SK287385B6 - 1,3-Disubstituted ureas, process for their preparation and their use - Google Patents

1,3-Disubstituted ureas, process for their preparation and their use Download PDF

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SK287385B6
SK287385B6 SK5133-2007A SK51332007A SK287385B6 SK 287385 B6 SK287385 B6 SK 287385B6 SK 51332007 A SK51332007 A SK 51332007A SK 287385 B6 SK287385 B6 SK 287385B6
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Slovakia
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2xch
chlorophenyl
nitrophenyl
pyridyl
4xch
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SK5133-2007A
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Slovak (sk)
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SK51332007A3 (en
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Ivan Kakalík
Pavol Valachovič
Ľudmila Schmidtová
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Hameln-Rds, A. S.
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Priority to SK5133-2007A priority Critical patent/SK287385B6/en
Priority to PCT/SK2008/000012 priority patent/WO2009070130A1/en
Priority to EP08855483A priority patent/EP2254861A1/en
Publication of SK51332007A3 publication Critical patent/SK51332007A3/en
Publication of SK287385B6 publication Critical patent/SK287385B6/en

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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract

The invention relates to 1,3-disubstituted ureas of general formula (I), process for their preparation and their use for the preparation of pharmaceutical compositions. The compounds of general formula (I) are inhibitors of the acyl-CoA:cholesterol acyltransferase (ACAT) and may be used as hypocholesterolemic and antiatherogenic agents.

Description

Vynález sa týka 1,3-disubstituovaných zlúčenín močoviny, spôsobu ich prípravy a použitia. Zlúčeniny sa vyznačujú vlastnosťou, že inhibujú aktivitu enzýmu acyl-koenzým A: cholesterol O-acyltransferázy (ACAT).The invention relates to 1,3-disubstituted urea compounds, processes for their preparation and use. The compounds have the property of inhibiting the activity of the enzyme acyl-coenzyme A: cholesterol O-acyltransferase (ACAT).

Doterajší stav technikyBACKGROUND OF THE INVENTION

Významným trendom v liečbe hypercholesterolémie sú látky, ktoré inhibujú aktivitu acyl-koenzým A: cholesterol O-acyltransferázy (ACAT, EC 2.3.1.26), kľúčového enzýmu esterifikácie cholesterolu v bunke. Ide o ovplyvnenia hladín cholesterolu a vplyv na metabolizmus exogénneho cholesterolu v tenkom čreve a endogénneho cholesterolu v pečeni cestou inhibície ACAT. Tento enzým hrá dôležitú úlohu v procese aterosklerózy a následne vzniku ateromatóznych plakov v cievach, najmä v aorte. Teda ACAT inhibítory môžu byť terapeuticky perspektívne hypolipidemiká, ktoré sú účinné ako hypocholesterolemické a antiaterogénne agens. Ich efekt sa hodnotí cez redukciu množstva absorbovaného cholesterolu v tenkom čreve, resp. zníženie sekrécie hepatálnych esterov cholesterolu hodnotením hladín lipidov v krvi, v pečeni resp. v aorte.Significant trends in the treatment of hypercholesterolemia are substances that inhibit the activity of acyl-coenzyme A: cholesterol O-acyltransferase (ACAT, EC 2.3.1.26), a key enzyme in cholesterol esterification in the cell. These are influencing cholesterol levels and the effect on the metabolism of exogenous cholesterol in the small intestine and endogenous cholesterol in the liver by inhibiting ACAT. This enzyme plays an important role in the process of atherosclerosis and consequently the formation of atheromatous plaques in the blood vessels, especially in the aorta. Thus, ACAT inhibitors may be therapeutically perspective hypolipidemics that are effective as hypocholesterolemic and antiatherogenic agents. Their effect is evaluated by reducing the amount of cholesterol absorbed in the small intestine, respectively. reduction of hepatic cholesterol ester secretion by assessing lipid levels in blood, liver and liver; in aorte.

Je opísané množstvo zlúčenín typu močovín ako látok inhibujúcich ACAT. Uvádzame niekoľko príkladov:A number of urea-type compounds as ACAT inhibitory agents are described. Here are some examples:

Patenty EP 506532, US 5219859 opisujú močoviny obsahujúce v skelete indol. Spojenie aromatickej časti s alifatickou je opísané v patentoch JP 95258199 a EP 665216.Patents EP 506532, US 5219859 disclose ureas containing indole in the scaffold. The association of the aromatic moiety with the aliphatic moiety is described in JP 95258199 and EP 665216.

1,3-Disubstituované močoviny podobného typu boli opísané v patente WO 9932437, ktoré obsahovali, 2,6-diizopropylfenylový, 4-(4-nitrofenylsulfanyl)-fenylový alebo 4-(4-aminofenylsulfanyl)-fenylový skelet.1,3-Disubstituted ureas of a similar type have been described in WO 9932437, which contained a 2,6-diisopropylphenyl, 4- (4-nitrophenylsulfanyl) -phenyl or 4- (4-aminophenylsulfanyl) -phenyl skeleton.

Spôsob prípravy uvedených derivátov bol uskutočnený reakciou 2,6-diizopropylfenylizokyanátu s príslušnými aromatickými amínmi.The process for preparing said derivatives was carried out by reacting 2,6-diisopropylphenyl isocyanate with the corresponding aromatic amines.

Podstata vynálezuSUMMARY OF THE INVENTION

Vynález sa týka 1,3-disubstituovaných močovín všeobecného vzorca (I),The invention relates to 1,3-disubstituted ureas of formula (I),

X= CH, NX = CH, N

R*= H,CO2H, CONH2, CO2Me, CO2Et kde R2 je 4-hydroxyfenyl, 4-karboxyfenyl, 4-metyloxykarbonylfenyl, 4-etyloxykarbonylfenyl, 4-fluórfenyl, 4-chlórfenyl, 4-brómfenyl, 4-jódfenyl, 4-metylfenyl, 4-metylaminofenyl, 4-metyIsulfofenyl, 4-metoxyfenyl, 4-karbamoylfenyl, 2,4-dinitrofenyl, 2-karboxy-4-nitrofenyl, 3-karboxy-4-nitrofenyl, 2-metyloxykarbonyl-4-nitrofenyl, 3-metyloxykarbonyl-4-nitrofenyl, 2-etyloxykarbonyl-4-nitrofenyl, 3-etyloxykarbonyl-4-nitrofenyl, 2-karbamoyl-4-nitrofenyl, 3-karbamoyl-4-nitrofenyl, 2-karbamoyl-4-chlórfenyl, 3-karbamoyl-4-chlórfenyl, 2-karboxy-4-chlórfenyl, 3-karboxy-4-chlórfenyl, 2-metyloxykarbonyl-4-chórfenyl, 3-metyloxykarbonyl-4-chlórfenyl, 2-etyloxykarbonyl-4-chórfenyl, 3-etyloxykarbonyl-4-chlórfenyl a R1 a X je vodík, kde R2 je 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-nitro-2-pyridyl, 3-nitro-2-pyridyl, 5-chlór-2-pyridyl, 3,5-dinitro-2-pyridyl, pyrazin-2-yl, pyrimidin-2-yl, 6-chlórpyridazin-3-yl, 5,6-dimetoxy-l,3,5-triazin-2-yl, chinolin-2-yl, chinoxalin-2-yl a R1 = H a X = CH, kde R2 je 4-nitrofenyl, 4-chlórfenyl, 5-nitro-2-pyridyl, 5-chór-2-pyridyl a R1 je vodík a X=N, kde R2 je 4-nitrofenyl, 4-chlórfenyl,4-brómfenyl a R’= COOH, COOMe, COOEt, CONH2 a X= H.R * = H, CO 2 H, CONH 2 , CO 2 Me, CO 2 Et wherein R 2 is 4-hydroxyphenyl, 4-carboxyphenyl, 4-methyloxycarbonylphenyl, 4-ethyloxycarbonylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl 4-iodophenyl, 4-methylphenyl, 4-methylaminophenyl, 4-methylsulfophenyl, 4-methoxyphenyl, 4-carbamoylphenyl, 2,4-dinitrophenyl, 2-carboxy-4-nitrophenyl, 3-carboxy-4-nitrophenyl, 2-methyloxycarbonyl 4-nitrophenyl, 3-methyloxycarbonyl-4-nitrophenyl, 2-ethyloxycarbonyl-4-nitrophenyl, 3-ethyloxycarbonyl-4-nitrophenyl, 2-carbamoyl-4-nitrophenyl, 3-carbamoyl-4-nitrophenyl, 2-carbamoyl-4 -chlorophenyl, 3-carbamoyl-4-chlorophenyl, 2-carboxy-4-chlorophenyl, 3-carboxy-4-chlorophenyl, 2-methyloxycarbonyl-4-chlorophenyl, 3-methyloxycarbonyl-4-chlorophenyl, 2-ethyloxycarbonyl-4-chlorophenyl , 3-ethyloxycarbonyl-4-chlorophenyl, and R 1 and X is hydrogen, wherein R 2 is 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-nitro-2-pyridyl, 3-nitro-2-pyridyl, 5- chloro-2-pyridyl, 3,5-dinitro-2-pyridyl, pyrazin-2-yl, pyrimidin-2-yl, 6-chloropyridazin-3-yl, 5,6-dimethoxy-1,3,5-triazine- 2-yl, quinolin-2 -yl, quinoxalin-2-yl, and R 1 = H and X = CH, wherein R 2 is 4-nitrophenyl, 4-chlorophenyl, 5-nitro-2-pyridyl, 5-chloro-2-pyridyl and R 1 is hydrogen and X = N, wherein R 2 is 4-nitrophenyl, 4-chlorophenyl, 4-bromophenyl and R '= COOH, COOMe, COOEt, CONH 2 and X = H.

Spôsob prípravy uvedených zlúčenín (I) podľa tohto vynálezu spočíva v reakcii izokyanátu (schéma 1) pripraveného in situ (D), resp. komerčne dostupného (A), s amínom (B) alebo (C) vznikajú močoviny, resp. močoviny, ktoré v skelete obsahujú ešte estery kyseliny sa bázickou hydrolýzou modifikujú na kyseliny.The process for the preparation of the compounds (I) according to the invention consists in the reaction of an isocyanate (Scheme 1) prepared in situ (D) and (II), respectively. commercially available (A), with the amine (B) or (C) to form ureas, respectively. ureas which still contain acid esters in the skeleton are converted to acids by basic hydrolysis.

Reakcia sa uskutočňuje v prítomnosti inertného rozpúšťadla, ako je tetrahydrofurán, dietyléter, diizopropyléter, chloroform, dichlórmetán, toluén, dioxán, etylacetát a acetón výhodne tetrahydrofuránu a chloroformu. Reakčný čas sa pohybuje od 4 až po 120 hodín v závislosti od zvolenej reakčnej teploty a rozpúšťadla. Reakčná teplota sa pohybuje od laboratórnej až po teplotu refluxu použitého rozpúšťadla (20 až 120 °C) výhodne 50 až 80 °C.The reaction is carried out in the presence of an inert solvent such as tetrahydrofuran, diethyl ether, diisopropyl ether, chloroform, dichloromethane, toluene, dioxane, ethyl acetate and acetone, preferably tetrahydrofuran and chloroform. The reaction time varies from 4 to 120 hours, depending on the reaction temperature and solvent selected. The reaction temperature ranges from room temperature to the reflux temperature of the solvent used (20 to 120 ° C), preferably 50 to 80 ° C.

Izokyanát sa používa priamo komerčne dostupný alebo sa vyrába in situ z príslušného aromatického amínu a fosgénu alebo 3-bis(trichlórmetyl)karbonátu (trifosgénu) s použitím bázy, ako je trietylamín alebo pyridín v inertnom rozpúšťadle (toluén, tetrahydrofurán, dioxán, chloroform, dietyléter, acetón, dichlórmetán).The isocyanate is used directly commercially available or is produced in situ from the corresponding aromatic amine and phosgene or 3-bis (trichloromethyl) carbonate (triphosgene) using a base such as triethylamine or pyridine in an inert solvent (toluene, tetrahydrofuran, dioxane, chloroform, diethyl ether). , acetone, dichloromethane).

Schéma 1Scheme 1

Bázická hydrolýza esterov kyselín na kyseliny sa uskutočňuje s vodným roztokom hydroxidu sodného alebo draselného v prostredí C1 až C5 alkoholu (metanol, etanol, 2-propanol atď.) alebo tetrahydrofuránu, resp dioxánu. Reakčná teplota sa udržuje od 20 až do 80 °C výhodne pri laboratórnej teplote. Reakčný čas sa pohybuje od 1 až 10 hodín v závislosti od zvolenej reakčnej teploty.The basic hydrolysis of the acid esters to the acids is carried out with an aqueous solution of sodium or potassium hydroxide in a C 1 to C 5 alcohol medium (methanol, ethanol, 2-propanol, etc.) or tetrahydrofuran or dioxane. The reaction temperature is maintained from 20 to 80 ° C, preferably at room temperature. The reaction time varies from 1 to 10 hours, depending on the reaction temperature selected.

Príklady uskutočnenia vynálezuDETAILED DESCRIPTION OF THE INVENTION

Príklad 1 jV-(4-(4-[3-(2,6-Diizopropylfenyl)-ureido]-fenylsulfanyl)fenyl)-metánsulfónamid laExample 1 N- (4- (4- [3- (2,6-Diisopropylphenyl) -ureido] -phenylsulfanyl) phenyl) methanesulfonamide 1a

Do roztoku 7V-[4-(4-aminofenylsulfanyl)fenyl)-metánsulfónamidu (1 g, 3.4 mmol) v 20 ml tetrahydrofuránu sa za laboratórnej teploty prikvapká roztok 2,6-diizopropylfenylizokyanátu (0.69 g, 3.4 mmol.) v 10 ml tetrahydrofuránu a zmes sa refluxuje cez noc. Po ochladení na 10 °C sa vypadnutý produkt odsaje a premyje dietyléterom (10 ml). Surový produkt sa dočistí kryštalizáciou v etylacetáte. Získame 1.3 g (76 %) s t.t.= = 205 - 208 °C 'HNMR (200 Hz, DMSO) δ: 1.2 (12H, 4xCH3, d), 3.2 (2H, 2xCH, m), 3.3 (3H, CH3, s), 7.1-7.3 (7H, 7xCHar, m), 7.3 (2H,2xCHar, d), 7.5 (2H, 2xCHar, d), 7.7 (1H, NH, br), 9.0 (1H, NH, br) 13CNMR, δ: 23.59 (4xCH3), 28.09 (2xCH), 40.48 (CH3) 118.96 (2xCHJ, 122.79 (CJ, 123.0 (2xCHJ,To a solution of N - [4- (4-aminophenylsulfanyl) phenyl) methanesulfonamide (1 g, 3.4 mmol) in 20 mL tetrahydrofuran was added dropwise a solution of 2,6-diisopropylphenylisocyanate (0.69 g, 3.4 mmol) in 10 mL tetrahydrofuran at room temperature. and the mixture is refluxed overnight. After cooling to 10 ° C, the precipitated product is filtered off with suction and washed with diethyl ether (10 ml). The crude product was purified by crystallization in ethyl acetate. Obtain 1.3 g (76%) with mp = 205 - 208 ° C 1 H NMR (200 Hz, DMSO) δ: 1.2 (12H, 4xCH 3 , d), 3.2 (2H, 2xCH, m), 3.3 (3H, CH 3 , s), 7.1-7.3 (7H, 7xCH ar , m), 7.3 (2H, 2xCH ar , d), 7.5 (2H, 2xCH ar , d), 7.7 (1H, NH, br), 9.0 (1H, NH, br) 13 CNMR, δ: 23.59 (4xCH 3 ), 28.09 (2xCH), 40.48 (CH 3 ) 118.96 (2xCHJ, 122.79 (CJ, 123.0 (2xCHJ,

123.18 (2xCHJ, 127.46 (CHJ, 128.85 (2xCHar), 132.16 (CJ, 135.04 (2xCHJ, 137.52 (CJ, 141.44 (CJ, 146.71 (2xCJ, 147.15 (CJ, 154.13 (CO)123.18 (2xCHJ, 127.46 (CHJ, 128.85 (2xCH ar )), 132.16 (CJ, 135.04 (2xCHJ, 137.52 (CJ, 141.44 (CJ, 146.71 (2xCJ, 147.15 (CJ, 154.13 (CO)))

