Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/06—Antimigraine agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/08—Antiepileptics; Anticonvulsants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/20—Hypnotics; Sedatives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/22—Anxiolytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

• the present invention relates to derivatives of 2,3,4,4a-tetrahydro-lH- pyrazino[l,2,-a]quinoxalin-5(6H)ones which are serotonin 5-hydroxytryptamine 2 C
• (5HT 2C ) receptor agonists useful for the treatment of disorders such as obsessive - compulsive disorder, depression, anxiety, schizophrenia, migraine, sleep disorders,
• Obesity is a medical disorder characterized by an excess of body fat or adipose tissue.
• Comorbidities associated with obesity are Type II diabetes, cardiovascular disease, hypertension, hyperlipidemia, stroke, osteoarthritis, sleep
• the serotonin 5- hydroxytryptamine (5-HT) receptor is a G-protein coupled receptor which is expressed in neurons in many regions of the human central nervous system.
• the 5HT, c receptor (formerly called the 5HT 1C receptor) is a prominent subtype of the serotonin receptor found in the central nervous system of both rats and humans. It is expressed widely in both cortical and subcortical regions. [Julius, D. MacDermott, A.
• 5HT 2r receptor subtype selective agonists which are selective over other monoamine receptors, causes a reduction in food intake and result in a reduction in weight gain.
• Other therapeutic indications for 5HT 2 c agonists are obsessive compulsive disorder, depression, panic disorder, schizophrenia, sleep disorders, eating disorders, and epilepsy.
• Indian J. Chem. 17B, 244-245 (1979) discloses 3-Substituted 2,3,4,4a,5,6- Hexahydro-l(H)-pyrazino[l,2-a]quinoxalines which exhibit no anorexigenic or stimulant activity at 60 mg/kg i.p. dose. Weak CNS depressant activity and significant hypotensive activity in anaesthetized animals. Tachyphylaxis was observed.
• R is hydrogen or alkyl of 1-6 carbon atoms
• R' is hydrogen, alkyl of 1-6 carbon atoms, acyl of 2-7 carbon atoms, or aroyl
• R ] , R 2 , R3, and R4 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, trilluoroalkyl, -CN, alkyl sulfonamide of 1-6 carbon atoms, alkyl amide of 1-6 carbon atoms, amino, alkylamino of
• 1-6 carbon atoms dialkylamino of 1-6 carbon atoms per alkyl moiety, trifiuoroalkoxy of 1-6 carbon atoms, acyl of 2-7 carbon atoms, or aroyl;
• X is CR 5 R 6 or a carbonyl group
• R 5 and R 6 are each, independently, hydrogen or alkyl of 1-6 carbon atoms; or a pharmaceutically acceptable salt thereof, with the proviso that at least one of R j ,
• R 2 , R 3 , or R 4 are not hydrogen; which are 5HT 2C receptor agonists useful for the treatment of disorders involving the central nervous system such as obsessive-compulsive disorder, depression, anxiety, panic disorder, schizophrenia, migraine, sleep disorders, eating disorders, obesity, type II diabetes, and epilepsy.
• the compounds of this invention may contain an asymmetric carbon atom and some of the compounds of this invention may contain one or more asymmetric centers and may thus give rise to optical isomers, enantiomers and diastereoisomers. While shown without respect to stereochemistry in Formula I, the present invention includes such optical isomers and diastereoisomers; as well as the racemic and resolved, enantiomerically pure R and S stereoisomers; as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof.
• alkyl includes both straight- and branched-chain saturated aliphatic hydrocarbon groups. Preferred alkyl groups are methyl, ethyl, propyl or butyl, most preferably methyl.
• aroyl is defined as an aryl ether, where aryl is defined as an aromatic system of 6-14 carbon atoms, which may be a single ring or multiple aromatic rings fused or linked together as such that at least one part of the fused or linked rings forms the conjugated aromatic system.
• Preferred aryl groups include phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, phenanthryl groups.
• Halogen is defined as Cl, Br, F, and I, preferably chlorine or fluorine.
• Pharmaceutically acceptable salts can be formed from organic and inorganic acids, for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known acceptable acids.
• organic and inorganic acids for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known acceptable
• Preferred compounds of this invention are those in which at least one of Ri , R , R 3 , or R 4 are not hydrogen, and the non-hydrogen substituents of R1, R , R 3 , and R 4 are halogen or trifluoromethyl.
• Preferred enantiomerically pure compounds of formulas IA and IB are provided as follows:
• R, Rj, R , R 3 , and R 4 are as described above.
• the compounds of this invention can be prepared according to the following schemes from commercially available starting materials or starting materials which can be prepared using literature procedures. These schemes show the preparation of representative compounds of this invention.
