WO2003006489A2 - Promedicaments d'acides amines excitateurs - Google Patents

Promedicaments d'acides amines excitateurs Download PDF

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Publication number
WO2003006489A2
WO2003006489A2 PCT/US2002/019825 US0219825W WO03006489A2 WO 2003006489 A2 WO2003006489 A2 WO 2003006489A2 US 0219825 W US0219825 W US 0219825W WO 03006489 A2 WO03006489 A2 WO 03006489A2
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compound
amino
formula
bicyclo
hexane
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PCT/US2002/019825
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English (en)
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WO2003006489A3 (fr
Inventor
Ana Belen Bueno Melendo
Alfonso De Dios
Carmen Dominguez-Fernandez
Rafael Ferritto Crespo
Marc Herin
Jose Alfredo Martin
Luisa Maria Martin-Cabrejas
Maria Angeles Martinez-Grau
Steven Marc Massey
James Allen Monn
Carlos Montero Salgado
Concepcion Pedregal-Tercero
Matthew John Valli
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Eli Lilly And Company
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Priority to EP02744537A priority Critical patent/EP1423411A2/fr
Priority to US10/480,517 priority patent/US20040176459A1/en
Publication of WO2003006489A2 publication Critical patent/WO2003006489A2/fr
Publication of WO2003006489A3 publication Critical patent/WO2003006489A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06104—Dipeptides with the first amino acid being acidic
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
    • C07C2602/40—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing six carbon atoms