Príklad 2 l-(2,6-Diizopropylfenyl)-3-[4-(4-brómfenylsulfanyl)fenyl]-močovina lbExample 2 1- (2,6-Diisopropylphenyl) -3- [4- (4-bromophenylsulfanyl) phenyl] urea 1b

Do roztoku 2,6-diizopropylanilínu (0.65 g, 3.6 mmol) v 20 ml dioxánu sa pridá 4-(4-fluórfenylsulfanyljfenylizokyanát (0.84 g, 3.6 mmol) a zmes sa refluxuje 30 hodín. Po ochladení na laboratórnu teplotu sa vypadnutý produkt odsaje a premyje dietyléterom (15 ml). Získame 1.3 g (76 %) s t.t.= 236 - 238 °C. 'HNMR (200 Hz, DMSO) δ:1.2 (12H, 4xCH3, d), 3.15 (2H, 2xCH, m), 6.8 (2H, 2xCHar, d), 7.1-7.3 (7H,7xCHar, m), 7.4 (2H, 2xCHar, d), 7.75 (1H, NH, br), 9.95 (1H, NH, br) 13CNMR, δ: 23.5 (4xCH3), 28.0 (2xCH), 116.46 (2xCHJ, 118.61 (2xCHJ, 122.87 (2xCHJ, 123.57 (CJ,To a solution of 2,6-diisopropylaniline (0.65 g, 3.6 mmol) in 20 mL dioxane was added 4- (4-fluorophenylsulfanyl) phenyl isocyanate (0.84 g, 3.6 mmol) and the mixture was refluxed for 30 hours. Wash with diethyl ether (15 mL) to give 1.3 g (76%) of mp = 236-238 ° C. 1 H (200 Hz, DMSO) δ: 1.2 (12H, 4xCH 3 , d), 3.15 (2H, 2xCH, m) 6.8 (2H, 2xCH ar , d), 7.1-7.3 (7H, 7xCH ar , m), 7.4 (2H, 2xCH ar , d), 7.75 (1H, NH, br), 9.95 (1H, NH, br) ) 13 CNMR, δ: 23.5 (4xCH 3 ), 28.0 (2xCH), 116.46 (2xCHJ, 118.61 (2xCHJ, 122.87 (2xCHJ, 123.57 (CJ,

127.25 (CHJ, 128.17 (CJ, 130.89 (2xCHJ, 132.29 (CJ, 133.52 (2xCJ, 139.50 (CJ, 146.64 (2xCar), 154.2 (C J, 157.39 (CO)127.25 (CHJ, 128.17 (CJ, 130.89 (2x CHJ, 132.29) (CJ, 133.52 (2xCJ, 139.50 (CJ, 146.64 (2xC ar )), 154.2 (CJ, 157.39 (CO))

Príklad 3 l-(2,6-Diizopropylfenyl)-3-[4-(4-fluórfenylsulfanyl)fenyl]-močovina lcExample 3 1- (2,6-Diisopropylphenyl) -3- [4- (4-fluorophenylsulfanyl) phenyl] urea 1c

Do roztoku (4-fluórfenylsulfanyl)fenylamínu (0.8 g, 3.6 mmol) v 20 ml chloroformu sa za laboratórnej teploty prikvapká roztok 2,6-diizopropylfenylizokyanátu (0.69 g, 3.6 mmol.) v 10 ml chloroforme. Zmes sa mieša dva dni a vypadnutý produkt sa odsaje a premyje dietyléterom (10 ml). Výťažok 76 %, t. t. = 198 - 200 °C ’HNMR (200 Hz, DMSO) δ:1.25 (12H, 4xCH3, d), 3.2 (2H, 2xCH, m), 7.1 (2H, 2xCIIar, d), 7.1-7.3 (7H, 7xCHar, m), 7.3 (2H, 2xCHar, d), 7.7 (1H, NH, br), 9.1 (1H, NH, br) 13CNMR, δ: 23.5 (4xCH3), 28.0 (2xCH), 118.54 (2xCHJ, 124.46 (2xCHar), 126.87 (2xCHar), 124.21 (CJ, 126.2 (CHJ, 128.98 (CJ, 132.64 (2xCHJ, 132.98 (CJ, 133.78 (2xCJ, 140.1 (CJ, 148.36 (2xCJ, 154.8 (C J, 155.46 (CO)To a solution of (4-fluorophenylsulfanyl) phenylamine (0.8 g, 3.6 mmol) in 20 mL chloroform was added dropwise a solution of 2,6-diisopropylphenyl isocyanate (0.69 g, 3.6 mmol) in 10 mL chloroform at room temperature. The mixture was stirred for two days and the precipitated product was filtered off with suction and washed with diethyl ether (10 ml). Yield 76%, mp = 198-200 DEG C. NMR (200 MHz, DMSO) δ: 1.25 (12 H, 4xCH 3, d), 3.2 (2H, 2 x CH, m), 7.1 (2H, 2xCI ar, d), 7.1-7.3 (7H, ar 7xCH, m), 7.3 (2H, 2 x CH ar, d), 7.7 (1H, NH, br), 9.1 (1H, NH, br) 13 C NMR, δ: 23.5 (4xCH 3), 28.0 (2xCH), 118.54 (2xCHJ, 124.46 (2xCH ar )), 126.87 (2xCH ar ), 124.21 (CJ, 126.2 (CHJ, 128.98 (CJ, 132.64 (2xCHJ), 132.98 (CJ, 133.78 (2xCJ, 140.1 (CJ, 148.36) (2xCJ, 154.8 (CJ), 155.46 (CO)

Príklad 4 l-(2,6-Diizopropylfenyl)-3-[4-(4-chlórfenylsulfanyl)fenyl]-močovina liExample 4 1- (2,6-Diisopropylphenyl) -3- [4- (4-chlorophenylsulfanyl) phenyl] urea 1i

Do roztoku 4-(4-chlórfenylsulfanyl)fenylamínu (2,5 g, 10.6 mmol) a trietylamínu (6 ml, 42.4 mmol) v 25 ml toluénu sa prikvapká bis-(trichlórmetyl)karbonát (1.05g, 3.5 mmol) rozpustený v 10 ml toluénu pri teplote 5 °C. Roztok sa mieša pri laboratórnej teplote 10 hodín a potom sa pridá 2,6-diizopropylanilin (2 ml, 10.6 mmol). Zmes miešame pri 70 °C cez noc a po zahustení produkt sa získa chromatografiou (EtOAc : n-hexán-1 : 2). Výťažok 3.2 g (68 %) po kryštalizácii (acetón-éter), 1.1.= 208 - 210 °C.To a solution of 4- (4-chlorophenylsulfanyl) phenylamine (2.5 g, 10.6 mmol) and triethylamine (6 mL, 42.4 mmol) in 25 mL of toluene was added dropwise bis- (trichloromethyl) carbonate (1.05g, 3.5 mmol) dissolved in 10 ml of toluene at 5 ° C. The solution was stirred at room temperature for 10 hours and then 2,6-diisopropylaniline (2 mL, 10.6 mmol) was added. Stir the mixture at 70 ° C overnight and concentrate the product by chromatography (EtOAc: n-hexane-1: 2). Yield 3.2 g (68%) after crystallization (acetone-ether), m.p. = 208-210 ° C.

‘HNMR (200 Hz, CDC13) δ: 1.2 (12H, 4xCH3, d), 3.2 (2H, 2xCH, m), 7.25 (1H, CH^, s), 7.1-7.4 (9^9x01^ m), 7.54 (2H, 2xCHar, d), 7.7 (1H, NH, br), 9.9 (1H, NH, br) 13CNMR, δ: 23.58 (4xCH3), 28.11 (2xCH), 118.97 (CHJ, 123.03 (2xCHJ, 127.48 (CHJ, 129.21 (5xCHJ, 130.61 (CJ, 132.17 (CJ, 134.87 (2xCHJ, 137.3 (CJ, 141.37 (2xCJ, 146.72 (2xCHar), 154.15 (CO)1 HNMR (200 Hz, CDCl 3 ) δ: 1.2 (12H, 4xCH 3 , d), 3.2 (2H, 2xCH, m), 7.25 (1H, CH 4, s), 7.1-7.4 (9 ^ 9x01 → m) 7.54 (2H, 2xCH ar , d); 7.7 (1H, NH, br); 9.9 (1H, NH, br); 13 CNMR, δ: 23.58 (4xCH 3 ), 28.11 (2xCH), 118.97 (CHJ, 123.03 ( 2xCHJ, 127.48 (CHJ, 129.21 (5xCHJ, 130.61 (CJ), 132.17 (CJ, 134.87 (2xCHJ, 137.3 (CJ, 141.37 (2xCJ, 146.72 (2xCH ar )), 154.15 (CO))

Príklad 5 l-(2,6-Diizopropylfenyl)-3-[4-(4-metylfenylsulfanyl)fenyl]-močovina lhExample 5 1- (2,6-Diisopropylphenyl) -3- [4- (4-methylphenylsulfanyl) phenyl] urea 1h

Pripravila sa analogickým postupom ako v príklade 1 z 2,6-diizopropylfenylizokyanátu a 4-(4-metylfenylsulfanyl)fenylamínu.Prepared in analogy to Example 1 from 2,6-diisopropylphenylisocyanate and 4- (4-methylphenylsulfanyl) phenylamine.

'HNMR (200 Hz, DMSO) δ:1.15 (12H, 4xCH3, d), 2.2 (3H, CH3, s), 3.2 (2H, 2xCH, m), 7.1-7.4 (9H, 9xCHar, m), 7.5 (2H,2xCHar, d), 7.7 (1H, NH, br), 8.9 (1H, NH, br) I3CNMR, δ: 20.46 (CH3), 23,46 (4xCH3), 27.97 (2xCH), 118.66 (2xCHJ, 122.86 (2xCHJ, 124.93 (CJ,1 HNMR (200 Hz, DMSO) δ: 1.15 (12H, 4xCH 3 , d), 2.2 (3H, CH 3 , s), 3.2 (2H, 2xCH, m), 7.1-7.4 (9H, 9xCH ar , m) , 7.5 (2H, 2 x CH ar, d), 7.7 (1H, NH, br), 8.9 (1H, NH, br) I3 C NMR, δ: 20.46 (CH3), 23.46 (4xCH 3), 27.97 (2 x CH ), 118.66 (2xCHJ, 122.86 (2xCHJ, 124.93 (CJ,

127.26 (CHJ, 128.95 (2xCHJ, 129.85 (2xCHj, 132.13 (CJ, 133.9 (2xCHJ, 133.57 (CJ, 135.84 (CJ, 140.47 (CJ, 146.58 (2xCJ, 154.03 (CO)127.26 (CHJ, 128.95 (2xCHJ, 129.85 (2xCHJ, 132.13) (CJ, 133.9 (2xCHJ, 133.57 (CJ, 135.84 (CJ, 140.47 (CJ, 146.58 (2xCJ, 154.03 (CO)))

Výťažok 67 %, 1.1. = 204 - 206 °CYield 67%, m.p. Mp = 204-206 ° C

Príklad 6Example 6

Metyl ester 4-(4-[3-(2,6-diizopropylfenyl)-ureido]fenylsulfanyl) benzoovej kyseliny ld4- (4- [3- (2,6-Diisopropyl-phenyl) -ureido] -phenylsulfanyl) -benzoic acid methyl ester 1d

Pripravila sa analogickým postupom ako v príklade 2 z 2,6-diizopropylfenylizokyanátu a 4-(4-metoxykarbonylfenylsulfanyl)fenylamínu.Prepared in analogy to Example 2 from 2,6-diisopropylphenylisocyanate and 4- (4-methoxycarbonylphenylsulfanyl) phenylamine.

’HNMR (200 Hz, CDC13) δ: 1.2 (12H, 4xCH3, d), 3.2 (2H, 2xCH, m), 3.7 (3H, CH3O, s), 7.1 (2H, 2xCHa„ d), 7.75-7.5 (7H,7xCHar, m), 7.9 (2H, 2xCHar, d) 13CNMR, δ:23,74 (4xCH3), 28.51 (2xCH), 34.12 (CH3O), 120.36 (2xCHJ, 121.02 (CJ, 124.4 (2xCHJ, 126.58 (2xCHJ, 127.85 (CJ, 129.41 (CHJ, 129.9 (2xCHJ, 130.23 (CJ, 135.26 (2xCHar), 139.26 (CJ, 145.04 (CJ, 147.9 (2xCJ, 154.8 (CO), 165.76 (CO)1 HNMR (200 Hz, CDCl 3 ) δ: 1.2 (12H, 4xCH 3 , d), 3.2 (2H, 2xCH, m), 3.7 (3H, CH 3 O, s), 7.1 (2H, 2xCH 3 d), 7.75-7.5 (7H, 7xCH ar , m), 7.9 (2H, 2xCH ar , d) 13 CNMR, δ: 23.74 (4xCH 3 ), 28.51 (2xCH), 34.12 (CH 3 O), 120.36 (2xCHJ, 121.02 (CJ, 124.4 (2xCHJ, 126.58 (2xCHJ, 127.85) (CJ, 129.41 (CHJ, 129.9 (2xCHJ, 130.23 (CJ, 135.26 (2xCH ar ))), 139.26 (CJ, 145.04 (CJ, 147.9 (2xCJ, 154.8 (CO)) , 165.77 (CO)

Výťažok 43 %, 1.1. = 215 - 217 °CYield 43%, m.p. Mp = 215-217 ° C

Príklad 7Example 7

4-(4-[3-(2,6-Diizopropylfenyl)-ureido]fenylsulfanyl) benzoova kyselina le4- (4- [3- (2,6-Diisopropylphenyl) -ureido] phenylsulfanyl) benzoic acid le

Metyl ester 4-(4-[3-(2,6-diizopropylfenyl)-ureido]fenylsulfanyl) benzoovej kyseliny (0.5 g, 1.1 mmol) sa refluxuje spolu s KOH (0.15 g, 2.7 mmol) v 60 ml etanolu a 10 ml vody 24 hodín. Zmes sa okyslí 1 ml IM roztoku kyseliny chlorovodíkovej a vypadnutá zrazenina sa odsaje a prekryštalizuje z metanolu. Získame 0.35 g (71 %) s 1.1. = 325 - 327 °C ’HNMR (200 Hz, DMSO) δ: 1.2 (12H, 4xCH3, d), 3.2 (2H, 2xCH, m), 7.3-7.6 (5H, 5xCHar, m), 7.75 (2H,2xCHar, d), 7.9 (2H, 2xCHar, d), 8.1 (3H, 2xCHar, NH, m), 9.3 (1H, NH, br) ’3CNMR, δ:23,59 (4xCH3), 28.1 (2xCH), 119.03 (2xCHJ, 121.07 (CJ, 123.0 (2xCHJ, 125.79 (2xCHar), 127.46 (CHJ, 127.62 (CJ, 130.06 (2xCHar), 132.13 (CJ, 135.84 (2xCHJ, 141.88 (CJ, 145.15 (CJ, 146.7 (2xCJ, 154.1 (CO), 166.96 (CO)4- (4- [3- (2,6-Diisopropylphenyl) -ureido] phenylsulfanyl) benzoic acid methyl ester (0.5 g, 1.1 mmol) was refluxed together with KOH (0.15 g, 2.7 mmol) in 60 mL ethanol and 10 mL water 24 hours. The mixture is acidified with 1 ml of 1M hydrochloric acid solution and the precipitate is filtered off with suction and recrystallized from methanol. Obtain 0.35 g (71%) of m.p. = 325 - 327 ° C 1 H NMR (200 Hz, DMSO) δ: 1.2 (12H, 4xCH 3 , d), 3.2 (2H, 2xCH, m), 7.3-7.6 (5H, 5xCH ar , m), 7.75 (2H , 2xCH ar , d), 7.9 (2H, 2xCH ar , d), 8.1 (3H, 2xCH ar , NH, m), 9.3 (1H, NH, br) ' 3 CNMR, δ: 23.59 (4xCH 3 ) , 28.1 (2xCH), 119.03 (2xCHJ, 121.07 (2xCHJ, 123.0 (2xCHJ, 125.79 (2xCH ar ))), 127.46 (CHJ, 127.62 (CJ, 130.06 (2xCH ar )), 132.13 (CJ, 135.84 (2xCHJ, 141.88 (CJ, 145.15 (CJ, 146.7 (2xCJ), 154.1 (CO), 166.96 (CO)

Príklad 8 l-(2,6-Diizopropylfenyl)-3-[4-(4-metánsulfonyloxyfenylsulfanyl)fenyl]-močovina lfExample 8 1- (2,6-Diisopropylphenyl) -3- [4- (4-methanesulfonyloxyphenylsulfanyl) phenyl] urea 1f

Pripravila sa analogickým postupom ako v príklade 4 z 2,6-diizopropylanilínu a 4-(4-metánsulfonyloxyfenylsulfanyl)fenylamínu.Prepared in analogy to Example 4 from 2,6-diisopropylaniline and 4- (4-methanesulfonyloxyphenylsulfanyl) phenylamine.

