US 7,320,971 B2 | ||
2″ oxo-voruscharin and derivatives thereof | ||
Eric Van Quaquebeke, Woluwe-Saint-Lambert (Belgium); Jean-Claude Braekman, Rhode-Saint-Genèse (Belgium); Gentiane Simon, Brussels (Belgium); Pierre Guissou, Ouagadougou (Burkina Faso); Odile Germaine Nacoulma, Ouagadougou (Burkina Faso); Janique Dewelle, Luttre (Belgium); Francis Darro, Uccle (Belgium); and Robert Kiss, St-Pieters Leeuw (Belgium) | ||
Assigned to Unibioscreen S.A., Brussels (Belgium) | ||
Appl. No. 10/530,904 PCT Filed Oct. 09, 2003, PCT No. PCT/EP03/11194 § 371(c)(1), (2), (4) Date Dec. 23, 2005, PCT Pub. No. WO2004/033465, PCT Pub. Date Apr. 22, 2004. |
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Claims priority of provisional application 60/420067, filed on Oct. 21, 2002. | ||
Claims priority of application No. 02447192 (EP), filed on Oct. 09, 2002. | ||
Prior Publication US 2006/0166952 A1, Jul. 27, 2006 | ||
Int. Cl. A61K 31/585 (2006.01); C07J 71/00 (2006.01) |
U.S. Cl. 514—175 [540/61] | 28 Claims |
1. A compound of the formula I or a pharmaceutically acceptable salt thereof,
![]() wherein R1 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkyloxy, alkyloxyalkyl, alkylthioalkyl, alkyloxycarbonyl,
alkylthiocarbonyl, alkanoyl, cycloalkylalkyl, cycloalkylcarbonyl, cycloalkylalkanoyl, cycloalkyithiocarbonyl, cycloalkylalkoxycarbonyl,
cycloalkylalkoxythiocarbonyl, cycloalkylthioalkyl, alkylcarbonyloxyalkyl, arylcarbonyloxyalkyl, cycloalkylcarbonyloxyalkyl,
silyloxyalkyl, aralkyl, arylalkenyl, arylcarbonyl, aryloxycarbonyl, arylthiocarbonyl, aralkoxycarbonyl, arylalkylthiocarbonyl,
aryloxyalkyl, arylthioalkyl, haloalkyl, hydroxyalkyl, aralkanoyl, aroyl, aryloxycarbonylalkyl, aryloxyalkanoyl, carboxyl,
formyl, alkenylcarbonyl, alkynylcarbonyl, Het1, Het1alkyl, Het1oxyalkyl, Het1aryl, Het1aralkyl, Het1cycloalkyl, Het1carbonyl, Het1alkoxycarbonyl, Het1alkylthiocarbonyl, Het1oxycarbonyl, Het1thiocarbonyl, Het1alkanoyl, Het1aralkanoyl, Het1aryloxyalkyl, Het1alkyloxyalkyl, Het1arylthioalkyl, Het1aryloxycarbonyl, Het1aralkoxycarbonyl, Het1aroyl, Het1oxyalkylcarbonyl, Het1alkyloxyalkylcarbonyl, Het1aryloxyalkylcarbonyl, Het1carbonyloxyalkyl, Het1alkylcarbonyloxyalkyl, Het1aralkylcarbonyloxyalkyl, Het2alkyl; Het2oxyalkyl, Het2alkyloxyalkyl, Het2aralkyl, Het2carbonyl, Het2oxycarbonyl, Het2thiocarbonyl, Het2alkanoyl, Het2alkylthiocarbonyl, Het2alkoxycarbonyl, Het2aralkanoyl, Het2aralkoxycarbonyl, Het2aryloxycarbonyl, Het2aroyl, Het2aryloxyalkyl, Het2arylthioalkyl, Het2oxyalkylcarbonyl, Het2alkyloxyalkylcarbonyl, Het2aryloxyalkylcarbonyl, Het2carbonyloxyalkyl, Het2alkylcarbonyloxyalkyl, Het2aralkylcarbonyloxyalkyl, cyano, aminocarbonyl, aminoalkanoyl, aminoalkyl, CR6═NR7 and CR6═N(OR7), with R6 and R7 being independently selected from the group consisting of hydrogen, hydroxyl, alkyl, aryl, Het1, Het1alkyl, Het1aryl, alkenyl, alkynyl, amino alkyl, aminoaryl, alkylcarbonylamino, arylcarbonylamino, alkylthiocarbonylamino and arylthiocarbonylamino;
