# US 7,407,982 B2 · Oligo or polyalkylene glycol-coupled thrombin inhibitors

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- Number: US 7,407,982 B2
- Document ID: US7407982B2
- Status: Granted
- Kind: B2
- Application number: 10/344,722
- Filed: 2002-01-23
- Published: 2005-03-31
- Granted: 2008-08-05
- Earliest claimed: 2001-01-23
- Assignees: HaemoSys GmbH
- Inventors: Torsten Steinmetzer; Götz Nowak
- Web page: https://patentgrep.com/patent/US7407982B2

## CPC

- C08G 65/329: with organic compounds
- A61K 47/60: the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- C08G: MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to novel covalent oligo and polyalkylene glycol conjugates with synthetic inhibitors of trypsin-type serine proteases, in particular inhibitors of the hemocoagulation protease thrombin, synthetic intermediates stages required in their production and their use for producing active ingredients for the treatment or prophylaxis of thrombotic complications.

## Claims

### Claim 1

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 *.

### Claim 2 (depends on 1)

Compound according to claim 1, wherein B represents one of the following structures

### Claim 3 (depends on 1)

Compound according to claim 1, wherein D represents one of the following structures

### Claim 4 (depends on 1)

Compound according to claim 1, wherein X has a cyclic structure of the formula
and f and g are as defined in claim 1.

### Claim 5 (depends on 1)

Compound according to claim 1 having one of the following formulas Ia to Ih
wherein R1 is a 4-methoxy-phenylsulfonyl, 4-methoxy-3 -chioro-phenylsulfonyl, 4-methoxy-3-methyl-phenylsulfonyl or 4-methoxy-2,3,6-trimethyl-phenylsulfonyl group,
Q is —(CH2)s′—, wherein s′=0, 1, 2, 3 or 4, —O—CH2— or —CH2—CH2—CO—NH—CH2,
and
PEG is a polyethylene glycol structure of the formula —[O—C2H4]i—, wherein i is 3 to 1,000, h represents 1, 2, 3 or 4
and R10 is