CA2328984A1 - Cubane derivatives as metabotropic glutamate receptor antagonists and process for their preparation - Google Patents

Abstract

The present invention relates to therapeutically active cubane compounds, a method of preparing the same, and to pharmaceutical compositions comprising the compounds. The novel compounds are useful in treating diseases of the central nervous system related to the metabotropic glutamate receptor system.

Description

28-07-1999 PCT~CA99/00311 P~~ ~ ~~ y ~ lISA-DESC2S~.'._;' ;JU~.I~ 1999 ~ 0 9 ~ 0 ? y~
CUBANS ANALOGS WTTH ACTIVITY AT THE
METABOTROPIC GLUTAMATE RECEPTORS
FIELD OF THE INVENTION
This invention pertains to therapeutically active cubane derivatives, a method for preparing the same, pharmaceutical compositions comprising the compounds and a method of treating diseases of the Central Nervous System (CNS) therewith.
BACKGROUND OF THE INVENTION
The acidic amino acid L-Glutamate is recognized as the major excitatory neurotransmitter in the CNS. The receptors that respond to L-Glutamate are called excitatory amino acid receptors. The excitatory amino acid receptors are thus 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, respiratory and cardiovascular regulation, and sensory perception.
Excitatory amino acid receptors are classified into two general types and both are activated by L-Glutamic acid and its analogs. Receptors activated by L-Glutamic acid 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 (I~1MDA), oc-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 Pharmacological Science, 14:13, 1993). Both types of receptors appear not only to mediate normal synaptic transmission along excitatory pathways but also to participate in the modification of synaptic connections during development and throughout life.
So far eight different clones of the G-proxein-coupled metabotropic. glutamate receptors . (mGluRs) have been identified (Knopfel et al., 1995, J. Meci' Chem., 38,~-1417-1426). These receptors function to modulate the presynaptic release of L-Glutamate, and the postsynaptic Printed:'t 2- ",-~""~ ~r 28=07-1999 ~ PCT/CA99/00311 ~'~~ ~ ~~ 7 ~ ISA=DESC26 ~~
_ 0 0 ,~~C~ 1999 ~0 9 ~ 0 ~ . ~9~
sensitivity of the neuronal cell to L-Glutamate excitation. Based on pharmacology, sequence homology and the signal transduction pathway that they activate, the mGluRs have been subclassified into three groups. The mGluR1 and mGluRS receptors form group I.
They are coupled to hydrolysis of phosphatidylinositol (PI) and are selectively activated by (R,S~-3,5-dihydroxyphenylglycine (Brabet et al., Neuropharmacology, 34, 895-903, 1995).
Group II
comprises mGluR2 and mGluR; receptors. They are negatively coupled to adenylate cyclase and are selectively activated by (2S,1'R,2'R,3'R)-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV;
Hayashi et al., Nature, 366, 687-690, 1993). Finally, the mGluR~, mGluRs, mGluR, and mGluR$
receptors belong to group III. They are also negatively coupled to adenylate cyclase and are selectively activated by (L)-2-amino-4-phosphonobutyric acid (L-AP4; Knopfel et al., 1995, J.
Med Chem., 38, 1417-1426).
Agonists and antagonists of these receptors are believed useful for the treatment of acute and chronic neurodegenerative conditions, and as antipsychotic, anticonvulsant, analgesic, anxiolytic, antidepressant, and anti-emetic agents. Antagonists and agonists of neural receptors are classified as selective for a particular receptor or receptor subtype, or as non-selective. Antagonists may also be classified as competitive or non-competitive. While competitive and non-competitive antagonists act on the receptors in a different manner to produce similar results, selectivity is based upon the observations that some antagonists exhibit high levels of activity at a single receptor type, and little or no activity at other receptors. In the case of receptor-specific diseases and conditions, the selective agonists and antagonists are of the most value.
Compounds such as L-Glutamic acid, Quisqualic acid and Ibotenic acid are known to act as non-selective agonists on the mGluRs, while selective ionotropic glutamate receptor agonists such as NMDA, AMPA and Kainic acid have little effect on these receptors. Recently a few compounds without activity at the ionotropic glutamate receptors but with activity at the metabotropic receptors have been identified. These include traps-ACPD (traps (1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid), the partial agonist L-AP3 (L-2-amino-phosphonopropionic acid, Palmer, E., Monaghan, D. T. and Cotman, C. W. Eur.
.I. Pharmacol..
166, 585-587, 1989; Desai, M. A and Conn, P. J. Neuroscience Lett. 109, 157-162, 1990, Schoepp, D. D. et al., J. Neurochemistry. 56, 1789-1796, 1991; Schoepp D. D.
and Johnson B.
ii ,%. IVeurochejoi.sn~: ~3, 186-1613, 1989), 1.-.~P4 (L-2-anuno-4-phospilonobutyric acid) which is an agonist at the mGluR4 receptor (Thomsen C. et al., Errr. .l. Phar-nracol. 227, 361-362, 199?l and some of the isomers of CCG (?-(carbo~~~cvclopropyf jliycin°sl especially L-CCG-I and r_-CCG-Il (Hayashi, Y. et al., Br. .l. Pharmacol. 107, 539-543, 1992) ..s~_ :. ~. . .
Printed:l2.cA o2s2sss4 2ooo-io-is ~ ~~ y:; _ ~: _ ~~ _; 'J ';, i; F; r :-:~ , 28-07-1999 PCT/CA991003~ 1 ~~~- ~ ~~ 'o g ISA-DESC26 ~' 9 ~JU~Y 1999 ~~ g - D '~ .. ~~
Very few selective antagonists at the mGluRs have been reported. However some phenylglycine derivatives, S-4CPG (S-4-carboxyphenylglycine), S-4C3HPG (S-4-carboxy -3-hydroxyphenylglycine) and S-MCPG (S-a-methyl-4-carboxyphenylglycine) have been reported to antagonize bans-ACPD- stimulated phosphoinositide hydrolysis and thus possibly act as antagonists at mGluR~ and mGluRs subtypes (Thomsen, C. and Suzdak, P, Eur. J.
Pharmacol. ' 245, 299, 1993).
Research directed towards mGluRs is beginning to show that mGluRs may be implicated in a number of normal as well as pathological mechanisms in the brain and spinal cord. For example, activation of these receptors on neurons can: influence levels of alertness, attention and cognition; protect nerve cells from excitotoxic damage resulting from ischemia, hypoglycemia and anoxia; modulate the level of neuronal excitation; influence central mechanisms involved in controlling movement; reduce sensitivity to pain; reduce levels of anxiety.
The use of compounds active at the mGluRs for the treatment of epilepsy is corroborated by investigations of the influence of traps-ACPD on the formation of convulsions (Sacaan and Schoepp, Neurascierrce Lett. 139, 77, 1992) and that phosphoinositide hydrolysis mediated via mGluR is increased after kindling experiments in rats (Akiyama et al. Brain Res. 569, 71, 1992).
Traps-ACPD has been shown to increase release of dopamine in the rat brain, which indicates that compounds acting on the mGluRs might be usable for the treatment of Parkinson's disease and Huntington's Chorea (Sacaan et al , J. Neurochemistfy 59, 245, 1992).
Traps-ACPD has also been shown to be a neuroprotective agent in a medial cerebral artery occlusion {MCAO) model in mice (Chiamulera et al. Ern-. J. Plurrmacvl. 215, 353, 1992), and it has been shown to inhibit NMDA-induced neurotoxicity in nerve cell cultures (Koh et al., Proc. Natl Acad. Sci. LISA 88, 943 l, 199I). The mGluR-active compounds are also implicated in the treatment of pain. This is proved by the fact that antagonists at the metabotropic glutamate receptors antagonize sensory synaptic response to noxious stimuli of thalamic neurons (Eaton, S. A. et al , Ear. J. Nenro.s~cience, 5, 186, 1993).
The use of compounds active at the mGluRs for treatment of neurological diseases such as senile dem°nna gave aiso peen indicated dy tile nndings of Zi~en~ and Galiaji~er (IVeIII'O77 9, 103, 1992) and Bashir et al. (Nature 363, 347, 1993) who demonstrated that activation of rnGluRs is . necessart- for the induction of lop;-term potentiation (LTP) in nen~e cells (septal nucleus, hippocampusj and the finding that long-term depression is induced after activation of metabotropic glutamate receptors in cerebellar granule cells (Linden et al.
Nelll'UTl 7, 81, 1991 ).

Printed:l 2~ X2328984 2000-10-16 ~ ~ ~j ~4~ :.~~' '~~ ; 'tj- ar; '~' ;"~ e',,;
: -_. a,:~ -, .:~~ ~,~ ~ ~:. ::.s a 28-07-1999 PCT/CA99/00311 ~''' ~ W'~ ' IS~4-DESC26.'~ ~t Thus compounds that demonstrate either activating or inhibiting activity at mGIuRs have therapeutic potential for the treatment of neurological disorders. These compounds have application as new drugs to treat both acute and chronic neurological disorders, such as stroke and head injuries; epilepsy; movement disorders associated with Parkinson's disease and Huntington's chorea; pain; anxiety; AIDS dementia; and Alzheimer's disease.
Since the mGluRs can influence levels of alertness, attention and cognition; protect nerve cells from excitotoxic damage resulting from ischemia, hypoglycemia and anoxia; modulate the level of neuronal excitation; influence central mechanisms involved in controlling movement;
reduce sensitivity to pain; and reduce levels of anxiety, these compounds can also be used to influence these situations and also find use in learning and memory deficiencies such as senile dementia.
mGluRs may also be involved in addictive behavior, alcoholism, drug addiction, sensitization and drug withdrawal (Science, 280:2045, 1998), so compounds acting at mGluRs might also be used to treat these disorders.
The current pharmaceutical options for treating neurological disorders tend to be very general and non-specific in their actions in that, although they may reduce the clinical symptoms associated with a specific neurological disorder, they may also negatively impact normal function of the central nervous system of patients. Thus new cellular targets and drugs that are more specific in their actions require to be identified and developed and thus a need remains for chemical compounds that demonstrate specific binding characteristics towards mGluRs.