wherein R2 and R3 are independently selected from the group consisting of hydroxyl, alkyloxy, alkylsilyloxy, arylsilyloxy, alkyloxyalkyloxy,
cycloalkyloxy cycloalkylalkyloxy, aralkyloxy, aryloxyalkyloxy, silyloxy, alkylcarbonyloxy, arylcarbonyloxy, cycloalkylcarbonyloxy,
haloalkyloxy, hydroxyalkyloxy, aralkanoyloxy, aroyloxy, aryloxycarbonylalkyloxy, formyloxy, Het1alkyloxy, Het1oxy, Het1oxyalkyloxy, Het1aryloxy, Het1aralkyloxy, Het1cycloalkyloxy, Het1carbonyloxy, Het1oxycarbonyloxy, Het1alkanoyloxy, Het1aralkanoyloxy, Het1aryloxyalkyloxy, Het1aroyl, Het2oxy, Het2alkyloxy; Het2oxyalkyloxy, Het2aralkyloxy, Het2cycloalkyloxy, Het2alkanoyloxy, Het2aralkanoyloxy, Het2carbonyloxyl, Het2aryloxy, and Het2aryloxyalkyloxy,
wherein R1 R2 and R3 are unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, aralkyl,
aryl, Het1, Het2, cycloalkyl, alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(alkyl)aminocarbonyl, aminosulfonyl, alkylS(═O)t, hydroxy, cyano, halogen and amino, unsubstituted, mono- or disubstituted wherein the substituents are independently selected
from the group consisting of alkyl, aryl, aralkyl, aryloxy, arylamino, arylthio, aryloxyalkyl, arylaminoalkyl, aralkoxy, alkylthio,
alkoxy, aryloxyalkoxy, arylaminoalkoxy, aralkylamino, aryloxyalkylamino, arylaminoalkylamino, arylthioalkoxy, arylthioalkylamino,
aralkylthio, aryloxyalkylthio, arylaminoalkylthio, arylthioalkylthio, alkylamino, cycloalkyl, cycloalkylalkyl, Het1, Het2, Het1alkyl, Het2alkyl, Het1amino, Het2amino, Het1alkylamino, Het2alkylamino, Het1thio, Het2thio, Het1alkylthio, Het2alkylthio, Het1oxy and Het2oxy, OR8, SR8, SO2NR8R9, SO2N(OH)R8, CN, CR8═NR9, S(O)R8, SO2R8, CR8═N(OR9), N3, NO2, NR8R9, N(OH)R8, C(O)R8, C(S)R8, CO2R8, C(O)SR8, C(O)NR8R9, C(S)NR6R9, C(O)N(OH)R9, C(S)N(OH)R8, NR8C(O)R9, NR8C(S)R9, N(OH)C(O)R9, N(OH)C(S)R8, NR8CO2R9, NR8C(O)NR9R10, NR8C(S)NR9R10, N(OH)CO2R8, NR8C(O)SR9, N(OH)C(O)NR8R9, N(OH)C(S)NR8R9, NR8C(O)N(OH)R9, NR8C(S)N(OH)R9, NR8SO2NHR9, NHSO2NR8R9, NR8SO2NHR9, and P(O)(OR8)(OR9),
with t being an integer between 1 and 2, and R8 R9 and R10 being each independently selected from the group consisting of hydrogen, hydroxyl, alkyl, aryl, Het1, Het1alkyl, Het1aryl, alkenyl, alkynyl, aminoalkyl, amino aryl, alkylcarbonylamino, arylcarbonylamino, alkylthiocarbonylamino and arylthiocarbonylamino;
wherein R4 is selected from the group consisting of oxo, hydroxyl, alkyl, alkenyl, alkynyl, alkanediyl, alkyloxy, alklylthio, alkylamino,
alkyloxyalkyl, arylcarbonylalkyl, alkylcarbonylalkyl, alkanoyl, cycloalkylcarbonylalkyl, cycloalkyl, cycloalkyloxy, cycloalkylthio,
cycloalkylamino, cycloalkylalkyl, cycloalkylalkanoyl, aryl, aralkyl, arylalkenyl, arylcarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy,
aryloxyalkyl, haloalkyloxy, haloalkylthio, haloalkylamino , hydroxyalkyl, aralkanoyl, aryloxycarbonylalkyl, aryloxyalkanoyl,