Definitions

  • This invention relates to synthetic excitatory amino acid prodrugs (and their pharmaceutically acceptable salts) and processes for their preparation.
  • the invention further relates to methods of using, and pharmaceutical compositions comprising, the compounds for the treatment of neurological disorders and psychiatric disorders.
  • the present invention provides for a prodrug form of LY354740 which enhances the oral exposure of LY354740.
  • the present invention also provides for prodrug forms of other compounds which possess improved oral exposure.
  • Compounds of the present invention represent an improved approach for maintaining LY354740-like safety and efficacy in humans with increased oral bioavailability . Preclinical studies with compounds of the present invention, has shown greatly enhanced oral exposure of the parent compound. Accordingly, the present invention provides a compound of the formula I
  • RU is C(0)YRl and R ⁇ 2 ⁇ s hydrogen or fluoro; or R ⁇ is hydrogen or fluoro and
  • R!3 and R ⁇ -4 are, independently, hydrogen, (1-lOC) alkyl, (2-4C) alkenyl, (2-4C) alkynyl, or aryl;
  • A-L is hydrogen or an amino acyl bonded through the carbonyl to form an amine terminus ;
  • X and Y are, independently, 0 or A ⁇ •
  • a ⁇ is an amino acyl bonded through the amine to form a carboxlyate terminus; provided when X is 0, Y is not 0; or a pharmaceutically acceptable salt thereof.
  • this invention provides methods of treating neurological or psychiatric disorders, comprising: administering to a patient in need thereof an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. That is, the present invention provides for the use of a compound of Formula I, or a pharmaceutical composition thereof, for the treatment of psychiatric or neurological disorders.
  • the present invention provides for the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating neurological or psychiatric disorders.
  • the present invention provides for use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of neurological or psychiatric disorders.
  • Compounds of the invention have been found to be useful prodrugs for selective agonists of metabotropic glutamate receptors and are therefore useful in the treatment of diseases of the central nervous system such as neurological diseases, for example neurodegenerative diseases, and as antipsychotic, anxiolytic, drug-withdrawal, antidepressant, anticonvulsant, analgesic and anti-emetic agents.
  • the compounds of formula (I) contain at least four asymmetric carbon atoms, three being in the cyclopropane ring and one being at the ⁇ -carbon of the amino acid group within the cyclopentane ring. Additional asymmetric carbons may be present in the generic radicals as defined. Accordingly, the compounds of the invention may exist in and be isolated in enantiomerically pure form, in racemic form, or in a diastereoisomeric mixture .
  • the amino acid moiety within the cyclopentane ring preferably has the natural amino acid configuration, i.e. the L-configuration relating to D-glyceraldehyde .
  • the present invention includes pharmaceutically acceptable salts of the compound of formula I. These salts can exist in conjunction with the acidic or basic portion of the molecule and can exist as acid addition, primary, secondary, tertiary, or quaternary ammonium, alkali metal, or alkaline earth metal salts. Generally, the acid addition salts are prepared by the reaction of an acid with a compound of formula I .
  • the alkali metal and alkaline earth metal salts are generally prepared by the reaction of the hydroxide form of the desired metal salt with a compound of formula I.
  • Acids commonly employed to form such salts include inorganic acids, for example hydrochloric, hydrobromic, nitric, sulphuric or phoshoric acids, or with organic acids, such as organic carboxylic acids, for example, glycollic, maleic, hydroxymaleic, fumaric, malic, tartaric, citric, salicyclic, o-acetoxybenzoic, or organic sulphonic, 2-hydroxyethane sulphonic, toluene-p-sulphonic, methane- sulfonic or naphthalene-2-sulphonic acid.
  • other salts are included in the invention. They may serve as intermediates in the purification of compounds or in the preparation of other, for example pharmaceutically- acceptable, acid addition salts, or are useful for identification, characterization or purification.
  • the compounds of formula I the present invention are believed to have the ability to treat a variety of neorological disorders in mammals associated with this condition, including acute neurological disorder such as cerebral deficits subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, and hypoglycemic neuronal damage.
  • the compounds of formula I are believed to have the ability to treat a variety of chronic neurological disorders, such as Alzheimer's disease, Huntington's Chorea, amyotrophic lateral sclerosis, AIDS-induced dementia, ocular damage and retinopathy, cognitive disorders, and idiopathic and drug-induced Parkinson's.
  • the present invention also provides methods for treating these disorders which comprises administering to a patient in need thereof an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof .
  • Compounds of formula I of the present invention are also believed to have the ability to treat a variety of other neurological disorders in patients that are associated with glutamate dysfunction, including muscular spasms, convulsions, migraine headaches, urinary incontinence, psychosis, (such as schizophrenia), drug tolerance and withdrawal (such as nicotine, opiates and benzodiazepines) , anxiety and related disorders, premenstural dysphoric disorder (PDD) , emesis, brain edema, chronic pain, and tardive dyskinesia.
