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Elfucose

May 24, 2025 2:58 am / Leave a comment

Elfucose

Cas 87-96-7

Chemical Formula: C6H12O5
Exact Mass: 164.07
Molecular Weight: 164.157

L-fucopyranose (6-deoxy-L-galactopyranose)

(3S,4R,5S,6S)-6-methyloxane-2,3,4,5-tetrol

6-Deoxy-L-galactose (ACI)
Fucose, L- (8CI)
(-)-Fucose
46: PN: US20220380460 SEQID: 47 claimed sequence
6-Desoxygalactose
L-(-)-Fucose
L-Fucose
L-Galactomethylose
L-Galactopyranose, 6-deoxy-
CERC 803
Elfucose
Fucose
NSC 1219
congenital glycosylation disorders
6-Deoxy-L-galactopyranose
L-galactomethylose
87-96-7
Fucose, L-
6-deoxy-galactose

Fucose is under investigation in clinical trial NCT03354533 (Study of ORL-1F (L-fucose) in Patients With Leukocyte Adhesion Deficiency Type II).

L-fucopyranose is the pyranose form of L-fucose. It has a role as an Escherichia coli metabolite and a mouse metabolite. It is a L-fucose and a fucopyranose.

SCHEME

PATENT

PATENT

WO2016150629

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016150629&_cid=P10-MB1MYE-34318-1

Examples

The invention will now be illustrated in more detail by the following non-limiting examples.

Example 1: Production of L-fucose by biocatalytic oxidation of L-fucitol with galactose oxidase in the presence of peroxidase and catalase

A solution of L-fucitol (6.0 mL aqueous solution containing 600 mg L-fucitol, CAS 13074-06-1, Santa Cruz Biotechnology) was added to a round-bottom three-neck bottle (50 mL), followed by the addition of 1.2 mL K2HPO4 _/ KH2PO4 ₍₁₀₀₀_mM , pH=7.0) and 0.095 mL catalase (from bovine liver, SIGMA, 21,300 U/mg, 34 mg/mL), 0.120 mL peroxidase (from horseradish, 173 U/mg solid, SIGMA ) and 2.218 mL galactose oxidase (38.4 mg/mL, 2,708 U/mL). The resulting solution was purged with O ₂ at room temperature until all L-fucitol was converted to L-fucose. The reaction was monitored by HLPC. The final product was isolated and analyzed by 1 H and 13C NMR. The results are summarized in Table 1.

[Table 1]

Reaction time [h] Conversion [%]

3,5 54,0

24 95,8

29 96,0

PATENT

WO2010022244

WO2007021879

////////////Elfucose, 6-Deoxy-L-galactose, Fucose, L- , (-)-Fucose, 6-Desoxygalactose, L-(-)-Fucose, L-Fucose, L-Galactomethylose, L-Galactopyranose, 6-deoxy-, CERC 803, Elfucose, Fucose, NSC 1219, congenital glycosylation disorders, 6-Deoxy-L-galactopyranose, L-galactomethylose, 87-96-7, Fucose, L-, 6-deoxy-galactose

Deupsilocin

May 17, 2025 2:57 am / Leave a comment

Deupsilocin, Psilocin-d10

Psilocin-D10
Deupsilocin
Psilocine-d10

Molecular Formula	C12H16N2O
Molecular Weight	214.3299

KXD3HS8D6X

CAS 1435934-64-7

3-[2-[Di(methyl-d₃)amino]ethyl-1,1,2,2–d₄]-1H-indol-4-ol

3-[2-[bis(trideuteriomethyl)amino]-1,1,2,2-tetradeuterioethyl]-1H-indol-4-ol

1H-Indol-4-ol, 3-[2-[di(methyl-d3)amino]ethyl-1,1,2,2-d4]-

Mental health disorders, or mental illness, refer to a wide range of disorders that include, but are not limited to, depressive disorders, anxiety and panic disorders, schizophrenia, eating disorders, substance misuse disorders, post-traumatic stress disorder, attention deficit/hyperactivity disorder and obsessive compulsive disorder. The severity of symptoms varies such that some individuals experience debilitating disease that precludes normal social function, while others suffer with intermittent repeated episodes across their lifespan. Although the presentation and diagnostic criteria among mental illness conditions are distinct in part, there are common endophenotypes of note across the diseases, and often comorbidities exist. Specifically, there exist phenotypic endophenotypes associated with alterations in mood, cognition and behavior. Interestingly, many of these endophenotypes extend to neurological conditions as well. For example, attentional deficits are reported in patients with attention deficit disorder, attention deficit hyperactivity disorder, eating disorders, substance use disorders, schizophrenia, depression, obsessive compulsive disorder, traumatic brain injury, Fragile X, Alzheimer’s disease, Parkinson’s disease and frontotemporal dementia.
      Many mental health disorders, as well as neurological disorders, are impacted by alterations, dysfunction, degeneration, and/or damage to the brain’s serotonergic system, which may explain, in part, common endophenotypes and comorbidities among neuropsychiatric and neurological diseases. Many therapeutic agents that modulate serotonergic function are commercially available, including serotonin reuptake inhibitors, selective serotonin reuptake inhibitors, antidepressants, monoamine oxidase inhibitors, and, while primarily developed for depressive disorders, many of these therapeutics are used across multiple medical indications including, but not limited to, depression in Alzheimer’s disease and other neurodegenerative disease, chronic pain, existential pain, bipolar disorder, obsessive compulsive disorder, anxiety disorders and smoking cessation. However, in many cases, the marketed drugs show limited benefit compared to placebo, can take six weeks to work and for some patients, and are associated with several side effects including trouble sleeping, drowsiness, fatigue, weakness, changes in blood pressure, memory problems, digestive problems, weight gain and sexual problems.
      The field of psychedelic neuroscience has witnessed a recent renaissance following decades of restricted research due to their legal status. Psychedelics are one of the oldest classes of psychopharmacological agents known to man and cannot be fully understood without reference to various fields of research, including anthropology, ethnopharmacology, psychiatry, psychology, sociology, and others. Psychedelics (serotonergic hallucinogens) are powerful psychoactive substances that alter perception and mood and affect numerous cognitive processes. They are generally considered physiologically safe and do not lead to dependence or addiction. Their origin predates written history, and they were employed by early cultures in many sociocultural and ritual contexts. After the virtually contemporaneous discovery of (5R,8R)-(+)-lysergic acid-N,N-diethylamide (LSD) and the identification of serotonin in the brain, early research focused intensively on the possibility that LSD and other psychedelics had a serotonergic basis for their action. Today there is a consensus that psychedelics are agonists or partial agonists at brain serotonin 5-hydroxytryptamine 2 A (5-HT2A) receptors, with particular importance on those expressed on apical dendrites of neocortical pyramidal cells in layer V, but also may bind with lower affinity to other receptors such as the sigma-1 receptor. Several useful rodent models have been developed over the years to help unravel the neurochemical correlates of serotonin 5-HT2A receptor activation in the brain, and a variety of imaging techniques have been employed to identify key brain areas that are directly affected by psychedelics.
      Psychedelics have both rapid onset and persisting effects long after their acute effects, which includes changes in mood and brain function. Long lasting effects may result from their unique receptor affinities, which affect neurotransmission via neuromodulatory systems that serve to modulate brain activity, i.e., neuroplasticity, and promote cell survival, are neuroprotective, and modulate brain neuroimmune systems. The mechanisms which lead to these long-term neuromodulatory changes are linked to epigenetic modifications, gene expression changes and modulation of pre- and post-synaptic receptor densities. These, previously under-researched, psychedelic drugs may potentially provide the next-generation of neurotherapeutics, where treatment resistant psychiatric and neurological diseases, e.g., depression, post-traumatic stress disorder, dementia and addiction, may become treatable with attenuated pharmacological risk profiles.
      Although there is a general perception that psychedelic drugs are dangerous, from a physiologic safety standpoint, they are one of the safest known classes of CNS drugs. They do not cause addiction, and no overdose deaths have occurred after ingestion of typical doses of classical psychotic agents, such as LSD, psilocybin, or mescaline (Scheme 1). Preliminary data show that psychedelic administration in humans results in a unique profile of effects and potential adverse reactions that need to be appropriately addressed to maximize safety. The primary safety concerns are largely psychologic, rather than physiologic, in nature. Somatic effects vary but are relatively insignificant, even at doses that elicit powerful psychologic effects. Psilocybin, when administered in a controlled setting, has frequently been reported to cause transient, delayed headache, with incidence, duration, and severity increased in a dose-related manner [Johnson et al., Drug Alcohol Depend, 2012, 123 (1-3):132-140]. It has been found that repeated administration of psychedelics leads to a very rapid development of tolerance known as tachyphylaxis, a phenomenon believed to be mediated, in part, by 5-HT2A receptors. In fact, several studies have shown that rapid tolerance to psychedelics correlates with downregulation of 5-HT2A receptors. For example, daily LSD administration selectively decreased 5-HT2 receptor density in the rat brain [Buckholtz et al., Eur. J. Pharmacol., 1990, 109:421-425. 1985; Buckholtz et al., Life Sci. 1985, 42:2439-2445].

SCHEME

PATENT

Mindset Pharma Inc., US11591353

https://patentscope.wipo.int/search/en/detail.jsf?docId=US376433397&_cid=P10-MARMO8-36145-1

PATENT

WO2021155470

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021155470&_cid=P10-MARMST-39096-1

PATENT

Cybin IRL Limited, WO2023247665

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2023247665&_cid=P10-MARMVV-41020-1

PATENT

WO2023078604

WO2022195011

Classic psychedelics and dissociative psychedelics are known to have rapid onset antidepressant and anti-addictive effects, unlike any currently available treatment. Randomized clinical control studies have confirmed antidepressant and anxiolytic effects of classic psychedelics in humans. Ketamine also has well established antidepressant and anti-addictive effects in humans mainly through its action as an NMDA antagonist. Ibogaine has demonstrated potent anti-addictive potential in pre-clinical studies and is in the early stages of clinical trials to determine efficacy in robust human studies [Barsuglia et al., Prog Brain Res, 2018, 242:121-158; Corkery, Prog Brain Res, 2018, 242:217-257].

Psilocybin (4-phosphoryloxy-N,N-dimethyltrypatmine (iii, Scheme 1) has the chemical formula C ₁₂H ₁₇N ₂O ₄P. It is a tryptamine and is one of the major psychoactive constituents in mushrooms of the psilocybe species. It was first isolated from psilocybe mushrooms by Hofmann in 1957, and later synthesized by him in 1958 [Passie et al. Addict Biol., 2002, 7 (4):357-364], and was used in psychiatric and psychological research and in psychotherapy during the early to mid-1960 s up until its controlled drug scheduling in 1970 in the US, and up until the 1980 s in Germany [Passie 2005; Passie et al., Addict Biol., 2002, 7 (4):357-364]. Research into the effects of psilocybin resumed in the mid-1990 s, and it is currently the preferred compound for use in studies of the effects of serotonergic hallucinogens [Carter et al. J. Cogn. Neurosci., 2005 17 (10):1497-1508; Gouzoulis-Mayfrank et al. Neuropsychopharmacology 1999, 20 (6):565-581; Hasler et al, Psychopharmacology (Berl) 2004, 172 (2):145-156], likely because it has a shorter duration of action and suffers from less notoriety than LSD. Like other members of this class, psilocybin induces sometimes profound changes in perception, cognition and emotion, including emotional lability.

In humans as well as other mammals, psilocybin is transformed into the active metabolite psilocin, or 4-hydroxy-N,N-dimethyltryptamine (iv, Scheme 1). It is likely that psilocin partially or wholly produces most of the subjective and physiological effects of psilocybin in humans and non-human animals. Recently, human psilocybin research confirms the 5HT2A activity of psilocybin and psilocin, and provides some support for indirect effects on dopamine through 5HT2A activity and possible activity at other serotonin receptors. In fact, the most consistent finding for involvement of other receptors in the actions of psychedelics is the 5-HT1 A receptor. That is particularly true for tryptamines and LSD, which generally have significant affinity and functional potency at this receptor. It is known that 5-HT1 A receptors are colocalized with 5-HT2A receptors on cortical pyramidal cells [Martin-Ruiz et al. J Neurosci. 2001, 21 (24):9856-986], where the two receptor types have opposing functional effects [Araneda et al. Neuroscience, 1991, 40 (2):399-412].

