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Patent Issued for Pyridine Non-Classical Cannabinoid Compounds and Related Methods of Use

2013 JAN 23 (NewsRx) -- By a News Reporter-Staff News Editor at Biotech Week -- According to news reporting originating from Alexandria, Virginia, by NewsRx journalists, a patent by the inventors Moore, II, Bob M. (Nesbit, MS); Gurley, Steven (Memphis, TN); Mustafa, Suni (Memphis, TN), filed on October 14, 2009, was cleared and issued on January 8, 2013.

The assignee for this patent, patent number 8349876, is The University of Tennesee Research Foundation (Knoxville, TN).

Reporters obtained the following quote from the background information supplied by the inventors: "The classical cannabinoid, delta-9-tetrahydrocannabinol (.DELTA..sup.9-THC), is the major active constituent extracted from Cannabis sativa. The effects of cannabinoids are due to an interaction with specific high-affinity receptors. Presently, two cannabinoid receptors have been characterized: CB-1, a central receptor found in the mammalian brain and a number of other sites in the peripheral tissues; and CB-2, a peripheral receptor found principally in cells related to the immune system. In addition, it has recently been reported that the GPR35 and GPR55 orphan receptors bind cannabinoid type ligands and have been proposed as a third receptor subtype. The CB-1 receptor is believed to mediate the psychoactive properties associated with classical cannabinoids. Characterization of these receptors has been made possible by the development of specific synthetic ligands such as the agonists WIN 55212-2 (D'Ambra et al., J. Med. Chem. 35:124 (1992)) and CP 55,940 (Melvin et al., Med. Chem. 27:67 (1984)).

"Pharmacologically, cannabinoids can be used to affect a variety of targets such as the central nervous system, the cardiovascular system, the immune system and/or endocrine system. More particularly, compounds possessing an affinity for either the CB-1 or the CB-2 receptors and potentially the GPR35 and GPR55 receptors are useful as anticancer agents, antiobesity agents, analgesics, myorelaxation agents and antiglaucoma agents. Such compounds can also be used for the treatment of thymic disorders, vomiting; various types of neuropathy, memory disorders, dyskinesia, migraine, multiple sclerosis; asthma, epilepsy, ischemia, angor, orthostatic hypotension, osteoporosis, liver fibrosis, inflammation and irritable bowel disease, and cardiac insufficiency.

"However, certain cannabinoids such as .DELTA..sup.9-THC also affect cellular membranes, producing undesirable side effects such as drowsiness, impairment of monoamine oxidase function, and impairment of non-receptor mediated brain function. The addictive and psychotropic properties of some cannabinoids tend to limit their therapeutic value.

"A number of structurally distinct non-classical bi- and triaryl cannabinoids are described in U.S. Pat. No. 7,057,076 to Makriyannis et al. Makriyannis identifies a range of binding affinities for two or more compounds, but does not provide any supporting data that shows the binding data of individual compounds on both the CB-1 and CB-2 receptors. It is difficult to assess, therefore, whether any of the compounds are selective for one receptor over another.

"There still remains an ongoing need in the art for compounds, whether classical or non-classical cannabinoid analogs, that can be used for therapeutic purposes to affect treatment of conditions or disorders that are mediated by the CB-1 receptor and/or the CB-2 receptor."

In addition to obtaining background information on this patent, NewsRx editors also obtained the inventors' summary information for this patent: "In light of the foregoing, it is an object of the present invention to provide a range of heterocyclic cannabinoid analog compounds, compositions and/or related methods, thereby overcoming various deficiencies and shortcomings of the prior art, including those outlined above. It will be understood by those skilled in the art that one or more aspects of this invention can meet certain objectives, while one or more other aspects can meet certain other objectives. Each objective may not apply equally, in all its respects, to every aspect of this invention. As such, the following objects can be viewed in the alternative with respect to any one aspect of this invention.

"It can be an object of the present invention to identify one or more classes of cannabinoid compounds exhibiting affinity for cannabinoid and related receptors found in human cells and tissues.

"It is also an object of the present invention to provide one or more pyridine non-classical cannabinoid receptor ligands comprising a B-ring pyridine system, such compounds can comprise bi- or triaryl ring system.

"It can be another object of the present invention to identify such compounds exhibiting cannabinoid receptor selectivity for directed therapeutic use.

"Other objects, features, benefits and advantages of the present invention will be apparent from this summary and the following descriptions of certain embodiments, and will be readily apparent to those skilled in the art having knowledge of various cannabinoid compounds and related therapeutic methods. Such objects, features, benefits and advantages will be apparent from the above as taken into conjunction with the accompanying examples, data, figures and all reasonable inferences to be drawn therefrom, alone or with consideration of the references incorporated herein.

"In part, the present invention can be directed to a cannabinoid analog compound selected from compounds of a formula (I) below

"##STR00002## wherein one of W and V can be N and the other can be C; X can be selected from H, substituted and unsubstituted alkyl, and cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, wherein each alkyl portion can be optionally substituted up to three times and the ring portion of each can be optionally substituted with one, two, three, four or five substituents; Y can be selected from S, O, CH.sub.2, CH(CH.sub.3), CH(OH), C(CH.sub.3)(OH), C(CH.sub.3).sub.2, C(--U(CH.sub.2).sub.nU--), C(O), NH, S(O), and S(O).sub.2; n can be an integer .gtoreq.1, and preferably from 1 to 6; U can be selected from CH.sub.2, S, and O; Z can be selected from H, substituted and unsubstituted alkyl, and cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, wherein each alkyl portion can be optionally substituted up to three times and the ring portion of each can be optionally substituted with one, two, three, four or five substituents; and R.sub.1 and R.sub.2 are independently selected from H and substituted and unsubstituted alkyl.

