Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-09-23
2003-07-22
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S235800, C514S236200, C514S236500, C514S253090, C514S255050, C514S255060, C514S256000, C514S326000, C514S340000, C514S381000, C514S382000, C514S836000
Reexamination Certificate
active
06596750
ABSTRACT:
Various disorders of warm-blooded animals are linked with an excess of metals, in particular trivalent metals, in the body tissues. For example, aluminum in dialysis encephalopathy and osteomalacia, as well as in Alzheimer's disease is representative. In other illnesses, in particular of man, an excess of iron occurs in the various tissues. This is designated as iron overload (formerly haemosiderosis). It occurs, e.g., after parenteral administration of iron (especially repeated blood transfusions) or after increased uptake of iron from the gastrointestinal tract. Repeated transfusions are necessary in serious anemias, especially in thalassaemia major, the severe form of &bgr;-thalassaemia, but also in other anemias. Increased iron absorption from the gastrointestinal tract either takes place primarily, e.g. on account of a genetic defect (so-called haemochromatosis), or secondarily, such as after anemias in which blood transfusions are not necessary, e.g. thalassaemia intermedia, a milder form of &bgr;-thalassaemia.
Untreated iron overload can cause severe organ damage, in particular of the liver, the heart and the endocrine organs, and can lead to death. Iron chelators are able to mobilize and excrete the iron deposited in the organs and thus lower the iron-related morbidity and mortality.
A reduction in the iron(III) concentration is also of interest for the treatment of disorders due to iron(III)-dependent microorganisms and parasites, which is of key importance not only in human medicine, such as in particular in malaria, but also in veterinary medicine. Complexing of other metals, in partcular trivalent metals, can also be used for excretion thereof from the organism. A number of further applications are also described in the literature, e.g. by Kontoghiorghes, Toxicology Lett. 80:1-18 (1995).
Desferrioxamine B has already been known for a long time and used therapeutically for these purposes [Bickel et al., Helv. Chim. Acta 46:1385-1389 (1963)]. A disadvantage of this preparation, however, turns out to be the fact that desferrioxamine and its salts only have a low, inadequate activity on oral administration and require a parenteral administration form in all of the abovementioned application possibilities. It is thus recommended, e.g., as a particularly effective method to administer the active substance by means of a slow (8 to 12 hour) subcutaneous infusion, which, however, demands the use of a portable mechanical device, such as an infusion syringe actuated by an electrical drive. Apart from their awkwardness, such solutions are affected by a high treatment cost, which severely restricts their use; in particular a comprehensive treatment of the thalassaemias in the countries of the Mediterranean region, of the Middle East, India and South-East Asia, of malaria worldwide and of sickle-cell anemia in African countries is made impossible. These widespread diseases are furthermore a serious problem for the health service in these countries and make the search for a simpler and more inexpensive therapy, preferably by means of an orally active preparation, the urgent object in this area.
Various 3,5-diphenyl-1,2,4-triazoles have been known for a long time and their use is described for herbicides, e.g. in EP 185,401, as angiotensin II receptor antagonists in EP 480,659, or very generally as intermediates and starting compounds for fine chemicals, e.g. in JP 06345728.
It has now been found that certain substituted 3,5-diphenyl-1,2,4-triazoles have valuable pharmacological properties when used in the treatment of disorders which cause an excess of metal in the human or animal body or are caused by it, primarily a marked binding of trivalent metal ions, in particular those of iron [Martell and Motekaitis, Determination and Use of Stability Constants, VCH Publishers, New York (1992)]. They are able, e.g. in an animal model using the non-iron overloaded cholodocostomized rat [Bergeron et al., J. Med. Chem. 34:2072-2078 (1991)] or the iron-overloaded monkey [Bergeron et al., Blood 81:2166-2173 (1993)] in doses from approximately 5 &mgr;mol/kg, inter alia, to prevent the deposition of iron-containing pigments and in the case of existing iron deposits in the body cause excretion of the iron.