r :.. S, ~~.,::r t i 1r ~ :02328984 2000-10-16 ~ ~ . , . . ~ ~' ~. ~' ~' ~'~.a s._: ~;,.,, -..
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~~ ~~~ .. . :. ,-:._ 28-07-199 ~PCT/CA99/00371 ~ ISA-DESC26 ' P~'~/tr~ 9~/UUSi a SUMMARY OF THE INVENTION o 9 JULY - 1999 ~0 9 y 0 7 ~ ~9 It is an object of this invention to provide novel compounds that demonstrate activity at the various metabotropic glutamate receptors (mGluRs). In particular, a compound of Formula I
and stereoisomers thereof (I) wherein:
Rl can be an acidic group selected from the group consisting of carboxyl, phosphono, phosphino, sulfono, sulfino, borono, tetrazol, isoxazol, -CHz-carboxyl, -CHZ-phosphono, -CH2-phosphino, -CHz-sulfono, -CHZ-sulfino, -CHz-borono, -CHZ-tetrazol, -CH2-isoxazol and higher homologues thereof R2 can be a basic group selected from the group consisting-of 1° amino, 2° amino, 3° amino, quaternary ammonium salts, aliphatic 1° amino, aliphatic 2°
amino, aliphatic 3° amino, aliphatic quaternary ammonium salts, aromatic 1° amino, aromatic 2° amino, aromatic 3° amino, aromatic quaternary ammonium salts, imidazol, guanidino, boronoamino, allyl, urea, thiourea, R3 can be H, aliphatic, aromatic or heterocyclic, R4 can be an acidic group selected from the group consisting of carboxyl,' phosphono, phosphino, sulfono, sulfino, borono, tetrazoi, isoxazol;
and pharmaceutically acceptable salts thereof.
DETAILED DESCRIPTION OF TI3E ~1VENTTON
The terms and abbreviations used in the instant examples have their normal meanings unless otherwise desi,nated For e:~ample "°C" refers to de;rees Celsius, "N"
refers to normal or normality; "mmol" refers to millimole or millimoles; "g" refers to gram or grams; "mL" means milliliter or milliliters; "M" refers to molar or molarity, "MS" refers to mass spectrometry, "1R"
Printed:l 2~ X2328984 2000-10-16 ~ ~ ~ (~ i'. . _ .lr i. 1':.., y.~:~;~~~ !y ~--. ~. : r,"~ ~~.' ~ s.c' ~ a ~-= is' ~, 28-07-~ 999 - PCTlCA99/003'11 f'~T I_ ~'oe~ '~ ~ ISA-DESC26' Q 9 JULY 1999 ~0 g - 0 ~ . 99 ) refers to infrared spectroscopy; and "IVMR" refers to nuclear magnetic resonance spectroscopy.
As would be understood by the skilled artisan throughout the synthesis of the compounds of Formula I, it may be necessary to employ an amino-protecting group or a carboxy-protecting group in order to reversibly preserve a reactively susceptible amino or carboxy functionality while reacting other functional groups on the compound.
Examples of such amino-protecting groups include fonmyl, trityl, phthalimido, trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl, and urethane-type blocking groups such as benzyioxycarbonyl, 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 4-methoxybenzyloxycarbonyI, 4- fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl, t-butoxycarbonyl, 2-(4-xenyl)-isopropoxycarbonyl, 1, I-diphenyleth-1-yloxycarbonyl, I, I-diphenylprop-1-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl, 2-(p-toluyl)-prop-2-yloxycarbonyl, cyclopentanyloxy-carbonyl, I-methyicyclopentanyloxycarbonyl, cyclohexanyloxycarbonyl, 1-methylcyclohexanyloxycarbonyl, 2-methylcyclohexanyioxycarbonyl, 2-(4-toluylsulfono)-ethoxycarbonyl, 2-(methylsulfono)ethoxycarbonyl, 2-(triphenylphosphino)-ethoxycarbonyl, fluorenylmethoxycarbonyl ("FMOC"), 2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl, 1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl, 5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-ethynyl-Z-propoxycarbonyl, cyclopropylmethoxycarbonyl, 4-(decycloxy)benzyloxycarbonyl, isobornyloxycarbonyl, 1-piperidyloxycarbonlyl and the like; benzoylmethylsulfono group, 2-nitrophenylsulfenyl, diphenylphosphine oxide and like amino-protecting groups. The species of amino-protecting group employed is not critical so long as the derivatized amino group is stable to the condition of subsequent reactions) on other positions of the intermediate molecule and can be selectively removed at the appropriate point without disrupting the remainder of the molecule including any other amino-protecting group(s). Preferred amino-protecting groups are t-butoaycarbonyl (t-Boc), allyloxycarbonyl and benzyloxycarbonyl (CbZ) Further examples of these groups are found in E. Haslam in Protective Groups in Organic Syf~thesi.s; McOmie, J. G.
W., Ed. 1973, at Chapter 2; and Greene, T.W. and Wuts, P. G. M., Protective Grasps in Organic Synthesis, Second eaition; Whey-interscience: 1991; Chapter 7.
Examples of such carboxyl-protecting groups include methyl, p-nitrobenzyl, p-methylbenzyl, p-methoavbenzvl, 3,4-dimethoxybenzyl_ ~,4-dimethoxybenzvl, 2.4,6-trimethoxybenzyl, 2,4,G-trimethylbenzyl, pentamethylbenzyl, 3,4-methylenedioxybenzyl, benzhydryl, 4,4'-dimethoxybenzhydryl, 2,2',4,4'-tetramethoxybenzhydryl, ~-butyl, ~-amyl, trityl, ' - r ~~: ..
.~ '; ~ w~. y_ ~ ~ .. . '.~ ;. . .w 0..a G~
Pr~nted:l2~ 02328984 2000-10-16 . . ._-28-Q7-1999 PCT/CA99/003'11 - ~ ~ ISA-DESC26~~
0 ~ JULY 199 C 0 9 - 0 7 - 99 . _ 4-methoxytrityl, 4,4'-dimethoxytrityl, 4,4',4"-trimethoxytrityl, 2-phenyiprop-2-yl, trimethylsilyl, t-butyldimethylsilyl, phenacyl, 2,2,2-trichloroethyl, (3-(di(n-butyl)methylsilyl)ethyl, p-toluenesulfonoethyl, 4-nitrobenrylsulfonoethyl, allyl, cinnamyl, I-(trimethylsilylmethyl)prop-1-en-3-yl and like moieties. Preferred carboxyl-protecting groups are allyl, benryl and t-butyl. Further examples of these groups are found in E.
Hasiam, supra, at Chapter 5; and T. W. Greene and P. G. M. Wuts, supra, at Chapter S.
The present invention provides a compound of the formula:
RI
(I) wherein:
R1 can be an acidic group selected from the group consisting of carboxyl, phosphono, phosphino, sulfono, sulfino, borono, tetrazol, isoxazol, -CH2-carboxyl, -CHZ-phosphono, -CHz-phosphino, -CHZ-sulfono, -CH2-sulfino, -CHZ-borono, -CHZ-tetrazol, -CHZ-isoxazol and higher analogues thereof R2 can be a basic group selected from the group consisting of I° amino, 2° amino, 3° amino, quaternary ammonium salts, aliphatic 1° amino, aliphatic 2°
amino, aliphatic 3° amino, aliphatic quaternary ammonium salts, aromatic I° amino, aromatic 2° amino, aromatic 3° amino, aromatic quaternary ammonium salts, imidazol, guanidino, boronoamino, allyl, urea, thiourea ;
R3 can be H, aliphatic, aromatic or heterocyclic;
R4 can be an acidic group selected from the group consisting of carboxyl, phosphono, phosphino, sulfono, sulfino, borono, tetrazol, isoxazol;
any pl;a-ma~~a;i:.aliv a;,~°p~abie ~ai:~ :~°r~o Printed:l2-~ ~2s2sss4 2ooo-io-is '~' ~';t-~ ~. ~~- a: L~ L ~' ~ ~ ~ ~'"~
,'u'.: ~. ~

