Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-07-14
2002-06-18
Peselev, Elli (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S456000, C514S457000
Reexamination Certificate
active
06407073
ABSTRACT:
This Application is a 371 of PCT/GB98/03169 filed Oct. 22, 1998.
The present invention relates to coumarin derivatives, particularly hymecromone, to pharmaceutical compositions containing them and to their use in the treatment of disorders of the liver, kidney, pancreas, bladder and gastro-intestinal tract.
The liver is a complex organ with many diverse functions. It is the central organ of metabolism of carbohydrates, proteins, and fat. It stores glycogen and takes part in regulating blood sugar, and stores other essential substances such as vitamins and factors concerned in haemopoiesis. It synthesises fibrinogen, prothrombin, heparin, and plasma proteins, and is a site of destruction of deteriorated red blood cells. It is also the chief detoxicating organ of the body rendering unwanted substances innocuous.
Viral hepatitis refers to infection of the liver caused by a group of hepatitis viruses. Those so far identified are designated A, B, C, D and E. Other viruses such as Epstein-Barr virus and yellow fever virus may be secondary causes of hepatitis and nonviral infections, drugs, chemicals and alcoholism may also cause hepatitis. One of the main treatments for the various viral hepatitis infections is alpha or beta interferon, but in many cases it is not particularly effective. Other drugs that may produce a therapeutic response include lamivudine, ursodeoxycholic acid and vidarabine.
Primary biliary cirrhosis is a chronic liver disease of unknown aetiology, which develops due to progressive destruction of small and intermediate bile ducts within the liver, subsequently evolving to fibrosis and cirrhosis. Over 90% of patients are female, usually aged between 40 and 60 years. The disease is thought to be autoimmune in nature, perhaps triggered by a micro-organism in the environment and most patients exhibit autoantibodies to mitochondria. The disease is slowly progressive but no specific treatment is available.
Wilson's disease is due to an inborn error of liver metabolism leading to the accumulation of toxic concentrations of copper. Gilbert's syndrome is an inherited disorder that affects the way bilirubin is handled by the liver. Symptoms include mild jaundice, fatigue and abdominal pain. Again in both Wilson's disease and Gilbert's syndrome, there is no real effective treatment.
Accordingly there is a constant need for new compounds to treat the various liver disorders.
The inventor has now found that certain organic compounds (including naturally occurring extracts are effective in the treatment of various liver and other disorders.
Accordingly in a first aspect of the invention there is provided use of a compound of the Formula 2:
wherein:
W is H or a &bgr;-D-glucopyranosyloxy group,
X is OH, and
Y and Z are independently H, C
1-6
alkyl, or C
1-6
alkoxy and pharmacologically acceptable derivatives thereof in the manufacture of a medicament for the treatment or prophylaxis of a disease selected from liver, kidney, pancreatic, bladder, and gastro-intestinal disorders and disorders treatable by reducing the concentration or activity of transaminase enzymes, said disease not being treatable with a choleretic or biliary antispasmodic agent.
Preferably Z is methyl.
Examples of known compounds covered by Formula 2 are. as follows: fraxin (7,8-dihydroxy-6-methoxycoumarin-8-&bgr;-D-glucoside), umbelliferone (7-hydroxycoumarin), skimmin (7-(glucosyloxy)coumarin), and hymecromone (7-hydroxy-4-methylcoumarin).
All compounds of Formula 2 are hereinafter referred to as “compounds of the invention”.
The compound that the inventor has done most work on and which has been found to be particularly effective is hymecromone (CAS Registry no. 90-33-5).
Although hymecromone is primarily used for the fluorometric determination of enzyme activity (Clin. Chim. Acta., 39,49 (1972); Anal. Biochem., 54,40 (1973)) it is also known as a choleretic (agent which aids the excretion of bile) and a biliary antispasmodic, and has been administered in doses of 300 mg-400 mg. (The Merck Index, 12th Edition, 4903 and Martindale, The Extra Pharmacopoeia, 31st Edition p1715). A more soluble form of hymecromone is disclosed in EP-A-0240874, and tablets of hymecromone for improving the excretion of bile are known from U.S. Pat. No. 3,175,943. The choleretic and biliary antispasmodic activity of hymecromone also is referred to in Petrioli (Fortschr. Med. 1979 Jul. 5; 97 (25-26):1174-8) and U.S. Pat. No. 4,241,047.
