EP1409452A1 - Sulfamidderivate - Google Patents

Sulfamidderivate

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Publication number
EP1409452A1
EP1409452A1 EP02729195A EP02729195A EP1409452A1 EP 1409452 A1 EP1409452 A1 EP 1409452A1 EP 02729195 A EP02729195 A EP 02729195A EP 02729195 A EP02729195 A EP 02729195A EP 1409452 A1 EP1409452 A1 EP 1409452A1
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EP
European Patent Office
Prior art keywords
alkyl
mmol
compound according
compound
scheme
Prior art date
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EP02729195A
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English (en)
French (fr)
Inventor
Joshua Zwick Davison
Eric George Tromiczak
Hamideh Zarrinmayeh
Dennis Michael Zimmerman
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Eli Lilly and Co
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Eli Lilly and Co
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Publication of EP1409452A1 publication Critical patent/EP1409452A1/de
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/07Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/14Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16Anti-Parkinson drugs
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/18Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/24Antidepressants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/28Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/30Drugs for disorders of the nervous system for treating abuse or dependence
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/03Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C311/04Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms to acyclic carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/03Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C311/05Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms to acyclic carbon atoms of hydrocarbon radicals substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/46Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having at least one of the nitrogen atoms, not being part of nitro or nitroso groups, further bound to other hetero atoms
    • C07C323/49Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having at least one of the nitrogen atoms, not being part of nitro or nitroso groups, further bound to other hetero atoms to sulfur atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00Systems containing only non-condensed rings
    • C07C2601/06Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Definitions

  • the present invention relates to the potentiation of glutamate receptor function using certain sulfonamide derivatives. It also relates to novel 5 sulfonamide derivatives, to processes for their preparation and to pharmaceutical compositions containing them.
  • EAA receptors excitatory amino acid receptors
  • Excitatory amino acid receptors are classified into two general types. Receptors that are directly coupled to the opening of cation channels in the cell membrane of the neurons are termed "ionotropic". This type of receptor has been subdivided into at least three subtypes, which are defined by the 5 depolarizing actions of the selective agonists ⁇ /-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), and kainic acid (KA).
  • NMDA ⁇ /-methyl-D-aspartate
  • AMPA alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid
  • KA kainic acid
  • the second general type of receptor is the G-protein or second messenger-linked "metabotropic" excitatory amino acid receptor.
  • This second type is coupled to multiple second messenger systems that lead to enhanced o phosphoinositide hydrolysis, activation of phospholipase D, increases or decreases in c-AMP formation, and changes in ion channel function.
  • Schoepp and Conn Trends in Pharmacol. Sci., 14, 13 (1993). Both types of receptors appear not only to mediate normal synaptic transmission along excitatory pathways, but also participate in the modification of synaptic connections during development and throughout life. Schoepp, Bockaert, and Sladeczek, Trends in Pharmacol. Sci., 11 , 508 (1990); McDonald and Johnson, Brain Research Reviews, 15, 41 (1990).
  • AMPA receptors are assembled from four protein sub-units known as GluR1 to GluR4, while kainic acid receptors are assembled from the sub-units GluR5 to GluR7, and KA-1 and KA-2. Wong and Mayer, Molecular Pharmacology 44: 505-510, 1993. It is not yet known how these sub-units are combined in the natural state. However, the structures of certain human variants of each sub-unit have been elucidated, and cell lines expressing individual sub- unit variants have been cloned and incorporated into test systems designed to identify compounds which bind to or interact with them, and hence which may modulate their function. Thus, European patent application, publication number EP-A2-0574257 discloses the human sub-unit variants GluR1 B, GluR2B,
  • AMPA and kainic acid receptors are their rapid deactivation and desensitization to glutamate. Yamada and Tang, The Journal of Neuroscience, September 1993, 13(9): 3904-3915 and Kathryn M. Partin, J. Neuroscience, November 1 , 1996, 16(21): 6634-6647. The physiological implications of rapid desensitization, and deactivation if any, are not fully understood.
  • AMPA receptor potentiators have been shown to improve memory in a variety of animal tests. Staubli et al., Proc. Natl. Acad. Sci., Vol. 91 , pp 777-781 , 1994, Neurobiology, and Arai et al., The Journal of Pharmacology and Experimental Therapeutics, 278: 627-638, 1996.
  • the present invention provides compounds of formula I:
  • A represents
  • X represents O, NR, or S:
  • R represents hydrogen, (1-6C)alkyl, or -(1-4C)alkylaromatic;
  • R 1 represents (1-6C)alkyl, (2-6C)alkenyl, halo(1-4C)a!kyl, or NR 9 R 10 ;
  • R 2 and R 3a each independently represent hydrogen, (1-4C)alkyl, F, or
  • R 3b represents hydrogen, (1-4C)alkyl, or -OR 12 ;
  • R 4a and R 4b each independently represent hydrogen, (1-4C) alkyl, (1-4C)alkoxy,
  • R 5 and R 6 each independently represent hydrogen, (1-4C)alkyl, F, or
  • R 7 represents hydrogen, (1-4C)alkyl or -(1-4C)alkylaromatic
  • R 8 represents (1-6C)alkyl,-(1-4C)alkylphenyl, halo(1-4C)alkyl, unsubstituted or substituted aromatic group, unsubstituted or substituted heteroaromatic group, cycloalkyl, alkylcycloalkyl or NR 9 R 10
  • n is zero or an integer 1 , 2, 3, 4, or 5
  • m is zero or an integer 1 , 2, 3, 4, or 5
  • p is an integer 1 or 2;
  • R 9 and R 10 each independently represent hydrogen or (1-4C)alkyl
  • R 11 represents hydrogen or (1-4C)alkyl
  • R 2 represents (1-4C)alkyl
  • R 3 represents phenyl or (1-6C)alkyl
  • R 14 represents (1 -6C)alkyl
  • R 15 represents (1-4C)alkyl
  • R 16 represents (1-4C)alkyl or -(1-4C)alkylphenyl; or a pharmaceutically acceptable salt thereof, with the proviso that when W is
  • the present invention further provides a method of potentiating glutamate receptor function in a patient, which comprises administering to said patient an effective amount of a compound of formula I.
  • the present invention provides a method of treating cognitive disorders in a patient, which comprises administering to said patient an effective amount of a compound of formula I.
  • the present invention provides a method of treating depression in a patient, which comprises administering to said patient an effective amount of a compound of formula I.
  • the present invention provides a method of treating Alzheimer's disease in a patient, which comprises administering to said patient an effective amount of a compound of formula I.
  • the present invention further provides a method of treating psychosis or cognitive deficits associated with psychosis in a patient, which comprises administering to said patient an effective amount of a compound of formula I.
  • the present invention provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for potentiating glutamate receptor function.
  • the present invention provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof for potentiating glutamate receptor function.
  • the invention further provides pharmaceutical compositions comprising, a compound of formula I and a pharmaceutically acceptable diluent or carrier.
  • This invention also encompasses novel intermediates and processes for the synthesis of the compounds of formula I.
  • the present invention includes compounds of the formula:
  • X represents O, NR, or S:
  • R represents hydrogen, (1-6C)alkyl, or -(1-4C)alkylaromatic
  • R 1 represents (1-6C)alkyl, (2-6C)alkenyl, halo(1-4C)alkyl, or NR 9 R 10 ;
  • R 2 and R 3a each independently represent hydrogen, (1-4C)alkyl, F, or -OR 11 ;
  • R 3b represents hydrogen, (1-4C)alkyl, or -OR 12 ;
  • R 4a and R 4 each independently represent hydrogen, (1-4C) alkyl, (1-4C)alkoxy, I,
  • R 5 and R 6 each independently represent hydrogen, (1-4C)alkyl, F, or -OR 11 ;
  • R 7 represents hydrogen
  • R 8 represents (1-6C)alkyl; n is zero or an integer 1 , 2, 3, 4, or 5; m is zero or an integer 1 , 2, 3, 4, or 5; p is an integer 1 or 2;
  • R 9 and R 10 each independently represent hydrogen or (1-4C)aIkyl
  • R 1 represents hydrogen or (1-4C)alkyl
  • R 12 represents (1-4C)alkyl; or a pharmaceutically acceptable salt thereof. Included within the scope of the present invention are compounds of the formula X:
  • X represents O, NR, or S:
  • R represents hydrogen, (1-6C)alkyl, or -(1-4C)alkylaromatic
  • R 1 represents (1-6C)alkyl, (2-6C)alkenyl, halo(1-4C)aikyl, or NR 9 R 10 ;
  • R 2 and R 3a each independently represent hydrogen, (1-4C)alkyl, F, or
  • ,3b R represents hydrogen, (1-4C)alkyl, or -OR 12.
  • R 4a and R 4b each independently represent hydrogen, (1-4C) alkyl, (1-4C)alkoxy, I,
  • R 5 and R 6 each independently represent hydrogen, (1-4C)alkyl, F, or
  • R 7 represents hydrogen, (1-4C)alkyl or -(1-4C)alkylaromatic
  • R 8 represents (1-6C)alkyl,-(1-4C)alkylphenyl, halo(1-4C)alkyl, unsubstituted or substituted aromatic group, unsubstituted or substituted heteroaromatic group, cycloalkyl, alkylcycloalkyl, or NR 9 R 10 ; n is zero or an integer 1 , 2, 3, 4, or 5; m is zero or an integer 1 , 2, 3, 4, or 5; p is an integer 1 or 2;
  • R 9 and R 10 each independently represent hydrogen or (1-4C)alkyl
  • R ,11 represents hydrogen or (1-4C)alkyl;
  • R >12 represents (1-4C)alkyl;
  • R ,13 represents phenyl or (1-6C)alkyl
  • R )1 1 4 represents (1-6C)alkyl
  • R > 15 represents (1-4C)alkyl
  • R ⁇ 1'6 D represents (1-4C)alkyl or -(1-4C)alkylphenyl; or a pharmaceutically acceptable salt thereof, with the proviso that when W is
  • X represents O, NR, or S:
  • R represents hydrogen, (1-6C)alkyl, or -(1-4C)alkylaromatic;
  • R 1 represents (1 -6C)alkyl, (2-6C)alkenyl, halo(1 -4C)alkyl, or NR 9 R 10 ;
  • R 2 and R 3a each independently represent hydrogen, (1-4C)alkyl, F, or
  • R 3 represents hydrogen, (1-4C)alkyl, or -OR 12 ;
  • R 4a and R 4b each independently represent hydrogen, (1-4C) alkyl, (1-4C)alkoxy, I, Br, CI, or F;
  • R 5 and R 6 each independently represent hydrogen, (1-4C)alkyl, F, or
  • R 7 represents hydrogen, (1-4C)alkyl or -(1-4C)alkylaromatic
  • R 8 represents (1-6C)alkyl,-(1-4C)alkylphenyl, halo(1-4C)alkyl, unsubstituted or substituted aromatic group, unsubstituted or substituted heteroaromatic group, cycloalkyl, alkylcycloalkyl, or NR 9 R 10 ; n is zero or an integer 1 , 2, 3, 4, or 5; m is zero or an integer 1 , 2, 3, 4, or 5; p is an integer 1 or 2; R 9 and R 10 each independently represent hydrogen or (1-4C)alkyl;
  • R 11 represents hydrogen or (1-4C)alkyl
  • R 12 represents (1-4C)alkyl
  • R 13 represents phenyl or (1-6C)alkyl
  • R 14 represents (1-6C)alkyl
  • R 15 represents (1-4C)alkyl
  • R 16 represents (1-4C)alkyl or -(1-4C)alkylphenyl; or a pharmaceutically acceptable salt thereof, with the proviso that when W is
  • R represents hydrogen, (1-6C)alkyl, or -(1-4C)alkylaromatic
  • R 1 represents (1-6C)alkyl, (2-6C)alkenyl, halo(1-4C)alkyl, or NR 9 R 10 ;
  • R 2 and R 3a each independently represent hydrogen, (1-4C)alkyl, F, or -OR 11 ;
  • R 3b represents hydrogen, (1-4C)alkyl, or -OR 12 ;
  • R 4a and R 4b each independently represent hydrogen, (1-4C) alkyl, (1-4C)alkoxy, I,
  • R 5 and R 6 each independently represent hydrogen, (1-4C)alkyl, F, or R 7 represents hydrogen, (1-4C)alkyl or -(1-4C)alkylaromatic;
  • R 8 represents (1-6C)alkyl,-(1-4C)alkylphenyl, halo(1-4C)alkyl, unsubstituted or substituted aromatic group, unsubstituted or substituted heteroaromatic group, cycloalkyl, alkylcycloalkyl, or NR 9 R 10 ; n is zero or an integer 1 , 2, 3, 4, or 5; m is zero or an integer 1 , 2, 3, 4, or 5; p is an integer 1 or 2;
  • R 9 and R 10 each independently represent hydrogen or (1-4C)alkyl;
  • R 11 represents hydrogen or (1-4C)alkyl;
  • R 12 represents (1-4C)alkyl
  • R 3 represents phenyl or (1-6C)alkyl
  • R 14 represents (1-6C)alkyl
  • R 15 represents (1-4C)alkyl; and R 16 represents (1-4C)alkyl or -(1-4C)alkylphenyl; or a pharmaceutically acceptable salt thereof, with the proviso that when W is
  • glutamate receptor function refers to any increased responsiveness of glutamate receptors, for example AMPA receptors, to glutamate or an agonist, and includes but is not limited to inhibition of rapid desensitization or deactivation of AMPA receptors to glutamate.
