U.S. patent application number 14/359366 was filed with the patent office on 2016-02-11 for pharmaceutical compositions comprising deuterium-enriched perillyl alcohol, iso-perillyl alcohol and derivatives thereof.
The applicant listed for this patent is NEONC TECHNOLOGIES INC.. Invention is credited to Thomas Chen, Daniel Levin, Satish Pupalli.
Application Number | 20160039731 14/359366 |
Document ID | / |
Family ID | 45724091 |
Filed Date | 2016-02-11 |
United States Patent
Application |
20160039731 |
Kind Code |
A1 |
Chen; Thomas ; et
al. |
February 11, 2016 |
Pharmaceutical Compositions Comprising Deuterium-Enriched Perillyl
Alcohol, Iso-Perillyl Alcohol and Derivatives Thereof
Abstract
The present invention, provides for a deuterium-enriched
monoterpene or sesquiterpene such as perillyl alcohol, or a
deuterium-enriched isomer or analog of monoterpenes or
sesquiterpenes, such as isoperillyl alcohol. The present invention
also provides for a deuterium-enriched derivative of a monoterpene
or sesquiterpene, such as a perillyl alcohol carbamate or a
deuterium-enriched derivative of an isomer or analog of a
monoterpene or sesquiterpene, such as an isoperillyl alcohol
carbamate. The deuterium-enriched derivative may be perillyl
alcohol or isoperillyl alcohol conjugated with a therapeutic agent
such as a chemotherapeutic agent. The present invention also
provides for a method of treating a disease such as cancer,
comprising the step of delivering to a patient a therapeutically
effective amount of a deuterium-enriched compound.
Inventors: |
Chen; Thomas; (La Canada,
CA) ; Levin; Daniel; (La Canada, CA) ;
Pupalli; Satish; (Rancho Cucamonga, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
NEONC TECHNOLOGIES INC. |
Los Angeles |
CA |
US |
|
|
Family ID: |
45724091 |
Appl. No.: |
14/359366 |
Filed: |
November 21, 2012 |
PCT Filed: |
November 21, 2012 |
PCT NO: |
PCT/US12/66379 |
371 Date: |
May 20, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13566731 |
Aug 3, 2012 |
8916545 |
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14359366 |
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PCT/US2011/049392 |
Aug 26, 2011 |
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13566731 |
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61562105 |
Nov 21, 2011 |
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61377747 |
Aug 27, 2010 |
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61471402 |
Apr 4, 2011 |
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Current U.S.
Class: |
514/393 ;
514/406; 514/423; 514/729; 544/179; 548/377.1; 548/531; 568/826;
600/1 |
Current CPC
Class: |
A61K 47/54 20170801;
A61P 25/00 20180101; A61K 31/495 20130101; A61K 47/543 20170801;
C07C 2601/16 20170501; C07C 33/14 20130101; A61K 31/415 20130101;
A61P 35/02 20180101; C07D 487/04 20130101; A61N 5/10 20130101; A61K
31/4188 20130101; A61K 47/542 20170801; C07D 231/12 20130101; A61K
9/0043 20130101; A61K 31/045 20130101; A61P 35/00 20180101; A61K
31/4015 20130101; A61K 45/06 20130101; C07B 59/00 20130101; C07D
207/26 20130101; C07B 2200/05 20130101 |
International
Class: |
C07C 33/14 20060101
C07C033/14; A61K 31/4188 20060101 A61K031/4188; A61K 31/4015
20060101 A61K031/4015; A61N 5/10 20060101 A61N005/10; A61K 31/415
20060101 A61K031/415; A61K 45/06 20060101 A61K045/06; C07B 59/00
20060101 C07B059/00; A61K 47/48 20060101 A61K047/48; A61K 31/045
20060101 A61K031/045 |
Claims
1. A deuterium-enriched compound of Formula I or Formula II
##STR00024## or a pharmaceutically acceptable salt thereof;
wherein: R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6,
R.sub.7, R.sub.8, R.sub.9, R.sub.10, R.sub.11, R.sub.12, R.sub.13,
R.sub.14, R.sub.15 and R.sub.16 are independently selected from the
group consisting of hydrogen-1 and deuterium, and at least one of
R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7,
R.sub.8, R.sub.9, R.sub.10, R.sub.11, R.sub.12, R.sub.13, R.sub.14,
R.sub.15 and R.sub.16 is deuterium; and wherein the abundance of
deuterium is at least about 10%.
2. The deuterium-enriched compound of claim 1, selected from the
group consisting of: ##STR00025##
3. A deuterium-enriched perillyl alcohol or isoperillyl alcohol,
wherein the abundance of deuterium is at least about 10%.
4. The deuterium-enriched compound of claim 1, conjugated with a
therapeutic agent to form a carbamate.
5. A deuterium-enriched perillyl alcohol carbamate or isoperillyl
alcohol carbamate, wherein the abundance of deuterium is at least
about 10%.
6. The deuterium-enriched compound of claim 1, wherein the
abundance of deuterium is at least about 20% or at least about
30%.
7. The deuterium-enriched compound of claim 5, wherein perillyl
alcohol or isoperillyl alcohol is conjugated with a therapeutic
agent to form a carbamate.
8. The deuterium-enriched compound of claim 4, wherein the
therapeutic agent is a chemotherapeutic agent selected from the
group consisting of a DNA alkylating agent, a topoisomerase
inhibitor, an endoplasmic reticulum stress inducing agent, a
platinum compound, an antimetabolite, an enzyme inhibitor, and a
receptor antagonist.
9. The deuterium-enriched compound of claim 4, wherein the
therapeutic agent is selected from the group consisting of dimethyl
celocoxib (DMC), temozolomide (TMZ) and rolipram.
10. A pharmaceutical composition comprising the deuterium-enriched
compound of claim 3.
11. The pharmaceutical composition of claim 10, further comprising
a chemotherapeutic agent selected from the group consisting of a
DNA alkylating agent, a topoisomerase inhibitor, an endoplasmic
reticulum stress inducing agent, a platinum compound, an
antimetabolite, an enzyme inhibitor, and a receptor antagonist.
12. The pharmaceutical composition of claim 10, further comprising
a therapeutic agent selected from the group consisting of dimethyl
celocoxib (DMC), temozolomide (TMZ) and rolipram.
13. A pharmaceutical composition comprising the deuterium-enriched
compound of claim 5.
14. A method for treating a disease in a mammal, comprising the
step of administering to the mammal a pharmaceutical composition
comprising a therapeutically effective amount of a
deuterium-enriched perillyl alcohol, a deuterium-enriched
isoperillyl alcohol, a deuterium-enriched perillyl alcohol
carbamate, and/or a deuterium-enriched isoperillyl alcohol
carbamate.
15. A method for treating a disease in a mammal, comprising the
step of administering to the mammal a pharmaceutical composition of
claim 10.
16. The method of claim 14, wherein the disease is cancer.
17. The method of claim 16, wherein the cancer is a tumor of the
nervous system.
18. The method of claim 17, wherein the disease is
glioblastoma.
19. The method of claim 14, wherein the pharmaceutical composition
is administered by inhalation, intranasally, orally, intravenously,
subcutaneously or intramuscularly.
20. The method of claim 14, further comprising the step of treating
the mammal with radiation.
21. The method of claim 20, wherein the pharmaceutical composition
is administered before, during or after radiation.
22. The method of claim 14, further comprising the step of
administering to the mammal a chemotherapeutic agent.
23. The method of claim 22, wherein the pharmaceutical composition
is administered before, during or after the administration of a
chemotherapeutic agent.
24. The method of claim 22, wherein the chemotherapeutic agent is
selected from the group consisting of a DNA alkylating agent, a
topoisomerase inhibitor, an endoplasmic reticulum stress inducing
agent, a platinum compound, an antimetabolite, an enzyme inhibitor,
and a receptor antagonist.
25. The method of claim 22, wherein the chemotherapeutic agent is
selected from the group consisting of dimethyl celocoxib (DMC),
temozolomide (TMZ) and rolipram.
26. The method of claim 14, wherein the pharmaceutical composition
is administered using a nasal delivery device.
27. The method of claim 26, wherein the nasal delivery device is
selected from the group consisting of an intranasal inhaler, an
intranasal spray device, an atomizer, a nebulizer, a metered dose
inhaler (MDI), a pressurized dose inhaler, an insufflator, a unit
dose container, a pump, a dropper, a squeeze bottle and a
bi-directional device.
28. The deuterium-enriched compound of claim 3, conjugated with a
therapeutic agent to form a carbamate.
29. The deuterium-enriched compound of claim 3, wherein the
abundance of deuterium is at least about 20% or at least about
30%.
30. The deuterium-enriched compound of claim 5, wherein the
abundance of deuterium is at least about 20% or at least about
30%.
31. The deuterium-enriched compound of claim 7, wherein the
therapeutic agent is a chemotherapeutic agent selected from the
group consisting of a DNA alkylating agent, a topoisomerase
inhibitor, an endoplasmic reticulum stress inducing agent, a
platinum compound, an antimetabolite, an enzyme inhibitor, and a
receptor antagonist.
32. The deuterium-enriched compound of claim 7, wherein the
therapeutic agent is selected from the group consisting of dimethyl
celocoxib (DMC), temozolomide (TMZ) and rolipram.
33. The deuterium-enriched compound of claim 28, wherein the
therapeutic agent is a chemotherapeutic agent selected from the
group consisting of a DNA alkylating agent, a topoisomerase
inhibitor, an endoplasmic reticulum stress inducing agent, a
platinum compound, an antimetabolite, an enzyme inhibitor, and a
receptor antagonist.
34. The deuterium-enriched compound of claim 28, wherein the
therapeutic agent is selected from the group consisting of dimethyl
celocoxib (DMC), temozolomide (TMZ) and rolipram.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional
Application No. 61/562,105 (filed on Nov. 21, 2011), and U.S.
application Ser. No. 13/566,731 (filed on Aug. 3, 2012), each of
which is incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to deuterium-enriched perillyl
alcohol (POH), deuterium-enriched isoperillyl alcohol (iso-POH) and
derivatives thereof.
BACKGROUND OF THE INVENTION
[0003] Malignant gliomas, the most common form of central nervous
system (CNS) cancers, are currently considered essentially
incurable. Among the various malignant gliomas, anaplastic
astrocytomas (Grade III) and glioblastoma multiforme (GBM; Grade
IV) have an especially poor prognosis due to their aggressive
growth and resistance to currently available therapies. The present
standard of care for malignant gliomas consists of surgery,
ionizing radiation, and chemotherapy. Despite recent advances in
medicine, the past 50 years have not seen any significant
improvement in prognosis for malignant gliomas. Wen et al.
Malignant gliomas in adults, New England J Med., 359; 492-507,
2008. Stupp et al., Radiotherapy plus concomitant and adjuvant
temozolomide for glioblastoma, New England J Med., 352; 987-996,
2005.
[0004] The poor response of tumors, including malignant gliomas, to
various types of chemotherapeutic agents is often due to intrinsic
drug resistance. Additionally, acquired resistance of initially
well-responding tumors and unwanted side effects are other problems
that frequently thwart long-term treatment using chemotherapeutic
agents. Perillyl alcohol (POH), a naturally occurring monoterpene,
has been suggested to be an effective agent against a variety of
cancers, including CNS cancer, breast cancer, pancreatic cancer,
lung cancer, melanomas and colon cancer. Gould, M., Cancer
chemoprevention and therapy by monoterpenes, Environ. Health
Perspect., 1997 June; 105 (Suppl 4); 977-979. Hybrid molecules
containing both perillyl alcohol and retinoids were prepared to
increase apoptosis-inducing activity. Das et al., Design and
synthesis of potential new apoptosis agents: hybrid compounds
containing perillyl alcohol and new constrained retinoids,
Tetrahedron Letters 2010, 51, 1462-1466.
[0005] However, POH is rapidly metabolized. In order to improve
performance over perillyl alcohol and its derivatives, e.g., using
a lower dose, there is a need to prepare deuterated forms of
perillyl alcohol, including isomers or analogs, such as perrillyl
alcohol or isoperillyl alcohol conjugated with other therapeutic
agents, and use this material in the treatment of cancers such as
malignant gliomas, as well as other brain disorders such as
Parkinson's and Alzheimer's disease.
SUMMARY
[0006] The present disclosure provides for a deuterium-enriched
compound of Formula I or Formula II
##STR00001##
or a pharmaceutically acceptable salt thereof; wherein: R.sub.1,
R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8,
R.sub.9, R.sub.10, R.sub.11, R.sub.12, R.sub.13, R.sub.14, R.sub.15
and R.sub.16 are independently selected from the group consisting
of hydrogen-1 and deuterium, and at least one of R.sub.1, R.sub.2,
R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9,
R.sub.10, R.sub.11, R.sub.12, R.sub.13, R.sub.14, R.sub.15 and
R.sub.16 is deuterium.
[0007] For example, the deuterium-enriched compound may be the one
of the following.
##STR00002##
[0008] The present disclosure provides for a deuterium-enriched
perillyl alcohol or isoperillyl alcohol.
[0009] The present deuterium-enriched compounds may be conjugated
with a therapeutic agent to form a carbamate. The present
disclosure also provides for a deuterium-enriched perillyl alcohol
carbamate or isoperillyl alcohol carbamate. For example, perillyl
alcohol or isoperillyl alcohol is conjugated with a therapeutic
agent to form a carbamate. The therapeutic agent may be a
chemotherapeutic agent, including, but not limited to, a DNA
alkylating agent, a topoisomerase inhibitor, an endoplasmic
reticulum stress inducing agent, a platinum compound, an
antimetabolite, an enzyme inhibitor, and a receptor antagonist. For
example, the therapeutic agent can be dimethyl celocoxib (DMC),
tenozolomide (TMZ) or rolipram.
