US 2004/0002539 A1Published application

Process for preparing aminoguanidines and alkoxyguanidines as protease inhibitors

Assignee3-Dimensional Pharmaceuticals, Inc.

InventorsBruce E. Tomczuk, Richard M. Soll, Tianbao Lu, Cynthia L. Fedde, Carl R. Illig, Thomas P. Markotan

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Abstract

Aminoguanidine and alkoxyguanidine compounds, including compounds of the formula: 1 wherein X is O or NR9 and R1-R4, R6-R9, R11, R12, Ra, Rb, Rc, Y, Z, n and m are set forth in the specification, as well as hydrates, solvates or pharmaceutically acceptable salts thereof, that inhibit proteolytic enzymes such as thrombin are described. Also described are methods for preparing the compounds of Formula L The novel compounds of the present invention are potent inhibitors of proteases, especially trypsin-like serine proteases, such as chymotrypsin, trypsin, thrombin, plasmin and factor Xa. Certain of the compounds exhibit antithrombotic activity via direct, selective inhibition of thrombin, or are intermediates useful for forming compounds having antithrombotic activity. The invention includes a composition for inhibiting loss of blood platelets, inhibiting formation of blood platelet aggregates, inhibiting formation of fibrin, inhibiting thrombus formation, and inhibiting embolus formation in a mammal, comprising a compound of the invention in a pharmaceutically acceptable carrier. Other uses of compounds of the invention are as anticoagulants either embedded in or physically linked to materials used in the manufacture of devices used in blood collection, blood circulation, and blood storage, such as catheters, blood dialysis machines, blood collection syringes and tubes, blood lines and stents.

Claims82

Dependent claims

A compound having the Formula I:

59
or a solvate, hydrate or pharmaceutically acceptable salt thereof;
wherein:
R1 is one of C3-8 alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl or heteroaryl, any of which may be optionally substituted;
Z is one of —NR10SO2—, —SO2NR10—, —NR10C(RyRz)—, —C(RyRz)NR10—, —OSO2—, —SO2O—, —OC(RyRz)—, —C(RyRz)O—, —NR10CO— or —CONR10—;
Ry and Rz are each independently one of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, hydroxyalkyl, carboxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or carboxy;
R2, R3 and R4 are each independently one of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, trifluoromethyl, halogen, hydroxyalkyl, cyano, nitro, carboxamido, —CO2Rx, —CH2ORx or —ORx, or when present on adjacent carbon atoms, R2 and R3 may also be taken together to form one of —CH═CH—CH═CH— or —(CH2)q—, where q is from 2 to 6, and R4 is defined as above;
Rx, in each instance, is independently one of hydrogen, alkyl or cycloalkyl wherein said alkyl or cycloalkyl groups may optionally have one or more unsaturations;
Y is one of —O—, —NR10—, —S—, —CHR10— or a covalent bond;
X is oxygen or NR9;
R9 is one of hydrogen, alkyl, cycloalkyl or aryl, wherein said alkyl, cycloalkyl or aryl can be optionally substituted with amino, monoalkylamino, dialkylamino, alkoxy, hydroxy, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, aryl, heteroaryl, acylamino, cyano or trifluoromethyl;
R6 is one of hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylamino(C2-10)alkyl, dialkylamino(C2-10)alkyl or carboxyalkyl;
R7, R8, R11 and R12 are each independently one of hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or carboxyalkyl;
or R7 and R8 are taken together to form —(CH2)y—, where y is zero (a bond), 1 or 2, while R11 and R12 are defined as above;
or R7 and R12 are taken together to form —(CH2)q—, where q is zero (a bond), or 1 to 8, while R8 and R11 are defined as above;
or R8 and R11 are taken together to form —(CH2)r—, where r is 2-8, while R7 and R12 are defined as above;
R10, in each instance, is independently one of hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylamino(C2-10)alkyl, dialkylamino(C2-10)alkyl or carboxyalkyl;
Ra, Rb and Rc are independently hydrogen, alkyl, hydroxy, alkoxy, aryloxy, aralkoxy, alkoxycarbonyloxy, cyano or —CO2Rw;
Rw is alkyl, cycloalkyl, phenyl, benzyl,
60
where
Rd and Re are independently hydrogen, C1-6 alkyl, C2-6 alkenyl or phenyl, Rf is hydrogen, C1-6 alkyl, C2-6 alkenyl or phenyl, Rg is hydrogen, C1-6 alkyl, C2-6 alkenyl or phenyl, and Rh is aralkyl or C1-6 alkyl;
n is from zero to 8;
and m is from zero to 4.

