Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D498/08—Bridged systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • 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
  • A61P25/06—Antimigraine agents
• • 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
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
• • 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
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
• • 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
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • 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
  • A61P25/22—Anxiolytics
• • 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
  • A61P25/24—Antidepressants
• • 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
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

• the present invention relates generally to a certain polymorphic form and pharmaceutical science.
• Polymorphism relates to the occurrence of different crystal forms for a molecule. These different crystalline forms have distinct crystal structures and vary in physical properties like melting point and XRPD spectrum. A particular polymorph may have advantageous properties for the manufacture and use of the drug substance.
• the present invention relates to a particular polymorphic form of 1 -( 1 -methyl- 1 H- pyrazol-4-yl)-N-((lR,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-lH-indole-3- carboxamide, free base, which is an antagonist of the 5-HT3 receptor.
• the present polymorphic form l-(l-methyl-lH-pyrazol-4-yl)-N-((lR,5S,7S)-9- methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-lH-indole-3-carboxamide, Form G, provides an anhydrate form, that can be readily and reproducibly produced and is stable to prolonged thermal stress.
• the present invention provides a novel polymorph of 1 -( 1 -methyl- 1 H-pyrazol-4- yl)-N-((lR,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-lH-indole-3- carboxamide. More specifically, the present invention provides 1 -(1 -methyl- 1 H-pyrazol-4- yl)-N-((lR,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-lH-indole-3- carboxamide, Form G.
• the present invention also provides a pharmaceutical composition
• a pharmaceutical composition comprising 1- (l-methyl-lH-pyrazol-4-yl)-N-((lR,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)- lH-indole-3-carboxamide, Form G, and a pharmaceutically acceptable excipient.
• the present invention also provides a methods of treating a disease treatable by administration of a 5-HT3 receptor antagonist which method comprises administrating to the patient l-(l-methyl-lH-pyrazol-4-yl)-N-((lR,5S,7S)-9-methyl-3-oxa-9- azabicyclo[3.3.1]nonan-7-yl)-lH-indole-3-carboxamide, Form G.
• the present invention provides a method of treating a disease treatable by administration of a 5-HT3 receptor antagonist comprising: administrating to a patient in need thereof a therapeutically effective amount of l-(l-methyl-lH-pyrazol-4-yl)-N-((lR,5S,7S)-9-methyl-3-oxa-9- azabicyclo[3.3.1]nonan-7-yl)-lH-indole-3-carboxamide, Form G.
• the invention is directed to the use of l-(l-methyl-lH-pyrazol-4-yl)-N-((lR,5S,7S)-9-methyl-3-oxa-9- azabicyclo[3.3.1]nonan-7-yl)-lH-indole-3-carboxamide, Form G, to treat a disease treatable by administration of a 5-HT3 receptor antagonist as disclosed herein, that is, the use of 1-(1- methyl- 1 H-pyrazol-4-yl)-N-(( 1 R,5 S ,7S)-9-methyl-3 -oxa-9-azabicyclo [3.3.1 ]nonan-7-yl)- 1 H- indole-3-carboxamide, Form G, for the manufacture of a medicament to treat diseases treatable by administration of a 5-HT3 receptor antagonist as disclosed herein.
• the drawing shows X-ray powder diffraction patterns (counts vs. degrees 2-theta) of 1 -( 1 -methyl- 1 H-pyrazol-4-yl)-N-(( 1 R,5 S ,7S)-9-methyl-3 -oxa-9-azabicyclo [3.3.1 ]nonan-7- yl)-lH-indole-3-carboxamide, Form G, which was prepared from a hydrate of l-(l-methyl- lH-pyrazol-4-yl)-N-((lR,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-lH-indole- 3-carboxamide using different solvents and/or conditions for crystallization: (a) starting material heated to 50°C in DMSO, followed by aqueous NaOH (4 M); mixture stirred at 50°C for 30 minutes and then allowed to cool to room temperature over a 4-
