WO2015083129A1

WO2015083129A1 - Derivatives of gamma-hydroxybutyric acid, preparation thereof and medical use thereof

Info

Publication number: WO2015083129A1
Application number: PCT/IB2014/066631
Authority: WO
Inventors: Roberto Cacciaglia; Francesca CLERICI; Vincenzo Calderone; Silvio CHERICONI; Milo MEINI; Marco MONCINI
Original assignee: Laboratorio Farmaceutico C.T. S.R.L.
Priority date: 2013-12-06
Filing date: 2014-12-05
Publication date: 2015-06-11
Also published as: ITMI20132041A1

Abstract

There are described derivatives of gamma-hydroxybutyric acid (GHB), their preparation and their use as GHB pro drugs in the treatment of ethanol addiction. In particular, the derivatives of gamma-hydroxybutyric acid (GHB) have formula (I).

Description

DERIVATIVES OF GAMMA-HYDROXYBUTYRIC ACID, PREPARATION THEREOF AND MEDICAL USE THEREOF

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FIELD OF THE INVENTION

The present invention relates to derivatives of gamma-hydroxybutyric acid (GHB), the preparation thereof and the medical use thereof.

The present invention falls within the pharmaceutical field, in particular in the field of medicinal products acting on the central nervous system (CNS) and on addictions, in particular ethanol addiction.

BACKGROUND ART

The gamma-hydroxybutyric acid is a known hypnotic agent which finds application in the treatment of some pathological conditions of the central nervous system among which narcolepsy, sleep disorders, obstructive sleep apnoea syndrome, insomnia associated with schizophrenia, excessive sedation, essential tremor, chronic fatigue syndrome and chronic insomnia.

The gamma-hydroxybutyric acid is known by the acronym of GHB.

The gamma-hydroxybutyric acid finds specific indication for use in the treatment of ethanol addiction, in particular to reduce or prevent symptoms of alcohol withdrawal. GHB is also indicated to reduce the incidence of alcoholism relapse, reducing the desire and chronic alcohol dependence and in the ethyl withdrawal syndrome.

Generally, the gamma-hydroxybutyric acid is used in the salinized form, typically as sodium salt, also known by the name of sodium oxybate.

Sodium oxybate for the treatment of alcohol-related disorders has had excellent feedback in the medical field because its administration is largely free from side effects that accompany the intake of disulfiram, an active ingredient in the treatment of alcohol dependence whose intake is connected to the "syndrome of acetaldehyde", a side effect that in some cases has proved fatal for the patient that took it. Further pharmacological substances with psychotropic activity, approved by the FDA and the EMA for treating alcohol-related disorders, such as Naltrexone and Acamprosate, have shown, in recent international trials, a modest clinical activity. From a pharmacological point of view, the use of GHB in the salinized form is not entirely free from drawbacks. In particular, the GHB in the salinized form, with a modest toxicity for the organism, has a rather inadequate pharmacokinetic (PK) profile. In fact, the drug is absorbed in a particularly rapid manner along the gastrointestinal tract, so you get the peak of maximum concentration of active ingredient after only 30-45 minutes from the intake. Since the half-life of GHB is limited to about 20-25 minutes, this active ingredient needs to be administered several times during the day. Directions of use provide a frequency of administration in any case not less than 3 times a day.

Specifically, the expected minimum dosage for alcohol addiction is equal to 3 administrations per day while for narcolepsy, the drug is administered at bedtime and in the subsequent 2.5-4 hours during the night, considerably reducing patient compliance and in some cases endangering the success of the therapy.

The non-favourable pharmacokinetic profile of GHB reduces the compliance of the drug for the patient, and considering that the target population of the treatment is often reluctant to take medications regularly, it represents a limit to the effective use and, not least, to its commercial success.

Currently, therefore, there is the need to have new drugs or prodrugs for treating alcoholism and alcohol addiction syndrome that have no severe side effects like those found with the use of disulfiram and at the same time that have a more favourable pharmacokinetic profile of GHB.

One of the general objects of the present invention is to provide new drugs for the treatment of alcoholism and alcohol addiction syndrome with a favourable risk/benefit ratio, whose intake does not lead to serious side effects.

Another object of the invention is to provide prodrugs of GHB provided with a more favourable pharmacokinetic profile of GHB.

SUMMARY OF THE INVENTION

The inventors have discovered the possibility to create prodrugs of GHB provided with a molecular portion or structure that can be eliminated through one or more reactions leading to the release of pharmacologically active molecule.

The compounds of the invention have an improved pharmacokinetic profile compared to GHB, therefore they have a longer duration of action than the GHB and its salts.

Accordingly, the compounds of the invention find application in the medical field, in particular in the treatment of addiction to psychotropic substances and/or in the treatment of alcoholism and alcohol withdrawal syndrome.

According to a first aspect, the present invention provides a derivative of gamma- hydroxybutyric acid (GHB) of formula (I):

(I) a pharmaceutically acceptable salt or an isomer thereof, in which

X is R1 . -NHR1 ,

where R1 is H, C1 -C16 alkyl group, alkenyl, alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle; and

Y is O,

or a residue of formula (i)

where A, if present, is -(CR2R3)-, or -(CR2R3)-(CR'2R'3)-,

R2, R3, R'2 and R'3 are, independently of one another, H, C1-C16 alkyl group, alkenyl, alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, or R2 and R3 and/or R'2 and R'3 are fused together to form an C5-C8 aliphatic, aromatic or heteroaromatic optionally substituted ring, or a residue of formula (ii)

where R4 is a C1 -C 6 alkyl group, alkenyl, alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle,

or a residue of formula (iii)

where (B) is -(CR5R6)-, or -(CR5R6)-(CR'5R'6)-,

R5, R6, R'5 and R'6 are, independently of one another, H, C1-C16 alkyl group, alkenyl, alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, or R5 and R6 and/or R'5 and R6 are fused together to form an C5-C8 aliphatic, aromatic or heteroaromatic optionally substituted ring, or a residue of formula (iv)

where R7 is H, a C1 -C16 alkyl group, alkenyl, alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle,

According to another aspect, the present invention relates to a process for the preparation of such derivative of the gamma-hydroxybutyric acid (GHB) of formula (I), comprising the steps of:

a) providing a precursor of formula (Z)

wherein Z is -0(A)COOH, -NHR4, -0(B)OH, -NHCH₂(R7)COOH; and b) reacting the precursor of formula (Z) with tetrahydrofuran (THF) or with dihydrofuran (DHF) to give the derivative of formula (I).

