Patent EA-004884-B1 (EA)
Title: Pyrazinone compounds, pharmaceutical composition and medicament, method of inhibiting serine protease, method of reducing thrombogenicity of a surface, method of treating aberrant proteolysis and thrombosis associated with different diseases, method of reducing blood coagulation in a mammal
Inventor: LU TIANBAO
IPC: A61P7/02
Filed: 1999-06-11
Abstract: 1. A compound of Formula I: or a solvate, hydrate or pharmaceutically acceptable salt thereof; wherein: W is R<1>; R<1> is R<2>, R<2>(CH2)tC(R<12>)2, wherein t is 0-3 and each R<12> is the same or different, (R<2>) (OR<12>) CH (CH2)p, wherein p is 1-4, (R<2>)2(OR<12>) C (CH,)p, wherein p is 1-4, R<2>C(R<12>)2(CH2)t, wherein t is 0-3, and each R<12> is the same or different, and wherein (R<12>)2, together with the C to which they are attached, can also form a 3-to 7-membered cycloalkyl ring; R<2>CH2C(R<12>)2(CH2)q, wherein q is 0-2, and each R<12> is the same or different, and wherein (R<12>)2, together with the C to which they are attached can also form a 3-to 7-membered cycloalkyl ring; R<2>CF2C(R<12>)2(CH2)q, wherein q is 0-2, and each R<12> is the same or different, and wherein (R<12>)2, together with the C to which they are attached, can also form a 3-to 7-membered cycloalkyl ring; (R<2>)2CH(CH2)r, wherein r is 0-4, and each R<2> is the same or different, and wherein (R<2>)2, together with the C to which they are attached, can also form a 5-to 7-membered, saturated or unsaturated, having from one to three heteroatoms selected from N, O, and S; (R<2>)2CF (CH2)r, wherein r is 1-3 and each R<2> is the same of different or R<2>CF2C(R<12>)2 R<2> is phenyl or naphthyl, each of which is optionally substituted with one or more of the following groups: C1-4alkyl, C1-4alkoxy, halogen, CF3, a 5-to 7-membered, saturated or unsaturated, mono- or a 9-to 10-membered bi-cyclic ring optionally having one or two heteroatoms selected from N or O, C1-7alkyl, optionally substituted with one or more of the following groups: aryl, C1-3alkylaryl or heterocycle; R<3> is hydrogen, C1-4alkyl, halogen or cyano; R<4> is hydrogen or halogen; R<12> is hydrogen, phenyl or C1-4alkyl; R<5> is hydrogen; R<6> is hydrogen or alkyl; R<7>, R<8>, R<9> and R<10> are independently hydrogen or alkyl; X is oxygen or -CH(CN-; R<A>, R<B> and R<C> are independently hydrogen or -CO2R<W>, wherein R<W> is wherein R<D> and R<E> are independently hydrogen, R is C1-6alkyl, n is 0-4 and m is 0-4. 2. The compound according to claim 1, wherein R<3> is hydrogen or C1-4alkyl; m is 0 and n is 0. 3. The compound according to claim 2, wherein R<3> is C1-4alkyl. 4. The compound according to claim 2, wherein R<4> is hydrogen. 5. The compound according to claim 1, wherein R<3> is R<2>, R<2>(CH2)tC(R<12>)2, wherein t is 0-3 and each R<12> is the same or different, R<2>C(R<12>)2(CH2)t, wherein t is 1-3 and each R<12> is the same or different, wherein (R<12>)2, together with the C to which they are attached, can also form a 3-to 7-membered cycloalkyl ring; R<2>CH2C(R<12>)2(CH2)q, wherein q is 0-2, and each R<12> is the same or different, and wherein (R<12>)2, together with the C to which they are attached can also forma 3-to 7-membered cycloalkyl ring; R<2>CF2C(R<12>)2(CH2)q, wherein q is 0-2, and each R<12> is the same or different, and wherein (R<12>)2, together with the C to which they are attached, can also form a 3-to 7-membered cycloalkyl ring; (R<2>)2CH(CH2)r, wherein r is 