• the intermediate (III) is cyclized by a process involving reduction of the nitro group to an amino group, preferably by reaction of a metal, such as iron, in an acid, such as acetic acid, followed by heating at elevated temperature, such as 50- 100°C, to effect cyclization to (IV).
• a metal such as iron
• an acid such as acetic acid
• elevated temperature such as 50- 100°C
• a base such as sodium hydride
• an alkyl halide such as methyl iodide
• Compounds (VI) can also be alkylated a second time using a base, such as sodium hydride, and an alkyl halide, such as methyl iodide, to give compounds of this invention (VIII).
• a base such as sodium hydride
• an alkyl halide such as methyl iodide
• compounds (VI) can be reduced with a reducing agent, such as borane in THF, to compounds of this invention (VII).
• Compounds (VIII) can also be reduced with borane in THF to give (IX) which are compounds of this invention.
• the amide of compounds (V) can also be reduced to amines (VII) using a reducing agent, such as borane in tetrahydrofuran, at 0-50°C.
• a reducing agent such as borane in tetrahydrofuran, at 0-50°C.
• Compounds (VII) are also compounds of this invention.
• the amide of compounds (VI) can be reduced to amines (VIII) which are compounds of this invention.
• amines (VIII) which are compounds of this invention.
• R' is acyl this group is put on, as already described, after reduction of amides (VI) where R' is hydrogen.
• the enantiomerically pure compounds of this invention can be prepared according to the following Scheme 3 from commercially available starting materials or starting materials which can be prepared using literature procedures.
• This scheme shows the preparation of representative (R)-compounds of formula IA of this invention, starting with the known 2-(R)-piperazinecarboxylic acid (reference below).
• Starting from the known 2-(S)-piperazinecarboxylic acid gives the (S)-compounds of formula IB of this invention.
• the reaction is carried out in an inert organic solvent, such as dimethylformamide, in the presence of a base, such as triethylamine, at a temperature above ambient temperature, such as 50-70°C.
• a base such as triethylamine
• the intermediate (XVIII) is cyclized by a process involving reduction of the nitro group to an amino group, preferably by reaction of a metal, such as iron, in an acid, such as acetic acid, followed by heating at elevated temperature, such as 50- 70°C, to effect cyclization to (XIX). Removal of the Cbz protecting group using 30% HBr in acetic acid, boron tribromide, or catalytic reduction, gives chiral products of this invention (IA).
• Ovary cell line transfected with the cDNA expressing the human 5-hydroxy- tryptamine 2 c (h5HT 2C ) receptor was maintained in DMEM (Dulbecco's Modified Eagle Media) supplied with fetal calf serum, glutamine, and the markers: guaninephosphoribosyl transf erase (GTP) and hypoxanthinethymidine (HT).
• DMEM Dulbecco's Modified Eagle Media
• GTP guaninephosphoribosyl transf erase
• HT hypoxanthinethymidine
• the cells were allowed to grow to confluence in large culture dishes with intermediate changes of media and splitting. Upon reaching confluence, the cells were harvested by scraping. The harvested cells were suspended in half volume of fresh physiological phosphate buffered saline (PBS) solution and centrifuged at low speed (900 x g). This operation was repeated once more.
• PBS physiological phosphate buffered saline
• the collected cells were then homogenized with a polytron at setting #7 for 15 sec in ten volumes of 50 mM Tris.HCl, pH 7.4 and 0.5 mM EDTA.
• the homogenate was centrifuged at 900 x g for 15 min to remove nuclear particles and other cell debris. The pellet was discarded and the supernatant fluid recentrifuged at 40,000 x g for 30 min. The resulting pellet was resuspended in a small volume of Tris.HCl buffer and the tissue protein content was determined in aliquots of 10-25 microliter ( ⁇ l) volumes.
• Bovine Serum Albumin (BSA) was used as the standard in the protein determination by the method of Lowry et al., (J. Biol.
• the volume of the suspended cell membranes was adjusted with 50 mM Tris.HCl buffer containing: 0.1% ascorbic acid, 10 mM pargyline and 4 mM CaCl, to give a tissue protein concentration of 1-2 mg per ml of suspension.
• the preparation membrane suspension (many times concentrated) was aliquoted in 1 ml volumes and stored at -70°C until used in subsequent binding experiments.
• Binding measurements were performed in a 96 well microtiter plate format, in a total volume of 200 ⁇ l. To each well was added: 60 ⁇ l of incubation buffer made in 50 mM Tris.HCl buffer, pH 7.4 and containing 4 mM CaCl,: 20 ⁇ l of [ 125 I] DOI (S.A., 2200 Ci/mmol, NEN Life Science).