'HNMR (200 Hz, DMSO) δ: 1.2 (12H, 4xCH3, d), 3.2 (2H, 2xCH, m), 3.5 (CH3), 7.0 (2H, 2xCHar, d), 7.1-7.3 (7H,7xCHar, m), 7.5 (2H, CHar, d), 7.7 (1H, NH, br), 8.9 (1H, NH, br) 13CNMR, δ:23,61 (4xCH3), 28.5 (2xCH), 40.62 (CH3), 116.27 (2xCHJ, 118.64 (CHJ, 123.04 (2xCHJ, 123.54 (CJ, 126.99 (CHJ, 128.59 (CJ, 131.09 (2χΟΗ„), 132.11 (CJ, 133.76 (2xCHar), 140.51 (CJ, 146.43 (2xCJ, 153.99 (CJ, 156.68 (CO)1 H NMR (200 Hz, DMSO) δ: 1.2 (12H, 4xCH 3 , d), 3.2 (2H, 2xCH, m), 3.5 (CH 3 ), 7.0 (2H, 2xCH ar , d), 7.1-7.3 (7H) 7xCH ar , m), 7.5 (2H, CH ar , d), 7.7 (1H, NH, br), 8.9 (1H, NH, br) 13 CNMR, δ: 23.61 (4xCH 3 ), 28.5 (2xCH ), 40.62 (CH 3 ), 116.27 (CH 2 , 118.64 (CH CH, 123.04 (CH 2 , 123.54 (CH, 126.99), 128.59 (CH, 131.09 (2 .09)), 132.11 (CH, 133.76 (2 CH ar )), 140.51 ( CJ, 146.43 (2xCJ, 153.99 (CJ, 156.68 (CO))

Výťažok 75 %, 1.1. = 208 - 210 °CYield 75%, m.p. Mp = 208-210 ° C

Príklad 9 l-(2,6-Diizopropylfenyl)-3-[4-(4-hydroxyfenylsulfanyl)fenyl]-močovina lg l-(2,6-Diizopropylfenyl)-3-[4-(4-metánsulfonyloxyfenylsulfanyl)fenyl]-močovina (0.5 g, 1.0 mmol) sa refluxuje spolu s NaOH (0.2 g, 5.0 mmol) v 80 ml 96 % etanolu okolo 2 hodín. Zmes sa okyslí 2 ml IM roztoku kyseliny chlorovodíkovej a vypadnutá zrazenina sa odsaje a prekryštalizuie z etylacetátu. Získame 0.38 g (90 %) s 1.1. = 218 - 220 °C 'HNMR (200 Hz, DMSO) δ: 1.2 (12H, 4xCH3, d), 3.2 (2H, 2xCH, m), 6.8 (2H, 2xCHar, d, 8.6 Hz), 7.1-7.3 (7H,7xCHar, m), 7.45 (2H, CH^, d, 8.6 Hz), 7.7 (1H, NH, br), 8.9 (1H, NH, br) 13CNMR, δ: 23,56 (4xCH3), 28.05 (2xCH), 116.49 (2xCHJ, 118.56 (CHJ, 122.94 (2xCHJ, 123.61 (CJ,Example 9 1- (2,6-Diisopropylphenyl) -3- [4- (4-hydroxyphenylsulfanyl) phenyl] urea 1g 1- (2,6-Diisopropylphenyl) -3- [4- (4-methanesulfonyloxyphenylsulfanyl) phenyl] - urea (0.5 g, 1.0 mmol) was refluxed together with NaOH (0.2 g, 5.0 mmol) in 80 mL of 96% ethanol for about 2 hours. The mixture was acidified with 2 ml of 1M hydrochloric acid solution and the precipitated precipitate was filtered off with suction and recrystallized from ethyl acetate. Obtain 0.38 g (90%) of m.p. = 218-220 ° C 1 HNMR (200 Hz, DMSO) δ: 1.2 (12H, 4xCH 3 , d), 3.2 (2H, 2xCH, m), 6.8 (2H, 2xCH ar , d, 8.6 Hz), 7.1- 7.3 (7H, 7xCH ar , m), 7.45 (2H, CH3, d, 8.6 Hz), 7.7 (1H, NH, br), 8.9 (1H, NH, br) 13 CNMR, δ: 23.56 (4xCH 3 ), 28.05 (2xCH), 116.49 (2xCHJ, 118.56 (CHJ, 122.94 (2xCHJ), 123.61 (CJ,

127.33 (CHJ, 128.51 (CJ, 130.96 (2xCHJ, 132.28 (CJ, 133.57 (2xCHJ, 139.51 (CJ, 146.68 (2xCJ, 154.22 (CJ, 157.36 (CO)127.33 (CHU, 128.51 (CJ, 130.96 (2x CHJ, 132.28 (CJ, 133.57 (2x CHJ, 139.51 (CJ, 146.68))

Príklad 10 l-(2,6-Diizopropylfenyl)-3-[4-(2-nitrofenylsulfanyl)fenyl]-močovina 2bExample 10 1- (2,6-Diisopropylphenyl) -3- [4- (2-nitrophenylsulfanyl) phenyl] urea 2b

Pripravila sa analogickým postupom ako v príklade 2 z 2,6-diizopropylanilínu a 4-(2-nitrofenylsulfanyl)fenylizokyanátu.Prepared in analogy to Example 2 from 2,6-diisopropylaniline and 4- (2-nitrophenylsulfanyl) phenyl isocyanate.

'HNMR (200 Hz, DMSO) 0:1.15 (12H, 4xCH3, d), 3.2 (2H, 2xCH, m), 7.1-7.3 (4H, 4xCHar, m), 7.4-7.6 (5H,5xCHar, m), 7.7 (1H, NH, br), 7.9 (1H, CHar, m), 8.3 (1H, CHar, d), 8.9 (1H, NH, br) 13CNMR, δ: 23,55 (4xCH3), 28.08 (2xCH), 118.73 (CHJ, 123.0 (2xCHJ, 125.35 (CJ, 126.41 (CHJ, 127.21 (CHJ, 127.51 (2xCHJ, 131.21 (2xCHJ, 132.12 (CJ, 135.21 (2xCHJ, 135.47 (CJ, 141.26 (CJ, 144.98 (CJ, 146.59 (2xCJ, 154.10 (CO)1 HNMR (200 Hz, DMSO) δ: 1.15 (12H, 4xCH 3 , d), 3.2 (2H, 2xCH, m), 7.1-7.3 (4H, 4xCH ar , m), 7.4-7.6 (5H, 5xCH ar , m), 7.7 (1 H, NH, br), 7.9 (1 H, CH ar , m), 8.3 (1 H, CH ar , d), 8.9 (1 H, NH, br) 13 CNMR, δ: 23.55 (4xCH 3 ), 28.08 (2xCH), 118.73 (CHJ, 123.0 (2xCHJ, 125.35 (CH, 126.41 (CHJ, 127.21 (CHJ, 127.51) (2xCHJ, 131.21 (2xCHJ, 132.12 (CH, 135.21 (2xCHJ, 135.47 (CH, 141.26 ( CJ, 144.98 (CJ, 146.59 (2xCJ, 154.10 (CO))

Výťažok 85 %, 1.1. = 218 - 220 °CYield 85%, m.p. Mp = 218-220 ° C

Príklad 11 l-(2,6-Diizopropylfenyl)-3-[4-(2-etoxykarbonyl-4-nitrofenylsulfanyl)fenyl]-močovina 2cExample 11 1- (2,6-Diisopropylphenyl) -3- [4- (2-ethoxycarbonyl-4-nitrophenylsulfanyl) phenyl] urea 2c

Pripravila sa analogickým postupom ako v príklade 1 z 2,6-diizopropylfenylizokyanátu a 4-(2-etoxykarbonyl-4-nitrofenylsulfanyl)fenylamínu.Prepared in analogy to Example 1 from 2,6-diisopropylphenylisocyanate and 4- (2-ethoxycarbonyl-4-nitrophenylsulfanyl) phenylamine.

‘HNMR (200 Hz, DMSO) 0:1.15 (12H, 4xCH3, d), 1,35 (3H, CH3, t), 3.2 (2H, 2xCH, m), 4.4 (2H, CH2, q), 7.05-7.3 (4H, 4xCHar, m), 7.4-7.6 (3^3x01^, m), 7.7 (1H, NH, br), 8.4-8.5 (2H, ŽxCH^, m), 8.6 (1H, CHar, ds), 8.9 (1H, NH, br) 13CNMR, δ: 14.04 (CH3), 23,52 (4xCH3), 28.09 (2xCH), 62.33 (CH2), 118.73 (2xCHJ, 122.99 (2xCHJ,1 HNMR (200 Hz, DMSO) δ: 1.15 (12H, 4xCH 3 , d), 1.35 (3H, CH 3 , t), 3.2 (2H, 2xCH, m), 4.4 (2H, CH 2 , q) , 7.05-7.3 (4H, 4xCH ar, m), 7.4-7.6 (3x01 ^ 3 ^, m), 7.7 (1H, NH, br), 8.4-8.5 (2H, ŽxCH ^, m), 8.6 (1H, CH ar, d), 8.9 (1H, NH, br) 13 C NMR, δ: 04.14 (CH3), 23.52 (4xCH 3), 28.09 (2 x CH), 62.33 (CH2), 118.73 (2xCHJ, 122.99 ( 2xCHJ.

125.33 (CJ, 125.84 (CHJ, 127.01 (CJ, 127.15 (CHJ, 127.38 (CHJ, 127.45 (CHJ, 131.51 (2xCHJ, 132.13 (CJ, 141.38 (CJ, 145.28 (CJ, 146.69 (2xCJ, 149.1 (CHJ, 154.11 (CO), 164.1 (CO)125.33 (CJ, 125.84 (CJ, 127.01) (CJ, 127.15 (CJ, 127.38 (CJ, 127.45 (CJ, 131.51 (2x CJ, 132.13) (CJ, 141.38 (CJ, 145.28 (CJ, 146.69 (CJ, 149.1) CO), 164.1 (CO)

Výťažok 73 %Yield 73%

Príklad 12 l-(2,6-Diizopropylfenyl)-3-[4-(2-karboxy-4-mtrofenylsulfanyl)fenyl]-močovina 2dExample 12 1- (2,6-Diisopropylphenyl) -3- [4- (2-carboxy-4-morphenylsulfanyl) phenyl] urea 2d

Pripravila sa analogickým postupom ako v príklade 7 z l-(2,6-diizopropylfenyl)-3-[4-(2-etoxykarbonyl-4-nitrofenylsulfanyl)fenyl]-močoviny. 'HNMR (200 Hz, DMSO) δ:1.2 (12H, 4xCH3, d), 3.2 (2H, 2xCH, m), 6.9 (1H, CHjr, d), 7.1-7.3 (3^3x0^, m), 7.5 (2H, 2xCHar, d), 7.65 (2H, 2xCHar, d), 7.8 (1H, NH, br), 8.2 (1H, CIIar, d), 8.6 (1H, CHar, s), 9.2 (1H, NH, br) 13CNMR, δ: 23,50 (4xCH3), 28.01 (2xCH), 119.2 (CHJ, 119.99 (CJ, 122.92 (2xCHJ, 125.5 (CHJ, 125.67 (CJ, 126.66 (2xCHJ, 127.08 (CHJ, 127.36 (CHJ, 132.01 (CJ, 136.58 (2xCHar), 142.61 (CJ, 143.72 (CJ, 166.58 (2xCJ, 152.97 (CJ, 153.94 (CO), 163.88 (CO)Prepared in analogy to Example 7 from 1- (2,6-diisopropylphenyl) -3- [4- (2-ethoxycarbonyl-4-nitrophenylsulfanyl) phenyl] urea. 1 H NMR (200 Hz, DMSO) δ: 1.2 (12H, 4xCH 3 , d), 3.2 (2H, 2xCH 3, m), 6.9 (1H, CH 3 ', d), 7.1-7.3 (3 × 3x0 ^, m), 7.5 (2H, 2 x CH ar, d), 7.65 (2H, 2 x CH ar, d), 7.8 (1H, NH, br), 8.2 (1 H, CII ar, d), 8.6 (1 H, CH ar, s), 9.2 (1H, NH, br) 13 CNMR, δ: 23.50 (4xCH 3 ), 28.01 (2xCH), 119.2 (CHJ, 119.99 (CJ, 122.92 (2xCHJ, 125.5 (CHJ, 125.67 (CJ, 126.66 (2xCHJ, 127.08))) (CHJ, 127.36 (CHJ, 132.01 (CJ, 136.58 (2xCH ar ))), 142.61 (CJ, 143.72 (CJ, 166.58 (2xCJ, 152.97 (CJ, 153.94 (CO)), 163.88 (CO))

Výťažok 89 %Yield 89%

Príklad 13 l-(2,6-Diizopropylfenyl)-3-[4-(2,4-dinitrofenylsulfanyl)fenyl]-močovina 2eExample 13 1- (2,6-Diisopropylphenyl) -3- [4- (2,4-dinitrophenylsulfanyl) phenyl] urea 2e

Pripravila sa analogickým postupom ako v príklade 1 z 2,6-diizopropylfenylizokyanátu a 4-(2,4-dinitrofenylsulfanyl)fenylamínu.Prepared in analogy to Example 1 from 2,6-diisopropylphenylisocyanate and 4- (2,4-dinitrophenylsulfanyl) phenylamine.

‘HNMR (200 Hz, DMSO) δ:1.15 (12H, 4xCH3, d), 3.2 (2H, 2xCH, m), 7.0-7,3 (4H,4xCHar, m), 7.5 (2H,2xCHar, d, 8.8 Hz), 7.7 (2H, 2xCHar, d, 8.8 Hz), 7.85 (1H, NH,br), 8.3 (1H, CHar, dd, 2 Hz), 8.85 (1H, CHar, ds, 2 Hz) 13CNMR, δ: 23,68 (4xCH3), 29.01 (2xCH), 118.73 (CJ, 119.34 (CHar), 121.24 (CHJ, 122.91 (2xCHar), 127.38 (CHar), 127.68 (CHar), 128.74 (CHar), 131.98 (Car), 136.63 (2x0^), 143.3 (C»), 143.54 (Car), 143.98 (Car), 146.58 (2xCar), 147.6 (Car), 147.43 (CHar), 153.92 (CO)1 H NMR (200 Hz, DMSO) δ: 1.15 (12H, 4xCH 3 , d), 3.2 (2H, 2xCH, m), 7.0-7.3 (4H, 4xCH ar , m), 7.5 (2H, 2xCH ar , d, 8.8 Hz), 7.7 (2H, 2xCH ar , d, 8.8 Hz), 7.85 (1H, NH, br), 8.3 (1H, CH ar , dd, 2 Hz), 8.85 (1H, CH ar , ds, 2 Hz) 13 CNMR, δ: 23.68 (4xCH 3 ), 29.01 (2xCH), 118.73 (CHJ), 121.24 (CHJ), 122.91 (2xCH ar ), 127.38 (CHar), 127.68 (CHar), 128.74 (C ar ), 131.98 (C ar ), 136.63 (2x0 ^), 143.3 (C »), 143.54 (Car), 143.98 (Car), 146.58 (2xC ar ), 147.6 (C ar ), 147.43 (CHar) , 153.93 (CO)

Výťažok 68 %, 1.1. = 243 - 245 °CYield 68%, m.p. Mp = 243-245 ° C

Príklad 14 l-(2,6-Diizopropylfenyl)-3-[4-(3-metoxykarbonyl-4-nitrofenylsulfanyl)fenyl]-močovina 2fExample 14 1- (2,6-Diisopropylphenyl) -3- [4- (3-methoxycarbonyl-4-nitrophenylsulfanyl) phenyl] urea 2f

Pripravila sa analogickým postupom ako v príklade 3 z 2,6-diizopropylfenylizokyanátu a 4-(3-metoxykarbonyl-4-nitrofenylsulfanyl)fenylamínu.Prepared in analogy to Example 3 from 2,6-diisopropylphenylisocyanate and 4- (3-methoxycarbonyl-4-nitrophenylsulfanyl) phenylamine.

