WO2010115869A1 - Propofol phosphonyl derivatives, synthesis, and use in long acting formulations - Google Patents

Abstract

This invention relates to compounds represented by the structural formula (I), and the salts and stereoisomers thereof, wherein: - L is a linker selected from the group consisting of -(CH₂)_P-O-, a single bond, formula (IA), -(CH₂)_1-8-O-X(O)-, and - p is an integer from 1 to 8, - each R³ and each R⁴ is independently selected from the group consisting of C_1-20alkyl, C_3-12alkyl, C_3-12cycloalkyl-C_1-4alkyl, saturated heterocyclyl and saturated heterocyclyl-C_1-4alkyl, and - X and Y are each independently C or S(O), - Z is selected from the group consisting of O, S(O) and NR⁵, - W is selected from the group consisting of halogen, OH, S(O)H and O^-M⁺ wherein M⁺ is a monovalent cation; and - R⁵ is selected from the group consisting of hydrogen and C_1-10 alkyl. These compounds are useful pharmaceutical agents with improved oral bioavailability.

Description

PROPOFOL PHOSPHONYL DERIVATIVES, SYNTHESIS, AND USE IN ORAL FORMULATIONS

Field of the invention

The invention relates to organic chemistry and in particular to prodrugs and pharmaceutical formulations.

Background of the invention Propofol (2,6-diisopropylphenol) is a low molecular weight phenol (178.27) with a low melting point that is widely used as an intravenous sedative-hypnotic agent in the induction and maintenance of anesthesia or sedation in humans and other mammals. Among its advantages as an anesthetic are rapid onset of anesthesia, rapid clearance, and minimal side effects (Baker et al, Anesthesiology 2005, 103, 860-876). Propofol has a broad range of biological and medical applications, being reported to be an anti-emetic, an anti-epileptic, an anti-pruritic, and an antimigraine agent. Propofol has also been used as an antioxidant.

Propofol is slightly soluble in water, has a pKa of 11, and its octano I/water partition coefficient is 6761 : 1 at a pH of 6-8.5. Therefore, it is formulated in oil-in-water emulsions for injectables (Diprivan®, Astra-Zeneca), with emulsifϊers such as the lecithin mixture Intralipid®.

Alternatively, propofol prodrugs have also been proposed in order to improve propofol aqueous solubility.

Prodrugs of propofol have been reported (e.g., Gallop et al, WO2005/023204; Gibiansky et al., WO2007008869; Rogers et al., UA 76 802 C2; Wozniak et al., CA 2 548 216 Al).

Alkyl phosphate prodrugs of propofol e.g., Aquavan®, have been described in the literature (Baker et al., Anesthesiology 2005,103,860-876; Gibiansky et al., Anesthesiology 2005, 103,718- 729; Struys et al., Anesthesiology 2005, 103, 730-743; Schywalsky et al., Eur J Anaesthesiol 2003, 20, 182-190; Stella et al., International Publication No. WO200008033; Kumpulainen et al., Eur J Pharm Sci. 2008, 34(2-3): 110-7). Patent US6204257 (University of Kansas) discloses O-pho sphononoxymethy lpropo fo 1 derivatives .

Patent applications WO199958555 and WO2002013810 (Vyrex) disclose methods for treating or preventing migraine headaches using propofol prodrugs, such as mono(propofol)phosphate and di(propofol)phosphate, that are much more soluble in water than propofol and that metabolize in vivo into the active propofol.

To date, propofol formulations are in injectable form due to the poor oral bioavailability of propofol. Injectable drug delivery systems are less conveninent than oral formulations due to several factors, particularly because they require assistance for administration, the painful application thereof, the extemporaneous preparation that such formulations usually require, or otherwise, the need for special storage at cool temperatures that readily prepared injectables demand.

There is a need in the art for improving propofol pharmacokinetics, in particular its oral bioavailability such that oral formulations are feasible.

It is an object of the present invention to provide derivatives and formulations of propofol that can be administered orally.

It is an object of the present invention to provide propofol derivatives and formulations that deliver the drug over a sustained period of time at concentrations efficacious for treatment of mammals including humans. Such propofol forms and formulations must be safe, i.e. having minimal side effects, and with appropriate pharmacokinetic profiles.

It is an object of the present invention to provide propofol derivatives and formulations that can improve one or more of the following pharmacokinetic parameters in respect of the currently available formulations: a longer half- life, increased volume of distribution, extended drug release, sustained plasma concentration, or a longer duration of action.

It is an object of the present invention to provide chemically stable derivatives of propofol. It is a further object of the present invention to provide chemically stable formulations of propofol. It is also an object of the present invention to provide soluble derivatives of propofol.

Summary of the invention

The present invention is based on the surprising finding that propofol can be derivatized, onto the phenolic group, with specific phosphonic moieties which show completely different solubility properties in certain pharmaceutically acceptable solvents, and improved oral bioavailability. Preferably the specific phosphonic moieties of the phosphonyl-containing propofol derivatives of this invention comprise a saturated acyclic, homocyclic or heterocyclic group, or a combination thereof, attached to the phosphorus atom through a linker which may comprise one or more carbonyl or sulfonyl groups. The present invention provides oral formulations as well as injectable forms of propofol.

Description of the invention

As used herein, and unless otherwise stated, the term ' ' aryl ' ' designates any mono- or polycyclic aromatic monovalent hydrocarbon group having from 6 to 15 carbon atoms such as, but not limited to, phenyl, naphthyl, anthracenyl, phenanthracyl, fluoranthenyl, chrysenyl, pyrenyl, biphenyl, terphenyl, picenyl, indenyl, biphenyl, indacenyl, benzocyclobutenyl, benzocyclooctenyl and the like. Within this definition are also included groups wherein a phenyl ring is fused to a C₄-S cycloalkyl group (the latter being as defined below) such as, for instance, indanyl, tetrahydronaphthyl, fluorenyl and the like. Within this definition are also included groups wherein a phenyl ring is fused to one or more saturated or unsaturated heterocyclic rings each containing at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur such as, for instance, benzothienyl, thianthrenyl, chromenyl, xanthenyl, phenoxathiinyl, benzofuranyl, isobenzofuranyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, carbolinyl, acridinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, chromanyl, isochromanyl, phenoxazinyl, phenothiazinyl, isoindolinyl, benzoisoquinolinyl and the like. Each of said aryl groups may be optionally substituted, in particular at the ortho, meta and/or para positions of the phenyl ring, with one or more substituents independently selected from the group consisting of chloro, bromo, iodo, trifluoromethyl, trifluoromethoxy, Ci_6 alkyl and Ci_6 alkoxy (the latter being as defined below) such as for instance bromochlorophenyl, bromotolyl, chlorotolyl, iodotolyl, dibromophenyl, dichlorophenyl, diiodophenyl, dimethoxyphenyl, dimethylphenyl (xylyl), diisopropylphenyl, 2,4,6-trimethylphenyl (mesityl), trimethoxyphenyl and the like.

As used herein with respect to a substituent, and unless otherwise stated, the term "Ci_4 alkyl" refers to a straight or branched chain saturated acyclic hydrocarbon monovalent group having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, n-butyl, 1-methylethyl (isopropyl), 2-methylpropyl (isobutyl) and 1,1-dimethylethyl (tert-butyϊ).

As used herein with respect to a substituent, and unless otherwise stated, the term "Ci_6 alkyl" refers to straight and branched chain saturated acyclic hydrocarbon monovalent groups having from 1 to 6 carbon atoms such as, for example, methyl, ethyl, propyl, n-butyl, 1-methylethyl (isopropyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), 2-methyl-butyl, n-pentyl, dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, and the like. The terms "C_1-10 alkyl" and "Ci_2o alkyl" similarly refer to straight and branched chain saturated acyclic hydrocarbon monovalent groups having from 1 to 10 and from 1 to 20 carbon atoms, respectively, thus including those already listed for Ci_6 alkyl and the like, as well as n-octyl, n-nonyl, n-decyl, for "Ci_io alkyl", and n-undecyl, n-dodecyl, n-tetradecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n- pentadecyl, n-nonadecyl and 1-eicosanyl for "Ci_2o alkyl".

As used herein, and unless otherwise stated, the term "Ci_6alkoxy" refers to substituents wherein a carbon atom of a Ci_6 alkyl group (such as defined herein), is attached to an oxygen atom through a single bond such as, but not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy, isopropoxy, sec-butoxy, tert-butoxy and isopentoxy.

As used herein with respect to a substituent, and unless otherwise stated, the term "C3_ i₂cycloalkyl" means a mono- or polycyclic saturated hydrocarbon monovalent radical having from 3 to 12 carbon atoms, such as for instance cyclopropyl, eye Io butyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cycloundecyl, cyclododecyl and the like, or a C₇-Io polycyclic saturated hydrocarbon monovalent radical having from 7 to 10 carbon atoms such as, for instance, norbornyl, fenchyl, trimethyltricycloheptyl or adamantyl.

