Note: Descriptions are shown in the official language in which they were submitted.
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PHOSPHONATE SUBSTITUTED KINASE INHIBITORS
PRIORITY OF INVENTION
This patent documents claims priority to United States Provisional
Applications 60/623,098; 60/622,992; 60/622,881; 60/622,960; 60/622,811;
60/622,942; and 60/622,943, all of which were filed on 26 October 2004, and
all
of which are herein incorporated by reference.
FIELD OF THE INVENTION
The invention relates generally to phosphonate-containing compounds
with kinase-inhibitory activity, i.e., compounds that inhibit at least one
kinase.
BACKGROUND OF THE INVENTION
Improving the delivery of drugs and other agents to target cells and
tissues has been the focus of considerable research for many years. Though
many attempts have been made to develop effective methods for importing
biologically active molecules into cells, both in vivo and in vitro, none has
proved to be entirely satisfactory. Optimizing the association of the
inhibitory
drug with its intracellular target, while minimizing intercellular
redistribution of
the drug, e.g., to neighboring cells, is often difficult or inefficient.
Most agents currently administered to a patient parenterally are not
targeted, thereby resulting in systemic delivery of the agent to cells and
tissues
of the body where the agent is unnecessary, and often undesirable. This
systemic delivery may result in adverse side effects and often limits the dose
of
an agent that can be administered. By comparison, oral administration of
agents
is generally recognized as a convenient and economical method of
administration. However, oral administration of agents can result in (a) the
upt4:::; C;f '?:c- ag ~ through cellular and tissue barriers, such as the
blood-brain
barrier, epithelial, or the cell membrane, resulting in undesirable system c
distribution, and/or (b) temporary residence of the agent within the
gastrointestinal tract. Accordingly, a major goal has been to develop methods
for specifically targeting agents to cells and tissues. Benefits of such
treatment
include avoiding the general physiological effects of inappropriate delivery
of
such agents to other cells and tissues, such as uninfected cells.
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Thus, there is a need for therapeutic agents, e.g., agents that inhibit at
least one kinase, with improved pharmacological properties, e.g., having
improved kinase-inhibitory activity and/or pharmacokinetic properties,
including
improved oral bioavailability, greater potency and extended effective half-
life in
vivo. Such inhibitors would have therapeutic uses, for example, as anti-cancer
agents. Thus, new kinase inhibitors should have fewer side effects, less
complicated dosing schedules, and be orally active. In particular, there is a
need
for a less onerous dosage regimen, such as one pill, once per day.
Assay methods capable of determining the presence, absence or amounts
of kinase inhibition are of practical utility in the search for kinase
inhibitors as
well as for diagnosing the presence of conditions associated with kinase
activity.
SUMMARY OF CERTAIN EMBODIMENTS OF THE INVENTION
Intracellular targeting may be achieved by methods and compositions
that allow accumulation or retention of biologically active agents inside
.cells.
Certain embodiments of the present invention provide novel analogs of kinase-
inhibitory compounds, i.e., compounds that inhibit the activity of at least
one
kinase. Such novel kinase-inhibitory analogs possess utilities of the kinase-
inhibitory compounds and optionally provide cellular accumulation. In
addition,
certain embodiments of the present invention provide compositions and methods
useful for inhibiting at least one kinase that may have therapeutic activity
against
diseases associated with kinase activity, such as cancer.
The present invention relates generally to the accumulation or retention
of therapeutic compounds inside cells. The invention is more particularly
related
to attaining high concentrations of phosphonate-containing molecules in target
cells. Such effective targeting may be applicable to a variety of therapeutic
formulations and procedures.
Compositions of the invention include kinase-inhibitory compounds
having at least one phosphonate group. Accordingly, in one embodiment the
invention provides a conjugate comprising a compound that is linked to one or
more phosphonate groups; or a pharmaceutically acceptable salt or solvate
thereof.
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In another embodiment the invention provides a compound comprising at
least one phosphonate group and a substructure of any one of formulae 100-106:
R29 R3: N. R32
-O-N 0
R33 N H
N~,w N N sa N J ~\ N -
~R
R30
100 101 102
N H N
S
v N\S / NH
103 104 105
O
R56 H
106
wherein:
the bond represented by -_ is a single or double bond;
R29 is hydrogen, alkyl, or -C(=O)R36;
R30 is hydrogen or substituted alkyl; and
R3 1 and R32 are independently hydrogen, alkyl, or substituted aryl; or R3 1
and R32 taken together with the nitrogen atom to which they are attached form
a
substituted or unsubstituted heterocyclic ring;
R33 is -0-, -NR35- or absent;
R34 is -0- or absent;
R35 is hydrogen or alkyl;
R36 is hydrogen, alkyl, alkenyl, or alkynyl;
R56 is -N-, or -CR68-; and
R68 is hydrogen or alkyl;
or a pharmaceutically acceptable salt thereof.
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The invention provides a pharmaceutical composition comprising.an
effective amount of a compound of the invention, or a pharmaceutically
acceptable salt thereof, in combination with a pharmaceutically acceptable
diluent or carrier.
This invention provides a method of increasing cellular accumulation and
retention of drug compounds, thus improving their therapeutic and diagnostic
value, comprising linking the compound to one or more (e.g., 1, 2, 3, or 4)
phosphonate groups.
The invention also provides a method of inhibiting the activity of at least
one kinase, comprising administering to a mammal an amount of a compound of
the invention.
The invention also provides a compound of the invention for use in
medical therapy (preferably for use in treating a condition associated with
kinase
activity, e.g., elevated kinase activity), as well as the use of a compound of
the
invention for the manufacture of a medicament useful for the treatment of a
condition associated with kinase activity, e.g., associated with elevated
kinase
activity. The invention also provides the use of a compound of the invention
to
prepare a medicament for treating cancer in an animal.
The invention also provides processes and novel intermediates disclosed
herein which are useful for preparing compounds of the invention. Some of the
compounds of the invention are useful to prepare other compounds of the
invention.
In another aspect of the invention, the activity of a kinase is inhibited by
a method comprising the step of treating a sample suspected of containing a
kinase with a compound or composition of the invention.
DETAILED DESCRIPTION OF THE INVENTION
Reference will now be made in detail to certain embodiments of the
invention, examples of which are illustrated in the accompanying structures
and
formulas. While the invention will be described in conjunction with the
enumerated embodiments, it will be understood that they are not intended to
limit
the invention to those embodiments. On the contrary, the invention is intended
to cover all alternatives, modifications, and equivalents, which may be
included
within the scope of the present invention as defined by the embodiments.
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Many of the current treatment regimes for cell proliferation diseases such
as psoriasis and cancer utilize compounds that inhibit DNA synthesis. Such
compounds are toxic to cells generally, but their toxic effect on rapidly
dividing
cells, such as tumor cells, can be beneficial. Alternative approaches to anti-
proliferative agents that act by mechanisms other than the inhibition of DNA
synthesis have the potential to display enhanced selectivity of action.
In recent years it has been discovered that a cell may become cancerous
by virtue of the transformation of a portion of its DNA into an oncogene i.e.
a
gene that, on activation, leads to the formation of malignant tumor cells
(Bradshaw, Mutagenesis 1986, 1, 91). Several such oncogenes give rise to the
production of peptides which are receptors for growth factors. The growth
factor
receptor complex subsequently leads to an increase in cell proliferation. For
example, several oncogenes encode tyrosine kinase enzymes, and certain growth
factor receptors are also tyrosine kinase enzymes (Yarden et al., Ann. Rev.
Biochem., 1988, 57, 443; Larsen et al., Ann. Reports in Med. Chem. 1989, Chpt.
13).
Receptor tyrosine kinases are important in the transmission of
biochemical signals that initiate cell replication. They are large enzymes
that
span the cell membrane and possess an extracellular binding domain for growth
factors such as epidermal growth factor (EGF), and an intracellular portion
that
functions as a kinase to phosphorylate tyrosine amino acids in proteins and
hence influence cell proliferation. Various classes of receptor tyrosine
kinases
are known (Wilks, Advances in Cancer Research, 1993, 60, 43-73) based on
families of growth factors that bind to different receptor tyrosine kinases.
The
classification includes Class I receptor tyrosine kinases comprising the EGF
family of receptor tyrosine kinases such as the EGF, TGFa, NEU, erbB, Xmrk,
HER and 1et23 receptors, Class II receptor tyrosine kinases comprising the
insulin family of receptor tyrosine kinases such as the insulin, IGFI and
insulin-
related receptor (IRR) receptors and Class III receptor tyrosine kinases
comprising the platelet-derived growth factor (PDGF) family of receptor
tyrosine kinases such as the PDGFa, PDGF(3 and colony-stimulating factor 1
(CSFI) receptors.
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Class I kinases, such as the EGF family of receptor tyrosine kinases, are
frequently present in common human cancers such as breast cancer (Sainsbury et
al., Brit. J. Cancer, 1988, 58, 458; Guerin et al., Oncogene Res., 1988, 3, 21
and
Klijn et al., Breast Cancer Res. Treat., 1994, 29, 73), non-small cell lung
cancers (NSCLCs) including adenocarcinomas (Cerny et al., Brit: J. Cancer,
1986, 54, 265; Reubi et al., Int. J. Cancer, 1990, 45, 269; and Rusch et al.,
Cancer Research, 1993, 53, 2379) and squamous cell cancer of the lung
(Hendler et al., Cancer Cells, 1989, 7, 347), bladder cancer (Neal et al.,
Lancet,
1985; 366), oesophageal cancer (Mukaida et al., Cancer, 1991, 68, 142),
gastrointestinal cancer such as colon, rectal or stomach cancer (Bolen et al.,
Oncogene Res., 1987, 1, 149), cancer of the prostate (Visakorpi et al.,
Histochem. J., 1992, 24, 481), leukaemia (Konaka et al., Cell, 1984, 37, 1035)
and ovarian, bronchial or pancreatic cancer (European Patent Specification No.
0400586). As further human tumor tissues are tested for the EGF family of
receptor tyrosine kinases, it is expected that their widespread prevalence
will be
established in further cancers such as thyroid and uterine cancer. EGF type
tyrosine kinase activity is rarely detected in normal cells, whereas it is
more
frequently detected in malignant cells (Hunter, Cell, 1987, 50, 823). EGF
receptors that possess tyrosine kinase activity are overexpressed in many
human
cancers such as brain, lung squamous cell, bladder, gastric, breast, head and
neck, oesophageal, gynaecological and thyroid tumors (W. J. Gullick, Brit.
Med.
Bull., 1991, 47, 87).
Accordingly, an inhibitor of receptor tyrosine kinases would be of value
as a selective inhibitor of the growth of mammalian cancer cells (Yaish et al.
Science, 1988, 242, 933). Support for this view is provided by the
demonstration
that erbstatin, an EGF receptor tyrosine kinase inhibitor, specifically
attenuates
the growth in athymic nude mice of a transplanted human mammary carcinoma
that expresses EGF receptor tyrosine kinase but is without effect on the
growth
of another carcinoma that does not express EGF receptor tyrosine kinase (Toi
et
al., Eur. J. Cancer Clin. Oncol., 1990, 26, 722.) Various derivatives of
styrene
also possess tyrosine kinase inhibitory properties (European Patent
Application
Nos. 0 211 363, 0 304 493 and 0 322 738) and may be used as anti-tumor agents.
The in vivo inhibitory effect of two such styrene derivatives that are EGF
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receptor tyrosine kinase inhibitors has been demonstrated against the growth
of
human squamous cell carcinoma inoculated into nude mice (Yoneda et al.,
Cancer Research, 1991, 51, 4430). Various known tyrosine kinase inhibitors are
disclosed in a more recent review by T. R. Burke Jr. (Drugs of the Future,
1992,
17,119).
Kinase inhibitors have valuable pharmacological properties and can be
used, e.g., as anti-tumor drugs and as drugs against atherosclerosis. The
phosphorylation of proteins has long been known as an important step in the
differentiation and proliferation of cells. Phosphorylation is catalyzed by
protein
kinases that are divided into serine/threonine kinases and tyrosine kinases.
The
serine/threonine kinases include protein kinase C and the tyrosine kinases
include PDGF (platelet-derived growth factor)-receptor tyrosine kinase and Bcr-
Abl kinase.
Chronic myelogenous Leukemia (CML) is a hematological stem cell
disorder associated with a specific chromosomal translocation known as the
Philadelphia chromosome that is detected in 95% of patients with CML and 20%
with acute lymphocytic leukemia (ALL). The molecular consequences of the
translocation is the fusion of the abl protooncogene to the bcr gene resulting
in
the production of an activated from of Abl tyrosine protein kinase. The Bcr-
Abl
protein is capable of inducing leukemias in mice, thus implicating the protein
as
the cause of these diseases. Thus, kinase inhibitors inhibit cellular kinases
that
are involved in disease states, for example, Bcr-Abl. As the tyrosine kinase
activity of the Bcr-Abl protein is essential to its transforming ability, an
inhibitor
would be useful therapy for these disorders.
In addition, kinase inhibitors prevent the development of resistance (e.g.,
multi-drug resistance) in cancer treatment with other chemotherapeutic drugs
or
remove existing resistance to other chemotherapeutic drugs.
Two processes, the de novo formation of vessels from differentiating
endothelial cells or angioblasts in the developing embryo (vasculogenesis) and
the growth of new capillary vessels from existing blood vessels
(angiogenesis),
are involved in the development of the vascular systems of animal organs and
tissues. Transient phases of new vessel formation (neovascularization) also
occur
in the adult body, for example, during the menstrual cycle, pregnancy and
wound
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healing. On the other hand, a number of diseases are known to be associated
with deregulated angiogenesis, for example, retinopathies, psoriasis,
hemangioblastoma, hemangioma, and neoplastic diseases (e.g., solid tumors).
The complex processes of vasculogenesis and angiogenesis have been found to
involve a whole range of molecules, especially angiogenic growth factors and
their endothelial receptors, as well as cell adhesion molecules.
Recent findings show that at the center of the network regulating the
growth and differentiation of the vascular system and its components, both
during embryonic development and normal growth and in a wide number of
pathological anomalies and diseases, lies the angiogenic factor known as
vascular endothelial growth factor (VEGF), along with its cellular receptors
(see
Breier, G., et al., Trends in Cell Biology 6, 454-6 (1996) and the references
cited
therein).
VEGF is a dimeric, disulfide-linked 46-kDa glycoprotein and is related to
platelet-derived growth factor (PDGF). It is produced by normal cell lines and
tumor cell lines, is an endothelial cell-specific mitogen, shows angiogenic
activity in in vivo test systems (e.g. rabbit cornea), is chemotactic for
endothelial
cells and monocytes, and induces plasminogen activators in endothelial cells,
which are then involved in the proteolytic degradation of extracellular matrix
during the formation of capillaries. A number of isoforms of VEGF show
comparable biological activity, but differ in the type of cells that secrete
them
and in their heparin-binding capacity. In addition, there are other members of
the
VEGF family, such as placenta growth factor (PLGF) and VEGF-C.
VEGF receptors are transmembranous receptor tyrosine kinases. They
are characterized by an extracellular domain with seven immunoglobulin-like
domains and an intracellular tyrosine kinase domain. Various types of VEGF
receptor are known, e.g. VEGFR-1, VEGFR-2, and VEGFR-3.
A large number of human tumors, especially gliomas and carcinomas,
express high levels of VEGF and its receptors. This has led to the hypothesis
that
the VEGF released by tumor cells could stimulate the growth of blood
capillaries
and the proliferation of tumor endothelium in a paracrine manner and thus,
through the improved blood supply, accelerate tumor growth. Increased VEGF
expression could explain the occurrence of cerebral edema in patients with
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glioma. Direct evidence of the role of VEGF as a tumor angiogenesis factor in
vivo has been obtained from studies in which VEGF expression or VEGF
activity was inhibited. This was achieved with antibodies that inhibit VEGF
activity, with dominant-negative VEGFR-2 mutants that inhibited signal
transduction, or with the use of antisense-VEGF RNA techniques. All
approaches led to a reduction in the growth of glioma cell lines or other
tumor
cell lines in vivo as a result of inhibited tumor angiogenesis.
In addition, hypoxia, a large number of growth factors and cytokines, e.g.
Epidermal Growth Factor, Transforming Growth Factor a, Transforming Growth
Factor A, Interleukin 1, and Interleukin 6, induce the expression of VEGF in
cell
experiments. Angiogenesis is regarded as a prerequisite for those tumors that
grow beyond a maximum diameter of about 1-2 mm; up to this limit, oxygen and
nutrients may be supplied to the tumor cells by diffusion. Every tumor,
regardless of its origin and its cause, is thus thought to be dependent on
angiogenesis for its growth after it has reached a certain size.
Three principal mechanisms play important parts in the activity of
angiogenesis inhibitors against tumors: 1) inhibition of the growth of
vessels,
especially capillaries, into avascular resting tumors, with the result that
there is
no net tumor growth owing to the balance that is achieved between apoptosis
and
proliferation; 2) prevention of the migration of tumor cells owing to the
absence
of bloodflow to and from tumors; and 3) inhibition of endothelial cell
proliferation, thus avoiding the paracrine growth-stimulating effect exerted
on
the surrounding tissue by the endothelial cells that normally line the
vessels.
Inhibitors of cyclin-dependent kinases, e.g., Alvocidib (US Patent No.
4,900,727; also known as flavopiridol) have been identified as a potentially
useful therapeutic agents for a variety of cancers, including gastrointestinal
and
colon tumors, leukemias and myelomas (see, for example, Intl. J. Oncol., 1996,
9, 1143).
Inhibitors of tyrosine kinases, including Bcr-Abl, e.g., Gleevec, are
useful for the treatment of chronic myeloid leukemia (CML), and potentially
for
treatment of other cancers that express these kinases, including acute
lymphocytic leukemia (ALL) and certain solid tumors. Gleevec was approved
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for the treatment of inoperable and/or metastatic malignant gastrointestinal
stromal tumors (GISTs).
Inhibitors of Flt3 tyrosine kinase, e.g., CEP-701 (US Patent No.
4,923,986) and Midostaurin (US Patent No. 5,093,330), have potential utility
for
the treatment of a variety of cancers (Cancer Res., 1999, 59, 10).
Inhibitors of MAP Erk kinase, e.g., PD-184352 (U.S. Patent No.
6,251,943), have been identified as potentially useful therapeutic agents for
a
variety of oncological disorders, including colon, breast, pancreatic and non-
small-cell lung cancers (see, for example, Proc. Am. Soc. Clin. Oncol., 2003,
22,
abstract 816).
Other kinase inhibitors, e.g., doramapimod (U.S. Patent No. 6,319,921),
have been identified as potentially useful therapeutic agents for the
treatment of
inflammatory diseases such as rheumatoid arthritis, psoriasis and Crohn's
disease.
Other kinase inhibitors, e.g., BAY-43-9006 (U.S. Publication No.
2002/0165394) have been identified as potentially useful therapeutic agents
for a
variety of cancers including gastrointestinal and colon tumors, leukemia and
carcinoma (Curr. Pharm. Design, 2002, 8, 2269).
Cytokine receptors are critical for the development and homeostasis of
immune cells. These receptors all require the cytoplasmic tyrosine kinase JAK3
for signaling (Changelian, P. S. et al., Science, 2003, 302, 875). CP-690,550
(WO 02,096,909) is an orally available Janus kinase (JAK)-3 inhibitor, for the
potential treatment of transplant rejection and psoriasis.
Thus, there is a need for therapeutic agents that are kinase inhibitors with
improved pharmacological properties, e.g., drugs having improved kinase-
inhibitory activity and/or pharmacokinetic properties, including improved oral
bioavailability, greater potency and extended effective half-life in vivo.
Such
inhibitors would have therapeutic potential as, e.g., anticancer agents. The
kinase inhibitory compounds provided herein may be used, e.g., to treat breast
cancer, non-small cell lung cancers (NSCLCs), adenocarcinomas, squamous cell
cancer of the lung, oesophageal cancer, gastrointestinal cancer, colon cancer,
rectal cancer, stomach cancer, prostate cancer, leukaemia, ovarian cancer,
bronchial cancer, pancreatic cancer, thyroid cancer, uterine cancer, brain
cancer,
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lung squamous cell cancer, bladder cancer, gastric cancer, head and neck
cancer,
gynaecological and thyroid tumors, to prevent the development of resistance
(multi-drug resistance) in cancer treatment with other chemotherapeutic drugs
or
remove existing resistance to other chemotherapeutic drugs, retinopathies,
hemangioblastoma, hemangioma, and neoplastic diseases, gliomas, to inhibit
tumor angiogenesis, myelomas, chronic myeloid leukemia (CML), acute
lymphocytic leukemia (ALL), inoperable and/or metastatic malignant
gastrointestinal stromal tumors (GISTs), treatment of inflammatory diseases
such
as rheumatoid arthritis, Crohn's disease, treatment of cell proliferation
diseases,
and for the treatment of transplant rejection and psoriasis; and to prepare
medicaments for such treatments.
DEFINITIONS
Unless stated otherwise, the following terms and phrases as used herein
are intended to have the following meanings:
When tradenames are used herein, applicants intend to independently
include the tradename product and the active pharmaceutical ingredient(s) of
the
tradename product.
"Bioavailability" is the degree to which the pharmaceutically active agent
becomes available to the target tissue after the agent's introduction into the
body.
Enhancement of the bioavailability of a pharmaceutically active agent can
provide a more efficient and effective treatment for patients because, for a
given
dose, more of the pharmaceutically active agent will be available at the
targeted
tissue sites.
The terms "phosphonate" and "phosphonate group" include functional
groups or moieties within a molecule that comprises a phosphorous that is 1)
single-bonded to a carbon, 2) double-bonded to a heteroatom , 3) single-bonded
to a heteroatom, and 4) single-bonded to another heteroatom, wherein each
heteroatom can be the same or different. The terms "phosphonate" and
"phosphonate group" also include functional groups or moieties that comprise a
phosphorous in the same oxidation state as the phosphorous described above, as
well as functional groups or moieties that comprise a prodrug moiety that can
separate from a compound so that the compound retains a phosphorous having
the characteristics described above. For example, the terms "phosphonate" and
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"phosphonate group" include phosphonic acid, phosphonic monoester,
phosphonic diester, phosphonamidate, and phosphonthioate functional groups.
In one specific embodiment of the invention, the terms "phosphonate" and
"phosphonate group" include functional groups or moieties within a molecule
that comprises a phosphorous that is 1) single-bonded to a carbon, 2) double-
bonded to an oxygen, 3) single-bonded to an oxygen, and 4) single-bonded to
another oxygen, as well as functional groups or moieties that comprise a
prodrug
moiety that can separate from a compound so that the compound retains a
phosphorous having such characteristics. In another specific embodiment of the
invention, the terms "phosphonate" and "phosphonate group" include functional
groups or moieties within a molecule that comprises a phosphorous that is 1)
single-bonded to a carbon, 2) double-bonded to an oxygen, 3) single-bonded to
an oxygen or nitrogen, and 4) single-bonded to another oxygen or nitrogen, as
well as functional groups or moieties that comprise a prodrug moiety that can
separate from a compound so that the compound retains a phosphorous having
such characteriatics.
The term "prodrug" as used herein refers to any compound that when
administered to a biological system generates the drug substance, i.e. active
ingredient, as a result of spontaneous chemical reaction(s), enzyme catalyzed
chemical reaction(s), photolysis, and/or metabolic chemical reaction(s). A
prodrug is thus a covalently modified analog or latent form of a
therapeutically-
active compound.
"Prodrug moiety" refers to a labile functional group that separates from the
active inhibitory compound during metabolism, systemically, inside a cell, by
hydrolysis, enzymatic cleavage, or by some other process (Bundgaard, Hans,
"Design and Application of Prodrugs" in A Textbook of Drug Design and
Development (1991), P. Krogsgaard-Larsen and H. Bundgaard, Eds. Harwood
Academic Publishers, pp. 113-191). Enzymes that are capable of an enzymatic
activation mechanism with the phosphonate prodrug compounds of the invention
include, but are not limited to, amidases, esterases, microbial enzymes,
phospholipases, cholinesterases, and phosphases. Prodrug moieties can serve to
enhance solubility, absorption and lipophilicity to optimize drug delivery,
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bioavailability and efficacy. A prodrug moiety may include an active
metabolite
or drug itself.
Exemplary prodrug moieties include the hydrolytically sensitive or labile
acyloxymethyl esters -CH2OC(=O)R9 and acyloxymethyl carbonates
-CH2OC(=O)OR9 where R9 is CI-C6 alkyl, C1-C6 substituted alkyl, C6-C20 aryl
or C6-C20 substituted aryl. The acyloxyalkyl ester was first used as a prodrug
strategy for carboxylic acids and then applied to phosphates and phosphonates
by Farquhar et al. (1983) J. Pharm. Sci. 72: 324; also U.S. Patent Nos.
4816570,
4968788, 5663159 and 5792756. Subsequently, the acyloxyalkyl ester was used
to deliver phosphonic acids across cell membranes and to enhance oral
bioavailability. A close variant of the acyloxyalkyl ester, the
alkoxycarbonyloxyalkyl ester (carbonate), may also enhance oral
bioavailability
as a prodrug moiety in the compounds of the combinations of the invention. An
exemplary acyloxymethyl ester is pivaloyloxymethoxy, (POM)
-CHZOC(=O)C(CH3)3. An exemplary acyloxymethyl carbonate prodrug moiety
is pivaloyloxymethylcarbonate (POC) -CH2OC(=O)OC(CH3)3.
The phosphonate group may be a phosphonate prodrug moiety. The
prodrug moiety may be sensitive to hydrolysis, such as, but not limited to a
pivaloyloxymethyl carbonate (POC) or POM group. Aiternatively, the prodrug
moiety may be sensitive to enzymatic potentiated cleavage, such as a lactate
ester or a phosphonamidate-ester group.
Aryl esters of phosphorus groups, especially phenyl esters, are reported
to enhance oral bioavailability (De Lombaert et al. (1994) J. Med. Chem. 37:
498). Phenyl esters containing a carboxylic ester ortho to the phosphate have
also been described (Khamnei and Torrence, (1996) J. Med. Chem. 39:4109-
4115). Benzyl esters are reported to generate the parent phosphonic acid. In
some cases, substituents at the ortho-orpara-position may accelerate the
hydrolysis. Benzyl analogs with an acylated phenol or an alkylated phenol may
generate the phenolic compound through the action of enzymes, e.g., esterases,
oxidases, etc., which in turn undergoes cleavage at the benzylic C-O bond to
generate the phosphoric acid and the quinone methide intermediate. Examples
of this class of prodrugs are described by Mitchell et al. (1992) J. Chem.
Soc.
Perkin Trans. II2345; Glazier WO 91/19721. Still other benzylic prodrugs have
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been described containing a carboxylic ester-containing group attached to the
benzylic methylene (Glazier WO 91/19721). Thio-containing prodrugs are
reported to be useful for the intracellular delivery of phosphonate drugs.
These
proesters contain an'ethylthio group in which the thiol group is either
esterified
with an acyl group or combined with another thiol group to form a disulfide.
Deesterification or reduction of the disulfide generates the free thio
intermediate
which subsequently breaks down to the phosphoric acid and episulfide (Puech et
al. (1993) Antiviral Res., 22: 155-174; Benzaria et al. (1996) J. Med. Chem.
39:
4958). Cyclic phosphonate esters have also been described as prodrugs of
phosphorus-containing compounds (Erion et al., US Patent No. 6312662).
"Protecting group" refers to a moiety of a compound that masks or alters
the properties of a functional group or the properties of the compound as a
whole. Chemical protecting groups and strategies for protection/deprotection
are
well known in the art. See e.g., Protective Groups in Organic Chemistry,
Theodora W. Greene, John Wiley & Sons, Inc., New York, 1991. Protecting
groups are often utilized to mask the reactivity of certain functional groups,
to
assist in the efficiency of desired chemical reactions, e.g., making and
breaking
chemical bonds in an ordered and planned fashion. Protection of functional
groups of a compound alters other physical properties besides the reactivity
of
the protected functional group, such as the polarity, lipophilicity
(hydrophobicity), and other properties which can be measured by common
analytical tools. Chemically protected intermediates may themselves be
biologically active or inactive.
Protected compounds may also exhibit altered, and in some cases,
optimized properties in vitro and in vivo, such as passage through cellular
membranes and resistance to enzymatic degradation or sequestration. In this
role, protected compounds with intended therapeutic effects may be referred to
as prodrugs. Another function of a protecting group is to convert the parental
drug into a prodrug, whereby the parental drug is released upon conversion of
the prodrug in vivo. Because active prodrugs may be absorbed more effectively
than the parental drug, prodrugs may possess greater potency in vivo than the
parental drug. Protecting groups are removed either in vitro, in the instance
of
chemical intermediates, or in vivo, in the case of prodrugs. With chemical
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intermediates, it is not particularly important that the resulting products
after
deprotection, e.g., alcohols, be physiologically acceptable, although in
general it
is more desirable if the products are pharmacologically innocuous.
Any reference to any of the compounds of the invention also includes a
reference to a physiologically acceptable salt thereof. Examples of
physiologically acceptable salts of the compounds of the invention include
salts
derived from an appropriate base, such as an alkali metal (for example,
sodium),
an alkaline earth (for example, magnesium), ammonium and NX4+ (wherein X is
CI-C4 alkyl). Physiologically acceptable salts of a hydrogen atom or an amino
group include salts of organic carboxylic acids such as acetic, benzoic,
lactic,
fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and
succinic
acids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic,
benzenesulfonic and p-toluenesulfonic acids; and inorganic acids, such as
hydrochloric, sulftiric, phosphoric and sulfamic acids. Physiologically
acceptable salts of a compound of an hydroxy group include the anion of said
compound in combination with a suitable cation such as Na+ and NX4+ (wherein
X is independently selected from H or a C1-C4 alkyl group).
For therapeutic use, salts of active ingredients of the compounds of the
invention will be physiologically acceptable, i.e. they will be salts derived
from a
physiologically acceptable acid or base. However, salts of acids or bases
which
are not physiologically acceptable may also find use, for example, in the
preparation or purification of a physiologically acceptable compound. All
salts,
whether or not derived form a physiologically acceptable acid or base, are
within
the scope of the present invention.
As used herein, the term "substructure" refers to a residue wherein any
hydrogen atom(s) or replaceable group(s) has been or can be removed to provide
an open valence for the substitution of a group including a phosphonate group,
e.g., the substructure is a scaffold, to which a substituent -link-P(O)(OR')2
is
attached. The substructures can have additional groups attached. For a kinase
inhibiting compound that comprises at least one phosphonate group and a
substructure, it is understood that the compound includes the substructure as
at
least part of the overall structure of the compound.
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"Alkyl" is C 1-C 18 hydrocarbon containing normal, secondary, tertiary or
cyclic carbon atoms. Examples are methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-
propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-
butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-l-propyl (i-Bu, i-butyl,-
CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-
propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3),
2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-
butyl(-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-
1-butyl(-CH2CH2CH(CH3)2), 2-methyl-l-butyl (-CH2CH(CH3)CH2CH3), 1-
hexyl(-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-
hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-
C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-
methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-
C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-
dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-
CH(CH3)C(CH3))3.
"Alkenyl" is C2-C 18 hydrocarbon containing normal, secondary, tertiary
or cyclic carbon atoms with at least one site of unsaturation, i.e. a carbon-
carbon,
sp2 double bond. Examples include, but are not limited to, ethylene or vinyl
(-CH=CH2), allyl (-CH2CH=CH2), cyclopentenyl (-C5H7), and 5-hexenyl (-CH2
CH2CH2CH2CH=CH2).
"Alkynyl" is C2-C 18 hydrocarbon containing normal, secondary, tertiary
or cyclic carbon atoms with at least one site of unsaturation, i.e. a carbon-
carbon,
sp triple bond. Examples include, but are not limited to, acetylenic (-C=CH)
and
propargyl (-CH2C-CH).
"Alkylene" refers to a saturated, branched or straight chain or cyclic
hydrocarbon radical of 1-18 carbon atoms, and having two monovalent radical
centers derived by the removal of two hydrogen atoms from the same or two
different carbon atoms of a parent alkane. Typical alkylene radicals include,
but
are not limited to, methylene (-CH2-) 1,2-ethyl (-CH2CH2-), 1,3-propyl
(-CH2CH2CH2-), 1,4-butyl (-CH2CH2CH2CH2-), and the like.
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"Alkenylene" refers to an unsaturated, branched or straight chain or cyclic
hydrocarbon radical of 2-18 carbon atoms, and having two monovalent radical
centers derived by the removal of two hydrogen atoms from the same or two
different carbon atoms of a parent alkene. Typical alkenylene radicals
include, but
are not limited to, 1,2-ethylene (-CH=CH-).
"Alkynylene" refers to an unsaturated, branched or straight chain or cyclic
hydrocarbon radical of 2-18 carbon atoms, and having two monovalent radical
centers derived by the removal of two hydrogen atoms from the same or two
different carbon atoms of a parent alkyne. Typical alkynylene radicals
include, but
are not limited to, acetylene (-C=C-), propargyl (-CH2C=C-), and 4-pentynyl
(-CH2CH2CH2C=CH-).
"Aryl" means a monovalent aromatic hydrocarbon radical of 6-20 carbon
atoms derived by the removal of one hydrogen atom from a single carbon atom of
a
parent aromatic ring system. Typical aryl groups include, but are not limited
to,
radicals derived from benzene, substituted benzene, naphthalene, anthracene,
biphenyl, and the like.
"Arylalkyl" refers to an acyclic alkyl radical in which one of the
hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon
atom, is.replaced with an aryl radical. Typical arylalkyl groups include, but
are
not limited to, benzyl, 2-phenylethan-1-yl, , naphthylmethyl, 2-naphthylethan-
l-
yl, naphthobenzyl, 2-naphthophenylethan-1-yl and the like. The arylalkyl group
comprises 6 to 20 carbon atoms, e.g., the alkyl moiety, including alkanyl,
alkenyl or alkynyl groups, of the arylalkyl group is 1 to 6 carbon atoms and
the
aryl moiety is 5 to 14 carbon atoms.
