Classifications

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  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/10—Spiro-condensed systems
  • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
  • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
  • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
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  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/404—Indoles, e.g. pindolol
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  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/404—Indoles, e.g. pindolol
  • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
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  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• • A—HUMAN NECESSITIES
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  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
  • A61K31/428—Thiazoles condensed with carbocyclic rings
• • A—HUMAN NECESSITIES
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  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
• • A—HUMAN NECESSITIES
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  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
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  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • 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
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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
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
  • C07D491/20—Spiro-condensed systems
• • C—CHEMISTRY; METALLURGY
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

• the present invention relates to pharmacologically active spirochromane compounds, or pharmaceutically acceptable salts, biologically active metabolites, pro-drugs, racemates, enantiomers, diastereomers, solvates and hydrates thereof, as well as to pharmaceutical compositions containing them and to their use as modulators of a7 nicotinic acetylcholine receptor activity in a mammalian subject.
• Acetylcholine exerts its functions as a neurotransmitter in the mammalian central nervous system (CNS) by binding to cholinergic receptors.
• the mammalian CNS contains two predominant types of ACh receptors: muscarinic (mAChR) and nicotinic (nAChR) receptors, based on the agonist activities of muscarine and nicotine, respectively.
• Nicotinic acetylcholine receptors are ligand-gated ion channels made up of five subunits (Purves et al. Neuroscience 4th ed. (2008) 122-126).
• the subunits of the nicotinic receptors belong to a multigene family and have been divided into two groups based on their amino acid sequences; one containing alpha, and another containing beta subunits. Pentameric assemblies of different subunit combinations result in large number of receptor subtypes with various pharmacological properties. Assembly of the most broadly expressed subtypes include muscle-type ((a1)2.bide), ganglion-type ((a3)2(b4)3) and CNS-type (a4)2(b2)3 or (a7)s) nAChR subtypes (Le Novere N et al . Journal of Molecular Evolution 40 (1995) 155-172). a7 subunits have been shown to form functional receptors when expressed alone, and thus are presumed to form homoo!igomerie pentameric receptors.
• Activation of the nACh ion channel is primarily controlled by binding of ligands at conventional agonist binding sites, but is also regulated by either negative, or positive allosteric modulators (NAMs and PAMs).
• the allosteric transition state model of the nAChR involves at least a resting state, an activated state and a "desensitized” closed channel state, a process by which receptors become insensitive to the agonist.
• Different nAChR ligands can stabilize the 1 conformational state of a receptor, to which they preferentially bind.
• the agonists ACh and (-)-nicotine respectively stabilize the active and desensitized states.
• nicotinic receptors Changes of the activity of nicotinic receptors have been implicated in a number of diseases. Reductions in nicotinic receptors have been hypothesized to mediate cognitive deficits seen in diseases, such as Alzheimer's disease and schizophrenia. The effects of nicotine from tobacco are also mediated by nicotinic receptors, and since the effect of nicotine is to stabilize receptors in a desensitized state, an increased activity of nicotinic receptors may reduce the desire to smoke.
• nicotinic receptor agonists which act at the same site as ACh
• ACh not only activates, but also blocks receptor activity through processes, which include desensitization and uncompetitive blockade.
• prolonged activation appears to induce a long-lasting inactivation. Therefore, agonists of ACh can be expected to lose effectiveness upon chronic administration.
• nAChR While the a? nAChR is characterized by its fast activation kinetics and high permeability to Ca 2 ⁇ compared to other subtypes (Delbono et al . J. Pharmacol Exp. Ther. 280 (1997) 428-438), it also exhibits rapid desensitization following exposure to agonists at the orthosteric site (Castro et al. Neurosci. Lett. 164 (1993) 137-140; Couturier et al. Neuron 5 (1990) 847-856).
• the compounds of the present invention may be useful for the treatment of diseases and conditions mediated by, or associated to the positive allosteric modulation of the al nAChR, including, but not limited to psychotic disorders, for example schizophrenia (Deutsch SI et al. Schizophr Res 148 (2013) 138-144), schizophreniform disorder (Rowe AR et al. J Psychopharmacol 29 (2015) 197-211), schizoaffective disorder (Martin LF et al. Am J Med Genet B Neuropsychiatr Genet 144B (2007) 611-614), delusional disorder (Carson R et al.
• Cognitive impairment including, for example the treatment of impairment of cognitive functions, as well as cognitive impairment as a result of stroke, Alzheimer's disease (Lewis AS et al. Prog Neuropsychopharmacol Biol Psychiatry 75 (2017) 45-53), Huntington's disease (Foucault-Fruchard L et al Neural Regen Res 13 (2016) 737-741), Pick disease (Feher A et al. Dement Geriatr Cogn Disord 28 (2009) 56-62), HIV associated dementia (Capo- Velez CM et al.
• depression and Anxiety 16 (2002) 89-92 substance-induced mood disorder and mood disorder not otherwise specified, anxiety ' disorders (Picciotto MR et al. Neuropharmacology 96 (2015) 235-243), panic disorder and panic attacks (Zvolensky MJ et al. Clin Psychol Rev 25 (2005) 761-789), obsessive compulsive disorder (Tizabi Y et al. Biol Psychiatry 51 (2002) 164-171), posttraumatic stress disorder (Sun R et al. Neuroscience 344 (2017) 243-254), acute stress disorder (Mineur YS et al.
• narcolepsy such as narcolepsy (Krahn et al j Clin Sleep Med 5 (2009) 390), dyssomnias, primary hypersomnia, breathing-related sleep disorders, circadian rhythm sleep disorder, and dyssomnia not otherwise specified; parasomnias, sleep terror disorder, sleepwalking disorder, and parasomnia not otherwise specified, sleep disorders related to another mental disorder (including insomnia related to another mental disorder and hypersomnia related to another mental disorder), sleep disorder due to a general medical condition and substance-induced sleep disorder; metabolic and eating disorders (Somm E Arch Immunol Ther Exp 62 (2014) 62: 87-101), such as anorexia nervosa (Cuesto G et al.
