US Patent 6630507 - Cannabinoids as antioxidants and neuroprotectants

[FreeMind]

US Patent 6630507 - Cannabinoids as antioxidants and neuroprotectants

Link
http://www.patentstorm.us/patents/6630507.html

C&P

Abstract
Cannabinoids have been found to have antioxidant properties
, unrelated to NMDA receptor antagonism. This new found property makes cannabinoids useful in the treatment and prophylaxis of wide variety of oxidation associated diseases, such as ischemic, age-related, inflammatory and autoimmune diseases. The cannabinoids are found to have particular application as neuroprotectants, for example in limiting neurological damage following ischemic insults, such as stroke and trauma, or in the treatment of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and HIV dementia. Nonpsychoactive cannabinoids, such as cannabidoil, are particularly advantageous to use because they avoid toxicity that is encountered 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, CH3, and COCH3. ##STR1##
Other References

* Windholz et al., The Merck Index, Tenth Edition (1983) p. 241, abstract No. 1723.
* Mechoulam et al., "A Total Synthesis of d1-Ɗ1 -Tetrahydrocannabinol, the Active Constituent of Hashish1," Journal of the American Chemical Society, 87:14:3273-3275 (1965)
* Mechoulam et al., "Chemical Basis of Hashish Activity," Science, 18:611-612 (1970)
* Ottersen et al., "The Crystal and Molecular Structure of Cannabidiol," Acta Chem. Scand. B 31, 9:807-812 (1977)
* Cunha et al., "Chronic Administration of Cannabidiol to Healthy Volunteers and Epileptic Patients1," Pharmacology, 21:175-185 (1980)
* Consroe et al., "Acute and Chronic Antiepileptic Drug Effects in Audiogenic Seizure-Susceptible Rats," Experimental Neurology, Academic Press Inc., 70:626-637 (1980)
* Turkanis et al., "Electrophysiologic Properties of the Cannabinoids," J. Clin. Pharmacol., 21:449S-463S (1981)
* Carlini et al., "Hypnotic and Antielpileptic Effects of Cannabidiol," J. Clin. Pharmacol., 21:417S-427S (1981)
* Karler et al., "The Cannabinoids as Potential Antiepileptics," J. Clin. Pharmacol., 21:437S-448S (1981)
* Consroe et al., "Antiepileptic Potential of Cannabidiol Analgos," J. Clin. Pharmacol., 21:428S-436S (1981)
* Colasanti et al., "Ocular Hypotension, Ocular Toxicity,a nd Neurotoxicity in Response to Marihuana Extract and Cannabidiol," Gen Pharm., Pergamon Press Ltd., 15(6):479-484 (1984)
* Colasanti et al., "Intraocular Pressure, Ocular Toxicity and Neurotoxicity after Administration of Cannabinol or Cannabigerol," Exp. Eye Res., Academic Press Inc., 39:251-259 (1984)
* Volfe et al., "Cannabinoids Block Release of Serotonin from Platelets Induced by Plasma frm Migraine Patients," Int. J. Clin. Pharm. Res., Bioscience Ediprint Inc., 4:243-246 (1985)
* Agurell et al., "Pharmacokinetics and Metabolism of Ɗ1 -Tetrahydrocannabinol and Other Cannabinoids with Emphasis on Man*," Pharmacological Reviews, 38(1):21-43 (1986)
* Karler et al., "Different Cannabinoids Exhibit Different Pharmacological and Toxicological Properties,"NIDA Res. Monogr., 79:96-107 (1987)
* Samara et al., "Pharmacokinetics of Cannabidiol in Dogs," Drug Metabolism and Disposition, 16(3):469-472 (1988)
* Choi, "Glutamate Neurotoxicity and Diseases of the Nervous System," Neuron, Cell Press, 1:623-634 (1988)
* Eshhar et al., "Neuroprotective and Antioxidant Activities of HU-211, A Novel NMDA Receptor Antagonist," European Journal of Pharmacology, 283:19-29 (1995)
* Skaper et al., "The ALIAmide Palmitoylethanolamide and Cannabinoids, but not Anandamide, are Protective in a Delayed Postglutamate Paradigm of Excitotoxic Death in Cerebellar Granule Neurons," Neurobiology, Proc. Natl. Acad. Sci. USA, 93:3984-3989 (1996)
* Alonso et al., "Simple Synthesis of 5-Substituted Resorcinols: A Revisited Family of Interesting Bioactive Molecules," J. Org. Chem., American Chemical Society, 62(2):417-421 (1997)
* Combes et al. "A Simple Synthesis of the Natural 2,5-Dialkylresorcinol Free Radical Scavenger Antioxidant: Resorstation," Synthetic Communications, Marcel Dekker, Inc., 27(21):3769-3778 (1997)
* Shohami et al., "Oxidative Stress in Closed-Head Injury: Brain Antioxidant Capacity as an Indicator of Functional Outcome," Journal of Cerebral Blood Flow and Metabolism, Lippincott-Raven Publishers, 17(10):1007-1019 (1997)
* Zurier et al., "Dimethylheptyl-THC-11 OIC Acid," Arthritis & Rheumatism, 41(1):163-170 (1998)
* Hampson et al., "Dual Effects of Anandamide on NMDA Receptor-Mediated Responses and Neurotransmission," Journal of Neurochemistry, Lippincott-Raven Publishers, 70(2):671-676 (1998)
* Hampson et al., "Cannabidiol and (-)Ɗ9 -tetrahydrocannabiono are Neuroprotective Antioxidants," Medical Sciences, Proc. Natl. Acad. Sci. USA, 8268-8273 (1998)

