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  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
  • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D207/36—Oxygen or sulfur atoms
  • C07D207/38—2-Pyrrolones

Definitions

• CBi receptor agonists have been associated with stimulation of feeding, anemetic properties, analgesia, reduction in intraocular pressure in glaucoma, and alleviation of muscle spasms in multiple sclerosis.
• CBi receptor antagonists have been shown effective for reducing feeding and body weight in animal models of obesity.
• most compounds that modulate CBl receptor activity have the pharmacological property of inverse agonism which reduces basal CBl receptor signal transduction as well as the activity of blocking CBl agonist dependent receptor stimulation.
• CBi receptor compounds A number of selective, centrally acting CBi receptor compounds are currently in development for the treatment of obesity. Nevertheless, there still remains a need for CBi receptor compounds which have increased in vivo potency which are low molecular weight, and have pharmacokinetic and pharmacodynamic properties that provide therapeutic benefit while minimizing adverse events. See for example WO 2007/020502.
• CBi inverse agonists have been shown to further potentiate the activity of antipsychotic agents in assays.
• current antipsychotic therapies are more or less effective at controlling positive symptoms, such therapies are not as effective in treating the negative and cognitive symptoms, rendering many patients incapable of leading normal lives.
• Convergent evidence suggests drugs that enhance neuronal activation in specific brain areas, hippocampal, striatal, and cortical areas in particular, would be effective in treating both negative and cognitive symptoms.
• the weight loss effects of CBi receptor compounds have been demonstrated in animal models of antipsychotic treatment-induced weight gain and therefore may also be effective in controlling the treatment-emergent weight gain and metabolic syndrome seen with current antipsychotic therapies.
• CBi receptor compounds have been shown to reduce alcohol consumption in animal models of alcohol drinking and therefore may be useful in the treatment of substance abuse.
• CBi receptor compounds While oral administration is a preferred route of drug delivery, many CBi receptor compounds suffer from poor oral bioavailability as a consequence of their limited solubility in aqueous media and their metabolic lability. Because of the high lipophilicity of the endogenous cannabinoid ligands and the complementary site to which they bind in the CBi receptor, known CBi receptor compounds are also highly lipophilic. This high lipophilicity leads to poor solubility in aqueous media which limits oral absorption and bioavailability. See for example WO 2007/020502.
• the present invention provides a compound of Formula (I)
• the present invention further provides a compound of Formula (Ia)
• the present invention provides an intermediate of the compound of Formula (II)
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound according to any of Formulas (I) or (Ia) and a pharmaceutically acceptable carrier, diluent, or excipient.
• the present invention provides the pharmaceutical composition, wherein the compound of Formula (Ia) is present in optical purity greater than 90%ee.
• the pharmaceutical composition wherein the compound of Formula (Ia) is present in optical purity greater than 95%ee.
• An embodiment of the present invention provide a compound according to any one of Formula (I) or (Ia) for use therapy.
• the present invention provides a compound according to any one of Formula (I) or (Ia) for use in the treatment of a disorder selected from: an eating disorder associated with excessive food intake, obesity, schizophrenia, cognitive impairment associated with -A-
• the present invention provides the use of a compound according to any one of Formula (I) or (Ia) in the manufacture of a medicament for the treatment of a disorder selected from: an eating disorder associated with excessive food intake, obesity, schizophrenia, cognitive impairment associated with schizophrenia, substance abuse or alcohol dependence, smoking cessation and treatment emergent weight gain observed during treatment with an atypical antipsychotic.
• An embodiment of the invention provides a method of treating a condition in a mammal which is treatable by blockade of CBi receptors via an inverse agonism mechanism, the method comprising administering to a patient an effective amount of a compound according to any one of Formula (I) or (Ia), or a pharmaceutically acceptable salt thereof.
• An embodiment of the invention provides a method of treating a condition in a mammal an effective amount of a compound, according to any of Formulas (I) or (Ia), in simultaneous, separate, or sequential combination with an antipsychotic agent, or a pharmaceutically acceptable salt thereof.
• An embodiment of the invention provides the method, wherein the condition is an eating disorder associated with excessive food intake.
• An embodiment of the invention provides the method, wherein the condition is obesity.
• An embodiment of the invention provides the method, wherein the condition is schizophrenia.
• An embodiment of the invention provides the method, wherein the condition is cognitive impairment associated with schizophrenia.
• An embodiment of the invention provides the method, wherein the condition is substance abuse or alcohol dependence.
• An embodiment of the invention provides the method, wherein the condition is smoking cessation.
• An embodiment of the invention provides the method, wherein the condition is treatment emergent weight gain observed during smoking cessation.
