EP1370519A1 - Synthetische excitatorische aminosäuren - Google Patents

Synthetische excitatorische aminosäuren

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Publication number
EP1370519A1
EP1370519A1 EP02705812A EP02705812A EP1370519A1 EP 1370519 A1 EP1370519 A1 EP 1370519A1 EP 02705812 A EP02705812 A EP 02705812A EP 02705812 A EP02705812 A EP 02705812A EP 1370519 A1 EP1370519 A1 EP 1370519A1
Authority
EP
European Patent Office
Prior art keywords
mmol
hexane
bicyclo
dicarboxylic acid
product
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Withdrawn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
EP02705812A
Other languages
English (en)
French (fr)
Inventor
Steven Marc Massey
James Allen Monn
Lourdes Prieto
Matthew John Valli
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
Original Assignee
Eli Lilly and Co
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Filing date
Publication date
Application filed by Eli Lilly and Co filed Critical Eli Lilly and Co
Publication of EP1370519A1 publication Critical patent/EP1370519A1/de
Withdrawn legal-status Critical Current

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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
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    • C07C229/48—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 of the same non-condensed ring
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    • C07C235/54—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
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    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/84—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07C237/14—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being saturated and containing rings
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    • C07C237/38—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to a carbon atom of a ring other than a six-membered aromatic ring
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    • C07C271/32—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C271/38—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of rings other than six-membered aromatic rings with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
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    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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Definitions

  • EAA receptors excitatory amino acid receptors
  • 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, increases or decreases in cAMP 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 metabotropic glutamate receptors are a highly heterogeneous family of glutamate receptors that are linked to multiple second-messenger pathways. Generally, these receptors function to modulate the presynaptic release of glutamate, and the postsynaptic sensitivity of the neuronal cell to glutamate excitation.
  • the metabotropic glutamate receptors (mGluR) have been pharmacologically divided into two subtypes. One group of receptors is positively coupled to phospholipase C, which causes hydrolysis of cellular phosphoinositides (PI) . This first group are termed Plunked metabotropic glutamate receptors.
  • the second group of receptors is negatively coupled to adenyl cyclase, which prevents the forskolin-stimulated accumulation of cyclic adenosine monophosphate (cAMP) .
  • cAMP cyclic adenosine monophosphate
  • Schoepp and Conn Trends Pharmacol . Sci . , 14, 13 (1993).
  • Receptors within this second group are termed cAMP-linked metabotropic glutamate receptors. Agonists of the cAMP-linked metabotropic glutamate receptors should be useful for the treatment of acute and chronic neurological conditions and psychiatric conditions .
  • (2S,3S,4S) -2- (carboxycyclopropyl) glycine (L- CCG-I) was recently described as a selective cAMP-linked metabotropic glutamate receptor agonist; however, at higher concentrations, this compound has activity at PI -linked metabotropic receptors.
  • Nakagawa, et al . Eur. J " . Pharmacol . , 184, 205 (1990); Hayashi, et al . , Br. J. Pharmacol . , 107, 539 (1992); Schoepp et al . , J. Neurochem. , 63., page 769-772 (1994).
  • United States Patent No. 5,958,960 discloses that certain 2-aminobicyclo [3.1.0] hexane-2 , 6-dicarboxylic acid derivatives are modulators of metabotropic glutamate function, in particular agonists or antagonists of glutamate at metabotropic glutamate receptors and as such are useful in the treatment of a neurological disorder or a psychartic disorder that has been linked to the excitatory amino acid receptors .
  • the present invention provides compounds that selectively affect the negatively coupled cAMP-linked metabotropic glutamate receptors. More specifically, the present invention relates to compounds of the formula
  • X is CH 2 , O, or NH
  • Y is O, S, N or H
  • A is a bond, 0, N, (1-lOC) alkyl, (2-10C) alkenyl or (2 -IOC) alkynyl;
  • R is hydrogen, (1-lOC) akyl , (2-10C) alkenyl, (3-6C) alkynyl, aryl, heterocyclyl or substituted aryl; or the group XC(Y)AR is
  • Q is 0, S or NH; or a pharmaceutically acceptable metabolically labile ester or amide thereof; or a pharmaceutically acceptable salt thereof.
  • a particular compound of formula I is one wherein (1-lOC) alkyl is methyl, ethyl, n-propyl, isopropyl, n- butyl, t-butyl, n-pentyl, isopentyl, n-hexyl, heptyl, n-octyl, nonyl or decyl; (2 -10C) alkenyl is allyl, allenyl, 1-butenyl, 1-pentenyl, 3-nonenyl or 5-decenyl; (2-6C) alkynyl is ethynyl, propynyl , butynyl or pentynyl ; aryl is phenyl, substituted phenyl or naphthyl ; and arylalkyl is benzyl, 2-nitro benzyl, or 1-phenylethyl .
  • Another particular compound of formula I is one wherein R is 2-methoxyphenyl, 3-methoxyphenyl , 4- methoxyphenyl , 3-methylphenyl , 4-methylphenyl , 2- chlorophenyl , 3-chlorophenyl , 4-chlorophenyl , 3- fluorophenyl , 2 -fluorophenyl, 4-fluorophenyl , 2,6- dichlorophenyl , 2 , 4-dichlorophenyl , 3 , 5-dichlorophenyl ,
  • A is a bond, methyl, O, NH, ethenyl or ethynyl ;
  • Y is 0, S or H,H; and X is CH 2 , O or NH.
  • Another particular compound of formula I is one wherein R is heterocyclyl or substituted aryl.
  • Another particular compound of formula I is one wherein R is lH-indolyl, 2-napthyl, 3-chlorophenyl or 2-methoxyphenyl .
  • Another particular compound of formula I is one wherein Y is 0 or S.
  • Another particular compound of formula I is one wherein A is CH 2 or a bond.
  • a preferred compund of formula I is one wherein (IS*, 2S*, 4S*, 5R*, 6S*) 2-amino-4- [3-3 - chlorophenyl) ureido] bicyclo [3.1.0] hexane-2 , 6- dicarboxylic acid.
  • the compounds of formula I are modulators of metabotropic glutamate receptor function with improved activity, in particular potent agonists of mGluR2 and mGluR3 receptors.
  • the present invention provides a method of modulating metabotropic glutamate receptor function in a mammal including a human, which comprises administering an effective amount of a compound of formula I, or a non-toxic metabolically labile ester or amide thereof, or a pharmaceutically acceptable salt thereof.
  • the present invention provides the use of a compound of formula I as defined hereinabove for the manufacture of a medicament for use in modulating metabotropic glutamate receptor function.
  • the present invention also includes all physical forms of the compounds of formula I, including crystalline solvates .
  • the compounds of formula I contain at least five asymmetric carbon atoms.
  • a wedge line refers to a bond projecting from the plain of the paper to the reader's eyes and is referred to as "beta” stereochemistry.
  • a dashed line refers to a bond projecting into the plain of the paper away from the reader's eyes and is referred to as "alpha" stereochemistry.
  • a plain line refers to a bond lying within the plain of the paper.
  • the stereoisomer of compounds of formula I have the configuration I with functional groups attached at C-4 possesing beta stereochemistry, as shown below.
  • the present invention also provides pharmaceutical formulations comprising a compound of formula I in combination with one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • Further aspects of the present invention include a method for affecting the cAMP-linked metabotropic glutamate receptors, as well as methods for treating a neurological disorder or a psychiatric disorder that has been linked to the excitatory amino acid receptors, which comprises administering a compound of formula I .
