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Conjugates useful in treatment of prostate cancer

A technology of prostate cancer and conjugates, applied in the direction of drug combinations, animal/human peptides, medical preparations of non-active ingredients, etc., can solve problems such as unclear importance in the body

Inactive Publication Date: 2001-02-14
MERCK & CO INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

PSA also forms a stable complex with α2-macroglobulin, but since this results in PSA encapsulation and complete loss of the PSA epitope, the in vivo importance of this complex formation is unclear

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0111] Example 1 Deacetylvinblastine-4-O-(N-acetyl-4-trans-L-Hyp-Ser-Ser-Chg-Gln-Ser-Ser-Pro) Ester Step A: 4-Deacetylvinblastine preparation of

[0112] A 2.40 g (2.63 mmol) sample of vinblastine sulfate (Sigma V-1377) was dissolved in 135 ml of pure methanol under nitrogen and treated with 45 ml of anhydrous hydrazine, and the solution was stirred at 20-25°C for 18 hours. The reaction was evaporated to a thick syrup which was partitioned between 300ml dichloromethane and 150ml saturated sodium bicarbonate. The aqueous layer was washed with 2 100 mL portions of dichloromethane, each of the 3 dichloromethane layers was washed with 100 mL of water (2×) and saturated NaCl (1×). The combined organic layers were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to give the title compound as an off-white crystalline solid. The material was stored at -20°C until use. Step B: Preparation of 4-deacetylvinblastine-4-O-(prolyl) est...

Embodiment 1A

[0121] Example 1A deacetylvinblastine-4-O-(N-acetyl-4-trans-L-Hyp-Ser-Ser-Chg-Gln-Ser-Ser-Pro) ester acetate

[0122] Under nitrogen, a 4.50 g (3.7 mmol) sample of 4-O-(prolyl)desacetylvinblastine TFA salt prepared as described in step B of Example 1 was dissolved in 300 ml DMF and the solution was cooled to 0 ℃. Then add 1.72g (10.5 mmol) 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine (ODHBT), adjust the pH with N-methylmorpholine (NMM) Adjust to 7.0 (wet pH test paper with a range of 5-10), then add 4.95 g (5.23 mmol) of N-acetyl-heptapeptide from Step D of Example 1 in portions, allowing complete dissolution between each addition. Use NMM to adjust the pH to 7.0, add 1.88g (9.8mmol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), and then The solution was stirred until the coupling was complete as monitored by analytical HPLC (System A), the pH was maintained at about 7 by periodic addition of NMM. Analysis showed a major component wit...

Embodiment 4

[0138] Example 4 Evaluation of free PSA on the recognition of oligopeptide-vinca alkaloid drug conjugates

[0139] The conjugate prepared as in Example 3 was separately dissolved in PSA digestion buffer (50 mM tris(hydroxymethyl)-aminomethane pH 7.4, 140 mM NaCl), and this solution was added to PSA at a molar ratio of 100:1 middle. Alternatively, the PSA digestion buffer used was 50 mM Tris(hydroxymethyl)-aminomethane pH 7.4, 140 mM NaCl. After each reaction time, the reaction was quenched by adding trifluoroacetic acid (TFA) to a final 1% (v / v). Alternatively, use 10mM ZnCl 2 Quenches the reaction. The quenched reaction was analyzed by HPLC on a reverse phase C18 column using a 0.1% TFA / acetonitrile in water gradient. The time (in minutes) required for 50% cleavage of the oligopeptide-cytotoxic agent conjugate with enzymatically active free PSA was then calculated. The results are shown in Table 1.

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PUM

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Abstract

Chemical conjugates which comprise oligopeptides, having amino acid sequences that are selectively proteolytically cleaved by free prostate specific antigen (PSA) and known cytotoxic agents are disclosed. The conjugates of the invention are characterized by attachment of the cleavable oligopeptide to the oxygen atom at the 4-position on a vinca drug that has be desacetylated. Such conjugates are useful in the treatment of prostatic cancer and benign prostatic hypertrophy (BPH).

Description

Background of the invention [0001] In 1996, an estimated 317,000 men in the United States were diagnosed with prostate cancer and 42,000 American men died from the disease (Garnick, M.B. (1994). The Dilemmas of Prostate Cancer. Scientific American, April: 72- 81). Thus, prostate cancer is the most commonly diagnosed malignancy (besides skin cancer) among US men and is the second leading cause of cancer-related death (after lung cancer) in this group. [0002] Prostate-specific antigen (PSA) is a single-chain 33 kDa glycoprotein produced almost exclusively by human prostate epithelium at levels of 0.5-2.0 mg / ml in human semen (Nadji, M., Taber, S.Z., Castro, A. et al. (1981) Cancer 48:1229; Papsidero, L., Kruiyana, M., Wang, M. et al. (1981). JNCI 66:37; Qui, SD., Young, C.Y.F., Bihartz, D.L., et al. (1990) (1979). Invest. Urol. 17:159). A single sugar unit is attached to asparagine residue No. 45, constituting a total molecular weight of 2-3 kDa. PSA is a protease with chy...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/00A61K47/48A61P13/08A61P35/00C07K5/10C07K7/06C07K14/47
CPCC07K7/02C07K7/06C07K14/47C07K5/1016A61K38/00C07K5/1013A61K47/48338A61K47/65A61P13/08A61P35/00
Inventor S·F·布拉迪冯冬梅V·M·加斯基
Owner MERCK & CO INC
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