Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-10-21
2002-03-19
Gerstl, Robert (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S225000, C544S258000, C544S261000
Reexamination Certificate
active
06358953
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to novel pterin and pterin analog metal complexes that possess potent antineoplastic activity. This invention also relates to the preparation and use of these complexes in the treatment and prevention of cancer and viral infections.
BACKGROUND AND INTRODUCTION TO THE INVENTION
Hundreds of thousands of people die every year from cancer and for decades scientists have been searching for effective treatments. There are a wide variety of antineoplastic agents available. These agents are generally classified as alkylating agents, DNA binders, antimetabolites, and mitotic inhibitors.
While none have become an FDA approved cancer drug, it was known that several pteridine derivatives possessed some antineoplastic activity. For example, U.S. Pat. No. 5,534,514 teaches that xanthopterin, isoxanthopterin, and neopterin derivatives have antineoplastic activity. Also, 10-deazaminopterin, and 10-ethyl-10-deazaminopterin could be used in the treatment of leukemia according to U.S. Pat. Nos. 4,393,064 and 4,753,939, respectively. Pterin suspensions were tested by the NIH but showed no significant antineoplastic activity. None of these references disclose metal complexes of pterin or pterin analogs to treat cancer.
Metal complexes with specific ligands have been used successfully as antitumor agents. Cisplatin and carboplatin are two of such compounds.
Although there are a number of anticancer agents on the market, there will always be certain cancers which are resistant. Thus, there is a need for new antineoplastic agents.
SUMMARY OF THE INVENTION
The present invention is directed to novel metal pterin and pterin analog complexes of the formula I
(MX
a
)
y
(Pterins)
z
(I)
wherein
M is a bivalent metal ion selected from the group consisting of Ca
2+
, Cu
2+
, Mg
2+
, V
2+
, Cr
2+
, Mn
2+
, Fe
2+
, Co
2+
, Zn
2+
, Mo
2+
, Sr
2+
, Ba
2+
, Ra
2+
, Ru
2+
, Rh
2+
, Pd
2+
, Cd
2+
, Sn
2+
, W
2+
, Re
2+
, Os
2+
, Ir
2+
, Pt
2+
, Si
2+
, and Sm
2+
;
X is an anion of an acid and has a charge of−1 or −2 when ionized;
a is an integer of from 1 to 2;
y is an integer of from 1 to 6; and
z is an integer of from 1 to 6.
Also within the scope of the invention are suspensions prepared from Pterins and metal salts. Such suspensions are administered as antineoplastic and/or antiviral agents.
Definitions
“Pterins” refers to the following compounds which can exist as the tautomers
wherein
R
1
and R
2
are independently selected from the group consisting of hydrogen, alkyl, perhaloalkyl, carboxyl, amido, carboxamido, oxo, carboxy esters, amino, halogen, haloalkyl, hydroxy, alkoxy, azido, acylalkyl, hydroxyalkyl, —C(O)H, aryl, alicyclic, aralkyl, thioalkyl, sulfhydryl (—SH), sulfonyl (SO
2−
3
), —CN, perhaloalkoxy, and acyl;
R
5
and R
6
are independently selected from the group consisting of hydrogen, alkyl, perhaloalkyl, carboxyl, amido, carboxamido, oxo, carboxy esters, amino, halogen, haloalkyl, hydroxy, alkoxy, azido, acylalkyl, hydroxyalkyl, —C(O)H, aryl, alicyclic, aralkyl, thioalkyl, sulfhydryl (—SH), sulfonyl (SO
2−
3
), —CN, perhaloalkoxy, acyl, and null;
R
3
and R
4
are independently selected from the group consisting of —H, alkyl, —C(O)H, acyl, hydroxyalkyl, aryl, alkylaryl, hydroxy, oxo, acylalkyl, haloalkyl, perhaloalkyl, haloaryl, carboxyl, and null.
The dotted lines in the above structures represent optional bonds. The nitrogens in the B-ring can be neutral or positively charged. Thus, “Pterins” refers to both Pterin and pterin analogs including, but not limited to pterin, xanthopterin, and isoxanthopterin.
“Suspension” refers to the state of a substance when its particles are mixed but undissolved in a fluid or solid.
