CS242050B1 - Antineoplastically effective esters of 5-(2-amino-4-oxo-6-alkyl-3,4-dihydropyrimidine-5-yl)-pentanoic acids - Google Patents
Antineoplastically effective esters of 5-(2-amino-4-oxo-6-alkyl-3,4-dihydropyrimidine-5-yl)-pentanoic acids Download PDFInfo
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- CS242050B1 CS242050B1 CS8410292A CS1029284A CS242050B1 CS 242050 B1 CS242050 B1 CS 242050B1 CS 8410292 A CS8410292 A CS 8410292A CS 1029284 A CS1029284 A CS 1029284A CS 242050 B1 CS242050 B1 CS 242050B1
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- dihydropyrimidin
- pentanoic acid
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- 150000002148 esters Chemical class 0.000 title claims description 3
- -1 3-chloropropyl Chemical group 0.000 claims description 52
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 41
- 206010028980 Neoplasm Diseases 0.000 description 39
- 150000001875 compounds Chemical class 0.000 description 11
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 230000000118 anti-neoplastic effect Effects 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- XQCZBXHVTFVIFE-UHFFFAOYSA-N 2-amino-4-hydroxypyrimidine Chemical class NC1=NC=CC(O)=N1 XQCZBXHVTFVIFE-UHFFFAOYSA-N 0.000 description 2
- YZQXFAHRCJIPQZ-UHFFFAOYSA-N 5-(2-amino-6-methyl-4-oxo-1h-pyrimidin-5-yl)pentanoic acid Chemical compound CC=1NC(N)=NC(=O)C=1CCCCC(O)=O YZQXFAHRCJIPQZ-UHFFFAOYSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 239000012429 reaction media Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000002054 transplantation Methods 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- 206010003445 Ascites Diseases 0.000 description 1
- OKJADYKTJJGKDX-UHFFFAOYSA-N Butyl pentanoate Chemical compound CCCCOC(=O)CCCC OKJADYKTJJGKDX-UHFFFAOYSA-N 0.000 description 1
- ICMAFTSLXCXHRK-UHFFFAOYSA-N Ethyl pentanoate Chemical compound CCCCC(=O)OCC ICMAFTSLXCXHRK-UHFFFAOYSA-N 0.000 description 1
- 208000009916 Yoshida Sarcoma Diseases 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 238000012925 biological evaluation Methods 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- FGPPDYNPZTUNIU-UHFFFAOYSA-N pentyl pentanoate Chemical compound CCCCCOC(=O)CCCC FGPPDYNPZTUNIU-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Vynález se týká antineoplasticky účinných esterů kyselin 5-(2-amino-4-oxo-6-alkyl-3,4-dihydropyrimidin-5-yl) pentanových obecného vzorce I, η2ν*Λ\ ^ch^ch.coorThe invention relates to an antineoplastic active ester of 5- (2-amino-4-oxo-6-alkyl-3,4-dihydropyrimidine-5-yl) pentane of formula I, 2 ν η Λ * \ ^ CH ^ ch.coor
N~\ rZ (I) ve kterémN ~ \ rZ (I) in which
R1 značí alkylovou skupinu s 1 až 6 atomy uhlíku s řetězcem přímým nebo rozvětveným, allylovou, benzylovou, 3-chlorpropylovou, cyklohexylovou nebo 2-fenylethylovou skupinou aR 1 represents alkyl having 1 to 6 carbon atoms, a straight-chained or branched, allyl, benzyl, 3-chloropropyl, cyclohexyl or 2-phenylethyl radical and
R2 značí přímý alkylový řetězec s 1 až 6 atomy uhlíku.R 2 is a straight-chain alkyl having 1 to 6 carbon atoms.
