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EP1097149A1 - Bicyclohexane derivatives - Google Patents

Bicyclohexane derivatives

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Publication number
EP1097149A1
EP1097149A1 EP99933048A EP99933048A EP1097149A1 EP 1097149 A1 EP1097149 A1 EP 1097149A1 EP 99933048 A EP99933048 A EP 99933048A EP 99933048 A EP99933048 A EP 99933048A EP 1097149 A1 EP1097149 A1 EP 1097149A1
Authority
EP
European Patent Office
Prior art keywords
group
compound
carboxyl group
formula
protected
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.)
Withdrawn
Application number
EP99933048A
Other languages
German (de)
French (fr)
Inventor
Stephen Richard Baker
James Allen Monn
Jesus Ezquerra Carrera
Carmen Dominguez Fernandez
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eli Lilly and Co Ltd
Eli Lilly and Co
Original Assignee
Eli Lilly and Co Ltd
Eli Lilly and Co
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Filing date
Publication date
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Publication of EP1097149A1 publication Critical patent/EP1097149A1/en
Withdrawn legal-status Critical Current

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    • C07D317/72—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 spiro-condensed with carbocyclic rings
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    • 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
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/52—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
    • 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
    • C07D317/44—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 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/70—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 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with ring systems containing two or more relevant rings
    • 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

  • the present invention relates to novel bicyclohexane derivatives useful as pharmaceutical intermediates or as pharmaceuticals, to processes for preparing bicyclohexane derivatives, to pharmaceutical compositions comprising bicyclohexane derivatives and to use of bicyclohexane derivatives as pharmaceuticals.
  • 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 control, 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 (NMDA) , ⁇ -amino-3 -hydroxy-5- methylisoxazole-4-propionic acid (AMPA) , and kainic acid (KA) .
  • the second general type of receptor is the G-protein or second messenger-linked "metabotropic" excitatory amino acid receptor. This second type is coupled to multiple second messenger systems that lead to enhanced phosphoinositide hydrolysis, activation of phospholipase D or C, increases or decreases in c-AMP formation, and changes in ion channel function. Schoepp and Conn, Trends in Pharmacol .
  • the excessive or inappropriate stimulation of excitatory amino acid receptors leads to neuronal cell damage or loss by way of a mechanism known as excitotoxicity .
  • This process has been suggested to mediate neuronal degeneration in a variety of conditions.
  • the medical consequences of such neuronal degeneration makes the abatement of these degenerative neurological processes an important therapeutic goal .
  • the metabotropic glutamate receptors are a highly heterogeneous family of glutamate receptors that are linked to multiple second-messenger pathways. These receptors function to modulate the presynaptic release of glutamate, and the postsynaptic sensitivity of the neuronal cell to glutamate excitation.
  • Compounds which modulate the function of these receptors are useful for the treatment of acute and chronic neurodegenerative conditions, and as antiischaemic, antipsychotic, anticonvulsant , analgesic, anxiolytic, antidepressant , and anti-emetic agents.
  • EP 0696577 Al discloses certain bicyclohexane derivatives which are agonists of metabotropic glutamate receptors that are negatively-coupled to cAMP, and are useful in the treatment of a wide variety of disorders of the central nervous system, including anxiety and substance dependence.
  • EP 0696577 Al also discloses a process for the preparation of the bicyclohexane derivatives which comprise hydrolyzing a compound of formula:
  • Re represents a carboxyl group or a protected carboxyl group and either Ra represents an amino group and Rb represents a protected carboxyl group or Ra and Rb together represent a group of formula NHCONHCO.
  • the compounds of formula lb are prepared from a compound of formula:
  • Dominguez et al . , Tetrahedron: Assymmetry, Vol. 8, No. 4, pp. 511-514, 1997 disclose a process for preparing (+) -2-aminobicyclo [3.1.0] hexane-2 , 6-dicarboxylic acid, starting from D(+)-ribonic ⁇ -lactone.
  • the process involves the formation of a compound of formula
  • the present invention provides a process for the preparation of a compound of formula
  • R 1 represents an amino group
  • R 2 represents a carboxyl group
  • R 3 represents a carboxyl group
  • R 4 and R 5 each represents a hydrogen atom; or a pharmaceutically acceptable salt thereof, which comprises (a) reacting a compound of formula
  • R 3 represents a carboxyl group or a protected carboxyl group ;
  • R 4 represents OR 6 ;
  • R 5 represents OR 7 ; and R ⁇ and R 7 each represents a hydrogen atom or together represent a diol protecting group; with a haloform in the presence of a strong base, to afford a compound of formula I in which: -
  • R 1 represents a trihalomethyl group
  • R 2 represents a hydroxyl group
  • R 3 represents a carboxyl group or a protected carboxyl group ;
  • R 4 represents OR 6 ;
  • R 5 represents OR 7 ; and R 6 and R 7 each represents a hydrogen atom or together represent a diol protecting group;
  • R 1 represents a trihalomethyl group
  • R 2 represents a hydroxyl group
  • R 3 represents a carboxyl group or a protected carboxyl group ;
  • R 4 represents OR 6 ;
  • R 5 represents OR 7 ; and R 6 and R 7 each represents a hydrogen atom or together represent a diol protecting group; with an azide salt in the presence of a base and a hydroxylic compound, to afford a compound of formula I in which:
  • R 1 represents an azido group
  • R 2 and R 3 each independently represents a carboxyl group or a protected carboxyl group
  • R 4 represents OR 6 ;
  • R 5 represents OR 7 ; and R 6 and R 7 each represents a hydrogen atom or together represent a diol protecting group;
  • R 1 represents an azido group
  • R 2 and R 3 each independently represents a carboxyl group or a protected carboxyl group; either R 4 represents OR 6 and R 5 represents OR ; or R 4 and R 5 each represents a hydrogen atom or together represent a bond; and R 6 and R 7 each represents a hydrogen atom or together represent a diol protecting group; to afford a compound of formula I in which:- R 1 represents an amino group;
  • R 2 and R 3 each independently represents a carboxyl group or a protected carboxyl group; either R 4 represents OR 6 and R 5 represents OR 7 ; or R and R each represents a hydrogen atom or together represent a bond; and R 6 and R 7 each represents a hydrogen atom or together represent a diol protecting group;
  • R 1 represents an azido group, an amino group or a protected amino group
  • R 2 and R 3 each independently represents a carboxyl group or a protected carboxyl group; and R 4 and R 5 each represents a hydroxyl group; with an orthoformate to afford a compound of formula I in which: -
  • R 1 represents an azido group, an amino group or a protected amino group
  • R 2 and R 3 each independently represents a carboxyl group or a protected carboxyl group
  • R 4 represents OR 6 , R 5 represents OR 7 and R 6 and R 7 together represents an organo-oxymethylidene group;
  • R 1 represents an azido group, an amino group or a protected amino group
  • R 2 and R 3 each independently represents a carboxyl group or a protected carboxyl group
  • R 4 represents OR 6 , R s represents OR 7 ; and R 6 and R 7 together represents an organo-oxymethylidene; to afford a compound of formula I in which:- R 1 represents an azido group, an amino group or a protected amino group;
  • R 2 and R 3 each independently represents a carboxyl group or a protected carboxyl group
  • R 4 and R 5 together represent a bond
  • R 1 represents an azido group, an amino group or a protected amino group
  • R 2 and R 3 each independently represents a carboxyl group or a protected carboxyl group
  • R 1 represents an azido group, an amino group or a protected amino group
  • R 2 and R 3 each represents a carboxyl group or a protected carboxyl group
  • R 4 and R s each represents a hydrogen atom
  • the process according to the invention may comprise one or more additional process steps, for example a step in which a carboxyl, amino or diol group is protected, or a protected carboxyl, amino or diol group is deprotected. It will also be appreciated that the order of steps in the process according to the invention may be varied. For example the azido group in a compound of formula I in which R 1 represents an azido group may be reduced to an amino group before, after or at the same time that a double bond in a compound of formula I in which R 4 and R 5 together represent a bond is reduced.
  • Examples of protected carboxyl groups are groups of formula COOR a in which R a represents an alkyl group such as methyl, ethyl, t-butyl or t-amyl; an aralkyl group such as benzyl, 4-nitrobenzyl , 4-methoxybenzyl , 3,4- dimethoxybenzyl , 2,4 -dimethoxybenzyl , 2,4,6- trimethoxybenzyl , 2 , 4 , 6-trimethylbenzyl , benzhydryl or trityl; a silyl group such as trimethylsilyl or t- butyldimethylsilyl; and an allyl group such as allyl or 1- (trimethylsilylmethyl)prop-l-en-3-yl .
