CS225537B1 - Antineoplastic effective ethyl 5-/2-chlorethylcarbamyol/ amine-4-oxo-6-hydroxy-3,4-dihydropyrimidine-5-yl/pentanoate and its manufacture - Google Patents
Antineoplastic effective ethyl 5-/2-chlorethylcarbamyol/ amine-4-oxo-6-hydroxy-3,4-dihydropyrimidine-5-yl/pentanoate and its manufacture Download PDFInfo
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- CS225537B1 CS225537B1 CS655982A CS655982A CS225537B1 CS 225537 B1 CS225537 B1 CS 225537B1 CS 655982 A CS655982 A CS 655982A CS 655982 A CS655982 A CS 655982A CS 225537 B1 CS225537 B1 CS 225537B1
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- hydroxy
- pentanoate
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 title claims description 5
- 238000004519 manufacturing process Methods 0.000 title claims description 4
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 title claims description 3
- 230000000118 anti-neoplastic effect Effects 0.000 title description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 17
- BCMYXYHEMGPZJN-UHFFFAOYSA-N 1-chloro-2-isocyanatoethane Chemical compound ClCCN=C=O BCMYXYHEMGPZJN-UHFFFAOYSA-N 0.000 claims description 4
- 239000011541 reaction mixture Substances 0.000 claims description 4
- 239000012442 inert solvent Substances 0.000 claims description 3
- 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 claims description 3
- -1 2- (2-chloroethylcarbamoyl) amino-4-oxo-6-hydroxy-3,4-dihydropyrimidin-5-yl Chemical group 0.000 claims description 2
- 238000009835 boiling Methods 0.000 claims description 2
- 206010028980 Neoplasm Diseases 0.000 description 11
- 150000001875 compounds Chemical class 0.000 description 9
- 238000000034 method Methods 0.000 description 4
- 206010039491 Sarcoma Diseases 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- BITBMHVXCILUEX-UHFFFAOYSA-N 2-chloroethylurea Chemical compound NC(=O)NCCCl BITBMHVXCILUEX-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- AVQQQNCBBIEMEU-UHFFFAOYSA-N 1,1,3,3-tetramethylurea Chemical compound CN(C)C(=O)N(C)C AVQQQNCBBIEMEU-UHFFFAOYSA-N 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 230000008512 biological response Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 238000012750 in vivo screening Methods 0.000 description 1
- WWECJGLXBSQKRF-UHFFFAOYSA-N n,n-dimethylformamide;methanol Chemical compound OC.CN(C)C=O WWECJGLXBSQKRF-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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Description
Vynález se týká antineoplasticky účinného ethyl 5-/2-(2-chlorethylkarbamoyl) amino-4-oxo-6-hydroxy-3>4-dihydropyriraidin-5-yl/pentanoátu vzorce I,The invention relates to an antineoplastically active ethyl 5- [2- (2-chloroethylcarbamoyl) amino-4-oxo-6-hydroxy-3,4-dihydropyriraidin-5-yl] pentanoate of the formula I,
(Uih WbJtf (i) jakož i způsobu jeho výroby.(Uih WbJtf (i)) as well as a method for its manufacture.
Látka vzorce I je derivátem kyseliny 5'-(2-araino-4-oxo-6-hydroxy-3»4-dihydropyrimidin-5-yl)p®utanové (Československé autorské osvědčení Č. 176667), která vykázala některé farmakologické vlastnosti, využitelné při léčbě nádorových onemocnění zvířat i lidí (Semonský M. a sp. s Cancer chemotherapy, Part 2, 8, 1976, s. 107, Collection Czech.Chem.Commun. 45.3583 (1980)} Semonská S.: Sborník IX. Ostravského chemického symposia, 3. sekce, 1980, s. 22) a která je považována za modulátor biologické odpovědi farmak, podaných s ní v kombinaci. Struktura látky vzorce I představuje derivát ÉF-súbstituované N-(2-chlorethyl)močoviny, kde substituce na atomu N'představuje zbytek pyrimidinového antimetábolitu. Látka vzorce 1 byla testována na antineoplastickou aktivitu obvyklým screeningovým postupem in vivo, za užití experimentálních transplantovatelných nádorů u myší (Crockerův sarkom S 180, ascitickýThe compound of formula I is a derivative of 5 '- (2-araino-4-oxo-6-hydroxy-3,4-dihydropyrimidin-5-yl) butanoic acid (Czechoslovakian Patent Certificate No. 176667), which has shown some pharmacological properties, useful in the treatment of cancer in animals and humans (Semonský M. et al. with Cancer chemotherapy, Part 2, 8, 1976, p. 107, Collection Czech.Chem.Commun. 45.3583 (1980)} Semonská S .: Proceedings of IX. chemical symposium, Section 3, 1980, p. 22) and which is considered to modulate the biological response of drugs administered in combination. The structure of the compound of formula (I) is a derivative of the N -butstituted N- (2-chloroethyl) urea wherein the substitution at the N 'atom represents the remainder of the pyrimidine antimetabolite. Compound 1 was tested for antineoplastic activity by a conventional in vivo screening procedure using experimental transplantable tumors in mice (Crocker sarcoma S 180, ascites)
225 537 sarkom Sa 137, Krebsův ascitický sarkom Kr 2) a krys (Yoshidův ascitický nádor Y) způsob testování viz například Jelínek V.: Neoplasma 12. 469 (1965)? J, 146 (1960).225 537 sarcoma Sa 137, Krebs ascitic sarcoma Kr 2) and rat (Yoshid's ascitic tumor Y) for a test method see, for example, Jelínek V .: Neoplasma 12. 469 (1965)? J, 146 (1960).