• the dissociation constant, KD of [ 125 I] DOI at the human serotonin 5HT C receptor was 0.4 nM by saturation binding with increasing concentrations of [ 125 I] DOI.
• the reaction was initiated by the final addition of 100.0 ⁇ l of tissue suspension containing 50 ⁇ g of receptor protein. Nonspecific binding is measured in the presence of 1 ⁇ M unlabeled DOI added in 20.0 ⁇ l volume. Test compounds were added in 20.0 ml. The mixture was incubated at room temperature for 60 min. The incubation was stopped by rapid filtration. The bound ligand-receptor complex was filtered off on a 96 well unifilter with a Packard ® Filtermate 196 Harvester.
• the bound complex caught on the filter disk was dried in a vacuum oven heated to 60°C and the radioactivity measured by liquid scintillation with 40 ⁇ l Microscint-20 scintillant in a Packard TopCount® equipped with six (6) photomultiplier detectors.
• Ketanserin 94.8 (70.7 - 127.0) nM
• Methiothepin 4.6 (4.0 - 6.0) nM Methysergide 6.3 (4.6 - 8.6) nM
• CHO cells transfected with the cDNA expressing the human 5-HT, c receptor were cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum and non-essential amino acids. Upon reaching confluence the cells were harvested using PBS/EDTA and plated in 24 well plates at an initial density of 2.5 x 10 5 cells per well. One (1) ml of maintenance medium containing l ⁇ Ci ml myo-[ 3 H] inositol was added to each well.
• DMEM Dulbecco's modified Eagle's medium
• the cells were washed once with 0.5 ml DMEM containing 25 mM HEPES and 10 mM LiCl, then preincubated with the medium for 30 min (antagonists were included in this period if tested). At the end of the preincubation, the medium was removed, the cells were then incubated with test compounds (in presence of antagonists if needed) for 30 min. The reaction was terminated by removal of the incubation solution and addition of 0.5 ml ice-cold 5% PCA, followed by 15 to 30 min incubation on ice. 200 ⁇ l of 0.5 M Tes/1.5 M K,CO 3 was added to each well to neutralize to pH 7, and plates were left on ice for another 15 to 30 min to precipitate all salts. The liquid and solid phases were separated by centrifugation.
• a portion (350 ⁇ l) of the upper aqueous phase was applied to Dowex AG-1X8 (formate form, 100-200 mesh) columns. The columns were then washed stepwise with 10 ml of water and 10 ml of 25 mM ammonium formate to remove free myo- [TTJinositol and deacylated phosphoinositol, respectively. Finally 10 ml of 0.2 M ammonium formate solution was applied to the columns to elute [ 3 H] inositol monophosphate ([ 3 H] IP,) directly into scintillation vials. Of this eluate, 1 ml was used to determine radioactivity by scintillation counting.
• IP [ 3 H]inositol monophosphate
• ED50 values were calculated. The ED50 value is the dose that produces a 50% reduction in food intake during the test period.
• the compounds of this invention are 5HT 2C receptor agonists useful for the treatment of diseases involving the central nervous system such as obsessive- compulsive disorder; depression; anxiety; panic disorder; schizophrenia; migraine; sleep disorders, such as sleep apnea; eating disorders, such as hyperphagia; obesity; type II diabetes; and epilepsy.
• the compounds are for treatment of diseases of a mammal, preferably a human.
• the compounds of this invention can be formulated neat or with a pharmaceutical carrier for administration, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmacological practice.
• the pharmaceutical carrier may be solid or liquid.
• a solid carrier can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material.
• the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.
• the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient.
• Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
• Liquid carriers are used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions.
• the active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats.
• the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
• suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
• suitable examples of liquid carriers for oral and parenteral administration include water (partially containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, lecithins, and oils (e.g. fractionated coconut oil and arachis oil).
• the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate.
• Sterile liquid carriers are useful in sterile liquid form compositions for parenteral administration.
• the liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellant.
• Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously.
• the compounds of this invention can also be administered orally either in liquid or solid composition form.
• the compounds of this invention may be administered rectally or vaginally in the form of a conventional suppository.
• the compounds of this invention may be formulated into an aqueous or partially aqueous solution, which can then be utilized in the form of an aerosol.
• the compounds of this invention may also be administered transdermally through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is non toxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin.
• the carrier may take any number of forms such as creams and ointments, pastes, gels, and occlusive devices.
• the creams and ointments may be viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil type.
• Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable.
• a variety of occlusive devices may be used to release the active ingredient into the blood stream such as a semipermeable membrane covering a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient. Other occlusive devices are known in the literature.
