WO2006113471A2 - Antagonistes de nmda/nr2b a base de n-alkyl-azacycloalkyle - Google Patents

Antagonistes de nmda/nr2b a base de n-alkyl-azacycloalkyle Download PDF

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WO2006113471A2
WO2006113471A2 PCT/US2006/014139 US2006014139W WO2006113471A2 WO 2006113471 A2 WO2006113471 A2 WO 2006113471A2 US 2006014139 W US2006014139 W US 2006014139W WO 2006113471 A2 WO2006113471 A2 WO 2006113471A2
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group
alkyl
halogen
optionally substituted
hydrogen
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PCT/US2006/014139
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WO2006113471A3 (fr
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Mark E. Layton
Kevin J. Rodzinak
Michael J. Kelly Iii
Philip E. Sanderson
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Merck & Co., Inc.
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Priority to EP06750229A priority Critical patent/EP1874318A2/fr
Priority to US11/918,336 priority patent/US20090124600A1/en
Priority to AU2006236625A priority patent/AU2006236625A1/en
Priority to JP2008507751A priority patent/JP2008536927A/ja
Priority to CA002603876A priority patent/CA2603876A1/fr
Publication of WO2006113471A2 publication Critical patent/WO2006113471A2/fr
Publication of WO2006113471A3 publication Critical patent/WO2006113471A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
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    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
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    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates to N-alkyl-azacycloalkyl compounds.
  • this invention relates to N-alkyl-azacycloalkyl compounds that are NMDA/NR2B antagonists useful for the treatment of neurological conditions such as pain, Parkinson's disease, Alzheimer's disease, epilepsy, depression, anxiety, ischemic brain injury including stroke, and other conditions.
  • NMDA receptors are heteromeric assemblies of subunits, of which two maj or subunit families designated NRl and NR2 have been cloned.
  • NMDA receptors in the mammalian central nervous system are only fo ⁇ ned by combinations of NRl and NR2 subunits, which respectively express glycine and glutamate recognition sites.
  • the NR2 subunit family is in turn divided into four individual subunit types: NR2A, NR2B, NR2C, and NR2D. T. Ishii, et al., J. Biol. Chem., 268:2836-2843 (1993), and DJ. Why et al., MoI.
  • Brain Res., 51:23-32 (1997) describe how the various resulting combinations produce a variety of NMDA receptors differing in physiological and pharmacological properties such as ion gating properties, magnesium sensitivity, pharmacological profile, as well as in anatomical distribution.
  • NR2 subunits are differentially distributed, hi particular, it is believed that the distribution map for NR2B lowers the probability of side effects while treating Parkinson's disease or pain.
  • NMDA antagonists that target the NR2B receptor.
  • the present invention relates to compounds represented by Formula I:
  • This invention further provides methods to treat and prevent neurological conditions, including pain, Parkinson's disease, Alzheimer's disease, epilepsy, depression, anxiety, ischemic brain injury including stroke, and other conditions, utilizing the present compounds and compositions.
  • W is aryl or heteroaryl, wherein said aryl or heteroaryl is optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, C ⁇ - ⁇ cycloalkyl, cyano, Ci -4 alkoxy, and Ci_6 alkyl, wherein said alkoxy is optionally substituted with one or more halogen, and said alkyl is optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen and hydroxyl;
  • A is a bond or Cu alkyl, optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, hydroxyl, and Ci_3 alkyl, wherein said alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, C 1-4 alkoxy, and cyano;
  • B is Ci alkyl, optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, hydroxyl, and Cl .3 alkyl, wherein said alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, Cj -4 alkoxy, and cyano, where a ring is formed comprising A and B, where an individual carbon atom in A and an individual carbon atom in B optionally can join to bridge said ring;
  • R 1 and R 2 each is independently selected from the group consisting of hydrogen and Cl .3 alkyl
  • R3 and R 4 each is independently selected from the group consisting of hydrogen, hydroxyl, cyano, and Ci_3 alkyl, wherein said alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, Ci -4 alkoxy, and cyano,
  • R 3 and R 4 along with the ring to which they are attached, optionally can join to fo ⁇ n a bridged cycloalkyl.
  • One embodiment of the present invention provides a compound described by the chemical Formula (I), and/or a pharmaceutically acceptable salt, individual enantiomer and stereoisomer thereof, wherein:
  • W is aryl, optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, C3.6 cycloalkyl, Ci -4 alkoxy, and Cl_6 alkyl, wherein said alkyl is optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen and hydroxyl;
  • R 3 and R 4 each is independently hydrogen
  • A is a bond or Ci -3 alkyl, optionally substituted with one or more substituents selected from the group consisting of hydrogen and halogen;
  • B is Qalkyl, optionally substituted with one or more substituents selected from the group consisting of hydrogen and halogen, where a ring is formed comprising A and B, where an individual carbon atom in A and an individual carbon atom in B optionally can join to bridge said ring.
  • W is aryl, optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, C3_6 cycloalkyl, C 1-4 alkoxy, and C ⁇ . ⁇ alkyl, wherein said alkyl is optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen and hydroxyl;
  • R 1 and R 2 each is independently selected from the group consisting of hydrogen and C ⁇ .3 alkyl
  • A is a bond or Cu alkyl, optionally substituted with one or more substituents selected from the group consisting of hydrogen and halogen.
  • Another embodiment of this invention includes compounds represented by Formula Ib: w x/ ⁇ / ⁇ /
  • W is aryl, optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, C ⁇ - ⁇ cycloalkyl, C 1-4 alkoxy, and Ci-6 alkyl, wherein said alkyl is optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen and hydroxyl;
  • B is Qalkyl, optionally substituted with one or more substituents selected from the group consisting of hydrogen and halogen.
  • W is aryl, optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, C3-6 cycloalkyl, Cj -4 alkoxy, and Cj_6 alkyl, wherein said alkyl is optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen and hydroxyl; and
  • W is aryl, optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, C3_6 cycloalkyl, C ⁇ alkoxy, and C ⁇ . ⁇ alkyl, wherein said alkyl is optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen and hydroxyl;
  • X is C 1-3 alkyl optionally substituted with one or more substituents selected from the group consisting of hydrogen and halogen;
  • A is a bond or Ci -3 alkyl, optionally substituted with one or more substituents selected from the group consisting of hydrogen and halogen;
  • R3 and R 4 each is independently selected from the group consisting of hydrogen, hydroxyl, cyano, and Ci_3 alkyl, wherein said alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, C 1-4 alkoxy, and cyano, where R 3 and R 4 , along with the ring to which they are attached, can join to form a bridged cycloalkyl.