’HNMR (200 Hz, DMSO) δ:1.15 (12H, 4xCH3, d), 3.14 (2H, 2xCH, m), 3.6 (3H, CH3O, s), 7.1-7.5 (7H, 7xCHar, m), 7.85(2H,2xCHar, d), 8.35 (1H, lxCHar, d), 9.2 (NH, br) 13CNMR, δ: 23.48 (4xCH3), 27.98 (2xCH), 33.64 (CH3O), 116.08 (CHar), 118.29 (CH^), 121.11 (CHar), 121.6 (Car), 122.84 (2xCHar), 126.48 (CHar), 127.22 (CHar), 127.42 (Car), 131.26 (2x01^), 132.22 (C^), 133.96 (CHar), 141.03 (2xCar), 142.3 (Car), 146.59 (2χΟ„), 154.1 (2xCO)1 HNMR (200 Hz, DMSO) δ: 1.15 (12H, 4xCH 3 , d), 3.14 (2H, 2xCH, m), 3.6 (3H, CH 3 O, s), 7.1-7.5 (7H, 7xCH ar , m) ), 7.85 (2H, 2xCH ar , d), 8.35 (1H, 1xCH ar , d), 9.2 (NH, br) 13 CNMR, δ: 23.48 (4xCH 3 ), 27.98 (2xCH), 33.64 (CH 3 O) , 116.08 (CH ar), 118.29 (CH), 121.11 (CH ar), 121.6 (Car), 122.84 (2 x CH ar), 126.48 (CH ar), 127.22 (CH ar), 127.42 (C ar), 131.26 (2x01 ^) , 132.22 (C ^), 133.96 (CHCl), 141.03 (2xCar), 142.3 (Car), 146.59 (2χ²), 154.1 (2xCO)

Výťažok 46 %, 1.1. = 238-240 °CYield 46%, m.p. MP 238-240 ° C

Príklad 15 l-(2,6-Diizopropylfenyl)-3-[4-(3-karbamoyl-4-nitrofenylsulfanyl)fenyl]-močovina 2hExample 15 1- (2,6-Diisopropylphenyl) -3- [4- (3-carbamoyl-4-nitrophenylsulfanyl) phenyl] urea 2h

Pripravila sa analogickým postupom ako v príklade 1 z 2,6-diizopropylfenylizokyanátu a 4-(3-karbamoyl-4-nitrofenylsulfanyl)fenylamínu.Prepared in analogy to Example 1 from 2,6-diisopropylphenylisocyanate and 4- (3-carbamoyl-4-nitrophenylsulfanyl) phenylamine.

’HNMR (200 Hz, CDC13) 0:1.15 (12H, 4xCH3, d), 3.2 (2H, 2xCH, m), 7.25 (1H, CHar, s), 7.3-7.6 (4H,4xCHar, m), 7.7 (2H, 2xCHar, d, 8.6 Hz), 8.1 (2H, 2xCHar, d, 8.6 Hz), 8.25 (1H, CHar) ’3CNMR, δ: 22.43 (2xCH3), 23,68 (2xCH3), 29.01 (2xCH), 119.1 (2χΟΗ„), 119.33 (Car), 122.93 (2xCHar), 124.69 (CHar), 125.1 (CHar), 126.07 (CH»), 127.37 (CHar), 132.04 (Car), 133.94 (C^), 136.16 (2xCHar),1 HNMR (200 Hz, CDCl 3 ) δ: 1.15 (12H, 4xCH 3 , d), 3.2 (2H, 2xCH, m), 7.25 (1H, CH ar , s), 7.3-7.6 (4H, 4xCH ar , m) ), 7.7 (2H, 2xCH ar , d, 8.6 Hz), 8.1 (2H, 2xCH ar , d, 8.6 Hz), 8.25 (1H, CH ar ) ' 3 CNMR, δ: 22.43 (2xCH 3 ), 23,68 (2xCH 3 ), 29.01 (2xCH), 119.1 (2 CH 2), 119.33 (CH 3), 122.93 (2 CH 3), 124.69 (CH 3), 126.1 (CH 3), 126.07 (CH 3), ar ), 133.94 (C ^), 136.16 (2xCH ar ),

142.41 (Car), 143.35 (Car), 146.6 (2XCJ, 147.43 (CHar), 153.9 (CONH2), 166.91 (CO)142.41 (Car), 143.35 (C ar), 146.6 (2XCJ, 147.43 (CH ar), 153.9 (CONH 2), 166.91 (CO)

Výťažok 43 %, 1.1. = 237 - 240 °CYield 43%, m.p. Mp = 237-240 ° C

Príklad 16 l-(2,6-Diizopropylfenyl)-3-[4-(2-karbamoyl-4-nitrofenylsulfanyl)fenyl]-močovina 2iExample 16 1- (2,6-Diisopropylphenyl) -3- [4- (2-carbamoyl-4-nitrophenylsulfanyl) phenyl] urea 2i

Pripravila sa analogickým postupom ako v príklade 3 z 2,6-diizopropylfenylizokyanátu a 4-(2-karbamoyl-4-nitrofenylsulfanyl)fenylamínu.Prepared in analogy to Example 3 from 2,6-diisopropylphenylisocyanate and 4- (2-carbamoyl-4-nitrophenylsulfanyl) phenylamine.

’HNMR (200 Hz, DMSO) δ: 1.15 (12H, 4xCH3, d), 3.2 (2H, 2xCH, m), 6.89 (1H, CHar, d, 8.8 Hz), 7.15-7.4 (3H,3xCHar, m), 7.45 (2H, 2xCHar, d), 7.64 (2H, 2xCHar, d, 8.8 Hz), 7.76 (2H, CONH2, br), 8.1 (1H, CH^, 2.4 Hz), 8.3 (1H, NH, br), 8.35 (1H, ds, 2.4 Hz), 9.15 (1H, NH, br) 13CNMR, δ: 23.34 (2xCH3), 23,55 (2xCH3), 28.02 (2xCH), 119.14 (2xCHar), 121.15 (Car), 122.71 (2xCHar), 122.93 (2xCHar), 124.78 (CHar), 126.88 (CHar), 127.32 (CHar), 132.06 (Car), 132.73 (Car), 136.4 (2x0^),1 HNMR (200 Hz, DMSO) δ: 1.15 (12H, 4xCH 3 , d), 3.2 (2H, 2xCH, m), 6.89 (1H, CH ar , d, 8.8 Hz), 7.15-7.4 (3H, 3xCHar, m), 7:45 (2H, 2xCHar, d), 7.64 (2H, 2 x CH ar, d, 8.8 Hz), 7.76 (2 H, CONH 2, br), 8.1 (1 H, CH, 2.4 Hz), 8.3 (1H, NH, br), 8.35 (1 H, ds, 2.4 Hz), 9.15 (1 H, NH, br) 13 CNMR, δ: 23.34 ( 2 × CH 3 ), 23.55 ( 2 × CH 3 ), 28.02 (2 × CH), 119.14 (2 × CHar) ), 121.15 (Car), 122.71 (2 x CH ar), 122.93 (2xCHar), 124.78 (CH ar), 126.88 (CH ar), 127.32 (CH ar), 132.06 (C ar), 132.73 (Car), 136.4 (2x0 ^),

142.27 (Car), 143.64 (Car), 146.6 (2x0^), 150.03 (CHar), 154 (CONH2), 167.31 (CO)142.27 (C ar), 143.64 (Car), 146.6 (2x0 ^), 150.03 (CH ar), 154 (CONH2), 167.31 (CO)

Výťažok 39 %, 1.1. = 198 - 200 °CYield 39%, m.p. Mp = 198-200 ° C

Príklad 17 l-(2, 6-Diizopropylfenyl)-3-[4-(pyridín-2-ylsulfanyl)fenyl]-močovina 3aExample 17 1- (2,6-Diisopropylphenyl) -3- [4- (pyridin-2-ylsulfanyl) phenyl] urea 3a

Pripravila sa analogickým postupom ako v príklade 1 z 2,6-diizopropylfenylizokyanátu a 4-(pyridin-2-ylsulfanyl)fenylamínu.Prepared in analogy to Example 1 from 2,6-diisopropylphenylisocyanate and 4- (pyridin-2-ylsulfanyl) phenylamine.

’HNMR (200 Hz, DMSO) δ:1.2 (12H, 4xCH3, d), 3.2 (2H, 2xCH, m), 6.8 (1H, CHar, d), 7.05-7.3 (4H, 4xCHar, m), 7.5 (2H,2xCHar, d), 7.6 (3H, 3xCHar, m), 7.7 (1H, NH, br),8.3 (1H, CHar, ds), 9.1 (1H, NH, br), i3CNMR, δ: 23.44 (2xCH3), 23.48 (2xCH3), 27.99 (2xCH), 118.78 (CHar), 119.81 (CHar), 119.96 (CHar),1 HNMR (200 Hz, DMSO) δ: 1.2 (12H, 4xCH 3 , d), 3.2 (2H, 2xCH, m), 6.8 (1H, CH 2 d), 7.05-7.3 (4H, 4x CH 3, m), 7.5 (2H, 2xCH ar , d), 7.6 (3H, 3xCH ar , m), 7.7 (1H, NH, br), 8.3 (1H, NH, br), 9.1 (1H, NH, br), 13 CNMR, δ : 23.44 (2 x CH 3), 23:48 (2 x CH 3), 27.99 (2 x CH), 118.78 (CH ar), 119.81 (CH ar), 119.96 (CH ar);

120.41 (C^, 122.88 (2xCHar), 127.30 (Car), 132.07 (Car), 136.27 (2x0^), 137.16 (CHar), 141.82 (CJ, 146.58 (2xCHar), 149.27 (CHar), 153.99 (2xCar), 161.48 (CO)120.41 (C ^, 122.88 (2 x CH ar), 127.30 (C ar), 132.07 (Car), 136.27 (2x0 ^), 137.16 (CH ar), 141.82 (CU, 146.58 (2 x CH ar), 149.27 (CH ar), 153.99 (2xC ar ), 161.47 (CO)

Výťažok 57 %, 1.1. = 217 - 220 °CYield 57%, m.p. Mp = 217-220 ° C

Príklad 18 l-(2,6-Diizopropylfenyl)-3-[4-(pyridin-3-ylsulfanyl)fenyl]-močovina 3bExample 18 1- (2,6-Diisopropylphenyl) -3- [4- (pyridin-3-ylsulfanyl) phenyl] urea 3b

Pripravila sa analogickým postupom ako v príklade 2 z 2,6-diizopropylanilínu a 4-(pyridin-3-ylsulfanyl)fenylizokyanátu.Prepared in analogy to Example 2 from 2,6-diisopropylaniline and 4- (pyridin-3-ylsulfanyl) phenyl isocyanate.

'HNMR (200 Hz, DMSO) ô:1.2 (12H, 4xCH3, d), 3.2 (2H, 2xCH, m), 7.1-7.3 (5H, 5x0^, m), 7.4 (2H,2xCHar, d), 7.5 (3H, 3xCHar, m), 7.75 (1H, NH, br),8.4 (1H, CHar, ds), 9.0 (1H, NH, br), 13CNMR, δ: 23.37 (2xCH3), 23.48 (2xCH3), 27.97 (2xCH), 118.83 (CHa,), 122.29 (CJ, 122.86 (2x01,,),1 HNMR (200 Hz, DMSO) δ: 1.2 (12H, 4xCH 3 , d), 3.2 (2H, 2xCH, m), 7.1-7.3 (5H, 5xO 4, m), 7.4 (2H, 2xCH ar , d) , 7.5 (3H, 3xCH ar, m), 7.75 (1 H, NH, br), 8.4 (1 H, CH ar, d), 9.0 (1H, NH, br), 13 C NMR, δ: 23.37 (2 x CH 3), 23:48 (2 x CH 3), 27.97 (2 x CH), 118.83 (CH,), 122.29 (CJ 122.86 (2x01 ,,).

124.18 (2xCHa,), 127.29 (Ca,), 132.08 (Car), 134.53 (CHa,), 134.97 (Ca,), 135.53 (CHar), 141.31 (CJ, 146.57 (2xCHa,), 147.01 (CH^), 148.31 (CHJ, 153.98 (2xCar)124.18 (2 x CH,), 127.29 (Ca), 132.08 (C ar), 134.53 (CH,), 134.97 (Ca), 135.53 (CH ar), 141.31 (CU, 146.57 (2 x CH,), 147.01 (CH) , 148.31 (CHJ, 153.97 (2xCar)

Výťažok 29 %, 1.1. = 226 - 228 °CYield 29%, 1.1. Melting point = 226-228 ° C

Príklad 19 l-(2,6-Diizopropylfenyl)-3-[4-(pyridin-4-ylsulfanyl)fenyl]-močovina 3cExample 19 1- (2,6-Diisopropylphenyl) -3- [4- (pyridin-4-ylsulfanyl) phenyl] urea 3c

Pripravila sa analogickým postupom ako v príklade 1 z 2,6-diizopropylfenylizokyanátu a 4-(pyridin-4-ylsulfanyl)fenylamínu.Prepared in analogy to Example 1 from 2,6-diisopropylphenylisocyanate and 4- (pyridin-4-ylsulfanyl) phenylamine.

'HNMR (200 Hz, DMSO) δ: 1.2 (12H, 4xCH3, d), 3.2 (2H, 2xCH, m), 6.9 (2H, CHar, d, 4.2 Hz), 7.1-7.3 (3H, 3xCHar, m), 7.5 (2H,2xCHar, d, 8.8 Hz), 7.6 (2H, 2xCHar, d, 8.8 Hz), 7.8 (1H, NH, br),8.3 (2H, 2xCHar, d, 4.2 Hz), 9.2 (1H, NH, br), 13CNMR, δ: 23.54 (2xCH3), 23.67 (2xCH3), 27.42 (2xCH), 120.78 (2xCHar), 123.87 (2xCHar), 123.56 (CH»), 126.16 (2xCHar), 128.1 (C^), 129.4 (2xCHar) 133.80 (Car), 135.26 (Car), 139.27 (Car), 141.16 (CHJ, 148.21 (2XCHJ, 152.76 (2xCar), 158.63 (CO)1 HNMR (200 Hz, DMSO) δ: 1.2 (12H, 4xCH 3 , d), 3.2 (2H, 2xCH, m), 6.9 (2H, CH ar , d, 4.2 Hz), 7.1-7.3 (3H, 3xCH ar) m), 7.5 (2H, 2xCH ar , d, 8.8 Hz), 7.6 (2H, 2xCH ar , d, 8.8 Hz), 7.8 (1H, NH, br), 8.3 (2H, 2xCH ar , d, 4.2 Hz) ), 9.2 (1H, NH, br), 13 CNMR, δ: 23.54 (2xCH 3 ), 23.67 (2xCH 3 ), 27.42 (2xCH 3), 120.78 (2xCH ar ), 123.87 (2xCH ar ), 123.56 (CH ») , 126.16 (2xCH ar ), 128.1 (C ^), 129.4 (2xCH ar ), 133.80 (C ar ), 135.26 (C ar ), 139.27 (CJ), 141.16 (CHJ), 148.21 (2XCHJ, 152.76 (2xCar)), 158.63 ( WHAT)

Výťažok 48 %, 1.1. = 231 - 233 °CYield 48%, m.p. Mp = 231-233 ° C

Príklad 20 l-(2,6-Diizopropylfenyl)-3-[4-(5-nitropyridin-2-ylsulfanyl)fenyl]-močovina 3dExample 20 1- (2,6-Diisopropylphenyl) -3- [4- (5-nitropyridin-2-ylsulfanyl) phenyl] urea 3d

Pripravila sa analogickým postupom ako v príklade 1 z 2,6-diizopropylfenylizokyanátu a 4-(5-nitropyridin-2-ylsulfanyl)fenylaminu.Prepared in analogy to Example 1 from 2,6-diisopropylphenylisocyanate and 4- (5-nitropyridin-2-ylsulfanyl) phenylamine.

