U.S. patent application number 12/643752 was filed with the patent office on 2010-04-29 for dipterinyl calcium pentahydrate (dcp) and therapeutic methods based thereon.
Invention is credited to Phillip Moheno, Wolfgang Pfleiderer.
Application Number | 20100105692 12/643752 |
Document ID | / |
Family ID | 39344907 |
Filed Date | 2010-04-29 |
United States Patent
Application |
20100105692 |
Kind Code |
A1 |
Moheno; Phillip ; et
al. |
April 29, 2010 |
Dipterinyl Calcium Pentahydrate (DCP) and Therapeutic Methods Based
Thereon
Abstract
Provided herein is dipterinyl calcium pentahydrate (DCP) and
therapeutic methods based thereon. Also provided herein is the
compound dipterinyl calcium pentahydrate (DCP) or an analog or
polymorph thereof.
Inventors: |
Moheno; Phillip; (La Jolla,
CA) ; Pfleiderer; Wolfgang; (Konstanz, DE) |
Correspondence
Address: |
WILSON, SONSINI, GOODRICH & ROSATI
650 PAGE MILL ROAD
PALO ALTO
CA
94304-1050
US
|
Family ID: |
39344907 |
Appl. No.: |
12/643752 |
Filed: |
December 21, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11981398 |
Oct 30, 2007 |
7662820 |
|
|
12643752 |
|
|
|
|
60863547 |
Oct 30, 2006 |
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Current U.S.
Class: |
514/249 |
Current CPC
Class: |
C07D 475/04 20130101;
A61P 35/00 20180101; A61P 31/00 20180101 |
Class at
Publication: |
514/249 |
International
Class: |
A61K 31/4985 20060101
A61K031/4985; A61P 31/00 20060101 A61P031/00; A61P 35/00 20060101
A61P035/00; A61P 37/00 20060101 A61P037/00 |
Claims
1.-3. (canceled)
4. A method of treating disease in a subject comprising the
administration of a therapeutically effective amount of a compound
of formula (I): M(pterin).sub.x(H2O).sub.y wherein: M is a bivalent
metal ion selected from the group consisting of Ca.sup.2+,
Cu.sup.2+, Mg.sup.2+, V.sup.2+, Cr.sup.2+, Mn.sup.2+, Fe.sup.2+,
Mo.sup.2+, Zn.sup.2+, Sr.sup.2+, Ba.sup.2+, Ra.sup.2+, Ru.sup.2+,
Rh.sup.2+, Pd.sup.2+, Cd.sup.2+, Sn.sup.2+, W.sup.2+, Re.sup.2+,
Os.sup.2+, Ir.sup.2+, Pt.sup.2+, Si.sup.2+, and Sm.sup.2+; X is an
integer from 1 to 8; and y is an integer of from 1 to 8.
5. The method of claim 4 wherein the compound of formula (I) is
dipterinyl calcium pentahydrate (DCP).
6. The method of claim 5 wherein the disease is a neoplastic
disease.
7. The method of claim 5 wherein the disease is an infectious
disease.
8. The method of claim 6 comprising modulating tryptophan
degradation.
9. The method of claim 6 comprising modulating neopterin
production.
10. The method of claim 6 comprising modulating IFN-.gamma.
production.
11. The method of claim 6 comprising modulating the activity of the
enzyme IDO.
12. The method of claim 6 comprising modulating immune resistance
in human solid tumors.
13.-21. (canceled)
Description
RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional
Application No. 60/863,547, filed on Oct. 30, 2006, which is
incorporated by reference in its entirety.
SUMMARY OF THE INVENTION
[0002] One embodiment provides dipterinyl calcium pentahydrate
(DCP) and therapeutic methods based thereon. Another embodiment
provides the compound dipterinyl calcium pentahydrate (DCP) or an
analog or polymorph thereof. Another embodiment provides a method
of synthesizing dipterinyl calcium pentahydrate (DCP) comprising:
dissolving pterin in an aqueous solution of NaOH, adding
CaCl.sub.2.2H.sub.2O to the solution with stirring at a pH of about
11, continuing stirring for about 1 day, and collecting the
precipitate as DCP. One embodiment provides a method of modulating
tryptophan production comprising administering to a subject an
effective amount of DCP. Another embodiment provides a method of
modulating tryptophan production comprising administering to a
subject an effective amount of DCP suspension. Additional
embodiments provide a method of modulating tryptophan degradation
comprising administering to a subject an effective amount of DCP.
Another embodiment provides method of modulating tryptophan
degradation comprising administering to a subject an effective
amount of DCP suspension. Another embodiment provides a method of
modulating neopterin production comprising administering to a
subject an effective amount of DCP. An additional embodiment
provides a method of modulating neopterin production comprising
administering to a subject an effective amount of DCP
suspension.
[0003] Yet another embodiment provides a method of modulating
IFN-.gamma. production comprising administering to a subject an
effective amount of DCP. An additional embodiment provides a method
of modulating IFN-.gamma. production comprising administering to a
subject an effective amount of DCP suspension. One embodiment
provides a method of modulating the activity of the enzyme IDO
comprising administering to a subject an effective amount of DCP.
Another embodiment provides a method of modulating the activity of
the enzyme IDO comprising administering to a subject an effective
amount of DCP suspension. One embodiment provides a method of
modulating oxidants production comprising administering to a
subject an effective amount of DCP. Another embodiment provides a
method of modulating oxidants production comprising administering
to a subject an effective amount of DCP suspension. Yet another
embodiment provides a method of modulating free radical production
comprising administering to a subject an effective amount of DCP.
An additional embodiment provides a method of modulating free
radical production comprising administering to a subject an
effective amount of DCP suspension
[0004] One embodiment provides a method of modulating release of
reactive oxygen species (ROS) comprising administering to a subject
an effective amount of DCP. Another embodiment provides a method of
modulating release of reactive oxygen species (ROS) comprising
administering to a subject an effective amount of DCP suspension.
