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Definitions

• the present invention provides oxazinocarbazole derivatives having a ring connecting position 8 (C-8) and position 9 (N-9), and more specifically, provides compounds of formula (I) described herein below. These compounds are 5-HT ligands, and are useful for treating diseases wherein modulation of 5-HT activity is desired.
• serotonin has been implicated in a number of diseases and conditions which originate in the central nervous system. These include diseases and conditions related to sleeping, eating, perceiving pain, controlling body temperature, controlling blood pressure, depression, anxiety, schizophrenia, and other bodily states.
• diseases and conditions related to sleeping, eating, perceiving pain including sleeping, eating, perceiving pain, controlling body temperature, controlling blood pressure, depression, anxiety, schizophrenia, and other bodily states.
• receptor-specific agonists and antagonists are of interest for the treatment of a wide range of disorders, including anxiety, depression, hypertension, migraine, obesity, compulsive disorders, schizophrenia, autism, neurodegenerative disorders (e.g. Alzheimer's disease, Parkinsonism, and Huntington's chorea), and chemotherapy-induced vomiting.
• disorders including anxiety, depression, hypertension, migraine, obesity, compulsive disorders, schizophrenia, autism, neurodegenerative disorders (e.g. Alzheimer's disease, Parkinsonism, and Huntington's chorea), and chemotherapy-induced vomiting.
• M. D. Gershon, et al. The Peripheral Actions of 5-Hydroxytryptamine, 246 (1989); P. R. Saxena, et al., Journal of Cardiovascular Pharmacology, 15:Supplement 7 (1990).
• the major classes of serotonin receptors (5-HT 1-7 ) contain fourteen to eighteen separate receptors that have been formally classified. See Glennon, et al., Neuroscience and Behavioral Reviews, 1990, 14, 35; and D. Hoyer, et al. Pharmacol. Rev. 1994, 46, 157-203. Recently discovered information regarding subtype identity, distribution, structure, and function suggests that it is possible to identify novel, subtype specific agents, having improved therapeutic profiles (e.g. fewer side effects). For example, the 5-HT 6 receptor was identified in 1993 (Monsma et al., Mol. Pharmacol. 1993, 43, 320-327; and Ruat, M. et al., Biochem. Biophys. Res. Com. 1993, 193, 269-276).
• 5-HT 6 receptor has been linked to generalized stress and anxiety states (Yoshioka et al., Life Sciences 1998, 17/18, 1473- 1477). Together these studies and observations suggest that compounds that antagonize the 5-HT 6 receptor will be useful in treating disorders of the central nervous system.
• Compounds of the present invention are radioligands of the 5-HT receptor (e.g., receptor-specific agonists or antagonists). Thus they are useful for identifying diseases wherein modulation of 5-HT activity is desired. Specifically, the compounds of this invention are useful in the diagnosis of psychosis, paraphrenia, psychotic depression, mania, schizophrenia, schizophreniform disorders, anxiety, migraine headache, drug addiction, convulsive disorders, personality disorders, post-traumatic stress syndrome, alcoholism, panic attacks, obsessive-compulsive disorders, and sleep disorders. The compounds of this invention are also useful to identify psychotic, affective, vegetative, and psychomotor symptoms of schizophrenia and the extrapyramidal motor side effects of other antipsychotic drugs. The compounds of this invention are also useful in the identification of eating behavior disorders.
• 5-HT receptor e.g., receptor-specific agonists or antagonists
• the present invention provides a compound of formula I
• aryl is phenyl or naphthyl, optionally substituted with one or more R1 0 ;
• R 8 and R 9 is independently
• Y is H or Ci-6 alkyl
• isotopic atoms that can be incorporated into compounds of the invention include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, iodine, and chlorine, such as 3 H, U C, 14 C, 18 F, 123 I, and 125 I.
• compounds such as N-methyl-2-[(l -phenyl- 1,2- dihydro [ 1 ,4] oxazino [2,3 ,4-j k] carbazol-7-yl)oxy] - 1 -ethanamine, 2- [( 1 -phenyl- 1,2- dihydro[l,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]ethanamine, N-ethyl-2-[(l-phenyl- l,2-dihydro[l,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]ethanamine, 2-[(8-chloro-l- phenyl-l,2-dihydro[l,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]ethanamine, 7-[2-(4- methylpiperazin- 1 -yl)ethoxy] - 1 -phenyl)
• the invention also provides a method of utilizing an isotopically labeled compound of formula I to perform diagnostic screening, such as positron emission tomography, single photon emission computed tomography, and nuclear magnetic resonance spectroscopy.
• the compounds of the present invention are useful in diagnostic analysis of a disease or condition of the central nervous system in a mammal.