  • a wide variety of conditions may be treated or prevented by compounds of formula I and their pharmaceutically acceptable salts through their action as potentiators of glutamate receptor function.
  • Such conditions include those associated with glutamate hypofunction, such as psychiatric and neurological disorders, for example cognitive disorders and neuro-degenerative disorders such as Alzheimer's disease; age-related dementias; age-induced memory impairment; cognitive deficits due to autism, Down's syndrome and other central nervous system disorders with childhood onset, cognitive deficits post electroconvulsive therapy, movement disorders such as tardive dyskinesia, Hungtington's chorea, myoclonus, dystonia, spasticity, and Parkinson's disease; reversal of drug-induced states (such as cocaine, amphetamines, alcohol- induced states); depression; attention deficit disorder; attention deficit hyperactivity disorder; psychosis; cognitive deficits associated with psychosis, drug-induced psychosis, obesity, stroke, and sexual dysfunction.
  • Compounds of formula I may also be useful for improving memory (both short term and long term) and learning ability.
  • the present invention provides the use of compounds of formula I for the treatment of each of these conditions.
  • the present invention includes the pharmaceutically acceptable salts of the compounds defined by formula I.
  • a compound of this invention can possess a sufficiently acidic group, a sufficiently basic group, or both functional groups, and accordingly react with any of a number of organic and inorganic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salt refers to salts of the compounds of the above formula which are substantially non-toxic to living organisms.
  • Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceutically acceptable mineral or organic acid or an organic or inorganic base. Such salts are known as acid addition and base addition salts.
  • Such salts include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science.
  • Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic, methanesulfonic acid, benzenesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like
  • organic acids such as p-toluenesulfonic, methanesulfonic acid, benzenesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and
  • salts examples include the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, bromide, iodide, acetate, propionate, decanoate, caprate, caprylate, acrylate, ascorbate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, propionate, phenylpropionate, salicylate, oxalate, malonate, succinate, suberate, sebacate, fumarate, malate, maleate, hydroxymaleate, mandelate, nicotinate, isonicotinate, cinnamate, hippurate, nitrate, phthalate, teraphthalate, butyne-1 ,4-dioate, butyne-1 ,
  • Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like.
  • bases useful in preparing the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like.
  • the potassium and sodium salt forms are particularly preferred. It should be recognized that the particular counterion forming a part of any salt of this invention is usually not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole.
  • the above salts may form hydrates or exist in a substantially anhydrous form.
  • stereoisomer refers to a compound made up of the same atoms bonded by the same bonds but having different three- dimensional structures which are not interchangeable. The three-dimensional structures are called configurations.
  • enantiomer refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another.
  • chiral center refers to a carbon atom to which four different groups are attached.
  • diastereomers refers to stereoisomers which are not enantiomers.
  • racemate two diastereomers which have a different configuration at only one chiral center are referred to herein as “epimers”.
  • racemate racemic mixture
  • racemic modification refer to a mixture of equal parts of enantiomers.
  • enantiomeric enrichment refers to the increase in the amount of one enantiomer as compared to the other.
  • a convenient method of expressing the enantiomeric enrichment achieved is the concept of enantiomeric excess, or "ee”, which is found using the following equation:
  • E 1 is the amount of the first enantiomer and E 2 is the amount of the second enantiomer.
  • the initial ratio of the two enantiomers is 50:50, such as is present in a racemic mixture, and an enantiomeric enrichment sufficient to produce a final ratio of 50:30 is achieved, the ee with respect to the first enantiomer is 25%.
  • the final ratio is 90:10, the ee with respect to the first enantiomer is 80%.
  • An ee of greater than 90% is preferred, an ee of greater than 95% is most preferred and an ee of greater than 99% is most especially preferred.
  • Enantiomeric enrichment is readily determined by one of ordinary skill in the art using standard techniques and procedures, such as gas or high performance liquid chromatography with a chiral column. Choice of the appropriate chiral column, eluent and conditions necessary to effect separation of the enantiomeric pair is well within the knowledge of one of ordinary skill in the art.
  • the specific stereoisomers and enantiomers of compounds of formula I can be prepared by one of ordinary skill in the art utilizing well known techniques and processes, such as those disclosed by J. Jacques, et al., "Enantiomers. Racemates. and Resolutions". John Wiley and Sons, Inc., 1981 , and E.L. Eliel and S.H. Wilen," Stereochemistry of Organic Compounds". (Wiley- Interscience 1994), and European Patent Application No. EP-A-838448, published April 29, 1998. Examples of resolutions include recrystallization techniques or chiral chromatography.
  • Some of the compounds of the present invention have one or more chiral centers and may exist in a variety of stereoisomeric configurations. As a consequence of these chiral centers, the compounds of the present invention occur as racemates, mixtures of enantiomers and as individual enantiomers, as well as diastereomers and mixtures of diastereomers. All such racemates, enantiomers, and diastereomers are within the scope of the present invention.
  • the terms "R” and "S” are used herein as commonly used in organic chemistry to denote specific configuration of a chiral center.
  • R rectus
  • S sinister
  • the priority of groups is based upon their atomic number (in order of decreasing atomic number). A partial list of priorities and a discussion of stereochemistry is contained in "Nomenclature of Organic Compounds: Principles and Practice", (J.H. Fletcher, et al., eds., 1974) at pages 103-120.
  • aromatic group means the same as aryl, and includes phenyl and a polycyclic aromatic carbocyclic ring such as 1- or 2- naphthyl, 1 ,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, and the like.
  • heteromatic group includes an aromatic 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen, and a bicyclic group consisting of a 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen fused with a benzene ring or another 5-6 membered ring containing one to four atoms selected from oxygen, sulfur and nitrogen.
  • heteroaromatic groups are thienyl, furyl, oxazolyl, isoxazolyl, oxadiazoyl, pyrazolyl, thiazolyl, thiadiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidyl, benzofuryl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, and quinolyl.
  • substituted as used in the term “substituted aromatic or heteroaromatic group” herein signifies that one or more (for example one or two) substituents may be present, said substituents being selected from atoms and groups which, when present in the compound of formula I, do not prevent the compound of formula I from functioning as a potentiator of glutamate receptor function.
  • substituents which may be present in a substituted aromatic or heteroaromatic group include halogen; nitro; cyano; (1-10C) alkyl; (2- 10C)alkenyl; (2-10C)alkynyl; (3-8C)cycloalkyl; halo(1-10C)alkyl; and (1- 6C)alkoxy.
  • (1-10C)alkyl includes (1-8C)alkyl, (1-6C)alkyl and (1-4C)alkyl. Particular values are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl.
  • (2-10C)alkenyl includes (3-10C)alkenyl, (2-8C)alkenyl, (2- 6C)alkenyl and (2-4C)alkenyl. Particular values are vinyl and prop-2-enyl.
  • (2-10C)alkynyl includes (3-10C)alkynyl, (2-8C)alkynyl, (2- 6C)alkynyl and (3-4C)alkynyl.
  • a particular value is prop-2-ynyl.
  • (3-8C)cycloalkyl, as such or in the term (3-8C)cycloalkyloxy includes monocyclic and polycyclic groups. Particular values are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and bicyclo[2.2.2]octane.
  • the term includes (3-6C)cycloalkyl: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • (5-8C)cycloalkyl includes cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • hydroxy(3-8C)cycloalkyl includes hydroxy-cyclopentyl, such as 3- hydroxycyclopentyl.
  • oxo(3-8C)cycloalkyl includes oxocyclopentyl, such as 3- oxocyclopentyl.
  • halogen include fluorine, chlorine, bromine and iodine unless otherwise specified.
  • halo(1-10C)alkyl includes halo(1-6C)alkyl, halo(1-4C)alkyl, fluoro(1-10C)alkyl, fluoro(1-6C)alkyl, fluoro(1-4C)alkyl, chloro(1-6C)alkyl and chloro(1-4C)alkyl, such as trifluoromethyl, 2,2,2-trifluoroethyl, and chloromethyl.
  • (1-10C)alkoxy includes (1-6C)alkoxy and (1-4C)alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy and isobutoxy;
  • cyano(2-10C)alkenyl includes 2-cyanoethenyl.
  • (2-4C)alkylene includes ethylene, propylene and butylene.
  • a preferred value is ethylene.
  • thienyl includes thien-2-yl and thien-3-yl.
  • furyl includes fur-2-yl and fur-3-yl.
  • oxazolyl includes oxazol-2-yl, oxazol-4-yl and oxazol-5-yl.
  • isoxazolyl includes isoxazol-3-yl, isoxazol-4-yl and isoxazol-5-yl.
  • oxadiazolyl includes [1 ,2,4]oxadiazol-3-yl and [1,2,4]oxadiazol-5- yi-
  • pyrazolyl includes pyrazol-3-yl, pyrazol-4-yl and pyrazol-5-yl.
  • thiazolyl includes thiazol-2-yl, thiazol-4-yl and thiazol-5-yl.
  • thiadiazolyl includes [1 ,2,4]thiadiazol-3-yl, and [1 ,2,4]thiadiazol-
  • isothiazolyl includes isothiazol-3-yl, isothiazol-4-yl and isothiazol- 5-yl.
  • imidazolyl includes imidazol-2-yl, imidazolyl-4-yl and imidazolyl-
  • triazolyl includes [1 ,2,4]triazol-3-yl and [1 ,2,4]triazol-5-yl.
  • tetrazolyl includes tetrazol-5-yl.
  • pyridyl includes pyrid-2-yl, pyrid-3-yl and pyrid-4-yl.
  • pyridazinyl includes pyridazin-3-yl, pyridazin-4-yl, pyridazin-5-yl and pyridazin-6-yl.
  • pyrimidyl includes pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl and pyrimidin-6-yl.
  • benzofuryl includes benzofur-2-yl and benzofur-3-yl.
  • benzothienyl includes benzothien-2-yl and benzothien-3-yl.
  • benzimidazolyl includes benzimidazol-2-yl.
  • benzoxazolyl includes benzoxazol-2-yl.
  • benzothiazolyl includes benzothiazol-2-yl.
  • indolyl includes indol-2-yl and indol-3-yl.
  • quinolyl includes quinol-2-yl.
  • dihydrothiazolyl includes 4,5-dihydrothiazol-2-yl
  • (1- 4C)alkoxycarbonyldihydrothiazolyl includes 4-methoxycarbonyl-4,5- dihydrothiazol-2-yl.
  • -(1-4C)alkyl(3-8C)cycloalkyl includes the following:
  • -(1-4C)alkylaromatic includes the following:
  • -(1-4C)alkylaromatic is -(1-4C)alkylphenyl.
  • R 1 is preferably (1-6C)alkyI, with methyl, ethyl, propyl, 2-propyl, and butyl being most preferred, and 2-propyl being most especially preferred. Examples of particular values for y are 0 and 1.
  • the compounds of the present invention can be prepared by one of ordinary skill in the art following art recognized techniques and procedures such as those that can be found, for example, in International Patent Application Publications: WO 98/33496 published August 6, 1998; WO 99/43285 published September 2, 1999; WO 00/06539; WO 00/06537, WO 00/06176, WO 00/06159, WO 00/06158, WO 00/06157, WO 00/06156, WO 00/06149, WO 00/06148, and WO 00/06083, all published February 10, 2000; and WO 00/66546 published November 9, 2000. More specifically, compounds of formula la and lb can be prepared as set forth in Scheme I. The rea
  • step A the compound of structure (1 ) is alkylated under standard conditions to provide the compound of structure (2).
