Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
2001-12-20
2003-09-23
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C558S155000
Reexamination Certificate
active
06624151
ABSTRACT:
This application is a 371 of PCT/FR00/00837 Apr. 4, 2000.
The invention relates to compounds selectively inhibiting the T&ggr;9&dgr;2 lymphocytes carriers of receivers at variable regions V&ggr;9 and V&dgr;2.
The T&ggr;&dgr; lymphocytes of primates present in the peripheral blood (humans, monkeys) represent, in the healthy individual, conventionally 1 to 5% of the lymphocytes of the blood and play a role in the immune system. It has been shown that they recognize their antigenic ligands by direct interaction with the antigen, without presentation by molecules of CMH of a presenting cell. The T&ggr;9&dgr;2 lymphocytes (sometimes also called T&ggr;2&dgr;2 lymphocytes) are the T&ggr;&dgr; lymphocytes carrying TCR receivers at variable regions V&ggr;9 and V&dgr;2. They represent the majority of the T&ggr;&dgr; lymphocytes of human blood.
When they are activated, the T&ggr;&dgr; lymphocytes exert a strong cytotoxic activity unrestrained by CMH, particularly effective to kill various types of cells, particularly pathogenic cells. Nevertheless, the massive activation of the T&ggr;&dgr; lymphocytes accompanying sometimes the development of certain pathologies, can have or lead to a pathogenic character. Such is the case in particular for the auto-immune maladies such as plaque sclerosis (Wucherpfennig K. et al “&ggr;&dgr;T cell receptor repertoire in acute multiple scerosis lesion” 1992, PNAS 89, 4588) or the Behçet malady (Yamashita N. et al “Role of &ggr;&dgr;T lymphocytes in the development of Behçet disease” Clinical Experimental, Immunology, 107(2), 241-247).
Such is the case moreover for a certain number of bacterial pathologies such as brucellosis, tularemia, salmonelloses, tuberculosis, ehrlichiosis, or parasitic pathologies such as malaria (malarial attack), visceral leishmaniosis, toxoplasmosis (for example Morita C. T. et al, “Direct presentation of non peptide prenyl pyrophosphate antigens to human gamma delta T cells”, 1996, Research in Immunology, Vol. 147, p 347-353).
Various antigens of T&ggr;9&dgr;2 lymphocytes have been described (WO-9520673, U.S. Pat. No. 5,639,653, “Natural and synthetic non peptide antigens recognized by human &ggr;&dgr;T cells”, Yoshimasa Tanaka et al, Nature, 375, 1995, pp 155-158). Nevertheless, these natural antigens are not completely identified. Moreover, it is known that the mechanism of activation of the T&ggr;9&dgr;2 lymphocytes by these antigens is particular, because it does not imply any known molecule of CMH (major complex of histocompatibility). But the nature of this mechanism remains unexplained, such that the problem of adjusting inhibitors of T&ggr;9&dgr;2 lymphocytes remains unsolved.
WO-95/20673 also indicates that the principals having a phosphatase enzymatic activity (phosphohydrolase phosphoric monoester and/or pyrophosphatase nucleotide and/or phosphohydrolase phosphoric diester) such as the alkaline phosphatase, are adapted to inhibit the antigenic activity of natural origin, the so-called TUBag, from a mycobacterial extract, vis-à-vis T&ggr;9&dgr;2 lymphocytes. Nevertheless, this inhibition takes place by cleaving the antigens and thus does not act on the T&ggr;9&dgr;2 lymphocytes themselves. Moreover, it is not specific and poses problems of uncontrollable secondary effects to the extent that the biological or physiological media themselves include numerous phosphorylated compounds and natural phosphatase enzymatic activities.
The invention thus seeks to provide compounds for selective inhibition of the T&ggr;9&dgr;2 lymphocytic stimulation, which is to say specific immunosuppressive compounds for T&ggr;9&dgr;2 lymphocytes.
The invention seeks more particularly to provide such compounds which will be compatible, on the one hand, with administration to a primate and, on the other hand, with considerations of profitability for industrial use (which must be produced in a simple manner, in large quantities, at an acceptable cost on an industrial scale).
Moreover, it is also desirable that the inhibition of the T&ggr;9&dgr;2 lymphocytes for the treatment of an excess of activation of the T&ggr;9&dgr;2 lymphocytes does not destroy definitively the immune system of the patient or of the lymphocytic biological medium. Thus, the invention also seeks to provide compounds having an inhibitory activity which will be not only selective with respect to T&ggr;9&dgr;2 lymphocytes, but also reversible, such that the activity of the T&ggr;9&dgr;2 lymphocytes may ultimately be restored.