Látka vzorce I vykázala v dávce 50 mg/kg s.c. prodloužení přežití myší s nádorem S 180 o 19 %, u nádoru Sa 37 o 56 % při současném zmenšení velikosti nádoru o 12 % a u nádoru Kr 2 hodnotu totálního ascitokritu 72 % ve srovnání s kontrolní skupinou. V dávce 100 mg/kg s.c. snižovala velikost nádoru Sa 37 o 41 %, pří hodnotě totálního ascitokritu 72 %. Při perorálním podání dávky 200 mg/kg u nádoru Kr 2 snižovala velikost nádoru o 17 % při hodnotě totálního ascitokritu 80 %, ve srovnání s kontrolní skupinou. Srovnáním antineoplastické aktivity látky vzorce X s aktivitou kyseliny 5-(2-amino-4-oxo-6-hydroxy-3,4-dihydropyrimidin-5-yl) pentanovou vyplynula vyšší aktivita testované látky vzorce I, způsobená přítomností 2-ohlorethylkarbaraoylového zbytku v molekule.The compound of formula I exhibited a dose of 50 mg / kg s.c. prolonged survival of mice with S 180 tumor by 19%, Sa 37 tumor by 56% while reducing tumor size by 12% and total tumor ascitocrit 72% compared to control group. At a dose of 100 mg / kg s.c. reduced the tumor size of Sa 37 by 41%, at a total ascitocrit value of 72%. When administered orally at a dose of 200 mg / kg in a Kr2 tumor, it reduced the tumor size by 17% at a total ascitocrit value of 80% compared to the control group. Comparison of the anti-neoplastic activity of the compound of formula X with that of 5- (2-amino-4-oxo-6-hydroxy-3,4-dihydropyrimidin-5-yl) pentanoate showed a higher activity of the test compound of formula I caused by the presence of the 2-chloroethylcarbaraoyl residue in molecule.
Látka vzorce I, i když sama vykazuje zajímavý antineoplastický účinek, je zároveň vhodným meziproduktem pro synthesu dalších látek s potenciálním antineoplastickým účinkem.The compound of formula (I), while itself exhibiting an interesting antineoplastic effect, is also a suitable intermediate for the synthesis of other substances having a potential antineoplastic effect.
Podle vynálezu se látka vzorce I připravuje tím způsobem, že se nechá reagovat látka vzorce IIAccording to the invention, a compound of formula I is prepared by reacting a compound of formula II
(tt-Jv IMtlr (II) s 1 až 2 molekvivalenty 2-chlorethylisokyanátu vzorce III, ci-oh2-oh2-n=o=o (III) výhodně s 1,1 molekvivalentem, v prostředí inertního rozpouštědla,(tt-Jv IMtlr (II) with 1 to 2 mol equivalents of 2-chloroethyl isocyanate of formula III, c 1 -h 2 -oh 2 -n = o = o (III) preferably with 1.1 mol equivalents, in an inert solvent medium,
- 3 '- 3 '
225 537 výhodně v dimethylformamidu, v rozmezí teplot od 20 °G až do teploty varu reakční směsi.225 537 preferably in dimethylformamide, in the temperature range from 20 ° C to the boiling point of the reaction mixture.
Po ukončení reakce se reakční směs zpracuje oddestilovaním inertního rozpouštědla a surový produkt se přečistí krystalizací.After completion of the reaction, the reaction mixture is worked up by distilling off the inert solvent and the crude product is purified by crystallization.
