EP0859773A1

EP0859773A1 - Phenol derivatives with pharmaceutical activity

Info

Publication number: EP0859773A1
Application number: EP96921012A
Authority: EP
Inventors: Bertrand Leo Chenard
Original assignee: Pfizer Inc
Current assignee: Pfizer Inc
Priority date: 1995-09-15
Filing date: 1996-07-11
Publication date: 1998-08-26
Also published as: CA2232059A1; MX9802025A; JPH11509839A; WO1997010240A1

Abstract

Compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein R is as defined herein, are prodrugs for a competitive N-methyl-D-aspartic acid antagonist which blocks NMDA receptor sites and is useful in the treatment of certain conditions and diseases that respond to the blocking of NMDA receptor sites, including head trauma, stroke, multiinfarct dementia, and other disorders.

Description

PHENOL DERIVATIVES WITH PHARMACEUTICAL ACTIVITY

Background of the Invention The present invention relates to prodrugs for the neuroprotective agent (3R.4S)- 3-[4-(4-fluorophenyl)-4-hydroxy-piperidin-1-yl]-chroman-4,7-diol which is a N-methyl-D- aspartic acid (NMDA) antagonist. The present invention further relates to methods of using, and pharmaceutical compositions containing, the prodrugs described herein. Prodrugs are compounds that have little or no intrinsic biological activity until converted into another, biologically active chemical species in the body of a recipient (e.g. a human). Upon delivery to a recipient by any of several routes (such as orally, parenterally, or rectally), the prodrug is transformed into a new compound (parent drug) that possesses desirable bioiogical activity. Conversion of the prodrug into the parent drug can occur in the body at a variety of locations (e.g. gut wall, Iiver, kidney, blood, etc.) and by any of a number of mechanisms (e.g. enzymatic hydrolysis, oxidative metabolism, etc.). Prodrugs can be useful to overcome a variety of limitations of the parent drug.

For example, the parent drug may not have an acceptable bioavailability when delivered by an otherwise desirable route of administration. The parent drug may suffer from extensive first pass metabolism that effectively removes the drug from the body at an excessively rapid rate that inhibits effective therapy. The parent drug may have undesirable physical properties, such as poor solubility or stability, or it may have other properties that make formulation of the parent drug difficult or expensive to administer. In some instances, the prodrug may be easier to synthesize.

Once administered to an appropriate recipient, the prodrugs of the present invention are converted into (3R,4S)-3-[4-(4-fluorophenyl)-4-hydroxy-piperidin-1-yl]- chroman-4,7-diol (parent chromanol) by one or more of the mechanisms described above. The prodrugs of the present invention overcome the limitations of the parent chromanol including one or more of the limitations associated with parent drugs as described above. In particular, the prodrugs of the present invention are more stable in solution than the parent chromanol and, as a result, are better suited for intravenous administration.

The parent chromanol is an NMDA antagonist and, as such, is useful in the treatment of head trauma, stroke and CNS degenerative diseases such as Alzheimer's disease, Huntington's disease, Parkinson's disease and other conditions alleviated by blocking the NMDA receptor.

NMDA antagonists are compounds that block the NMDA receptor by interacting with the glutamate binding site or other sites on the receptor molecule. The ability of a particular compound to competitively bind to the NMDA glutamate receptor can be evaluated using a radioligand binding assay. See Murphy et al.. British J. Pharmacol. 95, 932-938 (1988). The antagonists can be distinguished from the agonists using a rat cortical wedge assay. See Harrison and Simmonds, British J. Pharmacol.. 84, 381- 391 (1984). [Examples of competitive NMDA antagonists include D-2-amino-5- phosphonopentanoic acid (D-AP5), and D-2-amino-7-phosphonoheptanoic acid, Schoepp et al.. J. Neur. Transm.. 85, 131-143 (1991).

Antagonists of neurotransmission at NMDA receptors are useful therapeutic agents for the treatment of neurological disorders. U.S. Pat. No. 4,902,695 is directed to a series of competitive NMDA antagonists useful for the treatment of neurological disorders, including epilepsy, stroke, anxiety, cerebral ischemia, muscular spasms, and neurodegenerative disorders such as Alzheimer's disease and Huntington's disease. U.S. Pat. No. 4,968,878 is directed to a second series of competitive NMDA receptor antagonists useful for the treatment of similar neurological disorders and neurodegenerative disorders. U.S. Pat. No. 5,192,751 provides a method of treating urinary incontinence through use of a competitive NMDA antagonist.

NMDA antagonists are also useful therapeutic agents with anticonvulsant, anxiolytic, muscle relaxant, and antipsychotic activity. J. Lehmann, The NMDA Receptor. Drugs of the Future. 14(11), 1059 (1989). NMDA antagonists have also been reported to be effective for treating migraine (Can. J. Neurol. Sci.. 19(4), 487 (1992)); drug addiction (Science. 251 , 85 (1991)); and neuro-psychiatric disorders related to AIDS (PIPS. 11 , 1 , (1990)). Summary of the Invention The invention relates to compounds of the formula

and pharmaceutically acceptable salts thereof, wherein R is C,-C_β alkyl, C -C₈ cycloalkyl, R'CfO)-, or R'OCfO)-; and,

R¹ is C C_β alkyl, C₄-C₈ cycloalkyl, benzyl, C_β-C₁₀ aryl, or C₃-C₈ heteroaryl wherein said aryl, heteroaryl and the phenyl moiety of said benzyl are optionally substituted with from one to three substituents selected from the group consisting of hydroxy, chloro, bromo, fluoro, and -NR²R³, wherein R² and R³ are independently selected from the group consisting of hydrogen, C,-C_β alkyl, (C,-C_β alkyl)C(O)-, (C,-C_β alkyl)OC(O)-, (C_β-C₁₀ aryl)C(O)-, (benzyl)OC(O)-, and (C_β-C₁₀ aryl)OC(O)-.