'HNMR (200 Hz, CDC13) δ: 1.2 (12H, 4xCH3, d), 3.3 (2H, 2xCH, m), 6.2 (1H, NH, br), 6.5 (1H, NH, br), 6.9 (1H, CHar, d), 7.1-7.6 (7H,7xCHar, m), 8.15 (1H, CHan dd), 9.2 (1H, CHar, ds) 13CNMR, δ: 23.84 (2xCH3), 24.21 (2xCH3), 28.54 (2xCH), 119.56 (CHar), 120.55 (2XCHJ, 124.5 (CH,,), 129.67 (2χΟΗ„), 131.16 (CHar), 136.52 (2x01,,), 140.86 (CJ, 141.02 (C,,), 145.04 (CH,,), 147.92 (2χΟ„), 154.64 (2XCJ, 170.95 (CO)1 HNMR (200 Hz, CDCl 3 ) δ: 1.2 (12H, 4xCH 3 , d), 3.3 (2H, 2xCH, m), 6.2 (1H, NH, br), 6.5 (1H, NH, br), 6.9 ( 1H, CH ar , d), 7.1-7.6 (7H, 7xCHar, m), 8.15 (1H, CH and dd), 9.2 (1H, CH ar , ds) 13 CNMR, δ: 23.84 (2xCH 3 ), 24.21 ( 2xCH 3 ), 28.54 (2xCH), 119.56 (CHar), 120.55 (2XCHJ, 124.5 (CH ,,), 129.67 (2χΟΗ), 131.16 (CH ar ), 136.52 (2x01 ,,), 140.86 (CJ, 141.02 ( C,), 145.04 (CH), 147.92 (2χΟ), 154.64 (2XCJ, 170.95 (CO))

Výťažok 75 %, 1.1. = 219 - 220 °CYield 75%, m.p. Mp = 219-220 ° C

Príklad 21 l-(2,6-Diizopropylfenyl)-3-[4-(3-nitropyridin-2-ylsulfanyl)fenyl]-močovina 3eExample 21 1- (2,6-Diisopropylphenyl) -3- [4- (3-nitropyridin-2-ylsulfanyl) phenyl] urea 3e

Pripravila sa analogickým postupom ako v príklade 1 z 2,6-diizopropylfenylizokyanátu a 4-(3-nitropyridin-2-ylsulfanyl)fenylamínu.Prepared in analogy to Example 1 from 2,6-diisopropylphenylisocyanate and 4- (3-nitropyridin-2-ylsulfanyl) phenylamine.

'HNMR (200 Hz, DMSO) δ:1.15 (12H, 4xCH3, d), 3.2 (2H, 2xCH, m), 7.1-7.3 (3H, 3xCHar, m), 7.3-7.4 (3H,3xCHar, m), 7.52 (2H, 2xCHar, d), 7.8 (1H, NH, br), 8.6 (2H, 2x0^, d), 9.1 (1H, NH, br) 13CNMR, δ: 23.54 (4xCH3), 28.07 (2xCH), 118.43 (CHa,), 119.85 (C,,), 120.59 (2x01,,), 122.96 (2χΟΗ„), 127.39 (CH,,), 132.16 (Car), 134.27 (CHJ, 136.73 (2xCHa,), 141.3 (CJ, 141.9 (C,,), 146.66 (2xCar), 153.81 (CHar), 154.12 (Car), 156.97 (CO)H NMR (200 MHz, DMSO) δ 1.15 (12 H, 4xCH 3, d), 3.2 (2H, 2 x CH, m), 7.1-7.3 (3H, 3xCH ar, m), 7.3-7.4 (3H, 3xCH ar, m), 7:52 (2H, 2 x CH ar, d), 7.8 (1H, NH, br), 8.6 (2H, 2x0 ^, d), 9.1 (1H, NH, br) 13 C NMR, δ: 23.54 (4xCH 3) 28.07 (2xCH), 118.43 (CH3), 119.85 (C ,,), 120.59 (2x01 ,,), 122.96 (2 ΟΗ), 127.39 (CH ,,), 132.16 (C ar ), 134.27 (CHJ, 136.73) (2xCH 2,), 141.3 (CJ), 141.9 (C ,,), 146.66 (2x C ar ), 153.81 (CHar), 154.12 (Car), 156.97 (CO)

Výťažok 49 %, 1.1. = 236 - 238 °CYield 49%, m.p. Mp = 236-238 ° C

Príklad 22 l-(2,6-Diizopropylfenyl)-3-[4-(5-chlórpyridin-2-ylsulfanyl)fenyl]-močovina3gExample 22 1- (2,6-Diisopropylphenyl) -3- [4- (5-chloropyridin-2-ylsulfanyl) phenyl] urea3g

Pripravila sa analogickým postupom ako v príklade 1 z 2,6-diizopropylfenylizokyanátu a 4-(5-chlórpyridin-2-ylsulfanyl)fenylamínu.Prepared in analogy to Example 1 from 2,6-diisopropylphenylisocyanate and 4- (5-chloropyridin-2-ylsulfanyl) phenylamine.

'HNMR (200 Hz, DMSO) δ: 1.2 (12H, 4xCH3, d), 3.2 (2H, 2xCH, m), 6.8 (ΙΗ,ΟΗ,τ, d), 7.1-7.3 (2H, 2χΟΪ„, m), 7.5 (2H, CHa,, d, 8.8 Hz), 7.57 (2H, CHa„ d, 8.8 Hz), 7.65 (3H, NH, 2x01,,, m), 8.4 (1H, CHar, ds), 9.1 (ΙΗ,ΝΗ, br) 13CNMR, δ: 23.61 (4xCH3), 28.16 (2xCH), 119.05 (CHa,), 120.17 (Ca,), 121.51 (CHa,), 123.07 (2x0^), 127.38 (Ca,), 127.54 (CHa,), 132.15 (Ca,), 136.42 (2xCHar), 137.1 (2xCHar), 142.16 (C»), 146.76 (2χΟ„),1 HNMR (200 Hz, DMSO) δ: 1.2 (12H, 4xCH 3 , d), 3.2 (2H, 2xCH, m), 6.8 (ΙΗ, ΟΗ, τ, d), 7.1-7.3 (2H, 2χ ΟΪ, m) 7.57 (2H, CH a, d, 8.8 Hz), 7.57 (2H, CH a , d, 8.8 Hz), 7.65 (3H, NH, 2x01, m), 8.4 (1H, CH ar , ds) , 9.1 (ΙΗ, ΝΗ, br) 13 C NMR, δ: 23.61 (4xCH 3), 28.16 (2 x CH), 119.05 (CH,), 120.17 (Ca), 121.51 (CH,), 123.07 (2x0 ^), 127.38 (Ca,), 127.54 (CHa,), 132.15 (Ca,), 136.42 (2xCH ar ), 137.1 (2xCH ar ), 142.16 (C »), 146.76 (2χΟ),

147.8 (CHa,), 154.17 (Ca,), 160.27 (CO)147.8 (CH3), 154.17 (Ca), 160.27 (CO)

Výťažok 56 %, 1.1. = 235 - 237 °CYield 56%, m.p. Mp = 235-237 ° C

Príklad 23 l-(2,6-Diizopropylfenyl)-3-[4-(pyrazin-2-ylsulfanyl)fenyl]-močovina 3hExample 23 1- (2,6-Diisopropylphenyl) -3- [4- (pyrazin-2-ylsulfanyl) phenyl] urea 3h

Pripravila sa analogickým postupom ako v príklade 1 z 2,6-diizopropylfenylizokyanátu a 4-(pyrazin-2-ylsulfanyl)fenylamínu.Prepared in analogy to Example 1 from 2,6-diisopropylphenylisocyanate and 4- (pyrazin-2-ylsulfanyl) phenylamine.

‘HNMR (200 Hz, DMSO) δ: 1.2 (12H, 4xCH3, d), 3.2 (2H, 2xCH, m), 7.0-7.3 (5H,5xCHar, m), 7.4-7.6 (5H, 4xCHar, m), 7.7 (1H, NH, br), 9.0 (1H, NH, br) 13CNMR, δ: 23.32 (4xCH3), 28.26 (2xCH), 118.33 (Car), 119.09 (CHar), 122.77 (2xCHar), 123.08 (2χΟΗ„), 126.64 (CH^, 127.76 (CHJ, 129.01 (CHJ, 131.5 (CHar), 133.64 (CJ, 136.39 (CHar), 142.19 (Car), 146.33 (2xCar), 154.02 (Car), 160.2 (CO) Výťažok 45 %, 1.1. = 235 - 238 °C1 HNMR (200 Hz, DMSO) δ: 1.2 (12H, 4xCH 3 , d), 3.2 (2H, 2xCH, m), 7.0-7.3 (5H, 5xCH ar , m), 7.4-7.6 (5H, 4xCH ar , m), 7.7 (1 H, NH, br), 9.0 (1 H, NH, br) 13 CNMR, δ: 23.32 (4xCH 3 ), 28.26 (2xCH), 118.33 (C ar ), 119.09 (CH ar ), 122.77 ( 2 x CH ar), 123.08 (2χΟΗ '), 126.64 (CH, 127.76 (CH, 129.01 (CH, 131.5 (CH ar), 133.64 (CU, 136.39 (CH ar), 142.19 (C ar), 146.33 (2xCar), 154.02 (Car), 160.2 (CO) Yield 45%, mp = 235-238 ° C

Príklad 24 l-(2,6-Diizopropylfenyl)-3-[4-(pyrimidin-4-ylsulfanyl)fenyl]-močovina 3iExample 24 1- (2,6-Diisopropylphenyl) -3- [4- (pyrimidin-4-ylsulfanyl) phenyl] urea 3i

Pripravila sa analogickým postupom ako v príklade 1 z 2,6-diizopropylfenylizokyanátu a 4-(pyrimidin-4-ylsulfanyl)fenylamínu.Prepared in analogy to Example 1 from 2,6-diisopropylphenylisocyanate and 4- (pyrimidin-4-ylsulfanyl) phenylamine.

*HNMR (200 Hz, DMSO) ó: 1.2 (12H, 4xCH3, d), 3.2 (2H, 2xCH, m), 7.1-7.3 (3H,3xCHar, m), 7.4-7.65 (4H, 4xCHar, m), 7.7 (1H, NH, br), 8.1 (1H, CHar, s), 8.3 (1H, CHar, d), 8.4 (1H, CHar, d), 9.1 (1H, NH, br) 13CNMR, ô: 23.66 (4xCH3), 28.2 (2xCH), 118.91 (Car), 118.92 (2xCHar), 123.19 (2xCHar), 127.61 (CHar),HNMR (200 MHz, DMSO) delta 1.2 (12 H, 4xCH 3, d), 3.2 (2H, 2 x CH, m), 7.1-7.3 (3H, 3xCH ar, m), 7.4-7.65 (4H, 4xCH ar, m), 7.7 (1H, NH, br), 8.1 (1 H, CH ar, s), 8.3 (1 H, CH ar, d), 8.4 (1 H, CH ar, d), 9.1 (1H, NH, br) 13 C NMR, delta: 23.66 (4xCH 3), 28.2 (2 x CH), 118.91 (C ar), 118.92 (2 x CH ar), 123.19 (2xCHar), 127.61 (CH ar);

132.18 (CHar), 136.38 (2xCHar), 140.56 (CHar), 141.36 (CHar), 140.23 (C^), 144.25 (CHar), 146.81 (2xCar), 154.23 (0^), 158.39 (CO)132.18 (CHar), 136.38 (2CH ar ), 140.56 (CHar), 141.36 (CHar), 140.23 (CH 2), 144.25 (CH 2), 146.81 (2 C ar ), 154.23 (0 ^), 158.39 (CO)

Výťažok 63 %, 1.1. = 195 - 198 °CYield 63%, m.p. Mp = 195-198 ° C

Príklad 25 l-[4-(6-Chlórpyrazin-3-ylsulfanyl)fenyl]-3-(2,6-diizopropylfenyl)-močovina 3jExample 25 1- [4- (6-Chloro-pyrazin-3-ylsulfanyl) -phenyl] -3- (2,6-diisopropyl-phenyl) -urea 3j

Pripravila sa analogickým postupom ako v príklade 1 z 2,6-diizopropylfenylizokyanátu a 4-(6-chlórpyrazin-3 -ylsulfanyl)fenylamínu.Prepared in analogy to Example 1 from 2,6-diisopropylphenylisocyanate and 4- (6-chloropyrazin-3-ylsulfanyl) phenylamine.

‘HNMR (200 Hz, DMSO) δ: 1.2 (12H, 4xCH3, d), 3.2 (2H, 2xCH, m), 7.0-7.3 (5H,5xCHar, m), 7.4-7.7 (4H, 4xCHar, m), 7.8 (1H, NH, br), 9.0 (1H, NH, br) l3CNMR, δ: 23.66 (4xCH3), 28.2 (2xCH), 118.13 (Car), 118.98 (CHar), 122.72 (2xCHar), 122.91 (2xCHar), 126.83 (CH»), 127.35 (CHar), 129.09 (CHar), 132.05 (Car), 133.02 (C^), 136.39 (CHar), 142.51 (Car), 146.61 (2xCar), 153.98 (Car), 165.5 (CO)1 HNMR (200 Hz, DMSO) δ: 1.2 (12H, 4xCH 3 , d), 3.2 (2H, 2xCH, m), 7.0-7.3 (5H, 5xCHar, m), 7.4-7.7 (4H, 4xCHar, m) 7.8 (1H, NH, br), 9.0 (1H, NH, br), 13 CNMR, δ: 23.66 (4xCH 3 ), 28.2 (2xCH), 118.13 (Car), 118.98 (CHar), 122.72 (2xCHar), 122.91 (2 x CH ar), 126.83 (CH '), 127.35 (CH ar), 129.09 (CH ar), 132.05 (Car), 133.02 (C ^), 136.39 (CH ar), 142.51 (C ar), 146.61 (2xCar), 153.98 (C ar), 165.5 (CO)

Výťažok 45 %, 1.1. = 216 - 218 °CYield 45%, m.p. Mp = 216-218 ° C

Príklad 26 l-(2,6-Diizopropylfenyl)-3-[4-(4,6-dimetoxy-[l,3,5]triazin-2-ylsulfanyl)fenyl]-močovina 3kExample 26 1- (2,6-Diisopropylphenyl) -3- [4- (4,6-dimethoxy- [1,3,5] triazin-2-ylsulfanyl) phenyl] urea 3k

Pripravila sa analogickým postupom ako v príklade 1 z 2,6-diizopropylfenylizokyanátu a 4-(4,6-dimetoxy-[ 1,3,5]triazin-2-ylsulfanyl)fenylamínu.Prepared in analogy to Example 1 from 2,6-diisopropylphenylisocyanate and 4- (4,6-dimethoxy- [1,3,5] triazin-2-ylsulfanyl) phenylamine.

‘HNMR (200 Hz, DMSO) Ô:1.2 (12H, 4xCH3, d), 3.2 (2H, 2xCH, m), 3.5 (6H, 2xCH3O, s), 7.1-7.3 (5H,5xCHar, m), 7.4 (2H, 2xCHar, d), 7.7 (1H, NH, br), 8.75 (1H, NH, br) 13CNMR, δ: 23.66 (4xCH3), 28.2 (2xCH), 56.83 (2xCH3O), 118.59 (2x0^), 122.86 (2χΟΗ„), 127.22 (CH^), 128.02 (2xCHar), 129.2 (C^), 132.3 (C^), 138.2 (Car), 146.6 (2xCar), 154.98 (CO), 176.5 (Car), 181.43 (Car)1 HNMR (200 Hz, DMSO) Ô: 1.2 (12H, 4xCH 3 , d), 3.2 (2H, 2xCH 3 m), 3.5 (6H, 2xCH 3 O, s), 7.1-7.3 (5H, 5xCH ar , m) ), 7.4 (2H, 2xCH ar , d), 7.75 (1H, NH, br), 8.75 (1H, NH, br) 13 CNMR, δ: 23.66 (4xCH 3 ), 28.2 (2xCH 3), 56.83 (2xCH 3 O) ), 118.59 (2x0 ^), 122.86 (2χ²), 127.22 (CH ^), 128.02 (2xCH ar ), 129.2 (C ^), 132.3 (C ^), 138.2 (Car ^), 146.6 (2xC ar ), 154.98 (CO), 176.5 (Car)

Výťažok 57 %Yield 57%

Príklad 27 l-(2,6-Diizopropylfenyl)-3-[4-(chinolin-2-ylsulfanyl)fenyl]-močovina 31Example 27 1- (2,6-Diisopropylphenyl) -3- [4- (quinolin-2-ylsulfanyl) phenyl] urea 31

Pripravila sa analogickým postupom ako v príklade 1 z 2,6-diizopropylfenylizokyanátu a 4-(chinolin-2-ylsulfanyl)fenylamínu.Prepared in analogy to Example 1 from 2,6-diisopropylphenylisocyanate and 4- (quinolin-2-ylsulfanyl) phenylamine.

