Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Reexamination Certificate
2000-01-11
2001-10-30
Ford, John M. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
Reexamination Certificate
active
06310202
ABSTRACT:
The present invention relates to novel molecules which can convey and release nitrogen monoxide (NO) in a biological medium, to their use for carrying out a therapeutic treatment method or a diagnostic method applied to the human or animal body, as well as for the manufacture of medicinal products which can be used for treating or preventing disorders of the cardiovascular, nervous, immune, renal or pulmonary system in man or animals.
Although the nitrogen monoxide (NO) molecule has been known for a long time, its therapeutic properties have only been demonstrated since the end of the 1980s.
Thus, the first notable studies can be attributed to T. Higenbottam, who published, in “American Review of Respiratory Diseases, 1988, Volume 137”, tests showing the pulmonary vasodilatory effect of NO inhaled at concentrations of about 40 ppm (parts per million by volume) and suggesting the use of inhaled NO in the therapeutic treatment of the respiratory system. However, the author comments that inhaled NO has no systemic effect, but only a local effect limited to the lungs.
Document WO-A-92/10228 pursues the previous studies and describes the use of NO gas for the preparation of medicinal products which can be administered by inhalation, for the purpose of treating or preventing reversible pulmonary bronchoconstriction or vasoconstriction in man or animals. However, the description in that document places the emphasis, on the one hand, on the unstable nature of NO which, in the presence of air, becomes oxidized very rapidly to nitrogen dioxide NO
2
, and, on the other hand, on the toxic nature to man or animals of said NO
2
formed by oxidation of NO.
In order to avoid this problem of oxidation of NO in the presence of air, that document suggests coupling the NO molecule to a carrier molecule, thus allowing the NO to be conveyed to its site of use, and then releasing it thereat. Examples of such NO carriers are, in particular, S-nitrosocysteine, nitroprusside, nitrosoguanidine or azide.
In addition, the use of the NO molecule for therapeutic purposes has been the subject of many other documents, for example: WO-A-93/15779, WO-A-94/22499, WO-A-95/26768, WO-A-94/00180, WO-A-95/10315.
However, although these various publications recognize the therapeutic effects of the NO molecule, they moreover underline the persistent problem of oxidation of NO in the presence of air and the purely local, i.e. not systemic, effects of the inhaled NO molecule, i.e. the molecule administered by inhalation.
There is thus a need for molecules capable of:
combining irreversibly with the NO molecule;
conveying the NO molecule to its site of action;
releasing the NO molecule at said site of action;
avoiding the oxidation of NO in the presence of air;
being pharmaceutically acceptable.
The fact of coupling the NO molecule with such a carrier makes it possible to fully exploit the beneficial therapeutic effects of said NO molecule, without thereby running any risk of poisoning the patient with NO which has become oxidized to NO
2
.
Currently, the only NO-carrier molecule used as a medicinal product is sodium nitroprusside. However, although this compound is of appreciable therapeutic value on account of its considerable vasodilatory activity, it has a major drawback, namely its potential toxicity resulting from the release of cyanide ions; said release of cyanide ions being due, in vivo, to a reaction of sodium nitroprusside with a reducing agent.
The result of this is that prolonged administration of such a medicinal product cannot be envisaged.
Moreover, it has been noted that the formation of cyanide ions also took place by photo-reaction. This therefore entails storing the compound and handling it under protection from light.
It is easily appreciated that such contraindications make this product relatively unappealing in therapeutic terms.
The aim of the present invention is thus to overcome the problems and drawbacks of the compounds of the prior art, by proposing novel molecules for conveying to and releasing the NO molecule at its site of use in the body, which are pharmaceutically acceptable, which are not toxic or which do not release toxic compounds, which make it possible to avoid the oxidation of NO, which are of high stability, and which are easy to synthesize, store and handle.
The invention thus relates to a molecule intended for conveying and releasing nitrogen monoxide (NO) in a biological medium, characterized in that it corresponds to formula (I) below:
in which
x=0 or 1;
x=2 or 3;
y=0, 2 or 3;
z=0 or 1;
with the condition that,
if y=0 (or z=0) then z=0 (or y=0; respectively);
R is a group chosen from the group formed by: a hydrogen atom, —(CH
2
)
2
COOH and
R1, R2, R3 and R4 are groups chosen from the group formed by: a hydrogen atom and alkyl groups comprising from 1 to 4 carbon atoms; and
M
2+
represents a divalent cation of a metal atom.
Preferably, the divalent cation M
2+
is Fe
2+
or Co
2+
.
The molecule according to the invention will advantageously be chosen from the group formed by:
The molecules according to the invention may be used to carry out a therapeutic treatment method for the human or animal body, or to carry out a diagnostic method applied to the human or animal body.
The invention also relates to the use of one of the above molecules for the manufacture of a medicinal product which can be used for treating or preventing disorders of the cardiovascular system, the central or peripheral nervous system, the immune system, the renal system or the pulmonary system.
REFERENCES:
Friederich et al, Anesth. Analg. 81(1) (1995) 152-162 (Medline abstract only).*
Sanders et al, Perfusion 15(2) (2000) 97-104 (Medline abstract only).*
Granier, C,; Guilard, R. Microchemical Journal 53 (1996) 109-121.*
Hodges, K. D.; Wollmann, R. G.; Kessel, S. L.; Hendrickson, D. N.; Van Derveer, D. G.; Barefield, E. K. Journal of the American Chemical Society 101(4) (1979) 906-917.*
Pomp, C.; Wieghardt, K. Inorganic Chemistry 27(21) (1998) 3796-3804.*
Watkins Jr., D. D.; Riley, D. P.; Stone, J. A.; Busch, D. H. Inorganic Chemistry 15(2) 1976 387-393.
Cocolios Panayotis
Guilard Roger
Siri Olivier
Tabard Alain
Ford John M.
L'Air Liquide, Societe Anonyme pour l'Etude Et l'
Young & Thompson
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