-7,66 7.28-7.66 X;=3 -Br. X,=X-=H. X = 3 -Br. X1 = X- = H. singletas singlet singletas singlet J_6?= 8,45 6,93 dubletas H-4J _6? = 8.45 6.93 doublet H-4 multipletas multiplet Y=R-H Y = R-H I I

Lentelė (tęsinys)Table (continued)

Preparato struktūros formulė Preparation structures formula PMR - spektru duomenys(sausame DMS0-D6),m.d. PMR - spectral data (in dry DMS0-D6), m.d. -och₃ -och ₃ -ch₂ -ch ₂ Aromatinio benzolo žiedo protonai 4,6,7 padėtyse Protons of aromatic benzene ring at 4,6,7 positions Aromatinio žiedo protonai Aromatic ring protons -CHg -CHg VBŠ-69 X.-,=4 -Br, Χ,=Χ_;=Η, Y=R-HVBŠ-69 X .-, = 4 -Br, Χ, = Χ _; = Η, Y = RH 3.73 singletas 3.73 singlet 5,06 singletas 5.06 singlet 6.81 dubletas 11-6 R?= 8,45 7.07 dubletas H-4 J«, = 2,35 7.40 dubletas H-7 J₇₆= 8,456.81 doublet 11-6 R? = 8.45 7.07 doublet H-4 J «, = 2.35 7.40 doublet H-7 J ₇₆ = 8.45 7,54-7,79 multipletas 7.54-7.79 multiplet VBŠ-123 X;=2-I. X; = X-, = H, Y=R-H VBŠ-123 X = 2-I. X; = X-, = H, Y = R-H 3,74 singletas 3.74 singlet 5.06 singletas 5.06 singlet 6.81 dubletas H-6 2,35 Js?= 8,69 7,04 dubletas H-4 Jas =2,35 6.81 doublet H-6 2.35 Js? = 8.69 7.04 doublet H-4 Jas = 2.35 7,11-7,99 multipletas 7.11-7.99 multiplet VBŠ-124 X'=3 -I, X_;=X,=H, Y=R-HVBŠ-124 X '= 3 -I, X _; = X, = H, Y = RH 3.74 singletas 3.74 singlet 5.06 singletas 5.06 singlet 6.81 dubletas H-6 J«= 2,35 Λτ= 8.69 7,04 dubletas H-4 J4i6 = 2,11 6.81 doublet H-6 J 2 = 2.35 Λτ = 8.69 7.04 doublet H-4 J4i6 = 2.11 7,11-7.79 multipletas 7.11-7.79 multiplet VBŠ-125 X-,=4 -I. χ.=χ, = Η, Y=R-H VBŠ-125 X -, = 4 -I. χ. = χ, = Η, Y = R-H 3,73 singletas 3.73 singlet 5,05 singletas 5.05 singlet 6.80 dubletas H-6 J„= 2,35 J₆₇= 8,69 7,03 dubletas H-4 Jas = 2,356.80 doublet H-6 J „= 2.35 J ₆₇ = 8.69 7.03 doublet H-4 Jas = 2.35 7,23-7,78 multipletas 7.23-7.78 multiplet VBŠ-62 X;=2-Cl, X;= H, X,=4-CI Y=R-H VBŠ-62 X = 2-Cl, X; = H, X 1 = 4-Cl Y = R-H 3,74 singletas 3.74 singlet 5,13 singletas 5.13 singlet 6,81 dubletas H-6 J_w= 2,58 J_it-= 8,69 7,04 dubletas H-4 Jas = 2,58 7,29 dubletas H-7 J₇₆= 8,696.81 doublet H-6 J _w = 2.58 J _it - = 8.69 7.04 doublet H-4 Jas = 2.58 7.29 doublet H-7 J ₇₆ = 8.69 7,40-7,69 7.40-7.69 VBŠ-107 X; = H, X; = 3-C1, X;=4-C1 Y=R-H VBŠ-107 X; = H, X; = 3-C1, X; = 4-C1-Y = R-H 3,75 singletas 3.75 singlet 5,10 singletas 5.10 singlet 6,81 dubletas H-6 J„= 2,11 J₆₇= 8,69 7,04 dubletas H-4 1.6=2,35 7,28 dubletas H-7 J₇₆= 8,696.81 doublet H-6 J „= 2.11 J ₆₇ = 8.69 7.04 doublet H-4 1.6 = 2.35 7.28 doublet H-7 J ₇₆ = 8.69 7.38-7,71 multipletas 7.38-7.71 multiplet i i VBŠ-101 VBŠ-101 3.74 3.74 5,05 5.05 6,80 dubletas H-6 6.80 doublet H-6 7,17-7,22 7.17-7.22 2.33 2.33 X;=2-CH-„ X; = X, = H. Y=R-H X; = 2-CH- X; = X, = H. Y = R-H singletas singlet singletas singlet J_M= 2,35 J₆₇= 8,69 7.06 dubletas H-4 Jas = 2,35 7,28 dubletas H-7 J ₇₆= 8.69J _M = 2.35 J ₆₇ = 8.69 7.06 doublet H-4 Jas = 2.35 7.28 doublet H-7 J ₇₆ = 8.69 multipletas 7,36-7.99 multipletas multiplet 7.36-7.99 multiplet 1 1

Lentelė, (tęsinys)Table, (continued)