'HNMR (200 Hz, DMSO) δ:1.17 (12H, 4xCH3, d), 3.2 (2H, 2xCH, m), 7.1-7.3 (3H,3xCHar, m), 7.5-8.1 (8H, 8xCHar, m), 8.5 (1H, CH„, s), 9.0 (2H, 2xNH, br) 13CNMR, ô: 23.51 (4xCH3), 28.03 (2xCH), 118.54 (CHar), 118.79 (2x0^), 120.15 (CJ, 122.91 (2χΟΗ„),1 HNMR (200 Hz, DMSO) δ: 1.17 (12H, 4xCH 3 , d), 3.2 (2H, 2xCH, m), 7.1-7.3 (3H, 3xCH ar , m), 7.5-8.1 (8H, 8xCH ar , m), 8.5 (1H, CH 2, s), 9.0 (2H, 2x NH, br) 13 CNMR, δ: 23.51 (4xCH 3 ), 28.03 (2xCH), 118.54 (CH ar ), 118.79 (2x0 ^), 120.15 (CJ, 122.91 (2χΟΗ "),

125.42 (Car), 125.66 (CHar), 127.34 (CHJ, 127.47 (CHj, 127.96 (CHJ, 130.22 (CHar), 132.1 (CJ, 136.32 (2xCHar), 136.82 (CHJ, 141.99 (CJ, 146.62 (2x0^), 147.38 (CJ, 154.03 (OJ, 161.73 (CO)125.42 (Car), 125.66 (CH ar), 127.34 (CH, 127.47 (CH, 127.96 (CH, 130.22 (CH ar), 132.1 (CJ 136.32 (2 x CH ar), 136.82 (CH, 141.99 (CJ 146.62 (2x0 ^ ), 147.38 (CJ, 154.03 (OJ, 161.73 (CO))

Výťažok 74 %Yield 74%

Príklad 28 l-(2,6-Diizopropylfenyl)-3-[4-(chinoxalin-2-ylsulfanyl)fenyl]-močovina 3mExample 28 1- (2,6-Diisopropylphenyl) -3- [4- (quinoxalin-2-ylsulfanyl) phenyl] urea 3m

Pripravila sa analogickým postupom ako v príklade 1 z 2,6-diizopropylfenylizokyanátu a 4-(chinoxalin-2-y lsulfany 1) fény lamí nu.Prepared in analogy to Example 1 from 2,6-diisopropylphenylisocyanate and 4- (quinoxalin-2-ylsulfanyl) phenylamine.

‘HNMR (200 Hz, DMSO) δ: 1.17 (12H, 4xCH3, d), 3.2 (2H, 2xCH, m), 7.1-7.3 (3H,3xCH», m), 7.5-8.1 (8H, 8xCHar, m), 8.5 (1H, CH», s), 9.0 (2H, 2xNH, br) 13CNMR, δ: 23.37 (4xCH3), 27.93 (2xCH), 118.49 (C»), 118.82 (2xCH»), 122.81 (2xCH»), 127.25 (CH»), 127.60 (CH»), 128.79 (2xCH»), 130.68 (CH»), 131.98 (C»), 135.83 (2xCH»), 139.22 (C»), 141.39 (C»), 142.04 (C»), 143.01 (CH»), 146.57 (2xCar), 153.93 (C»), 157.18 (CO)1 HNMR (200 Hz, DMSO) δ: 1.17 (12H, 4xCH 3 , d), 3.2 (2H, 2xCH, m), 7.1-7.3 (3H, 3xCH 3, m), 7.5-8.1 (8H, 8xCH ar , m), 8.5 (1H, CH », s), 9.0 (2H, 2x NH, br) 13 CNMR, δ: 23.37 (4xCH 3 ), 27.93 (2xCH), 118.49 (C»), 118.82 (2xCH »), 122.81 (2xCH »), 127.25 (CH»), 127.60 (CH »), 128.79 (2xCH»), 130.68 (CH »), 131.98 (C»), 135.83 (2xCH »), 139.22 (C»), 141.39 (C) », 142.04 (C»), 143.01 (C »), 146.57 (2xC ar ), 153.93 (C»), 157.18 (CO)

Výťažok 41 %Yield 41%

Príklad 29Example 29

Metyl ester 2-(3-(2,6-diizopropylfenyl)-ureido]-5-(4-mtrofenylsulfanyl)-benzoovej kyseliny 4a2- (3- (2,6-Diisopropylphenyl) -ureido] -5- (4-morphophenylsulfanyl) -benzoic acid methyl ester 4a

Pripravila sa analogickým postupom ako v príklade 1 z 2,6-diizopropylfenylizokyanátu a metylesteru 2-(4-nitrofenylsulfanyl)-5-aminobenzoovej kyseliny.Prepared in analogy to Example 1 from 2,6-diisopropylphenylisocyanate and 2- (4-nitrophenylsulfanyl) -5-aminobenzoic acid methyl ester.

'HNMR (200 Hz, DMSO) δ: 1.15 (12H, 4xCH3, d), 3.15 (2H, 2xCH, m), 3.7 (3H, CH3O, s) 7.1-7.35 (7H,7xCH„, m), 7.6 (1H, CHar, d), 7.8 (1H, NH, br), 8.1 (2H, 2xCH»,d), 9.3 (1H, NH, br), 13CNMR, δ: 23.49 (2xCH3), 23,53 (2xCH3), 28.08 (2xCH), 52.44 (CH3O), 118.94 (CH»), 120.97 (C»), 122.99 (2xCHar), 124.18 (2xCH»), 127.54 (CH»), 128.89 (2xCHar), 131.97 (C»), 134.83 (C»), 136.43 (CH»),H NMR (200 MHz, DMSO) δ 1.15 (12 H, 4xCH 3, d), 3.15 (2H, 2 x CH, m), 3.7 (3H, CH 3 O, s), 7.1-7.35 (7H, 7xCH ', m) , 7.6 (1 H, CH ar, d), 7.8 (1H, NH, br), 8.1 (2H, 2 x CH ', d), 9.3 (1H, NH, br), 13 C NMR, δ 23.49 (2 x CH 3), 23.53 (2 x CH 3), 28.08 (2 x CH), 52.44 (CH 3 O), 118.94 (CH '), 120.97 (C'), 122.99 (2 x CH ar), 124.18 (2 x CH '), 127.54 (CH'), 128.89 (2xCH ar ), 131.97 (CH »), 134.83 (CH»), 136.43 (CH »),

141.71 (C»), 145.2 (Car), 146.68 (2xC»), 147.72 (C»), 154.04 (CO), 169.76 (CO)141.71 (C '), 145.2 (C ar), 146.68 (2xC'), 147.72 (C '), 154.04 (CO), 169.76 (CO)

Výťažok 67 %, 1.1. = 176 - 178 °CYield 67%, m.p. M.p. = 176-178 ° C

Príklad 30Example 30

5-(3-(2,6-Diizopropylfenyl)-ureido]-2-(4-nitrofenylsulfanyl)-benzoová kyselina 4b5- (3- (2,6-Diisopropyl-phenyl) -ureido] -2- (4-nitrophenylsulfanyl) -benzoic acid 4b

Pripravila sa analogickým postupom ako v príklade 7 z metyl esteru 2-(3-(2,6-diizopropylfenyl)-ureido]-5-(4-nitrofenylsulfanyl)-benzoovej kyseliny.Prepared in analogy to Example 7 from 2- (3- (2,6-diisopropylphenyl) -ureido) -5- (4-nitrophenylsulfanyl) -benzoic acid methyl ester.

'HNMR (200 Hz, DMSO) δ: 1.15 (12H, 4xCH3, d), 3.2 (2H, 2xCH, m), 7.1-7.4 (7H,7xCHar, m), 7.6 (1H, CH», d), 7.8 (1H, NH, br), 8.0-8.2 (2H, 2xCHar,m), 9.3 (1H, NH, br), 13CNMR, δ: 23.58 (4xCH3), 28.09 (2xCH), 118.96 (CH»), 119.01 (C»), 121.19 (CH»), 123.02 (2xCH»), 124.2 (2xCH»)> 127.53 (CH»), 128.06 (2xCH»), 132.02 (C»), 135.95 (CH»), 141.48 (C»), 145.2 (C»),1 HNMR (200 Hz, DMSO) δ: 1.15 (12H, 4xCH 3 , d), 3.2 (2H, 2xCH, m), 7.1-7.4 (7H, 7xCH ar , m), 7.6 (1H, CH », d) 7.8 (1H, NH, br), 8.0-8.2 (2H, 2xCH ar , m), 9.3 (1H, NH, br), 13 CNMR, δ: 23.58 (4xCH 3 ), 28.09 (2xCH), 118.96 (CH) »), 119.01 (C»), 121.27 (CH »), 123.02 (2xCH»), 124.2 (2xCH ») , 141.48 (C »)

146.71 (2xC»)> 148.0 (C»), 154.08 (CO), 167.7 (CO)146.71 (2xC »)> 148.0 (C»)

Výťažok 89 %, 1.1. = 168 - 170 °CYield 89%, m.p. Mp = 168-170 ° C

Príklad 31Example 31

2-(3-(2,6-Diizopropylfenyl)-ureido]-5-(4-chlórfenylsulfanyl)-benzamid 4c2- (3- (2,6-Diisopropylphenyl) -ureido] -5- (4-chlorophenylsulfanyl) -benzamide 4c

Pripravila sa analogickým postupom ako v príklade 1 z 2,6-diizopropylfenylizokyanátu a 4-(2-karbamoyl-4-chlórfenylsulfanyl)fenylamínu.Prepared in analogy to Example 1 from 2,6-diisopropylphenylisocyanate and 4- (2-carbamoyl-4-chlorophenylsulfanyl) phenylamine.

‘HNMR (200 Hz, DMSO) δ: 1.1 (12H, 4xCH3, d), 3.15 (2H, 2xCH, m), 7.15 (2H,2xCH», d, 8.6 Hz), 7.2 (2H, 2xCH», d), 7.4 (2H, 2xCH»,d, 8.6 Hz), 7.5 (1H, CH», dd), 7.6 (1H, CH», m), 7.8 (1H, CH», m), 8.3 (1H, NH, br), 8.8 (1H, NH, s), 10.7 (2H, CONH2, s) 13CNMR, δ: 23.07 (2xCH3), 23,78 (2xCH3), 27.88 (2xCH), 120.79 (2xCH»)> 121.97 (C»), 122.8 (2xCH»),1 HNMR (200 Hz, DMSO) δ: 1.1 (12H, 4xCH 3 , d), 3.15 (2H, 2xCH 3, m), 7.15 (2H, 2xCH 3, d, 8.6 Hz), 7.2 (2H, 2xCH 3, d) ), 7.4 (2H, 2xCH 2, d, 8.6 Hz), 7.5 (1H, CH 2, dd), 7.6 (1H, CH 2, m), 7.8 (1H, CH 2, m), 8.3 (1H, NH) , br), 8.8 (1 H, NH, s), 10.7 (2 H, CONH 2 , s) 13 CNMR, δ: 23.07 ( 2 × CH 3 ), 23,78 (2 × CH 3 ), 27.88 (2 × CH), 120.79 (2 × CH) )> 121.97 (C »), 122.8 (2xCH»),

127.18 (CH»), 129.1 (2xCH»), 130.58 (C»), 131.24 (C»), 134.12 (CH»), 136.69 (C»), 137.52 (2xCH»), 142.06 (2xC»)> 146.67 (2xC»), 153.82 (CONH2), 169.76 (CO)127.18 (CH »), 129.1 (2xCH»), 130.58 (C »), 131.24 (C»), 134.12 (C »), 136.69 (2xCH»), 142.06 (2xC »)> 146.67 ( 2xC », 153.82 (CONH 2 ), 169.76 (CO)

Výťažok 48 %, 1.1. = 221 - 223 °CYield 48%, m.p. Mp = 221-223 ° C

Príklad 32Example 32

5-(3-(2,6-Diizopropylfenyl)-ureido]-2-(4-chlórfenylsulfanyl)-benzamid 4d5- (3- (2,6-Diisopropylphenyl) -ureido] -2- (4-chlorophenylsulfanyl) -benzamide 4d

Pripravila sa analogickým postupom ako v príklade 1 z 2,6-diizopropylfenylizokyanátu a 4-(3-karbamoyl-4-chlórfenylsulfanyl)fenylamínu.Prepared in analogy to Example 1 from 2,6-diisopropylphenylisocyanate and 4- (3-carbamoyl-4-chlorophenylsulfanyl) phenylamine.

‘HNMR (200 Hz, DMSO) δ: 1.1 (12H, 4xCH3, d), 3.15 (2H, 2xCH, m), 7.1-7.5 (9H,9xCHar, m), 7.6 (1H, CH», s), 7.7 (1H, NH, s), 7.8 (1H, NH), 9.1 (2H, CONH2, s) 13CNMR, δ: 23.07 (2xCH3), 23,78 (2xCH3), 27.88 (2xCH), 116.58 (CH»), 119.34(CH»), 121.62 (C»),122.13 (CHar) 122.93 (2xCH»), 127.39 (CH»), 129.03 (2xCH»), 13077 (2xCH»), 132.05 (C»), 134.78 (CH»),1 HNMR (200 Hz, DMSO) δ: 1.1 (12H, 4xCH 3 , d), 3.15 (2H, 2xCH, m), 7.1-7.5 (9H, 9xCH ar , m), 7.6 (1H, CH », s) 7.7 (1H, NH, s), 7.8 (1H, NH), 9.1 (2H, CONH 2 , s) 13 CNMR, δ: 23.07 (2xCH 3 ), 23.78 (2xCH 3 ), 27.88 (2xCH), 116.58 (CH '), 119.34 (CH'), 121.62 (C '), 122.13 (CH ar) 122.93 (2 x CH'), 127.39 (CH '), 129.03 (2 x CH'), 13077 (2 x CH '), 132.05 (C », 134.78 (CH»),

136.71 (C»), 140.44 (C»), 141.91 (C»), 146.61 (2xC»), 154.03 (CONH2), 169.54 (CO) Výťažok 59 %, 1.1. = 200 - 205 °C136.71 (C '), 140.44 (C'), 141.91 (C '), 146.61 (2xC'), 154.03 (CONH2), 169.54 (CO) Yield: 59%, 1.1. Mp = 200-205 ° C

Príklad 33 l-(2,6-Diizopropylfenyl)-3-[6-(4-nitrofenylsulfanyl)-pyridin-3-yl]-močovina 5aExample 33 1- (2,6-Diisopropylphenyl) -3- [6- (4-nitrophenylsulfanyl) -pyridin-3-yl] -urea 5a

Pripravila sa analogickým postupom ako v príklade 1 z 2,6-diizopropylfenylizokyanátu a 6-(4-nitrofenylsulfanyl)-3-aminopyridín. ‘HNMR (200 Hz, DMSO) δ: 1.17 (12H, 4xCH3, d), 3.2 (2H, 2xCH, m), 7.13-7.2 (4H,4xCH», m), 7.3-7.5 (3H, 3xCH», m), 7.8 (NH, br) 7.95 (1H, CH», dd, 8.8 Hz), 8.1 (1H, CH», dd,Prepared in analogy to Example 1 from 2,6-diisopropylphenylisocyanate and 6- (4-nitrophenylsulfanyl) -3-aminopyridine. H NMR (200 MHz, DMSO) δ: 1.17 (12 H, 4xCH 3, d), 3.2 (2H, 2 x CH, m), 7.13-7.2 (4H, 4xCH ', m), 7.3-7.5 (3H, 3xCH », m), 7.8 (NH, br), 7.95 (1H, CH3, dd, 8.8 Hz), 8.1 (1H, CH3, dd,

8.8 Hz, 2 Hz), 8.5 (1H, CH, d, 2 Hz), 9.1 (NH, br) 13CNMR, δ: 23.50 (4xCH3), 28.14 (2xCH), 123.1 (2χΟΗ„), 124.51 (CHa,), 127.61 (CHar), 129.58 (2x0^), 130.12 (CH»), 132.08 (Car), 132.1 (C*), 132.93 (Car), 133.99 (2χΟΗΜ), 135.76 (Car), 136.13(CHar), 146.77 (2XCJ, 147.24 (CJ, 154.27 (CO) Výťažok 63 %, 1.1 = 192 - 194 °C8.8 Hz, 2 Hz), 9.1 (NH, br) 13 CNMR, δ: 23.50 (4xCH 3 ), 28.14 (2xCH), 123.1 (2 χCH), 124.51 (CHa) ,), 127.61 (CH ar), 129.58 (2x0 ^), 130.12 (CH '), 132.08 (Car), 132.1 (C *), 132.93 (C ar), 133.99 (2χΟΗ Μ), 135.76 (C ar), 136.13 (CH ar ), 146.77 (2XCJ, 147.24 (CJ, 154.27 (CO)) Yield 63%, mp = 192-194 ° C

Príklad 34 l-(2,6-Diizopropylfenyl)-3-[6-chlórfenylsulfanyl)-pyridin-3-yl]-močovina 5bExample 34 1- (2,6-Diisopropylphenyl) -3- [6-chlorophenylsulfanyl) -pyridin-3-yl] -urea 5b

Pripravila sa analogickým postupom ako v príklade 1 z 2,6-diizopropylfenylizokyanátu a 6-(4-chlórfenylsulfanyl)-3 -aminopyridín.Prepared in analogy to Example 1 from 2,6-diisopropylphenylisocyanate and 6- (4-chlorophenylsulfanyl) -3-aminopyridine.