According to a further aspect, the present invention relates to the use of such derivative of the gamma-hydroxybutyric acid (GHB) of formula (I) in the treatment of disorders or diseases of the CNS sensitive to a treatment with GHB, as well as addiction to ethanol or treatment or prevention of alcoholism, in general.

In accordance with a yet further aspect, the present invention relates to a pharmaceutical composition comprising at least a derivative of formula (I) and at least a pharmaceutically acceptable carrier.

The features and the advantages of the present invention will become apparent from the following detailed description and from the examples provided as an illustrative and non limiting process and from the accompanying Figures 1 -5, in which:

- Figure 1 shows the curve of the serum concentration of GHB vs time, recorded after the i.v. administration of GHB 50 mg/Kg, as per Example 4; - Figure 2 shows the curve of the serum concentration of GHB vs time, recorded after the oral administration of GHB 50 mg/Kg, as per Example 4;

- Figure 3 shows the curve of the serum concentration of GHB vs time, recorded after the oral administration of the equivalent dose of a derivative of the invention, as per Example 4;

- Figure 4 shows the curve of GHB concentration measured in plasma of rat both after the administration of GHB 50 mg/Kg (dotted line, white squares), and after the oral administration of a dose (equivalent in GHB) of the prodrug of the invention PRO-GHB 8 (solid line, black squares);

- Figure 5 shows the curve of GHB concentration measured in plasma of primate both after the oral administration of GHB 50 mg/Kg (dotted line, white squares), and after oral administration of a dose (equivalent in GHB) of the prodrug PRO-GHB 8 (solid line, black squares).

DETAILED DESCRIPTION OF THE INVENTION

In a first aspect the present invention relates to a compound or derivative of gamma- hydroxybutyric acid (GHB) of formula (I):

a pharmaceutically acceptable salt thereof or an isomer thereof, wherein

X is R1 , -NHR1 ,

where R1 is H, C1 -C 6 alkyl group, alkenyl, alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle; and

Y is O,

or a residue of formula (i)

where A, if present, is -(CR2R3)-, or -(CR2R3)-(CR'2R'3)-,

R2, R3, R'2 and R'3 are, independently of one another, H, C1 -C16 alkyl group, alkenyl, alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, or R2 and R3 and/or R'2 and R'3 are fused together to form a C5-C8 aliphatic, aromatic or heteroaromatic, optionally substituted ring, or a residue of formula (ii)

where R4 is a C1 -C16 alkyl group, alkenyl, alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle,

or a residue of formula (iii)

where (B) is -(CR5R6)-, or -(CR5R6)-(CR'5R'6)-,

R5, R6, R'5 and R'6 are, independently of one another, H, C1 -C16 alkyl group, alkenyl, alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, or R5 and R6 and/or R'5 and R'6 are fused together to form a C5-C8 aliphatic, aromatic or heteroaromatic, optionally substituted ring, or a residue of formula (iv)

where R7 is H, a C1-C16 alkyl group, alkenyl, alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle.

In some embodiments, the present invention relates to a derivative of gamma- hydroxybutyric acid (GHB) of formula (II)

wherein

Y is O,

X is R1 , -NHR1 , where R1 is H, C1 -C16 alkyl group, C1 -C6 alkenyl,

cycloalkyl selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane, aryl selected from phenyl, alpha- or beta-naphthyl, biphenyl;

heteroaryl selected from pyrrolyl, oxazolyl, thiazolyl, benzofuranyl, oxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzothiophenyl,

heterocycle selected from tetrahydrofuran, tetrahydropyran, azetidine, pyrrolidine, piperidine, morpholine.

In some embodiments of the compound of formula (II), Y is O, X is R1 or NHR1 where R1 is H, C1-C6 alkyl group, aryl selected from phenyl, alpha or beta naphthyl, biphenyl, each optionally substituted with a C1-C6 alkyl or C1-C4 alkyl. In some embodiments of the compound of formula (II), Y is O and R1 is H, a C1 -C6 alkyl group, aryl selected from phenyl, alpha or beta naphthyl, biphenyl, preferably a phenyl.

For the purposes of the present invention, the term "alkyl", as used herein, means a saturated aliphatic hydrocarbon radical, including a straight or branched chain from 1 to 16 carbon atoms. In certain embodiments, "alkyl" refers to a linear or branched-chain from 1 to 12 carbon atoms, in particular from 1 to 6 C. Non-limiting examples of alkyl are methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, n- amyl, iso-amyl, n-hexyl, n-eptyl, n-octyl and the like.

Any alkyl group may be unsubstituted or substituted with one or more substituents. Thus, the term "alkyl" Includes alkyl groups as defined above in which one or more atoms or functional groups of the alkyl portion are substituted with another atom or functional group including, for example, alkyl, particularly C1-C6 alkyl, halogen in particular CI or F, aryl in particular phenyl, substituted aryl, hydroxyl, amine, alcoxyl in particular, CH30-, alkylamino, sulfate.

In certain embodiments, the alkyl is substituted with one or more substituents independently selected from the group consisting of halogen, trifluoromethyl, hydroxy, alkoxy, trifluoromethoxy, amino, C1 -C6 monoalkylamino or C1-C6 dialkylamino.

