OA20785A - Thiadiazine derivatives - Google Patents
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Abstract
The invention relates to thiadiazine derivatives, or pharmaceutical 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.
Description
THIADIAZINE DERIVATIVES
FIELD OF THE INVENTION
The présent invention relates to pharmacologicaiiy active thiadiazine compounds, or pharmaceutically acceptable salts, biologically active métabolites, pro-drugs, racemates, enantiomers, diastereomers, solvatés and hydrates thereof, as well as to pharmaceutical compositions containing them and to their use as modulators of a7 nîcotinic acétylcholine receptor activity in a mammalian subject.
BACKGROUND OF THE INVENTION
Acétylcholine (ACh) exerts its fonctions as a neurotransmitter in the mammalian central nervous System (CNS) by binding to cholinergic receptors. The mammalian CNS contains two prédominant types of ACh receptors: muscarinic (mAChR) and nîcotinic (nAChR) receptors, based on the agonist actîvities of muscarine and nicotine, respectîvely. Nîcotinic acétylcholine receptors are ligand-gated ion channels made up of five subunîts (Purves et al. Neuroscience 4th ed. (2008) 122-126). The subunits of the nîcotinic receptors belong to a multîgene family and hâve been divided into two groups based on their amino acid sequences; one containing alpha, and another containing beta subunits. Pentameric assemblîes of different subunit combinations resuit in large number of receptor subtypes with varions pharmacological properties. Assembly of the most broadly expressed subtypes include muscle-type ((α1)2β]δε), ganglion-type ((α3)2(β4)3) and CNS-type (α4)2(β2)3 or (a7)s) nAChR subtypes (Le Novère N et al. Journal of Molecular Evolution 40 (1995) 155-172). al subunits hâve been shown to form functional receptors when expressed alone, and thus are presumed to form homooligomeric pentameric receptors.
Activation of the nAChR ion channel is primarily controlled b y binding of ligands at conventional agonist binding sites, but is also regulated by either négative, 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 confonnational State of a receptor, to which they preferentially bind. For example, the agonists ACh and (-)-nicotine respectively stabilize the active and desensitized States. Changes of the activity of nicotinic receptors hâve been implicated in a number of diseases. Réductions in nîcotinic receptors hâve been hypothesized to médiate cognitive déficits seen in diseases, such as Alzheimer's disease and schizoplirenia. 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 încreased activity of nicotinic receptors may reduce the desire to smoke.
However, treatment with nicotinic receptor agonists, which act at the same site as ACh is problematîc, because ACh not only activâtes, but also blocks receptor activity through processes, which înclude desensitization and un compétitive blockade. Furthermore, prolonged activation appears to induce a long-lasting inactivation. Therefore, agonists of ACh can be expected to lose effectîveness upon chronic administration.
While the a 7 nAChR is characterized by its fast activation kinetics and high permeability to Ca2+ compared to other subtypes (Delbono et al. J. Pharmacol. Exp. Ther. 280 (1997) 428438), it also exhibîts rapîd 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). In spite that development of a variety of «7-selective agonists and partial agonists has been carried out in the recent years, their clinical efficacy proved to be suboptimal, due to this receptor blockade (desensitisation) following the agonist activation. This problem may be overcomed by treatment with PAMs, enhancîng a 7 nAChR activation mediated by the endogenous agonist. The positive modulation of a7 nAChRs has been shown to hâve cognitive benefîts in varions preclînical models (Thomsen et al. Curr Pharm Des 16 (2010) 323-343; Lendvai et al. Brain Res Bull 93 (2013) 86-96).
The compounds of the présent invention may be usefui for the treatment of diseases and conditions mediated by, or associated to the positive allosteric modulation of the «7 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 Genei B Neuropsychiatr Genet 144B (2007) 611-614), delusional disorder (Carson R et al. Neuromolecular Med 10 (2008) 377-384), brief psychotic disorder, psychotic disorder due to a general medical condition, substance-induced psychotic disorder, or psychotic disorder not otherwîse specified, cognitive împaimient including, for example the treatment of impairment of cognitive fonctions, as well as cognitive impairment as a resuit 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 (2018) 737-741), Pick disease (Fehér A et al. Dement Geriatr Cogn Disord 28 (2009) 56-62), HIV associated démenti a (Capô-Vêlez CM et al. Soi Rep 8 (2018) 1829), frontotemporal dementia (Minami SS et al. Biochem Pharmacol 97 (2015) 454-462), Lewy body dementia (Perry EK et al. Neuroscience 64 (1995) 385-395), vascular dementia (Putîgnano S et al. Clin Interv Aging 7 (2012) 113-118), cerebrovascular disease (Si ML and Lee TJF Cire Res 91 (2002) 62-69) or other dementia States, and dementia associated to other degenerative disorders (amyotrophie latéral sclerosis (Kawamata et al. Ther Adv Chronic Dis 2 (2011) 197-208), etc.), other acute or sub-acute conditions that may cause cognitive décliné such as delirium (Sfera A et al. Front Med 2 (2015) 56), traumatic brain injury (Shîn SS et al. Neural Regen Res 10 (2015) 1552-1554), senile dementia (Whitehouse PJ et et al. Science 215 (1982) 1237-1239), mild cognitive impairment (Ikonomovic MD et al. Arch Neurol 66 (2009) 646-651), Down’s syndrome (Deutsch SI et al. Clin Neuropharmacol 26 (2003) 277-283), dépréssion and cognitive déficit related to other diseases and dyskinetic disorders (Parameswaran N et al. Soc Neurosci Abstr (2007)), such as Parkinson’s disease (Quik M et al. Biochem Pharmacol 97 (2015) 399-407), as well as neuroleptic-induced parkinsonism, or tardive dyskinesias (Terry AV and Gearhart DA Ew J Pharmacol 571 (2007) 29-32), dépréssion and mood disorders, including dépressive disorders and épisodes (Philip NS et al. Psychopharmacology 212 (2010) 1-12), bipolar disorders (Leonard S and Freedman R. Biol Psychiatry 60 (2006) 115-122), cyclothymie disorder (Ancin I et al. J Affect Disord 133 (2011) 340-345), and bipolar disorder not otherwîse specified, other mood disorders (Shytle RD et al. Dépréssion and Anxiety 16 (2002) 89-92), substance-induced mood disorder, and mood disorder not otherwîse 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. Neuropsychopharmacology 41 (2015) 1579-1587), generalized anxiety disorder (Cocores JA Prim Care Companion J Clin Psychiatry 10 (2008) 253-254), anxiety disorder due to a general medical condition, substance-induced anxiety disorder, phobias, and anxiety disorder not otherwîse specified, substance related disorders for example substance use or substance-induced disorders, e.g., alcohol- (de Fiebre NC and de Fiebre CM Alcohol 31 (2003) 149-153; Diaper AM et al. Br J Clin Pharmacol 77 (2014) 302-314) nicotine- (Leslie FM et al. Mol Pharmacol 83 (2013) 753-758), amphétamine- (Pubill D et al. Pharmaceuticals 4 (2011) 822-847), phencyclidine- (Thomson MS et al, Neuropharmacology 56 (2009) 1001-1009), opioid- (Zhang W, Int J Clin Exp Med 8 (2015) 1871-1879), cannabis- (Solinas M et al. J Neurosci 27 (2007) 5615-5620), cocaïne- (Francis MM et al. Mol Pharmacol 60 (2001) 71-79), caffeine-, hallucinogen-, inhalant-, sédative-, hypnotic-, anxiolytic-, polysubstance- or other substance-related disorders, sleep disorders (McNamara JP et al. Psychol Health Med 19 (2014) 410-419), such as narcolepsy (Krahn et al J Clin Sleep Med 5 (2009) 390), dyssomnias, prîmary hypersomnia, breathing-related sleep disorders, circadian rhythm sleep disorder, and dyssomnia not otherwise specified, parasomnias, sleep terror disorder, sleepwalking disorder, and parasomnîa not otherwise specified, sleep disorders related to another mental disorder (including, însomnia 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. J Neurogenet 31 (2017) 266-287), bulimia nervosa, obesity (Lakhan SE and Kirchgessner A J Transi Med 9 (2011) 129-139), compulsive eating disorder, binge eating disorder, and eating disorder not otherwise specified, diabètes mellitus (Marrero MB et al. J Pharmacol Exp Ther 332 (2010) 173-180), ulcerative colitis (Salaga et al. JPET 356 (2016) 157-169), Crohn’s disease (Bencherif M et al. Cell Mol Life Sci 68 (2011) 931-949), irritable bowel syndrome (Keszthelyi D et al. Neurogastroenterol Motil 21 (2009) 1239-1249), autism spectrum disorders (Deutsch et al. Clin Neuropharmacol 33 (2010) 114-120), including autistic disorder, Asperger's disorder, Rett's disorder, childhood disintegrative disorder and pervasive developmental disorder not otherwise specified, attention déficit hyperactivity disorder (Wilens TE and Decker MW Biochem Pharmacol 74 (2007) 1212-1223), disruptive behaviour disorders, oppositional défiant disorder, and disruptive behaviour disorder not otherwise specified, and tic disorders such as Tourette's disorder (Gotti C and Clementi F Prog Neurobiol 74 (2004) 363-396), personalîty disorders (Kamens HM et al. Behav Genet 46 (2016) 693-704), sexual dysfiinctions, 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 al. Biol Reprod 73 (2005) 807-814), premenstrual syndrome (Gündisch D and Eibl C Expert Opin Ther Pat 21 (2011) 1867-1896), and sexual disorders not otherwise specified, disorders of the respîratory System like cough (Canning BJ Am J Respir Crit Care Med 195 (2017) A4498), asthma (Santana FPR et al. Eur Respir J 48 (2016) PA5066), chronic obstructive pulmonary disease (Maouche K et al. Proc Natl Acad Sci USA 110 (2013) 4099-4104), lung inflammation (Enioutina EY et al. PLoS One 10 (2015) eOl 21128), disorders of the cardiovascular System such as cardiac failure (Mai XK et al. J Immunol 200 (2018) 108.11), heart arrhythmîa (Mazloom R et al. PLoS One 8 (2013) e82251), and hypertension (Chen JK et al. BMC Cardiovasc Disord 12 (2012)38).
The compounds of the invention are also useful in treating inflammation, inflammatory and neuropathie 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. PLoS One 9 (2014) e85888), sarcoidosis (Nicotine Treatment for Pulmonary Sarcoidosis: A Clînical Trial Pilot Study Elliott Crouser 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. Front Syst Neurosci II (2017) 43), systemic lupus erythematosus (Fairley AS and Mathîs KW Physiol Rep 5 (2017) el3213), mania (Janowsky DS et al. Lancet 2 (1972) 632-635), restless legs syndrome (Buchfuhrer MJ Neurotherapeutics 9 (2012) 776-790), progressive supranuclear palsy (Warren NM et al. Brain 128 (2005) 239-245), epîlepsy (Bertrand D Epilepsy Curr 2 (2002) 191-193), myoclonus (Leppik IE Epilepsia 44 (2003) 2-6), migraine (Liu Q et al. J Pain Res 11 (2018) 1129-1140), amnesia (Bali Zs K et al. Front Cell Neurosci 11 (2017) 271), chronic fatigue syndrome (Shan ZY et al. J Magn Reson Imaging 44 (2016) 1301-1311), cataplexy (Ebben MR and Krieger AC J Clin Sleep Med 8 (2012) 195-196), brain ischemia (Han Z et al. J Neurochem 131 (2014) 498-508), multiple sclerosis (Di Bari M et al. Cent Nerv Syst Agents Med Chem 17 (2017) 109-115), encephalomyelitis (Hao J et al. Exp Neurol 227 (2011): 110-119), jetlag (Shi M et al. eLife 3 (2014) e01473), cérébral amyloid angiopathy (Clifford PM et al. Brain Res 1234 (2008) 158-171), sepsis (Ren C et al. Int J Biol Sci 14 (2018) 748-759), and in general, in treating ail types of diseases and disorders connected to the positive allosteric modulation of the a7 nAChR.
Furthermore, these compounds can also be combined with other therapeutic agents including, but not limited to acetylcholinestérase inhibitors (such as galantamine, rivastigmine, donepezil, tacrine, phenserine, ladostigil and ABT-089); NMDA receptor agonists or antagonists (such as memantine, neramexane, EVT101, and AZD4282);
anti-amyloid antibodies including anti-amyloid humanized monoclonal antibodies (such as bapineuzumab, ACCOO1, 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, rofecoxib, valdecoxib, 406381 and 644784); LRRK2 inhibitors; HMG-CoA reductase inhibitors; NSAIDs (such as ibuprofen); vitamin E; glycine transport inhibitors; glycine site antagonists (such as lacosamide); LXR β agonists; androgen receptor modulators; blockers of Αβ oligomer formation; NR2B antagonists, anti-inflammatory compounds (such as (R)-flurbiprofen, nitroflurbiprofen, ND-1251, VP-025, HT-0712, and EHT-202); PPAR gamma agonists (such as pioglitazone and rosiglîtazone); CB-1 receptor antagonists or inverse agonists (such as AVE1625); CB-2 agonists (such as 842166 and SAB378); VR-1 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 (such as ibutamoren, ibutamoren mesylate, and capromorelin); potassium channel openers; AMPA agonists or AMP A modulators (such as CX-717, LY 451395, LY404187 and S-18986); GSK3 inhibitors (such as AZDI080, SAR502250 and CEP 16805); neuronal nicotinic agonists; MARK ligands; Mi or M4 mAChR agonists or PAMs; mGluR2 antagonists or NAMs or PAMs; mGluR5 antagonists (such as AZD9272); alpha-adrenerg agonists; ADAM-10 ligands; sédatives, hypnotics, anxiolytics, antipsychotics, cyclopyrrolones, imidazopyridines, pyrazolopyrimi dînes, mînor tranquilizers, melatonin agonists and antagonists, melatonergic agents; orexin antagonists and agonists; prokineticin agonists and antagonists; T-type calcium channel antagonists; triazolopyri dînes benzodiazépines, barbiturates; 5-HT,a antagonists (such as lecozotan); 5-HT2 antagonists; 5-HT4 agonists (such as PRX-03140); 5-HT6 antagonists (such as GSK 742467, SGS-518, FK962, SL-65.0155, SRA- 333 and xaliproden); histamine H3 receptor antagonists and inverse agonists (such as S38093, ABT-834, ABT 829, GSK 189254 and CEP16795); PDE4 inhibitors (such as HT0712); PDE9 inhibitors (such as BI40936); PDE|0 inhibitors; HDAC inhibitors; KCNQ antagonists; GABAa inverse agonists; GABA signalling enhancers; GABA agonists, GABAa receptor alpha5 subunit NAMs or PAMs, antipsychotics; MAO-B inhibitors; dopamine transport inhibitors; noradrenaline transport inhibitors; D2 agonists and partial agonists; anticholinergics (such as biperiden); COMT inhibitors (such as entacapone); A2a adenosine receptor antagonists; cholinergic agonists; compounds from the phenothiazine, thioxanthene (such as chlorprothixene and thîothixene), heterocyclic dibenzazepîne (such as clozapîne), butyrophenone (such as haloperidol), diphenylbutylpiperidine (such as pimozide) and indolone (such as molindolone) classes of neuroleptic agents; loxapine, sulpiride and rispéridone; levodopa; calcium channei blockers (such as zîconotide and NMED160); MMP inhibitors; thrombolytic agents; opioid analgésies (such as codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, pentazocine, propoxyphene); pramipexole; ropinirole; neutrophil inhibitory factor; SSRIs or SSNRIs; tricyclic antidepressant drugs; norepinephrine modulators; lithium; valproate; gabapentin; pregabalin; rizatriptan; zolmitriptan; naratriptan and sumatriptan or other drugs that affect receptors or enzymes that either increase the efficacy, safety, convenience, or reduce unwanted side effects or toxicity of the compounds of the présent invention.
Known positive allosteric modulators of the u7 nicotinic acétylcholine receptor include 2-anilîne-4-aryl thiazole dérivatives (WO 2007/031440 A2, JANSSEN PHARMACEUTICA NV), amide dérivatives (WO 2009/100294 A2, ABBOT LAB.), trisubstituted 1,2,4-triazoles (WO 2009/115547 Al, JANSSEN PHARMACEUTICA NV), indole dérivatives (WO 2009/127678 Al, GLAXO GROUP LTD. and WO 2009/127679 Al, GLAXO GROUP LTD.), tetrazole-substîtuted aryl amide dérivatives (WO 2009/043780 Al, HOFFMANN LA ROCHE), cyclopropyl aryl amide dérivatives (WO 2009/043784 Al, HOFFMANN LA ROCHE), trisubstiuted pyrazoles (WO 2009/135944 Al, JANSSEN PHARMACEUTICA NV), pyrrole dérivatives (WO 2014/141091 Al, LUPIN LTD), cyclopropylbenzene dérivatives (WO 2017/165256 Al, MERCK SHARP & DOHME CORP.), and substituted bicyclic heteroaryl dérivatives (WO 2018/085171 Al, MERCK SHARP & DOHME CORP.).
The présent invention is directed to a novel class of compounds that exhibit positive allosteric modulation of the a7 nicotinic acétylcholine receptor.