• the present invention further provides compounds that are useful in diagnostic analysis of a disease or condition in a mammal, such as where a 5-HT receptor is implicated and modulation of a 5-HT function is desired or where a 5-HT 6 receptor is implicated and modulation of a 5-HT 6 function is desired.
• Diseases or disorders of the central nervous system include, but are not limited to the following: obesity, depression, schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, a stress related disease (e.g. general anxiety disorder), panic disorder, a phobia, obsessive compulsive disorder, post- traumatic-stress syndrome, immune system depression, a stress induced problem with the urinary, gastrointestinal or cardiovascular system (e.g., stress incontinence), neurodegenerative disorders, autism, chemotherapy-induced vomiting, hypertension, migraine headaches, cluster headaches, sexual dysfunction in a mammal (e.g.
• a human addictive disorder and withdrawal syndrome
• an adjustment disorder an age- associated learning and mental disorder, anorexia nervosa, apathy, an attention-deficit disorder due to general medical conditions, attention-deficit hyperactivity disorder, behavioral disturbance (including agitation in conditions associated with diminished cognition (e.g., dementia, mental retardation or delirium)), bipolar disorder, bulimia nervosa, chronic fatigue syndrome, conduct disorder, cyclothymic disorder, dysthymic disorder, fibromyalgia and other somatoform disorders, generalized anxiety disorder, an inhalation disorder, an intoxication disorder, movement disorder (e.g.,
• Huntington's disease or Tardive Dyskinesia oppositional defiant disorder, peripheral neuropathy, post-traumatic stress disorder, premenstrual dysphoric disorder, a psychotic disorder (brief and long duration disorders, psychotic disorder due to medical condition, psychotic disorder NOS), mood disorder (major depressive or bipolar disorder with psychotic features) seasonal affective disorder, a sleep disorder, a specific developmental disorder, agitation disorder, selective serotonin reuptake inhibition (SSRI) "poop out” syndrome or a Tic disorder (e.g., Tourette's syndrome).
• SSRI selective serotonin reuptake inhibition
• C i_ j indicates a moiety of the integer 'i" to the integer "j" carbon atoms, inclusive.
• C 1-7 alkyl refers to alkyl of one to seven carbon atoms, inclusive.
• Halo is fluoro, chloro, bromo, or iodo.
• Alkyl denotes both straight and branched groups; but reference to an individual radical such as "propyl” embraces only the straight chain radical, a branched chain isomer such as "isopropyl” being specifically referred to.
• C 1-7 alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3- pentyl, or hexyl.
• C 3-6 cycloalkyl denotes a cycloalkyl having three to six carbon atoms. Specifically, C 3-6 cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
• Aryl denotes a phenyl or a naphthyl radical.
• aryl is substituted with one or more halo, OH, CN, CF 3 , C 1-6 alkyl, or NH 2 .
• Pharmaceutically acceptable salts denote acid addition salts useful for administering the compounds of this invention and include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, propionate, lactate, mesylate, maleate, malate, succinate, tartrate, citric acid, 2-hydroxyethyl sulfonate, fumarate, methanesulfonic acid salt and etc.
• pharmaceutically acceptable salts can be maleate, methanesulfonic acid salt and etc.
• Mammal denotes human and animals.
• a specific value for Ri includes H or halo.
• a specific value for Ri includes H or chloro.
• a specific value for R 2 includes H or C 1-6 alkyl.
• a specific value for R 2 includes H, or methyl.
• R 3 includes -(CH 2 ) m -NR 8 R 9 , wherein R 8 and R 9 are independently H, or C 1-6 alkyl optionally substituted with -OH, or where one of R 8 or R 9 is CHO and the other is H, or where R 8 and R 9 taken together with the nitrogen to which they are attached form a five-, six-, or seven-membered heterocyclic ring wherein the heterocyclic ring includes an additional heteroatom N(Y), wherein Y is H or C 1-6 alkyl.
• a specific value for R 3 includes -(CH 2 ) 2 -NR 8 R 9 , wherein R 8 and R 9 is independently H, C 1-4 alky, or R 8 and R 9 taken together with the nitrogen to which they are attached form piperazinyl, wherein one of the nitrogen atoms on the piperazinyl ring is substituted with H or C 1-4 alkyl.
• a specific value for R 3 includes -(CH 2 ) 2 -NR 8 R 9 , wherein R 8 and R 9 is independently H, methyl, ethyl, ethanol, or R 8 and R taken together with the nitrogen to which they are attached form 4-methyl-l -piperazinyl.
• R 4 is phenyl.
• examples of the present invention include:
• optically active forms for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation (using a chiral stationary phase, for example) and to determine 5-HT 6 activity using the standard tests described herein, or using other similar tests which are well known in the art.
