Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
  • A61P25/36—Opioid-abuse
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
  • C07D471/14—Ortho-condensed systems

Definitions

• the invention relates to the use of particular substituted heterocycle fused gammacarbolines, in free or pharmaceutically acceptable salt and/or substantially pure form as described herein, pharmaceutical compositions thereof, for the treatment and/or prevention of fentanyl-analog induced overdose and related sequelae.
• Substituted heterocycle fused gamma-carbolines are known to be agonists or antagonists of 5-HT2 receptors, particularly 5-HT2A receptors, in treating central nervous system disorders. These compounds have been disclosed, for example, in U.S. Pat. No. 6,552,017; 7,183,282; and RE39680, as novel compounds useful for the treatment of disorders associated with 5-HT2A receptor modulation such as anxiety, depression, and psychosis.
• U.S. Patent 7,081,455 discloses other gamma-carbolines as serotonin agonists and antagonists useful for the control and prevention of central nervous system disorders such as addictive behavior and sleep disorders.
• Patent 8,598,119 discloses use of particular substituted heterocycle fused gamma-carbolines for the treatment of a combination of psychosis and depressive disorders as well as sleep, depressive and/or mood disorders in patients with psychosis or Parkinson's disease.
• U.S. Patent 8,309,722 discloses methods of making substituted heterocycle fused gamma-carbolines.
• U.S. Patent 8,648,077 also discloses methods of preparing toluenesulfonic acid addition salt crystals of these substituted heterocycle fused gamma-carbolines.
• BDNF brain-derived neurotrophic factor
• mTORCl kinase pathways Several downstream effects involve the brain-derived neurotrophic factor (BDNF) and mTORCl kinase pathways. Similar to ketamine, recent evidence suggests that compounds related to those of the present disclosure enhance both NMDA and AMPA-induced currents in rat medial prefrontal cortex pyramidal neurons via activation of DI receptors, and that this is associated with increased mTORCl signaling.
• BDNF brain-derived neurotrophic factor
• U.S. Patents 10,245,260, and 10,799,500 disclose additional novel fused heterocycle gamma carbolines, which, in addition to providing serotonin receptor inhibition, SERT inhibition, and dopamine receptor modulation, were also unexpectedly found to show significant activity at mu- opioid receptors.
• Analogs of these novel compounds have also been disclosed, for example, in publications U.S. Patents 10,961,245 and 10,906,906, and 11,376,249, and 11,427,587, and in publication US 2021/0163481, the contents of each of which are incorporated by reference in their entireties.
• the indications disclosed in these publications are, generally, the treatment of pain, neuropathic pain, and chronic pain.
• the Compound of Formula A is a potent serotonin 5-HT2A receptor antagonist and mu-opioid receptor partial, biased agonist. This compound also interacts with dopamine receptors, in particular dopamine DI receptors.
• dopamine receptors in particular dopamine DI receptors.
• the Compound of Formula A via its DI receptor activity, may also enhance NMDA and AMP A mediated signaling through the mTOR pathway.
• the Compound of Formula A is thus useful for the treatment or prophylaxis of central nervous system disorders, including opioid addiction, such as opioid use disorder, and for the treatment of pain disorders, such as chronic pain and neuropathic pain.
• the compound of Formula A, and related compounds are particularly useful because of their property of biased mu-opioid receptor activity.
• the intracellular domain of an activated mu opioid receptor can interact either with inhibitory G proteins or with beta-arrestin.
• the binding of a non-biased agonist to the mu-opioid receptor will result in approximately equal activation of both G-protein signaling and beta-arrestin signaling.
• a biased agonist binds to a mu opioid receptor, it binds in such a way as to bias the intracellular domain of the receptor to interact with the G protein instead of the betaarrestin.
• the compound of Formula A, and related compounds act as partial or full agonists of the mu-opioid receptor’s G-protein coupled signaling, but as an antagonist of the receptor’s betaarrestin signaling. This is in contrast to traditional opioid agonists, such as morphine and fentanyl, which tend to strongly activate both G-protein signaling and beta-arrestin signaling pathways.
• beta-arrestin signaling by such drugs is thought to mediate the gastrointestinal dysfunction, addiction, and respiratory depression effects typically mediated by opioid drugs, while the analgesic and anesthetic effects of mu-opioid receptor agonists are mediated by the G-protein signaling pathway.
• biased agonists antagonize the beta-arrestin pathway
• they are known to be generally useful in treating opioid overdose — by reversing the respiratory depression caused by the opioid. Beneficially, however, they will do so while still providing pain relief.
• Biased beta-arrestin antagonists are expected to be useful in treating opioid overdose, because they will inhibit the most severe opioid adverse effects but still provide pain relief.
• the United States is currently in the throes of a widespread opioid abuse epidemic that began in the late 1990’s and is fueled by a combination of overprescribed prescription opioids (such as oxycodone, sold as OxyContin by Purdue Pharma), cheap imported illicit heroin, and a combination of licit and illicit fentanyl.
• fentanyl was the first and most prominent of a newer class of synthetic opioids. Unlike the natural and semi-synthetic opioids, fentanyl and fentanyl analogs do not have the complete classic pentacyclic core skeleton of morphine. Instead, fentanyl and fentanyl analogs share a common 4-aminophenyl(piperidine) core. The most common fentanyl analogs are sufentanil, alfentanil, remifentanil, and carfentanil:
• Fentanyl and its analogs are substantially more potent than both morphine and heroin, due to either stronger mu-opioid receptor binding, higher lipophilicity, or both.
• Fentanyl is generally considered about 50 times more potent than heroin and 100 times more potent than morphine (some sources indicate it as 150 times more potent than morphine).
• Sufentanil is considered 5 to 10 times more potent than fentanyl, and carfentanil about 100 times more potent than fentanyl (and thus 10,000 times more potent than morphine).
• fentanyl-induced overdose is much more difficult to treat than morphine, heroin or oxycodone overdose.
• Fentanyl has an extraordinarily rapid onset of action, which makes reversal via mu-receptor antagonist (e.g., naloxone or naltrexone) treatment difficult in the outpatient setting (response time for EMS or police often being longer than the time for severe respiratory depression to develop).
• mu-receptor antagonists are also required to reverse fentanyl overdose, and there are limits on the rate and dose of mu-opioid antagonists that can be safely administered. While morphine takes an average of 19 minutes to reach 80% of peak effect, fentanyl produces severe respiratory depression much more rapidly.
• fentanyl and its analogs have an additional mechanism of action that has become extremely important in the ongoing opioid epidemic. While all opioids cause respiratory depression via mu-opioid receptor activation of the beta-arrestin signaling pathway in the brain, for reasons that are not yet entirely clear, fentanyl and its analogs can also cause a rapid combination of vocal cord closure (laryngospasm) and severe muscle rigidity in the chest wall and diaphragm. This can result from intravenous, transdermal, or inhalational administration of fentanyl and fentanyl analogs. Neither morphine, heroin, nor any other opioids having the classic morphine skeleton have this property.
• fentanyl-induced respiratory muscle rigidity FIRMR
• FIMR fentanyl-induced respiratory muscle rigidity
• WCS wooden chest syndrome
• Laryngospasm is defined as the involuntary closure or occlusion of the glottic opening, and this is controlled by the intrinsic muscles of the larynx. These muscles are innervated by both sympathetic (adrenergic) and parasympathetic (cholinergic) nerve fibers, and the ultimate activity of these muscles is thus determined by the balance of sympathetic and parasympathetic input.
• naloxone Unfortunately, however, high doses of naloxone are not practical for therapeutic use because the rapid injection of as little as 0.4 mg of naloxone (0.0057 mg/kg for a 70 kg adult) in active opioid users commonly results in laryngospasm, pulmonary edema, hemodynamic instability, and cardiac anythmia (all due to catecholamine release). High-dose naloxone treatment is therefore contraindicated, especially in the field. Thus, in the field — without additional medical and pharmacological support — it is normally quite difficult, if not impossible to, to use naloxone to reverse fentanyl-induced overdose before it becomes fatal.
