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HETEROPOLYCYCUC COMPOUNDS AMD THEIR USE AS MATABOTROPIC GLUTAMATE RECEPTOR ANTAGONIST
FIELD OF THE ftTONTION
The invention provides compounds active at metabotropic ghttunaee receptors and that are useful for treating neurological and psychiatric diseases and disorders.
BACKGROUND OF THE INVENTION
Recent advances in the elucidation of the neurophysiologicai roles of metabotropic glutamate receptors have established these receptors as promising drug targets in the therapy of acute and chronic neurological and psychiatric disorders and diseases. However, die major challenge to the realization of this promise has been the development of metabotropic glutamate receptor subtype-selective compounds.
Ghitamate is the major excitatory neurotransmitter in the m^tflmaiian central nervous system (CMS). Glutamate produces its effects on central neurons by binding to and thereby activating cell surface receptors. These receptors have been divided into two major classes, the iowxropic and metabotropic glutamate receptors, based on the structural features of the receptor proteins, the means by which the receptors transduce signals into the cell, and pharmacological profiles.
Hie metabotropic gmtamate receptors (mGluRj) are G protein-coupled receptors mat activate a variety of iatraceUular second messenger systems following the binding of ghnamate. Activation of mGtuIU hi intact «nm1T>*al'ftl neurons elicits one or more of the Mowing responses: activation of phospholipase C; increases in phosphouwsitide (PI) hydrolysis; intracellular calcium release; activation of phosphoiipase O; activation or inhibition of adeoyl cydase; increases or decreases in the formation of cyclic adenosme monophosphate (cAMP); activation of guanylyl cydase; increases in the formation of cyclic guanosine monophosphate (cGMP); activation of phosphoiipase A»; increases in
aiachidonk acid release; and increases or decreases in the activity of voltage- and ligand-gated ion channel*, Schcepp et al., Trends PharmacoL Set 14:13 (1993); Schoepp, Newochem. Int. 2*439 (1994); Pin et at., Neunphamacohgy 34:1 (1995).
Eight distinct mGtuR subtypes, termed mGluRl through mGluRS, nave been identified by molecular cloning. See, for example, Nakanuni, Neuron /J:1031 (1994); Pin et al, Neumpfarmacotogy 34:1 (1995); Knopfel et al., J. MetL Chm, 3*1417 (1995). Further receptor diversny occurs via expression of alternatively spliced forms of certain mGluR subtypes. Pin et al., PNAS 89:10331 (1992); Minakuni et al,, BBRC ;99rll36 (1994); Joly et al,, J. Neurosd. /5:3970 (1995).
Metabotropic giutamate receptor subtypes may be subdivided into three groups, Group I, Group n, and Group ni oaGIuRs, based on amino acid sequence bomology, the second messenger systems utilized by the receptors, and by their pharmacological characteristics. Nakanishi, Neuron 73:1031 (1994); Pin et ol.t Nfurapharmacology 34;l (1995); Knopfd etal., J. Med. Own, J&1417 (1995).
Group I mGluRs comprise mGluRl, mGluRS, and their alternatively spliced variants. The binding of agonists to these receptors results in die activation of phospholipase C and the subsequent mobilization of intracdlular calcium. Electrophysiological measurements have been used to demonstrate these effects, for example, in Xenopus oocytes that express recombiaant mGluRl receptors. See, for example. Masu etaL> Nature 349:760 (1991); Pin et al., PNAS 89:10331 (1992). Similar results have been achieved with oocytes expressing recombinant mGluR5 receptors. Abe et al.t /. BiaL Otem. 267:13361 (1992); Minakami et al., BBRC 199:1136 (1994); Joly et al., J. Neurosd. /5:3970 (1995). Alternatively, agonist activation of recombinant mGluRl receptors expressed in Chinese hamster ovary (CHO) cells stimulates PI hydrolysis, cAMP fonnanon, and arachidooic acid release » measured by standard biochemical assays. Aramori etaL, Neuron «:737 (1992).
By comparison, the activation of mGluR5 receptors, expressed in CHO cells,
stimulates PI hydrolysis and subsequent intraceUular calcium transients, but no stimulation
of cAMP formation or aracbidonic acul release is obsaved. Abe et al., J. BioL Qtem.
267:13361 (1992). However, activation of mGluRS receptors expressed in LLC-PKi cells
results in PI hydrolysis and increased cAMP formation. Joly etal.,J. Neurosd. 15:3970
(1995). The agonist potency profile for Group I mGluRs is quisqualate > giuamate -
ibotenate amiiio(7clopentane-l,3-dicarboxylic acid (ACPD). Quisqualate is relatively selective for. Group I receptors, as compared to Group II and Group in mGluRs, but it also is a potent activator of ionotropic AMPA receptors. Pin et aL, Neuraphamacolagy 34:1, Knopfel et aL, J. Med. Chan. 58:1417 (1995).
TTie lack of subtype-specific mGluR agonists and antagonists has impeded elucidation of the physiological roles of particular mGhiRs, and the raGraR-assotiated pathophysiological processes that affect the CNS have yet to be defined. However, work with die available non-specific agonists and antagonists has yielded some general insights about the Group I xaGluRs as compared to the Group II and Group HI mGhiRs,
Attempts at elucidating the physiological roles of Group I mGlaRs suggest that activation of these receptors elicits neuronal excitation. Various studies have demonstrated that ACPD can produce postsynaptic excitation upon application to ncurous in the hippocampus, cerebral cortex, cerebellum, and thalamus, as well as other brain regions. Evidence indicates that this excitation is due to direct activation of postsynaptic mGluRs, but it also has been suggested mat activation of presyoaptic mGluRs occurs, resulting is increased neurotransmitter release. Baskys, Trends fharmacol Sti. 15:92 (1992); Schoepp, Neurochem. Int. 24:439 (1994); Pin et oL
Pharmacological experiments implicate Group I mGluRs as the mediators of this excitatory mechanism. The effects of ACPD can be reproduced by low concentrations of quisqualate in the presence of iGluR antagonists. Hu et at., Brain Res. 568:339 (1991); Greene et al., Eur. J. Pharmacol. 226:719 (1992). Two phenylglyciae compounds known to activate ujGIuRl, namely (5;-3-hydroxyphenylglycine ((3J-3HPG) and
nociception and analgesia also has been demonstrated. Meiler et at., Nftiroreport 4: 879 (1993). In addition, mGluR activation has been suggested to play a modulatory rote in a variety of other normal processes including synaptic transmission, neuroaal developmeni, apoptodc neuional death, synaptic plasticity, spatial learning, olfactory memory, central control of cardiac activity, waiting, motor control, and control of die vesabuto-ccular reflex. Generally, see Nakanishi, Neuron 13:1031 (1994); Pin et al., Neuropharmacoiogy 34:1: Knopfel ft
Metabotropic glutamate receptors also have been suggested to play roles in a variety of pathophyjiological processes and disease states affecting the CNS. These include stroke, head trauma, anoxic and ischemic injuries, hypoglycemia, epilepsy, and neurodegeneraove diseases such as Alzheimer's disease. Schoiepp et al,, Trends PharmacoL Sd. 14:13 (1993); Cunningham ft al., Life Sd. 54:135 (1994); HoUman et at, Ann. Rev. Neurosd. 17:31 (1994); Pin et al., Neurophamacology 34:1 (1995); Knopfd etaL,J. Med. Chem. 38:1417 (1995). Much of die pathology in these conditions is thought to be due to excessive ghjamace-induced excitation of CNS neurons. Brcause Group I mGluRs appear to increase g^|am?n*-ffMt-
Preliminary snidifft assessing therapeutic potentials with toe available mGluR agonists and antagonists have yielded seemingly contradictory results. For example, it has been reported that application of ACPD onto hippocampal neurons leads to seuures and oeuroaal damage (Sacaan et al., Neurosa. Lett. 139:77 (1992); Lippartt ft al., Life Sd. 52:85 (1993). Other studies indicate, however, that ACPD inhibits epfleptiform activity, and also can exhibit neuroprotectrve properties. Taschenberger ft al,, Newntreport 3:629 (1992); Sheardown, Neuroreport 3:916 (1992); Koh et al,, Proc. NatL Acad. ScL USA 3&9431 (1991); Chiainulera et al., Ear. L PharmacoL 216:335 (1992); Siliprandi etal., Eur. J. PharmacoL 219:113 (1992); Pirzi etat., J. Neurockem. 52:683 (1993).
It is likely that these conflicting results are due to the lack of selectivity of ACPD, which causes activation of several different mGluR subtypes. In the studies finding neuronal damage it appears mat Group I mGluR* were activated, mereby enhancing undesirable excitatory neurotransmissiou. In the studies showing neuroprotecdve effects it
appears that activation of Group II and/or Group HI mGluRs occurred, inhibiting, presynaptic glutamate release, and diminishing excitatory neutotra&sxnission.
This interpretation is consistent with the observation that (5>4C3HPG, a Group ! mGluR antagonist and Group II mGluR agonist, protects against audiogenic seizures in DBA/2 mice, while the Group II mGluR selective agonises DCG-IV and L-CCG-I protect neurons from NMDA- and KA-iaduced toxiciry. Thomson eta/,, /. Neurochem, 62:2492 (1994); Bruno et d., Eur. /. Phamacol, 256-.IG9 (1994); Pizsd et al., J. Neurochem. 67:683 (1993).
Based on die foregoing, it is clear that currently available rtiGluR agonists and antagonists have limited value, due to their lack of potency and selectivity. In addition, most currently available compounds are amino acids or amino acid derivatives that have limited bioavaiJabilities, thereby hampering in vivo studies to assess mGhiR physiology, pharmacology and their therapeutic potential. Compounds that selectively inhibit activation of metabotropic glutamate receptor Group I subtypes should be useful for treatment of neurological disorders and diseases such as senile dementia, Parkinson's disease, Alzheimer's disease, Huntington's Chorea, pain, migraine headaches, epilepsy, head trauma, anoxic and iscbcmic injuries, psychiatric disorders such as schizophrenia, depression, and anxiety, ophthalmological disorders such as various retinopathies, for example, diabetic retinopathies, glaucoma, and neurological disorders of a auditory nature such as tiniiftis, and neuropathic pain disorders, including neuropathic diseases states such as diabetic neuropathies, chemotherapy induced neuropathies, post-herpedc neuralgia, and trigeminal neuralgia.
Accordingly, a need exists for potent mGluR agonists and antagonists that display a high selectivity for a mGluR subtype, particularly a Group 1 receptor subtype.
SUMMARY OF THE INVENTION
It is an object of the present invention, therefore, to identify metabocopic glucamate receptor-active compounds which exhibit a high degree of potency and selectivity for individual metabotropic glutamate receptor subtypes, and to provide methods of making these compounds.
It is a further object of this invention to provide pharmaceutical compositions containing compounds which exhibit a high degree of potency and selectivity for individual
gunamaie receptor subtypes, and to provide methods of making these pharmaceutical compositions.
It is yet another object of this invention to provide methods of inhibiting activation of an mGluR Group I receptor, and of inhibiting neuronal damage caused by excitatory activation of an mGluR Group I receptor, specifically mGluRS.
It is still another object of the invention to provide methods of treating a disease associated with excitatory activation of an mGluR Group I receptor, specifically mGluRS.
To accomplish .these and other objectives, the present invention provides potent antagonists of Group I mGluRs, specifically, mGluRS. These antagonists may be represented by the formula I,
wherein Ar1 is an optionally substituted heteroaromatic moiety and Ar is an optionally substituted benzene ring. The G moiety is a group that not only covalently binds to the Ar1 and Ar2 moieties, and facilitates adoption of the correct spatial orientation of Ar1 and Ar3, but also itself may interact with the protein, to effect receptor binding.
In one embodiment of the invention, G is selected tram the group consisting of -NH-, -S-, -O-, -CO-, -CONH-, -CONHCHa-, -CHaCONH-, -CNHNH-, -CNHNHCH*-, -ONO-CH*-, -CHiNHCHb-, -CHzCHaNH-, -NHCHaCO-, -NHCifeCHOH-, -NHCNHNH.-, -NHCONH-, cyclopentane, cyclopentadiene, furan, thiofuran, pyrroiidine, pyrrole, 2-imidazoline, 3-imidazoline, 4~imidazoUne, imidarole, pyrazoline, pyrazolidme, inudazoUdine, oxazole, 2-oxazole, thiazole, isoxazole, isothiazole, UEM,2,4~triazole, Ift-U,3-triazole, 1,2,4-oxamiazole, 1,3,4-oxathiazole, 1,4,2-diojazole, 1,4,2-oxaehiajole, l,2,4^aadiazole, U,4-miadiazokt l,2>o»diazole, 1,2,5-tniadiazole, 1,3,4-oxadiazole, 13,4-thiadiazole. IB-tetrazole, i^clohesane, piperidine, tBirahydropyridine, 1,4-dlhydrqpvridine, pyridine, benzene, tetrahydropyran, 3,4-dihydro-2ff-pyran, 2ff-pyran, 4Jjf-pyran, tetrahydrothiopyran, 3,4-dihydro-2H-thiopyrant 2ff-miin, 4flr-miopyran, morphoUne, thiomorpholme, piperazine, pyridazine, pyrimidine, pyrazine, 1,2,4-triaariue, 1^,3-triazine, It3.5-triazine, and 1,2,4,5-tetrazme.