• Nitrophenol 1 can be alkylated with an alpha halo ketone 2 using a base such as sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium hydride, and sodium hydroxide in solvents such as DMF, THF, acetone, dichloromethane, or acetonitrile to give nitro ether 3.
• a base such as sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium hydride, and sodium hydroxide in solvents such as DMF, THF, acetone, dichloromethane, or acetonitrile
• solvents such as DMF, THF, acetone, dichloromethane, or acetonitrile
• oxazine imine 5 which upon further treatment with reducing agents such as hydrogen and palladium on carbon or sodium borohydride in solvents such as ethanol, methanol, and water gives benzoxazine 6.
• reducing agents such as hydrogen and palladium on carbon or sodium borohydride in solvents such as ethanol, methanol, and water gives benzoxazine 6.
• oxazine imine 5 is prepared from amino phenol 4 and alpha halo ketone 2 in the presence of a phase transfer catalyst and dichloromethane and aqueous potassium carbonate (see Sabitha and Rao, Synthetic Communications 1987, 17, 341).
• Benzoxazine 6 contains a chiral center.
• the individual enantiomers may be obtained by several methods. One method is chromatography on a chiral stationary phase to give the individual enantiomers (see Chiral Separations by Liquid Chromatography, Ahuja, S., ed., American Chemical Society, Washington, D.C.:
• benzoxazine 6 is stirred in an acidic solvent such as TFA, acetic acid, or aq. sulfuric acid.
• a nitrite such as sodium nitrite, isoamylnitrite, t-butylnitrite, or n- butylnitrite is added to give N-nitrosoamine 7.
• N-nitrosoamine 7 is reduced with lithium aluminum hydride in ether or THF to give the hydrazine 8, which can be reacted with cyclohexane-1 ,3-dione under Fischer indole conditions to give the oxotetrahydrooxazinocarbazole 9 (see Sundberg, R.J.; Indoles, Academic Press: London; 1996, and in Hughes, D.L. Progress in the Fischer Indole Reaction: A Review. Org. Prep. Proceed. Int. 1993, 25, 609-632).
• phenol 12 can be prepared from structure 9 in a single step using Raney nickel in solvents such as cumene, mesitylene, 1,2,3-trimethylbenzene, 1,2,4- trimethylbenzene, decalin, and diphenyl ether at temperatures between 130-270°C to give phenol 12 directly.
• a second method is heating 9 in 2-(ethoxyefhoxy)ethanol at about 160-210°C in the presence of Pd on carbon or Darco, or a mixture thereof (see European patent EP839806).
• structure 9 is first treated with a copper (U) halide, preferably CuCl 2 or CuBr 2 , in either their anhydrous or hydrated form, in solvents such as ethylene glycol, ethylene glycol/doixane, ethylene glycol/THF, DMF, acetonitrile, ethyl acetate, chloroform, acetic acid, or acetic acid/water at temperatures between 40°C and 120°C to give halo ketones 10 and 11.
• a copper (U) halide preferably CuCl 2 or CuBr 2
• Halo ketones 10 and 11 may be separated by chromatography on silica gel and carried on to 12 and 13, or they may be carried forward as a mixture in the next step and separated in at that time.
• halo ketones 10 and 11 are then treated with lithium chloride or lithium bromide (anhydrous LiCl or LiBr are preferred, but hydrated forms also may be used) in the presence of lithium carbonate, or with potassium carbonate with or without added lithum halide salts in a solvent such as DMF at 100-270 °C to give phenols 12 and 13.
• 9 may be alkylated using an alkylating agent such as methyl iodide in the presence of a base such as NaH, KO-t-Bu, or LDA in solvents such as THF at temperature ranging from about -78°C to room temperature to give 10, which may be converted to 12 using the methods described for the direct conversion of 9 to 12.
• Phenols 12 and 13 may be alkylated with various alkylating agents to give oxazino amines 16, 17, 19, 20, and 24 directly or after several steps. Which method is used will depend on the type of amine which is desired and on the availability of alkylating agents and amines. As shown in Scheme B phenols 12 and 13 are alkylated with dialkylaminoalkylchlorides in the presence of bases such as sodium hydride, potassium carbonate, cesium carbonate, or sodium carbonate in solvents such as DMF, acetonitrile, or acetone at room temperature to 120°C using methods well- known to those versed in the art to give oxazine amines 16 and 17.
• bases such as sodium hydride, potassium carbonate, cesium carbonate, or sodium carbonate in solvents such as DMF, acetonitrile, or acetone at room temperature to 120°C using methods well- known to those versed in the art to give oxazine amines 16 and 17.
• phenols 12 and 13 are alkylated with chloro or bromoalkylnitrile in the presence of bases such as sodium hydride, potassium carbonate, cesium carbonate, or sodium carbonate in solvents such as DMF, acetonitrile, or acetone to give nitriles 14 and 15.