  • the compounds of formula I are also useful as antidepressant and analgesic agents. Therefore, the present invention also provides methods for treating these disorders which comprise administering to a patient in need thereof an effective amount of the compound of formula I, or a pharmaceutically acceptable salt thereof.
  • a compound of formula I may be made by a process which is analogous to one known in the chemical art for the production of structurally analogous heterocyclic compounds or by a novel process described herein. Such processes and intermediates useful for the manufacture of a compound of formula I as defined above are provided as further features of the invention and are illustrated by the following procedures in which, unless otherwise specified, the meanings of the generic radicals are as defined above. (A) For a compound of formula I in which A ⁇ is hydrogen and X is A ⁇ , deprotecting the amine group of a compound of formula III
  • R m is an amine-protecting group as descibed in General Procedures 6-8.
  • amine-protecting group refers to those groups intended to protect or block the amine group against undesirable reactions during synthetic procedures .
  • Choice of the suitable amine protecting group used will depend upon the conditions that will be employed in subsequent reaction steps wherein protection is required, as is well within the knowledge of one of ordinary skill in the art. Commonly used amine protecting groups are disclosed in T. . Greene and P.G.M. Wuts, Protective Groups In Organic Synthesis, 3rd Ed. (John Wiley & Sons, New York (1999) ) .
  • Suitable amine 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-toluene ⁇ ulfonyl and the like, carbamate forming groups such as benzyloxycarbonyl, p- chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p- nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p- bromo
  • Preferred suitable amine protecting groups are acetyl, methyloxycarbonyl, benzoyl, pivaloyl, allyloxycarbonyl, t- butylacetyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz) .
  • the amine protecting group is decomposed by using a conventional procedure which does not affect another portion of the molecule.
  • carboxy-protecting group refers to one of the ester derivatives of the carboxylic acid group commonly employed to block or protect the carboxylic acid group while reactions are carried out on other functional groups of the compound. Particular values include, for example, methyl, ethyl, tert-butyl, benzyl, methoxymethyl , tri ethylsilyl, allyl, and the like. Further examples of such groups may be found in T.W. Greene and P.G.M. Wuts, Protecting Groups in Organic Synthesis, 3rd. Ed. (John Wiley & Sons, N.Y. (1999)) . Preferred carboxy protecting groups are methyl and allyl.
  • the ester is decomposed by using a conventional procedure which does not affect another portion of the molecule.
  • a pharmaceutically acceptable salt of a compound of formula I when required, it is obtained by reacting the acid of formula I with a physiologically acceptable base or by reacting a basic compound of formula I with a physiologically acceptable acid or by any other conventional procedure.
  • (1-lOC) alkyl represents a straight, branched, or cyclic alkyl chain having from one to ten carbon atoms.
  • Typical straight or branched (1-lOC) alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, ripentyl, isopentyl, neopentyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2 , 2-dimethyIbutyl, 2,3- dimethylbutyl , 3 , 3-dimeth lb tyl, heptyl, n-octyl, 2,2- dimethylhexyl , 2 , 5-dimethylhexyl, 2-methylheptyl, 4- methylheptyl , 2 , 2 , 4-trimethylpen
  • Typical cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
  • the term " (1- 10C) alkyl” includes within it the terms “ (1-6C) alkyl” and " (1-4C) alkyl”.
  • Typical (1-6C) alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl .
  • an amino acyl bonded through the carbonyl to form an amine terminus means an amino acyl bonded through it's carbonyl to an amine containing molecule to form a new amine terminus.
  • an amino acyl bonded through the amine to form an carboxy terminus means an amino acyl bonded through it's amine to a carbonyl containing molecule to ' forma new carboxy terminus .
  • amino acyl means an amino acyl derived from, an amino acid selected from the group consisting of natural and unnatural amino acids as defined herein. Preferred amino acids are those possessing an ⁇ -amino group. The amino acids may be neutral, positive or negative depending on the substituents in the side chain. "Neutral amino acid"
  • • means an amino acid containing uncharged side chain substituents.
  • neutral amino acids include alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine, glycine, serine, threonine and cysteine.
  • Positive amino acid means an amino acid in which the side chain substituents are positively charged at physiological pH.
  • positive amino acids include lysine, arginine and histidine.
  • Negative amino acid means an amino acid in which the side chain substituents bear a net negative charge at physiological pH.
  • Exemplary negative amino acids include aspartic acid and glutamic acid.
