U.S. patent application number 10/824563 was filed with the patent office on 2004-09-30 for methods of treating leukemia.
This patent application is currently assigned to BioChem Pharma Inc.. Invention is credited to Giles, Francis J., Gourdeau, Henriette.
Application Number | 20040192654 10/824563 |
Document ID | / |
Family ID | 26824972 |
Filed Date | 2004-09-30 |
United States Patent
Application |
20040192654 |
Kind Code |
A1 |
Gourdeau, Henriette ; et
al. |
September 30, 2004 |
Methods of treating leukemia
Abstract
The present invention provides a novel method for treating
leukemia and more particularly acute myelogenous leukemia (AML) in
a host comprising administering to the host a therapeutically
effective amount of a compound having the formula I: 1 wherein B is
cytosine or 5-fluorocytosine and R is selected from the group
comprising H, monophosphate, diphosphate, triphosphate, carbonyl
substituted with a C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.6-10 aryl, and 2 wherein each Rc is independently
selected from the group comprising H, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl and an hydroxy protecting group; and
wherein said compound is substantially in the form of the
enantiomer.
Inventors: |
Gourdeau, Henriette;
(Montreal, CA) ; Giles, Francis J.; (Houston,
TX) |
Correspondence
Address: |
MILLEN, WHITE, ZELANO & BRANIGAN, PC
2200 CLARENDON BLVD
SUITE 1400
ARLINGTON
VA
22201
US
|
Assignee: |
BioChem Pharma Inc.
Laval
CA
|
Family ID: |
26824972 |
Appl. No.: |
10/824563 |
Filed: |
April 15, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10824563 |
Apr 15, 2004 |
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09536459 |
Mar 28, 2000 |
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6630480 |
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60126734 |
Mar 29, 1999 |
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60126813 |
Mar 30, 1999 |
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Current U.S.
Class: |
514/85 ;
514/269 |
Current CPC
Class: |
A61K 31/506 20130101;
A61K 31/70 20130101; C12N 2501/145 20130101; A61K 31/675 20130101;
A61K 38/13 20130101; A61K 38/2013 20130101; C12N 2501/03 20130101;
A61K 38/193 20130101; A61K 31/704 20130101; A61K 38/212 20130101;
A61P 35/02 20180101; A61K 38/32 20130101; C12N 5/0644 20130101;
A61K 39/39541 20130101; A61K 38/202 20130101; A61K 45/06 20130101;
A61K 2035/124 20130101; A61K 38/1816 20130101; A61K 31/704
20130101; A61K 31/675 20130101; A61K 31/704 20130101; A61K 31/505
20130101; A61K 38/1816 20130101; A61K 31/70 20130101; A61K 31/675
20130101; A61K 31/505 20130101; A61K 38/19 20130101; A61K 31/70
20130101; A61K 31/675 20130101; A61K 31/505 20130101; A61K 38/193
20130101; A61K 31/70 20130101; A61K 31/675 20130101; A61K 31/505
20130101; A61K 38/2013 20130101; A61K 31/70 20130101; A61K 31/675
20130101; A61K 31/505 20130101; A61K 38/212 20130101; A61K 31/70
20130101; A61K 31/675 20130101; A61K 31/505 20130101; A61K 39/39541
20130101; A61K 31/70 20130101; A61K 31/675 20130101; A61K 31/505
20130101; A61K 45/06 20130101; A61K 31/70 20130101; A61K 31/70
20130101; A61K 31/506 20130101; A61K 2300/00 20130101; A61K 31/675
20130101; A61K 2300/00 20130101; A61K 31/70 20130101; A61K 2300/00
20130101; A61K 31/704 20130101; A61K 2300/00 20130101; A61K 38/1816
20130101; A61K 2300/00 20130101; A61K 38/193 20130101; A61K 2300/00
20130101; A61K 38/20 20130101; A61K 2300/00 20130101; A61K 38/2013
20130101; A61K 2300/00 20130101; A61K 38/212 20130101; A61K 2300/00
20130101; A61K 39/39541 20130101; A61K 2300/00 20130101; A61K 38/13
20130101; A61K 2300/00 20130101; A61K 38/32 20130101; A61K 2300/00
20130101; A61K 38/202 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/085 ;
514/269 |
International
Class: |
A61K 031/675; A61K
031/513 |
Claims
1-10 (Cancelled)
11. A method for treating leukemia in a host comprising
administering to the host having leukemia a therapeutically
effective amount of cytarabine and at least one compound of general
formula I 8wherein B is cytosine or 5-fluorocytosine and R is
selected from the group comprising H, monophosphate, diphosphate,
triphosphate, carbonyl substituted with a C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl, and 9wherein
each Rc is independently selected from the group comprising H,
C.sub.1-4 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl and hydroxy
protecting groups, and wherein said compound is substantially in
the form of the (-) enantiomer.
12. A method according to claim 11, wherein the leukemia is chronic
myelogenous leukemia.
13. A method according to claim 11, wherein the leukemia is acute
myelogenous leukemia.
14. A method according to claim 11, further comprising the step of
administering a multidrug resistance reversing agent or a
biological response modifier.
15. A method according to claim 14, wherein the multidrug
resistance agent is PSC 833.