• An embodiment of the invention provides a compound according to any one of Formula (I) or (Ia) for use in simultaneous, separate or sequential combination with an antipsychotic agent in the treatment of a disorder selected from: weight gain, obesity, schizophrenia, cognitive impairment associated with schizophrenia, substance abuse or alcohol dependence, smoking cessation and treatment emergent weight gain observed during treatment with an atypical antipsychotic.
• the invention provides the use of a compound according to any one of Formula (I) or (Ia) in the manufacture of a medicament for use in combination therapy for the treatment of a disorder selected from: weight gain, obesity, schizophrenia, cognitive impairment associated with schizophrenia, substance abuse or alcohol dependence, smoking cessation and treatment emergent weight gain observed during treatment with an atypical antipsychotic, wherein said medicament is to be administered in simultaneous, separate or sequential combination with an antipsychotic agent.
• the present invention provides a method of treating a condition in a mammal which is treatable by blockade of CBi receptors via an inverse agonism mechanism in simultaneous, separate or sequential combination with an antipsychotic agent, the method comprising administering to a patient an effective amount of a compound according to any one of Formula (I) or (Ia), or a pharmaceutically acceptable salt thereof.
• the present invention provides a method of treating a condition in a mammal comprising administering to the mammal an effective amount of a compound, according to any one of Formulas (I) or (Ia), or a pharmaceutically acceptable salt thereof.
• An embodiment of the invention provides the method, wherein the condition is schizophrenia.
• An embodiment of the invention provides the method, wherein the condition is weight gain.
• An embodiment of the invention provides the method, wherein the condition is obesity.
• An embodiment of the invention provides the method, wherein the condition is cognitive impairment associated with schizophrenia.
• An embodiment of the invention provides the method, wherein the condition is substance abuse or alcohol dependence.
• An embodiment of the invention provides the method, wherein the condition is smoking cessation.
• An embodiment of the invention provides the method, wherein the condition is treatment emergent weight gain observed during treatment with an atypical antipsychotic.
• Compounds of Formula (I) contain asymmetric centers and can thus occur as diastereomeric mixtures, racemic mixtures, single enantiomers, and individual diastereomers, such as compounds of Formula Ia. All such isomeric forms of the compounds of Formula (I) are contemplated as aspects of the present invention.
• a preferred aspect of this invention provides compounds of Formula (Ia) that are substantially pure enantiomers.
• each of the following specific classes of compounds of Formulas (I) and (Ia) are contemplated as aspects of the present invention: (a) Those where enantiomeric purities are greater than 80% enantiomeric excess;
• enantiomeric purities are greater than 99% enantiomeric excess.
• These enantiomerically pure compounds may be prepared by purification of the desired enantiomer of a compound of Formula (I) from a mixture of enantiomers of this compound.
• the desired enantiomer of a compound of Formula (I) may also be prepared by synthesis according to the following general schemes by using precursors that are substantially enantiomerically pure. Those skilled in the art will recognize that either resolution of final compounds or of intermediates will provide compounds of Formula (I) in substantially enantiomerically pure form, to yield for example, compounds of Formulas (Ia), and will employ the method which is most convenient.
• a substantially pure diastereomer may be isolated from a mixture of diastereomers using methods known in the art.
• Methods for purification of diastereomers include chromatography and crystallization.
• a mixture of enantiomers may be separated into the individual substantially pure enantiomers by the process known as resolution.
• Enantiomers may be resolved through the use of chromatography using a chiral stationary phase. Suitable chiral solid phases include polysaccharide-based stationary phases such as Chiralpak AD and Chiracel OJ (sold by Chiral Technologies, Inc.).
• enantiomers of basic compounds may be resolved by conversion to a mixture of diastereomeric salts by treatment with a chiral acid.
• the desired diastereomeric salt is isolated by, for example, crystallization.
• the substantially enantiomerically pure basic compound may be isolated by treatment with base.
• Examples of chiral acids include (-)-tartaric acid, (+)-tartaric acid, (-)-mandelic acid, (+)-mandelic acid, (-)-ditoluoyltartaric acid and (+)-ditoluoyltartaric acid.
• Enantiomers of acidic compounds may be resolved in an analogous manner using a substantially enantiomerically pure base. Examples of such bases include R-alpha- methylbenzylamine, S-alpha-methylbenzylamine, and brucine.
• Another method for the resolution of a racemic mixture involves reaction with a substantially enantiomerically pure chiral reagent (referred to here as a chiral auxiliary) to form a covalent bond.
• a substantially enantiomerically pure chiral reagent referred to here as a chiral auxiliary
• This reaction results in a mixture of diastereomers, which is purified according to methods known in the art. All, or a portion, of the chiral auxiliary may then be cleaved from the molecule to generate a compound which is substantially enantiomerically pure. In some cases, the asymmetric center introduced by the chiral auxiliary may be retained in the final product.