  • R a represents an alkyl group such as methyl, ethyl, t-butyl or t-amyl
  • an aralkyl group such as benzyl
  • a (1- 6C) alkoxycarbonyl group may be deprotected using an acid, such as hydrochloric acid.
  • the temperature is conveniently in the range of from 50 to 150°C.
  • Examples of protected amino groups include acylamino groups, such as groups of formula R b CONH in which R b represents (1-6C) alkyl, such as methyl or ethyl; (3-10C) cycloalkyl, such as cyclohexyl ; phenyl (1-6C) alkyl, such as benzyl; phenyl; (1-6C) alkoxy, such as t-butoxy; phenyl (1- 6C) alkoxy, such as benzyloxy; or (3 -10C) cycloalkoxy, such as cyclohexyloxy; wherein a phenyl group may optionally be substituted by one or two substituents independently selected from amino, hydroxy, nitro, halogeno, (1-6C) alkyl, (1-6C) alkoxy, carboxy, (1-6C) alkoxycarbonyl , carbamoyl , (1-6C) alkanoylamino, (1-6C) alkylsulphony
  • an amino group may be acylated using a conventional acylating agent, for example an acyl halide or anhydride such as acetyl chloride.
  • a conventional acylating agent for example an acyl halide or anhydride such as acetyl chloride.
  • the reaction is conveniently performed in the presence of a base, for example an amine such as triethylamine, diisopropylamine or pyridine.
  • the temperature is conveniently in the range of from 0 to 100°C.
  • An acylamino group may be deprotected by hydrolysis using an acid catalyst, such as hydrochloric acid, in an aqueous reaction medium, such as water. The hydrolysis is conveniently performed at a temperature of from 0 to 100°C.
  • diol protecting groups are unsubstituted or substituted alkylidene groups, for example (1-6C) alkylidene, such as ethylidene or isopropylidene, and (3-6C) cycloalkylidene, such as cyclopentylidene and cyclohexylidene .
  • Methods for the protection and deprotection of diols are well known.
  • a diol may be protected by reaction with a ketone in the presence of an acid catalyst, such as hydrochloric acid.
  • a protected diol may be deprotected by hydrolysis in the presence of an acid catalyst, such as trifluoroacetic acid in an aqueous reaction medium, such as water. The hydrolysis is conveniently performed at a temperature of from 0 to 100 °C.
  • alkyl as used herein means a straight or branched alkyl group and includes a (1-6C) alkyl group.
  • values for a (1- 6C) alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl and t-butyl.
  • R 2 when it represents a protected carboxyl group examples are (1-6C) alkoxycarbonyl groups such as methoxycarbonyl and ethoxycarbonyl .
  • R 3 when it represents a protected carboxyl group are (1-6C) alkoxycarbonyl groups such as methoxycarbonyl and ethoxycarbonyl .
  • R 1 when it represents a protected amino group examples are (1-6C) alkanoyl groups such as acetylamino.
  • R 6 and R 7 when they together represent a diol protecting group is cyclohexylidene .
  • the haloform may be any compound of formula HCX'X'X 3 in which each of X 1 , X 2 and X 3 independently represents chlorine, bromine or iodine, for example chloroform, bromoform and iodoform. Preferably it is chloroform.
  • the compound of formula II is conveniently reacted with the haloform in an anhydrous organic solvent , for example an ether such as diethyl ether or tetrahydrofuran. The reaction is conveniently conducted at a temperature in the range of from -100 to -10°C, preferably from -80 to -30°C.
  • Suitable bases include alkali metal amides such as lithium hexamethyldisilazide and lithium diisopropylamide, and alkyl lithiums such as butyl lithium.
  • the azide salt may be, for example, an alkali metal azide, such as lithium, sodium or potassium azide, or a quaternary ammonium azide, such as tetrabutyl ammonium azide.
  • the base may be, for example an amine such as 1 , 8-diazabicyclo [5.4.0] undec-7-ene (DBU) , or an alkali metal hydroxide, such as lithium, sodium or potassium hydroxide.
  • the hydroxylic compound may be water or an alcohol, for example a (1-4C) alkanol such as methanol or ethanol . The reaction is preferably performed in the hydroxylic compound as solvent.
  • reaction is performed in the presence of water, a compound of formula I in which R 2 represents a carboxyl group will be obtained.
  • reaction is performed in the presence of an alcohol, a compound of formula I in which R 2 represents an ester group (a protected carboxyl group) will be obtained.
  • the reaction is conveniently performed at a temperature in the range of from 0 to 120°C. If the reaction is performed in an alcohol, it is preferably performed in the presence of a phase transfer catalyst, such as 18-crown-6.
  • Step (c) of the process according to the invention is conveniently performed by catalytic hydrogenation in the presence of a Group VIII metal catalyst, for example palladium on charcoal.
  • Suitable solvents include esters, such as ethyl acetate and alcohols such as ethanol.
  • the hydrogenation is conveniently performed at a temperature of from 0 to 100°C and a pressure of from 15 to 45 p.s.i. (from 1 to 3 x 10 s Pa) .
  • Other convenient reducing agents include triphenylphosphine and thiols.
  • R 4 represents OR 6 ;
  • R 5 represents OR 7 ; and
  • R 6 and R 7 together represent a diol protecting group, for example a cyclohexylidene group. It will be appreciated that under these circumstances, the diol protecting group should be removed before performing step (d) .
  • the orthoformate used in step (d) of the process may be, for example, a tri (1-6C) alkyl orthoformate, such as triethylorthoformate. It will be appreciated that when a tri(l-6C)- alkyl orthoformate is used, R 6 and R 7 in the resultant compound of formula I will represent (1- 6C) alkoxymethy1idene group.
  • the temperature at which the reaction is performed is conveniently in the range of from 0 to 100°C.
  • step (d) may conveniently be decomposed according to step (e) of the process by heating at a temperature of from 150 to 200°C.
  • the process is conveniently performed in the absence of a solvent or in the presence of a high boiling point solvent such as diethylene glycol diethyl ether.
  • Step (f) of the process according to the invention is conveniently performed by catalytic hydrogenation in the presence of a Group VIII metal catalyst, for example palladium on charcoal.
  • Suitable solvents for the reaction include alcohols such as ethanol and esters such as ethyl acetate.
  • the temperature is conveniently in the range of from 0 to 100°C.
  • the pressure is conveniently in the range of from 15 to 45 p.s.i (from 1 to 3 x 10 5 Pa) .
  • step (f) of the process according to the invention can be performed using tritium instead of hydrogen, and that the compound of formula I in which R 4 and R 5 together represent a bond is thus useful for preparing radiolabelled (tritiated) (+)-2- aminobicyclo [3.1.0] hexane-2 , 6-dicarboxylic acid.
  • R 1 represents an amino group or a protected amino group, for example a protected amino group, such as acetylamino.
  • Step (g) of the process need only be performed if any one of the groups represented by R 1 to R 7 is protected.
  • the groups may be deprotected by any conventional method, as described hereinabove.
  • a (1-6C) alkoxycarbonyl group may be deprotected by acid-catalysed hydrolysis, for example using hydrochloric acid.
  • a (1-6C) alkanoylamino group may also be deprotected in this way.
  • the compounds of formula II used as starting material in the process according to the invention are known and may be prepared as described in C. Dominguez, J. Ezquerra, L. Prieto, C. Pedregal and M. Espada., Tetrahedron; Asymmetry, 511, 1997, or by methods analogous thereto, starting from a compound of formula
  • the compounds of formula III may be prepared by the method described in Borcherding, D.R., Scholtz, S.A., Borchard, R.T., J " . Org. Che . , 52, 5457, 1987, or by methods analogous thereto, starting from the inexpensive, commercially available sugar, D (+) -ribonic- ⁇ -lactone .
  • the present invention provides a compound of formula
  • R represents an azido group, an amino group or a protected amino group
  • R 2 represents a carboxyl group or a protected carboxyl group
  • R 1 represents a trihalomethyl group and R 2 represents a hydroxyl group
  • R 3 represents a carboxyl group or a protected carboxyl group ; either R 4 represents OR 6 and R 5 represents OR 7 ; or R 4 and R 5 each represents a hydrogen atom or together represent a bond; and either R 6 and R 7 each represents a hydrogen atom; or R 6 and R 7 together represent a (2-6C) alkylidene group, a (3-6C) cycloalkylidene group or a (1-
  • R 6C alkoxymethylidene group; or a salt thereof, provided that when R and R 5 each represents a hydrogen atom, R 1 does not represent an amino group.
