IP Library › Granted Patent US 7,964,628

Granted Patent B2

US 7,964,628 · App. 12/795,824 · Granted Jun 21, 2011

Fibrinogen receptor antagonists and their use

Assignee: Piramal Life Sciences Limited

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Quick Facts

Patent No.: US 7,964,628
App. No.: 12/795,824
Granted: Jun 21, 2011
Kind: B2

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Abstract

This invention relates to novel fused bicyclic compounds of the general formula (I): wherein the symbols are defined herein, to pharmaceutical compositions containing the compounds, processes for preparing the compounds, and to methods of using the compounds, alone or in combination with other therapeutic agents. The compounds are antagonists of the platelet glycoprotein IIb/IIIa fibrinogen receptor complex, and are therefore useful for the inhibition of platelet aggregation, and for the treatment of thrombotic diseases and other diseases.

Claims (669)

1. A method of inhibiting binding of fibrinogen to blood platelets, comprising administering to blood platelets effective amount of a compound of the formula (I) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof;

wherein

ring A is phenyl;

R A is a group of formula (3):

wherein p is 0;

s is 1;

R 1 is selected from: H, hydroxy, alkyl, partially or fully fluorinated alkyl, alkoxy, alkenyl, alkynyl, carboxy, —C(═O)OR 5 , cycloalkyl, cycloalkylalkyl, aryl, arylalkyl and heterocycle;

R 3 and R 4 are independently selected from: H, alkyl, partially or fully fluorinated alkyl, alkenyl, alkynyl, —C(═O)OR 5 , cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycle, —OR 5 , —SR 5 , —NR 5 R 6 , —S(═O) 2 NR 5 R 6 , —S(═O) 2 R 5 , —C(═O)R 5 , —C(═O)NR 5 R 6 , —C(═O)OR 5 , —C(═O)SR 5 , —OC(═O)R 5 , —OC(═O)OR 5 , —OC(═O)NR 5 R 6 , —OS(═O) 2 R 5 , —S(C═O)NR 5 and —OS(═O) 2 NR 5 R 6 , or R 3 and R 1 or R 4 , together with the respective nitrogen atoms to which they are attached, form an unsubstituted or substituted 5-, 6- or 7-membered partially saturated or aromatic heterocycle, optionally having one or more additional heteroatoms selected from: N, O and S, wherein the substituents are selected from: hydroxy, halogen, alkyl, alkoxy, alkenyl, alkynyl, oxo, carboxy and —C(═O)OR 5 ;

R 5 and R 6 are independently selected from: H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl and heterocycle, wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkylalkyl group optionally contains at least one hetero atom selected from: N, S and O anywhere in the chain, including the terminal position;

R B is H;

Y 1 and Y 2 , together, are selected from: ═O and ═S;

Z is N;

W is CH;

R C is H;

n is 0, 1, 2 or 3;

R D and R E are independently selected from: H and an unsubstituted or substituted group selected from: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl and heterocycle, wherein the substituents are selected from: hydroxy, halogen, alkyl, alkenyl, alkynyl, oxo, carboxy,

—C(═O)OR 5 , —OR 17 , —SR 17 , —NR 17 R 18 , —NHC(═O)R 17 , —NHC(═O)OR 17 , —OC(═O)R 17 , —SC(═O)R 17 , —OS(═O) 2 R 17 and —NHS(═O) 2 R 17 ;

R 17 and R 18 have the same meaning as R 5 and R 6 , defined above;

R F is selected from: O, S and N(OR 19 );

R 19 has the same meaning as R 5 , defined above;

R G is selected from: aryl, heteroaryl, and partially or fully saturated heterocycle, where said aryl, heteroaryl and heterocycle are substituted by one or more groups of the formula (5):