[0010] In the deuterium-enriched compound, the abundance of
deuterium may be at least about 10%, at least about 20% or at least
about 30%.
[0011] The present disclosure also provides for a pharmaceutical
composition comprising the present deuterium-enriched compound. The
pharmaceutical composition may further comprise a chemotherapeutic
agent selected from the group consisting of a DNA alkylating agent,
a topoisomerase inhibitor, an endoplasmic reticulum stress inducing
agent, a platinum compound, an antimetabolite, an enzyme inhibitor,
and a receptor antagonist. For example, the pharmaceutical
composition may further comprise a therapeutic agent such as
dimethyl celocoxib (DMC), temozolomide (TMZ) and rolipram.
[0012] The present disclosure further provides for a method for
treating a disease in a mammal, comprising the step of
administering to the mammal a therapeutically effective amount of a
deuterium-enriched perillyl alcohol, a deuterium-enriched
isoperillyl alcohol, a deuterium-enriched perillyl alcohol
carbamate, and/or a deuterium-enriched isoperillyl alcohol
carbamate.
[0013] The present disclosure provides for a method for treating a
disease in a mammal, comprising the step of administering to the
mammal a pharmaceutical composition disclosed in the present
disclosure.
[0014] The methods may further comprise the step of treating the
mammal with radiation, and/or the step of administering to the
mammal a chemotherapeutic agent. The pharmaceutical composition or
deuterium-enriched compound may be administered before, during or
after radiation and/or the administration of a chemotherapeutic
agent. The chemotherapeutic agent may be a DNA alkylating agent, a
topoisomerase inhibitor, an endoplasmic reticulum stress inducing
agent, a platinum compound, an antimetabolite, an enzyme inhibitor,
or a receptor antagonist. For example, the chemotherapeutic agent
may be dimethyl celocoxib (DMC), temozolomide (TMZ) or
rolipram.
[0015] The disease may be cancer, such as a tumor of the nervous
system (e.g., glioblastoma).
[0016] The pharmaceutical composition or deuterium-enriched
compound may be administered by inhalation, intranasally, orally,
intravenously, subcutaneously or intramuscularly.
[0017] The pharmaceutical composition or deuterium-enriched
compound may be administered using a nasal delivery device, such as
an intranasal inhaler, an intranasal spray device, an atomizer, a
nebulizer, a metered dose inhaler (MDI), a pressurized dose
inhaler, an insufflator, a unit dose container, a pump, a dropper,
a squeeze bottle and a bi-directional device.
DETAILED DESCRIPTION OF THE INVENTION
[0018] The present invention provides for deuterium-enriched
compounds and pharmaceutical compositions comprising the
deuterium-enriched compounds. Specifically, the present invention
provides for deuterium-enriched monoterpenes or sesquiterpenes
(e.g., deuterium-enriched perillyl alcohol) and deuterium-enriched
isomers or analogs of monoterpenes or sesquiterpenes (e.g.,
deuterium-enriched isoperillyl alcohol).
[0019] The present invention also provides for deuterium-enriched
derivatives of monoterpenes or sesquiterpenes, such as a
deuterium-enriched perillyl alcohol derivative. For example, the
deuterium-enriched perillyl alcohol derivative may be a
deuterium-enriched perillyl alcohol carbamate. The perillyl alcohol
derivative may be perillyl alcohol conjugated with a therapeutic
agent such as a chemotherapeutic agent.
[0020] The present invention further provides for
deuterium-enriched derivatives of isomers or analogs of
monoterpenes or sesquiterpenes, such as a deuterium-enriched
isoperillyl alcohol derivative. For example, the deuterium-enriched
isoperillyl alcohol derivative may be a deuterium-enriched
isoperillyl alcohol carbamate. The isoperillyl alcohol derivative
may be isoperillyl alcohol conjugated with a therapeutic agent such
as a chemotherapeutic agent.
[0021] Also encompassed by the present invention is a
pharmaceutical composition comprising a therapeutically effective
amount of a deuterium-enriched compound of the present invention
(or a pharmaceutically acceptable salt thereof) and a
pharmaceutically acceptable carrier.
[0022] The invention provides for methods of using the
deuterium-enriched compounds or the pharmaceutical compositions to
treat a disease, such as cancer or other nervous system disorders.
The compounds or pharmaceutical compositions of the present
invention may be administered alone, or in combination with
radiation, surgery or chemotherapeutic agents. The
deuterium-enriched molecule may also be co-administered with
antiviral agents, anti-inflammatory agents or antibiotics. The
agents may be administered concurrently or sequentially. The
compounds of the present invention can be administered before,
during or after the administration of the other active
agent(s).
[0023] One of ordinary skill in the art recognizes that in all
chemical compounds with an H atom, the H atom represents a mixture
of .sup.1H (hydrogen-1, protium) and D (deuterium, hydrogen-2,
.sup.2H), with about 0.015% being D. Thus, a deuterium-enriched
compound (or a deuterated compound) has a level of deuterium
greater than its natural abundance of 0.015%. As used herein, all
percentages given for the abundance of deuterium are mole
percentages.
[0024] The isomer or analog of monoterpene or sesquiterpene can be
an isoperillyl alcohol (iso-POH). Isoperillyl alcohols include any
isomers or analogs of perillyl alcohol. In one embodiment, the
isoperillyl alcohol is (4-isopropylidene cyclohex-1-enyl)methanol.
Other examples of isoperillyl alcohol include, but are not limited
to, (4-isopropyl cyclohexa-1,3-dienyl)methanol, (4-isopropyl
cyclohexa-1,4-dienyl)methanol, (4-isopropylphenyl)methanol and
(4-isopropenylphenyl)methanol.
[0025] The present invention provides for deuterium-enriched
isoperillyl alcohol where the compound is enriched with deuterium
in at least one position. In one embodiment, the deuterium-enriched
isoperillyl alcohol is represented by Formula I shown below:
##STR00003##
[0026] or a pharmaceutically acceptable salt thereof; wherein:
R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7,
R.sub.8, R.sub.9, R.sub.10, R.sub.11, R.sub.12, R.sub.13, R.sub.14,
R.sub.15 and R.sub.16 are independently selected from the group
consisting of hydrogen-1 (.sup.1H) and deuterium; and at least one
of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7,
R.sub.8, R.sub.9, R.sub.10, R.sub.11, R.sub.12, R.sub.13, R.sub.14,
R.sub.15 and R.sub.16 is deuterium.
[0027] Non-limiting examples of the deuterium-enriched isoperillyl
alcohol are illustrated as follows.
##STR00004##
[0028] The deuterium-enriched isoperillyl alcohol may be prepared
by oxidation of commercially sourced perillyl alcohol or
isoperillyl alcohol followed by reduction of the oxidized
intermediates using deuterium-enriched hydride reducing agents or
by use of deuterohydrogen gas with a suitable catalyst or by other
means.
[0029] The present invention provides for deuterium-enriched
perillyl alcohol, wherein the compound is enriched with deuterium
in at least one position. In one embodiment, the deuterium-enriched
perillyl alcohol is represented by Formula II, shown below.
##STR00005##
[0030] or a pharmaceutically acceptable salt thereof, wherein:
R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7,
R.sub.8, R.sub.9, R.sub.10, R.sub.11, R.sub.12, R.sub.13, R.sub.14,
R.sub.15 and R.sub.16 are independently selected from the group
consisting of hydrogen-1 (.sup.1H) and deuterium; and at least one
of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7,
R.sub.8, R.sub.9, R.sub.10, R.sub.11, R.sub.12, R.sub.13, R.sub.14,
R.sub.15 and R.sub.16 is deuterium.
[0031] Non-limiting examples of the deuterium-enriched perillyl
alcohol are illustrated as follows.
##STR00006##
[0032] The term "is/are deuterium," when used to describe a given
position in a molecule such as R.sub.1, R.sub.2, R.sub.3, R.sub.4,
R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.10, R.sub.11,
R.sub.12, R.sub.13, R.sub.14, R.sub.15 and R.sub.16 the symbol "D,"
when used to represent a given position in a drawing of a molecular
structure, means that the specified position is enriched with
deuterium greater than its natural abundance of 0.015%.
[0033] The term "abundance of deuterium" herein refers to the mole
percentage of incorporation of deuterium (D, or .sup.2H) at a given
position in a molecule in the place of hydrogen. For example, the
abundance of deuterium of about 6% at a given position means that
about 6% of molecules in a given sample contain deuterium at the
specified position.
[0034] The abundance of deuterium in the present deuterium-enriched
compound may be at least about 1%, at least about 5%, at least
about 10%, at least about 20%, at least about 30%, at least about
40%, at least about 50%, at least about 60%, at least about 70%, at
least about 80%, at least about 90%, at least about 95%, at least
about 98%, at least about 99%, about 0.5% to about 100%, about 1%
to about 100%, about 5% to about 100%, about 6% to about 100%,
about 7% to about 100%, about 10% to about 100%, about 20% to about
100%, about 30% to about 100%, about 40% to about 100%, about 50%
to about 100%, about 60% to about 100%, about 70% to about 100%,
about 80% to about 100%, or about 90% to about 100%.
[0035] Deuterium enrichment can be determined using analytical
methods, such as mass spectrometry, nuclear magnetic resonance
spectroscopy and infrared spectrometry. In one embodiment,
deuterium enrichment is determined by .sup.1H NMR.
[0036] The deuterium-enriched perillyl alcohol of the present
invention may be synthesized with deuterium incorporated in place
of hydrogen atoms. For example, the deuterium may be incorporated
in place of hydrogen atoms at the carbinol side chain where
metabolic degradation takes place in vivo. The deuterium atoms
retard or slow down the metabolic processes when compared with the
rate of metabolism for conventional perillyl alcohol or isoperillyl
alcohol. Without being limited to any specific physiologic
mechanism, it is believed that this slow-down is due to the kinetic
isotope effects at the active site of perillyl alcohol
dehydrogenase enzyme. Deuterium can also be incorporated at a
number of different centers in the molecule. In an embodiment,
deuterium is incorporated at the carbinol moiety where 1, 2 or 3
deuterium atoms can be incorporated in place of hydrogen atoms to
give any of the isotopic analogs of perillyl alcohol or isoperillyl
alcohol.
[0037] Because of its slower metabolism, the deuterated forms of
perillyl alcohol or isoperillyl alcohol will demonstrate
significant improvement in the therapeutic effectiveness as
compared with conventional non-deuterated material.
[0038] The deuterium-enriched compounds described herein may
contain one or more deuterium atoms. The compounds may be partially
or fully deuterated. Any chemical compound described herein may be
deuterium-enriched.
[0039] Monoterpenes include terpenes that consist of two isoprene
units. Monoterpenes may be linear (acyclic) or contain rings.
Derivatives of monoterpenoids are also encompassed by the present
invention. Monoterpenoids may be produced by biochemical
modifications such as oxidation or rearrangement of monoterpenes.
Examples of monoterpenes and monoterpenoids include, perillyl
alcohol (S(-)) and (R(+)), ocimene, myrcene, geraniol, citral,
citronellol, citronellal, linalool, pinene, terpineol, terpinen,
limonene, terpinenes, phellandrenes, terpinolene, terpinen-4-ol (or
tea tree oil), pinene, terpineol, terpinen; the terpenoids such
asp-cymene which is derived from monocyclic terpenes such as
menthol, thymol and carvacrol, bicyclic monoterpenoids such as
camphor, borneol and eucalyptol.
[0040] Monoterpenes may be distinguished by the structure of a
carbon skeleton and may be grouped into acyclic monoterpenes (e.g.,
myrcene, (Z)- and (E)-ocimene, linalool, geraniol, nerol,
citronellol, myrcenol, geranial, citral a, neral, citral b,
citronellal, etc.), monocyclic monoterpenes (e.g., limonene,
terpinene, phellandrene, terpinolene, menthol, carveol, etc.),
bicyclic monoterpenes (e.g., pinene, myrtenol, myrtenal, verbanol,
verbanon, pinocarveol, carene, sabinene, camphene, thujene, etc.)
and tricyclic monoterpenes (e.g. tricyclene). See Encyclopedia of
Chemical Technology, Fourth Edition, Volume 23, page 834-835.
[0041] A specific example of a monoterpene is perillyl alcohol
(POH).
[0042] Sesquiterpenes of the present invention include terpenes
that consist of three isoprene units. Sesquiterpenes may be linear
(acyclic) or contain rings. Derivatives of sesquiterpenoids are
also encompassed by the present invention. Sesquiterpenoids may be
produced by biochemical modifications such as oxidation or
rearrangement of sesquiterpenes. Examples of sesquiterpenes include
farnesol, farnesal, farnesylic acid and nerolidol. PCT Application
Nos. PCT/US2011/027051 and PCT/US2011/049392. U.S. application Ser.
No. 13/040,059. All these applications are incorporated herein by
reference in their entirety.
[0043] The present invention also provides for deuterium-enriched
derivatives of monoterpenes or sesquiterpenes, such as a
deuterium-enriched perillyl alcohol derivative. For example, the
deuterium-enriched perillyl alcohol derivative may be a
deuterium-enriched perillyl alcohol carbamate. The perillyl alcohol
derivative may be perillyl alcohol conjugated with a therapeutic
agent such as a chemotherapeutic agent.
[0044] The present invention further provides for
deuterium-enriched derivatives of isomers or analogs of
monoterpenes or sesquiterpenes, such as a deuterium-enriched
isoperillyl alcohol derivative. For example, the deuterium-enriched
isoperillyl alcohol derivative may be a deuterium-enriched
isoperillyl alcohol carbamate. The perillyl alcohol derivative may
be isoperillyl alcohol conjugated with a therapeutic agent such as
a chemotherapeutic agent.
