HK40081003A - Kv3 modulators - Google Patents

Kv3 modulators Download PDF

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HK40081003A
HK40081003A HK62023069926.1A HK62023069926A HK40081003A HK 40081003 A HK40081003 A HK 40081003A HK 62023069926 A HK62023069926 A HK 62023069926A HK 40081003 A HK40081003 A HK 40081003A
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Hong Kong
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compound
disorders
benzofuran
dione
imidazolidine
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HK62023069926.1A
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Chinese (zh)
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HK40081003B (en
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Alvaro Giuseppe
Marasco Agostino
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Autifony Therapeutics Limited
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Publication of HK40081003A publication Critical patent/HK40081003A/en
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Kv3 modulators
Technical Field
The present invention relates to novel compounds, pharmaceutical compositions comprising them and their use in therapy, in particular in the prevention or treatment of hearing disorders including hearing loss and tinnitus as well as schizophrenia, substance abuse disorders, pain and fragile X syndrome.
Invention backLandscape
The Kv3 family of voltage-gated potassium channels includes four members, Kv3.1, Kv3.2, Kv3.3, and Kv 3.4. The Kv3 channel is activated by depolarizing the plasma membrane to a voltage more positive than-20 mV; in addition, the channels are rapidly inactivated upon membrane repolarization. These biophysical properties ensure that the channel opens towards the peak of the depolarised phase of the neuron action potential to initiate repolarisation. The rapid termination of action potentials mediated by Kv3 channels allows neurons to recover faster to reach sub-threshold membrane potentials from which further action potentials can be triggered. As a result, the presence of Kv3 channels in certain neurons contributes to their ability to fire at high frequencies (Rudy et al, 2001). The Kv3.1-3 subtype predominates in the CNS, whereas the Kv3.4 channel is also found in skeletal muscle and sympathetic neurons (Weiser et al, 1994). The Kv3.1-3 channel subtypes are differentially expressed by subsets of interneurons in cortical and hippocampal brain regions (e.g., Chow et al, 1999; Martina et al, 1998; McDonald et al, 2006; Chang et al, 2007), thalamus (e.g., Kasten et al, 2007), cerebellum (e.g., Sacco et al, 2006; Puente et al, 2010), and auditory brainstem nuclei (Li et al, 2001).
Tetraethylammonium (TEA) has been shown to inhibit the channel at low millimolar concentrations (Rudy et al, 2001), and blood inhibitory substance (BDS) toxins from sea anemones (Anemonia sulcata) (Diochot et al, 1998) have been shown to selectively inhibit Kv3 channel with high affinity (Yeung et al, 2005).
The Kv3 channel is an important determinant of cerebellar function, the brain region important for motor control (john et al, 2009). Characterization of mice in which one or more of the Kv3 subtypes are absent suggests that the absence of Kv3.1 results in increased motor activity, altered electroencephalographic activity, and fragmented sleep patterns (john et al, 1999). The absence of Kv3.2 results in a decrease in seizure threshold and altered cortical electroencephalographic activity (Lau et al, 2000). The absence of Kv3.3 is associated with mild ataxia and motor deficits (McMahon et al, 2004). The double deletion of Kv3.1 and Kv3.3 produces a severe phenotype characterized by spontaneous seizures, ataxia and increased sensitivity to the effects of ethanol (Espenosa et al, 2001; Espenosa et al, 2008). Spontaneous mutations in the Kv3.1 gene (KCNC1) cause progressive myoclonic epilepsy (Muona et al, 2014). Human Kv3.3 gene (KCNC3) mutations were associated with a form of spinocerebellar ataxia (SCA13) (Figuerioa et al, 2010).
Bipolar disorders, schizophrenia, anxiety and epilepsy are serious disorders of the central nervous system that are associated with reduced function of inhibitory interneurons and gamma-aminobutyric acid (GABA) transmission (Reynolds et al, 2004; Benes et al, 2008; Brambilla et al, 2003; Aroniadou-anderijaska et al, 2007; Ben-Ari, 2006). Murine osteocalcin positive basket cells expressing Kv3 channels in the cortex and hippocampus play a key role in generating feedback inhibition in local loops (Markram et al, 2004). Given the relative advantage of excitatory synaptic inputs over inhibitory inputs to glutamatergic pyramidal neurons in these circuits, rapid firing of interneurons that provide inhibitory inputs is essential to ensure equilibrium inhibition. Furthermore, accurate timing of inhibitory inputs is necessary to maintain network synchronization, for example, in generating gamma frequency field potential oscillations associated with cognitive function (Fisahn et al, 2005; Engel et al, 2001). Notably, a reduction in gamma oscillations was observed in schizophrenia patients (Spencer et al, 2004) and evidence suggests that expression of kv3.1, but not kv3.2, was reduced in the dorsolateral prefrontal cortex of schizophrenia patients who did not take antipsychotic drugs at least 2 months prior to death (Yanagi et al, 2014). Thus, positive modulators of Kv3 channels may be expected to enhance the firing capability of a specific group of rapidly firing neurons in the brain. These effects may be beneficial in diseases associated with abnormal activity of these neuronal groups. Furthermore, kv3.2 channels have been shown to be expressed by neurons of the optically crossed nucleus (SCN) of the major circadian pacemaker in the CNS (Schulz et al, 2009).
The Kv3 family of voltage-gated ion channels are expressed at high levels in the auditory brainstem nucleus (Li et al, 2001), where they allow rapid firing of neurons that transmit auditory information from the cochlea to higher brain regions. Phosphorylation of kv3.1 and kv3.3 channels in auditory brainstem neurons has been shown to contribute to a rapid physiological adaptation to sound levels, which may play a protective role during exposure to noise (Desai et al, 2008; Song et al, 2005). Loss of kv3.1 channel expression in central auditory neurons was observed in hearing-impaired mice (von Hehn et al, 2004); furthermore, a decrease in Kv3.1 expression may be associated with hearing loss in older mice (Jung et al 2005), and a loss of Kv3 channel function may also occur after noise trauma-induced hearing loss (pilat et al 2012). Furthermore, the pathological plasticity of the auditory brainstem network may contribute to the symptoms experienced by many people with different types of hearing loss. Recent studies have shown that modulation of kv3.1 channel function and expression has a major role in controlling auditory neuron excitability (Kaczmarek et al, 2005; Anderson et al, 2018; Glait et al, 2018; Olsen et al, 2018, Chambers et al, 2017), suggesting that this mechanism may account for some of the plastic changes that cause tinnitus. Tinnitus may occur following noise-induced hearing loss due to adaptive changes in the central auditory pathway from the brainstem to the auditory cortex (Roberts et al, 2010). The kv3.1 and/or kv3.2 channels are expressed in many of these circuits and contribute to the function of GABA-inhibitory interneurons that control the function of these circuits.
Kv3.1 and/or Kv3.2 modulators are known to be useful in the treatment of pain (WO 2017/098254). In the broadest sense, pain can be classified as acute pain and chronic pain. Acute pain is defined as self-limiting pain and usually requires treatment for no more than a few weeks, e.g. post-operative or acute musculoskeletal pain, e.g. fractures (us food and drug administration, 2014). Chronic pain may be defined as pain that persists for more than 1 month after the initial trauma has subsided, or pain that persists for more than 3 months. Chronic pain is usually not of definite cause, and many other health problems such as fatigue, depression, insomnia, mood changes and reduced exercise are often accompanied by chronic pain.
Chronic pain can be subdivided into the following groups: neuropathic pain, chronic musculoskeletal pain, and miscellaneous chronic pain. Neuropathic pain is often accompanied by tissue damage and is caused or caused by damage to the nervous system (peripheral nervous system and/or central nervous system), such as amputation, stroke, diabetes, or multiple sclerosis. Chronic musculoskeletal pain may be a symptom of diseases such as osteoarthritis and chronic low back pain, and may occur following muscle tissue injury as well as regional trauma (e.g., fractures, sprains, and dislocations). Miscellaneous chronic pain includes all other types of chronic pain, and includes non-neuropathic pain conditions such as cancer pain and fibromyalgia as well as headache and tendonitis.
Chronic pain is a highly heterogeneous disorder that remains one of the most troublesome and difficult to manage clinical indications (McCarberg et al, 2008; Woolf, 2010; Finnerup et al, 2015). Despite years of research and drug development, there has been little progress in identifying treatments that can be matched in efficacy to opioids without significant side effects and risk of dependence. Voltage-gated ion channels have become important targets for managing specific pain indications, particularly neuropathic pain states. Furthermore, genetic mutations in specific ion channels are associated with some chronic pain disorders (Bennett et al, 2014). Examples of voltage-gated ion channels being explored as drug targets include: sodium channels (particularly nav1.7) -Sun et al, 2014; Dib-Hajj et al, 2013; n-type calcium channels-Zamponi et al, 2015; kv7 potassium channel-Devulder, 2010; wickenden et al, 2009; and SLACK-Lu et al, 2015.
A potential hypothesis for these approaches is that chronic pain states are associated with increased excitability and/or abnormal firing of peripheral sensory neurons, particularly neurons involved in the transmission of painful sensory stimuli, such as the C-fibers of the dorsal root ganglia and specific circuits within the spinal cord (Baranauskas et al, 1998; Cervero, 2009; Woolf et al, 2011; Baron et al, 2013). Animal models of neuropathic and inflammatory chronic pain provide the major support for this hypothesis, but there is still a lack of proof of causal relationships (Cervero, 2009).
Drugs that target hyperexcitability, such as sodium channel blockers (e.g., CNV1014802, lamotrigine, carbamazepine and local anesthetics), Kv7 positive modulators (e.g., flupirtine (flupenteritine) and retigabine) and N-type calcium channel modulators (e.g., gabapentin interacting with the α 2 δ subunit of N-type calcium channels and ziconide derived from conotoxin) show efficacy in inflammatory and/or neuropathic pain models. However, in these drugs there is mixed evidence of clinical efficacy, such as balanced efficacy and increased burden on the central nervous system side effects. The difference between efficacy in animal models and efficacy in humans may be due to a range of factors, but in particular the achievable drug concentration in humans (due to poor tolerance) and the different kinds of pain conditions in humans may be the main cause. There is also a need for identification of targets by which pain relief can be achieved with reduced tolerance or tachytolerance and reduced abuse liability and/or risk of dependence for pain indications.
Thus, pharmacological management concerns that improve pain may deliver mechanisms of good efficacy, with reduced side effect burden, reduced tolerance or tachytolerance, and reduced abuse liability and/or risk of dependence.
More recently, kv3.4 channels have become a target of interest for the treatment of chronic pain. The Kv3.4 channels are expressed on neurons of the dorsal root ganglia (Ritter et al, 2012; Chien et al, 2007), where they are expressed predominantly on sensory C-fibers (Chien et al, 2007). Kv3 channels are also expressed by specific subsets of neurons in the spinal cord. In particular, Kv3.1b (Deuchars et al, 2001; Brooke et al, 2002), Kv3.3(Brooke et al, 2006) and Kv3.4 subunits (Brooke et al, 2004) have been identified in rodent spinal cords, but are not always associated with circuits involving sensory processing. The Kv3 channel may contribute to the firing characteristics of spinal neurons, including motor neurons.
Furthermore, recent studies have shown that kv3.4 channels expressed in DRG nociceptors have a significant effect on glutamatergic synaptic transmission (Muqeem et al, 2018). Animal model data indicate that kv3.4 channel surface expression is down-regulated in DRG neurons following spinal cord injury associated with hypersensitivity to pain stimuli (Ritter et al 2015; Zemel et al 2017; Zemel et al 2018). Similarly, a down-regulation of kv3.4 expression has been observed in DRGs in rodents after spinal cord ligation (Chien et al, 2007). The latter study also showed that intrathecal administration of rat antisense oligonucleotides to inhibit expression of kv3.4 results in hypersensitivity to mechanical stimuli. It has been shown that kv3.4 channel inactivation may be affected by protein kinase C-dependent phosphorylation of the channel, and that this physiological mechanism may allow DRG neurons to change their firing characteristics in response to painful stimuli (Ritter et al, 2012). These studies indicate a causal relationship between the occurrence of mechanical allodynia and a decrease in kv3.4 channel expression or function. Expression of kv3.1, kv3.2, or kv3.3 in SC or DRG neurons was not assessed in any of these studies, and expression of these two subtypes was not clearly demonstrated on DRG neurons (although, as noted above, they were abundant in specific regions of the spinal cord). The in vivo studies reported above provide the rationale for modulating kv3.4 as a novel approach to the treatment of certain neuropathic pain states.
Dementia with lewy bodies (DLB) and Parkinson's Disease (PD) are serious neurodegenerative diseases that are associated with the accumulation of the protein a-synuclein in lewy bodies, which leads to loss of connectivity and neuronal cell death. Symptoms of DLB include progressive cognitive deficits, particularly planning and attention difficulties. Pseudoscopic vision is also common, occurring in approximately 60% of patients. PD was initially associated with motor deficits, primarily due to loss of dopamine neurons. While no studies have been currently made to directly correlate the Kv3 channel with DLB or PD, the location and role of Kv3 channels, particularly Kv3.1, in the cortical and basal ganglia circuits suggests that modulators of these channels may ameliorate the symptoms of DLB or PD, either alone or in combination with current therapies (e.g., acetylcholinesterase inhibitors for DLB or L-DOPA for PD).
Patent applications WO2011/069951, WO2012/076877, WO2012/168710, WO2013/175215, WO2013/083994, WO2013/182850, WO2017/103604, WO2018/020263 and WO2018/109484 disclose compounds that are modulators of kv3.1 and kv 3.2. Furthermore, the utility of such compounds is demonstrated in animal models of seizures, hyperactivity, sleep disorders, psychosis, hearing disorders, and bipolar disorders.
Patent application WO2013/182851 discloses the modulation of kv3.3 channels by certain compounds.
Patent application WO2013/175211 discloses that modulation of kv3.1, kv3.2 and/or kv3.3 channels has been found to be beneficial in preventing or limiting the establishment of permanent hearing loss caused by acute noise exposure. Such a prophylactic benefit can be observed even after discontinuing administration of the kv3.1, kv3.2, and/or kv3.3 modulators.
Patent application WO2017/098254 discloses that modulation of kv3.1, kv3.2 and/or kv3.3 channels has been found to be beneficial in the prevention or treatment of pain, in particular neuropathic or inflammatory pain.
Patent application WO2019/222816 discloses 'meta-linked' pyridinyl compounds of the general formula:
it is considered to be a modulator of Kv3.1 and/or Kv3.2 channels.
Patent application WO2020/000065 discloses 'meta-linked' diazine and triazine compounds of the general formula:
it is considered to be a modulator of Kv3.1 and/or Kv3.2 channels.
There remains a need to identify alternative modulators of kv3.1, kv3.2 and/or kv3.3, in particular modulators of kv3.1 and/or kv 3.2. Such modulators may exhibit high in vivo efficacy, channel selectivity, improved safety profiles or desirable pharmacokinetic parameters, such as high intracerebral availability and/or low clearance, which reduces the dose required for in vivo therapeutic effect. Alternative modulators may provide benefits by having different metabolites from known modulators. Compounds having balanced kv3.1, kv3.2, and/or kv3.3 modulating properties may be desirable, for example compounds that modulate kv3.1 and kv3.2 to the same or similar extent. For certain therapeutic indications, it is also desirable to identify compounds that have different modulating effects on kv3.1, kv3.2, and/or kv3.3 channels, e.g., compounds that alter the kinetics of channel gating or channel inactivation and may act in vivo as negative modulators of channels.
Summary of The Invention
The present invention provides compounds of formula (I):
wherein:
R 1 is H or methyl;
R 2 and R 3 Are both methyl, or R 2 And R 3 Together with the carbon atom to which it is attached is a spiro cyclopropyl ring;
R 4 is methyl or ethyl;
R 5 is H or methyl;
or R 4 And R 5 Together with the carbon atom to which they are attached form C 3 -C 4 A spiro carbocyclyl group.
The compounds of formula (I) may be provided in the form of salts and/or solvates thereof. Suitably, the compound of formula (I) may be provided in the form of a pharmaceutically acceptable salt and/or solvate thereof and/or a derivative thereof. In one embodiment of the invention, the compounds of formula (I) are provided in the form of pharmaceutically acceptable salts.
The compounds of formula (I) may be used as medicaments, in particular for the prevention or treatment of hearing disorders, including hearing loss and tinnitus, as well as schizophrenia, substance abuse disorders, pain or fragile X syndrome.
In addition, methods of preventing or treating hearing disorders (including hearing loss and tinnitus) and hearing disorders (including hearing loss and tinnitus) as well as schizophrenia, substance abuse disorders, pain or fragile X syndrome are provided.
The compounds of formula (I) are useful for the preparation of a medicament for the prevention or treatment of hearing disorders including hearing loss and tinnitus as well as schizophrenia, substance abuse disorders, pain or fragile X syndrome.
Also provided are pharmaceutical compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier or excipient.
Also provided are processes for preparing compounds of formula (I) and novel intermediates useful for preparing compounds of formula (I).
Also provided are prodrug derivatives of the compounds of formula (I).
Detailed Description
The present invention provides compounds of formula (I):
wherein:
R 1 is H or methyl;
R 2 and R 3 Are both methyl, or R 2 And R 3 Together with the carbon atom to which it is attached is a spiro cyclopropyl ring;
R 4 is methyl or ethyl;
R 5 is H or methyl;
or R 4 And R 5 Together with the carbon atom to which they are attached form C 3 -C 4 A spiro carbocyclyl group;
or a pharmaceutically acceptable salt and/or solvate and/or derivative thereof.
The following relates to the radicals (including R) 1 、R 2 、R 3 、R 4 、R 5 ) Are contemplated to be independently, i.e., chemically sensitive, and fully combinable with each other to form additional embodiments of the present invention, where appropriate. Such embodiments are equally applicable to the following intermediates: which can be used for the synthesis of compounds of formula (I), for example compounds of formulae (II), (IV), (VI), (VII) and (XVI).
The compounds of formula (I) may optionally be provided in the form of pharmaceutically acceptable salts and/or solvates. In one embodiment of the invention, the compounds of formula (I) are provided in the form of pharmaceutically acceptable salts. In a second embodiment of the invention, there is provided a compound of formula (I) in the form of a pharmaceutically acceptable solvate. In a third embodiment of the invention, the compound of formula (I) is not in the form of a salt or solvate.
In one embodiment, R 1 Is H. In a second embodiment, R 1 Is methyl.
In one embodiment, R 2 Is methyl, and R 3 Is methyl. In another embodiment, R 2 And R 3 Is spirocyclopropyl, so as to form the following moiety:
in one embodiment, R 4 Is a methyl group. In a second embodiment, R 4 Is ethyl.
In one embodiment, R 5 Is hydrogen. In a second embodiment, R 5 Is a methyl group.
In one embodiment, R 4 And R 5 The same (i.e., methyl).
In which R is 4 And R 5 In various embodiments, they may have the following stereochemical arrangement:
in this embodiment, for example, R 4 Is methyl and R 5 Is H, R 4 Is ethyl and R 5 Is H, or R 4 Is ethyl and R 5 Is methyl.
In which R is 4 And R 5 In various embodiments, they may also have the following stereochemical arrangement:
in this embodiment, for example, R 4 Is methyl and R 5 Is H, R 4 Is ethyl and R 5 Is H, or R 4 Is ethyl and R 5 Is methyl.
In one embodiment, R 4 And R 5 Together with the carbon atom to which it is attached form a spirocyclopropyl group.
In another embodiment, R 4 And R 5 Together with the carbon atom to which it is attached form a spirocyclobutyl group.
In one embodiment, the compound of formula (I) is selected from:
5, 5-dimethyl-3- [5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yl) oxypyrazin-2-yl ] imidazolidine-2, 4-dione;
3- [5- [ (3, 3-dimethyl-2H-benzofuran-4-yl) oxy ] pyrazin-2-yl ] -5, 5-dimethyl-imidazolidine-2, 4-dione;
(5R) -5-ethyl-5-methyl-3- (5-spiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-oxopyrazin-2-yl) imidazolidine-2, 4-dione;
5, 5-dimethyl-3- (5-spiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yloxypyrazin-2-yl) imidazolidine-2, 4-dione;
(5R) -5-ethyl-5-methyl-3- [5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yl) oxopyrazin-2-yl ] imidazolidine-2, 4-dione;
(5R) -3- [5- [ (3, 3-dimethyl-2H-benzofuran-4-yl) oxy ] pyrazin-2-yl ] -5-ethyl-5-methyl-imidazolidine-2, 4-dione;
5, 5-dimethyl-3- [5- [ (3,3, 7-trimethyl-2H-benzofuran-4-yl) oxy ] pyrazin-2-yl ] imidazolidine-2, 4-dione;
(5R) -5-ethyl-5-methyl-3- [5- [ (3,3, 7-trimethyl-2H-benzofuran-4-yl) oxy ] pyrazin-2-yl ] imidazolidine-2, 4-dione;
(5R) -5-ethyl-3- [5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yl) oxopyrazin-2-yl ] imidazolidine-2, 4-dione;
(5R) -5-ethyl-3- (5-spiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yloxypyrazin-2-yl) imidazolidine-2, 4-dione;
(5R) -3- [5- [ (3, 3-dimethyl-2H-benzofuran-4-yl) oxy ] pyrazin-2-yl ] -5-ethyl-imidazolidine-2, 4-dione;
(5R) -5-ethyl-3- [5- [ (3,3, 7-trimethyl-2H-benzofuran-4-yl) oxy ] pyrazin-2-yl ] imidazolidine-2, 4-dione;
7- [5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yl) oxypyrazin-2-yl ] -5, 7-diazaspiro [3.4] octane-6, 8-dione;
or a pharmaceutically acceptable salt and/or solvate and/or derivative thereof.
In one embodiment, the compound of formula (I) is:
6- [5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yl) oxypyrazin-2-yl ] -4, 6-diazaspiro [2.4] heptane-5, 7-dione;
or a pharmaceutically acceptable salt and/or solvate and/or derivative thereof.
In one embodiment, the compound of formula (I) is:
(5S) -5-ethyl-3- [5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yl) oxypyrazin-2-yl ] imidazolidine-2, 4-dione;
or a pharmaceutically acceptable salt and/or solvate and/or derivative thereof.
When the compound contains C 1-3 When an alkyl group, either alone or as part of a larger group, the alkyl group may be straight-chain, branched-chain, or cyclic. C 1-3 Examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl and cyclopropyl. Reference to "propyl" includes n-propyl, isopropyl and cyclopropyl.
The term "halo" or "halogen" as used herein refers to a fluorine, chlorine, bromine or iodine atom. Specific examples of halogen are fluorine, chlorine and bromine, for example chlorine or bromine.