Látky obecného vzorce I, o výše uvedeném významu R1 a R2, jsou deriváty isocytosinu a lze u nich očekávat, v analogii s dřívějšími zjištěními u strukturně podobných látek se strukturou 5- a 6-substitučních derivátů 2-amino-4-oxopyrimidinu (čs. autorské osvědčení č. 226 946, č. 225 537, č. 231 636, č. 221 432, č. 221 324] antineoplastickou aktivitu.The compounds of formula (I), as defined above for R 1 and R 2 , are derivatives of isocytosine and can be expected, in analogy with earlier findings, to structurally similar compounds having the structure of 5- and 6-substitution derivatives of 2-amino-4-oxopyrimidine ( Czech Patent Author No. 226 946, No. 225 537, No. 231 636, No. 221 432, No. 221 324] antineoplastic activity.
Tento předpoklad byl potvrzen při biologickém hodnocení antineoplastického účinku u zvířat s experimentálními transplantovatelnými nádory, z něhož vyplynulo, že testované látky jsou potenciálními chemoterapeutiky lidských nádorových onemocnění. Látky obecného vzorce I, o výše uvedeném významu R1, R2 byly testovány na myších s ascitickými nádory KR 2, S 37, s ascitickou formou leukémie L 1210, se solidními nádory HK, STE a na krysách s Yoshidovým sarkomem.This assumption was confirmed in a biological evaluation of the antineoplastic effect in animals with experimental transplantable tumors, which showed that the test substances are potential chemotherapeutic agents for human cancer. Compounds of formula I having the above meanings of R 1, R 2 were tested in mice with ascitic tumors KR 2, S 37, in the form of ascites L 1210 leukemia, solid tumors HK, STE, and rats with Yoshida Sarcoma.
Při těchto pokusech byly látky podávány níže uvedeným způsobem jednou denně, a to u myších ascitických nádorů 8krát, počínaje prvním dnem po transplantaci, u krysího Yoshidova nádoru 5krát, u myší leukémie L 1210 4 x. Podobné schéma bylo voleno pro myší solidní nádory, u nichž látky byly podávány 8krát, počínaje 5 dnem po transplantaci. Velikost nádoru byla stanovena v den po skončení aplikace. Velikost nádoru a doba přežívání byly porovnány s hodnotami u neléčených kontrolních zvířat.In these experiments, the compounds were administered once daily as follows, in mouse ascitic tumors 8 times, starting on the first day after transplantation, in rat Yoshid's tumor 5 times, in L 1210 leukemia mice 4 times. A similar scheme was chosen for mouse solid tumors in which the compounds were administered 8 times, starting 5 days after transplantation. Tumor size was determined the day after the end of administration. Tumor size and survival time were compared to values in untreated control animals.
Uvádíme příklady protinádorového účinku některých látek:Here are examples of the antitumor effect of some substances:
Methylester kyseliny 5-(2-amino-4-oxo-6-methyl-3,4-dihydropyrimidin-5-yl J pentanové snížil v dávkách 200 a 100 mg/kg p. o. a 100 mg/kg s. c. velikost nádoru Kr 2 o 59, 35 a 33 % a nádoru STE o 49, 41 a 37 °/o.5- (2-Amino-4-oxo-6-methyl-3,4-dihydropyrimidin-5-yl) pentanoic acid methyl ester reduced the tumor size Kr 2 by 59 and 200 mg / kg po and 100 mg / kg sc, respectively. , 35 and 33%, and a STE tumor of 49, 41 and 37%.
Ethylester kyseliny 5-(2-amino-4-oxo-6-methyl-3,4-dihydropyrimidin-5-yl ] pentanové snížil v dávce 200 mg/kg p. o. velikost nádoru STE o 37 %, S 37 o 41 % a Kr 2 o 60 %. V dávce 100 mg/kg p. o. snížil velikost nádoru S 37 o 24 °/o. V dávce 100 mg/ /kg s. c. snížil velikost nádoru Kr 2 o 31 %.5- (2-Amino-4-oxo-6-methyl-3,4-dihydropyrimidin-5-yl) pentanoic acid ethyl ester decreased at a dose of 200 mg / kg after tumor size of STE by 37%, S 37 by 41% and Kr At a dose of 100 mg / kg po reduced tumor size S 37 by 24% / o At a dose of 100 mg / kg sc reduced tumor size Kr 2 by 31%.