  • W is aryl, optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, C3_6 cycloalkyl, Q -4 alkoxy, and C ⁇ . ⁇ alkyl, wherein said alkyl is optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen and hydroxyl;
  • A is a bond or Cu alkyl, optionally substituted with one or more substituents selected from the group consisting of hydrogen and halogen;
  • B is Qalkyl, optionally substituted with one or more substituents selected from the group consisting of hydrogen and halogen, where a ring is formed comprising A and B, where an individual carbon atom in A and an individual carbon atom in B optionally can join to bridge said ring.
  • alkyl as well as other groups having the prefix “alk” such as, for example, alkane, alkanoyl, alkenyl, and alkynyl means carbon chains that may be linear or branched or combinations thereof.
  • alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, and heptyl.
  • Ci_galkyl is defined to identify the group as having 1, 2, 3, 4, 5 or 6 carbons in a linear or branched arrangement, such that Ci-galkyl includes methyl, ethyl, n- propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, pentyl and hexyl.
  • Ci_4alkyl is defined to identify the group as having 1, 2, 3 or 4 carbons in a linear or branched arrangement, such that Ci-4alkyl specifically includes methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl and tert-butyl.
  • C 0 is a hydrogen atom substituent when the alkyl is a terminal group and is a direct bond when the alkyl is a bridging group.
  • Alkenyl alkynyl and other like terms include carbon chains containing at least one unsaturated C-C bond.
  • alkoxy as used herein, alone or in combination, includes alkyl ether groups, wherein the term 'alkyl' is defined above, and 'ether' means two alkyl groups with an oxygen atom between them.
  • suitable alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n- butoxy, s-butoxy, t-butoxy, methoxymethane (also referred to as 'dimethyl ether'), and methoxyethane (also referred to as 'ethyl methyl ether').
  • cycloalkyl is intended to mean carbocycles containing no heteroatoms, and includes mono-, bi- and tricyclic saturated carbocycles, as well as fused ring systems.
  • fused ring systems can include one ring that is partially or fully unsaturated such as a benzene ring to form fused ring systems such as benzofused carbocycles.
  • Cycloalkyl includes such fused ring systems as spirofused ring systems.
  • cycloalkyl examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalene, adamantane, indanyl, indenyl, fluorenyl, and 1,2,3,4- tetrahydronaphalene.
  • aryl is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic. Examples of such aryl elements include phenyl, napthyl and tolyl.
  • bridged cycloalkyF' is intended to mean two or more cycloalkyl groups, heterocycloalkyl groups, or a combination thereof joined via adjacent or non-adjacent atoms.
  • bridged cycloalkyl groups include 8-azabicyclo[3.2.1]oct-3-yl and 3-azabicyclo[3.1.0]hex-6-yl.
  • heteroaryl as used herein except where noted, is intended to mean a stable 5- to 7-membered monocyclic- or stable 9- to 10-membered fused bicyclic heterocyclic ring system which contains an aromatic ring, any ring of which may be saturated, such as piperidinyl, partially saturated, or unsaturated, such as pyridinyl, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
  • heteroaryl groups include, but are not limited to, pyridine, pyrimidine, pyrazine, thiophene, oxazole, thiazole, triazole, thiadiazole, oxadiazole, pyrrole, 1,2,4-oxadiazole, 1,3,4- oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, and 1,2,4-triazole.
  • hetero includes one or more O, S, or N atoms.
  • heterocycloalkyl and heteroaryl include ring systems that contain one or more O, S, or N atoms in the ring, including mixtures of such atoms.
  • the hetero atoms replace ring carbon atoms.
  • a heterocycloC 5 alkyl is a five-member ring containing from 4 to no carbon atoms.
  • heterocycloalkyls examples include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, imidazolinyl, pyrolidin-2-one, piperidin-2-one, and thiomorpholinyl.
  • halo or halogen as used herein is intended to include chloro, fluoro, bromo and iodo.
  • optionally substituted is intended to include both substituted and unsubstituted.
  • optionally substituted aryl could represent a pentafluorophenyl or a phenyl ring.
  • optionally substituted multiple moieties such as, for example, alkylaryl are intended to mean that the alkyl and the aiyl groups are optionally substituted. If only one of the multiple moieties is optionally substituted then it will be specifically recited such as "an alkylaryl, the aryl optionally substituted with halogen or hydroxyl.”
  • Compounds described herein may contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers.
  • the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof.
  • Formula I (including Formulas Ia, Ib, Ic, Id, and Ie) is shown without a definitive stereochemistry at certain positions.
  • the present invention includes all stereoisomers of Formula I and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.
  • racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated.
  • the separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to fo ⁇ n a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography.
  • the coupling reaction is often the formation of salts using an enantiomerically pure acid or base.
  • the diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue.
  • the racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art.
  • any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.
  • inorganic bases include aluminum, ammonium, calcium, copper (ic and ous), ferric, ferrous, lithium, magnesium, manganese (ic and ous), potassium, sodium, zinc and the like salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines.
  • Other pharmaceutically acceptable organic non-toxic bases from which salts can be formed include ion exchange resins such as, for example, arginine, betaine, caffeine, choline, N, N -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine
  • the compound of the present invention When the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p- toluenesulfonic acid and the like.
  • Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound fo ⁇ ned, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like
  • organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic,
  • the subject or patient treated in the present methods is generally a mammal such as a human being, male or female, in whom antagonism of NMDA/NR2B receptor activity is desired.
  • the subject or patient treated in the present methods can also be an animal such as a dog, cat, horse, pig, or cow.
  • the term "therapeutically effective amount” means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • treatment refers both to the treatment and to the prevention or prophylactic therapy of the mentioned conditions, particularly in a patient who is predisposed to such disease or disorder.
  • composition as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • Such term in relation to pharmaceutical composition is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • administering a should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need of treatment.
  • compositions of the present invention comprise a compound represented by Formula I (and/or pharmaceutically acceptable salt(s) thereof) as an active ingredient, a pharmaceutically acceptable carrier, and, optionally, other therapeutic ingredients or adjuvants.
  • the instant compositions include those suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
  • the pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
  • the present invention is further directed to a method for the manufacture of a medicament for the antagonism of NMDA/NR2B receptor activity in humans and animals comprising combining a compound of the present invention with a pharmaceutical carrier or diluent.
  • the compounds represented by Formula I, or pharmaceutically acceptable salts thereof, of this invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the fonn of preparation desired for administration, e.g., oral or parenteral (including intravenous).
  • the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient.
  • compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion or as a water-in-oil liquid emulsion.
  • the compound represented by Fo ⁇ nula I, and/or pharmaceutically acceptable salt(s) thereof may also be administered by controlled release means and/or delivery devices.