BRIEF DESCRIPTION OF THE DRAWINGS
An exemplary embodiment of the présent invention is illustrated by way of example in the accompanying drawings in which like reference numbers indicate the same or similar éléments and in which:
Figure 1 illustrâtes the results of place récognition test of compound Example 1. Exploration times spent in the novel [N] vs. familiar [O] anns of the Y maze are depicted). Scop: scopolamine (1 mg/kg, ip.). ”p<0.05; H*p<0.01; ^pO.OOl.
Figure 2 illustrâtes the results of place récognition test of compound Example 21. 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 3 illustrâtes the results of place récognition test of compound Example 29. 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 4 illustrâtes the results of place récognition test of compound Example 33. Exploration times spent in the novel [N] vs. familiar [O] anns of the Y maze are depicted). Scop: scopolamine (1 mg/kg, ip.). +p<0.05; +,p<0.01; ++4p<0.001.
Figure 5 illustrâtes the results of place récognition test of compound Example 37. Exploration times spent in the novel [N] vs. familiar [O] anns of the Y maze are depicted). Scop: scopolamine (1 mg/kg, ip.). p<0.05;++p<0.01; ^pO.OOl.
Figure 6 illustrâtes the results of place récognition test of compound Example 86. 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; ^pO.Ol; +++p<0.001.
Figure 7 illustrâtes the results of place récognition test of compound Example 89. 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.
SUMMARY OF THE INVENTION
The présent invention relates to compounds of formula (I),
(I) wherein
A is saturated, unsaturated or aromatic, monocyclic or bycyclic, fused or bridged carbocyclyl, or a saturated, unsaturated or aromatic monocyclic or bycyclic, fused or bridged heterocyclyl, optionally substituted by one or more halogen atom or halogen atoms, Ci.6alkyl, Ci-&alkoxy, or haloCi^alkyl;
B is saturated, unsaturated or aromatic, monocyclic or bycyclic, fused or bridged carbocyclyl, or a saturated, unsaturated or aromatic monocyclic or bycyclic, fused or bridged heterocyclyl, optionally substituted by one or more halogen atom or halogen atoms, C^alkyl, C|.6alkoxy, haloCj-éalkyl, CN, C(O)Ci.f,alkyl, or haloCi-6alkoxy;
R1 is Ci-galkyl, Ci-6alkenyl, haloCi^alkyl, C3.8cycloalkylC|.6alkyl, Ci-éalkoxyCi^alkyl, or C4.6heterocyclyl;
or phannaceutically acceptable salts, biologîcally active métabolites, pro-drugs, racemates, enantiomers, diastereomers, solvatés and hydrates thereof.
In a further aspect, the présent invention provides a compound of formula (I), as defmed above for use in the treatment or prévention of a disease associated with «7 nicotinic acétylcholine receptor activity.
In a further aspect, the présent invention provides the use of a compound of formula (I), as defmed above, for the manufacture of a médicament for the treatment or prévention of a disease associated with a 7 nicotinic acétylcholine receptor activity.
In a further aspect, the présent invention provides a method for the treatment or prévention of a disease associated with a7 nicotinic acétylcholine receptor activity comprising administering to a mammal in need of such treatment or prévention an effective amount of at least one compound of formula (I), as defmed above.
In a further aspect, the compounds of fonnula (I) as defmed above, can be administered in combination with other compounds used for the treatment or prévention of a disease associated with a7 nicotinic acétylcholine receptor activity.
In a further aspect, the présent invention provides a process for the manufacture of the compounds of formula (I).
DETAILED DESCRIPTION OF THE INVENTION
The présent invention relates to compounds of formula (I),
(I) wherein
A is saturated, unsaturated or aromatic, monocyclic or bycyclic, fused or bridged carbocyclyl, or a saturated, unsaturated or aromatic monocyclic or bycyclic, fused or bridged heterocyclyl, optionally substituted by one or more halogen atom or halogen atoms, C^alkyl, Ci.^alhoxy, or haloCi-ealkyl;
B is saturated, unsaturated or aromatic, monocyclic or bycyclic, fused or bridged carbocyclyl, or a saturated, unsaturated or aromatic monocyclic or bycyclic, fused or bridged heterocyclyl, optionally substituted by one or more halogen atom or halogen atoms, Ci^alkyl, Ci^alkoxy, haloCi.6alkyl, CN, C(O)Ci-6alkyl, or haloC].6alkoxy;
R1 is Ci-6alkyl, Ci^alkenyl, haloC|_6alkyl, C3.8cycloalkylCi.6alkyl, Ci-6alkoxyCi.6alkyl, or C^heterocyclyl;
or pharmaceutically acceptable salts, biologically active métabolites, pro-drugs, racemates, enantiomers, dîastereomers, solvatés and hydrates thereof.
The tenu “saturated, unsaturated or aromatic, monocyclic or bycyclic, fused or bridged carbocyclyl” refers alone or in combination with other groups to a monovalent monocyclic or bicyclic, fused or bridged, saturated, mono-, or bi-unsaturated, or aromatic ring System comprising 3 to 10 carbon ring atoms. Saturated carbocycles include monovalent monocyclic or bicyclic, fused or bridged, saturated carbocyclic groups comprising 3 to 10 carbon ring atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[3.1.0]hexanyl, bicyclo[2.2.I]heptanyl, bicyclo[2.2.2]octanyl or adamantanyl and the like. Unsaturated carbocycles include monovalent monocyclic or bicyclic, fused or bridged, mono-, or bi-unsaturated carbocyclic groups comprising 4 to 10 carbon ring atoms. Ex amples include cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl and the like. Aromatic carbocycles include monovalent, mono- or bicyclic aromatic carbocyclic groups comprising 6 to 10 carbon ring atoms. Examples include phenyl and naphthyl.
The term “saturated, unsaturated or aromatic monocyclic or bycyclic, fused or bridged heterocyclyl” refers alone or in combination with other groups to a monovalent monocyclic or bicyclic, fused or bridged, saturated, mono-, or bi-unsaturated, or aromatic ring System comprising 3 to 12 ring atoms, having at least one ring comprising one, two, or three or four ring heteroatoms, chosen from nitrogen, oxygen or sulphur, preferably nitrogen and oxygen. Saturated heterocycles include monovalent monocyclic or bicyclic, fused or bridged, saturated heterocyclic groups comprising 3 to 12 ring atoms, having at least one ring comprising one, two, or three or four ring heteroatoms, chosen from nitrogen, oxygen or sulphur, preferably nitrogen and oxygen. Examples include, azetidinyl, oxetanyl, pyrrolidinyl, pirazolidinyl, izoxasolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, decahydroquinolinyl, decahydroisoquinolinyl, azaadamantanyl. Unsaturated heterocycles include monovalent monocyclic or bicyclic, fused or bridged, mono-, or bi-unsaturated heterocyclic groups comprising 5 to 12 ring atoms, having at least one ring comprising one, two, or three or four ring heteroatoms, chosen from nitrogen, oxygen or sulphur, preferably nitrogen and oxygen. Examples include, pyrrolinyl, pyrazolinyl, benzoxazolyl, benzthiazolyl, indolyl, isoindolyl, azaindolyl, benzodioxolyl, pyrazolo[l,5-a]pyrimidinyl, pyrazolo[l,5-a]pyridinyl, 1,2,3,4tetrahydro-isoquinolinyl. Aromatic heterocycles include monovalent, mono- or bicyclic aromatic heterocyclic groups comprising 5 to 12 ring atoms, having at least one ring comprising one, two, or three or four ring heteroatoms, chosen from nitrogen, oxygen or sulphur, preferably nitrogen and oxygen. Examples include, pyrrolyl, pyrazolyl, imidazolyl, furyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridazyl, pyrimidinyl, pyrazinyl, benzimidazolyl, quinolinyl, isoquinoiinyL
The term “halo” or “halogen”, as used herein as such or as part of another group, refers to fluoro, chlore, bromo or iodo.
The term “CMalkyl”, as used herein as such or as part of another group, refers to a branched or straîght chaîn saturated hydrocarbon group having one, two, three, four, five or six carbon atoms including, but not limited to, methyl, ethyl, n-propyl, z-propyl, n-butyl, sec-butyl, and rerZ-butyl.
The term “haloCMalkyl”, as used herein, refers to at least one halogen, as defined above, bonded to the parent molecular moiety through an “Ci^alkyl” group, as deftned above. When there are several halogens, 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. HaloCMalkyl groups include, but are not limited to, difluoromethyl, trifluoromethyl, trifluoroethyl and 2-chloroethyl.
The term “CMalkoxy”, as used herein refers to an CMalkyl group, as defmed above, bonded to the parent molecular moiety through an oxygen atom including, but not limited to, methoxy, ethoxy, n-propoxy, i-propoxy and zm-butoxy.
The term “haloCMalkoxy”, as used herein refers to at least one halogen, as defmed above, bonded to the parent molecular moiety through a “CMalkoxy” group, as defined above. When there are several halogens, 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. HaloCMalkoxy groups include, but are not limited to, trifluoromethoxyl, difluoromethoxyl, trifluoroethoxyl.
The term “CMalkenyl”, as used herein refers to linear or branched-chain monovalent hydrocarbon radical of two to six carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon, sp double bond, wherein the alkenyl radical includes radicals having “cis” and “trans” orientations, or alternative!y, “E” and “Z” orientations. Examples include, but are not limited to, ethylenyl or vinyl (—CH=CH2), allyl (—CH2CH=CH2), and the like.
The terrn “Cs^cycloalkyl”, as used herein as such or as part of another group, refers to cyclopropyl, cyclobutyl or cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.
The terrn “Cs-gcycloalkylCi^ alkyl”, as used herein refers to refers to a Q-gcycIoalkyl group, as defined above, bonded to the parent molecular moiety through a “Ci^alkyl” group, as 5 defined above, including, but not limited to, cyclopropylmethyl and cyclobutylmethyl.
The terrn “C।_&alkoxyC].6alkyl”as used herein refers to refers to a Ci.6alkoxy group, as defined above, bonded to the parent molecular moiety through a “C|-6alkyl” group, as defined above, including, but not limited to, -C2H5-O-CH3t -CH3-O-C2H5, -CH3-O-CH3, -C2H5-O-C2H5, -C3H7-O-CH3, -CH3-O-C3H7, -C3H7-O-C2H5, -C2H5-O-C3H7.
The terrn “C^heterocyclyl”, as used herein refers to an optionally substîtuted moiety, consisting of 4-6 atoms fonning one to two rings, incorporating one, two, or three or four hetcroatoms, chosen from nitrogen, oxygen or sulfur. Examples of heterocyclyl moieties include, but are not limited to, optionally substîtuted piperidinyl, piperazinyl, homopiperazînyl, azepinyl, pyrrolidinyl, pyrazolidinyl, imidazolinyl, imidazolîdinyl, pyridinyl, pyridazinyl, pyrimidinyl, 15 oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, thiadiazolylidinyl, dihydrofuryl, tetrahydrofuryl, dihydropyranyl, tetrahydropyranyl, thiamorpholinyl.
The terrn “pharmaceutically acceptable” describes an ingrédient that is useful in preparîng a pharmaceutical composition, is generally safe, non-toxic and neither biologically nor otherwîse undesirable, and includes those acceptable for veterinary use as well as human 20 pharmaceutical use.
The terrn “hydrate” means non-covalent combinations between water and soluté.
The terrn “solvaté” means non-covalent combinations between solvent and soluté. Solvents include, but are not limited to, éthanol, 2-propanol, acetonitrile and tetrahydrofuran.
Optional or optionally means that the subsequently described event or circumstance 25 may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
Optionally substîtuted means unsubstituted or substîtuted with one or more of the substituents as described herein. Here, one or more means from one to the highest possible number of substitution, that is, from replacing one hydrogen to replacing ail hydrogens. One, two or three substituents on a given atom are preferred.
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 expérience 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 régression of the disease state or its clinical symptoms.
The term pharmaceutically acceptable sait refers to a conventional acid addition sait or a base addition sait, which préserves the biological efficacy and properties of the compounds of formula (I) and which can be formed with suitable non-toxic organic or inorganic acids or organic or inorganic bases. Examples of 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 varions organic acids, such as, but not limited to, acetic acid, propionic acid, benzoic acid, glycolic acid, phenylacetic acid, salicylic acid, malonic acid, maleic acid, oleîc acid, pamoîc acid, palmitic acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, oxalic acid, tartaric acid, succinic acid, cîtric acid, malic acid, lactic acid, glutamic acid, fumaric acid and the like. Examples of base addition salts are salts derived from ammonium-, potassium-, sodium- and quatemary ammonium hydroxides such as tétraméthylammonium hydroxide.
The term “pro-drug” refers to dérivatives of compounds of formula (I) according to the invention which themselves hâve no therapeutic effect but containing such groups which, after in vivo Chemical or metabolic dégradation (bîotransformation) become “biologically active métabolite” which is responsible for the therapeutic effect. Such decomposing groups associaied with the compounds of formula (I) of the présent invention, in particular those suitable for prodrugs, are known in the art and may also be applied for the compounds of the présent invention (Rautio et al., Nature Reviens - Drug Discovery 2008, 7:255-270).
In one embodiment, the présent invention relates to compounds of formula (I), wherein A is saturated, unsaturated or aromatic, monocyclic or bycyclic, fused or bridged carbocyclyl, or a saturated, unsaturated or aromatic monocyclic or bycyclic, fused or bridged heterocyclyl, containing 1-3 heteroatoms selected from the group nitrogen, oxygen and sulphur, optionally 5 substituted by one or more halogen atom or halogen atoms, Ci-3alkyl, Ci.3alkoxy, or haloCi_3alkyl;
B is saturated, unsaturated or aromatic, monocyclic or bycyclic, fused or bridged carbocyclyl, or a saturated, unsaturated or aromatic monocyclic or bycyclic, fused or bridged heterocyclyl, containing 1-3 heteroatoms selected from the group nitrogen, oxygen and sulphur, optionally 10 substituted by one or more halogen atom or halogen atoms, C|.3alkyl, Ci.3alkoxy, haloC|_3alkyl, CN, C(O)Ci.3alkyl, orhaloC|_3alkoxy;
R1 is Ci^alkyl, Ci.3alkenyl, haIoC|.3alkyl, C3.5cycloalkylC|.3 alkyl, C|_3alkoxyCi.3alkyl, or C46heterocyclyl;
or pharmaceutically acceptable salts, biologically active métabolites, pro-drugs, racemates, 15 enantiomers, diastereomers, solvatés and hydrates thereof.
In one embodiment, the présent invention relates to compounds of fonnula (I), wherein A is saturated, unsaturated or aromatic, 4-9 membered, monocyclic or bycyclic, fused or bridged carbocyclyl, or a saturated, unsaturated or aromatic 4-9 membered, monocyclic or bycyclic, fused or bridged heterocyclyl containing 1-3 heteroatoms selected from the group nitrogen and 20 oxygen, optionally substituted by one or more halogen atom or halogen atoms, Ci^alkyl, C;. 6alkoxy, or haloCi-ôalkyl;
B is saturated, unsaturated or aromatic, 4-9 membered, monocyclic or bycyclic, fused or bridged carbocyclyl, or a saturated, unsaturated or aromatic 4-9 membered, monocyclic or bycyclic, fused or bridged heterocyclyl containing 1 -3 heteroatoms selected from the group of nitrogen 25 and oxygen, optionally substituted by one or more halogen atom or halogen atoms, C].6alkyl, C|_ 6alkoxy, haloC^alkyl, CN, C(O)C|.6alkyl, or haloCi^alkoxy;
R1 is C|.6alkyl, Cj^alkenyl, haloC1.6aIkyl, C3.8cycloalkylCi.6alkyl, Ci.6alkoxyCi-6alkyl, or C^heterocyclyl;
or pharmaceutically acceptable salts, biologically active métabolites, pro-drugs, racemates, 30 enantiomers, diastereomers, solvatés and hydrates thereof.
In one embodiment, the présent invention relates to compounds of formula (I), wherein
A is saturated, unsaturated or aromatic, 4-9 membered, monocyclic or bycyclic, fused or bridged carbocyclyl, or a saturated, unsaturated or aromatic 4-9 membered, monocyclic or bycyclic, fiised or bridged heterocyclyl containîng 1-3 heteroatoms selected from the group of nitrogen, and oxygen optionally substituted by one or more halogen atom or halogen atoms, Ci.3alkyl, Ci. 3alkoxy, or haloC|_3alkyl;
B is saturated, unsaturated or aromatic, 4-9 membered, monocyclic or bycyclic, fused or bridged carbocyclyl, or a saturated, unsaturated or aromatic 4-9 membered, monocyclic or bycyclic, fused or bridged heterocyclyl containîng 1-3 heteroatoms selected from the group nitrogen, and oxygen, optionally substituted by one or more halogen atom or halogen atoms, Ci^alkyl, C|. 3alkoxy, haloC|.3alkyl, CN, C(O)Cj.3alkyl, or haloCi.3alkoxy;
R1 is C].4alkyl, Ci-3alkenyl, haloCi.3alkyl, C3-5cycloalkylC].3alkyl, C].3 alkoxyC|.3alkyl, or C4. gheterocyclyl;
or pharmaceutically acceptable salts, biologically active métabolites, pro-drugs, racemates, enantiomers, diastereomers, solvatés and hydrates thereof.