Hymecromone is commercially available from ABCR GmbH & Co Kg (Karlsruhe, Germany, Acros organics (Geel, Belgium), Loba Feinchemie AG (Fischamend, Austria), Sigma-Aldrich Fine Chemicals (Poole, Dorset, UK). Hymecromone is also available as a natural occurring extract of Manna Ash known as Fraxin.
By pharmacologically acceptable derivatives of the compounds of Formula 2, it is meant to include prodrugs, salts, solvates, esters, ethers, amides, glycosylated derivatives, and including methylated, aminated and acetylated derivatives.
By prodrug is meant any compound, which is capable of being metabolised in vivo to give a compound of Formula 1.
By salt it is meant to include pharmaceutically acceptable salts derived from an appropriate base such as alkali metal salts (e.g. sodium or potassium), alkaline earth metals (e.g. magnesium or calcium), ammonium and NX
4
(wherein X is C
1-4
alkyl), or salzs of a hydrogen atom including salts formed from organic and inorganic acids such as those formed from hydrochloric, hydrobromic, sulphuric, citric, tartaric, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, succinic, oxalic, fumaric, maleic, xaloacetic, methanesulphonic, ethanesulphonic, &rgr;-toluenesulphonic, benzenesulphonic and isethionic acids.
The compounds of the invention, particularly hymecromone, have hepatoprotective and/or hepatoregenerative properties. Liver disorders which can be treated comprise hepatitis including infective hepatitis (e.g. viral hepatitis of types A, B, C, D and E), chronic active hepatitis, acute infective hepatitis, toxic hepatitis (e.g. as caused by drugs and narcotics X-rays, solvents, chemotherapy, and alcohol abuse), steatosis hepatitis, acute parenchymatous hepatitis, amoebic hepatitis, cytomegalic hepatitis, enzootic hepatitis, familial hepatitis, homologous serum hepatitis, intestitial hepatitis, suppurative hepatitis, and trophopathic hepatitis. Various cirrhosis of the liver conditions which can be treated include primary and secondary biliary cirrhosis, alcoholic cirrhosis, annular cirrhosis, atrophic cirrhosis, bacterial cirrhosis, capsular cirrhosis, cardiac cirrhosis, fatty cirrhosis lymphatic cirrhosis and pigmentary cirrhosis. Yet further liver disorders against which the compounds of the invention are effective are Wilson's disease and Gilbert's svndrome.
The compounds of the invention are particularly effective in protecting the liver from the toxic effects of anabolic steroids, alcohol, chemotherapy, solvents, drugs, and environmental pollution.
Early investigations also suggest that compounds of the invention such as hymecromone will also be effective in the treatment or prophylaxis of disorders of the kidney (e.g. cirrhosis of the kidney), pancreas (e.g. pancreatitis), bladder and castrointestinal tract (e.g. cirrhosis of the stomach).
The invention can also be used to rejuvenate healthy people, especially those ex posed to heavy physical labour, the elderly a nd otherwis e healthy people recovering from illness, and sportsmen (especially those using anabolic steroids).
Without being bound by theory, it is thought that the corpounds of the invention are at least partly effective by reducing the concentration or activity in the peripheral blo od of transaminase enzymes, such as serum glutamic oxaloacetic transaminase (SGOT) or aspartate aminotransferase (AST), serum glutamic pyruvic transaminase (SGPT) or alanine transaminase (ALT), and gamma glutamyl traospe)tidase (GGT).
The invention also provides a composition comprising a compound of Formula 2 in combination with one or more of bee pollen, matricaria camomile, asper
Trkovnik Miroslav
Trkovnik Mladen
Bio-Monde Preparations Limited
Jones,Tullar & Cooper. P.C.
Peselev Elli
LandOfFree
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