Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-03-27
2002-05-07
Solola, T. A. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S341100
Reexamination Certificate
active
06384232
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to compounds containing a heteroatom-bearing bridge, and to complexes of these compounds with metals. In particular, the invention relates to improved and simplified methods of synthesizing such compounds using a novel intermediate.
BACKGROUND OF THE INVENTION
Metal complexes, such as those containing radioactive metals, are useful as diagnostic and therapeutic agents. Complexes containing bioactive moieties capable of being selectively taken up at a desired site to facilitate evaluation or treatment of a subject are of particular interest. For example, U.S. Pat. No. 5,608,110 discloses compounds containing a heteroatom-bearing bridge which may be complexed with a metal and used in diagnostic and therapeutic methods. Although U.S. Pat. No. 5,741,912 discloses methods for preparing a variety of such compounds, there remains a need for simplified methods of synthesizing these compounds. The present invention addresses the need in the art for improved and simplified methods of synthesizing ligands for use in metal complexes, particularly complexes containing hypoxia-localizing moieties.
SUMMARY OF THE INVENTION
The present invention features methods of making compounds, also referred to herein as ligands, using a novel intermediate. In particular, the invention features improved and simplified methods of making compounds having the structure of Formula I:
where all R and R* groups are independently:
(i) R
2
;
(ii) halogen, especially fluoro;
(iii) —OR
2
;
(iv) —C(O)—OR
2
;
(v) —C(O)—N(R
2
)
2
;
(vi) —N(R
2
)
2
;
(vii) -alkyl-C(O)—OR
2
;
(viii) -alkyl-C(O)—N(R
2
)
2
;
(ix) -alkyl-N(R
2
)
2
;
(x) -aryl-C(O)—OR
2
;
(xi) -aryl-C(O)—N(R
2
)
2
;
(xii) -aryl-N(R
2
)
2
;
(xiii) acyl;
(xiv) acyloxy;
(xv) heterocyclo;
(xvi) hydroxyalkyl;
(xvii) —SO
2
—R
2
;
(xviii) -alkyl-SO
2
—R
2
;
(xix) —(A)
p
—R
3
, where A is a linking group, p is 0 or a positive integer, and R
3
is a bioactive moiety; or
(xx) two R groups, or an R group and an R* group, taken together with the one or more atoms to which they are bonded, form a saturated or unsaturated, spiro or fused, carbocyclic (such as fused 1,2-phenyl) or heterocyclic ring which may be unsubstituted or substituted by one or more groups selected from the groups (i) to (xix) above;
with the proviso that a carbon atom bearing an R group is not directly bonded to more than one heteroatom; and
R
2
is independently hydrogen, alkyl, alkenyl, alkynyl, or aryl.
The synthetic method of the invention provides compounds of Formula I through the following novel intermediate compound (Formula II):
In the synthetic scheme of the present invention, the intermediate compound of Formula II may be isolated and purified. The synthetic method of the invention also provides stereoisomers of the intermediate compound, such as 2-{(1R)-2-(1,3-dioxoisoindolin-2-yl)-1-[(2-nitroimidazolyl)methyl]ethoxy}isoindoline-1,3-dione:
and 2-{(1S)-2-(1,3-dioxoisoindolin-2-yl)-1-[(2-nitroimidazolyl)methyl]ethoxy}isoindoline-1,3-dione:
The intermediate compound of Formula II may also be used to make a variety of compounds of Formula I. Preferred compounds are obtained by first reacting the intermediate of Formula II with hydrazine of the formula:
NH
2
—NH
2
to yield 1-[3-amino-2-(aminooxy)propyl]-2-nitro-1H-imidazole dihydrochloride, which is then reacted with a compound of Formula III. Compounds of Formula III may include compounds of Formula IIIa or Formula IIIb, set forth below, or a mixture of these two compounds:
where X is halogen (preferably Cl, Br or I) and R and R* are defined above, to yield a compound of Formula I. A preferred compound of Formula III is 3-chloro-3-methyl-2-nitrosobutane.