As used herein with respect to a substituent, and unless otherwise stated, the term "saturated heterocyclyl" refers to a mono- or polycyclic, saturated monovalent hydrocarbon group having from 2 up to 15 carbon atoms and including one or more heteroatoms in one or more heterocyclic rings, each of said rings having from 3 to 10 atoms (and optionally further including one or more heteroatoms attached to one or more carbon atoms of said ring, for instance in the form of a carbonyl or thiocarbonyl or selenocarbonyl group, and/or to one or more heteroatoms of said ring, for instance in the form of a sulfone, sulfoxide, N-oxide, phosphate, phosphonate or selenium oxide group), each of said heteroatoms being independently selected from the group consisting of nitrogen, oxygen, sulfur, selenium and phosphorus; representative but non-limiting examples within this group are 1,2-oxathiolanyl, oxiranyl, aziridinyl, imidazolidinyl, pyrazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, quinuclidinyl, morpholinyl, l,3-dioxa-4- cyclohexyl and the like.

As used herein with respect to a substituent, and unless otherwise stated, the term "halogen" refers to any one of fluoro, chloro, bromo and iodo.

According to a first aspect, the present invention relates to a class of phosphonyl-containing propofol derivatives represented by the structural formula (I):

and the salts and stereoisomers thereof, wherein:

- a single bond,

- p is an integer from 1 to 8,

- each R³ and each R⁴ is independently selected from the group consisting of Ci_₂oalkyl, C₃. 1₂alkyl, C3-i2cycloalkyl-Ci_4alkyl, saturated heterocyclyl and saturated heterocyclyl-Ci_ 4alkyl, and - X and Y are each independently C or S(O),

- Z is selected from the group consisting of O, S(O) and NR⁵,

- W is selected from the group consisting of halogen, OH, S(O)H and 0^"M⁺ wherein M⁺ is a monovalent cation (such as, but not limited to, an alkali metal cation, e.g. Na⁺ or K⁺); and

- R⁵ is selected from the group consisting of hydrogen and C_1-10 alkyl.

Within this class, a useful embodiment is a phosphonyl-containing phenolic derivative represented by the structural formula (I) wherein R³ and R⁴ are independently -(CH₂)_n-CH₃ wherein n is an integer from 8 to 16.

Specifically useful embodiments of this first aspect of the present invention include, but are not limited to, these wherein: a single bond,

- p is an integer from 2 to 3;

- each R³ and each R⁴ is independently selected from the group consisting of Ci_₂oalkyl and C₃. 1₂alkyl;

- X and Y are each independently C;

- Z is O;

- W is selected from the group consisting of halogen and OH.

Several specific embodiments as described herein-above may be combined independently together, especially with respect to the choice of L, p, R³, and R⁴.

It should be noted that the radical positions on any molecular moiety used in the definitions may be anywhere on such moiety as long as it is chemically stable. When any variable occurs more than one time in any moiety, each definition is independent. Radicals used in the definitions of the variables include all possible isomers unless otherwise indicated. For instance pentyl includes 1 -pentyl, 2-pentyl and 3 -pentyl.

Whenever used hereinafter, the term "compounds of formula (I)", or "the present compounds" or similar terms, it is meant to include the compounds of formula (I), the salts thereof; and the stereo chemically isomeric forms thereof.

The compounds of formula (I) may have several centers of chirality, particularlyin respect to the L group when branched, and exist as stereochemically isomeric forms. The term "stereochemically isomeric forms" as used herein defines all the possible compounds made up of the same atoms bonded by the same sequence of bonds but having different three-dimensional structures which are not interchangeable, which the compounds of formula (I) may possess. With reference to the instances where (R) or (S) is used to designate the absolute configuration of a chiral atom within a substituent, the designation is done taking into consideration the whole compound and not the substituent in isolation. Unless otherwise mentioned or indicated, the chemical designation of a compound encompasses the mixture of all possible stereo chemically isomeric forms, which said compound might possess. Said mixture may contain all diastereomers and enantiomers of the basic molecular structure of said compound. All stereo chemically isomeric forms of the compounds of the present invention both in pure form or mixed with each other are intended to be embraced within the scope of the present invention.

Pure stereoisomeric forms of the compounds and intermediates as mentioned herein are defined as isomers substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure of said compounds or intermediates. In particular, the term

"stereoisomerically pure" concerns compounds or intermediates having a stereoisomeric excess of at least 80% (i.e. minimum 80% of one isomer and maximum 20% of the other possible isomers) up to a stereoisomeric excess of 100% (i.e. 100% of one isomer and none of the other), more in particular, compounds or intermediates having a stereoisomeric excess of 90% up to 100%, even more in particular having a stereoisomeric excess of 94% up to 100% and most in particular having a stereoisomeric excess of 97% up to 100%. The terms "enantiomerically pure" and "diastereomerically pure" should be understood in a similar way, but then having regard to the enantiomeric excess, and the diastereomeric excess, respectively, of the mixture in question.

Pure stereoisomeric forms of the compounds and intermediates of this invention may be obtained by the application of art-known procedures. For instance, enantiomers may be separated from each other by the selective crystallization of their diastereomeric salts with optically active acids or bases. Examples thereof are tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid and camphorsulfonic acid. Alternatively, enantiomers may be separated by chromatographic techniques using chiral stationary phases. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occur stereospecifically. Preferably, if a specific stereoisomer is desired, said compound will be synthesized by stereospecifϊc methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.

The diastereomeric racemates of the compounds of formula (I) can be obtained separately by conventional methods. Appropriate physical separation methods that may advantageously be employed are, for example, selective crystallization and chromatography, e.g. column chromatography. The present invention is also intended to include all isotopes of atoms occurring on the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-B and C-14.

For therapeutic use, salts of the compounds of formula (I) are those wherein the counter-ion is pharmaceutically acceptable, which salts can be referred to as pharmaceutically acceptable acid and base addition salts. However, salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not, are included within the ambit of the present invention.

The pharmaceutically acceptable acid and base addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid and base addition salt forms that the compounds of formula (I) are able to form. The pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid in an anion form. Appropriate anions comprise, for example, acetate, benzenesulfonate , benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsyiate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, triethiodide, and the like. Conversely said salt forms can be converted by treatment with an appropriate base into the free base form.

The compounds of formula (I) containing an acidic proton may also be converted into their nontoxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases in a cation form. Appropriate basic salts comprise those formed with organic cations such as benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, and the like; and those formed with metallic cations such as aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and the like. Conversely said salt forms can be converted by treatment with an appropriate acid into the free form. Some of the compounds of formula (I) may also exist in their tautomeric form. Such forms, although not explicitly indicated in the above formula, are intended to be included within the scope of the present invention.

According to another aspect, the present invention relates to various methods for making the phosphonyl-containing propofol derivatives defined in any one of the above embodiments, in particular wherein the linker L may have any one of the above meanings. These methods usually proceed in at least two steps.

According to a first method of the present invention, phosphonyl-containing propofol derivatives represented by the structural formula (I) wherein L is a single bond can be made according to the following sequence of steps:

- reacting propofol with a phosphorus oxyhalide (e.g. phosphorus oxychloride or phosphorus oxybromide) preferably in the presence of a catalytic amount of a tertiary amine such as, but not limited to, triethylamine, to produce a phosphorus oxyhalide intermediate with the structural formula (II), wherein Q is a halogen, preferably chloro or bromo; and

(H) reacting the phosphorus oxyhalide intermediate (II) with a saturated acyclic, homocyclic or heterocyclic mono-alcohol R³OH wherein R³ is preferably selected from the group consisting of Ci_₂oalkyl, C₃_i₂cycloalkyl, C₃_i₂cycloalkyl-Ci_₄alkyl, saturated heterocyclyl and saturated heterocyclyl-Ci_₄ alkyl, in particular R³ may be -(CH₂)_n-CH₃ wherein n is an integer preferably from 8 to 16.

An illustrative embodiment of the first production method of the present invention, wherein L is a single bond and R³ is a dodecyl group, is schematically shown in figure 1.