• C 2 -4 alkylnitrile refers to a straight or branched alkyl chain having a nitrile, and having a total of from two to four carbon atoms, for example acetonitrile and propionitrile.
• C 3 _ 7 alkylacetate refers to straight or branched alkyl esters of acetic acid having a total of three to seven carbons, for example, ethyl acetate, isopropyl acetate, and the like.
• Ci_ 6 alcohol a straight or branched alcohols having from one to six carbon atoms, for example methanol, ethanol, n-propanol, iso-propanol, 1,3-propanediol, and the like.
• C 2 -8 ether refers to a straight, branched, or cyclic alkyl ethers having a total of from two to eight carbon atoms, for example diethyl ether, methyl-t-butyl ether, THF, dioxane, and the like.
• C 6 -9 aromatic hydrocarbons refers to benzene and alkyl substituted benzene, such a toluene, xylene, and the like.
• C 3 _ 5 ⁇ , ⁇ -dimethylcarboxamides refers to ⁇ , ⁇ -dimethylamides of a Ci_ 3 carboxylic acid, for example N,N-dimethylformamide.
• C 3 _ 7 alkanones refers to a straight or branched alkyl chain having an oxo group and having a total of from three to seven carbon atoms, for example acetone and methyl ethyl ketone.
• a "pharmaceutically acceptable carrier or excipient” means a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, nontoxic and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use.
• pharmaceutically acceptable excipient as used in the specification and claims includes both one and more than one such excipient.
• Pharmaceutically acceptable excipients are well known in the art, such as those in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985.
• condition relate to any unhealthy or abnormal state.
• Treatment of a disease includes:
• treating and “treatment,” do not necessarily indicate a total elimination of any or all symptoms or a cure of the disease.
• patient and “subject” includes humans and non-human animals, for example, mammals, such as mice, rats, guinea pigs, dogs, cats, rabbits, cows, horses, sheep, goats, and pigs.
• mammals such as mice, rats, guinea pigs, dogs, cats, rabbits, cows, horses, sheep, goats, and pigs.
• the term also includes birds, fish, reptiles, amphibians, and the like. It is understood that a more particular patient is a human. Also, more particular patients and subjects are non-human mammals, such as mice, rats, and dogs.
• substantially pure refers to greater than 90%, preferably greater than 97%, and more preferably greater than 99% polymorphic purity.
• a “therapeutically effective amount” means the amount of 1 -(1 -methyl- 1 H- pyrazol-4-yl)-N-((lR,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-lH-indole-3- carboxamide, Form G, that when administered in single or multiple doses, to a mammal for treating a disease, is sufficient to effect such treatment for the disease.
• the “therapeutically effective amount” can vary depending on the disease and its severity; the age, weight, etc., of the mammal to be treated; the degree of or involvement or the severity of the condition, disorder, or disease; the response of the individual patient; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.
• the term "disease treatable by administration of a 5-HT3 receptor antagonist” includes emesis, migraine, substance abuse and addiction, neurodegenerative and psychiatric disorders such as anxiety and depression, eating disorders, schizophrenia, cognitive dysfunction associated with schizophrenia, Parkinson's disease, Huntington's Chorea, presenile dementias and Alzheimer's disease, and pain; GI disorders such as dyspepsia, gastroesophagal reflux disease, and irritable bowel syndrome; and immunological disorders and inflammation such as atherosclerosis, tendomyopathies and fibromyalgia.
