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Title:  Synthetic endogenous cannabinoids analogues and uses thereof

United States Patent:  6,531,636

Issued:  March 11, 2003

Inventors:  Mechoulam; Raphael (Jerusalem, IL); Fride; Esther (Efrat, IL); Ben Shabat; Shimon (Jerusalem, IL); Sheskin; Tzviel (Jerusalem, IL); Breuer; Aviva (Jerusalem, IL)

Assignee:  Yissum Research Development Company of the Hebrew University of Jerusalem (Jerusalem, IL)

Appl. No.:  678120

Filed:  October 3, 2000

Abstract

The present invention relates to a compound of the general formula (I) which is a non-hydrolysable analogue of endogenous cannabinoids, which are found to be more potent therapeutic agents as they are more stable, for example, to hydrolytic cleavage in the gastrointestinal tract. The cannabinoid analogues of the invention have a therapeutic value. Therefore, pharmaceutical compositions comprising as active ingredient a therapeutically effective amount of at least one compound of the invention may be prepared. Such compositions may be used as anti-inflammatory, anti-asthmatic, analgetic, hypotensive, antiemetic or anti-spasmodic compositions, and as compositions for treating and/or preventing glaucoma or migraine, or as compositions for relieving symptoms of multiple sclerosis and mood stimulating compositions.

DETAILED DESCRIPTION OF THE INVENTION

Cannabinoids are organic substances present in Cannabis sativa, having a variety of pharmacological properties. Endogenous cannabinoids are fatty acid derivatives present in mammals, which have pharmacological properties similar to those of the plant cannabinoids. The present invention relates to non-hydrolysable derivatives of endogenous cannabinoids.

In particular, the invention relates to a compound of the general formula (I):

R1 --CH2 --O--CHR2 R3 (I)

wherein the moiety R1 --CH2 -- represents an alkenyl moiety derived from a polyunsaturated fatty alcohol of form 18 to 28 carbon atoms, the alkenyl moiety 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; R2 represents a hydrogen atom or a lower C1 -C5 alkyl group; and R3 represents a 2-glyceryl group, or an alkoxyalkyl group, wherein the R3 alkoxyalkyl group includes a branched or straight chain alkyl moiety; wherein said C1 -C5 alkyl and said 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 sulphate group.

Preferably, the alkenyl moiety within the compound of the invention is selected from the group consisting of octadecatrienyl, eicosapentaenyl, docosahexaenyl, eicosatrienyl or eicosatetraenyl.

As disclosed in the following Examples, the specific embodiments of the invention, are 2-dihomo-.gamma.-linolenyl glyceryl ether and arachidonyl-2-isopropoxypethyl and particularly, 2-arachidonyl glyceryl ether. These compounds are shown to have a therapeutic value as they are capable of binding for a prolonged period of time to the CB1 and CB2 cannabinoid receptors.

The compounds of the invention may be radiolabeled and employed in numerous biological, clinical and diagnostic procedures. As the derivatives of the invention have the chemical nature of an ether, they are more stable than the endogenous cannabinoid 2-arachidonoyl glycerol and therefore may allow observation of their pharmaceological profile over a longer period of time compared to the corresponding endogenous compounds.

In a second aspect, the invention relates to a process for the preparation of a compound of general formula (I):

R1 --CH2 --O--CHR2 R3 (I)

wherein R1 --CH2 -- represents an alkenyl moiety derived from a polyunsaturated fatty alcohol of form 18 to 28 carbon atoms with 3 to 6 double bonds with the first double bond at the C-3, C-6 or C-9 position counting from the free end of said alkenyl moiety; R2 represents a hydrogen atom or a lower C1 -C5 alkyl group; and R3 represents a 2-glyceryl group, or an alkoxyalkyl group, wherein the R3 alkoxyalkyl group includes a branched or straight chain alkyl moiety; wherein said C1 -C5 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, said hydroxyl group may be further substituted to form an ester or be converted to a phosphonate or to an alkyl sulphonate; which process comprises the steps of: (a) reacting a compound of general formula (II):

R1 --CH2 --OH (II)

wherein R1 is as defined above, 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):

R2 R3 CHOH (III)

wherein R2 and R3 are as defined above, 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; (c) optionally, when said product of step (a) is reacted in step (b) with said 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).

The alkylsulfonyl halide utilized in the process of the invention is preferably methanesulfonyl chloride, whereas, the arylsulfonyl halide employed is preferably para-toluene sulfonyl chloride.

In the process of the invention, the preferred alcohol employed is an isoalkoxy alcohol, and more preferably, 2-isopropoxy alcohol or propanol. The arylidene glycerol employed is preferably cis-1,3-benzylidene glycerol.