Suitable mono-alcohols R³OH for use in the first production methods of the present invention include, but are not limited to: - acyclic, linear or branched, mono-alcohols such as, but not limited to, methanol, ethanol, n- propanol, n-butanol, n-pentanol, n-hexanol, n-heptanol, 2,2-dimethyl-3-pentanol, 2,3- dimethyl-3-pentanol, 2,4-dimethyl-3-pentanol, 4,4-dimethyl-2-pentanol, n-octanol, n- nonanol, n-decanol, n-decanol, n-undecanol, n-dodecanol, n-tridecanol, n-tetradecanol, n- pentadecanol, n-hexadecanol, n-heptadecanol, and n-octadecanol;

- homocyclic mono-alcohols such as, but not limited to, cyclobutanol, cyclopentanol, 1- methylcyclopentanol, 2-methylcyclopentanol, 3-methyl-cyclopentanol, cyclohexanol, 1- methylcyclohexanol, 2-methylcyclohexanol, 3-methylcyclohexanol, 4-methylcyclohexanol, 2-te/t-butylcyclohexanol, 4-te/t-butylcyclohexanol, 1-adamantanol, 2-adamantanol, 1,3,3- trimethyl-2-norbornanol, cycloheptanol, cyclooctanol, and cyclododecanol;

- mixed acyclic-homocyclic mono-alcohols such as, but not limited to, cyclopropanemethanol, cyclobutanemethanol, cyclopentanemethanol, cyclohexylmethanol, 2-cyclohexylethanol, 3-cyclohexyl- 1 -propanol, 3-cyclopentyl- 1 -propanol, cycloundecanemethanol, 2-norbornanemethanol, 1-adamanemethanol, 1-adamaneethanol, cycloheptanemethanol, and cyclododecanemethanol;

- saturated heterocyclyl mono-alcohols such as, but not limited to, 4-hydroxypiperidine, 3- hydroxypiperidine, 3 -hydroxy- 1-methylpiperidine, 4-hydroxy-l-methylpiperidine, 1-methyl- 3-pyrrolidinol, tetrahydro-4H-pyran-4-ol and 3-quinuclidinol ;

- mixed acyclic-saturated heterocyclic mono-alcohols such as, but not limited to, l-(2- hydro xyethyl)piperazine, 4-(2-hydroxyethyl)morpholine, l-(2-hydroxyethyl)pyrrolidine, 1- methyl-2-pyrrolidineethanol, (S)- 1 -methyl-2-pyrrolidinemethanol, (2- hydroxyethyl)piperidine, (hydro xymethyl)-piperidine, tetrahydropyran-2-methano 1, tetrahydro-3-furanmethanol, tetrahydrofurfuryl alcohol, dihydro-5-(hydroxymethyl)-2(3H)- furanone and 1-aziridineethanol.

According to a second method of the present invention, phosphonyl-containing propofol derivatives represented by the structural formula (I), wherein L is -(CΗ₂)_P-O-X(O)-, X is C or S(O) and p is an integer from 1 to 8, can be made according to the following sequence of steps:

- reacting a carbonyl chloride R³COCl or sulfonyl chloride R³SO₂Cl (wherein R³ is preferably selected from the group consisting of Ci_₂oalkyl, C₃-₁₂CVC Io alkyl, C₃-i₂cycloalkyl-Ci_₄alkyl, saturated heterocyclyl and saturated heterocyclyl-Ci_₄alkyl, in particular R³ may be -(CH₂)_n-CH₃ wherein n is an integer preferably from 8 to 16), with a linear acyclic diol represented by the structural formula HO-(CH₂)_P-OH wherein p is an integer from 1 to 8, to form an intermediate represented by the structural formula R³X(O)O-(CH₂)_P-OH; and - this intermediate R X(0)0-(CH₂)_p-0H is then reacted with a phosphorus oxyhalide intermediate with the structural formula (II) (wherein Q is a halogen, preferably chloro or bromo), itself obtainable in the same way as in the first step of the first production method of the present invention described above, to form a phosphonyl-containing propofol derivative wherein W is a halogen; this reaction preferably takes place in the presence of a catalytic amount of a tertiary amine such as, but not limited to, triethylamine, and in the presence of an organic solvent such as (but not limited to) toluene.

The second method of the present invention may further comprise a final step of transforming, e.g. through hydrolysis, the phosphonyl-containing propofol derivative wherein W is a halogen into the corresponding phosphonyl-containing propofol derivative wherein W is hydroxyl.

An illustrative embodiment of the second production method of the present invention, wherein R³ is an undecyl group, X is C and p is 2, is schematically shown in figure 2A (first step) and figure 2B (second step and hydrolysis step).

Suitable acyclic diols for use in the second production method of the present invention include, but are not limited to, ethylene glycol, 1,3-propanediol, 1,4-butanediol, 1,5-pentanediol, 2,4- dimethyl-2,4-pentanediol, 2,5-dimethyl-2,5-hexanediol, 1,6-hexanediol, and 1,8-octanediol.

Suitable carbonyl chlorides R³COCl for use in the second production method of the present invention include, but are not limited to, those wherein R³ is preferably selected from the group consisting of Ci_₂oalkyl, C₃_i₂cycloalkyl, C₃_i₂cycloalkyl-Ci_₄alkyl, saturated heterocyclyl and saturated heterocyclyl-C^alkyl, in particular R³ may be -(CH₂)_n-CH₃ wherein n is an integer preferably from 8 to 16. Particularly suitable examples thereof include:

- acyclic, linear or branched, carbonyl chlorides including alkanoyl chlorides such as, but not limited to, acetyl chloride, propionyl chloride, butyryl chloride, isobutyryl chloride, valeryl chloride, isovaleryl chloride, pivaloyl chloride, capryloyl chloride, nonanoyl chloride, decanoyl chloride, lauroyl chloride, myristoyl chloride, palmitoyl chloride, stearoyl chloride and the like;

- homocyclic carbonyl chlorides including cycloalkanoyl chlorides such as, but not limited to, cyclobutanecarbonyl chloride, cyclopentanecarbonyl chloride, cyclohexanecarbonyl chloride,

1 -methyl- 1 -eye Io hexanecarbonyl chloride, 2 -methyl- 1 -cyclohexanecarbonyl chloride, 3- methyl-1 -cyclohexanecarbonyl chloride, 4-methyl-l-cyclo-hexanecarbonyl chloride, cycloheptanecarbonyl chloride, 1-adamantanecarbonyl chloride and the like;

- mixed acyclic-homocyclic carbonyl chlorides including cycloalkyl-alkanoyl chlorides such as, but not limited to, cyclohexylacetyl chloride, cyclopentylacetyl chloride, 2- norbornaneacetyl chloride, 1-adamantane-carbonyl chloride and the like; - saturated heterocyclyl carbonyl chlorides such as, but not limited to, 4-morpholinylcarbonyl chloride, 1-pyrrolidinecarbonyl chloride, tetrahydro-2-furancarbonyl chloride and the like; and

- mixed acyclic-heterocyclic carbonyl chlorides including saturated heterocyclyl-alkanoyl chlorides such as, but not limited to, 3-(l,3-dioxan-2-yl)-propionyl chloride and 3-(l,3- dioxan-2-yl)-2-methylpropionyl chloride.

Suitable sulfonyl chlorides R³SO₂Cl for use in the second production method of the present invention include, but are not limited to, the following: - acyclic, linear or branched, sulfonyl chlorides including alkanesulfonyl chlorides such as, but not limited to, methanesulfonyl chloride, ethanesulfonyl chloride, 1-propanesulfonyl chloride, 1-butanesulfonyl chloride, 1-hexanesulfonyl chloride, 1-octanesulfonyl chloride, 1- decanesulfonyl chloride and the like;

- homocyclic sulfonyl chlorides including cycloalkanesulfonyl chlorides such as, but not limited to, cyclopentanesulfonyl chloride, cyclohexanesulfonyl chloride and the like;

- saturated heterocyclyl sulfonyl chlorides such as, but not limited to, 4-morpholinesulfonyl chloride, pyrrolidine- 1 -sulfonyl chloride and the like.

According to a third method of the present invention, phosphonyl-containing propofol derivatives represented by the structural formula (I), wherein L is -(CH₂)_P-O- and p is an integer from 1 to 8, can be made according to the following sequence of steps:

- reacting a saturated acyclic, homocyclic or heterocyclic mono-alcohol R³OH wherein R³ is preferably selected from the group consisting of Ci_₂oalkyl, C3_i₂cycloalkyl, C3_i₂cycloalkyl- Ci_₄alkyl, saturated heterocyclyl and saturated heterocyclyl-Ci_₄ alkyl, in particular R³ may be -(CH₂)_n-CH₃ wherein n is an integer preferably from 8 to 16, with an ω-halo (preferably ω-bromo) α-alcohol represented by the structural formula Q-(CH₂)_P-OH wherein p is an integer from 1 to 8 and Q is a halogen (preferably bromo); this reaction may take place in the presence of sodium hydride and a suitable solvent such as (but not limited to) tetrahydrofuran and results into a substituted alcohol intermediate represented by the structural formula R³O-(CH₂)_p-OH;

- this substituted alcohol intermediate represented by the structural formula R O-(CH₂)_P-OH is then reacted with a phosphorus oxyhalide intermediate with the structural formula (II)

(wherein Q is a halogen, preferably chloro or bromo), itself obtainable in the same way as in the first step of the first production method of the present invention described above, to form a phosphonyl-containing propofol derivative wherein W is a halogen; this reaction preferably takes place in the presence of a catalytic amount of a tertiary amine such as, but not limited to, triethylamine, and in the presence of an organic solvent such as (but not limited to) toluene.