The term "alkenyl" means an alkyl group, as defined herein, consisting of at least two carbon atoms and containing at least one carbon-carbon double bond. Suitable examples are ethenyl, 1 -propenyl, 2-propenyl, 1-or 2-butenyl, and the like. Any alkenyl group may be non substituted or substituted with one or more substituents independently selected from the group consisting of halogen, trifluoromethyl, hydroxy, alkoxy, trifluoromethoxy, amino, monoalkylamino or dialkylamino.

The term "alkynyl" means an alkyl group, as defined herein, consisting of at least two carbon atoms and containing at least one carbon-carbon double bond. Suitable examples are ethinyl, 1 -propinyl, 2-propinyl, 1 -or 2-butinyl, and the like. Any alkynyl group may be non substituted or substituted with one or more substituents independently selected from the group consisting of halogen, trifluoromethyl, hydroxy, alkoxy, trifluoromethoxy, amino, monoalkylamino or dialkylamino.

The term "cycloalkyl", as used herein, means a 3-7 member or 3-6 member monocyclic ring which may contain one or more double bonds, but does not have a fully conjugated system of ττ-electrons.

Examples of cycloalkyl groups include cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cyclohexadiene and cycloheptane.

In some embodiments, a suitable cycloalkyl group is selected from cyclopropane, cyclopentane, cyclohexane, cyclobutane, and cycloheptane.

A cycloalkyl group may be non substituted or substituted with one to three substituents independently selected from the group consisting of C1-C6 alkyl, halogen, trifluoromethyl, hydroxy, alkoxy, trifluoromethoxy, amino, monoalkylamino or dialkylamino.

The term "aryl", as used herein, means a hydrocarbon consisting of a mono-, bi- or tricyclic ring system, wherein the rings are fused together or covalently linked to each other and at least one of the carbocyclic rings is aromatic. In particular embodiments, the term "aryl" indicates a cyclic aromatic such as a 6-member hydrocarbon, a hydrocarbon having two 6-member rings fused together or a hydrocarbon having two 6-member rings covalently linked to each other.

Examples of aryl groups include phenyl, alpha- or beta-naphthyl, 9,10- dihydroantracenyl, indanyl, fluorenyl, biphenyl and the like.

The aryl group may be optionally substituted ("substituted aryl") with one or more aryl substituents, which may be identical or different, in which the term "aryl substituent" includes alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, hydroxyl, alkoxy, aryloxyl, aralkyloxyl, carboxyl, acyl, halogen, nitro, alkoxycarbonyl, aryloxycarbonyl, aralcoxycarbonyl, acyloxy, acylamino, arylamino, carbamoyl, alkylcarbamoyl, dialchilcarbamoyl, arylthio, alkylthio, alkylene, and -NK'K ", wherein K' and K" can be each independently of the other hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, and aralkyl.

In some embodiments, the aryl group is substituted with C1 -C6 alkyl, halogen, trifluoromethyl, hydroxy, C1 -C3 alkoxy, trifluoromethoxy, amino, C1 -C6 monoalkylamino or C1 -C6 dialkylamino.

The term "heteroaryl", as used herein, means a mono-, bi- or tricyclic ring system containing one to three heteroatoms selected from nitrogen, oxygen and sulfur, wherein the rings are fused together or covalently linked to each other and at least one of the rings is aromatic.

Examples of heteroaryl groups include pyrrolyl, furoyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isotiazolyl, indolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzopyrazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, triazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, piridazinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl.

In certain embodiments, a suitable heteroaryl group is selected from thiophenyl, furoyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, benzofuranyl, benzothiophenyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, piridazinyl, and quinazolinyl. A heteroaryl group can be unsubstituted or substituted ("substituted heteroaryl") with one or more heteroaryl substituents which may be identical or different, wherein the term "heteroaryl substituent" includes alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, hydroxyl, alkoxy, aryloxyl, aralkyloxyl, carboxyl, acyl, halogen, nitro, alkoxycarbonyl, aryloxycarbonyl, aralcoxycarbonyl, acyloxy, acylamino, arylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, arylthio, alkylthio, alkylene, and - NK'K", where K\ K" can be each independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, or aralkyl.

The terms "heterocycle" or "heterocyclic ring", as used herein, means a 3 to 7 member carbocyclic ring, either saturated or partially unsaturated, wherein one or more carbon atoms are independently substituted by nitrogen, oxygen or sulfur. Examples of heterocyclic groups include radicals derived from oxirane, aziridine, oxetane, azetidine, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, pyrrolidine, dihydropyrrole, pyran, dihydropyran, tetrahydropyran, tetrahydrothiopyran, piperidine, pyrazoline, oxazoline, isoxazolidine, isoxazoline, thiazolidine, thiazoline, isothiazoline, dioxane, piperazine, morpholine, thiomorpholine, hexamethyleneimine, homopiperazine, and the like.

A heterocycle or heterocyclic ring may be non substituted or substituted with one to three substituents independently selected from the group consisting of C1-C3 alkyl, halogen, trifluoromethyl, hydroxy, alkoxy, trifluoromethoxy, amino, monoalkylamino or dialkylamino.

In certain embodiments, a suitable heterocycle is selected from oxetane, tetrahydrofuran, pyran, dihydropyran, tetrahydropyran, dioxane, oxazoline, azetidine, pyrrolidine, piperidine, piperazine, and morpholine.

The term "aromatic" refers to a compound in which the constituent atoms form an unsaturated ring system, all atoms in the ring system are hybridized sp² and the total number of electrons π is equal to 4n + 2, wherein n is an integer.

It has in fact surprisingly been observed that the release kinetics of gamma- hydroxybutyric acid (GHB) is influenced by the presence of a protective group of the -OH group of slow removal in vivo, i.e. having a very slow hydrolysis kinetics. In the derivative of formula (I) of the invention, such a protecting group is represented by the residue:

In addition, the release kinetics of GHB has been further and suitably improved by a second protecting group, in this case having a rapid hydrolysis kinetics. In the derivative of formula (I) of the invention, such a second protecting group is represented by the residue:

In fact, as will be seen from the following examples, the administration of the derivative of the invention has led to an early detection of GHB in the systemic circulation, indicating a real and effective biotransformation of the derivative itself into GHB. This demonstrated that the derivatives of the invention effectively act as prodrugs of GHB. In particular, the bioavailability in GHB, consequent to the oral administration of the prodrug, was increased compared to the oral administration of GHB as such. Moreover, at a distance of 120 minutes after administration, the serum concentration of GHB resulting from the prodrug was higher than that resulting from the administration of GHB as such.

