Patent EA-004512-B1 (EA)
Title: Cyclocarbamate derivatives as progesterone receptor modulators
Inventor: ZHANG PUWEN
IPC: C07D417/04
Filed: 2000-05-01
Abstract: 1. A compound of the formula (I): wherein: R<1> and R<2> are independent substituents selected from the group of H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C2 to C6 alkenyl, substituted C1 to C6 alkenyl, C2 to C6 alkynyl, substituted C1 to C6 alkynyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, COR<A>, or NR<B>COR<A>; or R<1> and R<2> are fused to form: a) an optionally substituted 3 to 8 membered spirocyclic alkyl ring, containing a carbon skeleton; b) a 3 to 8 membered spirocyclic ring, containing a skeleton with one or more double bonds; c) a 3 to 8 membered spirocyclic ring containing in its skeleton one to three heteroatoms selected from the group of O, S and N; the spirocyclic rings of a), b) and c) being optionally substituted by from 1 to 4 groups selected from fluorine, C1 to C6 alkyl, C1 to C6 alkoxy, C1 to C6 thioalkyl, -CF3, -OH, -CN, NH2, -NH (C1 to C6alkyl), or -N (C1 toC6 alkyl)2; R<A> is H, C1 to C3 alkyl, substituted C1 to C3 alkyl, aryl, substituted aryl, C1 toC3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, or substituted C1 to C3 aminoalkyl; R<B> is H, C1 to C3 alkyl, or substituted C1 to C3 alkyl; R<3> is H, OH, NH2, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C6 alkenyl, substituted C1 toC6 alkenyl, alkynyl, or substituted alkynyl, COR<C>; R<C> is H, C1 to C3 alkyl, substituted C1 toC3 alkyl, aryl, substituted aryl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 toC3 aminoalkyl, or substituted C1 toC3 aminoalkyl; R<4> is H, halogen, CN, NO2, C1 toC6 alkyl, substituted C1 to C6 alkyl, alkynyl, or substituted alkynyl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, amino, C1 to C6 aminoalkyl, or substituted C1 to C6 aminoalkyl; R<5> is selected from a) or b) a) is a substituted benzene ring containing the substituents X, Y and Z as shown below: wherein: X is taken from the group including halogen, CN, C1 to C3 alkyl, substituted C1 to C3 alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 thioalkoxy, substituted C1 to C3 thioalkoxy, amino, C1 to C3 aminoalkyl, substituted C1 toC3 aminoalkyl, NO2, C1 to C3 perfluoroalkyl, 5 or 6 membered heterocyclic ring containing 1 to 3 heteroatoms, SO2NH2 COR<D>, OCOR<D>, or NR<E>COR<D>; R<D> is H, C1 to C3 alkyl, substituted C1 to C3 alkyl, aryl, substituted aryl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, or substituted C1 toC3 aminoalkyl; R<E> is H, C1 to C3 alkyl, or substituted C1 toC3 alkyl; Y and Z are independent substituents taken from the group including H, halogen, CN, NO2, amino, aminoalkyl, C1 toC3 alkoxy, C1 to C3 alkyl, or C1 to C3 thioalkoxy; or b) R<5> is a five or six membered ring with 1,2 or 3 heteroatoms from the group including O, S, SO, SO2 or NR<6> and containing one or two independent substituents from the group including H, halogen, CN, NO2, amino, and C1 to C3 alkyl, C1 to C3 alkoxy, C1 to C3 aminoalkyl, SO2NH2, C(N(OH), COR, or NR<G>COR; provided that when R<5> is a 5-membered ring containing in its skeleton two heteroatoms NR<6>, R<1> and R<2> are both not H; provided that when R<5> is a 5-membered ring containing in its skeleton one heteroatom NR<6>, and when R<5> is attached to the second position on said ring, then in the fifth position of said ring there can be no CN substituent; R is H, C1 to C3 alkyl, substituted C1 to C3 alkyl, aryl, substituted aryl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, or substituted C1 to C3 aminoalkyl; R<G> is H, C1 to C3 alkyl, or substituted C1 to C3alkyl; provided that when R<5> is a benzene ring a), substituted by one or two substituents or 5 or 6-membered ring b) containing in its skeleton 1, 2 or 3 heteroatoms, selected from the group of O, S and NR<6> and R<1> is alkenyl, substituted alkenyl, alkynyl or substituted alkynyl, R<2> is not alkenyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl; or if R<2> is alkenyl, substituted alkenyl, alkynyl or substituted alkynyl, R<1>is not alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl or substituted alkynyl, provided that when R<5> is a benzene ring a), substituted by one or two substituents or 5 or 6-membered ring b) containing in its skeleton 1, 2 or 3 heteroatoms, selected from the group of O, S and NR<6> and R<1> is alkenyl, substituted alkenyl, alkynyl or substituted alkynyl, R<2> is not cycloalkyl, substituted cycloalkyl; or if R<2> is alkyl or substituted alkyl, R<1> is not cycloalkyl, substituted cycloalkyl; R<6> is absent or is H, O, C(O)(C1 to C4 alkoxy) or C1 to C3 alkyl; wherein aryl is selected from the group of phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, phenanthryl; heterocyclyl is 5-membered ring, 6-membered ring or a polycyclic ring; wherein 