• the disease is cognitive dysfunction associated with schizophrenia also known as cognitive impairment associated with schizophrenia.
• l-(l-Methyl-lH-pyrazol-4-yl)-N-((lR,5S,7S)-9-methyl-3-oxa-9- azabicyclo[3.3.1]nonan-7-yl)-lH-indole-3-carboxamide, Form G can be characterized by X- ray powder diffraction. See the drawing. The peaks were measured using a powder diffractometer equipped with a copper X-ray source, primary beam monochromator, and position sensitive detector. The incident beam was collimated using a 1° divergence slit. The Cu KV source was operated at 45 kV and 40 mA.
• X-ray powder diffraction data were collected from 3 degrees to 45 degrees in a step width of 0.02 degrees and a time per step of 10 seconds.
• the diffractometer was well calibrated with a silicon standard.
• a typical precision of the 2-theta values is in the range of about ⁇ 0.2 degrees 2-theta.
• an X-ray diffraction peak that appears at 8.13 degrees 2-theta can appear between 7.93 and 8.33 degrees 2-theta on typical X-ray diffractometers under standard conditions.
• Form G of 1 -(1 -methyl- lH-pyrazol-4- yl)-N-((lR,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-lH-indole-3-carboxamide may be characterized by X-ray diffraction peaks at 8.13 and 18.39 degrees 2-theta, each ⁇ 0.2 degrees 2-theta.
• l-(l-methyl-lH-pyrazol-4-yl)-N-((lR,5S,7S)-9-methyl-3-oxa-9- azabicyclo[3.3.1]nonan-7-yl)-lH-indole-3-carboxamide, Form G may be characterized by peaks at 8.13, 17.01, and 18.39 degrees 2-theta, each ⁇ 0.2 degrees 2-theta; by peaks at 8.13, 17.49, and 18.39 degrees 2-theta, each ⁇ 0.2 degrees 2-theta; and by peaks at 8.13, 18.39, and 20.91 degrees 2-theta, each ⁇ 0.2 degrees 2-theta.
• l-(l-methyl-lH-pyrazol-4-yl)-N-((lR,5S,7S)-9-methyl-3-oxa-9- azabicyclo[3.3.1]nonan-7-yl)-lH-indole-3-carboxamide, Form G may be characterized by peaks at 8.13, 17.01, 17.49, and 18.39 degrees 2-theta, each ⁇ 0.2 degrees 2-theta; by peaks at 8.13, 17.01, 18.39, and 20.91 degrees 2-theta, each ⁇ 0.2 degrees 2-theta; and by peaks at 8.13, 17.49, 18.39, and 20.91 degrees 2-theta, each ⁇ 0.2 degrees 2-theta.
• Form G may also be characterized by peaks at 8.13, 17.01, 17.49, 18.39, and 20.91 degrees 2-theta, each ⁇ 0.2 degrees 2-theta.
• Form G of l-(l-methyl-lH-pyrazol-4-yl)-N-((lR,5S,7S)-9-methyl-3-oxa-9- azabicyclo[3.3.1]nonan-7-yl)-lH-indole-3-carboxamide may also be characterized by differential scanning calorimetry.
• thermogram of 1 -(1 -methyl- 1 H-pyrazol-4-yl)-N- ((lR,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-lH-indole-3-carboxamide, Form G provides a single endothermic event at about 214.5°C, which is consistent with a melt.
• the present invention also provides a process for making 1 -(1 -methyl- 1 H-pyrazol- 4-yl)-N-((lR,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-lH-indole-3- carboxamide, Form G, comprising crystallizing 1 -(1 -methyl- 1 H-pyrazol-4-yl)-N- ((lR,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-lH-indole-3-carboxamide.
• Suitable solvents may include DMSO, NMP, C 2 _4 alkylnitrile, C3_ 7 alkylacetate, Ci_ 6 alcohol, C 2 _8 ether, C 3 _ 7 alkanone, C 6 -9 aromatic hydrocarbons, and C 3 _ 5 N, N-dimethylcarboxamide.
• the selected solvent may contain anti-solvents, that is, a solvent or solvents in which the compound is less soluble than in the selected solvent.
• an anti-solvent should be miscible in the selected solvent(s).
• water may be an anti-solvent for DMSO, NMP, and Ci_ 6 alcohol
• C 2 _g ether, in particular MTBE may be an anti-solvent for C2-4 alkylnitrile, C3-7 alkylacetate, Ci_ 6 alcohol, C2-8 ether, such as THF or 2-MeTHF, C3-7 alkanone, and C 6 -9 aromatic hydrocarbons
• n-heptane may be an anti-solvent for C3_ 7 alkylacetate, Ci_ 6 alcohol, C 2 -8 ether, and C 3 _ 7 alkanone.
• Specific solvent/anti-solvent combinations may include the following:
• l-(l-methyl-lH-pyrazol-4-yl)-N-((lR,5S,7S)-9-methyl-3-oxa-9- azabicyclo[3.3.1]nonan-7-yl)-lH-indole-3-carboxamide, Form G is crystallized from a solvent.
• the temperature can range from about 30°C to up to the reflux temperature of the selected solvent and is usually less than 115°C.