Although the exact role of the 5-HT2A receptor, and other 5-HT2 receptor family members, is not well understood with respect to the amygdala, it is evident that the 5-HT2A receptor plays an important role in emotional responses and is an important target to be considered in the actions of 5-HT2A agonist psychedelics. In fact, a majority of known 5HT2A agonists produce hallucinogenic effects in humans, and rodents generalize from one 5HT2A agonist to others, as between psilocybin and LSD [Aghajanian et al., Eur J Pharmacol., 1999, 367 (2-3):197-206; Nichols at al., J Neurochem., 2004, 90 (3):576-584]. Psilocybin has a stronger affinity for the human 5HT2A receptor than for the rat receptor and it has a lower K(i) for both 5HT2A and 5HT2C receptors than LSD. Moreover, results from a series of drug-discrimination studies in rats found that 5HT2A antagonists, and not 5HT1 A antagonists, prevented rats from recognizing psilocybin [Winter et al., Pharmacol Biochem Behav., 2007, 87 (4):472-480]. Daily doses of LSD and psilocybin reduce 5HT2 receptor density in rat brain.

Clinical studies in the 1960 s and 1970 s showed that psilocybin produces an altered state of consciousness with subjective symptoms such as “marked alterations in perception, mood, and thought, changes in experience of time, space, and self.” Psilocybin was used in experimental research for the understanding of etiopathogenesis of selective mental disorders and showed psychotherapeutic potential [Rucker et al., Psychopharmacol., 2016, 30 (12):1220-1229]. Psilocybin became increasingly popular as a hallucinogenic recreational drug and was eventually classed as a Schedule I controlled drug in 1970. Fear of psychedelic abuse led to a significant reduction in research being done in this area until the 1990 s when human research of psilocybin was revived when conditions for safe administration were established [Johnson et al., Psychopharmacol., 2008, 22 (6):603-620]. Today, psilocybin is one of the most widely used psychedelics in human studies due to its relative safety, moderately long active duration, and good absorption in subjects. There remains strong research and therapeutic potential for psilocybin as recent studies have shown varying degrees of success in neurotic disorders, alcoholism, depression in terminally ill cancer patients, obsessive compulsive disorder, addiction, anxiety, post-traumatic stress disorder and even cluster headaches. It could also be useful as a psychosis model for the development of new treatments for psychotic disorders. [Dubovyk and Monahan-Vaughn, ACS Chem. Neurosci., 2018, 9 (9):2241-2251].

Recent developments in the field have occurred in clinical research, where several double-blind placebo-controlled phase 2 studies of psilocybin-assisted psychotherapy in patients with treatment resistant, major depressive disorder and cancer-related psychosocial distress have demonstrated unprecedented positive relief of anxiety and depression. Two recent small pilot studies of psilocybin assisted psychotherapy also have shown positive benefit in treating both alcohol and nicotine addiction. Recently, blood oxygen level-dependent functional magnetic resonance imaging and magnetoencephalography have been employed for in vivo brain imaging in humans after administration of a psychedelic, and results indicate that intravenously administered psilocybin and LSD produce decreases in oscillatory power in areas of the brain’s default mode network [Nichols D E. Pharmacol Rev., 2016 68 (2):264-355].

Preliminary studies using positron emission tomography (PET) showed that psilocybin ingestion (15 or 20 mg orally) increased absolute metabolic rate of glucose in frontal, and to a lesser extent in other, cortical regions as well as in striatal and limbic subcortical structures in healthy participants, suggesting that some of the key behavioral effects of psilocybin involve the frontal cortex [Gouzoulis-Mayfrank et al., Neuropsychopharmacology, 1999, 20 (6):565-581; Vollenweider et al., Brain Res. Bull. 2001, 56 (5):495-507]. Although 5HT2A agonism is widely recognized as the primary action of classic psychedelic agents, psilocybin has lesser affinity for a wide range of other pre- and post-synaptic serotonin and dopamine receptors, as well as the serotonin reuptake transporter [Tyls et al., Eur. Neuropsychopharmacol. 2014, 24 (3):342-356]. Psilocybin activates 5HT1 A receptors, which may contribute to antidepressant/anti-anxiety effects.

Depression and anxiety are two of the most common psychiatric disorders worldwide. Depression is a multifaceted condition characterized by episodes of mood disturbances alongside other symptoms such as anhedonia, psychomotor complaints, feelings of guilt, attentional deficits and suicidal tendencies, all of which can range in severity. According to the World Health Organization, the discovery of mainstream antidepressants has largely revolutionized the management of depression, yet up to 60% of patients remain inadequately treated. This is often due to the drugs’ delayed therapeutic effect (generally 6 weeks from treatment onset), side effects leading to non-compliance, or inherent non-responsiveness to them. Similarly, anxiety disorders are a collective of etiologically complex disorders characterized by intense psychosocial distress and other symptoms depending on the subtype. Anxiety associated with life-threatening disease is the only anxiety subtype that has been studied in terms of psychedelic-assisted therapy. This form of anxiety affects up to 40% of individuals diagnosed with life-threatening diseases like cancer. It manifests as apprehension regarding future danger or misfortune accompanied by feelings of dysphoria or somatic symptoms of tension, and often coexists with depression. It is associated with decreased quality of life, reduced treatment adherence, prolonged hospitalization, increased disability, and hopelessness, which overall contribute to decreased survival rates. Pharmacological and psychosocial interventions are commonly used to manage this type of anxiety, but their efficacy is mixed and limited such that they often fail to provide satisfactory emotional relief. Recent interest into the use of psychedelic-assisted therapy may represent a promising alternative for patients with depression and anxiety that are ineffectively managed by conventional methods.

Generally, the psychedelic treatment model consists of administering the orally-active drug to induce a mystical experience lasting 4-9 h depending on the psychedelic [Halberstadt, Behav Brain Res., 2015, 277:99-120; Nichols, Pharmacol Rev., 2016, 68 (2): 264-355]. This enables participants to work through and integrate difficult feelings and situations, leading to enduring anti-depressant and anxiolytic effects. Classical psychedelics like psilocybin and LSD are being studied as potential candidates. In one study with classical psychedelics for the treatment of depression and anxiety associated with life-threatening disease, it was found that, in a supportive setting, psilocybin, and LSD consistently produced significant and sustained anti-depressant and anxiolytic effects.

Psychedelic treatment is generally well-tolerated with no persisting adverse effects. Regarding their mechanisms of action, they mediate their main therapeutic effects biochemically via serotonin receptor agonism, and psychologically by generating meaningful psycho-spiritual experiences that contribute to mental flexibility. Given the limited success rates of current treatments for anxiety and mood disorders, and considering the high morbidity associated with these conditions, there is potential for psychedelics to provide symptom relief in patients inadequately managed by conventional methods.

Further emerging clinical research and evidence suggest psychedelic-assisted therapy, also shows potential as an alternative treatment for refractory substance use disorders and mental health conditions, and thus may be an important tool in a crisis where existing approaches have yielded limited success. A recent systematic review of clinical trials published over the last 25 years summarizes some of the anti-depressive, anxiolytic, and anti-addictive effects of classic psychedelics. Among these, are encouraging findings from a meta-analysis of randomized controlled trials of LSD therapy and a recent pilot study of psilocybin-assisted therapy for treating alcohol use disorder [dos Santos et al., Ther Adv Psychopharmacol., 2016, 6 (3):193-213]. Similarly encouraging, are findings from a recent pilot study of psilocybin-assisted therapy for tobacco use disorder, demonstrating abstinence rates of 80% at six months follow-up and 67% at 12 months follow-up [Johnson et al., J Drug Alcohol Abuse, 2017, 43 (1):55-60; Johnson et al., Psychopharmacol. 2014, 28 (11):983-992], such rates are considerably higher than any documented in the tobacco cessation literature. Notably, mystical-type experiences generated from the psilocybin sessions were significantly correlated with positive treatment outcomes. These results coincide with bourgeoning evidence from recent clinical trials lending support to the effectiveness of psilocybin-assisted therapy for treatment-resistant depression and end-of-life anxiety [Carhart-Harris et al. Neuropsychopharmacology, 2017, 42 (11):2105-2113]. Research on the potential benefits of psychedelic-assisted therapy for opioid use disorder (OUD) is beginning to emerge, and accumulating evidence supports a need to advance this line of investigation. Available evidence from earlier randomized clinical trials suggests a promising role for treating OUD: higher rates of abstinence were observed among participants receiving high dose LSD and ketamine-assisted therapies for heroin addiction compared to controls at long-term follow-ups. Recently, a large United States population study among 44,000 individuals found that psychedelic use was associated with 40% reduced risk of opioid abuse and 27% reduced risk of opioid dependence in the following year, as defined by DSM-IV criteria [Pisano et al., J Psychopharmacol., 2017, 31 (5):606-613]. Similarly, a protective moderating effect of psychedelic use was found on the relationship between prescription opioid use and suicide risk among marginalized women [Argento et al., J Psychopharmacol., 2018, 32 (12):1385-1391]. Despite the promise of these preliminary findings with classical psychedelic agents, further research is warranted to determine what it may contribute to the opioid crisis response given their potential toxicity. Meanwhile, growing evidence on the safety and efficacy of psilocybin for the treatment of mental and substance use disorders should help to motivate further clinical investigation into its use as a novel intervention for OUD.

Regular doses of psychedelics also ameliorate sleep disturbances, which are highly prevalent in depressive patients with more than 80% of them having complaints of poor sleep quality. The sleep symptoms are often unresolved by first-line treatment and are associated with a greater risk of relapse and recurrence. Interestingly, sleep problems often appear before other depression symptoms, and subjective sleep quality worsens before the onset of an episode in recurrent depression. Brain areas showing increased functional connectivity with poor sleep scores and higher depressive symptomatology scores included prefrontal and limbic areas, areas involved in the processing of emotions. Sleep disruption in healthy participants has demonstrated that sleep is indeed involved in mood, emotion evaluation processes and brain reactivity to emotional stimuli. An increase in negative mood and a mood-independent mislabeling of neutral stimuli as negative was for example shown by one study while another demonstrated an amplified reactivity in limbic brain regions in response to both negative and positive stimuli. Two other studies assessing electroencephalographic (EEG) brain activity during sleep showed that psychedelics, such as LSD, positively affect sleep patterns. Moreover, it has been shown that partial or a full night of sleep deprivation can alleviate symptoms of depression suggested by resetting circadian rhythms via modification of clock gene expression. It further was suggested that a single dose of a psychedelic causes a reset of the biological clock underlying sleep/wake cycles and thereby enhances cognitive-emotional processes in depressed people but also improving feelings of well-being and enhances mood in healthy individuals [Kuypers, Medical Hypotheses, 2019, 125:21-24].

In a systematic meta-analysis of clinical trials from 1960-2018 researching the therapeutic use of psychedelic treatment in patients with serious or terminal illnesses and related psychiatric illness, it was found that psychedelic therapy (mostly with LSD) may improve cancer-related depression, anxiety, and fear of death. Four randomized controlled clinical trials were published between 2011 and 2016, mostly with psilocybin treatment, that demonstrated psychedelic-assisted treatment can produce rapid, robust, and sustained improvements in cancer-related psychological and existential distress. [Ross S, Int Rev Psychiatry, 2018, 30 (4):317-330]. Thus, the use of psychedelics in the fields of oncology and palliative care is intriguing for several reasons. First, many patients facing cancer or other life-threatening illnesses experience significant existential distress related to loss of meaning or purpose in life, which can be associated with hopelessness, demoralization, powerlessness, perceived burdensomeness, and a desire for hastened death. Those features are also often at the core of clinically significant anxiety and depression, and they can substantially diminish quality of life in this patient population. The alleviation of those forms of suffering should be among the central aims of palliative care. Accordingly, several manualized psychotherapies for cancer-related existential distress have been developed in recent years, with an emphasis on dignity and meaning-making. However, there are currently no pharmacologic interventions for existential distress per se, and available pharmacologic treatments for depressive symptoms in patients with cancer have not demonstrated superiority over placebo. There remains a need for additional effective treatments for those conditions [Rosenbaum et al., Curr. Oncol., 2019, 26 (4): 225-226].