In another embodiment of the invention, Ar1 is selected from the group consisting of phenyl, benzyl, naphthyl, fluorenyl, anthrenyl, tndenyl, phenanmienyl, and benxooaphthenyl, and Ar2 is selected from me group consisting of diiazoyl, furyi, pyranyl 2H-pyrrolyl, thienyl, pyrroyl, imidazoyi, pyrazoyl, pyridyl, pyrazinyt, pyrimiduiyl, pyridazinyl, benzothiazole, benzimidazole, 3H-indolyl, indolyl, indazoyl, purinyl.
quinoiizmyl, isoquinolyl, quinolyl, phthalttinyl, naphmyridmyl, quinazolinyl, dnnolinylfc isothiazolyl, quinoxalinyl indolizinyl, isoindolyl, benzomienyl, benzoraranyl, isobenzofUranyl, and chromeayl.
la yet another embodiment, compounds of die present invention can be represented by formula 0:
(Figure Remove)
wherein X, Y, and Z are independently selected from the group consisting of N, 0, S, C, and CO wherein at least one of X, Y, and Z is a heccroatora;
Ar1 and Ar3 are independently selected from the group consisting of a aeterocyclic or fused hcterocyclic moiety containing 1 to 4 heteroatoms selected from the group consisting of N, 0, and S and an aromatic moiety selected from the group consisting of phenyl, benzyl, 1-naphthyl, 2-naphthyl, fluorenyl, aathrenyl, indenyl, phenanthrenyl, and benzonaphtbenyl, wherein the Ar4 and Ar2 moieties are optionally substituted with one or more moieties selected from the group consisting of -F, -Cl, -Br, -I, -OR, -SR, -SOR, -SOaR, -SOiNRR', -OCOR. -OCONRR', -NRCOR', -NRCCbR', -CN, -NOi, -COiR, <:onrr and wherein r or is selected from the group consisting of h cfs g-cw alkyl cydoalkyr aucyl-aryl aucyl-heteroaryl heterocycloalky aryl where may combine to form a ring defined as cha o nh s so soi n i heterocycac fused heterocyiic moiety preferably me quinoryu quinazolyl ouinoxalyl andpyrazyl.>
[p » pn>fam>ri mhn«fanant nf the hivenaon. die compound tt Selected ftOffl the
group consisting of S-CZ-pyridyD.SKS.S-dicblorophenyD-l ,2,4-o»diazole, H2-pyndyl)-5-
, 3-
(trifluoromethyl)phcnyQ-l,2f 4-oxadiazok, 3-(2-pyridyl)-5-5K2,5-difluoropheiiy^l,2,4H3xadiazole, 3-(2-pyridyl)-5-{3,5-difhiorophenyl)4,2,4-(wadiazole, 3^2-pyridyl>5K3-cyanophenyl)-l,2,4-oxadiazole, 3-(2-
1,2,4-oxadiazole, 3K2-pyridyl^5K3^oro-5-cyanopheiryO^^ 3-(2-
pyridyl)-S-(3-flttoro-5-qranophenyl)-i ,2,4-oxadiazole, 3-{2-pyridyl)-5-{3-diloro-5-fluoraphenyO-l,2,4-oxadiazole, 3^5-^orq?yrid-2-yI)-5-(3-cyaiK3phcnyl)-l,2,4-oxadiazole, 3-(5-fhoropyridr2-yl)-5H3-cyanopbenyi)-l,2,4- 1,2,4-oxadiazoJe, 3^5-fluoropyrid-2-yl).5^3^-
In another embodiment of the invention, the compound is selected from the group consisting of 2-(3,5-dichiorophenyl)-4-(2-pyridyl)-l,3-oxazoie, 2-(3-chlorophenyl)-4-l,3-oxazole, 2-(3«cyaQophenyl)-4-(2^>yridyl)-l,3-oxazole, 2-(3^-dunethoxyphenyIH-yridyl)-l ,3-oxazole, 2-{2,3-dicWoropbienyl)-4-(2-pyridyl)-l ,3-oxazole, 2-(3-chloro-5^yanopheayl>4K2-pyridyl)-l,3HJxazole, 2-(3'fluoro-5-cyanophenyl)-4-(2-pyridyl)-l,3-oxazole, 2-(3
oxazole, 2-C24-4-(2-pyridylH,3-oxazote, 2H3-mtroph«nyI)^2-pyriclyl-l,3-oxazole1 2-(3-bromopheayl)-4-(2-pyridyl)-l,3-oxazole and pharmaceutically acceptable salts thereof.
In accordance with another embodiment of the invention, there has been provided a pharmaceutical composition comprising a compound as set form above in Formula I and formula II, together with a pharmaceuncally acceptable diluent or exctpient.
In accordance with still another embodiment of the invention, mere has been provided a method of making a compound as set forth above. Specifically, compounds of the invention generally can be prepared by formation of the G moiety between two precursor compounds containing suinble Ar1 and Ar3 moieties. When the linker contains an 1,2,4-oxadiazole, tbe heterocyck may be fonned using well known techniques, such as reaction between an amidoxime and an acid chloride, or by the reactioa of an amidoxime and an acylimidazole. An illustration of such a transformation is provided in Examples 3 through 6, below.
Amidoximes can be prepared using well known techniques by the reaction of an Ar1 substituted nitrile with hydroxylamine. An illustration of such a transformation is provided below in Example 1.
In most cases, the precursor Ar1 carbonyl chlorides are readily available, or may be prepared using straightforward techniques of organic chemistry. For example, carboxyiic atida may be convened into the corresponding acid chlorides by reaction with, for example, duooyl chloride or oxalyl chloride.
In die case where the linker contains a 1,3-oxazoIe, compounds were prepared from the procedure similar to that given by Kelly ft aL, J. Org. Chan. 61. 4623-4633 (1996). 3,5>DisubsHmtrd-lT3-Ox2Lzoles were prepared by reacting a haloketone with carboxamide in refluxing toluene for 3 days. The resulting mixture was allowed to cool to room temperature, the solvent was removed and die residue was purified.
In accordance with a still further embodiment of the invention, there has been provided a method of inhibiting activation of an mGIuR Group I receptor, specifically mGluRS, comprising treating a cell containing said mGIuR Group I receptor with an effective amount of a compound as set forth above.
In yet another embodiment of the invention, there has been provided a method of-inhibiting neuronal damage caused by excitatory activation of an mGhiR Group I receptor, comprising Treating neurons with an effective amount of a compound as set forth above.
In accordance with a further embodiment of the invention, there has been provided a method of treating a disease or disorder associated with ghitamate^induced neuronal damage, or a method of treating a disease or disorder associated with Group I mGhiR activation or amenable to therapeutic intervention with a mGhiR Group I antagonist, comprising administering to a patient suffering from said disease or disorder an effective amount of a composition as set forth above, wherein said disease or disorder is selected from the group consisting of as senile dementia, Parkinson's disease, Alzheimer's disease, Huntington's Chorea, pain, migraine headaches, epilepsy, head trauma, anoxic and ischemic injuries, psychiatric disorders such as schizophrenia, depression, anxiety, diabetic reonopaihies, glaucoma, tinnitus, diabetic neuropathies, chemotherapy induced neuropathies, post-berpetic neuralgia, and trigeminal neuralgia.
Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.
BRIEF DESCRIPTION OP THE DRAWINGS
Figure 1 shows illustrative compounds of the invention. DETAnJED DESCMPTION OF THE INVENTION
The present invention provides compounds mat are potent and selective antagonists of mGhiBS. The compounds contemplated by the invention can be represented by the general formula I:
Ar'-G-Ar3 (I)
where Ar1 is an optionally substituted heterocyclic moiety and AT" Is an optionally substituted carbocyclic moiety. The G moiety is a group that not only covalently binds to
the Ar* and Ar1 moieties and facilitates adoption of the correa spatial orientation of Ar1 and-Ar3, but may itself interact with the protein to allow receptor binding.
Structure of the Ar1 and Ar2 moieties
The Ar1 moiety is generally defined as a heterocycUc moiety, and the Ar3 moiety is generally defined as a carbocylic moiety. Ar1 and Ar3 can be monocyclic or fused bicyclic groups. Ar1 is preferably defined as an ary! or alkaryl moiety. Ar1 is preferably defined as a heterocyclic, beteroaryl or heteroarylalkyl moiety. The ring systems encompassed by Ar1 can contain up to four heteroatoms, independently selected from the group consisting of N, S, and 0. When Ar1 is a heteroaryl ring or ring system, it preferably contains one or two heteroatoms. At least one of the heccroatoms preferably is nitrogen (N). The heterocyclic or fused heterocylic moiety preferably is selected from the group consisting of quiaoJyl, quiaazolyl, quinoxalyl, 2-pyrimidyl, 4-pyrimidylt S^yrimidyl, 2-pyridylt 3-pyridyl, 4-pyridyl, and pyrazyl.
Monocyclic Ar1 groups include, but are not limited to: thiazoyl. furyl, pyranyl, 2H-pyrroiyl, thienyl, pyrroyl, imidazoyl, pyrazoyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl moieties. Monocyclic Ar3 group include but are not limited to phenyl and benzyl. Fused bicyclic Ar1 include, but are not limited to, naphthyl, fluorcayl, anthrenyl, indenyl, phenanthrenyl, and benzonaphthenyl. Fused bicyclic Ar1 groups include, but are not limited to: bcnzotbiazole, benzimidazole, 3H-indolyl, indolyl, indazoyi, purinyl, qumoliiinyl, isoquinolyl, quinolyl, phthalizinyl. naphthyridinyl, quinazolinyl, cinnolinyl, isotbiazolyl, quinoxajinyl indolizinyl, isoindolyl, benzomienyl, benzofuranyl, isobenzofuranyl, and chromenyl moieties. Ar1 preferably is a 2-pyridyl moiety. Ai3 preferably is a sabstiAtted pheayl moiety.
The Ar1 and Ar3 moieties optionally may independently be substituted with one or more moieties selected from the group consisting of halogen, d-O alkyl, Q-O O-alkyl, -OH, -OCR, -COOR, -COR, -SOR, -SOaNRR', -NRR', -CN, -CR, -CO-NRR', -A-[CHiVNRR*. wherein A is C, 0, N, SO, SOi, and R and R' arc independently selected rom the group consisting of Ci-G alkyl, H , cycloalkyl, heterocycloalkyl, aryl, and n is 1, !, 3, or 4.
Structure of the G moiety
The G moiety is generally made up of 1-14 atoms. G can be independently selected from the group of atoms: C, H, N, 0, and S.
The G moiety can thus be made of a non-cyclic mokty. Several examples of these are -NH- (amine), -S- (thioether), -O- (ether), -CO- (ketone), -CONH- (amide), -CONHCJfc-, -CHaCONH-, -CNHNH- (amidine), -CNHNHCH*-, -ONO-CH*-(methoxime), -CHaNHOfc-, -CHjCHsNH-, -NHCHaCO-, -NHOfcCHOH-, -NHCNHNH.- (suanidine), and -NHCONH- (area), for example.
The atomic arrangement in me G moiety can also be made to form a five-membered ring. Several examples of these are cyclopentane, cyclopentadiene, furan, thiofuran, pyrrolidine, pyrrole, 2-imidazoline, 3-imidazoline, 4~imidazolii>e, imidazole, pyrazoline, pyrazolidine, imidazoUdine, oxazole, 2-oxaioie, thiazole, isoxazole, isothiazole, IH-1,2,4-triazole, L£f-l,2,3-oiazoie, 1,2,4-oxathiazole, 1,3,4-oxamiazoie, l,4,2-dioxazolet 1,4,2-oxathiazole, 1,2,4-oxadiazole, 1,2,4-miadiaxole, 1,2,5-oxadiazole, l,2,5-thiadia2ole, l,3,4H3iadiazoJe. 1,3,4-miadiazole, and 1/f-tetrazole, for example. The 1,2,4-oxadiazole is most preferred.
The atomic arrangement in the G moiety can also be made to form a six-membered ring. Several examples of these are cyclohexane, piperidine, tetrahydropyridine, 1,4-dihydropyridine, pyridine, benzene, tetrahydropyraa, 3,4-drnydn>2J?-pyran, Iff-pyran, 4H-pyran, tetrahydrothiopyran, 3»4-dihydro-2Jff^niopYraa, 2JSr-tbim, 4H-ihiopyran, morphoUne, miomorpholine, piperazinc, pyridazine, pyrimidine, pyrazine, 1,2,4-triarine, 1,2,3-oiazine, 1,3,5-triazine, and l,2,4>tetrazme, for example.
The atomic arrangement in the G moiety can also be made to form a five- or six-membered ring containing one or more carbonyl groups. Several examples of these are 2-azeridinone, l,2-diazetidin-3-one, cydopentanone, 2-cyclopentenone, 2-pynolidinone, 3-pytrolin-2-one, succinimide, maleimide, 3-pyrazolidiDone, 2-imidazolidone, 4-imidtzolin-2-one, 2/f-imidazol-2-one, 4-imidazoIinone, 3-pyrazolin-5~one, hydamoin, IH-imidazole-2,5-dione, 2-oxazoUne-4-onet 2-oxazoIidiuone, 3-oxazolm-5-one, 3(2H)-isoxazolone, 2,4-oxazolidinedione, l,2,4-triazoUne-3,5-dione, 2,4-dihydro-3fir-U2,4-triazol-3-one, 2H-pyran-2-one, 2
In a preferred embodiment, G comprises a hecerocyclic 5-membered ring system.-Preferably, G is an oxazole or an 1,2,4-oxadiazole ring. The G moiety may have either one of two-possible orientations with respect to the Ar1 and Ar* groups. Thus, for example, the invention prefers compounds having tbe configuration 4-(Ar1)-2-xadiazole.
