EP1463713A1 - Promedicaments d'acides amines excitateurs - Google Patents

Promedicaments d'acides amines excitateurs

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Publication number
EP1463713A1
EP1463713A1 EP02789239A EP02789239A EP1463713A1 EP 1463713 A1 EP1463713 A1 EP 1463713A1 EP 02789239 A EP02789239 A EP 02789239A EP 02789239 A EP02789239 A EP 02789239A EP 1463713 A1 EP1463713 A1 EP 1463713A1
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EP
European Patent Office
Prior art keywords
compound
formula
hydrogen
ester
acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP02789239A
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German (de)
English (en)
Inventor
Ana Belen Lilly S. A. BUENO MELENDO
Alfonso Lilly S. A. De Dios
Carmen Lilly S. A. DOMINGUEZ-FERNANDEZ
Marc Lilly MSG Development Centre S. A. HERIN
Luisa Maria Lilly S. A. MARTIN-CABREJAS
Jose Alfredo Lilly S. A. MARTIN
Maria Angeles Lilly S. A. MARTINEZ-GRAU
Steven Marc Massey
James Allen Monn
Carlos Lilly S. A. MONTERO SALGADO
Concepcion Lilly S. A. PEDREGAL-TERCERO
Matthew John Valli
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Eli Lilly and Co
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Eli Lilly and Co
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Priority to EP02789239A priority Critical patent/EP1463713A1/fr
Publication of EP1463713A1 publication Critical patent/EP1463713A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/46—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C229/50—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups and carboxyl groups bound to carbon atoms being part of the same condensed ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/24—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
    • C07D307/89—Benzo [c] furans; Hydrogenated benzo [c] furans with two oxygen atoms directly attached in positions 1 and 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/32—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings 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 ring carbon atoms
    • C07D317/34—Oxygen atoms
    • C07D317/40—Vinylene carbonate; Substituted vinylene carbonates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/14—All rings being cycloaliphatic
    • C07C2602/18—All rings being cycloaliphatic the 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 have shown greatly enhanced oral exposure of the parent compound.
  • the present invention provides a compound of the formula I
  • R 11 is CO2R 14 and R 12 is hydrogen or fluoro; or R 11 is hydrogen or fluoro and R 12 i s CO2R 14 ;
  • R 13 and R 14 are, independently, hydrogen, -CHR 15 0 2 CXR 16 or a group selected from 3-phthalidyl or
  • X is 0, N, S, or a bond
  • R 15 is hydrogen, (1-lOC) alkyl, (2-4C) alkenyl , aryl, or arylalkyl;
  • R 16 is (1-lOC) alkyl, (2-4C) alkenyl, (2-4C) alkynyl , or aryl ;
  • R 17 is hydrogen, (1-lOC) alkyl, or phenyl ; provided when R 14 is hydrogen, R 13 is not hydrogen; or a pharmaceutically acceptable salt thereof.
  • Compounds of the present 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.
  • 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 acids, such as 2-hydroxyethane sulphonic, toluene-p-sulphonic, methanesulfonic, ethanesulfonic or naphthalene-2-sulphonic acid.
  • organic acids such as organic carboxylic acids, for example, glycollic, maleic, hydroxymaleic, fumaric, malic, tartaric, citric, salicyclic, o-acetoxybenzoic, or organic sulphonic acids, such as 2-hydroxyethane sulphonic, toluene-p-sulphonic, methanes
  • salts are included in the invention. They may serve as intermediates in the purification of compounds or in the preparation of other, for example phar aceutically- acceptable, acid addition salts, or are useful for identification, characterization or purification.
  • the formula I compounds of the present invention are believed to have the ability to treat a variety of neurological 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 formula I compounds 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.
  • the formula I compounds of the present invention treat a variety of other neurological disorders in mammals 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, emesis, brain edema, chronic pain, and tardive dyskinesia.
  • the formula I compounds 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.
  • the compounds of formula I of the present invention are believed to have the ability to treat a variety of neurological 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.
  • the compounds of formula I of the present invention are also believed to have the ability to treat a variety of other neurological disorders in mammals 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, 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.
  • R 13 ls n ester, R ⁇ 4 is a carboxy protecting ester group as described in General Procedure 2 for Examples 13-18.
