Synthetic endogenous cannabinoids analogues and uses thereof

Details Synthetic endogenous cannabinoids analogues and uses thereof Synthetic endogenous cannabinoids analogues and uses thereof

2000-10-03

2003-03-11

Keys, Rosalynd (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Oxygen containing

C514S723000, C424S001650, C568S616000

Reexamination Certificate

active

06531636

ABSTRACT:

STATEMENT OF THE INVENTION
The present invention relates to compounds of the general formula (I), to a process for their preparation, to pharmaceutical compositions containing at least one compound of the invention and to the different uses of said compounds.
BACKGROUND OF THE INVENTION
Anandamide and 2-arachidonoyl glycerol (2-Ara-Gl) represent the two types of endogenous cannabinoid constituents discovered so far [Devane W. A. et al., Science 258:1946-1949 (1992a); Mechoulam R. et al., Biochem. Pharmacol 50:83-90 (1995); Mechoulam R. et al., U.S. Pat. No. 5,618,858 (corresponding to IL 103932)]. These compounds and related amides and esters thereof cause numerous effects which have therapeutic potential [Mechoulam R. et al., Progress in Medicinal Chemistry 35:501-545, GP Ellis Ed. (1998); Mechoulam R. (ed.,), Cannabinoids as therapeutic agents CRC Press Coca Ratio Florida (1986)]. It has been recently shown that anandamide may be an endogenous modulator of blood pressure [Wagner J. A. et al., Nature 390:518-521 (1997)]. When administered to rats it was shown to reduce blood pressure [Varga K. et al., Eur. J. Pharmacol 278:279-283 (1995)]. These findings were confirmed by the inventors [see Table 3]. However, both anandamide and 2-arachidonoyl glycerol are prone to easy and rapid enzymatic hydrolysis. This represents a serious drawback in their eventual use as drugs, inter alia, because substances which are susceptible to hydrolytic cleavage may undergo changes in the gastrointestinal tract.
The inventors have discovered a novel group of related synthetic derivatives of 2-archidonoyl glycerol which are stable to hydrolysis. These are ethers derived from long chain fatty alcohols (in particular archidonyl alcohol). These compounds bind to the CB
1
and CB
2
cannabinoid receptors and exhibit in vivo effects similar to those of anandamide and 2-Ara-Gl. The compounds disclosed herein reduced intraocular pressure in rabbits (a model for glaucoma), reduce pain and vomiting, lower blood pressure, exhibit anti-inflammatory properties, have anti-spasticity effects and may thus be useful in the treatment of multiple sclerosis. Moreover, the effect of the novel compounds is prolonged, which for some diseases is a distinct advantage.
SUMMARY OF THE INVENTION
The present invention relates to a compound of the general formula (I):
R
1
—CH
2
—O—CHR
2
R
3
  (I)
wherein R
1
—CH
2
— represents an alkenyl moiety derived form a polyunsaturated fatty alcohol of form 18 to 28 carbon atoms containing 3 to 6 double bonds, wherein the first double bond is positioned at C-3, C-6 or C-9 when counting from the free end of said alkenyl moiety; R
2
represents a hydrogen atom or a lower C
1
-C
5
alkyl group; and R
3
represents a 2-glyceryl group, or an alkoxyalkyl group, wherein the R
3
alkoxyalkyl group includes a branched or straight chain alkyl moiety; said C1-C
5
alkyl and alkoxyalkyl groups may be, independently, substituted by one or more hydroxyl groups, amino groups or alkylamino groups on any one of the carbon atoms therein, said hydroxyl group may be further substituted to form an ester or be converted into a phosphonate or alkyl sulphonate group.
Further, the invention relates to a process for preparing the compounds of the invention, which process comprises the steps of (a) reacting a compound of general formula (II):
R
1
—CH
2
—OH  (II)
wherein R
1
is as defined above for compounds of general formula (I), with an alkylsulfonyl halide or arylsulphonyl halide; (b) reacting the product obtained in step (a) with either (i) an alcohol of the general formula (III):
R
2
R
3
CHOH  (III)
wherein R
2
and R
3
are as defined above for compounds of general formula (I), in the presence of a base; or with (ii) a alkylidene or arylidene glycerol having one free hydroxyl group at the 2-position, in the presence of a base; and optionally (c) when said product of step (a) is reacted in step (b) with alkylidene or arylidene glycerol, the product of said step (b) is further reacted with an acidic reagent to obtain the compound of general formula (I):
Yet further, the invention relates to a pharmaceutical composition comprising as active ingredient an therapeutically effective amount of at least one compound of the invention and optionally further comprising pharmaceutically acceptable carriers, adjuvants, diluents and additives.


