Use of aminoadamantane compounds as immunoregulators

Details Use of aminoadamantane compounds as immunoregulators Use of aminoadamantane compounds as immunoregulators

2000-09-22

2001-07-03

Higel, Floyd D. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Nitrogen containing other than solely as a nitrogen in an...

C564S461000

Reexamination Certificate

active

06255348

ABSTRACT:

The invention relates to the use of aminoadamantane compounds as immunoregulators, especially for the regulation and modulation of already activated neutrophils.
Neutrophils, a subclass of leukocytes, are involved in immune defense and other reactions in the blood vessel system and bordering tissues (Roitt, I.M, Leitfaden der Immunologie, Steinkopf-Verlag Darmstadt, 2nd edition, 1984)
Neutrophils can be activated by exogenous substances, such as for example cell wall components (a commercially obtainable product is “Zymosan”). In connection with this, reactive oxygen species are formed in the so-called respiratory burst.
FIG. 1 describes a simplified scheme of neutrophil stimulation: After binding of a ligand (for example, Zymosan A) to a specific receptor on the neutrophil membrane, guanosine triphosphate (GTP) is activated, which in turn activates the phosphatidyl-inositol-4,5-biphosphate (PIP
2
)-specific phospholipase C (PLC). PLC catalyses the hydrolysis of PIP
2
to inositol-1,4,5-triphosphate (IP
3
) and diacylglycerol (DG). IP
3
stimulates the release of Ca
2+
ions from intracellular stores. Ca
2+
ions, together with DG, activate the enzyme protein kinase C (PC) which phosphorylates numerous proteins and in this manner activates NADPH oxidase complex among others. NADPH oxidase catalyses in turn the reaction:
2O
2
+NADPH→2 O
2
−
+NADP
+
+H
+
wherein the reactive oxygen species O
2
−
results.
Although activated neutrophils are important for a functioning immune defense, disease symptoms such as acute or chronic inflammations or other allergic reactions can result by overreactions caused especially by reactive oxygen species. On the other hand, neutrophil activity can be too low or insufficient for a successful immune defense with a general immune deficiency such as for example with AIDS. Hence, a need exists, especially from the medical standpoint, to be able to influence the regulative and/or modulating activity of neutrophils in vivo and in vitro. In this connection, the neutrophil activity should be either increased or decreased depending on the indication, i.e. should be controllable at will.
Therefore, the object of the present invention is to make available an agent for the regulation and/or modulation of the activity of neutrophils.
It has now been surprisingly found that certain aminoadamantane compounds have a regulative and/or modulating effect on the activity of neutrophils. The present invention relates to this finding. It is decisive for this that the neutrophils have already been activated by other stimulants. The aminoadamantanes themselves do not demonstrate any activating effect on neutrophils.
The above object is accordingly solved by the use of aminoadamantane compounds of formula (I)
wherein R
1
, R
2
, R
3
and R
4
are selected independently from each other from —NR
5
R
6
, —NR
5
R
6
R
7
+
, hydrogen, aryl or heteroaryl with up to 7 ring members, C
1
-C
20
-alkyl, C
1
-C
20
-alkenyl and C
1
-C
20
-alkinyl, wherein the alkyl, alkenyl and alkinyl residues can be branched, unbranched or cyclized and optionally substituted with halogen, aryl or heteroaryl with up to 7 ring members, with the proviso that at least one of the residues R
1
, R
2
, R
3
and R
4
are represented by —NR
5
R
6
or —NR
5
R
6
R
7
; and
R
5
, R
6
and R
7
are selected independently from each other from hydrogen, aryl or heteroaryl with up to 7 ring members, C
1
-C
20
-alkyl, C
1
-C
20
-alkenyl, C
1
-C
20
-alkinyl, wherein the alkyl, alkenyl and alkinyl residues can be branched, unbranched or cyclized and optionally substituted with halogen, aryl or heteroaryl with up to 7 ring members, or R
5
and R
6
, together with the nitrogen atom, form a heterocyclic group with up to 7 ring members;
for the regulation of the activity of already activated neutrophils.