• the solvent should be one in which 1-(1- methyl- 1 H-pyrazol-4-yl)-N-(( 1 R,5 S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1 ]nonan-7-yl)- 1 H- indole-3-carboxamide, Form G, is somewhat soluble.
• the volume of solvent is not critical but is typically minimized as a matter of convenience.
• An anti-solvent may be added to the heated solvent or as the mixture cools. Where the crystallization involves complete dissolution, the rate of cooling is not critical; however, slow cooling is preferred (e.g., cooling at a rate of about 20°C/hour to ambient temperature and then allowed to equilibrate at ambient temperature for about 16 hours).
• Slurry processing may be used.
• the crystallization may be seeded with l-(l-methyl-lH-pyrazol-4-yl)-N-((lR,5S,7S)-9-methyl-3- oxa-9-azabicyclo[3.3.1]nonan-7-yl)-lH-indole-3-carboxamide, Form G.
• l-(l-methyl-lH-pyrazol-4-yl)-N-((lR,5S,7S)-9-methyl-3-oxa-9- azabicyclo[3.3.1]nonan-7-yl)-lH-indole-3-carboxamide, Form G may be prepared in substantially pure form.
• EXAMPLE 1 l-(l-methyl-lH-pyrazol-4-yl)-N-((lR,5S,7S)-9-methyl-3-oxa-9- azabicyclo[3.3.1 ]nonan-7-yl)- lH-indole-3-carboxamide [0037] l-(l-Methyl-lH-pyrazol-4-yl)-lH-indole-3-carboxylic acid (128.7 g, 0.53 mol,) and anhydrous THF (645 mL) was heated to about 43°C.
• Oxalyl chloride (137.7 g, 92 mL, 1.08 mol) was added dropwise between 40 and 50°C. Gas evolution ceased in approximately 30 minutes. The resulting suspension was stirred for 2 hours at 50°C, allowed to cool to room temperature, and then stirred overnight. The suspension was diluted with heptane (1.5 L), stirred for 10 minutes, and allowed to settle. The supernatant was removed. The addition of heptane (1.5 L), followed by stirring, settling, and decanting was repeated two more times.
• the resulting suspension was diluted with anhydrous THF (645 mL) and the ratio between THF and heptane was determined by NMR to be 3:2.
• the reaction mixture was cooled to 5°C and to the mixture was added DIPEA base (138 g, 1.07 mol) at such a rate that the temperature did not exceed 20°C.
• DIPEA base 138 g, 1.07 mol
• the reaction mixture was warmed to ambient temperature and stirred at 20 to 23°C overnight to give a suspension.
• EXAMPLE 2 l-(l-methyl-lH-pyrazol-4-yl)-N-((lR,5S,7S)-9-methyl-3-oxa-9- azabicyclo[3.3.1 ]nonan-7-yl)- lH-indole-3-carboxamide
• EXAMPLE 3 l-(l-methyl-lH-pyrazol-4-yl)-N-((lR,5S,7S)-9-methyl-3-oxa-9- azabicyclo[3.3.1]nonan-7-yl)-lH-indole-3-carboxamide, Form G
• EXAMPLE 4 l-(l-methyl-lH-pyrazol-4-yl)-N-((lR,5S,7S)-9-methyl-3-oxa-9- azabicyclo[3.3.1]nonan-7-yl)-lH-indole-3-carboxamide, Form G
• EXAMPLE 6 l-(l-methyl-lH-pyrazol-4-yl)-N-((lR,5S,7S)-9-methyl-3-oxa-9- azabicyclo[3.3.1]nonan-7-yl)-lH-indole-3-carboxamide, Form G [0050] l-(l-Methyl-lH-pyrazol-4-yl)-N-((lR,5S,7S)-9-methyl-3-oxa-9- azabicyclo[3.3.1]nonan-7-yl)-lH-indole-3-carboxamide (31.0 mg) and MeOH (1.0 mL) were combined and heated to 60°C. MTBE (2.0 mL) was added and the mixture was stored at 4°C overnight. The solids were collected by centrifugation, dried in vacuo at ambient temperature to give the title compound.
• EXAMPLE 15 l-(l-methyl-lH-pyrazol-4-yl)-N-((lR,5S,7S)-9-methyl-3-oxa-9- azabicyclo[3.3.1]nonan-7-yl)-lH-indole-3-carboxamide, Form G [0068] l-(l-Methyl-lH-pyrazol-4-yl)-N-((lR,5S,7S)-9-methyl-3-oxa-9- azabicyclo[3.3.1]nonan-7-yl)-lH-indole-3-carboxamide (58.3 mg) and IPA (1.0 mL) were combined and heated to 70°C. MTBE (2.0 mL) was added and the mixture was stored at 4°C overnight. The solids were collected by centrifugation, dried in vacuo at ambient temperature to give the title compound.
• Receptors of 5-HT3 are known to be expressed in the central nervous system in regions involving vomiting reflex, processing of pain, cognition and anxiety control and play a role in the pathogenesis of diseases such as emesis, migraine, drug addiction, and neurodegenerative and psychiatric disorders such as anxiety and depression (see Hewlett et al, 2003 J. Clin. Psychiatry 64, 1025-1030; Kelley et al, 2003a, Eur J.
