NO330097B1 - Compound with short-acting sedative hypnotic effect for anesthesia and sedation, use of the compound, intermediate and pharmaceutical composition comprising the compound - Google Patents

Description

The present invention is directed to new substituted phenylacetic acid ester compounds which are useful as short-acting sedative hypnotics for anesthesia and sedation. The invention is also directed to pharmaceutical preparations comprising such compounds, the use of such compounds to prepare pharmaceutical preparations for inducing or maintaining anesthesia or sedation; and intermediates for the production of such compounds.

Propofol, 2,6-diisopropylphenyl, (Diprivin® injectable emulsion, AstraZeneca) is an injectable anesthetic agent that has hypnotic properties. It can be used to induce and maintain general anaesthesia, and for sedation. Although propofol is a widely used anesthetic, its utility is somewhat limited due to its long and unpredictable duration of action after infusion. This unpredictable duration of action leads to irregular and often long patient recovery times which are undesirable.

Propanidide [4-[(N,N-diethylcarbamoyl)methoxy]-3-methoxypheny 1]acetic acid propyl ester), is another injectable anesthetic that has been approved for use in several countries outside the United States. Although propanidide provides a much shorter and more predictable recovery time than propofol, it is not as effective as an anesthetic agent. In addition, Epontol®, an injectable emulsion formulation of propanidide, marketed by Bayer, was withdrawn from the UK market in 1983 due to concerns about anaphylactoid reactions. Consequently, despite the fact that propanidide provides shorter and more predictable convalescence times than propofol, it has not been widely accepted as an injectable anesthetic agent.

There is currently a need for new injectable anesthetic agents. Preferred agents will have a shorter and more predictable duration of action than propofol. Preferred agents will also be more effective than propanidide.

New substituted phenylacetic acid ester compounds have now been discovered which are useful as short-acting sedative hypnotics. The agents have a shorter and more predictable duration of action than propofol, and are also more effective than propanidide.

Accordingly, the present invention provides a compound of formula (I):

in which:

R<1> is (C2-C6)alkyl;

R<2> and R<3> are each independently (C1-C6)alkyl, and

R<4> is (C1-C6)alkyl;

provided that the sum of the carbon atoms in R1, R<2>, R<3> and R<4> is greater than 7.

The invention is also directed to the intermediate which is useful for the preparation of compounds of formula (I). Accordingly, the invention provides a compound of formula

(II):

where R1 is ethyl, R<4> is propyl, and R<5> is hydrogen.

The invention further provides a pharmaceutical preparation comprising a pharmaceutically acceptable carrier, and a therapeutically effective amount of a compound of formula (I).

The compounds according to the invention are very effective, short-acting, sedative hypnotics for use in the induction and maintenance of anesthesia and sedation. Accordingly, the compounds of the invention can be used in a method for inducing or maintaining anesthesia or sedation in a mammal, which comprises administering to the mammal an effective amount of a compound of the invention.

The invention also encompasses the use of a compound of formula (I) to prepare a medicament useful for inducing or maintaining anesthesia or sedation in a mammal. Fig. 1 compares the dose in mg/kg of compounds of the invention to induce a mean loss of writhing reflex in 2 minutes in rats with the dose required for the previously known compound, propanidide. Fig. 2 compares the total convalescence time in minutes after termination of infusions at 20 minutes, 2 hours and 5 hours in rats, of compound 1 according to the present invention with the convalescence time after termination of infusion with compounds according to prior art, propanidide and propofol.

When the compounds, preparations and applications according to the invention are described, the following designations have the following meanings, unless otherwise stated.

The term "(C 1 -C 6 )alkyl" refers to a monoresidue branched or unbranched, saturated hydrocarbon chain containing from 1 to 6 carbon atoms. The term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, n-hexyl and the like. As the term is used here, "Me" means methyl, "Et" means ethyl, "propyl" and "Pr" means n-propyl and "iPr" means iso-propyl.

The compounds according to the present invention may contain one or more chiral centers. Accordingly, the present invention is intended to encompass racemic mixtures, diastereomers, enantiomers and mixtures enriched in one or more stereoisomers. The scope of the disclosure as described and claimed includes the racemic forms of the compounds as well as the individual enantiomers, and the non-racemic mixtures thereof.

The term "hypnotic" generally refers to a compound that promotes sleep. As used in pharmacology, the term "hypnotic agents" describes agents used to induce or maintain anaesthesia, sedation or sleep.

The term "anesthesia" as used herein refers to a loss of sensation or consciousness resulting from pharmacological suppression of nerve function.

The term "sedation" is defined here as the calming of mental agitation or reduction of physiological function with the administration of a drug.

The term "effective amount" refers to an amount sufficient to induce or maintain anesthesia or sedation when administered to a mammal. The effective amount will vary depending on the object and the mode of administration, and can be determined routinely by one of ordinary skill in the art.

The term "analgesia" refers to a compound that relieves pain by altering the perception of nociceptive stimuli without inducing significant anesthesia or loss of consciousness.

The term "opioid" refers to synthetic narcotic agents that have opiate-like activities (eg, analgesia) but are not derived from opium.

The term "short-acting" as used herein refers to agents that are pharmacokinetically responsive. When short-acting agents are administered by infusion, the effects of the agents cease quickly upon termination of the infusion.

While a broad definition of the invention is set forth in the summary of the invention, certain agents or preparations may be preferred. Specific preferred values set forth herein for residues, substituents and ranges are for illustration purposes only, they do not exclude other defined values or other values within defined ranges for the residues and substituents.

A preferred agent which can be incorporated into the preparations according to the invention is a compound of formula (I) as described above, where the sum of the number of carbon atoms in R1, R<2>, R<3> and R<4> varies from 8 to 12.

In another more preferred embodiment, R<1> is (C2-C4)alkyl.

Most preferred is R<1>ethyl or propyl.

Preferably, R<2> is (C1-C4)alkyl.

Preferably, R<3> is (C1-C4)alkyl.

Preferably, R<4> is (C1-C4)alkyl.

In a preferred embodiment, R<1> is (C2-C4)alkyl; R2 and R<3> are independently (C1-C4)alkyl and R<4> is (d-C4)alkyl.

A preferred subset of compounds is that wherein R<1> is (C2-C4)alkyl; R<2> and R<3> are independently (C1-C4)alkyl; R<4> is (Ci-C4)alkyl and the sum of the number of carbon atoms in R<1>, R2, R<3> and R<4> varies from 8 to 12.

Within this subgroup, R<1> is preferably ethyl or propyl; R<2>, R3 and R<4> are independently selected from the group consisting of methyl, ethyl and propyl, and the sum of the number of carbon atoms in R<1>, R2, R <3> and R<4> vary from 9, 10 or 11.

Preferred compounds according to the invention are compounds of formula (I) in which R<1>, R<2>, R<3> and R<4> represent the values shown in Table I below.

Particularly preferred are compounds in which R is ethyl or propyl, R and R are each ethyl and R<4> is propyl. Compound 1 is most particularly preferred.

GenereUe synthetic methods

The intermediates and compounds according to the present invention can be prepared from readily available starting material by using known synthesis methods. For example, the compounds may be prepared as generally indicated below, and further described in the examples. It will be obvious that where typical or preferred process conditions (ie reaction temperatures, times, molar ratio between reactants, solvents, pressure, etc.) are stated, other process conditions may also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents employed, but such conditions may be determined by one of ordinary skill in the art by routine

optimization methods.

As will also be apparent to those skilled in the art, in addition, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The selection of a suitable protecting group for a particular functional group, as well as suitable conditions for protection and deprotection, are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and the references cited therein.

The present synthesis methods make use of new intermediates of formula (II), more specifically (Ila) or (Ilb):

In a first synthesis method, compound of formula (I) is prepared by alkylating a compound of formula (Ila) with the required compound of formula X-

CH2C(=0)NR R , where X is a suitable leaving group (for example chlorine, bromine, tosyl or mesyl).

In another synthetic procedure, compounds of formula (IIb) are alkylated with the required acetamide compounds of formula X-CH2C(=O)NR2R3 to prepare a compound of formula (III):

which is reduced to form a compound of formula (I). As exemplified in Examples 4A, 4B and 10-13, a useful reduction procedure proceeds by a two-step reaction in which the hydroxyl of formula (III) is first acetylated, prior to reaction with hydrogen.

The intermediate of formula (IIb) used in the above-mentioned process is prepared from commercially available starting materials and reagents using conventional methods. For example, the intermediate can be prepared as shown in Scheme A:

Form A

As shown above, catechol is coupled with a compound of formula R<!>X, where X is a leaving group, to form the ether (IV) which is reacted with glyoxylic acid to produce compound (V). Subsequent reaction of (V) with an excess of the alcohol R<4>OH gives the intermediate of formula (IIb). The intermediate (IIb) can be alkylated as described above to prepare a compound of formula (III).

