Classifications

• • 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
  • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
• • 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
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/433—Thidiazoles
• • 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
• • 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
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with 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
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
  • A61K31/52—Purines, e.g. adenine
  • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• • 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
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5355—Non-condensed oxazines 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
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/16—Central respiratory analeptics
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
  • C07D239/50—Three nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
  • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
  • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
  • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
  • C07D251/40—Nitrogen atoms
  • C07D251/54—Three nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/08—Bridged systems
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
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  • 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
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Definitions

• Normal control of breathing is a complex process that involves, in part, the body's interpretation and response to chemical stimuli such as carbon dioxide, pH and oxygen levels in blood, tissues and the brain. Breathing control is also affected by other factors such as wakefulness (i.e., whether the patient is awake or sleeping), emotion, posture and vocalization.
• breath control is also affected by other factors such as wakefulness (i.e., whether the patient is awake or sleeping), emotion, posture and vocalization.
• Within the brain medulla there are respiratory control centers that interpret various feedforward and feedback signals that affect respiration and issues commands to the muscles that perform the work of breathing. Key muscle groups are located in the abdomen, diaphragm, pharynx and thorax. Sensors located centrally and peripherally then provide input to the brain's central respiration control areas that enables response to changing metabolic requirements.
• apneas central, mixed or obstructive; where the breathing repeatedly stops for 10 to 60 seconds
• congenital central hypoventilation syndrome congenital central hypoventilation syndrome
• Sleep disordered breathing is an example of where abnormalities in the control of breathing lead to a serious and prevalent disease in humans.
• Sleep apnea is characterized by frequent periods of no or partial breathing.
• Key factors that contribute to these apneas include anatomical factors (such as obesity), decreased hypercapnic and hypoxic ventilatory responses (e.g., decreased response to high carbon dioxide and low oxygen levels, respectively) and loss of "wakefulness" (i.e., drive to pharyngeal dilator muscles).
• Apneic events result in hypoxia (and the associated oxidative stress) and eventually severe cardiovascular consequences (high blood pressure, stroke, heart attack).
• the invention includes a composition comprising at least one compound selected from the group consisting of: N-(2,4-bis- «-propylamino)-N-(6- methylamino)-[l,3,5]triazine (CLXXII), N-(2,4,6-tris-w-propylamino)-[l,3,5]triazine (CLXXIII), N-(2,4,6-tris- «-propylamino)-l,3-pyrimidine (CLXXIV), N-(2,4-bis- «- propylamino)-N-(6-z ' -propylamino)-l,3-pyrimidine (CLXXV), a salt thereof, and any combinations thereof.
• the salt is hydrogen sulfate, hydrochloride, phosphate, hydrogen phosphate or dihydrogen phosphate.
• the composition further comprises at least one pharmaceutically acceptable carrier.
• the invention also includes a method of preventing or treating a breathing control disorder or disease in a subject in need thereof.
• the method comprises administering to the subject an effective amount of a pharmaceutical formulation comprising at least one pharmaceutically acceptable carrier and at least one compound selected from the group consisting of: N-(2,4-bis- «-propylamino)-N- (6-methylamino)-[l,3,5]triazine (CLXXII), N-(2,4,6-tris- «-propylamino)- [l,3,5]triazine (CLXXIII), N-(2,4,6-tris- «-propylamino)-l,3-pyrimidine (CLXXIV), N-(2,4-bis- «-propylamino)-N-(6- -propylamino)-l,3-pyrimidine (CLXXV), a salt thereof, and any combinations thereof.
• the breathing control disorder or disease is selected from the group consisting of respiratory depression, sleep apnea, apnea of prematurity, obesity -hypoventilation syndrome, primary alveolar hypoventilation syndrome, dyspnea, hypoxia, and hypercapnia.
• the respiratory depression is caused by an anesthetic, a sedative, an anxiolytic agent, a hypnotic agent, alcohol or a narcotic.
• the subject is further administered a composition comprising at least one additional compound useful for treating the breathing control disorder or disease.
• the invention also includes a method of preventing destabilization or stabilizing breathing rhythm in a subject in need thereof.
• the method comprising administering to the subject an effective amount of a pharmaceutical formulation comprising at least one pharmaceutically acceptable carrier and at least one compound selected from the group consisting of: N-(2,4-bis- «-propylamino)-N-(6- methylamino)-[l,3,5]triazine (CLXXII), N-(2,4,6-tris-w-propylamino)-[l,3,5]triazine (CLXXIII), N-(2,4,6-tris- «-propylamino)-l,3-pyrimidine (CLXXIV), N-(2,4-bis- «- propylamino)-N-(6-z ' -propylamino)-l,3-pyrimidine (CLXXV), a salt thereof, and any combinations thereof.
• the destabilization is associated with a breathing control disorder or disease selected from the group consisting of respiratory depression, sleep apnea, apnea of prematurity, obesity -hypoventilation syndrome, primary alveolar hypoventilation syndrome, dyspnea, hypoxia, and hypercapnia.
• the respiratory depression is caused by an anesthetic, a sedative, an anxiolytic agent, a hypnotic agent, alcohol or a narcotic.
• the subject is further administered a composition comprising at least one additional compound useful for treating the breathing control disorder or disease.
• the at least one additional compound is selected from the group consisting of acetazolamide, almitrine, theophylline, caffeine, methyl progesterone, a serotinergic modulator, a cannabinoid and an ampakine.
• the formulation is administered in conjunction with the use of a mechanical ventilation device or positive airway pressure device on the subject.
• the subject is a mammal.
• the mammal is a human.
• the formulation is administered to the subject by an inhalational, topical, oral, buccal, rectal, vaginal, intramuscular, subcutaneous, transdermal, intrathecal, intraperitoneal, intrathoracic, intrapleural or intravenous route.
• 4,6-bis-(w-propylamino)-l,3,5-triazin-2-ol is present at a level equal to or lower than about 0.5% (w/w) with respect to (XXXV) or the salt thereof.
• 4,6-bis-( «-propylamino)- l,3,5-triazin-2-ol is present at a level equal to or lower than about 0.3% (w/w) with respect to (XXXV) or the salt thereof.
• 4,6- bis-( «-propylamino)-l,3,5-triazin-2-ol is present at a level equal to or lower than about 0.2% (w/w) with respect to (XXXV) or the salt thereof.
• 4,6-bis-( «-propylamino)-l,3,5-triazin-2-ol is present at a level equal to or lower than about 0.15% (w/w) with respect to (XXXV) or the salt thereof.
• the invention also includes a composition comprising N-(4,6-bis- «- propylamino-[l,3,5]triazin-2-yl)-N,0-dimethyl-hydroxylamine (XXXV) or a salt thereof, further comprising a buffer and a liquid carrier.
• the salt of (XXXV) is the hydrogen sulfate salt
• the composition further comprises citric acid.
• the pH of the composition is adjusted with a base.
• the base comprises sodium hydroxide.
• the liquid carrier comprises water.
• the pH of the composition ranges from about 2.5 to about 6. In yet another embodiment, the pH of the composition ranges from about 2.5 to about 5. In yet another embodiment, the pH of the composition ranges from about 3 to about 4. In yet another
• the concentration of (XXXV) or the salt thereof in the composition is about 1-10 mg/mL. In yet another embodiment, the concentration of (XXXV) or the salt thereof in the composition is about 5-10 mg/mL. In yet another embodiment, the concentration of (XXXV) or the salt thereof in the composition is about 10 mg/mL. In yet another embodiment, the composition comprises less than 0.5% (w/w)
• less than 0.5% (w/w) of N-(4,6-Bis-n-propylamino)-[l,3,5]-triazin-2-ol (CLXXVIII) with respect to (XXXV) forms over an eighteen-month period of storage of the composition at 2-8°C.
• less than 0.5% (w/w) of N- (4,6-Bis-n-propylamino)-[l,3,5]-triazin-2-ol (CLXXVIII) with respect to (XXXV) forms over a twenty-four-month period of storage of the composition at 2-8°C.
• the invention also includes a crystalline free base of N-(4,6-Bis- «- propylamino-[l,3,5]triazin-2-yl)-N,0-dimethyl-hydroxylamine (XXXV), Form A, with a XRPD spectrum as per Figure 22.