21 more elements

A compound having the formula:

64
or a solvate, hydrate, pharmaceutically acceptable salt or prodrug thereof:
wherein
R21 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, amino or dimethylamino;
and when R21 is phenyl, said phenyl can be optionally substituted by C1-6 alkylsulfonyl, C6-10 arylsulfonyl, C6-10 ar(C1-6) alkylsulfonyl, C6-10 arylsulfonamido, C6-10 ar(C1-6) alkylsulfonamido, N-morpholinosulfonyl, or R22R23NSO2—, where R22 and R23 are independently selected from the group consisting of hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C6-10 ar(C1-4)alkyl, pyridyl, pyridyl(C1-4)alkyl, carboxy(C1-6)alkyl, C1-4 alkoxycarbonyl(C1-4)alkyl, cyano(C1-4)alkyl, hydroxy(C1-4)alkyl, C1-4 alkoxy(C1-4)alkyl, mono- and di-(C1-4)alkylamino(C1-4)alkyl, or R22 and R23 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 N′ substituted with C1-6 alkyl, C1-6 hydroxyalkyl, C6-10 aryl, C6-10 aryl(C1-6)alkyl, C1-6 alkylsulfonyl, C6-10 arylsulfonyl, C1-6 alkylcarbonyl, morpholino or C6-10 arylcarbonyl), N-pyrrolylsulfonyl, N-piperidinylsulfonyl, N-pyrrolidinylsulfonyl, N-dihydropyridylsulfonyl, N-indolylsulfonyl, wherein said heterocyclic ring can be optionally substituted with one or two of C1-4 alkyl, C3-7 cycloalkyl, C6-10 aryl, C6-10 ar(C1-4)alkyl, heterocycle, heterocycloalkyl, carboxy(C1-6)alkyl, C1-4)alkoxycarbonyl(C1-4)alkyl, cyano(C1-6)alkyl, hydroxy(C1-6)alkyl, C1-4 alkoxy(C1-4)alkyl, mono- and di-(C1-4)alkylamino(C1-4)alkyl, carboxy, C1-6 alkoxycarbonyl, carboxamido, formyl, C1-6 alkanoyl, C6-10 aroyl, C6-10 ar(C1-4)alkanoyl, sulfonyl, C1-6 alkylsulfonyl, C1-6 alkoxysulfonyl, sulfonamido, phosphonyl, phosphoramido, or phosphinyl;
R24 is hydrogen or C1-4 alkyl;
Y′ is one of O, NR10 or a covalent bond hydrogen, C1-6 alkyl, C6-10 ar(C1-6)alkyl, C6-10 aryl, C2-10 hydroxyalkyl C2-10 aminoalkyl, C2-7 carboxyalkyl, mono(C1-4 alkyl)amino(C1-8)alkyl, and di(C1-4 alkyl)amino(C1-8)alkyl;
and
a and b are 0, 1 or 2;
X′ is O or NR29;
and
R29 is hydrogen or C1-4 alkyl.