In one embodiment, the présent invention relates to compounds of formula (I), A is a cyclopentenyl, cyclohexyl, phenyl, cycloheptyl, bicyclo[3.1.0]hexanyl or indazolyl, optionally substituted by one or more halogen atom or halogen atoms, Ci-3alkyl, C].3alkoxy, or haloCi.3aIkyl;
B is a phenyl, pyridyl, pyrazyl, pyrazinyl, pyrimidinyl, benzodioxolyl, 1,2,3,4-tetrahydroisoquinolinyl, or pyrazolo[l ,5-a]pyridinyl, optionally substituted by one or more halogen atom or halogen atoms, C).3alkyl, Ci-3alkoxy, haloC].3alkyl, CN, C(O)Cp3alkyl, or haloCi.3alkoxy;
R1 is CH3, CsHs, nPr, iPr, «Bu, secBu, allyl, -CH2-CF3, -CFB-cBu, -CH2-cPr, -C2H5-O-CH3, or tetrahydrofuryl;
or pharmaceutically acceptable salts, biologically active métabolites, pro-drugs, racemates, enantiomers, diastereomers, solvatés and hydrates thereof.
In one embodiment, the présent invention relates to compounds of formula (I) selected from the group of:
5-(3,4-dimethoxyphenyl)-2-rnethyl-jV-(3-methylpheny])-l,l-dioxo-2H-lX6,2,6-thiadîazine-3carboxamide;
5-( 1,3-dimethyl-1 H- indazol-5-yl)-2-methyl-77-(3-methyl ph en yl )-l, 1 -dioxo-2/7-1 λ6,2,6thiadiazine-3-carboxamide;
5-(3,4-dimethoxyphenyI)-2-ethyl-jV-(3-inethylphenyl)-l, 1 -dioxo-2/7-1 X6,2,6-thiadiazine-3carboxamide;
5-(3,4-dimethoxyphenyl)-2-ethyl-l, l-dioxo-V-[6-(trifluoromethyl)pyridin-2-yl]-2//-1λ6,2,6thiadiazine-3-carboxamide;
2-ethyl-5-[4-methoxy-3-(trifluoromethyl)phenyl]-?/-(3-methoxyphenyl)-l,l-dioxo-277-]Z6,2,6thiadiazine-3-carboxamide;
2-ethyl-5-[4-methoxy-3-(trifluoromethyl)phenyl]-7V-(4-methoxyphenyl)-1,1 -dioxo-277-lX6,2,6thiadiazine-3-carboxamide;
2-ethyl-l, 1 -dioxo-5-[( 1 r,4r)-4-(trifluoromethyl)cyclohexyl]-7/-[6-(trifluoromethyl)pyridin-2-yl]2/7-lZ6,2,6-thîadiazine-3-carboxamide;
jV-(6-cyanopyridin-2-yl)-2-ethyl-l,I-dioxo-5-[(lr,4r)-4-(trifluoromethyl)cyclohexyl]-2F71 Z6,2,6-thi adiazine- 3 -carboxami de;
5-(3,4-dimethoxyphenyl)-l,l-dioxo-2-(propan-2-yl)-JV'-[6-(trifluoromethyl)pyridin-2~yl]-2/7lX6,2J6-thiadiazîne-3-carboxamide;
5-(354-dimethoxyphenyl)-l,l-dioxo-2-propyl-7V-[3-(trifluoromethyl)phenyl]-2J7-lX6,2,6thiadiazine-3-carboxamide;
5-(3,4-dimethoxyphenyl)-l, 1 -dioxo-2-propyl-N-[6-(trifluoromethyl)pyridin-2-yl]-2H-l λ6,2,6thiadiazine-3-carboxamide;
5-[4-methoxy-3-(triflnoromethyl)phenyl]’l,l-dioxo-2-propyl-y-[6-(tritluoromethyl)pyridin-2yl]-277-lÀ6,2,6-thiadiazine-3-carboxamide;
5-(4-methoxy-3-methylphenyl)-l)l-dioxo-2-propyl-Ar-[6-(trifluoromethyl)pyridin-2-yl]-2/7lZ6,2,6-thiadiazine-3-carboxamide;
5-(3-chloro-4-methoxyphenyl)-l,l-dioxo-2-propyl-W-[6-(trifluoromethyl)pyridin-2-yl]-2/7lZ6,2,6-thiadiazine-3-carboxamide;
2-(cyclopropylmethyl)-l, l-dioxo-5-[(l r,4r)-4-(tri fl uo rom ethyl)cyclohexyl ]-Æ-[6(trif]uoromethyl)pyridin-2-yl]-27ï-lZ6,2,6-thiadiazine-3-carboxamide;
5-(3,4-dimethoxyphenyl)-l,l-dioxo-2-(prop-2-en-l-yl)-7V-[6-(tri fl uoromethyl)pyridin-2-yl]-2//lX6,2,6-thiadiazine-3-carboxamide;
5-(3,4-dimethoxyphenyl)-7V-(4-methoxyphenyl)-I,l-dioxo-2-propyl-2//-lX6,2,6-thiadiazine-3carboxamide;
5-(3,4-dimethoxyphenyl)-Ar-(3-methylphenyl)-l,l-dioxo-2-propyl-2//-lX6,2,6-thiadiazine-3carboxamide;
5-[4-methoxy-3-(trifluoromethyl)phenyl]-l}l-dioxo-2-propyl-?/-[3-(trifluoromeihyl)phenyl]-2//lL6,2,6-thiadiazine-3-carboxamide;
5-(3,4-dimethoxyphenyl)-A-(6-fluoropyridin-2-yl)-l,l-dioxo-2-(propan-2-yl)-2//-iÀ6,2}6thîadiazine-3-carboxamide;
7V-(6-fluoropyridin-2-yl)-l,l-dioxo-2-(piOpan-2-yI)-5-[(lr,4r)-4-(trifluoromethyl)cyclohexyl]2//-lÀ6,2,6-thiadiazine-3-carboxamide;
2-(cyclopropylmethyl)-7V-(6-fluoropyrazin-2-yl)-l,l-dioxo-5-[(Ir,4r)-4(trifluoromethyl)cyclohexyl]-2//-l λ6,2,6-thiadiazine-3 -carboxamide;
2-[(2R)-butan-2-yl]-5-(3,4-dimethoxyphenyl)-l,l-dioxo-N-[6-(trifluoromethyl)pyridin-2-y1]-2HlZ6,2,6-thiadiazine-3-carboxamide;
2-ethyl-5-[4-methoxy-3-(trifluoromethyl)phenyl]-l,l-dioxo-N-[6-(trifluoromethyl)pyridin-2-yl]2H-lk6,2,6-thiadiazine-3-carboxamide;
l,l-dioxo-2-(propan-2-yl)-5-[(lr,4r)-4-(triflLioromethyl)cyclohexyl]-N-[6( tri fluoromethyl)pyrazin-2-yl] -2H-1 λ6,2,6-thiadiazine-3 -carboxamide;
2-(cyclopropylmethyl)-5-(4,4-difluorocyclohexyl)-l,l-dioxo-N-[6-(trifluoromethyl)pyridin-2yl]-2H-l λ6,2,6-thiadiazine-3-carboxamide;
2-(cyclopropylmethyl)-l,l-dioxo-5-[(lr,4r)-4-(trifluoromethyl)cyclohexyl]-N-[2(trifluoromethyl)pyrimidin-4-yI]-2H-lZ6,2,6-thiadiazine-3-carboxamide;
or pharmaceutically acceptable salts, biologically active métabolites, pro-drugs, racemates, enantiomers, diastereomers, solvatés and hydrates thereof.
In a further aspect, the présent invention provides a compound of formula (I), as defmed above for use in the treatment or prévention of a disease associated with «7 nicotînic acétylcholine receptor activity.
In a further aspect, the présent invention provides the use of a compound of formula (I), as defined above, for the manufacture of a médicament for the treatment or prévention of a disease associated with a 7 nicotinic acétylcholine receptor activîty.
In a further aspect, the présent invention provides a method for the treatment or prévention of a disease associated with «7 nicotinic acétylcholine receptor activîty comprising administering to a mammal in need of such treatment or prévention an effective amount of at least one compound of formula (I), as defined above.
In one embodiment, the disease associated with a 7 nicotinic acétylcholine receptor activîty 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-înduced psychotic disorder or psychotic disorder not otherwise specified; cognitive impairment, including, but not limited to, cognitive impairment as a resuit of stroke, Alzheimer's disease, Huntington’s disease, Pick disease, HIV associated démenti a, fronto temporal dementia, Lewy body dementia, vascular dementia, cerebrovascular disease or other dementia States and dementia associated to other degenerative disorders, including, but not limited to, amyotrophie latéral sclerosis, other acute or sub-acute conditions that may cause cognitive décliné, including, but not limited to, delirium, traumatic brain injury, senile dementia, mîld cognitive impairment, Down’s syndrome, dépréssion and cognitive déficit related to other diseases, and dyskinetîc disorders including, but not limited to, Parkinson’s disease, neuroleptic-induced parkinsonism, or tardive dyskinesias, dépréssion and mood disorders, including, but not limited to, dépressive disorders and épisodes, bipolar disorders, cyclothymie 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, and anxiety disorder not otherwise specified; substance related disorders, including, but not limited to, substance use or substance-induced disorders, including, but not limited to, alcohol-, nicotine-, amphétamine-, phencyclidine-, opioid-, cannabis-, cocaine-, caffeine-, hallucinogen-, inhalant-, sédative-, hypnotic-, anxiolytic-, polysubstance- or other substance-related disorders; sleep disorders, including, but not limited to, narcolepsy, dyssomnias, primary hypersomnia, breathing-related sleep disorders, circadian rhythm sleep disorder and dyssomnia not otherwise specified; parasomnias, sleep ténor disorder, sleepwalking disorder and parasomnia not otherwise specified; sleep disorders related to another mental disorder; sleep disorder due to a general medical condition and substance-induced sleep disorder; metabolic and eating disorders, including, but not limited to, anorexia nervosa, bulimia nervosa, obesity, compulsive eating disorder, binge eating disorder and eating disorder not otherwise specified; diabètes mellitus, ulcerative colitis, Crohn’s disease, irritable bowel syndrome; autism spectrum disorders, including, but not limited to, autistic disorder, Asperger's disorder, Rett's disorder, childhood disintegrative disorder and pervasive developmental disorder not otherwise specified; attention déficit hyperactivity disorder, disruptive behaviour disorders, oppositional défiant disorder and disruptive behaviour disorder not otherwise specified; and tic disorders, including, but not limited to, Tourette's disorder; personality disorders; 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, premenstrual syndrome and sexual disorders not otherwise specified; disorders of the respiratory System like cough, asthma, chronic obstructive pulmonary disease, lung inflammation, disorders of the cardîovascular System such as cardiac failure, heart arrhythmîa, hypertension; inflammation, inflammatory and neuropathie pain, rheumatoid arthritis, osteoarthritis, allergy, sarcoidosis, psoriasis, ataxia, dystonîa, systemic lupus erythematosus, mania, restless legs syndrome, progressive supranuclear palsy, epilepsy, myoclonus, migraine, amnesia, chronic fatigue syndrome, cataplexy, brain ischemia, multiple sclerosis, encephalomyelitis, jetlag, cérébral amyloid angiopathy, and sepsis.
In one embodiment, the disease associated with a7 nicotinic acétylcholine receptor activity is selected from the group of cognitive impairment, schizophrenia and autism.
The invention, further relates to combination thérapies 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 indîcated. Such 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 β agonists, androgen receptor modulators, blockers of Αβ oligomer formation, NR2B antagonîsts, anti-inflammatory compounds, PPAR gamma agonists, CB-1 receptor antagonists or inverse agonists, CB-2 agonists, VR-1 antagonists, bradykinin B1 receptor antagonists, sodium channel blockers and antagonists, NOS inhibitors, antibiotics, growth hormone secretagogues, potassium channel openers, AM PA agonists or AMPA modulators, GSK3 inhibitors, neuronal nicotinic agonists, MARK ligands, Mj or M4 mAChR agonists or PAMs, mGluR2 antagonists or NAMs or PAMs, mGluR5 antagonists, alpha-ad renerg agonists, ADAM-10 ligands, sédatives, hypnotics, anxiolytics, antipsychotics, cyclopyrrolones, imîdazopyridines, pyrazolopyrimidines, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, orexin antagonists and agonists, prokineticin agonists and antagonists, T-type calcium channel antagonists, triazolopyridines benzodiazépines, barbiturates, 5-HTia antagonists, 5-HT2 antagonists, 5-HT4 agonists, 5-HTô receptor antagonists, histamine H3 receptor antagonists and inverse agonists, PDE4 inhibitors, PDE9 inhibitors, PDE10 inhibitors, HDAC inhibitors, KCNQ antagonists, GABAa inverse agonists, GABA signalling enhancers, GABA agonists, GABAa receptor alpha5 subunit NAMs or PAMs, antipsychotics, MAO-B inhibitors, dopamine transport inhibitors, noradrenaline transport inhibitors, D2 agonists and partial agonists, anticholinergics, COMT inhibitors, A2a adenosine receptor antagonists, chohnergic agonists, neuroleptic agents, loxapine, sulpiride and rispéridone, levodopa, calcium channel blockers, MMP inhibitors, thrombolytic agents, opioid analgésies, pramipexole, ropinirole, neutrophil inhibitory factor, S S Ris or SSNRIs, tricyclic antidepressant drugs, norepînephrine modulators, lithium, valproate, gabapentin, pregabalin, rizatriptan, zolmitriptan, naratriptan, and sumatriptan.
In one embodiment, the therapeutic agents are selected from the goup of: acetylcholinesterase inhibitors, NMDA receptor antagonists, beta- secretase inhibitors, antipsychotics, GABAa receptor alpha5 subunit NAMs or PAMs, histamine H3 receptor antagonists, 5-HT6 receptor antagonists, Ml or M4 mAChR agonists or PAMs, mGluR2 antagonists or NAMs or PAMs, and levodopa.
In a further aspect the présent invention provides a process for the manufacture of the compounds of fonnula (1) according to the following reaction route:
Throughout the spécification, general formulae are designated by Roman mimerais (I), (II), (III) etc.
Route a)
Route b)
Reacting a carboxylic acid of formula (Ha) or a carboxylic acid dérivative of formula (11b) - wherein the meaning of A is described above for compound of formula (I) - with methyl lithium, or reacting compound of formula (Ile) - wherein the meaning of A is an aromatic, monocyclic or bycyclic, fused or bridged carbocyclyl or a saturated, unsaturated or aromatic, 5 monocyclic or bycyclic, fused or bridged heterocyclyl, optionally substituted by one or more of Ci.6alkyl, CMalkoxy, or haloCMalkyl - with tributyl(l -ethoxyvinyl)tin, or reacting compound of formula (lld) with acetyl chloride - wherein the meaning of A is an aromatic, monocyclic or bycyclic, fused or bridged carbocyclyl or a saturated, unsaturated or aromatic, monocyclic or bycyclic, fused or bridged heterocyclyl, optionally substituted by one or more of CMalkyl, Cj.
6alkoxy, haloCMalkyl, or halogen - ketone dérivative of formula (III) was obtained
H (HD
- wherein the meaning of A is as described above for formula (I) - and compound of formula (III) is reacted with diethyl oxalate to provide 2,4-dioxo ester dérivative of formula (IV)
- wherein the meaning of A is as described above for formula (I) - which is reacted with sulfamide, then the obtained l,l-dioxo-l,3-thiadiazine carboxylic acid ester dérivative of formula (V)
(V)
- wherein the meaning of A is as described above for formula (I) - can be transformed to the desired end product of the formula (I) in different ways:
Route a) compound of formula (V) is alkylated to furnish TV-alkyl thiadiazine dérivative 5 of formula (VI)
(VI)
- wherein the meaning of A and R1 is as described above for formula (I) - which is hydrolysed leading to carboxylic acid dérivative of formula (VII)
(Vil)
0 - wherein the meaning of A and R1 is as described above for formula (I) - which is coupled with an appropriate amine (B-NH2) - wherein the meaning of B is as described above for formula (I) - to provide the desired amide of formula (I);
or
ROUTE b) the ester dérivative of formula (V) is hydrolysed to furnish the carboxylic acid 15 dérivative of formula (VIII)
HO
A
O O (Vill)
- wherein ihe meaning of A is as described above for formula (I) - which is then N,Odialkylated in one step resulting the corresponding ester compound of formula (X)
(X)
- wherein the meaning of A and R1 is as described above for formula (1) - which is then either hydrolysed to dérivative of formula (VII)
HO
(VU)
- wherein the meaning of A and R1 is as described above for formula (I) - and then reacted with the appropriate amine (B-NH2) resulting in the targeted amide dérivative of formula (I), or compound of formula (X) is transformed directly to the amide dérivative of the formula (I) by reaction with the appropriate amine (B-NH2).