With respect to the compounds of formula I, and their pharmaceutically acceptable salts, as used in accord with the present invention, it is to be understood that there are stereoisomeric forms such as optical and geometric isomers due to asymmetric carbon atoms and that the use of such isomers is also included within the scope of the invention.

The term "alkyl^*, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight or branched moieties.

The term "cycloalkyl", as used herein, includes saturated monovalent cyclic hydrocarbon radicals including cyclobutyl, cyclopentyl and cycloheptyl.

The term "aryl", as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, including phenyl and naphthyl.

The term "heteroaryl", as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic heterocyclic compound by removal of one hydrogen, such as pyridyl, furyl, pyrryl, thienyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, indolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benzthiazolyl or benzoxazolyl. Examples of C₃-C₉ heteroaryl moieties include thiazolyl (C₃ heteroaryl), furyl (C₄ heteroaryl), and quinolyl (C₉ heteroaryl).

The term treatment" as used herein, unless otherwise indicated, includes (i) methods to cure a condition or disease that is actively occurring in a mammal, such as a human, or to relieve the symptoms associated with such condition or disease, (ii) methods to prevent said condition or disease from occurring in a mammal, and (iii) methods to slow the onset of said condition or disease in a mammal.

The term "therapeutically effective amount" as used herein, unless otherwise indicated, means an amount effective to block NMDA sites in a mammal, such as a human, or an amount that is effective in treating or preventing the specific conditions for which the mammal is being treated.

Preferred compounds of formula I include those in which R is R¹C(0)- or R¹OC(0)-.

Other preferred compounds of formula I include those in which R is R¹C(0)- and R¹ is benzyl, C_β-C,₀ aryl, or C₃-C_β heteroaryl.

Other preferred compounds of formula I include those in which R is R¹C(0)- and R¹ is C,-C_β alkyl or C₄-C₈ cycloalkyl, and more preferably those in which R¹ is C,-C_β alkyl.

Other preferred compounds of formula I include those in which R is R¹OC(0)- and R¹ is benzyl, C_β-C,₀ aryl, or C₃-C₉ heteroaryl.

Other preferred compounds of formula i include those in which R is R¹OC(0)- and R¹ is C,-C_β alkyl or C₄-C₈ cycloalkyl, and more preferably those in which R is C,- C₀ alkyl, and still more preferably those in which R¹ is ethyl.

Specific compounds of formula I include those selected from the group consisting of:

(3R,4S)-7-Ethoxy-3-[4-(4-fluorophenyl)-4-hydroxyl-piperidin-1-yl]-chroman-4-ol, (3R,4S)-7-Propoxy-3-[4-(4-fluorophenyl)-4-hydroxyl-piperidin-1-yl]-chroman-4-ol, (3R,4S)-7-lsopropoxy-3-[4-(4-fluorophenyl)-4-hydroxyl-piperidin-1-yl]-chroman-4-ol, (3R,4S)-7-Cyclopentyloxy-3-[4-(4-fluorophenyl)-4-hydroxyl-piperidin-1-yl]-chroman-4-ol, and pharmaceutically acceptable salts of said compounds.

Other specific compounds of formula I include those selected from the group consisting of: (3R,4S)-7-Acetoxy-3-[4-(4-fluorophenyl)-4-hydroxyl-piperidin-1-yl]-chroman-4-ol, (3R,4S)-7-Pivaloxy-3-[4-(4-fluorophenyl)-4-hydroxyl-piperidin-1 -yl]-chroman-4-ol,

(3R,4S)-7-Benzoyloxy-3-[4-(4-fluorophenyl)-4-hydroxyl-piperidin-1-yl]-chroman-4-ol, and pharmaceutically acceptable salts of said compounds.

Other specific compounds of formula I include those selected from the group consisting of:

(3R,4S)-7-Methoxycarbonyloxy-3-[4-(4-fluorophenyl)-4-hydroxyli3iperidin-1-yl]-chromarH^ ol,

(3R,4S)-7-Ethoxycan onyloxy-3-[4-(4-fluorophenyl)-4-hydroxyl-piperidin-1-yl]-chroman-4- ol, (3R,4S)-7-Propoxycari3onyloxy-3-[4-(4-fluorophenyl)-4-hydroxyl-piperidin-1 -yl]-chroman-4- ol,

(3R,4S)-7-lsopropoxycarbonyloxy-3-[4-(4-fluorophenyl)-4-hydroxyl-piperidin-1-yl]- chroman-4-ol, and pharmaceutically acceptable salts of said compounds.

(3R,4S)-7-Butyloxycarbonyloxy-3-[4-(4-fluorophenyl)-4-hydiOxyl-piperidin-1-yl]-cn ol,

(3R,4S)-7-teχt-Butyloxycarbonyloxy-3-[4-(4-fluorophenyl)-4-hydroxyl-piperidin-1 -yl]- chroman-4-ol, (3R,4S)-7-Pentyloxycarbonyloxy-3-[4-(4-fluorophenyl)-4-hydroxyl-piperidin-1-yl]-chroman-

4-ol,

(3R,4S)-7-PhenoxyM-rbonyloxy-3-[4-(4-fluorophenyl)-4-hydroxyl-piperidin-1-yl]-chroman-

4-ol, and pharmaceutically acceptable salts of said compounds.