Propylester kyseliny 5-(2-amino-4-oxo-6-methyl-3,4-dihydropyrimidin-5-yl) pentanové v dávce 200 mg/kg p. o. snížil velikost nádoru STE o 45 %.5- (2-Amino-4-oxo-6-methyl-3,4-dihydropyrimidin-5-yl) pentanoic acid propyl ester at a dose of 200 mg / kg p.o. reduced STE tumor size by 45%.
3-Chlorpropylester kyseliny 5-(2-amino-4-oxo-6-methyl-3,4-dihydropyrimidin-5-yl) pentanové snížil v dávce 200 a 100 mg/kg p. o. velikost nádorů Kr 2 o 60 a 20 %; v dávce 100 mg/kg s. c. snížil velikost Kr 2 o 30 %. V dávce 200 mg/kg p. o. prodloužil přežití zvířat s Kr 2 o 27 %.5- (2-Amino-4-oxo-6-methyl-3,4-dihydropyrimidin-5-yl) pentanoic acid 3-chloropropyl ester reduced the Kr 2 tumor size by 60 and 20% at a dose of 200 and 100 mg / kg p. at a dose of 100 mg / kg s. c. reduced the Kr 2 size by 30%. At a dose of 200 mg / kg p.o., prolonged survival of animals with Kr 2 by 27%.
Allylester kyseliny 5-(2-amino-4-oxo-6-methyl-3,4-dihydropyrimidin-5-yl) pentanové v dávce 200 mg/kg p. o. snížil velikost nádoru Kr 2 o 64 °/o.5- (2-Amino-4-oxo-6-methyl-3,4-dihydropyrimidin-5-yl) pentanoic acid allyl ester at a dose of 200 mg / kg p.o. reduced the Kr 2 tumor size by 64%.
Butylester kyseliny 5-(2-amino-4-oxo-6-methyl-3,4-dlhydropyrimidin-5-yl) pentanové v dávce 200 mg/kg p. o. zmenšil velikost nádoru Kr 2 o 58 % a STE o 26 %. V dávce 100 mg/kg p. o. S 37 o 20 %.5- (2-Amino-4-oxo-6-methyl-3,4-dlhydropyrimidin-5-yl) pentanoic acid butyl ester at a dose of 200 mg / kg p.o. reduced the tumor size Kr 2 by 58% and STE by 26%. At a dose of 100 mg / kg p.o. S 37 by 20%.
Isobutylester kyseliny 5-(2-amino-4-oxo-6-methyl-3,4-dihydropyrimidin-5-yl) pentano vé v dávce 200 mg/kg p. o. zmenšil velikost nádoru STE o 31 °/o.5- (2-Amino-4-oxo-6-methyl-3,4-dihydropyrimidin-5-yl) pentanoic acid isobutyl ester at a dose of 200 mg / kg p.o. reduced the tumor size of STE by 31%.
Cyklohexylester kyseliny 5-(2~amino-4-oxo-6-methyl-3,4-dihydropyrimidin-5-yl j pentanové v dávce 200 mg/kg p. o. snížil velikost nádoru Kr 2 o 26 % a STE o 33 %.5- (2-Amino-4-oxo-6-methyl-3,4-dihydropyrimidin-5-yl) pentanoic acid cyclohexyl ester at a dose of 200 mg / kg p.o. reduced the Kr 2 tumor size by 26% and the STE by 33%.
2-Fenylethylester kyseliny 5-(2-amino-4-oxo-6-methyl-3,4-dlhydropyrimidin-5-yl)pentanové snížil v dávkách 200 mg/kg p. o., resp. 100 mg/kg s. c., statisticky nevýznamně velikosti nádoru Kr 2 o 33, resp. 25 %.5- (2-Amino-4-oxo-6-methyl-3,4-dihydropyrimidin-5-yl) pentanoic acid 2-phenylethyl ester reduced in doses of 200 mg / kg p.o. 100 mg / kg s.c., statistically insignificant tumor size Kr 2 of 33, respectively. 25%.