• compounds of the present invention described below may exist as distinct crystal forms prepared by crystallization under controlled conditions.
• Compounds of Formulas (I) and (Ia) are selective for the CBi receptor in preference to the CB 2 receptor.
• CBi receptor ligands act as antagonists of CBi receptor function and have inverse agonists properties as well.
• compounds of Formulas (I) and (Ia) are modulators of the CBi receptor, and as such are useful for prevention and treatment of conditions associated with the CBi receptor.
• Such conditions include, for example, memory deficits, cognitive disorders, negative symptoms of schizophrenia, substance abuse disorders (particularly to opiates, alcohol, and nicotine), obesity, metabolic disorders and eating disorders associated with excessive food intake.
• An effective amount of the compounds of Formulas (I) or (Ia), may be administered to a patient in need of such treatment or prophylaxis in order to practice the present methods of therapy.
• the need for a prophylactic administration according to the methods of the present invention is determined via the use of well-known risk factors.
• the effective amount of an individual compound is determined, in the final analysis, by the physician in charge of the case, but depends on factors such as the exact disease to be treated, the severity of the disease and other diseases or conditions from which the patient suffers, the chosen route of administration, other drugs and treatments which the patient may concomitantly require, and other factors in the physician's judgment.
• the prophylactic or therapeutic dosage of a compound of Formula (I) or (Ia) will, of course, vary with the nature of the severity of the condition to be treated and with the particular compound of Formula (I) or (Ia) and its route of administration.
• the dose may be administered in a single daily dose or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, based on the properties of the individual compound selected for administration and/or the characteristics of the dosage form (i.e., modified release), the dose may be administered less frequently, e.g., weekly, twice weekly, monthly, etc. The unit dosage may be correspondingly larger for the less frequent administration. When administered via, transdermal routes, or through a continual intravenous solution, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
• Antagonists and agonists shall refer to those compounds which stimulate the functional response of a receptor.
• Negtral antagonists and neutral antagonists shall refer to those compounds which do not alter the basal activity of a receptor but block the functional activity of agonists and inverse agonists by returning the functional response to that of the basal state.
• Inverse agonist and inverse agonists shall refer to those compounds which possess negative intrinsic activity by reversing the constitutive activity of the receptor. Inverse agonists act as antagonists to reverse the activity of agonists.
• Antagonist or “antagonists” shall refer to those compounds which are neutral antagonists.
• Obsity refers to the condition of having a high amount of body fat.
• a person is considered obese if he or she has a body mass index (BMI) of 30 kg/m 2 or greater.
• BMI body mass index
• BMI body mass index
• those persons with normal weight have a BMI of 19.9 to 25.9.
• the obesity may be due to any cause, whether genetic or environmental. Examples of disorders that may result in obesity or be the cause of obesity include overeating, decreased physical activity and pathological conditions showing reduced metabolic activity.
• “Pharmaceutically acceptable salts” and “salts” refer to the relatively non-toxic, inorganic and organic acid addition salts, and base addition salts, of compounds of the present invention. See, for example S.M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. ScL, 66, 1-19 (1977).
• compositions are intended to encompass a product comprising the active ingredient, preferably present in pharmaceutically effective amounts, and the inert ingredient(s) (pharmaceutically acceptable excipients) 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.
• the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of Formula (I) or (Ia) and any pharmaceutically acceptable excipients.
• Prevention refers to preventing obesity from occurring if the treatment is administered prior to the onset of the obese condition. Moreover, if treatment is commenced in already obese subjects, such treatment is expected to prevent, or to prevent the progression of, the medical sequelae of obesity (e.g., arteriosclerosis, Type II diabetes, polycystic ovarian disease, cardiovascular diseases, osteoarthritis, dermatological disorders, hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia, and cholelithiasis).
• arteriosclerosis e.g., arteriosclerosis, Type II diabetes, polycystic ovarian disease, cardiovascular diseases, osteoarthritis, dermatological disorders, hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia, and cholelithiasis.
• Treating means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
• treatment refers to the act of treating as “treating” is defined immediately above.
• IL heptane
• A- methylbenzenesulfonate (1 : 1) can also be synthesized by utilizing:
• Example 2 [ 1 -methyl- 1 -(6-trifluoromethyl-pyridin-3 -yl)-ethylamino]- 1 -(4-trifluoromethyl-phenyl)-5- (3-trifluoromethoxy-phenyl)-pyrrolidin-2-one 4-methylbenzenesulfonate (referred to as "Example 2”) for its antagonist/inverse agonist functional GTP-binding.