The third method of the present invention may further comprise a final step of transforming, e.g. through hydrolysis, the phosphonyl-containing propofol derivative wherein W is a halogen into the corresponding phosphonyl-containing propofol derivative wherein W is hydroxyl.

An illustrative embodiment of the third production method of the present invention, wherein R is a linear alkyl group -(CH₂)_n-CH₃, and p is 3, is schematically shown in figure 3 A (first step) and figure 3 B (second step and hydrolysis step).

Suitable mono-alcohols R³OH for use in the third production method of the present invention are the same as previously detailed with respect to the first production method of the present invention.

Suitable an ω-halo-α-alcohols for use in the third production method of the present invention include, but are not limited to, 2-bromoethanol (p = 2), 3-bromopropan-l-ol (p = 3), A- bromobutan-1-ol (p = 4), 5-bromopentan-l-ol (p = 5), 6-bromohexan-l-ol (p = 6), 7- bromoheptan-1-ol (p = 7), 8-bromooctan-l-ol (p = 8), and isomers thereof. For reactivity and yield optimisation purposes, ω-bromo alcohols are preferred. The type of alkyl group present in said alcohols is not important but may be limited in practice by commercial availability.

According to a fourth method of the present invention, phosphonyl-containing propofol derivatives represented by the structural formula (I), wherein:

R⁴ is selected from the group consisting of Ci_2oalkyl, C3-i2alkyl, C3-i2cycloalkyl-Ci_4 alkyl, saturated heterocyclyl and saturated heterocyclyl-Ci_4 alkyl, and

X or Y are each independently C or S(O), can be made according to the following sequence of steps: reacting 1,2,3-propanetriol is reacted with one or more carbonyl chlorides R'COCl and/or sulfonyl chlorides R⁵SO₂Cl (wherein R' is defined in the same meaning as R³ and R⁴) to form a R³,R⁴-containing l,3-di(acyloxy)-propan-2-ol and/or a R³,R⁴-containing l,3-di(sulfoxy)- propan-2-ol intermediate; and reacting the latter l,3-di(acyloxy)-propan-2-ol or l,3-di(sulfoxy)-propan-2-ol intermediate, with a phosphorus oxyhalide intermediate with the structural formula (II) wherein Q is a halogen (preferably chloro or bromo),

(H) itself obtainable in the same way as in the first step of the first production method of the present invention described above, to form a phosphonyl-containing propofol derivative represented by the structural formula (I), wherein W is a halogen; this reaction preferably takes place in the presence of a catalytic amount of a tertiary amine such as, but not limited to, triethylamine, and in the presence of an organic solvent such as (but not limited to) toluene.

The fourth method of the present invention may further comprise a final step of hydro lysing the phosphonyl-containing propofol derivative wherein W is a halogen into the corresponding phosphonyl-containing propofol derivative, wherein W is hydroxyl. According to the first step of this fourth method of this invention it is preferable, although this is not a required feature, that one single carbonyl chloride or sulfonyl chloride is used, thus introducing the same R³-containing and R⁴-containing moieties into the molecule (i.e. R³ = R⁴ and X = Y). Using two or more carbonyl chlorides and/or sulfonyl chlorides in this first step will usually result into the production of a complex mixture of intermediates, itself resulting after the second step into a complex mixture of phosphonyl-containing propofol derivatives represented by the structural formula (I), which may be difficult to separate into pure distinct entities. Alternatively, it may be possible to introducing different R³-containing and R⁴-containing moieties into the molecule (i.e. R³ differs from R⁴ and/or X differs from Y) by dividing the first step into two successive sub-steps wherein the R³-containing moiety and the R⁴-containing moiety are introduced in each sub-step, respectively, by adding different carbonyl chlorides and/or sulfonyl chlorides. This alternative method may however require that a hydroxyl group of 1,2,3-propanetriol is first protected by a conventional hydro xy-protecting group before performance of the first sub-step and then deprotected before performance of the second sub-step to avoid the formation of undesirable by-products. Upon observing this precaution, both R³ and R⁴, and both X and Y may independently be selected at will in the structural formula (I), depending upon the easiness of each sub-step and the desirable physical characteristics of the propofol derivative to be produced.

Suitable carbonyl chlorides R³COCl and R⁴COCl, and suitable sulfonyl chlorides R³SO₂Cl and R⁴SO₂Cl for use in the fourth method of this invention are the same as previously detailed with respect to the second production method of the present invention.

An illustrative embodiment of the fourth production method of the present invention, wherein R³ and R > 4 are both tridecyl groups and X and Y are both C, is schematically shown in figure 4 A (first step) and figure 4B (second step and hydrolysis step).

When a phosphonyl-containing propofol derivative of this invention, wherein W is hydroxyl, has been obtained e.g. according to any one of the four above-described methods, this derivative can be converted into a monovalent salt, i.e. a corresponding derivative wherein W is 0^"M⁺ wherein M⁺ is a monovalent cation (such as, but not limited to, an alkali metal cation, e.g. Na⁺ or K⁺), by using techniques well known to the skilled person.

The type of reaction conditions, e.g. temperature, reaction time, molar ratio between the reactants, solvent of choice and the like, and the type of extraction and/or purification methods generally suitable for each synthetic step in any of the four above described production methods of the present invention are well known to the skilled person. If necessary for optimisation of the reaction yield, a reaction step may be performed in the presence of an effective amount of a catalyst well known to the skilled person.

The resulting compounds may be optionally converted into a pharmaceutically acceptable salt or vice versa according to the methods known by the skilled in the art.

Further, compounds of formula (I) may be converted into each other following art-known functional group transformation reactions. For example, amino groups may be N-alkylated, nitro groups reduced to amino groups, a halo atom may be exchanged for another halo.

Pure stereo chemically isomeric forms of the compounds of formula (I) may be obtained by the application of art-known procedures. Diastereomers may be separated by physical methods such as selective crystallization and chromatographic techniques, e.g., counter-current distribution, liquid chromatography and the like.

The compounds of formula (I) may be obtained as racemic mixtures of enantiomers, which can be separated from one another following art-known resolution procedures. The racemic compounds of formula (I) that are sufficiently basic or acidic may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid, respectively chiral base. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali or acid. An alternative manner of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography, in particular liquid chromatography using a chiral stationary phase. Said pure stereochemical^ isomeric forms may also be derived from the corresponding pure stereo chemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifϊcally. Preferably if a specific stereoisomer is desired, said compound may be synthesized by stereospecific methods of preparation. These methods may advantageously employ enantiomerically pure starting materials.

In another aspect the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of a propofol derivative according to any of the above-referred embodiments, and one or more pharmaceutically acceptable excipients.

The pharmaceutical compositions according to this invention may be administered orally or in any other suitable fashion. In case of oral administration, the preparation may have the form of a tablet, aqueous dispersion, dispersable powder or granule, emulsion, hard or soft capsule, syrup, elixir or gel. The dosing forms may be prepared using any method known in the art for manufacturing these pharmaceutical compositions and may comprise as additives sweeteners, flavoring agents, coloring agents, preservatives and the like. Carrier materials and excipients are detailed hereinbelow and may include, inter alia, calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, binding agents and the like. The pharmaceutical composition of this invention may be included in a gelatin capsule mixed with any inert solid diluent or carrier material, or has the form of a soft gelatin capsule, in which the ingredient is mixed with a water or oil medium. Aqueous dispersions may comprise the biologically active composition or combined preparation in combination with a suspending agent, dispersing agent or wetting agent. Oil dispersions may comprise suspending agents such as a vegetable oil. Rectal administration is also applicable, for instance in the form of suppositories or gels.

Due to the significantly modified physico-chemical properties of the propofol derivatives of the present invention allowing their inclusion into complex types of pharmaceutical formulations such as, but not limited to, microemulsions, microsuspensions and nanosuspensions, injection (e.g. intramuscularly or intraperiteneously) is also applicable as a mode of administration, for instance in the form of injectable aqueous solutions or dispersions, depending upon the disorder to be treated and the condition of the patient. Examples of aqueous solutions include, for example, water, saline, phosphate buffered saline, Hank's solution, Ringer's solution, dextrose/saline, glucose solutions and the like. The pharmaceutical injectable compositions may contain one or more pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions or to improve stability, appearance or ease of administration, such as buffering agents, tonicity adjusting agents, wetting agents, detergents and the like. Additives can also include additional active ingredients such as bactericidal agents, or stabilising agents. For example, the aqueous solution of the invention may contain one or more additives selected from the group consisting of sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, sorbitan monolaurate and triethanolamine oleate. These aqueous compositions can be sterilised by conventional, well-known sterilisation techniques, or can be sterile filtered. The resulting aqueous solutions can be packaged for use as such, or can be lyophilised, the lyophilised preparation being combined with a sterile aqueous solution prior to administration. Such aqueous solutions are appropriate for injection and, in particular, for intravenous injection. Intravenous injection is a particularly appropriate means of delivery for using a propofol derivative of this invention as an anti-migraine agent. The intravenous solution can include detergents and emulsifiers such as lipids. Aqueous solutions also are useful for oral and enteral and other routes of administration as tonics, and for administration to mucous or other membranes as, e.g., nose or eye drops. The aqueous composition of this invention may contain the phenol derivative in an amount from about 1 mg/ml to about 100 mg/ml, preferably from about 5 to 20 mg/ml. Suitable dosages of the pharmaceutical compositions of the present invention, in particular injectable formulations, may range from 0.05 to 100 mg/Kg.

