Use of known agonists of the central cannabinoid receptor CB1

Details Use of known agonists of the central cannabinoid receptor CB1 Use of known agonists of the central cannabinoid receptor CB1

1998-02-17

2001-09-04

Criares, Theodore J. (Department: 1617)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S315000, C514S449000, C514S460000

Reexamination Certificate

active

06284788

ABSTRACT:

The present invention relates to the use of known agonists of the central cannabinoid receptor CB1 for the prophylaxis and treatment of neurodegenerative disorders, in particular for the treatment of cerebral apoplexy and craniocerebral trauma.
&Dgr;
9
-Tetrahydrocannabinol (&Dgr;
9
-THC) and, to a small extent, also &Dgr;
8
-THC are the biologically active constituents in extracts of the plant Cannabis sativa (marihuana, hashish) and are responsible for the effects on the human central nervous system (CNS). Potential historical and contemporary therapeutic uses of cannabis preparations include, inter alia, analgesia, emesis, anorexia, glaucoma and motor disorders.
Up to now, two subtypes of cannabinoid receptors and a splice variant have been identified. The CB1 receptor (Nature
−
1990, 346, 561) and a splice variant CB1a (J. Biol. Chem. 1995, 270, 3726) are mainly localized in the central nervous system. The CB2 receptor was mainly found in the peripheral tissue, in particular in leucocytes, spleen and macrophages (Eur. J. Biochem. 1995, 232, 54). CB1 and CB2 receptors have seven transmembrane regions and belong to the family of G protein receptors. Both receptors are negatively coupled via G
i
/G
o
protein to adenylate cyclase and possibly negatively coupled to the presynaptic release of glutamate [cf. J. Neurosci. 1996, 16, 4322]. CB1 receptors are moreover positively coupled to potassium channels and negatively coupled to N- and Q-type calcium channels.
It is moreover known that the cannabinoid CB1 receptor agonists are subdivided into 4 classes, the classical and nonclassical cannabinoids, the aminoalkylindoles and the icosanoids [cf. Pharmacol. Rev. 1986, 38, 75; Curr. Med. Chem. 1996, 3, 101; Cannabinoid Receptors, R. Pertwee (Ed.), Academic Press, San Diego, 1995; J. Med. Chem. 1976, 19, 445; J. Med. Chem. 1976, 19, 454; J. Med. Chem. 1976, 19, 461;WO 95/33429; DE 2416491; J. Med. Chem. 1996, 39, 3875; U.S. Pat. No. 4,371,720; Curr. Med. Chem. 1996, 3, 101; Curr. Pharm. Design 1995, 1, 343; Tetrahedr. Lett. 1994, 50 2671; Life Sci. 1995, 56, 2007; Johnson, M. R., Melvin, L. S. in “Cannabinoids as Therapeutic Agents; Mechoulam R., Ed.; CRC Press, Boca Raton Fla. 1986, pp. 121-145; J. Med. Chem. 1984, 27, 67; Pharmacol. Rev. 1986, 38, 1; Exp. Opin. Invest. Drugs 1996, 5, 1245; Pharmacol. Rev. 1986, 38, 151; Drug Design and Discovery 1995, 13, 155; J. Pharm. Exp. Ther. 1993, 265, 218; U.S. Pat. No. 4,391,827; J. Med. Chem. 1995, 38, 3094; Bioorg. Med. Chem. Lett. 6, 1996, 17; J. Med. Chem. 1992, 35, 124; J. Med. Chem. 1991, 34, 1099; Bioorg. Med. Chem. Lett. 4, 1994, 563; Bioorg. Med. Chem. Lett. 5, 1995, 381; U.S. Pat. No. 5,112,820; Tetrahedr. Lett. 1995, 1401; J. Med. Chem. 1996, 39, 4515; Drugs of Today 32, 1996, 275; J. Med. Chem. 1996, 39, 471; J. Med. Chem. 1994, 37, 1889; Mol. Pharmacol. 46, 516, 1994; Biochem. Pharmacol. 1995, 50, 83; J. Med. Chem. 1993, 36, 3032; Biochem. Pharmacol. 1994, 48, 1537; J. Biol. Chem. 1994, 269, 22937; Proc. Natl. Acad. Sci 1993, 90, 7656; J. Prostagl. Leukotr. Essen. Fatty Acids 1995, 52, 83; Science 1992, 258, 1946; Life Sci 1995, 56, 2041; FEBS Lett. 1994, 350, 240; Showalter V. M.; J. Pharmacol. Exp. Therap. 1996, 989; Pharm. Res. 13, 1996, 62; J. Med. Chem. 1997, 40, 659].
It is additionally known that cerebral apoplexy is a result of a sudden circulatory disorder of a human brain area with subsequent functional losses, with corresponding neurological and/or psychological symptoms. The causes of cerebral apoplexy can lie in cerebral haemorrhages (e.g. after a vascular tear in hypertension, arteriosclerosis and apoplectic aneurysms) and ischaemias (e.g. due to a blood pressure drop crisis or embolism). The functional losses in the brain lead to a degeneration or destruction of the brain cells (cf. Journal of Cerebral Blood Flow and Metabolism 1981, 1, 155; Chem. Eng. News 1996 (May 13), 41; Trends Pharmacol. Sci. 1996, 1, 227). Craniocerebral trauma is understood as meaning covered and open cranial injuries with involvement of the brain [cf. Schweiz. med. Wschr. 1993, 123 449].
