Patent Application
20110124661
The excitatory amino acid L-glutamate (sometimes referred to herein simply as glutamate) through its many receptors mediates most of the excitatory neurotransmission within the mammalian central nervous system (CNS). The excitatory amino acids, including glutamate, are of great physiological importance, playing a role in a variety of physiological processes, such as long-term potentiation (learning and memory), the development of synaptic plasticity, motor control, respiration, cardiovascular regulation, and sensory perception.
Glutamate acts via at least two distinct classes of receptors. One class is composed of the ionotropic glutamate (iGlu) receptors that act as ligand-gated ionic channels. Via activation of the iGlu receptors, glutamate is thought to regulate fast neuronal transmission within the synapse of two connecting neurons in the CNS. The second general type of receptor is the G-protein or second messenger-linked “metabotropic” glutamate (mGluR) receptor. Both types of receptors appear not only to mediate normal synaptic transmission along excitatory pathways, but also participate in the modification of synaptic connections during development and throughout life. Schoepp, Bockaert, and Sladeczek, Trends in Pharmacol. Sci., 11, 508 (1990); McDonald and Johnson, Brain Research Reviews, 15, 41 (1990).
The present invention relates to potentiators of mGlu receptors, in particular mGluR2 receptors. The mGluR receptors belong to the Type III G-protein coupled receptor (GPCR) superfamily. This superfamily of GPCR's including the calcium-sensing receptors, GABAB receptors and pheromone receptors, which are unique in that they are activated by binding of effectors to the amino-terminus portion of the receptor protein. The mGlu receptors are thought to mediate glutamate's demonstrated ability to modulate intracellular signal transduction pathways. Ozawa, Kamiya and Tsuzuski, Prog. Neurobio., 54, 581 (1998). They have been demonstrated to be localized both pre- and post-synaptically where they can regulate neurotransmitter release, either glutamate or other neurotransmitters, or modify the post-synaptic response of neurotransmitters, respectively.
At present, there are eight distinct mGlu receptors that have been positively identified, cloned, and their sequences reported. These are further subdivided based on their amino acid sequence homology, their ability to effect certain signal transduction mechanisms, and their known pharmacological properties. Ozawa, Kamiya and Tsuzuski, Prog. Neurobio., 54, 581 (1998). For instance, the Group I mGluR receptors, which include the mGlu1R and mGlu5R, are known to activate phospholipase C (PLC) via Gag-proteins thereby resulting in the increased hydrolysis of phosphoinositides and intracellular calcium mobilization. There are several compounds that are reported to activate the Group I mGlu receptors including DHPG, (R/S)-3,5-dihydroxyphenylglycine. Schoepp, Goldworthy, Johnson, Salhoff and Baker, J. Neurochem., 63, 769 (1994); Ito, et al., keurorep., 3, 1013 (1992). The Group II mGlu receptors consist of the two distinct receptors, mGluR2 and mGluR3 receptors. Both have been found to be negatively coupled to adenylate cyclase via activation of Gαi-protein. These receptors can be activated by a selective compound such as 1S,2S,5R,6S-2 aminobicyclo[3.1.0]hexane-2,6-dicarboxylate. Monn, et al., J. Med. Chem., 40, 528 (1997); Schoepp, et al., Neuropharmacol., 36, 1 (1997). This activation leads to inhibition of glutamate release in the synapse (Cartmell et al, J Neurochem 75, 889 (2000)). Similarly, the Group III mGlu receptors, including mGluR4, mGluR6, mGluR7 and mGluR8, are negatively coupled to adenylate cyclase via Gαi and are potently activated by L-AP4 (L-(+)-2-amino-4-phosphonobutyric acid). Schoepp, Neurochem. Int., 24, 439 (1994).
Nonselective mGluR2/mGluR3 receptor agonists (Mann, et al., J. Med. Chem., 43, 4893, (2000)) have shown efficacy in numerous animal models of anxiety and psychosis as well as human clinical trials in schizophrenia patients (Patil et al, Nature Medicine, 13, 1102 (2007)). Recent reports indicate that mGluR2 but not the mGluR3 receptor mediates the actions of the dual mGluR2/mGluR3 agonist LY379268 in mouse models predictive of antipsychotic activity. (Woolley et al, Psycopharmacology, 196, 431 (2008)) Additionally, recent animal studies demonstrate that selective potentiation of the mGluR2 receptor has similar effects to such non-selective agonists (Galici et al, Journal of Pharmacology and Experimental Therapeutics, 315, 1181 (2005) suggesting an alternative strategy concerning the discovery of selective, positive allosteric modulators (PAM's or allosteric potentiators) of mGluR2 (Johnson et al, J. Med. Chem. 46, 3189, (2003); Pinkerton et al., J. Med. Chem., 47, 4595 (2004). These potentiators act by enabling the receptor to produce an enhanced response to endogenous glutamate. Such allosteric potentiators do not bind at the glutamate binding site also known as the “orthosteric site”, and may benefit by binding to a site other than the highly conserved orthosteric site. A potential advantage to this approach includes the opportunity to have a distinct pharmacological profile by enhancing the activity of the endogenous ligand upon its binding to the orthosteric site. The pharmacological distinctions include the potential for pharmacological specificity between related receptor types that share the same endogenous ligand. In addition, positive allosteric modulators of mGluR2 have been shown to potentiate the response of mGluR2 agonists such as LY379268 (Johnson et. Al. Biochemical Soc. Trans. 32, 881 (2004) and this represents an alternative strategy for treatment using mGluR2 selective PAMs.
It has become increasingly clear that there is a link between modulation of excitatory amino acid receptors, including the glutamatergic system, through changes in glutamate release or alteration in postsynaptic receptor activation, and a variety of neurological and psychiatric disorders. e.g. Monaghan, Bridges and Cotman, Ann. Rev. Pharmacol. Toxicol., 29, 365-402 (1989); Schoepp and Sacann, Neurobio. Aging, 15, 261-263 (1994); Meldrum and Garthwaite, Tr. Pharmacol. Sci., 11, 379-387 (1990). The medical consequences of such glutamate dysfunction makes the abatement of these neurological processes an important therapeutic goal.
The present invention is directed to oxazolobenzimidazole derivatives which are potentiators of metabotropic glutamate receptors, particularly the mGluR2 receptor, and which are useful in the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which metabotropic glutamate receptors are involved. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which metabotropic glutamate receptors are involved.
The invention encompasses a compound according to Formula I
or a pharmaceutically acceptable salt thereof, wherein:
n is 0, 1, 2 3, or 4;
p is 1, 2, 3, 4 or 5;
X1, X2, X3, X4 X5, X6, X7, X8 and X9 are independently selected from the group consisting of:
C and N, provided that at least one of X1, X2, X3, X4 X5, X6, X7, X8 and X9 is N;
each R1 and R2 is independently selected from the group consisting of:
In an embodiment, the invention encompasses a genus of compounds of Formula I
or a pharmaceutically acceptable salt thereof, wherein:
n is 0, 1, 2 3, or 4;
p is 1, 2, 3, 4 or 5;
X1, X2, X3, X4 X5, X6, X7, X8 and X9 are independently selected from the group consisting of:
C and N, provided that at least one of X1, X2, X3, X4 X5, X6, X7, X8 and X9 is N;
each R1 and R2 is independently selected from the group consisting of:
Within the genus, the invention encompasses a first sub-genus of compounds of Formula I wherein each R3, R4 and R5 is H and Y is O.
Within the first sub-genus, the invention encompasses a first class of compounds of Formula Ia
or a pharmaceutically acceptable salt thereof, wherein:
X5, X6, X8 and X9 are independently selected from the group consisting of: C and N, provided that at least one of X5, X6, X8 and X9 is N.
Within the first class, the invention encompasses a first sub-class of compounds of Formula Ia wherein:
R2 is independently selected from the group consisting of:
Within the first subclass, the invention encompasses compounds of Formula Ia wherein R1 is selected from the group consisting of: halo, —CN and methoxy.
Also within the genus, the invention encompasses a second sub-genus of compounds of Formula Ib
or a pharmaceutically acceptable salt thereof.
Within the second sub-genus, the invention encompasses a second class of compounds of Formula Ic
or a pharmaceutically acceptable salt thereof.
Within the second class, the invention encompasses a second sub-class of compounds of Formula Ic wherein:
R2 is independently selected from the group consisting of:
Within the second subclass, the invention encompasses compounds of Formula Ic wherein R1 is selected from the group consisting of: halo, —CN and methoxy.
Also within the genus, the invention encompasses a third sub-genus of compounds of Formula Id
or a pharmaceutically acceptable salt thereof, wherein:
X1, X2, X3, X4 and X5 are independently selected from the group consisting of C and N, provided that at least one of X1, X2, X3 and X4 is N.
Also within the genus, the invention encompasses a fourth sub-genus of compounds of Formula Ie
or a pharmaceutically acceptable salt thereof.
Within the fourth sub-genus, the invention encompasses a third class of compounds of Formula Ie wherein R2 is tert-butyl.
Within the third subclass, the invention encompasses compounds of Formula Ie wherein R1 is selected from the group consisting of: halo, —CN and methoxy.
The invention also encompasses a compound of Formula Ic
or a pharmaceutically acceptable salt thereof, wherein
n is 0, 1 or 2;
each R1 is independently selected from the group consisting of: halo, —CN and methoxy, and
R2 is selected from phenyl or pyridyl, each optionally substituted with 1 to 3 groups independently selected from methyl, CN, CF3, OCH3, OCF3 and halo.
The invention also encompasses a compound selected from the group consisting of:
The invention also encompasses a pharmaceutical composition comprising a compound of Formula I in combination with a pharmaceutically acceptable carrier.