In yet another embodiment, compounds of the present invention can be represented by formula II:
Y - Z (U)
wherein X, Y, and Z are independently selected from the group consisting of N, O, S, C, and CO wherein at least one of X, Y. and Z is a hetcroatom;
Ar1 and Ar3 are independently selected from the group consisting of a heterocyclic or fused heterocycUc moiety containing 1 to 4 heteroatoms selected from me group consisting of N, 0, and S and an aromatic moiety selected from the group consisting of phenyl, benzyl, 1-naphthyl, 2-naphthyl, fluorenyl. anthrenyl, indenyl, pheaanihrenyl, and benzonaphthenyl, wherein the Ar1 and Ar2 moieties are optionally substituted with one or more moieties selected from tbe group consisting of-F, -Cl, -Br, -I, -OR, -SR, -SOR, -SChR, -SOaNRR', -OCOR, -OCONRR', -NRCOR1, -NRCOiR', -CN, -NOi, -CChR, -CONRR', -C(0)R. -CH(OR)R'. -CHa(OR), -R, and -A-(CHiVNRR'; wherein R or R1 is selected from the group consisting of H, CFi, Ci-Ct« alkyl, cycloalkyr alkyl-aryl, alkyl-heteroaryl, hetexocycloalkyl, aryl and where R and R* may combine to form a ring, and A is defined as CHa, O, NH, S, SO, SOiaadnis 1, 2, 3, 01 4,
In & preferred embodiment of me invention, tine compound Is selected from the group consisting of K2-pyridyl)-5K3,5-dichlc^c)phenyl^l,2t4-aicadiai»le, 3-
oxadiazole, 3-C2-^dyr)-5-(l-naphthyl)-l,2,4^xadiazole, 3-(2-pyridyl}-5-[> (trmuoromethoxy)pbenyrj-l ,2,4xjxadiazole, 3-a-pyridyl^5-(2,3-difluorophenyl)-l,2,4-oxadiazole, 3-(2-pyridyl)-5K2,5-difluorophenyI)-l,2,4-cFxa5-(3-cyanopheiryl)- 1,2,4-oxadiazole, 3-(2-
3-(2-pyridyl)-5-(2,3'dichlorophenyl)- •
1,2,4-oxadiazok, 3K2^»ytidyI>-5-5-l,2,4-oxadiazole, 3^5-fhw«^yrid"2-yl)-5K3herryl>l,2,4-oxadiatole, 3-{2-pyridyl)-5-(5-cMon>-2-incibOTyphenyl)-l,2,4-oxadiazole, M2-i^dyl)-5^2-5-methyithiophenyI)-l,2,4^Jxadia2ole, 3-(2-pyridyl>-5K2-bn»no-5-meito3syphenyl)-l ,2,4-oxadiazole, S^-pyridylVS^S.S-trifluorophenyl)-1,2,4-oxadiazole, 2-[3-
la another embodiment of the invention, the compound is selected from the group consisting of 2^3^slidiiorophenyI)-4-(2^>yridyi)-l,3-oxa2oie, 2- 4-(2-pyridyl)-l,3-oxazole, 2-0-trifluorophenylH-(2-pyridyI)-l,3-oxazole, 2-(3-methylphenyi)-4-
,^
1,3-oxazole, 2K24-diftooropb«yl)-4^-pyridyl^lt3-oxazole 2-(3,5-difluorophenyiH-(2-pyridyD-l,3-oxazolef
oxazote, 2^-chtoro-5I,3-oxazolef 2--5-fluorophenyl)-4K5-nuoropyrid-2-yl)-l ,3-oxazole, 2K3^2-^uinoIinyl)-l,3-oxarole, 2-(3-cyanophenyl)-4-(3-chloro-5-trifiuoromethylpyrid-2-yl)-l13-oxazole, 2K5-cMoro-2-methoxypbeByl)-4-(2-pyridyl)-U3-
oxaaile, 2-(21.3-oxazole, 2-[3-^^rophenyi]-4-Cpyridin-2-yI]-l,3-oxazole and 2-{215,6-trifluorophenyl)-4-(2-pyridyl)-l,3-oxazole, 2-
Preparation of mGhiR Group I antagonists
Many starting materials for preparing the compounds of the present invention are available from commercial sources, such as Aldrich Chemical Company (Milwaukee, WI). Moreover, compounds of the invention are readily prepared, from available precursors, using straightforward transformations which are well known in the art. The skilled artisan will recognize that mGluR Group I antagonists, according to the invention, can be prepared via methodology that is well known, using widely recognized techniques of organic chemistry. Suitable reactions are described in standard textbooks of organic chemistry. For example, see March, ADVANCED ORGANIC CHEMISTRY, 2d ed., McGraw Hill (1977).
More specifically, compounds of the invention generally can be prepared by fonnaaon of the G moiety between two precursor compounds containing suitable Ar1 and Ar2 moieties. When the linker contains a 1,2,4-oxadiazole, the heterocycle may be formed using well known techniques, such as reaction between an amidoxime and an acid chloride, or by the reaction of an amidoxime and an acylimidazole. An illustration of such a transformation is provided in Examples 3 through 6, below.
Amidoximes can be prepared using well known techniques by the reaction of an Ar1 substituted nitrile with hydroxylamine. An illustration of such a transformation is provided below in Example 1.
In most cases, the precursor Ar3 acid chlorides are readily available, or may be prepared using straightforward techniques of organic chemistry. For example, carboxylic acids may be converted into the corresponding acid chlorides by reaction with, for ixample, thionyl chloride or oxalyl chloride.
In the case where the linker contains a 1,3-oxazole, compounds were prepared using a. procedure similar to that given by Kelly et oL, J. Org. Chan. 61, 4623-4633 (1996). Thus. 3,5-Disubstimted-l,3-Oxazoles were prepared by mixing a haloketone widi
carboxamide in refluxing toluene for 3 days. The resulting mixture was allowed to cool to room temperature, the solvent was removed and the residue was purified.
Testing of compounds for mGluR Group I antagonist activity
The pharmacological properties of the compounds of the invention can be analyzed using standard assays for functional activity. Examples of glutamate receptor assays are well known in the art, for example, see Aramori ft al.t Neuron 8:757 (1992); Tanabe et al., Neuron 8:169 (1992); Miller et al., J. Neurosdence 15: 6103 (1995); Balazs, efal., J, Neurochematry 69:151 (1997). The methodology described in those publications is incorporated herein by reference.
Conveniently, the compounds of the invention can be studied by means of an assay that measures the mobilization intracellular calcium, [Ca**]i in cells expressing mGhiK5 that can bind the compounds. A well-known cell line which is suitable for this purpose is described in Miller et al.. J. Neurosdence 15: 6103 (1995), the contents of which are hereby incorporated by reference. It has been shown that exposure of rat astrocytes to the growth factors basic fibrobkst growth factor, EOF, or transforming growth factor-a markedly increased die protein expression and functional activity of endogenous mGluRS (Miller et at., J. Neurosdence, 15(9): 6103-6109, 1995).
In brief, primary astrocytc cultures were prepared from 3-5 day old Sprague-Dawley rat pups using a modification of Miller et al. and were plated on poly-L lysine coated flasks in Dulbccco's modified Eagle's medium (DMEM) containing fetal calf serum (PCS). For cuvette analysis, cultures were up-regulated with growth factors in flasks for 3-5 days, then harvested and prepared for measurement of [Ca'*Ji mobilization as previously described (Nemetfa et al, 1998).
For fluorescent Imaging plate reader (FLJPR) analysis, cells were seeded on poly-D lysine coated dear bottom 96-well plates with black sides and analysis of [CaJ*J« mobilization was performed 3 days following the growth factor up-reguladon.
FUPR experiments were carried out using a laser setting of 0.800 W and a 0.4 second CCD camera shutter speed. Each FUPR experiment was initiated with 180 jiL of buffer present in each well of the ceil plate. After each addition of compound, me luorescence signal was sampled 50 times at 1 second intervals followed by 3 samples at 5 second intervals. Responses were measured as the peak height of the response within the sample period.
EC* and IC» detenninations were made from data obtained from 8 point-concentration response curves (CRQ performed in duplicate. Agonist CRC were generated by scaling all responses to the maximal response observed for the plate. Antagonist block of the agonist challenge was normalized to the average response of the agonist challenge in 14 control wells on the same plate. A detailed protocol for testing the compounds of me invention is provided below at Example 4.
Preparation of pharmaceutical compositions containing mGbiR antagonists) and tlwir nse in treating neurological dlsonfers
The compounds of me present invention are useful for creating neurological disorders or diseases. While these compounds typically will be used in therapy for human patients, they also fflp be used in veterinary medicine, to treat $igiUar or 'dmtK^l diseases.
In therapeutic and/or diagnostic applications, the compounds of the invention can be formulated for a variety of modes of administration, including systemic and topical or localized administration. Techniques and formulations generally may be found in REMINGTON'S PHARMACEUTICAL SCIENCES (18th ed.). Mack Publishing Co. (1990).
The compounds according to the invention are effective over a wide dosage range. For example, in the treatment of adult humans, dosages from about 0.01 to about 1000 mg per 60-70 kg adult, preferably from about 0.5 to about 100 mg per 60-70 kg adult, per [day] dose may be used. A more preferable dosage is about 2 mg to about 70 mg per 60-70 kg adult per (day] dose. The exact dosage will depend upon the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.
PhannaceuticaUy acceptable salts are generally well known to those of ordinary skill in the art, and may include, by way of example but not limitation, acetate, benzenesulfanate, besylate, benzoate, bicarbonate, •bitartrate, bromide, calcium edetate, camsyiate, carbonate, citrate, edetate, edisylate, estolate, esyiate, ftunarate, gtaceptate, ghiconate, glutamate, glycollylarsanilate, bexylresorcinate, hydrabamine, hydrobiomide, hydrochtoride, hydroxynaphmoate, iodide, isethionate, iactate, lactobionate, malate, maleate, mandelate, mesylate, mucaie, napsylate, nitrate, pamoate (embonate), pantotheoate, phosphate/disphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, or teoclate. Other pharmaceutically acceptable salts
may be found, for example, in REMINGTON'S PHARMACEUTICAL SCIENCES (18ih ed.); supra.
Preferred phannaceutically acceptable sala include, for example, acetate, beozoate, bromide, carbonate, citrate, glucooaie, hydrobromide, hydrochloride, maleate, mesyiate, napsylate, pamoate (exnbonate), phosphate, salicylare, succinate, sulfate, or tartrate.
Depending on the specific conditions being treated, such agents may be formulated into liquid or solid dosage forms and administered systemicaily or locally. The agents may be delivered, for example, in a timed- or sustained-release form as is known to those skilled in the art. Techniques for formulation and administration may be found in REMINGTON'S PHARMACEUTICAL SCIENCES; (18th ed), supra. Suitable routes may include oral, buccal,. sublingual, rectal, transderxnal, vaginal, transmucpsal, nasal or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intrapehtoneal, intranasal, or intraocular injections, truer alia.
For injection, the agents of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution. Ringer's solution, or physiological saline buffer. For transctmcosal administration, peaetxams appropriate to the barrier to be permeated are used in the formulation. Such penetrants generally are known in the an.
Use of phannaceutically acceptable carriers to formulate the compounds herein disclosed for the practice of the invention into dosages suitable for systemic administration s within the scope of the invention. With proper choice of carrier and suitable juoxnfacturing practice, the compositions of the present invention, in particular, those formulated as solutions, may be administered parenterally, such as by intravenous injection. The compounds can be formulated readily using phannaceutically acceptable carriers well known in the art into dosages suitable for oral administration. Such carriers enable the compounds of the invention to be formulated as tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingesrion by a patient to be treated,
Pharmaceutical compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an effective amount to achieve its intended purpose. Determination of the effective amounts is well within the capability of those skilled in die art, especially in light of the derailed disclosure provided herein.
In addition ID the active ingredients, rhesc pharmaceutical compositions may contain-suitable pharmaceutically acceptable carriers comprising exripients aad auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. The preparations formulated for oral administration may be in die form of tablets. dragees, capsules, or solutions.
Pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipienis, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gun tragacanth, methyl cellulose, hydroxypropylmetbyl-cellulose, sodium carboxymethyl-ceUulose (CMC), and/or polyvinylpyrroUdone (PVP: povidone). If desired, disintegrating agents may be added, such as the cross-linked polyvinylpyrroUdone, agar, or alginic acid or a salt thereof such as sodium alginate.
Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arable, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol (PEG), and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dye-stuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin, and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or stcaratfi and, optionally, stabilizers. In soft capsules, the active compounds
may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols (PEGs). In addition, stabilizers may be added.
The present invention, thus generally described, will be understood more readily by reference to the following examples, which are provided by way of illustration and are not intended to be limiting of the present invention.
EXAMPLES
Capillary gas chromaiographic and mass spectral data were obtained using a Hewlett-Packard (HP) 5890 Series II Gas Chromatograph coupled to an HP 5971 Series Mass Selective Detector [Ultra-2 Ultra Performance Capillary Column (crosslinked 5% PhMe siliconc); column length, 25 m; column i.d., 0.20 mm; helium flow rate, 60 mL/min; injector temp., 250 °C; temperamre program, 20 °C/min from 125 to 325 "C for 10 min, then held constant at 325 °C for 6 min]. Thin-layer chromatography was performed using Analtech Uniplate 250-nni silica gel HF TLC plates. UY light sometimes in conjunction with ninhydrin and Dragendorff s spray reagents (Sigma Chemical Co.) were used for detecting compounds oa die TLC plates. Most reagents used in reactions were purchased from the Aldrich Chemical Co. (Milwaukee, WI), Sigma Chemical Co. (Saint Louis, MO), Fluka Chemical Corp. (Milwaukee, WI), Fisher Scientific (Pittsburgh, PA), TCI America (Portland, OR), or Lancaster Synthesis (Windham, NH).