T-(CH 2 ) q —CR 23 R 24 —COR 25 (5)

and optionally, further substituted by one or more groups selected from: —R 5 , halogen, —CN, —SCN, —CNO, —OR 21 , —OC(═O)R 21 , —OS(═O) 2 R 21 , —OS(═O) 2 NR 21 R 22 , —OC(═O)OR 21 , —OC(═O)SR 21 , —OC(═O)NR 21 R 22 , —SR 21 , —S(═O)R 21 , —NO 2 , —NR 21 (OR 22 ), —NR 21 R 22 , —NR 21 C(═O)R 22 , —N(R 21 )C(═O)OR 22 , —N[S(═O) 2 R 21 ]R 23 , C(═O)OR 21 , —S(═O) 2 R 21 and —S(═O) 2 OR 21 ;

R 21 has the same meaning as R 1 , defined above, and R 22 is selected from: H, hydroxy, alkyl, partially or fully fluorinated alkyl, alkoxy, alkenyl, alkynyl, carboxy, —C(═O)OR 5 , cycloalkyl, cycloalkylalkyl, aryl, arylalkyl and heterocycle:

T is selected from: —CH 2 , O, S and NH;

q is 0, 1, 2 or 3;

R 23 and R 24 are independently selected from: H, alkyl alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycle and C(═O)R 25 , wherein said alkyl and alkenyl optionally contain at least one hetero atom selected from: O, S and N, in any position of the alkyl or alkenyl chain, and said alkyl and alkenyl are unsubstituted or substituted with at least one group selected from: —OR 1 , —OC(═O)R 1 , —OS(═O) 2 R 1 , —S(═O) 2 NR 1 R 2 , —OC(═O)OR 1 , —OC(═O)SR 1 ,

—OC(═O)NR 1 R 2 , —SR 1 , —S(═O)R 1 , —SC(═O)H, —SC(═O)OR 1 , —NR 1 (OR 2 ), —NR 1 R 2 , —NR 1 C(═O)R 2 , —N(R 1 )C(═O)OR 2 , —NR 1 S(═O) 2 R 2 , C(═O)OR 1 , —S(═O) 2 R 1 and —S(═O) 2 OR 1 ;

R 25 is selected from: OR 5 , SR 5 , —OCR 3 R 4 and —NR 5 R 6 , wherein R 3 , R 4 , R 5 and R 6 are as defined above and wherein optionally, R 3 and R 4 , together with the carbon to which they are attached, form an unsubstituted or substituted 5-, 6- or 7-membered saturated, partially saturated or aromatic heterocycle having one or more heteroatoms selected from: N, O and S, wherein the substituents are selected from: hydroxy, halogen, alkyl, alkoxy, alkenyl, alkynyl, oxo, carboxy and —C(═O)OR 5 ; and the group NR 5 R 6 is, optionally, a heterocycle containing at least one additional heteroatom selected from: O, S, and N.

2. The method according to claim 1 , wherein in the compounds of formula (I), R G is selected from: phenyl, piperidinyl and piperazinyl, and said phenyl, piperidinyl and piperazinyl are substituted by one or more groups of the formula (5):

T-(CH 2 ) q —CR 23 R 24 —COR 25 (5)

3. The method according to claim 1 , wherein in the compounds of formula (I),

R 1 is hydrogen;

R 3 and R 4 are independently selected from: H, OH, —C(O)OH and —C(O)Oalkyl;

R B ═R C ═R D ═R E =hydrogen;

Y 1 and Y 2 , together are ═O;

n is the integer 0 or 1;

R G is phenyl, substituted with one or more of the group of formula (5):

T-(CH 2 ) q —CR 23 R 24 —COR 25 (5)

wherein R 23 is H and R 24 is H, and, optionally, the compound is further substituted with one or more of the groups selected from: hydroxy, halogen, alkyl, alkoxy, alkenyl, alkynyl, oxo, carboxy, —C(═O)OR 5 , SR 21 , S(═O) 2 R 21 and —N(R 21 )—C(O)CH 3 , —CH 2 C(O)R 25 ; and R 25 is selected from: OR 5 , OCR 3 R 4 and NR 5 R 6 , wherein R 3 and R 4 , together with the carbon to which they are attached form an unsubstituted or substituted 5-, 6- or 7-membered saturated, partially saturated or aromatic heterocycle having one or more heteroatoms selected from: N, O and S, wherein the substituents are selected from: hydroxy, halogen, alkyl, alkoxy, alkenyl, alkynyl, oxo, carboxy, —C(═O)OR 5 ; and

R 5 , R 6 and R 21 are independently selected from: H, alkyl and phenyl.