According to one embodiment of the invention, the reaction steps are carried out in the presence of KOH as the base, at room temperature, under nitrogen atmosphere. When necessary to use an acidic reagent, the preferred reagent is a mixture of HCl and methanol, preferably with a ratio of 1:7.

Evidently, any compound obtained by the method of the invention, is within the scope of the invention.

In a third aspect, the invention relates to a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of at least one compound of general formula (I):

R1 --CH2 --O--CHR2 R3 (I)

wherein R1 --CH2 -- represents an alkenyl moiety derived from a polyunsaturated fatty alcohol of from 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; R2 represents a hydorgen atom or a lower C1 -C5 alkyl group; and R3 represents a 2-glyceryl group, or an alkoxyalkyl group, wherein the R3 alkoxyalkyl group includes a branched or straight chain alkyl moiety; wherein said C1 -C5 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, which composition may further comprise acceptable carriers, adjuvants, additives, diluents and/or preserving agents.

The pharmaceutical composition of the invention may be used for numerous therapeutic purposes, inter alia, as anti-inflammatory, anti-asthmatic, analgesic, hypotensive, antiemetic or anti-spasmodic compositions, as compositions for treating and/or preventing glaucoma or migraine, as compositions for relieving symptoms of multiple sclerosis and mood-stimulating compositions.

According to some particular embodiments of the invention, the composition comprise as active ingredient 2-arachidonyl glyceryl either, 2-dihomo-.gamma.-linolenyl glyceryl ether, 2-isopropoxyethyl ether, a combination of the same or a combination of the same with other therapeutically active ingredients.

The compositions of the invention may be administered and dosed in accordance with good medical practice, taking into account the clinical condition of the individual patient, the site and method of administration, scheduling of administration, patient's age, sex, body weight and other factors known to medical practitioners. The pharmaceutically "effective amount" for purposes herein is thus determined by such considerations as are known in the art. The amount must be effective to achieve improvement including but not limited to improved survival rate or more rapid recovery, or improvement or elimination of symptoms and other indicators as are selected as appropriate measures by those skilled in the art, for example, inflammation, hypertension, glaucoma and other disorders and symptoms.

The doses may be single doses or multiple doses over a period of several days, but single doses may be preferred.

The pharmaceutical composition of the invention can be administered in various ways and may comprise, in addition to the active ingredient, pharmaceutically acceptable carriers, diluents, adjuvants, preserving agents and vehicles. The pharmaceutical compositions can be administered subcutaneously or parentally including intravenous, intraaterial, intramuscular, and intraperitoneal administration, as well as intrathecal techniques. Implants of the pharmaceutical preparations may also be useful. The pharmaceutically acceptable carriers, diluents, adjuvants and vehicles as well as implant carriers generally refer to inert, non-toxic solid or liquid fillers, diluents, or encapsulating material not reacting with the active ingredients of the invention.

When administering the pharmaceutical composition of the invention parentally, it will generally be formulated in a unit dosage injectable form (solution, suspension, emulsion). The pharmaceutical formulations suitable for injection include sterile aqueous solutions and sterile powders for reconstitution into sterile injectable solutions. The carrier can be any physiologically acceptable suitable carrier, for example, water, or aqueous buffer solutions.

In addition, various additives which enhance the stability, sterility or/and isotonicity of the compositions, including antimicrobial preservatives, antioxidants, chelating agents and buffers can be added. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid and the like. In many cases it will be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like. Prolonged absorption of the pharmaceutical form and be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin. According to the present invention, any vehicle, diluent, or additive used would have to be compatible with the compositions.

Conventional forms such as administering the composition as tablets, suspensions, solutions, emulsions, capsules, powders, syrups and the like may also be used. Known techniques which deliver it orally or intravenously and retain the biological activity are preferred.

According to one preferred embodiment, the compositions of the invention comprise from about 1 mg to about 100 mg of the active ingredient per dosage unit form.

In yet a further aspect, the invention relates to the use of the compound of general formula (I) as herein before defined in the preparation of a pharmaceutical composition. Nonetheless, the compound of the invention may be used for diagnostic purposes as well known to the man of the art and as also briefly described herein before. Accordingly, the compound will be labeled by a suitable labeling moiety, such as 3 H or 13 C.

The present invention is defined by the claims, the contents of which are to be read as included within the disclosure of the specification.

Claim 1 of 20 Claims

We claim:

1. A compound of the general formula:

R1 CH2 --O--CHR2 R3 (I)

wherein

R1 --CH2 represents an alkenyl moiety derived from a polyunsaturated fatty alcohol of from 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;

R2 represents a hydrogen atom or a lower C1 -C5 alkyl group; and

R3 represents an alkoxyalkyl group;

or the group CHR2 R3 represents a 2-glyceryl group;

C1 -C5 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, which each hydroxyl group may be further substituted to form an ester or may be converted into a phosphonate group.
 


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