• Autism spectrum disorders Autism spectrum disorders (Deutsch et at. Clin New opharmacol 33 (2010) 114-120), including autistic disorder, Asperger's disorder, Rett's disorder, childhood disintegrative disorder and pervasive developmental disorder not otherwise specified; attention deficit hyperactivity disorder (Wiiens TE and Decker MW Biochern Pharmacol 74 (2007) 1212-1223), disruptive behaviour disorders, oppositional defiant disorder and disruptive behaviour disorder not otherwise specified; and tic disorders such as Tourette's disorder (Gotti C and dementi F Prog Neurobiol 74 (2004) 363-396), personality disorders (Kamens HM et al .
• sexual dysfunctions such as sexual desire disorders, sexual arousal disorders, orgasmic disorders, sexual pain disorder, sexual dysfunction not otherwise specified, paraphilias, gender identity disorders, infertility (Bray C et ai. Biol Reprod 73 (2005) 807-814), premenstrual syndrome (Gundisch D and Eibl C Expert Opin Ther Pal 21 (2011) 1867-1896), and sexual disorders not otherwise specified, disorders of the respiratory system like cough (Canning BJ Am J Respir Crit Care Med 195 (2017) A4498), asthma (Santana I PR et al. Eur Respir J 48 (2016) PA5066), chronic obstructive pulmonary disease (Maouehe K et al.
• the compounds of the invention are also useful in treating inflammation, inflammatory and neuropathic pain (Alsharari SD et al. Biochem Pharmacol 86 (2013) 1201-1207), rheumatoid arthritis (van Maanen MA et al. Arthritis & Rheumatism 60 (2009) 1272-1281), osteoarthritis (Lee SE Neurosci Lett 548 (2013) 291-295), allergy (Yamamoto T et al.
• sarcoidosis Nicotine Treatment for Pulmonary Sarcoidosis: A Clinical Trial Pilot Study Elliott Grouser MD, Principal Investigator, Ohio State University ClinicalTrials.gov Identifier: NCT02265874
• psoriasis Westman M et al. Scand J Immunol 70 (2009) 136-140
• ataxia Taslim N et al. Behav Brain Res 217 (2011) 282-292
• dystonia Zimmerman CN et al.
• these compounds can also be combined with other therapeutic agents including, but not limited to acetylcholinesterase inhibitors (such as galantamine, rivastigrnine, donepezil, tacrine, phenserine, ladostigil and ABT-089); NMD A receptor agonists or antagonists (such as memantine, neramexane, EVTlOl and AZD4282); anti-anryloid antibodies including anti-amyloid humanized monoclonal antibodies (such as bapineuzumab, ACCOOl, CAD 106, AZD3102, H12A11V1); beta- (such as verubecestat, and AZD3293) or gamma-secretase inhibitors (such as LY450139 and TAK 070) or modulators; tau phosphorylation inhibitors; ApoE4 conformation modulators; p25/CDK5 inhibitors; NK1/NK3 receptor antagonists; COX-2 inhibitors (such as celecoxib,
• PPAR gamma agonists such as pioglitazone and rosiglitazone
• CB-l receptor antagonists or inverse agonists such as AVE1625
• CB-2 agonists such as 842166 and SAB3708
• VR-l antagonists such as AMG517, 705498, 782443, PAC20030, VI 14380 and A425619
• bradykinin B1 receptor antagonists such as SSR240612 and NVPSAA164
• sodium channel blockers and antagonists such as VX409 and SPI860
• NOS inhibitors such as SD6010 and 274150
• antibiotics growth hormone secretagogues
• growth hormone secretagogues such as ibutamoren, ibutamoren mesylate, and capromorelin
• potassium channel openers such as AMPA agonists or AMPA modulators (such as CX- 717, LY 451395, LY404187 and S- 18986): GSK3 inhibitors
• 5-HTe antagonists such as GSK 742467, SGS-518, FK-962, SL-65.0155, SRA- 333 and xaliproden); histamine Eh receptor antagonists and inverse agonists (such as S38093, ABT-834, ABT 829, GSK 189254 and CEP16795); PDE 4 inhibitors (such as HT0712); PDEv inhibitors (such as B 140936), PDEio inhibitors; HD AC inhibitors; KCNQ antagonists; GAB A A inverse agonists; GABA signalling enhancers; GABA agonists, GABAA receptor alphaS subunit NAMs or PAMs, antipsychotics; MAO-B inhibitors; dopamine transport inhibitors; noradrenaline transport inhibitors; E >2 agonists and partial agonists; anticholinergics (such as biperiden); COMT inhibitors (such as entacapone); A2a adenosine receptor antagonists, cholinergic agonists
• Known positive allosteric modulators of the a7 nicotinic acetylcholine receptor include 2-aniline-4-aryl thiazole derivatives (WO 2007/031440 A2, JANSSEN PHARMACEUTIC A NV), amide derivatives (WO 2009/100294 A2, ABBOT LAB.), trisubstituted 1,2,4-triazoles (WO 2009/115547 Al , JANSSEN PHARMACEUTIC A NV), indole derivatives (WO 2009/127678 Al, GLAXO GROUP LTD.
• the present invention is directed to a novel class of compounds that exhibit positive allosteric modulation of the a 7 nicotinic acetylcholine receptor.
• Figure 1 illustrates the results of place recognition test of compound Example 1. Exploration times spent in the novel [N] vs. familiar [O] arms of the Y maze are depicted). Scop: scopolamine
• Figure 2 illustrates the results of place recognition test of compound Example 6 Exploration times spent in the novel [N] vs. familiar [O] arms of the Y maze are depicted). Scop: scopolamine (1 mg/kg, ⁇ r ). ⁇ p ⁇ 0.05; r 0.01. ++ r ⁇ 0.001.
• Figure 3 illustrates the results of place recognition test of compound Example 7. Exploration times spent in the novel [N] vs. familiar [O] arms of the Y maze are depicted). Scop: scopolamine .