Example 1: Synthesis of amidoxune intermediates
PyTid-2-ylainidoxime
(Figure Remove)
Using the procedure of Shine et al., /. Heteroeyctic Chan, (1989) 26:125-128, hydroxylamine ilydrochloride (7.65 g. 110 mmol) in ctfaanol (100 mL) was treated with a solution of sodium hydroxide (11 mL of 10 N, 110 mmol). A precipitate quickly formed and the reaction mixture was stirred at ambient temperature for 30 min. The inorganic precipitate was filtered and rinsed with ethanol (100 mL). The filtrate and ethanol washings were combined and treated with 2-cyanopyridine (10.4 g, 100 mmol). The reaction mixture was heated at reflux for 20 hours. The volatile* were then removed in
L
vacua to afford 13.3 g (97%) of pyrid-2-ylamidoxime.
\Using the general procedure for the synthesis of amidoximes, hydroxylamine hydrochioride (7.65 g, 110 mmol), sodium hydroxide (11 mL of 10 N, 110 mmol), and 3-methoxybenzylnitnie (12.2 mL. 100 mmol) afforded 9.9 g (60%) of 3-methoxybeDzamidoxinie.
(Figure Remove)
A mixture of 2,5-dichloropyridine (1.48 g, 10 mmol), zinc cyanide (705 mg, 6 mmol), zinc (dust, 29 mg, 0.45 mmol), fl,l'-bis(diphenylphosphino)fBrrocene] dichloropalladium(II), complex with dichlorometbane (1:1) (0.18 g, 0.22 mmol) in N,N-dunethylformamide (10 mL) was heated at reflux for 5 hours. After cooling, the reacdon was diluted with ethyl acetate and extracted with water and brine. Silica gel chromatograpny afforded 735 mg (53 %) of 2-cyano-5-chloropyridine.
Using the general procedure for the synthesis of amidoximes, 2-cyano-5-chloropyridine (735 mg, 5.3 mmol), a solution of hydroxylamine hydrochioride (1.2 mL of 5 M. 6 mmol) in etbanol (7 mL), and sodium hydroxide (0.61 mL of 10 N. 6.1 mmol), were heated at reflux for 24 hours. Standard work up afforded 707 mg (77%) of 5-chloropyrid-2-ylamidoxime.
(Figure Remove)
A mixture of 2-cyano-5-diIoropyridine (1 g, 7.22 mmol) and potassium fluoride (1.26 g. 21.68 mmol) in l-methyl-2-pyrrolidinone (25 mL) was heated at reflux 18 hours. After cooling, the reaction was diluted with ethyl acetate and extracted with water and
brine. The organic solvents were then removed in vacua. Silica gel chromatography of the" residue afforded 425 mg (48%) of 2-cyauo-5-ftuoropyridine.
Using the general procedure for the synthesis of amidoximes, 2-cya&o~5-fluoropyridine (425 mg, 3.48 mmo!), a solution of hydroxylamine hydrochloride (0.79 ml of 5 M, 3.95 mmoi) in ethanoi (5 mL), and sodium hydroxide (0.398 mL of 10 N, 3.98 mmol) were heated at reflux for 24 hours. Standard work up afforded 330 mg (61 %) of 5-fluoropyrid-2-ylamidoxime.
(Figure Remove)
A solution of 2-cyano-5-fluoropvridine (0.65 g, 5.3 mmol) in sodium metboxide (1.83 mL of 25% wt. solution in methanol, 7.95 mmol) was stirred at 0 *C for 1.5 hours and 2 hours at ambient temperature. The reaction was then diluted with ethyl acetate and washed with water and brine. Removal of the solvent in itaoco afforded 304 mg (43%) of 2-cyano-5-metboxvpyridine.
Using the general procedure for the synthesis of amidoximes, 2-cyaoo-5-.methoxypyridine (270 mg, 2.01 mmol), a solution of hydroxylamine hydrochloride (0.457 ml of 5 M, 2.28 mmoi) in ethanoi (4 mL), and sodhim hydroxide (0.230 mL of 10 N, 2.30 mmol) were heated at reflux for 24 hours. Standard work up afforded 79 mg (24%) of 5-methoxypyrid-2-ylamidoxune.
J-Fluoropyrid-l-ylamidarime
(Figure Remove)
A mixtare of 2,3-dichloropyridme (1.48 g, 10 mmol), zinc cyanide (705 mg, 6 mmol,), zinc (dust, 29 mg, 0.45 mmol), [l,IT^is(dvh^yb^hosphino)ferrocene] dichloropalladnim(n), complex with dichloromethane (1:1) (0.18 g, 0.22 mol) in N,N-dimethylfonnamide (10 mL) was heated at reflux for 5 hours. After cooling, the reaction was diluted with ethyl acetate and extracted with water and brine. Removal of the solvent and silica gel chromatography afforded 1.05 g (76%) of 2-cyano-3-chloropyridine.
A solution of 2-cyano-3-chloropyridme (1 g, 732 mmol) in l-methyl-2-. pyrrolidinone (25 mL) was treated with potassium fluoride (1.26 g, 21.68 mmol) and heated at reflux for 18 hours. After cooling, the reaction was diluted with ethyl acetate and extracted with water and brine. Silica gel chromatography afforded 442 mg (50%) of 2-cyano-3-fluoropyridine.
Using the general procedure for the synthesis of amidoxiines, 2-cyano-3-fiuoropyridine (442 mg, 3.62 mmol), a solution of hydraxytamine hydrochloride (0.82 mL of 5 M, 4.1 mmol) in ethanol (5 mL), and sodium hydroxide (0.415 ml of 10 Nt 4.15 mmol) were heated at reflux for 24 hours. Standard work up afforded 368 mg (66 %) of 3-fluoropyrid-2-ylamidoxime.
(Figure Remove)
Using the general procedure for the synthesis of amidoximes, 2-quinolinecarbonitrile (1.02 g, 6.6 mmol), a solution of hydroxylamme hydrochloride (1.44 mL of 5 tf solution, 7.2 nunol) in ethanol (10 raL), and sodium hydroxide (0.72 mL of 10 N solution, 7.2 mmol) were heated at reflux for 18 hours. Standard work up afforded 990 mg (80 %) of qainol-2-ylamidoxinic.
Example 2: Synthesis of carboxyfic acid mtermediates
3-Chlon>-5-cyanobtnzoic add
(Figure Remove)
A mixture of methyl 3,5-dichlorobenzoate (14.66 g, 7L5 mmol), zinc cyanide (5.04 g, 42.9 mmol) zinc (dust, 0.21 g, 3.21mmol), [l,l'Bis(dipheirylphosphino)ferrocene] dichloropalladium(n), complex with dichloromethane (1:1) (1.3 g, 1.57 mmol) in N.K-dimetbylformamide (70 mL) was heated at reflux for 5 hours. After cooling the reaction was diluted with ethyl acetate and extracted with water and brine. Silica gel chromatography afforded 2.34g (17%) methyl 2-chloro-5-cyanobenzoate.
The intermediate ester was treated with a solution of sodium hydroxide (7.5 mL of 4 ff solution, 30 mmol) ia methanol (50 mL) aod stirred at ambient temperature forlS houn. The solvent was removed In vacua and the residue dissolved in ethyl acetate. The organic solution was washed with 5% KG and brine. Removal of the solvent afforded 1.8 g (83 %) of 3-chloro-5-cyanobenzoic add.
3-Chloro-5-fluorobeflzaic add
(Figure Remove)
A mixture of l-bromo-3-chloro-5-fluorobenzene (25.0 g, 120 mmol), zinc cyanide (8.45 g, 72 mmol) zinc (dust, 235 mg, 3.6 mmol), [1,1'Bis(diphenylphosphino)ferrocene] dichloropailadhimdD, complex with dichloromethane (1:1) (1.5 g, 1.8 mmol) in N,N-dimethyifbrmanude (70 ml) was heated at refiux for 1 hour. After cooling the reaction was diluted with ethyl acetate and extracted with water and brine. Silica gel chromatography afforded 15.9g (85%) 3-chloro-5-fluorobenzonitrilc.
The intermediate nitrile was treated with a solution of sodium hydroxide (100 mL of 10 //solution, 1 mol) in 100 mL water and heated at reflux for 2 hours. After this time the solution was cooled and acidified with concentrated hydrochloric acid. Extraction with dichloromethane aod evaporation of the solvent, afforded 15.14g (85%) of 3-chioro-S-fhiorobenzoic acid.
(Figure Remove)
3-Chloro-5-flucrobenzoic acid (13.74g, 78.7 mmol) was treated with SO ml thionyl chloride and heated at refiux for 2 hours. The excess thionyl chloride was removed in vacua and the residue treated with 100 ml dry methanol to afford 13.6g (92%) of methyl 3-chioro-5-fluorobenzoate.
A mixtnre of me methyl 3-cMoro-5-fluorobenzoate, zinc cyanide (8.46g, 72.3-mmol) zinc (dust, 235 mg, 3.6mmol), [l,l'bis(diphenylpli05Phiiio)ferroceiie] dichloropalladiumdl), complex with dichloromethane (1:1) (1.5 g, 1.8 mmol) in Af.Af-dimethylfonnamide (70 ml) was heated at reflux for 1 hour. The reaction was cooled to ambient temperature and diluted with ethyl acetate. The organic solution was extracted with water and brine and concentrated in vaato, to afford crude methyl 3-chloro-5-cyanobenzoate.
The crude methyl 3-chloro-S-cyanobenzoate was treated with a solution of sodium hydroxide (45 ml of 4 AT solution, 180 mmol) in methanol (350 mL) at ambient temperature for 4 hours. The solvent was removed in vacua and the residue dissolved in ethyl acetate. The organic solution was washed with 5% aqueous HC1 and brine. Silica gel chromatography afforded 7.0 g (54%) of 3-fluoro-5-cyanobenzoic acid,
Example 3: Synthesis of 3,f-disuljstitnted-l^,4-oxadiazoles from acid chlorides
In general, modifications were made from die procedures given Shine et al., J. Heterocydic Chan. (1989) 25:125-128. 3,5-Disubstituted-U,4-oxadiazoles were typically made by adding an acyichloride to a solution of an amidoxime in pyridine after which the reaction mixture was either heated to reflux or placed in a sealed tube and heated Typically, the oxadiazoles were isolated by precipitating with cold water and filtering or by extraction with an organic solvent If necessary, the oxadiazoles were purified by chromatography or recrystaUization.
3^-PyridyI)-5-(3T5-dicfalorophenyI)-lt2,4^»dia2ote (NPS 64982) (404) B2
(Figure Remove)
A mixture of 3,5-dichlorobenzoyI chloride (2.1 g, 10 mmol) and pyrid-2-ylamidoxime (1.37 g, 10 mmol) in pyridine (5 mL) was heated in sealed tube at 190 °C for 2 hours. After this time, the reaction mixture was added to ice cold water to precipitate the oxadiazole. The solid was collected by filtration, washed with water and men recrystallized from ethanol to yield 2.1 g (7255) of 3-(2-pvridyO-5-(3,5-dichlorophenyl)-
1,2,4-oxadiazote: mp 162-166 °C; GC/H-MS gave m/z (rel. int.) 291 (M*. 38), 293 (25), 261 (1), 173 (6), 145 (13), 120 (100), 90 (20), 78 (28), 51 (15).
3-O-PyridyD-5-(3-chJorophenyD-U,4-OMdiazok (NPS 64983) (405) B3
(Figure Remove)
M-O
Using the general procedure for the synthesis of 1,2,4-oxadiazoIes, 3-cnlorobenzoyl chloride (127 pL, 1 mmol) and pyrid-2-ylamidoxime (137 mg, 1 mmol) in pyridine (1 mL) were heated at reflux for 4 hours. Standard work up afforded 156 mg (61%) of 3-(2-pyridyI)-5-(3-daorophenyl)-l,2,4-oxadiazole: mp 136-140 °C; GC/EI-MS gave m/z (rel. int.) 257 (M+, 64), 259 (21), 227 (3), 120 (100), 111 (22), 90 (24), 78 (32), 75 (26), 51 (20).
3-(2-PyridyD-5-(3-ineth
(Figure Remove)
Using the general procedure for the synthesis of 1,2,4-oxadiazoles, 3-anisoyl cbloride (151 pL, 1 mmol) and pyrid-2-ylamidoxime (137 mg, 1 mmol) in pyridine (1 mL) were heated at reflux for 4 hours. Standard work up afforded 200 mg (79%) of 3-(2-pvridyl)-5-
(Figure Remove)
Using the general procedure for the synthesis of I,2,4oxadia2oles. 2-chlorobenzoyl chloride (127 ftL, 1 mmol) and pyrid-2-ylamidoxime (137 mg, 1 mmol) in pyridine (1 mL) were heated at reflux for 4 hours. Standard work up afforded 157 mg (61%) of 3-
int.) 257 (\T. 76), 259 (26), 227 (4), 139 (11), 120 (100), 111 (21), 90 (27), 78 (35), 75-(29), 51 (21).Using the general procedure for the synthesis of 1,2,4-oxadiazoles, 3-(trifluoroQj«hyl)benzoyI chloride (151 fiL, 1 nunol) and pyrid-2-ylamidoxime (137 mg, 1 nunoi) in pyridine (1 mL) were heated at reflux for 16 hours. Standard work up afforded 233 mg (80%) of 3^2-pyridyl)-5-[3Kaifluoromethyl)phenyI]-l,2,4^xadiazoIe: mp 116-118 °C; GC/EI-MS gave m/z (rel. int.) 291 (M*. 81), 272 (7), 173 (6), 145 (25), 120 (100), 90 (20), 78 (23), 51 (11).
