CS201187B1 - Lactones of 7-ethyl-4-/4-ethylphenyl/-1-methoxyhydroxymethynaphthalencarboxylic acids - Google Patents
Lactones of 7-ethyl-4-/4-ethylphenyl/-1-methoxyhydroxymethynaphthalencarboxylic acids Download PDFInfo
- Publication number
- CS201187B1 CS201187B1 CS127278A CS127278A CS201187B1 CS 201187 B1 CS201187 B1 CS 201187B1 CS 127278 A CS127278 A CS 127278A CS 127278 A CS127278 A CS 127278A CS 201187 B1 CS201187 B1 CS 201187B1
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- CS
- Czechoslovakia
- Prior art keywords
- ethylphenyl
- ethyl
- lactones
- methoxyhydroxymethynaphthalencarboxylic
- acids
- Prior art date
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- 125000004860 4-ethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])C([H])([H])[H] 0.000 title description 2
- 150000002596 lactones Chemical class 0.000 title description 2
- -1 7-ethyl-4- (4-ethylphenyl) -1-methoxyhydroxymethylnaphthalenecarboxylic acid lactones Chemical class 0.000 claims description 11
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 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 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 238000012925 biological evaluation Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- OFGGZGXWRWYORO-UHFFFAOYSA-N methanol;tetrachloromethane Chemical compound OC.ClC(Cl)(Cl)Cl OFGGZGXWRWYORO-UHFFFAOYSA-N 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Furan Compounds (AREA)
Description
Vynález se týká laktonů kyselin 7-etbyl-4-/4-ethylfenyl/-1-methoxy-hydroxynaftalenkarboxylových obecného vzorce I,The present invention relates to 7-ethyl-4- (4-ethylphenyl) -1-methoxy-hydroxynaphthalenecarboxylic acid lactones of the formula I:
Co Ht Co H t
Λ J Λ «4 ve kterém buď X1 značí atom kyslíku a X* značí dva atomy vodíku, nebo X značí dva ato2 my vodíku a X značí atom kyslíku.Λ J Λ 4 4 in which either X 1 denotes an oxygen atom and X * denotes two hydrogen atoms, or X denotes two ato2 my hydrogen and X denotes an oxygen atom.
•i p• i p
Látky obecného vzorce I, ve kterém X a X mají výše uvedený význam, vykázaly při biologickém hodnocení na zvířatech s transplantovanými nádory antineoplastický účinek a jsou potenciálními chemoterapeutiky lidských nádorových onemocnění. Například lakton kyseliny 7-ethyl-4-/4-ethylfenyl/-3-hydroxymethyl-3-methoxynaftalen-2-karboxylové, v dávce 100 mg/kg/d, podávané subkutánně myším kontinuálně po dobu 10 dnů prodloužil významně dobu života léčených zvířat se sarkomem S 180 ve srovnání s kontrolní skupinou zvířat neléČených. Mimo to jsou látky obecného vzorce I, o výše uvedeném významu XThe compounds of formula I, in which X and X are as defined above, have shown an antineoplastic effect in biological evaluation in animals transplanted with tumors and are potential chemotherapeutic agents for human cancer. For example, 7-ethyl-4- (4-ethylphenyl) -3-hydroxymethyl-3-methoxynaphthalene-2-carboxylic acid lactone, at a dose of 100 mg / kg / d, administered subcutaneously to mice continuously for 10 days significantly increased the life span of treated animals. sarcoma S 180 compared to the untreated control group. In addition, the compounds of formula I are as defined above X
201 187201 187
- 2 201 187 a X^ cennými technickými meziprodukty pro synthésu dalších farmakologicky účinných látek.2 201 187 and X 0 are valuable technical intermediates for the synthesis of other pharmacologically active substances.
22
Látky obecného vzorce I, ve kterém X a X mají výše uvedený význam, se připravují z látky vzorce II,Compounds of formula I in which X and X are as defined above are prepared from a compound of formula II,
/ II / H5 C2 působením minimálně 1 molekvivalentu borohydridu sodného, výhodně s 15 až 30 molekviValenty, v prostředí nižšího alkoholu, výhodně methanolu, při teplotě od 20 °C až do teploty varu reakční směsi, po dobu 2 až 8 hodin.(II) H 5 C 2 by treating at least 1 mol equivalents of sodium borohydride, preferably with 15 to 30 mol equivalents, in a lower alcohol, preferably methanol, at a temperature of from 20 ° C to the boiling point of the reaction mixture for 2 to 8 hours.
Reakční směs po redukci borohydridem sodným se zpracuje obvyklým způsobem pro tento typ reakcí, například po oddestilování alkoholu se surový produkt rozpustí ve vodě, okyselí se zředěnou kyselinou solnou a vyloučená látka se vyjme do chloroformu nebo benzenu a směs laktonů se rozdělí chromatografii na sloupci silikagelu a přečistí krystalizací z vhodného rozpouštědla nebo směsi rozpouštědel.The reaction mixture after reduction with sodium borohydride is worked up in the usual manner for this type of reaction, for example, after distilling off the alcohol, the crude product is dissolved in water, acidified with dilute hydrochloric acid and the precipitated substance is taken up in chloroform or benzene. purified by crystallization from a suitable solvent or solvent mixture.
Látka vzorce II je snadno získatelná) její příprava je popsána v popise vynálezu k čs. autorskému osvědčení č. 195 766.The compound of formula (II) is readily obtainable. Certificate No. 195 766.
