CS196852B1 - Esters of n-/delta-/6-purinylthio/butyl/carbamic acid and method for producing thereof - Google Patents
Esters of n-/delta-/6-purinylthio/butyl/carbamic acid and method for producing thereof Download PDFInfo
- Publication number
- CS196852B1 CS196852B1 CS781577A CS781577A CS196852B1 CS 196852 B1 CS196852 B1 CS 196852B1 CS 781577 A CS781577 A CS 781577A CS 781577 A CS781577 A CS 781577A CS 196852 B1 CS196852 B1 CS 196852B1
- Authority
- CS
- Czechoslovakia
- Prior art keywords
- butyl
- purinylthio
- carbamic acid
- esters
- ester
- Prior art date
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- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 title claims description 7
- 150000002148 esters Chemical class 0.000 title description 3
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 title 1
- 238000004519 manufacturing process Methods 0.000 title 1
- KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 title 1
- -1 6-purinylthio Chemical group 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- JOYRKODLDBILNP-UHFFFAOYSA-N urethane group Chemical group NC(=O)OCC JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 claims description 6
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 4
- 229940112021 centrally acting muscle relaxants carbamic acid ester Drugs 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- SKKTUOZKZKCGTB-UHFFFAOYSA-N butyl carbamate Chemical compound CCCCOC(N)=O SKKTUOZKZKCGTB-UHFFFAOYSA-N 0.000 claims description 3
- OCAAZRFBJBEVPS-UHFFFAOYSA-N prop-2-enyl carbamate Chemical compound NC(=O)OCC=C OCAAZRFBJBEVPS-UHFFFAOYSA-N 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims 2
- 239000002253 acid Substances 0.000 claims 1
- 150000001540 azides Chemical class 0.000 claims 1
- PUJDIJCNWFYVJX-UHFFFAOYSA-N benzyl carbamate Chemical compound NC(=O)OCC1=CC=CC=C1 PUJDIJCNWFYVJX-UHFFFAOYSA-N 0.000 claims 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 241000700157 Rattus norvegicus Species 0.000 description 2
- 241000700159 Rattus Species 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 201000008274 breast adenocarcinoma Diseases 0.000 description 1
- 230000003327 cancerostatic effect Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 244000144993 groups of animals Species 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 125000000561 purinyl group Chemical class N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Vynález se týká esterů kyseliny N-/á(6-purinylthio) butyl/karbamové obecného vzorce I ve kterém R značí alkylskupinu s 1 až 4 atomy uhlíku, allyl- nebo benzylskupinu a způsob jejich výroby.The invention relates to N- (a-6 (purinylthio) butyl) carbamic esters of the general formula I in which R represents a C 1 -C 4 alkyl, allyl or benzyl group and a process for their preparation.
Estery kyseliny N-/ó-(6-purinulthio) butyl/karbamové obecného vzorce I jsou antimetabolity purlnových baží nukleových kyselin a vyznačují se kancerostatickým účinkem vůči experimentálním nádorům myší a krys. Na příklad butylester kyseliny N-/á-(6-purinylthio) butyl/karbamové prodlužuje, při orální aplikaci v dávce 200 mg/ kg, dobu života krys kmene Wistar s Yoshidovým ascitickým sarkomem na 145 °/o, ve srovnání s dobou života kontrolní neléčené skupiny zvířat, jejichž doba života = 100 %. Obdobný účinek u krysy Wistar se stejným nádorem má při aplikaci ve stejné dávce např. ethylester kyseliny N7d-(6-purinylthio) butyl/karbamové, který prodlužuje doÍ)U ŠiYOtS léčených zvířat na 133 %. Allylester kyseliny N-/<5-(6-purinylthio) butyl/ karbamové má příznivý therapeutický účinek u myší kmene H s adenokarcinomem mléčné žlázy; při dávce 100 mg/kg p. o. zmenšuje velikost nádoru na 73 % oproti kontrolní skupině zvířat neléčených a prodlužuje dobu života léčených zvířat na 124 %.The N- [6- (6-purinulthio) butyl] carbamic acid esters of formula (I) are antimetabolites of purine bases of nucleic acids and exhibit a cancerostatic effect against experimental tumors of mice and rats. For example, N- (a- (6-purinylthio) butyl) carbamic acid butyl ester prolongs the life of Wistar rats with Yoshida ascitic sarcoma to 145 ° / o compared to the control life when administered orally at 200 mg / kg. untreated groups of animals whose lifespan = 100%. A similar effect in Wistar rats with the same tumor has, for example, ethyl N7d- (6-purinylthio) butyl / carbamic acid ethyl ester, which extends to 133% of the treated animals at the same dose. Allyl N - [? - (6-purinylthio) butyl] carbamic acid allyl ester has a beneficial therapeutic effect in mice strain H with mammary adenocarcinoma; at a dose of 100 mg / kg p.o., it reduces the tumor size to 73% compared to the untreated control group and extends the lifespan of the treated animals to 124%.