An additional embodiment provides a method of modulating release
pro-inflammatory transcription factor NF-.kappa.B comprising
administering to a subject an effective amount of DCP. A further
embodiment provides a method of modulating release pro-inflammatory
transcription factor NF-.kappa.B comprising administering to a
subject an effective amount of DCP suspension. Another embodiment
provides a method of modulating the expression of down-stream genes
for a cytokine, a chemokine, adhesion molecule, growth factor,
enzyme and/or immune receptor comprising administering to a subject
an effective amount of DCP. An additional embodiment provides a
method of modulating the expression of down-stream genes for a
cytokine, a chemokine, adhesion molecule, growth factor, enzyme
and/or immune receptor comprising administering to a subject an
effective amount of DCP suspension. Another embodiment provides a
method of reducing inflammatory activity in a subject comprising
administering to a subject an effective amount of DCP. A further
embodiment provides a method of reducing inflammatory activity in a
subject comprising administering to a subject an effective amount
of DCP suspension. Yet another embodiment provides a method of
reducing or suppressing expression of the enzyme IDO comprising
administering to a subject an effective amount of DCP. Another
embodiment provides a method of reducing or suppressing expression
of the enzyme IDO comprising administering to a subject an
effective amount of DCP suspension. One embodiment provides a
method of modulating human T-cell response comprising administering
to a subject an effective amount of DCP. Another embodiment
provides a method of modulating human T-cell response comprising
administering to a subject an effective amount of DCP
suspension.
[0005] One embodiment provides a method of reducing or suppressing
allogeneic immune tolerance comprising administering to a subject
an effective amount of DCP. Another embodiment provides a method of
reducing or suppressing allogeneic immune tolerance comprising
administering to a subject an effective amount of DCP suspension.
Another embodiment provides a method of modulating immune
resistance in human solid tumors comprising administering to a
subject an effective amount of DCP. Another embodiment provides a
method of modulating immune resistance in human solid tumors
comprising administering to a subject an effective amount of DCP
suspension. Another embodiment provides a method of modulating
antiproliferative activity comprising administering to a subject an
effective amount of DCP. Another embodiment provides a method of
modulating antiproliferative activity comprising administering to a
subject an effective amount of DCP suspension.
[0006] One embodiment provides a compound of formula (I):
M(pterin).sub.x(H.sub.2O).sub.y [0007] wherein: [0008] M is a
bivalent metal ion selected from the group consisting of Ca.sup.2+,
Cu.sup.2+, Mg.sup.2+, V.sup.2+, Cr.sup.2+, Mn.sup.2+, Fe.sup.2+,
Mo.sup.2+, Zn.sup.2+, Sr.sup.2+, Ba.sup.2+, Ra.sup.2+, Ru.sup.2+,
Rh.sup.2+, Pd.sup.2+, Cd.sup.2+, Sn.sup.2+, W.sup.2+, Re.sup.2+,
Os.sup.2+, Ir.sup.2+; Pt.sup.2+, Si.sup.2+; and Sm.sup.2+; [0009] X
is an integer from 1 to 8; and [0010] y is an integer of from 1 to
8.
[0011] Another embodiment provides a method of inhibiting tumor
cells in an animal comprising the administration of a
therapeutically effective amount of a compound of formula (I):
M(pterin).sub.x(H.sub.2O).sub.y [0012] wherein: [0013] M is a
bivalent metal ion selected from the group consisting of Ca.sup.2+,
Cu.sup.2+, Mg.sup.2+, V.sup.2+, Cr.sup.2+, Mn.sup.2+, Fe.sup.2+,
Mo.sup.2+, Zn.sup.2+, Sr.sup.2+, Ba.sup.2+, Ra.sup.2+, Ru.sup.2+,
Rh.sup.2+, Pd.sup.2+, Cd.sup.2+, Sn.sup.2+, W.sup.2+, Re.sup.2+,
Os.sup.2+, Ir.sup.2+, Pt.sup.2+, Si.sup.2+, and Sm.sup.2+; [0014] X
is an integer from 1 to 8; and [0015] y is an integer of from 1 to
8.
[0016] One embodiment provides a method of treating a viral
infection comprising the administration of a therapeutically
effective amount of a compound of formula (I):
M(pterin).sub.x(H.sub.2O).sub.y
wherein: [0017] M is a bivalent metal ion selected from the group
consisting of Ca.sup.2+, Cu.sup.2+, Mg.sup.2+, V.sup.2+, Cr.sup.2+,
Mn.sup.2+, Fe.sup.2+, Mo.sup.2+, Zn.sup.2+, Sr.sup.2+, Ba.sup.2+,
Ra.sup.2+, Ru.sup.2+, Rh.sup.2+, Pd.sup.2+, Cd.sup.2+, Sn.sup.2+,
W.sup.2+, Re.sup.2+, Os.sup.2+, Ir.sup.2+, Pt.sup.2+, Si.sup.2+,
and Sm.sup.2+; [0018] X is an integer from 1 to 8; and [0019] y is
an integer of from 1 to 8.
[0020] Another embodiment provides a pharmaceutical composition
comprising a pharmaceutically acceptable excipient and a compound
of formula (I):
M(pterin).sub.x(H.sub.2O).sub.y [0021] wherein: [0022] M is a
bivalent metal ion selected from the group consisting of Ca.sup.2+,
Cu.sup.2+, Mg.sup.2+, V.sup.2+, Cr.sup.2+, Mn.sup.2+, Fe.sup.2+,
Mo.sup.2+, Zn.sup.2+, Sr.sup.2+, Ba.sup.2+, Ra.sup.2+, Ru.sup.2+,
Rh.sup.2+, Pd.sup.2+, Cd.sup.2+, Sn.sup.2+, W.sup.2+, Re.sup.2+,
Os.sup.2+, Ir.sup.2+, Pt.sup.2+, Si.sup.2+, and Sm.sup.2+; [0023] X
is an integer from 1 to 8; and [0024] y is an integer of from 1 to
8.