The ketone dérivative of formula (III) can be purchased or synthesized in the following ways:
i. The reaction of a carboxylic acid dérivative of formula (lia) with methyl lithium is preferably carried out in a suitable solvent, e.g., diethyl ether. The réaction is preferably 15 carried out at -15 °C. The necessary reaction time is 2-4 hours. The reactions are followed by thin layer chromatography. The reaction mixture is preferably quenched by addition of saturated ammonium chloride solution. The product is isolated by extraction with a suitable organic solvent, e.g., diethyl ether.
iî. The reaction of Weinreb amide of formula (Ilb) with methyl lithium is preferably carried out in a suitable solvent, e.g., diethyl ether. The reaction is preferably carried out at - 78 °C. The necessary reaction time is 2-4 hours. The reactions are followed by thin layer chromatography. The reaction mixture is preferably quenched by addition of aqueous hydrogen chloride solution. The product is isolated by extraction with a suitable organic solvent, e.g., diethyl ether.
iii. The reaction of the corresponding halogenide of formula (Ile) with tributyl(lethoxyvinyl)tin in the presence of a suitable palladium catalyst, e.g., tetrakis(triphenylphosphine)palladium(0) and a base, preferably tri potassium phosphate in a suitable solvent, e.g., toluene or V-m ethyl-2-pyrrolid one. The reaction is preferably carried out at 80-90 °C. The necessary reaction time is 6-7 hours. The reactions are followed by thin layer chromatography. The reaction mixture is diluted with water and extracted with an appropriate organic solvent, e.g., ethyl acetate. The organic phase is treated with 1 M hydrochlorîc acid solution at room température by vigorously stirring for 30 minutes. The pH of the mixture is adjusted to 7-8 by the addition of 25 % aqueous ammonîa solution and extracted with a suitable organic solvent, e.g., ethyl acetate and purified by column chromathography.
iv. The Friedel-Crafts reaction of the corresponding aromatic compound of formula (Ild) with acetyl chloride in the presence of a suitable base, preferably aluminium chloride in a suitable solvent, preferably dichloromethane is carried out at 40 °C. The necessary reaction time is 2 hours. The reaction mixture is poured onto 3 M HCl solution and extracted with diethyl ether. The combined organic layer is washed with saturated NaHCCb solution and brine, dried and evaporated to dryness.
The synthesis of compounds of formula (I) is described in more detail below:
Step 1
The Claisen condensation reaction of the acetyl dérivative of formula (III) with diethyl oxalate to dioxoester dérivative of formula (IV) is preferably carried out in the presence of a strong base, preferably sodium ethylate in a suitable solvent, e.g., éthanol. The reaction is preferably carried out at room température. The necessary reaction time is 6-15 hours. The reaction is followed by thin layer chromatography. The reaction mixture is quenched by pouring onto diluted aqueous hydrochloric acid solution (pH=l-3), and the product is isolated by filtration or by extraction with a suitable organic solvent, e.g., ethyl acetate.
Step 2
Cyclisation of the dioxoester of formula (IV) with sulfamide providing l,l-dioxo-l,3thiadiazine carboxylic acid ester dérivative of formula (V) is performed in the presence of anhydrous éthanol saturated with hydrochloric acid in éthanol, as the solvent. The reaction is preferably carried out at 60-80 °C. The necessary reaction time is 2-15 hours. The reactions are followed by thin layer chromatography. The product is isolated eîther by filtration, or by extraction.
The 1,1-dioxo-1,3-thiadiazine carboxylic acid ester dérivative of formula (V) can be transformed to the desired end product of formula (I) in different ways:
ROUTE A)
V-alkylation of l,l-dioxo-l,3-thiadiazine carboxylic acid ester dérivative of formula (V) is executcd in different methods:
Step 3
Thiadiazine dérivative of formula (V) is reacted with a suitable alkyl halogenide in a suitable solvent, preferably acetone, acetonitrile or XTV-dimethylfonnamide in the presence of a suitable amine, e.g., triethyl amine, diisopropyl ethylamine at 65-80 °C. The necessary reaction time is 2-24 hours. The reaction mixture is diluted with water and acidified with aqueous hydrochloric acid solution. The product is isolated by extraction with a suitable organic solvent, preferably ethyl acetate and the isomers of product are separated by column chromatography. The structures of the products are determined by NMR spectroscopy and mass spectrometry.
Thiadiazine dérivative of formula (V) is reacted with a secondary alcohol in the presence of triphenyl phosphine and diisopropyl azodicarboxylate in a suitable solvent, preferably tetrahydrofuran at 25-67 °C. The necessary reaction time is 20-72 hours. The solvent is evaporated in vacuo and the procuct is isolated by column chromatography.
Step 4
Hydrolysis of V-alkylated ester of formula (VI) is carried out with base, e.g., 1-5 M NaOH or LiOH solution in a suitable solvent, e.g., tetrahydrofuran, or preferably éthanol at room température. The necessary reaction tîme is 1-3 hours. The reaction mixture is neutralised with aqueous hydrochloric acid solution. The organic solvent is evaporated in vacuo, the aqueous residue is acidifïed to pH=l-2, and the product is isolated by filtration or extraction with a suitable organic solvent, preferably ethyl acetate.
Step 5
The carboxylic acid of formula (Vil) is coupled with the correspondîng amine using a suitable coupling agent, such as HATU (l-[bis(dimethylamino)methylene]-177-l,2,3triazolo[4,5-6]pyridiniuiTi 3-oxide hexafluorophosphate) or EDC ( 1 -ethyl-3-(3dimethylaminopropyl)carbodiimide) in the presence of a suitable base, e.g., triethylamine, diisopropylethylamine, in a suitable solvent, preferably AW-dimethylformamide. The reaction is preferably carried out at room température. The necessary reaction time is 6-48 hours. The réaction mixture is worked up either by évaporation of the solvent, or poured onto aqueous hydrochloric acid solution and extracted with a suitable organic solvent, preferably ethyl acetate. The product is isolated by column chromatography. The structures of the products are determined by NMR and mass spectrometry.
The amidation of carboxylic acid of formula (VII) can be performed via the correspondîng carboxylic acid chloride as follows:
Carboxylic acid of formula (VII) îs treated with oxalyl chloride using a catalytic amount of V,V-dimethylformamide in a suitable organic solvent, preferably dichloromethane. After évaporation of the volatile components, the acyl chloride is reacted with the correspondîng amine in the presence of a suitable base, e.g., triethylamine, diisopropylethylamine or tripotassium phosphate in a suitable solvent, e.g., dichloromethane, 1,2-dichloroethane or tetrahydrofuran. The reaction is carried out at 25-80 °C. The necessary reaction time is 3-16 hours. The reaction mixture is worked up either by évaporation of the solvent, or poured onto aqueous hydrochloric acid solution, and extracted with a suitable organic solvent, e.g., ethyl acetate or dichloromethane. The product is isolated by column chromatography. The structures of the products are determined by NMR and mass spectrometry.
Step 6
The reaction of V-alkylated ester of formula (VI) with the corresponding amine is carried out in the presence of a strong base, preferably triethyl aluminium, in a suitable solvent, e.g., 1,2dichloroethane or toluene at 50-110 °C. The necessary reaction time is
6-4S hours. The reaction mixture is vigorously stirred with aqueous hydrochloric acid solution at 25-40 °C. The product is isolated by extraction with a suitable organic solvent, e.g., ethyl acetate or dichloromethane and by subséquent column chromatography. The structures of the products are determined by NMR and mass spectrometry.
Route b)
Step 7
Hydrolysis of l,l-dioxo-l,3-thiadiazine carboxylic acid ester dérivative of formula (V) is carried out with a base, e.g., 5 M aqueous NaOH solution in a suitable solvent, e.g., tetrahydrofuran, or preferably éthanol at room température. The necessary reaction time is 1-3 hours. The product is isolated in two different ways.
i) The reaction mixture is neutralised with aqueous hydrochloric acid solution, and evaporated to dryness in vacuo, the product -which contains sodium chloride-, obtained in this way was used in the next step without further purification.
ii) The reaction mixture is neutralised with aqueous hydrochloric acid solution. The organic solvent is evaporated in vacuo, the aqueous residue is acidified to pH=l-2 and the product is isolated by filtration.
Step 8
V,O-dialkylation of 1,1-dioxo-1,3-thiadiazine carboxylic acid dérivative of formula (VIII) with a suitable primary alkyl halogenide or pseudohalogenide, such as propyl bromide, butyl bromide or 2-bromoethyl methylether is carried out in a suitable solvent, preferably acetonitrile or 7V,jV-dimethyl formamide, in the presence of a suitable amine, e.g., triethyl amine, diisopropyl ethyl ami ne or sodium hydride at 65-80 °C. The necessary reaction time is 2-24 hours. The reaction mixture is diluted with water and acidified with aqueous hydrochloric acid solution. The product is isolated by extraction with a suitable organic solvent, preferably ethyl acetate, and the isomers of product are separated b y column chromatography. The structures of the products are determined by NMR spectroscopy and mass spectrometry.
Step 9
Hydrolysis of Λ-alkylated ester of fonnula (X) is carried ont with a base, e.g., 1-2 M NaOH or LiOH solution in a suitable solvent, e.g., tetrahydrofuran, or preferably éthanol at room température. The necessary reaction time is 1-3 hours. The reaction mixture is neutralised with aqueous hydrochloric acid solution. The organic solvent is evaporated in vacuo, the aqueous residue is acidified to pH=l-2, and the product is isolated by filtration or extraction with a suitable organic solvent, preferably ethyl acetate.
Amidation of Λ'-alkylated carboxylic acid of formula (VII) to provide amide of formula (I) is perfonned as described in Step 5 above.
The reaction of jV-alkylated ester of fonnula (X) with the corresponding amine is carried out as described in Step 6 above.
The présent disclosure încludes within its scope ail the possible isotopically labelled fonns of the compounds.
The compounds of the présent invention can be administered by oral, parentéral (e.g., intramuscular, intraperitoneal, intravenous, intraarticular, intrathecal, intraperitoneal, direct întraventricular, intracerebroventicular, intramedullary injection, intracistemal injection or infusion, subeutaneous injection or implant), ophtalmie, 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.
Altematively, one may administer the compounds in a local rather than systemic manner, for example, via injection of the compound dîrectly in the rénal or cardiac area, often in a modified release formulation. Furthermore, one may administer the drug in a targeted drug delivery System, for example, in a liposome coated with a tissue-specific antibody. The liposomes are taken up selectively by the targeted organ.
The pharmaceutical compositions of the présent invention usually contaîn 0.01 to 500 mg of the active ingrédient in a single dosage unît. However, it is possible that the amount of the active ingrédient in some compositions exceeds the upper or lower limits defmed 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 spécifie dose level and frequency of dosage for any particular patient may be varied and will dépend upon a variety of factors including the activity of the spécifie compound employed, the metabolic stability and length of action of that compound, the âge, body weight, general health, sex, dîet, mode and time of administration, rate of excrétion, drug combination, the severity of the particular condition and the host undergoing therapy.
As a further aspect of the invention, there is provided the pharmaceutical manufacture of médicaments containing the compounds of formula (I) or pharmaceutically acceptable salts, biologically active métabolites, pro-drugs, racemates, enantiomers, diastereomers, solvatés and hydrates thereof.
The pharmaceutical compositions of the présent 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, émulsions, suspensions, syrups, élixirs, oral drops; parentéral dosage forms, including, but not limited to, intravenous injections, intramuscular injections, subeutaneous injections; other dosage forms, including, but not limited to, eye drops, semi-solid eye préparations, nasal drops or sprays, transdermal dosage forms, suppositories, rectal capsules, rectal solutions, émulsions and suspensions, etc.
The pharmaceutical compositions of the présent invention can be manufactured in any conventîonal manner, e.g., by mixing, dissolving, emulsifying, suspending, entrapping, freezedrying, extruding, laminating, film-castîng, granulating, grinding, encapsulatîng, dragee-making or tabletting processes.
Pharmaceutical compositions for use in accordance with the présent 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 préparation of the dosage forms may be seiected from the following categories, including, but not limited to, tablet and capsule fillers, tablet and capsule binders, release modifying agents, disintegrants, glidants, lubricants, sweetenîng agents, tastemasking agents, flavorîng agents, coating agents, surfactants, antioxidants, buffering agents, complexing agents, emulsifyîng agents, lyophilization aids, microencapsulating agents, ointment bases, pénétration enhancers, solubilizing agents, solvents, suppository bases, and suspendîng agents.
In one embodiment, the invention relates to the use of spécifie excipients which are capable of improving the solubility, dissolution, pénétration, 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, emulsifyîng agents, lyophilization aids, superdîsintegrants, microencapsulating agents, pénétration enhancers, solubilizing agents, co-solvents, and suspendîng agents.
The above described ingrédients and different routes of manufacture are merely représentative. Other materials as well as processing techniques and the like well known in the art can also be used.
EX AMP LES
The invention is further defined in the following Examples. It should be understood that the Examples are given by way of illustration only. From the above discussion and the Examples, one skilled in the art can ascertain the essential characteristics of the invention, and without departing from the spirit and scope thereof, can make various changes and modifications to adapt the invention to various uses and conditions. As a resuit, the invention is not limited by the illustrative examples set fbrth herein below, but rather defined by the daims appended hereto.
In general, the compounds of formula (I) 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, températures, pressures, and other reaction conditions can readily be selected by one of ordinary skill in the art. Starting materials are commercial!y available and/or readily prepared by one skilled in the art.
The présent invention will be now illustrated by the followîng not limiting examples.
In the followîng examples “room température” dénotés a température in the range from 20 °C to 25 °C.
The abbreviations used in the spécifie examples hâve the followîng meanings:
AlEt3 tri ethyl aluminium conc. concentrated
DMSO dimethyl sulfoxide
EDC (l-ethyl-3-(3-dimethylaminopropyl)carbodiimide)
ESI electronspray ionisation
HATU (l-[bis(dimethylamino)methylene]-177-l,2,3-trÎazolo[4,5-6]pyridinium 3oxide hexafluorophosphate)
HEPES (4-(2-hydroxyethyl)-l-piperazineethanesulfonic acid)
LC-MS liquid chromatography coupled with mass spectroscopy
THF tetrahydrofuran
Step 1
Intermediate 1
diethyl ûxalate
Et,0 -----------*
NaOEt/EtOH
intermediate 1
Ethyl 4-(3,4-dimethoxyphenyI)-2,4-dioxobutanoate
In an inert atmosphère, diethyl oxalate (20 ml, 0.15 mol) was added to a sodium ethylate solution freshly prepared from sodium (3.5 g, 0.15 mol) and éthanol (300 mL). A solution of 1(3,4-dimethoxyphenyl)ethanone (9,20 g, 0.05 mol) in diethyl ether (150 mL) was added 5 dropwise, and the mixture was stirred for 2 hours at room température.
The reaction mixture was poured onto ice-water (500 mL) and acidified to pH=l-2 by the addition of 6 M HCl solution during cooling with ice. The yellow precipitate was collected by filtration, washed with water, and dried under vacuum at room température. Yield: 13.5 g (94 %) yellow solid, m/z (M+H)*: 281.2
The intennediates in Table 1 were synthesized according to the procedure described for
Intermediate 1. Ail necessary starting materials were purchased from different vendors.
Intermediate 12
Ethyl 4- (4- methoxy-3-methyIph enyl)-2,4-dioxo butano ate
The title compound was prepared from l-(4-methoxy-3-methylphenyl)ethanone according to the method described for Intermediate I.
l-(4-methoxy-3-methylphenyl)ethanone was synthesized according to the following method:
o
Under an inert atmosphère, to a solution of 2-methylanisol (7.92 g, 64.8 mmol) in dichloromethane (40 mL), aluminium chloride (9.45 g, 70.9 mmol) was added. To the obtained mixture (5.1 mL, 71.5 mmol) acetyl chloride was added dropwise, and the mixture was heated under reflux for 2 hours.
The reaction mixture was poured slowly onto 3 M HCl solution and extracted with diethyl ether. The combined organic layer was washed with saturated NaHCO3 solution and brine, dried over NajSOi and evaporated to dryness. Yield: 10.33 g (97 %) light yellow oil.
Intermediate 13
Ethyl 4-(3-methoxy-4-methylphenyl)-2,4-dioxobutanoate
The title compound was prepared from l-(3-methoxy-4-methylphenyl)ethanone according to the method described for Intermediate 1.
I-(3-methoxy-4-methylphenyl)ethanone was synthesized according to the following method:
Under an inert atmosphère, to a solution of 3-methoxy-4-methylbenzonitrile (2.00 g, 13.6 mmol) in tetrahydrofuran (50 mL), a méthylmagnésium chloride solution (5 niL, 3M in tetrahydrofuran) was added dropwise during cooling with ice at 0-2 °C, and the mixture was stîrred at 40 °C for 12 hours.
The reaction mixture was quenched b y dropwise addition of 6 M HCl solution (3.4 mL), and was stirred stîrred at 40 °C for another hour. The mixture was extracted with ethyl acetate, the combined organic layer was washed with brine, dried over Na2SO4, evaporated, and the crude residue was purified with column chromatography on silica gel with gradient elution, using a mixture of dichloromethane and cyclohexane as eluent. Yield: 356 mg (16 %).