The invention also encompasses a method for treating a neurological or psychiatric disorder associated with glutamate dysfunction in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound of Formula I. The invention also encompasses this method wherein the neurological or psychiatric disorder associated with glutamate dysfunction is schizophrenia.
“Alkyl”, as well as other groups having the prefix “alk”, such as alkoxy, alkanoyl, means carbon chains which may be linear or branched or combinations thereof. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and the like.
“Alkylene” means a straight or branched chain of carbon atoms with a group substituted at both ends, such as —CH2CH2— and —CH2CH2CH2—.
“Alkenyl” means carbon chains which contain at least one carbon-carbon double bond, and which may be linear or branched or combinations thereof. Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like.
“Alkynyl” means carbon chains which contain at least one carbon-carbon triple bond, and which may be linear or branched or combinations thereof. Examples of alkynyl include ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl and the like.
“Cycloalkyl” means mono-, bi- or tri-cyclic structures, optionally combined with linear or branched structures, having the indicated number of carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclopentyl, cycloheptyl, adamantyl, cyclododecylmethyl, 2-ethyl-1-bicyclo[4.4.0]decyl, and the like.
“Alkoxy” means alkoxy groups of a straight or branched having the indicated number of carbon atoms. C1-6alkoxy, for example, includes methoxy, ethoxy, propoxy, isopropoxy, and the like.
“Cycloalkoxy” means cycloalkyl as defined above bonded to an oxygen atom, such as cyclopropyloxy.
“Aryl” means mono- or bicyclic aromatic rings containing only carbon atoms. Examples of aryl include phenyl, naphthyl, indanyl, indanyl, tetrahydronaphthyl, 2,3-dihydrobenzofuranyl, dihydrobenzopyranyl, 1,4-benzodioxanyl, and the like.
“Heteroaryl” means mono- or bicyclic aromatic rings with at least one ring containing a heteroatom selected from N, O and S, and each ring containing 5 or 6 atoms. Examples of heteroaryl include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, furo(2,3-b)pyridyl, quinolyl, indolyl, isoquinolyl, and the like.
“Halogen” and “halo” includes fluorine, chlorine, bromine and iodine.
The compounds of the present invention are potentiators of metabotropic glutamate (mGluR) receptor function, in particular they are potentiators of mGluR2 receptors. That is, the compounds of the present invention do not appear to bind at the glutamate recognition site on the mGluR receptor, but in the presence of glutamate or a glutamate agonist, the compounds of the present invention increase mGluR receptor response. The present potentiators are expected to have their effect at mGluR receptors by virtue of their ability to increase the response of such receptors to glutamate or glutamate agonists, enhancing the function of the receptors. It is recognized that the compounds of the present invention would be expected to increase the effectiveness of glutamate and glutamate agonists of the mGluR2 receptor. Thus, the potentiators of the present invention are expected to be useful in the treatment of various neurological and psychiatric disorders associated with glutamate dysfunction described to be treated herein and others that can be treated by such potentiators as are appreciated by those skilled in the art,
The compounds of the present invention may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the ambit of this invention. Any formulas, structures or names of compounds described in this specification that do not specify a particular stereochemistry are meant to encompass any and all existing isomers as described above and mixtures thereof in any proportion. When stereochemistry is specified, the invention is meant to encompass that particular isomer in pure form or as part of a mixture with other isomers in any proportion.
The independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration.
If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base. The diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art.
Alternatively, any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.
The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts in the solid form may exist in more than one crystal structure, and may also be in the form of hydrates. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N′-dibenzylethylene-diamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glutamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids. It will be understood that, as used herein, references to the compounds of Formula I are meant to also include a pharmaceutically acceptable salts.
Exemplifying the invention are Examples 1-6 to 1-21, 2-8 to 2-21 and 3-3 to 3-48, described herein. The subject compounds are useful in a method of potentiating metabotorpic glutamate receptor activity in a patient such as a mammal in need of such inhibition comprising the administration of an effective amount of the compound. The present invention is directed to the use of the subject compounds disclosed herein as potentiators of metabotropic glutamate receptor activity. In addition to primates, especially humans, a variety of other mammals can be treated according to the method of the present invention.
The present invention is further directed to a method for the manufacture of a medicament for potentiating metabotropic glutamate receptor activity in humans and animals comprising combining a compound of the present invention with a pharmaceutical carrier or diluent.
The subject treated in the present methods is generally a mammal, preferably a human being, male or female, in whom potentiation of metabotropic glutamate receptor activity is desired. The term “therapeutically effective amount” means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. It is recognized that one skilled in the art may affect the neurological and psychiatric disorders by treating a patient presently afflicted with the disorders or by prophylactically treating a patient afflicted with the disorders with an effective amount of the compound of the present invention. As used herein, the terms “treatment” and “treating” refer to all processes wherein there may be a slowing, interrupting, arresting, controlling, or stopping of the progression of the neurological and psychiatric disorders described herein, but does not necessarily indicate a total elimination of all disorder symptoms, as well as the prophylactic therapy of the mentioned conditions, particularly in a patient who is predisposed to such disease or disorder.
The term “composition” as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Such term in relation to pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier. By “pharmaceutically acceptable” it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The terms “administration of” and or “administering a” compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need of treatment.
The utility of the compounds in accordance with the present invention as inhibitors of metabotropic glutamate receptor activity, in particular mGluR2 activity, may be demonstrated by methodology known in the art. Inhibition constants are determined as follows. The compounds of the present invention may be tested in a fluorescence laser imaging plate reader (FLIPR) based assay. This assay is a common functional assay to monitor Ca2+ mobilization in whole cells expressing recombinant receptor coupled with a promiscuous G-protein. CHO dhfr-cells stably expressing recombinant human mGluR2 and Gα16 loaded with Fluo-4 AM (Invitrogen, Carlsbad Calif.) are treated with dose responses of compounds and the Ca2+ response is monitored on a FLIPR384 (Molecular Devices, Sunnydale Calif.) for agonist activity. The potentiation response is monitored after a subsequent addition of an EC20 concentration of glutamate (900 nM). The maximum calcium response at each concentration of compound for agonist or potentiation are plotted as dose responses and the curves are fitted with a four parameters logistic equation giving EC50 and Hill coefficient using the iterative non linear curve fitting software program.
The compounds of the present invention may also be tested in a [35S]-GTPγS assay. The stimulation of [35S]-GTPγS binding is a common functional assay to monitor Gαi-coupled receptor in native and recombinant receptor membrane preparation. Membrane from cells stably expressing hmGlu2 CHO-K1 (50 μg) are incubated in a 96 well plate for 1 hour in the presence of GTPγS35 (0.05 nM), GDP (5 μM) and compounds. The reaction is stopped by rapid filtration over Unifilter GF/B plate (Packard, Bioscience, Meriden Conn.) using a 96-well cell harvester (Brandel Gaithersburg, Md.). The filter plates are counted using Topcount counter (Packard, Bioscience, Meriden Conn., USA). When compounds are evaluated as potentiators they are tested in the presence of glutamate (1 μM). The activation (agonist) or the potentiation of glutamate (potentiator) curves are fitted with a four parameters logistic equation giving EC50 and Hill coefficient using the iterative non linear curve fitting software GraphPad (San Diego Calif., USA).
In particular, Examples 1-6 to 1-21, 2-8 to 2-21 and 3-3 to 3-48 were tested and demonstrated activity in potentiating the mGluR2 receptor in the FLIPR assay, generally with an EC50 of less than about 10 μM. Compounds within the present invention had activity in potentiating the mGluR2 receptor in the FLIPR and GTPγS assays with an EC50 of less than about 1 μM. Examples 1-6 to 1-21, 2-8 to 2-21 and 3-3 to 3-48 resulted in a minimum 1.8-fold potentiation of glutamate response in the presence of an EC20 concentration of glutamate (900 nM). Such results are indicative of the intrinsic activity of the compounds in use as potentiators of mGluR2 receptor activity.
The reference examples is (2S)-2-(phenoxymethyl)-2,3-dihydro[1,3]oxazolo[3,2-a]benzimidazole.
Metabotropic glutamate receptors including the mGluR2 receptor have been implicated in a wide range of biological functions. This has suggested a potential role for these receptors in a variety of disease processes in humans or other species.
The compounds of the present invention have utility in treating, preventing, ameliorating, controlling or reducing the risk of a variety of neurological and psychiatric disorders associated with glutamate dysfunction, including one or more of the following conditions or diseases: acute neurological and psychiatric disorders such as cerebral deficits subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, dementia (including AIDS-induced dementia), Alzheimer's disease, Huntington's Chorea, amyotrophic lateral sclerosis, ocular damage, retinopathy, cognitive disorders, idiopathic and drug-induced Parkinson's disease, muscular spasms and disorders associated with muscular spasticity including tremors, epilepsy, convulsions, migraine (including migraine headache), urinary incontinence, substance tolerance, substance withdrawal (including, substances such as opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.), psychosis, schizophrenia, anxiety (including generalized anxiety disorder, panic disorder, and obsessive compulsive disorder), mood disorders (including depression, mania, bipolar disorders), trigeminal neuralgia, hearing loss, tinnitus, macular degeneration of the eye, emesis, brain edema, pain (including acute and chronic pain states, severe pain, intractable pain, neuropathic pain, and post-traumatic pain), tardive dyskinesia, sleep disorders (including narcolepsy), autism, autism spectrum disorders, attention deficit/hyperactivity disorder, and conduct disorder.