• the invention also includes at least one crystalline salt of N-(4,6-Bis- «-propylamino-[l,3,5]triazin-2-yl)-N.O-dimethyl-hydroxylamine (XXXV) selected from the group consisting of: crystalline hydrogen sulfate salt (XXXVI) Form A, with a XRPD spectrum as per Figure 14; crystalline hydrogen sulfate salt (XXXVI) comprising a mixture of Form A and Form B, with a XRPD spectrum as per Figure 23; crystalline hydrogen sulfate salt (XXXVI) Form C, with a XRPD spectrum as per Figure 24; crystalline hydrogen sulfate salt (XXXVI) Form D, with a XRPD spectrum as per Figure 25; crystalline hydrogen sulfate salt (XXXVI) comprising a mixture of Form A and Form D, with a XRPD spectrum as per Figure 26; crystalline phosphoric acid salt (CLXXX)
• the invention also includes a salt of N-(4,6-Bis-w-propylamino- [l,3,5]triazin-2-yl)-hydroxylamine (XXXV), comprising approximately one mole equivalent of sulfuric acid.
• the salt further comprises one mole equivalent of water.
• the invention also includes a salt of N-(4,6-Bis-w-propylamino- [l,3,5]triazin-2-yl)-N.O-dimethyl-hydroxylamine (XXXV), comprising at least one mole equivalent of phosphoric acid.
• the salt comprises about one mole equivalent of phosphoric acid.
• the invention also includes a method of reducing or minimizing the open channel fraction of the potassium maxi-K or BK channel in a subject in need thereof.
• the method comprises administering to the subject an effective amount of a pharmaceutical formulation comprising at least one pharmaceutically acceptable carrier and at least one compound of formula (I):
• R 1 and R 2 are independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl or substituted heteroaryl; or R 1 and R 2 combine as to form a biradical selected from the group consisting of 3- hydroxy-pentane- 1 ,5 -diyl, 6-hydroxy-cycloheptane- 1 ,4-diyl, propane- 1 ,3 -diyl, butane- 1,4-diyl and pentane-l,5-diyl; R 3 is H, alkyl, substituted alkyl, cycloalkyl, substituted
• bond b 1 is nil and: (i) Z is H, bond b 2 is a single bond, and A is CH; or, (ii) Z is nil, bond b 2 is nil, and A is a single bond; and,
• bond b 1 is a single bond, and: (i) Z is CH 2 , bond b 2 is a single bond, and A is CH; or, (ii) Z is CH, bond b 2 is a double bond, and A is C; or a salt thereof.
• the invention also includes a method of inhibiting the TASK- 1 (KCNK3) channel in a subject in need thereof.
• the method comprises administering to the subject an effective amount of a pharmaceutical formulation comprising at least one pharmaceutically acceptable carrier and at least one compound of formula (I):
• R 1 and R 2 are independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl or substituted heteroaryl; or R 1 and R 2 combine as to form a biradical selected from the group consisting of 3- hydroxy-pentane- 1 ,5 -diyl, 6-hydroxy-cycloheptane- 1 ,4-diyl, propane- 1 ,3 -diyl, butane- 1,4-diyl and pentane-l,5-diyl; R 3 is H, alkyl, substituted alkyl, cycloalkyl, substituted
• bond b 1 is nil and: (i) Z is H, bond b 2 is a single bond, and A is CH; or, (ii) Z is nil, bond b 2 is nil, and A is a single bond; and,
• bond b 1 is a single bond, and: (i) Z is CH 2 , bond b 2 is a single bond, and A is CH; or, (ii) Z is CH, bond b 2 is a double bond, and A is C; or a salt thereof.
• the invention also includes a method of increasing minute ventilation in a subject in need thereof.
• the method comprises administering to the subject an effective amount of a pharmaceutical formulation comprising at least one
• R 1 and R 2 are independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl or substituted heteroaryl; or R 1 and R 2 combine as to form a biradical selected from the group consisting of 3- hydroxy-pentane- 1 ,5 -diyl, 6-hydroxy-cycloheptane- 1 ,4-diyl, propane- 1 ,3 -diyl, butane- 1,4-diyl and pentane-l,5-diyl; R 3 is H, alkyl, substituted alkyl, cycloalkyl, substituted
• bond b 1 is nil and: (i) Z is H, bond b 2 is a single bond, and A is CH; or, (ii) Z is nil, bond b 2 is nil, and A is a single bond; and,
• bond b 1 is a single bond, and: (i) Z is CH 2 , bond b 2 is a single bond, and A is CH; or, (ii) Z is CH, bond b 2 is a double bond, and A is C; or a salt thereof.
• the compound of formula (I) is N-(4,6-Bis- «- propylamino-[l,3,5]triazin-2-yl)-N,0-dimethyl-hydroxylamine, or a salt thereof.
• Figure 2 comprising Figures 2A-B, illustrates arterial blood gas analysis results for administration of Compound (XXXVI) [labeled as cmpd (A)] in the opioid-treated rat.
• Figure 2A - PaC0 2 (mmHg);
• Figure 2B - Sa0 2 (%).
• Figure 3 is a graph illustrating results of plethysmography experiments monitoring minute ventilation in the rat upon administration of Compound (XXXVI) [labeled as cmpd (A)] under conditions of hypoxia.
• Figure 4 is a graph illustrating end-tidal CO 2 and minute ventilation in the opioid-treated monkey upon administration of Compound (XXXVI) [labeled as cmpd (A)].
• Figure 6 is a graph illustrating the dose-dependent effect of Compound (XXXVI) [labeled as cmpd (A)] and Compound (CXXI) [labeled as cmpd (C)] on minute ventilation, in terms of maximum peak response, in the rat.
• Figure 7 comprising Figures 7A-D, illustrates the dose-dependent effect of Compound (L) [labeled as cmpd (B)] on blood gases and pH in the opioid- treated rat.
• Figure 7A - pH; Figure 7B - Sa0 2 ; Figure 7C - PO 2 ; Figure 7D - pC0 2 .
• Figure 8 comprising Figures 8A-D, illustrates the dose-dependent effect of Compound (CXLII) [labeled as cmpd (D)] on blood gases and pH in the opioid-treated rat.
• Figure 9 is a graph illustrating the effect of Compound (CXLII)
• cmpd (D) [labeled as cmpd (D)] in the minute ventilation of the opioid-treated rat.
• Figure 10 illustrates the l H -NMR spectrum for Compound (XXXVI) in DMSO-d 6 at 25°C.
• Figure 1 1 illustrates the 13 C-NMR spectrum for Compound (XXXVI) in DMSO-d 6 at 25°C.
• Figure 12 illustrates the FTIR spectrum for Compound (XXXVI).
• Figure 13 illustrates the thermal analysis by DSC of N-(4,6-bis- «- propylamino-[l,3,5]triazin-2-yl)-N,0-dimethyl-hydroxylamine hydrogen sulfate (XXXVI).
• Figure 14 illustrates the X-ray diffraction spectrum of Compound (XXXVI) Form A (hydrogen sulfate salt Form A).
• Figure 15 is a graph illustrating the effect of Compound (XXXVI) on reversing the effects of midazolam on minute ventilation (MV) in the rat.
• Figure 16 is a graph illustrating the effect of Compound (XXXVI) on reversing the effects of midazolam on tidal volume (TV) in the rat.
• Figure 17 is a graph illustrating the effect of Compound (XXXVI) on reversing the effects of midazolam on respiratory frequency (f) in the rat.
• Figure 18 is a graph illustrating the effect of Compound (XXXVI) infusion on the minute volume response to acute hypercapnia (3% CO 2 ).
• Figure 19A is a graph illustrating the effect of pH on aqueous solubility of Compound (XXXV) at ambient temperature.
• Figure 19B is a graph illustrating the effect of pH on aqueous solubility of Compound (XXXV) at ambient temperature
• Figure 20A is a graph illustrating the effect of pH on degradation of
• Figure 20B is a graph illustrating the effect of pH on degradation of Compound (XXXV) at pH 2-3.6.
• Figure 21 is a graph illustrating the formation rate of Compound (CLXXVIII) from Compound (XXXV) in solution at 2-8°C, pH 3-4.
• Figure 23 is a graph illustrating the X-ray powder diffraction spectrum of a mixture of Compound (XXXVI) Form A and Compound (XXXVI) Form B.
• Figure 24 is a graph illustrating the X-ray powder diffraction spectrum of Compound (XXXVI) Form C.
• Figure 25 is a graph illustrating the X-ray powder diffraction spectrum of Compound (XXXVI) Form D.
• Figure 26 is a graph illustrating the X-ray powder diffraction spectrum of a mixture of Compound (XXXVI) Form A and Compound (XXXVI) Form D.
• Figure 27 is a graph illustrating the X-ray powder diffraction spectrum of Compound (CLXXX) Form A.
• Figure 28 is a graph illustrating the X-ray powder diffraction spectrum of Compound (CLXXX) Form C.