"Substituted alkyl", "substituted aryl", and "substituted arylalkyl" mean
alkyl, aryl, and arylalkyl respectively, in which one or more hydrogen atoms
are
each independently replaced with a non-hydrogen substituent. Typical
substituents include, but are not limited to, -X, -R, -0-, -OR, -SR, -S', -
NRZ,
-NR3, =NR, -CX3, -CN, -OCN, -SCN, -N=C=O, -NCS, -NO, -NO2, =N2, -N3,
NC(=O)R, -C(=O)R, -C(=O)NRR -S(=O)20-, -S(=O)20H, -S(=O)2R, -
OS(=O)20R, -S(=O)zNR, -S(=O)R, -OP(=O)O2RR, -P(=O)O2RR -P(=O)(O )2,
-P(=O)(OH)2, -C(=O)R, -C(=O)X, -C(S)R, -C(O)OR, -C(O)O", -C(S)OR,
-C(O)SR, -C(S)SR, -C(O)NRR, -C(S)NRR, -C(NR)NRR, where each X is
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independently a halogen: F, Cl, Br, or I; and each R is independently -H,
alkyl,
aryl, heterocycle, protecting group or prodrug moiety. Alkylene, alkenylene,
and
alkynylene groups may also be similarly substituted.
"Heterocycle" as used herein includes, by way of example and not
limitation, those heterocycles described in Paquette, Leo A.; Principles of
Modern Heterocyclic Chemistry (W.A. Benjamin, New York, 1968), particularly
Chapters 1, 3, 4, 6, 7, and 9; The Chemistry of Heterocyclic Compounds, A
Series of Monographs" (John Wiley & Sons, New York, 1950 to present), in
particular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960)
82:5566. In one specific embodiment of the invention "heterocycle" includes a
"carbocycle" as defined herein, wherein one or more (e.g., 1, 2, 3, or 4)
carbon
atoms have been replaced with a heteroatom (e.g., 0, N, or S).
Examples of heterocycles include, by way of example and not limitation,
pyridyl, dihydroypyridyl, tetrahydropyridyl (piperidyl), thiazolyl,
tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl,
furanyl,
thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl,
thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl,
benzimidazolyl,
piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl,
tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,
decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-
thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thienyl, thianthrenyl, pyranyl,
isobenzofuranyl, chromenyl, xanthenyl, phenoxathinyl, 2H-pyrrolyl,
isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-
indolyl, 1 H-indazoly, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl,
quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl,
carbazolyl, (3-
carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl,
phenazinyl,
phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl,
imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl,
indolinyl,
isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl,
benzisoxazolyl, oxindolyl, benzoxazolinyl, isatinoyl, and bis-
tetrahydrofuranyl:
0
O
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By way of example and not limitation, carbon bonded heterocycles are
bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a
pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of
a
pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran,
thiophene,
pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or
thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole,
position 2 or
3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5,
6, 7, or 8
of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline. Still
more
typically, carbon bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl,
5-
pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-
pyridazinyl, 2-
pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-
pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.
By way of example and not limitation, nitrogen bonded heterocycles are
bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-
pyrroline,
3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole,
pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole,
indoline,
1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of a
morpholine,
and position 9 of a carbazole, or 0-carboline. Still more typically, nitrogen
bonded heterocycles include 1 -aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl,
1-
pyrazolyl, and 1-piperidinyl.
"Carbocycle" refers to a saturated, unsaturated or aromatic ring having 3
to 7 carbon atoms as a monocycle, 7 to 12 carbon atoms as a bicycle, and up to
about 20 carbon atoms as a polycycle. Monocyclic carbocycles have 3 to 6 ring
atoms, still more typically 5 or 6 ring atoms. Bicyclic carbocycles have 7 to
12
ring atoms, e.g., arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system,
or 9 or
10 ring atoms arranged as a bicyclo [5,6] or [6,6] system. Examples of
monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1-
cyclopent-l-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-
cyclohex-l-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, phenyl, spiryl and
naphthyl.
"Linker" or "link" refers to a chemical moiety comprising a covalent
bond or a chain or group of atoms that covalently attaches a phosphonate group
to a drug. Linkers include portions of substituents A' and A3, which include
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moieties such as: repeating units of alkyloxy (e.g., polyethylenoxy, PEG,
polymethyleneoxy) and alkylamino (e.g., polyethyleneamino, JeffamineTM); and
diacid ester and amides including succinate, succinamide, diglycolate,
malonate,
and caproamide.
The term "chiral" refers to molecules which have the property of non-
superimposability of the mirror image partner, while the term "achiral" refers
to
molecules which are superimposable on their mirror image partner.
The term "stereoisomers" refers to compounds which have identical
chemical constitution, but differ with regard to the arrangement of the atoms
or
groups in space.
"Diastereomer" refers to a stereoisomer with two or more centers of
chirality and whose molecules are not mirror images of one another.
Diastereomers have different physical properties, e.g., melting points,
boiling
points, spectral properties, and reactivities. Mixtures of diastereomers may
separate under high resolution analytical procedures such as electrophoresis
and
chromatography.
"Enantiomers" refer to two stereoisomers of a compound which are non-
superimposable mirror images of one another.
The term "treatment" or "treating," to the extent it relates to a disease or
condition includes preventing the disease or condition from occurring,
inhibiting
the disease or condition, eliminating the disease or condition, and/or
relieving
one or more symptoms of the disease or condition.
Stereochemical definitions and conventions used herein generally follow
S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-
Hill Book Company, New York; and Eliel, E. and Wilen, S., Stereochemistry of
Organic Compounds (1994) John Wiley & Sons, Inc., New York. Many organic
compounds exist in optically active forms, i.e., they have the ability to
rotate the
plane of plane-polarized light. In describing an optically active compound,
the
prefixes D and L or R and S are used to denote the absolute configuration of
the
molecule about its chiral center(s). The prefixes d and 1 or (+) and (-) are
employed to designate the sign of rotation of plane-polarized light by the
compound, with (-) or 1 meaning that the compound is levorotatory. A
compound prefixed with (+) or d is dextrorotatory. For a given chemical
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structure, these stereoisomers are identical except that they are mirror
images of
one another. A specific stereoisomer may also be referred to as an enantiomer,
and a mixture of such isomers is often called an enantiomeric mixture. A 50:50
mixture of enantiomers is referred to as a racemic mixture or a racemate,
which
may occur where there has been no stereoselection or stereospecificity in a
chemical reaction or process. The terms "racemic mixture" and "racemate" refer
to an equimolar mixture of two enantiomeric species, devoid of optical
activity.
Protecting Groups
In the context of the present invention, protecting groups include prodrug
moieties and chemical protecting groups.
Protecting groups are available, commonly known and used, and are
optionally used to prevent side reactions with the protected group during
synthetic procedures, i.e. routes or methods to prepare the compounds of the
invention. For the most part the decision as to which groups to protect, when
to
do so, and the nature of the chemical protecting group "PG" will be dependent
upon the chemistry of the reaction to be protected against (e.g., acidic,
basic,
oxidative, reductive or other conditions) and the intended direction of the
synthesis. The PG groups do not need to be, and generally are not, the same if
the compound is substituted with multiple PG. In general, PG will be used to
protect functional groups such as carboxyl, hydroxyl, thio, or amino groups
and
to thus prevent side reactions or to otherwise facilitate the synthetic
efficiency.
The order of deprotection to yield free, deprotected groups is dependent upon
the
intended direction of the synthesis and the reaction conditions to be
encountered,
and may occur in any order as determined by the artisan.
Various functional groups of the compounds of the invention may be
protected. For example, protecting groups for -OH groups (whether hydroxyl,
carboxylic acid, phosphonic acid, or other functions) include "ether- or ester-
forming groups". Ether- or ester-forming groups are capable of functioning as
chemical protecting groups in the synthetic schemes set forth herein. However,
some hydroxyl and thio protecting groups are neither ether- nor ester-forming
groups, as will be understood by those skilled in the art, and are included
with
amides, discussed below.
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A very large number of hydroxyl protecting groups and amide-forming
groups and corresponding chemical cleavage reactions are described in
Protective Groups in Organic Synthesis, Theodora W. Greene (John Wiley &
Sons, Inc., New York, 1991, ISBN 0-471-62301-6) ("Greene"). See also
Kocienski, Philip J.; Protecting Groups (Georg Thieme Verlag Stuttgart, New
York, 1994), which is incorporated by reference in its entirety herein. In
particular Chapter 1, Protecting Groups: An Overview, pages 1-20, Chapter 2,
Hydroxyl Protecting Groups, pages 21-94, Chapter 3, Diol Protecting Groups,
pages 95-117, Chapter 4, Carboxyl Protecting Groups, pages 118-154, Chapter
5, Carbonyl Protecting Groups, pages 155-184. For protecting groups for
carboxylic acid, phosphonic acid, phosphonate, sulfonic acid and other
protecting groups for acids see Greene as set forth below. Such groups include
by way of example and not limitation, esters, amides, hydrazides, and the
like.
Ether- and Ester-forming protecting groups
Ester-forming groups include: (1) phosphonate ester-forming groups,
such as phosphonamidate esters, phosphorothioate esters, phosphonate esters,
and phosphon-bis-amidates; (2) carboxyl ester-forming groups, and (3) sulphur
ester-forming groups, such as sulphonate, sulfate, and sulfinate.
The phosphonate moieties of the compounds of the invention may or
may not be prodrug moieties, i.e. they may or may be susceptible to hydrolytic
or enzymatic cleavage or modification. Certain phosphonate moieties are stable
under most or nearly all metabolic conditions. For example, a
dialkylphosphonate, where the alkyl groups are two or more carbons, may have
appreciable stability in vivo due to a slow rate of hydrolysis.
Within the context of phosphonate prodrug moieties, a large number of
structurally-diverse prodrugs have been described for phosphonic acids
(Freeman and Ross in Progress in Medicinal Chemistry 34: 112-147 (1997)) and
are included within the scope of the present invention. An exemplary
phosphonate ester-forming group is the phenyl carbocycle in substructure A3
having the formula:
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R2
O
P
R,
m1 Y~ _-'r OR,
R, R,
wherein Rl may be H or C1-C1Z alkyl; ml is 1, 2, 3, 4, 5, 6, 7 or 8, and
the phenyl carbocycle is substituted with 0 to 3 R2 groups. Where Y, is 0, a
lactate ester is formed, and where Y, is N(R2), N(ORZ) or N(N(R2)2, a
phosphonamidate ester results.
In its ester-forming role, a protecting group typically is bound to any
acidic group such as, by way of example and not limitation, a-CO2H or
-C(S)OH group, thereby resulting in -CO2R" where R' is defined herein. Also,
R' for example includes the enumerated ester groups of WO 95/07920.
Examples of protecting groups include:
C3-C12 heterocycle (described above) or aryl. These aromatic groups
optionally are polycyclic or monocyclic. Examples include phenyl, spiryl, 2-
and 3-pyrrolyl, 2- and 3-thienyl, 2- and 4-imidazolyl, 2-, 4- and 5-oxazolyl,
3-
and 4-isoxazolyl, 2-, 4- and 5-thiazolyl, 3-, 4- and 5-isothiazolyl, 3- and 4-
pyrazolyl, 1-, 2-, 3- and 4-pyridinyl, and 1-, 2-, 4- and 5-pyrimidinyl,
C3-C 12 heterocycle or aryl substituted with halo, Rl, R' -O-C 1-C 12
alkylene, C 1-C 12 alkoxy, CN, NO2, OH, carboxy, carboxyester, thiol,
thioester,
C1-C12 haloalkyl (1-6 halogen atoms), C2-C12 alkenyl or C2-C12 alkynyl. Such
groups include 2-, 3- and 4-alkoxyphenyl (C1-C12 alkyl), 2-, 3- and 4-
methoxyphenyl, 2-, 3- and 4-ethoxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-
diethoxyphenyl, 2- and 3-carboethoxy-4-hydroxyphenyl, 2- and 3-ethoxy-4-
hydroxyphenyl, 2- and 3-ethoxy-5-hydroxyphenyl, 2- and 3-ethoxy-6-
hydroxyphenyl, 2-, 3- and 4-0-acetylphenyl, 2-, 3- and 4-dimethylaminophenyl,
2-, 3- and 4-methylmercaptophenyl, 2-, 3- and 4-halophenyl (including 2-, 3-
and 4-fluorophenyl and 2-, 3- and 4-chlorophenyl), 2,3-, 2,4-, 2,5-, 2,6-, 3,4-
and
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3,5-dimethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-
biscarboxyethylphenyl,
2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-dimethoxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-,
3,4-
and 3,5-dihalophenyl (including 2,4-difluorophenyl and 3,5-difluorophenyl), 2-
,
3- and 4-haloalkylphenyl (1 to 5 halogen atoms, C 1-C 12 alkyl including 4-
trifluoromethylphenyl), 2-, 3- and 4-cyanophenyl, 2-, 3- and 4-nitrophenyl, 2-
,
3- and 4-haloalkylbenzyl (1 to 5 halogen atoms, C I -C 12 alkyl including 4-
trifluoromethylbenzyl and 2-, 3- and 4-trichloromethylphenyl and 2-, 3- and 4-
trichloromethylphenyl), 4-N-methylpiperidinyl, 3-N-methylpiperidinyl, 1-
ethylpiperazinyl, benzyl, alkylsalicylphenyl (Cl-C4 alkyl, including 2-, 3-
and 4-
ethylsalicylphenyl), 2-,3- and 4-acetylphenyl, 1,8-dihydroxynaphthyl (-C1oH6-
OH) and aryloxy ethyl [C6-C9 aryl (including phenoxy ethyl)], 2,2'-
dihydroxybiphenyl, 2-, 3- and 4-N,N-dialkylaminophenol, -C6H4CH2-N(CH3)2,
trimethoxybenzyl, triethoxybenzyl, 2-alkyl pyridinyl (C 1 -4 alkyl);
N R10(O)C
H -CH2-O-C(O)
O ;C4-C8
esters of 2-carboxyphenyl; and C1-C4 alkylene-C3-C6 aryl (including benzyl, -
CH2-pyrrolyl, -CH2-thienyl, -CH2-imidazolyl, -CH2-oxazolyl, -CH2-isoxazolyl,
-CH2-thiazolyl, -CH2-isothiazolyl, -CH2-pyrazolyl, -CH2-pyridinyl and -CH2-
pyrimidinyl) substituted in the aryl moiety by 3 to 5 halogen atoms or 1 to 2
atoms or groups selected from halogen, C 1-C 12 alkoxy (including methoxy and
ethoxy), cyano, nitro, OH, C1-C12 haloalkyl (1 to 6 halogen atoms; including -
CH2CC13), C1-C12 alkyl (including methyl and ethyl), C2-C12 alkenyl or C2-C12
alkynyl; alkoxy ethyl [C i-C6 alkyl including -CH2-CH2-O-CH3 (methoxy
ethyl)]; alkyl substituted by any of the groups set forth above for aryl, in
particular OH or by 1 to 3 halo atoms (including -CH3, -CH(CH3)2, -C(CH3)3, -
CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -(CH2)4CH3, -(CH2)SCH3, -CH2CH2F, -
O
CH2CH2C1, -CH2CF3, and -CH2CC13); \-/ ; -N-2-
propylmorpholino, 2,3-dihydro-6-hydroxyindene, sesamol, catechol monoester, -
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CH2-C(O)-N(R1)2, -CH2-S(O)(R1), -CH2-S(O)2(Rl), -CH2-CH(OC(O)CH2RI)-
CH2(OC(O)CH2RI), cholesteryl, enolpyruvate (HOOC-C(=CH2)-), glycerol;
a 5 or 6 carbon monosaccharide, disaccharide or oligosaccharide (3 to 9
monosaccharide residues);
triglycerides such as a-D-0-diglycerides (wherein the fatty acids
composing glyceride lipids generally are naturally occurring saturated or
unsaturated C6-26, C6-18 or C6-10 fatty acids such as linoleic, lauric,
myristic,
palmitic, stearic, oleic, palmitoleic, linolenic and the like fatty acids)
linked to
acyl of the parental compounds herein through a glyceryl oxygen of the
triglyceride;
phospholipids linked to the carboxyl group through the phosphate of the
phospholipid;
phthalidyl (shown in Fig. 1 of Clayton et al., Antimicrob. Agents Chemo.
(1974) 5(6):670-671);
cyclic carbonates such as (5-Rd-2-oxo-l,3-dioxolen-4-yl) methyl esters
(Sakamoto et al., Chem. Pharm. Bull. (1984) 32(6)2241-2248) where Rd is RI,
R4 or aryl; and
-CH2C(O)N0
The hydroxyl groups of the compounds of this invention optionally are
substituted with one of groups III, IV or V disclosed in WO 94/21604, or with
isopropyl.
Table A lists examples of protecting group ester moieties that for example
can be bonded via oxygen to -C(O)O- and -P(O)(O-)2 groups. Several amidates
also are shown, which are bound directly to -C(O)- or -P(O)2. Esters of
structures 1-5, 8-10 and 16, 17, 19-22 are synthesized by reacting the
compound
herein having a free hydroxyl with the corresponding halide (chloride or acyl
chloride and the like) and N,N-dicyclohexyl-N-morpholine carboxamidine (or
another base such as DBU, triethylamine, CsCO3, N,N-dimethylaniline and the
like) in DMF (or other solvent such as acetonitrile or N-methylpyrrolidone).
When the compound to be protected is a phosphonate, the esters of structures 5-
7,
11, 12, 21, and 23-26 are synthesized by reaction of the alcohol or alkoxide
salt
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(or the corresponding amines in the case of compounds such as 13, 14 and 15)
with the monochlorophosphonate or dichlorophosphonate (or another activated
phosphonate).
TABLE A
1. -CH2-C(O)-N(Rl)2 * 10. -CH2-O-C(O)-C(CH3)3
2. -CH2-S(O)(Rl) 11. -CH2-CC13
3. -CH2-S(O)2(R1) 12. -C6H5
4. -CH2-O-C(O)-CH2-C6H5 13. -NH-CH2-C(O)O-CH2CH3
5. 3-cholesteryl 14. -N(CH3)-CH2-C(O)O-CH2CH3
6. 3-pyridyl 15. -NHRI
7. N-ethylmorpholino 16. -CH2-O-C(O)-C10H15
8. -CH2-O-C(O)-C6H5 17. -CH2-O-C(O)-CH(CH3)2
9. -CH2-O-C(O)-CH2CH3 18. -CH2-C#H(OC(O)CH2R1)-CH2-
-(OC(O)CH2R1)*
HO
o
-CH2C(O)N O N OH Ho
19. 20. O H 21. HO
N N
-CH2-O-C(O) -CH2CHz
22. 23. -
CH3O(O)C CH3CH2O(O)C
24. - 25. -
OCH3
-CH2 0 OCH3
26. OCH3
# - chiral center is (R), (S) or racemate.
Other esters that are suitable for use herein are described in EP 632048.
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Protecting groups also includes "double ester" forming profunctionalities
such as -CH2OC(O)OCH3, 0 -CH2SCOCH3, -CH2OCON(CH3)2, or
alkyl- or aryl-acyloxyalkyl groups of the structure -CH(Rl or WS)O((CO)R37) or
-CH(RI or WS)((CO)OR38) (linked to oxygen of the acidic group) wherein R37
and R38 are alkyl, aryl, or alkylaryl groups (see U.S. Patent No. 4968788).
Frequently R37 and R38 are bulky groups such as branched alkyl, ortho-
substituted aryl, meta-substituted aryl, or combinations thereof, including
normal, secondary, iso- and tertiary alkyls of 1-6 carbon atoms. An example is
the pivaloyloxymethyl group. These are of particular use with prodrugs for
oral
administration. Examples of such useful protecting groups are
alkylacyloxymethyl esters and their derivatives, including -
ylg
CH(CH2CH2OCH3)OC(O)C(CH3)3, 0
CH2OC(O)C1oH15, -CH2OC(O)C(CH3)3, -CH(CH2OCH3)OC(O)C(CH3)3, -
CH(CH(CH3)2)OC(O)C(CH3)3, -CH2OC(O)CH2CH(CH3)2, -
CH2OC(O)C6H11, -CH20C(O)C6H5, -CH2OC(O)C10H15,-
CH2OC(O)CH2CH3, -CH2OC(O)CH(CH3)2 , -CH2OC(O)C(CH3)3 and -
CH2OC(O)CH2C6H5.
In some embodiments the protected acidic group is an ester of the acidic
group and is the residue of a hydroxyl-containing functionality. In other
embodiments, an amino compound is used to protect the acid functionality. The
residues of suitable hydroxyl or amino-containing functionalities are set
forth
above or are found in WO 95/07920. Of particular interest are the residues of
amino acids, amino acid esters, polypeptides, or aryl alcohols. Typical amino
acid, polypeptide and carboxyl-esterified amino acid residues are described on
pages 11-18 and related text of WO 95/07920 as groups L1 or L2. WO
95/07920 expressly teaches the amidates of phosphonic acids, but it will be
understood that such amidates are formed with any of the acid groups set forth
herein and the amino acid residues set forth in WO 95/07920.
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WO 2006/047507 PCT/US2005/038348
Typical esters for protecting acidic functionalities are also described in
WO 95/07920, again understanding that the same esters can be formed with the
acidic groups herein as with the phosphonate of the '920 publication. Typical
ester groups are defined at least on WO 95/07920 pages 89-93 (under R31 or
R35), the table on page 105, and pages 21-23 (as R). Of particular interest
are
esters of unsubstituted aryl such as phenyl or arylalkyl such benzyl, or
hydroxy-,
halo-, alkoxy-, carboxy- and/or alkylestercarboxy-substituted aryl or
alkylaryl,
especially phenyl, ortho-ethoxyphenyl, or C1-C4 alkylestercarboxyphenyl
(salicylate C 1-C 12 alkylesters).
The protected acidic groups, particularly when using the esters or amides
of WO 95/07920, are useful as prodrugs for oral administration. However, it is
not essential that the acidic group be protected in order for the compounds of
this
invention to be effectively administered by the oral route. When the compounds
of the invention having protected groups, in particular amino acid amidates or
substituted and unsubstituted aryl esters are administered systemically or
orally
they are capable of hydrolytic cleavage in vivo to yield the free acid.
One or more of the acidic hydroxyls are protected. If more than one
acidic hydroxyl is protected then the same or a different protecting group is
employed, e.g., the esters may be different or the same, or a mixed amidate
and
ester may be used.
Typical hydroxy protecting groups described in Greene (pages 14-118)
include substituted methyl and alkyl ethers, substituted benzyl ethers, silyl
ethers, esters including sulfonic acid esters, and carbonates. For example:
= Ethers (methyl, t-butyl, allyl);
= Substituted Methyl Ethers (Methoxymethyl, Methylthiomethyl, t-
Butylthiomethyl, (Phenyldimethylsilyl)methoxymethyl, Benzyloxymethyl, p-
Methoxybenzyloxymethyl, (4-Methoxyphenoxy)methyl, Guaiacolmethyl, t-
Butoxymethyl, 4-Pentenyloxymethyl, Siloxymethyl, 2-
Methoxyethoxymethyl, 2,2,2-Trichloroethoxymethyl, Bis(2-
chloroethoxy)methyl, 2-(Trimethylsilyl)ethoxymethyl, Tetrahydropyranyl, 3-
Bromotetrahydropyranyl, Tetrahydropthiopyranyl, 1-Methoxycyclohexyl, 4-
Methoxytetrahydropyranyl, 4-Methoxytetrahydrothiopyranyl, 4-
Methoxytetrahydropthiopyranyl S, S-Dioxido, 1- [(2-Chloro-4-
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methyl)phenyl] -4-methoxypiperidin-4-yl, 1,4-Dioxan-2-yl,
Tetrahydrofuranyl, Tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-Octahydro-
7, 8, 8-trimethyl-4,7-methanobenzofuran-2-yl));
= Substituted Ethyl Ethers (1-Ethoxyethyl, 1-(2-Chloroethoxy)ethyl, 1-Methyl-
1-methoxyethyl, 1-Methyl-l-benzyloxyethyl, 1-Methyl-l-benzyloxy-2-
fluoroethyl, 2,2,2-Trichloroethyl, 2-Trimethylsilylethyl, 2-
(Phenylselenyl)ethyl,
= p-Chlorophenyl, p-Methoxyphenyl, 2,4-Dinitrophenyl, Benzyl);
= Substituted Benzyl Ethers (p-Methoxybenzyl, 3,4-Dimethoxybenzyl, o
Nitrobenzyl, p-Nitrobenzyl, p-Halobenzyl, 2,6-Dichlorobenzyl, p-
Cyanobenzyl, p-Phenylbenzyl, 2- and 4-Picolyl, 3-Methyl-2-picolyl N-
Oxido, Diphenylmethyl, p,p'-Dinitrobenzhydryl, 5 -Dibenzosuberyl,
Triphenylmethyl, a-Naphthyldiphenylmethyl, p-
methoxyphenyldiphenylmethyl, Di(p-methoxyphenyl)phenylmethyl, Tri(p-
methoxyphenyl)methyl, 4-(4'-Bromophenacyloxy)phenyldiphenylmethyl,
4,4',4"-Tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4"-
Tris(levulinoyloxyphenyl)methyl, 4,4',4"-Tris(benzoyloxyphenyl)methyl, 3-
(Imidazol-1-ylmethyl)bis(4',4"-dimethoxyphenyl)methyl, 1,1-Bis(4-
methoxyphenyl)-1'-pyrenylmethyl, 9-Anthryl, 9-(9-Phenyl)xanthenyl, 9-(9-
Phenyl-l0-oxo)anthryl, 1,3-Benzodithiolan-2-yl, Benzisothiazolyl S,S-
Dioxido);
= Silyl Ethers (Trimethylsilyl, Triethylsilyl, Triisopropylsilyl,
Dimethylisopropylsilyl, Diethylisopropylsilyl, Dimethylthexylsilyl, t-
Butyldimethylsilyl, t-Butyldiphenylsilyl, Tribenzylsilyl, Tri-p-xylylsilyl,
Triphenylsilyl, Diphenylmethylsilyl, t-Butylmethoxyphenylsilyl);
= Esters (Formate, Benzoylformate, Acetate, Choroacetate, Dichloroacetate,
Trichloroacetate, Trifluoroacetate, Methoxyacetate,
Triphenylmethoxyacetate, Phenoxyacetate, p-Chlorophenoxyacetate, p-poly-
Phenylacetate, 3-Phenylpropionate, 4-Oxopentanoate (Levulinate), 4,4-
(Ethylenedithio)pentanoate, Pivaloate, Adamantoate, Crotonate, 4-
Methoxycrotonate, Benzoate, p-Phenylbenzoate, 2,4,6-Trimethylbenzoate
(Mesitoate));
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WO 2006/047507 PCT/US2005/038348
= Carbonates (Methyl, 9-Fluorenylmethyl, Ethyl, 2,2,2-Trichloroethyl, 2-
(Trimethylsilyl)ethyl, 2-(Phenylsulfonyl)ethyl, 2-
(Triphenylphosphonio)ethyl, Isobutyl, Vinyl, Allyl, p-Nitrophenyl, Benzyl,
p-Methoxybenzyl, 3,4-Dimethoxybenzyl, o-Nitrobenzyl, p-Nitrobenzyl, S-
Benzyl Thiocarbonate, 4-Ethoxy-l-naphthyl, Methyl Dithiocarbonate);
= Groups With Assisted Cleavage (2-Iodobenzoate, 4-Azidobutyrate, 4-Nitro-
4-methylpentanoate, o-(Dibromomethyl)benzoate, 2-
Formylbenzenesulfonate, 2-(Methylthiomethoxy)ethyl Carbonate, 4-
(Methylthiomethoxy)butyrate, 2-(Methylthiomethoxymethyl)benzoate);
Miscellaneous Esters (2,6-Dichloro-4-methylphenoxyacetate, 2,6-Dichloro-
4-(1,1,3,3 tetramethylbutyl)phenoxyacetate, 2,4-Bis(1,1-
dimethylpropyl)phenoxyacetate, Chlorodiphenylacetate, Isobutyrate,
Monosuccinate, (E)-2-Methyl-2-butenoate (Tigloate), o-
(Methoxycarbonyl)benzoate, p-poly-Benzoate, a-Naphthoate, Nitrate, Alkyl
N,N,N;N'-Tetramethylphosphorodiamidate, N-Phenylcarbamate, Borate,
Dimethylphosphinothioyl, 2,4-Dinitrophenylsulfenate); and
= Sulfonates (Sulfate, Methanesulfonate (Mesylate), Benzylsulfonate,
Tosylate).
Typical 1,2-diol protecting groups (thus, generally where two OH groups
are taken together with the protecting functionality) are described in Greene
at
pages 118-142 and include Cyclic Acetals and Ketals (Methylene, Ethylidene, 1-
t-Butylethylidene, 1-Phenylethylidene, (4-Methoxyphenyl)ethylidene, 2,2,2-
Trichloroethylidene, Acetonide (Isopropylidene), Cyclopentylidene,
Cyclohexylidene, Cycloheptylidene, Benzylidene, p-Methoxybenzylidene, 2,4-
Dimethoxybenzylidene, 3,4-Dimethoxybenzylidene, 2-Nitrobenzylidene); Cyclic
Ortho Esters (Methoxymethylene, Ethoxymethylene, Dimethoxymethylene, 1-
Methoxyethylidene, 1-Ethoxyethylidine, 1,2-Dimethoxyethylidene, a-
Methoxybenzylidene, 1-(N,N-Dimethylamino)ethylidene Derivative, a -(NN-
Dimethylamino)benzylidene Derivative, 2-Oxacyclopentylidene); Silyl
Derivatives (Di-t-butylsilylene Group, 1,3-(1,1,3,3-
Tetraisopropyldisiloxanylidene), and Tetra-t-butoxydisiloxane-1,3-diylidene),
Cyclic Carbonates, Cyclic Boronates, Ethyl Boronate and Phenyl Boronate.
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More typically, 1,2-diol protecting groups include those shown in Table
B, still more typically, epoxides, acetonides, cyclic ketals and aryl acetals.
Table B
r~c r~ r~c r~c o
o O O o O O /O O\ o
~ y S.
0 0 0
r~c r~c r~c r~' o 0
~ 'O R90_N O R90-N\ /O R9O-N~ ~O
P,
R9O/ ~ 0 A' R90~P~~0
0 O O
wherein R9 is C 1-C(, alkyl.
Amino protecting ,groups
Another set of protecting groups include any of the typical amino
protecting groups described by Greene at pages 315-385. They include:
= Carbamates: (methyl and ethyl, 9-fluorenylmethyl, 9(2-
sulfo)fluorenylmethyl, 9-(2,7-dibromo)fluorenylmethyl, 2,7-di-t-butyl-[9-
(10, 1 0-dioxo- 10, 10, 10, 1 0-tetrahydrothioxanthyl)]methyl, 4-
methoxyphenacyl);
= Substituted Ethyl: (2,2,2-trichoroethyl, 2-trimethylsilylethyl, 2-
phenylethyl,
1-(1=adamantyl)-1-methylethyl, 1,1-dimethyl-2-haloethyl, 1,1-dimethyl-2,2-
dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl, 1-methyl-l-(4-
biphenylyl)ethyl, 1-(3,5-di-t-butylphenyl)-1-methylethyl, 2-(2'- and 4'-
pyridyl)ethyl, 2-(N,N-dicyclohexylcarboxamido)ethyl, t-butyl, 1-adamantyl,
vinyl, allyl, 1-isopropylallyl, cinnamyl, 4-nitrocinnamyl, 8-quinolyl, N-
hydroxypiperidinyl, alkyldithio, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-
bromobenzyl, p-chlorobenzyl, 2,4-dichlorobenzyl, 4-methylsulfinylbenzyl,
9-anthrylmethyl, diphenylmethyl);
= Groups With Assisted Cleavage: (2-methylthioethyl, 2-methylsulfonylethyl,
2-(p-toluenesulfonyl)ethyl, [2-(1,3-dithianyl)]methyl, 4-methylthiophenyl,
2,4-dimethylthiophenyl, 2-phosphonioethyl, 2-
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triphenylphosphonioisopropyl, 1,1-dimethyl-2-cyanoethyl, m-choro p-
acyloxybenzyl, p-(dihydroxyboryl)benzyl, 5-benzisoxazolylmethyl, 2-
(trifluoromethyl)-6-chromonylmethyl);
= Groups Capable of Photolytic Cleavage: (m-nitrophenyl, 3,5-
dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, phenyl(o-
nitrophenyl)methyl); Urea-Type Derivatives (phenothiazinyl-(10)-carbonyl,
N p-toluenesulfonylaminocarbonyl, N'-phenylaminothiocarbonyl);
= Miscellaneous Carbamates: (t-amyl, S-benzyl thiocarbamate, p-cyanobenzyl,
cyclobutyl, cyclohexyl, cyclopentyl, cyclopropylmethyl, p-decyloxybenzyl,
diisopropylmethyl, 2,2-dimethoxycarbonylvinyl, o-(N,N-
dimethylcarboxamido)benzyl, 1,1-dimethyl-3-(N,N-
dimethylcarboxamido)propyl, 1,1-dimethylpropynyl, di(2-pyridyl)methyl, 2-
furanylmethyl, 2-lodoethyl, Isobornyl, Isobutyl, Isonicotinyl, p-(p'-
Methoxyphenylazo)benzyl, 1-methylcyclobutyl, 1-methylcyclohexyl, 1-
methyl-l-cyclopropylmethyl, 1-methyl-l-(3,5-dimethoxyphenyl)ethyl, 1-
methyl-l-(p-phenylazophenyl)ethyl, 1-methyl-l-phenylethyl, 1-methyl-l-(4-
pyridyl)ethyl, phenyl, p-(phenylazo)benzyl, 2,4,6-tri-t-butylphenyl, 4-
(trimethylammonium)benzyl, 2,4,6-trimethylbenzyl);
= Amides: (N-formyl, N-acetyl, N-choroacetyl, N-trichoroacetyl, N-
trifluoroacetyl, N-phenylacetyl, N-3-phenylpropionyl, N-picolinoyl, N-3-
pyridylcarboxamide, N-benzoylphenylalanyl, N-benzoyl, N p-
phenylbenzoyl);
= Amides With Assisted Cleavage: (N-o-nitrophenylacetyl, N-o-
nitrophenoxyacetyl, N-acetoacetyl, (N'-
dithiobenzyloxycarbonylamino)acetyl, N-3-(p-hydroxyphenyl)propionyl, N-
3-(o-nitrophenyl)propionyl, N-2-methyl-2-(o-nitrophenoxy)propionyl, N-2-
methyl-2-(o-phenylazophenoxy)propionyl, N-4-chlorobutyryl, N-3-methyl-3-
nitrobutyryl, N-o-nitrocinnamoyl, N-acetylmethionine, N-o-nitrobenzoyl, N-
o-(benzoyloxymethyl)benzoyl, 4,5-diphenyl-3-oxazolin-2-one);
= Cyclic Imide Derivatives: (N-phthalimide, N-dithiasuccinoyl, N-2,3-
diphenylmaleoyl, N-2,5-dimethylpyrrolyl, N- 1, 1,4,4-
tetramethyldisilylazacyclopentane adduct, 5-substituted 1,3-dimethyl-1,3,5-
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triazacyclohexan-2-one, 5-substituted 1,3 -dibenzyl- 1,3 -5 -triazacyclohexan-
2-
one, 1-substituted 3,5-dinitro-4-pyridonyl);
= N-Alkyl and N-Aryl Amines: (N-methyl, N-allyl, N-[2-
(trimethylsilyl)ethoxy]methyl, N-3-acetoxypropyl, N-(1-isopropyl-4-nitro-2-
oxo-3-pyrrolin-3-yl), Quaternary Ammonium Salts, N-benzyl, N-di(4-
methoxyphenyl)methyl, N-5-dibenzosuberyl, N-triphenylmethyl, N-(4-
methoxyphenyl)diphenylmethyl, N-9-phenylfluorenyl, N-2,7-dichloro-9-
fluorenylmethylene, N-ferrocenylmethyl, N-2-picolylamine N-oxide);
= Imine Derivatives: (N-1,1-dimethylthiomethylene, N-benzylidene, N-p-
methoxybenylidene, N-diphenylmethylene, N-[(2-pyridyl)mesityl]methylene,
N,(N,N-dimethylaminomethylene, N,N'-isopropylidene, N-p-
nitrobenzylidene, N-salicylidene, N-5-chlorosalicylidene, N-(5-chloro-2-
hydroxyphenyl)phenylmethylene, N-cyclohexylidene);
= Enamine Derivatives: (N-(5,5-dimethyl-3-oxo-l-cyclohexenyl));
= N-Metal Derivatives (N-borane derivatives, N-diphenylborinic acid
derivatives, N-[phenyl(pentacarbonylchromium- or -tungsten)] carbenyl, N-
copper or N-zinc chelate);
= N-N Derivatives: (N-nitro, N-nitroso, N-oxide);
= N-P Derivatives: (N-diphenylphosphinyl, N-dimethylthiophosphinyl, N-
diphenylthiophosphinyl, N-dialkyl phosphoryl, N-dibenzyl phosphoryl, N-
diphenyl phosphoryl);
= N-Si Derivatives, N-S Derivatives, and N-Sulfenyl Derivatives: (N-
benzenesulfenyl, N-o-nitrobenzenesulfenyl, N-2,4-dinitrobenzenesulfenyl, N-
pentachlorobenzenesulfenyl, N-2-nitro-4-methoxybenzenesulfenyl, N-
triphenylmethylsulfenyl, N-3-nitropyridinesulfenyl); and N-sulfonyl
Derivatives (N-p-toluenesulfonyl, N-benzenesulfonyl, N-2,3,6-trimethyl-4-
methoxybenzenesulfonyl, N-2,4,6-trimethoxybenzenesulfonyl, N-2,6-
dimethyl-4-methoxybenzenesulfonyl, N-pentamethylbenzenesulfonyl, N-
2,3,5,6,-tetramethyl-4-methoxybenzenesulfonyl, N-4-
methoxybenzenesulfonyl, N-2,4,6-trimethylbenzenesulfonyl, N-2,6-
dimethoxy-4-methylbenzenesulfonyl, N-2,2,5,7,8-pentamethylchroman-6-
sulfonyl, N-methanesulfonyl, N-[i-trimethylsilyethanesulfonyl, N-9-
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anthracenesulfonyl, N-4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonyl,
N-benzylsulfonyl, N-trifluoromethylsulfonyl, N-phenacylsulfonyl).
