Cannabinoid-containing compounds for treating pain

Abstract

The invention discloses a compound having the general formula (I): wherein X is a cannabinoid or derivative thereof, Y is C1-C10-alkyl, optionally substituted with O, N, S and / or halogen, C1-C10- heteroalkyl, optionally substituted with O, N, S and / or halogen, C2-C10-alkenyl, optionally substituted with O, N, S and / or halogen, C2-C10-heteroalkenyl, optionally tionally substituted with O, N, S and / or halogen, C3-C12-cycloalkyl optionally substituted with O, N, S and / or halogen, or C6-C12-aryl optionally substituted with O, N, S and / or halogen, and [Z+] is an anion exchange resin. Further disclosed is a pharmaceutical composition comprising one or more compounds of the invention. Further disclosed is a compound of the invention or pharmaceutical composition of the invention for use in treating various diseases.

Description

[0001] N30052

[0002] 1

[0003] Cannabinoid-containing compounds

[0004] Field of the invention

[0005] The present invention relates to cannabinoid-containing compounds. The invention further relates to a pharmaceutical composition comprising one or more compounds of the invention. The invention further relates to a compound of the invention or pharmaceutical composition of the invention for use in treating various diseases.

[0006] Background of the invention

[0007] The medical use of cannabinoids is a field of growing interest. Several medicaments that contain an individual cannabinoid, in particular delta-9-tetrahydro- cannabinol (D9-THC, also known as THC), as drug have been approved, for example for use as painkillers in chronic pain patients.

[0008] It is known that D9-THC, due to its high lipophilicity, has a low bioavailability of only 6-8% when administered orally. Therefore, D9-THC-containing oral formulations have to be taken several times a day. In order to overcome the low bioavailability of D9-THC and other cannabinoids, prodrugs of D9-THC and other cannabinoids have been developed. For example, amino acid esters of D9-THC, that can be administered as rectal suppositories, have been prepared. Although suppositories work quickly, they are not the preferred method of administration for adults. Transdermal and sublingual forms of administration have also been developed. However, transdermal and sublingual applications have the disadvantage, among others, of causing local intolerance and irritation.

[0009] Therefore, new ways for the medical use of cannabinoids are needed.

[0010] Summary of the invention

[0011] In a first aspect, the invention relates to a compound having the general formula (I): N30052

[0012] 2 wherein

[0013] X is a cannabinoid or derivative thereof,

[0014] Y is Ci -Cw-alkyl, optionally substituted with 0, N, S and / or halogen, C1-C10- heteroalkyl, optionally substituted with 0, N, S and / or halogen, C2-Cw-alkenyl, optionally substituted with 0, N, S and / or halogen, C2-Cio-heteroalkenyl, optionally substituted with 0, N, S and / or halogen, C3-Ci2-cycloalkyl optionally substituted with 0, N, S and / or halogen, or Ce-Ci2-aryl optionally substituted with 0, N, S and / or halogen, and

[0015] [Z+] is an anion exchange resin.

[0016] In a second aspect, the present invention relates to a pharmaceutical composition comprising one or more compounds of the invention, optionally further comprising a pharmaceutically acceptable excipient.

[0017] In a third aspect, the present invention relates to a compound of the invention or pharmaceutical composition of the invention for use in treating pain, particularly chronic, inflammatory, visceral and / or nociceptive pain, neuropathic pain, sleep disorders, post-traumatic disorder, anxiety, nausea, muscular spasms, multiple sclerosis, uterine cramps, Crohn’s disease, inflammatory bowel disorders, bowel cramps, migraine headache, cluster headache, glaucoma, asthma, epilepsy, addiction, cancer, renal fibrosis, inflammation, insomnia, high blood pressure, convulsions, obsessive compulsive disorders, schizophrenia, neurodegenerative disorders, psychiatric disorders, fibromyalgia, Tourette syndrome, depression and / or psychosis. N30052

[0018] Detailed description of the invention

[0019] In a first aspect, the invention relates to a compound having the general formula (I): wherein

[0020] X is a cannabinoid or derivative thereof,

[0021] Y is Ci -Cw-alkyl, optionally substituted with 0, N, S and / or halogen, C1-C10- heteroalkyl, optionally substituted with 0, N, S and / or halogen, C2-Cw-alkenyl, optionally substituted with 0, N, S and / or halogen, C2-Cio-heteroalkenyl, optionally substituted with 0, N, S and / or halogen, C3-Ci2-cycloalkyl optionally substituted with 0, N, S and / or halogen, or Ce-Ci2-aryl optionally substituted with 0, N, S and / or halogen, and

[0022] [Z+] is an anion exchange resin.

[0023] X is a cannabinoid or derivative thereof. The term “cannabinoid” as used herein refers to natural compounds of various structural classes that are found in the cannabis plant as well as synthetic, semisynthetic, biosynthetic or endogenous compounds structurally related thereto or derived therefrom. The cannabinoid has at least one hydroxyl group that is used for linking the cannabinoid to the chemical group N30052

[0024] 4

[0025] (in the following also referred to as ..bridge”).

[0026] Accordingly, the cannabinoid has at least one hydroxyl group that is suitable for making a linkage with the bridge in the compound according to the invention. The term “hydroxyl group” as used herein refers to a phenolic or aliphatic hydroxyl group (OH). Preferably, the cannabinoid has at least one phenolic hydroxyl group.

[0027] The term “derivative” as used herein refers to a compound that is derived from a similar compound by a chemical reaction. Accordingly, a cannabinoid derivative is a compound that is derived from a similar cannabinoid (“basic cannabinoid”) by a chemical reaction. The term “derivative” as used herein also comprises compounds that have a similar structure as the basic cannabinoid or possess the structure of the basic cannabinoid as a partial structure.