• Figure 4 illustrates the results of place recognition test of compound Example 26. Exploration times spent in the novel [N] vs. familiar [O] arms of the Y maze are depicted). Scop: scopolamine (1 mg/kg, ip.). ⁇ p ⁇ 0.05; +i p ⁇ O.01; ++ t p ⁇ 0.001.
• Figure 5 illustrates the results of place recognition test of compound Example 41. Exploration times spent in the novel [N] vs. familiar [O] arms of the Y maze are depicted). Scop: scopolamine (1 mg/kg, ip.). p ⁇ 0.05; + ⁇ p ⁇ 0.01; ++ ⁇ p ⁇ 0.00l .
• Figure 6 illustrates the results of place recognition test of compound Example 43. Exploration times spent in the novel [N] vs. familiar [O] arms of the Y maze are depicted). Scop: scopolamine (1 mg/kg, ip.). ⁇ p ⁇ 0.05; + ⁇ p ⁇ 0.01; ++ ⁇ p ⁇ 0.001.
• Figure 7 illustrates the results of place recognition test of compound Example 52. Exploration times spent in the novel [N] vs. familiar [O] arms of the Y maze are depicted). Scop: scopolamine (1 g/kg, ip.). ⁇ p ⁇ () Q5; + ⁇ p ⁇ 0.01 ; ++ ⁇ p ⁇ 0.00l .
• Figure 8 illustrates the results of place recognition test of compound Example 61. Exploration times spent in the novel [N] vs. familiar [O] arms of the Y maze are depicted). Scop: scopolamine (1 mg/kg, ip.). ⁇ p ⁇ 0 Q5; + ⁇ p ⁇ 0.01 ; ++ ⁇ p ⁇ 0.001.
• the present invention relates to compounds of formula (I),
• A is a five or six membered heterocycle
• R is a six membered carbocycle or heterocycle
• X is C or N
• Y is C or N
• Z is C or N
• W is O or S
• R 1 is H, Ci-ealkyl, halogen or haloCi-ealkyl
• R 2 is H or O
• R 3 is H, Ci-ealkyl, halogen, haloCi-ealkyl or Ci-ealkoxy;
• R 4 is H or Ci-ealkyl
• R 5 is H or Ci-6aikyi
• n and m are independently 1 or 2;
• —— is a single - or double-bond, or pharmaceutically acceptable salts, biologically active metabolites, pro-drugs, racemates, enantiomers, diastereomers, solvates and hydrates thereof.
• V is C or S
• Z is C or N
• W is O or S
• R la is H, Ci-ealkyl, or haloCi-ealkyl
• R n> is H, Ci-ealkyl, halogen, or haloCi-ealkyl
• R lc is H, Ci-ealkyl, halogen, or haloCi-e.alkyl when V is C, or R lc is absent when V is S;
• R 2 is H or O
• R 3 is H, Ci-ealkyl, halogen, haloCi-ealkyl, or Ci-e.alkoxy;
• n and m independently 1 or 2;
• —— is a single - or double-bond
• the present invention provides a compound of formula (I) or formula (II), as defined above for use in the treatment or prevention of a disease associated with a7 nicotinic acetylcholine receptor activity.
• the present invention provides the use of a compound of formula (I) or formula (II), as defined above, for the manufacture of a medicament for the treatment or prevention of a disease associated with a? nicotinic acetylcholine receptor activity.
• the present invention provides a method for the treatment or prevention of a disease associated with l nicotinic acetylcholine receptor activity comprising administering to a mammal in need of such treatment or prevention an effective amount of at least one compound of formula (I) or formula (II), as defined above.
• the compounds of formula (I) or formula (II), as defined above can be administered in combination with other compounds used for the treatment or prevention of a disease associated with cx7 nicotinic acetylcholine receptor activity.
• the present invention provides a process for the manufacture of the compounds of formula (II).
• the present invention relates to compounds of formula (I),
• A is a five or six membered heterocycle
• B is a six membered carbocycle or heterocycle
• X is C or N
• Y is C or N
• Z is C or N; W is O or S;
• R 1 is H, Ci-ealkyl, halogen or haloCi-ealkyl,
• R 2 is H or O
• R 3 is H, Ci ⁇ alkyl, halogen, haloCi-6alkyl or Ci-ealkoxy;
• R 4 is H or Ci-ealkyl
• R 5 is H or Ci-ealkyl
• n and rn are independently 1 or 2;
• five membered heterocycle refers to to an optionally substituted saturated, unsaturated or aromatic ring system having five atoms and incorporating one, two, three or four heteroatoms (chosen from nitrogen, oxygen or sulfur).
• five membered heterocyclyc moieties include, but are not limited to, pyrrolydinyl, pyrrolyl, tetrahydrofuryl, dihydrofuryl, fury!, tetrahydrothiophenyl, thiophenyl, imidazolidiny!, imidazolyi, pyrazolidinyl, pyrazolyl, oxazolidinyl, isoxazolidinyl, oxazolyl, isoxazolyl, thiazolidinyl, isothiazolidinyl, thiazolyl, isothiazolyl, dioxolanyl, dithiolanyl, triazolyl, oxadiazolyl,
• six membered heterocycle refers to an optionally substituted saturated, unsaturated or aromatic ring system having six atoms and incorporating one, two, three or four heteroatoms (chosen from nitrogen, oxygen or sulfur).
• six membered heterocycles include, but are not limited to, piperidinyl, pyridinyl, pyridazinyl, pyrimidinyl, dihydropyranyl, tetrahdydropyranyl, pyranyl, thiopyranyl, piperazinyl, homopiperazinyl, morpholinyl, thiomorpholinyl.
• ix membered carbocycle refers to an optionally substituted saturated, unsaturated or aromatic ring system having six carbon atoms including, cyclohexyl, cyclohexenyl, cyclohexadieny!, and phenyl.
• halo or“halogen”, as used herein as such or as part of another group, refers to fluoro, chloro, bromo or iodo.
