CZ294094B6 - }SB@}FenylacetamidoB@}@pyridylBpropionová kyselina a způsob její připravy - Google Patents

}SB@}FenylacetamidoB@}@pyridylBpropionová kyselina a způsob její připravy Download PDF

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CZ294094B6
CZ294094B6 CZ20021311A CZ20021311A CZ294094B6 CZ 294094 B6 CZ294094 B6 CZ 294094B6 CZ 20021311 A CZ20021311 A CZ 20021311A CZ 20021311 A CZ20021311 A CZ 20021311A CZ 294094 B6 CZ294094 B6 CZ 294094B6
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pyridyl
phenylacetamido
propionic acid
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general formula
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Costanzoámichaeláj
Hoekstraáwilliamáj
Maryanoffábruceáe
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Ortho@Mcneilápharmaceuticalźáinc
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    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
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    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Abstract

}SB@}FenylacetamidoB@}@pyridylBpropionová kyselina vzorce AG@ a způsob její přípravyŹ při němž se @}fenylacetamidoB@}@pyridylBpropionová kyselina vzorce AG@ nechá reagovat s penicilinamidázouŹ výhodně takŹ že se penicilinamidázou působí na vodný roztok sloučeniny vzorce AG@Ź jehož hodnota pH byla předběžně nastavena na asi @ŹQ@ Kyselina vzorce AG@ slouží jako meziprodukt pro přípravu karboxamidových derivátů pyrrolidinuŹ piperidinu a hexahydroazepinuŹ které mohou být použity jako léčiva pro léčení trombotických poruch zprostředkovaných destičkamiŕ