In one embodiment, the pharmaceutical composition of the present invention is in the form of an injectable. In another embodiment, the injectable is administered intravenously, intramuscularly, subcutaneously, intraperitoneally, intra-articularly, intralesionally, intraventricular^, by spinal injection, by intraosseous infusion, or transdermally.

The term "pharmaceutically acceptable carrier or excipient" as used herein in relation to any type of pharmaceutical compositions means any material or substance with which the active principle, i.e. the propofol derivative of this invention, may be formulated in order to facilitate its application or dissemination to the locus to be treated, for instance by dissolving, dispersing or diffusing the said composition, and/or to facilitate its storage, transport or handling without impairing its effectiveness. The pharmaceutically acceptable carrier may be a solid or a liquid or a gas which has been compressed to form a liquid, i.e. the compositions of this invention can suitably be used as concentrates, emulsions, solutions, granulates, dusts, sprays, aerosols, pellets or powders.

Suitable pharmaceutical carriers for use in the said pharmaceutical compositions and their formulation are well known to those skilled in the art. There is no particular restriction to their selection within the present invention although special attention may be paid to the selection of suitable carrier combinations that can assist in properly formulating the propofol derivative in view of the expected time release profile. Suitable pharmaceutical carriers include additives such as wetting agents, dispersing agents, stickers, adhesives, emulsifying or surface-active agents, thickening agents, complexing agents, gelling agents, solvents, coatings, antibacterial and antifungal agents (for example phenol, sorbic acid, chlorobutanol), isotonic agents (such as sugars or sodium chloride) and the like, provided the same are consistent with pharmaceutical practice, i.e. carriers and additives which do not create permanent damage to mammals.

The pharmaceutical compositions of the present invention may be prepared in any known manner, for instance by homogeneously mixing, dissolving, spray-drying, coating and/or grinding the active ingredients, in a one-step or a multi-steps procedure, with the selected carrier material and, where appropriate, the other additives such as surface-active agents. The compositions may also be prepared by micronisation, for instance in view to obtain them in the form of microspheres usually having a diameter of about 1 to 10 μm, namely for the manufacture of microcapsules for controlled or sustained release of the biologically active agent.

Suitable surface-active agents to be used in the pharmaceutical compositions of the present invention are non-ionic, cationic and/or anionic surfactants having good emulsifying, dispersing and/or wetting properties. Suitable anionic surfactants include both water-soluble soaps and water-soluble synthetic surface-active agents. Suitable soaps are alkaline or alkaline-earth metal salts, unsubstituted or substituted ammonium salts of higher fatty acids (C₁₀-C₂₂), e.g. the sodium or potassium salts of oleic or stearic acid, or of natural fatty acid mixtures obtainable form coconut oil or tallow oil. Synthetic surfactants include sodium or calcium salts of polyacrylic acids; fatty sulphonates and sulphates; sulphonated benzimidazole derivatives and alkylarylsulphonates. Fatty sulphonates or sulphates are usually in the form of alkaline or alkaline-earth metal salts, unsubstituted ammonium salts or ammonium salts substituted with an alkyl or acyl radical having from 8 to 22 carbon atoms, e.g. the sodium or calcium salt of lignosulphonic acid or dodecylsulphonic acid or a mixture of fatty alcohol sulphates obtained from natural fatty acids, alkaline or alkaline-earth metal salts of sulphuric or sulphonic acid esters (such as sodium lauryl sulphate) and sulphonic acids of fatty alcohol/ethylene oxide adducts. Suitable sulphonated benzimidazole derivatives preferably contain 8 to 22 carbon atoms. Examples of alkylarylsulphonates are the sodium, calcium or alcanolamine salts of dodecylbenzene sulphonic acid or dibutyl-naphthalenesulphonic acid or a naphtalene-sulphonic acid/formaldehyde condensation product. Also suitable are the corresponding phosphates, e.g. salts of phosphoric acid ester and an adduct of p-nonylphenol with ethylene and/or propylene oxide, or phospholipids. Suitable phospholipids for this purpose are the natural (originating from animal or plant cells) or synthetic phospholipids of the cephalin or lecithin type such as e.g. phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerine, lysolecithin, cardiolipin, dioctanyl-phosphatidylcholine, dipalmitoylphoshatidylcholine and their mixtures.

Suitable non-ionic surfactants include polyethoxylated and polypropoxylated derivatives of alkylphenols, fatty alcohols, fatty acids, aliphatic amines or amides containing at least 12 carbon atoms in the molecule, alkylarenesulphonates and dialkylsulphosuccinates, such as polyglycol ether derivatives of aliphatic and cycloaliphatic alcohols, saturated and unsaturated fatty acids and alkylphenols, said derivatives preferably containing 3 to 10 glycol ether groups and 8 to 20 carbon atoms in the (aliphatic) hydrocarbon moiety and 6 to 18 carbon atoms in the alkyl moiety of the alkylphenol. Further suitable non-ionic surfactants are water-soluble adducts of polyethylene oxide with poylypropylene glycol, ethylenediamino -polypropylene glycol containing 1 to 10 carbon atoms in the alkyl chain, which adducts contain 20 to 250 ethyleneglycol ether groups and/or 10 to 100 propyleneglycol ether groups. Such compounds usually contain from 1 to 5 ethyleneglycol units per propyleneglycol unit. Representative examples of non-ionic surfactants are nonylphenol-polyethoxyethanol, castor oil poly-glycolic ethers, polypropylene/polyethylene oxide adducts, tributylphenoxy-polyethoxyethanol, polyethyleneglycol and octylphenoxypolyethoxyethanol. Fatty acid esters of polyethylene sorbitan (such as polyoxyethylene sorbitan trioleate), glycerol, sorbitan, sucrose and pentaerythritol are also suitable non-ionic surfactants.

Suitable cationic surfactants include quaternary ammonium salts, preferably halides, having four hydrocarbon radicals optionally substituted with halo, phenyl, substituted phenyl or hydroxy; for instance quaternary ammonium salts containing as N-substituent(s) at least one Cs-C₂₂ alkyl radical (e.g. cetyl, lauryl, palmityl, myristyl, oleyl and the like) and, as further substituents, unsubstituted or halogenated lower alkyl, benzyl and/or hydroxy-Ci_4 alkyl radicals.

A more detailed description of surface-active agents suitable for this purpose may be found for instance in «McCutcheon's Detergents and Emulsifiers Annual» (MC Publishing Crop., Ridgewood, New Jersey, 1981), «Tensid-Taschenbuch», 2^nd ed. (Hanser Verlag, Vienna, 1981) and «Encyclopaedia of Surfactants)) (Chemical Publishing Co., New York, 1981).

Structure-forming, thickening or gel- forming agents may be included into the pharmaceutical compositions and combined preparations of the invention. Suitable such agents are in particular highly dispersed silicic acid, such as the product commercially available under the trade name Aerosil; bentonites; tetraalkyl ammonium salts of montmorillonites (e.g. products commercially available under the trade name Bentone), wherein each of the alkyl groups may contain from 1 to 20 carbon atoms; cetostearyl alcohol and modified castor oil products (e.g. the product commercially available under the trade name Antisettle).

Gelling agents which may be included into the pharmaceutical compositions of the present invention include, but are not limited to, cellulose derivatives such as carboxymethylcellulose, cellulose acetate and the like; natural gums such as arabic gum, xanthum gum, tragacanth gum, guar gum and the like; gelatin; silicon dioxide; synthetic polymers such as carbomers, and mixtures thereof. Gelatin and modified celluloses represent a preferred class of gelling agents.

Other optional excipients which may be included in the pharmaceutical compositions of the present invention include additives such as magnesium oxide; azo dyes; organic and inorganic pigments such as titanium dioxide; UV-absorbers; stabilisers; odor masking agents; viscosity enhancers; antioxidants such as, for example, ascorbyl palmitate, sodium bisulfite, sodium metabisulfite and the like, and mixtures thereof; preservatives such as, for example, potassium sorbate, sodium benzoate, sorbic acid, propyl gallate, benzylalcohol, methyl paraben, propyl paraben and the like; sequestering agents such as ethylene-diamine tetraacetic acid; flavoring agents such as natural vanillin; buffers such as citric acid and acetic acid; extenders or bulking agents such as silicates, diatomaceous earth, magnesium oxide or aluminum oxide; densification agents such as magnesium salts; and mixtures thereof.

