CS218548B1 - Alpha-substituted derivatives of the 5-/4-oxo-3,4-dihydropyrimidin-5-yl/pentane acid and method of making the same - Google Patents
Alpha-substituted derivatives of the 5-/4-oxo-3,4-dihydropyrimidin-5-yl/pentane acid and method of making the same Download PDFInfo
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- CS218548B1 CS218548B1 CS787681A CS787681A CS218548B1 CS 218548 B1 CS218548 B1 CS 218548B1 CS 787681 A CS787681 A CS 787681A CS 787681 A CS787681 A CS 787681A CS 218548 B1 CS218548 B1 CS 218548B1
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- Czechoslovakia
- Prior art keywords
- oxo
- acid
- dihydropyrimidin
- hydroxy
- mercapto
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- 239000002253 acid Substances 0.000 title claims description 16
- 238000004519 manufacturing process Methods 0.000 title claims 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims description 15
- -1 5- (2-mercapto-6-hydroxy-4-oxo-3,4-dihydropyrimidin-5-yl) -α-butylpentanoic acid Chemical compound 0.000 claims description 14
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- 239000004202 carbamide Substances 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims description 3
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N Valeric acid Natural products CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 1
- 150000005602 pentanoic acid derivatives Chemical class 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 5
- 238000000034 method Methods 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 230000000118 anti-neoplastic effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 206010003445 Ascites Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 230000008512 biological response Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 230000001085 cytostatic effect Effects 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- HDMIPESLVQBMCL-UHFFFAOYSA-N ethyl 5-bromo-2-methylpentanoate Chemical compound CCOC(=O)C(C)CCCBr HDMIPESLVQBMCL-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 150000005603 pentanoic acids Chemical class 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Vynález se týká «-substitučních derivátů kyseliny 5- (4-oxo-3,4-dihydropyrinndi8i-5-yljpentamové obecného vzorce IThe present invention relates to 5- (4-oxo-3,4-dihydropyrrolidin-5-yl) pentamic acid derivatives of the formula I
ve kterém R1 značí hydroxy- nebo merkaptoskupinu a R2 alkyl s 1 až 5 atomy uhlíku nebo hydroxyskupinu, jakož i způsobu výroby uvedených látek.wherein R @ 1 is hydroxy or mercapto and R @ 2 is C1 -C5 alkyl or hydroxy, and a process for the preparation of said compounds.
Deriváty obecného vzorce I jsou odvozeny od kyseliny 5-(2-amino-6-hydfroxy-4-oxo-3,4-dihydropyrl·midm-5-yl)pentan.ové, tj. sloučeniny, ve které R1 značí aminoskupinu a R2 atom vodíku a která se projevila jako významný potenciátor účinku klinicky užívaných cytostatik. Látky obecného vzoirce I ma-jí podobné vlastnosti a jsou potenciálně využitelné jako chemoterapeutika a modulátory biologické odpovědi jiných farmak.Compounds of formula I are derived from 5- (2-amino-6-hydfroxy-4-oxo-3,4-dihydropyrl · midm-5-yl) pentan.ové, i.e. compounds in which R 1 is amino and R 2 is a hydrogen atom and has been shown to be a potent potentiator of the action of clinically used cytostatics. The compounds of formula (I) have similar properties and are potentially useful as chemotherapeutic agents and modulators of the biological response of other drugs.
Látky obecného vzorce I, o výše uvedeném významu R1 a R2, vykazovaly při screeningovém hodnocení na antineoplastický účinek u zvířat s experimentálními nádory mírný antineoplastický účinek, v dávkovém rozmezí 50 až 100 mg/kg při s. c. aplikaci, projevující se zmenšením hmoty nádoru. Nej výraznější aktivitu z látek obecného vzorce I o výše uvedeném významu R1 a R2 vykázíala látka vzorce I, kde R1 značí merkaptoskupinu a R2 značí pentylskupiinu, která v dávce 100 mg/kg aplikovaná s. c. myším s nádorem Kr 2 zmenšila velikost nádoru o 22 %. Podobně látka obecného vzorce I, kde R1 značí merkaptoskupinu a R2 značí methylskupinu, prodloužila dobu přežití zvířat s nádorem Kr 2 v dávce 50 m‘g/kg s. c. o 21 %. Látka obecného vzorce I, kde R1 značí hydroxyskupinu a R2 značí me.tylskupinu podobně prodloužila přežití zvířat s ascitickou formou Yoshidova nádoru v dávce 100 mg/kg s. c. o 27 %.Compounds of formula I having the above meanings of R 1 and R 2, exhibited a screening evaluation for antineoplastic activity in animals with experimental tumors slight antineoplastic effect, in the dose range 50-100 mg / kg sc, manifested by reduction in tumor mass. The most significant activity of the compounds of formula (I), R 1 and R 2, was the compound of formula (I), wherein R 1 is a mercapto group and R 2 is a pentyl group which reduced the tumor size at 100 mg / kg. by 22%. Similarly, a compound of formula I, wherein R 1 is mercapto and R 2 is methyl, increased the survival time of Kr 2 tumor animals at 50 mg / kg sc by 21%. Similarly, the compound of formula I, wherein R 1 is hydroxy and R 2 is methyl, has extended the survival of the animals with ascites form of Yoshida tumor at a dose of 100 mg / kg sc by 27%.