  • Examples of neurological disorders that are treated with a formula I compound include cerebral deficits subsequent to cardiac bypass surgery and grafting, cerebral ischemia (e.g.
  • psychiatric disorders that are treated with a formula I compound include schizophrenia, anxiety and related disorders (e.g. panic attack and stress- related disorders) , depression, bipolar disorders, psychosis, and obsessive compulsive disorders.
  • the present invention also provides a process for producing a compound of formula I, or a pharmaceutically salt thereof, which comprises:
  • R 1 is a nitrogen protecting group such t- butoxycarbonyl ;
  • R2 and R ⁇ are both carboxy protecting groups such as ethyl ;
  • (1-lOC) alkyl represents a straight, branched, or cyclic alkyl chain having from one to ten carbon atoms.
  • Typical straight or branched Ci-Cio alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 2-methylpentyl , 3-methylpentyl, 4- methylpentyl , 2 , 2-dimethylbutyl , 2 , 3-dimethylbutyl, 3,3- dimethylbutyl , heptyl , n-octyl, 2 , 2-dimethylhexyl , 2,5- dimethylhexyl , 2-methylheptyl , 4-methylheptyl , 2,2,4- trimethylp
  • (1-lOC) alkyl includes within it the terms "Cx-C ⁇ alkyl” and "C1-C 4 alkyl".
  • Typical cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
  • Typical Ci-C ⁇ alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl. .
  • (2-10C) alkenyl represents straight or branched unsaturated alkyl chains having from two to ten carbon atoms, and having one or more carbon-carbon double bond, such as, dienes and trienes . This group also includes both E and Z isomers.
  • radicals for this group include ethenyl, allyl, allenyl, 1-butenyl, 2-butenyl, 2 -methyl-1-propenyl, 3-butenyl, 2-methyl-2-propenyl, butadienyl , 1-pentenyl, 2-pentenyl, 2 -methyl -2-butenyl , 4- pentenyl, 3 -methyl -2-butenyl , 3 -methyl -1 , 2 -butadienyl , 3- hexenyl, 2-hexenyl, 4 -methyl-3 -pentenyl , 4-hexenyl, 5- hexenyl, 3 -methyl -1-penten-3 -yl , 4 -methyl-3 -pentenyl , 6- methyl-5-heptene-2-yl , 7-octenyl, l-octen-3-yl , 3-nonenyl, 2 , 4-dimethyl-2 ,
  • (2-6C) alkynyl represents ethynyl , propynyl , butynyl or pentynyl .
  • stereoisomeric compound represents an optical isomer of a Formula I compound, which includes the IS, 2S, 4S, 5R, 6R isomer.
  • carboxy protecting group refers to one of the ester derivatives of the carboxylic acid group commonly employed to block or protect the carboxylic acid group while reactions are carried out on other functional groups.
  • the protection of carboxylic acid 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.
  • carboxy protecting groups include methyl, ethyl, methoxymethyl , methylthiomethyl, triphenylmethyl, benzyl, 4-nitrobenzyl, 4- methoxybenzyl , 3 , 4-dimethoxy-benzyl, 2 , 4-dimethoxybenzyl, 2 , 4, 6-trimethoxybenzyl, 2 , 4 , 6-trimethylbenzyl , benzhydryl , t-butyl, t-amyl, trityl, trimethylsilyl , t-butyldimethyl- silyl, allyl, 1- (trimethylsilylmethyl) -prop-l-en-3-yl , and the like.
  • carboxy protecting groups are (C ⁇ -C6) alkyl groups such as ethyl.
  • protected carboxy refers to a carboxylic acid group having a carboxy protecting group.
  • nitrogen protecting group refers to substituents on amino groups that are commonly employed to block or protect the amino functionality while reactions are carried out in other functional groups. The protection of amino 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.
  • nitrogen protecting groups include benzyl, t-butyl, allyl, triphenylmethyl, t-butyldimethylsilyl, triphenylsilyl, formyl, trityl, phthalimido, trichloroacetyl , chloroacetyl , phthaloyl, 2- nitrophenoxyacetyl , benzyloxycarbonyl , methoxycarbonyl , 2- methylbenzyloxycarbonyl , t-butoxycarbonyl , allyloxy- carbonyl , 2 , 2 , 2-trichloroethoxycarbonyl , and the like.
  • protected amino refers to a primary or secondary amine having a nitrogen protecting group.
  • heterocyclyl includes heteroaromatics an aromatic 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen, and a bicyclic group consisting of a 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen fused with a benzene ring or a 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen.
  • heteroaromatic groups are furyl, thiophenyl, oxazolyl, isoxazolyl, thiazoyl, isothiazolyl, imidazolyl, pyrimidyl, benzofuryl, benzothiophenyl , benzimidazolyl , benzoxazolyl, benzo- thiazolyl and indolyl .
  • Examples of particular values are 2- thienyl, 3-thienyl, 2-indolyl, 3-indolyl, 2-pyridyl, 3- pyridyl, 4-pyridyl, 1-isoquinolinyl , 3-isoquinolinyl , 2- benzothiazolyl, benzoxazoyl and 4 -imidazolyl .
  • aryl includes phenyl and a polycyclic aromatic carbocyclic ring such as 1-naphthyl or 2-naphthyl.
  • substituted as used in the term “substituted heterocycles or aromatic group”, herein signifies that one, two or more substituents may be present, said substituents being selected from atoms and groups which, when present in the compound of formula I, do not prevent the compound of formula I from functioning as a modulator of metabotropic glutamate receptor function.
  • Examples of atoms and groups which may be present in an optionally substituted heteroaromatic or aryl group are amino, hydroxy, nitro, halogeno, (1-6C) alkyl, (1-6C) alkoxy, (1-6C) alkylthio, carboxy, (1-6C) alkoxycarbonyl , carbamoyl, (1-6C) alkanoylamino, (1-6C) alkylsulphonyl , (1- 6C) alkylsulphonylamino, (1-6C) alkanoyl , phenyl, phenoxy, phenylthio, phenylsulphonyl , phenylsulphonylamino, toluene- sulphonylamino, and (1-6C) fluoroalkyl .
  • Examples of particular values are hydroxy, fluoro, chloro, bromo, iodo, methyl, methoxy, carboxy, acetyl, phenyl, phenoxy, tetrazoyl and trifluoromethyl .
  • Examples of values for substituted aryl groups are 1- naphthyl , 2-naphthyl, phenyl, 2-hydroxyphenyl , 3- hydroxyphenyl , 4 -hydroxyphenyl , 3 , 5-dihydroxyphenyl , 2 - fluorophenyl, 3-fluorophenyl , 4 -fluorophenyl 3,5- difluorophenyl, 2-chlorophenyl , 3-chlorophenyl, 4- chlorophenyl , 2 , 4-dichlorophenyl, 3 , 4-dichlorophenyl , 3,5- dichlorophenyl , 2 -methylphenyl , 3 -methylphenyl , 4- methy1phenyl , 2 -methoxyphenyl , 3-methoxyphenyl , 4- methoxyphenyl, 3 -trifluoromethylphenyl , 4- trifluoromethylphenyl, 2 -methylphenyl
  • heterocyclyl also includes non-aromatic heterocyclyl which includes a 4 to 7 membered ring containing one or two heteroatoms selected from oxygen, sulphur and nitrogen, for example azetidin-1-yl or -2-yl, pyrrolidin-1-yl , -2-yl or -3-yl, piperidin-1-yl , -2-yl, -3- yl or -4-yl, hexahydroazepin-1-yl , -2-yl, -3-yl or -4-yl, oxetan-2-yl or -3-yl, tetrahydro-furan-2-yl or -3-yl, tetrahydropyran-2-yl , -3-yl or -4-yl, hexahydrooxepin-2-yl , -3-yl or -4-yl, thietan-2-yl or -3-
  • affecting refers to a formula I compound acting as an agonist at an excitatory amino acid receptor.
