Combined preparation for the therapy of immune diseases

Details Combined preparation for the therapy of immune diseases Combined preparation for the therapy of immune diseases

1999-07-20

2002-01-08

Celsa, Bennett (Department: 1627)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S262100, C514S263370, C514S264110, C514S826000, C514S885000, C514S889000

Reexamination Certificate

active

06337325

ABSTRACT:

The invention relates to pharmaceutical combination preparations for the treatment of immunological diseases in the broadest sense, which determine syndromes differing in their causes or symptoms. These combination preparations are determined by the pharmacological mechanisms of action on which the individual components are each based, and can be characterized by an
-inhibitory action on phosphodiesterases combined with a
-lowering of the biologically effective intracellular Ca
2+
concentration.
The activation of immunocompetent cells, which is the basis of any immune response, proceeds via the so-called signal chain: An extracellular stimulus (e.g. a toxin, an antigen or else complement, inflammation mediators, arachidonic acid derivatives or other metabolic products) reaches the cell as an “information carrier” and transfers the material information—usually via suitable receptors—to the target cell. This information is transmitted inside the cell to the nucleus via various intermediate stages within the signal chain, the nucleus reacts to this stimulus with proliferation and/or the formation of specific activators and the immune response is thus initiated in an appropriate way. However, the individual steps in this intracellular transmission of the information are still poorly understood, particularly as there are obviously different paths which can be followed within the cell in order to trigger an immune response. Thus, for example, depending on the type of receptor and the subunits coupled thereto (guanine nucleotide-binding proteins or “G proteins”), inositol triphosphate (IP
3
), diacylglycerol (DAG), phosphatidylcholine (PC) or phosphatidylinositol (PI) can be detected in the sequence, said compounds arising from a stimulus-induced activation of phospholipase C or D and being associated with an increase in intracellular free Ca
2+
, while an activation of phospholipase A
2
incurs the formation of arachidonic acid derivatives (prostaglandins, leukotrienes), which in turn can trigger their own stimulus via suitable receptors, with corresponding consequences. A second type of receptor is coupled via corresponding G proteins to adenylate cyclase (AC), the activation of which results in the formation of cyclic 3′,5′-adenosine monophosphate (cAMP), while a third type seems to trigger effects which are again independent thereof (for survey see Roitt (ed.): Essential Immunology, Blackwell Scient. Publ. Oxford 1991, and Foreman, Fan (eds.): Textbook of Immunopharmacology, Blackwell Scient. PubI. Oxford 1994).
Both Ca
2+
and cAMP are thus important information transmitters (second messenger) in signal transduction, although the processes subsequently taking place inside the cell are so complex that it is impossible to make a general prediction of the resulting cytobiological events. In any case the majority of downstream activation phenomena seem to depend on phosphorylation steps in the cell, which in turn are regulated via corresponding protein kinases or phosphatases. Particular mention may be made here of protein kinase C (PKC), whose activity is controlled via DAG and IP
3
/Ca
2+
in a concerted action, whereby the availability of intracellular free Ca
2+
takes on a key role in the cascade of cell activation, irrespective of the fact that usually the Ca
2+
/calmodulin complex subsequently mediates the Ca
2+
effects (Hidaka et al.: Cell Calcium 13, 465-472 (1992); Kun et al.: Endocrin. Rev. 14, 40-58 (1993)). Phosphorylations do not have to lead to activations in every case, however, but can also induce inhibitory effects. Thus, for example, the cAMP-dependent protein kinase A (PKA) counter-acts cell activation in the way that really only the complex interplay of phosphorylation and dephosphorylation allows efficient regulation of cell activity and thereby makes it possible for the organism to react usefully to variable external influences (Sitkovsky et al.: Ann. NY Acad. Sci. 532, 350-358 (1988); Takayama et al.: J. Pharm. Sci. 78, 8-10 (1989)). One and the same substance can have both agonistic and antagonistic effects. Thus, for example, cAMP inhibits activation induced by interleukin-2 (IL-2) (Friedrich et al.: Eur. J. Immunol. 19, 1111-1116 (1979)); on the other hand, it not only potentiates IL-1-induced activation but, under certain circumstances, can even act as an IL-1 agonist itself (Shirakawa et al.: Proc. Natl. Acad. Sci. 85, 8201-8205 (1988); Schlegel-Häuter et al.: Cell. Sign. 2, 489-496 (1990)). With such mechanistic considerations, however, it must not be forgotten that the appearance of a second messengers in response to a corresponding stimulus does not in itself allow any conclusions about its functional involvement; rather, this can also merely represent an epiphenomenon (Hansen et al.: Brit. J. Cancer 69, 291-298 (1994); Baumgold et al.: J. Neurochem. 58,1754-1759 (1992)). This statement is supported by Example 3 of the present patent application, where it is shown that the effect of a phosphodiesterase inhibitor (pentoxifylline) definitely cannot always be explained by an increase in cAMP, but rather, under certain conditions, is to be sought in the general inhibitory action of this group of substances on dephosphorylation processes. Accordingly, the extent to which certain mechanisms can gain importance in signal transduction depends on a variety of factors; correspondingly unpredictable are the effects of substances which pharmacologically influence signal substances involved at various sites of the process, especially when they act in combination.
Substances with a phosphodiesterase-inhibiting action are known and some are already used in therapeutics. They represent a heterogeneous class of substances which are characterized in that they inhibit the cleavage of cyclic mononucleotides by phosphodiesterases (PDE), leading to a concentration of cAMP or cGMP inside the cell; it must be emphasized, however, that the inhibitory actions of PDE inhibitors (as already mentioned above) does not stop here but generally extends to a wide variety of enzymes having whatever type of phosphatase activity, with all the resulting consequences on the diverse regulatory (de)phosphorylation processes inside the cell. However, even as far as the narrower reaction of the cleavage of a phosphodiester bond is concerned, this reaction is catalyzed not by a single enzyme but by a whole enzyme system comprising at least 5 different families of isoenzymes and more than 20 individual enzymes (for survey see Beavo et al.: Trends Pharmacol. Sci. 11, 150-155 (1990)). As the underlying enzymatic reaction (=hydrolytic cleavage of a phosphoester bond) is always the same, all PDE inhibitors exhibit a correspondingly overlapping inhibitory action; thus there are e.g. PDE inhibitors, like theophylline, pentoxifylline or papaverine, which also very non specifically inhibit very different phosphodiesterases. However, even when PDE inhibitors are termed “induced specific” in the scientific literature, this merely indicates a certain preference for a particular family of isoenzymes without immediately implying a claim to exclusivity. There are many examples of this: Thus the Ca
2+
/calmodulin-dependent PDE I cleaves both cGMP and cAMP and is inhibited e.g. by phenothiazine, vinpocetine or IBMX. The cGMP-stimulatable PDE II also cleaves cGMP and cAMP, but no selective inhibitors are known for this enzyme; this is in contrast to PDE III, which has an identical substrate specificity to PDE II but can be inhibited by cGMP and a large number of other substances. The sometimes considerable structural differences between PDE III inhibitors, such as cilostamide, milrinone, trequinsine, indolidane or quazinone, suggest that on the one hand there must be different inhibiting regions on PDE III, but that on the other hand there must also be a variety of isoenzymes in this PDE family. Other inhibitors to be found are PDE IV, which has a strong preference for the hydrolysis of cAMP, e.g. Ro 201724 and rolipram in the literature, while PDE V,

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