Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • 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
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/404—Indoles, e.g. pindolol
  • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• • 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
  • A61K31/4965—Non-condensed pyrazines
  • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
• • 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
  • A61K31/50—Pyridazines; Hydrogenated pyridazines
  • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
• • 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
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
• • 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
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
  • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
  • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

• the present disclosure relates to methods of using fatty acid amide hydrolase (FAAH) inhibitors of Formula I and pharmaceutically acceptable salts thereof, alone or in combination with one or more additional therapeutic agents, for the treatment or prevention of neuronal injury or neurodegeneration in patients in need thereof.
• the disclosure is also directed to pharmaceutical compositions comprising FAAH inhibitors of Formula I for use in the treatment and or prevention of neuronal injury or neurodegeneration in patients in need thereof.
• the disclosure is also directed to kits comprising FAAH inhibitors of Formula I and their use in the treatment of patients in need thereof.
• Cannabinoids are a class of diverse chemical compounds that activate cannabinoid receptors. These include the endocannabinoids (eCBs, produced naturally in the body by humans and animals), the phytocannabinoids (produced by various plants), and synthetic cannabinoids (produced chemically by man).
• eCBs endocannabinoids
• the most notable plant cannabinoid is the phytocannabinoid A9-tetrahydrocannabinol (THC), the primary psychoactive compound of cannabis.
• THC phytocannabinoid A9-tetrahydrocannabinol
• the most important known endocannabinoids are anandamide (AEA) and 2-arachidonoyl glycerol (2- AG).
• CBRs cannabinoid receptors
• CB 1 and CB2 are G-protein-coupled receptors (GPCRs) identified as receptors for cannabinoids.
• CBl is preferentially expressed in the brain where it mediates the psychoactivity of cannabinoids.
• High levels of CBl receptors are found in the basal ganglia, hippocampus, cerebellum and cortical structures.
• CB2 is highly expressed in immune cells (e.g., B cells, natural killer cell, monocytes, microglial cells, neutrophils, T cells, dendritic cells, mast cells). Interactions with these receptors may be responsible for the anti-inflammatory and possibly other therapeutic effects of cannabis.
• CB1 is expressed by some cells of the immune system and that CB2 is expressed by some cells of the central nervous system (CNS).
• neuroinflamrnatory diseases This can be achieved by preventing the immune response from either being generated or from entering the CNS. This will prevent direct CNS damage by the immune system. Another route is to slow nerve damage that occurs as a consequence of the immune attack. Cannabinoids have the potential to inhibit both of these pathways, suggesting that cannabinoids could influence the development of progressive neurodegenerative disorders such as multiple sclerosis (MS).
• MS multiple sclerosis
• FAAH fatty acid amide hydrolase
• CBl receptor populations have been shown to be significantly decreased in the basal ganglia during Huntington's disease (HD) progression, leading to the hypothesis that enhancement of CBl receptor signaling may result in symptomatic improvement.
• HD Huntington's disease
• Cannabinoid agonists have been proposed as potential neuroprotective agents in the setting of Huntington's disease, due to their ability to activate CB2 receptors on glial cells, thereby reducing inflammatory events, and to normalize glutamate homeostasis via CBl receptor modulation, hence limiting excitotoxicity.
• CB agonists are currently being studied in the clinic for the treatment of HD.
• CREAE chronic relapsing experimental autoimmune encephalomyelitis
• the re-uptake inhibitors OMDM1, OMDM2 and UCM707 were shown to down-regulate inflammatory responses in the spinal cord and ameliorate motor symptoms in experimental models of MS, through the enhancement of AEA levels.
• UCM707 treatment during established disease significantly improved the motor function of diseased mice.
• TMED-IDD Theiler's murine encephalomyelitis virus induced demyelinating disease
• nitric oxide (NO) levels decreased production of proinflammatory cytokines
• iNOsynthase inducible nitric oxide synthase
• Cannabinoid agonists are currently under development for the treatment of neuropathic pain and spasticity in MS.
• mice lacking the FAAH enzyme were found to exhibit a more substantial clinical remission than wild-type animals in the CRAE animal model of MS, further suggesting that elevation of endocannabinoid tone may have a neuroprotective effect in MS.
• Disease-modifying drugs which include anti-inflammatory, immunomodulating and immunosuppressive agents, are administered for the purpose of preventing or postponing long-term disability and have the potential to significantly alter the course of disease when administered to patients in the early stages of multiple sclerosis or following a clinically isolated syndrome, before irreversible axonal injury occurs.
• Their treatment effect in the progressive stages of the disease appears to be modest, and in fact no long-term studies yet have demonstrated that these drugs are actually able to decrease the incidence of secondary progression.
• the results of clinical studies with CBs on humans are somewhat equivocal, showing improvements of patient reported subjective measures of pain and spasticity, whereas objective measures failed to be significantly changed.
• cannabinoids or compounds acting on the CB system are still very promising agents to target the aforementioned human diseases.
• the invention provides a method of treating or preventing neuronal injury or neurodegeneration in a patient in need thereof, comprising administering a therapeutically or prophylactically effective amount of a FAAH inhibitor of Formula I, or pharmaceutically acceptable salt thereof, alone or in combination with a therapeutically or prophylactically effective amount of one or more additional therapeutic agents to said patient, wherein the compound of Formula I has the structure depicted below:
• Formula I and V, W, X, Y are either C or N; Z, J, K, L are C; and M is N; Q 1 is N; Q 2 , Q 4 and Q 5 are C; and Q 3 is either C or N; a) each of P 1 , P 2 , P 3 , P 4 , P 5 and P 6 are C; or b) up to two of P 1 , P 2 , P 3 , P 4 , P 5 and P 6 are N and the rest are C:
• R 2 is hydroxyl, an optionally independently substituted Ci-3 alkyl, an optionally
• each of R 4 , R 5 , R 6 and R 7 is independently: H, a halogen, -N0 2 , -CN, -C(0)OH, hydroxyl, an optionally independently substituted Ci -5 alkyl, an optionally independently substituted C 2- 5 alkenyl, an optionally independently substituted C 2-5 alkynyl, an optionally independently substituted C l-5 alkoxy, -OC(0)(C, -5 alkyl) , -C(0)(C, -5 alkyl), -C(0)NR a R b ,
• each of R 8 , R 9 , R 10 , R 1 ' and R 12 when bonded to C, is independently: H, a halogen, -N0 2 , -CN, -C(0)OH, hydroxyl, -S0 2 (Ci- 4 alkyl), an optionally independently substituted Ci -5 alkyl, an optionally independently substituted
• R 14 is selected from H, a halogen, -NO?, -CN, -C(0)OH, hydroxyl, an optionally independently substituted Ci -5 alkyl, an optionally independently substituted C 2 . 5 alkenyl, an optionally independently substituted C 2 . 5 alkynyl, an optionally independently substituted Q.5 alkoxy, -C(0)NR a R b or -NR R b , wherein R 8 and R b are independently H, an optionally independently substituted C
• R 16 is selected from H, a halogen, -N0 2 , -CN, -C(0)OH, hydroxyl, an optionally independently substituted Ci -5 alkyl, an optionally independently substituted C 2- 5 alkenyl, an optionally independently substituted C 2-5 alkynyl, an optionally independently substituted C 1 .5 alkoxy, -C(0)NR a R b or -NR a R b , wherein R a and R b are independently H, optionally independently substituted Ci_ 6 alkyl, or an optionally independently substituted C 3 . 6 cycloalkyi;
• R 15 is missing
• R 13 is selected from H, a halogen, -NO 2 , -CN, -C(0)OH, hydroxyl, an optionally independently substituted C ⁇ s alkyl, an optionally independently substituted C 2- 5 alkenyl, an optionally independently substituted C 2- 5 alkynyl, an optionally independently substituted Ci_5 alkoxy, -C(0)NR a R b , or-NR a R b , wherein R a and R b are independently H, optionally
• R 17 is selected from H, a halogen, -N0 2 , -CN, -C(0)OH, hydroxy 1, an optionally
• Ci -5 alkyl an optionally independently substituted C 2- 5 alkenyl, an optionally independently substituted C2-5 alkynyl, an optionally independently substituted Ci -5 alkoxy, -C(0)NR a R b or -NR a R b , wherein R a and R b are independently H, optionally
• Ci -6 alkyl independently substituted Ci -6 alkyl, or an optionally independently substituted C 3-6