Description

Oblast techniky
Vynález se týká (S)-3-(fenylacetamido)-3-(3-pyridyl)-propionové kyseliny a způsobu její přípravy. Tato kyselina slouží jako meziprodukt pro přípravu karboxamidových derivátů pyrrolidinu, piperidinu a hexahydroazepinu. Posledně uvedené sloučeniny mohou být použity jako léčiva pro léčení trombotických poruch zprostředkovaných destičkami.
Dosavadní stav techniky
Racemickou 3-(fenylacetamido)-3-(3-pyridyl)propionovou kyselinu je možno připravit podle E. Profft, J, Prakt. Chem. 1965, 30, 18. Její S-enantiomer, který je předmětem tohoto vynálezu však dosud nebyl popsán.
Podstata vynálezu
Předmětem vynálezu je (S)-3-(fenyIacetamido)-3-(3-pyridyl)propionová kyselina vzorce AG4
(AG4)
Dalším předmětem vynálezu je také způsob výroby sloučeniny AG4, jehož podstata spočívá v tom, že se 3-(fenylacetamido)-3-(3-pyridyl)propionová kyselina vzorce AG3
(AG3) nechá reagovat s penicilinamidázou.
Ve výhodném provedení tohoto způsobu se postupuje tak, že se se penicilinamidázou působí na vodný roztok sloučeniny vzorce AG3, jehož hodnota pH byla předběžně nastavena na asi 7,5.
Výchozí 3-(fenylacetamido)-3-(3-pyridyl)propionová kyselina vzorce AG3 se připravuje za použití modifikovaného Knoevanagelova postupu (schéma AG; E. Profft, J. Prakt. Chem. 1965, 30, 18). Kyselina vzorce AG3 se způsobem podle vynálezu obohatí o S-enantiomer selektivním štěpením pomocí penicilinamidázy (V. A. Soloshonok, Tetrahedron:Asymmetry 1965, 6, 1601).
-1 1
Nežádoucí R-enantiomer se pomocí amidázy hydrolyzuje, zatímco S-enantiomer si udrží fenylacetylovou skupinu.
Schéma AG
CH2(CO2H)2
NH4OAc
EtOHrcflux
PhCH2COCl
EtjN, vodný aceton
H
AG3
Penícilinamídáza pH7,5 (aq.)
Kyselina vzorce AG4 slouží jako meziprodukt pro přípravu karboxamidových derivátůpyrrolidonu, piperidinu a hexahydroazepinu obecného vzorce I:
ť (CH^-A (l) kde:
A je zvolen ze souboru zahrnujícího 2-piperidyl, 3—piperidyl, 4-piperidyl, 1-piperazinyl, 2-pyrrolidinyl, 3-pyrrolidinyl a NHR2;
R2 je zvolen ze souboru zahrnujícího H, alkyl s 1 až 8 atomy uhlíku a acyl se 2 až 6 atomy uhlíku a přednostně znamená vodík;
m je celé číslo 1, 2 nebo 3 a přednostně znamená 1 nebo 2;
X je zvolen ze souboru zahrnujícího C(O), C(O)O, C(O)NH, CH2 a SO2;
n je celé číslo 1, 2 nebo 3;
R1 je zvolen ze souboru zahrnujícího vodík a cykloalkyl s 5 až 8 atomy uhlíku;
Y je zvolen ze souboru zahrnujícího (CH2)P, CH(R3)(CH2)q, (CH2)qCH(R3), (CH(COR4)CH2)q, (CH2)qCHOH a 3-piperidinkarboxylovou kyselinu; s výhradou, že když Y je (CH2)P a p je 2, X je jiný než C(O), nebo když X je C(O), potom buď R1 je jiný než H, nebo R2 je jiný než H, a s další výhradou, že když X je (CH(CO2R4)CH2)q, X je jiný než C(O) nebo CH2;
p je 2 nebo 3;
q je 1, 2 nebo 3 a přednostně 1;
R3 je alkyl s 1 až 8 atomy uhlíku, alkenyl se 2 až 8 atomy uhlíku, alkinyl se 2 až 8 atomy uhlíku, fenyl, naftyl, fenylalkyl s 1 až 8 atomy uhlíku v alkylové části, naftylalkyl s 1 až 8 atomy uhlíku v alkylové části nebo heteroaryl, kterým může být pyridyl, thienyl, furyl, nebo chinolyl;
R4 je vodík nebo alkyl s 1 až 8 atomy uhlíku nebo cykloalkyl s 5 až 8 atomy uhlíku a přednostně znamená vodík;
Z je CO2H, CO2alkyl, SO3H, PO3H2 nebo 5-tetrazol.
Sloučeniny obecného vzorce I, které jsou předmětem základního patentu, jsou inhibitory agregace destiček a jako takové jsou užitečné při léčbě trombotických poruch zprostředkovaných destičkami, jako je arteriální a venózní trombóza, akutní infarkt myokardu, nestabilní angína, reokluze následující trombolytickou terapii a angioplastiku, zápal a různé vazookluzivní poruchy. Tyto sloučeniny jsou užitečné také jako antitrombotická činidla použitá v souvislosti s fibrinolytickou terapií (například t-PA nebo streptokináza).
Přiklad provedení vynálezu (S)-3-(Fenylacetamido)-3-(3-pyridyl)propionová kyselina
3-(Fenylacetamido)-3-(3-pyridyl)propionová kyselina vzorce AG3 se připraví za použití standardních způsobů, jak jsou znázorněny ve schématu AG (E. Profft, J. Prakt. Chem. 1965, 30, 18). Roztok sloučeniny AG3 (0,225 mol) ve vodě (600 ml) se při teplotě místnosti nastaví na pH 7,5 za použití KOH (3,0 N) a nechá reagovat s penicilinamidázou (91 502 jednotek, Sigma). Tato směs se míchá 47 hodin, okyselí na pH 1 pomocí HC1 (konc.) a výsledná sraženina se odfiltruje přes celatom FW-14. Filtrát se extrahuje Et2O (3 x 300 ml) a zkoncentruje ve vakuu.
PATENTOVÉ NÁROKY

Claims (3)

  1. PATENTOVÉ NÁROKY
    1. (S)-3-(Fenylacetamido)-3-(3-pyridyl)propionová kyselina vzorce AG4 (AG4)
  2. 2. Způsob přípravy (S)-3-(fenylacetamido)-3-(3-pyridyl)-propionové kyseliny vzorce AG4, vyznačující se tím, že 3-(fenylacemitado)-3-(3-pyridyl)propionová kyselina vzorce AG3 (AG3) nechá reagovat s penicilinamidázou.
  3. 3. Způsob podle nároku 2, v y z n a č u j í c í se tím, že se se penicilinamidázou působí na vodný roztok sloučeniny vzorce AG3, jehož hodnota pH byla předběžně nastavena na 7,5.
    Konec dokumentu
CZ20021311A 1996-05-01 1997-04-29 }SB@}FenylacetamidoB@}@pyridylBpropionová kyselina a způsob její připravy CZ294094B6 (cs)

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CZ20021311A CZ294094B6 (cs) 1996-05-01 1997-04-29 }SB@}FenylacetamidoB@}@pyridylBpropionová kyselina a způsob její připravy

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HUP0201347A3 (en) * 1999-03-22 2002-12-28 Ortho Mcneil Pharm Inc Process of preparing 3s-3-amino-3-aryl propionic acid and derivatives thereof
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