  • compound (1) is dissolved in a suitable organic solvent, such as THF, cooled to about -78°C and treated with about 1.1 to 2.1 equivalents of a suitable base, such as hexamethylsilylazide.
  • a suitable base such as hexamethylsilylazide.
  • the mixture is stirred for about 30 minutes and then treated with about 1 to 2 equivalents of a suitable alkylating agent, such as iodomethane.
  • the mixture is allowed to warm to room temperature and stirred for about 4 to 12 hours.
  • the reaction is then quenched with water and extracted with a suitable organic solvent, such as ethyl acetate.
  • the organic extracts are washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the crude compound (2).
  • This crude material can then be purified by chromatography on silica gel to with a suitable eluent, such as hexanes/ethyl acetate to provide the purified compound (2).
  • step B compound (2) is reduced under standard conditions well known in the art to provide the compound (3b).
  • compound (2) is dissolved in a suitable organic solvent, such as THF and treated with about 2.1 equivalents of a suitable reducing agent, such as boron dimethylsulfide.
  • a suitable reducing agent such as boron dimethylsulfide.
  • the reaction is heated at reflux for about 4 to 14 hours, then cooled to room temperature, and quenched with a saturated solution of HCl in methanol.
  • the quenched reaction mixture is then treated with a suitable organic solvent, such as diethyl ether, cooled to about 0°C, and the precipitated product (3b) collected by filtration as the dihydrochloride salt.
  • step C compound (3b) is sulfonylated under conditions well known in the art to provide the compound of formula lb.
  • compound (3b) dissolved in a suitable organic solvent.
  • suitable organic solvents include methylene chloride, tetrahydrofuran, and the like.
  • the solution is treated with about 2.0 to about 5 equivalents of a suitable base, and then cooled to about - 5°C to about 0°C.
  • suitable bases include triethylamine, pyridine, 1 ,8- diazabicyclo[5.4.0]undec-7-ene (DBU), and the like.
  • LgSO 2 R 1' wherein R 1' and R 8' are equivalent
  • Lg refers to a suitable leaving group.
  • suitable leaving groups include, CI, Br, and the like.
  • CI is the preferred leaving group.
  • the reaction mixture is stirred at about 0°C to about 25°C for about 0.5 hours to about 16 hours.
  • the compound of formula lb is then isolated and purified by techniques well known in the art, such as extraction techniques and chromatography. For example, the mixture is washed with 10% sodium bisulfate, the layers separated and the aqueous extracted with several times with a suitable organic solvent, such as methylene chloride.
  • step B' the compound (1) is reduced to the compound (3a) in a manner analogous to the procedure set forth in Scheme I, step B.
  • step C the compound (3a) is sulfonylated to provide the compound of formula la in a manner analogous to the procedure set forth in Scheme I, step C.
  • Compounds of formula I' can be prepared as set forth in Scheme II. The reagents and starting materials are readily available to one of ordinary skill in the art. All substituents, unless otherwise specified are as previously defined.
  • step A diamino compound (4) is protected with a suitable protecting group "Pg" under standard conditions to provide the mono-protected compound of structure (5).
  • Pg refers to suitable protecting groups on the amine which are commonly employed to block or protect the amine while reacting other functional groups on the compound. Examples of suitable protecting groups used to protect the amino group and their preparation are disclosed by T. W. Greene, "Protective Groups in Organic Synthesis,” John Wiley & Sons, 1981 , pages 218-287. Choice of the suitable protecting group used will depend upon the conditions that will be employed in subsequent reaction steps wherein protection is required, and is well within the knowledge of one of ordinary skill in the art.
  • Preferred protecting groups are t- butoxycarbonyl also known as a BOC protecting group, and benzyloxycarbonyl, also known as CBz.
  • the diamino compound (4) is dissolved in a suitable organic solvent, such as methylene chloride and treated with about 1.2 equivalents of triethylamine. The solution is then cooled to about -5 °C and treated with one equivalent of as suitable protecting group, such as benzylchloroformate. The reaction mixture was warmed up to room temperature while stirring overnight.
  • the reaction is then diluted with a suitable organic solvent, such as ethyl acetate, rinsed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the crude mono-protected compound (5) wherein Pg represents a CBz protecting group.
  • a suitable organic solvent such as ethyl acetate
  • the crude material can then be purified by techniques well known in the art, such as flash chromatography on silica gel with a suitable eluent, such as methanol/methylene chloride.
  • step B the protected compound (5) is sulfonylated with a compound of formula LgSO 2 R 1 to provide sulfonamide (6) in a manner analogous to the procedure described in Scheme I, step C.
  • step C sulfonamide (6) is deprotected under conditions well known in the art as disclosed by T. W. Greene, "Protective Groups in Organic Synthesis,” John Wiley & Sons, 1981 , pages 218-287 to provide the amino derivative of structure (7).
  • the conditions employed for deprotection will depend upon the protecting group that needs to be removed and the substituents present on the compound itself which must remain unaffected by the deprotection reaction conditions, the conditions of which are well within the knowledge of one of ordinary skill in the art.
  • sulfonamide (6) wherein Pg represents a CBz protecting group is dissolved in a suitable organic solvent, such as ethanol and treated with a catalytic amount of 10% palladium on carbon.
  • step D the amino compound (7) is sulfonylated with a compound of formula LgSO 2 R 8 to provide sulfonamide of formula I' in a manner analogous to the procedure described in Scheme I, step C.
  • step A the cyclopentene of structure (8) is converted to the borane of structure (9) under standard conditions.
  • cyclopentene (8) is dissolved in a suitable organic solvent, such as dry methylene chloride under an atmosphere of nitrogen and cooled to about 0°C.
  • a suitable organic solvent such as dry methylene chloride under an atmosphere of nitrogen and cooled to about 0°C.
  • the solution is treated with about 0.5 equivalents of monochloroborane-methyl sulfide.
  • the reaction mixture is allowed to warm to room temperature and stirred for about 8 to 16 hours.
  • the solvent is removed under vacuum under a nitrogen atmosphere to provide borane (9).
  • step B borane (9) is methylated to provide the methylborane of structure (10).
  • borane (9) is dissolved in a suitable organic solvent, such as dry hexanes under an atmosphere of nitrogen. The solution is cooled to about 0°C and treated with about 0.3 equivalents of trimethylaluminum in hexanes. The reaction mixture is allowed to warm to room temperature and stirred for about 1.5 hours. A precipitate results and the supernatant is transferred via cannula to a nitrogen flushed separatory funnel containing saturated aqueous ammonium chloride. The organic phase is then transferred via cannula to a flask containing anhydrous sodium sulfate.
  • a suitable organic solvent such as dry hexanes under an atmosphere of nitrogen.
  • the solution is cooled to about 0°C and treated with about 0.3 equivalents of trimethylaluminum in hexanes.
  • the reaction mixture is allowed to warm to room temperature and stirred for about 1.5 hours. A precipitate
  • step C the methylated borane (10) is hydrolyzed to the trans-cyclopentylamine of structure (13).
  • a suitable organic solvent such as dry tetrahydrofuran and cautiously treated in small portions with a slight excess of hydroxylamine-O- sulfonic acid (referred to herein as "HAS") dissolved in tetrahydrofuran.
  • HAS hydroxylamine-O- sulfonic acid
  • the filtrate is concentrated under vacuum and the residue is treated with concentrated HCI:methanol:water:diethyl ether (30:15:20:60, by volume).
  • the mixture is stirred at room temperature for about 30 minutes.
  • the layers are separated, the organic phase is washed with water and the water wash is combined with the aqueous phase.
  • the aqueous phase is cooled to about 0°C, diethyl ether is added and the aqueous is made basic with sodium hydroxide.
  • the organic phase is separated and the aqueous phase is extracted with diethyl ether and ethyl acetate.
  • the organic phase and organic extracts are combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide the cyclopentylamine (13).
  • step D the cyclopentene of structure (8) is nitrated under standard conditions to provide the compound of structure (11).
  • step E the nitrated compound of structure (11 ) is reduced under standard conditions to provide the amine of structure (12).
  • compound (11) is dissolved in a suitable organic solvent, such as ethanol, treated with a suitable hydrogenation catalyst, such as palladium on carbon, the solution is placed under hydrogen at about 413.69 kPa (60 psi). After about 8 to 16 hours, the reaction mixture is filtered and the filtrate is concentrated under vacuum to provide the compound (12).
  • the compound of structure (12) can be prepared by the alternative procedures set forth in Schemes IIIA and IIIB below.
  • the reagents and starting materials are readily available to one of ordinary skill in the art. All substituents, unless otherwise specified are as previously defined.
  • step A the cyclopentanone of structure (14) is converted to the corresponding oxime of structure (15) under conditions well known in the art.
  • cyclopentanone (14) is dissolved in a suitable organic solvent, such as ethanol, treated with about 2 equivalents of aqueous sodium hydroxide and about 1.5 equivalents of hydroxylamine hydrochloride.
  • the reaction mixture is stirred for about 8 to 16 hours at room temperature. It is then diluted with water and the precipitated oxime (15) is collected by filtration and dried under vacuum at about 35°C.
  • step B oxime (15) is hydrogenated under standard conditions to provide the amine of structure (12).
  • oxime (15) is dissolved in a suitable organic solvent, such as ethanol, treated with a suitable catalyst, such as palladium on carbon, and placed under hydrogen at about 413.69 kPa (60 psi). The hydrogenation is carried out at about 40°C for about 8 to 16 hours. The reaction mixture is then filtered and the filtrate concentrated under vacuum to provide the amine (12).
  • a suitable organic solvent such as ethanol
  • a suitable catalyst such as palladium on carbon
  • step A the epoxide (14) is coupled with the Grignard reagent (15) to provide the alcohol (16).
  • Grignard (15) is dissolved in a suitable organic solvent, such as tetrahydrofuran and treated with a catalytic amount of copper iodide.
  • a suitable organic solvent such as tetrahydrofuran
  • copper iodide a catalytic amount of copper iodide
  • the reaction is exothermic.
  • the reaction is stirred until the temperature reaches room temperature and it is quenched with aqueous ammonium chloride.
  • the quenched reaction is extracted with a suitable organic solvent, such as diethyl ether.
  • the organic extracts are combined, washed with aqueous ammonium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide alcohol (16).
  • step B alcohol (16) is converted to the compound of structure (17) under standard conditions well known in the art.
  • a suitable organic solvent such as tetrahydrofuran.
  • the solution is cooled to about 0°C and a solution of about one equivalent of diisopropyl azodicarboxylate in tetrahydrofuran is added dropwise to the solution with stirring.
  • To this reaction mixture is added about one equivalent of phthalimide followed by addition of about one equivalent of alcohol (16) dissolved in tetrahydrofuran maintaining the temperature between about 5°C and 0°C.
  • reaction is then stirred at about 0°C for about 4 hours, warmed to room temperature, and stirred for 4 to 12 hours.
  • reaction is then quenched with water and extracted with a suitable organic solvent, such as chloroform.
  • a suitable organic solvent such as chloroform.
  • the organic extracts are combined, washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide compound (17).
  • step C compound (17) is converted to compound (12) in an exchange reaction well known in the art.
  • compound (17) is dissolved in a suitable organic solvent, such as toluene, and an excess of anhydrous hydrazine is added dropwise over about 15 minutes with stirring.
  • the reaction mixture is stirred for about one hour at room temperature and then heated at about 90-95°C for about 6 hours.
  • the reaction mixture is then cooled to room temperature, filtered, the precipitate rinsed with toluene, the filtrates combined, concentrated under vacuum to provide compound (12).
  • step D compound (16) oxidized to the ketone of structure (14) under standard conditions well known in the art.
  • compound (16) is added dropwise to a suspension of an excess of pyridinium chlorochromate in a suitable organic solvent, such as methylene chloride. The reaction is stirred for about 8 to 48 hours at room temperature.
  • crude compound (14) is then diluted with a diethyl ether, filtered through a pad of silica gel and the filtrate concentrated under vacuum to provide crude compound (14).
  • This material can be purified by standard techniques, such as flash chromatography on silica gel with a suitable eluent, such as ethyl acetate/hexane.
  • step E compound (16) is converted to the amine (13) using standard techniques and reactions well known in the art.
