Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1987-08-17
1989-07-25
Phillips, Delbert R.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
530331, A61K 3702, C07K 508
Patent
active
048513881
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to certain novel acyltripeptides useful as antiinfective agents and immunomodulators for stimulation of host defenses in patients with an increased risk of bacterial infection, to intermediates therefor and to a process for making said acyltripeptides.
2. Description of the Prior Art
The relatively new field of immunopharmacology, and particularly that segment thereof which deals with immunomodulation, continues to develop at a rapid pace. A variety of naturally occurring compounds has been investigated, including the tetrapeptide tuftsin, known chemically as N.sup.2 -[1-(N.sup.2 -L-threonyl-L-lysyl)-L-prolyl]-L-arginine. Much attention has been directed to synthetic peptidoglycan derivatives, especially those known as muramyl dipeptides. For summaries of the wide range of compounds investigated as immunomodulators, and especially as immunostimulants, attention is directed to Dukar et al., Annu. Rep. Med. Chem., 14, 146-167 (1979), Lederer, J. Med. Chem., 23, 819-825 (1980) and to J. Kralovec, Drugs of the Future, 8, 615-638 (1983).
Immunostimulant peptides have been described in a number of patent specifications: 3,024,355, published Jan. 15, 1981; L-alanyl-D-glutamyl moieties in Brit. Pat. No. 2,053,231, published Feb. 4, 1981 and German Pat. No. 3,024,281, published Jan. 8, 1981, respectively; and C-terminal amino acid is lysine or diaminopimelic acid in Ger. Pat. No. 3,024,369, published Jan. 15, 1981; and and carboxymethylamino components in EP-11283, published May 28, 1980.
Further immunostimulant polypeptides having the formula (A) ##STR1## wherein R.sup.1 is hydrogen or acyl; R.sup.2 is inter alia hydrogen, lower alkyl, hydroxymethyl, benzyl; R.sup.3 and R.sup.4 are each hydrogen, carboxy, --CONR.sup.7 R.sup.8 wherein R.sup.7 is hydrogen, lower alkyl optionally substituted with hydroxy; and R.sup.8 is mono- or dicarboxy lower alkyl; R.sup.5 is hydrogen or carboxy with the proviso that when one of R.sup.4 and R.sup.5 is hydrogen, the other is carboxy or --CONR.sup.7 R.sup.8 ; R.sup.6 is hydrogen; m is 1 to 3 and n is 0 to 2, and derivatives thereof in which the carboxy and amino groups are protected are disclosed in U.S. Pat. Nos. 4,311,640 and 4,322,341; EP applications Nos. 25,482; 50,856; 51,812; 53,388; 55,846 and 57,419.
Kitaura et al., J. Med. Chem., 25, 335-337 (1982) report N.sup.2 -(gamma-D-glutamyl)-meso-2(L),2'(D)-diaminopinemic acid as the minimal structure capable of eliciting a biological response characteristic of the compound of formula (A) wherein n is 1; R.sup.1 is CH.sub.3 CH(OH)--CO--; R.sup.2 is CH.sub.3 ; each of R.sup.3 and R.sup.5 is --COOH; R.sup.4 is --CONHCH.sub.2 COOH; and R.sup.6 is H. Said compound of formula (A) is known as FK-156.
SUMMARY OF THE INVENTION
It has now been found that compounds of formula (I) wherein each of Y, Z, R.sup.1 and R.sup.2 is hydrogen are efficient immunomodulators. ##STR2## wherein R.sup.1 is hydrogen or benzyl; R.sup.2 is hydrogen or methyl; R.sup.3 is ##STR3## wherein Z is hydrogen; and Y is hydrogen and pharmaceutically acceptable salts of those compounds wherein at least one of Y, Z, R.sup.1 or R.sup.2 is hydrogen. Formula (I) compounds wherein at least one of Y, Z, R.sup.1 and R.sup.2 is other than hydrogen are intermediates for those compounds wherein Y, Z, R.sup.1 and R.sup.2 are hydrogen.
Also included in this invention are certain other compounds useful as intermediates for production of compounds of formula (I). The intermediates have formulae (II) and (III): ##STR4## wherein X is hydrogen or tert-butyl; and ##STR5## wherein Z is hydrogen or carbobenzyloxy.
The configuration of the amino acid moieties which make up the formula (I) compounds is significant as regards the pharmacological activity of said compounds. The most potent activity is observed in formula (I) compounds having the stereochemistry indicated in said formula. The stereochemistry, relative to that of the natural amino acid, is designated as D- or L-.
Also included in this invention are
REFERENCES:
patent: 4354966 (1982-10-01), Kitaura
patent: 4394308 (1983-07-01), Sampathkumar
patent: 4399066 (1983-08-01), Nakaguchi
Chem. Pharm. Bull. 17, 1679-1686 (1969), "Peptides. I. Selective Protection of Alpha- or Side-Chain Carboxyl Groups of Aspartic and Glutamic Acid."
Kitaura, J. Med. Chem. 25,335-337 (1982).
Akers Lawrence C.
Frost Albert E.
Pfizer Inc.
Phillips Delbert R.
Richardson Peter C.
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