20-07-2000 ~ ~~ ~ . PCT/CA99/00311 DESC
In particular compounds whcr~cin the compound of Formula I i.9 sclecacd from the group consisting of:
R
(I) wherein: ' >K1 is COOl-t K2 is Nf~li R3 can bc: I! or methyl c>r xankhyl c>r thicyxanthyl or-C:IIZ-xanlhyl or-GHZ-thioxanthyt and R4 is COdH
While all of lhr com~unds.~f I~'ormula I area bc;lier~e~i tn de;mnnstraie at.tivity et the rnctabt~trc~pic glutam~ctc receptors (rnCIuRs), certain groups of Formula I compounds arc more preferred for such use.
As noted above, this invcntirrn includes the pharmaceutically acceptable .salts of the compounds defined by Formula 1. A e4mpound of thin inventicm cari posses a sufficiently acidic, a sufficie~nil3~ x~asic, car both functional groups, and accordingly rt;act with any of a number of organic and inorganic baso.s, and inorganic and or~aryic acids, io form a pharmaceutically acc;epta.ble salt. c The term "pharmaceutically acreptablc salt" as uscxi herein, rcfrrs to salts of the compounds of the: above fc~rmul:~ which are sululantially non-toxic to living organisms.
Typical pharrnacxutic:aJiy aax;ptablc saris include; those;.salts prepared by rcaclionof the cor~our~ds of the pnsinl invention with a pharmaceutically acceptable mineral or organic acid nr cure c>rganic or inorganic base. Such salts toe known as acid addition ancJ base addition salts.
Arias a>nmx>nfy crnpioycxi ic> iorrrt acid aaditicm salts ~ itnNgdnic arias Surh as hydr;~"hloric; acid, . .
hydrotm~mic acid hydriodic acid, sulfuric acid, pht~sphoric acid, anct the like, and organic acici~ such as p-u~tucr~ulfonic a;.-id, t~"than~'ulfnnic avid, oxalic a:;irl, ~-bromoplx:nyLsulfonic a:..id, c~uhonic Pruted:l2-cA o2s2sss4 2ooo-io-is 28-07-1999 PCT1Ci499/00311 P~~ ~ ~~ ~ ~ ' ' ISA-DESC26 ~ 9 . Jl9LY ~~99 ~ ~ 9 ° ~ 7 ° ~~
acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
Examples of such pharmaceutically acceptable salts are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, bromide, iodide, acetate, propionate, decanoate, caprylate, acryiate, fonnate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate, phenylacetate, phenylpropionate, phenyibutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, napththalene-2-sulfonate, mandelate and the like.
Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as malefic acid and methanesulfonic acid Salts of amine groups may also comprise quarternary ammonium salts in which the amino nitrogen carries a suitable organic group such as an alkyl, alkenyl, alkynyl, or, aralkyl moiety.
Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like. Such bases useful in preparing the salts ofthis invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like. The potassium and sodium salt forms are particularly preferred It should be recognized that the particular counterion forming a part of any salt of this invention is usually not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole. This invention further encompasses the pharmaceutically acceptable solvates of the compounds of Formula I. Many of the Formula I compounds can combine with solvents such as water, methanol, ethanol and acetonitrile to form pharmaceutically acceptable solvates such as the corresponding hydrate, methanolate, ethanolate and acetonitrilate.
The compounds of the present invention have multiple asymmetric {chiral) centers As a consequence of these chiral centers, the compounds of the present invention occur as racemates.
mixtures of enantiomers and as individual enantiomers, as well as diastereomers and mixtures of _.
r r'~
.p t~~ ~~c=' E.. l !E; ~~vcl, ~ - ,: . ,. : .
iii ~s 4i ale, ~y Pr~r~ted.~2~ 02328984 2000-10-16 28-07 1999 PCT/CA99/003j 1 p~.l.. ! C~ 9 g / ~iS~,-o:ES~2s~
JULY 1999 ~,0 9 - 07 . 99) diastereomers. All asymmetric forms, individual isomers and combinations thereof, are within the scope of the present invention.
The prefixes "R" and "S" are used herein as commonly used in organic chemistry to denote the absolute configuration of a chiral center, according to the Cahn-Ingold-Prelog system. The stereochemical descriptor R {rectus) refers to that configuration of a chiral center with a clockwise relationship of groups tracing the path from highest to second-lowest priorities when viewed from the side opposite to that of the lowest priority group. The stereochemical descriptor S (sinister) refers to that configuration of a chiral center with a counterclockwise relationship of groups tracing the path from highest to second-lowest priority when viewed from the side opposite to the lowest priority group. The priority of groups is decided using sequence rules as described by Cahn et al., Arrgew. t:henr., 78, 413-447, 1966 and Prelog, V. and Helmchen, G , Afr~ew.
Chenr. Irrr. Ed End., 21, 567-583, 1982).
In addition to the R,S system used to designate the absolute configuration of a chiral center, the older D-L system is also used in this document to denote relative configuration, especially with reference to amino acids and amino acid derivatives. In this system a Fischer projection of the compound is oriented so that carbon-1 of the parent chain is at the top. The prefix "D" is useø to represent the relative configuration of the isomer in which the functional (determining) group is on the right side of the carbon atom at the chiral center and "L", that of the isomer in which it is on the left.
As would be expected, the stereochemistry of the Formula I compounds is critical to their potency as agonists or antagonists. The relative stereochemistry is established early during synthesis, which avoids subsequent stereoisomer separation problems later in the process.
Further manipulation of the molecules then employs stereospecific procedures so as to maintain the preferred chirality. The preferred methods of this invention are the methods employing those preferred compounds.
Non-toxic metabolically-labile esters and amides of compounds of Formula I are ester or amide derivatives of compounds of Formula I that are hvdrolvzed in vivo to afford said compounds of Formula I and a pharmaceutically acceptable alcohol or amine. Examples of metabolically-labile esters include esters formed with (1-6C) alkanols in which the alkanol moiety may be optionally substituted by a~( 1-SC) alko~ry ;roup, for exampi:; methanol, ethanol.
propanol and methoxvethanol Examples of metabolically-labile amides include amides formed with amines such as methvlamine (i5 ;. ~ 5.~~., ':-. a~:: ~ r_~~,a ~. r~ r~~ ~Z ;.-.y : ; . .: , a CA 02328984 2000-10-16 ':~ 'J~ ~ .; ~'~ 1~ ;~ r? ~,i" ~ '~ ~ -.., ~ ~, j - ~_ r Pr~nted:l2 , v ",~" '- ~~ :l ~

20-07-2000 ' ~ PCT/CA99100311 'DESC
4ccordinb to another aspoet, the prr,9cnt inventicm provides a Prcx;eaa for the preparation of a compound of F~~rmu(a I, cn a pharataceutically acceptable mctabca(icaliy-labile ester ur amide therc.~,of, or a pharmaceutically aceeptabla salt thercx~P, which eomprisos:
(a) hydmlyiing a ccwmpound of fcnmula. (TIa):
R'1 (lla) NC
k3 whcrcu~: It'1 i.~ an acidic gmnp seiec;tc;d from the gctmp wnsisling of carboxyl, phosplumu, pllL~Spt77110, suifonc~, sulfina, bomno, tetrd~Ul, i,9t~xazol, -t':,'H~-carboxyl, -CHa-phosphono, -CIiL-phosphino. -CHZ sulfnnu, -CHZ-suJfino, -CHZ-borr~nu, -CH2-tetr~ol, CHZ-i'oxazol and higher analogues nhereof, or a prcatc;cted form thereof, R:i can be H, aliphatic.
amrnatic or hcterocyclic and R5 rprescnU a hydrubTcn atom or an acyl group. 1'roferred values for RS
are hydrogen and (,2-6C) alhanoyl groups, such as acetyl; Ur (E~) dcprot.txting and hydrolysing a u~mpcsuntl c.~f forrnulti (TI b) R' 1 CN fllb?
x:~
H
H
Ph DH
a'hercin: >~ I :~n<i R~ are as deCii~;a acs: we; cr Printed:l2-~ 02328984 2()()()-1()-16 20-D7-2000 4~ ~ PCT1CA99/00311 'DESC
(c) hydrolyzing a compound ~f formula:
till) wherein: R'1 and R3 has the meaning defined atxwe, Rb arid R7 each uicielx,~ndenuy rGpresE;nt a hydrogen atom; a (2-6L) alkanoyi group, a (1-~C) alkyl group, a (3-4C) alkenyl grnup or d phenyl (1-4C) alkyl groin in which the phenyl is unsubstitutc~xi or substituted by haloge», (1-4C) alkyl ar (1-4C) alkoxy, or a salt thereat; nr V
i 1~$
Printed. 2-~ 02328984 2000-10-16 .~. r-, v v v 20-07-20Q0 ' ;/ PC~'/CA99/00311 DESC
(d) dcprotecting a cnmpc~und of formula:
R'1 (jV) R
~wherCin; R'1 dnd R3 has the meanlnb defined above, RS r~pr~cnta a hydrogen atom yr tz carboxyl protecting group, or a salt thereof, annd R9 rcpre~enls a hydrogen atom ar a nitrogen pmlecaing broup;
whcreafter, if necessary andwr desircxl:
(i) resolving the compound of Formula I;
(ii) c,.vnvcrting lhc cnmlx.~und of formula 1 into a non toxic rnctabolically-labile aster yr amide thereof;
and/or;
(iii) converting the compound of FcmnuIa I or a nun-tnxic metabolically-lalaile aster or 3midc thereat into a pharmaceutically aceel~table Bali Thereof.