The term' C as used herein 3-4 Spiro carbocyclyl' refers to a cyclic ring system containing 3 or 4 carbon atoms, i.e., cyclopropyl or cyclobutyl, wherein the cyclic ring system is attached to a secondary carbon via a spiro center such that the secondary carbon is one of 3 to 4 carbon atoms in the cyclic ring, as shown below:
it will be appreciated that for use in medicine, salts of the compounds of formula (I) should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art. Pharmaceutically acceptable salts include those described by Berge, Bighley, and Monkhouse j.pharm.sci. (1977)66, pp 1-19. Such pharmaceutically acceptable salts include acid addition salts formed with inorganic acids (e.g., hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acids) and organic acids (e.g., succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acids). Non-pharmaceutically acceptable salts may be used, for example, to isolate the compounds of formula (I) and are included within the scope of the invention.
Certain of the compounds of formula (I) may form acid addition salts with one or more equivalents of an acid. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.
The compounds of formula (I) may be prepared in crystalline or amorphous form and, if crystalline, may optionally be solvated, for example as a hydrate. The present invention includes within its scope stoichiometric solvates (e.g., hydrates) as well as compounds containing variable amounts of solvent (e.g., water).
It is to be understood that the present invention includes pharmaceutically acceptable derivatives of the compounds of formula (I) and that such derivatives are included within the scope of the present invention.
As used herein, "pharmaceutically acceptable derivative" includes any pharmaceutically acceptable ester of a compound of formula (I) or salt of such ester, which upon administration to a recipient is capable of providing (directly or indirectly) a compound of formula (I) or an active metabolite or residue thereof.
Pharmaceutically acceptable prodrugs can be prepared, for example, by using the group "L" (where R is R) as exemplified below 4 And R 5 As described above) functionalize the secondary nitrogen of the hydantoin to form:
in one embodiment of the invention, the compound of formula (I) is functionalized by a group L via the secondary nitrogen of the hydantoin, wherein L is selected from:
a)–PO(OH)O - ·M + wherein M is + Is a pharmaceutically acceptable univalent counter ion,
b)–PO(O - ) 2 ·2M + ，
c)–PO(O - ) 2 ·D 2+ wherein D is 2+ Is a pharmaceutically acceptable divalent counterion,
d)–CH(R X )–PO(OH)O - ·M + wherein R is X Is hydrogen or C 1-3 An alkyl group, a carboxyl group,
e)–CH(R X )–PO(O - ) 2 ·2M + ，
f)–CH(R X )–PO(O - ) 2 ·D 2+ ，
g)–SO 3 - ·M + ，
h)–CH(R X )–SO 3 - ·M + and is and
i)–CO–CH 2 CH 2 –CO 2 ·M + 。
it is to be understood that the present invention encompasses all isomers of formula (I) and pharmaceutically acceptable derivatives thereof, including all geometric, tautomeric and optical forms and mixtures thereof (e.g. racemic mixtures). When additional chiral centers are present in the compounds of formula (I), all possible diastereomers, including mixtures thereof, are included within the scope of the invention. The different isomeric forms may be separated or resolved from each other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric synthesis.
The present application includes all isotopic forms of the compounds of the present invention provided herein, whether in the form of: (i) wherein all atoms of a given atomic number have a mass number (or mixture of mass numbers) that predominates in nature (referred to herein as "the natural isotopic form") or (ii) wherein one or more atoms are replaced by an atom having the same atomic number but a mass number different from the mass number of the atom predominating in nature (referred to herein as "the non-natural variant isotopic form"). It is understood that atoms may occur naturally as a mixture of mass numbers. The term "non-natural variant isotopic form" also includes embodiments in which the proportion of atoms of a given atomic number having a mass number less common in nature (referred to herein as "uncommon isotopes") is increased relative to the proportion of atoms that are naturally present, for example to a level of > 20%, > 50%, > 75%, > 90%, > 95% or > 99% (by atomic number of that atomic number) (the latter embodiment being referred to as "isotopically enriched variant form"). The term "non-natural variant isotopic form" also includes embodiments in which the proportion of an uncommon isotope has been reduced relative to the proportion that is naturally present. Isotopic forms can include radioactive forms (i.e., they incorporate a radioisotope) and nonradioactive forms. The radioactive form is typically an isotopically enriched variant form.
Thus, the non-natural variant isotopic form of a compound can contain one or more artificial or unusual isotopes, such as deuterium (b) in one or more atoms 2 H or D), carbon-11 ( 11 C) Carbon-13 (C) 13 C) Carbon-14 (C) 14 C) Nitrogen-13 ( 13 N), nitrogen-15 ( 15 N), oxygen-15 ( 15 O), oxygen-17 ( 17 O), oxygen-18 ( 18 O), phosphorus-32 ( 32 P), sulfur-35 ( 35 S), chloro-36 ( 36 Cl), chloro-37 ( 37 Cl), fluorine-18 ( 18 F) Iodine-123 ( 123 I) Iodine-125 ( 125 I) Or may contain an increased proportion of the isotope as compared to the proportion which predominates in one or more atoms in nature.
The non-natural variant isotopic forms comprising the radioactive isotope can be used, for example, in drug and/or substrate tissue distribution studies. Radioisotope tritium, i.e. 3 H and carbon-14, i.e. 14 C in view of itThey are easy to incorporate and ready to use detection means, particularly suitable for this purpose. Non-natural variant isotopic forms incorporating deuterium, i.e. 2 H or D may provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and thus may be preferred in some circumstances. In addition, unnatural variant isotopic forms can be prepared which incorporate positron-emitting isotopes, e.g. 11 C、 18 F、 15 O and 13 n, and can be used in Positron Emission Tomography (PET) studies to examine substrate receptor occupancy.
In one embodiment, the compounds of the invention are provided in the form of natural isotopes.
In one embodiment, the compounds of the invention are provided in the form of a non-natural variant isotope. In a particular embodiment, the non-natural variant isotopic form is one in which deuterium is incorporated (i.e., where deuterium is incorporated) 2 H or D), wherein hydrogen is specified in the chemical structure of one or more atoms of the compounds of the invention. In one embodiment, the atoms of the compounds of the present invention are in a non-radioactive isotopic form. In one embodiment, one or more atoms of the compounds of the present invention are in a radioactive isotopic form. Suitably, the radioisotope is a stable isotope. Suitably, the non-natural variant isotopic form is a pharmaceutically acceptable form.
In one embodiment, compounds of the invention are provided wherein a single atom of the compound is present in the form of a non-natural variant isotope. In another embodiment, compounds of the invention are provided wherein two or more atoms are present in the form of a non-natural variant isotope.
The non-natural isotopic variant forms can generally be prepared by conventional techniques known to those skilled in the art or by the methods described herein, e.g., analogous to the methods described in the accompanying examples for preparing the natural isotopic forms. Thus, non-natural isotopic variant forms can be prepared by using appropriate isotopic variant (or labeled) reagents in place of the conventional reagents used in the examples. Since the compounds of formula (I) are intended for use in pharmaceutical compositions, it will be readily understood that they are each preferably provided in substantially pure form, e.g. at least 60% pure, more suitably at least 75% pure, preferably at least 85%, especially at least 98% pure (% is weight% on a weight basis). Impure preparations of the compounds may be used to prepare more pure forms for use in pharmaceutical compositions.
Since the compounds of formula (I) are intended for use in pharmaceutical compositions, it will be readily understood that they are each preferably provided in substantially pure form, e.g. at least 60% pure, more suitably at least 75% pure, and preferably at least 85%, especially at least 98% pure (% is weight% on a weight basis). Impure preparations of the compounds may be used to prepare more pure forms for use in pharmaceutical compositions.
In general, the compounds of formula (I) may be prepared according to organic synthesis techniques known to those skilled in the art, as well as by the representative methods set forth below, those in the examples, and modifications thereof.
Patent applications WO2011/069951, WO2012/076877, WO2012/168710, WO2013/175215, WO2013/083994, WO2013/182850, WO2017/103604, WO2018/020263 and WO2018/109484 provide methods for synthesizing intermediates useful in producing the compounds of the present invention.
General synthetic schemes
The following schemes detail the synthetic routes to the compounds of the invention and intermediates in the synthesis of such compounds. In the following schemes, the reactive groups may be protected with protecting groups and deprotected according to established techniques well known to those skilled in the art.
Compounds of formula (I) and salts and solvates thereof may be prepared by the general methods outlined below. In the following description, the radical R 1 、R 2 、R 3 、R 4 And R 5 Have the meanings as defined above for the compounds of formula (I), unless otherwise indicated.
Scheme 1a
Step (i):the compounds of formula (I) may be prepared by metal-catalysed coupling reactions. In this reaction, a halo-pyrazine derivative of formula (II), wherein typically X ═ Br, is reacted with a hydantoin of formula (III) in the presence of a metal catalyst such as copper (I) oxide in a suitable solvent such as N, N-dimethylformamide using conventional heating or microwave heating.
Scheme 1b
A compound of formula (I) wherein R 4 And R 5 Other than H, may be prepared by nucleophilic aromatic substitution. In this reaction, a halo-pyrazine derivative of formula (IV), wherein typically Y ═ Cl, is reacted with a phenol of formula (V) in the presence of a suitable base, such as potassium carbonate, in a suitable solvent, such as N, N-dimethylformamide or acetonitrile, using conventional heating or microwave heating.
Scheme 1c
Step (ii):the compounds of formula (I) may be prepared by: the compound of formula (VI) is cyclized with a carbonylation reagent (e.g. triphosgene, preferably pre-diluted in the same solvent and added twice at 0 ℃) in the presence of a suitable base such as triethylamine in a suitable solvent such as dichloromethane. Alternatively, compounds of formula (I) may be prepared by cyclisation of a compound of formula (VI) using a carbonylation reagent such as carbonyldiimidazole in a suitable solvent such as ethyl acetate in the presence of a base such as triethylamine or DIPEA.
Step (i):compounds of formula (VI) may be prepared by deprotecting a compound of formula (VII), wherein PG is a protecting group,suitably, the protecting group is BOC, which can be removed under acidic conditions, such as TFA, in a suitable solvent, such as dichloromethane, at a temperature of about 0 ℃ to room temperature.
Scheme 1d
Step (ii):the compounds of formula (I) may be prepared by reacting a urea of formula (XVII) with a suitable base, such as sodium methoxide in a suitable solvent, such as methanol, at a temperature in the range of 0 ℃ to room temperature.
Step (i):the urea of formula (XVII) can be prepared by reacting an aniline of formula (XVI) and an amino ester of formula (IX) (e.g. the hydrochloride salt) in a suitable solvent such as dichloromethane or ethyl acetate in the presence of a suitable base such as triethylamine or diisopropylethylamine at a temperature of from 0 ℃ to room temperature with a carbonylation reagent such as triphosgene, preferably pre-diluted in the same solvent.
Scheme 2a
Step (ii):the compound of formula (IV) may be prepared by reacting a urea of formula (VIII) with a suitable base, such as sodium methoxide in a suitable solvent, such as methanol, at a temperature in the range of 0 ℃ to room temperature.
Step (i):the urea of formula (VIII) may be prepared by reacting a commercially available halo-pyrazine derivative of formula (X) (where typically Y ═ Cl) and an amino ester of formula (IX) (e.g. the hydrochloride salt) in a suitable solvent such as dichloromethane or ethyl acetate with a carbonylation reagent such as triphosgene, preferably pre-diluted in the same solvent in the presence of a suitable base such as triethylamine or diisopropylethylamine at a temperature in the range of 0 ℃ to room temperature.
Scheme 2b
Step (ii):the compound of formula (IV) may be prepared by cyclisation of a compound of formula (XI) with a carbonylation reagent such as triphosgene, preferably pre-diluted in the same solvent and added a second time, in a suitable solvent such as dichloromethane, in the presence of a suitable base such as triethylamine at 0 ℃.
Step (i):compounds of formula (XI) may be prepared from anilines of formula (X) wherein typically Y ═ Cl and amino acids of formula (XII) as free bases or hydrochloride salts by amide coupling in the presence of a coupling agent such as T3P in a suitable solvent such as ethyl acetate, acetonitrile or mixtures thereof.
Scheme 3
Step (ii):the compounds of formula (IV) may be prepared by metal-catalyzed cross-coupling reactions. In this reaction, in the presence of a metal catalyst such as tris (dibenzylideneacetone) dipalladium (0), a suitable ligand such as dicyclohexyl- [2- (2,4, 6-triisopropylphenyl) phenyl]Halo-pyrazine derivatives of formula (II) (where typically X ═ Br) and amides of formula (XIII) are reacted in the presence of phosphine (XPhos) and a suitable base such as cesium carbonate in a suitable solvent such as 1, 4-dioxane using conventional or microwave heating. Alternatively, in this reaction, a halo-pyrazine derivative of formula (II) (where typically X ═ Br) and an amide of formula (XIII) are reacted in the presence of a metal catalyst such as copper (I) iodide, a suitable ligand such as N, N' -dimethylethane-1, 2-diamine and a suitable base such as potassium carbonate in a suitable solvent, for example in 1-butanol, with conventional heating or microwave heating. Another method for preparing the compounds of formula (IV) is in the presence of a metal catalyst such as palladium (II) acetate, a suitable ligandFor example, a halopyrazine derivative of formula (II) (wherein typically X ═ Br) is reacted with an amide of formula (XIII) in the presence of Xantphos and a suitable base such as cesium carbonate in a suitable solvent such as 1, 4-dioxane, using conventional heating or microwave heating.
Step (i):compounds having formula (XIII) can be prepared from N-protected (e.g., Boc) amino acids having formula (XIV) and amines (e.g., hexamethyldisilazane) by amide coupling in a solvent (e.g., N-dimethylformamide) in the presence of a base (e.g., DIPEA) and a coupling agent (e.g., HATU or TBTU).
Scheme 4
Step (i):compounds of formula (II), wherein typically X ═ Br, can be prepared by nucleophilic aromatic substitution. In this reaction, a halo-pyrazine derivative of formula (XV) (where typically X ═ Z ═ Br) is reacted with a phenol of formula (V) in the presence of a base such as potassium carbonate in a suitable solvent, for example N, N-dimethylformamide, under conventional heating or microwave heating.
Scheme 5
Step (i):the anilines of formula (XVI) may be prepared by metal-catalyzed cross-coupling reactions. In this reaction, a halo-pyrazine derivative of formula (XVIII) (wherein typically Z ═ Br) and a phenol of formula (V) are reacted in the presence of a metal catalyst such as copper (I) iodide, a suitable ligand such as picolinic acid, in a suitable solvent such as N, N-dimethylformamide or N, N-dimethylacetamide under conventional or microwave heating, optionally a suitable base such as potassium carbonate or cesium carbonate may be used.
Scheme 6
In scheme 6 shown above, PG 1 And PG represents a suitable protecting group. PG in steps (i) to (iii) 1 May be different from PG in steps (iv) - (vii) 1 . Suitable protecting groups include benzyl, tetrahydropyranyl or methoxymethyl. Suitably, PG 2 And PG 1 The same, for example both are benzyl.
1 2 Scheme description of PG and PG being both benzyl
Step (vii):phenols of formula (V) may be prepared from benzylated compounds of formula (XIX) by deprotection, for example using a metal catalyst such as palladium on carbon and a hydrogen source such as a hydrogen atmosphere or ammonium formate in a suitable solvent such as ethanol or methanol at a temperature in the range from room temperature to reflux.
Step (vi):benzylated compounds of formula (XIX) can be prepared from a diol of formula (XX) using a base such as potassium tert-butoxide and a suitable solvent such as dimethyl carbonate at a temperature in the range from room temperature to reflux.
Step (v):the diol of formula (XX) may be prepared from the lactone of formula (XXI) using a reducing agent such as lithium aluminium hydride in a suitable solvent such as THF at a temperature of from 0 deg.C to room temperature.
Step (iv):lactones of formula (XXI) can be prepared from phenols of formula (XXII) using a benzylating agent such as benzyl bromide in the presence of a base such as potassium carbonate in a suitable solvent such as acetonitrile or THF or mixtures thereof at a temperature in the range of from room temperature to reflux.
Step (iii):phenols of formula (XXII) can be prepared from dibenzylated esters of formula (XXIII) where Rx is a suitable alkyl group, such as methyl or ethyl, using a metal catalyst such as palladium on carbon and a hydrogen source such as hydrogen atmosphere or ammonium formate in a suitable solvent such as ethanol or methanol at a temperature in the range of room temperature to reflux.
Step (ii):dibenzylated esters of formula (XXIII) where Rx is a suitable alkyl group, such as methyl or ethyl, can be prepared from dibenzylated bromide derivatives of formula (XXIV) by using a preformed organozinc derivative of formula (XXVI) where Rx is a suitable alkyl group, such as methyl or ethyl, in the presence of a metal catalyst complex, such as bis (tri-tert-butylphosphine) palladium (0), in a suitable solvent, such as THF or DMF, or a mixture thereof, at a temperature in the range of room temperature to reflux.
Step (i):dibenzylated bromide derivatives of formula (XXIV) can be prepared from commercially available derivatives of formula (XXV) using benzylating agents such as benzyl bromide in the presence of a base such as potassium carbonate in a suitable solvent such as acetonitrile or THF or acetone or mixtures thereof at temperatures ranging from room temperature to reflux.
When PG is used 1 And/or PG 2 When a protecting group such as tetrahydropyranyl or methoxymethyl, the usual protecting/deprotecting conditions apply:
the conditions for protecting the phenol with tetrahydropyranyl group include reacting the phenol with dihydro-2H-pyran over a catalyst such as C, Py.p-MePhSO 3 In the presence of H in a suitable solvent such as dichloromethane at a temperature of from 0 ℃ to reflux.
The conditions for cleaving the tetrahydropyranyl protecting group from the phenol include subjecting the THP-protected phenol to an acid such as sulphuric acid or p-MePhSO 3 H or HCl in a suitable solvent such as methanol or ethanol at a temperature of 0 ℃ to reflux.
The conditions for protecting phenol with methoxymethyl groups include reacting phenol with chloromethyl methyl ether in the presence of a base such as potassium carbonate in a suitable solvent such as tetrahydrofuran or acetonitrile at a temperature of 0 ℃ to reflux.
Cleavage conditions for the methoxymethyl protecting group from phenol include subjecting the MOM-protected phenol to an acid such as sulfuric acid or p-MePhSO 3 H or HCl in a suitable solvent such as methanol or ethanol at a temperature of 0 ℃ to reflux.
Scheme 7
Step (i):organozinc derivatives of formula (XXVI) wherein Rx is a suitable alkyl group, such as methyl or ethyl, can be prepared by adding a commercially available bromo ester of formula (XXVII) to a refluxing suspension of zinc (0) in the presence of 1, 2-dibromoethane and chlorotrimethylsilane in a suitable solvent, such as THF.
Method of the invention
Other aspects of the invention provide processes for the preparation of compounds of formula (I) and derivatives thereof and processes for the preparation of intermediates in the synthesis of compounds of formula (I).
The method of the invention is as described above and includes any single step of the multi-step protocol.
Intermediates
The invention also relates to novel intermediates in the synthesis of compounds of formula (I). Such novel intermediates include compounds of formula (II), (IV), (VI), (VII), (VIII), (XI), (XVI) and (XVII). Intermediates of formula (XIX) - (XXIV) are also of interest. The invention also provides salts, e.g., pharmaceutically acceptable salts, of such intermediates.
Thus, the intermediates of the present invention include:
-a compound of formula (II):
wherein R is 1 、R 2 And R 3 As defined above, X is halogen, such as Br;
-a compound of formula (IV):
wherein R is 1 、R 2 And R 3 As defined above, Y is halogen, such as Cl;
-a compound of formula (VI):
wherein R is 1 、R 2 、R 3 、R 4 And R 5 As defined above;
-a compound of formula (VII):
wherein R is 1 、R 2 、R 3 、R 4 And R 5 PG, as defined above, is a suitable protecting group, such as BOC;
-a compound of formula (XVI):
wherein R is 1 、R 2 And R 3 As defined above.
Kv3.1, Kv3.2 and/or Kv3.3 modulation
The compounds of formula (I) of the present invention are modulators of Kv3.1. The compounds of formula (I) may also be modulators of kv3.2 and/or kv 3.3. The compounds of the invention can be tested in the assay of biological example 1 to determine their modulating properties on kv3.1 and/or kv3.2 and/or kv3.3 channels.
As used herein, a "modulator" refers to a compound capable of producing at least a 10% enhancement, and suitably at least a 20% enhancement, of the whole cell current mediated by human kv3.1 and/or human kv3.2 and/or human kv3.3 channels recombinantly expressed in mammalian cells.
The terms "Kv3.1, Kv3.2 and/or Kv3.3" shall be considered to have the same meaning as "Kv3.1 and/or Kv3.2 and/or Kv3.3" and may also be referred to as "Kv3.1/Kv3.2/Kv3.3".
In one embodiment, the modulator is capable of producing at least a 10% enhancement, suitably at least a 20% enhancement, of the whole cell current mediated by a human kv3.1 channel recombinantly expressed in mammalian cells. Suitably, pEC of the modulator 50 In the range of 4-7 (e.g., 5-6.5).
In one embodiment, the modulator is capable of producing at least a 10% enhancement, suitably at least a 20% enhancement, of the whole cell current mediated by a human kv3.2 channel recombinantly expressed in mammalian cells. Suitably, pEC of the modulator 50 In the range of 4-7 (e.g., 5-6.5).
In one embodiment, the modulator is capable of producing at least a 10% enhancement, suitably at least a 20% enhancement, of the whole cell current mediated by a human kv3.3 channel recombinantly expressed in mammalian cells. Suitably, pEC of the modulator 50 In the range of 4-7 (e.g., 5-6.5).
In another embodiment, the modulator is capable of producing at least a 10% enhancement, suitably at least a 20% enhancement, of the whole cell current mediated by human kv3.1 and kv3.2 channels recombinantly expressed in mammalian cells.
In another embodiment, the modulator is capable of producing at least a 10% enhancement, suitably at least a 20% enhancement, of the whole cell current mediated by human kv3.1 and kv3.3 channels recombinantly expressed in mammalian cells.
In another embodiment, the modulator is capable of producing at least a 10% enhancement, suitably at least a 20% enhancement, of the whole cell current mediated by human kv3.2 and kv3.3 channels recombinantly expressed in mammalian cells.
In another embodiment, the modulator is capable of producing at least a 10% enhancement, suitably at least a 20% enhancement, of the whole-cell current mediated by human kv3.1, kv3.2, and kv3.3 channels recombinantly expressed in mammalian cells.
Compounds of formula (I) or pharmaceutically acceptable salts and/or solvates and/or derivatives thereof, are useful in the treatment or prevention of diseases or conditions in which modulators of kv3.1 or kv3.2 or kv3.1 and kv3.2 channels are required. As used herein, modulators of kv3.1 or kv3.2 or kv3.1 and kv3.2 are compounds that positively or negatively alter the properties of these channels. In a particular aspect of the invention, the compounds of formula (I) are positive modulators. The compounds of the invention can be tested in the assay of biological example 1 to determine their modulating properties.