Recently, there has been growing interest in a new dosing paradigm for psychedelics such as psilocybin and LSD referred to colloquially as microdosing. Under this paradigm, sub-perceptive doses of the serotonergic hallucinogens, approximately 10% or less of the full dose, are taken on a more consistent basis of once each day, every other day, or every three days, and so on. Not only is this dosing paradigm more consistent with current standards in pharmacological care, but may be particularly beneficial for certain conditions, such as Alzheimer’s disease and other neurodegenerative diseases, attention deficit disorder, attention deficit hyperactivity disorder, and for certain patient populations such as elderly, juvenile and patients that are fearful of or opposed to psychedelic assisted therapy. Moreover, this approach may be particularly well suited for managing cognitive deficits and preventing neurodegeneration. For example, subpopulations of low attentive and low motivated rats demonstrate improved performance on 5 choice serial reaction time and progressive ratio tasks, respectively, following doses of psilocybin below the threshold for eliciting the classical wet dog shake behavioral response associated with hallucinogenic doses (Blumstock et al., WO 2020/157569 A1). Similarly, treatment of patients with hallucinogenic doses of 5HT2A agonists is associated with increased BDNF and activation of the mTOR pathway, which are thought to promote neuroplasticity and are hypothesized to serve as molecular targets for the treatment of dementias and other neurodegenerative disorders (Ly et al. Cell Rep., 2018, 23 (11):3170-3182). Additionally, several groups have demonstrated that low, non-hallucinogenic and non-psychomimetic, doses of 5HT2A agonists also show similar neuroprotective and increased neuroplasticity effects (neuroplastogens) and reduced neuroinflammation, which could be beneficial in both neurodegenerative and neurodevelopmental diseases and chronic disorders (Manfredi et al., WO 2020/181194, Flanagan et al., Int. Rev. Psychiatry, 2018, 13:1-13; Nichols et al., 2016, Psychedelics as medicines; an emerging new paradigm). This repeated, lower, dose paradigm may extend the utility of these compounds to additional indications and may prove useful for wellness applications.

Psychosis is often referred to as an abnormal state of mind that is characterized by hallucinatory experiences, delusional thinking, and disordered thoughts. Moreover, this state is accompanied by impairments in social cognition, inappropriate emotional expressions, and bizarre behavior. Most often, psychosis develops as part of a psychiatric disorder, of which, it represents an integral part of schizophrenia. It corresponds to the most florid phase of the illness. The very first manifestation of psychosis in a patient is referred to as first-episode psychosis. It reflects a critical transitional stage toward the chronic establishment of the disease, that is presumably mediated by progressive structural and functional abnormalities seen in diagnosed patients. [ACS Chem. Neurosci. 2018, 9, 2241-2251]. Anecdotal evidence suggests that low, non-hallucinogenic, doses (microdosing) of psychedelics that are administered regularly can reduce symptoms of schizophrenia an

/////////Deupsilocin, Psilocin-d10, KXD3HS8D6X, Psilocin-D10, Deupsilocin, Psilocine-d10

Demannose

May 16, 2025 10:22 am / Leave a comment

Demannose

CAS 530-26-7,
3458-28-4

180.16 g/mol

D-Mannopyranose
Carubinose
Seminose
mannopyranose
(3S,4S,5S,6R)-6-(hydroxymethyl)oxane-2,3,4,5-tetrol
C₆H₁₂O₆

D-mannopyranose congenital glycosylation disorders

D-mannopyranose is d-Mannose in its six-membered ring form. It has a role as a metabolite. It is a D-aldohexose, a D-mannose and a mannopyranose.

SCHEME

LIT

Tetrahedron Letters (1987), 28(31), 3569-72

///////////Demannose, D-Mannopyranose, Carubinose, Seminose, mannopyranose

Dasminapant

May 11, 2025 1:19 pm / Leave a comment

Dasminapant

CAS 1570231-89-8

Molecular Weight	1157.40
Formula	C₆₀H₇₂N₁₀O₁₀S₂

APG-1387, SM-1387, E53VN70K2X, INN 12430,
APG-1387
UNII-E53VN70K2X
APG-1387 (SMAC MIMETIC)
SMAC-mimetic APG-1387
IAP Inhibitor APG-1387

PYRROLO(1,2-A)(1,5)DIAZOCINE-8-CARBOXAMIDE, 3,3′-(1,3-PHENYLENEBIS(SULFONYL))BIS(N-(DIPHENYLMETHYL)DECAHYDRO-5-(((2S)-2-(METHYLAMINO)-1-OXOPROPYL)AMINO)-6-OXO-, (5S,5’S,8S,8’S,10AR,10’AR)-

(5S,5’S,8S,8’S,10aR,10’aR)-3,3′-[1,3-phenylenebis(sulfonyl)]bis{N-(diphenylmethyl)-5-[(2S)-2-(methylamino)propanamido]-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide}

(5S,8S,10aR)-3-[3-[[(5S,8S,10aR)-8-(benzhydrylcarbamoyl)-5-[[(2S)-2-(methylamino)propanoyl]amino]-6-oxo-1,2,4,5,8,9,10,10a-octahydropyrrolo[1,2-a][1,5]diazocin-3-yl]sulfonyl]phenyl]sulfonyl-N-benzhydryl-5-[[(2S)-2-(methylamino)propanoyl]amino]-6-oxo-1,2,4,5,8,9,10,10a-octahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide

Dasminapant (APG-1387), a bivalent SMAC mimetic and an IAP antagonist, blocks the activity of IAPs family proteins (XIAP, cIAP-1, cIAP-2, and ML-IAP). Dasminapant induces degradation of cIAP-1 and XIAP proteins, as well as caspase-3 activation and PARP cleavage, which leads to apoptosis. Dasminapant can be used for the research of hepatocellular carcinoma, ovarian cancer, and nasopharyngeal carcinoma.

Dasminapant, also known as APG-1387 and SM-1387, is a IAP inhibitor. APG-1387 promotes the rapid degradation of cIAP1/2 and XIAP, and it exerts an antitumor effect on nasopharyngeal carcinoma cancer stem cells. Further studies show that APG-1387 enhances the chemosensitivity and promotes apoptosis in combination with CDDP and 5-FU of NPC in vitro and vivo.

PATENTS

WO2022012671

PATENT

WO2014031487 …

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014031487&_cid=P11-MAJOJ5-33000-1

PATENT

US20140057924

SCHEME

[1]. Chen Z, et, al. The SMAC Mimetic APG-1387 Sensitizes Immune-Mediated Cell Apoptosis in Hepatocellular Carcinoma. Front Pharmacol. 2018 Nov 6; 9:1298. [Content Brief][2]. Li BX, et, al. Novel smac mimetic APG-1387 elicits ovarian cancer cell killing through TNF-alpha, Ripoptosome and autophagy mediated cell death pathway. J Exp Clin Cancer Res. 2018 Mar 12;37(1):53. [Content Brief][3]. Li N, et, al. A novel Smac mimetic APG-1387 demonstrates potent antitumor activity in nasopharyngeal carcinoma cells by inducing apoptosis. Cancer Lett. 2016 Oct 10;381(1):14-22. [Content Brief][4]. Li Q, et, al. Abstract 6216: Therapeutic potential of IAP inhibitor APG-1387 in combination with PARP- or MEK-targeted therapy, or chemotherapy in pancreatic cancer. American Association for Cancer Research. Aug 2020. 80(16).[5]. Pan w, et, al. Abstract 1754: Smac mimetics APG-1387 synergizes with immune checkpoint inhibitors in preclinical models. American Association for Cancer Research. Jul 2018. 78(13).

///////////////Dasminapant, APG-1387, SM-1387, E53VN70K2X, INN 12430, APG 1387, UNII-E53VN70K2X, APG-1387 (SMAC MIMETIC), SMAC-mimetic APG-1387, IAP Inhibitor APG-1387, SM 1387

Civorebrutinib

May 7, 2025 9:05 am / Leave a comment

Civorebrutinib

WS-413, 933NK55FMX

5-amino-3-[4-(5-chloropyridin-2-yl)oxyphenyl]-1-[(6R)-4-cyano-4-azaspiro[2.5]octan-6-yl]pyrazole-4-carboxamide

Molecular Weight	463.92
Formula	C₂₃H₂₂ClN₇O₂
CAS No.	2155853-43-1

Civorebrutinib (WS-413) is a Bruton’s tyrosine kinase inhibitor with antineoplastic effect.

Scheme

Patent

Zhejiang Yukon Pharma Co., Ltd. WO2017198050

WO2019091440

WO2019091438

PATENT

WO2019091441

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019091441&_cid=P10-MADPL7-76599-1

Example 1

[0116]Preparation of (R)-5-amino-3-(4-((5-chloropyridin-2-yl)oxy)phenyl)-1-(4-cyano-4-azaspiro[2.5]octan-6-yl)-1H-pyrazole-4-carboxamide (Compound 1)

Step 1

[0119]

[0120]DIPEA (185 g, 1.44 mol, 250 mL, 3 eq) was added to a solution of intermediate compound 11 (167 g, 479 mmol, 1 eq) in EtOH (1670 mL) at 0 ° C. Intermediate compound 17 (187 g, 575 mmol, 1.2 eq) was added to the mixture. The mixture was then stirred at 25 ° C for 12 h under a N2 atmosphere. LCMS (ET14245-55-P1A2, product: RT = 1.723 min) showed that the reaction was complete. The reaction was filtered to obtain the product. The product was used directly in the next step without purification. Intermediate compound 18 (243 g, 407 mmol, yield 85%, purity 93.1%) was obtained as a white solid.

[0121]Step 2

[0122]

[0123]Intermediate compound 18 (121 g, 218 mmol, 1 eq) was stirred in H

₂ SO

₄ (1200 mL) at 30° C. for 36 h. TLC (DCM: MeOH=10:1, Rf=0.9) showed that compound 18 was completely consumed and only one desired spot was formed (DCM: MeOH=10:1, Rf=0.2). Multiple batches of reaction mixtures were combined, and the combined mixture was poured into MTBE (20 L), solids were precipitated and the filtrate was collected by suction filtration. The pH of the filtrate was adjusted to 10 with aqueous ammonia, extracted with EtOAc (2 L x 10), dried with Na

₂ SO

₄ , filtered and concentrated under reduced pressure to give intermediate compound 19 (crude product 311 g, equivalent to 238 g product) as a yellow solid.

[0124]Step 3

[0125]

[0126]To a solution of intermediate compound 19 (199 g, 453 mmol, 1 eq) in DMF (1400 mL) was added cesium carbonate (295 g, 907 mmol, 2 eq) and stirred at 15 ° C for 0.5 hours. Then BrCN (52.8 g, 499 mmol, 36.7 mL, 1.1 eq) was added and stirred at 15 ° C for 2 hours. TLC (DCM: MeOH = 10: 1, R

_f = 0.2) showed that compound 19 was completely reacted and only one desired spot was generated (DCM: MeOH = 10: 1, R

_f = 0.6). Multiple batches of reaction mixtures were combined and the resulting mixture was filtered to remove cesium carbonate. The filtrate was then concentrated under reduced pressure to remove DMF. The residue was diluted with water (2 L) and extracted with ethyl acetate (1 L × 4). The organic phases were combined and washed with water (2 L × 2) and brine (2 L), dried over sodium sulfate, filtered and concentrated under reduced pressure. Acetonitrile (1 L) was added to the residue to precipitate a white solid, which was filtered and the filter cake was washed with acetonitrile (200 mL×2) to give Compound 1 (140 g, 302 mmol, yield 55%, purity 97.0%).