16. A method according to claim 14, wherein the biological response
modifiers are selected from the group consisting of monoclonal
antibodies and cytokines.
17. A method according to claim 14, wherein the cytokines are
selected from the group consisting of interferons, interleukins and
colony-stimulating factors.
18. A method according to claim 14, wherein the biological response
modifiers are selected from the group consisting of Rituxan,
CMA-676, Interferon-alpha recombinant, Interleukin-2,
Interleukin-3, Erythropoetin, Epoetin, G-CSF, GM-CSF, Filgrastim,
Sargramostim and Thrombopoietin.
19. A method according to claim 11, wherein the compound of formula
I and cytarabine are administered sequentially.
20. A method according to claim 11, wherein the compound of formula
I and cytarabine are administered simultaneously.
21. A method according to claim 11, wherein said compound is
(-)-.beta.-L-Dioxolane-Cytidine (.beta.-L-oddC) or a
pharmaceutically acceptable salt thereof.
22. A method according to claim 21, wherein said compound is
(-)-.beta.-Dioxolane-5-fluoro-Cytidine (5-FddC).
23. A method according to claim 11, wherein said compound is at
least 97% free of the corresponding (+) enantiomer.
24. A method according to claim 11, wherein said compound is at
least 99% free of the corresponding (+) enantiomer.
25. A method according to claim 21, wherein said compound is at
least 97% free of the corresponding (+) enantiomer.
26. A method according to claim 21, wherein said compound is at
least 99% free of the corresponding (+) enantiomer.
27. A pharmaceutical composition comprising cytarabine and at least
one compound of formula I 10wherein B is cytosine or
5-fluorocytosine, R is H, monophosphate, diphosphate, triphosphate,
carbonyl substituted with a C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.6-10 aryl, or Rc is in each case
independently H, C.sub.1-6 11 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl or a hydroxy protecting group, and wherein said compound is
substantially in the form of the (-) enantiomer.
28. A composition according to claim 27, further comprising a
pharmaceutically acceptable carrier.
29. A composition according to claim 27, further comprising a
multidrug resistance reversing agent or a biological response
modifier.
30. A composition according to claim 29, wherein the multidrug
resistance agent is PSC 833.
31. A composition according to claim 29, wherein said biological
response modifier is a monoclonal antibody or a cytokine.
32. A composition according to claim 31, wherein said cytokine is
an interferon, an interleukin or a colony-stimulating factor.
33. A composition according to claim 29, wherein the biological
response modifier is Rituxan, CMA-676, Interferon-alpha
recombinant, Interleukin-2, Interleukin-3, Erythropoetin, Epoetin,
G-CSF, GM-CSF, Filgrastim, Sargramostim or Thrombopoietin.
34. A composition according to claim 27, wherein said compound is
(-)-.beta.-L-Dioxolane-Cytidine (.beta.-L-oddC) or a
pharmaceutically acceptable salt thereof.
35. A composition according to claim 28, wherein said compound is
(-)-.beta.-L-Dioxolane-Cytidine (.beta.-L-oddC) or a
pharmaceutically acceptable salt thereof.
36. A composition according to claim 34, wherein said compound is
(-)-.beta.-Dioxolane-5-fluoro-Cytidine (5-FddC) or a
pharmaceutically acceptable salt thereof.
37. A composition according to claim 35, wherein said compound is
(-)-.beta.-L-Dioxolane-Cytidine (.beta.-L-oddC).
38. A composition according to claim 27, wherein said compound is
at least 97% free of the corresponding (+) enantiomer.
39. A composition according to claim 27, wherein said compound is
at least 99% free of the corresponding (+) enantiomer.
40. A composition according to claim 28, wherein said compound is
at least 97% free of the corresponding (+) enantiomer.
41. A composition according to claim 28, wherein said compound is
at least 99% free of the corresponding (+) enantiomer.
42. A composition according to claim 34, wherein said compound is
at least 97% free of the corresponding (+) enantiomer.
43. A composition according to claim 34, wherein said compound is
at least 99% free of the corresponding (+) enantiomer.
44. A composition according to claim 35, wherein said compound is
at least 97% free of the corresponding (+) enantiomer.
45. A composition according to claim 35, wherein said compound is
at least 99% free of the corresponding (+) enantiomer.
46. A composition according to claim 27, wherein said composition
is in unit dosage and contains 10 to 1500 mg of said compound per
unit dosage form.
47. A composition according to claim 27, wherein said composition
is in unit dosage and contains 20 to 1000 mg of said compound per
unit dosage form.
48. A composition according to claim 27, wherein said composition
is in unit dosage and contains 50 to 700 mg of said compound per
unit dosage form.
49. A pharmaceutical combination comprising cytarabine and at least
one compound of formula 12wherein B is cytosine or
5-fluorocytosine, R is H, monophosphate, diphosphate, triphosphate,
carbonyl substituted with a C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.6-10 aryl, or 13Rc is in each case
independently H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl or a hydroxy protecting group, and wherein said compound is
substantially in the form of the (-) enantiomer.