• 5-HT3 receptors are expessed in the GI tract and hence may play a role in GI disorders such as dyspepsia, gastroesophagal reflux disease and irritable bowel syndrome (see Graeff 1997 Psychiatr Clin North Am 20, 723; Thompson and Lummis 2007 Exp Opin Ther Targets, 11, 527-540; Barnes et al. 2009 Neuropharmacology 56, 273).
• 5-HT3A subunit has also been discovered extraneuronally in immune cells such as monocytes, chondrocytes, T-cells, synovial tissue and platelets (Fiebich et al, 2004 Scan J Rheumatol Suppl, 9-11, Stratz et al, 2008 Thromb Haemost 99, 784) and of 5-HT3A, C-E within the lamina propia in the epithelium of the gut mucose (Kapeller et al, J Comp Neuro, 2008; 509: 356-371) thus suggesting they may be involved in immunological and
• inflammatory diseases like atherosclerosis, tendomyopathies and fibromyalgia.
• the 5-HT3 inhibitory activity of l-(l-methyl-lH-pyrazol-4-yl)-N-((lR,5S,7S)-9- methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-lH-indole-3-carboxamide, Form G may be tested using the in vitro assay and in vivo assay described in PCT Publication No. WO 2014/014951, published January 23, 2014.
• Therapeutically effective amounts of 1 -(1 -methyl- 1 H-pyrazol-4- yl)-N-((lR,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-lH-indole-3- carboxamide, Form G may range from about 0.01 to about 75 mg per kg patient body weight per day, which can be administered in single or multiple doses.
• the dosage level will be about 0.01 to about 10 mg/kg per day; more preferably about 0.5 to about 5 mg/kg per day or 0.1-2 mg/kg/day.
• compositions are preferably provided in the form of tablets containing about 0.5 to about 200 milligrams of the active ingredient, from about 0.5, 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, or 200 milligrams of the active ingredient.
• the actual amount of l-(l-methyl-lH-pyrazol-4-yl)-N-((lR,5S,7S)-9-methyl-3- oxa-9-azabicyclo[3.3.1]nonan-7-yl)-lH-indole-3-carboxamide, Form G i.e., the active ingredient
• the dosages are based on an average human subject having a mass of about 60 kg to about 70 kg, the physician will be able to determine the appropriate dose for a patient (e.g., an infant) whose mass falls outside of this weight range.
• compositions will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration.
• oral systemic
• parenteral e.g., intramuscular, intravenous or subcutaneous
• the preferred manner of administration is oral dosing using a convenient daily dosage regimen, which can be adjusted according to the degree of affliction.
• Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.
• formulations depend on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules are preferred) and the bioavailability of the drug substance. Recently, the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules are preferred) and the bioavailability of the drug substance. Recently, the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules are preferred) and the bioavailability of the drug substance. Recently, the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules are preferred) and the bioavailability of the drug substance. Recently, the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules are preferred) and the bioavailability of the drug substance. Recently, the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules are preferred) and
• compositions are comprised of in general, 1 -(1 -methyl- 1 H-pyrazol-4-yl)-N- ((lR,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-lH-indole-3-carboxamide, Form G, in combination with at least one pharmaceutically acceptable excipient.
• Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of l-(l-methyl-lH-pyrazol-4-yl)-N-((lR,5S,7S)-9-methyl-3-oxa-9- azabicyclo[3.3.1]nonan-7-yl)-lH-indole-3-carboxamide, Form G.
• excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
• Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like.
• Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.