  • amine protecting group refers to those groups intended to protect or block the nitrogen 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.W. 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 benz ' enesulfonyl, p-toluenesulfonyl and the like, carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p- methoxybenzyloxycarbonyl , p-nitrobenzyloxycarbonyl, 2- nitrobenzyloxy
  • Preferred suitable amine protecting groups are formyl , acetyl, methyloxycarbonyl , benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, allyloxycarbonyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz) .
  • 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 of R 13 and R 14 carboxyl protecting ester groups include, for example, methyl, ethyl, tert-butyl, benzyl, methoxymethyl , trimethylsilyl, 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, 3 rd . Ed. (John Wiley & Sons, N.Y. (1999)) .
  • the ester is decomposed by using a conventional procedure which does not affect another portion of the molecule.
  • 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, n- pentyl , isopentyl, neopentyl , ⁇ -hexyl, 2-methylpentyl , 3-methylpentyl, 4-methylpentyl, 2 , 2-dimethylbutyl, 2,3- dimethylbutyl , 3 , 3-dimethylbutyl , heptyl , n-octyl, 2,2- dimethylhexyl , 2 , 5-dimethylhexyl, 2-methylheptyl , 4- methylheptyl , 2 , 2-trifluoride
  • (1-lOC) alkyl includes within it the terms " (1-6C) alkyl” and " (1-4C) alkyl".
  • Typical cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
  • 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 .
  • (2-4C) alkenyl represents straight or branched unsaturated alkyl chains having from two to ten 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, and the like.
  • (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. 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 polycyclic aromatic rings such as 1- naphthyl or 2-naphthyl.
  • arylalkyl represents a (1-4C) alkyl group bearing one or more aryl groups. Representatives of this latter group include benzyl, 2-nitrobenzyl , 4- nitrobenzyl, 1-phenylethyl , 2-phenylethyl, 3- phenylpropyl , 4-phenylbutyl , 2-methyl-2-phenylpropyl, (4 -chlorophenyl) methyl, (2 , 6-dichlorophenyl) - methyl, bis (2, 6-dichlorophenyl) methyl, (4-hydroxyphenyl) - methyl, (2 , 4-dinitrophenyl) methyl, triphenylmethyl, (4- methoxypheny1 ) diphenylmethyl , bis (4 - methoxyphenyl) methyl , ⁇ -naphthyldiphenylmethy1 , bis (2- nitrophenyl) methyl, and the like.
  • substituted phenyl represents a phenyl group substituted with one or two moieties chosen from the group consisting of halogen, hydroxy, cyano, nitro, (1-lOC) alkyl, (1-4C) alkoxy, alkoxycarbonyl , protected carboxy, carboxymethyl , hydroxymethyl, amino, protected amino, aminomethyl , or trifluoromethyl .
  • Examples of a substituted phenyl group include 4-chlorophenyl , 2 , 6-dichlorophenyl , 2,5- dichlorophenyl, 3 , 4-dichlorophenyl , 3 -chlorophenyl, 3- bromophenyl , 4-bromophenyl , 3 , 4-dibromophenyl , 3 - chloro-4-fluorophenyl, 2-fluorophenyl , 4-hydroxyphenyl, 3 -hydroxy-phenyl , 2 , 4-dihydroxyphenyl , 3 -nitrophenyl , 4-nitrophenyl, 4 -cyanopheny1 , 4-methylphenyl , 4- ethy1phenyl , 4-ethoxy-phenyl , 4-carboxyphenyl , 4- (hydroxymethyl) henyl , 4 -aminophenyl , 4-propylphenyl , 4-butylphenyl, 4- t
  • R 11 is C0 2 R 14 ;
  • R 12 is hydrogen;
  • R 13 and R 14 are, independently, 3 ' -phthalidyl , hydrogen, -CHR 15 0 2 CXR 16 , or R 15 is hydrogen or methyl;
  • R 16 is (1-lOC) alkyl or aryl; and
  • X is O or a bond.
  • Representative compounds from this preferred group of formula I compounds include (IS, 2S, 5R, 6S) -2-amino- bicyclo [3.1.0] hexane-2 , 6-dicarboxylic acid 2,6- dibenzoyloxymethyl ester hydrochloride, (IS, 2S, 5R, 6S) - 2-amino-bicyclo [3.1.0] hexane-2, 6-dicarboxylic acid 2,6- dicyclohexyloxycarbonyloxymethyl ester, (IS, 2S, 5R, 6S) - 2-amino-bicyclo [3.1.0] hexane-2, 6-dicarboxylic acid 2,6- di (1' -cyclohexyloxycarbonyloxy-ethyl) ester hydrochloride, (IS, 2S, 5R, 6S) -2-amino- bicyclo [3.1.0] hexane-2 , 6-dicarboxylic acid 2,6-di-(3'- phthali
  • Certain compounds of the present invention are more preferred for use in providing prodrug forms. More preferably, R 15 is hydrogen and X is a bond.
