Patent EA-002740-B1 (EA)
Title: Guanidine derivatives, process for preparing the same, pharmaceutical composition for inhibiting proteolysis in a mammal, method of treating, method of inhibiting: proteolysis in a mammal, thrombin-induced platelet aggregation and clotting of fibrinogen in plasma, thrombin in blood, formation of blood platelet aggregates in blood, thrombus formation, a device used in blood collection, blood circulation and blood storage
Inventor: ILLIG CARL R
IPC: A61K31/18
Filed: 1997-11-26
Abstract: 1. A compound having the Formula I:   or a solvate, hydrate or pharmaceutically acceptable salt or prodrug thereof; wherein R<1> is phenyl, naphthyl, dihydrodioxobenzo[b]thiophenyl or heteroaryl group, each of which is optionally substituted with at least one substituent, independently selected from the group, consisting of C1-6 alkyl, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, halo, C1-6 alkoxy, cyano, amino, hydroxyamino, mono (C1-6) alkylamino, di(C1-6) alkylamino, heterocycle, aryl(C1-6) alkoxy, (C1-6) alkylsulfonyl, (C1-6) alkylsulfinyl, (C1-6) alkylcarbonyl, arylsulfonyl, and R<13>R<14>NSO2, wherein R<13> and R<14> are independently selected from the group consisting of hydrogen, C1-6alkyl, C2-6alkenyl, aryl, optionally substituted C1-6 alkyl, C1-6alkoxy, C1-6alkoxycarbonyl, or carboxy group, ar(C1-6)alkyl, wherein aryl group is optionally substituted with C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxycarbonyl or carboxy group, heterocycle, optionally substituted with benzyl or C1-6 alkyl, heterocyclo (C1-6)alkyl, carboxy (C1-6)alkyl, C1-6 alkoxycarbonyl (C1-6)alkyl, cyano(C1-6)alkyl, hydroxy(C1-6)alkyl, C1-6alkoxy(C1-6)alkyl, mono- and di(C1-6)alkylamino-(C1-6)alkyl, or R<13> and R<14> can be taken together with the nitrogen atom to atom to which they are attached to form a four to seven membered ring, optionally containing at least one heteroatom in addition to said nitrogen, such as oxygen, sulfur, or nitrogen (NR<15>), said ring being saturated, and said ring having at least one optional substituent, wherein said optional substituents and R<15> are independently selected from the group consisting of hydrogen, C1-6alkyl, aryl, optionally substituted C1-6alkoxy, ar(C1-6)alkyl, heterocycle, carboxy(C1-6)alkyl, C1-6alkoxycarbonyl(C1-6)alkyl, carboxy, C1-6. alkoxycarbonyl, carboxamido, C1-6alkoxysulfonamido, sulfonamido, C1-6. alkanoyl, and C1-6. alkylsulfonyl. Z is one of -NR<10>SO2-, -SO2NR<10>-, -OSO2-, -SO2O-, -OCH2-, -CH2O-, -NR<10>CO- or -CONR<10>-; R<4> is hydrogen, alkyl, halo, hydroxyalkyl, amino, alkoxy, or hydroxy; R<2> and R<3> are each hydrogen; Y is one of -O-, -NH-, -S-, or -CH2-; X is oxygen or NH; R<6> and R<7> are hydrogen; R<12> is hydrogen or C1-6alkyl; R<8> and R<12> are each independently hydrogen, hydroxy, hydroxymethyl, or R<8> and R<12> are joined to form -(CH2)r-, wherein r is from 2 to 5; R<10> is hydrogen or C1-6alkyl; R<a>, R<b> and R<c> are independently hydrogen, C1-6 alkyl or -CO2R<w >group; R<w> - C1-6 alkyl; n is from 0 to 8, m is from 0 to 4. 2. A compound of Claim 1, wherein R<1> is phenyl or naphthyl, each of which is optionally substituted as it is defined in Claim 1. 3. A compound of Claim 1, wherein R<1> is heteroaryl which is optionally substituted by at least one substituents independently selected from the group consisting of hydroxy, nitro, trifluoromethyl, trifluoromethoxy, halogen, C1-6alkoxy, C1-6alkyl, amino, mono(C1-6)alkylamino, di(C1-6)alkylamino, or cyano group. 