Ethylester kyseliny 5-(2-amino-4-oxo-6-ethyl-3,4-dihydropyrimidin-5-yl) pentanové v dávce 50 mg/kg p. o. zmenšil velikost nádoru S 37 o 17 % a v dávce 100 mg/kg p. o. o 15 %.5- (2-Amino-4-oxo-6-ethyl-3,4-dihydropyrimidin-5-yl) pentanoic acid ethyl ester at 50 mg / kg after reducing tumor size S 37 by 17% and at 100 mg / kg 15%.
Ethylester kyseliny 5-(2-amino-4-oxo-6-butyl-3,4-dihydropyrimidin-5-yl] pentanové v dávce 200 mg/kg p. o. snížil velikost nádoru Kr 2 o 36 % a STE o 32 °/o.5- (2-Amino-4-oxo-6-butyl-3,4-dihydropyrimidin-5-yl) pentanoic acid ethyl ester at a dose of 200 mg / kg after reducing the Kr 2 tumor size by 36% and STE by 32% / o .
Methylester kyseliny 5-(2-amino-4-oxo-6-pentyl-3,4-dihydropyrimidin-5-yl) pentanové v dávce 200 mg/kg p. o. snížil velikost nádoru STE o 39 θ/ο. V dávce 100 mg/kg p. o. snížil velikost nádoru STE o 41 % a nádoru Kr 2 o 38 %. V dávce 100 mg/kg s. c. snížil velikost nádoru Kr 2 o 63 °/o.Methyl 5- (2-amino-4-oxo-6-pentyl-3,4-dihydropyrimidine-5-yl) pentanoic acid, 200 mg / kg reduced tumor size by 39 STE θ / ο. At a dose of 100 mg / kg po reduced the size of the STE tumor by 41% and the Kr 2 tumor by 38%. At a dose of 100 mg / kg sc, it reduced the Kr 2 tumor size by 63 ° / o.
4,2 O 5 O4.2 O 5 O
Ethylester kyseliny 5-(2-amino-4-oxo-8-pentyl-3,4-dihydropyrimidin-5-yl)pentanové v dávce 200 mg/kg p. o. snížil velikost nádoru HK o 28 % a v dávce 100 mg/kg p. o. Kr 2 o 64 %, S 37 o 45 % a HK o 18 %.5- (2-Amino-4-oxo-8-pentyl-3,4-dihydropyrimidin-5-yl) pentanoic acid ethyl ester at 200 mg / kg po reduced HK tumor size by 28% and at 100 mg / kg po Kr 2 by 64%, S 37 by 45% and HK by 18%.
Allylester kyseliny 5-(2-amino-4-oxo-6-pentyl-3,4-dihydropyrimidin-5-yl)pentanové snížil v dávce 200 mg/kg p. o. velikost nádoru STE o 48 % a Kr 2 o 26 %. V dávce 50 mg/kg s. c. snížil velikost nádoru Kr 2 o 20 %.5- (2-Amino-4-oxo-6-pentyl-3,4-dihydropyrimidin-5-yl) pentanoic acid allyl ester reduced the tumor size of STE by 48% and Kr2 by 26% at a dose of 200 mg / kg p.o. At a dose of 50 mg / kg s.c., it reduced the Kr 2 tumor size by 20%.
Butylester kyseliny 5-(2-amino-4-oxo-S-pentyl-3,4-dihydropyrimidin-5-yl) pentanové dávce 200 mg/kg p. o. snížil velikost nádoru STE o 32 % a Kr 2 o 44 %. V dávce 100 mg/kg p. o. snížil velikost nádoru Kr 2 o 34 % a prodloužil přežiti zvířat s tímto nádorem o 24 %. V dávce 100 mg/kg s. c, snížil velikost nádoru Kr 2 o 25 %.5- (2-Amino-4-oxo-5-pentyl-3,4-dihydropyrimidin-5-yl) pentanoic acid butyl ester at a dose of 200 mg / kg p.o. reduced the tumor size of STE by 32% and Kr 2 by 44%. At a dose of 100 mg / kg p.o., it reduced Kr 2 tumor size by 34% and prolonged the survival of animals with this tumor by 24%. At a dose of 100 mg / kg s.c, it reduced Kr 2 tumor size by 25%.