In some embodiments, Y is O.

In some embodiments, the substituent group X of formula (I) is R1 , or -NHR1 , where R1 is preferably optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycle.

According to preferred embodiments, R1 is an optionally substituted aryl.

In preferred embodiments, R1 is phenyl or substituted phenyl, for example with a halogen, typically CI.

In other embodiments, Y is O, a residue of formula (i) where (A) is -(CR2R3)- (CR'2R'3)-, a residue of formula (ii) where R4 is optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle, a residue of formula (Hi) where (B) is -(CR5R6)-, or a residue of formula (iv) where is R7 is H, a C1 -C16 alkyl, alkenyl, alkynil or cycloalkyl group optionally substituted.

According to preferred embodiments, Y is O, a residue of formula (i) where (A) is - (CR2R3)-(CR'2R'3)- and R2 and R2' are fused together to form a C5-C8 aliphatic, aromatic, or heteroaromatic optionally substituted ring, a residue of formula (ii) where R4 is optionally substituted aryl, or a residue of formula (iv) where is R7 is H or a C1-C16 alkyl group.

In some embodiments, B is C1 -C6 alkyl, C1 -C3 alkyl.

In some embodiments, X is an aryl, typically a phenyl optionally substituted with a halogen, such as CI and Y is O.

In other preferred embodiments, X is R1 , or -NHR1 and Y is O.

f formula "PROGHB8":

the formula:

In further preferred embodiments, X is R1 , and Y is a residue of formula (i), where (A) is -(CR2R3)-(CR'2R'3)-. More preferably, (A) is -(CR2R3)-(CR'2R'3)- and R2 and R2" are fused together to form a C5-C8 aliphatic, aromatic, or heteroaromatic optionally substituted ring.

Particularly preferred is the derivative of formula:

In further preferred embodiments, X is R1 , or -NHR1 and Y is a residue of formula

(ii) . More preferably, R4 is a C1 -C16 alkyl, alkenyl, alkynyl, cycloalkyi optionally substituted group. Particularly preferred are the derivatives where R4 is optionally substituted aryl.

In further preferred embodiments, X is R1 , or -NHR1 , and Y is a residue of formula

(iii) , where (B) is -(CR5R6)-, R5 and R6 are, independently of one another, H, C1 - C16 alkyl group, alkenyl, alkynyl, optionally substituted cycloalkyi, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle. In some embodiments, B is C1 -C6 alkyl, C1 -C3 alkyl. In further preferred embodiments, X is R1 , or -NHR1 and Y is a residue of formula

(iv) . More preferably, R7 is H or a C1 -C 6 alkyl group.

Particularly preferred is the derivative of formula:

In another aspect thereof, the present invention relates to a process for preparing the derivative of gamma-hydroxybutyric acid (GHB) of formula (I), comprising the steps of:

a) providing a precursor of formula (Z)

In particular, in step a), if it is not already commercially available, said precursor of formula (Z) can be prepared by reactions known in the art, for example as shown hereafter.

In step b), the precursor of formula (Z) is directly reacted with tetrahydrofuran (THF) or with dihydrofuran (DHF) to give the derivative of formula (I).

For example, in the case of derivatives where X is -NHR1 , the precursor of formula (Z) can be prepared by reacting a benzyl ester of formula I (CH2)3COOCH2Ph and a reagent of formula R1 NCO. This gives an intermediate of formula R1 NCOO(CH2)3COOCH2Ph. Such an intermediate is then reacted with dioxane in the presence of Pd/C at 10%, obtaining a precursor (Z) of formula R1 NCOO(CH₂)₃COOH.

In the case of some derivatives of formula (l)(i), i.e. where Y is a residue of formula (i), where A is -(CR2R3)-(CR'2R'3)-, it is possible to react 4-benzoyl butyric acid and a reagent of formula HO-(CR2R3)-(CR'2R'3)-COOH, obtaining a precursor (Z) of formula PhCH2COO(CH2)₃COO-(CR2R3)-(CR'2R'3)-COOH.

In the case of derivatives of formula (l)(iv), i.e. where Y is a residue of formula (iv), it is possible to react an acid of formula XC(O)0(CH2)3COOH with 1 -[3- dimethylaminopropyl]-3-ethylcarbodiimide hydrochloride (EDC HCI) and 1 - hydroxybenzotriazole (OHBt), and then with para-benzoylglycine and diisopropylethylamine toluenesulfonate (DIPEA) up to basic pH, thus obtaining an intermediate of formula:

Such an intermediate is then reacted with dioxane in the presence of Pd/C at 10%, obtaining a precursor (Z) of formula:

In a further aspect thereof, the present invention relates to the use of said derivative of gamma-hydroxybutyric acid (GHB) of formula (I) as a prodrug to treat ethanol addiction. In yet a further aspect, the present invention relates to a pharmaceutical composition comprising at least one derivative of formula (I) and suitable pharmaceutically acceptable carriers and/or excipients.

Suitable pharmaceutically acceptable carriers comprise diluents, glidants, binders, lubricants, stabilizers, adsorbents and preservatives. In particular, said carriers may be natural starch, partially hydrolyzed starch, lactose, glucose, sucrose, mannitol, sorbitol, cellulose and derivatives thereof, microcrystalline cellulose and derivatives thereof, calcium phosphate, calcium carbonate, calcium sulfate, magnesium stearate, maltodextrin , gelatin, gum tragacanth, arabic gum, xanthan gum, talc, silica, colloidal silica, precipitated silica, magnesium silicates, aluminum silicates, sodium lauryl sulfate, magnesium lauryl sulfate, methacrylate copolymers, and mixtures thereof.