3. A compound of Claim 1, wherein R<1> is pyridyl, pyrazolyl, thiophenyl, chromenyl, benzoxazolyl, benzthiadiazolyl, quinazolinyl, quinolinyl, isoquinolinyl or tetrahydroquinolinyl, any of which is optionally substituted by one or more substituents independently selected from the group consisting of hydroxy, nitro, trifluoromethyl, trifluoromethoxy, halogen, C1-6alkoxy, C1-6alkyl, amino, mono(C1-6)alkylamino, di(C1-6)alkylamino, and cyano. 5. A compound of Claim 1, wherein Y is -O- or -NH-. 6. A compound of Claim 5, wherein Y is -O-. 7. A compound of Claim 1, wherein Z is -SO2NR<10>-, -SO2O- or -CH2O-. 8. A compound of Claim 1, wherein R<a>, R<b> and R<c> are hydrogen. 9. A compound of Claim 1, wherein n is from 1 to 4. 10. A compound of Claim 1, wherein m is zero, 1, 2 or 3. 11. A compound of Claim 1, wherein m and n are each zero and R<7>, R<8>, R<11> and R<12> are each hydrogen. 12. A compound of Claim 1, wherein R<2> and R<3> are hydrogen and R<4> is methyl or chloro. 13. A compound of Claim 1, wherein R<1> is one of the following groups phenyl, naphtyl, pyridinyl, thiophenyl (i.e., thiophene), quinazolinyl, quinolinyl or tetrahydroquinolinyl, any of which is optionally substituted by one or two of hydroxy, nitro, trifluoromethyl, trifluoromethoxy, halo, C1-6 alkyl, phenyl, C1-6 alkoxy, amino, mono (C1-4) alkylamino, di(C1-4) alkylamino, hydroxyamino, C6-10 ar(C1-6) alkoxy, C1-6 alkylcarbonyl, C1-6 alkylsulfonyl, C1-6alkylsulfinyl, cyano and R<13>R<14>NSO2-; R<13> and R<14> are independently selected from the group consisting of hydrogen, C1-6alkyl, C2-6alkenyl, aryl, optionally substituted C1-6 alkyl, C1-6alkoxy, C1-6alkoxycarbonyl, or carboxy group, ar(C1-6)alkyl, wherein aryl group is optionally substituted with C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxycarbonyl or carboxy group, heterocycle, optionally substituted with benzyl or C1-6 alkyl, heterocyclo (C1-6)alkyl, carboxy (C1-6)alkyl, C1-6 alkoxycarbonyl (C1-6)alkyl, cyano(C2-6)alkyl, hydroxy(C2-6)alkyl, C1-6alkoxy(C2-6)alkyl, mono- and di(C1-6)alkylamino-(C2-6)alkyl, or R<13> and R<14> can be taken together with the nitrogen atom to which they are attached to form a four to seven membered ring, optionally containing at least one heteroatom in addition to said nitrogen, such as oxygen, sulfur, or nitrogen (NR<15>), said ring being saturated, and said ring having one or two optional substituents, wherein said optional substituents and R<15> are independently selected from the group consisting of hydrogen, C1-6alkyl, ar(C1-6)alkyl, heterocycle, C1-6alkoxycarbonyl(C1-6)alkyl, carboxy, (C1-6.)alkoxycarbonyl, carboxamido, C1-6. alkanoyl, C1-6. alkylsulfonyl, C1-6. alkoxysulfonyl, and sulfonamido. Z is one of -SO2O-, -SO2NR<10>-, -CH2O- or -OCH2-; R<4> is hydrogen, C1-4alkyl, halo, hydroxy(C1-4)alkyl, or C1-4alkoxy; R<10> is hydrogen or alkyl; Y is one of -O-, -S-, or -NH-; and R<a>, R<b> and R<c> are each hydrogen or C1-4 alkyloxycarbonyl. 14. A compound of Claim 1, wherein R<1> is one of phenyl, naphthyl, pyridyl, thiophenyl, quinolinyl or isoquinolinyl, optionally substituted by one or two of chloro, methoxy, methyl, trifluoromethyl, cyano, nitro, or amino; Z is one of -SO2O-, -SO2NR<10>-, -CH2O- or -OCH2-; R<2> and R<3> are hydrogen; R<4> is one of hydrogen, methyl, methoxy; Y is one of -O- or -NH-; R<a>, R<b> and R<c> are hydrogen; R<6> and R<7> are hydrogen; R<12> is hydrogen or C1-6 alkyl; R<8> and R<11> are independently one of hydrogen, hydroxy, hydroxymethyl, or C1-4 alkoxy, or R<8> and R<11> are joint with forming -(CH2)r-, wherein r is 2, 3 or 4; R<10> is hydrogen or C1-6 alkyl; n is 0-4, m is zero, 1, 2, 3. 