USOO6964958B2 (12) United States Patent (10) Patent No.: US 6,964,958 B2 Auta et al. (45) Date of Patent: Nov. 15, 2005

(54) METHOD OF SIMULTANEOUSLY (51) Int. Cl." ...... A61K 31/55 TREATING SENSORY AUDITORY GATING (52) U.S. Cl...... 514/220; 514/962; 424/451; DEFICT AND ASSOCATED PSYCHOSIS IN 424/464 SCHIZOPHRENIA AND BIPOLAR (58) Field of Search ...... 514/220,962; DSORDER PATIENTS WITH MANIA 424/451, 464 (76) Inventors: James Auta, 2314 W. Flournoy St., Chicago, IL (US) 60612; Erminio (56) References Cited Costa, 333 E. Ontario (#3302b), Chicago, IL (US) 60611; John M. U.S. PATENT DOCUMENTS Davis, 442 Webster Ave., Chicago, IL 4,180,668 A 12/1979 Hester, Jr...... 540/566 (US) 60614; Alessandro Guidotti, 859 5,317,018 A * 5/1994 Walser et al...... 514/220 N. Dearborn, Chicago, IL (US) 60610; 6,528,649 B2 3/2003 Cai et al...... 546/84 Patricia Tueting, 488 Ash St., Winnetka, IL (US) 60693 FOREIGN PATENT DOCUMENTS (*) Notice: Subject to any disclaimer, the term of this EP O 573 982 12/1993 patent is extended or adjusted under 35 * cited by examiner U.S.C. 154(b) by 0 days. Primary Examiner Frederick Krass (21) Appl. No.: 10/252,030 (74) Attorney, Agent, or Firm-Ladas and Parry LLP (22) Filed: Sep. 20, 2002 (57) ABSTRACT (65) Prior Publication Data Schizophrenia and bipolar disorders with mania may be US 2003/0119821 A1 Jun. 26, 2003 treated by imidazenil or other -3- Related U.S. Application Data carboxamide derviatives. (60) Provisional application No. 60/325,672, filed on Sep. 28, 2001. 5 Claims, 6 Drawing Sheets U.S. Patent Nov. 15, 2005 Sheet 1 of 6 US 6,964,958 B2

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U.S. Patent Nov. 15, 2005 Sheet 2 of 6 US 6,964,958 B2

ZCHRITIÐIH

U.S. Patent US 6,964,958 B2

U.S. Patent Nov. 15, 2005 Sheet 5 of 6 US 6,964,958 B2

Table 1. Proposed roles of GABAA-receptor subtypes in benzodiazepine actions

O. Cl2 C Ocs

Sedation -- - --

Amnesia -- -

Seizure protection -- -H

Anxiolysis --

From Mohler 1999, 2001 (modified)