• Figure 29 is a graph illustrating the X-ray powder diffraction spectrum of a mixture of Compound (CLXXX) Form A and Compound (CLXXX) Form B.
• Figure 30 is a graph illustrating the X-ray powder diffraction spectrum of a mixture of Compound (CLXXX) Form C and Compound (CLXXX) Form D.
• Figure 31 is a graph illustrating the X-ray powder diffraction spectrum of a mixture of Compound (CLXXX) Form C and Compound (CLXXX) Form E.
• Figure 32 comprising Figures 32A-D, are graphs illustrating the effect of Compound (XLII) on respiratory rate (Figure 32A), tidal volume (Figure 32B), minute volume (Figure 32C) and 5 min average change in minute volume (Figure 32D) respectively, in rat.
• XLII Compound
• Figure 32A tidal volume
• Figure 32B tidal volume
• Figure 32C minute volume
• Figure 32D 5 min average change in minute volume
• Figure 33 comprising Figures 33A-D, are graphs illustrating the effect of Compound (CLXXII) on respiratory rate (Figure 33A), tidal volume (Figure 33B), minute volume (Figure 33C) and 5 min average change in minute volume (Figure 33D) respectively, in rat.
• Figure 34 comprising Figures 34A-C, illustrates the effect of BK channel activity in response to Compound (XXXV) at a concentration of 1 ⁇ .
• Figure 34A sample recordings of channel activity in control conditions and with 1 ⁇ (XXXV). Arrow, closed state.
• Figure 34B all points histogram obtained from 1 min of recording in control condition.
• Figure 34C all points histogram obtained from 1 min of ecording with 1 ⁇ (XXXV). Patch ID: C 05 SP 101008 0000.
• Figure 35 illustrates the design of study GAL-021-101 : infusion rates and duration by study period and group (cohort). The dose levels that were pooled for PD analyses are delineated on the left side.
• Figure 36 is an illustrative design diagram of respiratory depression Proof-of-Concept study (GAL-021-104).
• Figure 37 is a graph illustrating tidal volume during first 2 hour after starting the infusion.
• Figure 38 is a set of graphs illustrating the integrated percent change from baseline during the first hour (0-lh) and first 2 hours (0-2h) after starting the infusion for minute ventilation (Figure 38A), end tidal CO 2 (Figure 38B), respiratory rate (Figure 38C), and tidal volume (Figure 38D) in the initial clinical study (GAL-021-101). Data from the first hour of period 9 (0.96 mg/kg/h) was pooled with data from similar infusion rate subjects in groups 6 and 7 for the 0-lh assessments.
• Figure 39 is a set of graphs illustrating integrated percent change from baseline during the first hour (0-lh) and during first 2 hours (0-2h) after starting the infusion for minute ventilation (Figure 39A), end tidal CO 2 (Figure 39B), respiratory rate (Figure 39C), and tidal volume (Figure 39D) in the second clinical study (GAL-021-102).
• Figure 40 is a graph illustrating transcutaneous hemoglobin oxygen saturation (GAL-021-102).
• Figure 41 illustrates results for Part I of the GAL-021-104 clinical study: integrated percent change from baseline during the last ten minutes of each segment for minute ventilation (Figure 41 A), tidal volume (Figure 4 IB) and respiratory rate (Figure 41C). Segments were thirty minutes in durantion, except for the segment labeled (XXXVI)-high, which had duration of 40 minutes due to a twenty -minute loading dose infusion. The end-tidal was clamped during the study and was largely invariant.
• Figure 43 comprising Figures 43A-D, illustrates results for Part 2 of the GAL-021-104 study: Integrated percent change from baseline during the last ten- minutes of each segment for minute ventilation (Figure 43 A), end-tidal CO 2 (Figure 43B), respiratory rate (Figure 43C), and tidal volume (Figure 43D).
• Figure 44 comprising Figures 44A-B, illustrate mean plasma concentration-time profiles of N-(4,6-/? «- «-propylamino-[l,3,5]triazin-2-yl)-N,0- dimethyl-hydroxylamine hydrogen sulfate (XXXVI) following IV infusion to healthy volunteers during the First-in-Human study ( Figure 44A) and the second study ( Figure 44B).
• XXXVI dimethyl-hydroxylamine hydrogen sulfate
• the present invention relates in one aspect to the unexpected discovery that the compounds of the invention are respiratory stimulants and useful in the treatment of breathing control disorders or diseases. Definitions
• the articles “a” and “an” refer to one or to more than one (i.e. to at least one) of the grammatical object of the article.
• an element means one element or more than one element.
• the term "about” is understood by persons of ordinary skill in the art and varies to some extent on the context in which it is used. As used herein when referring to a measurable value such as an amount, a temporal duration, and the like, the term “about” is meant to encompass variations of ⁇ 20% or ⁇ 10%, more preferably ⁇ 5%, even more preferably ⁇ 1 %, and still more preferably ⁇ 0.1 % from the specified value, as such variations are appropriate to perform the disclosed methods.
• a "subject" may be a human or non-human mammal.
• Non-human mammals include, for example, livestock and pets, such as ovine, bovine, porcine, canine, feline and murine mammals.
• the subject is human.
• an “effective amount”, “therapeutically effective amount” or “pharmaceutically effective amount” of a compound is that amount of compound that is sufficient to provide a beneficial effect to the subject to which the compound is administered.
• the term to "treat,” as used herein, means reducing the frequency with which symptoms are experienced by a patient or subject or administering an agent or compound to reduce the severity with which symptoms are experienced.
• treating a disease or disorder means reducing the frequency with which a symptom of the disease or disorder is experienced by a subject.
• Disease and disorder are used interchangeably herein.
• alkyl by itself or as part of another substituent means, unless otherwise stated, a straight or branched chain hydrocarbon having the number of carbon atoms designated (i.e. Ci-Cio means one to ten carbon atoms) and includes straight, branched chain, or cyclic substituent groups. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, and cyclopropylmethyl. Most preferred is (Ci-C6)alkyl, such as, but not limited to, ethyl, methyl, isopropyl, isobutyl, w-pentyl, w-hexyl and
• cycloalkyl by itself or as part of another substituent means, unless otherwise stated, a cyclic chain hydrocarbon having the number of carbon atoms designated (i.e. C 3 -C6 means a cyclic group comprising a ring group consisting of three to six carbon atoms) and includes straight, branched chain or cyclic substituent groups. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Most preferred is
• alkenyl employed alone or in combination with other terms, means, unless otherwise stated, a stable mono-unsaturated or di-unsaturated straight chain or branched chain hydrocarbon group having the stated number of carbon atoms. Examples include vinyl, propenyl (or allyl), crotyl, isopentenyl, butadienyl, 1,3-pentadienyl, 1,4-pentadienyl, and the higher homologs and isomers.
• alkoxy employed alone or in combination with other terms means, unless otherwise stated, an alkyl group having the designated number of carbon atoms, as defined above, connected to the rest of the molecule via an oxygen atom, such as, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy (isopropoxy) and the higher homologs and isomers.
• oxygen atom such as, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy (isopropoxy) and the higher homologs and isomers.
• halo or halogen alone or as part of another substituent means, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom, preferably, fluorine, chlorine, or bromine, more preferably, fluorine or chlorine.
• heteroalkyl by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain alkyl group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized.
• the heteroatom(s) may be placed at any position of the heteroalkyl group, including between the rest of the heteroalkyl group and the fragment to which it is attached, as well as attached to the most distal carbon atom in the heteroalkyl group.
• Up to two heteroatoms may be consecutive, such as, for example, -CH 2 -NH-OCH 3 , or -CH 2 -CH 2 -S-S-CH 3
• heteroaryl or “heteroaromatic” refers to a heterocycle having aromatic character.
• a polycyclic heteroaryl may include one or more rings that are partially saturated. Examples include tetrahydroquinoline and
• heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl (such as, but not limited to, 2- and 4-pyrimidinyl), pyridazinyl, thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.
• heterocyclyl and heteroaryl moieties are intended to be representative and not limiting.
• 4,6-bis-( «-propylamino)-l,3,5-triazin-2-ol is present at a level equal to or lower than about 0.5% (w/w) with respect to (XXXV) or the salt thereof.
• 4,6-bis-( «-propylamino)-l,3,5-triazin-2-ol is present at a level equal to or lower than about 0.3% (w/w) with respect to (XXXV) or the salt thereof.
• 4,6-bis-(w-propylamino)-l,3,5-triazin-2- ol is present at a level equal to or lower than about 0.2% (w/w) with respect to
• the invention also includes a composition comprising N-(4,6-bis- «- propylamino-[l,3,5]triazin-2-yl)-N,0-dimethyl-hydroxylamine (XXXV) or a salt thereof, further comprising a buffer and a liquid carrier.
