Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Sulfur – selenium or tellurium compound
Reexamination Certificate
2001-01-06
2001-07-03
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Sulfur, selenium or tellurium compound
C514S706000, C514S707000
Reexamination Certificate
active
06255355
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a method for inhibiting angiogenesis. The method involves administering an effective amount of a disulfide or thiol-containing compound to a patient in need of angiogenesis inhibition.
BACKGROUND OF THE INVENTION
Angiogenesis is defined as the formation and differentiation of new blood vessels. It has been linked to a number of diseases and conditions, in particular to cancer and certain retinal disorders.
Angiogenesis inhibitors have recently become high profile agents in the fight against cancer, with several compounds drawing significant attention from the research and business communities. Several compounds, most notably angiostatin, endostatin, combretastatin, SU5416, TNP470, and others, have advanced into clinical trials as anticancer agents.
Mesna (sodium 2-mercaptoethene sulfonate) and dimesna (disodium 2,2′-dithiobis ethane sulfonate) are known therapeutic compounds that have heretofore demonstrated a wide variety of therapeutic uses. Both mesna and dimesna have been shown to be effective protective agents against certain specific types of toxicity associated with the administration of cytotoxic drugs used to treat patients for various types of cancer.
In particular, mesna has been used with some success in mitigating the toxic effects of cytotoxic agents such as ifosfamide, oxazaphosphorine, melphalane, cyclophosphamide, trofosfamide, sulfosfamide, chlorambucil, busulfan, triethylene thiophosphamide, triaziquone, and others, as disclosed in U.S. Pat. No. 4,220,660, issued Sep. 2, 1980.
The near absence of toxicity of dimesna further underscores the usefulness of this compound, as large doses can be given to a patient without increasing the risk of adverse effects from the protective agent itself.
Further, pharmacological profiles of each compound indicate that, if proper conditions are maintained, mesna and dimesna do not prematurely inactivate primary therapeutic drugs to a significant degree. Thus, neither compound will significantly reduce activity of the chemotherapeutic agent, and in many cases, act to potentiate the effect of the main drug on targeted cancer cells.
The molecular structures of both mesna and dimesna are shown below as Structure I and Structure II respectively.
HS—CH
2
—CH
2
—SO
3
Na (I)
NaSO
3
—CH
2
—CH
2
—S—S—CH
2
—CH
2
—SO
3
Na (II)
As shown, dimesna is a dimer of mesna, with the optimum conditions for oxidation occurring in the slightly basic (pH~7.3), oxygen rich environment found in blood plasma. In mildly acidic, low oxygen conditions, in the presence of a reducing agent such as glutathione reductase, conditions prevalent in the kidneys, the primary constituent is mesna.
Mesna acts as a protective agent for a number of cytotoxic agents by substituting a nontoxic sulfhydryl moiety for a toxic hydroxy (or aquo) moiety. This action is particularly evidenced in the coadministration of mesna and oxazaphosphorine, and in the administration of dimesna along with certain platinum agents and/or taxanes.
Dimesna, as well as some analogues, have excellent toxicity profiles in mammalian species. In fact, dimesna has been administered intravenously to mice and dogs in doses higher than the accepted oral LD
50
for common table salt (3750 mg/kg), with no adverse effects. Dimesna has also been administered to humans in doses exceeding 40 g/m
2
, with no adverse effects.
Mesna, and other analogues with free thiol moieties, constitute the more physiologically active form of the two types of compounds described in this specification. These compounds manifest their activity by providing free thiol moieties for terminal substitution at locations where a terminal leaving group of appropriate configuration, usually a hydroxy, aquo or superoxide is located. Mesna also tends to form conjugates with naturally occurring biochemicals that contain a free thiol moiety, such as cysteine, glutathione, homocysteine, and others.
Dimesna and other disulfides can be activated intracellularly by glutathione reductase, a ubiquitous enzyme, thereby generating high concentrations of intracellular free thiols. These free thiols act to scavenge the free radicals and other nucleophilic compounds often responsible for causing cell damage.
This profile is especially significant in explaining the success of dimesna in controlling and mitigating the toxic effects of platinum complex antitumor drugs. The mechanism for action in the case of cisplatin (cis-diammine dichloro platinum) is explained in U.S. Pat. No. 5,789,000, which is incorporated herein by reference.
Mesna, dimesna, and analogues of these compounds have been the subject of several prior pharmaceutical uses described in the literature and in prior patents, both in the United States and around the world. In addition to the cytotoxic agent protection uses, one or more of these compounds have proven effective, in vitro, against a multiplicity of biological targets, and have been effective, in vivo, in the treatment of sickle cell disease, radiation exposure, chemical agent exposure, and other uses.
Mesna, dimesna, and analogues thereof are synthesized from commonly available starting materials, using acceptable routes well known in the art. One such method involves the two-step, single pot synthetic process for making dimesna and like compounds of the following formula:
R
1
—S—R
2
;
wherein:
R
1
is hydrogen, X-lower alkyl, or X-lower alkyl-R
3
;
R
2
is -lower alkyl-R
4
;
R
3
and R
4
are each individually SO
3
M or PO
3
M
2
;
X is absent or X is sulfur; and
M is an alkali metal.
The process essentially involves a two-step single pot synthetic process, which results in the conversion of an alkenyl sulfonate salt or acid to the desired formula I compound. The process in the case of mesna is a single step process that converts the alkenyl sulfonate salt to mesna or a mesna derivative by reacting with an alkali metal sulfide or with hydrogen sulfide.
If the desired end product is dimesna or a dimesna analogue, a two-step single pot process is involved. Step 1 is as described above. Step 2 of the process is performed in the same reaction vessel as Step 1 without the need to purify or isolate the mesna formed during that step. Step 2 includes the introduction of oxygen gas into the vessel, along with an increase in pressure and temperature above ambient values, at least 20 pounds per square inch (psi) and at least 60° C. Dimesna or a derivative thereof is formed in essentially quantitative yield.
Other processes, well known and documented in the prior art, may be employed to make either mesna or dimesna, or derivatives and analogues thereof.
SUMMARY OF THE INVENTION
This invention involves the administration of an effective amount of a compound of formula I, below, to inhibit angiogenesis:
wherein:
R
1
is hydrogen, lower alkyl or
R
2
and R
4
are each individually SO
3
−
M
+
, PO
3
2−
M
2
2+
, or PO
2
S
2−
M
2
2+
;
R
3
and R
5
are each individually hydrogen, hydroxy or sulfhydryl;
Each m is individually 1, 2, 3, 4, 5 or 6 with the proviso that if m is 1, then R
3
is hydrogen; and
M is hydrogen or an alkali metal ion; or
a pharmaceutically acceptable salt thereof.
Effective amounts of the formula I compound to be administered according to the method of this invention are variable, and depend upon the individual patient's response. However, due to the excellent toxicity profile of the formula I compounds, large amounts of drug may be administered, such as by continuous IV drip, without risk of untoward side effects commonly associated with other drugs used to treat this condition.
Accordingly, it is an object of this invention to provide for a method of safely and effectively inhibiting angiogenesis.
Another object is to provide a method of inhibiting angiogenesis by administration of a thiol or reducible disulfide to the patient desirous of treatment.
Other objects will become apparent upon a reading of the following description.
REFERENCES:
patent: 6143796 (2000-11-01), Hausheer
patent: 6172119 (2001-01
Dodd Thomas J.
Henley III Raymond
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