[0127]

¹H NMR：CDCl ₃400MHzδ8.05(d，J＝2.4Hz，1H)，7.60(dd，J＝2.4，8.8Hz，1H)，7.51(d，J＝8.8Hz，2H)，7.15(d，J＝8.8Hz，2H)，6.86(d，J＝8.8Hz，1H)，5.60(s，2H)，5.23(br.s.，2H)，4.22-4.16(m，1H)，3.59-3.41(m，2H)，2.39-2.24(m，2H)，2.12-2.09(m，1H)，1.23-1.10(m，2H)，0.80-0.74(m，2H)，0.62-0.61(m，1H).

[1]. Wu Y, et al. 5-Aminopyrazole carboxamide derivative as BTK inhibitor and its preparation. World Intellectual Property Organization, WO2017198050 A1 2017-11-23.

////////Civorebrutinib, WS-413, WS 413, 933NK55FMX

Canlitinib

April 30, 2025 1:06 pm / Leave a comment

Canlitinib

Cas 2222730-78-9

Molecular Weight	619.61
Formula	C₃₃H₃₁F₂N₃O₇

Kanitinib
PFR26A3AWM
GTPL12865
CX1003
CX-1003

6-[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxyquinolin-7-yl]oxyhexanoic acid

CANLITINIB is a small molecule drug with a maximum clinical trial phase of II and has 1 investigational indication.

Canlitinib is a tyrosine kinase inhibitor, extracted from patent WO2018072614 (IV-2). Canlitinib has the potential for cancer study.

Kanitinib is a tyrosine kinase inhibitor targeting the oncoprotein c-Met (hepatocyte growth factor receptor; HGFR; MET) and vascular endothelial growth factor receptor 2 (VEGFR2), with potential anti-angiogenic and antineoplastic activities. Upon oral administration, kanitinib targets and binds to c-Met and VEGFR2, thereby disrupting c-Met- and VEGFR2-dependent signal transduction pathways. This may induce cell death in tumor cells overexpressing c-Met and/or VEGFR2 protein. c-Met and VEGFR2 are both overexpressed in many tumor cell types and play key roles in tumor cell proliferation, survival, invasion, metastasis, and tumor angiogenesis

SCHEME

INT

PATENT

WO2020216188

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020216188&_cid=P20-MA3XXD-35471-1

Example 1

[0064]The preparation method of compound 1 is shown in Example 9 of compound patent WO 2018/072614 A1. Specifically, the preparation method of compound 1 is as follows.

[0065]

[0066]Under stirring, NaOH (4.4 g, 110 mmol) was added dropwise to a solution of methyl 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]hexanoate (IV-1, 35.0 g, 55.2 mmol, prepared according to the method described in WO2013/040801A1) in ethanol (350 mL). After the addition was complete, water (50 mL) was added. The resulting mixture was stirred at 20-25°C for 18 h, the reaction solution was diluted with water (100 mL), stirred for 20 min, and the pH was adjusted to 3-4 with 1N HCl. The reaction mixture was concentrated under reduced pressure to distill off about 300 mL of ethanol. The solid product was collected by filtration to give 28.4 g of crude product, which was purified by silica gel column chromatography (eluent: ethyl acetate:methanol = 1:1, v/v) to give 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]hexanoic acid (Compound 1), 9.6 g (yield: 28.1%).

[0067]Analytical data of compound 1: molecular weight 619.61; NMR hydrogen spectrum is shown in Figure 1, and NMR hydrogen spectrum data are as follows:

[0068]

¹H-NMR(δ,DMSO-d6,400MHz):12.03(s,1H,OH),10.40(s,1H,NH),10.02(s,1H,NH),8.47～8.46(d,J＝4,1H,CH),7.89-7.92(d,J＝12,1H,CH),7.63-7.67(d,J＝16,2H,2CH),7.51-7.52(d,J＝4,2H2CH),7.39-7.43(t,2H,2CH),7.13-7.17(t,2H,2CH),6.41-6.42(d,J＝4,1H,CH),4.12-4.15(t,2H,CH ₂),3.95(s,3H,CH ₃),2.24-2.28(t,2H,CH ₂),1.78-1.85(m,2H,CH ₂),1.57-1.64(m,2H,CH ₂),1.43-1.51(m,6H,3CH ₂)。

PATENT

CN111825609

PATENT

WO2018072614

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018072614&_cid=P20-MA3XZQ-37082-1

Example 9

[0438]Preparation of 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]hexanoic acid (IV-2), the reaction formula is as follows:

[0439]

[0440]Under stirring, NaOH (4.4 g, 110 mmol) was added dropwise to a solution of methyl 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]hexanoate (IV-1, 35.0 g, 55.2 mmol, prepared according to the method described in WO2013/040801A1) in ethanol (350 mL). After the addition was complete, water (50 mL) was added. The resulting mixture was stirred at 20-25°C for 18 h, the reaction solution was diluted with water (100 mL), stirred for 20 min, and the pH was adjusted to 3-4 with 1N HCl. The reaction mixture was concentrated under reduced pressure to distill off about 300 mL of ethanol. The solid product was collected by filtration to give 28.4 g of crude product, which was purified by silica gel column chromatography (eluent: ethyl acetate:methanol = 1:1, v/v) to give 6-[[4-[2-fluoro-4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropanecarbonyl]amino]phenoxy]-6-methoxy-7-quinolyl]oxy]hexanoic acid (IV-2), 9.6 g (yield: 28.1%). Analytical data:

¹ H-NMR (400 MHz, DMSO-d

₆ ): δ=8.17 (d, J=8.0 Hz, 1H), 7.81 (dd, J=2.8, 13.4 Hz, 1H) 7.62 (m, 2H), 7.51 (m, 4H), 7.39 (t, J=2.4 Hz, 2H), 6.44 (d, J=20.0 Hz, 1H), 4.13 (t, J=8.5 Hz, 2H), 3.85 (s, 3H), 2.27 (t, J=4.0 Hz, 2H), 1.83 (m, 2H), 1.68-1.46 (m, 8H). Mass spectrum (ESI) m/z: 620.2 [M+H]

⁺ .

PATENT

WO2013/040801

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2013040801&_cid=P20-MA3Y3E-39505-1

[1]. Zhang, Zhiqiang, et al. Quinolinyl-substituted carboxylic acid compound or pharmaceutically acceptable salt thereof, pharmaceutical composition thereof, and use thereof. WO2017-CN104518

////////Canlitinib, GTPL12865, CX1003, CX-1003

BRIGIMADLIN

April 28, 2025 9:03 am / Leave a comment

BRIGIMADLIN

Cas 2095116-40-6

WeightAverage: 591.46
Monoisotopic: 590.1287742

Chemical FormulaC₃₁H₂₅Cl₂FN₄O₃

9A934ZAN94

Spiro[3H-indole-3,2′(1′H)-pyrrolo[2′,3′:4,5]pyrrolo[1,2-b]indazole]-7′-carboxylic acid, 6-chloro-3′-(3-chloro-2-fluorophenyl)-1′-(cyclopropylmethyl)-1,2,3′,3′a,10′,10′a-hexahydro-6′-methyl-2-oxo-, (2′S,3′S,3′aS,10′aS)-

(2′S,3′S,3′aS,10′aS)-6-Chloro-3′-(3-chloro-2-fluorophenyl)-1′-(cyclopropylmethyl)-1,2,3′,3′a,10′,10′a-hexahydro-6′-methyl-2-oxospiro[3H-indole-3,2′(1′H)-pyrrolo[2′,3′:4,5]pyrrolo[1,2-b]indazole]-7′-carboxylic acid (

Brigimadlin (BI-907828) is a small molecule MDM2–TP53 inhibitor developed for liposarcoma.^{[2][3][4][5][6]}

Brigimadlin is an orally available inhibitor of murine double minute 2 (MDM2), with potential antineoplastic activity. Upon oral administration, brigimadlin binds to MDM2 protein and prevents its binding to the transcriptional activation domain of the tumor suppressor protein p53. By preventing MDM2-p53 interaction, the transcriptional activity of p53 is restored. This leads to p53-mediated induction of tumor cell apoptosis. Compared to currently available MDM2 inhibitors, the pharmacokinetic properties of BI 907828 allow for more optimal dosing and dose schedules that may reduce myelosuppression, an on-target, dose-limiting toxicity for this class of inhibitors.

SCHEME

PATENT

US10717742,

https://patentscope.wipo.int/search/en/detail.jsf?docId=US231206177&_cid=P10-MA0ULZ-04263-1

PATENT

WO2017060431A1]

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017060431&_cid=P10-MA0TY5-76812-1

intermediates B-7

Experimental procedure for the synthesis of B-7 a (method E)

To a solution of cyclopropanecarbaldehyde (1.7 mL, 22.7 mmol) in AcOH (19.5 mL) is added intermediate B-6a (1.60 g, 3.8 mmol) and the reaction mixture is stirred for 15 min. Sodium triacetoxyborohydride (1.34 g, 6.3 mmol) is added and the reaction mixture is stirred overnight. Water is added to the reaction mixture and it is extracted with EtOAc. The combined organic layer is dried (MgSO₄), filtered, concentrated in vacuo and the crude product B-7a is purified by chromatography if necessary.

Experimental procedure for the synthesis of B-3a (method A)

6-Chloroisatin S-1a (5 g, 27,0 mmol), 1-(3-chloro-2-fluoro-phenyl)-2-nitroethene B-2a (5.5 g, 27.0 mmol) and amino acid B-1a (4.4 g, 27.0 mmol) are refluxed in MeOH for 4 h. The reaction mixture is concentrated in vacuo and purified by crystallization or chromatography if necessary.

Synthesis of compounds (la) according to the invention

Experimental procedure for the synthesis of la-1 (method J)

To a solution of intermediate B-12a (329 mg, 0.65 mmol) in DCM (7 mL) is added a solution of Oxone^® (793 mg, 1.29 mmol) in H₂O (7 mL) at 0 °C dropwise. The biphasic reaction mixture is stirred vigorously for 20 min at 0 °C and for additional 2 h at rt. The reaction mixture is diluted with H₂O and is extracted with DCM. The combined organic layer is dried (MgSO₄), filtered, concentrated in vacuo and the crude product is purified by chromatography which gives compound la-1.

Experimental procedure for the synthesis of la-20 (method J + method K)

* The location of overoxidation/N-oxid formation is not entirely clear. B-13a as depicted seems to be probable.

To a solution of intermediate B-12j (417 mg, 0.68 mmol) in DCM (10 mL) is added a solution of Oxone^® (841 mg, 1.37 mmol) in H₂O (7 mL) at 0 °C dropwise. The biphasic reaction mixture is stirred vigorously for 20 min at 0 °C and for additional 6 h at rt. The reaction mixture is diluted with H₂O and extracted with DCM. The combined organic layer is dried (MgSO₄), filtered, concentrated in vacuo which gives a crude mixture of la-20 and an oxidized form B-13a (M+H = 621). This mixture is dissolved in MeCN (4.2 mL) and bis(pinacolato)diborone (326 mg, 1.28 mmol) is added. The reaction mixture is heated under microwave irradiation to 100 °C for 30 min. The reaction mixture is diluted with H₂O and extracted with DCM. The combined organic layer is dried (MgSO₄), filtered, concentrated in vacuo and the crude product is purified by chromatography which gives compound la-20.

References

^ “Brigimadlin”. pubchem.ncbi.nlm.nih.gov.