Incorporation by Reference
[0025] All publications and patent applications mentioned in this
specification are herein incorporated by reference to the same
extent as if each individual publication or patent application was
specifically and individually indicated to be incorporated by
reference.
BRIEF DESCRIPTION OF THE DRAWINGS
[0026] FIGS. 1A and 1B (with SEMs): Twenty-nine athymic nude
(nu/nu) female mice, ages 3-4 weeks, were inoculated with
10.times.106 MDA-MB-231 cancer cells subcutaneously into the right
flank of each mouse. When tumors reached 3-5 mm in size,
twenty-five of the mice were divided into five treatment groups of
five mice each. Four mice were assigned as controls. Four mice with
outlying tumor sizes or non-tumor takes were subsequently excluded.
Experimental groups were treated by oral gavage once daily with the
indicated test suspensions or solution. The control group was
untreated.
[0027] FIG. 2: Structure of DCP as determined by single crystal
X-ray diffraction.
[0028] FIG. 3: Nude mice treated with DCP showed no significant
weight loss.
[0029] FIG. 4: Determination of optimum dose in nude mice.
[0030] FIG. 5: Comparison of DCP to other forms of calcium pterin
after 46 days of treatment.
[0031] FIG. 6: Comparison of DCP to other forms of calcium pterin
after 57 days of treatment.
[0032] FIG. 7: Treatment/Control (T/C) values in nude mice
w/MDA-MB-231 after 11 days of treatment.
[0033] FIG. 8: Treatment/Control (T/C) values in nude mice
w/MDA-MB-231 after 36 days of treatment
[0034] FIG. 9: Treatment/Control (T/C) values in nude mice
w/MDA-MB-231 after 47 days of treatment
DETAILED DESCRIPTION OF THE INVENTION
Glossary
[0035] To more readily facilitate an understanding of the invention
and its embodiments, the meanings of terms used herein will become
apparent from the context of this specification in view of common
usage of various terms and the explicit definitions of other terms
provided in the glossary below or in the ensuing description.
[0036] As used herein, the terms "comprising," "including," and
"such as" are used in their open, non-limiting sense.
[0037] The use of the term "about" in the present disclosure means
"approximately," and illustratively, the use of the term "about"
indicates that values slightly outside the cited values may also be
effective and safe, and such dosages are also encompassed by the
scope of the present claims.
[0038] "Binders" impart cohesive qualities and include, e.g.,
alginic acid and salts thereof; cellulose derivatives such as
carboxymethylcellulose, methylcellulose (e.g., Methocel.RTM.),
hydroxypropylmethylcellulose, hydroxyethylcellulose,
hydroxypropylcellulose (e.g., Klucel.RTM.), ethylcellulose (e.g.,
Ethocel.RTM.), and microcrystalline cellulose (e.g., Avicel.RTM.);
microcrystalline dextrose; amylose; magnesium aluminum silicate;
polysaccharide acids; bentonites; gelatin;
polyvinylpyrrolidone/vinyl acetate copolymer; crospovidone;
povidone; starch; pregelatinized starch; tragacanth, dextrin, a
sugar, such as sucrose (e.g., Dipac.RTM.), glucose, dextrose,
molasses, mannitol, sorbitol, xylitol (e.g., Xylitab.RTM.), and
lactose; a natural or synthetic gum such as acacia, tragacanth,
ghatti gum, mucilage of isapol husks, polyvinylpyrrolidone (e.g.,
Polyvidone.RTM. CL, Kollidon.RTM. CL, Polyplasdone.RTM. XL-10),
larch arabogalactan, Veegum.RTM., polyethylene glycol, waxes,
sodium alginate, and the like.
[0039] "Carrier materials" include any commonly used excipients in
pharmaceutics and should be selected on the basis of compatibility
with the active pharmaceutical ingredient and the release profile
properties of the desired dosage form. Exemplary carrier materials
include, e.g., binders, suspending agents, disintegration agents,
filling agents, surfactants, solubilizers, stabilizers, lubricants,
wetting agents, diluents, and the like. "Pharmaceutically
compatible carrier materials" may comprise, e.g., acacia, gelatin,
colloidal silicon dioxide, calcium glycerophosphate, calcium
lactate, maltodextrin, glycerine, magnesium silicate, sodium
caseinate, soy lecithin, sodium chloride, tricalcium phosphate,
dipotassium phosphate, sodium stearoyl lactylate, carrageenan,
monoglyceride, diglyceride, pregelatinized starch, and the like.
See, e.g., Remington: The Science and Practice of Pharmacy,
Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover,
John E., Remington's Pharmaceutical Sciences, Mack Publishing Co.,
Easton, Pa. 1975; Liberman, H. A. and Lachman, L., Eds.,
Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980;
and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh
Ed. (Lippincott Williams & Wilkins 1999).
[0040] The term "controlled release" includes any non-immediate
release formulation, including but not limited to enteric-coated
formulations and sustained release, delayed-release and pulsatile
release formulations.
[0041] The term "delayed-release" includes any non-immediate
release formulation, including but not limited to, film-coated
formulations, enteric-coated formulations, encapsulated
formulations, sustained release formulations and pulsatile release
formulations.
[0042] "Diffusion facilitators" and "dispersing agents" include
materials that control the diffusion of an aqueous fluid through a
coating. Exemplary diffusion facilitators/dispersing agents
include, e.g., hydrophilic polymers, electrolytes, Tween.RTM. 60 or
80, PEG and the like. Combinations of one or more erosion
facilitator with one or more diffusion facilitator can also be used
in the present invention.
