Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Acyclic nitrogen double bonded to acyclic nitrogen – acyclic...
Reexamination Certificate
1999-03-30
2001-08-07
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Acyclic nitrogen double bonded to acyclic nitrogen, acyclic...
Reexamination Certificate
active
06271218
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a process for inhibiting deoxyribonucleotide triphosphate biosynthesis by cells, in particular animal, human or plant cells.
2. The Prior Art
It is known that genetic information is carried by the deoxyribonucleic acid (DNA) present in the cell nucleus. DNA comprises a double helix composed of nucleotides, which is fundamental to living organisms, whether animals or plants.
As is known, nucleotides are formed from a sugar, a heterocyclic nitrogenous base and at least one phosphate group. Four phosphates are present in the nucleotides which constitute DNA: deoxyguanidine triphosphate (dGTP), deoxythymidine trisphosphate (dTTP), deoxyadenosine triphosphate (DATP) and deoxycytidine triphosphate (dCTP).
It was noted some years ago that cancerous cells, because they are dividing rapidly, consume a large quantity of nucleotide triphosphates. Research has consequently focused on medicines capable of inhibiting the formation of the deoxyribonucleotides, such as for example 5-fluorouracil, aminopterin and amethopterin (c.f. J. David Rawn,
Biochemistry
, page 648). Hydroxyurea may also be mentioned, which non-selectively inhibits ribonucleotide reductase, and consequently all the nucleotides involved in DNA synthesis (c.f. “DRUG, Facts and comparisons”, J.B. Lippincott Company, 1990, pages 2258 and 2259; P. Reichard, “From RNA to DNA, why so many ribonucleotide reductases?”,
Science
, volume 260, 1993, pages 1773-1776).
The disadvantage of these products is that, given their lack of selectivity, they inhibit mechanisms which are indispensable to healthy, non-cancerous cells and relate to deoxynucleotides, such as for example intracellular energy transport and the enzymatic reactions catalyzed thereby. Treatment with these products consequently entails considerable toxicity for all cells.
The effect of an analogue of dCTP, cytosine arabinoside or cytarabine, which acts by taking the place of the natural molecule in cellular DNA by means of a competitive phenomenon has already been investigated (c.f. “DRUG” op. cit., pages 2192-2196). This product is not active when taken orally and must be administered with great caution.
Fundamental studies have moreover been undertaken to attempt to combine hydroxyurea with cytarabine. The expected effect was to replace with cytarabine the quantity of dCTP reduced by the action of hydroxyurea (c.f. abstract supplied by the database Medline Express of Schilsky, R. L. et al. “Laboratory and clinical studies of biochemical modulation by hydroxyurea”,
Semin. Onc
. Jun. 19, 1992 (3, suppl. 9), 84-89).
Cell lines other than those which are cancerous may have a greatly elevated proliferation rate. Such is the case for lymphocyte cells and the smooth muscle cells of blood vessels during organ transplants (allografts).
Attempts have already been made to control these cells by restricting their level of deoxynucleotides. Mycophenolic acid (MPA) or one of the derivatives thereof which blocks inosine monophosphate dehydrogenase, so bringing about a reduction in intracellular dGTP and consequently blocking DNA synthesis by these cells may be mentioned by way of example (c.f. Pichimayr, R., “Placebo-controlled study of mycophenolate mofetil combined with cyclosporin and corticosteroids for prevention of acute rejection”,
The Lancet
, volume 345, May 27, 1995, pages 1321-1325; Sollinger, H. W., “Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients”,
Transplantation
, volume 60, 225-232, number 3, 1995; Gregory, C. R., “Treatment with rapamycin and mycophenolic acid reduces arterial intimal thickening produced by mechanical injury and allows endothelial replacement”,
Transplantation
, volume 59, 655-661, number 5, 1995).