• Preferred liquid carriers, particularly for injectable solutions include water, saline, aqueous dextrose, and glycols.
• Compressed gases may be used to disperse 1 -(1 -methyl- 1 H-pyrazol-4-yl)-N- ((lR,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-lH-indole-3-carboxamide, Form G, in aerosol form.
• Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
• Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990).
• the formulation will contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of 1 -(1 -methyl- 1 H- pyrazol-4-yl)-N-((lR,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-lH-indole-3- carboxamide, Form G, based on the total formulation, with the balance being one or more suitable pharmaceutical excipients.
• l-(l-methyl-lH-pyrazol-4-yl)-N-((lR,5S,7S)- 9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-lH-indole-3-carboxamide, Form G is present at a level of about 1-80 wt %.
• Such other drug(s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with 1 -(1 -methyl- 1 H-pyrazol- 4-yl)-N-((lR,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-lH-indole-3- carboxamide, Form G.
• 1 -(1 -methyl- 1 H-pyrazol- 4-yl)-N-((lR,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-lH-indole-3-carboxamide Form G.
• a pharmaceutical composition in unit dosage form containing such other drugs and l-(l-methyl-lH-pyrazol-4-yl)-N-((lR,5S,7S)-9- methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-lH-indole-3-carboxamide, Form G may be used.
• the combination therapy may also include therapies in which l-(l-methyl- lH-pyrazol-4-yl)-N-((lR,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-lH-indole- 3-carboxamide, Form G, and one or more other drugs are administered on different overlapping schedules.
• l-(l-methyl-lH-pyrazol-4-yl)-N-((lR,5S,7S)-9-methyl-3-oxa- 9-azabicyclo[3.3.1]nonan-7-yl)-lH-indole-3-carboxamide, Form G, and the other active ingredients may be used in lower doses than when each is used singly.
• compositions of the present invention also include those that contain one or more other active ingredients, in addition to l-(l-methyl- lH-pyrazol-4-yl)-N-((lR,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-lH-indole-
• the above combinations include combinations of 1 -(1 -methyl- 1 H-pyrazol-4-yl)-N- ((lR,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-lH-indole-3-carboxamide, Form G, not only with one other active compound, but also with two or more other active compounds.
• l-(l-methyl-lH-pyrazol-4-yl)-N-((lR,5S,7S)-9-methyl-3-oxa-9- azabicyclo[3.3.1]nonan-7-yl)-lH-indole-3-carboxamide, Form G may be used in
• Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with 1 -(1 -methyl- 1 H-pyrazol-4-yl)-N- ((lR,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-lH-indole-3-carboxamide, Form G.
• the pharmaceutical compositions of the present invention also include those that also contain one or more other active ingredients, in addition to 1 -(1 -methyl- 1 H-pyrazol-
• l-(l-methyl-lH-pyrazol-4-yl)-N-((lR,5S,7S)-9-methyl-3-oxa- 9-azabicyclo[3.3.1]nonan-7-yl)-lH-indole-3-carboxamide, Form G may be administered in combination with anti-Alzheimer's agents, beta-secretase inhibitors, gamma-secretase inhibitors, HMG-CoA reductase inhibitors, NSAID's including ibuprofen, vitamin E, and anti-amyloid antibodies.
• 1 -(1 -methyl- 1 H-pyrazol-4-yl)-N- ((lR,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-lH-indole-3-carboxamide, Form G may be administered in combination with sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, cyclopyrrolones, imidazopyridines, pyrazolopyrimidines, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, benzodiazepines, barbiturates, mGlu2/3 agonists, 5HT-2 antagonists, PDE10 antagonists, GlyTl inhibitors, and the like, such as: adinazolam, allobarbital, alonimid, alprazolam, amisulpride, amitriptyline, amobarbital, amox