More typically, protected amino groups include carbamates and amides,
still more typically, -NHC(O)Rl or -N=CR'N(R')2. Another protecting group,
also useful as a prodrug for amino or -NH(R5), is:
0
o"lk o 0
ws o
See for example Alexander, J. et al. (1996) J. Med. Chem. 39:480-486.
Amino acid and polypeptide protectinggroup and conjugates
An amino acid or polypeptide protecting group of a compound of the
invention has the structure R15NHCH(R16)C(O)-, where R15 is H, an amino acid
or polypeptide residue, or R5, and R16 is defined below.
R16 is lower alkyl or lower alkyl (CI-C6) substituted with amino,
carboxyl, amide, carboxyl ester, hydroxyl, C6-C7 aryl, guanidinyl, imidazolyl,
indolyl, sulfhydryl, sulfoxide, and/or alkylphosphate. R10 also is taken
together
with the amino acid a N to form a proline residue (R10 = -(CH2)3-). However,
R10 is generally the side group of a naturally-occurring amino acid such as H,
-
CH3, -CH(CH3)2, -CH2-CH(CH3)2, -CHCH3-CH2-CH3, -CH2-C6H5, -CH2CH2-
S-CH3, -CH2OH, -CH(OH)-CH3, -CH2-SH, -CH2-C6H4OH, -CH2-CO-NH2, -
CH2-CH2-CO-NH2, -CH2-COOH, -CH2-CH2-COOH, -(CH2)4-NH2 and -
(CH2)3-NH-C(NH2)-NH2. Rlp also includes 1-guanidinoprop-3-yl, benzyl, 4-
hydroxybenzyl, imidazol-4-yl, indol-3-yl, methoxyphenyl and ethoxyphenyl.
Another set of protecting groups include the residue of an amino-
containing compound, in particular an amino acid, a polypeptide, a protecting
group, -NHSO2R, NHC(O)R, -N(R)2, NH2 or -NH(R)(H), whereby for example
a carboxylic acid is reacted, i.e. coupled, with the amine to form an amide,
as in
C(O)NR2. A phosphonic acid may be reacted with the amine to form a
phosphonamidate, as in -P(O)(OR)(NR2).
In general, amino acids have the structure R17C(O)CH(R16)NH-, where
R17 is -OH, -OR, an amino acid or a polypeptide residue. Amino acids are low
molecular weight compounds, on the order of less than about 1000 MW and
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which contain at least one amino or imino group and at least one carboxyl
group.
Generally the amino acids will be found in nature, i.e., can be detected in
biological material such as bacteria or other microbes, plants, animals or
man.
Suitable amino acids typically are alpha amino acids, i.e. compounds
characterized by one amino or imino nitrogen atom separated from the carbon
atom of one carboxyl group by a single substituted or unsubstituted alpha
carbon
atom. Of particular interest are hydrophobic residues such as mono-or di-alkyl
or aryl amino acids, cycloalkylamino acids and the like. These residues
contribute to cell permeability by increasing the partition coefficient of the
parental drug. Typically, the residue does not contain a sulfhydryl or
guanidino
substituent.
Naturally-occurring amino acid residues are those residues found
naturally in plants, animals or microbes, especially proteins thereof.
Polypeptides most typically will be substantially composed of such naturally-
occurring amino acid residues. These amino acids are glycine, alanine, valine,
leucine, isoleucine, serine, threonine, cysteine, methionine, glutamic acid,
aspartic acid, lysine, hydroxylysine, arginine, histidine, phenylalanine,
tyrosine,
tryptophan, proline, asparagine, glutamine and hydroxyproline. Additionally,
unnatural amino acids, for example, valanine, phenylglycine and homoarginine
are also included. Commonly encountered amino acids that are not gene-
encoded may also be used in the present invention. All of the amino acids used
in the present invention may be either the D- or L- optical isomer. In
addition,
other peptidomimetics are also useful in the present invention. For a general
review, see Spatola, A. F., in Chemistry and Biochemistry of Amino Acids,
Peptides and Proteins, B. Weinstein, eds., Marcel Dekker, New York, p. 267
(1983).
When protecting groups are single amino acid residues or polypeptides
they optionally are substituted at R3 of substituents A', or A3 in a compound
of
the invention. These conjugates are produced by forming an amide bond
between a carboxyl group of the amino acid (or C-terminal amino acid of a
polypeptide for example). Similarly, conjugates are formed between R3 and an
amino group of an amino acid or polypeptide. Generally, only one of any site
in
the parental molecule is amidated with an amino acid as described herein,
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although it is within the scope of this invention to introduce amino acids at
more
than one permitted site. Usually, a carboxyl group of R3 is amidated with an
amino acid. In general, the a-amino or a-carboxyl group of the amino acid or
the terininal amino or carboxyl group of a polypeptide are bonded to the
parental
functionalities, i.e., carboxyl or amino groups in the amino acid side chains
generally are not used to form the amide bonds with the parental compound
(although these groups may need to be protected during synthesis of the
conjugates as described further below).
With respect to the carboxyl-containing side chains of amino acids or
polypeptides it will be understood that the carboxyl group optionally will be
blocked, e.g., by R~, esterified with RS or amidated. Similarly, the amino
side
chains R16 optionally will be blocked with R' or substituted with R5.
Such ester or amide bonds with side chain amino or carboxyl groups, like
the esters or amides with the parental molecule, optionally are hydrolyzable
in
vivo or in vitro under acidic (pH <3) or basic (pH >10) conditions.
Alternatively, they are substantially stable in the gastrointestinal tract of
humans
but are hydrolyzed enzymatically in blood or in intracellular environments.
The
esters or amino acid or polypeptide amidates also are useful as intermediates
for
the preparation of the parental molecule containing free amino or carboxyl
groups. The free acid or base of the parental compound, for example, is
readily
formed from the esters or amino acid or polypeptide conjugates of this
invention
by conventional hydrolysis procedures.
When an amino acid residue contains one or more chiral centers, any of
the D, L, meso, threo or erythro (as appropriate) racemates, scalemates or
mixtures thereof may be used. In general, if the intermediates are to be
hydrolyzed non-enzymatically (as would be the case where the amides are used
as chemical intermediates for the free acids or free amines), D isomers are
useful. On the other hand, L isomers are more versatile since they can be
susceptible to both non-enzymatic and enzymatic hydrolysis, and are more
efficiently transported by amino acid or dipeptidyl transport systems in the
gastrointestinal tract.
Examples of suitable amino acids whose residues are represented by RX
or Ry include the following:
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Glycine;
Aminopolycarboxylic acids, e.g., aspartic acid, (3-hydroxyaspartic acid,
glutamic acid, (3 -hydroxyglutamic acid, P-methylaspartic acid, (3-
methylglutamic
acid, (3, (3-dimethylaspartic acid, y-hydroxyglutamic acid, (3, y-
dihydroxyglutamic
acid, (3 -phenylglutamic acid, y-methyleneglutamic acid, 3-aminoadipic acid, 2-
aminopimelic acid, 2-aminosuberic acid and 2-aminosebacic acid;
Amino acid amides such as glutamine and asparagine;
Polyamino- or polybasic-monocarboxylic acids such as arginine, lysine,
(3 -aminoalanine, y -aminobutyrine, omithine, citruline, homoarginine,
homocitrulline, hydroxylysine, allohydroxylsine and diaminobutyric acid;
Other basic amino acid residues such as histidine;
Diaminodicarboxylic acids such as a, a'-diaminosuccinic acid, a, a'-
diaminoglutaric acid, a, a'-diaminoadipic acid, a, a'-diaminopimelic acid, a,
a'-
diamino- 0-hydroxypimelic acid, a, a'-diaminosuberic acid, a, a'-
diaminoazelaic
acid, and a, a'-diaminosebacic acid; _
Imino acids such as proline, hydroxyproline, allohydroxyproline, y-
methylproline, pipecolic acid, 5-hydroxypipecolic acid, and azetidine-2-
carboxylic acid;
A mono- or di-alkyl (typically C 1-C8 branched or normal) amino acid
such as alanine, valine, leucine, allylglycine, butyrine, norvaline,
norleucine,
heptyline, a-methylserine, a-amino-a-methyl-y-hydroxyvaleric acid, a-amino- a-
methyl-S-hydroxyvaleric acid, a-amino- a-methyl-E-hydroxycaproic acid,
isovaline, a-methylglutamic acid, a-aminoisobutyric acid, a-aminodiethylacetic
acid, a-aminodiisopropylacetic acid, a-aminodi-n-propylacetic acid, a-
aminodiisobutylacetic acid, a-aminodi-n-butylacetic acid, a-
aminoethylisopropylacetic acid, a-amino-n-propylacetic acid, a-
aminodiisoamyacetic acid, a-methylaspartic acid, a-methylglutamic acid, 1-
aminocyclopropane-l-carboxylic acid, isoleucine, alloisoleucine, tert-leucine,
(3-
methyltryptophan and a-amino- (3-ethyl-(3-phenylpropionic acid;
0-phenylserinyl;
Aliphatic a-amino-o-hydroxy acids such as serine, (3-hydroxyleucine, 0-
hydroxynorleucine, (3 -hydroxynorvaline, and a-amino-(3-hydroxystearic acid;
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a-Amino, a-, y-, 6- or s-hydroxy acids such as homoserine, S-
hydroxynorvaline, y-hydroxynorvaline and s-hydroxynorleucine residues;
canavine and canaline; y -hydroxyornithine;
2-hexosaminic acids such as D-glucosaminic acid or D-galactosaminic
acid;
a-Amino-p-thiols such as penicillamine, (3-thiolnorvaline or (3-
thiolbutyrine;
Other sulfur containing amino acid residues including cysteine;
homocystine, (3-phenylmethionine, methionine, S-allyl-L-cysteine sulfoxide, 2-
thiolhistidine, cystathionine, and thiol ethers of cysteine or homocysteine;
Phenylalanine, tryptophan and ring-substituted a-amino acids such as the
phenyl- or cyclohexylamino acids a-aminophenylacetic acid, a-
aminocyclohexylacetic acid and a-amino-(3-cyclohexylpropionic acid;
phenylalanine analogues and derivatives comprisirig aryl, lower alkyl,
hydroxy,
guanidino, oxyalkylether, nitro, sulfur or halo-substituted phenyl (e.g.,
tyrosine,
methyltyrosine and o-chloro-, p-chloro-, 3,4-dichloro, o-, m- orp-methyl-,
2,4,6-
trimethyl-, 2-ethoxy-5-nitro-, 2-hydroxy-5 -nitro- and p-nitro-phenylalanine);
furyl-, thienyl-, pyridyl-, pyrimidinyl-, purinyl- or naphthyl-alanines; and
tryptophan analogues and derivatives including kynurenine, 3-
hydroxykynurenine, 2-hydroxytryptophan and 4-carboxytryptophan;
a-Amino substituted amino acids including sarcosine (N-methylglycine),
N-benzylglycine, N-methylalanine, N-benzylalanine, N-methylphenylalanine, N-
benzylphenylalanine, N-methylvaline and N-benzylvaline; and
a-Hydroxy and substituted a -hydroxy amino acids including serine,
threonine, allothreonine, phosphoserine and phosphothreonine.
Polypeptides are polymers of amino acids in which a carboxyl group of
one amino acid monomer is bonded to an amino or imino group of the next
amino acid monomer by an amide bond. Polypeptides include dipeptides, low
molecular weight polypeptides (about 1500-5000 MW) and proteins. Proteins
optionally contain 3, 5, 10, 50, 75, 100 or more residues, and suitably are
substantially sequence-homologous with human, animal, plant or microbial
proteins. They include enzymes (e.g., hydrogen peroxidase) as well as
immunogens such as KLH, or antibodies or proteins of any type against which
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one wishes to raise an immune response. The nature and identity of the
polypeptide may vary widely.
The polypeptide amidates are useful as immunogens in raising antibodies
against either the polypeptide (if it is not immunogenic in the animal to
which it
is administered) or against the epitopes on the remainder of the compound of
this
invention.
Antibodies capable of binding to the parental non-peptidyl compound are
used to separate the parental compound from mixtures, for example in diagnosis
or manufacturing of the parental compound. The conjugates of parental
compound and polypeptide generally are more immunogenic than the
polypeptides in closely homologous animals, and therefore make the polypeptide
more immunogenic for facilitating raising antibodies against it. Accordingly,
the
polypeptide or protein may not need to be immunogenic in an animal typically
used to raise antibodies, e.g., rabbit, mouse, horse, or rat, but the final
product
conjugate should be immunogenic in at least one of such animals. The
polypeptide optionally contains a peptidolytic enzyme cleavage site at the
peptide bond between the first and second residues adjacent to the acidic
heteroatom. Such cleavage sites are flanked by enzymatic recognition
structures, e.g., a particular sequence of residues recognized by a
peptidolytic
enzyme.
Peptidolytic enzymes for cleaving the polypeptide conjugates of this
invention are well known, and in particular include carboxypeptidases.
Carboxypeptidases digest polypeptides by removing C-terminal residues, and are
specific in many instances for particular C-terminal sequences. Such enzymes
and their substrate requirements in general are well known. For example, a
dipeptide (having a given pair of residues and a free carboxyl terminus) is
covalently bonded through its a-amino group to the phosphorus or carbon atoms
of the compounds herein. In embodiments where W I is phosphonate it is
expected that this peptide will be cleaved by the appropriate peptidolytic
enzyme, leaving the carboxyl of the proximal amino acid residue to
autocatalytically cleave the phosphonoamidate bond.
Suitable dipeptidyl groups (designated by their single letter code) are
AA, AR, AN, AD, AC, AE, AQ, AG, AH, AI, AL, AK, AM, AF, AP, AS, AT,
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AW, AY, AV, RA, RR, RN, RD, RC, RE, RQ, RG, RH, RI, RL, RK, RM, RF,
RP, RS, RT, RW, RY, RV, NA, NR, NN, ND, NC, NE, NQ, NG, NH, NI, NL,
NK, NM, NF, NP, NS, NT, NW, NY, NV, DA, DR, DN, DD, DC, DE, DQ, DG,
DH, DI, DL, DK, DM, DF, DP, DS, DT, DW, DY, DV, CA, CR, CN, CD, CC,
CE, CQ, CG, CH, CI, CL, CK, CM, CF, CP, CS, CT, CW, CY, CV, EA, ER,
EN, ED, EC, EE, EQ, EG, EH, EI, EL, EK, EM, EF, EP, ES, ET, EW, EY, EV,
QA, QR, QN, QD, QC, QE, QQ, QG, QH, QI, QL, QK, QM, QF, QP, QS, QT,
QW, QY, QV, GA, GR, GN, GD, GC, GE, GQ, GG, GH, GI, GL, GK, GM, GF,
GP, GS, GT, GW, GY, GV, HA, HR, HN, HD, HC, HE, HQ, HG, HH, HI, HL,
HK, HM, HF, HP, HS, HT, HW, HY, HV, IA, IR, IN, ID, IC, IE, IQ, IG, IH, II,
IL, IK, IM, IF, IP, IS, IT, IW, IY, IV, LA, LR, LN, LD, LC, LE, LQ, LG, LH,
LI, LL, LK, LM, LF, LP, LS, LT, LW, LY, LV, KA, KR, KN, KD, KC, KE,
KQ, KG, KH, KI, KL, KK, KM, KF, KP, KS, KT, KW, KY, KV, MA, MR,
MN, MD, MC, ME, MQ, MG, MH, MI, ML, MK, MM, MF, MP, MS, MT,
MW, MY, MV, FA, FR, FN, FD, FC, FE, FQ, FG, FH, Fl, FL, FK, FM, FF, FP,
FS, FT, FW, FY, FV, PA, PR, PN, PD, PC, PE, PQ, PG, PH, PI, PL, PK, PM,
PF, PP, PS, PT, PW, PY, PV, SA, SR, SN, SD, SC, SE, SQ, SG, SH, SI, SL, SK,
SM, SF, SP, SS, ST, SW, SY, SV, TA, TR, TN, TD, TC, TE, TQ, TG, TH, TI,
TL, TK, TM, TF, TP, TS, TT, TW, TY, TV, WA, WR, WN, WD, WC, WE,
WQ, WG, WH, WI, WL, WK, WM, WF, WP, WS, WT, WW, WY, WV, YA,
YR, YN, YD, YC, YE, YQ, YG, YH, YI, YL, YK, YM, YF, YP, YS, YT, YW,
YY, YV, VA, VR, VN, VD, VC, VE, VQ, VG, VH, VI, VL, VK, VM, VF, VP,
VS, VT, VW, VY and VV.
Tripeptide residues are also useful as protecting groups. When a
phosphonate is to be protected, the sequence -X4-pro-X5- (where X4 is any
amino
acid residue and X5 is an amino acid residue, a carboxyl ester of proline, or
hydrogen) will be cleaved by luminal carboxypeptidase to yield X4 with a free
carboxyl, which in turn is expected to autocatalytically cleave the
phosphonoamidate bond. The carboxy group of X5 optionally is esterified with
benzyl.
Dipeptide or tripeptide species can be selected on the basis of known
transport properties and/or susceptibility to peptidases that can affect
transport to
intestinal mucosal or other cell types. Dipeptides and tripeptides lacking an
a-
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amino group are transport substrates for the peptide transporter found in
brush
border membrane of intestinal mucosal cells (Bai, J.P.F., (1992) Pharm Res.
9:969-978). Transport competent peptides can thus be used to enhance
bioavailability of the amidate compounds. Di- or tripeptides having one or
more
amino acids in the D configuration are also compatible with peptide transport
and can be utilized in the amidate compounds of this invention. Amino acids in
the D configuration can be used to reduce the susceptibility of a di- or
tripeptide
to hydrolysis by proteases common to the brush border such as aminopeptidase
N. In addition, di- or tripeptides alternatively are selected on the basis of
their
relative resistance to hydrolysis by proteases found in the lumen of the
intestine.
For example, tripeptides or polypeptides lacking asp and/or glu are poor
substrates for aminopeptidase A, di- or tripeptides lacking amino acid
residues
on the N-terminal side of hydrophobic amino acids (leu, tyr, phe, val, trp)
are
poor substrates for endopeptidase, and peptides lacking a pro residue at the
penultimate position at a free carboxyl terminus are poor substrates for
carboxypeptidase P. Similar considerations can also be applied to the
selection
of peptides that are either relatively resistant or relatively susceptible to
hydrolysis by cytosolic, renal, hepatic, serum or other peptidases. Such
poorly
cleaved polypeptide amidates are immunogens or are useful for bonding to
proteins in order to prepare immunogens.
Specific Embodiments of the Invention
Specific values described for radicals, substituents, and ranges, as well as
specific embodiments of the invention described herein, are for illustration
only;
they do not exclude other defined values or other values within defined
ranges.
In one specific embodiment the invention provides a compound
comprising at least one phosphonate group, and a substructure of formula 100:
~~N N N~
+1 100
wherein: the bond represented by _ is a single or double bond; or a
pharmaceutically acceptable salt thereof.
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In another specific embodiment the invention provides a compound
comprising at least one phosphonate group, and a substructure of formula:
R N
R20~
N N N R23
R21 R22
wherein:
R20 and R21 are independently hydrogen, alkyl, substituted alkyl, aryl,
or substituted aryl;
R22 is absent, hydrogen, alkyl, or substituted alkyl;
R23 is 0, or NRZSR26;
R24 is aryl, or substituted aryl;
R25 is hydrogen, or alkyl;
R26 is hydrogen, alkyl, or -C(=0)NR2'R2g;
R27 and R28 are independently hydrogen, alkyl, or substituted alkyl;
and
the bond represented by --- is a single or double bond; wherein R22 is
absent when the bond represented by -_ is a double bond. In another specific
embodiment of the invention R20 is hydrogen; R21 is substituted alkyl, or
substituted aryl; R22 is alkyl; R 23 is 0, or NHR26; R26 is hydrogen, alkyl,
or -
C(=0)NHR27; R27 is alkyl; and R24 is substituted aryl.
In another specific embodiment the invention provides a compound that
comprises at least one phosphonate, and a substructure of substructure of
formula II, III, or IV
OMe
CI CI
N ~ N N OMe
~S \ I NN N O CI HO ~ I NN N O CI NN N NH
H H H
II III O-~-NH
IV
/N'
or a pharmaceutically acceptable salt thereof.
In another specific embodiment, the invention provides a compound of
any one of formulae 1-4:
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b
CI ~ CI N~
N, alb-01
N~~ HN'~I I N I HNI I HN~~1 I NH HN~~I ~ H
do ~o ~o A O~NH
1 2 3 4
/N'
wherein:
A is A';
A1 is:
Yz Y2\
W6
RZ
T2~
M12a
M12b
A3 1S:
1 Y Y
rY2 P 11 P Rx
l Y2 IZ Y2
TR 2 R2 ~Rx
M2 2
!M12a]
M12b
Y' is independently 0, S, N(R"), N(OR"), or N(N(R")( R"));
Y2 is independently a bond, 0, N(R"), N(OR"), N(N(R")( R")), or -
S(O)M2-; and when YZ joins two phosphorous atoms Y2 can also be C(R2)(R2);
R' is independently H, R2, W3, a protecting group, or the formula:
Y~ RY Ry Y1
RY
A YZ y2 Y2
A: M12c M1c Mld
M1a
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RY is independently H, W3, R2 or a protecting group;
R2 is independently H, R3 or R4 wherein each R4 is independently
substituted with 0 to 3 R3 groups;
R3 is R3a, R3b, R3o or R3d, provided that when R3 is bound to a
heteroatom, then R3 is R3o or R3d;
R3a is F, Cl, Br, I, -CN, N3 or -NOz;
R3b is Y';
R3 is -RX, -N(R")(RX), -SRX, -S(O)R", -S(O)ZR"; -S(O)(OR"), -
S(O)2(ORX), -OC(Y')R", -OC(Y')OR", -OC(Y')(N(R")(RX)), -SC(Y')R", -
SC(Y')ORX, -SC(Y')(N(R")(R")), -N(RX)C(Y')RX, -N(R't)C(Y')OR", or -
N(RX)C(Y1)(N(R")(R")) ;
R3d is -C(Y')R", -C(Y')ORX or -C(Y')(N(RX)(RX));
R4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms,
or alkynyl of 2 to 18 carbon atoms;
R5 is R4 wherein each R4 is substituted with 0 to 3 R3 groups;
W3 is W4 or W5;
W4 is R5, -C(Y')R5, -C(Y')W5, -S02R5, or -S02W5;
W5 is carbocycle or heterocycle wherein W5 is independently substituted
with 0 to 3 R2 groups;
w 6 is W3 independently substituted with 1, 2, or 3 A3 groups;
M2 is 0, 1 or 2;
M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
M 1 a, M 1 c, and M 1 d are independently 0 or 1;
M12cis0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; and
R21 is substituted alkyl or substituted aryl;
or a pharmaceutically acceptable salt thereof.
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In another specific embodiment the invention provides a compound that
comprises at least one phosphonate, and a substructure of formula 101:
R3: R32
R29 N.
R33
N
R3o~R~ J
101
wherein: R29 is hydrogen, alkyl, or -C(=O)R36;
R30 is hydrogen or substituted alkyl; and
R31 and R32 are independently hydrogen, alkyl, or substituted aryl; or
R31 and R32 taken together with the nitrogen atom to which they are attached
form a substituted or unsubstituted heterocyclic ring;
R33 is -0-, -NR35- or absent;
R34 is -0- or absent;
R35 is hydrogen or alkyl; and
R36 is hydrogen, alkyl, alkenyl, or alkynyl;
or a pharmaceutically acceptable salt thereof.
In another specific embodiment the invention provides a compound that
comprises at least one phosphonate, and a substructure of formula 101 wherein
R29 is -C(=0)R36; R30 is alkyl substituted with -CHR37R38, or NR37R38; R31 and
R32 are independently hydrogen, or substituted aryl; or R3 1 and R32 taken
together with the nitrogen atom to which they are attached form a substituted
heterocyclic ring, wherein the heterocyclic ring is substituted with hydrogen
or
alkyl; R33 is-NR3s-; R 34 is -0-; R35 is hydrogen; R36 is alkenyl; and each
R37 and
R38 is independently hydrogen, alkyl, or substituted alkyl; or NR37R38 forms a
substituted or unsubstituted heterocyclic ring; or a pharmaceutically
acceptable
salt thereof.
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In another specific embodiment the invention provides a compound that
comprises at least one phosphonate, and a substructure of formula 101 wherein:
-NR31R32 forms a substituted piperazyl ring having the formula:
R67
3~
L
CN)
N
1
wherein L3 is -C(=O)NH-; and R67 is hydrogen, substituted alkyl =or
substituted
aryl; or a pharmaceutically acceptable salt thereof.
In another specific embodiment the invention provides a compound that
comprises at least one phosphonate, and a substructure of formula V or VI:
Br F
~ / ~
HN ~0 HN \ CI
F HN
N
r~GO N or 0~~O N
v VI
or a pharmaceutically acceptable salt thereof.
In another specific embodiment the invention provides a compound that
comprises at least one phosphonate, and a substructure of formula VII:
H
O\/N.Rs7
~N(
)
N
0 I )
N~~O NJ
G
VII
wherein R67 is substituted aryl; or a pharmaceutically acceptable salt
thereof.
In another specific embodiment, the invention provides a compound of
formula 101 that is a compound of formula 5, 6, or 7:
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R3: R32 R3\ R32 R3\ Ao
29 N' N" N
R Rs3 A \ R2s~R33
N \
N N
o ~ R30 R30 I ~ J
A N ~R3a N --'R34
N
6 7
wherein:
A is A';
A' is:
5
Y2 Y2
VV6
2'R2
M12a
M12b
A3 is:
Y Y~
r2 P P R"
Y2 I2 Y2
R2 R2 \
RX
M2 2 - ( _ M12a
M12b
Y' is independently 0, S, N(R"), N(OR"), or N(N(RX)( R"));
YZ is independently a bond, 0, N(R"), N(OR"), N(N(R")( R")), or -
S(O)M2-; and when Y2 joins two phosphorous atoms Y2 can also be C(RZ)(RZ);
R' is independently H, R2, W3, a protecting group, or the formula:
Yi RY Ry Yi
Ry
Y2 Y2 Yz
M12c M1c M1d
iMla
RY is independently H, W3, R 2 or a protecting group;
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R2 is independently H, R3 or R4 wherein each R4 is independently
substituted with 0 to 3 R3 groups;
R3 is R3a~ R3b~ R3o or R3d, provided that when R3 is bound to a
heteroatom, then R3 is R3o or R3a;
R3a is F, Cl, Br, I, -CN, N3 or -NO2;
R3b 1S YI ;
R3c is -Rx, -N(RX)(R"), -SR", -S(O)R", -S(O)2R", -S(O)(OR"),
S(O)2(OR"), -OC(Y')R", -OC(Y1)ORX, -OC(Yl)(N(R")(RX)), -SC(Y')RX, -
SC(Y')ORX, -SC(Y')(N(R")(R")), -N(R")C(Y1)R", -N(R")C(Y')OR", or -
N(R")C(Y1)(N(RX)(RX)) ;
R3d is -C(Y~)R", -C(Y1)ORX or -C(Y1)(N(RX)(RX));
R4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms,
or alkynyl of 2 to 18 carbon atoms;
R5 is R4 wherein each R4 is substituted with 0 to 3 R3 groups;
W3isW4orW5;
W4 is R5, -C(Y')R5, -C(Yl)W5, -SO2R5, or -SOzWS;
W5 is carbocycle or heterocycle wherein W5 is independently substituted
with 0 to 3 R2 groups;
W6 is W3 independently substituted with 1, 2, or 3 A3 groups;
M2 is 0, 1 or 2;
M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
M 1 a, M 1 c, and M 1 d are independently 0 or 1; and
M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
wherein R29-R34 have any of the values defined herein; or a
pharmaceutically acceptable salt thereof.
In another specific embodiment the invention provides a compound that
comprises at least one phosphonate, and a substructure of formula 102;
-O-N 0
H
N
102
or a pharmaceutically acceptable salt thereof.
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In another specific embodiment the invention provides a compound that
comprises at least one phosphonate, and a substructure of formula VIII:
-0-N 0
H
N
(R39)na ~0
(R )ma
Vlll
wherein each R39 and R40 is independently hydrogen, fluorine, chlorine,
bromine
or iodine; and na and ma are each independently 1, 2, 3, or 4; or a
pharmaceutically acceptable salt thereof.
In another specific embodiment the invention provides a compound that
comprises at least one phosphonate, and a substructure of formula IX:
-0-N 0 R 43
N
Ra2 R44
R 41
IX
wherein R4i, R42, R43 and R44 are independently hydrogen, fluorine, chlorine,
bromine or iodine; or a pharmaceutically acceptable salt thereof. Specific
values
for R41, R42, and R43 are fluorine; and a specific value for R44 is iodine.
In another specific embodiment, the invention provides a compound of
any one of formulae 8-10:
A O,N O F HO O,N O F A~O,N H
O F
HO~ N A ~ N N
F I I F I~~ F I~ I
F F F
8 9 10
wherein:
A is A';
A' is:
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Y2 Y2
\~
l
2
TRRR2
M12a
M12b
A3 is:
Y Y
Y2 P P R"
l Y2 I2 Y2
R2 R2 RX
M2 2
M12a
M12b
Y' is independently 0, S, N(R"), N(OR"), or N(N(R')( R'));
Y2 is independently a bond, 0, N(R"), N(OR"), N(N(R")( R")), or -
S(O)M2-; and when Y2 joins two phosphorous atoms, Y2 can also be C(R2)(R2);
R" is independently H, R2, W3, a protecting group, or the formula:
Yi Ry RY Yi
Ry
Yz 2 YZ
_V M1a M12c 1c M1d
.
,
Ry is independently H, W3, R2 or a protecting group;
R2 is independently H, R3 or R4 wherein each R4 is independently
substituted with 0 to 3 R3 groups;
R3 is R3a, R3b, R3c or R3d, provided that when R3 is bound to a
heteroatom, then R3 is R3o or R3d;
R3a is F. Cl, Br, I, -CN, N3 or -NO2;
R3b is Yl;
R3a is -R", -N(R")(RX), -SR", -S(O)RX, -S(O)2R", -S(O)(OR"), -
S(O)2(OR"), -OC(Y')R", -OC(Y')ORX, -OC(Y')(N(RX)(RX)), -SC(Y')Rx, -
SC(Y')OR", -SC(Y')(N(RX)(R")), -N(RX)C(Y')R", -N(R")C(Y')OR", or -
N(R")C(Y')(N(R")(R")) ;
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R3d is -C(Y')R", -C(Y1)OR" or -C(Y1)(N(RX)(R"));
R4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms,
or alkynyl of 2 to 18 carbon atoms;
R5 is R4 wherein each R4 is substituted with 0 to 3 R3 groups;
W3 is W4 or W5;
w 4 is R5, -C(Y~)R5, -C(Y)W5, -SOZRS, or -S02W5;
W5 is carbocycle or heterocycle wherein W5 is independently substituted
with 0 to 3 R2 groups;
W6 is W3 independently substituted with 1, 2, or 3 A3 groups;
M2 is 0, l or 2;
M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
M12bis0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
M 1 a, M 1 c, and M 1 d are independently 0 or 1; and
M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; or a pharmaceutically
acceptable salt thereof.