'HNMR (200 Hz, DMSO) δ: 1.13 (12H, 4xCH3, d), 3.13 (2H, 2xCH, m), 6.88 (lH,CHar, d), 7.1-7.35 (2H, 2xCHar, m), 7.45 (2H, 2xCHar, d, 8.8 Hz), 7.6 (2H, 2xCHar, d, 8.8 Hz), 7.6-7.8 (2H, 2xCHar, m), 8.4 (1H, CHar, s), 9.1 (NH, br) 13CNMR, δ: 23.50 (4xCH3), 28.14 (2xCH), 119.05 (CHar), 120.17 (Car), 121.51 (CHJ, 123.07 (2XCHJ, 127.38 (C»), 127.55 (CHar), 132.15 (CJ, 136.42 (2χΟΗ„), 137.1 (2xCHar), 142.16 (Car), 146.76 (2xCar),1 H NMR (200 Hz, DMSO) δ: 1.13 (12H, 4xCH 3 , d), 3.13 (2H, 2xCH, m), 6.88 (1H, CH ar , d), 7.1-7.35 (2H, 2xCH ar , m) 7.45 (2H, 2xCH ar , d, 8.8 Hz), 7.6 (2H, 2xCH ar , d, 8.8 Hz), 7.6-7.8 (2H, 2xCH ar , m), 8.4 (1H, CH ar , s), 9.1 (NH, broad) 13 C NMR, δ: 23.50 (4xCH 3), 28.14 (2 x CH), 119.05 (CH ar), 120.17 (C ar), 121.51 (CH, 123.07 (2XCHJ, 127.38 (C '), 127.55 (CH ar ), 132.15 (CJ, 136.42 (2χ²)), 137.1 (2xCH ar ), 142.16 (Car), 146.76 (2xCar),

147.8 (CHar), 154.17 (CJ, 160.27 (CO)147.8 (CH), 154.17 (CJ, 160.27 (CO))

Výťažok 49 %, 1.1. =195 - 200 °CYield 49%, m.p. Mp = 195-200 ° C

Príklad 35 l-(2,6-Diizopropylfenyl)-3-[6-(5-chlórpyridin-2-ylsulfanyl)-pyridin-3-yl]-močovina 6bExample 35 1- (2,6-Diisopropylphenyl) -3- [6- (5-chloropyridin-2-ylsulfanyl) -pyridin-3-yl] -urea 6b

Pripravila sa analogickým postupom ako v príklade 1 z 2,6-diizopropylfenylizokyanátu a 6-(5-chlórpyridin-2-ylsulfanyl)-3-aminopyridín.Prepared in analogy to Example 1 from 2,6-diisopropylphenylisocyanate and 6- (5-chloropyridin-2-ylsulfanyl) -3-aminopyridine.

‘HNMR (200 Hz, DMSO) δ: 1.2 (12H, 4xCH3, d), 3.2 (2H, 2xCH, m), 6.2 (ΙΗ,ΝΗ, br), 6.4 (1H, NH, br), 7.1-7.3 (3H, 3xCHar, m), 7.45-7.55 (3H, 3xCHar, m), 8.0 (1H, CHar, d), 8.2-8.4 (2H, 2xCHar, m) 13CNMR, δ: 23.37 (2xCH3), 24.31 (2xCH3), 28.59 (2xCH), 124.78 (2χΟΗ„), 128.44 (CHar), 129.03 (CHJ, 129.74 (0^), 129.89 (C^), 135.55 (Ο„), 136.77 (CHar), 136.92 (CH^), 142.15 (Car), 148.03 (Cai), 148.61 (3xCHar), 154.57 (2x0^), 156.73 (CO)1 HNMR (200 Hz, DMSO) δ: 1.2 (12H, 4xCH 3 , d), 3.2 (2H, 2xCH, m), 6.2 (1H, NH, br), 6.4 (1H, NH, br), 7.1-7.3 (3H, 3xCHar, m), 7.45-7.55 (3H, 3xCH ar , m), 8.0 (1H, CH ar , d), 8.2-8.4 (2H, 2xCH ar , m) 13 CNMR, δ: 23.37 (2xCH 3 ), 24.31 (2 x CH 3), 28.59 (2 x CH), 124.78 (2χΟΗ '), 128.44 (CH ar), 129.03 (CH, 129.74 (0?), 129.89 (C ^), 135.55 (Ο'), 136.77 (CH ar ), 136.92 (CH 2), 142.15 (C ar ), 148.03 (C ai ), 148.61 (3x CH ar ), 154.57 (2x0 ^), 156.73 (CO)

Výťažok 32 %, 1.1. = 187 - 190 °CYield 32%, 1.1. Mp = 187-190 ° C

Takto pripravené močoviny majú inhibičný účinok na acyl-koenzým A: cholesterol acyltransferázu (ACAT).The ureas thus prepared have an inhibitory effect on acyl-coenzyme A: cholesterol acyltransferase (ACAT).

Kritériom je inhibičný účinok látok na špecifickú aktivitu ACAT pečene potkana in vitro. Zvýšenie esterifikačného procesu cholesterolu v pečeni zvierat sa dosiahlo aktiváciou enzýmu ACAT podávaním potravy s obsahom cholesterolu. Model aktivácie ACAT je opísaný v práci Krausa a spol. (J. Lipid Res.: 1993, 267, 734). Na stimuláciu aktivity ACAT v pečeni bola potkanom (Wistar) podávaná 1 % cholesterolová diéta 10 dní. Mikrozomálna frakcia pečene sa izoluje diferenciálnou ultracentrifugáciou subcelulámych komponentov podľa Galia a spol. (Proc. Soc. Exp. Biol. Med.: 1984, 177, 188 - 196). V izolovaných mikrozomálnych frakciách sú kvantifíkované bielkoviny modifikovanou Lowryho metódou pre stanovenie membránovo viazaných bielkovín.The criterion is the inhibitory effect of the substances on the specific activity of rat liver ACAT in vitro. An increase in the esterification process of cholesterol in the liver of animals was achieved by activating the enzyme ACAT by administering a diet containing cholesterol. The ACAT activation model is described in Kraus et al. (J. Lipid Res .: 1993,267,734). To stimulate ACAT activity in the liver, a 1% cholesterol diet was administered to rats (Wistar) for 10 days. The microsomal fraction of the liver is isolated by differential ultracentrifugation of the subcellular components according to Galia et al. (Proc. Soc. Exp. Biol. Med. 1984, 177, 188-196). In the isolated microsomal fractions, the quantified proteins are a modified Lowry method for the determination of membrane bound proteins.

Pri stanovení ACAT v pečeni in vitro sa postupovalo metódou Ericksona a spoluautorov (J. Lipid Res.: 1980, 21, 930). Aktivita ACAT bola stanovená so substrátmi endogénnym cholesterolom a exogénnym 14C-značeným oleoylCo A bez prítomnosti hovädzieho sérového albumínu, z dôvodu aby neprišlo k väzbe na bielkovinu. Lipidy boli extrahované zmesou chloroform: metanol (2 : 1) a separované tenkovrstevnou chromatografiou. 14C-cholesteryl oleát bol kvantifikovaný rádiometricky. V tabuľke 1, 2 a 3 sú uvedené percentá inhibície aktivity ACAT v pečeni potkana pri určitej koncentrácii testovaných látok. Účinnosť látok je vyjadrená ako % inhibície aktivity enzýmu ACAT v pečeni potkana pri určitej koncentrácii látky. Látky sú rozpustené v koncentrovanom dimetylsulfoxide (DMSO) a pridané do reakčnej zmesi na výslednú koncentráciu 1 % DMSO. Pri najúčinnejších derivátoch bola stanovená ich IC50, ktorá bola vypočítaná zo závislosti % inhibície aktivity enzýmu od log koncentrácie testovanej látky (najmenej pri štyroch koncentráciách inhibítora) metódou lineárnej regresie.The in vitro liver ACAT assay was followed by the method of Erickson et al. (J. Lipid Res .: 1980, 21, 930). ACAT activity was determined with substrates endogenous cholesterol and exogenous 14 C-labeled oleoylCo A in the absence of bovine serum albumin to avoid protein binding. The lipids were extracted with chloroform: methanol (2: 1) and separated by thin layer chromatography. 14 C-cholesteryl oleate was quantified radiometrically. Tables 1, 2 and 3 show percent inhibition of ACAT activity in rat liver at a certain concentration of test substances. The potency of the agents is expressed as% inhibition of ACAT enzyme activity in the rat liver at a certain concentration of the agent. The substances are dissolved in concentrated dimethylsulfoxide (DMSO) and added to the reaction mixture to a final concentration of 1% DMSO. For the most potent derivatives, their IC 50 was determined, calculated from the% inhibition of enzyme activity versus the log concentration of the test substance (at least four inhibitor concentrations) by the linear regression method.

Tabuľka 1: Inhibičný účinok na ACAT v pečeni potkanaTable 1: Inhibitory effect on ACAT in rat liver

R2 R 2 Číslo zlúčeniny Compound number R1 R 1 R2 R 2 % inhibície pri 1 gmol.ľ’ % inhibition at 1 gmol.¾ ' % inhibície pri 0,5 /imol.ľ1 % inhibition at 0.5 µmol -1 IC5O ,(/*M)IC 50 , (/ * M) la la NHO2SCH3 NHO 2 SCH 3 H H 53 53 21 21 0.95 0.95

T H H íj π Τη / R THH j π / R Číslo zlúčeniny Compound number R1 R 1 R2 R 2 % inhibície pri 1 gmol.ľ1 % inhibition at 1 gmol -1 % inhibície Pri 0,5 gmol.ľ1 % inhibition At 0.5 gmol -1 ICS0 .(μΜ)IC S0 (μΜ) lb lb Br br H H 69 69 24 24 0.86 0.86 lc lc F F H H 63 63 - - - - ld ld COOEt COOEt H H 16 16 - - - - le le COOH COOH H H 54 54 21 21 - - lf lf OO2SCH3 OO 2 SCH 3 H H 52 52 - - - - ig ig OH OH H H 70 70 43 43 0.66 0.66 lh lh CH3 CH 3 H H 47 47 - - - - li when Cl Cl H H 56 56 55 55 0.16 00:16 2a 2 H H 2-OMe 2-OMe 39 39 21 21 - - 2b 2b H H 2-NO2 2-NO 2 41 41 - - - - 2c 2c no2 no 2 2-COOEt 2-COOEt 82 82 42 42 0.67 0.67 2d 2d no2 no 2 2-COOH 2-COOH 82 82 48 48 0.77 0.77 2e 2e no2 no 2 no2 no 2 47 47 34 34 2f 2f no2 no 2 3-C00Me 3-C00Me 68 68 30 30 2g 2 g no2 no 2 3-COOH 3-COOH 32 32 8 8 2h 2h no2 no 2 3-CONH2 3-CONH 2 30 30 20 20 2i 2i no2 no 2 2-CONH2 2-CONH 2 19 19 12 12 2j 2J Cl Cl 3-CONH2 3-CONH 2 43 43 32 32 2k 2k Cl Cl 2-CONH2 2-CONH 2 28 28 16 16

Tabuľka 2: Inhibičný účinok na ACAT v pečeni potkanaTable 2: ACAT inhibitory effect in rat liver

ČčíX... CCIX ... Číslo zlúčeniny Compound number R R % inhibície pri lgmol.l1 % inhibition at lgmol.l 1 % inhibície pri 0,5 gmol.ľ1 % inhibition at 0.5 gmol -1 IC50 .(μΜ) IC50 (μΜ) 3a 3a 2-pyridinyl 2-pyridinyl 73 73 46 46 0.54 00:54 3b 3b 3-pyridinyl 3-pyridinyl 68 68 21 21 - - 3c 3c 4-pyridinyl 4-pyridinyl 76 76 48 48 - - 3d 3d 5-nitro-2-pyridinyl 5-nitro-2-pyridinyl 85 85 49 49 0.63 0.63 3e 3e 3 -nitro-2-pyridinyl 3-nitro-2-pyridinyl 51 51 44 44 - - 3f 3f 3,5-dinitro-2-pyridinyl 3,5-dinitro-2-pyridinyl 43 43 0 0 - - 3g 3 g 5-chlór-2-pyridinyl 5-chloro-2-pyridinyl 73 73 66 66 0.64 0.64 3h 3h pyrazin-2-yl pyrazin-2-yl 41 41 40 40 0.78 0.78 3i 3i pyrimidin-2-yl pyrimidin-2-yl 47 47 0 0 3j 3J 6-chlór-pyridazin-3-yl 6-chloro-pyridazin-3-yl 20 20 24 24 3k 3k 5,6-dimetoxy-1,3,5-triazin-2-yl 5,6-dimethoxy-1,3,5-triazin-2-yl 37 37 12 12 31 31 chinolin-2-yl quinolin-2-yl 35 35 35 35 3m 3 m chinoxalin-2-yl quinoxalin-2-yl 32 32 39 39

Tabuľka 3: Inhibičný účinok na ACAT v pečeni potkanaTable 3: ACAT inhibitory effect in rat liver

Číslo zlúčeniny Compound number X X Y Y R1 R 1 R2 R 2 % inhibície pri 0,5 gmol.ľ1 % inhibition at 0.5 gmol -1 ic50 .(μΜ)ic 50 (μΜ) 4a 4a CH CH CH CH 3-COOMe 3-COOMe no2 no 2 25 25 4b 4b CH CH CH CH 3-COOH 3-COOH no2 no 2 6 6 4c 4c CH CH CH CH 2-CONH2 2-CONH 2 Cl Cl 0 0 4d 4d CH CH CH CH 3-CONH2 3-CONH 2 Cl Cl 25 25 4e 4e CH CH CH CH 3-CONH2 3-CONH 2 no2 no 2 18 18 4f 4f CH CH CH CH 2-CONH2 2-CONH 2 no2 no 2 12 12 5a 5a N N CH CH H H no2 no 2 57 57 0.78 0.78 5b 5b N N CH CH H H Cl Cl 61 61 0.16 00:16 6a 6a N N N N H H no2 no 2 38 38 - - 6b 6b N N N N H H Cl Cl 49 49 - -

Stanovenie aktivity ACAT:Determination of ACAT activity:

1. Mikrozomálna frakcia sa pred použitím rozmrazuje pri 4 °C a zriedi sa v inkubačnom tlmivom roztoku 0,04 M KH2PO4, 0,05 M KC1, 0,03 mM EDTA a 0,3 M sacharózy, pH = 7,4 na požadovanú koncentráciu bielkovín pre daný počet vzoriek.1. The microsomal fraction is thawed at 4 ° C before use and diluted in incubation buffer 0.04 M KH 2 PO 4, 0.05 M KCl, 0.03 mM EDTA and 0.3 M sucrose, pH = 7.4 to the desired the protein concentration for a given number of samples.