[FreeMind]

US Patent 7109245 - Vasoconstrictor cannabinoid analogs

Link
http://www.patentstorm.us/patents/7109245/fulltext.html

C&P


Abstract
Methods and compounds for reversing pathological vasodilation of blood vessels, for example vasodilation caused by activation of CB1-like receptors, by administering to a subject a therapeutically effective amount of a compound sufficient to induce vasoconstriction, the compound comprising:
wherein dashed lines independently represent either a single or a double bond, R1 is a lower alkyl, R2 is a lower alkyl, R3 is a lower alkyl or halogen, R4 is a lower alkyl or hydrogen, R5 is a lower alkyl or hydrogen, R6 is a hydrogen, lower alkyl or halogen, and R7 is a hydrogen, lower alkyl or halogen. The vasoconstrictor can be used for a variety of purposes, including hemostasis or the treatment of shock, for example vasodilatory shock syndromes such as septic shock.
Claims


We claim:


2. A compound having the chemical structure ##STR00020## wherein dashed lines independently represent either a single or a double bond; R1 is a lower alkyl; R2 is a lower alkyl; R3 is a halogen or a lower alkyl having 1 to 3carbons; R4 is a lower alkyl or hydrogen; R5 is a lower alkyl or hydrogen, and wherein the compound is an enantiomerically pure (-) stereoisomer.

3. A compound having the chemical structure ##STR00021## wherein R1 is a lower alkyl; R2 is a lower alkyl; R3 is a halogen or lower alkyl having 1 to 3 carbons, and wherein the compound is an enantiomerically pure (-)stereoisomer.

4. The compound of claim 3, wherein R3 is a methyl and the compound comprises: ##STR00022##

5. The compound of claim 3, wherein R1 is a methyl or propyl; R2 is a methyl or propyl; and R3 is a methyl.

6. The compound of claim 3, wherein said compound has the chemical structure ##STR00023##

7. A method of vasoconstricting blood vessels by selectively antagonizing the CB1-like receptor, comprising administering to a subject a therapeutically effective amount of a compound sufficient to induce vasoconstriction, the compoundcomprising: ##STR00024## wherein dashed lines independently represent either a single or a double bond; R1 is a lower alkyl; R2 is a lower alkyl; R3 is a lower alkyl or halogen; R4 is a lower alkyl or hydrogen; R5 is a loweralkyl or hydrogen; R6 is a hydrogen, lower alkyl or halogen; R7 is a hydrogen, lower alkyl or halogen, and thereby selectively antagonizing the CB1-like receptor.

8. The method of claim 7, wherein the compound comprises: ##STR00025## wherein dashed lines independently represent either a single or a double bond; R1 is a lower alkyl; R2 is a lower alkyl; R3 is a halogen or a lower alkyl; R4 is a lower alkyl or hydrogen; and R5 is a lower alkyl or hydrogen.


9. The method of claim 8, wherein the compound comprises: ##STR00026## wherein R1 is a lower alkyl; R2 is a lower alkyl; and R3 is a halogen or lower alkyl.

10. The method of claim 9, wherein the compound comprises: ##STR00027##

11. The method of claim 7, wherein the method comprises administering the compound to a subject experiencing or at risk of experiencing shock.

12. The method of claim 8, wherein the method comprises administering the compound to a subject experiencing or at risk of experiencing vasodilatory shock.

13. The method of claim 12, wherein the method comprises administering the compound to a subject experiencing or at risk of experiencing septic shock.

14. The method of claim 7, wherein the method is a method of vasoconstricting blood vessels that are dilated by the activation of a CB1-like receptor.

15. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1.

16. The pharmaceutical composition of claim 15, comprising an enantiomerically pure (-) stereoisomer of a compound having the chemical structure ##STR00028##

17. A kit for vasoconstricting blood vessels in a subject comprising a container comprising the compound of claim 1.

18. The kit of claim 17, further comprising a container comprising another vasoconstrictive, inotropic, or antibiotic agent.