• Example 2 4-methylbenzenesulfonate
• the GTP-binding assay buffer (20 mM Hepes, 100 mM NaCl, 5 mM MgCl 2 , pH 7.4), the CHO or Sf9 cell membranes expressing CBi or CB 2 , (Applied Cell Sciences, Gaithersburg, MD; PerkinElmer Life Sciences, Boston, MA; prepare membranes as previously described (DeLapp et al., 1999)), Example 2 and the 500 pM GTP- ⁇ - 35 S (PerkinElmer Life Sciences, Boston, MA). Perform antagonist dose reponses in the presence of a saturating dose of a full agonist (methanandamide).
• SEM standard error of the mean
• Example 2 exhibits potent human and rat CBi antagonism with no measurable antagonism of the human CB 2 receptor.
• the data indicates Example 2 is a potent CBi antagonist/inverse agonist at both rat and human receptors with no antagonism of human CB 2 receptors.
• Example 2 summarizes the agonist properties of Example 2 in Sf9 cell membranes from cells expressing human CBi or CB 2 receptors. These data demonstrate that Example 2 is an inverse agonist at the human CBi receptor as evidenced by agonist efficacy (Table 2) less than zero which indicates that the compound decreased basal constitutive activity of the CBi receptor in vitro. Example 2 does not have any measurable CB 2 agonist activity (Table T).
• mice Receive NIH male Swiss mice (Harlan Sprague-Dawley, weight 20-25g) 7 to 10 days prior to testing. House 12 mice per cage. Test only animals that weigh 25-3Og. On the day of testing, bring animals to the testing room at least lhour prior to dosing. When dosing starts, dose at 6-8 minute intervals between each dose with each mouse receiving either Administer vehicle (1% CMC, 0.5% SLS, 0.08% povidone, 0.05% antifoam) or Example 2, p.o. Next, place mice in a clean cage (4 mice per cage). After 90 minutes, start the test following a 90 minute pre-treatment with Example 2 or vehicle.
• Administer vehicle 1% CMC, 0.5% SLS, 0.08% povidone, 0.05% antifoam
• MED minimum effective dose
• Cortical Activation cFos Activation.
• Example 2 Characterize Example 2 for its ability to activate gene expression and neurochemical efflux in cortical and subcortical regions and to interact with the prototypical atypical antipsychotic agent clozapine.
• PFC prefrontal cortex
• NAc nucleus accumbens
• DL-Str dorsolateral striatum
• Clozapine and Example 2 both individually tend to or significantly enhance cortical and subcortical Fos reactivity. Observe Example 2 enhancing the effects of clozapine alone at both 1 and 10 mg/kg, p.o.
• Example 2 Increases cFos expression in rat brain in both prefrontal cortex and subcortical regions by Example 2.
• Addition of Example 2 to clozapine results in augmentation of cFos expression induced by clozapine in brain areas critical to cognitive function and negative symptom control.
• Example 2 Evaluate Example 2 for its ability to reduce consumption of ethanol in rats selectively bred for high oral ethanol intake (P rats). In addition, study the effects of Example 2 under conditions in which effects of the compound on motivation or the control of behavior by ethanol could be assessed.
• Methods Study the effects of Example 2 on female, alcohol-preferring (P) rats on alcohol consumption under a continuous free access paradigm. For comparative purposes test the standard opioid antagonist naltrexone. Monitor voluntary consumption of 15% (v/v) ethanol. Suspend Example 2 in vehicle (1% CMC, 0.5% SLS, 0.08% povidone, 0.05% Dow Corning antifoam 1510 US) and give p.o.3 hours prior to the onset of the dark cycle. In addition, measure locomotor activity via infrared sensor.
• Example 2 Assess the ability of Example 2 to reduce the motivational drive controlling ethanol intake.
• Methods Study female alcohol-preferring (P) rats under a progressive ratio schedule in which responding produces 15% ethanol (v/v). Under the progressive ratio schedule, the response requirement for ethanol delivery increases from 1 to 2 and then increments by 2 after 3 ethanol presentations.
• Results Decrease cumulative food intake by administrating Example 2 once daily orally throughout the 14-day study. Consistent with reduced food intake, observe reduction of cumulative body weight following the 14-day oral treatment with Example 2, producing an estimated T 17 of 0.13 mg/kg. Measure body composition analysis by quantitative nuclear magnetic resonance (QNMR) showing significant reductions in fat mass at doses ranging from 0.1 - 10 mg/kg with minimal changes in fat free mass at one of the highest doses.
• QNMR quantitative nuclear magnetic resonance

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• 2007
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• 2011
  • 2011-01-27 CY CY20111100093T patent/CY1111140T1/el unknown

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