WO2003024934A2 - Antagonistes des recepteurs d'aminoacides excitatoires - Google Patents

Antagonistes des recepteurs d'aminoacides excitatoires Download PDF

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WO2003024934A2
WO2003024934A2 PCT/US2001/045858 US0145858W WO03024934A2 WO 2003024934 A2 WO2003024934 A2 WO 2003024934A2 US 0145858 W US0145858 W US 0145858W WO 03024934 A2 WO03024934 A2 WO 03024934A2
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compound according
alkyl
compound
pharmaceutically acceptable
acceptable salt
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PCT/US2001/045858
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WO2003024934A3 (fr
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Thomas John Bleisch
Ana Maria Castano Mansanet
Esteban Dominguez-Manzanares
Ana Maria Escribano
Paul Leslie Ornstein
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Eli Lilly And Company
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Priority to EP01274482A priority Critical patent/EP1351689A2/fr
Priority to US10/450,669 priority patent/US6924294B2/en
Priority to AU2001298029A priority patent/AU2001298029A1/en
Publication of WO2003024934A2 publication Critical patent/WO2003024934A2/fr
Publication of WO2003024934A3 publication Critical patent/WO2003024934A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Definitions

  • EAA receptors excitatory amino acid receptors
  • excitatory amino acids are of great physiological importance, playing a role in a variety of physiological processes, such as long-term potentiation (learning and memory), the development of synaptic plasticity, motor confrol, respiration, cardiovascular regulation, and sensory perception.
  • 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 depolarizing actions of the selective agonists N- methyl-D-aspartate ( ⁇ MDA), ⁇ -amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), and kainic acid (KA).
  • ⁇ MDA N- methyl-D-aspartate
  • AMPA ⁇ -amino-3-hydroxy-5-methylisoxazole-4-propionic acid
  • KA kainic acid
  • kainate receptors Five kainate receptors have been identified which are classified as either High Affinity (KA1 and KA2) or Low Affinity (composed of GIUR5, GluRg, and or GluR subunits). Bleakman et al., Molecular Pharmacology, 49, ⁇ o.4, 581,(1996).
  • the second general type of receptor is the G-protein coupled or second messenger-linked
  • excitatory amino acid receptor excitotoxicity has been implicated in the pathophysiology of numerous neurological disorders, including the etiology of cerebral deficits subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord lesions resulting from trauma or inflammation, perinatal hypoxia, cardiac arrest, and hypoglycemic neuronal damage.
  • excitotoxicity has been implicated in chronic neurodegenerative conditions including Alzheimer's Disease, Huntington's Chorea, inherited ataxias, AIDS-induced dementia, amyotrophic lateral sclerosis, idiopathic and drug-induced Parkinson's Disease, as well as ocular damage and retinopathy.
  • Other neurological disorders implicated with excitotoxicity and/or glutamate dysfunction include muscular spasticity including tremors, drug tolerance and withdrawal, brain edema, convulsive disorders including epilepsy, depression, anxiety and anxiety related disorders such as post-traumatic stress syndrome, tardive dyskinesia, and psychosis related to depression, schizophrenia, bipolar disorder, mania, and drug intoxication or addiction (see generally United States Patent No.
  • Excitatory amino acid receptor antagonists may also be useful as analgesic agents and for treating or preventing various forms of headache, including cluster headache, tension-type headache, and chronic daily headache.
  • excitatory amino acid receptor excitotoxicity participates in the etiology of acute and chronic pain states including severe pain, intractable pain, neuropathic pain, post-traumatic pain.
  • trigeminal ganglia and their associated nerve pathways, are associated with painful sensations of the head and face such as headache and, in particular, migraine.
  • Moskowitz (Cephalalgia, 12, 5-7, (1992) proposed that unknown triggers stimulate the trigeminal ganglia which in turn innervate vasculature within cephalic tissue, giving rise to the release of vasoactive neuropeptides from axons innervating the vasculature.
  • These neuropeptides initiate a series of events leading to neurogenic inflammation of the meninges, a consequence of which is pain. This neurogenic inflammation is blocked by sumatriptan at doses similar to those required to treat acute migraine in humans.
  • a neuroprotective agent such as an excitatory amino acid receptor antagonist
  • an excitatory amino acid receptor antagonist is believed to be useful in treating or preventing all of the aforementioned disorders and/or reducing the amount of neurological damage associated with these disorders.
  • AMPA receptor antagonists are neuroprotective in focal and global ischemia models.
  • the competitive AMPA receptor antagonist NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo
  • the noncompetitive AMPA receptor antagonists GKYI 52466 has been shown to be an effective neuroprotective agent in rat global ischemia models. LaPeillet et al, Brain Research, 571, 115 (1992). European Patent Application Publication No. 590789A1 and United States Patents No. 5,446,051 and 5,670,516 disclose that certain decahydroisoquinoline derivative compounds are AMPA receptor antagonists and, as such, are useful in the treatment of a multitude of disorders conditions, including pain and migraine headache. WO 98/45270 discloses that certain decahydroisoquinoline derivative compounds are selective antagonists of the iGluR5 receptor and are useful for the treatment of various types of pain, including; severe, chronic, intractable, and neuropathic pain.
  • Applicants have discovered novel compounds that are antagonists of the iGluR.5 receptor subtype and, thus, could be useful in treating the multitude of neurological disorders or neurodegenerative diseases, as discussed above. Such antagonists could address a long felt need for safe and effective treatments for neruological disorders, without attending side effects. The treatment of neurological disorders and neurodegenerative diseases is hereby furthered.
  • the present invention provides a compound of Formula I
  • Rl is H, CO 2 H, tetrazole, OH, or ( -C ⁇ alkyltetrazole;
  • R 2 is H, (C C 6 )alkyl, aryl, halo, CO 2 H, (C 1 -C 6 )alkyl-heterocycle, (C ⁇ -C 6 )al yl- (substituted)heterocycle, (C 1 -C 4 )alkyl-N-SO 2 -aryl, NO 2 , NH 2 , CF 3 , or (C 1 -C 6 )alkoxy carbonyl, NSO2aryl;
  • W, X, and Y each independently represent H, (Ci-C 6 )alkyl, CO 2 H, halo, OH, heterocycle, substituted heterocycle, CF3, (CH2) n CO2H, (Ci-C 6 )alkoxy, or (C 1 -C 6 )alkoxy carbonyl; or optionally, X and R 2 together, along with the carbon atoms to which they are attached, form a fused-benzo group, or optionally, W and Rl together, along with the carbon atoms to which they are attached, form a fused-benzo group or a fused-triazole group; n is O, 1, or 2, or a pharmaceutically acceptable salt or prodrug thereof.
  • the present invention provides a method of treating or preventing a neurological disorder, or neurodegenerative condition, comprising administering to a patient in need thereof an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.
  • neurological disorders, or neurodegenerative conditions include: cerebral deficits subsequent to cardiac bypass surgery and grafting; stroke; cerebral ischemia; spinal cord lesions resulting from trauma or inflammation; perinatal hypoxia; cardiac arrest; hypoglycemic neuronal damage; Alzheimer's Disease; Huntington's Chorea; inherited ataxias; ATDS-induced dementia; amyotrophic lateral sclerosis; idiopathic and drug-induced Parkinson's Disease; ocular damage and retinopathy; muscular spasticity including tremors; drug tolerance and withdrawal; brain edema; convulsive disorders including epilepsy; depression; anxiety and anxiety related disorders such as post-traumatic stress syndrome; tardive dyskinesia; psychosis related to depression, schizophrenia, bipolar disorder, mania, and drug intoxic
  • the present invention provides a method of treating or preventing pain or migraine comprising administering to a patient in need thereof an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or prodrug thereof.
  • compositions of compounds of Formula I including the pharmaceutically acceptable salts, prodrugs, and hydrates thereof, comprising, a compound of Formula I in combination with a pharmaceutically acceptable carrier, diluent or excipient.
  • This invention also encompasses novel intermediates, and processes for the synthesis of the compounds of Formula.
  • the present invention also provides the use of a compound of Formula I for the manufacture of a medicament for treating or preventing a neurological disorder, or neurodegenerative condition. More specifically, the present invention provides the use of a compound of
  • Formula I for the manufacture of a medicament for treating or preventing pain or migraine.
  • the present invention provides compounds functional as iGluR5 receptor antagonists as well as pharmaceutically acceptable salts, prodrugs, and compositions thereof. These compounds are useful in treating or preventing neurological disorders, or neurodegenerative diseases, particularly pain and migraine. As such, methods for the treatment or prevention of neurological disorders, or neurodegenerative diseases, are also provided by the present invention.
  • prodrug refers to a compound of Formula I which has been structurally modified such that in vivo the prodrug is converted, for example, by hydrolytic, oxidative, reductive, or enzymatic cleavage into the parent compound (e.g. the carboxylic acid (drug), or as the case may be the parent dicarboxylic acid (drug) ) as given by Formula I.
  • parent compound e.g. the carboxylic acid (drug), or as the case may be the parent dicarboxylic acid (drug)
  • prodrugs may be, for example, metabolically labile mono- or di-ester derivatives of the parent compounds having a carboxylic acid group.
  • the present invention includes any such prodrugs, such as metabolically labile ester or diester derivatives of compounds of the Formula.
  • prodrugs such as metabolically labile ester or diester derivatives of compounds of the Formula.
  • the use of the compounds described herein as prodrugs is contemplated, and often is preferred, and thus, the prodrugs of all of the compounds provided are encompassed in the names of the compounds herein.
  • Conventional procedures for the selection and preparation of suitable prodrugs are well known to one of ordinary skill in the art.
  • R 3 is hydrogen, (C 1 -C 20 )alkyl, (C 2 -C 6 )alkenyl, (C 1 -C 6 )alkylaryl, ( -C f alky Cs- C 10 )cycloalkyl, dialkylamine, (C 1 -C 6 )alkyl-pyrrolidine, ( - C 6 )alkyl-piperidine, or (C 1 -C 6 )alkyl-morpholine;
  • R 4 is H, CO 2 R 6 , tetrazole, OH, or ( -C ⁇ alkyltetrazole;
  • R 5 is H, (Ci-C 6 )alkyl, aryl, halo, CO 2 R 7 , (C 1 -C 6 )alkyl-heterocycle, (C 1 -C 6 )alkyl-
  • W ⁇ X', and Y' each independently represent H, (C 1 -C 6 )alkyl, CO 2 R 8 , halo, OH, heterocycle, substituted heterocycle, CF3, (CH2) n CO2R ⁇ , (C 1 -C 6 )alkoxy or (Ci- C 6 )alkoxy carbonyl;
  • R° Rl, and R 8 each independently represent hydrogen, ( -C ⁇ alkyl, (C 2 - C 6 )alkenyl, (C 1 -C 6 )alkylaryl, (C 1 -C 6 )alkyl(C 3 -C 10 )cycloalkyl, dialkylamine, (C 1 -C 6 )alkyl-pyrrolidine, morpholine; or optionally, X' and R ⁇ together, along with the carbon atoms to which they are attached, form a benzo-fused group, or optionally, W and R 4 together, along with the carbon atoms to which they are attached, form a benzo-fused group or a triazole-fused group, and n is O, l, or 2; with the proviso that where R 4 is CO 2 R 6 , or R 5 is CO 2 R 7 , or W', X', or Y' is CO 2 R8 then at least one, but no more than two of R 3 , R°
  • iGluR5 receptor antagonists of the present invention may exist as pharmaceutically acceptable salts and, as such, salts are therefore included within the scope of the present invention.
  • pharmaceutically acceptable salt refers to salts of the compounds provided by, or employed in the present invention 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.
  • 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, 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, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
  • salts examples include the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, bromide, iodide, hydroiodide, dihydroiodide, acetate, propionate, decanoate, caprylate, acrylate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate, phenylacetate,
  • 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. It is further understood that such salts may exist as a hydrate.
  • 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.
  • 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 enantiomers of compounds of Formula I can be resolved by one of ordinary skill in the art using standard techniques well known in the art, such as those described by J. Jacques, et al., "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc., 1981.
  • 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 page's 103-120.
  • 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 Eliel and Wilen, "Stereochemistry of Organic Compounds", John Wiley & Sons, hie, 1994, Chapter 7, Separation of Stereoisomers. Resolution. Racemization, and by Collet and Wilen, "Enantiomers, Racemates, and Resolutions", John Wiley & Sons, Inc., 1981.
  • the specific stereoisomers and enantiomers can be prepared by stereospecific syntheses using enantiomerically and geometrically pure, or enantiomerically or geometrically enriched starting materials.
  • the specific stereoisomers and enantiomers can be resolved and recovered by techniques such as chromatography on chiral stationary phases, enzymatic resolution or fractional recrystallization of addition salts formed by reagents used for that purpose.
  • Pg refers to a suitable nitrogen protecting group.
  • suitable nitrogen protecting group refers to those groups intended to protect or block the nitrogen group against undesirable reactions during synthetic procedures. Choice of the suitable nitrogen 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. Commonly used nitrogen protecting groups are disclosed in Greene, "Protective Groups In Organic Synthesis,” (John Wiley & Sons, New York (1981)).
  • Suitable nitrogen protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t- butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o- nitrophenoxyacetyl, .alpha.-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4- nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming groups such as benzyloxycarbonyl, p- chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2- nitrobenzyloxycarbonyl, p-
  • Preferred suitable nitrogen protecting groups are formyl, acetyl, methyloxycarbonyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
  • (Ci-C ⁇ alkyl) refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 4 carbon atoms and includes, but is not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like.
  • (C 1 -C 6 )alkyl refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms and includes, but is not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl, and the like.
  • (Cr c alkyl) refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 10 carbon atoms and includes, but is not limited to methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, pentyl, isopentyl, hexyl, 2,3-dimethyl-2-butyl, heptyl, 2,2-dimethyl-3-pentyl, 2-methyl-2-hexyl, octyl, 4-methyl-3-heptyl and the like.
  • (C 1 -C 2 o)alkyl refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 20 carbon atoms and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, 3-methylpentyl, 2-ethylbutyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n- dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-nonadecyl, n- eicosyl and the like. It is not limited to, methyl,
  • the terms “Me”, “Et”, “Pr”, “iPr”, “Bu” and “t-Bu” refer to methyl, ethyl, propyl, isopropyl, butyl and tert-butyl respectively.
  • the term “( -C ⁇ alkoxy” refers to an oxygen atom bearing a straight or branched, monovalent, saturated aliphatic chain of 1 to 4 carbon atoms and includes, but is not limited to methyoxy, ethyoxy, n-propoxy, isopropoxy, n-butoxy, and the like.
  • (C 1 -C 6 )alkoxy refers to an oxygen atom bearing a straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms and includes, but is not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, n- pentoxy, n-hexoxy, and the like.
  • (C 1 -C 6 )alkyl(C 1 -C 6 )alkoxy refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms which has a ( - C 6 )alkoxy group attached to the aliphatic chain.
  • Halo As used herein, the terms "Halo”, “Halide” or “Hal” refer to a chlorine, bromine, iodine or fluorine atom, unless otherwise specified herein.
  • (C 2 -C 6 )alkenyl refers to a straight or branched, monovalent, unsaturated aliphatic chain having from two to six carbon atoms.
  • Typical C 2 -C 6 alkenyl groups include ethenyl (also known as vinyl), 1-methylethenyl, 1-methyl-l- propenyl, 1-butenyl, 1-hexenyl, 2-methyl-2-propenyl, 1-propenyl, 2-propenyl, 2-butenyl,
  • aryl refers to a monovalent carbocyclic group containing one or more fused or non-fused phenyl rings and includes, for example, phenyl, 1- or 2-naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tefrahydronaphthyl, and the like.
  • substituted aryl refers to an aryl group substituted with one or two moieties chosen from the group consisting of halogen, hydroxy, cyano, nitro, (C ⁇ -C6)alkyl, (Ci- C4)alkoxy, (C 1 -C 6 )alkyl(C 3 -C 10 )cycloalkyl, (C 1 -C 6 )alkylaryl, (C 1 -C 6 )alkoxycarbonyl, protected carboxy, carboxymethyl, hydroxymethyl, amino, aminomethyl, or trifluoromethyl.
  • (C 1 -C 6 )alkylaryl refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms which has an aryl group attached to the aliphatic chain. Included within the term “Ci-C ⁇ alkylaryl” are the following:
  • ary - )alkyl refers to an aryl group which has a straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms attached to the aryl group. Included within the term “aryl Ci-C ⁇ )alkyl” are the following:
  • (C 3 -C 10 )cycloalkyl refers to a saturated hydrocarbon ring structure composed of one or more fused or unfused rings containing from three to ten carbon atoms.
  • Typical C 3 -C 10 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantanyl, and the like.
  • -C ⁇ alkyl(C 3 -C 1 o)cycloalkyl refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms which has a (C 3 - C 1 o)cycloalkyl attached to the aliphatic chain. Included within the term “Ci-C ⁇ alkyl(C 3 - Cio)cycloalkyl” are the following:
  • ( -C ⁇ ) alkoxycarbonyl refers to a carbonyl group having a (C ⁇ -Cg)alkyl group attached to the carbonyl carbon through an oxygen atom. Examples of this group include t-buoxycarbonyl, methoxycarbonyl, and the like.
  • heterocycle refers to a five- or six-membered ring, which contains one to four heteroatoms selected from the group consisting of oxygen, sulfur, and nitorgen. The remaining atoms of the ring are recognized as carbon by those of skill in the art. Rings may be saturated or unsaturated.
  • heterocycle groups include thiophenyl, furyl, pyrrolyl, imidazolyl, pyrrazolyl, thiazolyl, thiazohdinyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridiazinyl, triazinyl, imidazolyl, dihydropyrimidyl, tetrahydropyrimdyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrazolidinyl, pyrimidinyl, imidazolidimyl, morpholinyl, pyranyl, thiomorpholinyl, and the like.
  • substituted heterocycle represents a heterocycle group substituted with one or two moieties chosen from the group consisting of halogen, hydroxy, cyano, nitro, oxo, aryl, (C ⁇ -C 6 )alkyl, (C ⁇ -C 4 )alkoxy, -Ce alkyl(C 3 -C 10 )cycloalkyl, (C 1 -C 6 )alkylaryl, ( - C 6 )alkoxycarbonyl, protected carboxy, carboxymethyl, hydroxymethyl, amino, aminomethyl, or trifluoromethyl.
  • the heterocycle group can be optionally fused to one or two aryl groups to form a benzo-fused group. Examples of substituted heterocycle include 1,2,3,4-tefrahydrodibenzeofuranyl, 2-methylbezylfuranyl, and 3,5 dimethylisoxazolyl, and the like.
  • (CrC 6 )alkyl-heterocycle refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms bearing a heterocycle group.
  • (C 1 -C 6 )alkyl- (substituted)heterocycle refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms bearing a substituted heterocycle group.
  • (C 1 -C 6 )alkyltetrazole refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms bearing a tetrazole group.
  • benzo-fused group refers to a phenyl group fused to an aromatic radical or a heterocycle group. Included within the term “benzo-fused group” are the following:
  • triazole-fused group refers to a triazole group fused to an aromatic radical or a heterocycle group. Included within the term “triazole-fused group” are the following:
  • dialkylamine refers to a nitrogen atom substituted with two straight or branched, monovalent, saturated aliphatic chains of 1 to 6 carbon atoms. Included within the term “N,N-C ! -C 6 dialkylamine” are -N(CH 3 ) , - N(CH 2 CH 3 ) 2 , -N(CH 2 CH 2 CH 3 ) 2 , -N(CH 2 CH 2 CH 2 CH 3 ) 2 , and the like.
  • Ci-Cealkyl-NjN- -Cedialkylamine refers to straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms which has an N,N- CrC 6 dialkylamine attached to the aliphatic chain. Included within the term “ - alkyl- N- -Ce dialkylamine” are the following:
  • (C 1 -C 6 )alkyl-pyrrolidine refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms which has a pyrrolidine attached to the aliphatic chain. Included within the scope of the term “(C 1 -C 6 )alkyl- pyrrolidine” are the following:
  • (C 1 -C 6 )alkyl-morpholine refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms which has a morpholine attached to the aliphatic chain. Included within the scope of the term “Ci-C ⁇ alkyl-morpholine” are the following:
  • iGluR5 refers to the kainate ionotropic glutamate receptor, subtype 5, of the larger class of excitatory amino acid receptors.
  • migraine refers a disorder of the nervous system characterized by recurrent attacks of head pain (which are not caused by a structural brain abnormalitiy such as those resulting from tumor or stroke), gasrointestinal disturbances, and possibly neurological symptoms such as visual distortion. Characteristic headaches of migraine usually last one day and are commonly accompanied by nausea, emesis, and photophobia.
  • Migraine may represent a "chronic" condition, or an "acute” episode.
  • chronic means a condition of slow progress and long continuance.
  • a chronic condition is treated when it is diagnosed and treatment continued throughout the course of the disease.
  • acute means an exacerbated event or attack, of short course, followed by a period of remission.
  • the treatment of migraine contemplates both acute events and chronic conditions.
  • compound is administered at the onset of symptoms and discontinued when the symptoms disappear.
  • a chronic condition is treated throughout the course of the disease.
  • patient refers to a mammal, such a mouse, gerbil, guinea pig, rat, dog or human. It is understood, however, that the preferred patient is a human.
  • iGluR5 receptor antagonist refers to those excitatory amino acid receptor antagonists which bind to, and antagonize the activity of, the iGluR5 kainate receptor subtype.
  • the present invention further provides selective iGluR5 receptor antagonists.
  • Selective iGluR5 receptor antagonist or “selective iGluR5 antagonist” as used herein, includes those excitatory amino acid receptor antagonists which selectively bind to, and antagonize, the iGluR5 kainate receptor subtype, relative to the iGluR2 AMPA receptor subtype.
  • the "selective iGluR5 antagonists" for use according to the methods of the present invention have a binding affinity at least 10 fold greater for iGluR5 than for iGluR2, more preferably at least 100 fold greater.
  • WO 98/45270 provides examples of selective iGluR5 receptor antagonists and discloses methods for synthesis.
  • the terms "treating”, “treatment”, or “to treat” each mean to alleviate symptoms, eliminate the causation of resultant symptoms either on a temporary or permanent basis, and to prevent, slow the appearance, or reverse the progression or severity of resultant symptoms of the named disorder.
  • the methods of this invention encompass both therapeutic and prophylactic administration.
  • the term "effective amount” refers to the amount or dose of the compound, upon single or multiple dose administration to the patient, which provides the desired effect in the patient under diagnosis or treatment.
  • 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. In determining the effective amount or dose of compound administered, 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 degree of involvement or the severity of the disease involved; 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.
  • a typical daily dose will contain from about 0.01 mg/kg to about 100 mg/kg of each compound used in the present method of treatment.
  • 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.
  • Oral administration is a preferred route of administering the compounds employed in the present invention whether administered alone, or as a combination of compounds capable of acting as an iGluR5 receptor antagonist. Oral administration, however, is not the only route, nor even the only preferred route. Other preferred routes of administration include transdermal, percutaneous, pulmonary, intravenous, intramuscular, intranasal, buccal, sublingual, or intrarectal routes. Where the iGluR5 receptor antagonist is administered as a combination of compounds, one of the compounds may be administered by one route, such as oral, and the other may be administered by the transdermal, percutaneous, pulmonary, intravenous, intramuscular, intranasal, buccal, sublingual, or intrarectal route, as particular circumstances require. The route of administration rnay be varied in any way, limited by the physical properties of the compounds and the convenience of the patient and the caregiver.
  • compositions may take any physical form that is pharmaceutically acceptable, but orally administered pharmaceutical compositions are particularly preferred.
  • Such pharmaceutical compositions contain, as an active ingredient, an effective amount of a compound of Formula I, including the pharmaceutically acceptable salts, prodrugs, and hydrates thereof, which effective amount is related to the daily dose of the compound to be administered.
  • Each dosage unit may contain the daily dose of a given compound, or may contain a fraction of the daily dose, such as one-half or one-third of the dose.
  • each compound to be contained in each dosage unit depends on the identity of the particular compound chosen for the therapy, and other factors such as the indication for which it is given.
  • the pharmaceutical compositions of the present invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing well known procedures.
  • compositions are preferably formulated in a unit dosage form, each dosage containing from about 1 to about 500 mg of each compound individually or in a single unit dosage form, more preferably about 5 to about 300 mg (for example 25 mg).
  • unit dosage form refers to a physically discrete unit suitable as unitary dosages for a patient, 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.
  • compositions contain from about 0.5% to about 50% of the compounds in total, depending on the desired doses and the type of composition to be used.
  • the amount of the compound is best defined as the "effective amount", that is, the amount of each compound which provides the desired dose to the patient in need of such treatment.
  • the activity of the compounds employed in the present invention do not depend on the nature of the composition, hence, the compositions are chosen and formulated solely for convenience and economy.
  • Capsules are prepared by mixing the compound with a suitable diluent and filling the proper amount of the mixture in capsules.
  • suitable diluents include inert powdered substances such as starches, powdered cellulose especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain flours, and similar edible powders.
  • Tablets are prepared by direct compression, by wet granulation, or by dry granulation. Their formulations usually incorporate diluents, binders, lubricants and disintegrators as well as the compound. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders are substances such as starch, gelatin and sugars such as lactose, fructose, glucose and the like.
  • Natural and synthetic gums are also convenient, including acacia, alginates, methylcellulose, polyvinylpyrrolidine and the like. Polyethylene glycol, ethylcellulose and waxes can also serve as binders. Tablets are often coated with sugar as a flavor and sealant.
  • the compounds may also be formulated as chewable tablets, by using large amounts of pleasant-tasting substances such as mannitol in the formulation, as is now well-established practice.
  • Instantly dissolving tablet-like formulations are also now frequently used to assure that the patient consumes the dosage form, and to avoid the difficulty in swallowing solid objects that bothers some patients.
  • a lubricant is often necessary in a tablet formulation to prevent the tablet and punches from sticking in the die.
  • the lubricant is chosen from such slippery solids as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils.
  • Tablet disintegrators are substances which swell when wetted to break up the tablet and release the compound. They include starches, clays, celluloses, algins and gums. More particularly, corn and potato starches, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation-exchange resins, alginic acid, guar gum, citrus pulp and carboxymethylcellulose, for example, may be used, as well as sodium lauryl sulfate.
  • Enteric formulations are often used to protect an active ingredient from the strongly acid contents of the stomach. Such formulations are created by coating a solid dosage form with a film of a polymer which is insoluble in acid environments, and soluble in basic environments. Exemplary films are cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate.
  • Cocoa butter is a traditional suppository base, which may be modified by addition of waxes to raise its melting point slightly.
  • Water-miscible suppository bases comprising, particularly, polyethylene glycols of various molecular weights are in wide use, also.
  • Transdermal patches have become popular recently. Typically they comprise a resinous composition in which the drugs will dissolve, or partially dissolve, which is held in contact with the skin by a film which protects the composition. Many patents have appeared in the field recently. Other, more complicated patch compositions are also in use, particularly those having a membrane pierced with innumerable pores through which the drugs are pumped by osmotic action.
  • the following table provides an illustrative list of formulations suitable for use with the compounds employed in the present invention. The following is provided only to illustrate the invention and should not be interpreted as limiting the present invention in any way.
  • Hard gelatin capsules are prepared using the following ingredients:
  • a tablet is prepared using the ingredients below:
  • Active Ingredient 250 Cellulose, microcrystalline 400
  • An aerosol solution is prepared containing the following components:
  • Propellant 22 70.00 (Chlorodifluoromethane)
  • the active compound is mixed with ethanol and the mixture added to a portion of the Propellant 22, cooled to -30°C and transferred to a filling device. The required amount is then fed to a stainless steel container and diluted with the remainder of the propellant. The valve units are then fitted to the container.
  • Tablets each containing 60 mg of active ingredient are made as follows:
  • the active ingredient, starch, and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly.
  • the solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. sieve.
  • the granules so produced are dried at 50°C and passed through a No. 18 mesh U.S. sieve.
  • the sodium carboxymethyl starch, magnesium stearate, and talc previously passed through a No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.
  • Capsules each containing 80 mg medicament are made as follows:
  • Suppositories each containing 225 mg of active ingredient may be made as follows:
  • the active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool.
  • the medicament is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste.
  • the benzoic acid solution, flavor and color are diluted with some of the water and added, with stirring. Sufficient water is then added to produce the required volume.
  • An intravenous formulation may be prepared as follows:
  • Scheme I provides procedures for the synthesis of compounds of Formula I and Formula la, wherein R represents H, OH, or CO 2 H, and R 4 represents H, OH, or respectively.
  • step A the compound of structure (1) is freated with a compound of structure (2) (wherein U represents H, OH, or CO 2 R6 and R ⁇ , W', X', and Y' are as previously defined), under reductive amination conditions, to provide the compound of structure (3).
  • a solution of ethyl 6-oxo-2-(methoxycarbonyl)- decahydroisoquinoline-3-carboxylate dissolved in a suitable organic solvent such as 1,2- dichloroethane at room temperature is treated with about 0.5-10.0 equivalents of a compound of structure (2) (wherein U represents H, OH, or CO 2 R6 and R ⁇ , W', X', and Y' are as previously defined) and then the reaction mixture is freated with about 0.5-10.0 equivalents of glacial acetic acid and about 2.0 equivalents of sodium triacethoxyborohydride.
  • the reaction mixture is stirred under nitrogen for about 10 to 48 hours, quenched with sodium bicarbonate until pH 8.
  • the compound of structure (3) (wherein U represents H, OH, or CO 2 R6 and R$, W', X', and Y' are as previously defined) is then isolated using standard procedures. For example, after treatment with sodium bicarbonate, the organic layer is separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide concentrated compound (3). Column chromatography may then be performed on silica gel with a suitable eluent such as 25% ethyl acetate/hexane to provide the purified compound (3).
  • the compound of structure (3) can be prepared by following the sequence of procedures described in Steps B and C.
  • Step B compound (4) is obtained in a two step procedure. First, reductive amination is performed under conditions described above, followed by hydrogenolysis of the resulting benzyl amine to provide the compound of structure (4).
  • a solution of ethyl 6-oxo-2- (methoxycarbonyl)-decahydroisoquinoline-3-carboxylate (compound (1)) dissolved in a suitable organic solvent such as 1,2-dichloroethane at room temperature is treated with about 1.1 equivalents of BnNH 2 (benzyl amine) and then treated with about 1.5 equivalents of glacial acetic acid and about 1.6 equivalents of sodium triacethoxyborohydride.
  • BnNH 2 benzyl amine
  • the reaction mixture is stirred under nitrogen at room temperature for about 15 hours and then the reaction mixture is treated with sodium bicarbonate until pH 8, the organic layer separated, and the aqueous phase extracted with ethyl acetate.
  • the combined organic phases are dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum.
  • the resulting crude material is used in the next step without further purification.
  • a mixture of this intermediate dissolved in a suitable organic solvent, such as ethanol, at room temperature is treated with about 0.1 equivalents of 10% palladium on carbon, and hydrogenated at 50 psi at room temperature for about 18 hours.
  • the compound of sfructure (4) is then isolated using standard procedures. For example, the catalyst is removed by filtration through celite and the solvent evaporated under vacuum to provide the compound of structure (4).
  • Step C compound (4) is freated with a compound of structure (5) (wherein U represents hydrogen, OH, or CO 2 R6 and R5, W', X', and Y' are as defined hereinabove) to provide the compound of structure (3).
  • a solution of compound (4) dissolved in a suitable organic solvent such as dimethylsulfoxide is treated with about 0.2-4.0 equivalents of compound (5) (wherein U represents hydrogen, OH, or CO R ⁇ and R ⁇ , W', X', and Y' are as defined hereinabove) and then freated with about 1.0 equivalent of sodium bicarbonate.
  • the reaction mixture is heated at 120°C for 20-70 hours.
  • the compound of structure (3) (as previously defined in Step A) is then isolated using standard procedures. For example, the reaction mixture is treated with ammonium chloride and extract with ethyl acetate, the organic layer is separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide concentrated compound (3). Column chromatography may then be performed on silica gel with a suitable eluent such as 33% ethyl acetate/hexane to provide the purified compound (3).
  • a suitable eluent such as 33% ethyl acetate/hexane
  • Step D compound (3) is concomitantly hydrolyzed and deprotected under standard conditions well known in the art to provide the compounds of Formula I, wherein R* , for purposes of this Scheme, represents hydrogen, OH, or CO 2 H.
  • R* for purposes of this Scheme, represents hydrogen, OH, or CO 2 H.
  • compound (3) is treated with 6N hydrochloric acid and stirred at 90°C for 10-24 hours. The mixture is then concentrated under vacuum to provide the compounds of Formula I, wherein Rl represents hydrogen, OH, or CO 2 H and R 2 , W, X, and Y are as previously defined.
  • the compound of Formula I (wherein for purposes of the present Scheme Rl represents hydrogen, OH, or CO 2 H and R 2 , W, X, and Y are as previously defined) may be esterified under standard conditions known in the art to provide the compound of Formula la, wherein for purposes of the present Scheme R 4 represents hydrogen, OH, or CO 2 R6 and R 3 , R5, W', X', and Y' are as previously defined.
  • R 4 represents hydrogen, OH, or CO 2 R6 and R 3 , R5, W', X', and Y' are as previously defined.
  • the compound of Formula I is dissolved in a suitable base such as 2-ethylbutanol, isobutanol, or ethanol, and freated with an excess of a dehydrating agent, such as thionyl chloride.
  • the reaction mixture is heated at 120°C for about 2-24 hours.
  • reaction mixture is then concentrated under vacuum to provide the crude compound of Formula la (wherein for purposes of the present Scheme R 4 represents hydrogen, OH, or CO R6 and R 3 , R5, W', X', and Y' are as previously defined.)
  • This material may then be precipitated with diethyl ether and filtered to provide the purified compound of Formula la.
  • the compound of Formula la (wherein for purposes of the present Scheme R 4 represents hydrogen, OH, or CO 2 R6 and R 3 , R ⁇ , W', X', and Y' are as previously defined) may be hydrolyzed under standard conditions well known in the art to provide the compound of Formula I.
  • the compound of Formula la is dissolved in a suitable organic solvent such as methanol, and treated with an excess of a suitable base.
  • suitable bases include aqueous lithium hydroxide, sodium hydroxide, potasium hydroxide, and the like with lithium hydroxide being preferred. The reaction is stirred for about 10-20 hours.
  • reaction mixture is then neutralized to pH 6 with IN HCl and concentrated under vacuum to provide the crude of compound of Formula I, wherein for purposes of the present Scheme R* represents hydrogen, OH, or CO 2 H and R 2 , W, X, and Y are as previously defined.
  • This material may then be purified by techniques well known in the art, such as cation exchange chromatography eluting with methanol/water followed by 2.0 N ammonia in methanol to provide the purified compound of Formula I.
  • the compound (7) is then isolated and concentrated under standard conditions, and may then be purified, all as described in Scheme I, Step A.
  • the compound of structure (7) can be prepared by following the sequence of procedures described in Steps B and C.
  • Step B compound (4) is obtained in a two step procedure as previously described in Scheme I, Step B above.
  • the compound of structure (4) is then isolated using standard procedures, again as described in Scheme I, Step B above.
  • the compound of Formula I or Formula la contain a tetrazole or a (Ci -C4)alkyltetrazole at R 1
  • Compound (9) is then concomitantly hydrolyzed and deprotected in Step E, to provide the compounds of Formula I, wherein R is tetrazole or (C - C4)alkyltetrazole.
  • compound (7) is treated with about 3 to 5 equivalents of azido-tri-n-butyl stannane at about 70 to 100°C for about 12 to 48 hours under an atmosphere of nitrogen to give the compound of structure (9).
  • Compound (9) is then treated with IN hydrochloric acid, extracted with ethyl acetate, the organic layer separated, and the aqueous phase extracted with ethyl acetate. The combined organic phases are dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide concentrated compound (9).
  • Column chromatography may then be performed on silica gel with a suitable eluent such as 33% ethyl acetate/hexane to provide the purified compound (9).
  • Step E Compound (9) is then concomitantly hydrolyzed and deprotected under standard conditions well known in the art, and as described in Scheme I, Step D above, and the resulting compound of Formula I (wherein Rl is tetrazole or (Cj-C ⁇ alkyltetrazole) may then be purified.
  • a solution of compound (9) dissolved in 6.0 N hydrochloric acid is heated at 90°C for 10-24 hours.
  • reaction mixture is then allowed to cool to room temperature and concentrated under vacuum to provide the compound of Formula I, wherein for the purposes of the present Scheme Rl is tetrazole or (C ⁇ -C4)alkyltetrazole and R 2 , W, X, and Y are as previously defined.
  • Rl is tetrazole or (C ⁇ -C4)alkyltetrazole and R 2 , W, X, and Y are as previously defined.
  • This material may then be purified by techniques well known in the art, such as cation exchange chromatography eluting with methanol/water followed by 2.0 N ammonia in methanol to provide the purified compound of Formula I.
  • the compound of Formula I is dissolved in a suitable base such as 2-ethylbutanol, isobutanol, or ethanol, and treated with an excess of a dehydrating agent, such as thionyl chloride.
  • a dehydrating agent such as thionyl chloride.
  • the reaction mixture is heated at 120°C for about 2-24 hours.
  • the reaction mixture is then concentrated under vacuum to provide the crude compound of Formula la (wherein for purposes of the present Scheme R 4 represents tetrazole or (C ⁇ -C4)alkyltetrazole and R 3 , RX W, X', and Y' are as previously defined.)
  • This material may then be precipitated with diethyl ether and filtered to provide the purified compound of Formula la.
  • This material may then be purified by techniques well known in the art, such as cation exchange chromatography eluting with methanol/water followed by 2.0 N ammonia in methanol to provide the purified compound of Formula I, wherein R 4 tetrazole or (C ⁇ C4)alkyltetrazole and R 3 , R ⁇ , W', X', and Y' are as previously defined.
  • the Formula I compounds of the present invention may be chemically synthesized from a common intermediate, a 6-oxo-2-methoxycarbonyl-decahydroisoquinoline-3- carboxylate.
  • This intermediate in turn, may be synthesized from a 6-oxo- decahydroisoquinoline-3-carboxylic acid, the synthesis of which is described in United States Patents No. 4,902,695 , No. 5,446,051, and No. 5,356,902, the contents of which are all herein incorporated by reference.
  • a route for the synthesis of the 6-oxo-2- methoxycarbonyl-decahydroisoquinoline-3-carboxylate intermediate, useful for the synthesis of the compounds of the present invention, is shown in Scheme JJ below.
  • Scheme JJ Scheme JJ
  • Step A 6-oxo-2-(Pg)-decahydroisoquinoline-3-carboxylic acid (Pg is as defined hereinabove)is esterified by reaction with a compound of formula R 3 -Br (where R is as herein defined above) to provide the 6-oxo-2-(Pg)-decahydroisoquino ⁇ ine- 3-carboxylate intermediate of compound (1).
  • R 3 -Br where R is as herein defined above
  • 6-oxo-2-methoxycarbonyl- decahydroisoquinoline-3-carboxylic acid is dissolved in acetonitrile and treated with tiethylamine and bromoethane.
  • the reaction is heated at 50°C for about 3 hours, cooled and partitioned between 50:50 ethyl acetate/heptane and IN HCL.
  • the organic phase is isolated and washed 3 times with water, saturated sodium bicarbonate, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide Ethyl 6- oxo-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylate, a compound of structure (1).
  • This crude material may then be purified under standard conditions well known in the art.
  • the crude material is dissolved in 10% ethyl acetate/heptane and applied to a plug of silica gel (10 g in 10% ethyl acetate/heptane).
  • the plug is eluted with, 10% ethyl acetate/heptane, 15% ethyl acetate/heptane, and 25% ethyl acetate/heptane.
  • the eluents are combined and concentrated under vacuum to provide the purified compound of structure ( 1 ) .
  • Ethyl (3S, 4aR, 6S, 8ai?) 6-benzylamino-2-methoxycarbonyl- 1,2,3,4 ,4a,5,6,7, 8, 8a-decahydroisoquinoline-3-carboxylate To a room temperature solution of ethyl 6-oxo-2-methoxycarbonyl- decahydroisoquinoline-3-carboxylate (4 g, 14.1 mmol), benzylamine (1.71 g, 15.9 mmol), and acetic acid (1.27 g, 21.2 mmol) in 1,2-dichloroethane (20 ml), sodium triacetoxyborohydride (5 g, 23.3 mmol) was added.
  • Anhydrous isobutyl alcohol (20 mL) was bubble with ⁇ C1 (g) for about 5 to 10 min.
  • Example 8A To the product from Example 8A (50 mg, 0.124 mmol) was added neat azidotributyltin (0.068 mL, 0,248 mmol) and the reaction heated at 100°C overnight. A 6N ⁇ C1 solution was added and heated at the same temperature for 24 hours, followed by extraction with ethyl ether (2x). The aqueous phase was concenfrate in vacuo to afford the title compound as dihydrochloride. This crude material was purified by HPLC (using as eluent a gradient of acetonitrile-1% TFA and water) to afford 15 mg (3%) of the title compound
  • the binding affinity of the panel compounds to the iGluR5 receptor is first measured using standard methods.
  • the activity of compounds acting at the iGluR5 receptor can be determined by radiolabelled ligand binding studies at the cloned and expressed human iGluR5 receptor (Korczak et al., 1994, Recept. Channels 3; 41-49), and by whole cell voltage clamp electrophysiological recordings of currents in acutely isolated rat dorsal root ganglion neurons (Bleakman et al., 1996, Mol. Pharmacol. 49; 581-585).
  • the selectivity of compounds acting at the iGluR5 receptor subtype can then be determined by comparing antagonist activity at the iGluR5 receptor with antagonist activity at other AMPA and kainate receptors.
  • Methods useful for such comparison studies include: receptor-ligand binding studies and whole-cell voltage clamp electrophysiological recordings of functional activity at human GluRj, GluR2,GluR3 and GhiR.4 receptors (Fletcher et al., 1995, Recept. Channels 3; 21-31); receptor-ligand binding studies and whole-cell voltage clamp electrophysiological recordings of functional activity at human GluRg receptors (Hoo et al., Recept.
  • iGluR5 antagonist binding affinity profiles Cell lines (HEK293 cells) stably transfected with human iGluR receptors are employed. Displacement of 3[H] AMPA by increasing concentrations of antagonist is measured on iGluRi , iGluR2, iGluR3, and iGluR4 expressing cells, while displacement of 3[H] kainate (KA) is measured on iGluR.5, iGluRg, iGluR , and KA2-expressing cells.
  • Kj antagonist binding activity in ⁇ M, for example, is determined for Compounds of Formula I.
  • the ratio of binding affinity to the iGluR2 AMPA receptor subtype, versus the binding affinity to iGluR5 kainate receptor subtype is also determined.
  • the iGluR5 receptor antagonist compounds, as provided by the present invention provide a Kj at the iGluR5 receptor subtype of less than 5000 ⁇ M , preferably less than 500 ⁇ M , even more preferably less than 50 ⁇ M, and most preferably less than 5 ⁇ M.
  • the preferred selective iGluR5 receptor antagonists compounds display a greater binding affinity (lower K ) for iGh ⁇ .5 than that for iGluR2 , preferably at least 10 fold greater for iGluR.5 than that for iGluR.2, and even more preferably at least 100 fold, and most preferably at least 1000 fold, than that for iGluR2-
  • the following animal model may be employed to determine the ability of each of the compounds of Formula I to inhibit protein extravasation, an exemplary functional assay of the neuronal mechanism of migraine.
  • Harlan Sprague-Dawley rats (225-325 g) or guinea pigs from Charles River Laboratories (225-325 g) are anesthetized with sodium pentobarbital infraperitoneally (65 mg/kg or 45 mg kg respectively) and placed in a stereotaxic frame (David Kopf
  • test compound is injected intravenously (i.v.) at a dosing volume of lml/Kg or, in the alternative, test compound is administered orally (p.o) via gavage at a volume of 2.0ml/Kg .
  • a 50 mg Kg dose of Evans Blue a fluorescent dye, is also injected intravenously.
  • the Evans Blue complexes with proteins in the blood and functions as a marker for protein extravasation.
  • the left trigeminal ganglion is stimulated for 3 minutes at a current intensity of 1.0 mA (5 Hz, 4 msec duration) with a Model 273 potentiostat/ galvanostat (EG&G Princeton Applied Research).
  • the animals are euthanized by exsanguination with 20 mL of saline.
  • the top of the skull is removed to facilitate the collection of the dural membranes.
  • the membrane samples are removed from both hemispheres, rinsed with water, and spread flat on microscopic slides. Once dried, the tissues are coverslipped with a 70% glycerol/water solution.
  • a fluorescence microscope (Zeiss) equipped with a grating monchromator and a specfrophotometer is used to quantify the amount of Evans Blue dye in each sample.
  • An excitation wavelength of approximately 535 nm is utilized and the emission intensity at 600 nm is determined.
  • the microscope is equipped with a motorized stage and also interfaced with a personal computer. This facilitates the computer-controlled movement of the stage with fluorescence measurements at 25 points (500 mm steps) on each dural sample. The mean and standard deviation of the measurements are determined by the computer.
  • the extravasation induced by the electrical stimulation of the trigeminal ganglion has an ipsilateral effect (i.e. occurs only on the side of the dura in which the trigeminal ganglion was stimulated).
  • Dose-response curves are generated for each of the compounds of Formula I and the dose that inhibits the exfravasation by 50% (ID50) or 100% (ID ⁇ o ⁇ ) * s approximated.
  • Example 17 Dose-response curves are generated for each of the compounds of Formula I and the dose that inhibits the exfravasation by 50% (ID50) or 100% (ID ⁇ o ⁇ ) * s approximated.
  • mice male Sprague-Dawley rats (200-250g; Charles River,Portage, MI) are housed in group cages and maintained in a constant temperature and a 12 hour light/12 hour dark cycle 4-7 days before studies are performed. Animals have free access to food and water at all times prior to the day of the experiment.
  • Drugs or vehicles are administered intraperitoneally (i.p.) or orally (p.o.) by gavage in a volume of about 1 ml/kg.
  • the test is performed in custom made Plexiglas® boxes about 25 x 25 x 20 cm in size (according to Shibata et al, Pain 38;347-352, 1989,
  • Test compounds are administered about 30 minutes prior to the formalin injection.
  • Formalin (50 micoliters of a 5% solution in saline) is injected subcutaneously into the dorsal lateral surface of the right hind paw with a 27 gauge needle. Observation is started immediately after the formalin injection. Formalin-induced pain is quantified by recording, for example, in 5 minute intervals, the number of formalin injected pawlicking events and the number of seconds each licking event lasts. These recordings are made for about 50 minutes after the formalin injection. Several different scoring parameters have been reported for the formalin test. The total time spent licking and biting the injected paw is demonstrated to be most relevant (Coderre et al, Eur. J. Neurosci.
  • the early phase score is the sum of time spent licking, in seconds, from time 0 to 5 minutes.
  • the late phase is scored in 5 minute blocks from 15 minutes to 40 minutes and is expressed accordingly or also by adding the total number of seconds spent licking from minute 15 to minute 40 of the observation period.
  • Data may be presented as means with standard errors of means ( ⁇ SEM).
  • Data may also be evaluated by one-way analysis of variance (ANOVA) and the appropriate contrasts analyzed by Dunnett "t" test for two sided comparisons. Differences are considered to be significant if, for example, the P-value is less than 0.05.
  • Statistics may be determined at the 5 minute time point and at 5 minute intervals between 15 and 40 minutes. Where data are expressed as total amount of time spent licking in the late phase, statistics may be performed on the total time spent licking as well and may be indicated accordingly.
  • mice An accepted procedure for detecting and comparing the analgesic activity of different classes of analgesic drugs, for which there is a good correlation with human analgesic activity, is the prevention of acetic acid-induced writhing in mice.
  • Mice are orally administered various doses of a test compound or placebo prior to testing.
  • the mice are then injected intraperitoneally with acetic acid (0.55% solution, 10 mlikg) five minutes prior to a designated observation period.
  • Inhibition of writhing behavior is demonstrative of analgesic activity.
  • Haubrich et al. "Pharmacology of pravadoline: a new analgesic agent", The Journal of Pharmacology and Experimental Therapeutics, 255 (1990) 511-522.
  • "writhe” is indicated by whole body stretching or contracting of the abdomen during an observation period beginning about five minutes after receiving the acetic acid.
  • ED50 values and their standard error of means (SEM) are determined using accepted numerical methods for all test compounds administered. For example, see R.E. Kirk (1982) "Experimental Design: Procedures for the behavioral sciences," 2nd ed. One method to establish the significance of the analgesic activity of a given test compound compared to that of another is to calculate the SEM values for each ED50 value. If the
  • Rats are administered a dose test compound or vehicle and then injected subcutaneously into one hindpaw, with carrageenan (1.5% w/v, 100 ⁇ l).
  • the response to noxious thermal stimulus is determined two hours later using a commercially available thermal plantar device (Ugo Basil, Italy) according to established methods (Hargreaves et al. Pain 32:77-88, 1988). Briefly, animals are habituated to a plastic behavioral enclosure for 5 min. A heat source is positioned directly beneath a hindpaw and the time taken for hindpaw withdrawal monitored automatically. If the animal does not respond within 20 sec, the stimulus is automatically terminated to prevent tissue damage. Measurements for both the injured and contralateral (control) hindpaw are recorded.
  • Thermal hyperalgesia is evidenced by a shorter response latency by the injured as compared to the confrol paw.
  • ED50 values and their standard error of means (SEM) are determined using accepted numerical methods. For example, see R.E. Kirk (1982) "Experimental Design: Procedures for the behavioral sciences," 2nd ed.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de nouveaux composés correspondant à la formule (I), ou bien les sels pharmaceutiquement acceptables et promédicaments de ceux-ci, ainsi que des procédés de traitement de troubles neurologiques et de maladies neurodégénératives, en particulier la douleur et la migraine.
PCT/US2001/045858 2001-01-05 2001-12-19 Antagonistes des recepteurs d'aminoacides excitatoires WO2003024934A2 (fr)

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EP01274482A EP1351689A2 (fr) 2001-01-05 2001-12-19 Antagonistes des recepteurs d'aminoacides excitatoires
US10/450,669 US6924294B2 (en) 2001-01-05 2001-12-19 Excitatory amino acid receptor antagonists
AU2001298029A AU2001298029A1 (en) 2001-01-05 2001-12-19 Derivatives of the (3s, 4ar, 6s, 8ar) 6-phenylamino-1, 2, 3, 4, 4a, 5, 6, 7, 8, 8a-decahydro isoquinoline-3-carboxylic acid as excitatory amino acid receptor antagonists for the treatment of neurological disorders and neurodegenerative diseases

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EP01500003.7 2001-01-05
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7247644B2 (en) 2002-04-26 2007-07-24 Eli Lilly And Company Ester derivatives of a decahydroisoquinoline-3-carboxylic acid as analgestics
AU2006302174B2 (en) * 2005-10-06 2013-06-20 Exelixis, Inc. Pyridopyrimidinone Inhibitors of PIM-1 and/or PIM-3

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
O'NEILL M J ET AL: "DECAHYDROISOQUINOLINES: NOVEL COMPETITIVE AMPA/KAINATE ANTAGONISTS WITH NEUROPROTECTIVE EFFECTS IN GLOBAL CEREBRAL ISCHAEMIA" NEUROPHARMACOLOGY, PERGAMON PRESS, OXFORD, GB, vol. 37, October 1998 (1998-10), pages 1211-1222, XP000997636 ISSN: 0028-3908 *
ORNSTEIN, PAUL L. ET AL: "Structure-Activity Studies of 6-(Tetrazolylalkyl)-Substituted Decahydroisoquinoline-3-carboxylic Acid AMPA Receptor Antagonists. 1. Effects of Stereochemistry, Chain Length, and Chain Substitution" JOURNAL OF MEDICINAL CHEMISTRY, vol. 39, no. 11, 1996, pages 2219-2231, XP002223743 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7247644B2 (en) 2002-04-26 2007-07-24 Eli Lilly And Company Ester derivatives of a decahydroisoquinoline-3-carboxylic acid as analgestics
AU2006302174B2 (en) * 2005-10-06 2013-06-20 Exelixis, Inc. Pyridopyrimidinone Inhibitors of PIM-1 and/or PIM-3

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WO2003024934A3 (fr) 2003-07-24
AU2001298029A1 (en) 2003-04-01
EP1351689A2 (fr) 2003-10-15

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