50. A combination according to claim 49, wherein said compound of
formula I is (-)-.beta.-L-Dioxolane-Cytidine (.beta.-L-oddC) or a
pharmaceutically acceptable salt thereof.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to methods for treating
leukemia, and more particularly, to the use of nucleoside analogues
as an effective treatment for acute or chronic myelogenous
leukemia.
BACKGROUND OF THE INVENTION
[0002] Leukemia is a malignant cancer of the bone marrow and blood.
It is characterized by the uncontrolled growth of blood cells. The
common types of leukemia are divided into four categories: acute or
chronic myelogenous, involving the myeloid elements of the bone
marrow (white cells, red cells, megakaryocytes) and acute or
chronic lymphocytic, involving the cells of the lymphoid
lineage.
[0003] Acute leukemia is a rapidly progressing disease that results
in the massive accumulation of immature, functionless cells
(blasts) in the marrow and blood. The marrow often can no longer
produce enough normal red and white blood cells and platelets.
Anemia, a deficiency of red cells, develops in virtually all
leukemia patients. The lack of normal white cells impairs the
body's ability to fight infections. A shortage of platelets results
in bruising and easy bleeding. In contrast, chronic leukemia
progresses more slowly and leads to unregulated proliferation and
hence marked overexpansion of a spectrum of mature (differentiated)
cells. In general, acute leukemia, unlike the chronic form, is
potentially curable by elimination of the neoplastic clone.
[0004] It is estimated that there will be 28,700 new cases of
leukemia in the United States this year; about equal proportions
are acute leukemia and chronic types. Most cases occur in older
adults. Leukemia is expected to strike ten times as many adults as
children in 1998. (About 26,500 cases compared to 2,200 in
children) More than half of all cases of leukemia occur in persons
over 60. The most common types of leukemia in adults are acute
myelogenous leukemia (AML) with an estimated 9,400 new cases
annually, chronic lymphocytic leukemia (CLL), with some 7,300 new
cases this year and chronic myeloid leukemia (CML). The most common
type of leukemia in children is acute lymphocytic leukemia
(ALL).
[0005] Standard treatment for leukemia usually involves
chemotherapy and/or bone marrow transplantation and/or radiation
therapy.
[0006] The two major types of bone marrow transplants are autologus
(uses the patient's own marrow ) and allogeneic (uses marrow from a
compatible donor). Radiation therapy, which involves the use of
high-energy rays, is usually given before bone marrow
transplantation to kill all leukemic cells.
[0007] Chemotherapy in leukemia usually involves a combination of
two or more anti-cancer drugs. Approximately 40 different drugs are
now being used in the treatment of leukemia. Some common
combinations include cytarabine with either doxorubicin or
daunorubicin or mitoxantrone or thioguanine, mercaptopurine with
methotrexate, mitroxantrone with etoposide, asparaginase with
vincristine, daunorubicin and prednisone, cyclophosphamide with
vincristine, cytarabine and prednisone, cyclophosphamide with
vincristine and prednisone, daunorubicin with cytarabine and
thioguanine and daunorubicin with vincristine and prednisone.
[0008] New treatments for leukemia also include the reversal of
multidrug resistance, involving the use of agents which decrease
the mechanisms allowing the malignant cells to escape the damaging
effects of the chemotherapeutic agent (and leads to refractoriness
or relapses); and biological therapy, involving the use of
substances known as biological response modifiers (BRMs). These
substances are normally produced in small amounts as part of the
body's natural response to cancer or other diseases. Types of BRMs
include monoclonal antibodies, in which toxins are attached to
antibodies that react with the complementary antigen carried by the
malignant cells; and cytokines (e.g. interferons, interleukins,
colony-stimulating factors CSFs) which are naturally occuring
chemicals that stimulate blood cell production and help restore
blood cell counts more rapidly after treatment. Examples of these
drugs include multidrug resistance reversing agent PSC 833, the
monoclonal antibody Rituxan and the following cytokines:
Erythropoetin and Epoetin, which stimulate the production of red
cells; G-CSF, GM-CSF, filgrastim, and Sargramostim which stimulate
the production of white cells; and thrombopoietin, which stimulate
the production of platelets.
[0009] Many nucleoside analogues have been found to possess
anticancer cancer activity. Cytarabine, Fludarabine, Gemcitabine
and Cladribine are some examples of nucleoside analogues which are
currently important drugs in the treatment of leukemia.
(-)-.beta.-L-Dioxolane-Cytidine(.beta.-L-Od- dC) is also a
nucleoside analogue that was first described as an antiviral agent
by Belleau et al. (EP 337713) and has been shown to have potent
antitumor activity (K. L. Grove et al., Cancer Res., 55(14),
3008-11, 1995; K. L. Grove et al., Cancer Res., 56(18), 4187-4191,
1996, K. L. Grove et al., Nucleosides Nucleotides, 16:1229-33,
1997; S. A Kadhim et al., Can. Cancer Res., 57(21), 4803-10,
1997).
[0010] Treatment of leukemia is very complex and depends upon the
type of leukemia. Tremendous clinical variability among remissions
is also observed in leukemic patients, even those that occur after
one course of therapy. Patients who are resistant to therapy have
very short survival times, regardless of when the resistance
occurs. Despite improvements in outcome with current treatment
programs, the need to discover novel agents for the treatment of
all types of leukemia continues.
