Macrocyclic compounds made from suboxide units

Details Macrocyclic compounds made from suboxide units Macrocyclic compounds made from suboxide units

1999-04-15

2001-02-13

McKane, Joseph K. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S922000, C514S950000, C549S415000, C585S019000

Reexamination Certificate

active

06187810

ABSTRACT:

This APPLN. is a 371 of PCT/EP96/05867 filed Dec. 30, 1996.
FIELD OF THE INVENTION
The invention relates to macrocyclic substances which are bioregulatory active and a method for their synthetic production as well as its isolation from various starting materials. The application of these active substances as such or in combination with other active substances for enzyme regulation and bioregulation is also described.
BACKGROUND OF THE INVENTION
The proper course of biochemical processes and the optimal function of biological immune mechanisms is ensured by numerous bioregulatory active substances (Rompp Lexikon page 3826 “Regulation”). From a chemical standpoint, bioregulatory active substances known up to now are peptides, carbohydrates, steroids or lipids, whereby these structural elements can also occur together (for example, glycopeptides, lipoproteins). Furthermore, the application of bioregulatory active substances for the therapy of diseases which are caused by disturbed functions of one or more of these regulation mechanisms is known. The therapeutic use of steroid hormones, corticosteroids and cardiac glycosides as well as growth hormones or blood coagulation factors are some of the many examples in this sense. However, pharmacotherapy with substances of this type is very often accompanied by damaging side-effects, and therewith, considerably limited. A detailed consideration of these aspects is to be found in Goodman and Gilman's “The Pharmacological Basis of Therapeutics”, 8th Ed., New York, 1991. For example, with cardiac glycosides, the positive inotropic, therapeutically useful action is compromised by a cardiotoxic side-effect, and consequently, therapeutic doses must be very rigorously limited. As a further example, the application of corticosteroids may be mentioned where the therapeutic use is only recommended in very severe cases and only for a limited time due to a series of very severe side-effects such as myopathy, osteoporosis, psychic disturbances, increased infection susceptibility, etc.
Despite considerable efforts to treat immunologically caused disease syndromes with immunoregulatory active substances, previous clinical tests are not convincing. The purpose of such immunotherapeutic applications would be to accomplish the basic therapy for autoimmune diseases such as rheumatoid arthritis and multiple sclerosis, among others, which has not been found to date. According to E. Sercarz and S. K. Datta “Autoimmunity” in Current Biology 6, 875-881 (1995), these autoimmune diseases have mostly been caused by disturbed immunoregulation. For fighting severe disease syndromes which are characterized by a considerably weakened immune system, such as carcinosis or AIDS, the previous therapeutical uses of immunoregulatory substances has yielded little.
Several bioregulatory peptides and proteins have been characterized as reported in the Monograph from M. J. Clemens “Cytokines”, Oxford 1991. That cytokines play an important role in different carcinoses, in autoimmune diseases and in viral infections (including AIDS) has also already been reported several times. Despite this, wider therapeutic applications of these and other bioregulatory proteins and peptides are still lacking to a large extent. One of the causes for this certainly lies in the often very laborious production technologies: the extractions and subsequent purifications of bioregulatory active substances from human or animal tissue fluids, where they are present in only very small amounts, is completely unsuitable for providing therapeutically needed amounts. The danger of allergic side-effects and/or anaphylactic reactions which, despite their rare occurrence, represent a considerable risk factor for human therapy that still exists with gene technologically produced bioregulatory polypeptides or glycoproteins. The fundamental problem of the therapeutic applications of several “in vitro” highly active polypeptide factors lies in the fact that they demonstrate “in vivo” entirely different, mostly very much weaker activity. On the one hand, numerous physical and enzymatic barriers impede the externally administered peptides and proteins from reaching the location of the pathological event (focus of inflammation, cancerous ulcer, etc.). On the other hand, they are quickly neutralized and metabolized by the endogenous enzymes and other factors present there. With peroral administration of active substances of a peptide, glycopeptide and glycosidic nature, these substances are already rendered practically ineffective in the gastrointestinal system by several degradation processes.
However, a relatively fast degradation of bioregulatory active substances of peptidic or glycopeptidic nature must also be taken into account with a delivery “per os”. In order to entirely target the therapeutically effective concentration to the location of the pathological event or manifestations, such as at the focus of inflammation or at the cancerous ulcer, a masked delivery of the active substance has been performed for example. Something similar was described by R. Collier and D. Kaplan in “Immuntoxine”, Heidelberg 1988, in connection with the use of toxins which could be purposefully employed bound to monoclonal antibodies(drug targeting). However, the treatment technique is still very complicated and only remains restrictively applicable for specific cases. For regulatory active substances, the bioavailability is not only dependent on stability, but also on purely physical processes, such as solubility and membrane permeability. This concerns making the water solubility of lipophilic substances possible in plasma or making the membrane permeability of hydrophilic active ingredients such as Na
+
or K
+
ions possible. For example, the mitochondria membrane is normally not permeable to potassium ions. Macrocyclic antibiotics such as nonactin or valinomycin make this permeability possible through the organic envelopment of the corresponding ions.
Since 1967, the year of discovery of the “crown ethers”, numerous new compounds have been produced which have a macroring structure and make a crown or cryptate-like covering of inorganic ions or smaller molecules possible. However, important prerequisites for a direct therapeutic application of such cryptate-forming macrocyclic substances are a low toxicity and good bioassimilation, which is only seldom fulfilled by the synthetically produced cryptand reagents.
Many fundamental bioregulatory mechanisms are controlled by the so-called sodium pump. This enzyme has the ability to pump sodium ions from the insides of cells to the outside and simultaneously transport potassium ions in the opposite direction. The energy consumption is delivered by a coupled hydrolysis of adenosine triphosphate (ATP). This pump is identical with the enzyme referred to as the Na
+
,K
+
-ATPase and is ubiquitously distributed. Several important cellular functions are controlled by this Na
+
,K
+
-ATPase such as cell volume, heat production, intracellular free Ca
2+
ion concentration, neuronal transmission, muscle contraction or membrane potential.
In numerous immunoregulatory processes, important phases are also controlled by the Na
+
,K
+
-ATPase, and thus, the sodium pump also acquires a fundamental roll in immunoregulation. Despite this general distribution and significance, the regulation mechanism of this enzyme has not yet been clarified. The so-called “cardiac glycoside receptor site” of the enzyme is suspected as the functional location for the bioregulation of the sodium pump. The cardiac glycosides present in several plant species are bound to this site with high affinity and exert their cardiotonic, but also their cardiotoxic effect. However, their toxicity proves that they are not identical with the endogenous ligands of this enzyme. In the paper “Endogenous digitalis-like factors” by W. Schoner in Progress in Drug Research, 41, 249-291 (1993), it is reported that the chemical nature and the structure of these endogenous bioregulatory subst

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