Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1999-06-14
2000-10-17
Henley, III, Raymond
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
A61K 31535
Patent
active
061332674
DESCRIPTION:
BRIEF SUMMARY
This invention relates to a method of inhibiting the formation of advanced glycosylation end-products.
According to the present invention there is provided a method of inhibiting the formation of advanced glycosylation end-products comprising administering, to a human in need thereof, a therapeutically effective amount of a compound of formula I ##STR2## including pharmaceutically acceptable salts thereof, in which R.sub.1 and R.sub.2 are independently H or methyl, in conjunction with a pharmaceutically acceptable diluent or carrier.
Compounds of formula I may exist as salts with pharmaceutically acceptable acids. Examples of such salts include hydrochlorides, hydrobromides, sulphates, methanesulphonates, nitrates, maleates, acetates, citrates, fumarates, tartrates [e.g. (+)-tartrates, (-)-tartrates or mixtures thereof including racemic mixtures], succinates, benzoates and salts with amino acids such as glutamic acid. Compounds of formula I and their salts may exist in the form of solvates (for example hydrates).
Certain compounds of formula I and their salts may exist in more than one crystal form and the present invention includes each crystal form and mixtures thereof. Certain compounds of formula I and their salts may also exist in the form of solvates, for example hydrates, and the present invention includes each solvate and mixtures thereof.
A preferred compound of formula I is 1,1-dimethyl-2(2-morpholinophenyl)guanidine or a salt thereof, preferably the fumarate salt.
The preparation and use of compounds of formula 1, such as 1,1-dimethyl-2(2-morpholinophenyl)guanidine and salts thereof, as hypoglycaemic agents is described in British Patent Specification 2226562. This document discloses data which supports the utility of compounds of formula I in the treatment of hyperglycaemia.
Advanced glycosylation end-products (AGEs) are precursors of protein crosslinking. The formation of AGEs occurs at an accelerated rate in people with elevated blood glucose levels, such as people with impaired glucose tolerance, insulin dependent diabetes mellitus or non-insulin dependent diabetes mellitus. This accelerated rate is due to chronic hyperglycaemia. The accumulation of AGEs contributes to the long-term complications associated with diabetes, such as atherosclerosis, nephropathy, neuropathy and retinopathy. It is therefore desirable to prevent accelerated AGE formation in such people.
Surprisingly, it has now been found that compounds of formula I inhibit the formation of AGEs and therefore have utility in the prophylaxis and treatment of long-term complications associated with diabetes, such as atherosclerosis, nephropathy, neuropathy and retinopathy.
The present invention therefore provides a method of treatment and/or prophylaxis of long-term complications associated with diabetes, such as atherosclerosis, nephropathy, neuropathy and retinopathy, in which a therapeutically effective amount of a compound of formula I ##STR3## including pharmaceutically acceptable salts thereof, in which R.sub.1 and R.sub.2 are independently H or methyl, is administered in conjunction with a pharmaceutically acceptable diluent or carrier to a human in need thereof.
The compound of formula I may be administered in any of the known pharmaceutical dosage forms. The amount of the compound to be administered will depend on a number of factors including the age of the patient, the severity of the condition and the past medical history of the patient and always lies within the sound discretion of the administering physician but it is generally envisaged that the dosage of the compound to be administered will be in the range 10 mg to 3 g, preferably 100 mg to 1 g of free base equivalents per day given in one or more doses.
Oral dosage forms are the preferred compositions for use in the present invention and these are the known pharmaceutical forms for such administration, for example tablets, capsules, granules, syrups and aqueous or oil suspensions. The excipients used in the preparation of these compositions are the excipients known
REFERENCES:
Richard Bucala, Diabetes Res. Clin. Prac., vol. 30, supp. 1996, pp. S123-S130.
Jones Robert Brian
Simpson Annemarie Elizabeth Claire Merryman
Henley III Raymond
Knoll Aktiengesellschaft
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