CA2422067A1 - Aminoheterocycles (factor xa inhibitors 14) - Google Patents
Aminoheterocycles (factor xa inhibitors 14) Download PDFInfo
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- CA2422067A1 CA2422067A1 CA002422067A CA2422067A CA2422067A1 CA 2422067 A1 CA2422067 A1 CA 2422067A1 CA 002422067 A CA002422067 A CA 002422067A CA 2422067 A CA2422067 A CA 2422067A CA 2422067 A1 CA2422067 A1 CA 2422067A1
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- yloxy
- aminoisoquinolin
- amide
- methanesulfonylbiphenyl
- pentanoic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
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Abstract
The invention relates to compounds of formula (I), wherein the substituents R1, R2, R3, R4, W, D and I are defined as per claim (1). The compounds are suitable for producing medicaments for combating thrombo-embolic disorders.
Description
as originally filed Aminoheterocycles (factor Xa inhibitors 14) The invention relates to aminoheterocycles of the general formula I
Ra \
E
D ~ ~ \ W \ Rs Ra R' R2 in which:
-D=E- is -N=C(NH2)- or -C(NH2)=N-l0 R', independently of one another are H, A, OR6, N(R6)2, N02, R2 CN, Hal, NR6COA, NR6COAr', NR6S02A, NR6S02Ar', COORS, CON(R6)2, CONR6Ar', COR', COAr', S(O)~A
R3 IS S02(NR6)2, S(O)"A, CF3, COOR6, OA, CN, R4, R5 independently of one another are H, A, OR6, N(R6)2, N02, CN, Hal, NR6COA, NR6COAr', NR6S02A, NR6S02Ar', COOR6, CON(R6)2, CONR6Ar', COR', COAr', S(O)"A
R6 is H, A, [C(R')2]"Ar' or [C(R')2]~Het R' is H or A
W is CONRsC(R6)2CONR6[C(Rs)2li-, -NR6C(R6)ZCONR6[C(R6)2li-, 2 0 -[C(Rs)2]mCONR6[C(R6)2]i- or -OC(R6)2CONR6(C(Rs)2],-A is alkyl having 1-20 C atoms, in which one or two CH2 groups can be replaced by O or S atoms or by CH=CH groups and also 1-7 H atoms can be replaced by F, Ar is phenyl or naphthyl, which is unsubstituted or mono-, di- or trisubstituted by A, Ar', Het, ORS, N(R6)2, N02, CN, Hal, NR6COA, NRsCOAr', NR6S02A, NR6S02Ar', COOR6, CON(R6)2, CONRsAr', COR', COAr', S02NR6, S(O)r,Ar' or S(O)DA
Ar' is phenyl or naphthyl, which is unsubstituted or mono-, di- or trisubstituted by A, OR', N(R')2, N02, CN, Hal, NR'COA, NR'S02A, COOR', CON(R')2, COR', S02NR' or S(O)"A
Het is a mono- or binuclear, saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms, bonded via N or C, which can be unsubstituted or mono-, di- or trisubstituted by A, OR', N(R')2, N02, CN, Hal, NR'COA, NR'S02A, COOR', CON(R')2, COR', S02NR', S(O)DA
andlor carbonyl oxygen, Hal is F, CI, Br or I
n is 0, 1 or 2 m is 1 or 2 I is0or1 1 o and their pharmaceutically tolerable salts and solvates.
The radicals Rs indicated above should in this case, if they occur a number of times in a compound, be independent of one another and in each case can individually assume any of the meanings indicated for R6.
The invention also relates to the optically active forms, the racemates, the diastereomers and the hydrates and solvates, e.g. alcoholates, of these compounds.
2 o For the control of haemorrhages caused by injuries, the human body has a mechanism by means of which a rapid wound closure is achieved by means of blood clots. Blood clots are formed by a series of zymogen activations. In the course of this enzymatic cascade, the activated form of one factor in each case catalyses the activation of the next. Since this process is of catalytic nature, very 2 5 small amounts of the inducing factors are sufficient in order to set the cascade in motion. As a result of the large number of steps, a great increase is achieved, which guarantees a rapid response to the injury. Plasmatic clotting after a tissue lesion can take place exogeneously through the release of tissue thrombokinase.
The corresponding reaction sequence is designated as an extravascular system 30 (extrinsic system) and proceeds within seconds. Clotting can also be induced endogeneously by thrombocytolysis. This reaction sequence, which is designated as an intravascular system, proceeds within minutes. Both systems lead to a final common sequence of steps, which leads to the formation of a fibrin clot. The intravascular and the extravascular system influence each other in vivo. Both are 35 necessary for blood clotting to proceed completely.
Ra \
E
D ~ ~ \ W \ Rs Ra R' R2 in which:
-D=E- is -N=C(NH2)- or -C(NH2)=N-l0 R', independently of one another are H, A, OR6, N(R6)2, N02, R2 CN, Hal, NR6COA, NR6COAr', NR6S02A, NR6S02Ar', COORS, CON(R6)2, CONR6Ar', COR', COAr', S(O)~A
R3 IS S02(NR6)2, S(O)"A, CF3, COOR6, OA, CN, R4, R5 independently of one another are H, A, OR6, N(R6)2, N02, CN, Hal, NR6COA, NR6COAr', NR6S02A, NR6S02Ar', COOR6, CON(R6)2, CONR6Ar', COR', COAr', S(O)"A
R6 is H, A, [C(R')2]"Ar' or [C(R')2]~Het R' is H or A
W is CONRsC(R6)2CONR6[C(Rs)2li-, -NR6C(R6)ZCONR6[C(R6)2li-, 2 0 -[C(Rs)2]mCONR6[C(R6)2]i- or -OC(R6)2CONR6(C(Rs)2],-A is alkyl having 1-20 C atoms, in which one or two CH2 groups can be replaced by O or S atoms or by CH=CH groups and also 1-7 H atoms can be replaced by F, Ar is phenyl or naphthyl, which is unsubstituted or mono-, di- or trisubstituted by A, Ar', Het, ORS, N(R6)2, N02, CN, Hal, NR6COA, NRsCOAr', NR6S02A, NR6S02Ar', COOR6, CON(R6)2, CONRsAr', COR', COAr', S02NR6, S(O)r,Ar' or S(O)DA
Ar' is phenyl or naphthyl, which is unsubstituted or mono-, di- or trisubstituted by A, OR', N(R')2, N02, CN, Hal, NR'COA, NR'S02A, COOR', CON(R')2, COR', S02NR' or S(O)"A
Het is a mono- or binuclear, saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms, bonded via N or C, which can be unsubstituted or mono-, di- or trisubstituted by A, OR', N(R')2, N02, CN, Hal, NR'COA, NR'S02A, COOR', CON(R')2, COR', S02NR', S(O)DA
andlor carbonyl oxygen, Hal is F, CI, Br or I
n is 0, 1 or 2 m is 1 or 2 I is0or1 1 o and their pharmaceutically tolerable salts and solvates.
The radicals Rs indicated above should in this case, if they occur a number of times in a compound, be independent of one another and in each case can individually assume any of the meanings indicated for R6.
The invention also relates to the optically active forms, the racemates, the diastereomers and the hydrates and solvates, e.g. alcoholates, of these compounds.
2 o For the control of haemorrhages caused by injuries, the human body has a mechanism by means of which a rapid wound closure is achieved by means of blood clots. Blood clots are formed by a series of zymogen activations. In the course of this enzymatic cascade, the activated form of one factor in each case catalyses the activation of the next. Since this process is of catalytic nature, very 2 5 small amounts of the inducing factors are sufficient in order to set the cascade in motion. As a result of the large number of steps, a great increase is achieved, which guarantees a rapid response to the injury. Plasmatic clotting after a tissue lesion can take place exogeneously through the release of tissue thrombokinase.
The corresponding reaction sequence is designated as an extravascular system 30 (extrinsic system) and proceeds within seconds. Clotting can also be induced endogeneously by thrombocytolysis. This reaction sequence, which is designated as an intravascular system, proceeds within minutes. Both systems lead to a final common sequence of steps, which leads to the formation of a fibrin clot. The intravascular and the extravascular system influence each other in vivo. Both are 35 necessary for blood clotting to proceed completely.
As important as rapid blood clotting is for the closure of injuries, nevertheless in certain conditions it is necessary to inhibit blood clotting in order, for example, to avoid the formation of thrombi in vessels. Intervention should in this case take place as specifically and selectively as possible in the blood clotting cascade in order to be able to control the inhibition as precisely as possible and to be able to avoid undesired side effects.