• the patient in need thereof is a person who has suffered one or more sudden or acute neuronal events selected from a stroke, brain or spinal cord injury, traumatic brain injury, brain ischemia, ischemia of the eyes, epileptic seizure, seizures associated with brain injury, epileptic seizure of genetic origin, brain damage due to drug abuse or brain damage due to excitotoxic insult.
• the patient in need thereof is a person who has been diagnosed with or is believed to be at risk of developing a neurodegenerative disorder selected from: a motor neuron disease, multiple sclerosis, Huntington's disease, Parkinson's disease, Alzheimer's disease or a dementia, a neuroinflammatory disease, or an autoimmune disease.
• the method results in halting or slowing down of neuronal degeneration in a patient that exhibits symptoms associated with neuronal injury or neurodegeneration, prolonged survival or delayed disease progression; in neurogenesis; or in a measurable improvement in a symptom selected from: a cognitive dysfunction, a motor dysfunction, lack of coordination, de- myelination or diminished strength; and in some aspects, also results in an observable or measurable reduction in neuroinfiammation or neuroinflammatory processes or spasticity.
• the invention also provides a method for the use of a FAAH inhibitor of Formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of neuronal injury or neurodegeneration in a patient in need thereof.
• the invention provides pharmaceutical compositions comprising a FAAH inhibitor of Formula I, or a pharmaceutically acceptable salt thereof, alone or in combination with one or more additional therapeutic agents, for use in the treatment of neuronal injury or
• the invention provides the use of a FAAH inhibitor of Formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of neuronal injury or neurodegeneration in a patient in need thereof.
• the invention provides a FAAH inhibitor of Formula I, or a
• the invention provides a kit comprising at least two separate unit dosage forms (A) and (B), wherein (A) is a therapeutic agent, a combination of more than one therapeutic agent, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and (B) is a FAAH inhibitor of Formula I, pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
• Figure 1 is an illustrative diagram of assessment using the clinical scoring scale used in the Examples below, as well as typical daily average responses in the chronic relapsing experimental allergic encephalomyelitis animal model post induction;
• Figure 2 is a graph of mean clinical scores of 2-(5-chloro-l-(4-chlorobenzyl)-2-methyl-lH- indol-3-yl)-N-(2-methoxypyridin-4-yl)-2-oxoacetamide [Compound No. 13], THC and vehicle treatment groups in relapse phase EAE;
• Figure 3 is a graph of mean RotoRod performance of 2-(5-chloro- 1 -(4-chlorobenzyl)-2- methyl-lH-indol-3-yl)-N-(2-methoxypyridin-4-yl)-2-oxoacetamide [Compound No. 13], THC- and vehicle treatment groups in pre and post relapse phase EAE;
• Figure 4 is a graph of mean RotoRod performance of 2-(5-chloro-l-(4-chlorobenzyl)-2- methyl-lH-indol-3-yl)-N-(2-methoxypyridin-4-yl)-2-oxoacetamide [Compound No. 13], THC- and vehicle treatment groups;
• the terms "subject” and “patient” are used interchangeably to refer to an animal (e.g., a bird such as a chicken, quail or turkey, or a mammal), preferably a
• mammal including a non-primate (e.g., a cow, pig, horse, sheep, rabbit, guinea pig, rat, cat, dog, and mouse) and a primate (e.g., a monkey, chimpanzee and a human), and more
• a non-primate e.g., a cow, pig, horse, sheep, rabbit, guinea pig, rat, cat, dog, and mouse
• a primate e.g., a monkey, chimpanzee and a human
• the subject is a non-human animal such as a farm animal (e.g., a horse, cow, pig or sheep), or a pet (e.g., a dog, cat, guinea pig or rabbit).
• a farm animal e.g., a horse, cow, pig or sheep
• a pet e.g., a dog, cat, guinea pig or rabbit
• the subject or patient is a human.
• a patient in need thereof is used to refer to a patient
• neuronal injury or neurodegeneration that occurs as a result of an acute event (e.g., a stroke or central nervous system injury/trauma) or as a result of a chronic acute event (e.g., a stroke or central nervous system injury/trauma) or as a result of a chronic acute event (e.g., a stroke or central nervous system injury/trauma) or as a result of a chronic acute event (e.g., a stroke or central nervous system injury/trauma) or as a result of a chronic occurrence of an acute event (e.g., a stroke or central nervous system injury/trauma) or as a result of a chronic acute event (e.g., a stroke or central nervous system injury/trauma) or as a result of a chronic acute event (e.g., a stroke or central nervous system injury/trauma) or as a result of a chronic acute event (e.g., a stroke or central nervous system injury/trauma) or as
• Said acute neuronal injury or progressive neurodegenerative process may affect the neurons of the central nervous system (CNS), composed of the brain and spinal cord, or the peripheral nervous system, and may eventually progress to neuronal death.
• CNS central nervous system
• neuronal injury refers to the damage to the function or structure (e.g., cytoskeletal damage) of neurons as a result of an insult (e.g., exposure to neurotoxins) or trauma (e.g., traumatic brain injury, concussive head trauma) to the nervous system.
• an insult e.g., exposure to neurotoxins
• trauma e.g., traumatic brain injury, concussive head trauma
• Neuronal injury is associated with, for instance: stroke, ischemic events (e.g., brain ischemia, ischemia of the eyes), seizures of diverse etiology (epileptic, associated with brain injury, of genetic origin), spinal cord injury or trauma, brain damage due to drugs of abuse, or excitotoxic insults of diverse nature.
• neurodegeneration is an umbrella term used to refer to the progressive loss of individual or collective structure or function of neurons, up to and including the death of neurons that is associated with many neurodegenerative diseases.
• neurodegenerative disease(s) is used to refer to medical conditions that are characterized clinically by their insidious onset and chronic progression. In many instances, particular parts of the brain, spinal cord, or peripheral nerves functionally fail and the neurons of the dysfunctional region die. Neuroanatomically localizable functional impairment and "neurodegeneration” associate with recognizable syndromes or conditions that are ideally distinct, although in clinical and even neuropathologic practice substantial overlap exists. Neurodegenerative diseases are often categorized by whether they initially affect cognition, movement, strength, coordination, sensation, or autonomic control.
• neurodegenerative implies the loss of neurons that cause disease.
• neuronal demise is merely the final stage of a preceding period of neuron dysfunction. It is difficult to know whether clinical decline associates with actual neuron loss, or with a period of neuron dysfunction that precedes neuron loss.
• particular neurodegenerative diseases are etiologically heterogeneous. In addition to syndromically defining neurodegenerative diseases by what neuro-anatomical system is involved, these disorders are broken down along other clinical lines. Early (childhood, young adulthood, or middle aged adulthood) versus late (old age) onset is an important distinction. Some clinically similar neurodegenerative diseases are sub-categorized by their age of onset, despite the fact that at the molecular level different forms of a particular disease may have very little in common. Sporadic onset versus Mendelian (genetic) inheritance constitutes another important distinction, and many named neurodegenerative diseases have both sporadic (wherein Mendelian inheritance is not recognizable) and Mendelian subtypes.
• a list of example neurodegenerative diseases has been collected below, grouped by their main symptom(s) or impairment(s) in affected subjects. This list is not inclusive, and diseases can present in ways in which they have not been listed herein.
• AD Alzheimer's Parkinson's Amyotrophic Spinocerebellar Multiple disease
• PD PD
• MS lateral sclerosis atrophies Sclerosis
• Some common symptoms of degenerative disorders of the brain are memory loss, personality changes, problems with movement, weakness, or poor balance or coordination.
• neurodegenerative diseases may present with memory loss or personality change: Alzheimer's disease, Frontotemporal Dementias, Dementia with Lewy Bodies, Prion diseases.
• neurodegenerative diseases may present as problems with movement: Parkinson's disease, Huntington's disease, Progressive Supranuclear Palsy, Corticobasal Degeneration, Multiple System Atrophy.
• neurodegenerative diseases may present as weakness: amyotrophic lateral sclerosis, inclusion body myositis, degenerative myopathies.
• the following neurodegenerative diseases can present as poor balance: the spinocerebellar atrophies.
• disorders of myelin include multiple sclerosis and Charcot-Marie-Tooth disease.
• motor neuron diseases refers to a group of progressive neurological disorders that destroy motor neurons, the cells that control essential voluntary muscle activity such as speaking, walking, breathing, and swallowing.