19. The kit of claim 18, wherein the vasoconstrictive or inotropic agent is norepinephrine, dopamine, or dobutamine.

20. The kit of claim 17, further comprising instructions for administering the compound to a subject.

21. The method of claim 7, wherein the compound is an enantiomerically pure (-) stereoisomer.

22. The method of claim 7, wherein the compound is a substantially pure antagonist of the CB1-like receptor.

23. The method of claim 7, wherein the compound does not block the CB1 receptor.

24. A selective and substantially pure antagonist of the CB1-like receptor, comprising an enantiomerically pure (-) stereoisomer having the chemical structure: ##STR00029##
Description


FIELD OFTHE DISCLOSURE

The present disclosure concerns pharmaceutical compounds and compositions that are useful as vasoconstrictors, and the use of these compounds, for example in the treatment of shock.





Septic shock is a type of vasodilatory shock that is often accompanied by a clinical presentation that suggests infection, such as fever, chills, warm, flushed skin, and hemodynamic instability (characterized by a falling and rising bloodpressure). Septic shock is an often fatal condition that accompanies severe microbial infections, frequently with gram-negative bacteria such as Escherichia coli, Pseudomonas aeruginosa and Klebsiella or Bacteroides species. Gram-positive bacterialinfections can also lead to septic shock, particularly those infections caused by Staphylococcus aureus and the Pneumococcus. The bacterial infections can be acquired by routes such as ingestion, personal contact, or trauma, but infections are oftennosocornial consequences of therapeutic procedures, including implantation of indwelling catheters or prosthetic devices. Septic shock often occurs in immunocompromised subjects, and therefore has been an increasing problem in recent years because ofthe increasing number of individuals who are immunocompromised. For example, subjects with HIV disease or who are taking immunosuppressive drugs for the treatment of cancer or organ transplantation rejection are at increased risk of developing septicshock.

In view of the above, there exists a need for agents that counteract the vasodilation associated with shock.

SUMMARY OF THE DISCLOSURE

The present inventors have demonstrated that abnormal cannabidiol (Abn-cbd) is a selective agonist and cannabidiol is a selective antagonist of an as yet unidentified cannabinoid-like or non-classical receptor distinct from the known cannabinoidreceptors CB1 and CB2. Agonists of these receptors, such as Abn-cbd, are believed to cause vasodilation. Even cannabidiol itself, which is generally an antagonist of the putative receptor, has been found to cause some vasodilation, and it thereforeacts as a partial agonist, or mixed agonist/antagonist. It would therefore be desirable to have an agent that acts as a pure, or substantially pure, antagonist at the CB1-like receptor. Such an agent would be particularly useful in the treatment ofdiseases in which hypotension is the result of the action of endogenous cannabinoids and drug-induced vasoconstriction is desirable, for example in hypotensive states, such as shock. The antagonist would have particular application in vasodilatory shockstates, such as septic shock, but it could also be used to achieve selective hemostasis to stop bleeding induced by trauma or surgery.




Inventors

* Kunos, George
* Razdan, Raj K.

Assignee

* The United States of America as represented by the Secretary of the Department of Health and Human Services
* Organix Inc.

Application
No. 10486810 filed on 08/14/2002


Attorney, Agent or Firm

* Klarquist Sparkman LLP

US Patent References
2304669, 3919322, 4025516, Process for the preparation of (-)-6a,10a-trans-6a,7,8,10a-tetrahydrodibenzo[b,d]-pyrans
Issued on: 05/24/1977
Inventor: Razdan , et al.4978332, Treatments employing vasoconstrictive substances in combination with cytotoxic agents for introduction into cellular lesion areas
Issued on: 12/18/1990
Inventor: Luck, et al.5227537, Method for the production of 6,12-dihydro-6-hydroxy-cannabidiol and the use thereof for the production of trans-delta-9-tetrahydrocannabinol
Issued on: 07/13/1993
Inventor: Stoss, et al.5296466, Inhibition of nitric oxide-mediated hypotension and septic shock with iron-containing hemoprotein
Issued on: 03/22/1994
Inventor: Kilbourn, et al.5342971, Process for the preparation of dibenzo[b,d]pyrans
Issued on: 08/30/1994
Inventor: Herlt, et al.5747524, Cannabinoid receptor antagonists
Issued on: 05/05/1998
Inventor: Cullinan, et al.5939429Cardiovascular uses of cannabinoid compounds
Issued on: 08/17/1999
Inventor: Kunos, et al.

Foreign Patent References

* WO 99/53917 WO 10/01/1999
* WO 01/03690 WO 01/01/2001

International Classes
A61K 31/075
C07C 43/205

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I edited out alot of this one as it is huge if wanting to view it all simply use the link at the top.

Enjoy

[FreeMind]

Ok now that we have in fact proven that cannabis is medicine, I think now is the time to seriously look at this and then let everyone come to their own conclusions.

Since the US health Dept. ie the US government holds at least these, plus who knows how many others.

Now you see why they insist it isn't medicine since they are the ones trying to synthesize it and make money just like they did with Marinol.

People need to pass this information on to their doctors their lawmakers and so on and so forth.


I'm just trying to learn more about this.