In one embodiment of the invention, the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate and/or derivative thereof is selective for the modulation of the kv3.1 channel over the kv3.2 channel. By selective is meant that the compound is at least 2-fold, 5-fold or 10-fold more active on the kv3.1 channel than on the kv3.2 channel. The activity of a compound is suitably quantified by its potency as indicated by the Ec50 value.
In another embodiment of the invention, the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof and/or derivative thereof is selective for modulation of the kv3.2 channel over modulation of the kv3.1 channel. Likewise, selective refers to a compound that is at least 2-fold, 5-fold, or 10-fold more active on the kv3.2 channel than on the kv3.1 channel.
In a particular embodiment of the invention, the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof and/or derivative thereof shows an activity which is comparable between the modulation of kv3.1 and kv3.2 channels, e.g. the activity of one channel is less than 2 times, e.g. less than 1.5 times or less than 1.2 times the activity of the other channel.
In certain disorders, it may be beneficial to use modulators of Kv3.3 or Kv3.1 or Kv3.3 and Kv3.1 that exhibit a specific selective profile between the two channels. For example, modulation of a kv3.3 channel by a compound may be selective over modulation of a kv3.1 channel, exhibiting, for example, at least 2-fold, 5-fold, or 10-fold activity for a kv3.3 channel over kv3.1 channel.
In another embodiment of the invention, the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof and/or derivative thereof is selective for the modulation of the kv3.1 channel over the kv3.3 channel. Likewise, by selective is meant that a compound, e.g., a kv3.1 channel, is at least 2-fold, 5-fold, or 10-fold more active than a kv3.3 channel.
In a particular embodiment of the invention, the compounds may exhibit comparable activity between the modulation of kv3.3 and kv3.1 channels, e.g. each channel is less than 2-fold, e.g. less than 1.5-fold or less than 1.2-fold, the activity of the other channel.
In certain disorders, it may be beneficial to use modulators of Kv3.3 or Kv3.2 or Kv3.3 and Kv3.2 that exhibit a specific selective profile between the two channels. Modulation of a kv3.3 channel by a compound may be selective over modulation of a kv3.2 channel, exhibiting, for example, at least 2-fold, 5-fold, or 10-fold activity for a kv3.3 channel over a kv3.2 channel.
In another embodiment of the invention, the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof and/or derivative thereof is selective for modulation of the kv3.2 channel over modulation of the kv3.3 channel. Likewise, by selective is meant that the compound is at least 2-fold, 5-fold, or 10-fold more active on the kv3.2 channel than on the kv3.3 channel.
In another specific embodiment, the compounds may exhibit comparable activity between the modulation of kv3.3 and kv3.2 channels, e.g., each channel is less than 2-fold, e.g., less than 1.5-fold or less than 1.2-fold, the activity of the other channel.
In another specific embodiment of the invention, the compounds may exhibit comparable activity between the modulation of kv3.3, kv3.2 and kv3.1 channels, e.g. each channel is less than 2-fold, e.g. less than 1.5-fold or less than 1.2-fold, the activity of any other channel. The activity of a compound is suitably quantified by its potency as indicated by the EC50 value.
Method of treatment
The invention also provides a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate (e.g. salt) and/or derivative thereof for use in the treatment or prevention of a disease or condition in which a kv3.1, kv3.2 and/or kv3.3 modulator is required, for example those mentioned below.
The present invention provides a method of treating or preventing a disease or condition in which a kv3.1, kv3.2 and/or kv3.3 modulator is required, such as those mentioned below, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate (e.g. salt) and/or derivative thereof.
The invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate (e.g. salt) and/or derivative thereof in the manufacture of a medicament for the treatment or prevention of diseases or conditions in which a kv3.1, kv3.2 and/or kv3.3 modulator is required, for example those mentioned below.
In one embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate and/or derivative thereof for use as a medicament.
The term "treating" as used herein includes the control, alleviation, reduction or modulation of a disease state or its symptoms.
The term "preventing" is used herein to refer to preventing symptoms of a disease or disorder in an individual or preventing recurrence of symptoms of a disease or disorder in a diseased individual and is not limited to preventing the disease entirely.
Suitably, the subject is a human.
Diseases or conditions that may be mediated by modulation of kv3.1 and/or kv3.2 channels may be selected from the following list. The numbers in parentheses after the Diseases listed below refer to Classification codes in the diagnostic and statistical manual for mental disorders 4 th edition (DSM-IV) and/or the International Classification of Diseases 10 th edition (ICD-10) published by the American psychiatric Association.
In one embodiment of the invention, the compounds of formula (I) or a pharmaceutically acceptable salt and/or solvate and/or derivative thereof may be used for the treatment or prevention of a disease or condition selected from: hearing disorders, schizophrenia, depression and mood disorders, bipolar disorder, substance abuse disorders, anxiety disorders, sleep disorders, auditory hypersensitivity and loudness perception disorders, meniere's disease, balance disorders and inner ear disorders, impulse control disorders, personality disorders, attention deficit hyperactivity disorder, autism spectrum disorders, eating disorders, cognitive disorders, ataxia, pain such as neuropathic pain, inflammatory pain and miscellaneous pain, dementia with lewy bodies and parkinson's disease.
In one embodiment of the invention, the compounds of formula (I) or a pharmaceutically acceptable salt and/or solvate and/or derivative thereof may be used for the treatment or prevention of a disease or condition selected from: hearing disorders (including hearing loss and tinnitus), schizophrenia, substance abuse disorders, pain (e.g., neuropathic pain, inflammatory pain, and miscellaneous pain), dementia with lewy bodies, and parkinson's disease.
In one embodiment of the invention, the compounds of formula (I) or a pharmaceutically acceptable salt and/or solvate and/or derivative thereof may be used for the treatment or prevention of a disease or condition selected from: fragile X chromosome, rett disorder, and alzheimer's disease.
The present invention provides a method for preventing or treating a disease or condition selected from the group consisting of: hearing disorders, schizophrenia, depression and mood disorders, bipolar disorder, substance abuse disorders, anxiety disorders, sleep disorders, auditory hypersensitivity and loudness perception disorders, meniere's disease, balance disorders and inner ear disorders, impulse control disorders, personality disorders, attention deficit/hyperactivity disorder, autism spectrum disorders, eating disorders, cognitive disorders, ataxia, pain such as neuropathic pain, inflammatory pain and miscellaneous pain, dementia with lewy bodies and parkinson's disease, comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and/or a solvate (e.g. salt) thereof and/or a derivative thereof.
The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof and/or a solvate (e.g. salt) and/or derivative thereof in the manufacture of a medicament for the treatment or prevention of a disease or condition selected from: hearing disorders, schizophrenia, depression and mood disorders, bipolar disorder, substance abuse disorders, anxiety disorders, sleep disorders, auditory hypersensitivity and loudness perception disorders, meniere's disease, balance disorders and inner ear disorders, impulse control disorders, personality disorders, attention deficit hyperactivity disorder, autism spectrum disorders, eating disorders, cognitive disorders, ataxia, pain such as neuropathic pain, inflammatory pain and miscellaneous pain, dementia with lewy bodies and parkinson's disease.
In a particular embodiment of the invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate (e.g. salt) thereof and/or derivative thereof for use in the treatment or prevention of a hearing disorder. Hearing disorders include auditory neuropathy, auditory processing disorders, hearing loss, including sudden hearing loss, noise-induced hearing loss, substance-induced hearing loss, and hearing loss (presbycusis) and tinnitus in adults over 60, 65, 70, or 75 years of age.
Compounds of formula (I) or pharmaceutically acceptable salts and/or solvates (e.g. salts) and/or derivatives thereof may have use in the treatment or prevention of meniere's disease, balance disorders and inner ear disorders.
In a particular embodiment of the invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate (e.g. salt) thereof and/or derivative thereof for use in the treatment or prevention of schizophrenia. Schizophrenia includes paranoid (295.30), disorganized (295.10), catatonic (295.20), undifferentiated (295.90) and residual (295.60) subtypes; schizophreniform disorder (295.40); schizoaffective disorder (295.70), including bipolar and depressive subtypes; delusional disorders (297.1) including erogenous, exaggerated, jealous, perigenic, somatotype, mixed and unidentified subtypes; brief psychotic disorder (298.8); sensorimotor disorder (297.3); psychotic disorders caused by general medical conditions including subtypes with delusions and hallucinations; substance-induced psychotic disorder, including subtypes with delusions (293.81) and hallucinations (293.82); and mental disorder of unknown type (298.9).
A compound of formula (I) or a pharmaceutically acceptable salt and/or solvate (e.g. salt) and/or derivative thereof may have use in the treatment or prevention of depression and mood disorders including major depressive episodes, manic episodes, mixed episodes and hypomanic episodes; depression, including major depressive disorder, dysthymic disorder (300.4), unspecified depression (311); bipolar disorders including bipolar I disorder, bipolar II disorder (recurrent major depressive episode with hypomanic episodes) (296.89), cyclothymic disorder (301.13), and bipolar disorder not otherwise specified (296.80); other mood disorders, including mood disorders due to general medical conditions (293.83) including subtypes with depressive features, with major depressive-like episodes, with manic features, and with mixed features, substance-induced mood disorders (including subtypes with depressive features, with manic features, and with mixed features), and mood disorders not otherwise specified (296.90); seasonal affective disorder.
The compounds of formula (I) or pharmaceutically acceptable salts and/or solvates (e.g. salts) and/or derivatives thereof may have use in the treatment or prevention of epilepsy, (including but not limited to localized epilepsy, generalized epilepsy, epilepsy with generalized and localized seizures, and the like), epilepsy associated with renoxer-garget syndrome, epilepsy as a complication of a disease or disorder (e.g. epilepsy associated with encephalopathy, phenylketonuria, juvenile gaucher's disease, Lundborg's progressive myoclonic epilepsy, stroke, head injury, stress, hormonal changes, drug use or withdrawal, alcohol use or withdrawal, sleep deprivation, fever, infection, and the like), essential tremor, restless leg syndrome, partial and generalized seizures (including tonic, clonic, tonic-clonic, partial, and generalized seizures, including, Dystonia, myoclonic, absence seizures), secondary generalized seizures, temporal lobe epilepsy, absence epilepsy (including childhood, juvenile, myoclonic, photoinduced and pattern-induced), severe epileptic encephalopathy (including hypoxia-related and Rasmussen syndrome), febrile seizures, partial status epilepticus, progressive myoclonic epilepsy (including Pulsatilla-Lorentz and Laforra), post-traumatic seizures/epilepsy (including those associated with head injury), simple reflex epilepsy (including photosensitivity, somatosensory and proprioception, audiogenesis and vestibular), metabolic disorders commonly associated with epilepsy (such as pyridoxine-dependent epilepsy), Mengkian leukodystrophy, seizures due to alcohol and drug abuse (such as cocaine), cortical malformations associated with epilepsy (such as Bipidermal syndrome or subcortical chromosomal ectopy), a chromosomal abnormality associated with seizures or epilepsy such as partial monosomy (15 q)/angleman syndrome).
A compound of formula (I) or a pharmaceutically acceptable salt and/or solvate (e.g. salt) and/or derivative thereof may have use in the treatment or prevention of substance-related disorders, including psychotic disorders due to substance use, such as substance dependence, substance craving and substance abuse; substance-induced disorders such as substance intoxication, substance withdrawal, substance-induced delirium, substance-induced persisting dementia, substance-induced persisting amnestic disorder, substance-induced psychotic disorder, substance-induced mood disorder, substance-induced anxiety disorder, substance-induced sexual dysfunction, substance-induced sleep disorder and hallucinogen persisting perception disorder (flashback); alcohol-related diseases such as alcohol dependence (303.90), alcohol abuse (305.00), alcohol intoxication (303.00), alcohol withdrawal (291.81), alcohol intoxication delirium, alcohol withdrawal delirium, alcohol-induced persisting dementia, alcohol-induced persisting amnestic disorder, alcohol-induced psychotic disorder, alcohol-induced mood disorder, alcohol-induced anxiety disorder, alcohol-induced sexual dysfunction, alcohol-induced sleep disorder and alcohol-related diseases not otherwise specified (291.9); amphetamine (or amphetamine-like) related disorders such as amphetamine dependence (304.40), amphetamine abuse (305.70), amphetamine intoxication (292.89), amphetamine withdrawal (292.0), amphetamine intoxication delirium, amphetamine-induced sensory psychotic disorder, amphetamine-induced mood disorder, amphetamine-induced anxiety disorder, amphetamine-induced sexual dysfunction, amphetamine-induced sleep disorder and amphetamine-related disorder not otherwise specified (292.9); caffeine-related disorders such as caffeine intoxication (305.90), caffeine-induced anxiety disorder, caffeine-induced sleep disorder and caffeine-related disorder not otherwise specified (292.9); cannabis-related disorders, such as cannabis dependence (304.30), cannabis abuse (305.20), cannabis intoxication (292.89), cannabis intoxication delirium, cannabis-induced psychotic disorder, cannabis-induced anxiety disorder and cannabis-related disorder not otherwise specified (292.9); cocaine-related disorders such as cocaine dependence (304.20), cocaine abuse (305.60), cocaine intoxication (292.89), cocaine withdrawal (292.0), cocaine neurotoxic delirium, cocaine-induced psychotic disorder, cocaine-induced mood disorder, cocaine-induced anxiety disorder, cocaine-induced sexual dysfunction, cocaine-induced sleep disorder and cocaine-related disorder not otherwise specified (292.9); hallucinogenic agent-related disorders, such as hallucinogenic agent dependence (304.50), hallucinogenic agent abuse (305.30), hallucinogenic agent intoxication (292.89), hallucinogenic agent persistent perception disorder (flashback) (292.89), hallucinogenic agent intoxication delirium, hallucinogenic agent-induced psychotic disorder, hallucinogenic agent-induced mood disorder, hallucinogenic agent-induced anxiety disorder and hallucinogenic agent-related disorder not otherwise specified (292.9); inhalant-related diseases such as inhalant dependence (304.60), inhalant abuse (305.90), inhalant intoxication (292.89), inhalant intoxication delirium, inhalant-induced persisting dementia, inhalant-induced psychosis, inhalant-induced mood disorder, inhalant-induced anxiety disorder and inhalant-related disease not otherwise specified (292.9); nicotine-related disorders such as nicotine dependence (305.1), nicotine withdrawal (292.0) and nicotine-related disorders not otherwise specified (292.9); opioid-related disorders such as opioid dependence (304.00), opioid abuse (305.50), opioid intoxication (292.89), opioid withdrawal (292.0), opioid intoxication delirium, opioid-induced psychosis, opioid-induced mood disorder, opioid-induced sexual dysfunction, opioid-induced sleep disorder and opioid-related disorder not otherwise specified (292.9); phencyclidine (or phencyclidine-like) related diseases such as phencyclidine dependence (304.60), phencyclidine abuse (305.90), phencyclidine intoxication (292.89), phencyclidine intoxication delirium, phencyclidine-induced psychosis, phencyclidine-induced mood disorder, phencyclidine-induced anxiety disorder and phencyclidine related disease not otherwise specified (292.9); sedative-, hypnotic-, or anxiolytic-related disorders, such as sedative-, hypnotic-, or anxiolytic dependence (304.10), sedative-, hypnotic-, or anxiolytic abuse (305.40), sedative-, hypnotic-, or anxiolytic intoxication (292.89), sedative-, hypnotic-, or anxiolytic withdrawal (292.0), sedative-, hypnotic-, or anxiolytic intoxication delirium, sedative-, hypnotic-, or anxiolytic withdrawal delirium, sedative-, hypnotic-, or anxiolytic persisting dementia, sedative-, hypnotic-, or anxiolytic persisting amnestic disorder, sedative-, hypnotic-, or anxiolytic-induced psychotic disorder, sedative-, hypnotic-, or anxiolytic-induced mood disorder, sedative-, hypnotic-, or anxiolytic-induced anxiety disorder, sedative-, hypnotic-, or anxiolytic-induced sleep disorder, and sedative-, hypnotic-, or anxiolytic-induced sleep disorder, Hypnotic or anxiolytic induced related disorders not otherwise specified (292.9); multiple substance related diseases, such as multiple substance dependence (304.80); and other (or unknown) substance-related disorders such as anabolic steroids, nitrate inhalants, and nitrous oxide.
Compounds of formula (I) or a pharmaceutically acceptable salt and/or solvate (e.g. salt) and/or derivative thereof may have use in the treatment or prevention of anxiety disorders, including panic attacks; panic disorders, including phobic disorders without agoraphobia (300.01) and phobic disorders with agoraphobia (300.21); agoraphobia; history of agoraphobia without phobic conditions (300.22), specific phobias (300.29, formerly known as simple phobias), including animal type, natural environment type, blood-injection-damage type, situational type, and other types of subtypes, social phobia (social anxiety disorder, 300.23), obsessive-compulsive disorder (300.3), post-traumatic stress disorder (309.81), acute stress disorder (308.3), generalized anxiety disorder (300.02), anxiety disorder caused by general medical conditions (293.84), substance-induced anxiety disorder, separation anxiety disorder (309.21), adjustment disorder with anxiety (309.24), and anxiety disorder not otherwise specified (300.00).
A compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof (e.g. salt) and/or derivative thereof may have use in the treatment or prevention of sleep disorders, including primary sleep disorders, such as sleep disorders, for example, primary insomnia (307.42), primary narcolepsy (307.44), narcolepsy (347), respiratory-related sleep disorders (780.59), circadian rhythm sleep disorders (307.45) and sleep disorders not otherwise specified (307.47); primary sleep disorders, such as parasomnia, e.g. nightmare disorder (307.47), sleep terror disorder (307.46), sleepwalking disorder (307.46) and parasomnia not otherwise indicated (307.47); sleep disorders associated with another psychiatric disorder, such as insomnia associated with another psychiatric disorder (307.42) and hypersomnia associated with another psychiatric disorder (307.44); sleep disorders due to medical conditions in general, in particular sleep disorders associated with diseases such as neurological disorders, neuropathic pain, restless leg syndrome, heart and lung diseases; and substance-induced sleep disorders including insomnia, hypersomnia, parasomnia and mixed subtypes; sleep apnea and jet lag syndrome.
Compounds of formula (I) or pharmaceutically acceptable salts and/or solvates (e.g. salts) and/or derivatives thereof may have use in the treatment or prevention of hyperacusis and loudness sensory disorders, including fragile X syndrome and autism.
A compound of formula (I) or a pharmaceutically acceptable salt and/or solvate (e.g. salt) and/or derivative thereof may have use in the treatment or prevention of impulse control disorders, including: intermittent manic-depressive disorder (312.34), kleptomania (312.32), pathological gambling (312.31), pyromania (312.33), trichotillomania (312.39), impulse control disorder not otherwise specified (312.3), binge eating, compulsive purchasing, compulsive behavior, and compulsive stockpiling.
Compounds of formula (I) or a pharmaceutically acceptable salt and/or solvate (e.g. salt) and/or derivative thereof may have use in the treatment or prevention of sexual dysfunction, including sexual desire disorders, such as hypoactive sexual desire disorder (302.71) and sexual aversion disorder (302.79); sexual arousal disorders such as female arousal disorder (302.72) and male erectile disorder (302.72); sexual desire disorders such as female orgasmic disorder (302.73), male orgasmic disorder (302.74) and premature ejaculation (302.75); sexual pain disorders such as dyspareunia (302.76) and vaginismus (306.51); sexual dysfunction not otherwise specified (302.70); paraphilias such as exubertal (302.4), fetishism (302.81), frotteurism (302.89), fetishism (302.2), sexual fetishism (302.83), sexual fetishism (302.84), barnyard (302.3), voyeurism (302.82) and paraphilia not otherwise specified (302.9); sexual acceptance abnormalities, such as childhood sexual identity disorder (302.6) and juvenile or adult sexual identity disorder (302.85); and sexual dysfunction not otherwise specified (302.9).
A compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof (e.g. salt) and/or derivative thereof may have use in the treatment or prevention of personality disorders, including paranoid personality disorder (301.0), schizotypal personality disorder (301.20), schizotypal personality disorder (301,22), antisocial personality disorder (301.7), borderline personality disorder (301,83), performance personality disorder (301.50), self-attaching personality disorder (301,81), avoidance personality disorder (301.82), dependent personality disorder (301.6), obsessive-compulsive personality disorder (301.4) and subtypes of personality disorder not otherwise specified (301.9).
A compound of formula (I) or a pharmaceutically acceptable salt thereof and/or solvate thereof (e.g., salt) and/or derivative thereof may have use in the treatment or prevention of attention deficit/hyperactivity disorder, including the combined attention deficit/hyperactivity disorder (314.01), attention deficit/hyperactivity disorder-attention disorder major (314.00), attention deficit/hyperactivity disorder hyperactivity-impulse type (314.01), and subtypes of attention deficit/hyperactivity disorder not otherwise specified (314.9); hyperactivity disorder; disruptive behavior disorders, such as behavior disorders, including subtypes of childhood onset (321.81), juvenile onset (312.82), and undefined onset (312.89), oppositional defiant disorder (313.81), and disruptive behavior disorder not otherwise specified; and tic dyskinesias, such as Tourette's disease (307.23) subtype.
Compounds of formula (I) or pharmaceutically acceptable salts and/or solvates (e.g. salts) and/or derivatives thereof may have use in the treatment or prevention of disorders of the autism spectrum, including autism (299.00), asperger's disease (299.80), rett disorder (299.80), childhood disintegrative disorder (299.10) and a broad range of disorders not otherwise specified (299.80, including atypical autism).
Compounds of formula (I) or a pharmaceutically acceptable salt and/or solvate (e.g. salt) and/or derivative thereof may have use in the treatment or prevention of eating disorders, such as anorexia nervosa (307.1), including the restrictive and binge eating/purging subtypes; bulimia nervosa (307.51), including purging and non-purging subtypes; obesity; compulsive eating disorders; overeating; and eating disorders not otherwise indicated (307.50).
Compounds of formula (I) or pharmaceutically acceptable salts and/or solvates (e.g. salts) and/or derivatives thereof may have cognitive enhancing utility, including the treatment of cognitive disorders in other diseases such as schizophrenia, bipolar disorder, depression, other psychotic disorders and psychosis associated with cognitive impairment, such as alzheimer's disease. Alternatively, a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof may have use in the prevention of cognitive impairment, for example cognitive impairment as may be associated with diseases such as schizophrenia, bipolar disorder, depression, other psychotic disorders and psychosis associated with cognitive impairment, for example alzheimer's disease.