[0028] The cannabinoid preferably is selected from the group consisting of delta-9- tetrahydrocannabinol (D9-THC, also known as THC). delta-8-tetrahydrocan- nabinol (D8-THC), cannabidiol (CBD). cannabinol (CBN), cannabinolic acid (CBNA), cannabinerolic acid, cannabigerol (CBG). cannabigerovarin (CBGV), cannabichromene (CBC). cannabicyclol (CBL). canabivarol (CBV). delta-9-tet- rahydrocannabivarin (D9-THCV), delta-8-tetrahydrocannabivarin (D8-THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabichromevarinic acid A. cannabigerol monomethyl ether, cannabigerol monoethyl ether (CBGM), cannabigerolic acid A. cannabigerolic acid monomethyl ether, can- nabigerolic acid monoethyl ether (CBGAM), cannabidiolic acid (CBDA), can- nabidiolic acid A cannabitriol ester, cannabigerovarinic acid (CBGV A), canna- bichromenic acid (CBCA), cannabidiol monomethylether (CBDM), N30052

[0029] 5 cannabidiol-C4 (CBD-C4), cannabidivarinic acid (CBDV A), cannabidiorcol (CBD-C1 ), delta-9-tetrahydrocannabinolic acid A (THCA-A), delta-9-tetrahy- drocannabinolic acid B (THCA-B), delta-9-tetrahydrocannabinolic acid-C4 (THCA-C4), delta-8-tetrahydrocannabinolic acid (D8-THCA), delta-9-tetrahy- drocannabinol-C4 (THC-C4), 8,9-dihydroxy-delta-6a(1 Oa)-tetrahydrocanna- binol, 6a, 7, 10a-trihydroxy-delta-9-tetrahydrocannabinol, 10-oxo-delta-

[0030] 6a(1 Oa)-tetrahydrocannabinol, delta-7-isotetrahydrocannabinol, delta-7-isotet- rahydrocannabivarin, delta-9-tetrahydrocannabiorcolic acid (THCA-C1 ), delta- 9-tetrahydrocannabiorcol (THC-C1 ), delta-9-tetrahydrocannabivarinic acid (THCVA), cannabicycolic acid (CBLA), cannbicyclol (CBL), cannabicyclovarin (CBLV), cannabielsoic acid A (CBEA-A), cannabielsoic acid B (CBEA-B), can- nabielsoin (CBE), cannabielsoin-C3 (CBE-C3), cannabielsoic acid A, cannabielsoic acid B, cannabielsoic acid B-C3, cannabivarin, cannabinol-C4 (CBN- C4), cannabinol methylether (CBNM), cannabiorcol (CBN-C1 ), cannabinol-C2 (CBN-C2), cannabinodiol (CBND), cannabinodivarin (CBVD), cannabitriol (CBT), 10-O-ethyl-cannabitriol, cannabitriol-C3, cannabitriolvarin (CBTV), de- hydrocannabifuran (DCBF), cannabifuran, cannabicitran (CBT), cannabiripsol (CBR), cannabichromanon, cannabichromanon-C3, ‘11 -hydroxytetrahydro- cannabinor (11 -OH-THC), and ‘11 -nor-9- carboxy-tetrahydrocannabinol’ (THC-COOH).

[0031] Delta-9-tetrahydrocannabinolic acid-C4 (THCA-C4) refers to the A and / or B acid variant. Delta-9-tetrahydrocannabiorcolic acid (THCA-C1 ) refers to the A and / or B acid variant.

[0032] Y is Ci -Cw-alkyl, optionally substituted with 0, N, S and / or halogen, C1-C10- heteroalkyl, optionally substituted with 0, N, S and / or halogen, C2-Cw-alkenyl, optionally substituted with 0, N, S and / or halogen, C2-Cio-heteroalkenyl, optionally substituted with 0, N, S and / or halogen, C3-Ci2-cycloalkyl optionally substituted with 0, N, S and / or halogen, or Ce-Ci2-aryl optionally substituted with 0, N, S and / or halogen. N30052

[0033] 6

[0034] The term “optionally substituted” as used herein denotes that the group may or may not be further substituted with one or more non-hydrogen substituents as indicated. For example, a “Ci-Cw-alkyl optionally substituted with 0, N, S and / or halogen” refers to a Ci -Ci o-alkyl that may or may not be substituted with one or more substituents independently selected from the group consisting of 0, N, S and halogen.

[0035] The term “halogen” refers to chlorine, fluorine, bromine or iodine.

[0036] The term “alkyl” as used herein refers to a straight or branched aliphatic hydrocarbon group. Examples of straight and branched C1-C10 alkyl are methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl.

[0037] The term “heteroalkyl” as used herein refers to a straight-chain or branched- chain alkyl group having the indicated range of carbons in the chain, one or more of which has been replaced by a heteroatom selected from N, 0, P and S. Examples of heteroalkyls are alkyl ethers, secondary and tertiary alkyl amines, amides, alkyl sulfides, and the like.

[0038] The term “alkenyl” as used herein refers to a straight or branched aliphatic hydrocarbon group having at least one carbon-carbon double bond. The group may contain a plurality of double bonds and the orientation about each is independently E or Z. Examples of C2-Cw-alkenyl groups are ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl and decenyl.

[0039] The term “heteroalkenyl” as used herein refers to a straight-chain or branched- chain alkenyl group having the indicated range of carbons in the chain, one or more of which has been replaced by a heteroatom selected from N, 0, P and S.