• bases such as sodium hydride, potassium carbonate, cesium carbonate, or sodium carbonate in solvents such as DMF, acetonitrile, or acetone
• solvents such as DMF, acetonitrile, or acetone
• Scheme C discloses further functionalization of oxazino amine 16 (or 17) by several methods:
• acylation with acylation agents such as ethyl formate, acetic anhydride, and the like to give acyl oxazinocarbazole 18.
• the carbonyl group of acyl oxazinocarbazole 18 is reduced to an alkyl group using reagents such as borane in THF or borane-methyl sulfide complex in THF at room temperature to 80°C to give alkylamino oxazinocarbazole 19.
• Another method is reduction using lithium aluminum hydride in ethereal solvents to effect the reduction of 18 to alkylamino oxazinocarbazole 19.
• Another method for the preparation of oxazinocarbazole 19 is reductive animation of 16 with an equivalent amount of an aldehyde or ketone in the presence of reducing agents such as sodium cyanoborohydride or sodium triacetoxyborohydride in solvents such as dichloromethane, dichloroethane, and THF at 0 to 80°C, or Pd/C under a hydrogen atmosphere in solvents such as methanol, ethanol, or ethyl acetate, to give 19.
• reducing agents such as sodium cyanoborohydride or sodium triacetoxyborohydride
• solvents such as dichloromethane, dichloroethane, and THF at 0 to 80°C, or Pd/C under a hydrogen atmosphere in solvents such as methanol, ethanol, or ethyl acetate, to give 19.
• a third method is alkylation of oxazino amine 16 with alkyl halides or mesylates or tosylates in the presence of base in solvents such as THF, acetonitrile, dichloromethane, DMF and the like using methods well known to those versed in the art, to give 19.
• Q is hydrogen, alkyl, or aryl.
• Z is hydrogen or alkyl.
• X is halo or sulfonate.
• dialkylamino oxazinocarbazole 20 is desired, a second equivalent of the same or a different aldehyde or alkylating agent is added to alkylamino oxazinocarbazole 19 using the conditions described above. Alternatively, excess alkylating agent or aldehyde or ketone may be used starting with 16 to give 20 directly.
• Scheme D describes two other methods of preparing mono or dialkylamino oxazines 24:
• Phenol 12 (or 13) is alkylated with halo alkyl halides in the presence of bases such as potassium carbonate, cesium carbonate, and NaH in solvents such as DMF, acetonitrile, THF, dichloromethane, and acetone at room temperature to 120°C to give oxazine halide 21.
• Halo oxazine 21 is then treated with an amine in the presence of a base such as potassium carbonate, TEA, DIEA in solvents such as DMF, acetonitrile, THF, dichloromethane, or acetone at room temperature to 120°C to give amino oxazine 24.
• Another route to amino oxazine 24 is by way of alkylation of phenol 12 with hydroxyalkyl halide to give oxazine alcohol 22.
• the alcohol group is converted to a leaving group with methane sulfonyl halide or toluene sulfonyl halide to give oxazine sulfonate 23.
• the O-sulfonate group is then displaced by amines to give amino oxazine 24.
• the invention also includes isotopically-labeled compounds, which are identical to those recited in Formula I, where one or more atoms is replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
• isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, iodine, and chlorine, such as 3 H, U C, 14 C, 13 N, 15 0, 18 F, 99 Tc, 123 I, and 125 I.
• Isotopically- labeled compounds can be prepared as follows. Carbon, nitrogen, oxygen, and fluorine atoms in a molecule may be replaced by isotopic versions of carbon, nitrogen, oxygen, and fluorine, respectively. Of particular usefulness are reagents containing isotopic carbon.
• the primary amine of Example 2 may be alkylated with n CH 3 I to give [ ⁇ C]Example 8A.
• ⁇ CH 3 I is in turn obtained from ⁇ CH 3 OH which is produced in a radioisoptope facility due to its short half -life by methods well known to those versed in the radioisotope art.
• (R)-(-)-[(l -phenyl- 1,2- dihydro[l,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]ethanamine (Example 2) may be alkylated by this method to give N-[ ⁇ C]methyl-N-(2- ⁇ [(lR)-l-phenyl-l,2- dihydro[l,4]oxazino[2,3,4-jk]carbazol-7-yl]oxy ⁇ ethyl)amine (Example 8A).
• Carbon- 13 labelled compounds are useful as well. They may be prepared, for example, by alkylation of a primary amine with 13 CH 3 I using methods well known to those versed in the art. Another method of preparing 13 C-labelled compounds is by formylation or acylation of amines using commercially available ethyl [ Cjformate or ethyl [ 13 C]acetate, respectively, to give amides, which are subsequently reduced as discussed elsewhere in this document to give amines. This is illustrated using ethyl formate and ethyl acetate by the conversion of Example 2 to Example 8A and the conversion of Example 4 to Example 6.