9 more elements

A compound having the formula:

65
or a solvate, hydrate, pharmaceutically acceptable salt or prodrug thereof;
wherein
R21 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, amino or dimethylamino;
and when R21 is phenyl, said phenyl can be optionally substituted by C1-6 alkylsulfonyl, C6-10 arylsulfonyl, C6-10 ar(C1-6) alkylsulfonyl, C6-10 arylsulfonamido, C6-10 ar(C1-6) alkylsulfonamido, N-morpholinosulfonyl, or R22R23NSO2—, where R22 and R23 are independently selected from the group consisting of hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C6-10 ar(C1-4)alkyl, pyridyl, pyridyl(C1-4)alkyl, carboxy(C1-6)alkyl, C1-4 alkoxycarbonyl(C1-4)alkyl, cyano(C1-4)alkyl, hydroxy(C1-4)alkyl, C1-4 alkoxy(C1-4)alkyl, mono- and di-(C1-4)alkylamino(C1-4)alkyl, or R22 and R23 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 N′ substituted with C1-6 alkyl, C1-6 hydroxyalkyl, C6-10 aryl, C6-10 aryl(C1-6)alkyl, C1-6 alkylsulfonyl, C6-10 arylsulfonyl, C1-6 alkylcarbonyl, morpholino or C6-10 arylcarbonyl), N-pyrrolylsulfonyl, N-piperidinylsulfonyl, N-pyrrolidinylsulfonyl, N-dihydropyridylsulfonyl, N-indolylsulfonyl, wherein said heterocyclic ring can be optionally substituted with one or two of C1-4 alkyl, C3-7 cycloalkyl, C6-10 aryl, C6-10 ar(C1-4)alkyl, heterocycle, heterocycloalkyl, carboxy(C1-6)alkyl, C1-4)alkoxycarbonyl(C1-4)alkyl, cyano(C1-6)alkyl, hydroxy(C1-6)alkyl, C1-4 alkoxy(C1-4)alkyl, mono- and di-(C1-4)alkylamino(C1-4)alkyl, carboxy, C1-6 alkoxycarbonyl, carboxamido, formyl, C1-6 alkanoyl, C6-10 aroyl, C6-10 ar(C1-4)alkanoyl, sulfonyl, C1-6 alkylsulfonyl, C1-6 alkoxysulfonyl, sulfonamido, phosphonyl, phosphoramido, or phosphinyl;
R24 is hydrogen or C1-4 alkyl;
X′ is O or NR29;
and
R29 is hydrogen or C1-4 alkyl;
Y′ is one of O, NR10 or a covalent bond hydrogen, C1-6 alkyl, C6-10 ar(C1-6)alkyl, C6-10 aryl, C2-10 hydroxyalkyl C2-10 aminoalkyl, C2-7 carboxyalkyl, mono(C1-4 alkyl)amino(C1-8)alkyl, and di(C1-4 alkyl)amino(C8)alkyl;
and
bis O, 1 or 2.

9 more elements

A compound having the Formula I:

66
or a solvate, hydrate or pharmaceutically acceptable salt thereof, wherein:
R1 is one of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl or heteroaryl, any of which may be optionally substituted;
Z is one of —NR10SO2—, SO2NR10—, —NR10C(RyRz)—, —C(RyRz)NR10-, —OSO2—, —SO2O—, —OC(RyRz)—, —C(RyRz)O—, —NR10CO— or —CONR10—;
Ry and Rz are each independently one of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, hydroxyalkyl, carboxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or carboxy;
R2, R3 and R4 are each independently one of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, trifluoromethyl, halogen, hydroxyalkyl, cyano, nitro, carboxamido, —CO2Rx, —CH2ORx or —ORx, or when present on adjacent carbon atoms, R2 and R3 may also be taken together to form one of-CH═CH—CH═CH— or (CH2)q—, where q is from 2 to 6, and R4 is defined as above;
Rx, in each instance, is independently one of hydrogen, alkyl or cycloalkyl wherein said alkyl or cycloalkyl groups may optionally have one or more unsaturations;
Y is one of —O—, —NR10—, —S—, —CHR10— or a covalent bond;
Rw is alkyl, cycloalkyl, phenyl, benzyl,
67
where Rd and Re are independently hydrogen, C1-6 alkyl, C2-6 alkenyl or phenyl, Rf is hydrogen, C1-6 alkyl, C2-6 alkenyl or phenyl, Rg is hydrogen, C1-6 alkyl, C2-6 alkenyl or phenyl, and Rh is aralkyl or C1-6 alkyl;
and:
A. R7 and R12 are taken together to form —(CH2)o—, where o is 1, 2 or 3;
R11 is hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl or carboxyalkyl;
R8 is hydrogen;
Ra, Rb and Rc are hydrogen, hydroxy,
68
where Rh is benzyl or t-butyl, and where Rf is hydrogen or methyl;
and
R6 is hydrogen, C1-4 alkyl, C2-4 hydroxyalkyl, C2-4 carboxyalkyl, C2-4 aminoalkyl, dimethylamino(C2-8)alkyl, or methylamino(C2,)alkyl;
or
B. R7 is hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl or carboxyalkyl;
R8 and R12 are taken together to form —CH2—CH2—(CH2)p—, where p is 1, 2 or 3;
R7 is hydrogen;
and
Ra, Rb and Rc are hydrogen, hydroxy,
69
where Rh is benzyl or t-butyl, and where Rf is hydrogen or methyl;
and
R6 is hydrogen, C1-4 alkyl, C2-4 hydroxyalkyl, C2-4 carboxyalkyl, C2-4 aminoalkyl, dimethylamino(C2-8)alkyl, or methylamino(C2-8)alkyl;
or
C. R6 and Rb are taken together to form ═CH—N═CH—NH— or —CH2—(CH2)r—,
where r is 1, 2 or 3;
Ra is hydrogen or hydroxy;
Rc is hydrogen, alkyl, hydroxy, alkoxy, aryloxy, aralkoxy, alkoxycarbamoyloxy, cyano or —CO2Rw—, where Rw is as defined above;
R7 and R8 are each independently one of hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl or carboxyalkyl, or R7 and R8 are taken together to form —(CH2)y—, where y is zero, 1 or 2;
R11 is hydrogen;
and R12 is one of hydrogen, alkyl, cycloalkyl or aryl, wherein said alkyl, cycloalkyl or aryl can be optionally substituted with amino, monoalkylamino, dialkylamino, alkoxy, hydroxy, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, aryl, heteroaryl, acylamino, cyano or trifluoromethyl;
or
D. Ra and Rc are taken together to form —CH2—(CH2)s—, where s is 1 or 2;
and R6 is hydrogen, alkyl, alkoxy, aryloxy, aralkoxy, alkoxycarbonyloxy, cyano or —CO2Rw—, where Rw is as defined above;
R7 and R8 are each independently one of hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl or carboxyalkyl, or R7 and R8 are taken together to form —(CH2)y—, where y is zero, 1 or 2;
R11 is hydrogen;
and R12 is one of hydrogen, alkyl, cycloalkyl or aryl, wherein said alkyl, cycloalkyl or aryl can be optionally substituted with amino, monoalkylamino, dialkylamino, alkoxy, hydroxy, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, aryl, heteroaryl, acylamino, cyano or trifluoromethyl.

41 more elements

A process for preparing an aminoguanidine or an alkoxyguanidine compound having the Formula I:

74
or a solvate, hydrate, prodrug, or pharmaceutically acceptable salt thereof;
wherein:
R1 is one of aryl substituted by R13R14NSO2—, or heteroaryl, any of which may be optionally substituted;
R13 and R14 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycle, heterocycloalkyl, carboxyalkyl, alkoxycarbonylalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, mono- and di-alkylaminoalkyl, provided that at least one of R13 and R14 is heterocycle or heterocycloalkyl, or R13 and R14 can be taken together with the nitrogen atom to which they are attached to form a three to seven membered ring, optionally containing one or more heteroatoms in addition to said nitrogen, such as oxygen, sulfur, or nitrogen (NR15), said ring being unsaturated or saturated, and said ring having one or two optional substituents, wherein said optional substituents and R15 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycle, heterocycloalkyl, carboxyalkyl, alkoxycarbonylalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, mono- and di-alkylaminoalkyl, carboxy, alkoxycarbonyl, carboxamido, formyl, alkanoyl, aroyl, aralkanoyl, alkylsulfonyl, alkoxysulfonyl, sulfonamide, phosphonyl, phosphoramido, or phosphinyl;
Z is one of —NR10SO2—, —SO2NR10—, —NR10C(RyRz)—, —C(RyRz)NR10—, —OSO2—, —SO2O—, —OC(RyRz)—, —C(RyRz)O—, —NR10CO— or —CONR10—;
Ry and Rz are each independently one of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, hydroxyalkyl, carboxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or carboxy;
R2, R3 and R4 are each independently one of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, trifluoromethyl, halogen, hydroxyalkyl, cyano, nitro, carboxamido, —CO2Rx, —CH2ORx or —ORx, or when present on adjacent carbon atoms, R2 and R3 may also be taken together to form one of —CH═CH—CH═CH— or —(CH2)q—, where q is from 2 to 6, and R4 is defined as above;
Rx, in each instance, is independently one of hydrogen, alkyl or cycloalkyl wherein said alkyl or cycloalkyl groups may optionally have one or more unsaturations;
Y is one of —O—, —NR10—, —S—, —CHR10— or a covalent bond;
X is oxygen or NR9;
R9 is one of hydrogen, alkyl, cycloalkyl or aryl, wherein said alkyl, cycloalkyl or aryl can be optionally substituted with amino, monoalkylamino, dialkylamino, alkoxy, hydroxy, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, aryl, heteroaryl, acylamino, cyano or trifluoromethyl;
R6 is one of hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylamino(C2-10)alkyl, dialkylamino(C2-10)alkyl or carboxyalkyl;
or R6 and R12 are taken together to form —(CH2)w—, where w is 1-5;
R7 is one of hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, hydroxy, alkoxy, aralkoxy, aryloxy, heteroaryloxy, or mono- or di-alkylamino, provided that n is other than zero when R7 is hydroxy, alkoxy, aralkoxy, aryloxy, heteroaryloxy, or mono- or di-alkylamino;
R8, R11 and R12 are each independently one of hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or carboxyalkyl;
or R7 and R8 are taken together to form —(CH2)y—, where y is zero (a bond), 1 or 2, while R11 and R12 are defined as above;
or R7 and R12 are taken together to form —(CH2)q—, where q is zero (a bond), or 1 to 8, while R8 and R11 are defined as above;
or R8 and R11 are taken together to form —(CH2)r—, where r is 2-8, while R7 and R12 are defined as above;
R10, in each instance, is independently one of hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylamino(C2-10)alkyl, dialkylamino(C2-10)alkyl or carboxyalkyl;
Ra, Rb and Rc are independently hydrogen, alkyl, hydroxy, alkoxy, aryloxy, aralkoxy, alkoxycarbonyloxy, cyano or —CO2Rw;
Rw is alkyl, cycloalkyl, phenyl, benzyl,
75
where
Rd and Re are independently hydrogen, C1-6 alkyl, C2-6 alkenyl or phenyl, Rf is hydrogen, C1-6 alkyl, C2-6 alkenyl or phenyl, Rg is hydrogen, C1-6 alkyl, C2-6 alkenyl or phenyl, and Rh is aralkyl or C1-6 alkyl;
n is from zero to 8;
and m is from zero to 4, comprising
(a) reacting an aminoguanidine of the formula
76
wherein R6, Ra, Rb and Rc are as defined above, with a carbonyl-containing compound of the formula
77
wherein R1-R4, Z, Y, n, m, R7, R8, R11 and R12 are as defined above to form an amidinohydrazone, and thereafter selectively reducing the hydrazone carbon to nitrogen double bond of the amidinohydrazone;
or
(b) reacting an alkoxyamine compound of the formula
78
wherein R1-R4, Z, Y, n, m, R7, R8, R11 and R12 are as defined above, with a guanidinylating reagent.