• the salt of (XXXV) is the hydrogen sulfate salt
• the composition further comprises citric acid.
• the pH of the composition is adjusted with a base.
• the base comprises sodium hydroxide.
• the liquid carrier comprises water.
• the pH of the composition ranges from about 2.5 to about 6. In yet another embodiment, the pH of the composition ranges from about 2.5 to about 5. In yet another embodiment, the pH of the composition ranges from about 3 to about 4. In yet another
• the invention also includes a crystalline free base of N-(4,6-Bis-w- propylamino-[l,3,5]triazin-2-yl)-N,0-dimethyl-hydroxylamine (XXXV), Form A, with a XRPD spectrum as per Figure 22.
• the invention also includes at least one crystalline salt of N-(4,6-Bis- «-propylamino-[l,3,5]triazin-2-yl)-N.O-dimethyl-hydroxylamine (XXXV) selected from the group consisting of: crystalline hydrogen sulfate salt (XXXVI) Form A, with a XRPD spectrum as per Figure 14; crystalline hydrogen sulfate salt (XXXVI) comprising a mixture of Form A and Form B, with a XRPD spectrum as per Figure 23; crystalline hydrogen sulfate salt (XXXVI) Form C, with a XRPD spectrum as per Figure 24; crystalline hydrogen sulfate salt (XXXVI) Form D, with a XRPD spectrum as per Figure 25; crystalline hydrogen sulfate salt (XXXVI) comprising a mixture of Form A and Form D, with a XRPD spectrum as per Figure 26; crystalline phosphoric acid salt (CLXXX)
• the invention also includes a salt of N-(4,6-Bis-w-propylamino- [l,3,5]triazin-2-yl)-hydroxylamine (XXXV), comprising approximately one mole equivalent of sulfuric acid.
• the salt further comprises one mole equivalent of water.
• bond b 1 is nil and: (i) Z is H, bond b 2 is a single bond, and A is CH; or, (ii) Z is nil, bond b 2 is nil, and A is a single bond; and,
• bond b 1 is a single bond, and: (i) Z is CH 2 , bond b 2 is a single bond, and A is CH; or, (ii) Z is CH, bond b 2 is a double bond, and A is C.
• R 3 is H, alkyl, substituted alkyl, alkenyl, cycloalkyl, substituted cycloalkyl, or substituted alkenyl.
• R 5 is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, acyl, cycloalkyl or substituted cycloalkyl.
• Y is N
• bond b 1 is nil
• Z is H
• bond b 2 is a single bond
• A is CH
• the compound of the invention is a 1,3,5-triazine of formula (Il-a) or a salt thereof: R1 ⁇ / X - N
• Y is N
• bond b 1 is nil
• Z is nil
• bond b 2 is nil
• A is a bond
• the compound of the invention is a 1,3,5-triazine of formula (Il-b) or a salt thereof:
• Y is CR 6
• bond b 1 is nil
• Z is H
• bond b 2 is a single bond
• A is CH
• the compound of the invention is a pyrimidine of formula (Ill-a) or a salt thereof:
• Y is C
• bond b 1 is a single bond
• Z is CH 2
• bond b 2 is a single bond
• A is CH
• the compound of the invention is a
• Y is C
• bond b 1 is a single bond
• Z is CH
• bond b 2 is a double bond
• A is C
• the compound of the invention is a pyrrolopyrimidine of formula (V) or a salt thereof:
• the compound of formula (I) is selected from the group consisting of: N-(4,6-Bis-methylamino-[l,3,5]triazin-2-yl)-N,0-dimethyl- hydroxylamine, N-(4,6-Bis-ethylamino-[l,3,5]triazin-2-yl)-N,0-dimethyl- hydroxylamine, N-(4-Cyclopropylmethyl)-N-(6- «-propylamino) [l,3,5]triazin-2-yl)- ⁇ , ⁇ -dimethyl-hydroxylamine, N-(4-Ethylamino)-N-(6- «-propylamino)-[l,3,5]triazin- 2-yl)-N,0-dimethyl-hydroxylamine, N-(Bis-4,6-(2-methylpropylamino))
• the at least one compound is 2,6-bis-(N- «- propylamino)-[l,3]pyrimidin-4-yl)-N,0-dimethyl-hydroxylamine or a salt thereof.
• the salt is hydrogen sulfate, hydrochloride, phosphate, hydrogen phosphate or dihydrogen phosphate.
• the at least one compound is selected from the group consisting of: 2-( «-Propyl)amino-4-( -propylamino-7-methyl-pyrrolidino[2,3- d]pyrimidine (CXXVI), 2-( «-Propyl)amino-4-dimethylamino-7-methyl- pyrrolidino[2,3-d]pyrimidine (CXXVIII), 2-( «-Propyl)amino-4-methylamino-7- methyl-pyrrolidino[2,3-d]pyrimidine (CXXXI), 2-( «-Propyl)amino-4-( - propyl)amino-7- -propyl-pyrrolidino[2,3-d]pyrimidine (CXXXVI), 2,4-Bis-( «- propyl)amino-7H-pyrrolidino[2,3-d]pyrimidine (CXLIX), 2-( «-Propyl)amin
• the at least one compound is selected from the group consisting of: N-(2-Propylamino-7H-pyrrolo[2,3d]pyrimidin-4-yl)-0,N- dimethyl-hydroxylamine (CXLI), N-(2-(Propen-2-yl)amino-7-methyl- pyrrolo[2,3d]pyrimidin-4-yl)-N,0-dimethyl-hydroxylamine (CLVIII), N-(2-(Propen- 2-yl)amino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-0-methyl-hydroxylamine (CLX), N-(2-«-Propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-0,N-dimethyl- hydroxylamine (CLXII), N-(2- «-Propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)- O-methyl-hydroxylamine (CLXLI), N
• the compounds of the invention may be prepared according to the general methodology illustrated in the synthetic schemes described below.
• the reagents and conditions described herein may be modified to allow the preparation of the compounds of the invention, and such modifications are known to those skilled in the art.
• the scheme included herein are intended to illustrate but not limit the chemistry and methodologies that one skilled in the art may use to make compounds of the invention.
• a compound of formula (IV) or (V) may be prepared by reductive alkylation of a suitably chlorinated amino-pyrrolidino-pyrimidine or amino-pyrrolo-pyrimidine, respectively (Scheme 2).
• a solution of 2,4,6-trichlorotriazine in an appropriate aprotic or protic solvent containing an inorganic or organic base is added a solution of a primary amine (VII) and the reaction is allowed to proceed at ambient temperature or heated, to isolate mono-amine adduct (VIII) or bis-amine adduct (IX).
• VIP primary amine
• a pyrrolidino-pyrimidine of formula (IV) or a pyrrolo-pyrimidine compounds of formula (V) may be prepared from an appropriately chlorinated aminopyrrolidinopyrimidine or aminopyrrolopyrimidine intermediate, respectively.
• 2-chloroacetaldehyde may be added to a solution of 2,6-diamino-4-hydroxy-l,3-pyrimidine (XIV) in a polar protic solvent, at ambient temperature or under heating, to yield cyclized adduct (XV).
• a chlorinating agent such as, but not limited to, phosphorous oxychloride produces the chloro intermediate (XVI).
• Intermediate (XVI) may be submitted to reductive alkylation with an aldehyde in the presence of a reducing agent, such as a borohydride (in a non-limiting example, cyanoborohydride) in a protic solvent, at ambient temperature or elevated temperature, to produce the amino substituted adduct (XVII).
• a reducing agent such as a borohydride (in a non-limiting example, cyanoborohydride) in a protic solvent, at ambient temperature or elevated temperature, to produce the amino substituted adduct (XVII).
• amino substituted adduct (XVII) is reacted with (i) a N-alkoxy-N-alkylamine, (ii) a hydrazine H 2 N-NHR 2 , or (iii) a hydrazine ⁇ HN-NHR 2 in an appropriate aprotic or protic solvent containing an inorganic or organic base to produce desired compounds of formula (V), wherein R 3 and R 4 are H (Scheme 6).
• a pyrrolidinopyrimidine compound of the formula (IV) may be prepared from the corresponding pyrrolopyrimidine analog via reduction (Scheme 7).
• the manufacture of active pharmaceutical ingredients may introduce or generate impurities in an intermediate or final active pharmaceutical compound.
• impurities may include trace metals, processing aide residuals (e.g., silica, cellulose fibers), or solvents derived from purchased starting materials.