  • step E compound (16) is subjected to Mitsunobu conditions to provide the cis-benzoate derivative. More specifically, compound (16) is dissolved in a suitable organic solvent, such as THF and combined with about 1.05 equivalents of diethyl azodicarboxylate (referred to herein as "DEAD"), about 1.2 equivalents of benzoic acid and about 1.2 equivalents of triphenylphosphine at about 0°C. The reaction is stirred for about 2 hours, allowed to warm to room temperature and then concentrated under vacuum. The crude residue can be purified by chromatography on silica gel with a suitable eluent, such as hexanes/methylene chloride to provide the cis-benzoate derivative.
  • a suitable organic solvent such as THF
  • step F the cis-benzoate is hydrolyzed under standard conditions to provide the cis-alcohol.
  • the cis-benzoate is combined with 5% NaOH/methanol and stirred at room temperature for about 3 hours.
  • the reaction mixture is then concentrated under vacuum, the residue dissolved in a suitable organic solvent, such as diethyl ether, which is washed with water.
  • the organic phase is then dried over potassium carbonate, filtered, and concentrated under vacuum.
  • the residue can be purified by chromatography on silica gel with a suitable eluent, such as hexanes/methylene chloride to provide the cis-alcohol.
  • step G the cis-alcohol is converted to the phthalimide derivative in a manner analogous to the procedure described above in Scheme IVB, step B.
  • step H the phthalimide derivative is converted to the trans-amine (13) in a manner analogous to the procedure described above in Scheme IIIB, step C.
  • the compound (16) is subjected to an enzymatic resolution to provide the unreacted optically active alcohol (16a) and the optically active acetate (16b).
  • a suitable organic solvent such as tert-butyl methyl ether
  • a suitable enzyme such as Candida antartctica B lipase.
  • step A the compound of structure (18) is sulfonylated to provide the compound of structure (19) in a manner analogous to the procedure set forth in Scheme I, step C.
  • step B the compound (19) is nitrated under standard conditions well known in the art to provide the nitro derivative of structure (20).
  • compound (19) is dissolved in trifluoroacetic acid and treated with excess sodium nitrate.
  • the reaction mixture is stirred for about 3 to 8 hours and then diluted with water.
  • the quenched reaction mixture is extracted with a suitable organic solvent, such as methylene chloride, the organic extracts are combined, washed with saturated sodium carbonate, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide crude nitro derivative (20).
  • This crude material can then be purified by chromatography on silica gel with a suitable eluent, such as hexanes/ethyl acetate.
  • step C the nitro derivative (20) is reduced to the amine of structure (21) under standard conditions.
  • the nitro derivative (20) is dissolved in a suitable organic solvent, such as ethanol and treated with a suitable hydrogenation catalyst, such as 5% palladium on carbon.
  • a suitable hydrogenation catalyst such as 5% palladium on carbon.
  • the mixture is placed under about 40 psi of hydrogen and agitated for 8 to 14 hours.
  • the reaction mixture is then filtered through Celite ® to remove the catalyst and the filtrate is concentrated under vacuum to provide the crude amine (21).
  • the crude material can then be purified by chromatography on silica gel with a suitable eluent, such as hexanes/ethyl acetate.
  • step D the amine (21) is alkylated under conditions well known in the art to provide the compound of structure (22).
  • amine (21) is dissolved in a suitable organic solvent, such as methanol, and treated with an equivalent of an aldehyde, such as benzaldehyde and treated with a catalytic amount of acetic acid.
  • a suitable organic solvent such as methanol
  • the reaction mixture is stirred for about 4 hours and then treated with about 2 equivalents of a suitable reducing agent, such as sodium borohydride.
  • the reaction mixture is then stirred for about 8 to 14 hours at room temperature.
  • the reaction is then diluted with water, extracted with a suitable organic solvent, the organic extracts are combined, dried over potassium carbonate, filtered, and concentrated under vacuum to provide the crude compound (22).
  • This crude material can then be purified by chromatography on silica gel with a suitable eluent, such as hexanes/ethyl acetate.
  • step E compound (22) is again alkylated under standard conditions well known in the art to provide the nitrile of structure (23).
  • compound (22) dissolved in a suitable organic solvent such as methanol
  • a suitable organic solvent such as methanol
  • hydrochloric acid and about 1.1 equivalents of formaldehyde is added.
  • the reaction mixture is stirred for about 3 hours at 0°C, warmed to room temperature and stirred for about 14 hours.
  • the reaction is then quenched with water and extracted with as suitable organic solvent, such as methylene chloride.
  • step F the nitrile (23) is reduced to the amine of structure
  • step G the amine (24) is sulfonylated to provide the compound of structure (25) in a manner analogous to the procedure described in Scheme I, step C.
  • step H the compound (25) is dealkylated under standard conditions to provide the compound of formula lc.
  • compound (25) is dissolved in a suitable organic solvent, such as THF, treated with a slight excess of ammonium formate and a catalytic amount of palladium on carbon.
  • the reaction mixture is stirred at room temperature for about 14 hours and then heated at reflux for about 8 hours. After cooling, the reaction mixture is filtered through Celite ® which is washed is water. The filtrate is extracted with a suitable organic solvent, such as ethyl acetate.
  • step A the compound of structure (26) is converted to the alcohol of structure (27) under standard conditions.
  • compound (26) is treated with excess trimethylsilylcyanate and zinc iodide under a nitrogen atmosphere at room temperature.
  • the mixture is stirred for about 14 hours and treated with methylene chloride and saturated sodium carbonate.
  • the layers are separated and the organic layer is washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum.
  • the residue is dissolved in a suitable organic solvent and treated with a suitable reducing agent, such as borane-dimethylsulfide.
  • the reaction mixture is stirred at room temperature for about 14 hours and then treated with concentrated hydrochloric acid until a pH of about 2 is achieved.
  • a suitable organic solvent, such as diethyl ether is then added and the resulting precipitate is collected by filtration, rinsed with diethyl ether and dried under vacuum to provide compound (27) as the hydrochloride salt.
  • step B the compound (27) is sulfonylated to provide the compound of structure (28) in a manner analogous to the procedure described in Scheme I, step C.
  • step C the compound (28) is reduced to provide the amine of structure (29) in a manner analogous to the procedure described in Scheme IV, step C.
  • step D the amine (29) is alkylated to provide the compound of structure (30) in a manner analogous to the procedure described in Scheme IV, step D.
  • step E the compound (30) is again alkylated to provide the nitrile of structure (31) in a manner analogous to the procedure described in Scheme IV, step E.
  • step F the nitrile (31) is reduced to the amine of structure (32) in a manner analogous to the procedure described in Scheme IV, step F.
  • step G the amine (32) is sulfonylated to provide the compound of formula Id in a manner analogous to the procedure described in Scheme IV, step G.
  • step H the compound of formula Id is dealkylated to provide the compound of formula le in a manner analogous to the procedure described in Scheme IV, step H.
  • the reaction is diluted with water and methylene chloride.
  • the layers are separated and the organic layer is washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide the crude compound of formula Ig.
  • This crude material can then be purified by standard techniques, such as recrystallization from a suitable eluent, or flash chromatography or radial chromatography on silica gel, with a suitable eluent, such as hexane/ethyl acetate or methylene chloride to provide purified compound of formula Ig.
  • step A the compound of structure (7) is acylated under standard conditions to provide the compound of formula lh.
  • the compound (7) is dissolved in a suitable organic solvent, such as methylene chloride, the solution is cooled to about 0°C, and about 2 to 3 equivalents of a suitable base, such as triethylamine is added.
  • a suitable organic solvent such as methylene chloride
  • the reaction mixture is then stirred for about 4 to 14 hours, quenched with water and the layers separated.
  • the organic phase is rinsed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the crude compound of formula lh.
  • This crude material can be purified by chromatography on silica gel with a suitable eluent, such as hexanes/ethyl acetate to provide the purified compound of formula lh.
  • step B the compound (7) is converted to the compound of formula Ii under conditions well known in the art.
  • compound (7) is combined with about 2 equivalents of sodium cyanate in a suitable organic solvent, such as toluene and heated to about 50°C.
  • a suitable organic solvent such as toluene
  • the mixture is then treated with about 1.4 equivalents of trifluoroacetic acid and the mixture is heated to about 70°C for about one hour.
  • the reaction is then concentrated under vacuum and the residue is treated with aqueous sodium hydroxide and methylene chloride.
  • the layers are separated and the organic phase is rinsed with brine, filtered through potassium carbonate, and the filtrate is concentrated under vacuum to provide the crude compound of formula Ii.
  • This crude material can be purified by chromatography on silica gel with a suitable eluent, such as hexanes/ethyl acetate to provide the purified compound of formula Ii.
  • step C the compound (7) is converted to the secondary or tertiary amine of formula Ij under standard conditions well known in the art.
  • the secondary amine can be prepared via reductive alkylation as described by Jerry
  • reaction No. 6-15 For example, compound (7) is dissolved in a suitable organic solvent, such as methanol and treated with about one equivalent of an aldehyde or ketone, such as benzaldehyde and treated with about 0.05 equivalents of acetic acid (catalytic amount).
  • a suitable organic solvent such as methanol
  • an aldehyde or ketone such as benzaldehyde
  • acetic acid catalytic amount
  • the reaction mixture is stirred for about 2 to 8 hours and then treated with a suitable reducing agent, such as about 2 equivalents of sodium borohydride.
  • a suitable reducing agent such as about 2 equivalents of sodium borohydride.
  • the reaction mixture is then stirred for about 8 to 14 hours at room temperature and then diluted with water.
  • the quenched reaction is extracted with a suitable organic solvent, such as methylene chloride, the organic extracts are combined, filtered through potassium carbonate, and concentrated under vacuum to provide the crude secondary amine of formula Ij.
  • a suitable organic solvent such as methylene chloride
  • This crude material can be purified by chromatography on silica gel with a suitable eluent, such as ethyl acetate to provide the purified compound of formula Ij.
  • the tertiary amine can be prepared via dialkylation conditions as described by Jerry March, "Advanced Organic Chemistry: Reactions. Mechanisms, and Structure," Fourth Edition, John Wiley & Sons, (1992), pages 411-413, 476 and 899-900.
  • compound (7) is dissolved in a suitable organic solvent, such as methanol and treated with an excess of formaldehyde.
  • a suitable organic solvent such as methanol
  • the reaction mixture is stirred at room temperature for about 1 to 3 hours.
  • About 2 to 8 equivalents of a suitable reducing agent, such as sodium borohydride is then added and the reaction mixture is stirred for about 6 to 14 hours at room temperature.
  • the reaction is then concentrated under vacuum and the residue is dissolved in water and a suitable organic solvent, such as methylene chloride.
  • step D compound (7) is converted to the carbamate of formula Ik under conditions well known in the art such as those described by Theodora W. Greene, "Protective Groups in Organic Synthesis.” John Wiley & Sons, (1981), Chapter 7.
  • compound (7) is dissolved in a suitable organic solvent such as methylene chloride, the solution is cooled to about 0°C and about 2.5 equivalents of a suitable base, such as triethylamine is added. To this stirring solution is then added about 1.5 equivalents of a suitable chloroformate, such as methyl chloroformate, and the reaction is stirred for about 8 to 14 hours. The reaction is then quenched with water and the product is isolated and purified using standard techniques and procedures, such as extraction and chromatography. For example, the quenched reaction is extracted with a suitable organic solvent, such as methylene chloride, the combined organic extracts are dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide crude compound of formula Ik. This crude material can be purified by chromatography on silica gel with a suitable eluent, such as ethyl acetate to provide the purified compound of formula Ik.
  • a suitable organic solvent such as methylene chloride
  • step E compound (7) is converted to the substituted urea of formula Im under conditions well known in the art.
  • compound (7) 5 is dissolved in a suitable organic solvent, such as methylene chloride, the solution is cooled to about 0°C and treated with about 2.5 equivalents of a suitable base, such as triethylamine.
  • a suitable base such as triethylamine.
  • To this stirring solution is then added about 1.5 equivalents of a carbamoyl chloride, such as N-methyl-N-phenylcarbamoyl chloride and the reaction is stirred for about 8 to 14 hours.
  • the reaction is then 0 quenched with water and the product is isolated and purified using standard techniques and procedures, such as extraction and chromatography.
  • the quenched reaction is extracted with a suitable organic solvent, such as methylene chloride, the combined organic extracts are dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide crude 5 compound of formula Im.