Preparato struktūro s formulė Formula for structure of preparation PMR - spektrų duomenys(sausame DMSO-D₆).m.d.PMR - spectral data (in dry DMSO-D ₆ ) .md och₃ and ₃ -ch₂ -ch ₂ Aromatinio benzolo žiedo protonai 4,6,7 padėtyse Protons of aromatic benzene ring 4,6,7 positions [ Aromati- nio žiedo protonai [Aromatic protons -CH₃ -CH ₃ VBŠ-58 VBŠ-58 3,74 3.74 5,03 5.03 6,79 dubletas H-6 6.79 doublet H-6 7,05-7,62 7.05-7.62 2,36 2.36 X_:=3-CH-„ X,=X-,=H. Y=R-HX _: = 3-CH-, X, = X -, = H. Y = RH singletas singlet singletas singlet J_w= 2,35 J_ft7= 8,69 7,02 dubletas H-4 J₄₍, = 2,11J _w = 2.35 J _ft 7 = 8.69 7.02 doublet H-4 J _{4 {} , = 2.11 multipletas multiplet singletas m-CH.i singlet m-CH.i. VBŠ-82 VBŠ-82 3,74 3.74 5.0 5.0 6,76 dubletas H-6 6.76 doublet H-6 7.13-7,47 7.13-7.47 2.29 2.29 X.-, = 4 - CH-,. Xi = X- = H. Y=R-H X.-, = 4 - CH-,. Xi = X- = H. Y = R-H singletas singlet singletas singlet J_w= 2,35 J₆;= 8,45 7,03 dubletas H-4 J46 = 2,35J _w = 2.35 J ₆ ; = 8.45 7.03 doublet H-4 J46 = 2.35 multipletas multiplet singletas p-CH-, singlet p-CH-, VBŠ-126 VBŠ-126 3,74 3.74 4,99 4.99 6,79 dubletas H-6 6.79 doublet H-6 7,04 7.04 2,26 2.26 X; = 3 - CH-,. X.,=5 - CH.-.. Y=R-H X; = 3 - CH-,. X., = 5 - CH.- .. Y = R-H singletas singlet singletas singlet J₆;= 8,45 6,94 dubletas H-4 J₄₆ = 2.35 7,4S dubletas H-7 J₇₍,= 8,45J ₆ ; = 8.45 6.94 doublet H-4 J ₄₆ = 2.35 7.4S doublet H-7 J _{7 {} , = 8.45 singletas singlet singletas 5-CH; singlet 5-CH; VBŠ-127 VBŠ-127 3,75 3.75 4,97 4.97 6,76 dubletas H-6 6.76 doublet H-6 6.87 6.87 2,27 2.27 Xi=2-ch_;. X; = 4-CH,. X_?=6-CH; Y=R-HX 1 = 2-ch _; . X; = 4-CH 2. X _? = 6-CH; Y = RH singletas singlet singletas singlet J_w= 2.35 J₆₇= 8,69 7,10 dubletas H-4 J₄₆ = 2,35 7,30dubletas H-7 J 76= 8,69J _w = 2.35 J ₆₇ = 8.69 7.10 doublet H-4 J ₄₆ = 2.35 7.30 doublet H-7 J 76 = 8.69 singletas singlet singletas ο-CH-, Į 2,23 singletas p-CH-, singlet ο-CH-, In 2.23 singlet p-CH-, VBŠ-163 VBŠ-163 3,76 3.76 5,09 5.09 7.03-7.46 7.03-7.46 7,03-7,46 7.03-7.46 X,=X; = X-. =H. Y=H R=C₆H,X 1 = X; = X-. = H. Y = HR = C ₆ H, singletas singlet singletas singlet multipletas multiplet multipletas multiplet VBŠ-164 VBŠ-164 3.78 3.78 5,31(-CH- 5.31 (-CH- 6.9-7.79 6.9-7.79 6.9-7,79 6.9-7.79 a-CH; a-CH; X,=X; = X-. =H. Y=H R=CH-, X 1 = X; = X-. = H. Y = H R = CH-, singletas singlet ) kvadruple tas J_i: =5, 05) quadruple it J _i: = 5, 05 multipletas multiplet multipletas multiplet 1.56 J= 8,34 2.25 1.56 J = 8.34 2.25 VBŠ-166 VBŠ-166 3.75 3.75 J-,=6,34 J -, = 6.34 6.7-7,6 6.7-7.6 6,7-7,6 6.7-7.6 singletas singlet Xl=X; = X, =H Y=CH-, R = H į X1 = X; = X, = H Y = CH-, R = H to singletas singlet 5,52 singletas 5.52 singlet multipletas multiplet multipletas multiplet 6 - CH-, 6 for CH,

Lentelė, (tęsinys)Table, (continued)

PMR - spektrų duomenys(sausame DMSO-D₆),m.d-PMR - spectral data (dry DMSO-D ₆ ), md-

Preparato struktūros formulė Formulation structure of the preparation -OCH; -OCH; -CH_; -CH _; Aromatinio benzolo žiedo protonai 4,6,7 padėtyse Protons of aromatic benzene ring at 4,6,7 positions Aromatinio žiedo protonai Aromatic ring protons -CH. -CH. VBŠ-322 VBŠ-322 3,73 3.73 4,98 4.98 6,80 Dubletas H- 6.80 Dublet H- 6,71-6,80 6.71-6.80 3 - 3 - X₂ —3 -OCH;,,X ₂ -C 3 -OCH; singletas singlet 6 6th CH;O CH; O X;=4-0CH-„ X; = 4-0CH- " ^-2,11 Hz ^ -2.11 Hz -3,75 -3.75 X,=Y = R = H X, = Y = R = H J67-8.7 J67-8.7 4'- 4'- 7,05- dubletas H- 7.05- doublet H- CH;O CH; O 6 J4s=2,58 7,31-dubletas H-7 6th J4s = 2.58 7.31-doublet H-7 -3,76 -3.76 VBŠ-310 VBŠ-310 3,73 3.73 4,97 4.97 J?6-8,69 J? 6-8.69 6,65-7,32 6.65-7.32 X₂.;=3 -OCH₂O- 4,X ₂ ; = 3 -OCH ₂ O-4, singletas singlet singletas singlet multipletas multiplet X, = Y = R=H X, = Y = R = H (benzilo) (benzyl) 7,27 dubletas H-7 J?_o=97.27 doublet H-7 J? _o = 9 ir 6,01 and 6.01 6,75 dubletas H-6 6.75 doublet H-6 singletas singlet Jb4=2,5 Jb4 = 2.5 (metilendioksi (methylenedioxy Jb7 = 9 Jb7 = 9 ) ) 6,95 -dubletas-H- 6.95-doublet-H- VBŠ-165 VBŠ-165 3,73 3.73 4 4 6,50-7,42 6.50-7.42 X_:.;=3 -0(CH,),0-4, _X:.; 3 = -0 (CH,) 0-4, singletas singlet 4,94-singletas 4.94-singlet J₆4=2,5J ₆ 4 = 2.5 multipletas multiplet X,=Y=R=H X, = Y = R = H 3,56- multipletas 3.56- multiplet 6,50-7,42 6.50-7.42 VBŠ-312 VBŠ-312 -C‘H- 1,36-dubletas 2,65-2,88- multipletas -C'H- 1.36-doublet 2.65-2.88- multiplet multipletas multiplet -CH₂--CH ₂ - X_z-,=3-0(CH, )-,0-4X _z -, = 3-0 (CH,) -, 0-4 3,74 3.74 6,48-7,40 6.48-7.40 X, = Y=R=H X, = Y = R = H singletas singlet 4,96 singletas 4.96 singlet multipletas multiplet ......2,60-2,90- ...... 2,60-2,90- 6,48-7,40 6.48-7.40 VBŠ-244 VBŠ-244 multipletas multiplet multipletas multiplet CH;- CH; - X, ;=3-CH,CHO-4, 1 X 1 = 3-CH, CHO-4, 1 3,73 3.73 multipletas multiplet 6,47-7,38 6.47-7.38 CH; CH; singletas singlet 4,98 4.98 multipletas multiplet X,=Y=R=H X, = Y = R = H singletas singlet CH₂-CH ₂ - 6,47-7,38 multipletas 6.47-7.38 multiplet

