Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-07-21
2002-03-12
Qazi, Sabiha (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S277000, C514S449000, C514S451000, C514S453000, C514S454000, C546S026000, C546S079000, C546S101000, C549S356000, C549S385000, C549S388000
Reexamination Certificate
active
06355650
ABSTRACT:
TECHNICAL FIELD
The present invention relates to non-psychoactive derivatives of tetrahydro-cannabinol, which exhibit anti-inflammatory, analgesic and leukocyte anti-adhesion activities. The invention includes novel derivatives of (3R,4R)-&Dgr;
8
-tetrahydrocannabinol-11-oic acids [hereinafter referred to as (3R,4R)-&Dgr;
8
-THC-11-oic acid], as well as pharmaceutical compositions containing the (3R,4R)-&Dgr;
8
-THC-11-oic acid derivatives. The invention further includes methods of administering the novel derivatives and pharmaceutical compositions as therapeutic agents in the treatment of pain, tissue inflammation, leukocyte anti-adhesion activity, and the like.
BACKGROUND OF THE INVENTION
&Dgr;
9
-Tetrahydrocannabinol [THC], depicted in Formula I under alternate numbering systems, is the major psychoactive constituent of marijuana.
In addition to mood-altering effects, THC has been reported to exhibit other activities, some of which may have therapeutic value. The potential therapeutic value of THC has led to a search for related compounds which, while devoid of psychoactive effects, retain the activities of potential medicinal value.
Previous work with A
8
-Tetrahydrocannabinol [(3R,4R) 6a,7,10,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol, hereinafter referred to as &Dgr;
8
-THC], which is depicted in Formula II below, has indicated that certain derivatives of this compound depicted in Formula II below, may prove clinically useful. The 11-carboxy derivative of &Dgr;
8
-THC [&Dgr;
8
-THC-11-oic acid] has been reported to be a non-psychoactive, potent antagonist to endogenous platelet activating factor and, thus, a useful treatment for PAF-induced disorders, such as asthma, systemic anaphylaxis, and septic shock. (U.S. Pat. No. 4,973,603, issued to the present inventor). Another derivative, (3S,4S)-11-hydroxy-&Dgr;
8
-THC-1′,1′ dimethylheptyl essentially free of the (3R,4R) form, has been reported to possess analgesic and anti-emetic activities. (U.S. Pat. No. 4,876,276).
U.S. Pat. No. 4,847,290, issued to the present inventor, discloses a method of relieving pain in mammals by administering an effective analgesic amount of &Dgr;
9
-THC-11-oic acid or an analog thereof. These THC derivatives are disclosed to be non-psychoactive metabolites.
U.S. Pat. No. 5,338,753, also issued to the present inventor, discloses (3R,4R)-&Dgr;
8
-Tetrahydrocannabinol-11-oic acid derivatives having Formula II below:
wherein R
1
is a hydrogen atom, —COCH
3
or —COCH
2
CH
3
; R
2
is a straight chain or branched C
5
-C
12
alkyl, which may have a terminal aromatic ring; a group —(CH
2
)
m
—O—R
3
, wherein m is an integer from 0 to 7 and R
3
is a straight chain or branched alkyl group containing from 1 to 12 carbon atoms, which may have a terminal aromatic ring; or a group CH—(CH
3
)—(CH
2
)
n
—O—R
4
, wherein n is an integer from 0 to 7 and R
4
is a straight chain or branched alkyl containing from 1 to 12 carbon atoms, which may have a terminal aromatic ring. These &Dgr;
8
-THC-11-oic acid derivatives are also discussed in an article by Sumner H. Burstein, et al., entitled “Synthetic Nonpsychotropic Cannabinoids with Potent Antiinflammatory, Analgesic, and Leukocyte Antiadhesion Activities.” [
J. Medicinal Chem
., 35(17):3135-3136 (1992).
It is desired, however, to obtain compounds, pharmaceutical compositions, and methods of treatment using compounds substantially devoid of psychoactive effect and with improved therapeutic effects compared to those achieved by conventional &Dgr;
8
-THC-11-oic acid derivatives, such as those described above. The present invention advantageously affords such compounds, pharmaceutical compositions, and methods of treatment using the compounds and compositions.
SUMMARY OF THE INVENTION
The present invention relates to a compound having the formula:
wherein R
1
is hydrogen, —COCH
3
, or —COCH
2
CH
3
; R
2
is a branched C
5-12
alkyl compound which may have a terminal aromatic ring, or a branched —OCHCH
3
(CH
2
)
m
alkyl compound which may have a terminal aromatic ring, wherein m is 0 to 7; R
3
is hydrogen, a C
1-8
alkyl compound, or a C
1-8
alkanol compound; and Y is nil or a bridging group of NH or oxygen; provided that where Y is oxygen and R
2
is a branched C
5-12
alkyl compound, R
3
is not —CHCH
3
.
In one preferred embodiment, R
1
is hydrogen, R
2
is 1′,1′-dimethylheptyl, and Y is nil. In another preferred embodiment, R
2
is a branched —O(CHCH
3
)(CH
2
)
m
alkyl compound terminated with a phenyl ring, wherein m is 0 to 7, and R
3
is —CHCH
3
. This embodiment includes the stereoisomers of such compounds, as well as a racemic mixture or any other percentage mixture of the stereoisomers between 0 and 100 weight percent.
The invention also relates to pharmaceutical compositions that include the compound and its two preferred embodiments described above.
The invention further relates to methods of relieving pain in a mammal by administering to the mammal a therapeutically effective analgesic amount of the compound or pharmaceutical composition, or either of the preferred embodiments, described above.
The invention also relates to methods of relieving inflammation of bodily tissue of a mammal by administering to the mammal a therapeutically effective anti-inflammatory amount of the compound or pharmaceutical composition, or either of the preferred embodiments, described above.
REFERENCES:
patent: 4284829 (1981-08-01), Althuis et al.
patent: 4371720 (1983-02-01), Johnson et al.
patent: 4391827 (1983-07-01), Harbert et al.
patent: 4831059 (1989-05-01), Johnson et al.
patent: 4847290 (1989-07-01), Burstein
patent: 4876276 (1989-10-01), Mechoulam et al.
patent: 4921994 (1990-05-01), Johnson et al.
patent: 4973603 (1990-11-01), Burstein
patent: 5219747 (1993-06-01), McNally et al.
patent: 5338753 (1994-08-01), Burstein et al.
patent: 5605928 (1997-02-01), Mechoulam et al.
Blanc, et al., CA 119:219267 abstract ofClin. Chem.(Washington, D.C.) (1993), 39(8), 1705-12.
S.H. Burstein et al., “Synthetic Nonpsychotropic Cannabinoids with Potent Antiinflammatory, Analgesic, and Leukocyte Antiadhesion Activities,”J. Medicinal. Chem.(1992), 35(17):3135-3136.
Jones et al., CA 102:41075 abstract ifJ. Anal. Toxicol.(1984), 8(6), 252-4.
L.S. Melvin et al., “A Cannabinoid Derived Prototypical Analgesic,”J. Med. Chem.(1984), 27:67-71.
Matsumoto et al. CA 77:126882 abstract of Chem. Lett. (1972), (7), 581-6.
Defaye, Genevieve, CA 72:79254 abstract of Publ. Sci. Tech. Min. Air (Fr.), Notes Tech. (1969), No. N.T. 165, 78 pages.
Atlantic Technology Ventures, Inc.
Lyon & Lyon LLP
Neuman Kristin H.
Qazi Sabiha
Shalek James H.
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