“RCOOH” refers to carboxylic acids, where R is alkyl, aryl, or aralkyl. Suitable anion carboxylic acids include CH
3
COO
−
, and phenyl-COO
−
.
“Alkyl” refers to saturated and unsaturated aliphatic groups including straight-chain, branched chain, and cyclic groups. Alkyl groups may be optionally substituted. Alkyl groups may contain double or triple bonds. Suitable alkyl groups include methyl.
“Aryl” refers to aromatic groups which have 5-14 ring atoms and at least one ring having a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl, and biaryl groups, which may be optionally substituted. Suitable aryl groups include phenyl.
Carbocyclic aryl groups are groups wherein the ring atoms on the aromatic ring are carbon atoms. Carbocyclic aryl groups include monocyclic and carbocyclic aryl groups and polycyclic or fused compounds such as optionally substituted naphthyl groups.
Heterocyclic aryl or heteroaryl groups are groups having from 1 to 4 heteroatoms as ring atoms in the aromatic ring and the remainder of the ring atoms being carbon atoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen. Suitable heteroaryl groups include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolyl, pyridyl-N-oxide, pyrimidyl, pyrazinyl, imidazolyl, and the like, all optionally substituted.
The term “biaryl” represents aryl groups containing more than one aromatic ring including both fused ring systems and aryl groups substituted with other aryl groups. Such groups may be optionally substituted. Suitable biaryl groups include naphthyl and biphenyl.
The term “alicyclic” means compounds which combine the properties of aliphatic and cyclic compounds. Such cyclic compounds include but are not limited to, aromatic, cycloalkyl and bridged cycloalkyl compounds. The cyclic compound includes heterocycles. Cyclohexenylethyl and cyclohexylethyl are suitable alicyclic groups. Such groups may be optionally substituted.
The term “optionally substituted” or “substituted” includes groups substituted by one to four substituents, independently selected from lower alkyl, lower aryl, lower aralkyl, lower alicyclic, hydroxy, lower alkoxy, lower aryloxy, perhaloalkoxy, aralkoxy, halo, azido, amino, acyl, lower alkylthio, oxo, acylalkyl, carboxy esters, carboxyl, carboxamido, nitro, acyloxy, alkylaryl, alkoxyaryl, phosphono, sulfonyl, hydroxyalkyl, haloalkyl, cyano, lower alkoxyalkyl, lower perhaloalkyl, and aralkyloxyalkyl.
The term “aralkyl” refers to an alkyl group substituted with an aryl group. Suitable aralkyl groups include benzyl, picolyl, and the like, and may be optionally substituted. The term “-aralkyl-” refers to a divalent group -aryl-alkylene-.
The term “lower” referred to herein in connection with organic radicals or compounds respectively defines such as with up to and including 10, preferably up to and including 6, and advantageously one to four carbon atoms. Such groups may be straight chain, branched, or cyclic.
The term “acyl” refers to —C(O)R where R is H, alkyl, and aryl.
The term “carboxy esters” refers to —C(O)OR where R is alkyl, aryl, aralkyl, and alicyclic, all optionally substituted.
The term “carboxyl” refers to —C(O)OH.
The term “oxo” refers to ═O in an alkyl group.
The term “amino” refers to —NRR′ where R and R′ are independently selected from hydrogen, alkyl, aryl, aralkyl and alicyclic, all except H are optionally substituted; and R and R
1
can form a cyclic ring system.
The term “halogen” or “halo” refers to —F, —Cl, —Br and —I.
The term “cyclic alkyl” or “cycloalkyl” refers to alkyl groups that are cyclic. Suitable cyclic groups include norbornyl and cyclopropyl. Such groups may be substituted.
The term “heterocyclic” and “heterocyclic alkyl” refer to cyclic groups containing at least one heteroatom. Suitable heteroatoms include oxygen, sulfur, and nitrogen. Heterocyclic groups may be attached through a nitrogen or through a carbon atom in the ring. Suitable heterocyclic groups include pyrrolidinyl, morpholino, morpholinoethyl, and pyridyl.
The term “phosphono” refers to —PO
3
R
2
, where R is selected from the group consisting of —H, alkyl, aryl, aralkyl, and alicyclic.
The term “sulphonyl” or “sulfonyl” refers to
Brobeck Phleger & Harrison LLP
Gerstl Robert
Moheno Phillip B. B.
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