Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1988-06-17
1991-01-22
Springer, David B.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 16, 514 17, 514 18, 530328, 530329, 530330, C07K 510, C07K 706, A61K 3702
Patent
active
049871226
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to novel peptides having a stimulatory effect on haemopoiesis and to a process for their preparation.
The bone marrow cells derive from pluripotent stem cells which mature to form a complex population of morphologically distinct cells, namely megakaryocytes, erythrocytes, granulocytes and lymphocytes. Only about 10% of the stem cells are in cell division at any time. In an initial phase of maturation each of the proliferating stem cells becomes "committed" to a particular morphologically distinct form eventually leading to one of the above four mature cell types. As the cells proliferate they gradually lose the power of further proliferation and the mature cells, for example, erythrocytes or granulocytes, can no longer divide. Consequently, since the mature cells are continually dying, it is essential that the proliferative ability of the less mature cells, and in particular the stem cells committed for myelopoesis, is maintained.
We have now found a group of novel peptides which are capable of stimulating the proliferation of myelopoietic stem cells.
According to the present invention, therefore, we provide compounds of the formula (I): ##STR1## wherein all amino acid units are in the L-configuration, A represents ##STR2## or a hydrogen atom; B represents ##STR3## or a hydroxy group; n and m independently represent the integers 1 or 2; a and b independently represent the integers 0 or 1; R, R' and R" independently represent a hydroxy group or an amino group; and the physiologically acceptable salts thereof with the proviso that when A and B represent a hydrogen atom and a hydroxy group respectively, b may not represent the integer 0.
The compounds of formula (I) are thus symmetrical dimers.
When A represents a glutamine residue or a proline residue it is preferred that a=b=1, n=2, m=1, R and R' represent hydroxy groups and B represents a lysine residue.
When B represents an arginine residue it is preferred that A represents a pyroglutamate residue, a=b=1, n=2, m=1 and R and R' represent hydroxy groups.
A preferred group of compounds are those in which b=1, m=1 and R, R' and R" represent hydroxy groups. Particularly preferred compounds according to the invention are as follows (using the conventional biochemical notation for the amino acids and reading from the N-terminus):
A further particularly preferred compound is (pGlu-Glu-Asp-Cys-Lys).sub.2 i.e. the compound in which a=b=1, m=1, n=2, R and R' represent hydroxy groups, A represents a pyroglutamate residue and B represents a lysine redidue.
Physiologically acceptable salts of the peptides of the invention include acid addition salts such as the hydrochloride, hydrobromide, sulphate, etc. as well as salts with bases such as alkali metal salts, e.g. sodium or potassium salts, alkaline earth metal salts, e.g. the calcium salt or amine salts.
Some of the compounds of formula (I) are dimers of compounds described and claimed in our European Patent Application No. 83307210.1. This latter application relates to a small group of haemoregulatory peptides having an inhibitory effect on granulopoiesis.
Due to the minute amounts of the natural granulopoiesis factor available, the structure of the natural substance has never been determined. It has never been obtained in crystalline or completely pure form and it is not known whether this could be achieved using material from natural sources only. It has been postulated as having the structure pyroGlu-Asp-Asp-Cys-LysOH but, as reported in our above European patent application, the synthetic compound having this structure proved to be inactive. It has been observed that when the natural granulopoiesis inhibition factor is subjected to oxidising conditions, a compound having stimulatory action was produced. However, this product has also never been isolated or identified. In contrast, the peptides of the invention can be obtained in pure form suitable for pharmaceutical use and in relatively large quantities.
It has also been reported (Exp. Hematol. 12 7 (1981)) that when one of the pept
REFERENCES:
Paukovits et al., Chem. Absts., vol. 98, No. 9, Abst. No. 67383u, 1983.
Foa et al., Chem. Absts., vol. 99, No. 1, Abst. No. 1022q, 1983.
Nycomed /AS
Springer David B.
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