FIGURE 5 U.S. Patent Nov. 15, 2005 Sheet 6 of 6 US 6,964,958 B2

US 6,964,958 B2 1 2 METHOD OF SIMULTANEOUSLY and may contribute to Sensory gating deficits and to the TREATING SENSORY AUDITORY GATING presence of Visual and auditory hallucinations, cognitive DEFICT AND ASSOCATED PSYCHOSIS IN impairment, and Social withdrawal. As a general Strategy, SCHIZOPHRENIA AND BIPOLAR our Studies are directed at testing whether drugs that tend to DSORDER PATIENTS WITH MANIA normalize a deficient GABAergic System may also be ben eficial in correcting the deficit of auditory gating in Schizo phrenia. This deficit, commonly known as a defective Priority is claimed from U.S. Provisional patent appli prepulse inhibition of startle (PPI) is considered the most cation 60/325,672 filed Sep. 28, 2001. important among the few objective measurements of brain FIELD OF THE INVENTION neuronal network functional alterations that can be mea Sured in patients with psychotic disorders and in their The present invention relates to the treatment of patients relatives (Swerdlow & Geyer, 1998). Suffering from Schizophrenia and patients Suffering from New therapeutic opportunities arise today due to increas bipolar disorders with mania. ing insights into the molecular architecture and diversity of 15 components involved in Signal transduction at GABAA BACKGROUND OF THE INVENTION receptors (FIG. 2). Based on the brain expression of seven GABAergic inhibition is increasingly considered one of Subunit families comprising at least 18 different Subunits the most important factors in controlling the mode of (c. 1-6, B1–3, 6, e, 0, p1-3) that are assembled in hetero operation of thalamo-cortical and re-entrant cortico pentameric GABAA receptors, an extraordinary Structural thalamic pathways as well as of the afferent Septal heterogeneity of the target for GABA is operative in the hippocampus and of the re-entrant hippocampal-Septal CNS (Barnard, 2001). Most GABAA receptor subtypes in glutamatergic pathways that are Substrates for the regulation brain are believed to be composed of C. By Subunits associ of complex brain functions, including normal Sensory, ated to form the above-mentioned heteropentameric Struc gating, cognition, Vigilance, Spatial Orientation, Volition, and tures termed GABAA receptors (FIG. 2). Although the consciousness. These functions are altered in Schizophrenia 25 physiological Significance of this heterogeneity is only par and bipolar disorder patients with mania. Thus, one may tially understood, the pharmacological Significance of the attribute the appearance of psychotic Symptoms in these various Subunits with respect to, their association with mental disorders to a deficit in GABAergic modulation in various actions of and congeners critical cortico-thalamic and cortico-hippocampal brain cir is beginning to be quite well understood. For example, cuits. GABAA receptors containing C. and Y Subunits are Substrates Indeed, Schizophrenia and bipolar disorder patients with for a wide Spectrum of actions elicited by clinically available mania who manifest an auditory gating deficit and who agonists acting at the modulatory benzodiazepine binding Suffer from other associated problems, Such as auditory Sites. These sites are located at the interface of the postsyn hallucinations, cognitive impairment, delusions, and defects aptic ectodomains of contiguous C. and Y Subunits on of volition (lack of motivation, flat affect, and Social 35 GABAA receptors composed of C. By subunits (FIG. 2). withdrawal), express downregulation of GABAergic Syn Benzodiazepine-Sensitive GABAA receptors are character thesis and function in their cortical, thalamic, Septal, and ized by the expression of C., C. C. or C. Subunits in their hippocampal circuits (Guidotti et al., 2000). The neuroana heteropentameric Structure and by the contiguity of these C. tomical and neurochemical abnormalities of the GABAergic subunits with Y subunits. The GABA-gated ion channel System in postmortem brain of patients with Schizophrenia 40 opening frequency of these receptorS is promptly enhanced and bipolar disorder with mania can be Summarized as to maximal efficacy by agonists of benzodiazepine Sites follows: 1) decreased GABA release and uptake (Reynolds currently available on the US market and this is the basis for et al., 1990; Sherman et al., 1991; Simpson et al., 1998); 2) their therapeutic effectiveness