Patent EA-005034-B1 (EA)
Title: Thio-oxindole derivatives
Inventor: FENSOME ANDREW
IPC: A61P7/04
Filed: 2000-05-01
Abstract: 1. A compound of the formula: wherein: R1 and R2 are chosen independently from the group of H, C1-C8 alkyl, substituted C1-C8 alkyl; OH, O (C1-C8 alkyl), O(substituted C1-C8 alkyl), OAc, aryl, optionally substituted aryl, heteroaryl, optionally substituted heteroaryl, C1-C8 alkylaryl, C1-C8 alkylheteroaryl, 1-propynyl and 3-propynyl: or R1 and R2 are joined to form a ring comprising one of the following: -CH2(CH2)nCH2-, -CH2CH2C(CH3)CH2CH2-, -CH2CH2OCH2CH2-, -O(CH2)mCH2-, O(CH2)pO-, -CH2CH2N(H)COCH2CH2-, or -CH2CH2N(alkyl)CH2CH2-; m is an integer from 1 to 4; n is an integer from 1 to 5; p is an integer from 1 to 4; or R1 and R2 together comprise a double bond to one of the following: C(CH3)2; C(cycloalkyl), O or C (cycloether); R3 is selected from H, OH, NH2, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 alkenyl, alkynyl or substituted alkynyl, or COR<A>; R<A> is selected from H, C1-C3 alkyl, substituted C1-C3 alkyl, C1-C3 alkoxy, substituted C1-C3 alkoxy, C1-C3 aminoalkyl, or substituted C1-C3 aminoalkyl; R4 is selected from H, halogen, CN, NH2, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy, substituted C1-C6 alkoxy, C1-C6 aminoalkyl, or substituted C1-C6 aminoalkyl; R5 is selected from the groups a), b) or c): a ) is a benzene ring containing the substituents X, Y and Z as shown below: X is selected from H, halogen, OH, CN, C1-C3 alkyl, substituted C1-C3 alkyl, C1-C3 alkoxy, substituted C1-C3 alkoxy, C1-C3 thioalkyl, substituted C1-C3 thioalkyl, S(O) alkyl, S(O)2alkyl, C1-C3 aminoalkyl, substituted C1-C3 aminoalkyl, NO2, C1-C3 perfluoroalkyl, 5 or 6 membered heterocyclic ring containing 1 to 3 heteroatoms, CONH2, CSNH2, CONH(C1-C8) alkyl, CSNH(C1-C8) alkyl, CON(C1-C8 alkyl)2, CSN (C1-C8 alkyl)2, COR<B>, OCOR<B>, or NR<C>COR<B>; R<B> is selected from H, C1-C3 alkyl, substituted C1-C3 alkyl, aryl, substituted aryl, C1-C3 alkoxy, substituted C1-C3 alkoxy, C1-C3 aminoalkyl, or substituted C1-C3 aminoalkyl; R<C> is H, C1-C3 alkyl, or substituted C1-C3 alkyl; where all X, Y and Z can not be H; b) a five or six membered heterocyclic ring with 1, 2, or 3 heteroatoms selected from O, S, SO, SO2 or NR6 and containing one or two independent substituents from the group of H, halogen, CN, NO2 and C1-C3 alkyl, C1-C3 alkoxy, C1-C3 aminoalkyl, COR<D>, or NR<E>COR<D>; R<D> is H, C1-C3 alkyl, substituted C1-C3 alkyl, aryl, substituted aryl, C1-C3 alkoxy, substituted C1-C3 alkoxy, C1-C3 aminoalkyl, or substituted C1-C3 aminoalkyl; R<E> is H, C1-C3 alkyl, or substituted C1-C3 alkyl; R<6> is absent or is H, COR<D> or C1-C3 alkyl; or c) indol-4-yl, indol-7-yl or benzo-2-thiophene moiety, the moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C6 alkyl, CN, NO2, C1-C6 alkoxy, or CF3; Q<1> is S, NR7 or CR8R9; R7 is selected from the group including CN, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C8 cycloalkyl, substituted C3-C8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, acyl, substituted acyl, aroyl, substituted aroyl, SO2CF3, OR<11> or NR<11>R<12>; R8 and R9 are independent substituents selected from the group of H, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C8 cycloalkyl, substituted C3-C8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, NO2, CN, or CO2R<10>, R10 is C1-C3 alkyl; or CR8R9 comprises a six membered ring as shown by the structure below R<11> and R<12> are independently selected from H, C1-C6 alkyl, substituted C1-C6 alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyl, substituted acyl, aroyl or substituted aroyl or sulfonyl; said aryl is selected from the group consisting of phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl and phenanthryl; said heterocyclic or heteroaryl is selected from the group consisting of tetrahydrofuran, piperidinyl, piperazinyl, 2-oxopiperidinyl, azepinyl, pyrrolidinyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, morpholinyl, indolyl, quinolinyl, thienyl, furyl, benzofuranyl, benzothienyl, thiamorpholinyl, thiamorpholinyl, sulfoxide, and isoquinolinyl; said substituted alkyl and substituted alkynyl comprise 1 or more substituents selected from the group consisting of halogen, CN, OH, NO2, amino, aryl, heterocyclic, substituted aryl, substituted heterocyclic, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, and arylthio; said substituted aryl comprises 1 to 4 substituents selected from the group consisting of halogen, CN, OH, NO2, amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, and arylthio; said substituted heterocyclic or heteroaryl comprises 1 to 4 substituents selected from the group consisting of halogen, CN, OH, NO2, amino, alkyl, substituted alkyl, cycloalkyl, alkenyl, substituted alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino and arylthio; said substituted acyl and aroyl comprise 1 to 6 groups selected from the group consisting of halogen, CN, OH and NO2; said substituted alkoxy, substituted aminoalkyl and substituted thioalkyl comprise 1 to 3 substituents selected from the group consisting of alkyl and substituted alkyl; or a pharmaceutically acceptable salt thereof. 