(Figure Remove)
Using the general procedure for the synthesis of 1,2,4-oxadiazoles, 3-fluorobcnzoyl chloride (122 /iL, 1 mmol) and pyrid-2-ylamidoxime (137 mg, 1 mmol) hi pyridine (1 mL) were heated at reflux for 16 hours. Standard work up afforded 176 mg (73%) of 3-{2-pyridyl>5-(3-fluorophenylH,2.4-oxadiaa>le: mp 88-98 °C; GC/EI-MS gave mk (rel. int.) 241 (NT, 95), 211 (5), 120 (100), 107 (13), 95 (30), 90 (21), 78 (27). 75 (19), 51 (15).
3-C2-Pyridjl)-5-
Using the general procedure for die synthesis of 1,2,4-oxadiazoles, 3-toluoyl chloride (264 /iL, 2 mmol) and pyrid-2-ylamidoxime (274 mg, 2 mmol) in pyridine (1 mL) were heated in a sealed tube at 200 °C for 2 hours. Standard work up afforded 387 mg (82$) of 3-(2-pyrictyO-5
mil (rel. int.) 237 (M+, 100), 222 (2), 207 (8), 120 (68), 117 (24), 91 (29), 90 (29), 78' (32), 65 (26), 51 (23).
(Figure Remove)
N-C
Using the general procedure for the synthesis of 1,2,4-oxadiazoies, 1-naphthoyl chloride (150 pL, 1 mmol) and pyrid-2-ytamidoxime (137 mg, 1 mmol) in pyridine (1 mL) were heated in a sealed lube at 200 °C tor 3 hours. Standard work up afforded 50 mg (18%) of 3-(2-pyridyI)-5-(l-naphmyI)-l,2,4-oxadia2ole: mp 132-136 °C; GC/EI-MS gave m/z (id. int.) 273 (M*. 75), 195 (5), 169 (88), 153 (100), 139 (12), 127 (66), 126 (29), 105 (23). 78 (14), 51 (14).
3-{2-Pyrid7J)-5-[3-(triflnoromcthoxy)phenyI]-l^,4-oxadiazole (Bll)
N-0
Using the general procedure for the synthesis of 1,2,4-ojodiazoles, 3-(Difhjoramcthoxy)benzoyl chloride (220 mg, 1 mmol), and pyrid-2-ylamidoxime (137 mg, 1 mmol) in pyridine (1 mL) were heated in a sealed tube at 200 °C for 3 hours. Standard work up afforded 175 mg (5756) of 3^2-pyridyl)-5-[Xtrifluoromethoxy)phenyri-l,2,4-oxadiaznle: mp 86-88 °C; GC/EI-MS gave m/z (rel. int.) 307 (M+. 73), 277 (3), 222 (3), 189 (6). 161 (5), 120 (100). 78 (21), 69 (17), 51 (10).
Using the general procedure for the synthesis of 1,2,4-oxadiazoles, 2,3-difluorobenzoyl chloride (124 yL, 1 mmol) and pyrid-2-ylamidoxime (137 mg, 1 mmol) in pyridine (1 mL) were heated at 100 °C for 16 hours. Standard work up afforded 158 mg
(61%)of3^-pyfldyl)-H2,3-difluoropbeaylH.2,4-cxadia2ole: mp 120-121 *C; GC/EK MS gave m/t (rel ini) 259 (KT, 97), 229 (5), 228 (4), 141 (11),. 120 (100), 113 (26), 90 (27), 78 (34), 51 (17).
3
(Figure Remove)
N-O
Using the general procedure for the synthesis of 1,2,4-oxadiazoles, 2,5-difluorobeazoyl chloride (124 /iL, 1 mmol) and pyrid-2-ylamidoxime (137 mg, 1 mmol) in pyridine (1 mL) were hcaiad at 100 °C tor 16 hours. Standard work up afforded 3-(2-pyridyI)-S-{2,5-difluorophenyl)-lt2,4-o3tadiazole: mp 120-126 *C; GC/EI-MS gave mfc (rei. int) 259 (M*. 91), 229 (5), 228 (4), 141 (13), 120 (100), H3.(25), 90 (23), 78 (27), 51 (14).
3-(2-PyridyD-5-(3,S-difluoroplienyI)-M,4-oxadiazole (Big)
F
(Figure Remove)
Using the general procedure for the synthesis of 1,2,4-oxadiazoles, 3,5-difiuorobenzoyl chloride (1.25 mL, 10 mmol) and pyrid-2-ylamidoxime (1.37 g, 10 mmol) in pyridine (5 mL) were heated in a sealed tube at 200 °C for 4 hours. Standard work up afforded 1.2 g (46%) of 3K2-i>yridyl)-5-0,5-difluorophenyl)-lf2,4-oxadiazole: mp 115-119 «C; GOEI-MS gave m/z (rel. int) 259 (M*. 100), 229 (4). 228 (5), 141 (9), 125 (13), 113 (30), 90 (19), 78 (27), 63 (23), 51 (15).
(Figure Remove)
CN
Using the ^neral procedure for the synthesis of 1,2,4-oxadiazoles, 3-cyanobenzoyI chloride (165 mg, 1 mmol) and pyrid-2-ylamidoxime (137 mg, 1 mmol) hi pyridine (1 mL) were heated at 100 °C for 72 hours. Standard work up afforded 158 mg (64%) of 3-(2-
pyridyI).5^3^7anophenylH.2,4^xa(liazole: mp 148-149 «C; GC/EI-MS gave m/z (rel. int.) 248 (M*, 85), 218 (5), 130 (6), 120 (100), 114 (9), 102 (28), 90 (26), 78 (37) 75 (19), 51 (30).
(Figure Remove)
sing the general procedure for the synthesis of 1,2,4-oxadiazoles, 3,5-dimethoxybenzoyi chloride (200 mg, 1 mmol) and pyrid-2-ylamidoxime (137 rag, 1 mmol) in pyridine (1 mL) were heated at 100 "C for 72 hours. Standard work up afforded 210 mg (74%) of 3^-pyridyl)-5-
3-
(Figure Remove)
N-O
Using the general procedure for me synthesis of 1,2,4-oxadiazoles, 2,3* dichlorobenzoyl chloride (209 mg, 1 mmol) and pyrid-2-ylamidoxime (137 mg, 1 mmol) in pyridine (1 mL) were heated at 100 °C for 48 hours. Standard work up afforded 236 mg (81%)of3^2-pyridyi)-5X2,3^cMorc^hcnyl)-U,4Kradiazole: mp 128-133 °C; GC/EI-MS gave m/z (rel. int.) 291 (M", 66), 293 (43), 256 (6), 173 (10), 145 (11), 120 (100), 90 (19), 78 (27), 51 (14).
(Figure Remove)
3-Chloro-5~cyanobenzoic acid (0.82 g, 4.97 mmol) was treated with a solution of oxalyl chloride (10 mL of 2.5 M in dichloromethane, 25 mmol) and a catalytic amount of
5. The reaction was stirred at ambient temperature for 2.5 hours.-The excess oxalyl chloride was removed in vacua to afford 3-chloro-5-cyanobenzoyl chloride.
Using the general procedure for the synthesis of 1,2,4-cxadiazoles. the 3-chloro-S-cyanobenzoyl chloride and pyrid-2-ylamidoxime (682 mg, S mmol, 1 equivalent) in pyridine (5 mL) were heated in a seated tabe at 175 °C for 4 hours. Standard work up and recrysallization from 2-propanol afforded 250 mg (19%) of 3-{2-pyridyl)-5-(3-chloro-5-cyanophenyl)-l,2,4-oxadiazole: GC/EI-MS gave m/z (rel. int.) 282 (M*, 100), 283 (18), 284 (34), 251 (4), 136 (10), 120 (53), 100 (10), 78 (15), 51 (6),
(B27)
(Figure Remove)
N-O
3-Fluoro-5-cyanobenzoic acid (2.5 g, 15.14 mmol) was treated with a solution of oxalyl chloride (30 mL of 2.5 M in dichloromethane, 75 mmol) and a catalytic amount of MA^dimethylfonnamide. The reaction was stirred at ambient temperature for 2.5 hours. The excess oxalyl chloride was removed in vacua to afford 3-fluoro-5-cyanobcnzoyl chloride.
Using die general procedure for the synthesis of 1,2,4-oxadiazoles, the 3-fiuoro-S-cyanobenzoyl chloride and pyrid-2-ylamidoxime (2.076 g, 15.15 mmol, 1 equivalent) in pyridine (5 mL) were heated in a sealed tube at 175 °C for 4 hours. Standard work up and recrysallization from 2-propanol afforded 1.5 g (37%) of 3-(2-pyridyl)-5-(3-fluoro-5-cyanopfaenyl}-l,2,4-oxadiazole: GC/EI-MS gave m/z (rel, int.) 266 (M*, 81), 267 (13), 235 (5), 132 (12), 120 (100), 100 (18), 90 (18), 78 (35), 51 (20).
3-Chloro-5-fluorobenzoic acid (400 mg. 2.3 mmoi) was treated with a solution of oxalyl chloride (4.6 ml of 2.5 M in dichloromethane, 11.5 mmol) and a catalytic amount of A^dimethylformamide. The reaction was stirred at ambient temperature for 2.5 hours. The excess oxalyl chloride was removed in vacuo to afford 3-chloro-5.-fluorobenzoyl chloride.
Using the general procedure for the synthesis of 1,2,4-oxadiazoles, the 3-chloro-5-fluorobenzoyl chloride and pyrid-2-yIamidoxime (314 mg, 2.3 ramol, 1 equivalent) in pyridine (5 mL) were heated in a sealed tube at 175 °C for 4 hours. Standard work up and recrystallizarion from 2-propano! afforded 250 mg (39%) of 3-(2-pyridyl)-5-(3-chloro-5-fluorophenylM,2,4-oxadiazole: GC/EI-MS gave m/z (rd. int.) 275(M+, 89), 276 (14), 277 (29), 129 (26), 120 (100), 109 (7), 90 (20). 78 (31), 51 (14).Using the general procedure for the synthesis of 1,2,4-oxadiazoles. 3-cyanobenzoyl chloride (675 mg, 4mmol) and 5-chloropyrid-2-yIamidoxime'(686 mg, 4 mmol) in pyridine (5 mL) were heated in a sealed tube at 175 °C for 4 hours. Standard work up and recrystallization from 2-propanol afforded 357 mg (32%) of 3-(5-cbloropyrid-2-yl)-5-(3-cyanophenylM,2,4-oxadiazole: GC/EI-MS gave m/z (rel. int.) 282 (M*, 85). 283 (14), 284 (27), 156 (31), 154 (100), 112 (19), 102 (30), 76 (28), 64 (13).
(Figure Remove)Using the general procedure for the synthesis of 1,2,4-oxadiazoles, 3-cyanobenzoyl chloride (0.534 g, 3.2 mmol) and 5-fluoropyrid-2-yiamidoxime (0.5 g, 3.2 mmol) in
pyridine (5 mL) were heated in a sealed tube at 175 "C for 4 hours. Standard work up and-recrysallizarion from 2-propanol afforded 370 mg (43%) of 3-(5-fluoropyrid-2-yI)-5K3-cyanophenyl)-l,2,4xjxadiazole: GC/EI-MS gave m/z (rel. int.) 266 (M+, 100), 267 (10), 138 (80), 114 (8), 102 (19), 96 (22), 76 (17), 57 (8).
(Figure Remove)
3-Huoro-5-cyanobenzoic acid (1.0 g, 6 mmol) was treated with a solution of oxalyl chlonde (12 mL of 2.5 M in dichJoromethane, 30 mmol) and a catalytic amount of N,N-dunethylfonnamide. The reaction was stirred at ambient temperature for 2.5 hours. The excess oxalyl chlonde was removed in vacua to afford 3-fluoro~5-cyanbenzoyl chlonde.
Using die general procedure for the synthesis of 1,2,4-oxadiazoles, die 3-fluoro-5-cyanbenzoyl chloride (1.1 g, 6 mmol) and 5-fluoropyrid-2-ylamidoxime (0.93 g, 6 mmol) in pyridine (5 mL) were heated in a sealed tube at 175 °C for 4 hours. Standard worlc up and recrystallization from 2-propanoi afforded 0.41 g (24%) of 3-(5-fluoropyrid-2-yl>-5-(3-cyano-5-fluorophenyl)-l,2,4-oxadia2ole: GC/EI-MS gave m/z (rel. int.) 284 (M*, 100), 285 (16), 253 (2), 138 (99), 120 (23), 108 (16), 96 (25), 82 (15), 57 (11).