  • a suitable organic solvent such as methylene chloride
  • This crude material can be purified by chromatography on silica gel with a suitable eluent, such as ethyl acetate to provide the purified compound of formula Im.
  • Chromatotron ® (Harrison Research Inc., 840 Moana Court, Palo Alto California 94306) is recognized by one of ordinary skill in the art as an instrument which is used to perform centrifugal thin-layer 5 chromatography.
  • step B Chloro-bis-(2-phenyl-cyclopentyl)-borane from preparation 1 was diluted with 60 mL of dry hexanes under nitrogen. The solution was cooled to 0°C and a 2M solution of trimethylaluminum in hexanes (5.8 mL) was added dropwise causing the reaction to turn orange. The reaction was allowed to warm to room temperature and stirred for 1.5 hours. During this time a red-brown mass precipitated out of solution, leaving a yellow supernatant. The hexane supernatant was transferred via cannula to a nitrogen flushed separatory funnel containing 50 mL of saturated aqueous ammonium chloride.
  • the organic phase becomes colorless and was transferred via cannula to a dry flask containing sodium sulfate for drying. The solution was then transferred via cannula to a dry, nitrogen-flushed flask and the solvent removed under aspirator vacuum and nitrogen. The clear oil was used directly without further characterization.
  • step C Methyl-bis-(2-phenyl-cyclopentyl)-borane (theoretical 34.7 mmoL) from preparation 2 was diluted with 40 mL of dry tetrahydrofuran. 8.3 g (72.9 mmol) of hydroxylamine-O-sulphonic acid (HSA) was slurried in a separate dry flask in 60 mL of THF and small portions are transferred via cannula to control the exothermic reaction. The cloudy white solution was stirred at room temperature for 24 hours. The reaction mixture was filtered and the THF removed in vacuo.
  • HSA hydroxylamine-O-sulphonic acid
  • step D (5-Nitro-cyclopent-1-enyl)-benzene was prepared according to the procedure of F. G. Bordwell et. al., J. Org. Chem., 1765-1769, 1963.
  • the title compound was prepared by nitration of 1-phenylcyclopentene (3.0 g, 20.8 mmol) and purified by radial chromatography eluting with 85:15 hexanes:ethyl acetate to yield 0.63 g (12%) as a yellow oil.
  • step E (5-Nitro-cyclopent-1-enyl)-benzene (0.63 g, 3.3 mmol) from preparation 4 above, was hydrogenated in 25 mL of ethanol using 0.16 g of 5% Pd/C at room temperature overnight at 413.69 kPa (60 psi). The solution was filtered over celite and concentrated in vacuo to 230 mg (43%) of the title compound as a colorless oil.
  • step A 2-Phenyl-cyclopentanone (prepared according to R. Sudha et. al. J. Org. Chem., 61 , 1877-1879, 1996) (1.0 g, 6.2 mmol) was dissolved in 20 mL of absolute ethanol. To this solution was added sodium hydroxide (0.5 g, 12.5 mmol) dissolved in 10 mL water followed by hydroxylamine hydrochloride (0.65 g, 9.36 mmol) and stirred overnight at room temperature. The reaction was diluted with water and the precipitate collected by filtration. The white solid was vacuum oven-dried at 35°C for 30 minutes to give 0.75 g (69%) of the title compound. Analysis calculated for C ⁇
  • step A A one liter three necked round bottom flask equipped with a mechanical stirrer, addition funnel, thermometer is charged with 1M THF solution of phenylmagnesium bromide (300 mL, 300.0 mmol) and copper iodide (3.8 g, 20.0 mmol). To this reaction mixture was then added cyclopentene oxide (25.23 g, 300.0 mmol) dissolved in THF (50.0 mL) dropwise over a period of 60 minutes (reaction was quite exothermic, reaching THF reflux by the end of addition). The reaction mixture was then stirred to room temperature and quenched with 25% solution of ammonium chloride (200.0 mL).
  • step B A 500 mL three necked round bottom flask equipped with a mechanical stirrer, thermometer, reflux condenser, addition funnel and a nitrogen blanket is charged with triphenylphosphine (16.19 g, 61.73 mmol) and THF (200 mL). To the solution at 0°C was added dropwise, a solution of diisopropyl azodicarboxylate (12.15 mL, 61.73 mmol) dissolved in THF (30 mL) over a period of 10 minutes. A massive precipitate formed immediately after addition.
  • step B Into a 100 mL single neck flask a solution of 4- (cyanoethoxy)benzenecarbonitrile (1 g, 5.8 mmol) in THF (20 mL) is treated with boron dimethylsulfide 10 M in THF (1.3 mL, 12.8 mmol) and the mixture is heated to reflux overnight. The reaction mixture is cooled down to room temperature and quenched with saturated solution of HCl in methanol (10 mL). Diethyl ether (20 mL) is added to the mixture and it is cooled down to 0 °C. The product is precipitated out of the solution as dihydrochloride salt. The salt is filtered and dried in vacuum to provide the intermediate title compound (1.35 g, 88%) as a white solid crystal. Electron spray M.S. 181 (M*+1).
  • step C Into a 25 mL single neck flask is placed 2-[4- (aminomethyl)phenoxy]propylamine dihydrochloride (0.5 g, 1.97 mmol) in methylene chloride (10 mL) and the solution is cooled down to 0 °C. DBU, (1.75 mL, 11.8 mmol) is added to the mixture and after 30 minutes isopropylsulfonyl chloride (0.62 mL, 4.33 mmol) is added to the reaction mixture. The mixture is warmed up to RT while stirring for 12 hour. The reaction mixture is quenched with a 1 N HCl until pH is below 4-5.
  • step B 2-[4-(Cyanomethyl)phenoxy]propanenitrile (2 g, 10.7 mmol) in THF (50 mL) is treated with boron dimethylsulfide 2 M in THF (11.8 mL, 23.6 mmol) in a manner analogous to the procedure described in example 1 to provide the intermediate title compound (2.7 g, 95%) as a white crystalline solid.
  • step C 2-[4-(2-Aminoethyl)phenoxy]propylamine dihydrochloride (1 g, 3.74 mmol), DBU (3.4 mL, 22.4 mmol), and isopropylsulfonyl chloride (0.92 mL, 8.2 mmol) in methylene chloride (20 mL) at
  • step B 2-[4-(2-Cyanoethyl)phenoxy]propanenitrile (1 g, 5 mmol) in THF (20 mL) is treated with boron dimethylsulfide 2 M in THF (5.5 mL, 11 mmol) in a manner analogous to the procedure described in example 1 to provide the intermediate title compound (1.3 g, 93%) as a white crystalline solid.
  • step B' 4-(Cyanomethoxy)benzenecarbonitrile (1 g, 6.3 mmol) in THF (25 mL) is treated with boron dimethylsulfide 2 M in THF (7 mL, 13.9 mmol) in a manner analogous to the procedure described in example 1 to provide the intermediate title compound (1.4 g, 93%) as a white crystalline solid.
  • step C 2-[4-(Aminomethyl)phenoxy]ethylamine dihydrochloride (500 mg, 2.1 mmol), DBU (1.9 mL, 12.5 mmol), and isopropylsulfonyl chloride (0.52 mL, 4.6 mmol), in methylene chloride (10 mL) at
  • step B' 2-[4-(Cyanomethyl)phenoxy]ethanenitrile (1 g, 5.8 mmol) in THF (25 mL) is treated with boron dimethylsulfide 2 M in THF (6.4 mL, 12.8 mmol) in a manner analogous to the procedure described in example 1 to provide the intermediate title compound (1.25 g, 85%) as a white crystalline solid.
  • step C 2-[4-(2-Aminoethoxy)phenyl]ethylamine dihydrochloride (300 mg, 1.18 mmol), DBU (1.05 mL, 7.08 mmol), and isopropylsulfonyl chloride (0.29 mL, 2.6 mmol), in methylene chloride (6 mL) at 0°C are combined in a manner analogous to the procedure described in example 1 to provide the final title compound (158 mg, 34%) as a white crystalline solid. Electron spray M.S.
  • step B' 3-[4-(Cyanomethoxy)phenyl]propanenitrile (1 g, 5.37 mmol) in THF (25 mL) is treated with boron dimethylsulfide 2 M in THF (6 mL, 11.8 mmol) in a manner analogous to the procedure described in example 1 to provide the intermediate title compound (1.33 g, 93%) as a white crystalline solid.
  • step C 3-[4-(2-Aminoethoxy)phenyl]propylamine dihydrochloride (300 mg, 1.12 mmol), DBU (1 mL, 6.72 mmol), and isopropylsulfonyl chloride (0.28 mL, 2.47 mmol), in methylene chloride (6 mL) at
  • step A In a 50 mL round-bottomed flask fitted with a stir bar, at room temperature, and under a nitrogen atmosphere, a solution of 2-[4- (cyanomethyl)phenoxy]ethanenitrile (1.4 g, 8.13 mmol) in THF (25 mL) is cooled down to -78 °C and is then treated with 1M solution of hexamethylsilylazide (8.9 mL, 8.9 mmol) in THF. The mixture is stirred at -78 °C for 30 minutes prior to the addition of iodomethane (0.51 mL, 8.13 mmol). The reaction mixture is allowed to warm up to RT overnight while stirring.
  • step B 2-[4-(Cyanomethoxy)phenyl]propanenitrile (690 mg, 3.7 mmol) in THF (15 mL) is treated with boron dimethylsulfide 10 M in THF (0.815 mL, 8.15 mmol) in a manner analogous to the procedure described in example 1 to provide the intermediate title compound (800 mg, 81%) as a white crystalline solid. Electron spray M.S. 195 (M+1). Preparation of the final compound.
  • step C 2-[4-(2-Aminoethoxy)phenyl]propylamine dihydrochloride (500 mg, 1.87 mmol), DBU (1.67 mL, 11.2 mmol), and isopropylsulfonyl chloride (0.4 mL, 4.11 mmol), in methylene chloride (10 mL) at
  • step B' 2-[4-(Cyanomethylthio)phenyl]ethanenitrile (360 mg, 1.9 mmol) in THF (10 mL) is treated with boron dimethylsulfide 2 M in THF (2.1 mL, 4.2 mmol) in a manner analogous to the procedure described in example 1 to provide the intermediate title compound (500 mg, 98%) as a white crystalline solid.
  • step C 2-[4-(2-Aminoethylthio)phenyl]ethylamine dihydrochloride (500 mg, 1.85 mmol), DBU (1.7 mL, 11.1 mmol), and isopropylsulfonyl chloride (0.46 mL, 4.1 mmol) in methylene chloride (10 mL) at 0
  • step B' 2- ⁇ 4-[(Cyanomethyl)methylamino]phenyl ⁇ ethanenitrile (600 mg, 3.24 mmol) in THF (15 mL) is treated with boron dimethylsulfide 2 M in THF (3.6 mL, 7.13 mmol) in a manner analogous to the procedure described in example 1 to provide the intermediate title compound as a white crystalline solid.
  • step B' 2- ⁇ 4-[(Cyanomethyl)benzylamino]phenyl ⁇ ethanenitrile (1 g, 3.8 mmol) in THF (20 mL) is treated with boron dimethylsulfide 2 M in THF (4.2 mL, 8.4 mmol) in a manner analogous to the procedure described in example 1 to provide the intermediate title compound (1.3g, 100%) as a white crystalline solid.
  • step C (2-Aminoethyl)[4-(2-aminoethyl)phenyl]benzylamine dihydrochloride (1.3 g, 3.8 mmol), DBU (3.4 mL, 22.8 mmol), and isopropylsulfonyl chloride (0.95 mL, 8.4 mmol), in methylene chloride (20 mL) at
  • step C Into a 25 mL single neck flask is placed [(methylethyl)sulfonyl](2- ⁇ 4-[(2- ⁇ [(methylethyl)sulfonyl]amino ⁇ ethyl)benzylamino]phenyl ⁇ ethyl)amine (0.465 g,
  • step A In a 3-neck round bottomed flask fitted with a condenser, a thermometer, a mechanical stirrer, a solution of 1 ,2-epoxy cyclopentane (25.0 g, 297.2 mmol) in tetrahydrofuran (60 mL) is added dropwise to a mixture of phenylmagnesium bromide (99.1 mL) and copper (II) iodide (4.0 g, 20.8 mmol). After an hour of addition, the temperature inside the vessel exceeds the reflux temperature of 60° C, and the reaction mixture ceases foaming.