Additional ingredients may be included in order to control the duration of action of the bio logically- active agent (phenol derivative) in the compositions of the invention. Control release compositions may thus be achieved by selecting appropriate polymer carriers such as for example polyesters, polyamino-acids, polyvinyl-pyrrolidone, ethylene-vinyl acetate copolymers, methylcellulose, carboxy-methylcellulose, protamine sulfate and the like. The rate of drug release and duration of action may also be controlled by incorporating the active agent into particles, e.g. microcapsules, of a polymeric substance such as hydrogels, polylactic acid, hydroxymethylcellulose, polymethylmethacrylate and the other above-described polymers. Such methods include colloid drug delivery systems like liposomes, microspheres, microemulsions, nanoparticles, nanocapsules and so on. Depending upon the route of administration, the pharmaceutical composition of this invention may also require protective coatings.

Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation thereof. Typical carriers for this purpose therefore include biocompatible aqueous buffers, ethanol, glycerol, propylene glycol, polyethylene glycol, complexing agents such as cyclodextrins and the like, and mixtures thereof in any suitable proportions.

Other modes of local drug administration can also be used. For example, the selected propofol derivative active agent may be administered topically, in an ointment, gel or the like, or transdermally, using a conventional transdermal drug delivery system.

The compounds of the present invention are useful because they possess pharmacological activity in animals, including humans. In particular, the compounds are useful as anesthetic, sedative-hypnotic, or as anti-migraine agent. For example, they are useful in inducing and maintaining general anesthesia, initiation and maintenance of Monitored Anesthesia Care (MAC) sedation, initiation and maintenance of Intensive Care Unit (ICU) sedation in intubated mechanically ventilated subjects, combined sedation and regional anesthesia, cardiac anesthesia, neuroanesthesia. They can also be used in the treatment or prevention of migraine headache, for reducing post-operative nausea and vomiting, for providing anti-emetic activity, for treating refractory status epilepticus, or for use as an anti-convulsant in a mammal.

The compounds of the present invention, pharmaceutically acceptable salts thereof, or any subgroup thereof may therefore be used as a medicament. Said use as a medicament or method of treatment comprises the systemic administration to a subject in need thereof, of an amount effective to induce or maintain anesthesia, to treat or prevent migraine headache, to reduce post- operative nausea and vomiting, for providing anti-emetic activity, for treating refractory status epilepticus, or for use as an anti-convulsant in a mammal

The present invention also relates to the use of the present compounds, pharmaceutically acceptable salts thereof, or any subgroup thereof for the manufacture of a medicament for the induction or maintenance of anesthesia, for the treatment or prevention of migraine headache, to reduce post-operative nausea and vomiting, for providing anti-emetic activity, for treating refractory status epilepticus, or for use as an anti-convulsant in a mammal. In other words, the present invention further relates to the compound of formula (I), pharmaceutically acceptable salts thereof, or any subgroup thereof, for use as an anesthetic agent, sedative-hypnotic, or as anti-migraine agent. Also, the present invention relates to a a method of induction or maintenance of anesthesia, which comprises administering an effective amount of a compound according to any one of the embodiments herein, to a patient in need of such induction or maintenance.

In addition, the present invention relates to a method of extending the release of propofol, which comprises converting propofol into a compound of formula (I), a pharmaceutically acceptable salt thereof, or any subgroup thereof.

The following examples are merely illustrative of some non- limiting embodiments of the present invention.

Examples

Example 1 - Production of propofol phosphonyl derivatives wherein L is a single bond Figure 1

This example illustrates the production of propofol derivatives of the present invention being represented by the structural formula (I) wherein L is a single bond and R³ is a dodecyl group, as schematically shown in Figure 1 and following the principles of the first production method of the present invention, as outlined herein-above.

In this way, 2,6-diisopropylphenyl dodecyl hydrogen phosphate was obtained with a 60% yield, and was characterised by proton nuclear magnetic resonance and mass spectrometry as follows:

¹H NMR (500 MHz, CDCl₃): peaks δ at 7.05-7.02 (m), 3.79-3.61 (m), 3.59-3.54 (m), 1.42-1.15 (m), 1.14 (d, J=6.5 Hz), and 0.88 (t, J=7 Hz) ppm; and

EMI-MS m/z: 425 [M-I]^"

Example 2 - Production of propofol phosphonyl derivatives wherein L is

-(CHz)₂-O-C(O)- Figure 2 A

OH CH₂Ci₂

C-_{j 1}H₂₃COQ -. OH

_HO " ^\-^{UM »} -*^■ C₁₁H₂₃COO rt, overnight ^{] 1} ^

Figure 2B

This example illustrates the production of propofol derivatives of the present invention being represented by the structural formula (I) wherein L is -(CH₂)₂-O-C(O)- and R³ is a undecyl group, as schematically shown in figures 2A and 2B, and following the principles of the second production method of the present invention, as outlined herein-above. In this way the final compound was obtained, after hydrolysis, with a 45% yield, and was characterised by proton nuclear magnetic resonance and mass spectrometry as follows:

¹H NMR (500 MHz, CDCl₃): peaks δ at 7.06 (bs), 4.03 (bs), 3.93 (bs), 3.51 (bs), 2.20- 2.17 (m), 1.53 (s), 1.25 (s), 1.14 (d, J=7 Hz), and 0.88 (t, J= 7 Hz) ppm; and

ESI-MS nVz: 483.2 [M]^"

Example 3 - Production of propofol phosphonyl derivatives wherein L is -(CH₂)3-O-

Figure 3A

r.t., overnight

Figure 3 B

This example illustrates the production of propofol derivatives of the present invention being represented by the structural formula (I) wherein L is -(CH₂)S-O- and R³ is a dodecyl group, as schematically shown in figures 3 A and 3B and following the principles of the third production method of the present invention, as outlined herein-above.

In this way the final compound was obtained, after hydrolysis, with a 25% yield, and was characterised by proton nuclear magnetic resonance and mass spectrometry as follows:

¹H NMR (500 MHz, DMSO.d₆): peaks δ at 6.99-6.93 (m), 3.83 (bs), 3.71-3.69 (m), 3.34 (m), 1.70 (bs), 1.44 (bs), 1.23-1.10 (m), 1.12 (d, J = 6.5Hz), and 0.84 (t, J = 7) ppm; and

MS nVz: 485 [M + I]⁺

Example 4 - Production of propofol phosphonyl derivatives

Figure 4A

*">

C₁₃H₂₇COOH + SOCi_; C^Hg^CGCI rt₍ overnight CH₂Ci₂

C₁₃H27COCI + HO ^OH C₁₃H₂₇COO^{' '} 0OC₁₃H₂₇ rt, overnight

OH OH

Figure 4B

represented by the structural formula (I) wherein L is O _s x and Y are a carbon atom, R³ and R⁴ are a tridecyl group each, as schematically shown in figures 4A and 4B and following the principles of the fourth production method of the present invention, as outlined herein-above.

In this way the final compound was obtained, after hydrolysis, with a 20% yield, and was characterised by proton nuclear magnetic resonance and mass spectrometry as follows: - ¹H NMR (500 MHz, DMSO.d₆): peaks δ at 6.98-6.91 (s), 4.51 (bs), 4.16-4.14 (m), 4.08-

4.05 (m), 3.72-3.70 (m), 2.27-2.24 (m), 1.50-1.48 (s), 1.22-1.07 (m), 1.12 (d, J= 7 Hz), and 0.75 (t, J= 7 Hz) ppm; and

EMS-MS m/z: 753 [M + I]⁺

Example 5 - Solubility of propofol derivatives in pharmaceutical solvents

Table 1 provides the solubility data at 25°C, expressed in mg/ml, of the final propofol derivatives produced and characterised in examples 1-4 respectively. The solubility determination method used was as follows: a suspension of 6 mg of the relevant propofol derivative in 500 μl of the relevant pharmaceutical solvent was rotatively shaken for 24 hours at 800 rpm at 25°C. The saturated propofol derivative solution was filtered (0.45 μm) and 150 μl of the filtrate was diluted in dimethylsulfoxide (50 μl DMSO). This solution was assayed, each assay being carried out in three-fold, by measurement with Liquid Chromatography-Mass Spectrometry (LCMS, lμl and 10 μl injection). Standards were prepared by dissolving the relevant propofol derivative in DMSO (1 mg/ml). To determine the solubility, four aliquots (0.5, 1, 2, 4 μl) of the standard solution were injected using the same LCMS conditions as for the above exemplary samples.