"In part, the present invention can be directed to a salt of a compound in accordance herewith.

"In part, the present invention can be directed to a pro-drug of a compound in accordance herewith.

"In part, the present invention can also be directed to a pharmaceutical composition comprising a compound of the sort described herein, a salt and/or a pro-drug thereof; and a pharmaceutically acceptable carrier component.

"In part, the present invention can be directed to a method of modifying the activity of a cannabinoid receptor. Such a method can comprise providing a compound, salt and/or pro-drug of the present invention or any other compound disclosed herein that has activity at a cannabinoid or related receptor, a salt and/or pro-drug thereof; and contacting a cell and/or cannabinoid receptor of a cell with such a compound. As illustrated below, such contact can be at least partially sufficient to at least partially modify activity of such a cannabinoid receptor.

"In part, the present invention can also be directed to a method of treating a cannabinoid receptor-mediated condition. Such a method can comprise providing a compound in accordance herewith or any other compound disclosed herein that has activity at a cannabinoid receptor, a salt and/or pro-drug thereof; and administering to a patient an amount of such a compound, salt and/or pro-drug, that can be at least partially effective to treat a cannabinoid receptor-mediated condition. This aspect of the invention can relate to the use of agonists of a CB-1 or a related receptor, antagonists of a CB-1 or related receptor, agonists of a CB-2 or related receptor, and/or antagonists of a CB-2 or related receptor to treat or prevent disease conditions mediated by hyperactivity of CB-1 and/or CB-2 (or related) receptors or either inactivity or hypoactivity of the CB-1 and/or CB-2 (or related) receptors.

"In part, the present invention can also be directed to a compound selected from compounds of a formula

"##STR00003## wherein one of W and V can be N and the other can be C; X can be selected from phenyl, benzyl, C.sub.3-C.sub.8 cycloalkyl and thiophenyl, the ring portion of each can be optionally substituted with one to five substituents independently selected from halo, carbonyl, hydroxyl, alkyl and alkoxy moieties; R.sub.1 and R.sub.2 can be independently selected from H or alkyl; Y can be selected from carbonyl, dimethylmethylene and hydroxymethylene; and Z can be alkyl or can be selected from cycloalkyl, phenyl and thiophenyl, each of which can be optionally substituted with one to five substituents as would be understood by those skilled in the art made aware of this invention, including but not limited to those described elsewhere herein. In certain embodiments, X can be selected from phenyl optionally substituted with from one to five groups independently selected from chloro, methyl and methoxy substituents. In certain such embodiments, Z can be an alkyl or a phenyl moiety and, optionally, X can be a benzyl or dichlorophenyl moiety. Regardless, such a compound can be selected from salts and/or pro-drugs of such a compound.

"Without limitation, this invention can also be directed to a method of cancer treatment. Such a method can comprise providing a cancer cell comprising a cannabinoid receptor, such a cell of a growth of cancer cells; and contacting such a growth with a cannabinoid compound selected from compounds of a formula

"##STR00004## wherein R.sub.2, V, W, X, Y and Z can be as defined above. In an embodiment, X can be selected from phenyl, cycloalkyl and thiophenyl, each of which can be optionally substituted with one to five substituents independently selected from halo, carbonyl, hydroxyl, alkyl and alkoxy moieties; R.sub.1 and R.sub.2 can be independently selected from H or alkyl; Y can be selected from carbonyl, dimethylmethylene and hydroxymethylene; and Z can be alkyl or can be selected from cyclohexyl, phenyl and thiophenyl, each of which can be optionally substituted with one to five substituents as would be understood by those skilled in the art made aware of this invention, including but not limited to those described elsewhere herein; and salts and pro-drugs of said compounds and combinations thereof, such compound(s) in an amount at least partially sufficient to induce death of a cell of such a growth. In certain embodiments, X can be cycloalkyl and Z can be phenyl, each of which is optionally substituted with from one to five groups independently selected from chloro, carbonyl, hydroxy and methoxy. In certain such embodiments, R.sub.1 and R.sub.2 can be independently selected from H and methyl moieties. In certain such embodiments, at least one of R.sub.1 and R.sub.2 can be a moiety other than methyl. Regardless, without limitation and as illustrated elsewhere herein, Y can be carbonyl or dimethylmethylene."

For more information, see this patent: Moore, II, Bob M.; Gurley, Steven; Mustafa, Suni. Pyridine Non-Classical Cannabinoid Compounds and Related Methods of Use. U.S. Patent Number 8349876, filed October 14, 2009, and issued January 8, 2013. Patent URL: http://patft.uspto.gov/netacgi/nph-Parser'Sect1=PTO2&Sect2=HITOFF&p=73&u=%2Fnetahtml%2FPTO%2Fsearch-bool.html&r=3609&f=G&l=50&co1=AND&d=PTXT&s1=20130108.PD.&OS=ISD/20130108&RS=ISD/20130108

Keywords for this news article include: Cancer, Oncology, Terpenes, Cannabinoids, Therapeutics, The University of Tennesee Research Foundation.

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