• WCS is not simply the result of mu-opioid receptor agonism — since other powerful mu-opioid agonists do not cause WCS (e.g., morphine), and since powerful mu-opioid antagonists (e.g., naloxone) do not reverse WCS at normal dose ranges. Thus, fentanyl and its analogs must cause WCS by some other mechanism which involves other neurotransmitter systems. [00023] There is evidence, both from in vitro studies and from various animal models, which indicates that fentanyl exerts these effects via the stimulation of noradrenergic activity, and possibly cholinergic activity, in the locus coeruleus (LC) region of the brain.
• LC locus coeruleus
• fentanyl acts as an agonist of mu-opioid receptors, and the resulting hyperpolarization of the LC neuron results in efferent noradrenergic neuron activity, specifically, in coerulospinal fibers connected to spinal motor neurons terminating in the chest wall and abdomen, as well as laryngeal nerve fibers contributing to the vagal nerve via the superior cervical and middle cervical ganglia.
• These laryngeal nerve fibers directly innervate the intrinsic muscles of the larynx.
• GABA interneurons are part of an inhibitory network throughout the brain, and they are particularly abundant in the LC.
• the LC is responsible for maintaining basal skeletal muscle tone in the torso via the noradrenergic activation of spinal motor neurons, but norepinephrine release from the LC presynaptic terminals is inhibited by the GABA efferent signaling. Inhibition of the GABA interneurons, therefore, results in increased skeletal muscle tone via increased LC noradrenergic activity.
• fentanyl binds to mu- opioid receptors on GABA interneurons, and that this results in inhibition of GABA interneuron afferents, resulting in release of the inhibition on LC sympathetic neurons.
• LC neurons are also high in muscarinic and nicotinic acetylcholine receptors. It is believed that as the LC receives cholinergic input from other brain regions, such as the pontine reticular formation, fentanyl-induced mu-receptor agonism in these neighboring regions may stimulate acetylcholine release, which results in further stimulation of norepinephrine release by the LC. There is also some evidence that fentanyl acts directly as an M3 muscarinic receptor antagonist, which may result in inhibition of parasympathetic tone at the laryngeal intrinsic muscles, further increasing the spasm resulting from sympathetic activation of these muscles.
• NMDA and non-NMDA glutamate receptor activity has also been implicated in the pathogenesis of WCS.
• fentanyl but not morphine, has some activity as a norepinephrine reuptake inhibitor. It has been shown in various neural cell lines that this effect is not antagonized by naloxone, indicating that it is not an indirect effect of mu-receptor agonism. Thus, it is also possible that fentanyl is exerting a direct effect on neurons in the LC and stimulating hyperactivity of the muscles involved in FIMR and WCS.
• Fentanyl analogs include, but are not limited to, the compounds sufentanil, alfentanil, remifentanil, carfentanil, as well as derivatives of these compounds, as further explained herein.
• Fentanyl and fentanyl analogs are collectively referred to herein as “F/FA.”
• the present disclosure provides a method for one or more of the following:
• anesthetic recovery (e.g., following surgery); the method comprising administering to a patient in need thereof an effective amount of a Compound of Formula I, or a pharmaceutical composition thereof, wherein the Compound of Formula I is: wherein:
• R 1 is H, Ci-6alkyl, -C(O)-O-C(R a )(R b )(R c ), -C(O)-O-CH2-O-C(R a )(R b )(R c ) or -C(R 6 )(R 7 )-O- C(O)-R 8 ;
• R 2 and R 3 are independently selected from H, D, C1-6alkyl (e.g., methyl), Ci-6alkoxy (e.g., methoxy), halo (e.g., F), cyano, or hydroxy;
• L is C1-6alkylene (e.g., ethylene, propylene, or butylene), Ci-6alkoxy (e.g., propoxy or butoxy), C2-3alkoxyCi-3alkylene (e.g., CH2CH2OCH2), Ci-6alkylamino or/V-Ci-6alkyl Ci- 6alkylamino (e.g., propylamino or N-methylpropylamino), Ci-6alkylthio (e.g., - CH2CH2CH2S-), C1-6alkylsulfonyl (e.g., -CH2CH2CH2S(O)2-), each of which is optionally substituted with one or more R 4 moi eties; each R 4 is independently selected from C 1-6 alkyl (e.g., methyl), C1-6alkoxy (e.g., methoxy), halo (e.g., F), cyano, or hydroxy;
• R 4 is independently selected from C
• Z is selected from aryl (e.g., phenyl) and heteroaryl (e.g., pyridyl, indazolyl, benzimidazolyl, benzisoxazolyl), wherein said aryl or heteroaryl is optionally substituted with one or more R 4 moieties;
• aryl e.g., phenyl
• heteroaryl e.g., pyridyl, indazolyl, benzimidazolyl, benzisoxazolyl
• R 8 is -C(R a )(R b XR c ), -O-C(R a )(R b XR c ), or -N(R d )(R e );
• R a , R b and R c are each independently selected from H and Ci-24alkyl;
• R d and R e are each independently selected from H and Ci-24alkyl
• R 6 and R 7 are each independently selected from H, Ci-6alkyl, carboxy and Ci- ealkoxy carbonyl; in free or salt form (e.g., pharmaceutically acceptable salt form), for example in an isolated or purified free or salt form (e.g., pharmaceutically acceptable salt form).
• the present disclosure further provides use of a Compound of the present disclosure, e.g., a Compound of Formula I, in the manufacture of a medicament for the methods disclosed herein.
• the present disclosure further provides a Compound of the present disclosure, e.g., a Compound of Formula I, for use in the methods disclosed herein.
• the present disclosure provides a method for one or more of the following:
• anesthetic recovery (e.g., following surgery); the method comprising administering to a patient in need thereof an effective amount of a Compound of Formula I, or a pharmaceutical composition comprising a Compound of Formula I, wherein the Compound of Formula I is: wherein:
• R 1 is H, C1-6alkyl, -C(O)-O-C(R a )(R b )(R c ), -C(0)-0-CH2-0-C(R a )(R b )(R c ) or -C(R 6 )(R 7 )-O- C(O)-R 8 ;
• R 2 and R 3 are independently selected from H, D, C1-6alkyl (e.g., methyl), C1-6alkoxy (e.g., methoxy), halo (e.g., F), cyano, or hydroxy;
• L is C1-6alkylene (e.g., ethylene, propylene, or butylene), C1-6alkoxy (e.g., propoxy or butoxy), C2-3alkoxyCi-3alkylene (e.g., CH2CH2OCH2), C1-6alkylamino or N-C1-6alkyl C16 6alkylamino (e.g., propylamino or N-methylpropylamino), C1-6alkylthio (e.g., - CH2CH2CH2S-), C1-6alkylsulfonyl (e.g., -CH2CH2CH2S(O)2-), each of which is optionally substituted with one or more R 4 moi eties; each R 4 is independently selected from C 1-6 alkyl (e.g., methyl), C1-6alkoxy (e.g., methoxy), halo (e.g., F), cyano, or hydroxy;
• R 4 is independently selected from C 1-6 al
• Z is selected from aryl (e.g., phenyl) and heteroaryl (e.g., pyridyl, indazolyl, benzimidazolyl, benzisoxazolyl), wherein said aryl or heteroaryl is optionally substituted with one or more R 4 moieties;
• R 8 is -C(R a )(R b XR c ), -O-C(R a )(R b XR c ), or -N(R d )(R e );
• R a , R b and R c are each independently selected from H and Ci-24alkyl;
• R d and R e are each independently selected from H and Ci-24alkyl
• R 6 and R 7 are each independently selected from H, C1-6alkyl, carboxy and Ci- 6alkoxy carbonyl; in free or salt form (e.g., pharmaceutically acceptable salt form), for example in an isolated or purified free or salt form (e.g., pharmaceutically acceptable salt form).