[0040] The term “cycloalkyl” as used herein refers to a saturated or partially saturated, monocyclic or fused or spiro polycyclic, carbocycle (ring structure having ring N30052

[0041] 7 atoms that are all carbon) preferably containing from 3 to 9 carbons per ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. It includes monocyclic systems such as cyclopropyl and cyclohexyl, bicyclic systems such as decalin, and polycyclic systems such as adamantane.

[0042] The term “aryl” as used herein refers to (i) an optionally substituted monocyclic, or fused polycyclic, aromatic carbocycle (ring structure having ring atoms that are all carbon), such as phenyl and naphthyl; (ii) an optionally substituted partially saturated bicyclic aromatic carbocyclic moiety in which a phenyl and a C5-7 cycloalkyl or C5-7 cycloalkenyl group are fused together to form a cyclic structure, such as tetrahydronaphthyl, indenyl and indanyl.

[0043] The family of compounds having the general formula (I) includes all possible isomers (stereo or structural) including diastereoisomers, enantiomers, tautomers, and geometrical isomers in “E” or“Z” configurational isomer or a mixture of E and Z isomers. It is understood that some isomers such as diastereomers, enantiomers, and geometrical isomers can be separated by physical and / or chemical methods and by those skilled in the art.

[0044] The family of compounds having the general formula (I) further includes compounds in which the cannabinoid is linked to two bridges, each bridge being linked via one hydroxyl group of the cannabinoid. The two bridges are of the same type.

[0045] As mentioned above, the cannabinoid is linked to the bridge via a suitable hydroxyl group. In case the cannabinoid has two suitable hydroxyl groups, the cannabinoid may be linked to the bridge via either one of the two suitable hydroxyl groups (i.e. , one free hydroxyl group remains), or the cannabinoid may be linked to two bridges, each bridge being linked via one hydroxyl group of the cannabinoid. Examples of cannabinoids that have two suitable hydroxyl groups are CBD and CBG. N30052

[0046] 8

[0047] The linkage of the bridge to the cannabinoid may be, for example, an ester linkage, a carbonate linkage or a carbamate linkage. The linkage of the bridge to the cannabinoid preferably is an ester linkage.

[0048] Derivatives of the cannabinoids comprise compounds that have a similar structure as the basic cannabinoid. In particular, in case the basic cannabinoid has a cyclohexene structural element, the derivatives may have one of the following cyclohexene elements, which are all similar to each other: (a) the cyclohexene is completely hydrogenated (i.e. , no double bond), (b) the cyclohexene has a double bond and the double bond has the same location as in the basic cannabinoid, (c) the cyclohexene has a double bond and the double bond has a different location compared to the basic cannabinoid (regioisomers), (d) the cyclohexene has two double bonds, including regioisomers, (e) the cyclohexene has three double bonds and is therefore aromatic (benzene ring). In the case of (b), water may be added to the double bond in the sense of an electrophilic addition or two hydroxy groups can be formally introduced, for example via peracids or permanganates. In the case of (e), the benzene ring may be optionally substituted with 0, N, S, halogen and / or Ci-Cs-alkyl. 0, N and S may be optionally substituted with H or Ci-Cs-alkyl. Ci-Cs-alkyl may be optionally substituted with 0, N, S and / or halogen.

[0049] [Z+] is an anion exchange resin. The term “anion exchange resin” as used herein refers to an insoluble resin or polymer that acts as a medium for anion exchange. The anion exchange resin is present as cation. Examples of anion exchange resins are styrene-divinylbenzene copolymer resins that have quaternary ammonium cations as an integral part of the resin matrix.

[0050] The compound of the invention has salt character. There is an ionic interaction between the anion and the anion exchange resin. The anion exchange resin is loaded with the anion during the manufacturing process of the compound.

[0051] In the body, the anion will be released from the anion exchange resin by bile acids, which displace the anion from the anion exchange resin. N30052

[0052] 9

[0053] The invention provides an improved way for the medical use of cannabinoids as will be further explained in the following.

[0054] The compound of the invention is particularly suitable for oral administration, which is the preferred method of administration for adults.

[0055] The targeted release of the anion from the anion exchange resin occurs in the small intestine. This ensures that the anion is protonated at the prevailing pH value, which is approximately 5.5 to slightly alkaline. The protonated anion can easily cross membranes. Therefore, an increased concentration of the protonated anion reaches the liver via the portal vein and is metabolized, among others, via the so-called first-pass effect. In other words, the protonated anion is cleaved in the liver. By cleavage of the anion, the cannabinoid is released from the bridge. The cannabinoid then enters the bloodstream and acts as the active ingredient, in particular as active pharmaceutical ingredient (API).

[0056] The compound of the invention may be regarded as a so-called “double prodrug”. A prodrug is often designed to improve bioavailability when the drug itself is poorly absorbed from the gastrointestinal tract. A prodrug may be obtained, for example, by adding to the drug a further chemical group, which is split off again in the body by the conditions prevailing there, thereby releasing the drug in a targeted manner. In the “double prodrug” of the invention, the cannabinoid is the drug (or active pharmaceutical ingredient). In a first step, a first chemical group is added synthetically to the cannabinoid. The first chemical group is the bridge. In a second step, a salt structure is built up at the end of the bridge via ionic interaction with a second chemical group, namely the anion exchange resin. As described above, upon oral administration of the compound of the invention, the “cannabinoid-bridge entity” (the anion) is released from the anion exchange resin in the gastrointestinal tract and then absorbed from the gastrointestinal tract. Afterwards, in the liver, the cannabinoid is released from the bridge. In this way, the “double pro-drug” of the N30052

[0057] 10 invention overcomes the low bioavailability of orally administered cannabinoids.

[0058] Of note, the addition of the bridge to the cannabinoid serves not only to increase the bioavailability and solubility of the cannabinoid, but also and primarily to introduce an acidic functionality to the cannabinoid so that it can form a salt with the anion exchange resin and so that it can also be released from the anion exchange resin again.

