Oligo or polyalkylene glycol-coupled thrombin inhibitors

Compound of the general structure (I)

• wherein
• m is 0, 1, 2, 3 or 4;
• n is 0, 1, 2, 3, 4 or 5;
• A is either a methylene, ethylene or propylene group and the ring formed therewith can be unsubstituted or substituted with a hydroxyl group, which is optionally etherified with an alkyl or aralkyl,
• or one of the groups —CH2—O—, —CH2—S—, —CH2—SO—, —CH2—O—CH2—, —CH2—S—CH2—, —CH2—SO—CH2—;
• B is a bond or
• wherein R5 is alkyl comprising 1 to 4, preferably 1 or 2 and especially preferred one carbon atom, and can be substituted with one or more identical or different halogen atoms or with a group
• D represents a group
• wherein a is 0 or 1, b is 0, 1 or 2, and R6 and R8 are independently bivalent groups selected from aromatic or saturated 6-membered rings which can comprise a heteroatom in addition to carbon and can carry one or more identical or different alkyl substituents, and wherein R6 can furthermore be —NH— if a is 0, and R7 is a hydrogen atom or —NH2;
• R1 is a hydrogen atom or arylsulfonyl, aralkylsulfonyl, cycloalkylmethylsulfonyl, cyclo-alkylethylsulfonyl or alkylsulfonyl group, the aryl portion of which can optionally carry one, two, three, four or five substituents independently selected from halogen atoms, alkyl or alkoxy groups or is linked with another aryl,
• and either:
• R2 is —(CH2)p—CO—NH—(CH2)q-—X, —(CH2)r—NH—CO—(CH2)s—V—X or —(CH2)r—NH—CO—O—(CH2)s—V—X
• wherein
• p is an integer from 1 to 5 and q is an integer from 2 to 5;
• r is an integer from 2 to 5 and s is an integer from 1 to 5;
• V is a bond or —CO—NH—(CH2)c— and c is an integer from 2 to 5;
• and
• X is an oligo or polyalkylene glycol with the structure —[O—(CH2)d]e—OZ or —[O—CH(CH3)—CH2]e—OZ or a cycle with the structure
• and d is an integer from 2 to 6, e is an integer from 3 to 1,000, Z is a hydrogen atom or alkyl or replicates the entire inhibitor structure bonded to the free valence of the group X, f is an integer from 2 to 6 and g is an integer from 3 to 10;
• and
• R3 is a phenyl or cyclohexyl group which can be substituted with 1 to 5 identical or different substituents independently selected from halogen atoms, alkyl, alkoxy or hydroxyl groups and R4 is a hydrogen atom, phenyl or cyclohexyl group which can be substituted with 1 to 5 identical or different substituents independently selected from halogen atoms, alkyl, alkoxy or hydroxyl groups,
• m is 0, 1, 2, 3 or 4 and
• a D-configuration is present at the carbon atom marked with *;
• or
• R2 is a hydrogen atom and
• R3 is —CO—NH—(CH2)q—X, —CO—W1—W2—(CH2)q—X, —NH—CO—(CH2)s—V—X, —NH—CO—O—(CH2)s—V—X, —S—CH2—CO—NH—(CH2)t—X or —S—S—CH2—CH2—X,
• wherein q, s, X and V are as defined above and t is an integer from 2 to 5, and the group W1 is —O— or —NH— and W2 represents a bond or has the structure —(CH2)v—Ph—(CH2)v′-amide-, wherein v and v′ are independently 0, 1 or 2, Ph represents a 1,2-, 1,3- or 1,4-substituted phenyl and amide represents —HN—(O)C— or —C(O)NH—,
• and R4 is a hydrogen atom,
• m is 1, 2, 3, 4 or 5 and
• an L-configuration is present at the carbon atom marked with *.