K redukci karbonylové skupiny látky vzorce II lze rovněž použít i jiných činidel, běžně používaných v organické chemii jako acetyloxyborohydridu sodného v prostředí kyseliny octové a dioxanu, synhydridu v prostředí benzenu, lithiumaluminiumhydridu v tetrahydrofuranu, atd. Tyto způsoby jsou však z hlediska ekonomického i výtěžkového méně výhodné.Other reagents commonly used in organic chemistry such as sodium acetyloxyborohydride in acetic acid and dioxane, synhydride in benzene, lithium aluminum hydride in tetrahydrofuran, etc. may also be used to reduce the carbonyl group of the compound of formula II. conveniently.
«I"AND
Podrobnější údaje o přípravě látek obecného vzorce I, o výše uvedeném významu X o a X , vyplynou z následujícího příkladu provedení. V příkladu uvedené teploty tání jsou stanoveny na Koflerově bloku a nejsou korigovány) hodnoty teplot jsou uvedeny ve stupních Celsia.More detailed information on the preparation of the compounds of formula I, with the meanings given above, of X o and X, will be apparent from the following exemplary embodiment. In the example, the melting points are determined on the Kofler block and are not corrected) the temperature values are given in degrees Celsius.
PříkladExample
Lakton kyseliny 7-ethyl-4-/4-ethylfenyl/-2-hydroxymethyl-1-methoxynaftalen-3-karboxylové a lakton kyseliny 7-ethyl-4-/4-ethylfenyl/-3-hydrooymethyl-1-methoxynaftalenv2-karboxylové.7-Ethyl-4- (4-ethylphenyl) -2-hydroxymethyl-1-methoxynaphthalene-3-carboxylic acid lactone and 7-ethyl-4- (4-ethylphenyl) -3-hydrooymethyl-1-methoxynaphthalene-2-carboxylic acid lactone.
K roztoku 6,0 g (16,7 mmol) anhydridu kyseliny 7-ethyl-4-/4-ethylfenyl/-1-methoxynaftalen-2,3-dikarboaqrlové v 600 ml methanolu, ohřátému na 40 °C, se přidá po malých dávkách, postupně, 12,0 g (0,316 mol) borohydridu sodného a po ukončení vývoje vodíku se reakční směs refluxuje 2 hodiny. Po ochlazení reakční směsi a oddestilování methanolu ve vakuu vodní vývěvy se odparek rozpustí v 600 ml vody a okyselí se zředěnou ky- 3 201187 selinou solnou (1:1) na pH 3, vyloučený produkt se vyjme do chloroformu, chloroformový roztok se protřepe s vodou a chloroformová vrstva se vysuší bezvodým síranem sodným a odpaří se do sucha. Získaná směs laktonů se rozdělí chromátografií na sloupci * silikagélu za užití směsi tetrachlormethanu a 5 % benzenu jako elučního činidla. V prvních podílech se oddělí lakton kyseliny 7-ethyl-4-/4-ethylfenyl/-3-hydroxymethyl-1-methoxynaftalen-2-karboxylové, který po krystalizaci ze směsi tetrachlormethan-methanol (1:5) vykázal teplotu tání 93 až 94 °C. V dalších frakcích se získá lakton kyseliny 7-ethyl-4-/4-ethylfenyl/-2-hydroxymethyl-1-methoxynaftalen-3-karboxylové, který po krystalizaci ze směsi stejných rozpouštědel vykázal teplotu tání 101 až 103 °C.To a solution of 6.0 g (16.7 mmol) of 7-ethyl-4- (4-ethylphenyl) -1-methoxynaphthalene-2,3-dicarboxylic acid in 600 ml of methanol heated to 40 ° C was added in small portions. of sodium borohydride, and after completion of hydrogen evolution, the reaction mixture was refluxed for 2 hours. After cooling the reaction mixture and distilling off methanol in a water pump vacuum, the residue is dissolved in 600 ml of water and acidified with dilute hydrochloric acid (1: 1) to pH 3, the precipitated product is taken up in chloroform, the chloroform solution is shaken with water. and the chloroform layer was dried over anhydrous sodium sulfate and evaporated to dryness. The resulting lactone mixture was separated by silica gel column chromatography using a mixture of carbon tetrachloride and 5% benzene as eluent. 7-Ethyl-4- (4-ethylphenyl) -3-hydroxymethyl-1-methoxynaphthalene-2-carboxylic acid lactone, which, after crystallization from tetrachloromethane-methanol (1: 5), showed a melting point of 93-94 in the first fractions. Deň: 32 ° C. In other fractions, 7-ethyl-4- (4-ethylphenyl) -2-hydroxymethyl-1-methoxynaphthalene-3-carboxylic acid lactone was obtained which, after crystallization from a mixture of the same solvents, had a melting point of 101-103 ° C.
Claims (3)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS127278A CS201187B1 (en) | 1978-02-28 | 1978-02-28 | Lactones of 7-ethyl-4-/4-ethylphenyl/-1-methoxyhydroxymethynaphthalencarboxylic acids |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS127278A CS201187B1 (en) | 1978-02-28 | 1978-02-28 | Lactones of 7-ethyl-4-/4-ethylphenyl/-1-methoxyhydroxymethynaphthalencarboxylic acids |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CS201187B1 true CS201187B1 (en) | 1980-10-31 |
Family
ID=5346685
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS127278A CS201187B1 (en) | 1978-02-28 | 1978-02-28 | Lactones of 7-ethyl-4-/4-ethylphenyl/-1-methoxyhydroxymethynaphthalencarboxylic acids |
Country Status (1)
| Country | Link |
|---|---|
| CS (1) | CS201187B1 (en) |
-
1978
- 1978-02-28 CS CS127278A patent/CS201187B1/en unknown
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