• Ci-ealkyl refers to a branched or straight chain saturated hydrocarbon group having one, two, three, four, five or six carbon atoms including, but not limited to, methyl, ethyl, «-propyl, /-propyl, «-butyl, sec-butyl, and /er/-butyi.
• haioCi-ealkyl refers to at least one halogen, as defined above, bonded to the parent molecular moiety through an“Ci-ealkyl” group, as defined above.
• the halogens can be identical or different and the halogens can be attached to different carbon atoms or several halogens can be attached to the same carbon atom
• HaloCi-ealkyl groups include, but are not limited to, difluoromethyl, trifluorom ethyl and 2- chloroethyl.
• Ci-ealkoxy refers to an“Ci-ealkyl” group, as defined above, bonded to the parent molecular moiety through an oxygen atom including, but not limited to, methoxy, ethoxy, «-propoxy, /-propoxy and tert- butoxy.
• pharmaceutically acceptable describes an ingredient that is useful in preparing a pharmaceutical composition, is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes those acceptable for veterinary use as well as human pharmaceutical use.
• pharmaceutically acceptable salt refers a conventional acid addition salt or a base addition salt, which preserves the biological efficacy and properties of the compounds of formula (I) or formula (II) and which can be formed with suitable non-toxic organic or inorganic acids or organic or inorganic bases.
• acid addition salts include salts derived from inorganic acids, such as, but not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulphamic acid, phosphoric acid, nitric acid and perchloric acid and derived from various organic acids, such as, but not limited to, acetic acid, propionic acid, benzoic acid, glycolic acid, phenyl acetic acid, salicylic acid, maionic acid, maleic acid, oleic acid, pamoic acid, palmitic acid, benzenesulfonic acid, toiuenesuifomc acid, methanesuifonic acid, oxalic acid, tartaric acid, succinic acid, citric acid, malic acid, lactic acid, glutamic acid, fumaric acid and the like.
• inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulphamic
• Examples of base addition salts are salts derived from ammonium-, potassium-, sodium- and quaternary' ammonium hydroxides such as tetramethylammonium hydroxide.
• the term“pro-drug” refers to derivatives of compounds of formula (I) or formula (II) according to the invention which themselves have no therapeutic effect but containing such groups which, after in vivo chemical or metabolic degradation (biotransformation) become a “biologically active metabolite” which is responsible for the therapeutic effect.
• decomposing groups associated with the compounds of formula (I) or formula (II) of the present invention are known in the art and may also be applied for the compounds of the present invention (Rautio et ah, Nature Reviews - Drug Discovery 2008, 7:255-270).
• hydrate means non-covalent combinations between water and solute.
• solvate means non-covalent combinations between solvent and solute.
• Solvents include, but are not limited to, ethanol, 2-propanol, acetonitrile and tetrahydrofuran.
• Treating" or “treatment” of a disease state includes: a) preventing the disease state, i.e. causing the clinical symptoms of the disease state not to develop in a subject that may be exposed to or predisposed to the disease state, but does not yet experience or display symptoms of the disease state, b) inhibiting the disease state, i.e., arresting the development of the disease state or its clinical symptoms, or c) relieving the disease state, i.e., causing temporary or permanent regression of the disease state or its clinical symptoms.
• the present invention relates to compounds of formula (I), wherein A is five membered heterocycle, wherein the members of the ring are selected from the group consisting of carbon, nitrogen, oxygen, and sulphur;
• B is a six membered carbocycle or a heterocycle, wherein the members of the ring are selected from the group consisting of carbon, nitrogen, oxygen, and sulphur;
• X is C
• Y is C
• Z is C or N
• W is O or S
• R* is H, Ci-ealkyl, halogen or haloCi-ealkyl
• R 2 is H or O
• R 3 is H, Ci-ealkyl, halogen, haloCi-ealkyl or Ci-ealkoxy;
• R 4 is H; n a d in are independently 1 or 2;
• the present invention relates to compounds of formula (II),
• V is C or S
• Z is C or N
• W is O or S
• R la is H, Ci-e.alkyl, or haloCi-ealkyl
• R > is H, Ci-6alkyl, halogen, or haloCi-ealkyl
• R 5c is H, Ci-ealkyl, halogen, or haloCi-ealkyl when V is C; or R lc is absent when V is S;
• R 2 is H or O
• R 3 is H, Ci-ealkyl, halogen, haloCi-6 alkyl, or Ci-ealkoxy;
• n and m are independently 1 or 2;
• —— is a single - or double-bond
• the present invention relates to compounds of formula (II), wherein V is C or S;
• Z is C or N
• W is O or S
• R la is H, Ci-4alkyl, or haloCi-safkyf;
• R lb is H, C - 4 alkyl, halogen, or haloCi-ralkyl
• R lc is H, Ci- 4 alkyl, halogen, or haloCi-ialkyl when V is C; or R lc is absent when V is S;
• R 2 is H;
• R 3 is H, Ci- 4 alkyl, halogen, haloCi- 4 alkyl, or Ci-4alkoxy;
• n and rn are independently 1 or 2;
• the present invention relates to compounds of formula (II), wherein
• V is C or S
• Z is C or N
• W is O or S
• R la is H, Ciualkyl, or haloCiuaikyl
• R ! l> is H, Ci-ralkyl, halogen, or haloCi-ralkyl
• R ic is H, Ci-4alkyl, halogen, or haioCiualkyl when V is C; or R lc is absent when V is S;
• R 2 is H
• R 3 is H, Ciuaikyl, halogen, haloCiuaikyl, or Ci-ralkoxy;
• n 3 ⁇ 4md m are 1 ;
• the present invention relates to compounds of formula (II), wherein
• V is C or S
• Z is C or N
• R ia is H, Chalky!, or haloCi ⁇ alkyl
• R 5b is H, Cwiaikyl, halogen, or haloCi-4alkyl
• R lc is H, Ci- 4 alkyl, halogen, or haloCi ⁇ a!ky! when V is C; or R ic is absent when V is S;
• R 2 is H
• R 3 is H, Ci-4alkyl, halogen, haloCi-4alkyl, or Ci-4alkoxy;
• n and m are 2; - is a single bond when it is attached to R 2 , and a single - or double bond within the ring; or pharmaceutically acceptable salts, biologically active metabolites, pro-drugs, racemates, enantiomers, diastereomers, solvates and hydrates thereof.