^ Rinnenthal, Joerg; Rudolph, Dorothea; Blake, Sophia; Gollner, Andreas; Wernitznig, Andreas; Weyer-Czernilofsky, Ulrike; Haslinger, Christian; Garin-Chesa, Pilar; Moll, Jürgen; Kraut, Norbert; McConnell, Darryl; Quant, Jens (1 July 2018). “Abstract 4865: BI 907828: A highly potent MDM2 inhibitor with low human dose estimation, designed for high-dose intermittent schedules in the clinic”. Cancer Research. 78 (13_Supplement): 4865. doi:10.1158/1538-7445.AM2018-4865. S2CID 56768874.
^ Rudolph, Dorothea; Reschke, Markus; Blake, Sophia; Rinnenthal, Jörg; Wernitznig, Andreas; Weyer-Czernilofsky, Ulrike; Gollner, Andreas; Haslinger, Christian; Garin-Chesa, Pilar; Quant, Jens; McConnell, Darryl B.; Norbert, Kraut; Moll, Jürgen (1 July 2018). “Abstract 4866: BI 907828: A novel, potent MDM2 inhibitor that induces antitumor immunologic memory and acts synergistically with an anti-PD-1 antibody in syngeneic mouse models of cancer”. Cancer Research. 78 (13_Supplement): 4866. doi:10.1158/1538-7445.AM2018-4866. S2CID 80770832.
^ Cornillie, J.; Wozniak, A.; Li, H.; Gebreyohannes, Y. K.; Wellens, J.; Hompes, D.; Debiec-Rychter, M.; Sciot, R.; Schöffski, P. (April 2020). “Anti-tumor activity of the MDM2-TP53 inhibitor BI-907828 in dedifferentiated liposarcoma patient-derived xenograft models harboring MDM2 amplification”. Clinical and Translational Oncology. 22 (4): 546–554. doi:10.1007/s12094-019-02158-z. PMID 31201607. S2CID 189862528.
^ Schöffski, Patrick; Lahmar, Mehdi; Lucarelli, Anthony; Maki, Robert G (March 2023). “Brightline-1: phase II/III trial of the MDM2–p53 antagonist BI 907828 versus doxorubicin in patients with advanced DDLPS”. Future Oncology. 19 (9): 621–629. doi:10.2217/fon-2022-1291. PMID 36987836. S2CID 257802972.
^ Schoeffski, P.; Lorusso, P.; Yamamoto, N.; Lugowska, I.; Moreno Garcia, V.; Lauer, U.; Hu, C.; Jayadeva, G.; Lahmar, M.; Gounder, M. (October 2023). “673P A phase I dose-escalation and expansion study evaluating the safety and efficacy of the MDM2–p53 antagonist brigimadlin (BI 907828) in patients (pts) with solid tumours”. Annals of Oncology. 34: S472 – S473. doi:10.1016/j.annonc.2023.09.1859. S2CID 264392338.

Names

IUPAC name(3S,10’S,11’S,14’S)-6-chloro-11′-(3-chloro-2-fluorophenyl)-13′-(cyclopropylmethyl)-6′-methyl-2-oxospiro[1H-indole-3,12′-8,9,13-triazatetracyclo[7.6.0.0^2,7.0^10,14]pentadeca-1,3,5,7-tetraene]-5′-carboxylic acid
Identifiers
CAS Number	2095116-40-6
3D model (JSmol)	Interactive image
ChemSpider	128922236
DrugBank	DB18578
EC Number	826-645-5
KEGG	D12842
PubChem CID	129264140
UNII	9A934ZAN94
showInChI
showSMILES
Properties
Chemical formula	C₃₁H₂₅Cl₂FN₄O₃
Molar mass	591.46 g·mol⁻¹
Hazards
GHS labelling:^[1]
Pictograms
Signal word	Danger
Hazard statements	H300, H360Df, H372, H413
Precautionary statements	P203, P260, P264, P270, P273, P280, P301+P316, P318, P319, P321, P330, P405, P501
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

/////////////BRIGIMADLIN, BI-907828, BI 907828, 9A934ZAN94

Bocodepsin

April 25, 2025 9:25 am / Leave a comment

Bocodepsin, OKI-179

CAS 1834513-65-3

1834513-67-5 (besylate)

K5D067O1SW

S-((3E)-4-((6S,9S)-12,12-DIMETHYL-4,8,11,14-TETRAOXO-9-(PROPAN-2-YL)-7-OXA -3,10,13-TRIAZA-1(2,4)-(1,3)THIAZOLACYCLOTETRADECAPHAN-6-YL)BUT-3-EN-1-YL) (2S)-2-AMINO-3-METHYLBUTANETHIOATE
S-(4-((7S,10S)-4,4-DIMETHYL-2,5,8,12-TETRAOXO-7-(PROPAN-2-YL)-9-OXA-16-THIA- 3,6,13,18-TETRAAZABICYCLO(13.2.1)OCTADECA-15(18),17-DIEN-10-YL)BUT-3-EN-1-YL) (2S)-2-AMINO-3-METHYLBUTANETHIOATE

Molecular Weight	581.75
Formula	C₂₆H₃₉N₅O₆S₂

Originator OnKure Therapeutics
Class Antineoplastics; Small molecules
Mechanism of ActionHDAC1 protein inhibitors

Phase I/II Malignant melanoma; Solid tumours

No development reportedHaematological malignancies

29 Jan 2025 OnKure Therapeutics completes the phase-I/II Nautilus trial in Malignant melanoma (Late-stage disease, Metastatic disease, Second-line therapy or greater, Combination therapy) in USA (PO) (NCT05340621),

11 Oct 2023Pharmacodynamics data from a preclinical studies in Solid tumours presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics 2023 (AACR-NCI-EORTC-2023 2023)
11 Oct 2023Initial efficacy and adverse events data from a phase Ib/II NAUTILUS trial in Melanoma presented at the International Conference on Molecular Targets and Cancer Therapeutics 2023 (AACR-NCI-EORTC-2023)

Bocodepsin (OKI-179) is an orally active and selective HDAC inhibitor, with antitumor activity. Bocodepsin can be used for suppression on solid tumor and hematologic malignancies.

SCHEME

PATENT

WO2017201278

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017201278&_cid=P12-M9WKU5-87067-1

Examples

[00127] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention.

[00128] Example 1: Preparation of (R)-S-((E)-4-((7S,10S)-7-isopropyl-4,4-dimethyl-2,5,8,12- tetraoxo-9-oxa-16-thia-3,6,13,18-tetraazabicyclo[13.2.1]octadeca-l(17),15(18)-dien-10- yl)but-3-en-l-yl) 2-amino-3-methylbutanethioate hydrochloride.

Step 1 : Preparation of (R)-S-((E)-4-((7S,10S)-7-isopropyl-4,4-dimethyl-2,5,8,12- tetraoxo-9-oxa-16-thia-3,6,13,18-tetraazabicyclo[13.2.1]octadeca-l(17),15(18)-dien-10- yl)but-3-en-l-yl) 2-((tert-butoxycarbonyl)amino)-3-methylbutanethioate. (7S,10S)-10-((E)- 4- chlorobut-l-en-l-yl)-7-isopropyl-4,4-dimethyl-9-oxa-16-thia-3,6,13,18- tetraazabicyclo[13.2.1]octadeca-l(17),15(18)-diene-2,5,8,12-tetraone (15 g, 0.03 mol), (R)-2- ((tert-butoxycarbonyl)amino)-3-methylbutanethioic S-acid (12.5 g, 0.06 mol), K2CO₃ (11.2 g, 0.09 mol), and KI (0.89 g, 0.006 mol) were dissolved in 150mL of acetonitrile and the resulting mixture was warmed to 60-65°C and stirred under nitrogen. After 16 hours, the mixture was cooled to 20°C, 300 mL of water was added, and the resulting suspension was extracted with ethyl acetate (2X200 mL). The combined organic phases were dried with anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (elution with ethyl acetate/petroleum ether = 1/1 to 4/1) to give (R)- 5- ((E)-4-((7S,10S)-7-isopropyl-4,4-dimethyl-2,5,8,12-tetraoxo-9-oxa-16-thia-3,6,13,18- tetraazabicyclo[13.2.1] octadeca-l(17),15(18)-dien-10-yl)but-3-en-l-yl) 2-((tert- butoxycarbonyl)amino)-3-methylbutanethioate (17.0 g, 80% yield).

Step 2: Preparation of (R)-S-((E)-4-((7S,10S)-7-isopropyl-4,4-dimethyl-2,5,8,12- tetraoxo-9-oxa-16-thia-3,6,13,18-tetraazabicyclo[13.2.1]octadeca-l(17),15(18)-dien-10- yl)but-3-en-l-yl) 2-amino-3-methylbutanethioate hydrochloride. (R)-S-((E)-4-((7S,10S)-7- isopropyl-4,4-dimethyl-2,5,8,12-tetraoxo-9-oxa-16-thia-3,6,13,18- tetraazabicyclo[l 3.2.1] octadeca- 1 ( 17), 15 (18)-dien- 10-y l)but-3-en- 1 -y 1) 2-((tert-butoxy carbony l)amino)-3-methylbutanethioate (1.7 g, 0.025 mol) was dissolved in 150 mL of dichloromethane and trifluoroacetic acid (22.5 mL) was added at 10°C. After stirring at 10°C for 4 hours under nitrogen, the mixture was concentrated to dryness and the residue was dissolved in 100 mL of ethyl acetate and treated with 10 mL of 4M HCl/ethyl acetate solution. The mixture was then treated with petroleum ether (100 mL) and the resulting white solid was collected by filtration and dried to give (R)-S-((E)-4-((7S,10S)-7-isopropyl-4,4-dimethyl-2,5,8,12-tetraoxo-9-oxa-16-thia-3,6,13,18- tetraazabicyclo[13.2.1] octadeca-l(17),15(18)-dien-10-yl)but-3-en-l-yl) 2-amino-3-methylbutanethioate hydrochloride (0.40 g, 26% yield). Mass Spec(m/z): 582.8 (M+l).

129] Example 2: Preparation of (S)-S-((E)-4-((7S,10S)-7-isopropyl-4,4-dimethyl-2,5,8,12-tetraoxo-9-oxa-16-thia-3,6,13,18-tetraazabicyclo[13.2.1]octadeca-l(17),15(18)-dien-10-yl)but-3-en-l-yl) 2-amino-3-methylbutanethioate hydrochloride.

Step 1 : (S)-S-((E)-4-((7S,10S)-7-isopropyl-4,4-dimethyl-2,5,8,12-tetraoxo-9-oxa-16-thia-3,6,13,18-tetraazabicyclo[13.2.1]octadeca-l(17),15(18)-dien-10-yl)but-3-en-l-yl) 2-((tert-butoxy carbony l)amino)-3 -methy lbutanethioate. (7S,10S)-10-((E)-4-chlorobut- 1 -en- 1 -yl)-7-isopropyl-4,4-dimethyl-9-oxa-16-thia-3,6,13,18-tetraazabicyclo[13.2.1]octadeca-l(17),15(18)-diene-2,5,8,12-tetraone (40 g, 0.0825 mol), (S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanethioic S-acid (38.5 g, 0.165 mol), K₂C0₃ (34.1 g, 0.247 mol), and KI (2.7 g, 0.0163 mol) were dissolved in 400 mL of acetonitrile and stirred at 60-65°C under nitrogen for 20 hours. The mixture was cooled to 20°C, water (300 mL) was added and the resulting suspension was extracted with ethyl acetate (2X200 mL). The organic phases were combined, dried with anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (elution with ethyl acetate/petroleum ether = 1/1 to 4/1) to give (S)-S-((E)-4-((7S,10S)-7-isopropyl-4,4-dimethyl-2,5,8,12-tetraoxo-9-oxa-16-thia-3,6,13,18-tetraazabicyclo[13.2.1]octadeca-l(17),15(18)-dien-10-yl)but-3-en-l-yl) 2-((tert-butoxycarbonyl)amino)-3-methylbutanethioate (49.8 g, 89% yield).