SUMMARY OF THE INVENTION
[0011] The present invention provides a novel method for treating
leukemia in a host comprising administering a therapeutically
effective amount of a compound having the formula I: 3
[0012] wherein B is cytosine or 5-fluorocytosine and R is selected
from the group comprising H, monophosphate, diphosphate,
triphosphate, carbonyl substituted with a C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl, and 4
[0013] wherein each Rc is independently selected from the group
comprising H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl
and an hydroxy protecting group; and
[0014] wherein said compound is substantially in the form of the
(-) enantiomer.
[0015] In another embodiment, there is provided a method for
treating leukemia in a host comprising administering to the host a
therapeutically effective amount of at least one compound according
to formula I and at least one further therapeutic agent selected
from the group comprising chemotherapeutic agents; multidrug
resistance reversing agents; and biological response modifiers.
[0016] Still another embodiment, there is provided a pharmaceutical
composition for treating leukemia comprising at least one compound
according to formula I together with at least one pharmaceutically
acceptable carrier or excipient.
[0017] In another embodiment, there is provided a pharmaceutical
composition for treating leukemia comprising at least one compound
according to formula I and at least one further therapeutic agent
selected from the group comprising chemotherapeutic agents;
multidrug resistance reversing agents; and biological response
modifiers.
[0018] In another embodiment of the invention is the use of a
compound according to formula I for the manufacture of a medicament
for treating leukemia.
DETAILED DESCRIPTION OF THE INVENTION
[0019] The present invention provides a novel method for treating
leukemia in a host comprising administering a therapeutically
effective amount of a compound having the formula I: 5
[0020] wherein B is cytosine or 5-fluorocytosine and R is selected
from the group comprising H, monophosphate, diphosphate,
triphosphate, carbonyl substituted with a C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl, and 6
[0021] wherein each Rc is independently selected from the group
comprising H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl
and an hydroxy protecting group; and
[0022] wherein said compound is substantially in the form of the
(-) enantiomer.
[0023] In another embodiment of the invention, R is H.
[0024] In another embodiment, B is cytosine.
[0025] Alternatively, in another embodiment, B is
5-fluorocytosine.
[0026] In one embodiment, a compound of formula I is
(-)-.beta.-L-Dioxolane-Cytidine (.beta.-L-oddC).
[0027] In another embodiment, a compound of formula I is
(-)-.beta.-Dioxolane-5-fluoro-Cytidine (5-FddC)
[0028] It will be appreciated by those skilled in the art that the
compounds of formula (I) contain at least two chiral centres which
are marked by an asterisk (*) on formula (I). The compounds of
formula (I) thus exist in the form of two different optical isomers
(i.e. (+) or (-) enantiomers or .beta.-L and .beta.-D). All such
enantiomers and mixtures thereof including racemic mixtures are
included within the scope of the invention. The single optical
isomer or enantiomer can be obtained by method well known in the
art, such as chiral HPLC, enzymatic resolution and the use of
chiral auxiliary.
[0029] According to one embodiment, compounds of formula I of the
present invention are provided substantially in the form of the (-)
enantiomer.
[0030] By "substantially" is meant that there is more of the (-)
enantiomer then the (+) enantiomer.
[0031] In another embodiment, the compounds of formula I of the
present invention are at least 95% free of the corresponding (+)
enantiomer.
[0032] In another embodiment, the compounds of formula I of the
present invention are at least 97% free of the corresponding (+)
enantiomer.
[0033] Still in another embodiment, the compounds of formula I of
the present invention are at least 99% free of the corresponding
(+) enantiomer.
[0034] There is also provided pharmaceutically acceptable salts of
the compounds of formula I of the present invention. By the term
pharmaceutically acceptable salts of the compounds of formula (I)
are meant those derived from pharmaceutically acceptable inorganic
and organic acids and bases. Examples of suitable acids include
hydrochloric, hydrobromic, sulphuric, nitric, perchloric, fumaric,
maleic, phosphoric, glycollic, lactic, salicylic, succinic,
toluene-p-sulphonic, tartaric, acetic, citric, methanesulphonic,
formic, benzoic, malonic, naphthalene-2-sulphonic and
benzenesulphonic acids.
[0035] Salts derived from appropriate bases include alkali metal
(e.g. sodium), alkaline earth metal (e.g. magnesium), ammonium and
NR.sub.4+ (where R is C.sub.1-4 alkyl) salts. As used in this
application, the term "alkyl" represents an unsubstituted or
substituted (by a halogen, nitro, CONH.sub.2, COOH, O--C.sub.1-6
alkyl, O--C.sub.2-6 alkenyl, O--C.sub.2-6 alkynyl, hydroxyl, amino,
or COOQ, wherein Q is C.sub.1-6 alkyl; C.sub.2-6 alkenyl; C.sub.2-6
alkynyl) straight chain, branched chain or cyclic hydrocarbon
moiety (e.g. isopropyl, ethyl, fluorohexyl or cyclopropyl). The
term alkyl is also meant to include alkyls in which one or more
hydrogen atoms is replaced by an halogen, more preferably, the
halogen is fluoro (e.g. CF.sub.3-- or CF.sub.3CH.sub.2--).