After a cerebral vascular occlusion, only a part of the tissue volume is destroyed as a direct result of the restricted circulation and the decreased oxygen supply associated therewith [cf. Neurology 1996, 47, 884]. This tissue area designated as the infarct core can only be kept from dying off by immediate recanalization of the vascular closure, e.g. by local thrombolysis, and is therefore only limitedly accessible to therapy. The outer peripheral zone, which is as least just as large in terms of volume, also designated as the penumbra, admittedly also discontinues its function immediately after onset of the vascular occlusion, but is initially still adequately supplied with oxygen by the collateral supply and irreversibly damaged only after a few hours or even only after days. Since the cell death in this area does not occur immediately, a therapeutic opportunity reveals itself to block the unfavourable development of the course of the disease both after stroke and after trauma.
The numerous therapeutic starting points for the reduction of the infarct volume include, for example, the blocking of glutamate receptors or glutamate release, free radical scavengers, anti-inflamatory substances, substances for blocking voltage-dependent calcium or sodium channels, and GABA agonists [cf. Trends Pharmacol. Sci. 17, 1996, 227].
The inhibition of glutamatergic neurotransmission or inhibition of glutamate release can be achieved by a multiplicity of substances having differing pharmacological actions and thus differing mechanisms of action [GABA receptor ligands (Neurosci. Lett 1990, 118, 99, Br. J. Pharmacol. 1997, 120, 60), aluminium (Neurotoxicol. 1992, 13, 413), ethanol (Eur. J. Pharmacol. 1992, 219, 469), barbiturates, for example thiopental (Br. J. Pharmacol. 1996, 119, 1498), adenosine A1 receptors (Neurosci. Lett. 1996, 220, 163), &agr;
2
-agonists (Anesthesiol. 1996, 85, 551), cannabinoid receptor agonists (J. Neurosci. 1996, 16, 4322).
For kynurenic acid (Brain Res. 1992, 592, 333) and theophylline (Brain Res 1991, 565, 353), it has been shown that these substances, although they markedly inhibit glutamate release in vitro, have no neuroprotective action in vivo.
In contrast to the speculation by Shen et al. (J. Neurosci. 1996, 16, 4322) the cannabinoid receptor agonist HU210, the (−)-enantiomer of HU-211, which is inactive on the cannabinoid receptor, is non-neuroprotective in a craniocerebral trauma model (J. Neurotrauma 1993, 10, 109).
It has now been found that the known cannabinoid CB1 receptor agonists cited above are surprisingly suitable for the prophylaxis and treatment of neurodegenerative disorders, in particular of cerebral apoplexy and craniocerebral trauma.
Preferably, [A] known agonists of the central cannabinoid receptor CB1 of the general formula (I)
in which
A and D are identical or different and, depending on the position of a single or double bond, represent a C atom or the CH group,
E depending on the position of a single or double bond, represents the CH or CH
2
group or a sulphur atom,
G, L and M are identical or different and, depending on the position of a single or double bond, represent a radical of the formula —CR
5
, —CR
6
R
7
or N—R
8
, in which
R
5
, R
6
, R
7
and R
8
are identical or different and denote hydrogen, hydroxyl, formyl, (C
2
-C
6
)-alkenyl, (C
2
-C
6
)-alkinyl, or denote (C
1
-C
6
)-alkyl which is optionally substituted by hydroxyl or (C
1
-C
4
)-alkoxy, or
R
6
and R
7
together represent a radical of the formula ═O,
a represents a number 0 or 1,
R
1
represents hydrogen or hydroxyl, or represents (C
1
-C
11
)-alkyl, (C
1
-C
6
)-alkoxy, (C
1
-C
6
)-alkoxycarbonyl or (C
1
-C
4
)-acyloxy, each of which is optionally substituted by hydroxyl, (C
1
-C
10
)-alkoxy or by a group of the formula —NR
9
R
10
, in which
R
9
and R
10
are identical or different and denote hydrogen, phenyl, (C
1
-C
4
)-alkyl, or
R
9
and R
10
, togethe

Affiliated with

Also associated with

Rating

Use of known agonists of the central cannabinoid receptor CB1 does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Use of known agonists of the central cannabinoid receptor CB1, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Use of known agonists of the central cannabinoid receptor CB1 will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2483850