[0045] The derivatives may be deuterated at any desired atom
position, including the atom positions of perillyl alcohol or
isoperillyl alcohol, as well as the atom positions of the
therapeutic agent conjugated with the perillyl alcohol or
isoperillyl alcohol.
[0046] A deuterium-enriched compound can be prepared by, e.g.,
exchanging hydrogens with deuterium, or synthesizing the compound
with deuterium-enriched starting materials or intermediates. In one
embodiment, deuterium can be introduced by deuterium-containing
reagents including, but not limited to, lithium aluminium
deuteride, deuterium gas or other reagents. In another embodiment,
depending on the desired sites of deuteration, deuterium from
D.sub.2O can be exchanged directly into finished drug compounds or
into reagents that are used to synthesize drug molecules.
[0047] The deuterated derivatives of monoterpene or sesquiterpene
(or deuterated derivatives of isomers or analogs of monoterpene or
sesquiterpene) include, but are not limited to, carbamates, esters,
ethers, alcohols and aldehydes of the monoterpene or sesquiterpene
(or of isomers or analogs of monoterpene or sesquiterpene). The
present invention also provides for derivatives and conjugates of a
deuterium enriched perillyl alcohol or isoperillyl alcohol.
[0048] Derivatives include, but are not limited to, carbamates,
esters, ethers, alcohols and aldehydes of a monoterpene or
sesquiterpene (e.g., POH), or of the isomer or analog of a
monoterpene or sesquiterpene (e.g., iso-POH). Alcohols may be
derivatized to carbamates, esters, ethers, aldehydes or acids.
[0049] Carbamates refer to a class of chemical compounds sharing
the functional group
##STR00007##
based on a carbonyl group flanked by an oxygen and a nitrogen.
R.sup.1, R.sup.2 and R.sup.3 can be a group such as alkyl, aryl,
etc., which can be substituted. The R groups on the nitrogen and
the oxygen may form a ring. R.sup.1--OH may be a monoterpene, e.g.,
POH or iso-POH. The R.sup.2--N--R.sup.3 moiety may be a therapeutic
agent.
[0050] Carbamates may be synthesized by reacting isocyanate and
alcohol, or by reacting chloroformate with amine. Carbamates may be
synthesized by reactions making use of phosgene or phosgene
equivalents. For example, carbamates may be synthesized by reacting
phosgene gas, diphosgene or a solid phosgene precursor such as
triphosgene with two amines or an amine and an alcohol. Carbamates
(also known as urethanes) can also be made from reaction of a urea
intermediate with an alcohol. Dimethyl carbonate and diphenyl
carbonate are also used for making carbamates. Alternatively,
carbamates may be synthesized through the reaction of alcohol
and/or amine precursors with an ester-substituted diaryl carbonate,
such as bismethylsalicylcarbonate (BMSC). U.S. Patent Publication
No. 20100113819.
[0051] Carbamates may be synthesized by the following approach:
##STR00008##
Suitable reaction solvents include, but are not limited to,
tetrahydrofuran, dichloromethane, dichloroethane, acetone, and
diisopropyl ether. The reaction may be performed at a temperature
ranging from about -70.degree. C. to about 80.degree. C., or from
about -65.degree. C. to about 50.degree. C. The molar ratio of
isoperillyl chloroformate (or perillyl chloroformate) to the
substrate R--NH.sub.2, may range from about 1:1 to about 2:1, from
about 1:1 to about 1.5:1, from about 2:1 to about 1:1, or from
about 1.05:1 to about 1.1:1. Suitable bases include, but are not
limited to, organic bases, such as triethylamine, potassium
carbonate, N,N'-diisopropylethylamine, butyl lithium, and
potassium-t-butoxide.
[0052] Alternatively, carbamates may be synthesized by the
following approach:
##STR00009##
Suitable reaction solvents include, but are not limited to,
dichloromethane, dichloroethane, toluene, diisopropyl ether, and
tetrahydrofuran. The reaction may be performed at a temperature
ranging from about 25.degree. C. to about 110.degree. C., or from
about 30.degree. C. to about 80.degree. C., or about 50.degree. C.
The molar ratio of isoperillyl alcohol to the substrate
R--N.dbd.C.dbd.O may range from about 1:1 to about 2:1, from about
1:1 to about 1.5:1, from about 2:1 to about 1:1, or from about
1.05:1 to about 1.1:1.
[0053] Esters of a monoterpene or sesquiterpene alcohol, or esters
of the alcohol of the isomers or analogs of a monoterpene or
sesquiterpene, can be derived from an inorganic acid or an organic
acid. Inorganic acids include, but are not limited to, phosphoric
acid, sulfuric acid, and nitric acid. Organic acids include, but
are not limited to, carboxylic acid such as benzoic acid, fatty
acid, acetic acid and propionic acid, and any therapeutic agent
bearing at least one carboxylic acid functional group. Examples of
the esters of alcohols include, but are not limited to, carboxylic
acid esters (such as benzoate esters, fatty acid esters (e.g.,
palmitate ester, linoleate ester, stearate ester, butyryl ester and
oleate ester), acetates, propionates (or propanoates), and
formates), phosphates, sulfates, and carbamates (e.g.,
N,N-dimethylaminocarbonyl).
[0054] The derivatives of perillyl alcohol include, perillyl
alcohol carbamates, perillyl alcohol esters, perillic aldehydes,
dihydroperillic acid, perillic acid, perillic aldehyde derivatives,
dihydroperillic acid esters and perillic acid esters. The
derivatives of perillyl alcohol may also include its oxidative and
nucleophilic/electrophilic addition derivatives. U.S. Patent
Publication No. 20090031455. U.S. Pat. Nos. 6,133,324 and
3,957,856.
[0055] The derivatives of isoperillyl alcohol include isoperillyl
alcohol carbamates, isoperillyl alcohol esters, isoperillyl alcohol
ethers, isoperillic aldehydes, isoperillic acid, isoperillic
aldehyde derivatives, and isoperillic acid esters. The derivatives
of isoperillyl alcohol may also include its oxidative and
nucleophilic/electrophilic addition derivatives. Few examples of
derivatives of isoperillyl alcohol are reported in the chemistry
literature. See U.S. Pat. No. 5,994,598 and Japanese Patent No.
07048264A.
[0056] In certain embodiments, a POH carbamate (or an iso-POH
carbamate) is synthesized by a process comprising the step of
reacting a first reactant of perillyl chloroformate (or isoperillyl
chloroformate) with a second reactant such as dimethyl celocoxib
(DMC), temozolomide (TMZ) and rolipram. The reaction may be carried
out in the presence of tetrahydrofuran and a base such as n-butyl
lithium. Perillyl chloroformate (or isoperillyl chloroformate) may
be made by reacting POH (or iso-POH) with phosgene. For example,
POH (or iso-POH) conjugated with temozolomide through a carbamate
bond may be synthesized by reacting temozolomide with oxalyl
chloride followed by reaction with perillyl alcohol (or iso-POH).
The reaction may be carried out in the presence of
1,2-dichloroethane.
[0057] POH carbamates encompassed by the present invention include,
but not limited to, 4-(bis-N,N'-4-isopropenyl
cyclohex-1-enylmethyloxy carbonyl[5-(2,5-dimethyl
phenyl)-3-trifluoromethyl pyrazol-1-yl]benzenesulfonamide,
4-(3-cyclopentyloxy-4-methoxy
phenyl)-2-oxo-pyrrolidine-1-carboxylic acid 4-isopropenyl
cyclohex-1-enylmethyl ester, and (3-methyl
4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbonyl)carbamic
acid-4-isopropenyl cyclohex-1-enylmethyl ester.
[0058] Iso-POH carbamates encompassed by the present invention
include, but are not limited to, (3-Methyl
4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbonyl)-carbamic
acid-4-isopropylidene cyclohex-1-enylmethyl ester,
4-(3-Cyclopentyloxy-4-methoxyphenyl)-2-oxo-pyrrolidine-1-carboxylic
acid 4-isopropylidene cyclohex-1-enylmethyl ester,
4-(Bis-N,N'-4-isopropylidene cyclohex-1-enylmethyloxy
carbonyl[5-(2,5-dimethyl phenyl)-3-trifluoromethyl
pyrazol-1-yl]benzenesulfonamide. The details of the chemical
reactions generating these compounds are described in the Examples
below.
[0059] In certain embodiments, perillyl alcohol derivatives may be
perillyl alcohol fatty acid esters, such as palmitoyl ester of POH
and linoleoyl ester of POH; iso-perillyl alcohol derivatives may be
isoperillyl alcohol fatty acid esters, such as palmitoyl ester of
iso-POH and linoleoyl ester of iso-POH.
[0060] The deuterium-enriched perillyl alcohol or isoperillyl
alcohol may also be conjugated with other therapeutic moieties such
as anti-cancer agents (such as temozolomide) by means of carbamate
or other chemical linkage between the deuterated isoperillyl
alcohol moiety and the other therapeutic moiety with net
therapeutic advantage compared with either moiety or both moieties
in their own right.
[0061] The monoterpene (or sesquiterpene) derivative may be a
monoterpene (or sesquiterpene) conjugated with a therapeutic agent.
A monoterpene (or sesquiterpene) conjugate encompassed by the
present invention is a molecule having a monoterpene (or
sesquiterpene) covalently bound via a chemical linking group to a
therapeutic agent.
[0062] The derivative of an isomer or analog of monoterpene or
sesquiterpene may be an isomer or analog of monoterpene or
sesquiterpene conjugated with a therapeutic agent. A conjugate
encompassed by the present invention may be a molecule having an
isomer or analog of monoterpene or sesquiterpene covalently bound
via a chemical linking group to a therapeutic agent.
[0063] The molar ratio of the monoterpene or sesquiterpene (or an
isomer or analog of monoterpene or sesquiterpene) to the
therapeutic agent in the conjugate may be 1:1, 1:2, 1:3, 1:4, 2:1,
3:1, 4:1, or any other suitable molar ratios. The monoterpene or
sesquiterpene (or an isomer or analog of monoterpene or
sesquiterpene) and the therapeutic agent may be covalently linked
through carbamate, ester, ether bonds, or any other suitable
chemical functional groups. When the monoterpene or sesquiterpene
(or an isomer or analog of monoterpene or sesquiterpene) and the
therapeutic agent are conjugated through a carbamate bond, the
therapeutic agent may be any agent bearing at least one carboxylic
acid functional group, or any agent bearing at least one amine
functional group. In a specific example, a perillyl alcohol (or an
iso-POH) conjugate is perillyl alcohol (or iso-POH) covalently
bound via a chemical linking group to a chemotherapeutic agent.
[0064] According to the present invention, the therapeutic agents
that may be conjugated with a monoterpene or sesquiterpene (or an
isomer or analog of monoterpene or sesquiterpene) include, but are
not limited to, chemotherapeutic agents, therapeutic agents for
treatment of CNS disorders (including, without limitation, primary
degenerative neurological disorders such as Alzheimer's,
Parkinson's, multiple sclerosis, Attention-Deficit Hyperactivity
Disorder or ADHD, psychological disorders, psychosis and
depression), immunotherapeutic agents, angiogenesis inhibitors, and
anti-hypertensive agents. Anti-cancer agents that may be conjugated
with a monoterpene or sesquiterpene (or an isomer or analog of
monoterpene or sesquiterpene) can have one or more of the following
effects on cancer cells or the subject: cell death; decreased cell
proliferation; decreased numbers of cells; inhibition of cell
growth; apoptosis; necrosis; mitotic catastrophe; cell cycle
arrest; decreased cell size; decreased cell division; decreased
cell survival; decreased cell metabolism; markers of cell damage or
cytotoxicity; indirect indicators of cell damage or cytotoxicity
such as tumor shrinkage; improved survival of a subject; or
disappearance of markers associated with undesirable, unwanted, or
aberrant cell proliferation. U.S. Patent Publication No.
20080275057.
[0065] Chemotherapeutic agents include, but are not limited to, DNA
alkylating agents, topoisomerase inhibitors, endoplasmic reticulum
stress inducing agents, a platinum compound, an antimetabolite,
vincalkaloids, taxanes, epothilones, enzyme inhibitors, receptor
antagonists, tyrosine kinase inhibitors, boron radiosensitizers
(i.e. velcade), and chemotherapeutic combination therapies.
[0066] Non-limiting examples of DNA alkylating agents are nitrogen
mustards, such as Cyclophosphamide (Ifosfamide, Trofosfamide),
Chlorambucil (Melphalan, Prednimustine). Bendamustine, Uramustine
and Estramustine; nitrosoureas, such as Carmustine (BCNU),
Lomustine (Semustine), Fotemustine. Nimustine, Ranimustine and
Streptozocin; alkyl sulfonates, such as Busulfan (Mannosulfan,
Treosulfan); Aziridines, such as Carboquone, Triaziquone,
Triethylenemelamine; Hydrazines (Procarbazine); Triazenes such as
Dacarbazine and Temozolomide; Altretamine and Mitobronitol.
[0067] Non-limiting examples of Topoisomerase I inhibitors include
Campothecin derivatives including SN-38, APC, NPC, campothecin,
topotecan, exatecan mesylate, 9-nitrocamptothecin,
9-aminocamptothecin, lurtotecan, rubitecan, silatecan, gimatecan,
diflomotecan, extatecan, BN-80927, DX-8951 f, and MAG-CPT as
described in Pommier Y. (2006) Nat. Rev. Cancer 6(10):789-802 and
U.S. Patent Publication No. 200510250854; Protoberberine alkaloids
and derivatives thereof including berberrubine and coralyne as
described in Li et al. (2000) Biochemistry 39(24):7107-7116 and
Gatto et al. (1996) Cancer Res. 15(12):2795-2800; Phenanthroline
derivatives including Benzo[i]phenanthridine, Nitidine, and
fagaronine as described in Makhey et al. (2003) Bioorg. Med. Chem.