  • Preferred amino acids are ⁇ -amino acids.
  • the most preferred amino acids are ⁇ -amino acids having L stereochemistry at the ⁇ -carbon.
  • Exemplary natural ⁇ -amino acids are L-valine, L-isoleucine, L-proline,
  • Unnatural amino acid means an amino acid for which there is no nucleic acid codon.
  • unnatural amino acids include, for example, the D-isomers of the natural ⁇ - amino acids as indicated above; Aib (aminobutyric acid) , ⁇ Aib (3-aminoisobutyric acid) , Nva (norvaline) , ⁇ -Ala, Aad (2-aminoadipic acid) , ⁇ Aad (3-aminoadipic acid) , Abu (2- aminobutyric acid), Gaba ( ⁇ -aminobutyric acid), Acp (6- aminocaproic acid), Dbu (2 , 4-diaminobutryic acid), ⁇ - aminopimelic acid, TMSA ( trimethylsilyl-Ala) , alle (allo- isoleucine) , Nle (norleucine) , tert-Leu, Cit (citrulline) , Orn, Dpm (2 , 2 '
  • (2-4C) alkenyl represents straight or branched unsaturated alkyl chains having from two to four carbon atoms, and having one or more carbon-carbon double bond, such as, dienes.
  • This group also includes both E and Z isomers.
  • Representative radicals for this group include vinyl, allyl, allenyl, 1-butenyl, 2- butenyl, 2-methyl-1-propenyl, 3-butenyl, 2-methyl-2- propenyl, butadienyl.
  • (2-4C) alkynyl means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched having about 2 to about 4 carbon atoms in the chain. Preferred alkynyl groups have 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl or ethyl are attached to a linear alkynyl chain .
  • aryl represents groups such as phenyl, substituted phenyl, and naphthyl.
  • arylalkyl represents a (1-4C) alkyl group bearing one or more aryl groups. Representatives of this latter group include benzyl .
  • RU is C(0)YR1 ⁇
  • R ⁇ -2, R13 an 3 ⁇ 1 are hydrogen
  • X is A ⁇
  • Representative compounds from this preferred group of ' formula I compounds include (IS, 2S, 5R, 6S) 2-amino-2- ( (l'S) 1-carboxy-3-methylbutylcarbamoyl) - bicyclo [3.1.0]hexane-6-carboxylic acid.
  • R is tert-butoxycarbonyl, X and Y are 0, R 13 is hydrogen and R 14 is (1-lOC) alkyl, for example a methyl group; or R m is allyloxycarbonyl, X and Y are 0, R 13 is hydrogen and R 14 is (2-10C) alkenyl group, for example an allyl group.
  • Also useful for the synthesis of compounds of formula I are compounds where the C-2 amino and carboxy groups of the cyclopentane ring are protected in the form of a cyclized ring.
  • the cyclized ring is an oxazolidinone that is spiro fused to the 2-postion of bicyclo [3.1. Ojhexane-6-carboxylic acid, for example a compound of formula IV.
  • the compounds of formula I of the present invention are generally synthesized from compounds of formula II where Y is 0, and R 12 , R 13 and R 14 are all hydrogen.
  • the compounds of formula II are prepared as described in U. S. Patent No. 5,750,566 which is incorporated by reference in its entirety.
  • compounds of formula I in which X is A 2 may be prepared by reacting compounds of formula III in which X is 0, R ⁇ - 3 is hydrogen and R 1 * 1 is an amine protecting group.
  • compounds of formula I in which X is A 2 may be prepared by reacting compounds of formula IV.
  • compounds of formula II are reacted with amine protecting agents such as allyl chloroformate in the presence of a suitable aqueous ' base such as sodium bicarbonate in a suitable solvent such as dioxane to produce compounds of formula III in which R m is allyloxycarbonyl.
  • amine protecting agents such as allyl chloroformate
  • a suitable aqueous ' base such as sodium bicarbonate
  • a suitable solvent such as dioxane
  • Compounds of formula III are then reacted with carboxy protecting agents such as allyl alcohol, EDCI and HOBt in the presence of a suitable base such as triethyla ine in a convenient solvent such as dichloromethane to provide compounds of formula V as shown in scheme 2.
  • reaction in which X is A 2 and Y is 0.
  • a metal catalyst regenerating agent such as 1, 3-dimethylbarbituric acid in a convenient solvent such as dichloromethane.
  • the acid addition salts may be prepared by the reaction of an acid such as hydrogen chloride gas . with a compound of formula I.
  • Convenient solvents include ethyl acetate.
  • Compounds of formula I in which X is A 2 may also 15 be prepared from compounds of formula III in which R m is an amine-protecting group such as tert-butyl- oxycarbonyl . More specificly, compounds of formula II are reacted with carboxy protecting agents such as hydrogen chloride gas in methanol to provide a compound of formula VII, as shown • in scheme 4.
  • compounds of formula I in which X is A 2 may be prepared by reacting compounds of formula IV in which Y is 0 and R ⁇ 4 is hydrogen as shown in scheme 6. More specifically, compounds of formula IV may be prepared by reacting compounds of formula III m which R is an amme protecting group such as allyloxycarbonyl with an aldehyde such as paraformaldehyde in the presence of a suitable acid catalyst such as para-toluenesulphonic acid. The reaction may be carried out in a suitable solvent such as benzene with convenient removal of water such as azetropic distillation.
  • a metal catalyst such as tetrakistriphenyl phosphine palladium(0) to produce compounds of formula I in which X is A 2 and Y is 0.
  • the reaction is performed in the presence of a metal catalyst regenerating agent such as 1, 3-dimethylbarbituric acid in a convenient solvent such as dichloromethane.
  • the acid addition salts may be prepared by the reaction of an acid such as hydrogen chloride gas with a compound of formula I.