  • excitatory amino acid receptor refers to a metabotropic glutamate receptor, a receptor that is coupled to cellular effectors via GTP-binding proteins.
  • cAMP-linked metabotropic glutamate receptor refers to a metabotropic receptor that is coupled to inhibition of adenylate cyclase activity.
  • neurodegenerative disorder refers to both acute and chronic neurodegenerative conditions, including cerebral deficits subsequent to cardiac bypass surgery and grafting, cerebral ischemia (for example stroke resulting from cardiac arrest), spinal cord trauma, head trauma, Alzheimer's Disease, Huntington's Chorea, amyotrophic lateral sclerosis, AIDS-induced dementia, perinatal hypoxia, hypoglycemic neuronal damage, ocular damage and retinopathy, cognitive disorders, idiopathic and drug-induced Parkinson's Disease.
  • This term also includes other neurological conditions that are caused by glutamate dysfunction, including muscular spasms, migraine headaches, urinary incontinence, drug tolerance, withdrawal, and cessation (i.e.
  • opiates, benzodiazepines, nicotine, cocaine, or ethanol) smoking cessation, emesis, brain edema, chronic pain, sleep disorders, convulsions, Tourette's syndrome, attention deficit disorder, and tardive dyskinesia.
  • psychiatric disorder refers to both acute and chronic psychiatric conditions, including schizophrenia, anxiety and related disorders (e.g. panic attack and stress- related cardiovascular disorders) , depression, bipolar disorders, psychosis, and obsessive compulsive disorders.
  • the term "effective amount” refers to the amount or dose of the compound, upon single or multiple dose administration to the patient, which provides the desired effect in the patient under diagnosis or treatment.
  • an effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances.
  • determining the effective amount or dose of compound administered a number of factors are considered by the attending diagnostician, including, but not limited to: the species of mammal; its size, age, and general health; the specific disease involved; the degree of or involvement or the severity of the disease; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.
  • a typical daily dose may contain from about 150 micrograms to about 150 mg of the active ingredient.
  • the compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, bucal or intranasal routes. Alternatively, the compound may be administered by continuous infusion.
  • patient refers to a mammal, such as a mouse, guinea pig, rat, dog or human. It is understood that the preferred patient is a human.
  • treating includes its generally accepted meaning which encompasses prohibiting, preventing, restraining, and slowing, stopping, or reversing progression of a resultant symptom. As such, the methods of this invention encompass both therapeutic and prophylactic administration.
  • the present invention includes pharmaceutically- acceptable salts of the formula I compounds. These salts can exist in conjunction with the acidic or basic portion of the molecule and can exist as acid addition, primary, secondary, tertiary, or quaternary ammonium, alkali metal, or alkaline earth metal salts. Generally, the acid addition salts are prepared by the reaction of an acid with a compound of formula I .
  • 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.
  • Such pharmaceutically-acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, ammonium, monohydrogenphosphate , dihydrogenphosphate, meta-phosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, furmarate, hippurate, maleate, butyne- 1,4-dioate, hexyne-1, 6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate , phthalate, sulfonate, xylenesulfonate, phenylacetate, phen
  • X is NH, O or CH
  • Y is O
  • Z is NH or a bond
  • R is aryl, heteroaryl, fused aryl or substituted aryl.
  • Representative compounds from this preferred group of formula I compounds include (IS*, 2S*, 4S*, 5R* , 6S*) 2- amino-4- (3 -chloro-benzoylamino) -bicyclo [3.1.0] hexane-2 , 6- dicarboxylic acid, (IS*, 2S*, 4S*, 5R* , 6S*) 2-amino-4- (3- methoxy-benzoylamino) -bicyclo [3.1.0] hexane-2, 6-dicarboxylic acid, (IS*, 2S*, 4S*, 5R* , 6S*) 2 -amino-4- (3 -hydroxy- benzoylamino) -bicyclo [3.1.0] hexane-2 , 6-dicarboxylic acid, (IS*, 2S*, 4S*, 5R*, 6S*) 2 -amino-4- (3 , 4-dichloro- benzoylamino) -bicyclo
  • Certain compounds of the present invention are more preferred for use in affecting the cAMP- linked metabotropic glutamate receptors. More preferably, R is heteroaromatic, aryl or substituted aryl. Representative compounds from this more preferred group of compounds include (IS*, 2S*, 4S*, 5R* , 6S*) 2-amino-4- [ (lH-indole-3- carbonyl) -amino] -bicyclo [3.1.0] hexane-2 , 6-dicarboxylic acid,
  • R 1 is t-butoxycarbonyl. More preferably, R 2 and R3 are C 1 -C 10 alkyl groups for example ethyl groups.
  • the compounds of formula I of the present invention are generally synthesized from compounds of formula III or formula X where R 1 , R 2 and R 3 are as previously described.
  • the compounds of formula III and formula X are prepared as described in U. S. Patent No. 5,958,960 which is incorporated by reference in its entirety.
  • compounds of formula II in which X and Y are 0, and A is N may be prepared by directly reacting compounds of formula III.
  • Compounds of formula II in which X and A are N, and Y is 0 may be prepared by reacting compounds of formula IX.
  • Compounds of formula IX may be prepared by reacting compounds of formula III in a series of steps to convert the hydroxyl to an amine while retaining the stereochemistry at point of attachment.
  • compounds of formula VII may be prepared by reacting compounds of formula III with halogenating agents such as bromine and triphenyl phosphine in the presence of a suitable base such as pyridine in a reaction solvent such as methylene chloride to produce compounds of formula VIII.
  • halogenating agents such as bromine and triphenyl phosphine
  • a suitable base such as pyridine
  • a reaction solvent such as methylene chloride
  • an azide salt such as sodium azide for example in dimethylsulfoxide as a reaction solvent to produce compounds of formula VII .
  • the compounds of formula IX may be prepared by reducing a corresponding compound of formula VII.
  • the reduction is conveniently performed using triphenylphosphine in a suitable solvent such as tetrahydrofuran at a temperature in the range of 0 to 100°C.
  • Convenient solvents include dichloromethane.
  • Convenient solvents include dichloromethane.
  • Compounds of formula II in which X is N, Y is 0 and A is a bond may be prepared by reacting compounds of formula IX, an amine, with an acyl halide of formula RCOX ⁇ in which X 1 is, for example, chlorine or bromine.
  • the reaction is conveniently performed in the presence of a base, such as diisopropylethyl amine and in a solvent such as dichloromethane.
  • the amine may be reacted with an acyl isourea such as obtained by the reaction of a carboxylic acid of the formula RCOOH with a carbodiimide such as dicyclohexylcarbodiimide .
  • the reaction is conveniently performed in the presence of an activating agent such as hydroxybenzotriazole and in a solvent such as dichloromethane .
  • compounds of formula II in which X is CH 2 , Y is O, and A is N may be prepared by reacting, in a series of steps, compounds of formula X.
  • compounds of formula XI where R 4 is not hydrogen may be prepared from compounds of formula X by a Wadsworth-Emmons reaction, for example by reaction with an alkali metal salt of a dialkyl phosphono acetate ester, such as the sodium salt of allyl diethylphosphonoacetate .
  • the reaction is conveniently performed in an anhydrous solvent such as anhydrous THF.