Of the disorders above, the treatment of migraine, anxiety, schizophrenia, and epilepsy are of particular importance. In a preferred embodiment the present invention provides a method for treating migraine, comprising: administering to a patient in need thereof an effective amount of a compound of formula I. In another preferred embodiment the present invention provides a method for preventing or treating anxiety, comprising: administering to a patient in need thereof an effective amount of a compound of formula I. Particularly preferred anxiety disorders are generalized anxiety disorder, panic disorder, and obsessive compulsive disorder. In another preferred embodiment the present invention provides a method for treating schizophrenia, comprising: administering to a patient in need thereof an effective amount of a compound of formula I. In yet another preferred embodiment the present invention provides a method for treating epilepsy, comprising: administering to a patient in need thereof an effective amount of a compound of formula I.
Of the neurological and psychiatric disorders associated with glutamate dysfunction which are treated according to the present invention, the treatment of migraine, anxiety, schizophrenia, and epilepsy are particularly preferred. Particularly preferred anxiety disorders are generalized anxiety disorder, panic disorder, and obsessive compulsive disorder.
In an embodiment, the present invention provides a method for the treatment of schizophrenia comprising: administering to a patient in need thereof an effective amount of a compound of formula I or a pharmaceutical composition thereof. In one of the available sources of diagnostic tools, The Merck Manual (2006-2007), schizophrenia is characterized by psychosis (loss of contact with reality), hallucinations (false perceptions), delusions (false beliefs), disorganized speech and behavior, flattened affect (restricted range of emotions), cognitive deficits (impaired reasoning and problem solving), and occupational and social dysfunction. The skilled artisan will recognize that there are alternative nomenclatures, nosologies, and classification systems for neurological and psychiatric disorders, including migraine, and that these systems evolve with medical scientific progress.
Thus, in an embodiment the present invention provides a method for treating migraine, comprising: administering to a patient in need thereof an effective amount of a compound of formula I or a pharmaceutical composition thereof. In one of the available sources of diagnostic tools, Dorland's Medical Dictionary (23′ d Ed., 1982, W. B. Saunders Company, Philidelphia, Pa.), migraine is defined as a symptom complex of periodic headaches, usually temporal and unilateral, often with irritability, nausea, vomiting, constipation or diarrhea, and photophobia. As used herein the term “migraine” includes these periodic headaches, both temporal and unilateral, the associated irritability, nausea, vomiting, constipation or diarrhea, photophobia, and other associated symptoms. The skilled artisan will recognize that there are alternative nomenclatures, nosologies, and classification systems for neurological and psychiatric disorders, including migraine, and that these systems evolve with medical scientific progress.
In another embodiment the present invention provides a method for treating anxiety, comprising: administering to a patient in need thereof an effective amount of a compound of Formula I or a pharmaceutical composition thereof. At present, the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (1994, American Psychiatric Association, Washington, D.C.), provides a diagnostic tool including anxiety and related disorders. These include: panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety disorder due to a general medical condition, substance-induced anxiety disorder and anxiety disorder not otherwise specified. As used herein the term “anxiety” includes treatment of those anxiety disorders and related disorder as described in the DSM-IV. The skilled artisan will recognize that there are alternative nomenclatures, nosologies, and classification systems for neurological and psychiatric disorders, and particular anxiety, and that these systems evolve with medical scientific progress. Thus, the term “anxiety” is intended to include like disorders that are described in other diagnostic sources.
In another embodiment the present invention provides a method for treating depression, comprising: administering to a patient in need thereof an effective amount of a compound of Formula I or a pharmaceutical composition thereof. At present, the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (1994, American Psychiatric Association, Washington, D.C.), provides a diagnostic tool including depression and related disorders. Depressive disorders include, for example, single episodic or recurrent major depressive disorders, and dysthymic disorders, depressive neurosis, and neurotic depression; melancholic depression including anorexia, weight loss, insomnia and early morning waking, and psychomotor retardation; atypical depression (or reactive depression) including increased appetite, hypersomnia, psychomotor agitation or irritability, anxiety and phobias; seasonal affective disorder; or bipolar disorders or manic depression, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder. As used herein the term “depression” includes treatment of those depression disorders and related disorder as described in the DSM-IV.
In another embodiment the present invention provides a method for treating epilepsy, comprising: administering to a patient in need thereof an effective amount of a compound of Formula I or a pharmaceutical composition thereof. At present, there are several types and subtypes of seizures associated with epilepsy, including idiopathic, symptomatic, and cryptogenic. These epileptic seizures can be focal (partial) or generalized. They can also be simple or complex. Epilepsy is described in the art, such as Epilepsy: A comprehensive textbook. Ed. by Jerome Engel, Jr. and Timothy A. Pedley. (Lippincott-Raven, Philadelphia, 1997). At present, the International Classification of Diseases, Ninth Revision, (ICD-9) provides a diagnostic tool including epilepsy and related disorders. These include: generalized nonconvulsive epilepsy, generalized convulsive epilepsy, petit mal status epilepticus, grand mal status epilepticus, partial epilepsy with impairment of consciousness, partial epilepsy without impairment of consciousness, infantile spasms, epilepsy partialis continua, other forms of epilepsy, epilepsy, unspecified, NOS. As used herein the term “epilepsy” includes these all types and subtypes. The skilled artisan will recognize that there are alternative nomenclatures, nosologies, and classification systems for neurological and psychiatric disorders, including epilepsy, and that these systems evolve with medical scientific progress.
The subject compounds are further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the diseases, disorders and conditions noted herein.
The subject compounds are further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the aforementioned diseases, disorders and conditions in combination with other agents, including an mGluR agonist.
The term “potentiated amount” refers to an amount of an mGluR agonist, that is, the dosage of agonist which is effective in treating the neurological and psychiatric disorders described herein when administered in combination with an effective amount of a compound of the present invention. A potentiated amount is expected to be less than the amount that is required to provided the same effect when the mGluR agonist is administered without an effective amount of a compound of the present invention.
A potentiated amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of conventional techniques and by observing results obtained under analogous circumstances. In determining a potentiated amount, the dose of an mGluR agonist to be administered in combination with a compound of formula I, a number of factors are considered by the attending diagnostician, including, but not limited to: the mGluR agonist selected to be administered, including its potency and selectivity; the compound of formula I to be coadministered; the species of mammal; its size, age, and general health; the specific disorder involved; the degree of involvement or the severity of the disorder; the response of the individual patient; the modes of administration; the bioavailability characteristics of the preparations administered; the dose regimens selected; the use of other concomitant medication; and other relevant circumstances.
A potentiated amount of an mGluR agonist to be administered in combination with an effective amount of a compound of formula I is expected to vary from about 0.1 milligram per kilogram of body weight per day (mg/kg/day) to about 100 mg/kg/day and is expected to be less than the amount that is required to provided the same effect when administered without an effective amount of a compound of formula I. Preferred amounts of a co-administered mGlu agonist are able to be determined by one skilled in the art.
The compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of diseases or conditions for which compounds of Formula I or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone. Such other drug(s) may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of Formula I. When a compound of Formula I is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of Formula I is preferred. However, the combination therapy may also includes therapies in which the compound of Formula I and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of Formula I.
The above combinations include combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds.
Likewise, compounds of the present invention may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which compounds of the present invention are useful. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present invention. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of the present invention is preferred. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention.
The weight ratio of the compound of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of the compound of the present invention to the other agent will generally range from about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.
In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).
The compounds of the present invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration. In addition to the treatment of warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, monkeys, etc., the compounds of the invention are effective for use in humans.
The pharmaceutical compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
Pharmaceutical compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. Compositions for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Oily suspensions may be formulated by suspending the active ingredient in a suitable oil. Oil-in-water emulsions may also be employed. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
Pharmaceutical compositions of the present compounds may be in the form of a sterile injectable aqueous or oleagenous suspension. The compounds of the present invention may also be administered in the form of suppositories for rectal administration. For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention may be employed. The compounds of the present invention may also be formulated for administered by inhalation. The compounds of the present invention may also be administered by a transdermal patch by methods known in the art.
The pharmaceutical composition and method of the present invention may further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above mentioned pathological conditions.
In the treatment, prevention, control, amelioration, or reduction of risk of conditions which require potentiation of metabotorpic glutamate receptor activity an appropriate dosage level will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 to about 250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day. A suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
When treating, preventing, controlling, ameliorating, or reducing the risk of neurological and psychiatric disorders associated with glutamate dysfunction or other diseases for which compounds of the present invention are indicated, generally satisfactory results are obtained when the compounds of the present invention are administered at a daily dosage of from about 0.1 milligram to about 100 milligram per kilogram of animal body weight, preferably given as a single daily dose or in divided doses two to six times a day, or in sustained release form. For most large mammals, the total daily dosage is from about 1.0 milligrams to about 1000 milligrams, preferably from about 1 milligrams to about 50 milligrams. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 milligrams to about 350 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.
It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
Several methods for preparing the compounds of this invention are illustrated in the following Schemes and Examples. Starting materials are made according to procedures known in the art or as illustrated herein. The compounds of the present invention can be prepared in a variety of fashions.
According to general scheme A, glycidol (A-1) may be reacted with a variety of substituted phenols (A-2) under Mitsunobu conditions to provide substituted epoxides (A-3). Such epoxides can be reacted with substituted 2-chloro or 2-bromobenzimidazoles (A-4) in the presence of cesium carbonate in a polar solvent at high temperature to provide, in one pot, the desired oxazolobenzimidazoles (A-5).