The pharmaceutical composition of the invention may be in the form of unit dose. The composition of the invention may be in the form of drops, pearl, suspension, elixir, syrup, tablet, capsule, solution, mini-tablet, micro-tablet, granule, micro- granule, powder, pellet, multiparticulate, or micronized particulate.

A suitable pharmaceutical composition is a formulation in the form for oral administration of the active compound according to the invention.

In certain embodiments, the composition of the invention comprises from 5 to 50% by weight, from 10 to 40%, or from 20 to 35% by weight of derivative of gamma- hydroxybutyric acid (GHB) of formula (I).

According to some embodiments, the derivative of gamma-hydroxybutyric acid (GHB) of formula (I) may be administered to an individual in need of treatment at a dosage ranging from 1 to 50 mg/kg/day, from 5 to 30 mg/kg/day depending on the age and health of the subject.

According to another aspect thereof, the present invention provides a derivative of gamma-hydroxybutyric acid (GHB) of formula (I) for use as a medicament.

According to some embodiments, the derivative of gamma-hydroxybutyric acid (GHB) of formula (I) is used in the treatment of a CNS disease and/or in the treatment of addictions.

In some embodiments, the derivative of gamma-hydroxybutyric acid (GHB) of formula (I) is used in the treatment of one or more diseases or disorders of the CNS selected from catalepsy, narcolepsy, insomnia, obstructive sleep apnea syndrome, insomnia associated with schizophrenia, excessive sedation, essential tremor, chronic fatigue syndrome and chronic insomnia. It is to be understood that all aspects identified as preferred and advantageous for the derivative of the invention should be deemed as similarly preferred and advantageous also for the production process, the pharmaceutical compositions and the relevant uses.

Moreover, it is understood that all possible combinations of the aspects identified as preferred and advantageous for the substituent group X and the substituent group Y of the derivative of formula (I) of the invention are similarly preferred, and thus included.

Below are Examples of preparation of derivatives according to the present invention, as well as examples of evaluation of their effectiveness as prodrugs of GHB, provided for illustrative and not limiting purpose.

EXAMPLES

Example 1.

- Preparation of the compound "PROGHB8":

100 mg of 4-benzoyl butyric acid were dissolved in toluene (1 M solution) and DHF was added (1.2 eq).

The mixture was left to react 24 hours at 50 °C. The appearance of the final product was followed by TLC (AcOEt: Hexane 1/1 ). The reaction was resumed in toluene and three washings were performed with a saturated solution of NaHC03 until disappearance of the unreacted starting acid. Anhydrous sodium sulfate was added for anhydrification, the product was filtered and the solvent was evaporated under reduced pressure. The final product was obtained in pure form as confirmed by the spectroscopic analysis:

1 H-NMR, CDCI3, 200MHz: 1.94-2.20 m, 6H; 2.43-2.51 , m, 2H; 3.89-4.06, m, 2H; 4.36, 2H, t, J = 6.3 Hz; 6.30, s, H; 7.39-7.56, m, 3H, aryl-H; 8.00-8.05, m, 2H, aryl- H; 13C-NMR: 23.07; 24.22; 31 .42; 32.28; 64.12; 69.13; 99.28; 128.57; 129.78; 130.40; 133.17; 166.67; 172.50; Mass (ESI+): m/z 301.1 (100%); IR 3431 , 1719 cm- 1 .

Example 2.

- Preparation of compoun

Benzyl ester 1 (100 mg) was dissolved in dichloromethane and placed to react under magnetic stirring at room temperature and in nitrogen atmosphere with an equimolecular amount of p-CI-phenyl isocyanate 2.

The reaction was monitored by TLC (AcOEt/cyclohexane 4: 6) and completed in about 24 hours. Product 3 was purified by flash chromatographic column (AcOEt/Cyclohexane 4: 6) and then crystallized by a mixture of Et20/petroleum ether.

Compound 3 was solubilized in dioxane and hydrogenated with 10% Pd/C as catalyst. The reaction completed in about 2 hours. The mixture was filtered on celite and the solution obtained was evaporated under reduced pressure. The raw product obtained was crystallized by DCM/Et20 providing acid 4 in pure form.

Once obtained acid 4, the same procedure as in Example 1 was followed in order to obtain the final compound, in which the acid is dissolved in toluene (1 m) and .2 eq of DHF are added and allowed to react at 50 °C for 24 hours.

The final product was obtained in pure form as confirmed by the spectroscopic analysis.

Example 3.

- Preparation of the compound of formula:

20 eq of THF and 2.54 ml_ of AcOEt were added to compound 1 (200 mg, 0.609 mmoles), generated through esterification reaction of 4-benzoyl butyric acid with 2- hydroxybenzoic acid.

BU NI (20% in moles; 44.9 mg) and 2.2 eq of TBHP (70% acqueous solution) were then added. It was left to react at 80 °C following in TLC (AcOEt:Hexane 1 : 1 ) the disappearance of the starting acid 1. Once the reaction was complete, the solvent was evaporated under vacuum and then ran a flash chromatographic column was performed (AcOEt hexane), obtaining the desired product. Example 4.

- Preparation of the compounds of formula:

A 1 m solution was prepared in DCM of RCOOCH₂CH2CH₂CONHPh (3 mmoles) to which 1 .2 eq of DHF and para-toluenesulfonic acid monohydrate are added in catalytic amounts. The reaction was left to react at room tem erature for 1 -3 h.

The disappearance of the starting amide was evaluated by TLC analysis (AcOEtHexane 1/2). The reaction was processed by washing 3 times the DCM with a saturated baking soda solution. Finally, purification was carried out on flash chromatography column.

Example 5.

- Preparation of the compound of formula:

A 0.1 M solution of HOOC-(CH2)3-OCOPh was prepared in DCM and was cooled down to 0 °C. HOBT (1 .1 eq) and EDC HCI (1 .1 eq) were added and the solution was left to react 1 h at 0 °C. Benzoylglycine p-toluenesulfonate (1 eq) and 4 eq of DIPEA (basic pH) were then added. It was left to react at room temperature. The reaction was processed in TLC (AcOEt:Hexane 1 :1 ) and disappearance of the starting acid was observed.