  • reaction mixture is cooled down to room temperature overnight and is then treated dropwise with a 25% solution of ammonium chloride (45 mL) until 'blue' copper chloride precipitates out.
  • the organic layer is washed with H 2 O, filtered it through magnesium sulfate (MgSO 4 ), and concentrated under vacuum to yield 26.61 g of the crude product.
  • This crude material is further purified by Prep HPLC 2000 (Hexanes:EtOAc, 3:1 , isocratic) to provide the intermediate title compound (22.4 g, 46.5 %) as an orange oil.
  • step B In a 2-Liter 3-neck round bottomed flask fitted with a condenser, a thermometer, and a mechanical stirrer a solution of diisopropyl azodicarboxylate (95 mL, 481.4 mmol) in THF (100 mL) is added to a solution of triphenylphosphine (126.3 g, 481.4 mmol) in THF (1400 mL). This mixture is l o treated with a phthalimide (70.8 g, 481.4 mmol) and a solution of trans-2- phenylcyclopentan-1-ol (78.1 g, 481.4 mmol) in THF (100 mL).
  • reaction temperature is kept between 0°C and 5°C during the addition and the mixture is warmed up to room temperature gradually.
  • the reaction mixture is then quenched with H 2 O (460 mL), and extracted with CH 2 CI 2 (3 x 300 mL).
  • step C In a 2-Liter 3-neck round bottomed flask fitted with a mechanical stirrer, condenser, thermometer, a solution of cis-2-(2- phenylcyclopentyl)isoindoline-1 ,3-dione (30.8 g, 105.72 mmol) in toluene (423 mL, Aldrich) is treated with hydrazine (33.2 mL, 105.72 mmol). The mixture is heated at reflux (90°C) for 6 hours and then cooled to room temperature. The resulting precipitate is filtered and rinsed with an additional 200 mL toluene. The combined filtrate is concentrated under vacuum yielding 18.6 g of yellow oil. The crude material is purified by flash chromatography (CH 2 CI 2 : methanol, 9:1) to provide the intermediate title compound (11.52 g, 68 %) as a yellow oil.
  • step A In a 2-Liter, 3-neck, round bottomed flask fitted with a thermometer, a solution of cis-2-phenylcyclopentylamine (11.52 g, 71.42 mmol,) in CH 2 CI 2 (476 mL) is treated with DBU (10.7 mL, 71.42 mmol) via additional funnel. The reaction is cooled down to 0 °C and isopropylsulfonyl chloride (8.0 mL, 71.42 mmol) is added. The mixture is gradually warmed to room temperature while stirring over night. The reaction mixture is then quenched with H 2 O (476 mL), and the mixture is extracted with CH 2 CI 2 (2 x 300 mL).
  • step B In a 2-Liter round bottomed flask fitted with a stirrer, a solution of cis-[(methylethyl)sulfonyl](2-phenylcyclopentyl)amine (10.37 g, 38.78 mmol) in trifluoroacetic acid (260 mL) is treated with sodium nitrate (9.9 g, 116.35 mmol) and the mixture is stirred at room temperature for five hours. The reaction mixture then quenched with H 2 O (200 mL) and the mixture is extracted with CH 2 CI 2 (2x200 mL).
  • step C A solution of cis-[(methylethyl)sulfonyl][2-(4- nitrophenyl)cyclopentyl]amine (7.8 g, 24.97 mmol) and palladium on carbon (390 mg, 5 mole%) in absolute ethanol (200 mL) is combined in a Parr bottle. The mixture is shaken on a Parr shaker at room temperature under 40 psi of hydrogen for 12 hours. The reaction mixture is filtered through the Celite ® and the filtrate is concentrated under vacuum to yield 5.9 g of brown crystals. This material is further purified by Prep HPLC 2000 (Hexanes: EtOAc, 1 :1) to provide the intermediate title compound (3.4 g, 48 %) as white crystals. EMS 284.0 (M*+1).
  • step D A solution of benzaldehyde (1.22 mL, 12.0 mmol) in acetic acid (36 mg, 0.6 mmol) is added to a solution of cis-[2-(4- aminophenyl)cyclopentyl][(methylethyl)sulfonyl]amine (3.4 g, 12.0 mmol) in methanol (48 mL). The reaction is stirred for four hours, then sodium borohydride (910 mg, 24 mmol) is added, and the mixture is stirred overnight at room temperature. The reaction mixture is then diluted with H 2 0 (150 mL), and the mixture is extracted with CH 2 CI 2 (3 x 100 mL). The combined organic layers are dried over K 2 CO 3 , filtered, and concentrated under vacuum to yield 4.36 g as a brown oil. This material is further purified by Prep HPLC 2000 (Hexanes:
  • step E In a 250 mL 3-neck round bottom flask fitted with a thermometer and stirbar, a solution of sodium cyanide (401 mg, 8.17 mmol) in H 2 O (20 mL) is treated with a solution of cis-[(methylethyl)sulfonyl](2- ⁇ 4- [benzylamino]phenyl ⁇ cyclopentyl)amine (2.9 g, 7.79 mmol) in methanol (20 mL). The reaction mixture is cooled to 0 °C in an ice bath, and hydrochloric acid (2.32 mL) is added by syringe followed by formaldehyde, 37 %, (0.23 mL, 8.17 mmol).
  • step F A solution of cis-2- ⁇ [4-(2- ⁇ [(methylethyl)sulfonyl]amino ⁇ cyclopentyl)phenyl]benzylamino ⁇ ethanenitrile (760 mg, 1.85 mmol) in THF (6.2 mL) is treated with a solution of borane- tetrahydrofuran 1M (1.85 mL, 1.85 mmol) and the mixture is heated at reflux (65°C) overnight. The reaction mixture is cooled to room temperature and treated with a 1 :1 mixture THF: MeOH (5.6 mL).
  • step G A solution of cis-(2- ⁇ 4-[(2- aminoethyl)benzylamino]phenyl ⁇ cyclopentyl)[(methylethyl)sulfonyl]amine (175 mg, 0.4211 mmol) in CH 2 CI 2 (2.8 mL) and DBU (0.23 mL, 1.053 mmol) is treated with isopropylsulfonyl chloride (0.07 mL, 0.6317 mmol) at 0 °C. The reaction mixture is warmed to room temperature while stirring overnight. The mixture is then quenched with H 2 0 (5 mL) and the mixture is extracted with CH 2 CI 2 (2 x 10 mL).
  • step G In a round bottom flask, a solution of cis-(2- ⁇ 4-[(2- aminoethyl)benzylamino]phenyl ⁇ cyclopentyl)[(methylethyl)sulfonyl]amine (175 mg, 0.4211 mmol, prepared in example 12) in CH 2 CI 2 (3 mL) is combined with DBU (0.23 mL, 1.053 mmol) at 0 °C and treated with isopropylsulfonyl chloride (0.07 mL, 0.6317 mmol). The mixture is then gradually warmed to room temperature overnight.
  • step H In a round bottom flask, a solution of cis-(2- ⁇ [4-(2- ⁇ [(methylethyl)sulfonyl]amino ⁇ cyclopentyl)phenyl]benzylamino ⁇ ethyl)(methylsulfon yl)amine (65 mg, 0.132 mmol) in THF (10 mL) is treated with ammonium formate (42 mg, 0.66 mmol) and palladium on carbon (10 mg). The reaction mixture is stirred at room temperature overnight and then heated at reflux (65°C) for 8 hours. The mixture is then filtered through Celite ® , and the Celite ® cake is washed with H2O (10 mL).
  • step A Trimethylsylilcyanate (100 mL, 703.05 mmol, Aldrich) is added to 4-nitroacetophenone (38.75 g, 234.35 mmol) and zinc iodide (7.5 g, 23.44 mmol) in a 1L round bottomed flask, neat, fitted with a stirbar, and under a nitrogen atmosphere, at room temperature. The mixture is stirred overnight and diluted with 100 mL dichloromethane, followed by slow addition of 100 mL saturated sodium carbonate. The layers are separated, and the organic layer is washed once with deionized water, filtered through magnesium sulfate (MgSO 4 ), and concentrated under vacuum, yielding 25.9 g orange oil.
  • MgSO 4 magnesium sulfate
  • step B 1-Amino-2-(4-nitrophenyl)propan-2-ol hydrochloride (11.6 g, 59.12 mmol), is added to THF (394 mL) in a 2-Liter, 3-neck, round bottomed flask fitted with a thermometer, addition funnel, and under a nitrogen atmosphere. Triethylamine (20.6 mL, 147.8 mmol) is added, and the reaction temperature is reduced to 0°C in an ice bath. Isopropylsulfonyl chloride (10.0 mL, 88.68 mmol) is added by addition funnel at 0°C, and gradually warmed to room temperature overnight in the ice bath.
  • step C [2-Hydroxy-2-(4- nitrophenyl)propyl][(methylethyl)sulfonyl]amine (2.41 g, 7.97 mmol) is dissolved into absolute ethanol (200 mL) and added to 5 % palladium on carbon, wetted with ethanol (2 mL) in a nitrogen flushed Parr bottle. The reaction vessel is stopped off and shaken on a Parr shaker at room temperature under 40 psi of hydrogen, overnight. The reaction mixture is then filtered through Celite ® to remove the catalyst, and the filtrate is concentrated under vacuum, yielding 1.82 g colorless oil.
  • step D A mixture of benzaldehyde (0.52 mL, 5.14 mmol) and acetic acid (15 mg, 0.257 mmol), is added to a solution of [2-(4-aminophenyl)-2- hydroxypropyl][(methylethyl)sulfonyl]amine (1.4 g, 5.14 mmol) in MeOH (23 mL), in a 250 mL round bottomed flask fitted with a stirbar, and under a nitrogen atmosphere. The reaction is stirred for four hours, then sodium borohydride is added, and stirred overnight, at room temperature. The reaction is then diluted with water (150 mL), and extracted with CH 2 CI 2 (3 x 100 mL).
  • step E A solution of (2-hydroxy-2- ⁇ 4- [benzylamino]phenyl ⁇ propyl)[(methylethyl)sulfonyl]amine (1.0 g, 2.76 mmol) in MeOH (7 mL) is added to sodium cyanide (142 mg, 2.90 mmol) dissolved in H 2 O (7 mL) in a 100 mL 3-neck round bottomed flask fitted with a thermometer, stirbar, and under a nitrogen atmosphere.
  • the reaction vessel is cooled to 0°C in an ice bath, and hydrochloric acid (0.8 mL) is added by syringe, followed by addition of formaldehyde, 37 %, (0.2 mL, 2.90 mmol) by syringe, and the reaction mixture is stirred for an additional three hours at 0°C.
  • the ice bath is removed and the reaction mixture is gradually warmed to room temperature overnight.
  • the reaction is then poured into H 2 O (50 mL) and extracted with CH 2 CI 2 (3 x 25 mL). The organic extracts are combined, washed with brine (1 x 100 mL), filtered through MgSO 4 , and concentrated under vacuum, yielding 939 g of a brown foam.
  • This material is further purified by running it over a 6000 ⁇ m rotor on a Chromatotron ® , in 1 :1 hexanes : ethyl acetate solvent system to provide the intermediate title compound (690 mg, 62 %) as a colorless foam.
  • step F A solution of 2- ⁇ [4-(1-hydroxy-1-methyl-2- ⁇ [(methylethyl)sulfonyl]amino ⁇ ethyl)phenyl]benzylamino ⁇ ethanenitrile (600 mg, 1.5 mmol) in warm THF (3 mL) is added to lithium aluminum hydride (57 mg, 1.5 mmol) in THF (7mL) in a 100 mL 3 neck round bottomed flask, fitted with a thermometer, addition funnel, stirbar, under a nitrogen atmosphere, in an ice bath (0°C). The reaction mixture is stirred overnight at room temperature.
  • step G A solution of (2- ⁇ 4-[(2- aminoethyl)benzylamino]phenyl ⁇ -2-hydroxypropyl)[(methylethyl)sulfonyl]amine (80 mg, 0.1973 mmol) in THF (1.3 mL) is treated with DBU (0.08 mL, 0.4933 mmol), and the reaction temperature is reduced to 0°C with an ice bath. Methanesulfonyl chloride (0.02 mL, 0.1973 mmol) is added by syringe at 0°C, and gradually warmed to room temperature overnight in the ice bath. The reaction is then quenched with H 2 O (2 mL), and the layers are separated.