  • Convenient solvents include ethyl acetate.
  • compounds of formula I in which Y is A 2 may be prepared by reacting compounds of formula IV in which Y is 0 and R ⁇ - ⁇ is hydrogen. More specifically, compounds of formula IV are reacted with a carbodiimide such as EDCI and an amino acyl of formula HA R14 in the presence of a suitable base such as triethyl amine to provide compounds of formula XI in which Y is A 2 , as shown in scheme 7.
  • the reaction is conveniently performed in the presence of activating agents such as hydroxybenzotriazole and dimethylaminopyridine .
  • Convenient solvents include dichloromethane.
  • a metal catalyst such as tetrakistriphenyl phosphine palladium(0) to produce compounds of formula I in which Y is A 2 and X is O.
  • the reaction is performed in the presence of a metal catalyst regenerating agent such as 1, 3-dimethylbarbituric acid in a convenient solvent such as dichloromethane .
  • the acid addition salts may be prepared by the reaction of an acid such as hydrogen chloride gas with a compound of formula I.
  • Convenient solvents include ethyl acetate.
  • affecting refers to a formula I compound acting as an agonist at an excitatory amino acid receptor.
  • excitatory amino acid receptor refers to a metabotropic glutamate receptor, a receptor that is coupled to cellular effectors via GTP-binding proteins.
  • cAMP-linked metabotropic glutamate receptor refers to a metabotropic receptor that is coupled to inhibition of adenylate cyclase activity.
  • neuroological disorder refers to both acute and chronic neurodegenerative conditions, including cerebral deficits subsequent to cardiac bypass surgery and grafting, cerebral ischemia (for example stroke resulting from cardiac arrest) , spinal cord trauma, head trauma, Alzheimer's Disease,
  • Huntington's Chorea amyotrophic lateral sclerosis, AIDS-induced dementia, perinatal hypoxia, hypoglycemic neuronal damage, ocular damage and retinopathy, cognitive disorders, idiopathic and drug-induced Parkinson's Disease.
  • This term also includes other neurological conditions that are caused by glutamate dysfunction, including muscular spasms, migraine headaches, urinary incontinence, drug tolerance, withdrawal, and cessation (i.e. opiates, benzodiazepines, nicotine, cocaine, or ethanol), smoking cessation, emesis, brain edema, chronic pain, sleep disorders, convulsions, Tourette ' s syndrome, attention deficit disorder, and tardive dyskinesia.
  • psychiatric disorder refers to both acute and chronic psychiatric conditions, including schizophrenia, anxiety and related disorders (e.g. panic attack, stress-related cardiovascular disorders or generalized anxiety disorder (GAD) ) , depression, bipolar disorders, psychosis, and obsessive compulsive disorders.
  • schizophrenia, anxiety and related disorders such as GAD or panic attack, depression, bipolar disorder, psychosis and obsessive compulsive disorders are preferred.
  • drug tolerance, withdrawal and cessation are preferred.
  • the present invention provides a method for treating anxiety and related disorders such as panic attack or GAD comprising: administering to a patient in need thereof an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • 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 .
  • 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 specific disease involved; the degree of or involvement or the severity of the disease; 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 may contain from about 25 mg to about 300 mg of the active ingredient.
  • the compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, bucal or intranasal routes. Alternatively, the compound may be administered by continuous infusion.
  • patient refers to a mammal, such as a mouse, guinea pig, rat, dog or human. It is understood that the preferred patient is a human.
  • treating includes its generally accepted meaning which encompasses prohibiting, preventing, restraining, and slowing, stopping, or reversing progression of a resultant symptom. As such, the methods of this invention encompass both therapeutic and prophylactic administration.
  • the necessary starting materials for the above procedures may be made by procedures which are selected from standard techniques of organic and heterocyclic chemistry, techniques which analogous to the syntheses of known, structurally similar compounds, and the procedures described in the Examples, including novel procedures .
  • a further aspect of the present invention provides for a method of administering an effective amount of a compound of formula II, where R ⁇ -3 an( j R14 are both hydrogen (a di- acid) , which comprises administering to a patient requiring modulated excitatory amino acid neurotrans ission a pharmaceutically-effective amount of a compound of formula I.
  • the ability of compounds to modulate metabotropic glutamate receptor function may be demonstrated by examining their ability to influence either cAMP production (mGluR 2, 3, 4, 6, 7 or 8) or phosphoinositide hydrolysis (mGluR 1 or 5) in cells expressing these individual human metabotropic glutamate receptor (mGluR) subtypes. (D. D. Schoepp, et al . , Neuropharmacol . , 1996, 35, 1661-1672 and 1997, 36, 1- 11) .
  • formula I compounds to treat anxiety or a related disorder may be demonstrated using the well known fear potentiated startle and elevated plus maze models of anxiety described respectively in Davis, Psychopharmacology, 62:1;1979 and Lister, Psychopharmacol, 92:180-185; 1987