• l-(l-methyl-lH-pyrazol-4-yl)-N-((lR,5S,7S)-9-methyl-3- oxa-9-azabicyclo[3.3.1]nonan-7-yl)-lH-indole-3-carboxamide, Form G may be administered in combination with levodopa (with or without a selective extracerebral decarboxylase inhibitor such as carbidopa or benserazide), anticholinergics such as biperiden (optionally as its hydrochloride or lactate salt) and trihexyphenidyl (benzhexol) hydrochloride, COMT inhibitors such as entacapone, MOA-B inhibitors, antioxidants, A2a adenosine receptor antagonists, cholinergic agonists, NMDA receptor antagonists, serotonin receptor antagonists and dopamine receptor agonists such as alentemol, bromocriptine, f
• the dopamine agonist may be in the form of a pharmaceutically acceptable salt, for example, alentemol hydrobromide, bromocriptine mesylate, fenoldopam mesylate, naxagolide hydrochloride and pergolide mesylate.
• a pharmaceutically acceptable salt for example, alentemol hydrobromide, bromocriptine mesylate, fenoldopam mesylate, naxagolide hydrochloride and pergolide mesylate.
• Lisuride and pramipexol are commonly used in a non-salt form.
• l-(l-methyl-lH-pyrazol-4-yl)-N-((lR,5S,7S)-9-methyl-3- oxa-9-azabicyclo[3.3.1]nonan-7-yl)-lH-indole-3-carboxamide, Form G may be administered in combination with a compound from the phenothiazine, thioxanthene, heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine and indolone classes of neuroleptic agent.
• Suitable examples of phenothiazines include chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine and trifluoperazine.
• Suitable examples of thioxanthenes include chlorprothixene and thiothixene.
• An example of a dibenzazepine is clozapine.
• An example of a butyrophenone is haloperidol.
• An example of a diphenylbutylpiperidine is pimozide.
• An example of an indolone is molindolone.
• Other neuroleptic agents include loxapine, sulpiride and risperidone.
• the neuroleptic agents when used in combination with 1 -(1 -methyl- 1 H-pyrazol-4-yl)-N- ((lR,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-lH-indole-3-carboxamide, Form G may be in the form of a pharmaceutically acceptable salt, for example, chlorpromazine hydrochloride, mesoridazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, flurphenazine enathate, fluphenazine decanoate, trifluoperazine hydrochloride, thiothixene hydrochloride, haloperidol decanoate, loxapine succinate and molindone hydrochloride.
• a pharmaceutically acceptable salt for example, chlorpromazine hydrochloride, mesoridazine bes
• Perphenazine, chlorprothixene, clozapine, haloperidol, pimozide and risperidone are commonly used in a non-salt form.
• 1 -(1 -methyl- 1 H-pyrazol-4-yl)- N-((lR,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-lH-indole-3-carboxamide, Form G may be administered in combination with acetophenazine, alentemol, aripiprazole, amisulpride, benzhexol, bromocriptine, biperiden, chlorpromazine, chlorprothixene, clozapine, diazepam, fenoldopam, fluphenazine, haloperidol, levodopa, levodopa with benserazide, levodopa with carbidopa,
• l-(l-methyl-lH-pyrazol-4-yl)-N-((lR,5S,7S)-9-methyl-3- oxa-9-azabicyclo[3.3.1]nonan-7-yl)-lH-indole-3-carboxamide, Form G may be administered in combination with an anti-depressant or anti-anxiety agent, including norepinephrine reuptake inhibitors (including tertiary amine tricyclics and secondary amine tricyclics), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRls), corticotropin releasing factor (CRF) antagonists, adrenoreceptor antagonists, neurokinin- 1 receptor antagonists, atypical anti-depressants
• Specific agents include: amitriptyline, clomipramine, doxepin, imipramine and trimipramine; amoxapine, desipramine, maprotiline, nortriptyline and protriptyline; fluoxetine, fluvoxamine, paroxetine and sertraline; isocarboxazid, phenelzine, tranylcypromine and selegiline; moclobemide, venlafaxine; duloxetine; aprepitant;
• bupropion lithium, nefazodone, trazodone and viloxazine; alprazolam, chlordiazepoxide, clonazopam, chlorazepate, diazopam, halazepam, lorazepam, oxazopam and prazepam; buspirone, flesinoxan, gepirone and ipsapirone, and pharmaceutically acceptable salts thereof.