At the end of reaction, a first washing was conducted with a saturated solution of NH4CI, then with a saturated solution of NaHC03 up to pH = 8 then with a saturated solution of NaCI. The product was purified by chromatographic column (eluent AcOEt/ Exane).

Subsequent debenzylation was performed by solubilising 2 g of compound 1 in about 100 ml of dioxane, to which 1 g of 10% Pd/C is then added. The reaction was left to react at room temperature for 3 h. Disappearance of the starting product was followed in TLC (AcOEt: Hexane 1 :1 ). The Pd/c was filtered on celite, and the filter was carefully washed with dioxane and ethyl acetate. The solvent was

The final product was obtained in pure form as confirmed by the spectroscopic analysis:

Clear Oil; 1 H-NMR, CDCI3, 200MHz: ppm 1 .95-2.20, m, 2H; 2.35-2.42, m, 2H; 4.05, d, 2H, J=6.3 Hz; 4.35, d, 2H, J= 6.3 Hz; 5.15, s, 2H; 6.40, bs, 1 H; 7.32-7.53, m, 8H; 8.02-8.04, m, 2H. Mass: 355,38 m/z: 355.14 (100.0%),

Example 6. Evaluation of the derivative of gamma-hydroxybutyric acid (GHB) of formula (la)

For the study of the pharmacokinetic profile of PROGHB8 (Example ) male albino rats Wistar Kyoto weighing between 300-350 g were used. The animals were raised in cages of appropriate size, where they have freedom of movement, with free access to food and water and exposed to alternating 12-hour cycles of light/dark.

The experiment was conducted in compliance with Community legislation (EEC

Directive 86-609) and with the Italian law (LD. No. 1 16/92).

The animals were anesthetized with sodium pentobarbital 70 mg/kg i.p. and operated in order to perform tracheal and carotid artery cannulation.

The tracheal cannula was connected to a ventilation device (Basile MOD. 7025) and the parameters applied for ventilation were as follows:

70 breaths/minute;

- 1 ml of air/100 g of body weight, per breath.

The carotid artery cannula allowed taking of blood samples at selected times, administering saline, sodium citrate 3.8% w/v and pentobarbital 10 mg/kg i.v., when necessary for the maintenance of anesthesia.

The drugs under test were administered in two ways:

- INTRAVENOUS administration (i.v.) performed via the jugular vein.

ORAL administration (p.o.) by gavage. For the oral administration the compounds under test were dispersed in a suspension of 1 % carboxymethylcellulose.

Once the procedure described above was performed and after waiting a period of stabilization (15 minutes), aliquots of blood (300 μΙ) were withdrawn. The drawings were performed before administration of the test compound (basal) and at the following times: 5, 15, 35 minutes, 1 , 2, 4 hours after administration of GHB or the test compound.

GHB was administered i.v. and p.o. at a dose of 50 mg/Kg, while PROGHB8 was administered p.o. at a dose equivalent to GHB (the equivalent dose of PROGHB8 is equal to 1/2 of the molarity of GHB, as a molecule of PROGHB8 is theoretically capable of freeing two molecules of GHB after biotransformation).

After drying, the blood samples were centrifuged at 4 °C and 2040 rpm for 20 minutes, so as to separate the serum (100 μΙ), and then deproteinized with acetonitrile (AcCN 500 μΙ) in which a-hydroxy-isovaleric acid is present (Internal Standard, IS), in a concentration of 100 ng/500 μΙ (Fig. 11 ). Finally, the sample was treated with sodium sulfate (Na2SO4), to remove water present, and again subjected to centrifugation at 9000 rpm for 10 minutes at 22 °C. The supernatant thus obtained was collected and stored at a temperature of -20 °C, until gas-chromatographic analysis was performed.

In order to carry out the GC-MS analysis, the samples were dried, removing the acetonitrile by a nitrogen flow, and subsequently derivatized with 50 μΙ of BSTFA w/1 % TMCS at 70 °C for half an hour, with introduction of trimethyl-silyl groups. The gas-chromatographic parameters used for these analyses were:

Injected volume: 1 μΙ,

Splitless injection mode with injector at 280 °C,

- Initial temperature: 65 °C for 1 min,

22 °C/min. up to 140 °C,

140 °C for 3 min,

50 °C/min. up to 290 °C,

290 °C for 5 min,

- Transfer line 290°C,

Ionic Source 250°C.

The identification ions of GHB are: 73, 147, 233 (m/z).

Ion for quantification of GHB (SIM or Mass Range) is: 233 (m/z).

The identification ions of the a-hydroxy-isovaleric acid are: 73, 145, 219 (m/z). Ion for quantification of a-hydroxy-isovaleric acid (SIM or Mass Range) is: 145 (m/z).

The instruments used for testing were:

- Breathing apparatus (Ugo Basile Sri)

- Centrifuge Universal 32 (Euro Clone, Speed Master 14 R centrifuge),

- Gas chromatograph Trace GC with autosampler model AS2000, mass detector Polaris-Q with ion trap and Xcalibur management software (Thermo Finnigan),

- Gas chromatograph Focus-GC with autosampler model TriPlus, mass detector DSQ II with single quadrupole and Xcalibur management software (Thermo Finnigan),

- Restek Rtx-5MS column (30m X 025mm X 025pm). - Evaporation system under nitrogen flow (Reacti-vap with Reacti-Therm,

Thermo).