According to general scheme B, silyl-protected epoxide (B-1) undergoes reaction with substituted benzimidazoles (A-4) to provide silyl protected oxazolobenzimidazole (B-2). Deprotection of the silyl group produces hydroxyl oxazolobenzimidazole (8-3) which can undergo a Mitsunobu reaction with a variety of phenols (A-2) to give substituted oxazolobenzimidazoles (B-4)
According to general scheme C, various heterocyclic derivatives can be synthesized. Substituted azabenzimidazolones (C-2) can be alkylated with benzyl glycidols (C-1) under microwave conditions to provide a mixture of separable alkylated products (C-3 and C-4). Either of these products can be carried forward in an intramolecular Mitsunobu ring-closure to provide oxazolobenzimidaozles (C-5). If an alternative phenolic group is desired, then benzyl glycidol is preferred as F-1, and can be deprotected using Pd(OH)2 to provide substituted oxazolobenzimidazoles (F-6). Alternatively, glycidol C-1 can already be conjugated to the phenol of choice as shown in scheme A. These primary alcohols can then under a second Mitsunobu reaction with substituted phenols (A-2) to yield oxazolobenzimidazoles (C-7)
According to general scheme D, oxazolobenzimidazole (D-1) can undergo a variety of metal mediated coupling reactions such as the palladium-catalyzed Suzuki reaction as shown. Using Pd(PPh3)4 in the presence of aqueous Na2CO3 in DMF at elevated temperature (e.g. 100° C.), oxazolobenzimidazole (D-1) can be coupled to a variety of substituted boronic acids and esters to give substituted oxazolobenzimidazole (D-2).
Certain reagents (phenols, epoxides and chlorobenzimidazoles) in the schemes below had to be synthesized prior to their incorporation in the inhibitor synthetic schemes. Specific procedures are described or referred to below:
1-methoxy-4-(2,2,2-trifluoro-1,1-dimethylethyl)benzene (P1-1) is a literature compound reported in Tanka, H.; Shishido, Y. Bioorg. Med. Chem. Lett. 2007, 17, 6079-6085. The corresponding phenol (P1-2) was prepared by this protocol: 1-methoxy-4-(2,2,2-trifluoro-1,1-dimethylethyl)benzene (P1-1, 1.03 g, 4.72 mmol) was dissolved in anhydrous dichloromethane and cooled to −78° C. under nitrogen gas. BBr3 (9.44 mL, 9.44 mmol, 1M in dichloromethane) was added dropwise and the reaction was stirred to 0° C. for 2 h. Water (2 mL) was added to quench excess reagent, followed by aqueous ammonium hydroxide (5 mL). The reaction was then acidified with 6N HCl to a final pH=1 and extracted with dichloromethane (3×10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to provide 4-(2,2,2-trifluoro-1,1-dimethylethyl)phenol (P1-2) of reasonable purity. LRMS m/z (M+H) 204.9 found, 205.2 required.
A mixture of (4-hydroxyphenyl)acetonitrile (5.00 g, 37.6 mmol, 1 equiv), imidazole (3.83 g, 56.3 mmol, 1.50 equiv), and tert-butyldimethylsilyl chloride (6.79 g, 45.1 mmol, 1.20 equiv in N,N-dimethylformamide (50 mL) was stirred at 23° C. for 20 h. The reaction mixture was concentrated and the residue partitioned between a 70:30 mixture of ethyl acetate and hexanes (200 mL) and water (2×200 mL). The organic layer was washed with brine, then dried over sodium sulfate and concentrated to give (4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)acetonitrile (P2-2) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 6.98 (d, 2H, J=8.7 Hz), 6.63 (d, 2H, J=8.7 Hz), 3.48 (s, 2H), 0.80 (s, 9H), 0.00 (s, 6H). LRMS m/z (M+H) 248.0 found, 248.1 required.
A solution of sodium bis(trimethylsilyl)amide (1.0 M, 36.4 mL, 36.4 mmol, 3.00 equiv) was added to a solution of (4-{[tert-butyl(dimethyl)silyl]oxy}phenyl(acetonitrile (P2-2, 3.00 g, 12.1 mmol, 1 equiv) in THF (100 mL) pre-cooled to 0° C. The orange-colored mixture was stirred for 20 minutes and iodomethane (3.79 mL, 60.6 mmol, 5.00 equiv) was added. The resulting mixture was stirred at 0° C. for 1 h and then partitioned between saturated aqueous ammonium chloride solution (200 mL) and a 70:30 mixture of ethyl acetate and hexanes (2×200 mL). The combined organic layers were washed with brine, then dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (hexanes initially, grading to 100% ethyl acetate) to give 2-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-2-methylpropanenitrile (P2-3) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.17 (d, 2H, J=8.6 Hz), 6.63 (d, 2H, J=8.6 Hz), 1.50 (s, 6H), 0.78 (s, 9H), 0.00 (s, 6H).
A solution of {[tert-butyl(dimethyl)silyl]oxy}phenyl)-2-methylpropanenitrile (P2-3, 2.20 g, 7.99 mmol, 1 equiv) and triethylamine trihydrofluoride (3.90 mL, 24.0 mmol, 3.00 equiv) in acetonitrile (50 mL) was stirred at 23° C. for 3 h. The reaction mixture was concentrated and the residue carefully partitioned between saturated aqueous sodium bicarbonate solution (200 mL) and ethyl acetate (2×100 mL). The combined organic layers were was with brine, then dried over sodium sulfate and concentrated to give 2-(4-hydroxyphenyl)-2-methylpropanenitrile (P2-4) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.33 (d, 2H, J=8.6 Hz), 6.84 (d, 2H, J=8.6 Hz), 4.90 (s, 1H), 1.70 (s, 6H).
To a mixture of 6-bromopyridin-3-ol (P3-1) (19.8 g, 114 mmol, 1.00 eq), PS-triphenylphosphine (2.2 mmol/gram) (111 g, 244 mmol, 2.15 eq) and benzyl alcohol (14.2 mL, 137 mmol, 1.20 eq) in dichloromethane (1.30 L) was added DIAD (28.8 mL, 148 mmol, 1.30 eq) and the reaction was stirred at 23° C. under nitrogen for 48 hours. The reaction was filtered and the filtrate was concentrated and purified by silica gel chromatography (0-100% ethyl acetate/hexanes) to yield 5-(benzyloxy)-2-bromopyridine (P3-2) as a yellow solid. LRMS m/z (M+H) 263.9 found, 264.0 required.
To a stirring suspension of copper cyanide (680 mg, 7.6 mmol, 4.0 eq) in THF (10 ml) at −78° C. under nitrogen was added tert-butylmagnesium chloride (1.0 M in THF) (15.1 mL, 15.1 mmol, 8.0 eq). After 20 minutes was added a solution of 5-(benzyloxy)-2-bromopyridine (P3-2) (500 mg, 1.9 mmol, 1.0 eq) in THF (10 ml) and the reaction was stirred at −78° C. for 2 hours and at room temperature for 20 hours. The excess Grignard reagent was quenched by the addition of water (25 ml). Ethyl acetate (200 ml) was added and the organic layer was separated, dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes) to yield 5-(benzyloxy)-2-tert-butylpyridine (P3-3) as an orange oil. LRMS m/z (M+H) 242.0 found, 242.1 required.
A mixture of 5-(benzyloxy)-2-tert-butylpyridine (P-3) (150 mg, 0.62 mmol, 1.0 eq), and palladium hydroxide on carbon (350 mg, 0.50 mmol, 0.80 eq) in ethanol (50 ml) was stirred at room temperature under a hydrogen balloon atmosphere for 16 hours. The reaction was filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes) to yield 4-tert-butylphenol (P3-4) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.16 (d, 1H, J=3.0 Hz), 7.26-7.13 (m, 3H); 1.34 (s, 9H). LRMS m/z (M+H) 151.9 found, 152.1 required.
In a flame dried flask charged with anhydrous argon was added 2-bromo-5-methoxypyridine (1.46 g, 7.77 mmol). Anhydrous tetrahydrofuran (40 mL) was added via syringe and the resulting solution was cooled to −78° C. under argon pressure. n-BuLi (5.34 mL, 1.6M in hexanes, 8.54 mmol) was added dropwise and the resulting pale yellow solution was stirred 30 min before addition of chlorotrimethylsilane (neat, 1.19 mL, 9.32 mmol). The reaction stirred 10 min at −78° C. and then 30 min at 0° C. The reaction was quenched with the addition of 5% aqueous NaHCO3 (20 mL) and extracted with EtOAc (2×25 mL). The combined organic fractions were washed with saturated brine (20 mL), dried over MgSO4, filtered and concentrated to provide crude P4-2. Flash chromatography (SiO2, ISCO Redisep 40 g column, 0-20% EtOAc/hexanes gradient) provided 5-methoxy-2-(trimethylsilyl)pyridine (P4-2) as a clear oil. LRMS m/z (M+H) 182.1 found, 182.3 required.
In a round bottom flask under nitrogen, 5-methoxy-2-(trimethylsilyl)pyridine (P4-2, 0.10 g, 0.55 mmol) was dissolved in anhydrous dimethylformamide (3 mL). Sodium ethanethiolate (0.23 g, 2.76 mmol) was added in one portion and the resulting solution was heated to 150° C. for 30 minutes. Upon completion, the reaction was cooled to ambient temperature, diluted with 50 mL EtOAc and washed with 100 mL 5% aqueous NaHCO3. The aqueous layer was washed with EtOAc three additional times to recover all phenol, and the combined washings were dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography (SiO2, 40 g ISCO column, 0-80% EtOAc/hexanes) to provide 5-Hydroxy-2-(trimethylsilyl)pyridine (P4-3) as a light yellow solid. NMR (500 MHz, CDCl3) δ 8.33 (d, 1H, J=2.9 Hz), 7.43 (d, 1H, J=8.4 Hz), 7.19 (dd, 1H, 8.2 Hz, 3.0 Hz) 0.30 (s, 9H). LRMS m/z (M+H) 168.1 found, 168.3 required.