[0059] Due to the physiological release of the anion from the anion exchange resin by bile acids, the anion is slowly released after ingestion. In other words, the anion is released in a sustained manner. The sustained release can also be referred to as retard effect or retardation effect. The retardation effect is achieved through the physiologically slowed release of the anion, and thus of the cannabinoid. The sustained release ensures a constant supply of the anion, and thus of the cannabinoid, over a certain period of time. In other words, the sustained release facilitates a desired plasma level of the cannabinoid over a longer period of time compared to known cannabinoid formulations. In this way, the compound of the invention facilitates a long-lasting effect of the cannabinoid over the course of the day.

[0060] As mentioned above, the compound of the invention also shows an increased bioavailability of the cannabinoid. Accordingly, the compound of the invention provides an increased bioavailability of the cannabinoid in combination with the retardation effect described above upon oral administration of the compound.

[0061] Taken together, the compound of the invention facilitates an increased bioavailability of the cannabinoid over a longer period of time. This also allows a higher dosage of the cannabinoid (for example, a dosage that is 2- to 3-fold the dosage of known cannabinoid formulations). In turn, taking the respective medication several times a day can be avoided. The compound of the invention allows to reduce the frequency of medication intake to one or at most two N30052

[0062] 11 times per day. This is particularly advantageous for chronic pain patients, who need to take known cannabinoid medicaments as painkillers several times a day. It is also advantageous for patients with vomiting due to chemotherapy, patients with multiple sclerosis or patients with loss of appetite. In addition, the reduction of the frequency of medication intake often increases the compliance of the patients with their medication scheme.

[0063] In addition, in the compound of the invention, the cannabinoid is present in a form that, as a salt, is significantly more stable compared to the respective cannabinoid in its pure form, which tends to oxidize quickly. The compound of the invention thus achieves an improved stability of the cannabinoid in air.

[0064] Due to the physiological release of the anion from the anion exchange resin, there is no need for a special pharmaceutical formulation (i.e., a special retard capsule or tablet preparation) that enables a controlled release of the drug. Therefore, there are no special requirements for a capsule or the like, so that any standard capsule may be used. Given the high stability of the compound of the invention, it can even be envisaged that pharmacists may fill the compound of the invention into capsules themselves.

[0065] In a preferred embodiment, the cannabinoid is of the cannabigerol-type, can- nabichromene-type, cannabidiol-type, cannabinodiol-type, tetrahydrocannabinol-type, cannabinol-type, cannabitriol-type, cannabielsoin-type, isocanna- binoide-type, cannabicyclol-type or cannabichromanon-type.

[0066] In a preferred embodiment, the cannabinoid is selected from the group consisting of delta-9-tetrahydrocannabinol, cannabinol, cannabidiol, canna- bichromene, cannabigerol, cannabigerol monomethyl ether, cannabinerolic acid, cannabigerovarin, cannabigerolic acid A, cannabigerolic acid monomethyl ether, cannabigerovarinic acid, cannabichromenic acid, cannabichrome- varin, cannabichromevarinic acid A, cannabidiolic acid, cannabidivarinic acid, cannabidiol-C4, cannabidivarin, cannabidiorcol, cannabinodiol, cannabinodi- varin, delta-9-tetrahydrocannabinol-C4, delta-9-tetrahydrocannabivarin, delta- N30052

[0067] 12

[0068] 9-tetrahydrocannabiorcol, delta-9-tetrahydrocannabinolic acid A, delta-9-tetra- hydrocannabinolic acid B, delta-9-tetrahydrocannabinolic acid-C4, delta-9-tet- rahydrocannabivarinic acid, delta-9-tetrahydrocannabiorcolic acid, delta-8-tet- rahydrocannabinol, cannabivarin, cannabinol-C2, cannabiorcol, cannabinolic acid, cannabinol-C4, cannabitriol, 10-O-ethyl-cannabitriol, cannabitriol-C3, 8,9-dihydroxy-delta-6a(10a)-tetrahydrocannabinol, cannabidiolic acid A cannabitriol ester, cannabiripsol, 6a, 7,10a-trihydroxy-delta-9-tetrahydrocanna- binol, 10-oxo-delta-6a(10a)-tetrahydrocannabinol, cannabielsoin, cannabiel- soin-C3, cannabielsoic acid A, cannabielsoic acid B, cannabielsoic acid B-C3, delta-7-isotetrahydrocannabinol, delta-7-isotetrahydrocannabivarin, cannbicy- clol, cannabicycolic acid, cannabicyclovarin, cannabichromanon, cannabichro- manon-C3, isomers and derivatives thereof.

[0069] More preferably, the cannabinoid is delta-9-tetrahydrocannabinol (D9-THC), cannabinol (CBN), cannabidiol (CBD), cannabichromene (CBC) or can- nabigerol (CBG), most preferably D9-THC, CBN or CBD.

[0070] In a preferred embodiment, X is selected from the group consisting of: N30052 N30052 N30052 N30052 N30052 N30052 N30052 N30052 N30052 N30052 N30052 N30052 N30052 N30052 N30052 N30052 N30052 N30052 N30052 N30052 N30052 N30052 N30052 N30052

[0071] N30052 N30052

[0072] 40 isomers and derivatives thereof.

[0073] As mentioned above, the cannabinoid may be a synthetic, semisynthetic or endogenous cannabinoid. The semisynthetic cannabinoid may be, for example, dronabinol (semisynthetic D9-THC). The synthetic cannabinoid may be, for example, nabilone (fully synthetic D9-THC). The endogenous cannabinoid may be, for example, N-arachidonoyl dopamine (NADA), anandamide (ANA), 2-arachidonoylglycerol (2-AG) or 2-arachidonyl glyceryl ether (2-AGE).