2. Vzorky 80 - 150 pg mikrozomálnych bielkovín pečene potkana v objeme 50 μΐ sú predinkubované 10 min. pri 37 °C za stáleho miešania v biologickom termostate.2. Samples of 80-150 pg of rat liver microsomal proteins in a volume of 50 μΐ are preincubated for 10 min. at 37 ° C with stirring in a biological thermostat.

3. Pridá sa 50 μΐ 0,5 mg inaktivovaného hovädzieho sérového albumínu (bez mastných kyselín) Pridá sa 50 μΐ fosfátového tlmivého roztoku a ďalej sa inkubuje 5 min. pri 37 °C s 2 μΐ roztoku látky alebo rozpúšťadla (2 μΐ koncentrovaného DMSO) za stáleho miešania v termostate v otvorených skúmavkách na stolovej miešačke.3. Add 50 μΐ 0.5 mg inactivated bovine serum albumin (without fatty acids) Add 50 μΐ phosphate buffer and incubate for 5 min. at 37 ° C with 2 μΐ of a solution of the substance or solvent (2 μΐ of concentrated DMSO) with stirring in a thermostat in open tubes on a bench mixer.

4. Enzýmová reakcia je štartovaná pridaním substrátu 50 μΐ 10 nmolov oleoyl koenzým A (Sigma) a 50 μΐ C-oleoyl CoA (Amersham, 180 000 - 250 000 dpm).4. The enzyme reaction is started by adding a substrate of 50 μΐ 10 nmoles oleoyl coenzyme A (Sigma) and 50 μΐ C-oleoyl CoA (Amersham, 180,000 - 250,000 dpm).

5. Enzýmová reakcia prebieha 10 min. pri 37 °C za stáleho miešania v konečnom objeme 0,2 ml.5. Enzyme reaction is carried out for 10 min. at 37 ° C with stirring in a final volume of 0.2 ml.

Extrakcia lipidov:Lipid extraction:

6. Enzýmová reakcia sa zastaví 2 ml chloroform - metanolom (2:1)6. Stop the enzyme reaction with 2 ml of chloroform-methanol (2: 1)

7. Znova sa pridá 3 ml zmesi chloroform - metanolu (2 : 1) a silne sa vytrepáva za stáleho miešania 30 min. na stolovej trepačke pri laboratórnej teplote v uzavretých skúmavkách.7. Add 3 ml of chloroform-methanol (2: 1) again and shake vigorously with stirring for 30 min. on a table shaker at room temperature in closed tubes.

8. Pridá sa 1 ml acidifikovanej vody s H2SO4 a znova sa intenzívne mieša 30 min. pri laboratórnej teplote.8. Add 1 ml of acidified water with H 2 SO 4 and mix again vigorously for 30 min. at room temperature.

9. Organická chloroformová fáza (spodná) je odsatá do druhej skúmavky a vodná fáza reextrahovaná s 2 ml zmesi chloroform - metanolu (2 : 1).9. The organic chloroform phase (bottom) is aspirated into a second tube and the aqueous phase reextracted with 2 ml of chloroform-methanol (2: 1).

10. Organické fázy sa spoja a vzorky sa nechajú stáť uzatvorené pod N2 v chladničke.10. Combine the organic phases and allow the samples to stand closed under N 2 in a refrigerator.

11. Chloroform je odparený pod N2.11. Chloroform is evaporated under N 2 .

Tenkovrstevná chromatografia:Thin-layer chromatography:

12. Odparok sa rozpustí v 100 μΐ chloroformu a nanáša sa v šírke 1 cm na TLC Silikagél 60 F platne.12. Dissolve the residue in 100 μΐ of chloroform and apply to a width of 1 cm on TLC Silica gel 60 F plates.

13. Tenkovrstevná chromatografia prebieha do výšky 15 cm v hexán-etylacetáte (9 : 1) v uzatvorenej vyvíjacej komore.13. Thin layer chromatography is carried out to a height of 15 cm in hexane-ethyl acetate (9: 1) in a closed developing chamber.

14. TLC platňa je rozdelená na 10 pásov 2 x 1,5 cm a zóny s RF0,7 - 1 pre 14C-cholesteryl oleát sú vyškriabané do označených scintilačných fľašiek a extrahované do 1 ml metanolu.14. The TLC plate is divided into strips 10 x 1.5 cm 2 and the area of Rf 0.7 to 1 to 14 C-cholesteryl oleate vyškriabané to be identified and extracted scintillation flasks in 1 ml of methanol.

Rádiometria:radiometry:

Vzorky po doplnení s 10 ml scintilačného toluénového roztoku SLT a vychladení sú merané na kvapalinovom scintilačnom spektrometri Packard TriCarb 2000 CA (USA).Samples after topping up with 10 ml of SLT scintillation solution and cooling are measured on a Packard TriCarb 2000 CA liquid scintillation spectrometer (USA).

14C-rádioaktivita každej vzorky je meraná v dpm 5 min. Rádioaktivita zásobných roztokov 14C-oleoyl Co A je meraná priamo v 10 ml zmesného scintilačného roztoku. 14 C-radioactivity of each sample is measured at dpm 5 min. The radioactivity of 14 C-oleoyl Co A stock solutions is measured directly in 10 mL of mixed scintillation solution.

Výpočet špecifickej aktivity A CA T:Calculation of specific activity A CA T:

Špecifická aktivita ACAT je vyjadrená množstvom vzniknutého cholesteryl oleátu počas enzýmovej reakcie na mg bielkovín za minútu (nmol 14C-cholesteryl oleát.min'.mg'1 bielkovín).The specific activity of ACAT is expressed by the amount of cholesteryl oleate formed during the enzyme reaction per mg of protein per minute (nmol of 14 C-cholesteryl oleate.min -.m- 1 protein).

Špecifická aktivita enzýmu sa vypočíta podľa vzorca:The specific activity of the enzyme is calculated according to the formula:

__________14C-cholesteryl oleát (dpm) x množstvo oleovl CoA (nmol) x 103________ 14C-oleoyl CoA (dpm) x doba inkubácie (10 min) x množstvo bielkovín (pg)__________ 14 C-cholesteryl oleate (dpm) x amount of oleovl CoA (nmol) x 10 3 ________ 14 C-oleoyl CoA (dpm) x incubation time (10 min) x amount of protein (pg)

Hypocholesterolemický účinok látok in vivoHypocholesterolemic effect of substances in vivo

Rozsah zmeny sérových hladín cholesterolu (Tab. 4) bol kritériom na hodnotenie in vivo účinku látok v akútnom modeli potkana (J. Lipid Res.: 1993, 267, 734). Látky (dávka 50 mg.kg’1) boli podané jednorazovo v olivovom oleji Spraque Dawley potkanom (samci), kŕmených potravou s obsahom 1 % cholesterolu, 0,5 % kyseliny cholovej a 5,5 % arašidového oleja (20 g/zviera), ako prekurzorov syntézy cholesterolu a žlčových kyselín.The extent of alteration of serum cholesterol levels (Table 4) was a criterion for evaluating the in vivo effect of compounds in an acute rat model (J. Lipid Res .: 1993, 267, 734). The substances (dose 50 mg.kg -1 ) were administered once in Spraque Dawley olive oil to rats (male) fed a diet containing 1% cholesterol, 0.5% cholic acid and 5.5% peanut oil (20 g / animal). , as precursors for the synthesis of cholesterol and bile acids.

Tabuľka 4.Table 4.

TESTOVANÁ LÁTKA TESTED SUBSTANCE PARAMETER PARAMETERS ATC (%) ATC (%) AHV (%) AHV (%) lb lb 0 0 0 0 ig ig 0 0 0 0 3h 3h 37 37 54 54 li when 55 55 85 85 3d 3d 40 40 61 61 3a 3a 71 71 81 81 3g 3 g 44 44 65 65 3m 3 m 11 11 16 16 3e 3e 0 0 0 0 5a 5a 17 17 27 27 5b 5b 49 49 72 72

Výsledky sú uvedené ako % zmeny hladiny sérového cholesterolu (ATC), n = 4-5 zvierat. Antihypercholesterolemická hodnota (J. Med. Chem.: 1994, 37, 3511) AHV =(B-A)/(B-C) x 100, kde A - je TC látkovej skupiny, B- TC cholesterolovej kontroly, a C- TC normálovej kontroly.Results are reported as% change in serum cholesterol (ATC), n = 4-5 animals. Antihypercholesterolemic value (J. Med. Chem .: 1994, 37, 3511) AHV = (B-A) / (B-C) x 100, where A - is TC of the substance group, B-TC cholesterol control, and C-TC normal control.

Inhibičná účinnosť látok na sérové hladiny cholesterolu bola v poradí 3a > li > 5b > 3g > 3d > 3h > 5a > > 3m. Najvyššiu inhibičnú aktivitu na sérové hladiny celkového cholesterolu vykazovali látky 3a (Δ TC -71 %, AHV 81 %) a li (A TC - 55 %, AHV 85 %), ktoré mali výraznejší efekt ako látky 5b (Δ TC - 49 %, AHV 72 %), 3g (A TC - 44 %, AHV 65 %) 3d (ATC - 40 % s AHV 61 %) a 3h (A TC - 37 %, AHV 54 %). Najnižšiu účinnosť mali látky 5a a 3m (A TC - 17 a 11 %, AHV 27 a 16 %), pričom testované látky lb, lg, 3e vykazovali nulový inhibičný efekt.The inhibitory activity of the substances on serum cholesterol levels was 3a> li> 5b> 3g> 3d> 3h> 5a>> 3m. The highest inhibitory activity on serum total cholesterol levels was shown by substances 3a (li TC -71%, AHV 81%) and li (A TC - 55%, AHV 85%), which had a more pronounced effect than 5b (Δ TC - 49%, AHV 72%), 3g (A TC - 44%, AHV 65%) 3d (ATC - 40% with AHV 61%) and 3h (A TC - 37%, AHV 54%). The 5a and 3m compounds (A TC-17 and 11%, AHV 27 and 16%, respectively) exhibited the lowest efficacy, whereas the test compounds 1b, 1g, 3e showed no inhibitory effect.

Priemyselná využiteľnosťIndustrial usability

Vynález je priemyselne využiteľný pri výrobe farmaceutických substancií a liekových foriem obsahujúcich tieto substancie v terapii hyperlipidémie.The invention is industrially useful in the manufacture of pharmaceutical substances and dosage forms comprising these substances in the treatment of hyperlipidemia.

PATENTOVÉ NÁROKYPATENT CLAIMS

Claims (4)

1. 1,3-Disubstituované močoviny všeobecného vzorca (I), kde R2 je 4-hydroxyfenyl, 4-karboxyfenyl, 4-metyloxykarbonylfenyl, 4-etyloxykarbonylfenyl, 4-fluórfenyl, 4-chlórfenyl, 4-brómfenyl, 4-jódfenyl, 4-metylfenyl, 4-metylaminofenyl, 4-metylsulfofenyl, 4-metoxyfenyl, 4-karbamoylfenyl, 2,4-dinitrofenyl, 2-karboxy-4-nitrofenyl, 3-karboxy-4-nitrofenyl, 2-metyloxykarbonyl-4-nitrofenyl, 3-metyloxykarbonyl-4-nitrofenyl, 2-etyloxykarbonyl-4-nitrofenyl, 3-etyloxykarbonyl-4-nitrofenyl, 2-karbamoyl-4-nitrofenyl, 3-karbamoyl-4-nitrofenyl, 2-karbamoyl-4-chlórfenyl, 3-karbamoyl-4-chlórfenyl, 2-karboxy-4-chlórfenyl, 3-karboxy-4-chlórfenyl, 2-metyloxykarbonyl-4-chórfenyl, 3-metyloxykarbonyl-4-chlórfenyl, 2-etyloxykarbonyl-4-chórfenyl, 3-etyloxykarbonyl-4-chlórfenyl a R1 je vodík a X je CH skupina, kde R2 je 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-nitro-2-pyridyl, 3-nitro-2-pyridyl, 5-chlór-2-pyridyl, 3,5-dinitro-2-pyridyl, pyrazin-2-yl, pyrimidin-2-yl, 6-chlórpyridazin-3-yl, 5,6-dimetoxy-l,3,5-triazin-2-yl, chinolin-2-yl, chinoxalin-2-yl a R1= H a X=CH, kde R2 je 4-nitrofenyl, 4-chlórfenyl, 5-nitro-2-pyridyl, 5-chór-2-pyridyl a R1 je vodík a X=N, kde R2 je 4-nitrofenyl, 4-chlórfenyl,4-brómfenyl a R1= COOH, COOMe, COOEt, CONH2 a X= CH.1. 1,3-Disubstituted ureas of general formula (I) wherein R 2 is 4-hydroxyphenyl, 4-carboxyphenyl, 4-metyloxykarbonylfenyl, 4-etyloxykarbonylfenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-iodophenyl, 4-methylphenyl, 4-methylaminophenyl, 4-methylsulfophenyl, 4-methoxyphenyl, 4-carbamoylphenyl, 2,4-dinitrophenyl, 2-carboxy-4-nitrophenyl, 3-carboxy-4-nitrophenyl, 2-methyloxycarbonyl-4-nitrophenyl, 3-methyloxycarbonyl-4-nitrophenyl, 2-ethyloxycarbonyl-4-nitrophenyl, 3-ethyloxycarbonyl-4-nitrophenyl, 2-carbamoyl-4-nitrophenyl, 3-carbamoyl-4-nitrophenyl, 2-carbamoyl-4-chlorophenyl, 3- carbamoyl-4-chlorophenyl, 2-carboxy-4-chlorophenyl, 3-carboxy-4-chlorophenyl, 2-methyloxycarbonyl-4-chlorophenyl, 3-methyloxycarbonyl-4-chlorophenyl, 2-ethyloxycarbonyl-4-chlorophenyl, 3-ethyloxycarbonyl- 4-chlorophenyl and R 1 is hydrogen and X is CH group wherein R 2 is 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-nitro-2-pyridyl, 3-nitro-2-pyridyl, 5-chloro- 2-pyridyl, 3,5-dinitro-2-pyridyl, pyrazin-2-yl, pyrimidin-2-yl, 6-chloropyridazin-3-yl, 5,6-dimethyl oxy-1,3,5-triazin-2-yl, quinolin-2-yl, quinoxalin-2-yl and R 1 = H and X = CH, wherein R 2 is 4-nitrophenyl, 4-chlorophenyl, 5-nitro -2-pyridyl, 5-chloro-2-pyridyl and R 1 is hydrogen and X = N, wherein R 2 is 4-nitrophenyl, 4-chlorophenyl, 4-bromophenyl and R 1 = COOH, COOMe, COOEt, CONH 2 and X = CH. 2. Spôsob prípravy 1,3-disubstituovaných močovín všeobecného vzorca (I), podľa nároku 1, vyznali u j ú c i sa tým, že na aromatické amíny sa pôsobí izokyanátom v inertných rozpúšťadlách pri teplote 20 až 120 °C.A process for the preparation of 1,3-disubstituted ureas of formula (I) according to claim 1, characterized in that aromatic amines are treated with isocyanate in inert solvents at a temperature of 20 to 120 ° C. 3. Spôsob prípravy 1,3-disubstituovaných močovín všeobecného vzorca (I), podľa nároku 2, vyznačuj úci sa tým, že 1,3-disubstituované močoviny obsahujúce estery karboxylových kyselín sa hydrolyzujú na kyseliny s roztokom alkalického hydroxidu v prostredí C] až C5 alkoholu alebo tetrahydrofuránu, resp. dioxánu.A process for the preparation of 1,3-disubstituted ureas of formula (I) according to claim 2, characterized in that the 1,3-disubstituted ureas containing carboxylic acid esters are hydrolyzed to acids with an alkali hydroxide solution in a C 1 to C environment. 5 alcohol or tetrahydrofuran, respectively. dioxane. 4. Použitie 1,3-disubstituovaných močovín všeobecného vzorca (I) podľa nároku 1, na prípravu farmaceutických kompozícií s inhibičným účinkom na enzým acyl-koenzým A: cholesterol O-acyltransferázu (ACAT) na reguláciu koncentrácie plazmatického cholesterolu.Use of 1,3-disubstituted ureas of formula (I) according to claim 1, for the preparation of pharmaceutical compositions having an acyl-coenzyme A: cholesterol O-acyltransferase (ACAT) inhibitory effect for the regulation of plasma cholesterol concentration.
SK5133-2007A 2007-11-27 2007-11-27 1,3-Disubstituted ureas, process for their preparation and their use SK287385B6 (en)

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