• the best-known motor neuron disease is amyotrophic lateral sclerosis (ALS).
• ALS amyotrophic lateral sclerosis
• Upper motor neurons direct the lower motor neurons to produce movements such as walking or chewing.
• Lower motor neurons control movement in the arms, legs, chest, face, throat, and tongue.
• Spinal motor neurons are also called anterior horn cells.
• Upper motor neurons are also called corticospinal neurons.
• ALS Amyotrophic lateral sclerosis
• PLS Primary lateral sclerosis
• SMA spinal muscular atrophy
• SMA type I also called Werdnig-Hoffmann disease
• SMA type II also called SMA type III
• Kugelberg-Welander disease congenital SMA with arthrogryposis
• Kennedy's disease also known as progressive spinobulbar muscular atrophy and post-polio syndrome (PPS)
• neuronal injury or degeneration includes the set of mechanisms and strategies used to protect against neuronal injury or degeneration in the CNS, following acute events (e.g., stroke or nervous system injury/trauma) or that occurs as a symptom of chrome neurodegenerative diseases (e.g., Parkinson's, Alzheimer's, Multiple Sclerosis, Huntington's, ALS).
• the goal of neuroprotection is to limit neuronal dysfunction/death after CNS injury or onset of neuronal degeneration and attempt to maintain the highest possible integrity of cellular interactions in the brain resulting in an undisturbed neural function.
• neuroprotection products there is a wide range of neuroprotection products available or under investigation and some products can potentially be used in more than one disorder, as many of the underlying mechanisms of damage to neural tissues (in both acute disorders and in chronic neurodegenerative diseases) are similar.
• "neuroprotection” is achieved by using a FAAH inhibitor of Formula I or a pharmaceutically acceptable salt or composition thereof, either alone or in combination with another therapeutic agent, to impart a protective effect in the CNS against neurodegenerative disease or neuronal injury.
• a “neuroprotecting agent” is any pharmaceutical product that is used to achieve partial or complete neuroprotection.
• products with neuroprotective effects may be grouped into one or more of the following categories:
• Neurotoxicity is used to define what occurs when exposure to natural or artificial toxic substances, which are called “neurotoxins", alters the normal activity of the nervous system in such a way as to cause damage to nervous tissue. This can eventually disrupt or kill neurons. Neurotoxicity can result, for instance, from exposure to substances used in chemotherapy, radiation treatment, drug therapies, abuse of certain drugs, and organ transplants, as well as exposure to heavy metals, certain foods and food additives, pesticides, industrial and/or cleaning solvents, cosmetics, and also to some endogenous substances that occur in the body.
• neurotoxic is used to describe a substance, condition or state that damages the nervous system, usually by killing or disrupting the normal structure or function of neurons.
• the term is generally used to describe a condition or substance that has been shown to result in observable physical damage.
• the presence of neurocognitive deficits, alone, is not usually considered sufficient evidence of neurotoxicity, as many existing substances may impair neurocognitive performance without resulting in the death of neurons. This may be due to the direct action of the substance, with the impairment and neurocognitive deficits being temporary, and resolving when the substance is metabolized from the body.
• the level or exposure-time may be critical, with some substances only becoming neurotoxic in certain doses or time periods.
• Some of the most common naturally occurring brain toxins that lead to neurotoxicity as a result of excessive dosage are endogenous substances such as beta amyloid ( ⁇ ), glutamate and oxygen radicals. When present in excessive concentrations in the CNS they can lead to neurotoxicity and neuronal death (apoptosis).
• excitotoxicity is used to refer to the pathological process by which nerve cells are damaged and/or killed by excessive stimulation by neurotransmitters such as glutamate and similar substances. This occurs when receptors for the excitatory neurotransmitter glutamate (glutamate receptors) such as the NMDA receptor and A PA receptor are over-activated.
• glutamate receptors glutamate receptors
• Excitotoxins like NMDA and kainic acid which bind to these receptors, as well as pathologically high levels of endogenous glutamate, can cause excitotoxicity by allowing high levels of calcium ions (Ca2+) to enter the cell. Ca2+ influx into cells activates a number of enzymes.
• Excitotoxicity occurs in many diseases or conditions that may be acute (e.g., hypoglycemia, seizures, stroke, epileptic seizures, or spinal cord injury, traumatic brain injury) or chronic neurodegenerative disease (e.g., dementias, amyotrophic lateral sclerosis, Huntington's disease, Alzheimer's disease, multiple sclerosis and Parkinson's disease).
• acute e.g., hypoglycemia, seizures, stroke, epileptic seizures, or spinal cord injury, traumatic brain injury
• chronic neurodegenerative disease e.g., dementias, amyotrophic lateral sclerosis, Huntington's disease, Alzheimer's disease, multiple sclerosis and Parkinson's disease.
• this pathologic phenomenon can occur after brain injury and spinal cord injury, wherein, within minutes after spinal cord injury, damaged neurons within the lesion site spill glutamate into the extracellular space where glutamate can stimulate presynaptic glutamate receptors to enhance the release of additional glutamate.
• Brain trauma or stroke can cause ischemia, in which blood flow is reduced to inadequate levels. Ischemia is then followed by accumulation of glutamate and aspartate in the extracellular fluid, causing cell death, which is aggravated by lack of oxygen and glucose.
• the biochemical cascade resulting from ischemia and involving excitotoxicity is called the ischemic cascade.
• Glial cells sometimes called “neuroglia” or simply “glia” are non-neuronal cells that maintain homeostasis, form myelin, and provide support and protection for neurons in the brain and in other parts of the nervous system such as in the autonomic nervous system.
• glial cells In the human brain, there is roughly one glia for every neuron. There is currently believed to be four main functions of glial cells: to surround neurons and hold them in place, to supply nutrients and oxygen to neurons, to insulate one neuron from another, and to destroy pathogens and remove dead neurons (immunoregulation). For over a century, it was believed that they did not play any role in neurotransmission. That idea is now discredited; it is known that they do modulate neurotransmission, although the mechanisms are not yet well understood.
• neuroinflammation refers to the process in which the brain responds to infections, diseases and injuries (collectively usually referred to as "insults).
• Neuroinflammation involves immune cells of the hematopoietic system (lymphocytes, monocytes and macrophages) as well as microglial cells of the CNS. Neuroinflammation disrupts the blood-brain barrier (BBB), allowing cells from the hematopoietic system to leave the blood stream and come in contact to the injury site.
• BBB blood-brain barrier
• the immune cells respond to injuries by eliminating debris and, synthesizing and releasing a host of powerful regulatory substances, like the complements, cytokines, chemokines, glutamate, interleukins, nitric oxide, reactive oxygen species and transforming growth factors. These substances may have both beneficial and harmful effects on the cellular environment, creating further damages.
• Mature astrocytes are also activated following injury to the CNS. Astrocytic activation is believed to be necessary for containing the immune response, repairing the BBB and attenuating further neuronal death.
• neuroinflammation occurs following traumatic brain injuries, spinal cord injuries and cerebral strokes. It involves immune cells from the hematopoietic and central nervous system. It is now also well documented that neuroinflammation is actively involved in neurological diseases and disorders, like AD, PD, ALS, depression, epilepsy, HD, MS and PD. For instance, in AD, there is a correlation between local inflammation, and presence of amyloid plaques and neurofibrillary tangles.
• Chronic neuroinflammation includes not only long-standing activation of microglia and subsequent sustained release of inflammatory mediators, but also the resulting increased oxidative and nitrosative stress.
• the sustained release of inflammatory mediators works to perpetuate the inflammatory cycle, activating additional microglia, promoting their proliferation, and resulting in further release of inflammatory factors.
• Neurodegenerative CNS disorders including multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), tauopathies, and age-related macular degeneration (ARMD), are associated with chronic neuroinflammation and elevated levels of several cytokines.