  • the present invention provides a compound of formula I in which R 1 represents an amino group, R represents a carboxyl group, R 3 represents a carboxyl group and both of R and R represent hydroxyl groups, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable salts of the formula I compounds 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 such as hydrochloric, hydrobromic, hydriodic, sulfuric, and phosphoric acid, as well as organic acids such as para-toluenesulfonic, methanesulfonic, oxalic, para-bromophenylsulfonic, carbonic, succinic, citric, benzoic, and acetic acid, and related inorganic and organic acids .
  • inorganic acids such as hydrochloric, hydrobromic, hydriodic, sulfuric, and phosphoric acid
  • organic acids such as para-toluenesulfonic, methanesulfonic, oxalic, para-bromophenylsulfonic, carbonic, succinic, citric, benzoic, and acetic acid, and related inorganic and organic acids .
  • the present invention also provides a method of modulating metabotropic glutamate receptor function in a mammal requiring such treatment, which comprises administering an effective amount of a compound of formula I in which R 1 represents an amino group, R 2 represents a carboxyl group, R 3 represents a carboxyl group and both of R 4 and R 5 represent hydroxyl groups, or a pharmaceutically acceptable salt thereof (hereinafter referred to as an active compound of formula I) .
  • an active compound of formula I a pharmaceutically acceptable salt thereof
  • it provides the use of such compounds for the manufacture of a medicament for modulating metabotropic glutamate receptor function.
  • the particular dose, or effective amount, of compound administered according to this invention will of course be determined by the particular circumstances surrounding the case, including the compound administered, the route of administration, the particular condition being treated, and similar considerations.
  • the compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, or intranasal routes. Alternatively, the compound may be administered by continuous infusion.
  • a typical daily dose will contain from about 0.01 mg/kg to about 100 mg/kg of the active compound of this invention. Preferably, daily doses will be about 0.05 mg/kg to about 50 mg/kg, more preferably from about 0.1 mg/kg to about 25 mg/kg.
  • the active 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 disorders 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 active 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 an active compound of formula I or a pharmaceutically acceptable metabolically labile ester or amide thereof, or a pharmaceutically acceptable salt thereof .
  • the active formula I compounds 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, nicotine withdrawal, psychosis, (such as schizophrenia) opiate tolerance and withdrawal, anxiety, emesis, brain edema, chronic pain, and tardive dyskinesia.
  • the active 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 active compound of formula I, or a pharmaceutically acceptable metabolically labile ester or amide thereof, or a pharmaceutically acceptable salt thereof .
  • treating for purposes of the present invention, includes prophylaxis, amelioration or elimination of a named condition once the condition has been established.
  • patient for purposes of the present invention is defined as any warm blooded mammal such as, but not limited to, a mouse, guinea pig, dog, horse, or human. Preferably, the patient is human.
  • compositions comprising a compound of formula I in which R 1 represents an amino group
  • R represents a carboxyl group
  • R 3 represents a carboxyl group
  • both of R and R 5 represent hydroxyl groups, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient .
  • the present pharmaceutical compositions are prepared by known procedures using well-known and readily available ingredients.
  • the active ingredient will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, and may be in the form of a capsule, sachet, paper, or other container.
  • the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments containing, for example, up to 10% by weight of active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders .
  • Suitable carriers, excipients, and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum, acacia, calcium phosphate, alginates, 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.
  • 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.
  • suitable pharmaceutical carrier diluent, or excipient.
  • Hard gelatin capsules are prepared using the following ingredients :
  • the above ingredients are mixed and filled into hard gelatin capsules in 460 mg quantities.
  • 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.
  • the following Examples further illustrate the invention.
  • Example 2 To a solution of the product of Example 1 (150 mg, 0.53 mmol) and chloroform (0.107 ml, 1.32 mmol) in dry tetrahydrofuran (THF) (30 ml) at -78°C, was added a 1M solution of lithium hexamethyldisilazide in THF (1.05 ml, 1.06 mmol) . The reaction mixture was stirred for lh and quenched with saturated ammonium chloride solution (20ml) . The reaction was allowed to warm to ambient temperature and was then extracted with diethyl ether (3x20 ml) . The combined organic phases were then dried over NaS0 4 , filtered and evaporated to dryness .
  • THF dry tetrahydrofuran

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Abstract

Compounds of formula (I) and salts thereof in which R?1, R2, R3, R4 and R5¿ have the meanings given in the specification, are useful as pharmaceutical intermediates or as modulators of metabotropic glutamate receptor function.

Description

BICYCLOHEXANE DERIVATIVES
The present invention relates to novel bicyclohexane derivatives useful as pharmaceutical intermediates or as pharmaceuticals, to processes for preparing bicyclohexane derivatives, to pharmaceutical compositions comprising bicyclohexane derivatives and to use of bicyclohexane derivatives as pharmaceuticals.
In the mammalian central nervous system (CNS) , the transmission of nerve impulses is controlled by the interaction between a neurotransmitter, that is released by a sending neuron, and a surface receptor on a receiving neuron, which causes excitation of this receiving neuron. L-Glutamate, which is the most abundant neurotransmitter in the CNS, mediates the major excitatory pathway in mammals, and is referred to as an excitatory amino acid (EAA) . The receptors that respond to glutamate are called excitatory amino acid receptors (EAA receptors) . See atkins & Evans, Ann . Rev. Pharmacol . Toxicol . , 21, 165 (1981); Monaghan, Bridges, and Cotman, Ann. Rev. Pharmacol . Toxicol . , 29, 365 (1989) ; Watkins, Krogsgaard- arsen, and Honore, Trans . Pharm . Sci . , 11, 25 (1990). The 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 control, 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 (NMDA) , α-amino-3 -hydroxy-5- methylisoxazole-4-propionic acid (AMPA) , and kainic acid (KA) . The second general type of receptor is the G-protein or second messenger-linked "metabotropic" excitatory amino acid receptor. This second type is coupled to multiple second messenger systems that lead to enhanced phosphoinositide hydrolysis, activation of phospholipase D or C, increases or decreases in c-AMP formation, and changes in ion channel function. Schoepp and Conn, Trends in Pharmacol . Sci . , 14, 13 (1993) . Both types of receptors appear not only to mediate normal synaptic transmission along excitatory pathways, but also participate in the modification of synaptic connections during development and throughout life. Schoepp, Bockaert, and Sladeczek, Trends in Pharmacol . Sci . , 11, 508 (1990); McDonald and Johnson, Brain Research Reviews, 15, 41 (1990).
The excessive or inappropriate stimulation of excitatory amino acid receptors leads to neuronal cell damage or loss by way of a mechanism known as excitotoxicity . This process has been suggested to mediate neuronal degeneration in a variety of conditions. The medical consequences of such neuronal degeneration makes the abatement of these degenerative neurological processes an important therapeutic goal . The metabotropic glutamate receptors are a highly heterogeneous family of glutamate receptors that are linked to multiple second-messenger pathways. These receptors function to modulate the presynaptic release of glutamate, and the postsynaptic sensitivity of the neuronal cell to glutamate excitation. Compounds which modulate the function of these receptors, in particular agonists and antagonists of glutamate, are useful for the treatment of acute and chronic neurodegenerative conditions, and as antiischaemic, antipsychotic, anticonvulsant , analgesic, anxiolytic, antidepressant , and anti-emetic agents.
European patent application publication number EP 0696577 Al discloses certain bicyclohexane derivatives which are agonists of metabotropic glutamate receptors that are negatively-coupled to cAMP, and are useful in the treatment of a wide variety of disorders of the central nervous system, including anxiety and substance dependence. The enantiomer (+) -2-aminobicyclo [3.1.0] hexane-2 , 6-dicarboxylic acid, also known as the (IS, 2S, 5R, 6S) enantiomer, is most preferred. This enantiomer has the structural formula:
EP 0696577 Al also discloses a process for the preparation of the bicyclohexane derivatives which comprise hydrolyzing a compound of formula:
in which Re represents a carboxyl group or a protected carboxyl group and either Ra represents an amino group and Rb represents a protected carboxyl group or Ra and Rb together represent a group of formula NHCONHCO.
The compounds of formula lb are prepared from a compound of formula:
by a Strecker or a Bucherer-Bergs reaction.