Pentylester kyseliny 5-(2-amlno-4-oxo-C-pentyl-3,4-dihydropyrimidin-5-yl)pentano· vé v dávce 200 mg/kg p. o. snížil velikost nádoru STE o 36 % a Kr 2 o 46 %. V dávce 100 mg/kg p. o. snížil velikost nádoru STE o 37 % a Kr 2 o 53 %.5- (2-Amino-4-oxo-C-pentyl-3,4-dihydropyrimidin-5-yl) pentanoic acid pentyl ester at a dose of 200 mg / kg after reducing the tumor size of STE by 36% and Kr 2 by 46% . At a dose of 100 mg / kg p.o., the tumor size was reduced by STE by 37% and Kr2 by 53%.
Ethylester kyseliny 5-(2-amino-4-oxo-6-hexyl-3,4-dihydropyrimidin-5-yl)pentanové v dávce 50 mg/kg p. o. snížil velikost nádoru Kr 2 o 29 %.5- (2-Amino-4-oxo-6-hexyl-3,4-dihydropyrimidin-5-yl) pentanoic acid ethyl ester at a dose of 50 mg / kg p.o. reduced the Kr 2 tumor size by 29%.
Benzylester kyseliny 5-(2-amino-4-oxo-6 -pentyl-3,4-dihydropyrimldin-5-yl) pentanové v dávce 200 mg/kg p. o. snížil velikost nádoru Kr 2 o 36 % a rovněž v dávce 10(1 miligramů na kilogram p. o. o 36 %. V dávkách 100 mg/kg s. c., resp. 50 mg/kg s. c. snížil velikost nádoru Kr 2 o 35 %, resp. o 23 %.5- (2-Amino-4-oxo-6-pentyl-3,4-dihydropyrimidin-5-yl) pentanoic acid benzyl ester at 200 mg / kg after reducing Kr 2 tumor size by 36% and also at 10 (1) At doses of 100 mg / kg sc and 50 mg / kg sc, the tumor size of Kr 2 was reduced by 35% and 23%, respectively.
Látky obecného vzorce I, o výše uvedeném významu R1 a R2, se vyrábějí tím způsobem, že se thionylchlorid v množství 1 až 3 molekvivalentů, výhodně 1,1 molekvi· valentu, přidá do přebytku látek obecného vzorce II,Compounds of formula I having the above meanings of R 1 and R 2 are manufactured by way that the thionyl chloride in an amount of 1-3 molar equivalents, preferably 1.1 mol eq · Valenta added to an excess of compounds of formula II,
R1—OH (lij ve kterémR 1 -OH (wherein ij
R1 má výše uvedený význam, ochlazené na teplotu —5 až —40 °C, přičemž látka obecného vzorce II, o výše uvedeném významu R1, se použije jako reakční prostředí, načež se vzniklý reaktivní derivát ponechá reagovat s látkami obecného vzorce III,R 1 has the abovementioned meaning, cooled to -5 to -40 ° C, wherein the compound of formula II, on the abovementioned meaning of R 1 is used as the reaction medium and then the resulting reactive derivative is reacted with compounds of formula III
ve kterémin which
R2 má výše uvedený význam, nejprve při teplotě —5 až —40 °C a poté při teplotě od 40 °C až do teploty varu použitého reakčního prostředí.R 2 has the abovementioned meaning, initially at -5 to -40 ° C and then at a temperature from 40 ° C to the boiling point of the reaction medium.
Látky obecného vzorce III jsou látky známé a snadno získatelné postupem podle čs. autorského osvědčení č. 226 946.Compounds of formula (III) are known and readily obtainable by the process of U.S. Pat. Certificate No. 226 946.