Factor Xa is a serine protease of the blood-clotting cascade which is formed by activation of factor X. In the intravascular pathway, this activation takes place 1 o through factor IXa, this reaction being stimulated by the antihaemophilic factor (Villa). Prothrombin is then converted into thrombin by factor Xa. The proteolytic enzyme thrombin cleaves fibrinogen into fibrin monomers which spontaneously assemble to give ordered fibrous structures, which are designated as fibrin.
The clot which is formed by the spontaneous aggregation of fibrin monomers is stabilized by covalent crosslinkages between the side chains of various molecules in the fibrin fibres. To this end, peptide bonds form between specific glutamine and lysine side chains in a transamidation reaction. This crosslinkage is catalysed by an enzyme which is called factor Xllla.
2 0 In the extravascular system, the activation of factor X takes place through the tissue factor and factor VII.
An inhibition of factor Xa allows a specific intervention in blood clotting, since no other processes are influenced here. This is more advantageous than, for example, inhibition of thrombin, since thrombin not only catalyses the conversion of fibrinogen to fibrin, and also the conversion of factor VIII into Villa, factor V into Va and factor XI into Xla, but, for example, also activates platelets. A
variety of research activities are therefore being undertaken to develop inhibitors of factor Xa, which has led to the development of various classes of substance.
WO 99111657 describes 1-amino-7-isoquinoline derivatives which act as inhibitors of serine proteases. WO 99111658 describes m-benzamidine derivatives which act as serine protease inhibitors. Furthermore, WO 99110316 describes 3 amidinoaniline derivatives which act as inhibitors of the activated blood clotting 3 5 factor Xa.
Factor Xa is a serine protease of the blood-clotting cascade which is formed by activation of factor X. In the intravascular pathway, this activation takes place 1 o through factor IXa, this reaction being stimulated by the antihaemophilic factor (Villa). Prothrombin is then converted into thrombin by factor Xa. The proteolytic enzyme thrombin cleaves fibrinogen into fibrin monomers which spontaneously assemble to give ordered fibrous structures, which are designated as fibrin.
The clot which is formed by the spontaneous aggregation of fibrin monomers is stabilized by covalent crosslinkages between the side chains of various molecules in the fibrin fibres. To this end, peptide bonds form between specific glutamine and lysine side chains in a transamidation reaction. This crosslinkage is catalysed by an enzyme which is called factor Xllla.
2 0 In the extravascular system, the activation of factor X takes place through the tissue factor and factor VII.
An inhibition of factor Xa allows a specific intervention in blood clotting, since no other processes are influenced here. This is more advantageous than, for example, inhibition of thrombin, since thrombin not only catalyses the conversion of fibrinogen to fibrin, and also the conversion of factor VIII into Villa, factor V into Va and factor XI into Xla, but, for example, also activates platelets. A
variety of research activities are therefore being undertaken to develop inhibitors of factor Xa, which has led to the development of various classes of substance.
WO 99111657 describes 1-amino-7-isoquinoline derivatives which act as inhibitors of serine proteases. WO 99111658 describes m-benzamidine derivatives which act as serine protease inhibitors. Furthermore, WO 99110316 describes 3 amidinoaniline derivatives which act as inhibitors of the activated blood clotting 3 5 factor Xa.
It is an object of the invention to discover novel compounds having valuable properties, in particular those which can be used for the production of medicaments.
It has been found that the compounds of the formula I and their salts have very valuable pharmacological properties together with good tolerability. In particular, they exhibit inhibitory properties for factors Xa and Vlla and can therefore be employed for the control and prevention of thromboembolic conditions, such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina 1 o pectoris, restenosis after angioplasty and intermittent claudication.
Particularly preferred compounds are mentioned below:
2-(1-aminoisoquinolin-7-yloxy)-N (2'-methanesulfonylbiphenyl-4-yl)acetamide (1), 2-(1-aminoisoquinolin-7-yloxy)-N (2'-sulfamoylbiphenyl-4-yl)acetamide (2), 2-(1-aminoisoquinolin-7-yloxy)hexanoic acid (2'-methanesulfonylbiphenyl-4.-yl)-amide (3), 2-(1-aminoisoquinolin-7-yloxy)pentanoic acid (2'-methanesulfonylbiphenyl-4-yl)-amide (4), 2-(1-aminoisoquinolin-7-yloxy)pentanoic acid (2'-sulfamoylbiphenyl-4-yl)amide (5), 2-(1-aminoisoquinolin-7-yloxy)-N-(2'-methanesulfonylbiphenyl-4-yl)-2-phenyl-acetamide (6), 2-(1-aminoisoquinolin-7-yloxy)-N-(2'-methanesulfonylbiphenyl-4-yl)-3-methylbutyr-amide (7), 2-(1-aminoisoquinolin-7-yloxy)-3-methyl-N-(2'-sulfamoylbiphenyl-4-yl)butyramide (9), 2-(1-aminoisoquinolin-7-yloxy)-4-methylpentanoic acid (2'-methanesulfonylbi-phenyl-4-yl)amide (11), 2-(1-aminoquinolin-7-yloxy)-2-phenyl-N-(2'-sulfamoylbiphenyl-4-yl)acetamide (12), 2-(1-aminoisoquinolin-7-ylamino)-N-(2'-methanesulfonylbiphenyl-4-yl)-3-phenyl-propionamide (14), 2-(2-aminoquinolin-7-yloxy)pentanoic acid (2'-methanesulfonylbiphenyl-4-yl)amide (21 ), 2-(1-aminoisoquinolin-5-yloxy)hexanoic acid (2'-methanesulfonylbiphenyl-4-yl)-3 5 amide (81 ), 2-(1-aminoisoquinolin-5-yloxy)hexanoic acid (2'-sulfamoylbiphenyl-4-yl)amide (82), 2-(1-aminoisoquinolin-5-yloxy)pentanoic acid (2'-methanesulfonylbiphenyl-4-yl)-amide (83), 2-(1-aminoisoquinolin-5-yloxy)pentanoic acid (2'-sulfamoylbiphenyl-4-yl)amide (84), 2-(1-aminoisoquinolin-7-ytoxy)pentanoic acid (2'-methanesulfonylbiphenyl-4-yl-methyl)amide (85), 2-(1-aminoisoquinolin-7-yloxy)pentanoic acid (2'-methanesulfonylbiphenyl-2-yl-methyl)amide (86), 2-(1-aminoisoquinolin-7-yloxy)pentanoic acid (2'-ethanesulfonylbiphenyl-4-yl)-1 o amide (87), 2-(1-aminoisoquinolin-7-yloxy)pentanoic acid (2'-methoxybiphenyl-4-yl)amide (88), 2-(1-aminoisoquinolin-7-yloxy)pentanoic acid (2'-cyanobipheny!-4-yl)amide (89}, 2-(1-aminoisoquinolin-7-yloxy)pentanoic acid (3'-cyanobiphenyl-4-yl)amide (90).
Particular embodiments of the compounds of the formula I are listed below, a generalized form of the group of compounds in each case being indicated in the tables. The radical R6 indicated in the formula in this case has the meaning indicated above. The letter A further stands for the group -O- or -NH- and X
stands for -CH3 or -NH2.
A first preferred group of compounds of the formula I is listed in Table 1, the compounds in each case being covered by the general formula II.
Table 1 /I
NHZ O / \
N \ \ A N \ I O- I -O
H X
/ / Rs I I
Number A R6 X ESI-MS
2 O -H -NH2 449 a 3 O *\/\/ -CH3 504 4 O *~/ -CH3 490 O *~ -NH2 491 a * ~ /
It has been found that the compounds of the formula I and their salts have very valuable pharmacological properties together with good tolerability. In particular, they exhibit inhibitory properties for factors Xa and Vlla and can therefore be employed for the control and prevention of thromboembolic conditions, such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina 1 o pectoris, restenosis after angioplasty and intermittent claudication.