• the dosage requirements vary with the particular compositions employed, the route of administration, the severity of the symptoms presented and the particular subject being treated.
• the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules.
• the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient;
• the unit dosage forms can be packaged compositions, for example, packaged powders, vials, ampoules, pre filled syringes or sachets containing liquids.
• the unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
• a mixture of 10.4 g of 4-carbobenzyloxypiperazine-2-carboxylic acid, copper chelate and 7.9 g of ethylenediaminetetraacetic acid, disodium salt in 800 mL of H 2 O is heated to 80°C for 3 hours. After cooling to room temperature, the mixture is concentrated to dryness.
• a mixture of this solid, 7.3 g of l,2-dichloro-4-fluoro-5- nitrobenzene, and 20 mL of triethylamine in 100 mL of dimethylsulfoxide is heated to 60°C for 12 hours. After cooling to ambient temperature, the resulting mixture is treated with HCl to pH 3. The mixture is then diluted with H,O and extracted with ethyl acetate. The combined extracts are dried over MgSO 4 and concentrated to give 16 g of crude product.
• a solution of 20 g of KOH in 50 mL of H,O is added to a solution of 4.2 g of 3-carbobenzyloxy-8,9-dichloro-2,3,4,4a-tetrahydro-lH-pyrazino[l,2-a]quinoxalin- 5(6H)-one in 50 mL of methanol.
• the resulting reaction mixture is heated to reflux for 3 hours and then is allowed to cool to ambient temperature.
• the solution is concentrated and the crude solid is partitioned between water and ethyl acetate. The phases are separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are concentrated.
• the crude solid is dissolved in a minimum amount of hot ethanol and then a solution of HCl in ethanol is added to pH 3.
• the solid is collected and dried in a vacuum oven at 80°C to give 2.4 g of product as its hydrochloride salt.
• Example 2 (R)-8.9-Dichloro-2.3.4.4a-Tetrahvdro-lH-Pyrazino ⁇ .2-alOuinoxalin-5(6H)-One Method A (Separation Method)
• the enantiomers of the compound of Example 1 were separated by HPLC using a Chiracel AD column with 100% ethanol at a flow rate of 0.5 mL/min to provide the compounds of Example 2 and 3.
• the first enantiomer (Example 2) elutes at 10.4 min ([ ⁇ ] 25 D +27.8) and the second (Example 3) at 13.7 min ([ ⁇ ] 25 D -25.5).
• Method B (Chiral Synthesis)
• Example 2 The enantiomers of the compound of Example 1 were separated by HPLC using a Chiracel AD column with 100% ethanol at a flow rate of 0.5 mL/min to provide the compounds of Example 2 and 3.
• the first enantiomer (Example 2) elutes at 10.4 min ([ ⁇ ] 25 D +27.8) and the second (Example 3) at 13.7 min ([ ⁇ ] 25 D -25.5).
• Method B (Chiral Synthesis)
• the solids are slurried in 100 mL of 1:1 methanol : water mixture and the pH adjusted to ⁇ 4 by the addition of 2.5 N HCl.
• the solution is applied to a column of 400 g of AG 50W-8X resin that had been pre- washed with a mixture of 1 :16:16 pyridine : methanol : water.
• the product was eluted with the same solvent mixture and the combined product fractions are concentrated under reduced pressure ( ⁇ 50°C) to give a semi-solid residue.
• This material is slurried with 50 mL of methanol to obtain crystalline solids.
• the solids are collected and dried to give 4.0 g (50%) of white solid, mp 247°C decomposed.
• This oil is dissolved in 100 mL of ethyl acetate and washed with 20 mL of 1 N HCl (2X), with 100 mL of water (2X), and 100 mL of brine. The organic layer is dried over MgSO 4 , filtered and concentrated to give 2.5 g (99%) an orange solid foam.
• the enantiomers were be separated by HPLC using a Chirapak AD column with
• Example 8 85:15 methano water (+0.1% diethylamine) at a flow rate of 0.5 mL/min.
• the first enantiomer (Example 9) eluted at 17.5 min ([ ⁇ ] 25 D + 43) and the second (Example 8) at 22.0 min ([ ⁇ f D -40).
• Example 8
• the enantiomers were separated by HPLC using a Chirapak AD column with 85:15 methanol.'water (+0.1% diethylamine) at a flow rate of 0.5 mL/min.
• the first enantiomer (Example 9) eluted at 17.5 min ([ ⁇ ] 25 D + 43) and the second (Example 8) at 22.0 min ([ ⁇ ] 25 D -40).
• the hydrochloride salt was prepared from HCl and MeOH as a light green solid, mp decomposed 270-280°C.

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• 1999
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• 2001
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