[0036] The terms "alkenyl" and "alkynyl" represent an alkyl
containing at least one unsaturated group (e.g. allyl).
[0037] The term "hydroxy protecting group" is well known in the
field of organic chemistry. Such protecting groups may be found in
T. Greene, Protective Groups In Organic Synthesis, (John Wiley
& Sons, 1981). Example of hydroxy protecting groups include but
are not limited to acetyl-2-thioethyl ester, pivaloyloxymethyl
ester and isopropyloxycarbonyloxymethyl ester.
[0038] The term "aryl" represent an unsaturated carbocyclic moiety,
optionally mono- or di-substituted with OH, SH, amino, halogen or
C.sub.1-6 alkyl, and optionally substituted by at least one
heteroatom (e.g. N, O, or S).
[0039] In one embodiment, the present invention provides a method
for treating myelogenous leukemia.
[0040] In another embodiment, the present invention provides a
novel method for treating acute myelogenous leukemia.
[0041] In another embodiment, the present invention provides a
novel method for treating chronic myelogenous leukemia.
[0042] Still in another embodiment, the present invention provides
a novel method for treating multidrug resistant leukemia.
[0043] The term "leukemia" represent acute myelogenous leukemia
(AML), chronic myelogenous leukemia (CML), acute lymphocytic
leukemia (ALL), chronic lymphocytic leukemia (CLL), hairy cell
leukemia (HCL) and all subtypes of these leukemias which are
defined by morphological, histochemical and immunological
techniques that are well known by those skilled in the art.
[0044] The term "myelogenous leukemia" represent both acute and
chronic myelogenous leukemias (AML, CML) which involve the myeloid
elements of the bone marrow (e.g. white cells, red cells and
megakaryocytes) and includes all subtypes which are defined by
morphological, histochemical and immunological techniques that are
well known by those skilled in the art.
[0045] The term "multidrug resistant leukemia" represent a leukemia
which is non responsive to treatment with chemotherapeutic
agents.
[0046] The term "host" represent any mammals including humans.
[0047] In one embodiment, the host is human.
[0048] According to one embodiment, the patient treated has been
previously treated with cytarabine (Ara-C). The patient is treated
according to any one of the method set forth herein.
[0049] According to one embodiment, the patient that has been
previously treated is resistant to cytarabine (Ara-C). The patient
is treated according to any one of the methods set forth
herein.
[0050] According to another embodiment, the patient is refractory
to Ara-C.
[0051] According to one embodiment, it will be appreciated that the
amount of a compound of formula I of the present invention required
for use in treatment will vary not only with the particular
compound selected but also with the route of administration, the
nature of the condition for which treatment is required and the age
and condition of the patient and will be ultimately at the
discretion of the attendant physician or veterinarian. In general
however a suitable dose will be in the range of from about 0.01 to
about 750 mg/kg of body weight per day, preferably in the range of
0.5 to 60 mg/kg/day, most preferably in the range of 1 to 20
mg/kg/day.
[0052] The desired dose according to one embodiment is conveniently
presented in a single dose or as divided dose administered at
appropriate intervals, for example as two, three, four or more
doses per day.
[0053] In another embodiment, the compound is conveniently
administered in unit dosage form; for example containing 10 to 1500
mg, conveniently 20 to 1000 mg, most conveniently 50 to 700 mg of
active ingredient per unit dosage form.
[0054] According to another embodiment of the present invention,
the active ingredient is administered to achieve peak plasma
concentrations of the active compound of from about 1 to about 75
.mu.M, preferably about 2 to 50 .mu.M, most preferably about 3 to
about 30 .mu.M. This may be achieved, for example, by the
intravenous injection of a 0.1 to 5% solution of the active
ingredient, optionally in saline, or orally administered as a bolus
containing about 1 to about 500 mg of the active ingredient.
Desirable blood levels may be maintained by a continuous infusion
to provide about 0.01 to about 5.0 mg/kg/hour or by intermittent
infusions containing about 0.4 to about 15 mg/kg of the active
ingredient.
[0055] While it is possible that, for use in therapy, a compound of
formula I of the present invention may be administered as the raw
chemical, it is preferable according to one embodiment of the
invention, to present the active ingredient as a pharmaceutical
formulation. The embodiment of the invention thus further provides
a pharmaceutical formulation comprising a compound of formula (I)
or a pharmaceutically acceptable salt thereof together with one or
more pharmaceutically acceptable carriers therefor and, optionally,
other therapeutic and/or prophylactic ingredients. The carrier(s)
must be "acceptable" in the sense of being compatible with the
other ingredients of the formulation and not deleterious to the
recipient thereof.
[0056] According to one embodiment of the present invention,
pharmaceutical formulations include but are not limited to those
suitable for oral, rectal, nasal, topical (including buccal and
sub-lingual), transdermal, vaginal or parenteral (including
intramuscular, sub-cutaneous and intravenous) administration or in
a form suitable for administration by inhalation or insufflation.
The formulations may, where appropriate, be conveniently presented
in discrete dosage units and may be prepared by any of the methods
well known in the art of pharmacy. All methods according to this
embodiment include the step of bringing into association the active
compound with liquid carriers or finely divided solid carriers or
both and then, if necessary, shaping the product into the desired
formulation.