  • compounds of formula XI may exist in the (E) or (Z) isomeric form or as a mixture of (E) and (Z) isomers and, as such, are included in the present invention.
  • the formula I compounds of the present invention are agonists of certain metabotropic excitatory amino acid receptors. Specifically, the formula I compounds are agonists of the negatively-coupled cAMP-linked metabotropic glutamate receptors. Therefore, another aspect of the present invention is a method of affecting an excitatory amino acid receptor in mammals, which comprises administering to a mammal requiring modulated excitatory amino acid neurotransmission a pharmaceutically-effective amount of a compound of formula I .
  • pharmaceutically-effective amount is used to represent an amount of the compound of the invention which is capable of affecting the excitatory amino acid receptors.
  • a compound of the invention is acting as an agonist .
  • the interaction of the compound with the EAA receptor mimics the response of the interaction of this receptor with its natural ligand (i.e. L-glutamate) .
  • the particular dose 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.
  • the formula I compounds of the present invention are believed to have the ability to treat a variety of neurological disorders in mammals associated with this condition, including acute neurological disorders such as cerebral deficits subsequent to cardiac bypass surgery and grafting, cerebral ischemia (e.g. stroke and cardiac arrest), spinal cord trauma, head trauma, perinatal hypoxia, and hypoglycemic neuronal damage.
  • acute neurological disorders such as cerebral deficits subsequent to cardiac bypass surgery and grafting, cerebral ischemia (e.g. stroke and cardiac arrest), spinal cord trauma, head trauma, perinatal hypoxia, and hypoglycemic neuronal damage.
  • the formula I compounds are believed to have the ability to treat a variety of chronic neurological disorders, such as Alzheimer's disease, Hungington's Chorea, amyotrophic lateral sclerosis, AIDS- induced dementia, ocular damage and retinopathy, cognitive ⁇ ⁇ H ⁇ - rt fi SD CQ rt ⁇ - 3 SD ⁇ ⁇ 0 O rt H SD ⁇ SD CO 0 13 ⁇ £ 0 SD rt Si 13 fi
  • CD rt l-h 3 CQ ⁇ CQ hi SD CD ⁇ CD 3
  • CD h ⁇ - CD 0 co CD Si ⁇ - 3 ⁇ CD SD CQ ⁇ J rt Si 0 - SD rt hi 0 3 Si 3 in ⁇ ⁇ CQ rt 3 ⁇ 0 hi tr CQ 0 IQ CD 3 3 ⁇ 13 ⁇ ⁇ ⁇ ⁇ hi 3 CQ hi ⁇ 3 LQ CO ⁇
  • an anatgonist blocks the agonist induced decrease in forskolin-stimulated accumulation of cyclic adenosine monophosphate (cAMP) and is reported as the concentration necessary to inhibit the reduction of C-AMP accumulation to 50% of the controls (IC50, nM) .
  • cAMP cyclic adenosine monophosphate
  • Salhofff C. R., Mayne N. G. , Wu S . , Cockerham S. L., Burnett J. P., Belagaje R. , Bleakman D., and Monn J. , LY354740 is a potent and highly selective group II metabotropic glutamate receptor agonist in cells expressing human glutamate receptors. Neuropharmacology 36: 1-11 (1997)). As shown in table 2, compounds of the current invention have agonist effects on cells expressing mGlu2 and mGlu3 receptors where as compounds of United States Patent No. 5,958,960 have antagonist effects on cells expressing mGlu2 and mGlu3 receptors .
  • Each of the compounds of the current invention possess a primary amino group at the C2 -position of the bicyclic ring and two carboxylic acid groups, one at the C2 -position and one at the C6 -position.
  • ester and/or amide derivatives of these functional groups are inactive in the receptor binding test.
  • these compounds are converted in vivo to the corresponding amino diacid and can therefore function as pro-drugs.
  • the present invention provides the active amino diacid as well as any pro-drug forms that are capable of generating the active amino diacid in vivo.
  • compositions of the present invention 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, dermal patch, subcutaneous implant, 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, stearic acid, and mineral oil.
  • the formulations can additionally include lubricating agents, wetting agents (surfactants) , emulsifying and suspending agents, preserving agents, sweetening agents, or flavoring agents.
  • Compositions of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art .
  • compositions are preferably formulated in a unit dosage form, each dosage containing from about 5 mg to about 500 mg, more preferably about 25 mg to about 300 mg of the active ingredient.
  • active ingredient refers to a compound included within the scope of formula I .
  • unit dosage form refers to a physically discrete unit suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier, diluent, or excipient .
  • Proton nuclear magnetic resonance ( ⁇ -H NMR) spectra were obtained on a GE QE-300 spectrometer at 300.15 MHz, a Bruker AM-500 spectrometer at 500 MHz, or a Bruker AC-200P spectrometer at 200 MHz.
  • Free atom bombardment mass spectroscopy (FABMS) was performed on a VG ZAB-2SE instrument.
  • Field desorption mass spectroscopy (FDMS) was performed using either a VG 70SE or a Varian MAT 731 instrument.
  • Optical rotations were measured with a Perkin-Elmer 241 polarimeter.
  • Chromatographic separation on a Waters Prep 500 LC was generally carried out using a linear gradient of the solvents indicated in the text.
  • TLC thin layer chromatography
  • Thin layer chromatography was performed using E. Merck Kieselgel 60 F 254 plates, 5 cm X 10 cm, 0.25 mm thickness. Spots were detected using a combination of UV and chemical detection (plates dipped in a eerie ammonium molybdate solution [75 g of ammonium molybdate and 4 g of cerium (IV) sulfate in 500 mL of 10% aqueous sulfuric acid] and then heated on a hot plate) . Flash chromatography was performed as described by Still, et al . Still, Kahn, and Mitra, J. Org. Chem. , 43, 2923 (1978).
  • Elemental analyses for carbon, hydrogen, and nitrogen were determined on a Control Equipment Corporation 440 Elemental Analyzer, or were performed by the Universidad Complutense Analytical Centre (Facultad de Farmacia, Madrid, Spain) . Melting points were determined in open glass capillaries on a Gallenkamp hot air bath melting point apparatus or a B ⁇ chi melting point apparatus, and are uncorrected.
  • D 2 0 deuterium oxide
  • DCC dicyclohexylcarbodiimide
  • DIBAL-H diisobutyl aluminum hydride
  • FAB Fast Atom Bombardment (Mass Spectrascopy)
  • HOAt 1-hydroxy-7 -azabenzotriazole
  • HOBt 1-hydroxybenzotriazole
  • NBS N-bromosuccinimide
  • NMDBA 1, 3-dimethylbarbituric acid
  • NMR Nuclear Magnetic Resonance
  • p-TsCl para-toluenesulfonyl chloride
  • p-TsOH para-toulenesulfonic acid
  • i-Pr isopropyl
  • TBS tert-butyldime .
  • thylsilyl TEA triethylamine
  • p-Toluenesulfonyl chloride (3.8 g, 20 mmol) was added in one portion to a 0° C solution of the product from lb (3.6 g, 10 mmol) in pyridine (15 mL) . Upon complete addition the reaction mixture was allowed to warm to room temperature as it stirred overnight.
  • reaction mixture was diluted with EtOAc (500 mL) , washed with cold aqueous NaHS0 4 (3X) then brine, dried over MgS0 4 , concentrated in vacuo and purified by Si0 2 chromatography (HPLC: 10 % EtOAc/hexanes to 50 % EtOAc/hexanes) to yield 4.71 g (9.2 mmol, 92 %) of a white foam.