[0074] In a preferred embodiment, the atom at the first position of Y is a carbon. In other words, in case Y is Ci-Cio-heteroalkyl, the first position of the heteroalkyl is not substituted. Likewise, in case Y is C2-Cio-heteroalkenyl, the first position of the heteroalkenyl is not substituted. The term “first position of Y” as used herein refers to the atom of Y that is linked to the carbon atom which links the cannabinoid to Y. Accordingly, the last position of Y corresponds to the atom of Y that is linked to the carbon atom of the carboxylate group.

[0075] When the first position of Y is a carbon, the linkage of the bridge to the cannabinoid is an ester linkage. The ester linkage renders the compound of the invention particularly physiologically acceptable.

[0076] In a preferred embodiment, Y is Ci-Cw-alkyl, optionally substituted with 0, N, S and / or halogen, Ci-C -heteroalkyl, optionally substituted with 0, N, S and / or halogen, C2-Cw-alkenyl, optionally substituted with 0, N, S and / or halogen, or C2-Cio-heteroalkenyl, optionally substituted with 0, N, S and / or halogen. N30052

[0077] 41

[0078] In a preferred embodiment, Y is Ci -Cw-alkyl, optionally substituted with 0, N, S and / or halogen, or C2-Cw-alkenyl, optionally substituted with 0, N, S and / or halogen.

[0079] In a preferred embodiment, Y is Ci-C4-alkyl, optionally substituted with 0, N, S and / or halogen, Ci-C4-heteroalkyl, optionally substituted with 0, N, S and / or halogen, C2-C4-alkenyl, optionally substituted with 0, N, S and / or halogen, or C2-C4-heteroalkenyl, optionally substituted with 0, N, S and / or halogen. In this case, Y is rather short. Such forms of Y are particularly physiologically acceptable.

[0080] In a preferred embodiment, Y is C2-alkyl, optionally substituted with 0, N, S and / or halogen, C2-heteroalkyl, optionally substituted with 0, N, S and / or halogen, C2-alkenyl, optionally substituted with 0, N, S and / or halogen, or C2- heteroalkenyl, optionally substituted with 0, N, S and / or halogen.

[0081] More preferably, Y is C2-alkyl, optionally substituted with 0, N, S and / or halogen, or C2-alkenyl, optionally substituted with 0, N, S and / or halogen. In this case, the bridge has four carbon atoms. A bridge of four carbon atoms is particularly physiologically suitable due to the degradation of C4-units in the body via the citrate cycle.

[0082] Examples of a bridge with four carbon atoms include hemisuccinate, hemifumarate, hemimaleate, hemimalate, hemitartrate and hemimethylmalonate.

[0083] In a preferred embodiment, Y is selected from the group consisting of:

[0084] In this case, Y is Ci -alkyl, C2-alkyl or C2-alkenyl. The corresponding bridges are (from left to right) hemimalonate, hemisuccinate, hemifumarate and hemimaleate. N30052

[0085] More preferably, Y is C2-alkyl or C2-alkenyl. In case Y is C2-alky I, the bridge is hemisuccinate. In case Y is C2-alkenyl, the bridge may be hemifumarate or hemimaleate.

[0086] It is preferred that the bridge is hemisuccinate or hemifumarate, preferably hemisuccinate. Both hemisuccinate and hemifumarate are well studied with respect to their pharmacological properties. Various drug conjugates of hemisuccinate and hemifumarate, in particular of hemisuccinate, have been approved for use in humans.

[0087] In a preferred embodiment, is selected from the group consisting of delta-9-tetrahydrocannabinol hemisuccinate (D9-THC hemisuccinate), delta-9-tetrahydrocannabinol hemifumarate (D9-THC hemifumarate), cannabinol hemisuccinate (CBN hemisuccinate), cannabinol hemifumarate (CBN hemifumarate), cannabidiol hemisuccinate (CBD hemisuccinate), cannabidiol hemifumarate (CBD hemifumarate), isomers and derivatives thereof.

[0088] In a preferred embodiment, N30052

[0089] 43 is selected from the group consisting of: N30052

[0090] 44 N30052

[0091] 45 isomers and derivatives thereof.

[0092] The structural formulas above correspond to D9-THC hemifumarate, D9-THC hemisuccinate, CBN hemifumarate, CBN hemisuccinate, CBD hemisuccinate in three possible variants (namely a first, a second and a third variant), and CBD hemifumarate in a first of three possible variants, respectively. CBD has two suitable hydroxyl groups, giving rise to a first, a second and a third possible variant as shown for CBD hemisuccinate: CBD is linked to the bridge via either one of the two hydroxyl groups (first and second variant) or CBD is linked to N30052

[0093] 46 two bridges, each bridge being linked via one hydroxyl group (third variant). The third variant corresponds to CBD bishem isuccinate. In the case of CBD hemifumarate, the third variant corresponds to CBD bishem ifumarate (structural formula not shown).

[0094] In a preferred embodiment, [Z+] is a bile acid sequestrant. A bile acid seques- trant exchanges anions for bile acids in the body. By doing so, (i) the anion will be released from [Z+] in the body and can then act as active ingredient, and (ii) [Z+] binds bile acids and sequesters them from the enterohepatic circulation. The liver then produces more bile acids to replace those that have been lost.

[0095] Bile acid sequestrants are not significantly absorbed from the gut into the bloodstream. Therefore, bile acid sequestrants, along with any bile acids bound thereto, are excreted via the feces after passage through the gastrointestinal tract.

[0096] Examples of bile acid sequestrants are cholestyramine, colesevelam and colestipol.