The present invention further relates to a pharmaceutical composition for treating a disease or condition, the treatment of which can be facilitated by blocking NMDA sites in a mammal, such as a human, comprising a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

The present invention further relates to a pharmaceutical composition for treating a disease or condition selected from degenerative CNS disorders such as stroke,

Alzheimer's disease, Parkinson's disease, and Huntington's disease; epilepsy, anxiety, muscular spasms, multiinfarct dementia, head trauma, traumatic brain injury, pain, AIDS related dementia, hypoglycemia, migraine, amyotrophic lateral sclerosis, drug and alcohol addiction, drug and alcohol withdrawal symptoms, psychotic conditions, tinnitus and urinary incontinence in a mammal, such as a human, comprising a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The present invention further relates to a pharmaceutical composition for treating an ischemic event arising from CNS surgery, open heart surgery or any procedure during which the function of the cardiovascular system is compromised in a mammal, such as a human, comprising a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

The present invention further relates to a method of treating a disease or condition, the treatment of which can be facilitated by blocking NMDA sites in a mammal, such as a human, comprising administering to said mammal a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.

The present invention further relates to a method of treating a disease or condition selected from degenerative CNS disorders such as stroke, Alzheimer's disease, Parkinson's disease, and Huntington's disease; epilepsy, anxiety, muscular spasms, muttiinfarct dementia, head trauma, traumatic brain injury, pain, AIDS related dementia, hypoglycemia, migraine, amyotrophic lateral sclerosis, drug and alcohol addiction, drug and alcohol withdrawal symptoms, psychotic conditions, tinnitus and urinary incontinence in a mammal, such as a human, comprising administering to said mammal a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof. The present invention further relates to a method of treating an ischemic event arising from CNS surgery, open heart surgery or any procedure during which the function of the cardiovascular system is compromised in a mammal, such as a human, comprising administering to said mammal a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof. Examples of diseases or conditions susceptible to treatment by a compound of formula I, or a pharmaceutically acceptable salt thereof, include degenerative CNS disorders such as stroke, Alzheimer's disease, Parkinson's disease, and Huntington's disease; epilepsy, anxiety, muscular spasms, murtiinfarct dementia, head trauma, traumatic brain injury, pain, AIDS related dementia, hypoglycemia, migraine, amyotrophic lateral sclerosis, drug and alcohol addiction, drug and alcohol withdrawal symptoms, psychotic conditions, tinnitus and urinary incontinence.

Another disease or condition susceptible to treatment by a compound of formula I, or a pharmaceutically acceptable salt thereof, is an ischemic event arising from CNS surgery, open heart surgery or any procedure during which the function of the cardiovascular system is compromised.

Detailed Description of the Invention The prodrugs of formula I are readily prepared using (3R,4S)-3-[4-(4- fluorophenyl)-4-hydroxy-piperidin-1-yl]-chroman-4,7-diol (the parent chromanol) as a starting material. This chromanol can be prepared as described in U.S. Patent No. 5,356,905 (issued October 18, 1994), U.S. patent application serial no. 08/189,479 (filed January 31 , 1994), and U.S. provisional patent application of M. Meltz et al., which is entitled "Process For The Resolution Of Cis-Racemic 7-Benzyloxy-3-[4-(4-Fluorophenyl)- 4-Hydroxy-Piperidin-1-yl]-Chroman-4-ol Dibenzoyl-D-Tartrate" (filed July 20, 1995), all three of which are herein incoφorated by reference in their entirety. The starting materials and reagents required for the synthesis of the parent chromanol are readily available, either commercially, according to synthetic methods disclosed in the literature, or by synthetic methods exemplified in the description provided below. The parent chromanol can be prepared by fractional crystallization of the L- proline ester of racemic cis-7-benzyloxy-3-[4-(4-fluorophenyl)-4-hydroxy-piperidin-1-yl]- chroman-4-ol, as described in U.S. patent application serial no. 08/189,479, referred to above. In a preferred method, the resolution method described in U.S. provisional patent application entitled "Process For The Resolution Of Cis-Racemic 7-Benzyloxy-3- [4-(4-Fluorophenyl)-4-Hydroxy-Piperidin-1 -yl]-Chroman-4-ol Dibenzoyl-D-Tartrate", referred to above, is followed. In this method, the parent chromanol is prepared by dissolving racemic cis-7-benzyloxy-3-[4-(4-fluorophenyl)-4-hydroxy-piperidin-1 -yl]- chroman-4-ol with an equal molar amount of dibenzoyl-D-tartaric acid in boiling aqueous ethanol. Racemic cis-7-benzyloxy-3-[4-(4-fluorophenyl)-4-hydroxy-piperidin-1 - yi]-chroman-4-ol is prepared as described in U.S. patent application serial no. 08/189,479, referred to above. The concentration of aqueous ethanol is not critical and may be varied between 75% and 95% ethanol (ETOH). A concentration of 9:1 /ETOH :H₂0 has been found to be effective and is preferred. A sufficient amount of the aqueous ethanol solvent to dissolve the racemic compound is required. This amount has been found to be about 17ml per gram of racemic compound.

Upon stirring while heating under reflux, the racemic compound dissolves to form a hazy solution which is allowed to cool with stirring whereupon the (+) isomer, (3R,4S)-7-bβrιzyloxy-3-[4-(4-fluorophenyl)-4-ty^ dibenzoyl-

D-tartrate, precipitates and may be collected by filtration and washed with aqueous ethanol. This initial product is of about 90% optical purity. If a higher purity is desired, the product may be heated again with aqueous ethanol, cooled and the product collected and washed. Two such treatments were found to yield the (+) isomer of 99.4% optical purity in an overall yield of 74%. This procedure is preferred over the procedure described in U.S. patent application serial no. 08/189,479, referred to above, in that it avoids a reduction step with lithium aluminum hydride and is therefore more suitable for bulk operations. This procedure also produces a significantly higher yield of the desired product. The above described (+) isomer can be converted to the parent chromanol by standard procedures. For example, treatment with dilute base can be used to free the piperidinyi base and subsequent hydrogeneration removes the 7-benzyl group to yield the parent chromanol.