Data analysis

The levels of GHB determined in the serum samples have been reported in terms of concentration expressed in ng/ml. These concentrations can be used to extrapolate the main descriptive pharmacokinetic parameters. These parameters are:

Cmax, i.e. the maximum plasma concentration observed in the concentration/time curve derived from the various samples,

- Co (calculated for the intravenous way only) represents the theoretical concentration at time To extrapolated from the extension of the concentration/time curve, until the intercept with the ordinate axis,

Tmax which is the time, between the various test sample drawings, in which

Cmax OCCUrS,

- C at 120' which is the concentration measured at 120 minutes and that provides additional information on the permanence of GHB in the blood stream, after the administration of the molecules under test,

Bioavailability was calculated for GHB administered via os, as

AUCGHBPO/AUCGHBIVX 100,

where AUCGHB_PO indicates the area under the curve of serum concentrations vs time, which is obtained after administration via os of GHB, and AUCGHBIV indicates the area under the curve of serum concentration vs. time relative to the administration of GHB intravenously.

The bioavailability referred to the prodrug was calculated as

AUCGHBpo/AUCcHBiv x 100,

where AUCGHB_PO indicates the area under the curve of serum concentrations of GHB vs time, registered after the administration of PROGHB8 via p.p., and AUCGHBIV indicates the area under the curve of serum concentration vs. time relative to the administration of GHB intravenously.

Results

The administration of GHB 50 mg/kg i.v. led to detect a Co of about 35000 ng/ml (equal to a distribution volume of about 1.4 l/kg). The concentration of GHB is rapidly decreased with a value of h/2 of approximately 9 minutes. The administration of GHB 50 mg/kg orally showed a bioavailability of approximately 30%. The administration of PROGHB8 has led to an early detection of GHB in the systemic circulation, indicating a real and effective biotransformation of PROGHB8 into GHB. This shows that PROGHB8 acts effectively as a prodrug of GHB. In particular, it is noted that the bioavailability in GHB, following oral administration of the prodrug, is increased compared to the oral administration of GHB as such. Furthermore, it is noteworthy that at 120' after the administration, the serum concentration of GHB resulting from the prodrug is greater than that resulting from the administration of GHB as such. The results are shown in the following tables.

Table 1.

Table 2.

Compound Cmax Tmax C at Bioavailability Figure

(GHB (min) 120'

ng/ml)

2: Curve of serum concentration of GHB curve vs. time, recorded

GHB 768 ± 169 48 ± 18 337 33 ± 5

following oral administration of GHB 50 mg/Kg

3: Curve of serum concentration of GHB curve vs. time, recorded

ProGHB8 1621 ± 308 20 ± 5 470 40 ± 12 (II) following oral administration of the equivalent dose of PROGHB8

Claims

1. A derivative of gamma-hydroxybutyric acid (GHB) of formula (I):

(I) a pharmaceutically acceptable salt thereof or an isomer thereof, wherein

X is R1 , -NHR1 ,

where R1 is H, an optionally substituted C1-C16 alkyl group, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle;

Y is O,

or a residue of formula (i)

where A, if present, is -(CR2R3)-, or -(CR2R3)-(CR'2R'3)-,

R2, R3, R'2 and R'3 are, independently of one another, H, C1 -C16 alkyl group, alkenyl, alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, or R2 and R3 and/or R'2 and R'3 are fused together to give an optionally substituted C5-C8 aliphatic, aromatic or heteroaromatic ring, or a residue of formula (ii)

or a residue of formula (iii)

where (B) is -(CR5R6)-, or -(CR5R6)-(CR'5R'6)-,

R5, R6, R'5 and R'6 are, independently of one another, H, C1 -C16 alkyl group, alkenyl, alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, or R5 and R6 and/or R'5 and R'6 are fused together to give an optionally substituted C5-C8 aliphatic, aromatic or heteroaromatic ring, or a residue of formula (iv)

where R7 is H, a C1 -C16 alkyl group, alkenyl, alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle.

2. A derivative of the gamma-hydroxybutyric acid (GHB) of formula (I) of claim 1 , wherein X is R1 , or -NHR1 , and Y is O, and wherein

R1 is

- H,

- C1-C16 alkyl, optionally substituted with C1 -C6 alkyl, halogen, phenyl optionally substituted with halogen or C1 -C6 alkyl, hydroxyl, amino, C1 -C3 alkoxy, C1 -C6 alkylamino, sulfate; - C1 -C6 alkenyl, optionally substituted with halogen, trifluoromethyl, hydroxy, C1 -C3 alkoxy, trifluoromethoxy, amino, C1 -C6 monoalkylamino or C1 -C6 dialkylamino;

- C3-C7 cycloalkyl, optionally substituted with C1-C6 alkyl, halogen, trifluoromethyl, hydroxy, C1 -C3 alkoxy, trifluoromethoxy, amino, C1 -C6 monoalkylamino or C1-C6 dialkylamino;

- aryl selected from phenyl, alpha- or beta-naphthyl, 9,10-dihydroantracenyl, indanyl, fluorenyl, biphenyl, each optionally substituted with halogen, hydroxy, C1-C6 alkyl, C1 -C3 alkoxy, trifluoromethoxy, amino, C1 -C6 monoalkylamino or C1 -C6 dialkylamino;

- heteroaryl, selected from thiophenyl, furoyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, benzofuranyl, benzothiophenyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and quinazolinyl, each optionally substituted with one to three substituents selected from halogen, hydroxy, C1 -C6 alkyl, C1-C3 alkoxy, trifluoromethoxy, amino, C1-C6 monoalkylamino or C1-C6 dialkylamino;

- heterocycle selected from oxirane, aziridine, oxetane, azetidine, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, pyrrolidine, dihydropyrrole, pyran, dihydropyran, tetrahydropyran, tetrahydro thiopyran, piperidine, pyrazoline, oxazoline, isoxazolidine, isoxazoline, thiazolidine, thiazoline, isothiazoline, dioxane, piperazine, morpholine, thiomorpholine, hexamethyleneimine, homopiperazine each optionally substituted with one to three substituents selected from halogen, hydroxy, C1 -C6 alkyl, C1 -C3 alkoxy, trifluoromethoxy, amino, C1 -C6 monoalkylamino or C1 -C6 dialkylamino.