Intermediate 14
Ethyl 4-[3-methoxy-4-(trifluorometliyl)pheiiyl]-2,4-dioxobutanoate
The tîtle compound was prepared from l-(3-methoxy-4-trifluoromethylphenyl)ethanone according to the method described for Intermediate 1.
l-[3-methoxy-4-(trifluoromethyl)phenyl]ethanone was synthesized according to the following method:
Under an inert atmosphère, to a solution of 3-methoxy-4-(trifluoromethyI)benzonitrile (4.11 g, 20.4 mmol) in diethyl ether (100 mL), a méthylmagnésium chloride solution (7.5 mL, 3M in tetrahydrofuran) was added dropwise during coolîng with ice at 0-2 °C, and the mixture was stirred at room température further for 2 hours.
The reaction mixture was quenched by dropwise addition of 6 M HCl solution (100 mL), and was stirred at room température for another hour. The mixture was extracted with ethyl acetate, the combined organic layer was washed with brine, dried over Na2SO4, evaporated, and the crude residue was purified with column chromatography on silica gel, using a 1:9 mixture of ethyl acetate and cyclohexane as eluent. Yield: 600 mg (13 %) yellow solid.
Intermediate 15
Ethyl 4-(l-methyl-lH-indazoI-5-yl)-2,4-dioxobutanoate
The title compound was prepared from l-(l-methyl~l/7-indazol-5-yl)ethanone according to the method described for Intennedîate 1.
-( 1 -methyl-1 /7-indazol-5-yl)ethanone was synthesized according to the following method:
A solution of 5-bromo-l-methyl-1/f-indazole (2.91 g, 13.8 mmol) in A-methyl-2pynolidone (55 mL) was purged with argon gas for 15 minutes. Tripotassium phosphate (5.85 g, 27.6 mmol), tributyl(l-ethoxyvinyl)tin (4.7 mL, 13.9 mmol) and tetrakis(triphenylphosphine)palladîum(0) (0.80 g, 0.69 mmol) were added, and the mixture was stirred at 80-90 °C for 6 hours under argon atmosphère. The réaction mixture was diluted with water, and extracted with ethyl acetate. The organic phase was treated with 1 M hydrochloric acid solution at room température by vîgorously stirring for 30 minutes. The pH of the mixture was adjusted to 7-8 by the addition of 25 % w/w aqueous ammonia solution, and extracted with ethyl acetate. The organic phase was washed with water, dried over Na2SO4, and evaporated to dryness. The residue was purified by column chromathography on silica gel using a mixture of ethyl acetate and cyclohexane (3:1) as eluent. Yield: 1.64 g (68 %).
Intermediate 16
Ethyl 4-(l,3-dimethyl-lZ/-inclazol-5-yl)-2,4-dioxobutanoate
The title compound was prepared from l-(l,3-dimethyl-l/f-mdazol-5-yl)ethanone according to the method described for Intermediate 1.
l-(l,3-dimethyl-l/7-indazol-5-yi)ethanone was prepared from 5-bromo-l,3-dimethyI-lj7indazol according to the method described for Intermediate 15.
5-bromo-l,3-dimethyl-17f-indazol was synthesized according to the following method:
To a suspension of sodium hydride (0.98 g, 24.5 mmol, 60 % in minerai oil) in YjV-dimethylformamide (70 mL), 5-bromo-3-methyl-IH-indazol (4.30 g, 20.4 mmol) was added în portions under an inert atmosphère at room température, and the obtained suspension was stirred further for 15 minutes, lodomethane (1.7 ml, 27.5 mmol) was added, and the mixture was stirred further for 3 hours at room température. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with 2 M Na2S2O3 solution and water, dried over Na2SO4, and evaporated to dryness. The regioisomeric products were separated by column chromathography on silica gel, using a mixture of ethyl acetate and cyclohexane (2:1) as eluent. Yîeld: 3.16 g (69 %) for the desired product 5-bromo-l,3-dimethyl-17/-indazol and 1.26 g (27 %) for 5-bromo-2,3-dimethyl-177-indazol.
Intermediate 17
o o
Ethyl 2,4-dioxo-4- [ ( 1 r,4 r)-4-(triflu o romethyl)cyclohexyl] butanoate
The title compound was prepared from l-[/rans-4-(trifluoromethyl)cyclohexyl]ethanone according to the method described for Intermediate 1.
l-[/rani-4-(trifluoromethyl)cyclohexyl]ethanone was synthesized according to the following method:
Under argon, atmosphère to a solution of Zran$-4-(trifIuoromethyl)cyclohexanecarboxylic acid (3.14 g, 16 mmol) in dry diethyl ether (75 mL), a methyl lithium solution in diethyl ether (1.6 M, 25 mL, 40 mmol) was added dropwise at
-20 °C to 15 °C for 45-60 minutes, and the mixture was stirred further at -15 °C for 1 hour. The reaction mixture was quenched by addition of saturated NH4CI solution (25 mL) (pH ~8) and water (25 mL) at 0 °C, and extracted with diethyl ether. The combined organic layer was dried over NasSOi, fïltered and concentrated in vacuo (at 350-400 mbar at room température). Yield: 3.075 g (99 %) colourless oil.
Intermediate 18
Ethyl 4-(cyclopent-3-en-l-yl)-2,4-dioxobutanoate
The title compound was prepared from l-(cyclopent-3-en-l-yl)ethanone according to the method described for Intermédiare 1.
l-(cyclopent-3-en-l-yl)ethanone was synthesized according to the following method:
To a solution of cyclopent-3-ene-l-carboxylic acid (1.346 g, 12 mmol) and a few drops of A(7V-dimethylformamide in dry dichloromethane (30 mL), oxalyl chloride (2.03 mL, 24 mmol) in dichloromethane (5 mL) was added dropwise at 25 °C under argon atmosphère. The reaction mixture was stirred for 30 minutes and the volatile components were removed in vacuo. The obtained cyclopent-3-ene-l-carbonyl chloride was dissolved in dichloromethane (25 mL), and the solution was added dropwise to a mixture of MO-dimethylhydroxylamine hydrochloride (1.117 g, 12 mmol) and triethylamine (3.68 mL, 26.41 mmol) in dry dichloromethane (25 mL) at 25 °C. The reaction mixture was concentrated in vacuo and suspended in ethyl acetate (30 mL). The suspension was fïltered, and the filtrate was concentrated in vacuo. The residue was chromatographed on silica gel, elutîng with a mixture of cyclohexane and ethyl acetate (7:3) to yield 1.043 g (78 %) of the Weinreb amide.
To a solution of Weinreb amide (1.043 g, 6.1 mmol) in diethyl ether (50 mL), a methyl lithium solution in diethyl ether (1.6 M, 4.54 mL, 7.26 mmol) was added dropwise at -65 °C to 78 °C, and the mixture was stirred further at -78 °C for 2 hours. The reaction mixture was allowed to warm to 0 °C, and quenched by the addition of 1 M HCl solution (10 mL) and water (10 mL) during ice cooling. The reaction mixture was extracted with diethyl ether, the combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo (at 350-400 mbar at room température). The title compound was obtained (0.663 g, 99 %) as an oil.
Step 2
Intermediate 19
intermediate 1
intermediate 19
Ethyl 5-(3,4-dimethoxyphenyI)-l,l-dioxo-2//-lL6,2,6-thiadiazine-3-carboxylate
To a suspension of Intermediate 1 (ethyl 4-(3,4-dimethoxyphenyl)-2,4-dioxobutanoate, 13.5 g, 48,2 mmol) in éthanol (280 mL), sulfamide (9.4 g, 98 mmol) and éthanol saturated with hydrogen chloride (30 %, 35 mL) was added, and the mixture was stirred at 60 °C (inner) ovemight. The obtained suspension was cooled in an ice-water bath, and the yellow precipîtate was collected by filtration, washed with cold éthanol, and dried in vacuo at 40 °C. Yield: 15,79 g (96 %) yellow solid, m/z (M+H)+: 341.1
The following intermediates in Table 2 were synthesized from the corresponding intermediates (1-18) according to the procedure described for Intermediate 19.
Table 2
Intermédiare | Structure | Starting intermediate | Intermediate | Structure | Starting intermediate |
20 | ,CL ΊΗ 1 Cl ^' ^ N NH X 0 0 | 2 | 29 | ^τ^χΥ FL JJH X 0 O | 17 |
21 | / o Q Ύ O._ /Z=\ 37 O ° ) | 3 | 30 | F 6L >ΝΗ X 0 O | 6 |
22 | ( J C ω< ^7 —o | 12 | 31 | X/ o^< YY° | 7 |
23 | ΎΥ JC NL .NH X □ 0 | 13 | 32 | 1 Υγ^γΥο N. ,NH X 0 O | 8 |
24 | YY 1 FaC^^'^>Y^>Y^Û a II 1 N^ -NU YY 0 0 | 4 | 33 | O ΥΥργΥο ,NH x 0 0 | 9 |
25 | F,C. X^ YY 1 N., ^NH X Û 0 | 14 | 34 | 1 0-r -X\ X^ T 1 o /Y 0 O | 10 |
26 | / O O— Y( O-, aY Z \ A— O °) | 5 | 35 | O-^^- 0 „NH X 0 0 | 11 |
27 | Z /z 'Z'” ° ) | 15 | 36 | /A ''^γΥΑο N ,'ΊΗ X O 0 | 18 |
28 | αΛΑ λ a N. -NU X O O | 16 |
Step 3
Intermediate 37
intermediate 19
intermediate 37
Ethyl 5-(3,4-diinethoxyphenyI)-2-methyH,l-dioxo-2/7-lX6,2,6-thiadiazine-3-carboxylate
A mixture of Intermediate 19 (8.26 g, 24.27 mmol), triethylamine (3.7 mL, 26.7 mmol) and iodomethane (17 mL, 273 mmol) in acetone (430 mL) was stirred at 56 °C for 4.5 hours.
The solvent was removed under reduced pressure, to the residue 5 % HCl solution (120 10 mL) was added, and the mixture was extra et ed with dichloromethane. The organic phase was washed with water, 5 % Na2S2O3 solution and water again. The combined organic layer was dried over Na2SO4, filtered, concentrated in vacuo and the residue was purified by column chromatography on silica gel, using a stepwise gradient of a mixture of cyclohexane and diisopropyl ether (40:1 to 10:1) as the eluent, to give 5.60 g (65 %) of the product as yellow 15 crystals.
The following intermediates in Table 3 were synthesized from the corresponding intermediates (see them in step 2) according to the procedure described for Intermediate 37.
Table 3
Intermediate | Structure | Starting intermediate | Inter- mediate | Structure | Starting intermediate |
38 | Z yj CK /Z=\ Λ ° ) | 28 | 48 | <T ° X /- <O v w< X/'0 O O iT / | 25 |
39 | va Τι T N. X X O O | 27 | 49 | Tl T N. A X Ί ο ο l | 23 |
40 | 1 I A 1 N, TL X 0 O | 22 | 50* | FsC'T ΤΑ|^γΑ:0 N. X Ί ο ο 1 | 29 |
41 | 1 î 0. Ak Ί 0 r< ,N. X O O | 20 | 51* | 1 °ΤΊ ΧΊ 0 0 1 | 34 |
42 | 0^ Cl /K Tl 1 hL _bh X O O | 21 | 52* | / η o'^' t< „r< X1 ο ο 1 | 31 |
43* | FaC, λ. λ. γη o '' l/Y K X O 0 | 29 | 53* | N. x η ο ο 1 | 32 |
44* | F F-yy lT'- T^xA, JT A O 0 | 30 | 54* | F f—yy >k X Ί ο ο 1 | 30 |
45 | / \ c c À ° ) | 19 | 55* | '.-y—, Q·^' Ty^%yo .N. x η ο ο 1 | 35 |
46 | XX X’ X Ί ο ο 1 | 24 | 56 | X^X ^ Tl ° ο ο 1 | 33 |
47 | >û... „-... XX 1 N. „N... ο ο 1 | 22 | 57* | / \ >ω /> —/ ° ° / | 36 |
W-dimethylfonnamide was applied as solvent instead of acetone
Intermediate 58
intermediate 19
Ethyl 2-[(25)-butan-2-yl]-5-(3,4-dimcthoxyphenyl)-l,l-dioxo-2j6r-lZ6,2,6-tliiadiazme-3carboxylate
To a suspension of Intermediate 19 (ethyl 5-(3,4-dimethoxyphenyl)-î,l-dioxo-2Z7lX6,2,6-thiadiazine-3-carboxylate, 3.74 g, 11 mmol), triphenyl phosphine (2.88 g, 11 mmol) and Æ-(-)-butan-2-ol (0.92 mL, 10 mmol) in a mixture of tetrahydrofuran (50 mL) and N,N10 dim ethyl formamide (10 mL) diisopropyl azodi carboxylate (2.2 mL, 11 mmol) was added dropwise during cooling with ice under an inert atmosphère. The obtained solution was heated under reflux for 7 hours, evaporated to dryness and the residue was purified by flash column chromatography on silica gel in two stages. At First, dichloromethane was used as the eluent, and in the second stage a slow gradient of a mixture of ethyl acetate and dichloromethane was 15 applied. Yield: 460 mg (12 %) yellow oil.
The optical purity was not determined in this stage, the product was used in the next step without separating the enantiomers.
The following intermediates in Table 4 were synthesized in Mitsunobu reaction from the Intermediate 19 according to the procedure described for Intermediate 58.
Table 4
Intermediate | Structure |
59 | hf s ο ο l |
60 | / \ O Cl o./M /) |
61 | J \ ό O |
Step 4
Intermediate 62
Intermediate 40
Intermediate 62
5-(4-methoxy-3-methyIphenyl)-2-niethyl-l,l-dioxo-2ff-lL6,2,6-thiadiazine-3-carboxylic acid
To a suspension of intermediate 40 (ethyl 5-(4-methoxy-3-methyIphenyl)-2-methyl-l,l10 dioxo-27¥-lX6,2,6-thiadiazine-3-carboxylate, 520 mg, 1.54 mmol) in éthanol (35 mL), 1 M aqueous NaOH solution (3 mL) was added, and the mixture was stirred at room température for 1 hour. The pH of the mixture was adjusted to 4-5 by the addition of 1 % HCl solution during cooling with ice. Ethanol was removed under reduced pressure, water was added, and the mixture was acidified further by the addition of 10 % HCI to pH=l-2. The mixture was extracted with ethyl acetate, the combined organic layer was washed with brine, dried over Na2SO4, fîltered and evaporated to dryness to give the product in a quantitative yield.
The followîng intermediates in Table 5 were synthesized via the hydrolysis of the 5 corresponding ester intermediates according to the procedure described for Intermediate 62.
Table 5
Intermediate | Structure | Starting intermediate | Intermediate | Structure | Starting intermediate |
63* | \ HO MLA A O O | 38 | 75 | F<C, x* HO Il Ί^° N .N. ΛΊ | 50 |
64* | Z O o, // / O | 39 | 76 | p— Os 7 \ z-!< / T ---' /7 ° O | 51 |
65 | 1 O H / —o | 37 | 77 | H0 N. .N. X Ί ο ο 1 | 52 |
66 | O / v yï —O | 41 | 78 | JHO N. X Ί ο ο 1 | 53 |
67 | 7 /r° O | 42 | 79 | F F—HÛ X Ί ο ο 1 | 54 |
68 | X'0 n. 0 0 | 43 | 80 | ':;yx ho 0 hL ο ο 1 | 55 |
69 | F F—HO N. AL A | 44 | 81 | HO Μγ^Αο r< .K X Ί ο ο । | 56 |
70 | / \ O O O o^=T oax —X° | 45 | 82 | HO SL X X Ί 0 o 1 | 57 |
71* | -Ύχ a SL ο ο 1 | 46 | 83 | XL YX T N, AL X T ο o L | 58 |
72* | n .o. ' Ί H° N. ο o l | 47 | 84 | / \ o o o >CA /) x / / \— o / o | 59 |
73* | N. AL X Ί ο ο 1 | 48 | 85 | U 9 o o \ / | 60 |
74 | ° \ /— V u>< W~Û o ' O / | 49 | 86 | o o—¥ W0 0 o o \ / | 61 |
*5 mol équivalents 5 M cône, aqueous NaOH solution
Step 5
Example 1
intermediate 65
Example 1
5-(3,4-dimethoxyphen yl)-2-methyl-7V-(3-methylpheny 1)-1, l-dioxo-2/f-l λ6,2,6-thiadiazine-3carboxamide
Under an inert atmosphère, to a suspension of Intermediate 65 (5-(3,4-dimethoxyphenyl)2-methyl-l,l-dioxo-2//-l λ6,2,6-thiadiazîne-3-carboxylic acid, 700 mg, 2.15 mmol) and 15 [bis(dimethylamino)methylene]-lÆ-l,2,3-triazolo[4,5-6]pyridinium 3-oxid hexafluorophosphate (HATU, 1.06 g, 2.79 mmol) in MA-dimethylformamide (20 mL) m-toluidine (0.46 mL, 4.3 mmol) and MAMiisopropylethylamine (1.48 mL, 8.50 mmol) was added during cooling with ice, and the obtained solution was stirred at room température for 2 days. 10 % HCl solution (100 mL) was added, and the mixture was extracted with ethyl acetate, the combined organic layer 10 was washed with water, dried over Na2SO4, and evaporated to dryness. The residue was purified by flash column chromatography on silica gel, applying gradient elution with a 0 to 2.5 % V/V ethyl acetate - dichloromethane mixture as eluent, and a subséquent crystallization from a mixture of dichloromethane and diethyl ether. Yield: 460 mg (52 %) yellow crystals, m/z (M+Hf: 416.1.