Lentelė. Infraraudonojo diapazono virpesių spektrų duomenysTable. Infrared vibration spectral data

Preparato šifras Preparation code IR- virpesių spektro duomenys v , cm'¹ IR spectral data v, cm < ^{-1 &} gt ;. VBŠ-57 VBŠ-57 (N-H) 3319, (CH,) 2959, (CH.) 2850, (C=O) 1712. (-O-) 1263. 1090, ( C- F ) 1047 (N-H) 3319, (CH 2) 2959, (CH 2) 2850, (C = O) 1712. (-O-) 1263. 1090, (C-F) 1047 VBŠ-67 VBŠ-67 (N-H) 3320, (CH,) 2961, (CH_;) 2851, (C=O) 1713, (-O-) 1264 1092, (C - F ) 1038(NH) 3320, (CH,) 2961, (CH _; ) 2851, (C = O) 1713, (-O-) 1264 1092, (C-F) 1038 VBŠ-14 VBŠ-14 (N-H) 3332, (CH,)2958, (CH_:) 2850, (C=O) 1711, (-O-) 1262, 1089, (C-F) 1025(NH), 3332 (CH), 2958 _(CH) 2850 (C = O) 1711 (-O-) 1262, 1089 (CF) 1025 VBŠ-39 VBŠ-39 (N-H) 3316, (CH-,) 2962, (CH_;) 2850, (C=O) 1714. (-O-) 1267, 1093, (C-Cl)482(NH) 3316, (CH-) 2962, (CH _; ) 2850, (C = O) 1714. (-O-) 1267, 1093, (C-Cl) 482 VBŠ-13 VBŠ-13 (N-H) 3324, (CH-,) 2963, (CH.) 2850, (C=O) 1712. (-O-) 1266, 1094, (C-<21)480 (N-H) 3324, (CH-) 2963, (CH) 2850, (C = O) 1712. (-O-) 1266, 1094, (C- <21) 480 VBŠ-61 VBŠ-61 (N-H) 3321, (CH;) 2961, (CH.) 2850, (C=O) 1712. (-O-) 1263, 1090. (C-Cl) 1047 (N-H) 3321, (CH 2) 2961, (CH 2) 2850, (C = O) 1712. (-O-) 1263, 1090. (C-Cl) 1047 VBŠ-102 VBŠ-102 (N-H) 3320, (CH-,) 2960, (CH_;) 2850, (C=O) 1715. (-O-) 1263, 1089, (C-Br ) 583(NH) 3320, (CH-) 2960, (CH _; ) 2850, (C = O) 1715. (-O-) 1263, 1089, (C-Br) 583. VBŠ-70 VBŠ-70 (N-H) 3318, (CH,) 2962, (CH.) 2850, (C=O) 1714. (-O-) 1262, 1091, (C-Br)536 (N-H) 3318, (CH 2) 2962, (CH 2) 2850, (C = O) 1714. (-O-) 1262, 1091, (C-Br) 536 VBŠ-69 VBŠ-69 (N-H) 3319, (CH;) 2961, (CH-) 2852, (C=O) 1712, (-O-) 1263, 1090, (C-Br)540 (N-H) 3319, (CH-) 2961, (CH-) 2852, (C = O) 1712, (-O-) 1263, 1090, (C-Br) 540 VBŠ-123 VBŠ-123 (N-H) 3322, (CH;) 2963, (CH.) 2851, (C=O) 1710. (-O-) 1264, 1089, (C -1) 598 (N-H) 3322, (CH 2) 2963, (CH 2) 2851, (C = O) 1710. (-O-) 1264, 1089, (C -1) 598 VBŠ-124 VBŠ-124 (N-H) 3320, (CH,) 2962, (CH_;) 2851, (C=O) 1711. (-O-) 1262, 1093, (C -1) 602(NH) 3320, (CH,) 2962, (CH _; ) 2851, (C = O) 1711. (-O-) 1262, 1093, (C -1) 602 VBŠ-125 VBŠ-125 (N-H) 3321, (CH-,) 2960, (CH.) 2850. (C=O) 1713. (-O-) 1261, 1090, (C-I) 575 1 (N-H) 3321, (CH-) 2960, (CH) 2850. (C = O) 1713. (-O-) 1261, 1090, (C-I) 575 1 VBŠ-62 VBŠ-62 (N-H) 3326, (CH.-,) 2963, (CH₂) 2849, (C=O) 1712. (-O-) 1263, 1091, (C - Cl) 763, 772(NH) 3326, (CH.-,) 2963, (CH ₂ ) 2849, (C = O) 1712. (-O-) 1263, 1091, (C - Cl) 763, 772. VBŠ-107 VBŠ-107 (N-H) 3326, (CH,,)2962, (CH,) 2850, (C=O) 1713. (-O-) 1260, 1093, (C - Cl) 762, 770 (N-H) 3326, (CH,) 2962, (CH,) 2850, (C = O) 1713. (-O-) 1260, 1093, (C-Cl) 762, 770 VBŠ-101 VBŠ-101 (N-H) 3323, (CH,) 2959. (CH_;) 2848, (C=O) 1715. (-O-) 1262, 1092(NH) 3323, (CH 2) 2959. (CH _; ) 2848, (C = O) 1715. (-O-) 1262, 1092 VBŠ-58 VBŠ-58 (N-H) 3322. (CFI,) 2963, (CHj 2850, (C=O) 1710. (-O-) 1261, 1090 (N-H) 3322. (CFI,) 2963, (CH 3 2850, (C = O) 1710). (-O-) 1261, 1090