In a flame dried flask charged with anhydrous argon was added 2-bromo-5-methoxypyridine (4.81 g, 25.6 mmol) and anhydrous THF (100 mL). The resulting solution was cooled to −78° C. in an acetone/dry ice bath and treated dropwise with n-butyllithium (19.2 mL, 30.7 mmol, 1.6M in hexanes). The resulting orange solution was stirred 10 min at −78° C., and was treated dropwise with α,α,α-trifluoroacetone (2.64 mL, 29.4 mmol). The reaction became dark brown and was warmed to ambient temperature over 1 hour. The intense color dissipated to a feint yellow and the reaction was recooled to −78° C. Methanesulfonyl chloride (2.39 mL, 30.7 mmol) was added dropwise and the reaction was warmed to ambient temperature for 1 hour. The reaction was partitioned between EtOAc and 5% NaHCO3, and the organic layer was dried over MgSO4, filtered and concentrated. Flash chromatography (SiO2, 120 g ISCO Redisep column, 0-40% EtOAc/hexane provided 2,2,2-trifluoro-1-(5-methoxypyridin-2-yl)-1-methylethylmethanesulfonate (P5-1) as a clear oil. LRMS m/z (M+H) 299.9 found, 300.2 required.
In a flame dried flask charged with anhydrous argon, 2,2,2-trifluoro-1-(5-methoxypyridin-2-yl)-1-methylethylmethanesulfonate (P5-1, 2.20 g, 7.35 mmol) was dissolved in anhydrous dichloromethane (100 mL) and cooled to 0° C. The resulting solution was treated with trimethylaluminum (5.51 mL, 11.03 mmol, 2M in toluene) and the ice bath warmed to ambient temperature for 16 h. The reaction was quenched with 100 mL of 5% aqueous NaHCO3 and 30 mL of saturated brine solution. The slurry was filtered through celite with copious washing of the celite with EtOAc. The layers were separated and the organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The crude residue was purified by flash column chromatography (SiO2, 40 g ISCO column, 0-10% EtOAc/hexanes) to provide 5-methoxy-2-(2,2,2-trifluoro-1,1-dimethylethyl)pyridine (P5-2) as a yellow oil. LRMS m/z (M+H) 219.9 found, 220.2 required.
In a round bottom flask under nitrogen, 5-methoxy-2-(2,2,2-trifluoro-1,1-dimethylethyl)pyridine (P5-2, 0.35 g, 1.60 mmol) was dissolved in anhydrous dimethylformamide (10 mL). Sodium ethanethiolate (0.40 g, 4.79 mmol) was added in one portion and the resulting solution was heated to 150° C. for 30 minutes. Upon completion, the reaction was cooled to ambient temperature, diluted with 50 mL EtOAc and washed with 100 mL 5% aqueous NaHCO3. The aqueous layer was washed with EtOAc three additional times to recover all phenol, and the combined washings were dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography (SiO2, 40 g ISCO column, 0-30% EtOAc/hexanes) to provide 6-(2,2,2-trifluoro-1,1-dimethylethyl)pyridin-3-ol (P5-3) as an off-white solid. 1H NMR (500 MHz, CDCl3) δ 8.10 (d, 1H, J=2.9 Hz), 7.38 (d, 1H, J=8.8 Hz), 7.20 (dd, 1H, J=8.7 Hz, 2.9 Hz) 1.59 (s, 6H). LRMS m/z (M+H) 206.1 found, 206.2 required.
A mixture of 2-bromo-5-methoxypyridine (P6-1, 5.00 g, 26.6 mmol, 1 equiv), isopropenyl boronic acid pinacol ester (6.70 g, 39.9 mmol, 1.50 equiv), tetrakis(triphenylphosphine)palladium (0.615 g, 0.532 mmol, 0.02 equiv), and aqueous sodium carbonate solution (2.0 M, 39.9 mL, 80.0 mmol, 3.00 equiv) in dioxane (100 mL) was heated at 90° C. for 20 h. The reaction mixture was partitioned between ethyl acetate (250 mL) and brine. The organic layer was dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (hexanes, grading to 100% ethyl acetate) to give 2-isopropenyl-5-methoxypyridine (P6-2) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 8.29 (d, 1H, J=3.0 Hz), 7.43 (d, 1H, J=8.8 Hz), 7.16 (dd, 1H, J=8.8, 3.0 Hz), 5.73 (s, 1H), 5.20 (fine m, 1H), 3.86 (s, 3H), 2.19 (s, 3H). LRMS m/z (M+H) 149.9 found, 150.1 required.
A solution of diethylzinc (1.0 M in hexanes, 67.0 mL, 67.0 mmol, 10.0 equiv) was added to a solution of 2-isopropenyl-5-methoxypyridine (P6-2, 1.00 g, 6.70 mmol, 1 equiv) and chloroiodomethane (4.87 mL, 67.0 mmol, 10.0 equiv) in anhydrous toluene (50 mL) pre-cooled to 0° C. The resulting mixture was warmed to 23° C. and stirred for 3 h, then cooled to 0° C. where excess diethylzinc was carefully quenched with saturated aqueous ammonium chloride solution (200 mL). The aqueous mixture was extracted with ethyl acetate (3×200 mL), and the combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (hexanes initially, grading to 100% ethyl acetate) to give 5-methoxy-2-(1-methylcyclopropyl)pyridine (P6-3) as a colorless oil. δ 8.19 (d, 1H, J=2.8 Hz), 7.19 (dd, 1H, J=8.8, 0.6 Hz), 7.11 (dd, 1H, J=8.8, 3.0 Hz), 3.83 (s, 3H), 1.48 (s, 3H), 1.13 (q, 21-1, J=3.8 Hz), 0.75 (q, 2H, J=3.8 Hz). LRMS m/z (M+H) 163.9 found, 164.1 required.
A mixture of 5-methoxy-2-(1-methylcyclopropyl)pyridine (P6-3, 450 mg, 2.76 mmol, 1 equiv) and sodium ethanethiolate (464 mg, 5.51 mmol, 2.00 equiv) in DMF (10 mL) was heated at 150° C. for 1 h. The reaction mixture was partitioned between a 5:1 mixture of brine and saturated aqueous ammonium chloride solution (200 mL) and ethyl acetate (3×100 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (hexanes, grading to 100% EtOAc) to give 6-(1-methylcyclopropyl)pyridin-3-ol (P6-4) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 8.09 (1:2:1 triplet, 1H. J=1.8 Hz), 7.18 (d, 2H, J=1.8 Hz), 1.44 (s, 3H), 1.03 (q, 2H, J=3.8 Hz), 0.75 (q, 2H, J=3.8 Hz). LRMS m/z (M+H) 149.9 found, 150.1 required.
To 6-tert-butylpyridin-3-ol (P3-4) (99 mg, 0.65 mmol, 1.00 eq) in pyridine (1.9 mL) was slowly added a solution of bromine (41 μL, 0.79 mmol, 1.20 eq) in pyridine (1 mL) and the reaction was stirred at 23° C. for 1 hour. The reaction mixture was partitioned between EtOAc (20 mL) and brine. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography (SiO2, 12 g ISCO column, 0-50% EtOAc/hexanes) to give 2-bromo-6-tert-butylpyridin-3-ol (P7-1) as a white solid and 2,4-dibromo-6-tert-butylpyridin-3-ol (P7-2) as a pale yellow solid. 1H NMR (P7-1) (500 MHz, CDCl3) δ 7.20 (m, 1H), 5.61 (s, 1H), 1.32 (s, 9H). LRMS m/z (M+H) 229.9 found, 230.0 required.
1H NMR (P7-2) (500 MHz, CDCl3) δ 7.39 (s, 1H), 5.69 (s, 1H), 1.32 (s, 9H). LRMS m/z (M+H) 309.8 found, 309.9 required.
To a mixture of 6-tert-butylpyridin-3-ol (P3-4) (95 mg, 0.63 mmol, 1.00 eq) and sodium carbonate (140 mg, 1.32 mmol, 2.1 eq) in water (5 mL) was added iodine (320 mg, 1.26 mmol, 2 eq), and the reaction was stirred at 23° C. overnight. The mixture was slightly acidified with 1 N HCl and extracted with EtOAc (3×25 mL). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated to afford 6-tert-butyl-2,4-diiodopyridin-3-ol (P8-1) as a white solid. No purification was necessary. 1H NMR (500 MHz, CDCl3) δ 7.54 (s, 1H), 5.34 (s, 1H), 1.30 (s, 9H). LRMS m/z (M+H) 403.6 found, 403.9 required.
To a solution of 2-aminopyridin-3-ol (P9-1) (4.25 g, 38.6 mmol, 1 eq) in tetrafluoroboric acid (150 mL) at 0° C. was slowly added sodium nitrite (20 g, 290 mmol, 7.5 eq), and the reaction was stirred at the same temperature for 1 hour. The mixture was carefully basified with 12 M NaOH, extracted with EtOAc (5×125 mL), dried over Na2SO4, filtered and concentrated to afford 2-fluoropyridin-3-ol (P9-2) as a yellow solid. No purification was necessary. 1H NMR (500 MHz, DMSO-d6) δ 10.42 (s, 1H), 7.61 (d, 1H, J=4.5 Hz), 7.38 (t, 1H, J=8.5 Hz), 7.16 (dd, 1H, J=8.0 Hz, 3.0 Hz).
To a solution of 2-fluoropyridin-3-ol (P9-2) (3.5 g, 30.9 mmol, 1 eq) and sodium acetate (2.5 g, 30.9 mmol, 1 eq) in acetic acid (30 mL) at 0° C. was added bromine (1.3 mL, 24.8 mmol, 0.8 eq) dropwise, and the reaction was stirred at 23° C. for 4 hours. The mixture was poured over a cold, 1N solution of NaOH and extracted with EtOAc (3×100 mL). The combined organics were dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography (SiO2, 80 g ISCO column, 0-70% EtOAc/hexanes) to give 6-bromo-2-fluoropyridin-3-ol (P9-3) as a yellow solid. 1H NMR (500 MHz, CDCl3) δ 7.28 (d, 2H, J=8.5 Hz), 5.52 (brs, 1H). LRMS m/z (M+H) 191.9 found, 191.9 required.