The intermediate of formula (Ia) can, for example, be prepared as described in example 1 subsection (1), and also as shown in scheme B in example 1 subsection (2) below.

Pharmaceutical preparations

The compounds of formula I may be formulated as pharmaceutical preparations and administered to a mammalian host, such as an animal or a human patient, in a variety of forms adapted to the chosen route of administration, i.e. orally or parenterally, by intravenous, intramuscular, topical or subcutaneous methods .

Accordingly, the present compounds may be administered systemically, for example, orally, in combination with a pharmaceutically acceptable carrier, such as an inert diluent or an edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets or may be incorporated directly with the nutrients in the patient's diet. For oral therapeutic administration, the active compound can be combined with one or more excipients and used in the form of digestible tablets, buccal tablets, drops, capsules, elixirs, suspensions, syrups, wafers and the like. Such compositions and preparations should contain at least 0.1% active compound. The percentages of the compositions and preparations can of course vary, and can suitably be between approx. 2 and approx. 60% by weight of a given dosage unit form. The amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be achieved. The tablets, drops, pills, capsules and the like may also contain the following: binding agents, such as gum tragacanth, acacia, corn starch or gelatin; excipients, such as dicalcium phosphate; a blasting agent, such as corn starch, potato starch, alginic acid and the like; a lubricant, such as magnesium stearate; and a sweetener such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen or cherry flavor may be added. When the dosage unit form is a capsule, it may, in addition to the materials of the above type, contain a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings, or to otherwise modify the physical form of the solid dosage unit form. For example, tablets, pills or capsules can be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetener, methyl and propyl parabens as preservatives, a coloring agent and flavoring such as cherry or orange flavor. Naturally, any material used in the preparation of any dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts used. In addition, the active compound can be incorporated into preparations and devices for prolonged release.

Active agents described herein are typically formulated as pharmaceutical preparations suitable for intravenous administration. The present active agents are relatively insoluble in water. Accordingly, for intravenous administration, the agents are typically formulated in aqueous media using one or more water-miscible solvents and one or more emulsifiers. Some emulsifiers are sometimes called surfactants in the literature. Individual formulations may include one or more additional components, such as stabilizers, tonicity modifiers, bases or acids to adjust pH, and solubilizing agents. The formulations may also optionally contain a preservative, such as ethylenediaminetetraacetic acid (EDTA) or sodium metabisulfite, to name a few.

A wide range of water-immiscible solvents can be used in the preparations according to the present invention. The water-immiscible solvent may be a vegetable oil, for example soybean, safflower, cottonseed, corn, sunflower, arachis, castor or olive oil. Alternatively, the water-immiscible solvent is an ester of a medium or long chain fatty acid, for example a mono-, di- or triglyceride; an ester of a combination of a medium or long chain fatty acid or is a chemically modified or manufactured material, such as ethyl oleate, isopropyl myristate, isopropyl palmitate, a glycerol ester, polyoxyl or hydrogenated castor oil. The water-immiscible solvent can also be a marine oil, for example cod liver or other fish-derived oil. Suitable solvents also include fractionated oil, for example fractionated coconut oil or modified soybean oil.

The preparations may also include an emulsifier. Suitable emulsifiers include synthetic nonionic emulsifiers, for example ethoxylated ethers and esters and polyoxypropylene-polyoxyethylene block copolymers and phospholipids. Both naturally occurring phospholipids, such as egg and soy phospholipids, and modified or artificially manipulated phospholipids, for example produced by physical fractionation and/or chromatography, or mixtures thereof can be used. Phospholipids are alternatively called phosphatides. Preferred emulsifiers are egg phospholipids and soy phospholipids. Yolk phospholipids are mainly composed of phosphatidylcholine and phosphatidylethanolamine. Lecithin, which is classified as a phosphatidylcholine and may be derived from egg yolk or soybeans, is another commercially used emulsifier.

The pharmaceutical preparations can also include stabilizers, which can alternatively be considered co-emulsifiers. Anionic stabilizers include phosphatidylethanolamines, conjugated with polyethylene glycol, (PEG-PE) and phosphatidylglycerols, a specific example of which is dimyristol phosphatidylglycerol (DMPG). Additional examples of useful stabilizers include oleic acid and its sodium salt, cholic acid and deoxycholic acid and their respective salts, cationic lipids, such as stearylamine and oleylamine, and 3β-[N-(N',N'-dimethylaminoethane)-carbamoylcholesterol (DC-Chol) .

The pharmaceutical preparations according to the invention can be made isotonic with blood by incorporating a suitable tonicity modifier. Glycerol is most frequently used as a tonicity modifier. Alternative tonicity modifiers include xylitol, mannitol and sorbitol. The pharmaceutical preparations are typically formulated to be at a physiologically neutral pH, typically in the range 6.0-8.5. The pH can be adjusted by adding base, such as NaOH or NaHCO 3 , or in some cases acid, such as HCl. Pharmaceutically safe oil-in-water emulsions comprising a vegetable oil, a phosphatide emulsifier, typically egg lecithin or soybean lecithin, and a tonicity modifier are available commercially for parenteral nutrition, for example, under the trade names Liposyn® II and Liposyn® III (Abbott Laboratories, North Chicago, IL) and Intralipid® (Fresenius Kabi AB, Uppsala, Sweden). The agents described here can be formulated with these other corresponding oil-water emulsions, as shown for example in injections 5 to 9 inclusive of example 16 below.

A compound according to the invention can also be formulated in a triglyceride comprising esters of at least one fatty acid of medium chain length (C6-C12). Preferably, the triglyceride comprises an ester of a C 8 -C 10 fatty acid. Triglycerides suitable for formulating a compound according to the invention are supplied under the trade name Miglyol® by Condea Chemie GmbH (Witten, Germany). For example, Miglyol® 810 or 812 (caprylic (Cio)/capric (Cg) glyceride) are useful for formulating the present agents. Injection 11 of example 16 below shows a formulation comprising egg yolk phosphatides as an emulsifier, DMPG as an anionic stabilizer and glycerol as the tonicity modifying agent, in which Miglyol® 810 is used as the oil phase.

In addition, the agents described here can be formulated analogously to pharmaceutical preparations of propanidide which are known in the art. For example, the compounds according to the invention can be formulated in mixtures comprising an ester of a fatty acid of medium chain length, as discussed in US patent no. 4,711,902. Furthermore, the compounds described here can be formulated analogously to preparations of propofol known in the art as described, for example, in US patents no. 4,056,635; 4,452,817; 4,452,817 and 4,798,846.

According to yet another alternative, the present compound can be formulated using a solubilizing agent, for example hydroxypropyl-p-cyclodextrin, to form an inclusion complex.

Additional other suitable formulations for use in the present invention can be found in Remington's Pharmaceutical Sciences, Mace Publishing Company, Philadelphia, PA, 17th ed. (1985).

Compounds according to the present invention are potent hypnotic agents which are rapidly metabolized in vivo to an inactive and well-tolerated carboxylic acid metabolite (formula

I where R<4>is hydrogen). The present compound exhibits one or more of the following advantageous properties compared to prior agents; increased potency, shorter convalescence times, reduced cardiovascular effects, lower toxicity and a higher therapeutic index, where the therapeutic index is defined as the ratio between the maximum tolerated dose and the effective dose.

Accordingly, the compounds of the present invention can be used to induce and/or maintain general anesthesia, to initiate and/or maintain conscious sedation with spontaneously breathing patients, and to induce and/or maintain sedation for intubated, mechanically ventilated patients.

The amount of an active agent required for use in such a method will vary with the mode of administration, the age and condition of the patient, and the degree of anesthesia or sedation required, and will ultimately be determined by the attending physician or clinician.

In general, the agents may be administered as an initial bolus dose to induce anesthesia or sedation, followed by a continuous infusion of agent at a rate sufficient to achieve and maintain the level of anesthesia or sedation desired. Alternatively, a continuous infusion of an agent according to the present invention can be used to maintain anesthesia or sedation after induction, or induction of maintenance with another sedative, hypnotic (for example, propofol, a barbiturate, such as nembutal® (pentobarbital sodium) or brevital® sodium (methohexital sodium) or a benzodiazepine (such as Valium®). For example, a suitable bolus dose of the present agent for a human patient will typically range from about 0.1 to about 50 milligrams/kilogram (mg/kg ), preferably about 0.5 to about 20 mg/kg. The infusion rate will typically be in the range of about 5 to about 5000 micrograms/kilogram/minute (ug/kg/min.), preferably about 10 to about .2000 ug/kg/min.

The compounds according to the invention can also be administered in combination with other therapeutic agents, such as, for example, other sedative hypnotic agents, analgesic agents (for example, an opioid such as the u-opioid agonist remifentanil, fentanyl, sulfentanil or alfentanil), or paralytic agents, such as atracurium besylate or pancuronium bromide. Consequently, the preparations according to the invention can optionally be used together with another therapeutic agent, for example a sedative hypnotic agent, analgesic agent or paralytic agent. Correspondingly, the therapeutic methods described here can also optionally also be performed simultaneously with the administration of another therapeutic agent (for example a sedative hypnotic agent, analgesic agent or paralytic agent) to the mammal.