15. A compound of Claim 1, wherein R<1> is phenyl, substituted by C1-6 alkylsulfonyl, phenylsulfonyl, or R<13>R<14>NSO2-, wherein R<13> and R<14> are independently selected from the group consisting of hydrogen, C1-6 alkyl, C2-6alkenyl, C6-10 aryl, optionally substituted C1-6alkyl, C1-6alkoxy, C1-6 alkoxycarbonyl or carboxy group, C6-10 ar(C1-4)alkyl, wherein aryl group is optionally substituted with C1-6alkyl, C1-6alkoxy, C1-6 alkoxycarbonyl or carboxy group, pyridyl, pyridyl(C1-4)alkyl, carboxy(C1-6)alkyl, C1-4 alkoxycarbonyl(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> can be taken together with the nitrogen atom to which they are attached to form a heterocyclic ring, which is selected from the group comprising N-morpholino, N-piperazinyl (optionally N' substituted with C1-6 alkyl, C6-10 aryl, C6-10 aryl (C1-6)alkyl, C1-6alkylsulfonyl, or C1-6alkylcarbonyl), N-pyrrolyl, N-piperidinyl, N-pyrrolidinyl, N-dihydropyridyl, N-indolyl, wherein said heterocyclic ring can be optionally substituted with one or two of C1-4 alkyl, C6-10 aryl, optionally substituted C1-6alkoxy, C6-10 ar(C1-4)alkyl, heterocycle, carboxy(C1-6)alkyl, C1-4 alkoxycarbonyl(C1-4)alkyl, carboxy, C1-6 alkoxycarbonyl, carboxamido, C1-6alkanoyl, or C1-6alkylsulfonyl; Z is one of -SO2O-, -SO2NR<10>-, -CH2O- or -OCH2-; R<2> and R<3> are hydrogen; R<4> is one of hydrogen, methyl, methoxy; Y is one of -O-, -NH-; R<a>, R<b> and R<c> are hydrogen, C1-6alkyl or -CO2R<w>; R<w> - C1-6alkyl; R<6> and R<7> are hydrogen; R<12> is hydrogen or C1-6alkyl; R<8> and R<11> are independently hydrogen, hydroxy, hydroxymethyl, or C1-4alkoxy, or R<8> and R<11> are taken together to form -(CH2)r- where r is 2, 3 or 4 R<10> is hydrogen or alkyl; n is from zero to 4; and m is zero, 1, 2 or 3. 16. A compound of Claim 1, wherein the moiety -Z-R<1> is attached to the benzene ring in a position meta- to Y. 17. A compound having the formula:   or a solvate, hydrate, pharmaceutically acceptable salt or prodrug thereof: wherein R<21> is one of phenyl, naphthyl, thiophenyl, quinolinyl or isoquinolinyl, optionally substituted by one or two substituents independently selected from the group consisting of halogen, C1-4 alkyl, C1-4 alkoxy, methoxy, trifluoromethyl, cyano, nitro, or amino; and when R<21> is phenyl, said phenyl can be optionally substituted by C1-6 alkylsulfonyl, arylsulfonyl, or R<22>R<23>NSO2-, where R<22> and R<23 >are independently selected from the group consisting of hydrogen, C1-6 alkyl, C6-10 aryl, optionally substituted C1-6alkyl, C1-6alkoxy, C1-6alkoxycarbonyl, or carboxy, C6-10ar(C1-4)alkyl, wherein aryl group is optionally substituted with C1-6alkyl, C1-6alkoxy, C1-6alkoxycarbonyl, or carboxy, pyridyl, pyridyl(C1-4)alkyl, carboxy(C1-6)alkyl, C1-4 alkoxycarbonyl(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<22> and R<23> can be taken together with the nitrogen atom to which they are attached to form a heterocyclic ring, which is selected from the group comprising N-morpholino, N-piperazinyl (optionally N' substituted with C1-6 alkyl, C6-10 aryl, C6-10 aryl (C1-6)alkyl, C1-6alkylsulfonyl, or C1-6alkylcarbonyl), N-pyrrolyl, N-piperidinyl, N-pyrrolidinyl, N-dihydropyridyl, N-indolyl, wherein said heterocyclic ring can be opti