  • the compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the earner that constitutes one or more necessary ingredients. Li general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.
  • compositions of this invention may include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt of Formula I.
  • the compounds of Formula I, or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.
  • the pharmaceutical carrier employed can be, for example, a solid, liquid, or gas.
  • solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • liquid carriers are sugar syrup, peanut oil, olive oil, and water.
  • gaseous carriers include carbon dioxide and nitrogen.
  • any convenient pharmaceutical media may be employed.
  • water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like may be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets.
  • carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets.
  • tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical earners are employed.
  • tablets may be coated by standard aqueous or nonaqueous techniques.
  • a tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants.
  • Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • Each tablet preferably contains from about 0.5mg to about 5g of the active ingredient and each cachet or capsule preferably containing from about 0.5mg to about 5g of the active ingredient.
  • compositions of the present invention comprise a compound represented by Formula I (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally one or more additional therapeutic agents or adjuvants.
  • the instant compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
  • the pharmaceutical compositions may be conveniently presented in unit dosage fo ⁇ n and prepared by any of the methods well known in the art of pharmacy.
  • Pharmaceutical compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water.
  • a suitable surfactant can be included such as, for example, hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.
  • compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions.
  • the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions.
  • the final injectable form must be sterile and must be effectively fluid for easy syringability.
  • the pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.
  • compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like. Further, the compositions can be in a fo ⁇ n suitable for use in transdermal devices. These formulations may be prepared, utilizing a compound represented by Formula I of this invention, or pharmaceutically acceptable salts thereof, via conventional processing methods. As an example, a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt% to about 10 wt% of the compound, to produce a cream or ointment having a desired consistency.
  • compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable earners include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in moulds.
  • the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
  • other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient
  • NRla/NR2B receptor transfected L(tk-) cells were plated in 96-well format at 3 x 10 4 cells per well and grown for one to two days in normal growth medium (Dulbeccos MEM with Na pyruvate, 4500 mg glucose, pen/strep, glutamine, 10% FCS and 0.5 mg/mL geneticin).
  • NRla/NR2B- expression in these cells was induced by the addition of 4-20 nM dexamethasone in the presence of 500 ⁇ M ketamine for 16 - 24 hours.
  • Solutions of NR2B antagonists were prepared in DMSO and serially diluted with DMSO to yield 10 solutions differing by 3-fold in concentration.
  • a 96-well drug plate was prepared by diluting the DMSO solution 250-fold into assay buffer (Hanks Balanced Salt Solution
  • HBSS HBSS Mg 2+ free (Gibco #14175-079) containing 20 mM HEPES, 2 mM CaCl 2 , 0.1 % BSA and 250 ⁇ M Probenecid (Sigma # P-8761)).
  • the cells were washed twice (Labsystem cell washer, 3 fold dilutions leaving 100 ⁇ L) with assay buffer and loaded with 4 ⁇ M of the calcium fluorescence indicator fluo-3 AM (Molecular Probes # P-1241) in assay buffer containing Pluronic F- 127 (Molecular Probes # P-3000) and 10 ⁇ M ketamine at 37 0 C for one hour.
  • the cells were then washed eight times with assay buffer leaving 100 ⁇ L of buffer in each well.
  • Fluorescence intensity was immediately measured in a FLIPR (Fluorometric Imaging Plate Reader, Molecular Devices) using an excitation of 488 nm and emission at 530 nm. Five seconds after starting the recording of fluorescence intensity, 50 ⁇ L of agonist solution (40 ⁇ M glutamate /glycine, the final concentration 10 ⁇ M) was added and after one minute, when fluorescence signal was stable, 50 ⁇ L of NR2B antagonists and control solutions from the drug plate were added and the fluorescence intensity recorded for another 30 minutes. The IC 50 values were determined by a non-linear least squares fitting of the endpoint fluorescence values to Equation #1 below.
  • Endpoint Florescence + Ymin l + ([Drug] / IC 5 o) nH where, Ymin is average endpoint fluorescence of the control wells containing 1 ⁇ M of AMD-2 and Ymax is the average endpoint fluorescence of wells containing 0.1% DMSO in assay buffer.
  • the radioligand binding assay was performed at room temperature in 96-well microtiter plates with a final assay volume of 1.0 mL in 20 mM Hepes buffer (pH 7.4) containing 150 mM NaCl.
  • Solutions of NR2B antagonists were prepared in DMSO and serially diluted with DMSO to yield 20 ⁇ L of each of 10 solutions differing by 3-fold in concentration.
  • Non-specific binding (NSB) was assessed using AMD-I (10 ⁇ M final concentration), and total binding (TB) was measured by addition of DMSO (2% final concentration).
  • Membranes expressing NRla/NR2B receptors (40 pM final concentration) and tritiated AMD-2 (1 nM final concentration) were added to all wells of the microtiter plate.
  • Tritiated AMD-2 was prepared by the following procedure, illustrated above in Reaction 2: The precursor E (2mg, O.OOSmmol) dissolved in dimethylformamide (0.6mL) and potassium carbonate (1.2mg) for Ih. High specific activity tritiated methyl iodide (5OmCi, 0.0006mmol, in toluene ImL, commercially available from American Radiolabeled Chemicals, St. Louis, Missouri) was added at room temperature and stirred for 2 hours. The reaction mixture was filtered using a Whatman PTFE 0.45 ⁇ m syringeless filter device to remove any insoluble potassium carbonate, washed with Abs.
  • AMD-I can be synthesized according to the general procedure described by C. F. Claiborne et al (Bioorganic & Med. Chem. Letters 13, 697-700 (2003). Unlabelled AMD-2 is prepared as follows:
  • the IC 50 and Ki values be less than 1 ⁇ M in the functional and binding assays, respectively. It is still more advantageous that the IC 50 and Ki values be less than 0.1 ⁇ M in the functional and binding assays, respectively.
  • the present compounds are NMDA NR2B receptor antagonists, and as such are useful for treating, preventing, controlling, ameliorating or reducing the risk of diseases and disorders mediated through the NR2B receptor.