11 (8): 1809-1820; Terbenzimidazole and derivatives thereof as
described in Xu (1998) Biochemistry 37(10):3558-3566; and
Anthracycline derivatives including Doxorubicin, Daunorubicin, and
Mitoxantrone as described in Foglesong et al. (1992) Cancer
Chemother. Pharmacol. 30(2): 123-125, Crow et al. (1994) J. Med.
Chem. 37(19):31913194, and Crespi et al. (1986) Biochem. Biophys.
Res. Commun. 136(2):521-8. Topoisomerase II inhibitors include, but
are not limited to Etoposide and Teniposide. Dual topoisomerase I
and II inhibitors include, but are not limited to, Saintopin and
other Naphthecenediones, DACA and other Acridine-4-Carboxamindes,
Intoplicine and other Benzopyridoindoles, TAS-I03 and other
7H-indeno[2,1-c]Quinoline-7-ones, Pyrazoloacridine, XR 11576 and
other Benzophenazines, XR 5944 and other Dimeric compounds,
7-oxo-7H-dibenz[f,ij]Isoquinolines and
7-oxo-7H-benzo[e]pyrimidines, and Anthracenyl-amino Acid Conjugates
as described in Denny and Baguley (2003) Curr. Top. Med. Chem.
3(3):339-353. Some agents inhibit Topoisomerase II and have DNA
intercalation activity such as, but not limited to, Anthracyclines
(Aclarubicin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin,
Amrubicin, Pirarubicin, Valrubicin, Zorubicin) and Antracenediones
(Mitoxantrone and Pixantrone).
[0068] Examples of endoplasmic reticulum stress inducing agents
include, but are not limited to, dimethyl-celecoxib (DMC),
nelfinavir, celecoxib, and boron radiosensitizers (i.e. velcade
(Bortezomib)).
[0069] Platinum based compounds are a subclass of DNA alkylating
agents. Non-limiting examples of such agents include Cisplatin,
Nedaplatin, Oxaliplatin, Triplatin tetranitrate, Satraplatin,
Aroplatin, Lobaplatin, and JM-216, (see McKeage et al. (1997) J.
Clin. Oncol. 201; 1232-1237 and in general, CHEMOTHERAPY FOR
GYNECOLOGICAL NEOPLASM, CURRENT THERAPY AND NOVEL APPROACHES, in
the Series Basic and Clinical Oncology, Angioli et al. Eds.,
2004).
[0070] "FOLFOX" is an abbreviation for a type of combination
therapy that is used to treat colorectal cancer. It includes 5-FU,
oxaliplatin and leucovorin. Information regarding this treatment is
available on the National Cancer Institute's web site, cancer.gov,
last accessed on Jan. 16, 2008.
[0071] "FOLFOX/BV" is an abbreviation for a type of combination
therapy that is used to treat colorectal cancer. This therapy
includes 5-FU, oxaliplatin, leucovorin and Bevacizumab.
Furthermore, "XELOX/BV" is another combination therapy used to
treat colorectal cancer, which includes the prodrug to 5-FU, known
as Capecitabine (Xeloda) in combination with oxaliplatin and
bevacizumab. Information regarding these treatments are available
on the National Cancer Institute's web site, cancer.gov or from 23
the National Comprehensive Cancer Network's web site, nccn.org,
last accessed on May 27, 2008.
[0072] Non-limiting examples of antimetabolite agents include Folic
acid based, i.e. dihydrofolate reductase inhibitors, such as
Aminopterin, Methotrexate and Pemetrexed; thymidylate synthase
inhibitors, such as Raltitrexed, Pemetrexed; Purine based, i.e. an
adenosine deaminase inhibitor, such as Pentostatin, a thiopurine,
such as Thioguanine and Mercaptopurine, a
halogenated/ribonucleotide reductase inhibitor, such as Cladribine,
Clofarabine, Fludarabine, or a guanine/guanosine: thiopurine, such
as Thioguanine; or Pyrimidine based, i.e. cytosine/cytidine:
hypomethylating agent, such as Azacitidine and Decitabine, a DNA
polymerase inhibitor, such as Cytarabine, a ribonucleotide
reductase inhibitor, such as Gemcitabine, or a thymine/thymidine:
thymidylate synthase inhibitor, such as a Fluorouracil (5-FU).
Equivalents to 5-FU include prodrugs, analogs and derivative
thereof such as 5'-deoxy-5-fluorouridine (doxifluroidine),
l-tetrahydrofuranyl-5-fluorouracil (ftorafur). Capecitabine
(Xeloda), S-I (MBMS-247616, consisting of tegafur and two
modulators, a 5-chloro-2,4-dihydroxypyridine and potassium
oxonate), ralititrexed (tomudex), nolatrexed (Thymitaq, AG337),
LY231514 and ZD9331, as described for example in Papamicheal (1999)
The Oncologist 4; 478-487.
[0073] Examples of vincalkaloids include, but are not limited to
Vinblastine, Vincristine, Vinflunine, Vindesine and
Vinorelbine.
[0074] Examples of taxanes include but are not limited to
docetaxel, Larotaxel, Ortataxel, Paclitaxel and Tesetaxel. An
example of an epothilone is iabepilone.
[0075] Examples of enzyme inhibitors include, but are not limited
to farnesyltransferase inhibitors (Tipifarnib); CDK inhibitor
(Alvocidib, Seliciclib); proteasome inhibitor (Bortezomib);
phosphodiesterase inhibitor (Anagrelide; rolipram); IMP
dehydrogenase inhibitor (Tiazofurine); and lipoxygenase inhibitor
(Masoprocol). Examples of receptor antagonists include, but are not
limited to ERA (Atrasentan); retinoid X receptor (Bexarotene); and
a sex steroid (Testolactone).
[0076] Examples of tyrosine kinase inhibitors include, but are not
limited to inhibitors to ErbB: HER1/EGFR (Erlotinib, Gefitinib,
Lapatinib, Vandetanib, Sunitinib, Neratinib); HER2/neu (Lapatinib,
Neratinib); RTK class III: C-kit (Axitinib. Sunitinib, Sorafenib),
FLT3 (Lestaurtinib), PDGFR (Axitinib, Sunitinib, Sorafenib); and
VEGFR (Vandetanib, Semaxanib, Cediranib, Axitinib, Sorafenib);
bcr-abl (Imatinib, Nilotinib, Dasatinib); Src (Bosutinib) and Janus
kinase 2 (Lestaurtinib).
[0077] "Lapatinib" (Tykerb.RTM.) is a dual EGFR and erbB-2
inhibitor. Lapatinib has been investigated as an anticancer
monotherapy, as well as in combination with trastuzumab,
capecitabine, letrozole, paclitaxel and FOLFIRI (irinotecan,
5-fluorouracil and leucovorin), in a number of clinical trials. It
is currently in phase III testing for the oral treatment of
metastatic breast, head and neck, lung, gastric, renal and bladder
cancer.
[0078] A chemical equivalent of lapatinib is a small molecule or
compound that is a tyrosine kinase inhibitor (TKI) or alternatively
a HER-1 inhibitor or a HER-2 inhibitor. Several TKIs have been
found to have effective antitumor activity and have been approved
or are in clinical trials. Examples of such include, but are not
limited to, Zactima (ZD6474), Iressa (gefitinib), imatinib mesylate
(ST1571; Gleevec), erlotinib (OSI-1774; Tarceva), canertinib (CI
1033), semaxinib (SU5416), vatalanib (PTK787/ZK222584), sorafenib
(BAY 43-9006), sutent (SUI 1248) and lefltmomide (SU101).
[0079] PTK/ZK is a tyrosine kinase inhibitor with broad specificity
that targets all VEGF receptors (VEGFR), the platelet-derived
growth factor (PDGF) receptor, c-KIT and c-Fms. Drevs (2003) Idrugs
6(8):787-794. PTK/ZK is a targeted drug that blocks angiogenesis
and lymphangiogenesis by inhibiting the activity of all known
receptors that bind VEGF including VEGFR-1 (Flt-1), VEGFR-2
(KDR/Flk-1) and VEGFR-3 (Flt-4). The chemical names of PTK/ZK are
1-[4-Chloroanilino]-4-[4-pyridylmethyl]phthalazine Succinate or
1-Phthalazinamine,
N-(4-chlorophenyl)-4-(4-pyridinylmethyl)-butanedioate (1:1).
Synonyms and analogs of PTK/TK are known as Vatalanib. CGP79787D,
PTK787/ZK 222584, CGP-79787, DE-00268, PTK-787, PTK787A, VEGFR-TK
inhibitor, ZK 222584 and ZK.
[0080] Chemotherapeutic agents that can be conjugated with a
monoterpene or sesquiterpene (or an isomer or analog of monoterpene
or sesquiterpene) may also include amsacrine, Trabectedin,
retinoids (Alitretinoin, Tretinoin), Arsenic trioxide, asparagine
depleter Asparaginase/Pegaspargase), Celecoxib, Demecolcine,
Elesclomol, Elsamitrucin, Etoglucid, Lonidamine, Lucanthone,
Mitoguazone, Mitotane, Oblimersen, Temsirolimus, and
Vorinostat.
[0081] A monoterpene or sesquiterpene (or an isomer or analog of
monoterpene or sesquiterpene) may be conjugated with angiogenesis
inhibitors. Examples of angiogenesis inhibitors include, but are
not limited to, angiostatin, angiozyme, antithrombin III, AG3340,
VEGF inhibitors, batimastat, bevacizumab (avastin), BMS-275291,
CAI, 2C3, HuMV833 Canstatin, Captopril, carboxyamidotriazole,
cartilage derived inhibitor (CDI), CC-5013,
6-O-(chloroacetyl-carbonyl)-fumagillol, COL-3, combretastatin,
combretastatin A4 Phosphate, Dalteparin, EMD 121974 (Cilengitide),
endostatin, erlotinib, gefitinib (Iressa), genistein, halofuginone
hydrobromide, Id1, Id3, IM862, imatinib mesylate, IMC-IC11
Inducible protein 10, interferon-alpha, interleukin 12, lavendustin
A, LY317615 or AE-941, marimastat, mspin, medroxpregesterone
acetate, Meth-1, Meth-2, 2-methoxyestradiol (2-ME), neovastat,
oteopontin cleaved product, PEX, pigment epithelium growth factor
(PEGF), platelet factor 4, prolactin fragment, proliferin-related
protein (PRP), PTK787/ZK 222584, ZD6474, recombinant human platelet
factor 4 (rPF4), restin, squalamine, SU5416, SU6668, SU11248
suramin, Taxol, Tecogalan, thalidomide, thrombospondin, TNP-470,
troponin-1, vasostatin, VEG1, VEGF-Trap, and ZD6474.
[0082] Non-limiting examples of angiogenesis inhibitors also
include, tyrosine kinase inhibitors, such as inhibitors of the
tyrosine kinase receptors Flt-1 (VEGFR1) and Flk-1/KDR (VEGFR2),
inhibitors of epidermal-derived, fibroblast-derived, or platelet
derived growth factors, MMP (matrix metalloprotease) inhibitors,
integrin blockers, pentosan polysulfate, angiotensin 11
antagonists, cyclooxygenase inhibitors (including non-steroidal
anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen, as
well as selective cyclooxygenase-2 inhibitors such as celecoxib and
rofecoxib), and steroidal anti-inflammatories (such as
corticosteroids, mineralocorticoids, dexamethasone, prednisone,
prednisolone, methylpred, betamethasone).
[0083] Other therapeutic agents that modulate or inhibit
angiogenesis include agents that modulate or inhibit the
coagulation and fibrinolysis systems, including, but not limited
to, heparin, low molecular weight heparins and carboxypeptidase U
inhibitors (also known as inhibitors of active thrombin activatable
fibrinolysis inhibitor [TAFIa]). U.S. Patent Publication No.
20090328239. U.S. Pat. No. 7,638,549.
[0084] Non-limiting examples of the anti-hypertensive agents
include angiotensin converting enzyme inhibitors (e.g., captopril,
enalapril, delapril etc.), angiotensin II antagonists (e.g.,
candesartan cilexetil, candesartan, losartan (or Cozaar), losartan
potassium, eprosartan, valsartan (or Diovan), termisartan,
irbesartan, tasosartan, olmesartan, olmesartan medoxomil etc.),
calcium antagonists (e.g., manidipine, nifedipine, amlodipine (or
Amlodin), efonidipine, nicardipine etc.), diuretics, renin
inhibitor (e.g., aliskiren etc.), aldosterone antagonists (e.g.,
spironolactone, eplerenone etc.), beta-blockers (e.g., metoprolol
(or Toporol), atenolol, propranolol, carvedilol, pindolol etc.),
vasodilators (e.g., nitrate, soluble guanylate cyclase stimulator
or activator, prostacycline etc.), angiotensin vaccine, clonidine
and the like. U.S. Patent Publication No. 20100113780.
[0085] Other therapeutic agents that may be conjugated with a
monoterpene or sesquiterpene (or an isomer or analog of monoterpene
or sesquiterpene) include, but are not limited to, Sertraline
(Zoloft), Topiramate (Topamax), Duloxetine (Cymbalta), Sumatriptan
(Imitrex), Pregabalin (Lyrica), Lamotrigine (Lamictal),
Valaciclovir (Valtrex), Tamsulosin (Flomax), Zidovudine (Combivir),
Lamivudine (Combivir), Efavirenz (Sustiva), Abacavir (Epzicom),
Lopinavir (Kaletra), Pioglitazone (Actos), Desloratidine
(Clarinex), Cetirizine (Zyrtec), Pentoprazole (Protonix),
Lansoprazole (Prevacid), Rebeprazole (Aciphex), Moxifloxacin
(Avelox), Meloxicam (Mobic), Dorzolamide (Truspot), Diclofenac
(Voltaren), Enlapril (Vasotec), Montelukast (Singulair), Sildenafil
(Viagra), Carvedilol (Coreg), Ramipril (Delix), and L-DOPA.