[0097] Cholestyramine is a styrene-divinylbenzene copolymer that has quaternary ammonium cations (in the form of quaternary trimethylbenzylammonium groups) attached to the copolymer.

[0098] Colesevelam is a modified polyallylamine, more specifically an allylamine polymer with 1 -chloro-2,3-epoxypropane, (6-(allylamino)hexyl)trimethylammo- nium chloride and N-allyldecylamine. It is made by crosslinking polyallylamine with epichlorohydrin, and then modifying it with bromodecane and (6-bromo- hexyl)trimethylammonium bromide. The bromide ions are then replaced with chloride ions when the material is washed. Like cholestyramine, colesevelam has quaternary ammonium cations (in the form of quaternary trimethylbenzylammonium groups) attached to the polymer. N30052

[0099] 47

[0100] Colestipol is a copolymer of diethylenetriamine (DETA) and epichlorohydrin or of tetraethylenepentamine and epichlorohydrin.

[0101] In a preferred embodiment, [Z+] comprises a quaternary ammonium ion. The quaternary ammonium ion serves as the functional group of the anion exchange resin. Examples of such a resin are cholestyramine and colesevelam.

[0102] In a preferred embodiment, [Z+] comprises one or more of N+R’R”R”’R””, wherein R’, R”, R’” and R”” are the same or independently of each other Ci- Cw-alkyl, optionally substituted with 0, N, S, halogen, hydroxyl, an optionally substituted carbocyclyl and / or an optionally substituted aryl, Ci-Cio-heteroal- kyl, optionally substituted with 0, N, S and / or halogen, C2-Cw-alkenyl, optionally substituted with 0, N, S and / or halogen, C2-Cio-heteroalkenyl, optionally substituted with 0, N, S and / or halogen, C3-Ci2-cycloalkyl optionally substituted with 0, N, S and / or halogen, or Ce-Ci2-aryl optionally substituted with 0, N, S and / or halogen. An example of such a resin is cholestyramine.

[0103] The term “carbocyclyl” as used herein refers to a ring structure having ring atoms that are all carbon.

[0104] In a preferred embodiment, [Z+] comprises one or more of N+R’R”R”’R””, wherein R’, R”, R’” and R”” are the same or independently of each other H, Ci-Cw-alkyl, optionally substituted with 0, N, S, halogen, hydroxyl, an optionally substituted carbocyclyl and / or an optionally substituted aryl, Ci-Cw-het- eroalkyl, optionally substituted with 0, N, S and / or halogen, C2-Cw-alkenyl, optionally substituted with 0, N, S and / or halogen, C2-Cio-heteroalkenyl, optionally substituted with 0, N, S and / or halogen, C3-Ci2-cycloalkyl optionally substituted with 0, N, S and / or halogen, or Ce-Ci2-aryl optionally substituted with 0, N, S and / or halogen. An example of such a resin is colesevelam.

[0105] In a preferred embodiment, [Z+] is selected from the group consisting of cholestyramine, colesevelam and colestipol. Cholestyramine, colesevelam and N30052

[0106] 48 colestipol have been approved as bile acid sequestrants for use in humans.

[0107] Most preferably, [Z+] is cholestyramine.

[0108] In a preferred embodiment, is selected from the group consisting of delta-9-tetrahydrocannabinol hemisuccinate (D9-THC hemisuccinate), delta-9-tetrahydrocannabinol hemifumarate (D9-THC hemifumarate), cannabinol hemisuccinate (CBN hemisuccinate), cannabinol hemifumarate (CBN hemifumarate), cannabidiol hemisuccinate (CBD hemisuccinate), cannabidiol hemifumarate (CBD hemifumarate), isomers and derivatives thereof, and [Z+] is cholestyramine.

[0109] More preferred, the compound of the invention is D9-THC hemisuccinate cholestyramine or CBD hemisuccinate cholestyramine.

[0110] In a preferred embodiment, the stoichiometric ratio of and [Z+] is 2:1 to 1 :5, preferably 2:1 to 1 :2, more preferably 1.3:1 to 1 :1. N30052

[0111] 49

[0112] In a second aspect, the present invention relates to a pharmaceutical composition comprising one or more compounds of the invention, optionally further comprising a pharmaceutically acceptable excipient.

[0113] The term “pharmaceutically acceptable excipient” as used herein refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, preservative, flavoring or encapsulating material. The excipient must be “acceptable” in the sense of being compatible with the one or more compounds of the invention and of not being harmful to a subject to which the pharmaceutical composition is to be administered. An example of a material which may serve as pharmaceutically acceptable excipient is magnesium stearate.

[0114] In a third aspect, the present invention relates to a compound of the invention or pharmaceutical composition of the invention for use in treating pain, particularly chronic, inflammatory, visceral and / or nociceptive pain, neuropathic pain, sleep disorders, post-traumatic disorder, anxiety, nausea, muscular spasms, multiple sclerosis, uterine cramps, Crohn’s disease, inflammatory bowel disorders, bowel cramps, migraine headache, cluster headache, glaucoma, asthma, epilepsy, addiction, cancer, renal fibrosis, inflammation, insomnia, high blood pressure, convulsions, obsessive compulsive disorders, schizophrenia, neurodegenerative disorders, psychiatric disorders, fibromyalgia, Tourette syndrome, depression and / or psychosis.