in the treatment of increased denervation-dependent GABAA receptor density disorders, Sleep disturbances, muscle Spasms, and epilepsy. measured by H-muscimol binding, particularly in layer II 45 However, maximal amplification of GABA-gated channels of the prefrontal cortex (PFC) and in superficial layers of by benzodiazepines is also the basis of undesirable Side other adjacent cortical areas (Benes et al., 1992, Benes, effects, Such as Sedation, , tolerance, and depen 2000); 3) increased expression of the Cl GABAA receptor dence (Costa and Guidotti, 1996). subunit mRNA in the PFC (Impagnatiello et al., 1998); 4) a In present clinical practice the consensus is that in Schizo dorsolateral PFC decrease of presynaptic GABA transporter 50 phrenia protracted benzodiazepine monotherapy is not 1-positive cartridges in GABAergic axon terminals of chan effective, despite anecdotical reports of antipsychotic effi delier cells impinging on the initial Segments of pyramidal cacy in the first few days of treatment. The lack of antip axons (Woo et al., 1998), and decreased GAD, expression Sychotic action after protracted benzodiazepine treatment is (this enzyme is important in the Synthesis of GABA and is presumably attributable to the well known phenomenon of one of the two molecular forms of glutamic acid decarboxy 55 tolerance that inevitably and rapidly occurs after adminis lase expressed in GABAergic neurons, the other being tration of clinically-available benzodiazepine. Moreover GADs) (Akbarian et al., 1995; Impagnatiello et al., 1998; their use is generally contraindicated because dlinically Benes 2000; Bunney and Bunney, 2000; Guidotti et al., available benzodiazepine drugs also elicit Sedation and 2000; Volk et al., 2000), which taken together suggest that amnesia, and if used repeatedly in addition to tolerance GABAergic function may be downregulated; and 5) an 60 produce dependence (Costa et al., 2001). altered cortical distribution of adenine dinucle Recent studies (Mohler, 2001) have established that the otide phosphate-positive GABAergic cells (Akbarian et al., and amnestic action of benzodiazepines is related to 1996). the amplification of GABA action at GABA. C. receptors Collectively, these data Support the hypothesis that including C. Subunits contiguous to the Y. Subunits, whereas GABAergic downregulation in cortical and hippocampal 65 their anxiolytic and and antipsychotic actions networks involved in Sensory information processing act as are mediated presumably by Similar actions at GABAA a Vulnerability factor in the etiopathogenesis of psychosis receptors having C, Cl- or Cs receptor Subunits (Table 1). US 6,964,958 B2 3 4 Thus, opportunities for the design of a new generation of FIG. 2 is a diagram of a GABAA receptor. benzodiazepine binding site ligands that are partial agonists FIG. 3 is a Table showing the effect of imidazenil on and act specifically at GABAA receptor Subtypes, are now prepulse inhibition of Startle in wild type mice and heterozy emerging. These new drugs have reduced tolerance and gous reeler mice. dependence liability and Selectively act on GABAA receptor FIG. 4 is a Table showing the effect of on Subtypes to control psychotic Symptoms in Schizophrenia prepulse inhibition of Startle in wild type mice and heterozy patients without Sedative or amnestic action. gous reeler mice. U.S. Pat. No. 5,317,018 of May 31, 1994 describes the use of imidazol,5-abenzodiazepine-3carboxamide derivatives FIG. 5 is a Table showing the possible roles of GABAA and compositions containing Such compounds for treating recptor Subtypes in benzodiazepine actions. anxiety and panic disorders and idiopathic and psychomotor FIG. 6 is a Table Summarizing anatomical abnormalities epilepsy. One Such compound is 6-(2 bromophenyl)-8- in prefrontal cortex of Schizophrenic patients and heterozy fluoro-4H-imidazo 1,5a 1,4)benzodiazepine-3- gous reeler mice. carboxamide which is often referred to as imidazenil. DETAILED DESCRIPTION OF THE 15 Unlike other partial allosteric modulators, imidazenil has INVENTION a high affinity for the receptor, does not act on GABAA C. Subunit and is slowly metabolized in compounds that may The compounds for use in the present invention are act on GABA. C. Subunit. Thus, imidazenil does not described in U.S. Pat. No. 5,317,018 which, as noted above, produce Sedation and does not produce tolerance or depen