[0086] Also encompassed by the present invention are admixtures
and/or coformulations of the present deuterium-enriched compound
and at least one therapeutic agent discussed above.
[0087] The purity of the present compounds may be assayed by gas
chromatography (GC) or high pressure liquid chromatography (HPLC).
Other techniques for assaying purity and for determining the
presence of impurities include, but are not limited to, mass
spectrometry (MS), GC-MS, infrared spectroscopy (IR), nuclear
magnetic resonance (NMR) spectroscopy, and thin layer
chromatography (TLC). Chiral purity can be assessed by chiral GC or
measurement of optical rotation.
[0088] The present compounds may be purified by methods such as
crystallization, or by separating the compounds from impurities
according to the unique physicochemical properties (e.g.,
solubility or polarity) of compounds. Accordingly, the present
compound can be separated by suitable separation techniques known
in the art, such as preparative chromatography, (fractional)
distillation, or (fractional) crystallization.
[0089] The compounds and methods of the present invention may be
used to inhibit the Ras protein. The Ras family is a protein family
of small GTPases that are involved in cellular signal transduction.
Activation of Ras signaling causes cell growth, differentiation and
survival. Mtations in ras genes can permanently activate it and
cause inappropriate transmission inside the cell even in the
absence of extracellular signals. Because these signals result in
cell growth and division, dysregulated Ras signaling can ultimately
lead to oncogenesis and cancer. Activating mutations in Ras are
found in 20-25% of all human tumors and up to 90% in specific tumor
types. Goodsell D S (1999). Downward J., "The molecular
perspective: the ras oncogene". Oncologist 4 (3): 263-4. (January
2003). "Targeting RAS signaling pathways in cancer therapy". Nat.
Rev. Cancer 3 (1): 11-22. Ras family members include, but are not
limited to, HRAS; KRAS; NRAS; DIRAS1; DIRAS2; DIRAS3; ERAS; GEM;
MRAS; NKIRAS1; NKIRAS2; NRAS; RALA; RALB; RAP1A; RAP1B; RAP2A;
RAP2B; RAP2C; RASD1; RASD2; RASL10A; RASL10B; RASL11A; RASL11B;
RASL12; REM1; REM2; RERG; RERGL; RRAD; RRAS; and RRAS. Wennerberg
K, Rossman K L, Der C J (March 2005). "The Ras superfamily at a
glance". J. Cell. Sci. 118 (Pt 5); 843-6.
[0090] The present deuterium-enriched compounds may be formulated
into a pharmaceutical composition. The deuterium-enriched compound
may be present in the pharmaceutical composition in an amount
ranging from about 0.01% (w/w) to about 100% (w/w), from about 0.1%
(w/w) to about 80% (w/w), from about 1% (w/w) to about 70% (w/w),
from about 10% (w/w) to about 60% (w/w), or from about 0.1% (w/w)
to about 20% (w/w).
[0091] The present compounds or pharmaceutical compositions may be
administered by any route known in the art, including, without
limitation, inhalation, intranasal, oral, transdermal, ocular,
intraperitoneal, inhalation, intravenous, ICV, intracisternal
injection or infusion, subcutaneous, implant, vaginal, sublingual,
urethral (e.g., urethral suppository), subcutaneous, intramuscular,
intravenous, rectal, sub-lingual, mucosal, ophthalmic, spinal,
intrathecal, intra-articular, intra-arterial, sub-arachinoid,
bronchial and lymphatic administration. Intranasal formulation can
be delivered as a spray or in a drop; inhalation formulation can be
delivered using a nebulizer or similar device; topical formulation
may be in the form of gel, ointment, cream, aerosol, etc;
transdermal formulation may be administered via a transdermal patch
or iontorphoresis. Compositions can also take the form of tablets,
pills, capsules, semisolids, powders, sustained release
formulations, solutions, suspensions, elixirs, aerosols, or any
other appropriate compositions.
[0092] To prepare such pharmaceutical compositions, one or more of
compound of the present invention may be mixed with a
pharmaceutical acceptable carrier, adjuvant and/or excipient,
according to conventional pharmaceutical compounding techniques.
Pharmaceutically acceptable carriers that can be used in the
present compositions encompass any of the standard pharmaceutical
carriers, such as a phosphate buffered saline solution, water, and
emulsions, such as an oil/water or water/oil emulsion, and various
types of wetting agents. The compositions can additionally contain
solid pharmaceutical excipients such as starch, cellulose, talc,
glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk,
silica gel, magnesium stearate, sodium stearate, glycerol
monostearate, sodium chloride, dried skim milk and the like. Liquid
and semisolid excipients may be selected from glycerol, propylene
glycol, water, ethanol and various oils, including those of
petroleum, animal, vegetable or synthetic origin, e.g., peanut oil,
soybean oil, mineral oil, sesame oil, etc. Liquid carriers,
particularly for injectable solutions, include water, saline,
aqueous dextrose, and glycols. For examples of carriers,
stabilizers and adjuvants, see Remington's Pharmaceutical Sciences,
edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990).
The compositions also can include stabilizers and
preservatives.
[0093] The present invention also provides for a method of treating
a disease comprising the step of administering to a patient a
therapeutically effective amount of a deuterium-enriched compound,
e.g., deuterium-enriched perillyl alcohol, deuterium-enriched
isoperillyl alcohol, a deuterium-enriched perillyl alcohol
carbamate or a deuterium-enriched isoperillyl alcohol
carbamate.
[0094] As used herein, the term "therapeutically effective amount"
is an amount sufficient to treat a specified disorder or disease or
alternatively to obtain a pharmacological response treating a
disorder or disease. Methods of determining the most effective
means and dosage of administration can vary with the composition
used for therapy, the purpose of the therapy, the target cell being
treated, and the subject being treated. Treatment dosages generally
may be titrated to optimize safety and efficacy. Single or multiple
administrations can be carried out with the dose level and pattern
being selected by the treating physician. Suitable dosage
formulations and methods of administering the agents can be readily
determined by those of skill in the art. For example, the
composition are administered at about 0.01 mg/kg to about 200
mg/kg, about 0.1 mg/kg to about 100 mg/kg, or about 0.5 mg/kg to
about 50 mg/kg. When the compounds described herein are
co-administered with another agent or therapy, the effective amount
may be less than when the agent is used alone.
[0095] Transdermal formulations may be prepared by incorporating
the active agent in a thixotropic or gelatinous carrier such as a
cellulosic medium, e.g., methyl cellulose or hydroxyethyl
cellulose, with the resulting formulation then being packed in a
transdermal device adapted to be secured in dermal contact with the
skin of a wearer. If the composition is in the form of a gel, the
composition may be rubbed onto a membrane of the patient, for
example, the skin, preferably intact, clean, and dry skin, of the
shoulder or upper arm and or the upper torso, and maintained
thereon for a period of time sufficient for delivery of the present
compound to the blood serum of the patient. The composition of the
present invention in gel form may be contained in a tube, a sachet,
or a metered pump. Such a tube or sachet may contain one unit dose,
or more than one unit dose, of the composition. A metered pump may
be capable of dispensing one metered dose of the composition.
[0096] This invention also provides the compositions as described
above for intranasal administration. As such, the compositions can
further comprise a permeation enhancer. Southall et al.
Developments in Nasal Drug Delivery, 2000. The present compound may
be administered intranasally as an aerosol, in a liquid form such
as a solution, an emulsion, a suspension, drops, or in a solid form
such as a powder, gel, or ointment.
[0097] Devices to deliver intranasal medications are well known in
the art. Nasal drug delivery can be carried out using devices
including, but not limited to, intranasal inhalers, intranasal
spray devices, atomizers, nasal spray bottles, unit dose
containers, pumps, droppers, squeeze bottles, nebulizers, metered
dose inhalers (MDI), pressurized dose inhalers, insufflators, and
bi-directional devices. The nasal delivery device can be metered to
administer an accurate effective dosage amount to the nasal cavity.
The nasal delivery device can be for single unit delivery or
multiple unit delivery. In a specific example, the ViaNase
Electronic Atomizer from Kurve Technology (Bethell, Wash.) can be
used in this invention. The compounds of the present invention may
also be delivered through a tube, a catheter, a syringe, a
packtail, a pledget, a nasal tampon or by submucosal infusion. U.S.
Patent Publication Nos. 20090326275, 20090291894, 20090281522 and
20090317377.
[0098] The present compound can be formulated as aerosols using
standard procedures. The compound may be formulated with or without
solvents, and formulated with or without carriers. The formulation
may be a solution, or may be an aqueous emulsion with one or more
surfactants. For example, an aerosol spray may be generated from
pressurized container with a suitable propellant such as,
dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, hydrocarbons, compressed air, nitrogen,
carbon dioxide, or other suitable gas. The dosage unit can be
determined by providing a valve to deliver a metered amount. Pump
spray dispensers can dispense a metered dose or a dose having a
specific particle or droplet size. As used herein, the term
"aerosol" refers to a suspension of fine solid particles or liquid
solution droplets in a gas. Specifically, aerosol includes a
gas-borne suspension of droplets of a monoterpene (or
sesquiterpene), as may be produced in any suitable device, such as
an MDI, a nebulizer, or a mist sprayer. Aerosol also includes a dry
powder composition of the composition of the instant invention
suspended in air or other carrier gas. Gonda (1990) Critical
Reviews in Therapeutic Drug Carrier Systems 6; 273-313. Raeburn et
al., (1992) Pharmacol. Toxicol. Methods 27; 143-159.
[0099] The present compound may be delivered to the nasal cavity as
an aerosol, such as a liquid aerosol, or a solid aerosol. The
present compound may be delivered to the nasal cavity as a powder
in a form such as microspheres delivered by a nasal insufflator.
The present compound may be absorbed to a solid surface, for
example, a carrier. The powder or microspheres may be administered
in a dry, air-dispensable form. The powder or microspheres may be
stored in a container of the insufflator. Alternatively the powder
or microspheres may be filled into a capsule, such as a gelatin
capsule, or other single dose unit adapted for nasal
administration.
[0100] The pharmaceutical composition can be delivered to the nasal
cavity by direct placement of the composition in the nasal cavity,
for example, in the form of a gel, an ointment, a nasal emulsion, a
lotion, a cream, a nasal tampon, a dropper, or a bioadhesive strip.
In certain embodiments, it can be desirable to prolong the
residence time of the pharmaceutical composition in the nasal
cavity, for example, to enhance absorption. Thus, the
pharmaceutical composition can optionally be formulated with a
bioadhesive polymer, a gum (e.g., xanthan gum), chitosan (e.g.,
highly purified cationic polysaccharide), pectin (or any
carbohydrate that thickens like a gel or emulsifies when applied to
nasal mucosa), a microsphere (e.g., starch, albumin, dextran,
cyclodextrin), gelatin, a liposome, carbamer, polyvinyl alcohol,
alginate, acacia, chitosans and/or cellulose (e.g., methyl or
propyl; hydroxyl or carboxy; carboxymethyl or hydroxylpropyl).
[0101] The composition containing the present compound can be
administered by oral inhalation into the respiratory tract, i.e.,
the lungs.
[0102] Typical delivery systems for inhalable agents include
nebulizer inhalers, dry powder inhalers (DPI), and metered-dose
inhalers (MDI).
[0103] Nebulizer devices produce a stream of high velocity air that
causes a therapeutic agent in the form of liquid to spray as a
mist. The therapeutic agent is formulated in a liquid form such as
a solution or a suspension of particles of suitable size. In one
embodiment, the particles are micronized. The term "micronized" is
defined as having about 90% or more of the particles with a
diameter of less than about 10 .mu.m. Suitable nebulizer devices
are provided commercially, for example, by PARI GmbH (Starnberg,
Germany). Other nebulizer devices include Respimat (Boehringer
Ingelheim) and those disclosed in, for example, U.S. Pat. Nos.
7,568,480 and 6,123,068, and WO 97/12687. The present compound can
be formulated for use in a nebulizer device as an aqueous solution
or as a liquid suspension.
[0104] DPI devices typically administer a therapeutic agent in the
form of a free flowing powder that can be dispersed in a patient's
air-stream during inspiration. DPI devices which use an external
energy source may also be used in the present invention. In order
to achieve a free flowing powder, the present compound can be
formulated with a suitable excipient (e.g., lactose). A dry powder
formulation can be made, for example, by combining dry lactose
having a particle size between about 1 .mu.m and 100 .mu.m with
micronized panicles of the present compound and dry blending.
Alternatively, the compound can be formulated without excipients.
The formulation is loaded into a dry powder dispenser, or into
inhalation cartridges or capsules for use with a dry powder
delivery device. Examples of DPI devices provided commercially
include Diskhaler (GlaxoSmithKline, Research Triangle Park, N.C.)
(see, e.g., U.S. Pat. No. 5,035,237); Diskus (GlaxoSmithKline)
(see, e.g., U.S. Pat. No. 6,378,519; Turbuhaler (AstraZeneca,
Wilmington, Del.) (see, e.g., U.S. Pat. No. 4,524,769); and
Rotahaler (GlaxoSmithKline) (see, e.g., U.S. Pat. No. 4,353,365).
Further examples of suitable DPI devices are described in U.S. Pat.