  • a solution of 6-(bromomethyl)-2-methoxynaphthalene (3.923 g, 15.62 mmol) in dimethylsulfoxide (10 mL) is added to a solution of sodium cyanide (1.15 g, 23.43 mmol) in DMSO (15 mL), heated to 50°C, in a 250 mL 3-neck round bottomed flask, fitted with a stirbar, thermometer, condenser, and addition 5 funnel, under a nitrogen atmosphere.
  • the reaction mixture is stirred at 50°C for 0.5 hr, then the temperature is increased to 70°C, and stirred an additional 1.0 hr.
  • the reaction is then cooled to room temperature and poured over ice.
  • 2-(6-Methoxy-2-naphthyl)ethanenitrile (5.0 g, 25.35 mmol) is dissolved into absolute ethanol (200 mL), saturated with ammonia, and added to Rainey nickel (2.5 g) wetted with ethanol (2 mL), in a nitrogen flushed Parr bottle.
  • the reaction vessel is stopped off and shaken on a Parr shaker at 50°C and 60 psi hydrogen overnight.
  • the catalyst is then filtered off with Celite ® , and the organic layer is concentrated under vacuum yielding 6.1 g greenish oil.
  • step D ⁇ 2-[6-(2-Aminoethoxy)(2- naphthyl)]ethyl ⁇ (methylsulfonyl)amine (0.571 mmol) is dissolved in methylene 5 chloride in a 15 mL round bottomed flask, under a nitrogen system. The reaction mixture is cooled to 0°C, and triethylamine (0.2 mL, 2.5 equivalents) is added by syringe, followed by methanesulfonyl chloride (0.07 mL, 1.5 Eq.), also by syringe, and mixed overnight. The reaction is quenched with 20 mL water, and layers are separated.
  • 2-(6-Methoxy-2-naphthyl)ethylamine (2.85 g, 14.16 mmol) is added to THF (95 mL) in a 250 mL 3-neck round bottomed flask fitted with a thermometer, addition funnel, and under a nitrogen atmosphere.
  • Triethylamine (3.94 mL, 28.32 mmol) is added, and the reaction temperature is reduced to 0°C in an ice bath.
  • Isopropylsulfonyl chloride (1.64 mL, 21.24 mmol) is added by addition funnel at 0°C, and gradually warmed to room temperature overnight. The reaction is quenched with deionized water (100 mL), and the layers are separated.
  • This material is further purified by silica gel chromatography, employing the Water's Prep 2000 while eluting with a solvent of hexanes/ethyl acetate 3:1 to yield the intermediate title compound.
  • step D ⁇ 2-[6-(2-Aminoethoxy)(2- naphthyl)]ethyl ⁇ [(methylethyl)sulfonyl]amine (0.571 mmol) is dissolved in methylene chloride in a 15 mL round bottomed flask, under a nitrogen system.
  • the reaction mixture is cooled to 0°C, and triethylamine (0.2 mL, 2.5 eq) is added by syringe, followed by methanesulfonyl chloride (0.07 mL, 1.5 Eq.), also by syringe, and mixed overnight.
  • the reaction is quenched with 20 mL water, and the layers are separated.
  • step D ⁇ 2-[6-(2-Aminoethoxy)(2- naphthyl)]ethyl ⁇ (methylsulfonyl)amine (0.571 mmol) is dissolved in methylene chloride in a 15 mL round bottomed flask, under a nitrogen system. The reaction mixture is cooled to 0°C, and triethylamine (0.2 mL, 2.5 eq.) is added by syringe, followed by isopropylsulfonyl chloride (0.095 mL, 1.5 eq.), also by syringe, and mixed overnight. The reaction is quenched with 20 mL water, and the layers are separated.
  • step D ⁇ 2-[6-(2-Aminoethoxy)(2- naphthyl)]ethyl ⁇ [(methylethyl)sulfonyl]amine (0.571 mmol) is dissolved in methylene chloride in a 15 mL round bottomed flask, under a nitrogen system.
  • the reaction mixture is cooled to 0°C, and triethylamine (0.2 mL, 2.5 eq.) is added by syringe, followed by isopropylsulfonyl chloride (0.095 mL, 1.5 eq.), also by syringe, and mixed overnight.
  • the reaction is quenched with 20 mL water, and layers are separated.
  • 2-(6-Methoxy-2-naphthyl)propylamine (35.32 g, 164.05 mmol) is dissolved in methylene chloride in a 3000 mL round bottomed flask, under a nitrogen system. The mixture is cooled to 0°C, and triethylamine (68.5 mL, 492.15 mmol) is added by syringe, followed by isopropylsulfonyl chloride (36.85 mL, 328.1 mmol), also by syringe, and the reaction mixture is stirred overnight. The reaction is quenched with 1000 mL water, and the layers are separated.
  • This material is purified by silica gel chromatography, with a Waters Prep 2000, employing one Prep-Pak's® in a 9:1 methylene chloride:methanol solvent system, to provide the intermediate title compound (1.17 g, 59%) as a brown foam.
  • step D ⁇ 2-[6-(2-Aminoethoxy)(2- naphthyl)]propyl ⁇ [(methylethyl)sulfonyl]amine (0.571 mmol) is dissolved in methylene chloride in a 15 mL round bottomed flask, under a nitrogen system. The mixture is cooled to 0°C, and triethylamine (0.2 mL, 2.5 eq) is added by syringe, followed by methanesulfonyl chloride (0.07 mL, 1.5 eq.), also by syringe, and mixed overnight. The reaction is quenched with 20 mL water, and layers are separated.
  • step D ⁇ 2-[6-(2-Aminoethoxy)(2- naphthyl)]propyl ⁇ [(methylethyl)sulfonyl]amine (0.571 mmol) is dissolved in methylene chloride in a 15 mL round bottomed flask, under a nitrogen system. The mixture is cooled to 0°C, and triethylamine (0.2 mL, 2.5 equivalents) is added by syringe, followed by isopropylsulfonyl chloride (0.095 mL, 1.5 eq.), also by syringe, and mixed overnight. The reaction is quenched with 20 mL water, and the layers are separated.
  • step D ⁇ 2-[6-(2-Aminoethoxy)(2- naphthyl)]ethyl ⁇ (methylsulfonyl)amine (0.571 mmol, prepared in example 15) is dissolved in methylene chloride in a 15 mL round bottomed flask, under a nitrogen system. The mixture is cooled to 0°C, and triethylamine (0.2 mL, 2.5 eq) is added by syringe, followed by trifluoromethylsulfonyl chloride (0.09 mL, 1.5 eq.), also by syringe, and mixed overnight. The reaction is quenched with 20 mL water, and layers are separated.
  • step A ⁇ 2-[6-(2-Aminoethoxy)(2- naphthyl)]ethyl ⁇ (methylsulfonyl)amine (0.571 mmol) is dissolved in methylene chloride in a 15 mL round bottomed flask, under a nitrogen system. The mixture is cooled to 0°C, and triethylamine (0.2 mL, 2.5 eq.) is added by syringe, followed by acetyl chloride (0.06 mL, 1.5 eq.), also by syringe, and mixed overnight. The reaction is quenched with 20 mL water, and layers are separated.
  • step D ⁇ 2-[6-(2-Aminoethoxy)(2- naphthyl)]ethyl ⁇ (methylsulfonyl)amine (0.571 mmol) is dissolved in methylene chloride in a 15 mL round bottomed flask, under a nitrogen system. The mixture is cooled to 0°C, and triethylamine (0.2 mL, 2.5 eq.) is added by syringe, followed by phenylsulfonyl chloride (0.11 mL, 1.5 eq.), also by syringe, and mixed overnight. The reaction is quenched with 20 mL water, and layers are separated.
  • step A ⁇ 2-[6-(2-Aminoethoxy)(2- naphthyl)]ethyl ⁇ (methylsulfonyl)amine (0.571 mmol) is dissolved in methylene chloride in a 15 mL round bottomed flask, under a nitrogen system. The mixture is cooled to 0°C, and triethylamine (0.2 mL, 2.5 eq.) is added by syringe, followed by benzoyl chloride (0.04 mL, 1.5 eq.), also by syringe, and mixed overnight. The reaction is quenched with 20 mL water, and layers are separated.
  • step A ⁇ 2-[6-(2-Aminoethoxy)(2- naphthyl)]ethyl ⁇ (methylsulfonyl)amine (0.571 mmol) is dissolved in methylene chloride in a 15 mL round bottomed flask, under a nitrogen system. The mixture is cooled to 0°C, and triethylamine (0.2 mL, 2.5 eq.) is added by syringe, followed by butyryl chloride (0.05 mL, 1.5 eq.), also by syringe, and mixed overnight. The reaction is quenched with 20 mL water, and layers are separated.
  • step D ⁇ 2-[6-(2-Aminoethoxy)(2- naphthyI)]ethyl ⁇ (methylsulfonyl)amine (0.571 mmol) is dissolved in methylene chloride in a 15 mL round bottomed flask, under a nitrogen system. The mixture is cooled to 0°C, and triethylamine (0.2 mL, 2.5 eq.) is added by syringe, followed by methyl chloroformate (0.06 mL, 1.5 eq.), also by syringe, and mixed overnight. The reaction is quenched with 20 mL water, and layers are separated.
  • step E ⁇ 2-[6-(2-Aminoethoxy)(2- naphthyl)]ethyl ⁇ (methylsulfonyl)amine (0.571 mmol) is dissolved in methylene chloride in a 15 mL round bottomed flask, under a nitrogen system. The mixture is cooled to 0°C, and triethylamine (0.2 mL, 2.5 equivalents) is added by syringe, followed by N-methyl-N-phenylcarbamoyl chloride (80 mg, 1.5 Eq.), also by syringe, and mixed overnight. The reaction is quenched with 20 mL water, and layers are separated.
  • step D The title compound is prepared in a manner analogous to the procedure set forth in example 21 from ⁇ 2-[6-(2-aminoethoxy)(2- naphthyl)]ethyl ⁇ [(methylethyl)sulfonyl]amine (prepared in example 16).
  • step A The title compound is prepared in a manner analogous to the procedure set forth in example 22 from ⁇ 2-[6-(2-aminoethoxy)(2- naphthyl)]ethyl ⁇ [(methylethyl)sulfonyl]amine (prepared in example 16).
  • step D The title compound is prepared in a manner analogous to the procedure set forth in example 23 from ⁇ 2-[6-(2-aminoethoxy)(2- naphthyl)]ethyl ⁇ [(methylethyl)sulfonyl]amine (prepared in example 16).
  • step A The title compound is prepared in a manner analogous to the procedure set forth in example 24 from ⁇ 2-[6-(2-aminoethoxy)(2- naphthyl)]ethyl ⁇ [(methylethyl)sulfonyl]amine (prepared in example 16).
  • step A The title compound is prepared in a manner analogous to the procedure set forth in example 25 from ⁇ 2-[6-(2-aminoethoxy)(2- naphthyl)]ethyl ⁇ [(methylethyl)sulfonyl]amine (prepared in example 16).
  • step A The title compound is prepared in a manner analogous to the procedure set forth in example 26 from ⁇ 2-[6-(2-aminoethoxy)(2- naphthyl)]ethyl ⁇ [(methylethyl)sulfonyl]amine (prepared in example 16).
  • step E The title compound is prepared in a manner analogous to the procedure set forth in example 27 from ⁇ 2-[6-(2-aminoethoxy)(2- naphthyl)]ethyl ⁇ [(methylethyl)sulfonyl]amine (prepared in example 16).
  • step D The title compound is prepared in a manner analogous to the procedure set forth in example 21 from ⁇ 2-[6-(2-aminoethoxy)(2- naphthyl)]propyl ⁇ [(methylethyl)sulfonyl]amine (prepared in example 19).
  • step A The title compound is prepared in a manner analogous to the procedure set forth in example 22 from ⁇ 2-[6-(2-aminoethoxy)(2- naphthyl)]propyl ⁇ [(methylethyl)sulfonyl]amine (prepared in example 19).
  • step D The title compound is prepared in a manner analogous to the procedure set forth in example 23 from ⁇ 2-[6-(2-aminoethoxy)(2- naphthyl)]propyl ⁇ [(methylethyl)sulfonyl]amine (prepared in example 19).