In general, the parent chromanol is converted to the prodrugs of formula I using simple alkylation and acylation methods well known to those skilled in the art and described in the literature. See, for example, J. March, Advanced Organic Chemistry. 4th edition, J. Wiley and Sons, New York, chapter 10 (pages 293-500) (1992).

To prepare the compounds of formula I wherein R is C,-C_β alkyl or C₄-C₈ cycloalkyl, the parent chromanol is reacted with 1 molar equivalent (preferably a slight excess) of RX where X is an appropriate leaving group, such as halogen, tosylate, triflate, or mesylate. The reaction is performed in a reaction inert solvent, such as dimethylformamide (DMF), dimethylsulfoxide (DMSO), acetone, methyl ethyl ketone, or tetrahydrofuran (THF) at a temperature from about 0°C up to the reflux temperature of the solvent. To facilitate this reaction, it is preferable to include 1-2 molar equivalents of a base, such as an alkali metal carbonate (e.g. potassium carbonate), trialkylamine (e.g. triethylamine), or sodium hydride.

In another method, compounds of formula I wherein R is C,-C_β alkyl or C₄-C₈ cycloalkyl are prepared by reacting the parent chromanol with a C,-C_β alcohol (e.g. ethanol) or a C₄-C₈ cyclic alcohol (e.g. cyclopentanol) in the presence of triphenylphosphine and a dialkyl azodicarboxylate (e.g. diethyl azodicarboxylate). This is the so-called Mitsunobu reaction which is well known in the literature (Synthesis. 1 , 1981). To prepare the compounds of formula I wherein R is R¹C(0)- or R'OC(O)-, the parent chromanol is reacted with an appropriate acylating agent such as an anhydride (e.g. acetic anhydride) or an acid halide (e.g. benzoyl chloride or ethyl chloroformate) in a reaction inert solvent (e.g. THF or methylene chloride) at a temperature ranging from about 0°C to the reflux temperature of the solvent. This reaction can be facilitated by the addition of a base such as sodium hydride or a trialkylamine (e.g. triethylamine).

Another method to prepare compounds of formula I wherein R is R¹C(0)- is to react the parent chromanol with an acid corresponding to the group to be added (e.g. pivalic acid or phenylacetic acid) employing a reagent, such as dicyclohexylcarbodiamide or carbonyl diimidazole, to activate the acid prior to coupling with the chromanol. In this reaction the acylating agent is prepared in sjtu. This process is described in J. March, Advanced Organic Chemistry. 4th Ed., chapter 10, referred to above, and is well known to those skilled in the art. The preferred conditions for the reactions in this method are the same as those described in the preceding paragraph. DMF can be added as a cosolvent to facilitate dissolution of the reagents if necessary.

The prodrugs of the present invention are converted in vivo into the parent chromanol, a selective NMDA antagonist. They are therefore useful in the treatment of disorders and conditions, the treatment of which can be facilitated by blocking NMDA sites in a mammal. Examples of such diseases and conditions include degenerative CNS disorders such as stroke, Alzheimer's disease, Parkinson's disease, and Huntington's disease; epilepsy, anxiety, muscular spasms, muttiinfarct dementia, head trauma, traumatic brain injury, pain, AIDS related dementia, hypoglycemia, migraine, amyotrophic lateral sclerosis, drug and alcohol addiction, drug and alcohol withdrawal symptoms, psychotic conditions, tinnitus and urinary incontinence. The prodrugs of the present invention can be administered as pharmaceutically acceptable salts of the compounds of formula I. Such salts include conventional acid addition salts and cation salts. The compounds of formula I contain an amine group which is basic, and so are capable of forming such salts. Said salts include, but are not limited to, those with HCl, HBr, HN0₃, H₂S0₄, H₃P0₄, CH₃S0₃H, β-CH₃C_βH₄S0₃H, CH₃C0₂H, gluconic acid, tartaric acid, lactic acid, maleic acid and succinic acid. The salts can be prepared by conventional methods, e.g., by combining a compound of formula I with at least one molar equivalent of the acid in a suitable solvent. The prodrugs of formula I convert to the parent chromanol through metabolic processes within the body of a mammal. The parent chromanol has selective neuroprotective antiischemic and excitatory amino acid blocking activity that reflects its valuable utility in the treatment of neurological disorders such as epilepsy and stroke, and degenerative CNS disorders such as Alzheimer's disease, Parkinson's disease and Huntington's disease. In the systemic treatment of such diseases employing a therapeutically effective amount of a compound of formula I, the dosage is typically from about 0.02 to 20 mg/kg/day (0.001 -1 g/day for a typical human weighing about 50 kg) in single or divided doses, regardless of the route of administration. Of course, depending upon the exact compound and the exact nature of the individual illness, doses outside this range may be prescribed by the attending physician.

The compounds of the present invention are generally administered in the form of pharmaceutical compositions comprising at least one of the compounds of the formula I, together with a pharmaceutically acceptable vehicle or diluent. Such compositions are generally formulated in a conventional manner utilizing solid or Iiquid vehicles or diluents as appropriate to the mode of desired administration: for oral administration, in the form of tablets, hard or soft gelatin capsules, suspensions, granules, powders and the like; suppositories, including rectal; for parenteral administration (intravenous, subcutaneous, intramuscular), in the form of injectable solutions or suspensions, and the like; and for topical administration, in the form of solutions, lotions, ointments, salves and the like.