3. A derivative of the gamma-hydroxybutyric acid (GHB) of formula (I) of claim 1 , wherein X is R1 , and Y is a residue of formula (i), where (A) is -(CR2R3)- (CR'2R'3)-.

4. A derivative of the gamma-hydroxybutyric acid (GHB) of formula (I) of claim 1 , wherein X is R1 , or -NHR1 , and Y is a residue of formula (ii).

5. A derivative of the gamma-hydroxybutyric acid (GHB) of formula (I) of claim 1 , wherein X is R1 , or -NHR1 , and Y is a residue of formula (iii), where (B) is - (CR5R6)-;

R5 and R6 are, independently of one another, H, C1 -C 6 alkyl group, alkenyl, alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle.

6. A derivative of the gamma-hydroxybutyric acid (GHB) of formula (I) of claim 1 , wherein X is R1 , or -NHR1 , and Y is a residue of formula (iv).

7. A derivative of the gamma-hydroxybutyric acid (GHB) according to claim 1 or 2, of formula (II)

(II) wherein

Y is O,

X is R1 . -NHR1 ,

wherein R1 is

- H,

- C1-C16 alkyl group, optionally substituted with C1 -C6 alkyl, halogen, phenyl optionally substituted with halogen or C1 -C6 alkyl, hydroxyl, amino, C1 -C3 alkoxy, C1 -C6 alkylamino, sulfate,

- C1-C16 alkenyl, optionally substituted with C1-C6 alkyl, halogen, phenyl optionally substituted with halogen or C1 -C6 alkyl, hydroxyl, amino, C1 -C3 alkoxy, C1 -C6 alkylamino, sulfate;

- cycloalkyl selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane, each being optionally substituted with C1 -C6 alkyi, halogen, trifluoromethyl, hydroxy, C1 -C3 alkoxy, trifluoromethoxy, amino, C1-C6 monoalkylamino or C1-C6 dialkylamino;

- aryl selected from phenyl, alpha- or beta-naphthyl, biphenyl, each optionally substituted with halogen, hydroxy, C1 -C6 alkyi, C1-C3 alkoxy, trifluoromethoxy, amino, C1 -C6 monoalkylamino or C1 -C6 dialkylamino;

- heteroaryl selected from pyrrolyl, oxazolyl, thiazolyl, benzofuranyl, oxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzothiophenyl, each being optionally substituted with one to three substituents selected from halogen, hydroxy, C1-C6 alkyi, C1 -C3 alkoxy, trifluoromethoxy, amino, C1 -C6 monoalkylamino or C1-C6 dialkylamino;

- heterocycle selected from tetrahydrofuran, tetrahydropyran, azetidine, pyrrolidine, piperidine, morpholine, each being optionally substituted with one to three substituents selected from halogen, hydroxy, C1 -C6 alkyi, C1 -C3 alkoxy, trifluoromethoxy, amino, C1-C6 monoalkylamino or C1-C6 dialkylamino.

8. A derivative of the gamma-hydroxybutyric acid according to claim 7, wherein Y is O,

X is R1 , -NHR1 ,

wherein R1 is selected from

H, C1 -C16 alkyi group, optionally substituted with C1 -C6 alkyi, halogen, hydroxyl, NH2, C1 -C3 alkoxy, C1-C6 alkylamino, sulphate, phenyl optionally substituted with halogen or C1-C6 alkyi;

- cycloalkyl selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane, optionally substituted with C1 -C6 alkyi, halogen, trifluoromethyl, hydroxy, C1 -C3 alkoxy, trifluoromethoxy, amino, C1 -C6 monoalkylamino or C1-C6 dialkylamino; phenyl optionally substituted with halogen, hydroxy, C1 -C6 alkyl, C1 -C3 alkoxy, trifluoromethoxy, amino, C1-C6 monoalkylamino or C1 -C6 dialkylamino; heteroaryl selected from pyrrolyl, oxazolyl, thiazolyl, benzofuranyl, oxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzothiophenyl, each optionally substituted with halogen, hydroxy, C1 -C6 alkyl, C1 -C3 alkoxy, trifluoromethoxy, amino, C1 -C6 monoalkylamino or C1 -C6 dialkylamino; heterocycle selected from tetrahydrofuran, tetrahydropyran, azetidine, pyrrolidine, piperidine, morpholine, each optionally substituted with halogen, hydroxy, C1 -C6 alkyl, C1-C3 alkoxy, trifluoromethoxy, amino, C1 -C6 monoalkylamino or C1-C6 dialkylamino.

9. A derivative of the gamma-hydroxybutyric acid according to claim 7 or 8, wherein Y is O,

X is R1 , -NHR1 , wherein R1 is selected from H, C1 -C16 alkyl group, phenyl optionally substituted with halogen, C1 -C6 alkyl, C1 -C3 alkoxy or methoxy.

10. A derivative of the gamma-hydroxybutyric acid (GHB) according to claim 1 or 7, having the formula:

1 1. A process for the preparation of a derivative of the gamma-hydroxybutyric acid (GHB) of formula (I), comprising the steps of:

a) providing a precursor of formula (Z)

12. A derivative of the gamma-hydroxybutyric acid (GHB) of formula (I) or (II) according to any one of claims 1 -10, for use in the treatment or prevention of one or more disorders or diseases of the central nervous system selected from narcolepsy, cataplexy, sleep disorders, obstructive sleep apnea syndrome, insomnia associated with schizophrenia, excessive sedation, essential tremor, chronic fatigue syndrome and chronic insomnia.

13. A derivative of the gamma-hydroxybutyric acid (GHB) of formula (I) or (II) according to any one of claims 1 -10 for use in the treatment of alcohol addiction.

14. A derivative of the gamma-hydroxybutyric acid (GHB) for the use of claim 12 or 3, having the formul

15. A pharmaceutical composition comprising a derivative of the gamma- hydroxybutyric acid (GHB) of formula (I) or (II) according to any one of claims 1 -10 and a pharmaceutically acceptable excipient and/or carrier, preferably in the form for oral administration.