The prottcvion of ~arbnxylic acid and amino gn~ups is generally described in MeOmie, Prvtecling C~rrouhs in Urgaraic Chemistry, Plenum Prc;ss, NY, 197:3, and Greenc and Wets, Prvtc;cting Gmulrs in Urganic Synthr;sis, 2nd. Td., John Wiley & Son.,, NY, 1991. Examplss of carboxyl protecting groups include alkyl groups such as methyl, ethyl, r-butyl and i-amyl: aralkyi groups such as bcn2yl, 4-nitrabencyl, d-molhc~xybenryl, 3,4-dimc;thoxybcnzyl, 2,4-dimc;thoxybunzyl, x,4,6-trimcthoxybcrztyn, Z,4,6-irimethylbc;ruyl, benchydryl and trityl; silyl groups such as trimcehylSilyl and t-butyldimcthylsilyl; and allyl groups serch as allyl and '1-(trimethylsilylmclhyl)prop-1-en-3-yl. , Examples of arninc-protecting groups in~;tude aryl groups, such as groups of formula R9 CO in ~svhich RSi re;pra~nW (1-6C) alkyl, (3-tOCj cycloalkyl, phenyl(I-bC) ailcyi, phenyl(1-bC) alKOxy, or a (3-lOC) cyclaalkaxy, wherein a phenyl group may optionally tx: substituted by or~~ or lwu ' I2 Ptinted:l 2-10-2000 2D-07-2000 ~f ~ PCT/CAg9/00311 DESC
Pub9tituents indc;pendentty sekxtc;d from amiro~. hydroxy. vitro, halogeno, (1-6C) alkyl, (I-6C) alkc~xy, carboxyl, (1-6C) alkoxyc;arbonyl, carbamoyt, (I-6C) alkannylamino. (i-6C) alkylsuiph~rtylamino, plienylsulphonylarttino. toluenc;,s-utphanylarnino, and (1-6C) fluoraalkyl.
The con-vpourtds of Formula II are convonicntly hydrcflyred in the prc;sence of an acid, such a.~
hydrochloric acid or sulfuric acid, or a base, .ouch as an alkali metal hydroxide, for example sodium hydroxide. The hydrolysis i.y c~nv~niently porformcd in an aduenus solvent such as water and at a temperature; in the rangt; of 5U to 200 °C.
1'he compounds of Formula 1II arc vonveniently hydrt~lyic;d in the prc;sencc of a base, for example an alkali tneWl hydroxide such as l.ithiurn, sodium ur pota.~situ~n hydroxide, or an alkaline easth mct,al hydroxide such as barium hydroxide, Suiictblc reaction rncdia include water.
The tcmpc;rature is amvedicntty in the range of from 50 to I50 °C.
The cornpc~unds of Formula 1V rrtay be deprotectcx3 by a conventional method, Thus, an alkyl carboxyl protecting gmup may be rernovcxt by hydrolysis. 'fhc hydrolysis may conveniently be performc;d by heating the compound of 7~ormulx ) V in the presence ~~f either a base, for example an alkali ~nctal hydroxide ,such as lithium, snclium or puta.ssium hydroxide, or an alkaline metal hydroxide, leech as barium hydroxide, ar an acid such as hydrochloric acid, The hydrolysis is conveniently perfonned at a temFx;rature in the range from 10 to 300 °C. An aralkyl carboxyl protecting group may ct~nvenicntly be remcwed by hydrogenolysis. The hydrobenolysis may conveniently be cffectod by reacting tt~ compound of P'urmuta IV with hydrogen in the premxe co a Gtvup VIII rnotal catalyse, for examplo a palladium catalyse sucty as palladium on charcoal.
Suitable sc~ivents fur the reaction include alcohuLs such as ethanol. 'fhe reaction is convcnicnily performed at a temperature in the range From 4 tot Ua °C. An aryl, amine protecting group is also ccmvc:nienl(y removexJ by bydraolysis, for exdml~ic a.~ dcscribod for the;
removal of an alkyl carboxyl pmtectcng gmup.
The compounds of Formula f ( rnay he prt;pared by re:ucting t~ compound of furrnultt (V):
fVi li PriTited:l2-X2328984 2ooo-io-is i 20-07-2000 ~ PCTlCA99/003'i 1 DESC
with an alkali mrtal c.~yanide, such as Iil,hium, sodium or ptitussiurn cya~zidc, acxi an amrnanium Jlaiide, ouch as nannocaum chloride, convecucnrly in the prcscnce esL
ultres~und. Thus, the ammonium halide is mixed wish chrcxna.tcsgraphy grade aluznina in the presence; of a suitable dituent Such as ac;otonitrile. The mixture iv then irradiateel with uttras~ound, whereafic,~r the compound of Formula t1 is added, and the rni~:cure is again irradiatc;d. 1'he alkali mesa( cyanide is ihcan added, t«llowed by farther irrediati~~rt with ulCrasound.
lndividuat isc~mcrs of compUCmds of Formula I muy be mado by reacting a compound of the hurmccla V with the St~I~UiSa1118rS Uf tllC ClllTal agent {.S')- anti (R)-phc;nylgiycinnt and a reac~ive cyanide such a~ trimeUiylsityl cyanide.
The compounds of Formula 111 may be prepared by rcactu~g a cc~mpc~und of Formula V with an alkali metal cyanide, such ac lilhimn, sodium or potassium cyanide;, and ammoni;nn carbnn~tie ur anmc.~nium c:arhamate. Convenient solvents include water, dilute ammonium hydroxide, alcnlu~ls such as m~tharn~l, a.quasus methanol and arlut~us ethanol. ~Convenic,,nlly the rcaCtion is perfcarrned r at a temLxrature in the range of from 10 to 1$d ° C'.. If dr,~sirod, the contpaunds of Formula I1I may then be atkylatc,~d, l~or c;xample using an appropriate compnmd of fnrrriula RG Cl andlor k7 C1, The cconpounds of C'orrnula V ion be preparut by reacting acc~rnpc~und of formula:
'1 tvn CCz~
with a chlorinating agent such as th:onyi chlvridc or phc~sphoncms {t~
Chloride. followed by r~c:actiun with urgano copper or vrgancs rnetaI car (3rignard roagent iferived from R:~ X
or by raaetion wifih ethyl hydrogc;n malUnatr in the: presence of orgdnolithium, wherein R3 has the rneuning definr:d aix~r~e 1~
ar,a .. i~ ttalvgvr.
!4 Printed:l 2-10-2000 g / , 20-07-2000 ~ '~ 'PCT/CA99100311 DESK
The compouzta5 of F'c~rmuta V can ats~ trc3 prcparrd by oxidixinbT a compound of formula R'i (~) CI3,GH
under Swcm ccms3ition~. ' The er~mlx~nnds of Fornwla VI ran be prepanxl from compounds of formula:
R' 1 tV I~1) GOzR
by reduction.
Whc~ R'I is C~OZMe, this ccampoundcan be ix~ught commercially. Wtx:n R'1 as ar:Uthc~r5ubst~tuc~nt, the ccampuund of Formula VIII can be made usin6 standard proceciurc;s.
Many of the intermcx~tiates dc:,scribtxl heni.n, for c~mple: the cr~mpvunds of Formula II,11i and IV
arc lyclicved to be: newel, and arc provided as further aspects of lhc invc;nlion.
'fhe Formula 1 compounds of the presfant invention ~e agonist, Ar antagonists at crrtau~
metabatropic excitatory amino acid rec:c~tor5 (mGluK,S). Tl~rcfore, another aspect ut the present invention is a method of aifccting mGlults in mt~mrnal~. which comprises adrninistcrin~ to s mamtrtal rc;quiring mocfulatc~ excitptory amino acid neur~c~transmission a pharmaculcyically-eflcetive amount c~f a ec>m-puund c~f Forrnvla 1. The torni "pharmacologically-cifc;ctive amount" i~ used to represent an amount of the onmpound of the invention that is capabic of afFc.;aing the rnuluF;s, By afi;;cting, a cornp:~urtd tit tim irtvc:rtzon it atcting as an agc~nist or antagonist. When a compcwnd of the:
~1 Printed:l 2-10-2000 ?8-07-1999 PCT/CA99/D0311 ~ 9 1SA-DESC26 PCTi /~A ~iuu~ls JULY 1999 ~ 0 9 - 0 7 . 99) invention acts as an agonist, the interaction of the compound with the excitatory amino acid receptor mimics the response ofthe interaction ofthis receptor with its natural ligand (i.e. 1.-Glutamic acid).
When a compound of the invention acts as an antagonist, the interaction of the compound with the excitatory amino acid receptor blocks the response of the interaction of this receptor with its natural 1 ligand (i.e. L-Glutamic acid).
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. A typical daily dose will contain from about 0.001 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/lg to about 20 mg/kg .
A variety of physiological fiznctions have been shown to be subject to influence by excessive or inappropriate stimulation of excitatory amino acid transmission. The Formula I
compounds of the present invention are believed (through their interactions at the mGIuRs) 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. The Formula I compounds are believed to have the ability to treat a variety of chronic neurological disorders, such as Alzheimer's disease, Huntin~on's Chorea, amyotrophic lateral sclerosis, AIDS-induced dementia, ocular damage and retinopathy, cognitive disorders, and idiopathic and drug-induced Parkinson's disease. The present invention also provides methods for treating these disorders which comprises administering to a patient in need thereof an effective amount of a compound of Formula I.
The Formula I compounds of the present invention (through their interactions at the mGluRs) are aisc believed to hive the ability tc tr °at a \'arl°t~' or oth°- neurolo~i;,a' disorders it mammals t hat are associated with glutamate dysfunction, including muscular spasms, convulsions, migraine headaches, urinary incontinence, psychosis, drug tolerance, withdrawal. and cessation (i a opiates, benzodiazepines, nicotine, cocaine, or ethanol), srnokin~ cessation, anxiety and related disorders (e g. panic attack), emesis, brain edema, clVOnic pain, sleep disorders, Tourette's syndrome, attention CA 02328984 2000-10-16 u- t _~ . . ...
Printed:l2-!V-GVVV ~ . r ~1' , ~ ~ ~ ~~.1 ; ..~
.. ~ ;. ~y . ~:'' 1' ~8-07-1999 ~PCTlCA99/0031'1 p~-~ ~ C~ 9 g ~ ISA-DESC26 0 9 JULY 1999 CO 9 ~ 0 7 . 99J
deficit disorder, and tardive dyskinesia. Therefore, the present invention also provides methods for treating these disorders which comprise administering to a patient in need thereof an effective amount of the compound of Formula I.
The Formula I compounds of the present invention (through their interactions at the mGIuRs) are also believed to have the ability to treat a variety of psychiatric disorders, such as schizophrenia, anxiety and related disorders (e.g. panic attack), depression, bipolar disorders, psychosis, and obsessive compulsive disorders. The present invention also provides methods for treating these disorders which comprises administering to a patient in need thereof an effective amount of a compound of Formula I.
The pharmacological properties of the compounds of the invention can be illustrated by determining their effects in various functional in vitro assays. The compounds of the invention were studied in an in vitro assay that measured the inhibition of PI hydrolysis or the formation of cyclic AMP in Chinese hamster ovary cell lines expressing mGluRlQ, mGluRz and mGluR4, cloned metabotropic glutamate receptors.
Principle So far eight different clones of the G-protein-coupled mGluRs have been identified (Knopfel et al , 1995, J. Med Chem., 38, 1417-1426). These receptors function to modulate the presynaptic release of L-Glutamate, and the postsynaptic sensitivity of the neuronal cell to L-Glutamate excitation.
Based on pharmacology, sequence homology and the signal transduction pathway that they activate, the mGluRs have been subclassified into three groups. The mGluRl and mGluRS
receptors form group I. They are coupled to hydrolysis of phosphatidyfinositol (PI) and are selectively activated by (RS)-3,5-dihydroxyphenylglycine (Brabet et al., Neuropharmacology, 34, 895-903,.1995). Group II comprises mGluR2 and mGluR3 receptors. They are negatively coupled to adenylate cyclase and are selectively activated by (2S,1'R,2'R,3'R)-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV; Hayashi et al., Nature, 366, 687-690, 1993). Finally, the mGluR4, mGluR~, mGluR~ and mGluRs receptors belong to group III. They are also negatively coupled to adenylate cyclase and are selectively a;,ti~~ate~ h~~ ~S'-?-amine-4-nhosph~m~lbut~-ric acid (L-:4P4; Knopfel. e~
al., ' 995. J. .Ailed Chem 38, 1417-1426).
!7 °Printedl2-10-2000 ~~ ~~ ~ ~ -. . . ~ ~ ~ .. ~ .._. '"~ ~~ 1.7'' 28-07-1999 'PCT/CA99/00311 ~~-~- / ~~ 4 9 / ISA-DE5C26 Cell Culture The Chinese hamster ovary cell lines expressing mGIuR~Q, mGluRz and mGIuR4~
receptors have been described previously (Aramori and Nakanishi, Neuron 8, 757-765; 1992; Tanabe et al., Neuron 8, 169-179, 1992; Tanabe et al., J. Neurosci. 13, 1372-1378). They were maintained at 37°C in a humified 5% COZ incubator in Dulbecco's Modified Eagle Medium (DMEM) containing a reduced concentration of (S}-glutamine (2mlV~ and were supplemented with 1% proline, penicillin (100 U/ml), streptomycin (100 mglml) and 10% dialyzed fetal calf serum (all GIBCO, Paisley). Two days before assay 1.8 x 106 cells were divided into the wells of 24 well plates.
Second Messenger Assays PI hydrolysis was measured as described previously (Hayashi et al., Br. J.
Pharmacol. 107, 539-543, 1992; Hayashi et al., J. Neurosci. 14, 3370-3377, 1994). Briefly, the cells were labeled with ['I-i~inositol (2 pCi/ml) 24 h prior to the assay. For agonist assays, the cells were incubated with ligand dissolved in phosphate-buffered saline (PBS)-LiCI for 20 min, and agonist activity was determined by measurement of the level of'H-labeled mono-, bis- and tris-inositol phosphates by ion-exchange chromatography. For antagonist assays, the cells were preincubated with the ligand dissolved in PBS-LiCI for 20 min prior to incubation with ligand and 10 p.M
(L)-Glutamic acid for 20 min. The antagonist activity was then determined as the inhibitory effect of the (L)-Glutamic acid-mediated response. The assay of cyclic AMP formation was performed as described previously (Hayashi et al., Br. J. Pharnracol. 107, 539-543, 1992; Hayashi et al., J.
Neurosci. 14, 3370-3377, 1994). Briefly, the cells were incubated for 10 min in PBS containing the ligand and 10 ~M forskolin and 1mM 3-Isobutyl-1-methyxanthine (IBMX; both Sigma, St. Louis, MO, USA). The agonist activity was then determined as the inhibitory effect of the forskolin-induced cyclic AMP formation.
For antagonist assay, the cells were preincubated with ligand dissolved in PBS
containing 1 mM
IBMX for 20 min prior to a 10 min incubation in PBS containing the ligand, 20 pM (mGluR2) or 50 uIJ (m iiur~,}, (L,i-:Tiutami;, acid, lu- uiJ ~ orsi:oiin any i rr>Tv IBlvi:~:
Results Some of the compounds of the invention were tested for antagonist activity against Chinese hamster Printed:l 2-1 U-~UUU ', y~ Lv. 4__ I. ; ~., s_ _ , v__ _. ; :. ~~- ~.~ ~ ~ g 28-07=1999 PCT/CA99/003'11 PCs. ~ ~~ 9 g I ISA-DESC26 ' ~9 ;IULY 1999 (0 9 ~ 07.99) ovary cell lines expressing mGluRrQ, mGluR2 and mGiuR~, cloned mGluRs at a concentration of 1 mM. When tested as antagonists of the increase in PI hydrolysis evoked by 10 ~.tM (L)-Giutamic acid, some compounds of the invention effectively blocked this increase in PI
hydrolysis by an action at the mGluR,~ receptor. The data for one of the compounds of the invention is shown in Figure 1 below.
According to another aspect, the present invention provides a method of modulating one or more metabotropic glutamate receptor functions in a warm-blooded mammal 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 compounds of the present invention are preferably formulated prior to administration.
Therefore, another aspect of the present invention is a pharmaceutical formulation comprising a compound of Formula I and a pharmaceutically-acceptable carrier, diluent, or excipient The present pharmaceutical formulations are prepared by known procedures using well-known and readily available ingredients. In making the compositions of the present invention, the active ingredient will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, and may be in the form of a capsule, sachet, paper, or other container. When the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active ingredient The compounds of Formula I are usually administered in the form of pharmaceutical compositions.
These compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. These compounds are effective as both injectable and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
The present invention also provides pharmaceutical compositions containing compounds as disclosed in the claims in combination with one or more pharmaceutically acceptable, inert or physiologically a:,tiv°. aiiu°n~ or adit!van:. ':~h° compound: o~
th° invention can bfreez°-dri°~and, i' d°sired.
combined with other pharmaceutically acceptable excipients to prepare formulations for administration. These compositions may be presented in any form appropriate for the administration route envisaged The parenteral and the intravenous route are the preferential routes for administration CA 02328984 2000-10-16 ~ -.- c5-n ~ .rs,s ~ G'~ ~''~' 'Y. ~~~ s_~' ~ ~
Printed: ~ 2-10-2000 ~~ ~l ~ ~ ~ ~ ~ ~ ~ °~'" ~ ~ 1 g _ o 28-0?-1999 PCT/CA99/00311 p~~-~- p ~~ ~ g / 1SA-DESC26 ~9 JULY 1999 09 ° ~7~~~D) C
Compounds of the general Formula I may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. In addition, there is provided a pharmaceutical formulation comprising a compound of general Formula I and a pharmaceutically acceptable carrier. One or more compounds of general Formula I may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients, The pharmaceutical compositions containing compounds of general Formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
Compositions intended for oral use may be prepared according to any known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate:
granulating and disintegrating agents for example, corn starch, or alginic acid' binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate o- l:aolir:: o- as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain active materials in admixture v~~ith excipients suitable for the manufacture of aqueous suspensions Such excipients are suspending agents, for example sodium CA 02328984 2000-10-16 , E., ~:, . , a.r:~.- l., f; 'b j 4~" ~' ~ i~ ~ 3 Printed:l2=10-2000. ~ y- ~~ i ~ ~ . ~~'r '_ . ' ... ~- ~ 2p 28-07-1999 PCT/CA99/0031 y P~,~ ~ ~~ 9 9 f ~IS~1-DESC26 °4To~~~
carboxylmethylcellulose, methyl cellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia: dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example hepta-decaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or rt-propyl-p-hydroxy benzoate, one or more colouring agents, one or more flavouring agents or one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavouring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition ofan anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavouring and colouring agents, may also be present.
Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, for example olive oil or peanut oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide; for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents 2l ... - °.~-.;: y :: r:~.:W ..,z, V~
Printed:lG V?GVVV 200-10-16 ._ __ ._ ~. ~ ~ -- w ' 21 28-07-1999 PCT/CA99/00311 ~ ~~ ~ ~ ~~ ~ ~ .1SA_DESC2G' 0 9 ;9flLY 1999 ~ 0 9 ~ 0 7 _ 9g Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavouring and colouring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to known art using those suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or a suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compounds) of the general Formula I may be administered, together or separately, in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
Compounds) of general Formula I may be administered, together or separately, parenterally in sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anaesthetics, preservatives and buffering agents can be dissolved in the vehicle.
The dosage to be administered is not subject to defined limits, but it will usually be an effective amount. It will usually be the equivalent, on a molar basis of the pharmacologically active free form produced from a dosage formulation upon the metabolic release of the active free drug to achieve its desired pharmacological and physiological effects. The compositions are preferably formulated in a unit dosage form, each dosage containing from about 0.05 to about 100 mg, more usually about 1.0 to about 30 mg, of the active ingredient. The term "unit dosage form"
refers to physically discrete units 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 °f'~r°ct. in asso,iation with a suitable phar~nac°utical excipi~nt ~ 02328984 2000-10-16 ~~ '.- ~~ - ~ , ; ~ , - . . . ,. ...< Li Printed:l2-10-2000 28-07-1999 PCT/CA99/00311 PCs, ' ~~ 9 g ~ISA-DESC26 d 9 JI~LY 1999 ~ 0 9 - 0 7 . 99 , The active compound is effective over a wide dosage range. For examples, dosages per day normally fall within the range of about 0.01 to about 30 mgJkg of body weight. 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. In the treatment of adult humans, the range of about 0. I to about 1 S
mg/kg/day, in single or divided dose, is especially preferred. However, it will be understood that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way. In some instances dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several smaller doses for administration throughout the day.
The compositions are preferably formulated in a unit dosage form, each dosage containing from about 5 mg to about 500 mg, more preferably about 25 mg to about 300 mg of the active ingredient.
The term "unit dosage form" refers to a physically discrete unit suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier, diluent, or excipient The following formulation examples are illustrative only and are not intended to limit the scope of the invention in any way ~ 02328984 2000-10-16 ., .
Printed:l2-10-2000 ~ .. ~... ; '~ , 28-07-199~J PCT/CA99/00317 ISA-DESC26' r'°yCT ~ ~'o~ ~ ~ r a v . . m Formulation 1 Hard gelatin capsules are prepared using the following ingredients:
Quantity (mg/capsule) Active Ingredient 250 Starch, dried 200 Magnesium stearate 10 Total 460 The above ingredients are mixed and filled into hard gelatin capsules in 460 mg quantities Fornuclation 2 A tablet is prepared using the ingredients below:
Quantity (mg/tablet) Active Ingredient 250 Cellulose, microcrystalline 400 Silicon dioxide, fumed 10 Stearic acid 5 Total 665 The components are blended and compressed to form tablets each weighing 665 mg.
Fornxulal~ion 3 An aerosol solution is prepared containing the following components:

CA 02328984 2000-10-16 i~~ . ~: ' _ .. .~ _ ,_,-. ~_ .. . . , ' .. _'. ~;~.
Printed:l2-102000 ~= ~'~ ~ ~_ ~ ,: ~, ~._a l~ ~ ;:~: ~, ~~ ~ ~ ~ 24'' 28-07-1999 PCT/CA99/00311- 15A-DESC26 '°
P C'~' / ~A ° 9 / 0 0 31 ~
J~~'~ 19~g C(~ 9 ~ a ~ _ ~~
l Weight Active Ingredient 0.25 Ethanol 29.75 Propellant 22 (Chlorodifluoromethane) 70.00 Total The active compound is mixed with ethanol and the mixture added to a portion of the Propellant 22, cooled to -30 °C and transferred to a filling device The required amount is then fed to a stainless steel container and diluted with the remainder of the propellant. The valve units are then fitted to the container.
Forntulaiion 4 Tablets each containing 60 mg of active ingredient are made as follows:
Quantity (mgltablet) Active Ingredient 60 Starch 45 Microcrystalline cellulose ~5 PolyvinylpyrroIidone 4 Sodium carboxymethyl starch 4.5 Magnesium stearate 0 5 Talc 1.0 Total 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 that are then passed through a No. 14 mesh U.S sieve. The granules so produced are dried at ~0°C and passed Printed:l 2 1 ~ ;,~.,._ , , . : .. _ . _. , CA 02328984 2000-10-16 r.=, . ; , . . ~- , ._ ,. ..
. , , t, .' f:_~. . , . ., ...