33 more elements

The process for preparing a compound having the Formula I:

87
or a solvate, hydrate, prodrug, or pharmaceutically acceptable salt thereof;
wherein:
R1 is one of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl or heteroaryl, any of which may be optionally substituted;
Z is one of —NR10SO2—, —SO2NR10—, —NR10C(RyRz)—, —C(RyRz)NR10—, —OSO2—, —SO2O—, —OC(RyRz)—, —C(RyRz)O—, —NR10CO— or —CONR10—;
Ry and Rz are each independently one of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, hydroxyalkyl, carboxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or carboxy;
R2, R3 and R4 are each independently one of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, trifluoromethyl, halogen, hydroxyalkyl, cyano, nitro, carboxamido, —CO2Rx, —CH2ORx or —ORx, or when present on adjacent carbon atoms, R2 and R3 may also be taken together to form one of —CH═CH—CH═CH— or —(CH2)q—, where q is from 2 to 6, and R4 is defined as above;
Rx, in each instance, is independently one of hydrogen, alkyl or cycloalkyl wherein said alkyl or cycloalkyl groups may optionally have one or more unsaturations;
Y is one of —O—, —NR10—, —S—, —CHR10— or a covalent bond;
R10, in each instance, is independently one of hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylamino(C2-10)alkyl, dialkylamino(C2-10)alkyl or carboxyalkyl;
Rw is alkyl, cycloalkyl, phenyl, benzyl,
88
where Rd and Re are independently hydrogen, C1-6 alkyl, C2-6 alkenyl or phenyl, Rf is hydrogen, C1-6 alkyl, C2-6 alkenyl or phenyl, Rg is hydrogen, C1-6 alkyl, C2-6 alkenyl or phenyl, and Rh is aralkyl or C1-6 alkyl;
and:
C. R6 and Rb are taken together to form —CH2—(CH2)r—, where r is 1, 2 or 3;
Ra is hydrogen or hydroxy;
Rc is hydrogen, alkyl, hydroxy, alkoxy, aryloxy, aralkoxy, alkoxycarbamoyloxy, cyano or —CO2Rw, where Rw is as defined above;
R7, R8, R11 and R12 are each independently one of hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl or carboxyalkyl, or R7 and R8 are taken together to form —(CH2)y—, where y is zero, 1 or 2;
or
D. Ra and Rc are taken together to form —CH2—(CH2),-, where s is 1 or 2;
and Rb is hydrogen, alkyl, alkoxy, aryloxy, aralkoxy, alkoxycarbonyloxy, cyano or —CO2Rw, where Rw is as defined above;
R6 is hydrogen, C1-4 alkyl, C2-4hydroxyalkyl, C2-4 carboxyalkyl, C2-4 aminoalkyl, dimethylamino(C2-8)alkyl, or methylamino(C2-8)alkyl;
R7, R8, R11 and R12 are each independently one of hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl or carboxyalkyl, or R7 and R8 are taken together to form —(CH2)y—, where y is zero, 1 or 2;
comprising
(a) reacting an aminoguanidine of the formula
89
wherein R6, Ra, Rb and Rc are as defined above, with a carbonyl-containing compound of the formula
90
wherein R1-R4, Z, Y, n, m, R7, R8, R11 and R12 are as defined above to form an amidinohydrazone, and thereafter selectively reducing the hydrazone carbon to nitrogen double bond of the amidinohydrazone;
or
(b) reacting an alkoxyamine compound of the formula
91
wherein R1-R4, Z, Y, n, m, R7, R8, R11 and R12 are as defined above, with a guanidinylating reagent.

30 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/419,972Filed 22 Apr 2003
Priority: 26 Nov 1996
Published: 1 Jan 2004
Term ends: Not estimatedThe source records don’t support an estimate.

Classification31 codes

C07C 309/73
Having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton: to carbon atoms of…
A61P 7/00
Drugs for disorders of the blood or the extracellular fluid
A61P 7/02
Drugs for disorders of the blood or the extracellular fluid: antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
A61P 7/04
Drugs for disorders of the blood or the extracellular fluid: antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents

Family

Application60/031,822Us provisional application · filed 26 Nov 1996
Application08/979,234Division · filed 26 Nov 1997
Application09/722,363Division · filed 28 Nov 2000
Application10/419,972Division · filed 22 Apr 2003
US 6,235,778 B1Related patent
US 6,638,931 B1Related patent
US 6,730,783 B2Related patent
US 2004/0002539 A1This patent

From the US filing history. Foreign family members aren’t listed.