  • Such diseases and disorders include, but are not limited to, neuropathic pain (such as postherpetic neuralgia, nerve injury, the "dynias", e.g., vulvodynia, phantom limb pain, root avulsions, painful diabetic neuropathy, compressive mononeuropathy, ischemic neuropathy, painful traumatic mononeuropathy, or painful polyneuropathy), central pain syndromes (potentially caused by virtually any lesion at any level of the nervous system), and postsurgical pain syndromes (eg, postmastectomy syndrome, postthoracotomy syndrome, stump pain), bone and joint pain (osteoarthritis, rheumatoid arthritis, ankylosing spondylitis), repetitive motion pain, carpal tunnel syndrome, dental pain, cancer pain, myofascial pain (muscular injury, fibromyalgia), perioperative pain (general surgery, gynecological), chronic pain, dysmenorrhea, as well as pain associated with angina,
  • osteoarthritis rheumatoid arthritis, rheumatic disease, teno-synovitis and gout
  • headache migraine and cluster headache
  • depression anxiety, schizophrenia, stroke, traumatic brain injury, Alzheimer's disease, cerebral ischemia, spinal cord injury, cerebral vascular disease, Meniere's disease, vertigo, amyotrophic lateral sclerosis, Huntington's disease, sensorineural hearing loss, tinnitus, macular degeneration, glaucoma, neurological damage caused by epileptic seizures or by neurotoxin poisoning or by impairment of glucose and/or oxygen to the brain, vision loss caused by neurodegeneration of the visual pathway, Restless Leg Syndrome, multi-system atrophy, non-vascular headache, primary hyperalgesia, secondary hyperalgesia, primary allodynia, secondary allodynia, or other pain caused by central sensitization.
  • Compounds of Formula I are useful for treating or preventing movement disorders such as Parkinson's disease, dyskinesias (including the side effects accompanying normal doses of L- Dopa), tardive diskinesia, drug-induced parkinsonism, postencephalitic parkinsonism, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, parkinsonian-ALS dementia complex, basal ganglia calcification, akinesia, akinetic-rigid syndrome, bradykinesia, dystonia, medication-induced parkinsonian, Gilles de Ia Tourette syndrome, Huntingon disease, tremor, chorea, myoclonus, tick disorder, and dystonia.
  • Parkinson's disease dyskinesias (including the side effects accompanying normal doses of L- Dopa), tardive diskinesia, drug-induced parkinsonism, postencephalitic parkinsonism, progressive supranuclear palsy, multiple system atrophy, cortico
  • movement disorders includes akinesias and akinetic-rigid syndromes, dyskinesias and medication-induced parkinsonism (such as neuroleptic-induced parkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-induced tardive dyskinesia and medication-induced postural tremor).
  • akinetic-rigid syndromes include Parkinson's disease, drug-induced parkinsonism, postencephalitic parkinsonism, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, parkinsonism-ALS dementia complex and basal ganglia calcification.
  • Examples of “dyskinesias” include tremor (including rest tremor, postural tremor and intention tremor), chorea (such as Sydenham's chorea, Huntington's disease, benign hereditary chorea, neuroacanthocytosis, symptomatic chorea, drug-induced chorea and hemiballism), myoclonus (including generalised myoclonus and focal myoclonus), tics (including simple tics, complex tics and symptomatic tics),and dystonia (including generalised dystonia such as iodiopathic dystonia, drug-induced dystonia, symptomatic dystonia and paroxymal dystonia, and focal dystonia such as blepharospasm, oromandibular dystonia, spasmodic dysphonia, spasmodic torticollis, axial dystonia, dystonic writer's cramp and hemiplegic dystonia).
  • chorea such as Sydenham's chorea, Huntington
  • compounds of Formula I may be used to treat substance abuse disorders, including by decreasing tolerance and/or dependence to opioid treatment of pain, and/or by treating withdrawal syndrome of e.g., alcohol, opioids, heroin, and cocaine.
  • substance abuse disorders includes substance dependence or abuse with or without physiological dependence.
  • the substances associated with these disorders are: alcohol, amphetamines (or amphetamine-like substances), caffeine, cannabis, cocaine, hallucinogens, inhalants, marijuana, nicotine, opioids, phencyclidine (or phencyclidine-like compounds), sedative-hypnotics or benzodiazepines, and other (or unknown) substances and combinations of all of the above.
  • the term "substance abuse disorders” includes drug withdrawal disorders such as alcohol withdrawal with or without perceptual disturbances; alcohol withdrawal delirium; amphetamine withdrawal; cocaine withdrawal; nicotine withdrawal; opioid withdrawal; sedative, hypnotic or anxiolytic withdrawal with or without perceptual disturbances; sedative, hypnotic or anxiolytic withdrawal delirium; and withdrawal symptoms due to other substances. It will be appreciated that reference to treatment of nicotine withdrawal includes the treatment of symptoms associated with smoking cessation.
  • substance abuse disorders include substance-induced anxiety disorder with onset during withdrawal; substance-induced mood disorder with onset during withdrawal; and substance- induced sleep disorder with onset during withdrawal.
  • compounds of structural formula I are useful for aiding in stopping consumption of tobacco and are useful in treating nicotine dependence and nicotine withdrawal.
  • the compounds of formula I produce in consumers of nicotine, such as tobacco smokers, a total or partial abstinence from smoking. Further, withdrawal symptoms are lessened and the weight gain that generally accompanies quitting tobacco comsumption is reduced or nonexistent.
  • the compound of form I may be used in combination with a nicotine agonist or a partial nicotine agonist, or a monoamine oxidase inhibitor (MAOI), or another active ingredient demonstrating efficacy in aiding cessation of tobacco consumption; for example, an antidepressant such as bupropion, doxepine, ornortriptyline; or an anxiolytic such as buspirone or clonidine.
  • a nicotine agonist or a partial nicotine agonist or a monoamine oxidase inhibitor (MAOI)
  • MAOI monoamine oxidase inhibitor
  • the compounds of this invention are also useful for treating or preventing HIV- and FIIV treatment-induced neuropathy, chronic pelvic pain, neuroma pain, complex regional pain syndrome, chronic arthritic pain and related neuralgias, treating or preventing chronic lower back pain, and treating or preventing pain resulting from, or associated with, traumatic nerve injury, nerve compression or entrapment, postherpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, cancer and chemotherapy.
  • compounds of this invention can be administered at prophylactically effective dosage levels to prevent the above-recited conditions, as well as to prevent other conditions mediated through the NMDA NR2B receptor.
  • Compounds of Fo ⁇ nula I may be used in combination with other drugs that are used in the treatment/prevention/suppression or amelioration of the diseases or conditions for which compounds of Formula I are useful. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of Formula I.
  • a pharmaceutical composition containing such other drugs in addition to the compound of Fo ⁇ nula I is preferred.
  • the pharmaceutical compositions of the present invention include those that also contain one or more other drugs or therapeutic agents, in addition to a compound of Formula I.