• Neurogenesis occurs in the brain and neuronal stem cells (NSCs) reside in the CNS of adult mammals, in various species including humans. NSCs are the self-renewing multipotent cells that generate the main phenotypes of the nervous system. Neurogenesis is known to be modulated in the brain of patients and in animal models of neurological diseases and disorders, like Alzheimer's disease (AD), epilepsy and Huntington's disease (HD). This suggests that the adult brain may be amenable to repair and that adult neurogenesis may contribute to the functioning, and physiology and pathology of the CNS, particularly to the etiology of neurological diseases and disorders.
• AD Alzheimer's disease
• HD Huntington's disease
• the term “treat”, “treating” or “treatment” with regard to a disorder or disease refers to alleviating or abrogating the cause and/or the effects of the disorder or disease.
• the terms “treat”, “treatment” and “treating” refer to the reduction or amelioration of the progression, severity and/or duration of a condition that can be treated with a FAAH inhibitor of Formula I or a pharmaceutically acceptable salt thereof, or the amelioration of one or more symptoms (preferably, one or more discernible symptoms) of said condition, resulting from the administration of one or more therapies (e.g., one or more therapeutic agents such as a compound of Formula I or a pharmaceutically acceptable salt or pharmaceutical composition thereof ).
• treatment and “treating” refer to the amelioration of at least one measurable physical parameter of a condition that can be treated with a FAAH inhibitor of Formula I.
• the terms “treat”, “treatment” and “treating” refer to the inhibition of the progression of said condition, either physically by, e.g., stabilization of a discernible symptom, physiologically by, e.g., stabilization of a physical parameter, or both.
• FAAH inhibitor of Formula I as a neuroprotecting agent as described in the instant disclosure refers to the halting, ameliorating or slowing down of neuronal degeneration in a patient that exhibits the symptoms associated with neuronal injury or neurodegeneration, or achieving prolonged neural survival, or delayed disease progression.
• the treatment with a neuroprotecting agent refers to the halting, ameliorating or slowing down of neuronal degeneration in a patient that exhibits the symptoms associated with neuronal injury or neurodegeneration, or achieving prolonged neural survival, or delayed disease progression.
• FAAH inhibitor of Formula I or a pharmaceutically acceptable salt or composition thereof may also result in neurogenesis or creation of new neurons. These processes manifest themselves in a halting or slowing of progression of the disease or in the improving of one or more symptoms associated with it.
• pharmaceutically acceptable salt or composition thereof refer to averting the cause and/or effects of a disease or disorder prior to the disease or disorder manifesting itself.
• prophylaxis or “prophylactic use”, as used herein, refer to any medical or public health procedure whose purpose is to prevent, rather than treat or cure a disease.
• the invention provides a method of treating or preventing neuronal injury or neurodegeneration in a patient in need thereof, comprising administering a therapeutically or prophylactically effective amount of a FAAH inhibitor of Formula I, or pharmaceutically acceptable salt thereof, alone or in combination with a therapeutically or prophylactically effective amount of one or more additional therapeutic agents to said patient.
• the invention provides a FAAH inhibitor of Formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of neuronal injury or neurodegeneration in a patient in need thereof.
• the invention provides pharmaceutical compositions comprising a FAAH inhibitor of Formula I, or pharmaceutically acceptable salt thereof, alone or in combination with one or more additional therapeutic agents, for use in the treatment of neuronal injury or neurodegeneration in a patient in need thereof.
• the invention provides a kit comprising at least two separate unit dosage forms (A) and (B), wherein (A) is a therapeutic agent, a combination of more than one therapeutic agent, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and (B) is a FAAH inhibitor of Formula I, pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
• the patient in need thereof is a person who has suffered one or more sudden or acute neuronal events selected from a stroke, brain or spinal cord injury, traumatic brain injury, brain ischemia, ischemia of the eyes, epileptic seizure, seizures associated with brain injury, epileptic seizure of genetic origin, brain damage due to drug abuse or brain damage due to excitotoxic insults of diverse nature.
• the sudden or acute neuronal event is a stroke.
• the sudden or acute neuronal event is brain or spinal cord injury.
• the sudden or acute neuronal event is an epileptic seizure.
• the sudden or acute neuronal event is brain damage due to abuse of one or more drugs.
• the sudden or acute neuronal event is brain damage due to an excitotoxic insult.
• the excitotoxic insult is caused by excessive concentrations of endogenous neurotransmitters.
• the excitotoxic insult is caused by an exogenous substance.
• the patient in need thereof is a person who has been diagnosed or is believed to be at risk of developing a neurodegenerative disorder selected from: a motor neuron disease, multiple sclerosis, Huntington's disease, Parkinson's disease, Alzheimer's disease or a dementia.
• a neurodegenerative disorder selected from: a motor neuron disease, multiple sclerosis, Huntington's disease, Parkinson's disease, Alzheimer's disease or a dementia.
• the neurodegenerative disease or disorder is a motor neuron disease.
• said motor neuron disease is selected from Amyotrophic lateral sclerosis (ALS), also called Lou Gehrig's disease, progressive bulbar palsy, also called progressive bulbar atrophy, pseudobulbar palsy, Primary lateral sclerosis (PLS), progressive muscular atrophy, spinal muscular atrophy (SMA) and some of its variants (e.g., SMA type I, also called Werdnig-Hoffrnann disease, SMA type II, SMA type III also called Kugelberg- Welander disease, congenital SMA with arthrogryposis, Kennedy's disease, also known as progressive spinobulbar muscular atrophy and post- polio syndrome (PPS)).
• ALS Amyotrophic lateral sclerosis
• PLS Primary lateral sclerosis
• SMA type I also called Werdnig-Hoffrnann disease
• SMA type II also called Kugelberg- Welander disease
• congenital SMA with arthrogryposis Kennedy
• the neurodegenerative disease or disorder is multiple sclerosis. [0075] In some embodiments, the neurodegenerative disease or disorder is Parkinson's disease.
• the neurodegenerative disease or disorder is Huntington's disease.
• the neurodegenerative disease or disorder us Alzheimer's disease or a dementia.
• the neurodegenerative disease is a neuroinflammatory disease. In other embodiments, the neurodegenerative disease is an autoimmune disease.
• the administration of a FAAH inhibitor of Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, alone or in combination with another therapeutic agent results in: halting or slowing down of neuronal degeneration in a patient that exhibits symptoms associated with neuronal injury or neurodegeneration, prolonged survival or delayed disease progression. In other embodiments, it may result in neurogenesis.
• the administration of a FAAH inhibitor of Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, alone or in combination with another therapeutic agent results in the improvement of a symptom selected from: a cognitive dysfunction, a motor dysfunction, lack of coordination, de-myelination or diminished strength.
• the administration of a FAAH inhibitor of Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, alone or in combination with another therapeutic agent, to a patient in need thereof is aimed at treating a symptom selected from: sleep disturbances, depression, anxiety, pain, erectile dysfunction, spasticity, bladder dysfunctions, fatigue, acute exacerbations, itching, nausea, vomiting, dizziness, walking difficulties, tremors.
• a symptom selected from: sleep disturbances, depression, anxiety, pain, erectile dysfunction, spasticity, bladder dysfunctions, fatigue, acute exacerbations, itching, nausea, vomiting, dizziness, walking difficulties, tremors.
• the patient has been diagnosed with multiple sclerosis.
• the administration of a FAAH inhibitor of Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, alone or in combination with another therapeutic agent also results in an observable or measurable reduction in neuroinflammation or neuroinflammatory processes.
• the administration of a FAAH inhibitor of Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, alone or in combination with another therapeutic agent also results in a simultaneous observable or measurable reduction in spasticity.
• the FAAH inhibitor is a compound of Formula I, or a pharmaceutically acceptable salt thereof:
• Formula I and V, W, X, Y are either C or N; Z, J, K, L are C; and M is N;
• Q 1 is N; Q 2 , Q 4 and Q 5 are C; and Q 3 is either C or N; a) each of P 1 , P 2 , P 3 , P 4 , P 5 and P 6 are C; or b) up to two of P 1 , P 2 , P 3 , P 4 , P 5 and P 6 are N and the rest are C;
• R 2 is hydroxyl, an optionally independently substituted Ci -3 alkyl, an optionally
