Patent EA-003461-B1 (EA)
Title: Aminoguanidine and alkoxyguanidine derivatives, process for preparing them, pharmaceutical composition, method of inhibiting proteolysis in a mammal, method of treating different diseases in a mammal, method of inhibiting thrombin-induced platelet aggregation and clotting of fibrinogen in plasma, thrombin, platelet aggregation and thrombus formation in blood, blood collection tube, blood line or extracorporeal blood circuit and blood storage
Inventor: LU TIANBAO
IPC: A61K31/496
Filed: 1999-04-05
Abstract: 1. A compound having the Formula I: or a solvate, hydrate or pharmaceutically acceptable salt thereof; wherein: L represents -C(O) or -SO2- ; R<1> represents a group: R<2> represents a group: ] or R<1> and R<2> can be taken together with the nitrogen atom to which they are attached to form a three to seven membered ring, either of which contains an additional nitrogen or oxygen atom, and which is optionally benzo- or pyrido-fused, said ring being saturated or partially unsaturated, and said ring having one or two optional substituents on either a ring carbon or nitrogen selected from the group consisting of halogen, hydroxy, acyloxy, C1-20alkoxy, C6-12aryloxy, C1-12alkyl, C3-9cycloalkyl, C2-20alkenyl, C2-20alkynyl, C6-12aryl, C6-12ar(C1-12)alkyl, heteroaryl, having 5-14-membered ring, heteroar(C1-4)alkyl, carboxy(C1-12)alkyl, C1-20alkoxycarbonyl(C1-12)alkyl, hydroxy(C1-20)alkoxy(C1-12)alkyl, cyano(C2-10)alkyl, hydroxy(C2-10)alkyl, C1-20alkoxy(C2-10)alkyl, C1-20alkoxy(C1-12)alkyl, mono(C1-12) alkylamino(C2-10)alkyl, di(C1-12)alkylamino(C2-10)alkyl, carboxy, C1-20alkoxycarbonyl, carboxamido, formyl, C1-12alkanoyl, C6-12)aroyl, C6-12ar(C1-12)alkanoyl, sulfonyl, (C1-12)alkylsulfonyl, C1-20alkoxysulfonyl, and when said optional substituent is present on a ring carbon, NR<13>N<14>; R<12> represents hydrogen, C3-7cycloalkyl, C3-7cycloalkenyl, C3-7heterocycloalkyl, C3-7heterocyclo(C2-20)alkenyl, C6-12aryl, or heteroaryl, having 5-14-membered ring, which groups are optionally substituted with C1-6 alkyl or hydroxy, or R<12> represents di(C3-9)arylmethyl, di(heteroaryl, having 5-14-membered ring)methyl, di(C3-9)cycloalkylmethyl or (C6-12aryl)(heteroaryl, having 5-14-membered ring)CH-; Z and Z' independently represent a bond, a C1-6alkyl chain, a C3-6alkenyl chain, or a C3-6alkynyl chain, where one or two nitrogen, oxygen, or sulfur atoms may be optionally contained within each chain, and the chains are optionally substituted by one or more groups selected from halogen, hydroxy, CN, C1-6alkyl, C1-6alkoxy, C1-6alkoxy(C1-6)alkyl, C1-6acyloxy, NR<13>R<14>, NHCOR<15>, NHSO2R<16>, COR<15>, CO2R<15>, CONR<13>R<14>, and SO2NR<17>R<18>; provided that when one of R<1> or R<2> is C3-8alkyl, C3-9cycloalkyl, C3-8alkenyl, C3-8alkynyl, C6-12aryl, C6-12ar(C1-12)alkyl, or heteroaryl, having 5-14membered ring, any of which is optionally substituted, then the other of R<1> or R<2> is other than hydrogen, C1-12alkyl, C6-12ar(C1-12)alkyl, C6-12aryl, hydroxy(C2-10)alkyl, amino(C2-10)alkyl, mono(C1-12)alkylamino(C2-10)alkyl, di(C1-12)alkylamino(C2-10)alkyl or carboxy(C1-12)alkyl; R<13>-R<16> represent hydrogen, C1-6alkyl, C3-7cycloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, mono- or di-hydroxy(C6-10)aryl, C6-10ar(C1-4)alkyl, pyridyl, pyridyl(C1-4)alkyl, carboxy(C1-6)-alkyl, C1-4alkoxycarbonyl(C1-4)alkyl, cyano(C2-6)alkyl, hydroxy(C2-6)alkyl, C1-4alkoxy(C2-6)alkyl, mono- and di-(C1-4)alkylamino(C2-6)alkyl; or R<13> and R<14> together with the nitrogen