• Isotopically-labeled compounds of the present invention are useful in drug and/or substrate tissue distribution and target occupancy assays.
• isotopically labeled compounds are particularly useful in SPECT (single photon emission computed tomography) and in PET (positron emission tomography).
• Single-photon emission computed tomography acquires information on the concentration of isotopically labeled compounds introduced to a mammal's body.
• SPECT dates from the early 1960's, when the idea of emission traverse section tomography was introduced by D.E. Kuhl and R.Q. Edwards prior to either PET, x-ray CT, or MRI.
• SPECT requires isotopes that decay by electron capture and/or gamma emission.
• Example of viable SPECT isotopes include, but are not limited to, 123-iodine ( 123 I) and 99m-technetium ( 99m Tc).
• the nuclear decay resulting in the emission of a single gamma ray which passes through the tissue and is measured externally with a SPECT camera.
• the uptake of radioactivity reconstructed by computers as a tomogram shows tissue distribution in cross-sectional images.
• PET Positron emission tomography
• Synesizing a compound to include a positron-emitting isotope is a technique for measuring the concentrations of positron-emitting isotopes within the tissues. Like SPECT, these measurements are, typically, made using PET cameras outside of the living subjects. PET can be broken down into several steps including, but not limited to, synthesizing a compound to include a positron-emitting isotope; administering the isotopically labeled compound to a mammal; and imaging the distribution of the positron activity as a function of time by emission tomography. PET is described, for example, by Alavi et al. in Positron Emission Tomography, published by Alan R. Liss, Inc. in 1985.
• Positron-emitting isotopes used in PET include, but are not limited to, Carbon- 11, Nitrogen-13, Oxygen-15, and Fluorine-18.
• positron-emitting isotopes should have short half-lives to help minimize the long term radiation exposure that a patient receives from high dosages required during PET imaging.
• PET imaging can be used to measure the binding kinetics of compounds of this invention with 5-HT 6 serotonin receptors.
• administering an isotopically labeled compound of the invention that penetrates into the body and binds to a 5-HT 6 serotonin receptor creates a baseline PET signal which can be monitored while administering a second, different, non-isotopically labeled compound.
• the baseline PET signal will decrease as the non-isotopically labeled compound competes for the binding to the 5-HT 6 serotonin receptor.
• compounds of formula I that are useful in performing PET or SPECT are those which penetrate the blood-brain barrier, exhibit high selectivity and modest affinity to 5-HT 6 serotonin receptors, and are eventually metabolized.
• SPECT include N-methyl-2-[(l-phenyl-l,2-dihydro[l,4]oxazino[2,3,4-jk]carbazol-7- yl)oxy]- 1 -ethanamine, 2- [( 1 -phenyl- 1 ,2-dihydro [ 1 ,4] oxazino [2,3 ,4-jk]carbazol-7- yl)oxy]ethanamine, N-ethyl-2-[(l-phenyl-l,2-dihydro[l,4]oxazino[2,3,4-jk]carbazol- 7-yl)oxy]ethanamine, 2-[(8-chloro-l-phenyl-l,2-dihydro[l,4]oxazino[2,3,4- jk]carbazol-7-yl)oxyjethanamine, 7-[2-(4-methylpiperazin-l-yl)ethoxyj-l-phenyl-
• nuclear magnetic resonance spectroscopy (MRS) imaging can be used to detect the overall concentration of a compound or fragment thereof containing nuclei with a specific spin.
• MRS imaging include, but are not limited to, hydrogen-1, carbon-13, phosphorus-31, and fluorine- 19.
• Examples of compounds useful for MRS include N-methyl-2-[(l-phenyl- l,2-dihydro[l,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]-l-ethanamine, 2- [(1 -phenyl- 1,2- dihydro [1,4] oxazino [2, 3 ,4-jk] carbazol-7-yl)oxy] ethanamine, N-ethyl-2- [( 1 -phenyl- 1 ,2-dihydro[ 1 ,4] oxazino [2,3 ,4-jk]carbazol-7-yl)oxy]ethanamine, 2- [(8-chloro- 1 - phenyl-l,2-dihydro[l,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]ethanamine, 7-[2-(4- methylpiperazin- 1 -yl)ethoxy]
• substitution with heavier isotopes such as deuterium, i.e., H can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half -life or reduced dosage requirements and, hence, maybe preferred in some circumstances.
• Isotopically labeled compounds of Formula I of this invention can generally be prepared by carrying out the synthetic procedures described above by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
• Isotopically labeled reagents are described, for example, by Langstrom in Acta Chem. Scand. S37: 147 (1990).