[0043] "Diluents" increase bulk of the composition to facilitate
compression. Such compounds include e.g., lactose; starch;
mannitol; sorbitol; dextrose; microcrystalline cellulose such as
Avicel.RTM.; dibasic calcium phosphate; dicalcium phosphate
dihydrate; tricalcium phosphate; calcium phosphate; anhydrous
lactose; spray-dried lactose; pregelatinzed starch; compressible
sugar, such as Di-Pac.RTM. (Amstar); mannitol;
hydroxypropylmethylcellulose; sucrose-based diluents;
confectioner's sugar; monobasic calcium sulfate monohydrate;
calcium sulfate dihydrate; calcium lactate trihydrate; dextrates;
hydrolyzed cereal solids; amylose; powdered cellulose; calcium
carbonate; glycine; kaolin; mannitol; sodium chloride; inositol;
bentonite; and the like.
[0044] "Filling agents" include compounds such as lactose, calcium
carbonate, calcium phosphate, dibasic calcium phosphate, calcium
sulfate, microcrystalline cellulose, cellulose powder, dextrose;
dextrates; dextran, starches, pregelatinized starch, sucrose,
xylitol, lactitol, mannitol, sorbitol, sodium chloride,
polyethylene glycol, and the like. The terms "therapeutically
effective amount" and "effective amount" in relation to the amount
of active pharmaceutical ingredient mean, consistent with
considerations known in the art, the amount of active
pharmaceutical ingredient effective to elicit a pharmacologic
effect or therapeutic effect without undue adverse side
effects.
[0045] An "enteric-coating" is a substance that remains
substantially intact in the stomach but dissolves and releases at
least some of the drug once reaching the small intestine.
Generally, the enteric-coating comprises a polymeric material that
prevents release in the low pH environment of the stomach but that
ionizes at a slightly higher pH, typically a pH of 4 or 5, and thus
dissolves sufficiently in the small intestines to gradually release
the active agent therein.
[0046] The term "immediate release" is intended to refer to any
formulation in which all or part of the active pharmaceutical
ingredient is in solution either before administration or
immediately (i.e., within about 30 minutes) after administration.
For example, with an "immediate release" formulation, oral
administration results in immediate release of the agent from the
composition into gastric fluid. For delayed-release formulations,
the opposite is generally true, the rate of release of drug from
the dosage form is the rate-limiting step in the delivery of the
drug to the target area.
[0047] "Lubricants" are compounds which prevent, reduce or inhibit
adhesion or friction of materials. Exemplary lubricants include,
e.g., stearic acid; calcium hydroxide; talc; sodium stearyl
fumerate; a hydrocarbon such as mineral oil, or hydrogenated
vegetable oil such as hydrogenated soybean oil (Sterotex.RTM.);
higher fatty acids and their alkali-metal and alkaline earth metal
salts, such as aluminum, calcium, magnesium, zinc, stearic acid,
sodium stearates, glycerol, talc, waxes, Stearowet.RTM., boric
acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a
polyethylene glycol or a methoxypolyethylene glycol such as
Carbowax.TM., sodium oleate, glyceryl behenate, polyethylene
glycol, magnesium or sodium lauryl sulfate, colloidal silica such
as Syloid.TM., Carb-O-Sil.RTM., a starch such as corn starch,
silicone oil, a surfactant, and the like.
[0048] The term "pharmaceutically acceptable" is used adjectivally
herein to mean that the modified noun is appropriate for use in a
pharmaceutical product.
[0049] "Solubilizers" include compounds such as citric acid,
succinic acid, fumaric acid, malic acid, tartaric acid, maleic
acid, glutaric acid, sodium bicarbonate, sodium carbonate and the
like.
[0050] "Stabilizers" include compounds such as any antioxidation
agents, buffers, acids, and the like.
[0051] "Suspending agents" or "thickening agents" include compounds
such as polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12,
polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or
polyvinylpyrrolidone K30; polyethylene glycol, e.g., the
polyethylene glycol can have a molecular weight of about 300 to
about 6000, or about 3350 to about 4000, or about 7000 to about
5400; sodium carboxymethylcellulose; methylcellulose;
hydroxy-propylmethylcellulose; polysorbate-80;
hydroxyethylcellulose; sodium alginate; gums, such as, e.g., gum
tragacanth and gum acacia; guar gum; xanthans, including xanthan
gum; sugars; cellulosics, such as, e.g., sodium
carboxymethylcellulose, methylcellulose, sodium
carboxymethylcellulose, hydroxypropylmethylcellulose,
hydroxyethylcellulose; polysorbate-80; sodium alginate;
polyethoxylated sorbitan monolaurate; polyethoxylated sorbitan
monolaurate; povidone and the like.
[0052] "Surfactants" include compounds such as sodium lauryl
sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate,
polysorbates, polaxomers, bile salts, glyceryl monostearate,
copolymers of ethylene oxide and propylene oxide, e.g.,
Pluronic.RTM. (BASF); and the like.
[0053] As used herein, the terms "suspension" and "solution" are
interchangeable with each other and generally mean a solution
and/or suspension of the substituted benzimidazole in an aqueous
medium.
[0054] The term "sustained release" is used in its conventional
sense to refer to a drug formulation that provides for gradual
release of a drug over an extended period of time, and, may
sometimes, although not necessarily, result in substantially
constant blood levels of a drug over an extended time period.
[0055] The term "treat" or "treatment" as used herein refers to any
treatment of a disorder or disease associated with gastrointestinal
disorder, and includes, but is not limited to, preventing the
disorder or disease from occurring in a mammal which may be
predisposed to the disorder or disease, but has not yet been
diagnosed as having the disorder or disease; inhibiting the
disorder or disease, for example, arresting the development of the
disorder or disease; relieving the disorder or disease, for
example, causing regression of the disorder or disease; or
relieving the condition caused by the disease or disorder, for
example, stopping the symptoms of the disease or disorder.