• Method 1 including:
• R 1 is C1-6alkyl, e.g., methyl
• R a is H and R b and R c are each independently selected from Ci-24alkyl, e.g., C1-2oalkyl, C5-2oalkyl, C9-18alkyl, C10- realkyl, or Cualkyl, Cualkyl, Cualkyl, Ci4alkyl, C15alkyl or Cualkyl;
• R a and R b are H and R c is Ci- 24alkyl, e.g., C1-2oalkyl, C5-20alkyl, C9-18alkyl, C10-16alkyl, or C11alkyl, Cualkyl, Cualkyl, Cualkyl, Cisalkyl or C16alkyl;
• R a , R b and R c are each independently selected from Ci-24alkyl, e.g., C1-20alkyl, C5-20alkyl, C9-18lkyl, Cio- ualkyl, or Cualkyl, Cualkyl, Cualkyl, Ci4alkyl, salkyl or C16alkyl;
• R a is H and R b and R c are each independently selected from C1-24alkyl, e.g., C1-20alkyl, C5-20alkyl, C9-18alkyl, Cio- ualkyl, or Cualkyl, Cualkyl, Cualkyl, Ci4alkyl, C15alkyl or Cualkyl;
• R a is H and R b and R c are each independently selected from C1-24alkyl, e.g., C1-20alkyl, C5-2oalkyl, C9- 18alkyl, Cio-iealkyl, or Cualkyl, Cualkyl, Cualkyl, Ci4alkyl, Cisalkyl or Ciealkyl;
• R a and R b are H and R c is C1-24alkyl, e.g., C1-20alkyl, C5-20alkyl, C9-18alkyl, Cio-iealkyl, or Cualkyl, Cualkyl, Cualkyl, Cualkyl, Cisalkyl or Ciealkyl;
• R a , R b and R c are each independently selected from C1-24alkyl, e.g., C1-20alkyl, C5-20alkyl, C9-18alkyl, C10- 16alkyl, or Cualkyl, Cualkyl, Cualkyl, Ci4alkyl, Cisalkyl or Ciealkyl;
• R d is H and R e is independently selected from C1-24alkyl, e.g., C1-20alkyl, C5-20alkyl, C9-18alkyl, C10-16alkyl, or Cualkyl, Cualkyl, Cualkyl, Cualkyl, Cisalkyl or C16alkyl;
• R d and R e are each independently selected from C16alkyl, e.g., C1-20alkyl, C5-2oalkyl, C9-18alkyl, C10- 16alkyl, or Cualkyl, Cualkyl, Cualkyl, Ci4alkyl, Cisalkyl or Ciealkyl;
• L is Ci- ealkylene (e.g., ethylene, propylene, or butylene), C1-6alkoxy (e.g., propoxy), C2- 3alkoxyCi-3alkylene (e.g., CH2CH2OCH2) C1-6alkylamino (e.g., propylamino orN- methylpropylamino), or C1-6alkylthio (e.g., -CH2CH2CH2S-), optionally substituted with one or more R 4 moieties;
• Ci- ealkylene e.g., ethylene, propylene, or butylene
• C1-6alkoxy e.g., propoxy
• C2- 3alkoxyCi-3alkylene e.g., CH2CH2OCH2
• C1-6alkylamino e.g., propylamino orN- methylpropylamino
• C1-6alkylthio e.g., -CH2CH2CH
• L is unsubstituted C1-6alkylene (e.g., ethylene, propylene, or butylene);
• L is C1-6alkylene (e.g., ethylene, propylene, or butylene), substituted with one or more R 4 moieties;
• L is C1-6alkoxy (e.g., propoxy or butoxy), substituted with one or more R 4 moieties;
• Method 1 or any of 1.1-1.40, wherein in the compound of Formula I, L is -(CH2)n- X-, and wherein n is an integer selected from 2, 3, and 4, and X is selected from -O-, -S-, -NH-, -N(Ci ⁇ alkyl)-, and CH2;
• Method 1.41 wherein in the compound of Formula I, L is -(CH2)n-X-, and wherein n is 3, and X is selected from -O-,-S-, -NH- and -N(Ci -ealkyl)- (e.g., -N(CH3)-);
• Z is phenyl substituted with one R 4 moiety selected from halo (e.g., fluoro, chloro, bromo or iodo) and cyano (e.g., Z is 4-fluorophenyl, or 4-chlorophenyl, or 4-cyanophenyl);
• Method I or any of 1.1-1.44, wherein in the compound of Formula I, Z is heteroaryl (e.g., pyridyl, indazolyl, benzimidazolyl, benzisoxazolyl), optionally substituted with one or more R 4 moieties; 1.53 Method 1.52, wherein in the compound of Formula I, said heteroaryl is a monocyclic 5-membered or 6-membered heteroaryl (e.g., pyridyl, pyrimidyl, pyrazinyl, thiophenyl, pyrrolyl, furanyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl);
• heteroaryl e.g., pyridyl, indazolyl, benzimidazolyl, benzisoxazolyl
• said heteroaryl is a monocyclic 5-membered or 6-membered heteroaryl (e.g., pyri
• said heteroaryl is a bicyclic 9- membered or 10-membered heteroaryl (e.g., indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, benzodioxolyl, 2-oxo-tetrahydroquinolinyl);
• indolyl isoindolyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, benzodioxolyl,
• Method 1 or any of 1.1-1.70, wherein the compound of Formula I is in isolated or purified form (e.g., in at least 90% pure form, or at least 95% or at least 98% or at least 99%);
• Method 1.72 wherein the compound of Formula I is in pharmaceutically acceptable salt form in admixture with a pharmaceutically acceptable diluent or carrier;
• compositions 1.72-1.74 wherein the pharmaceutical composition is formulated for single dose administration (e.g., tablets, capsules, wafers, single-use injections, single-use ampules or vials for intranasal administration, single use ampules or vials for injection, single use intranasal sprays);
• single dose administration e.g., tablets, capsules, wafers, single-use injections, single-use ampules or vials for intranasal administration, single use ampules or vials for injection, single use intranasal sprays
• compositions 1.72-1.75 wherein the pharmaceutical composition is in the form of a tablet, capsule or wafer (e.g., an oral, sublingual, or buccal tablet, capsule, or wafer);
• Method 1.76 wherein the pharmaceutical composition is a rapidly-dissolving oral tablet (e.g., a rapidly dissolving sublingual tablet);
• Methods 1.72-1.75 wherein the pharmaceutical composition is formulated for intranasal or intrapulmonary administration (e.g., as an aerosol, mist, or powder for inhalation); 1.79 Any of Methods 1.72-1.75, wherein the pharmaceutical composition is formulated for administration by injection, for example, as a sterile aqueous solution, e.g., for intravenous, subcutaneous, or intramuscular injection;
• Method 1.79 wherein the pharmaceutical composition is formulated for intravenous, intrathecal, intramuscular, subcutaneous or intraperitoneal injection.
• Methods 1.72 to 1.80 wherein the pharmaceutical composition is formulated for and/or packaged as a pre-filled syringe for injection, as an auto-injector, or as a sterile solution in a vial for injection or intranasal administration.
• kits for administration by the general public e.g., a single-use take-home kit, such as for drug abusers, family members and friends of drug-abusers, and for public venues, such as places of worship, community centers, sporting event venues).
• Compound of the present disclosure refers any of the compounds described in Method 1 or the compounds described in any of the embodiments of Methods 1.1 to 1.71.
• Fentanyl and fentanyl analogs are collectively referred to herein as “F/FA.”
• Fentanyl analogs include all chemical compounds recognized as-such by the U.S. Drug Enforcement Administration and/or by the United Nations Office on Drug and Crime (UNODC).
• F/FA compounds include, but are not limited to: fentanyl, alpha-methylfentanyl, 3 -methylfentanyl, acetylfentanyl (also known as desmethylfentanyl), acetyl-alpha-methylfentanyl, thiofentanyl, alpha- methylthiofentanyl, beta-hydroxyfentanyl, para-fluorofentanyl, beta-hydroxy-3 -methylthiofentanyl, beta-hydroxythiofentanyl, butyrylfentanyl, furanylfentanyl, 4-fluoroisobutyrylfentanyl, 4- fluorobutyrylfentanyl, 4-methoxybutyrylfentanyl, 4-methylbutyrylfentanyl, acrylfentanyl, 4- chloroisobutyrylfentanyl, tetrahydrofuranylfentanyl, cyclopentylfentanyl, valerylfentanyl, methoxyacetylfentany
• F/FA also include all drug compositions or mixtures containing any F/FA compound, such as morphine, heroin, codeine, hydrocodone, oxycodone, hydromorphone, marijuana or cannabis products, tetrahydrocannabinol, cocaine, amphetamine, methamphetamine, methylenedioxymethamphetamine, alprazolam, or other illicit or licit drugs, contaminated with or mixed with any F/FA compound described herein.