• each of R 4 , R 5 , R 6 and R 7 is independently: H, a halogen, -N0 2 , -CN, -C(0)OH, hydroxyl, an optionally independently substituted C1.5 alkyl, an optionally independently substituted C 2- 5 alkenyl, an optionally independently substituted C 2-5 alkynyl, an optionally independently substituted C1.5 alkoxy, -OC(0)(C (-5 alkyl) , -C(0)(C,. 5 alkyl), -C(0)NR a R b ,
• each of R 4 , R 5 , R 6 and R 7 that is optionally substituted is independently selected from hydroxyl, halogen, -0(CO)(Ci-6 alkyl), Ci ⁇ alkoxy, or -NR a R b , with R a and R b as defined above; each of R 8 , R 9 , R 10 , R 11 and R 12 , when bonded to C, is independently: H, a halogen, -N0 2 , -CN, -C(0)OH, hydroxyl, -S0 2 (C 1.4 alkyl), an optionally independently substituted C ⁇ .s alkyl, an optionally independently substituted C 2 .
• R 14 is selected from H, a halogen, -N0 2 , -CN, -C(0)OH, hydroxyl, an optionally independently substituted Ci -5 alkyl, an optionally independently substituted C 2-5 alkenyl, an optionally independently substituted C 2- s alkynyl, an optionally independently substituted Ci. $ alkoxy, -C(0)NR R or -NR a R b , wherein R a and R b are independently H, an optionally independently substituted Ci -6 alkyl, or an optionally independently substituted C 3-6 cycloalkyl;
• R 16 is selected from H, a halogen, -N0 2 , -CN, -C(0)OH, hydroxyl, an optionally independently substituted Q.5 alkyl, an optionally independently substituted C 2 . 5 alkenyl, an optionally independently substituted C 2-5 alkynyl, an optionally independently substituted Ci -5 alkoxy, -C(0)NR a R b , or -NR a R b , wherein R a and R b are independently H, optionally independently substituted Ci- 6 alkyl, or an optionally independently substituted C 3- 6
• R 15 is missing
• R 13 is selected from H, a halogen, -N0 2 , -CN, -C(0)OH, hydroxyl, an optionally independently substituted .5 alkyl, an optionally independently substituted C 2- s alkenyl, an optionally independently substituted C 2-5 alkynyl, an optionally independently substituted Ci -5 alkoxy, -C(0)NR a R b or -NR a R b , wherein R a and R b are independently H, optionally independently substituted Ci-6 alkyl, or an optionally independently substituted C 3-6 cycloalkyl;
• R 17 is selected from H, a halogen, -N0 2 , -CN, -C(0)OH, hydroxyl, an optionally independently substituted Ci -5 alkyl, an optionally independently substituted C 2-5 alkenyl, an optionally independently substituted C2.5 alkynyl, an optionally independently substituted Ci_5 alkoxy, -C(0)NR a R b or -NR a R b , wherein R a and R b are independently H, optionally independently substituted Ci -6 alkyl, or an optionally independently substituted C 3-6 cycloalkyl.
• compositions, kits and uses up to two of up to one of P 1 , P 2 , P 3 , P 4 , P 5 and P 6 is N and the rest are C in said FAAH inhibitor of Formula I.
• one of P 1 , P 2 , P 3 , P 4 , P 5 and P 6 is N and the rest are C in said FAAH inhibitor of Formula I.
• each of Pi, P 2 , P3, P 4 , P5 and P 6 is C in said FAAH inhibitor of Formula I.
• R 2 is a C 1.3 alkyl or cyclopropyl in said FAAH inhibitor of Formula I. In other embodiments, R 2 is methyl in said FAAH inhibitor of Formula I.
• one or two of R 8 , R 9 , R 10 , R 1 1 and R 12 are independently selected from a halogen and the rest are H in said FAAH inhibitor of Formula I.
• one or two of R 8 , R 9 , R 10 , R 1 1 and R 12 are CI or F and the rest are H in said FAAH inhibitor of Formula I.
• R 10 is a halogen in said FAAH inhibitor of Formula I.
• one of R 8 and R is a halogen and the other is H in said FAAH inhibitor of Formula I.
• R 10 is CI or F; and R 8 , R 9 , R 11 and R 12 are H in said compound of Formula I.
• R 10 is CI or F; R 8 is CI or F; and R 9 , R 1 1 and R 12 are H in said compound of Formula I.
• compositions, kits and uses, R 4 and R 7 are H in said FAAH inhibitor of Formula I.
• R 6 is H in said FAAH inhibitor of Formula I.
• R 5 is selected from: ethoxy, methoxy, ethyl, methyl, halogen and H in said FAAH inhibitor of Formula I. In other embodiments, R 5 is selected from chloro, methoxy, methyl and H in said compound of Formula I. In still other embodiments, R 5 is methoxy in said compound of Formula I. In a further embodiment, R 5 is methyl in said compound of Formula I.
• R 14 or R 16 is selected from a halogen or an optionally independently substituted methoxy and both R ]3 and R
• R 14 or R 16 is -OCH 3 and the other is hydrogen in said compound of Formula I.
• 6 is halogen or an optionally independently substituted methoxy and the other is hydrogen, and both Ri 3 and R
• the FAAH inhibitor of Formula I is selected from the following list of compounds of Table 1:
• the FAAH inhibitor of Formula I is selected from those depicted in Table 2 below:
• halo or halogen refers to any radical of fluorine, chlorine, bromine or iodine.
• cyano refers to -CN or -C ⁇ N.
• alkyl refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, C
• haloalkyl refers to an alkyl in which one or more hydrogen atoms are replaced by halo, and includes alkyl moieties in which all hydrogen atoms have been replaced by halo (e.g., perfluoroalkyl).
• arylalkyl or “aralkyl” refer to an alkyl moiety in which an alkyl hydrogen atom is replaced by an aryl group.
• arylalkyl or “aralkyl” include, but are not limited to, benzyl and 9-fluorenyl groups.
• alkenyl refers to a linear or branched-chain monovalent hydrocarbon radical with at least one site of unsaturation, i.e., a carbon-carbon, sp2 double bond, wherein the alkenyl radical includes radicals having "cis” and “trans” orientations, or alternatively, "E” and “Z” orientations.
• an alkenyl group contains 2-20 carbon atoms (e.g., 2-20 carbon atoms, 2-10 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms, 2-4 carbon atoms or 2-3 carbon atoms). Examples include, but are not limited to, vinyl, allyl and the like.
• alkynyl refers to a linear or branched monovalent hydrocarbon radical with at least one site of unsaturation, i.e., a carbon-carbon sp triple bond. Unless otherwise specified, an alkynyl group contains 2-20 carbon atoms (e.g., 2-20 carbon atoms, 2-10 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms, 2-4 carbon atoms or 2-3 carbon atoms).
• Examples include, but are not limited to, ethynyl, propynyl, and the like.
• alkoxy refers to an -O-(alkyl) radical.
• alkoxy or alkoxyl can refer to groups of 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms of a straight, branched, or cyclic configuration and combinations thereof attached to the parent structure through an oxygen atom. Examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like.
• Lower alkoxy refers to groups containing one to four carbons.
• cycloalkyl as employed herein includes saturated monocyclic, bicyclic, tricyclic, or polycyclic hydrocarbon groups having 3 to 12 carbons, wherein any ring atom capable of substitution can be substituted by a substituent.
• cycloalkyl moieties include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, norbornyl, cyclohexyl and adamantyl.
• Carbocycle as employed herein includes saturated, partially unsaturated or unsaturated monocyclic, bicyclic, tricyclic, or polycyclic hydrocarbon groups having 3 to 12 carbons, wherein any ring atom capable of substitution can be substituted by a substituent.
• Carbocycles can be aromatic, e.g., a phenyl ring is an example of a carbocycle.
• a subset of the carbocycles is the non-aromatic carbocycles.
• two independent occurrences of a variable may be taken together with the atom(s) to which each variable is bound to form a 5-8-membered, heterocyclyl, aryl, or heteroaryl ring or a 3-8-membered cycloalkyl ring.
• Example rings that are formed when two independent occurrences of a substituent are taken together with the atom(s) to which each variable is bound include, but are not limited to the following: a) two independent occurrences of a substituent that are bound to the same atom and are taken together with that atom to form a ring, where both occurrences of the substituent are taken together with the atom to which they are bound to form a heterocyclyl, heteroaryl, carbocyclyl or aryl ring, wherein the group is attached to the rest of the molecule by a single point of attachment; and b) two independent occurrences of a substituent that are bound to different atoms and are taken together with both of those atoms to form a heterocyclyl, heteroaryl, carbocyclyl or aryl ring, wherein the ring that is formed has two points of attachment with the rest of the molecule.
• a phenyl group is substituted with two occurrences of -OR 0 as in Formula ⁇
• substituted refers to a group "substituted" on an alkyl, cycloalkyl, alkenyl, alkynyl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, aryl, or heteroaryl group or other group at any atom of the group.
• the group can be singly or multiply substituted and where multiply substituted, the substituents are independent.
• Suitable substituents include, without limitation : F, CI, Br, I, alkyl, alkenyl, alkynyl, alkoxy, acyloxy, halo, hydroxy, cyano, nitro, amino, SO 3 H, sulfate, phosphate, perfluoroalkyl, perfluoroalkoxy,
• the substituents on a group are independently any one single, or any subset of the aforementioned substituents.
• the substituents are selected from: F, CI, Br and I.
• the substituents are selected from: halogen, optionally independently halogen substituted C 1 .C 3 alkyl, optionally independently halogen substituted Ci.C 3 alkoxy, hydroxy, cyano, nitro and amino.