1-3, and each R<2> is the same or different, and wherein (R<2>)2, together with the C to which they are attached, can also form a 5-to 7-membered, saturated or unsaturated, mono- or bi cycloheterocyclic ring having from one to three heteroatoms selected from N, O, and S; R<2>CF2C(R<12>)2(CH2)q, where q is 0-2 and each R<12> is the same or different, and wherein (R<12>)2, together with the C to which they are attached, can also form a 3-to 7-membered cycloalkyl ring; R<2> is phenyl or naphthyl, each of which is optionally substituted with one or more the following groups: C1-4alkyl, C1-4alkoxy, halogen, CF3, a 5-to 7-membered, saturated or unsaturated, mono- or a 9-to 10-membered bi-cycloheterocyclic ring optionally having one or two heteroatoms selected from N or O, C1-7alkyl, optionally substituted with one or more of the following groups: C1-3alkylaryl or heterocycle; and R<12> is hydrogen or C1-4alkyl. 6. The compound according to claim 5, wherein R<3> is H, CH3, or CH2CH3; R<4> is hydrogen or chloro; and W is OOCCH2, CF3CH3, (CH2)2N(CH2)2, PhCH2O(CH2)2, (CH3)3C, PhCH(CH3), PhCH(CH3), PhCH2CH(COOH), H, CH3(CH2)4, PhCH2, PhCH2CH(CH3), PhCH(CH3)CH2, CH3CH2CH(CH3)CH2, (Ph)2CHCH2, (CH3)2CH, PhCH(OH) CH2, PhC (CH3)2CH2, (Ph)2CHCH2, or W is 7. A compound of any of claims 1-6, wherein X is CH=N-. 8. A compound of any of claims 1-6, wherein X is oxygen. 9. A compound of any of claims 1-6, wherein R<6> is hydrogen or C1-6alkyl. 10. A compound of any of claims 1-6, wherein R<7>, R<8>, R<9> and R<10> are independently one of hydrogen or C1-6alkyl. 11. A compound of claim 10, wherein R<7>, R<8>, R<9> and <10>are independently one of hydrogen, methyl, ethyl, propyl or n-butyl. 12. A compound of any of claims 1-6, wherein R<A>, R<B> and R<C> are independently hydrogen. 13. A compound of claim 12, wherein R<A>, R<B> and R<C> are independently where R<D>-R are defined as in claim 1. 14. A compound of claim 13, wherein R<D> and R<E> are hydrogen and R is methyl. 15. A compound of claim 1, having the structure of Formula II: or a solvate, hydrate or pharmaceutically acceptable salt thereof, wherein R<3>, R<4>, W, X, n and m are as defined in claim 1. 16. A compound of claim 15, wherein W is W is OOCCH2, CF3CH3, (CH2)2N(CH2)2, PhCH2O(CH2)2, (CH3)3C, PhCH(CH3), PhCH(CH3), PhCH2CH(COOH), H, CH3(CH2)4, PhCH2, PhCH2CH(CH3), PhCH(CH3)CH2, CH3CH2CH(CH3)CH2, (Ph)2CHCH2, (CH3)2CH, PhCH(OH) CH2, PhC (CH3)2CH2, (Ph)2CHCH2, or W is 17. A compound of claim 1, which is one of 1-{N-[2-(amidinoaminooxy)ethyl]amino}carbonylmethyl-6-methyl-3-(phenethylamino)-pyrazinone, 1-{N-[2-(amidinoaminooxy)ethyl]amino}carbonylmethyl-6-methyl-3-(2,2-diphenylethylamino)-pyrazinone, 1-{N-[2-(amidinoaminooxy)ethyl]amino}carbonylmethyl-6-methyl-3-(4-methylphenethylamino)-pyrazinone, 1-{N-[2-(amidinoaminooxy)ethyl]amino}carbonylmethyl-6-methyl-3-(4-methoxyphenethylamino)-pyrazinone, 1-{N-[2-(amidinoaminooxy) ethyl] amino} carbonylmethyl-6-methyl-(1-phenylcyclobutyl) methylamino-pyrazinone, 1-{N-[2-(amidinoaminooxy) ethyl] amino} carbonylmethyl-6-methyl-[2-(1-naphthalene) ethyl] amino-pyrazinone, 1-{N-[2-(amidinoaminooxy) ethyl] amino} carbonylmethyl-6-methyl-3-(2-phenyl-1-butylamino)-pyrazinone, 1-{N-[2-(amidinoaminooxy) ethyl]amino} carbonylmethyl-6-methyl-3-(2-[3,4-methylenedioxyphenyl] ethylamino)-pyrazinone, 1-{N-[2-(amidinoaminooxy)ethyl]amino}carbonylmethyl-6-methyl-3-(2-[2-pyridyl] ethylamino)-pyrazinone, 