Lentelė, (tęsinys)Table, (continued)

Preparato šifras Preparation code IR- virpesių spektro duomenys v , cm'¹ IR spectral data v, cm < ^{-1 &} gt ;. VBŠ-82 VBŠ-82 (N-H) 3320, (CH?) 2961, (CH_;) 2849, (C=O) 1712,5, (-O-) 1262, 1091(NH), 3320 (CH?) 2961 _(CH;) 2849 (C = O), 1712.5 (-O-) 1262, 1091 VBŠ-126 VBŠ-126 (N-H) 3306, (CH-,) 2962. (CH_:) 2850, (C=O) 1711, (-O-) 1263, 1092(NH) 3306 (CH,) 2962nd _(CH) 2850 (C = O) 1711 (-O-) 1263, 1092 VBŠ-127 VBŠ-127 (N-H) 3380, (CH?) 2958, (CH_:) 2849, (C=O) 1714, (-O-) 1261, 1090(NH), 3380 (CH?) 2958 _(CH) 2849 (C = O) 1714 (-O-) 1261, 1090 VBŠ-163 VBŠ-163 (N-H) 3351, (CH-,) 2960, (CH_:) 2850, (C=O) 1705, (-O-) 1263, 1090(NH) 3351 (CH,) 2960 _(CH) 2850 (C = O) 1705 (-O-) 1263, 1090 VBŠ-164 VBŠ-164 (N-H) 3332, (CH-,) 2961, (CH-) 2850, (C=O) 1712, (-O-) 1259, 1088. (N-H) 3332, (CH-) 2961, (CH-) 2850, (C = O) 1712, (-O-) 1259, 1088. VBŠ-166 VBŠ-166 (N-H) 3360, (CH,) 2960, (CH_;) 2850, (C=O) 1708, (-O-) 1262, 1091.(NH), 3360 (CH), 2960 _(CH;) 2850 (C = O) 1708 (-O-) 1262, 1091st VBŠ-322 VBŠ-322 (N-H) 3302, (CH,) 2925, (CH_;) 2840, (C=O) 1718, (-O-) 1265, 1096.(NH), 3302 (CH), 2925 _(CH;) 2840 (C = O) 1718 (-O-) 1265 1096th VBŠ-310 VBŠ-310 (N-H) 3370, (CH-,) 2956, (CH·.) 2850, (C=O) 1708, (-O-) 1250, 1093. (N-H) 3370, (CH-) 2956, (CH 2) 2850, (C = O) 1708, (-O-) 1250, 1093. VOŠ-165 VOŠ-165 (N-H) 3324, (CH_?) 2956, (CH_;) 2840, (C=O) 1703. (-O-) 1252, 1086(NH), 3324 _(CH?) 2956 _(CH;) 2840 (C = O) 1703. (-O-) 1252, 1086 VBŠ-312 VBŠ-312 (N-H) 3321, (CH-,) 2940, (CH_:) 2850. (C=O) 1704, (-O-) 1260, 1086.(NH) 3321 (CH,) 2940 _(CH) 2850th (C = O) 1704 (-O-) 1260 1086th VBŠ-244 VBŠ-244 (N-H) 3326, (CH-,) 2958, (CH_;) 2846 (C=O) 1713, (-O-) 1264, 1089.(NH) 3326, (CH-) 2958, (CH _; ) 2846 (C = O) 1713, (-O-) 1264, 1089.

*Spektrai užrašyti infraraudonojo diapazono spektrofotometru Specord 75 IR (CarI Ceis Jena, Vokietija ‘ II. BIOLOGINIAI TYRIMAI* Spectra recorded on an infrared spectrophotometer Specord 75 IR (CarI Ceis Jena, Germany 'II. BIOLOGICAL STUDIES

Siūlomų junginių toksiškumas baltosioms žiurkėms, sveriančioms 50-100 g, buvo tiriamas pagal standartinę metodiką / Litchfield J. T., Wilsoxom F.J., Fharmacol. Exp. Therap. 1949, 96, p. 99-113 / Įvedant įvairias tiriamos medžiagos dozes baltosioms žiurkėms į skrandį. Vandeninės preparatų suspensijos buvo įvedamos individualiai, peroraliai, dozuojant 4000 mg/kg gyvo svorio. Gyvūnų būklė buvo stebima savaitę laiko.The toxicity of the proposed compounds to white rats weighing 50-100 g was investigated according to standard methodology / Litchfield J. T., Wilsoxom F.J., Fharmacol. Exp. Therap. 1949, 96, p. 99-113 / Administration of various doses of test substance to the stomach of white rats. Aqueous suspensions of the preparations were administered orally, at a dose of 4000 mg / kg body weight, orally. The condition of the animals was monitored weekly.

Nurodyta siūlomų preparatų dozė nesukėlė bandomųjų žiurkių žuvimo. Nebuvo pastebimų nukrypimų nuo normalios gyvūnų būklės, jie liko judrūs, gerai ėdė pašarą.The indicated dose of the proposed formulations did not result in death of the rat rats. There were no noticeable deviations from the normal condition of the animals, they remained agile and ate the feed well.