Particularly preferred compounds are mentioned below:
2-(1-aminoisoquinolin-7-yloxy)-N (2'-methanesulfonylbiphenyl-4-yl)acetamide (1), 2-(1-aminoisoquinolin-7-yloxy)-N (2'-sulfamoylbiphenyl-4-yl)acetamide (2), 2-(1-aminoisoquinolin-7-yloxy)hexanoic acid (2'-methanesulfonylbiphenyl-4.-yl)-amide (3), 2-(1-aminoisoquinolin-7-yloxy)pentanoic acid (2'-methanesulfonylbiphenyl-4-yl)-amide (4), 2-(1-aminoisoquinolin-7-yloxy)pentanoic acid (2'-sulfamoylbiphenyl-4-yl)amide (5), 2-(1-aminoisoquinolin-7-yloxy)-N-(2'-methanesulfonylbiphenyl-4-yl)-2-phenyl-acetamide (6), 2-(1-aminoisoquinolin-7-yloxy)-N-(2'-methanesulfonylbiphenyl-4-yl)-3-methylbutyr-amide (7), 2-(1-aminoisoquinolin-7-yloxy)-3-methyl-N-(2'-sulfamoylbiphenyl-4-yl)butyramide (9), 2-(1-aminoisoquinolin-7-yloxy)-4-methylpentanoic acid (2'-methanesulfonylbi-phenyl-4-yl)amide (11), 2-(1-aminoquinolin-7-yloxy)-2-phenyl-N-(2'-sulfamoylbiphenyl-4-yl)acetamide (12), 2-(1-aminoisoquinolin-7-ylamino)-N-(2'-methanesulfonylbiphenyl-4-yl)-3-phenyl-propionamide (14), 2-(2-aminoquinolin-7-yloxy)pentanoic acid (2'-methanesulfonylbiphenyl-4-yl)amide (21 ), 2-(1-aminoisoquinolin-5-yloxy)hexanoic acid (2'-methanesulfonylbiphenyl-4-yl)-3 5 amide (81 ), 2-(1-aminoisoquinolin-5-yloxy)hexanoic acid (2'-sulfamoylbiphenyl-4-yl)amide (82), 2-(1-aminoisoquinolin-5-yloxy)pentanoic acid (2'-methanesulfonylbiphenyl-4-yl)-amide (83), 2-(1-aminoisoquinolin-5-yloxy)pentanoic acid (2'-sulfamoylbiphenyl-4-yl)amide (84), 2-(1-aminoisoquinolin-7-ytoxy)pentanoic acid (2'-methanesulfonylbiphenyl-4-yl-methyl)amide (85), 2-(1-aminoisoquinolin-7-yloxy)pentanoic acid (2'-methanesulfonylbiphenyl-2-yl-methyl)amide (86), 2-(1-aminoisoquinolin-7-yloxy)pentanoic acid (2'-ethanesulfonylbiphenyl-4-yl)-1 o amide (87), 2-(1-aminoisoquinolin-7-yloxy)pentanoic acid (2'-methoxybiphenyl-4-yl)amide (88), 2-(1-aminoisoquinolin-7-yloxy)pentanoic acid (2'-cyanobipheny!-4-yl)amide (89}, 2-(1-aminoisoquinolin-7-yloxy)pentanoic acid (3'-cyanobiphenyl-4-yl)amide (90).
Particular embodiments of the compounds of the formula I are listed below, a generalized form of the group of compounds in each case being indicated in the tables. The radical R6 indicated in the formula in this case has the meaning indicated above. The letter A further stands for the group -O- or -NH- and X
stands for -CH3 or -NH2.
A first preferred group of compounds of the formula I is listed in Table 1, the compounds in each case being covered by the general formula II.
Table 1 /I
NHZ O / \
N \ \ A N \ I O- I -O
H X
/ / Rs I I
Number A R6 X ESI-MS
2 O -H -NH2 449 a 3 O *\/\/ -CH3 504 4 O *~/ -CH3 490 O *~ -NH2 491 a * ~ /
7 O *~ -CH3 490 b 8 O ~ -CH3 9 O *~ -NH2 491 a O ~ -NH2 11 O *~ -CH3 504 12 O -NH2 525 a * ~ /
13 NH *~/ -CH3 14 NH *~ -CH3 NH ~ -CH3 14 NH * I ~ -CH3 537 b * ~ /
16 NH *~/ -NH2 17 NH *~ -NH2 18 NH ~ -NH2 * ~ /
_ 7 _ 20 NH * I \ -NH2 A further preferred group of compounds is formed by the quinoline derivatives of the formula III. Particularly preferred embodiments are summarized in Table 2.
Table 2 i o ~ \
HZN N~ \ A N \
R
III
Number A R6 X ESI-MS
21 O *~ -CH3 490 22 O *~ -CH3 23 O ~ -CH3 * ~ /
25 O * I \ -CHs 26 O *~ -NH2 27 O *~ -NH2 28 O ~ -NH2 * ~ /
_ g _ 30 O * I \ -NH2 i 31 NH *~/ -CHI
32 NH *~ -CH3 33 NH ~ -CH3 * ~ /
35 NH * I \ -CH3 i 36 NH *~/ -NH2 37 NH *~ -NH2 38 NH ~ -NHZ
* ~ /
40 NH * I \ -NH2 A further group of preferred isoquinoline derivatives can be represented by the formula IV. Specific compounds which come into this group are summarized in Table 3.
Table 3 NH2 O Rs H
N \
\ \ ~N
H
O ~ ~ \
OS
X~ ~O
IV
_ g _ Number A R6 X ESI-MS
41 O *~ -CHs 42 O ~ -CHs 43 O ~ -CHs 44 O -CHs * ~ /
45 O * ( w -CHs.
46 O *~ -NH2 47 O ~ -NH2 48 O ~ -NH2 * ~ /
50 O * I ~ -NH2 51 NH *~ -CHs 52 NH -CHs *~
53 NH -CHs 54 NH -CHs * ~ /
55 NH * ( w -CHs i 56 NH *~ -NH2 58 NH ~ -NH2 * ~ /
60 NH * I \ -NH2 /
The corresponding quinoline derivatives of the formula V form a further group of preferred compounds. Preferred compounds are summarized in Table 4.
Table 4 ~ Rs H
HzN ~ N~ \ N N ~ \
H
/ / ~ / \
O~ ~ /
X/SO
V
Number A R6 X ESI-MS
61 O *~ -CHs 62 O *~ -CH3 63 O -CHs 64 O -CHs 65 O * I \ -CHs /
66 O *~ -NH2 67 O *~ -NH2 68 O ~ -NH2 70 O * I w -NH2 i 71 NH *~/ -CH3 72 NH *~ -CH3 73 NH ~ -CH3 75 NH * I ~ -CH3 76 NH *~ -NH2 77 ~ NH *~ -NH2 78 NH ~ -NH2 80 NH * I ~ -NH2 Finally, a preferred group is additionally formed by the isoquinoline derivatives of the formula VI. In Table 5, preferred representatives of this group are summarized in tabular form.
13 NH *~/ -CH3 14 NH *~ -CH3 NH ~ -CH3 14 NH * I ~ -CH3 537 b * ~ /
16 NH *~/ -NH2 17 NH *~ -NH2 18 NH ~ -NH2 * ~ /
_ 7 _ 20 NH * I \ -NH2 A further preferred group of compounds is formed by the quinoline derivatives of the formula III. Particularly preferred embodiments are summarized in Table 2.
Table 2 i o ~ \
HZN N~ \ A N \
R
III
Number A R6 X ESI-MS
21 O *~ -CH3 490 22 O *~ -CH3 23 O ~ -CH3 * ~ /
25 O * I \ -CHs 26 O *~ -NH2 27 O *~ -NH2 28 O ~ -NH2 * ~ /
_ g _ 30 O * I \ -NH2 i 31 NH *~/ -CHI
32 NH *~ -CH3 33 NH ~ -CH3 * ~ /
35 NH * I \ -CH3 i 36 NH *~/ -NH2 37 NH *~ -NH2 38 NH ~ -NHZ
* ~ /
40 NH * I \ -NH2 A further group of preferred isoquinoline derivatives can be represented by the formula IV. Specific compounds which come into this group are summarized in Table 3.
Table 3 NH2 O Rs H
N \
\ \ ~N
H
O ~ ~ \
OS
X~ ~O
IV
_ g _ Number A R6 X ESI-MS
41 O *~ -CHs 42 O ~ -CHs 43 O ~ -CHs 44 O -CHs * ~ /
45 O * ( w -CHs.
46 O *~ -NH2 47 O ~ -NH2 48 O ~ -NH2 * ~ /
50 O * I ~ -NH2 51 NH *~ -CHs 52 NH -CHs *~
53 NH -CHs 54 NH -CHs * ~ /
55 NH * ( w -CHs i 56 NH *~ -NH2 58 NH ~ -NH2 * ~ /
60 NH * I \ -NH2 /
The corresponding quinoline derivatives of the formula V form a further group of preferred compounds. Preferred compounds are summarized in Table 4.
Table 4 ~ Rs H
HzN ~ N~ \ N N ~ \
H
/ / ~ / \
O~ ~ /
X/SO
V
Number A R6 X ESI-MS
61 O *~ -CHs 62 O *~ -CH3 63 O -CHs 64 O -CHs 65 O * I \ -CHs /
66 O *~ -NH2 67 O *~ -NH2 68 O ~ -NH2 70 O * I w -NH2 i 71 NH *~/ -CH3 72 NH *~ -CH3 73 NH ~ -CH3 75 NH * I ~ -CH3 76 NH *~ -NH2 77 ~ NH *~ -NH2 78 NH ~ -NH2 80 NH * I ~ -NH2 Finally, a preferred group is additionally formed by the isoquinoline derivatives of the formula VI. In Table 5, preferred representatives of this group are summarized in tabular form.