Bližší podrobnosti o způsobu přípravy látek obecného vzorce I, o výše uvedeném významu R1 a R2, vyplynou z následujících příkladů provedení.Further details of the process for preparing compounds of formula I having the above meanings of R 1 and R 2 will emerge from the following examples.
Příklad 1Example 1
Ethylester kyseliny 5-(2-amino-4-oxo-6-methyl-3,4-dihydropyrimidin-5-yl )pentanové5- (2-Amino-4-oxo-6-methyl-3,4-dihydropyrimidin-5-yl) pentanoic acid ethyl ester
K 50 ml ethanolu, ochlazenému na —20 stupňů Celsia, se za míchání přikape 3,93 g (0,033 mol) thionylchloridu a k takto připravenému reaktivnímu derivátu se za chlazení přisype po částech 6,76 g (0,03 mol) kyseliny 5- (2-amino-4-oxo-6-methyl-3,4-dihydropyrimidin-5-yl) pentanové a vzniklá suspenze se míchá při téže teplotě 1 hodinu. Poté se reakční teplota zvýší na 40 OC, reakční směs se míchá další 2 hodiny a reakce se dokončí 2 hodiny refluxem, přičemž se suspenze rozpustí. Přebytečný ethanol se z reakční směsi odstraní odpařením na rotačním vakuovém zařízení při vakuu vodní pumpy, vzniklý odparek se rozmíchá v 75 ml vody, vzniklá suspenze se zneutralizuje hydrogenuhličitanem sodným a odfiltruje se. Po promytí odfiltrované látky vodou a vysušení se získá surový produkt, který se přečistí krystalizaci z ethanolu. Získá se látka o teplotě tání 197 až 199 °C.3.93 g (0.033 mol) of thionyl chloride are added dropwise with stirring to 50 ml of ethanol cooled to -20 degrees Celsius, and 6.76 g (0.03 mol) of 5- ( 2-Amino-4-oxo-6-methyl-3,4-dihydropyrimidin-5-yl) pentanoic acid and the resulting suspension was stirred at the same temperature for 1 hour. The reaction temperature was raised to 40 ° C, the reaction mixture was stirred for another 2 hours and the reaction is complete two hours reflux, the suspension dissolved. Excess ethanol is removed from the reaction mixture by evaporation on a rotary vacuum apparatus under a water pump vacuum, the residue is stirred in 75 ml of water, the suspension is neutralized with sodium bicarbonate and filtered. After washing the filtered material with water and drying, a crude product is obtained which is purified by crystallization from ethanol. M.p. 197-199 ° C.
Stejným způsobem za užití příslušných alkoholů a výchozích kyselin obecného vzorce III k esterifikaci se připraví následující látky:In the same manner, using the appropriate alcohols and starting acids of formula III for esterification, the following compounds are prepared:
methylester kyseliny 5-(2-amino-4-oxo-6-methyl-3,4-dihydropyrimidin-5-yl) pentanové, teplota tání 207 až 208°C, (ethanol);5- (2-Amino-4-oxo-6-methyl-3,4-dihydropyrimidin-5-yl) pentanoic acid methyl ester, m.p. 207-208 ° C, (ethanol);
propylester kyseliny 5-(2-amino-4-oxo-6-methyl-3,4-dihydropyrimidin-5-yl) pentanové, teplota tání 193 až 194°C, (ethanol);5- (2-Amino-4-oxo-6-methyl-3,4-dihydropyrimidin-5-yl) pentanoic acid propyl ester, m.p. 193-194 ° C, (ethanol);
butylester kyseliny 5-(2-amino-4-oxo-6-methyl-3,4-dihydropyrimidin-5-yl j pentanové, teplota tání 188 až 190 °C, (ethanol);5- (2-Amino-4-oxo-6-methyl-3,4-dihydropyrimidin-5-yl) pentanoic acid butyl ester, m.p. 188-190 ° C, (ethanol);