to which they are attached form a C3-7heterocycloalkyl ring, or R<16> additionally may represent trifluoromethyl; R<17> and R<18> are independently selected from the group consisting of hydrogen, C1-6alkyl, C3-7cycloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C6-10ar(C1-4)alkyl, pyridyl, pyridyl(C1-4)alkyl, carboxy(C1-6)alkyl, C1-4alkoxycarbony(C1-4)alkyl, cyano(C2-6)alkyl, hydroxy(C2-6)alkyl, C1-4alkoxy(C2-6)alkyl, and mono-and di-(C1-4)alkylamino(C2-6)alkyl, or R<17> and R<18> can be taken together with the nitrogen atom to which they are attached to form a heterocyclic ring selected from the group consisting of N-morpholinosulfonyl; N-piperazinylsulfonyl, optionally substituted in the 4-position with C1-6alkyl, C1-6hydroxyalkyl, C6-10aryl, C6-10aryl(C1-6)alkyl, C1-6alkylsulfonyl, C6-10arylsulfonyl, C1-6alkylcarbonyl, morpholino or C6-10arylcarbonyl; N-pyrrolylsulfonyl; N-piperidinylsulfonyl; N-pyrrolidinylsulfonyl; N-dihydropyridylsulfonyl; N-indolylsulfonyl; wherein any of said heterocyclic rings can be optionally C-substituted; R<3>, R<4>, R<5> and R<6> are each independently hydrogen, C1-12alkyl, C3-9cycloalkyl, C2-20alkenyl, C2-20alkynyl, optionally substituted C6-12aryl, optionally substituted C6-12ar(C1-12) alkyl, optionally substituted heteroaryl, having 5-14-membered ring, trifluoromethyl, halogen, hydroxy(C1-12)alkyl, cyano, nitro, carboxamido, -CO2R<x>, -CH2OR<x> or -OR<x>, or when present on adjacent carbon atoms, R<3> and R<4> may also be taken together to form -CH=CH-CH=CH- or -(CH2)q-, where q is from 2 to 6, and R<5> and R<6> are defined as above; R<x> is hydrogen, C1-12alkyl or C3-9cycloalkyl wherein said C1-12alkyl or C3-9cycloalkyl may optionally have one or more unsaturations; Y is-O-, -NR<19>-, -S-, -CHR<19>- or a covalent bond; R<19>, is hydrogen, C1-6 alkyl, benzyl, phenyl, hydroxy(C2-10)alkyl, amino(C2-10)alkyl, mono(C1-4)alkylamino(C2-8)alkyl, di(C1-4) alkylamino(C2-8)alkyl or carboxy(C2-10)alkyl; R<7> is hydrogen, C1-12alkyl, C6-12ar(C1-12)alkyl, C6-12aryl, hydroxy(C1-12)alkyl, amino(C1-12)alkyl, mono(C1-12)alkylamino(C1-12)alkyl, di(C1-12)alkylamino(C1-12)alkyl, carboxy(C1-12)alkyl, hydroxy, C1-20alkoxy, C6-12ar(C1-20)alkoxy, C6-12aryloxy, heteroaryloxy, having 5-14-membered ring, or mono- or di(C1-12)alkylamino, provided that n is other than zero when R<7> is hydroxy, C1-20alkoxy, C6-12ar(C1-20)alkoxy, C6-12)aryloxy, heteroaryloxy, having 5-14-membered ring or mono- or di(C1-12)alkylamino; R<8>, R<9> and R<10> are each independently hydrogen, C1-12alkyl, C6-12ar(C1-12)alkyl, C6-12aryl, hydroxy(C1-12)alkyl, amino(C1-12)alkyl, mono(C1-12)alkylamino(C1-12)alkyl, di(C1-12)alkylamino(C1-12)alkyl or carboxy(C1-12)alkyl; or R<7> and R<8> are taken together to form -(CH2)y-, where y is zero (a bond), 1 or 2, while R<9> and R<10> are defined as above; or R<7> and R<10> are taken together to form -(CH2)t-, where t is zero (a bond), or 1 to 8, while R<8> and R<9> are defined as above; or R<8> and R<9> are taken together to form -(CH2)r-, where r is 2-8, while R<7> and R<10> are defined as above; X is oxygen or NH; R<11> is hydrogen, C1-12alkyl, C6-12ar(C1-12)alkyl, C6-12aryl, hydroxy(C1-12)alkyl, amino(C1-12)alkyl, mono(C1-12)alkylamino(C1-12)alkyl, di(C1-12)alkylamino(C1-12)alkyl or carboxy(C1-12)alkyl; R<a>, R<b> and R<c> are independently hydrogen, C1-12alkyl, hydroxy, C1-20alkoxy, C6-12aryloxy, C6-12ar(C1-20)alkoxy, C1-20alkoxycarbonyloxy, cyano or -CO2R<w>; R<w> is C1-12alkyl, trichloroethyl, C3-9cycloalkyl, phenyl, benzyl,  or  where R<d> and R<e> are independently hydrogen, C1-6alkyl, C2-6alkenyl or phenyl, R is hydrogen, C1-6alkyl, C2-6alkenyl or phenyl, R<g> is hydrogen, C1-6alkyl, C2-6alkenyl or phenyl, and R<h> is C6-12ar(C1-12)alkyl or C1-6alkyl; n is from zero to 8; and m is from zero to 4. 