Table 5 /
\ 0 / \
o \ ~ o s=o H2N I \ 'H X
/ Rs V
Number Rs X ESI-MS
g1 *\/~/ -CH3 504 g2 *\/~/ -NH2 505 83 *~ -CH3 490 84 *~ -NH2 491 a The distance between the biphenyl moiety and the isoquinoline moiety can be increased by inserting CH2 groups. Two examples are shown in Tables 6 and 7.
Table 6 NHZ ~
X
N ~ / ( ~ N / ~ p-S=O
\ \ Rs H \ /
\
VII
Number Rs X ESI-MS
85 ~ *~ -CH3 ( 504 Table 7 i NHZ O \ ~S\X
O
N~ ~ I O N ~
H
\ \ R6 \
VIII
Number R6 X ESI-MS
g6 *~/ -CH3 504 To vary the activity of the compounds according to the invention, the group in the biphenyl moiety can also be varied. Examples are presented in Table 8. The groups shown there can also be combined with the substitution patterns shown in Tables 1 to 6.
l0 Table 8 NHZ O \
O ~ / Rs N ~ ~ ~N
H
\ \ ~ Rs IX
Number Rs R3 ESI-MS
87 *~ -S02CH2CH3 504 88 *~ -OCH3 442 8g *~/ -CN 437 The substitution pattern in the biphenyl moiety is not restricted to a particular position. Another possible structure of the compounds according to the invention is shown in Table 9.
\ 0 / \
o \ ~ o s=o H2N I \ 'H X
/ Rs V
Number Rs X ESI-MS
g1 *\/~/ -CH3 504 g2 *\/~/ -NH2 505 83 *~ -CH3 490 84 *~ -NH2 491 a The distance between the biphenyl moiety and the isoquinoline moiety can be increased by inserting CH2 groups. Two examples are shown in Tables 6 and 7.
Table 6 NHZ ~
X
N ~ / ( ~ N / ~ p-S=O
\ \ Rs H \ /
\
VII
Number Rs X ESI-MS
85 ~ *~ -CH3 ( 504 Table 7 i NHZ O \ ~S\X
O
N~ ~ I O N ~
H
\ \ R6 \
VIII
Number R6 X ESI-MS
g6 *~/ -CH3 504 To vary the activity of the compounds according to the invention, the group in the biphenyl moiety can also be varied. Examples are presented in Table 8. The groups shown there can also be combined with the substitution patterns shown in Tables 1 to 6.
l0 Table 8 NHZ O \
O ~ / Rs N ~ ~ ~N
H
\ \ ~ Rs IX
Number Rs R3 ESI-MS
87 *~ -S02CH2CH3 504 88 *~ -OCH3 442 8g *~/ -CN 437 The substitution pattern in the biphenyl moiety is not restricted to a particular position. Another possible structure of the compounds according to the invention is shown in Table 9.
Table 9 O
N
\ \ Rs X
Number Rs R3 ESI-MS
90 ~ *~/ -CN ~ 437 The compounds of the formulae I to X shown above do not necessarily have to be present in optically pure form. The racemates also exhibit an inhibitory action. In the case of the optically pure forms, the R and S forms can have an inhibitory action of different strength.
1 o The compounds of the formula I can be prepared by processes known per se.
Some exemplary synthesis routes are presented below.
A first synthesis route is shown in Scheme 1. The Compound 4, for example, was prepared by this route.
N
\ \ Rs X
Number Rs R3 ESI-MS
90 ~ *~/ -CN ~ 437 The compounds of the formulae I to X shown above do not necessarily have to be present in optically pure form. The racemates also exhibit an inhibitory action. In the case of the optically pure forms, the R and S forms can have an inhibitory action of different strength.
1 o The compounds of the formula I can be prepared by processes known per se.
Some exemplary synthesis routes are presented below.
A first synthesis route is shown in Scheme 1. The Compound 4, for example, was prepared by this route.
° J; . cszc03 OH Br O ~ N w w O O
N \ \ -~ s ~ I
I / /
/ / Aoetonitrile HzN ~ O,~~i I /
O
HCl/dioxane O 205 I /
N ~ ~ OH
I
/ / DAPECI/HOBtINMM
Hydrochloride /
O / w ( MCPBA _ O / I
I ~. °~N~ w w °~ ~ ~ O :, w N W W O W O :y ( s O
I s ~ O / /
/ /
- ~I
O:S
w I \ O ~p I
I ~ N+ O
N
N ~ ~ O ~ ~ 00~~
I
/
CI~S I /
/I
NHz O /
Ethanolamine O
N ~ ~ O~ ~
I
Scheme 1 The synthesis starts from 7-hydroxyisoquinoline 201, which is reacted under the action of a base, such as Cs2C03, with a suitable oc-bromocarboxylic acid ester 202 in a solvent, such as acetonitrile, to give the isoquinoline derivative 203. The carboxylic acid function is liberated from the ester function of the isoquinoline derivative 203 with the aid of acid. The reaction can be carried out, for example, in HClldioxane. Compound 204 is then obtained as a hydrochloride. To introduce the biphenyl group, it is then reacted with 2'-methanesulfonylbiphenyl-4-ylamine (DAPECI, tert-butanol, N-methylmorpholine) with obtainment of the compound 206. The amino group is introduced into the isoquinoline ring by a process which is described in WO 98/57951. Firstly, the nitrogen of the isoquinoline ring is oxidized using m-chloroperbenzoic acid (207) and then the pyridinium salt 208 is prepared 1 o by reaction with pyridine and p-toluenesulfonyl chloride. The active compound 209 is finally obtained in ethanolamine.
For the preparation of the compounds which have a sulfamoyl group in the biphenyl radical the synthesis first follows the synthesis shown in Scheme 1 up to the hydrochloride 204. The further course of the synthesis follows the synthesis shown above analogously, where, however, another biphenyl unit is used. The synthesis is summarized in Scheme 2.
N \ \ -~ s ~ I
I / /
/ / Aoetonitrile HzN ~ O,~~i I /
O
HCl/dioxane O 205 I /
N ~ ~ OH
I
/ / DAPECI/HOBtINMM
Hydrochloride /
O / w ( MCPBA _ O / I
I ~. °~N~ w w °~ ~ ~ O :, w N W W O W O :y ( s O
I s ~ O / /
/ /
- ~I
O:S
w I \ O ~p I
I ~ N+ O
N
N ~ ~ O ~ ~ 00~~
I
/
CI~S I /
/I
NHz O /
Ethanolamine O
N ~ ~ O~ ~
I
Scheme 1 The synthesis starts from 7-hydroxyisoquinoline 201, which is reacted under the action of a base, such as Cs2C03, with a suitable oc-bromocarboxylic acid ester 202 in a solvent, such as acetonitrile, to give the isoquinoline derivative 203. The carboxylic acid function is liberated from the ester function of the isoquinoline derivative 203 with the aid of acid. The reaction can be carried out, for example, in HClldioxane. Compound 204 is then obtained as a hydrochloride. To introduce the biphenyl group, it is then reacted with 2'-methanesulfonylbiphenyl-4-ylamine (DAPECI, tert-butanol, N-methylmorpholine) with obtainment of the compound 206. The amino group is introduced into the isoquinoline ring by a process which is described in WO 98/57951. Firstly, the nitrogen of the isoquinoline ring is oxidized using m-chloroperbenzoic acid (207) and then the pyridinium salt 208 is prepared 1 o by reaction with pyridine and p-toluenesulfonyl chloride. The active compound 209 is finally obtained in ethanolamine.
For the preparation of the compounds which have a sulfamoyl group in the biphenyl radical the synthesis first follows the synthesis shown in Scheme 1 up to the hydrochloride 204. The further course of the synthesis follows the synthesis shown above analogously, where, however, another biphenyl unit is used. The synthesis is summarized in Scheme 2.
HZN ~ O.~S~N
/
O
p 210 I / O /
N ~ ~ ~OH
Rs N ~ ~ O~ H \ OOS~NH
/ / R
2~ 211 O /
O~N~ w w OY \ N ~ I O%S~NH
O
Rs H
O~
p N O /
N ~ ~ O~ N \ O~ ~NH
Rs H
CI~ ~ /
O'0 213 /) N ~ ~ O~ N \ ( O~S~NH
Rs H . w-_.