Landscapes

• Health & Medical Sciences (AREA)
• Organic Chemistry (AREA)
• Chemical & Material Sciences (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Neurology (AREA)
• Biomedical Technology (AREA)
• Neurosurgery (AREA)
• Psychiatry (AREA)
• Pain & Pain Management (AREA)
• Psychology (AREA)
• Hospice & Palliative Care (AREA)
• Vascular Medicine (AREA)
• Cardiology (AREA)
• Urology & Nephrology (AREA)
• Heart & Thoracic Surgery (AREA)
• Addiction (AREA)
• Orthopedic Medicine & Surgery (AREA)
• Physical Education & Sports Medicine (AREA)
• Otolaryngology (AREA)
• Nutrition Science (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Priority Applications (10)

Applications Claiming Priority (2)

Publications (1)

Family

ID=54289137

Family Applications (1)

Country Status (12)

Citations (4)

Family Cites Families (41)

• 2015
  • 2015-09-29 CN CN201580052611.3A patent/CN106795172B/zh active Active
  • 2015-09-29 JP JP2017516693A patent/JP7055017B2/ja active Active
  • 2015-09-29 MA MA40771A patent/MA40771B1/fr unknown
  • 2015-09-29 US US15/515,263 patent/US10329306B2/en active Active
  • 2015-09-29 CA CA2962429A patent/CA2962429C/en active Active
  • 2015-09-29 WO PCT/US2015/052806 patent/WO2016053947A1/en not_active Ceased
  • 2015-09-29 PL PL15778162T patent/PL3201203T3/pl unknown
  • 2015-09-29 HU HUE15778162A patent/HUE055175T2/hu unknown
  • 2015-09-29 PT PT157781626T patent/PT3201203T/pt unknown
  • 2015-09-29 EP EP15778162.6A patent/EP3201203B1/en active Active
  • 2015-09-29 ES ES15778162T patent/ES2883295T3/es active Active
  • 2015-09-29 DK DK15778162.6T patent/DK3201203T3/da active
• 2021
  • 2021-11-19 JP JP2021188428A patent/JP2022036978A/ja not_active Withdrawn

Patent Citations (4)

Non-Patent Citations (29)

Also Published As

Similar Documents

Legal Events