• the isotopically label is part of the R 3 substitutent of formula I and involves an alkylation of the phenols 12 and 13 described above or alkylation of the oxazino amines 16 and 17 described above.
• an oxazino amine can be alkylated with ⁇ CH I to form a N-methyl oxazino amine, e.g., R 8 or R 9 in formula I is ⁇ CH 3 .
• Other synthetic routes for incorporating an isotopic label can include nucleophilic fluoronation. See for example Skaddan et al., Nucl. Med. Biol. 28, 753 (2001); Hwang et al., J. Nucl. Med. 32, 1730 (1991); and McCarthy et al., J. Nucl. Med. 2002.
• compositions may be obtained using standard procedures well known in the art, for example by mixing a compound of the present invention with a suitable acid.
• Compounds of the present invention may be administered in a pharmaceutical composition containing the compound in combination with a suitable vehicle.
• Such pharmaceutical compositions can be prepared by methods and contain excipients which are well known in the art. A generally recognized compendium of such methods and ingredients is Remington's Pharmaceutical Sciences by E.W. Martin (Mark Publ. Co., 15th Ed., 1975).
• the compounds and compositions of the present invention are administered parenterally (for example, by intravenous, intraperitoneal or intramuscular injection).
• the compounds or compositions may be administered by infusion or injection. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant.
• Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils.
• Pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage.
• the liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof.
• a polyol for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like
• vegetable oils nontoxic glyceryl esters, and suitable mixtures thereof.
• isotonic agents for example, sugars, buffers or sodium chloride.
• Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization.
• Useful liquid carriers include water, alcohols or glycols or water- alcohol/glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants.
• a mammal is injected with a radioactively labeled agent at tracer doses.
• Tracer doses are doses sufficient to allow the receptor occupancy to be measured (e.g., to allow detection of the labeled compound) but are not sufficient to have a therapeutic effect on the mammal.
• Tracer dosage is between approximately 1/100 to 1/10 of the therapeutic dose.
• Useful dosages for unlabeled compounds of formula I can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949.
• the therapeutic dosage range for the compound is from about 0.05 mg to about 500 mg, or any range therein, of active ingredient per unit dosage form (e.g., per kg of mammal body weight).
• the compound of formula I (radiolabeled) is generally administered once daily and is generally administered intravenously.
• the radiolabled compounds are presented in aqueous solution in a concentration of from about 0.1 to about 10%, more preferably about 0.1 to about 7%.
• the solution may contain other ingredients, such as emulsifiers, antioxidants or buffers.
• the exact regimen for administration of the compounds and compositions disclosed herein will necessarily be dependent upon the needs of the individual subject being diagnosed, of course, the judgment of the attending practitioner.
• compounds of the invention are 5-HT ligands.
• the ability of a compound of the invention to bind or act at a 5-HT receptor, or to bind or act selectively at a specific 5-HT receptor subtype can be determined using in vitro and in vivo assays that are known in the art.
• the term "bind selectively” means a compound binds at least 2 times, preferably at least 10 times, and more preferably at least 50 times more readily to a given 5-HT subtype than to one or more other subtypes.
• Preferred compounds of the invention bind selectively to one or more 5-HT receptor subtypes.
• the ability of a compound of the invention to act as a 5-HT receptor agonist or antagonist can also be determined using in vitro and in vivo assays that are known in the art.
• the invention provides isotopically labeled compounds of formula I that act as either agonists or as antagonists of one or more 5-HT receptor subtypes.
• the layers are separated and the aqueous extracted with 25 ml of dichloromethane.
• the organic extracts are combined and washed twice with 25 ml of saturated aqueous sodium bicarbonate, and once each with 25 ml of 1 N HCI, 25 ml of saturated sodium chloride, and 25 ml of water.
• the washed organic solution is dried over anhydrous sodium sulfate, filtered and then concentrated to an oil by vacuum distillation.
• the oil is reconstituted with 25 ml of methyl t-butyl ether and 4.8 ml of methanol.
• Chiral HPLC is performed using a Chiralcel OD 250x 4.6mm column eluted at 0.5 ml/min. with a solvent mixture consisting of 25% vol. isopropanol, 75% vol. n- heptane and 0.1% vol. diethylamine.
• the ratio of enantiomers for the isolated PNU-280715A was determined to be 99.5: 0.5, giving an enantiomeric excess of 99% for the product.
• the mixture is stirred for 1 h and transferred to a separatory funnel to which is slowly added potassium carbonate (2.6 g, 18.8 mmol) in water (200 mL). Solids formed in the ether layer. The layers are separated and ethyl ether (100 mL) is added to dissolve the solids. The ether layer is washed twice with water (200 mL), dried over magnesium sulfate, filtered and concentrated. The resulting oil is chilled in the refrigerator overnight. The solids formed from the oil are ground-up in hexanes and collected by filtration to give 15.7 g (81%) of 4-nitroso-3- phenyl-3 ,4-dihydro-2H- 1 ,4-benzoxazine.