Since the prodrugs ofthe present invention are more stable in solution than the parent chromanol, the prodrugs are better suited than the parent chromanol for intravenous administration. Intravenous administration is the preferred parenteral method of administration. The preparation of solutions for intravenous administration is known to those skilled in the art. The intravenous solution should be osmotically balanced and have a neutral pH. Appropriate solutions include 5% dextrose solution, isotonic saline, and phosphate-buffered saline. In the following Preparation and Examples, unless otherewise indicated, reactions and other procedures were run at ambient temperature (20-25 °C), and all non-aqueous reactions were run under nitrogen for convenience and generally to maximize yields. All solvents/diluents were dried according to standard published procedures or purchased in a predried form. All reactions were stirred either magnetically or mechanically. NMR spectra are recorded at 250 or 300 MHz and are reported in ppm. The NMR solvent was CDCI₃ unless otherwise specified. IR spectra are reported in cm^'1, generally specifying only strong signals. The following abbreviations are used: DMF for dimethylformamide, THF for tetrahydrofuran, HRMS for high resolution mass spectrum.

PREPARATION (3R.4S)-7-Benzyloxy-3-f4-(4-fluorophenyl)-4-hvdroxy-piperidin-vπ-chroman-

4-ol dibenzoyl-D-tartrate

A. Racemic cis-7-benzyloxy-3-[4-(4-fluorophenyl)-4-hydroxy-piperidin-1 -yl]- chroman-4-ol (2.07g, 4.6 mmol) and dibenzoyl-D-tartaric acid (1.65g, 4.6 mmol) were suspended in 30 ml, 90% ethanol/water. The resulting mixture was stirred and heated to reflux; an additional 5 ml, 90% ethanol/water was added and a hazy solution was obtained. The resulting solution was stirred overnight at room temperature. The solid which formed was collected by filtration and washed twice with 3ml, 95% ethanol to yield 1.55g (83.4%) of the title product which was shown to be of 87% purity by HPLC.

B. The above product (1.2g) was suspended in 21.4 ml of 90% EtOH:H₂0, stirred and heated under reflux for 1.5 hours and then cooled to room temperature. The solid product was collected by filtration and washed with two 3 ml portions of 90% ETOH:H₂0. The yield was 1 Jg of 98.0% optical purity. C. The procedure of step B was repeated with the product of step B yielding

97% of a product which had 99.4% optical purity.

Optical purity was determined by HPLC using a 250 x 4.6 mm Chiralpak^® AD column (Chiral Technologies, Exton, PA) with the mobile phase comprising 600 ml hexane, 400 ml isopropanol, 1 ml trifluoroacetic acid and 0.5 ml diethylamine. The flow rate was 0.7 ml/min with an injection volume of 20 jA containing 0J to 0.4 mg sample/ml. Detection was set for 220 nm. EXAMPLE 1 (3R.4S)-7-Acetoxy-3-f4-(4-fluorophenyl)-4-hvdroxyl-piperidin-1-vn-chroman-4-ol A mixture of (3R,4S)-3-[4-(4-fluorophenyl)-4-hydroxy]-piperidin-1-yl-chroman-4, 7-diol (0.50 g, 1.39 mmol), 2-acetoxybenzoic acid (0.26 g, 1.44 mmol). 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.28 g. 1.46 mmol) and 4- dimethylaminopyridine (0J7 g, 1.39 mmol) in methylene chloride (25 mL) was stirred at ambient temperature overnight. The reaction was concentrated and the residue was partitioned between ether/ethyl acetate (2:1) and water. The phases were separated and the organic layer was washed with brine, dried over calcium sulfate, and concentrated to afford a white solid. The solid was triturated with ether/ethyl acetate (2:1) and then recrystallized from methanol/ethyl acetate to give 0.062 g (12%) of (3R,4S)-6-acetoxy-3-[4-(4-fluorophenyl)-4-hydroxy]piperidin-1-yl-chroman-4-ol which had the following characteristics: melting point 181.5-182°C: [σ]_D = +86.13° (c = 0.31 in methano!). Analysis calculated for C₂₂H₂₄FNO_s; C, 65.82; H, 6.03; N, 3.49. Found: C, 65.33; H, 6J 2; N, 3.41.

EXAMPLE 2 (3R.4S)-7-Pivaloxy-3-f4-(4-fluorophenyl)-4-hvdroxy-piperidin-1-yll-chroman-4-ol A mixture of (3R,4S)-3-[4-(4-fluorophenyl)-4-hydroxy]-piperidin-1-yl-chroman-4, 7-diol (0.30 g, 0.83 mmol), pivalic acid (0J95 mL, 1.70 mmol), 1-(3- dimethyiaminopropyl)-3-ethylcarbodiimide hydrochloride (0.33 g, 1.72 mmol) and 4- dimethylaminopyridine (0.20 g. 1.64 mmol) in methylene chloride (15 mL) was stirred at ambient temperature ovemight. The reaction was concentrated and the residue was partitioned between ether and water. The phases were separated and the organic layer was washed with brine, dried over calcium sulfate, and concentrated to afford an oily white solid. The solid was triturated with ethyl acetate and then flash chromatographed on silica gel (1 x 4 inches, packed with 25% ethyl acetate/hexane). Elution proceeded as follows: 25% ethyl acetate/hexane (200 mL), nil; 50% ethyl acetate/hexane (200 mL), nil; 75% ethyl acetate/hexane (200 mL) and ethyl acetate (200 mL), white solid product. This solid was further triturated with ether/hexane (1 :1) and air dried to afford 0.10 g (22%)of(3R,4S)-7-pivaloxy-3-[4-(4-fluorophenyl)-4-hydroxy-piperidin-1-yl]-chroman-4-ol which had the following characteristics: melting point 219-220 °C; [σ]_D = +83.9° (c = 0.31 in methanol). Analysis calculated for C₂₅H₂₈FN0₆; C, 67.70; H, 6.82; N, 3J6. Found: C, 67.61 : H, 6.88: N, 3.24. EXAMPLE 3