[0056] Pterin has been a point of interest in the biomedical
research community for some time. Xanthopterin was found to inhibit
sarcoma growth in mice over 60 years ago (Lewisohn et al, Proc.
Soc. Exp. Biol. Med. (1944) 56, 144-145). Isoxanthopterin was also
shown to inhibit tumor growth (Kokolis et al, Z. Naturforsch.
(1972) B27, 292-95). The National Cancer Institute subsequently
tested xanthopterin, isoxanthopterin and pterin but obtained
inconsistent results (Drug Evaluation Branch, Developmental
Therapeutics Program, Division of Cancer Treatment, National Cancer
Institute, Bethesda, Md. 1957, 1958, 1959, 1960, 1964, 1969, 1971,
1972, 1973, 1974, 1975, 1977. NSC 41836, 91557, 118090, 11540,
18696, 170929). In 1996, Moheno disclosed the strong antitumor
efficacy of a 2:1 (w/w) xanthopterin/isoxanthopterin suspension in
female C3H/HeOuJ mice (U.S. Pat. No. 5,534,514).
##STR00001##
[0057] Further investigations by Moheno demonstrated the importance
of selecting an immunocompetent mouse strain for the evaluation of
anti-tumor efficacy of pterin and related analogs (Moheno, Int. J.
Pharm. (2004), 271, 293-300). In this study, a suspension of
calcium pterin in the molar ratio of 1:4/calcium:pterin (known as
CaPterin) was found to possess significant antitumor efficacy
against MDA-MB-231 human breast xenographs in nude mice, as well as
highly significant activity against spontaneous mammary gland
tumors in C3H/HeN-MTV+ mice, based upon National Cancer Institute
standards. Immunomodulatory action for CaPterin was deduced by
comparing the antitumor efficacy of CaPterin in four different
mouse/tumor systems: i.e., the two cited above, as well as Balb/c
mice with EMT6 xenographs and SCID mice with MDA-MB-231 xenographs.
Comparison of results obtained by testing CaPterin in either nude
or SCID mice (severely compromised immunodeficient) implanted with
MDA-MB-231 human cancer cells showed a significant antitumor
response in the nudes and no response in the SCIDs. This comparison
argues for B-cell immunological involvement in the mechanism of
CaPterin antitumor activity since nude mice possess B-cell
capability while SCID mice do not. This comparison also indicates
that there is no measurable direct cancer cell toxicity from the
CaPterin. Results showing no CaPterin antitumor efficacy against
EMT6 tumor cells implanted in Balb/c mice also suggest an antitumor
mechanism involving B-cells, since transforming growth factor beta
(TGF-beta), produced by EMT6 cells, is known to cause B-cell
apoptosis. These results indicate that CaPterin's antitumor
mechanism involves antibody-dependent cellular cytotoxicity (ADCC)
mediated, for example, by natural killer (NK) cells,
interlukin-2.
[0058] Further study of the immunomodulatory properties of CaPterin
was performed by Moheno and co-workers (Winkler et al,
Immunobiology (2006) 211, 779-84). They found that CaPterin was
able to suppress both the activity of IDO, the degradation of
tryptophan and the production of neopterin in PHA- and Con
A-stimulated PBMC in a dose-dependent manner. In PHA- and Con
A-stimulated PBMC, the production of IFN-.gamma. is increased and
induces the degradation of tryptophan and the production of
neopterin. Accelerated tryptophan degradation and high IDO
expression levels have been associated with poor prognosis in
cancer patients.
[0059] Provided herein is dipterinyl calcium pentahydrate (DCP),
which is suitable as an antitumor agent. Antitumor dose-response
data are presented for dipterinyl calcium pentahydrate (DCP) at two
dosages.
[0060] Therapeutically effective amounts of dipterinyl calcium
pentahydrate may be administered as the aqueous suspension. As
well, it is contemplated to administer DCP as the active ingredient
in a pharmaceutical composition. Accordingly, provided herein are
pharmaceutical compositions, which include therapeutically
effective amounts of dipterinyl calcium pentahydrate and one or
more pharmaceutically acceptable carriers, diluents, or excipients.
The carrier(s), diluent(s) or excipient(s) must be acceptable in
the sense of being compatible with the other ingredients of the
formulation and not deleterious to the recipient thereof. According
to another aspect of the invention there is also provided a process
for the preparation of a pharmaceutical formulation including
admixing dipterinyl calcium pentahydrate with one or more
pharmaceutically acceptable carriers, diluents or excipients.
[0061] Pharmaceutical formulations adapted for oral administration
may be presented as discrete units such as capsules or tablets;
powders or granules; solutions or suspensions in aqueous or
non-aqueous liquids; edible foams or whips; or oil-in-water liquid
emulsions or water-in-oil liquid emulsions.
[0062] For instance, powders are prepared by comminuting the
compound to a suitable fine size and mixing with a similarly
comminuted pharmaceutical carrier such as an edible carbohydrate,
as, for example, starch or mannitol. Flavoring, preservative,
dispersing and coloring agents can also be present.
[0063] Capsules are made by preparing a powder mixture as described
above, and filling formed gelatin sheaths. Glidants and lubricants
such as colloidal silica, talc, magnesium stearate, calcium
stearate or solid polyethylene glycol can be added to the powder
mixture before the filling operation. A disintegrating or
solubilizing agent such as agar-agar, calcium carbonate or sodium
carbonate can also be added to improve the availability of the
medicament when the capsule is ingested.
[0064] Moreover, when desired or necessary, suitable binders,
lubricants, disintegrating agents and coloring agents can also be
incorporated into the mixture. Suitable binders include starch,
gelatin, natural sugars such as glucose or beta-lactose, corn
sweeteners, natural and synthetic gums such as acacia, tragacanth
or sodium alginate, carboxymethylcellulose, polyethylene glycol,
waxes and the like. Lubricants used in these dosage forms include
sodium oleate, sodium stearate, magnesium stearate, sodium
benzoate, sodium acetate, sodium chloride and the like.