REFERENCES:
patent: 9412466 (1994-06-01), None
Gideon Halperin, The Sythesis of Polyunsaturated . . . Triated at C-2, Journal of Labelled Compounds and Radiopharmaceuticals, vol. XX, No. 2, Feb. 1983, pp269-275.*
Richard B. Silverman, The Organic Chemistry of Drug Design and Drug Action, 1992, pp. 15-22.*
Mechoulam et al., Identification of . . . Cannabinoid Receptors, Biochemical Pharmacology, vol. 50, No. 1, Jun. 1995, pp. 83-90.*
J.G. Turcotte: “Synthesis of Lysophosphatidylethanolamine Analogs that Inhibit Renin Activity” Journal of Medicinal Chemistry, vol. 18, No. 12, Dec. 1975, pp. 1184-1190, XP002109045, Washington, US, p. 1189, col. 1, Table I.
F.R. Pfeiffer; “Lysophosphatidylethanolamine and 2-desoxylysophosphatidylethanolamine Derivatives. 1. Potential Renin Inhibitors” Journal of Medicinal Chemistry, vol. 14, No. 6, Jun. 1971, pp. 493-499, XP002109046, Washington, US; Tables V and VI, Compounds 12c and 13c.
J.R. Surles: “Facile Synthesis of Platelet-Activating Factor and Racemic Analogues Containing Unsaturation in the sn-1-alkyl chain” Journal of Medicinal Chemistry, vol. 28, No. 1, Jan. 1985, pp. 73-78, XP002109047, Washington, US, Scheme I; Tables I and II.
A. Wissner: “Analogues of Platelet Activating Factor. 6. Mono- and bis-aryl Phosphate Antagonists of Platelet Activating Factor” Journal of Medicinal Chemistry, vol. 35, No. 9, May 1 1992, pp. 1650-1662, XP002109048, Washington, US, p. 1651, Scheme II, R=d.
P. Sperling: “In vivo Desaturation of cis-delta-9-monounsaturated to cis-delta-9, 12-diunsaturated alkenylether glycerolipids” Journal of Biological Chemistry, vol. 268, No. 36, Dec. 25, 1993, pp. 26935-26940, XP002109049, American Society of Biological Chemists, Baltimore, MD., US, ISSN: 0021-9258, p. 26935, Abstract; Fig. 2.
W.J. Baumann: “Reactions of Aliphatic Methanesulfonates. I. Syntheses of Long-Chain Glyceryl-(1) ethers”, Journal of Organic Chemistry, vol. 29, No. 10, Oct. 1964, pp. 3055-3057, XP002109050, Easton, US, Table II, Compounds XXI and XXII, p. 3057, col. 2.
R. Mechoulam: “Identification of an Endogenous 2-monoglyceride, present in Canine Gut, that Binds to Cannabinoid Receptors” Biochemical Pharmacology, vol. 50, No. 1, 1995, pp. 83-90, XP002109088, cited in the application, p. 83-p. 84.
Devane et al. Science 258: 1946-1949 (1992a).
Wagner et al, Nature 390: 518-521 (1997).
Varga et al. Eur. J. Pharmacol. 278: 279-283 (1995).
Feigenbaum et al. Eur. J. Pharmacol. 169: 159-165 (1989).
Mechoulam et al. The Therapeutic Potential of Marihuana, eds. S. Cohen, R.C. Stillman, Plenum Press, NY; pp 35-48.
Avidor et al.; J. Biol. Chem. 271: 21309-21315 (1996).
Rhee et al.; J. Med. Chem. 40: 3228-3233 (1997).

Affiliated with

Also associated with

Rating

Synthetic endogenous cannabinoids analogues and uses thereof does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Synthetic endogenous cannabinoids analogues and uses thereof, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Synthetic endogenous cannabinoids analogues and uses thereof will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3085699