To a mixture of 6-bromo-2-fluoropyridin-3-ol (P9-3) (730 mg, 3.8 mmol, 1 eq) and imidazole (285 mg, 4.2 mmol, 1.1 eq) in DMF (4 mL) was added TIPS-Cl (845 μL, 4.0 mmol. 1.05 eq) and the reaction was stirred at 23° C. overnight. The mixture was poured over water and extracted with EtOAc (3×35 mL). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography (SiO2, 24 g ISCO column, 0-50% EtOAc/hexanes) to give 6-bromo-2-fluoro-3-(triisopropylsilyloxy)pyridine (P9-4) as a colorless oil. NMR (500 MHz, CDCl3) δ 7.15-7.23 (m, 2H), 1.25 (m, 2H), 1.07 (d, 18H, J=18.5 Hz).
To a stirring suspension of copper cyanide (206 mg, 2.3 mmol, 2.0 eq) in THF (10 ml) at −78° C. under nitrogen was added tert-butylmagnesium chloride (1.0 M in THF) (4.6 mL, 4.6 mmol, 4.0 eq). After 20 minutes was slowly added a solution of 6-bromo-2-fluoro-3-(triisopropylsilyloxy)pyridine (P9-4) (500 mg, 1.1 mmol, 1.0 eq) in THF (10 ml) and the reaction was warmed to room temperature over 20 hours. The excess Grignard reagent was quenched by the addition of 1:1 NH4OH/water (25 ml). The mixture stirred for 20 minutes to complete deprotection. EtOAc (150 ml) was added and the mixture was filtered through celite to remove the salts. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The residue was by flash column chromatography (SiO2, 40 g ISCO column, 0-100% EtOAc/hexanes) to give 6-tert-butyl-2-fluoropyridin-3-ol (P9-5) as a white solid. NMR (500 MHz, CDCl3) δ 7.26 (m, 1H), 7.06 (dd, 1H, J=2 Hz, 10 Hz), 5.26 (brs, 1H), 1.31 (s, 9H). LRMS m/z (M+H) 170.1 found, 170.1 required.
In a flame dried flask under nitrogen was added potassium tert-butoxide (95 mg, 0.85 mmol, 1.5 eq). Anhydrous THF (1 mL) was added followed by diisopropylamine (120 μL, 0.85 mmol, 1.5 eq) and the resulting mixture was cooled to −55° C. under nitrogen. n-BuLi (1.6M in hexanes) (530 μL, 0.85 mmol, 1.5 eq) was added dropwise and the resulting solution stirred 15 minutes before addition of 2-cyclopentyl-5-methoxypyridine (P10-1) (100 mg, 0.56 mmol, 1 eq) in anhydrous THF (1 mL). After an additional 30 minutes of stirring methyl iodide (105 μL, 1.7 mmol, 3.0 eq) was added. The reaction stirred for 1 hour at −78° C. The reaction was quenched with the addition of water (1 mL) and extracted with EtOAc (3×10 mL). The combined organic fractions were washed with saturated brine (20 mL), dried over Na2SO4, filtered and concentrated to provide 5-methoxy-2-(1-methylcyclopentyl)pyridine (P10-2) as a white solid. No further purification was necessary. NMR (500 MHz, CDCl3) δ 8.26 (d, 1H, J=3 Hz), 7.22 (d, 1H, J=8.5 Hz), 7.13 (dd, 1H, J=3 Hz, 9 Hz), 3.84 (s, 3H), 2.07 (m, 2H), 1.69-1.79 (m, 6H), 1.30 (s, 3H). LRMS m/z (M+H) 192.1 found, 192.1 required.
In a round bottom flask under nitrogen, 5-methoxy-2-(1-methylcyclopentyl)pyridine (P10-2) (100 mg, 0.47 mmol, 1 eq) was dissolved in anhydrous dimethylformamide (1.5 mL). Sodium ethanethiolate (120 mg, 1.41 mmol, 3 eq) was added in one portion and the resulting solution was heated to 150° C. for 1 hour. Upon completion, the reaction was cooled to ambient temperature, diluted with 50 mL EtOAc and washed with 50 mL 5% aqueous NaHCO3. The aqueous layer was washed with EtOAc three additional times to recover all phenol, and the combined washings were dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography (SiO2, 12 g ISCO column, 0-100% EtOAc/hexanes) to provide 6-(1-methylcyclopentyl)pyridin-3-ol (P10-3) as a pale yellow solid. LRMS m/z (M+H) 178.1 found, 178.1 required.
In a flame dried flask charged with nitrogen was added 2-bromo-5-methoxypyridine (P4-1) (1.5 g, 8.0 mmol, 1 eq) and anhydrous THF (16 mL). The resulting solution was cooled to −78° C. in an acetone/dry ice bath and treated dropwise with n-butyllithium (1.6M in hexanes) (5.5 mL, 8.8 mmol, 1.1 eq). The resulting solution was stirred 20 min at −78° C., and was treated dropwise with cyclobutanone (840 mL, 12 mmol, 1.5 eq). The reaction became green and was warmed to ambient temperature over 1 hour. The reaction was partitioned between EtOAc and 5% NaHCO3, and the organic layer was dried over Na2SO4, filtered and concentrated. Flash chromatography (SiO2, 40 g ISCO Redisep column, 0-80% EtOAc/hexanes) provided 1-(5-methoxypyridin-2-yl)cyclobutanol (P11-1) as a colorless oil. NMR (500 MHz, CDCl3) δ 8.20 (d, 1H, J=3.5 Hz), 7.50 (d, 1H, J=11 Hz), 7.27 (dd, 1H, J=4 Hz, 11 Hz), 4.96 (brs, 1H), 3.87 (s, 3H), 2.50 (m, 4H), 2.08 (m, 1H), 1.84 (m, 1H). LRMS m/z (M+H) 180.1 found, 180.1 required.
In a flame dried flask charged with nitrogen was added 1-(5-methoxypyridin-2-yl)cyclobutanol (P11-1) (176 mg, 0.98 mmol, 1 eq) and anhydrous THF (3.3 mL). The resulting solution was cooled to 0° C. and sodium hydride (50 mg, 1.97 mmol, 2 eq) was added. The resulting mixture was stirred at ambient temperature for 1 hour and 40° C. for 2 hours. The reaction was recooled to ambient temperature. Methanesulfonyl chloride (153 μL, 1.97 mmol, 2 eq) was added dropwise and the reaction was warmed to 40° C. for 2 hours. The reaction was quenched with water and extracted with EtOAc (3×25 mL). The organic layers were dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography (SiO2, 12 g ISCO column, 0-100% EtOAc/hexanes) to afford 2-cyclobutenyl-5-methoxypyridine (P11-2) as a yellow solid.
NMR (500 MHz, CDCl3) δ 8.31 (d, 11-1, J=3.0 Hz), 7.33 (d, 1H, J=10.5 Hz), 7.28 (dd, 1H, J=3.5 Hz, 10.5 Hz), 6.60 (s, 1H), 3.89 (s, 3H), 2.91 (t, 2H, J=4 Hz), 2.58 (brt, 2H, J=3 Hz). LRMS m/z (M+H) 162.1 found, 162.1 required.
A mixture of 2-cyclobutenyl-5-methoxypyridine (P11-2) (60 mg, 0.37 mmol, 1.0 eq), and palladium on carbon (50 mg, 0.47 mmol, 1.26 eq) in methanol (5 ml) was stirred at room temperature under a hydrogen balloon atmosphere for 16 hours. The reaction was filtered through celite and the filtrate was concentrated to yield 2-cyclobutyl-5-methoxypyridine (P11-3) as a yellow solid with no further purification required. LRMS m/z (M+H) 164.1 found, 164.1 required.
In a flame dried flask under nitrogen was added potassium tert-butoxide (54 mg, 0.48 mmol, 1.5 eq). Anhydrous THF (1 mL) was added followed by diisopropylamine (68 μL, 0.48 mmol, 1.5 eq) and the resulting mixture was cooled to −55° C. under nitrogen. n-BuLi (1.6M in hexanes) (300 μL, 0.48 mmol, 1.5 eq) was added dropwise and the resulting solution stirred 15 minutes before addition of -cyclobutyl-5-methoxypyridine (P11-3) (52 mg, 0.32 mmol, 1 eq) in anhydrous THF (1 mL). After an additional 30 minutes of stirring methyl iodide (60 μL, 0.96 mmol, 3.0 eq) was added. The reaction stirred for 1 hour at −78° C. The reaction was quenched with the addition of water (1 mL) and extracted with EtOAc (3×10 mL). The combined organic fractions were washed with saturated brine (20 mL), dried over Na2SO4, filtered and concentrated to provide 5-methoxy-2-(1-methylcyclobutyl)pyridine (P11-4) as a white solid. No further purification was necessary. NMR (500 MHz, CDCl3) δ 8.25 (d, 1H, J=2.5 Hz), 7.15 (dd, 1H, J=3.0 Hz, 8.5 Hz), 7.09 (d, 1H, J=8.5 Hz), 3.84 (s, 3H), 2.49 (m, 2H), 2.05 (m, 2H), 1.55 (m, 2H), 1.49 (s, 3H). LRMS m/z (M+H) 178.1 found, 178.1 required.