A compound of formula (I) or a pharmaceutically acceptable salt and/or solvate (e.g. salt) and/or derivative thereof may have use in the treatment or prevention of ataxia, including ataxia, particularly spinocerebellar ataxia, particularly ataxia associated with mutations R420H, R423H or F448L.
Compounds of formula (I) or a pharmaceutically acceptable salt and/or solvate (e.g. salt) and/or derivative thereof may have use in the treatment or prevention of pain, including nociceptive pain, neuropathic pain, inflammatory pain or miscellaneous pain.
Nociceptive pain represents a normal response to noxious injury or damage to tissues such as skin, muscle, internal organs, joints, tendons or bones. Examples of nociceptive pain that forms part of the present invention include somatic pain: musculoskeletal pain (joint pain, myofascial pain) or skin pain, which is often well-localized; or visceral pain: hollow organs or smooth muscles.
Neuropathic pain is pain that is caused or caused by a primary lesion or disease in the somatosensory nervous system. Paresthesias range from defects perceived as paresthesias (numbness) to hypersensitivity (hyperalgesia or allodynia) and dysesthesias (tingling and other sensations). Examples of neuropathic pain that forms part of the present invention include, but are not limited to, diabetic neuropathy, post-herpetic neuralgia, spinal cord injury pain, phantom limb (post-amputation) pain, and post-stroke central pain. Other causes of neuropathic pain include trauma, chemotherapy, and heavy metal exposure.
Inflammatory pain occurs as a result of activation and sensitization of nociceptive pain pathways by various mediators released at sites of tissue inflammation. Mediators involved as key players in inflammatory pain are pro-inflammatory cytokines such as IL-1-alpha, IL-1-beta, IL-6 and TNF-alpha, chemokines, reactive oxygen species, vasoactive amines, lipids, ATP, acids and other factors released by infiltrating leukocytes, vascular endothelial cells or tissue resident mast cells. Example causes of inflammatory pain that form part of the present invention include appendicitis, rheumatoid arthritis, inflammatory bowel disease, and herpes zoster.
Miscellaneous pain refers to a pain condition or disorder that is not easily classified. The current understanding of their underlying mechanisms is still rudimentary, however, specific therapies for these diseases are well known; they include cancer pain, migraine and other primary headaches, and extensive pain of the fibromyalgia type.
Suitably, the specific pain indication which may be mediated by a modulator of kv3.1 and/or kv3.2 and/or kv3.3 channels is neuropathic pain and/or inflammatory pain.
Pain is a subjective condition and tends to be measured in a clinical setting by the patient's self-assessment. Thus, it may be difficult to measure and quantify the pain threshold. For chronic pain, a subjective 11-point rating scale is typically used, with 0 being no pain and 10 being the most severe pain imaginable. Individuals typically record their most severe pain over a given period of time, typically a day. A minimum mean baseline score is also recorded, and the response to the drug is measured relative to baseline, e.g., at least a 10%, 20%, 30%, 40%, or 50% reduction in pain from the baseline score can be observed.
Since the individual's response to the drug may vary, not all individuals may experience a reduction in pain from the baseline score. Thus, suitably, a reduction is observed in at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or all of the individuals tested.
Thus, in one embodiment of the invention, when a kv3.1/kv3.2/kv3.3 modulator, e.g., a compound of formula (I) or a pharmaceutically acceptable salt, solvate, and/or derivative thereof, is administered to an individual in need thereof, at least a 10%, 20%, 30%, 40%, or 50% reduction in pain from baseline score is observed.
Administration of the Kv3.1/Kv3.2/Kv3.3 modulator may occur before or after the onset of the anticipated pain. A kv3.1/kv3.2/kv3.3 modulator, e.g., a compound of formula (I) or a pharmaceutically acceptable salt, solvate, and/or derivative thereof, may be administered in situations where it is expected that the development of the disease or disorder may result in increased pain experienced by the individual. In cases where the subject has experienced pain, a kv3.1/kv3.2/kv3.3 modulator, e.g., a compound of formula (I) or a pharmaceutically acceptable salt, solvate, and/or derivative thereof, may be administered to the subject in need thereof.
Treatment of an individual in need thereof may be continued for as long as treatment is needed, e.g., 1 day, 1 week, 2 weeks, 3 weeks, 1 month, 6 months, 1 year, more than 2 years, more than 5 years, or more than 10 years. Thus, in one embodiment of the invention, a therapeutically effective amount of a kv3.1/kv3.2/kv3.3 modulator, e.g., a compound of formula (I) or a pharmaceutically acceptable salt, solvate, and/or derivative thereof, is administered to a subject in need thereof for 1 day to 1 month, 1 week to 3 months, 1 month to 6 months, 3 months to 1 year, or more than 1 year.
The reduction of pain in an individual can be measured by assessing the response to an external stimulus such as a mechanical or thermal (e.g. cold) stimulus (as described in the experimental section). The reduction can be considered as a percent reversal (calculated by measuring pre-and post-dose thresholds for affected versus unaffected pain sites, e.g., as described in more detail under data analysis in the experimental section) or by measuring withdrawal thresholds for affected pain sites. Preferably, a percentage inversion calculation is used.
Thus, in one embodiment of the invention, sensitivity to pain (e.g. neuropathic or inflammatory pain) is reversed by more than 20%, more than 30%, more than 40%, more than 50%, more than 60%, more than 70%, more than 80% or more than 90% after administration of a therapeutically effective amount of a kv3.1/kv3.2/kv3.3 modulator, e.g. a compound of formula (I) or a pharmaceutically acceptable salt, solvate and/or derivative thereof. Suitably, the sensitivity to pain is reversed by more than 80% or more than 90%.
Individuals receiving kv3.1/kv3.2/kv3.3 modulators may experience subsequent benefits, such as one or more of improved function, mood, sleep, quality of life, reduced working hours.
In a particular embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof and/or a solvate thereof (e.g. a salt) and/or a derivative thereof may have use in the treatment or prevention of neuropathic pain.
In a particular embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof and/or a solvate (e.g. salt) and/or derivative thereof may have use in the treatment or prevention of inflammatory pain.
In a particular embodiment, the compounds of formula (I) or a pharmaceutically acceptable salt thereof and/or a solvate thereof (e.g. a salt) and/or a derivative thereof may have use in the treatment or prevention of miscellaneous pain.
In one embodiment, there is provided a compound of formula (I) for use in the prevention of acute noise-induced hearing loss.
In one embodiment, there is provided a method of preventing acute noise-induced hearing loss comprising administering to a subject in need thereof a compound of formula (I).
In one embodiment, there is provided the use of a compound of formula (I) in the manufacture of a medicament for the prevention of acute noise-induced hearing loss.
Acute noisy hearing loss may be caused by an event such as exposure to loud noise or an explosion. In these cases, when a future event is expected to result in acute noise-induced hearing loss, the compound of formula (I) or a pharmaceutically acceptable salt, solvate and/or derivative thereof may be administered prior to the event to prevent or reduce acute noise-induced hearing loss. Administration of compound (I) or a pharmaceutically acceptable salt, solvate and/or derivative thereof may prevent any acute noise-induced hearing loss, or may reduce the severity of acute noise-induced hearing loss, or may alleviate other symptoms caused by acute noise-induced hearing loss, such as tinnitus.
"acute hearing loss" is defined as a hearing loss that occurs rapidly within hours or days. For example, hearing loss may occur over a time period of minutes, hours, or days (e.g., over a time period of up to 1 day, such as up to 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days). Acute hearing loss is typically caused by exposure to loud sounds or explosions. Hearing loss caused by exposure to loud sounds or explosions is referred to herein as "noisy hearing loss". Thus, "acute noisy hearing loss" refers to a hearing loss that occurs rapidly over hours or days due to exposure to loud sounds or explosions.
Important symptoms of acute hearing loss include:
1. a shift in hearing threshold, i.e. an increase in the minimum sound level of pure tones that can be heard without the presence of other sounds;
2. tinnitus; and
3. degradation of central auditory processing, such as auditory temporal processing and/or speech understanding, is impaired.
The "loud" noise or blast may be at least 90dB, such as at least 100dB, at least 110dB, at least 120dB, or at least 130 dB.
In one embodiment, administration of a compound of formula (I) or a pharmaceutically acceptable salt, solvate and/or derivative thereof may begin before an event is expected to cause noisy acute hearing loss. For example, administration of a compound of formula (I) or a pharmaceutically acceptable salt, solvate and/or derivative thereof may be initiated up to 2 weeks in advance, e.g. up to 1 week, 6 days, 5 days, 4 days, 3 days, 2 days, 24h, 12h, 6h, 5h, 4h, 3h, 2h, 1h, 30 minutes or up to 15 minutes before an event that is expected to cause noise-induced acute hearing loss. The compound of formula (I) or a pharmaceutically acceptable salt, solvate and/or derivative thereof may be administered multiple times before an event that is expected to cause noisy acute hearing loss.
In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt, solvate and/or derivative thereof is administered prior to potential exposure to noise or an explosion expected to cause acute noise-induced hearing loss, for preventing or reducing the development of permanent tinnitus; for preventing or reducing the development of permanent shifts in the hearing threshold; or for preventing or reducing the development of permanently degenerated central auditory processes, including, for example, auditory temporal processing and/or speech understanding.
It will be appreciated that pre-administration may be where an individual is deemed to be at risk of exposure to noise or explosions expected to cause acute noisy hearing loss, and is not limited to those situations where such exposure ultimately occurs.
In one embodiment, administration of the compound of formula (I) or a pharmaceutically acceptable salt, solvate and/or derivative thereof is initiated during an event expected to cause noisy acute hearing loss. The compound of formula (I) or a pharmaceutically acceptable salt, solvate and/or derivative thereof may be administered multiple times during an event that is expected to cause noisy acute hearing loss.
In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt, solvate and/or derivative thereof is initially administered during a noise or explosion expected to cause acute noise-induced hearing loss, for preventing or reducing the development of permanent tinnitus; for preventing or reducing the development of permanent shifts in the hearing threshold; or for preventing or reducing the development of permanently degenerated central auditory processes, including, for example, auditory temporal processing and/or speech understanding.
In one embodiment, administration of the compound of formula (I) or a pharmaceutically acceptable salt, solvate and/or derivative thereof is initiated after an event expected to cause acute noise-induced hearing loss.
Thus, in one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt, solvate and/or derivative thereof is initially administered after a noise or explosion that is expected to cause acute noise-induced hearing loss, for preventing or reducing the development of permanent tinnitus; for preventing or reducing the development of permanent shifts in the hearing threshold; or for preventing or reducing the development of permanently degenerated central auditory processes, including, for example, auditory temporal processing and/or speech understanding.
When the compound of formula (I) is administered after an event expected to cause acute noise-induced hearing loss, such administration is typically performed during the "acute phase", i.e. before hearing loss has been established.
In one embodiment, administration of the compound of formula (I) or a pharmaceutically acceptable salt, solvate and/or derivative thereof may begin at most 2 months after the event expected to cause acute noise-induced hearing loss, e.g., at most 1 month, 2 weeks, 1 week, 6 days, 5 days, 4 days, 3 days, 2 days, 24h, 12h, 6h, 5h, 4h, 3h, 2h, 1h, 30 minutes or at most 15 minutes after the event expected to cause acute noise-induced hearing loss. The compound of formula (I) or a pharmaceutically acceptable salt, solvate and/or derivative thereof may be administered multiple times after an event that is expected to cause noisy acute hearing loss.
A compound of formula (I) or a pharmaceutically acceptable salt, solvate, and/or derivative thereof may be administered over a period of up to 7 days (e.g., up to 1 day, up to 2 days, up to 3 days, up to 4 days, up to 5 days, up to 6 days, or up to 7 days), 1-2 weeks (e.g., 7-8 days, 7-9 days, 7-10 days, 7-11 days, 7-12 days, 7-13 days, or 7-14 days), 2-4 weeks (e.g., 2-3 weeks or 2-4 weeks), or 1-2 months (e.g., 4-6 weeks or 4-8 weeks).
The compound of formula (I) or a pharmaceutically acceptable salt, solvate and/or derivative thereof may be administered initially up to 1 day, such as up to 2 days, up to 3 days, up to 5 days, up to 1 week, up to 2 weeks or up to 1 month before a noise or explosion expected to cause acute noisy hearing loss, administration beginning at any point before exposure to a noise or explosion expected to cause acute noisy hearing loss typically lasting up to 2 months, such as up to 1 month, up to 3 weeks, up to 2 weeks, up to 1 week, up to 5 days, up to 3 days, up to 2 days or up to 1 day after exposure to a noise or explosion expected to cause acute noisy hearing loss.
In one embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt, solvate and/or derivative thereof, for use in preventing or reducing the development of a permanent shift of the hearing threshold, wherein the permanent shift of the hearing threshold is reduced by at least 10dB, such as at least 15dB, at least 20dB, at least 30dB, at least 40dB or completely reduced.
Pharmaceutical composition
For use in therapy, the compounds of the invention are typically administered as pharmaceutical compositions. The invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate (e.g. salt) and/or derivative thereof and a pharmaceutically acceptable carrier or excipient.
In one embodiment, there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate (e.g. salt) and/or derivative thereof for use in the treatment or prevention of a disease or condition selected from: hearing disorders, schizophrenia, depression and mood disorders, bipolar disorder, substance abuse disorders, anxiety disorders, sleep disorders, auditory hypersensitivity and loudness perception disorders, meniere's disease, balance disorders and inner ear disorders, impulse control disorders, personality disorders, attention deficit hyperactivity disorder, autism spectrum disorders, eating disorders, cognitive disorders, ataxia, pain such as neuropathic pain, inflammatory pain and miscellaneous pain, dementia with lewy bodies and parkinson's disease.
In another embodiment, a method is provided for preventing or treating a disease or condition selected from the group consisting of: hearing disorders, schizophrenia, depression and mood disorders, bipolar disorder, substance abuse disorders, anxiety disorders, sleep disorders, auditory hypersensitivity and loudness perception disorders, meniere's disease, balance disorders and inner ear disorders, impulse control disorders, personality disorders, attention deficit/hyperactivity disorder, autism spectrum disorders, eating disorders, cognitive disorders, ataxia, pain such as neuropathic pain, inflammatory pain and miscellaneous pain, lewy body dementia and parkinson's disease, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate (e.g. salt) and/or derivative thereof.
The invention also provides the use of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate (e.g. salt) and/or derivative thereof in the manufacture of a medicament for the treatment or prevention of a disease or condition selected from: hearing disorders, schizophrenia, depression and mood disorders, bipolar disorder, substance abuse disorders, anxiety disorders, sleep disorders, auditory hypersensitivity and loudness perception disorders, meniere's disease, balance disorders and inner ear disorders, impulse control disorders, personality disorders, attention deficit/hyperactivity disorders, autism spectrum disorders, eating disorders, cognitive disorders, ataxia, pain such as neuropathic pain, inflammatory pain and miscellaneous pain, dementia with lewy bodies and parkinson's disease.
The compound of formula (I) or a pharmaceutically acceptable salt and/or solvate and/or derivative thereof may be administered by any convenient method, for example by oral, parenteral, buccal, sublingual, nasal, rectal or transdermal administration, with corresponding adjustment of the pharmaceutical composition. Other possible routes of administration include intratympanic and intracochlear.
When administered orally, the active compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof and/or derivative thereof may be formulated as a liquid or solid, such as a syrup, suspension, emulsion, tablet, capsule or lozenge.
Liquid formulations typically consist of a suspension or solution of the active ingredient (e.g. a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate (e.g. salt) and/or derivative thereof) in a suitable liquid carrier, for example an aqueous solvent (such as water, ethanol or glycerol) or a non-aqueous solvent (such as polyethylene glycol or oil). The formulation may also contain suspending agents, preservatives, flavouring and/or colouring agents.
Compositions in tablet form may be prepared using any suitable pharmaceutical carrier conventionally used for the preparation of solid formulations, for example magnesium stearate, starch, lactose, sucrose and cellulose.
Compositions in the form of capsules may be prepared using conventional encapsulation methods, for example pellets containing the active ingredient (e.g. a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate (e.g. salt) and/or derivative thereof) may be prepared using standard carriers and then filled into hard gelatin capsules; alternatively, the dispersion or suspension may be prepared using a suitable pharmaceutical carrier, such as an aqueous gum, cellulose, silicate or oil, and the dispersion or suspension filled into a soft gelatin capsule.
Typical parenteral compositions consist of a solution or suspension of the active ingredient, for example a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate (e.g. salt) and/or derivative thereof, in a sterile aqueous carrier or a parenterally acceptable oil (e.g. polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil or sesame oil). Alternatively, the solution may be lyophilized and then reconstituted with a suitable solvent just prior to administration.
Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders. Aerosol formulations typically comprise a solution or fine suspension of the active ingredient in a pharmaceutically acceptable aqueous or non-aqueous solvent, and are usually presented in sterile form in single or multiple doses in a sealed container which may take the form of a cartridge or refill for use with the atomising device. Alternatively, the sealed container may be a disposable dispensing device, such as a single dose nasal inhaler or an aerosol dispenser equipped with a metering valve. When the dosage form comprises an aerosol dispenser, it comprises a propellant which may be a compressed gas, for example air, or an organic propellant, for example a chlorofluorocarbon or a hydrofluorocarbon. Aerosol dosage forms may also take the form of pump-atomizers.
Compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier, such as sugar and acacia, tragacanth or gelatin and glycerin.
Compositions for rectal administration are conveniently in the form of suppositories containing conventional suppository bases such as cocoa butter.
Compositions suitable for transdermal administration include ointments, gels, and patches. In one embodiment, the composition is in unit dosage form, such as a tablet, capsule or ampoule.
Depending on the method of application, the compositions may contain from 0.1% to 100% by weight, for example from 10 to 60% by weight, of active substance. Depending on the method of application, the composition may contain from 0% to 99%, for example from 40% to 90% by weight of the carrier. Depending on the method of administration, the composition may contain from 0.05mg to 1000mg, for example from 1.0mg to 500mg, of active substance. Depending on the method of administration, the composition may contain from 50mg to 1000mg, for example from 100mg to 400mg, of the carrier. The dosage of the compounds used to treat the above conditions will vary in the usual manner with the severity of the condition, the weight of the patient and other similar factors. However, as a general guideline, suitable unit doses may be in the range of from 0.05mg to 1000mg, more suitably from 1.0mg to 500mg, and such unit doses may be administered more than once per day, for example twice or three times per day. This therapy may extend for weeks or months.
The dose provided to an individual is typically a safe and effective dose, i.e., an acceptable balance of desired benefit and undesirable side effects.
In another aspect, the present invention provides a combination comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate, and/or derivative thereof (e.g., a combination comprising a compound of formula (I), or a pharmaceutically acceptable derivative thereof), and additionally one or more pharmaceutically acceptable active ingredients.
The present invention provides a compound of formula (I) for use in combination with one or more additional pharmaceutically acceptable active ingredients.
When the compounds are used in combination with other therapeutic agents, the compounds may be administered sequentially or simultaneously by any convenient route. Alternatively, the compounds may be administered separately.
The above combinations may conveniently be presented for use in the form of a pharmaceutical formulation and thus a pharmaceutical formulation comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient forms a further aspect of the invention. The individual components of such combinations may be administered sequentially or simultaneously in separate or combined pharmaceutical formulations. The individual components of the combination may also be administered separately, by the same or different routes.
When a compound of formula (I) or a pharmaceutically acceptable derivative thereof is used in combination with a second therapeutic agent active against the same disease state, the dosage of each compound may be different from the dosage of the compound when used alone. Appropriate dosages will be readily understood by those skilled in the art.
Suitably, the compound of formula (I) or a pharmaceutically acceptable salt, solvate and/or derivative thereof is administered orally.
Suitably, the compound of formula (I) or a pharmaceutically acceptable salt, solvate and/or derivative thereof is administered at 2 to 400mg per day, for example 2 to 300mg per day, especially 5 to 250mg per day.
Suitably, the compound of formula (I) or a pharmaceutically acceptable salt, solvate and/or derivative thereof is administered once or twice daily.
Suitably, the compound of formula (I) or a pharmaceutically acceptable salt, solvate and/or derivative thereof is administered for a period of at least three months.
Desirably, the compound of formula (I) or a pharmaceutically acceptable salt, solvate and/or derivative thereof is administered orally, once or twice daily, at 2-400mg daily, for example 2-300mg daily, especially 5-250mg daily.
The human subject may be an adult, for example 18 to 65 years old. Alternatively, the human individual may be 66 years old or older. A compound of formula (I) or a pharmaceutically acceptable salt, solvate and/or derivative thereof may be administered to a human subject less than 18 years of age, for example 4-17 years of age. In the case of progressive myoclonic epilepsy and fragile X syndrome, administration to human individuals under 18 years of age may be of particular relevance.
For convenience and to aid in patient compliance, a compound of formula (I) or a pharmaceutically acceptable salt, solvate and/or derivative thereof may be delivered over a sustained period of time, for example at least 1 week or at least 4 weeks, using a delivery technique such as a patch or implant.
Experiment of
The invention is exemplified by the compounds described below. The following examples describe the laboratory synthesis of specific compounds of the invention and are not meant to limit the scope of the invention in any way with respect to the compounds or methods. It will be appreciated that, although specific reagents, solvents, temperatures and time periods are employed, there are many possible equivalent alternatives that may be used to produce similar results. The present invention is intended to include such equivalents.
Analytical instrument
Unless otherwise indicated, starting materials, reagents, and solvents were obtained from commercial suppliers and used without further purification. Unless otherwise indicated, all compounds having a chiral center are racemic. When the reaction is described as having been carried out in a manner analogous to the more fully described reactions previously, the general reaction conditions employed are essentially the same. The work-up conditions used are of the type standard in the art but can be adjusted from one reaction to another. The starting materials may not necessarily have been prepared from the mentioned batches. The synthesized compounds may have different purities, e.g., 85% -99%. In some cases, the molar and yield calculations are adjusted for this.
HPLC-mass spectra (HPLC-MS) were acquired on an Agilent1100 series LC/MSD mass spectrometer coupled to an HPLC instrument Agilent1100 series, operating in positive electrospray ionization mode and acidic gradient conditions.
Quality control (3 min method): LC/MS-ES + was performed on a Zorbax SB C18 column (1.8 μm 3X 50mm) under acidic conditions. Mobile phase A (H2O +0.05 vol.% TFA)/B (CH3CN +0.05 vol.% TFA). Gradient t ═ 0min 0% (B), from 0 to 95% (B) within 2.5min, 95% (B) for 0.2min, from 95 to 100% (B) within 0.2min, 100% (B) for 0.4min, from 100% to 0% (B) within 0.1 min. The stop time was 4 min. Column T60 ℃. The flow rate was 1.5 ml/min. Mass range ES + (100-. UV detection wavelength: DAD 1A-220.8 and DAD 1B-254.8. In the analytical characterization of the compounds, the application of this method is denoted by "QC _3_ MIN".
