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Thiazoline acid derivatives

a technology of thiazoline acid and derivatives, applied in the field of thiazoline acids, can solve the problems of inability to cyclic siderophores, low efficiency and marginal oral activity, and inability to tolerate cyclic siderophores,

Inactive Publication Date: 2006-06-13
BRITISH TELECOMM PLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides compounds of formula (I) and their salts with pharmaceutically acceptable acids or complexes. These compounds can be used to prevent or heal pathological conditions associated with an excess of trivalent metals, ions, or compounds. The compounds have the ability to chelate with these metals, ions, or compounds, thereby reducing their toxicity and promoting their excretion. The compounds can be administered in pharmaceutical compositions or used in various methods of treatment.

Problems solved by technology

However, there are iron-overload syndromes secondary to chronic transfusion therapy, e.g., aplastic anemia and thalassemia, in which phlebotomy is not an option [Iron in Biochemistry and Medicine, Vol.
Although the drug's efficacy and long-term tolerability are well-documented, it suffers from a number of shortcomings associated with low, efficiency and marginal oral activity.
Unfortunately, both of these cyclic siderophores exhibited unacceptable toxicity, and neither possessed any oral activity.
They was abandoned as there were any number of synthetic chelators with equally unsatisfactory properties from which to choose.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

[0054]2,4-Dihydroxybenzonitrile was prepared according to the method of Marcus in Ber. disch. chem. Ges. 1981, 24, 3651, as follows:

[0055]A mixture of 2,4-dihydroxybenzaldehyde (5.0 g, 36.2 mmol), sodium acetate (5.94 g, 72.4 mmol), nitroethane (5.44 g, 72.4 mmol) and glacial acetic acid (10 ml) was refluxed for 6 hours. After cooling, the mixture was poured onto ice (100 g) and extracted with ethyl acetate (4×50 ml). The combined organic layers were washed with saturated NaHCO3 until the pH of the aqueous layer remained at 8, dried (Na2SO4) and the solvent removed in vacuo. Flash chromatography (SiO2cyclohexane:ethyl acetate=1:1) afforded 2,4-dihydroxybenzonitrile (2.87 g, 59%) as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 6.33 (d, 1H, J=8.6 Hz), 6.43 (s, 1H), 7.37 (d, 1H, J=8.6 Hz), 10.35 (s, 1H), 10.78 (s, 1H), IR (KBc) 2200 cm−1.

example 2

[0056]4,5-Dihydro-2-(2,4-dihydroxyphenyl)-thiazole-4-(S)-carboxylic acid was prepared as follows:

[0057]D-cysteine hydrochloride monohydrate (6.8 g, 38.7 mmol) was added to a solution of 2,4-dihydroxybenzonitrile (3.5 g, 25.9 mmol) prepared in Example 1, in a mixture of degassed methanol (105 ml) and 0,2 To phosphate buffer, pH 5.95 (70 ml). NaHCO3 (3.25 g, 38.7 mmol) was carefully added and the mixture was slimed at 70° C. under Ar for 54 hours. Volatile components were removed under reduced pressure and the solution was acidified with 1 N NCL to pH 2. The resulting brown precipitate was vacuum filtered and the solid was washed with water (40 ml) and ethanol (20 ml). The crude product was dissolved in saturated NaHCO3 (700 ml) and the aqueous solution washed with ethyl acetate (2×200 ml). The aqueous layer was filtered through a fine frit and acidified with 1 N HCI to pH 2. The precipitated product was vacuum filtered. The aqueous layer was extracted with ethyl acetate (4×400 ml), t...

example 3

In Rats

[0060]Initial besting of 1 was performed in the non-iron-overloaded, bile duct-cannulated rat [J. Med. Chem., Vol. 34, Bergeron et al, “Synthesis and Biological Evaluation of Hydroxamate-Based Iron Chelators,” pages 3182-3187 (1991)]. The drug was prepared as a solution in 40% Cremophor-H2O and administered at a dose of 150 μmol / kg p.o. The rats were fasted for 24 hours before dosing. The efficiency of iron excretion induced by 1 was 2.4±0.92%.

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Abstract

Phenyl- and pyridyl-substituted thiazoline acid derivatives useful in diagnosing and treating pathological conditions associated with an excess of trivalent metals in humans and animals.

Description

RELATED APPLICATIONS[0001]This application contains subject matter related in that disclosed and claimed in copending U.S. patent application Ser. No. 08 / 624,289 filed Mar. 29, 1996.[0002]Research leading to the completion of the invention was supported in put by Grant Nos. 3203522-12, RO1HL42817 and RO1DK49108 awarded by the National Institutes of Health (NIH). The United States Government has certain rights in and to the claimed invention.BACKGROUND OF THE INVENTION[0003]1. Field of the Invention[0004]The present invention relates to novel thiazoline acids and derivatives thereof useful as chelators of trivalent metals in therapeutic applications.[0005]2. Discussion of the Prior Art[0006]While many organisms are auxotrophic for Fe (III), because of the insolubility of the hydroxide (Ksf=1×10−38) [Acc. Chem. Res., Vol, 12, Raymond et al, “Coordination Chemistry and Microbial Iron Transport,” pages 183-190 (1979)] formed under physiological conditions nature has developed rather sop...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A61K31/425C07D277/56A61K31/426C07D277/10A61K31/4412A61K31/4433A61K49/00A61K49/04A61K51/00A61P3/00C07D277/12C07D409/04
CPCC07D277/12A61K31/426A61P1/16A61P19/08A61P25/00A61P25/28A61P3/00A61P3/12A61P39/04
Inventor BERGERON, JR., RAYMOND J.
Owner BRITISH TELECOMM PLC
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