Fluoro-alkyl-cyclopeptide derivatives having anti-integrin activity

Abstract

Compounds of formula (I) cyclo [NX1-R1-CO-NX2-R2-CO-NX3-R3-CO-NX4-CO-NX5-R5-CO], wherein at least one x-fluoroalkylated amino acid is present, are inhibitors of integrins, particularly those belonging to the alphavbeta3 and alphavbeta5 family, and thus are useful as medicaments, particularly for the treatment of the underlying diseases responsible for abnormal angiogenesis, such as retinopathy, acute kidney failure, osteoporosis and metastases. The compounds described herein are also useful as diagnostic agents, when appropriately labelled, especially for the detection and location of small tumour masses and arterial occlusion events.

Description

[0001] The invention described here relates to fluoro-alkyl-cyclic peptide derivatives having anti-integrin activity, in particular to cyclic peptide compounds containing a fluoro-alkyl group at the nitrogen and / or C-alpha position of the peptide bond, as follows Shown in the formula (I). The invention described here also relates to processes for the preparation of said compounds, their use as medicaments, especially as integrin receptor inhibitors, as anti-angiogenic and anti-metastatic agents, and to pharmaceutical compositions comprising them. Background of the invention

[0002] Integrins are a class of receptors involved in the phenomenon of cell adhesion. They are glycoproteins composed of two subunits, D and β, that combine to form distinct families. For a more detailed description see Kessler, H., et al., Angew. Chem. Int. Ed. Engl., 1997, 36, 1374-89.

[0003] All integrins have a "universal cellular recognition site" that recognizes the common peptide sequence Arg-...

Examples

Embodiment 1

[0079] C(Arg-Glv-Asp-D-Phe-(R or S)-Tfm-Phe) (ST1930 / ST1931)

[0080] Preparation of Pht-D-Phe-Br (Dal Pozzo, A., Bergonzi, R. and Ni, M.H., Tetrahedron Lett., 2001, 42, 3925-7).

[0081] 1.4 g (4.75 mmol) Pht-D-Phe-OH were dissolved in 19 ml of a 0.5 M solution of bromoenamine in DCM under argon. After 10 minutes, the solution is ready to use.

[0082] Add 248mg (0.950mmol) of H-α-Tfm-Phe-OEt and collidine (1 equivalent) to 12.5ml of bromide solution (prepared as above) cooled to 0°C, stir the mixture at room temperature (a.t.), after 10 minutes Another 6.5 ml portion of the bromide solution and 1 equivalent of collidine were added. After 2 h the mixture was dried with 15 ml of 5% NaHCO 3 and 15 ml EtOAc, and stirred for 30 minutes. The solvent was washed with water, 1N HCl and water, then evaporated and the residue was purified on a flash column using 8:2 hexane-EtOAc as solvent.

[0083] 4.3ml of 1M BBr 3 The DCM solution of 460 mg of dipeptide Pht-D-Phe-α-Tfm-Phe-O...

Embodiment 2

[0110] c(Arg-Gly-Asp-D-Phe-(R,S)-Dfm-Phe) (ST1932)

[0111] Proceed as described in Example 1 starting from H-(R,S)-Dfm-Phe-OEt. A mixture of the two diastereoisomers was obtained which had not yet been resolved.

[0112] 1 H-NMR (CD 3 OD): δ8.00-7.05 (d, NH), 7.35-7.15 (m, aromatics), 6.42-5.6 (t, CHF 2 ), 4.74-4.32 (m, α-CH), 4.32-3.96 (2 dd, CH 2 -Gly), 3.68-2.50(m), 1.75-1.45(m, CH 2 -CH 2 -Arg).

[0113] 19 F-NMR (CD 3 OD): δ -54.4 to -55.5.

[0114] MS (M+H + ): 673.14.

Embodiment 3

[0116] c(Arg-Gly-(R or S)-Tfm-Asp-D-Phe-Val)(ST2189 / 2190)

[0117] H-(R,S)-Tfm-Allgly-Oet was condensed with Pth-Gly-Br and then worked up as described in Example 1. With preparative HPLC, containing 22% CH 3 CN in water + 0.1% TFA resolved and purified the mixture of two diastereoisomers.

[0118] Diastereomer I (Rt 20.76)

[0119] 1 H-NMR (DMSOD 6 +D 2 O): δ7.30-7.12, 4.70, 4.26, 4.10, 3.86, 3.60-2.70, 1.72, 1.52-1.12, 0.65.