Chiral control: in thatLC/MS-ES + was performed on OD-H (250X4,6mm-5um) under acidic conditions. Mobile phase A (H2O +0.05 vol.% TFA)/B (CH3CN +0.05 vol.% TFA). Gradient t is 0-6 min 35% (B), t is 6-40 min from 35% to 50% (B), t is 6-40 min from 50% to 70% (B), t is 45-50 min from 70% to 35% (B), t is 50-55 min 35% (B). The stop time was 60 min. Column T-40 ℃. The flow rate was 1.0 ml/min. UV detection wavelength: DAD 1A is 220.8, and DAD 1B is 254.8.
Proton magnetic resonance (NMR) spectra were recorded at 300, 400, 500 or 600MHz on Varian Instruments or at 400MHz on Bruker Instruments. Chemical shifts are reported in ppm (δ) using the residual solvent line as an internal standard. The splitting modes were designed as s (singlet), br.s (broad singlet), d (doublet), t (triplet), q (quartet), dd (doublet), dt (doublet triplet) and m (multiplet). NMR spectra were recorded at temperatures in the range of 25-60 ℃.
2D NMR NOESY experiments were acquired at 500ms mixing time using a spectral width of 3355Hz in both f1 and f 2. A total of 256 increments were collected and processed to 1K with linear prediction, 8 scans each. Data was processed with a sine-bell offset in two dimensions and with LB ═ 0.3Hz in f 1. In many preparations, purification was performed using Biotage automated Flash chromatography (SP1 and SP4) or Flash Master Personal system.
Flash chromatography was performed on 230-400 mesh silica gel (supplied by Merck AG Darmstadt, Germany) or 300-400 mesh silica gel (supplied by Sinopharm Chemical Reagent Co., Ltd.), Varian Mega BE-Si pre-packed columns, pre-packed Biotage silica gel columns (e.g., Biotage SNAP columns).
Abbreviations
AIBN azobisisobutyronitrile
BuLi butyl lithium
CDCl 3 Deuterated chloroform
CCl 4 Carbon tetrachloride
D 2 Heavy O water
DCM dichloromethane
DIPEA N, N-diisopropylethylamine
DMAP 4-dimethylaminopyridine
DMF N, N-dimethylformamide
DMSO dimethyl sulfoxide
DMSO-d 6 Deuterated dimethyl sulfoxide
Et 2 O Ether
EtOAc ethyl acetate
h hours
HATU (O-7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate)
HCl hydrogen chloride
K 2 CO 3 Potassium carbonate
MeCN/CH 3 CN acetonitrile
MeOH methanol
MOM methoxymethyl group
NaH sodium hydride
Na 2 SO 4 Sodium sulfate
Na 2 CO 3 Sodium carbonate
NaOH sodium hydroxide
NaOMe sodium methoxide
NMR nuclear magnetic resonance
r.t. room temperature
T3P propylphosphonic anhydride
MTBE methyl tert-butyl ether
TBTU benzotriazol-1-yl-N, N, N ', N' -tetramethyluronium tetrafluoroborate
TEA Triethylamine
TFA trifluoroacetic acid
THF tetrahydrofuran
THP tetrahydropyrans
weight (wt.)
Examples of the Compounds
Intermediate 1
2-bromo-5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane)]-4-yl) oxy-pyrazines
Reacting 7-methyl spiro [ 2H-benzofuran-3, 1' -cyclopropane]A mixture of-4-ol (intermediate 156WO2012076877,1.11g,6,30mmol), 2, 5-dibromopyrazine (1.5g,6,30mmol) and dipotassium carbonate (1.31g,9.46mmol) in N, N-dimethylformamide (14mL) was stirred at 120 ℃ for 3 hours. After cooling, the reaction mixture was diluted with MTBE (100ml) and washed with brine (50 ml). The phases were separated and the aqueous layer was washed with MTBE (100ml) and EtOAc (100 ml). Collecting all organic phase, and adding Na 2 SO 4 Dried, filtered and evaporated. The residue was purified by flash chromatography on silica gel (Biotage System) using SNAP 100g as column and cyclohexane: ethyl acetate 100:0-90:10 as eluent to give 2-bromo-5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane]-4-yl) oxy-pyrazine (1.8g) as a white solid.
LC/MS:QC_3_MIN:Rt＝2.705min；m/z 333&335[M+H]+。
The following compounds were prepared using the above procedure, substituting the appropriate phenol for 7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-ol. The final product was purified by flash chromatography (silica gel column; cyclohexane/EtOAc or other suitable solvent system).
Intermediate 5 route 1
3- (5-chloropyrazin-2-yl) -5, 5-dimethyl-imidazolidine-2, 4-dione
To a solution of bis (trichloromethyl) carbonate (950mg,3.20mmol) in ethyl acetate (30mL) was added dropwise a solution of 5-chloropyrazin-2-amine (0.75g,5.79mmol)/N, N-diisopropylethylamine (6.05mL,34.74mmol) in ethyl acetate (12mL) at 0 deg.C, and the reaction mixture was stirred at the same temperature for 15 minutes. The reaction mixture was maintained at 0 ℃ and vacuum was applied (5 minutes) to remove excess phosgene. A solution of 4- (dimethylamino) pyridine (710mg,5.81mmol) in ethyl acetate (8 mL)/dichloromethane (2mL) was added and the reaction mixture was stirred at the same temperature for 5 minutes. 2-amino-2-methyl-propionic acid methyl ester hydrochloride (1.4g,9.1mmol) was then added at 0 ℃ and the reaction mixture was stirred at the same temperature for 30 minutes. The reaction was stopped with 0.2N HCl solution (100ml) and the two phases were separated. The organic layer was washed with brine (100ml) and Na 2 SO 4 Drying, filtering and evaporating to obtain the urea intermediate.
Urea was dissolved in dichloromethane (20mL) and sodium methoxide (315mg,5.83mmol) was added at 0 ℃. The reaction mixture was stirred at the same temperature for 15 minutes; with saturated NH 4 The Cl solution brought the pH to 3-4 to stop the reaction. The mixture was extracted with ethyl acetate (50 ml); the phases were separated and the organic layer was washed with brine (50ml) and Na 2 SO 4 Drying, filtering and steamingAnd (4) sending. The residue was purified by reverse phase flash chromatography of C-18 phase (Biotage System) using SNAP 30g as column and water acetonitrile 95:5-40:60 as eluent. The appropriate fractions were combined and evaporated to dryness to give 3- (5-chloropyrazin-2-yl) -5, 5-dimethyl-imidazolidine-2, 4-dione (220mg) as a light brown solid.
LC/MS:QC_3_MIN:Rt＝1.649min；m/z 241&243[M+H]+。
Using the procedure described above, the following compounds were prepared using the appropriate amino ester hydrochloride instead of 2, 2-dimethylglycine methyl ester hydrochloride. The final product was purified by flash chromatography (silica gel column; cyclohexane/EtOAc or other suitable solvent system) or trituration in or crystallization from a suitable solvent.
Intermediate 5 route 2
3- (5-Chloropyrazin-2-yl) -5, 5-dimethyl-imidazolidine-2, 4-dione
To a solution of 5-chloropyrazin-2-amine (500mg,3.86mmol) and 2-amino-2-methyl-propionic acid hydrochloride (646mg,4.63mmol) in acetonitrile (10mL) at RT was slowly added a solution of >50 wt% propylphosphonic anhydride in ethyl acetate (3.68g,5.78 mmol). The reaction mixture was stirred at 80 ℃ for 6 h. The reaction mixture was diluted with ethyl acetate (10ml), and aqueous NaOH 1N was added to bring ph to 8. The phases were separated and the organic phase was washed with brine (10ml) and Na 2 SO 4 Drying, concentration in vacuo and purification of the crude product by flash chromatography on silica gel (Biotage system) using SNAP 25g as column and DCM: MEOH 99/1-90/10 as eluent gave 2-amino-N- (5-chloropyrazin-2-yl) -2-methyl-propionamide (190mg) as a yellow solid.
LC/MS:QC_3_MIN:Rt＝1.181min；m/z 215&217[M+H]+。
To a solution of 2-amino-N- (5-chloropyrazin-2-yl) -2-methyl-propionamide (190mg,0.88mmol) and triethylamine (268mg,2,6555mmol) in dichloromethane (5mL) was slowly added a solution of bis (trichloromethyl) carbonate (105,07mg,0,3541mmol) in dichloromethane (4mL) at 0 ℃, and the reaction mixture was stirred at the same temperature for 30 minutes. The reaction mixture was diluted with DCM (10mL) and washed with 0.2N aqueous HCl (10mL) and brine (10 mL). The organic phase was concentrated in vacuo and the crude product was purified by flash chromatography on silica gel (Biotage system) using SNAP 25g as column and cyclohexane/EtOAc 80/20-0/100 as eluent to give 3- (5-chloropyrazin-2-yl) -5, 5-dimethyl-imidazolidine-2, 4-dione (130mg) as a white solid.
LC/MS:QC_3_MIN:Rt＝1.598min；m/z 241&243[M+H]+。
Intermediate 7
N- [ (1R) -1-carbamoylpropyl group]Carbamic acid tert-butyl ester
A mixture of [ dimethylamino- (3-oxotriazolo [4,5-b ] pyridin-3-ium-1-yl) methylene ] -dimethyl-ammonium tetrafluoroborate (1,1084g,3,4415mmol), N-diisopropylethylamine (0,7939g,6,1431mmol) and (2R) -2- (tert-butoxycarbonylamino) butyric acid (0,5000g,2,4601mmol) in dry N, N-dimethylformamide (8mL) was stirred at room temperature for 10 minutes. Hexamethyldisilazane (0,5960g,3,6928mmol) was added and the mixture was stirred for 18 h.
The reaction mixture was separated in MTBE (30mL) and brine (20 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was removed. The resulting oil was triturated in MTBE (3mL), the resulting precipitate washed with MTBE and dried in vacuo to give tert-butyl N- [ (1R) -1-carbamoylpropyl ] carbamate (0,3000g,1,4833mmol,60,294%) as a white solid.
LC/MS:QC_3_MIN:m/z 147[M-tBu+H]+。
The following compounds were prepared using the above procedure, substituting the appropriate protected amino acid for (2R) -2- (tert-butoxycarbonylamino) butanoic acid.
Intermediate 9 (route 1)
N- [ (1R) -1- [ [5- (7-Methylspiro [ 2H-benzofuran-3, 1' -cyclopropane)]-4-yl) oxypyrazin-2-yl] Carbamoyl radical]Propyl radical]Carbamic acid tert-butyl ester
A mixture of 2-bromo-5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yl) oxy-pyrazine (intermediate 1,50mg,0.15mmol), N- [ (1R) -1-carbamoylpropyl ] carbamic acid tert-butyl ester (intermediate 7,46mg,0.23mmol), tris (dibenzylideneacetone) dipalladium (0) (10.3mg,0.011mmol), dicyclohexyl- [2- (2,4, 6-triisopropylphenyl) phenyl ] phosphine (phosphane) (XPhos) (5.4mg,0.011mmol) and cesium carbonate (73mg,0.22mmol) in 1, 4-dioxane (2mL) was stirred at 80 ℃ for 3H under a nitrogen atmosphere.
The reaction was partitioned between ethyl acetate and brine. The organic layer was separated, dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography on silica gel (Biotage system) using SNAP 10g column with cyclohexane and EtOAc 100/0-0/100 as eluent. The appropriate fractions were combined and evaporated to dryness to give tert-butyl N- [ (1R) -1- [ [5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yl) oxypyrazin-2-yl ] carbamoyl ] propyl ] carbamate (10 mg).
LC/MS:QC_3_MIN:Rt＝2.696min；m/z 455[M+H]+。
Intermediate 9 (route 2)
N- [ (1R) -1- [ [5- (7-Methylspiro [ 2H-benzofuran-3, 1' -cyclopropane)]-4-yl) oxypyrazin-2-yl] Carbamoyl radical]Propyl radical]Amino group(iv) Carboxylic acid tert-butyl ester
After purging with argon, 2-bromo-5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane)]-4-yl) oxy-pyrazine (intermediate 1,16g,48.0mmol), N- [ (1R) -1-carbamoylpropyl]To a mixture of tert-butyl carbamate (intermediate 7,10g,49.4mmol), cesium carbonate (24.16g,74.17mmol) in 1, 4-dioxane (150mL) was added diacetoxypalladium (0.555g,2.47mmol) and (5-diphenylphosphino-9, 9-dimethyl-xanthen-4-yl) -diphenyl-phosphine (2.15g,3.71 mmol). The reaction mixture was stirred at 95 ℃ for 1.5h with 3 vacuum-argon cycles applied. The reaction mixture was cooled using an external ice bath and then filtered under vacuum to remove cesium carbonate. The filtrate was collected, diluted with EtOAc (150mL), and saturated NH 4 Aqueous Cl (100ml) and then saturated aqueous NaCl (100ml) were washed, dried over sodium sulphate, filtered and evaporated to dryness. The residue was purified by flash chromatography on silica gel (Biotage system) using a 2 × SNAP 100g column (200g silica) using cyclohexane/EtOAc 0-40% as eluent to give N- [ (1R) -1- [ [5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane)]-4-yl) oxypyrazin-2-yl]Carbamoyl radical]Propyl radical]Tert-butyl carbamate (16.8g) as a yellow solid.
Using the above procedure (scheme 1 or scheme 2), the following compounds were prepared using the appropriate bromopyrazine instead of 2-bromo-5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yl) oxy-pyrazine (intermediate 1). The final product was purified by flash chromatography (silica gel column; cyclohexane/EtOAc or other suitable solvent system).
Intermediate (II)Body 13
(2R) -2-amino-N- [5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane)]-4-yl) oxypyrazine-2- Base of]Butylamide
A mixture of tert-butyl N- [ (1R) -1- [ [5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yl) oxopyrazin-2-yl ] carbamoyl ] propyl ] carbamate (intermediate 9,16mg,0.035mmol) and 2,2, 2-trifluoroacetic acid (0.50mL,6.53mmol) in dichloromethane (2mL) was stirred at room temperature for 2H.
The reaction mixture was diluted with dichloromethane (20ml) and NaHCO was added 3 The solution (aqueous solution) was saturated while the pH was brought to 8. The phases were separated, the organic layer was washed with brine (20ml), Na 2 SO 4 Drying, filtering and evaporating to obtain (2R) -2-amino-N- [5- (7-methyl spiro [ 2H-benzofuran-3, 1' -cyclopropane)]-4-yl) oxypyrazin-2-yl]Butanamide (13mg), used in the next step without further purification.
LC/MS:QC_3_MIN:Rt＝2.009min；m/z 355[M+H]+。
The following compounds were prepared using the above procedure substituting the appropriate Boc amine for tert-butyl N- [ (1R) -1- [ [5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yl) oxopyrazin-2-yl ] carbamoyl ] propyl ] carbamate (intermediate 9).
Intermediate 17
(5R) -5-Ethyl-5-methyl-imidazolidine-2, 4-dione
Reacting N- [ (1R) -1-aminomethylAcyl-1-methyl-propyl]A mixture of tert-butyl carbamate (intermediate 8,100mg,0,4624mmol) and potassium carbonate (191,71mg,1,3871mmol) in 1-butanol (5mL) was stirred under nitrogen at 95 deg.C overnight. After cooling, the potassium carbonate was filtered off, and the reaction mixture was diluted with ethyl acetate (30ml), washed with 0.1N aqueous HCl (30ml) and then brine (30 ml). The phases were separated and the organic layer was collected over Na 2 SO 4 Drying, filtration and evaporation gave (5R) -5-ethyl-5-methyl-imidazolidine-2, 4-dione (60mg,0,4221mmol,91,283%).
LC/MS:QC_3_MIN:m/z 285[2M+H]+。
Intermediate 18
N- (1-carbamoylcyclobutyl) carbamic acid tert-butyl ester
Intermediate 18 was prepared using the procedure described for intermediate 7, substituting 1- (tert-butoxycarbonylamino) cyclobutanecarboxylic acid for (2R) -2- (tert-butoxycarbonylamino) butanoic acid.
LC/MS:QC_3_MIN:m/z 159[M-tBu+H]+。
Intermediate 19
N- [1- [ [5- (7-Methylspiro [ 2H-benzofuran-3, 1' -cyclopropane)]-4-yl) oxypyrazin-2-yl]Amino-methyl Acyl radical]Cyclobutyl radical]Carbamic acid tert-butyl ester
2-bromo-5- (7-methyl spiro [ 2H-benzofuran-3, 1' -cyclopropane)]A mixture of (4-yl) oxy-pyrazine (intermediate 1,50mg,0.1501mmol), tert-butyl N- (1-carbamoylcyclobutyl) carbamate (intermediate 18,64mg,0.2987mmol), dipotassium carbonate (62mg,0,4486mmol), copper (I) iodide (2.9mg,0.0152mmol) and N, N' -dimethylethylene-1, 2-diamine (0.0065mL,0.0601mmol) in 1-butanol (1mL)Stirring was carried out at 95 ℃ for 4h under a nitrogen atmosphere. After cooling, the reaction mixture was diluted with ethyl acetate (30ml), washed with 0.1M aqueous HCl (30ml) and then brine (30 ml). The phases were separated and the organic layer was collected and washed with Na 2 SO 4 Drying, filtering and evaporating. The residue was purified by flash chromatography on silica gel (Biotage System) using SNAP 10g as column and cyclohexane: ethyl acetate 100:0-30:70 as eluent to give N- [1- [ [5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane)]-4-yl) oxypyrazin-2-yl]Carbamoyl radical]Cyclobutyl radical]Carbamic acid tert-butyl ester (18 mg).
LC/MS:QC_3_MIN:Rt＝2.675min；m/z 467[M+H]+。
Intermediate 20
1-amino-N- [5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane)]-4-yl) oxypyrazin-2-yl]Ring (C) Butane carboxamide
Intermediate 20 was prepared using the method described for intermediate 13 substituting tert-butyl N- [1- [ [5- (7-methylspiro [ 2H-benzofuran-3, 1 '-cyclopropane ] -4-yl) oxypyrazin-2-yl ] carbamoyl ] cyclobutyl ] carbamate (intermediate 19) for tert-butyl N- [ (1R) -1- [ [5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yl) oxypyrazin-2-yl ] carbamoyl ] propyl ] carbamate (intermediate 9).
LC/MS:QC_3_MIN:Rt＝1.979min；m/z 367[M+H]+。
Intermediate 21
N- (1-carbamoylcyclopropyl) carbamic acid tert-butyl ester
Intermediate 21 was prepared using the procedure described for intermediate 7, substituting 1- (tert-butoxycarbonylamino) cyclopropanecarboxylic acid for (2R) -2- (tert-butoxycarbonylamino) butyric acid.
Intermediate 22
N- [1- [ [5- (7-Methylspiro [ 2H-benzofuran-3, 1' -cyclopropane)]-4-yl) oxypyrazin-2-yl]Amino-methyl Acyl radical]Cyclopropyl group]Carbamic acid tert-butyl ester
Dicyclohexyl- [2- (2,4, 6-triisopropylphenyl) phenyl]Phosphine (12mg,0.0252mmol), tert-butyl N- (1-carbamoylcyclopropyl) carbamate (intermediate 21,67mg,0.3346mmol), tris (dibenzylideneacetone) dipalladium (0) (22mg,0.0240mmol), 2-bromo-5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane)]A mixture of-4-yl) oxy-pyrazine (intermediate 1,79.518mg,0.2387mmol) and cesium carbonate (116mg,0.3560mmol) in 1, 4-dioxane (1mL) was stirred under nitrogen atmosphere at 95 ℃ for 2 h. Tert-butyl N- (1-carbamoylcyclopropyl) carbamate (intermediate 21,67mg,0.3346mmol) and tris (dibenzylideneacetone) dipalladium (0) (22mg,0.0240mmol) were then added and the reaction mixture was stirred at 95 ℃ under a nitrogen atmosphere for a further 2h, followed by the addition of dicyclohexyl- [2- (2,4, 6-triisopropylphenyl) phenyl ] phenyl]Phosphine (12mg,0.0252mmol), tris (dibenzylideneacetone) dipalladium (0) (22mg,0.0240mmol) and cesium carbonate (58mg), and the mixture was stirred under a nitrogen atmosphere for a further 2 h. Then water (10mL), NH 4 The reaction mixture was quenched with Cl (10mL) and extracted with ethyl acetate (20 mL). The organic layer was then washed with brine (15mL) and Na 2 SO 4 Dried, filtered and then concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (Biotage System) using SNAP 10g as column and cyclohexane ethyl acetate 90:10-70:30 as eluent to give N- [1- [ [5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane)]-4-yl) oxypyrazin-2-yl]Carbamoyl radical]Cyclopropyl group]Tert-butyl carbamate (55mg) as a yellow solid.
LC/MS:QC_3_MIN:Rt＝2.634min；m/z 453[M+H]+。
Intermediate 23
1-amino-N- [5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane)]-4-yl) oxypyrazin-2-yl]Ring (C) Propane carboxamide
Reacting N- [1- [ [5- (7-methyl spiro [ 2H-benzofuran-3, 1' -cyclopropane)]-4-yl) oxypyrazin-2-yl]Carbamoyl radical]Cyclopropyl group]Tert-butyl carbamate (intermediate 22,55mg,0.1215mmol) was dissolved in dichloromethane (4mL) and cooled to 0 ℃.2, 2, 2-trifluoroacetic acid (1154.7mg,10.026mmol) (0.8mL) was added dropwise and the reaction was stirred at room temperature for 1 hour. The reaction mixture was then cooled to 0 ℃ and NaHCO was added 3 Until a pH of 8 is reached. The mixture was then warmed to room temperature and extracted with DCM (10 mL). With Na 2 SO 4 Drying the organic layer, filtering, and vacuum concentrating to obtain 1-amino-N- [5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane)]-4-yl) oxypyrazin-2-yl]Cyclopropanecarboxamide (40mg) was used as a yellow oil. LC/MS QC _3_ MIN Rt 1.935 MIN; m/z 353[ M + H ]]+。
Intermediate 24
1, 3-dibenzyloxy-2-bromo-benzene
To a solution of 2-bromobenzene-1, 3-diol (20g,105.8mmol) in acetone (200mL) was added potassium carbonate (43.87g,317.4mmol) followed by benzyl bromide (40.72g,238.1mmol) (28mL) and the reaction mixture refluxed for 1.5 hours. After cooling, the reaction mixture was filtered under vacuum and the filtrate was concentrated to dryness. The residue was diluted with ethyl acetate (100ml), which was washed with water (100ml) and then brine (100 ml). Separating the phases with Na 2 SO 4 The organic layer was dried, filtered and concentrated. The residue was suspended in isopropanol (8 volumes), the mixture was heated at 80 ℃ and stirred at this temperature for 1 hour (to obtainTo a clear solution). The mixture was then allowed to reach room temperature (over 1 h) and the resulting suspension was filtered. The solid was washed with ice cold isopropanol and then dried to give the title compound 1, 3-dibenzyloxy-2-bromo-benzene (34g) as a pink solid.