Aminoadamantane compounds of this type are known. Thus, 1-aminoadamantanes are described in DE 22 19 256, DE 28 56 393, DE 22 32 735, U.S. Pat. No. 3,450,761 or U.S. Pat. No. 4,122,193. The production of compounds of formula (I) generally occurs by known methods, such as for example the alkylation of halogen adamantanes. Subsequent further halogenation and alkylation produce the individual di- and/or tri-substituted adamantanes. EP 392 059, whose teaching is explicitly incorporated herein by reference, is referred to for the production of aminoadamantanes.
Aminoadamantane compounds have also already been used for pharmaceutical purposes. Thus, EP 392 059 discloses the use of 1-aminoadamantane compounds for the treatment of Alzheimer's disease or brain cell damage as a result of cerebral ischemia. U.S. Pat. No. 3,450,761 describes aminoadamantanes with anti-viral activity.
Whether the activity of neutrophils is increased or partially or entirely inhibited depends on the concentration of the aminoadamantane compound used. Thus, concentrations from 10
−6
to 10
−5
M have an activity increasing effect. A concentration of about 5·10
−6
M has proven especially effective for increasing neutrophil activity—a concentration which can be well achieved in vivo in blood plasma. In contrast, an inhibition of activity results with an increase of the aminoadamantane concentration. A concentration suitable for this purpose is 10
−4
to 10
−3
M.
The invention comprises adamantane compounds substituted with one or with more amino groups, wherein monoaminoadamantanes are preferred. Hence, suitable compounds of formula (I) are those wherein R
1
represents an amino group such as for example 1-amino-3-ethyl-5,7-dimethyl-adamantane; as well as compounds wherein R
1
represents an amino group and R
3
and R
4
represent a hydrogen atom, such as for example 1-amino-3-cyclohexyl-adamantane or 1-amino-3-ethyl-adamantane.
Preferred adamantane compounds are 1-amino-3,5-dimethyl-adamantane, 1-amino-3,5-diethyl-adamantane and the N-substituted compounds 1-N-methylamino-3,5-dimethyl-adamantane and the compound 1-N-ethylamino-3,5-dimethyl-adamantane. Particularly preferred is 1-amino-3,5-dimethyl-adamantane referred to as memantine (INN, Akatinol Memantine®). Görtelmeyer, R., et al, describe the treatment of Demens syndrome with memantine in Spectrum of Neurorehabilitation, W. Zuckschwerdt Publishers, Munich, 1993, 50ff.
As explained above, the aminoadamantane compounds according to the invention only have a regulating effect on neutrophils which are pre-activated or have been stimulated by special activators.
Natural substances, such as Zymosan, N-formyl-Met-Leu-Phe (N-FLMP) or A 23187 (a Ca antagonist) are known as activators. These substances can be used if one intends to specifically and more intensely activate neutrophils in vitro, but also in vivo. By this, it is possible to detect neutrophils in a sample, for example in a sample of body fluid, especially a blood sample, even when only few neutrophils are present or when their activity is very weak. In this connection, the activator can be present in combination with the aminoadamantane compound: The degree of activation of the neutrophils stimulated by the activator is intensified by the simultaneous addition of aminoadamantane compound.
A further field of application is the improvement of immune defense in persons with various forms of immune deficiencies, especially AIDS patients. Here, a pharmaceutical composition can be administered which comprises a aminoadamantane compound according to the invention, optionally in combination with a neutrophil activator. Furthermore, the use in CGD (agranulomatosis), Wegenerts granulomatosis and/or glycogen storage diseases is possible.
As a matter of course, the neutrophils can also be activated as a consequence of a natural immune response of the organism as a reaction to diverse immunogens and trigger allergic reactions, inflammations and rheumatic symptoms due to overreaction. Here, the neutrophil activity can be attenuated with suitably increased aminoadamantane concentrations and the patient can be given relief. Internal and external inflammation conditions,

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