Nos. 5,415,162, 5,239,993, and 5,715,810 and references
therein.
[0105] MDI devices typically discharge a measured amount of the
stored composition using compressed propellant gas. Formulations
for MDI administration include a solution or suspension of an
active ingredient in a liquefied propellant. Examples of
propellants include hydrofluoroalklanes (HFA), such as
1,1,1,2-tetrafluoroethane (HFA 134a) and
1,1,1,2,3,3,3-heptafluoro-n-propane (HFA 227), and
chlorofluorocarbons, such as CCl.sub.3F. Additional components of
HFA formulations for MDI administration include co-solvents, such
as ethanol, pentane, water; and surfactants, such as sorbitan
trioleate, oleic acid, lecithin, and glycerin. (See, for example,
U.S. Pat. No. 5,225,183, EP 0717987, and WO 92/22286). The
formulation is loaded into an aerosol canister, which forms a
portion of an MDI device. Examples of MDI devices developed
specifically for use with HFA propellants are provided in U.S. Pat.
Nos. 6,006,745 and 6,143,227. For examples of processes of
preparing suitable formulations and devices suitable for inhalation
dosing see U.S. Pat. Nos. 6,268,533, 5,983,956, 5,874,063, and
6,221,398, and WO 99/53901, WO 00/61108, WO 99/55319 and WO
00/30614.
[0106] The present compound or pharmaceutical composition may be
encapsulated in liposomes or microcapsules for delivery via
inhalation. A liposome is a vesicle composed of a lipid bilayer
membrane and an aqueous interior. The lipid membrane may be made of
phospholipids, examples of which include phosphatidylcholine such
as lecithin and lysolecithin; acidic phospholipids such as
phosphatidylserine and phosphatidylglycerol; and
sphingophospholipids such as phosphatidylethanolamine and
sphingomyelin. Alternatively, cholesterol may be added. A
microcapsule is a particle coated with a coating material. For
example, the coating material may consist of a mixture of a
film-forming polymer, a hydrophobic plasticizer, a surface
activating agent or/and a lubricant nitrogen-containing polymer.
U.S. Pat. Nos. 6,313,176 and 7,563,768.
[0107] The present compound or pharmaceutical composition may also
be used alone or in combination with other chemotherapeutic agents
via topical application for the treatment of localized cancers such
as breast cancer or melanomas. The present compound may also be
used in combination with narcotics or analgesics for transdermal
delivery of pain medication.
[0108] This invention also provides the compound or the
compositions as described above for ocular administration. As such,
the compositions can further comprise a permeation enhancer. For
ocular administration, the compositions described herein can be
formulated as a solution, emulsion, suspension, etc. A variety of
vehicles suitable for administering compounds to the eye are known
in the art. Specific non-limiting examples are described in U.S.
Pat. Nos. 6,261,547; 6,197,934; 6,056,950; 5,800,807; 5,776,445;
5,698,219; 5,521,222; 5,403,841; 5,077,033; 4,882,150; and
4,738,851.
[0109] The present compound or pharmaceutical composition can be
given alone or in combination with other drugs for the treatment of
the above diseases for a short or prolonged period of time. The
present compound or pharmaceutical compositions can be administered
to a mammal, preferably a human. Mammals include, but are not
limited to, murines, rats, rabbit, simians, bovines, ovine,
porcine, canines, feline, farm animals, sport animals, pets,
equine, and primates.
[0110] The present compounds or compositions can be administered
alone, or may be co-administered together with radiation or another
agent (e.g., a chemotherapeutic agent), to treat a disease such as
cancer. Treatments may be sequential, with the present compounds or
compositions being administered before or after the administration
of other agents. For example, a deuterium-enriched perillyl alcohol
(or isoperillyl alcohol) may be used to sensitize a cancer patient
to radiation or chemotherapy. Alternatively, agents may be
administered concurrently.
[0111] The present deuterium-enriched compounds may be used in
combination with radiation therapy. In one embodiment, the present
invention provides for a method of treating tumor cells, such as
malignant glioma cells, with radiation, where the cells are treated
with an effective amount of a deuterium-enriched compound of the
present invention (such as deuterium-enriched perillyl alcohol or
deuterium-enriched isoperillyl alcohol), and then exposed to
radiation. Treatment by the compounds of the present invention may
be before, during and/or after radiation. For example, the
compounds of the present invention may be administered continuously
beginning one week prior to the initiation of radiotherapy and
continued for two weeks after the completion of radiotherapy. U.S.
Pat. Nos. 5,587,402 and 5,602,184.
[0112] In one embodiment, the present invention provides for a
method of treating tumor cells, such as malignant glioma cells,
with chemotherapeutical agent, where the cells are treated with an
effective amount of a deuterium-enriched compound of the present
invention (such as deuterium-enriched perillyl alcohol or
deuterium-enriched isoperillyl alcohol), and then exposed to
chemotherapeutical agent. Treatment by the compounds of the present
invention may be before, during and/or after chemotherapy.
[0113] The compounds or pharmaceutical compositions of the present
invention may be used for the treatment of nervous system cancers,
such as a malignant glioma (e.g., astrocytoma, anaplastic
astrocytoma, glioblastoma multiforme), retinoblastoma, pilocytic
astrocytomas (grade 1), meningiomas, metastatic brain tumors,
neuroblastoma, pituitary adenomas, skull base meningiomas, and
skull base cancer.
[0114] Cancers that can be treated by the present compounds or
pharmaceutical compositions include, but are not limited to, lung
cancer, ear, nose and throat cancer, leukemia, colon cancer,
melanoma, pancreatic cancer, mammary cancer, prostate cancer,
breast cancer, hematopoietic cancer, ovarian cancer, basal cell
carcinoma, biliary tract cancer; bladder cancer; bone cancer;
breast cancer; cervical cancer; choriocarcinoma; colon and rectum
cancer; connective tissue cancer; cancer of the digestive system;
endometrial cancer; esophageal cancer; eye cancer; cancer of the
head and neck; gastric cancer; intra-epithelial neoplasm; kidney
cancer; larynx cancer; leukemia including acute myeloid leukemia,
acute lymphoid leukemia, chronic myeloid leukemia, chronic lymphoid
leukemia; liver cancer; lymphoma including Hodgkin's and
Non-Hodgkin's lymphoma; myeloma; fibroma, neuroblastoma; oral
cavity cancer (e.g., lip, tongue, mouth, and pharynx); ovarian
cancer; pancreatic cancer; prostate cancer; retinoblastoma;
rhabdomyosarcoma; rectal cancer; renal cancer; cancer of the
respiratory system; sarcoma; skin cancer; stomach cancer;
testicular cancer; thyroid cancer; uterine cancer; cancer of the
urinary system, as well as other carcinomas and sarcomas. U.S. Pat.
No. 7,601,355.
[0115] The present invention also provides methods of treating CNS
disorders, including, without limitation, primary degenerative
neurological disorders such as Alzheimer's, Parkinson's,
psychological disorders, psychosis and depression. Autism may also
be treated by the present compositions and methods. Treatment may
consist of the use of a compound of the present invention alone or
in combination with current medications used in the treatment of
Parkinson's, Alzheimer's, or psychological disorders.
[0116] The present invention also provides a method of improving
immunomodulatory therapy responses, comprising the steps of
exposing cells to an effective amount of a compound (such as
deuterium-enriched perillyl alcohol or deuterium-enriched
isoperillyl alcohol) or pharmaceutical compositions of the present
invention, before or during immunomodulatory treatment. Preferred
immunomodulatory agents are cytokines, such interleukins,
lymphokines, monokines, interfereons and chemokines.
[0117] The invention also provides a method for inhibiting the
growth of a cell in vitro, ex vivo or in vivo, where a cell, such
as a cancer cell, is contacted with an effective amount of the
present compound as described herein.
[0118] Pathological cells or tissue such as hyperproliferative
cells or tissue may be treated by contacting the cells or tissue
with an effective amount of the compound or composition of this
invention. The cells, such as cancer cells, can be primary cancer
cells or can be cultured cells available from tissue banks such as
the American Type Culture Collection (ATCC). The pathological cells
can be cells of a systemic cancer, gliomas, meningiomas, pituitary
adenomas, or a CNS metastasis from a systemic cancer, lung cancer,
prostate cancer, breast cancer, hematopoietic cancer or ovarian
cancer. The cells can be from a vertebrate, preferably a mammal,
more preferably a human. U.S. Patent Publication No. 2004/0087651.
Balassiano et al. (2002) Intern. J. Mol. Med. 10; 785-788. Thorne,
et al. (2004) Neuroscience 127; 481-496. Fernandes, et al. (2005)
Oncology Reports 13; 943-947. Da Fonseca, et al. (2008) Surgical
Neurology 70; 259267. Da Fonseca, et al. (2008) Arch. Immunol.
Ther. Exp. 56; 267-276. Hashizume, et al. (2008) Neuroncology 10;
112-120.
[0119] Efficacy of the present composition can be determined using
methods well known in the art. For example, the cytoxicity of the
present compound may be studied by MTT
[3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide]
cytotoxicity assay. MTT assay is based on the principle of uptake
of MTT, a tetrazolium salt, by metabolically active cells where it
is metabolized into a blue colored formazon product, which can be
read spectrometrically. J. of Immunological Methods 65; 55 63,
1983. The cytoxicity of the present compound may be studied by
colony formation assay. Functional assays for inhibition of VEGF
secretion and IL-8 secretion may be performed via ELISA. Cell cycle
block by the present compound may be studied by standard propidium
iodide (PI) staining and flow cytometry. Invasion inhibition may be
studied by Boyden chambers. In this assay a layer of reconstituted
basement membrane, Matrigel, is coated onto chemotaxis filters and
acts as a barrier to the migration of cells in the Boyden chambers.
Only cells with invasive capacity can cross the Matrigel barrier.
Other assays include, but are not limited to, cell viability
assays, apoptosis assays, and morphological assays.
[0120] The following are examples of the present invention and are
not to be construed as limiting.
Example 1
Synthesis of Deuterated Perillyl Alcohol
##STR00010##
[0121] Synthesis of
(S)-4-Isopropenyl-1-cyclohexene-1-methan-.alpha.-d1-ol (2)
[0122] Lithium aluminum deuteride (LAD, 1.0M in THF, 21.2 mL, 21.3
mmol) was added slowly to a cold solution of (S)-Perilladehyde (1,
2.0 g, 13.3 mmol) in dry THF (20 mL) while maintaining the
temperature below 10.degree. C. under N.sub.2. The reaction mixture
was slowly warmed to room temperature and then heated to reflux for
2.0 h. The reaction mixture was quenched with saturated sodium
sulfate solution carefully and the resulting lithium salts were
filtered and washed with ethyl acetate. The organic layer was dried
over sodium sulfate and filtered. The filtrate was concentrated and
the resulting oil was passed through a Thomson single StEP 40 g
column and eluted with 7% ethyl acetate/hexanes (120 mL). The clean
fractions were combined and concentrated under vacuum to give
compound 2 as colorless oil. Weight: 1.78 g. Yield: 88%.
.sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. 1.48 (m, 1H), 1.73 (s,
3H), 1.84-1.99 (m, 2H), 2.11 (m, 4H), 3.99 (d, 1H), 4.71 (m, 2H),
5.71 (bs, 1H). MS (APCI +ve mode): Molecular ion peak was
observed.
##STR00011##
Synthesis of
(S)-4-Isopropenyl-1-cyclohexene-1-methan-.alpha.,.alpha.'-d2-ol
(2)
[0123] Lithium aluminum deuteride (LAD, 1.0M in THF, 16.6 mL, 16.6
mmol) was added slowly to a cold solution of (S)-Methylperillate
(1, 2.0 g, 1 mmol) in dry THF (20 mL) while maintaining the
temperature below 10.degree. C. under N.sub.2. The reaction mixture
was slowly warmed to room temperature and then stirred at room
temperature for 2.0 h. The reaction mixture was quenched with
saturated sodium sulfate solution carefully and the resulting
lithium salts were filtered and washed with ethyl acetate. The
organic layer was dried over sodium sulfate and filtered. The
filtrate was concentrated and the resulting oil was passed through
a Thomson single StEP 40 g column and eluted with 5% ethyl
acetate/hexanes (150 mL). The clean fractions were combined and
concentrated under vacuum to give compound 2 as colorless oil.
Weight: 1.34 g. Yield: 79%. .sup.1H-NMR (400 MHz, CDCl.sub.3):
.delta. 1.45-1.49 (m, 1H), 1.73 (s, 3H), 1.84-1.98 (m, 2H),
2.11-2.17 (m, 4H), 4.71 (m, 2H), 5.69 (bs, 1H). MS (APCI +ve mode):
Molecular ion peak was observed.
##STR00012##
Synthesis of (S)-4-Isopropenyl-1-cyclohexene-1-deutero
methan-.alpha.-d1-ol (2)
[0124] Lithium aluminum deuteride (LAD, 1.0M in THF, 21.2 mL, 21.3
mmol) will be added slowly to a cold solution of (S)-Perilladehyde
(1, 2.0 g, 13.3 mmol) in dry THF (20 mL) while maintaining the
temperature below 10.degree. C. under N.sub.2. The reaction mixture
will be slowly warmed to room temperature and heated to reflux for
2.0 h. The reaction will be quenched with 5% sodium deuteroxide in
D.sub.2O (6.0 mL) carefully. The resulting lithium salts will be
filtered and washed with ethyl acetate. The organic layer will be
dried over sodium sulfate and filtered. The filtrate will be
concentrated and the resulting oily residue will be passed through
a Thomson single StEP 40 g column and will be eluted with 7% ethyl
acetate/hexanes (120 mL). The clean fractions will be combined and
concentrated under vacuum to give compound 2 as colorless oil.