  • Examples of other therapeutic agents or drugs that may be combined with a compound of Formula I, either administered separately or in the same pharmaceutical compositions include, but are not limited to: (1) non-steroidal antiinflammatory agents; (2) COX-2 inhibitors; (3) bradykinin Bl receptor antagonists; (4) sodium channel blockers and antagonists; (5) nitric oxide synthase (NOS) inhibitors; (6) glycine site antagonists; (7) potassium channel openers; (8) AMPA/kainate receptor antagonists; (9) calcium channel antagonists; (10) GABA-A receptor modulators (e.g., a GABA- A receptor agonist); (11) matrix metalloprotease (MMP) inhibitors; (12) thrombolytic agents; (13) opioids such as morphine; (14) neutrophil inhibitory factor (NlF); (15) L-Dopa; (16) carbidopa; (17) levodopa/carbidopa; (18) dopamine agonists such as bromocriptine, pergolide, pramipexole
  • Suitable antiparkinsonian agents of use in combination with deramcicline include levodopa (with or without a selective extracerebral decarboxylase inhibitor such as carbidopa or benserazide), anticholinergics such as biperiden (optionally as its hydrochloride or lactate salt) and trihexyphenidyl (benzhexol) hydrochloride, and dopamine agonists such as alentemol, bromocriptine, fenoldopam, lisuride, naxagolide, pergolide and pramipexole.
  • levodopa with or without a selective extracerebral decarboxylase inhibitor such as carbidopa or benserazide
  • anticholinergics such as biperiden (optionally as its hydrochloride or lactate salt) and trihexyphenidyl (benzhexol) hydrochloride
  • dopamine agonists such as alentemol
  • the dopamine agonist may be in the form of a pharmaceutically acceptable salt, for example, alentemol hydrobromide, bromocriptine mesylate, fenoldopam mesylate, naxagolide hydrochloride and pergolide mesylate.
  • a pharmaceutically acceptable salt for example, alentemol hydrobromide, bromocriptine mesylate, fenoldopam mesylate, naxagolide hydrochloride and pergolide mesylate.
  • Lisuride and pramipexol are commonly used in a non-salt form.
  • Deramciclane or a pharmaceutically acceptable salt thereof may be administered in combination with a compound selected from the group consisting of: acetophenazine, alentemol, benzhexol, bromocriptine, biperiden, chlorpromazine, chlorprothixene, clozapine, diazepam, fenoldopam, fluphenazine, haloperidol, levodopa,levodopa with benserazide, levodopa with carbidopa, lisuride, loxapine, mesoridazine, molindolone, naxagolide, olanzapine, pergolide, perphenazine, pimozide, pramipexole, risperidone, sulpiride, tetrabenazine, trihexyphenidyl, thioridazine, thiothixene and trifluoperazine
  • Suitable neuroleptic agents of use in combination with deramcicline or a pharmaceutically acceptable salt thereof include the phenothiazine, thioxanthene, heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine and indolone classes of neuroleptic agent.
  • Suitable examples of phenothiazines include chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine and trifluoperazine.
  • Suitable examples of thioxanthenes include chlorprothixene and thiothixene.
  • An example of a dibenzazepine is clozapine.
  • An example of a butyrophenone is haloperidol.
  • An example of a diphenylbutylpiperidine is pimozide.
  • An example of an indolone is molindolone.
  • Other neuroleptic agents include loxapine, sulpiride and risperidone.
  • the neuroleptic agents when used in combination with deramcicline may be in the form of a pharmaceutically acceptable salt, for example, chlorpromazine hydrochloride, mesoridazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, flurphenazine ⁇ nathat ⁇ , fluphenazine decanoate, trifluoperazine hydrochloride, thiothixene hydrochloride, haloperidol decanoate, loxapine succinate and molindone hydrochloride.
  • Perphenazine, chlorprothixene, clozapine, haloperidol, pimozide and risperidone are commonly used in a non-salt form.
  • Creams, ointments, jellies, solutions, or suspensions containing the instant compounds can be employed for topical use. Mouth washes and gargles are included within the scope of topical use for the purposes of this invention.
  • a formulation intended for the oral administration to humans may conveniently contain from about 0.05mg to about 5g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition.
  • Unit dosage forms can generally contain between from about 0.05mg to about lOOOmg of the active ingredient.
  • the conditions recited herein can be treated or prevented by the administration of from about 0.0 lmg to about 140mg of the instant compounds per kilogram of body weight per day.
  • inflammatory pain may be effectively treated by the administration of from about O.Olmg to about 75mg of the present compound per kilogram of body weight per day, or alternatively about 0.5mg to about 3.5g per patient per day.
  • Neuropathic pain may be effectively treated by the administration of from about O.Olmg to about 125mg of the present compound per kilogram of body weight per day, or alternatively about 0.5mg to about 5.5g per patient per day.
  • the compounds of the present invention can be prepared readily according to the following Schemes and specific examples, or modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art but are not mentioned in greater detail.
  • the general procedures for making the compounds claimed in this invention can be readily understood and appreciated by one skilled in the art from viewing the following Schemes.
  • intermediate II is alkylated with 4-chloro-lH-pyrazolo[3,4 ⁇ d]pyrimidine 1 under standard alkylation conditions (R.K. Robins, J. Amer. Chem. Soc. 78, 784-790 (1956)) such as hot alcoholic solvent, including isopropanol or 1-butanol, in the presence of base, including sodium carbonate or diisopropylethylamine.
  • Intermediate II may also be alkylated with a suitably protected derivative of compound 1. Suitable protecting groups include alkoxymethyl derivatives such as N-tetrahydropyranyl, as illustrated by compound 2 and its isomer 3.
  • ester 10 The synthesis of certain aryl-difiuoro-ethyl containing compounds is depicted in Scheme 3.
  • arylation of 2-bromo-2,2-difluoroacetate 8 with 4-chloroiodobenzene 9 in the presence of copper bronze provides ester 10.
  • An alternate synthesis of ester 10 involves acylation of an aryl ring with an acid chloride such as ethyl oxalylchloride in the presence of a Lewis acid such as aluminum trichloride, followed by halogenation of the ketoester with a reagent such as DAST. Hydrolysis of ester 10 under basic conditions provides acid 11.
  • Carboxylic acid 11 is converted to acid chloride 12, which is used to acylate suitably protected amine 13 under standard conditions to yield amide 14.
  • Amide 14 is deprotected under standard conditions such as acid hydrolysis to give amine 15.
  • Amine 15 is reduced under standard conditions such as treatment with borane-THF complex or LAH to yield intermediate 16.
  • Intermediate 16 is converted to the final compound through the reaction sequence illustrated in Scheme 1.
  • ketone 17 is converted to silylenol-ether 18 by treatment with a silyl triflate under basic conditions.
  • Treatment of 18 with an electrophilic fluorine source such as Selectfluor® provides ⁇ -fluoroketone 19.
  • Reduction of 19 under standard conditions provides alcohol 20.