The ability of an agent to function as an anesthetic or sedative agent can be determined using an assay known in the art. See, for example, US patent no. 5,908,869 or R. James and J. Glen, J. Med. Chem., 23, 1350 (1980)) or by using the assay described in Test A. below.

TEST

Procedures

Formulation

Test compounds, for example representative compounds of the invention as well as the comparison compound, propanidide, were formulated in (1) 10% cremophor in EL/90% D5W (5% dextrose in distilled water;) (2) 10% Liposyn® III (intravenous fat emulsion , containing (per 100 ml) 10 g soybean oil, 1.2 g egg phosphatides and 25 g glycerol), available from Abbott Laboratories, North Chicago, IL and (3) injections (10) or (11) (as described in Example 16) with Miglyol ® 810 (caprylic/capric glyceride). Typically, formulation (1) above was used for bolus dosing and formulations (2) or (3) for infusion dosing. Compounds according to the invention and propanidide were synthesized as described in examples 1-15 below. Propofol formulated in soybean oil, sold as Diprivan® injectable emulsion, was obtained from AstraZeneca (Wilmington, DE).

Bolus administration (rats)

Male rats (adult Sprague-Dawley) were placed in perspex cages and injected (1 or 2 ml/kg over about 3 seconds) with the relevant compound via the tail vein. The time before onset of anesthesia (defined as loss of righting reflex), duration of anesthesia (that is, duration of righting reflex) and behavioral convalescence (that is, duration of ataxia, sedation and/or lethargy after return of righting reflex) were recorded. Duration of anesthesia was measured by placing the rats on their back after the onset of anesthesia, and the time until recovery of the righting reflex was recorded using a stopwatch. The depth of anesthesia was assessed intermittently by observing the magnitude of the withdrawal reflex on painful pinching of the hind paw. Behavioral recovery was assessed by visual administration.

Bolus administration (guinea pig)

Adult male guinea pigs were dosed by bolus administration (0.1-0.25 ml volume) via an ear vein. The duration of loss of righting reflex was measured as described above for rats.

Administration by infusion (rats)

Rats (adult Sprague-Dawley) were placed in a Perspex cage and anesthesia was induced by bolus injection via the tail vein (0.15-0 ml/kg over approximately 3 seconds at a dose, estimated from the previous bolus trials, to induce anesthesia of approximately 2 minutes duration). Immediately after bolus administration, an infusion (with a duration of typically 20, 180 or 300 minutes), via the tail vein was started (0.075-0.5 ml/kg/min at half a bolus dose/minute). In some trials, the initial infusion rate was maintained throughout the trial, while in others the rate was modified as needed to maintain a consistent depth of anesthesia (as defined by moderate paw withdrawal in response to painful pinch). After completion of the infusion, duration of anesthesia (ie duration of loss of righting reflex) and behavioral recovery (ie duration of ataxia, sedation or lethargy after return of righting reflex) were recorded.

Results

Bolus administration (rats): The dose-response curve for duration of loss of righting reflex in rats resulting from bolus injection of test compounds prepared in formulation (1) was determined. To quantify anesthetic potency, the dose of test compound that produced a mean loss of righting reflex in 2 minutes was calculated. Figure 1 compares the bolus dose of compounds of the invention in mg/kg that induces a 2 minute loss of righting reflex with the required dose of the comparison compound, propanidide.

Bolus administration (guinea pig): The potency of compound 1 was also tested in guinea pigs by the analogous procedure. The dose of compound 1 required to induce a 2 minute loss of righting reflex in guinea pigs was calculated to be 8 mg/kg, compared to a dose of 13 mg/kg for propanidide.

Administration by infusion (rats): Convalescence times after termination of administration by infusion in rats were determined for compound 1, and for the comparison compounds propofol and propanidid. The duration of loss of righting reflex (in minutes) after termination of infusion is given as a function of duration of infusion in Table 2 below.

Figure 2 shows overall recovery times in minutes after termination of infusion of specific duration in rats, as the sum of the duration of the loss of righting reflex, as given in Table 2, and the duration of behavioral convalescence after return of the righting reflex.

As demonstrated by the above data in rat and guinea pig animal models, the tested compounds of the invention are more potent general anesthetics than propanidide, and provide significantly shorter total convalescence rates than propofol, even after long (5 hour) infusions. In addition, the duration of the loss of the righting reflex after termination of infusion for the tested compound of the invention, regardless of the duration of infusion, was within the experimental uncertainty.

The in vitro stability of representative compounds according to the invention can be determined in test B.

TEST B

Source of whole blood samples

Whole blood samples from rats and guinea pigs, obtained by cardiac puncture, were collected in vacutainer tubes containing sodium heparin. The samples were kept on ice and used on the day of collection. Canine, monkey, human whole blood, purchased from commercial sources, was kept on wet ice and used the day after collection.

Metabolism analysis

The test compounds, propanidide and a representative compound according to the invention, were loaded into 300 µl of a whole blood sample to a final concentration of 100 uM. The proteins were immediately precipitated by the addition of twice the volume of ice-cold ethanol and vortexed. This constitutes time zero. In identical 300 ul incubations, added blood samples were then incubated at 37°C for 30 seconds to 60 minutes. At a predetermined time, 600 ul of ice-cold ethanol was added to the mixture to terminate the incubation. After termination of the incubation, the samples were centrifuged and the supernatants were dried over a stream of nitrogen at room temperature. The residue was reconstituted in 150 µl of sterile water and then centrifuged. An aliquot (50 µl) of the supernatant was injected into the HPLC-UV for analysis.

HPLC method

One Cig, 5 um, 2 x 150mm LD. (LUNA, Phenomenex) reverse phase HPLC column was used and a gradient from 10% to 68% acetonitrile over 15 minutes followed by a 5 minute isocratic run at 10% acetonitrile was used. The mobile phase component contained 0.1% TF A. The analytes were monitored by UV detection at 214 nm.

Data analysis

Concentrations of the substrate in incubates were measured as peak area ratios using the internal standard method, and percent degradation was measured relative to the zero time values.

Results

The tested compounds of formula (I) were metabolized rapidly to the corresponding carboxylic acids (formula (I) where R<4>= hydrogen). The acid metabolites were found to be inactive as anesthetic agents in test A. The rapid conversion of the compounds of formula (I) to their acid metabolites, and the inactivity of these acid metabolites as anesthetic agents, may be at least partially responsible for the shorter and more predictable convalescence rates which is observed for the compounds of formula (I).

The invention will now be illustrated by means of the following examples.

EXAMPLES

In the examples below, the following abbreviations have the following meanings. Any abbreviations not defined have their generally accepted meanings. Unless otherwise stated, all temperatures are in °C.

DMSO = dimethyl sulfoxide

EtOAc = ethyl acetate

DCM = dichloromethane

PPTS = pyridinium para-toluenesulfonate

DMF = dimethylformamide

General: Unless otherwise noted, reagents, starting materials, and solvents were purchased from commercial sources, such as Sigma-Aldrich (St. Louis, MO) and Trans World Chemicals, Inc. (TCI) (Rockville, MD), and used without further purification; reactions were run under a nitrogen atmosphere; reaction mixtures were monitored by thin layer chromatography (silica TLC); analytical high-performance liquid chromatography (anal. HPLC) or mass spectrometry; reaction mixtures were usually purified by flash column chromatography on silica gel or by vacuum distillation; NMR samples were dissolved in deuterated solvent (CD 3 OD, CDCl 3 or DMSO-d 6 ) and spectra were obtained with a Varian Gemini 2000 instrument (300 MHz) using the listed solvents as internal standards, unless otherwise indicated; and mass spectrometric identification was performed using an electrospray ionization method (ESMS) with a Perkin Elmer instrument (PE SCIEX API 150 EX).

Example 1; Compound 1: [4-[(N,N-diethylcarbamoyl)methoxy]-3-ethoxyphenyl]acetic acid propyl ester.

In a 50 mL round bottom flask equipped with a magnetic stir bar, 3-ethoxy-4-hydroxyphenylacetic acid propyl ester (800 mg, 3.4 mmol, 1.0 eq.) was dissolved in dry acetone (20 mL). To the solution was added K2CO3 (705 mg, 5.1 mmol, 1.5 equiv.) followed by 2-chloro-N,N-diethylacetamide (0.55 mL, 4.0 mmol, 1.2 equiv., available from Aldrich ). Under vigorous stirring, the suspension was heated to reflux and kept under these conditions for 15 hours. After cooling to room temperature, the reaction mixture was filtered through a folded filter paper and the remaining solution was freed of solvent under reduced pressure. The oily product was purified by column chromatography (SiCl 2 , 50% EtOAc/hexane) to give 630 mg (53% of theory) of colorless oil which was 99.6% pure by HPLC.