  • Representative compounds from this more preferred group of compounds include (IS, 2S, 5R, 6S) -2-amino- bicyclo [3.1.0] hexane-2, 6-dipropanoyloxymethyl ester hydrochloride, (IS, 2S, 5R, 6S) -2-amino- bicyclo [3.1.0] hexane-2 , 6-dicarboxylic acid 2-(4'- methoxybenzoyloxy) methyl ester hydrochloride, and
  • R m is tert-butoxycarbonyl and R 13 and R 14 are H; or R m is allyloxycarbonyl, R 13 is hydrogen and R 14 is (2-4C) alkenyl group, for example an allyl group.
  • cyclic ring is an oxazolidinone that is spiro fused to the 2-postion of bicyclo [3.1.0] hexane-6-carboxylic acid, for example a compound of formula IV.
  • the compounds of formula II of the present invention are generally synthesized from compounds of formula III where R 13 and R 14 are both hydrogen.
  • the compounds of formula III are prepared as described in U. S. Patent No. 5,750,566 which is incorporated by reference in its entirety.
  • compounds of formula II in which R13 is -CHR 15 0 2 CXR 16 may be prepared by directly reacting compounds of formula II where R ⁇ 3 is hydrogen and R- 1 - 4 is a carboxy protecting group.
  • Compounds of formula II in which R 13 and R 14 are -CHR 15 0 2 CXR 16 may be prepared by reacting compounds of formula II where R ⁇ and R ⁇ are both hydrogen.
  • compounds of formula III 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 II.
  • amine protecting agents such as allyl chloroformate
  • a suitable aqueous base such as sodium bicarbonate
  • a suitable solvent such as dioxane
  • carboxy protecting agents such as allyl alcohol, EDCI and HOBt
  • a suitable base such as triethylamine in a convenient solvent such as dichloromethane
  • Compounds of formula VI may be prepared from compounds of formula V, a carboxlic acid, with a substituted alkyl halide of formula QCHR 15 0 2 CXR 16 in which Q is, for example, chlorine or bromine as shown in scheme 3.
  • the reaction is conveniently performed in the presence of a base, such as potassium carbonate and an activating agent, such as sodium iodide.
  • Convenient solvents include dimethylformamide .
  • Compounds of formula VI are reacted with a metal catalyst such as tetrakistriphenylphosphine palladium (0) to produce compounds of formula I where R 11 is C0 2 R 14 , R 12 and R14 are hydrogen, and R13 is -CHR 15 0 2 CXR 16 .
  • 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 II in which R 13 and R 14 are both -CHR 15 0 2 CXR 16 may be prepared by reacting compounds of formula II where R 13 and R 14 are both hydrogen as shown in scheme 4. More specially, compounds of formula II may be prepared by reacting compounds of formula III with amine protecting agents such as di-tert-butyl dicarbonate in the presence of a suitable aqueous base such as sodium hydroxide in a suitable solvent such as dioxane to produce compounds of formula II where R m is tert-butyloxycarbonyl .
  • amine protecting agents such as di-tert-butyl dicarbonate
  • a suitable aqueous base such as sodium hydroxide
  • a suitable solvent such as dioxane
  • Compounds of formula VII may be prepared from compounds of formula II, a dicarboxlic acid, with a substituted alkyl halide of formula QCHR 15 0 2 CXR 16 in which Q is a suitable leaving group such as chlorine.
  • the reaction is conveniently performed in the presence of a base, such as potassium carbonate and an activating agent, such as sodium iodide.
  • Convenient solvents include dimethylformamide .
  • amine deprotecting agents such as an acid to provide compounds of formula I in which R 11 is C0 2 R 14 , R 13 and R 14 are both -CHR 15 0 2 CXR 16 or 5-methyl-2-oxo- [1, 3] dioxolen-4-ylmethyl and R 12 is hydrogen.
  • Convenient acids include trifluoroacetic acid or hydrogen chloride gas saturated in a convenient solvent such as ethyl acetate. Such conditions may produce the corresponding acid salt of the compound of formula I as an amorphous or, directly, a crystalline solid. In the case of an amorphous solid, subsequent crystallization may occur from suitable solvents.