• the mixture is then stirred at 130-140 °C with lithium carbonate (0.106 g, 1.44 mmol), lithium chloride (0.061 g, 1.44 mmol), and DMF (3 mL). After cooling, the mixture is partitioned between dichloromethane and sat'd aq. ammonium chloride.
• bromoacetonitrile 0.074 mL
• potassium carbonate 0.074 g
• Bromoacetonitrile and potassium carbonate 0.074 mL and 0.074 g, respectively
• the mixture is heated at that temperature for 5.5 h and then allowed to cool and stir overnight, after which the mixture is partitioned between ethyl acetate, aq. ammonium chloride, and brine.
• the mixture is then poured into water (600 mL), forming solids.
• the solids are dissolved in ethyl acetate (50 mL) and filtered to remove inorganic solids.
• the filtrates are concentrated to dryness and the resulting solids are dissolved in DMF (60 mL), to which is added lithium bromide (12.4 g, 143 mmol) and lithium carbonate (10.6 g, 143 mmol).
• the mixture is heated at 120 °C for 6 h, cooled, then partitioned between water and CH 2 CI 2 , and the organic layer washed three times with water (200 mL).
• Isomer 1 R f (EtOAc/CH 2 Cl 2 /hexane (5:45:50): 0.33; MS (ESI+) m/z 338 (M+H) + ; 1H NMR (CDC1 3 ) ⁇ 2.44, 3.00, 4.50-4.63, 5.42, 6.82, 7.04, 7.21, 7.37, 7.78.
• Isomer 2 R f (EtOAc/CH 2 Cl 2 /hexane (5:45:50): 0.21; MS (ESI+) m/z 338 (M+H) + ; 1H NMR (CDC1 3 ) ⁇ 2.30-2.75, 4.45-4.60, 5.40, 6.82, 7.13, 7.21, 7.41, 7.77.
• PREPARATION 13 1 -Phenyl- 1 ,2-dihydro [ 1 ,4] oxazino [2,3 ,4-jk]carbazol-7-ol
• Method A A mixture of 8-chloro-l-phenyl-l,2,9,10-tetrahydro[l,4]oxazino[2,3,4- jk]carbazol-7(8H)-one (0.235 g, 0.697 mmol), anhydrous LiCl (0.0355 g, 0.837 mmol), Li 2 CO 3 (0.0618 g, 0.837 mmol), and DMF (1.8 mL) is stirred at 140 °C for 3.5 h.
• Method B To l-phenyl-l,2,9,10-tetrahydro[l,4]oxazino[2,3,4-jk]carbazol-7(8H)- one (4.0 g, 13.19 mmol) in ethyl acetate/ acetonitrile (30 mL/15 mL) is added trifluoroacetic acid (2 mL) and anhydrous cupric chloride (3.56 g, 26.4 mmol). The mixture is heated to reflux at 80 °C for 1.5 h. The mixture is concentrated. The residue is dissolved in ethyl acetate (50 mL) and filtered to remove inorganic solids.
• Method C Water is decanted from wet Raney nickel (2.5 g) and toluene is added and additional water is azeotroped off under vacuum. Toluene and decalin (4 mL) are added to the damp Raney nickel and toluene is again azeotroped off. 1-Phenyl- l,2,9,10-tetrahydro[l,4]oxazino[2,3,4-jk]carbazol-7(8H)-one (0.180 g, 0.593 mmol) is added and the mixture is heated at 180°C (additional toluene/water azeotroping occurs). After 3 h, the mixture is cooled.
• Method D A mixture of l-phenyl-l,2,9,10-tetrahydro[l,4]oxazino[2,3,4-jk]carbazol- 7(8H)-one (0.0586 g, 0.193 mmol) and 10% Pd/C (0.058 g) in 2- (ethoxyethoxy)ethanol (1 mL) is heated at 190-200 °C for 4 h and then cooled and partitioned between dichloromethane and water.
• diethylaminoethyl chloride hydrochloride (0.033 g, 0.191 mmol) in aliquots over 1 h. After 5.5 h, an additional 0.011 g of diethylaminoethyl chloride hydrochloride is added, and one hour later, a few crystals of sodium iodide are added. After heating for ten hours, the mixture is allowed to stir at room temperature for the remainder of the night.
