Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2001-06-04
2003-03-11
Qazi, Sabiha (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S172000, C514S174000, C514S175000, C514S178000
Reexamination Certificate
active
06531461
ABSTRACT:
TECHNICAL FIELD
The present invention relates to compounds for use as medicaments in the treatment of diabetes.
PRIOR ART
Diabetes is a potentially life threatening condition in mammals brought about by an inability of the mammals to produce insulin. Insulin, a polypeptide hormone produced in the pancreas of the mammal, controls the amounts of glucose present in the blood by stimulating the uptake of glucose by the muscle and adipose tissue.
The production of insulin is ultimately controlled by the brain. Biosynthesised insulin has been the drug of choice for the treatment of diabetes mellitus or hyperglycemia (the term imparted to an excess of glucose in the blood), for many years. Biosynthesised insulin is manufactured by recombinant DNA technology at a high cost.
The administration of biosynthesised insulin to the patient occurs via injection directly into the muscle, since it is partially digested if administered orally. This administration method further elevates costs due to the requirement for needles and furthermore, increases the likelihood of infection and/or contamination.
More recently thiazolidine derivatives, as described in U.S. Pat. No. 4,387,101, have been introduced for the treatment of hyperglycemia. However, there are some concerns relating to the toxicity of these derivatives.
WO9857636 teaches of an oral antidiabetic agent, rosiglitazone maleate which when administrated in conjunction with insulin acts primarily by increasing insulin sensitivity.
None of the aforementioned methods of treatment offer any remission for diabetes. The present invention has been made from a consideration of this problem.
According to the present invention there is provided a compound for use as a medicament, having general structure ‘A’, and metal salts thereof;
wherein R, R
1
, R
2
, R
3
and R
4
are any of the following combinations.
TABLE 1
N.B Z denotes the point at which substituent R
4
couples to general
structure ‘A’.
R
R
1
R
2
R
3
R
4
H or 3-o-&bgr;-
H or alkyl
H or alkyl
H or alkyl
Substituent I,
D-Gluco-
(C
1
—C
4
) or
(C
1
—C
4
)
(C
1
—C
4
)
Substituent II,
pyranoside
—OCOCH
3
Substituent III,
Substituent IV or
Substituent V.
and wherein substituents I, II, III, IV and V and are as shown below:
DISCLOSURE OF INVENTION
It has been found that the compounds of the present invention, as isolated from the leaf of the common
Vernonia amygdalina
plant and having the general structure ‘A’, as identified in G. Igile et al., J. Nat. Prod., 1995, 58, 1438, R. Sanogo et al., Phytochemistry, 1998, 47, 73, M. Jisalca et al., Phytochemistry, 1993, 34, 409 and D. Ponglux et al., Chem. Pharm. Bull., 1992, 40, 553 are particularly useful for the treatment of hyperglycemia.
In general structure ‘A’, a number of sites are capable of substitution and modification. For example R
1
may be H or alkyl and R
4
may be a heterocyclic enone or a fused difuran system, as detailed hereinafter.
It has been found that the compounds of the present invention having general structure ‘A’ where R=H, R
1
=H, R
2
=Me, R
3
=Me and R
4
=substituent III in which R
7
=OH and R
6
=Me, or substituent I in which R
5
=OH, or substituent IV in which R
8
=Me or substituent II or substituent V in which R
9
H and R
10
=Me exemplified in table 1, are highly effective in the treatment of hyperglycemia.
Furthermore, the compounds of the present invention may bring about cell regeneration as trials involving hyperglycemic mammals have resulted in the restoration of complete insulin activity within six months.
It is thought that these compounds enhance insulin sensitisation and may even replace insulin whist initiating beta cell regeneration.
Advantageously, the compounds of the present invention exhibit no known toxicity when administered to either hyperglycemic or non-hyperglycemic mammals.
The compounds of the present invention may be used in the management of type I and type II diabetes mellitus.
The compounds of the present invention may be in the form of one or more cationic salts, for example sodium, potassium, lithium. The compounds may also be in the form of a hydrate or solvate.
The compounds of the present invention may be conveniently isolated and purified using conventional separation—purification, such as solvent extraction, phasic transfer or redistribution, concentration, concentration under reduced pressure, crystallisation, chromatography and recrystallisation.
Furthermore, since the compounds of the present invention are derived from the common
Vernonia amygdalina
plant, they are easily and cost effectively obtained, particularly when compared with the compounds of the prior art.
The compounds of the present invention may be administered by any convenient parenteral route.
Preferably, the compounds of the present invention will be administered orally. The dose may be varied depending upon the patient, but will generally be 100 mg, three times daily.
According to a second aspect of the present invention there is provided a pharmaceutical composition which may find utility in the treatment of hyperglycemia in mammals comprising a therapeutic amount of any of the compounds of the present invention and a pharmaceutically acceptable carrier excipient or diluent for example a sodium salt, glucose syrup, sugar solution, alcohol solution, CMC or starch.
According to a third aspect of the present invention there is provided a method for the treatment of hyperglycemia in mammals which utilises any of the compounds of the present invention.
REFERENCES:
patent: 4387101 (1983-06-01), Kawamatsu et al.
patent: 9507694 (1995-03-01), None
patent: WO 98/57636 (1998-12-01), None
Schmittamann et al. (DN 121:153368, HCAPLUS, abstract of J. Prakt. Chem./Chem.-Ztg. (1994), 336,(3), 225-32).*
Ohigashi, Masanori et al. (DN 121:270, abstract of J. Chem. Ecol. (1994), 20(3), 541-53).
Barlow Josephs & Holmes, Ltd.
Qazi Sabiha
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