[0120] MS (M+H + ): 643.2.

[0121] Diastereomer II (Rt 25.44)

[0122] 1 H-NMR (DMSOD 6 +D 2 O): δ7.30-6.96, 4.50, 4.15, 4.10-2.75, 1.90, 1.62, 1.43-1.20, 0.82.

[0123] MS (M+H + ): 643.2.

[0001] The invention described here relates to fluoro-alkyl-cyclic peptide derivatives having anti-integrin activity, in particular to cyclic peptide compounds containing a fluoro-alkyl group at the nitrogen and / or C-alpha position of the peptide bond, as follows Shown in the formula (I). The invention described here also relates to processes for the preparation of said compounds, their use as medicaments, especially as integrin receptor inhibitors, as anti-angiogenic and anti-metastatic agents, and to pharmaceutical compositions comprising them. Background of the invention

[0002] Integrins are a class of receptors involved in the phenomenon of cell adhesion. They are glycoproteins composed of two subunits, D and β, that combine to form distinct families. For a more detailed description see Kessler, H., et al., Angew. Chem. Int. Ed. Engl., 1997, 36, 1374-89.

[0003] All integrins have a "universal cellular recognition site" that recognizes the common peptide sequence Arg-...

Examples

Embodiment 1

[0079] C(Arg-Glv-Asp-D-Phe-(R or S)-Tfm-Phe) (ST1930 / ST1931)

[0080] Preparation of Pht-D-Phe-Br (Dal Pozzo, A., Bergonzi, R. and Ni, M.H., Tetrahedron Lett., 2001, 42, 3925-7).

[0081] 1.4 g (4.75 mmol) Pht-D-Phe-OH were dissolved in 19 ml of a 0.5 M solution of bromoenamine in DCM under argon. After 10 minutes, the solution is ready to use.

[0082] Add 248mg (0.950mmol) of H-α-Tfm-Phe-OEt and collidine (1 equivalent) to 12.5ml of bromide solution (prepared as above) cooled to 0°C, stir the mixture at room temperature (a.t.), after 10 minutes Another 6.5 ml portion of the bromide solution and 1 equivalent of collidine were added. After 2 h the mixture was dried with 15 ml of 5% NaHCO 3 and 15 ml EtOAc, and stirred for 30 minutes. The solvent was washed with water, 1N HCl and water, then evaporated and the residue was purified on a flash column using 8:2 hexane-EtOAc as solvent.

[0083] 4.3ml of 1M BBr 3 The DCM solution of 460 mg of dipeptide Pht-D-Phe-α-Tfm-Phe-O...

Embodiment 2

[0110] c(Arg-Gly-Asp-D-Phe-(R,S)-Dfm-Phe) (ST1932)

[0111] Proceed as described in Example 1 starting from H-(R,S)-Dfm-Phe-OEt. A mixture of the two diastereoisomers was obtained which had not yet been resolved.

[0112] 1 H-NMR (CD 3 OD): δ8.00-7.05 (d, NH), 7.35-7.15 (m, aromatics), 6.42-5.6 (t, CHF 2 ), 4.74-4.32 (m, α-CH), 4.32-3.96 (2 dd, CH 2 -Gly), 3.68-2.50(m), 1.75-1.45(m, CH 2 -CH 2 -Arg).

[0113] 19 F-NMR (CD 3 OD): δ -54.4 to -55.5.

[0114] MS (M+H + ): 673.14.

Embodiment 3

[0116] c(Arg-Gly-(R or S)-Tfm-Asp-D-Phe-Val)(ST2189 / 2190)

[0117] H-(R,S)-Tfm-Allgly-Oet was condensed with Pth-Gly-Br and then worked up as described in Example 1. With preparative HPLC, containing 22% CH 3 CN in water + 0.1% TFA resolved and purified the mixture of two diastereoisomers.

[0118] Diastereomer I (Rt 20.76)

[0119] 1 H-NMR (DMSOD 6 +D 2 O): δ7.30-7.12, 4.70, 4.26, 4.10, 3.86, 3.60-2.70, 1.72, 1.52-1.12, 0.65.

[0120] MS (M+H + ): 643.2.

[0121] Diastereomer II (Rt 25.44)

[0122] 1 H-NMR (DMSOD 6 +D 2 O): δ7.30-6.96, 4.50, 4.15, 4.10-2.75, 1.90, 1.62, 1.43-1.20, 0.82.

[0123] MS (M+H + ): 643.2.

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