• the present invention relates to compounds of formula (II), wherein V is C or S;
• Z is C or N
• R ia is H, Ci-aa!ky!, or haloCi- 4 alkyl
• R lb is H, Ci- 4 alkyl, halogen, or haloCi-ialkyl
• R lc is H, Ci- 4 alkyl, halogen, or haloCi-aalkyl when V is C; or R lc is absent when V is S;
• R 2 is H
• R 3 is H, Ci- 4 alkyl, halogen, haloCi- 4 alkyl, or Ci- 4 alkoxy;
• n 1;
• n 2;
• the present invention relates to compounds of formula (II), wherein V i s C or S;
• Z is C or N
• W is O or S
• R la is H, Ci- 4 alkyl, or haloCi- 4 alkyl
• R ib is H, Ci- 4 alkyl, halogen, or haloCi-aa!ky!;
• R 5c is H, Cwiaikyi, halogen, or haloCi- 4 alkyl when V is C; or R lc is absent when V is S;
• R 2 is O
• R 3 is H, Ci- 4 alkyl, halogen, haloCi- 4 alkyl, or Ci- 4 alkoxy;
• n and m are independently 1 or 2; - is a double bond when it is attached to R 2 , and a single bond within the ring; or pharmaceutically acceptable salts, biologically active metabolites, pro-drugs, racemates, enantiomers, diastereomers, solvates and hydrates thereof.
• the present invention relates to compounds of formula (II), wherein
• V is C or S
• Z is C or N
• R ia is H, Ci-aa!ky!, or haloCi- 4 alkyl
• R lb is H, Ci- 4 alkyl, halogen, or haloCi-ialkyl
• R lc is H, Ci- 4 alkyl, halogen, or haloCi-aa!ky! when V is C; or R lc is absent when V is S;
• R 2 is O
• R 3 is H, Ci- 4 alkyl, halogen, haloCi- 4 alkyl, or Ci- 4 alkoxy;
• n and rn are 1;
• the present invention relates to compounds of formula (II), wherein
• V is C or S
• Z is C or N
• W is O or S
• R la is H, Ci- 4 alkyl, or haloCi- 4 aIkyl
• R lb is H, Ci-4alkyl, halogen, or haloCi- 4 alkyl
• R ic is H, C - 4 alkyl, halogen, or haloCi- 4 alkyl when V is C; or R lc is absent when V is S;
• R 2 is O
• R 3 is H, Ci- 4 aikyi, halogen, haloCi- 4 aikyi, or Ci- 4 alkoxy;
• n 3 ⁇ 4md m are 2;
• the present invention relates to compounds of formula (II), wherein
• V is C or S
• Z is C or N
• R la is H, Cuialkyl, or haloCi- 4 alkyl
• R 5b is H, Ci-4alkyl, halogen, or haloCi-ialkyl
• R le is H, Cwalkyl, halogen, or haloCi- 4 alkyl when V is C; or R ic is absent when V is S;
• R 2 is O
• R 3 is H, Ci- 4 alkyl, halogen, haloCi- 4 alkyl, or Ci- 4 alkoxy;
• n 1;
• n 2;
• ----- is a double bond when it is attached to R 2 , and a single bond within the ring;
• the present invention relates to compounds of formula (II), wherein
• V is C
• Z is C or N
• W is O
• R ia is H, Ci-e.alkyl, or haloCi-ealkyl,
• R lb is H, Ci-ealkyl, halogen, or haloCi-ealkyl
• R 5c is H, Ci-ealkyl, halogen, or haloCi-ealkyi;
• R 2 is H or O
• R 3 is H, Ci-ealkyl, halogen, or haloCi-ealkyi,
• a d m are independently I or 2;
• the present invention relates to compounds of formula (II), wherein V is C;
• Z is C or N
• W is O
• R la is H, Ci- 4 alkyl, or haloCiualkyl
• R lb is H, Ci-4alkyl, halogen, or haloCi- 4 alkyl
• R lc is H, C - 4 alkyl, halogen, or haloCi- 4 alkyl
• R 2 is H or O
• R 3 is H, Ci-4aikyi, halogen, or haloCi- 4 alkyl
• n and m are independently 1 or 2;
• the present invention relates to compounds of formula (II), wherein
• V is C
• Z is C or N
• R ia is H, Ci- 4 alkyl, or haloCi- 4 alkyl
• R lb is H, Ci- 4 alkyl, halogen, or haloCi-ralkyl
• R lc is H, Ci- 4 alkyl, halogen, or haloCi- 4 alkyl
• R 2 is O
• R 3 is H, Ci- 4 alkyl, halogen, haloCi- 4 alkyl, or Ci-4alkoxy;
• n and m are 1;
• the present invention relates to compounds of formula (II), wherein
• V is C
• Z is C or N
• W is O or S;
• R la is H, Ci-4alkyl, or haloCi- 4 alkyl;
• R n> is H, Ci-4alkyl, halogen, or haloCwialkyl
• R lc is H, Ci-4alkyl, halogen, or haloCi-4alkyl
• R 2 is O
• R 3 is H, Ci-4alkyl, halogen, haloCi-4alkyl, or Ci-4alkoxy;
• n and m are 2;
• —— is a double bond when it is attached to R 2 , and a single bond within the ring;
• the present invention relates to compound s of formula (II), wherein
• Z is C or N
• W is O or S
• R la is H, Ci-ralkyl, or haloCiualkyl
• R lb is H, Ci-4alkyl, halogen, or haloCi-4alkyl
• R lc is H, Ci- 4 alkyl, halogen, or haloCi-ralkyl
• R 2 is O
• R 3 is H, Ci- 4 aikyl, halogen, haloCi- 4 aikyl, or Ci-ralkoxy;
• n 1;
• the present invention relates to compounds of formula (I) or formula (II) selected from the group of:
• the present invention provides a compound of formula (I) or formula (II), as defined above for use in the treatment or prevention of a disease associated with a7 nicotinic acetylcholine receptor activity.