N ~ ~ O~ N ~ I ~ ~NHZ
/ / Rs H
Scheme 2 Firstly, the compound 204 is reacted with a suitably protected biphenyl derivative 210 to give the compound 211. As already described above, to introduce the amino group into the isoquinoline structure the nitrogen is first oxidized (212) and then reacted further to give the pyridinium salt 213. The amino group is then liberated in ethanolamine (214). As the last stage of the synthesis, the tert-butyl protected group on the sulfamoyl group is removed by the action of acid (trifluoroacetic acid/anisole) with obtainment of the active compound 215.
A further synthesis route is shown in Scheme 3. This route makes possible the preparation of 1,7-diaminoisoquinoline derivatives.
In a first step, introduction of the carboxylic acid ester function by reaction of 7-aminoisoquinoline 216 with the a-diazocarboxylic acid ester 217 with catalysis by rhodium(II) acetate in toluene takes place to give the compound 218. The 1 o synthesis was carried out analogously to B.R. Henke et al., J. Med. Chem.
1998, 41, 5020-5036. After cleavage of the ester 219 using HCl/dioxane, the carboxylic acid 219 is obtained as a hydrochloride. As already described above, the introduction of the biphenyl moiety into the molecule is then carried out by reaction with the compound 205 (DAPECI/HOBtINMM) to give the compound 220. The nitrogen adjacent to the isoquinoline moiety is then protected selectively by reaction with trifluoroacetic anhydride in dichloromethane. The compound 221 is obtained. The reaction is carried out analogously to M. Pailer and W.J.
Hiibsch, Monatshefte fur Chemie, 1966, 97, 1541-1553. The amino group is then introduced in the isoquinoline by first oxidizing it with MCPBA to give the 2 o compound 222. The amino group is then introduced by reaction with p-toluenesulfonyl chloridelpyridine and subsequent liberation using ethanolamine.
Finally, the trifluoroacetyl group is removed using HCl/isopropanol. The active compound 223 is obtained.
/
O
p 210 I / O /
N ~ ~ ~OH
Rs N ~ ~ O~ H \ OOS~NH
/ / R
2~ 211 O /
O~N~ w w OY \ N ~ I O%S~NH
O
Rs H
O~
p N O /
N ~ ~ O~ N \ O~ ~NH
Rs H
CI~ ~ /
O'0 213 /) N ~ ~ O~ N \ ( O~S~NH
Rs H . w-_.
N ~ ~ O~ N ~ I ~ ~NHZ
/ / Rs H
Scheme 2 Firstly, the compound 204 is reacted with a suitably protected biphenyl derivative 210 to give the compound 211. As already described above, to introduce the amino group into the isoquinoline structure the nitrogen is first oxidized (212) and then reacted further to give the pyridinium salt 213. The amino group is then liberated in ethanolamine (214). As the last stage of the synthesis, the tert-butyl protected group on the sulfamoyl group is removed by the action of acid (trifluoroacetic acid/anisole) with obtainment of the active compound 215.
A further synthesis route is shown in Scheme 3. This route makes possible the preparation of 1,7-diaminoisoquinoline derivatives.
In a first step, introduction of the carboxylic acid ester function by reaction of 7-aminoisoquinoline 216 with the a-diazocarboxylic acid ester 217 with catalysis by rhodium(II) acetate in toluene takes place to give the compound 218. The 1 o synthesis was carried out analogously to B.R. Henke et al., J. Med. Chem.
1998, 41, 5020-5036. After cleavage of the ester 219 using HCl/dioxane, the carboxylic acid 219 is obtained as a hydrochloride. As already described above, the introduction of the biphenyl moiety into the molecule is then carried out by reaction with the compound 205 (DAPECI/HOBtINMM) to give the compound 220. The nitrogen adjacent to the isoquinoline moiety is then protected selectively by reaction with trifluoroacetic anhydride in dichloromethane. The compound 221 is obtained. The reaction is carried out analogously to M. Pailer and W.J.
Hiibsch, Monatshefte fur Chemie, 1966, 97, 1541-1553. The amino group is then introduced in the isoquinoline by first oxidizing it with MCPBA to give the 2 o compound 222. The amino group is then introduced by reaction with p-toluenesulfonyl chloridelpyridine and subsequent liberation using ethanolamine.
Finally, the trifluoroacetyl group is removed using HCl/isopropanol. The active compound 223 is obtained.
O H O
N
N ~ ~ NH2 N~O~.- , N ~ ~ N~O~:: , t -~' Rs ~ / / R6 HzN
I /
O I
N ~ ~ N~OH
j / R
OII O
I F3C~O~CF3 O / I
N ~ ~ N~ N ~ O;S
RIs H O
/ /
F /
F F
O / ~ I ~ F~O O / I w I ~ _ j' I
W W N N ~ O :Sw O.N~ ~ ~ N~ N w O ;Sw R~H O ~ / / Rs H O
/) NH2 H O / w N ~ ~ N~ N ~ I OOSw I 'S H
/ / R
x HCI
Scheme 3 The reaction schemes indicated above can be varied by the person skilled in the art without problems. For example, other suitable protective groups can also be employed for the protection of the ester or amine function: If racemic mixtures are obtained in the reactions, it is possible by reaction with an optically active resolving agent to form diastereomers from these in the customary manner, which are then separated by customary processes. Chromatographic resolution of enantiomers 1o with the aid of an optically active resolving agent (e.g.
dinitrobenzoylphenylglycine, cellulose triacetate or other derivatives of carbohydrates or chirally derivatized methacrylate polymers attached to silica gel) is also advantageous.
The invention further relates to the use of the compounds of the formula I
and/or their physiologically acceptable salts for the production of pharmaceutical preparations, in particular by a non-chemical route. In this connection, they can be brought into a suitable administration form together with at least one solid, liquid andlor semi-liquid vehicle or excipient and if appropriate in combination with one or more further active compounds.
l0 The invention further relates to pharmaceutical preparations comprising at least one compound of the formula I andlor one of its physiologically acceptable salts.
These preparations can be used as medicaments in human or veterinary medicine. Possible vehicles are organic or inorganic substances which are suitable for enteral (e.g. oral) or parenteral administration or topical application and do not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glyceryl triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc and petroleum 2o jelly. In particular, tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops are suitable for oral administration, suppositories are suitable for rectal administration, solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants, are suitable for rectal administration, and ointments, creams or powders are suitable for topical 2 5 application. The novel compounds can also be lyophilized and the lyophilizates obtained used, for example, for the production of injection preparations. The preparations indicated can be sterilized andlor can contain excipients, such as lubricants, preservatives, stabilizers andlor wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colorants, flavourings and/or 30 one or more further active compounds, e.g. one or more vitamins.
The compounds of the formula I and their physiologically acceptable salts can be used in the control and prevention of thromboembolic conditions such as thrombosis, myocardial infarction, arteriosclerosis, inflammations, apoplexy, 35 angina pectoris, restenosis after angioplasty and intermittent claudication.
N
N ~ ~ NH2 N~O~.- , N ~ ~ N~O~:: , t -~' Rs ~ / / R6 HzN
I /
O I
N ~ ~ N~OH
j / R
OII O
I F3C~O~CF3 O / I
N ~ ~ N~ N ~ O;S
RIs H O
/ /
F /
F F
O / ~ I ~ F~O O / I w I ~ _ j' I
W W N N ~ O :Sw O.N~ ~ ~ N~ N w O ;Sw R~H O ~ / / Rs H O
/) NH2 H O / w N ~ ~ N~ N ~ I OOSw I 'S H
/ / R
x HCI
Scheme 3 The reaction schemes indicated above can be varied by the person skilled in the art without problems. For example, other suitable protective groups can also be employed for the protection of the ester or amine function: If racemic mixtures are obtained in the reactions, it is possible by reaction with an optically active resolving agent to form diastereomers from these in the customary manner, which are then separated by customary processes. Chromatographic resolution of enantiomers 1o with the aid of an optically active resolving agent (e.g.
dinitrobenzoylphenylglycine, cellulose triacetate or other derivatives of carbohydrates or chirally derivatized methacrylate polymers attached to silica gel) is also advantageous.
The invention further relates to the use of the compounds of the formula I
and/or their physiologically acceptable salts for the production of pharmaceutical preparations, in particular by a non-chemical route. In this connection, they can be brought into a suitable administration form together with at least one solid, liquid andlor semi-liquid vehicle or excipient and if appropriate in combination with one or more further active compounds.
l0 The invention further relates to pharmaceutical preparations comprising at least one compound of the formula I andlor one of its physiologically acceptable salts.
These preparations can be used as medicaments in human or veterinary medicine. Possible vehicles are organic or inorganic substances which are suitable for enteral (e.g. oral) or parenteral administration or topical application and do not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glyceryl triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc and petroleum 2o jelly. In particular, tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops are suitable for oral administration, suppositories are suitable for rectal administration, solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants, are suitable for rectal administration, and ointments, creams or powders are suitable for topical 2 5 application. The novel compounds can also be lyophilized and the lyophilizates obtained used, for example, for the production of injection preparations. The preparations indicated can be sterilized andlor can contain excipients, such as lubricants, preservatives, stabilizers andlor wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colorants, flavourings and/or 30 one or more further active compounds, e.g. one or more vitamins.