Table 1

Example Ex. 1 Ex. 2 Ex. 4 Ex. 3

Pharmaceutical solvent

H₂O (pH = 2) 24.4 0.8 4.8 1.7

H₂O (pH = 7) 17.7 9.6 7.3 1.7

H₂O (pH = 10) 2.1 2.4 10.0 2.4

H₂O/hydroxypropyl-β-cyclodextrin (60/40) 5.1 2.7 0.0 1.4

H₂O/Vitamin E TPGS (90/10) 16.3 7.5 15.6 1.9

H₂O/Cremophor RH 40 ^a (80/20) 39.4 0.1 0.0 3.3

H₂O/Polysorbate 80 (80/20) 16.3 29.0 0.0 1.8

Polyethylene glycol MW 400 34.5 12.1 13.0 2.3

Miglyol 812 ^b 28.1 7.7 0.0 4.3 ^a an emulsifying agent obtained by reacting 45 moles of ethylene oxide with 1 mole of hydrogenated castor oil, commercially available from BASF AG (Germany). b a caprylic/capric acid triglyceride, commercially available from SASOL GmbH (Germany).

Example 6 - Chemical stability of a propofol derivative wherein L is a single bond in pharmaceutical solvents Table 2 provides the chemical stability data in some pharmaceutical solvents, expressed as the weight percentage of the final propofol derivative produced and characterised in example 1 that remained in solution after a certain period of time. The test was carried out twice, and the remaining weight % was determined by Liquid Chromatography-Mass Spectrometry (LCMS).

Table 2

4 hours 1 day 2 days 7 days 14 days Pharmaceutical solvent H₂O (pH = 2) 99. 6 100 .0 99 .5 99 .2 98. 9 H₂O (pH = 7) 99. 1 98. 9 98 .9 97 .0 95. 0 H₂O (pH = 10) 95. 8 95. 2 94 .8 93 .1 90. 9 H₂O/hydroxypropyl-β-cyclodextrin (60/40) 99.9 97.3 96.9 96.6 95.6 Polyethylene glycol 400 99.8 99.6 99.4 99.0 98.7

Table 2 shows that at most 9% of the propofol derivative did not remain in the relevant aqueous or hydro xypropyl-β-cyclodextrin or polyethylene glycol solution after 14 days.

Example 7 - Chemical stability in pharmaceutical solvents of a propofol derivative wherein L is -(CHz)₂-O-C(O)-

Table 3 provides the chemical stability data in some pharmaceutical solvents, expressed as the weight percentage of the final propofol derivative produced and characterised in example 2 that remained in solution after a certain period of time. The test was carried out twice, and the remaining weight % was determined by Liquid Chromatography-Mass Spectrometry (LCMS).

Table 3

4 hours 1 day 2 days 7 days 14 days

Pharmaceutical solvent

H₂O (pH = 2) 99.6 98.5 98.1 97.2 97.1

H₂O (pH = 7) 98.1 97.7 97.3 97.2 96.5

H₂O (pH = 10) 99.2 99.4 98.8 98.8 98.4

H₂O/hydro xypropyl-β-cyclodextrin (60/40) 98.6 98.9 98.6 98.3 97.7

Polyethylene glycol 400 99.6 99.8 98.9 98.8 99.9

Table 3 shows that at most 3.5% of the propofol derivative did not remain in the relevant aqueous or hydro xypropyl-β-cyclodextrin or poly-ethylene glycol solution after 14 days.

Example 8 - Chemical stability, in some pharmaceutical solvents, of a propofol derivative wherein L is -(CH₂)₃-O-

Table 4 provides the chemical stability data in some pharmaceutical solvents, expressed as the weight percentage of the final propofol derivative produced and characterised in example 3 that remained in solution after a certain period of time. The test was carried out twice, and the remaining weight % was determined by Liquid Chromatography-Mass Spectrometry (LCMS).

Table 4

4 hours 1 day 2 days 7 days 14 days Pharmaceutical solvent H₂O (pH = 2) 98.7 97.9 98.2 96.8 96.2 H₂O (pH = 7) 96.8 95.0 93.9 93, .5 92.6

H₂O (pH = 10) 96. 9 96 .3 96. 3 95, .9 95 .0

H₂θ/hydroxypropyl-β-cyclodextrin (60/40) 96. 9 95 .4 95. 0 94, .0 92 .0

Polyethylene glycol 400 98. 6 98 .0 97. 1 96, .0 95 .2

Table 4 shows that at most 8% of the propofol derivative did not remain in the relevant aqueous or hydro xypropyl-β-cyclodextrin or polyethylene glycol solution after 14 days.

Example 9 - Chemical stability of a propofol derivative prepared in Example 4 in pharmaceutical solvents

Table 5 provides the chemical stability data in some pharmaceutical solvents, expressed as the weight percentage of the final propofol derivative produced and characterised in example 4 that remained in solution after a certain period of time. The test was carried out twice, and the remaining weight % was determined by Liquid Chromatography-Mass Spectrometry (LCMS).

Table 5

4 hours 1 day 2 days 7 days 14 days

Pharmaceutical solvent

H₂O (pH = 2) 98 .3 99. 3 97 .9 95 .4 95 .0

H₂O (pH = 7) 96 .4 95. 5 94 .5 91 .7 88 .4

H₂O (pH = 10) 98 .0 98. 8 97 .1 97 .5 97 .1

Polyethylene glycol 400 97 .2 97. 5 97 .1 97 .0 96 .8

Table 5 shows that at most 12% of the propofol derivative did not remain in the relevant aqueous or hydro xypropyl-β-cyclodextrin or polyethylene glycol solution after 14 days.

Example 10 - Pharmacokinetic profile characterization of the propofol derivatives prepared in Examples 1-4

The pharmacokinetic (PK) parameters of the propofol prodrugs prepared in Examples 1-4 were measured after a single oral dose (po) in male rats and the relative oral bioavailability was determined.

A total of 36 rats, randomly assigned to 12 treatment groups, were given a single oral dose of the propofol prodrugs prepared in Examples 1-4. The rats were fed a standard diet and fastened overnight prior to the administration of the test material. On the day of dosing ,food was provided approximately 4 hours following dosing. Prodrugs were dissolved either in mygliol 812, PBS, 0.5% polysorbate 80, 10% vitamin E TPGS or PEG 400. The propofol prodrugs were provided separately, and each solution was prepared freshly just before the start of each experiment in a concentration ranging from eq 1.75 - 3.33 mg propofol/mL. An overview of the prodrug solutions is given in Table 6. All rats were dosed by oral gavage and the volume was calculated based on the rats body weight 10 minutes prior to administration. Furthermore, during the course of the experiment, the individual body weights of the rats were also recorded at regular time periods.

Blood samples were taken preferably from the tail vein from each rat 5 minutes before the start of dosing (= predose) and, 10 min, 20 min, 30 min, Ih, 2h, 3h, 4h, 5h, 6h and 8h after dose administration. Bioanalytical analysis was perfomed using a validated HPLC-MS method which consisted on the quantification of propofol in rat whole-blood by high pressure liquid chromatography and fluorescence detection (excitation wavelength 270 nm, emission wavelength 314 nm). Thymol and 2, 4 -di-tert-butylphenol (DTBP) were used as internal standard.

Table 6. Overview of the prodrug formulations used.

Compound of Example Dissolved in Prodrug Cone Eq. Propofol Cone (mg/ml) (mg/mL)

1 PBS (pH=7.0) 7.15 3

2 PBS (pH=7.0) 8.13 3

4 ^a 10% Vitamin E TPGS 14.81 1.75

3 miglyol 812 9.51 2.44 ^a D-alpha-tocopheryl polyethylene glycol 1000 succinate solution

PK analysis

Non-compartmental PK analysis of the propofol plasma concentrations was performed using WinNonlin Phoenix 6.1 in order to estimate peak plasma concentration and systemic exposure of propofol after the administration of each propofol prodrug. Based on the individual propofol plasma concentration-time data, at least the following PK parameters of propofol were estimated in all rats receiving a dose of propofol prodrug:

C_max peak plasma concentration, determined by visual inspection of the data t_max time to reach the peak plasma concentration, determined by visual inspection of the data AUC last area under the plasma concentration-time curve from 0 to t hours post dosing, calculated by trapezoidal summation (time t is the time of the last quantifiable concentration Ci_ast).

AUCa_Il area under the plasma concentration-time curve from 0 to t hours post dosing, calculated by trapezoidal summation (time t is the time of the last sampling point).

If the last concentration is non-zero AUC_aii=AUCi_ast. Otherwise, AUC_an will be greater than AUCi_ast as it includes the additional area from the last measurable concentration down to zero.

Auα AUCt extrapolated to infinity, calculated as AUC_t + Ci_ast/λ_z λ_z elimination rate constant, determined by linear regression of the terminal points of the In- linear plasma concentration-time curve terminal half-life, defined as 0.693/λ_z

PK parameters were calculated for propofol after the administration of the propofol prodrugs pepared in Examples 1-4. The PK parameters ± SEM obtained with WinNonlin Phoenix 6.1 after the administration of the propofol prodrugs are summarized in Table 7. This table also includes the mean PK parameters ± SEM of propofol after iv and po administration of Diprivan®.

