Quinone derivatives

Details Quinone derivatives Quinone derivatives

1999-05-21

2002-08-13

Qazi, Sabiha (Department: 1616)

Organic compounds -- part of the class 532-570 series

Organic compounds

Cyclopentanohydrophenanthrene ring system wherein two...

C548S516000, C548S302700

Reexamination Certificate

active

06433199

ABSTRACT:

BACKGROUND OF THE INVENTION
Based on the statistics provided by the American Cancer Society, approximately four million people have died from cancer since 1990, and cancer, after heart disease, is the second leading cause of death in the United States. Treatments of cancer usually include chemotherapy, radiation, hormones, immunotherapy, and surgery. Chemotherapy remains a preferred treatment, especially in cancer types that are in inoperable or metastatic forms.
Many cytotoxic agents, including antimetabolites, antibiotics, alkylating agents, and mitotic inhibitors, are now available in chemotherapy. These agents usually destroy both normal and tumor cells. It is desirable to develop an antitumor agent that preferentially destroys tumor cells over normal cells.
Due to their pathological conditions, tumor cells differ from normal cells in that their surrounding blood vessels are poorly organized, resulting in inefficient delivery of oxygen to the tumor site. In other words, tumor cells are hypoxic (oxygen deficient). This unique physiology opens the door to the design of cytotoxic agents that are specific for tumor cells.
SUMMARY OF THE INVENTION
An aspect of this invention relates to a cytotoxic compound which consists of three components: (1) a proactive alkylating moiety containing an electron-withdrawing group; (2) a bioreductive moiety containing at least two double bonds; and (3) a linker joining together the proactive alkylating moiety and the bioreductive moiety. A “proactive alkylating moiety” refers to a functional group which, once activated, replaces an active hydrogen atom of another compound, such as DNA, with one of its alkyl groups in a covalent manner. A “bioreductive moiety” refers to a moiety that is capable of undergoing an in vivo reduction (electron-accepting reaction), i.e., bioreduction. The double bonds of the bioreductive moiety, either by themselves, or together with that of the linker, form a conjugated system. The conjugated system allows electrons to flow from the bioreductive moiety to the electron-withdrawing group of the proactive alkylating moiety upon reduction of the bioreductive moiety. This results in breaking the bond between the electron-withdrawing group and the linker and converting the proactive alkylating moiety into an active alkylating compound.
An example of the proactive alkylating moiety is an aromatic group (e.g., phenyl group or naphthyl) substituted with an electron-withdrawing group (e.g., ester, urethane, or carbonate) and a bis(haloethyl)amino group (e.g., a bis(chloroethyl)amino group or nitrogen mustard). The bis(haloethyl)amino group, upon bioreduction, becomes an alkylating group. When the aromatic moiety is a phenyl, each of the two substituents is preferred to be at a meta or para position with respect to each other. Each of the remaining positions of the phenyl, independently, is optionally substituted with alkyl, alkenyl, aryl, aralkyl, heteroaryl, heteroaralkyl, amino, aminoalkyl, hydroxyl, hydroxylalkyl, alkoxy, aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy, oligoalkylene glycol, amido, ester, aralkoxycarbonylamino, ureido, thio, alkylthio, arylthio, or heteroarylthio. Among them, alkyl, alkoxy, oligoalkylene glycol, aryloxy, heteroaryloxy, and amino are preferred. It is preferable that each of these substituents is at an ortho position with respect to the bis(haloethyl)amino group.
