Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1998-06-03
2001-05-08
Travers, Russell (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S660000, C514S661000
Reexamination Certificate
active
06228890
ABSTRACT:
The present invention relates to novel uses for alicyclic diamines.
FR-A-1 387 971 describes novel alicyclic diamines and a process for the preparation thereof.
Alicyclic diamines represented by a formula with general structure:
R-NH-K-Q-K-NH-R (I)
where Q represents a divalent radical with the following formulae II to V:
K represents a methylene group or, when the symbol Q is represented by formula II, a valence bond and the symbol R is a radical selected from the group formed by the following radicals VI to XVII:
VI Benzyl;
VII Benzyl substituted by one, two or three trihalomethyl groups;
VIII Substituted trihalomethyl benzyl;
IX Indanyl;
X Alkyl;
XI Cycloalkyl;
XII Cycloalkylalkyl;
XIII Alkenyl;
XIV Cycloalkenylalkyl;
XV Bicycloalkyl;
XVI Bicycloalkenylalkyl;
XII Bicycloalkylalkyl;
and their addition salts with mineral or organic acids, have properties which affect lipid metabolism.
After a great deal of research, the applicant has discovered that the products defined above have remarkable, original immunomodulating properties.
In particular, the above products are capable of restoring expression of cytokine genes and/or their receptor in the event of a dysfunction of such genes connected with an exogenous or endogenous pathology. These properties are illustrated in the experimental section below.
They can also stimulate the production of inflammatory molecules which are essential for defending the human organism, such as chimiokines (MIP1 &agr;, &bgr;, and Rantes, the antiviral properties of which have been described, for example, by Cocchi et al., Science, 270, 1811-1518, 1995).
Diamines with formula I appear to act as a stimulator for type TH1 cytokines which are known to be greatly disturbed in AIDS (IL
2
, IL
12
, for example); the apoptosis effect induced by HIV and other pathologies could be limited by this mechanism.
For this reason, the present invention concerns the use of a compound with formula I as defined above for preparing an immunomodulating drug, which is in particular capable of modulating the expression of cytokine genes and/or their receptor in the event of a dysfunction connected with an exogenous or endogenous pathology, and for stimulating cytokine production.
This pathology could be connected with a viral infection such as type I or type II AIDS, herpes, hepatitis, papilloma, or to a parasitic infection such as leishmaniosis, malaria or bilharziosis. It can also be of iatrogenic origin, for example, induced by the action of immunosuppressors such as cyclosporin or by the action of corticoids or by a tumor, in particular a haematological tumor such as myeloma or a tissue tumor.
In particular, the pathology concerned is an autoimmune disease such as rheumatoid polyarthritis, lupus erythematosus or autoimmune diabetes.
A more detailed definition of compounds with formula I above and a process for the preparation thereof and known applications is given, for example, in FR-A-1 387 971 and its French and foreign equivalents, in particular French special drug patent N
o
3559 M. There is also a great deal of literature concerning these compounds, in particular trans-1,4-bis [2-chlorobenzylaminomethyl] cyclohexane dihydrochloride, also known as AY 9944.
In particular, data relating to the pharmacology and toxicology of this product have been widely described in the literature.
The present invention particularly concerns the use of a compound as above for preparing a drug for the treatment of:
a viral disease;
a parasitic disease;
an iatrogenic disease;
a tumor;
an autoimmune disease.
For these uses in particular, a compound with formula I is used in which the symbol Q represents a 1,4-cyclohexanedi-yl radical, i.e. where the symbol Q corresponds to the above formula II, in particular a compound with formula I in which the symbol R is a benzyl radical or a benzyl radical substituted with a halogen such as fluorine, bromine and in particular chlorine, or by one, two or three trihalomethyl groups, or by a trihalomethyl benzyl radical substituted with one or more, for example one, two or three halogens or C
1
-C
5
alkyl or alkoxy radicals, and more particularly the compound AY 9944, namely the dihydrochloride of the compound with formula:
These properties of restoring expression of cytokine genes and/or their receptor in the event of a dysfunction of these genes connected with an exogenous or endogenous pathology, which are illustrated below in the experimental section, justify the use of derivatives with formula I described above and salts thereof as a drug for correcting the expression of cytokine genes and/or their receptor in the event of a dysfunction connected with an exogenous or endogenous pathology.
The drugs of the present invention can be used, for example, for curative or preventative treatment of the pathologies listed above.
They are of particular use in the treatment of autoimmune diseases.
The usual dose, which varies depending on the subject treated and the affliction under consideration, can be 10 mg to 2 g per day, orally in man, of the compound known as AY 9944, for example, as required.
As a drug, the above compounds with formula I and the salts thereof can be incorporated into pharmaceutical compositions for digestive or parenteral administration. These pharmaceutical compositions can be solids or liquids, for example, in pharmaceutical forms which are routinely used in human medicine, such as simple or sugar-coated tablets, capsules, granules, syrups, suppositories, or injectable preparations; they are prepared using the normal methods. The active ingredient or ingredients can be incorporated with excipients which are normally used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non aqueous vehicles, animal or vegetable fats, paraffin derivatives, glycols, various wetting agents, dispersing agents or emulsifiers, and preservatives.
We have also discovered that when an immunomodulating compound with formula I as defined above is combined with a compound with anti-viral properties, such as DDI, DDC, antiproteases, 3TC and, preferably, AZT, their respective effects are potentiated as illustrated below in the experimental section.
For this reason, the present application also concerns a combination characterized in that it comprises a compound as defined above, in particular trans-1,4-bis [2-chlorobenzylaminomethyl] cyclohexane dihydrochloride and a compound with anti-viral properties.
The antiviral compound is preferably selected from DDI, DDC, antiproteases, 3TC and, in particular, AZT.
REFERENCES:
patent: 3244750 (1966-04-01), Humber
patent: 4060639 (1977-11-01), Jacobus et al.
patent: 5116823 (1992-05-01), Calabresi et al.
patent: 1387971 (1965-12-01), None
Popp et al 67 CA: 53793a, 1967.*
Elwell et al 106 CA:135100k, 1987.*
Science, vol. 270, Dec. 15, 1995, pp. 1811-1815, XP000616644. Cocchi, F. et al., “Identification of Rantes, MIP-1alpha, and MIP-1beta as the major HIV-suppressive factors produced by CD8+ T cells.”
Achour Amar
Landureau Jean-Charles
Maziere Jean-Claude
Zagury Daniel
Browdy and Neimark
NEOVACS
Travers Russell
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