In a round bottom flask under nitrogen, 5-methoxy-2-(1-methylcyclobutyl)pyridine (P11-4) (42 mg, 0.24 mmol, 1 eq) was dissolved in anhydrous dimethylformamide (1 mL). Sodium ethanethiolate (60 mg, 0.71 mmol, 3 eq) was added in one portion and the resulting solution was heated to 150° C. for 1 hour. Upon completion, the reaction was cooled to ambient temperature, diluted with 25 mL EtOAc and washed with 25 mL 5% aqueous NaHCO3. The aqueous layer was washed with EtOAc three additional times to recover all phenol, and the combined washings were dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography (SiO2, 12 g ISCO column, 0-100% EtOAc/hexanes) to provide 641-methylcyclobutyl)pyridin-3-ol (P11-5) as a pale yellow solid. LRMS m/z (M+H) 164.1 found, 164.1 required.
In a flame dried flask under nitrogen was added 5-(benzyloxy)-2-(prop-1-en-2-yl)pyridine (P12-1) (500 mg, 2.22 mmol, 1 eq) followed by diglyme (1.5 mL). The mixture was refluxed at 190° C. Sodium chlorodifluoroacetate (4.1 g, 26.6 mmol, 12 eq) in diglyme (4 mL) was added via syringe pump (2 mL/hour) to the refluxing mixture. Once the addition was complete, the black mixture was cooled to ambient temperature and partitioned between EtOAc and 5% NaHCO3. The combined organic layers were separated, dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography (SiO2, 40 g ISCO column, 0-100% EtOAc/hexanes) to provide 5-(benzyloxy)-2-(2,2-difluoro-1-methylcyclopropyl)pyridine (P12-2). NMR (500 MHz, CDCl3) δ 8.33 (s, 1H), 7.34-7.43 (m, 5H), 7.24 (m, 2H), 5.10 (s, 21-1), 2.13 (m, 1H), 1.58 (s, 3H), 1.38 (m, 1H). LRMS m/z (M+H) 276.0 found, 276.1 required.
A mixture of 5-(benzyloxy)-2-(2,2-difluoro-1-methylcyclopropyl)pyridine (P12-2) (100 mg, 0.36 mmol, 1.0 eq), and palladium on carbon (39 mg, 0.36 mmol, 1.0 eq) in methanol/chloroform (10 ml) was stirred at room temperature under a hydrogen balloon atmosphere for 30 minutes. The reaction was filtered through celite and the filtrate was concentrated. The residue was purified by flash column chromatography (SiO2, 12 g ISCO column, 0-100% EtOAc/hexanes) to provide 6-(2,2-difluoro-1-methylcyclopropyl)pyridin-3-ol (P12-3) as a white solid. NMR (500 MHz, CDCl3) δ 8.22 (s, 1H), 7.25 (m, 2H), 1.92 (m, 1H), 1.55 (s, 31-1), 1.43 (m, 1H). LRMS m/z (M+H) 224.0 found, 224.1 required.
Several chlorobenzimidazoles were not commercially available and had to be synthesized from their corresponding ortho-di-anilines as described for 2-chloro-5-cyanobenzimidazole in Ognyanov, V. I. et ai J. Med. Chem. 2006, 49, 3719-3742.
A solution of 5-methoxy-2-nitroaniline (C-1) (25 g, 150 mmol, 1.0 eq) in acetic anhydride (45 ml, 480 mmol, 3.1 eq) was heated at 120° C. for 16 hours. The reaction mixture was cooled to room temperature, poured into water (500 ml) and the resulting precipitate was collected by filtration and dissolved in chloroform (250 ml). The organic layer was washed with water (250 ml) and brine (100 ml), then dried over sodium sulfate and concentrated to yield N-(5-methoxy-2-nitrophenyl)acetamide (C-2)
as a yellow solid. 1H NMR (400 MHz, DMSO): δ 10.30 (s, 1H); 8.04 (d, J=9.3 Hz, 1H); 7.53 (d, J=2.8 Hz, 1H); 6.87 (dd, J=9,3, 2.8 Hz, 1H); 3.86 (s, 3H); 2.13 (s, 3H). LRMS m/z (M+H) 210.9 found, 211.1 required.
(27 g, 130 mmol, 1.0 eq) in acetic acid (200 ml) was slowly added bromine (20 ml, 390 mmol, 3.1 eq) and the reaction was stirred at room temperature for 16 hours. The reaction mixture was poured into water (200 ml) and the precipitate was collected by filtration to yield N-(4-bromo-5-methoxy-2-nitrophenyl)acetamide (C-3) as a yellow solid. 1H NMR (400 MHz, DMSO): δ 10.37 (s, 1H); 8.25 (s, 1H); 7.64 (s, 1H); 3.94 (s, 3H); 2.13 (s, 3H). LRMS m/z (M+H) 288.9 found, 289.0 required.
(28 g, 98 mmol, 1.0 eq) and copper cyanide (8.8 g, 98 mmol, 1.0 eq) in DMF (150 ml) was heated at 150° C. for 16 hours. The reaction was cooled to room temperature, poured into water (500 ml) and the precipitate was collected by filtration. The precipitate was recrystallized from ethyl acetate to yield N-(4-cyano-5-methoxy-2-nitrophenyl)acetamide (C-4) as a yellow solid. 1H NMR (400 MHz, DMSO): δ 10.59 (s, 1H); 8.53 (s, 1H); 7.77 (s, 1H); 3.99 (s, 3H); 2.17 (s, 3H). LRMS m/z (M+H) 236.0 found, 236.0 required.
A solution of N-(4-cyano-5-methoxy-2-nitrophenyl)acetamide (C-4) (9.5 g, 40 mmol, 1.0 eq) and conc. HCl (17 ml) in ethanol (120 ml) was refluxed for 1 hour. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue washed with ethyl acetate (300 ml) and a minimal amount of water to yield 4-amino-2-methoxy-5-nitrobenzonitrile (C-5) as a yellow solid. LRMS m/z (M+H) 193.9 found, 194.0 required.
A mixture of 4-amino-2-methoxy-5-nitrobenzonitrile (C-5) (5.4 g, 28 mmol, 1.0 eq) and tin (II) chloride (20 g, 100 mmol, 3.8 eq) in ethanol (100 ml) was heated at reflux for 3 hours. The reaction mixture was cooled, poured into water and made neutral with addition of aqueous saturated sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate (2×200 ml) and the combined organic extracts were dried over sodium sulfate and concentrated to yield 4,5-diamino-2-methoxybenzonitrile (C-6). 1H NMR (400 MHz, DMSO): δ 6.62 (s, 1H); 6.28 (s, 1H); 5.58 (s, 2H); 4.36 (s, 2H); 3.70 (s, 3H). LRMS m/z (M+H) 164.1 found, 164.1 required.
A mixture of 4,5-diamino-2-methoxybenzonitrile (C-6) (4.0 g, 25 mmol, 1.0 eq) and CDI (4.6 g, 28 mmol, 1.2 eq) in THF (150 ml) was stirred for 16 hours at 23° C. The solvent was removed by evaporation under reduced pressure and the residue was washed with diethyl ether (50 ml), dichloromethane (50 ml) and a minimal amount of methanol in ethyl acetate to afford 6-methoxy-2-oxo-2,3-dihydro-1H-benzimidazole-5-carbonitrile (C-7) as a white solid. 1H NMR (400 MHz, DMSO): δ 11.15 (s, 1H); 10.78 (s, 1H); 7.14 (s, 1H); 6.73 (s, 1H); 3.86 (s, 3H). LRMS m/z (M+H) 189.9 found, 190.0 required.
A mixture of 6-methoxy-2-oxo-2,3-dihydro-1H-benzimidazole-5-carbonitrile (C-7) (4.1 g, 22 mmol, 1.0 eq) in POCl3 (40 ml, 430 mmol, 20 eq) was heated at 100° C. for 3.5 hours. The reaction mixture was cooled to room temperature and the precipitate was collected by filtration to yield 2-chloro-6-methoxy-1H-benzimidazole-5-carbonitrile (G8) as an off-white solid, 1H NMR (400 MHz, DMSO): δ 11.66 (br s, 1H); 7.98 (s, 1H); 7.22 (s, 1H); 3.93 (s, 3H). LRMS m/z (M+H) 207.9 found, 208.0 required.
Synthesis of mGluR2Potentiators: Oxazolobenzimidazoles
To a solution of TBDMS chloride (21.6 g, 143 mmol, 1.05 eq) in a 1:1 mixture of DMF:dichloromethane (120 ml) at 0° C. was added imidazole and the solution was stirred for 15 minutes under nitrogen. (R)-glycidol (1-1) (25 mL, 320 mmol, 2.0 eq) was added and the solution was stirred at 0° C. for 4.5 hours, Ethyl acetate (300 ml) was added and the organic layer was washed with 5% aqueous ammonium chloride solution (100 ml), water (3×100 ml) and brine (100 ml). The organic layer was dried over sodium sulfate and concentrated to yield tert-butyl(dimethyl)[(2S)-oxiran-2-ylmethoxy]silane (1-2) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 3.78 (dd, 1H, J=11.9, 3.1 Hz), 3.68-3.55 (m, 1H), 3.01 (d, 1H, J=4.1 Hz), 2.69 (t, 1H, J=4.6 Hz), 0.83 (s, 9H), 0.02 (m, 61-1).