• the present invention provides the use of a compound of formula (I) or formula (II), as defined above, for the manufacture of a medicament for the treatment or prevention of a disease associated with a7 nicotinic acetylcholine receptor activity.
• the present invention provides a method for the treatment or prevention of a disease associated with cx7 nicotinic acetylcholine receptor activity comprising administering to a mammal in need of such treatment or prevention an effective amount of at least one compound of formula (I) or formula (II), as defined above.
• the disease associated with a7 nicotinic acetylcholine receptor activity is selected from the group of psychotic disorders, including, but not limited to, schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, psychotic disorder due to a general medical condition, substance-induced psychotic disorder or psychotic disorder not otherwise specified; cognitive impairment, including, but not limited to, cognitive impairment as a result of stroke, Alzheimer's disease, Huntington's disease.
• psychotic disorders including, but not limited to, schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, psychotic disorder due to a general medical condition, substance-induced psychotic disorder or psychotic disorder not otherwise specified
• cognitive impairment including, but not limited to, cognitive impairment as a result of stroke, Alzheimer's disease, Huntington's disease.
• Pick disease HIV associated dementia, frontotemporal dementia, Lewy body dementia, vascular dementia, cerebrovascular disease or other dementia states and dementia associated to other degenerative disorders, including, but not limited to, amyotrophic lateral sclerosis, other acute or sub-acute conditions that may cause cognitive decline, including, but not limited to, delirium, traumatic brain injury, senile dementia, mild cognitive impairment, Down’s syndrome, depression and cognitive deficit related to other diseases, and dyskinetic disorders including, but not limited to, Parkinson's disease, neuroleptic-induced parkinsonism, or tardive dyskinesias, depression and mood disorders, including, but not limited to, depressive disorders and episodes, bipolar disorders, cyclothymic disorder, and bipolar disorder not otherwise specified, other mood disorders, substance-induced mood disorder and mood disorder not otherwise specified; anxiety disorders, panic disorder and panic attacks, obsessive compulsive disorder, posttraumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety disorder due to a general medical condition, substance-induced anxiety disorder, phobias
• the disease associated with a? nicotinic acetylcholine receptor activity is selected from the group of cognitive impairment, schizophrenia, and autism.
• the invention further relates to combination therapies wherein a compound of the invention or a pharmaceutical composition or formulation comprising a compound of the invention is administered with another therapeutic agent or agents, for the treatment of one or more of the conditions previously indicated.
• therapeutic agents may be selected from: acetylcholinesterase inhibitors, NMDA receptor agonists or antagonists, anti-amyloid antibodies including anti-amyloid humanized monoclonal antibodies, beta- or gamma-secretase inhibitors or modulators, tau phosphorylation inhibitors, ApoE4 conformation modulators, p25/CDK5 inhibitors, NK1/NK3 receptor antagonists, COX-2 inhibitors, LRRK2 inhibitors, HMG-CoA reductase inhibitors, NSAIDs, vitamin E, glycine transport inhibitors, glycine site antagonists, LXR b agonists, androgen receptor modulators, blockers of Ab oligomer formation, NR2B antagonists, anti-inflammatory' compounds, PPAR gamm
• the therapeutic agents are selected from the goup of acetylcholinesterase inhibitors, NMDA receptor antagonists, beta- secretase inhibitors, antipsychotics, GABAA receptor alphaS subunit NAMs or PAMs, histamine H3 receptor antagonists, 5-HTe receptor antagonists, Ml or M4 mAChR agonists or PAMs, mGluR2 antagonists or NAMs or PAMs, and levodopa.
• the present invention provides a process for the manufacture of the compounds of formula (II) according to the following reaction route:
• the reaction mixture is quenched by evaporation of the solvent.
• the product of formula (V) is isolated by extraction with a suitable organic solvent, or by fdtration, after removing the organic solvent, or by column chromatography.
• a suitable solvent e.g., tetrahydrofuran
• a strong base e.g., lithium diisopropyl amide
• the progress of the reaction is followed by thin layer chromatography.
• the reaction mixture is quenched by addition of saturated ammonium chloride solution.
• the product of formula (VII) is isolated by extraction with a suitable organic solvent and by fdtration, after removing the organic solvent.
• dehydrocyciization of the derivatives of formula (VII) is preferably carried out in suitable solvents, in the presence of, e.g., trifluoroacetic anhydride and DBU
• reactions may be further processed in a conventional manner, e.g., by- eliminating the solvent from the residue and further purifying according to methodologies generally known in the art, including, but not limited to, crystallization, extraction, trituration and chromatography.
• the desired deproteeted spirochroman-4-on salts of formula (VI) can be obtained by using different methodologies from the prior art. It is preferably carried out in EtOAc with hydrochloric acid in the range of 0 °C to room temperature. The necessary reaction time is 2-3 hours. The progress of the reaction is followed by thin layer chromatography, and the product is isolated by filtration.
• Reduction of the derivatives of formula (V) is preferably carried out in suitable solvents e.g., ethanol with NaBITs.
• suitable solvents e.g., ethanol with NaBITs.
• the progress of the reaction is followed by TLC.
• the crude spirochroman-4-ol is isolated by eliminating the solvent, then the residue is partitioned between DCM and water, and evaporating the organic phase to obtain the title compound, which is used without purification in the forthcoming step.