• the substituents are selected from aryl groups.
• the substituents are selected from heteroaryl groups.
• the substituents are selected from:
• substituents are selected from:
• diastereomeric, atropoisomeric and cis-trans isomeric) forms of the structure for example, the R and S configurations for each asymmetric center, Ra and Sa configurations for each asymmetric axis, (Z) and (E) double bond configurations, and cis and trans conformational isomers. Therefore, single stereochemical isomers as well as racemates, and mixtures of enantiomers, diastereomers, and cis-trans isomers (double bond or conformational) of the present compounds are within the scope of the present disclosure. Unless otherwise stated, all tautomeric forms of the compounds of the present disclosure are within the scope of the disclosure.
• the present disclosure also embraces the use of isotopically labeled compounds which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention, and their uses.
• Example isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2 H, 3 H, 1 'c, l3 C, 14 C, ,3 N, ,5 N, 15 0, 17 0, ,8 0, 32 P, 33 P, 35 S, l8 F, 36 C1, l23 I and ,25 I, respectively.
• Certain isotopically-labeled compounds of the present invention e.g., those labeled with 3 H and 14 C) are useful in compound and/or substrate tissue distribution assays.
• Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
• Positron-emitting isotopes such as l5 0, 13 N, U C, and 18 F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy.
• Isotopically labeled compounds of the present invention can generally be prepared by following procedures known to those having ordinary skill in the art, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
• the FAAH inhibitor of Formula I is administered before a symptom of neurodegeneration develops in said patient. In other embodiments, it is administered after the symptom develops. In further embodiments, the FAAH inhibitor of Formula I is administered before a symptom of neurodegeneration develops in said patient. In other embodiments, it is administered after the symptom develops.
• the FAAH inhibitor of Formula I is administered prior to, at the same time or after the initiation of treatment with another therapeutic agent. In some embodiments of the above methods and uses, the FAAH inhibitor is administered after one or more symptoms of neurodegeneration develops in said patient.
• the additional therapeutic agent and the FAAH inhibitor of Formula I are administered simultaneously. In other embodiments of the above methods and uses, the additional therapeutic agent and the FAAH inhibitor are administered sequentially or separately.
• the above pharmaceutical compositions or kits comprise (a) a FAAH inhibitor as discussed above or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier, vehicle or adjuvant.
• the pharmaceutical composition or kit comprises (a) an additional therapeutic agent as discussed above, or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier, vehicle or adjuvant.
• the pharmaceutical composition comprises (i) a FAAH inhibitor as discussed above, or a pharmaceutically acceptable salt thereof, (ii) an additional therapeutic agent as discussed above, or a pharmaceutically acceptable salt thereof, and (iii) a pharmaceutically acceptable carrier, vehicle or adjuvant.
• the pharmaceutical composition further comprises at least one additional therapeutic agent.
• the FAAH inhibitor may be provided as (i) the compound itself (e.g., as the free base); (ii) a pharmaceutically acceptable salt of the compound; or (iii) part of a pharmaceutical composition.
• uses, pharmaceutical compositions or kits uses, pharmaceutical compositions or kits.
• the additional therapeutic agent may be provided as (i) the compound itself (e.g., as the free base); (ii) a pharmaceutically acceptable salt of the compound; (iii) or part of a pharmaceutical composition.
• pharmaceutically acceptable salt refers to pharmaceutically acceptable organic or inorganic salts of a compound described herein.
• the salts of the compounds described herein will be pharmaceutically acceptable salts.
• Other salts may, however, be useful in the preparation of the compounds described herein or of their pharmaceutically acceptable salts.
• a pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counter ion.
• the counter ion may be any organic or inorganic moiety that stabilizes the charge on the parent compound.
• a pharmaceutically acceptable salt may have more than one charged atom in its structure. Instances where multiple charged atoms are part of the pharmaceutically acceptable salt can have multiple counter ions. Hence, a
• pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counter ion.
• salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases.
• the salts can be prepared in situ during the final isolation and purification of the compounds.
• the salts can be prepared from the free form of the compound in a separate synthetic step.
• suitable “pharmaceutically acceptable salts” refers to salts prepared form pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases.
• Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc and the like. Particular embodiments include ammonium, calcium, magnesium, potassium and sodium salts.
• Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N, N'-dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediarnine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimemylamine tripropylamine, tromethamine and the like.
• basic ion exchange resins such as
• salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
• acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like.
• Particular embodiments include citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids.
• Other exemplary salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate,
• benzenesulfonate p-toluenesulfonate, and pamoate (i.e., l,l'-methylene-bis-(2-hydroxy-3- naphthoate)) salts.
• compositions and kits of the invention are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including, without limitation, dogs, cats, mice, rats, hamsters, gerbils, guinea pigs, rabbits, horses, pigs and cattle.
• the compounds and pharmaceutical compositions described herein can be used in combination therapy with one or more additional therapeutic agents.
• the active agents may be administered separately or in conjunction.
• the administration of one agent may be prior to, concurrent to, or subsequent to the administration of the other agent.
• an "effective amount" of the second agent will depend on the type of drug used. Suitable dosages are known for approved agents and can be adjusted by the skilled artisan according to the condition of the subject, the type of condition(s) being treated and the amount of a compound described herein being used. In cases where no amount is expressly noted, an effective amount should be assumed.
• compounds described herein can be administered to a subject in a dosage range from between about 0.001 to about 100 mg/kg body weight/day, from about 0.001 to about 50 mg/kg body weight/day, from about 0.001 to about 30 mg/kg body weight/day, from about 0.001 to about 10 mg/kg body weight/day.
• an effective amount can be achieved using a first amount of a compound of Formula I or a pharmaceutically acceptable salt thereof and a second amount of an additional suitable therapeutic agent (e.g. another neuroprotective or neuroprotecting agent).
• an additional suitable therapeutic agent e.g. another neuroprotective or neuroprotecting agent
• the compound described herein and the additional therapeutic agent are each administered in an effective amount (i.e., each in an amount which would be therapeutically effective if administered alone).
• the compound described herein and the additional therapeutic agent are each administered in an amount which alone does not provide a therapeutic effect (a subtherapeutic dose).
• the compound described herein can be administered in an effective amount, while the additional therapeutic agent is administered in a sub-therapeutic dose.
• the compound described herein can be admimstered in a sub-therapeutic dose, while the additional therapeutic agent, for example, a suitable anti-inflammatory agent is administered in an effective amount.
• the terms “in combination” or “co-administration” can be used interchangeably to refer to the use of more than one therapy (e.g., one or more prophylactic and/or therapeutic agents).
• the use of the terms does not restrict the order in which therapies (e.g., prophylactic and/or therapeutic agents) are administered to a subject.
• Co-administration encompasses administration of the first and second amounts of the compounds in an essentially simultaneous manner, such as in a single pharmaceutical composition, for example, capsule or tablet having a fixed ratio of first and second amounts, or in multiple, separate capsules or tablets for each.
• co-administration also encompasses use of each compound in a sequential mariner in either order.
• coadministration involves the separate administration of the first amount of a compound described herein and a second amount of an additional therapeutic agent, the compounds are administered sufficiently close in time to have the desired therapeutic effect.