• any F/FA compound such as morphine, heroin, codeine, hydrocodone, oxycodone, hydromorphone, marijuana or cannabis products, tetrahydrocannabinol, cocaine, amphetamine, methamphetamine, methylenedioxymethamphetamine, alprazolam, or other illicit or licit drugs, contaminated with or mixed with any F/FA compound described herein.
• Method 1 or any of Methods 1.1-1.84, wherein the patient is suspected of suffering from an acute F/FA overdose;
• Method 1 or any of Methods 1.1-1.88, wherein the patient is diagnosed with or suspected or having wooden chest syndrome (WCS);
• Method 1 or any of Methods 1.1-1.88, wherein the patient is diagnosed with or suspected or having fentanyl-induced muscle rigidity (FIMR) or fentanyl-induced respiratory muscle rigidity (FIRMR) (wherein said FIMR or FIRMR is caused by fentanyl or by a fentanyl analog);
• FIMR fentanyl-induced muscle rigidity
• FIRMR fentanyl-induced respiratory muscle rigidity
• Method 1 or any of Methods 1.1-1.90, wherein the patient is in a non-hospital or nonemergency clinic setting;
• Method 1 or any of Methods 1.1-1.91, wherein the patient is suspected of suffering from opioid use disorder, or has a history of opioid use disorder;
• Method 1 or any of Methods 1.1-1.92, wherein the patient is suspected of being a naive opioid user;
• Method 1 or any of Methods 1.1-1.93, wherein the patient has, or is suspected of having, overdosed on a licit or illicit drug contaminated with or admixed with F/FA (e.g., morphine, heroin, codeine, hydrocodone, oxycodone, hydromorphone, marijuana or cannabis products, tetrahydrocannabinol, cocaine, amphetamine, methamphetamine, methylenedioxymethamphetamine, alprazolam, or other illicit or licit drugs);
• F/FA e.g., morphine, heroin, codeine, hydrocodone, oxycodone, hydromorphone, marijuana or cannabis products, tetrahydrocannabinol, cocaine, amphetamine, methamphetamine, methylenedioxymethamphetamine, alprazolam, or other illicit or licit drugs
• Method 1 or any of Methods 1.1-1.94, wherein the F/FA is or was administered as general anesthesia (e.g., surgical anesthesia);
• general anesthesia e.g., surgical anesthesia
• the general anesthesia further comprises or comprised one or more of an inhalational anesthetic (e.g., isoflurane, sevoflurane, desflurane, nitrous oxide, halothane, methoxyflurane), another opioid agonist (e.g., morphine, oxycodone), a sedative or hypnotic (e.g., propofol, midazolam, ketamine, etomidate), or a muscle relaxant (e.g., atracurium, mivacurium, pancuronium, rocuronium, vecuronium, cistracurium, succinylcholine);
• an inhalational anesthetic e.g., isoflurane, sevoflurane, desflurane, nitrous oxide, halothane, methoxyflurane
• another opioid agonist e.g., morphine, oxycodone
• Method 1 or any of Methods 1.1-1.97, wherein the patient has not responded to, or has not responded adequately to (e.g., with respect to signs or symptoms of respiratory depression) a single dose of a mu-opioid antagonist (e.g., naloxone or naltrexone, e.g., 0.1 to 4 mg) administered by any route (e.g., intranasal, intravenous, subcutaneous, or intramuscular);
• a mu-opioid antagonist e.g., naloxone or naltrexone, e.g., 0.1 to 4 mg
• any route e.g., intranasal, intravenous, subcutaneous, or intramuscular
• Method 1 or any of Methods 1.1-1.97, wherein the patient has not responded to, or has not responded adequately to (e.g., with respect to signs or symptoms of respiratory depression) multiple doses of a mu-opioid antagonist (e.g., naloxone or naltrexone, e.g., 0.4 to 20 mg in total) administered by any route (e.g., intranasal, intravenous, subcutaneous, or intramuscular);
• a mu-opioid antagonist e.g., naloxone or naltrexone, e.g., 0.4 to 20 mg in total
• any route e.g., intranasal, intravenous, subcutaneous, or intramuscular
• Method 1 or any of Methods 1.1-1.99, wherein the patient has experienced recrudescence of respiratory depression following a single dose or multiple doses of a mu- opioid antagonist administered by any route (e.g., naloxone or naltrexone, e.g., intranasal, intravenous, subcutaneous, or intramuscular);
• a mu- opioid antagonist administered by any route (e.g., naloxone or naltrexone, e.g., intranasal, intravenous, subcutaneous, or intramuscular);
• Method 1 or any of Methods 1.1-1.100, wherein the patient has experienced one or more opioid withdrawal symptoms or other adverse events (e.g., agitation, combativeness, laryngospasm, pulmonary edema, hemodynamic instability, or cardiac arrythmia) following a single dose or multiple doses of a mu-opioid antagonist administered by any route (e.g., naloxone or naltrexone, e.g., intranasal, intravenous, subcutaneous, or intramuscular); 1.102 Any of Methods 1.98-1.101, wherein said mu-opioid antagonist is naloxone, naltrexone, or nalmefene;
• opioid withdrawal symptoms or other adverse events e.g., agitation, combativeness, laryngospasm, pulmonary edema, hemodynamic instability, or cardiac arrythmia
• a mu-opioid antagonist administered by any route (e.g.,
• Method 1 or any of 1.1-1.106 wherein said patient is confirmed to be suffering from F/FA overdose by toxicological or forensic methods (e.g., by confirming the presence of F/FA in the patient’s blood, or in the patient’s drugs or drug paraphernalia);
• the effective amount of the Compound of Formula I is an amount effective to reverse one or more of: respiratory arrest, respiratory depression, skeletal muscle spasm, chest wall rigidity, laryngospasm, pupillary constriction, cardiac arrest, bradycardia, or unconsciousness;
• Method 1 or any of 1.1-1.108 wherein the effective amount of the Compound of Formula I is 0.1 mg-200 mg, for example, 1-200 mg, or 10-150 mg, or 25-100 mg, or 50-100 mg, or 75-100 mg, or 25-75 mg, or 25-50mg, or 1-50 mg, or 1-25 mg, 0.1 to 50 mg, 2.5mg- 50mg, or for a long-acting formulation, 25mg-1500mg, for example, 50mg to 500mg, or 250mg to lOOOmg, or 250mg to 750mg, or 75mg to 300mg;
• Method 1.109 wherein the effective amount is administered as a single dose
• Method 1.109 wherein the effective amount is administered in two or more doses over a period of less than 30 minutes (e.g., less than 20 minutes, or less than 15 minutes, or less than 10 minutes);
• Method 1 or any of 1.1-1.111, wherein the effective amount of the Compound of Formula I is administered by intranasal administration (e.g., as an aerosol, mist, or powder for inhalation); 1.113 Method 1 or any of 1.1-1.111, wherein the effective amount of the Compound of Formula I is administered across the oral mucosa, such as, by a rapidly-dissolving oral tablet (e.g., a rapidly dissolving sublingual tablet);
• a rapidly-dissolving oral tablet e.g., a rapidly dissolving sublingual tablet
• any other opioid antagonist e.g., naloxone, naltrexone, nalmefene, methadone, nalorphine, levallorphan, samidorphan, nalodeine, cyprodime, or norbinaltorphimine
• opioid antagonist e.g., naloxone, naltrexone, nalmefene, methadone, nalorphine, levallorphan, samidorphan, nalodeine, cyprodime, or norbinaltorphimine
• the method comprises administering a pharmaceutical composition comprising both a Compound of Formula I, wherein R 1 is H, and a prodrug of the same Compound of Formula I (i.e., wherein R 1 is -C(O)-O- C(R a )(R b XR c ), -C(O)-O-CH2-O-C(R a )(R b XR c ) or -C(R 6 )(R 7 )-O-C(O)-R 8 , as hereinbefore described);
• the method is a method for reversing or inhibiting binding of F/FA to mu-opioid receptors in the central nervous system (e.g., in the locus coeruleus); 1.123 Any foregoing method, wherein the method is a method for inhibiting F/FA-induced beta-arrestin signaling in the central nervous system (e.g., in the locus coeruleus);
• the method is a method for anesthetic recovery (e.g., anesthetic emergence, such as, following surgery)
• F/FA is selected from fentanyl, sufentanil, alfentanil, remifentanil, carfentanil, thiafentanil, lofentanil, ocfentanil, trefantinil, and brifentanil;
• Method 1 Any of Method 1, or 1.1-1.130, wherein the source of the F/FA is another illicit drug which is adulterated with the F/FA, such as cocaine, heroin, oxycodone, amphetamine, methamphetamine, or marijuana;
• another illicit drug such as cocaine, heroin, oxycodone, amphetamine, methamphetamine, or marijuana;
• Method 1.132 or 1.133 wherein the overdose, respiratory depression, muscle rigidity, laryngospasm, and/or risk of death is due primarily or exclusively to the F/FA adulterant in the illicit drug (e.g., but for the F/FA adulterant, said illicit drug would not have caused said overdose, respiratory depression, muscle rigidity, laryngospasm, and/or risk of death).