• spirochroman-4-ol derivatives of formula (VIII) is accomplished by the well-known reducing method called“ionic hydrogenation”: by the treatment of the hydroxy derivatives with the EtsSiH/CFbCQOH system at 90 °C for 6-18 hours. The progress of the reaction is followed by thin layer chromatography. The reaction mixture is evaporated, the residue is treated with saturated NaHCCh solution, and the product of formula (IX) is isolated by extraction with a suitable organic solvent.
• the compounds of formula (II) above can be prepared by the activation of the appropriate primary amine compounds of formula (X) using standard procedures and reagents, e.g., CD! (I, G-carbonyldiimidazole), chloroformates or I, G-thiocarbonyl diimidazole in suitable solvents, e.g., DCM under argon athmosphere followed by the addition of the reactant (formula (VI) or formula (IX)).
• the reaction is carried out at a temperature in the range of 0 °C to room temperature.
• the necessary reaction time is 15-20 hours.
• the progress of the reactions is followed by thin layer chromatography.
• the work up of the reaction mixture can be carried out by different methods, usually it is quenched by the addition of water.
• the product is isolated by extraction with a suitable organic solvent, and purified by crystallization or column chromatography.
• the present disclosure includes within its scope all the possible isotopically labelled forms of the compounds.
• the compounds of the present invention can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, intraarticular, intrathecal, intraperitoneal, direct intraventricular, intracerebroventicular, intramedullary injection, intraci sternal injection or infusion, subcutaneous injection or implant), ophtalmic, nasal, vaginal, rectal, sublingual and topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations comprising pharmaceutically acceptable excipients suitable for each route of administration.
• parenteral e.g., intramuscular, intraperitoneal, intravenous, intraarticular, intrathecal, intraperitoneal, direct intraventricular, intracerebroventicular, intramedullary injection, intraci sternal injection or infusion, subcutaneous injection or implant
• ophtalmic nasal, vaginal, rectal, sublingual and topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations comprising pharmaceutically acceptable excipient
• compositions of the present invention usually contain 0.01 to 500 mg of the active ingredient in a single dosage unit. However, it is possible that the amount of the active ingredient in some compositions exceeds the upper or lower limits defined above.
• the compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
• This dosage level and regimen can be adjusted to provide the optimal therapeutic response. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition and the host undergoing therapy.
• compositions of the present invention may be formulated as different pharmaceutical dosage forms, including, but not limited to, solid oral dosage forms like tablets (e.g., buccal, sublingual, effervescents, chewable, orodispersible, freeze dried), capsules, lozenges, pastilles, pills, orodispersible films, granules, powders; liquid oral dosage forms, including, but not limited to, solutions, emulsions, suspensions, syrups, elixirs, oral drops; parenteral dosage forms, including, but not limited to, intravenous injections, intramuscular injections, subcutaneous injections; other dosage forms, including, but not limited to, eye drops, semi-solid eye preparations, nasal drops or sprays, transdermal dosage forms, suppositories, rectal capsules, rectal solutions, emulsions and suspensions, etc.
• solid oral dosage forms like tablets (e.g., buccal, sublingual, effervescents, chewable, orodispersible, freeze dried), capsule
• compositions of the present invention can be manufactured in any conventional manner, e.g., by mixing, dissolving, emulsifying, suspending, entrapping, freeze- drying, extruding, laminating, film-casting, granulating, grinding, encapsulating, dragee making or tabletting processes.
• compositions for use in accordance with the present invention thus can be formulated in any conventional manner using one or more physiologically acceptable excipients. Any of the well-known techniques and excipients may be used as suitable and as understood in the art.
• Suitable excipients for the preparation of the dosage forms may be selected from the following categories, including, but not limited to, tablet and capsule fillers, tablet and capsule binders, release modifying agents, disintegrants, glidants, lubricants, sweetening agents, taste- masking agents, flavoring agents, coating agents, surfactants, antioxidants, buffering agents, complexing agents, emulsifying agents, lyophilization aids, microencapsulating agents, ointment bases, penetration enhancers, solubilizing agents, solvents, suppository bases, and suspending agents.
• the invention relates to the use of specific excipients which are capable of improving the solubility, dissolution, penetration, absorption and/or bioavailability of the active ingredient(s), including, but not limited to, hydrophilic polymers, hot melt extrusion excipients, surfactants, buffering agents, complexing agents, emulsifying agents, iyophilization aids, superdi sintegrants, microencapsulating agents, penetration enhancers, solubilizing agents, co-solvents, and suspending agents.
• specific excipients which are capable of improving the solubility, dissolution, penetration, absorption and/or bioavailability of the active ingredient(s), including, but not limited to, hydrophilic polymers, hot melt extrusion excipients, surfactants, buffering agents, complexing agents, emulsifying agents, iyophilization aids, superdi sintegrants, microencapsulating agents, penetration enhancers, solubilizing agents, co-solvents, and suspending agents.
• the compounds of formula (I) and formula (II) can be prepared in accordance with the general knowledge of one skilled in the art and/or using methods set forth in the Example and/or Intermediate sections that follow. Solvents, temperatures, pressures, and other reaction conditions can readily be selected by one of ordinary skill in the art. Starting materials are commercially available and/or readily prepared by one skilled in the art.
• room temperature denotes a temperature in the range from 20 °C to 25 °C.
• Step 1 fer/-Butyi 6’-cMoro-4 ! -oxo-3',4 , -dihvdiOspiro[azetidine-3,2 l -[11benzopyran]-l- carboxylate
• Step 1 7er/-butyl 4'-oxo-3 , .4 l -dihvdiOSpirol azetidjne-3 2 ! -pyranoi3.2-bjpyridine]-l- carboxyl ate
• Step 2 3 ! 4' ⁇ Dihvdrospiro b jpyridtn) ⁇ 4'-one hydrochloride
• Step 1 tert- Butyl 3- (4-iiuoro-2-hvdiOxyphenyl)-2-oxoethvH-3-hvdroxyazetidine-l-
• Step 2 fer -Butyl 7 ! -fluoro-4'-oxo-3'.4'-dihvdrospiro[azetidme-3.,2 ! -n]benzopyran]-l- carboxylate
• reaction mixture was diluted with ethanol (80 mL), and treated with 49 g (48 mL) of l ,8-diazabicyc!o[5 4.0]undee-7 ⁇ ene.