28-07-1999 PCT/CA99/00311 I SA-~DESC26 PC's«A ~9/003~1 0 9 'JUDY 1999 0 9 - 0 7 . 99, through a No. 18 mesh U.S. sieve. The sodium carboxymethyi 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 1 SO
mg.
Formulation S
Capsules each containing 80 mg medicament are made as follows:
Quantity (mg/capsufe) Active Ingredient 80 Starch 59 Microcrystalline cellulose 59 Magnesium stearate 2 Total 200 The active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 45 sieve, and filled into hard gelatin capsules in 200 mg quantities.
Formulation 6 Suppositories each containing 225 mg of active ingredient may be made as follows:
Quantity (mg/suppository) Active Ingredient 225 Saturated fatty acid glycerides 2000 Total 2225 The active ingredient is passed through a No 60 mesh U.S. sieve and suspended in the saturated fatty acid giycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool ' Printed:l 2-10-2000 ~~, c ~; ~:. rw ~ ~ 1- ,;- r. l~ ~ j r~-- - , Y ~- '; ;' 'R!:~
. - _ . 1 . ~ ,' ! " . ' ~ : - ._. . :v 28-Ors-1999 PCT/CA99/00311 ~~~ ! ~~ 9 9 ~ ISA-DESC26 09 JULY 1999 (D 9 - 0 7 . 9g Formulation 7 Suspensions each containing 50 mg of medicament per 5 mI, dose are made as follows:
Active Ingredient 50 mg Sodium carboxyimethyl cellulose 50 mj Syrup 1.25 mL

Benzoic acid solution 0.10 mL

Flavour q. v.

Color q.v.

Purified water to total 5 mL

The medicament is passed through a No. 45 mesh U. S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste. The benzoic acid soiution, flavor and color are diluted with some of the water and added, with stirring. Suf~'~cient water is then added to produce the required volume.
Formulation 8 An intravenous formulation may be prepared as follows:
Quantity Active Ingredient 100 mg Mannitol 100 mg N Sodium hydroxide 200 mL
Purified water to total ~ 5 ~, Formulation 9 A topical formulation may be prepared as follows CA 02328984 2000-10-16 _ Printed:l 2-10-2000 .~ ~ ~ r ~ ~~ ~ ~' c~ r ~~ ~ ~'" iL....~ ~ ~ ~..: ~~

c8-07-1999 PCTlCA99/00311 ~~~ , C~ 9 9 / ISA-DESC26 °
Quantity Active Ingredient 1-10 g Emulsifying Wax 30 g Liquid Paraffin 20 g White soft parafftn to 100 g The white soft para$'tn is heated until molten. The liquid paraffin and emulsifying wax are incorporated and stirred until dissolved. The active ingredient is added and stirring is continued until dispersed. The mixture is then cooled until solid.
Formulation 1 D
Sublingual or buccal tablets, each containing 10 mg of active ingredient, may be prepared as follows:
Quantity (mg/tablet) Active Ingredient 10.0 Glycerol 210.5 Water 143.0 Sodium Citrate 4.5 Polyvinyl Alcohol 26 5 Polyvinylpyrrolidone 15. 5 Total 410 0 The glycerol, water, sodium citrate, polyvinyl alcohol, and polyvinylpyrrolidone are admixed together by continuous stirring and rnaintairung the temperature at about 90 °C. When the polymers have gone into solution, the solution is cooled to about 50°-55 °C and the medicament is slowly admixed. The homogenous mixture is poured into forms made of an inert material to produce a drug-containing diffusion matrix havin;; a thickness of about 2-4 mm. This diffusion matrix is then cut to form individual tablets having the appropriate size .. ~ n n y _ ~ ~ Le_ ~ i, ~ '._ V.;m Lsrr. IL"

P.rinted:'Y2-10-200D

99 / p- ' 28-07-1999 PCT/CA99/003'11 PCB / C~ ISA-DESC26 -JULY 1999CO9~07.9gI
Another preferred formulation employed in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts.
The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art (see, for example, U.S. Pat No. 5,023,252, issued Jun. 11, 1991) herein incorporated by reference. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
Frequently, it will be desirable or necessary to introduce the pharmaceutical composition to the brain, either directly or indirectly. Direct techniques usually involve placement of a drug delivery catheter into the host's ventricular system to bypass the blood-brain barrier.
One such implantable delivery system, used for the transport of biological factors to specific anatomical regions of the body, is described in U.S. Pat. No. 5,011,472, issued Apr. 30, 1991, which is herein incorporated by reference.
Indirect techniques, which are generally preferred, usually involve formulating the compositions to provide for drug latentiation by the conversion of hydrophilic drugs into lipid-soluble drugs or prodrugs. Latentiation is generally achieved through blocking of the hydroxy, carbonyl, sulfate, and primary amine groups present on the drug to render the drug more lipid soluble and amenable to transportation across the blood-brain barrier. Alternatively, the delivery of hydrophilic drugs may be enhanced by intra-arterial infusion of hypertonic solutions that can transiently open the blood-brain barrier.
EXAMPLES
The following Examples illustrate the invention. The following abbreviations are used in the Examples: EtOAc, ethyl acetate; THF, tetrahydrofuran; EtOH, ethanol; TLC, thin layer chromatography; GC, gas chromatography; HPLC, high pressure liquid chromatography; m-CPBA, m-chloroperbenzoic acid, Et~O, diethyl ether; DMSO, dimethyl sulfoxide; DBU, 1.8-diazabicyclo-[5.4.0)undec-7-ene, MTBE, methyl t-butyl ether, FDMS, f eld desorption mass spectrornetrv and r t , room temperature. .

CA 02328984 2000-10-16 _ -..n .~ ~ ~ ~ rn . :a Pr=inted:l 2-~ -~ ~;~ tt CJ..~-i ct.,.L- ~7 ~~I ~~ ~~~ ~ o,.
U UUU '"
. 29 z8-07-1999 PCT/CA99/0031'I ~~"~' / ~,4 y 9 ISi4-DESC26 0 9 JULY 1999 ~~ 9 - 0 7 . 99 Example 1: Synthesis of Cubanylglycinates IGT 1.0 series a b C -~ Me02C
~'~OOZMe ~OO~I