3-
(Figure Remove)
Using the general procedure for the synthesis of 1,2,4-oxadiazoles, 3-cyanobenzoyl chloride (107 mg, 0.64 mmol) and 3-fluoropyrid-2-yIamido*ime (0.1 g, 0.64 mmol) in pyridine (5 mL) were heated in a sealed tube at 175 °C for 4 hours. Standard work up, silica gel chromaiography, and recrystallization from 2-propanol, afforded 32 mg (19%) of 3-(3-fluoropyrid-2-yl)-5-(3-qranopheiiyl)-l,2.4-
3-(5-rkon)pyrid-2.yn-5-(3,5Hlimethoxyp]ienyI)-l^,4-oxadiazole(B33)
(Figure Remove)
Using the general procedure for the synthesis of l,2,4-oxadiazole3, 3,5-dimethoxybenzoyl chloride (0.10 g, 0.5 mmol) and 5-fhioropyrid-2-ylamidoxime (78 mg, 0.5 mmol) in pyridine (3 mL) were heated in a sealed tube at 175 °C for 4 hours. Standard work up, sittca gel chromatography, and recrystaliization from 2-propanol afforded 94 mg (62%) of 3-(5-fluoropyrid-2-yl)-5-(3,5-dimethoxyphenyi)-l,2,4-oxadiazole: GC/EI-MS gave miz (rel. int.) 301 (M*, 100), 302 (17), 165 (41), 137 (23), 122 (27), 96 (15), 77 (11), 63 (12).
Using me general procedure for the synthesis of 1 ,2,4-oxadiazoles, 3-cyaoobenzoyI chloride (79 mg, 0.47 mmol) and 5-methoxypyrid-2-ylanudoxime (79 mg, 0.47 mmol) in pyridine (2.5 mL) were heated in a sealed tube at 175 °C for 4 hours. Standard work" up, silica gel chromatography, and recrystallizanon from 2-propanol afforded 59 mg (45%) of 3^5-methoxypyrid-2-yl)-5K3
(Figure Remove)
Using the general procedure for the synthesis of 1,2,4-oxadiatotes, 3-cyanobenzoyl chloride (68 mg, 0.41 mmol) and quinol-2-ylamidoxime (75.9 mg, 0.405 mmol) in pyridine (0.5 mL) were beared in a sealed tube at 165 °C for 22 hours. Standard work up, recrystallizau'on from etnanol, and solid phase extraction (SPE) afforded 23.7 mg (20%) of 3^-quinolinyl)-5-(3-cyanophenyl)-l,2,4-oxadiazole. !H-NMR (CDCb), 5 (ppm): 8.62 (s,
IH), 8.54 (d, IH), 8.36 (d. 2H), 8.28 (d, IH), 7.90 (d, 2H), 7.80 (t, IH), 7.72 (t, 7.64 (t, IH).
Using the general procedure for the synthesis of 1,2,4-oxadiazoles, 3-cyanobenzoyl
chloride (66 mg, 0.40 mmol) and 3-chIoro-5-trifluoromethylpyrid-2-ylamidoxime (96.5
mg, 0.403 mmol) in pyridine (0.5 mL) were heated in a sealed tube at 165 "C for 22
hours. Standard work up and solid phase extraction (SPE) afforded 45.9 mg (33%) of 3-
(3^±lon>-5-trifluoroinediylpyrid-2-yI)-5-(3-cyanopiieiiyl)-l ,2,4-oxadiazoIc. 'H-NMR
(CDCb), 6 (ppm): 8.99 (s, IH), 8.57 (s, IH), 8.49 (d, IH), 8.19 (s, IH). 7.92 (d, IH), 7.72 (t, IH).
(Figure Remove)
5-ChJoro-O-aoisic acid (187 mg, 1 nunol) was treated with a solution of oxalyl chloride (1.5 mL of 2 M in dichloromethane, 3 mmol) and a catalytic amount of N,N-dimethylfonnamide. The reaction was stirred at ambient temperature for 2 hours. The excess oxalyl chloride was removed in vacua to afford 5-chloro-2-raethoxybenzoyl chloride.
Using the general procedure for the synthesis of 1,2,4-oxadiazoles, the 5-cUoro-Z-methoxybenzoyl chloride and pyrid-2-ylamidoxime (137 mg, 1 mmol) in pyridine (1 mL) were heated at 115 °C for 17 hours. Standard work up, and silica gel chromatography afforded 49 mg (17%) of 3K2-pyridyl)-5K5-chloro-2-meihoxyphenyl)-l^,4-oxadiazole. 'H-NMR (CDCb), 5 (ppm): 4.00(s, 3H), 7.03 (d, J= 8.9 Hz, IH), 7.42-7.47 (m, IH), 7.50 (dd, J=8.9 Hz, 2.8 Hz, IH), 7.87 (ddd, J« 1.4 Hz, 7.4 Hz, 8.2 Hz, IH), 8.22 (d, J- 8.2 Hz, IH ), 8.28 ( d, J - 2.4 Hz, IH), 8.84 (m, IH).
le (B38)
(Figure Remove)
2,3-Dimethoxybenzoic acid (182 mg, 1 mmol) was treated wito a solution of oxalyl chloride (1.5 mL of 2 M in dichloromethane. 3 mmol) and a catalytic amount of N,N-dimethylformamide. The reaction was stirred at ambient temperature for 2 boors. The excess oxalyl chloride was removed in vacua to afford 2,3-dimcthoxybenzoyl chloride.
Using the general procedure for the synthesis of 1,2,4-oxadiazoles. the 2,3-dimethoxybenzoyl chloride and pyrid-2-ylamidoxime (137 mg, 1 mmol) in pyridine (I mL) were heated at 115 °C for 17 hours. Standard work up and silica gel cinematography afforded 120 mg (42%) of 3K2-pvridyl)-5^2,3KhmeAc^}^henyl)-l,2,4-oxadiazoie.
(Figure Remove)
N-0
2-Chloro-5-methylthiobenzoic acid (182 mg, 1 mmol) was treated with a solution of oxalyl chloride (1.5 mL of 2 M in dichloromedlane, 3 mmol) and a catalytic amount of A'IMdimethylforraamide. The reaction was stirred at ambient temperature for 2 hours. The excess oxalyl chloride was removed in vacua to afford 2-chloro-5-methylthipbenzoyl chloride.
Using the general procedure for the synthesis of 1,2,4-oxadiazoles, die 2~chloro-5-methylthiobenzoyl chloride and pyrid-2-ylamidoxime (137 mg, 1 mmol) in pyridine (1 mL) were heated at 1 15 °C for 17 hours. Standard work up and silica gel chromatography afforded 250 mg
»H-NMR (CDCb), 8 (ppm): 7.37( dd, J« 2.4Hz, 8.2 Hz, 1H), 7.40-7.50 (m, 2H), 7.89 (ddd, J« 1.4 Hz, 7.4 Hz, 8.2 Hz, 1H ), 8.05 (d, J«2.4 Hz, 1H), 8.23 (dd, J*2,2 Hz, 8.0 Hz, 1 x H ), 8.85 (m, 1H).
(B40)
(Figure Remove)
3-Phecoxybenzoic add (214 mg, 1.0 mmol) was treated with a solution of oxalyl chloride (1.5 mL of 2 M in dichloromethane, 3 mmol) and a catalytic amouni of N,N-dmtemylfbrmamide. The reaction was stirred overnight at ambient temperamre. The excess oxalyl chloride was removed in vacua to afford 3-phenoxybenzoyl chloride.
Using the general procedure for the synthesis of 1,2,4-oxadiazoies, die 3-phenoxybenzoyl chloride and pyrid-2-ylamidoxime (137 mg, 1 mmol) in pyridine (1 ml) were heated in a sealed vial overnight at 110 °C. Standard work up afforded 118 mg (37%) of 3-(2-pyridyl)-5^3-pbenoxYphenylMi2,4-c*adiazole as a white solid.
(Figure Remove)
3-Benzoylbeazoic add (226 mg, 1.0 mmol) in dichloromemane (1.S mL) was treated with a solution of oxalyl chloride (1,5 mL of 2 M in dichloromethane, 3 mmol) and a catalytic amount of M&dtaethylforaamide. The reaction was stirred overnight at ambient temperature. The excess oxalyl chloride was removed in vacua to afford 3-benzoylbenzoyl chloride.
Using the general procedure for the synthesis of 1,2,4-oxadiazoles, the 3-benzoytbenzoyl chloride and pyrid-2-ylamidoxime (137 mg, 1 mmol) in pyridine (1 mL) were healed in a sealed vial overnight at 110 °C. Standard work op and filtration through silica gel (with dichloromethane) afforded 200 mg (61%) of 3-(2-pyndyO-S-(3-bettzoyhihenylH^,4
(B42)
(Figure Remove)
2-Bromo-5-methoxybenzoic acid (231 mg, 1.0 mmol) in dichloromethane (1.5 mL) was treated with a solution of oxalyl chloride (1.5 mL of 2 M in dichloromethane, 3 mmol) and a catalytic amount of N.^-dimethylfonnamide. The reaction was stirred overnight at ambient temperature. The excess oxalyl chloride was removed in vacua to afford 2-bromo-5-methoxybenzoyl chloride.
Using the general procedure for the synthesis of 1,2,4-oxadiazoles, the 2-bromo-5-methoxybenzoyl chloride and pyrid-2-ylamidoxime (137 mg, 1 mmol) in pyridine (1 mL) were heated in a sealed vial overnight at 1 10 °C. Standard work up and filtration through silica gel (with dichloromethane) afforded 147 mg (44%) of 3-(2-pyridyl)-5-(2-bromo-5-methoxyphenyi)-lr2,4-oxadiazole. 'H NMR (CDCb), 8 (ppm): 8.85 (d, 1H), 8.24 (d, 1H), 7.89 (m, 1H), 7.65 (m, 2H), 7.47 (m, 1H), 6.99 (m, 1H), 3.89 (s, 3H).
(B43)
(Figure Remove)
N-O
2-Chloro-5-(trifluoromethyl)benzoic acid (224 mg, 1.0 mmol) in dichloromemane (1.5 mL) was treated with a solution of oxalyl chloride (1.5 mL of 2 M in dichloromethane, 3 mmol) and a catalytic amount of tf.A^dimethylformamide. The reaction was stiired overnight at ambient temperature. The excess oxalyl chloride was removed in vacua to afford 2-chloro-5~(trifIuoromethyl)benzoyl chloride.
Using the general procedure for the synthesis of 1,2,4-oxadiazoles, die 2-chloro-5-(trifluoromemyQbenzoyl chloride and pyrid-2-ylamidoxime (137 mg, 1 mmol) in pyridine (1 mL) were heated in a sealed vial overnight at 110 °C. Standard work up and filtration through silica gel (with dichloromediane) afforded 136 mg (42%) of 3-(2-pyridyl)-5-(2-chloix>5-(trifluoromethyl)phenyl)-l,2,4-oxadiazole as a beige solid, 1H NMR (CDCb), 6 (ppm): 8.87 (d, 1H), 8.56 (s, 1H), 8.25 (d, 1H), 7.89 (m, 1H), 7.78 (m, 2H), 7.50 (m. 1H).
(B44)
(Figure Remove)
N-0
3,4>Trifluorobenzoie acid (0.176 g, 1.0 mmol) in dichloromethane (1.5 mL) was treated with a solution of oralyl chloride (1.5 mL of 2 M in dichloromethane, 3 mmol) and a catalytic amount of MAf^liinemyljformaniide. The reaction was stirred overnight at ambient temperature. The excess oxalyl chloride was removed in vacua to afford 3,4,5-trifluorobenzoyl chloride.
Using the general procedure for the synthesis of 1,2,4-oxadiazoles, the 3,4,5-nifluorobenzoyl chloride and pyrid-2-ylamidoxime (137 mg, 1 mmol) in pyridine (1 mL) were heated in a sealed vial overnight at 110 °C. Standard work up and silica gel chromatography (with 10-30% ethyl acetate in hexane) afforded 15 mg (5%) of 3-(2-pyridyl)-5K3,4,5-trirluorophenyD-l,2,4-oxadia2de as a white solid.
3-(2-pyridyT)-5-(2,5,6-trifluorophaiyI)-l^14-oxadiazole (B45)
(Figure Remove)
F
2,5,6-Trifluorolbenzoic acid (176 mg, 1 mmol) was treated with a solution of oxalyl chloride (1.5 mL of 2 M in dichloromethane, 3 mmol) and a catalytic amount of N,/V^UmeUiyliannamide. The reaction was stirred at ambient temperature for 16 hours. The excess oxalyl chloride was removed in vacuo to afford 2,5,6-trifluoroIbenzoyl chloride.
A solution of the intermediate 2,5,6-trifluorolbenaoyl chloride and pyrid-2-ylamidoxime (137 mg, 1 mmol) in dichloromethane was stirred at ambient temperature fat 0.5 hours. Silica gel chromatography afforded 151 mg (51%) of JV-[(2,5,6-trifluorobenzoyl) oxyjpyridine-2-caffaoximidanfiirir..
A solution of ^[(2,5,6- trifluoroben*C7l)oxy]pyridine-2-(^boxiiaidamide (SO mg, 0.169 mmol) in pyridine (0.3 mL) was heated at 115 *C for 17 hours. Standard work up, and silica gel cbromatography, afforded 9.5 mg (20%) of 3-(2-pyridyl)-5-(2,5,6-crifluorophenyl)-! ,2,4-audiazole.
