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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
  • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/02—Nasal agents, e.g. decongestants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/06—Antimigraine agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/22—Anxiolytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants
• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
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  • A61P27/06—Antiglaucoma agents or miotics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
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  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

• the present invention relates to benzodioxan analogues useful as alpha-2C (or ⁇ ⁇ 2C") adrenergic receptor modulators, methods for making these compounds, pharmaceutical compositions containing the compounds, and methods of treatment and prevention using the compounds and compositions to treat disease states associated with the modulation of the alpha-2C receptor, such as congestion (including nasat), migraine, congestive heart failure, cardiac ischemia, glaucoma, stress-induced urinary incontinence, Alzheimer's disesase, Parkinson's disease, attention deficit hyperactivity disorder, pain and psychotic disorders (e.g., depression and schizophrenia).
• congestion including nasat
• migraine congestive heart failure
• cardiac ischemia ischemia
• glaucoma stress-induced urinary incontinence
• Alzheimer's disesase Parkinson's disease
• attention deficit hyperactivity disorder e.g., depression and schizophrenia.
• ⁇ -adrenergic receptors were shown to be associated with most of the excitatory functions (vasoconstriction, stimulation of the uterus and pupil dilation), ⁇ -adrenergic receptors were implicated in vasodilation, bronchodilation and myocardial stimulation (Lands et at., "Differentiation of Receptor Systems Activated by Sympathomimetic amines," Nature 214:597-598 (1967)). Since this early work, ⁇ -adrenergic receptors have been subdivided into ⁇ 1 - and ⁇ 2-adre ⁇ ergic receptors.
• ⁇ -adrenergic receptors Cloning and expression of ⁇ -adrenergic receptors have confirmed the presence of multiple subtypes of both ⁇ 1 -( ⁇ 1A, ⁇ 1B, ⁇ 1D) and ⁇ 2-( ⁇ 2A, ⁇ 2B, ⁇ 2C) adrenergic receptors (Michel et af., "Classification of ⁇ t -Adrenoceptor Subtypes," Naunyn-Schmiedeberg's Arch. Pharmacol, 352: 1-10 (1995); Macdonald et al., "Gene Targeting-Homing in on ⁇ 2 -Adrenoceptor-Subtype Function, * TIPS, 18:211- 219 (1997)).
• ⁇ -2 adrenergic receptor drugs involve the ability of those drugs to mediate many of the physiological actions of the endogenous catecholamines. There are many drugs that act on these receptors to control hypertension, intraocular pressure, eye reddening and nasal congestion and induce analgesia and anesthesia.
• ⁇ 2 adrenergic receptors can be found in the rostral ventrolateral medulla, and are known to respond to the neurotransmitter norepinephrine and the antihypertensive drug cfonidine to decrease sympathetic outflow and reduce arterial blood pressure (Bousquet et al., "Role of the Ventral Surface of the Brain Stem in the Hypothesive Action of Clonidine," Eur. J.
• Imidazoline Receptors From Basic Concepts to Recent Developments," 26:S1-S6 (1995); Reis etal., "The Imidazoline Receptor: Pharmacology, Functions, Ligands, and Relevance to Biology and Medicine," Ann. N. Y. Acad. ScL, 763:1-703 (1995).
• Compounds having adrenergic activity are well-known in the art and are described in numerous patents and scientific publications, it is generally known that adrenergic activity is useful for treating animals of the mammalian species, including humans, for curing or alleviating the symptoms and conditions of numerous diseases and conditions.
• compositions having an adrenergic compound or compounds as the active ingredient are useful for treating, among other things, glaucoma, chronic pain, migraines, heart failure, and psychotic disorders (e.g., schizophrenia).
• R '-R 3 represent hydrogen, halogen hydroxy, atkyl or alkoxy, and R 5 is hydrogen or alkyl.
• ft is also known that compounds having adrenergic activity, such as ⁇ 2A agonists, may be associated with undesirable side effects.
• side effects include hyper-and hypotension, sedation, locomotor activity, psychotic disorders (e.g., schizophrenia).
• Another class of compounds reported to have affinity for ⁇ 2 receptors includes the following two compounds ⁇ Miller et.al., J. Med. Chem. 1994, 37:2328-2333; J. Med. Chem. 1996, 39:3001-3013; J. Med. Chem. 1997, 37:3014-3024):
• indane and tetrahyrdonaphthalene type compounds having ⁇ 2- agonist properties is disclosed in PCT application WO 97/12874 and WO20040506356.
• This class specifically includes MPV-2426 (fadolmidine) and its prodrug esters: wherein R is optionally substituted lower alkyl, aryl, cycloalkyl, heteroaryl, lower alkyiamino, and saturated 5- or 6-membered heterocyclic groups containing 1 or 2 N atoms.
• R is optionally substituted lower alkyl, aryl, cycloalkyl, heteroaryl, lower alkyiamino, and saturated 5- or 6-membered heterocyclic groups containing 1 or 2 N atoms.
• R is optionally substituted lower alkyl, aryl, cycloalkyl, heteroaryl, lower alkyiamino, and saturated 5- or 6-membered heterocyclic groups containing 1 or 2 N atoms.
• Ailergan has three published patent applications that describe methylimidazole derivatives that are said to be usedful in treating disease states such as glaucoma, ocular hypertension and congestion. These published applications are: WO
• WO 2008/086131 fNaphthyiimidazoles as Therapeutic agents
• WO 2008/088936 u Quinoiynylmethylimidazoles as Therapuetic Agents
• WO 2008/088937 Quinolynyimethyiimidazoles as Therapeutic Agents
• WO 2003/082825 indicates alpha-2C receptor antagonists have utility in treating symptoms of disorders and conditions with sensorimotor-gating deficits.
• Selii ⁇ er era/. indicate that acridin-9-yl-[4-(4-methylpiperazinai-1-yl)- phenyijamrne is a highly selective alpha-2C adrenergic receptor antagonist and may be useful Entreating neuropsychiatric disorders (Salliner etai, British J. Pharmacol. 150 :391-402 (2007)).
• ⁇ 2A agonists may be associated with undesirable side effects.
• side effects include hyper-and hypotension, sedation, locomotor activity, and body temperature variations.
• WO 2006/044556 to Gaifileo Pharmaceuticals discloses dual lipoxygenase inhibitors of the formula:
• Gentili etai disclose ⁇ 2 adreneroreceptors antagonists of the formula:
• R 1 is phenyl
• This compound is said to possess oc2 antagonistic activity.
• U.S. Patent 6,673,337 describes and claims an ophthalmic composition comprising an a!pha-2C agonist component and a solubility enhancing component other than cyclodextrin.
• the patent does not specifically describe alpha-2C receptor agonists.
• the inventive compounds act as modulators of of the afpha-2C receptor (i.e., they can act as alpha-2C receptor agonists or as alpha-2C receptor antagonists) and are useful in treating disorders modulated by the alpha-2C receptor.
• the present invention provides a novel class of heterocyclic compounds that are modulators of the ⁇ 2C adrenergic receptor, or metabolites, stereoisomers, salts, solvates or polymorphs thereof, methods of preparing such compounds, pharmaceutical compositions comprising one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention, inhibition or amelioration of one or more conditions associated with ⁇ 2C receptors using such compounds or pharmaceutical compositions.
• the present application discloses a compound, or pharmaceutically acceptable salts or metabolites, solvates, prodrugs or polymorphs of said compound, said compound having the genera ⁇ structure shown m Formula
• J', J 2 . J 3 and J 4 are independently -N-, -N(O)-, or -C(R 2 )-;
• X is -C(R 6 XR 6' )-, -N(R 6 V, -O- or -S -;
• W iS -N(R 14 K -O- Or-S-; is a single or double bond, provided that there cannot be two continuous double bonds;
• R 1 is a ring selected from the group consisting of cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heterocycienyl, and heteroaryf, each of which is optionally substituted with at least one (preferably 1 to 5, more preferably 1 to 3) R 12 ;
• R c is H oralkyi
• R 3 is independently selected from the group consisting of H, -OH, halo, -CN, -NO 2 , -S(O) P R 7 , -NR 7 R 7' and -S(O) P NR 7 R 7- , and alkyl. alkoxy, alkenyl, aikenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclyjalkyl groups optionally substituted with at least one (preferably 1 to 5, more preferably 1 to 3) R 5 ;
• R 3' is independently selected from the group consisting of H, -OH, halo, and alkyl, and alkoxy; or
• R 11' is independently selected from the group consisting of H, aikyl, alkoxy, alkenyl, alkenyloxy, aikynyl, cycloalkyl, cycloalkoxy, aryi, aryloxy, arylalkyl, heteroaryi, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;
• R 13 is independently H, aikyl, or aryi;
• the compounds of Formula I can be useful as ⁇ 2C adrenergic receptor modulators and can be useful in the treatment or prevention of one or more conditions associated with the ⁇ 2C receptor by administering at least one compound of Formula I to a mammal in need of such treatment.