A preferred compound of Formula I is compound Ia, 3,3,9,9-tetramethyl-6-[(2-nitro-1H-imidazol-1-yl)methyl]-5-oxa-4,8-diazaundecane-2,10-dione dioxime:
The invention also provides methods of synthesizing stereoisomers of compound Ia, such as (S)-(−)-3,3,9,9-tetramethyl-6-[(2-nitro-1H-imidazol-1-yl)methyl]-5-oxa-4,8-diazaundecane-2,10-dione dioxime:
and R-(−)-3,3,9,9-tetramethyl-6-[(2-nitro-1H-imidazol-1-yl)methyl]-5-oxa-4,8-diazaundecane-2,10-dione dioxime:
Compounds of Formula I may be complexed with metals, preferably radioactive metals discussed below, such as rhenium or technetium, and used in diagnostic and therapeutic methods. Compounds of Formula I are derivatized with a 2-nitro-imidazole hypoxia-localizing moiety. This hypoxia-localizing moiety retains the biochemical behavior and affinity of the free moiety. Compounds of Formula I are capable of rapidly providing increased amounts of a desired radionuclide selectively to targeted areas, may be labeled at ambient temperature with suitable radionuclides, and are membrane permeable, allowing intracellular delivery. Compounds of Formula I may include one or more additional bioactive moieties.
As discussed in more detail below, the novel synthetic method disclosed herein is improved over the previously available methods in that it is simpler and provides better yields than those previously available.
DETAILED DESCRIPTION
Definitions
The following definitions apply to the terms as they are used throughout the specification, unless otherwise indicated.
The terms “alkyl” or “alk,” as used herein alone or as part of another group, denote optionally substituted, straight and branched chain saturated hydrocarbon groups, preferably having 1 to 12 carbons in the normal chain, most preferably lower alkyl groups. Exemplary unsubstituted groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl and the like. Exemplary substituents include one or more of the following groups: halo, alkoxy, arylalkyloxy (e.g., benzyloxy), alkylthio, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, hydroxy, carboxyl (—COOH), amino, alkylamino, dialkylamino, formyl, alkylcarbonyloxy, alkylcarbonyl, heterocyclo, aryloxy or thiol (—SH). Preferred alkyl groups are unsubstituted alkyl, haloalkyl, arylalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkyloxyalkyl, aryloxyalkyl, hydroxyalkyl and alkoxyalkyl groups.
The terms “lower alk” or “lower alkyl,” as used herein, denote such optionally substituted groups as described above for alkyl having 1 to 4 carbon atoms in the normal chain.
The terms “alkoxy” or “alkylthio” denote an alkyl group as described above bonded through an oxygen linkage (—O—) or a sulfur linkage (—S—), respectively. The term “alkylcarbonyl,” as used herein, denotes an alkyl group bonded through a carbonyl group. The term “alkylcarbonyloxy,” as used herein, denotes an alkyl group bonded through a carbonyl group which is, in turn, bonded through an oxygen linkage.
The term “alkenyl,” as used herein alone or as part of another group, denotes optionally substituted, straight and branched chain hydrocarbon groups containing at least one carbon to carbon double bond in the chain, and preferably having 2 to 10 carbons in the normal chain. Exemplary unsubstituted such groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, and the like. Exemplary substituents include one or more alkyl groups as described above, and/or one or more groups described above as alkyl substituents.
The term “alkynyl,” as used herein alone or as part of another group, denotes optionally substituted, straight and branched chain hydrocarbon groups containing at least one carbon to carbon triple bond in the chain, and preferably having 2 to 10 carbons in the normal chain. Exemplary unsubstituted such groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptenyl, octenyl, nonenyl, decenyl, and the like. Exemplary substituents include one or more alkyl groups as described above, and/or one or more groups described above as alkyl substituents.
The term “cycloalkyl,” as used herein alone or as part of another group, denotes optionally substituted, satu
Bracco International B.V.
Clark & Elbing LLP
Douros Timothy J.
Saeed Kamal
Solola T. A.
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