  • reaction mixture was chilled to 0 °C and a solution of ( IS* , 2S* , 4S* , 5R* , 6R* ) diethyl 2- (N- -butyloxycarbonylamino) -4 -hydroxy- bicyclo [3.1.0] hexane-2, 6-dicarboxylic acid (0.36 g, 1.0 mmol) in a 1:1 mixture of CH 2 Cl 2 /pyridine (20 mL total volume) was added dropwise to the reaction mixture. Upon complete addition the reaction mixture was allowed to warm to room temperature as it stirred overnight.
  • reaction mixture was diluted with Et 2 0 (500 mL) , washed with cold aqueous NaHS0 4 (3X) then brine, dried over MgS0 4 , concentrated in vacuo and purified by Si0 2 chromatography (PC-TLC: 10 % EtOAc/hexanes to 50 % EtOAc/hexanes) to yield 0.41 g (0.98 mmol, 97 %) of a white foam.
  • PC-TLC 10 % EtOAc/hexanes to 50 % EtOAc/hexanes
  • the product was eluted from the column with 3N AcOH and concentrated to dryness in vacuo to afford crude product.
  • the product was eluted from the column with 3N AcOH and concentrated to dryness in vacuo to afford crude product .
  • the product was eluted from the column with 3N AcOH and concentrated to dryness in vacuo to afford crude product .
  • the resulting solids were reconstituted in a 1:1 mixture of IN NaOH:THF (15 mL total volume) and stirred at room temperature overnight.
  • the product was eluted from the column with 3N AcOH and concentrated to dryness in vacuo to afford crude product .
  • Trituration in 2-propanol :water (5:1) followed by drying under vacuum at 80 °C afforded 0.04 g (0.11 mmol, 19 %) of the desired product as a white solid.
  • the product was eluted from the column with 3N AcOH and concentrated to dryness in vacuo to afford crude product.
  • the product was eluted from the column with 3N AcOH and concentrated to dryness in vacuo to afford crude product.
  • the resulting solids were reconstituted in a 1:1 mixture of IN NaOH:THF (15 mL total volume) and stirred at room temperature overnight.
  • the product was eluted from the column with 3N AcOH and concentrated to dryness in vacuo to afford crude product .
  • Trituration in 2-propanol :water (5:1) followed by drying under vacuum at 80 °C afforded 0.10 g (0.30 mmol, 59 %) of the desired product as a white solid.
  • the resulting solids were reconstituted in a 1:1 mixture of IN NaOH:THF (15 mL total volume) and stirred at room temperature overnight.
  • the product was eluted from the column with 3N AcOH and concentrated to dryness in vacuo to afford crude product .
  • Trituration in 2-propanol :water (5:1) followed by drying under vacuum at 80 °C afforded 0.17 g (0.50 mmol, 83 %) of the desired product as a white solid.
  • the resulting solids were reconstituted in a 1:1 mixture of IN NaOH:THF (15 mL total volume) and stirred at room temperature overnight.
  • the product was eluted from the column with 3N AcOH and concentrated to dryness in vacuo to afford crude product .
  • Trituration in 2-propanol :water (5:1) followed by drying under vacuum at 80 °C afforded 0.17 g (0.50 mmol, 83 %) of the desired product as a white solid.
  • the resulting solids were reconstituted in a 1:1 mixture of IN NaOH:THF (15 mL total volume) and stirred at room temperature overnight.
  • the product was eluted from the column with 3N AcOH and concentrated to dryness in vacuo to afford crude product .
  • Trituration in 2-propanol/H0 (9:1) followed by drying under vacuum at 80 °C afforded 0.12 g (0.32 mmol, 45 %) of the desired product as a white solid.
  • step (a) the product of Preparation 1 (0.34 g, 0.95 mmol) and phenyl isocyanate (0.12g, 1.0 mmol) were reacted to afford (IS*, 2S*, 4S*, 5R*, 6S*) -2-tert-butoxycarbonylamino-4- (3 -phenyl-ureido) - bicyclo [3.1.0] hexane-2, 6-dicarboxylic acid diethyl ester in 88.2% yield.
  • step (b) the intermediate urea (0.4 g, 0.84 mmol) was converted to the title compound and isolated as a solid in a 69% yield (0.186 g, 0.58 mmol) by cation exchange chromatography (Dowex 50X8-100: 10% Pyridine/H0) .
  • step (a) the product of Preparation 1 (0.25 g, 0.7 mmol) and methyl isocyanate (0.044 g, 0.77 mmol) were reacted to afford (IS*, 2S*, 4S*, 5R*, 6S*) -2-tert-butoxycarbonylamino-4- (3 -methyl -ureido) - bicyclo [3.1.0] hexane-2 , 6-dicarboxylic acid diethyl ester in 73.7% yield.
  • step (b) the intermediate urea (0.2 g, 0.45 mmol) was converted to the title compound and isolated as a solid in a 95% yield (0.11 g, 0.43 mmol) by cation exchange chromatography (Dowex 50X8-100: 10% Pyridine/H 2 0) .
  • 3-Thiophenecarboxylic acid was dissolved in 3 ml of anhydrous DMF and cooled to ODC under a nitrogen atmosphere .
  • 1, 3-Dicyclohexylcarbodiimide (0.133 g, 1.05 mmol) and hydroxybenztriazole (0.19 g, 1.4 mmol) were added sequentially to the acid.
  • the reaction was allowed to warm to ambient temperature for 15 minutes, then cooled to ODC again.
  • the product of Preparation 1 (0.25 g, 0.7 mmol) in 2 ml of anhydrous DMF was added to the cooled reaction mixture above and allowed to stir over night. Partitioned the reaction between EtOAc and H 2 0, washed with brine and the organics dried over MgS0 4 .
  • the isolated crude material was triturated with EtOAc and the solids were filtered.
  • the product was purified using PT-TLC (10% EtOAc/hexanes to 50% EtOAc/hexanes) to give 100% yield (0.33 g, 0.7 mmol).
  • step (a) the product of Preparation 1 (0.2 g, 0.56 mmol) and acetyl chloride (0.053 g, 0.67 mmol) were reacted to afford (IS*, 2S*, 4S*, 5R* , 6S*) -4-acetylamino-2-tert-butoxycarbonylamino- bicyclo [3.1.0] hexane-2 , 6-dicarboxylic acid diethyl ester in 99% yield.
  • step (b) the intermediate amide (0.19 g, 0.48 mmol) was converted to the title compound in a 61.9% yield (0.072 g, 0.3 mmol) .
  • step (a) the product of Preparation 1 (0.32 g, 0.8 mmol) and benzoyl chloride (0.15 g, 1.0 mmol) were reacted to afford (IS*, 2S*, 4S*, 5R*, 6S*) -4 -benzoylamino-2-tert-butoxycarbonylamino- bicyclo [3.1.0] hexane-2, 6-dicarboxylic acid diethyl ester in 99% yield.
  • step (b) the intermediate amide (0.39 g, 0.85 mmol) was converted to the title compound in a 46.6% yield (0.12 g, 0.39 mmol) .
  • step (a) the product of Preparation 1 (0.34 g, 0.95 mmol) and 4-chlorobenzoyl chloride (0.2 g, 1.15 mmol) were reacted to afford (IS*, 2S*, 4S*, 5R*, 6S*) -2-tert-butoxycarbonylamino-4- (4-chloro- benzoylamino) -bicyclo [3.1.0] hexane-2 , 6-dicarboxylic acid diethyl ester in 86.9% yield.