(3R.4S)-7-Propoxy-3-f4-(4-fluorophenyl)-4-hvdroxy-piperidin-1-yll-chroman-4-ol

In a dry three-neck flask, sodium hydride (60% dispersion in oil, 0.043 g, 1.07 mmol) was washed with hexane to remove the oil. DMF (3 mL) was added and the mixture was chilled to 0°C. (3R,4S)-3-[4-(4-Fluorophenyl)-4-hydroxy- piperidin-1-yl]- chroman-4,7-diol (0.350 g, 0.974 mmol) was added and the mixture was stirred for 30 min. Propyl iodide (OJ04 mL, 1.07 mmol) was added and the reaction was allowed to stir at ambient temperature for 1 hour. The mixture was diluted with ethyl acetate and extracted with 1 N aqueous lithium chloride. The aqueous lithium chloride was back extracted with ethyl acetate (twice) and the combined organic phase was washed ith 1N aqueous lithium chloride and brine. The organic layer was dried over calcium sulfate and concentrated to a white solid. The solid was recrystallized from isopropanol/methanol to afford 0J30 g (33%) of (3R,4S)-7-propoxy-3-[4-(4- fluorophenyl)-4-hydroxy-piperidin-1-yl]-chroman-4-ol as a white solid which had the following characteristics: melting point 148.5-149.5 °C; [σ]_D = + 83.33° (c = 0.27 in methanol). Analysis calculated for C₂₅H₂₈FN0₄: C, 68.81 ; H, 7.03; N, 3.49. Found: C, 68.65; H, 7.05; N, 3.38.

EXAMPLE 4 (3R.4S)-7-Methoxy-3-r4-(4-fluorophenyl -hvdroxy-piperidin-1-yl]-chroman-4-ol In a dry three neck flask, sodium hydride (60% dispersion in oil, 0.0275 g, 0.689 mmol) was washed with hexane to remove the oil. DMF (2 mL) was added and the mixture was chilled to 0°C. (3R,4S)-3-[4-(4-Fluorophenyl)-4-hydroxy-piperidin-1-yl]- chroman-4,7-diol (0.225 g, 0.626 mmol) was added and the mixture was stirred for 30 minutes. Methyl iodide (0.043 mL, 0.689 mmol) was added and the reaction was allowed to stir at ambient temperature for 1 hour. The mixture was diluted with ethyl acetate and extracted with 1N aqueous lithium chloride. The aqueous lithium chloride was back extracted with ethyl acetate (twice) and the combined organic phase was washed with 1 N aqueous lithium chloride and brine. The organic layer was dried over calcium sulfate and concentrated to a white solid. The solid was recrystallized from methanol to afford 0J 05 g (44%) of (3R,4S)-7-methoxy-3-[4-(4-fluorophenyl)-4-hydroxy- piperidin-1-yl]-chroman-4-ol as a white solid which had a melting point of 181-182°C. Analysis calculated for C₂,H₂₄FN0₅: C, 67.55; H, 6.48; N, 3.75. Found: C, 67.41 ; H, 6.47; N, 3.60. EXAMPLE 5

(3R.4S)-7-Ethoxy-3-[4-(4-fluorophenyl)-4-hydroxy-piperidin-1-yll-chroman-4-ol

In a dry three-neck flask, sodium hydride (60% dispersion in oil, 0.037 g, 0.918 mmol) was washed with hexane to remove the oil. DMF (3 mL) was added and the mixture was chilled to 0°C. (3R,4S)-3-[4-(4-Fluorophenyl)-4-hydroxy-piperidin-1-yl]- chroman-4,7-diol (0.300 g, 0.835 mmol) was added and the mixture was stirred for 30 min. Ethyl iodide (0.073 mL, 0.918 mmol) was added and the reaction was allowed to stir at ambient temperature for 1 hour. The mixture was diluted with ethyl acetate and extracted with 1 N aqueous lithium chloride. The aqueous lithium chloride was back extracted with ethyl acetate (twice) and the combined organic phase was washed with 1N aqueous lithium chloride and brine. The organic layer was dried over calcium sulfate and concentrated to a white solid. The solid was recrystallized from methanol to afford 0J75 g (54%) of (3R,4S)-7-ethoxy-3-[4-(4-fluorophenyl)-4-hydroxy-piperidin-1- yl]-chroman-4-ol as a white solid which had the following characteristics: melting point 191-192°C; [σ]_D = + 87.47° (c = 0.375 in methanol). Analysis calculated for C₂₂H_2βFN0₄: C, 68.20; H, 6.76; N, 3.62. Found: C, 68.02; H, 6.76; N, 3.40.