5-membered ring is selected from the group of tetrahydrofuran, pyrrolidinyl, imidazilyl, oxazolyl, izoxazolyl, thienyl, thiophene, pyrrole, thiazole and furyl; 6-membered ring is selected from the group of piperidinyl, piperazinyl, 2-oxopiperidinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, morpholinyl, thiamorpholinyl, thiamorphilinylsulfoxide; polycyclic ring is selected from indolyl, quinolinyl, benzofuranyl, benzothienyl and izoquinolyl; substituted alkyl, substituted alkenyl and substituted alkynyl contain from 2 to 3 substituents selected from the group of halogen, CN, OH, NO2, amino, aryl, heterocyclyl, substituted aryl, substituted heterocycle, alkoxy, aryloxy, substituted alkoxy, alkylcarbonyl, alkylcarboxy, alkylamino and arylthio; substituted alkoxy, substituted aminoalkyl and substituted thioalkoxy contain from 2 to 3 substituents selected from the group of alkyl and substituted alkyl; substituted aryl contains from 1 to 4 substituents selected from the group of halogen, CN, OH, NO2, amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino and arylthio; substituted cycloalkyl contains from 1 to 3 substituents selected from the group of halogen, CN, OH, NO2, amino, aryl, heterocyclyl, alkoxy, aryloxy, alkylcarbonyl, alkylcarboxy, alkylamino and arylthio; substituted heterocyclyl contains from 1 to 4 substituents selected from the group of halogen, CN, OH, NO2, amino, alkyl, substituted alkyl, cycloalkyl, alkenyl, substituted alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino and arylthio; substituted alkyloxy contains from 1 to 3 substituents selected from the group of halogen, CN, OH, NO2, amino, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, alkoxy, aryloxy, alkylcarbonyl, alkylcarboxy, alkylamino and arylthio; or a pharmaceutically acceptable salt thereof. 2. A compound of Claim 1 having the structure: R<1> and R <2> are independent substituents selected from the group of H, C1 to C6alkyl, substituted C2 to C6alkyl, C2 to C6 alkenyl, substituted C2 to C6 alkenyl, C2 to C6 alkynyl, substituted C2 to C6 alkynyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, COR<A>, or NR<B>COR<A>; R<1> and R<2> are fused to form a spirocyclic ring selected from a), b) or c): a) a 3 to 8 membered spirocyclic ring, containing a carbon skeleton; b) a 3 to 8 membered spirocyclic ring, containing a skeleton with one or more double bonds; c) a 3 to 8 membered spirocyclic ring containing in its skeleton one to three heteroatoms selected from the group of O, S and N; a), b) or c) rings being optionally substituted by from 1 to 4 substituents selected from fluorine, C1 to C6alkyl, C1 to C6alkoxy, C1 to C6thiaoalkyl, CF3, OH, CN, NH2, NH(C1 to C6alkyl) or N(C1 to C6alkyl)2; R<A> is selected from H, C1 to C3 alkyl, substituted C1 to C3 alkyl, aryl, substituted aryl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, amino, C1 to C3 aminoalkyl, or substituted C1 to C3 aminoalkyl; R<B> is H, C1 to C3 alkyl, or substituted C1 to C3 alkyl; R<3> is H, OH, NH2, C1 to C6alkyl, substituted C1 to C6 alkyl, C3 to C6 alkenyl, substituted C3 to C6 alkenyl, alkynyl, or substituted alkynyl, or COR<C>; R<C> is selected from H, C1 to C4 alkyl, substituted C1 to C4 alkyl, aryl, substituted aryl, C1 to C4 alkoxy, substituted C1 to C4 alkoxy, C1 to C4 aminoalkyl, or substituted C1 to C4 aminoalkyl; R<4> is selected from H, halogen, CN, NO2, C1 to C6 alkyl, substituted C1 to C6 alkyl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, C1 to C6 aminoalkyl, or substituted C1 to C6 aminoalkyl; R<5> is selected from groups a) and b) below: a) is a substituted benzene ring containing the substituents X, Y and Z as shown below: wherein: X is selected from the group including halogen, CN, C1 to C3 alkyl, substituted C1 to C3 alkyl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 thioalkoxy, substituted C1 to C3 thioalkoxy, C1 to C3 aminoalkyl, substituted C1 to C3 aminoalkyl, NO2, C1 to C3 perfluoroalkyl, 5-membered heterocyclic ring containing 1 to 3 heteroatoms, COR<D>, OCOR<D>, or NR<E>COR<D>; R<D> is H, C1 to C3 alkyl, substituted C1 to C3 alkyl, aryl, substituted aryl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, or substituted C1 to C3 aminoalkyl; R<E> is H, C1 to C3 alkyl, or substituted C1 to C3 alkyl; Y and Z are independent substituents selected from the group of H, halogen, CN, NO2, C1 to C3 alkoxy, C1 to C3 alkyl, or C1 to C3 thioalkoxy; b) is a five or six membered heterocyclic ring with 1, 2, or 3 heteroatoms in the skeleton selected from the group of O, S, S(O), S(O2) or NR<6> and containing one or two independent substituents from the group of H, halogen, CN, NO2, amino, C1 to C3 alkyl and C1 to C3 alkoxy; provided that when R<5> is a 5-membered ring containing in its skeleton two heteroatoms NR<6>, R<1> and R<2> are both not H; provided that when R<5> i