• the one or more second therapeutic agents may be administered as a part of the pharmaceutical composition comprising the Compound of the present disclosure.
• the one or more second therapeutic agents may be administered in separate pharmaceutical compositions (such as pills, tablets, capsules and injections) administered simultaneously, sequentially or separately from the administration of the Compound of the present disclosure.
• the present disclosure provides use of a Compound of the present disclosure, e.g., a Compound of Formula I or any of the compounds described in any of the embodiments of Methods 1.1 to 1.71, in the manufacture of a medicament for use according to Method 1 or any of Methods 1.1-1.134.
• a Compound of the present disclosure e.g., a Compound of Formula I or any of the compounds described in any of the embodiments of Methods 1.1 to 1.71, in the manufacture of a medicament for use according to Method 1 or any of Methods 1.1-1.134.
• the present disclosure provides a Compound of the present disclosure, e.g., a Compound of Formula I or any of the compounds described in any of the embodiments of Methods 1.1 to 1.71, for use according to Method 1 or any of Methods 1.1-1.134.
• a Compound of the present disclosure e.g., a Compound of Formula I or any of the compounds described in any of the embodiments of Methods 1.1 to 1.71, for use according to Method 1 or any of Methods 1.1-1.134.
• the Compounds of the present disclosure due to their potent 5-HT2A, Di and Mu opioid modulation activity, and especially due to their biased mu-opioid receptor activity, are unexpectedly effective in reversing the symptoms of F/FA overdose, especially respiratory depression, chest wall rigidity and laryngospasm. This is particularly believed to be due to these compounds’ activity as mu-receptor antagonists via the beta-arrestin signaling. It is also believed that these compounds’ activity as alphal -adrenergic antagonists, as indirect NMD A and AMP A antagonists, and potentially due to indirect effects on GABA expressing neurons. These properties are highly unique and are not shared by the traditional mu-opioid receptor antagonists which are used for both opioid overdose treatment and surgical reversal of opioid agonism, such as naloxone.
• opioid withdrawal syndrome can be very severe on addicted patients, and can include symptoms such as tachycardia, nausea, vomiting, diarrhea, extreme anxiety, restless legs, muscle aches, and profuse sweating. These withdrawal symptoms are the result of the body’s adaptation to the presence of opioids resulting in tolerance and physical dependence. In severe cases, sudden cessation of opioid abuse or treatment with opioid antagonists can result in withdrawal symptoms lasting for weeks or months.
• opioid antagonists such as naloxone or naltrexone
• high doses can precipitate acute withdrawal effects, especially in patients suffering from an acute overdose with F/FA.
• antagonist treatment can be administered using small repeated doses in order to avoid or minimize such withdrawal syndromes.
• small doses of antagonist are ineffective, and thus, in order to have any chance of reversing the overdose, it is often impossible to avoid severe withdrawal with traditional antagonist treatments.
• the compounds of Formula I have one or more biologically labile functional groups positioned within the compounds such that natural metabolic activity will remove the labile functional groups, resulting in another Compound of Formula I.
• group R 1 is C(O)-O-C(R a )(R b )(R c ), -C(O)-O-CH2-O-C(R a )(R b )(R c ) or -C(R 6 XR 7 )-O-C(O)-R 8 , under biological conditions this substituent will undergo hydrolysis to yield the same compound wherein R 1 is H, thus making the original compounds prodrugs of the compound wherein R 1 is H.
• prodrug compounds may have little-to-no or only moderate biological activity but upon hydrolysis to the compound wherein R 1 is H, the compound may have strong biological activity.
• administration of the compounds of the present disclosure to a patient in need thereof may result in immediate biological and therapeutic effect, or immediate and delayed biological and therapeutic effect, or only delayed biological and therapeutic effect.
• prodrug compounds will thus serve as a reservoir of the pharmacologically active compounds of Formula I wherein R 1 is H.
• the nature of the group R 1 may be such that the resulting compound of Formula I is substantially more lipophilic than the corresponding compound of Formula I wherein R 1 is H, and as a result, the prodrug compound may cross the blood brain barrier and accumulate in the central nervous system (CNS) tissues much more rapidly, followed by rapid hydrolysis of the labile group win the CNS. Overall, this may result in more rapid action of the compound to reverse the effects of mu-receptor activation.
• CNS central nervous system
• the methods of the present disclosure provide for the administration of a pharmaceutical composition comprising both a Compound of Formula I and a prodrug of the same compound.
• the composition may comprise a particular compound of Formula I wherein R 1 is H, and a second compound of Formula 1 wherein R 1 is -C(O)-O- C(R a )(R b XR c ), -C(O)-O-CH2-O-C(R a )(R b XR c ) or -C(R 6 )(R 7 )-O-C(O)-R 8 , but wherein the compounds are otherwise the same.
• the composition may provide an immediate release effect owing to rapid absorption and action of the compound of Formula I wherein R 1 is H, combined with a sustained or delayed release effect owing to the slower hydrolysis of the prodrug version of the compound, generating additional compound of Formula I wherein R 1 is H over a course of time (e.g., 1-3 hours, 6-12 hours, 12-48 hours, 2-3 days).
• the present disclosure also provides a pharmaceutical composition
• a pharmaceutical composition comprising a first compound of Formula I, wherein R 1 is H, and a second compound of Formula 1, wherein R 1 is -C(O)-O-C(R a )(R b )(R c ), -C(0)-0-CH2-0- C(R a )(R b )(R c ) or -C(R 6 )(R 7 )-O-C(O)-R 8 .
• both the compound of Formula I wherein R 1 is H, and the prodrug compound of Formula I may be as described in any of embodiments 1.1-1.70, and the pharmaceutical composition comprising same may be as described in any other pharmaceutical composition embodiments described herein.
• Alkyl as used herein is a saturated or unsaturated hydrocarbon moiety, e.g., one to twenty-one carbon atoms in length, unless indicated otherwise; any such alkyl may be linear or branched (e.g., n-butyl or tert-butyl), preferably linear, unless otherwise specified.
• Ci-21 alkyl denotes alkyl having 1 to 21 carbon atoms.
• alkyl is optionally substituted with one or more hydroxy or C 1-22 alkoxy (e.g., ethoxy) groups.
• alkyl contains 1 to 21 carbon atoms, preferably straight chain and optionally saturated or unsaturated, for example in some embodiments wherein Ri is an alkyl chain containing 1 to 21 carbon atoms, preferably 6-15 carbon atoms, 16-21 carbon atoms, e.g., so that together with the - C(O)- to which it attaches, e.g., when cleaved from the compound of Formula I, forms the residue of a natural or unnatural, saturated or unsaturated fatty acid.