LC/MS:QC_3_MIN:Rt＝2.688min。
Intermediate 25
Bromo- (1-methoxycarbonylcyclopropyl) zinc
Activated zinc powder (6.84g,104.6mmol) was added to a two-necked round bottom flask and the powder was heated in vacuo. The system was placed under an argon atmosphere and anhydrous tetrahydrofuran (58mL) was added. 1, 2-dibromoethane (2.18g,11.62mmol) was then added and the mixture was heated to reflux. Chlorotrimethylsilane (505mg,4.65mmol) was added in one portion and the mixture was kept under stirring at reflux temperature. A solution of methyl 1-bromocyclopropylcarboxylate (10.4g,58.1mmol) in anhydrous tetrahydrofuran (12mL) was added slowly at the same temperature and the reaction mixture was refluxed for 1.5 h. The reaction mixture is cooled to room temperature and the zinc is allowed to settle, giving 70ml of a 0.83M (theoretical) solution of bromo- (1-methoxyoxycyclopropyl) zinc in THF, which is used in the next step without further work-up.
Intermediate 26
1- (2, 6-dibenzyloxyphenyl) cyclopropanecarboxylic acid methyl ester
To a preheated solution of 1, 3-dibenzyloxy-2-bromo-benzene (intermediate 24,16g,43.33mmol) and bis (tri-tert-butylphosphino) palladium (0) (221mg,0.43mmol) in N, N-dimethylformamide (150mL) at 70 deg.C was added 0.83M (theoretical) solution of bromo- (1-methoxycarbonylcyclopropyl) zinc in THF (intermediate 25,60mL) (viaThrough a cannula) the reaction mixture was stirred at the same temperature for 40 minutes. After cooling, the reaction mixture was concentrated in vacuo to-30 ml, the residue was diluted with ethyl acetate (450ml), washed twice with 1N aqueous HCl (2x100ml) and then three times with ice cold brine (3x100 ml). The phases were separated and the organic layer was vacuum filtered using a Gooch filter equipped with filter paper and cellulose and washed with ethyl acetate. With Na 2 SO 4 The filtrate was dried, filtered and evaporated to give the title compound methyl 1- (2, 6-dibenzyloxyphenyl) cyclopropanecarboxylate (15.5g), which was used in the next step without further purification.
LC/MS:QC_3_MIN:Rt＝2.606min；m/z 389[M+H]+。
Intermediate 27
4-hydroxy spiro [ benzofuran-3, 1' -cyclopropane]-2-ketones
The reaction was carried out in three different runs, using approximately 20g of starting material each time.
The general method comprises the following steps: to a mixture of methyl 1- (2, 6-dibenzyloxyphenyl) cyclopropanecarboxylate (intermediate 26,20.4g,52.52mmol) and 5 wt% palladium on carbon (1.02g) in ethanol (200ml) was added ammonium formate (16.56g,262.6mmol) and the reaction mixture was stirred at 80 ℃ for 1 hour. After cooling, the catalyst was filtered off through a cellulose pad and the filtrate was concentrated to-20 ml in vacuo.
The residue from 3 runs was collected together, diluted with ethyl acetate (400ml) and washed twice with water (2 × 300 ml). The phases were separated and the organic phase was washed with brine (300ml) and Na 2 SO 4 Drying, and vacuum concentrating to obtain 4-hydroxy spiro [ benzofuran-3, 1' -cyclopropane]-2-ketone (27.55g) (containing about 10-15% of the uncyclized methyl 1- (2, 6-dihydroxyphenyl) cyclopropanecarboxylate intermediate) was used in the next step without further purification.
LC/MS:QC_3_MIN:Rt＝1.707min。
Intermediate 28
4-benzyloxyspiro [ benzofuran-3, 1' -cyclopropane]-2-ketones
To 4-hydroxy spiro [ benzofuran-3, 1' -cyclopropane]To a solution of-2-one (intermediate 27,28.5g,161.8mmol) (containing-10-15% of the uncyclized methyl 1- (2, 6-dihydroxyphenyl) cyclopropanecarboxylate intermediate) in acetonitrile (200 mL)/tetrahydrofuran (50mL) was added potassium carbonate (33.54g,242,7mmol) and the reaction mixture was stirred at 70 ℃ for 1.5 h. The reaction mixture was then cooled to room temperature and benzyl bromide (27.67g,161.8mmol) was added slowly. The reaction mixture was stirred at 60 ℃ for 5 hours. After cooling, the reaction mixture was filtered under vacuum, the solids discarded, and the filtrate concentrated to 50ml, diluted with ethyl acetate (250ml) and washed twice with brine (2 × 100 ml). Separating the phases with Na 2 SO 4 The organic layer was dried, filtered and evaporated to give the title compound 4-benzyloxyspiro [ benzofuran-3, 1' -cyclopropane]-2-ketone (42,4g), used in the next step without further purification.
LC/MS:QC_3_MIN:Rt＝2.389min；m/z 267[M+H]+。
Intermediate 29
3-benzyloxy-2- [1- (hydroxymethyl) cyclopropyl ] group]Phenol and its preparation
To 4-benzyloxyspiro [ benzofuran-3, 1' -cyclopropane at 0 DEG C]To a solution of-2-one (intermediate 28,42.4g,159.2mmol) in dry tetrahydrofuran (300mL) was slowly added a 1M solution of lithium aluminum hydride in THF (79.6mL,79,6mmol) and the reaction mixture was stirred at the same temperature for 30 min. The reaction was quenched with ice, water (400ml) and 1M aqueous HCl (160ml) and then diluted with ethyl acetate (700 ml). The phases were separated and the aqueous layer was back-extracted with ethyl acetate (500 ml). The combined solution was washed with brine (600ml) containingOrganic phase, with Na 2 SO 4 Drying, filtering and evaporating to obtain the title compound 3-benzyloxy-2- [1- (hydroxymethyl) cyclopropyl]Phenol (43g) was used in the next step without further purification.
LC/MS:QC_3_MIN:Rt＝2.148min；m/z 271[M+H]+,m/z 293[M+Na]+,m/z 253[M-OH]+。
Intermediate 30
4-benzyloxyspiro [ 2H-benzofuran-3, 1' -cyclopropane]
To the 3-benzyloxy-2- [1- (hydroxymethyl) cyclopropyl group]To a solution of phenol (intermediate 29,43g,159.1mmol) in dimethyl carbonate (430mL) was slowly added potassium tert-butoxide (35.7g,318.1mmol) and the reaction mixture was stirred at 85 ℃ for 3.5 h. The reaction mixture was cooled to room temperature, concentrated to 150mL in vacuo, diluted with MTBE (400mL) and washed with water (400 mL). The phases were separated and the aqueous layer was back-extracted with MTBE (250 ml). The combined organic layers were washed with brine (350ml) and Na 2 SO 4 Drying, filtering and concentrating to obtain the title compound 4-benzyloxy spiro [ 2H-benzofuran-3, 1' -cyclopropane](40g) And used in the next step without further purification.
LC/MS:QC_3_MIN:Rt＝2.457min；m/z 253[M+H]+。
Intermediate 31 (intermediate 85WO2012/076877)
1-spiro [ 2H-benzofuran-3, 1' -cyclopropane]-4-alcohols
The reaction was carried out in two portions, using 20g of starting material each time.
To 4-benzyloxyspiro [ 2H-benzofuran-3, 1' -cyclopropane](intermediate 30,20g,79.27mmol) and ammonium formate (24.99g,396.34mmol) in ethanol (160ml) was added 5%Weight palladium on carbon (2.0g) and the reaction mixture was stirred at 80 ℃ for 10 minutes. After cooling, the catalyst was filtered off through a cellulose pad and the filtrate was concentrated to-20 ml in vacuo. The residues from both reactions were combined and the mixture was diluted with ethyl acetate (300ml), washed three times with water (3 × 200ml) and then with brine (200 ml). Separating the two phases with Na 2 SO 4 The organic phase was dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (Biotage System) using cyclohexane: ethyl acetate 99:1-85:15 as eluent to give spiro [ 2H-benzofuran-3, 1' -cyclopropane]-4-ol (17,75g) as a white solid.
LC/MS:QC_3_MIN:Rt＝1.723min；m/z 163[M+H]+。
Intermediate 32
N- [ (1S) -1-carbamoylpropyl]Carbamic acid tert-butyl ester
The title compound was synthesized according to the same method as that used for the synthesis of intermediate 7, substituting (2S) -2- (tert-butoxycarbonylamino) butanoic acid for (2R) -2- (tert-butoxycarbonylamino) butanoic acid.
LC/MS:QC_3_MIN:m/z 147[M-tBu+H]+,m/z 427[2M+Na]+
Intermediate 33
N- [ (1S) -1- [ [5- (7-Methylspiro [ 2H-benzofuran-3, 1' -cyclopropane)]-4-yl) oxypyrazin-2-yl] Carbamoyl radical]Propyl radical]Carbamic acid tert-butyl ester
The title compound was synthesized following the procedure "scheme 1" for the synthesis of intermediate 9, substituting tert-butyl N- [ (1S) -1-carbamoylpropyl ] carbamate (intermediate 32) for tert-butyl N- [ (1R) -1-carbamoylpropyl ] carbamate (intermediate 7).
LC/MS:QC_3_MIN:Rt＝2.65min；m/z 455[M+H]+。
Intermediate 34
(2S) -2-amino-N- [5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane)]-4-yl) oxypyrazine-2- Base of]Butylamide
The title compound was synthesized according to the same method as that used for the synthesis of intermediate 13, substituting tert-butyl N- [ (1S) -1- [ [5- (7-methylspiro [ 2H-benzofuran-3, 1 '-cyclopropane ] -4-yl) oxypyrazin-2-yl ] carbamoyl ] propyl ] carbamate (intermediate 33) for tert-butyl N- [ (1R) -1- [ [5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yl) oxypyrazin-2-yl ] carbamoyl ] propyl ] carbamate (intermediate 9).
LC/MS:QC_3_MIN:Rt＝1.98min；m/z 355[M+H]+。
Example 1 route 1
5, 5-dimethyl-3- [5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane)]-4-yl) oxypyrazine-2- Base of]Imidazolidine-2, 4-diones
To a solution of 2-bromo-5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yl) oxy-pyrazine (intermediate 1,30mg,0.069mmol) in N, N-dimethylacetamide (1mL) was added 5, 5-dimethylimidazolidine-2, 4-dione (44.4mg,0.345mmol) and copper (I) oxide (5mg,0.035 mmol). The flask was purged with nitrogen and kept stirring at 135 ℃ overnight. The reaction was diluted with EtOAc (10mL) and washed first with saturated aqueous ammonium chloride (20mL) and then with brine (20 mL). The organic layer was collected, dried over sodium sulfate and evaporated to dryness. The residue was then purified by flash column chromatography using cyclohexane ethyl acetate 80:20-40:60 as eluent to give 5, 5-dimethyl-3- [5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yl) oxypyrazin-2-yl ] imidazolidine-2, 4-dione (17mg) as a white solid.
1 H-NMR(400MHz；DMSO-d6):δppm 8.72(bs,1H),8.51(d,1H),8.30(d,1H),6.95(dd,1H),6.53(d,1H),4.46(s,2H),2.14(s,3H),1.42(s,6H),1.07-1.14(m,2H),0.89-0.95(m,2H)。
Using the above procedure, the following compounds were prepared using the appropriate bromopyrazine instead of 2-bromo-5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yl) oxy-pyrazine (intermediate 1) and the appropriate hydantoin instead of 5, 5-dimethylimidazolidine-2, 4-dione. The final product was purified by flash chromatography (silica gel column; cyclohexane/EtOAc or other suitable solvent system) and/or reverse phase chromatography (C-18 column; water/acetonitrile or other suitable solvent system).
EXAMPLE 1 route 2
5, 5-dimethyl-3- [5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane)]-4-yl) oxypyrazine-2- Base of]Imidazolidine-2, 4-diones
To a solution of 3- (5-chloropyrazin-2-yl) -5, 5-dimethyl-imidazolidine-2, 4-dione (intermediate 5,20mg,0.083mmol) and 7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-ol (intermediate 156, WO2012076877,22mg,0.125mmol) in acetonitrile (1mL) was added dipotassium carbonate (17.2mg,0.12 mmol). The reaction mixture was stirred at 60 ℃ overnight and then at 80 ℃ for 3 h. The reaction mixture was concentrated in vacuo and the crude product was purified by flash chromatography on silica gel (BIOTAGE SYSTEM) using SNAP 10g as column and cyclohexane/EtOAc 80/20-20/80 as eluent. Fractions were still impure and they were purified by reverse phase chromatography using SNAP C-18 as column and H2O/ACN 95/5-5/95 as eluent to give 5, 5-dimethyl-3- [5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yl) oxypyrazin-2-yl ] imidazolidine-2, 4-dione (9.4mg) as a white solid.
LC/MS:QC_3_MIN:Rt＝2.224min；m/z 381[M+H]+。
Using the above method, the following compounds were prepared using the appropriate phenol instead of 7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-ol and using 3- (5-chloropyrazin-2-yl) -5, 5-dimethyl-imidazolidine-2, 4-dione (intermediate 5) or using the appropriate chloropyrazine intermediate instead of it. The final product was purified by flash chromatography (silica gel column; cyclohexane/EtOAc or other suitable solvent system) and/or reverse phase chromatography (C-18 column; water/acetonitrile or other suitable solvent system).
Example 9 (route 1)
(5R) -5-Ethyl-3- [5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane)]-4-yl) oxypyrazine-2- Base of]Imidazolidine-2, 4-diones
Mixing (2R) -2-amino-N- [5- (7-methyl spiro [ 2H-benzofuran-3, 1' -cyclopropane)]-4-yl) oxypyrazin-2-yl]A mixture of butyramide (intermediate 13,13mg,0.037mmol) and N, N-diethylethylamine (11mg,0.11mmol) in dichloromethane (2mL) was cooled to 0 ℃. Dripping deviceA solution of bis (trichloromethyl) carbonate (4,5mg,0.015mmol) in dichloromethane (0.5mL) was added and the reaction mixture was stirred at the same temperature for 1 hour. Bis (trichloromethyl) carbonate (1.5mg) in dichloromethane (0.5mL) was added thereto, and stirring was continued for 30 minutes. The mixture was warmed to room temperature. The reaction mixture was diluted with dichloromethane (20ml) and the organic phase was washed with 0.1N aqueous HCl (20ml) then brine (20 ml). Separating the phases with Na 2 SO 4 The organic layer was dried, filtered and evaporated. The residue was purified by reverse phase chromatography using a SNAP C-18 column eluting with water acetonitrile 90:10-0: 100. The appropriate fractions were combined and evaporated to dryness to give (5R) -5-ethyl-3- [5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane)]-4-yl) oxypyrazin-2-yl]Imidazolidine-2, 4-dione (7.5mg) as a white solid.
LC/MS QC _3_ MIN Rt 2.305 MIN; m/z 381[ M + H ] +. Enantiomeric purity was confirmed to be > 95% using chiral control method.
Example 9 (route 2)
(5R) -5-Ethyl-3- [5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane)]-4-yl) oxypyrazine-2- Base of]Imidazolidine-2, 4-diones
To a solution of (2R) -2-amino-N- [5- (7-methylspiro [ 2H-benzofuran-3, 1 '-cyclopropane ] -4-yl) oxopyrazin-2-yl ] butanamide (intermediate 13,21g,59.26mmol) in ethyl acetate (500mL) was added 1,1' -carbonyldiimidazole (10.57g,65.18mmol) in 5 portions of about 2g each, and stirred at room temperature for 4H. The reaction was quenched with ice and 0.2N aqueous HCl (250ml) was added. The phases were separated and the organic layer was washed with 0.2N aqueous HCl (250ml) and brine (200ml), then dried over sodium sulfate, filtered and evaporated to dryness. The crude product was divided into 4-4.2G aliquots, each of which was purified by flash chromatography on silica gel using SNAP (100G) as column and cyclohexane/ethyl acetate 80/20-20/80 as eluent. The desired fractions from each run were collected and the solvent was evaporated to dryness. The resulting pale yellow solid was suspended in a cyclohexane/ethyl acetate solution (1/1,3 volumes) (90ml) and stirred at 50 ℃ for 2 h. The mixture was then allowed to cool to room temperature and filtered under vacuum. The wet cake was washed with ice-cold cyclohexane (15ml), and the solid was collected and dried to give the title compound (5R) -5-ethyl-3- [5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yl) oxypyrazin-2-yl ] imidazolidine-2, 4-dione (13.6g) as a white solid.
1 H-NMR(500MHz；DMSO-d6):δppm 8.69(bs,1H),8.52(d,1H),8.26(d,1H),6.94(d,1H),6.53(d,1H),4.46(s,2H),4.26-4.30(m,1H),2.14(s,3H),1.77-1.86(m,1H),1.65-1.76(m,1H),1.07-1.12(m,2H),0.90-0.99(m,5H)。
The following compounds are prepared using the above procedure (scheme 1 or scheme 2) substituting the appropriate butyramide for (2R) -2-amino-N- [5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yl) oxopyrazin-2-yl ] butyramide (intermediate 13). The final product was purified by flash chromatography (silica gel column; cyclohexane/EtOAc or other suitable solvent system) and/or reverse phase chromatography (C-18 column; water/acetonitrile or other suitable solvent system).
Example 15
(5S) -5-Ethyl-3- [5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane)]-4-yl) oxypyrazine-2- Base of]Imidazolidine-2, 4-diones
The title compound was synthesized according to the procedure of "scheme 1" substituting (2S) -2-amino-N- [5- (7-methylspiro [ 2H-benzofuran-3, 1 '-cyclopropane ] -4-yl) oxypyrazin-2-yl ] butanamide (intermediate 34) for (2R) -2-amino-N- [5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yl) oxypyrazin-2-yl ] butanamide (intermediate 13).
LC/MS:QC_3_MIN:Rt＝2.29min；m/z 381[M+H]+。
Biological examples
Biological example 1: determination of Kv3.1, Kv3.2 and Kv3.3 channel modulation
The ability of the compounds of the invention to modulate the voltage-gated potassium channel subtype Kv3.3/Kv3.2/Kv3.1 can be determined using the following assay. Similar methods can be used to study the ability of the compounds of the invention to modulate other channel subtypes.
Cell biology
To evaluate the effect of compounds on human Kv3.3 channel (hKv3.3), Chinese Hamster Ovary (CHO) -K1 cells were transfected with pBacMire _ KCNC-3 vector to generate a stable cell line expressing human Kv3.3 channel. Cells were cultured in DMEM/F12(Gibco) supplemented with 10% fetal bovine serum (Gibco), 1X non-essential amino acids (Invitrogen) and geneticin (G418)400 ug/mL. Cells were allowed to contain 5% CO in air at 37 deg.C 2 And growing and maintaining in a humidified environment.
To evaluate the effect of compounds on the human Kv3.2 channel (hKv3.2), a stable cell line expressing the human Kv3.2 channel (hKv3.2) was generated by transfecting CHO-K1 cells with pCIH5-hKv3.2 vector. Cells were cultured in DMEM/F12 medium supplemented with 10% fetal bovine serum, 1 Xnon-essential amino acids (Invitrogen) and 500ug/ml hygromycin-B (Invitrogen). Cells were allowed to contain 5% CO in air at 37 deg.C 2 And growing and maintaining in a humidified environment.
To evaluate the effect of compounds on human Kv3.1 channel (hKv3.1):
by transfecting HEK-293 cells with an expression vector with human Kv3.1 (NM-004976.4)Cells were used to generate Human Embryonic Kidney (HEK) -HKv3.1 cell line. Cells were cultured in MEM supplemented with 10% heat-inactivated FBS, 2mM L-glutamine, 1% penicillin-streptomycin, and 0.6mg/ml geneticin (G418). MEM amplification Medium containing G418 selection antibiotics (0.6mg/ml) was used in T175cm2 flasks at 37 ℃ with 5% CO 2 HEK-hKV3.1B cells were amplified. The cells were detached every 3-4 days, washed twice with DPBS, and detached from the wall with TrypLE at 2-4X 10 6 The density of individual cells/vial was replated.
For IonWorksQuattro TM Preparation of cells for experiments
On the day of the experiment, cells were removed from the incubator and the medium was removed. Cells were washed with 5ml of calcium and magnesium free Dulbecco PBS (DPBS) and detached by addition of 3ml of edetic acid (Versene) (Invitrogen, Italy) followed by a brief incubation at 37 ℃ for 5 minutes. The flask was tapped to detach the cells from the wall and 10ml of DPBS containing calcium and magnesium was added to prepare a cell suspension. The cell suspension was then placed in a15 ml centrifuge tube and centrifuged at 1200rpm for 2 min. After centrifugation, the supernatant was removed and the cell pellet was resuspended in 4mL DPBS containing calcium and magnesium using a 5mL pipette to disperse the pellet. The cell suspension volume was then corrected to give a cell concentration of about 300 ten thousand cells/ml for the assay.
All solutions added to the cells were pre-warmed to 37 ℃.
Electrophysiology
Ionworks
The experiment was performed at room temperature using a PatchPlate with PatchPlate TM IonWorks Quattro of PPC TM Planar array electrophysiology (Molecular Devices Corp.). Stimulation protocols and data collection were performed using a microcomputer (Dell Pentium 4). The planar electrode pore resistance (Rp) was determined by applying a10 mV voltage step across each pore. These measurements were made prior to cell addition. After cell addition and seal formation, the seal test was performed by applying a voltage step from-80 mV to-70 mV for 160 ms. Thereafter, amphotericin-B solution was added to the intracellular surface of the electrode to achieve intracellular access. Cells were maintained at-70 mV. In all experiments, by applyingA 50ms hyperpolarized (10mV) pre-pulse to induce leakage current, followed by a 20ms period at the sustain potential to perform leakage subtraction prior to the test pulse.
For hKV3.2 and hKV3.1, a first test pulse of-15 mV was applied for 100ms, and a second pulse of +40mV was applied for 50ms after 100ms of-70 mV, as determined from the maintenance potential of-70 mV. The cells were then maintained at-100 mV for 100ms, and another pulse from-70 mV to +40mV (duration 50ms) was applied to clamp the voltage at-40 mV during 200 ms.