Podle vynálezu se estery kyseliny N-/5(6-purinylthio) butyl/karbamové vyrobí tak, že azid kyseliny á-(6-purinylthio) valerové vzorce IIAccording to the invention, N- (5- (6-purinylthio) butyl) carbamic esters are prepared by the formation of the α- (6-purinylthio) valeric acid azide of formula II
S-(CHj)»,— CON3 ú?S- (CH3) », - CON 3 ú?
se zahřívá s přebytkem příslušného alkoholu ROH (III), ve kterém R má výše uvedený význam, na teplotu 60 až 120 °C. Meziproduktem táto reakce je á-(6-purinylthio) butylisokyanát vzorce IV ,-NCOis heated with an excess of the corresponding alcohol ROH (III), in which R is as defined above, to a temperature of 60 to 120 ° C. The intermediate of this reaction is the α- (6-purinylthio) butyl isocyanate of formula IV, -NCO
Estery kyseliny N-/<S-(6-purinylthio) butyl/ karbamové I se isolují z reakčních směsí známými způsoby, např. oůůestilováním po196 8S2N - [(S) - (6-purinylthio) butyl] carbamic acid esters I are isolated from the reaction mixtures by known methods, e.g.
196 852 užitého přebytečného alkoholu a krystalisací získaného produktu, případně čištěním sloupcovou chromatografii.196 852 of the excess alcohol used and crystallization of the product obtained, optionally by column chromatography.
Potřebný výchozí azid kyseliny 6-(6-purinylthio) valerové vzorce II se dá připravit podle čsl. patentového spisu 128123.The required starting 6- (6-purinylthio) valeric acid azide of formula II can be prepared according to art. No. 128123.
Bližší podrobnosti způsobu podle vynálezu vyplynou z následujících příkladů provedení, které však rozsah tohoto vynálezu nijak neomezují. Teploty tání uvedených sloučenin jsou stanoveny na Koflerově bloku a jsou uvedeny, stejně jako ostatní údaje teplot, ve °C.Further details of the process according to the invention will be apparent from the following non-limiting examples. The melting points of the compounds are determined on the Kofler block and are given, as with other temperature data, in ° C.
PŘÍKLADY PROVEDENIEXAMPLES OF EXECUTION
Ethylester kyseliny N-/í-(6-purinylthio) butyl/karbamové 2,77 g (0,01 mol] azidu kyseliny í-(6-purinylthio) valerové se suspenduje v 60 ml ethanolu a za vyloučení vzdušné vlhkosti a za míchání se směs vaří pod zpětným chladičem 5 hodin. Horký roztok se sfiltruje přes fritu a z filtrátu se oddestiluje většina ethanolu za sníženého tlaku, při teplotě lázně 30 až 40°. Odparek poskytne po překrystalování ze směsi ethanol — heptan, za užití karborafinu, čistý ethylester kyseliny N-/á-(6-purinylthio) butyl/karbamové ve formě bílých krystalků o b1. t. 113—115°.N- (N- (6-purinylthio) butyl) carbamic acid ethyl ester 2.77 g (0.01 mol) of az- (6-purinylthio) valeric acid azide is suspended in 60 ml of ethanol, with exclusion of air humidity and stirring. The mixture was refluxed for 5 hours, the hot solution was filtered through a frit, and most of the ethanol was distilled off under reduced pressure at a bath temperature of 30-40 ° C. - / a- (6-purinylthio) butyl / butyl ester as white crystals ob first t. 113-115.
Stejným způsobem, za použití příslušných alkoholů místo ethanolu, byly připraveny např. butylester kyseliny N-/5-(6-puriniylthio) butyl/karbamové, t. t. 119 až 121° (z acetonu), benzylester kyseliny N-/á(6-purinylthio) butyl/karbamové, při reakční teplotě 120°, ť. t. 130 až 131° (z acetonu), allylester kyseliny N-/á-(6-purinylthio) butyl/karbamové, t. t. 92 až 94° (z acetonu).In the same way, using the appropriate alcohols instead of ethanol, for example, N- [5- (6-puriniylthio) butyl] carbamic acid butyl ester, mp 119-121 [deg.] (From acetone), N- [alpha] (6-purinylthio) benzyl ester were prepared. butyl / carbamic, at a reaction temperature of 120 °, m.p. 130-131 ° (from acetone), allyl N- (6-purinylthio) butyl / carbamic acid allyl ester, mp 92-94 ° (from acetone).
Claims (5)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS781577A CS196852B1 (en) | 1977-11-25 | 1977-11-25 | Esters of n-/delta-/6-purinylthio/butyl/carbamic acid and method for producing thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS781577A CS196852B1 (en) | 1977-11-25 | 1977-11-25 | Esters of n-/delta-/6-purinylthio/butyl/carbamic acid and method for producing thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CS196852B1 true CS196852B1 (en) | 1980-04-30 |
Family
ID=5427972
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS781577A CS196852B1 (en) | 1977-11-25 | 1977-11-25 | Esters of n-/delta-/6-purinylthio/butyl/carbamic acid and method for producing thereof |
Country Status (1)
| Country | Link |
|---|---|
| CS (1) | CS196852B1 (en) |
-
1977
- 1977-11-25 CS CS781577A patent/CS196852B1/en unknown
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