n H02C CO~"1 MeOzC CN MeOzC
'"'H ~--- -~- ~CHO
a H d Ph OH .
Preparation l: 4-methoxycarbonylcubane carboxylic acid _ A solution of cubane dimethyl ester (6.Og, 27.24 mmol) in 182 mL of dry THF is stirred under Nz at room temperature. A solution of methanolic NaOH (26.7 mmol, 10.7 mL 2.5 Iv>) is added dropwise from a pressure equalized addition funnel and the resulting solution stirred at room temperature for 16 h. The mixture is evaporated under reduced pressure at r.t., the residue is taken up in 66 mL of water and extracted with 3 x 25 mL of chloroform. The aqueous layer is acidified to pH 3 with concentrated HCl and extracted with 3 x 30 mL of chloroform. The combined organic layers were dried over magnesium sulphate, filtered and evaporated to give (2) 182-183 °C: 'H
NMR (CDCI;) 8 3.72 (s, 3H), 4.27 (m, 6H).
Yield 5 1 g (91%).
Pr-eparatior~ 2: 4-methoaycarbonyl-1-(hydrox~~rnethyl) cubane The mono acid (2) (0 48 g) is dissolved in dr<- THF (5 mL) and cooled to -70 °C A solution of BH: in THF is added slowly with stirring. The reaction mixture is stirred at -78 °C for 4 hrs and --~ 02328984 2000-10-16 Printed:l 2-10-2000 y~ ,, ~'.' .. 'y 'v r r.'~° ~ ~.' '-"_.:. ~ "
!~:'~'' 30'' . . t :- ~ , . y. :;"' 20-07-:2000 ~ ~ PCT/CA99/00311 pFgC
allowed to come w rrtr~m temperature. Water (3 mL) is added and stirred for 30 rnin, potassium carbonate (0.85 g) is added antl the solution exirdetcd with Ft,,O. 'fhc organic phase is driai over magnesitus? sulfate and evaporated to give the alc:ahol (3) 0.46 g (!00%) m.p.
83-85 °C. '~I
NMR(200IvII~~, solvent) c~: l.Sg (s, 11i), 3.62 (s, 3f1). 3,72 (s, 2H), 3.8t (m, 31~), 4.1 (m, 3H).
Pre~xwadnn,?; 4-rnc;thoxycarfictnyt-1-(formyl) cubane DA450 (0.7 mL. 9.68 mrtxtl) is added to s~xalyl chloride (0.42 mL, d.~ mmat) in 12 mL afi Chi=CIz at -7$ °C. 'fhc alcohol (3) (0.4G g. 2,42 rnmol) in 3 mL CH; CIZ is addcxl and stirred at -78 °C for t.5 h. '1'riethylamine (2.0 rnL, 14.4 mmol) is adddd and the miotur~ is allowed to come to 0°C.
Saturated ammar<ium chloridre salutitrn is added and the phases separated, thc~ dqutous layer is extracted with CH,CI, and the c<mt~inetl organic layers are dcied (M$SfJ~), then c,~-apr>rattxi to give crude: prnduct which ir; purified by flash chromatc~~~raphy (i :1 hexanes:dicthyl ether) is give 0.35 g (7blo) of pure product (4). 'H NMR (200 M!-lr. solvent) 8: ,3.7 (s, 3H), d.Z
(m, 3H ), 4.32 (m.
3H), ~.~z (~.1JK).
Preparutiun 4: ~t-tncthc>xycat~uny-1-I~2'-hydroxy-1'-phenylcrhyl) mothylnittilocubane a (R)-hhcnytglyeinol (2a7 mg. 1.87 mrnul) is added t~ a solution of the aldehyde; (4) (0.35 g, 1.84 rntnot) in 14 mL. of methanol. 'T'tu, soluticm is cooiod to 0 "C and TNiSCN
(O.d9 inL, 3.68 mmoJ) is added and the nuxeurc; stirred ai 0 °C overnight. F,vapordtion of the solvent leaves a ncsidue which is purifiotJ by chrz~matography (diethyl cther:hexancs, 3:1) to gise G.48 g (77%) of pure product {5). tIl NMR (C~UCI,~ b: 2.23 (s. l I-1.), 2.6 (br, llrl), 3.S-3.75 (m, 2H?, 3.7 (s, 31~). 3.9 (m.
3H), 4.1 i (dd. 1H), 4.2 (m, 311), 'l.3 (s, 5H).
Preparadion ~~ ~4-carboxy-1-cubanylglycine Lead rtceta~tc (O.E~9 g, 1.57 mmt~t) is added W a stirred solution t>f niirile (5) (G.48 g, 1.42 tnmol) in dry methanc~tldichic~romcahane 1:L (1.2 mL). After 10 min IO mL of water is added and the suspension fittc:red thrt~ugh ectitc. 'fhe organic layer is dried and euapr~rated to give the crude inunc. The crude imine is refluxed with 6N HC.I (30 mL) for 6 hr. The solutiorl i.5 evaporated tn dryness and ptaeEd cm anicyn exchange resin, elating with IN acetic acid to yield the prc~d~uct (6).
rnp. 241 °-C', (dcc;.) lIi rilMlZ (DZU) b 3.9G (s, 1H), 4.01 (m, 3H), 4.14 Lm, 3t-1).

Printed:l 2-~ U-~~UU g 28-07-199 PCT/CA99/003"I'1 ISA-DESG26 PC'6'/CA ~9~ v ~ 9 ;lt.~Ll~ aa~g (.0 9 - 0 ~ ° 99'~
Example 2 Me02C Me02C Me02C MeO2C
--COzMe C02H

H02C MeOzC
' N '.0 COZH - IIN~H
H2N ~ Ol Preparation l: 4-methoxycarbonylcubane carboxylic acid A solution of cubane dimethyl ester (6.Og, 27.24 mmol) in 182 mL of dry THF is stirred under N2 at r.t. a solution of methanolic NaOH (26 7 mmol, 10.7 mL 2 S 1V>7 is added dropwise from a pressure equalised addition funnel and the resulting solution stirred at r.t. for 16 h.
The mixture is evaporated under reduced pressure at r.t., the residue is taken up in 66 mL of water and extracted with 3 x 25 mL of chloroform. The aqueous layer is acidified to pH 3 with concentrated HCl and extracted with 3 x 30 mL of chloroform. The combined organic layers were dried over magnesium sulphate, filtered and evaporated to give (2) 182-183 °C: 1H NMR (CDCl3) 8 3.72 (s, 3H), 4.27 (m, 6H).
Yield 5.1 g (91 %).
Preparation 2: 4-methoxycarbonylcubane-1-carbonyl chloride The monomethyl ester (2) (1.37 g, 6 65 mmol) is dissolved in 1~ mL ofthionyl chloride and Qently refluxed overnight. The thionyl chloride is evaporated off and the resultant residue containing (3 j was used immediately without further purincation.

CA 02328984 2000-10-16 '' ' ' ' . ... , ~ .~ ..._, r Printed:l2-10-2000 ~~=' ~-~' i~=r _: i', i. i~ ~~_~ El ~~~ ~. ~'..:
'° i ;~
- -. .__.:...

28-07-1999 PCT/CA99/00311 ~C.~. ~ ~~ o g ISA-DE5C26 JULY 1999 (0 9 ~ 07. gg1 Preparation 3: 4-methoxycarbonylcubane-1-methyl ketone A suspension of copper iodide (1.49 g, 7.83 mmol) in 30 mL of dry THF is stirred at 0°C
Methyl lithium (15.75 mmol, 11.2 mL of 1.4 M) was added and stirred at 0°C for 30 min, then cooled to -78°C. A solution of 1.6 g, 7.12 mmol of (3) in 10 mL dry THF is added and the resultant mixture stirred for 1 h. at -78°C. The mixture was quenched with saturated ammonium chloride solution (15 mL) and extracted with 3 x 30 mL of diethyl ether. The combined organic layers were dried over magnesium sulphate, filtered and evaporated to give crude (4).
The product was purified by silica chromatography (hexanes:ethyl acetate, 2:1 ) to give 1.0 g of product (yield 69%). m.p. 87-89°C. 'H NMR (CDC13) 8 2.17 (s, 3H), 3.7 (s, 3H), 4.21 (m, 6H).
Preparation -~: 4-methoxycarbonylcubane-1-methyl-1-(5,5'-hydantoin) A solution of the methyl ketone (4) (1.0 g, 4.9 mmol) in 40 mL of ethanol and 5 8 mL of 1 N
NaOH, is stirred at 70°C for 4 h. The resulting solution is evaporated to dryness under reduced pressure and redissolved in 1 1 ethanol: water (20 mL). To this solution is added potassium cyanide (0.35 g, 5.4 mmol) and ammonium carbonate (0.96 g, 9.8 mmol) and the mixture heated in a sealed tube at 85°C for 24 h. The reaction is cooled, acidified with 6 N HCl and reduced in volume until a precipitate forms. The precipitate is filtered and the filtrate evaporated to dryness and extracted with ethyl acetate. The solvent is evaporated and. the product combined with the residue from above to give (S) as a white solid.
Yield 0.95 g (75%) m.p. 244-248°C. NMR'H (DMSO) S 1.18 (s, 3H) 3.9 (m, 3H), 4.0 (m, 3H), 8 1 (s, 1H), 10.6 (s, 1 H).
Preparation 5: 4-carboxycubane-1-methylglycine The hydantoin (5) (0.95 g, 3.65 mrnol) is dissolved in 30 mL of 2 N NaOH and heated to 170°C
in a sealed tube for 20 h. The reaction is cooled and filtered to remove precipitate and the filter cake washed with 3 x 10 mi. of water. The combined aqueous washings are evaporated to Qive crude (6) which is applied to Spectrum 1 X4 anion exchange resin, eluted with 0 ~ N acetic acid.
Isolation by evaporation and crystallization Gives (6) as colorless crystals.
m.p. >250°C
(decomp ) NMR. 'H (DZO) 0 1 38 (s. 3H), 3 95 (s, 6H) -JJ

Printedl2-10-2000 ;~ ; ~ :.=~ . ,:~,~:,--~. ~-~~.. .. . 33 28-07-1999 ~ PCT/CA99/00311 1SA=DESC26 PAC-riCA 99/0031 ~
09 JULY 1999 C09-67.qg) Example 3 MeOZC Me02C
COCI 'COzEt 2 O - U I:VZC.t Preparation l: 4-methoxycarbonylcubane-1-acet3rl ethylcarboxylate.
n-butyl lithium (34.83 mmol, 23.5 mL of 1.5 1Vn is added dropwise to a stirred solution of ethyl hydrogen malonate (2.32 g, 17.41 mmol) in 80 mL of dry THF under Nz at -78°C. The mixture was warmed to -30°C over 0.5 ~h and then re-cooled to -78°C. The acid chloride of cubane monomethyl ester from example (2) above (2.35 g, 10.46 mmol) in 7 mL of THF is added dropwise to the stirred solution. The reaction is warmed slowly to r.t and stirred for a further 1 h.
The solution is poured into 50 mL of 1 N HCI and extracted with 3 x 50 mL of diethyl ether.
The combined organic extracts are further extracted with 20 mL of saturated sodium hydrogen carbonate and brine, dried over magnesium sulphate, filtered and evaporated to give crude (2).
The product is purified by column chromatography on silica with hexanes: ethyl acetate 2:1 to yield 2.5 g (86%) of (2). LH NMR (CDCI3) 8 1.2 (t, 3H) 3.4 (s, 2H), 3.65 (s, 3H), 4.2 (m, 8H).