Step 2: (S)-S-((E)-4-((7S,10S)-7-isopropyl-4,4-dimethyl-2,5,8,12-tetraoxo-9-oxa-16-thia-3,6,13,18-tetraazabicyclo[13.2.1]octadeca-l(17),15(18)-dien-10-yl)but-3-en-l-yl) 2-amino-3-methylbutanethioate hydrochloride. (S)-S-((E)-4-((7S,10S)-7-isopropyl-4,4-dimethyl-2,5,8,12-tetraoxo-9-oxa-16-thia-3,6,13,18-tetraazabicyclo[13.2.1]octadeca-1 ( 17), 15( 18)-dien- 10-y l)but-3-en- 1 -y 1) 2-((tert-butoxy carbony l)amino)-3 -methylbutanethioate (47.8 g, 0.07 mol) was dissolved in dichloromethane (400 mL) and trifluoroacetic acid (65 mL) was added dropwise at 10 to 20°C while stirring under nitrogen. After the addition, the mixture was stirred at 15 to 20°C for 3 hours at which time an additional aliquot of trifluoroacetic acid (20 mL) was added and stirring at 15 to 20°C was continued for an additional 1.5 hours. The solution was then concentrated under vacuum to near dryness and the residue dissolved in ethyl acetate (250 mL). 20 mL of 4M HCl/ethyl acetate solution was then added while stirring at a temperature between 10 to 15°C resulting in the formation of a slurry. 250 mL n-heptane was then added and the solids were filtered, rinsed with n-heptane and dried in vacuo to give (S)-S-((E)-4-((7S,10S)-7-isopropyl-4,4-dimethyl-2,5,8,12-tetraoxo-9-oxa-16-thia-3,6,13,18- tetraazabicyclo[13.2.1] octadeca-l(17),15(18)-dien-10-yl)but-3-en-l-yl) 2-amino-3 -methylbutanethioate hydrochloride as a white solid which contained some residual heptane. (49.0 g, 100% yield). Mass Spec(m/z): 582.8 (M+l)

130] Example 3: Preparation of (S)-S-((E)-4-((7S,10S)-7-isopropyl-4,4-dimethyl-2,5,8,12-tetraoxo-9-oxa-16-thia-3,6,13,18-tetraazabicyclo[13.2.1]octadeca-l(17),15(18)-dien-10-yl)but-3-en-l-yl) 2-amino-3 -methylbutanethioate benzenesulfonate.

The product of Example 2, step 1 ((S)-S-((E)-4-((7S,10S)-7-isopropyl-4,4-dimethyl-2,5,8,12-tetraoxo-9-oxa-16-thia-3,6,13,18-tetraazabicyclo[13.2.1]octadeca-l(17),15(18)-dien-10-yl)but-3-en-l-yl) 2-((tert-butoxycarbonyl)amino)-3-methylbutanethioate) (1 eq.) was dissolved in acetonitrile (10 vol) at 20-25°C and the mixture was treated with

benzenesulfonic acid (3 eq.). After stirring at room temperature for 5 hours, the solvent was removed by decanting, the residual oil was treated with THF (5vol), and the resulting mixture was stirred over night at room temperature. The resulting white solid was collected by filtration and dried in vacuo to give (S)-S-((E)-4-((7S,10S)-7-isopropyl-4,4-dimethyl-2,5,8,12-tetraoxo-9-oxa-16-thia-3,6,13,18-tetraazabicyclo[13.2.1]octadeca-l(17),15(18)-dien-10-yl)but-3-en-l-yl) 2-amino-3-methylbutanethioate benzenesulfonate (90% yield; 98% purity). ¹HNMR (d₆-DMSO) δ: 0.56 to 0.57 (m, 3H), 0.76 to 0.78 (m, 3H), 0.92 to 0.94 (m, 3H), 0.96 to 0.98 (m, 3H), 1.45 to 1.48 (m, 3H), 1.70 to 1.72 (m, 3H), 2.07 to 2.16 (m, 2H), 2.27 to 2.28 (m, 2H), 2.93 to 2.95 (m, 1H), 2.94 to 2.95 (m, 1H), 2.97 to 3.1 (m, 1H), 4.13 to 4.15 (m, 1H), 4.28 to 4.33 (1H), 4.92 to 5.0 (m, 1H), 5.61 to 5.64 (m, 3H), 7.29 to 7.32 (m, 3H), 7.57 to 7.60 (m, 2H), 7.88 to 7.92 (m, 1H), 8.17 (s, 1H), 8.32 (s, 3H), 8.48 to 8.50 (m, 1H).

[1]. Diamond JR, et al. Preclinical Development of the Class-I-Selective Histone Deacetylase Inhibitor OKI-179 for the Treatment of Solid Tumors. Mol Cancer Ther. 2022 Mar 1;21(3):397-406. [Content Brief]

///////////Bocodepsin, K5D067O1SW, OKI-179, Malignant melanoma, Solid tumours, OnKure Therapeutics, OKI 006

Tegeprotafib

April 24, 2025 6:23 am / Leave a comment

Tegeprotafib

CAS 2407610-46-0

Molecular Weight	326.30
Formula	C₁₃H₁₁FN₂O₅S

PTPN2/1-IN-1, YGY4WEM0NZ

5-(1-fluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one

Tegeprotafib (PTPN2/1-IN-1) (Compound 124) is an orally active PTPN1 and PTPN2 inhibitor with IC₅₀s of 4.4 nM and 1-10 nM against PTPN2 and PTP1B, respectively.

Cancer immunotherapy regimens targeting immune evasion mechanisms including checkpoint blockade (e.g., PD-1/PD-L1 and CTLA-4 blocking antibodies) have been shown to be effective in treating in a variety of cancers, dramatically improving outcomes in some populations refractory to conventional therapies. However, incomplete clinical responses and the development of intrinsic or acquired resistance will continue to limit the patient populations who could benefit from checkpoint blockade.

Protein tyrosine phosphatase non-receptor type 2 (PTPN2), also known as T cell protein tyrosine phosphatase (TC-PTP), is an intracellular member of the class 1 subfamily of phospho-tyrosine specific phosphatases that control multiple cellular regulatory processes by removing phosphate groups from tyrosine substrates. PTPN2 is ubiquitously expressed, but expression is highest in hematopoietic and placental cells (Mosinger, B. Jr. et al., Proc NatlAcad Sci USA 89:499-503; 1992). In humans, PTPN2 expression is controlled post-transcriptionally by the existence of two splice variants: a 45 kDa form that contains a nuclear localization signal at the C-terminus upstream of the splice junction, and a 48 kDa canonical form which has a C-terminal ER retention motif (Tillmann U. et al., Mol Cell Biol 14:3030-3040; 1994). The 45 kDa isoform can passively transfuse into the cytosol under certain cellular stress conditions. Both isoforms share an N-terminal phospho-tyrosine phosphatase catalytic domain. PTPN2 negatively regulates signaling of non-receptor tyrosine kinases (e.g., JAK1, JAK3), receptor tyrosine kinases (e.g., INSR, EGFR, CSF1R, PDGFR), transcription factors (e.g., STAT1, STAT3, STAT5a/b), and Src family kinases (e.g., Fyn, Lck). As a critical negative regulator of the JAK-STAT pathway, PTPN2 functions to directly regulate signaling through cytokine receptors, including IFNγ. The PTPN2 catalytic domain shares 74% sequence homology with PTPN1 (also called PTP1B), and shares similar enzymatic kinetics (Romsicki Y. et al., Arch Biochem Biophys 414:40-50; 2003).

Data from a loss of function in vivo genetic screen using CRISPR/Cas9 genome editing in a mouse B16F10 transplantable tumor model show that deletion of Ptpn2 gene in tumor cells improved response to the immunotherapy regimen of a GM-CSF secreting vaccine (GVAX) plus PD-1 checkpoint blockade (Manguso R. T. et al., Nature 547:413-418; 2017). Loss of Ptpn2 sensitized tumors to immunotherapy by enhancing IFNγ-mediated effects on antigen presentation and growth suppression. The same screen also revealed that genes known to be involved in immune evasion, including PD-L1 and CD47, were also depleted under immunotherapy selective pressure, while genes involved in the IFNγ signaling pathway, including IFNGR, JAK1, and STAT1, were enriched. These observations point to a putative role for therapeutic strategies that enhance IFNγ sensing and signaling in enhancing the efficacy of cancer immunotherapy regimens.

Protein tyrosine phosphatase non-receptor type 1 (PTPN1), also known as protein tyrosine phosphatase-1B (PTPiB), has been shown to play a key role in insulin and leptin signaling and is a primary mechanism for down-regulating both the insulin and leptin receptor signaling pathways (Kenner K. A. et al., J Biol Chem 271: 19810-19816, 1996). Animals deficient in PTP1B have improved glucose regulation and lipid profiles and are resistant to weight gain when treated with a high fat diet (Elchebly M. et al., Science 283: 1544-1548, 1999). Thus, PTP1B inhibitors are expected to be useful for the treatment of type 2 diabetes, obesity, and metabolic syndrome.

SCHEME

PATENT

Calico Life Sciences LLC; AbbVie Inc. , WO2021127499

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021127499&_cid=P21-M9UYU6-17583-1

Example 25: 5-(1-fluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-1λ⁶,2,5-thiadiazolidine-1,1,3-trione (Compound 124)

Example 25A: benzyl 3-(benzyloxy)-7-methoxynaphthalene-2-carboxylate

A mixture of 3-hydroxy-7-methoxy-2-naphthoic acid (75 g, 344 mmol) and cesium carbonate (336 g, 1031 mmol) in N,N-dimethylformamide (687 mL) was rapidly stirred for 5 minutes at 23 °C. Thereafter, benzyl bromide (84 mL, 705 mmol) was added. After 90 minutes, the mixture was poured into H₂O (1 L) and extracted with ethyl acetate (4 × 300 mL). The combined organic layers were washed with saturated aqueous ammonium chloride (3 × 100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford a brown solid. The crude solid was collected by filtration, slurried with tert-butyl methyl ether/heptanes (1:2, 3 × 100 mL), then dried in vacuo (12 mbar) at 40 °C to afford the title compound (122.5 g, 307 mmol, 89% yield) as a beige solid. MS (APCI⁺) m/z 399 [M+H]⁺.

Example 25B: 3-(benzyloxy)-7-methoxynaphthalene-2-carboxylic acid

To a suspension of the product of Example 25A (122.5 g, 307 mmol) in methanol (780 mL) was added 6 M aqueous sodium hydroxide (154 mL, 922 mmol). The heterogeneous, brown slurry was agitated with an overhead mechanical stirrer and heated to an internal temperature of 68 °C. After 15 minutes, the mixture was cooled to room temperature in an ice bath, and 6 M HCl (250 mL) was added over 5 minutes. The off-white solid was collected by filtration, washed with H2O (3 × 500 mL), and dried to constant weight in vacuo at 65 °C to afford the title compound (84.1 g, 273 mmol, 89% yield) as a white solid. MS (APCI⁺) m/z 309 [M+H]⁺.

Example 25C: 3-(benzyloxy)-7-methoxynaphthalen-2-amine

To a suspension of the product of Example 25B (84.1 g, 273 mmol), in toluene (766 mL) and tert-butanol (766 mL) was added triethylamine (40.3 mL, 289 mmol). The homogeneous black solution was heated to an internal temperature of 80 °C under nitrogen, and diphenyl phosphorazidate (62.2 mL, 289 mmol) was added dropwise over 90 minutes with the entire

reaction behind a blast shield. After 5 hours, the reaction was cooled to room temperature, diluted with H₂O (1.5 L), and extracted with ethyl acetate (3 × 150 mL). The combined organic layers were washed with brine (2 × 100 mL), dried over sodium sulfate, filtered and concentrated to give 180.1 g of a dark brown solid. The solid was carried forward to hydrolysis without further purification.