Podle vynálezu lze látky obecného vzorce I o výše uvedeném významu R1 a R2 vyrobit tím způsobem, že se triester trikarboxylové kyseliny obecného vzorce II ^OOC>H-(CHJíCH-COORi According to the invention compounds of formula I having the above meanings of R 1 and R 2 can be formed in such a way that the tricarboxylic acid triester of the formula II ^ OOC> H - (i CHJíCH -COOR
Rbocx lRz: (li ) ve kterém R3 značí methyl- nebo ethylskupinu a R2‘ má stejný význam jako R2 v obecném vzorci I nebo značí acetoxyskupinu, kondenzuje s močovinou, resp. s thiomočovinou v přítomnosti alkoholátu sodného, výhodně methylátu sodného, načež se surový kondenzát zmýdelní a látka obecného vzorce I o výše uvedeném významu R1 a R2 se z roztoku uvolní minerální kyselinou a přečistí se krystalizaci.RbOC xl Rz (Ii) wherein R 3 represents methyl or ethyl and R 2 'has the same meaning as R 2 in formula I or represents an acetoxy group, is condensed with urea, respectively. with thiourea in the presence of sodium alcoholate, preferably sodium methylate, whereupon the crude condensate is saponified and the product of formula I having the above meanings of R 1 and R 2 from solution released with mineral acid and purified by crystallization.
Látky obecného vzorce II o výše uvedeném významu R2‘ a R3 lze připravit, většinou ve velmi dobrém výtěžku, metodou popsanou například pro syntézu triéthylesteru kyseliny 2-ka,rboxy-l,7-heptandiové [Karrer P. a spol.: Helv. Chim Acta 27, 237 (1944)], tj. kondenzací sodné soli diethyl-l,3-dioátu nebo dimethyl-l,3-dioátu s methyl- nebo ethylestery 5-halogenovaných pentanových kyselin, výhodně hromovaných, obecného vzorce IIICompounds of formula (II), R 2 'and R 3 , as described above, can be prepared, mostly in very good yield, by a method described, for example, for the synthesis of 2-ca, rboxy-1,7-heptanedioic acid triethyl ester [Karrer P. et al .: Helv . Chim Acta 27, 237 (1944)], i.e. by condensation of the sodium salt of diethyl 1,3-dioate or dimethyl 1,3-dioate with the methyl or ethyl esters of 5-halogenated pentanoic acids, preferably thickened, of the general formula III
Br— (CH2]3—CH—COOR3 ,Br - (CH 2) 3 —CH — COOR 3 ,
R2‘ (Hl) kde R2‘ a R3 mají stejný význam jak výše uvedeno. Látky obecného vzorce III lze připravit metodou popsianou například pro syntézu ethylesteru kyseliny 2-methyl-5-brompentanové [Kessar S. V. a spo!l.: Tetrahedron 24, 899 (1968)].R2 '(HI) wherein R 2' and R 3 have the same meanings as described above. Compounds of formula III may be prepared by the method described for example for the synthesis of 2-methyl-5-bromopentanoic acid ethyl ester [Kessar SV et al . 1: Tetrahedron 24, 899 (1968)].
Bližší podrobnosti o způsobu přípravy látek obecného vzorce I o výše uvedeném významu R1 a R2 vyplynou z následujícího příkladu provedení, který však rozsah tohoto vynálezu nikterak neomezuje.Further details of the process for the preparation of the compounds of the formula I with the above-mentioned meanings of R 1 and R 2 are given by the following non-limiting example.
Kyselina 5- (2-merk!apto-6-hydroxy-4-oxo-3,4-dihydrojpyrimidin-5-yl) -«-butylpentanoivá5- (2-Merk! Apto-6-hydroxy-4-oxo-3,4-dihydrojpyrimidin-5-yl) - «- butylpentanoivá
K roztoku methylátu sodného, připraveného rozpuštěním 27,6 g (1,20 molu) sodíku ve 400 ml methanolu se při teplotě 40 až 50°C za míchání vnese 91,35 g (1,20 molu) thiomočoviny a pak 137,78 g (0,40 molu) triethylesteru kyseliny 2-butyl-6-kairboxy-l,7-heptandio:vé. Reakční směs se míchá 4 hodiny při teplotě místnosti a pak se nechá stát přes noc. Po oddestilování methanolu za sníženého tlaku se odpíarek zmýdelní 800 ml 0,5 N NaOH při teplotě 20 až 25 °C, zfiltruje se a filtrát se okyselí zředěnou kyselinou chlorovodíkovou (1:1) na pH 3. Vyloučená látka se po ochlazení odfiltruje, promyje vodou a vysuší. Získaná látka se přečistí krystalizaci z 50% vodného ethanolu. T. t. 165 až 167 °C.To a solution of sodium methylate prepared by dissolving 27.6 g (1.20 mol) of sodium in 400 ml of methanol at 40-50 ° C was added with stirring 91.35 g (1.20 mol) of thiourea and then 137.78 g. (0.40 mole) of triethyl 2-butyl-6-kairboxy-l, 7-heptandio By. The reaction mixture was stirred at room temperature for 4 hours and then allowed to stand overnight. After distilling off the methanol under reduced pressure, the residue is saponified with 800 ml of 0.5 N NaOH at 20-25 ° C, filtered and the filtrate is acidified with dilute hydrochloric acid (1: 1) to pH 3. The precipitate is filtered off, washed water and dried. The material was purified by crystallization from 50% aqueous ethanol. Mp 165-167 ° C.