• Conditions that my be treated by modulating the ⁇ 2C receptor include allergic rhinitis, congestion (including congestion associated with perennial allergic rhinitis, seasonal allergic rhinitis, non-allergic rhinitis, vasomotor rhinitis, rhinitis medicamentosa, sinusitis, acute rhinosinusitis, or chronic rhinosinusitis, congestion caused by polyps, or caused by the common cold), pain (e.g..
• neuropathy neuropathy, inflammation, arthritis, or diabetes
• diarrhea glaucoma
• congestive heart failure chronic heart failure
• cardiac ischemia manic disorders
• depression anxiety, migraine
• stress-induced urinary incontinence neuronal damage from ischemia
• schizophrenia attention deficit hyperactivity disorder
• symptoms of diabetes post traumatic stress disorder
• Parkinson's disease or a dementia (e.g., Alzheimer's disease).
• Another embodiment of this invention is the treatment or prevention of one or more conditions associated with the ⁇ 2C receptor by administering at least one compound of Formula I to a mammal in need of such treatment by selectively modulating ⁇ 2C adrenergic receptors in the mammal.
• Another embodiment of this invention is the treatment or prevention of one or more conditions associated with the ⁇ 2C receptor by administering an effective amount at least one compound of Formula I to a mammal in need of such treatment without modifying blood pressure at the therapeutic dose.
• Another embodiment of the present invention is a method for selectively modulating ⁇ 2C adrenergic receptors in a ceil in a mammal in need thereof, comprising contacting said ceil with a therapeutically effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt, ester, prodrug or salt thereof.
• Another embodiment of the present invention is a method for the treatment of congestion in a mammal in need thereof without modifying the blood pressure at therapeutic doses which comprises administering to the mammal an effective dose of at least one compound having adrenergic activity wherein said compound is a selective agonist of the ⁇ 2C receptor.
• the present invention discloses certain spiroamtnooxazoline derivatives, which are represented by structural Formula I, or a pharmaceutically acceptable salt or solvate thereof, wherein the various moieties are as described above.
• J 1 , J 2 , and J 3 are each -C(R 2 )-.
• J 2 , J 3 and J 4 are each -CH-.
• J 2 and J 3 are -CH- and J 1 is -N-. In another embodiment, J 2 and J 3 are -CH- and J 2 is -N-.
• J 1 , J 2 and J 3 are independently -C(R) 2 - or -N-.
• J 1 and J 2 are -CH- and J 3 is -N-.
• J 1 and J 4 are -CH- and J 3 is -N-.
• n is 1. In another embodiment, n is 2. in another embodiment, q is 0 or 1.
• p is 1 or 2.
• w is 1 , 2 or 3.
• X is -NH-.
• X is -O-. In another embodiment, X is -S-.
• X is -N(R 6' ).
• W is -NH-.
• W is -O-. In another embodiment, W is -S-.
• R 1 is optionally substituted (preferably 1 to 5 times) aryt (e.g., substituted phenyl) or optionally substituted (preferably 1 to 5 times) heteroaryl, wherein the optional substituents are, for example, any of the "ring system substituents" identified below.
• heteroaryl rings examples include pyridine, pyrimidine, furan, pyrrole, thiophene, pyridazine, pyrazine, indoiizine, oxazole, pyrazole, isoxazoie, indole, isoindole, imidazole, indoline, benzofuran, benzothiophene, indazole, benzimidazole, benzthiazole, quinoline, isoquinoiine, cinnoline, phthalazine, quinazoline, quinoxaline, and naphthyridine.
• Preferred heteroaryl rings include pyridine, pyrimidine, furan, pyrrole, thiophene, pyridazine, pyrazine, indole, indoline, benzofuran, benzothiophene, benzimidazole, and benzthiazole. More preferred heteroaryl rings include pyridine, pyrimidine, pyrazole, pyrazine, isoxazoie, and oxazole.
• Preferred optional substituents include alkyl, haloalkyl, nitro, cyano, halo, hydroxy!, alkoxy, amino, alkylamino, dialkylamtno, haloaikoxy, aryl, and heteroaryl, wherein said aryl and heteroaryl are optionally substituted 1 to 5, preferably 1 to 3, times by alkyl, haloalkyl, nitro, cyano, halo, hydroxy!, alkoxy, amino, alkylamino, dtalkylamino and haloaikoxy.
• R 1 is an optionally substituted (preferably 1 to 5 times) cycloalkyl or cycloalkenyl ring.
• rings include cyclopentane, cyclohexane and cyclohexene.
• substituents include any of the "ring system substituents" identified below.
• Preferred optional substituents include alkyj, haloalkyl, nitro, cyano, halo, hydroxyl, alkoxy, amino, alkylamino, dialkyjamino, haloafkoxy, aryi, and heteroaryl, wherein said aryl and heteroaryl are optionally substituted 1 to 5, preferably 1 to 3, times by alkyf, haioalkyl, nitro, cyano, halo, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and haloaikoxy.
• R 1 is an optionaity substituted (preferably 1 to 5 times) heterocyclyf or heterocyclenyl ring or cydoaikenyi ring.
• rings include morpholine, piperazine, 2-pyrrofidine and tetrahydrofurane.
• subststit ⁇ ents include any of the "ring system substituents" identified below.
• Preferred optional substituents include aikyi, hatoalkyl, nitro, cyano, haio, hydroxy!, alkoxy, amino, alkylamino, diaikylamino, haloalkoxy, aryl, and heteroaryl, wherein said aryf and heteroaryl are optionally substituted 1 to 5, preferably 1 to 3, times by alky!, haloalkyl, nitro, cyano, halo, hydroxy!, alkoxy, amino, alkylamino, dialkyiamino and haloalkoxy.
• R 1 is an optionally substituted pyridine ring.
• R f is an optionally substituted pyrimidine ring.
• R 1 is an optionally substituted pyrazine ring. In another embodiment, R 1 is an optionally substituted oxazoie ring.
• R 1 is an optionally substituted phenyl ring.
• R 1 is an optionally substituted napthylene ring.
• R 1 is an optionally substituted isoxazole ring.
• R 1 is an optionally substituted pyrazole ring. in another embodiment, R 1 is bonded to J 1 ; J 2 , J 3 and J 4 are -CH-; and X is -
• R 1 is bonded to J 1 ; J a , J 3 and J 4 are -CH-; and X is - NH-.
• R 1 is bonded to J 1 ; J 2 , J 3 and J 4 are -CH-; and X is -O-. in another embodiment, R 1 is bonded to J 1 JJ 2 , J 3 and J 4 are -CH-; and X is -S-.
• R 1 is bonded to J 4 ; J 1 , J 2 and J 3 are -CH-; and X is - CH2'-
• R 1 is bonded to J 4 ; J 1 , J 2 and J 3 are -CH-; and X is - NH-. In another embodiment, R 1 is bonded to J 4 ; J 1 , J 2 and J 3 are -CH-; and X is -G-.
• R 1 is bonded to J 4 ; J 1 , J 2 and J 3 are -CH-; and X is -S-.
• R 1 is bonded to J 2 ; J*, J 3 and J 4 are -CH-; and X is - CH 2 -.
• R 1 is bonded to J 2 ; J 1 , J 3 and J 4 are -CH-; and X is - NH-.
• R 1 is bonded to J 2 ; J 1 , J 3 and J 4 are -CH-; and X is -O-.