• the mixture temperature was raised to 50 °C and kept at this temperature for 1 hour.
• the mixture was concentrated in vacuo, and the residue was dissolved in EtOAc (160 mL), and washed with water (2x80 mL), 1 N HC1 (80 mL), 1 M NaHCCL solution (80 mL) and brine (40 mL).
• the organic layer was dried over anhydrous NaiiSOr, filtered and concentrated in vacuo.
• Step 3 7 ! -Fluoro- dihydrospiro[azetidine-3.2 , -[l]benzopyran
• reaction mixture volume was reduced to 15-20 mL in vacuo, and was diluted with diethyl ether (30 mL)
• Step 1 ten- Butyl 4 , -oxo-3'.4’-dlhydrospiroiazetldine-3.2'-ri lbenzopyTanl-l-carboxyiate
• This intermediate was prepared from the appropriate 2 -hydroxy-acetophenone and tert- butyl 3-oxoazetidine-l-carboxylate with pyrrolidine according to the method described for Intermediate 1.
• the compound is commercially available from Sigma Aldrich (catalog no.: 655864).
• the compound is commercially available from Maybridge (catalog no.: CC41413DA).
• the compound is commercially available from Enamine (catalog no.: EN300-209649).
• Step 1 3.3 -Dibromo-2-oxo-2.3 -dihydro- indole-S-earbonitriie
• Step 2 2-Qxo ⁇ 2 3 ⁇ dihydro-l// ⁇ indole ⁇ 5 ⁇ carbomtriie
• Step 1 te/7-Butyl 7V-r(l-methyl- indol-5-yl methvHcarbamate
• Step 3 (3-Chloro-l -methyl- indol-5-yi)methanamine
• Step 1 1 -Methyl- l/T-indole-S-earbonitrile
• Step 2 1 -Methyl -2.3-dioxo-2.3-dihvdro- indole-5-carbonitrile
• Step 3 3.3-Difluoro-l-methyl-2-oxo-2 3-dihvdro-1 /j r -indoie-5-carbonitriie
• Step 4 f3-Fluoro-l -methyl- indol-5-v3 ⁇ 4)methanamine
• Step 1 Pyrrolo[2 3-3 ⁇ 4lpyridine-5-carhonitrile
• Step 3 ⁇ l-Methv3 ⁇ 4-l /-pyrro3 ⁇ 4o[2,3- >]pyridin-5-v3 ⁇ 4 ⁇ methanamine
• the intermediate is prepared as described in WO 2012/042915 Al (RAQUALIA PHARMA INC).
• Step 2 1 -Methyl - Iff-pyrroloF 2 3 -Zripyridine-S-carbonitriie
• Step 3 3-Chloro-l -methyl- lif-pyrrolor2.3- ?lpyridine-5-carbonitrile
• Step 4 13-Chl oro-1 -methyl- lif-pyrrolor2.3- ?lpyridin-5-
• the intermediate is prepared as described in WO 2012/042915 .41 (RAQUALIA PHARMA INC).
• Step 3 3 - 1 ⁇ 1 /-pyrrol o [ 2 3 -A] py ri di n e ⁇ 5 -c arb on itri 1 e
• the intermediate is prepared as described in WO 2012/042915 A1 (RAQUALIA PHARMA INC).
• Step 3 2-Methvi-l //-pyrroiol2.3-/flpyridine-5-carbonitrile
• Step 4 1 2-Dimethyl- li7-pyrrolo[2 3-/2lpyridine-5-carbonitrile
• Step 5 l-3 ⁇ 4 L2-Dimethyl- pyrro3 ⁇ 4o[2,3-61i3yridin-5-yl)methanamine
• Step 1 (5-Bromo-l //-indol- -yj Imethanol
• Step 3 tert- Butyl 5-bromo-2-formyl- 1 //-indole- 1 -carboxylate
• Step 4 fe -Butyl 5-bromo-2-(difluoromethyl -l/ -indole-l-carboxylate
• the compound is commercially available from Enamine (catalog no.: EN300-572Q6).
• Example 5 aThe racemic form of the title compound Example 5 was prepared from Intermediate 26 and Intermediate 3 according to the methods described for Example 1 .
• the two (A and B) enantiomers were separated using chiral preparative HPLC. Their absolute configuration is not determined.
• Active ingredient(s) 0.01 - 90 %
• Active ingredient(s) 0.01 - 90 %
• Active ingredient(s) 0.01 - 50 %
• Buffering agent quantum satis Osmotic agent 0 - 50 %
• Active ingredient(s) 0.01 - 50 %
• Active ingredient(s) 0.01 - 50 % Suppository base 1 - 99.9 % Surface-active agents 0 - 20 % Lubricants 0 - 20 %
• Active ingredient(s) 0.01 - 50 %
• Buffering agent quantum satisfies
• Flp-In 293 cells stably expressing human a7 nAchR and human RIC-3 (a7 cells, generated in house.)
• a.7 cells cells stably expressing human a7 nAchR were cultured in the medium detailed above, and were split twice a week.
• cytosolic Ca 2+ ion concentration ([Ca ⁇ + ]i) ceils were seeded in 96-well microplates at a density of 60000 cells/well and maintained overnight in a tissue culture incubator at 37 °C under an atmosphere of 95 % air/5 % CO2.
• the plating medium was identical with the culture medium. 50 m ⁇ of the growth medium was aspirated with a cell washer (BioTek Elx405UCVWS).
• Scopolamine was dissolved in saline and administered at 1 mg/kg dose i.p. Test compounds were administered 30 minutes before the acquisition trial (Tl) and scopolamine after the acquisition trial at a volume of 0 1 ml/10 g.
• Table 5 shows the reversal of the scopolamine-induced amnesia in the place recognition assay in mice:

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