  • the zwitterionic compound of formula I may be prepared by treatment of the acid salt of formula I with a suitable reagent such as a base, for example aqueous sodium bicarbonate, or propylene oxide. Additional acid salts may be prepared by treating the zwitterionic compound of formula I with a suitable acid. Suitable acids include ethanesulfonic acid in a convenient solvent such as methylene chloride .
  • compounds of formula I in which R 13 is hydrogen and R 14 is -CHR 15 0 2 CXR 16 may be prepared by reacting compounds of formula IV where R 14 is hydrogen as shown in scheme 5. More specially, compounds of formula IV may be prepared by reacting compounds of formula II where R m is an amine protecting group such as allyloxycarbonyl with an aldehyde such as paraformaldehyde in the presence of a suitable acid catalyst such as p-toluene sulphonic acid. The reaction may be carried out in a suitable solvent such as benzene with convenient removal of water such as azeotropic distillation.
  • Compounds of formula IIX may be prepared from compounds of formula IV where R 14 is hydrogen with a substituted alkyl halide of formula QCHR 15 0 2 CXR 16 in which Q is a suitable leaving group such as chlorine.
  • the reaction is conveniently performed in the presence of a base, such as potassium carbonate.
  • An activating agent, such as sodium iodide may be added to facilitate the reaction.
  • Convenient solvents include dimethylformamide .
  • 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.
  • neurodegenerative 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.
  • psychiatric disorder refers to both acute and chronic psychiatric conditions, including schizophrenia, anxiety and related disorders (e.g. panic attack and stress-related cardiovascular disorders) , depression, bipolar disorders, psychosis, and obsessive compulsive disorders.
  • 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 .
  • 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.
  • cAMP production mGluR 2, 3, 4, 6, 7 or 8
  • mGluR 1 or 5 phosphoinositide hydrolysis
  • the abililty of 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) .
  • SAX support methanol/water/dilute acetic acid
  • the plasma concentrations (ng/ml) 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.
  • 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, microcrystallme 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.
  • the 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.
  • 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 spectroscopy was performed on a VG ZAB-2SE instrument.
  • Field desorption mass spectroscopy FDMS 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 Waters Prep 500 LC was generally carried out using a linear gradient of the solvents indicated in the text. The reactions were generally monitored for completion using thin layer chromatography (TLC) . Thin layer chromatography was performed using E. Merck Kieselgel 60 F 254 plates, 5 cm X 10 cm, 0.25 mm thickness.
  • Elemental analyses for carbon, hydrogen, and nitrogen were determined on a Control Equipment Corporation 440 Elemental Analyzer, or were performed by the Universidad Complutense Analytical Centre (Facultad de Farmacia, Madrid, Spain) . Melting points were determined in open glass capillaries on a Gallenkamp hot air bath melting point apparatus or a B ⁇ chi melting point apparatus, and are uncorrected. The number in parenthesis after the compound name refers to the compound number.
  • DIBAL-H diisobutyl aluminum hydride
  • DMAP dimethylaminopyridine
  • DMF dimethylformamide
  • DMSO dimethylsulfoxide
  • EDCI N-ethyl-N' N' -dimethylaminopropyl carbodiimide
  • Et ethyl
  • HOBt 1-hydroxybenzotriazole
  • HPLC High -Performance Liquid Chromatography
  • HRMS high resolution mass spectrum
  • i-PrOH isopropanol
  • NBS N-bromosuccinimide
  • NMDBA 1, 3-dimethylbarbituric acid
  • TBS tert-butyldimethylsilyl
  • the title compound was prepared according to General Procedure 1 using 3-bromophthalide (which was obtained from phthalide as described by Koten et al . Org. Synth . Coll . Vol . V, 145-147) .
  • the tile compound was prepared according to General
  • the tile compound was prepared according to General Procedure 3 using (1' S, 2 ' S, 5 ' R, 6 ' ) -3 -allyloxycarbonyl -5- oxo-oxazolidine-4-spiro-2 ' -bicyclo [3.1.0] hexane-6' - carboxylic acid 6' - (5-methyl-2 -oxo- [1, 3] dioxolen-4 - enyl) methyl ester.
  • the crude was purified by reverse phase chromatography using a C18 support eluting with mixtures of methanol and water. White solid. Yield 22%. mp 180 °C (decomposition) .
  • the combined organic extracts were washed with cold water, dried over magnesium sulfate and concentrated to dryness.