The bioreductive moiety is converted into a second alkylating agent upon bioreduction. Some examples of the bioreductive moiety are 1,4-benzoquinone (i.e., quinone), nitrobenzene, or 1,2-dioxocyclohex-3,5-diene. When the bioreductive moiety is quinone, each of the non-oxo positions of the quinone ring, independently, is optionally substituted with alkyl, alkenyl, aryl, aralkyl, heteroaryl, heteroaralkyl, amino, aminoalkyl, hydroxyl, hydroxylalkyl, alkoxy, aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy, carboxylate, acyloxyalkyl, ester, amido, amidoalkyl, sulfoamido, sulfonylamino, thio, alkylthio, arylthio, aralkylthio, heteroarylthio, or heteroaralkylthio. The preferred substituents are alkyl, amino, aminoalkyl, alkoxy, hydroxylalkyl, and acyloxyalkyl. If both 2-C and 3-C positions or both 5-C and 6-C positions of the quinone are substituted, the two substituents optionally together form a ring. Two fused rings can be formed with the quinone ring if all non-oxo positions of the quinone are substituted and each pair of the substituents together form a fused ring. The fused ring can be either aliphatic or aromatic. It is also optionally substituted with alkyl, alkenyl, aryl, aralkyl, heteroaryl, heteroaralkyl, amino, aminoalkyl, hydroxyl, hydroxylalkyl, alkoxy, aryloxy, aralkoxy, heteroaryloxy, heteroaralkoxy, carboxylate, acyloxyalkyl, ester, amido, amidoalkyl, sulfoamido, sulfonylamino, thio, alkylthio, arylthio, aralkylthio, heteroarylthio, or heteroaralkylthio. The fused ring optionally contains 1-3 heteroatoms, such as nitrogen, oxygen, or sulfur.
The linker which links the proactive alkylating moiety and the bioreductive moiety together can be one of the following: a methylene group, a C
3
hydrocarbon chain containing a double bond, or a C
5
hydrocarbon chain containing two alternate double bonds. This linker is optionally substituted with alkyl, alkenyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or oligoalkylene glycol. If the linker contains more than two substituents, two of them can join together to form a 5-6 membered ring. The ring can be aliphatic or aromatic and is optionally substituted with alkyl, alkenyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or oligoalkylene glycol. One to three heteroatoms such as nitrogen, oxygen, or sulfur, can form part of the ring.
A salt of a cytotoxic compound is also within the scope of this invention. For example, the salt can be formed between an amino substituent of a cytotoxic compound and a negatively charged counterion. Suitable counterions include, but are not limited to, chloride, hydrochloride, bromide, iodide, sulfate, nitrate, phosphate, or acetate. Likewise, a negatively charged substituent, e.g., carboxylate, of a compound of this invention can also form a salt with a cation, e.g., an alkali metal cation such as sodium ion or potassium ion; an alkaline earth metal cation such as magnesium cation or calcium cation; or an ammonium cation that can be substitued with one or more organic groups such as tetramethylammonium ion or diisopropylethylammonium ion.
The term “alkyl” in this disclosure denotes a straight or branched hydrocarbon chain containing 1 to 8 carbon atoms, or cyclic hydrocarbon chain containing 3 to 8 carbon atoms. The cyclic hydrocarbon chain may contain 1-3 heteroatoms such as nitrogen, oxygen, or sulfur and may also contain fused rings. Fused rings are rings that share a common carbon-carbon bond. Examples of alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, amyl, isopentyl, hexyl, isohexyl, heptyl, octyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, isobornyl, cyclohexylmethyl, 1- or 2-cyclohexylethyl, 1-, 2-, or 3-cyclohexylpropyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholino and pyrrolindinyl groups.
By the term “alkenyl” is meant a straight or branched hydrocarbon chain containing 2 to 8 carbon atoms or cyclic hydrocarbon chain, i.e., “cycloalkenyl,” containing 3 to 8 carbon atoms, which is characterized by having one or more double bonds. The cycloalkenyl may contain 1-3 heteroatoms such as nitrogen, oxygen, or sulfur, i.e., “heterocycloalkenyl,” and may also contain fused rings. Typically alkenyl groups include allyl, 2-butenyl, 2-pentenyl, 2-hexenyl, cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclo-octenyl, and norbornylenyl.
“Aryl” is an cyclic aromatic moiety containing 3-8 carbon atoms and may also contain fused rings. Fused aryl denotes an aromatic ring that shares a common carbon-carbon bond with another cyclic moiety. This cyclic moiety can be either an aryl, a cycloalkyl, or a heterocycloalkyl. Typically aryl groups include pheny

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