Het1, Het1alkyl, Het1oxy, Het1oxyalkyl, Het1aryl, Het1aralkyl, Het1cycloalkyl, Het1aryloxyalkyl, Het1aroyl, Het2, Het2oxy, Het2alkyl; Het2oxyalkyl, Het2aralkyl, Het2cycloalkyl, Het2aryl, Het2alkanoyl, Het2aralkanoyl, Het2aroyl, Het2aryloxyalkyl, aminocarbonyl, aminoalkanoyl, and aminoalkyl, unsubstituted or substituted by one or more substituents independently
selected from the group consisting of alkyl, aralkyl, aryl, Het1, Het2, cycloalkyl, alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(alkyl)aminocarbonyl, aminosulfonyl, alkylS(═O)t, hydroxy, cyano, halogen and amino, unsubstituted, mono- or disubstituted wherein the substituents are independently selected
from the group consisting of alkyl, aryl, aralkyl, aryloxy, arylamino, arylthio, aryloxyalkyl, arylaminoalkyl, aralkoxy, alkylthio,
alkoxy, aryloxyalkoxy, arylaminoalkoxy, aralkylamino, aryloxyalkylamino, arylaminoalkylamino, arylthioalkoxy, arylthioalkylamino,
aralkylthio, aryloxyalkylthio, arylaminoalkylthio, arylthioalkylthio, alkylamino, cycloalkyl, cycloalkylalkyl, Het1, Het2, Het1alkyl, Het2alkyl, Het1amino, Het2amino, Het1alkylamino, Het2alkylamino, Het1thio, Het2thio, Het1alkylthio, Het2alkylthio, Het1oxy and Het2oxy, OR11, SR11, SO2NR11R12, SO2N(OH)R11, CN, CR11═NR12, S(O)R11, SO2R11, CR11═N(OR12), N3, NO2, NR11R12, N(OH)R11, C(O)R11, C(S)R11, CO2R11, C(O)SR11, C(O)NR11R12, C(S)NR11R12, C(O)N(OH)R12, C(S)N(OH)R11, NR11C(O)R12, NR11C(S)R12, N(OH)C(O)R12, N(OH)C(S)R11, NR11CO2R12, NR11C(O)NR12R13, and NR11C(S)NR12R13, N(OH)CO2R11, NR11C(O)SR12, N(OH)C(O)NR11R12, N(OH)C(S)NR11R12, NR11C(O)N(OH)R12, NR11C(S)N(OH)R12, NR11SO2R12, MHSO2NR11R12, NR11SO2NHR12, P(O)(OR11)(OR12), wherein t is an integer between 1 and 2, R11, R12 and R13 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, and alkynyl; and
wherein R5 is selected from the group consisting of hydrogen, oxo, hydroxyl, alkyl, alkenyl, alkynyl, alkanediyl, alkyloxy, alkyloxyalkyl,
arylcarbonylalkyl, alkylcarbonylalkyl, alkanoyl, cycloalkylcarbonylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkanoyl,
aryl, aralkyl, arylalkenyl, arylcarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aryloxyalkyl, halo alkyl, hydroxyalkyl,
aralkanoyl, aryloxycarbonylalkyl, aryloxyalkanoyl, Het1, Het1alkyl, Het1oxy, Het1oxyalkyl, Het1aryl, Het1aralkyl, Het1cycloalkyl, Het1aryloxyalkyl, Het1aroyl, Het2, Het2oxy, Het2alkyl; Het2oxyalkyl, Het2aralkyl, Het2cycloalkyl, Het2aryl, Het2alkanoyl, Het2aralkanoyl, Het2aroyl, Het2aryloxyalkyl, aminocarbonyl, amino alkanoyl, and amino alkyl, unsubstituted or substituted by one or more substituents independently
selected from the group consisting of alkyl, aralkyl, aryl, Het1, Het2, cycloalkyl, alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(alkyl)aminocarbonyl, aminosulfonyl, alkylS(═O)t, hydroxy, cyano, halogen and amino, unsubstituted, mono- or disubstituted wherein the substituents are independently selected
from the group consisting of alkyl, aryl, aralkyl, aryloxy, arylamino, arylthio, aryloxyalkyl, arylaminoalkyl, aralkoxy, alkylthio,