4. The method according to claim 1 , wherein in the compounds of formula (I)

R 1 is hydrogen;

R 3 and R 4 are independently selected from: H, OH, —C(O)OH and —C(O)Oalkyl;

R B ═R C ═R D ═R E =hydrogen;

Y 1 and Y 2 , together are ═O;

n is the integer 0 or 1;

R G is selected from: piperidinyl and piperazinyl, wherein said piperidinyl and piperazinyl are substituted with one or more of the group of formula (5):

T-(CH 2 ) q —CR 23 R 24 —COR 25 (5)

wherein R 23 is H and R 24 is H and, optionally, further substituted with one or more groups selected from: hydroxy, halogen, alkyl, alkoxy, alkenyl, alkynyl, oxo, carboxy and —C(═O)OR 5 ; and

R 25 is OR 5 , wherein R 5 is selected from: H, alkyl and phenyl.

5. The method according to claim 1 , wherein the compounds of formula (I) are selected from the group consisting of:

(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid methyl ester;

(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid methyl ester;

(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid ethyl ester;

(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid ethyl ester;

4-(2-{5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl}-acetyl]-phenoxy)-acetic acid isopropyl ester;

(4-{2-[5-(Imino-methoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid isopropyl ester;

(4-{2-[5-(Imino-isobutoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid isopropyl ester;

(4-{2-[5-(Benzyloxycarbonylamino-imino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid isopropyl ester;

(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid isopropyl ester;

(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid isobutyl ester;

(4-{2-[5-(Imino-methoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid isobutyl ester;

(4-{2-[5-(Imino-isobutoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid isobutyl ester;

(4-{2-[5-(Benzyloxycarbonylamino-imino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid isobutyl ester;

(4-{2-[5-(Imino-methanesulfonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid isobutyl ester;

(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid isobutyl ester;

(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid benzyl ester;

(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid;

(4-{2-[5-(Imino-methoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid benzyl ester;

(4-{2-[5-(Imino-isobutoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid benzyl ester;

(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-ethoxy carbonyl methoxy-phenoxy)-acetic acid ethyl ester;

(2-Ethoxycarbonylmethoxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid ethyl ester;

(2-Ethoxycarbonylmethoxy-4-{2-[5-(imino-{3-methyl-butyrylamino}-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid ethyl ester;

(2-Ethoxycarbonylmethoxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-1-hydroxyimino-ethyl}-phenoxy)-acetic acid ethyl ester;

(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-isobutoxy carbonyl methoxy-phenoxy)-acetic acid isobutyl ester;

2-(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-N,N-diethyl-acetamide;

4-(2-{4-[2-(5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl)-acetyl]-phenoxy}-acetoxy)-piperidine-1-carboxylic acid benzyl ester;

4-Benzyloxycarbonylamino-2-(4-{2-[5-carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-butyric acid ethyl ester;

4-Benzyloxycarbonylamino-2-(4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-butyric acid ethyl ester;

(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenylsulfanyl)-acetic acid methyl ester;

(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-chloro-phenoxy)-acetic acid ethyl ester;

(2-Chloro-4-{2-[5-(imino-isobutoxycarbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid ethyl ester;

(2-Chloro-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid ethyl ester;

(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-ethyl sulfanyl-phenoxy)-acetic acid ethyl ester;

(2-Ethylsulfanyl-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid ethyl ester;

(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-ethane sulfonyl-phenoxy)-acetic acid ethyl ester;

(2-Ethanesulfonyl-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid ethyl ester;