TLC (silica, 50% EtOAc/hexane) Rf 0.25; <J>H NMR (CDCl 3 , 300 MHz) d 0.90 (3H, t, propylate CH 3 ), 1.13 and 1.20 (each 3H, t, N-ethyl CH 3 ), 1.43 (3H, t, ethoxy CH3), 1.60-1.67 (2H, m, propylate CH2), 3.35-3.46 (4H, m, N-ethyl CH2), 3.53 (2H, s, OCH2CO), 4.01-4.11 (4H , m, 2xOCH2), 4.70 (2H, s, ArCH2CO), 6.75-6.91 (3H, m, ArH). M/z [M+H<+>] calcd. For C19H29N05352.22; found 352.

Preparation of the intermediate of formula (IIa), R<1;=>etvl and R<4=>propvl (3-ethoxys-4-hydroxyphenvledikx<y>repropvlester)

A 30 mL glass pressure tube with a Teflon screw cap was fitted with a magnetic stir bar and filled with 3-ethoxy-4-hydroxyphenylacetic acid (2.5 g, 12.7 mmol, 1.0 equiv, available from Trans World Chemicals). 1-propanol (20 mL, 270 mmol, ~20 equiv) was added and the mixture was stirred to dissolve. Concentrated sulfuric acid (2 drops) was added. The pipe screw was turned down by hand, and the pipe was immersed in an oil bath. The reaction was allowed to stir at 90°C for 15 hours. The tube was allowed to cool to room temperature, after which the contents were transferred to a round-bottomed flask, and the excess alcohol distilled off in vacuo. The remaining oil was taken up in ethyl acetate (50 mL) and washed with saturated sodium bicarbonate solution. After drying over magnesium sulfate and filtration, the solvent was distilled off under reduced pressure to leave 2.6 g (85% yield) of the ester as a pale yellow oil.

( 2) Preparation of the intermediate product of formula (Ila), R<1;=>ethyl and R<4=>propyl (3-ethoxys-4-hydroxysphenvled acetic acid propyl ester.

The title intermediate was also prepared according to Scheme B below.

(a) Preparation of compound Bl

2-Ethoxyphenyl (56.6, 0.401 mol, 1 eq.), glycosylic acid (50% aqueous solution) (41.0 mL, 0.396 mol, 0.99 eq.) and distilled water (110 mL) were combined. The mixture was cooled in an ice bath and a solution of 10% NaOH (32.2 g NaOH in 300 ml distilled water, 0.805 mol, 2 eq.) was slowly added via addition funnel. The reaction was allowed to warm slowly to room temperature, and after -18 hours the solution was washed with ethyl acetate (4x250 mL), then acidified with 6N HCL until pH~3. NaCl was added and the product was then extracted into ethyl acetate (4x200 mL). The organic phase was washed with brine, dried over magnesium sulfate and the solvent was removed under vacuum to give 51.8 g of B1 as a light pink solid.

<J>H NMR (DMSO-de, 300 MHz): δ 1.24 (t, 3H), 3.90 (q, 2H), 4.79 (s, 1H), 5.59 (bs, 1H), 6.67 (q, 2H), 6.86 (s, 1H), 8.81 (s, 1H), 12.35 (bs, 1H).

(b) Preparation of compound B2

Compound B1 (45.0 g, 0.212 mol, 1 eq.) was dissolved in DCM (225 mL), pyridine (80 mL, 0.989 mol, 6 eq.) was added, and the mixture was cooled in an ice bath under nitrogen. Acetic anhydride (100 mL, 1.06 mol, 4 equiv.) was slowly added via addition funnel. The mixture was stirred (∼3 h) until the reaction was complete, then diluted with diethyl ether (500 mL) and washed with 1N HCl (4x250 mL). The mixture was extracted into 8% sodium bicarbonate solution (4x80 mL), acidified to ~pH 4 with 6N HCl, and the product extracted into diethyl ether, yielding 41.4 g of B2 as a white, crystalline solid.

<J>H NMR (DMSO-d6, 300 MHz): δ 1.12 (t, 3H), 2.05 (s, 3H), 2.17 (s, 3H), 3.95 (q, 2H), 5.72 (s, 1H), 6.96 (d, 1H), 7.04 (d, 1H), 7.12 (s, 1H).

(c) Preparation of compound B3

Compound B2 (30.9 g, 0.104 mol) was dissolved in methanol (500 mL), Pd(OH) 2 (5.0 g) moistened with distilled water was added, and the mixture was placed under hydrogen at 30 psi with shaking. After 48 hours, the Pd(OH) 2 was removed by filtration and the solvent was removed under vacuum to give 22 g of B 3 as a yellow oil.

<J>H NMR (DMSO-d6, 300 MHz): δ 1.19 (t, 3H), 2.16 (s, 3H), 3.47 (s, 2H), 3.92 (q, 2H), 6.74 (d, 1H), 6.91 (m, 2H).

(d) Preparation of 4-hydroxyphenylenediamine esters

Compound B3 (1.40 g, 5.87 mmol) was dissolved in an excess of 1-propanol (50 mL), concentrated H2SO4 (3 drops) was added, and the mixture was heated to 90 °C for -18 h . The volume of 1-propanol was reduced under vacuum, then the mixture was diluted with diethyl ether, washed with saturated sodium bicarbonate solution (2x), distilled water (lx), brine solution (lx), dried over magnesium sulfate and the solvent was removed under vacuum, to give 3 -ethoxy-4-hydroxyphenylacetic acid propyl ester as a yellow oil.

<J>H NMR (DMSO-d6, 300 MHz): δ 0.78 (t, 3H), 1.25 (t, 3H), 1.48 (q, 2H), 3.44 (s, 2H), 3.92 (m, 4H), 6.58 (d, 1H), 6.64 (d, 1H), 6.74 (s, 1H), 8.73 (s, 1H).

Example 2: Compound 2: [4-[(N,N-diethylcarbamoyl)methoxy]-3-ethoxyphenyl]acetic acid ethyl ester

Using a method similar to that described in Example 1, except for replacing 1-propanol with ethanol in the synthesis of the intermediate, to prepare an intermediate of formula (Ila) with R<1>= ethyl and R<4>= propyl , the title compound was prepared in 81% yield as a colorless oil that was 96% pure as determined by

HPLC.

TLC (silica gel, 50% EtOAc/hexane) Rf 0.25;

<J>H NMR (CDC13, 300 MHz) d 1.13-1.22 (6H, m, N-ethyl CH3), 1.25 (3H, t, ethyl ester CH3), 1.43 (3H, t, ethoxy CH3), 3.38-3.45 ( 4H, m, N-ethyl CH2), 3.52 (2H, s, OCH2CO), 4.05-4.17 (4H, m, 2xOCH2), 4.71 (2H, s, ArCH2CO), 6.78-6.91 (3H, m, ArH). M/z:

[M+H<+>] calculated for Ci8H27N05338.20; found 338.

Example 3; Compound 3 [4-[(N,N-diethylcarbamoyl)methoxy]-3-ethoxyphenyl]acetic acid isopropyl ester

By using a method similar to that described in example 1, but by replacing 1-propanol with isopropanol in the synthesis of the intermediate to prepare an intermediate of formula (Ila) with R<1=>ethyl and R<4=>isopropyl was the title compound prepared in 63% yield as a colorless oil which was 99% pure, by HPLC.

TLC (silica, 50% EtOAc/hexane) Rf 0.25;

<!>H NMR (CDC1, 300 MHz) d 1.06-1.19 (6H, m, N-ethyl CH3), 1.14 and 1.16 (2x3H, 2s, isopropyl ester CH3), 1.36 (3H, t, ethoxy CH3), 3.30- 3.36 (4H, m, N-ethyl CH2), 3.42 (2H, s, OCH2CO), 3.98-4.03 (2H, m, OCH2), 4.64 (2H, s, ArCH2CO), 4.90-4.98 (1H, m, CH ), 6.71-6.84 (3H, m, ArH). M/z: [M+H<+>] calculated for Ci9H29N05352.22, found 352.

Example 4A; Compound 4: [4-[(N,N-diethylcarbamoyl)methoxy]-3-propoxyphenyl]acetic acid propyl ester.

Compound 4 was prepared according to Scheme C below.

(1) Preparation of compound Cl (formula (IV) R1=propyr)

A solution of catechol (81.0 g, 0.74 mol) in DMF (1.5 mL) in a 3 L flask fitted with a stirrer top was prepared and cooled in an ice bath. Slowly NaH (60% in oil) (29 g, 0.73 mol) was added to the solution, when fully reacted (about 1 hour after final addition) 1-bromopropane (72 mL, 0.74 mol) was added. The reaction mixture was stirred overnight and allowed to slowly warm to room temperature.