isobutylester kyseliny 5-(2-amino-4-oxo-6-methyl-3,4-dihydropyrimidin-5-yl)pentanové, teplota tání 181 až 183 °C, (70% vodný ethanol j;5- (2-Amino-4-oxo-6-methyl-3,4-dihydropyrimidin-5-yl) pentanoic acid isobutyl ester, m.p. 181-183 ° C, (70% aqueous ethanol;
allylester kyseliny 5-(2-amino-4-oxo-6-methyl-3,4-dihydropyrimidin-5-yljpentanové, teplota tání 183 až 185 °C, (ethanol);5- (2-Amino-4-oxo-6-methyl-3,4-dihydropyrimidin-5-yl) pentanoic acid allyl ester, m.p. 183-185 ° C, (ethanol);
4 2 O 5 O4 2 O 5 O
3-chlorpropylester kyseliny 5-(2-amino-4-oxo-6-methyl-3,4-dihydropyrimidin-5-yl) pentanové, teplota tání 160 až 162 °C, (ethanol);5- (2-Amino-4-oxo-6-methyl-3,4-dihydropyrimidin-5-yl) pentanoic acid 3-chloro ester, m.p. 160-162 ° C, (ethanol);
cyklohexylester kyseliny 5-(2-amino-4-oxo-6-methyl-3,4-dihydropyrimidln-5-yl)pentanové, teplota tání 193 až 195 °C, (ethanol);5- (2-amino-4-oxo-6-methyl-3,4-dihydropyrimidin-5-yl) pentanoic acid cyclohexyl ester, m.p. 193-195 ° C, (ethanol);
2-fenylethylester kyseliny 5-(2-amino-4-oxo-6-methyl-3,4-dihydropyrimidin-5-yl) pentanové, teplota tání 172 až 174 °C, (ethanol);5- (2-Amino-4-oxo-6-methyl-3,4-dihydropyrimidin-5-yl) pentanoic acid 2-phenylethyl ester, m.p. 172-174 ° C, (ethanol);
ethylester kyseliny 5-(2-amino-4-oxo-6-ethyl-3,4-dihydropyrimidin-5-yl) pentanové, teplota tání 74 až 77 °C, (20% vodný ethanol);5- (2-Amino-4-oxo-6-ethyl-3,4-dihydropyrimidin-5-yl) pentanoic acid ethyl ester, m.p. 74-77 ° C, (20% aqueous ethanol);
ethylester kyseliny 5-(2-amino-4-oxo-6-butyl-3,4-dihydropyrimidin-5-yl) pentanové, teplota tání 116 až 119 °C, (70% vodný ethanol);5- (2-Amino-4-oxo-6-butyl-3,4-dihydropyrimidin-5-yl) pentanoic acid ethyl ester, m.p. 116-119 ° C, (70% aqueous ethanol);
ethylester kyseliny 5-(2-amino-4-oxo-6-hexyl-3,4-dihydropyrimidin-5-yl) pentanové, teplota tání 197 až 199 °C, (70% vodný ethanol).5- (2-Amino-4-oxo-6-hexyl-3,4-dihydropyrimidin-5-yl) pentanoic acid ethyl ester, m.p. 197-199 ° C, (70% aqueous ethanol).
Příklad 2Example 2
Ethylester kyseliny 5-(2-amino-4-oxo-6-pentyl-3,4-dihydropyrimidin-5-yl) pentanové5- (2-Amino-4-oxo-6-pentyl-3,4-dihydropyrimidin-5-yl) pentanoic acid ethyl ester
K 30 ml ethylalkoholu, ochlazenému na —10 °C, se za míchání přikape 1,31 g (0,011 mol) thionylchloridu a přidá se po částech 2,81 g (0,01 mol) kyseliny 5-(2-amino-4-oxo-6-pentyl-3,4-dihydropyrimidin-5-yl) pentanové a vzniklá suspenze se ponechá reagovat 1 hodinu při téže teplotě. Další průběh reakce i zpracování reakční směsi se provede stejným postupem jako v příkladu 1. Získá se látka o teplotě tání 201 až 204 °C, po krystalizaci surového produktu ze 40% vodného roztoku ethanolu.To thionyl chloride (1.31 g, 0.011 mol) was added dropwise to 30 ml of cooled ethanol at -10 ° C and 5- (2-amino-4-) (2.81 g, 0.01 mol) was added dropwise with stirring. oxo-6-pentyl-3,4-dihydropyrimidin-5-yl) pentane and the resulting suspension was allowed to react for 1 hour at the same temperature. Further work-up and work-up of the reaction mixture were carried out in the same manner as in Example 1. A material having a melting point of 201-204 ° C was obtained after crystallization of the crude product from 40% aqueous ethanol.