(2,6-Bis-ethylsulfanyl-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid ethyl ester;

(2-Acetylamino-4-{2-[5-N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid ethyl ester;

(2-(Ethoxycarbonylmethyl-methanesulfonyl-amino)-4-{2-[5-(imino-isobutoxy carbonylamino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid ethyl ester;

(2-(Ethoxycarbonylmethyl-methanesulfonyl-amino)-4-{2-[5-(N-hydroxy carbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid ethyl ester;

(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-phenoxy)-acetic acid ethyl ester;

(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid ethyl ester;

(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid benzyl ester;

(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-phenoxy)-acetic acid;

(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-methoxy-phenoxy)-acetic acid ethyl ester;

(4-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-propoxy-phenoxy)-acetic acid ethyl ester;

(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-ethoxy carbonylmethoxy-phenoxy)-acetic acid ethyl ester;

(3-Ethoxycarbonylmethoxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid;

(2-Ethylsulfanyl-3-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid ethyl ester;

(2-Ethyl-5-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid ethyl ester;

(5-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-isopropyl-phenoxy)-acetic acid ethyl ester;

(2-tert-Butyl-5-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid ethyl ester;

(2-Chloro-5-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid ethyl ester;

(2-Chloro-3-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid ethyl ester;

(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-methyl-phenoxy)-acetic acid ethyl ester;

(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-methyl-phenoxy)-acetic acid benzyl ester;

(2-Ethyl-3-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid ethyl ester;

(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-propyl-phenoxy)-acetic acid ethyl ester;

(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-propyl-phenoxy)-acetic acid benzyl ester;

(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-2-propyl-phenoxy)-acetic acid;

(4-Hydroxy-3-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid ethyl ester;

(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-5-methoxy-phenoxy)-acetic acid ethyl ester;

(3,5-Dihydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid ethyl ester;

(2-Ethoxycarbonylmethoxy-3-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid ethyl ester;

(2-Ethoxycarbonylmethoxy-5-hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid ethyl ester;

(1-{2S-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(4-hydroxy-phenyl)-propionyl}-piperidin-4-yloxy)-acetic acid ethyl ester;

(1-{2-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-acetic acid ethyl ester;

(1-{3-[5-(N-Hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-propionyl}-piperidin-4-yloxy)-acetic acid ethyl ester;

(1-{2-[5-(5-Methyl-isoxazol-3-yl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-acetic acid ethyl ester;

(1-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-acetic acid ethyl ester;

(1-{2-[5-(tert-Butoxycarbonylamino-imino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-piperidin-4-yloxy)-acetic acid ethyl ester;

(1-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]acetyl}-piperidin-4-yloxy)-acetic acid;

(3-Ethoxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid ethyl ester;

(4-[2-(5-carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl)-acetyl]-3-ethoxy-phenoxy}-acetic acid ethyl ester;

(4-{2-[5-Carbamimdoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-ethoxy-phenoxy)-acetic acid;

(3-Hydroxy-4-{2-[1-oxo-5-(5-oxo-2,5-dihydro-[1,2,4]oxadiazol-3-yl)-1,3-dihydro-isoindol-2-yl]acetyl}-phenoxy)-acetic acid ethyl ester;

(4-{2-[5-(Acetylamino-imino-methyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-phenoxy)-acetic acid ethyl ester;

(3-Acetoxy-4-{2-[5-(5-methyl-[1,2,4]oxadiazol-3-yl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid ethyl ester;

(4-{2-[5-Carbamimidoyl-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-3-hydroxy-2-propyl-phenoxy)-acetic acid ethyl ester;

(3-Hydroxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-2-propyl-phenoxy)-acetic acid; and

(3-Allyloxy-4-{2-[5-(N-hydroxycarbamimidoyl)-1-oxo-1,3-dihydro-isoindol-2-yl]-acetyl}-phenoxy)-acetic acid ethyl ester.

6. The method according to claim 3 , wherein the compounds of formula (I) are selected from the group consisting of