The reaction mixture was poured into a separatory funnel containing diethyl ether, and was washed with water (3x), then extracted into 1N NaOH (3x), the aqueous portion was acidified with 6N HCl to pH~1 and the product was extracted into DCM (3x). The DCM was washed with brine (1x), dried over magnesium sulfate and the solvent was removed in vacuo to give a red oil. The oil was purified through a 6 inch plug of silica gel, washing with 10% ethyl acetate/hexane and the solvent was then removed under vacuum to give 26.8 g of colorless oil Cl.

( 2) Preparation of compound C2 ( formula ( V) R<1:=>propvD

To a mixture of Cl (26.8 g, 0.176 mol) and glyoxylic acid (50% solution in water)

(17.6 mL, 0.160 mol) cooled in an ice bath, a solution of 10% NaOH (128 mL, 0.320 mol) was added. The mixture was stirred overnight and allowed to slowly warm to room temperature. After -15 hours, 150 mL of distilled water was added to solubilize the mixture, and the reaction was again stirred overnight at room temperature.

The reaction mixture was washed with ethyl acetate (4x), the aqueous portion was acidified with glacial acetic acid until pH~3, and the product was extracted into ethyl acetate (3x). Ethyl acetate was washed with brine, dried over magnesium sulfate and the solvent was removed under vacuum to give 12 g of a white solid C2.

(3) Preparation of compound C3 (formula (IIb) R<1>and R<4>= propyl)

PPTS (0.47 g, 1.87 mmol) was added to a solution of C2 (3.27 g, 1.44 mmol) dissolved in an excess of 1-propanol (90 mL). The solution was heated at 50°C overnight.

The volume of 1-propanol was reduced under vacuum, it was diluted with ethyl acetate and washed with 1N HCl (3x), saturated sodium bicarbonate solution (3x) and brine (1x) and dried over magnesium sulfate. The solvent was removed under vacuum and the mixture was purified by column chromatography to give 1.7 g of colorless oil C3.

(4) Preparation of compound C4 (formula (III) R<1>and R<4>= propyl.R<2>and R<3>= ethyl) Cesium carbonate (10 g, 30.7 mmol) was added with a solution of C3 (1.70 g, 6.36 mmol) dissolved in acetone (100 mL). After stirring for 10 minutes, 2-chloro-N,N-diethylacetamide (0.95 mL, 6.91 mmol) was added and the reaction mixture was heated at 60°C overnight.

When the reaction was complete, cesium carbonate was filtered off and the solvent was removed under vacuum, the mixture was purified by column chromatography to give 0.82 g of colorless oil C4.

(5) Preparation of compound C5

To a solution of C4 (0.512 g, 1.40 mmol) dissolved in DCM (50 mL) and pyridine (0.35 mL, 4.33 mmol) and cooled in an ice bath was added acetyl bromide (0.21 mL, 2.84 mmol). The reaction mixture was stirred overnight and allowed to slowly warm to room temperature.

The mixture was poured into diethyl ether and washed with IN HCl (3x), saturated sodium bicarbonate (3x), distilled water (lx) and brine (lx), then dried over magnesium sulfate and the solvent removed under vacuum to give 0.517 g of pink oil C5.

( 6) Synthesis of compound 4

To a solution of C5 (0.167 g, 0.394 mmol) in 1-propanol (25 mL) was added 10% Pd/C (20 mg) wetted with 1-propanol, and treated under hydrogen at 28 psi. After 1 hour, the Pd/C was removed and replaced with another portion of 10% Pd/C (20 mg) moistened with 1-propanol, and was again treated with hydrogen at 28 psi for 3 hours. The Pd/C was removed by filtration and the solvent removed under vacuum. The mixture was then purified by column chromatography to give 90 mg of colorless oil 4.

Alternatively, compound 4 can be prepared as in the following example.

Example 4B: Compound 4: [4-[(N,N-diethylcarbamoyl)methoxy]-3-propoxyphenyl]acetic acid propyl ester

Preparation of compound Cl (formula (IV) R<1;=>propvl)

To a solution of catechol (100.1 g, 0.91 mol) dissolved in acetone (11) was slowly added potassium carbonate (125.1 g, 0.91 mol) with vigorous stirring; 1-Bromopropane (90.01, 0.92 mol) was added with heating and the mixture was heated to reflux overnight.

When the reaction was cooled to room temperature and the potassium carbonate removed by filtration, the solvent was removed under vacuum. The product was then diluted with diethyl ether, washed with distilled water (4x), then extracted into 1N NaOH. The aqueous phase was collected and acidified to pH~1 with 6N HCl, and the product was extracted into diethyl ether, dried over magnesium sulfate, and the solvent was removed under vacuum. The product was purified through a 6 inch plug of silica gel, washing with 10% ethyl acetate/hexane, and the solvent was removed under vacuum to give 45 g (0.30 mol, 32% yield) of off-white solid Cl.

TLC (silica, 20% EtOAc/hexane) Rf 0.67;

<!>H NMR (DMSO-d6, 300 MHz): δ 0.90 (t, 3H), 1.64 (q, 2H), 3.80 (t, 2H), 6.61-6.81 (m, 4H), 8.70 (s, 1H ).

( 2) Preparation of compound C2 ( formula ( V) R1:=propvl)

To a mixture of Cl (100 g, 0.657 mol) and glyoxylic acid (50% solution in water) (67 mL, 0.648 mol) in 1 L of distilled water cooled in an ice bath, a solution of 10% NaOH (52 g NaOH in 500 ml deionized water, 1.30 mol) using an addition funnel. The mixture was stirred overnight while slowly warming to room temperature.

The reaction mixture was washed with ethyl acetate (4x), the aqueous portion was collected and acidified with 6N HCl until pH~3, and the product was then extracted into ethyl acetate (3x). The ethyl acetate was washed with brine, dried over magnesium sulfate and the solvent was removed under vacuum to give 70 g (0.31 mol, 47% yield) of a pale pink solid C2.

<!>H NMR (DMSO-d6, 300 MHz): δ 0.90 (t, 3H), 1.64 (q, 2H), 3.79 (t, 2H), 4.79 (s, 1H), 5.58 (bs, 1H), 6.63-6.71 (m, 2H), 6.85 (s, 1H), 8.77 (s, 1H), 12.3 (bs, 1H).

(3) Preparation of compound C3 (formula (IIb) R<1>and R<4=>propvl)

To a solution of C2 (70 g, 0.289 mol) dissolved in an excess of 1-propanol (550 mL) was added PPTS (7.5 g, 29.8 mmol) and heated to 50°C overnight.

The volume of 1-propanol was reduced under vacuum, then diluted with ethyl acetate and washed with IN HCl (3x), saturated sodium bicarbonate solution (3x) and brine, then dried over magnesium sulfate. The solvent was removed under vacuum and the mixture was then purified by column chromatography to give 55 g (0.20 mL, 71% yield) of a beige solid C3.

TLC (silica, 50% EtOAc/hexane) Rf 0.56;

<J>H NMr (DMSO-de, 300 MHz): δ 0.69 (t, 3H), 0.89 (t, 3H), 1.43 (q, 2H), 1.64 (q, 2H), 3.79 (t, 2H), 3.89 (t, 2H), 4.89 (d, 1H), 5.76 (d, 1H), 6.63-6.60 (m, 2H), 6.84 (s, 1H), 8.80 (s, 1H).

( 4) Preparation of compound C4 ( formula ( IIP R<1>and R<4>= propyl.R2 and R<3>= ethyl) Potassium carbonate (95 g, 0.69 mol) was slowly added to a solution of C3 (85 g, 0.32 mol) dissolved in acetone (500 mL).The mixture was then heated to 60°C, after stirring for 1 hour, 2-chloro-N,N-diethylacetamide (43.5 mL, 0 .32 mol), and the reaction mixture was heated to 60°C for 48 hours.

When the reaction was complete, the potassium carbonate was removed by filtration, and the solvent was removed under vacuum. The mixture was purified by column chromatography to give 50 g (0.13 mol, 46% yield) of colorless oil C4.

TLC (silica, 50% EtOAc/hexane) Rf 0.18;

<!>H NMR (DMSO-d 6 ), 300 MHz); 8 0.70 (t, 3H), 0.87-0.96 (m, 6H), 1.03-1.09 (m, 3H), 1.44 (q, 2H), 1.64 (q, 2H), 3.17-3.26 (m, 4H), 3.82 (t, 2H), 3.88 8t, 2H), 4.66 (s, 2H), 4.95 (d, 1H), 5.86 (d, 1H), 6.71 (d, 1H), 6.78 (d, 1H), 6.92 (s , 1H).

(5) Preparation of compound C5

To a solution of C4 (50 g, 0.13 mol) dissolved in DCM (600 mL) and pyridine (30 mL, 0.37 mol) and cooled in an ice bath was added acetyl bromide (20 mL, 0.27 mol ). The reaction mixture was stirred overnight while slowly warming to room temperature.