Dominguez et al . , Tetrahedron: Assymmetry, Vol. 8, No. 4, pp. 511-514, 1997 disclose a process for preparing (+) -2-aminobicyclo [3.1.0] hexane-2 , 6-dicarboxylic acid, starting from D(+)-ribonic γ-lactone. The process involves the formation of a compound of formula
Attempts to convert the ketone group into an amino acid group with the desired stereochemistry failed. Both the Bucherer-Bergs reaction and the Strecker reaction afforded a compound with the stereochemistry opposite to that desired. The authors postulated that the stereo- electronic effect of the oxygen atom at the c-position of the ketone must drive the 1, 2-nucleophilic attack to the imine intermediate of both reactions.
A new process has now been found for the preparation of (+) -2-aminobicyclo [3.1.0] hexane-2 , 6- dicarboxylic acid starting from the compound of formula Id. It has also been found that certain novel intermediates used in the process may be used to prepare further novel bicyclohexane derivatives having use as pharmaceuticals.
According to one aspect, therefore, the present invention provides a process for the preparation of a compound of formula
in which: R1 represents an amino group;
R2 represents a carboxyl group;
R3 represents a carboxyl group; and
R4 and R5 each represents a hydrogen atom; or a pharmaceutically acceptable salt thereof, which comprises (a) reacting a compound of formula
in which: -
R3 represents a carboxyl group or a protected carboxyl group ;
R4 represents OR6;
R5 represents OR7; and Rδ and R7 each represents a hydrogen atom or together represent a diol protecting group; with a haloform in the presence of a strong base, to afford a compound of formula I in which: -
R1 represents a trihalomethyl group;
R2 represents a hydroxyl group;
R3 represents a carboxyl group or a protected carboxyl group ;
R4 represents OR6;
R5 represents OR7; and R6 and R7 each represents a hydrogen atom or together represent a diol protecting group;
(b) reacting a compound of formula I in which: -
R1 represents a trihalomethyl group;
R2 represents a hydroxyl group;
R3 represents a carboxyl group or a protected carboxyl group ;
R4 represents OR6;
R5 represents OR7; and R6 and R7 each represents a hydrogen atom or together represent a diol protecting group; with an azide salt in the presence of a base and a hydroxylic compound, to afford a compound of formula I in which:
R1 represents an azido group;
R2 and R3 each independently represents a carboxyl group or a protected carboxyl group;
R4 represents OR6;
R5 represents OR7; and R6 and R7 each represents a hydrogen atom or together represent a diol protecting group;
(c) reducing a compound of formula I in which: -
R1 represents an azido group;
R2 and R3 each independently represents a carboxyl group or a protected carboxyl group; either R4 represents OR6 and R5 represents OR ; or R4 and R5 each represents a hydrogen atom or together represent a bond; and R6 and R7 each represents a hydrogen atom or together represent a diol protecting group; to afford a compound of formula I in which:- R1 represents an amino group;
R2 and R3 each independently represents a carboxyl group or a protected carboxyl group; either R4 represents OR6 and R5 represents OR7; or R and R each represents a hydrogen atom or together represent a bond; and R6 and R7 each represents a hydrogen atom or together represent a diol protecting group;
(d) reacting a compound of formula I in which: -
R1 represents an azido group, an amino group or a protected amino group;
R2 and R3 each independently represents a carboxyl group or a protected carboxyl group; and R4 and R5 each represents a hydroxyl group; with an orthoformate to afford a compound of formula I in which: -
R1 represents an azido group, an amino group or a protected amino group;
R2 and R3 each independently represents a carboxyl group or a protected carboxyl group; and
R4 represents OR6, R5 represents OR7 and R6 and R7 together represents an organo-oxymethylidene group;
(e) decomposing a compound of formula I in which: -
R1 represents an azido group, an amino group or a protected amino group;
R2 and R3 each independently represents a carboxyl group or a protected carboxyl group; and
R4 represents OR6, Rs represents OR7; and R6 and R7 together represents an organo-oxymethylidene; to afford a compound of formula I in which:- R1 represents an azido group, an amino group or a protected amino group;
R2 and R3 each independently represents a carboxyl group or a protected carboxyl group;
R4 and R5 together represent a bond; and
(f) reducing a compound of formula I in which: -
R1 represents an azido group, an amino group or a protected amino group;
R2 and R3 each independently represents a carboxyl group or a protected carboxyl group; and
R4 and R5 together represent a bond; to afford a compound of formula I in which: -
R1 represents an azido group, an amino group or a protected amino group;
R2 and R3 each represents a carboxyl group or a protected carboxyl group; and
R4 and Rs each represents a hydrogen atom, and
(g) if necessary, removing any protecting group to afford a compound of formula I in which R1 represents an amino group, R2 and R3 each represents a carboxyl group, and R4 and R5 each represents a hydrogen atom; and optionally forming a pharmaceutically acceptable salt.
It will be appreciated that the process according to the invention may comprise one or more additional process steps, for example a step in which a carboxyl, amino or diol group is protected, or a protected carboxyl, amino or diol group is deprotected. It will also be appreciated that the order of steps in the process according to the invention may be varied. For example the azido group in a compound of formula I in which R1 represents an azido group may be reduced to an amino group before, after or at the same time that a double bond in a compound of formula I in which R4 and R5 together represent a bond is reduced.
The protection of carboxyl, amino and diol groups, and the deprotection of protected carboxyl, amino and diol groups, is generally described in McOmie, Protecting Groups in Organic Chemistry, Plenum Press, NY, 1973, and Greene and Wuts, Protecting Groups in Organic Synthesis, 2nd. Ed., John Wiley & Sons, NY, 1991.
Examples of protected carboxyl groups are groups of formula COORa in which Ra represents an alkyl group such as methyl, ethyl, t-butyl or t-amyl; an aralkyl group such as benzyl, 4-nitrobenzyl , 4-methoxybenzyl , 3,4- dimethoxybenzyl , 2,4 -dimethoxybenzyl , 2,4,6- trimethoxybenzyl , 2 , 4 , 6-trimethylbenzyl , benzhydryl or trityl; a silyl group such as trimethylsilyl or t- butyldimethylsilyl; and an allyl group such as allyl or 1- (trimethylsilylmethyl)prop-l-en-3-yl . Methods for the protection of carboxyl groups and the deprotection of protected carboxyl groups are well known. For example, a (1- 6C) alkoxycarbonyl group may be deprotected using an acid, such as hydrochloric acid. The temperature is conveniently in the range of from 50 to 150°C.
Examples of protected amino groups include acylamino groups, such as groups of formula RbCONH in which Rb represents (1-6C) alkyl, such as methyl or ethyl; (3-10C) cycloalkyl, such as cyclohexyl ; phenyl (1-6C) alkyl, such as benzyl; phenyl; (1-6C) alkoxy, such as t-butoxy; phenyl (1- 6C) alkoxy, such as benzyloxy; or (3 -10C) cycloalkoxy, such as cyclohexyloxy; wherein a phenyl group may optionally be substituted by one or two substituents independently selected from amino, hydroxy, nitro, halogeno, (1-6C) alkyl, (1-6C) alkoxy, carboxy, (1-6C) alkoxycarbonyl , carbamoyl , (1-6C) alkanoylamino, (1-6C) alkylsulphonylamino, phenylsulphonylamino, toluenesulphonylamino, and (1- 6C) fluoroalkyl; and groups of formula RCNH in which Rc represents an aralkyl group, such as benzyl or triphenylmethyl ; an allylgroup ; a t-butyl group; or a silyl group such as t-butyldimethylsilyl and triphenylsilyl . Methods for the protection of amino groups and the deprotection of protected amino groups are well known. For example, an amino group may be acylated using a conventional acylating agent, for example an acyl halide or anhydride such as acetyl chloride. The reaction is conveniently performed in the presence of a base, for example an amine such as triethylamine, diisopropylamine or pyridine. The temperature is conveniently in the range of from 0 to 100°C. An acylamino group may be deprotected by hydrolysis using an acid catalyst, such as hydrochloric acid, in an aqueous reaction medium, such as water. The hydrolysis is conveniently performed at a temperature of from 0 to 100°C.
Examples of diol protecting groups are unsubstituted or substituted alkylidene groups, for example (1-6C) alkylidene, such as ethylidene or isopropylidene, and (3-6C) cycloalkylidene, such as cyclopentylidene and cyclohexylidene . Methods for the protection and deprotection of diols are well known. For example, a diol may be protected by reaction with a ketone in the presence of an acid catalyst, such as hydrochloric acid. A protected diol may be deprotected by hydrolysis in the presence of an acid catalyst, such as trifluoroacetic acid in an aqueous reaction medium, such as water. The hydrolysis is conveniently performed at a temperature of from 0 to 100 °C.