[0115] In a further aspect, the present disclosure relates to a method of treating a condition or disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the invention or a pharmaceutical composition of the invention, wherein the condition or disease is selected from the group consisting of pain, particularly chronic, inflammatory, visceral and / or nociceptive pain, neuropathic pain, sleep disorders, post-traumatic disorder, anxiety, nausea, muscular spasms, multiple sclerosis, uterine cramps, Crohn’s disease, inflammatory bowel disorders, bowel cramps, migraine headache, cluster headache, glaucoma, N30052

[0116] 50 asthma, epilepsy, addiction, cancer, renal fibrosis, inflammation, insomnia, high blood pressure, convulsions, obsessive compulsive disorders, schizophrenia, neurodegenerative disorders, psychiatric disorders, fibromyalgia, Tourette syndrome, depression and psychosis.

[0117] The term “subject” as used herein refers to a human or an animal. The subject preferably is a human.

[0118] The term “therapeutically effective amount” as used herein refers to an amount sufficient to provide a therapeutic benefit in the treatment of the condition or disease or to delay, reduce or avoid one or more symptoms associated with the condition or disease.

[0119] The synthesis of the compound of the invention may be performed as described in the following.

[0120] In a first step, the cannabinoid of choice is linked to the bridge. In other words, the cannabinoid is converted, for example, with a C3-Ci2-dicarboxylic acid of choice to link the cannabinoid to the bridge via an ester linkage. To do so, the cannabinoid may be dissolved in a suitable solvent, mixed with an anhydride of the C3-Ci2-dicarboxylic acid and stirred at room temperature for several hours. The solvent is then distilled off, the residue is taken up in diethyl ether and mixed with silica gel. The dried slurry is chromatographed over silica gel using a suitable elution protocol. The last fraction is evaporated to obtain the cannabinoid linked to the bridge.

[0121] In a second step, the cannabinoid linked to the bridge is reacted with the anion exchange resin of choice to obtain the compound of the invention. To do so, the cannabinoid linked to the bridge is dissolved in ethanol and sodium hydroxide solution is added and stirred for a few hours at room temperature. The solvent is distilled off under vacuum, the residue is washed and vacuum-dried until constant in weight. In this way, a sodium salt of the cannabinoid linked to the bridge is obtained. The sodium salt is then dissolved in in a suitable solvent N30052

[0122] 51 and mixed with the anion exchange resin at a ratio of choice and stirred for about 24 h at room temperature. The mixture is then filtered under vacuum and washed. The obtained compound of the invention is then dried in a vacuum at 40-60°C until it remains constant in weight.

[0123] Further aspects of the invention will be apparent to the person skilled in the art by the enclosed description of the examples.

[0124] Examples

[0125] Synthesis of D9-THC-hemisuccinate cholestyramine

[0126] Step 1 :

[0127] Conversion of D9-THC (delta-9-tetrahydrocannabinol) with succinic anhydride to obtain D9-THC-hemisuccinate

[0128] Preparation:

[0129] 1 g D9-THC (95%) is dissolved in 20 ml dichloromethane, mixed with 0.46 g succinic anhydride, 0.7 ml triethylamine and 0.08 g 4-dimethylamino-pyridine and stirred at room temperature for 4 h. The solvent is then distilled off, the residue is taken up in 2 ml diethyl ether and mixed with 1 g silica gel. The dried slurry is chromatographed over silica gel (50 g silica gel, 230-400 mesh) under the following conditions: First eluted with hexane (100%) [100 ml], followed by hexane-ether (95:5) [100 ml] and finally with hexane-ether (80:20) [300 ml]. The last fraction is evaporated to obtain 1 .22 g D9-THC-hemisuccinate (92.5% yield); the purity is 98% (HPLC).

[0130] Step 2:

[0131] Reaction of D9-THC-hemisuccinate with DuPont Duolite 143 / 1096 Resin to obtain D9-THC-hemisuccinate cholestyramine

[0132] Preparation:

[0133] Step 2-1 : 10 g D9-THC-hemisuccinate are dissolved in 100 ml ethanol and

[0134] 10 ml 0.1 molar sodium hydroxide solution is added and stirred for 2 h at room temperature. The solvent is distilled off under vacuum, the residue is washed three times with 50 ml of water and vacuum-dried until constant in weight. 10.2 g of D9-THC-hemisuccinate sodium salt is obtained (yield: 96.9%). Step 2-2: 10 g of D9-THC-hemisuccinate sodium salt is dissolved in 1 liter of (water / isopropanol 90:10) and mixed with the same amount of Duolite 143 / 1096 resin and stirred for 24 h at room temperature. The mixture is then filtered under vacuum through a Buchner funnel and a 0.45 pm filter and washed three times with deionized water (100 ml). The residue, which is D9- THC-hemisuccinate cholestyramine, is then dried in a vacuum at 40-60°C until it remains constant in weight.

Claims

N3005253Claims1 . Compound having the general formula (I):whereinX is a cannabinoid or derivative thereof,Y is Ci-Cw-alkyl, optionally substituted with 0, N, S and / or halogen, Ci- Cw-heteroalkyl, optionally substituted with 0, N, S and / or halogen, C2- Cw-alkenyl, optionally substituted with 0, N, S and / or halogen, C2-C10- heteroalkenyl, optionally substituted with 0, N, S and / or halogen, C3- Ci2-cycloalkyl optionally substituted with 0, N, S and / or halogen, or Ce- Ci2-aryl optionally substituted with 0, N, S and / or halogen, and[Z] is an anion exchange resin.

2. The compound of claim 1 , wherein the cannabinoid is of the can- nabigerol-type, cannabichromene-type, cannabidiol-type, canna- binodiol-type, tetrahydrocannabinol-type, cannabinol-type, cannabitriol- type, cannabielsoin-type, isocannabinoide-type, cannabicyclol-type or cannabichromanon-type.