The solvent was reduced under vacuum, then diluted with diethyl ether and washed with 1N HCl (5x), saturated sodium bicarbonate (4x) and brine (1x), then dried over magnesium sulfate. The solvent was removed under vacuum to give a yellow oil, which was then purified by column chromatography to give 50 g (0.12 mol, 91% yield) of a yellow oil C5.

TLC (silica, 50% EtOAc/hexane) Rf 0.31;

<J>H NMR (DMSO-d6, 300 MHz): δ 0.70 (t, 3H), 0.87-0.96 (m, 6H), 1.03-1.09 (m, 3H), 1.44 (q, 2H), 1.64 (q , 2H), 2.02 (s, 3H), 3.17-3.26 (m, 4H), 3.84 (m, 2H), 3.95 (m, 2H), 4.71 (s, 2H), 5.73 (s, 1H), 6.76 ( d, 1H), 6.90 (d, 1H), 6.99 (s, 1H).

( 6) Synthesis of compound 4

To a solution of C5 (50 g, 0.12 mol) in 1-propanol (200 mL) was added 10% Pd/C (5 g) wetted with 1-propanol, and treated under hydrogen at 32 psi for 48 h while shaking. The Pd/C was removed and replaced with another portion of 10% Pd/C (2 g) moistened with 1-propanol, and again treated under hydrogen at 30 psi for 4 hours with shaking. The Pd/C was removed by filtration through a millipore filter and the solvent was removed under vacuum, the product was then purified by column chromatography to give 38 g (0.10 mol, 87% yield) of a colorless oil 4.

TLC (silica, 50% EtOAc/hexane) Rf 0.41;

<J>H NMR (DMSO-de, 300 MHz): δ 0.78 (t, 3H), 0.86-0.96 (m, 6H), 1.06 (t, 3H), 1.49 (q, 2H), 1.64 (q, 2H ), 3.17-3.26 (m, 4H), 3.48 (s, 2H), 3.82 (t, 2H), 3.90 (t, 2H), 4.64 (s, 2H), 6.65-6.79 (m, 2H), 6.80 ( pp, 1H).

HPLC (RP, 10-70% acetonitrile/water, 6 minute run, 214 nm) retention time 4.75 min. 100% purity according to HPLC.

Example 5; Compound 5: 4-[(N,N-dipropylcarbamoyl)methoxy]-3-ethoxyphenyl]acetic acid ethyl ester

Using the procedure of Example 2, using 2-chloro-N,N-dipropylacetamide instead of 2-chloro-N,N-diethylacetamide, compound 5 was prepared (54% yield).

<J>H NMR (DMSO-d6, 300 MHz): δ 0.69-0.80 (m, 6H), 1.09 (t, 3H), 1.24 (t, 3H), 1.37-1.47 (m, 4H), 3.09-3.17 (m, 4H), 3.46 (s, 2H), 3.90-4.02 (m, 4H), 4.66 (s, 2H), 6.65 (m, 2H), 6.78 (s, 1H). HPLC (RP, 30.90% acetonitrile/water, 6 minute run, 214 nm detection) retention time 3.20 minutes, 97% purity according to HPLC.

Example 6; Compound 6: [4-[(N,N-dipropylcarbamoyl)methoxy]-3-ethoxyphenyl]acetic acid propyl ester

Using the procedure of Example 1, but using 2-chloro-N,N-dipropylacetamide instead of 2-chloro-N,N-diethylacetamide, compound 6 was prepared (51% yield).

<J>H NMR (DMSO-d6, 300 MHz): δ 0.81-0.91 (m, 9H), 1.36 (t, 3H), 1.46-1.66 (m, 6H), 3.20-3.29 (m, 4H), 3.60 (s, 2H), 3.99-4.07 (m, 4H), 4.78 (s, 2H), 6.77 (m, 2H), 6.91 (s, 1H). HPLC (RP, 30-90% acetonitrile/water, 6 minute run, 214 nm detection) retention time 3.57 minutes, 100% purity according to HPLC.

Example 7: Compound 7: [4-[(N-ethyl-N-methylcarbamoyl)methoxy]-3-ethoxyphenyl]acetic acid propyl ester.

Using the procedure of Example 1, but using 2-chloro-N-ethyl-N-methylacetamide instead of 2-chloro-N,N-diethylacetamide, compound 7 was prepared (88% yield).

<J>H NMR (DMSO-d6, 300 MHz): δ 0.89 (t, 3H), 1.28 (dt, 3H), 1.36 (t, 3H), 1.60 (q, 2H), 2.92 (d, 3H), 3.35 (m, "H), 3.60 (s, 2H), 3.99-4.07 (m, 4H), 4.77 (s, 2H), 6.79 (m, 2H), 6.91 (s, 1H). HPLC (RP, 30 -90% acetonitrile/water, 6 minute run, 214 nm detection) retention time 2.45 minutes, 99% purity according to HPLC.

Example 8: Compound 8: [4-[(N-ethyl-N-propylcarbamoyl)methoxy]-3-ethoxyphenyl]acetic acid ethyl ester

Using the procedure of Example 2, but using 2-chloro-N-ethyl-N-propylacetamide instead of 2-chloro-N,N-diethylacetamide, compound 8 was prepared. (64% yield).

<J>H NMR (DMSO-d6, 300 MHz): δ 0.88 (m, 3H), 1.05 (t, 15H), 1.21 (m, 4.5H), 1.36 (t, 3H), 1.47-1.65 (m, 2H), 3.21-3.41 (m, 4H), 3.59 (s, 2H), 4.00-4.14 (m, 4H), 4.77 (d, 2H), 6.77 (m, 2H), 6.90 8s, 1H). HPLC (RP, 30-90% acetonitrile/water, 6 minute run, 214 nm detection) retention time 2.81 minutes, 95% purity according to HPLC.

Example 9: Compound 9: [4-[(N-ethyl-N-propylcarbamoyl)methoxy]-3-ethoxyphenyl]acetic acid propyl ester.

Using the procedure of Example 1, but using 2-chloro-N-ethyl-N-propylacetamide instead of 2-chloro-N,N-diethylacetamide, compound 9 was prepared. (92% yield).

<J>H NMR (DMSO-d6, 300 MHz): δ 0.89 (m, 6H), 1.12 (dt, 3H), 1.36 (t, 3H), 1.47-0.167 (7m, 4H), 3.21-3.39 (m , 4H), 3.60 (s, 2H), 4.77 (d, 2H), 6.79 (m, 2H), 6.91 (s, 1H). HPLC (RP, 30-90% acetonitrile/water, 6 minute run, 214 nm detection) retention time 2.95 minutes, 100% purity in HPLC.

Example 10: Compound 10. [4-[(N,N-Dimethylcarbamoyl)methoxy]-3-propoxyphenyl]acetic acid propyl ester.

( 1) Preparation of 2- r4- r( K. N- dimeWlkarbamovDmethoxvl- 3- propoxyvphenvl1- 2-hvdroxvedekvreprop<y>lester ( 10- D)

Using the procedure of Example 4B, subpart (4) with the reactants compound C (2.49 g, 9.28 mmol) acetone (60 mL), potassium carbonate (2.55 g, 18.5 mmol) and N,N- dimethylacetamide (1.42 g, 11.5 mmol), compound 10- D. was prepared (1.4

g)<.>

TLC (silica, 50% EtOAc/hexane) Rf 0.11;

<J>H NMR (DMSO-d6, 300 MHz): δ 0.71 (t, 3H), 0.89 (t, 3H), 1.44 (q, 2H), 1.65 (q, 2H), 2.75 (s, 3H), 2.91 (s, 3H), 3.80-3.91 (m, 4H), 4.69 (s, 2H), 4.95 (d, 1H), 5.86 (d, 1H), 6.72 (d, 1H), 6.77 (d, 1H) , 6.91 (p, 1H).

( 2) Preparation of 2- r4- r( N, N- dimethylcarbamoyl) methoxy- 3- propoxyphenone- 2-acetoxyacetic acid ester ( 10- E)

Using the procedure of Example 4B, subpart (5) with the reactants 10-D (1.4 g, 3.96 mmol), DCM (100 mL), pyridine (1.0 mL, 12.4 mmol) and acetyl bromide ( 0.55 ml, 7.44 mmol) compound 10-E was prepared (1.4 g).

TLC (silica, 50% EtOAc/hexane) Rf 0.20;

<!>H NMR (DMSO-d6, 300 MHz): δ 0.71 (t, 3H), 0.89 (t, 3H), 1.44 (q, 2H), 1.65 (q, 2H), 2.03 (s, 3H), 2.75 (s, 3H), 2.91 (s, 3H), 3.84 (t, 2H), 3.95 (m, 2H), 4.74 (s, 2H), 4.95 (d, 1H), 5.68 (s, 1H), 6.76 (d, 1H), 6.83 (d, 1H), 6.95 (s, 1H).

