Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Tripeptides – e.g. – tripeptide thyroliberin – etc.
Patent
1985-12-06
1987-09-01
Kight, John
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Tripeptides, e.g., tripeptide thyroliberin , etc.
530345, 548537, 548540, 548567, 548568, 548571, 548574, C07C10352, A61K 3702, C07D20700
Patent
active
046910077
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention comprises certain proline derivatives which are useful as human leukocyte elastase inhibitors, e.g. in the treatment of tissue degenerative diseases such as pulmonary emphysema, atherosclerosis, rheumatoid and osteo arthritis in humans, methods for their use, processes used for their synthesis, intermediates useful in such syntheses and pharmaceutical compositions prepared with such derivatives.
2. Description of the Prior Art
Peptide aldehyde inhibitors of both porcine pancreatic elastase (PPE) and human leukocyte elastase (HLE) have been previously reported. For example, Thompson, Biochemistry, 1973, vol. 12, pages 47-51 has described the synthesis of two peptide aldehyde inhibitors of porcine pancreatic elastase. One of these was N-acetyl-L-alanyl-L-prolyl-L-alaninal.
Szabo et al., Acta Biochimica et Biophysica Academiae Scientiarum Hungaricae, 1982, vol. 17 (1-2), page 98, reports the synthesis of five peptide aldehyde compounds, all of which proved to be inhibitors for pancreatic elastase and human leukocyte elastase. The most potent HLE inhibitor reported was N-succinyl-D-phenylalanyl-L-prolyl-L-valinal; this compound produced 10-100 times stronger inhibition (K.sub.i =4.times.10.sup.-5) than the other four aldehydes.
Although various peptide aldehydes have been reported in the literature, none has been found to be clinically useful in the treatment of any tissue degenerative disease to date.
It is generally accepted that proteolysis of lung elastin by elastases, such as human leukocyte elastase (HLE) and cathespin G, which are released from the granular fraction of polymorphonuclear leukocytes, is responsible for a major part of the tissue degradation seen in pulmonary emphysema. It is also believed that elastases are similarly involved in the initiation and progression of various other tissue degenerative diseases, such as atherosclerosis, osteo-arthritis and rheumatoid arthritis. Accordingly, the potent elastase inhibitors of this invention may be used in the treatment and/or prevention of any one or more of the above mentioned diseases. They may also be used as research tools in pharmacological and related studies.
SUMMARY OF THE INVENTION
The proline derivatives of the invention are of the following formulas (I), (II) or (III): ##STR2## wherein
R.sup.1, R.sup.5 and R.sup.9 are lower alkyl groups containing from 3 to 6 carbon atoms;
R.sup.2, R.sup.3, R.sup.6, R.sup.7 and R.sup.10 are alkyl groups of 1 to 10 carbon atoms which may optionally be substituted by a monocyclic aryl group or by an amide, urea or carbamate group via the nitrogen thereof;
R.sup.4 and R.sup.11 are lower alkyl, substituted lower alkyl, lower alkoxy or substituted lower alkoxy groups wherein the alkyl or alkoxy contains 1 to 6 carbon atoms, or monocyclic or bicyclic aryl groups; and
R.sup.8 is hydroxy, a lower alkoxy group containing 1 to 6 carbon atoms, or an aralkoxy group containing 7 to 12 carbon atoms; --CHR.sup.10 -- and the proline group are of the L-configuration; or a pharmaceutically-acceptable acid- or base-addition salt thereof or an equilibrium addition compound of the aldehyde group thereof.
The compounds of this invention of the formulas (I), (II) and (III) are highly potent, reversible, selective, competitive inhibitors of human leukocyte elastase (HLE). These compounds are up to 40,000 times more potent than the most potent aldehyde HLE inhibitors described in the prior art; see Szabo et al. cited above in this regard, and are useful in the treatment and/or prevention of tissue-degenerative diseases such as emphysema, atherosclerosis, osteo-arthritis and rheumatoid arthritis.
Also part of the present invention are processes for preparing compounds of the formula (I), (II) or (III); pharmaceutical compositions containing one or more compounds of the formula (I), (II) or (III) and a pharmaceutically acceptable diluent or carrier; methods for the treatment of pulmonary emphysema, atherosclerosis or osteo- or rheumatoid arthritis in
REFERENCES:
patent: 3867364 (1975-02-01), UMeazwa et al.
patent: 4316889 (1982-02-01), Bajusz et al.
Thompson, Biochemistry, vol. 12, No. 1, pp. 47-51 "Use of Peptide Aldehydes to Generate Transition-State Analogs of Elastase".
Thompson, Methods in Enzymology, (19) pp. 220-225 (1977) "Peptide Aldehydes: Potent Inhibitors of Serine and Cysteine Proteases".
Mancuso et al., J. Org. Chem., vol. 43, No. 12, pp. 2480-2482, 1978, "Oxidation of Long-Chain and Related Alcohols to Carbonyls by Dimethyl Sulfoxide Activated by Oxalyl Chloride".
Mancuso et al., J. Org. Chem., vol. 44, No. 23, pp. 4148-4150, 1979 "Structure of the Dimethyl Sulfoxide-Oxalyl Chloride Reaction Product, Oxidations of Heteroaromatic and Diverse Alcoholds to Carbonyl Compounds".
Unlisted Drugs, vol. 34, 1982, p. 136-d; "GYKI 14166"; Folia Haematol 109(1):22, Jan. 82; Unlisted Drugs 33: 129f/, Aug. 81.
Chemical Abstracts, vol. 86, 1977, p. 511, Abstract No. 5859x, Columbus, Ohio, U.S.; & HU-A-12 214 (Gyogyszerkutato Intezet) 09-28-1976.
Chemical Abstracts, vol. 85, 1976, p. 235, Abstract No. 105947x, Columbus, Ohio, U.S.; S. Bajusz et al.: "Peptide Aldehyde Inhibitors of the Fibrinogenthrombin Reaction", & Pept. Chem., Sruct. Biol. Proc. Am. Pept. Symp. 4th 1975, 603-8.
Chemical Abstracts, vol. 87, 1977, p. 278, Abstract No. 196211h, Columbus, Ohio, U.S.; R. C. Thompson: "Peptide Aldehydes: Potent Inhibitors of Serine and Cysteine Proteases", & Methods Enzymol. 1977, 46(Affinity Labeling), 220-5.
Chemical Abstracts, vol. 97, 1982, p. 339, Abstract No. 19651n, Columbus, Ohio, U.S.; S. Bajusz et al.: "Structure-Activity Relationships Among the Tripeptide Aldehyde Inhibitors of Plasmin and Thrombin", & Pept.: Synth., Struct., Funct. Proc., AM. Pept. Symp., 7th 1981, 417-20.
Dutta Anand S.
Stein Ross L.
Trainor Diane A.
Wildonger Richard A.
ICI Americas Inc.
Imperial Chemical Industries plc
Kight John
Miano Rosemary M.
Nutter Nathan M.
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