Stejným postupem za užití příslušných alkoholů se připraví následující látky:Using the same procedure using the appropriate alcohols, the following substances are prepared:
methylester kyseliny 5-(2-amino-4-oxo-6pentyl-3,4-dihydropyrimidin-5-yl) pentanové, teplota tání 207 až 209 °C, (50% vodný ethanol);5- (2-Amino-4-oxo-6-pentyl-3,4-dihydropyrimidin-5-yl) pentanoic acid methyl ester, m.p. 207-209 ° C, (50% aqueous ethanol);
butylester kyseliny 5-(2-amino-4-oxo-6-pentyl-3,4-dihydropyrimidin-5-yl) pentanové, teplota tání 184 až 186 °C, (60% vodný ethanol);5- (2-Amino-4-oxo-6-pentyl-3,4-dihydropyrimidin-5-yl) pentanoic acid butyl ester, m.p. 184-186 ° C, (60% aqueous ethanol);
pentylester kyseliny 5-(2-amino-4-oxo-6-pentyl-3,4-dihydropyrimídin-5-yl)pentanové, teplota tání 184 až 187 °C, (60% vodný ethanol);5- (2-Amino-4-oxo-6-pentyl-3,4-dihydropyrimidin-5-yl) pentanoic acid pentylester, m.p. 184-187 ° C, (60% aqueous ethanol);
allylester kyseliny 5-(2-amlno-4-oxo-6-pentyl-3,4-dihydropyrimidin-5-yl)pentanové, teplota tání 191 až 194 °C, (60% vodný ethanol);5- (2-Amino-4-oxo-6-pentyl-3,4-dihydropyrimidin-5-yl) pentanoic acid allyl ester, m.p. 191-194 ° C, (60% aqueous ethanol);
benzylester kyseliny 5-(2-amino-4-oxo-6-pentyl-3,4-dihydropyrimidin-5-yl)pentanové, teplota tání 200 až 202 °C, (50% vodný thanol).5- (2-Amino-4-oxo-6-pentyl-3,4-dihydropyrimidin-5-yl) pentanoic acid benzyl ester, m.p. 200-202 ° C, (50% aqueous thanol).
Claims (19)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS8410292A CS242050B1 (en) | 1984-12-22 | 1984-12-22 | Antineoplastically effective esters of 5-(2-amino-4-oxo-6-alkyl-3,4-dihydropyrimidine-5-yl)-pentanoic acids |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS8410292A CS242050B1 (en) | 1984-12-22 | 1984-12-22 | Antineoplastically effective esters of 5-(2-amino-4-oxo-6-alkyl-3,4-dihydropyrimidine-5-yl)-pentanoic acids |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CS1029284A1 CS1029284A1 (en) | 1985-08-15 |
| CS242050B1 true CS242050B1 (en) | 1986-04-17 |
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| Application Number | Title | Priority Date | Filing Date |
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| CS8410292A CS242050B1 (en) | 1984-12-22 | 1984-12-22 | Antineoplastically effective esters of 5-(2-amino-4-oxo-6-alkyl-3,4-dihydropyrimidine-5-yl)-pentanoic acids |
Country Status (1)
| Country | Link |
|---|---|
| CS (1) | CS242050B1 (en) |
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1984
- 1984-12-22 CS CS8410292A patent/CS242050B1/en unknown
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| Publication number | Publication date |
|---|---|
| CS1029284A1 (en) | 1985-08-15 |
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