[0057] According to another embodiment, pharmaceutical formulation
suitable for oral administration are conveniently presented as
discrete units such as capsules, cachets or tablets each containing
a predetermined amount of the active ingredient; as a powder or
granules. In another embodiment, the formulation is presented as a
solution, a suspension or as an emulsion. Still in another
embodiment, the active ingredient is presented as a bolus,
electuary or paste. Tablets and capsules for oral administration
may contain conventional excipients such as binding agents,
fillers, lubricants, disintegrants, or wetting agents. The tablets
may be coated according to methods well known in the art. Oral
liquid preparations may be in the form of, for example, aqueous or
oily suspensions, solutions, emulsions, syrups or elixirs, or may
be presented as a dry product for constitution with water or other
suitable vehicle before use. Such liquid preparations may contain
conventional additives such as suspending agents, emulsifying
agents, non-aqueous vehicles (which may include edible oils), or
preservatives.
[0058] The compounds of formula I according to an embodiment of the
present invention are formulated for parenteral administration
(e.g. by injection, for example bolus injection or continuous
infusion) and may be presented in unit dose form in ampoules,
pre-filled syringes, small volume infusion or in multi-dose
containers with an added preservative. The compositions may take
such forms as suspensions, solutions, or emulsions in oily or
aqueous vehicles, and may contain formulatory agents such as
suspending, stabilizing an/or dispersing agents. Alternatively, the
active ingredient may be in powder form, obtained by aseptic
isolation of sterile solid or by lyophilisation from solution, for
constitution with a suitable vehicle, e.g. sterile, pyrogen-free
water, before use.
[0059] For topical administration to the epidermis, the compounds
of formula I, according to one embodiment of the present invention,
are formulated as ointments, creams or lotions, or as a transdermal
patch. Such transdermal patches may contain penetration enhancers
such as linalool, carvacrol, thymol, citral, menthol and
t-anethole. Ointments and creams may, for example, be formulated
with an aqueous or oily base with the addition of suitable
thickening and/or gelling agents. Lotions may be formulated with an
aqueous or oily base and will in general also contain one or more
emulsifying agents, stabilizing agents, dispersing agents,
suspending agents, thickening agents, or colouring agents.
[0060] Formulations suitable for topical administration in the
mouth include lozenges comprising active ingredient in a flavoured
base, usually sucrose and acacia or tragacanth; pastilles
comprising the active ingredient in an inert base such as gelatin
and glycerin or sucrose and acacia; and mouthwashes comprising the
active ingredient in a suitable liquid carrier.
[0061] Pharmaceutical formulations suitable for rectal
administration wherein the carrier is a solid. In another
embodiment, they are presented as unit dose suppositories. Suitable
carriers include cocoa butter and other materials commonly used in
the art, and the suppositories may be conveniently formed by
admixture of the active compound with the softened or melted
carrier(s) followed by chilling and shaping in moulds.
[0062] According to one embodiment, the formulations suitable for
vaginal administration are presented as pessaries, tampons, creams,
gels, pastes, foams or sprays containing in addition to the active
ingredient such carriers as are known in the art to be
appropriate.
[0063] For intra-nasal administration the compounds, in one
embodiment of the invention, are used as a liquid spray or
dispersible powder or in the form of drops. Drops may be formulated
with an aqueous or non-aqueous base also comprising one more
dispersing agents, solubilising agents or suspending agents. Liquid
sprays are conveniently delivered from pressurized packs.
[0064] For administration by inhalation the compounds, according to
one embodiment Of the invention are conveniently delivered from an
insufflator, nebulizer or a pressurized pack or other convenient
means of delivering an aerosol spray. In another embodiment,
pressurized packs comprise a suitable propellant such as
dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In
another embodiment, the dosage unit in the pressurized aerosol is
determined by providing a valve to deliver a metered amount.
[0065] Alternatively, in another embodiment, for administration by
inhalation or insufflation, the compounds of formula I according to
the present invention are in the form of a dry powder composition,
for example a powder mix of the compound and a suitable powder base
such as lactose or starch. In another embodiment, the powder
composition is presented in unit dosage form in, for example,
capsules or cartridges or e.g. gelatin or blister packs from which
the powder may be administered with the aid of an inhalator or
insufflator.
[0066] In one embodiment, the above described formulations are
adapted to give sustained release of the active ingredient.
[0067] In another embodiment, there is provided a method for
treating leukemia in a host comprising administering to the host a
therapeutically effective amount of at least one compound according
to formula I and at least one further therapeutic agent selected
from the group comprising chemotherapeutic agents; multidrug
resistance reversing agents; and biological response modifiers.
[0068] In another embodiment, the chemotherapeutic agents are
selected from the group consisting of Asparaginase, Bleomycin,
Busulfan, Carmustine, Chlorambucil, Cladribine, Cyclophosphamide,
Cytarabine, Dacarbazine, Daunorubicin, Doxorubicin, Etoposide,
Fludarabine, Gemcitabine, Hydroxyurea, Idarubicin, Ifosfamide,
Lomustine, Mechlorethamine, Melphalan, Mercaptopurine,
Methotrexate, Mitomycin, Mitoxantrone, Pentostatin, Procarbazine,
6-Thioguanine, Topotecan, Vinblastine, Vincristine,
Dexamethasone,.Retinoic acid and Prednisone.