• R 1 is bonded to J 2 ; J*. J 3 and J* are -CH-; and X is -S-. In another embodiment, R 1 is bonded to J 3 ; J ⁇ J 2 and J 4 are -CH-; and X is - CH 2 -.
• R 1 is bonded to J 3 ; J 1 , J 2 and J 4 are -CH-; and X is - NH-. In another embodiment, R 1 is bonded to J 3 ; J 1 , J 2 and J 4 are -CH-; and X is -O-.
• R 1 is bonded to J 3 ; J 1 , J 3 and J 4 are -CH-; and X is -S-.
• R 1 is optionally substituted heteroaryf.
• m is 1 and n is 1.
• J 2 , J 3 , and J 4 are each -C(R 2 )- and R 2 is independently H or halo.
• R 3 is H.
• R 3 is H 1 halo, -OH or alkoxy.
• R 3' is H or halo.
• R 4 is H 1 -OH, halo, -CN, -NO 2 , -NR 7 B r t wherein R 7 and R 7" are independently H, alkyl, R 12 -aryl, and R 12 -cycloalkyl, alkyf, or haloalkyl
• R ⁇ is H, aikoxy, or alkyl.
• n is 1, m is 1 and W is -O-.
• n is 1
• m is 1
• W is -S-.
• n is 1
• m is 1
• W is -NH-.
• R 14 is H 1 optionally substituted alkyl, optionally substituted cycloalkyl (e.g., cyciopropyl, cyclopentyl, or cyclohexyl) or, optionally substituted aryi (e.g., phenyl), wherein the optional substitutednts are halo, hydroxyl, amino, alkyl amino, diaikyt amino, nitro, or cyano.
• cycloalkyl e.g., cyciopropyl, cyclopentyl, or cyclohexyl
• aryi e.g., phenyl
• R 14 is H or alkyl.
• R 2 is H, halo or aikyi.
• En another embodiment is a single bond.
• X is -O-
• W is -NH-
• the present invention discloses compounds which are represented by structural formulae H-V or a pharmaceutically acceptable salt, soivate or ester thereof, wherein the various definitions are those described above for Formula I:
• R 1 is optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted pyridyl, optionally substituted pyrimidyl, optionally substituted furanyl, optionally substituted thiophenyl, optionally substituted quinoiinyl, optionally substituted indolyl, optionally substituted pyrrolyt, and optionally substituted pyrrolidinyl, optionally substituted pyrazotyl, optionafiy substituted oxazolyl, optionally substituted isoxazolyl, optionafiy substituted imidazole, optionally substituted pyridazinyl, optionally substituted pyrazinyl, optionally substituted tetrazolyf, optionally substituted imidazopyrimidinyl, optionally substituted thiazolyl, optionally substituted isothiazofyi, optionally substituted indazolyt, optionally substituted benzofurany
• R 4 is H or aikyl (e.g., methyl or ethyl), alkoxy (e.g., methoxy or ethoxy), halo, - CN, -OH, NO 2 , amino, alkylamino or dialkyiamino. or a pharmaceutically acceptable ester, salt or solvate thereof.
• Another embodiment of compounds of Formulae H-V is a single bond.
• Another embodiment of compounds of Formulae H-V 1 W is -NH-, R 3 is H, R 4 is H or alkyl and is a single bond.
• the compound of Formula I or its pharmaceutically accept salt, solvate or ester thereof is present in its isolated and purified form.
• One embodiment of the present invention is compounds that act as agonists of the ⁇ 2C receptor.
• Alpha-2C receptor agonists can by used in the treatment or prevention of allergic rhinitis, congestion (including, but not limited to nasal congestion), migraine, congestive heart failure, chronic heart failure, cardiac ischemia, glaucoma, stress-induced urinary incontinence, attention deficit hyperactivity disorder, neuronal damage from ischemia and psychotic disorders.
• alpha-2C receptor agonists can be useful in the treatment of pain (both chronic and acute), such as pain that is caused by inflammation, neuropathy, arthritis (including osteo and rheumatoid arthritis), diabetes (e.g., diabetes mel ⁇ tus or diabetes insipidus) or pain of an unknown origin.
• pain both chronic and acute
• neuropathic pain may include but not limited to; diabetic neuropathy, neuralgia of any etiology (e.g. post-herpetic, trigeminal), chemotherapy- induced neuropathy, HIV, lower back pain of neuropathic origin (e.g. sciatica), traumatic peripheral nerve injury of any etiology, central pain (e.g. post-stroke, thalamic, spinal nerve injury).
• aipha-2C receptor agonists can be useful in the treatment of symptoms of diabetes.
• symptoms of diabetes may include but are not limited to: hyperglycemia, hypertriglyceridemia, increased levels of blood insulin and hyperlipidemia.
• a compound is defined to be an agonist of the a!pha-2c receptor if the compound's efficacy at the cr2C receptor is ⁇ 30% E max (GTP ⁇ S assay).
• a further embodiment of the present invention are that act selectively, and preferably even specifically, as agonists of the ⁇ 2C or the ⁇ 2B/ ⁇ 2C (hereinafter referred to as ⁇ 2C or ⁇ 2B/2C) receptor subtypes in preference over the ⁇ 2A receptor subtype and that act functionally selectively as agonists of the ⁇ 2C or the ⁇ 2B/2C receptor subtype in preference over the ⁇ 2A receptor subtype possess desirable therapeutic properties associated with adrenergic receptors but without having one or more undesirable side effects such as changes in blood pressure or sedation.
• a compound is defined to be a specific or at least functionally selective agonist of the ⁇ 2C receptor subtype over the ⁇ 2A receptor subtype if the compound's efficacy at the ⁇ 2C receptor is ⁇ 30% E max (GTP7S assay) and its efficacy at the ⁇ 2A receptor is ⁇ 35% Emax, (GTP-yS assay).
• the compound acts as an antagonist of the alpha-2C receptor.
• Alpha-2C receptor antagonists can be used in the treatment or prevention of disease states such as depression, schizophrenia, post tramauttc stress disorder, Parkinson's disease, dementias (e.g., Alzheimer's disease and neuropathic disorders.
• a compound is defined to be an antagonist of the aipha-2C receptor if the compounds's efficacy at the ⁇ 2C receptor is ⁇ 30% Emax (GTPyS assay) and the binding inhibition of at the ⁇ 2C receptor (K «) is ⁇ 500 nM, preferably ⁇ 200 ⁇ M, and most preferably ⁇ 20 nM.
• the ⁇ 2C receptor subtype antagonists possess desirable therapeutic properties associated with the ⁇ 2C adrenergic receptor but without having one or more undesirable side effects associated with ⁇ 2A agonism.
• compounds that act as antagonists at the ⁇ 2C receptor subtype preferably do not possess an efficacy at the ⁇ 2A receptor of 35% Emax or more (GTPyS assay).
• the present invention provides for a method for the treatment of congestion in a mammal in need thereof which comprises administering to a mammal an effective dose of at least one compound having adrenergic activity wherein said compound is a functionally selective agonist of the ⁇ 2c receptor or the ⁇ 2C/ ⁇ B adrenergic receptor.
• a further embodiment of the present invention is a method for the treatment of congestion in a mammal in need thereof which comprises administering to a mamma! an effective dose of at least one compound having adrenergic activity wherein said compound is a functionally selective agonist of the ⁇ 2C receptor or the ⁇ 2C/ ⁇ B adrenergic receptor, wherein the selective agonist of the ⁇ 2c receptor or the ⁇ 2C/ ⁇ B adrenergic receptor has an efficacy that is greater than or equal to 30% E max when assayed in the GTPyS assay and its efficacy at the ⁇ 2A receptor is ⁇ 35% E max (GTP ⁇ S assay).
• alpha-2C receptor agonist or "a2C receptor agonist” is a compound that has affinity for the ⁇ 2C receptor and elicits a biological response that mimics the response observed by the endrogenous iigand (e.g.. neurotransmitter) that binds to the same receptor.
• aipha-2C receptor antagonist or "a2C receptor antagonist” is a compound that has affinity for the Q2C receptor and elicits a biological response that blocks or dampens the response observed by the endrogenous Iigand (e.g., neurotransmitter) that binds to the same receptor.