Unless specified otherwise, the term "alkyl" as used herein means a straight or branched alkyl group and includes a (1-6C) alkyl group. Examples of values for a (1- 6C) alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl and t-butyl.
Examples of particular values for R2 when it represents a protected carboxyl group are (1-6C) alkoxycarbonyl groups such as methoxycarbonyl and ethoxycarbonyl .
Examples of particular values for R3 when it represents a protected carboxyl group are (1-6C) alkoxycarbonyl groups such as methoxycarbonyl and ethoxycarbonyl .
Examples of a particular values for R1 when it represents a protected amino group are (1-6C) alkanoyl groups such as acetylamino.
An example of a particular value for R6 and R7 when they together represent a diol protecting group is cyclohexylidene .
In step (a) of the process according to the invention, the haloform may be any compound of formula HCX'X'X3 in which each of X1 , X2 and X3 independently represents chlorine, bromine or iodine, for example chloroform, bromoform and iodoform. Preferably it is chloroform. The compound of formula II is conveniently reacted with the haloform in an anhydrous organic solvent , for example an ether such as diethyl ether or tetrahydrofuran. The reaction is conveniently conducted at a temperature in the range of from -100 to -10°C, preferably from -80 to -30°C. Suitable bases include alkali metal amides such as lithium hexamethyldisilazide and lithium diisopropylamide, and alkyl lithiums such as butyl lithium.
In Step (b) of the process, the azide salt may be, for example, an alkali metal azide, such as lithium, sodium or potassium azide, or a quaternary ammonium azide, such as tetrabutyl ammonium azide. The base may be, for example an amine such as 1 , 8-diazabicyclo [5.4.0] undec-7-ene (DBU) , or an alkali metal hydroxide, such as lithium, sodium or potassium hydroxide. The hydroxylic compound may be water or an alcohol, for example a (1-4C) alkanol such as methanol or ethanol . The reaction is preferably performed in the hydroxylic compound as solvent. It will be appreciated that if the reaction is performed in the presence of water, a compound of formula I in which R2 represents a carboxyl group will be obtained. However, if the reaction is performed in the presence of an alcohol, a compound of formula I in which R2 represents an ester group (a protected carboxyl group) will be obtained. The reaction is conveniently performed at a temperature in the range of from 0 to 120°C. If the reaction is performed in an alcohol, it is preferably performed in the presence of a phase transfer catalyst, such as 18-crown-6.
Step (c) of the process according to the invention is conveniently performed by catalytic hydrogenation in the presence of a Group VIII metal catalyst, for example palladium on charcoal. Suitable solvents include esters, such as ethyl acetate and alcohols such as ethanol. The hydrogenation is conveniently performed at a temperature of from 0 to 100°C and a pressure of from 15 to 45 p.s.i. (from 1 to 3 x 10s Pa) . Other convenient reducing agents include triphenylphosphine and thiols.
Conveniently, in steps (a) , (b) and (c) , R4 represents OR6; R5 represents OR7; and R6 and R7 together represent a diol protecting group, for example a cyclohexylidene group. It will be appreciated that under these circumstances, the diol protecting group should be removed before performing step (d) .
The orthoformate used in step (d) of the process may be, for example, a tri (1-6C) alkyl orthoformate, such as triethylorthoformate. It will be appreciated that when a tri(l-6C)- alkyl orthoformate is used, R6 and R7 in the resultant compound of formula I will represent (1- 6C) alkoxymethy1idene group. The temperature at which the reaction is performed is conveniently in the range of from 0 to 100°C.
The product of step (d) may conveniently be decomposed according to step (e) of the process by heating at a temperature of from 150 to 200°C. The process is conveniently performed in the absence of a solvent or in the presence of a high boiling point solvent such as diethylene glycol diethyl ether.
Step (f) of the process according to the invention is conveniently performed by catalytic hydrogenation in the presence of a Group VIII metal catalyst, for example palladium on charcoal. Suitable solvents for the reaction include alcohols such as ethanol and esters such as ethyl acetate. The temperature is conveniently in the range of from 0 to 100°C. The pressure is conveniently in the range of from 15 to 45 p.s.i (from 1 to 3 x 105 Pa) .
It will be appreciated that step (f) of the process according to the invention can be performed using tritium instead of hydrogen, and that the compound of formula I in which R4 and R5 together represent a bond is thus useful for preparing radiolabelled (tritiated) (+)-2- aminobicyclo [3.1.0] hexane-2 , 6-dicarboxylic acid.
Conveniently, in steps (d) , (e) and (f) , R1 represents an amino group or a protected amino group, for example a protected amino group, such as acetylamino.
It will be appreciated that Step (g) of the process need only be performed if any one of the groups represented by R1 to R7 is protected. The groups may be deprotected by any conventional method, as described hereinabove. For example, a (1-6C) alkoxycarbonyl group may be deprotected by acid-catalysed hydrolysis, for example using hydrochloric acid. A (1-6C) alkanoylamino group may also be deprotected in this way.
The compounds of formula II used as starting material in the process according to the invention are known and may be prepared as described in C. Dominguez, J. Ezquerra, L. Prieto, C. Pedregal and M. Espada., Tetrahedron; Asymmetry, 511, 1997, or by methods analogous thereto, starting from a compound of formula
The compounds of formula III may be prepared by the method described in Borcherding, D.R., Scholtz, S.A., Borchard, R.T., J". Org. Che . , 52, 5457, 1987, or by methods analogous thereto, starting from the inexpensive, commercially available sugar, D (+) -ribonic-γ-lactone .
All of the compounds of formula I described above are believed to be novel, except for those compounds of formula I in which R1 represents amino and R4 and R5 represent hydrogen, which are disclosed in European patent application publication number EP 0696577A1. These novel compounds of formula I are all provided as a further feature of the invention.
According to another aspect, therefore, the present invention provides a compound of formula
in which either: R represents an azido group, an amino group or a protected amino group; and R2 represents a carboxyl group or a protected carboxyl group; or R1 represents a trihalomethyl group and R2 represents a hydroxyl group; and
R3 represents a carboxyl group or a protected carboxyl group ; either R4 represents OR6 and R5 represents OR7; or R4 and R5 each represents a hydrogen atom or together represent a bond; and either R6 and R7 each represents a hydrogen atom; or R6 and R7 together represent a (2-6C) alkylidene group, a (3-6C) cycloalkylidene group or a (1-
6C) alkoxymethylidene group; or a salt thereof, provided that when R and R5 each represents a hydrogen atom, R1 does not represent an amino group.
Of particular interest are those novel compounds of formula I in which R1 represents an amino group, R represents a carboxyl group, R represents a carboxyl group and both of R4 and R5 represent hydroxyl groups . Such compounds have been found to possess activity as modulators of metabotropic glutamate receptor function.
According to a preferred aspect, therefore, the present invention provides a compound of formula I in which R1 represents an amino group, R represents a carboxyl group, R3 represents a carboxyl group and both of R and R represent hydroxyl groups, or a pharmaceutically acceptable salt thereof. The pharmaceutically acceptable salts of the formula I compounds 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 such as hydrochloric, hydrobromic, hydriodic, sulfuric, and phosphoric acid, as well as organic acids such as para-toluenesulfonic, methanesulfonic, oxalic, para-bromophenylsulfonic, carbonic, succinic, citric, benzoic, and acetic acid, and related inorganic and organic acids .
The present invention also provides a method of modulating metabotropic glutamate receptor function in a mammal requiring such treatment, which comprises administering an effective amount of a compound of formula I in which R1 represents an amino group, R2 represents a carboxyl group, R3 represents a carboxyl group and both of R4 and R5 represent hydroxyl groups, or a pharmaceutically acceptable salt thereof (hereinafter referred to as an active compound of formula I) . According to yet another aspect, it provides the use of such compounds for the manufacture of a medicament for modulating metabotropic glutamate receptor function. The particular dose, or effective amount, of compound administered according to this invention will of course be determined by the particular circumstances surrounding the case, including the compound administered, the route of administration, the particular condition being treated, and similar considerations. The compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, or intranasal routes. Alternatively, the compound may be administered by continuous infusion. A typical daily dose will contain from about 0.01 mg/kg to about 100 mg/kg of the active compound of this invention. Preferably, daily doses will be about 0.05 mg/kg to about 50 mg/kg, more preferably from about 0.1 mg/kg to about 25 mg/kg.
A variety of physiological functions have been shown to be subject to influence by excessive or inappropriate stimulation of excitatory amino acid transmission. The active 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 disorders 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 active 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 an active compound of formula I or a pharmaceutically acceptable metabolically labile ester or amide thereof, or a pharmaceutically acceptable salt thereof .