Gauti duomenys rodo, kad nauji junginiai, pasižymi labai žemu toksiškumu ir 4000 mg/kg dozėje (peroraliai) nesukelia žymesnių nukrypimų nuo fiziologinės normos.The data obtained indicate that the novel compounds with very low toxicity and at 4000 mg / kg (oral) do not cause significant deviations from the physiological norm.

Toksiškumo tyrimų rezultatai pateikiami 5 lentelėje.The results of the toxicity studies are presented in Table 5.

Naujų junginių antihelmintinis aktyvumas buvo ištirtas su žiurkėmis, vištomis ir avimis. Antihelmintinio aktyvumo tyrimams 50-60 g svorio baltosios žiurkės buvo eksperimentiškai užkrėstos helmintų Nippostrongylus braziliensis lervomis, po 2000 vnt. kiekvienai (individualiai). Po 7 dienų užkrėstoms parazitais žiurkėms peroraliai įvesdavo tiriamųjų junginių vandenines suspensijas,stabilizuotas emulgatoriumi Twin-80, dozuojant po 500 mg/kg individualiai. Po 5 dienų gyvūnai buvo užmušti, o junginių efektyvumas įvertintas, lyginant likusių helmintų skaičių kontroliniuose ir bandomuosiuose gyvūnuose.The anthelmintic activity of the new compounds was tested in rats, chickens and sheep. For anthelmintic activity assays, white rats weighing 50-60 g were experimentally infected with helminths larvae of Nippostrongylus braziliensis, 2,000 each. for each (individually). After 7 days, parasite-infected rats were orally administered aqueous suspensions of test compounds stabilized with Twin-80 emulsifier at a dose of 500 mg / kg individually. After 5 days, the animals were sacrificed and the efficacy of the compounds evaluated by comparing the number of residual helminths in control and experimental animals.

Bandymų su žiurkėmis rezultatai pateikti 6 lentelėje, iš kurios matyti, kad siūlomi junginiai turėjo antihelmintinį aktyvumą, nuo 35,8 iki 100% , esant dozei 500 mg/kg gyvo svorio.The results of the rat studies are shown in Table 6, which shows that the proposed compounds exhibited anthelmintic activity of 35.8 to 100% at a dose of 500 mg / kg body weight.

Antihelmintinis siūlomų junginių aktyvumas tirtas taip pat su viščiukais, eksperimentiškai apkrėstais helmintais Ascaridia gaili.The anthelmintic activity of the proposed compounds was also investigated in chickens experimentally infected with helminth Ascaridia gaili.

Invazinių askaridžių (Ascaridia gaili) kiaušinėlių kultūra gauta pagalThe culture of invasive ascaridia (Ascaridia gaili) eggs was obtained according to

P.T. Tverdochlebovo (1965) metodiką/'’MaTepuanbi κ HayuHon κοΗφερεΗΐιωιP.T. Tverdochlebov's (1965) methodology / '' MaTepuanbi κ HayuHon κοΗφερεΗΐιωι

BcecoK)3Horo očmecTBa re;ib\iHHTO.iorc>B M.,1965,n.l,c.206-210.) Kiekvienas eksperimentinis viščiukas gavo po 200 vnt. invazinių askaridžių kiaušinėlių. Helmintams pasiekus lytinio subrendimo stadiją (nustatomą pagal koprologinius tyrimus), bandomiesiems viščiukams įvesdavo individualiai per zondą į skilvį tiriamuosius junginius po 100 mg vienkartinę dozę 1 kg svorio. Po junginių įvedimo eksperimentinius viščiukus laikė po vieną atskirame narvelyje, jų ekskrementus surinkdavo ir perplaudavo ant tinklo vandeniu, tokiu būdu atskiriant žuvusius parazitus ir juos suskaičiuojant.BcecoK) 3Horo očmecTBa re; ib \ iHHTO.iorc> B M., 1965, n.l, c.206-210.) Each experimental chicken received 200 pieces each. of invasive ascarid eggs. Once the helminths reached the stage of sexual maturation (as determined by coprologic studies), the test chickens were individually injected intraperitoneally with a 100 mg single dose per kg body weight. Following the introduction of the compounds, experimental chickens were housed individually in separate cages, and their excrement was collected and washed on the net with water, thereby isolating and counting dead parasites.

Bandomuosius paukščius užmušdavo praėjus 7 dienoms nuo tiriamųjų preparatų jvedimmo ir atlikdavo helmintologinį jų žarnų skrodimą. Antihelmintinių junginių aktyvumą nustatydavo lygindami žuvusių helmintų, išsiskyrusių po preparato davimo, skaičių su helmintų, rastų atlikus helmintologinį skrodimą, skaičiumi.The test birds were sacrificed 7 days after the preparation of the test preparations and were subjected to helminth autopsy. The activity of anthelmintic compounds was determined by comparing the number of dead helminths released after administration of the preparation with the number of helminths found after anthelmintic autopsy.