• ⁇ ' Congestion * ' refers to all type of congestion including, but not limited to, congestion associated with perennsai allergic rhinitis, seasonal altergic rhmstis, no ⁇ - aftergic rhinitis, vasomotor rhinitis, rhmstls medicamentosa, sinusitis, acute rhinosinusitis, or chronic rhinosinusitis or when the congestion is caused by polyps or is associated with the common cold.
• Alkyl means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyi groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyt groups such as methyl, ethyl or propyl, are attached to a linear aikyl chain. "Lower alkyf” means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched.
• substituted alkyl means that the alkyl group may be substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, aryl, cycioafkyl, cyano, hydroxy, aikoxy, alkyithio, amino, -NH(alkyl), -NH(cycloalkyl), -N(aikyl) 2l carboxy and -C(O)O-alky1.
• suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl.
• Alkenyl means an aliphatic hydrocarbon group containing at least one carbon- carbon double bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain.
• Preferred alkenyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain.
• Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain.
• “Lower alkenyl” means about 2 to about 6 carbon atoms in the chain which may be straight or branched.
• alkenyl may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl. aryl, cycioalkyf, cyano, aikoxy and -S(afkyl).
• suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut- 2-enyl, n-pentenyi, octenyi and decenyl.
• Alkynyl means an aliphatic hydrocarbon group containing at least one carbon- carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain.
• Preferred alkynyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain.
• Branched means that one or more lower aikyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain.
• “Lower alkynyi” means about 2 to about 6 carbon atoms in the chain which may be straight or branched.
• Non-limiting examples of suitable alkynyl groups include ⁇ thynyl, propynyi, 2-butynyl and 3- methylbutynyf.
• substituted alkynyl means that the alkynyf group may be substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl, aryl and cycloalkyl.
• Aryl means an aromatic monocyclic or multicyclic ring system, in which at least one of the multicyclic rings is an aryl ring, comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms.
• the aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein.
• suitable aryl groups include phenyl and naphthyl.
• Non-limiting examples of aryi multicyclic ring systems include:
• heteroaryl means an aromatic monocyclic or multicyclic ring system, in which at least one of the multicyclic rings is aromatic, comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination.
• Preferred heteroaryls contain about 5 to about 6 ring atoms.
• the "heteroaryl” can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein.
• the prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom.
• a nitrogen atom of a heteroaryJ can be optionally oxidized to the corresponding N-oxide.
• Non-limiting examples of suitable heteroaryls include pyridyi, pyrazinyl, furanyl, thienyl, pyrimidinyi, isoxazoiyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazofyl, triazolyl, 1,2,4- thiadiazoiyi, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo ⁇ 1,2 ⁇ a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyi, indofyl, azaindofyl, benzimidazoiyl, benzothienyl, quinofinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrol
• Non-limiting examples of hetreroaryl multicyciic ring systems include:
• Aralkyl or “arylalkyl” means an aryl-alkyl- group in which the aryi and aikyj are as previously described.
• Preferred aratkyls comprise a lower alkyf group.
• suitable arafkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl. The bond to the parent moiety is through the aikyl.
• Alkylaryl* means an alkyl-aryl- group in which the aikyl and aryl are as previously described. Preferred alkylaryls comprise a lower aikyl group. Non-limiting example of a suitable alkylaryl group is tofyl. The bond to the parent moiety is through the aryt.
• Cycloalkyl means a non-aromatic mono- or multicyciic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycioalkyl rings contain about 5 to about 7 ring atoms.
• the cycloalkyl can be optionally substituted with one or more "ring system substttuents" which may be the same or different, and are as defined above.
• suitable monocyclic cycloalkyte include cyclopropyl, cyclopentyl, cyclohexyl, cycioheptyl and the like.
• suitable multicyciic cycloalkyls include 1-decalinyl, norborny), adamantyl and the like.
• Halogen and Halo mean fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine or bromine, and more preferred are fluorine and chlorine.
• Ring system substitue ⁇ f means a substituent attached to an aromatic or non- aromatic ring system which, for example, replaces an available hydrogen on the ring system.
• Ring system substituents may be the same or different, each being independently selected from the group consisting of aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, atkylheteroaryi, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryioxycarbonyl, aralkoxycarbonyJ, alkylsulfonyt, arylsulfo ⁇ yl, heteroarylsulfonyi, alkylthio, arylthio, heteroaryfthio, aralkyithio, heteroaralkyithio, cycioalkyl, heterocyclyl, Y 1 Y 2 N-, Y t Y 2 N ⁇ alkyh Y 1 Y 2 NC(O)- and YtYgNSOs-, wherein Y
• Heterocyclyl means a non-aromatic saturated monocyclic or multicycfic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system.
• Preferred heterocyclyls contain about 5 to about 6 ring atoms.
• the prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom.
• Any -NH in a heterocyclyl ring may exist protected such as, for example, as an -N(Boc), -N(CBz), -N(Tos) group and the like; such protected moieties are also considered part of this invention.
• the heterocyclyl can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein.
• the nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S 1 S- dtoxide.
• Non-limiting examples of suitable monocyclic heterocyclyl rings include piperidy!, pyrro ⁇ dtnyl, imidaz ⁇ lidinyj, pyrazolidinyl, ptperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyi, 1 ,4-dioxanyl, tetrahydrofuranyi, tetrahydrothiophenyl, and the like.
• tautomeric forms for example, as an amide or imino ether.
• AIi such tautomeric forms are contemplated herein as part of the present invention.
• Non- limiting examples of tautomeric forms that are part of this invention are as follows:
• Alkynylalkyi means an aikynyl-alkyf- group in which the alkynyl and alkyi are as previously described. Preferred alkynylalkyls contain a lower alkynyl and a lower alkyl group. The bond to the parent moiety is through the alkyl. Non-limiting examples of suitable alkynylaikyi groups include propargylmethyl. "Heteroaralkyf means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl, and quinoiin-3-ylmethyl. The bond to the parent moiety is through the alkyi.
• Heterocyclylalkyl means a heterocyclyl-alkyl group in which the heterocyclyl and the alkyl are as previously described. Preferred heterocyciylalkyls contain a lower alkyl group.
• suitable heterocyclylalkyl groups include piperidylmethyl, piperidyfethyl, pyrrolidylmethyl, morphofinylpropyi, piperazinylethyl, azindyimethyl, azetidylethyl, oxiranylpropyl and the like.
• the bond to the parent moiety is through the alkyl group.
• ⁇ eterocyclenyf ⁇ or "heterocycloalkeneyl” means a non-aromatic monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur atom, alone or in combination, and which contains at least one carbon-carbon double bond or carbon- nitrogen double bond. There are no adjacent oxygen and/or sulfur atoms present in the ring system.
• Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms.
• the prefix aza, oxa or thia before the heterocyclenyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom.
• the heterocyclenyl can be optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined above.
• the nitrogen or sulfur atom of the heterocyclenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S.S-dioxide.
• Non-limiting examples of suitable monocyclic azaheterocyclenyl groups include 1,2,3,4- tetrahydropyridyl, 1 ,2-dihydropyridyl, 1 ,4-dihydropyridyl, 1,2,3,6- tetrahydropyridyl, 1 ,4,5,6-tetrahydropyrimidyl, 2- ⁇ yrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazoiinyl, 2-oxazoiinyl, 2-thiazolinyl, and the like.
• Non-limiting examples of suitable oxaheterocycie ⁇ yi groups include 3,4-dihydro-2H-pyran, dihydrofuranyl, fiuorodihydrof ⁇ ranyi, and the like.
• Non-iimiting example of a suitable multicyclic oxaheterocyclenyl group is 7-oxabicyclo[2.2.1Jheptenyi.
• Non-limiting examples of suitable monocyclic thiaheterocyclenyi rings include dihydrothiophenyl, dihydrothiopyranyl, and the like.
• Heterocyctenylatkyl means a heterocyclenyl-alkyl group in which the heterocyclenyl and the alkyl are as previously described.
• Hydroxyalkyl means a HO-alkyl- group in which alkyl is as previously defined. Preferred hydroxyafkyts contain lower aikyt. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyf.