EXAMPLE 6 (3R.4Sl-7-Ethoxycarbonyloxy-3-f4-(4-fluorophenyl)-4-hvdroxy-piperidin-1-yl]-chroman-

4-ol A mixture of (3R,4S)-3-[4-(4-fluorophenyl)-4-hydroxy-piperidin-1-yl]-chroman-4,

7-diol (0.378 g, 1.05 mmol), potassium carbonate (0.345 g. 2.5 mmol) and 1 -chloroethyl ethyl carbonate (0J55 mL, 1 J5 mmol) in acetone (10 mL) was gently refluxed ovemight. The reaction mixture was diluted with ethyl acetate, filtered and concentrated. The residual solid was flash chromatographed on silica gel (1 x 3 inches) with elution proceeding as follows: 25% ethyl acetate/hexane (500 mL), nil; 50% ethyl acetate/hexane (50 mL), unweighed unidentified impurity; 50% ethyl acetate/hexane (600 mL), 0.355 g (78%) of (3R,4S)-7-ethoxycarbonyloxy-3-[4-(4- fluorophenyl)-4-hydroxy-piperidin-1-yl]-chroman-4-ol which had the following characteristics: melting point 153-154°C; [σ]_D = + 83.0° (c = 0.49 in methanol). Analysis calculated for C₂₃ll_2flFNO_β: C, 64.03; H, 6.07; N, 3.25. Found C, 63.75; H, 6J0; N, 2.95. EXAMPLE 7

(3R.4S)-7-lsopropoxy-3-f4-(4-fluorophenyπ-4-hvdroxy-piperidin-1-yn-chroman-4-ol

In a dry three-neck flask, sodium hydride (60% dispersion in oil, 0.037 g, 0.918 mmol) was washed with hexane to remove the oil. DMF (3 mL) was added and the mixture was chilled to 0°C. (3R,4S)-3-[4-(4-Fluorophenyl)-4-hydroxy- piperidin-1-yl]- chroman-4,7-diol (0.300 g, 0.835 mmol) was added and the mixture was stirred for 30 minutes. isopropyl bromide (0.086 mL, 0.918 mmol) was added and the reaction was allowed to stir at ambient temperature ovemight. Additional sodium hydride (0.01 g) and isopropyl bromide (0.016 mL) were added and the reaction was heated to 60° C ovemight. The mixture was diluted with ethyl acetate and extracted with 1 N aqueous lithium chloride. The aqueous lithium chloride was back extracted with ethyl acetate (twice) and the combined organic phase was washed with 1 N aqueous lithium chloride and brine. The organic layer was dried over calcium sulfate and concentrated to a white solid. The solid was flash chromatographed on silica gel (1 x 43 inches, packed in methylene chloride) with elution proceeding as follows: 3% methanol / methylene chloride (250 mL), 0J91 g of white solid product. This product was recrystallized from isopropanol to afford 0J54 g (46%) of (3R,4S)-7-isopropoxy-3-[4-(4-fluorophenyl)-4- hydroxy-pipβridin-1-yl]-chroman-4-oi as a white solid which had the following characteristics: melting point 151-152°C; [σ]_D = + 88.15° (c = 0.27 in methanol). Analysis calculated for C₂₃H₂₈FN0₄: C, 68.81 ; H, 7.03; N, 3.49. Found: C, 68.80; H, 7.07; N, 3.38.

EXAMPLE 8 (3R.4S)-7-Cvclopentyloxy-3-r4-(4-fluorophenyl)-4 hvdroxy-piperidin-1-vπ-chroman-4-ol In a dry three neck flask, sodium hydride (60% dispersion in oil, 0.037 g, 0.918 mmol) was washed with hexane to remove the oil. DMF (3 mL) was added and the mixture was chilled to 0°C. (3R,4S)-3-[4-(4-Fluorophenyl)-4-hydroxy- piperidin-1-yl]- chroman-4,7-diol (0.300 g, 0.835 mmol) was added and the mixture was stirred for 30 min. Cyclopentyl bromide (0.098 mL, 0.918 mmol) was added and the reaction was allowed to stir at ambient temperature ovemight. Additional sodium hydride (0.014 g) and cyclopentyl bromide (0.027 mL) were added and the reaction was heated to 60 °C overnight. The mixture was diluted with ethyl acetate and extracted with 1 N aqueous lithium chloride. The aqueous lithium chloride was back extracted with ethyl acetate (twice) and the combined organic phase was washed with 1 aqueous lithium chloride and brine. The organic layer was dried over calcium sulfate and concentrated to a white solid. The solid was flash chromatographed on silica gel (1 x 43 inches, packed in methylene chloride) with elution proceeding as follows: 3% methanol/methylene chloride (200 mL), 0.220 g of white solid product. A sample of the product was recrystallized from isopropanol/ethyl acetate to afford white crystals of (3R,4S)-7- cyclopentyloxy-3-[4-(4-fluorophenyl)-4-hydroxy-piperidin-1 -yl]-chroman-4-ol which had the following characteristics: melting point 180-181 °C; [σ]₀ = + 80.73° (c = 0.275 in methanol). Analysis calculated for C_2SH₃₀FNO : C, 70.24; H, 7.07; N, 3.28. Found: C, 69.98; H, 7.07; N, 3J3.

Claims

What is claimed is:

1. A compound of the formula

or a pharmaceutically acceptable salt thereof, wherein R is C,-C_fl alkyl, C₄-C₈ cycloalkyl, R'CfO)-, or R^CfO)-; and,

R¹ is 0,-Cg alkyl, C₄-C₈ cycloalkyl, benzyl, C_β-C,₀ aryl, or C₃-C_β heteroaryl wherein said aryl, heteroaryl and the phenyl moiety of said benzyl are optionally substituted with from one to three substituents selected from the group consisting of hydroxy, chloro, bromo, fluoro, and -NR²R³, wherein R² and R³ are independently selected from the group consisting of hydrogen, C,-C_β alkyl, (C,-C_β alkyl)C(O)-, (C,-C_β alkyl)OC(O)-, (C_β-C₁₀ aryl)C(O)-, (benzyl)OC(O)-, and (C_β-C₁₀ aryl)OC(O)-.