1-{N-[2-(amidinoaminooxy) ethyl]amino} carbonylmethyl-6-methyl-3-([2-methylphenyl] ethylamino)-pyrazinone, 1-{N-[2-(amidinoaminooxy) ethyl]amino} carbonylmethyl-6-methyl-3-([3-methylphenyl] ethylamino)-pyrazinone, 1-{N-[2-(amidinoaminooxy)ethyl]amino}carbonylmethyl-6-methyl-3-(2-[2-trifluoromethylphenyl] ethylamino)-pyrazinone, 1-{N-[2-(amidinoaminooxy)ethyl]amino}carbonylmethyl-6-methyl-3-([3-trifluoromethylphenyl] ethylamino)-pyrazinone, 1-{N-[2-(amidinoaminooxy) ethyl] amino} carbonylmethyl-6-methyl-3-([4-trifluoromethylphenyl] ethylamino)-pyrazinone, 1-{N-[2-(amidinoaminooxy)ethyl]amino}carbonylmethyl-6-methyl-(2-[3,5-dimethylphenyl] ethylamino)-pyrazinone, 1-{N-[2-(amidinoaminooxy) ethyl] amino} carbonylmethyl-6-methyl-3-(2-indanylamino)-pyrazinone, 1-{N-[2-(amidinoaminooxy)ethyl]amino}carbonylmethyl-6-methyl-3 (2-[3,4-difluorophenyl] ethylamino)-pyrazinone, 1-{N-[2-(amidinoaminooxy) ethyl] amino} carbonylmethyl-6-methyl-3-(2-[5-indanyl] ethylamino)-pyrazinone, 1-{N-[2-(amidinoaminooxy) ethyl] amino} carbonylmethyl-6-methyl-3-(2-fluorophenethylamino)-pyrazinone, 1-{N-[2-(amidinoaminooxy) ethyl] amino}carbonylmethyl-6-methyl-3-(3,4-dimethoxyphenethylamino)-pyrazinone, 1-{N-[2-(amidinoaminooxy) ethyl] amino}carbonylmethyl-6-methyl-3-(4-fluorophenethylamino)-pyrazinone, 1-{N-[2-(amidinoaminooxy)ethyl]amino}carbonylmethyl-6-methyl-3-(4-ethylphenethylamino)-pyrazinone, 1-{N-[2-(amidinoaminooxy) ethyl] amino} carbonylmethyl-6-methyl-3-(2-phenylpropylamino)-pyrazinone, 1-{N-[2-(amidinoaminooxy)ethyl]amino}carbonylmethyl-6-methyl-3-(3,4-dimethylphenethylamino)-pyrazinone, 1-{N-[2-(amidinoaminooxy) ethyl]amino} carbonylmethyl-6-methyl-3-(2-naphthaleneethylamino)-pyrazinone, 1-{N-[2-(amidinoaminooxy) ethyl] amino} carbonylmethyl-6-methyl-3 (2,2-diphenylpropylamino)-pyrazinone, 1-{N-[2-(amidinoaminooxy)ethyl]amino}carbonylmethyl-6-methyl-3-(2-(3indolyl)-ethylamino-pyrazinone, 1-{N-[2-(amidinoaminooxy) ethyl]amino} carbonylmethyl-6-methyl-3-(2-[1-(4-methylnaphthalene)]ethylamino)-pyrazinone, 1-{N-[2-(amidinoaminooxy) ethyl] amino} carbonylmethyl-6-methyl-3 (2-[2,4-difluorophenyl] ethylamino)-pyrazinone. 1-{N-[2-(amidino-N'-methylaminooxy) ethyl] amino}carbonylmethyl-6-methyl-3-(2-[4-methylphenyl] ethylamino)-pyrazinone, 1-{N-[2-(amidinoaminooxy)ethyl]amino}carbonylmethyl-5-chloro6-methyl-3-(phenethylamino)-pyrazinone, 1-{N-[2-(amidinoaminooxy){N-[2-(amidinoaminooxy) ethyl] amino} carbonylmethyl-5-chlor-6-methyl-3-(2,2-diphenylethylamino)-pyrazinone, 1-{N [2-(amidinohydrazino) ethyl] amino} carbonylmethyl-6-methyl-3 (phenethyl)-pyrazinone, 1-{N-[2-(amidinohydrazino) ethyl] amino} carbonylmethyl-6-methyl-(1-methyl-2-phenylethyl)-pyrazinone, 1-{N-[2-(amidinohydrazino) ethyl] amino} carbonylmethyl-6-ethyl-3 (phenethyl)-pyrazinone, 1-{N-[2-(amidinohydrazino) ethyl] amino} carbonylmethyl-6-methyl-3 (4-methylphenylethyl)-pyrazinone, 1-{N-[2-(amidinoaminooxy){N-[2-(amidinoaminooxy) ethyl]amino} carbonylmethyl-6-methyl-3-(1-methyl-2-(4-methylamino-3-pyridyl) ethyl-pyrazinone, 1-{N-[2-(amidinoaminooxy) ethyl]amino} carbonylmethyl-6-methyl-3-(1-methyl-2-(3-pyridyl) ethyl-pyrazinone, 1-{N-[2-(amidinoaminooxy) ethyl] amino} carbonylmethyl-6-methyl-3-(cyclopropyl-2-(3,4-dimethoxyphenyl) ethyl)-pyrazinone, 1-{N-[2-(amidinoaminooxy)ethyl]amino}carbonylmethyl-6-methyl-3-(2-cyclobutylethyl)-pyrazinone, 1-{N-[2-(amidinoaminooxy){N-[2-(amidinoaminooxy) ethyl]amino} carbonylmethyl-6-methyl-3-(2-cyclobutyl-2,2-difluoroethyl)-pyrazinone, 1-{N-[2-(amidinoaminooxy) eth