• processing aide residuals e.g., silica, cellulose fibers
• solvents derived from purchased starting materials e.g., ethanol, sulfate, sulfate, derived from purchased starting materials.
• Other impurities may form as a consequence of the conditions to which the starting materials, process intermediates, or active ingredient itself are exposed.
• These impurities may be problematic, affecting the manufacturing process as a whole and the active ingredient in particular (e.g., its purity and crystallinity, and conditions for its isolation or crystallization).
• Such impurities often carry forward into the isolated API.
• a series of chemical changes may occur to enable this substitution, such as a prior oxidation of the appended amine side chain, with hydrolytic replacement by hydroxyl as the final transformation.
• the ⁇ , ⁇ -dimethylhydroxylamino substituent of N-(4,6-Bis-n- propylamino-[l,3,5]triazin-2-yl)-N,0-dimethyl-hydroxylamine (XXXV) may be partially displaced by hydroxyl during processing in the presence of water, forming (CLXXVIII) as a process impurity.
• the level of (CLXXVIII) in the isolated (XXXVI) is less that 0.1% (w/w) with respect to (XXXVI).
• the isolated (XXXVI) is essentially free of 4,6-bis( «- propy lamino)- 1 , 3 , 5 -triazin-2 -ol (CLXXVIII) .
• Solubility was assessed for (XXXV) alone ( Figure 19A) or when admixed with citric acid and adjusted to pH 3-5.5 with 6N sodium hydroxide (Figure 19B). From the resulting data (Table 12A, Figure 19B), solubility of (XXXV) was calculated to be 10 mg/mL at ca. pH 3.86, 25 mg/mL at ca. pH 3.46, and 50 mg/mL at ca. pH 3.16. The solubility studies in water suggested solubility might be inadequate above a pH of ca. 3.6 to enable useful concentrations. Formulation at pH ⁇ 3.6 may be tolerable when the formulated drug is diluted prior to administration, however the drug stability could be an issue at such a low pH.
• formulations including a co-solvent matrix could be useful in providing good solubility for the salt and free base forms at a suitable pH.
• the solubilities of (XXXV) and (XXXVI) were evaluated in various solvents and standard IV solutions, including 0.9% NaCl, 5% dextrose, ethanol, methanol, acetonitrile, 30% PEG 400, 70% PEG 400 and 100% PEG 400, 5% Tween 80, and propylene glycol (Table 12D).
• the solubility of (XXXVI) exceeded 90 mg/mL in water (>400 mg/mL), IV solutions (0.9% saline and 5% dextrose), ethanol and methanol, and in 30%, 70% and 100% propylene glycol.
• hydrolytic degradants may be observed over time.
• N-(4,6-Bis-n- propylamino-[l,3,5]triazin-2-yl)-N,0-dimethyl-hydroxylamine (XXXV) may degrade to 4,6-Bis(propylamino)-l,3,5-triazin-2-ol (CLXXVIII) in water-based formulations.
• Degradation was increasingly more pronounced as the pH was reduced below a value of 3 ( Figures 20A and 20B).
• solubility was high at pH 3.5 or lower, and decreased rapidly at ca. pH 3.5 to ca. 4.4 ( Figures 19A and 19B).
• the pH of the mixture containing (XXXV) is adjusted to a specific range to balance solubility and hydrolytic stability at any temperature selected.
• the rate of degradation for (XXXV) was highest in the pH range where (XXXV) is soluble to clinically useful levels.
• the clinically useful concentration of (XXXV) in a liquid carrier is about 1-10 mg/mL. In another embodiment, the clinically useful concentration of (XXXV) in a liquid carrier is about 5-10 mg/mL.
• Degradation of (XXXV) in an aqueous environment was also highly temperature-dependent, wherein cold temperatures slowed degradation.
• (XXXV) as its hydrogen sulfate salt (XXXVI) in a liquid carrier is admixed with agents to adjust pH to optimize solubility and minimize degradation.
• (XXXV) as its hydrogen sulfate salt (XXXVI) in a liquid carrier is admixed with a buffering aid.
• Suitable buffering aids include, but are not limited to citric acid, ascorbic acid, monobasic phosphoric acid, and lactic acid. In an embodiment, the buffering aid is citric acid.
• (XXXV) as its hydrogen sulfate salt (XXXVI) is admixed with citric acid and a base to adjust pH as necessary to optimize solubility and minimize hydrolytic degradation.
• Suitable bases include, but are not limited to, sodium hydroxide, potassium hydroxide, ammonium hydroxide, and dibasic potassium hydrogen phosphate.
• the pH is adjusted with sodium hydroxide.
• the liquid carrier is a mixture of water and a suitable organic co-solvent. Suitable organic co-solvents include, but are not limited to, glycerin, propylene glycol, polyethylene glycol 400, ethanol, 1 ,4-butanediol, and dimethylsulfoxide.
• the mixture comprising (XXXV) as it hydrogen sulfate salt may be stored at low temperatures to retard the rate of degradation of the compound.
• the temperature may be in the range of about 0- 15°C.
• the cold temperature may be in the range of 2-8°C.
• the mixture comprising (XXXV) as its hydrogen sulfate salt (XXXVI) and citric acid and sodium hydroxide is adjusted to pH of about 3-4 and stored at about 2-8 °C. The rate of degradant growth was slow at 2-8°C and much faster at 25°C or above.
• the level of (CLXXVIII) formed when (XXXVI) is formulated for parenteral administration may be maintained below 0.5% for over 2 years by storing the preparation at 2-8°C ( Figure 21).
• the present invention includes a formulation comprising an active ingredient, salt former, admixed buffering aid, admixed base pH and liquid carrier, along with storage conditions necessary to optimize drug solubility and maintain hydrolytic degradants within acceptable levels.
• the compounds described herein may form salts with acids, and such salts are included in the present invention.
• the salts are pharmaceutically acceptable salts.
• salts embraces addition salts of free acids that are useful within the methods of the invention.
• pharmaceutically acceptable salt refers to salts that possess toxicity profiles within a range that affords utility in pharmaceutical applications. Pharmaceutically unacceptable salts may nonetheless possess properties such as high crystallinity, which have utility in the practice of the present invention, such as for example utility in process of synthesis, purification or formulation of compounds useful within the methods of the invention.
• Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid.
• inorganic acids include sulfate, hydrogen sulfate, hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, and phosphoric acids (including hydrogen phosphate and dihydrogen phosphate).
• Suitable pharmaceutically acceptable base addition salts of compounds of the invention include, for example, metallic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts.
• Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, ⁇ , ⁇ '- dibenzylethylene-diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine ( -methylglucamine) and procaine. All of these salts may be prepared from the corresponding compound by reacting, for example, the appropriate acid or base with the compound.
• the compounds of the invention or a salt thereof may be used in combination with one or more of the following drugs:
• ampakines are the pyrrolidine derivative racetam drugs such as piracetam and aniracetam; the "CX" series of drugs which encompass a range of benzoylpiperidine and benzoylpyrrolidine structures, such as CX-516 (6-(piperidin-l-yl- carbonyl)quinoxaline), CX-546 (2,3-dihydro-l,4-benzodioxin-7-yl-(l-piperidyl)- methanone), CX-614 (2H,3H,6aH-pyrrolidino(2, l-3',2')-l,3-oxazino-
• LY-451,646 and LY-503,430 (4'- ⁇ (l S)-l-fluoro-2-[(isopropylsulfonyl)amino]-l- methylethyl ⁇ -N-methylbiphenyl-4-carboxamide).
• the invention also includes a method of preventing destabilization or stabilizing breathing rhythm in a subject in need thereof.
• the method comprises administering to the subject an effective amount of a pharmaceutical formulation comprising at least one pharmaceutically acceptable carrier and at least one compound selected from the group consisting of: N-(2,4-bis- «-propylamino)-N-(6- methylamino)-[l,3,5]triazine (CLXXII), N-(2,4,6-tris-w-propylamino)-[l,3,5]triazine (CLXXIII), N-(2,4,6-tris- «-propylamino)-l,3-pyrimidine (CLXXIV), N-(2,4-bis- «- propylamino)-N-(6-z ' -propylamino)-l,3-pyrimidine (CLXXV), a salt thereof, and any combinations thereof.
• a pharmaceutical formulation comprising at least one pharmaceutically acceptable carrier and at least
• the breathing control disorder or disease is selected from the group consisting of respiratory depression, sleep apnea, apnea of prematurity, obesity -hypoventilation syndrome, primary alveolar hypoventilation syndrome, dyspnea, hypoxia, and hypercapnia.
• the respiratory depression is caused by an anesthetic, a sedative, an anxiolytic agent, a hypnotic agent, alcohol or a narcotic.