The active formula I compounds 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, nicotine withdrawal, psychosis, (such as schizophrenia) opiate tolerance and withdrawal, anxiety, emesis, brain edema, chronic pain, and tardive dyskinesia. The active 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 active compound of formula I, or a pharmaceutically acceptable metabolically labile ester or amide thereof, or a pharmaceutically acceptable salt thereof .
The term " treating" for purposes of the present invention, includes prophylaxis, amelioration or elimination of a named condition once the condition has been established.
The term " patient" for purposes of the present invention is defined as any warm blooded mammal such as, but not limited to, a mouse, guinea pig, dog, horse, or human. Preferably, the patient is human.
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) .
The pharmaceutically active compounds of the present invention are preferably formulated prior to administration. Therefore, another aspect of the present invention is a pharmaceutical composition comprising a compound of formula I in which R1 represents an amino group,
R represents a carboxyl group, R3 represents a carboxyl group and both of R and R5 represent hydroxyl groups, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient . The present pharmaceutical compositions are prepared by known procedures using well-known and readily available ingredients. In making the compositions of the present invention, 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. 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 .
Some examples of 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.
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. The term "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. The following formulation examples are illustrative only and are not intended to limit the scope of the invention in any way.
Formulation 1
Hard gelatin capsules are prepared using the following ingredients :
Quantity (mg/capsule)
Active Ingredient 250
Starch, dried 200
Magnesium stearate 10
Total 460 mg
The above ingredients are mixed and filled into hard gelatin capsules in 460 mg quantities.
Formulation 2
Tablets each containing 60 mg of active ingredient are made as follows:
Active Ingredient 60 mg
Starch 45 mg
Microcrystalline cellulose 35 mg
Polyvinylpyrrolidone 4 mg
Sodium carboxymethyl starch 4.5 mg
Magnesium stearate 0.5 mg
Talc 1 mg
Total 150 mg
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. The following Examples further illustrate the invention.
Example 1
Ethyl (IS, 3R, 4R, 5R, 6S) -2-oxo-3 , 4 -cyclohexylidenedioxy bicyclo [3.1.0] hexane-6-carboxylate
To a stirred solution of carboethoxymethyl dimethylsulfonium bromide (2.3g, 10.2 mmol) in chloroform (40 ml) under argon, at ambient temperature, was added dropwise 1.5 ml of 1,8- diazabicyclo [5.4.0] undec-7-ene (DBU) (10.2 mmol). The mixture was stirred for 1 hour at ambient temperature and then (-) -2 , 3- (cyclohexylidenedioxy) -4 -cyclopentenone (2g, 10 mmol) in chloroform (10 ml) was added. The reaction was stirred overnight and then it was quenched with HC1 0.5N (20 ml) . The organic layer was separated and the aqueous layer was back extracted with chloroform. The organic layer was dried, filtered and concentrated. The crude product was purified by chromatography (hexane : ethyl acetate 4:1) to give 2.7 g of the title compound as a white solid (96%) . m.p. : 74-75°C,
1H-NMR (CDC13) ; δ 4.78 (d) , 4.17 (m) , 2.85 (dd) , 2.44 (dd) , 1.96 (t) , 1.61-1.35(m) , 1.26 (t) ppm.
Example 2
Ethyl (1S,2S,312,4J2, 5J?,6S) -2-trichloromethyl-2 -hydroxy-3 , 4- cyclohexylidenedioxybicyclo [3.1.0] hexane-6-carboxylate
To a solution of the product of Example 1 (150 mg, 0.53 mmol) and chloroform (0.107 ml, 1.32 mmol) in dry tetrahydrofuran (THF) (30 ml) at -78°C, was added a 1M solution of lithium hexamethyldisilazide in THF (1.05 ml, 1.06 mmol) . The reaction mixture was stirred for lh and quenched with saturated ammonium chloride solution (20ml) . The reaction was allowed to warm to ambient temperature and was then extracted with diethyl ether (3x20 ml) . The combined organic phases were then dried over NaS04, filtered and evaporated to dryness . Purification of the crude product by flash chromatography (hexane: ethyl acetate 4:1) gave 200 mg (94%) of the title compound as a white solid, m.p.: 76-77°C. [α] D= -24.7 (c = 1.5, CHCl3) *H-NMR (CDC13) δ: 4.72 (d, IH, J = 5.5 Hz, H4) , 4.50 (d, IH, J = 5.5 Hz, H3) , 4.09 (c, 2H, J = 7.1 Hz, CH2CH3) , 2.47 (dd, IH, J = 3.5 and 6.3 Hz, H , 2.25 (dd, IH, J = 3.5 and 6.3 Hz, Hs) , 2.00 (m, 10 H) , 1.25 (t, 3H, J = 7.1 Hz, CH3CH2) ppm. Anal. calc. for (C16H21C1305) %C: 48.08, %H: 5.30. Found %C: 48.20, %H: 5.29
Example 3
Dimethyl (1S,2R,3S,4:R,5R, 6R) -2 -Azido- 3 , 4 - cyclohexylidenedioxybicyclo [3.1.0] hexane-2 , 6-dicarboxylate
To a solution of the product of Example 2 (100 mg, 0.25 mmol), NaN3 (48 mg, 0.75 mmol) and a catalytic amount of 18-crown-6 in methanol (5 ml), was added DBU (0.186 ml, 1.25 mmol) . After stirring for 6 h at ambient temperature the solution was extracted with diethyl ether (15 ml) and the ether layer was washed with saturated ammonium chloride solution. The combined organic phases were dried over Na2S04, filtered and evaporated to dryness . Purification of the crude product by flash chromatography (hexane : ethyl acetate 4:1) gave 73 mg (84%) of the title compound as a white solid m.p.: 111-133°C. [α] D= - 135.3 (c = 0.45, CHC13) 'H-NMR (CDClj) δ: 4.77 (d, IH, J = 5.2 Hz, H4) , 4.29 (d, IH, J = 5.2 Hz, H3) , 3.87 (s, 3H, CH3) 3.70 (s, 3H, CH3) ; 2.59 (dd, IH, J = 3.5 and 6.2 Hz, H , 2.50 (dd, IH, J = 3.5 and 6.2 Hz, HS) , 1.70-1.25 (m, 11 H) ppm. _ Anal . calc . for (C16H21N306) %C: 54.69, %H: 6.02, %N: 11.95. Found %C : 54.95, %H: 6.10, %N: 10.72.