To the crude intermediate was added diethylenetriamine (475 mL, 4.40 mol). The heterogeneous suspension was heated to an internal temperature of 130 °C under nitrogen, at which time a homogeneous dark orange solution formed. After 16 hours, the mixture was cooled to room temperature in an ice bath, and H₂O (1.5 L) was added slowly over 3 minutes, resulting in precipitation of a yellow solid and a concomitant exotherm to an internal temperature of 62 °C. Once the heterogeneous suspension had cooled to room temperature, the crude solid was dissolved in CH₂Cl₂ (1.5 L), and the layers were separated. The aqueous layer was back-extracted with CH₂Cl2 (3 × 150 mL), and the combined organic layers were washed with brine (3 × 100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford 78.8 g of an orange solid. The solid was slurried with isopropanol (50 mL), collected via filtration, re-slurried with isopropanol (1 × 50 mL), and dried in vacuo (15 mbar) at 35 °C to afford the title compound (60.12 g, 215 mmol, 79% yield over two steps) as a yellow solid. MS (APCI⁺) m/z 280 [M+H]⁺.

Example 25D: methyl {[3-(benzyloxy)-7-methoxynaphthalen-2-yl]amino}acetate

To a mixture of the product of Example 25C (59.2 g, 212 mmol) and potassium carbonate (58.6 g, 424 mmol) in dimethylformamide (363 mL) and H₂O (1.91 mL, 106 mmol) was added methyl 2-bromoacetate (30.1 mL, 318 mmol). The suspension was vigorously stirred at room temperature for 5 minutes and then heated to an internal temperature of 60 °C. After 70 minutes, the suspension was cooled to room temperature and diluted with H2O (600 mL) and ethyl acetate (500 mL). The aqueous layer was extracted with ethyl acetate (2 × 300 mL), and the combined organic layers were washed with saturated aqueous ammonium chloride (3 × 60 mL), dried over sodium sulfate, filtered, and concentrated to afford 104.3 g of a pale beige solid. The solid was triturated with heptanes (200 mL). The resulting beige solid was collected via filtration, washed with additional heptanes (2 × 30 mL), and dried in vacuo (15 mbar) at 35 °C to afford the title compound (72.27 g, 206 mmol, 97% yield) as an off-white solid. MS (APCI+) m/z 352 [M+H]⁺.

Example 25E: methyl {[3-(benzyloxy)-1-fluoro-7-methoxynaphthalen-2-yl]amino}acetate To a mixture of the product of Example 25D (30.0 g, 85 mmol) and N-fluorobenzenesulfonimide (26.9 g, 85 mmol) was added tetrahydrofuran (THF) (854 mL), and

the resulting homogeneous yellow solution was stirred at room temperature. After 90 minutes, residual oxidant was quenched by adding a solution of sodium thiosulfate pentahydrate (10.59 g, 42.7 mmol) in water (150 mL), and the mixture was stirred at room temperature for 30 minutes. Thereafter, ethyl acetate (600 mL) was added, the aqueous layer was separated, and the organic layer was washed with a solution of sodium carbonate (18.10 g, 171 mmol) in water (30 mL), followed by water:brine (1:1, 1 × 20 mL). The organic fraction was dried over sodium sulfate, filtered, and the concentrated in vacuo to afford a bright yellow/orange solid. The solids were triturated with tert-butyl methyl ether (300 mL), collected via filtration, and the filter cake (N-(phenylsulfonyl)benzenesulfonamide) was washed with tert-butyl methyl ether (2 × 100 mL). The filtrate was concentrated to afford 34.6 g of a dark red oil that was purified by flash chromatography (750 g SiO2, heptanes to 20% ethyl acetate/heptanes) to afford the title compound (16.07 g, 43.5 mmol, 51% yield) as a yellow solid. MS (APCI⁺) m/z 370 [M+H]⁺. Example 25F: methyl {[3-(benzyloxy)-1-fluoro-7-methoxynaphthalen-2-yl](sulfamoyl)amino}acetate

To a solution of chlorosulfonyl isocyanate (5.13 mL, 59.1 mmol) in dichloromethane (83 mL) at 0 °C was added tert-butanol (5.65 mL, 59.1 mmol) slowly so that the internal temperature remained less than 10 °C. After stirring for 30 minutes at 0 °C, a preformed solution of the product of Example 25E (14.55 g, 39.4 mmol) and triethylamine (10.98 mL, 79 mmol) in dichloromethane (68.9 mL) was added slowly via addition funnel so that the internal temperature remained below 10 °C. Upon complete addition, the addition funnel was rinsed with dichloromethane (23 mL). The resulting solution was stirred for 30 minutes at 0 °C, and then the reaction mixture was quenched with H₂O (20 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (2 × 30 mL). The combined organic layers were washed with brine (1 × 30 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give an orange oil. The residue was dissolved in ethyl acetate (200 mL) and washed with water:brine (1:1, 2 × 50 mL) to remove residual triethylamine hydrochloride. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give methyl {[3-(benzyloxy)-1-fluoro-7-methoxynaphthalen-2-yl][(tert-butoxycarbonyl)sulfamoyl]amino}acetate which was used without purification.

To a solution of methyl {[3-(benzyloxy)-1-fluoro-7-methoxynaphthalen-2-yl][(tert-butoxycarbonyl)sulfamoyl]amino}acetate in dichloromethane (98 mL) was added trifluoroacetic acid (45.5 mL, 591 mmol), and the resulting dark solution was stirred at room temperature. After 20 minutes, the reaction was quenched by slow addition of saturated aqueous sodium bicarbonate (691 mL) via an addition funnel. The layers were separated, and the aqueous layer was extracted with dichloromethane (2 × 50 mL). The combined organic layers were concentrated to give a dark red oil; upon addition of tert-butyl methyl ether (60 mL), a yellow solid precipitated that was collected via filtration, washed with tert-butyl methyl ether (2 × 30 mL) and dried in vacuo (15 mbar) at 35 °C to give the title compound (13.23 g, 29.5 mmol, 75% yield over two steps) as a light yellow solid. MS (ESI⁺) m/z 449 [M+H]⁺.

Example 25G: 5-(1-fluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-1λ⁶,2,5-thiadiazolidine-1,1,3-trione

To a solution of the product of Example 25F (13.23 g, 29.5 mmol) in tetrahydrofuran (THF) (355 mL) at room temperature was added solid potassium tert-butoxide (3.31 g, 29.5 mmol), and the resulting solution was stirred at room temperature. After 10 minutes, the reaction was quenched with 1 M hydrochloric acid (90 mL) and diluted with ethyl acetate (400 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2 × 120 mL). The combined organic layers were washed with brine (3 × 50 mL), then dried over sodium sulfate, filtered and concentrated. The crude 5-[3-(benzyloxy)-1-fluoro-7-methoxynaphthalen-2-yl]-1λ⁶,2,5-thiadiazolidine-1,1,3-trione was used in the subsequent reaction without further purification.

A mixture of crude intermediate, 5-[3-(benzyloxy)-1-fluoro-7-methoxynaphthalen-2-yl]-1λ⁶,2,5-thiadiazolidine-1,1,3-trione (12.28 g, 29.5 mmol) and pentamethylbenzene (13.11 g, 88 mmol) in dichloromethane (147 mL) was cooled to an internal temperature of –76 °C under an atmosphere of dry nitrogen. Subsequently, a 1 M solution of boron trichloride (59.0 mL, 59.0 mmol) in CH₂Cl₂ was added dropwise over 15 minutes, so as not to raise the internal temperature past –72 °C. Over the course of the addition, the reaction turned dark brown and became homogeneous. Incomplete conversion was observed, and additional boron trichloride (2 × 5.90 mL, 2 × 5.90 mmol) was added, resulting in full conversion. The reaction was quenched at –75 °C with CH₂Cl₂/methanol (10:1, 140 mL) via cannula transfer under nitrogen over 15 minutes, then slowly warmed to room temperature over 20 minutes under nitrogen. The volatiles were removed in vacuo to afford a brown/tan solid, which was collected by filtration, and slurried with heptanes (5 × 40 mL) and CH₂Cl₂ (3 × 40 mL). The crude solid was suspended in isopropanol (75 mL), warmed until the material dissolved, then allowed to cool slowly to room temperature over 1 hour. The solid was collected by filtration, washed with heptanes (2 × 30 mL), and dried in vacuo (15 mbar) at 60 °C to afford 5.11 g of a white solid. The mother liquor was concentrated, and the process was repeated to give an additional 1.96 g of a white solid. The batches were combined to obtain the title compound (7.07 g, 21.67 mmol, 73.5% yield over two steps). ¹H NMR (CD3OD) δ ppm 7.60 (dd, J = 9.1, 1.5 Hz, 1H), 7.25 (d, J = 2.6, 1H), 7.16 (dd, J = 9.1, 2.6 Hz, 1H), 7.04 (s, 1 H), 4.56 (s, 2H), 3.89 (s, 3 H); MS (ESI^–) m/z 325 [M–H]^–.

PATENT

WO2020186199

WO2019246513

PATENT

compound 124 [US20230019236A1]

https://patentscope.wipo.int/search/en/detail.jsf?docId=US389737555&_cid=P21-M9UYQD-14144-1

[1]. Elliot FARNEY, et al. Protein tyrosine phosphatase inhibitors and methods of use thereof. Patent WO2019246513A1.

///////Tegeprotafib, PTPN2/1-IN-1, YGY4WEM0NZ

Probenecid

April 24, 2025 3:03 am / Leave a comment

Probenecid

57-66-9
4-(Dipropylsulfamoyl)benzoic acid
Probenecid acid
Benemid

4-(dipropylsulfamoyl)benzoic acid

C₁₃H₁₉NO₄S, 285.359

HC 5006
NSC-18786

FDA APPROVED, 10/25/2024, sulopenem etzadroxil, probenecid, Orlynvah, To treat uncomplicated urinary tract infections (uUTI)
Drug Trial Snapshot

Probenecid, also sold under the brand name Probalan, is a medication that increases uric acid excretion in the urine. It is primarily used in treating gout and hyperuricemia.

Probenecid was developed as an alternative to caronamide^[1] to competitively inhibit renal excretion of some drugs, thereby increasing their plasma concentration and prolonging their effects.

Experimental Properties

Property	Value	Source
melting point (°C)	195 °C	PhysProp
water solubility	27.1 mg/L	Not Available
logP	3.21	HANSCH,C ET AL. (1995)
pKa	3.4	SANGSTER (1994)

Patent Number	Pediatric Extension	Approved	Expires (estimated)
US12109197	No	2024-10-08	2039-04-01
US11554112	No	2023-01-17	2039-04-01
US11478428	No	2022-10-25	2039-12-23
US7795243	No	2010-09-14	2029-06-03

PATENT

https://patents.google.com/patent/CN103613521A/en

At present, the production technique of probenecid mainly contains two kinds:

(1) p-methyl benzenesulfonic acid-dipropyl amine method

Take p-methyl benzenesulfonic acid as raw material, through potassium bichromate or potassium permanganate oxidation, then react generation with chlorsulfonic acid generation sulfonating chlorinating to carboxyl benzene sulfonyl chloride, amidate action occurs then in organic solvent and obtain the finished product probenecid.Reaction process route is as follows:

This technique in a large number with an organic solvent, seriously polluted; Heavy metal recovery and treatment cost are high; Chlorsulfonic acid transportation, storage and use are dangerous large, and acid mist is obvious.Along with the increasing of environmental protection pressure, people increase severely day by day to the concern of environment, and this route is substantially in end-of-life state.

(2) to methyl benzenesulfonamide-Halopropane method

To methyl benzenesulfonamide, through potassium bichromate or potassium permanganate oxidation, be P―Carboxybenzenesulfonamide, under the effect of alkali, with Halopropane generation alkylated reaction, after acidifying, obtain probenecid.Reaction process route is as follows:

Figure 201310587646X100002DEST_PATH_IMAGE003

This process using sodium dichromate 99 or potassium permanganate oxidation are to methyl benzenesulfonamide, and yield is on the low side (lower than 50%).In addition, the waste water that contains chromium or manganese is difficult to dispose, and these have all seriously restricted further developing of this technique.