  • step A The title compound is prepared in a manner analogous to the procedure set forth in example 24 from ⁇ 2-[6-(2-aminoethoxy)(2- naphthyl)]propyl ⁇ [(methylethyl)sulfonyl]amine (prepared in example 19).
  • step A The title compound is prepared in a manner analogous to the procedure set forth in example 25 from ⁇ 2-[6-(2-aminoethoxy)(2- naphthyl)]propyl ⁇ [(methyIethyl)sulfonyl]amine (prepared in example 19)
  • step D The title compound is prepared in a manner analogous to the procedure set forth in example 26 from ⁇ 2-[6-(2-aminoethoxy)(2- naphthyl)]propyl ⁇ [(methylethyl)sulfonyl]amine (prepared in example 19)
  • step E The title compound is prepared in a manner analogous to the procedure set forth in example 27 from ⁇ 2-[6-(2-aminoethoxy)(2- naphthyl)]propyl ⁇ [(methylethyl)sulfonyl]amine (prepared in example 19)
  • step C ⁇ 2-[6-(2-Aminoethoxy)(2- naphthyl)]ethyl ⁇ (methylsulfonyl)amine (0.343 mmol, prepared in example 15) dissolved in methanol (2 mL) is added to a 15 mL round bottomed flask fitted with a stirbar and under a nitrogen atmosphere.
  • Benzaldehyde (0.06 mL, 1.0 eq.) is treated with a catalytic amount of acetic acid and stirred at room temperature for 4 hours.
  • Sodium borohydride (26 mg, 2.0 eq.) is added, and the reaction is stirred overnight at room temperature.
  • reaction mixture is then diluted with water (5 mL), and extracted with methylene chloride (3 x 25 mL). The organic extracts are combined and filtered through potassium carbonate, and concentrated under vacuum. The residue is further purified by silica gel chromatography, employing a Chromatotron ® and a 2000 uM rotor in 100% ethyl acetate eluent to provide the title compound.
  • step C The title compound is prepared in a manner analogous to the procedure set forth in example 42 from ⁇ 2-[6-(2-aminoethoxy)(2- naphthyi)]ethyI ⁇ [(methyIethyl)sulfonyl]amine (prepared in example 16).
  • Example 44 Preparation of r(methylethv0sulfonv ⁇ r2-(6-(2-rbenzylaminolethoxy)(2- naphthyl))propynamine.
  • step C ⁇ 2-[6-(2-Aminoethoxy)(2- naphthyl)]propyl ⁇ [(methylethyl)sulfonyl]amine (0.343 mmol, prepared in example 19) dissolved in methanol (2 mL) is added to a 15 mL round bottomed flask fitted with a stirbar and under a nitrogen atmosphere.
  • Benzaldehyde (0.06 mL, 1.0 eq.) dissolved in acetic acid (1 mg, 0.05 eq.) is added by syringe and stirred at room temperature for 4 hours.
  • Sodium borohydride (26 mg, 2.0 eq.) is added, and the reaction is stirred overnight at room temperature.
  • step B Trifluoroacetic acid (0.06 mL, 1.4 eq.) in toluene (1 mL) is added dropwise to a solution of ⁇ 2 ⁇ [6-(2-aminoethoxy)(2- naphthyl)]ethyl ⁇ (methyIsulfonyl)amine (0.571 mmol, prepared in example 15) and sodium cyanate (74 mg, 2.0 eq.) in toluene (3 mL) with stirring, at 50°C, and under a nitrogen atmosphere in a 15 mL round bottomed flask. The solution is then heated to 70°C and stirred for one hour. The reaction mixture is concentrated under vacuum.
  • step B The title compound is prepared in a manner analogous to the procedure set forth in example 45 from ⁇ 2-[6-(2-aminoethoxy)(2- naphthyl)]ethyl ⁇ [(methylethyl)sulfonyl]amine (prepared in example 16).
  • step B Trifluoroacetic acid (0.06 mL, 1.4 eq.) in toluene (1 mL) is added dropwise to ⁇ 2-[6-(2-aminoethoxy)(2- naphthyl)]propyl ⁇ [(methylethyl)sulfonyl]amine (0.571 mmol, prepared in Example 19) and sodium cyanate (74 mg, 2.0 eq.) in toluene (3 mL) with stirring, at 50°C, and under a nitrogen atmosphere in a 15 mL round bottomed flask. Solution was heated to 70°C and stirred for one hour. The reaction mixture is concentrated under vacuum.
  • step E Methyl isocyanate (0.05 mL, 1.0 eq.) is added dropwise to ⁇ 2-[6-(2-aminoethoxy)(2-naphthyl)]ethyl ⁇ (methylsulfonyl)amine (0.7133 mmol, prepared in example 15) in THF (5 mL) at 0°C, in a 15 mL round bottomed flask fitted with a stirbar. The reaction is stirred overnight in an ice 5 bath, gradually warming to room temperature. The reaction mixture is then quenched with water (5 mL) and is extracted with methylene chloride (3 x 15 mL).
  • step E The title compound is prepared in a manner analogous to the procedure set forth in example 48 from ⁇ 2-[6-(2-aminoethoxy)(2- naphthyl)]ethyl ⁇ [(methylethyl)sulfonyl]amine (prepared in example 16).
  • step E Methyl isocyanate (0.05 mL, 1.0 eq.) is added dropwise to ⁇ 2-[6-(2-aminoethoxy)(2-naphthyl)]propyl ⁇ [(methylethyl)sulfonyl]amine (0.7133 mmol, prepared in Example 19) in THF (5 mL) at 0°C, in a 15 mL round bottomed flask fitted with a stirbar. The reaction is then stirred overnight in ice bath, gradually warming to room temperature. The reaction mixture is quenched with water (5 mL) and is extracted with methylene chloride (3 x 15 mL).
  • step C The title compound is prepared in a manner analogous to the procedure set forth in example 51 from ⁇ 2-[6-(2-aminoethoxy)(2- naphthyl)]ethyl ⁇ [(methylethyl)sulfonyl]amine (prepared in example 16).
  • Example 53 Preparation of (2-(6-r2-(dimethylamino)ethoxy1(2- naphthyl))propyl)F(methylethyl)sulfonvnamine.
  • step C To a stirring solution of ⁇ 2-[6-(2-aminoethoxy)(2- naphthyl)]propyl ⁇ [(methylethyl)sulfonyl]amine (0.713 mmol, prepared in Example 19) in methanol (5 mL) is added formaldehyde (0.85 mL, 16 eq.) over a 15 minute period and let the mixture to stirr at room temperature for one hour. Sodium borohydride (216 mg, 8 eq) is added to the reaction and the mixture is stirred at room temperature over night. The reaction is concentrated under vacuum and the crude product is dissolved in 2:1 methylene chloride:water (30 mL).
  • the ability of compounds of formula I to potentiate glutamate receptor- mediated response may be determined using fluorescent calcium indicator dyes (Molecular Probes, Eugene, Oregon, Fluo-3) and by measuring glutamate- evoked efflux of calcium into GluR4 transfected HEK293 cells, as described in more detail below.
  • Patent Application Publication Number EP-A1-583917 are prepared.
  • the tissue culture medium in the wells is then discarded, and the wells are each washed once with 200 ⁇ l of buffer (glucose, 10mM, sodium chloride, 138mM, magnesium chloride, 1 mM, potassium chloride, 5mM, calcium chloride, 5mM, N-[2- hydroxyethyl]-piperazine-N-[2-ethanesulfonic acid], 10mM, to pH 7.1 to 7.3).
  • the plates are then incubated for 60 minutes in the dark with 20 ⁇ M Fluo3-AM dye (obtained from Molecular Probes Inc., Eugene, Oregon) in buffer in each well. After the incubation, each well is washed once with 100 ⁇ l buffer, 200 ⁇ l of buffer is added and the plates are incubated for 30 minutes.
  • Solutions for use in the test are also prepared as follows. 30 ⁇ M, 10 ⁇ M, 3 ⁇ M and 1 ⁇ M dilutions of test compound are prepared using buffer from a 10 mM solution of test compound in DMSO. 100 ⁇ M cyclothiazide solution is prepared by adding 3 ⁇ l of 100 mM cyclothiazide to 3 mL of buffer. Control buffer solution is prepared by adding 1.5 ⁇ l DMSO to 498.5 ⁇ l of buffer.
  • Each test is then performed as follows. 200 ⁇ l of control buffer in each well is discarded and replaced with 45 ⁇ l of control buffer solution. A baseline fluorescent measurement is taken using a FLUOROSKAN II fluorimeter (Obtained from Labsystems, Needham Heights, MA, USA, a Division of Life Sciences International Pic). The buffer is then removed and replaced with 45 ⁇ l of buffer and 45 ⁇ l of test compound in buffer in appropriate wells. A second fluorescent reading is taken after 5 minutes incubation. 15 ⁇ l of 400 ⁇ M glutamate solution is then added to each well (final glutamate concentration 100 ⁇ M), and a third reading is taken.
  • test compounds and cyclothiazide solutions are determined by subtracting the second from the third reading (fluorescence due to addition of glutamate in the presence or absence of test compound or cyclothiazide) and are expressed relative to enhance fluorescence produced by 100 ⁇ M cyclothiazide.
  • HEK293 cells stably expressing human GluR4 are used in the electrophysiological characterization of AMPA receptor potentiators.
  • recording pipettes have a resistance of 2-3 M ⁇ .
  • whole-cell voltage clamp technique Hamill et al.(1981)Pfl ⁇ gers Arch., 391 : 85-100
  • cells are voltage-clamped at -60mV and control current responses to 1 mM glutamate are evoked.
  • the present invention provides a pharmaceutical composition, which comprises a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.
  • compositions are prepared by known procedures using well-known and readily available ingredients.
  • the active ingredient will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, and may be in the form of a capsule, sachet, paper, or other container.
  • the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments containing, for example, up to 10% by weight of active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • Suitable carriers, excipients, and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum, acacia, calcium phosphate, alginates, tragcanth, gelatin, calcium silicate, micro-crystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, methyl cellulose, methyl and propyl hydroxybenzoates, talc, magnesium stearate, and mineral oil.
  • the formulations can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents, or flavoring agents.
  • Compositions of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
  • compositions are preferably formulated in a unit dosage form, each dosage containing from about 1 mg to about 500 mg, more preferably about 5 mg to about 300 mg (for example 25 mg) of the active ingredient.
  • unit dosage form refers to a physically discrete unit suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier, diluent, or excipient.
  • patient refers to a mammal, such as a mouse, guinea pig, rat, dog or human. It is understood that the preferred patient is a human.
  • the terms “treating” or “to treat” each mean to alleviate symptoms, eliminate the causation either on a temporary or permanent basis, or to prevent or slow the appearance of symptoms of the named disorder.
  • the methods of this invention encompass both therapeutic and prophylactic administration.
  • the term "effective amount” refers to the amount of a compound of formula I which is effective, upon single or multiple dose administration to a patient, in treating the patient suffering from the named disorder.
  • An effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances.
  • a number of factors are considered by the attending diagnostician, including, but not limited to: the species of mammal; its size, age, and general health; the specific disease or disorder involved; the degree of or involvement or the severity of the disease or disorder; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.
  • the compounds of formula I can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, bucal or intranasal routes. Alternatively, the compounds of formula I may be administered by continuous infusion.
  • a typical daily dose will contain from about 0.01 mg/kg to about 100 mg/kg of the compound of formula I. Preferably, daily doses will be about 0.05 mg/kg to about 50 mg/kg, more preferably from about 0.1 mg/kg to about 25 mg/kg.
  • R is preferably hydrogen
  • R 1 is preferably (1 -4C)alkyl, CF 3 , N(CH 3 ) 2 , or NH(CH 3 ), most preferably methyl, ethyl, propyl, CF 3 , or 2-propyl, and it is most especially preferred that R 1 is 2-propyl;
  • R 2 is preferably hydrogen, F, methyl, ethyl, propyl, hydroxy, or methoxy, most preferably hydrogen, F, hydroxy, or methyl, and it is most especially preferred that R 2 is F or methyl;
  • R 3a is preferably hydrogen, F, methyl, ethyl, propyl, hydroxy, or methoxy, and most preferably hydrogen, F, hydroxy, or methyl;
  • R 3b is preferably hydrogen, methyl, ethyl, propyl, or methoxy, most preferably hydrogen, or methyl, and it is most especially preferred that R 3b is hydrogen;
  • R 4a is preferably hydrogen, F

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