• the subject is further administered a composition comprising at least one additional compound useful for treating the breathing control disorder or disease.
• the at least one additional compound is selected from the group consisting of acetazolamide, almitrine, theophylline, caffeine, methyl progesterone, a serotinergic modulator, a cannabinoid and an ampakine.
• the formulation is administered in conjunction with the use of a mechanical ventilation device or positive airway pressure device on the subject.
• the subject is a mammal.
• the mammal is a human.
• the formulation is administered to the subject by an inhalational, topical, oral, buccal, rectal, vaginal, intramuscular, subcutaneous, transdermal, intrathecal or intravenous route.
• the invention also includes a method of reducing or minimizing the open channel fraction of the potassium maxi-K or BK channel in a subject in need thereof.
• the method comprises administering to the subject an effective amount of a pharmaceutical formulation comprising at least one pharmaceutically acceptable carrier and at least one compound of formula (I).
• the invention also includes a method of inhibiting the TASK-1
• the method comprises administering to the subject an effective amount of a pharmaceutical formulation comprising at least one pharmaceutically acceptable carrier and at least one compound of formula (I).
• the invention also includes a method of increasing minute ventilation in a subject in need thereof.
• the method comprises administering to the subject an effective amount of a pharmaceutical formulation comprising at least one
• the compound of formula (I) is:
• R 1 and R 2 are independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl or substituted heteroaryl; or R 1 and R 2 combine as to form a biradical selected from the group consisting of 3- hydroxy-pentane- 1 ,5 -diyl, 6-hydroxy-cycloheptane- 1 ,4-diyl, propane- 1 ,3 -diyl, butane- 1,4-diyl and pentane-l,5-diyl; R 3 is H, alkyl, substituted alkyl, cycloalkyl, substituted
• bond b 1 is nil and: (i) Z is H, bond b 2 is a single bond, and A is CH; or, (ii) Z is nil, bond b 2 is nil, and A is a single bond; and,
• bond b 1 is a single bond, and: (i) Z is C3 ⁇ 4, bond b 2 is a single bond, and A is CH; or, (ii) Z is CH, bond b 2 is a double bond, and A is C; or a salt thereof.
• the compound of formula (I) is selected from the group consisting of: N-(4,6-Bis-n-propylamino-l,3,5]triazin-2-yl)- O-methyl-hydroxylamine; N-(4,6-Bis-n-propylamino-l,3,5]triazin-2-yl)-N',N'- dimethylhydrazine; N-(2,4-Bis-n-propylamino)-N-(6-methylamino)-[l,3,5]triazine; N-[(2,6-Bis-n-propylamino)-pyrimidin-4-yl]-N,0-dimethyl-hydroxylamine; N,N- Dimethyl-N'-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-hydrazine; a salt thereof and mixtures thereof.
• R 1 and R 2 are independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl or substituted heteroaryl; or R 1 and R 2 combine as to form a biradical selected from the group consisting of 3- hydroxy-pentane- 1 ,5 -diyl, 6-hydroxy-cycloheptane- 1 ,4-diyl, propane- 1 ,3 -diyl, butane- 1,4-diyl and pentane-l,5-diyl; R 3 is H, alkyl, substituted alkyl, cycloalkyl, substituted
• the destabilization is associated with a breathing control disorder or disease.
• physiologically acceptable cation or anion as is well known in the art.
• compositions of the invention will vary, depending upon the identity, size, and condition of the subject treated and further depending upon the route by which the composition is to be administered.
• the composition may comprise between 0.1% and 100% (w/w) active ingredient.
• compositions that are useful in the methods of the invention may be suitably developed for inhalational, oral, rectal, vaginal, parenteral, topical, transdermal, pulmonary, intranasal, buccal, ophthalmic, intrathecal, intravenous or another route of administration.
• a composition useful within the methods of the invention may be directly administered to the brain, the brainstem, or any other part of the central nervous system of a mammal.
• Other contemplated formulations include projected nanoparticles, liposomal preparations, resealed erythrocytes containing the active ingredient, and immunologically -based
• compositions are principally directed to pharmaceutical compositions which are suitable for ethical administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts.
• compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and perform such modification with merely ordinary, if any, experimentation.
• Subjects to which administration of the pharmaceutical compositions of the invention is contemplated include, but are not limited to, humans and other primates, mammals including commercially relevant mammals such as cattle, pigs, horses, sheep, cats, and dogs.
• compositions of the invention are formulated using one or more pharmaceutically acceptable excipients or carriers.
• the pharmaceutical compositions of the invention comprise a therapeutically effective amount of at least one compound of the invention and a pharmaceutically acceptable carrier.
• Pharmaceutically acceptable carriers include, but are not limited to, glycerol, water, saline, ethanol and other pharmaceutically acceptable salt solutions such as phosphates and salts of organic acids. Examples of these and other pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1991, Mack Publication Co., New Jersey).
• the carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
• the proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
• Prevention of the action of microorganisms may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
• isotonic agents for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol
• Prolonged absorption of the injectable compositions may be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate or gelatin.
• the pharmaceutically acceptable carrier is not DMSO alone.
• Formulations may be employed in admixtures with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, inhalational, intravenous, subcutaneous, transdermal enteral, or any other suitable mode of administration, known to the art.
• the pharmaceutical preparations may be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and/or aromatic substances and the like. They may also be combined where desired with other active agents, e.g., other analgesic agents.
• additional ingredients include, but are not limited to, one or more ingredients that may be used as a pharmaceutical carrier.
• composition of the invention may comprise a preservative from about 0.005% to 2.0% by total weight of the composition.
• the preservative is used to prevent spoilage in the case of exposure to contaminants in the environment.
• preservatives useful in accordance with the invention included but are not limited to those selected from the group consisting of benzyl alcohol, sorbic acid, parabens, imidurea and combinations thereof.
• a particularly preferred preservative is a combination of about 0.5% to 2.0% benzyl alcohol and 0.05% to 0.5% sorbic acid.
• the composition preferably includes an antioxidant and a chelating agent which inhibit the degradation of the compound.
• Preferred antioxidants for some compounds are BHT, BHA, alpha-tocopherol and ascorbic acid in the preferred range of about 0.01% to 0.3% and more preferably BHT in the range of 0.03% to 0.1% by weight by total weight of the composition.
• Liquid suspensions may be prepared using conventional methods to achieve suspension of the active ingredient in an aqueous or oily vehicle.
• Aqueous vehicles include, for example, water, and isotonic saline.
• Oily vehicles include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as arachis, olive, sesame, or coconut oil, fractionated vegetable oils, and mineral oils such as liquid paraffin.
• Liquid suspensions may further comprise one or more additional ingredients including, but not limited to, suspending agents, dispersing or wetting agents, emulsifying agents, demulcents, preservatives, buffers, salts, flavorings, coloring agents, and sweetening agents.
• Oily suspensions may further comprise a thickening agent.
• suspending agents include, but are not limited to, sorbitol syrup, hydrogenated edible fats, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, and cellulose derivatives such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose.
• Known dispersing or wetting agents include, but are not limited to, naturally-occurring phosphatides such as lecithin, condensation products of an alkylene oxide with a fatty acid, with a long chain aliphatic alcohol, with a partial ester derived from a fatty acid and a hexitol, or with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxy ethylene stearate, heptadecaethyleneoxycetanol, polyoxyethylene sorbitol monooleate, and polyoxyethylene sorbitan monooleate, respectively).
• Known emulsifying agents include, but are not limited to, lecithin, and acacia.
• Known preservatives include, but are not limited to, methyl, ethyl, or w-propyl para-hydroxybenzoates, ascorbic acid, and sorbic acid.
• Known sweetening agents include, for example, glycerol, propylene glycol, sorbitol, sucrose, and saccharin.
• Known thickening agents for oily suspensions include, for example, beeswax, hard paraffin, and cetyl alcohol.
• compositions may further comprise one or more emulsifying agents such as naturally occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soybean or lecithin phosphatide, esters or partial esters derived from combinations of fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of such partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate.
• emulsions may also contain additional ingredients including, for example, sweetening or flavoring agents.
• incorporating a chemical composition into the structure of a material during the synthesis of the material i.e., such as with a physiologically degradable material
• methods of absorbing an aqueous or oily solution or suspension into an absorbent material with or without subsequent drying.
• compositions of the present invention may be carried out using known procedures, at dosages and for periods of time effective to treat a breathing control disorder in the patient.
• An effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to factors such as the activity of the particular compound employed; the time of administration; the rate of excretion of the compound; the duration of the treatment; other drugs, compounds or materials used in combination with the compound; the state of the disease or disorder, age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well-known in the medical arts. Dosage regimens may be adjusted to provide the optimum therapeutic response.