K přípravě substituované 2-chlorethylmočoviny lze použít i jiných postupů, běžně používaných v synthetické organické chemii, avšak použití 2-chlorethylisokyanátu přináší značné výhody v jednoduchosti provedení reakce.Other methods commonly used in synthetic organic chemistry may be used to prepare substituted 2-chloroethylurea, but the use of 2-chloroethyl isocyanate provides considerable advantages in the ease of carrying out the reaction.
Jako inertní prostředí pro provedení reakce lze použít jakékoliv prostředí nereagující s látkou vzorce II nebo III, a reakci je možné provádět v homogenní i heterogenní fázi. Průběh v homogenní fázi vyžaduje taková prostředí, v nichž se látka vzorce II rozpouští, to znamená látky typu dimethylformamidu, dimethylacetamidu, hexamethylfosfortriamidu, tetramethylmočoviny a podobně. Použití dimethylformamidu je dávána přednost z ekonomických důvodů a vzhledem k příznivým fyzikálně chemickým vlastnostem.Any inert non-reactive species of formula (II) or (III) may be used as the inert reaction medium, and the reaction may be carried out in a homogeneous or heterogeneous phase. The homogeneous phase requires environments in which the compound of formula II dissolves, i.e., dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide, tetramethylurea and the like. The use of dimethylformamide is preferred for economic reasons and because of the favorable physicochemical properties.
Látka vzorce II je látka známá a snadno vyrobitelná podleThe compound of formula (II) is a substance known and easy to manufacture according to
Československého autorského osvědčení č. 2.45 55*+·Czechoslovak Authorial Certificate No. 2.45 55 * + ·
Způsob výroby látky vzorce I vyplyne z následujícího příkladu provedení, který však rozsah vynálezu nikterak neomezuje.The process for the preparation of the compound of formula (I) will be apparent from the following non-limiting example.
Ethyl 5-/2-(2-chlorethylkarbamoyl)amino-4-oxo-6-hydroxy-3,4dihydropyrimidin-5-yl/pentanoát.Ethyl 5- [2- (2-chloroethylcarbamoyl) amino-4-oxo-6-hydroxy-3,4-dihydropyrimidin-5-yl] pentanoate.
K roztoku 10,2 g (0,04 mol) ethyl 5-(2-amino-4-oxo-6-hydroxy-3,4-dihydropyrimidin-5-yl)pentanoátu ve 100 ml dimethylformamidu se přidá při teplotě 100 °0 4,6 g (0,044 mol) 2-chlorethylisokyanátu a reakční směs se míchá při téže teplotě 5 hodin. Po oddestilování dimethylformamidu zá vakua vodní pumpy se vzniklý odparek vyvaří v 90 % vodném roztoku ethanolu a nerozpuštěný zbytek se odfilt- 4 225 537 ruje, vysuší a překrystalizuje ze směsi dimethylformamid-methanol (1:2). Rekrystalizací se získá bílá krystalická látka o teplotě tání 240 až 242 °C.To a solution of 10.2 g (0.04 mol) of ethyl 5- (2-amino-4-oxo-6-hydroxy-3,4-dihydropyrimidin-5-yl) pentanoate in 100 ml of dimethylformamide was added at 100 ° C. 4.6 g (0.044 mol) of 2-chloroethyl isocyanate are added and the reaction mixture is stirred at the same temperature for 5 hours. After the DMF was distilled off under vacuum from a water pump, the resulting residue was boiled in 90% aqueous ethanol and the undissolved residue was filtered off, dried, and recrystallized from dimethylformamide-methanol (1: 2). Recrystallization gave a white crystalline solid, m.p. 240-242 ° C.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS655982A CS225537B1 (en) | 1982-09-10 | 1982-09-10 | Antineoplastic effective ethyl 5-/2-chlorethylcarbamyol/ amine-4-oxo-6-hydroxy-3,4-dihydropyrimidine-5-yl/pentanoate and its manufacture |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS655982A CS225537B1 (en) | 1982-09-10 | 1982-09-10 | Antineoplastic effective ethyl 5-/2-chlorethylcarbamyol/ amine-4-oxo-6-hydroxy-3,4-dihydropyrimidine-5-yl/pentanoate and its manufacture |
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| Publication Number | Publication Date |
|---|---|
| CS225537B1 true CS225537B1 (en) | 1984-02-13 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS655982A CS225537B1 (en) | 1982-09-10 | 1982-09-10 | Antineoplastic effective ethyl 5-/2-chlorethylcarbamyol/ amine-4-oxo-6-hydroxy-3,4-dihydropyrimidine-5-yl/pentanoate and its manufacture |
Country Status (1)
| Country | Link |
|---|---|
| CS (1) | CS225537B1 (en) |
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1982
- 1982-09-10 CS CS655982A patent/CS225537B1/en unknown
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