• the period of time between each administration which can result in the desired therapeutic effect can range from minutes to hours and can be determined taking into account the properties of each compound such as potency, solubility, bioavailability, plasma half-life and kinetic profile.
• a compound described herein and the second therapeutic agent can be administered in any order within about 24 hours of each other, within about 16 hours of each other, within about 8 hours of each other, within about 4 hours of each other, within about 1 hour of each other or within about 30 minutes of each other, within about 5 minutes of each other, etc.
• a first therapy e.g., a prophylactic or therapeutic agent such as a compound described herein
• a first therapy can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks prior to), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks subsequent to) the administration of a second therapy (e.g., a therapeutic agent) to a subject.
• a second therapy e.g., a therapeutic agent
• the compounds and pharmaceutical formulations described herein may be contained in a kit.
• the kit may include single or multiple doses of two or more agents, each packaged or formulated individually, or single or multiple doses of two or more agents packaged or formulated in combination.
• one or more agents can be present in first container, and the kit can optionally include one or more agents in a second container.
• the container or containers are placed within a package, and the package can optionally include administration or dosage instructions.
• a kit can include additional components such as syringes or other means for administering the agents as well as diluents or other means for formulation.
• kits can comprise: a) a pharmaceutical composition comprising a compound of Formula I described herein and a pharmaceutically acceptable carrier, vehicle or diluent; and b) another therapeutic agent and a pharmaceutically acceptable carrier, vehicle or diluent in one or more containers or separate packaging.
• the kits may optionally comprise instructions describing a method of using the pharmaceutical compositions in one or more of the methods described herein (e.g. preventing or treating one or more of the diseases and disorders described herein).
• the pharmaceutical composition comprising the compound described herein and the second pharmaceutical composition contained in the kit may be optionally combined in the same pharmaceutical composition.
• a kit includes a container or packaging for containing the pharmaceutical compositions and may also include divided containers such as a divided bottle or a divided foil packet.
• the container can be, for example a paper or cardboard box, a glass or plastic bottle or jar, a re-sealable bag (for example, to hold a "refill" of tablets for placement into a different container), or a blister pack with individual doses for pressing out of the pack according to a therapeutic schedule. It is feasible that more than one container can be used together in a single package to market a single dosage form. For example, tablets may be contained in a bottle which is in turn contained within a box.
• Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process, recesses are formed in the plastic foil. The recesses have the size and shape of individual tablets or capsules to be packed or may have the size and shape to accommodate multiple tablets and/or capsules to be packed. Next, the tablets or capsules are placed in the recesses accordingly and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are individually sealed or collectively sealed, as desired, in the recesses between the plastic foil and the sheet.
• the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
• a “daily dose” can be a single tablet or capsule or several tablets or capsules to be taken on a given day.
• a daily dose of one or more compositions of the kit can consist of one tablet or capsule while a daily dose of another one or other compositions of the kit can consist of several tablets or capsules.
• a kit can take the form of a dispenser designed to dispense the daily doses one at a time in the order of their intended use. The dispenser can be equipped with a memory-aid, so as to further facilitate compliance with the regimen.
• a memory-aid is a mechanical counter which indicates the number of daily doses that have been dispensed.
• a battery-powered micro-chip memory coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the last daily dose has been taken and/or reminds one when the next dose is to be taken.
• the additional therapeutic agent or agents may be selected from one or more of the following:
• anti-inflammatory and/or immunosuppressive/immunomodulatory agents such as methotrexate, cyclosporin A (including, for example, cyclosporin microemulsion), tacrolimus, corticosteroids, statins, interferon beta, infliximab (RemicadeTM), etanercept (Enbrel ) or adalimumab (Humira ); other FK-506 type immunosuppressants, and mycophenolate, e.g., mycophenolate mofetil (CellCeptTM, MyforticTM); rapamycin
• antidepressants such as SSRIs (e.g., fluoxetine, citalopram, femoxetine, fluvoxamine, paroxetine, indalpine, sertraline, zimeldine), a combined SSRI and 5HT1
• a partial agonist e.g., vilazodone
• a tricyclic antidepressant e.g., imipramine, amitriptiline (Elavil), chlomipramine and nortriptiline
• a therapeutic antidepressant e.g., bupropion and amineptine
• an SNRIs e.g., venlafaxine and reboxetine
• non-steroidal anti-inflammatory agents such as propionic acid derivatives (e.g., alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid and tioxaprofen), acetic acid derivatives (e.g., indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac, oxpinac, sulindac, tiopinac
• COX-2 (COX-2) inhibitors such as celecoxib (Celebrex®), rofecoxib (Vioxx®), valdecoxib, etoricoxib, parecoxib and lumiracoxib, and opioid analgesics such as codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, propoxyphene, buprenorphine, buto hanol, dezocine, nalbuphine and pentazocine;
• COX-2 (COX-2) inhibitors such as celecoxib (Celebrex®), rofecoxib (Vioxx®), valdecoxib, etoricoxib, parecoxib and lumiracoxib
• opioid analgesics such as codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxyco
• calcium channel blockers such as: dihydropyridine, Amlodipine (Norvasc), Aramdipine (Sapresta), Azelnidipine (Calblock), Barnidipine (HypoCa), Benidipine (Coniel), Cilnidipine (Atelec, Cinalong, Siscard), Clevidipine (Cleviprex), Diltiazem, Efonidipine (Landel), Felodipine (Plendil), Lacidipine (Motens, Lacipil), Lercanidipine (Zanidip), Manidipine (Calslot, Madipine), Nicardipine (Cardene, Carden SR.), Nifedipine (Procardia, Adalat), Nilvadipine (Nivadil), Nimodipine (Nimotop), Nisoldipine (Baymycard, Sular, Syscor), Nitrendipine (Cardif, Nitrepin, Baylotensin),
• Gallopamil Procorum, D600
• Benzothiazepines Diltiazem (Cardizem);
• nonselective calcium channel inhibitors such as: mibefradil, bepridil and fluspirilene, fendiline;
• endothelin receptor antagonists for instance the dual (ET A and ETB) endothelin receptor antagonist Bosentan (marketed as Tracleer®); sitaxentan, marketed under the name Thelin®; ambrisentan is marketed as Letairis® in U.S; dual/nonselective endothelin antagonist Actelion-1, that entered clinical trials in 2008;
• prostacyclin derivatives or analogues for instance prostacyclin (prostaglandin I 2 ), Epoprostenol (synthetic prostacyclin, marketed as Flolan®); Treprostinil (Remodulin®), Iloprost (Ilomedin®), Iloprost (marketed as Ventavis®); oral and inhaled forms of
• Remodulin® that are under development; Beraprost, an oral prostanoid available in Japan and South Korea;
• antihyperlipidemics such as: bile acid sequestrants (e.g., Cholestyramine,
• statins such as Atorvastatin, Simvastatin,
• Anticoagulants such as the following types:
• Phenindione ® Heparin and derivative substances such as: Heparin; low molecular weight heparin, Fondaparinux and Idraparinux; direct thrombin inhibitors such as: Argatroban, Lepirudin, Bivalirudin and Dabigatran; Ximelagatran (Exanta®), not approved in the US; Tissue plasminogen activators, used to dissolve clots and unblock arteries, such as Alteplase;
• Antiplatelet drugs for instance thienopyridines such as Lopidogrel and Ticlopidine; Dipyridamole; Aspirin;
• ACE inhibitors for example the following types:
• Sulfhydryl-containing agents such as Captopril (trade name Capoten®), the first ACE inhibitor and Zofenopril;
• Dicarboxylate-containing agents such as Enalapril (Vasotec/Renitec®); Ramipril (Altace/Tritace/Ramace/Ramiwin®); Quinapril (Accupril®), Perindopril (Coversyl/Aceon®); Lisinopril (Lisodur/Lopril/Novatec Prinivil/Zestril®) and Benazepril (Lotensin®);
• Phosphonate-containing agents such as: Fosinopril;
• Naturally occurring ACE inhibitors such as: Casokinins and lactokinins, which are breakdown products of casein and whey that occur naturally after ingestion of milk products, especially cultured milk;
• the Lactotripeptides Val-Pro-Pro and Ile-Pro-Pro produced by the probiotic Lactobacillus helveticus or derived from casein also have ACE-inhibiting and antihypertensive functions;
