Diastereomeric pure trifluoromethyl ketone peptide derivatives a

Details Diastereomeric pure trifluoromethyl ketone peptide derivatives a Diastereomeric pure trifluoromethyl ketone peptide derivatives a

1996-07-25

1998-04-14

Richter, Johann

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

548566, 548569, 548570, 548571, 548574, 548578, A61K 31165, A61K 3140, C07D20709

Patent

active

057391572

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/GB95/00242 filed Feb. 7, 1995.
The present invention relates to pyrrolidine derivatives, and more particularly the compound luoroacetyl)propyl!pyrrolidine-2-carboxamide, shown by the formula I (set out hereinafter) ##STR1## and having the S configuration at the chiral centres identified by the symbols * and #, and solvates thereof, which compound is an inhibitor of human leukocyte elastase (HLE), also known as human neutrophil elastase (HNE), which is of value, for example, as a research tool in pharmacological, diagnostic and related studies and in the treatment of diseases in mammals in which HLE is implicated. For example, HLE has been implicated causally in the pathogenesis of acute respiratory distress syndrome (ARDS), rheumatoid arthritis, atherosclerosis, pulmonary emphysema, and other inflammatory disorders, including airway inflammatory diseases characterized by increased and abnormal airway secretion such as acute and chronic bronchitis and cystic fibrosis. Also, HLE has been causally implicated in certain vascular diseases and related conditions (and their therapy) in which neutrophil participation is involved or implicated, for example, in hemorrhage associated with acute non-lymphocytic leukemia, as well as in reperfusion injury associated with, for example, myocardial ischaemia and related conditions associated with coronary artery disease such as angina and infarction, cerebrovascular ischaemia such as transient ischaemic attack and stroke, peripheral occlusive vascular disease such as intermittent claudication and critical limb ischaemia, venous insufficiency such as venous hypertension, varicose veins and venous ulceration, as well as impaired reperfusion states such as those associated with reconstructive vascular surgery, thrombolysis and angioplasty. The invention also concerns methods of treating one or more of these disease conditions and the use of the compound (or a solvate thereof) in the manufacture of a medicament for use in one or more of said conditions. The invention further concerns pharmaceutical compositions containing the compound, or a solvate thereof, as active ingredient, as well as processes for the manufacture of the compound (or a solvate thereof), novel intermediates useful in said processes and methods for the preparation of said intermediates.
Because of HLE's apparent role, there has been considerable research effort in recent years towards the development of HLE inhibitors. In U.S. Pat. No. 4,910,190 is disclosed a series of structurally related peptidoyl trifluoromethane derivatives which are HLE inhibitors. We have now discovered that the specific, pyrrolidine derivative named above is a potent inhibitor of HLE, possessing a surprising advantage in that it is a single diastereoisomer having a crystalline form. This provides a basis for the present invention. To use an HLE inhibitor which cannot be isolated in a crystalline form as, or in the formulation of, a medicament for treating the disease conditions referred to above, poses significant problems, for example, in the manufacture of the compound or formulation to the purity levels and uniformity required for regulatory approval. It is therefore highly desirable to find a novel crystalline HLE inhibitor and even more desirable to obtain a novel crystalline HLE inhibitor which is a single diastereoisomer. A further advantage of the compound of the invention is that it has been found to possess HLE inhibitory activity when administered orally. Prior to the present invention, the specific pyrrolidine derivative named above had not previously been prepared and therefore nothing was specifically known of its physical, chemical or pharmacological properties.


BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an X-ray powder diffraction spectrum of a typical sample of the SSS diastereoisomer of formula I when it is substantially or essentially free of solvent.
FIG. 2 shows an X-ray powder diffraction spectrum of a typical sample of the SSS diastereoisomer of the formula I when it is

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