Example 4
Dimethyl (IS, 2R, 3S, 4. , 5R, 6R) -2-Amino-3 , 4- cyclohexylidenedioxybicyclo [3.1.0] hexane-2 , 6-dicarboxylate
A solution of the product of Example 3 (300 mg, 0.85 mmol) in ethyl acetate (20 ml) and 10% palladium on charcoal catalyst (150 mg) was stirred under H2 at 30 p.s.i. (2 x 10s Pa) . for 20 h. The mixture was filtered through celite and concentrated to dryness . The crude product was chromatographed on silica gel with hexane: ethyl acetate (4:1) to give 178 mg (71%) of the title compound, [ ] D= - 79.2 (c = 0.5, CHC13 'H-NMR (CDCl3) δ: 4.72 (d, IH, J = 5.3 Hz, H4) , 4.09 (d, IH, J = 5.3 Hz, H3) , 3.79 (s, 3H, CH3) , 3.65 (s, 3H, CH3) , 2.50 (dd, IH, J = 3.4 and 6.3 Hz, H , 2.39 (dd, IH, J = 3.4 and 6.3 Hz, H5) , 1.84 (sa, 2H, NH2) , 1.68 (t, IH, J = 3.4 Hz, H6) , 1.65-1.28 (m, 10H, cyclohexyl) ppm. Anal. calc. for (C16H23N06) %C: 59.06, %H: 7.12, %N: 4.31. Found %C: 59.04, %H : 7.16, %N: 4.16 Example 5 Dimethyl (IS, 2R, 3 S, 4R, 5R, 6R) -2 -acetylamino-3 , 4- cyclohexylidenedioxybicyclo [3.1.0] hexane-2 , 6-dicarboxylate
To a solution of the product of Example 4 (0.78g, 0.6 mmol) in dry dichloromethane (20 ml) under a nitrogen atmosphere, was added triethylamine (0.125 ml, 0.9 mmol). After the reaction mixture had stirred at ambient temperature for 15 min, acetyl chloride (0.063 ml, 0.9 mmol) was added, and the reaction mixture was stirred for 5 h. The mixture was then washed with brine and dried with Na2S04. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (ethyl acetate) to give 165 mg of the title compound (75%) as a white solid m.p.: 223-225°C. [α] D= - 81.2 (c=1.5, CHC13) . IR (KBr) υ: 3304, 2938, 2858, 1735, 1655, 1541, 1447, 1372, 1276, 1246 cm"1. XH-NMR (CDC13) δ: 6.89 (s, IH, NH) , 4.70 (d, IH, J = 5.3 Hz, H4) , 4.18 (d, IH, J = 5.3 Hz, H3) , 3.71 (s, 3H, CH3) , 3.60 (s, 3H, CH3) , 3.10 (dd, IH, J = 3.4 and 6.2 Hz, H , 2.46 (dd, IH, J = 3.4 and 6.2 Hz, Hs) , 1.98 (s, 3H, CH3CO) , 1.70-1.30 (m, 10H, 9H, cyclohexyl, H6) ppm. Anal, cal . for (C1BH25N07) %C: 58.84, %H : 6.85, %N: 3.81. Found %C: 58.57, %H: 6.89, %N: 3.67 Example 6
Dimethyl (IS, 2R, 3S, 4R, 5R, 6R) -2-acetylamino-3 , 4- dihydroxybicyclo [3.1.0] hexane-2 , 6-dicarboxylate
A mixture of the product of Example 5 (0.115 g) and 5 ml of trifluoroacetic acid (TFA) :H20 (7:3) was stirred at ambient temperature for 6 h. The reaction mixture was then evaporated under reduced pressure and the residue was co-evaporated several times with H20. Purification of the crude product by flash chromatography gave 67 mg (90%) of the title compound as a white solid m.p.: 85-84°C. [ ] D= - 56.2 (c = 0.5, MeOH) . XH-NMR (CDC13) δ: 6.82 (s, IH, NH) , 4.71 (d, IH, J = 4.3 Hz, OH), 4.23 (dd, IH, J = 5.4 and 10.8 Hz, H4) , 3.98 (d, IH, J = 10.8 OH), 3.79 (m, 4H, H3 and CH30) , 3.65 (s, 3H, CH30) , 2.57 (dd, IH, J = 3.3 and 6.5 Hz, H , 2.32 (dd, IH, J = 3.3 and 6.5 Hz, Hs) , 2.10 (s, 3H, CH3CO) , 1.63 (t, IH, J = 3.3 Hz, H6) ppm. Anal, calc. for
(C12H17N07) %C: 50.17, %H: 5.96, %N: 4.87. Found %C : 49.62,
%H: 5.76, %N: 4.58. Example 7
Dimethyl (IS, 2R, 3S, 4R, 5R, GR) -2 -acetylamino-3 , 4 - ethoxymethylenedioxybicyclo [3.1.0] hexane-2 , 6-dicarboxylate, mixture of diastereomers
A mixture of the product of Example 6 (100 mg) and triethyl orthoformate (4 ml) was stirred at ambient temperature for 24 h. The reaction mixture was then evaporated to dryness and the residue was chromatographed on silica gel eluting with ethyl acetate as solvent to give the title compound (79%) .
XH-NMR (CDC13) δ: 6.96 (s, IH, NH) , 5.78 (s, IH, CH-OEt), 4.79 (d, IH, J = 5.4 Hz, H4) , 4.41 (d, IH, J = 5.4 Hz, H3) , 3.74 (s, 3H, CH30) , 3.61 (s, 3H, CH30) , 3.49 (c, 2H, J = 7.0 Hz, CH2CH3) , 3.08 (dd, IH, J = 3.4 and 6.2 Hz, Hx) , 2.47 (dd, IH, J = 3.4 and 6.2 Hz, Hs) , 1.98 (s, 3H, CH3CO) , 1.41 (t, IH, J = 3.4 Hz, H6) , 1.10 (t, 3H, J = 7.0 Hz, CH3CH2) ppm. and 'H-NMR (CDC13) δ: 6.75 (s, IH, NH) , 5.69 (s, IH, CH-OEt), 4.61 (d, IH, J = 5.3 Hz, H4) , 4.22 (d, IH, J = 5.3 Hz, H3) , 3.70 (s, 3H, CH30) , 3.60 (m, 5H, 3H, CH30 and 2H, CH2CH3) , 3.19 (dd,lH, J = 3.3 and 6.3 Hz, H , 2.51 (dd, IH, J = 3.3 and 6.3 Hz, Hs) , 1.92 (s, 3H, CH3CO) , 1.43 (t, IH, J = 3.3 Hz, H6) , 1.19 (t, 3H, J = 7.0 Hz, CH3CH2) ppm. Example 8
Dimethyl (IS, 2S, 5R, 6S) -2-acetylaminobicyclo [3.1.0] hex-3-ene-
2 , 6-dicarboxylate
54 mg of the product of Example 7 was heated at 170-190°C for 5 h in a closed vessel. After cooling, the residue was purified by flash chromatography (ethyl acetate) to give 20 mg of the title compound (40%) . *H-NMR (CDC13) δ: 6.21 (dd, IH, J = 2.0 and 5.4 Hz, H4) , 6.11 (s, IH, NH) , 5.49 (d, IH, J = 5.4 Hz, H3) , 3.75 (s, 3H, CH30) , 3.62 (s, 3H, CH30) , 2.97 (dd, IH, J = 2.9 and 5.4 Hz, H5) , 2.59 (m, IH) , 1.99 (s, 3H, CH3CO) , 1.42 (t, IH, J = 2.9 Hz, H6) ppm.
Example 9
Dimethyl (1S,2S, 5R, 6S) -2-acetylaminobicyclo [3.1.0]hexane-
2 , 6-dicarboxylate
A solution of the product of Example 8 (15 mg) in ethyl acetate (5 ml) and 5 mg of 10% palladium on charcoal, was stirred under H2 at 15 p.s.i. (1 x 10s Pa) . for 3 h to give the title compound (80%) . XH-NMR (CDC13) δ: 6.15 (s, IH, NH) , 3.72 (s, 3H, CH30) , 3.61 (s, 3H, CH30) , 2.51 (dd, IH, J = 8.2 and 13.9 Hz) , 2.39 (dd, IH, J = 2.7 and 6.3 Hz) , 2.12-1.78 (m, 5H, 3H, CH3CO and 2H) , 1.68 (m, 2H, H6 and IH) , 1.28 (m, IH) ppm, [ ]D= -7 (c = 0.6 CHC13) . _
Example 10
(1S,2S, 5R, 6S) -2-Aminobicyclo [3.1.0] hexane-2, 6-dicarboxylic
Acid
A mixture of the product of Example 9 and HCl IN was heated under reflux for 20 h. After cooling the solvent was evaporated and the residue was purified by ion exchange chromatography to afford the title compound (64%) m.p.: 277- 279°C (desc.) [α]D= +37.6 (c = 0.65 HCl IN). 'H-NMR
(D20+pyr-ds) δ: 1.91-1.49 (m, 5H) , 1.35 (t, IH J = 3.0 and 2.9 Hz, H6) , 1.20-1.04 (m, IH) ppm. Anal. calc. for %C: 47.29, %H : 6.45, %N: 6.89. Found %C: 47.47, %H: 6.40, %N: 6.86. Example 11
(1S,2R,3S,4R,5R, 6R) -2 -amino-3 , 4-dihydroxy bicyclo [3.1.0] hexane-2 , 6-dicarboxylate
A mixture of the product of Example 6 and HCl IN was heated under reflux overnight. The reaction mixture was then cooled, and then the solvent was evaporated to give the title compound (50%). XH-NMR (D20-Pyr-ds) δ 3.9 (m, 2H) , 2.0 (m, 2H) , 1.6 (m, IH) ppm; 13C-NMR (D20-Pyr-d5) δ 176.87, 171.28, 73.01, 70.33, 68.98, 29.66, 28.83, 22.27 ppm.

Claims

Claims
1. A compound of formula
in which: either R1 represents an azido group, an amino group or a protected amino group and R2 represents a carboxyl group or a protected carboxyl group; or R represents a trihalomethyl group and R2 represents a hydroxyl group;
R3 represents a carboxyl group or a protected carboxyl group; either R4 represents OR6 and R5 represents OR7; or R and R each represents a hydrogen atom or together represent a bond; and either R6 and R7 each represents a hydrogen atom; or R6 and R together represent a diol protecting group; or a salt thereof, provided that when R4 and R5 each represents a hydrogen atom, R1 does not represent an amino group .
