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United States Patent
Hampson et al.
US006630507B1
US 6,630,507 BL
Oct. 7, 2003,
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45) Date of Patent:
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CANNABINOIDS AS ANTIOXIDANTS AND
NEUROPROTECTANTS
Inventors: Aidan J. Hampson, Irvine, CA (US);
ius Axelrod, Rockville, MD (US
adi, Bethesda, MD
Assignee: The United States of America as
represented by the Department of
Health and Human S
‘Washington, DC (US)
Notice: Subject to any disclaimer, the term ofthis,
patent is extended or adjusted under 35
US.C. 154(b) by 0 days.
Appl. No 09/674,028
PCT Filed: Apr. 21, 1999
PCT No, PCT/US99/08769
§371 @),
Q), (4) Date: , 2001
PCT Pub, No: W099/53917
PCT Pub, Date: Oct. 28, 1999
Related U.S. Application Data
Provisional application No. 601082.589, filed om Ape. 21,
1098, and provisional application No, 60/95,995, fied on
‘Aug. 10, 1998,
Int. c? AGIK 31/35
US. Cl. 514/454
Field of Search 514454
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(List continued om next page.)
Primary Examiner—Kevia E. Weddington
(74) Attorney, Agent, or Firm—Klarquist Sparkman, LLP
6 ABSTRACT
Cannabinoids have been found to have antioxidant
properties, unrelated to NMDA receptor antagonism, This
new found property makes cannabinoids useful in the treat-
ment and prophylaxis of wide variety of oxidation associ
ated diseases, such as ischemic, age-related, inflammatory
and autoimmune diseases. The cannabinoids are found 10
have particular application as neuroprotectants, for example
in limiting neurological damage following ischemic insult,
Such as stroke and trauma, of in the treatment of neurode-
generative diseases, such as Alzheimer’s disease, Parkin-
son's disease and HIV dementia, Nonpsychoactive
‘cannabinoids, such as cannabidoil, are particularly advan-
tageous to use because they avoid toxicity that is encoun-
tered with psychoactive cannabinoids at high doses useful in
the method of the present invention. A particular disclosed
class of cannabinoids useful as neuroprotective antioxidants
is formula (I) wherein the R group is independently selected
from the group consisting of H, CHs, and COCHs,
26 Claims, 7 Drawing SheetsUS 6,630,507 BL
Page 2
OTHER PUBLICATIONS
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‘Cannabinoids, but not Anandamide, are Protective ina
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alkylesorcinol Free Radical Scavenger Antioxidant
Resorstaton,” Synthetic Communications, Marcel Dekker,
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Shohami etal, “Oxidative Sicess in Closed-Head Injury’
Brain Antioxidant Capacity as an Indicator of Functional
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(2997).
Zarier ot al.,“Dimethylheptyl-THC-11 OIC Acid,” Arthri-
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Hampson et al, “Dual Effeets of Anandamide on NMDA
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bono are Neuroprotective Antioxidants,” Medical Sciences,
Proc. Natl. Acad. Sci. USA, 8268-8273 (1998)
* cited by examinerU.S. Patent Oct. 7, 2003 Sheet 1 of 7 US 6,630,507 BL
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1
CANNABINOIDS AS ANTIOXIDANTS AND
NEUROPROTECTANTS
‘This application is a 371 of PCT/US99/08769 filed Apr.
21, 1999, which claims benefit of No. 60/082,589 filed Apr.
21, 1998, which claims benefit of No. 60/095,993 filed Aus
10, 1998.
FIELD OF THE INVENTION
‘The present invention concerns pharmaceutical com-
pounds and compositions that are useful as tissue
protectants, such as neuroprotectants and cardioprotectants.
‘The compounds and compositions may be used, for
‘example, in the treatment of acute ischemic neurological
insults oF chronic neurodegenerative diseases.
BACKGROUND OF THE INVENTION
Permanent injury to the central nervous system (CNS)
‘occurs in a variety of medical conditions, and has been the
subject of intense scientific scrutiny in recent years. It is
known that the brain has high metabolic requirements, and
that it can suffer permanent neurologic damage if deprived
‘of suflicient oxygen (hypoxia) for even a few minutes. Inthe
absence of oxygen (anoxia), mitochondrial production of
ATP cannot meet the metabolic requirements of the brain,
and tissue damage occurs. This process is exacerbated by
neuronal release of the neurotransmitter glutamate, which
stimulates NMDA_(N-methyl-D-aspartate), AMPA
(ceamino-3-hydroxy-5-methyl-4isoxazole propionate) and
Kainate receptors. Activation of these receptors initiates
calcium infix into the neurons, and production of reactive
‘oxygen species, which are potent toxins that damage impor-
tant cellular structures such as membranes, DNA and
enzymes.
‘The brain has many redundant blood supplies, which
means that its tissue is seldom completely deprived of
‘oxygen, even during acute iehemic events eaused by throm-
boembolie evens or trauma. A combination ofthe injury of
hypoxia with the added insult of glutamate toxicity is
therefore believed to be ultimately responsible for cellular
death. Hence ifthe addltive insult of glutamate toxicity ean
be alleviated, neurological damage could also be lessened.
Anti-oxidants and aatiinflammatory agents have been pro=
posed to reduce damage, but they often have poor access 10
Siructures such as the brain (which are protected by the
blood brain barrier).
Given the importance of the NMDA, AMPA and kainate
receptors in the mechanism of injury, research efforts have
focused on using antagonists to these receptors to interfere
with the receptor mediated caleium influx that ultimately
Jead to cellular death and tissue necrosis. Invitro studies
using cultured neurons. have demonsiated that glutamate
receplor antagonists reduce neurotoxicity, but NMDA and
AMPAtKainate receptor antagonists have different effects
‘Antagonists to NMDAr prevent neurotoxicity if present
‘uring the glutamate exposure period, but are les effective
if added after glutamate is removed. In contrast, AMPA/ §
Kainate recepior antagonists are not as elfetive as NMDA
antagonists during the glutamate exposure period, but are
more effective following glutamate exposure
‘Some of the research on these antagonists has focused on
‘cannabinoids, a subset of which have been found to be
NMDA receptor antagonists. US. Pat, No. 5,538,993 (3S,
4S-delta-6-tetrahydrocannabinol-7-oic acids), U.S. Pat. No.
5,521,215 (sterospecific (+) THC enantiomers), and US.
Pat. No. 5,284,867 (dimethylheptyl benzopyrans) have
reported thai these cannabinoids are effective NMDA recep-
tor blockers. U'S. Pat. No, 5,434,295 discloses thatthe 1,1
Fractional Differential Equations: An Introduction to Fractional Derivatives, Fractional Differential Equations, to Methods of Their Solution and Some of Their Applications