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Compounds having reversible inhibiting activity of carnitine palmitoyl-transferase

a technology of carnitine palmitoyltransferase and compound, which is applied in the direction of phosphorous compound active ingredients, drug compositions, metabolic disorders, etc., can solve the problem that none of the therapies currently used in the clinic is fully satisfying

Inactive Publication Date: 2002-05-02
SIGMA TAU IND FARMACEUTICHE RIUNITE SPA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

None of the therapies presently used in clinic is fully satisfying, in particular due to the onset of unwanted side effects, such as severe hypoglycaemia, allergic phenomena, oedema, diarrhoea, intestinal disturbances, kidney toxicity, etc.

Method used

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  • Compounds having reversible inhibiting activity of carnitine palmitoyl-transferase
  • Compounds having reversible inhibiting activity of carnitine palmitoyl-transferase
  • Compounds having reversible inhibiting activity of carnitine palmitoyl-transferase

Examples

Experimental program
Comparison scheme
Effect test

example 1

R,S-4-trimethylammonium-3-(nonylcarbamoyl)-aminobutyrate (ST 1251)

Nonyl Isocyanate

[0105] A solution of decanoyl chloride (20 g, 104.8 mmoles) in acetone (30 ml) was dropped into a solution of sodium azide (9.53 g, 146.6 mmoles) in water (30 ml), cooled in an ice bath. The temperature of the azide solution was kept between 10 and 15.degree. C. after one hour, the solution was transferred in a separatory funnel and the lower phase (the aqueous one) was eliminated. The higher phase was transferred into a flask containing 100 ml of toluene, previously warmed at 65.degree. C. After 1.5 hours, the solution was evaporated to dryness, giving 13.37 g crude product, which after vacuum distillation gave 8.3 g pure product in the form of colorless liquid.

[0106] Yield 47%.

[0107] .sup.1H-NMR (300 MHz; CDCl.sub.3):

[0108] .delta.: 3.3 (t, 2H), 1.6 (m, 2H), 1.45-1.2 (m, 12H), 0.9(brt, 3H).

R,S-4-trimethylammonium-3-(nonylcarbamoyl)-aminobutyrate

[0109] Nonyl isocyanate (15.42 g, 91.12 mmoles) was adde...

example 2

R,S-4-quinuclidinium-3-(tetradecyloxycarbonyl)-oxybutyrate (ST 1265)

ter-Butyl R,S-4-guinuclidinium-3-hydroxybutyrate iodide

[0120] Quinuclidine (2.40 g, 21.60 mmoles) was added to ter-Butyl R,S-4-iodo-3-hydroxybutyrate (6.18 g, 21.60mmoles) in acetonitrile (60 ml) and the solution was warmed to 60.degree. C. for 20 hours under stirring. After evaporation of the solvent, the residue was dissolved in acetonitrile and precipitated with ethyl ether several times to give 7.2 g of product, contaminated with about 13% by weight of quinuclidine iodide (as from NMR). After repeated crystallization from CH.sub.3CN / Et.sub.2O, 4.3 g of pure product were obtained.

[0121] Yield 50%.

[0122] M.p.: 124-127.degree. C.

[0123] .sup.1H-NMR (300 MHz; D.sub.2O):

[0124] .delta.: 4.50 (m, 1H), 3.40 (m, 2H), 2.42 (m, 2H), 2.08 (m, 1H), 1.88 (m, 6H), 1.34 (m, 9H).

[0125] FAB Mass=270, [M.sup.+].

[0126] Elemental analysis: responding to the expected formula

[0127] C.sub.15H.sub.28 INO.sub.3.

[0128] K.F.=0.5% water.

[012...

example 3

R,S-4-trimethylammonium-3-(nonylcarbamoyl)-oxybutyrate (ST 1298)

Benzyl ester of R,S-4-trimethylammonium-3-(nonylcarbamoyl)-oxybutyric acid Perchlorate

[0154] Nonyl isocyanate (7.39 g, 43.36 mmoles) was added to a solution of R,S-carnitine perchlorate, benzyl ester (7.69 g, 21.86 mmoles) in toluene (100 ml) and the solution was refluxed for 5 days under stirring. Nonyl isocyanate (1.84 g, 10.86 mmoles) was further added and the reaction mixture was left under reflux for other 5 days. The solvent was vacuum-evaporated and the residue was washed with ethyl ether and subsequently taken up with chloroform, washed with water and dried over anhydrous sodium sulfate. The oil resulting from the evaporation of the organic phase was purified through flash-chromatography column, using a gradient CHCl.sub.3 to CHCl.sub.3: MeOH 95:5. 4.4 g product were obtained in the form of a thick oil.

[0155] Yield 38.6%.

[0156] .sup.1H-NMR (200 MHz; CDCl.sub.3):

[0157] .delta.: 7.3 (s, 5H), 5.4 (m, 2H), 5.05 (m, ...

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Abstract

Compounds of formula (I) wherein the groups are as defined in the description are disclosed. The compounds of formula (I) are endowed with reversible inhibiting activity of carnitine palmitoyl-transferase and are useful in the preparation of medicaments useful in the pathologies related to a hyperactivity of carnitine palmitoyl-transferase, such as hyperglycemia, diabetes and pathologies related thereto, heart failure, ischemia.

Description

[0001] The present invention relates to compounds having inhibiting activity against carnitine palmitoyl transferase. The present invention relates also to pharmaceutical compositions containing at least one of these compounds active ingredients and to the use of said compounds in the preparation of medicaments useful in the treatment of pathologies related to a hyperactivity of carnitine palmitoyl-transferase, in particular hyperglycaemic states, such as diabetes and related pathologies and of congestive heart failure.[0002] To date, hypoglycaemic therapy is based on the use of drugs having different mechanism of action (Arch. Intern. Med., 1997, 157, 1802-1817).[0003] Insulin and its analogues represent the most used therapy, recurring to the direct hypoglycaemic action of this hormone.[0004] Other compounds act indirectly by stimulating insulin release (sulphonylureas). A different target of hypoglycaemic drugs is represented by the reduction of glucose intestinal absorption thro...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/195A61K31/197A61K31/41A61K31/66A61P3/04A61P3/06A61P3/10A61P9/10A61P43/00C07C229/22C07C229/26C07C271/12C07C271/22C07C275/16C07C307/06C07C311/06C07C311/13C07C335/08C07D257/04C07D295/15C07D453/02C07F9/38C07F9/54C07F9/576C07F9/58C07F9/6561
CPCC07C229/22C07C229/26C07C271/12C07C271/22C07C275/16C07F9/5407C07C335/08C07D257/04C07D295/15C07D453/02C07C311/06A61P3/04A61P3/06A61P43/00A61P9/10A61P3/10
Inventor GIANNESSI, FABIOMARZI, MAUROMINETTI, PATRIZIADE ANGELIS, FRANCESCOTINTI, MARIA ORNELLACHIODI, PIEROARDUINI, ARDUINO
Owner SIGMA TAU IND FARMACEUTICHE RIUNITE SPA
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