The compounds of the formula I and their physiologically acceptable salts can be used in the control and prevention of thromboembolic conditions such as thrombosis, myocardial infarction, arteriosclerosis, inflammations, apoplexy, 35 angina pectoris, restenosis after angioplasty and intermittent claudication.
In this case, the substances according to the invention are as a rule preferably administered in doses of between 1 and 500 mg, in particular between 5 and 100 mg, per dose unit. The daily dose is preferably between approximately 0.02 and 10 mg/kg of body weight. The specific dose for each patient, however, depends on all sorts of factors, for example on the efficacy of the specific compound employed, on the age, body weight, general state of health and sex, on the diet, on the time and route of administration, and on the excretion rate, pharmaceutical combination and severity of the particular condition to which the therapy relates. Oral administration is preferred.
The invention is illustrated in greater detail with the aid of examples.
Example 1 tert-But~~l2-~soguinolin-7-yloxy~pentanoate A solution of 1.00 g (6.89 mmol) of 7-hydroxyisoquinoline and 1.63 g (6.89 mmol) of tent butyl 2-bromopentanoate in 40 ml of acetonitrile is treated with 2.25 g (6.89 mmol) of caesium carbonate and stirred at room temperature for 18 hours.
2 0 The reaction mixture is filtered and the filtrate is evaporated: tent butyl 2-(isoquinolin-7-yloxy)pentanoate as a colourless solid; ESI-MS 302.
2-(Isoguinolin-7-yloxy)pentanoic acid hydrochloride 2 5 A solution of 1.80 g (5.97 mmol) of Pert butyl 2-(isoquinolin-7-yloxy)pentanoate in 10 ml of 4N hydrogen chloride in dioxane is allowed to stand at room temperature for 18 hours. The solvent is distilled off: 2-(isoquinolin-7-yloxy)pentanoic acid hydrochloride as a colourless solid; ESI-MS 246.
30 2-Isoguinolin-7-yloxy)pentanoic acid (2'-methanesulfonylbiphenyl-4-yl)amide A solution of 94.7 mg (0.386 mmol) of 2-(isoquinolin-7-yloxy)pentanoic acid hydrochloride, 95.5 mg (0.386 mmol) of 2'-methanesulfonylbiphenyl-4-ylamine, 74.0 mg (0.386 mmol) of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide 35 hydrochloride (DAPECI) and 52.1 mg (0.386 mmol) of 1-hydroxybenzotriazole (HOBt) in 1 ml of DMF is treated with 80.1 mg (0.800 mmol) of 4-methylmorpholine and stirred at room temperature for 18 hours. The reaction mixture is added to water and the precipitate is filtered off: 2-isoquinolin-7-yloxy)pentanoic acid (2'-methanesulfonylbiphenyl-4-yl)amide as a colourless solid; ESI-MS 475.
2-(2-Oxyisoquinolin-7-yloxy)pentanoic acid (2'-methanesulfonylbiphenyl-4-yl)amide A solution of 128 mg (0.270 mmol) of 2-(isoquinolin-7-yloxy)pentanoic acid (2'-methanesulfonylbiphenyl-4-yl)amide in 10 ml of acetone is treated with 81.4 mg (0.330 mmol) of 3-chloroperbenzoic acid and stirred at room temperature for 18 hours. The reaction mixture is concentrated, and the residue is partitioned 1 o between ethyl acetate and saturated sodium hydrogen carbonate solution.
The organic phase is evaporated: 2-(2-oxyisoquinolin-7-yloxy)pentanoic acid (2'-methanesulfonylbiphenyl-4-yl)amide as a colourless solid; ESI-MS 491.
1-~7-[1-(2'-Methanesulfonylbiphenyl-4-ylcarbamoyl)butoxylisoguinolin-1-yl~pyridinium toluene-4-sulfonate A solution of 130 mg (0.265 mmol) of 2-(2-oxyisoquinolin-7-yloxy)pentanoic acid (2'-methanesulfonylbiphenyl-4-yl)amide in 4 ml of pyridine is treated with 76 mg (0.40 mmol) of 4-toluenesulfonyl chloride and stirred at room temperature for hours. The solvent is distilled of: 1-{7-[1-(2'-methanesulfonylbiphenyl-4-ylcarbamoyl)butoxy]isoquinolin-1-yl}pyridinium toluene-4-sulfonate as a reddish solid; ESI-MS 552.
2-(1-Aminoisoguinolin-7-yloxy)pentanoic acid (2'-methanesulfonylbiphenyl-4-yl)amide (4) The crude 1-{7-[1-(2'-methanesulfonylbiphenyl-4-ylcarbamoyl)butoxy]isoquinolin-yl}pyridinium toluene-4-sulfonate thus obtained is dissolved in 10 ml of ethanolamine and the solution is stirred at room temperature for 42 hours. The 3o reaction mixture is added to water and the precipitate is filtered off: 2-(1-aminoisoquinolin-7-yloxy)pentanoic acid (2'-methanesulfonylbiphenyl-4-yl)amide (4) as a yellowish solid; ESI-MS 490.
The invention is illustrated in greater detail with the aid of examples.
Example 1 tert-But~~l2-~soguinolin-7-yloxy~pentanoate A solution of 1.00 g (6.89 mmol) of 7-hydroxyisoquinoline and 1.63 g (6.89 mmol) of tent butyl 2-bromopentanoate in 40 ml of acetonitrile is treated with 2.25 g (6.89 mmol) of caesium carbonate and stirred at room temperature for 18 hours.
2 0 The reaction mixture is filtered and the filtrate is evaporated: tent butyl 2-(isoquinolin-7-yloxy)pentanoate as a colourless solid; ESI-MS 302.
2-(Isoguinolin-7-yloxy)pentanoic acid hydrochloride 2 5 A solution of 1.80 g (5.97 mmol) of Pert butyl 2-(isoquinolin-7-yloxy)pentanoate in 10 ml of 4N hydrogen chloride in dioxane is allowed to stand at room temperature for 18 hours. The solvent is distilled off: 2-(isoquinolin-7-yloxy)pentanoic acid hydrochloride as a colourless solid; ESI-MS 246.
30 2-Isoguinolin-7-yloxy)pentanoic acid (2'-methanesulfonylbiphenyl-4-yl)amide A solution of 94.7 mg (0.386 mmol) of 2-(isoquinolin-7-yloxy)pentanoic acid hydrochloride, 95.5 mg (0.386 mmol) of 2'-methanesulfonylbiphenyl-4-ylamine, 74.0 mg (0.386 mmol) of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide 35 hydrochloride (DAPECI) and 52.1 mg (0.386 mmol) of 1-hydroxybenzotriazole (HOBt) in 1 ml of DMF is treated with 80.1 mg (0.800 mmol) of 4-methylmorpholine and stirred at room temperature for 18 hours. The reaction mixture is added to water and the precipitate is filtered off: 2-isoquinolin-7-yloxy)pentanoic acid (2'-methanesulfonylbiphenyl-4-yl)amide as a colourless solid; ESI-MS 475.
2-(2-Oxyisoquinolin-7-yloxy)pentanoic acid (2'-methanesulfonylbiphenyl-4-yl)amide A solution of 128 mg (0.270 mmol) of 2-(isoquinolin-7-yloxy)pentanoic acid (2'-methanesulfonylbiphenyl-4-yl)amide in 10 ml of acetone is treated with 81.4 mg (0.330 mmol) of 3-chloroperbenzoic acid and stirred at room temperature for 18 hours. The reaction mixture is concentrated, and the residue is partitioned 1 o between ethyl acetate and saturated sodium hydrogen carbonate solution.
The organic phase is evaporated: 2-(2-oxyisoquinolin-7-yloxy)pentanoic acid (2'-methanesulfonylbiphenyl-4-yl)amide as a colourless solid; ESI-MS 491.
1-~7-[1-(2'-Methanesulfonylbiphenyl-4-ylcarbamoyl)butoxylisoguinolin-1-yl~pyridinium toluene-4-sulfonate A solution of 130 mg (0.265 mmol) of 2-(2-oxyisoquinolin-7-yloxy)pentanoic acid (2'-methanesulfonylbiphenyl-4-yl)amide in 4 ml of pyridine is treated with 76 mg (0.40 mmol) of 4-toluenesulfonyl chloride and stirred at room temperature for hours. The solvent is distilled of: 1-{7-[1-(2'-methanesulfonylbiphenyl-4-ylcarbamoyl)butoxy]isoquinolin-1-yl}pyridinium toluene-4-sulfonate as a reddish solid; ESI-MS 552.