• Acyt means an organic acid group in which the -OH of the carboxyl group is replaced by some other substituent. Suitable non-limiting examples include H-C(O)-, afkyl-C(O)- , cycloalkyl-C(O)-, heterocyclyl-C(O)-, and heteroaryl-C(O)- groups in which the various groups are as previously described. The bond to the parent moiety is through the carbonyl. Preferred acyis contain a lower alkyl. Non-limiting examples of suitable acyl groups include formyl, acetyl and propanoyi. "Aroyl” means an aryl-C(O)- group in which the aryl group is as previously described. The bond to the parent moiety is through the carbonyl. Non-limiting examples of suitable groups include benzoyl and 1-naphthoyl.
• Alkoxy means an alkyl-O- group in which the alkyf group is as previously described.
• suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.
• the bond to the parent moiety is through the ether oxygen.
• Aryloxy means an aryl-O- group in which the aryl group is as previously described.
• suitable aryloxy groups include phenoxy and naphthoxy.
• the bond to the parent moiety is through the ether oxygen.
• Aralkytoxy or “arylalkyioxy” means an aralkyl-O- group in which the aralkyl group is as previously described.
• suitable aralkytoxy groups include benzyloxy and 1- or 2-naphthalenemethoxy. The bond to the parent moiety is through the ether oxygen.
• ⁇ eteroarylalkoxy means a heteroarylalkyl-O-group in which the heteroarylalky! group is as previously described.
• Heterocyclylaikoxy means a heterocyclylalkyl-0 group in which the hetrocyclyfaikyl group is as previously described.
• ⁇ eter ⁇ cyclenylalkoxy means a heterocyclenylalkyl-0 group in which the heterocyclenylalkyf group is as previously described.
• Alkylthio means an alkyl-S- group in which the alkyl group is as previously described.
• suitable alkylthio groups include methylthio and ethylthio.
• the bond to the parent moiety is through the sulfur.
• Arylthio means an aryl-S- group in which the aryl group is as previously described.
• suitable arylthio groups include phenylthio and naphthylthio.
• the bond to the parent moiety is through the sulfur.
• Aralkytthio means an aralkyl-S- group in which the aralkyl group is as previously described.
• a suitable aralkyithio group is benzylthio.
• the bond to the parent moiety is through the sulfur.
• Alkoxycarbonyl means an alkyl-O-CO- group. Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The bond to the parent moiety is through the carbonyf.
• Aryloxycarbonyl means an aryl-O-C(O)- group. Non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. The bond to the parent moiety is through the carbonyl.
• AlkoxycarbonyP means an aralkyl-O-C(O)- group.
• a suitable aralkoxycarbonyl group is benzyloxycarbonyl.
• the bond to the parent moiety is through the carbonyl.
• Alkylsulfonyl means an alkyl-S(O 2 )- group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfonyl.
• Arylsulfonyl means an aryl-S(O 2 )- group. The bond to the parent moiety is through the sulfonyl.
• substituted means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
• stable compound' or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
• carbons of Formula I can be replaced with 1-3 silicon atoms, provided all valency requirements are satisfied.
• optional substituted means optional substitution with the specified groups, radicals or moieties.
• the straight line as a bond generally indicates a mixture of, or either of, the possible isomers, non-limiting example(s) include, containing (R)- and (S)- stereochemistry.
• the possible isomers include, containing (R)- and (S)- stereochemistry.
• the indicated line (bond) may be attached to any of the substitutable ring atoms, non-limiting examples include carbon, nitrogen and sulfur ring atoms.
• any heteroatom with unsatisfied valences in the text, schemes, examples and Tables herein is assumed to have the hydrogen atom to satisfy the valences.
• a functional group in a compound is termed "protected”
• Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene era/, Protective Groups in organic Synthesis (1991), Wiley, New York.
• any variable e.g., aryt, h ⁇ terocycle, R 2 , etc.
• 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.
• Prodrugs and solvates of the compounds of the invention are aiso contemplated herein.
• the term "prodrug”, as employed herein, denotes a compound that is a drug precursor which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of formula I or a salt and/or solvate thereof.
• a discussion of prodrugs is provided in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems (1987) Volume 14 of the A. C. S. Symposium Series, and in Bioreversibfe Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, both of which are incorporated herein by reference thereto.
• a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (Ci-C 8 )alkyl, (C 2 - Ci 2 )alkanoyioxymethyt, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1- methyl-1-(alkanoyioxy)-ethyl having from 5 to 10 carbon atoms, alkoxycaroonyloxymethyl having from 3 to 6 carbon atoms, 1-(afkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-i-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, t-(
• a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (Ci-Ce)alkanoyloxymethyl, 1-((C 1 - C 6 )alkanoyfoxy)ethyl, 1 -methyl- 1 -((C 1 -C e )alkanoyloxy)ethyl, (C 1 - Ce)alkoxycarbonyloxymethyl, N-(Ci -Ce)alkoxycarbonylaminomethyl, succinoyl, (Ci- C 6 )alkanoyl, u-amino(Ci-C 4 )alkanyl, aryiacyl and ⁇ -aminoacyl, or ⁇ -aminoacyl- ⁇ - aminoacyi, where each ⁇ -aminoacyl group is independently selected from the naturally occurring L-amino acids, -P(O)(OH
• a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl, RO-carbonyf, NRR'- carbonyl where R and R' are each independently (CrC t o)alkyl, (C 3 -C 7 ) cycfoaikyl, benzyl, or R-carbonyl is a natural ⁇ -aminoacyf or natural ⁇ -aminoacyl, -C(OH)C(O)OY 1 wherein Y 1 is H, (C t -C e )aikyi or benzyl, -C(OY 2 JY 3 wherein Y 2 is (Ci-C 4 ) alkyl and Y 3 is (Cr
• One or more compounds of the invention may exist in unsolvated as weli as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
• “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of illustrative solvates include ethanolates, methanolates, and the like.
• “Hydrate” is a solvate wherein the solvent molecule is H 2 O.
• One or more compounds of the invention may optionally be converted to a solvate.
• Preparation of solvates is generally known.
• M. Caira et al, J. Pharmaceutical ScL, 93(3). 601-611 (2004) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water.
• Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder et al, AAPS PharmSciTech., 5Ql, article 12 (2004); and A. L. Bingham et a/, Chem. Comm ⁇ n., 603-604 (2001).
• a typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods.
• Analytical techniques such as, for example I. R. spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).
• Metabolic conjugates such as glucuronides and sulfates which can undergo reversible conversion to the compounds of of Formula I are contemplated in the present invention.
• Effective amount or “therapeutically effective amount” is meant to describe an amount of compound or a composition of the present invention effective in producing the desired therapeutic, ameliorative, inhibitory or preventative effect.
• purified in purified form 11 or “in isolated and purified form,” as used herein, for a compound refers to the physical state of said compound after being isolated from a synthetic process (e.g. from a reaction mixture), or natural source or combination thereof.
• the term “purified”, “in purified form” or “in isolated and purified form” for a compound refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan (e.g., chromatography, recrystal ⁇ zation and the like) , in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.
• “Capsule” is meant to describe a special container or enclosure made of methyl cellulose, polyvinyl alcohols, or denatured gelatins or starch for holding or containing compositions comprising the active ingredients.
• Hard shell capsules are typically made of blends of relatively high gel strength bone and pork skin gelatins. The capsule itself may contain small amounts of dyes, opaquing agents, pfasticizers and preservatives.
• Tablet is meant to describe a compressed or molded solid dosage form containing the active ingredients with suitable diluents.
• the tablet can be prepared by compression of mixtures or granulations obtained by wet granulation, dry granulation or by compaction.
• Oral gels is meant to describe to the active ingredients dispersed or solubilized in a hydrophillic semi-solid matrix.
• Powders for constitution refers to powder blends containing the active ingredients and suitable diluents which can be suspended in water or juices.
• “Diluent” refers to substances that usually make up the major portion of the composition or dosage form. Suitable diluents include sugars such as lactose, sucrose, mannitol and sorbitol; starches derived from wheat, corn, rice and potato; and celluloses such as microcrystalline cellulose.
• the amount of diluent in the composition can range from about 10 to about 90% by weight of the total composition, preferably from about 25 to about 75%, more preferably from about 30 to about 60% by weight, even more preferably from about 12 to about 60%.