2. A compound as claimed in Claim 1, in which R4 and Rs each represents a hydrogen atom.
3. A compound as claimed in Claim 2 in which R1 represents a (1-6C) alkanoylamino group and R2 and R3 each represents a carboxyl group or a (1-6C) alkoxycarbonyl group.
4. A compound as claimed in Claim 1, in which R4 and R5 together represent a bond.
5. A compound as claimed in Claim 4 , in which R1 represents an amino group or a (1-6C) alkanoylamino group and R2 and R3 each represents a carboxyl group or a (1-
6C) alkoxycarbonyl group .
6. A compound as claimed in Claim 1, in which R4 represents OR6 and R5 represents OR7.
7. A compound as claimed in Claim 6, in which R6 and R7 each represents hydrogen.
8. A compound as claimed in Claim 7 , in which R1 represents an amino group or a (1-6C) alkanoylamino group and R2 and R3 each represents a carboxyl group or a (1-
6C) alkoxycarbonyl group.
9. A compound as claimed in Claim 6, in which R6 and
R7 together represents a (1-6C) alkylidene group, a (3-6C) eyeloalkylidene group or a (1-6C) alkoxymethylidene group.
10. A compound as claimed in Claim 1, in which R1 represents a trichloromethyl group.
11. A compound as claimed in Claim 1, in which R1 represents an amino group, R2 represents a carboxyl group,
R3 represents a carboxyl group and both of R4 and R5 represent hydroxyl groups, or a pharmaceutically acceptable salt thereof.
12. A compound as claimed in Claim 11, which is (1S,2S, 5R, 6S) -2-amino-3 , 4-dihydroxybicyclo [3.1.0] hexane-2, 6- dicarboxylic acid, or a pharmaceutically acceptable salt thereof .
13. A pharmaceutical composition, which comprises a compound as claimed in Claim 11 or Claim 12 and a pharmaceutically acceptable carrier, diluent or excipient.
14. A method of modulating metabotropic glutamate receptor function in a mammal requiring treatment, which comprises administering an effective amount of a compound as claimed in Claim 11 or Claim 12.
15. Use of a compound as claimed in Claim 11 or Claim 12 for the manufacture of a medicament for modulating metabotropic glutamate receptor function
16. A process for the preparation of a compound of formula
in which :
R1 represents an amino group;
R2 represents a carboxyl group;
R3 represents a carboxyl group; and
R4 and R5 each represents a hydrogen atom; or a pharmaceutically acceptable salt thereof, which comprises (a) reacting a compound of formula
in which: -
R3 represents a carboxyl group or a protected carboxyl group;
R4 represents OR6;
R5 represents OR7; and R6 and R7 each represents a hydrogen atom or together represent a diol protecting group; with a haloform in the presence of a strong base, to afford a compound of formula I in which :-
R1 represents a trihalomethyl group;
R2 represents a hydroxyl group;
R3 represents a carboxyl group or a protected carboxyl group ;
R4 represents OR6;
R5 represents OR7; and R6 and R7 each represents a hydrogen atom or together represent a diol protecting group; (b) reacting a compound of formula I in which: -
R1 represents a trihalomethyl group;
R2 represents a hydroxyl group;
R3 represents a carboxyl group or a protected carboxyl group;
R4 represents OR6;
R5 represents OR7; and R6 and R7 each represents a hydrogen atom or together represent a diol protecting group; with an azide salt in the presence of a base and a hydroxylic compound, to afford a compound of formula I in which: -
R1 represents an azide group;
R2 and R3 each independently represents a carboxyl group or a protected carboxyl group;
R4 represents OR6;
R5 represents OR7; and R6 and R7 each represents a hydrogen atom or together represent a diol protecting group; (c) reducing a compound of formula I in which :-
R1 represents an azido group; R2 and R3 each independently represents a carboxyl group or a protected carboxyl group; either R4 represents OR6 and R5 represents OR7; or R and R each represents a hydrogen atom or together represent a bond; and R6 and R7 each represents a hydrogen atom or together represent a diol protecting group; to afford a compound of formula I in which: -
R1 represents an amino group;
R2 and R3 each independently represents a carboxyl group or a protected carboxyl group; either R4 represents OR6 and R5 represents OR7; or R4 and R5 each represents a hydrogen atom or together represent a bond; and R6 and R7 each represents a hydrogen atom or together represent a diol protecting group; (d) reacting a compound of formula I in which: -
R1 represents an azido group, an amino group or a protected amino group;
R2 and R3 each independently represents a carboxyl group or a protected carboxyl group; and R4 and R5 each represents a hydroxyl group; with an orthoformate to afford a compound of formula I in which : -
R1 represents an azido group, an amino group or a protected amino group;
R2 and R3 each independently represents a carboxyl group or a protected carboxyl group; and
R4 represents OR6, R5 represents OR7 and R6 and R7 together represents an organo-oxymethylidene group; (e) decomposing a compound of formula I in which: -
R1 represents an azido group, an amino group or a protected amino group;
R2 and R3 each independently represents a carboxyl group or a protected carboxyl group; and
R4 represents OR6, Rs represents OR7 and R6 and R7 together represents an organo-oxymethylidene to afford a compound of formula I in which: -
R1 represents an azido group, an amino group or a protected amino group;
R2 and R3 each independently represents a carboxyl group or a protected carboxyl group; and
R4 and R5 together represent a bond; and
(f) reducing a compound of formula I in which: -
R1 represents an azido group, an amino group or a protected amino group;
R2 and R3 each independently represents a carboxyl group or a protected carboxyl group; and
R4 and R5 together represent a bond; to afford a compound of formula I in which :-
R1 represents an azido group, an amino group or a protected amino group;
R2 and R3 each represents a carboxyl group or a protected carboxyl group; and
R4 and R5 each represents a hydrogen atom, and
(g) if necessary, deprotecting the product of step (f) to afford a compound of formula I in which R1 represents an amino group, R2 and R3 each represents a carboxyl group, and R4 and R5 each represents a hydrogen atom; and optionally forming a pharmaceutically acceptable salt.
17 A process as claimed in Claim 16, in which in steps (a) , (b) and (c) , R4 represents OR6; R5 represents OR7; and R6 and R7 together represent a diol protecting group .
18. A process as claimed in Claim 16 or Claim 17, in which the haloform is chloroform.
19. A process as claimed in any one of Claims 16 to
18, in which in steps (d) , (e) and (f) , R1 represents an amino group or a protected amino group.
20. A process as claimed in any one of Claims 16 to
19, in which the azide salt is an alkali metal azide.
21. A process as claimed in any one of Claims 16 to
20, in which the orthoformate is a tri (1-6C) alkyl orthoformate .
EP99933048A 1998-07-17 1999-07-14 Bicyclohexane derivatives Withdrawn EP1097149A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GBGB9815542.7A GB9815542D0 (en) 1998-07-17 1998-07-17 Bicyclohexane derivatives
GB9815542 1998-07-17
PCT/GB1999/002273 WO2000004010A1 (en) 1998-07-17 1999-07-14 Bicyclohexane derivatives

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EP1310482A1 (en) * 2001-11-07 2003-05-14 Eli Lilly And Company Prodrugs of excitatory amino acids
US7038077B2 (en) 2001-01-11 2006-05-02 Eli Lilly And Company Prodrugs of excitatory amino acids
IL156364A0 (en) 2001-01-11 2004-01-04 Lilly Co Eli Prodrugs of excitatory amino acids
EP1310480A1 (en) * 2001-11-07 2003-05-14 Eli Lilly & Company Prodrugs of excitatory amino acids
EP1423411A2 (en) * 2001-07-09 2004-06-02 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
AR083845A1 (en) 2010-11-18 2013-03-27 Lilly Co Eli 3-PHENYLSULPHANYLME-BICYCLE COMPOUNDS [3.1.0] HEXANE 4-REPLACED AS ANTAGONISTS OF mGluR2 / 3
KR101554793B1 (en) 2010-11-18 2015-09-21 일라이 릴리 앤드 캄파니 4-SUBSTITUTED-3-BENZYLOXY-BICYCLO[3.1.0]HEXANE COMPOUNDS AS mGluR 2/3 ANTAGONISTS

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PL182285B1 (en) * 1994-08-12 2001-12-31 Lilly Co Eli Synthetic amino acids and their esters and pharmaceutical preparations containing them. PL PL PL PL PL PL PL

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WO2000004010A1 (en) 2000-01-27
GB9815542D0 (en) 1998-09-16
AR029446A1 (en) 2003-07-02
CA2338054A1 (en) 2000-01-27
JP2002520406A (en) 2002-07-09
AU4922399A (en) 2000-02-07

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