2-(1-Aminoisoguinolin-7-yloxy)pentanoic acid (2'-methanesulfonylbiphenyl-4-yl)amide (4) The crude 1-{7-[1-(2'-methanesulfonylbiphenyl-4-ylcarbamoyl)butoxy]isoquinolin-yl}pyridinium toluene-4-sulfonate thus obtained is dissolved in 10 ml of ethanolamine and the solution is stirred at room temperature for 42 hours. The 3o reaction mixture is added to water and the precipitate is filtered off: 2-(1-aminoisoquinolin-7-yloxy)pentanoic acid (2'-methanesulfonylbiphenyl-4-yl)amide (4) as a yellowish solid; ESI-MS 490.
Example 2 2-(1-Aminoisopuinolin-7-yloxy)pentanoic acid (2'-sulfamoylbiphenyl-4-yl)amide-trifluoroacetate,~5) A solution of 150 mg (0.274 mmol) of 2-(1-aminoisoquinolin-7-yloxy)pentanoic acid (2'-Pert butylsulfamoylbiphenyl-4-yl)amide in 4 g of trifluoroacetic acid is treated with 1.0 g of anisole and stirred at room temperature for 18 hours. The reaction 1 o mixture is evaporated and the residue is taken up in diethylether. The precipitate is filtered off: 2-(1-aminoisoquinolin-7-yloxy)pentanoic acid (2'-sulfamoylbiphenyl-4-yl)amidetrifluoroacetate (5) as a yellowish solid; ESI-MS 491.
Claims (7)
1. Aminoheterocvcles of the general formula I
in which:
-D=E- is -N=C(NH2)- or -C(NH2)=N-R1, R2 independently of one another are H, A, OR6, N(R6)2, NO2, CN, Hal, NR6COA, NR6COAr', NR6S02A, NR6SO2Ar', COOR6, CON(R6)2, CONRsAr', COR', COAr', S(O)DA
R3 is SO2(NR6)2, S(O)DA, CF3, COOR6, OA, CN, R4, R5 independently of one another are H, A, OR6, N(R6)2, NO2, CN, Hal, NR6COA, NR6COAr'. NR6SO2A, NR6SO2Ar', COORS, CON(R6)2, CONR6Ar', COR7', COAr', S(O)nA
R6 is H, A, [C(R7)2]nAr' or [C(R7)2]nHet R7 is H or A
W is CONR6C(R6)2CONR6[C(R6)2]l-, -NR6C(R6)2CONR6[C(R6)2]l-, -[C(R6)2]mCONR6[C(R6)2]l- or -OC(R6)2CONR6[C(R6)z]l-A is alkyl having 1-20 C atoms, in which one or two CH2 groups can be replaced by O or S atoms or by CH=CH groups and also 1-7 H
atoms can be replaced by F, Ar is phenyl or naphthyl, which is unsubstituted or mono-, di- or trisubstituted by A, Ar', Het, OR6, N(R6)2, NO2, CN, Hal, NR6COA, NR6COAr', NR6SO2A, NR6SO2Ar', COOR6, CON(R6)2, CONR6Ar', COR7, COAr', SO2NR6, S(O)nAr' or S(O)nA
Ar' is phenyl or naphthyl, which is unsubstituted or mono-, di- or trisubstituted by A, OR7, N(R7)2, NO2, CN, Hal, NR7COA, NR7SO2A, COOR7, CON(R7)2, COR7, SO2NR7 or S(O)nA
Het is a mono- or binuclear, saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms, bonded via N or C, which can be unsubstituted or mono-, di- or trisubstituted by A, OR7, N(R7)2, NO2, CN, Hal, NR7COA, NR7SO2A, COOR7, CON(R7)2, COR7, SO2NR7, S(O)nA and/or carbonyl oxygen, Hal is F, Cl, Br or I
n is 0, 1 or 2 m is 1 or 2 is 0 or 1 and their pharmaceutically tolerable salts and solvates.
in which:
-D=E- is -N=C(NH2)- or -C(NH2)=N-R1, R2 independently of one another are H, A, OR6, N(R6)2, NO2, CN, Hal, NR6COA, NR6COAr', NR6S02A, NR6SO2Ar', COOR6, CON(R6)2, CONRsAr', COR', COAr', S(O)DA
R3 is SO2(NR6)2, S(O)DA, CF3, COOR6, OA, CN, R4, R5 independently of one another are H, A, OR6, N(R6)2, NO2, CN, Hal, NR6COA, NR6COAr'. NR6SO2A, NR6SO2Ar', COORS, CON(R6)2, CONR6Ar', COR7', COAr', S(O)nA
R6 is H, A, [C(R7)2]nAr' or [C(R7)2]nHet R7 is H or A
W is CONR6C(R6)2CONR6[C(R6)2]l-, -NR6C(R6)2CONR6[C(R6)2]l-, -[C(R6)2]mCONR6[C(R6)2]l- or -OC(R6)2CONR6[C(R6)z]l-A is alkyl having 1-20 C atoms, in which one or two CH2 groups can be replaced by O or S atoms or by CH=CH groups and also 1-7 H
atoms can be replaced by F, Ar is phenyl or naphthyl, which is unsubstituted or mono-, di- or trisubstituted by A, Ar', Het, OR6, N(R6)2, NO2, CN, Hal, NR6COA, NR6COAr', NR6SO2A, NR6SO2Ar', COOR6, CON(R6)2, CONR6Ar', COR7, COAr', SO2NR6, S(O)nAr' or S(O)nA
Ar' is phenyl or naphthyl, which is unsubstituted or mono-, di- or trisubstituted by A, OR7, N(R7)2, NO2, CN, Hal, NR7COA, NR7SO2A, COOR7, CON(R7)2, COR7, SO2NR7 or S(O)nA
Het is a mono- or binuclear, saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms, bonded via N or C, which can be unsubstituted or mono-, di- or trisubstituted by A, OR7, N(R7)2, NO2, CN, Hal, NR7COA, NR7SO2A, COOR7, CON(R7)2, COR7, SO2NR7, S(O)nA and/or carbonyl oxygen, Hal is F, Cl, Br or I
n is 0, 1 or 2 m is 1 or 2 is 0 or 1 and their pharmaceutically tolerable salts and solvates.
2. Compounds according to Claim 1:
2-(1-aminoisoquinolin-7-yloxy)-N-(2'-methanesulfonylbiphenyl-4-yl)acetami-de (1), 2-(1-aminoisoquinolin-7-yloxy)-N-(2'-sulfamoylbiphenyl-4-yl)acetamide (2), 2-(1-aminoisoquinolin-7-yloxy)hexanoic acid (2'-methanesulfonylbiphenyl-4-yl)amide (3), 2-(1-aminoisoquinolin-7-yloxy)pentanoic acid (2'-methanesulfonylbiphenyl-4-yl)amide (4), 2-(1-aminoisoquinolin-7-yloxy)pentanoic acid (2'-sulfamoylbiphenyl-4-yl)amide (5), 2-(1-aminoisoquinolin-7-yloxy)-N-(2'-methanesulfonylbiphenyl-4-yl)-2-phenylacetamide (6), 2-(1-aminoisoquinolin-7-yloxy)-N-(2'-methanesulfonylbiphenyl-4-yl)-3-methylbutyramide (7), 2-(1-aminoisoquinolin-7-yloxy)-3-methyl-N-(2'-sulfamoylbiphenyl-4-yl)butyramide (9), 2-(1-aminoisoquinolin-7-yloxy)-4-methylpentanoic acid (2'-methanesul-fonylbiphenyl-4-yl)amide (11), 2-(1-aminoisoquinolin-7-yloxy)-2-phenyl-N-(2'-sulfamoylbiphenyl-4-yl)-acetamide (12), 2-(1-aminoisoquinolin-7-ylamino)-N (2'-methanesulfonylbiphenyl-4-yl)-3-phenylpropionamide (14), 2-(2-aminoquinolin-7-yloxy)pentanoic acid (2'-methanesulfonylbiphenyl-4-yl)amide (21), 2-(1-aminoisoquinolin-5-yloxy)hexanoic acid (2'-methanesulfonylbiphenyl-4-yl)amide (81), 2-(1-aminoisoquinolin-5-yloxy)hexanoic acid (2'-sulfamoylbiphenyl-4-yl)amide (82), 2-(1-aminoisoquinolin-5-yloxy)pentanoic acid (2'-methanesulfonylbiphenyl-4-yl)amide (83), 2-(1-aminoisoquinolin-5-yloxy)pentanoic acid (2'-sulfamoylbiphenyl-4-yl)amide (84), 2-(1-aminoisoquinolin-7-yloxy)pentanoic acid (2'-methanesulfonylbiphenyl-4-ylmethyl)amide (85), 2-(1-aminoisoquinolin-7-yloxy)pentanoic acid (2'-methanesulfonylbiphenyl-2-ylmethyl)amide (86), 2-(1-aminoisoquinolin-7-yloxy)pentanoic acid (2'-ethanesulfonylbiphenyl-4-yl)amide (87), 2-(1-aminoisoquinolin-7-yloxy)pentanoic acid (2'-methoxybiphenyl-4-yl)amide (88), 2-(1-aminoisoquinolin-7-yloxy)pentanoic acid (2'-cyanobiphenyl-4-yl)amide (89), 2-(1-aminoisoquinolin-7-yloxy)pentanoic acid (3'-cyanobiphenyl-4-yl)amide (90).