• Disintegrants refers to materials added to the composition to help it break apart (disintegrate) and release the medicaments. Suitable disintegrants include starches; "cold water soluble” modified starches such as sodium carboxymethyl starch; natural and synthetic gums such as locust bean, karaya, guar, tragacanth and agar; cellulose derivatives such as methytcelfulose and sodium carboxymethyicellufose; microcrystaliine celluloses and cross-linked microcrystalline celluloses such as sodium croscarmeliose; alginates such as alginic acid and sodium alginate; clays such as bentonites; and effervescent mixtures.
• the amount of dtsintegrant in the composition can range from about 2 to about 15% by weight of the composition, more preferably from about 4 to about 10% by weight.
• Binders refers to substances that bind or "glue” powders together and make them cohesive by forming granules, thus serving as the "adhesive" in the formulation. Binders add cohesive strength already available in the diluent or bulking agent. Suitable binders include sugars such as sucrose; starches derived from wheat, corn rice and potato; natural gums such as acacia, gelatin and tragacanth; derivatives of seaweed such as alginic acid, sodium alginate and ammonium calcium alginate; cellulosic materials such as methylceliulose and sodium carboxymethylcellulose and hydroxypropylmethylcellulose; polyvinylpyrrolidone; and inorganics such as magnesium aluminum silicate.
• the amount of binder in the composition can range from about 2 to about 20% by weight of the composition, more preferably from about 3 to about 10% by weight, even more preferably from about 3 to about 6% by weight.
• “Lubricant” is meant to describe a substance added to the dosage form to enable the tablet, granules, etc. after it has been compressed, to release from the mold or die by reducing friction or wear.
• Suitable lubricants include metallic stearates such as magnesium stearate, calcium stearate or potassium stearate; stearic acid; high melting point waxes; and water soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols and d'Meucine.
• Lubricants are usually added at the very last step before compression, since they must be present on the surfaces of the granules and in between them and the parts of the tablet press.
• the amount of lubricant in the composition can range from about 0.2 to about 5% by weight of the composition, preferably from about 0.5 to about 2%, more preferably from about 0.3 to about 1.5% by weight.
• “Glidents” means materials that prevent caking and improve the flow characteristics of granulations, so that flow is smooth and uniform. Suitable glidents include silicon dioxide and talc.
• the amount of glident in the composition can range from about 0.1% to about 5% by weight of the total composition, preferably from about 0.5 to about 2% by weight
• Coloring agents refers to excipients that provide coloration to the composition or the dosage form. Such excipients can include food grade dyes and food grade dyes adsorbed onto a suitable adsorbent such as cfay or aluminum oxide. The amount of the coloring agent can vary from about 0.1 to about 5% by weight of the composition, preferably from about 0.1 to about 1%.
• Bioavailability refers to the rate and extent to which the active drug ingredient or therapeutic moiety is absorbed into the systemic circulation from an administered dosage form as compared to a standard or control.
• Conventional methods for preparing tablets are known. Such methods include dry methods such as direct compression and compression of granulation produced by compaction, or wet methods or other special procedures.
• Conventional methods for making other forms for administration ⁇ uch as, for example, capsules, suppositories and the like are also well known.
• the compounds of Formula I can form salts which are also within the scope of this invention.
• Reference to a compound of Formula I herein is understood to include reference to salts thereof, unless otherwise indicated.
• the term "SaIt(S)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases.
• a compound of of Formula I contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterro ⁇ s ("inner salts”) may be formed and are included within the term "SaIt(S)" as used herein.
• Salts of the compounds of Formula I or may be formed, for example, by reacting a compound of Formula I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
• Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesuifonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsuifonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesuifonates, naphthatenesuifonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like.
• Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as argi nine, lysine and the like.
• Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g.
• dimethyl, diethyl, and dibutyl sulfates dimethyl, diethyl, and dibutyl sulfates
• long chain halides e.g. decyl, iauryl, and stearyl chlorides, bromides and iodides
• aralkyl halides e.g. benzyl and phenethyl bromides
• All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.
• All stereoisomers for example, geometric isomers, optical isomers and the like
• of the present compounds including those of the salts, solvates and prodrugs of the compounds as well as the salts and solvates of the prodrugs, such as those which may exist due to asymmetric carbons or sulfurs on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diasiereomeric forms, are contemplated within the scope of this invention.
• a compound of Formula I incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention.
• Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers.
• the chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations.
• Diasteromeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization.
• Enantiomers can be separated by converting the enantiomeric mixture into a diasteromeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mother's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.
• an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mother's acid chloride
• converting e.g., hydrolyzing
• some of the compounds of Formula I may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention.
• Enantiomers can also be separated by
• the present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
• isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2 H, 3 H, 13 C. 14 C, 15 N, 18 0, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 CI, respectively.
• Certain isotopically-labelled compounds of Formula I are useful in compound and/or substrate tissue distribution assays.
• Tritiated (i.e., 3 H) and carbon- 14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectabriity.
• substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-fife or reduced dosage requirements) and hence may be preferred in some circumstances
• lsotopically labelled compounds of Formula I can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples hereinbelow, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent.
• the compounds according to the invention have pharmacological properties; in particular, the compounds of Formula I can be useful as ⁇ 2C adrenoceptor agonists.
• a preferred dosage is about 0.001 to 500 mg/kg of body weight/day of the compound of Formula I.
• An especially preferred dosage is about 0.01 to 25 mg/kg of body weight/day of a compound of Formula I, or a pharmaceutically acceptable salt or solvate of said compound.
• the compounds of this invention may also be useful in combination (administered together or sequentially) with one or more therapeutic agents such as, for example, glucocorticosteroids, PDE-4 inhibitors, anti-muscarinic agents, cromolyn sodium, H 1 receptor antagonists, 5-HT 1 agonists, NSAIDs, angiotensin-converting enzyme inhibitors, angiotensin Il receptor agonists, ⁇ -blockers, ⁇ -agontsts (including both long and short acting), leukotriene antagonists, diuretics, aldosterone antagonists, ionotropic agents, natriuretic peptides, pain management/analgesic agents, anti-anxiety agents, anti-migraine agents, and therapeutic agents suitable for treating heart conditions, psychotic disorders, and glaucoma.
• therapeutic agents such as, for example, glucocorticosteroids, PDE-4 inhibitors, anti-muscarinic agents, cromolyn sodium, H 1 receptor antagonists,
• Suitable steroids include prednisolone, fluticasone (including all ester such as the propionate or furoate esters), triamcinolone, beclomethasone, mometasone (including any ester form such as mometasone furoate), budasamine, ciclesonide betamethasone, dexamethasone, prednisone, flunisolide, and cortisone.
• Suitable PDE-4 inhibitors include roflumiiast, theophylline, rolipram, piclamiiast, cilomilast and CDP-840.
• Suitable antiimuscari ⁇ ic agents include ipratropium bromide and tiatropium bromide.
• Suitable Hi antagonists include astemizoie, azatadine, azelastine, acrivastine, brompheniramine, cetihzine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine, carbinoxamine, d ⁇ scarboethoxyloratidine, diphenhydramine, doxyiamine, dimethindene, ebastine, epi ⁇ astine, ⁇ ffetirizeine, fexofenadine, hydroxyzine, ketotifen, loratidine, levocabastin ⁇ , meclizine, fexofenadine, hydroxyzine, keiotifen, loratadine, levocabastine, meclizine, mizolastine, mequitazine, mianserin, noberastine, norastemizole, picumast, pyrilamine, promethazine, terf
• Suitable anti-inflammatory agents include aspirin, diclofenac, diflunisal, etodolac, flurbiprofen, ib ⁇ profen, indomethacin, ketoprofen, ketorolac, nabumetone, naproxen, oxaprozin, piroxicam, sulindac, and toimetrn.
• Suitable aldosterone antagonists include spironolactone.
• Suitable ionotropic agents include digitalis.
• Suitable angiotensin Il receptor agonists include irbesartan and losartan.