[0069] In another embodiment, the chemotherapeutic agents are
selected from the group consisting of Cytarabine, Etoposide,
Mitoxantron, Cyclophosphamide, Retinoic acid, Daunorubicin,
Doxorubicin and Idarubicin.
[0070] Still in another embodiment, the chemotherapeutic agent is
Doxorubicin.
[0071] In one embodiment, the multidrug resistance reversing agent
is PSC 833.
[0072] In another embodiment, the biological response modifiers are
selected from the group consisting of monoclonal antibodies and
cytokines.
[0073] In another embodiment, the cytokines are selected from the
group consisting of interferons, interleukins and
colony-stimulating factors.
[0074] In another embodiment, the biological response modifiers are
selected from the group consisting of Rituxan, CMA-676,
Interferon-alpha recombinant, Interleukin-2, Interleukin-3,
Erythropoetin, Epoetin, G-CSF, GM-CSF, Filgrastim, Sargramostim and
Thrombopoietin.
[0075] In one embodiment of the present invention, the combinations
referred to above are conveniently presented for use in the form of
a pharmaceutical composition comprising a combination as defined
above together with a pharmaceutically acceptable carrier.
[0076] In another embodiment, the individual components of such
combinations are administered either sequentially or simultaneously
in separate or combined pharmaceutical formulations.
[0077] In one embodiment of the present invention, when the
compound of formula I or a pharmaceutically acceptable salt thereof
is used in combination with a second therapeutic agent, the dose of
each compound is either the same as or differ from that when the
compound is used alone. Appropriate doses will be readily
appreciated by those skilled in the art.
[0078] The compounds of formula I of the present invention can be
prepared as follows.
[0079] The following examples are provided to illustrate various
embodiments of the present invention and shall not be considered as
limiting in scope.
EXAMPLE 1
Preparation of .beta.-L-oddC
[0080] 7
Compound #1:2S-Benzyloxymethyl-4R-Iodo-1,3 Dioxolane and
2SBenzyloxymethyl-4S-Iodo-1,3 Dioxolane
[0081] A mixture consisting of 2S-benzyloxymethyl-4S acetoxy-1,3
dioxolane and 2S-benzyloxymethyl-4R-acetoxy-1,3 dioxolane in 1:2
ratio (6 g; 23.8 mmol) was dried by azeotropic distillation with
toluene in vacuo. After removal of toluene, the residual oil was
dissolved in dry dichloromethane (60 ml) and iodotrimethylsilane
(3.55 ml; 1.05 eq) was added at -78.degree. C., under vigorous
stirring. The dry-ice/acetone bath was removed after addition and
the mixture was allowed to warm up to room temperature (15 min.).
The .sup.1H NMR indicated the formation of
2S-benzyloxymethyl-4R-iodo-1,3-dioxolane and
2S-benzyloxymethyl-4S-iodo-1- ,3 dioxolane.
[0082] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 3.65-4.25 (2H, m);
4.50-4.75 (4H, m) 5.40-5.55 (1H, overlapping triplets); 6.60-6.85
(1H, d of d); 7.20-7.32 (5H, m).
Compound #2:
.beta.-L-5'-Benzyl-2'-Deoxy-3'-Oxa-N-4-Acetyl-Cytidine
[0083] The previously prepared iodo intermediate (Compound #1) in
dichloromethane, was cooled down to -78.degree. C. Persylilated
N-acetyl cytosine (1.1 eq) formed by reflux in
1,1,1,3,3,3-hexamethyl disilazane (HMDS) and ammonium sulphate
followed by evaporation of HMDS was dissolved in 30 ml of
dichloromethane and was added to the iodo intermediate. The
reaction mixture was maintained at -78.degree. C. for 1.5 hours
then poured onto aqueous sodium bicarbonate and extracted with
dichloromethane (2.times.25 ml).
[0084] The organic phase was dried over sodium sulphate, the solid
was removed by filtration and the solvent was evaporated in vacuo
to produce 8.1 g of a crude mixture. Based on .sup.1H NMR analysis,
the .beta.-L-5'-benzyl-2'-deoxy-3'-oxacytidine and its .alpha.-L
isomer were formed in a ratio of 5:1 respectively. This crude
mixture was separated by chromatography on silica-gel (5% MeOH in
EtOAc) to generate the pure .beta.-L (cis) isomer (4.48 g).
Alternatively, recrystallization of the mixture from ethanol
produces 4.92 g of pure .beta. isomer and 3.18 g of a mixture of
.beta. and .alpha.-isomers in a ratio of 1:1.
[0085] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 2.20 (3H, S, Ac);
3.87 (2H, m, H-5'), 4.25 (2H, m, H-2'); 4.65 (2H, dd, OCH.sub.2Ph);
5.18 (1H, t, H-4'); 6.23 (1H, m, H-1'); 7.12 (1H, d, H-5);
7.30-7.50 (5H, m, Ph); 8.45 (2H, m, NH+H-6).