2-(1-aminoisoquinolin-7-yloxy)-N-(2'-methanesulfonylbiphenyl-4-yl)acetami-de (1), 2-(1-aminoisoquinolin-7-yloxy)-N-(2'-sulfamoylbiphenyl-4-yl)acetamide (2), 2-(1-aminoisoquinolin-7-yloxy)hexanoic acid (2'-methanesulfonylbiphenyl-4-yl)amide (3), 2-(1-aminoisoquinolin-7-yloxy)pentanoic acid (2'-methanesulfonylbiphenyl-4-yl)amide (4), 2-(1-aminoisoquinolin-7-yloxy)pentanoic acid (2'-sulfamoylbiphenyl-4-yl)amide (5), 2-(1-aminoisoquinolin-7-yloxy)-N-(2'-methanesulfonylbiphenyl-4-yl)-2-phenylacetamide (6), 2-(1-aminoisoquinolin-7-yloxy)-N-(2'-methanesulfonylbiphenyl-4-yl)-3-methylbutyramide (7), 2-(1-aminoisoquinolin-7-yloxy)-3-methyl-N-(2'-sulfamoylbiphenyl-4-yl)butyramide (9), 2-(1-aminoisoquinolin-7-yloxy)-4-methylpentanoic acid (2'-methanesul-fonylbiphenyl-4-yl)amide (11), 2-(1-aminoisoquinolin-7-yloxy)-2-phenyl-N-(2'-sulfamoylbiphenyl-4-yl)-acetamide (12), 2-(1-aminoisoquinolin-7-ylamino)-N (2'-methanesulfonylbiphenyl-4-yl)-3-phenylpropionamide (14), 2-(2-aminoquinolin-7-yloxy)pentanoic acid (2'-methanesulfonylbiphenyl-4-yl)amide (21), 2-(1-aminoisoquinolin-5-yloxy)hexanoic acid (2'-methanesulfonylbiphenyl-4-yl)amide (81), 2-(1-aminoisoquinolin-5-yloxy)hexanoic acid (2'-sulfamoylbiphenyl-4-yl)amide (82), 2-(1-aminoisoquinolin-5-yloxy)pentanoic acid (2'-methanesulfonylbiphenyl-4-yl)amide (83), 2-(1-aminoisoquinolin-5-yloxy)pentanoic acid (2'-sulfamoylbiphenyl-4-yl)amide (84), 2-(1-aminoisoquinolin-7-yloxy)pentanoic acid (2'-methanesulfonylbiphenyl-4-ylmethyl)amide (85), 2-(1-aminoisoquinolin-7-yloxy)pentanoic acid (2'-methanesulfonylbiphenyl-2-ylmethyl)amide (86), 2-(1-aminoisoquinolin-7-yloxy)pentanoic acid (2'-ethanesulfonylbiphenyl-4-yl)amide (87), 2-(1-aminoisoquinolin-7-yloxy)pentanoic acid (2'-methoxybiphenyl-4-yl)amide (88), 2-(1-aminoisoquinolin-7-yloxy)pentanoic acid (2'-cyanobiphenyl-4-yl)amide (89), 2-(1-aminoisoquinolin-7-yloxy)pentanoic acid (3'-cyanobiphenyl-4-yl)amide (90).
3. Pharmaceutical preparation, characterized in that it contains at least one compound according to one of Claims 1 or 2 and/or one of its physiologically acceptable salts.
4. Compounds according to one of Claims 1 or 2 and their physiologically acceptable salts or solvates as pharmaceutical active compounds.
5. Use of compounds according to one of Claims 1 or 2 and/or their physiologically acceptable salts for the production of a medicament for the control of thromboses, myocardial infarction, arteriosclerosis, inflammations, apoplexy, angina pectoris, restenosis after angioplasty and intermittent claudication.
6. Compounds according to one of Claims 1 or 2 and their physiologically acceptable salts as inhibitors of coagulation factor Xa.
7. Compounds according to one of Claims 1 or 2 and their physiologically acceptable salts as inhibitors of coagulation factor Vlla.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10046272.3 | 2000-09-19 | ||
| DE10046272A DE10046272A1 (en) | 2000-09-19 | 2000-09-19 | New biphenyl-substituted amino-(iso)quinoline derivatives, are factor Xa and factor VIIa inhibitors useful e.g. for treating thrombosis, myocardial infarction, inflammation, angina pectoris or restenosis |
| PCT/EP2001/010786 WO2002024654A1 (en) | 2000-09-19 | 2001-09-18 | Amino heterocyclic compounds (factor xa inhibitors 14) |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2422067A1 true CA2422067A1 (en) | 2003-03-12 |
Family
ID=7656743
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002422067A Abandoned CA2422067A1 (en) | 2000-09-19 | 2001-09-18 | Aminoheterocycles (factor xa inhibitors 14) |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP1322618A1 (en) |
| JP (1) | JP2004513888A (en) |
| CA (1) | CA2422067A1 (en) |
| DE (1) | DE10046272A1 (en) |
| WO (1) | WO2002024654A1 (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6906192B2 (en) | 2000-11-07 | 2005-06-14 | Bristol Myers Squibb Company | Processes for the preparation of acid derivatives useful as serine protease inhibitors |
| EP1332131A2 (en) | 2000-11-07 | 2003-08-06 | Bristol-Myers Squibb Company | Acid derivatives useful as serine protease inhibitors |
| US7030141B2 (en) | 2001-11-29 | 2006-04-18 | Christopher Franklin Bigge | Inhibitors of factor Xa and other serine proteases involved in the coagulation cascade |
| JP2006517589A (en) * | 2003-02-11 | 2006-07-27 | ブリストル−マイヤーズ スクイブ カンパニー | Benzeneacetamide compounds useful as serine protease inhibitors |
| ES2569660T3 (en) | 2007-06-08 | 2016-05-12 | Mannkind Corporation | IRE-1alpha inhibitors |
| WO2010117084A1 (en) * | 2009-04-10 | 2010-10-14 | Banyu Pharmaceutical Co.,Ltd. | Novel isoquinoline derivatives |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU8875398A (en) * | 1997-08-29 | 1999-03-22 | Proteus Molecular Design Ltd | 1-amino-7-isoquinoline derivatives as serine protease inhibitors |
| TW575567B (en) * | 1998-10-23 | 2004-02-11 | Akzo Nobel Nv | Serine protease inhibitor |
| CA2374646A1 (en) * | 1999-05-24 | 2000-11-30 | Cor Therapeutics, Inc. | Inhibitors of factor xa |
| AU5041300A (en) * | 1999-05-24 | 2000-12-12 | Cor Therapeutics, Inc. | Inhibitors of factor xa |
| JP2003500387A (en) * | 1999-05-24 | 2003-01-07 | シーオーアール セラピューティクス インコーポレイテッド | Factor Xa inhibitors |
| WO2001055146A1 (en) * | 2000-01-29 | 2001-08-02 | Lg Chem Investment Ltd. | FACTOR Xa INHIBITORS WITH ARYL-AMIDINES AND DERIVATIVES, AND PRODRUGS THEREOF |
-
2000
- 2000-09-19 DE DE10046272A patent/DE10046272A1/en not_active Withdrawn
-
2001
- 2001-09-18 CA CA002422067A patent/CA2422067A1/en not_active Abandoned
- 2001-09-18 JP JP2002529067A patent/JP2004513888A/en active Pending
- 2001-09-18 EP EP01985251A patent/EP1322618A1/en not_active Withdrawn
- 2001-09-18 WO PCT/EP2001/010786 patent/WO2002024654A1/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| JP2004513888A (en) | 2004-05-13 |
| DE10046272A1 (en) | 2002-03-28 |
| WO2002024654A1 (en) | 2002-03-28 |
| EP1322618A1 (en) | 2003-07-02 |
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