CA 02328984 2000-10-16 ~' y ~: ' . ;\ ;. -' ' ' , , ; ~. ~ ~ L _ ..
P~rinted:l 2-7 0-2000: ~: v~ ~-- c~~ ~ ~ ~., ~~~= ~ ~ ~ w'~'~ ~ 34 28-07-1999 P~TlCA99/00311 ~~'~ ~ ~~ 9 g i ISA-'DESC26 :IlILY 19991,09-07.99~~
Preparation 2: 4-methoxycarbonylcubane-1-(thioxanthyl)-acetyl ethylcarboxylate.
cubane-~i-ketoester (2) (1.158, 4.16 mmol) and thioxanthene-9-of (0.88g, 4.1 mmol) are dissolved in 18 mL of a 1:1 mixture of ethanol:acetic acid and stirred at r.t.
for 3 days. The resulting crystalline solid was filtered offto yield 1.52 g (77%) of pure (3) m.p. 147-149°C. 'H
NMR (CDCI;) 1 00 (t, 3H), 3.24 (s, 3H), 3.75 (m, 3H), 3.9 (q, 2H), 4.0 (m, 3H, 4.6 (d, 1 H), 5. 0 (d, 1 H), 7. 3 (m, 8H).
Preparation 3' 4-carboxycubane-I-methylthioxanthylketone The thioxanthylcubane adduct (3) (1.69 g, 3.57 mmol) is dissolved in ethanol 33 mL and 8.7 mL
of I N NaOH and heated at 70°C for 4 h. The resulting solution is evaporated and redissolved in 25 mL of water, acidified with 6 N HCl and extracted with 3 x 50 mL of diethyl ether. The combined organic layers are dried over magnesium sulphate, filtered and concentrated to give a crude product containing (4). Chromatography on silica using ethyl acetate gives 1.26 g (88%) of (4) 'H NMR (CDCI;) 8 2.8 (d, 2H), 3.8 (m, 3H), 4.0 (m, 3H), 4.7 (t, 1H), 7.3 (m, 8IT), 9.5 (br, 1H).
Preparatiorr ~f: 4-carboxycubane-I-thioxanthyl-I-(S,5'-hydantoin) The thioxanthyl cubane ketone (4) (1.24 g, 3.22 mmol) is dissolved in 1 I
ethanol:water (20 mL). Potassium cyanide (0.522 g, 8.0 mmol) and ammonium carbonate ( 1.39 g, 14.4 mmol) are added and the solution heated in a sealed tube at 85°C for 65 h The reaction is cooled and acidified with 2 N HC1 and extracted with 3 x 40 mL of ethyl acetate. The organic layers are combined, dried over magnesium sulphate, filtered and evaporated to give (5) 1.3 g (88%) as a crude product. This material was hydrolyzed in the next step without purification.
'H NMR (CD;OD) 8 1.7 (m, IH), 2.7 (m, 1H), 3.8 (m, 3H), 4.0 (m, 3H), 4.3 (m, 1H), 7.4 (m, 8H).
PrepcrJOruorr ~: 4-carboxycubane-1- thioxanthyl lglycine ~ 02328984 2000-10-16 Printed:l2=10-2000 ~''~ ~~ ~" 3~

28-07-1999 PCT1CA99/00311 ISA-D~SC26 PST ! CA 9 9 . ~ ~ . _ _ ~9 ;IULY 1999 (09-07_991 l The hydantoin adduct (5) (300 mg, 0.65 mmol) is taken up in 1 N NaOH (10 mL) and heated at 170 °C for 20 h in a sealed tube. The mixture is cooled and the pH
adjusted with 6 N HCl to between 7 and 8. The precipitate formed is filtered and washed with water. The combined filtrate and washings are combined and evaporated to dryness. The resulting residue is purified by column chromatography and finally by reverse phase chromatography to yield (6) as colorless crystals. 70 mg. 'H NMR (CD30D + 020) b 2.3 (m, 2H), 3.9 (s, 6H), 4 4 (m, l H), 7.4 (m, 8H) CA 02328984 2000-10-16 ~' ~~. ~ 1y ~ lt,, Printed:l 2-10-2000' ~'' '.36.

Claims (21)

We claim:

1. A compound of the formula:
wherein:
R1 can be an acidic grog selected from the group consisting of carboxyl, phosphono, phosphino, sulfono, sulfino, borono, tetrazol, isoxazol, -CH2-carboxyl, -CH2-phosphono, -CH2-phosphino, -CH2-sulfono -CH2-sulfino, -CH2-borono, -CH2-tetrazol, and -CH2-isoxazol;
R2 can be a basic group selected from the group consisting of 1° amino, 2° amino, 3°
amino, quaternary ammonium salts, aliphatic 1° amino, aliphatic 2° amino, aliphatic 3° amino, aliphatic quarternary ammonium salts, aromatic 1°
amino, aromatic 2°
amino, aromatic 3° amino, aromatic quaternary ammonium salts, imidazol, guanidino, boronoamino, allyl, urea, thiourea, R3 can be H, aliphatic, aromatic or heterocyclic;
R4 can be an acidic group selected from the group consisting of carboxyl, phosphono, phosphino, sulfono, sulfino, borono, tetrazol, isoxazol; and pharmaceutically acceptable salts thereof.

2. A compound as claimed in claim 1, wherein R1 is COOH.

3. A compound as claimed in claim 1, wherein R2 is NH2.

4. A compound as claimed in claim 1, wherein R3 can be -II, or -Me; or xanthyl or thioxanthyl or -CH2-xanthyl, or -CH2-thioxanthyl and R4 is -COOH.

5. A process for the preparation of a compound of Formula I, or a pharmaceutically acceptable metabolically-labile ester or amide thereof, or a pharmaceutically acceptable salt thereof, which comprises:
(a) hydrolyzing a compound of formula:
wherein: R'1 is an acidic group selected from the group consisting of carboxyl, phosphono, phosphino, sulfono, sulfino, borono, tetrazol, isoxazol, -CH2-carboxyl, -CH2-phosphono, -CH2-phosphino, -CH2-sulfono, -CH2-sulfino, -CH2-borono, -CH2-tetrazol, -CH2-isoxazol and higher analogues thereof, or a protected form thereof, R3 can be H, aliphatic, aromatic or heterocyclic and R5 represents a hydrogen atom or an acyl group, and wherein preferred values for R5 are hydrogen and (2-6C) alkanoyl groups, such as acetyl; or (b) deprotecting and hydrolying a compound of formula (II b) wherein: R'1 and R3 are as defined above; or (c) hydrolyzing a compound of formula:
wherein: R6 and R7 each independently represent a hydrogen atom, a (2-6C) alkanoyl group, a (1-4C) alkyl group, a (3-4C) alkenyl group or a phenyl (1-4C) alkyl group in which the phenyl is unsubstituted or substituted by halogen, (1-4C) alkyl or (1-4C) alkoxy, or a salt thereof, R'1 and R3 are as defined above; or (d) deprotecting a compound of formula:
wherein: R8 represents a hydrogen atom or a carboxyl protecting group, or a salt thereof, and R9 represents a hydrogen atom or a nitrogen protecting group, R'1 and R3 are as defined above;
whereafter, if necessary and/or desired:
(i) resolving the compound of Formula I;
(ii) converting the compound of Formula I into a non-toxic metabolically-labile ester or amide thereof; and/or (iii) converting the compound of Formula I or a non-toxic metabolically-labile ester or amide thereof into a pharmaceutically acceptable salt thereof.

6. A pharmaceutical formulation, which comprises a compound as claimed in claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.

7. A use of the compound according to claim 1 to modulate one or more metabotropic glutamato receptor functions in a warm blooded mammal, wherein said use comprises administering an effective amount of a compound of formula (I) as claimed in claim 1.

8. A compound of formula:
wherein: R'1, R3 and R5 have the meanings as defined in claim 5.

9. A compound of formula:
wherein: R'1, R3, R6 and R7 have meanings as defined in claim 5.

10. A compound of formula:
wherein: R'1, R3, R8 and R9 have meanings as defined in claim 5.

11. A compound according to claim 1, wherein R1 is -COOH, R2 is -NH2, R3 is H
and R4 is COOH.

12. A compound according to claim 1, wherein R1 is -COOH, R2 is -NH2, R3 is and R4 is COOH.

13. A compound according to claim 1, wherein R1 is -COOH, R2 is -NH2, R3 is -CH2-thioxanthy and R4 is COOH.

14. A use of the compound according to claim 1 for the treatment of a neurological disease of disorder selected from the group comprising: cerebral deficits subsequent to cardiac bypass surgery and grafting, cerebral ischemia, stroke, cardiac arrest, spinal cord trauma, head trauma, perinatal hypoxia, and hypoglycemic neuronal damage, Alzheimer's disease, Huntington's Chorea, amyotrophic lateral sclerosis, AIDS-induced dementia, ocular damage, retinopathy, cognitive disorders, idiophathic and drug-induced Parkinson's disease, muscular spasms, convulsions, migraine headaches, urinary incontinence, psychosis, drug tolerance, withdrawal, and cessation (i.e, opiates, benzodiazepines, nicotine, cocaine, or ethanol), smoking cessation, anxiety and related disorders, (e.g. panic attack), emesis, brain edema, chronic pain, sleep disorders, Tourette's syndrome, attention deficit disorder, and tardive dyskinesia, wherein said use comprises administering an effective amount of a compound of formula (I).

15. A use of the compound according to claim 1 for the treatment of a psychiatric disease or disorder selected from the group comprising: schizophrenia, anxiety and related disorders (e.g. panic attack), depression, bipolar disorders, psychosis, and obsessive compulsive disorders, wherein said use comprises administering an effective amount of compound of formula (I).

16. The use according to any one of claims 7, 14 or 15 wherein said compound is selected from the group of compounds comprising:

17. A use of the compound:
for the treatment of cerebral ischemia, stroke and cardiac arrest, wherein said use comprises administering an effective amount of the said compound.

18. A compound of formula:
wherein: R'1 and R3 have the meaning as defined in claim 5.

19. A compound according to claim 18, wherein: R'1 is -COOMe, R3 is H.

20. A compound according to claim 9, wherein: R'1 is -COOH, R3 is CH3, R6 = R7 is H.

21. A compound according to claim 9, wherein: R'1 is -COOH, R3 is -CH2-thioxanthyl, R6 = R7 is H.