  • Alcohol 20 can be converted into a competent leaving group such as mesylate 21 and reacted with azide to give azide 22.
  • Removal of the protecting group under standard conditions provides amine 23, which can be coupled with acid chloride 24 under standard conditions to provide amide 25.
  • Reduction of amide 25 under standard conditions provides intermediate 26.
  • Intermediate 26 is converted to the final compound through the reaction sequence illustrated in Scheme 1.
  • ketone 37 is reacted with hydroxylamine hydrochloride to give imine 38.
  • the imine 38 can be reduced under standard conditions to give endo 39.
  • the related exo amine to 39 (exemplified by Example 45) is available by altering the reduction conditions to sodium metal in an alcoholic solvent such as propanol. Blocking the primary amine of endo 39 with a suitable protecting group provides 40 and deprotection of the secondary amine under suitable conditions such as acid hydrolysis yields amine 41.
  • Amine 41 is coupled with 42 under standard conditions to give amide 43. Deprotection of amide 43 under standard conditions provides amide 44, and reduction of amide 44 gives intermediate 45.
  • Intermediate 45 is converted to the final compound through the reaction sequence illustrated in Scheme 1.
  • the final product may be further modified by, for example, manipulation of substituents.
  • manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, halogenation and hydrolysis reactions which are commonly known to those skilled in the art.
  • Step A tert-butyl ⁇ l-[2-(benzyloxy)ethyl]pyrrolidin-3-yl ⁇ carbamate
  • Step B l-[2-(benzyloxy)ethyl]pyrrolidin-3 -amine
  • Step C N- ⁇ l-[2-(benzyloxy)ethyl]pyrrolidin-3-yl ⁇ -lH-pyrazolo[3,4-(f
  • Step A tert-butyl [l-(2-hydiOxy-3-phenylpropyl)pyrrolidin-3-yl]carbamate:
  • Step B l-(3-aminopyrrolidin-l-yl)-3-phenylpropan-2-ol
  • Step C l-phenyl-3-[3-(lH-pyrazolo[3,4- ⁇ 5(]pyrimidin-4-ylamino)pyrrolidin-l-yl]propan-2-ol
  • Step A tert-bv ⁇ yl [l-(2-oxo-3-phenylpropanoyl)pyrrolidin-3-yl] carbamate
  • Step B tert-butyl [l-(2,2-difluoro-3-phenylpropanoyl)pyrrolidin-3-yl] carbamate
  • Step C l-(2,2-difluoro-3-phenylpropyl)pyrrolidin-3 -amine
  • Step A tert-butyl [l-(2-oxo-3 -pheny lpropanoyl)piperidin-4-yl] carbamate
  • Step B tot-butyl [l-(2,2-difluoro-3-phenylpropanoyl)piperidin-4-yl]carbamate
  • Step C l-(2,2-difluoro-3-phenylpropanoyl)piperidin-4-amine
  • Step D l-(2,2-difluoro-3-phenylpropyl)piperidin-4-amine
  • Step E N-[l-(2,2-difluoro-3-phenylpropyl)piperidin-4-yl]-lH-pyrazolo[3,4-(f]pyrimidin-4-amine
  • Step A tert-butyl ⁇ l-[2-(4-methylphenyl)ethyl]piperidin-4-yl ⁇ carbamate
  • Step A tert-butyl ⁇ l-[l-methyl-2-(4-methylphenyl)ethyl]piperidin-4-yl ⁇ carbamate
  • Step B N- ⁇ 1 -[ 1 -methyl-2-(4-methylphenyl)ethylJpiperidin-4-yl ⁇ - lH-pyrazolo[3,4-d]pyrimidin-4-amine
  • Step A tert-butyl [l-(2-oxo-2-phenylethyl)piperidin-4-yl] carbamate
  • Step B 2-(4-aminopiperidin-l-yl)-l-phenylethanone
  • Step D l-phenyl-2-[4-(lH-pyrazolo[3,4- ⁇ i]pyrimidin-4-ylamino)piperidm-l-yl]ethanol
  • Step A methyl fluoro(phenyl)acetate
  • Step C N-[l-(2-fluoro-2-phenylethyl)piperidin-4-yl]-lH-pyrazolo[3,4-(f]pyrimidin-4-amine
  • Step B tert-butyl ⁇ l-[(4-chlorophenyl)(difluoro)acetyl]piperidin-4-yl ⁇ carbamate
  • Step C l-[2-(4-chlorophenyl)-2,2-difluoroethyl]piperidin-4-amine
  • reaction mixture was cooled to room temperature, quenched with 6N HCl (20 mL) and heated to 7O 0 C. After 1 hour, the reaction mixture was basified to pH > 8 with 5M NaOH and extracted with ethyl acetate. The combined organics were washed with water and brine, dried over sodium sulfate, filtered, and concentrated to give the title compound (0.25 g). MS: 275 (MfH + ).
  • Step D N- ⁇ l-[2-(4-chlorophenyl)-2,2-difluoroethyl]piperidin-4-yl ⁇ -lH-pyrazolo[3,4-fi(
  • Step B N- ⁇ 1 -[2-(2,6-difluorophenyl)-2,2-difluoroethyl]piperidin-4-yl ⁇ - lH-pyrazolo[3 ,4- ⁇ f]pyrimidm-4- amine
  • Step A difluoro(4-bromophenyl)acetic acid
  • Step A benzyl 4- ⁇ [ter ⁇ -butyl(dimethyl)silyl]oxy ⁇ -3,6-dihydropyridine-l(2H)-carboxylate
  • Step C cis- and trans-benzyl 3 -fluoro-4-hydroxypiperidine-l -carboxylate
  • Step D cis-benzyl 3-fluoro ⁇ 4-[(methylsulfonyl)oxy]piperidine-l-carboxylate
  • Step E trans-benzyl 4-azido-3 -fluoropiperidine- 1 -carboxylate
  • Step G trans-4-azido-3-fluoro-l-(phenylacetyl)piperidine
  • Step I N- [trans-3 -fluoro- 1 -(2-phenylethyl)piperidin-4-yl] - lH-pyrazolo [3 ,4- ⁇ /]pyrimidin-4-amine
  • CD 3 OD ⁇ 8.30 (s, IH), 8.15 (s, IH), 7.38-7.18 (m, 5H), 4.70-4.40 (m, 2H), 3.40 (m, IH), 3.00 (m, IH), 2.85-2.58 ( m, 4H), 2.30 (m, 2H), 2.25 (m, IH), 1.60 (m, IH).
  • Step A cis-4-azido-3-fluoropiperidine
  • Step B N- [cis-3 -fluoro- 1 -(2-phenylethyl)piperidin-4-yl] - lH-pyrazolo [3 ,4- ⁇ f]pyrimidm-4-amme
  • Step A 2-[trans-4-azido-3 -fluoropiperidin- 1 -yl]- 1 -phenylethanol
  • Step B trans-4-azido-3 -fluoro- 1 -(2-fluoro-2-phenylethyl)piperidine
  • Step C trans-3 -fluoro- l-(2-fluoro-2-phenylethyl)piperidin ⁇ 4 ⁇ amine
  • Step D N-[trans-3-fluoro-l-(2-fluoro-2-phenylethyl)piperidin-4-yl]-lH-pyrazolo[3,4-(/
  • Step A trans-4-azido- 1 - [difluoro(phenyl)aceryl] -3 -fluoropiperidine
  • Step B N-[(3R,4i?)-l-(2,2-difluoro-2-phenylethyl)-3-fluoropiperidin-4-yl]-lH-pyrazolo[3,4-c(]pyrimidin- 4-amine
  • Step A l-[difluoro(phenyl)acetyl]azepan-4-one
  • Step B N-[ 1 -(2,2-difluoro-2-phenylethyl)azepan ⁇ 4-yl]- lH-pyrazolo [3 ,4- ⁇ f]pyrimidin-4-amine
  • the title compound was prepared from tert-buty ⁇ exo-3-azabicyclo[3.1.0]hex-6- ylcarbamate (prepared by literature procedure: ⁇ orris, T., Braish, T.F., Butters, M., DeVries, K.M., Hawkins, J.M., Massett, S. S., Rose, P.R., Santafianos, D., Sklavounos, C. J. Chem. Soc, Perkin Trans. 1 (2000) 1615-1622) using procedures similar to that reported in Example 19 above.
  • Step B racemic-(3aS*,4S*,6aR*)-2-benzyloctahydrocyclopenta[c]pyrrol-4-ol
  • Step C racemic-tert-butyl (3aS*,4S*,6ai?*)-4-hydroxyhexahydrocyclopenta[c]pyrrole-2(lH)-carboxylate
  • Step E racemic-N-[(3ajS',4R,6aR)-2-(2-phenylethyl)octahydrocyclopenta[c]pyrrol-4-yl]-lH-pyrazolo[3,4- (f]pyrimidm-4-amme
  • Step A tert-butyl 3-(hydroxyimino)-8-azabicyclo[3.2. l]octane-8-carboxylate
  • Step B endo-tert-butyl 3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate
  • Step C endo-tert-butyl 3- ⁇ [(benzyloxy)carbonyl]amino ⁇ -8-azabicyclo[3.2.1]octane-8-carboxylate
  • Step E endo-benzyl ⁇ 8-[difluoro(phenyl)acetyl]-8-azabicyclo[3.2.1]oct-3-yl ⁇ carbamate
  • Step F endo-N-[8-(2,2-difluoro-2-phenylethyl)-8-azabicyclo[3.2.1]oct-3-yl]-lH-pyrazolo[3,4- d]pyrimidin-4-amine
  • Step A exo-tert-butyl 3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate
  • Step B exo-N-[8-(2,2-difluoro-2-phenylethyl)-8-azabicyclo[3.2.1]oct-3-yl]-lH-pyrazolo[3,4- d]pyrimidin-4-amine

Abstract

La présente invention concerne des composés représentés par la formule (I) et/ou des sels, des énantiomères individuels et des stéréoisomères de ceux-ci, acceptables d'un point de vue pharmaceutique, qui sont efficaces comme antagonistes de NMDA/NR2B, utilisés pour traiter des pathologies comme la douleur, la maladie de Parkinson, la maladie d'Alzheimer, l'épilepsie, la dépression, l'anxiété et les lésions cérébrales d'origine ischémique, par exemple l'accident vasculaire cérébral.
PCT/US2006/014139 2005-04-19 2006-04-14 Antagonistes de nmda/nr2b a base de n-alkyl-azacycloalkyle WO2006113471A2 (fr)

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US11/918,336 US20090124600A1 (en) 2005-04-19 2006-04-14 N-Alkyl-Azacycloalkyl NMDA/NR2B Antagonists
AU2006236625A AU2006236625A1 (en) 2005-04-19 2006-04-14 N-alkyl-azacycloalkyl NMDA/NR2B antagonists
JP2008507751A JP2008536927A (ja) 2005-04-19 2006-04-14 Ｎ−アルキル−アザシクロアルキルｎｍｄａ／ｎｒ２ｂ拮抗物質
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WO2010062927A3 (fr) * 2008-11-26 2010-07-22 Abbott Laboratories Nouvelles octahydrocylopenta(c)pyrrol-4-amines substituées en tant que bloqueurs des canaux calciques
WO2011149995A1 (fr) * 2010-05-25 2011-12-01 Abbott Laboratories Nouvelles octahydrocyclopenta[c]pyrrol-4-amines substituées comme bloqueurs de canaux calciques
WO2011149993A3 (fr) * 2010-05-25 2012-04-05 Abbott Laboratories Octahydrocyclopenta [c] pyrroles substitués utilisés en tant que modulateurs des canaux calciques
WO2013135674A1 (fr) * 2012-03-12 2013-09-19 Syngenta Participations Ag Composés de 2-aryl-acétamide insecticides
WO2013156614A1 (fr) 2012-04-20 2013-10-24 Ucb Pharma S.A. Méthodes de traitement de la maladie de parkinson
WO2015187845A1 (fr) 2014-06-04 2015-12-10 Rugen Holdings (Cayman) Limited Dérivés de difluoroéthylpyridine en tant qu'antagonistes des récepteurs nmda sélectifs du site nr2b
WO2016044323A1 (fr) * 2014-09-15 2016-03-24 Rugen Holdings (Cayman) Limited Dérivés de pyrrolopyrimidine à titre d'antagonistes des récepteurs nmda nr2b
WO2016126869A1 (fr) * 2015-02-04 2016-08-11 Rugen Holdings (Cayman) Limited Dérivés 3,3-difluoro-pipéridine en tant qu'antagonistes des récepteurs nmda nr2b
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WO2017093354A1 (fr) 2015-11-30 2017-06-08 INSERM (Institut National de la Santé et de la Recherche Médicale) Antagonistes de nmdar pour le traitement de maladies associées à l'angiogenèse
EP3197440A4 (fr) * 2014-09-22 2018-04-18 Rugen Holdings (Cayman) Limited Traitement des troubles de l'anxiété et des troubles du spectre autistique
US10239835B2 (en) 2014-09-26 2019-03-26 Cadent Therapeutics, Inc. N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[c]pyrrole negative allosteric modulators of NR2B
WO2020027150A1 (fr) * 2018-07-31 2020-02-06 小野薬品工業株式会社 Dérivé de benzène
US11000526B2 (en) 2016-11-22 2021-05-11 Rugen Holdings (Cayman) Limited Treatment of autism spectrum disorders, obsessive-compulsive disorder and anxiety disorders
US11116749B2 (en) 2013-09-26 2021-09-14 Cadent Therapeutics, Inc Selective octahydro-cyclopenta[c]pyrrole negative modulators of NR2B
US11376258B2 (en) 2019-06-04 2022-07-05 Boehringer Ingelheim International Gmbh Purine derivatives and the use thereof as medicament
WO2022241188A1 (fr) * 2021-05-14 2022-11-17 Theravance Biopharma R&D Ip, Llc Synthèse énantiosélective d'un composé aminotropane
RU2811803C2 (ru) * 2018-07-31 2024-01-17 Оно Фармасьютикал Ко., Лтд. Производное бензола

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WO2020196828A1 (fr) * 2019-03-28 2020-10-01 武田薬品工業株式会社 Composé hétérocyclique contenant de l'azote

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US7723330B2 (en) 2006-03-07 2010-05-25 Array Biopharma Inc. Heterobicyclic pyrazole compounds and methods of use
WO2010062927A3 (fr) * 2008-11-26 2010-07-22 Abbott Laboratories Nouvelles octahydrocylopenta(c)pyrrol-4-amines substituées en tant que bloqueurs des canaux calciques
US8129417B2 (en) 2008-11-26 2012-03-06 Abbott Laboratories Substituted octahydrocyclopenta[C]pyrrol-4-amines as calcium channel blockers
US8691865B2 (en) 2008-11-26 2014-04-08 Abbvie Inc. Substituted octahydrocyclopenta[C]pyrrol-4-amines as calcium channel blockers
WO2011149995A1 (fr) * 2010-05-25 2011-12-01 Abbott Laboratories Nouvelles octahydrocyclopenta[c]pyrrol-4-amines substituées comme bloqueurs de canaux calciques
WO2011149993A3 (fr) * 2010-05-25 2012-04-05 Abbott Laboratories Octahydrocyclopenta [c] pyrroles substitués utilisés en tant que modulateurs des canaux calciques
US8796470B2 (en) 2010-05-25 2014-08-05 Abbvie Inc. Substituted octahydrocyclopenta[c]pyrroles as calcium channel modulators
WO2013135674A1 (fr) * 2012-03-12 2013-09-19 Syngenta Participations Ag Composés de 2-aryl-acétamide insecticides
WO2013156614A1 (fr) 2012-04-20 2013-10-24 Ucb Pharma S.A. Méthodes de traitement de la maladie de parkinson
US11116749B2 (en) 2013-09-26 2021-09-14 Cadent Therapeutics, Inc Selective octahydro-cyclopenta[c]pyrrole negative modulators of NR2B
WO2015187845A1 (fr) 2014-06-04 2015-12-10 Rugen Holdings (Cayman) Limited Dérivés de difluoroéthylpyridine en tant qu'antagonistes des récepteurs nmda sélectifs du site nr2b
CN106795163A (zh) * 2014-06-04 2017-05-31 卢郡控股(开曼)有限公司 作为nr2b nmda受体拮抗剂的二氟乙基吡啶衍生物
US10030026B2 (en) 2014-06-04 2018-07-24 Rugen Holdings (Cayman) Limited Difluoroethylpyridine derivatives as NR2B NMDA receptor antagonists
WO2016044323A1 (fr) * 2014-09-15 2016-03-24 Rugen Holdings (Cayman) Limited Dérivés de pyrrolopyrimidine à titre d'antagonistes des récepteurs nmda nr2b
US9567341B2 (en) 2014-09-15 2017-02-14 Rugen Holdings (Cayman) Limited Pyrrolopyrimidine derivatives as NR2B NMDA receptor antagonists
US9968610B2 (en) 2014-09-15 2018-05-15 Rugen Holdings (Cayman) Limited Pyrrolopyrimidine derivatives as NR2B NMDA receptor antagonists
US10420768B2 (en) 2014-09-15 2019-09-24 Rugen Holdings (Cayman) Limited Pyrrolopyrimidine derivatives as NR2B NMDA receptor antagonists
EP3197440A4 (fr) * 2014-09-22 2018-04-18 Rugen Holdings (Cayman) Limited Traitement des troubles de l'anxiété et des troubles du spectre autistique
US10239835B2 (en) 2014-09-26 2019-03-26 Cadent Therapeutics, Inc. N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[c]pyrrole negative allosteric modulators of NR2B
US10781174B2 (en) 2014-09-26 2020-09-22 Cadent Therapeutics, Inc. N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[C]pyrrole negative allosteric modulators of NR2B
WO2016126869A1 (fr) * 2015-02-04 2016-08-11 Rugen Holdings (Cayman) Limited Dérivés 3,3-difluoro-pipéridine en tant qu'antagonistes des récepteurs nmda nr2b
US10221182B2 (en) 2015-02-04 2019-03-05 Rugen Holdings (Cayman) Limited 3,3-difluoro-piperidine derivatives as NR2B NMDA receptor antagonists
US10294230B2 (en) 2015-06-01 2019-05-21 Rugen Holdings (Cayman) Limited 3,3-difluoropiperidine carbamate heterocyclic compounds as NR2B NMDA receptor antagonists
US10584127B2 (en) 2015-06-01 2020-03-10 Rugen Holdings (Cayman) Limited 3,3-difluoropiperidine carbamate heterocyclic compounds as NR2B NMDA receptor antagonists
WO2016196513A1 (fr) 2015-06-01 2016-12-08 Rugen Holdings (Cayman) Limited Composés hétérocycliques 3,3-difluoropipéridine carbamate utilisés en tant qu'antagonistes des récepteurs nmda nr2b
US11136328B2 (en) 2015-06-01 2021-10-05 Rugen Holdings (Cayman) Limited 3,3-difluoropiperidine carbamate heterocyclic compounds as NR2B NMDA receptor antagonists
WO2017093354A1 (fr) 2015-11-30 2017-06-08 INSERM (Institut National de la Santé et de la Recherche Médicale) Antagonistes de nmdar pour le traitement de maladies associées à l'angiogenèse
US11752155B2 (en) 2016-11-22 2023-09-12 Rugen Holdings (Cayman) Limited Treatment of autism spectrum disorders, obsessive-compulsive disorder and anxiety disorders
US11000526B2 (en) 2016-11-22 2021-05-11 Rugen Holdings (Cayman) Limited Treatment of autism spectrum disorders, obsessive-compulsive disorder and anxiety disorders
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