Peptide derivative, pharmaceutical preparation containing it and

Details Peptide derivative, pharmaceutical preparation containing it and Peptide derivative, pharmaceutical preparation containing it and

1992-07-20

1995-05-02

Warden, Jill A.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

514 8, 514 9, 514 11, 530330, 530317, 530322, A61K 3700, A61K 3702, C07K 500, C07K 700

Patent

active

054119421

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to hitherto unknown peptide derivatives, a process for the preparation thereof, pharmaceutical preparations containing these derivatives and a method for the treatment of glaucoma.
Glaucoma is a very common eye disease affecting millions of people in the later stages of their life. Glaucoma is characterized by abnormally high intraocular pressure and, if untreated, damage of the optic nerves which may cause narrowing of the visual field, and eventually irreversible blindness.
The intraocular pressure is determined by the rates of inflow and outflow, i.e. the dynamics of the aqueous humor. The aqueous humor enters into the posterior chamber of the eye, and then flows through the pupil to the anterior chamber, from where it eventually leaves the eye through the trabecular meshwork.
The aqueous humor supplies nutrients to the lens and cornea, and its proper supply is thus of the utmost importance to maintain healthy eye.
Any disturbance of aqueous humor dynamics by either excess inflow, or reduced outflow, results in a rise of the intraocular pressure above the normal value (for adults) of 17-20 mm Hg, i.e. the eye becomes hypertensive. A prolonged hypertensive state will result in nerve damage and blindness. Detailed descriptions on glaucoma can be found in "An Outline of Ophthalmology", by R. L. Coakes, and P. J. Holmer Sellars, published by Wright Bristol (1985), cf. pp. 54/57, and in the series: Current Topics in Eye Research", edited by J. A. Zadunaisky and K. Davson, Academic Press.
All known antiglaucoma drugs on the market lower the intraocular pressure, either by decreasing formation of aqueous humor, or by increasing the outflow, i.e. the elimination of aqueous humor from the eye. Glaucoma drugs are thus all hypotensive agents.
The most common class of antiglaucoma agents are adrenergic antagonists; many of them are .beta.-blockers (the most widely used of this type is timolol), adrenergic, agonists, dopaminergic agents, cholinergic agents (the most widely used of this type is pilocarpine), and several other classes of compounds. For detailed overviews, see for example Annual Reports in Medicinal Chemistry, Vol. 20, chapter 9: "Antiglaucoma Agents", by M. F. Sugrue and R. L. Smith (1985, Academic Press), and the text: "The Pharmacological Basis of Therapeutics" by A. Goodman and L. Gilmans.
One of the characteristics of glaucoma drugs is thus the fact that an enormously wide variety of chemical structural types can be used to reduce excessively high intraocular pressure.
None of the currently used drugs is fully satisfactory. There are serious side effects affecting the heart, the kidneys, the lungs and the libido. Furthermore, there are problems of metabolic stability which necessitates several applications of eye drops per day. Great efforts are therefore made to develop new antiglaucema agents which would be free of the above constraints. Recently, an entirely new chemical structural type of compounds, namely peptides and peptide derivatives, was described as having antiglaucoma acitivity, i.e. as hypotensive agents. Examples are carboxyal aldipeptides (European Patent No. 0088350) and the atrial natriuretic factor, a long peptide of 29 amino acids in length (Fortschritte der Ophthalmologie, Volume 89, pp. 89/91 (1989)).
Furthermore, hydrolysates of milkproteins were also described as having antiglaucoma activity (WO 86/04217).
The present invention describes hitherto unknown synthetic peptides consisting of up to 5 amino acids, and derivatives thereof, which lowers the intraocular pressure in a relevant animal model.
The present invention thus concerns a peptide derivative having the general formula linear dimer thereof, desamino-derivative thereof, which optionally is mono- or disubstituted on the nitrogen of the amide side chain with straight, branched, cyclic, substituted or unsubstituted alkyl, aralkyl or aryl, all of which are optionally mono- or polysubstituted with halogen, nitro, amino, sulfo, phospho or carboxyl, and each aralkyl- and arylsubstituent may fu

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