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Deuterated cyclosporine analogs and their use as immunodulating agents

a cyclosporine analog and immunomodulator technology, applied in the field of cyclosporin derivatives, can solve the problems of nothing to modify the immunologic basis, and achieve the effects of enhancing efficacy, modifying physicochemical and pharmacokinetic properties, and enhancing efficacy

Inactive Publication Date: 2003-11-27
NAICKER SELVARAJ +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0051] An object of the present invention is to provide new cyclosporine analogs which have enhanced efficacy and altered pharmacokinetic and pharmacodynamic parameters. Another object of the present invention is to provide a cyclosporine analog for the care of immunoregulatory disorders and diseases, including the prevention, control and treatment thereof. An additional object of the present invention is to provide pharmaceutical compositions for administering to a patient in need of the treatment one or more of the active immunosuppressive agents of the present invention. Still a further object of this invention is to provide a method of controlling graft rejection, autoimmune and chronic inflammatory diseases by administering a sufficient amount of one or more of the novel immunosuppressive agents in a mammalian species in need of such treatment. Finally, it is the object of this invention to provide processes for the preparation of the active compounds of the present invention.

Problems solved by technology

Anti-inflammatory agents, such as NSAID's (Non-Stcroidal Anti-inflammatory Drugs), and cotticosteroids act principally by blocking the effect of, or secretion of, these mediators, but do nothing to modify the immunologic basis of the disease.
However, it is nephrotoxic and is known to cause the following undesirable side effects:

Method used

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  • Deuterated cyclosporine analogs and their use as immunodulating agents
  • Deuterated cyclosporine analogs and their use as immunodulating agents
  • Deuterated cyclosporine analogs and their use as immunodulating agents

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0075]

[0076] To a stirred solution of cyclosporine 1(1.01 g, 0.84 mmol) in acetic anhydride (20 mL) at room temperature was added DMAP (150 mg, 1.23 mmol, 1.5 eq). After stirring overnight, the reaction mixture was partitioned between EtOAc (50 ml) and water (25 ml). The separated EtOAc layer was then washed with water (50 mL) and brine (50 mL), dried (MgSO.sub.4) and the solvent removed in vacuo to give the crude product as a glassy solid. Purification by flash chromatography through a short column of silica (2% MeOH / DCM) and lyophilisation from benzene yielded 2 (1.044 g, 0.84 mmol, quant.) as a fluffy, colourless solid; [.alpha.].sub.D.sup.25 -305.7 (c. 0.3, CHCl.sub.3); .nu..sub.max (CHCl.sub.3 cast) / cm.sup.-1 3328 m, 2963m, 1746 m, 1627 s, 1528 m, 1472 m, 1233 m; .delta..sub.u (600MHz, C.sub.6D.sub.6) 8.73 (1H, d,J=9.5Hz, NH), 8.30 (1H, d,J=7.0Hz, NH), 7.92 (1H, d,J=7.5Hz, NH), 7.49 (1H, d,J=7.5Hz, NH), 6.05 (1H, d,J=11.5Hz), 5.88 (1H, dd,J=3.5, 11.5Hz), 5.82 (1H, d,J=11.5Hz), ...

example 2

[0077] Example 2

[0078] To a solution of compound 2 (289 mg, 0.23 mmol) in a 1:1 mixture of dioxane and water (5 mL) was added firstly sodium metaperiodate (100 mg, 0.47 mmol, 2 eq) and secondly a solution of osmium tetraoxide (5 mL; 0.5 g OsO.sub.4 in 250 mL of solvent). Two-phase work-up, purification by flash column chromatography (40% acctone in petroleum ether) and lyophilisation from benzene gave compound 3, (226 mg, 0.18 mmol, 80%) as a fluffy, colourless solid; [.alpha.].sub.D.sup.25 -260.0 (c. 0.1, CHCl.sub.3); .nu..sub.max (CHCl.sub.3 cast) / cm.sup.-1 3325 m, 2962 m, 1748 w, 1724 w, 1677 m, 1626 s, 1228 m, 755 m; .delta..sub.H (300MHz, C.sub.6D.sub.6) 8.63 (1H, d,J=9.5Hz, NH), 8.16 (1H, d,J=7.0Hz, NH), 7.95 (1H, d,J=7.5Hz, NH), 7.48 (1H, d,J=9.0Hz, NH), 5.93 (1H, d,J=7.5Hz), 5.84(1H, dd,J=4.0, 11.5Hz), 5.70 (1H, d,J=11.5Hz), 5.56-5.54 (1H, m), 5.32 (1H, dd,J=5.5, 8.0Hz), 5.07-4.88 (3H, complex), 4.72 (1H, p,J=7.0Hz), 4,49 (1H, p,J=7.0Hz), 3.98 (1H, d,J=14.0Hz), 3.42 (3H, s, ...