• Suitable diuretics include spironolactone, methydothiazide, bumetanide, torsemide, hydroflumethiazide, trichlormethiazide, hydroclorothiazide, triamterene, ethacrynic acid, methydothiazide, hydrochlorothiazide, benzthiazide, hydrochlorothiazide, quinethazone, hydrochlorothiazide, chlorthalidone, furosemide, indapamide, hydroclorothiazide, triamterene, trichlormethiazide, hydrochlorothiazide, amiloride HCI, amiloride HCI, metolazone, trichlormethiazide, bendroflumethiazide, hydrochlorothiazide, polythiazide
• Suitable pain management/analgesic agents include Celecoxib, amitriptyfine, ibuprofen, naproxen, gabapentin, tramadol, rofecoxib, oxycodone HCI 1 acetaminophenoxycodone HCI 1 carbamazepine, amitriptyline, diclofenac, diclofenac, etodolac, fenoprofen calcium, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac tromethamine, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, piroxicam, sulindac, toimetin sodium, valdecoxib, diclofenac/ misoprostol, oxycontin, vicodi ⁇ , darvocet, percocet, morphine sulfate, dilaud
• Suitable ⁇ -biockers include acebutolol, atenolol, atenolol/chlorthalidone, betaxoloi, bisoproiol fumarate, bisoprolol/HCTZ, labetolol, metoprold tartrate, nadolol, pindolol, propranolol, propranolol/HCTZ, sotalol, and timolol.
• Suitable ⁇ -agonists include dobutamine, ritodrine, salbutamol, levalbuteroi, metaproternof, formoterol, fenoter ⁇ i, bambuterof, brocaterol, ctenbuterol, terbuta ⁇ ne, lulobuterol, epinephrine, isoprenaiin, and hexoprenalin.
• Suitable I ⁇ ucotriene antagonists include levamisole.
• Suitable anti-migraine agents ⁇ nciude rovatriptan succinate, naratriptan HCI, rizatriptan b ⁇ nzoate, sumatriptan succinate, zolmitriptan, atmotriptan malate, methysergide mateat ⁇ , dihydroergotamine mesylate, ergotamine tartrate, ergotamine tartrate/caffein ⁇ , Fiorieet ® , Fiorninai ® , Depakene ® , and Depakote ® .
• Suitable anti-anxiety and anti-depressant agents include arnitriptyiine HCI, bupropion HCI, citalopram hydrobromide, clomipramine HCI, desipramine, fluoxetine, fluvoxamine maleate, maprotiline HCI, mirtazapine, nefazodone HCI, nortriptyline, paroxetine HCl, prot ⁇ ptyline HCI, sertraline HC!, doxepin, and trimipramine maleate.
• Suitable angiotensin converting enzyme inhibitors include Captoprii, enalapril, enalapriS/HCTZ , Itsinopril, Iisinopril/HCT2, and Aceon ® .
• the pharmacological properties of the compounds of this invention may be confirmed by a number of pharmacological assays.
• the exemplified pharmacoiogical assays which are described later have been carried out with the compounds according to the invention and their salts.
• compositions which comprise at least one compound of Formula I, or a pharmaceutically acceptable salt or solvate of said compound and at least one pharmaceutically acceptable carrier.
• inert, pharmaceutically acceptable carriers can be either solid or liquid.
• Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories.
• the powders and tablets may be comprised of from about 5 to about 95 percent active ingredient.
• Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A.
• liquid form preparations include metal carboxymethylcelluloses, metal carboxymethylhydroxyethylcelloses, hydroxypropylmethyl celluloses derivative of these compounds, and cyclodextrins.
• liquid form preparations according to the invention may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions.
• Liquid form preparations may also include solutions or suspensions for intranasal administration.
• An aspect of this invention is that the pharmaceutical composition is in a solid dosage form comprising a compound of Formula I or a pharmaceutical acceptable salt, ester, solvate or prodrug thereof and a least one pharmaceutically acceptable carrier, adjuvant or vehicle.
• a liquid, aqueous pharmaceutical composition is comprising a compound of Formula I or a pharmaceutical acceptable salt, ester, solvate or prodrug thereof and a least one pharmaceutically acceptable carrier, adjuvant or vehicle provided that the adjuvant is not a solubility enhancing component, such as those described in US 6,673,337 (discussed above).
• a liquid, aqueous pharmaceutical composition is comprising a compound of Formula I or a pharmaceutical acceptable salt, ester, solvate or prodrug thereof and a least one pharmaceutically acceptable carrier, adjuvant or vehicle wherein if a solubility enhancement component is present it is cyclodextrin.
• Another aspect of this invention is a pharmaceutical formulation that is a nasal spray wherein the pH is equal to or less that about 6.5, more preferably between about 6.1 to 6.2.
• the formulation is a nasal spray wherein the adjuvants include a suspending agent (e.g., AVICEL (such as AVICIL RC-581, RC- 591 and CL-611), which are microcrystafline cellulose and carboxymethylceilul ⁇ se sodium; hydroxypropylmethyi cellulose; methyl cellulose; polyvinyl alcohol; or CARBOPOL) and a humectant (e.g., glycerin, propylene glycol; polyethylene glycol; povidone; or dextrose).
• AVICEL such as AVICIL RC-581, RC- 591 and CL-611
• a humectant e.g., glycerin, propylene glycol; polyethylene glycol; povidone; or dextrose
• Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions or suspensions for intranasal administration.
• Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen.
• a pharmaceutically acceptable carrier such as an inert compressed gas, e.g. nitrogen.
• transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
• the compounds of this invention may also be delivered subcutaneously. Preferably the compound is administered orally.
• the pharmaceutical preparation is in a unit dosage form.
• the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
• the quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1 mg to about 100 mg, preferably from about 1 mg to about 50 mg, more preferably from about 1 mg to about 25 mg, according to the particular application.
• the actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.
• a typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 500 mg/day, preferably 1 mg/day to 200 mg/day, in two to four divided doses.
• Another aspect of this invention is a kit comprising a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt or solvate of said compound and a pharmaceutically acceptable carrier, vehicle or diluent.
• kits comprising an amount of at least one compound of Formula I, or a pharmaceutically acceptable salt or solvate of said compound and an amount of at least one therapeutic agent listed above, wherein the amounts of the two or more ingredients result in desired therapeutic effect.
• the compounds in the invention may be produced by a variety of processes know to those skilled in the art and by know processes analogous thereto.
• the invention disclosed herein is exemplified by the following preparations and examples which should not be construed to limit the scope of the disclosure. Alternative mechanistic pathways and analogous structures will be apparent to those skilled in the art. The practitioner is not limited to these methods.
• the prepared compounds may be analyzed for their composition and purity as well as characterized by standard analytical techniques such as, for example, elemental analysis, NMR, mass spectroscopy and IR spectra.
• reagents and solvents actually used may be selected from several reagents and solvents well known in the art to be effective equivalents.
• solvent or reagent it is meant to be an illustrative example of the conditions desirable for that particular reaction scheme and in the preparations and examples described below.
• Boc te/t-butoxycarbonyl
• TBSCI t-butyfdimethylsifyl chloride
• TBS t-butyidimethyi silyl
• the compounds of this invention can be prepared through the general approach outlined in the following schemes. These schemes are being provided to illustrate the present invention. While the schemes depict J 1 -J 4 as -CH-, wherein the hydrogen may be replaced by A or R 2 , this is for exemplary purposes only and one of ordinary skill in the art would be able to prepare compounds containing the other definitions for J ⁇ J 4 by modifying these schemes using other procedures known to one in the art. To assist in one in this endeavor the ordinary practitioner would have full knowledge of literature sources such as Chemical Abstracts, B ⁇ ilstein, etc.
• Scheme 1 shows an approach in which a substituted catechol S1a, o- mercaptophenol S1b, or o-aminophenol S1c is converted to nitrile S2 by reaction with 2-chloroacryionitrile S4a (or similar reagent such as S4b) and a base (such as K 2 CO 3 )- Compound S2 is further reacted with diamine S5 (optionally substituted) under a variety of conditions such as heat, acid (HCI-MeOH 1 pTsOH or the like) or base (NaOMe or the like).
• the resulting imidazoline S3a may be further alkylated or acylated with an electrophife to provide S3b.
• Installation of the biaryi group may be done at various stages in the sequence.
• the functionalized R 2 groups may exist in the starting material SI or its precursor.
• S1 or its precursor may be functionalized with R 2 groups at various stages in the sequence.
