IP Library › Granted Patent US 8,476,306

Granted Patent B2

US 8,476,306 · App. 12/951,835 · Granted Jul 2, 2013

Urokinase inhibitors, production and use thereof

Inventors: Joerg Stuerzebecher (Erfurt, DE); Torsten Steinmetzer (Jena, DE); Andrea Schweinitz (Jena, DE)

Assignee: The Medicines Company (Leipzig) GmbH

A61K31/18 C07C31/738 C07D213/58

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Quick Facts

Patent No.: US 8,476,306
App. No.: 12/951,835
Granted: Jul 2, 2013
Kind: B2

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Abstract

The invention relates to novel inhibitors of urokinase and to their preparation and use for the therapy, prophylaxis and diagnosis of a tumor, in particular for reducing the formation of tumor metastases.

Claims (131)

1. A compound having a structure according to the following formula,

or a salt thereof, wherein

P 1 is an amino acid residue formed from glycine, alanine, serine, or proline; and

R 5 is selected from the group consisting of (3-pyridylmethyl)sulfonyl, (4-pyridylmethyl)sulfonyl, (2-pyridylmethyl)sulfonyl, ((3-(trifluoromethyl)phenyl)methyl)sulfonyl), ((4-(trifluoromethyl)phenyl)methyl)sulfonyl), 2-Cl-benzyl sulfonyl, 3-Cl-benzylsulfonyl, 4-Cl-benzylsulfonyl, 2-methylbenzylsulfonyl, 3-methylbenzylsulfonyl, and 4-methylbenzylsulfonyl.

2. The compound of claim 1 , wherein said compound is selected from the group consisting of:

(3-pyridylmethyl)sulfonyl-dSer-Gly-4-amidinobenzylamide;

(3-pyridylmethyl)sulfonyl-dSer-Ala-4-amidinobenzylamide;

(3-pyridylmethyl)sulfonyl-dSer-Ser-4-amidinobenzylamide;

(3-pyridylmethyl)sulfonyl-dSer-Pro-4-amidinobenzylamide;

(4-pyridylmethyl)sulfonyl-dSer-Ala-4-amidinobenzylamide;

(4-pyridylmethyl)sulfonyl-dSer-Ser-4-amidinobenzylamide;

(4-pyridylmethyl)sulfonyl-dSer-Pro-4-amidinobenzylamide;

(2-pyridylmethyl)sulfonyl-dSer-Gly-4-amidinobenzylamide;

(2-pyridylmethyl)sulfonyl-dSer-Ala-4-amidinobenzylamide;

(2-pyridylmethyl)sulfonyl-dSer-Ser-4-amidinobenzylamide;

(2-pyridylmethyl)sulfonyl-dSer-Pro-4-amidinobenzylamide;

((3-(trifluoromethyl)phenyl)methyl)sulfonyl-dSer-Gly-4-amidinobenzylamide;

((3-(trifluoromethyl)phenyl)methyl)sulfonyl-dSer-Ala-4-amidinobenzylamide;

((3-(trifluoromethyl)phenyl)methyl)sulfonyl-dSer-Ser-4-amidinobenzylamide;

((3-(trifluoromethyl)phenyl)methyl)sulfonyl-dSer-Pro-4-amidinobenzylamide;

((4-(trifluoromethyl)phenyl)methyl)sulfonyl-dSer-Gly-4-amidinobenzylamide;

((4-(trifluoromethyl)phenyl)methyl)sulfonyl-dSer-Ala-4-amidinobenzylamide;

((4-(trifluoromethyl)phenyl)methyl)sulfonyl-dSer-Ser-4-amidinobenzylamide;

((4-(trifluoromethyl)phenyl)methyl)sulfonyl-dSer-Pro-4-amidinobenzylamide;

2-Cl-benzylsulfonyl-dSer-Gly-4-amidinobenzylamide;

2-Cl-benzylsulfonyl-dSer-Ala-4-amidinobenzylamide;

2-Cl-benzylsulfonyl-dSer-Pro-4-amidinobenzylamide;

2-Cl-benzylsulfonyl-dSer-Ser-4-amidinobenzylamide;

3-Cl-benzylsulfonyl-dSer-Gly-4-amidinobenzylamide;

3-Cl-benzylsulfonyl-dSer-Ala-4-amidinobenzylamide;

3-Cl-benzylsulfonyl-dSer-Pro-4-amidinobenzylamide;