  • Plasma samples and internal standard compounds were pretreated by solid phase extraction (SAX support, methanol/water/dilute acetic acid) .
  • the plasma concentrations (ng/ l) of LY354740 for each test compound were determined by LC/MS/MS and are presented as a sum of the concentrations at the 0.5 and 1 hour or, alternatively, 1 and 3 hour sample time points as shown in table 1.
  • compositions of the present invention are preferably formulated prior to administration. Therefore, another aspect of the present invention is a pharmaceutical formulation comprising a compound of formula I a pharmaceutically acceptable metabolically labile ester thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically-acceptable carrier, diluent, or excipient.
  • the present pharmaceutical formulations are prepared by known procedures using well-known and readily available ingredients.
  • the active ingredient will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, and may be in the form of a capsule, sachet, paper, or other container.
  • the carrier When the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active ingredient.
  • the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments containing, for example, up to 10% by weight of active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders .
  • Suitable carriers, ' excipients, and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum, acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, methyl cellulose, methyl and propyl hydroxybenzoates, talc, magnesium stearate, and mineral oil.
  • the formulations can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents, or flavoring agents.
  • Compositions of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
  • compositions are preferably formulated in a unit dosage form, each dosage containing from about 5 mg to about 500 mg, more preferably about 25 mg to about 300 mg of the active ingredient.
  • active ingredient refers to a compound included within the scope of formula I .
  • unit dosage form refers to a physically discrete unit suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier, diluent, or excipient.
  • Free atom bombardment mass spectro ⁇ copy was performed on a VG ZAB-2SE instrument.
  • Field desorption mass spectroscopy was performed using either a VG 70SE or a Varian MAT 731 instrument. Optical rotations were measured with a Perkin- Elmer 241 polarimeter. Chromatographic separation on a
  • DIBAL-H diisobutyl aluminum hydride
  • DMAP dimethylaminopyridine
  • FAB Fast Atom Bombardment (Mass Spectrascopy)
  • HOBt 1-hydroxybenzotriazole
  • NBS N-bromosuccinimide
  • NMDBA 1, 3-dimethylbarbituric acid
  • i-Pr isopropyl
  • TBS tert-butyldimethylsilyl
  • Example Preparations 1-3 describe synthesis methods for intermediates .
  • the corresponding allylated compound (1.0 equiv) was dissolved in dry dichloromethane (0.1 M solution) under nitrogen. 1, 3-Dimethylbarbituric acid (3.0 equiv for each allyl group to be removed) and tetrakis (triphenylphosphine) - palladium(O) (0.03 equiv) were added and the solution was heated at 35 a C for 2 h. After cooling to room temperature, the solvent was removed under vacuum and the resulting residue was dissolved in a solution of ethyl acetate saturated with hydrogen chloride gas and stirred for 2 h. In the case where a solid appeared, the reaction was filtered and the filtrate was washed with ethyl acetate and ether. In the case where a solid did not appear, the solvent was removed under vacuum and the residue was stirred with ether overnight. The solid was filtered, washed thoroughly with ether and dried to provide the product .
  • the corresponding allylated compound (1.0 equiv) was dissolved in dry dichloromethane (0.1 M solution) under nitrogen. 1, 3-Dimethylbarbituric acid (0.5 equiv for each allyl group to be removed) and tetrakis (triphenylphosphine) - palladium(O) (0.02 equiv) were added and the resulting solution was heated at 35 2 C for 2 h. After cooling at room temperature, if a solid was formed, it was filtered and washed with dichloromethane, ethyl acetate, diethyl ether and dried to provide the product. In case the solid did not appear, the solvent was removed under vacuum and a large amount of ethyl, ether was added. After stirring for 30 min the solid was filtered and washed with ether, ethyl acetate and dried to provide the product.
  • the title compound was prepared from (15, 1' 5, 25, 52?, 65) -2- allyloxycarbonylamino-2- (ethoxycarbonylmethyl-carbamoyl) - bicyclo [3.1.0] hexane-6-carboxylic acid allyl ester as described in General Procedure 8. The residue was suspended in 2 mL of tetrahydrofuran and 4 mL of 2.5 N aqueous lithium hydroxide were added. The reaction was stirred for 2h, acidified to pH 3 with 6N HCI and concentrated to dryness. Purification by ion exchange chromatography provided the title compound. (70% yield) White solid.
  • the title compound was prepared from (15, 25, 52?, 65) -2- allyloxycarbonylamino-2- [ (l'R) -methoxycarbonylphenylmethyl] carbamoyl-bicyclo [3.1.0]hexane-6-carboxylic acid allyl ester as described in General Procedure 8. Half of the residue was suspended in 2 mL of tetrahydrofuran and 4 mL of 2.5N lithium hydroxide was added. The reaction was stirred for 2h, acidified to pH 3 with 6N HCI and evaporated to dryness. Purification by ion exchange chromatography provided the title compound. (40% yield) White solid.