  • step (a) the product of Preparation 1 (0.33 g, 0.93 mmol) and 3-chlorobenzoyl chloride (0.19 g, 1.11 mmol) were reacted to afford (IS*, 2S*, 4S*, 5R*, 6S*) -2-tert-butoxycarbonylamino-4- (3-chloro- benzoylamino) -bicyclo [3.1.0] hexane-2 , 6-dicarboxylic acid diethyl ester in 99% yield.
  • step (a) the product of Preparation 1 (0.3 g, 0.84 mmol) and 3-methoxybenzoyl chloride (0.17 g, 1.01 mmol) were reacted to afford (IS*, 2S*, 4S*, 5R*, 6S*) -2-tert-butoxycarbonylamino-4- (4-methoxy- benzoylamino) -bicyclo [3.1.0] hexane-2 , 6-dicarboxylic acid diethyl ester in 77.7% yield.
  • step (b) the intermediate amide (0.3 g, 0.61 mmol) was converted to the title compound in a 64.6% yield (0.132 g, 0.4 mmol).
  • step (a) the product of Preparation 1 (0.33 g, 0.93 mmol) and 1-naphthoy chloride (0.212 g, 1.1 mmol) were reacted to afford (IS*, 2S*, 4S*, 5R* , 6S*) -2-tert-butoxycarbonylamino-4- [ (naphthalene-1- carbonyl) -amino] -bicyclo [3.1.0] hexane-2 , 6-dicarboxylic acid diethyl ester in 99% yield.
  • step (b) the intermediate amide (0.39 g, 0.76 mmol) was converted to the title compound in a 51.7% yield (0.14 g, 0.4 mmol) .
  • step (a) the product of Preparation 1 (0.33 g, 0.93 mmol) and 2-naphthoy chloride
  • step (b) the intermediate amide (0.43 g, 0.84 mmol) was converted to the title compound and isolated as a white solid in an 88.7% yield
  • step (a) the product of Preparation 1 (0.15 g, 0.42 mmol) and 4-fluorobenzoyl chloride (0.08 g, 0.5 mmol) were reacted to afford (IS*, 2S*, 4S*, 5R*, 6S*) -2-tert-butoxycarbonylamino-4- (4-fluoro- benzoylamino) -bicyclo [3.1.0] hexane-2 , 6-dicarboxylic acid diethyl ester in 89.4% yield.
  • step (a) the product of Preparation 1 (0.15 g, 0.42 mmol) and 2-thiophenecarbonyl chloride (0.074 g, 0.51 mmol) were reacted to afford (IS*, 2S*, 4S*, 5R*, 6S*) -2-tert-butoxycarbonylamino-4- [ (thiophene-2 -carbonyl) -amino] -bicyclo [3.1.0] hexane-2 , 6- dicarboxylic acid diethyl ester in 79% yield.
  • step (b) the intermediate amide (0.14 g, 0.3 mmol) was converted to the title compound in a 49.4% yield (0.046 g, 0.16 mmol) .
  • step (a) the product of Preparation 1 (0.16 g, 0.45 mmol) and 2-methoxybenzoyl chloride (0.092 g, 0.54 mmol) were reacted to afford (IS*, 2S*, 4S*, 5R*, 6S*) -2-tert-butoxycarbonylamino-4- (2-methoxy- benzoylamino) -bicyclo [3.1.0] hexane-2 , 6-dicarboxylic acid diethyl ester in 86.1% yield.
  • step (b) the intermediate amide (0.15 g, 0.31 mmol) was converted to the title compound in a 40.9% yield (0.045 g, 0.14 mmol).
  • step (a) the product of Preparation 1 (0.16 g, 0.45 mmol) and 3-methoxybenzoyl chloride (0.092 g, 0.54 mmol) were reacted to afford (IS*, 2S*, 4S*, 5R*, 6S*) -2-tert-butoxycarbonylamino-4- (3-methoxy- benzoylamino) -bicyclo [3.1.0] hexane-2 , 6-dicarboxylic acid diethyl ester in 95.1% yield.
  • step (b) the intermediate amide (0.19 g, 0.39 mmol) was converted to the title compound in a 54.1% yield (0.070 g, 0.21 mmol).
  • step (a) the product of Preparation 1 (0.2 g, 0.56 mmol) and m-toluoyl chloride (0.104 g, 0.67 mmol) were reacted to afford (IS*, 2S*, 4S*, 5R*, 6S*) -2-tert-butoxycarbonylamino-4- (3 -methyl - benzoylamino) -bicyclo [3.1.0] hexane-2 , 6-dicarboxylic acid diethyl ester in 86.5% yield.
  • step (b) the intermediate amide (0.2 g, 0.42 mmol) was converted to the title compound in a 44.9% yield (0.060 g, 0.19 mmol).
  • step (a) the product of Preparation 1 (0.25 g, 0.7 mmol) and 3-
  • step (a) the product of Preparation 1 (0.23 g, 0.65 mmol) and 3-fluorobenzoyl chloride (0.1 g, 0.77 mmol) were reacted to afford (IS*, 2S*, 4S*, 5R*, 6S*) -2-tert-butoxycarbonylamino-4- (3-fluoro- benzoylamino) -bicyclo [3.1.0] hexane-2 , 6-dicarboxylic acid diethyl ester 80% yield.
  • step (a) the product of Preparation 1 (0.26 g, 0.73 mmol) and 3 , 4-dichlorobenzoyl chloride (0.183 g, 0.88 mmol) were reacted to afford (IS*, 2S*, 4S*, 5R*, 6S*) -2-tert-butoxycarbonylamino-4- (3,4- dichloro-benzoylamino) -bicyclo [3.1.0] hexane-2, 6-dicarboxylic acid diethyl ester in 95.7% yield.
  • step (a) the product of Preparation 1 (0.22 g, 0.62 mmol) and 3 , 5-dichlorobenzoyl chloride (0.155 g, 0.74 mmol) were reacted to afford (IS*, 2S*, 4S*, 5R*, 6S*) -2-tert-Butoxycarbonylamino-4- (3, 5- dichloro-benzoylamino) -bicyclo [3.1.0] hexane-2 , 6-dicarboxylic acid diethyl ester in 91% yield.
  • step (a) the product of Preparation 1 (0.24 g, 0.67 mmol) and 2 , 4-dichlorobenzoyl chloride (0.169 g, 0.81 mmol) were reacted to afford (IS*, 2S*, 4S*, 5R*, 6S*) -2-tert-butoxycarbonylamino-4- (2,4- dichloro-benzoylamino) -bicyclo [3.1.0] hexane-2 , 6-dicarboxylic acid diethyl ester in 87% yield.
  • step (a) the product of Preparation 1 (0.23 g, 0.65 mmol) and 2 , 3-dichlorobenzoyl chloride (0.162 g, 0.77 mmol) were reacted to afford (IS*, 2S*, 4S*, 5R*, 6S*) -2-tert-Butoxycarbonylamino-4- (2, 3- dichloro-benzoylamino) -bicyclo [3.1.0] hexane-2 , 6-dicarboxylic acid diethyl ester in 81% yield.
  • step (a) the product of Preparation 1 (0.245 g, 0.69 mmol) and 2-fluorobenzoyl chloride (0.131 g, 0.83 mmol) were reacted to afford (IS*, 2S*, 4S*, 5R*, 6S*) -2-tert-butoxycarbonylamino-4- (2-fluoro- benzoylamino) -bicyclo [3.1.0] hexane-2 , 6-dicarboxylic acid diethyl ester in 78% yield.