In another specific embodiment the invention provides a compound that
comprises at least one phosphonate, and a substructure of formula 103 or
formula 104;
S~ N
HN'~-
O~ g
103 104
or a pharmaceutically acceptable salt thereof.
In another specific embodiment the invention provides a
compound that comprises at least one phosphonate, and a
substructure of formula X:
HN' Aa R46
g' ~N
R45
x
51
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wherein R45 is hydrogen, -NH-(C6-C2o)aryl or NH-substituted(C6-CZO)aryl; Aa
is carbocycle or a heterocycle; and R46 is a substituted heterocycle; or a
pharmaceutically acceptable salt thereof.
In another specific embodiment the invention provides a compound that
comprises at least one phosphonate, and a substructure of formula X wherein Aa
is substituted (methyl)pyrimidyl; R46 is piperazyl substituted with alkyl or
substituted alkyl; and R45 is -NH-(substituted aryl); or a pharmaceutically
acceptable salt thereof.
In another embodiment the invention provides a compound comprising a
substructure of formula 103 or formula 104 and at least one phosphonate group;
which compound comprises a substructure of the formula XVIII:
0 S H
N// N N
H N \
CI
R47.N'R48
XVIII
wherein R47 and R48 are independently hydrogen or (CI -C4)alkyl, or R47 and
R48
take together with the nitrogen atom to which they are attached form a
substituted or unsubstituted heterocyclic ring; or a pharmaceutically
acceptable
salt thereof.
In another embodiment, the invention provides a compound of any one of
formulae 11-14:
52
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N" 'IN~ N" 'N
HN~I N~ ,q HN H~qo
N
S 'N N
O4~ O
Me NH Me NH
ci 11 / \ ci 12
A A
Nl"_NI NI~-NI
HN I~N\ HN~ N,,,_,OH
SN SN
Me NH Me NH
ci 13 14
wherein:
A isA';
A1 is:
Y2 Y2\
W6
R2 R2
M12a
M12b
A3 is:
Y~ Y~ 11
Y2 P P Rx
1 Y2 I2 Y2
R2 R2 Rx
M2 2
M12a
M12b
Y' is independently 0, S, N(RX), N(OR"), or N(N(R")( R"));
y2 is independently a bond, 0, N(R"), N(OR"), N(N(R")( R")), or -
S(O)M2-; and when Y2 joins two phosphorous atoms Yz can also be C(Rz)(R2);
53
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R' is independently H, R2, W3, a protecting group, or the formula:
Yi RY Ry Yi
Ry
YZ Y2 Y2
M12c M1c M1d
M1a
,
RY is independently H, W3, R2 or a protecting group;
R' is independently H or alkyl of 1 to 18 carbon atoms;
RZ is independently H, R', R3 or R4 wherein each R4 is independently
substituted with 0 to 3 R3 groups;
R3 is R3a~ R3b~ R3o or R3d, provided that when R3 is bound to a
heteroatom, then R3 is R3c or R3d;
R3a is F, Cl, Br, I, -CN, N3 or -NOz;
R3b 1S Yl;
R3o is -RX, -N(RX)(R"), -SR", -S(O)R", -S(O)zRX, -S(O)(ORX), -
S(O)Z(OR"), -OC(Y')R", -OC(Y1)OR", -OC(Y')(N(RX)(RX)), -SC(Y1)R", -
SC(Yl)ORX, -SC(Y')(N(R")(R")), -N(R")C(Y1)R", -N(R")C(Y1)ORX, or -
N(R")C(Y')(N(RX)(R")) ;
R3d is -C(Y')R", -C(Y')OR" or -C(Yl)(N(RX)(RX));
R4 isan alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms,
or alkynyl of 2 to 18 carbon atoms;
R5 is R4 wherein each R4 is substituted with 0 to 3 R3 groups;
W3 is W4 or W5;
W4 is R5, -C(Y')R5, -C(Yl)W5, -SOzR5, or -S02 W5;
W5 is carbocycle or heterocycle wherein W5 is independently substituted
with 0 to 3 R2 groups;
W6 is W3 independently substituted with 1, 2, or 3 A3 groups;
M2 is 0, 1 or 2;
M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
M12bis0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
M 1 a, M 1 c, and M 1 d are independently 0 or 1; and
M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; or a pharmaceutically
acceptable salt thereof.
54
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In another specific embodiment the invention provides a compound that
comprises at least one phosphonate, and a substructure of formula 105:
S NH
NL )/,'~
105
or a pharmaceutically acceptable salt thereof.
In another specific embodiment the invention provides a compound that
comprises at least one phosphonate, and a substructure of formula XI, XII,
or XIII:
R50
/ R50 50
/S NH i R
N~ ~ ,S NH ,S NH
N~ ~ N~ ~
R55 0 NH2
R49 / R55 ~
xi xii R49 xiii
wherein:
R49 is hydrogen, -(C6-C20)aryl or -(C6-C20)substituted aryl;
R50 is hydrogen, substituted alkyl, or -C(=O)NR5'R52;
R51 and R52 are independently hydrogen, alkyl, or substituted alkyl; and
R55 is a bond or alkylene;
or a pharmaceutically acceptable salt thereof.
In another specific embodiment the invention provides a compound that
comprises a substructure of formula XI, XII, or XIII and at least one
phosphonate group wherein: R49 is substituted aryl; R50 is -C(=0)NRS'R52; R51
is hydrogen; R52 is -NRs3R54(C1-C6)alkyl; R53 and R54 taken together with the
nitrogen atom to which they are attached form a substituted or unsubstituted
heterocyclic ring; and R55 is methylene; or a pharmaceutically acceptable salt
thereof.
In another*specific embodiment the invention provides a compound that
comprises at least one phosphonate, and a substructure of formula 105; which
compound comprises a substructure of the formula XIX:
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H
O-Y N~\N~
S NH
N\ /
O NHZ
F 0
F
Br
xix
or a pharmaceutically acceptable salt thereof.
In another specific embodiment, the invention provides a compound of
formula 15 or 16:
H H
OyN~A OyN~~No
N,S 1NH N,S 1NH
NHZ N'-o
F O F O ' '
F F
Br Br
15 16
wherein:
A isA';
A' is:
Y2 Y2
W6
R2 R2
M12a
M12b =
A3 1S:
Y Y
Y2 P 11 P R"
l Y2 I2 Y2
R2 R2 RX
M2 2
- ( _ M 12a
M12b
56
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Y' is independently 0, S, N(R"), N(OR"), or N(N(RX)( RX));
y2 is independently a bond, 0, N(R"), N(OR"), N(N(R")(,R")), or -
S(O)M2-; and when Y2 joins two phosphorous atoms Yz can also be C(R2)(RZ);
R' is independently H, R 2, W3, a protecting group, or the formula:
Yi Ry Ry Yi
RY
YZ Y2 Y2
M12c M1c M1d
M1a
,
RY is independently H, W3, R 2 or a protecting group;
R' is independently H or alkyl of 1 to 18 carbon atoms;
R2 is independently H, R', R3 or R4 wherein each R4 is independently
substituted with 0 to 3 R3 groups;
R3 is R3a, R3b' R3c or R3d, provided that when R3 is bound to a
heteroatom, then R3 is R3o or R3d;
R3a is F, Cl, Br, I, -CN, N3 or -NO2;
R3b is Y';
R3o is -RX, -N(RX)(R"), -SR", -S(O)RX, -S(O)zR", -S(O)(OR"), -
S(O)z(OR"), -OC(Y')R", -OC(Y')OR", -OC(Y')(N(Rx)(RX)), -SC(Y')RX, -
SC(Y')ORX, -SC(Y')(N(R't)(R")), -N(R")C(Y')RX, -N(R")C(Y')ORX, or -
N(RX)C(Y')(N(RX)(RX)) ;
R3d is -C(Y')R", -C(Y')ORX or -C(Y')(N(RX)(R"));
R4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms,
or alkynyl of 2 to 18 carbon atoms;
R5 is R4 wherein each R4 is substituted with 0 to 3 R3 groups;
W3 is W4 or W5;
W4 is R5, -C(Y')R5, -C(Y')W5, -S02R5, or -S02W5;
W5 is carbocycle or heterocycle wherein W5 is independently substituted
with 0 to 3 R2 groups;
W6 is W3 independently substituted with 1, 2, or 3 A3 groups;
M2 is 0, 1 or 2;
M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
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M 1 a, M 1 c, and M 1 d are independently 0 or 1; and
M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; or a pharmaceutically
acceptable salt thereof.
In another specific embodiment the invention provides a compound that
comprises at least one phosphonate, and a substructure of formula 106:
O
R56 H/
106
wherein: R56 is -N-, or -CR57-; and
R57 is hydrogen, or alkyl;
or a pharmaceutically acceptable salt thereof.
In another specific embodiment the invention provides a compound that
comprises at least one phosphonate, and a substructure of formula XIV:
R5s-Rs0-(Rs1)nb
~
R58 jI , O
R56 H XIV
wherein: R56 is -N-, or -CR57-;
R57 is hydrogen, or alkyl;
R58 is hydrogen, halo, alkyl, a fused carbocyclic ring or a fused
heterocyclic ring;
R59 is =CR64- or =N-NR64-;
R60 is phenyl or pyrrolyl;
each R61 is independently alkyl, or a polar group;
R64 is independently hydrogen, or alkyl; and
nb is 0, 1,2,or3;
or a pharmaceutically acceptable salt thereof.
In another specific embodiment the invention provides a compound that
comprises at least one phosphonate, and a substructure of formula XIV wherein:
R56 is -N-, or -CH-; R58 is hydrogen, halo, or a fused carbocyclic ring or a
fused
58
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heterocyclic ring; R59 is =CH- or =N-NH-; R60 is phenyl or pyrrolyl; each R61
is
independently alkyl, -C(=O)NR62R63; or -S(=O)ZNR62R63; and each R62 and R63 is
independently hydrogen, alkyl, or substituted alkyl; or a pharmaceutically
acceptable salt thereof.
In another specific embodiment the invention provides a compound that
comprises at least one phosphonate, and a substructure of formula XV, XVI, or
VII:
O
0=S-NH
O NN~/
H
S N-NH
CCN HH NO O O
H
H H /H
XV XVI XV11
or a pharmaceutically acceptable salt thereof.
In another specific embodiment the invention provides a compound of
formula 17, 18, or 19:
0
0=~-NH
0 A
N~A
R58 N ~ H R58 ,C~' / H NN-N H
OH O O
H H H
17 18 19
wherein:
A is A~;
A' is:
59
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Y2 Y
l W6
R2 R2
M12a
M12b
A 3 is:
Y~ Y
Y-Z P 11 P Rx
Y2 I2 Y2
R2 R2 Rx
M2
M12a 2
M12b
Y' is independently O, S, N(R'), N(OR"), or N(N(R')( R'));
Y2 is independently a bond, 0, N(R"), N(OR"), N(N(R")( R")), or -
S(O)M2-; and when YZ joins two phosphorous atoms Y2 can also be C(R2)(Rz);
R" is independently H, R2, W3, a protecting group, or the formula:
Yi RY Ry Yi t," RY
Y2 --~ Y2 ~' _ Y2
M1a M12c M1c M1d
,
RY is independently H, W3, R 2 or a protecting group;
R2 is independently H, R3 or R4 wherein each R4 is independently
substituted with 0 to 3 R3 groups;
R3 is R3a, R3b, R3o or R3d, provided that when R3 is bound to a
heteroatom, then R3 is R3o or R3d
R3a is F, Cl, Br, I, -CN, N3 or -NOZ;
R3bisY';
R3 is -RX, -N(R")(R"), -SR", -S(O)R", -S(0)2R", -S(O)(OR"), -
S(O)2(ORX), -OC(Y')R", -OC(Y')ORX, -OC(Y')(N(RX)(R")), -SC(Y')R", -
SC(Y')OR", -SC(Y')(N(RX)(R")), -N(R")C(Y')R", -N(R")C(Y')OR", or -
N(R't)C(Y')(N(R")(RX)) ;
R3d is -C(Y')R", -C(Y')OR" or -C(Y')(N(R")(R"));
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R4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms,
or alkynyl of 2 to 18 carbon atoms;
R5 is R4 wherein each R4 is substituted with 0 to 3 R3 groups;
W3 is W4 or W5;
W4 is R5, -C(Y')R5, -C(Y')W5, -SOzR5, or -S02W5;
W5 is carbocycle or heterocycle wherein W5 is independently substituted
with 0 to 3 R2 groups;
W6 is W3 independently substituted with 1, 2, or 3 A3 groups;
M2 is 0, 1 or 2;
M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, l l or 12;
M12bis0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
M 1 a, M 1 c, and M 1 d are independently 0 or 1;
M12cis0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; and
R58 is hydrogen, or halo; or a pharmaceutically acceptable salt thereof.
In another specific embodiment the invention provides a compound of
any one of formulae 20-24:
/ I
H / yo
N~ NY N ~ N~ I Ny N ~ N N I/ I I
y N / O
AO
A 21
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H
/ o A N~ N ia Rs5
N\ I NN \ N N Rs
s
N I / 0 23
22
N N Rs5
y Ao
N
24
~/~
N N OH
H
wherein:
A is A';
A' is:
Y2 Y \
l VV6
R2 R2
M12a
M12b
A3 is:
Y Y
Y2 P 11 P R"
l Y2 I2 Y2
R2 R2 ~Rx
M12a M2 2
M12b
Y' is independently 0, S, N(R"), N(OR"), or N(N(R')( RX));
y2 is independently a bond, 0, N(R"), N(OR"), N(N(R")( R")), or -
S(O)M2-; and when Y2 joins two phosphorous atoms Y2 can also be C(R2)(R2);
R" is independently H, R2, W3, a protecting group, or the formula:
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Y1 Rv Rv Y1
Ry IJI" Y2 Y2 YZ M1d
M1a M12c tic
RY is independently H, W3, R 2 or a protecting group;
R2 is independently H, R3 or R4 wherein each R4 is independently
substituted with 0 to 3 R3 groups;
R3 is R3a, R3b, R3o or R3d, provided that when R3 is bound to a
heteroatom, then R3 is R3o or R3a;
R3a is F, Cl, Br, I, -CN, N3 or -NO2i
R3b is Y';
R3c is -RX, -N(R")(RX), -SR', -S(O)R", -S(O)2R", -S(O)(ORX), -
S(O)2(ORX), -OC(Y')R", -OC(Y')ORX, -OC(Y')(N(RX)(RX)), =SC(Y')R", -
SC(Y')OR", -SC(Y')(N(R")(R")), -N(R")C(Y')R", -N(R")C(Y')ORX, or -
N(RX)C(I'1)(N(RX)(RX)) ~
R3d is -C(Y')R", -C(Y')OR" or -C(Y')(N(RX)(RX));
R4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms,
or alkynyl of 2 to 18 carbon atoms;
R5 is R4 wherein each R4 is substituted with 0 to 3 R3 groups;
W3isW4orW5;
W4 is R5, -C(Y')R5, -C(Y')W5, -SOzR5, or -S02W5;
W5 is carbocycle or heterocycle wherein W5 is independently substituted
with 0 to 3 R2 groups;
W6 is W3 independently substituted with 1, 2, or 3 A3 groups;
M2 is 0, 1 or 2;
M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
M l a, M l c, and M l d are independently 0 or 1;
M12cis0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
R65 is hydrogen, alkyl, or halo; and
R66 is carbocycle, heterocycle, substituted carbocycle, or substituted
heterocycle, and is substituted with one or more A ; or a pharmaceutically
acceptable salt thereof.
63
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In another specific embodiment the invention provides a compound that
comprises at least one phosphonate, and a substructure of any one of formulae
II-XVII:
CI CI
N \ \ \ ~ / N \ \ \ ~
CI HO \ I ~ ~ ci
S N N N O N N N O
H ~ H ~
II OMe III
Br
HN
q
N \ \ \ OMe
F
N N N N H )() NJ
H r\~O
N Iv O~NH N
V
H
Oy NRs7
/ N
O \ ~ CNIIJ ~ HN CI HN
N 0NO NNJ
G
VI VII
64
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-O-N O -O-N O R43 HN"qa R46
H H ~
N N I S" 'N
R42 5
R~
39 41 O
R )na (R40) ma R R4
VIII IX X
R50 R50
~S NH RS S NH
N~ ~ N,S NH N, /
O NH2
R55 R55 0
R49 R49
xi
XII XIII
R59-R60-(R61 )nb ' \
N
~
H
R58 O O
Oc>
R5s H H
XIV
XV
~ O O -NH
NN
H 0
H N-NH
O O
N ~ N
H H
XVI XVII
wherein:
each R39 and R40 is independently hydrogen, fluorine, chlorine, bromine
or iodine;
na and ma are each independently 1, 2, 3, or 4;
R41, R42, R43 and R44 are independently hydrogen, fluorine, chlorine,
bromine or iodine;
R45 is hydrogen, -NH-(C6-C20)aryl or NH-substituted(C6-C20)aryl;
Aa is carbocycle or a heterocycle;
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R46 is a substituted heterocycle;
R49 is hydrogen, -(C6-C20)aryl or -(C6-C20)substituted aryl;
R50 is hydrogen, substituted alkyl, or -C(=O)NR51R52; wherein R51 and
R52 are independently hydrogen, alkyl, or substituted alkyl;
R55 is a bond or alkylene;
R56 is -N-, or -CR57-;
R57 is hydrogen or alkyl;
R58 is hydrogen, halo, alkyl, a fused carbocyclic ring or a fused
heterocyclic ring;
R59 is =CR64- or =N-NR64-;
R60 is phenyl or pyrrolyl;
each R61 is independently alkyl, or a polar group;
each R64 is independently hydrogen or alkyl;
R67 is substituted aryl; and
nb is 0, 1, 2, or 3; or a pharmaceutically acceptable salt thereof.
In another specific embodiment the invention provides a compound that
comprises a substructure of any one of formulae 1-24:
"lo
ci ci b-
N~ NN~ Oi N~ Oi
HNN N O C~ HN'N N O ci HN~N ~N NH HNN N NH
R21 Ao Ao Ao A ONH
1 2 3 4
/N'
R3: , R32 R3: , R32 Rg: / Ao
R2R3s N A N R29,R33 N
\ I N N
\ A I/ NJ R3~Raa I~ NJ R30 (:: NJ
Rsa
5 6 7
66
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H r D. O H F
HO N A ~ N N
F F I/ ~ I F
F F F
8 9 10
N" '_NI NJ" N
H N ~ I N Z ~ ,A HN ~H-A
~
S ~ N N S" '_N
O~ O4~
Me NH Me NH
c i 11 ci 12
A A
Nli"N N)"N
HN~N\ HN~N ~ -~OH
N
N
N
O O~
Me NH Me NH
Ci 13 b-ci 14
H H
OYN\Ao OYN
NS NH NS NH
NH2 N'-'o
F O F O A
F F
Br Br
15 16
67
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0
O O -NH
p A ~ \
N A
H/ ' N ~S N-NH
R58 N R58 H N /
pH ON O O
N H H H
17 18 19
H / /
N~ N~N ~ N~ I N~ N N ~ I
I N I / I
Ao 20 Ao 21
H
/ yo, Ao N~ N Rss
N\ I N\ N \ N N R66
I N I/ O 23
22
H N N R65
yAo Ni: I ~
N
24
LNkNOH
H
wherein:
A is A';
A' is:
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Y2 Y2
\W6
R2 R2
M12a
M12b
A3 is:
Y Y
Y2 P P R"
l Y2 Y2 Y
R2 R2 Rx
M12a M2 2.
M12b
Y' is independently 0, S, N(R"), N(OR"), or N(N(R')( R"));
y 2 is independently a bond, 0, N(R'), N(OR"), N(N(R")( R")), or -
S(O)M2-; and when Y2 joins two phosphorous atoms Y2 can also be C(R2)(R2);
R' is independently H, R2, W3, a protecting group, or the formula:
Yi Ry Ry Yi
Ry
Yz Yz Yz
M1a M12c M1c M1d
.
~
RY is independently H, W3, R2 or a protecting group;
R2 is independently H, R3 or R4 wherein each R4 is independently
substituted with 0 to 3 R3 groups;
R3 is R3a~ R3b~ R3o or R3d, provided that when R3 is bound to a
heteroatom, then R3 is R3c or R3d;
R3a is F, Cl, Br, I, -CN, N3 or -NOZ;
R3b is Y';
R3o is -R", -N(R")(R"), -SRX, -S(O)R", -S(O)2RX, -S(O)(OR"), -
S(O)2(OR"), -OC(Y')R", -OC(Y')OR", -OC(Y')(N(RX)(RX)), -SC(Y')R", -
SC(Y')OR", -SC(Y')(N(R")(RX)), -N(R")C(Y')R", -N(RX)C(Y')OR", or -
N(R")C(Y')(N(R")(R")) ;
R3d is -C(Y')RX, -C(Y')ORX or -C(Y')(N(RX)(RX));
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R4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms,
or alkynyl of 2 to 18 carbon atoms;
R5 is R4 wherein each R4 is substituted with 0 to 3 R3 groups;
W3 is W4 or W5;
W4 is R5, -C(Y')R 5, -C(Y)W5, -SOZR5, or -S02W5;
W5 is carbocycle or heterocycle wherein W5 is independently substituted
with 0 to 3 R2 groups;
W6 is W3 independently substituted with 1, 2, or 3 A3 groups;
M2 is 0, 1 or 2;
M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
M12bis0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
M 1 a, M 1 c, and M 1 d are independently 0 or 1;
M12cis0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or12;
R21 is substituted alkyl or substituted aryl.
R29 is hydrogen, alkyl, or -C(=0)R36;
R30 is hydrogen or substituted alkyl;
R3 1 and R32 are independently hydrogen, alkyl, or substituted aryl; or R3 1
and R32 taken together with the nitrogen atom to which they are attached form
a
substituted or unsubstituted heterocyclic ring;
R33 is -0-, -NR35- or absent;
R34 is -0- or absent;
R35 is hydrogen or alkyl;
R36 is hydrogen, alkyl, alkenyl, or alkynyl;
R58 is hydrogen, or halo;
R65 is hydrogen, alkyl, or halo; and
R66 is carbocycle, heterocycle, substituted carbocycle, or substituted
heterocycle, and is substituted with one or more A ; or a pharmaceutically
acceptable salt thereof.
In one specific embodiment of the invention A.' is of the formula:
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Y2 2 A3
W5
R2 R2
M 12a
M12b
In another specific embodiment of the invention A' is of the formula:
YZ y2 A3
VV6
R2 RZ
M12a M12b
In another specific embodiment of the invention A' is of the formula:
Y2 W6
3
R2 Rz
M12a
M12b
In another specific embodiment of the invention A' is of the formula:
3
Nia.
In another specific embodiment of the invention A' is of the formula:
r a
\A3
R2 R2
M12a
and W5a is a carbocycle or a heterocycle where W5a is independently
substituted
with 0 or 1 R2 groups. A specific value for M 12a is 1.
In another specific embodiment of the invention A' is of the formula:
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2 W5
\
A3
RZ 2
R
M12a
M12b
In another specific embodiment of the invention A1 is of the formula:
3
R2 R2
M12a
In another specific embodiment of the invention A' is of the formula:
W5a
3
R2 R2
wherein W5a is a carbocycle independently substituted with 0 or 1 R2 groups.
In another specific embodiment of the invention A' is of the formula:
O R2
O P-11
Yzb O1-~ Rv
O
~HJH
212d
wherein y2b is 0 or N(R2); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
In another specific embodiment of the invention A' is of the formula:
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W5a
3
RZ RZ
M12a
wherein W5a is a carbocycle independently substituted with 0 or 1 R2 groups.
In another specific embodiment of the invention A' is of the formula:
W5a
3
R2 R2
wherein W5a is a carbocycle or heterocycle where W5a is independently
substituted with 0 or 1 R2 groups.
In another specific embodiment of the invention A' is of the formula:
O R2
O P Y2b 0 1--, Ry
o O
H H W3
M12d Y2b
wherein y2b is O or N(R2); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
In a specific embodiment of the invention A3 is of the formula:
Y
Y2 IP Rx
2
RZ 2 Y
R
M12 2
M 12b
In another specific embodiment of the invention A3 is of the formula:
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Y
Y2 IP R"
2
Y 2
R2 2
M12a
In another specific embodiment of the invention A3 is of the formula:
y la
2a IP R"
Y2 /
R2 R2 2
M12a
wherein Y" is 0 or S; and y2a is 0, N(R) or S.
In another specific embodiment of the invention A3 is of the formula:
O
O IP R"
Y2b/
R2 R2 2
M12a
wherein Y2b is 0 or N(R').
In another specific embodiment of the invention A3 is of the formula:
O
O IP R"
Y2b
R~ R~ 2
M 12d
wherein YZb is 0 or N(R"); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
In another specific embodiment of the invention A3 is of the formula:
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0
IP R"
Y2b/
H H 2
M12d
wherein y2b is O or N(R"); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
In another specific embodiment of the invention M12d is 1.
In another specific embodiment of the invention A3 is of the formula:
Yi
Y2 IP R"
\ 2/
Y
R2
R2
3
M12
Y2
M12b
In another specific embodiment of the invention A3 is of the formula:
Yi
2 Ip R"
Y2
Rz
R2
M12a
Y2
M12b
In another specific embodiment of the invention W5 is a carbocycle.
In another specific embodiment of the invention A3 is of the formula:
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Y1
Y2 IP Rx
\N/
R2 Rx
R2
M 12a /~
M12b
In another specific embodiment of the invention W5 is phenyl.
In another specific embodiment of the invention A3 is of the formula:
y la
Y2a IP R"
Y2 /
R2 R2 W3
M 12a Y2 a
wherein Yla is 0 or S; and Y2a is 0, N(RX) or S.
In another specific embodiment of the invention A3 is of the.formula:
0
O IP R" .
\ Y2b/
R2 R2 z W3
M12a Y2b
wherein y2b is 0 or N(R").
In another specific embodiment of the invention A3 is of the formula:
0
O IP Rx
\y2b/
l..
R~ R~
W3
M12d
y 2b
wherein Y2b is 0 or N(R'); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
In another specific embodiment of the invention R' is H.
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In another specific embodiment of the invention A3 is of the formula:
R2
I
O R'
M12d Y2b OR 1
O
wherein the phenyl carbocycle is substituted with 0, 1, 2, or 3 R2 groups.
In another specific embodiment of the invention A3 is of the fonnula:
R2
O ~
~P/O R
12d H OR
R R
M--Ir
O
In another specific embodiment of the invention A3 is of the formula:
O9
O ~P/O CH3
'
H OR1
H H
O
In.another specific embodiment of the invention A3 is of the formula:
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~I
~
O
/O CH3
OR'
H H
O
In another specific embodiment of the invention A3 is of the formula:
O O
O P /\ o 0 )~ 0 1-, R2
H H
2
In another specific embodiment of the invention A3 is of the formula:
Y1 a R2
2a Y2
\ RY
2a
Y
Yi
R2 R2 2
M12a
wherein Y" is 0 or S; and Y2a is 0, N(R2) or S.
In another specific embodiment of the invention A3 is of the formula:
O R2
O IP 2c
Y
2b
Y1 R
a
R2 R2
12
M12a
~
wherein Yla is 0 or S; y2b is 0 or N(R2); and Y2o is 0, N(Ry) or S.
In another specific embodiment of the invention A3 is of the formula:
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R2
O IP 2d
2b Ry
Y1a
Ri Ri
12
M12d
wheren Yla is O or S; y2b is O or N(RZ); y2d is O or N(RY); and M12d is 1, 2,
3,
4, 5, 6, 7 or 8.
In another specific embodiment of the invention A3 is of the formula:
O R2
II
O P Oll, Ry
Y2b
O
H H 2
M12d
wherein Y2b is O or N(RZ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
In another specific embodiment of the invention A3 is of the formula:
O R2
11
O P O~ 2
Y2b R
= ~ O
H H
2
wherein Y2b is 0 or N(R).
In another specific embodiment of the invention A3 is of the formula:
0
u
O P O,R2
H H 0
2
In another specific embodiment of the invention A3 is of the formula:
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Y~
Y2 IP Rx
\-~ Y 2
TR R2 M12a \7w3
In another specific embodiment of the invention A3 is of the formula:
y la R2 11
Y2a P Y2
Y2a
/ \ \Ry
Yi
R R
VV3
M12a Y2a
wherein Yla is 0 or S; and Y2a is 0, N(R2) or S.
In another specific embodiment of the invention A3 is of the formula:
O Rz
O IP Y~ -~Y \ Ry
Y2
Y1a
R2 R2 3
M12a Y2
wherein Yla is 0 or S; y2b is 0 or N(R2); and Y2c is 0, N(RY) or S.
In another specific embodiment of the invention A3 is of the formula:
O R2
O IP Y2d
Y2b Ry
Y1a
R~ R~
3
M12d Y2b
wherein Yla is 0 or S; y2b is 0 or N(R2); y2d is 0 or N(RY); and M12d is 1, 2,
3,
4,5,6,7or8.
In another specific embodiment of the invention A3 is of the formula:
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O R2
I I
O P
2b Ry
O
H H W3
M12d Y2b/
wherein y2b is O or N(RZ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
In another specific embodiment of the invention A3 is of the formula:
O R2
II
/O P O~ 2
Y2b R
H H iW3
y 2b
wherein y2b is 0 or N(R).
In another specific embodiment of the invention A3 is of the formula:
0
YZb IP R"
\\y2b/
R~ R~
W3
M12d Y2 b
wherein: Y2b is 0 or N(R'); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
In another specific embodiment of the invention A3 is of the formula:
9
~P/O R'
l~o
\ 2b
Y OR'
R' R' M12d
0
wherein the phenyl carbocycle is substituted with 0, 1, 2, or 3 R 2 groups.
In another specific embodiment of the invention A3 is of the formula:
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O
1 ~O \P/O R
OR1
W 1 ~jl12d
0
wherein the phenyl carbocycle is substituted with 0, 1, 2, or 3 R2 groups.
In another specific embodiment of the invention A3 is of the formula:
Me Me
O
~P/O CH3
\O OR'
H H
In a specific embodiment of the invention A is of the formula:
O
~ II O R
/CH2)F-io
OR
wherein each R is independently (CI -C6)alkyl.
In a specific embodiment of the invention R' is independently H,
R1, W3, a protecting group, or the formula:
Yi Ry R Yi
Ry
Y2 Y2 Y2
M1c M1d
M1a M12c
wherein:
RY is independently H, W3, R2 or a protecting group;
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R' is independently H or alkyl of 1 to 18 carbon atoms;
R2 is independently H, R1, R3 or R4 wherein each R4 is independently
substituted with 0 to 3 R3 groups or taken together at a carbon atom, two R2
groups form a ring of 3 to 8 carbons and the ring may be substituted with 0 to
3
R3 groups.
In a specific embodiment of the invention RX is of the formula:
R2
Y2c
'--1 RY
Y1a
wherein Yla is 0 or S; and YZc is 0, N(R}') or S.
In a specific embodiment of the invention R" is of the formula:
R2
2d
Ry
1.
yla
wherein Yla is 0 or S; and y2d is 0 or N(RY).
In a specific embodiment of the invention R" is of the formula:
R2
Ry
O
In a specific embodiment of the invention Ry is hydrogen or alkyl of 1 to
10 carbons.
In a specific embodiment of the invention R" is of the formula:
R2
O R2
O
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In a specific embodiment of the invention R' is of the formula:
R2 R Ry
Y2 Y 1 y2
M12a
In a specific embodiment of the invention R" is of the formula:
R2 R
Y2
Ry
M 12a
Y
In a specific embodiment of the invention Y' is 0 or S.
In a specific embodiment of the invention Y2 is 0, N(R}') or S.
In one specific embodiment of the invention R" is a group of the formula:
Y rRY\IR Y1
RY
jy2 Y2 Y2
M1a M1b M12c M1c M1d M1e
wherein:
m l a, m l b, m l c, m l d and m l e are independently 0 or 1;
ml2cis0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
RY is H, W3, R 2 or a protecting group;
provided that:
if m l a, m l 2c, and m l d are 0, then m l b, m l c and m l e are 0;
if m 1 a and m 12c are 0 and m l d is not 0, then m l b and m 1 c are 0;
if m 1 a and m l d are 0 and m l 2c is not 0, then m l b and at least one of
m l c and m l e are 0;
if m1a is 0 and m12c and m1d are not 0, then m1b is 0;
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if m12c and mld are 0 and mla is not 0, then at least two of mlb, mlc
and mle are 0;
if m l 2c is 0 and ml a and m l d are not 0, then at least one of m l b and
m l c are 0; and
if m 1 d is 0 and m l a and m l 2c are not 0, then at least one of m l c and
mle are 0.
In compounds of the invention W5 carbocycles and W5 heterocycles may
be independently substituted with 0 to 3 R2 groups. W5 may be a saturated,
unsaturated or aromatic ring comprising a mono- or bicyclic carbocycle or
heterocycle. W5 may have 3 to 10 ring atoms, e.g., 3 to 7 ring atoms. The W5
rings are saturated when containing 3 ring atoms, saturated or mono-
unsaturated
when containing 4 ring atoms, saturated, or mono- or di-unsaturated when
containing 5 ring atoms, and saturated, mono- or di-unsaturated, or aromatic
when containing 6 ring atoms.
A W5 heterocycle may be a monocycle having 3 to 7 ring members (2 to
6 carbon atoms and 1 to 3 heteroatoms selected from N, 0, P, and S) or a
bicycle
having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3 heteroatoms
selected from N, 0, P, and S). W5 heterocyclic monocycles may have 3 to 6 ring
atoms (2 to 5 carbon atoms and 1 to 2 heteroatoms selected from N, 0, and S);
or
5 or 6 ring atoms (3 to 5 carbon atoms and 1 to 2 heteroatoms selected from N
and S). W5 heterocyclic bicycles have 7 to 10 ring atoms (6 to 9 carbon atoms
an d 1 to 2 heteroatoms selected from N, 0, and S) arranged as a bicyclo
[4,5],
[5,5], [5,6], or [6,6] system; or 9 to 10 ring atoms (8 to 9 carbon atoms and
1 to 2
hetero atoms selected from N and S) arranged as a bicyclo [5,6] or [6,6]
system.
The W5 heterocycle may be bonded to Y2 through a carbon, nitrogen, sulfur or
other atom by a stable covalent bond.