example 3

[0079] Example 3

[0080] Method A:

[0081] To a solution of compound 3(315 mg, 0.26 mmol) in THF (5mL) at 0.degree. C. was added a solution of the deutero-phosphorus ylid (2.67mmol, .about.10 eq), prepared from d.sub.5-ethyltriphenylphosphonium iodide. After work-up, purification by flash column chromatography (30% to 60% acetone in PE) and HPLC (60% to 65% MeCN in water), then lyophilisation from benzene yielded compound 4(153 mg, 0.12 mmol, 47%) as a fluffy, colourless solid.

[0082] Method B:

[0083] To a stirred solution of compound 3 (287 mg, 0.23mmol) in THF (5mL) under Ar at -78.degree. C. was carefully added a solution of phosphorus ylid (formed by the addition of sodium hexamethyldisilylamide (1.0M; 2.25 mL, 2.25 mmol, .about.10 eq) to a supension of d.sub.5-ethyltriphenylphos-phonium iodide (480 mg, 1.13 mmol, .about.5 eq) in TH-F (10 mL) under Ar at room temperature), After stirring for 2 hr with gradual warming to room temperature, the reaction mixture was cooled to 0.degree. C....

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Abstract

Cyclosporine derivatives are disclosed which possess enhanced efficacy and reduced toxicity over naturally occurring and other presently known cyclosporins and cyclosporine derivatives. The cyclosporine derivatives of the present invention are produced by chemical and isotopic substitution of the cyclosporine A (CsA) molecule by: (1) Chemical substitution and optionally deuterium substitution of amino acid 1; and (2) deuterium substitution at key sites of metabolism of the cyclosporine A molecule such as amino acids 1, 4, 9. Also disclosed are methods of producing the cyclosporine derivatives and method of producing immunosuppression with reduced toxicity with the disclosed cyclosporine derivatives.

Description

INTRODUCTION AND BACKGROUND[0001] Cyclosporin derivatives of the present invention are disclosed which possess enhanced efficacy and reduced toxicity over naturally occurring and other presently known cyclosporins and cyclosporine derivatives. The cyclosporin derivatives of the present invention are produced by chemical and isotopic substitution of the cyclosporine A (CsA) molecule by:[0002] 1. Chemical substitution and optionally deuterium substitution of amino acid 1: and[0003] 2. Deuterium substitution at key sites of metabolism of the cyclosporine A molecule such as amino acids 1, 4, 9.[0004] The cyclosporins are a family of, neutral, hydrophobic cyclic undecapeptides, containing a novel nine-carbon anmino acid (MeBmt) at position 1 of the ring that exhibit potent immunosuppressive, antiparatitic, fungicidal, and chronic anti-inflammatory properties. The naturally occurring members of this family of structurally related compounds are produced by various fungi imperfecti. Cyclosp...

Claims

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Application Information

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IPC IPC(8): A61K38/00C07B59/00C07K1/13C07K7/64
CPCA61K38/00C07B59/008C07K1/13Y10S530/807C07K7/645Y10S530/806C07K7/64A61P37/00A61P37/06
Inventor NAICKER, SELVARAJYATSCOFF, RANDALL W.FOSTER, ROBERT T.
Owner NAICKER SELVARAJ
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