The present invention relates to the use of compounds of the formula I
in which
R
1
and R
5
simultaneously or independently of one another are hydrogen, halogen, hydroxyl, lower alkyl, halo-lower alkyl, lower alkoxy, halo-lower alkoxy, carboxyl, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl or nitrile; R
2
and R
4
simultaneously or independently of one another are hydrogen, unsubstituted or substituted lower alkanoyl or aroyl, or a radical which can be removed under physiological conditions, e.g. a protective group;
R
3
is hydrogen, lower alkyl, hydroxy-lower alkyl, halo-lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, R
6
R
7
N—C(O)-lower alkyl, unsubstituted or substituted aryl or aryl-lower alkyl, or unsubstituted or substituted heteroaryl or heteroaralkyl; R
6
and R
7
simultaneously or independently of one another are hydrogen, lower alkyl, hydroxy-lower alkyl, alkoxy-lower alkyl, hydroxyalkoxy-lower alkyl, amino-lower alkyl, N-lower alkylamino-lower alkyl, N,N-di-lower alkylamino-lower alkyl, N-(hydroxy-lower alkyl)amino-lower alkyl, N,N-di(hydroxy-lower alkyl)amino-lower alkyl or, together with the nitrogen atom to which they are bonded, form an azaalicyclic ring; and salts thereof; in the treatment of diseases which cause an excess of metal in the human or animal body or are caused by it; preferably in the form of pharmaceutically acceptable preparations, in particular in a method for the therapeutic treatment of the human body, and to a treatment method of this type.
Halogen is, e.g., chlorine, bromine or fluorine, but can also be iodine.
The prefix “lower” designates a radical having not more than 7 and in particular not more than 4 carbon atoms.
Alkyl is straight-chain or branched. Per se, e.g. lower alkyl, or as a constituent of other groups, e.g. lower alkoxy, lower alkylamine, lower alkanoyl, lower alkylaminocarbonyl, it can be unsubstituted or substituted, e.g. by halogen, hydroxyl, lower alkoxy, trifluoromethyl, cyclo-lower alkyl, azaalicyclyl or phenyl, it is preferably unsubstituted or substituted by hydroxyl.
Lower alkyl is, e.g., n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl or n-heptyl, preferably methyl, ethyl and n-propyl. Halo-lower alkyl is lower alkyl substituted by halogen, preferably chlorine or fluorine, in particular by up to,three chlorine or fluorine atoms.
Lower alkoxy is, e.g., n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-amyloxy, isoamyloxy, preferably methoxy and ethoxy. Halo-lower alkoxy is lower alkoxy substituted by halogen, preferably chlorine or fluorine, in particular by up to three chlorine or fluorine atoms.
Carbamoyl is the radical H
2
N—C(O)—, N-lower alkylcarbamoyl is lower alkyl-HN—C(O)— and N,N-di-lower alkylcarbamoyl is di-lower alkyl-N—C(O)—.
Lower alkanoyl is HC(O)— and lower alkyl-C(O)— and is, e.g., acetyl, propanoyl, butanoyl or pivaloyl.
Lower alkoxycarbonyl designates the radical lower alkyl-O—C(O)— and is, e.g., n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, n-amyloxycarbonyl, isoamyloxycarbonyl, preferably methoxycarbonyl and ethoxycarbonyl.
Aryl, per se, e.g. aryl, or as a constituent of other groups, e.g. aryl-lower alkyl or aroyl, is, e.g., phenyl or naphthyl, which is substituted or unsubstituted. Aryl is preferably phenyl which is unsubstituted or substituted by one or more, in particular one or two, substituents, e.g. lower alkyl, lower alkoxy, hydroxyl, nitro, halogen, trifluoromethyl, carboxyl, lower alkoxycarbonyl, amino, N-lower alkylamino, N,N-di-lower alkylamino, aminocarbonyl, lower alkylaminocarbonyl, di-lower alkylaminocarbonyl, heterocycloalkyl, heteroaryl or cyano. Primarily, aryl is unsubsti
Acklin Pierre
Lattmann Rene
Borovian Joseph J.
Krass Frederick
Novartis AG
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