( 3) Synthesis of compound 10

By treating compound 10-E with hydrogen according to the procedure of Example 4B subsection (6), compound 10 was prepared as a white solid (0.80 g, 2.37 mmol).

TLC (silica, 50% EtOAc/hexane) Rf 0.17;

<J>H NMR (DMSO-d6, 300 MHz): δ 0.71 (t, 3H), 0.89 (t, 3H), 1.44 (q, 2H), 1.65 (q, 2H), 2.75 (s, 3H), 2.91 (s, 3H), 3.48 8s, 2H), 3.84 (t, 2H), 3.90 (t, 2H), 4.67 (s, 2H), 6.64 (d, 1H), 6.70 (d, 1H), 6.79 ( pp, 1H). HPLC (RP, 10-70% acetonitrile/water, 6 minute run, 214 nm) retention time 4.23 minutes, 99.2% purity by HPLC.

Example 11; Compound 11: [4-[(N-ethyl-N-propylcarbamoyl)methoxy]-3-propoxyphenyl]acetic acid propyl ester

( 1) Preparation of 2- r4- r(^- eWl- N-propvlcarbamovyl") methoxyvl- 3- propoxysvphenvlll- 2-hydroxyacetic vreprop<y>lester ( 11- D)

Using the procedure of Example 4B, subpart (4) with reactants C (2.43 g, 9.06 mmol), acetone (60 mL), potassium carbonate (2.50 g, 18.1 mmol) and 2-chloro- N-ethyl-n-propylacetamide (1.94 g, 11.9 mmol) compound 11-D was prepared (1.75 g).

TLC (silica, 50% EtOAc/hexane) Rf 0.28;

<J>H NMR (DMSO-d6, 300 MHz): δ 0.67-0.79 (m, 6H), 0.87-0.99 8m,3H), 1.00-1.07 8m, 3H), 1.40-1.47 (m, 4H), 1.65 (q, 2H), 3.11-3.31 (m, 4H), 3.82 (t, 2H), 3.88 (t, "H), 4.66 (d, 2H), 4.94 (d, 1H), 5.85 (d, 1H) , 6.74 (d, 1H), 6.77 (d, 1H), 6.92 (s, 1H).

(2) Preparation of 2-r4-r(N-ethyl-N-propylcarbamoyl)methoxy-3-propoxyphenyl-2-acetoxyacetic acid propyl ester (11-E)

Using the procedure of Example 4B, subpart (5) with reactants 11-D (1.70 g, 4.29 mmol), DCM (100 mL), pyridine (1.0 mL, 12.4 mmol) and acetyl bromide ( 0.60 mL, 4.77 mmol), compound 11-E was prepared (2.0 g).

TLC (silica, 50% EtOAc/hexane) Rf 0.49;

<J>H NMR (DMSO-d6, 300 MHz): δ 0.67-0.79 (m, 6H), 0.87-0.92 (m, 3H), 1.00-1.07 (m, 3H), 1.43-1.46 (m, 4H) , 1.65 (q, 2H), 2.03 (s, 3H), 3.11-3.31 (m, 4H), 3.83 (t, "H), 3.95 (t, 2H), 4.72 (d, 2H), 5.72 (d, 1H), 6.74 (d, 1H), 6.77 (d, 1H), 6.92 (s, 1H).

( 3) Synthesis of compound 11

Treatment of compound 11-E with hydrogen according to the procedure of Example 4B, subpart (6) afforded compound 11 as a colorless oil (0.95 g, 2.50 mmol).

TLC (silica, 50% EtOAc/hexane) Rf 0.49;

<J>H NMR (DMSO-d6, 300 MHz): δ 0.70-0.80 (m, 6H), 0.87-0.95 (m, 4.5H), 1.05 (t, 1.5H), 1.45-1.52 (m, 4H) , 1.52-1.65 (m, 2H), 3.11-3.27 (m, 4H), 3.48 (s, 2H), 3.82 (t, 2H), 3.95 (t, 2H), 4.64 (d, 2H), 6.64-6.67 (q, 2H), 6.79 8s, 1H). HPLC (RP, 10-70% acetonitrile/water, 6 minute run, 214 nm) retention time 5.26 minutes, 100% purity by HPLC.

Example 12; Compound 12: [4-[(N,N-dipropylcarbamoyl)methoxy]-3-propoxyphenyl]acetic acid propyl ester

( 1) Preparation of 2- r4- rn^. N-dipropylcarbamovDrnetoxyl- 3- propoxysulfenyl- 2-hydroxyacetic acid propyl ester ( 12- D)

Using the procedure of Example 4B, subpart (4) with reactants C (2.27 g, 8.46 mmol), acetone (60 mL), potassium carbonate (2.50 g, 18.1 mmol) and 2-chloro- N,N-dipropylacetamide (1.65 g, 9.29 mmol), compound 12-D was prepared (1.0 g).

TLC (silica, 50% EtOAc/hexane) Rf 0.36;

<J>H NMR (DMSO-d6, 300 MHz): δ 0.67-0.79 (m, 6H), 0.87-0.92 (m, 3H), 1.43-1.46 (m, 4H), 1.65 (q, 2H), 2.03 (s, 3H), 3.11-3.31 (m, 4H), 3.81 (t, 2H), 3.89 (t, 2H), 4.67 (s, 2H), 4.49 (d, 1H), 5.86 (d, 1H), 6.71 (d, 1H), 6.78 (d, 1H), 6.91 (s, 1H).

(2) Preparation of 2-r4-r(N,N-dipropylcarbamoyl)methoxy-3-propoxyphenyl-2-acetoxyacetic acid propyl ester (12-E)

Using the procedure of Example 4B, subpart (5) with the reactants compound 12-D (1.70 g, 4.29 mmol), DCM (10 mL), pyridine (1.0 mL, 12.4 mmol) and acetyl bromide (0.60 mL, 4.77 mmol), compound 12-E was prepared (1.0 g).

TLC (silica, 50% EtOAc/hexane) Rf 0.57;

<J>H NMR (DMSO-d6, 300 MHz): δ 0.67-0.79 (m, 6H), 0.90 (t, 3H), 1.43-1.48 (m, 4H), 1.65 (q, 2H), 2.03 (s , 3H), 3.11-3.31 (m, 4H), 3.83 (t, 2H), 4.73 (s, 2H), 5.72 (d, !H), 6.74 (d, 1H), 6.85 (d, 1H), 6.96 (p, 1H).

( 3) Synthesis of compound 12

By treating compound 12-E with hydrogen according to the procedure of Example 4B, subpart (6), compound 12 was prepared as a colorless oil (0.80 g, 2.03 mmol).

TLC (silica, 50% EtOAc/hexane) Rf 0.63;

<J>H NMR (DMSO-d6, 300 MHz): δ 0.69-0.80 (m, 9H), 0.89 (t, 3H), 1.36-1.51 (m, 2H), 1.64 (q, 2H), 3.08-3.17 (m, 4H), 3.48 (s, 2H), 3.81 (t, 2H), 3.89 (t, 2H), 4.65 (s, 2H), 6.64-6.69 (m, 2H), 6.79 (s, 1H). HPLC (RP, 10-70% acetonitrile/water, 6 minute run, 214 nm) reaction time 5.45 minutes, 100% purity by HPLC.

Example 13: Compound 13: [4-[(N-ethyl-N-methylcarbamoyl)methoxy]-3-propoxyphenyl]acetic acid propyl ester

(1) Preparation of 2- r4- r(^-etvl- N- methylcarbarnoyl") methoxysvl- 3- propoxysulfenvl- 2-hydroxyacetic acid propyl ester (13-D)

Using the procedure of Example 4B, subpart (4) with the reactants compound C (2.26 g, 8.42 mmol), acetone (60 mL), potassium carbonate (2.50 g, 18.1 mmol) and 2-chloro -N-ethyl-N-methylacetamide (1.26 g, 9.29 mmol) compound 13-D was prepared (1.6 g).

TLC (silica, 50% EtOAc/hexane) Rf 0.16;

<J>H NMR (DMSO-d6, 300 MHz): δ 0.71 (t, 3H), 0.91 (q, 4.5H), 1.06 (t, 1.5H), 1.45 (q, 2H), 1.65 (q, 2H ), 2.80 (d, 3H), 3.20-3.28 8m, 2H), 3.84 (t, 2H), 3.96 (m, 2H), 4.73 (s, 2H), 4.95 (d, 1H), 5.73 (d, 1H ), 6.79 (d, 1H), 6.85 (d, 1H), 6.96 (s, 1H).

( 2) Preparation of 2-r4-r(N-ethyl-N-methylcarbamoyl)methoxy-3-propoxyphenyl-2-acetoxyacetic acid ester (13-E)

Using the procedure of Example 4B, subpart (5) with the reactants compound 13-D (1.60 g, 4.35 mmol), DCM (100 mL), pyridine (1.0 mL, 12.4 mmol) and acetyl bromide (0.60 mL, 4.77 mmol), compound 13-E was prepared (1.9 g).