W5 heterocycles include for example, pyridyl, dihydropyridyl isomers,
piperidine, pyridazinyl, pyrimidinyl, pyrazinyl, s-triazinyl, oxazolyl,
imidazolyl,
thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, furanyl, thiofuranyl, thienyl,
and
pyrrolyl. W5 also includes, but is not limited to, examples such as:
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N
\ I / I
N ~ ~ , / N
CH
~N H
S <N N
N S ~/~
and \~-S
W5 carbocycles and heterocycles may be independently substituted with
0 to 3 R2 groups, as defined above. For example, substituted W5 carbocycles
include:
OH
CI
N
1 1 ~H l
\ / \ /
ci
/-~
N0 NHz
1 \ N
NH l NH l-N NH
l-N O 1-N SH I -N SO2
Examples of substituted phenyl carbocycles include:
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HN--\-NHZ ~--NHZ S3N_>._NMe2
O
1 ~ ~
O O O~
O O
~NH
~ ~-N H2
~ ~-NH2 O
NHZ O
1 ~ ~
Linkin Groups and Linkers
The invention provides conjugates that comprise a kinase inhibiting
compound that is linked to one or more phosphonate groups either directly
(e.g.
through a covalent bond) or through a linking group (i.e. a linker). The
nature of
the linker is not critical provided it does not interfere with the ability of
the
phosphonate containing compound to function as a therapeutic agent. The
phosphonate or the linker can be linked to the compound at any synthetically
feasible position on the compound by removing a hydrogen or any portion of the
compound to provide an open valence for attachment of the phosphonate or the
linker.
In one embodiment of the invention the linking group or linker (which
can be designated "L") can include all or a portions of the group A , A', or
W3
described herein.
In another embodiment of the invention the linking group or linker has a
molecular weight of from about 20 daltons to about 400 daltons.
In another embodiment of the invention the linking group or linker has a
length of about 5 angstroms to about 300 angstroms.
In another embodiment of the invention the linking group or linker
separates the DRUG and a P(=Y1) residue by about 5 angstroms to about 200
angstroms, inclusive, in length.
. In another embodiment of the invention the linking group or linker is a
divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain,
having from 2 to 25 carbon atoms, wherein one or more (e.g. 1, 2, 3, or 4) of
the
carbon atoms is optionally replaced by (-0-), and wherein the chain is
optionally
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substituted on carbon with one or more (e.g. 1, 2, 3, or 4) substituents
selected
from (CI-C6)alkoxy, (C3-C6)cycloalkyl, (CI-C6)alkanoyl, (CI-C6)alkanoyloxy,
(C1-C6)alkoxycarbonyl, (C1-C6)alkylthio, azido, cyano, nitro, halo, hydroxy,
oxo (=0), carboxy, aryl, aryloxy, heteroaryl, and heteroaryloxy.
In another embodiment of the invention the linking group or linker is of
the formula W-A wherein A is (C I -C24)alkyl, (C2-C24)alkenyl, (C2-
C24)alkynyl,
(C3-Cg)cycloalkyl, (C6-Clo)aryl or a combination thereof, wherein W is -
N(R)C(=0)-, -C(=0)N(R)-, -OC(=0)-, -C(=0)O-, -0-, -S-, -S(O)-, -S(0)2-, -
N(R)-, -C(=O)-, or a direct bond; wherein each R is independently H or (C1-
C6)alkyl.
In another embodiment of the invention the linking group or linker is a
divalent radical formed from a peptide.
In another embodiment of the invention the linking group or linker is a
divalent radical formed from an amino acid.
In another embodiment of the invention the linking group or linker is a
divalent radical formed from poly-L-glutamic acid, poly-L-aspartic acid, poly-
L-
histidine, poly-L-ornithine, poly-L-serine, poly-L-threonine, poly-L-tyrosine,
poly-L-leucine, poly-L-lysine-L-phenylalanine, poly-L-lysine or poly-L-lysine-
L-tyrosine.
In another embodiment of the invention the linking group or linker is of
the formula W-(CH2)õ wherein, n is between about 1 and about 10; and W is -
N(R)C(=0)-, -C(=0)N(R)-, -OC(=0)-, -C(=0)O-, -0-, -S-, -S(O)-, -S(0)2-,
-
C(=0)-, -N(R)-, or a direct bond; wherein each R is independently H or (CI-
C6)alkyl.
In another embodiment of the invention the linking group or linker is
methylene, ethylene, or propylene.
In another embodiment of the invention the linking group or linker is
attached to the phosphonate group through a carbon atom of the linker.
Intracellular Targeting
The phosphonate group of the compounds of the invention may cleave in
vivo in stages, e.g., after they have reached the desired site of action, i.e.
inside a
cell. One mechanism of action inside a cell may entail a first cleavage, e.g.
by
esterase, to provide a negatively-charged "locked-in" intermediate. Cleavage
of
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a terminal ester grouping in a compound of the invention thus affords an
unstable intermediate which releases a negatively charged "locked in"
intermediate.
After passage inside a cell, intracellular enzymatic cleavage or
modification of the phosphonate or prodrug compound may result in an
intracellular accumulation of the cleaved or modified compound by a "trapping"
mechanism. The cleaved or modified compound may then be "locked-in" the
cell by a significant change in charge, polarity, or other physical property
change
which decreases the rate at which the cleaved or modified compound can exit
the
cell, relative to the rate at which it entered as the phosphonate prodrug.
Other
mechanisms by which a therapeutic effect is achieved may be operative as well.
Enzymes which are capable of an enzymatic activation mechanism with the
phosphonate prodrug compounds of the invention include, but are not limited
to,
amidases, esterases, microbial enzymes, phospholipases, cholinesterases, and
phosphatases.
From the foregoing, it will be apparent that many different drugs can be
derivatized in accord with the present invention. Numerous such drugs are
specifically mentioned herein. However, it should be understood that the
discussion of drug families and their specific members for derivatization
according to this invention is not intended to be exhaustive, but merely
illustrative.
Kinase-Inhibitory Compounds
The compounds of the invention include those with kinase-inhibitory
activity. The compounds of the inventions bear one or more (e.g. 1, 2, 3, or
4)
phosphonate groups, which may be a prodrug moiety.
The term "kinase-inhibitory compound" includes those compounds that
inhibit the activity of at least one kinase. In particular, the compounds
include
PD 173955, PD 166326, and PD 173074; as well as, Iressa, Tarceva, MLN-518,
ZD-6474 and Canertib; PD-0325901; BMS-354825; CP-547,632; and
Semaxanib, SU-1 1248, and GW 9499.
Typically, compounds of the invention have a molecular weight of from
about 400 amu to about 10,000 amu; in a specific embodiment of the invention,
compounds have a molecular weight of less than about 5000 amu; in another
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specific embodiment of the invention, compounds have a molecular weight of
less than about 2500 amu; in another specific embodiment of the invention,
compounds have a molecular weight of less than about 1000 amu; in another
specific embodiment of the invention, compounds have a molecular weight of
less than about 800 amu; in another specific embodiment of the invention,
compounds have a molecular weight of less than about 600 amu; and in another
specific embodiment of the invention, compounds have a molecular weight of
less than about 600 amu and a molecular weight of greater than about 400 amu.
The compounds of the invention also typically have a logD (polarity) less
than about 5. In one embodiment the invention provides compounds having a
logD less than about 4; in another embodiment the invention provides
compounds having a logD less than about 3; in another embodiment the
invention provides compounds having a logD greater than about -5; in another
embodiment the invention provides compounds having a logD greater than
about -3; and in another embodiment the invention provides compounds having
a logD greater than about 0 and less than about 3.
Selected substituents within the compounds of the invention are present
to a recursive degree. In this context, "recursive substituent" means that a
substituent may recite another instance of itself. Because of the recursive
nature
of such substituents, theoretically, a large number may be present in any
given
embodiment. For example, R' contains a RY substituent. RY can be R 2, which in
turn can be R3. If R3 is selected to be R3c, then a second instance of R' can
be
selected. One of ordinary skill in the art of medicinal chemistry understands
that
the total number of such substituents is reasonably limited by the desired
properties of the compound intended. Such properties include, by way of
example and not limitation, physical properties such as molecular weight,
solubility or log P, application properties such as activity against the
intended
target, and practical properties such as ease of synthesis.
By way of example and not limitation, W3, Ry and R3 are all recursive
substituents in certain embodiments. Typically, each of these may
independently occur 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5,
4, 3,
2, 1, or 0, times in a given embodiment. More typically, each of these may
independently occur 12 or fewer times in a given embodiment. More typically
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yet, W3 will occur 0 to 8 times, Ry will occur 0 to 6 times and R3 will occur
0 to
times in a given embodiment. Even more typically, W3 will occur 0 to 6
times, Ry will occur 0 to 4 times and R3 will occur 0 to 8 times in a given
embodiment.
5 Recursive substituents are an intended aspect of the invention. One of
ordinary skill in the art of medicinal chemistry understands the versatility
of
such substituents. To the degree that recursive substituents are present in an
embodiment of the invention, the total number will be determined as set forth
above.
10 Whenever a compound described herein is substituted with more than
one of the same designated group, e.g., "Rl" or "Rba", then it will be
understood
that the groups may be the same or different, i.e., each group is
independently
selected. Wavy lines indicate the site of covalent bond attachments to the
adjoining groups, moieties, or atoms.
15. In one embodiment of the invention, the compound is in an isolated and
purified form. Generally, the term "isolated and purified" means that the
compound is substantially free from biological materials (e.g. blood, tissue,
cells,
etc.). In one specific embodiment of the invention, the term means that the
compound or conjugate of the invention is at least about 50 wt.% free from
biological materials; in another specific embodiment, the term means that the
compound or conjugate of the invention is at least about 75 wt.% free from
biological materials; in another specific embodiment, the term means that the
compound or conjugate of the invention is at least about 90 wt.% free from
biological materials; in another specific embodiment, the term means that the
compound or conjugate of the invention is at least about 98 wt.% free from
biological materials; and in another embodiment, the term means that the
compound or conjugate of the invention is at least about 99 wt.% free from
biological materials. In another specific embodiment, the invention provides a
compound or conjugate of the invention that has been synthetically prepared
(e.g., ex vivo).
In one embodiment of the invention, the compound is not an anti-
inflammatory compound; in another embodiment the compound is not an anti-
infective; in another embodiment the compound is not a compound that is active
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against immune-mediated conditions; in another embodiment the compound is
not a compound that is active against metabolic diseases; in another
embodiment
the compound is not an antiviral agent; in another embodiment the compound is
not a nucleoside; in another embodiment the compound is not a IIVIPDH
inhibitor; in another embodiment the compound is not an antimetabolite; in
another embodiment the compound is not a PNP inhibitor; in another
embodiment the compound inhibits a serine/threonine kinase, tyrosine kinase,
Bcr-Abl kinase, cyclin-dependent kinase, F1t3 tyrosine kinase, MAP Erk kinase,
JAK3 kinase, VEGF receptor kinase, PDGF receptor tyrosine kinase, protein
kinase C, insulin receptor tyrosine kinase, or an EGF receptor tyrosine
kinase; in
another embodiment the compound is not Gefitinib, imatinib, erlotinib,
vatalanib, alvocidib, CEP-701, GLEEVEC, midostaurin, MLN-518, PD-184352,
doramapimod, BAY-43-9006, or CP-690,550 substituted with one or more
phosphonates.
Cellular Accumulation
In one embodiment, the invention is provides compounds capable of
accumulating in human PBMC (peripheral blood mononuclear cells). PBMC
refer to blood cells having round lymphocytes and monocytes. Physiologically,
PBMC are critical components of the mechanism against infection. PBMC may
be isolated from heparinized whole blood of normal healthy donors or buffy
coats, by standard density gradient centrifugation and harvested from the
interface, washed (e.g. phosphate-buffered saline) and stored in freezing
medium. PBMC may be cultured in multi-well plates. At various times of
culture, supematant may be either removed for assessment, or cells may be
harvested and analyzed (Smith R. etal (2003) Blood 102(7):2532-2540). The
compounds of this embodiment may further comprise a phosphonate or
phosphonate prodrug. More typically, the phosphonate or phosphonate prodrug
can have the structure A3 as described herein.
Typically, compounds of the invention demonstrate improved
intracellular half-life of the compounds or intracellular metabolites of the
compounds in human PBMC when compared to analogs of the compounds not
having the phosphonate or phosphonate prodrug. Typically, the half-life is
improved by at least about 50%; more typically at least in the range 50-100%;
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still more typically at least about 100%; more typically yet greater than
about
100%.
In some embodiments of the invention the intracellular half-life of a
metabolite of the compound in human PBMCs is improved when compared to an
analog of the compound not having the phosphonate or phosphonate prodrug. In
such embodiments, the metabolite may be generated intracellularly, e.g.
generated within human PBMC. The metabolite may be a product of the
cleavage of a phosphonate prodrug within human PBMCs. The phosphonate
prodrug may be cleaved to form a metabolite having at least one negative
charge
at physiological pH. The phosphonate prodrug may be enzymatically cleaved
within human PBMC to form a phosphonate having at least one active hydrogen
atom of the form P-OH.
Stereoisomers
The compounds of the invention may have chiral centers, e.g., chiral
carbon or phosphorus atoms. The compounds of the invention thus include
racemic mixtures of all stereoisomers, including enantiomers, diastereomers,
and
atropisomers. In addition, the compounds of the invention include enriched or
resolved optical isomers at any or all asymmetric, chiral atoms. In other
words,
the chiral centers apparent from the depictions are provided as the chiral
isomers
or racemic mixtures. Both racemic and diastereomeric mixtures, as well as the
.individual optical isomers isolated or synthesized, substantially free of
their
enantiomeric or diastereomeric partners, are all within the scope of the
invention.
The racemic mixtures are separated into their individual, substantially
optically
pure isomers through well-known techniques such as, for example, the
separation of diastereomeric salts formed with optically active adjuncts,
e.g.,
acids or bases followed by conversion back to the optically active substances.
In
most instances, the desired optical isomer is synthesized by means of
stereospecific reactions, beginning with the appropriate stereoisomer of the
desired starting material.
The compounds of the invention can also exist as tautomeric isomers in
certain cases. All though only one delocalized resonance structure may be
depicted, all such forms are contemplated within the scope of the invention.
For
example, ene-amine tautomers can exist for purine, pyrimidine, imidazole,
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guanidine, amidine, and tetrazole systems and all their possible tautomeric
forms
are within the scope of the invention.
Salts and Hydrates
The compositions of this invention optionally comprise salts of the
compounds herein, especially pharmaceutically acceptable non-toxic salts
containing, for example, Na+, Li+, K+, Ca+2 and Mg+2. Such salts may include
those derived by combination of appropriate cations such as alkali and
alkaline
earth metal ions or ammonium and quatemary amino ions with an acid anion
moiety, typically a carboxylic acid. Monovalent salts are preferred if a water
soluble salt is desired.
Metal salts typically are prepared by reacting the metal hydroxide with a
compound of this invention. Examples of metal salts which are prepared in this
way are salts containing Li+, Na+, and K+. A less soluble metal salt can be
precipitated from the solution of a more soluble salt by addition of the
suitable
metal compound. -
In addition, salts may be formed from acid addition of certain organic
and inorganic acids, e.g., HCI, HBr, H2SO4, H3P04 or organic sulfonic acids,
to
basic centers, typically amines, or to acidic groups. Finally, it is to be
understood that the compositions herein comprise compounds of the invention in
their un-ionized, as well as zwitterionic form, and combinations with
stoichiometric amounts of water as in hydrates.
Also included within the scope of this invention are the salts of the
parental compounds with one or more amino acids. Any of the amino acids
described above are suitable, especially the naturally-occurring amino acids
found as protein components, although the amino acid typically is one bearing
a
side chain with a basic or acidic group, e.g., lysine, arginine or glutamic
acid, or
a neutral group such as glycine, serine, threonine, alanine, isoleucine, or
leucine.
Methods of Kinase Inhibition
Another aspect of the invention relates to methods of inhibiting the
activity of at least one kinase comprising the step of treating a sample
suspected
of containing a kinase with a compound or composition of the invention.
Compounds of the invention may act as kinase inhibitors, as
intermediates for such inhibitors, or have other utilities as described
herein. The
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inhibitors will bind to at least one kinase. Compounds binding the kinase may
bind with varying degrees of reversibility. Those compounds binding
substantially irreversibly are ideal candidates for use in this method of the
invention. Once labeled, the substantially irreversibly binding compounds are
useful as probes for the detection of a kinase. Accordingly, the invention
relates
to methods of detecting at least one kinase in a sample suspected of
containing a
kinase including the steps of: treating a sample suspected of containing
kinase
with a composition including a compound of the invention bound to a label; and
observing the effect of the sample on the activity of the label. Suitable
labels are
well known in the diagnostics field and include stable free radicals,
fluorophores,
radioisotopes, enzymes, chemiluminescent groups and chromogens. The
compounds herein are labeled in conventional fashion using functional groups
such as hydroxyl or amino.
Within the context of the invention, samples suspected of containing at
least one kinase include natural or man-made materials such as living
organisms;
tissue or cell cultures; biological samples such as biological material
samples
(blood, serum, urine, cerebrospinal fluid, tears, sputum, saliva, tissue
samples,
and the like); laboratory samples; food, water, or air samples; bioproduct
samples such as extracts of cells, particularly recombinant cells synthesizing
a
desired glycoprotein; and the like. Typically the sample will be suspected of
containing a kinase. Samples can be contained in any medium including water
and organic solvent/water mixtures. Samples include living organisms such as
humans, and man made materials such as cell cultures.
The treating step of the invention comprises adding the compound or
composition of the invention to the sample or it comprises adding a precursor
of
the compound or composition to the sample. The addition step comprises any
method of administration as described above.
If desired, the activity of the kinase after application of the composition
can be observed by any method including direct and indirect methods of
detecting kinase activity. Quantitative, qualitative, and semiquantitative
methods of determining kinase activity are all contemplated. Typically one of
the screening methods described above are applied, however, any other method
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such as observation of the physiological properties of a living organism are
also
applicable.
Many organisms contain kinases. The compounds of this invention are
useful in the treatment or prophylaxis of conditions associated with kinase
activation in animals, e.g., mammals, e.g., humans.
However, in screening compounds capable of inhibiting kinase it should
be kept in mind that the results of enzyme assays may not correlate with cell
culture assays. Thus, a cell based assay should be the primary screening tool.
Screens for Kinase Inhibitors
Compositions of the invention are screened for inhibitory activity against
a kinase by any of the conventional techniques for evaluating enzyme activity.
Within the context of the invention, typically compositions are first screened
for
inhibition of kinase in vitro and compositions showing inhibitory activity are
then screened for activity in vivo. Compositions having in vitro Ki
(inhibitory
constants) of less then about 5 X 10'6 M, typically less than about 1 X 10'7 M
and preferably less than about 5 X 10-8 M are preferred for in vivo use.
Useful in vitro screens have been described, e.g., Bioorg. Med. Chem.
Lett., 2001, 11, 2775).
Pharmaceutical Formulations
The compounds of this invention can be formulated with conventional
carriers and excipients, which will be selected in accord with ordinary
practice.
Tablets will contain excipients, glidants, fillers, binders and the like.
Aqueous
formulations are prepared in sterile form, and when intended for delivery by
other than oral administration generally will be isotonic. All formulations
will
optionally contain excipients such as those set forth in the Handbook of
Pharmaceutical Excipients (1986). Excipients include ascorbic acid and other
antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin,
hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like.
The pH of the formulations ranges from about 3 to about 11, but is ordinarily
about 7 to 10.
While it is possible for the active ingredients to be administered alone, it
may be preferable to present them as pharmaceutical formulations. The
formulations, both for veterinary and for human use, of the invention comprise
at
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least one active ingredient, as above defined, together with one or more
acceptable carriers therefor and optionally other therapeutic ingredients. The
carrier(s) must be "acceptable" in the sense of being compatible with the
other
ingredients of the formulation and physiologically innocuous to the recipient
thereof.
The formulations include those suitable for the foregoing administration
routes. The formulations may conveniently be presented in unit dosage form and
may be prepared by any of the methods well known in the art of pharmacy.
Techniques and formulations generally are found in Remington's Pharmaceutical
Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of
bringing into association the active ingredient with the carrier which
constitutes
one or more accessory ingredients. In general the formulations are prepared by
uniformly and intimately bringing into association the active ingredient with
liquid carriers or finely divided solid carriers or both, and then, if
necessary,
shaping the product.
Formulations of the present invention suitable for oral administration
may be presented as discrete units such as capsules, cachets or tablets each
containing a predetermined amount of the active ingredient; as a powder or
granules; as a solution or a suspension in an aqueous or non-aqueous liquid;
or
as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The
active
ingredient may also be administered as a bolus, electuary or paste.
A tablet is made by compression or molding, optionally with one or more
accessory ingredients. Compressed tablets may be prepared by compressing in a
suitable machine the active ingredient in a free-flowing form such as a powder
or
granules, optionally mixed with a binder, lubricant, inert diluent,
preservative,
surface active or dispersing agent. Molded tablets may be made by molding in a
suitable machine a mixture of the powdered active ingredient moistened with an
inert liquid diluent. The tablets may optionally be coated or scored and
optionally are formulated so as to provide slow or controlled release of the
active
ingredient therefrom.
For administration to the eye or other external tissues e.g., mouth and
skin, the formulations are preferably applied as a topical ointment or cream
containing the active ingredient(s) in an amount of, for example, 0.075 to 20%
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w/w (including active ingredient(s) in a range between 0.1 % and 20% in
increments of 0:1 % w/w such as 0.6% w/w, 0.7% w/w, etc.), preferably 0.2 to
15% w/w and most preferably 0.5 to 10% w/w. When formulated in an
ointment, the active ingredients may be employed with either a paraffinic or a
water-miscible ointment base. Alternatively, the active ingredients may be
formulated in a cream with an oil-in-water cream base.
If desired, the aqueous phase of the cream base may include, for
example, at least 30% w/w of a polyhydric alcohol, i.e. an alcohol having two
or
more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol,
sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures
thereo~ The topical formulations may desirably include a compound which
enhances absorption or penetration of the active ingredient through the skin
or
other affected areas. Examples of such dermal penetration enhancers include
dimethyl sulphoxide and related analogs.
The oily phase of the emulsions of this invention may be constituted
from known ingredients in a known manner. While the phase may comprise
merely an emulsifier (otherwise known as an emulgent), it desirably comprises
a
mixture of at least one emulsifier with a fat or an oil or with both a fat and
an oil.
Preferably, a hydrophilic emulsifier is included together with a lipophilic
emulsifier which acts as a stabilizer. It is also preferred to include both an
oil
and a fat. Together, the emulsifier(s) with or without stabilizer(s) make up
the
so-called emulsifying wax, and the wax together with the oil and fat make up
the
so-called emulsifying ointment base which forms the oily dispersed phase of
the
cream formulations.
Emulgents and emulsion stabilizers suitable for use in the formulation of
the invention include Tween 60, Span 80, cetostearyl alcohol, benzyl
alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate.
The choice of suitable oils or fats for the formulation is based on
achieving the desired cosmetic properties. The cream should preferably be a
non-greasy, non-staining and washable product with suitable consistency to
avoid leakage from tubes or other containers. Straight or branched chain, mono-
or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene
glycol
diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl
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palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain
esters known as Crodamol CAP may be used, the last three being preferred
esters. These may be used alone or in combination depending on the properties
required. Alternatively, high melting point lipids such as white soft paraffin
and/or liquid paraffin or other mineral oils are used.
Pharmaceutical formulations according to the present invention comprise
one or more compounds of the invention together with one or more
pharmaceutically acceptable carriers or excipients and optionally other
therapeutic agents. Pharmaceutical formulations containing the active
ingredient
may be in any form suitable for the intended method of administration. When
used for oral use for example, tablets, troches, lozenges, aqueous or oil
suspensions, dispersible powders or granules, emulsions, hard or soft
capsules,
syrups or elixirs may be prepared. Compositions intended for oral use may be
prepared according to any method known to the art for the manufacture of
pharmaceutical compositions and such compositions may contain one or more
agents including sweetening agents, flavoring agents, coloring agents and
preserving agents, in order to provide a palatable preparation. Tablets
containing
the active ingredient in admixture with non-toxic pharmaceutically acceptable
excipient which are suitable for manufacture of tablets are acceptable. These
excipients may be, for example, inert diluents, such as calcium or sodium
carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone,
calcium or sodium phosphate; granulating and disintegrating agents, such as
maize starch, or alginic acid; binding agents, such as cellulose,
microcrystalline
cellulose, starch, gelatin or acacia; and lubricating agents, such as
magnesium
stearate, stearic acid or talc. Tablets may be uncoated or may be coated by
known techniques including microencapsulation to delay disintegration and
adsorption in the gastrointestinal tract and thereby provide a sustained
action
over a longer period. For example, a time delay material such as glyceryl
monostearate or glyceryl distearate alone or with a wax may be employed.
Formulations for oral use may be also presented as hard gelatin capsules
where the active ingredient is mixed with an inert solid diluent, for example
calcium phosphate or kaolin, or as soft gelatin capsules wherein the active
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ingredient is mixed with water or an oil medium, such as peanut oil, liquid
paraffin or olive oil.
Aqueous suspensions of the invention contain the active materials in
admixture with excipients suitable for the manufacture of aqueous suspensions.
Such excipients include a suspending agent, such as sodium
carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose,
sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and
dispersing or wetting agents such as a naturally occurring phosphatide (e.g.,
lecithin), a condensation product of an alkylene oxide with a fatty acid
(e.g.,
polyoxyethylene stearate), a condensation product of ethylene oxide with a
long
chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation
product of ethylene oxide with a partial ester derived from a fatty acid and a
hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous
suspension may also contain one or more preservatives such as ethyl or n-
propyl
p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents
and one or more sweetening agents, such as sucrose or saccharin.
Oil suspensions may be formulated by suspending the active ingredient
in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil,
or in a
mineral oil such as liquid paraffin. The oral suspensions may contain a
thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening
agents, such as those set forth above, and flavoring agents may be added to
provide a palatable oral preparation. These compositions may be preserved by
the addition of an antioxidant such as ascorbic acid.
Dispersible powders and granules of the invention suitable for
preparation of an aqueous suspension by the addition of water provide the
active
ingredient in admixture with a dispersing or wetting agent, a suspending
agent,
and one or more preservatives. Suitable dispersing or wetting agents and
suspending agents are exemplified by those disclosed above. Additional
excipients, for example sweetening, flavoring and coloring agents, may also be
present.
The pharmaceutical compositions of the invention may also be in the
form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as
olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture
of
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these. Suitable emulsifying agents include naturally=occurring gums, such as
gum acacia and gum tragacanth, naturally occurring phosphatides, such as
soybean lecithin, esters or partial esters derived from fatty acids and
hexitol
anhydrides, such as sorbitan monooleate, and condensation products of these
partial esters with ethylene oxide, such as polyoxyethylene sorbitan
monooleate.
The emulsion may also contain sweetening and flavoring agents. Syrups and
elixirs may be formulated with sweetening agents, such as glycerol, sorbitol
or
sucrose. Such formulations may also contain a demulcent, a preservative, a
flavoring or a coloring agent.
The pharmaceutical compositions of the invention may be in the form of
a sterile injectable preparation, such as a sterile injectable aqueous or
oleaginous
suspension. This suspension may be formulated according to the known art using
those suitable dispersing or wetting agents and suspending agents which have
been mentioned above. The sterile injectable preparation may also be a sterile
injectable solution or suspension in a non-toxic parenterally acceptable
diluent or
solvent, such as a solution in 1,3-butane-diol or prepared as a lyophilized
powder. Among the acceptable vehicles and solvents that may be employed are
water, Ringer's solution and isotonic sodium chloride solution. In addition,
sterile fixed oils may conventionally be employed as a solvent or suspending
medium. For this purpose any bland fixed oil may be employed including
synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid
may
likewise be used in the preparation of injectables.
The amount of active ingredient that may be combined with the carrier
material to produce a single dosage form will vary depending upon the host
treated and the particular mode of administration. For example, a time-release
formulation intended for oral administration to humans may contain
approximately 1 to 1000 mg of active material compounded with an appropriate
and convenient amount of carrier material which may vary from about 5 to about
95% of the total compositions (weight:weight). The pharmaceutical composition
can be prepared to provide easily measurable amounts for administration. For
example, an aqueous solution intended for intravenous infusion may contain
from about 3 to 500 g of the active ingredient per milliliter of solution in
order
that infusion of a suitable volume at a rate of about 30 mL/hr can occur.
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Formulations suitable for administration to the eye include eye drops
wherein the active ingredient is dissolved or suspended in a suitable carrier,
especially an aqueous solvent for the active ingredient. The active ingredient
is
preferably present in such formulations in a concentration of 0.5 to 20%,
advantageously 0.5 to 10% particularly about 1.5% w/w.
Formulations suitable for topical administration in the mouth include
lozenges comprising the active ingredient in a flavored basis, usually sucrose
and acacia or tragacanth; pastilles comprising the active ingredient in an
inert
basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes
comprising the active ingredient in a suitable liquid carrier.
Formulations for rectal administration may be presented as a suppository
with a suitable base comprising for example cocoa butter or a salicylate.
Formulations suitable for intrapulmonary or nasal administration have a
particle size for example in the range of 0.1 to 500 microns (including
particle
sizes in a range between 0.1 and 500 microns in increments microns such as
0.5,
1, 30 microns, 35 microns, etc.), which is administered by rapid inhalation
through the nasal passage or by inhalation through the mouth so as to reach
the
alveolar sacs. Suitable formulations include aqueous or oily solutions of the
active ingredient. Formulations suitable for aerosol or dry powder
administration may be prepared according to conventional methods and may be
delivered with other therapeutic agents such as compounds heretofore used in
the
treatment or prophylaxis of conditions associated with kinase activity.
Formulations suitable for vaginal administration may be presented as
pessaries, tampons, creams, gels, pastes, foams or spray formulations
containing
in addition to the active ingredient such carriers as are known in the art to
be
appropriate.
Formulations suitable for parenteral administration include aqueous and
non-aqueous sterile injection solutions which may contain anti-oxidants,
buffers,
bacteriostats and solutes which render the formulation isotonic with the blood
of
the intended recipient; and aqueous and non-aqueous sterile suspensions which
may include suspending agents and thickening agents.
The formulations are presented in unit-dose or multi-dose containers, for
example sealed ampoules and vials, and may be stored in a freeze-dried
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(lyophilized) condition requiring only the addition of the sterile liquid
carrier, for
example water for injection, immediately prior to use. Extemporaneous
injection.solutions and suspensions are prepared from sterile powders,
granules
and tablets of the kind previously described. Preferred unit dosage
formulations
are those containing a daily dose or unit daily sub-dose, as herein above
recited,
or an appropriate fraction thereof, of the active ingredient.
It should be understood that in addition to the ingredients particularly
mentioned above the formulations of this invention may include other agents
conventional in the art having regard to the type of formulation in question,
for
example those suitable for oral administration may include flavoring agents.
The invention further provides veterinary compositions comprising at
least one active ingredient as above defined together with a veterinary
carrier
therefor.
Veterinary carriers are materials useful for the purpose of administering
the composition and may be solid, liquid or gaseous materials which are
otherwise inert or acceptable in the veterinary art and are compatible with
the
active ingredient. These veterinary compositions may be administered orally,
parenterally or by any other desired route.
Compounds of the invention can also be formulated to provide controlled
release of the active ingredient to allow less frequent dosing or to improve
the
pharmacokinetic or toxicity profile of the active ingredient. Accordingly, the
invention also provides compositions comprising one or more compounds of the
invention formulated for sustained or controlled release.
Effective dose of active ingredient depends at least on the nature of the
condition being treated, toxicity, whether the compound is being used
prophylactically (lower doses), the method of delivery, and the pharmaceutical
formulation, and will be determined by the clinician using conventional dose
escalation studies. It can be expected to be from about 0.0001 to about 100
mg/kg body weight per day. Typically, from about 0.01 to about 10 mg/kg body
weight per day. More typically, from about .01 to about 5 mg/kg body weight
per day. More typically, from about .05 to about 0.5 mg/kg body weight per
day. For example, the daily candidate dose for an adult human of approximately
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70 kg body weight will range from 1 mg to 1000 mg, preferably between 5 mg
and 500 mg, and may take the form of single or multiple doses.
Routes of Administration
One or more compounds of the invention (herein referred to as the active
ingredients) are administered by any route appropriate to the condition to be
treated. Suitable routes include oral, rectal, nasal, topical (including
buccal and
sublingual), vaginal and parenteral (including subcutaneous, intramuscular,
intravenous, intradermal, intrathecal and epidural), and the like. It will be
appreciated that the preferred route may vary with for example the condition
of
the recipient. An advantage of compounds of some embodiments of the
invention is that they are orally bioavailable and can be dosed orally.
Combination Therapy
Active ingredients of the invention are also used in combination with
other active ingredients. Such combinations are selected based on the
condition
to be treated, cross-reactivities of ingredients and pharmaco-properties of
the
combination.
It is also possible to combine any compound of the invention with one or
more other active ingredients in a unitary dosage form for simultaneous or
sequential administration to a patient. The combination therapy may be
administered as a simultaneous or sequential regimen. When administered
sequentially, the combination may be administered in two or more
administrations.
The combination therapy may provide "synergy" and at least one
"synergistic effect", i.e. an effect achieved when the active ingredients used
together is greater than the sum of the effects that results from using the
compounds separately. A synergistic effect may be attained when the active
ingredients are: (1) co-formulated and administered or delivered
simultaneously
in a combined formulation; (2) delivered by alternation or in parallel as
separate
formulations; or (3) by some other regimen. When delivered in alternation
therapy, a synergistic effect may be attained when the compounds are
administered or delivered sequentially, e.g., in separate tablets, pills or
capsules,
or by different injections in separate syringes. In general, during
alternation
therapy, an effective dosage of each active ingredient is administered
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sequentially, i.e. serially, whereas in combination therapy, effective dosages
of
two or more active ingredients are administered together.
Metabolites of the Compounds of the Invention
Also falling within the scope of this invention are the metabolic products,
e.g., in vivo metabolic products, of the compounds described herein. Such
products may result, e.g., from the oxidation, reduction, hydrolysis,
amidation,
esterification and the like of the administered compound, primarily due to
enzymatic processes. Accordingly, the invention includes compounds produced
by a process comprising contacting a compound of this invention with a
mammal for a period of time sufficient to yield a metabolic product thereof.
