Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-07-02
2003-02-04
Lambkin, Deborah C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S102000
Reexamination Certificate
active
06514987
ABSTRACT:
TECHNICAL FIELD
This invention relates to compounds which are useful for inactivating pathogens in a material, such as a blood product, and to methods of use of the compounds.
BACKGROUND ART
The transmission of disease by blood products and other biological materials remains a serious health problem. While significant advances in blood donor screening and blood testing have occurred, viruses such as hepatitis B (HBV), hepatitis C (HCV), and human immunodeficiency virus (HIV) may escape detection in blood products during testing due to low levels of virus or viral antibodies. In addition to the viral hazard, there are currently no licensed tests to screen for the presence of bacteria or protozoans in blood intended for use in transfusions. The risk also exists that a hitherto unknown pathogen may become prevalent in the blood supply and present a threat of disease transmission, as in fact occurred before the recognition of the risk of HIV transmission via blood transfusions.
Exposure of laboratory workers to blood or other body fluids also presents a health hazard. Twelve thousand health-care workers whose jobs involve exposure to blood are infected with hepatitis B virus each year, according to estimates from the Centers for Disease Control (“Guidelines for Prevention of Transmission of Human Immunodeficiency Virus and Hepatitis B Virus to Health-Care and Public-Safety Workers,” Morbidity and Mortality Weekly Report, vol. 38, no. S-6, June 1989).
Several methods have been proposed to complement donor screening and blood testing to decrease the incidence of disease due to transfusions. The introduction of chemical agents into blood or blood plasma has been suggested to inactivate pathogens prior to clinical use of the blood product. Nitrogen mustard, CH
3
—N(CH
2
CH
2
Cl)
2
, was added to blood components in an investigation of potential virucidal agents. However, substantial hemolysis occurred at the concentrations necessary to inactivate one of the viruses studied, rendering nitrogen mustard unsuitable for use in blood. LoGrippo et al., Proceedings of the Sixth Congress of the International Society of Blood Transfusion, Bibliotheca Haematologica (Hollander, ed.), 1958, pp. 225-230.
A “solvent/detergent” (S/D) method for inactivating viruses was described in Horowitz et al.,
Blood
79:826 (1992) and in Horowitz et al.,
Transfusion
25:516 (1985). This method utilized 1% tri(n-butyl)phosphate and 1% Triton X-100 at 30° C. for 4 hours to inactivate viruses in fresh frozen plasma. Piquet et al., Vox Sang. 63:251 (1992), used 1% tri(n-butyl)phosphate and 1% Octoxynol-9 to inactivate viruses in fresh frozen plasma. Another method for inactivating viruses in blood involves the addition of phenol or formaldehyde to the blood. U.S. Pat. No. 4,833,165. However, both the solvent/detergent method and the phenol/formaldehyde method require removal of the chemical additives prior to clinical use of the blood product.
Inactivation of pathogens in blood products using photoactivated agents has also been described; see, e.g., Wagner et al.,
Transfusion
, 34:521 (1994). However, due to the absorption of light by hemoglobin in several regions in the ultraviolet and visible spectrum, phototreatment is limited in its application to materials containing red blood cells. There is also some indication that phototreatment of red blood cells alters the cells in some manner; see Wagner et al.,
Transfusion
33:30 (1993).
There is thus a need for compositions and methods for treating blood, blood-derived products, and other biological materials, which will inactivate pathogens present in the products or materials without rendering the products or materials unsuitable for their intended use. Compositions which do not need to be removed from the biological material prior to its use would be particularly useful, as equipment and supplies needed to remove the compositions would be obviated and the costs of handling the biological material would be reduced. This places an additional requirement on the composition, however, in that if the composition remains in the biological material, it must not pose a hazard when the biological material is used for its intended purpose. For example, a highly toxic compound which inactivates pathogens in a blood sample would preclude the use of that blood for transfusion purposes (although the blood sample may still be suitable for laboratory analysis).
It is one intention of this invention to provide compositions and methods of use of the compositions for inactivating pathogens in biological materials, without rendering the materials unsuitable for their intended purpose. Examples of how this may be accomplished include, but are not limited to, using the compounds in an ex vivo or in vitro treatment of the biological materials and then removing the compounds prior to the use of the material; by using a composition which, even though it remains in the material, does not render the material unsuitable for its intended use; or by using a composition which, after inactivating pathogens in the material, will break down to products, where the breakdown products can remain in the material without rendering the material unsuitable for its intended use.
DISCLOSURE OF THE INVENTION
Accordingly, it is an object of this invention to provide compounds for inactivating pathogens in a material, where such compounds comprise a nucleic acid binding moiety; an effector moiety, capable of forming a covalent bond with nucleic acid; and a frangible linker covalently linking the nucleic acid moiety and the effector moiety; wherein the frangible linker degrades so as to no longer covalently link the nucleic acid binding moiety and the effector moiety, under conditions which do not render the material unsuitable for its intended purpose.
It is an additional object of this invention to provide such compounds for inactivating pathogens in a material, wherein the nucleic acid binding moiety is selected from the group consisting of acridine, acridine derivatives, psoralen, isopsoralen and psoralen derivatives.
It is an additional object of this invention to provide such compounds for inactivating pathogens in a material, wherein the frangible linker comprises a functional unit selected from the group consisting of forward esters, reverse esters, forward amides, reverse amides, forward thioesters, reverse thioesters, forward and reverse thionoesters, forward and reverse dithioic acids, sulfates, forward and reverse sulfonates, phosphates, and forward and reverse phosphonate groups, as defined herein.
It is an additional object of this invention to provide such compounds for inactivating pathogens in a material, wherein the effector group comprises a functional unit which is an alkylating agent.
It is an additional object of this invention to provide such compounds for inactivating pathogens in a material, wherein the effector group comprises a functional unit selected from the group consisting of mustard groups, mustard group equivalents, epoxides, aldehydes, and formaldehyde synthons.
It is an additional object of this invention to provide compounds of the formula:
wherein at least one of R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
and R
9
is —V—W—X—E as defined below, and the remainder of R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
and R
9
are independently selected from the group consisting of —H, —R
10
, —O—R
10
, —NO
2
, —NH
2
, —NH—R
10
, —N(R
10
)
2
, —F, —Cl, —Br, —I, —C(═O)—R
10
, —C(═O)—O—R
10
, and —O—C(═O)—R
10
,
where —R
10
is independently H, —C
1-8
alkyl, —C
1-8
heteroalkyl, -aryl, -heteroaryl, —C
1-3
alkyl-aryl, —C
1-3
heteroalkyl-aryl, —C
1-3
alkyl-heteroaryl, —C
1-3
heteroalkyl-heteroaryl, -aryl-C
1-3
alkyl, -aryl-C
1-3
heteroalkyl, -heteroaryl-C
1-3
alkyl, -heteroaryl-C
1-3
heteroalkyl, —C
1-3
alkyl-aryl-C
1-3
alkyl, —C
1-3
heteroalkyl-aryl-C
1-3
alkyl, —C
1-3
alkyl-heteroaryl-C
1-3
alkyl, —C
1-3
alkyl-aryl-C
1-3
heteroalkyl, —C
1-3
heteroalkyl-heteroaryl-C
1-3
alkyl, —C
1-3
heteroalkyl-aryl-C
1-3
heteroalkyl, —C
1-3
alkyl-heteroaryl-C
1-3
heteroalkyl, o
Cook David
Denny William A.
Matejovic Jan
Merritt John E.
Nerio Aileen
Cerus Corporation
Lambkin Deborah C.
Tessman John W.
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