Finally, it is known that viral diseases, in particular AIDS, make significant use of the infected cell's genetic material to replicate the virus. It has recently been discovered that the above-mentioned mycophenolic acid had the ability, given its inhibitory action on the formation of dGTP in cells, to block the activity of reverse transcriptase in vitro and thus to have an anti-HIV effect (V. Hiroshi Ichimura and J. A. Levy, “Polymerase substrate depletion: A novel strategy for inhibiting the replication of the human immunodeficiency virus”,
Virology
211, 554-560, 1995).
The object of the present invention is to provide a process for inhibiting deoxyribonucleotide triphosphate biosynthesis by animal, human or plant cells which does not exhibit the above-stated disadvantages, in particular unacceptable toxicity for healthy cells, and which thus prevents the large-scale and abnormal cellular production of deoxyribonucleic acid, which may result, for example, in cancerous cell proliferation.
SUMMARY OF THE INVENTION
This object is achieved by a process as described above, comprising application onto said cells of at least one of the azo derivatives of the formula
in which R
1
, R
2
, R
3
and R
4
are identical or different and each represent a hydrogen or halogen atom or an optionally substituted aliphatic or aromatic hydrocarbon residue, R
1
and R
2
possibly being connected together to form a heterocyclic nucleus with the nitrogen atom adjacent thereto, and R
3
and R
4
possibly being connected together to form a heterocyclic nucleus with the nitrogen atom adjacent thereto, X
1
and X
2
are identical or different and each represent an oxygen atom or a group NR
5
, in which R
5
is a hydrogen or halogen atom, an optionally substituted aliphatic or aromatic hydrocarbon residue, or a nitro group, and in which, when two groups NR
5
are simultaneously present, each R
5
may be identical to or different from the other, as well as the isomers thereof.
Various of these azo derivatives are known compounds, in particular for their antiviral activity, in particular against viruses of the retrovirus group, in particular the AIDS virus (c.f. EP-A-0504184 and EP-A-0524961).
1,1-Azobisformamidine and 1,1′-azobisformamide were prepared as long ago as the end of the last century by J. Thiele (c.f. The Merck Index, 10
th
edition, 919, Rahway, 1983; F. C. Schmelkes et al., “N,N′-dichloroazocarbonamidine (azochloramide), a N-chloro derivative of the oxidant in an oxidation-reduction system”,
Journal of American Chemical Society
, 56, 1610, 1934; FR-B-2056874; U.S. Pat. No. 3,225,026; U.S. Pat. No. 3,684,713). 1,1′-Azobisformamide is known as an additive in flour for food use (U.S. Pat. No. 2,903,361). 1,1′-Azobisdimethylformamide has also long been known for its intracellular oxidising action on the glutathione in human blood cells (N. S. Kosower et al., “Diamide, a new reagent for the intracellular oxidation of glutathione to the disulfide”,
Biochemical
&
Biophysical Research Communications
, volume 37, number 4, 1969) and for its initiation of an additional Ca
2+
efflux from the liver of perfused rats (H. Sies et al., “Hepatic calcium efflux during cytochrome P-450-dependent drug oxidations at the endoplasmic reticulum in intact liver”,
Proc. Natl. Acad. Sci. USA
, volume 78, number 6, pages 3358-3362). This substance has also been studied for its inhibition of the repair of small breaks in DNA strands caused by cell irradiation in a hypoxic environment by means of ionizing radiation (R. E. Meyn et al., “Post-radiation treatment of CHO cells . . . ”,
Radiation Research
, volume 94, number 3, 1983, page 614; J. F. Ward et al., “Effects of inhibitors of DNA strand break repair . . . ”,
Cancer Research
, 44, 1984, pages 59-63). 1,1′-Azobisnitroformamidine has also long been known (W. D. Kumler, “The dipole moments, ultraviolet spectra and structure of azo-bis-(chloroformamidine) and azo-bis-(nitroformamidine)”,
Journal of American Chemical Society
, 75, 3092, 1953). Chloroazodin, which is used according to the invention, has also long been known as a disinfectant (c.f. U.S. Pat. No. 2,073,256 and GB-A-421006).
Observing the effects of these substances on cells i
Margery Helene
Vandevelde Michel
Dykema Gossett PLLC
Jones Dwayne C.
Previsan AG
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