For the hkv3.3 assay, starting from a maintenance potential of-70 mV, a first test pulse is applied to 0mV for 500ms and a further 100ms at-70 mV and a second pulse is applied to 40mV for 200 ms. These longer test pulses were used to study the inactivation of the hkv3.3 channels. The test pulse protocol can be performed in the absence (pre-addition reading) and in the presence (post-addition reading) of the test compound. The pre-addition reading and the post-addition reading can be separated by adding the compound, followed by incubation for 3 minutes.
Solutions and medicaments
The intracellular solutions contained the following (in mM): potassium gluconate 100, KCl 54, MgCl 2 3.2, HEPES 5, adjusted to pH 7.3 with KOH. amphotericin-B solution was prepared as a 50mg/mL stock solution in DMSO and diluted in intracellular solution to a final working concentration of 0.1 mg/mL. The external solution was Dulbecco Phosphate Buffered Saline (DPBS) and contained the following (in mM): CaCl 2 0.90,KCl 2.67,KH 2 PO 4 1.47,MgCl.6H 2 O 0.493,NaCl 136.9,Na 3 PO 4 8.06, having a pH of 7.4.
The compound to be used in the present invention (or a reference compound such as N-cyclohexyl-N- [ (7, 8-dimethyl-2-oxo-1, 2-dihydro-3-quinolyl) methyl]-N' -phenylurea) was dissolved in dimethyl sulfoxide (DMSO) at a stock concentration of 10 mM. These solutions were further diluted with DMSO in 384 well compound plates using a Biomek FX (Beckman Coulter). Each dilution (1 μ L) was transferred to another compound plate and an external solution containing 0.05% pluronic acid (66 μ L) was added. Add 3.5. mu.L of a composition comprising the invention from each plate and add to IonWorksQuattro TM Cells were incubated during the experiment. The final assay dilution was 200 and the final compound concentration was in the range of 50 μ M-50 nM.
Data analysis
In the absence of compounds, using a sealing resistor (>20M Ω) and peak current amplitude (C>500pA at a voltage step of 40 mV) and filtered to eliminate unsuitable cells from further analysis. For the hkv3.2 and hkv3.1 assays, paired comparisons of induced currents between before and after drug addition, measured on-15 mV voltage steps, were used to determine the positive modulating effect of each compound. The Kv3 channel-mediated outward current was measured as determined by subtracting the average baseline current of-70 mV over the 10ms period before the-15 mV step from the average amplitude of the current in the last 10ms of the-15 mV voltage pulse. These Kv3 channel currents after addition of the test compound were then compared to the currents recorded before addition of the compound. The data were compared to the reference compound (50uM N-cyclohexyl-N- [ (7, 8-dimethyl-2-oxo-1, 2-dihydro-3-quinolyl) methyl]-N' -phenylurea) and the effect of the vehicle control (0.5% DMSO) were normalized. The normalized data was analyzed using ActivityBase or Excel software. The concentration of compound (EC) required to increase the current by 50% from the maximum increase produced by the reference compound was determined by fitting the concentration-response data using a four-parameter logistic function in ActivityBase 50 ). For the hkv3.3 assay, paired comparisons of induced currents between before and after drug addition were measured for a 0mV step, taking into account the peak current and the decay of current (inactivation) over the duration of the 0mV test pulse (500 ms).
N-cyclohexyl-N- [ (7, 8-dimethyl-2-oxo-1, 2-dihydro-3-quinolinyl) methyl ] -N' -phenylurea was obtained from ASINEX (accession number: 552311-06-5).
As shown by testing of RE1-RE4, the incorporation of the pyrazine ring can adversely affect pEC50 and maxR of kv3.1 modulators.
+ For n-18, pEC50 is 5.56, and maxR% 152
As shown by the RE5-RE9 test compared to example 1, the incorporation of the para-pyrazine ring in example 1 surprisingly resulted in high pEC50 and high maxR in the kv3.1 assay. RE10 shows that the meta-pyrazine central loop has greatly reduced pEC50 and maxR compared to the para-pyrazine of example 1.
+ For n-18, pEC50 is 5.56, and maxR% 152
* n-4 for n-22 pEC50 is 5.90 and maxR% 146
$ 2.For n 26, 5.63 For pEC50, and 147% maxR
All test examples of compounds of formula (I) are shown above and show good pEC50 and maxR properties in the kv3.1 assay. The Kv3.1 data for the previously disclosed reference compound may be slightly different due to the smaller number of measurements.
Wherein saidSecondary analysis of the data determined for hkv3.1, hkv3.2 and hkv3.3 of (a) can be used to study the effect of the compound on the rate of current rise from the onset of a depolarising voltage pulse. The degree of action of a compound can be based on the time constant (Tau) act ) Determination of (Tau) act ) Obtained from a non-linear fit of the rise in Kv3.1, Kv3.2, and Kv3.3 currents after the start of the-15 mV depolarization voltage pulse using the equations given below.
Y＝(Y0-Ymax)*exp(-K*X)+Ymax
Wherein:
y0 is the current value at the beginning of the depolarization voltage pulse;
ymax is plateau current;
k is a rate constant, and Tau act The activation time constant is the inverse of K.
Similarly, the effect of compounds on the time taken for the Kv3.1, Kv3.2 or Kv3.3 current to decay at the end of the-15 mV depolarization voltage pulse when the channel is closed can also be studied. In the latter case, the magnitude of the effect of a compound on channel closure may be based on the time constant (Tau) of the non-linear fit of the current decay ("tail current") immediately after the end of the depolarising voltage pulse deact ) And (5) determining.
The kv3.1, kv3.2 and kv3.3 channels must be activated and deactivated very rapidly in order for neurons to release action potentials at high frequency (Rudy et al, 2001). Slowing of activation may delay the onset of repolarization of the action potential; slowing of inactivation may produce hyperpolarizing currents that reduce excitability of the neuron and delay the time before the neuron can release further action potentials. These two slowing effects on channel activation and inactivation together may result in a decrease in the ability of the neuron to discharge at high frequencies rather than promoting. Thus, compounds that have such a slowing effect on kv3.1 and/or kv3.2 and/or kv3.3 channels will effectively behave as negative modulators of the channels, resulting in a slowing of neuronal firing. The latter effect has been shown for certain compounds disclosed in WO2011/069951, wherein Tau act The significant increase in this level can be seen from recordings made using "fast-firing" interneurons in the rat cerebral cortex in vitro using electrophysiological techniquesAnd (5) observing. The addition of related compounds reduces the ability of neurons to discharge in response to 300Hz depolarization bursts.
Thus, although certain compounds may be identified as positive modulators in recombinant cell assays, Tau is significantly increased act Those compounds of value may reduce the ability of neurons in native tissue to discharge at high frequency.
Biological example 2: determination of blood and brain tissue binding
Materials and methods
Sprague Dawley rat whole blood collected during the week of the experiment using K3-EDTA as anticoagulant was diluted 1:1(v/v) with isotonic phosphate buffer. Sprague Dawley rats, stored frozen at-20 ℃, were thawed whole brain and homogenized in artificial cerebrospinal fluid (CSF) at 1:2 (w/v).
The appropriate amount of test compound was dissolved in DMSO to give a10 mmol solution. Further dilutions were then made using 50% acetonitrile in MilliQ water to obtain 166.7 micromolar working solution. The working solution was used to spike into blood to achieve a final concentration of 0.5 micromolar in whole blood. Similarly, the working solution was used to incorporate brain samples to achieve a final concentration of 5 micromolar in the whole brain. From these spiked blood and brain preparations, a control sample (n-3) was immediately extracted and used to calculate the initial yield of the test article.
150uL of compound-free buffer (isotonic phosphate buffer for blood or artificial CSF buffer for brain) was dispensed into one half-well and 150uL of matrix spiked (blood or brain) was loaded into the other half-well, where the two half-wells were separated by a semi-permeable membrane. After equilibration at 37 ℃ for 5h, 50uL of the dialyzed substrate (blood or brain) was added to 50uL of the corresponding compound-free buffer, and vice versa for the buffer, so that the volume of buffer and substrate (blood or brain) remained the same. Samples were then extracted by protein precipitation with 300uL of acetonitrile containing rolipram (control for positive ionization mode) or diclofenac (control for negative ionization mode) as an internal standard and centrifuged at 3000rpm for 10 min. The supernatant (100uL) was collected, diluted with 27% ACN (200uL) in MilliQ water, and then injected into an HPLC-MS/MS or UPLC-MS/MS system to determine the concentration of test compound present.
Analysis of
Blood and brain tissue binding was then determined using the following formula:
afu buffer/blood or Afu CSF/brain
Wherein Afu is the apparent fraction of unbound; buffer-analyte/internal standard ratio determined in buffer compartment; blood-analyte/internal standard ratio determined in the blood compartment; brain-analyte/internal standard ratio determined in brain compartment.
Wherein: fucor ═ corrected unbound fraction; d ═ stromal dilution factor (blood D ═ 2, brain D ═ 3).
Then:
bound% ((1-fucor) x 100)
Unbound% -100-bound%
Determination of brain/blood partition ratio (Kbb)
For compounds that freely permeate the blood/brain barrier (BBB), the unbound concentrations in the blood and brain should be equal under steady state distribution conditions. Thus, the Kbb value can be calculated as:
fu (blood)/Fu (brain)
If efflux pump transporters are not involved, it is expected to be equal to the brain to blood concentration ratio (Ct (brain)/Ct (blood)).
Results
Examples 1, 9 and 10 and certain reference compounds were tested to determine the unbound brain fraction using the methods described above. The results are as follows:
supernatant diluted with 18% AcN in water
Pyrazine compounds of the invention exhibit increased unbound brain fraction compared to their pyridine reference compounds.
Biological example 3: determination of in vivo pharmacokinetic parameters
Materials and methods
Adult male rats (Charles River, Italy) were given 1mg/kg (5ml/kg in 5% v/v DMSO, 0.5% w/v HPMC in water) orally and 0.5mg/kg (2ml/kg in 5% v/v DMSO, 40% w/v PEG400 in saline) intravenously test compounds. After oral administration, blood samples were taken from the portal vein and heart of each rat under deep isoflurane anesthesia (1 rat per time point). After intravenous administration, serial blood samples were collected from the lateral tail vein of each rat. Another group of rats (each test compound n ═ 1) received a single intravenous administration of the PgP transport inhibitor ectorada (3mg/kg) shortly before oral administration of 1mg/kg of test compound as above. Blood and brain samples were collected at a single time point of 0.5h after dose administration in these animals. In all cases, blood samples were collected into potassium EDTA tubes.
Test compound concentrations in blood and brain samples can be determined using methods based on acetonitrile to precipitate proteins, followed by HPLC/MS-MS analysis with optimized analytical methods.
Analysis of
The concentration of test compound in blood (expressed as ng/mL) and brain (expressed as ng/g) at different time points after oral or intravenous administration was analyzed using a non-compartmental pharmacokinetic model using WinNonlin Professional version 4.1. The following parameters were derived:
intravenous administration: maximum concentration over time (Cmax), integrated concentration over time (AUC), clearance (Clb), volume of distribution (Vss), and half-life (t 1/2).
Oral administration: cmax, time to maximum concentration (Tmax), AUC, bioavailability (F%), absorption fraction (Fa%), blood-to-brain ratio (AUC BB), and fold change in AUC BB in the presence of ectoin.
The compounds of the present invention can be expected to show good availability in brain tissue.
Biological example 4: metabolic stability in human hepatocytes in vitro
Method
The aim of this study was to determine the metabolic stability of cryopreserved hepatocytes in mixed sex humans. Testosterone and 7-hydroxycoumarin were used as positive controls for phase I and phase II metabolism, respectively.
An incubation medium was prepared by combining William medium E, HEPES buffer 1M and L-glutamine 200mM at the following ratio: 88%, 10% and 2%, respectively (440 mL, 50mL and 10mL, respectively). The obtained culture medium was mixed with oxygen and 5% carbon dioxide (5% CO) 2 ,95％O 2 ) Foamed for 30 minutes and then used. Cryopreserved hepatocytes were thawed and suspended in pre-warmed incubation medium at 37 ℃. The cells were centrifuged, resuspended in culture medium and counted by a hemocytometer (Burker chamber). Cell viability was measured using the trypan blue exclusion assay.
The test compounds were each dissolved in DMF to obtain 50mM stock solutions, which were further diluted in water/acetonitrile 50/50(v/v) to obtain the corresponding 50uM working solutions. Testosterone and 7-hydroxy-coumarin were dissolved in DMF to obtain a 50mM testosterone solution and a 5mM 7-hydroxy-coumarin solution. These solutions were then diluted in incubation medium to obtain 1mM testosterone working solution and 500uM 7-hydroxy-coumarin working solution.
10uL of each working solution, i.e. 50uM test compound, 1mM testosterone and 500uM 7-hydroxy-coumarin, was added to 990uL of 0.5X10 6 In the cell suspension, to obtain final concentrations of 0.5uM, 10uM and 5uM, respectively. The concentration of organic solvent is constant in each incubation and<1％(v/v)。
test compounds were incubated at 0.5uM with hepatocytes cryopreserved from mixed-sex humans at 37 ℃ in 24-well plates for 0,5, 10, 15, 20, 30, 45, 60, 90, 120, 150, and 180min (12 time points), respectively. At each time point, the robotic processor aspirates 50 μ L of incubation mixture from each well and dispenses it into a frozen 96-well plate containing 100 μ L of acetonitrile and the corresponding internal standard 150ng/mL to stop the reaction. An aliquot of water (120 μ L) was then added to balance the organic solvent content at 37%. The samples were centrifuged (about 3500g, 10 min) prior to LC MS/MS analysis.
Positive controls testosterone and 7-hydroxy-coumarin were incubated at 10 μ M and 5 μ M alone (n ═ 1), respectively, with cryopreserved hepatocytes of mixed-gender humans under the same conditions of the test items reported above for 0,5, 10, 15, 20, 30, 45, 60, 90, 120, 150, and 180min (12 time points) to demonstrate phase I and phase II metabolism in the hepatocyte system. At each time point, the robotic processor aspirates 50 μ Ι _ of incubation mixture from each well and dispenses it into a frozen 96-well plate containing 100 μ Ι _ of acetonitrile containing rolipram as an internal standard to terminate the reaction. An aliquot of water (120 μ L) was then added to balance the organic solvent content at 37%. The samples were centrifuged (about 3500g, 10 min) prior to LC MS/MS analysis.
Metabolic stability was calculated from the peak area ratio of the remaining test compound to the internal standard versus time.
Using the actual volume of incubation V (mL), the amount of hepatocytes in incubation M (million cells), and the number of hepatocytes per g liver Hn (for human 120), according to a first order elimination constant k (min) -1 ) Intrinsic clearance (Clint) was determined (obtained from GraphPad by plotting the natural logarithm of the peak area ratio of the remaining test article to the internal standard versus time).
The value of CLint is expressed as mL/min/g liver.
Examples 9 and 10 show low clearance compared to pyridine reference compounds RE11 and RE 13.
Biological example 5: ames test
Method
The in vitro study was aimed at assessing the potential of the test article to induce gene mutations in bacterial strains of Salmonella typhimurium (TA1535, TA1537, TA98 and TA100) and Escherichia coli (Escherichia coli) WP2 uvrA (pKM101) in vitro; the test method is based on a defined method of bacterial mutagenicity testing and is carried out in the presence and absence of the exogenous mammalian oxidative metabolic system (S9-mixture).
The study was designed according to national and international guidelines to meet the requirements of regulatory agencies for toxicity testing of new drugs. The study design complies with the following test guidelines:
ICH guidelidine M3(R2) on non-clinical safety students for the product of human clinical trials and marking administration for pharmaceuticals (CPMP/ICH/286/95,2009, 6 months).
ICH Topic S2(R1) guide on Genotoxicity Testing and Data Interpretation for pharmaceutical inputs for Human Use. Month 6 of 2012.
Bacterial strains
The following bacterial strains were used:
strains TA1535, TA100 and WP2 uvrA pKM101 detected base change mutations. Strains TA1537 and TA98 detected a frameshift mutation.
The bacterial inoculum was used to maintain the quality in 10mL nutrient broth (NB2, containing ampicillin, for the strains Salmonella typhimurium strain TA98 and TA100 containing the pKM101 plasmid and E.coli WP2 uvrA (pKM101) to maintain the qualityNumber of granular copies) were prepared. The bacteria were cultured in a shaking incubator at 37. + -. 2 ℃ for 10-12 hours to yield 1-2X10 9 Individual cells/mL.
The bacterial suspension was added to TOP agar (containing the trace amino acids required for the auxotrophy) in a volume of 100 μ L.
Mammalian oxidative metabolic system
Using a sample obtained from Molecular biology Incorporated, USA (MolTox) TM ) Phenobarbital, 56 benzoflavone-induced rat liver postmitochondrial fraction (S9) as an exogenous oxidative metabolic system. The portion of the batch of S9 stored as a frozen aliquot at about-80 ℃ was thawed immediately prior to use. The S9 mixture was prepared by adding S9 (10% v/v) to an NADPH producing system comprising NADP (3.15mg/mL), glucose-6-phosphate (1.5mg/mL) and 2% v/v of MgCl in phosphate buffer at pH 7.4 2 (81.3mg/mL) and KCl (123 mg/mL). For treatment in the presence of the S9 mixture, the S9 mixture was used at a final volume of 500 μ Ι/plate. For treatments where the S9 mixture was absent, an equal volume of sterile phosphate buffer pH 7.4 was added instead of the S9 mixture.
Positive control preparation
The following positive controls (from Moltox) were used TM Supplied by Trinova Biochem GmbH, Giesen, Germany and Sigma Aldrich, Milano, Italy) and formulated as follows:
positive controls were prepared from frozen (about-20 ℃) stock solutions and stored at ambient temperature during use.
Test article
The test consisted of 4 replicate plates for vehicle (DMSO) control and 2 replicate plates for test and positive control, treated in the absence and presence of S9-mix. The range of test article concentrations from 5 μ g/plate to 5000 μ g/plate was tested as follows:
vehicle, test article and positive control formulation were added to the plate at a volume of 100 μ l/plate.
Plate processing and incubation
Top agar was supplemented with traces of histidine and biotin or tryptophan, aliquots (2 mL/plate), and maintained at 46. + -. 2 ℃. The appropriate bacterial suspension was added to 2mL of top-agar, followed by the test article or vehicle/positive control solution and sterile phosphate buffer pH 7.4 or S9-mixture. Pouring the final treatment mixture onto a minimal agar plate (Bonner plates) and incubated at 37. + -. 2 ℃ for about 64 hours in the dark.
Plate scoring and analysis
At the end of the incubation period, the plates were evaluated for test article precipitation (by visual inspection). The plates were electronically scored for bacterial colony formation using a colony counter ProtoCOL3 Synbios. In the case of test article precipitation, bacterial colony counts were manually performed for each strain and stopped at the lowest treatment concentration that did not interfere with manual scoring.
After scoring, the plates were examined for signs of toxicity (i.e., reduction/shrinkage of background lawn growth, presence of pin/false-reverse colonies, and/or reduction in colony numbers).
Results should be considered positive if data at any of the treatment concentrations show that TA98, TA100 and WP2 UVRA (PKM101) responses ≧ 2 times the simultaneous vehicle control value or TA1535 and TA1537 responses ≧ 3 times the simultaneous vehicle control value in combination with dose-related responses. Results that only partially met these criteria or that data for any strain showed a dose-related response but did not exceed the detailed 2-or 3-fold threshold were considered ambiguous.
The following acceptance criteria apply:
1. the highest concentration tested should be 5000 μ g/plate or the solubility limit of the item tested in the vehicle.
2. If test item solubility is the limiting factor, the maximum concentration selected for plate scoring is the lowest concentration at which test item precipitation is observed on the treated plate at the end of the incubation period, and this concentration does not interfere with scoring.
If toxicity is the limiting factor, the maximum concentration at which a gene mutation can be assessed is the lowest concentration at which evidence of significant bacterial toxicity is observed during the plate scoring.
Results
Aniline associated with RE6/RE11 (which under certain conditions appears to be a degradant) was found to be mutagenic. This finding suggests a risk in the future development of RE6/RE11 and compounds that may produce related anilines, such as (5R) -5-ethyl-3- (6-spiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yloxy-3-pyridyl) imidazolidine-2, 4-dione, i.e. RE 13. Compounds that can be distinguished according to their associated aniline are advantageous.
The anilines of examples 1, 9 and 10 are non-mutagenic and are contemplated to be suitable for use with other compounds of the present invention that can produce the relevant anilines.
Additional animal models
Patent applications WO2011/069951, WO2012/076877, WO2012/168710, WO2013/083994, WO2013/175215 and WO2013/182851 (all incorporated by reference for the purpose of illustrating the potential utility of the compounds and providing an animal model for compound testing) demonstrate the activity of compounds as modulators of kv3.1 and kv3.2 in animal models of seizures, hyperactivity, sleep disorders, psychosis, hearing disorders and bipolar disorder.
Patent application WO2013/175211 (incorporated by reference for the purpose of illustrating the potential utility of compounds and providing an animal model for testing compounds) demonstrates the efficacy of compounds as modulators of kv3.1 and kv3.2 in a chestnut rat acute noise-induced hearing loss model, and also evaluates the efficacy of compounds in central auditory processing deficiency models and tinnitus models.
Glait et al 2018, Anderson et al 2018 and Chamber et al 2018 demonstrated the efficacy of kv3.1 and kv3.2 modulators in hearing related models.
Patent application WO2017/098254 (incorporated by reference for the purpose of illustrating the potential utility of compounds and providing an animal model for testing compounds) demonstrates the efficacy of compounds that are modulators of kv3.1 and kv3.2 in models of neuropathic pain and inflammatory pain.
Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer, step, group of integers or group of steps but not the exclusion of any other integer, step, group of integers or group of steps.
This application, including the specification and claims, may be used as a basis for priority in relation to any subsequent application. The claims of such subsequent application may be directed to any feature or combination of features described herein. They may take the form of product, composition, method or use claims and may include, for example and without limitation, the following claims.
The scheme of the invention is as follows:
scheme 1-compounds of formula (I):
wherein:
R 1 is H or methyl;
R 2 and R 3 Are both methyl, or R 2 And R 3 Together with the carbon atom to which it is attached is a spiro cyclopropyl ring;
R 4 is methyl or ethyl;
R 5 is H or methyl;
or R 4 And R 5 Together with the carbon atom to which they are attached form C 3 -C 4 A spiro carbocyclic group;
or a salt and/or solvate and/or derivative thereof.
Scheme 2-scheme 1 Compounds wherein R 1 Is H.
Scheme 3-Compounds of scheme 1 wherein R 1 Is methyl.
Scheme 4-Compounds of any of schemes 1-3, wherein R 2 And R 3 Is spiro cyclopropyl ring.
Scheme 5-Compounds of any of schemes 1-3, wherein R 2 Is methyl, and R 3 Is methyl.
Scheme 6-Compounds of any of schemes 1-5, wherein R 4 Is methyl.