Stejným způsobem jak uvedeno v příkladu, za použití odpovídajících triesterů trikarboxylových kyselin obecného vzorce II a močoviny, resp. thiomočoviny, byly připraveny následující sloučeniny:In the same manner as in the example, using the corresponding tricarboxylic acid triesters of the general formula II and urea respectively. thiourea, the following compounds were prepared:
kyselina 5-(2,6-dihydroxy-4-oxo-3,4-dihydiropyrimidin-5-yl)~«-methýlperitano'vá, t. t. 207 až 209 °C, kyselina 5- (2,6-dihydroxy-4-oxo-3,4-dihydropyrimidin-5-yl) -«-ethyrpentanoVá, t. t. 163 až 164 °C, kyselina 5-(2,6-dihydroxy-4-oxo-3,4-dihydropyrimidin-5-yl) -«-pr opyřpontanová, t. t. 137 až 138 °C, kyselina 5- (2,6-dihydr oxy-4-oxo-3,4-dihydropyrimidin-5-yl) -«-butylpentano.vá, t. t. 132 až 134 °C, kyselina 5- (2,6-dihydroxy-4-oxo-3,4-dihydropyrimidin-5-yl) -«-pentylipentanová, t. t. 144 až 145 °C, kyselina 5- (2-merkapto-6-hydroxy-4-oxo-3,4-dihydfropyrimidin-5-yl)-«-méthyipentanová, t. t. 193 až 194 °C, kyselina 5-(2-meirikapto-6-hydroxy-4-oxo-3,4-dihydropyrimidin-5-yl)-,«-pro'pylpentanová, t. t. 70 až 72 °C, kyselina 5- (2-merkápto-6-hydroxy-4-oxo-3,4-dihydrp;pyrimidin-5-yi)-a-pentylpemtanová, t. t. 75 až 77 °C, kyselina 5- (2-merkapto-6-hydroxy-4-oxo-3,4-dihydropy.rLmidin-5-yl)-a-hydroxypen-tanová (s 1 molekulou krystalové vody), t. t. 248 až 250 °C.5- (2,6-dihydroxy-4-oxo-3,4-dihydiropyrimidin-5-yl) -4-methylperitanoic acid, mp 207-209 ° C, 5- (2,6-dihydroxy-4- oxo-3,4-dihydropyrimidin-5-yl) - N-ethylpentanoic acid, mp 163-164 ° C, 5- (2,6-dihydroxy-4-oxo-3,4-dihydropyrimidin-5-yl) -. -propropanoic acid, mp 137-138 ° C, 5- (2,6-dihydroxy-4-oxo-3,4-dihydropyrimidin-5-yl) - n -butylpentanoic acid, mp 132-134 ° C, 5- (2,6-dihydroxy-4-oxo-3,4-dihydropyrimidin-5-yl) -4-pentylipentanoic acid, mp 144-145 ° C, 5- (2-mercapto-6-hydroxy-4- oxo-3,4-dihydfropyrimidin-5-yl) - «- méthyipentanová, mp 193-194 DEG C. 5- (2-Me i rikapto-6-hydroxy-4-oxo-3,4-dihydropyrimidine-5- 5- (2-mercapto-6-hydroxy-4-oxo-3,4-dihydrp ; pyrimidin-5-yl) -. alpha.-pentylpentanoic acid, m.p. mp 75-77 ° C, 5- (2-mercapto-6-hydroxy-4-oxo-3,4-dihydropyrimidin-5-yl) -α-hydroxypentanoic acid (with 1 crystal water molecule), mp Mp 248-250 ° C.
Claims (12)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS787681A CS218548B1 (en) | 1981-10-27 | 1981-10-27 | Alpha-substituted derivatives of the 5-/4-oxo-3,4-dihydropyrimidin-5-yl/pentane acid and method of making the same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS787681A CS218548B1 (en) | 1981-10-27 | 1981-10-27 | Alpha-substituted derivatives of the 5-/4-oxo-3,4-dihydropyrimidin-5-yl/pentane acid and method of making the same |
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| Publication Number | Publication Date |
|---|---|
| CS218548B1 true CS218548B1 (en) | 1983-02-25 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS787681A CS218548B1 (en) | 1981-10-27 | 1981-10-27 | Alpha-substituted derivatives of the 5-/4-oxo-3,4-dihydropyrimidin-5-yl/pentane acid and method of making the same |
Country Status (1)
| Country | Link |
|---|---|
| CS (1) | CS218548B1 (en) |
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1981
- 1981-10-27 CS CS787681A patent/CS218548B1/en unknown
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