• an effective dose range for a therapeutic compound of the invention is from about 0.01 mg/kg and 50 mg/kg of body weight/per day.
• One of ordinary skill in the art would be able to study the relevant factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation.
• the compound can be administered to an animal as frequently as several times daily, or it may be administered less frequently, such as once a day, once a week, once every two weeks, once a month, or even less frequently, such as once every several months or even once a year or less. It is understood that the amount of compound dosed per day may be administered, in non-limiting examples, every day, every other day, every 2 days, every 3 days, every 4 days, or every 5 days. For example, with every other day administration, a 5 mg per day dose may be initiated on Monday with a first subsequent 5 mg per day dose administered on
• a medical doctor e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required.
• physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
• Dosage unit form refers to physically discrete units suited as unitary dosages for the patients to be treated; each unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle.
• the dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding/formulating such a therapeutic compound for the treatment of breathing disorders in a patient.
• the dose of a compound of the invention is from about 0.5 ⁇ g and about 5,000 mg. In some embodiments, a dose of a compound of the invention used in compositions described herein is less than about 5,000 mg, or less than about 4,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg.
• a dose of a second compound as described herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any and all whole or partial increments thereof.
• compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration and the like. It should be understood that the formulations and compositions that would be useful in the present invention are not limited to the particular formulations and compositions that are described herein.
• Tablets may be non-coated or they may be coated using known methods to achieve delayed disintegration in the gastrointestinal tract of a subject, thereby providing sustained release and absorption of the active ingredient.
• a material such as glyceryl monostearate or glyceryl distearate may be used to coat tablets.
• tablets may be coated using methods described in U.S. Patents Nos. 4,256, 108; 4, 160,452; and 4,265,874 to form osmotically controlled release tablets.
• Tablets may further comprise a sweetening agent, a flavoring agent, a coloring agent, a preservative, or some combination of these in order to provide for pharmaceutically elegant and palatable preparation.
• Liquid preparation for oral administration may be in the form of solutions, syrups or suspensions.
• the liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agent (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl para-hydroxy benzoates or sorbic acid).
• suspending agents e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats
• emulsifying agent e.g., lecithin or acacia
• non-aqueous vehicles e.g., almond oil, oily esters or ethyl alcohol
• preservatives e.g., methyl or propyl para-hydroxy benzoates or sorbic acid
• Known granulating and disintegrating agents include, but are not limited to, corn starch and alginic acid.
• Known binding agents include, but are not limited to, gelatin, acacia, pre-gelatinized maize starch, polyvinylpyrrolidone, and hydroxypropyl methylcellulose.
• Known lubricating agents include, but are not limited to, magnesium stearate, stearic acid, silica, and talc.
• Granulating techniques are well known in the pharmaceutical art for modifying starting powders or other particulate materials of an active ingredient.
• the powders are typically mixed with a binder material into larger permanent free-flowing agglomerates or granules referred to as a "granulation.”
• solvent-using "wet" granulation processes are generally characterized in that the powders are combined with a binder material and moistened with water or an organic solvent under conditions resulting in the formation of a wet granulated mass from which the solvent must then be evaporated.
• parenteral administration of a pharmaceutical composition includes any route of administration characterized by physical breaching of a tissue of a subject and administration of the pharmaceutical composition through the breach in the tissue.
• Parenteral administration thus includes, but is not limited to, administration of a pharmaceutical composition by injection of the composition, by application of the composition through a surgical incision, by application of the composition through a tissue-penetrating non-surgical wound, and the like.
• parenteral administration is contemplated to include, but is not limited to, subcutaneous, intravenous, intraperitoneal, intramuscular, intrasternal injection, and kidney dialytic infusion techniques.
• the active ingredient is provided in dry (i.e., powder or granular) form for reconstitution with a suitable vehicle (e.g., sterile pyrogen-free water) prior to parenteral administration of the reconstituted composition.
• a suitable vehicle e.g., sterile pyrogen-free water
• compositions may be prepared, packaged, or sold in the form of a sterile injectable aqueous or oily suspension or solution.
• This suspension or solution may be formulated according to the known art, and may comprise, in addition to the active ingredient, additional ingredients such as the dispersing agents, wetting agents, or suspending agents described herein.
• Such sterile injectable formulations may be prepared using a non-toxic parenterally-acceptable diluent or solvent, such as water or 1,3-butane diol, for example.
• Other acceptable diluents and solvents include, but are not limited to, Ringer's solution, isotonic sodium chloride solution, and fixed oils such as synthetic mono- or di-glycerides.
• Formulations suitable for topical administration include, but are not limited to, liquid or semi-liquid preparations such as liniments, lotions, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes, and solutions or suspensions.
• Topically administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient may be as high as the solubility limit of the active ingredient in the solvent.
• Formulations for topical administration may further comprise one or more of the additional ingredients described herein. Enhancers of permeation may be used. These materials increase the rate of penetration of drugs across the skin.
• compositions of the invention may contain liposomes.
• the composition of the liposomes and their use are known in the art (for example, see Constanza, U.S. Patent No. 6,323,219).
• the topically active pharmaceutical composition should be applied in an amount effective to affect desired changes.
• amount effective shall mean an amount sufficient to cover the region of skin surface where a change is desired.
• An active compound should be present in the amount of from about 0.0001% to about 15% by weight volume of the composition. More preferable, it should be present in an amount from about 0.0005% to about 5% of the composition; most preferably, it should be present in an amount of from about 0.001% to about 1% of the composition.
• Such compounds may be synthetically-or naturally derived.
• a pharmaceutical composition of the invention may be prepared, packaged, or sold in a formulation suitable for rectal administration.
• a composition may be in the form of, for example, a suppository, a retention enema preparation, and a solution for rectal or colonic irrigation.
• Suppository formulations may be made by combining the active ingredient with a non-irritating pharmaceutically acceptable excipient which is solid at ordinary room temperature (i.e., about 20°C) and which is liquid at the rectal temperature of the subject (i.e., about 37°C in a healthy human).
• a non-irritating pharmaceutically acceptable excipient which is solid at ordinary room temperature (i.e., about 20°C) and which is liquid at the rectal temperature of the subject (i.e., about 37°C in a healthy human).
• pharmaceutically acceptable excipients include, but are not limited to, cocoa butter, polyethylene glycols, and various glycerides. Suppository formulations may further comprise various additional ingredients including, but not limited to, antioxidants, and preservatives.
• Retention enema preparations or solutions for rectal or colonic irrigation may be made by combining the active ingredient with a pharmaceutically acceptable liquid carrier.
• enema preparations may be administered using, and may be packaged within, a delivery device adapted to the rectal anatomy of the subject.
• Enema preparations may further comprise various additional ingredients including, but not limited to, antioxidants, and preservatives. Additional Administration Forms
• Additional dosage forms of this invention include dosage forms as described in U.S. Patents Nos. 6,340,475, 6,488,962, 6,451,808, 5,972,389, 5,582,837, and 5,007,790. Additional dosage forms of this invention also include dosage forms as described in U.S. Patent Applications Nos. 20030147952,
• Additional dosage forms of this invention also include dosage forms as described in PCT Applications Nos. WO 03/35041, WO 03/35040, WO 03/35029, WO 03/35177, WO 03/35039, WO 02/96404, WO 02/32416, WO 01/97783, WO 01/56544, WO 01/32217, WO 98/55107, WO 98/1 1879, WO 97/47285, WO 93/18755, and WO 90/11757.
• Controlled- or sustained-release formulations of a pharmaceutical composition of the invention may be made using conventional technology.
• the dosage forms to be used can be provided as slow or controlled-release of one or more active ingredients therein using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, or microspheres or a combination thereof to provide the desired release profile in varying proportions.
• Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the pharmaceutical compositions of the invention.
• single unit dosage forms suitable for oral administration such as tablets, capsules, gelcaps, and caplets, that are adapted for controlled-release are encompassed by the present invention.
• controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts.
• the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time.
• Advantages of controlled-release formulations include extended activity of the drug, reduced dosage frequency, and increased patient compliance.
• controlled-release formulations can be used to affect the time of onset of action or other characteristics, such as blood level of the drug, and thus can affect the occurrence of side effects.
• controlled-release formulations are designed to initially release an amount of drug that promptly produces the desired therapeutic effect, and gradually and continually release of other amounts of drug to maintain this level of therapeutic effect over an extended period of time.
• the drug In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body.