The following examples in Table 6 were synthesized according to the procedure (via
HATU coupling) described for Example 1.
Table 6
Example | Structure | LC-MS (ESI) ni/z (M+H)+ | Starting intermediate |
2 | / \ O O 7 \ | 485.1 | 65 |
3* | O XJ' K ,N^ X O O | purchased library compound* | - |
4 | Λλ JJ JL ta ta UN ta X □ O | 444.1 | 65 |
5 | θ o o X / | 430.2 | 65 |
6 | / \ û o J? 1 bv b | 430.1 | 65 |
7 | / \ 0 o ZZ=\ /) / Vi à | 442.1 | 65 |
8 | oZ Y b ^=r >w y) / ys ° P Z 1 | 427.1 | 65 |
9 | 8. X o o \ / | 446.0 | 65 |
10 | / X o o 4J1 z=\ >w Λ °Ύ ! />-* ^x s fl | 432.1 | 65 |
11 | X^-0Me XJ N N Λ O o | 432.1 | 65 |
12 | ,0^ XI N ^.N^ X Q 0 | 470.2 | 65 |
13 | 8» 5Xz Zv? Yz-0 b o o \ / | 450.1 | 65 |
14 | / \ ο ο yj ο,Χ ? / Τη | 416.1 | 65 |
15 | ο ? ο ο \ / | 417.1 | 65 |
16 | . Xk k| J ΗΝ Ν 'H^yy^A N Ν X Ο 0 | 417.1 | 65 |
17 | Μ> ο Α2 <° C/A θ ο ο X / | 417.1 | 65 |
18 | XX A Ap A un N J'L X ο Ο | 417.1 | 65 |
19 | / \ ο ο X* >ν> /? Ζ W / jH V 71 | 420.1 | 65 |
20 | οΖ \ yp/ CK ζζ=\ οϊΑα / V’ 0 □ | 436.1 | 65 |
21 | ' jOl %ΛΑ λ a Ζ^^ιΑί^0 N Ν X ο ο | 424.1 | 63 |
22 | ζ '‘Ζ' W1 >Μ /) °Μ Ζ Ai τ | 410.1 | 64 |
23 | ¢1 / /F A χο W'° —o | 454.1 | 62 |
24 | XX ^Ύ| HN — ' XX O 0 | 400.2 | 62 |
25 | o— cx / Ox /Z = \ >ω λ ° 'M / Vi δ ° 0 Q | 470.0 | 66 |
26 | । î A 0x A >is JV T| X HN ^ CFa ^XY^0 hL X O 0 | 474.0 | 66 |
27 | O— ÇX- \ // z—< 7 ys '0 | 420.0 | 66 |
28 | X । Ï Y_ z V ωί VZ^O | 420.2 | 67 |
29 | / \ O O *x o^2X // J h | 430.1 | 70 |
30 | XX x Tj HN Ci N^ >L X X ο ο 1 | 464.1 | 70 |
31 | / \ O O y_y CK / \ I X O | 484.2 | 70 |
32 | / \ ο ο Oh. /Z=\ T -—Λ— Z O 0 | 500.2 | 70 |
33 | XL γ[ UN N CF3 yYXpXo N. ,N. X Ί ο ο 1 | 485.2 | 70 |
34 | / \ O O / \ ^XJ / \ ^ X. | 444.2 | 70 |
35 | / \ O O X 0 O 0 | | 480.2 | 70 |
36 | o XI - Y| hN Cl ^YLrX° N^ >L K I ο ο 1 | 480.1 | 70 |
37 | J1 \ 0 O '0 O s D | 484.2 | 71 |
38 | £>Me xy 1^ HN Fi'Z'^Yf^Y0 JL J< 0 O l | 484.2 | 71 |
39 | XI Y^S HN CF, ρ,οΥΥγ^Υο N^ J< Ί ο ο 1 | 522.2 | 71 |
40 | XX Y| HN hL ,Ν^. X Ί ο ο 1 | 468.2 | 71 |
41 | 2, Z—Y y-Z \ / °\ ï | 468.2 | 71 |
42 | U 3 O Qj V trti O ' \ | 430.2 | 72 |
43 | XJ η UN N... J< X Ί ο ο 1 | 430.2 | 72 |
44 | & A Z—Y y— I \ / x5 <° (' «C \_ / vo 2—z O a ' \ | 468.2 | 72 |
45 | XX A| % HN ΑΛ^Αο N. >L X Ί ο ο 1 | 414.2 | 72 |
46 | U, Z—Y y-Z X / # X V \_ / ^-o )— Z O ' \ | 414.2 | 72 |
47 | XX HN v Tl χΧ^ΧγΑγΧ0 K j-N. .-M | 434.2 | 72 |
48 | Xi s HN ^ CF, x AJL^A A A ο ο 1 | 522.1 | 73 |
49 | xx XI X X ο ο 1 | 468.1 | 74 |
50 | F:,C r· N Λ Ί O O 1 | 498.2 | 75 |
51 | XX F—X UN CF3 N hL ο ο l | 466.1 | 79 |
52 | XI C ' χ-η UN F J bL Xk X Ί 0 O । | 428.1 | 80 |
*Purchased library compound from ChemDiv (compound ID: El35-0764)
Example 53
intermediate 75
2-ethyl-I,l-dioxo-5-[(lr,4F)-4-(trifluoromethyl)cyclohexyl]-Af-(6-(trifluoromethyI)pyridin-2yl]-2Zf-lX6,2,6-thiadiazine-3-carboxamide
In an inert atmosphère, to a solution of Intermediate 75 (2-ethyl-l,l-dioxo-5-[(lr,4r)-4(trifluoromethyl)cyclohexyl]-27/-lÀ6,2,6-thiadiazine-3-carboxylic acid; 500 mg, 1.41 mmol) and 10 W-dimethylformamide (3 drops) in dîchloromethane (20 mL), a solution of oxalyl chloride (0.24 mL, 2.82 mmol) in dîchloromethane (10 mL) was added dropwise at room température. After 15 minutes of stirring at room température, the reaction mixture was evaporated to dryness, dîchloromethane (20 mL) was added, and it was evaporated to dryness again. The residue (carbonyl chloride) was dissolved in tetrahydrofuran under an inert atmosphère, cooled to 0 °C, tripotassium phosphate (375 mg, 1.76 mmol) and 2-amino-6-(trifluormethyl)pyridine (229 mg, 1.41 mmol) was added, and the mixture was stirred at room température for 3 hours.
The inorganic salts were filtered off, the filtrate was concentrated, and the residue was purified by column chromatography on silica gel with a temer mixture of cyclohexane, ethyl 5 acetate and diisopropyl ether (40:10:1), as eluent. Yield: 440 mg (63 %), m/z (M+H) : 499.1.
The following examples in Table 7 were synthesized according to the procedure (via acid chloride coupling) described for Example 53.
Table 7
Example | Structure | LC-MS (ESI) m/z (M+H)+ | Starting intermediate |
54 | 4° ΕΥ / y 7 V * | 485.1 | 68 |
55 | v. jOl F—V > HN N XX0 0¾ | 453.1 | 69 |
56 | F XTlL ΗΝ'^Ν' ^F N, X O O | M+Na+ = 425.1 | 69 |
57 | FC Λ Λ 4 < > HN y CFj Y X. λ. Ys F N N. X Y ο ο 1 | 516.2 | 75 |
58 | O /) —/ Æ-Z ° | 499.1 | 75 |
59 | ^CFa YY F>c--Q K ^N. x η ο o l | 499.1 | 75 |
60* | Ρ^·-γη HnXXcF3 'ΎγγΥο X aî ί ο ο 1 | 500.1 | 75 |
61 | Gf o Z —Y /-- T \ / ίγ V ίΛ< \=J'° Ü | 449.2 | 75 |
62 | Cl F3c.._ X) 3 Ύ Y HN n N. J< Y Ί ο ο 1 | 465.1 | 75 |
63* | ,0 γΧ O' θ 0 n | 450.0 | 75 |
64* | ΡΑ'<·Ί hnXXf, 'XuY0 r< X Ί Q Ο 1 | 500.1 | 75 |
65 | u Χλ 'γη HN n xf3 N^ >L As ο ο 1 | 461.2 | 76 |
66 | _ Xjl· y N hn''^n’x^cf3 hL X Ί ο ο 1 | 445.2 | 77 |
67 | >w Λ A r | 445.2 | 78 |
68 | f F—ΗΝ·^^Ν' '€Ρ3 N N Ά Ί 0 0 1 | 467.1 | 79 |
69* | f Cl F-γ Y HN'^^N'^CFj XY° N X Ί ο ο 1 | 46S.2 | 79 |
70 | F Cl fCC HN'^'N' ^F N. ,N. X Y ο ο I | 417.1 | 79 |
71 | JÛL --h HN'^Tl' ’XF3 FL X Y ο ο 1 | 429.1 | 80 |
72 | Cl .Γ~η ΗΝ-^ΊΊ^^Ρ N, ,Ν„ X k ο ο 1 | 379.2 | 80 |
73 | Cl XX hn'^X'x^cf5 XX N^ -N. X Ί 0 0 ' | 431.1 | 81 |
74 | Cl <X ΗΜ'^ΝΖ T NL .N. χ η ο ο 1 | 381.1 | 81 |
75 | Cl Λ~η HN'^N'^'CFa ΧΥργΥο ,FL X Ί ο ο l | 415.1 | 82 |
76* | XL * P 3 UN N CN ΧχχΛ0 r< ne X J 0 0 1 | 456.1 | 75 |
77 | FC Λ XX N. .N. X J 0 0 1 | 463.1 | 75 |
78 | TT Ά Ί Û 0 1 | 495.1 | 75 |
79* | ^'γ-χ ™ΧΧ iXrX m JL «-y Ί | 450.1 | 75 |
80 | F. X1 5 'fj HN N^ CF.H χχ:;° N. X J 0 0 । | 481.3 | 75 |
81 | / \ 0 0 Xz O-. fX ÿ» /) X x X 0 i | 513.1 | 84 |
82 | / x | 0 0 w ~z.—l Οχ 7 —\ /) 0 | 513.1 | 83 |
83 | ,0^. n UN N CF, jh i 1 hk -N. oAo X) | 527.1 | 85 |
84 | XI v y HN N CF, Il J L NE _ Ό 0 0 LJ | 527.1 | 86 |
*Tri ethyl ami ne was applied (replacement of K3PO4 ) in dichloroethane, at 75 °C
Example 85
intermediate 65
Example 85
5-(3,4-d ime t hoxy pheny l)-2-met hy I-1, l-dioxo-TV-fl-propy 1-1 H-pyrazol-3-y 1)-2//- 1λδ,2,6thiadiazine-3-carboxamîde
Under an înert atmosphère, to a mixture of Intermediate 65 (5-(3,4-dimethoxyphenyl)-2methyl-l,l-dioxo-2//-ÎÀ6,2,6-thiadiazine-3-carboxylic acid; 210 mg, 0.64 mmol) and jV-(3dimethylaminopropyl)W^-ethylcarbodiimide hydrochloride (EDC, 248 mg, 1.29 mmol) in N,Ndimethylformamide (9 mL), l-propyl-lÆ-pyrazol-3-amine (99 mg, 0.79 mmol) and 4(dimethylamino)pyridine (209 mg, 1.71 mmol) was added, and the mixture was stirred at room température for 4 days. Another portion of l-propyL17/-pyrazol-3-amine (85 mg, 0.68 mmol) in A/AMimethyl formant! de (2mL) was added, and the mixture was stirred fiirther for 2 days. 10 % HCl solution was added, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with water, dried over Na2SO4, and evaporated to dryness. The residue was purified by column chromatography on silica gel with a mixture of ethyl acetate and cyclohexane (1:1), as eluent. Yield: 5 mg (2 %) yellow crystals, m/z (M+Hf: 434.1.
Example 86
Ar-(l-butyl-l//-pyrazol-4-yI)-5-(3,4-dimethoxyphenyl)-2-methyl-l,l-dioxo-2//-lL6,2,6thiadiazine-3-carboxamide (purchased library compound, Chemdiv (catalog no.: El35-0831)).
Step 6
Example 87
Intermediate 46
2-cthyl-5-[4-methoxy-3-(trifluorometliyl)phenyl]-l,l-dioxo-7V-[6-(trifluoromethyl)pyrÎdin2-yl|-2Z/-lL6,2,6-thiadiazine-3-carboxamide
To a solution of 2-amino-6-(triiluoromethyl)pyridine (389 mg, 2.4 mmol) in 1,2dichloroethane (3 mL), a solution of triethyl aluminium (L9M, 1.25 mL) in toluene was added dropwise at 20-25 °C during slight cooling under argon atmosphère, and the solution was stirred at room température for another hour. A solution of Intermediate 46 (ethyl 2-ethyl-5-[4methoxy-3-(tnfluoromethyl)phenyl]-l,l-dioxo-2H-]?'A2,6-thiadiazine-3-carboxylate, 203 mg, 0.5 mmol) in 1,2-dichloroethane (3 mL) was added, and the mixture was heated at 65 °C ovemight.
After cooling to room température. 1 M HCl solution (10 mL) was added dropwise, and the mixture was stirred at 35-40 °C for an hour. The phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic layer was washed with water, dried over Na2SO4, filtered, concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel, with a gradient of a mixture of diisopropyl ether and dichloromethane. Yield: 206 mg (79 %), m/z (M+H)1: 523.1.
Example 88 was synthesized from Intermediate 50 according to the procedure described for Example 82.
Example 88
2-e1hyl-V-(2-meUiylpyridin-4-yl)- l,l-dioxo-5-[( 1/,4/)-4- methylcyciohexyl]-2Æ-lk6,2,6thiadiazine-3-carboxamîdc, m/z (M+H)+: 499.1.
Step 7
Intermediate 87
intermediate 19 intermediate 87
5-(3,4-dimethoxyphenyl)-l,l-dioxo-2//-lX6,2,6-thiadiazin-3-carboxylic acid
To a suspension of Intermediate 19 (ethyl 5-(3,4-dimethoxyphenyl)-l,l-dioxo-2fflL6,2,6-thiadiazine-3-carboxylate, 8.00 g, 23.5 mmol) in éthanol (400 mL), an aqueous 5 M NaOH solution (19 mL) was added, and the mixture was stirred at room température for 2.5 hours. The pH of the mixture was adjusted to 5-6 by the addition of 3 M HCl solution during cooling with ice. The solvent was removed in vacuo, and dried at 40 °C in a drying oven until permanent mass had been achieved. The obtained product (containing significant amount of NaCi) was used in the next step without further purification (m/z (M+H)+: 313.1).
The following intermediates in Table 8 were synthesized according to the procedure described for Intermediate 87.
Table 8
Intermediate | Structure | Starting intermediate |
88 | ^yy H0 N. -NH X 0 0 | 29 |
89 | F F—HO N MH X O O | 30 |
90* | x j HO N NH X 0 0 | 26 |
91 | Il Ί H° pA^yy-o N. ^NH 0 O | 24 |
92 | - Ί| Ί H° bk ΉΗ Λ | 22 |
93* | ,0. TA A N NH X 0 O | 20 |
*2M conc. aqueous NaOH solution, 2-3 mol équivalents
Step 8
Intermediate 94
intermediate 87 intermediate 94
Propyl S-ia^-dimethoxyphenyO-lJ-dioxo-Z-propyl-lAT-lL^l^-thiadiazine-S-carboxylate
To a suspension of Intermediate 87 (5-(3,4-dimethoxyphenyl)-l,l-dioxo-2/f-lÀ6,2,6thiadiazine-3-carboxylic acid; 11.8 mmol) in y AMimethylformamîde (80 mL), sodium hydride (1.88 g, 47.0 mmol, 60 % in minerai oil) was added under an inert atmosphère.
1-bromopropane (21.3 mL, 235 mmol) was added, and the mixture was stirred at 80 °C ovemight. The reaction mixture was allowed to cool to room température, water (20 mL) and 10 % HCl solution (20 mL) was added, and it was extracted with ethyl acetate. The combined organic layer was washed with water, 1 M Na2S2O2 solution and brine, dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by column chromatography on silica gel, using a mixture of dichloromethane and diisopropyl ether (60:1) as eluent. Yîeld: 3.14 g (67 %) yellow crystals.
The following intermediates in Table 9 were synthesized according to the procedure described for Intennediate 94.