• ACE inhibitors such as Alacepril, Delapril, Cilazapril, Imidapril, Trandolapril, Temocapril, Moexipril, Spirapril;
• Beta blockers such as the following types:
• Non-selective agents Alprenolol®, Bucindolol®, Carteolol®, Carvedilol® (has additional ⁇ -blocking activity), Labetalol® (has additional a-blocking activity), Nadolol®, Penbutolol® (has intrinsic sympathomimetic activity), Pindolol® (has intrinsic
• Acebutolol® (has intrinsic sympathomimetic activity), Atenolol®, Betaxolol®, Bisoprolol®, Celiprolol®, Dobutamine hydrochloride, Irsogladine maleate, Carvedilol, Talinolol, Esmolol®, Metoprolol® and Nebivolol®;
• Butaxamine® weak a-adrenergic agonist activity
• Antiarrhythmic agents such as the following types:
• Type I sodium channel blockers: Quinidine, Lidocaine, Phenytoin, Propafenone
• Type III (potassium channel blockers): Amiodarone, Dofetilide, Sotalol
• Type V Adenosine, Digoxin
• Diuretics such as: Thiazide diuretics, e.g., Chlorothiazide, Chlorthalidone, and Hydrochlorothiazide, Bendroflumethiazide, Cyclopenthiazide, ethyclothiazide,
• Polythiazide Quinethazone, Xipamide, Metolazone, Indapamide, Cicletanine; Loop diuretics, such as Furosemide and Toresamide; potassium-sparing diuretics such as
• Direct acting vasodilators such as Hydralazine hydrochloride, Diazoxide, Sodium nitroprusside, Cadralazine; other vasodilators such as Isosorbide dinitrate and Isosorbide 5- mononitrate;
• Exogenous vasodilators such as:
• Adenocard® an adenosine agonist, primarily used as an anti-arrhythmic
• Alpha blockers which block the vasoconstricting effect of adrenaline
• Alpha- 1 -adrenoceptor antagonists such as Prazosin, Indoramin, Urapidil, Bunazosin, Terazosin, Doxazosin;
• Atrial natriuretic peptide ADP
• Histamine-inducers which complement proteins C3a, C4a and C5a work by triggering histamine release from mast cells and basophil granulocytes;
• THC Tetrahydrocannabinol
• Major active chemical in marijuana which has minor vasodilatory effects
• Papaverine an alkaloid found in the opium poppy papaver somniferum
• Bronchodilators there are two major types of bronchodilator, ⁇ 2 agonists and anticholinergics, exemplified below:
• Terbutaline® are short acting ⁇ 2 agonists for rapid relief of COPD symptoms.
• Long acting ⁇ 2 agonists such as Salmeterol® and Formoterol®;
• Ipratropium® is the most widely prescribed short acting
• Tiotropium® is the most commonly prescribed long-acting
• Theophylline® a bronchodilator and phosphodiesterase inhibitor
• Corticosteroids such as beclomethasone, methylprednisolone, betamethasone, prednisone, prenisolone, triamcinolone, dexamethasone, fluticasone, flunisolide and hydrocortisone, and corticosteroid analogs such as budesonide;
• Dietary supplements such as, for example: omega-3 oils; folid acid, niacin, zinc, copper, Korean red ginseng root, ginkgo, pine bark, Tribulus terrestris, arginine, Avena sativa, horny goat weed, maca root, muira puama, saw palmetto, and Swedish flower pollen; Vitamin C, Vitamin E, Vitamin K2; Testosterone supplements, Testosterone transdermal patch; Zoraxel, Naltrexone, Bremelanotide (formerly PT-141), Melanotan II, hMaxi-K;
• Prelox a Proprietary mix/combination of naturally occurring ingredients, L-arginine aspartate and Pycnogenol;
• Anti-diabetic agents such as insulin and insulin mimetics, sulfonylureas (e.g., Glyburide, Glybenclamide, Glipizide, Gliclazide, Gliquidone, Glimepiride, Meglinatide, Tolbutamide, Chlorpropamide, Acetohexamide, Tolazamide), biguanides, e.g., metformin (Glucophage®), a-glucosidase inhibitors (such as Acarbose, Epalrestat, Voglibose, Miglitol), thiazolidinone compounds, e.g., rosiglitazone (Avandia®), troglitazone (Rezulin®), ciglitazone, pioglitazone (Actos®) and englitazone; insulin sensitizers such as Pioglitazone and Rosiglitazone; Insulin secretagogues such as Repaglinide,
• Atorvastatin DP-IV Atorvastatin DP-IV
• HDL cholesterol-increasing agents such as Anacetrapib, MK-524A, CER-001, DRL- 17822, Dalcetrapib, JTT-302, RVX-000222, TA-8995;
• Antiobesity drugs such as Methamphetamine hydrochloride, Amfepramone hydrochloride (Tenuate ®), Phentermine (lonamin ®), Benzfetamine hydrochloride (Didrex ®), Phendimetrazine tartrate (Bontril®, Prelu-2 ®, Plegine ®), Mazindol (Sanorex ®), Orlistat (Xenical ®), Sibutramine hydrochloride monohydrate (Meridia ®, Reductil ®), Rimonabant (Acomplia ®), Amfepramone, Chromium picolinate, RM-493, TZP-301;
• Renin inhibitors such as Aliskiren hemifumirate
• Adrenergic neuron blockers such as Guanethidine, Guanadrel;
• Imidazoline 1-1 receptor agonists such as Rimenidine dihydrogen phosphate and Moxonidine hydrochloride hydrate;
• Aldosterone antagonists such as Spironolactone and Eplerenone
• Dopamine Dl agonists such as Fenoldopam mesilate
• other dopamine agonists such as Ibopamine, Dopexamine and Docarpamine
• NHE- 3 type 3 (NHE-3) Inhibitors
• VIP2 Vasomera PhaseBio (VIP2) Phase I
• Vasopressin antagonists such as Tolvaptan
• PDE-3 inhibitors such as Amrinone, Milrinone, Enoximone, Vesnarinone,
• Adenylate cyclase activators such as Colforsin dapropate hydrochloride
• Positive inotropic agents such as Digoxin and Metildigoxin; metabolic cardiotonic agents such as Ubidecarenone; brain naturetic peptides such as Nesiritide;
• Vasopressin A VP
• Drugs used for the treatment of erectile dysfunction such as Alprostadil, Aviptadil, Phentolamine mesilate, Weige, Alprostadil;
• Antiobesity drugs Methamphetamiae hydrochloride (DesoxynTM), Arafepramone hydrochloride (TenuaieTM), Phentermine (lonaminTM), Benzfetamine hydrochloride (DiclrexTM), Phendimetrazine tartrate (BontrilTM, Pre!u-2TM PlegineTM), Mazindol (SanorexTM), Orlistat (XenicalTM), Sibutramiue hydrochloride monohydrate (xMeridiaTM, ReductilTM), Rimonabant (AcompliaTM);
• Drugs marketed, for the treatment of Alzheimer's disease Idebenone (AvaaTM), Tacrine hydrochloride (CognexTM), Galanta.mi.ne hydrobroinide (RemiiiylTM), Donepezil hydrochloride (AriceptTM), Rivastigniine tartrate (ExelonTM), Memantine hydrochloride ( Axura, EbixaTM);
• muscle relaxants such as baclofen, tizanidine, and the benzodiazepines to reduce spasticity
• Botulinum toxin to treat jaw spasms or drooling
• excessive saliva can be treated with amitriptyline, glycopyolate, and atropine or by botulinum injections into tlie salivary glands
• Combtnations of dextroniethoiphan and quinidine to reduce pseudobulbar affect Nuedexta, a combination product incorporating the NMEA an ia gonis t/sigma- 1 agonist
• dextromethorphan hydrobromide and the CYP450 2D6 inhibitor quinidine sulfate, which was launched in 20.1 1 , and prolongs exposure of dextromethorphan is the first and only FDA- approved treatment for PBA, and whose safety and efficacy have been demonstrated in patients with MS and ALS; Anticonvulsatits and nonsteroidal anti-inflammatory drugs to relieve pain, and antidepressants for treating depression.
• Panic attacks can be treated with benzodiazepines: some individuals may eventually require stronger medicines such as tnorphirte to cope with musculoskeletal abnormalities or pain, and opiates to provide comfort care in terminal stages of the disease;
• Antispastic drugs (R)-(-)-Baclofen, Arbadofen, D-Baclotett, l-Baclofen Tiza dine hydrochloride (Sirdalud, Ternelin. Zanafiex), Eperisone hydrochloride (Myonal);
• Neuroprotective agents such as the antibiotic ceftriaxone, which may be neuroprotective in ALS, dexpramipexole.
• DHFR Reductase
• Interferons Interferon beta- lb (Extavia, Betaseron, Betaferon), Interferon beta- la (Avonex), Interferon beta- la (Rebif), Interferon alfa-nl (Sumiferon MP)); Copolymer- 1 Glatiramer acetate (Copaxone); Immunomodulators:
• Mitoxantrone hydrochloride Novantrone
• fingolimod hydrochloride Gadribine
• Movectro Cladribine
• Monoclonal antibodies Natalizumab (Tysabri); Symptomatic therapies:
• Cannabi.oo.ids such as the following: Tetrahydrocannabinol (THC), cannabidiol (CBD), cannabinol (CBN), and Dodeca-2E,4E,8Z, 10E/Z-tetraenoic--acid-isobutylaniides (from Echinacea species); Cannabigerol, Cannabichromene,Caniiabicyeiol, Cannabivarin,
• Cannabidivarin Tetrahydrocannabivarin, Cannabichromevarin, Cannabigerovarin,
• Cannabigerol onomethyl Ether Dronabinol (Marinol), Nabilone (Cesamet, a synthetic cannabinoid and an analog of Marinol), Sativex (cannabinoid extract oral spray containing THC, CBD, and other cannabmotds used for neuropathic pain and spasticity), Rimonabant (SR141716, a selective cannabinoid (CBj) receptor inverse agonist used as an anti-obesity drug under the proprietary name Acomplia, also used for smokin cessation); other notable synthetic cannabinoids include: JWH-018, CP-55940, Diraethylheplylpyran, HU-210, HU- 33.1 , SRI 44528, WIN 55,212-2, JWH-133, Levonantradol (Nantrodolum) and AM-2201 ;

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Epidemiology (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Biomedical Technology (AREA)
• Neurology (AREA)
• Neurosurgery (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Indole Compounds (AREA)

Applications Claiming Priority (2)

Publications (1)

Family

ID=48747801

Family Applications (1)

Country Status (1)

Cited By (11)

Citations (9)

• 2013
  • 2013-06-26 WO PCT/US2013/047895 patent/WO2014004676A1/fr not_active Ceased

Patent Citations (9)

Non-Patent Citations (22)

Similar Documents

Legal Events