##STR00013##
Synthesis of (S)-4-Isopropenyl-1-cyclohexene-1-deutero
methan-.alpha.,.alpha.'-d2-ol (2)
[0125] Lithium aluminum deuteride (LAD, 1.0M in THF, 16.6 mL, 16.6
mmol) will be added slowly to a cold solution of
(S)-Methylperillate (1, 2.0 g, 11 mmol) in dry THF (20 mL) while
maintaining the temperature below 10.degree. C. under N.sub.2. The
reaction mixture will be slowly warmed to room temperature and then
stirred at room temperature for 2.0 h. The reaction mixture will be
quenched with 5% sodium deuteroxide in D.sub.2O (6.0 mL) carefully.
The resulting lithium salts will be filtered and washed with ethyl
acetate. The organic layer will be dried over sodium sulfate and
filtered. The filtrate will be concentrated. The resulting oily
residue will be passed through a Thomson single StEP 40 g column
and will be eluted with 7% ethyl acetate/hexanes (120 mL). The
clean fractions will be combined and concentrated under vacuum to
give compound 2 as colorless oil.
Example 2
Synthesis of Deuterated iso-perillyl alcohol:
4-isopropylidene-1-cyclohexene-1-methan-.alpha.,.alpha.'-d2-ol
##STR00014##
[0126] Synthesis of trifluoromethanesulfonic acid
4-isopropylidenecyclohex-1-enyl ester (2)
[0127] A 2.5M solution of n-Butyl lithium in hexanes (5.6 mL, 14.1
mmol) was added to a solution of diisopropylamine (1.98 mL, 14.1
mmol) in dry THF (30 mL) at -78.degree. C. over a period of 0.5 hr.
After stirring for 1.0 h at -78.degree. C., a solution of ketone
(1, 1.3 g, 9.4 mmol) in dry THF (10 mL) was added over a period of
10 min while maintaining the temperature below -78.degree. C. The
reaction mixture was stirred for 1.0 h at -78.degree. C. A solution
of phenyltriflimide (3.53 g, 9.86 mmol) in dry THF (15 mL) was
added slowly while maintaining the temperature below -78.degree. C.
The reaction mixture was slowly warmed to 0.degree. C., maintained
for 2.0 h at 0.degree. C. and then quenched with saturated ammonium
chloride solution. The separated organic layer was washed with
water (15 mL), brine (15 mL) and dried over sodium sulfate. The
filtered organic layer was concentrated under vacuum. The resulting
residue was purified by column chromatography. [Column dimensions:
diameter: 6.0 cm, height: 12 cm, silica: 200 mesh, eluted with
hexanes (200 mL)] The similar fractions were combined and
concentrated under vacuum which gave 2 as an oil. Weight: 0.9 g.
Weight yield: 38%. .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. 1.68
(s, 3H), 1.71 (s, 3H), 2.37 (m, 2H), 2.46 (m, 2H), 2.91 (m, 2H),
5.73 (m, 1H). MS (APCI +ve mode): Molecular ion peak was
observed.
Synthesis of 4-isopropylidene cyclohex-1-ene carboxylic acid methyl
ester (3)
[0128] To a solution of compound 2 (0.2 g, 0.74 mmol) in
N'N-dimethylformamide (1.5 mL) were added methanol (1.0 mL),
triethylamine (0.17 mL, 1.2 mmol),
1,3-bis(diphenylphosphino)propane (0.03 g, 0.07 mmol) and palladium
acetate (0.04 g, 0.07 mmol). The reaction mixture was degassed and
then stirred at room temperature under carbon monoxide (balloon
pressure) for 5 h. The reaction mixture was diluted with ethyl
acetate (15 mL) and washed with 0.5N HCl (15 mL), brine (15 mL) and
dried over sodium sulfate. The filtered organic layer was
concentrated under vacuum and the resulting residue was purified by
column chromatography. [Column dimensions: diameter: 6.0 cm,
height: 12 cm, silica: 200 mesh, eluted with hexanes (100 mL)
followed by ethyl acetate:hexanes (2%, 150 mL)]. The similar
fractions were combined and concentrated under vacuum which gave an
oil. Weight: 0.07 g. Yield: 52%.
Synthesis of
4-isopropylidene-1-cyclohexene-1-mean-.alpha.,.alpha.'-d2-ol
(4)
[0129] Lithium aluminum deuteride (1.0M in THF, 16.6 mL, 16.6 mmol)
will be added slowly to a cold solution of methyl ester (3, 2.0 g,
11 mmol) in dry THF (20 mL) while maintaining the temperature below
10.degree. C. under N.sub.2. The reaction mixture will be slowly
warmed to room temperature and then stirred at room temperature for
2.0 h. The reaction mixture will be quenched with saturated sodium
sulfate solution carefully. The resulting lithium salts will be
filtered and washed with ethyl acetate. The organic layer will be
dried over sodium sulfate and filtered. The filtrate will be
concentrated and the resulting oil will be purified by column
chromatography to obtain compound 4.
Example 3
Synthesis of Deuterated iso-perillyl alcohol:
4-Isopropylidene-1-cyclohexene-1-deutero
methan-.alpha.,.alpha.'-d2-ol
##STR00015##
[0131] Lithium aluminum deuteride (1.0M in THF, 16.6 mL, 16.6 mmol)
will be added slowly to a cold solution of Methyl ester (3, 2.0 g,
11 mmol) in dry THF (20 mL) while maintaining the temperature below
10.degree. C. under N.sub.2. The reaction mixture will be slowly
warmed to room temperature and then it will be stirred at room
temperature for 2.0 h. The reaction mixture will be quenched with
5% sodium deuteroxide in D.sub.2O (6.0 mL) carefully. The resulting
lithium salts will be filtered, and washed with ethyl acetate. The
organic layer will be dried over sodium sulfate and filtered. The
filtrate will be concentrated and the resulting oily residue will
be purified by column chromatography to obtain compound 4A.
Example 4
Synthesis of Deuterated iso-perillyl alcohol:
4-isopropylidene-1-cyclohexene-1-methan-.alpha.-d1-ol
##STR00016##
[0132] Synthesis of 4-isopropylidene cyclohex-1-enyl methanol
(5)
[0133] Methyl ester (3, 1.0 g, 5.54 mmoL) in dry THF (10 mL) was
added to lithium aluminum hydride (0.25 g, 6.6 mmoL) in dry THF (20
mL) at 10.degree. C. over a period of 5 min. The mixture was slowly
heated to reflux and maintained for 2.0 h. The reaction mixture was
cooled and quenched with saturated sodium sulfate solution (2.0
mL). The lithium salts were filtered and washed with hot ethyl
acetate. The organic layer was dried over sodium sulfate, filtered
and concentrated under vacuum to give a colorless oil. Weight: 0.67
g. Yield: 80%. .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. 1.65 (s,
3H), 1.69 (s, 3H), 1.77 (bs, OH), 2.09 (m, 2H), 2.33 (t, 2H), 2.79
(br s, 2H), MS (APCI +ve mode): m/e: 152 (M, 3.5%), 135.07 (100%),
107.12 (5%).
Synthesis of 4-isopropylidene-cyclohex-1-ene carbaldehyde (6)
[0134] Dry DMSO (0.5 ml) will be added to a cold solution of oxalyl
chloride (0.67 mL, 7.8 mmol) in dichloromethane (15 mL) at
-78.degree. C. and the mixture will be stirred for 20 min. Alcohol
(5, 1.0 g, 6.5 mmol), in 5 mL of DCM will be added over 10 min and
the mixture will be stirred for 1.0 h followed by the addition of
triethylamine (0.8 mL). The reaction mixture will be stirred for
0.5 h and then warmed to room temperature. Water (20 mL) will be
added and the DCM layer will be separated. The aqueous layer will
be extracted with DCM (20 mL) and separated. The combined DCM layer
will be washed with water, separated, and will be dried over sodium
sulfate. The filtered organic layer will be concentrated under
vacuum and the resultant residue will be purified by column
chromatography to obtain compound 6.
Synthesis of 4-isopropylidene-1-cyclohexene-1-methan-.alpha.-d1-ol
(7)
[0135] Lithium aluminum deuteride (1.0M in THF, 21.2 mL, 21.3 mmol)
will be added slowly to a cold solution of adehyde (6, 2.0 g, 13.3
mmol) in dry THF (20 mL) while maintaining the temperature below
10.degree. C. under N.sub.2. The reaction mixture will be slowly
warmed to room temperature and then heated to reflux for 2.0 h. The
reaction mixture will be quenched with saturated sodium sulfate
solution carefully. The resulting lithium salts will be filtered
and washed with ethyl acetate. The organic layer will be dried over
sodium sulfate and filtered. The filtrate will be concentrated and
the resulting oil will be purified by column chromatography to
obtain compound 7.
Example 5
Synthesis of Deuterated iso-perillyl alcohol:
4-Isopropylidene-1-cyclohexene-1-deutero methan-.alpha.-d1-ol
##STR00017##
[0137] Lithium aluminum deuteride (1.0M in THF, 21.2 mL, 21.3 mmol)
will be added slowly to a cold solution of aldehyde (6, 2.0 g, 13.3
mmol) in dry THF (20 mL) while maintaining the temperature below
10.degree. C. under N.sub.2. The reaction mixture will be slowly
warmed to room temperature and then it will be heated to reflux for
2.0 h. The reaction will be quenched with 5% sodium deuteroxide in
D.sub.2O (6.0 mL) carefully and the resulting lithium salts will be
filtered, washed with ethyl acetate. The organic layer will be
dried over sodium sulfate and filtered. The filtrate will be
concentrated and the resulting oily residue will be purified by
column chromatography to obtain compound 7A.
Example 6
Synthesis of Dimethyl Celecoxib bisPOH Carbamate
(4-(bis-N,N'-4-isopropenyl cyclohex-1-enylmethyloxy
carbonyl[5-(2,5-dimethyl phenyl)-3-trifluoromethyl
pyrazol-1-yl]benzenesulfonamide)
[0138] The reaction scheme is the following:
##STR00018##
[0139] Phosgene (20% in toluene, 13 ml, 26.2 mmol) was added to a
mixture of perillyl alcohol (2.0 grams, 13.1 mmol) and potassium
carbonate (5.4 grams, 39.1 mmol) in dry toluene (30 mL) over a
period of 30 minutes while maintaining the temperature between
10.degree. C. to 15.degree. C. The reaction mixture was allowed to
warm to room temperature and stirred for 8.0 hours under N.sub.2.
The reaction mixture was quenched with water (30 mL) and the
organic layer was separated. The aqueous layer was extracted with
toluene (20 mL) and the combined organic layer was washed with
water (50 mL.times.2), brine (15%, 30 mL) and dried over sodium
sulfate (20 grams). The filtered organic layer was concentrated
under vacuum to give perillyl chloroformate as an oil. Weight: 2.5
grams; Yield: 89%. .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. 1.5
(m, 1H), 1.7 (s, 3H), 1.8 (m, 1H), 2.0 (m, 1H), 2.2 (m, 4H), 4.7
(dd, 4H); 5.87 (m, 1H).
[0140] Perillyl chloroformate (0.11 grams, 0.55 mmol) was added
slowly to a mixture of dimethyl celecoxib (0.2 grams, 0.50 mmol)
and potassium carbonate (0.13 grams, 1.0 mmol) in dry acetone (10
mL) over a period of 5 minutes under N.sub.2. The reaction mixture
was heated to reflux and maintained for 3 hours. Since TLC analysis
indicated the presence of dimethyl celecoxib (>60%), another 1.0
equivalent of perillyl chloroformate was added and refluxed for an
additional 5 hours. The reaction mixture was cooled and acetone was
concentrated under vacuum to give a residue.
[0141] The resulting residue was suspended in water (15 mL) and
extracted with ethyl acetate (3.times.15 mL). The combined organic
layer was washed with water (20 mL) followed by brine (15%, 20 mL)
and dried over sodium sulfate. The filtered organic layer was
concentrated under vacuum to give a residue which was purified by
column chromatography [column dimensions: diameter: 1.5 cm, height:
10 cm, silica: 230-400 mesh] and eluted with hexanes (100 mL)
followed by a mixture of hexanes/ethyl acetate (95:5, 100 mL). The
hexane/ethyl acetate fractions were combined and concentrated under
vacuum to give a gummy mass.
[0142] The product POH carbamate exhibited a weight of 120 mg and a
yield of 31%. .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. 0.9 (m,
2H), 1.4 (m, 2H), 1.7 (m, 7H*), 1.95 (m, 8H*), 2.1 (m, 4H), 2.3 (s,
3H), 4.4 (d, 2H), 4.7 (dd, 2H), 5.6 (br d, 2H), 6.6 (s, 1H), 7.0
(br s, 1H), 7.12 (d, 1H), 7.19 (d, 1H), 7.4 (d, 2H), 7.85 (d, 2H);
MS, m/e: 751.8 (M.sup.+ 3%), 574.3 (100%), 530.5 (45%), 396 (6%). *
N.B. further 2H overlapping from presumed impurity discounted in
NMR integration.
[0143] The product POH carbamate may be partially or fully
deuterated. For example, one or more of the H atoms may be
deuterium.