2. A compound of the formula wherein: R1 and R2 are joined to form a five or six-membered carbocyclic ring; R3 is selected from the group consisting of H, OH, NH2, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 alkenyl, alkynyl, substituted alkynyl, and COR<A>; R<A> is selected from the group consisting of H, C1-C3 alkyl, substituted C1-C3 alkyl, C1-C3 alkoxy, substituted C1-C3 alkoxy, C1-C3 aminoalkyl, and substituted C1-C3 aminoalkyl; R4 is selected from the group consisting of H, halogen, CN, NH2, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy, substituted C1-C6 alkoxy, C1-C6 aminoalkyl, and substituted C1-C6 aminoalkyl; R5 is a) or b): a) a substituted benzene ring of the formula: X is selected from the group consisting of H, halogen, CN, CONH2, CSNH2, CONH(C1-C8-alkyl), CSNH(C1-C8-alkyl), CON(C1-C8-alkyl)2, CSN(C1-C8-alkyl)2, C1-C3 alkoxy, C1-C3 alkyl, NO2, C1-C3 perfluoroalkyl, 5 membered heterocyclic ring containing in its backbone 1 to 3 heteroatoms, and C1-C3 thioalkoxy; Y is on the 4' or 5' position selected from the group consisting of H, halogen, CN, NO2, C1-C3 alkoxy, C1-C4 alkyl, and C1-C3 thioalkyl; wherein X and Y are not both H; or b) a six membered ring of the structure: wherein: X' is N or CX<2>, X<2> is halogen, CN, CONH2, CSNH2, CONH(C1-C8-alkyl), CSNH(C1-C8-alky), CON(C1-C8-alkyl)2, CSN(C1-C8-alkyl)2, or NO2; Q<1> is S, NR7, or CR8R9; R7 is selected from the group consisting of CN, C1-C6-alkyl, substituted C1-C6- alkyl, C3-C8-cycloalkyl, substituted C3-C8-cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, and SO2CF3; R8 and R9 are independent substituents selected from the group consisting of H, C1-C6-alkyl, substituted C1-C6-alkyl, C3-C8-cycloalkyl, substituted C3-C8-cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, NO2, CN, and CO2R10; R10 is C1-C3alkyl; or CR8R9 is a six membered ring of the structure below: wherein; said aryl is selected from the group consisting of phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, and phenanthryl; said heterocyclic is selected from the group consisting of tetrahydrofuran, piperidinyl, piperazinyl, 2-oxopiperidinyl, azepinyl, pyrrolidinyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, morpholinyl, indolyl, quinolinyl, thienyl, furyl, benzofuranyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, and isoquinolinyl; said substituted alkyl and substituted alkynyl comprise 1 or more substituents selected from the group consisting of halogen, CN, OH, NO2, amino, aryl, heterocyclic, substituted aryl, substituted heterocyclic, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino and arylthio; said substituted aryl comprises 1 to 4 substituents selected from the group consisting of halogen, CN, OH, NO2, amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino and arylthio; said substituted heterocyclic comprise 1 to 4 substituents selected from the group consisting of halogen, CN, OH, NO2, amino, alkyl, substituted alkyl, cycloalkyl, alkenyl, substituted alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino and arylthio; said substituted acyl and aroyl comprise 1 to 6 groups selected from the group consisting of halogen, CN, OH and NO2; said substituted alkoxy, substituted aminoalkyl, and substituted thioalkyl comprise 1 to 3 substituents selected from the group consisting of alkyl and substituted alkyl; or pharmaceutically acceptable salt thereof. 3. A compound of the formula: or a tautomer thereof wherein: R14 is selected from the group consisting of H, acyl, substituted acyl, aroyl, substituted aroyl, sulfonyl, and substituted sulfonyl; R5 is a), b), or c): a) a substituted benzene ring containing the substituents X and Y as shown below: wherein: X is selected from the group consisting of H, halogen, CN, CONH2, CSNH2, CONH(C1-C8-alkyl), CSNH(C1-C8-alkyl), CON(C1-C8-alkyl)2, CSN(C1-C8-alkyl)2, CNHNHOH, CNH2NOH, C1-C3-alkoxy, C1-C3-alkyl, NO2, C1-C3-perfluoroalkyl, 5 membered heterocyclic ring containing in its backbone 1 to 3 heteroatoms, and C1-C3-thioalkoxy; Y is on the 4' or 5' position and is selected from the group consisting of H, halogen, CN, NO2, C1-C3-alkoxy, C1-C3-alkyl, and C1-C3-thioalkyl; wherein X and Y are not both H; b) a five membered ring of the structure shown below: wherein: U is O, S, or NR6; R6 is H, C1-C3-alkyl, or alkoxycarbonyl(C1-C4)alkyl; X' is selected from the group consisting of halogen, CN, NO2, CONH2, CNHNHOH, CNH2NOH, CSNH2, CONH(C1-C8-alkyl), CSNH(C1-C8-alkyl), CON(C1-C8-alkyl)2, CSN(C1-C8-a