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    The term of this patent is extended or adjusted under 35 U.S.c. 154(b) by 0 days. Cannabinoids as antioxidants and neuroprotectants.

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    The term of this patent is extended or adjusted under 35 U.S.c. 154(b) by 0 days. Cannabinoids as antioxidants and neuroprotectants.

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    536 views26 pages

    US Patent 6,630,507

    Uploaded by

    CannabisIntl
    The term of this patent is extended or adjusted under 35 U.S.c. 154(b) by 0 days. Cannabinoids as antioxidants and neuroprotectants.

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    of 26
    (2) United States Patent Hampson et al. US006630507B1 US 6,630,507 BL Oct. 7, 2003, io) Patent No. 45) Date of Patent: G4) (75) cy en @) (86) (7) () (Sl) (2) (58) (6) 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 References Cited US, PATENT DOCUMENTS. 2304669 A 12/1942. Adams 568/743 487.276 A 10/1989 Mechoulam et al. 514/454 5.227537 A 7/1993. Sess etal Sossit 5.284857 A 2/1904 Kloog eta 514s 51434205 A 7/1905 Mechoulam et al. s-- 560/141 5.462.946 A 10/1995 Mitchell tal 5141s 5.512270 A 4/1996 Ghio eta 5521215 A 5/1996 Mechoulam ea. 51538993 A 7/1996 Mechoulam eta: 51535530 A 6/1907 Mechoulam eta: 5,696,109 A 12/1997 Malfioy-Camine eta. 6,410,588 BL 6/2002. Feldmann etal FOREIGN PATENT DOCUMENTS. 427518 AL 5/1991 516387 AL 12/1993 56358 AL 6/1995 658546 AL 6/1995 Wo930S031 AL 3/1993 WODd12667 AL 6/1998 WOR612485 AL 5/1996 WORGIBOD AL 6/1996 WO9T19063 AL 5/1997 99/53017 - * 10/1999 OTHER PUBLICATIO! ‘Windholz etal, The Merek Index, Tenth Edition (1983) p. 241, abstract No. 1723-* Mechoulam et al, “A Total mibesis of dl—ATetra- hydrocanabinl the Active Constituent of Mass” Jour hal of the American Chemical Society, 81:14:3273 2275 (1965). Mechoulam et al, “Chemical Basis of Hashish Activity, Science, 18:611-612 (1970) Ontersen et al, “The Crystal and Molecular Structure of Cannabidiol,” Acta Chem, Scand, B 31, 9807-812 (1977) Cunha et al, “Cheonie Administration of Cannabidiol to Healthy Volunteers and Epileptic Patients!” Pharmacology, 21: 175-185 (1980), Consroe et al, “Acute and Chronic Antipileptic Drug Eifects in Audiogenie Seizure-Susceptible Rats," Esperi- ‘mental Neurology, Academie Press Ine, 70:626-637 (1980), Turkanis etal, “Electrophysiologic Properties of the Can- nabinoids,”" J. Clin, Pharmacol, 21:4498-4638 (1981). Carlini et al, “Hypnotic and Aatilpileptic Eitects of Can- nabidil,” J Clin. Pharmacol, 21:417S-4278 (1981) Karler et al, “The Cannabinoids as Potential Antieplep- ties," J. Clin. Pharmacol, 21:437S—4488 (1981), Conscoe eta,“ Aatiepileptic Potential of Cannabidiol Anal- 0s," J. Clin Pharmacol, 21:428S-436S (1981), (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 Sheets US 6,630,507 BL Page 2 OTHER PUBLICATIONS Colasant tal, “Ocular Hypotension, Ocular Toxistya nd Neurotoxicity in Response to Marituana Extract and Can- nabidio:” “Gen Pharm, Pergamon Press Lid, 15(6):479—484 (1984). Colasant et al, “Intraocular Pressure, Ocular Toxicity and Neurotoxicity afiee Administration of Cannabinol or Can- nabigerl," Exp. Fye Res, Academic Press Ine, 39:251-259 (i984). Volfe et al., “Cannabinoids Block Release of Serotonin from Platelets Induced by Plasma frm Migraine Patients,” Ini. J. Clin, Pharm. Res, Bioscience Ediprint Inc, 4343-246 (1985). Agurcll ct al, “Pharmacokinetics and Metabolism of ‘\Tetrshydrocannabinol and. Other Cannabineids with Emphasis on. Man",” Pharmacological Reviews, 38(1)21-43 (1986). Karler ot al, “Different Canabinoids Exhibit Different Pharmacological and Toxicological Propcrtis,'NIDA Res. Monogr, 7996-107 (1987) Samara ota, "Pharmacokinetics of Cannsbitiol in Dogs,” Drug Metabolism and Disposition, 16(3):469-472 (1988). Choi, “Glutamate Neurotoxicity and Diseases of the Nev vous System,” Neuron, Cell Pres, 1:623-654 (1988), Esharet al, "Neuroprotective and Antioxidant Activities of HU-211, A Novel NMDA Receptor Antagonist,” European Journal of Pharmacology, 283:19-29 (1995). ‘Skapor etal, “The ALIAMide Palmitoylcthanolamide and ‘Cannabinoids, but not Anandamide, are Protective ina Delayed Posiglutamate Paradigm of Exeitotoxie Death ia Cerebellar Granule Neurons,” Neurobiology; Proc. Nall. ‘Acad. Sci. USA, 93:3984-3989 (1996). ‘Alonso et al, “Simple Synthesis of 5-Substiuted Resorei- nols: A Revisited Family of Interesting. Bioactive Mol- cates,” J. Ong. Chem, American Chemical Soci 162(2):417-421 (1997). ‘Combes et al. “A Simple Synthesis of the Natural 2,5-Di- alkylesorcinol Free Radical Scavenger Antioxidant Resorstaton,” Synthetic Communications, Marcel Dekker, Ine. 27(21):3769-3778 (1997). Shohami etal, “Oxidative Sicess in Closed-Head Injury’ Brain Antioxidant Capacity as an Indicator of Functional Outcome,” Journal of Cerebral Blood Flow and Metabo- Jism, Lippincott-Raven Publishers, 17(10):1007-1019 (2997). Zarier ot al.,“Dimethylheptyl-THC-11 OIC Acid,” Arthri- ty & Rheumatism, 41(1):163-170 (1998). Hampson et al, “Dual Effeets of Anandamide on NMDA Receptor-Medisted Responses and Neurotransmission,” Journal of Neurocenistry, Lippincott-Raven Publishers, 70(2):671-676 (1998). Hampson et al, “Cannabidiol and (-)A°-tetrahydrocanna- bono are Neuroprotective Antioxidants,” Medical Sciences, Proc. Natl. Acad. Sci. USA, 8268-8273 (1998) * cited by examiner U.S. Patent Oct. 7, 2003 Sheet 1 of 7 US 6,630,507 BL 5.0 [Cannabidiol] (M) 6.0 -5.5 125 B 100 7 5 2: 7.0 -6.5 FIG. 1 4.0 7 6.5 wo e 2 a a a asea]al HOT IO % US 6,630,507 B1 Sheet 2 of 7 Oct. 7, 2003, U.S. Patent FIG.2 S00nM SR | | So i | HC = BD Ge CBD THC Glo 100 uM SpMTHC spMcBD Giu US 6,630,507 B1 Sheet 3 of 7 Oct. 7, 2003 U.S. Patent st Or (Ww) [3ud)} Sh OS S'S Wi | 81 = OHL "Od os. WL F11=dado"Od wi 1 #81 =1Ha "Od pO 0'9- (GNU OLS) 9ouadsau0n] J SHOA oepruepueuy seaT wry € ‘OM sore (yn) qwoLn9 U.S. Patent Oct. 7, 2003 Sheet 4 of 7 US 6,630,507 BL FIG.5 A B 0 . 100 1s 25 8 = 3 8 | so EB so I eI z . g 2 as 0 7 65 60 $5 58 45 40 100uM_ CBD BHT Ascorbate Tacopherol [eannabidiel} (My Glu U.S. Patent Oct. 7, 2003 Sheet 5 of 7 US 6,630,507 BL [Linoleic acid (substrate)] (M) a rr nd e S o Ss a i dO WH | Aq uonqryut % Oo = ry 3 3 S z 2 Ey S = 5 3 Lo 2 3 ? [Cannabidiol] (M) 100 5 (wu pez) adueyo sqe [99 Jo % U.S. Patent Oct. 7, 2003 Sheet 6 of 7 US 6,630,507 BL + I 2 a Ss 3 iL 04 Le 3 T e [ eB | (uu 9¢z) |= vare yead [110 % . ‘E g = (? = 3 | = 5 ams) o é < 3 ° » 3 8 (ung eZ) ° : vore ead (49 % 4 & a aaa % 3 g (wu 9¢z) ‘vare yead p39 % U.S. Patent Oct. 7, 2003 Sheet 7 of 7 US 6,630,507 BL During & Post Post ischemia Time of 12-HETE application (0.5 g/ml) FIG. 8 During ischemia Ctrl uononpoid PCT [310 Jo % US 6,630,507 BL 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

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