alkoxy, aryloxyalkoxy, aylaminoalkoxy, aralkylamino, aryloxyalkylamino, arylaminoalkylamino, arylthioalkoxy, arylthioalkylamino,
aralkylthio, aryloxyalkylthio, arylaminoalkylthio, arylthioalkylthio, alkylamino, cycloalkyl, cycloalkylalkyl, Het1, Het2, Het1alkyl, Het2alkyl, Het1amino, Het2amino, Het1alkylamino, Het2alkylamino, Het1thio, Het2thio, Het1alkylthio, Het2alkylthio, Het1oxy and Het2oxy, OR11, SR11, SO2NR11R12, SO2N(OH)R11, CN, CR11═NR12, S(O)R11, SO2R11, CR11═N(OR12), N3, NO2, NR11R12, N(OH)R11, C(O)R11, C(S)R11, CO2R11, C(O)SR11, C(O)NR11R12, C(S)NR11R12, C(O)N(OH)R12, C(S)N(OH)R11, NR11C(O)R12, NR11C(S)R12, N(OH)C(O)R12, N(OH)C(S)R11, NR11CO2R12, NR11C(O)NR12R13, and NR11C(S)NR12R13, N(OH)CO2R11, NR11C(O)SR12, N(OH)C(O)NR11R12, N(OH)C(S)NR11R12, NR11C(O)N(OH)R12, NR11C(S)N(OH)R12, NR11SO2R12, NHSO2NR11R12, NR11SO2NHR12, and P(O)(OR11)(OR12), wherein t is an integer between 1 and 2, R11, R12 and R13 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, and alkynyl;
wherein Het1 is defined as a saturated or partially unsaturated monocyclic, bicyclic or polycyclic heterocycle consisting of 3 to 12 ring
members which comprise one or more heteroatom ring members selected from nitrogen, oxygen or sulfur, optionally substituted
on one or more carbon atoms by alkyl, alkyloxy, halogen, hydroxyl, oxo, optionally mono- or disubstituted amino, nitro, cyano,
haloalkyl, carboxyl, alkoxycarbonyl cycloalkyl, optionally mono- or disubstituted aminocarbonyl, methylthio, methylsulfonyl,
aryl and a saturated or partially unsaturated monocyclic, bicyclic or tricyclic heterocycle consisting of 3 to 12 ring members
which contain one or more heteroatom ring members selected from nitrogen, oxygen or sulfur and whereby the optional substituents
on any amino function are independently selected from alkyl, alkyloxy, Het2, Het2alkyl, Het2oxy, Het2oxyalkyl, aryl, aryloxy, aryloxyalkyl, aralkyl, alkyloxycarbonylamino, amino and aminoalkyl whereby each of the amino groups
may optionally be mono- or disubstituted with alkyl;
wherein Het2 is defined as an aromatic monocyclic, bicyclic or tricyclic heterocycle consisting of 3 to 12 ring members comprising one
or more heteroatom ring members selected from nitrogen, oxygen or sulfur and optionally substituted on one or more carbon
atoms by alkyl, alkyloxy, halogen, hydroxyl, optionally mono- or disubstituted amino, nitro, cyano, haloalkyl, carboxyl, alkoxycarbonyl,
cycloalkyl, optionally mono- or disubstituted aminocarbonyl, methylthio, methylsulfonyl, aryl, Het1 and an aromatic monocyclic, bicyclic, or tricyclic heterocycle consisting of 3 to 12 ring members, whereby the optional substituents
on any amino function are independently selected from alkyl, alkyloxy, Het1, Het1alkyl, Het1oxy, Het1oxyalkyl, aryl, aryloxy, aryloxyalkyl, aralkyl, alkyloxycarbonylamino, amino, and amionalkyl whereby each of the amino groups
may optionally be mono- or disubstituted with alkyl.
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