• pharmaceutically acceptable diluent or carrier is intended to mean diluents and carriers that are useful in pharmaceutical preparations, and that are free of substances that are allergenic, pyrogenic or pathogenic, and that are known to potentially cause or promote illness.
• Pharmaceutically acceptable diluents or carriers thus exclude bodily fluids such as example blood, urine, spinal fluid, saliva, and the like, as well as their constituent components such as blood cells and circulating proteins.
• Suitable pharmaceutically acceptable diluents and carriers can be found in any of several well-known treatises on pharmaceutical formulations, for example Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remington ’s Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000; and Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999); all of which are incorporated by reference herein in their entirety.
• purified refers to the physical state of said compound after being isolated from a synthetic process (e.g., from a reaction mixture), or natural source or combination thereof.
• purified refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan (e.g., chromatography, recrystallization, LC-MS and LC-MS/MS techniques and the like), in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.
• the Compounds of the present disclosure may exist in free base form or in salt form, such as a pharmaceutically acceptable salt form, e.g., as acid addition salts.
• An acid-addition salt of a compound of the present disclosure which is sufficiently basic for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric acid or toluenesulfonic acid.
• a salt of a compound of the present disclosure which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, or a salt with an organic base which affords a physiologically-acceptable cation.
• the salt of the Compounds of the present disclosure is a toluenesulfonic acid addition salt.
• the Compounds of the present disclosure may comprise one or more chiral carbon atoms.
• the compounds thus exist in individual isomeric, e.g., enantiomeric or diastereomeric form or as mixtures of individual forms, e.g., racemic/diastereomeric mixtures. Any isomer may be present in which the asymmetric center is in the (7?)-, (S)-, or (72,5)- configuration.
• the invention is to be understood as embracing both individual optically active isomers as well as mixtures (e.g., racemic/diastereomeric mixtures) thereof.
• the Compounds of the present disclosure may be a racemic mixture or it may be predominantly, e.g., in pure, or substantially pure, isomeric form, e.g., greater than 70% enantiomeric/diastereomeric excess (“ee”), preferably greater than 80% ee, more preferably greater than 90% ee, most preferably greater than 95% ee.
• ee enantiomeric/diastereomeric excess
• the purification of said isomers and the separation of said isomeric mixtures may be accomplished by standard techniques known in the art (e.g., column chromatography, preparative TLC, preparative HPLC, simulated moving bed and the like).
• Geometric isomers by nature of substituents about a double bond or a ring may be present in cis (Z) or trans (E) form, and both isomeric forms are encompassed within the scope of this invention.
• the compounds of the present disclosure encompass their stable and unstable isotopes.
• Stable isotopes are nonradioactive isotopes which contain one additional neutron compared to the abundant nuclides of the same species (i.e., element). It is expected that the activity of compounds comprising such isotopes would be retained, and such compound would also have utility for measuring pharmacokinetics of the non-isotopic analogs.
• the hydrogen atom at a certain position on the compounds of the disclosure may be replaced with deuterium (a stable isotope which is non-radioactive).
• Examples of known stable isotopes include, but not limited to, deuterium ( 2 H or D), 13 C, 15 N, 18 O.
• unstable isotopes which are radioactive isotopes which contain additional neutrons compared to the abundant nuclides of the same species (i.e., element), e.g., 123 1, 131 1, 125 I, n C, 18 F, may replace the corresponding abundant species of I, C and F.
• Another example of useful isotope of the compound of the present disclosure is the n C isotope.
• These radio isotopes are useful for radio-imaging and/or pharmacokinetic studies of the compounds of the present disclosure.
• the substitution of atoms of having the natural isotopic distributing with heavier isotopes can result in desirable change in pharmacokinetic rates when these substitutions are made at metabolically liable sites.
• the incorporation of deuterium ( ⁇ H) in place of hydrogen can slow metabolic degradation when the position of the hydrogen is a site of enzymatic or metabolic activity.
• an “effective amount” means a “therapeutically effective amount”, that is, any amount of the Compounds of the present disclosure (for example as contained in the pharmaceutical composition or dosage form) which, when administered to a subject suffering from a disease or disorder, is effective to cause a reduction, remission, or regression of the disease or disorder over the period of time as intended for the treatment.
• an amount of the Compound of the present disclosure for administration refers to or is based on the amount of the Compound of the present disclosure in free base form (i.e., the calculation of the amount is based on the free base amount).
• Compounds of the present disclosure may be administered by any satisfactory route, including orally, parenterally (intravenously, intramuscular or subcutaneous) or transdermally.
• the Compounds of the present disclosure e.g., in depot formulation, is preferably administered parenterally, e.g., by injection, for example, intramuscular or subcutaneous injection.
• the pharmaceutically acceptable salts of the Compounds of the present disclosure can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
• compositions comprising Compounds of the present disclosure may be prepared using conventional diluents or excipients (an example include, but is not limited to sesame oil) and techniques known in the galenic art.
• oral dosage forms may include tablets, capsules, solutions, suspensions and the like.
• the term “concurrently” when referring to a therapeutic use means administration of two or more active ingredients to a patient as part of a regimen for the treatment of a disease or disorder, whether the two or more active agents are given at the same or different times or whether given by the same or different routes of administrations. Concurrent administration of the two or more active ingredients may be at different times on the same day, or on different dates or at different frequencies.
• the term “simultaneously” when referring to a therapeutic use means administration of two or more active ingredients at or about the same time by the same route of administration. [0062] The term “separately” when referring to a therapeutic use means administration of two or more active ingredients at or about the same time by different route of administration.
• Isolation or purification of the diastereomers of the Compounds of the present disclosure may be achieved by conventional methods known in the art, e.g., column purification, preparative thin layer chromatography, preparative HPLC, crystallization, trituration, chiral salt resolution, simulated moving beds and the like.
• Salts of the Compounds of the present disclosure may be prepared as similarly described in U.S. Pat. No. 6,552,017; 7,183,282; 8,648,077; 10,654,854; and 11,014,925; the contents of each of which are incorporated by reference in their entirety.
• Diastereomers of prepared compounds can be separated by, for example, HPLC.
• HPLC for example, a CHIRALPAK® AY-H, 5p, 30x250mm column operated at room temperature and eluted with an ethanol / hexane / dimethylethylamine solvent system can be used.
• the resulting mixture is heated to 78 °C and stirred at this temperature for 2 h.
• the mixture is cooled to room temperature and then filtered.
• the filter cake is purified by silica gel column chromatography using a gradient of 0 - 100% ethyl acetate in a mixture of methanol/7N NH3 in methanol (1 : 0.1 v/v) as an eluent to produce partially purified product, which is further purified with a semi-preparative HPLC system using a gradient of 0 - 60% acetonitrile in water containing 0.1% formic acid over 16 min to obtain the title product as a solid (50mg, yield 30%).
• MS (ESI) m/z 406.2 [M+l] + .
• Step 1 To a stirred solution of BCh-MeS (10.8 g, 60 mmol) in toluene at 0-5 °C is added 3 -fluoroaniline (5.6 mL, 58 mmol), followed by 4-chlorobutyronitrile (7.12 g. 68.73 mmol) and aluminum chloride (AlCh) (8.0 g, 60.01 mmol). The mixture is stirred at 130 °C overnight and cooled to 50 °C. Hydrochloric acid (3N, 30 mL) is added carefully and the resulting solution is stirred at 90 °C overnight. The obtained brown solution is cooled to room temperature and evaporated to dryness.
• 3 -fluoroaniline 5.6 mL, 58 mmol
• AlCh aluminum chloride
• Step 2 To a suspension of 2'-amino-4-chloro-4'-fluorobutyrophenone (680 mg, 3.2 mmol) in concentrated HC1 (14 mL) at 0-5 °C, NaNCh (248 mg, 3.5 mmol) in water (3 mL) is added. The resulting brown solution is stirred at 0 - 5 °C for 1 h and then SnCh*2HzO (1.74 g, 7.7 mmol) in concentrated HC1 (3 mL) is added. The mixture is stirred at 0 - 5 °C for additional 1 hour and then dichloromethane (30 mL) is added.