describes their anti-anxiety and anti-epileptic properties. In dence as indeed occurs with other partial allosteric modu View of the general view that benzodiazepines are not useful lators of the action of GABA at GABAA receptors (Costa et in the treatment of schizophrenia or bipolar disorders with al. 2001). mania, however, it is Surprising that these can find use in Auta et al PNAS 97 (No.5) 2314-2319 (Feb. 29, 2000) treatment of these conditions. Therefore our invention and describe the use of imidazenil to prevent alprazolam the reasoning underlying it presents a novel approach to the induced acquisition in patas monkeys and note that during a 25 treatments in these diseases. Seventeen day treatment no tolerance of the effects of A preferred compound for use in the present invention is imidazenil were noted. Costa et al TiPS May 1996, 192–200 imidazenil which is a compound of the above formula Suggest that imidazenil may be a prototype of a new gen wherein R is hydrogen. eration of anxiolytic and anticonvulsant drugs that have Suitable pharmaceutically acceptable Salts include Salts minimal disruptive effects on learning and memory, and are with hydrochloric acid, hydrobromic acid, nitric acid, Sul virtually devoid of the tolerance liability and other unwanted furic acid, phosphoric acid, methaneSulfonic acid, paratolu Side-effects of classic benzodiazepines. As a reference eneSulfonic acid and other acids conventionally used for this compound, we used the clinically available benzodiazepine purpose. alprazolam, an 8chloro-1-methyl-6-phenyl-4-1,2,4-triazolo The choice of a therapeutically effective dose will be 4.3a1-4)benzodiazepine whose formula is also indicated 35 made by a physician and vary depending on the compound in FIG. 1. used and the precise condition of the patient. The determi SUMMARY OF THE INVENTION nation of a Suitable dose for a given patient can be made by conventional means for Selecting doses of compounds for The present invention provides a method of treatment of treatment of the condition in question. For example deter patients Suffering from Schizophrenia or bipolar disorder 40 mination of a Suitable dose may be effected by the degree of with mania which comprises administering to them a thera anxiety or by preexisting Susceptibility to Seizures. Guid peutically effective amount of a compound of the formula: ance as to the ways to determine Suitable doses for treatment NH-R of Schizophrenia and bipolar disorders with mania may be N 45 found in articles by Costa et al 2001. Typical doses are likely to be in the range of lug/kg, for (N , O example from 1 to 10 ug/kg. Doses will typically be taken 1-2 times per day. Suitable dosage units will contain from 0.05 to 0.5 mg of active compound. The compounds will be administered orally and will be formulated as pills or capsules. Such pills or capsules may Br contain from 0.05 to 0.5 mg of the inventive compound, and the remaining weight balance comprising a pharmaceuti cally acceptable carrier. 55 FIG. 1 compares the dose-response actions of alprazolam (a classic clinically utilized benzodiazepine ligand) with that wherein R is selected from hydrogen, CHCH-, of imidazenil (which is the inventive compound). An impor CH=CHCH-, (CH),CH-, CHCHCH- or tant aspect of the pharmacological profile of imidazenil that distinguishes this drug from alprazolam or other classic benzodiazepines is its ability to elicit potent anticonvulsant D-CH and anxiolytic pharmacological effects at doses that are Several orders of magnitude Smaller than doses eliciting or a pharmaceutically acceptable Salt thereof. sedation or amnesia (FIG. 1, Costa et al., 2001). In fact, imidazenil, in doses up to 60-fold greater than doses pro BRIEF DESCRIPTION OF THE DRAWINGS 65 ducing anxiolytic and anticonvulsant actions antagonizes the FIG. 1 is a graph comparing the pharmacological profiles Sedative and amnestic actions of alprazolam in rats and of imidazenil and a classical benzodiazepine, alprazolam. monkeys without causing tolerance (Auta et al., 2000; Costa US 6,964,958 B2 S 6 et al., 2001). A pharmacological profile similar to that of Swerdlow, 1995; Swerdlow and Geyer, 1998), PPI gating imidazenil is observed for its derivatives as reported in Table deficit in HRM can be attributed to a downregulation of 1 of U.S. Pat. No. 5,371,018. Imidazenil has been reported GABAergic transmission. A common PPI