Table 9
Intermediate | Structure | Starting intermediate | Intermediate | Structure | Starting intermediate |
95* | N N X Ί ο ο l O 1 | 88 | 104 | F!C^r^ 0^7 /Q | 88 |
96* | F—Y > O 6L >L A ο ο l ^0 1 | 89 | 105 | Y Y Z V | 89 |
97 | ° /— C O \ / | 87 | 106 | / \ O O O O—/ ) Ω V | 87 |
98 | 1 O / o—¥ t—' O O \ / | 90 | 107 | / \ O O Y/ Χη | 87 |
99 | Xk x\ x^-. x YY L hk X Ί ο o L | 91 | 108 | AA _ YY YY3 hh A | 87 |
100 | \ X ° w A Y /— /X° | 92 | 109 | —° \ o—\ /— A ° O □ \ / | 87 |
101 | 1 \ ° / ο—Y i—' V X O □ \ | 93 | 110 | oX K Y ο ο 1 | 88 |
102 | Y . O—Y i—<J //A R° | O O O \ / | 87 | 111 | F 1 F—XX 0^^ r< x X Y 0 0 1 | 89 |
103 | G x^ XX YY ΐν FL X Ί 0 0 A | 92 |
*DIPEA was applied as the replacement of NaH
Step 9
The following intermediates in Table 10 were synthesized according to the procedure described for Intennediate 62, except that 1.2-1.5 mol eqvivalent, 1-2 M NaOH or LiOH solution was used.
Table 10
Inter- mediate | Structure | Starting intermediate | Intermediate | Structure | Starting intermediate |
112 | / \ O O Xz —( X O | 109 | 119“ | Λ XK, kl Ί H° X Ί ο o L | 99 |
113 | F’c γ> 1+0 XÎ N, X X T ο ο 1 | 110 | 120 | XK Xx YÙ T X | 102 |
114 | F HO hk -N, x X T 0 0 1 | 111 | 121 | FaC, 8 γη HO NL N, X | 104 |
115 | F,C p η ho N, X Ί OO l 0 1 | 95 | 122 | F HO NL J< X | 105 |
116 | F F-Ÿ^> HO hL ^N, X Ί oo L O 1 | 96 | 123* | / \ O O O-, /) 1 O- A O | 106 |
117 | ï”^ / fi S X W | 97 | 124* | H \=2 -° 7/ O O \ / | 107 |
118* | JE Xx - II Ί H° n, ή, Ai Ί ο o L | 94 | 125 | XK x-k Yi x >1^ °x | 108 |
*LiOH, 1 M cône., 1.3-2 mol équivalents, in THF **NaOH, 5 M cône., 4 mol équivalents
Step 5
The following examples in Table 11 were synthesized according to the procedure (via ester amidation in the presence of AlEt3) described for Example 87.
Table 11
Example | Structure | LC-MS (ESI) m/z (M+H)+ | Starting intermediate |
89 | XI Z UN CF3 N .NL Λ Y | 498.1 | 109 |
* 90 | XIΛ X| J HN Ν μ N F Y ο o । | 541.2 | 109 |
* 91 | y V 1=2 ° γ\ O O \ / | 499.1 | 109 |
92 | XI Z -ν' -¾. un Cl N N A Y | 464.1 | 109 |
« 93 | f,c^ XX J Y η Hbr n xf3 Ύί^ Xï 0 0 । | 513.1 | 110 |
94 | A- -i X__ / A Λ V \=ZZ O O \ / | 498.2 | 94 |
95 | XX ' Il χ ΗΝ CFj >L Λ Ί ο ο L | 499.1 | 94 |
96 | / \ ο ο ο | 516.1 | 98 |
97 | J1 \ ο ο Ο* >07 /) X | 537.1 | 99 |
98 | \ L Ο γχ Οχ ο W | 482.1 | 100 |
99 | 1 0 ο # ζ Λ> \ \=ζ ο Ο \ \ | 483.1 | 100 |
100 | XX X Α> ΗΝ CR ϊι 1 ϊ ci N AL ΧΊ 0 0 L | 502.1 | 101 |
101 | X A I \ / κ X τ’2 θ’ Ο Ô \ | 503.1 | 101 |
102* | XX Υ| η HN ^-^ CF, Λ1 | 510.2 | 102 |
103 | / \ ο ο χζ Οχ /Ζ=\ /ζ \ j; | 511.1 | 102 |
104 | X| q HN Cl As X 0 °A | 476.1 | 102 |
105 | XX UN CF. IJ ï /Άγγο 4Y | 494.1 | 103 |
106* | XyX N. JL X ri °°À | 525.1 | 104 |
107 | / \ o O Xz /) -J | 497.1 | 107 |
*Toluene was applîed as solvent at 80-110 °C
The following examples in Table 12 were synthesized according to the procedure described for Example 1 (amide couplîng with HATU reagent).
Table 12
Example | Structure | LC-MS (ESI) m/z (M+H)+ | Starting intermediate |
108 | l o to /7 A C “X O o \ / | 460.2 | 112 |
109 | o O . —\ /— # ZS V V/'O b o o 1 \ / | 497.1 | 112 |
110 | Cl X ^p y HN N FL _N.. x T O 0 J | 465.2 | 112 |
111 | XI ^jP y UN CF, FL x< η ο o L | 512.1 | 117 |
112 | / \ O O 0 O. /Z=\ ° h O £ o | 460.1 | 118 |
113 | Xk % ' ta'^r^0 N. .FL OX X | 444.1 | 118 |
114 | XI < y UN Cl ''O‘ '0 FL .FL X Ί ο o L | 464.2 | 118 |
115 | J \ r> o f J / ’k 1 7---' Λ— - ‘ 0 O 1 | 536.2 | 119 |
116 | / \ O O X/ z=\ r^ / \ t ^0 0 s œ | 472.1 | 120 |
117 | J = ta^ V <o< taz/-o J? O O \ / | 456.1 | 120 |
118 | Y HN YY CF, Η JL X 0 0 CFj | 53S.O | 123 |
119 | Z—V I \__ / rv A ° /° | 4S4.2 | 123 |
120 | XX Y γ ;ί| HN N N. 0 0 k | 458.1 | 124 |
121 | IL* Y Y Xy° ! A, O O \ / | 496.2 | 124 |
122 | » /Y 2—V /—< ) 1 \ \/ /Γ\ 'O \f toC W° X 0 Q \ / | 409.2 | 125 |
The following examples in Table 13 were synthesized according to the procedure described for Example 53 (amide formation via acid chloride dérivatives).
Table 13
Example | Structure | LC-MS (ESI) m/z (M+H)+ | Starting intermediate |
123 | Xa f V FV χ, O O \ / | 449.1 | 112 |
124* | Λ V 0 0 ι | 514.2 | 113 |
125 | FC Λ XI 3 Υη HN'^TJ^^F Y Q Ο 1 | M+Na = 485.1 | 113 |
126 | Vx XX F-γη UN N CFa ^'Y N. JL >4 Y ο ο 1 | 481.2 | 114 |
127 | % ><Λ Λ cY \2_# Y H | M+Na+= 453.1 | 114 |
128 | 4 - -p | 529.1 | 115 |
129 | FC Λ Xi 3 J'-f] HN'^^N'^^F hL ^hL X Ί ο o L 0 1 | M+Na+ = 479.1 | 115 |
130 | F X1 F-V^y HN^N CF1 kAγ<¾γΛ0 X X ο o L 1 | 497.1 | 116 |
131 | -V^' ΗΝ'^ζΧ'Ρ X ,N, TS<C Ί ο o L 0 1 | 447.1 | 116 |
132 | FA/ | z z=\ Y 0 ° 0 Tl | M+Na+= 497.2 | 121 |
133 | . XJ > HN N lA N. ,N. X X 0 00 | 475.1 | 121 | |
134 | F F—X' | XX S HN N CF3 K JL X Ί °°A | 493.2 | 122 |
135 | F F— | XX η HN N F hk JL X Ί OO0 | M+Na+= 465.1 | 122 |
136* | 2=/ A “'zY X- Z 0 | 514.3 | 113 | |
137* | XX X HN'^^N'^^CFÎ ιΓί 0 r< /Q | 526.3 | 121 | |
138* | Xl HN'^XN'^xF x Y 0 0 1 | 464.3 | 113 | |
139* | F3C | Xi Il bh >L X Ί OO0 | 476.3 | 121 |
*Triethylamine was applied (replacement of K3PO4) in dichloroethane, at 75 °C
74 |
Préparation of pharmaceutical compositions
The following formulation examples îllustrate représentative pharmaceutical compositions of this invention. The présent invention, however, is not limited to the following pharmaceutical compositions.
A) Solid oral dosage forms
L, Tablets
Active ingredient(s) | 0.01-90% |
Fi lier | 1 - 99.9 % |
Binder | 0-20 % |
Disintegrant | 0-20 % |
Lubricant | 0-10% |
Other spécifie excipient(s) | 0-50 % |
IL, Orodispersible films Active ingredient(s) | 0.01 -90% |
Film forming agent | 1 - 99.9 % |
Plasticizer | 0-40 % |
Other spécifie excipient(s) | 0-50 % |
B) Liquid oral dosage forms
IIL, Oral suspensions
Active ingredient(s) | 0.01 - 50 % |
Liquid vehicle Wettîng agent | 10-99.9 % 0-50 % |
Thickener | 0-50 % |
Buffering agent | quantum satis |
Osmotic agent | 0-50 % |
Preservatives | quantum satis |
IV., Syrups
Active ingredient(s)
Solvent
Sugar component
Flavouring agents
C) Parentéral dosage fornis
K, Intravenous injections
Active ingredîent(s)
Solvent
Co-solvent
Osmotic agent
Buffering agent
D) Other dosage forms
VL, Suppositories
Active ingredîent(s)
Suppository base Surface-active agents
Lubricants
Preservatives
VIL, Nasal drops or nasal sprays
Active ingredient(s)
Water
Solvent
Co-solvent
Osmotic agent
Viscosity enhancer
Buffering agent
Preservatives
0.01 -50%
10-99.9%
- 20 %
0-10%
0.01-50%
10-99.9%
- 99.9 %
0-50 % quantum satis
0.01 -50%
- 99.9 %
0-20 %
0-20 % quantum satis
0.01 -50%
- 99.9 %
0-99.9 %
- 99.9 %
0-20 %
0-20 % quantum satis quantum satis
BIOLOGICAL ACTIVITY
Human a 7 nicotinic acétylcholine receptor [Ca h assay
Cells: Flp-In 293 cells stably expressing human a7 nAchR and human RÏC-3 (a7 cells, generated in house.)
Materials: 96-well plates coated with PDL (Falcon), culture medium, assay buffer, DMSO, FLIPR Calcium 5 kit (Molecular Devices), probenecid, agonist and PAM test compounds.
Culture medium:
- DMEM (Dulbecco's Modified Eagle Medium, Gibco)
- 10 % FBS (Fêtai Bovine Sérum, Gibco)
- 1 % glutamine (Sigma G)
- 50 pg/ml Hygromycin B
- 800 pg/ml G418
- 1 % penicillin-streptomycin-antimycotic sol.
(PSA, Sigma)
Assay buffer:
- 140 mM NaCl
- 5 mM KC1
- lOmMHEPES
- 2 mM MgCl2
- 2 mM CaCl2
- 10 mM glucose
- 2 mM probenecid, pH=7.4
Brief description of the method (Ca fluorometry) «7 cells cells stably expressing human a7 nAchR were cultured in the medium detaiied above, and were split twice a week. For the fluorometric measurements of cytosolic Ca2+ ion concentration ([Ca2+]j) cells were seeded in 96-well microplates at a density of 60000 cells/well and maintained ovemight in a tissue culture incubator at 37 °C under an atmosphère of 95 % air/5 % CO2. The plating medium was identical with the culture medium. 50 μΐ of the growth medium was aspirated with a cell washer (BioTek Elx405UCVWS). Then 50 μΐ/well Calcium 5 kit diluted 2-fold in assay buffer was added manually using an 8-channel pipette. After an incubation period (20 minutes, 37 °C) 50 μΐ/well assay buffer containing vehicle (DMSO, 4 % added) or reference a7 PAMs (4 x of the final concentration) were added manually and the cells were incubated for an additional 10 minutes at 37 °C. Baseline and agonist-evoked [Ca2+]i changes were monitored with FlexStation II (Molecular Devices, Sunnyvale, CA), a plate reader fluorometer with integrated 8-channel fluid addition capability. Fluorescence measurements were carried ouï at 37 °C. The dye was excited at
485 nm, émission was sampied at 525 nm at 1.4-s întervals. Baseline was recorded for 20 5 seconds foilowed by agonist stimulation. 50 μΐ 4 x concentrated agonist solution was added to the cells using the pipettor of FlexStation II and fluorescence was monitored for an addîtional 40 seconds. Final DMSO concentration was 1 % for ail treatments. To achieve this, a sériés of DMSO stock solutions were prepared from ail test compounds. These stocks were stored under 0 °C and were further diluted in assay buffer to obtain the desired final concentration immediately 10 before the measurement. Agonist and P AM concentration-response studies were conducted in the presence of saturating concentrations of PAMs (mostly PNU-120596, 5 μΜ) and agonists (mostly PNU-282987, 1 μΜ), respectively. Results were expressed as AF/F values using SoftMax Pro software (Molecular Devices), where F was the resting fluorescence preceding agonist application and AF was the increase in fluorescence at a given time (AF = maximum 15 fluorescence intensity values after stimulation minus average fluorescence intensity values before stimulation). In ail experiments, ail treatments were measured in multiple wells in parallel, and the mean AF/F values were used for analysis.
Table 14 shows the PAM EC50 values in the [Ca2+]i assay:
Table 14
Example | EC50 (nM) | Example | EC50 (nM) | Example | EQo (nM) |
1 | 430 | 48 | 330 | 95 | 45 |
2 | 1400 | 49 | 490 | 96 | 330 |
3 | 690 | 50 | 1100 | 97 | 30 |
4 | 980 | 51 | 810 | 98 | 100 |
5 | 210 | 52 | 1600 | 99 | 40 |
6 | 1300 | 53 | 90 | 100 | 150 |
7 | 2000 | 54 | 480 | 101 | 65 |
8 | 1800 | 55 | 470 | 102 | 320 |
9 | 1600 | 56 | 2500 | 103 | 110 |
10 | 670 | 57 | 2000 | 104 | 370 |
11 | 440 | 58 | 1200 | 105 | 120 |
12 | 230 | 59 | 1300 | 106 | 70 |
13 | 340 | 60 | 300 | 107 | 55 |
14 | 1400 | 61 | 100 | 108 | 1300 |
15 | 3000 | 62 | 2800 | 109 | 240 |
16 | 1400 | 63 | 190 | 110 | 640 |
17 | 2800 | 64 | 330 | 111 | 200 |
18 | 2900 | 65 | 1100 | 112 | 75 |
19 | 1600 | 66 | 430 | 113 | 80 |
20 | 940 | 67 | 220 | 114 | 380 |
21 | 230 | 68 | 140 | 115 | 85 |
22 | 370 | 69 | 1100 | 116 | 100 |
23 | 400 | 70 | 620 | 117 | 110 |
24 | 210 | 71 | 140 | 118 | 530 |
25 | 1400 | 72 | 430 | 119 | 380 |
26 | 360 | 73 | 390 | 120 | 120 |
27 | 110 | 74 | 1100 | 121 | 220 |
28 | 1200 | 75 | 960 | 122 | 320 |
29 | 340 | 76 | 85 | 123 | 55 |
30 | 440 | 77 | 1500 | 124 | 110 |
31 | 440 | 78 | 790 | 125 | 45 |
32 | 720 | 79 | 320 | 126 | 220 |
33 | 50 | 80 | 350 | 127 | 580 |
34 | 130 | 81 | 120 | 128 | 310 |
35 | 150 | 82 | 120 | 129 | 190 1 |
36 | 310 | 83 | 310 | 130 | 960 |
37 | 45 | 84 | 130 | 131 | 1800 |
38 | 45 | 85 | 2000 | 132 | 35 |
39 | 150 | 86 | 2900 | 133 | 230 |
40 | 60 | 87 | 10 | 134 | 80 |
41 | 100 | 88 | 1400 | 135 | 120 |
42 | 120 | 89 | 290 | 136 | 150 |
43 | 110 | 90 | 1200 | 137 | 130 |
44 | 360 | 91 | 35 | 138 | 140 |
45 | 210 | 92 | 290 | 139 | 150 |
46 | 170 | 93 | 120 | ||
47 | 500 | 94 | 340 |
In vivo pharmacology (place récognition test)
Animais: Male NMRI mice (Toxicoop, Hungary)
Substances: 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.
Procedure: The task was carried out in a transparent plexîglass Y-maze (each arm has a length of 40 cm, an înner width of 11 cm and a height of 30 cm). Numerous visual eues were 10 placed around the anns and were kept constant during the experiment. The test consisted of two trials (Tl and T2) separated by an intertrial interval of 30 minutes. Mice were placed in the starting ann of the maze at the beginnîng of each trial. In Tl, one of the symmetric arms ofthe maze was closed (it will be novel in T2) and the animais were allowed to explore the maze for 5 minutes (acquisition phase). In T2, mice had free access to ail three arms for 2 minutes (retrieval 15 phase). The time spent with exploration in the novel and familiar arms during T2 was measured.
Différences between the exploration tîmes spent in the familiar vs. novel arms of the maze for each group were evaluated by MANOVA, followed by Duncan post hoc test.