Compound #3: .beta.-L-5'-Benzyloxy-2'-Deoxy-3'-Oxacytidine
[0086] The protected .beta.-L isomer (4.4 g) (Compound #2) was
suspended in saturated methanolic ammonia (250 ml) and stirred at
room temperature for 18 hours in a closed vessel. The solvents were
then removed in vacuo to afford the deacetylated nucleoside in pure
form.
[0087] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 3.85 (2H, m,
H-5'); 4.20 (2H, m, H-2'); 4.65 (2H, dd, OCH.sub.2Ph); 5.18 (1H, t,
H-4'); 5.43 (1H, d, H-5); 5.50-5.90 (2H, br, S, NH.sub.2); 6.28
(1H, m, H-1'); 7.35-7.45 (5H, m, Ph); 7.95 (1H, d, H-6).
Compound #4: .beta.-L-OddC
[0088] .beta.-L-5'-Benzyl-2'-deoxy-3'-oxacytidine (Compound #3) was
dissolved in EtOH (200 ml) followed by addition of cyclohexene (6
ml) and palladium oxide (0.8 g). The reaction mixture was refluxed
for 7 hours then it was cooled and filtered to remove solids. The
solvents were removed from the filtrate by vacuum distillation. The
crude product was purified by flash chromatography on silica-gel
(5% MeOH in EtOAc) to yield a white solid (b-L-OddC) (2.33 g; 86%
overall yield, .alpha..sub.D.sup.22=-46.70.degree. (c=0.285; MeOH)
m.p.=192-194.degree. C.).
[0089] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 3.63 (2H; dd,
H-5'); 4.06 (2H, m, H-2'); 4.92 (1H, t, H-4'); 5.14 (1H, t, OH);
5.70 (1H, d, H-5); 6.16. (2H, dd, H-1'); 7.11-7.20 (2H, brS,
NH.sub.2); 7.80 (1H, d, H-6) .sup.13C NMR (75 MHZ, DMSO- d.sub.6)
.delta. 59.5 (C-2'); 70.72 (C-5'); 81.34 (C-4'); 93.49 (C-1');
104.49 (C-5); 140.35 (C-4); 156.12 (C-6); 165.43 (C-2).
EXAMPLE 2
Evaluation of .beta.-L-OddC in Patients with Advanced Leukemia
[0090] The study involved treatment of patients with advanced
leukemia that had been previously treated with Citarabine (Ara-C).
The previous treatment with Ara-C had failed to stop progression of
the disease. Twelve patients were treated with an initial course at
daily doses of 0.72 mg/m2 (4 patients), 1.08 mg/m.sup.2 (5
patients), 1.62 mg/m.sup.2 (3 patients) given as a daily infusion
over 30 minutes for 5 consecutive days. Five patients were treated
with second courses at daily doses of 1.08 mg/m.sup.2 (3 patients),
1.62 mg/m.sup.2 (2 patients) given over 5 consecutive days as
above. 1 patient was treated with a 3.sup.rd 5 day course at the
2.43 mg/m.sup.2 daily dose level. 4 patients (2 each at the 1.08
mg/m.sup.2 and 1,62 mg/m.sup.2 levels) have shown a transient
decrease in peripheral blood and bone marrow blasts. Of these four
patients, three had acute mylogenous leukemia and one had chronic
mylogenous leukemia.
EXAMPLE 3
.beta.-L-OddC/Doxorubicine Combination Study in a Human Leukemia
(HL60) Xenograft Model
[0091] A study was conducted to evaluate the synergistic or
additive therapeutic effect of .beta.-L-OddC in combination with
the currently known anticancer agent Doxorubicin. The model that
was utilized is a survival model consisting of female SCID mice
which are inoculated in the abdomen region (i.p.) with
15.times.10.sup.6 HL60 cells in log phase growth. This corresponds
to day 0 of the experiment. Administration of anti-cancer drug is
started 10 days after tumor cell inoculation.
[0092] 10 animals were used per group for .beta.-L-oddC alone,
Doxorubicin alone and the combination of .beta.-L-oddC with
Doxorubicin. Each groups received the drugs alone or in combination
intravenously once daily for 5 consecutive days.
[0093] Augmentation of survival time was calculated by substracting
from the median survival time of group two to six, which
corresponds to the day when the fifth mouse dies, the median
survival time of control group 1 and multiplying by 100.
[0094] In Table 1 below, we observe that the best treatment
corresponds to the combination of .beta.-L-oddC with Doxorubicin at
a dose of 2 mg/Kg. This combination extends the survival time of
the mice substantially compared to either single agents
.beta.-L-oddC and Doxorubicin.
1TABLE 1 COMBINATION STUDY .beta.-L-OddC/DOXORUBICI- N IN HUMAN
LEUKEMIA (HL60) Group Augmentation of Combination Survival Time 1
Saline i.p. 2 .beta.-L-OddC 1 mg/kg 55% 3 Doxorubicin 0.2 mg/kg 25%
4 .beta.-L-OddC 1 mg/kg + Doxorubicin 0.2 mg/kg 55% 5 Doxorubicin 2
mg/kg 50% 6 .beta.-L-OddC 1 mg/kg. + Doxorubicin 2 mg/kg 100%
* * * * *