2. A compound of claim 1, wherein the moiety -L-NR<1>R<2> is attached to the benzene ring in the meta- position. 3. A compound having the structure of Formula Ia: wherein: R<1> represents a group: R<2> represents a group: ] or R<1> and R<2> can be taken together with the nitrogen atom to which they are attached to form a three to seven membered ring, either of which contains an additional nitrogen or oxygen atom, and which is optionally benzo- or pyrido-fused, said ring being saturated or partially unsaturated, and said ring having one or two optional substituents on either a ring carbon or nitrogen selected from the group consisting of halogen, hydroxy, acyloxy, C1-20alkoxy, C6-12aryloxy, C1-12alkyl, C3-9cycloalkyl, C2-20alkenyl, C2-20alkynyl, C6-12aryl, C6-12ar(C1-12)alkyl, heteroaryl, having 5-14-membered ring, heteroar(C1-4)alkyl, carboxy(C1-12)alkyl, C1-20alkoxycarbonyl(C1-12)alkyl, hydroxy(C1-20)alkoxy(C1-12)alkyl, cyano(C2-10)alkyl, hydroxy(C2-10)alkyl, C1-20alkoxy(C2-10)alkyl, C1-20alkoxy(C1-12)alkyl, mono(C1-12)alkylamino(C2-10)alkyl, di(C1-12)alkylamino(C2-10)alkyl, carboxy, C1-20alkoxycarbonyl, carboxamido, formyl, C1-12alkanoyl, C6-12)aroyl, C6-12ar(C1-12)alkanoyl, sulfonyl, (C1-12)alkylsulfonyl, C1-20alkoxysulfonyl, and when said optional substituent is present on a ring carbon, NR<13>N<14>; R<12> represents hydrogen, C3-7cycloalkyl, C3-7cycloalkenyl, C3-7, heterocycloalkyl, C3-7heterocyclo(C2-20)alkenyl, C6-12 aryl, or heteroaryl, having 5-14-membered ring, which groups are optionally substituted with C1-6 alkyl or hydroxy, or R<12> represents di(C3-9)arylmethyl, di(heteroaryl, having 5-14-membered ring)methyl, di(C3-9)cycloalkylmethyl or (C6-12aryl)(heteroaryl, having 5-14-membered ring)CH-; Z and Z' independently represent a bond, a C1-6alkyl chain, a C3-6alkenyl chain, or a C3-6alkynyl chain, where one or two nitrogen, oxygen, or sulfur atoms may be optionally contained within each chain, and the chains are optionally substituted by one or more groups selected from halogen, hydroxy, CN, C1-6alkyl, C1-6alkoxy, C1-6alkoxy(C1-6)alkyl, C1-6acyloxy, NR<13>R<14>, NHCOR<15>, NHSO2R<16>, COR<15>, CO2R<15>, CONR<13>R<14>, and SO2NR<17>R<18>; provided that when one of R<1> or R<2> is C3-8alkyl, C3-9cycloalkyl, C3-8alkenyl, C3-8alkynyl, C6-12aryl, C6-12ar(C1-12)alkyl, or heteroaryl, having 5-14membered ring, any of which is optionally substituted, then the other of R<1> or R<2> is other than hydrogen, C1-12alkyl, C6-12ar(C1-12)alkyl, C6-12aryl, hydroxy(C2-10)alkyl, amino(C2-10)alkyl, mono(C1-12)alkylamino(C2-10)alkyl, di(C1-12)alkylamino(C2-10)alkyl or carboxy(C1-12)alkyl; R<13>-R<16> represent hydrogen, C1-6alkyl, C3-7cycloalkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, mono- or di-hydroxy(C6-10)aryl, C6-10ar(C1-4)alkyl, pyridyl, pyridyl(C1-4)alkyl, carboxy(C1-6)-alkyl, C1-4alkoxycarbonyl(C1-4)alkyl, cyano(C2-6)alkyl, hydroxy(C2-6)alkyl, C1-4alkoxy(C2-6)alkyl, mono- and di-(C1-4)alkylamino(C2-6)alkyl; or R<13> and R<14> together with the nitrogen to which they are attached form a C3-7 heterocycloalkyl ring, or R<16> additionally may represent trifluoromethyl; R<17> and R<18> are independently selected from the group consisting of hydrogen, C1-6alkyl, C3-7cycloalkyl, C2-6alke