2. The compound of claim 1 wherein R is R CfO)- or R'OC(O)-.

3. The compound of claim 2 wherein R is R¹C(0)- and R¹ is benzyl, C_β-C,₀ aryl, or C₃-C_a heteroaryl.

4. The compound of claim 2 wherein R is R'CfO)- and R¹ is C,-C_β alkyl or

C₄-C₈ cycloalkyl.

5. The compound of claim 4 wherein R¹ is C,-C_β alkyl.

6. The compound of claim 2 wherein R is R¹OC(0)- and R¹ is benzyl, C_β-C₁₀ aryl, or C₃-C₉ heteroaryl.

7. The compound of claim 2 wherein R is R¹OC(0)- and R¹ is C,-C_β alkyl or C₄-C₈ cycloalkyl.

8. The compound of claim 7 wherein R¹ is C^C_g alkyl.

9. The compound of claim 8 wherein R¹ is C,-C₃ alkyl.

10. The compound of claim 9 wherein R¹ is an ethyl group.

11. The compound of claim 1 wherein said compound is selected from the group consisting of:

(3R,4S)-7-Ethoxy-3-[4-(4-fluorophenyl)-4-hydroxyl-piperidin-1-yl]-chroman-4-ol, (3R,4S)-7-Propoxy-3-[4-(4-fluorophenyl)-4-hydroxyl-piperidin-1-yl]-chroman-4-ol, (3R,4S)-7-lsopropoxy-3-[4-(4-fluorophenyl)-4-hydroxyl-piperidin-1-yl]-chroman-4-ol,

(3R,4S)-7-Acetoxy-3-[4-(4-fluorophenyl)-4-hydroxyl-piperidin-1-yl]-chroman-4-ol,

(3R,4S)-7-Pivaloxy-3- [4-(4-fluorophenyl)-4-hydroxyl-piperidin-1 -yl] -chroman-4-ol ,

(3R,4S)-7-Benzoyloxy-3-[4-(4-fluorophenyl)-4-hydroxyl-piperidin-1-yl]-chroman-4-ol, (3R,4S)-7-Methoxycarbonyloxy-3-[4-(4-fluorophenyl)-4-hydroxyl-pipeιidin-1 -yl]-chroman-4- ol,

(3R,4S)-7-Ethoxycarbonyloxy-3-[4-(4-fluorophenyl)-4-hydroxyl-piperidin-1-yl]-chroman-4- ol,

(3R,4S)-7-Propoxyc«ul3onyloxy-3-[4-(4-fluorophenyl)-4-hydroxyl-piperidin-1-yl]-chroman-4- ol,

(3R,4S)-7-lsopropoxycarbonyloxy-3-[4-(4-fluorophenyl)-4-hydroxyl-piperidin-1-yl]- chroman-4-ol,

(3R,4S)-7-Cyclopentyloxy-3-[4-(4-fluorophenyl)-4-hydroxyl-piperidin-1 -yl] -chroman-4-ol , and pharmaceutically acceptable salts of said compounds.

12. The compound of claim 1 wherein said compound is selected from the group consisting of:

(3R,4S)-7-Butyloxycarbonyloxy-3-[4-(4-fluorophenyl)-4-hydroxyl-piperidin-1-yl]-chroman-4- ol,

(3R,4S)-7-tert-Butyloxycarbonyloxy-3-[4-(4-fluorophenyl)-4-hydroxyl-piperidin-1-yl]- chroman-4-ol,

(3R,4S)-7-Pentyloxycarbonyloxy-3-[4-(4-fluorophenyl)-4-hydroxyl-piperidin-1-yl]-chroman-

4-ol,

(3R,4S)-7-Phenoxycarbonyloxy-3-[4-(4-fluorophenyl)-4-hydroxyl-piperidin-1-yl]-chroman-

4-ol, and pharmaceutically acceptable salts of said compounds.

13. A pharmaceutical composition for treating a disease or condition, the treatment of which can be facilitated by blocking NMDA sites in a mammal, comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.

14. The pharmaceutical composition of claim 13 wherein said disease or condition is selected from the group consisting of degenerative CNS disorders, stroke,

Alzheimer's disease, Parkinson's disease, Huntington's disease, epilepsy, anxiety, muscular spasms, multiinfarct dementia, head trauma, traumatic brain injury, pain, AIDS related dementia, hypoglycemia, migraine, amyotrophic lateral sclerosis, drug and alcohol addiction, drug and alcohol withdrawal symptoms, psychotic conditions, tinnitus and urinary incontinence.

15. The pharmaceutical composition of claim 13 wherein said disease or condition is an ischemic event arising from CNS surgery, open heart surgery or any procedure during which the function of the cardiovascular system is compromised.

16. The pharmaceutical composition of claim 13 wherein said pharmaceutically acceptable carrier comprises a pharmaceutically acceptable solution that is osmotically balanced and has a neutral pH.

17. A method of treating a disease or condition, the treatment of which can be facilitated by blocking NMDA sites in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of claim 1.

18. The method of claim 17 wherein said disease or condition is selected from the group consisting of degenerative CNS disorders, stroke, Alzheimer's disease, Parkinson's disease, Huntington's disease, epilepsy, anxiety, muscular spasms, multiinfarct dementia, head trauma, traumatic brain injury, pain, AIDS related dementia, hypoglycemia, migraine, amyotrophic lateral sclerosis, drug and alcohol addiction, drug and alcohol withdrawal symptoms, psychotic conditions, tinnitus and urinary incontinence.

19. The method of claim 17 wherein said disease or condition is an ischemic event arising from CNS surgery, open heart surgery or any procedure during which the function of the cardiovascular system is compromised.

20. The method of claim 19 wherein said compound is administered intravenously.