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Abstract

La présente invention concerne des promédicaments d'acides aminés excitateurs de synthèse, et des procédés pour leur préparation. L'invention traite, en outre, de procédés d'utilisation et de compositions pharmaceutiques comprenant les composés permettant de traiter les troubles neurologiques et psychiatriques.
PCT/US2002/019825 2001-07-09 2002-07-02 Promedicaments d'acides amines excitateurs WO2003006489A2 (fr)

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EP02744537A EP1423411A2 (fr) 2001-07-09 2002-07-02 Promedicaments d'acides amines excitateurs
US10/480,517 US20040176459A1 (en) 2001-07-09 2002-07-02 Prodrugs of excitatory amino acids

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EP01500175 2001-07-09
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7038077B2 (en) 2001-01-11 2006-05-02 Eli Lilly And Company Prodrugs of excitatory amino acids
US7256217B2 (en) 2001-01-11 2007-08-14 Eli Lilly And Company Prodrugs of excitatory amino acids
US7456221B2 (en) 2001-12-21 2008-11-25 Eli Lilly And Company Prodrugs of excitatory amino acids

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000004010A1 (fr) * 1998-07-17 2000-01-27 Eli Lilly And Company Limited Derives de bicyclohexane
WO2000012464A1 (fr) * 1998-08-31 2000-03-09 Taisho Pharmaceutical Co., Ltd. Derives de 6-fluorobicyclo[3. 1.0]hexane

Patent Citations (2)

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Publication number Priority date Publication date Assignee Title
WO2000004010A1 (fr) * 1998-07-17 2000-01-27 Eli Lilly And Company Limited Derives de bicyclohexane
WO2000012464A1 (fr) * 1998-08-31 2000-03-09 Taisho Pharmaceutical Co., Ltd. Derives de 6-fluorobicyclo[3. 1.0]hexane

Non-Patent Citations (2)

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Title
COSTANTINO G ET AL.: "Pharmacorephore Models of Group I and Group II Metabotropic Glutamate Receptor Agonists. Analysis of Conformational, Steric, and Topological Parameters Affecting Potency and Selectivity" JOURNAL OF MEDICINAL CHEMISTRY, vol. 42, 1999, pages 2816-2827, XP002231618 *
NAKAZATO A ET AL.: "Synthesis, SARs, and Pharmacological Characterization of 2-Amino-3 or 6-fluorobicyclo[3.1.0Ühexane-2,6-dicarboxy lic Acid Derivatives as Potent, Selective, and Orally Active Group II Metabotropic Glutamate Receptor Agonists" JOURNAL OF MEDICINAL CHEMISTRY, vol. 43, 2000, pages 4893-4909, XP001093883 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7038077B2 (en) 2001-01-11 2006-05-02 Eli Lilly And Company Prodrugs of excitatory amino acids
US7256217B2 (en) 2001-01-11 2007-08-14 Eli Lilly And Company Prodrugs of excitatory amino acids
US7456221B2 (en) 2001-12-21 2008-11-25 Eli Lilly And Company Prodrugs of excitatory amino acids

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WO2003006489A3 (fr) 2003-09-25

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