# US 7,608,623 B2 · Hydroxyamidine and hydroxyguanidine compounds as urokinase inhibitors

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- Number: US 7,608,623 B2
- Document ID: US7608623B2
- Status: Granted
- Kind: B2
- Application number: 11/287,480
- Filed: 2005-11-28
- Published: 2006-06-29
- Granted: 2009-10-27
- Earliest claimed: 2003-05-26
- Assignees: Wilex AG
- Inventors: Stefan Sperl; Markus Buergle; Wolfgang Schmalix; Katja Wosikowski; Bernd Clement
- Web page: https://patentgrep.com/patent/US7608623B2

## CPC

- C07D 295/185: from aliphatic carboxylic acids
- A61P 35/00: Antineoplastic agents
- A61P 35/04: specific for metastasis
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 5/06078: {and aromatic or cycloaliphatic}
- C07K 5/06191: {containing heteroatoms different from O, S, or N}
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## Abstract

The present invention relates to novel compounds for inhibiting the urokinase plasminogen activator (uPA), which have high bioavailability and oral administerability, and also to the use thereof as therapeutic active compounds for the treatment of urokinase- or/and urokinase receptor-associated disorders such as, for example, tumors and metastasizing. The invention relates in particular to compounds containing hydroxyamidine or hydroxyguanidine groups.

## Claims

### Claim 1

A pharmaceutical composition, which comprises, as an active compound, one or more compounds of the formula
in which E is a group
R3 is —H,
R5 is —OR6, —N(R6)2, —C1-C6-alkyl, —C2-C6-alkenyl or —C2-C6-alkynyl, said alkyl, alkenyl and alkynyl moieties being straight-chained or branched and being unsubstituted or substituted by at least one substituent selected from the group consisting of halogen, —OR6, —OCOR6, —N(R6)2, —NR6COR6, —NR6CON(R6)2, COOR6, and a radical selected from the group consisting of a cycloalkyl-, aryl-, and bicyclic-radical which is unsubstituted or substituted by at least one substituent selected from the group consisting of —C1-C3-alkyl, —C1-C3-alkoxy, halogen, —OR6, ═O, —NO2, —CN, —COOR6, —N(R6)2, —NR6COR6, —NR6CON(R6)2 and —OCOR6,
R6 is —H, —C1-C6-alkyl, —C2-C6-alkenyl or —C2-C6-alkynyl, or a radical selected from the group consisting of a cycloalkyl-, aryl-, and bicyclic-radical which is unsubstituted or substituted by at least one substituent selected from the group consisting of —C1-C3-alkyl, —C1-C3-alkoxy, halogen, —OR6, ═O, —NO2, —CN, —COOR6, —N(R6)2, —NR6COR6, —NR6CON(R6)2 and —OCOR6,
said alkyl, alkenyl and alkynyl moieties being straight-chained or branched and being unsubstituted or substituted by at least one substituent selected from the group consisting of halogen, —OR6, —OCOR6, —N(R6)2, —NR6COR6, —NR6CON(R6)2, COOR6 , and a radical selected from the group consisting of a cycloalkyl-, aryl-, and bicyclic-radical which is unsubstituted or substituted by at least one substituent selected from the group consisting of —C1-C3-alkyl, —C1-C3-alkoxy, halogen, —OR6, ═O, —NO2, —CN, —COOR6, —N(R6)2, —NR6COR6, —NR6CON(R6)2 and —OCOR6,
or a salt of said compound
and a pharmaceutically customary carrier, diluent or/and adjuvant.

### Claim 2 (depends on 1)

The pharmaceutical composition of claim 1, wherein said active compound is selected from the group consisting of
N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamidino-(L)-phenylalanine-4-ethoxycarbonylpiperazide,
N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamidino-(D)-phenylalanine-4-ethoxycarbonylpiperazide,
N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamidino-(D,L)-phenylalanine-4-ethoxycarbonylpiperazide,
N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyguanidino-(L)-phenylalanine-4-ethoxycarbonylpiperazide,
N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyguanidino-(D)-phenylalanine-4-ethoxycarbonylpiperazide,
N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyguanidino-(D,L)-phenylalanine-4-ethoxycarbonylpiperazide,
N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyguanidino-(L)-phenylalanine-4-ethylaminocarbonylpiperazide,
N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyguanidino-(D)-phenylalanine-4-ethylaminocarbonylpiperazide, and
N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyguanidino-(D,L)-phenylalanine-4-ethylaminocarbonylpiperazide,
or a physiologically compatible salt thereof;
and a pharmaceutically acceptable carrier, diluent or/and adjuvant.

### Claim 3 (depends on 1)

The pharmaceutical composition as claimed in claim 1, wherein the composition is in an orally administrable form.

### Claim 4 (depends on 1)

The pharmaceutical composition as claimed in claim 1, wherein the compound is present as a sulfate or hydrogen sulfate salt.

### Claim 5 (depends on 2)

The pharmaceutical composition as claimed in claim 2, in which the compound is N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamidino-(L)-phenylalanine-4-ethoxycarbonylpiperazinium hydrogen sulfate or N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamidino-(L)-phenylalanine-4-ethoxycarbonylpiperazinium sulfate.

### Claim 6

A salt of a compound of the formula I,
in which E is
and R5 is ethoxy and wherein the salt is in the form of a hydrogen sulfate or sulfate.