• Controlled-release of an active ingredient can be stimulated by various inducers, for example pH, temperature, enzymes, water, or other physiological conditions or compounds.
• controlled-release component in the context of the present invention is defined herein as a compound or compounds, including, but not limited to, polymers, polymer matrices, gels, permeable membranes, liposomes, or microspheres or a combination thereof that facilitates the controlled-release of the active ingredient.
• the formulations of the present invention may be, but are not limited to, short-term, rapid-offset, as well as controlled, for example, sustained release, delayed release and pulsatile release formulations.
• sustained release is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that may, although not necessarily, result in substantially constant blood levels of a drug over an extended time period.
• the period of time may be as long as a month or more and should be a release that is longer that the same amount of agent administered in bolus form.
• delayed release is used herein in its conventional sense to refer to a drug formulation that provides for an initial release of the drug after some delay following drug administration and that may, although not necessarily, includes a delay of from about 10 minutes up to about 12 hours.
• short-term refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes and any or all whole or partial increments thereof after drug administration after drug administration.
• Mechanical ventilation is a method to mechanically assist or replace spontaneous breathing.
• Mechanical ventilation is typically used after an invasive intubation, a procedure wherein an endotracheal or tracheostomy tube is inserted into the airway. It is normally used in acute settings, such as in the operating room or ICU, for a short period of time during surgery, medical procedure, or serious illness. It may also be used at home or in a nursing or rehabilitation institution, if patients have chronic illnesses that require long-term ventilation assistance.
• the main form of mechanical ventilation is positive pressure ventilation, which works by increasing the pressure in the patient's airway and thus forcing air into the lungs.
• BIPAP Bi-level positive airway pressure
• IPPV Intermittent positive pressure ventilation
• range such as from 1 to 6 should be considered to have specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.
• a suitable glass reactor vessel equipped with a mechanical stirrer, thermocouple, condenser, addition funnel and a temperature control mantle was charged with 8 L of acetone followed by 1 kg (5.42 moles) of cyanuric chloride.
• the stirring mixture was pre-cooled to 15 °C and ⁇ -propylamine (at ambient temperature) was added slowly via addition funnel, to maintain the temperature below 45°C.
• a 2M NaOH solution was prepared and was added to the mixture at a rate to maintain the temperature below 45°C.
• the mixture was stirred at 40-50°C for 0.5 h and the reaction was monitored for completion by IPC HPLC analysis. The reaction was deemed complete when ⁇ 2% of cyanuric chloride was detected.
• a suitable round-bottom flask equipped with a mechanical stirrer, thermocouple, condenser and a heating mantle was charged with 6 L of N,N- dimethylacetamide (DMA) followed by 1 kg (4.35 moles) of 6-chloro-N,N-dipropyl- [l,3,5]-triazine-2,4-diamine (Stage 1 Product).
• DMA N,N- dimethylacetamide
• K2CO 3 1.2 kg, 6.53 moles, 2 eq.
• IPC Test 1 Temperature Chart Recording during additions - Maintain temperature control specified in process steps
• IPC Test 3 Residual amine analysis (by GC) - ⁇ -Propylamine and ⁇ , ⁇ -dimethylhydoxylamine levels NMT 0.1%
• IPC Test 1 Temperature Chart Recording during concentrated sulfuric acid addition - Maintain temperature control specified in process step
• IPC Test 2 OVI of MEK and DMAc by GC -
• the HPLC chromatographic purity of the RS was determined to be 100.0% by area, with no related substances detected.
• the water content was determined to be 0.04% by Karl Fischer titration.
• N-(4,6-bis- «-propylamino-[l,3,5]triazin-2-yl)-N,0-dimethyl- hydroxylamine hydrogen sulfate (XXXVI) was determined to be a white crystalline solid.
• 6-Amino-2,4-dichloro-[l,3,5]triazine (XXXVII) (30.0 g, 187 mmol) was dissolved in acetone (100 mL) and poured into ice-water (100 mL) to form a very fine suspension.
• acetone 100 mL
• ice-water 100 mL
• a solution of propan-1 -amine (11.0 g, 187 mmol) in acetone (20 mL) was added at 0°C.
• 2 N NaOH (94 mL, 187 mmol) was added dropwise at a rate to keep the temperature between 0°C and 5°C. The mixture was stirred for 30 min at ambient temperature and for an additional 60 min at 50°C.
• N-(4,6-Bis- «-propylamino-[l,3,5]triazin-2-yl)-N-isopropyl- hydroxylamine hydrogen sulfate (LVI) was prepared from N-(4,6-bis-w-propylamino- [l,3,5]triazin-2-yl)-N-isopropyl-hydroxylamine (LV) and 95% H2SO4 as described in Example 20 (95% yield).
• 6-[l,2]Oxazinan-2-yl-N,N'-di- «-propyl-[l,3,5]triazine-2,4-diamine hydrogen sulfate (LVIII) was prepared from 6-[l,2]oxazinan-2-yl-N,N'-di- «-propyl- [l,3,5]triazine-2,4-diamine (LVII) and 95% H 2 S0 4 as described in Example 20.
• O-Isopropyl-N-methyl-hydroxylamine hydrochloride (LXIII) O-Benzyl-N-methyl-Nisopropoxy carbamate (4.96 g, 22.22 mmol) and 33% HBr/AcOH (45 mL) were stirred at room temperature for 20 min. Saturated solution of NaHCC (400 mL) was added, the suspension was extracted with (3 ⁇ 4(3 ⁇ 4 (3 x 150 mL). The combined organic extracts were dried over a 2 S0 4 .
• N-(4,6-bis- «-propylamino-[l,3,5]triazin-2-yl)-0- isopropyl-N-methyl-hydroxylamine (LXIV, 1.93 g, 6.83 mmol) in 1,4-dioxane (6 mL) at 0°C was added 95% H 2 S0 4 (0.36 mL, 6.83 mmol) in a drop-wise manner.
• the mixture was stirred for 0.5 h at room temperature and then the volatiles were removed under reduced pressure.
• An ACE ® pressure tube was charged with benzyl isopropoxycarbamate (4.08 g, 19.50 mmol), anhydrous K 2 C0 3 (4.04 g, 29.25 mmol), ethyl iodide (7.0 mL, 87.75 mmol), and anhydrous acetone (30 mL).
• the reaction mixture was heated at 70 °C for 24 h.
• Ethyl iodide (7.0 mL, 87.75 mmol) and K 2 C0 3 (4.04 g, 29.25 mmol) were added and the reaction mixture was heated for 24 h.
• the reaction mixture was filtered, and the acetone was evaporated.
• 6-(Methyl(thiophen-2-ylmethoxy)amino)-N 2 ,N 4 -di- «-propyl-l,3,5- triazine-2,4-diamine may be prepared by reacting 2-chloro-N-(4,6-bis-( «- propylamino)-[l,3,5]triazine (XXXIV) and 0-(thiophen-2-yl-methyl)-N-methyl- hydroxylamine as exemplified in Example 13.
• N-(4,6-bis- «-propylamino-[l,3,5]triazin-2-yl)-0-(2,2-difluoro-ethyl)- hydroxylamine (C, 1.02 g, 3.51 mmol) was reacted with 95% H 2 S0 4 (0.19 mL, 3.51 mmol) in diethyl ether (3 mL) at 0°C.
• Example 51 4-N-Q -N-Methylimidazol-2-yl -methylamino-6-N-fa-propyl amino-r 1 ,3 ,51triazin-2- yl)-N,0-dimethyl-hydroxylamine (CVII)
• N-(4,6-Dichloro[l,3,5]triazin-2-yl)-N,0-dimethyl-hydroxylamine (XXX) (7 g, 33.5 mmol)
• K 2 C0 3 (10.2 g, 73.7 mmol) in THF (250 mL) were heated at 70 °C for 5 h, after which time the solvent was removed under reduced pressure.

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• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

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• 2013
  • 2013-05-29 AU AU2013267570A patent/AU2013267570A1/en not_active Abandoned
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  • 2013-05-29 CN CN201380040132.0A patent/CN104602694A/zh active Pending
  • 2013-05-29 CA CA2875012A patent/CA2875012A1/en not_active Abandoned
  • 2013-05-29 HK HK15109840.6A patent/HK1209118A1/xx unknown
  • 2013-05-29 EP EP13798039.7A patent/EP2855438A4/en not_active Withdrawn
  • 2013-05-29 KR KR20147036621A patent/KR20150020616A/ko not_active Withdrawn
  • 2013-05-29 JP JP2015515140A patent/JP2015521201A/ja active Pending
  • 2013-05-29 WO PCT/US2013/043052 patent/WO2013181217A2/en not_active Ceased
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