Such products typically are identified by preparing a radiolabelled (e.g., C14
or
H3) compound of the invention, administering it parenterally in a detectable
dose (e.g., greater than about 0.5 mg/kg) to an animal such as rat, mouse,
guinea
pig, monkey, or to man, allowing sufficient time for metabolism to occur
(typically about 30 seconds to 30 hours) and isolating its conversion products
from the urine, blood or other biological samples. These products are easily
isolated since they are labeled (others are isolated by the use of antibodies
capable of binding epitopes surviving in the metabolite). The metabolite
structures are determined in conventional fashion, e.g., by MS or NMR
analysis.
In general, analysis of metabolites is done in the same way as conventional
drug
metabolism studies well-known to those skilled in the art. The conversion
products, so long as they are not otherwise found in vivo, are useful in
diagnostic
assays for therapeutic dosing of the compounds of the invention even if they
possess no kinase inhibitory activity of their own.
Recipes and methods for determining stability of compounds in surrogate
gastrointestinal secretions are known. Compounds are defined herein as stable
in the gastrointestinal tract where less than about 50 mole percent of the
protected groups are deprotected in surrogate intestinal or gastric juice upon
incubation for 1 hour at 37 C. Simply because the compounds are stable to the
gastrointestinal tract does not mean that they cannot be hydrolyzed in vivo.
The
phosphonate prodrugs of the invention typically will be stable in the
digestive
system but are substantially hydrolyzed to the parental drug in the digestive
lumen, liver or other metabolic organ, or within cells in general.
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Exemplaa Methods of Making the Compounds of the Invention.
The invention also relates to methods of making the compounds and
compositions of the invention. The compounds and compositions are prepared
by any of the applicable techniques of organic synthesis. Many such techniques
are well known in the art. However, many of the known techniques are
elaborated in Compendium of Organic Synthetic Methods (John Wiley & Sons,
New York), Vol. 1, Ian T. Harrison and Shuyen Harrison, 1971; Vol. 2, Ian T.
Harrison and Shuyen Harrison, 1974; Vol. 3, Louis S. Hegedus and Leroy Wade,
1977; Vol. 4, Leroy G. Wade, jr., 1980; Vol. 5, Leroy G. Wade, Jr., 1984; and
Vol. 6, Michael B. Smith; as well as March, J., Advanced Organic Chemistry,
Third Edition, (John Wiley & Sons, New York, 1985), Comprehensive Organic
Synthesis. Selectivity, Strategy & Efficiency in Modern Organic Chemistry. In
9 Volumes, Barry M. Trost, Editor-in-Chief (Pergamon Press, New York, 1993
printing).
A number of exemplary methods for the preparation of the compounds
and compositions of the invention are provided below. These. methods are
intended to illustrate the nature of such preparations are not intended to
limit the
scope of applicable methods.
Schemes and Examples
General aspects of these exemplary methods are described below and in
the Examples. Each of the products of the following processes is optionally
separated, isolated, and/or purified prior to its use in subsequent processes.
Generally, the reaction conditions such as temperature, reaction time,
solvents, work-up procedures, and the like, will be those common in the art
for
the particular reaction to be performed. The cited reference material,
together
with material cited therein, contains detailed descriptions of such
conditions.
Typically the temperatures will be -100 C to 200 C, solvents will be aprotic
or
protic, and reaction times will be 10 seconds to 10 days. Work-up typically
consists of quenching any unreacted reagents followed by partition between a
water/organic layer system (extraction) and separating the layer containing
the
product.
Oxidation and reduction reactions are typically carried out at
temperatures near room temperature (about 20 C), although for metal hydride
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reductions frequently the temperature is reduced to 0 C to -100 C, solvents
are
typically aprotic for reductions and may be either protic or aprotic for
oxidations.
Reaction times are adjusted to achieve desired conversions.
Condensation reactions are typically carried out at temperatures near
room temperature, although for non-equilibrating, kinetically controlled
condensations reduced temperatures (0 C to -100 C) are also common.
Solvents can be either protic (common in equilibrating reactions) or aprotic
(common in kinetically controlled reactions).
Standard synthetic techniques such as azeotropic removal of reaction by-
products and use of anhydrous reaction conditions (e.g., inert gas
environments)
are common in the art and will be applied when applicable.
The terms "treated", "treating", "treatment", and the like, when used in
connection with a chemical synthetic operation, mean contacting, mixing,
reacting, allowing to react, bringing into contact, and other terms common in
the
art for indicating that one or more chemical entities is treated in such a
manner
as to convert it to one or more other chemical entities. This means that
"treating
compound one with compound two" is synonymous with "allowing compound
one to react with compound two", "contacting compound one with compound
two", "reacting compound one with compound two", and other expressions
common in the art of organic synthesis for reasonably indicating that compound
one was "treated", "reacted", "allowed to react", etc., with compound two. For
example, treating indicates the reasonable and usual manner in which organic
chemicals are allowed to react. Normal concentrations (0.01 M to l OM,
typically
0.1M to 1M), temperatures (-100 C to 250 C, typically -78 C to 150 C, more
typically -78 C to 100 C, still more typically 0 C to 100 C), reaction
vessels
(typically glass, plastic, metal), solvents, pressures, atmospheres (typically
air
for oxygen and water insensitive reactions or nitrogen or argon for oxygen or
water sensitive), etc., are intended unless otherwise indicated. The knowledge
of
similar reactions known in the art of organic synthesis are used in selecting
the
conditions and apparatus for "treating" in a given process. In particular, one
of
ordinary skill in the art of organic synthesis selects conditions and
apparatus
reasonably expected to successfully carry out the chemical reactions of the
described processes based on the knowledge in the art.
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Modifications of each of the exemplary schemes and in the examples
(hereafter "exemplary schemes") leads to various analogs of the specific
exemplary materials produced. The above-cited citations describing suitable
methods of organic synthesis are applicable to such modifications.
In each of the exemplary schemes it may be advantageous to separate
reaction products from one another and/or from starting materials. The desired
products of each step or series of steps is separated and/or purified
(hereinafter
separated) to the desired degree of homogeneity by the techniques common in
the art. Typically such separations involve multiphase extraction,
crystallization
from a solvent or solvent mixture, distillation, sublimation, or
chromatography.
Chromatography can involve any number of methods including, for example:
reverse-phase and normal phase; size exclusion; ion exchange; high, medium,
and low pressure liquid chromatography methods and apparatus; small scale
analytical; simulated moving bed (SMB) and preparative thin or thick layer
chromatography, as well as techniques of small scale thin layer and flash
chromatography.
Another class of separation methods involves treatment of a mixture with
a reagent selected to bind to or render otherwise separable a desired product,
unreacted starting material, reaction by product, or the like. Such reagents
include adsorbents or absorbents such as activated carbon, molecular sieves,
ion
exchange media, or the like. Alternatively, the reagents can be acids in the
case
of a basic material, bases in the case of an acidic material, binding reagents
such
as antibodies, binding proteins, selective chelators such as crown ethers,
liquid/liquid ion extraction reagents (LIX), or the like.
Selection of appropriate methods of separation depends on the nature of
the materials involved. For example, boiling point, and molecular weight in
distillation and sublimation, presence or absence of polar functional groups
in
chromatography, stability of materials in acidic and basic media in multiphase
extraction, and the like. One skilled in the art will apply techniques most
likely
to achieve the desired separation.
A single stereoisomer, e.g., an enantiomer, substantially free of its
stereoisomer may be obtained by resolution of the racemic mixture using a
method such as formation of diastereomers using optically active resolving
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agents (Stereochemistry of Carbon Compounds, (1962) by E. L. Eliel, McGraw
Hill; Lochmuller, C. H., (1975) J. Chromatogr., 113:(3) 283-302). Racemic
mixtures of chiral compounds of the invention can be separated and isolated by
any suitable method, including: (1) formation of ionic, diastereomeric salts
with
chiral compounds and separation by fractional crystallization or other
methods,
(2) formation of diastereomeric compounds with chiral derivatizing reagents,
separation of the diastereomers, and conversion to the pure stereoisomers, and
(3) separation of the substantially pure or enriched stereoisomers directly
under
chiral conditions.
Under method (1), diastereomeric salts can be formed by reaction of
enantiomerically pure chiral bases such as brucine, quinine, ephedrine,
strychnine, a-methyl-(3-phenylethylamine (amphetamine), and the like with
asymmetric compounds bearing acidic functionality, such as carboxylic acid and
sulfonic acid. The diastereomeric salts may be induced to separate by
fractional
crystallization or ionic chromatography. For separation of the optical isomers
of
amino compounds, addition of chiral carboxylic or sulfonic acids, such as
camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can result
in
formation of the diastereomeric salts.
Alternatively, by method (2), the substrate to be resolved is reacted with
one enantiomer of a chiral compound to form a diastereomeric pair (Eliel, E.
and
Wilen, S. (1994) Stereochemistry of Organic Compounds, John Wiley & Sons,
Inc., p. 322). Diastereomeric compounds can be formed by reacting asymmetric
compounds with enantiomerically pure chiral derivatizing reagents, such as
menthyl derivatives, followed by separation of the diastereomers and
hydrolysis
to yield the free, enantiomerically enriched xanthene. A method of determining
optical purity involves making chiral esters, such as a menthyl ester, e.g., (-
)
menthyl chloroformate in the presence of base, or Mosher ester, a-methoxy-a-
(trifluoromethyl)phenyl acetate (Jacob III. (1982) J. Org. Chem. 47:4165), of
the
racemic mixture, and analyzing the NMR spectrum for the presence of the two
atropisomeric diastereomers. Stable diastereomers of atropisomeric compounds
can be separated and isolated by normal- and reverse-phase chromatography
following methods for separation of atropisomeric naphthyl-isoquinolines
(Hoye, T., WO 96/15111). By method (3), a racemic mixture of two
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enantiomers can be separated by chromatography using a chiral stationary phase
(Chiral Liquid Chromatography (1989) W. J. Lough, Ed. Chapman and Hall,
New York; Okamoto, (1990) J. of Chromatogr. 513:375-378). Enriched or
purified enantiomers can be distinguished by methods used to distinguish other
chiral molecules with asymmetric carbon atoms, such as optical rotation and
circular dichroism.
Examples General Section
A number of exemplary methods for the preparation of compounds of the
invention are provided herein, for example, in the Examples hereinbelow. These
methods are intended to illustrate the nature of such preparations are not
intended to limit the scope of applicable methods. Certain compounds of the
invention can be used as intermediates for the preparation of other compounds
of
the invention. For example, the interconversion of various phosphonate
compounds of the invention is illustrated below.
Interconversions of the phosphonates R-link-P(O)(OR'),, R-link-
P(O)(OR')(OH) and R-link-P(O)(OH).2.
The following schemes 32-38 describe the preparation of phosphonate
esters of the general structure R-link-P(O)(ORl)Z, in which the groups R' may
be
the same or different. The R' groups attached to a phosphonate ester, or to
precursors thereto, may be changed using established chemical transformations.
The interconversion reactions of phosphonates are illustrated in Scheme S32.
The group R in Scheme 32 represents the substructure, i.e. the drug
"scaffold",
to which the substituent link-P(O)(OR')2 is attached, either in the compounds
of
the invention, or in precursors thereto. At the point in the synthetic route
of
conducting a phosphonate interconversion, certain functional groups in R may
be
protected. The methods employed for a given phosphonate transformation
depend on the nature of the substituent Rl, and of the substrate to which the
phosphonate group is attached. The preparation and hydrolysis of phosphonate
esters is described in Organic Phosphorus Compounds, G. M. Kosolapoff, L.
Maeir, eds, Wiley, 1976, p. 9ff.
In general, synthesis of phosphonate esters is achieved by coupling a
nucleophile amine or alcohol with the corresponding activated phosphonate
electrophilic precursor. For example, chlorophosphonate addition on to 5'-
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hydroxy of nucleoside is a well known method for preparation of nucleoside
phosphate monoesters. The activated precursor can be prepared by several well
known methods. Chlorophosphonates useful for synthesis of the prodrugs are
prepared from the substituted-1,3-propanediol (Wissner, et al, (1992) J. Med
Chem. 35:1650). Chlorophosphonates are made by oxidation of the
corresponding chlorophospholanes (Anderson, et al, (1984) J. Org. Chem.
49:1304) which are obtained by reaction of the substituted diol with
phosphorus
trichloride. Alternatively, the chlorophosphonate agent is made by treating
substituted-1,3-diols with phosphorusoxychloride (Patois, et al, (1990) J.
Chem.
Soc. Perkin Trans. I, 1577). Chlorophosphonate species may also be generated
in
situ from corresponding cyclic phosphites (Silverburg, et al., (1996)
Tetrahedron
lett., 37:771-774), which in turn can be either made from chlorophospholane or
phosphoramidate intermediate. Phosphoroflouridate intermediate prepared either
from pyrophosphate or phosphoric acid may also act as precursor in preparation
of cyclic prodrugs (Watanabe et al., (1988) Tetrahedron lett., 29:5763-66).
Phosphonate prodrugs of the present invention may also be prepared
from the free acid by Mitsunobu reactions (Mitsunobu, (1981) Synthesis, 1;
Campbell, (1992) J. Org. Chem. 57:633 1), and other acid coupling reagents
including, but not limited to, carbodiimides (Alexander, et al, (1994)
Collect.
Czech. Chem. Commun. 59:1853; Casara et al, (1992) Bioorg. Med. Chem. Lett.
2:145; Ohashi et al, (1988) Tetrahedron Lett., 29:1189), and
benzotriazolyloxytris-(dimetliylamino)phosphonium salts (Campagne et al
(1993) Tetrahedron Lett. 34:6743).
Aryl halides undergo Ni+2 catalyzed reaction with phosphite derivatives
to give aryl phosphonate containing compounds (Balthazar, et al (1980) J. Org.
Chem. 45:5425). Phosphonates may also be prepared from the
chlorophosphonate in the presence of a palladium catalyst using aromatic
triflates (Petrakis et al (1987) J. Am. Chem. Soc. 109:283 1; Lu et al (1987)
Synthesis 726). In another method, aryl phosphonate esters are prepared from
aryl phosphates under anionic rearrangement conditions (Melvin (1981)
Tetrahedron Lett. 22:3375; Casteel et al (1991) Synthesis, 691). N-Alkoxy aryl
salts with alkali met al derivatives of cyclic alkyl phosphonate provide
general
synthesis for heteroaryl-2-phosphonate linkers (Redmore (1970) J. Org. Chem.
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35:4114). These above mentioned methods can also be extended to compounds
where the W5 group is a heterocycle. Cyclic-1,3-propanyl prodrugs of
phosphonates are also synthesized from phosphonic diacids and substituted
propane-l,3-diols using a coupling reagent such as 1,3-
dicyclohexylcarbodiimide (DCC) in presence of a base (e.g., pyridine). Other
carbodiimide based coupling agents like 1,3-disopropylcarbodiimide or water
soluble reagent, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(EDCI) can also be utilized for the synthesis of cyclic phosphonate prodrugs.
The conversion of a phosphonate diester S32.1 into the corresponding
phosphonate monoester S32.2 (Scheme 32, Reaction 1) is accomplished by a
number of methods. For example, the ester S32.1 in which R' is an aralkyl
group
such as benzyl, is converted into the monoester compound S32.2 by reaction
with a tertiary organic base such as diazabicyclooctane (DABCO) or
quinuclidine, as described in J. Org. Chem. (1995) 60:2946. The reaction is
performed in an inert hydrocarbon solvent such as toluene or xylene, at about
110 C. The conversion of the diester S32.1 in which R' is an aryl group such
as
phenyl, or an alkenyl group such as allyl, into the monoester S32.2 is
effected by
treatment of the ester S32.1 with a base such as aqueous sodium hydroxide in
acetonitrile or lithium hydroxide in aqueous tetrahydrofuran. Phosphonate
diesters S32.1 in which one of the groups R' is aralkyl, such as benzyl, and
the
other is alkyl, is converted into the monoesters S32.2 in which R' is alkyl by
hydrogenation, for example using a palladium on carbon catalyst. Phosphonate
diesters in which both of the groups RI are alkenyl, such as allyl, is
converted
into the monoester S32.2 in which R' is alkenyl, by treatment with
chlorotris(triphenylphosphine)rhodium (Wilkinson's catalyst) in aqueous
ethanol
at reflux, optionally in the presence of diazabicyclooctane, for example by
using
the procedure described in J. Org. Chem. (1973) 3 8:3224, for the cleavage of
allyl carboxylates.
The conversion of a phosphonate diester S32.1 or a phosphonate
monoester S32.2 into the corresponding phosphonic acid S32.3 (Scheme 32,
Reactions 2 and 3) can be effected by reaction of the diester or the monoester
with trimethylsilyl bromide, as described in J. Chem. Soc., Chem. Comm.,
(1979) 739. The reaction is conducted in an inert solvent such as, for
example,
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dichloromethane, optionally in the presence of a silylating agent such as
bis(trimethylsilyl)trifluoroacetamide, at ambient temperature. A phosphonate
monoester S32.2 in which R' is aralkyl such as benzyl, is converted into the
corresponding phosphonic acid S32.3 by hydrogenation over a palladium
catalyst, or by treatment with hydrogen chloride in an ethereal solvent such
as
dioxane. A phosphonate monoester S32.2 in which R' is alkenyl such as, for
example, allyl, is converted into the phosphonic acid S32.3 by reaction with
Wilkinson's catalyst in an aqueous organic solvent, for example in 15% aqueous
acetonitrile, or in aqueous ethanol, for example using the procedure described
in
Helv. Chim. Acta. (1985) 68:618. Palladium catalyzed hydrogenolysis of
phosphonate esters S32.1 in which R' is benzyl is described in J. Org. Chem.
(1959) 24:434. Platinum-catalyzed hydrogenolysis of phosphonate esters S32.1
in which R' is phenyl is described in J. Am. Chem. Soc. (1956) 78:2336.
The conversion of a phosphonate monoester S32.2 into a phosphonate
diester S32.1 (Scheme 32, Reaction 4) in which the newly introduced R' group
is
alkyl, aralkyl, haloalkyl such as chloroethyl, or aralkyl is effected by a
number
of reactions in which the substrate S32.2 is reacted with a hydroxy compound
R'OH, in the presence of a coupling agent. Typically, the second phosphonate
ester group is different than the first introduced phosphonate ester group,
i.e. R,
is followed by the introduction of R2 where each of R' and R2 is alkyl,
aralkyl,
haloalkyl such as chloroethyl, or aralkyl (Scheme 32, Reaction 4a) whereby
S32.2 is converted to S32.1a. Suitable coupling agents are those employed for
the preparation of carboxylate esters, and include a carbodiimide such as
dicyclohexylcarbodiimide, in which case the reaction is preferably conducted
in
a basic organic solvent such as pyridine, or (benzotriazol-l-
yloxy)tripyrrolidinophosphonium hexafluorophosphate (PYBOP, Sigma), in
which case the reaction is performed in a polar solvent such as
dimethylformamide, in the presence of a tertiary organic base such as
diisopropylethylamine, or Aldrithiol-2 (Aldrich) in which case the reaction is
conducted in a basic solvent such as pyridine, in the presence of a triaryl
phosphine such as triphenylphosphine. Alternatively, the conversion of the
phosphonate monoester S32.2 to the diester S32.1 is effected by the use of the
Mitsunobu reaction, as described above (Scheme 7). The substrate is reacted
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with the hydroxy compound R1 OH, in the presence of diethyl azodicarboxylate
and a triarylphosphine such as triphenyl phosphine. Alternatively, the
phosphonate monoester S32.2 is transformed into the phosphonate diester S32.1,
in which the introduced R' group is alkenyl or aralkyl, by reaction of the
monoester with the halide R'Br, in which R' is as alkenyl or aralkyl. The
alkylation reaction is conducted in a polar organic solvent such as
dimethylformamide or acetonitrile, in the presence of a base such as cesium
carbonate. Alternatively, the phosphonate monoester is transformed into the
phosphonate diester in a two step procedure. In the first step, the
phosphonate
monoester S32.2 is transformed into the chloro analog RP(O)(ORl)Cl by
reaction with thionyl chloride or oxalyl chloride and the like, as described
in
Orszanic Phosphorus Compounds, G. M. Kosolapoff, L. Maeir, eds, Wiley, 1976,
p. 17, and the thus-obtained product RP(O)(OR')Cl is then reacted with the
hydroxy compound R' OH, in the presence of a base such as triethylamine, to
afford the phosphonate diester S32.1.
A phosphonic acid R-link-P(O)(OH)2 is transformed into a phosphonate
monoester RP(O)(OR1)(OH) (Scheme 32, Reaction 5) by means of the methods
described above of for the preparation of the phosphonate diester R-link-
P(O)(ORl)Z S32.1, except that only one molar proportion of the component
R'OH or R'Br is employed. Dialkyl phosphonates may be prepared according to
the methods of: Quast et al (1974) Synthesis 490; Stowell et al (1990)
Tetrahedron Lett. 3261; US 5663159.
A phosphonic acid R-link-P(O)(OH)2 S32.3 is transformed into a
phosphonate diester R-link-P(O)(ORl)Z S32.1 (Scheme 32, Reaction 6) by'a
coupling reaction with the hydroxy compound R'OH, in the presence of a
coupling agent such as Aldrithiol-2 (Aldrich) and triphenylphosphine. The
reaction is conducted in a basic solvent such as pyridine. Alternatively,
phosphonic acids S32.3 are transformed into phosphonic esters S32.1 in which
R' is aryl, by means of a coupling reaction employing, for example,
dicyclohexylcarbodiimide in pyridine at ca 70 C. Alternatively, phosphonic
acids S32.3 are transformed into phosphonic esters S32.1 in which R' is
alkenyl,
by means of an alkylation reaction. The phosphonic acid is reacted with the
alkenyl bromide R'Br in a polar organic solvent such as acetonitrile solution
at
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reflux temperature, the presence of a base such as cesium carbonate, to afford
the
phosphonic ester S32.1.
Scheme 32
0 O
R-link-p~ OR' ~ - R-link-P~ OR'
OR' S32.1 OH S32.2
O 2 O
R-link -p~ OR' R-Iink-P~ OH
OR1 S32.1 OH S32.3
O O
R-Iink-P~ OR' 3 = R-Iink-P~ OH
OH S32.2 OH S32.3
R-Iink-P OR' 4 R-link-P OR' OH OR1 S32.1
S32.2
O O
R-Iink-P~ OR' 4 R-Iink-p~ OR'
OH OR2 S32.1a
S32.2
0 5 0
R-Iink-P~ OH R-link-P~ OR'
OH S32.3 OH S32.2
O 6 0
R-Iink-P~ OH R-Iink-p~ OR'
OH S32.3 ORI S32.1
Preparation of phosphonate carbamates.
Phosphonate esters may contain a carbamate linkage. The preparation of
carbamates is described in Comprehensive Organic Functional Group
Transformations, A. R. Katritzky, ed., Pergamon, 1995, Vol. 6, p. 416ff, and
in
Organic Functional Group Preparations, by S. R. Sandler and W. Karo,
Academic Press, 1986, p. 260ff. The carbamoyl group may be formed by
reaction of a hydroxy group according to the methods known in the art,
including the teachings of Ellis, US 2002/0103378 Al and Hajima, US 6018049.
Scheme 33 illustrates various methods by which the carbamate linkage is
synthesized. As shown in Scheme 33, in the general reaction generating
carbamates, an alcohol S33.1, is converted into the activated derivative S33.2
in
which Lv is a leaving group such as halo, imidazolyl, benztriazolyl and the
like,
as described herein. The activated derivative S33.2 is then reacted with an
amine
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S33.3, to afford the carbamate product S33.4. Examples 1- 7 in Scheme 33
depict methods by which the general reaction is effected. Examples 8 - 10
illustrate alternative methods for the preparation of carbamates.
Scheme 33, Example 1 illustrates the preparation of carbamates
employing a chloroformyl derivative of the alcohol S33.5. In this procedure,
the
alcohol S33.5 is reacted with phosgene, in an inert solvent such as toluene,
at
about 0 C, as described in Org. Syn. Coll. Vol. 3, 167, 1965, or with an
equivalent reagent such as trichloromethoxy chloroformate, as described in
Org.
Syn. Coll. Vol. 6, 715, 1988, to afford the chloroformate S33.6. The latter
compound is then reacted with the amine component S33.3, in the presence of an
organic or inorganic base, to afford the carbamate S33.7. For example, the
chloroformyl compound S33.6 is reacted with the amine S33.3 in a water-
miscible solvent such as tetrahydrofuran, in the presence of aqueous sodium
hydroxide, as described in Org. Syn. Coll. Vol. 3, 167, 1965, to yield the
carbamate S33.7. Alternatively, the reaction is performed in dichloromethane
in
the presence of an organic base such as diisopropylethylamine or
dimethylaminopyridine.
Scheme 33, Example 2 depicts the reaction of the chloroformate
compound S33.6 with imidazole to produce the imidazolide S33.8. The
imidazolide product is then reacted with the amine S33.3 to yield the
carbamate
S33.7. The preparation of the imidazolide is performed in an aprotic solvent
such
as dichloromethane at 0 , and the preparation of the carbamate is conducted in
a
similar solvent at ambient temperature, optionally in the presence of a base
such
as dimethylaminopyridine, as described in .I. Med. Chem., 1989, 32, 357.
Scheme 33 Example 3, depicts the reaction of the chloroformate S33.6
with an activated hydroxyl compound R"OH, to yield the mixed carbonate ester
S33.10. The reaction is conducted in an inert organic solvent such as ether or
dichloromethane, in the presence of a base such as dicyclohexylamine or
triethylamine. The hydroxyl component R"OH is selected from the group of
compounds S33.19 - S33.24 shown in Scheme 33, and similar compounds. For
example, if the component R"OH is hydroxybenztriazole S33.19, N-
hydroxysuccinimide S33.20, or pentachlorophenol, S33.21, the mixed carbonate
S33.10 is obtained by the reaction of the chloroformate with the hydroxyl
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compound in an ethereal solvent in the presence of dicyclohexylamine, as
described in Can. J. Chem., 1982, 60, 976. A similar reaction in which the
component R"OH is pentafluorophenol S33.22 or 2-hydroxypyridine S33.23 is
performed in an ethereal solvent in the presence of triethylamine, as
described in
Syn., 1986, 303, and Chem. Ber. 118, 468, 1985.
Scheme 33 Example 4 illustrates the preparation of carbamates in which
an alkyloxycarbonylimidazole S33.8 is employed. In this procedure, an alcohol
S33.5 is reacted with an equimolar amount of carbonyl diimidazole S33.11 to
prepare the intermediate S33.8. The reaction is conducted in an aprotic
organic
solvent such as dichloromethane or tetrahydrofuran. The acyloxyimidazole
S33.8 is then reacted with an equimolar amount of the amine R'NHz to afford
the
carbamate S33.7. The reaction is performed in an aprotic organic solvent such
as
dichloromethane, as described in Tet. Lett., 42, 2001, 5227, to afford the
carbamate S33.7.
Scheme 33; Example 5 illustrates the preparation of carbamates by means
of an intermediate alkoxycarbonylbenztriazole S33.13. In this procedure, an
alcohol ROH is reacted at ambient temperature with an equimolar amount of
benztriazole carbonyl chloride S33.12, to afford the alkoxycarbonyl product
S33.13. The reaction is performed in an organic solvent such as benzene or
toluene, in the presence of a tertiary organic amine such as triethylamine, as
described in Synthesis., 1977, 704. The product is then reacted with the amine
RNH2 to afford the carbamate S33.7. The reaction is conducted in toluene or
ethanol, at from ambient temperature to about 80 C as described in
Synthesis.,
1977, 704.
Scheme 33, Example 6 illustrates the preparation of carbamates in which
a carbonate (R"O)2C0, S33.14, is reacted with an alcohol S33.5 to afford the
intermediate alkyloxycarbonyl intermediate S33.15. The latter reagent is then
reacted with the amine R'NHz to afford the carbamate S33.7. The procedure in
which the reagent S33.15 is derived from hydroxybenztriazole S33.19 is
described in Synthesis, 1993, 908; the procedure in which the reagent S33.15
is
derived from N-hydroxysuccinimide S33.20 is described in Tet. Lett., 1992,
2781; the procedure in which the reagent S33.15 is derived from 2-
hydroxypyridine S33.23 is described in Tet. Lett., 1991, 4251; the procedure
in
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which the reagent S33.15 is derived from 4-nitrophenol S33.24 is described in
Synthesis. 1993, 103. The reaction between equimolar amounts of the alcohol
ROH and the carbonate S33.14 is conducted in an inert organic solvent at
ambient temperature.
Scheme 33, Example 7 illustrates the preparation of carbamates from
alkoxycarbonyl azides S33.16. In this procedure, an alkyl chloroformate S33.6
is
reacted with an azide, for example sodium azide, to afford the alkoxycarbonyl
azide S33.16. The latter compound is then reacted with an equimolar amount of
the amine R'NH2 to afford the carbamate S33.7. The reaction is conducted at
ambient temperature in a polar aprotic solvent such as dimethylsulfoxide, for
example as described in Synthesis., 1982, 404.
Scheme 33, Example 8 illustrates the preparation of carbamates by means
of the reaction between an alcohol ROH and the chloroformyl derivative of an
amine S33.17. In this procedure, which is described in Synthetic Organic
Chemistry, R. B. Wagner, H. D. Zook, Wiley, 1953, p. 647, the reactants are
combined at ambient temperature in an aprotic solvent such as acetonitrile, in
the
presence of a base such as triethylamine, to afford the carbamate S33.7.
Scheme 33, Example 9 illustrates the preparation of carbamates by means
of the reaction between an alcohol ROH and an isocyanate S33.18. In this
procedure, which is described in Synthetic Organic Chemistry, R. B. Wagner, H.
D. Zook, Wiley, 1953, p. 645, the reactants are combined at ambient
temperature
in an aprotic solvent such as ether or dichloromethane and the like, to afford
the
carbamate S33.7.
Scheme 33, Example 10 illustrates the preparation of carbamates by
means of the reaction between an alcohol ROH and an amine R'NH2. In this
procedure, which is described in Chem. Lett. 1972, 373, the reactants are
combined at ambient temperature in an aprotic organic solvent such as
tetrahydrofuran, in the presence of a tertiary base such as triethylamine, and
selenium. Carbon monoxide is passed through the solution and the reaction
proceeds to afford the carbamate S33.7.
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Scheme 33. Preparation of carbamates.
General reaction
ROH , - ROCOLv R NH2 ROCONHR
S33.1 S33.2 S33.3 S33.4
Examples
R'NH2 S33.3
(1) RO H ROCOCI ROCONHR'
S33.5 S33.6 S33.7
H
N
CN~ R,O N Nz~ (2) ROH=r ROCOCI r S33.5 S33.6 O S33.8
R'NH2 S33.3 ROCONHR'
S33.7
R"OH R'NH2
(3) ROH-- ROCOCI ROCOOR'=; ROCONHR'
S33.5 S33.6 S33.9 S33.10 S33.3 S33.7
0
//'-N'k N
N IN
R-O N R'NHz S33.3
(4) ROH S33.11 r ROCONHR'
S33.5 0 S33.8 S33.7
N
N
N N
O~CI N N R'NH2 S33.3
(5) ROH ROCONHR'
S33.5 S33.12 533.130---0'R S33.7
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(6) ROH (R 02)C O ROCOR" R'NH2 ~ ROCONHR'
S33.5 S33.14 S33.15 S33.3 S33.7
(7) ROH -=- ROCOCI ROCON3
S33.5 S33.6 S33.16
R'NH2 33.3 ROCONHR'
- 33.7
(8) ROH R'NHCOCI ROCONHR'
S33.5 S33.17 S33.7
R'NCO
(9) ROH-=~ ROCONHR'
S33.5 S33.18 S33.7
(10) ROH R'NH2 ROCONHR'
S33.5 S33.3 S33.7
O OH
~ N CI CI
R"OH = (/ N N N-OH Xr
OH O CI CI
CI
S33.19 S33.20 S33.21
OH OH OH
F ~ F ~N ~
F F
F NO2
S33.22 S33.23 S33.24
Preparation of carboalkoxy-substituted phosphonate bisamidates, monoamidates,
diesters and monoesters.
A number of methods are available for the conversion of phosphonic
acids into amidates and esters. In one group of methods, the phosphonic acid
is
either converted into an isolated activated intermediate such as a phosphoryl
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chloride, or the phosphonic acid is activated in situ for reaction with an
amine or
a hydroxy compound.
The conversion of phosphonic acids into phosphoryl chlorides is
accomplished by reaction with thionyl chloride, for example as described in J.
Gen. Chem. USSR, 1983, 53, 480, Zh. Obschei Khim., 1958, 28, 1063, or J. Org.
Chem., 1994, 59, 6144, or by reaction with oxalyl chloride, as described in J.
Am. Chem. Soc., 1994, 116, 3251, or J. Org. Chem., 1994, 59, 6144, or by
reaction with phosphorus pentachloride, as described in J. Org. Chem., 2001,
66,
329; or in J. Med. Chem., 1995, 38, 1372. The resultant phosphoryl chlorides
are
then reacted with amines or hydroxy compounds in the presence of a base to
afford the amidate or ester products.
Phosphonic acids are converted into activated imidazolyl derivatives by
reaction with carbonyl diimidazole, as described in J. Chem. Soc., Chem. Comm.
(1991) 312, or Nucleosides & Nucleotides (2000) 19:1885. Activated
sulfonyloxy derivatives are obtained by the reaction of phosphonic acids with
trichloromethylsulfonyl chloride or with triisopropylbenzenesulfonyl chloride,
as
described in Tet. Lett. (1996) 7857, or Bioorg. Med. Chem. Lett. (1998) 8:663.
The activated sulfonyloxy derivatives are then reacted with amines or hydroxy
compounds to afford amidates or esters.
Alternatively, the phosphonic acid and the amine or hydroxy reactant are
combined in the presence of a diimide coupling agent. The preparation of
phosphonic amidates and esters by means of coupling reactions in the presence
of dicyclohexyl carbodiimide is described, for example, in J. Chem. Soc.,
Chem.
Comm. (1991) 312 or Coll. Czech. Chem. Comm. (1987) 52:2792. The use of
ethyl dimethylaminopropyl carbodiimide for activation and coupling of
phosphonic acids is described in Tet. Lett., (2001) 42:8841, or Nucleosides &
Nucleotides (2000) 19:1885.