• the maleic acid salt is prepared using maleic acid and crystallized from EtOH to give N,N-diethyl-2-[( 1 -phenyl- 1 ,2-dihydro [ 1 ,4]oxazino [2,3 ,4-jk]carbazol-7- yl)oxy]-l -ethanamine, maleic acid salt, mp 105-107 °C. Anal. Calcd for
• Acetone (12 mL) and 0.5 N HCI (6 mL) are added and the to the residue and the mixture is stirred at 65-70 °C for 15 min. Acetone is removed in vacuo and the residue is partitioned between dichloromethane and aq. sodium bicarbonate.
• the maleic acid salt is prepared using maleic acid (0.0204 g maleic acid, crystallization from dichloromethane/methanol/hexane) to give N- ⁇ 2-[(l-phenyl-l,2- dihydro[l,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]ethyl ⁇ -2-propanamine, maleic acid salt.
• maleic acid 0.0204 g maleic acid, crystallization from dichloromethane/methanol/hexane
• a slurry of lithium aluminum hydride (6.9 g, 183 mmol) in ethyl ether (300 mL) is stirred in an ice bath under an argon atmosphere.
• a solution of 7-methyl-4- nitroso-3-phenyl-3,4-dihydro-2H-l,4-benzoxazine (23.22 g, 91.3 mmol) in ethyl ether (250 mL) and dry THF (40 mL) is added dropwise over 1.5 h. The mixture is removed from the ice bath and allowed to stir for 18 h. Water (50 mL) is slowly added, forming solids. The solids are collected by filtration and washed with ethyl ether.
• HCI is added and the mixture is heated at 65 °C for 1 h.
• the mixture is removed from heat, neutralized with aqueous potassium carbonate and then partitioned between water and CH 2 C1 2 .
• the organic layer is washed with water, dried over magnesium sulfate, and concentrated.
• PREPARATION 27 4-Chlorobutyl l-phenyl-l,2-dihydro[l,4]oxazino[2,3,4- jk]carbazol-7-yl ether
• l-phenyl-l,2-dihydro[l,4]oxazino[2,3,4-jk]carbazol-7-ol 0.5 g, 1.66 mmol
• potassium carbonate 1.15 g, 8.3 mmol
• l-bromo-4-chlorobutane 1.4 g, 8.3 mmol
• PREPARATION 28 3-Chloro ⁇ ropyl l-phenyl-l,2-dihydro[l,4]oxazino[2,3,4- jk]carbazol-7-yl ether
• l-phenyl-l,2-dihydro[l,4]oxazino[2,3,4-jk]carbazol-7-ol (0.82 g, 2.7 mmol) in dry DMF (12 mL) is added l-bromo-3-chloropropane (1.28 g, 8.1 mmol) and potassium carbonate (1.12 g, 8.1 mmol).
• the mixture is heated at 80 °C for 6 h.
• Hela cells containing the cloned human 5-HT 6 receptor were acquired from Dr. David R. Sibley's laboratory in National Institute of Health (see Sibley, D.R., Neurochemistry. 66, 47-56, 1996). Cells were grown in high glucose Dulbecco's modified Eagle's medium, supplemented with L-glutamine, 0.5% sodium pyruvate, 0.3% penicillin-streptomycin, 0.025% G-418 and 5% Gibco fetal bovine serum and then were harvested, when confluent, in cold phosphate buffered saline.
• the combined supernatant (200ml) was centrifuged at 23,000 RPM (80,000 X g) for 1 hour in a Beck an Rotor (42.1 Ti).
• the membrane pellet was resupended in 50-8- ml of assay buffer containing HEPES 20 mM, MgC12 10 mM, ⁇ aCl 150 mM, EDTA lmM, pH 7.4 and stored frozen in aliqouts at -70°C.
• the radioligand binding assay used [ H] -lysergic acid diethylamide (LSD).
• the assay was carried out in Wallac 96-well sample plates by the addition of 11 ⁇ l of the test sample at the appropriate dilution (the assay employed 11 serial concentrations of samples run in duplicate), 11 ⁇ l of radioligand, and 178 ⁇ l of a washed mixture of WGA-coated SPA beads and membranes in binding buffer. The plates were shaken for about 5 minutes and then incubated at room temperature for 1 hour. The plates were then loaded into counting cassettes and counted in a Wallac MicroBeta Trilux scintillation counter. Binding Constant (Ki) Determination
• Pharmacokinetics of the compounds of formula I can be evaluated in mice to determine the ability of each compound to penetrate the blood-brain barrier. Each mouse receives a single intravenous administration at 5 mg/kg. Blood samples are collected by serial sacrifice at 5 min (IN only), 0.5, 1, 2, 4, and 8 h after dosing with two mice per collection time. Blood was placed into tubes containing heparin and centrifuged for plasma. Brain samples were also collected at 0.5 and 1 h increments from the same mouse used for blood collection. Plasma and brain samples were analyzed for drug concentrations using a LC-MS/MMS method.

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