• Scheme 2 shows an approach in which a substituted catechol S1 is converted to ester S ⁇ a by reaction with either a 2,3-dibromopropiante S7 or 2-bromoacrylate S8 (or similar reagent) and a base (such as KOH or K 2 CO 3 ).
• S6a is converted to the following hetercycles:
• ester S6a is saponified to add S6b by a standard method (such as treatment with HCI 1 NaOH 1 LJOH or other method known in the literature).
• S6b is converted to the following hetercycles:
• Scheme 3 shows an approach in which nitrile S2 is treated with HCI and EtOH (or other alcohol).
• the resulting imidate S12 is then sequentially treated with: an acetai or ketai (S15, optionally substituted), HCI 1 and then NaOH to provided imidazole S13.
• Compound S14 is obtained by the a ⁇ kyfation or acylation of S13 with an appropriate eiectrophile and strong base (such NaH, NaHMDS etc.).
• Scheme 4 shows an approach in which catechol S1a is treated with substituted ketone S16a and NaOH.
• the resulting ketal S17a is then sequentially treated with HCI ⁇ to give the chloride S17b) and then a cyanide source (such as TMSCN, NaCN etc) to provided the nitrite S17c. Conversion to to S18 is accomplished as described previously.
• catechol S1a is treated with epoxide S16b and NaOH.
• the resulting methylene alcohol S17d can be converted to the nitriie S17c by a four step sequence (oxidation with KMn ⁇ 4 to the acid, conversion to the acid chloride with SOCl 2 , arnidation with NH3, and dehydration with P 2 O 5 )
• the methylene alcohol Sl 7d is oxidized to the acid and converted to the methyl ester S17e. Conversion to to S18 is accomplished as described previously.
• nitrife S2 is reacted with an electrophiie and appropriate base to provide S17c (with R 3 substitution) which may be converted to S18 as described previously.
• nitrile S2 is brominated with NBS/CCI 4 to provide S19 which is then converted to S20a by treatment with HCI-EtOH.
• Subsequent reaction with an alcohol ROH and diamine SS provides S21.
• S19 is treated with the sodium salt of an appropriate alcohol, NaOR, and an alcohol ROH to provide S20b, which is then converted to S21 (by treatment with HCI and diamine S5).
• nitrile S1 treated with 2,3- dibromopropionamide (optionally substituted with R 3 ) and K 2 CO 3 to provide the carboxamide S22.
• Compound S22 is then dehydrated with triffuoroacetic anhydride and pyridine to give nitrile S23, which is further elaborated as previously described.
• Scheme 8 shows an approach in which the imidate S12 is condensed with diamine S25a (optionally substituted), aminoalcohof S25b (optionally substituted), or aminothtol S2Sc (optionally substituted) to give the corresponding imidazoline S24a, oxazotine S24b, or thiazotine S24c.
• an appropriately protected (PG - Me, MOM or the like) and substituted 2-methoxyphenoi (S26a), 2-methoxythiophenol (S26b) or 2-methoxyaniline (S2 ⁇ c) is alkylated with ally! bromide or homoaliy! bromide to provide S27 which is oxidized with mCPBA (or other related oxidant).
• Treatment of resulting epoxide S28 with HBr causes concomitant epoxide opening and phenol deprotection.
• R PG to R - H.
• R 1 OH
• R 1 a displacement occurs through activation of the benzylic alcohol (Mitsunobu or other related conditions).
• R OBn
• CN CN
• a subsequent metathesis reaction affects cyctization to S38.
• the nitrile or ester in S38 is then further elaborated into S39 as previously described.
• the double bond in S38 or S39 is optionally reduced to a single bond (by hydrogenation or other method).
• the vinyl phenol S36 is sequentially alkylated with BrCH 2 CO 2 Et and then an aiiyl bromide (optionally substituted).
• the resulting diene S40b undergoes a metathesis reaction to affect cyclization to S41 (wherein R 3 substitutents are independently defined as described in Formula I). Further elaboration of the ester occurs as previously described.
• the double bond in S41 or S42 is optionally reduced to a single bond (by hydrogenation or other method).
• a substituted alkene S43 undergoes a dihydroyxlation reaction (with OsO 4 ) or asymmetric dihydroxyiatton (AD) to provide S44a, which is then mono-protected with an appropriate protecting group (PG).
• PG protecting group
• S42 and S47 can be prepared by the general methods outlined above. Exemplary compounds were prepared as described in the examples below or from starting materials known in the art. These examples are being provided to further illustrate the present invention. They are for illustrative purposes only; the scope of the invention is not to be considered limited in any way thereby. PREPARATIVE EXAMPLE 1
• the mixture was concentrated, treated with 2N NH 3 -MeOH, concentrated and then subjected to chromatography (0- 4% of (7N NH 3 -MeOH) in DCM) to provide the title compound ( ⁇ )-1 (0.39 g, 66%, LCMS m/z 283, MH+) and a mixture of ( ⁇ M and ( ⁇ M F (0.9 g, 20%, 1 :2 ratio of ( ⁇ M and ( ⁇ )-1F (LCMS m/z 283, MH+)). The mixture is further purified to provide pure ( ⁇ )- 1F.
• racemic compounds ( ⁇ H and ( ⁇ )-1F, or their precursors, are resolved to pure enantiomers by HPLC separation on an appropriate chirai column, such as a Chiracei OD, Chtralpak AD, Lux CeHulose-2 or other related cellulose or amylase derivatized column, using the appropriate solvent system (such as IPA-hexane, EtOH- hexane, or MeOH-supercritical CO 2 ) and optional additive (such as 0.1% Et 2 NH or TEA).
• solvent system such as IPA-hexane, EtOH- hexane, or MeOH-supercritical CO 2
• optional additive such as 0.1% Et 2 NH or TEA
• Step i A mixture of 4-br ⁇ mocatechol 2A (5.00 g, 26.4 mmoi), 2-chforoacry!onitrile (3.0 mL, 26.4 mmoi), and K 2 CO 3 (3.66 g, 26.4 mmol) in acetone (50 mL) was refluxed overnight. The reaction was concentrated, diluted with water, and extracted with DCM (3x). The organic layer was washed with brine and concentrated. Chromatography (10-20% EtOAc/hex) provided 2B with a trace amount of 2C. Step 2
• compound 2B was coupled pyrimidine-5-boronic acid as described in Step 3 to provide 2E (LCMS m/z 240, MH+).
• Compound 2E is then converted to ( ⁇ )-2 with NaOMe and ethylenediamine (as described in Step 2) or with HCf gas/MeOH and ethyienediamine (as described in J. Med. Chem. 1983, 26, 823 or 1 Med. Chem. 2008, 57, 4289).
• a solution of compound 18 in dioxane (0.3M) in a microwave vial is treated with 2-tributyistannylpyrazine (2 eq), ⁇ PPh 3 ) 4 Pd (0.2 eq) and KF (3 eq).
• the reaction mixture is heated in an oil bath at 100 0 C overnight.
• the mixture is basified with 10% NaOH and diluted with DCM.
• the aqueous layer is extracted with DCM in three portions.
• the combined organic phase is dried over anhydrous sodium sulfate and concentrated to dryness to provide 3A, which is further elaborated to ( ⁇ )-3 as previously described.
• Efficacy agonist activity values (Emax, GTP ⁇ S assay) for ⁇ 2A and ⁇ 2C were determined by following the general procedure detailed by Urnland ⁇ t. at ("Receptor reserve analysis of the human c ⁇ -adrenoceptor using [ 3S S]GTP ⁇ S and cAMP functional assays" European Journal of Pharmacology 2001 , 411 , 211-221).
• a compound is defined to be a specific or at least functionally selective agonist of the ⁇ 2C receptor subtype if the compound's efficacy at the ⁇ 2C receptor is ⁇ 30% Emax (GTP ⁇ S assay) and its efficacy at the ⁇ 2A receptor is ⁇ 35% Emax (GTP ⁇ S assay).
• a compound is defined to be an antagonist of the ⁇ 2C receptor subtype if the compound's efficacy at the ⁇ 2C receptor is ⁇ 30% Emax (GTP ⁇ S assay) and the Ki at the ⁇ 2C receptor subtype is ⁇ 500 nM, preferentially ⁇ 200 nM, and most preferentially

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