3-Cl-benzylsulfonyl-dSer-Ser-4-amidinobenzylamide;

4-Cl-benzylsulfonyl-dSer-Ala-4-amidinobenzylamide;

4-Cl-benzylsulfonyl-dSer-Pro-4-amidinobenzylamide;

4-Cl-benzylsulfonyl-dSer-Ser-4-amidinobenzylamide;

2-methylbenzylsulfonyl-dSer-Gly-4-amidinobenzylamide;

2-methylbenzylsulfonyl-dSer-Ala-4-amidinobenzylamide;

2-methylbenzylsulfonyl-dSer-Pro-4-amidinobenzylamide;

2-methylbenzylsulfonyl-dSer-Ser-4-amidinobenzylamide;

3-methylbenzylsulfonyl-dSer-Gly-4-amidinobenzylamide;

3-methylbenzylsulfonyl-dSer-Ala-4-amidinobenzylamide;

3-methylbenzylsulfonyl-dSer-Pro-4-amidinobenzylamide;

3-methylbenzylsulfonyl-dSer-Ser-4-amidinobenzylamide;

4-methylbenzylsulfonyl-dSer-Ala-4-amidinobenzylamide;

4-methylbenzylsulfonyl-dSer-Pro-4-amidinobenzylamide; and

4-methylbenzylsulfonyl-dSer-Ser-4-amidinobenzylamide.

3. A pharmaceutical composition comprising the compound of claim 1 and pharmaceutically suitable auxiliary substances and/or additives.

4. The pharmaceutical composition of claim 3 , wherein said pharmaceutical composition is used in the form of a tablet, a sugar-coated tablet, a capsule, a pellet, a suppository, a solution, an injection solution or infusion solution, eyedrops, nose drops and ear drops, a juice, an emulsion or suspension, a globule, a stylus, an aerosol, a powder, a paste, a cream or an ointment.

5. A compound having a structure according to the following formula,

or a salt thereof, wherein P1 is an amino acid residue formed from a natural or artificial basic amino acid in the L-configuration, and wherein said amino acid is selected from the group consisting of: Lys, homoLys, Arg, norArg, homoArg, His, Orn, Orn(2-imidazolinyl), Dab, 4-[(2-amino)pyrimidinyl]butyric acid, Dap, Ala[3-(2-pyrrolidinyl)], Ala[3-pyrrolidinyl-(2-N-amidino)], Ala[3-(N-piperazine-4-N-amidino], Ala(4-Pip), Ala[4-Pip(N-amidino)], homoAla(4-Pip), Ala[3-Pip(N-amidino)], homoAla(3-Pip), homoAla[4-Pip(N-amidino)], Ala-(3-guanidino), Phe(3-amidino), Phe(4-amidino), Phe(3-NH 2 ), Phe(4-NH 2 ), Phe(3-guanidino), Phe(4-guanidino), Phe[4-(2-imidazolinyl)], Phe[3-CH 2 -(guanidino)], Phe[4-CH 2 -(guanidino)], homoPhe(3-amidino), homoPhe(4-amidino), hPhe(3-NH 2 ), hPhe(4-NH 2 ), hPhe(3-guanidino), hPhe(4-guanidino), cis-Cha(4-NH 2 ), trans-Cha(4-NH 2 ), cis-homoCha(4-NH 2 ), trans-homoCha(4-NH 2 ), trans-Cha(4-CH 2 NH 2 ), and trans-homoCha(4-CH 2 NH 2 ).

6. The compound of claim 5 , wherein P1 is an amino acid residue formed from arginine or lysine.

7. The compound of claim 5 , wherein said compound is selected from the group consisting of:

benzylsulfonyl-dSer-homoLys-4-amidinobenzylamide;

benzylsulfonyl-dSer-norArg-4-amidinobenzylamide;

benzylsulfonyl-dSer-homoArg-4-amidinobenzylamide;

benzylsulfonyl-dSer-Orn-4-amidinobenzylamide;

benzylsulfonyl-dSer-Orn(2-imidazolinyl)-4-amidinobenzylamide;

benzylsulfonyl-dSer-His-4-amidinobenzylamide;

benzylsulfonyl-dSer-Dab-4-amidinobenzylamide;