deficit in HRM to have a high affinity for benzodiazepines binding sites and and Schizophrenia is also consistent with the Similarities in a low clearance rate (in rats, T /390 min; in nonhuman neocortical alterations in HRM and Schizophrenia postmor primates TV2 longer than 6 hr) and to act as a partial agonist tem brain (FIG. 6), as well as with the role of reelin in at least eight Subtypes of GABAA receptors in which it has haploinsufficiency in the genesis of abnormal brain circuits been tested (Costa and Guidotti, 1996). Imidazenil never related to behavior. We have therefore chosen to test the maximizes the intensity of GABA-gated Cl currents and is efficacy of imidazenil compared with alprazolam on PPI Virtually devoid of tolerance and dependence liability (Auta deficit using the HRM model. et al., 2000; Costa et al., 2001). There are remarkably a) Procedures: distinct features in the pharmacological profile of imidazenil The startle apparatus (SR-Lab, San Diego Instruments) (compared with alprazolam) and warrant consideration of consisted of a Plexiglas cylinder resting on a Plexiglas frame imidazenil as a prospective drug to treat psychotic Symp within a ventilated Soundproof enclosure. Acoustic noise toms in Schizophrenia and bipolar disorder patients with 15 bursts were presented by. Speaker 24 cm above the animal. mania. In fact with alprazolam, Sedation, amnesia, and and a piezo-electric device transduced any consequent tolerance and dependence liability appear with doses that are motion (flinch) within the cylinder. Two stimulus trial types 1) 115 db startle stimulus only; or 2) 115 db stimulus very close to those that cause anxiolytic and anticonvulsant preceded by a 75 or 80 db prepulse 100 msec before startle actions (FIG. 1, Costa et al., 2001), whereas in the case of Simulut onset were randomly presented with a mean inter imidazenil, Sedation, amnesia, tolerance, and dependence trial interval of 20 Sec. Stimuli were 30 msec in duration and liability are virtually undetectable for a wide range of doses were presented over a constant 65 db white noise back Significantly higher than the doses used to elicit therapeutic ground also present during a 5-min adaptation period. responses (FIG. 1; Auta et al., 2000; Costa et al., 2001). Mean peak amplitude of the flinch response within a 200 Thus, imidazenil and its congenerS appear to possess an msec window following presentation of the 115 db stimulus ideal profile for Selectively targeting a partial alloSteric 25 was calculated Separately for each type of Startle trial. RatioS modulation of GABA-gated CI currents at GABAA recep reflecting the amount of inhibition due to the prepulse were tor Subtypes containing C and C receptors that are pre calculated by dividing the difference between mean ampli Sumably altered in Schizophrenia, leaving the GABAA tude for Startle and prepulse trials by the mean for the Startle receptor Subtype containing C. Subunits occupied but silent trials. PPI data are commonly presented in this ratio form to and unavailable for occupation by putative endogenous control for overall level of the startle reflex itself. Startle/ benzodiazepine ligands. intensity functions confirmed that the prepulse intensities Neocortical alterations, including decreased thickness, Selected failed to elicit startle when not paired with the increased neuronal packing density, and neuropil hypoplasia startle stimulus, and that the 115 db startle stimulus was asSociated with decreased expression density of apical den within the asymptotic range for Startle response magnitude dritic spines and of presynaptic afferents (GAD, 35 in both wild-type mice (WTM) and HRM. downregulation) impinging on postsynaptic spine densities Imidazenil or alprazolam was dissolved in DMSO, com have been reported in the postmortem brain of Schizophrenia bined with oil, and injected Subcutaneously at a Volume of patients. These changes are similar to those detected in the 0.1 ml/10 gm of body weight. The amount of DMSO was approximately 1% of total volume. Vehicle was prepared cortex of HRM (FIG. 6). Since there is a downregulation of Similarly and vehicle or drug was administered in counter extracellular matrix reelin at postsynaptic densities in both 40 balanced order using a within-Subject design. Following schizophrenia and HRM, these cortical abnormalities may drug administration, the mouse was placed