Example 4: Synthesis of 3f5-disobstitiited-l^,4^xadia2oles from acylimidazoks 3-(3-MethoxyphenyD-5-{2-p]rridyI)-l^,4-
(Figure Remove)
0-N
Using modifications of the method of Shine et al., J. Hetenxyclic Chem. (1989) 2(5:125-128, a solution of picolinic acid (123 mg, 1 mmol) in pyridine (1 mL) was treated with l,r-carbonyldiimidazole (162 mg, 1 mmoi) and the reaction stirred at ambient temperature until the evolution of carbon dioxide ceased (30 min). The intermediate acyiiinidazole was then treated with 3-methoxybenzamidoxime (166 mg, 1 mmol) and the reaction heated at reflux for 1 hour. Ice cold water was added to die reaction mixture to precipitate the oxadiazole. The solid was collected by filtration, washed with water and dried to afford 80 mg (32%) of 3K3-methoxyphenyl)-5-(2-pyridyl)-l,2,4-oxadia2ole: mp 90-94 °C; GC/EI-MS gave m/z (rel. int.) 253 (M+, 100), 254 (17), 179 (2), 175 (2), 149 (77), 133 (33), 119 (4), 106 (29), 78 (45), 51 (18).
Example 5: Synthesis of 3,5-disubstxtnted-l,2,4-oxadiazoIes from esters
>fe(B46)
(Figure Remove)
N-O
Using the method of Korbonits et al., /. Chan. Soc. Pcridn Trans. I (1982) 759-766, a mixture of ethyl aaticylate (200 mg, 1.2 mmol), pyrid-2-ylamidoxime (82.5 mg, 0.6 mmol), 21 % sodium ethoxide (19.4 mL, 6 mmol) hi ethanol (12mL) was heated at reflux for 16 hours. After cooling, the reaction mixture was diluted with dichloromethane (50 mL) and washed with water and saturated sodium hydrocarbonate. The organic layer was dried with sodium sulfate and concentrated in vacuo. Rccrystallizan'on from diethyl ether afforded 15 mg (5%) of 3^Pyrid^2-yl)-5-(2-hydroxypbenyl)-l,2,4^jxadiazoie,
HO.
In a similar fashion, methyl 5-chloro>2-bydroxybenzoate (372 mg, 2 mmd), pyrid-2-ylamidoxime (137 mg, 1 mmol), 21 % sodium ethoxide (32.4 mL, 10 mmol) in ethanol (20 mL) were heated at reflux for 16 hours. Standard work up and recrystallization from diethyl ether afforded 14.2 mg (5%) of 3-(2-pyridyl)-5-(5-chloro-2-hydroxyphenyl)-1,2,4-oxadiazole.
Example 6: Synthesis of 3,5-disubstituied-l,2,4-oxadiazoIes from isatoic anhydrides
H,N
(Figure Remove)
Using modifications from the procedure of Nagahara. et al., Chan. Pharm. Bull., (1975) 23:3178-3183, a mixture of isatoic anhydride (163 mg, 1 mmol) and pyrid-2-ylamidoxime (137 mg, 1 mmol) in pyridine (1 mL) was heated at 115 "C for 17 hours. After cooling the reaction, the mixture was diluted with 50 mL of dichloromethane and washed with water and saturated sodium hydrocarbonate. The organic layer was dried over sodium sul&te, filtered through silica gel and concentrated in vacua. Recrystallization from diethyl ether afforded 45.6 mg (19%) of 3-(2-pyridyl)-5-(2-aminophenylM ,2,4-oxadiazole.
(Figure Remove)
In a simitar fashion, 5-chloroisatoic anhydride (197 mg, 1 mmol) and pyrid-2-ylamidoxime (137 mg, 1 mmol) in pyridine (1 mL) was heated at 115 "C for 17 hours. Work up afforded 138 mg (51*) of 3-(2-pyridyl)-5-(2-aminophenyl)-l,2t4K)xadiazole.
Example?; Synthesis of 2,4-disuhstituted-l,3-oxazoles
2-p
(Figure Remove)
"a
Using the procedures of Kelly et ai., /. 0r$. Owm.. (1996) 67:4623-4633, a solution of 2-bromoacetyIpyridine (120 mg, 0.6 mmol) in toluene (5mL) was treated witb 3-chlorobcnzamide (300 mg, 1.9 tnraoO and the mixture heated in a sealed rial at reflux for 60 hours. The mixture was then cooled and the solvent was removed in vacua. Silica gel chromatography using a gradient of hexane to ethyl acetate afforded 38 mg (9%) of 2-[3-chlorophenyrj-4-[pyridin-2-yIJ-l,3-oxazole as a pale yellow solid. 'H-NMR (CDCb), 6 (ppm): 8.62 (d, 1H), 8.35 (s. 1H), 8,15 (m, 1H), 8.00 (m, 2H), 7.80 (td, 1H), 7.42 (m, 2H), 7.23 (m, 1H).
2-[3-BromophenyI]^Hpyridm-2-ylMr3-oxazole (B51)
(Figure Remove)
In a similar fashion 2-bromoacetylpyridine (500 mg, 2.5 mmol) and 3-cnlorobenzamide (1.2g, 6 mmol) in toluene (10 mL) was heated in a sealed vial at reflux for 60 hours. Work up and silica gel chromatDgraphy using a gradient of hexane to ethyl acetate afforded 50 mg (7S6) of 2-[3-bromophenyl]^(pyridin-2-yQ-l,3-oxazole as a white solid. 'H-NMR (CDCb), 6 (ppm): 8.60 (d, 1H), 8.34 (s, IH), 8.30 (t, 1H), 8.00 (m, 2H), 7.80 (td, IH), 7.60 (dd, IH), 7.35 (t, IH), 7.23 (m. IH).
(Figure Remove)
A mixture of 2-[3-bromophenyn-4-[pyridin-2-yI]-l13-oxazole (23 mg, 0.076 mmol) and zinc cyanide (112 mg, 0.% mmol) in Wfl-dimethylfbnnamide (2 mL) was treated with Pd(PPhs)* (74 mg, 0.064 mmol) and heated overnight at 80°C. Standard work up and chromatography afforded 6 mg (32 %) of 2-[3-cyanophenyl]-4-(pyridin-2-yI]-lt3-oxazole
as a white solid. 'H-NMR (CDCb), 5 (ppm): 8.61 (d, 1H), 8.45 (s, 1H), 8.38 (s, lH)r 8.36 (m, 1H),8.00 (d, 1H), 7.80 (m, 2H), 7.61 (t, 1H), 7.23 (m, 1H).
ExampIeS: Synthesis of 3,5-disnbstitnted.-1^2-oxazales
5-[3-hydroxyphenyI]-3-{pyridm-2-yI]-l^-oxazole (B53)
(Figure Remove)
A stirred solution of pyhdine-2
S-(3-cyadoPhcnyI]-3-[pyridio-2-yll-l>oxazole(BS4)
(Figure Remove)
A mixture of 5-p-*rifhjoromethanesulfOTylphrayrj-3-|pyn (98
mg, 0.26 mmol), KCN (230 mg, 4 mmol), NiBn(PPto)3 (52.4 mg, 0.07 mmol), and PPhi (42 mg, 0.16 mmol) in acetoaitrile (1 mL) was treated with aanc powder (20 mg, 0.3 mmol) and the mixture was heated overnight at 60 °C. Silica gel chromatography of the resulting mixture using a gradient of hexane to ethyl acetate afforded 15 mg (23 %) of 5-[3
Example 9: Synthesis of 3^-disalisthnttd-l^,4-triazoks
3>ChJorobenzhydnunde
(Figure Remove)
A mixmre of 3-cbIorobenzoic acid (0.5 g, 3.19 mmol), 1,3-diccydobexylcarbodiimide (0.72 g, 3.51 mmol), 4HJimethylamrnopyridine (0.04 g, 0.32 mmol) in etbanol was stirred at ambient temperature for 1.5 hour. The white solid was filtered off and the filtrate diluted with dichloromethane (100 mL). The organic solution was washed with 1 N sodium hydrogen sulfate (100 mL), saturated sodium bicarbonate (100 mL), water (100 mL) and brine (100 mL). The organic phase was dried over anhydrous magnesium sulfate and filtered The filtrate was concentrated in vacua. The crude residue was dissolved hi ethanol (15 mL) and treated with hydrazine monohydrate (0*46 mL, 9.58 mmol). The resulting dear solution was stirred overnight at ambient temperature. The reaction mixmre was then concentrated to dryness in vacua. Silica gel chromatogiaphy of the residue, using 3% methanol in dichloromethane, afforded 0.29 g (53%) of 3-chJorobenzhydrazide as a white solid.
Using the procedures of Browne et a!., Aast. J. Chan., (1975) 25:2543-2546, a solution of 2-cyanopyridinc (0.1 mL, 1.00 mmol) in methanol (5 mL) was treated with sodium metal (6.9 mg, 0.30 mmol) and stirred for at ambient temperature for 1 hour. After this time, a solution of 3-chlorobenzhyrazide (0.17 g, 1.0 mmol) in mrthanol (5 mL) was added and the resulting solution heated at reflux for 3 boon. The reaction mixmre was concentrated in vacua, and the resulting yellow solid (100 mg) dissolved in toluene (2 mL). The mixture was heated at 175 °C for 3 hours and then stirred overnight at ambient temperature. Evaporation of the solvent in vacuo and silica gel cnromatography using 1 % methanol in dichloromethane afforded 29 mg (11%) of 3-(2-pyridyl)-5-(3-chlorophenyl)-1,2,4-triazole as an off-white solid.
In a similar fashion, 2-cyanopyridine (0.15 mL, 1.53 mmol), sodium metal (10.5 mg, 0.46 mmol) and 3-iodobenzhydrazide (0.40 g, 1.53 mmol) afforded, after work up and chromatography, 210 mg (40%) of 3-(2-pyridy^5-(3-iodophenyI)-l,2,4-criazole as a white solid. Eiample Ifc Assays of Groap I receptor antagonist acthrity
Astrocyte Screening Assay
Primary astrocyte cultures were prepared from 3-5 day old Spngue-Dawiey rat pups using a modification of Miller (Miller ft al, J. Neuroscience, 15(9): 6103-6109, 1995). In brief, primary cultures were plated on poly-L lysine coated flasks in Dulbecco's modified Eagle's medium (DMEM) containing fetal calf serum (PCS). After 6 days, cell cultures were shaken over night at 280 rpm, then transferred to astrocyte-defiacd media (ADM) containing growth factors that up-regulate the expression of mGluR5 (Miller et al., 1995). For cuvette analysis, cultures were up-regulated with growth factors in flasks for 3-5 days, then harvested and prepared for measurement of [Ca**]i mobilization as previously described (Nemeth et al., 1998).
For FLEPR analysis, cells were seeded on poly-D lysine coated clear bottom 96-well plates with black sides and analysis of [Ca?*]i mobilization was performed 3 days following the growth factor up-regulatkm. Cell cultures in the 96-well plates were loaded with a 4 nM solution of acetoxymemyl ester form of the fluorescent calcium indicator fluo-3 (Molecular Probes, Eugene, Oregon) in 0.01 % pluronic. All assays were performed in a buffer rontaming 127 mM NaCl, 5 mM KC1, 2 mM MgCfa, 0.7 mM NaHiP(X 2 mM CaCla, 0.422 mg/ml NaHCOs, 2.4 mg/ml HEPES, 1.8 mg/ml glucose and 1 mg/ml BSA Fraction IV (pH 7.4).
FUPR experiments were done using a laser setting of 0.800 W and a 0.4 second CCD camera shutter speed. Each FLEPR experiment was initiated with 180 nL of buffer present in each well of the cell plate. A 20 uL addition from the antagonist plate was
followed by a 50 nL addition from the agonist plate. After each addition the fluorescence signal was sampled 50 times at 1 second intervals followed by 3 samples at 5 second intervals. Responses were measured as the peak height of the response within the sample period.
ECjo/ICw determinations were made from data obtained from 8 point concentration response carves (CRC) performed in duplicate. Agonist CRC were generated by scaling all responses to die maximal response observed for the plaie. Antagonist block of the agonist challenge was normalised to the average response of the agonist challenge in 14 control wells on the same plate.
CaR/mGiuR5d Screening Assay
HEK 293 cells expressing the chimeric CaR/mGIuR5d receptor (clonal cell line hCaR/hmGluRSd^heko) are plated 24 hours prior to assay at a density of 100,000 cells per well in Collagen I-coated 96-well black, clear bottom plates (Becton Dickenson) m DMEM supplemented with 10% FBS (Hyclone).
On the day of the assay, tissue culture medium is aspirated from the wells of a plate and 80 uL of Assay Buffer (Assay Buffer is: 20 mM HEPES, 146 mM Nad, 5 mM KCI, 1 mM MjCb, 1 mM CaCb, 1 mg/ml BSA, 1 mg/ml glucose, pH 7.4) supplemented with 6 jiM of the Ca^-sensitive dye, Fluo-3 AM (Molecular Probes) and 0.025% Pluronic (Molecular Probes) is added to each well. The plate is then incubated in the dark for 1 hour at room temperature to efficiently load the cells with Fluo-3. At the end of the incubation, extracellular Fluo-3 is removed by washing the plate with Assay buffer. Assay Buffer is added back to each well (final volume * 160 nL) prior to beginning the assay.
The place is loaded into a FUPR robotic device (Molecular Devices) with the laser setting at 0.8 Watts. At a time of 10 seconds after initiation of the assay, 40 pL of Assay Buffer containing 62.5 uM test substance and 2% DMSO is added to the 160 fiL of Assay Buffer in each well of the plate to yield a final concentration of 12 pM test substance and 0.4% DMSO. At a time of 75 seconds after initiation of the assay, 50 fiL of Assay Buffer containing 6 mM CaCh is added to the 200 \iL present in each well to yield a final Ca2* concentration of 2.0 mM, and a final concentration of test substance of 10 nM. Relative fluorescence intensity (excitation X = 488 am / emission X —510 nM) Is monitored at
relevant time intervals throughout the assay period to measure receptor activation and/or. inhibition.