N-(4-amidinobenzyl)benzylsulfonyl-dSer-4-[(2-amino)pyrimidinyl]butyramide;

benzylsulfonyl-dSer-Dap-4-amidinobenzylamide;

benzylsulfonyl-dSer-Ala[3-(2-pyrrolidinyl)]-4-amidinobenzylamide;

benzylsulfonyl-dSer-Ala[3-pyrrolidinyl-(2-N-amidino)]-4-amidinobenzylamide;

benzylsulfonyl-dSer-Ala[3-(N-piperazine-4-N-amidino]-4-amidinobenzylamide;

benzylsulfonyl-dSer-Ala(4-Pip)-4-amidinobenzylamide;

benzylsulfonyl-dSer-Ala[4-Pip(N-amidino)]-4-amidinobenzylamide;

benzylsulfonyl-dSer-homoAla(4-Pip)-4-amidinobenzylamide;

benzylsulfonyl-dSer-Ala[3-Pip(N-amidino)]-4-amidinobenzylamide;

benzylsulfonyl-dSer-homoAla(3-Pip)-4-amidinobenzylamide;

benzylsulfonyl-dSer-homoAla[4-Pip(N-amidino)]-4-amidinobenzylamide;

benzylsulfonyl-dSer-Ala-(3-guanidino)-4-amidinobenzylamide;

benzylsulfonyl-dSer-Phe(3-amidino)-4-amidinobenzylamide;

benzylsulfonyl-dSer-Phe(4-amidino)-4-amidinobenzylamide;

benzylsulfonyl-dSer-Phe(3-NH 2 )-4-amidinobenzylamide;

benzylsulfonyl-dSer-Phe(4-NH 2 )-4-amidinobenzylamide;

benzylsulfonyl-dSer-Phe(3-guanidino)-4-amidinobenzylamide;

benzylsulfonyl-dSer-Phe(4-guanidino)-4-amidinobenzylamide;

benzylsulfonyl-dSer-Phe[4-(2-imidazolinyl)]-4-amidinobenzylamide;

benzylsulfonyl-dSer-Phe[3-CH 2 -(guanidino)]-4-amidinobenzylamide;

benzylsulfonyl-dSer-Phe[4-CH 2 -(guanidino)]-4-amidinobenzylamide;

benzylsulfonyl-dSer-homoPhe(3-amidino)-4-amidinobenzylamide;

benzylsulfonyl-dSer-homoPhe(4-amidino)-4-amidinobenzylamide;

benzylsulfonyl-dSer-hPhe(3-NH 2 )-4-amidinobenzylamide;

benzylsulfonyl-dSer-hPhe(4-NH 2 )-4-amidinobenzylamide;

benzylsulfonyl-dSer-hPhe(3-guanidino)-4-amidinobenzylamide;

benzylsulfonyl-dSer-hPhe(4-guanidino)-4-amidinobenzylamide;

benzylsulfonyl-dSer-cis-Cha(4-NH 2 )-4-amidinobenzylamide;

benzylsulfonyl-dSer-trans-Cha(4-NH 2 )-4-amidinobenzylamide;

benzylsulfonyl-dSer-cis-homoCha(4-NH 2 )-4-amidinobenzylamide;

benzylsulfonyl-dSer-trans-homoCha(4-NH 2 )-4-amidinobenzylamide;

benzylsulfonyl-dSer-trans-Cha(4-CH 2 NH 2 )-4-amidinobenzylamide; and

benzylsulfonyl-dSer-trans-homoCha(4-CH 2 NH 2 )-4-amidinobenzylamide.

8. A pharmaceutical composition comprising the compound of claim 5 and pharmaceutically suitable auxiliary substances and/or additives.

9. The pharmaceutical composition of claim 8 , wherein the pharmaceutical composition is used in the form of a tablet, a sugar-coated tablet, a capsule, a pellet, a suppository, a solution, an injection solution or infusion solution, eyedrops, nose drops and ear drops, a juice, an emulsion or suspension, a globule, a stylus, an aerosol, a powder, a paste, a cream or an ointment.

10. A compound having a structure according to the following formula,

or a salt thereof, wherein

P 1 is an amino acid residue formed from glycine, alanine, serine, or proline; and

R 5 is selected from the group consisting of ((3-(trifluoromethyl)phenyl)methyl)sulfonyl), ((4-(trifluoromethyl)phenyl)methyl)sulfonyl), 2-Cl-benzyl sulfonyl, 3-Cl-benzylsulfonyl, 4-Cl-benzylsulfonyl, 2-methylbenzylsulfonyl, 3-methylbenzylsulfonyl, and 4-methylbenzylsulfonyl.

11. The compound of claim 10 , wherein said compound is selected from the group consisting of: