Substituted pyrimidines for treatment of a cough selected from chronic pathological cough, sub-acute pathological cough, acute pathological cough, neuronal hypersensitivity underlying chronic cough, neuronal hypersensitivity underlying sub-acute cough and neuronal hypersensitivity underlying acute cough

Methods for treating cough, chronic cough and urges to cough associated with respiratory diseases with a P2X3 and/or a P2X2/3 receptor antagonist, the methods comprising administering to a subject in need thereof an effective amount of a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are as defined herein.

METHODS OF USING DIAMINOPYRIMIDINE AS P2X3 AND P2X2/3 RECEPTOR MODULATORS FOR TREATMENT OF RESPIRATORY AND GASTROINTESTINAL DISEASES

Methods for treating respiratory and gastrointestinal diseases mediated by a P2Xand/or a P2Xreceptor antagonist, the methods comprising administering to a subject in need thereof an effective amount of a compound of formula (I): 139-. (canceled)41. The method of claim 40 , wherein R claim 40 , R claim 40 , Rand Rare hydrogen.42. A method for treating chronic obstructive pulmonary disease claim 40 , said method comprising administering to a subject in need thereof a compound selected from the group consisting of:5-(2-Isopropyl-4,5-dimethoxy-phenoxy)-pyrimidine-2,4-diamine;5-(5-Bromo-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine;5-(5-Chloro-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine;{'sup': '2', 'N-Benzyl-5-(5-chloro-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine;'}{'sup': '2', '5-(5-Chloro-2-isopropyl-4-methoxy-phenoxy)-N(tetrahydro-pyran-4-yl)-pyrimidine-2,4-diamine;'}{'sup': '2', '5-(5-Chloro-2-isopropyl-4-methoxy-phenoxy)-N-isopropyl-pyrimidine-2,4-diamine;'}{'sup': '2', 'N-Isopropyl-5-(2-isopropyl-4,5-dimethoxy-phenoxy)-pyrimidine-2,4-diamine;'}{'sup': '2', '5-(2-Isopropyl-4,5-dimethoxy-phenoxy)-N-phenyl-pyrimidine-2,4-diamine;'}{'sup': '2', 'N-Benzyl-5-(2-isopropyl-4,5-dimethoxy-phenoxy)-pyrimidine-2,4-diamine;'}N-[4-Amino-5-(2-isopropyl-4,5-dimethoxy-phenoxy)-pyrimidin-2-yl]-acetamide;{'sup': '2', '5-(2-Isopropyl-4,5-dimethoxy-phenoxy)-N-(2,2,2-trifluoro-ethyl)-pyrimidine-2,4-diamine;'}{'sup': '2', '5-(2-Isopropyl-4,5-dimethoxy-phenoxy)-N-(2-methoxy-ethyl)-pyrimidine-2,4-diamine;'}3-[4-Amino-5-(5-chloro-2-isopropyl-4-methoxy-phenoxy)-pyrimidin-2-ylamino]-pentane-1,5-diol;2-[4-Amino-5-(5-chloro-2-isopropyl-4-methoxy-phenoxy)-pyrimidin-2-ylamino]-butan-1-ol;1-[5-(2,4-Diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-phenyl]-ethanone;5-[5-(1H-Imidazol-2-yl)-2-isopropyl-4-methoxy-phenoxy]-pyrimidine-2,4-diamine;{'sup': '2', '5-(5-Chloro-2-isopropyl-4-methoxy-phenoxy)-N-(3-ethanesulfonyl-1-methyl-propyl)-pyrimidine-2,4-diamine;'}5-(2,4- ...

METHODS OF USING DIAMINOPYRIMIDINE P2X3 AND P2X2/3 RECEPTOR MODULATORS FOR TREATMENT OF RESPIRATORY AND GASTROINTESTINAL DISEASES

Methods for treating respiratory and gastrointestinal diseases mediated by a P2Xand/or a P2Xreceptor antagonist, the methods comprising administering to a subject in need thereof an effective amount of a compound of formula (I): 152-. (canceled)54. The method of claim 53 , wherein X is: —CH— or —O—.55. The method of claim 54 , wherein Y is —NRR.56. The method of claim 55 , wherein Ris alkyl claim 55 , alkenyl or cycloalkyl.57. The method of claim 56 , wherein Rand Rare hydrogen.58. The method of claim 57 , wherein Ris hydrogen.59. The method of claim 58 , wherein one of Rand Ris hydrogen and the other is hydrogen claim 58 , alkyl claim 58 , hydroxyalkyl or haloalkyl.60. The method of claim 58 , wherein one of Rand Ris hydrogen and the other is hydrogen claim 58 , alkyl claim 58 , hydroxyalkyl or haloalkyl.61. The method of claim 58 , wherein Rand Reach independently is halo claim 58 , alkoxy claim 58 , hydroxy claim 58 , haloalkoxy; aminosulfonyl; or alkylsulfonyl.62. The method of claim 58 , wherein R claim 58 , R claim 58 , Rand Rare hydrogen.63. The method of claim 59 , wherein Ris isopropyl.64. The method of claim 53 , wherein Ris heteroaryl.65. The method of claim 53 , wherein Rand Rtogether with the atoms to which they are attached form a five or six membered ring that includes one or two heteroatoms selected from O claim 53 , N and S.66. The method of claim 53 , wherein Rand Rtogether with the atoms to which they are attached form a five or six membered ring that includes one or two heteroatoms selected from O claim 53 , N and S.68. The method of claim 67 , wherein Ris isopropyl.69. The method of claim 68 , wherein Ris halo claim 68 , alkoxy claim 68 , haloalkoxy or hydroxy.7017. The method of claim claim 68 , wherein Ris halo claim 68 , alkoxy claim 68 , alkylsulfonyl claim 68 , aminosulfonyl or heteroaryl.71. The method of claim 53 , wherein said disease is a respiratory disease selected from chronic obstructive pulmonary disease (COPD) claim 53 , asthma ...

METHODS OF USING DIAMINOPYRIMIDINE P2X3 AND P2X2/3 RECEPTOR MODULATORS FOR TREATMENT OF RESPIRATORY AND GASTROINTESTINAL DISEASES

Methods for treating respiratory and gastrointestinal diseases mediated by a P2Xand/or a P2Xreceptor antagonist, the methods comprising administering to a subject in need thereof an effective amount of a compound of formula (I): 2. The method of claim 1 , wherein X is: —CH— or —O—.3. The method of claim 2 , wherein Y is —NRR.4. The method of claim 3 , wherein Ris alkyl claim 3 , alkenyl or cycloalkyl.5. The method of claim 4 , wherein Rand Rare hydrogen.6. The method of claim 5 , wherein Ris hydrogen.7. The method of claim 6 , wherein one of Rand Ris hydrogen and the other is hydrogen claim 6 , alkyl claim 6 , hydroxyalkyl or haloalkyl.8. The method of claim 6 , wherein one of Rand Ris hydrogen and the other is hydrogen claim 6 , alkyl claim 6 , hydroxyalkyl or haloalkyl.9. The method of claim 6 , wherein Rand Reach independently is halo claim 6 , alkoxy claim 6 , hydroxy claim 6 , haloalkoxy; aminosulfonyl; or alkylsulfonyl.10. The method of claim 6 , wherein R claim 6 , R claim 6 , Rand Rare hydrogen.11. The method of claim 9 , wherein Ris isopropyl.12. The method of claim 1 , wherein Ris heteroaryl.13. The method of claim 1 , wherein Rand Rtogether with the atoms to which they are attached form a five or six membered ring that includes one or two heteroatoms selected from O claim 1 , N and S.14. The method of claim 1 , wherein Rand Rtogether with the atoms to which they are attached form a five or six membered ring that includes one or two heteroatoms selected from O claim 1 , N and S.16. The method of claim 15 , wherein Ris isopropyl.17. The method of claim 16 , wherein Ris halo claim 16 , alkoxy claim 16 , haloalkoxy or hydroxy.18. The method of claim 17 , wherein Ris halo claim 17 , alkoxy claim 17 , alkylsulfonyl claim 17 , aminosulfonyl or heteroaryl.23. The method of claim 22 , wherein Ris halo claim 22 , alkoxy claim 22 , haloalkoxy or hydroxy.24. The method of claim 23 , wherein Ris halo claim 23 , alkoxy claim 23 , alkylsulfonyl or aminosulfonyl.27. The ...

Methods of Using Diaminopyrimidine P2X3 and P2X 2/3 Receptor Modulators for Treatment of Acute and Sub-Acute Cough, Urge to Cough and Chronic Cough, in Respiratory Diseases

Methods for treating cough, chronic cough and urges to cough associated with respiratory diseases with a P2X3 and/or a P2X2/3 receptor antagonist, the methods comprising administering to a subject in need thereof an effective amount of a compound of Formula (I): 2. The method of claim 1 , wherein the chronic cough is idiopathic or treatment resistant cough.3. The method of wherein the compound of Formula (I) is administered at about 600 mg twice daily.4. The method of claim 1 , wherein the compound of Formula (I) is administered for about 2 weeks.5. The method of claim 1 , wherein the compound of Formula (I) is administered at about 600 mg twice daily for about two weeks.6. The method of claim 1 , wherein the chronic cough is refractory chronic cough.7. The method of claim 1 , wherein the chronic cough is reduced by about 75%.8. The method of claim 1 , wherein the cough is daytime cough.9. The method of claim 1 , wherein Ris hydrogen or methyl.10. The method of claim 1 , wherein Ris haloalkyl claim 1 , aminosulfonyl claim 1 , alkylsulfonyl alkylcarbonyl or carboxyalkyl.14. The method of claim 13 , wherein the chronic cough is idiopathic or treatment resistant cough.15. The method of claim 13 , wherein the compound of Formula (I) is administered at about 600 mg twice daily.16. The method of claim 13 , wherein the compound of Formula (I) is administered for about 2 weeks.17. The method of claim 13 , wherein the compound of Formula (I) is administered at about 600 mg twice daily for about two weeks.18. The method of claim 13 , wherein the chronic cough is refractory chronic cough.19. The method of claim 13 , wherein the chronic cough is reduced by about 75%.20. The method of claim 13 , wherein the cough is daytime cough. This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application Ser. No. 61/869174, the disclosure of which is incorporated herein by reference in its entirety.This invention pertains to compounds and methods for ...

PYRIMIDINES AND VARIANTS THEREOF, AND USES THEREFOR

The present disclosure provides pyrimidine compounds of Formula 1 and uses thereof for example, for the potential treatment of diseases associated with P2X purinergic receptors. In certain aspects, the present disclosure provides P2X3 and/or P2X2/3 antagonists which are useful, for example, for the potential treatment of visceral organ, cardiovascular and pain-related diseases, conditions and disorders. 412-. (canceled)15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein W is O.16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein W is S.17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein W is CH.18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein W is NHR.24. A composition which comprises an inert carrier and a compound of claim 1 , or a pharmaceutically acceptable salt thereof.2530-. (canceled)31. The compound of claim 2 , or a pharmaceutically acceptable salt thereof claim 2 , wherein Xis CH.32. The compound of claim 15 , or a pharmaceutically acceptable salt thereof claim 15 , wherein Xis CH.33. The compound of claim 31 , or a pharmaceutically acceptable salt thereof claim 31 , wherein Xis N or CH. The present disclosure pertains to pyrimidine compounds and variants thereof, as well as the use thereof, for example, for the potential treatment of diseases associated with P2X purinergic receptors, and more particularly to P2X3 and/or P2X2/3 antagonists usable for the potential treatment of visceral, cardiovascular and pain-related diseases, conditions and disorders.The information provided herein and references cited are provided solely to assist the understanding of the reader, and does not constitute an admission that any of the references or information is prior art to the present invention.Purines, acting via cell surface purinoceptors, have been implicated as having a variety of physiological and ...

DIAMINOPYRIMIDINE P2X3 AND P2X2/3 RECEPTOR MODULATORS FOR USE IN THE TREATMENT OF COUGH

Methods for treating cough, chronic cough and urges to cough associated with respiratory diseases with a P2X3 and/or a P2X2/3 receptor antagonist, the methods comprising administering to a subject in need thereof an effective amount of a compound of Formula (I): 2. The method of claim 1 , wherein the chronic cough is idiopathic or treatment resistant cough.34-. (canceled)5. The method of claim 1 , wherein the compound of Formula (I) claim 1 , or the pharmaceutically acceptable salt thereof claim 1 , is administered twice daily for days claim 1 , weeks claim 1 , months or years.6. The method of claim 1 , wherein the chronic cough is refractory chronic cough.7. The method of claim 1 , wherein the reduced taste disturbance is relative to a taste disturbance resulting from administering about 100 mg of the compound of Formula (I) or the pharmaceutically acceptable salt thereof twice daily to a patient with chronic cough.8. The method of claim 1 , wherein the chronic cough is daytime cough.910-. (canceled)1320-. (canceled)22. The method of claim 21 , wherein the reduced taste disturbance is relative to a taste disturbance resulting from administering about 100 mg of the pharmaceutically acceptable salt of the compound of formula (I) twice daily to a patient with chronic cough.2326-. (canceled)27. The method of claim 21 , wherein the reduced taste disturbance is relative to a taste disturbance resulting from administering about 600 mg of the pharmaceutically acceptable salt of the compound of formula (I) twice daily to a patient with chronic cough. The present disclosure relates to methods for treatment of cough, chronic cough and urge to cough in respiratory conditions and disorders.The respiratory tract, or airways, participates in the vital process of gas exchange in order to support the demand for oxygen intake and carbon dioxide elimination. Vagal autonomic nerves control smooth muscles of the tracheobronchial tree, and thus caliber of airways, as well as liberation ...

BETA ADRENERGIC AGONIST AND METHODS OF USING THE SAME

The present disclosure is directed to chemical compounds and to the use of such compounds in the treatment of diseases associated with an adrenergic receptor. In certain embodiments of the methods disclosed herein, the methods include administering to the subject a compound as disclosed herein and a peripherally acting P-blocker (PABRA). 6. The compound according to any one of - , wherein R is halogen , —CN , or an optionally substituted Caliphatic.7. The compound according to claim 6 , wherein R is —CN.8. The compound according to claim 6 , wherein R is an optionally substituted Caliphatic.9. The compound according to claim 8 , wherein R is methyl.10. The compound according to claim 8 , wherein R is —CF.11. The compound according to any one of - claim 8 , wherein R and R together with the carbon form an optionally substituted 3-7 membered cycloalkyl or heterocycle ring.12. The compound according to any one of - claim 8 , wherein R is an optionally substituted Caliphatic.13. The compound according to claim 12 , wherein R is methyl.14. The compound according to any one of - claim 12 , wherein R is an optionally substituted Caliphatic.15. The compound according to claim 14 , wherein R is methyl.16. The compound according to any one of - claim 14 , wherein R is an optionally substituted Caliphatic.17. The compound according to claim 16 , wherein R is methyl.21. The compound according to any one of - wherein said compound is an agonist claim 16 , partial agonist or antagonist of an adrenergic receptor.22. The compound according to any one of - wherein said compound is a β1-adrenergic receptor agonist claim 16 , β2-adrenertic receptor agonist or non-selective β1/β2-adrenergic receptor agonist.23. The compound according to any one of - wherein said compound is a β1-adrenergic receptor agonist.24. The compound according to any one of - wherein said compound is a β2-adrenergic receptor agonist.25. The compound according to any one of - wherein said compound is a non- ...

METHODS FOR TREATING NEUROLOGICAL DISORDERS WITH a1A-AR PARTIAL AGONISTS

In various aspects and embodiments provided are compositions and methods for a disease or disorder in a patient such as a disease or disorder that affects the brain in a patient and treating such patient.

METHODS FOR TREATING NEUROLOGICAL DISORDERS WITH a1A-AR PARTIAL AGONISTS

In various aspects and embodiments provided are compositions and methods for a disease or disorder in a patient such as a disease or disorder that affects the brain in a patient and treating such patient. 1. A method comprising identifying a patient diagnosed with nOH or in need of treatment for nOH and administering to said patient an α-AR partial agonist , wherein the α1A-AR partial agonist is dabuzalgron.2. The method of claim 1 , wherein said patient meets at least one or more of the following diagnostic criteria: (1) demonstrate a >20-30 mmHg drop in SBP within 5 minutes of standing; (2) demonstrate impaired autonomic reflexes as determined by absence of BP overshoot during phase IV of the Valsalva maneuver; (3) experience dizziness claim 1 , light-headedness claim 1 , or fainting when standing; and (4) have an absence of other identifiable causes of autonomic neuropathy.3. The method of claim 1 , wherein peripheral vascular resistance in said patient is not significantly raised following administration of said α-AR partial agonist.4. The method of claim 1 , wherein the supine systolic blood pressure in said patient does not rise more than about 25% as compared to the patient's blood pressure prior to administration of the α-AR partial agonist.5. The method of claim 1 , wherein said nOH in said patient is associated with one or more of Parkinson's disease claim 1 , multiple system atrophy claim 1 , and pure autonomic failure.6. The method of claim 5 , wherein said nOH in said patient is associated with Parkinson's disease.7. The method of claim 1 , wherein said patient takes a dose of the α-AR partial agonist once daily.8. The method of claim 1 , wherein said patient takes a dose of the α-AR partial agonist twice daily.9. The method of claim 1 , wherein said patient takes a dose of the α-AR partial agonist three times daily.10. The method of claim 1 , wherein said patient takes a dose of the α-AR partial agonist four times daily.11. The method of claim 1 , ...

METHODS AND COMPOSITIONS FOR TREATING DISEASES AND CONDITIONS

Provided herein include methods and compositions for treating diseases or conditions. In some embodiments provided are methods for treating one or more diseases or conditions selected from the group consisting of hypertension, heart failure, dyspnea, and sleep apnea. In certain embodiments provided are methods that include administering a compound of formula (I) as disclosed herein. In some embodiments provided are methods that include administering a P2X3 and/or a P2X2/3 receptor antagonist. 143-. (canceled)45. The method of claim 44 , comprising administering to the subject an effective amount of a compound of formula (I) claim 44 , wherein Ris C-Calkyl optionally substituted with one to three halogens claim 44 , or a pharmaceutically acceptable salt thereof.46. The method of claim 44 , comprising administering to the subject an effective amount of a compound of formula (I) claim 44 , wherein Ris C-Calkyl claim 44 , or a pharmaceutically acceptable salt thereof.47. The method of claim 44 , comprising administering to the subject an effective amount of a compound of formula (I) claim 44 , wherein Ris selected from aminosulfonyl and C-Calkylsulfonyl claim 44 , or a pharmaceutically acceptable salt thereof.48. The method of claim 44 , comprising administering to the subject an effective amount of a compound of formula (I) claim 44 , wherein:{'sup': '1', 'sub': 1', '6, 'Ris C-Calkyl; and'}{'sup': '2', 'sub': 1', '6, 'Ris selected from aminosulfonyl and C-Calkylsulfonyl;'}or a pharmaceutically acceptable salt thereof. This application claims priority to and the benefit of U.S. Provisional Patent Application Ser. No. 62/020,839, filed on Jul. 3, 2014, and U.S. Provisional Patent Application Ser. No. 62/120,643, filed on Feb. 25, 2015, each of which is incorporated by reference herein in its entirety.The present disclosure relates to the field of altering physiological conditions and or treating diseases.The information provided herein and references cited are provided ...

Substituted pyrazole-pyrimidines, variants thereof, and uses therefore

Disclosed herein are substituted pyrazole-pyrimidine compounds of Formula I and variants thereof for the treatment, for example, of diseases associated with P2X purinergic receptors: In one embodiment, the P2X3 and/or P2X2/3 antagonists disclosed herein are potentially useful, for example, for the treatment of visceral organ, cardiovascular and pain-related diseases, conditions and disorders.

METHODS AND COMPOSITIONS FOR TREATING DISEASES AND CONDITIONS

Provided herein include methods and compositions for treating diseases or conditions. In some embodiments provided are methods for treating one or more diseases or conditions selected from the group consisting of hypertension, heart failure, dyspnea, and sleep apnea. In certain embodiments provided are methods that include administering a compound of formula (I) as disclosed herein. In some embodiments provided are methods that include administering a P2X3 and/or a P2X2/3 receptor antagonist. 2. The method of wherein said subject diagnosed with hypertension has a systolic blood pressure above 120 mmHg and/or a diastolic pressure above about 80 mmHg.3. The method of or claim 1 , wherein the subject diagnosed with hypertension is diagnosed with chronic treatment resistant hypertension.5. The method of claim 4 , wherein said subject diagnosed with heart failure is diagnosed with systolic heart failure.6. The method of claim 4 , wherein said subject diagnosed with heart failure is diagnosed with diastolic heart failure.7. The method of claim 4 , wherein said subject diagnosed with heart failure is diagnosed with chronic heart failure.8. The method of claim 4 , wherein said subject diagnosed with heart failure is diagnosed with acute heart failure.11. The method of claim 10 , wherein said subject diagnosed with sleep apnea is diagnosed with central sleep apnea.12. The method of claim 10 , wherein said subject diagnosed with sleep apnea is diagnosed with obstructive sleep apnea.13. The method of claim 10 , wherein said subject diagnosed with sleep apnea is diagnosed with mixed sleep apnea.14. The method of claim 10 , wherein said subject diagnosed with sleep apnea is diagnosed as having more than about 5 apneic events per hour of sleep.15. The method of claim 10 , wherein said subject diagnosed with sleep apnea is diagnosed as having more than about 15 apneic events per hour of sleep.16. The method of claim 10 , wherein said subject diagnosed with sleep apnea is diagnosed ...

Methods for improving neurological diseases and disorders

In various aspects and embodiments provided are compositions and methods for identifying patients in need of improving cognition and/or treating a neurodegenerative disease in a patient and treating such patient. More specifically, the disclosure in some embodiments includes administration of a β-AR agonist and a peripherally acting β-blocker (PABRA) to a patient in need thereof.

METHODS AND COMPOSITIONS FOR TREATING DISEASES AND CONDITIONS

Provided herein include methods and compositions for treating diseases or conditions. In some embodiments provided are methods for treating one or more diseases or conditions selected from the group consisting of hypertension, heart failure, dyspnea, and sleep apnea. In certain embodiments provided are methods that include administering a compound of formula (I) as disclosed herein. In some embodiments provided are methods that include administering a P2X3 and/or a P2X2/3 receptor antagonist. 122-. (canceled)24. The method of claim 23 , wherein the sleep apnea is central sleep apnea.25. The method of claim 23 , wherein the sleep apnea is obstructive sleep apnea.26. The method of claim 23 , wherein the sleep apnea is mixed sleep apnea.27. The method of claim 23 , wherein the sleep apnea occurs more than about 5 apneic events per hour of sleep.28. The method of claim 23 , wherein the sleep apnea occurs more than about 15 apneic events per hour of sleep.29. The method of claim 23 , wherein the sleep apnea occurs more than about 25 apneic events per hour of sleep. This application claims priority to and the benefit of U.S. Provisional Patent Application Ser. No. 62/020,839, filed on Jul. 3, 2014, and U.S. Provisional Patent Application Ser. No. 62/120,643, filed on Feb. 25, 2015, each of which is incorporated by reference herein in its entirety.The present disclosure relates to the field of altering physiological conditions and or treating diseases.The information provided herein and references cited are provided solely to assist the understanding of the reader, and does not constitute an admission that any of the references or information is prior art to the present invention.U.S. patent application Ser. No. 11/906,802 (Patented as U.S. Pat. No. 8,003,788) discloses methods and intermediates for the preparation of compounds that are P2X3 and P2X2/3 receptor modulators. U.S. application Ser. No. 11/187,753 discloses methods of diagnosing and treating pulmonary diseases ...

METHODS FOR DIAGNOSING, MONITORING AND TREATING NEUROLOGICAL DISEASES AND DISORDERS

In various aspects and embodiments provided are compositions and methods for identifying patients in need of improving cognition and/or treating a neurodegenerative disease in a patient and treating such patient. 167-. (canceled)68. A method comprising:subjecting a patient to brain imaging to determine cognitive function and/or to identify whether said patient is in need of or desiring improvement of cognitive function and/or treatment of a neurodegenerative disease;identifying a particular type of neurodegenerative disease based on a spatial pattern of the brain imaging result; andsubsequently administering to said patient a β2-ADR agonist and a peripherally acting β-blocker (PABRA).69. The method of claim 68 , further comprising: after administering to said patient said β2-ADR agonist re-subjecting said patient to brain imaging to determine any improvement in cognitive function and/or treatment of said neurodegenerative disease.70. The method of claim 68 , wherein said β2-ADR agonist is selected from the group consisting of salbutamol claim 68 , levosalbutamol claim 68 , terbutaline claim 68 , pirbuterol claim 68 , procaterol claim 68 , metaproterenol claim 68 , bitolterol mesylate claim 68 , oritodrine claim 68 , isoprenaline claim 68 , salmefamol claim 68 , fenoterol claim 68 , terbutaline claim 68 , albuterol claim 68 , isoetharine claim 68 , salmeterol claim 68 , bambuterol claim 68 , formoterol and clenbuterol claim 68 , indacaterol claim 68 , vilanterol and olodaterol claim 68 , tulobuterol claim 68 , mabuterol claim 68 , and ritodrine.71. The method of claim 68 , wherein said β2-ADR agonist is clenbuterol.72. The method of claim 68 , wherein said β2-ADR agonist is tulobuterol.73. The method of claim 68 , wherein said PABRA is one or more selected from the group consisting of nadolol claim 68 , atenolol claim 68 , sotalol claim 68 , labetalol claim 68 , acebutolol claim 68 , betaxolol claim 68 , bisoprolol claim 68 , celiprolol claim 68 , esmolol claim 68 , ...

METHODS FOR IMPROVING NEUROLOGICAL DISEASES AND DISORDERS

In various aspects and embodiments provided are compositions and methods for improving cognition and/or treating a neurodegenerative disease in a patient. In some embodiments the compositions and methods include identifying a patient in need of, or desiring improvement of, cognitive function and/or treatment of a neurodegenerative disease and administering to the patient a β agonist and optionally a peripherally acting β-blocker (PABRA). 127-. (canceled)28. A method of improving cognitive function and/or treating a neurodegenerative disease in a patient , said method comprising identifying a patient in need of or desiring improvement of cognitive function and/or treatment of a neurodegenerative disease and administering to said patient tulobuterol.29. The method of claim 28 , wherein the method further comprises administering to said patient a peripherally acting β-blocker (PABRA).30. The method of claim 29 , wherein said PABRA is one or more selected from the group consisting of nadolol claim 29 , atenolol claim 29 , sotalol claim 29 , labetalol claim 29 , acebutolol claim 29 , betaxolol claim 29 , bisoprolol claim 29 , celiprolol claim 29 , esmolol claim 29 , metaprolol and nevivolol.31. The method of claim 29 , wherein said PABRA is nadolol.32. The method of claim 29 , wherein said PABRA is labetalol.33. The method of claim 28 , wherein said neurodegenerative disease is one or more selected from the group consisting of MCI claim 28 , aMCI claim 28 , Vascular Dementia claim 28 , Mixed Dementia claim 28 , FTD (fronto-temporal dementia; Pick's disease) claim 28 , HD (Huntington disease) claim 28 , Rett Syndrome claim 28 , PSP (progressive supranuclear palsy) claim 28 , CBD (corticobasal degeneration) claim 28 , SCA (spinocerebellar ataxia) claim 28 , MSA (Multiple system atrophy) claim 28 , SDS (Shy-Drager syndrome) claim 28 , olivopontocerebellar atrophy claim 28 , TBI (traumatic brain injury) claim 28 , CTE (chronic traumatic encephalopathy) claim 28 , stroke ...

PYRIMIDINES AND VARIANTS THEREOF, AND USES THEREFOR

The present disclosure provides pyrimidine compounds of Formula 1 and uses thereof, for example, for the potential treatment of diseases associated with P2X purinergic receptors: 133-. (canceled)39. The compound of claim 34 , or a pharmaceutically acceptable salt thereof claim 34 , wherein W is O.40. The compound of claim 34 , or a pharmaceutically acceptable salt thereof claim 34 , wherein W is S.41. The compound of claim 34 , or a pharmaceutically acceptable salt thereof claim 34 , wherein W is NH.45. A composition which comprises an inert carrier and a compound of claim 34 , or a pharmaceutically acceptable salt thereof. The present disclosure pertains to pyrimidine compounds and variants thereof, as well as the use thereof, for example, for the potential treatment of diseases associated with P2X purinergic receptors, and more particularly to P2X3 and/or P2X2/3 antagonists usable for the potential treatment of visceral, cardiovascular and pain-related diseases, conditions and disorders.The information provided herein and references cited are provided solely to assist the understanding of the reader, and does not constitute an admission that any of the references or information is prior art to the present invention.Purines, acting via cell surface purinoceptors, have been implicated as having a variety of physiological and pathological roles. ATP, and to a lesser extent, adenosine, can stimulate sensory nerve endings resulting in intense pain and irritation and a pronounced increase in sensory nerve discharge. ATP receptors have been classified into two major families, the P2Y- and P2X-purinoreceptors, on the basis of molecular structure, transduction mechanisms, and pharmacological characterization. The P2Y-purinoceptors are G-protein coupled receptors, while the P2X-purinoceptors are a family of ATP-gated cation channels. Purinergic receptors, in particular, P2X receptors, are known to form homomultimers or heteromultimers. To date, cDNAs for seven P2X subunits ...

Substituted pyrazole-pyrimidines, variants thereof, and uses therefore

Disclosed herein are substituted pyrazole-pyrimidine compounds of Formula (I) and variants thereof for the treatment, for example, of diseases associated with P2X purinergic receptors. In one embodiment, the P2X3 and/or P2X2/3 antagonists disclosed herein are potentially useful, for example, for the treatment of visceral organ, cardiovascular and pain-related diseases, conditions and disorders.

Substituted pyrimidines for treatment of acute cough, chronic cough and urge to cough

Methods for treating cough, chronic cough and urges to cough associated with respiratory diseases with a P2X3 and/or a P2X2/3 receptor antagonist, the methods comprising administering to a subject in need thereof an effective amount of a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are as defined herein.

METHODS OF USING DIAMINOPYRIMIDINE P2X3 AND P2X2/3 RECEPTOR MODULATORS FOR TREATMENT OF RESPIRATORY AND GASTROINTESTINAL DISEASES

Methods for treating respiratory and gastrointestinal diseases mediated by a P2Xand/or a P2Xreceptor antagonist, the methods comprising administering to a subject in need thereof an effective amount of a compound of formula (I): 2. The method of claim 1 , wherein X is: —CH— or —O—.3. The method of claim 2 , wherein Y is —NRR.4. The method of claim 3 , wherein Ris alkyl claim 3 , alkenyl or cycloalkyl.5. The method of claim 4 , wherein Rand Rare hydrogen.6. The method of claim 5 , wherein Ris hydrogen.7. The method of claim 6 , wherein one of Rand Ris hydrogen and the other is hydrogen claim 6 , alkyl claim 6 , hydroxyalkyl or haloalkyl.8. The method of claim 6 , wherein one of Rand Ris hydrogen and the other is hydrogen claim 6 , alkyl claim 6 , hydroxyalkyl or haloalkyl.9. The method of claim 6 , wherein Rand Reach independently is halo claim 6 , alkoxy claim 6 , hydroxy claim 6 , haloalkoxy; aminosulfonyl; or alkylsulfonyl.10. The method of claim 6 , wherein R claim 6 , R claim 6 , Rand Rare hydrogen.11. The method of claim 9 , wherein Ris isopropyl.12. The method of claim 1 , wherein Ris heteroaryl.13. The method of claim 1 , wherein Rand Rtogether with the atoms to which they are attached form a five or six membered ring that includes one or two heteroatoms selected from O claim 1 , N and S.14. The method of claim 1 , wherein Rand Rtogether with the atoms to which they are attached form a five or six membered ring that includes one or two heteroatoms selected from O claim 1 , N and S.16. The method of claim 15 , wherein Ris isopropyl.17. The method of claim 16 , wherein Ris halo claim 16 , alkoxy claim 16 , haloalkoxy or hydroxy.18. The method of claim 17 , wherein Ris halo claim 17 , alkoxy claim 17 , alkylsulfonyl claim 17 , aminosulfonyl or heteroaryl.23. The method of claim 22 , wherein Ris halo claim 22 , alkoxy claim 22 , haloalkoxy or hydroxy.24. The method of claim 23 , wherein Ris halo claim 23 , alkoxy claim 23 , alkylsulfonyl or aminosulfonyl.27. The ...

CRYSTALLINE SALTS AND POLYMORPHS OF A P2X3 ANTAGONIST

Provided are novel salts and polymorphs of 5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzenesulfonamide, which are potentially useful for modulating a condition mediated by a P2X3 or P2X2/3 receptor. Also provided are pharmaceutical formulations and methods of administration and dosing of these salts and polymorphs to subjects in need thereof. 120-. (canceled)21. A crystalline citrate Form B of 5-(2 ,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzenesulfonamide characterized by having X-ray powder diffraction peaks at 2θ values of approximately 11.3 , 16.2 and 23.0 degrees.22. The crystalline citrate Form B of claim 21 , further characterized by having an X-ray powder diffraction peak at 2θ value of approximately 5.7 degrees.23. The crystalline citrate Form B of claim 22 , further characterized by having an X-ray powder diffraction peak at 2θ value of approximately 8.4 degrees.24. The crystalline citrate Form B of any of claim 23 , further characterized by having an X-ray powder diffraction peak at 2θ value of approximately 18.8 degrees.25. The crystalline citrate Form B of any of claim 24 , further characterized by having an X-ray powder diffraction peak at 2θ value of approximately 25.0 degrees.26. A crystalline citrate Form B characterized by having X-ray powder diffraction peaks at 2θ values of approximately 5.7 claim 24 , 8.4 claim 24 , 11.3 claim 24 , 16.2 18.8 claim 24 , 23.0 and 25.0 degrees.27. The crystalline citrate Form B of further characterized by having an X-ray powder diffraction pattern substantially as depicted in .28. A pharmaceutical composition comprising the crystalline citrate Form B of and a pharmaceutically acceptable carrier.29. A method of modulating a condition mediated by a P2X3 or P2X2/3 receptor claim 21 , said method comprising administering an effective amount of the crystalline citrate Form B of to a subject in need thereof.30. The method of claim 29 , wherein the condition mediated by a P2X3 or P2X2/3 receptor ...

DIAMINOPYRIMIDINE P2X3 AND P2X2/3 RECEPTOR MODULATORS FOR USE IN THE TREATMENT OF COUGH

Methods for treating cough, chronic cough and urges to cough associated with respiratory diseases with a P2X3 and/or a P2X2/3 receptor antagonist, the methods comprising administering to a subject in need thereof an effective amount of a compound of Formula (I): 2. The method of claim 1 , wherein the chronic cough is idiopathic or treatment resistant cough.3. The method of wherein the compound of Formula (I) claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , is administered at no greater than 50 mg twice daily.4. (canceled)5. The method of claim 1 , wherein the compound of Formula (I) claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , is administered at no greater than 50 mg twice daily for days claim 1 , weeks claim 1 , months or years.6. The method of claim 1 , wherein the chronic cough is refractory chronic cough.7. The method of claim 1 , wherein the chronic cough is reduced by about 75%.8. The method of claim 1 , wherein the cough is daytime cough.9. (canceled)10. (canceled)14. The method of claim 13 , wherein the chronic cough is idiopathic or treatment resistant cough.15. The method of claim 13 , wherein the compound of Formula (I) claim 13 , or a pharmaceutically acceptable salt thereof claim 13 , is administered at no greater than about 50 mg twice daily.16. (canceled)17. The method of claim 13 , wherein the compound of Formula (I) claim 13 , or a pharmaceutically acceptable salt thereof claim 13 , is administered at no greater than about 50 mg twice daily for days claim 13 , weeks claim 13 , months or years.18. The method of claim 13 , wherein the chronic cough is refractory chronic cough.19. The method of claim 13 , wherein the chronic cough is reduced by about 75%.20. The method of claim 13 , wherein the cough is daytime cough.22. The method of claim 21 , comprising administering to the patient at no greater than about 25 mg twice daily for days claim 21 , weeks claim 21 , months or years.24. The method of claim 23 , ...

METHODS OF USING DIAMINOPYRIMIDINE P2X3 AND P2X2/3 RECEPTOR MODULATORS FOR TREATMENT OF RESPIRATORY AND GASTROINTESTINAL DISEASES

Methods for treating respiratory and gastrointestinal diseases mediated by a P2Xand/or a P2Xreceptor antagonist, the methods comprising administering to a subject in need thereof an effective amount of a compound of formula (I): 2. The method of claim 1 , wherein X is: —CH— or —O—.3. The method of claim 2 , wherein Y is —NRR.4. The method of claim 3 , wherein Ris alkyl claim 3 , alkenyl or cycloalkyl.5. The method of claim 4 , wherein Rand Rare hydrogen.6. The method of claim 5 , wherein Ris hydrogen.7. The method of claim 6 , wherein one of Rand Ris hydrogen and the other is hydrogen claim 6 , alkyl claim 6 , hydroxyalkyl or haloalkyl.8. The method of claim 6 , wherein one of Rand Ris hydrogen and the other is hydrogen claim 6 , alkyl claim 6 , hydroxyalkyl or haloalkyl.9. The method of claim 6 , wherein Rand Reach independently is halo claim 6 , alkoxy claim 6 , hydroxy claim 6 , haloalkoxy; aminosulfonyl; or alkylsulfonyl.10. The method of claim 6 , wherein R claim 6 , R claim 6 , Rand Rare hydrogen.11. The method of claim 9 , wherein Ris isopropyl.12. The method of claim 1 , wherein Ris heteroaryl.13. The method of claim 1 , wherein Rand Rtogether with the atoms to which they are attached form a five or six membered ring that includes one or two heteroatoms selected from O claim 1 , N and S.14. The method of claim 1 , wherein Rand Rtogether with the atoms to which they are attached form a five or six membered ring that includes one or two heteroatoms selected from O claim 1 , N and S.16. The method of claim 15 , wherein Ris isopropyl.17. The method of claim 16 , wherein Ris halo claim 16 , alkoxy claim 16 , haloalkoxy or hydroxy.18. The method of claim 17 , wherein Ris halo claim 17 , alkoxy claim 17 , alkylsulfonyl claim 17 , aminosulfonyl or heteroaryl.23. The method of claim 22 , wherein Ris halo claim 22 , alkoxy claim 22 , haloalkoxy or hydroxy.24. The method of claim 23 , wherein Ris halo claim 23 , alkoxy claim 23 , alkylsulfonyl or aminosulfonyl.27. The ...

BETA ADRENERGIC AGONIST AND METHODS OF USING THE SAME

The present disclosure is directed to chemical compounds and to the use of such compounds in the treatment of diseases associated with an adrenergic receptor. 133.-. (canceled)43. The method of claim 40 , wherein the compound is a β2-adrenergic receptor agonist.44. The method of claim 40 , wherein the disease associated with an adrenergic receptor is a neurodegenerative disease.45. The method of claim 44 , wherein the neurodegenerative disease is selected from MCI (mild cognitive impairment) claim 44 , aMCI (amnestic MCI) claim 44 , Vascular Dementia claim 44 , Mixed Dementia claim 44 , FTD (fronto-temporal dementia; Pick's disease) claim 44 , HD (Huntington disease) claim 44 , Rett Syndrome claim 44 , PSP (progressive supranuclear palsy) claim 44 , CBD (corticobasal degeneration) claim 44 , SCA (spinocerebellar ataxia) claim 44 , MSA (Multiple system atrophy) claim 44 , SDS (Shy-Drager syndrome) claim 44 , olivopontocerebellar atrophy claim 44 , TBI (traumatic brain injury) claim 44 , CTE (chronic traumatic encephalopathy) claim 44 , stroke claim 44 , WKS (Wernicke-Korsakoff syndrome; alcoholic dementia & thiamine deficiency) claim 44 , normal pressure hydrocephalus claim 44 , hypersomnia/narcolepsy claim 44 , ASD (autistic spectrum disorders) claim 44 , FXS (fragile X syndrome) claim 44 , TSC (tuberous sclerosis complex) claim 44 , prion-related diseases (CJD etc.) claim 44 , depressive disorders claim 44 , DLB (dementia with Lewy bodies) claim 44 , PD (Parkinson's disease) claim 44 , PDD (PD dementia) claim 44 , ADHD (attention deficit hyperactivity disorder) claim 44 , Alzheimer's disease (AD) claim 44 , early AD claim 44 , and Down syndrome (DS).46. The method of claim 40 , wherein the subject is a human.47. The method of claim 40 , wherein the compound is administered to the subject through an oral claim 40 , enteral claim 40 , topical claim 40 , inhalation claim 40 , transmucosal claim 40 , intravenous claim 40 , intramuscular claim 40 , intraperitoneal claim ...

Beta adrenergic agonist and methods of using the same

The present disclosure is directed to chemical compounds and to the use of such compounds in the treatment of diseases associated with an adrenergic receptor.

SUBSTITUTED PYRIMIDINES FOR TREATMENT OF ACUTE COUGH, CHRONIC COUGH AND URGE TO COUGH

Methods for treating cough, chronic cough and urges to cough associated with respiratory diseases with a P2X3 and/or a P2X2/3 receptor antagonist, the methods comprising administering to a subject in need thereof an effective amount of a compound of Formula (I): 2. The method of claim 1 , wherein the chronic cough is idiopathic or treatment resistant cough.3. The method of wherein the compound of Formula (I) is administered at about 600 mg twice daily.4. The method of claim 1 , wherein the compound of Formula (I) is administered for about 2 weeks.5. The method of claim 1 , wherein the compound of Formula (I) is administered at about 600 mg twice daily for about two weeks.6. The method of claim 1 , wherein the chronic cough is refractory chronic cough.7. The method of claim 1 , wherein the chronic cough is reduced by about 75%.8. The method of claim 1 , wherein the cough is daytime cough.9. The method of claim 1 , wherein Ris hydrogen or methyl.10. The method of claim 1 , wherein Ris aminosulfonyl or alkylsulfonyl.14. The method of claim 13 , wherein the chronic cough is idiopathic or treatment resistant cough.15. The method of claim 13 , wherein the compound of Formula (I) is administered at about 600 mg twice daily.16. The method of claim 13 , wherein the compound of Formula (I) is administered for about 2 weeks.17. The method of claim 13 , wherein the compound of Formula (I) is administered at about 600 mg twice daily for about two weeks.18. The method of claim 13 , wherein the chronic cough is refractory chronic cough.19. The method of claim 13 , wherein the chronic cough is reduced by about 75%.20. The method of claim 13 , wherein the cough is daytime cough. This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application Ser. No. 61/869,174, the disclosure of which is incorporated herein by reference in its entirety.This invention pertains to compounds and methods for treatment of diseases associated with P2X purinergic ...

Crystalline salts and polymorphs of a p2x3 antagonist

Provided are novel salts and polymorphs of 5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzenesulfonamide, which are potentially useful for modulating a condition mediated by a P2X3 or P2X2/3 receptor. Also provided are pharmaceutical formulations and methods of administration and dosing of these salts and polymorphs to subjects in need thereof.

Pyrimidines and variants thereof, and uses therefor

The present disclosure provides pyrimidine compounds and uses thereof, for example, for the treatment of diseases associated with P2X purinergic receptors. In certain aspects, the present disclosure provides P2X3 and/or P2X2/3 antagonists which are useful, for example, for the treatment of visceral organ, cardiovascular and pain-related diseases, conditions and disorders.

METHODS FOR TREATING NEUROLOGICAL DISORDERS WITH ALPHA1A-AR PARTIAL AGONISTS

In various aspects and embodiments provided are compositions and methods for a disease or disorder in a patient such as a disease or disorder that affects the brain in a patient and treating such patient. 1. A method comprising identifying a patient diagnosed with nOH or in need of treatment for nOH and administering to said patient an α-AR partial agonist.2. The method of claim 1 , wherein identifying the patient diagnosed with nOH or in need of treatment for nOH comprises finding that the patient meets at least one or more of the following diagnostic criteria: (1) demonstrate a >20-30 mm Hg drop in SBP within 5 minutes of standing; (2) demonstrate impaired autonomic reflexes as determined by absence of BP overshoot during phase IV of the Valsalva maneuver; (3) experience dizziness claim 1 , light-headedness claim 1 , or fainting when standing; and (4) have an absence of other identifiable causes of autonomic neuropathy; and administering to said patient an α1A-AR partial agonist.3. The method of claim 1 , wherein peripheral vascular resistance in said patient is not significantly raised following administration of said α-AR partial agonist.4. The method of claim 1 , wherein the supine systolic blood pressure in said patient does not rise more than 5%; or more than 10%; or more than 15%; or more than 20%; or more than 25%; or more than 30%; or more than 35%; or more than 40%; or more than 45%; or more than 50%; or more than 60%; or more than 70%; or more than 75%; or more than 80%; or more than 90%; or more than 100% as compared to the patient's blood pressure prior to administration of the α-AR partial agonist.5. The method of claim 1 , wherein said nOH in said patient is associated with one or more of Parkinson's disease claim 1 , multiple system atrophy claim 1 , and pure autonomic failure; and administering to said patient an α1A-AR partial agonist.6. A method for treating a disease or condition associated with low cerebral blood flow (CBF) and/or fluctuations ...

Beta adrenergic agonist and methods of using the same

The present disclosure is directed to chemical compounds and to the use of such compounds in the treatment of diseases associated with an adrenergic receptor.

Beta adrenergic agonist and methods of using the same

The present disclosure is directed to chemical compounds and to the use of such compounds in the treatment of diseases associated with an adrenergic receptor.

Diaminopyrimidines as p2x3 and p2x2/3 modulators

Methods for treating respiratory and gastrointestinal diseases mediated by a P2X3 and/or a P2X2/3 receptor antagonist, the methods comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein D, X, Y, R1, R2, R3, R4, R5, R6, R7 and R8 are as defined herein.

Methods of using diaminopyrimidine P2X3 and P2X2/3 receptor modulators for treatment of respiratory and gastrointestinal diseases

Methods for treating respiratory and gastrointestinal diseases mediated by a P2X 3 and/or a P2X 2/3 receptor antagonist, the methods comprising administering to a subject in need thereof an effective amount of a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein D, X, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined herein.

Diaminopyrimidine P2x3 and P2x2/3 receptor modulators for use in the treatment of cough

Methods for treating cough, chronic cough and urges to cough associated with respiratory diseases with a P2X3 and/or a P2X2/3 receptor antagonist, the methods comprising administering to a subject in need thereof an effective amount of a compound of Formula (I): (I) or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are as defined herein.

Diaminopyrimidine p2x3 and p2x 2/3 receptor modulators for treatment of acute, sub-acute or chronic cough

This invention pertains to diaminopyrimidine compounds having activity as antagonists of P2X purinergic receptors, and to methods for treatment of diseases associated with P2X receptors comprising administering an effective amount of a diaminopyrimidine compound. More particularly, methods are provided for using P2X3 and/or P2X2/3 antagonists in the treatment of cough, chronic cough and urge to cough in respiratory conditions and disorders.