Disintegrators include, without limitation, starch, methyl
cellulose, agar, bentonite, xanthan gum and the like. Tablets are
formulated, for example, by preparing a powder mixture, granulating
or slugging, adding a lubricant and disintegrant and pressing into
tablets. A powder mixture is prepared by mixing the compound,
suitably comminuted, with a diluent or base as described above, and
optionally, with a binder such as carboxymethylcellulose, an
aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant
such as paraffin, a resorption accelerator such as a quaternary
salt and/or an absorption agent such as bentonite, kaolin or
dicalcium phosphate. The powder mixture can be granulated by
wetting with a binder such as syrup, starch paste, acadia mucilage
or solutions of cellulosic or polymeric materials and forcing
through a screen. As an alternative to granulating, the powder
mixture can be run through the tablet machine and the result is
imperfectly formed slugs broken into granules. The granules can be
lubricated to prevent sticking to the tablet forming dies by means
of the addition of stearic acid, a stearate salt, talc or mineral
oil. The lubricated mixture is then compressed into tablets. The
compounds of the present invention can also be combined with a free
flowing inert carrier and compressed into tablets directly without
going through the granulating or slugging steps. A clear or opaque
protective coating consisting of a sealing coat of shellac, a
coating of sugar or polymeric material and a polish coating of wax
can be provided. Dyestuffs can be added to these coatings to
distinguish different unit dosages.
[0065] Oral fluids such as solution, syrups and elixirs can be
prepared in dosage unit form so that a given quantity contains a
predetermined amount of the compound. Syrups can be prepared by
dissolving the compound in a suitably flavored aqueous solution,
while elixirs are prepared through the use of a non-toxic alcoholic
vehicle. Suspensions can be formulated by dispersing the compound
in a non-toxic vehicle. Solubilizers and emulsifiers such as
ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol
ethers, preservatives, flavor additive such as peppermint oil or
natural sweeteners or saccharin or other artificial sweeteners, and
the like can also be added.
[0066] Where appropriate, dosage unit formulations for oral
administration can be microencapsulated. The formulation can also
be prepared to prolong or sustain the release as for example by
coating or embedding particulate material in polymers, wax or the
like.
[0067] One embodiment provides dipterinyl calcium pentahydrate
(DCP) or a polymorph thereof. Another embodiment is a method of
synthesizing dipterinyl calcium pentahydrate (DCP) comprising
dissolving pterin in an aqueous solution of NaOH, adding CaCl2.2H2O
to the solution with stirring at a pH of about 11, continuing
stirring for about 1 day and collecting the precipitate as DCP.
[0068] In another embodiment is a method of modulating tryptophan
production comprising administering to a subject an effective
amount of DCP. In yet another embodiment is a method of modulating
tryptophan production comprising administering to a subject an
effective amount of DCP suspension. In another embodiment is a
method of modulating tryptophan degradation comprising
administering to a subject an effective amount of DCP. A further
embodiment is a method of modulating tryptophan degradation
comprising administering to a subject an effective amount of DCP
suspension.
[0069] In one embodiment is a method of modulating neopterin
production comprising administering to a subject an effective
amount of DCP. In a further embodiment is a method of modulating
neopterin production comprising administering to a subject an
effective amount of DCP suspension.
[0070] In an additional embodiment is a method of modulating
IFN-.gamma. production comprising administering to a subject an
effective amount of DCP. In yet another embodiment is a method of
modulating IFN-.gamma. production comprising administering to a
subject an effective amount of DCP suspension.
[0071] In one embodiment is a method of modulating the activity of
the enzyme IDO comprising administering to a subject an effective
amount of DCP. In another embodiment is a method of modulating the
activity of the enzyme IDO comprising administering to a subject an
effective amount of DCP suspension.
[0072] In one embodiment is a method of modulating oxidants
production comprising administering to a subject an effective
amount of DCP. In yet another embodiment is a method of modulating
oxidants production comprising administering to a subject an
effective amount of DCP suspension.
[0073] In one embodiment is a method of modulating free radical
production comprising administering to a subject an effective
amount of DCP. In a further embodiment is a method of modulating
free radical production comprising administering to a subject an
effective amount of DCP suspension. In another embodiment is a
method of modulating release of reactive oxygen species (ROS)
comprising administering to a subject an effective amount of DCP.
In yet another embodiment is a method of modulating release of
reactive oxygen species (ROS) comprising administering to a subject
an effective amount of DCP suspension.
[0074] In one embodiment is a method of modulating release
pro-inflammatory transcription factor NF-.kappa.B comprising
administering to a subject an effective amount of DCP. In another
embodiment is a method of modulating release pro-inflammatory
transcription factor NF-.kappa.B comprising administering to a
subject an effective amount of DCP suspension.
[0075] In another embodiment is a method of modulating the
expression of down-stream genes for a cytokine, a chemokine,
adhesion molecule, growth factor, enzyme and/or immune receptor
comprising administering to a subject an effective amount of DCP.
In a further embodiment is a method of modulating the expression of
down-stream genes for a cytokine, a chemokine, adhesion molecule,
growth factor, enzyme and/or immune receptor comprising
administering to a subject an effective amount of DCP
suspension.
[0076] In another embodiment is a method of reducing inflammatory
activity in a subject comprising administering to a subject an
effective amount of DCP. In still another embodiment is a method of
reducing inflammatory activity in a subject comprising
administering to a subject an effective amount of DCP
suspension.
[0077] In another embodiment is a method of reducing or suppressing
expression of the enzyme IDO comprising administering to a subject
an effective amount of DCP. In a further embodiment is a method of
reducing or suppressing expression of the enzyme IDO comprising
administering to a subject an effective amount of DCP
suspension.