Table 15 shows the reversai of the scopolamine-induced amnesîa in the place récognition assay in mice:
Table 15
Dose (i.p.) | |||
1 mg/kg | 3 mg/kg | 10 mg/kg | |
Example 1 | ++ | +++ | —H |
Example 21 | ++ | +++ | ++ |
Example 29 | +++ | ++ | +++ |
Example 33 | +++ | ++ | ++ |
Example 37 | +++ | ++ | +++ |
Examp le 91 | +++ | + | +-H- |
Example 94 | +++ | +++ | 4-++ |
+p<0.05; ++p<0.01; ^+p<0.001
Sigmficant différences (+p<0.05; ^p^ Ol; ^+p<0.001) were observed between the exploration times spent in the novel vs. familiar arms of the maze.
Claims (13)
1. A compound of formula (I),
(I) wherein
A is saturated, unsaturated or aromatic, monocyciic or bycyclic, fused or bridged carbocyclyl, or a saturated, unsaturated or aromatic monocyciic or bycyclic, fused or bridged heterocyclyl, optionally substituted by one or more halogen atom or halogen atoms, Cj. 6alkyl, Ci.6alkoxy, or haloCi.6alkyl;
B is saturated, unsaturated or aromatic, monocyciic or bycyclic, fused or bridged carbocyclyl, or a saturated, unsaturated or aromatic monocyciic or bycyclic, fused or bridged heterocyclyl, optionally substituted by one or more halogen atom or halogen atoms, Ci. 6alkyl, Ci.6alkoxy, haloCj.6alkyl, CN, CCCOC^alkyl, or haloC^alkoxy;
R1 is C|.6alkyl, Cj^alkenyl, haloC^alkyl, C3-8cycloalkylC].6alkyl, Cj-calkoxyCpéalkyl, or Coheterocyclyl;
or pharmaceutically acceptable salis, racemates, enantiomers, diastereomers, solvatés and hydrates thereof.
2. The compound according to claim 1, wherein
A is an optionally substituted saturated, unsaturated or aromatic, 4-9 membered monocyciic or bycyclic, fused or bridged carbocyclyl, or a saturated, unsaturated or aromatic 4-9 membered monocyciic or bycyclic, fused or bridged heterocyclyl containing 1-3 heteroatoms selected from the group of nitrogen, and oxygen;
B is an optionally substituted saturated, unsaturated or aromatic, 4-9 membered monocyciic or bycyclic, fused or bridged carbocyclyl, or a saturated, unsaturated or aromatic 4-9 membered monocyclic or bycyclic, fused or bridged heterocyclyl containing 1-3 heteroatoms selected from the group of nitrogen, and oxygen;
R1 is Cp6alkyl, Ci.6alkenyl, haloC].6alkyl, C3.8cycloalkylCi-6alkyl, Cj-6alkoxyCMalkyl, or C4_6heterocyclyl.
3. The compound according to any one of daims 1 or 2, wherein
A is an optionally substituted cyclopentenyl, cyclohexyl, phenyl, cycloheptyl, bicyclo[3.1.0]hexanyl or indazolyl;
B is an optionally substituted phenyl, pyridyl, pyrazyl, pyrazînyl, pyrîmidinyl, benzodioxolyl, 1,2,3,4-tetrahydro-isoquinolinyl, or pyrazolo[l,5-«]pyridinyl;
RI is CH3j C2H5, nPr, jPr, «Bu, secBu, allyl, -CH2-CF3, -CH2-cBu, -CH2-cPr, -C2H5-O-CH3, or tetrahydrofuryl.
4. The compound according to any one of daims 1 to 3, selected from tire group of:
5-(3,4-dimethoxyphenyl)-2-methyl-7V-(3-methylphenyl)-1,1 -dioxo-2i/-lL6,2,6-thiadîazine3-carboxamide;
5-(l ,3-dimethylJ #-mdazol-5-yl)-2-methyl-iV-(3-methylphenyl)-1,1 -dioxo-2/f-l λ6,2,6thiadiazine-3 -carboxamide;
5-(3,4-dimethoxyphenyl)-2-ethyl-A'-(3-methyiphenyl)-l,l-dioxo-2H-l?A2,6-thiadiazine-3carboxamide;
5-(3,4-diniethoxyphenyl)-2-ethy]-l,l-dioxo-AL[6-(trilluoromeihyl)pyridin-2-yl]-2Æ-lX6,2,6thiadiazine-3 -carboxamide;
2-ethyl-5-[4-inethoxy-3-(trifluoromethyl)phenyl]-A-(3-methoxypheny 1)-1,1-dioxo-2/71 X6,2,6-thiadîazine-3 -carboxami de;
2-ethyl-5-[4-methoxy-3-(trifluoromethyI)phenyl]-7V-(4-methoxyphenyl)-i,l-dioxo-2//l/?,2,6-thiadiazine-3-carboxamide;
2-ethyl-l,l-dioxo-5-[(lr,4r)-4-(trifluoromethyl)cyclohexyl]-A-[6-(trifluoromethyl)pyridiii2-yl]-2/7-lÀ6,2,6-thiadiazine-3-carboxamide;
Ar-(6-cyanopyridin-2-yl)-2-ethyl-l, 1 -dioxo-5-[(lr,4r)-4-(trifluoromethyl)cydohexyl]-2/7lX6,2,6-thiadiazine-3-carboxamide;
5-(3,4-dimethoxyphenyl)-1,1 -dioxo-2-(propan-2-yl)-À46-(trifluoromethyl)pyridm-2-yl]-2/^ l/?,2,6-thiadiazine-3-carboxamide;
5-(3,4-dimethoxyphenyl)-1,1 <1ίοχο-2-ρΓοργ1-Λ-[3 -(trifluoromethyl)phenyi]-2H-1 λ6,2,6thiadiazine-3-carboxamide;
5-(3,4-dimethoxyphenyl)-1,1 -dioxo-2-propyl-AL[6-(trifiuoromethyl)pyridin-2-yl]-2/7l?A2,6-thiadiazine-3-carboxamide;
5-[4.methoxy-3-(trifluoromethyI)phenyl]-l,l-dioxo-2-propyl-Ar-[6-(trifluoromethyl)pyridin2-yl]-2Æ-lXÊ,2,6-thiadiazine-3-carboxamide;
5-(4-methoxy-3-methylphenyl)-l,l-dioxo-2-propyl-jV-[6-(triiluoromethyl)pyridin-2-yl]-2/7lXX,6-thiadiazme-3-carboxamide;
5-(3-chloro-4-methoxyphenyl)-l,l-dioxo-2-piOpyl-jV-[6-(trinuoromethyl)pyridin-2-yl]-2/ïlX6,2,6-thiadiazine-3-carboxamide;
2-(cyclopiOpylmethyl)-l,l-dioxo-5-[(lr,4r)-4-(trifluoromethyl)cyclohexyl]-iV-[6(trifluoromethyl)pyridin-2-yl]-2//-lX6,2,6-thiadiazine-3-carboxamide;
5-(3,4-dimethoxyphenyl)-1,1 -dîoxo-2-(prop-2-en-1 -yl)-A^6-(trifluoromethyl)pyridin-2-yl] 2H-lL6,2,6-thiadiazine-3-carboxamide;
5 _(3,4-dimethoxyphenyl )-V-(4-methoxy phenyl)-1,1 -dioxo-2-propy 1-2/7-1 L6,2,6-thiadiazine3-carboxamide;
5.(354.dimeÎhoxyphenyl)-jV-(3-methylphenyl)-l,l-dioxo-2-piOpyl-2//-lk6,2,6-thiadiazine-3carboxamide;
5-[4-methoxy-3-(trifluoromethyl)phenyl]-lJ-dioxo-2-propyl-V-[3<trifluoromethyl)phenyl]2J/-lk6,2,6-thiadiazine-3-carboxamide;
5-(3,4-dimethoxyphenyl)-N-(6-fluoropyridin-2-yl)-1,1 -dioxo-2-(propan-2-yl)-2Æ-lλ6,2,6thi adîazine-3 -carboxamide ;
jV-(6-fluoropyridin-2-yl)-l,l-dioxo-2-(propan-2-yl)-5-[(lr,4r)-4(trifluoromethyl)cyclohexyl]-2/7-1 λ6,2,6-thiadiazine-3-carboxamide;
2-(cyclopropylmethyl)-A-(6-fiuoropyrazin-2-yl)-1,1 -dioxo-5-[(lr,4r)-4(trifluoromethyl)cyclohexyl]-2/7-1 λ6,2,6-thîadiazine-3-carboxamide;
2-[(2R)-butan-2-yl]-5-(3,4-dimethoxyphenyl)-l,l-dioxo-N-[6-(trjfluoiOmethyl)pyridin-2yl]2H-lZ6,2,6-thiadiazine-3-carboxamide;
2-ethyl-5-[4-methoxy-3-(trifluoromethyl)phenyl |-1,1 -dioxo-N-[6-(trifluorom ethyl )pyridin2-yl]-2H-lX6,2,6-thiadiazine-3-carboxamide;
l,l-dioxo-2-(propan-2-yl)-5-[(lr,4r)-4-(trifluoromethyl)cyclohexyl]-N-[6(Îrif1uoromethyl)pyrazin-2-yI]-2H-lZ6,2,6-thiadiazine-3-carboxamide;
2-(cyclopropylmethyI)-5-(4,4-difluorocyclohexyl)-l,l-dioxo-N-[6-(trifluoromethyl)pyridin2-yl]-2H-l À6,2,6-thiadiazine-3-carboxamide;
2-(cy clopropy 1 m ethyl )-1,1 -di oxo-5 - [( 1 r,4r)-4-(tri fl uoromethy 1 )cyclohexy 1 ] -N-[2(trifluoiOmeihyl)pyrimidii>4-yl]-2H-lXX,6-thiadiazine-3-carboxamide;
or pharmaceutically acceptable salts, racemates, enantiomers, diastereomers, solvatés and hydrates thereof.
5. A compound according to any one of claîms 1 to 4, for use in the treatment or prévention of a disease associated with «7 nicotinic acétylcholine receptor activîty.
6. A compound for use according to claim 5, wherein the disease 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 resuit of stroke, Alzheimer's disease, Huntîngton'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, amyotrophie latéral sclerosis, other acute or sub-acute conditions that may cause cognitive décliné, including, but not limited to, delirium, traumatic brain injury, senile dementia, mild cognitive impairment, Down’s syndrome, dépréssion and cognitive déficit related to other diseases, and dyskinetic disorders including, but not limited to, Parkînson's disease, neuroleptic-induced parkinsonism, or tardive dyskinesîas, dépréssion and mood disorders, including, but not limited to, dépressive disorders and épisodes, bipolar disorders, cyclothymie 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, and anxiety disorder not otherwise specified, 5 substance related disorders, including, but not limited to, substance use or substance-induced disorders, including, but not limited to, alcohol-, nicotine-, amphétamine-, phencyclidine-, opioid-, cannabis-, cocaïne-, caffeine-, hallucinogen-, inhalant-, sédative-, hypnotic-, anxiolytic-, polysubstance- or other substance-related disorders, sleep disorders, including, but not limited to, narcolepsy, dyssomnîas, prîmary hypersomnia, breathing-related sleep
10 disorders, circadian rhythin 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, sleep disorder due to a general medical condition and substance-induced sleep disorder, metabolîc and eating disorders, including, but not limited to, anorexia nervosa, bulimia nervosa, obesity, compulsive eating
15 disorder, binge eating disorder and eating disorder not otherwise specified, diabètes mellitus, ulcerative colitis, Crohn’s disease, irritable bowel syndrome, autîsm spectrum disorders, including, but not limited to, autistic disorder, Asperger's disorder, Retfs disorder, childhood disintegrative disorder and pervasive developmental disorder not otherwise specified, attention déficit hyperactivity disorder, disruptive behaviour disorders. oppositional défiant
20 disorder and disruptive behaviour disorder not otherwise specified, and tic disorders, including, but not limited to, Tourette's disorder, personality disorders, sexual dysfonctions such as sexual desire disorders, sexual arousal disorders, orgasmic disorders, sexual pain disorder, sexual dysfonction not otherwise specified, paraphilias, gender identity disorders, infertîlity, premenstrual syndrome and sexual disorders not otherwise specified. disorders of
25 the respiratory System like cough, asthma, chronic obstructive pulmonary disease, lung inflammation, disorders of the cardiovascular System such as cardiac failure, heart arrhythmia, hypertension, inflammation, inflammatory and neuropathie pain, rheumatoid arthritis, osteoarthritis, allergy, sarcoidosis, psoriasis, ataxia, dystonia. systemic lupus erythematosus, mania, restless legs syndrome, progressive supranuclear palsy, epilepsy, 30 myoclonus, migraine, amnesia, chronic fatigue syndrome, cataplexy, brain ischemia, multiple sclerosis, encephalomyelitis, jetlag, cérébral amyloid angiopathy, and sepsis.
7. A compound for use according to claim 6, wherein the disease is selected from the group of cognitive impairment, schizophrenia, and autism.
8. A pharmaceutical composition comprisîng as active ingrédient a compound according to any one of daims 1 to 4 and at least one pharmaceutically acceptable excipient.
9. A pharmaceutical composition according to daim 8, wherein the composition further comprises at least one other active ingrédient.
10. A pharmaceutical composition according to daim 9, wherein the other active ingredient(s) are selected from the group of acetylcholinestérase inhibitors, NMDA receptor antagonists, beta- secretase inhibitors, antipsychotics, GABAa receptor alpha5 subunit NAMs or PAMs, histamine H3 receptor antagonists, 5-HTô receptor antagonists, Ml or M4 mAChR agonists or PAMs, mGluR2 antagonists or NAMs or PAMs, and levodopa.
11. Combination of a compound according to any one of daims 1 to 4 and at least one other active ingrédient for use in the treatment or prévention of a disease associated with a 7 nicotinic acétylcholine receptor activity.
12. Combination for use according to daim 11, wherein the other active ingredient(s) are selected from the group of acetylcholinesterase inhibitors, NMDA receptor antagonists, beta- secretase inhibitors, antipsychotics, GABAa receptor alpha5 subunit NAMs or PAMs, histamine H3 receptor antagonists, 5-HT6 receptor antagonists, Ml or M4 mAChR agonists or PAMs, mGluR2 antagonists or NAMs or PAMs, and levodopa.
13. Process for the manufacture of compounds of formula (I) according to daim 1, characterized by, reacting formula (lia) or formula (Ilb) A^°H A. À ¥¥ ?
ο O (Ha)(Ilb) or
- wherein the meaning of A is a saturated, unsaturated or aromatic, monocyclic or bycyclîc, fused or bridged carbocyclyl or is saturated, unsaturated or aromatic, monocyclic or bycyclîc, fused or bridged heterocyclyl,- with methyl lithium, or reacting compound of formula (Ile)
A.
Br (Ile)
- wherein the meaning of A is an aromatic, monocyclic or bycyclic, fused or bridged carbocyclyl or an aromatic, monocyclic or bycyclic, fused or bridged heterocyclyl, optionally substituted by one or more Ci^alkyl, Ci-6alkoxy, haloCj^alkyl - with
5 tributyl(l -elhoxyvinyl)tin, or reacting compound of formula (Ild)
H (Hd) with acetyl chloride - wherein the meaning of A is an aromatic, monocyclic or bycyclic, fused or bridged carbocyclyl or an aromatic, monocyclic or bycyclic, fused or bridged heterocyclyl, optionally substituted by one or more Ci^alkyl, C].6alkoxy, haloCi-ealkyl,
10 halogen — to obtain the ketone dérivative of formula (III)
V
O (iii)
- wherein the meaning of A is as described above for formula (I) — which is reacted with diethyl oxalate to provide 2,4-dioxo ester dérivative of formula (IV)
O O (IV)
15 - wherein the meaning of A is as described above for formula (I) - which is reacted with sulfamide, and then the obtaîned l,l-dioxo-l,3-thiadiazine carboxylic acid ester dérivative of formula (V)
(V)
- wherein the meaning of A is as described above for formula (I) - is transformed to the desired end product of the formula (I) in different ways:
Route a) the compound of formula (V) is alkylated to furnîsh A-alkyl thiadiazine
5 derîvative of formula (VI)
(VI)
- wherein the meaning of A and R1 is as described above for formula (I) - which is hydrolysed leading to carboxylic acid derîvative of formula (VII)
(VII)
10 - wherein the meaning of A and R1 is as described above for formula (I) - which is coupled with an appropriate amine (B-NH2) - wherein the meaning of B is as described above for formula (I) - to provide tire desired amide of formula (I) or
Route B) the ester derîvative of fonnula (V) is hydrolysed to furnish the carboxylic acid derîvative of formula (VIII)
(VIII)
-wherein the meaning of A is as described above for the formula (I) - which is then N,0dialkylated in one step resulting the corresponding ester compound of formula (X)
(X)
-wherein the meaning of A and R1 is as described above for the formula (I) - which is either hydrolysed to dérivative of formula (VII)
(VII)
-wherein the meaning of A and R! is as described above for formula (I) - and then
10 reacted with the appropriate amine (B-NH2) resulting in the targeted amide dérivative of formula (I),
o o (1) or compound of formula (X)
-wherein the meaning of A and R1 is as described above for the formula (I) - is transformed directly to the amide dérivative of the formula (I) by reaction with the
5 appropriate amine (B-NH2).
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
HUP1800249 | 2018-07-13 |
Publications (1)
Publication Number | Publication Date |
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OA20785A true OA20785A (en) | 2023-05-05 |
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