Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-04-23
2003-05-13
Stockton, Laura L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S399000, C546S275100, C548S338100, C548S341500, C548S336100
Reexamination Certificate
active
06562846
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to bisarylimidazolyl derivatives and pharmaceutical compositions comprising said derivatives which inhibit fatty acid amide hydrolase and are useful for the treatment of conditions affected by inhibiting fatty acid amide hydrolase.
BACKGROUND
Neuropathic pain is caused by injury to nerves as the result of many factors including physical damage (e.g., trauma, surgery), drugs such as Zidovudine (AZT), Carmustine (BCNU) and disease (e.g., diabetes, herpes zoster). The prevalence in the United States of neuropathies associated with diabetes, herpes and amputation is estimated at 1.5 million. The worldwide prevalence of diabetic neuropathy alone is expected to reach 12 million by 2007. Nerve injury can result in both allodynia and hyperalgesia.
Current treatment of neuropathic pain involves the use of non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and acetaminophen) and other analgesics as well as anticonvulsants (e.g., carbamazepine, gabapentin) and tricyclic antidepressants (e.g., amitryptiline). Effective treatment of pain with current therapies is limited by adverse effects and a lack of efficacy against all components of pain.
Current research is aimed at understanding the molecular and physiological components of pain processing to develop more effective analgesics (Levine, J. D., New Directions in Pain Research: Meeting Report Molecules to Maladies,
Neuron
20: 649-654, 1998; Pasternak, G. W., The Central Questions in Pain Perception May Be Peripheral,
PNAS
95:10354-10355, 1998).
The analgesic properties of cannabinoids have been known for many years and to many cultures. Cannabinoids are active in many pre-clinical models of pain, including neuropathic pain. Within the last few years, several endogenous cannabinoids, including the fatty acid amides arachidonylethanolamide (anandamide), and arachidonyl amino acids such as N-arachidonylglycine, homo-&ggr;-linolenyl-ethanolamide and docosatetraenyl-ethanolamide, as well as 2-arachidonyl-glycerol, have been shown to induce analgesia in laboratory animals (DeVane, W. A. et. al., Isolation and Structure of a Brain Constituent That Binds to the Cannabinoid Receptors,
Science
258: 1946-1949, 1992; Hanus, L. et. al., Two New Unsaturated Fatty Acid Ethanolamides in Brain that Bind to the Cannabinoid Receptor,
J. Med. Chem.
36: 3032-3034, 1993; Machoulam, R. et. al., Identification of an Endogenous 2-Monoglyceride, Present in Canine Gut, That Binds To Cannabinoid Receptors,
Biochem. Pharmacol.
50: 83-90, 1995; Vogel, Z. et. al., Cannabinomimetic Behavioral Effects of and Adenylate Cyclase Inhibition By Two New Endogenous Anandamides,
Eur. J. Pharmacol.
287: 145-152, 1995; Hargreaves, K. M. et al., Cannabinoids Reduce Hyperalgesia and Inflammation Via Interaction With Peripheral CB1 Receptors,
Pain
75: 111-119, 1998; Rice, A. S. C., et. al., The Anti-Hyperalgesic Actions of the Cannabinoid Anandamide and the Putative CB2 Receptor Agonist Palmitoylethanolamide in Visceral and Somatic Inflammatory Pain,
Pain
76: 189-199, 1998; Huang, S. M., et al., Identification of a New Class of Molecules, the Arachidonyl Amino Acids, and Characterization of One Member That Inhibits Pain,
J. Biological Chemistry,
276: 46, 42639-42644, 2001). The ability of cannabinoid receptor antagonists and cannabinoid receptor antisense to induce hyperalgesia in animals suggests that endogenous cannabinoids regulate the nociceptive threshold (Hargreaves, K. M. et al., Hypoactivity of the Spinal Cannabinoid System Results in NMDA-Dependent Hyperalgesia,
J. Neurosci.
18: 451-457, 1998; Piomelli, D. et. al., Control of Pain Initiation By Endogenous Cannabinoids,
Nature
394: 277-281, 1998; Fields, H. L. et. al., An Analgesia Circuit Activated By Cannabinoids,
Nature
395: 381-383, 1998). Elevation of levels of neuroactive fatty acid amides such as anandamide may provide a unique mechanism to achieve analgesia. The mechanisms by which endogenous cannabinoids are synthesized are not well understood; therefore, targets for drugs aimed at increasing the synthesis of these compounds are slow to be identified.
Anandamide and the other identified endogenous cannabinoids are inactivated through a cleavage mechanism by a membrane-bound enzyme, fatty acid amide hydrolase (FAAH). FAAH, therefore, provides an important target for regulating the activity of endogenous cannabinoids. The inhibition of FAAH may elevate levels of anandamide or other endogenous cannabinoids to increase the nociceptive threshold. Furthermore, the inhibition of FAAH would also extend the therapeutic benefits of other cannabinoid agonists in the treatment of emesis, anxiety, feeding behaviors, movement disorders, glaucoma, neuroprotection and cardiovascular disease.
SUMMARY OF THE INVENTION
Thus according to a first embodiment of the first aspect of the present invention are provided compounds of Formula (I)
and pharmaceutically acceptable salts and solvates thereof
wherein
R
1
are R
2
are each independently H, C
1-3
alkyl or halo;
R
3
is C
1
-C
3
alkyl or C
3-7
cycloalkyl;
A is C
1-12
alkylene or L;
L is -phenyl-O—C
1-4
alkylene wherein said C
1-4
alkylene is attached to D;
provided that if A is L, then D is X(O)O and A—D is not interrupted with J—J′, —Z-phenyl- or —Z—C
1-3
alkylene;
D is X(O)O, X(O)N(G′), HYC(O)O or HYC(O)ON═C(G′);
X is C and is attached to A;
Y is N and is attached to A;
G is H, C
1-5
alkyl, C
1-5
haloalkyl, C
3-7
cycloalkyl, phenyl, —C
1-2
alkylene-phenyl, C-pyridyl or N-pyridyl, said phenyl or —C
1-2
alkylene-phenyl are each optionally and independently substituted with one or more of the same or different substitutents selected from the group consisting of halo, NO
2
, CN, —C(O)O—C
1-3
-alkyl, C
1-3
alkyl, hydroxy and C
1-3
alkoxy;
G′ is H, C
1-5
alkyl or C
1-5
haloalkyl;
wherein A—D is optionally interrupted with J—J′, —Z-phenyl- or —Z—C
1-3
alkylene;
wherein
Z is O or S and is attached to A;
J is CH and is attached to A, D and J′;
J′ is C
1-4
alkyl or phenyl; and
provided that
if A—D is interrpted with —Z-phenyl-, then A is C
1-5
alkylene;
if A—D is not interrpted with —Z-phenyl-, then A is C
5-12
alkylene.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R
1
and R
2
are each H.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R
1
and R
2
are each halo.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R
1
and R
2
are each fluoro.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R
3
is methyl.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R
3
is ethyl.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein A is L.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein A is C
3-10
alkylene.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein A is C
7-10
alkylene.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein A is C
4-8
alkylene.
According to another embodiment of the first aspect of the present invention are pro
Sit Sing-Yuen
Xie Kai
Bristol--Myers Squibb Company
Makujina Shah R.
Stockton Laura L.
LandOfFree
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