Table7. Mean PK parameters ± SEM of propofol after iv administration of Diprivan®, and oral administration of Di rivan®, and the ro ofol rodru s of Exam les 1-4

a Expressed in propofol equivalents b Corresponds to Co extrapolated from the data c Based on AUCo-2h d For prodrug of Example 1, the mean value of AUCi_ast is higher than the mean value of AUC∞.

Please note that the descriptive statistics on both parameters are based on different sample sizes because not all rats had both assessable AUCi_ast and AUC∞. For all rats that had assessable values for both parameters, the AUC∞ always exceeded the AUCi_ast

- Not estimable from the data

Claims

Claims

1. A compound represented by the structural formula (I):

and the salts and stereoisomers thereof, wherein:

- a single bond,

- p is an integer from 1 to 8,

- each R³ and each R⁴ is independently selected from the group consisting of Ci_₂oalkyl, C3_-12alkyl, C3-i2cycloalkyl-Ci_4alkyl, saturated heterocyclyl and saturated heterocyclyl- Ci_₄alkyl, and

- X and Y are each independently C or S(O), - Z is selected from the group consisting of O, S(O) and NR⁵,

- W is selected from the group consisting of halogen, OH, S(O)H and 0^"M⁺ wherein M⁺ is a monovalent cation; and

- R⁵ is selected from the group consisting of hydrogen and C_1-10 alkyl.

2. The compound according to claim 1, being represented by the structural formula (I), wherein a single bond,

- p is an integer from 2 to 3; - each R³ and each R⁴ is independently selected from the group consisting of Ci_₂oalkyl and C₃-i₂alkyl;

- X and Y are each independently C;

- Z is O;

- W is selected from the group consisting of halogen and OH.

3. A compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof, for use as a medicament.

4. A compound according to any one of claims 1 to 2, for use as an anesthetic agent, sedative- hypnotic, or as anti-migraine agent.

5. A method of induction or maintenance of anesthesia, which comprises administering an effective amount of a compound according to any one of claims 1 to 2, to a patient in need of such induction or maintenance.

6. A method of extending the release of propofol, which method comprises converting propofol into a compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 2, and one or more pharmaceutically acceptable excipients.

8. The pharmaceutical composition according to claim 7, wherein said pharmaceutical compostion is administered orally.

9. The pharmaceutical composition according to claim 7, being in the form of an injectable.

10. A method for producing a compound according to claim 1 and being represented by the structural formula (I), wherein L is a single bond, said method comprising the steps of : - reacting propofol with a phosphorus oxyhalide to produce a phosphorus oxyhalide intermediate with the structural formula (II), wherein Q is a halogen; and

- (H)

- reacting the phosphorus oxyhalide intermediate (II) with a saturated acyclic, homocyclic or heterocyclic mono-alcohol R³OH wherein R³ is as defined in claim 1.

11. A method for producing a compound according to claim 1 and being represented by the structural formula (I), wherein L is -(CH₂)_P-O-X(O)-, X is C or S(O) and p is an integer from 1 to 8, said method comprising the steps of: - reacting a carbonyl chloride R³COCl or sulfonyl chloride R³SO₂Cl, wherein R³ is as defined in claim 1, with a linear acyclic diol represented by the structural formula HO- (CH₂)_P-OH, to form an intermediate represented by the structural formula R³X(O)O- (CH₂)_p-OH;

- reacting propofol with a phosphorus oxyhalide to produce a phosphorus oxyhalide intermediate with the structural formula (II) as defined in claim 8; and

- reacting the intermediate R³X(O)O-(CH₂)_P-OH with the latter phosphorus oxyhalide intermediate (II) to form a compound of formula (I) according to claim 1, wherein W is a halogen.

12. The method according to claim 11, further comprising hydro lysing the compound of formula (I) wherein W is a halogen into the corresponding phosphonyl-containing propofol derivative (I) according to claim 1 , wherein W is hydro xyl.

13. The method according to any one of claims 10 to 12, wherein said acyclic diol is selected from the group consisting of ethylene glycol, 1,3-propanediol, 1,4-butanediol, 1,5- pentanediol, 2,4-dimethyl-2,4-pentanediol, 2,5-dimethyl-2,5-hexanediol, 1,6-hexanediol, and 1,8-octanediol.

14. The method according to any one of claims 10 to 13, wherein said carbonyl chloride R³COCl is selected from the group consisting of acetyl chloride, propionyl chloride, butyryl chloride, isobutyryl chloride, valeryl chloride, isovaleryl chloride, pivaloyl chloride, capryloyl chloride, nonanoyl chloride, decanoyl chloride, lauroyl chloride, myristoyl chloride, palmitoyl chloride, stearoyl chloride, cyclobutanecarbonyl chloride, cyclopentanecarbonyl chloride, cyclohexanecarbonyl chloride, 1 -methyl- 1- cyclohexanecarbonyl chloride, 2-methyl-l -cyclohexanecarbonyl chloride, 3-methyl-l- cyclohexane-carbonyl chloride, 4-methyl-l-cyclo-hexanecarbonyl chloride, cycloheptane- carbonyl chloride, 1-adamantanecarbonyl chloride, cyclohexylacetyl chloride, cyclopentylacetyl chloride, 2-norbornaneacetyl chloride, 1-adamantane-carbonyl chloride, 4- morpholinylcarbonyl chloride, 1-pyrrolidinecarbonyl chloride, tetrahydro-2-furancarbonyl chloride, 3-(l,3-dioxan-2-yl)-propionyl chloride, and 3-(l,3-dioxan-2-yl)-2-methylpropionyl chloride.

15. The method according to any one of claims 11 to 14, wherein said sulfonyl chloride R³SO₂Cl is selected from the group consisting of methanesulfonyl chloride, ethanesulfonyl chloride, 1-propanesulfonyl chloride, 1-butanesulfonyl chloride, 1-hexanesulfonyl chloride,

1-octanesulfonyl chloride, 1-decane-sulfonyl chloride, cyclopentanesulfonyl chloride, cyclohexanesulfonyl chloride, 4-morpholinesulfonyl chloride, and pyrrolidine- 1 -sulfonyl chloride.

16. A method for producing a compound according to claim 1 and being represented by the structural formula (I), wherein L is -(CH₂)_P-O- and p is an integer from 1 to 8, said method comprising the steps of:

- reacting a saturated acyclic, homocyclic or heterocyclic mono-alcohol R³OH wherein R³ is as defined in claim 1, with an ω-halo α-alcohol represented by the structural formula Q-(CH₂)_P-OH wherein p is an integer from 1 to 8 and Q is a halogen, to form a substituted alcohol intermediate represented by the structural formula R 0-(CH₂)_p-0H; and

- the latter substituted alcohol intermediate represented by the structural formula R O- (CH₂)_P-OH is reacted with a phosphorus oxyhalide intermediate with the structural formula (II), wherein Q is a halogen; and

to form a compound of formula (I) according to claim 1, wherein W is a halogen.

17. The method according to claim 16, further comprising hydro lysing the compound of formula (I) according to claim 1 wherein W is a halogen into the corresponding phosphonyl- containing propofol derivative (I) according to claim 1, wherein W is hydro xyl.

18. The method according to claim 16 or claim 17, wherein said ω-halo α-alcohol is selected from the group consisting of 2-bromoethanol, 3-bromopropan-l-ol, 4-bromobutan-l-ol, 5- bromopentan-1-ol, 6-bromohexan-l-ol, 7-bromoheptan-l-ol, 8-bromooctan-l-ol, and isomers thereof.

19. A method for producing a compound according to claim 1 and being represented by the

- R⁴, X, and Y are as defined in claim 1, said method comprising the steps of:

- reacting propan-l,2,3-triol with one or more carbonyl chlorides R⁴COCl and/or sulfonyl chlorides R⁴SO₂Cl to form a l,3-di(acyloxy)-propan-2-ol and/or l,3-di(sulfoxy)-propan-2-ol intermediate;

- reacting the latter l,3-di(acyloxy)-propan-2-ol or l,3-di(sulfoxy)-propan-2-ol intermediate, with a phosphorus oxyhalide intermediate with the structural formula (II), wherein Q is a halogen;

to form a compound of formula (I) according to claim 1, wherein W is a halogen.

20. A method according to claim 19, further comprising hydro lysing the compound of formula (I) according to claim 1 wherein W is a halogen into the corresponding phosphonyl- containing propofol derivative (I) according to claim 1, wherein W is hydro xyl.

21. A method according to any one of claims 12, 17 and 20, further comprising the step of converting the said phosphonyl-containing propofol derivative wherein W is hydroxyl into the corresponding salt wherein W is 0^"M⁺ and M⁺ is a monovalent cation.