Duomenys pateikti 7 lentelėje, rodo, kad siūlomi nauji junginiai yra aktyvūs prieš askaridžių invaziją viščiukams. Pažymėtina, kad šie preparatai parodė aukštą intens-efektyvumą vištų askaridiozės atveju, naudojant dozę 100 mg / kg. tuo tarpu, kai žinomas prototipas -mebendazolas- aukštu aktyvumu nepasižymi. Antihelmintinį siūlomų junginių aktyvumą tyrė taip pat ir ant ėriukų, spontaniškai užsikrėtusių skrandžio-žarnyno strongiliatais (Strongylata'). Ėriukų, užsikrėtusių skrandžiožarnyno trakto strongiliatais atrinkimą atliko avininkystės fermoje, pasižyminčioje aukštu strongiliatinės invazijos ekstensyvumu, pasinaudojant diagnostinių helmintoovoskopinių tyrimų rezultatais. Užkrėstus ėriukus laikė atskiruose narvuose. Preparatus įvesdavo individualiai, peroraliai 20 mg/kg gyvo svorio dozėje, vandeninės suspensijos pavidalu. Po jų įvedimo sekdavo gyvulių būklę. Antihelmintinio aktyvumo nustatymui, praėjus 7 ir 10 dienų po preparatų įvedimo, atlikdavo helmintoovoskopinius tyrimus.The data presented in Table 7 indicate that the proposed novel compounds are active against ascarid invasion in chickens. It is noteworthy that these preparations exhibited high intensity in the case of chicken ascaridiosis at a dose of 100 mg / kg. whereas the known prototype, mebendazole, does not exhibit high activity. The anthelmintic activity of the proposed compounds was also investigated in lambs spontaneously infected with gastrointestinal strongilates (Strongylata '). The selection of lambs infected with gastrointestinal strongilates was carried out on a sheep farm with a high degree of strongiliate invasion, using diagnostic helminthovoscopic results. The infected lambs were kept in separate cages. The formulations were administered orally individually at a dose of 20 mg / kg body weight in aqueous suspension. After their introduction, the condition of the animals was followed. Helminthovoscopic examinations were performed 7 and 10 days after administration of the products for anthelmintic activity.

Naujų junginių aktyvumo tyrimus atliko ir su paršeliais, užsikrėtusiais askaridėmis ( Ascaris suum). Paršelius eksperimentui parinko kiaulių firmoje su aukštu askaridozinės invazijos ekstens-efektyvumu. Tuo tikslu buvo atlikti helmintoovoskopinės diagnostikos tyrimai. Parinkti 2.5-3.5 mėn. amžiaus paršeliai, spontaniškai užsikrėtę askaridėmis buvo atskirti ir laikomi specialiai įrengtame vivariume, narveliuose po vieną. Tiriamuosius preparatus įvesdavo individualiai peroraliai dozėmis po 5; 25 arba 50 mg/kg gyvulio masės ir po jų įvedimo kasdien tyrinėjo fekalijas ir skaičiavo išsiskyrusias žuvusias askarides.The activity of the new compounds was also investigated in piglets infected with Ascaris suum. Piglets were selected for the experiment in a pig company with high extensiveness of ascaridotic invasion. To this end, helminthovoscopic diagnostic tests were performed. 2.5-3.5 months selected piglets, spontaneously infected with ascites, were separated and housed in a specially equipped vivarium, one at a time. Test preparations were administered orally individually at doses of 5; At 25 or 50 mg / kg of animal weight, and after their administration, daily examinations of faeces were performed and counts of ascites killed.

Po tiriamųjų preparatų įvedimo nebuvo pastebėta jokių nukrypimų nuo fiziologinės normos. Gyvuliai gerai ėdė pašarą ir gėrė vandenį.No physiological abnormalities were observed following the administration of the study agents. The animals ate the feed well and drank water.

Atlikti tyrimai rodo, kad 5-arilaIkiloksibenzimidazol-2-il-karbamino rūgščių metilo esteriai - yra netoksiški preparatai, turintys aukštą antihelmintinį aktyvumą. Šios grupės naujų junginių tyrimai pateikti žemiau 5-10 lentelėse.Studies have shown that 5-arylalkyloxybenzimidazol-2-yl-carbamic acid methyl esters are non-toxic preparations with high anthelmintic activity. Studies of novel compounds in this group are presented in Tables 5-10 below.

Lentelė. (I) Formulės junginių toksiškumo tyrimų rezultataiTable. (I) Results of toxicity studies of formula compounds

Eil. Nr. Yesterday No. Preparato šifras Preparation cipher Toksiškumas baltosioms žiurkėms Toxicity in white rats Dozė mg/kg The dose mg / kg Gyvūnų žuvimas Animal deaths 1 1 VBŠ-57 VBŠ-57 4000 4000 0 0 2 2 VBŠ-67 VBŠ-67 4000 4000 0 0 n J n J VBŠ-14 VBŠ-14 4000 4000 0 0 4 4 VBŠ-39 VBŠ-39 4000 4000 0 0 5 5 VBŠ-13 VBŠ-13 4000 4000 0 0 6 6th VBŠ-61 VBŠ-61 4000 4000 0 0 7 7th VBŠ-102 VBŠ-102 4000 4000 0 0 8 8th VBŠ-70 VBŠ-70 4000 4000 0 0 9 9th VBŠ-69 VBŠ-69 4000 4000 0 0 10 10th VBŠ-123 VBŠ-123 4000 4000 0 0 11 11th VBŠ-124 VBŠ-124 4000 4000 0 0 12 12th VBŠ-125 VBŠ-125 4000 4000 0 0 13 13th VBŠ-62 VBŠ-62 4000 4000 0 0 14 14th VBŠ-107 VBŠ-107 4000 4000 0 0 15 15th VBŠ-101 VBŠ-101 4000 4000 0 0 16 16th VBŠ-58 VBŠ-58 4000 4000 0 0 17 17th VBŠ-82 VBŠ-82 4000 4000 o ! oh! 18 18th VBŠ-126 VBŠ-126 4000 4000 0 ! 0! 19 19th VBŠ-127 VBŠ-127 4000 4000 0 i 0 i 20 20th VBŠ-163 VBŠ-163 4000 4000 o ! oh! 21 21st VBŠ-164 VBŠ-164 4000 4000 0 0 22 22nd VBŠ-166 VBŠ-166 4000 4000 0 0 23 23rd VBŠ-322 VBŠ-322 4000 4000 0 0 24 24th VBŠ-310 VBŠ-310 4000 4000 0 0 25 25th VBŠ-165 VBŠ-165 4000 4000 ⁰ 1 ⁰ 1 26 26th VBŠ-312 VBŠ-312 4000 4000 0 1 0 1 27 27th VBŠ-244 VBŠ-244 4000 4000 0 i Į i 0 i To i

Lentelė. (I) Formulės junginių antihelmintinio aktyvumo tyrimų rezultatai su žiurkėmis, užkrėstomis Nippostrongylus brasiliensisTable. (I) Results of anthelmintic activity studies of formula compounds in rats infected with Nippostrongylus brasiliensis