Reaction scheme of the present invention is as follows:

Figure 201310587646X100002DEST_PATH_IMAGE004

embodiment 1

(1) diazotization reaction

Get 68.6g para-amino benzoic acid (0.5mol), 250g water and 127.4ml hydrochloric acid (31%, 1.25mol) join in 2000ml there-necked flask, in ice-water bath, stir, be cooled to 0-5 ℃, drip sodium nitrite solution (34.5g Sodium Nitrite, 0.5mol, be dissolved in 190g water), control temperature at 10-20 ℃, it is 4 hours that time for adding is controlled, after dropping finishes, at this temperature, continue reaction 1 hour, obtain diazotization reaction liquid.

(2) sulfonating chlorinating reaction

In 5000ml there-necked flask, add 250g water, 765ml hydrochloric acid (31%, 7.5mol), in ice-water bath, stir, be cooled to-5 ℃, start to pass into liquid sulfur dioxide, control temperature at-3–1 ℃, when passing into 64g sulfurous gas (1mol), sulfurous gas absorbs complete, obtains sulfonating chlorinating reagent.

In sulfonating chlorinating reagent, add diazotization reaction liquid, adding the time control of diazotization reaction liquid is 5 hours, is warming up to gradually 5-10 ℃, continues reaction 8 hours at this temperature; Filtration obtains 121g to carboxyl benzene sulfonyl chloride.

(3) synthetic probenecid reaction

In 1000ml there-necked flask, add 350g water, 152g dipropyl amine (1.5mol), open and stir, when temperature is greater than 15 ℃, start to divide gradually 40 batches add step (2) gained to carboxyl benzene sulfonyl chloride, temperature control 40-50 ℃, adds and at this temperature, stirs 3 hours continuing after carboxyl benzene sulfonyl chloride.Drip hydrochloric acid (31%), regulate pH value to 2-3, continue to stir 1 hour.Filter, obtain 135g probenecid crude product, put in 500ml pure water, agitator treating 1 hour, heavy 122.8g after filtering, being dried, yield 86.2%(is in para-amino benzoic acid), purity 98.2%.

embodiment 2

(1) diazotization reaction

Get 68.6g para-amino benzoic acid (0.5mol), 250g water and 152.9ml hydrochloric acid (31%, 1.5mol) join in 2000ml there-necked flask, in ice-water bath, stir, be cooled to 0-5 ℃, drip sodium nitrite solution (36.0g Sodium Nitrite, 0.52mol, be dissolved in 190g water), control temperature at 0-10 ℃, it is 3 hours that time for adding is controlled, after dropping finishes, at this temperature, continue reaction 1 hour, obtain diazotization reaction liquid.

(2) sulfonating chlorinating reaction

In 5000ml there-necked flask, add 250g water, 887ml hydrochloric acid (31%, 8.7mol), in ice-water bath, stir, be cooled to-5 ℃, start to pass into liquid sulfur dioxide, control temperature at 0-5 ℃, when passing into 112g sulfurous gas (1.75mol), sulfurous gas absorbs complete, obtains sulfonating chlorinating reagent.

In sulfonating chlorinating reagent, add diazotization reaction liquid, adding the time control of diazotization reaction liquid is 4 hours, is warming up to gradually 5-15 ℃, continues reaction 5 hours at this temperature; Filtration obtains 150g to carboxyl benzene sulfonyl chloride.

(3) synthetic probenecid reaction

In 1000ml there-necked flask, add 350g water, 192g dipropyl amine (1.9mol), open and stir, when temperature is greater than 15 ℃, start to divide gradually 35 batches add step (2) gained to carboxyl benzene sulfonyl chloride, temperature control 40-50 ℃, adds and at this temperature, stirs 2 hours continuing after carboxyl benzene sulfonyl chloride.Drip hydrochloric acid (31%), regulate pH value to 2-3, continue to stir 1 hour.Filter, obtain 155.4g probenecid crude product, put in 500ml pure water, agitator treating 1 hour, heavy 129.5g after filtering, being dried, yield 90.9%(is in para-amino benzoic acid), purity 98.7%.

embodiment 3

(1) diazotization reaction

Get 68.6g para-amino benzoic acid (0.5mol), 250g water and 203.9ml hydrochloric acid (31%, 2mol) join in 2000ml there-necked flask, in ice-water bath, stir, be cooled to-10–5 ℃, drip sodium nitrite solution (38.0g Sodium Nitrite, 0.55mol, be dissolved in 190g water), control temperature at 0-10 ℃, it is 5 hours that time for adding is controlled, after dropping finishes, at this temperature, continue reaction 1 hour, obtain diazotization reaction liquid.

(2) sulfonating chlorinating reaction

In 5000ml there-necked flask, add 250g water, 968ml hydrochloric acid (31%, 9.5mol), in ice-water bath, stir, be cooled to-5 ℃, start to pass into liquid sulfur dioxide, control temperature at 5-10 ℃, when passing into 160g sulfurous gas (2.5mol), sulfurous gas absorbs complete, obtains sulfonating chlorinating reagent.

In sulfonating chlorinating reagent, add diazotization reaction liquid, adding the time control of diazotization reaction liquid is 3 hours, is warming up to gradually 10-15 ℃, continues reaction 20 hours at this temperature; Filtration obtains 146.7g to carboxyl benzene sulfonyl chloride, needn’t be dried, and directly enters next step reaction.

(3) synthetic probenecid reaction

In 1000ml there-necked flask, add 350g water, 202g dipropyl amine (2mol), open to stir, when temperature is greater than 30 ℃, start to divide gradually 30 batches add step (2) gained to carboxyl benzene sulfonyl chloride, temperature control 40-50 ℃, adds and at this temperature, stirs 4 hours continuing after carboxyl benzene sulfonyl chloride.Drip hydrochloric acid (31%), regulate pH value to 2-3, continue to stir 1 hour.Filtration obtains 151.7g probenecid crude product, puts in 500ml pure water, and agitator treating 1 hour, heavy 128.5g after filtering, being dried, yield 90.2%(is in para-amino benzoic acid), purity 98.8%.Medical uses

Probenecid is primarily used to treat gout and hyperuricemia.

Probenecid is sometimes used to increase the concentration of some antibiotics and to protect the kidneys when given with cidofovir. Specifically, a small amount of evidence supports the use of intravenous cefazolin once rather than three times a day when it is combined with probenecid.^[2]

It has also found use as a masking agent,^[3] potentially helping athletes using performance-enhancing substances to avoid detection by drug tests.

Adverse effects

Mild symptoms such as nausea, loss of appetite, dizziness, vomiting, headache, sore gums, or frequent urination are common with this medication. Life-threatening side effects such as thrombocytopenia, hemolytic anemia, leukemia and encephalopathy are extremely rare.^[4] Theoretically probenecid can increase the risk of uric acid kidney stones.

Drug interactions

Some of the important clinical interactions of probenecid include those with captopril, indomethacin, ketoprofen, ketorolac, naproxen, cephalosporins, quinolones, penicillins, methotrexate, zidovudine, ganciclovir, lorazepam, and acyclovir. In all these interactions, the excretion of these drugs is reduced due to probenecid, which in turn can lead to increased concentrations of these.^[5]

Pharmacology

Pharmacodynamics

In gout, probenecid competitively inhibits the reabsorption of uric acid through the organic anion transporter (OAT) at the proximal tubules. This leads to preferential reabsorption of probenecid back into plasma and excretion of uric acid in urine,^[6] thus reducing blood uric acid levels and reducing its deposition in various tissues.

Probenecid also inhibits pannexin 1.^[7] Pannexin 1 is involved in the activation of inflammasomes and subsequent release of interleukin-1β causing inflammation. Inhibition of pannexin 1 thus reduces inflammation, which is the core pathology of gout.^[7]

Pharmacokinetics

In the kidneys, probenecid is filtered at the glomerulus, secreted in the proximal tubule and reabsorbed in the distal tubule. Probenicid lowers the concentration of certain drugs in urine drug screens by reducing renal excretion of these drugs.

Historically, probenecid has been used to increase the duration of action of drugs such as penicillin and other beta-lactam antibiotics. Penicillins are excreted in the urine at proximal and distal convoluted tubules through the same organic anion transporter (OAT) as seen in gout. Probenecid competes with penicillin for excretion at the OAT, which in turn increases the plasma concentration of penicillin.^[8]

History

During World War II, probenecid was used to extend limited supplies of penicillin. This use exploited probenecid’s interference with drug elimination (via urinary excretion) in the kidneys and allowed lower doses of penicillin to be used.^[9]

Probenecid was added to the International Olympic Committee‘s list of banned substances in January 1988, due to its use as a masking agent.^[10]

References

^ Mason RM (June 1954). “Studies on the effect of probenecid (benemid) in gout”. Annals of the Rheumatic Diseases. 13 (2): 120–130. doi:10.1136/ard.13.2.120. PMC 1030399. PMID 13171805.
^ Cox VC, Zed PJ (March 2004). “Once-daily cefazolin and probenecid for skin and soft tissue infections”. The Annals of Pharmacotherapy. 38 (3): 458–463. doi:10.1345/aph.1d251. PMID 14970368. S2CID 11449580.
^ Morra V, Davit P, Capra P, Vincenti M, Di Stilo A, Botrè F (December 2006). “Fast gas chromatographic/mass spectrometric determination of diuretics and masking agents in human urine: Development and validation of a productive screening protocol for antidoping analysis”. Journal of Chromatography A. 1135 (2): 219–229. doi:10.1016/j.chroma.2006.09.034. hdl:2318/40201. PMID 17027009. S2CID 20282106.
^ Kydd AS, Seth R, Buchbinder R, Edwards CJ, Bombardier C (November 2014). “Uricosuric medications for chronic gout”. The Cochrane Database of Systematic Reviews (11): CD010457. doi:10.1002/14651858.CD010457.pub2. PMC 11262558. PMID 25392987.
^ Cunningham RF, Israili ZH, Dayton PG (March–April 1981). “Clinical pharmacokinetics of probenecid”. Clinical Pharmacokinetics. 6 (2): 135–151. doi:10.2165/00003088-198106020-00004. PMID 7011657. S2CID 24497865.
^ “Probenecid”. PubChem. U.S. National Library of Medicine. Retrieved 2022-06-12.
^ Jump up to:^a ^b Silverman W, Locovei S, Dahl G (September 2008). “Probenecid, a gout remedy, inhibits pannexin 1 channels”. American Journal of Physiology. Cell Physiology. 295 (3): C761 – C767. doi:10.1152/ajpcell.00227.2008. PMC 2544448. PMID 18596212.
^ Ho RH (January 2010). “4.25 – Uptake Transporters”. In McQueen CA, Kim RB (eds.). Comprehensive Toxicology (Second ed.). Oxford: Elsevier. pp. 519–556. doi:10.1016/B978-0-08-046884-6.00425-5. ISBN 978-0-08-046884-6.
^ Butler D (November 2005). “Wartime tactic doubles power of scarce bird-flu drug”. Nature. 438 (7064): 6. Bibcode:2005Natur.438….6B. doi:10.1038/438006a. PMID 16267514.
^ Wilson W, Derse E, eds. (2001). Doping in Elite Sport: The Politics of Drugs in the Olympic Movement. Human Kinetics. p. 86. ISBN 0-7360-0329-0.

Clinical data


Trade names	Probalan
AHFS/Drugs.com	Monograph
MedlinePlus	a682395
Routes of administration	By mouth
ATC code	M04AB01 (WHO)
Legal status
Legal status	In general: ℞ (Prescription only)
Pharmacokinetic data
Protein binding	75-95%
Elimination half-life	2-6 hours (dose: 0.5-1 g)
Excretion	kidney (77-88%)
Identifiers
showIUPAC name
CAS Number	57-66-9
PubChem CID	4911
IUPHAR/BPS	4357
DrugBank	DB01032
ChemSpider	4742
UNII	PO572Z7917
KEGG	D00475
ChEMBL	ChEMBL897
CompTox Dashboard (EPA)	DTXSID9021188
ECHA InfoCard	100.000.313
Chemical and physical data
Formula	C₁₃H₁₉NO₄S
Molar mass	285.36 g·mol⁻¹
3D model (JSmol)	Interactive image
showSMILES
showInChI

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