  • step (a) the product of Preparation 1 (0.25 g, 0.7 mmol) and 2-indolecarboxylic acid (0.123 g, 0.77 mmol) were reacted to afford (IS*, 2S*, 4S*, 5R*, 6S*) -2-tert-butoxycarbonylamino-4- [ (lH-indole-2- carbonyl) -amino] -bicyclo [3.1.0] hexane-2 , 6-dicarboxylic acid diethyl ester in 91.5% yield.
  • step (b) the intermediate amide (0.3 g, 0.6 mmol) was converted to the title compound in a 68.9% yield (0.137 g, 0.39 mmol).
  • step (a) the product of Preparation 1 (0.25 g, 0.7 mmol) and 4-hydroxybenzoic acid (0.106 g, 0.77 mmol) were reacted to afford (IS*, 2S*, 4S*, 5R* , 6S*) -2-tert-butoxycarbonylamino-4- (4-hydroxy- benzoylamino) -bicyclo [3.1.0] hexane-2, 6-dicarboxylic acid diethyl ester in 93% yield.
  • step (b) the intermediate amide (0.27 g, 0.56 mmol) was converted to the title compound in a 72.5% yield (0.131 g, 0.41 mmol) .
  • step (a) the product of Preparation 1 (0.25 g, 0.7 mmol) and 3-hydroxybenzoic acid (0.106 g, 0.77 mmol) were reacted to afford (IS*, 2S*, 4S*, 5R*, 6S*) -2-tert-butoxycarbonylamino-4- (3-hydroxy- benzoylamino) -bicyclo [3.1.0] hexane-2, 6-dicarboxylic acid diethyl ester in 93% yield.
  • step (b) the intermediate amide (0.31 g, 0.65 mmol) was converted to the title compound in a 62.9% yield (0.131 g, 0.41 mmol).
  • step (a) the product of Preparation 1 (0.25 g, 0.7 mmol) and 2-hydroxybenzoic acid (0.106 g, 0.77 mmol) were reacted to afford (IS*, 2S*, 4S*, 5R*, 6S*) -2-tert-butoxycarbonylamino-4- (2 -hydroxy- benzoylamino) -bicyclo [3.1.0] hexane-2, 6-dicarboxylic acid diethyl ester in 76% yield.
  • step (b) the intermediate amide (0.22 g, 0.46 mmol) was converted to the title compound in a 78.5% yield (0.116 g, 0.36 mmol).
  • step (a) the product of Preparation 1 (0.25 g, 0.7 mmol) and 4-biphenylcarboxylic acid (0.153 g, 0.77 mmol) were reacted to afford (IS*, 2S*, 4S*, 5R*, 6S*) -4- [ (biphenyl-4-carbonyl) -amino] -2-tert- butoxycarbonylamino-bicyclo [3.1.0] hexane-2 , 6-dicarboxylic acid diethyl ester in 98.5% yield.
  • step (b) the intermediate amide (0.36 g, 0.67 mmol) was converted to the title compound in a 76.5% yield (0.195 g, 0.51 mmol).
  • step (a) the product of Preparation 1 (0.25 g, 0.7 mmol) and indole-3 -carboxylic acid (0.124 g, 0.77 mmol) were reacted to afford (IS*, 2S*, 4S*, 5R*, 6S*) -2-tert-butoxycarbonylamino-4- [ (lH-indole-3- carbonyl) -amino] -bicyclo [3.1.0] hexane-2 , 6-dicarboxylic acid diethyl ester in 48.6% yield.
  • step (b) the intermediate amide (0.16 g, 0.32 mmol) was converted to the title compound in a 91.9% yield (0.101 g, 0.29 mmol).
  • step (a) the product of Preparation 1 (0.25 g, 0.7 mmol) and 1- isoquinalinecarboxylic acid (0.133 g, 0.77 mmol) were reacted to afford (IS*, 2S*, 4S*, 5R* , 6S*) -2-tert- butoxycarbonylamino-4- [ (isoquinoline-1-carbonyl) -amino] - bicyclo [3.1.0] hexane-2, 6-dicarboxylic acid diethyl ester 89.4% yield.
  • step (b) the intermediate amide (0.3 g, 0.59 mmol) was converted to the title compound and isolated as a solid in 56.8% yield (0.119 g, 0.34 mmol) by cation exchange chromatography (Dowex 50X8-100: 10% Pyridine/H 2 0) .
  • the title compound was prepared by the two step procedure in Example 1.
  • the product of Preparation 1 (0.30g, 0.84 mmol) was reacted with picolinoyl chloride hydrochloride (O.l ⁇ g, 1.02 mmol) in step (a).
  • Purification of the desired intermediate was by PC-TLC (13% EtOAc/Hexane to 100% EtOAc) with a 90% yield.
  • the title compound was prepared by the two step procedure in Example 1.
  • the product of Preparation 1 (0.30g, 0.84 mmol) was reacted with nicotinoyl chloride hydrochloride (0.18g, 1.01 mmol) in step (a) .
  • Purification of the desired intermediate was by PC-TLC (10% EtOAc/Hexane to 100% EtOAc) with a 90% yield.
  • the title compound was prepared by the two step procedure in Example 1.
  • the product of Preparation 1 (0.30g, 0.84 mmol) was reacted with isonicotinoyl chloride hydrochloride (0.18g, 1.01 mmol) in step (a).
  • Purification of the desired intermediate was by PC-TLC (25% EtOAc/Hexane to 100% EtOAc) with a 80% yield.
  • the title compound was prepared by the two step procedure in Example 1.
  • the product of Preparation 1 (0.30g, 0.84 mmol) was reacted with 2- (trifluoro-methyl) benzoyl chloride (0.21g, 1.01 mmol) in step (a).
  • Purification of the desired intermediate was by PC-TLC (10% EtOAc/Hexane to 50% EtOAc/Hexane) with a 99% yield (0.44g, 0.83 mmol).
  • the title compound was prepared by the two step procedure in Example 1.
  • the product of Preparation 1 (0.30g, 0.84 mmol) was reacted with 3, 5-difluorobenzoyl chloride (0.18g, 1.01 mmol) in step (a) .
  • Purification of the desired intermediate was by PC-TLC (10% EtOAc/Hexane to 50% EtOAc/Hexane) with a 67% yield.
  • the title compound was prepared by the two step procedure in Example 1.
  • the product of Preparation 1 (0.30g, 0.84 mmol) was reacted with o-toluoyl chloride. (0.16g, 1.01 mmol) in step (a) .
  • Purification of the desired intermediate was by PC-TLC (10% EtOAc/Hexane to 50% EtOAc/Hexane) with a 90% yield (0.36g, 0.76 mmol).
  • the title compound was prepared by the two step procedure in Example 1.
  • the product of Preparation 1 (0.30g, 0.84 mmol) was reacted with p-toluoyl chloride (0.16g, 1.01 mmol) in step (a).
  • Purification of the desired intermediate was by PC-TLC (10% EtOAc/Hexane to 30% EtOAc/Hexane) with a 95% yield (0.38g, 0.80 mmol).
  • the title compound was prepared by the two step procedure in Example 1.
  • the product of Preparation 1 (0.25g, 0.70 mmol) was reacted with 2-quinoxaloyl chloride (0.16g, 0.84 mmol) in step (a) .
  • Purification of the desired intermediate was by PC-TLC (25% EtOAc/Hexane to 100% EtOAc/Hexane) with a 84% yield (0.30g, 0.59 mmol).
  • the title compound was prepared by the two step procedure in Example 2.
  • the product of Preparation 1 (0.30g, 0.84 mmol) was reacted with monomethyl isophthalate (0.17g, 0.93 mmol) in step (a) .