Antihelmintinio aktyvumo prieš bandymų rezultatų ant eksperimentui užkrėstų žiurkių (dozė 500 mg/kg gyvo svorio) duomenys Data on anthelmintic activity in pre-test infected rats (500 mg / kg body weight) Ei.Nr. No. X! X! X₂ X ₂ Χ3 Χ3 R R Y Y Preparato šifras Preparation cipher Intensyvumo efektyvumas.% Intensity efficiency.% 1 1 2-F 2-F H H H H H H H H VBŠ-57 VBŠ-57 97,65 97.65 2 2 H H 3-F 3-F H H H H H H VBŠ-67 VBŠ-67 90,0 90.0 3 3 H H H H 4-F 4-F H H H H VBŠ-14 VBŠ-14 53 53 4 4 2-C1 2-C1 H H H H H H H H VBŠ-39 VBŠ-39 84,7 84.7 5 5 H H 3-C1 3-C1 H H H H H H VBŠ-13 VBŠ-13 87,7 87.7 6 6th H H H H 4-C1 4-C1 H H H H VBŠ-61 VBŠ-61 50 50 7 7th 2-Br 2-Br H H H H H H H H VBŠ102 VBŠ102 74,6 74.6 8 8th H H 3-Br 3-Br H H H H H H VBŠ-70 VBŠ-70 57.65 57.65 9 9th H H H H 4-Br 4-Br H H H H VBŠ-69 VBŠ-69 77.6 77.6 10 10th 2-1 2-1 H H H H H H H H VBŠ-123 VBŠ-123 55.9 55.9 11 11th H H 3-1 3-1 H H H H H H VBŠ-124 VBŠ-124 90.8 90.8 12 12th H H H H 4-1 4-1 H H H H VBŠ-125 VBŠ-125 69,6 69.6 13 13th 2-C1 2-C1 H H 4-C1 4-C1 H H H H VBŠ-62 VBŠ-62 64.7 64.7 14 14th H H 3-C1 3-C1 4-C1 4-C1 H H H H VBŠ-107 VBŠ-107 96.6 96.6 15 15th 2-CH3 2-CH3 H H H H H H H H VBŠ-101 VBŠ-101 100 100 16 16th H H 3-CHs 3-CHs H H H H H H VBŠ-58 VBŠ-58 95,7 95.7 17 17th H H H H 4-CHa 4-CHa H H H H VBŠ-82 VBŠ-82 95.0 95.0 18 18th 3-CH₃ 3-CH ₃ H H 5-CH₃ 5-CH ₃ H H H H VBŠ-126 VBŠ-126 75,8 75.8 19 19th 2-CH3 2-CH3 4-CH5 4-CH5 6-CH3 6-CH3 H H H H VBŠ-127 VBŠ-127 100 100 20 20th H H H H H H c₆h₅ c ₆ h ₅ H H VBŠ-163 VBŠ-163 59.3 59.3 21 21st H H H H H H ch₃ ch ₃ H H VBŠ-164 VBŠ-164 72.6 72.6 22 22nd H H H H H H H H ch₃ ch ₃ VBŠ-166 VBŠ-166 95.5 95.5 23 23rd 3-OCHj 4-OCH₃ 3-OCHj 4-OCH ₃ H H H H H H VBŠ-322 VBŠ-322 93.2 93.2 24 24th 3-OCH₂O-43-OCH ₂ O-4 H H H H H H VBŠ-310 VBŠ-310 89.0 89.0 25 25th 3-OCH2CH2O-4 3-OCH2CH2O-4 H H H H H H VBŠ-165 VBŠ-165 99.8 99.8 26 26th 3-O(CH2)₃0-43-O (CH 2) ₃₀ 0-4 H H H H H H VBŠ-312 VBŠ-312 81.7 81.7 27 27th 3-CH2-CHO-4 3-CH 2 -CHO-4 H H H H H H VBŠ-244 VBŠ-244 98.3 98.3 1 ch₃ 1 ch ₃

Lentelė. (I) Formulės junginių antihelmintinio aktyvumo tyrimų rezultatai su eksDerimentiškai užkrėstais viščiukais ( naudota dozė -Table. (I) Results of anthelmintic activity studies of formula compounds in experimentally infected chickens (dose used -

Eil. Nr. Yesterday No. X. X. X₂ X ₂ Χ3 Χ3 R R Y Y Preparato šifras Preparation cipher 1E,% 1E,% 1 1 2-F 2-F H H H H H H H H VBŠ-57 VBŠ-57 100 100 2 2 H H 3-F 3-F H H H H H H VBŠ-67 VBŠ-67 100 100 n J n J H H H H 4-F 4-F H H H H VBŠ-14 VBŠ-14 95,9 95.9 4 4 2-C1 2-C1 H H H H H H H H VBŠ-39 VBŠ-39 75,7 75.7 5 5 H H 3-C1 3-C1 H H H H H H VBŠ-13 VBŠ-13 96 96 6 6th H H H H 4-C1 4-C1 H H H H VBŠ-61 VBŠ-61 64 64 7 7th 2-Br 2-Br H H H H H H H H \^zBŠ-102\ ^z BP-102 97,8 97.8 8 8th H H 3-Br 3-Br H H H H H H VBŠ-70 VBŠ-70 76,7 76.7 9 9th H H H H 4-Br 4-Br H H H H VBŠ-69 VBŠ-69 80 80 10 10th 2-1 2-1 H H H H H H H H VBŠ-123 VBŠ-123 74,4 74.4 11 11th H H 3-1 3-1 H H H H H H VBŠ-124 VBŠ-124 100 100 12 12th H H H H 4-1 4-1 H H H H VBŠ-125 VBŠ-125 100 100 13 13th 2-C1 2-C1 H H 4-C1 4-C1 H H H H VBŠ-62 VBŠ-62 53,7 53.7 14 14th H H 3-C1 3-C1 4-C1 4-C1 H H H H VBŠ-107 VBŠ-107 95,3 95.3 15 15th 2-CH₃ 2-CH ₃ H H H H H H H H VBŠ-101 VBŠ-101 94 94 16 16th H H 3-CHj 3-CH3 H H H H H H VBŠ-58 VBŠ-58 100 100 17 17th H H H H 4-CH3 4-CH3 H H H H VBŠ-82 VBŠ-82 90,2 90.2 18 18th H H 3-CH; 3-CH; 5-CH3 5-CH3 H H H H VBŠ-126 VBŠ-126 96,7 96.7 19 19th 2-CH3 2-CH3 4-CH3 4-CH3 6-CH3 6-CH3 H H H H VBŠ-127 VBŠ-127 97,6 97.6 20 20th H H H H H H c₆h₅ c ₆ h ₅ H H VBŠ-163 VBŠ-163 52 52 21 21st H H H H H H ch₃ ch ₃ H H VBŠ-164 VBŠ-164 43 43 22 22nd H H H H H H H H ch₃ ch ₃ VBŠ-166 VBŠ-166 53,3 53.3 23 23rd H H 3-OCH3 3-OCH3 4-OCH3 4-OCH3 H H H H VBŠ-322 VBŠ-322 97,9 97.9 24 24th H H 3-OCH₂-3-OCH ₂ - -CH₂O-4-CH ₂ O-4 H H H H VBŠ-165 VBŠ-165 100 100 25 25th H H 3-O(CH₂)₂-3-O (CH ₂ ) ₂ - -CH₂O-4-CH ₂ O-4 H H H H VBŠ-312 VBŠ-312 80,3 80.3 26 26th H H 3-CH₂-3-CH ₂ - -CH(CH-,)O-4 -CH (CH -,) - O-4 H H H H VBŠ-244 VBŠ-244 100 100