• Step 33 AA mmiixxttuurree ooff (6bR,10aS)-6b,7,8,9,10,10a-hexahydro-lH- pyrido[3',4':4,5]pyrrolo[l,2,3-de]quinoxalin-2(3H)-one (lOOmg, 0.436 mmol), 3-(3- chloropropyl)-6-fluoro-12/-indazole(124 mg, 0.65 mmol) and KI (144mg, 0.87 mmol) is degassed with argon for 3 minutes and DIPEA (150 ⁇ L, 0.87 mmol) is added.
• the resulting mixture is stirred at 78 °C for 2 h and then cooled to room temperature.
• the generated precipitate is filtered.
• the filter cake is purified with a semi-preparative HPLC system using a gradient of 0 - 60% acetonitrile in water containing 0.1% formic acid over 16 minutes to yield (6bR,10aS)-8-(3-(6-fluoro-lH- indazol-3 -yl)propyl)-6b,7, 8,9, 10, 1 Oa-hexahy dro- lH-pyrido[3 ',4' :4, 5]pyrrolo[ 1,2,3- de]quinoxalin-2(3H)-one as an off-white solid (50 mg, yield 28%).
• Step 1 A degassed suspension of (4aS,9bR)-ethyl 6-bromo-3,4,4a,5-tetrahydro-lH- pyrido[4,3-b]indole-2(9bH)-carboxylate (21.5 g, 66.2mmol), chloroacetamide (9.3g, lOOmmol), and KI (17.7 g, 107mmol) in dioxane (60 mL) is stirred at 104 °C for 48 h. The solvent is removed and the residue is suspended in dichloromethane (200 mL) and extracted with water (100 mL).
• the separated dichloromethane phase is dried over potassium carbonate (K2CO3) for 1 h and then filtered.
• the filtrate is evaporated to give a crude product as a brown oil.
• ethyl acetate 100 m L
• the mixture is sonicated for 2 min.
• a yellow solid gradually precipitates from the mixture, which turns into a gel after standing at room temperature for an additional 2 h.
• Additional ethyl acetate (10 mL) is added and the resulting solid is filtered.
• Step 2 A mixture of (4aS,9bR)-ethyl 5-(2-amino-2-oxoethyl)-6-bromo-3,4,4a,5- tetrahydro-lH-pyrido[4,3-b]indole-2(9bH)-carboxylate (12.9 g, 33.7mmol), KI (10.6g, 63.8mmol), Cui (1.34g, 6.74 mmol) in dioxane (50 mL) is bubbled with argon for 5 min. To this mixture is added N,N,N,N’ -tetramethylethylenediamine (3 mL) and the resulting suspension is stirred at 100°C for 48 h.
• Step 3 (6bR, 10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-lH,7H- pyrido[3',4':4,5]pyrrolo[l,2,3-de]quinoxaline-8-carboxylic acid ethyl ester (6.4 g, 21.2 mmol) is suspended in HBr/acetic acid solution (64 mL, 33% w/w) at room temperature. The mixture is heated at 50 °C for 16 h. After cooling and treatment with ethyl acetate (300 mL), the mixture is filtered.
• Step 4 A mmiixxttuurree ooff (6bR,10aS)-6b,7,8,9,10,10a-hexahydro-lH- pyrido[3',4':4,5]pyrrolo[l,2,3-de]quinoxalin-2(3H)-one (lOOmg, 0.436 mmol), 4-(3- bromopropoxy)benzonitrile (99 mg, 0.40 mmol) and KI (97 mg, 0.44 mmol) in DMF (2 mL) is bubbled with argon for 3 minutes and diisopropylethylamine (DIPEA) (80 ⁇ L, 0.44 mmol) is added.
• DIPEA diisopropylethylamine
• Example 6 Synthesis of(6bR,10aS)-8-(3-(quinolin-8-yloxy)propyl)-6b,7,8,9,10,10a-hexahydro- 1H-pyrido[3',4':4,5]pyrrolo[l,23-de]quinoxalin-2(3H)-one [0077] A mixture of (6bR,10aS)-6b,7,8,9,10,10a-hexahydro-lH-pyrido[3',4':4,5]pyrrolo[l,2,3- de]quinoxalin-2(3H)-one (120 mg, 0.52 mmol), 8-(3-chloropropoxy)quinoline (110 mg, 0.50 mmol) and KI (120 mg, 0.72 mmol) in DMF (2.5 mL) is bubbled with argon for 3 minutes and DIPEA (100 ⁇ L, 0.57 mmol) is added.
• Receptor binding is determined for the Compound of Example 1 (the Compound of Formula A), and the Compounds of Examples 2 to 6.
• the following literature procedures are used, each of which reference is incorporated herein by reference in their entireties: 5-HT2A: Bryant, H.U. et al. (1996), Life Sci, 15:1259-1268; D2: Hall, D.A. and Strange, P.G. (1997), Brit. J. Pharmacol., 121:731-736; DI: Zhou, Q.Y. et al. (1990), Nature, 347:76-80; SERT: Park, Y.M. et al. (1999), Anal. Biochem., 269:94-104; Mu opioid receptor: Wang, J.B.
• results are expressed as a percent of control specific binding: measured specific binding x lOO control specific binding and as a percent inhibition of control specific binding: measured specific binding
• IC50 values concentration causing a half-maximal inhibition of control specific binding
• Example 1 The compound of Example 1 is tested in CHO-K1 cells expressing hOP3 (human mu- opioid receptor ⁇ l subtype) using an HTRF-based cAMP assay kit (cAMP Dynamic2 Assay Kit, from Cisbio, # 62AM4PEB). Frozen cells are thawed in a 37 °C water bath and are resuspended in
• Buprenorphine a mu-opioid receptor partial agonist
• naloxone a mu-opioid receptor antagonist
• DAMGO a synthetic opioid peptide full agonist
• agonist assays 12 ⁇ L of cell suspension (2500 cells/well) are mixed with 6 ⁇ L forskolin (10 pM final assay concentration), and 6 ⁇ L of the test compound at increasing concentrations are combined in the wells of a 384- well white plate and the plate is incubated for 30 minutes at room temperature. After addition of lysis buffer and one hour of further incubation, cAMP concentrations are measured according to the kit instructions. All assay points are determined in triplicate. Curve fitting is performed using XLfit software (IDBS) and EC50 values are determined using a 4-parameter logistic fit. The agonist assay measures the ability of the test compound to inhibit forskolin-stimulated cAMP accumulation.
• IDBS XLfit software
• Curve fitting is performed using XLfit software (IDBS) and IC50 values are determined using a 4-parameter logistic fit. Apparent dissociation constants (KB) are calculated using the modified Cheng-Prusoff equation.
• the antagonist assay measures the ability of the test compound to reverse the inhibition of forskolin- induced cAMP accumulation caused by DAMGO.
• Example 1 is a weak antagonist of the Mu receptor, showing much higher ICso compared to naloxone, and that it is a moderately high affinity, but partial agonist, showing only about 22% agonist activity relative to DAMGO (as compared to about 79% activity for buprenorphine relative to DAMGO).
• the compound of Example 1 is also shown to have moderately strong partial agonist activity.
• Buprenorphine is a drug used for opioid withdrawal, but it suffers from the problem that users can become addicted due to its high partial agonist activity.
• the commercial combination of buprenorphine with naloxone is used (sold as Suboxone).
• Suboxone the commercial combination of buprenorphine with naloxone.
• the Compound of Example 1 is studied using a beta-arrestin assay.
• the assay monitors the activation of a selected G-protein coupled receptor (GPCR) in a homogenous, non-imaging assay format using proprietary technology based on beta-galactosidase as a functional reporter.
• GPCR G-protein coupled receptor
• This enzyme is split into two inactive complementary portions, termed EA and PK, expressed as fusion proteins in the cell.
