EP1097149A1 - Derives de bicyclohexane - Google Patents

Derives de bicyclohexane

Info

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Withdrawn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)
English (en)
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
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Eli Lilly and Co Ltd, Eli Lilly and Co filed Critical Eli Lilly and Co Ltd
Publication of EP1097149A1 publication Critical patent/EP1097149A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • C07D317/72—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Psychiatry (AREA)
  • Addiction (AREA)
  • Pain & Pain Management (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Cardiology (AREA)
  • Psychology (AREA)
  • Hospice & Palliative Care (AREA)
  • Vascular Medicine (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Ophthalmology & Optometry (AREA)
  • Otolaryngology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés de la formule (1) suivante: dans laquelle R?1, R2, R3, R4 et R5¿ sont tels que définis dans la description, et des sels de ces derniers, qui sont utilisés comme intermédiaires pharmaceutiques ou comme modulateurs de la fonction de récepteur du glutamate métabotropique.
EP99933048A 1998-07-17 1999-07-14 Derives de bicyclohexane Withdrawn EP1097149A1 (fr)

Applications Claiming Priority (3)

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

Publications (1)

Publication Number Publication Date
EP1097149A1 true EP1097149A1 (fr) 2001-05-09

Family

ID=10835676

Family Applications (1)

Application Number Title Priority Date Filing Date
EP99933048A Withdrawn EP1097149A1 (fr) 1998-07-17 1999-07-14 Derives de bicyclohexane

Country Status (7)

Country Link
EP (1) EP1097149A1 (fr)
JP (1) JP2002520406A (fr)
AR (1) AR029446A1 (fr)
AU (1) AU4922399A (fr)
CA (1) CA2338054A1 (fr)
GB (1) GB9815542D0 (fr)
WO (1) WO2000004010A1 (fr)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1310480A1 (fr) * 2001-11-07 2003-05-14 Eli Lilly & Company Prodrugs d'aminoacides excitants
US7256217B2 (en) * 2001-01-11 2007-08-14 Eli Lilly And Company Prodrugs of excitatory amino acids
EP1351925A1 (fr) * 2001-01-11 2003-10-15 Eli Lilly And Company Promedicaments d'acides amines excitateurs
EP1310482A1 (fr) * 2001-11-07 2003-05-14 Eli Lilly And Company Promédicaments d'aminoacides synthétiques excitants
EP1423411A2 (fr) * 2001-07-09 2004-06-02 Eli Lilly And Company Promedicaments d'acides amines excitateurs
US7456221B2 (en) 2001-12-21 2008-11-25 Eli Lilly And Company Prodrugs of excitatory amino acids
TWI520935B (zh) 2010-11-18 2016-02-11 美國禮來大藥廠 作為ｍＧｌｕＲ２／３拮抗劑之４－經取代－３－苯基磺醯基甲基－雙環［３.１.０］己烷化合物
EP2640687B1 (fr) 2010-11-18 2018-06-27 Eli Lilly and Company Composés 3-benzyloxy-bicyclo[3.1.0]hexanes 4-substitués en tant qu'antagonistes de mglur 2/3

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0004010A1 *

Also Published As

Publication number Publication date
AU4922399A (en) 2000-02-07
GB9815542D0 (en) 1998-09-16
WO2000004010A1 (fr) 2000-01-27
JP2002520406A (ja) 2002-07-09
CA2338054A1 (fr) 2000-01-27
AR029446A1 (es) 2003-07-02

Similar Documents

Publication Publication Date Title
EP1000927B1 (fr) Modulateurs de recepteurs d'acides aminés excitateurs
US6160009A (en) Excitatory amino acid receptor modulators
EP1226110B1 (fr) Acides amines bicycliques utilises comme agents pharmaceutiques
US6498180B1 (en) Excitatory amino acid receptor modulators
EP0870760B1 (fr) Dérivés de la cyclopropyl glycine ayant des propriétés pharmaceutiques
US20040102521A1 (en) Excitatory amino acid receptor modulators
EP1082306A1 (fr) Composes d'acide amines soumis a une contrainte de conformation et presentant une affinite pour la sous-unite alpha 2 delta d'un canal calcique
GB2355982A (en) Heterocyclic amino acids
EP0774461B1 (fr) Dérivés des aminoacides excitateurs
WO2000004010A1 (fr) Derives de bicyclohexane
EA000894B1 (ru) Замещенные бициклогексанкарбоновые кислоты и их производные в качестве антагонистов рецептора возбуждающих аминокислот, способ их получения и применение
DE60017737T2 (de) Modulatoren von anregbaren aminosäurerezeptoren
EP0826663B1 (fr) Dérivés d'alkynylaminoacides et leur utilisation comme composés pharmaceutiques
EP1289940A2 (fr) Modulateurs de recepteur d'acide amine excitateur
MXPA99010380A (en) Excitatory amino acid receptor modulators
MXPA98003835A (en) Amino acid derivatives excited

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20001124

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

17Q First examination report despatched

Effective date: 20030912

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20050622