in an isolated stem from a downregulation of reelin expression in HRM cage for 10-15 min before being placed in the startle (Guidotti et al., 2000; Liu et al., 2001). apparatus. Animals were tested between 11:00 hr and 15:00 A robust reduction in the magnitude of the auditory startle hr. reflex can be achieved by presenting a weak auditory (or 45 b) Results visual or tactile) stimulus shortly before a loud stimulus FIGS. 3 and 4 show that imidazenil but not alprazolam eliciting Startle. Prepulse inhibition of Startle can be easily corrected the auditory PPI deficit in HRM, largely by and reliably measured in humans (eyeblink reflex) as well as increasing PPI. Imidazenil's ability to increase PPI in HRM in rodents (whole body flinch). PPI is reduced in psychotic is obtained with doses of imidazenil that have no primary patients and their relatives and PPI deficit is correlated with 50 effects on the PPI of WTM and fail to change the overall thought disorder (Perry and Braff, 1995; Perry et al., 1999). Startle level, indicating lack of Sedative effects for doses of Thus, PPI is an ideal objective animal model for exploration imidazenil (0.3, 0.6 mg/kg) that correct the deficit of PPI in of the effects of new drugs for the treatment of psychotic HRM. In contrast to imidazenil, our reference classical BZ, symptoms (Swerdlow and Geyer, 1998). The theory that alprazolam, which is Sedative and amnestic at the same Sensory gating deficit is a core characteristic of Schizophre 55 doses that presumably act on GABAA receptors that control nia is consistent with clinical and experiential reports indi sensory gating, decreased PPI in WTM and failed to revert cating that patients seem overwhelmed by Sensory Stimuli the PPI deficit in HRM (FIG. 4). The ability of alprazolam (from Sources outside in the environment and from within to induce a PPI deficit in WTM is consistent with the results their own bodies) and are seemingly unable to "gate in of human Studies following classical benzodiazepine admin relevant Stimuli and "gate out' irrelevant or constantly 60 istration (Abduljawad et al., 1997; Rodriguez-Fornells et al., present Stimuli. The end result according to gating theory is 1999; Schachinger et al., 1999), which also indicate that PPI thought disorder because of the “flooding” of higher order is decreased following administration of classical Sedative neuronal processing caused by excessive irrelevant Stimu benzodiazepine ligands. lation. We have recently reported that HRM, like schizophrenia 65 REFERENCES patients, exhibit PPI deficit (Tueting et al., 1999). As in Abduljawad KAF, Langely RW, Bradshaw CM, Szabadi Schizophrenia and other psychotic disorders (Kodsi and E (1997) Effects of and on the acoustic US 6,964,958 B2 7 8 Startle response and on its inhibition by prepossess in man. Perry W. BraffDL (1994) Information-processing deficits J Psychopharmacol 11:29-34. and thought disorder in Schizophrenia. Am J Psychiatry Akbarian S, Kim JJ, Potkin SG, Hagman J O, Tafazzoli 151:363-367. A, Bunney Jr WE, Jones E G (1995) Gene expression for Perry W. 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Meldrum BJ, Whiting D (2000) acting on the GABA system. In Möhler H (ed) Handbook of Experimental Pharmacology Vol. 150: Pharmacology of 60 GABA and Glycine Neurotransmission, Chapter 2, pp Br 173-188. Möhler H (2001) Functions of GABAA receptors: Phar macology and pathophysiology. In Mohler H (ed) Handbook of Experimental Pharmacology Vol. 150: Pharmacology of 65 GABA and Glycine Neurotransmission, Chapter 3, pp. wherein R is selected from hydrogen, CHCH-, 101-112. CH=CHCH-, (CH) CH-, CHCHCH- or US 6,964,958 B2 9 10 D-CH NH-R 5 / Y, or a pharmaceutically acceptable Salt thereof. 2. A method as claimed in claim 1 wherein R is hydrogen. Br 3. A method as claimed in claim 1 wherein the compound 10 is administered in the form of capsules or pills. 4. A method as claimed in claim 1 wherein the compound is administered at a dosage of from 1 to 10 ug/kg body wherein R is selected from hydrogen, CHCH-, weight/day. 15 CH=CHCH-, (CH) CH-, CHCHCH- or 5. A method of treating prepulse inhibition deficit in patients Suffering from Schizophrenia or bipolar disorder D-CH with mania which comprises administering to patients in 2O need thereof a therapeutically effective amount of a com- or a pharmaceutically acceptable Salt thereof. pound of the formula: k . . . .