3. The compound of claim 1 , wherein the cannabinoid is selected from the group consisting of delta-9-tetrahydrocannabinol, cannabinol, cannabidiol, cannabichromene, cannabigerol, cannabigerol monomethyl ether, cannabinerolic acid, cannabigerovarin, cannabigerolic acid A, cannabigerolic acid monomethyl ether, cannabigerovarinic acid,N3005254 cannabichromenic acid, cannabichromevarin, cannabichromevarinic acid A, cannabidiolic acid, cannabidivarinic acid, cannabidiol-C4, can- nabidivarin, cannabidiorcol, cannabinodiol, cannabinodivarin, delta-9- tetrahydrocannabinol-C4, delta-9-tetrahydrocannabivarin, delta-9-tetra- hydrocannabiorcol, delta-9-tetrahydrocannabinolic acid A, delta-9-tetra- hydrocannabinolic acid B, delta-9-tetrahydrocannabinolic acid-C4, delta-9-tetrahydrocannabivarinic acid, delta-9-tetrahydrocannabiorcolic acid, delta-8-tetrahydrocannabinol, cannabivarin, cannabinol-C2, can- nabiorcol, cannabinolic acid, cannabinol-C4, cannabitriol, 10-O-ethyl- cannabitriol, cannabitriol-C3, 8,9-dihydroxy-delta-6a(1 Oa)-tetrahydro- cannabinol, cannabidiolic acid A cannabitriol ester, cannabiripsol, 6a, 7, 10a-trihydroxy-delta-9-tetrahydrocannabinol, 10-oxo-delta-6a(1 Oa)- tetrahydrocannabinol, cannabielsoin, cannabielsoin-C3, cannabielsoic acid A, cannabielsoic acid B, cannabielsoic acid B-C3, delta-7-isotetra- hydrocannabinol, delta-7-isotetrahydrocannabivarin, cannbicyclol, can- nabicycolic acid, cannabicyclovarin, cannabichromanon, cannabichro- manon-C3, isomers and derivatives thereof.

4. The compound of any of claims 1 to 3, wherein Y is Ci -Ci o-alkyl, optionally substituted with 0, N, S and / or halogen, or C2-Cio-alkenyl, optionally substituted with 0, N, S and / or halogen.

5. The compound of any of claims 1 to 3, wherein Y is C2-alkyl, optionally substituted with 0, N, S and / or halogen, C2-heteroalkyl, optionally substituted with 0, N, S and / or halogen, C2-alkenyl, optionally substituted with 0, N, S and / or halogen, or C2-heteroalkenyl, optionally substituted with 0, N, S and / or halogen.

6. The compound of any of claims 1 to 4, wherein Y is selected from the group consisting of:andN30052557. The compound of any of claims 1 to 6, whereinis selected from the group consisting of:N30052N30052N3005258isomers and derivatives thereof.

8. The compound of any of claims 1 to 7, wherein [Z+] is a bile acid se- questrant.

9. The compound of any of claims 1 to 8, wherein [Z+] comprises a quaternary ammonium ion.

10. The compound of any of claims 1 to 8, wherein [Z+] comprises one or more of N+R’R”R”’R””, wherein R’, R”, R’” and R”” are the same or independently of each other Ci-Cw-alkyl, optionally substituted with 0,N, S, halogen, hydroxyl, an optionally substituted carbocyclyl and / or an optionally substituted aryl, Ci-Cio-heteroalkyl, optionally substituted with 0, N, S and / or halogen, C2-Cw-alkenyl, optionally substituted withO, N, S and / or halogen, C2-Cio-heteroalkenyl, optionally substituted with 0, N, S and / or halogen, C3-Ci2-cycloalkyl optionally substituted with 0, N, S and / or halogen, or Ce-Ci2-aryl optionally substituted with 0, N, S and / or halogen.

11. The compound of any of claims 1 to 8, wherein [Z+] comprises one or more of N+R’R”R”’R””, wherein R’, R”, R’” and R”” are the same or independently of each other H, Ci-Cw-alkyl, optionally substituted with 0, N, S, halogen, hydroxyl, an optionally substituted carbocyclyl and / or an optionally substituted aryl, Ci-Cio-heteroalkyl, optionally substitutedN3005259 with 0, N, S and / or halogen, C2-Cio-alkenyl, optionally substituted with 0, N, S and / or halogen, C2-Cio-heteroalkenyl, optionally substituted with 0, N, S and / or halogen, C3-Ci2-cycloalkyl optionally substituted with 0, N, S and / or halogen, or Ce-Ci2-aryl optionally substituted with 0, N, S and / or halogen.

12. The compound of any of claims 1 to 8, wherein [Z+] is selected from the group consisting of cholestyramine, colesevelam and colestipol.

13. The compound of any of claims 1 to 12, where the stoichiometric ratio of [X-0-C(0)-Y-C00 ] and [Z+] is 2:1 to 1 :5, preferably 2:1 to 1 :2, more preferably 1.3:1 to 1 :1.

14. Pharmaceutical composition comprising one or more compounds of any one of claims 1 to 13, optionally further comprising a pharmaceutically acceptable excipient.

15. Compound of any one of claims 1 to 13 or pharmaceutical composition of claim 14 for use in treating pain, particularly chronic, inflammatory, visceral and / or nociceptive pain, neuropathic pain, sleep disorders, post-traumatic disorder, anxiety, nausea, muscular spasms, multiple sclerosis, uterine cramps, Crohn’s disease, inflammatory bowel disorders, bowel cramps, migraine headache, cluster headache, glaucoma, asthma, epilepsy, addiction, cancer, renal fibrosis, inflammation, insomnia, high blood pressure, convulsions, obsessive compulsive disorders, schizophrenia, neurodegenerative disorders, psychiatric disorders, fibromyalgia, Tourette syndrome, depression and / or psychosis.

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