A number of additional coupling reagents have been described for the
preparation of amidates and esters from phosphonic acids. The agents include
Aldrithiol-2, and PYBOP and BOP, as described in J. Org. Chem., 1995, 60,
5214, and J. Med. Chem. (1997) 40:3842, mesitylene-2-sulfonyl-3 -nitro- 1,2,4-
triazole (MSNT), as described in J. Med. Chem. (1996) 39:4958,
diphenylphosphoryl azide, as described in J. Org. Chem. (1984) 49:1158, 1-
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(2,4,6-triisopropylbenzenesulfonyl-3 -nitro- 1,2,4-triazole (TPSNT) as
described
in Bioorg. Med. Chem. Lett. (1998) 8:1013,
bromotris(dimethylamino)phosphonium hexafluorophosphate (BroP), as
described in Tet. Lett., (1996) 37:3997, 2-chloro-5,5-dimethyl-2-oxo-1,3,2-
dioxaphosphinane, as described in Nucleosides Nucleotides 1995, 14, 871, and
diphenyl chlorophosphate, as described in J. Med. Chem., 1988, 31, 1305.
Phosphonic acids are converted into amidates and esters by means of the
Mitsunobu reaction, in which the phosphonic acid and the amine or hydroxy
reactant are combined in the presence of a triaryl phosphine and a dialkyl
azodicarboxylate. The procedure is described in Org. Lett., 2001, 3, 643, or
J.
Med. Chem., 1997, 40, 3842.
Phosphonic esters are also obtained by the reaction between phosphonic
acids and halo compounds, in the presence of a suitable base. The method is
described, for example, in Anal. Chem., 1987, 59, 1056, or J. Chem. Soc.
Perkin
Trans., I, 1993, 19, 2303, or J. Med. Chem., 1995, 38, 1372, or Tet. Lett.,
2002,
43, 1161.
Schemes 34-37 illustrate the conversion of phosphonate esters and
phosphonic acids into carboalkoxy-substituted phosphonbisamidates (Scheme
34), phosphonamidates (Scheme 35), phosphonate monoesters (Scheme 36) and
phosphonate diesters, (Scheme 37). Scheme 38 illustrates synthesis of gem-
dialkyl amino phosphonate reagents.
Scheme 34 illustrates various methods for the conversion of phosphonate
diesters S34.1 into phosphonbisamidates S34.5. The diester S34.1, prepared as
described previously, is hydrolyzed, either to the monoester S34.2 or to the
phosphonic acid S34.6. The methods employed for these transformations are
described above. The monoester S34.2 is converted into the monoamidate S34.3
by reaction with an aminoester S34.9, in which the group R2 is H or alkyl; the
group R4b is a divalent alkylene moiety such as, for example, CHCH3,
CHCH2CH3, CH(CH(CH3)2), CH(CH2Ph), and the like, or a side chain group
present in natural or modified aminoacids; and the group R5b is CI -C12 alkyl,
such as methyl, ethyl, propyl, isopropyl, or isobutyl; C6-C20 aryl, such as
phenyl
or substituted phenyl; or C6-C20 arylalkyl, such as benzyl or benzyhydryl. The
reactants are combined in the presence of a coupling agent such as a
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carbodiimide, for example dicyclohexyl carbodiimide, as described in J. Am.
Chem. Soc., (1957) 79:3575, optionally in the presence of an activating agent
such as hydroxybenztriazole, to yield the amidate product S34.3. The amidate-
forming reaction is also effected in the presence of coupling agents such as
BOP,
as described in J. Org. Chem. (1995) 60:5214, Aldrithiol, PYBOP and similar
coupling agents used for the preparation of amides and esters. Alternatively,
the
reactants S34.2 and S34.9 are transformed into the monoamidate S34.3 by means
of a Mitsunobu reaction. The preparation of amidates by means of the Mitsunobu
reaction is described inJ. Med. Chem. (1995) 38:2742. Equimolar amounts of
the reactants are combined in an inert solvent such as tetrahydrofuran in the
presence of a triaryl phosphine and a dialkyl azodicarboxylate. The thus-
obtained monoamidate ester S34.3 is then transformed into amidate phosphonic
acid S34.4. The conditions used for the hydrolysis reaction depend on the
nature
of the R' group, as described previously. The phosphonic acid amidate S34.4 is
then reacted with an aminoester S34.9, as described above, to yield the
bisamidate product S34.5, in which the amino substituents are the same or
different. Alternatively, the phosphonic acid S34.6 may be treated with two
different amino ester reagents simulataneously, i.e. S34.9 where R2, R4b or
Rsb
are different. The resulting mixture of bisamidate products S34.5 may then be
separable, e.g., by chromatography.
Scheme 34
O O 0
R-link-P~ OR' -- R-link-P~ OR'= R-Iink-P~ OH 34.7
OR~ OH OH
S34.1 S34.2 S34.6
S34.9
S34.
0 O O
~ R-link-P~ OH
R-link-P-OR' R-link-P-OR'
\ \ 2 N-RZ
Lv RZNH(R4b)CO2R5b N-R (R4b)
S34.8 S34.9 (R4 ), C02R5b 'COZRsb
S34.3 S34.4
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0 0 R2 0 R 2
R-link-P-Lv R-link-I'-N CO2R5b R-link-P-N,
l '(R4b)~ I (R4b)_ CO2R5b
S34.7 or OH) S34.9 (Rab~N RZ ~ (Lv or OH)
COZRSb S34.9
S34,11
S34.5
O
~ Hal(R4b)COZRSb R link-P~ NH
R-link-P~-NH2 S34.12 NH (R4b)CO2R5b
NH2 _- (R4b )
S34.10 Ex6 ~CO2R5b
S34.5
An example of this procedure is shown in Scheme 34, Example 1. In this
procedure, a dibenzyl phosphonate S34.14 is reacted with diazabicyclooctane
(DABCO) in toluene at reflux, as described in J. Org. Chem., 1995, 60, 2946,
to
afford the monobenzyl phosphonate S34.15. The product is then reacted with
equimolar amounts of ethyl alaninate S34.16 and dicyclohexyl carbodiimide in
pyridine, to yield the amidate product S34.17. The benzyl group is then
removed, for example by hydrogenolysis over a palladium catalyst, to give the
monoacid product S34.18 which may be unstable according to J. Med. Chem.
(1997) 40(23):3842. This compound S34.18 is then reacted in a Mitsunobu
reaction with ethyl leucinate S34.19, triphenyl phosphine and
diethylazodicarboxylate, as described in J. Med. Chem., 1995, 38, 2742, to
produce the bisamidate product S34.20.
Using the above procedures, but employing in place of ethyl leucinate
S34.19 or ethyl alaninate S34.16, different aminoesters S34.9, the
corresponding
products S34.5 are obtained.
Alternatively, the phosphonic acid S34.6 is converted into the bisamidate
S34.5 by use of the coupling reactions described above. The reaction is
performed in one step, in which case the nitrogen-related substituents present
in
the product S34.5 are the same, or in two steps, in which case the nitrogen-
related substituents can be different.
An example of the method is shown in Scheme 34, Example 2. In this
procedure, a phosphonic acid S34.6 is reacted in pyridine solution with excess
ethyl phenylalaninate S34.21 and dicyclohexylcarbodiimide, for example as
described in J. Chem. Soc., Chem. Comm., 1991, 1063, to give the bisamidate
product S34.22.
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Using the above procedures, but employing, in place of ethyl
phenylalaninate, different aminoesters S34.9, the corresponding products S34.5
are obtained.
As a further alternative, the phosphonic acid S34.6 is converted into the
mono or bis-activated derivative S34.7, in which Lv is a leaving group such as
chloro, imidazolyl, triisopropylbenzenesulfonyloxy etc. The conversion of
phosphonic acids into chlorides S34.7 (Lv = Cl) is effected by reaction with
thionyl chloride or oxalyl chloride and the like, as described in Organic
Phosphorus Compounds, G. M. Kosolapoff, L. Maeir, eds, Wiley, 1976, p. 17.
The conversion of phosphonic acids into monoimidazolides S34.7 (Lv =
imidazolyl) is described in J. Med. Chem., 2002, 45, 1284 and in J. Chem. Soc.
Chem. Comm., 1991, 312. Alternatively, the phosphonic acid is activated by
reaction with triisopropylbenzenesulfonyl chloride, as described in
Nucleosides
and Nucleotides, 2000, 10, 1885. The activated product is then reacted with
the
aminoester S34.9, in the presence of a base, to give the bisamidate S34.5. The
reaction is performed in one step, in which case the nitrogen substituents
present
in the product S34.5 are the same, or in two steps, via the intermediate
S34.11, in
which case the nitrogen substituents can be different.
Examples of these methods are shown in Scheme 34, Examples 3 and 5.
In the procedure illustrated in Scheme 34, Example 3, a phosphonic acid S34.6
is
reacted with ten molar equivalents of thionyl chloride, as described in Zh.
Obschei Khim., 1958, 28, 1063, to give the dichloro compound S34.23. The
product is then reacted at reflux temperature in a polar aprotic solvent such
as
acetonitrile, and in the presence of a base such as triethylamine, with butyl
serinate S34.24 to afford the bisamidate product S34.25.
Using the above procedures, but employing, in place of butyl serinate
S34.24, different aminoesters S34.9, the corresponding products S34.5 are
obtained.
In the procedure illustrated in Scheme 34, Example 5, the phosphonic
acid S34.6 is reacted, as described in J. Chem. Soc. Chem. Comm., 1991, 312,
with carbonyl diimidazole to give the imidazolide S34.32. The product is then
reacted in acetonitrile solution at ambient temperature, with one molar
equivalent of ethyl alaninate S34.33 to yield the monodisplacement product
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S34.34. The latter compound is then reacted with carbonyl diimidazole to
produce the activated intermediate S34.35, and the product is then reacted,
under
the same conditions, with ethyl N-methylalaninate S34.33a to give the
bisamidate product S34.36.
Using the above procedures, but employing, in place of ethyl alaninate
S34.33 or ethyl N-methylalaninate S34.33a, different aminoesters S34.9, the
corresponding products S34.5 are obtained.
The intermediate monoamidate S34.3 is also prepared from the
monoester S34.2 by first converting the monoester into the activated
derivative
S34.8 in which Lv is a leaving group such as halo, imidazolyl etc, using the
procedures described above. The product S34.8 is then reacted with an
aminoester S34.9 in the presence of a base such as pyridine, to give an
intermediate monoamidate product S34.3. The latter compound is then
converted, by removal of the R' group and coupling of the product with the
aminoester S34.9, as described above, into the bisamidate S34.5.
An example of this procedure, in which the phosphonic acid is activated
by conversion to the chloro derivative S34.26, is shown in Scheme 34, Example
4. In this procedure, the phosphonic monobenzyl ester S34.15 is reacted, in
dichloromethane, with thionyl chloride, as described in Tet. Letters., 1994,
35,
4097, to afford the phosphoryl chloride S34.26. The product is then reacted in
acetonitrile solution at ambient temperature with one molar equivalent of
ethyl
3-amino-2-methylpropionate S34.27 to yield the monoamidate product S34.28.
The latter compound is hydrogenated in ethylacetate over a 5% palladium on
carbon catalyst to produce the monoacid product S34.29. The product is
subjected to a Mitsunobu coupling procedure, with equimolar amounts of butyl
alaninate S34.30, triphenyl phosphine, diethylazodicarboxylate and
triethylamine
in tetrahydrofuran, to give the bisamidate product S34.31.
Using the above procedures, but employing, in place of ethyl 3-amino-2-
methylpropionate S34.27 or butyl alaninate S34.30, different aminoesters
S34.9,
the corresponding products S34.5 are obtained.
The activated phosphonic acid derivative S34.7 is also converted into the
bisamidate S34.5 via the diamino compound S34.10. The conversion of
activated phosphonic acid derivatives such as phosphoryl chlorides into the
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corresponding amino analogs S34.10, by reaction with ammonia, is described in
Organic Phosphorus Compounds, G. M. Kosolapoff, L. Maeir, eds, Wiley, 1976.
The bisamino compound S34.10 is then reacted at elevated temperature with a
haloester S34.12 (Hal = halogen, i.e. F, Cl, Br, I), in a polar organic
solvent such
as dimethylformamide, in the presence of a base such as 4, 4-
dimethylaminopyridine (DMAP) or potassium carbonate, to yield the bisamidate
S34.5. Alternatively, S34.6 may be treated with two different amino ester
reagents simulataneously, i.e. S34.12 where R4b or R5b are different. The
resulting mixture of bisamidate products S34.5 may then be separable, e.g., by
chromatography.
An example of this procedure is shown in Scheme 34, Example 6. In this
method, a dichlorophosphonate S34.23 is reacted with ammonia to afford the
diamide S34.37. The reaction is performed in aqueous, aqueous alcoholic or
alcoholic solution, at reflux temperature. The resulting diamino compound is
then reacted with two molar equivalents of ethyl 2-bromo-3-methylbutyrate
S34.38, in a polar organic solvent such as N-methylpyrrolidinone at ca. 150
C,
in the presence of a base such as potassium carbonate, and optionally in the
presence of a catalytic amount of potassium iodide, to afford the bisamidate
product S34.39.
Using the above procedures, but employing, in place of ethyl 2-bromo-3-
methylbutyrate S34.38, different haloesters S34.12 the corresponding products
S34.5 are obtained.
The procedures shown in Scheme 34 are also applicable to the
preparation of bisamidates in which the aminoester moiety incorporates
different
functional groups. Scheme 34, Example 7 illustrates the preparation of
bisamidates derived from tyrosine. In this procedure, the monoimidazolide
S34.32 is reacted with propyl tyrosinate S34.40, as described in Example 5, to
yield the monoamidate S34.41. The product is reacted with carbonyl diimidazole
to give the imidazolide S34.42, and this material is reacted with a further
molar
equivalent of propyl tyrosinate to produce the bisamidate product S34.43.
Using the above procedures, but employing, in place of propyl tyrosinate
S34.40, different aminoesters S34.9, the corresponding products S34.5 are
obtained. The aminoesters employed in the two stages of the above procedure
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can be the same or different, so that bisamidates with the same or different
amino substituents are prepared.
Scheme 35 illustrates methods for the preparation of phosphonate
monoamidates.
In one procedure, a phosphonate monoester S34.1 is converted, as
described in Scheme 34, into the activated derivative S34.8. This compound is
then reacted, as described above, with an aminoester S34.9, in the presence of
a
base, to afford the monoamidate product S35.1.
The procedure is illustrated in Scheme 35, Example 1. In this method, a
monophenyl phosphonate S35.7 is reacted with, for example, thionyl chloride,
as
described in J. Gen. Chem. USSR., 1983, 32, 367, to give the chloro product
S35.8. The product is then reacted, as described in Scheme 34, with ethyl
alaninate, to yield the amidate S35.10.
Using the above procedures, but employing, in place of ethyl alaninate
S35.9, different aminoesters S34.9, the corresponding products S35.1 are
obtained.
Alternatively, the phosphonate monoester S34.1 is coupled, as described
in Scheme 34, with an aminoester S34.9 to produce the amidate S35.1. If
necessary, the R' substituent is then altered, by initial cleavage to afford
the
phosphonic acid S35.2. The procedures for this transformation depend on the
nature of the R' group, and are described above. The phosphonic acid is then
transformed into the ester amidate product S35.3, by reaction with the hydroxy
compound R3OH, in which the group R3 is aryl, heterocycle, alkyl, cycloalkyl,
haloalkyl etc, using the same coupling procedures (carbodiimide, Aldrithiol-2,
PYBOP, Mitsunobu reaction etc) described in Scheme 34 for the coupling of
amines and phosphonic acids.
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Scheme 34 Example I
O O H2NCH(Me)CO2Et O H
R-link-p~ OBn R-link-p~ OH S34.16 R-link-p-N~Me
OBn OBn OBn COOEt
S34.14 S34.15 S34.17
O H
~ H Me H2NCH(CH2Pr')CO2Et R-link-p-N~Me
R-link -P~-N---~ i \NH
OH COOEt S34.19 Pr'H2C--~ COOEt
S34.18 COOEt
S34.20
Scheme 34 Example 2
Bn
O H2NCH(Bn)CO2Et O }--COOEt
R-link-p~ OH S34=21; R-link-p~ NH
OH NH
Bn-j\
COOEt
S34.6 S34.22
OH
Scheme 34 Example 3 ~-C0213u
H2NCH(CH2OH)CO2Bu O O O R-link-p~ OH R-link-p-CI S34.24
R-link-p~ NH
OH CI NH
S34.6 S34.23 /--~
HO COZBu
S34.25
Scheme 34 Example 4
O O H2NCH2CH(Me)CO2Et O
ii i1 S34.27 n
R-Iink-p~ OBn-; R-link-P- OBn -- R-link-P-OBn
OH CI NH
S34.15 S34.26 ~-CO2Et
Me
S34.28
0 Me~
R-link -p-OH
\NH H2NCH(Me)COZBu 0 C02Bu
R-link-P~-NH
~-C02Et S34.30 NH
Me ~CO2 Et
S34.29 Me
S34.31
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Scheme 34 Example 5
Me
0 0 H2NCH(Me)C02Et O ~-CO2Et
R-Iink-p~ OH =- R-link-p-OH R-link-P~ NH
OH Im S34.33 OH
S34.6 S34.32 S34.34
Me Me~
0 ~-C02Et MeNHCH(Me)C02Et ~ C02Et
11
R-link-P-NH R-link-P~ NH
Im S34.33a N-Me
S34.35 Me-~
C02Et
S34.36
Scheme 34 Example 6
Pr' ~
O O BrCH(Pr')CO2Et 0 C02Et
R-link-p-Cl -- R-Iink-p\-NHz R-link-P~ NH
CI NH2 S34.38 NH
S34.23 S34.37 Pr'-/ S34.39
C02Et
Scheme 34 Example 7
HO
I ~ R-link -p OH R-link -P-Im
~ H2N CO2Pr NH NH
R-link -p~ OH 0 - CO Pr -~- CO Pr
Im S34.40 2 z
S34.32 HO S34.41 HO S34.42
PrO2C
0
R-link-p~ NH
NH
CO2Pr OH
S34.43
r
HO
Examples of this method are shown in Scheme 35, Examples 1-3. In the
sequence shown in Example 2, a monobenzyl phosphonate S35.11 is
transformed by reaction with ethyl alaninate, using one of the methods
described
above, into the monoamidate S35.12. The benzyl group is then removed by
catalytic hydrogenation in ethylacetate solution over a 5% palladium on carbon
catalyst, to afford the phosphonic acid amidate S35.13. The product is then
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reacted in dichloromethane solution at ambient temperature with equimolar
amounts of 1-(dimethylaminopropyl)-3-ethylcarbodiimide and trifluoroethanol
S35.14, for example as described in Tet. Lett., 2001, 42, 8841, to yield the
amidate ester S35.15.
In the sequence shown in Scheme 35, Example 3, the monoamidate
S35.13 is coupled, in tetrahydrofuran solution at ambient temperature, with
equimolar amounts of dicyclohexyl carbodiimide and 4-hydroxy-N-
methylpiperidine S35.16, to produce the amidate ester product S35.17.
Using the above procedures, but employing, in place of the ethyl
alaninate product S35.12 different monoacids S35.2, and in place of
trifluoroethanol S35.14 or 4-hydroxy-N-methylpiperidine S35.16, different
hydroxy compounds R3OH, the corresponding products S35.3 are obtained.
Alternatively, the activated phosphonate ester S34.8 is reacted with
ammonia to yield the amidate S35.4. The product is then reacted, as described
in
Scheme 34, with a haloester S35.5, in the presence of a base, to produce the
amidate product S35.6. If appropriate, the nature of the R' group is changed,
using the procedures described above, to give the product S35.3. The method is
illustrated in Scheme 35, Example 4. In this sequence, the monophenyl
phosphoryl chloride S35.18 is reacted, as described in Scheme 34, with
ammonia, to yield the amino product S35.19. This material is then reacted in N-
methylpyrrolidinone solution at 170 with butyl 2-bromo-3-phenylpropionate
S35.20 and potassium carbonate, to afford the amidate product S35.21.
Using these procedures, but employing, in place of butyl 2-bromo-3-
phenylpropionate S35.20, different haloesters S35.5, the corresponding
products
S35.6 are obtained.
The monoamidate products S35.3 are also prepared from the doubly
activated phosphonate derivatives S34.7. In this procedure, examples of which
are described in Synlett., 1998, 1, 73, the intermediate S34.7 is reacted with
a
limited amount of the aminoester S34.9 to give the mono-displacement product
S34.11. The latter compound is then reacted with the hydroxy compound R3OH
in a polar organic solvent such as dimethylformamide, in the presence of a
base
such as diisopropylethylamine, to yield the monoamidate ester S35.3.
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The method is illustrated in Scheme 35, Example 5. In this method, the
phosphoryl dichloride S35.22 is reacted in dichloromethane solution with one
molar equivalent of ethyl N-methyl tyrosinate S35.23 and
dimethylaminopyridine, to generate the monoamidate S35.24. The product is
then reacted with phenol S35.25 in dimethylformamide containing potassium
carbonate, to yield the ester amidate product S35.26.
Using these procedures, but employing, in place of ethyl N-methyl
tyrosinate S35.23 or phenol S35.25, the aminoesters S34.9 and/or the hydroxy
compounds R3OH, the corresponding products S35.3 are obtained.
Scheme 35
O O 0
R-Iink-P-OR' ~ R-link-P-OR~ R-link-P~- OH -- S35.3
S34.~H S34.9 ~N-R2 N-RZ
(R4bi (R4bi RZNH(Rab)COZRsb CO2RSb CO2Rsb
S34.9 S35.1 S35.2
O O Hal(Rab)CO2RSb 0
R-link-P-OR1 R-link- POR' - R-link-P-OR'
\Lv \- NH2 S35.5 \NH
S35.4 (Rab)
COZRsb
S34.8 S35.6
O 0 R2 R3OH O
R-Iink-P-Lv-- R-link-P-N R-link-P-OR3
~Lv S34.9 Lv (Rab) \N-R2
S34.7 CO2RSb (Rab~
S34.11 COZRSb
S35.3
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Scheme 35 Example I
~
O 0 H2NCH(Me)CO2Et
R-link-P-OPh R-link-P-OPh -- R-link-P-OPh
OH ci S35.9 \NH
Me-~
S35.7 S35.8 CO2Et
S35.10
Scheme 35 Example 2
0
R link-P OBn -- R-link-P~NOBn R-link-P-OH
OH H NH
Me~ Me-~
COZEt CO2Et
S35.11 S35.12 S35.13
0
CF3CH2OH R-link-POCHZCF3
S35.14 NH
--~ Me-~OZEt
S35.15
Scheme 35 Example 3
O 0
R-Iink-POH OH R-link-PO-CN-Me
Me NH Me" N Me NH
-~ -- ~
CO2Et S35.16 COzEt
S35.13 S35.17
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Scheme 35 Example 4
O O BrCH(Bn)CO2Bu O
R-link-P~ OPh R-link-P~ OPh > R-link-P~ OPh
CI NH2 S35.20 NH
S35.18 S35.19 Bn-{
CO2Bu
S35.21
Scheme 35 Example 5
HO
~ Me,N COZEt 0
R-link-P-CI H R-link-P~ CI
CI S35.23 ~ ~ N-Me
HO
S35.22 C02Et S35.24
PhOH
S35.25
O
R-link-P",-O
& N-Me
HO
C02Et S35.26
Scheme 36 illustrates methods for the preparation of carboalkoxy-
substituted phosphonate diesters in which one of the ester groups incorporates
a
carboalkoxy substituent.
In one procedure, a phosphonate monoester S34.1, prepared as described
above, is coupled, using one of the methods described above, with a
hydroxyester S36.1, in which the groups R4b and R5b are as described in Scheme
34. For example, equimolar amounts of the reactants are coupled in the
presence
of a carbodiimide such as dicyclohexyl carbodiimide, as described in Aust. J.
Chem., 1963, 609, optionally in the presence of dimethylaminopyridine, as
described in Tet., 1999, 55, 12997. The reaction is conducted in an inert
solvent
at ambient temperature.
The procedure is illustrated in Scheme 36, Example 1. In this method, a
monophenyl phosphonate S36.9 is coupled, in dichloromethane solution in the
presence of dicyclohexyl carbodiimide, with ethyl 3-hydroxy-2-
methylpropionate S36.10 to yield the phosphonate mixed diester S36.11.
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Using this procedure, but employing, in place of ethyl 3-hydroxy-2-
methylpropionate S36.10, different hydroxyesters S33.1, the corresponding
products S33.2 are obtained.
The conversion of a phosphonate monoester S34.1 into a mixed diester
S36.2 is also accomplished by means of a Mitsunobu coupling reaction with the
hydroxyester S36.1, as described in Org. Lett., 2001, 643. In this method, the
reactants S34.1 and S36.1 are combined in a polar solvent such as
tetrahydrofuran, in the presence of a triarylphosphine and a dialkyl
azodicarboxylate, to give the mixed diester S36.2. The RI substituent is
varied
by cleavage, using the methods described previously, to afford the monoacid
product S36.3. The product is then coupled, for example using methods
described above, with the hydroxy compound R3OH, to give the diester product
S36.4.
The procedure is illustrated in Scheme 36, Example 2. In this method, a
monoallyl phosphonate S36.12 is coupled in tetrahydrofuran solution, in the
presence of triphenylphosphine and diethylazodicarboxylate, with ethyl lactate
S36.13 to give the mixed diester S36.14. The product is reacted with
tris(triphenylphosphine) rhodium chloride (Wilkinson catalyst) in
acetonitrile, as
described previously, to remove the allyl group and produce the monoacid
product S36.15. The latter compound is then coupled, in pyridine solution at
ambient temperature, in the presence of dicyclohexyl carbodiimide, with one
molar equivalent of 3-hydroxypyridine 536.16 to yield the mixed diester
S36.17.
Using the above procedures, but employing, in place of the ethyl lactate
S36.13 or 3-hydroxypyridine, a different hydroxyester S36.1 and/or a different
hydroxy compound R3OH, the corresponding products S36.4 are obtained.
The mixed diesters S36.2 are also obtained from the monoesters S34.1
via the intermediacy of the activated monoesters S36.5. In this procedure, the
monoester S34.1 is converted into the activated compound S36.5 by reaction
with, for example, phosphorus pentachloride, as described in J. Org. Chem.,
2001, 66, 329, or with thionyl chloride or oxalyl chloride (Lv = Cl), or with
triisopropylbenzenesulfonyl chloride in pyridine, as described in Nucleosides
and Nucleotides, 2000, 19, 1885, or with carbonyl diimidazole, as described in
J.
Med. Chem., 2002, 45, 1284. The resultant activated monoester is then reacted
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with the hydroxyester S36.1, as described above, to yield the mixed diester
S36.2.
The procedure is illustrated in Scheme 36, Example 3. In this sequence, a
monophenyl phosphonate S36.9 is reacted, in acetonitrile solution at 70 C,
with
ten equivalents of thionyl chloride, so as to produce the phosphoryl chloride
S36.19. The product is then reacted with ethyl 4-carbamoyl-2-hydroxybutyrate
S36.20 in dichloromethane containing triethylamine, to give the mixed diester
S36.21.
Using the above procedures, but employing, in place of ethyl 4-
carbamoyl-2-hydroxybutyrate S36.20, different hydroxyesters S36.1, the
corresponding products S36.2 are obtained.
The mixed phosphonate diesters are also obtained by an alternative route
for incorporation of the R30 group into intermediates S36.3 in which the
hydroxyester moiety is already incorporated. In this procedure, the monoacid
intermediate S36.3 is converted into the activated derivative S36.6 in which
Lv
is a leaving group such as chloro, imidazole, and the like, as previously
described. The activated intermediate is then reacted with the hydroxy
compound R3OH, in the presence of a base, to yield the mixed diester product
S36.4.
The method is illustrated in Scheme 36, Example 4. In this sequence, the
phosphonate monoacid S36.22 is reacted with trichloromethanesulfonyl chloride
in tetrahydrofuran containing collidine, as described in J. Med. Chem., 1995,
38,
4648, to produce the trichloromethanesulfonyloxy product S36.23. This
compound is reacted with 3-(morpholinomethyl)phenol S36.24 in
dichloromethane containing triethylamine, to yield the mixed diester product
S36.25.
Using the above procedures, but employing, in place of with 3-
(morpholinomethyl)phenol S36.24, different alcohols R3OH, the corresponding
products S36.4 are obtained.
The phosphonate esters S36.4 are also obtained by means of alkylation
reactions performed on the monoesters S34.1. The reaction between the
monoacid S34.1 and the haloester S36.7 is performed in a polar solvent in the
presence of a base such as diisopropylethylamine, as described in Anal. Chem.,
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1987, 59, 1056, or triethylamine, as described in J. Med. Chem., 1995, 38,
1372,
or in a non-polar solvent such as benzene, in the presence of 18-crown-6, as
described in Syn. Comm., 1995, 25, 3565.
The method is illustrated in Scheme 36, Example 5. In this procedure, the
monoacid S36.26 is reacted with ethyl 2-bromo-3-phenylpropionate S36.27 and
diisopropylethylamine in dimethylformamide at 80 C to afford the mixed
diester product S36.28.
Using the above procedure, but employing, in place of ethyl 2-bromo-3-
phenylpropionate S36.27, different haloesters S36.7, the corresponding
products
S36.4 are obtained.
Scheme 36
~Q HOR1 (1 equiv.) O
R-link-P-OR' R-link-P~ OH
(R
4b ' 0 S36.4 HO-R4b-COOR5b OH
CO2Rsb
HaI-R4b-COOR5b
S33.7
Q HO-R4b-COORSb O O
R-Iink-P-OR' R-Iink-P-OR1 R-Iink-P-OH
OH S36.1 ~ 4b Sb ~ 4b 5b
S34.1 O-R -COOR OR -COOR
S36.2 S36.3
S36,1 [
O I
R-link-P~ OR' O ~ O
Lv R-Iink-P-Lv R-Iink-P-OR3
O-R4b-COORSb O-R4b-COORSb
S36.5
S36.6 S36.4
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Scheme 36 Example 1 0
11
O R-Iink-P~-OPh
HOCH2CH(Me)CO2Et 0
R-link-P~-OPh 0.
OH S36.10 C02Et
S36.9 Me
S36.11
Scheme 36 Example 2
~ HOCH(Me)CO2Et 0 0
R-link-P-O ~ R-Iink-P-O ~ R-Iink-P-OH
OH\-\ S36.13 Me O Me
O
~ ~
S36.12 - C02Et C02Et
S36.14 S36.15
OH
N
S36.16
0
R-link-P~ O nEl
O
Me~ S36.17 C02Et
Scheme 36 Example 3
O 0
R-link-P~ OPh SOCI2 R-link-P-OPh
OH S36.18 CI
S36.9 S36.19
0
EtO2CCH(OH)CH2CH2CONH2 R-link-P~- OPh
0
S36.20
O
C02Et
H2N S36.21
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Scheme 36 Example 4
O 0
R-Iink-P~-OH R-Iink-P~-OSO2CC13
O 0
Me--{ Me~
C02Et CO2Et
S36.22 S36.23
HO I ~ N O
~
/ ~O R-link-P~ O ~ N
--~ O ~ / O
S36.24 Me-<
CO2Et
S36.25
Scheme 36 Example 5
BrCH(Bn)COZEt O,
O ---
R-link-P R-Iink-P~-OCH(Bn)CO2Et
~OH
OCH2CF3 S36.27 OCH2CF3
S36.26 S36.28
Scheme 37 illustrates methods for the preparation of phosphonate
diesters in which both the ester substituents incorporate carboalkoxy groups.
The compounds are prepared directly or indirectly from the phosphonic
acids S34.6. In one alternative, the phosphonic acid is coupled with the
hydroxyester S37.2, using the conditions described previously in Schemes 34-
36, such as coupling reactions using dicyclohexyl carbodiimide or similar
reagents, or under the conditions of the Mitsunobu reaction, to afford the
diester
product S37.3 in which the ester substituents are identical.
This method is illustrated in Scheme 37, Example 1. In this procedure,
the phosphonic acid S34.6 is reacted with three molar equivalents of butyl
lactate
S37.5 in the presence of Aldrithiol-2 and triphenyl phosphine in pyridine at
ca.
70 C, to afford the diester S37.6.
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Using the above procedure, but employing, in place of butyl lactate
S37.5, different hydroxyesters S37.2, the corresponding products S37.3 are
obtained.
Alternatively, the diesters S37.3 are obtained by alkylation of the
phosphonic acid S34.6 with a haloester S37.1. The alkylation reaction is
performed as described in Scheme 36 for the preparation of the esters S36.4.
This method is illustrated in Scheme 37, Example 2. In this procedure,
the phosphonic acid S34.6 is reacted with excess ethyl3-bromo-2-
methylpropionate S37.7 and diisopropylethylamine in dimethylformamide at ca.
80 C, as described in Anal. Chem., 1987, 59, 1056, to produce the diester
S37.8.
Using the above procedure, but employing, in place of ethyl 3-bromo-2-
methylpropionate S37.7, different haloesters S37.1, the corresponding products
S37.3 are obtained.
The diesters S37.3 are also obtained by displacement reactions of
activated derivatives S34.7 of the phosphonic acid with the hydroxyesters
S37.2.
The displacement reaction is performed in a polar solvent in the presence of a
suitable base, as described in Scheme 36. The displacement reaction is
performed in the presence of an excess of the hydroxyester, to afford the
diester
product S37.3 in which the ester substituents are identical, or sequentially
with
limited amounts of different hydroxyesters, to prepare diesters S37.3 in which
the ester substituents are different.
The methods are illustrated in Scheme 37, Examples 3 and 4. As shown
in Example 3, the phosphoryl dichloride S35.22 is reacted with three molar
equivalents of ethyl 3-hydroxy-2-(hydroxymethyl)propionate S37.9 in
tetrahydrofuran containing potassium carbonate, to obtain the diester product
S37.10.
Using the above procedure, but employing, in place of ethyl 3-hydroxy-
2-(hydroxymethyl)propionate S37.9, different hydroxyesters S37.2, the
corresponding products S37.3 are obtained.
Scheme 37, Example 4 depicts the displacement reaction between
equimolar amounts of the phosphoryl dichloride S35.22 and ethyl 2-methyl-3-
hydroxypropionate S37.11, to yield the monoester product S37.12. The reaction
is conducted in acetonitrile at 70 in the presence of diisopropylethylamine.
The
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product S37.12 is then reacted, under the same conditions, with one molar
equivalent of ethyl lactate S37.13, to give the diester product S37.14.
Using the above procedures, but employing, in place of ethyl 2-methyl-3-
hydroxypropionate S37.11 and ethyl lactate S37.13, sequential reactions with
different hydroxyesters S37.2, the corresponding products S37.3 are obtained.