Lentelė. I Formulės junginių antihelmintinio aktyvumo tyrimai su spontaniškai užkrėstais skerstinais paršeliaisTable. Studies on the anthelmintic activity of the compounds of the formula I in spontaneously infected piglets for slaughter

Preparatų išbandymas su spontaniškai užkrėstais skerstinais paršeliais Testing of preparations with spontaneously infected piglets for slaughter Eil. Nr. Yesterday No. X. X. X₂ X ₂ x₃ x ₃ Preparato šifras Preparation code Dozė mg/kg The dose mg / kg Intensyvumo efektyvumas,% Intensity efficiency,% 1 1 H H 4-F 4-F H H VBŠ-14 VBŠ-14 50 50 100 100 2 2 H H 3-C1 3-C1 H H VBŠ-13 VBŠ-13 50 50 100 100 o J o J H H 4-Br 4-Br H H VBŠ-69 VBŠ-69 50 50 100 100 4 4 H H 4-CH₃ 4-CH ₃ H H VBŠ-82 VBŠ-82 50 50 100 100 5 5 2-Br 2-Br H H H H VBŠ-102 VBŠ-102 50 50 100 100

Lentelė. I Formulės junginių Įvertinimas pagal helmintoovoskopinių tyrimų duomenis su spontaniškai užkrėstais skerstinais paršeliais, užkrėstais askaridėmis,Table. Evaluation of compounds of the formula I on the basis of helminthovoscopic data from spontaneously infected piglets infected with ascarids,

Eil. Nr. Yesterday No. Preparato šifras Preparation cipher Dozė mg/kg The dose mg / kg Askaridžių kiaušinėlių kiekis 1 g fekalijų Ascarid egg content per 1 g of faeces Intensyvumo efektyvumas, % Intensity efficiency, % Iki preparato Įvedimo By preparation Input Laikas, praėjęs po preparato įvedimo( paromis) Time after administration (in days) 4 4 5 5 6 6th 11 11th 1 1 VBŠ -14 VBŠ -14 25 25th 31 31st -> J -> J 9 9th 10 10th 0 0 100 100 2 2 VBŠ-13 VBŠ-13 25 25th 271 271 12 12th 31 31st 28 28th 2 2 99,3 99.3 J J VBŠ.-69 VBŠ-69 10 10th 1 1 0 0 0 0 0 0 0 0 100 100 4 4 VBŠ.-82 VBŠ-82 5 5 1 1 0 0 0 0 0 0 0 0 100 100 5 5 VBŠ.-102 VBŠ-102 25 25th 6 6th 4 4 3 3 3 3 0 0 100 100

Lentelė. Naujų preparatų toksiškumo palyginimas su prototipu IV (mebendazolu)Table. Toxicity comparison of new formulations with prototype IV (mebendazole)

Preparatas Preparation Dozė mg/kg Dose in mg / kg Efektyvumas vištų askaridozės atveju,% Efficacy in chicken ascaridosis,% Toksiškumas LDsi,, mg'kg Toxicity LDsi ,, mg'kg Mebendazolas Mebendazole 1000 1000 81,9 81.9 1280 1280 (IV) (prototipas) (IV) (prototype) Nauji preparatai New preparations 100 100 43-100 43-100 >4000 > 4000

Lentelėje pateikti duomenys rodo, kad siūloma naujų preparatų grupė turi mažesnį toksiškumą ir aukštesni efektyvumą.The data in the table show that the proposed group of new formulations have lower toxicity and higher efficacy.

Claims

DEFINITION OF INVENTION

1. 5-Substituted arylalkyloxybenzimidazol-2-ylcarbamic acid methyl esters of general structural formula (I):

R represents hydrogen, methyl, -CfH

Y represents hydrogen, methyl;

Xi. X ₂ , Χ 3 independently of one another may be hydrogen; A halogen, methyl, or methoxy substituent at the 0-, m-, p- positions;

also X _b X ₂ , Χ 3 may together form an alkylenedioxycyclic C 1 -C 3 ring.

5-Substituted arylalkyloxybenzimidazol-2-ylcarbamic acid methyl esters according to claim 1 for use in medicine and veterinary medicine as anthelmintics.

3. 5-Substituted arylalkyloxybenzimidazol-2-ylcarbamic acid methyl esters according to claims 1 and 2, characterized in that they do not deviate from the physiological dose at doses up to 4000 mg / kg.