  • the crude mixture was purified by silica gel flash- chromatography using the appropiate eluent (typically mixtures of hexanes/ethyl acetate) .
  • the title compound was prepared according to General Procedure 4 using commercially available 1-chloroethyl ethyl carbonate.
  • IR (KBr) V 3387, 3053, 2980, 2937, 2874, 1732, 1593, 1576, 1510, 1456, 1423, 1392, 1368, 1332, 1278, 1240, 1159, 1115, 1001 cm "1 .
  • IR (KBr) V 3383, 2940, 2863, 1760, 1716, 1506, 1450, 1367, 1321, 1277, 1259, 1163, 1078 cm "1 .
  • Example 45 (IS, 2S, 5J2,6S) -2-Amino-bicyclo [3.1.0] hexane-2, 6-dicarboxylic acid 2, 6-di- (1' -isopropyloxycarbonyloxylethyl) ester hydrochloride
  • Example 48 (IS, 2S, 512, 6S) -2-Amino-bicyclo [3.1.0] hexane-2, 6-dicarboxylic acid 2, 6-dimethoxycarbonyloxymethyl ester hydrochloride
  • Example 51 (IS, 2S, 512, 6S) -2-Amino-bicyclo [3.1.0] hexane-2, 6-dicarboxylic acid 2, 6-di- (2' -naphthoyloxymethyl) ester hydrochloride
  • Example 52 (IS, 2S, 512, 6S) -2-Amino-bicyclo [3.1.0] hexane-2, 6-dicarboxylic acid 2, 6-di- (1' -naphthoyloxy ethyl) ester hydrochloride
  • IR (KBr) V 3407, 3054, 2947, 2880, 1732, 1593, 1578, 1512, 1462, 1427, 1346, 1317, 1278, 1242, 1169, 1113 cm "1 .
  • IR (KBr) V 3500-2500, 2941, 2863, 1759, 1585, 1520, 1454, 1427, 1319, 1253, 1157, 1097 cm "1 .
  • Trifluoroacetic acid (9.07 mL, 118 mmol) was added to a solution of (IS, 2S, 5R, 6S) -bis- (5-methyl-2-oxo-
  • Ethanesulfonic acid (0.96 mL, 11.8 mmol) was then added followed by seed crystals.
  • the solution was concentrated to a slurry (total weight of 60 g) and stirred at rt for 1 h. Diethyl ether (60 mL) was then added. The resulting slurry was stirred at rt for 2.5 h, filtered and dried under vacuum at 45 °C to afford 4.43 g (72%) of the title compound as a white crystalline solid.

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Abstract

L'invention concerne des promédicaments d'acides aminés excitateurs de synthèse de formule (I), dans laquelle les résidus R11, R12 et R13 sont tels que définis dans la première revendication. L'invention se rapporte en outre à des procédés de préparation des composés de formule (I), ainsi qu'à des compositions pharmaceutiques comprenant ces composés et permettant de traiter des troubles neurologiques et psychiatriques.
EP02789239A 2001-11-23 2002-11-12 Promedicaments d'acides amines excitateurs Withdrawn EP1463713A1 (fr)

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EP01500276 2001-11-23
EP01500276 2001-11-23
PCT/US2002/033626 WO2003045898A1 (fr) 2001-11-23 2002-11-12 Promedicaments d'acides amines excitateurs
EP02789239A EP1463713A1 (fr) 2001-11-23 2002-11-12 Promedicaments d'acides amines excitateurs

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US7256217B2 (en) 2001-01-11 2007-08-14 Eli Lilly And Company Prodrugs of excitatory amino acids
AU2014251087B2 (en) 2013-04-09 2019-05-02 Lixte Biotechnology, Inc. Formulations of oxabicycloheptanes and oxabicycloheptenes
MX2017014549A (es) 2015-05-15 2018-09-11 Lixte Biotechnology Inc Farmacos precursores de oxabicicloheptanos.
PT3445743T (pt) * 2016-04-18 2021-08-24 Taisho Pharmaceutical Co Ltd Pró-fármaco de derivado de aminoácido

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PL182285B1 (pl) * 1994-08-12 2001-12-31 Lilly Co Eli Syntetyczne aminokwasy oraz ich estry i srodki farmaceutyczne je zawierajace PL PL PL PL PL PL PL
ES2222715T3 (es) * 1998-08-31 2005-02-01 Taisho Pharmaceutical Co. Ltd. Derivados de 6-fluorobiciclo(3.1.0)hexano.

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