A mixture of 2-chloro-1H-benzimidazole-5-carbonitrile (3.0 g, 17 mmol, 1.0 eq), (2S)-2-[(4-tert-butylphenoxy)methyl]oxirane (1-2) (3.5 g, 19 mmol, 1.1 eq) and cesium carbonate (0.10 g, 0.31 mmol, 0.020 eq) were heated under microwave irradiation at 130° C. for 45 minutes. Ethyl acetate was added (200 ml) and the organic layer was washed with water (50 ml) and dried over sodium sulfate. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes) followed by purification by super critical fluid chromatography (ChiralPak AS-H, 21×250 mm, 90/10 CO2/Methanol, 70 ml/min) to separate regioisomers and yield (2S)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,3-dihydro[1,3]oxazolo[3,2-a]benzimidazole-7-carbonitrile (1-3) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.80 (s, 1H), 7.42 (d, 111, J=8.2 Hz), 7.19 (d, 1H, J=8.2 Hz), 5.51-5.44 (m, 1H), 4.35-4.26 (m, 2H), 4.10 (dd, 11-1, J=11.8, 3.8 Hz), 3.95 (d, 1H, J=3.1 Hz), 0.76 (s, 9H), 0.00 (s, 6H). LRMS m/z (M+H) 330.0 found, 330.2 required. The alternative regioisomer (1-4) was also isolated and characterized.
To a solution of (2S)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,3-dihydro[1,3]oxazolo[3,2-a]benzimidazole-7-carbonitrile (1-3) (2.2 g, 6.8 mmol, 1.0 eq) in acetonitrile (50 ml) was added triethylamine trihydrofluoride (2.2 ml, 13 mmol, 2.0 eq) and the solution was stirred at 37° C. for 16 hours. The reaction mixture was cooled to 0° C. and the precipitate was collected by filtration and washed with cold acetonitrile to give (2S)-2-(hydroxymethyl)-2,3-dihydro[1,3]oxazolo[3,2-a]benzimidazole-7-carbonitrile (1-5) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.51 (s, 2H), 5.59-5.54 (m, 1H), 5.33 (t, 111, J=5.6 Hz), 4.44 (t, 11-1, J=9.1 Hz), 4.19 (dd, 1H, J=9.4, 6.4 Hz), 3.90-3.83 (m 1H), 3.72 (dt, 1H, J=12.7, 4.8 Hz). LRMS m/z (M+H) 215.9 found, 216.1 required.
To a mixture of (2S)-2-(hydroxymethyl)-2,3-dihydro[1,3]oxazolo[3,2-a]benzimidazole-7-carbonitrile (1-5) (370 mg, 1.7 mmol, 1.0 eq), 6-tert-butylpyridin-3-ol (260 mg, 1.7 mmol, 1.0 eq) and PS-triphenyl phosphine (2.15 mmol/gram) (2.4 g, 5.2 mmol, 3.0 eq) in dichloromethane (10 ml) was added DIAD (0.50 ml, 2.6 mmol, 1.5 eq) and the mixture was stirred at 23° C. for 16 hours. The resulting mixture was filtered and the filtrate was purified by silica gel chromatography (0-100% ethyl acetate/hexanes) to yield the product as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.20 (d, 1H, J=3.0 Hz), 7.76 (s, 11-1), 7.37 (d, 1H, J=8.2 Hz), 7.25-7.14 (m, 2H), 7.09 (dd, 1H, J=8.7, 3.1 Hz), 5.76-5.70 (m, 1H), 4.51-4.31 (m, 4H), 1.28 (s, 9H). LRMS m/z (M+H) 349.1 found, 349.2 required.
A mixture of (2S)-2-[(benzyloxy)methyl]oxirane (6-1, 608 mg, 3.7 mmol), cesium carbonate (608 mg, 3.7 mmol) and 1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (6-2, 500 mg, 3.7 mmol) in DMSO (10 mL) was heated at 100° C. in microwave for 40 minutes. The solid was filtered off, then purified by reverse phase liquid chromatography (H2O/CH3CN gradient w/0.1% TFA present) to yield 1-[(2S)-3-(benzyloxy)-2-hydroxypropyl]-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one(2-3) which is a TFA salt as well as by-product 3-[(2S)-3-(benzyloxy)-2-hydroxypropyl]-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one(2-4). TFA salt of (2-3) was then loaded onto polymeric cationic column to get free base of (2-3). 1H NMR (300 MHz, CDCl3) δ 8.31 (m, 2H), 7.33 (m, 51-1), 7.06 (d, 1H, J=5.4 Hz,), 4.55 (s, 2H), 4.22 (m, 1H), 4.04 (m, 2H), 3.56 (m, 2H). LRMS m/z (M+H) 300.0 found, 300.3 required.
The same procedure was used as for 1-6. Flash chromtagraphy (20% (C2H5OH/H2O/NH4OH=20/1/1)/EA) provided compound (2S)-2-[(benzyloxy)methyl]-2,3-dihydro[1,3]oxazolo[3′,2′:1,2]imidazo[4,5-c]pyridine (2-5). 1H NMR (300 MHz, CDCl3) δ 8.79 (s, 1H), 8.33 (d, 1H, J=5.7 Hz,), 7.26 (m, 5H), 7.09 (d, 1H, J=5.4 Hz), 5.5 4 (m, 1H), 4.62 (s, 2H), 4.36 (m, 2H). 3.89 (m, 2H). LRMS m/z (M+H) 282.0 found, 282.3 required.
To a clean, dry flask was added (2S)-2-[(benzyloxy)methyl]-2,3-dihydro[1,3]oxazolo[3′,2′:1,2]imidazo[4,5-c]pyridine (2-5, 100 mg, 0.36 mmol) and 5 mL of anhydrous methanol. The solution was degassed and purged with nitrogen three times before being charged with Pd(OH)2 (200 g). The suspension was degassed and purged with hydrogen gas three times, and left to stir overnight under a balloon of hydrogen at 37° C. After 12 h, the reaction was judged to be complete by LCMS, and was diluted with chloroform (20 mL) and filtered through celite with copious washing using methanol/chloroform mixtures. The filtrate was concentrated under reduced pressure to yield (2S)-2,3-dihydro[1,3]oxazolo[3′,2′:1,2]imidazo[4,5-c]pyridin-2-ylmethanol (2-6) as an insoluble white solid, 1H NMR (300 MHz, CDCl3) δ 8.61 (s, 1H), 8.29 (d, 1H, J=5.7 Hz,), 7.55 (d, 1H, J=5.7 Hz), 5.57 (m, 1H), 4.50 (m, 1H), 4.40 (m, 1H), 4.05 (m, 1H), 3.95 (m, 1H). LRMS m/z (M+H) 192.1 found, 192.2 required.
The same procedure was used as for 1-6. Flash chromtagraphy (15% (C2H5OH/H2O/NH4O=20/1/1)/EA) provided compound (2S)-2-{[4-(2,2,2-trifluoro-1,1-dimethylethyl)phenoxy]methyl}-2,3-dihydro[1,3]oxazolo[3′,2′:1,2]imidazo[4,5-c]pyridine (2-8). 1H NMR (300 MHz, CDCl3) δ 8.82 (brs, 1H), 8.42 (brs, 1H), 7.42 (d, 2H, J=9.0 Hz,), 7.25 (brs, 1H), 6.85 (d, 2H, J=9.0 Hz), 5.75 (m, 1H), 4.41 (m, 4H), 1.53 (s, 6H). LRMS m/z (M+H) 377.9 found, 378.1 required.
A mixture of (2S)-2-(hydroxymethyl)-2,3-dihydro[1,3]oxazolo[3,2-a]benzimidazole-7-carbonitrile(1-5, 600 mg, 2.8 mmol), 6-bromopyridin-3-ol (3-1, 631 mg, 3.6 mmol) and triphenylphosphine bound resin(contained 8.4 equivalent of triphenylphosine) in a mixture solvent of DMF (3.2 ml) and dichloromethane (32 ml) was added DIAD (780 mg, 3.6 mmol), then the mixture was rotated overnight. Filtered off solid and concentrated down solvent, then purified by flash chromtagraphy from 70% ethylacetate/henane, up to 100% ethyl acetate to provide compound (2S)-2-{[(6-bromopyridin-3-yl)oxy]methyl}-2,3-dihydro[1,3]oxazolo[3,2-a]benzimidazole-7-carbonitrile(3-2). 1H NMR (300 MHz, CDCl3) δ 8.52 (d, J=3.6 Hz, 1H), 7.80 (s, 1H), 7.52-7.40 (m, 2H), 7.39-7.20 (m, 5H), 5.87 (m, 1H), 4.41 (m, 4H). LRMS m/z (M+H) 373.0 & 371.0 found, 373.0& 371.0 required.
A mixture of (2S)-2-{[(6-bromopyridin-3-yl)oxy]methyl}-2,3-dihydro[1,3]oxazolo[3,2-a]benzimidazole-7-carbonitrile(3-2, 30 mg, 0.08 mmol), [2-fluoro-5-(trifluoromethyl)phenyl]boronic acid (33.6 mg, 0.16 mmol), sodium carbonate (61 ul, 2M solution, 0.12 mmol) and tetrakis (9.37 mg, 0.008 mmol) in DMA (2 mL) was heated at 100° C. overnight. The solid was filtered off, then purified by flash chromatography 60% theyl acetate/hexane to yield (2S)-2-[({6-[2-fluoro-5-(trifluoromethyl)phenyl]pyridin-3-yl}oxy)methyl]-2,3-dihydro[1,3]oxazolo[3,2-a]benzimidazole-7-carbonitrile(3-3).
1H NMR (300 MHz, CDCl3) δ 8.43 (m, 1H), 8.32 (m, 1H), 7.82 (m, 2H), 7.62 (m, 1H), 7.45 (m, 1H), 7.26 (m, 3H), 5.87 (m, 1H), 4.56 (m, 4H). LRMS m/z (M+H) 454.9 found, 455.1 required.
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/US09/43299 | 5/8/2009 | WO | 00 | 2/1/2011 |
| Number | Date | Country | |
|---|---|---|---|
| 61127770 | May 2008 | US |