[0078] In another embodiment is a method of modulating human T-cell
response comprising administering to a subject an effective amount
of DCP. In an additional embodiment is a method of modulating human
T-cell response comprising administering to a subject an effective
amount of DCP suspension.
[0079] In another embodiment is a method of reducing or suppressing
allogeneic immune tolerance comprising administering to a subject
an effective amount of DCP. In yet another embodiment is a method
of reducing or suppressing allogeneic immune tolerance comprising
administering to a subject an effective amount of DCP
suspension.
[0080] In another embodiment is a method of modulating immune
resistance in human solid tumors comprising administering to a
subject an effective amount of DCP. In an additional embodiment is
a method of modulating immune resistance in human solid tumors
comprising administering to a subject an effective amount of DCP
suspension.
[0081] In another embodiment is a method of modulating
antiproliferative activity comprising administering to a subject an
effective amount of DCP. In still another embodiment is a method of
modulating antiproliferative activity comprising administering to a
subject an effective amount of DCP suspension.
[0082] In another aspect of the invention is the compound of
formula (I): M(pterin).sub.x(H2O).sub.y wherein: M is a bivalent
metal ion selected from the group consisting of Ca.sup.2+,
Cu.sup.2+, Mg.sup.2+, V.sup.2+, Cr.sup.2+, Mn.sup.2+, Fe.sup.2+,
Mo.sup.2+, Zn.sup.2+, Sr.sup.2+, Ba.sup.2+, Ra.sup.2+, Ru.sup.2+,
Rh.sup.2+, Pd.sup.2+, Cd.sup.2+, Sn.sup.2+, W.sup.2+, Re.sup.2+,
Os.sup.2+, Ir.sup.2+, Pt.sup.2+, Si.sup.2+, and Sm.sup.2+; X is an
integer from 1 to 8; and y is an integer of from 1 to 8. In another
embodiment is a method of inhibiting tumor cells in an animal
comprising the administration of a therapeutically effective amount
of a compound of formula (I): M(pterin).sub.x(H.sub.2O).sub.y
wherein: M is a bivalent metal ion selected from the group
consisting of Ca.sup.2+, Cu.sup.2+, Mg.sup.2+, V.sup.2+, Cr.sup.2+,
Mn.sup.2+, Fe.sup.2+, Mo.sup.2+, Zn.sup.2+, Sr.sup.2+, Ba.sup.2+,
Ra.sup.2+, Ru.sup.2+, Rh.sup.2+, Pd.sup.2+, Cd.sup.2+, Sn.sup.2+,
W.sup.2+, Re.sup.2+, Os.sup.2+, Ir.sup.2+, Pt.sup.2+, Si.sup.2+,
and Sm.sup.2+; X is an integer from 1 to 8; and y is an integer of
from 1 to 8.
[0083] In another embodiment is a method of treating a viral
infection comprising the administration of a therapeutically
effective amount of a compound of formula (I):
M(pterin).sub.x(H2O).sub.y wherein: M is a bivalent metal ion
selected from the group consisting of Ca.sup.2+, Cu.sup.2+,
Mg.sup.2+, V.sup.2+, Cr.sup.2+, Mn.sup.2+, Fe.sup.2+, Mo.sup.2+,
Zn.sup.2+, Sr.sup.2+, Ba.sup.2+, Ra.sup.2+, Ru.sup.2+, Rh.sup.2+,
Pd.sup.2+, Cd.sup.2+, Sn.sup.2+, W.sup.2+, Re.sup.2+, Os.sup.2+,
Ir.sup.2+, Pt.sup.2+, Si.sup.2+, and Sm.sup.2+; X is an integer
from 1 to 8; and y is an integer of from 1 to 8.
[0084] In another embodiment is a pharmaceutical composition
comprising a pharmaceutically acceptable excipient and a compound
of formula (I): M(pterin).sub.x(H2O).sub.y wherein: M is a bivalent
metal ion selected from the group consisting of Ca.sup.2+,
Cu.sup.2+, Mg.sup.2+, V.sup.2+, Cr.sup.2+, Mn.sup.2+, Fe.sup.2+,
Mo.sup.2+, Zn.sup.2+, Sr.sup.2+, Ba.sup.2+, Ra.sup.2+, Ru.sup.2+,
Rh.sup.2+, Pd.sup.2+, Cd.sup.2+, Sn.sup.2+, W.sup.2+, Re.sup.2+,
Os.sup.2+, Ir.sup.2+, Pt.sup.2+, Si.sup.2+, and Sm.sup.2+; X is an
integer from 1 to 8; and y is an integer of from 1 to 8.
EXAMPLES
Example 1
Synthesis of Dipterinyl Calcium Pentahydrate (DCP)
[0085] Pure pterin (81.7 mg, 0.5 mmol) was dissolved in H.sub.2O
(50 ml) and 0.1 N NaOH (6 ml) and CaCl.sub.2.2H.sub.2O (36.7 mg,
0.25 mmol) was added to the clear solution with stirring (pH
10.93). A yellowish precipitate was formed within a few minutes.
Stirring was continued for 1 day and then the precipitate collected
and dried in a vacuum desiccator to give 75 mg. The elemental
analysis is consistent with
(C.sub.6H.sub.4N.sub.5O).sub.2Ca.5H.sub.2O (MW 454.4).
TABLE-US-00001 Calculated: C: 31.74 H: 4.00 N: 30.85 Found: C:
31.22 H: 3.97 N: 29.83.
[0086] The comparison of the extinctions of the UV spectra of
pterin and (C.sub.6H.sub.4N.sub.5O).sub.2Ca.5H.sub.2O taken at pH
13 show the following:
TABLE-US-00002 Pterin: 223 nm (8,700), 250 nm (21,380), 357 nm
(8,510) (C.sub.6H.sub.4N.sub.5O).sub.2Ca.cndot.5H.sub.2O: 223 nm
(14,450), 250 nm (39,810), 357 nm (13,490)
[0087] The structure of DCP as determined by single crystal x-ray
diffraction is shown in FIG. 2.