TLC (silica, 50% EtOAc/hexane) Rf 0.25;

<!>H NMR (DMSO-d6, 300 MHz): δ 0.71 (t, 3H), 0.91 8q, 4.5H), 1.06 (t, 1.5H), 1.45 (q, 2H), 1.65 (q, 2H) , 2.04 (s, 3H), 2.80 (d, 3H), 3.20-3.28 (m, 2H), 3.84 (t, 2H), 3.96 (m, 2H), 4.73 (s, 2H), 5.73 (s, 2H ), 5.73 (s, 1H), 6.79 (d, 1H), 6.85 (d, 1H), 6.96 (s, 1H).

( 3) Synthesis of compound 13

By treating compound 13-E with hydrogen according to the procedure of Example 4B, subpart (6), compound 13 was prepared as a colorless oil (1.5 g, 4.27 mmol).

TLC (silica, 50% EtOAc/hexane) Rf 0.28;

<J>H NMR (DMSO-d6, 300 MHz): δ 0.78 (t, 3H), 0.90 (m, 4.5H), 1.05 (t, 1.5H), 1.48 8q, 2H), 1.64 (q, 2H) , 2.80 (d, 3H), 3.20-3.28 (m, 4H), 3.48 (s, 3H), 3.82 (t, 2H), 3.89 (t, 2H), 4.65 (s, 2H), 6.65-6.69 (m , 2H), 6.79 (s, 1H). HPLC (RP, 10-70% acetonitrile/water, 6 minute run, 214 nm) retention time 4.47 minutes, 99% purity by HPLC.

Example 14: Compound 14: [4-[(N-ethyl-N-propylcarbamoyl)methoxy]-3-propoxyphenyl]acetic acid ethyl ester.

Compound 11 (0.201 g, 0.510 mmol) was saponified by dissolving it in (1:1) MeOH:deionized water (10 mL). While the mixture was immersed in an ice bath, 0.1N NaOH (5.1 mL, 0.51 mmol) was added and the mixture was stirred overnight, diluted with deionized water and washed with DCM. The aqueous portion was acidified with 1N HCl, the product extracted into DCM and dried over magnesium sulfate. The solvent was removed under vacuum.

The acidic product was redissolved in ethanol (20 mL), sulfuric acid (2 drops) was added and the mixture was heated to 110°C overnight. Solvent was removed under vacuum and the product was then purified by column chromatography to give compound 14 as a colorless oil (170 mg, 0.465 mmol).

TLC (silica, 50% EtOAc/hexane) Rf 0.59;

<J>H NMR (DMSO-d6, 300 MHz): δ 0.82 (q, 3H), 0.94-1.20 (m, 9H), 1.52 (m, 2H), 1.74 (m, 2H), 3.22 (d, 2H ), 3.34 (q, 2H), 3.45 (s, 2H), 3.89 (t, 2H), 4.07 (q, 2H), 4.63 (s, 2H), 6.68 8d, 1H), 6.76 (s, 12H), 6.81 (d, 1H). HPLC (RP, 10-70% acetonitrile/water, 6 minute run, 214 nm) retention time 4.88 minutes, 95% purity by HPLC.

Example 15: Comparative compound propanidide: [4-[(N,N-diethylcarbamoyl)methoxy]-3-methoxy phenyl]acetic acid propyl ester.

(1) Preparation of 3-methoxy-4-hydroxyphenylacetic acid ester (15-A) 4-hydroxy-3-methoxyphenethyl alcohol (Sigma-Aldrich) was dissolved in aqueous 1-propanol. Approximately 5 drops of concentrated sulfuric acid were added to this solution, and the solution was heated to 100°C for 3-5 hours in a pressure tube. When the reaction was complete, 1-propanol was removed under reduced pressure, the resulting oil was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution, distilled water and then brine. The solution was dried over magnesium sulfate and filtered, and the solvent was removed under reduced pressure to give 15-A as a red oil in approximately quantitative yield.

<!>H NMR (DMSO, 300 MHz): δ 0.77 (3H, t, CH3), 1.47 (2H, q, CH2), 3.44 (2H, s, ArCH2CO), 3.65 (3H, s, OCH3), 3.89 (2H, t, OCH2), 6.60 (2H, m, ArH), 6.73 (1H, s, ArH), 8.79 (1H, s, ArOH).

(2) Preparation of r4-r(N,N-diethylcarbamoyl)methoxysv-3-methoxysvphenyl acetic acid propyl ester

3-Methoxy-4-hydroxyphenylacetic acid propyl ester (15-A) was dissolved in acetone. To the solution was added two equivalents of K2CO3, followed by 1.2 equivalents of 2-chloro-N,N-diethylacetamide. Under vigorous stirring, the suspension was heated to reflux (60°C) for -15 hours. After cooling, the reaction mixture was filtered and the remaining solvent removed under reduced pressure, giving a 95% yield of a dark yellow oil. The oily product was purified by silica column chromatography to afford the title compound.

<J>H NMR (DMSO, 300 MHz): δ 0.78 (3H, t, CH3), 0.94 (3H, t, CH3), 1.05 (3H, t, CH3), 1.49 (2H, q, CH2), 3.20 (4H, m, N-ethyl CH2), 3.49 (2H, s, ArCH2CO), 3.66 (3H, s, OCH3), 3.90 (2H, t, OCH2), 4.63 (2H, s, OCH2CO), 6.72 (2H , m, ArH), 6.80 (1H, s, ArH).

Example 16; The following illustrate representative pharmaceutical dosage forms containing a compound of the invention "compound X".

The above formulations can be obtained by conventional methods well known in the pharmaceutical art. For example, a formulation of compound 1 according to reaction 9 was prepared by the following procedure.

A mixture of L-α-phosphatidylcholine 60% (lecithin) (2.40 g), glycerol (98%) (2.50 g), (both from Sigma-Aldrich), oleic acid (99%) (0.03 g) ( Fluka-Sigma-Aldrich), Buchs, Switzerland) and deionized water (71.1 g) were heated at 60°C until completely dissolved to give an opaque solution. The pH was adjusted to pH 8 while the solution was still warm by adding 0.1 N NaOH. A mixture of compound 1 (4.0 g) and soybean oil (Sigma-Adrich) (20.0 g) was heated to 60°C until miscible and then added to the first mixture. The solution was stirred briefly at 60°C, then transferred to a beaker and stirred with a Polytron tissue homogenizer for 5 minutes at maximum speed to provide a premixed solution.

A microfluidizer (Microfluidics Corp., Newton, MA, Model No. HOS) was washed with isopropanol and then deionized water.

The microfluidic separation device was primed with a minimal amount of the pretreated solution. The reservoir of the microfluidizer was filled with the premixed solution and the solution was circulated through the mixing chamber for 30 seconds at maximum pressure (~12000-15000 psi). The first ~10 drops of the microfluidized solution were collected and discarded, then all subsequent fractions were collected in a glass vial.

Claims (12)

1. Compound characterized by formula (I): in which: R<1> is (C2-C6)alkyl; R<2> and R3 are independently (C1-C6)alkyl, and R<4> is (C1-C6)alkyl; provided that the sum of the number of carbon atoms in R<1>, R<2>, R<3> and R<4> is greater than 7. 2. Compound according to claim 1, characterized in that R1 is ethyl or propyl. 3. Compound according to any one of claims 1-2, characterized in that R<2> and R3 independently of each other are (Ci-C4)alkyl. 4. Compound according to any one of claims 1-3, characterized in that R<4> is (Ci-C4)alkyl. 5. Compound according to claim 1, characterized in that R<1> is (C2-C4)alkyl; R<2>, R<3> and R<4> are each independently (C1-C4)alkyl; and the sum of the number of carbon atoms in R<1>, R<2>, R<3> and R<4> varies from 8 to 12. 6. Compound according to claim 5, characterized in that R<1> is ethyl or propyl; R<2>, R<3> and R<4> are independently selected from the group consisting of methyl, ethyl and propyl, and the sum of the number of carbon atoms in R<1>, R2, R<3> and R<4> is 9, 10 or 11. 7. Compound according to claim 6, characterized in that R<2> and R<3> are each ethyl and R<4> is propyl. 8. Compound according to claim 1, characterized in that it consists of [4-[(N,N-diethylcarbamoyl)methoxy]-3-ethoxyphenyl]acetic acid propyl ester. 9. Compound of formula (II): in which R<1> is ethyl, R<4> is propyl and R<5> is hydrogen. 10. Pharmaceutical preparation, characterized in that it comprises a compound according to any one of claims 1-8 and a pharmaceutically acceptable carrier. 11. A compound according to any one of claims 1-8 for use in medical therapy. 12. Use of a compound as described in any one of claims 1-8 for the manufacture of a medicament useful for inducing or maintaining anesthesia or sedation in a mammal.