Scheme 7-Compounds of any of schemes 1-5, wherein R 4 Is ethyl.
Scheme 8-Compounds according to any of schemes 1-7, wherein R 5 Is H.
Scheme 9-Compounds according to any one of schemes 1-7, wherein R 5 Is methyl.
Scheme 10-Compounds of any one of schemes 1-9, wherein when R 4 And R 5 At the same time, they have the following stereochemical arrangement:
scheme 11-Compounds of any of schemes 1-9, where R is 4 And R 5 At the same time, they have the following stereochemical arrangement:
scheme 12-Compounds of any of schemes 1-5, wherein R 4 And R 5 And is connected withThe attached carbon atoms together form a spirocyclopropyl group.
Scheme 13-Compounds of any of schemes 1-5, wherein R 4 And R 5 Together with the carbon atom to which it is attached form a spirocyclobutyl group.
Scheme 14-a compound of scheme 1 selected from:
5, 5-dimethyl-3- [5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yl) oxypyrazin-2-yl ] imidazolidine-2, 4-dione;
3- [5- [ (3, 3-dimethyl-2H-benzofuran-4-yl) oxy ] pyrazin-2-yl ] -5, 5-dimethyl-imidazolidine-2, 4-dione;
(5R) -5-ethyl-5-methyl-3- (5-spiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-oxopyrazin-2-yl) imidazolidine-2, 4-dione;
5, 5-dimethyl-3- (5-spiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yloxypyrazin-2-yl) imidazolidine-2, 4-dione;
(5R) -5-ethyl-5-methyl-3- [5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yl) oxypyrazin-2-yl ] imidazolidine-2, 4-dione;
(5R) -3- [5- [ (3, 3-dimethyl-2H-benzofuran-4-yl) oxy ] pyrazin-2-yl ] -5-ethyl-5-methyl-imidazolidine-2, 4-dione;
5, 5-dimethyl-3- [5- [ (3,3, 7-trimethyl-2H-benzofuran-4-yl) oxy ] pyrazin-2-yl ] imidazolidine-2, 4-dione;
(5R) -5-ethyl-5-methyl-3- [5- [ (3,3, 7-trimethyl-2H-benzofuran-4-yl) oxy ] pyrazin-2-yl ] imidazolidine-2, 4-dione;
(5R) -5-ethyl-3- [5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yl) oxopyrazin-2-yl ] imidazolidine-2, 4-dione;
(5R) -5-ethyl-3- (5-spiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yloxypyrazin-2-yl) imidazolidine-2, 4-dione;
(5R) -3- [5- [ (3, 3-dimethyl-2H-benzofuran-4-yl) oxy ] pyrazin-2-yl ] -5-ethyl-imidazolidine-2, 4-dione;
(5R) -5-ethyl-3- [5- [ (3,3, 7-trimethyl-2H-benzofuran-4-yl) oxy ] pyrazin-2-yl ] imidazolidine-2, 4-dione;
7- [5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yl) oxopyrazin-2-yl ] -5, 7-diazaspiro [3.4] octane-6, 8-dione;
6- [5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yl) oxypyrazin-2-yl ] -4, 6-diazaspiro [2.4] heptane-5, 7-dione;
(5S) -5-ethyl-3- [5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yl) oxypyrazin-2-yl ] imidazolidine-2, 4-dione;
or a salt and/or solvate and/or derivative thereof.
Scheme 15-a compound of scheme 1 which is:
5, 5-dimethyl-3- [5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yl) oxypyrazin-2-yl ] imidazolidine-2, 4-dione.
Scheme 16-a compound of scheme 1 which is:
3- [5- [ (3, 3-dimethyl-2H-benzofuran-4-yl) oxy ] pyrazin-2-yl ] -5, 5-dimethyl-imidazolidine-2, 4-dione.
Scheme 17-a compound of scheme 1 which is:
(5R) -5-Ethyl-5-methyl-3- (5-spiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yloxypyrazin-2-yl) imidazolidine-2, 4-dione.
Scheme 18-a compound of scheme 1 which is:
5, 5-dimethyl-3- (5-spiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yloxypyrazin-2-yl) imidazolidine-2, 4-dione.
Scheme 19-a compound of scheme 1 which is:
(5R) -5-ethyl-5-methyl-3- [5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yl) oxypyrazin-2-yl ] imidazolidine-2, 4-dione.
Scheme 20-a compound of scheme 1 which is:
(5R) -3- [5- [ (3, 3-dimethyl-2H-benzofuran-4-yl) oxy ] pyrazin-2-yl ] -5-ethyl-5-methyl-imidazolidine-2, 4-dione.
A compound of scheme 21-scheme 1 which is:
5, 5-dimethyl-3- [5- [ (3,3, 7-trimethyl-2H-benzofuran-4-yl) oxy ] pyrazin-2-yl ] imidazolidine-2, 4-dione.
Scheme 22-a compound of scheme 1 which is:
(5R) -5-ethyl-5-methyl-3- [5- [ (3,3, 7-trimethyl-2H-benzofuran-4-yl) oxy ] pyrazin-2-yl ] imidazolidine-2, 4-dione.
Scheme 23-the compound of scheme 1 which is:
(5R) -5-Ethyl-3- [5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yl) oxypyrazin-2-yl ] imidazolidine-2, 4-dione.
Scheme 24-a compound of scheme 1 which is:
(5R) -5-Ethyl-3- (5-spiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yloxypyrazin-2-yl) imidazolidine-2, 4-dione.
Scheme 25-the compound of scheme 1 which is:
(5R) -3- [5- [ (3, 3-dimethyl-2H-benzofuran-4-yl) oxy ] pyrazin-2-yl ] -5-ethyl-imidazolidine-2, 4-dione.
Scheme 26-a compound of scheme 1 which is:
(5R) -5-Ethyl-3- [5- [ (3,3, 7-trimethyl-2H-benzofuran-4-yl) oxy ] pyrazin-2-yl ] imidazolidine-2, 4-dione.
A compound of scheme 27-scheme 1 which is:
7- [5- (7-Methylspiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yl) oxypyrazin-2-yl ] -5, 7-diazaspiro [3.4] octane-6, 8-dione.
Scheme 28-a compound of scheme 1 which is:
6- [5- (7-Methylspiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yl) oxypyrazin-2-yl ] -4, 6-diazaspiro [2.4] heptane-5, 7-dione.
Scheme 29-a compound of scheme 1 which is:
(5S) -5-ethyl-3- [5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yl) oxypyrazin-2-yl ] imidazolidine-2, 4-dione.
Scheme 30-a compound of formula (I) according to any one of schemes 1-29 or a pharmaceutically acceptable salt and/or solvate thereof.
Scheme 31-the compound of any one of schemes 1-30 for use as a medicament.
A compound of scheme 32-scheme 31 for use in the prevention or treatment of a disease or condition selected from: hearing disorders, schizophrenia, depression and mood disorders, bipolar disorder, substance abuse disorders, anxiety disorders, sleep disorders, auditory hypersensitivity and loudness perception disorders, meniere's disease, balance disorders and inner ear disorders, impulse control disorders, personality disorders, attention deficit hyperactivity disorder, autism spectrum disorders, eating disorders, cognitive disorders, ataxia, pain such as neuropathic pain, inflammatory pain and miscellaneous pain, dementia with lewy bodies and parkinson's disease.
A compound of scheme 33-scheme 31 for use in the prevention or treatment of schizophrenia.
A compound of scheme 34-scheme 31 for use in the prevention or treatment of a hearing disorder.
A compound of scheme 35-scheme 31 for use in the prevention or treatment of pain.
A compound of scheme 36-scheme 31 for use in treating fragile X chromosome.
Scheme 37-a method for preventing or treating a disease or disorder selected from: hearing disorders, schizophrenia, depression and mood disorders, bipolar disorder, substance abuse disorders, anxiety disorders, sleep disorders, auditory hypersensitivity and loudness perception disorders, meniere's disease, balance disorders and inner ear disorders, impulse control disorders, personality disorders, attention deficit hyperactivity disorder, autism spectrum disorders, eating disorders, cognitive disorders, ataxia, pain such as neuropathic pain, inflammatory pain and miscellaneous pain, lewy body dementia and parkinson's disease, comprising administering to a subject in need thereof an effective amount of a compound of any of regimens 1-30.
Scheme 38-a method for preventing or treating schizophrenia comprising administering to an individual in need thereof a compound of any of schemes 1-30.
Scheme 39-a method for preventing or treating a hearing disorder comprising administering to an individual in need thereof an effective amount of a compound of any of schemes 1-30.
Scheme 40-a method for preventing or treating pain comprising administering to an individual in need thereof an effective amount of a compound of any of schemes 1-30.
Scheme 41-a method for treating fragile X chromosome comprising administering to an individual in need thereof a compound of any one of schemes 1-30.
Scheme 42-use of a compound of any one of schemes 1-30 for the manufacture of a medicament for the prevention or treatment of a disease or condition selected from: hearing disorders, schizophrenia, depression and mood disorders, bipolar disorder, substance abuse disorders, anxiety disorders, sleep disorders, auditory hypersensitivity and loudness perception disorders, meniere's disease, balance disorders and inner ear disorders, impulse control disorders, personality disorders, attention deficit/hyperactivity disorders, autism spectrum disorders, eating disorders, cognitive disorders, ataxia, pain such as neuropathic pain, inflammatory pain and miscellaneous pain, dementia with lewy bodies and parkinson's disease.
Scheme 43-use of a compound of any one of schemes 1-30 for the manufacture of a medicament for the prevention or treatment of schizophrenia.
Use of a compound of scheme 44-any of schemes 1-30 for the manufacture of a medicament for the prevention or treatment of a hearing disorder.
Scheme 45-use of a compound of any one of schemes 1-30 for the manufacture of a medicament for the prevention or treatment of pain.
Scheme 46-use of a compound of any one of schemes 1-30 for the manufacture of a medicament for the treatment of fragile X chromosome.
Scheme 47-a pharmaceutical composition comprising a compound of any one of schemes 1-30 and a pharmaceutically acceptable carrier or excipient.
Scheme 48-the compound of any one of schemes 1-30 for use in combination with another pharmaceutically acceptable chemical ingredient.
Scheme 49-Compounds of formula (II) or (XVI):
wherein R is 1 、R 2 And R 3 As defined in scheme 1, X is a halogen, e.g., Br.
Scheme 50-Compounds of formula (XVI):
wherein R is 1 、R 2 And R 3 As defined in scheme 1.
Scheme 51-compounds of formula (IV):
wherein R is 4 And R 5 As defined in scheme 1, Y is halogen, e.g., Cl.
Scheme 52-derivatives of compounds of formula (I) according to any of schemes 1-30, or salts and/or solvates thereof, by functionalizing the secondary nitrogen of a hydantoin or of a triazolone with a group L, wherein L is selected from:
a)–PO(OH)O - ·M + wherein M is + Is a pharmaceutically acceptable univalent counter ion,
b)–PO(O - ) 2 ·2M + ，
c)–PO(O - ) 2 ·D 2+ wherein D is 2+ Is a pharmaceutically acceptable divalent counterion,
d)–CH(R X )–PO(OH)O - ·M + wherein R is X Is hydrogen or C 1-3 An alkyl group, which is a radical of an alkyl group,
e)–CH(R X )–PO(O - ) 2 ·2M + ，
f)–CH(R X )–PO(O - ) 2 ·D 2+ ，
g)–SO 3 - ·M + ，
h)–CH(R X )–SO 3 - ·M + and are and
i)–CO–CH 2 CH 2 –CO 2 ·M + 。
scheme 53-the compound of any one of schemes 1-36, in its naturally isotopic form.
Scheme 54-the compound, method, use, composition or derivative of any one of schemes 1-48, 52 or 53 for oral administration.
Scheme 55-the compound, method, use, composition or derivative of any of schemes 1-48 or 52-54, for administration at 2-400 mg/day, e.g., 2-300 mg/day, especially 5-250 mg/day.
Scheme 56-the compound, method, use, composition or derivative of any of schemes 1-48 or 52-55, for once or twice daily administration.
Scheme 57-the compound of scheme 56, for once daily administration.
Scheme 58-the compound of scheme 56, for administration twice daily.
Scheme 59-the compound, method, use, composition or derivative of any one of schemes 1-48 or 52-58 for administration for a period of at least 3 months.
Scheme 60-the compound, method, use, composition or derivative of any one of schemes 1-48 or 52-58 for administration to a human subject.
Scheme 61-scheme 60 for administration to an adult aged 18-65 years.
Scheme 62-the compound, method, use, composition or derivative of scheme 60, for administration to a human aged 66 years or older.
Scheme 63-scheme 60 for administration to a human subject under 18 years of age, e.g., 4-17 years of age.
Scheme 64-the compound, method, use, composition or derivative of any one of schemes 1-48, 52, 53 or 59-63, wherein the compound of formula (I) or a pharmaceutically acceptable salt, solvate and/or derivative thereof is delivered by a patch or implant.
Reference to the literature
All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.
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Claims (41)

1. A compound of formula (I):
wherein:
R 1 is H or methyl;
R 2 and R 3 Are both methyl, or R 2 And R 3 Together with the carbon atom to which it is attached is a spiro cyclopropyl ring;
R 4 is methyl or ethyl;
R 5 is H or methyl;
or R 4 And R 5 Together with the carbon atom to which they are attached form C 3 -C 4 A spiro carbocyclyl group;
or a salt and/or solvate and/or derivative thereof.
2. The compound of claim 1, wherein R 1 Is H.
3. The compound of claim 1, wherein R 1 Is methyl.
4. A compound according to any one of claims 1 to 3, whereinR 2 And R 3 Is a spirocyclopropyl group.
5. A compound according to any one of claims 1 to 3, wherein R 2 Is methyl, and R 3 Is methyl.
6. The compound of any one of claims 1-5, wherein R 4 Is methyl.
7. The compound of any one of claims 1-5, wherein R 4 Is ethyl.
8. The compound of any one of claims 1-7, wherein R 5 Is H.
9. The compound of any one of claims 1-7, wherein R 5 Is a methyl group.
10. The compound of any one of claims 1-5, wherein R 4 And R 5 Together with the carbon atom to which it is attached form a spirocyclopropyl group.
11. The compound of any one of claims 1-5, wherein R 4 And R 5 Together with the carbon atom to which it is attached form a spirocyclobutyl group.
12. The compound of claim 1 selected from:
5, 5-dimethyl-3- [5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yl) oxypyrazin-2-yl ] imidazolidine-2, 4-dione;
3- [5- [ (3, 3-dimethyl-2H-benzofuran-4-yl) oxy ] pyrazin-2-yl ] -5, 5-dimethyl-imidazolidine-2, 4-dione;
(5R) -5-ethyl-5-methyl-3- (5-spiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-oxopyrazin-2-yl) imidazolidine-2, 4-dione;
5, 5-dimethyl-3- (5-spiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yloxypyrazin-2-yl) imidazolidine-2, 4-dione;
(5R) -5-ethyl-5-methyl-3- [5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yl) oxypyrazin-2-yl ] imidazolidine-2, 4-dione;
(5R) -3- [5- [ (3, 3-dimethyl-2H-benzofuran-4-yl) oxy ] pyrazin-2-yl ] -5-ethyl-5-methyl-imidazolidine-2, 4-dione;
5, 5-dimethyl-3- [5- [ (3,3, 7-trimethyl-2H-benzofuran-4-yl) oxy ] pyrazin-2-yl ] imidazolidine-2, 4-dione;
(5R) -5-ethyl-5-methyl-3- [5- [ (3,3, 7-trimethyl-2H-benzofuran-4-yl) oxy ] pyrazin-2-yl ] imidazolidine-2, 4-dione;
(5R) -5-ethyl-3- [5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yl) oxopyrazin-2-yl ] imidazolidine-2, 4-dione;
(5R) -5-ethyl-3- (5-spiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yloxypyrazin-2-yl) imidazolidine-2, 4-dione;
(5R) -3- [5- [ (3, 3-dimethyl-2H-benzofuran-4-yl) oxy ] pyrazin-2-yl ] -5-ethyl-imidazolidine-2, 4-dione;
(5R) -5-ethyl-3- [5- [ (3,3, 7-trimethyl-2H-benzofuran-4-yl) oxy ] pyrazin-2-yl ] imidazolidine-2, 4-dione;
7- [5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yl) oxypyrazin-2-yl ] -5, 7-diazaspiro [3.4] octane-6, 8-dione;
6- [5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yl) oxypyrazin-2-yl ] -4, 6-diazaspiro [2.4] heptane-5, 7-dione;
(5S) -5-ethyl-3- [5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yl) oxypyrazin-2-yl ] imidazolidine-2, 4-dione;
or a salt and/or solvate and/or derivative thereof.
13. The compound of claim 1 which is:
5, 5-dimethyl-3- [5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yl) oxypyrazin-2-yl ] imidazolidine-2, 4-dione.
14. The compound of claim 1 which is:
3- [5- [ (3, 3-dimethyl-2H-benzofuran-4-yl) oxy ] pyrazin-2-yl ] -5, 5-dimethyl-imidazolidine-2, 4-dione.
15. The compound of claim 1 which is:
(5R) -5-Ethyl-5-methyl-3- (5-spiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yloxypyrazin-2-yl) imidazolidine-2, 4-dione.
16. The compound of claim 1 which is:
5, 5-dimethyl-3- (5-spiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yloxypyrazin-2-yl) imidazolidine-2, 4-dione.
17. The compound of claim 1 which is:
(5R) -5-ethyl-5-methyl-3- [5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yl) oxypyrazin-2-yl ] imidazolidine-2, 4-dione.
18. The compound of claim 1 which is:
(5R) -3- [5- [ (3, 3-dimethyl-2H-benzofuran-4-yl) oxy ] pyrazin-2-yl ] -5-ethyl-5-methyl-imidazolidine-2, 4-dione.
19. The compound of claim 1 which is:
5, 5-dimethyl-3- [5- [ (3,3, 7-trimethyl-2H-benzofuran-4-yl) oxy ] pyrazin-2-yl ] imidazolidine-2, 4-dione.
20. The compound of claim 1 which is:
(5R) -5-ethyl-5-methyl-3- [5- [ (3,3, 7-trimethyl-2H-benzofuran-4-yl) oxy ] pyrazin-2-yl ] imidazolidine-2, 4-dione.
21. The compound of claim 1 which is:
(5R) -5-Ethyl-3- [5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yl) oxypyrazin-2-yl ] imidazolidine-2, 4-dione.
22. The compound of claim 1 which is:
(5R) -5-Ethyl-3- (5-spiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yloxypyrazin-2-yl) imidazolidine-2, 4-dione.
23. The compound of claim 1 which is:
(5R) -3- [5- [ (3, 3-dimethyl-2H-benzofuran-4-yl) oxy ] pyrazin-2-yl ] -5-ethyl-imidazolidine-2, 4-dione.
24. The compound of claim 1 which is:
(5R) -5-Ethyl-3- [5- [ (3,3, 7-trimethyl-2H-benzofuran-4-yl) oxy ] pyrazin-2-yl ] imidazolidine-2, 4-dione.
25. The compound of claim 1 which is:
7- [5- (7-Methylspiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yl) oxypyrazin-2-yl ] -5, 7-diazaspiro [3.4] octane-6, 8-dione.
26. The compound of claim 1 which is:
6- [5- (7-Methylspiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yl) oxypyrazin-2-yl ] -4, 6-diazaspiro [2.4] heptane-5, 7-dione.
27. The compound of claim 1 which is:
(5S) -5-ethyl-3- [5- (7-methylspiro [ 2H-benzofuran-3, 1' -cyclopropane ] -4-yl) oxypyrazin-2-yl ] imidazolidine-2, 4-dione.
28. A compound according to any one of claims 1 to 27 for use as a medicament.
29. A compound according to any one of claims 1-28 for use in the prevention or treatment of a disease or condition selected from the group consisting of hearing disorders, schizophrenia, depression and mood disorders, bipolar disorder, substance abuse disorders, anxiety disorders, sleep disorders, hyperacusis and loudness perception disorders, meniere's disease, balance disorders and inner ear disorders, impulse control disorders, personality disorders, attention deficit/hyperactivity disorders, autism spectrum disorders, eating disorders, cognitive disorders, ataxia, pain such as neuropathic pain, inflammatory pain and miscellaneous pain, lewy body dementia and parkinson's disease.
30. Use of a compound according to any one of claims 1-27 for the manufacture of a medicament for the prevention or treatment of a disease or condition selected from the group consisting of hearing disorders, schizophrenia, depression and mood disorders, bipolar disorders, substance abuse disorders, anxiety disorders, sleep disorders, hyperacusis and loudness perception disorders, meniere's disease, balance and inner ear disorders, impulse control disorders, personality disorders, attention deficit/hyperactivity disorder, autism spectrum disorders, eating disorders, cognitive disorders, ataxia, pain such as neuropathic pain, inflammatory pain and miscellaneous pain, lewy body dementia and parkinson's disease.
31. A method for the prevention or treatment of a disease or condition selected from the group consisting of hearing disorders, schizophrenia, depression and mood disorders, bipolar disorders, substance abuse disorders, anxiety disorders, sleep disorders, auditory hypersensitivity and loudness perception disorders, meniere's disease, balance disorders and inner ear disorders, impulse control disorders, personality disorders, attention deficit/hyperactivity disorder, autism spectrum disorders, eating disorders, cognitive disorders, ataxia, pain such as neuropathic pain, inflammatory pain and miscellaneous pain, lewy body dementia and parkinson's disease, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-27.
32. A pharmaceutical composition comprising a compound of any one of claims 1-27 and a pharmaceutically acceptable carrier or excipient.
33. The compound, use, method or composition of any one of claims 1-32, wherein said compound is administered orally.
34. A compound, use, method or composition according to any one of claims 1 to 33, wherein the compound is administered at 2 to 400 mg/day, such as 2 to 300 mg/day, especially 5 to 250 mg/day.
35. The compound, use, method or composition of any of claims 1-34, wherein said compound is administered 1 or 2 times per day.
36. The compound, use, method or composition of claim 35, wherein said compound is administered 1 time per day.
37. The compound, use, method or composition of claim 35, wherein said compound is administered 2 times per day.
38. The compound, use, method or composition of any of claims 1-37, wherein the compound is administered for a period of at least 3 months.
39. The compound, use, method or composition of any of claims 1-32, wherein the compound is administered orally 1 or 2 times daily at 2-400 mg/day, such as 2-300 mg/day, especially 5-250 mg/day.
40. A compound of formula (II) or (XVI):
wherein R is 1 、R 2 And R 3 As defined in claim 1, X is a halogen, such as Br.
41. A compound of formula (IV):
wherein R is 4 And R 5 As defined in claim 1, Y is halogen, such as Cl.
HK62023069926.1A 2020-02-06 Kv3 modulators HK40081003B (en)

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