[0088] Dipterinyl calcium pentahydrate (DCP) suspensions:
A 1.1 mg/ml suspension was prepared by mixing 44 mg dipterinyl
calcium pentahydrate in 40 ml distilled H.sub.2O. A 3.3 mg/ml
suspension was prepared by mixing 132 mg dipterinyl calcium
pentahydrate in 40 ml distilled H.sub.2O.
Example 2
In Vivo Testing
[0089] Cell Line Propagation and Inoculation: The MDA-MB-231 human
breast tumor cell lines were supplied by SRI International (Menlo
Park, Calif.) and propagated using standard in vitro cell expansion
methods. Briefly, cells were grown in L-15 media from Gibco (Cat.
No. 11415-064) supplemented with 2 mM L-Glutamine and 10% Fetal
Bovine Serum (FBS). The cells were cultured in an incubator with 5%
C02, 37.50 C, and 80% humidity. Cells were harvested with 0.25%
(w/v) Trypsin-0.03% (w/v) EDTA solution. Cells were prepared for
injection by standard methods to appropriate concentrations.
Animals were temporarily restrained but not anesthetized for the
inoculation of the tumor cells. Animals were subcutaneously
injected with the tumor cells in a 100-200 .mu.l volume.
[0090] Animal Care: The animals were housed 4 to a cage in approved
micro-isolator cages. Caging bedding and related items were
autoclaved prior to use. No other species were housed in the same
room(s) as the experimental animals. The rooms were well ventilated
(greater than 10 air changes per hour) with 100% fresh air (no air
recirculation). A 12-hour light/12-hour dark photoperiod was
maintained, except when room lights were turned on during the dark
cycle to accommodate study procedures. Room temperature was
maintained between 16-22.degree. C. Animal room and cage cleaning
was performed according to Perry Scientific SOP (Standard Operating
Procedure). Animals had ad libitum access to irradiated ProLab
mouse chow. Autoclaved and chlorinated, municipal tap water was
available ad libitum to each animal via water bottles. Treatment of
the animals was in accordance with Perry Scientific SOP, which
adhered to the regulations outlined in the USDA Animal Welfare Act
(9 CFR, Parts 1, 2 and 3) and the conditions specified in The Guide
for Care and Use of Laboratory Animals (ILAR publication, 1996,
National Academy Press). The protocol was approved by Perry
Scientific's Institutional Animal Care and Use Committee prior to
initiation of the study. The study conduct was in general
compliance with the US FDA Good Laboratory Practice Regulations
currently in effect (21 CFR, Part 58).
[0091] Antitumor efficacy was evaluated in nude mice with
MDA-MB-231 human tumor xenographs by Perry Scientific (San Diego,
Calif.). Twenty-nine athymic nude were each injected subcutaneously
with 10.times.106 MDA-MB-231 cancer cells into the right flank.
When tumors reached 3-5 mm in size, the mice were divided into five
treatment groups of five each and a control group of four mice.
Four of these with outlying tumor sizes or non-tumor takes were
excluded shortly after treatment began: one each from the (1:4
mol:mol) calcium pterin group, the (1:2 mol:mol) calcium pterin
group, the DCP (69 mg/kg/day) group, and one from the control
group. Experimental groups were treated by oral gavage once daily
with the indicated test suspensions or solutions. Control groups
were untreated. Daily dosing was for 7 days per week. Animals were
restrained but not anesthetized for oral dosing. Tumors were
measured twice weekly with calipers and body weights taken twice
weekly on the day of tumor measurements. Blood was collected from
all animals via cardiac puncture at termination (after 70 to 98
days of treatment) and processed to EDTA plasma for analysis.
[0092] Tumor Growth Rate Measurements: Each animal was individually
tracked for tumor growth by external caliper measurements of
protruding tumor. Primary tumor sizes were measured using calipers
and an approximate tumor volume calculated using the formula 1/2
(a.times.b2), where b was the smaller of two perpendicular
diameters.
[0093] For each group, the mean and standard error of the mean
(SEM) of the ratio V/Vo, Relative Tumor Volume (RTV), were plotted
as a function of treatment time after inoculation. V0 was the tumor
volume at Day 0, when treatment began. Time course statistical
analyses based upon repeated measures ANOVA models were used
(StatView SE+Graphics, v 1.03).
Results
[0094] FIG. 1 shows that calcium pterin (1:4 mol:mol form),
dipterinyl calcium pentahydrate (DCP) at both dosages tested, and
calcium chloride dihydrate all significantly inhibit MDA-MB-231
xenograph growth in nude mice. These findings identify a new
efficacious form of calcium pterin, dipterinyl calcium pentahydrate
(DCP). Tumor size data for the control group at days 4 and 7 were
missed due to a technical oversight.
[0095] There was no observed toxicity, as determined by body weight
changes (see FIG. 3), among any of the groups of mice in this
experiment.
FIG. 1 shows that the dipterinyl calcium pentahydrate (DCP) at 23
mg/kg/day has significantly greater anti tumor efficacy than the
original CaPterin, (1:4 mol:mol) calcium pterin. DCP at 69
mg/kg/day, however, has comparable efficacy. Taken together, these
findings imply that there appears to be an optimum dosage of DCP
for maximal antitumor activity.
[0096] Conclusion: Our results show that oral dipterinyl calcium
pentahydrate inhibits MDA-MB-231 xenograph tumors in nude mice
significantly greater than (1:4 mol:mol) calcium pterin
[CaPterin].
Determination of the optimum dose in nude mice is shown in FIG. 4.
Comparison of DCP to other forms of calcium pterin is shown in
FIGS. 5 and 6. Comparison to other common chemotherapeutics is
shown in the FIGS. 7, 8, and 9.
[0097] Comparative data for FIGS. 7, 8, and 9 was obtained from the
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* * * * *