The invention also seeks to provide new phosphorated compounds and their process for production.
The invention also seeks to provide applications of the compounds according to the invention for the selective and reversible inhibition of the T&ggr;9&dgr;2 lymphocytes. More particularly, the invention seeks to provide applications for the compounds according to the invention for therapeutic use, of the applications of the compounds according to the invention for diagnosis, and applications of the compounds according to the invention for the experimental study of T&ggr;9&dgr;2 lymphocytes, their antigens or specific immunosuppressive agents.
The invention seeks particularly to provide a treatment for pathologies implying an activation of the T&ggr;9&dgr;2 lymphocytes, and particularly selected from malaria (malarial attack), visceral leishmaniosis, toxoplasmosis, brucellosis, tularemia, salmonelloses, tuberculosis, ehrlichiosis, auto-immune maladies such as sclerosis by plaques or the Behçet malady.
To do this, the invention relates to new compounds of the formula:
CH
3
—R
1
—(CH
2
)
2
—R
2
(I)
in which R
1
is selected from the following functions:
and R
2
is selected from the following groups:
in which CAT+ represents one or more organic or mineral cations (including the proton) identical or different, in the same compound, except for 3-methyl-3-butene-1-yl-difluoromethylenediphosphonate, and 3-methyl-3-butene-1-yl-methylenediphosphonate.
The compounds according to formula (I) of the invention are the following (IUPAC nomenclature):
R
1
: tertiary alcohol function:
3-methyl-3-butanol-1-yl-methylenediphosphonate;
3-methyl-3-butanol-1-yl-monofluoromethylenediphosphonate;
3-methyl-3-butanol-1-yl-difluoromethylenediphosphonate;
R
1
: 1,2 diol function:
3-methyl-3,4-butanediol-1-yl-methylenediphosphonate;
3-methyl-3,4-butanediol-1-yl-monofluoromethylenediphosphonate;
3-methyl-3,4-butanediol-1-yl-difluoromethylenediphosphonate.
R
1
: halohydrin function wherein X=Cl, Br, I:
3-(chloromethyl)-3-butanol-1-yl-methylenediphosphonate;
3-(chloromethyl)-3-butanol-1-yl-monofluoromethylenediphosphonate;
3-(chloromethyl)-3-butanol-1-yl-difluoromethylenediphosphonate;
3-(bromomethyl)-3-butanol-1-yl-methylenediphosphonate;
3-(bromomethyl)-3-butanol-1-yl-monofluoromethylenediphosphonate;
3-(bromomethyl)-3-butanol-1-yl-difluoromethylenediphosphonate;
3-(iodomethyl)-3-butanol-1-yl-monofluoromethylenediphosphonate;
3-(iodomethyl)-3-butanol-1-yl-methylenediphosphonate;
3-(iodomethyl)-3-butanol-1-yl-difluoromethylenediphosphonate.
R
1
: epoxyd function:
3,4-epoxy-3-methyl-1-butyl-methylenediphosphonate;
3,4-epoxy-3-methyl-1-butyl-monofluoromethylenediphosphonate;
3,4-epoxy-3-methyl-1-butyl-difluoromethylenediphosphonate.
R
1
: alkene function:
3-methyl-3-butene-1-yl-methylenediphosphonate;
3-methyl-3-butene-1-yl-monofluoromethylenediphosphonate;
3-methyl-3-butene-1-yl-difluoromethylenediphosphonate.
R
1
: aldehyde function (R
3
=H):
3-formyl-1-butyl-methylenediphosphonate;
3-formyl-1-butyl-monofluoromethylenediphosphonate;
3-formyl-1-butyl-difluoromethylenediphosphonate.
R
1
: &agr;-hydroxyaldehyde (R
3
=OH):
3-formyl-3-butanol-1-yl-methylenediphosphonate;
3-formyl-3-butanol-1-yl-monofluoromethylenediphosphonate;
3-formyl-3-butanol-1-yl-difluoromethylenediphosphonate.
The 3-methyl-3-butene-1-yl-difluoromethylenediphosphonate has been described by “phosphorylation of isoprenoid alcohols” V. Jo Davisson et al., J. Org. Chem. 1986, 51, 4775.
The invention moreover relates to compounds of formula (I) above (including 3-methyl-3-butene-1-yl-difluo
Belmant Christian
Bonneville Marc
Fournie Jean-Jacques
Kozikowski Alan P.
Peyrat Marc Alix
Institut National de la Sante et de la Recherche Medicale
McKane Joseph K.
Shameem Golam M. M.
Young & Thompson
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