Scheme 37
O O
R-link- OH ~ R-Iink-P-Lv
O(R4b)CO2R5b O(R4)COZR5
S37.5 37.4
S37.1
S37.2 S37.2
O HO(R4b)CO2R5 O
11 S37.2 11 4b 5b
R-Iink-P~-OH R-link-P\ O(R )C02R
S34.6 OH Hal(R4 O R5b O(R4b)CO2R5b
S37.3
S37.1
S37.2
S37.2
O O
R-link-P~ Lv --- R-link-P-Lv
Lv S37.2 O(R4b)COzRSb
S34.7 S37.4
Scheme 37 Example 1
~ HOCH(CH3)CO2Bu 0
R-link-P~ OH ~ R-link-P-OCH(CH3)CO2Bu
OH S37.5 OCH(CH3)CO2Bu
S34.6 S37.6
Scheme 37 Example 2
~ BrCH2CH(CH3)CO2Et O
R-Iink-P~ OH R-link-P-OCH2CH(CH3)C02Et
OH S37.7 OCH2CH(CH3)CO2Et
S34.6
S37.8
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Scheme 37 Example 3
O (HOCH2)2CHCO2Et O
R-link-PCCI ~ R-link-P\ OCH2CH(CH2OH)CO2Et
S37.9
OCH2CH(CH2OH)CO2Et
S35.22
S37.10
Scheme 37 Example 4
O HOCH2CH(CH3)CO2Et O
R-link-P-OCH CO Et
3) 2
R-link-p~ CI S37.11 ~ 2CH(CH
CI CI
S35.22 S37.12
HOCH(CH3)CO2Et
O
S37.13 R-Iink-P\ OCHzCH(CH3)CO2Et
OCH(CH3)CO2Et
S37.14
2,2-Dimethyl-2-aminoethylphosphonic acid intermediates can be
prepared by the route in Scheme 38. Condensation of 2-methyl-2-
propanesulfinamide with acetone give sulfinyl imine S38.11 (J. Org. Chem.
1999, 64, 12). Addition of dimethyl methylphosphonate lithium to S38.11
afford S38.12. Acidic methanolysis of S38.12 provide amine S38.13. Protection
of amine with Cbz group and removal of methyl groups yield phosphonic acid
S38.14, which can be converted to desired S38.15 (Scheme 38a) using methods
reported earlier on. An alternative synthesis of compound S38.14 is also shown
in Scheme 38b. Commercially available 2-amino-2-methyl-l-propanol is
converted to aziridines S38.16 according to literature methods (J. Org. Chem.
1992, 57, 5813; Syn. Lett. 1997, 8, 893). Aziridine opening with phosphite
give
S38.17 (Tetrahedron Lett. 1980, 21, 1623). Reprotection of S38.17 affords
S38.14.
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Scheme 38a
0 0
acetone CH3P(O)(OCH3)2
S-NH2 --> S-N
S38.11 BuLi
O O
- yI _~OCH3 HCI ~~~~iOCH3
S N ~OCH3 CH OH H2N ~OCH3
H S38.12 3 S38.13
O O
1 /OH yI ~OPh COzEt
CbzHN OH ~ H2N 1-1O-<
S38.14 S38.15
Scheme 38b
O NI-I OH , HP(O)(OCH3)2 ~~/OCH3
H2N 11-1 NR NaH RHN I~IOCH3
S38.16R = Cbz, R'S02 S38.17
0
:J(OH
CbzHN ~OH
S38.14
The invention will now be illustrated by the following non-limiting
Examples.
General applicability of methods for introduction of phosphonate
substituents.
The procedures described herein for the introduction of phosphonate
moieties are, with appropriate modifications, known to one skilled in the art,
and
are transferable to different chemical substrates. Thus, the methods described
herein for the introduction of phosphonate groups onto compounds of the
invention are also applicable to the introduction of phosphonate moieties onto
anilines of the invention and the reverse is also true.
Protection of reactive substituents.
Depending on the reaction conditions employed, it may be necessary to
protect certain reactive substituents from unwanted reactions by protection
before the sequence described, and to deprotect the substituents afterwards,
according to the knowledge of one skilled in the art. Protection and
deprotection
of functional groups are described, for example, in "Protective Groups in
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Organic Synthesis," by T.W. Greene and P.G.M Wuts, Wiley, Third Edition
1996. Reactive substituents that may be protected are shown in the
accompanying schemes as, for example, [OH], [SH], etc.
Example 1
Pyridopyrimidines are a class of compounds that have activity against a
variety of kinases. Examples of compounds of this class are PD 173955, PD
166326, and PD 173074.
Compounds E 1.1- E 1.4 are representative compounds of the invention,
wherein R and R' are each individually hydrogen or alkyl.
CI CI
I N' ~
N' r -
HN~N N O CI R~ P-Link H~N N O CI
Ar Link\ OR, O
E1.1 0 O R E1.2
Me Me
N OMe N' OMe
HN~N N NH HN N N NH
ink I ink O--~-NH
I I
~ OR'
rNl O R
OR' O/ R
I
E1.3 E1.4
Example 2
Synthesis of Representative Compounds of Formula E1.1
In general, compounds of the formula E1.1 can be synthesized as
follows.
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~ CO Et H2N, Link~R, O Et NEtOH_ H
2 ~ 2
\SI TEA, THF S~N NH NH
E2.1 b E2.2b Lin i E2.3b Link
P=0 r =~O
R~~R, RO aR,
0
A'~H ArCH2CN, K2CO3 ry\ \ Ar
Mn02, CHCI3 \'1 N NH DMF, 105 C S 'N N NH
E2.4b Link E2.5b Link
RO'b0 RO'~O
Ar Ar
i 3-phenyl-2-(phenylsulfonyl) N ~ \
1. Ac20, reflux N N 0 oxaziridine, CHCI3 ~SL'=L_N N O
2. 6N HCI, reflux Link U Link
E2.6b R~-O E2.7b R~P=O
bR
m-CPBA
CHCI3
~ \ \ Ar
~~
n
O Link
xs neat R*NH2, heat N\ \ Ar E2.8b ROl~R
E2.7b or
E2.8b HN N N 0
R' = aromatic amines Link
R ~/ I RO'~R
*
E1.1, R* = 3-SMe as in PD-173955
R* = 3-Me-4-F as in PD-180970
Preparation of phosphonate E1.1 is illustrated above (see also Klutchko,
S. R. et al., J. Med. Chem., 1998, 41, 3276). Condensation of commercially
available 5-pyrimidinecarboxylic acid ester E2.lb with commercially available
amino phosphonates such as aminoethyl phosphonate, proceeds in THF to yield
compound E2.2b. Reduction of the ester group using NaBH4 in ethanol
provides benzyl alcohol E2.3b (Pfeiffer, F. R. et al., J. Med. Chem., 1974,
17,
112). Oxidation of the alcohol to aldehyde E2.4b is achieved using MnO2 which
is then condensed with a substituted phenylacetonitrile in DMF at high
temperature to provide 7-iminopyridopyrimidine E2.5b. Acetylation of the
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imine followed by hydrolysis under boiling 6 N HC1 provides the key
intermediate E2.6b. Addition of inactivated amines can be achieved directly
onto the thioether E2.6b, but inactivated aromatic amines are best condensed
with the more reactive sulfoxide E2.7b or sulfone E2.8b. Depending on the
aromatic amine added to such intermediates, phosphonate analogs of PD 173955
and PD 180970 can be prepared.
Example 3
Synthesis of Representative Compounds of Formula E1.2
In general, compounds of formula E1.2 can be synthesized as follows.
CI Rq
CI ~ I
RO-P-Link-NH2
~ ~
~ R' ~ I
S N N O DMF, heat RO.~Ink H N N. O
O
E3.6a E1.2
The compound provided below is an example of general structure E1.2 in
which the link contains an alkyl group.
CI EEto~"~NHZ CI i I
N 8 EtO N'
DMF, heat Et0 ~~~H-N I I I
As illustrated above, condensation of alkylamines proceed with sulfide
E3.6a (reported in Klutchko, S. R. et al., J. Med. Chem., 1998, 41, 3276)
under
forcing conditions proceeds to provide the target compound.
Example 4
Synthesis of Representative Compounds of Formula E1.3
The synthesis of a example of a compound of type E1.3 is illustrated
below.
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OMe OMe
T1NH2 i I
~J4
N~ / I \ OMe N OMe
HZNN N NHZ H2NSO3H, 140-180 C HNN N NHZ
OMe rNI
/ I
NaH, DMF, then N~ OMe
O=C=N HN~N N NH 0
O
~~-OEt P11
-OEt
OEt r N1 H OEt
The starting material (synthesis described in: J. Med. Chem., 1997, 40,
2296-2303), sulfamic acid (2 equivalents) and 4-(diethylamino)butylamine (-15
equivalents) are heated at 150 C according to the procedure described in J.
Med. Chem., 1997, 40, 2296-2303. At the end of the reaction excess amine is
removed in vacuo. The residue is suspended in a mixture of water and saturated
aqueous sodium bicarbonate solution. This mixture is extracted with
dichloromethane. The combined organic extracts are washed with saturated
aqueous sodium bicarbonate solution, brine, and dried over sodium sulfate.
Filtration and evaporation of the solvent yields a crude product. Further
purification was achieved by flash chromatography on silica gel.
The required isocyanate for step 2 is prepared from 2-amino ethyl
phosphonic acid diethyl ester and phosgene according to a procedure from
Organikum, 17th edition, VEB Deutscher Verlag der Wissenschaften, Berlin
1988, page 428. A solution of 2-amino ethyl phosphonic acid diethyl ester in
an
organic solvent such as dichloromethane or toluene is added to a cooled
solution
of phosgene in an organic solvent such as toluene or dichloromethane. After
the
addition of the amine, the cooling is removed and the solution was heated at
100
C with further phosgene addition. Upon cessation of hydrochloric acid
evolution, excess phosgene is removed and the solvents were removed in vacuo.
The product of step 1 is treated with sodium hydride (- 1.1 equivalents) in
an organic solvent such as dimethylformamide, according to the procedure
described in J. Med. Chem., 1997, 40, 2296-2303. The phosphonate-containing
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isocyanate is added and the reaction mixture is stirred at room temperature.
At
the end of the reaction, the mixture is filtered and the solvent is removed in
vacuo. The crude material is partitioned between water and ethyl acetate. The
aqueous layer is extracted with ethyl acetate and the combined organic layers
washed with brine and dried over sodium sulfate. Filtration and evaporation of
solvents yields the crude product. Further purification is achieved by flash
chromatography on silica gel.
The synthesis of an example of a compound of type E1.4 is illustrated
below.
OMe O OMe
~-OEt
H2N~i ~OEt
OMe N OMe 10 H2NSO3H, 140-180 C
H2N N N NH2 HN N N NH2
O;P-OEt
\OEt
OMe
NaH, DMF, then
O=C=N* N OMe
HN N N NH
O ;~ P,OEt H
OEt
The synthesis is performed using methods analogous to those described
hereinabove.
Example 5
Preparation of Representative Compounds of the Invention
Generally, compounds of the invention can be made as illustrated below:.
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Cbz
1. BBr3 O / 2. Ac20/C5H5N (N)
NI N'H
~O ~ NJ 3. SOCI2 "0 / N
4.1-Cbz-piperazine
5. NH4OH, MeOH HO NJ
Intermediate ES.A
H
N ~
. Mg(OtBu)2,
1
TfOCH2P(O)(OEt)2 N I OiPr
2. H2, Pd/C CN)
O / N
3. (4-O'Pr)PhNH2, E 0" Q ~ I
(4-N02)PhOCOCI P O NJ
0
6,7-Dimethoxy-3,4-dihydroquinazolin-4-one is reacted with boron
tribromide to provide a mixture of mono-demethylated products. Separation of
the products may be achieved by chromatography, or achieved on the mixture of
acetates that arises from reaction with and acetylating reagent such as acetyl
chloride in the presence of a base such as pyridine. The desired isomer is
reacted with thionyl chloride (see Bioorg. Med. Chem. Lett., 2001, 11, 1911)
and
the resulting 4-chloroquinazoline is treated with piperazine-l-carboxylic acid
benzyl ester. The acetyl protecting group is removed under standard conditions
such as by treatment with ammonia in methanol (see Greene, T., Protective
Groups in Organic Synthesis, Wiley-Interscience (1999)) to generate
Intermediate E5.A.
Upon treatment with a base such as magnesium tert-butoxide and diethyl
phosphonomethyltriflate (prepared according to Tetrahedron Lett., 1986, 27,
1477), the phosphonate-bearing moiety is introduced at the quinazoline 7-
position. Thereafter, removal of the benzyl carbamate protecting group by
hydrogenation over a catalyst such as palladium on charcoal in a solvent such
as
methanol (see Greene, ibid) and condensation with 4-isopropoxyaniline
(commercially available) and 4-nitrophenyl chloroformate provides the desired
compound.
A particular compound of the invention can be prepared as follows.
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N
Cbz DIy
CNJ 1. DIAD, PPh3,BOCN N-\- (N) OiPr
N 2. TFA OH N
~ \N 3. CHOCH2P(O)(OEt)2, NaBH3CN "" N
J 4. As in Scheme above I J
N
HO N
Intermediate E5.A
C
N
'OEt
O'P~OEt
Intermediate E5.A may be alkylated on the phenol by reaction with 4-(2-
hydroxy-ethyl)-piperazine-1-carboxylic acid tert-butyl ester in the presence
of an
azodicarboxylate diester such as diisopropyl azodicarboxylate and
triphenylphosphine, as described by Mitsunobu (Bull. Chem. Soc. Japan., 1971,
44, 3427). Following deprotection with trifluoroacetic acid, the liberated
secondary amine is condensed with (2-oxo-ethyl)-phosphonic acid diethyl ester
under reductive conditions such as those achieved through the use of sodium
cyanoborohydride in a solvent such as methanol or dimethylformamide (see
Tetrahedron Lett. 1990, 31, 5595). The remaining steps are similar to those
illustrated above.
Example 6
Synthesis of Representative Compounds of The Invention
Generally, compounds of the invention can be made as illustrated below:
Cbz
N
0 1. methionine/MeSO3H
',O , 2. AcZO/C5H5N ~N
O ~f 3. SOCI2 N
I
~ I JNH HO &N-'
4:1-Cbz-piperazine b 5. NH4OH, MeOH
1. KZC03, OEt H
BrCH2CH:CHCH2Br O, OEt OyN
IN ~ OiPr
2. P(OEt)3 'N~
3. H2, Pd/C
4
. (40 Pr)PhNHZ,
; O &11~1.-.,
(4-NO2)PhOCOCI b Following the selective demethylation, the synthesis steps
are similar to
those described in Example 2 up to the point where a phenol is alkylated.
Here,
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the alkylation is performed with E-1,4-dibromobutene, and the monobromide
product is reacted with triethylphosphite in a solvent such as toluene toluene
(or
other Arbuzov reaction conditions; see Engel, R., Synthesis of Carbon-
phosphorus Bonds, CRC Press, (1988)) to generate the diethyl ester of the
desired phosphonic acid. Thereafter, the steps are again similar to those
described in Example 5.
Example 7
Synthesis of Representative Compounds of the Invention
Generally, compounds of the invention can be made as illustrated below:
OH 1. TfOCH2P(O)(OEt)2, 0,_,P(O)(OEt)2
cr NaH,THF ~
02N - H2N
2. H2, Pd/C, EtOH CI
-O~
~O I N
O'-'P(O)(OEt)2
HN I
~O N
~O I N~
4-Nitrophenol is treated in a solvent such as tetrahydrofuran or
dimethylformamide with a base such as sodium hydride. When bubbling ceases,
diethyl phosphonomethyltriflate (prepared according to Tetrahedron Lett.,
1986,
27, 1477) is added, yielding the desired phosphonate diester. Following
hydrogenation to generate the aniline, condensation with the known 4-chloro-
6,7-dimethoxy-quinazoline yields the desired product.
Example 8
Synthesis of Representative Compounds of the Invention
Generally, compounds of the invention can be made as illustrated below:
H
HO O H F R,~.N O H F
1. a::mate . of ester /
F I F
F F
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Representative compounds of the invention, e.g., as shown above, can be
synthesized according to the following methods. The activation of 3,4-difluoro-
2-(2-fluoro-4-iodophenylamino)benzoic acid (obtained according to the
procedure described in patent application US 2004/0054172) can be achieved by
a variety of conventional methods which include initial treatment of the acid
with diphenylphosphoryl chloride in the presence of a base such as 1V
methylmorpholine in a solvent such as tetrahydrofuran. The subsequent
formation of the hydroxamic esters can be achieved by treating this activated
acid in situ with the corresponding phosphonate-containing N-alkoxyamines
under reaction conditions similar to those described in US 2004/0054172.
For example, the preparation of a specific compound of the invention is
illustrated below.
0
Ph I I
HO O TBDMSCI HO'~O- M9(OtBu)2 EtO,P~~O~O Ph
r~ J OEt
HO Ph Im / DMF TBDMSO TfOCH2P(O)(OEt)2 TBDMSO
O
p N O O -
HO'
H2, Pd/C
EtO' DEt /OrOH O EtO'P~i0 O,N ~
TBDMSO Ph3P, DEAD TBDMSO O
0
O H
P'O N O
NH2NHCH3 P O ---- EtO~ OEt O/ H F
EtO ~~~ ~O 1. RCOOH, HO N I
OEt HO NH2 Ph2P(O)CI,
NMM/THF I
F I
2.TFA F
(R)-(+)-3-Benzyloxy-1,2-propanediol can be selectively protected with
the t-butyldimethylsilyl group, as described in J. Org. Chem., 2003, 68, 6760.
The resulting secondary alcohol can be reacted with diethyl
phosphonomethyltriflate (prepared according to Tetrahedron Lett., 1986, 27,
1477) in the presence of a base such as magnesium t-butoxide, to yield the
phosphonate-containing ether. Subsequent debenzylation under hydrogen
followed by coupling with N-hydroxyphthalimide under Mitsunobu reaction
conditions affords the N-alkoxyphthalimide, which can then be converted to the
N-alkoxyamine by treatment with a hydrazine such as methylhydrazine at room
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temperature as described in patent application US 2004/0054172, in J. Org.
Chem., 2000, 65, 676, or in J. Med. Chem., 2000, 43, 971. The N-alkoxyamine
can be coupled with 3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzoic acid to
afford, after removal of t-butyldimethylsilyl group, the desired hydroxamate.
Another specific compound of the invention can be synthesized as
follows:
1. TBDMSCI Ph
TBDMSO r HO'~ O~ Im / DMF ~O~ M9(OtBu)2 EtOT OEtSO 0-\
HOJi Ph 2. TFA HO TfOCHzP(O)(OEt)Z,P~O Ph 11
0
O -
~ / O -
Hz, Pd/C TBDMSO O HO"N TBDMSO N \/
EtO.PiOr Ph 0 Et0.0Ei ~O
0 Ph3P, DEAD P 0 O
0
1. RCOOH, H
NH2NHCH3 TBDMSO O,NHZ NMM(/OTHIF OEtHOrO,N O H F
EtO,PnO \ N \
EtO,OE
P 0
O
,, 2.TBAF 0
F I
F
(R)-(+)-3-Benzyloxy-1,2-propanediol is bis-silylated by treatment with excess
t-
butyldimethylsilyl chloride, and the primary hydroxyl group is then
selectively
de-silylated, as described in Eur. J. Org. Chem., 2001, 20, 3797. The
resulting
intermediate is reacted with diethyl phosphonomethyltriflate (prepared
according
to Tetrahedron Lett., 1986, 27, 1477) in the presence of a base such as
magnesium t-butoxide, yielding the phosphonate-containing ether. The rest of
the molecule is elaborated in a manner similar to that described above.
Another specific compound of the invention can be synthesized as
follows:
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O - O
OEt \ / Cs2CO3 OEt
EtO, ~ ~ + , N -- EtO, 1
P OTf HO DMF P
O 0 O O
H
OEt RCOOH, Ph2P(O)CI, EtO.PEj~O.N 0 F
NH2NHCH3 EtO,P~O,NHz . NMM / THF O N
11
0 ~
F
F
N-Hydroxyphthalimide is reacted with diethyl phosphonomethyltriflate in the
presence of a base such as cesium carbonate to yield the phosphonate-
containing
N-alkoxyphthalimide, which is then converted to the N-alkoxyamine by
methylhydrazine. The N-alkoxyamine is coupled with 3,4-difluoro-2-(2-fluoro-
4-iodophenylamino)benzoic acid to afford the desired hydroxamate.
Example 9
Synthesis of Representative Compounds of the Invention
Generally, compounds of the invention can be made as illustrated below:
N"''NI NI"'N
NH2 HN IMCI HNN NH
S" "N WO 0062778 SJ~N piperazine S11 N
O=~~ - O~ O~
OEt
Me NH Me NH
/ \ CI / \ CI
O ~
P~OR N~N
O '' OR' HNMN N,Link,P-OR
S" N OR'
or
O O
Br P-OR Me NH
OR' / \ ol E9.1
Representative compounds of the invention, e.g., as shown above, can be
synthesized according to the following methods. 2-(6-Chloro-2-
methylpyrimidin-4-ylamino)thiazole-5-carboxylic acid (2-chloro-6-
methylphenyl)amide, obtained from 2-aminothiazole-5-carboxylic acid ethyl
ester according to a procedure described in WO 0062778, can be treated with
piperazine to afford 2-(2-methyl-6-piperazin-1-ylpyrimidin-4-ylamino)thiazole-
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5-carboxylic acid (2-chloro-6-methylphenyl)amide. This piperazine derivative
is
N-substituted by either reductive amination with an aldehyde or N-alkylation
with an alkyl bromide to afford the desired phosphonate-containing product
E9.1.
For example, the preparation of a specific compound of the invention is
illustrated below.
NIN N" \-N
O
IOI HN ~ N II
NH P~-OEt POOEt
S , N OEt S t N
O~ ' O4~
Me NH Me NH
CI CI
The piperazine intermediate can be added to a mixture of diethyl (2-
bromoethyl)
phosphonate and sodium carbonate in absolute ethanol and the mixture can be
heated at reflux for about 16 hours. The resulting reaction mixture can be
purified by silica gel chromatography to afford the diethyl 2-
(piperazinyl)ethyl
phosphonate (J. Med. Chem. 1998, 41, 236-246).
Another specific compound of the invention can be synthesized as
follows:
NJ"N NN O
CI K~NLink~P-OR
HN HN H OR'
S"' -N 1. substitution with aminoalcohol S" ' N
O~ 2. bromination of the alcohol 04~
Me NH Me NH
CI 3. Arbuzov reaction ~~Cl E9.2
The chloropyrimidine can be transformed to an (arhydroxyalkyl)
aminopyrimidine (according to a procedure similar to that described in WO
0062778), which can then be converted to the corresponding (t)-
phosphonoalkyl) aminopyrimidine E9.2 via bromination followed by an
Arbuzov reaction.
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For example, the preparation of a specific compound of the invention is
illustrated below.
N"'N N'\N 0
-~~CI 1. H2N-_,iOH HN"'~N_,iP~EEt
~ H
Sk N 2. CBr4, PPh3 S" \N
Me NH 3. P(OEt)3 O~
Me
/ \ CI / \ CI
A mixture of the chloropyrimidine and ethanolamine can be heated at about 80
C for 2 hours to afford the (2-hydroxyethyl)aminopyrimidine. The hydroxyl
group can then be converted to the bromide under conventional bromination
conditions such as carbon tetrabromide and triphenylphosphine (Org. Lett.
2003,
5, 3519). The bromide can be heated with triethylphosphite in a solvent such
as
toluene (or other Arbuzov reaction conditions: see Engel, R., Synthesis Of
Carbon-Phosphorus Bonds, CRC press, 1988) to generate the diethyl ester of the
desired phosphonic acid.
Another specific compound of the invention can be synthesized as
follows:
NZZ
r
Br NI_N~
NH2 S11 N I ~
S" 'N 04~ WO 0062778 SN
No
O~ Me NH O -
OEt tj-ci Me NH
t~ CI
O
Link-F-OR
OR'
.
olefin cross-metathesis N ,
or HN N
oxidative cleavage of S" 'N
the olefin followed by O~
reductive amination
Me NH E9.3
t~cl
2-(2-Allyl-6-dimethylamino-pyrimidin-4-ylamino)thiazole-5-carboxylic acid (2-
chloro-6-methyl-phenyl)amide can be obtained from 2-aminothiazole-5-
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carboxylic acid ethyl ester according to a procedure similar to that described
in
WO 0062778. The allyl group can then be utilized to attach a phosphonate
moiety to the molecule by conventional chemical methods such as olefin cross-
metathesis and oxidative cleavage followed by reductive amination to afford a
compound such as phosphonate E9.3.
For example, the preparation of a specific compound of the invention is
illustrated below.
O
I I
1'OEt
OEt
N 'N N 'N
0
HN ~
~ HN N
S" 'N \ OEt OEt S' N
O~ [Ru] O~
Me NH (Grubbs catalyst) Me NH
O-cl cl
A solution of the allypyrimidine, diethyl vinylphosphonate and 5 mole % of
[ 1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro
(phenylmethylene)-(trichlorohexylphosphine)ruthenium] in dichloromethane can
be refluxed for 12 hours and the resulting reaction mixture can be purified to
afford the desired phosphonate-containing compound (J. Am. Chem. Soc. 2003,
125, 11360).
Another specific compound of the invention can be synthesized as
follows:
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Br N 'N
NHz HN NfN--/-OH
~
SJ_~N WO 0062778 S" ' N
O Me NH O~
OEt O-cl Me NH
CI
0
Link-P-OR
OR'.
N'N
olefin cross-metathesis HNJI,41-~NfN,/'OH
or
oxidative cleavage of S11 N
the olefin followed by O~
reductive amination Me NH
E9.4
O-cl
2- { 2-Allyl-6-[4-(2-hydroxyethyl)-piperazin-l-yl]-pyrimidin-4-ylamino } -
thiazole-5-carboxylic acid (2-chloro-6-methyl-phenyl)-amide can be obtained
from 2-aminothiazole-5-carboxylic acid ethyl ester according to a procedure
similar to that described in.WO 0062778. The allyl group can then be utilized
to.
attach a phosphonate moiety to the molecule by conventional chemical methods
such as olefin cross-metathesis and oxidative cleavage followed by reductive
amination to afford a compound such as phosphonate E9.4.
For example, the preparation of a specific compound of the invention is
illustrated below.
O
ii
~ ~ P'OEt
OEt
N'N N'N
HNIX,--"L-N-~ ~ HN~~N~~
~ ~~N'OH
~ ~~N.~OH ~OOEt S N
S N
O=~~ [Ru] O~
Me NH (Grubbs catalyst) Me NH
CI CI
A solution of the allypyrimidine, diethyl vinylphosphonate and 5 mole % of
[1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)
dichloro(phenylmethylene)-(trichlorohexylphosphine)ruthenium] in
dichloromethane can be refluxed for 12 hours and the resulting reaction
mixture
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can be purified to afford the desired phosphonate-containing compound (J. Am.
Chem. Soc. 2003, 125, 11360).
Example 10
Synthesis of Representative Compounds of the Invention
Generally, compounds of the invention can be made as illustrated below:
H OEt
Oy OPh OyN
P-OEt
N,S NH HzN~\ OEt N-S NH 0
P-OEt
O NH2 O O NH2
F 0 0
F F
Br Br
Representative compounds of the invention, e.g., as shown above, can be
synthesized according to the following methods. [3-(4-Bromo-2,6-difluoro-
benzyloxy)-4-carbamoyl-isothiazol-5-yl]-carbamic acid phenyl ester (prepared
according to WO 09962890) can be heated with (2-amino-ethyl)-phosphonic
acid diethyl ester in an inert solvent such as THF to generate the desired
product.
Example 11
Synthesis of Representative Compounds of the Invention
3-Substituted indolinones are a class of compounds that have activity
against a variety of kinases. Examples of compounds of this class include, but
is
not limited to, Semaxanib, SU-1 1248, and GW 9499.
Compounds E11.1-E11.3 are representative compounds of the invention
wherein R and R' are each individually hydrogen or alkyl.
0
0 Link-P-OR
O 0 OA-NH OR'
A-OR Link"k - OROR
O ' ~ ~
Link' OR' ~
N N-NH
X N H X H N
OH I O O
H E11.1 H E11.2 H E11.3
X = H, F, CI, Br, I;
Link is 1-9 chain atoms
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Example 12
Synthesis of Representative Compounds of the Invention
In general, compounds such as E11.1 can be made according to the
general route outlined below.
0 0
O O A-OR
OH A_OR ~Link' OR'
N ::::tion H
H N
H
A particular compound of the invention can be prepared as follows:
0
OH
O J. Med. Chem. 2003, F N
__O 46,1116 H
N O
O H
O
HOBt, EDC H N/~POEtEt
DMF, rt z
O 0
~/P~ OEt
H OEt
F N
I / OH
N
H
5-(5-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1 H-
pyrrole-3-carboxylic acid is prepared from t-butyl acetoacetate as described
in J.
Med. Chem. 2003, 46, 1116. The acid is then condensed with a phosphonate-
containing amine by using amide-forming reagents such as 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide (EDC) and 1-hydroxybenzotriazole
(HOBt), affording the desired product.
Example 13
Synthesis of Representative Compounds of the Invention
In general, compounds of formula E11.2 can be synthesized as follows.
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CO2H 1. HN(Me)(OMe), CHO
CDI
2. DIBAL ~ \ H2NCH2CH2P(O)(OEt)2,
NaBH(OAc)3
H H
O
NH~t~~ OEt
~ OEt
~H\
0 '~ EXamP~e 2
NH A~ OEt as
~-~ OEt
Nzz H
N
H
Example 14
Synthesis of Representative Compounds of the Invention
The synthesis of an example of a compound of type E11.3 is illustrated
below.
O O O
O=S-CI 1. H2NCH2CH2P(O)(OEt)2, Et3N O~S-NH ~OEEt
2. NaNO2, H+
02N 3. SnCl2, EtOH HZN-NH HCI O O
O~S-NH b- OEt N S 0
OEt O
N
H
N S N-NH
O
N
H
Following condensation of 4-nitrophenylsulfonyl chloride with (2-amino-ethyl)-
phosphonic acid diethyl ester, the nitro group is converted to the aryl
hydrazine
by diazotization and reduction with sodium sulfite (Chem. Ber., 1960, 93, 540)
or tin(II) chloride (J. Med. Chem., 2001, 44, 4031). This reagent is then
condensed with 6H-thiazolo[5,4-e]indole-7,8-dione as described in
W009915500 to generate the desired product.
Example 15
Synthesis of Representative Compounds of the Invention
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0 OEt
~ I O.,P(O)(OEt)Z / O~-OEt N1O
O2N NH2 CIOC ~ N ~ ~ OEt
H '
ZN ~
2. SnCIZ O
O
/ OvP-OEt
HO NYN ~ N ~ ~ OEt
I~ IN I/ 0
O
u
/ / OP-OEt
N~ I NYN N ~ ~ OEt
~ ~ IN O
The route is similar to that described in WO 03040131. The (4-
Chlorocarbonyl-phenoxymethyl)-phosphonic acid diethyl ester is synthesized by
the reaction of methyl (4-hydroxy)benzoate with diethyl
phosphonomethyltriflate (prepared according to Tetrahedron Lett., 1986, 27,
1477) using a base such as sodium hydride in a solvent such as
dimethylformamide, followed by ester saponification with lithium hydroxide and
acid chloride formation by treatment of the carboxylic acid with oxalyl
chloride
in dichloromethane in the presence of a catalytic amount of dimethylformamide.
Example 16
Synthesis of Representative Compounds of the Invention
80CN N N H HO N N
HZN BOCNH BOCNyN 1. SnC14 Y, N ~/ POCI3
BOCNH/
2. EtO0 0 EtO OEt
EtOvO EtO~O EtO OEt
r +
EtO OEt
H
/
CI I NYN ni N~ I NYN ~ N~ NN DO
~ IN SnBu3 IIN 1. 3N HCI N Et0 OEt Pd(PPh3)4 2. CH2(P(O)(OEt)2)2
EtO OEt
O;P\ OEt
OEt
The route is similar to that described in WO 03040131. The (4-
Chlorocarbonyl-phenoxymethyl)-phosphonic acid diethyl ester is synthesized by
the reaction of methyl (4-hydroxy)benzoate with diethyl
phosphonomethyltriflate.(prepared according to Tetrahedron Lett., 1986, 27,
162
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WO 2006/047507 PCT/US2005/038348
1477) using a base such as sodium hydride in a solvent such as
dimethylformamide, followed by ester saponification with lithium hydroxide and
acid chloride formation by treatment of the carboxylic acid with oxalyl
chloride
in dichloromethane in the presence of a catalytic amount of dimethylformamide.
Example 17
Synthesis of Representative Compounds of the Invention
ic_cI HzN~i P OEt N I/
Et0
dioxane, heat O
N CI N H~'P~OEt
EtO
The (3-Chloro-phenyl)-[4-(2-chloro-pyridin-4-yl)-pyrimidin-2-yl]-amine
is heated with (2-amino-ethyl)-phosphonic acid diethyl ester in dioxane as
described in WO01093682 to generate the desired product.
Example 18
Synthesis of Representative Compounds of the Invention
0
N\ N Br P\ H / ~OEt
I I/ ~O OEt N N N ~ ~ Et0
I PdCL2(PPh3)2, Cul,'PrZNH ~
~~ 1
N H OH N N____~~OH
H
The 3-{4-[2-(3-Bromo-phenylamino)-pyrimidin-4-yl]-pyridin-2-
ylamino}-propan-l-ol is synthesized by methods analogous to those described in
WO01093682. Palladium-catalyzed coupling with but-3-ynyl-phosphonic acid
diethyl ester (prepared by heating 1-bromobut-3-yne with triethylphosphite in
a
solvent such as toluene or other Arbuzov reaction conditions: see Engel, R.,
Synthesis of carbon-phosphorus bonds, CRC press, 1988) under conditions
described by Sonogashira (Tetrahedron Lett., 1975, 4467) provides the desired
product.
All literature and patent citations herein are hereby expressly
incorporated by reference at the locations of their citation. Specifically
cited
sections or pages of the above cited works are incorporated by reference with
specificity. The invention has been described in detail sufficient to allow
one
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WO 2006/047507 PCT/US2005/038348
of ordinary skill in the art to make and use the subject matter of the
following
embodiments. It is apparent that certain modifications of the methods and
compositions of the following embodiments can be made within the scope and
spirit of the invention.
In the embodiments hereinbelow, the subscript and superscripts of a
given variable are distinct. For example, R, is distinct from R.
164