  • Purification of the desired intermediate was by PC-TLC (10% EtOAc/Hexane to 30% EtOAc/Hexane) with a 78% yield (0.34g, 0.66 mmol).
  • the title compound was prepared by the two step procedure in Example 2.
  • the product of Preparation 1 (0.25g, 0.70 mmol) was reacted with monomethyl phthalate (0.14g, 0.77 mmol) in step (a).
  • 1- [3- (Dimethylamino) propyl] -3-ethylcarboiimide hydrochloride was used (0.20g, 1.05 mmol) in the place of 1, 3-Dicyclohexylcarbodiimide .
  • the title compound was prepared by the two step procedure in Example 2.
  • the product of Preparation 1 (0.25g, 0.70 mmol) was reacted with monomethyl terephthalate (0.14g, 0.77 mmol) in step (a).
  • 1- [3- (Dimethylamino) propyl] -3-ethylcarboiimide hydrochloride was used (0.20g, 1.05 mmol) in the place of 1, 3-Dicyclohexylcarbodiimide .
  • the title compound was prepared by the two step procedure in Example 2.
  • the product of Preparation 1 (0.25g, 0.70 mmol) was reacted with imidazol-4-carboxylic acid (0.0.9g, 0.77 mmol) in step (a).
  • 1- [3- (Dimethylamino) propyl] -3- ethylcarboiimide hydrochloride was used (0.20g, 1.05 mmol) in the place of 1 , 3-Dicyclohexylcarbodiimide .
  • the organics were dried over anhydrous K 2 C0 3 .
  • the title compound was prepared by the two step procedure in Example 2.
  • the product of Preparation 1 (0.30g, 0.84 mmol) was reacted with trans-cinnamic acid (0.14g, 0.93 mmol) in step (a).
  • 1- [3- (Dimethylamino) propyl] -3 -ethylcarboiimide hydrochloride was used (0.24g, 1.26 mmol) in the place of 1, 3-Dicyclohexylcarbodiimide .
  • the title compound was prepared by the two step procedure in Example 2.
  • the product of Preparation 1 (0.25g, 0.70 mmol) was reacted with phenylpropiolic acid (O.llg, 0.77 mmol) in step (a).
  • 1- [3- (Dimethylamino) propyl] -3-ethylcarboiimide hydrochloride was used (0.20g, 1.05 mmol) in the place of 1, 3-Dicyclohexylcarbodiimide .
  • the title compound was isolated by isoelectric point crystalization from H 2 0, pH 3 , in a 57% yield (0.14g, 0.41 mmol) (A small amount of IPA was used to transfer the crystalsfrom the flask to drying funnel . ) .
  • Example Bick The title compound was prepared by the two step procedure in Example Bick. (IS*, 2S*,4S*, 5R* , 6R*)-2-tert- Butoxycarbonylamino-4 -hydroxy-bicyclo [3.1.0] hexane-2, 6- dicarboxylic acid diethyl ester (0.30g, 0.84 mmol) was reacted with 3-fluorophenyl isocyanate (0.19g, 1.35 mmol) in step (a) . Purification of the desired intermediate was by PC-TLC (10% EtOAc/Hexane to 25% EtOAc/Hexane) with a 65% yield (0.27g, 0.55 mmol).
  • Example Bick The title compound was prepared by the two step procedure in Example Bick. (IS*, 2S*,4S*, 5R* , 6R*)-2-tert- Butoxycarbonylamino-4-hydroxy-bicyclo [3.1.0] hexane-2 , 6- dicarboxylic acid diethyl ester (0.30g, 0.84 mmol) was reacted with 4-fluorophenyl isocyanate (0.18g, 1.11 mmol) in step (a) . Purification of the desired intermediate was by PC-TLC (10% EtOAc/Hexane to 25% EtOAc/Hexane) with a 43% yield (0.28g, 0.57 mmol).
  • Example Bick The title compound was prepared by the two step procedure in Example Bick. (IS*, 2S*,4S*, 5R* , 6R*)-2-tert- Butoxycarbonylamino-4-hydroxy-bicyclo [3.1.0] hexane-2 , 6- dicarboxylic acid diethyl ester (0.30g, 0.84 mmol) was reacted with meta-chlorophenyl isocyanate (0.16g, 1.01 mmol) in step (a) . Purification of the desired intermediate was by PC-TLC (10% EtOAc/Hexane to 25% EtOAc/Hexane) with a 85% yield (0.37g, 0.72 mmol).
  • Example Bick The title compound was prepared by the two step procedure in Example Bick. (IS*, 2S*,4S*, 5R* , 6R*)-2-tert- Butoxycarbonylamino-4-hydroxy-bicyclo [3.1.0] hexane-2 , 6- dicarboxylic acid diethyl ester (0.30g, 0.84 mmol) was reacted with p-chlorophenyl isocyanate (0.16g, 1.01 mmol) in step (a) . Purification of the desired intermediate was by PC-TLC (10% EtOAc/Hexane to 25% EtOAc/Hexane) with a 74% yield (0.32g, 0.62 mmol).
  • Example Bick The title compound was prepared by the two step procedure in Example Bick. (IS*, 2S*,4S*, 5R* , 6R*) -2- ert- Butoxycarbonylamino-4-hydroxy-bicyclo [3.1.0] hexane-2 , 6- dicarboxylic acid diethyl ester (0.30g, 0.84 mmol) was reacted with 1-naphthyl isocyanate (0.21g, 1.26 mmol) in step (a) . Purification of the desired intermediate was by PC-TLC (10% EtOAc/Hexane to 25% EtOAc/Hexane) with a 61% yield.
  • step (b) using LiOH for the ester hydrolysis, (IS*, 2S*,4S*, 5R*, 6R*) -2- tert-Butoxycarbonylamino-4- (naphthalen-1-ylcarbamoyloxy) -bicyclo [3.1.0] hexane-2 , 6- dicarboxylic acid diethyl ester (0.31g, 0.59 mmol) was converted to the Boc-protected di-acid. Purification of the desired intermediate was by PC-TLC (0-2 % AcOH in 50% EtOAc/Hexane) for a 61% yield (0.17g, 0.36 mmol). The Boc group was cleaved, giving the title compound in a 63% yield (O.O ⁇ g, 0.23 mmol) .
  • Example Bick The title compound was prepared by the two step procedure in Example Bick. (IS*, 2S*,4S*, 5R* , 6R*)-2-tert- Butoxycarbonylamino-4-hydroxy-bicyclo [3.1.0] hexane-2 , 6- dicarboxylic acid diethyl ester (0.25g, 0.70 mmol) was reacted with 2-naphthyl isocyanate (0.26g, 1.51 mmol) in step (a) . Purification of the desired intermediate was by PC-TLC (10% EtOAc/Hexane to 25% EtOAc/Hexane) with a 68% yield (0.25g, 0.47 mmol).
  • step (b) using LiOH for the ester hydrolysis, (IS*, 2S*,4S*, 5R* , 6R*)-2-tert- Butoxycarbonylamino-4- (naphthalen-2-ylcarbamoyloxy) - bicyclo [3.1.0] hexane-2, 6-dicarboxylic acid diethyl ester (0.28g, 0.53 mmol) was converted to the Boc-protected diacid followed by cleavage of the Boc group. The title compound was isolated using isoelectric point crystalization from H 2 0, pH 3 , in a 20% yield (0.04g, 0.11 mmol) .

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WO2005000790A1 (ja) * 2003-06-26 2005-01-06 Taisho Pharmaceutical Co., Ltd. ２－アミノビシクロ[３．１．０]ヘキサン－２，６－ジカルボン酸誘導体
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