By way of illustration, a 1,2,4-oxadiazole disclosed above, designated "B21* (see Example 3), had an ICu value of 43 nM in relation to CaR/mGluRu and an IGo value of 121 nM on the native receptor, mGluRM. A corresponding 1,3 oxazole, designated "851" (see Example 7), was found to be equipotent on me CaR/mGtuR* chimera, with an IC» value of 45 nM, but displayed increased potency on the native mGluR* receptor, with an IGo value of 74 nM.
The invention thus has been disclosed broadly and illustrated in reference to representative embodiments described above. Those skilled in the art will recognize that various modifications can be made to the present invention without departing from the spirit and scope thereof.
WE CLAIM:
1. A compound of Formula II:
wherein X, Y, and Z are independently selected from the group consisting of N, 0, S, C, and CO wherein ai least one of X, Y, and Z is a heteroatom;
Ar1 and Ar are independently selected from the group consisting of a heterocyclic or fused hcterocyclic moiecy containing 1 to 4 heteroatoms selected from the group consisting of N, 0, and S and an aromatic moiety selected from die group consisting of phcnyl, benzyl, 1-naphthyl, 2-naphthyl, fluorenyl, anthrenyl, indenyl, phenanthrenyl, and benzonaphtbeayl, wherein me Ar* and Ar3 moieties are opdonally substituted with one or more moieties selected from the group consisting of ~F, -Cl, -Br, -I, -OR, -SR, -SOR, -SOzR, -SOaNRR', -OCOR, -OCONRR', -NRCOR1, -NRCOsR', -CN, -N0», -COaR, -CONRR', -C(0)R, -CH(OR)R', -CHa(OR), -R, and -A-CCHiVNRR'; wherein R or R' is selected from the group consisting of H, CF3, Ci-Cio alkyl, cycloalkyr alkyl-aryl, alkyl-heteroaryi, heterocycloaUkyl, aryl and where R and R' may combine to form a ring, and A is defined as CHi, 0, NH, S, SO, SOi and n is 1, 2, 3, or 4,
with the proviso dial die compound is not 3-(2-PyridyJ)-5-{2-nitrophenyl)-l,2,4-
oxadiazde, 3-(2-Pyridyl)-5-{2-ctilorophenyl)-l,2,4-oiadiazole, 3-{2-Pyridy^5-(3-
memoxyphenyO-1,2,4-oxadiazole, 3~
oxadiazoie, or H2-Pyridyl)-5'(2^>romo-5-memoxyphenyl)-l,2,4Mixadiazole.
2. The compound of claim 1, wherein X is N, Y is N, and Z is 0.
3. The compound of claim 2, wherein Ar1 is 2-pyridyl and Ar3 is phenyl.
4. The compound of claim 3, wherein Ar3 is substituted with one or more
moieties selected from the group consisting of OCHj, CFi, Cl, F, Br, CHb, NOi, OCFj,
SCH3, and CN.
5. The compound of claim 3, wherein Ail is 2-pyridyl and substituted with'
one or more moieties selected from the group consisting of OCHi, CF3, F, and G.
6. The compound of claim 2, wherein Ar1 is 2-pyridyl and Ar3 is 1-naphthyl,
7. The compound of claim 1, wherein X is N, Y is C, and Z is 0.
8. The compound of claim 7, wherein Ar1 is 2-pyridyl and is-substituted with
one or more moieties selected from the group consisting of OCHi, CF3, F, and CJ. Ar is
phenyl and is substituted with one or more moieties selected from the group consisting of OCB, Cft, Cl, F, Br, CHi, NOs, OCFi, SCHi, and CN.
9. A pharmaceutical composition comprising a compound of Formula II:
wherein X, Y, and Z are independently selected from the group consisting of N, O, S, C, and CO wherein at least one of X, Y, and Z is a hetcroatom;
Ar1 and Ar*are independently selected from die group consisting of a heterocyclic or fused beterocyclic moiety containing 1 to 4 heteroatoms selected from die group consisting of N, 0, and S and an aromatic moiety selected from the group consisting of phenyl, benzyl, 1' naphthyl, 2-naphthyl, fhiorenyl, anthrenyl, indenyl, phenanthrenyl, and benzonaphthenyl, wherein the Ar1 and Ar3 moieties are optionally substituted with one or more moieties selected from the group consisting of -F, -Cl, -Br, -I, -OR, -SR, -SOR, -SChR, -SChKRR', -OCOR, -OCONRR', -NRCOR', -NRCOiR', -CN, -NOa, -CChR, -CONRR', -C(0)R, -CH(OR)R'. -CH3(OR), -R, and -A-COfcVNRR'; wherein R or R' is selected from the group consisting of H, CF:, Ci-CIO alkyl, cydoalkyf aUcyl-aryl, ilkyl-heteroaryl. heterocycloalkyl, aryl and where R and R' may combine to form a ring, and A is defined as CHi, 0, NH, S, SO, SOa and « is 1, 2, 3, or 4, and a phannaceuticaUy acceptable excipient, with the proviso that the compound is riot 3-(2-Pyridyl)-5-(2-nitrophenyl)-l,2,4-oxadiazole or 3-(2-Pyridyl)-5-(2-
10. The composition of claim 9, wherein X is N, Y is N, and Z is 0.
1 1 . The composition of claim 10, wherein Ar1 is 2-pyridyl and Ar* is phenyl.
12. The composition of claim 11, wherein Ar2 is substituted with one or more
moieties selected from the group consisting of OMe, CF>, Q, F, Br, CHs, NOi, CN,
OCFi, and SCHi.
13. The composition of ^aim 10, wherein Ar* is 2-pyridyl and substituted with
one or more moieties selected from die group consisting of OCHs, CFs, F, and Cl.
14. The composition of claim 10, wherein Ar1 is 2-pyridyl and Ar is 1-
naphthyl.
15. The composition of claim 9 wherein X is N, Y is C, and Z is 0.
16. The composition of claim 15, wherein Ar1 is 2-pyridyl and substituted with
one or more moieties selected from the group consisting of OCH3, CF3, F, Cl. Ar3 is
pbenyl and substituted with one or more moieties selected from the group consisting of
OCH>, CFi, Cl, F, Br, CHs, N0», CN, OCFi, and SCHi.
17. A method of treating diseases associated with metabotropic glutamaic
receptors comprising administering to a patient in need thereof a pharmaceutically
acceptable amount of a compound of formula II:
wherein X, Y, and Z are independently selected from the group consisting of N, O, S, C, and CO wherein at least one of X, Y, and Z is a heteroatom;
Ar1 and Ar*are independently selected from die group consisting of a heterocyclic or fused heterocyclic moiety containing 1 to 4 heteroatoms selected from the group consisting of N, 0, and S and an aromatic moiety selected from the group consisting of phenyl, benzyl, 1-naphthyl, 2-naphthyl, fluorenyl, anthrenyl, indenyl, phenanthrenyl, and benzonaphthenyl, wherein the Ar* and Ar* moieties are optionally substituted with one or more moieties selected from the group consisting of -F, -Cl, -Br, -I, -OR, -SR, -SOR, -SOaR, -SOiNRR', -OCOR, -OCONRR1, -NRCOR', -NRCOiR', -CN, -NOz, -COiR, -CONRR', -C(O)R, -
CH(OR)Rf, -CIfc(OR), -R, and -AKCHi^NRR1; wherein R or R' is selected from tnr group conasring of H, CFs, G-C10 alkyl, cydoalkyr alkyl-aryl, alkyi-heteroaryl, heterocycJoalkyl, aryl and where R and R' may combine to form a ring, and A is defined as CH2, 0, NH, S, SO, SOa and n is 1. 2, 3, or 4, with me proviso that the compound is not 3-(2-PYridyl)-5-(2-chlorophenyl)-l,2,4-oxadia2oIc.
18. The method of claim 17, wherein XisN, Y is N, and Z is 0.
19. The method of claim 18, wherein Ar1 is 2-pyridyl and Ar1 is phenyl.
20. The method of claim 18, wherein Ar3 is substituted with one or more
moieties selected from the group consisting of OMe, CFi, Cl, F, Br, CHs, NQs, CN,
OCFi, and SCJfc.
21. The method of claim 18, wherein Afl is 2-pyridyl and substituted with one
or more moieties selected from the group consisting of OCH3, CF3, F, and Q.
22. The method of claim 18, wherein Ar1 is 2-fyridyl and Ar2 is 1-naphthyl
23. The method of claim 17, wherein X is N, Y is C, and Z is O.
24. The method of claim 23, wherein Ar1 is 2-pyridyl and substituted with one
or more moieties selected from the group consisting of OCHi, CFj, F, and Q. Ar2 is
phenyl and substituted with one or more moieties selected from the group consisting of OCHs, CFi, a, F, Br, Ob, N0», CN, OCB, and SCHs.
25. The method of claim 17, wherein the disease associated with metabotropic
glutanutc receptors Is a neurological disease or disorder.
26. The method of claim 17, wherein the disease associated with metabotropic
ghxtamate receptors is a psychiatric disease.
27. The method of claim 17, wherein the disease or disorder is selected from the
group consisting of stroke, head trauma, anemic injury, ischcmic injury, hypoglycemia,
epilesy, pain, migraine headaches, Parkinson's disease, senile dementia, Hunnngton's
Chorea and Alzheimer's disease.
28. The method of claim 17, wherein the disease or disorder is selected from the*
group consisting of schizophrenia and depression.
29. A compound selected from the group consisting of 3-(2-pyridyl)-5-{3,5-
aMlorophenyl)-t,2,4xjxadiazole, 3-(2-pyridyl)-5-(3-cJilorophenyl).l,2,4-oxadia2ole, 3-(2-
pyridyl)-5-(3-methylphenyl)-lt2,4-oxadiazoIe, 3-
oxidiazole, 3-{2-pyridyl)-5-[3Ktrifta3roineth^ 3-(2-pyridyl)-5-
(2,3-difhjorophenyO-l,2,4-oxa
oxadiazole, 3-(2^yridyi)-5-(3,5HMuorophenyl)-l,2,4-oxadiazole, 3-{2-pyridyl)-5-(3-
cyanopheoylH,2,4-*xadiazole, 3K2-pyridyi)-5-(3,5HiimemoxypheiryO-l,2,4-
cyanophcnyl)- 1 ,2,4-oxadiazole, 3-(2-pyridyl)-5-(3-fluoro-5-cyanophenyl)- 1 ^,4-oxadiazole, 3-(2-pyridyl)-5-(3-chloro-5-fluorophenyl)-l , 2,4-oxad"a2S)lef 3-(5-chloropyrid-2-yl)-5-(3-cyaoophenyl>l,2,4-oxadia20le, 3-{5-fluoropyrid-2-yl)-5-(3-cyanophenyI)-l ,2,4-oxadiazole, 3-(5-fluoropyrid>2-yI)-5--5-- 1 ,2,4-oxadiazole, 3K2-pyridyl>5-(5-chloro-2-methoxyphenyl)-l,2,4-oxadiazole, 3-(2-pyridyl>SK2-cUonHS-methylthiophenyl)-l,2>4-oxadiazole, 3-(2-pyridyl>-5-trifluoropheiiyI>-l,214-oxadiazole, 3-(2-pyridyl}-S-(3-nitropbeayl)-l,2,4-oxadiazole, 3-(2-pyridyl)-5-
30. A compound selected from the group consisting of 2-(3,5-dichlorophenyl)-4-
(2-pyridyl)-l,3-oxazole, 2-(3-chlorophenyl)-4-(2-pyridyl)-l ,3-oxazole, 2-(3-
methoxyphenyl)-4-(2-pyridyl)-l,3-oxazole, 2-(2-chlorophenyl)-4-(2-pyridyl)-l,3-oxazole,
2^-oifluorophenylH-4-(2-pyridyl)-l,3-
oxazole. 2-(l-naphmyl>4.(2-pyridyl)-l,3-oxazole, 2-(3-trifhioromethoxyphenyl)-4-(2-
pyridyl)-! ,3-oxazole, 2-(2,3-difhiorophenyl)-4-(2-pyridyl)-l,3-oxazole, 2-
difhorophenyl)-4-(2^>yridyl)-l,3-oxazole1 2-(3,5-difluorophenyl)-4-(2-pyridyl)-l,3-
oxazole, 2-{3-cyanophenyl)-4-(2-pyridyI)-l,3-oxazoIc, 2-
pyridyl)-l,3-
cyanophenyl)-4-(2-pyridyl)-lf3-oxazole, 2-(3-fluoro-5-cyanophenyO-4-
oxazole, 2-(3-chloro-5-fluorophenyl)-4-(2^yridyl)-l,3-oxazole, 2-O-cyanophenyI)-4-{5-
chloropyrid-2-yl)-l,3-owzole, 2-(3-cyanophenyl)-4-(5-fluoropyrid-2-yl)-l,3-oxarole, 2-{3-
cyano-5-fluorophenyl)-4-
naoropyrid-2-yl)-l ,3-oxazoIe, 2-(3,5-dim«boxyphciiyl>4-(5-fluoropyrid-2-yl)-1,3-
oxazolc, 2-(3-cyanopheayl)-4-(5-incthoxypyrid-2-yl)-l,3-oxa2olef 2-(3-cyanophenyl)-4-{2-quinolinyl)-! ,3-oxaaoie, 2-(3l,3-oxazole, 2-(2-chJoro-5-methyJtIuophenyl)-4-
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