Example 7
Synthesis of Temozolomide POH Carbamate (3-methyl
4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbonyl)-carbamic
acid-4-isopropenyl cyclohex-1-enylmethyl ester)
[0144] The reaction scheme is the following:
##STR00019##
[0145] Oxalyl chloride (0.13 grams, 1.0 mmol) was added slowly to a
mixture of temozolomide (OChem Incorporation, 0.1 grams, 0.5 mmol)
m 1,2-dichloroethane (10 mL) over a period of 2 minutes while
maintaining the temperature at 10.degree. C. under N.sub.2. The
reaction mixture was allowed to warm to room temperature and then
heated to reflux for 3 hours. The excess of oxalyl chloride and
1,2-dichloroethane were removed by concentration under vacuum. The
resulting residue was re-dissolved in 1,2-dichlorethane (15 mL) and
the reaction mixture was cooled to 10.degree. C. under N.sub.2. A
solution of perillyl alcohol (0.086 grams, 0.56 mmol) in
1,2-dichloroethane (3 mL) was added over a period of 5 minutes. The
reaction mixture was allowed to warm to room temperature and
stirred for 14 hours. 1,2-dichloroethane was concentrated under
vacuum to give a residue, which was triturated with hexanes. The
resulting yellow solid was filtered and washed with hexanes.
Weight: 170 mg; Yield: 89%. .sup.1H-NMR (400 MHz, CDCl.sub.3):
.delta. 1.4-2.2 (m, 10H), 4.06 (s, 3H), 4.6-4.8 (m, 4H), 5.88 (br
s, 1H), 8.42 (s, 1H), 9.31 (br s, 1H); MS, no molecular ion peak
was observed. m/e: 314 (100%), 286.5 (17%), 136 (12%).
[0146] Alternatively, temozolomide POH carbamate was synthesized
according to the following procedure. Oxalyl chloride (0.13 grams,
1.0 mmol) was added slowly to a mixture of temozolomide (OChem
Incorporation, 0.1 grams, 0.5 mmol) in 1,2-dichloroethane (10 mL)
over a period of 2 minutes while maintaining the temperature at
10.degree. C. under N.sub.2. The reaction mixture was allowed to
warm to room temperature and then heated to reflux for 3 hours. The
excess of oxalyl chloride and 1,2-dichloroethane were removed by
concentration under vacuum. The resulting residue was re-dissolved
in 1,2-dichlorethane (15 mL) and the reaction mixture was cooled to
10.degree. C. under N.sub.2. A solution of perillyl alcohol (0.086
grams, 0.56 mmol) in 1,2-dichloroethane (3 mL) was added over a
period of 5 minutes. The reaction mixture was allowed to warm to
room temperature and stirred for 14 hours. 1,2-Dichloroethane was
concentrated under vacuum to give a residue, which was purified by
a short silica-plug column (column dimensions: diameter: 2 cm,
height: 3 cm, silica: 230-400 mesh) and eluted with a mixture of
hexanes/ethyl acetate (1:1, 100 mL). The hexane/ethyl acetate
fractions were combined and concentrated under vacuum to give a
white solid residue which was triturated with heptanes and filtered
to obtain a white solid. Weight: 170 mg; Yield: 89%. .sup.1H-NMR
(400 MHz, CDCl3): 1.4-2.2 (m, 10H), 4.06 (s, 3H), 4.6-4.8 (m, 4H),
5.88 (br s, 1H), 8.42 (s, 1H), 9.31 (br s, 1H); MS, no molecular
ion peak was observed, m/e: 314 (100%), 286.5 (17%), 136 (12%).
[0147] The product POH carbamate may be partially or fully
deuterated. For example, one or more of the H atoms may be
deuterium.
Example 8
Synthesis of Rolipram POH Carbamate (4-(3-cyclopentyloxy-4-methoxy
phenyl)-2-oxo-pyrrolidine-1-carboxylic acid 4-isopropenyl
cyclohex-1-enylmethyl ester)
[0148] The reaction scheme is the following:
##STR00020##
[0149] Phosgene (20% in toluene, 13 ml, 26.2 mmol) was added to a
mixture of perillyl alcohol (2.0 grams, 13.1 mmol) and potassium
carbonate (5.4 grams, 39.1 mmol) in dry toluene (30 mL) over a
period of 30 minutes while maintaining the temperature between
10.degree. C. to 15.degree. C. The reaction mixture was allowed to
warm to room temperature and stirred for 8.0 hours under N.sub.2.
The reaction mixture was quenched with water (30 mL) and the
organic layer separated. The aqueous layer was extracted with
toluene (20 mL) and the combined organic layer washed with water
(50 mL.times.2), brine (15%, 30 mL) and dried over sodium sulfate
(20 grams). The filtered organic layer was concentrated under
vacuum to give perillyl chloroformate as an oil. Weight: 2.5 grams;
Yield: 89%. .sup.1H-NMR (400 MHz, CDCl_): .delta. 1.5 (m, 1H), 1.7
(s, 3H), 1.8 (m, 1H), 2.0 (m, 1H), 2.2 (m, 4H), 4.7 (dd, 4H); 5.87
(m, 1H).
[0150] Butyl lithium (2.5M, 0.18 mL, 0.45 mmol) was added to a
solution of rolipram (GL synthesis, Inc., 0.1 grams, 0.36 mmol) in
dry THF at -72.degree. C. over a period of 5 minutes under N.sub.2.
After the reaction mixture was stirred for 1.0 hours at -72.degree.
C., perillyl chloroformate (dissolved in 4 mL THF) was added over a
period of 15 minutes while maintaining the temperature at
-72.degree. C. The reaction mixture was stirred for 2.5 hours and
quenched with saturated ammonium chloride (5 mL). The reaction
mixture was allowed to warm to room temperature and extracted with
ethyl acetate (2.times.15 mL). The combined organic layer was
washed with water (15 mL), brine (15%, 15 mL), and then dried over
sodium sulfate. The filtered organic layer was concentrated to give
an oil which was purified by column chromatography [column
dimensions: diameter: 1.5 cm, height: 10 cm, silica: 230-400 mesh]
and eluted with a mixture of 8% ethyl acetate/hexanes (100 mL)
followed by 12% ethyl acetate/hexanes (100 mL). The 12% ethyl
acetate/hexanes fractions were combined and concentrated under
vacuum to yield a gummy solid. Weight: 142 mg; Yield: 86%.
.sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. 1.5 (m, 1H) 1.6 (m, 2H),
1.7 (s, 3H), 1.9 (m, 6H), 2.2 (m, 5H), 2.7 (m, 1H), 2.9 (m, 1H),
3.5 (m, 1H), 3.7 (m, 1H), 3.8 (s, 3H), 4.2 (m, 1H), 4.7 (m, 6H),
5.8 (br s, 1H), 6.8 (m, 3H); MS, m/e: 452.1 (M.sup.+1 53%), 274.1
(100%), 206.0 (55%).
[0151] The product POH carbamate may be partially or fully
deuterated. For example, one or more of the H atoms may be
deuterium.
Example 9
Synthesis of Iso-POH Conjugated with Temozolamide (TMZ)
[0152] The reaction scheme is the following:
##STR00021##
Preparation of (3-Methyl
4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbonyl)-carbamic
acid-4-isopropylidene cyclohex-1-enylmethyl ester
[0153] Oxalyl chloride (0.26 g, 2.0 mmol) will be added slowly to a
mixture of Temozolamide (Source: OChem Incorporation, Lot
#0711185A; 0.2 g, 1.0 mmol) in 1,2-dichloroethane (IS mL) over a
period of 5 min while maintaining the temperature at 10.degree. C.
under N.sub.2. The reaction mixture will be allowed to warm to room
temperature and then heated to reflux for 2.5 h. The excess of
oxalyl chloride and 1,2-dichloroethane will be removed by
concentration under vacuum. The resulting residue will be
redissolved in 1,2-dichloroethane (20 mL) and the reaction mixture
cooled to 5.degree. C. under N.sub.2. A solution of isoperillyl
alcohol (0.17 g, 1.12 mmol) in 1,2-dichloroethane (5 mL) will be
added over a period of 10 min. The reaction mixture will be allowed
to warm to room temperature and stirred for 12 h.
1,2-Dichloroethane will be concentrated under vacuum to give a
residue which will be triturated with hexanes. The resulting pale
yellow solid will be filtered and washed with hexanes.
[0154] The product iso-POH carbamate may be partially or fully
deuterated. For example, one or more of the H atoms may be
deuterium.
Example 10
Synthesis of Iso-POH Conjugated with Rolipram
[0155] The reaction scheme is as follows.
##STR00022##
Preparation of
4-(3-(Cyclopentyloxy-4-methoxyphenyl)-2-oxo-pyrrolidine-1-carboxylic
acid 4-isopropylidene cyclohex-1-enylmethyl ester
[0156] Phosgene (20% in toluene, 19.5 ml, 39.4 mmol) will be added
to a mixture of isoperillyl alcohol (3.0 g, 19.7 mmol) and
potassium carbonate (8.1 g, 58.6 mmol) in dry toluene (415 mL) over
a period of 45 min while maintaining the temperature between
10-12.degree. C. The reaction mixture will be allowed to warm to
room temperature and stirred for 10 h under N.sub.2. The reaction
mixture will be quenched with water (40 mL) and the organic layer
separated. The aqueous layer will be extracted with toluene (30 mL)
and the combined organic layer washed with water (40 mL.times.2),
brine (10%, 40 mL), and dried over sodium sulfate (25 g). The
filtered organic layer will be concentrated under vacuum to give
isoperillyl chloroformate as an oil.
[0157] Butyl lithium (2.5M, 0.36 mL, 0.90 mmol) will be added to a
solution of rolipram (Source: GL synthesis, Inc. Lot
#GLS-SH-110809; 0.2 g, 0.72 mmol) in dry THF (8 mL) at -72.degree.
C. over a period of 10 min under N.sub.2. After the reaction
mixture being stirred for 1.0 h at -72.degree. C., isoperillyl
chloroformate (0.16 g, 0.76 mmol, dissolved in 4 mL THF) will be
added over a period of 10 min while maintaining the temperature at
-72.degree. C. The reaction mixture will be stirred for 3 h and
quenched with saturated ammonium chloride (10 mL). The reaction
mixture will be allowed to warm to room temperature and extracted
with ethyl acetate (2.times.20 mL). The combined organic layer will
be washed with water (20 mL), brine (10%, 25 mL), and dried over
sodium sulfate. The filtered organic layer will be concentrated to
give an oil which will be purified by column chromatography [Column
dimensions: dia: 1.5 cm, height: 15 cm, silica: 230-400 mesh] and
eluted with a mixture of 5% ethyl acetate/hexanes (120 mL) followed
by 10% ethyl acetate/hexanes (150 mL). The 10% ethyl
acetate/hexanes fractions will be combined and concentrated under
vacuum to give a gummy solid.
[0158] The product iso-POH carbamate may be partially or fully
deuterated. For example, one or more of the H atoms may be
deuterium.
Example 11
Synthesis of Dimethyl Celecoxib bis iso-POH carbamate conjugate
[0159] The reaction scheme is as follows.
##STR00023##
Preparation of 4-(Bis-N,N'-4-isopropylidene
cyclohex-1-enylmethyloxy carbonyl[5-(2,5-dimethyl
phenyl)-3-trifluoromethyl pyrazol-1-yl]benzenesulfonamide
[0160] Phosgene (20% in toluene, 19.5 ml, 39.4 mmol) will be added
to a mixture of isoperillyl alcohol (3.0 g, 19.7 mmol) and
potassium carbonate (8.1 g, 58.6 mmol) in dry toluene (45 mL) over
a period of 45 min while maintaining the temperature between
10-12.degree. C. The reaction mixture will be allowed to warm to
room temperature and stirred for 10 h under N.sub.2. The reaction
mixture will be quenched with water (40 mL) and the organic layer
separated. The aqueous layer will be extracted with toluene (30 mL)
and the combined organic layer washed with water (40 mL.times.2),
brine (10%, 40 mL), and dried over sodium sulfate (25 g). The
filtered organic layer will be concentrated under vacuum to give
isoperillyl chloroformate as an oil.
[0161] Isoperillyl chloroformate (0.22 g, 1.0 mmol) will be added
slowly to a mixture of dimethyl celecoxib (0.2 g, 0.50 mmol) and
potassium carbonate (0.14 g, 1.0 mmol) in dry acetone (25 mL) over
a period of 5 min under N.sub.2. The reaction mixture will be
heated to reflux and maintained for 4 h. The reaction mixture will
be cooled and the acetone concentrated under vacuum. The resulting
residue will be suspended in water (25 mL) and extracted with ethyl
acetate (3.times.20 mL). The combined organic layer will be washed
with water (40 mL), followed by brine (10%, 30 mL), and dried over
sodium sulfate. The filtered organic layer will be concentrated
under vacuum to give a residue which will be purified by column
chromatography [Column dimensions: dia: 1.5 cm, height: 15 cm,
silica: 230-400 mesh] and eluted with hexanes (100 mL) followed by
a mixture of hexanes/ethyl acetate (95:5, 100 mL). The hexane/ethyl
acetate fractions will be combined and concentrated under vacuum to
give a gummy mass.
[0162] The product iso-POH carbamate may be partially or fully
deuterated. For example, one or more of the H atoms may be
deuterium.
[0163] The scope of the present invention is not limited by what
has been specifically shown and described hereinabove. Those
skilled in the art will recognize that there are suitable
alternatives to the depicted examples of materials, configurations,
constructions and dimensions. Numerous references, including
patents and various publications, are cited and discussed in the
description of this invention. The citation and discussion of such
references is provided merely to clarify the description of the
present invention and is not an admission that any reference is
prior art to the invention described herein. All references cited
and discussed in this specification are incorporated herein by
reference in their entirety. Variations, modifications and other
implementations of what is described herein will occur to those of
ordinary skill in the art without departing from the spirit and
scope of the invention. While certain embodiments of the present
invention have been shown and described, it will be obvious to
those skilled in the art that changes and modifications may be made
without departing from the spirit and scope of the invention. The
matter set forth in the foregoing description and accompanying
drawings is offered by way of illustration only and not as a
limitation.
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