• EA portion is fused to beta-arrestin and the PK portion is fused to the GPCR of interest, the human mu-opioid receptor.
• the two portions of the enzyme are complemented restoring enzymatic activity, which is detected via chemiluminescence reagents.
• the proprietary cell lines are seeded in a volume of 20 ⁇ L in 384-cell microplates and incubated at 37 °C.
• For agonist determination cells are incubated with Compound of Example 1 to induce a response.
• Intermediate dilution of Compound stock is performed to generate 5X Compound in assay buffer.
• 5 ⁇ L of 5X Compound solution is added to cells and incubated at 37 °C for 1.5 to 3 hours. Vehicle concentration is 1%.
• cells are pre-incubated with Compound of Example 1 followed by agonist ([Met]-enkephalin) challenge at the EC80 concentration of the agonist.
• Intermediate dilution of Compound stock is performed to generate 5X Compound in assay buffer.
• Example 1 The Compound of Example 1 is tested in a human alphal A adrenergic receptor antagonist radioligand assay. Standard procedures are followed according to Schwinn, DA et al., J. Biol. Chem. 265:8183-89 (1990). Human recombinant CHO cells are used for the assay. Assay incubation is conducted for 60 minutes at room temperature. The antagonist radioligand is [ 3 H] prazosin and the non-specific control is epinephrine (0.1 mM). The Compound of Example 1 is used from a stock solution at 0.01M in DMSO.
• the Compound of Formula 1 is an antagonist of the alphal A adrenergic receptor with a binding Ki of 28 nM.
• CHO-K1 cells expressing human alphal A-adreneregic receptor are suspended in Ham’s F-12 medium containing 10% FBS. Cells are then recovered via centrifugation and resuspended in prewarmed assay buffer (DMEM/HAM’s F12 w/HEPES) at 3 x 10 5 cells/mL in a Falcon tube. Coelenterazine h is added to a final concentration of 5 pM, and the tube is wrapped in aluminum foil and placed on a rotating wheel for 4 hours at room temperature. Cells are then diluted 3x in assay buffer and transferred to a beaker wrapped in aluminum foil.
• prewarmed assay buffer DMEM/HAM’s F12 w/HEPES
• the antagonist assay 50 ⁇ L of cells (5,000 cells/well) are mixed with 50 ⁇ L of the Compound of Example 1 at increasing concentrations in a 96-well plate, and incubated for 15 minutes at room temperature. Then, 50 ⁇ L of phenylephrine is added for a final concentration of 50 nM (corresponding to the ECSO of phenylephrine). Light emission is immediately recorded for 20 seconds using a luminescence detector. Antagonist activity is measured by the decrease in light emission produced by the phenylephrine. Tamsulosin is used as a positive control.
• Example 10 Using the procedures described in Example 10, the ability of the Compound of Example 1 to functionally inhibit fentanyl-induced beta-arrestin signaling is examined.
• Example 1 The oral pharmacokinetics of the compound of Example 1 has been studied in cynomolgus monkeys using standard procedures. Oral dosing was performed using the compound of Example 1 in tosylate salt form at a dose of 2.8 mg/kg, formulated in PEG-400. Intravenous (IV) dosing was performed using the compound of Example 1 in tosylate salt form at a dose of 1 mg/kg in sterile water with 45% Trappsol (beta-cyclodextrin) and 1% DMSO. The results are shown in the following table:
• the compound of Formula I is also found to have human plasma protein binding of
• Oxycodone is administered to adult male C57BL/6J mice for 8 days at an increasing dose regimen of 9, 17.8, 23.7, and 33 mg/kg twice per day (7 hours between injections) on days 1-2, 3-4, 5-6 and 7-8 respectively.
• the mice are administered the compound of Example 1 at either 0.3, 1 or 3 mg/kg subcutaneous. This is followed 30 minute later by either an injection of vehicle or with an injection of 3 mg/kg of naloxone.
• Another cohort of mice serve as negative controls, and instead of oxycodone, these mice are administered saline on days 1 to 8. On day 9, these mice are administered either vehicle (followed by naloxone, as above) or the compound of Example 1 at 3 mg/kg, s.c. (followed by naloxone, as above).
• mice On day 9, immediately after the injection of naloxone (or vehicle), the mice are individually placed in clear, plastic cages and are observed continuously for thirty minutes. The mice are monitored for common somatic signs of opioid withdrawal, including jumping, wet dog shakes, paw tremors, backing, ptosis, and diarrhea. All such behaviors are recorded as new incidences when separated by at least one second or when interrupted by normal behavior. Animal body weights are also recorded immediately before and 30 minutes after the naloxone (or vehicle) injections. Data is analyzed with ANOVA followed by the Tukey test for multiple comparisons, when appropriate. Significant level is established at p ⁇ 0.05.
• Total number of signs includes paw tremors, jumps, and wet dog shakes.
• naloxone elicits a significant number of total signs, paw tremors, jumps and body weight change (p ⁇ 0.0001 for each), indicating precipitated withdrawal.
• the compound of Example 1 produces a significant decrease in total number of signs and paw tremors precipitated by naloxone.
• the compound also produces a significant decrease in jumps and attenuated body weight loss.
• Example 1 dose-dependently reduces the signs and symptoms of opioid withdrawal after the sudden cessation of opioid administration in opioid-dependent rats, and prevents the signs and symptoms of opioid withdrawal induced by naloxone.
• mice are chronically treated with oxycodone or saline were challenged with ITI-333 or vehicle (Veh) and observed for manifestation of somatic signs of withdrawal (including jumps, wet dog shakes, paw tremors, backing, ptosis and diarrhea).
• ITI-333 or vehicle Veh
• mice chronically administered oxycodone and given the compound of Example 1 do not differ from mice administered vehicle on the number of paw tremors or jumps.
• the compound of Example 1 ( ⁇ 10mg/kg) also does not induce further body weight loss in mice receiving oxycodone chronically.
• the compound of Example 1 induced greater total withdrawal signs (p ⁇ 0.0001).
• it induces significantly more total withdrawal signs compared with morphine alone (p ⁇ 0.05), mainly attributable to increases in wet dog shakes.
• the compound of Example 1 does not produce any significant effects on somatic signs or loss of body weight relative to mice administered vehicle on Day 9 (p>0.05).
• Animals are acclimated to their housing and the laboratory procedures over a minimum period of 5 days prior to initiation of dosing. Animals are selected by body weight and apparent good health and are randomly assigned to the study groups. Crl:CD rats from Charles River Laboratories weighing 150-255 grams at the initiation of dosing and aged 6-7 weeks are used in the study, and are divided into six groups.
• Group (1) the negative control, animals are pre-treated with 3 mL/kg vehicle (s.c.) and then treated with 5 mL/kg vehicle (i.v.).
• Group (2) the positive control, animals are pre-treated with 0.15 mg/kg fentanyl (s.c., 0.05 mg/mL) and then treated with vehicle (i.v.).
• Group (3) the first test group, animals are pre-treated with 0.15 mg/kg fentanyl (s.c., 0.05 mg/mL), and then treated with 1 mg/kg of the compound of Example 1 (i.v.).
• Group (4) and (5) the same protocol is administered as for Group (3), except using the higher doses of 3.0 mg/kg and 5.0 mg/kg of the compound of Example 1.
• Group (6) animals are pretreated with vehicle (i.v) and then treated with the compound of Example 1 at 5.0 mg/kg (i.v.). All intravenous treatment is administered by infusion over 5 minutes.
• the animals are trained initially for two days immediately preceding the study, in a head- out plethysmograph chamber for approximately 10-15 minutes on each day. On the day of dosing, each animal is weighed and placed in the plethysmograph chamber and allowed to stabilize for at least 5 minutes. Following stabilization, respiratory parameters (respiratory rate, tidal volume and minute volume) are measured for 5 minutes continuously to obtain the pre-dose baseline values. The animal is then removed from the chamber and dosed as per group assignments. Following dosing, each animal is returned to its designated plethysmograph chamber and the respiratory parameters are measured at 5-minute intervals for 15 minutes. After each reading the animal is removed from the plethysmograph chamber.

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