Modulators of the p2x3 and p2x2 / 3 diaminopyridine receptor for the treatment of acute, subacute or chronic cough. (Divisional application 201600400)

ESTA INVENCIÓN PERTENECE A COMPUESTOS DE DIAMINOPIRIMIDINA QUE TIENEN ACTIVIDAD COMO ANTAGONISTAS DE RECEPTORES PURINÉRGICOS DE P2X, YA MÉTODOS PARA EL TRATAMIENTO DE ENFERMEDADES ASOCIADAS CON RECEPTORES DE P2X QUE COMPRENDEN ADMINISTRAR UNA CANTIDAD EFECTIVA DE UN COMPUESTO DE DIAMINOPIRIMIDINA. MÁS PARTICULARMENTE, LOS MÉTODOS SE PROPORCIONAN PARA UTILIZAR ANTAGONISTAS DE P2X3 Y/O P2X2/3 EN EL TRATAMIENTO DE LA TOS, TOS CRÓNICA, UNA NECESIDAD PARA TOSER DURANTE PADECIMIENTOS Y TRASTORNOS RESPIRATORIOS. THIS INVENTION BELONGS TO DIAMINOPIRIMIDINE COMPOUNDS THAT HAVE ACTIVITY AS AN ANTHOGONISTS OF P2X PURINERGIC RECEPTORS, AND METHODS FOR THE TREATMENT OF DISEASES ASSOCIATED WITH P2X RECEPTORS THAT INCLUDE ADMINISTRATING A DIFFERENT ONE-SIZE. MORE PARTICULARLY, THE METHODS ARE PROVIDED TO USE P2X3 AND / OR P2X2 / 3 ANTAGONISTS IN THE TREATMENT OF THE TOS, CHRONIC TOS, A NEED TO TOSER DURING PATIENTS AND RESPIRATORY DISORDERS.

DIAMINOPYRIMIDINE P2X3 AND P2X2 / 3 RECEPTOR MODULATORS FOR THE TREATMENT OF ACUTE, SUB-ACUTE OR CHRONIC COUGH.

Esta invención pertenece a compuestos de diaminopiridina que tienen actividad como antagonistas de receptores purinérgicos de P2X, y a métodos para el tratamiento de enfermedades asociadas con receptores de P2X que comprenden administrar una cantidad efectiva de un compuesto de diaminopirimidina. Más particularmente, los métodos se proporcionan para utilizar antagonista de P2X3 y/o P2X2/3 en el tratamiento de la tos, tos crónica, una necesidad para toser durante padecimientos y trastornos respiratorios.

Use of purinergic receptor modulators and related reagents

The invention provides a method of treatment for an animal having a disease state associated with a genitourinary disorder with a purinergic receptor modulator. Also provided, is a transgenic animal having a disrupted purinergic receptor gene. The invention further provides for a method of screening using the transgenic animal as a positive control.

Diaminopyrimidines as p2x3 and p2x2/3 modulators

Methods for treating respiratory and gastrointestinal diseases mediated by a P2X3 and/or a P2X2/3 receptor antagonist, the methods comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein D, X, Y, R1, R2, R3, R4, R5, R6, R7 and R8 are as defined herein.

Beta adrenergic agonist and methods of using the same

The present disclosure is directed to chemical compounds and to the use of such compounds in the treatment of diseases associated with an adrenergic receptor. In certain embodiments of the methods disclosed herein, the methods include administering to the subject a compound as disclosed herein and a peripherally acting P-blocker (PABRA).

Pyrimidines and variants thereof, and uses therefor

The present disclosure provides pyrimidine compounds of Formula 1 and uses thereof, for example, for the potential treatment of diseases associated with P2X purinergic receptors:In certain aspects, the present disclosure provides P2X3 and/or P2X2/3 antagonists which are useful, for example, for the potential treatment of visceral organ, cardiovascular and pain-related diseases, conditions and disorders.

DIAMINOPYRIMIDINE P2X3 AND P2X2/3 RECEPTOR MODULATORS FOR USE IN THE TREATMENT OF COUGH

Beta adrenergic agonist and methods of using the same

The present disclosure is directed to chemical compounds and to the use of such compounds in the treatment of diseases associated with an adrenergic receptor. In certain embodiments of the methods disclosed herein, the methods include administering to the subject a compound as disclosed herein and a peripherally acting P-blocker (PABRA).

Compositions and methods for improving neurological diseases and disorders

In various aspects and embodiments provided are compositions and methods for identifying patients in need of improving cognition and/or treating a neurodegenerative disease in a patient and treating such patient. More specifically, the disclosure in some embodiments includes administration of a β-AR agonist (such as a β-agent) and a peripherally acting β-blocker (PABRA) to a patient in need thereof.

Beta adrenergic agonist and methods of using the same

The present disclosure is directed to chemical compounds and to the use of such compounds in the treatment of diseases associated with an adrenergic receptor.

Pyrimidines and variants thereof, and uses therefor

The present disclosure provides pyrimidine compounds and uses thereof, for example, for the treatment of diseases associated with P2X purinergic receptors. In certain aspects, the present disclosure provides P2X3 and/or P2X2/3 antagonists which are useful, for example, for the treatment of visceral organ, cardiovascular and pain-related diseases, conditions and disorders.

Diaminopyrimidine P2x3 and P2x2/3 receptor modulators for use in the treatment of cough

Methods for treating cough, chronic cough and urges to cough associated with respiratory diseases with a P2X3 and/or a P2X2/3 receptor antagonist, the methods comprising administering to a subject in need thereof an effective amount of a compound of Formula (I): (I) or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are as defined herein.

Diaminopyrimidine p2x3 and p2x 2/3 receptor modulators for treatment of acute, sub-acute or chronic cough

This invention pertains to diaminopyrimidine compounds having activity as antagonists of P2X purinergic receptors, and to methods for treatment of diseases associated with P2X receptors comprising administering an effective amount of a diaminopyrimidine compound. More particularly, methods are provided for using P2X3 and/or P2X2/3 antagonists in the treatment of cough, chronic cough and urge to cough in respiratory conditions and disorders.

Beta adrenergic agonist and methods of using the same

The present disclosure is directed to chemical compounds and to the use of such compounds in the treatment of diseases associated with an adrenergic receptor. Disclosed herein is a compound according to Formula (I) or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug thereof. Further disclosed herein is a compound according to Formula (II) or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug thereof.

Diaminopyrimidine p2x3 and p2x2/3 receptor modulators for use in the treatment of cough.

Metodos de tratamiento de la tos, tos cronica y deseo de toser asociados con enfermedades respiratorias, con un antagonista del receptor P2X3 y/o P2X2/3, los métodos comprendiendo administrarle a un sujeto que lo necesite una cantidad eficaz de 5 un compuesto de la formula (I): ver fórmula (I), o una sal farmaceuticamente aceptable del mismo, en donde R1 y R2 son como se define en la presente.

Diaminopyrimidine p2x3 and p2x 2/3 receptor modulators for treatment of acute, sub-acute or chronic cough

This invention pertains to diaminopyrimidine compounds having activity as antagonists of P2X purinergic receptors, and to methods for treatment of diseases associated with P2X receptors comprising administering an effective amount of a diaminopyrimidine compound. More particularly, methods are provided for using P2X3 and/or P2X2/3 antagonists in the treatment of cough, chronic cough and urge to cough in respiratory conditions and disorders.

Diaminopyrimidines as P2X3 and P2X2/3 modulators

METHODS FOR TREATING NEUROLOGICAL DISORDERS WITH α1A-AR PARTIAL AGONISTS

In various aspects and embodiments provided are compositions and methods for a disease or disorder in a patient such as a disease or disorder that affects the brain in a patient and treating such patient.

Pyrimidines and variants thereof, and uses therefor

The present disclosure provides pyrimidine compounds of Formula 1 and uses thereof, for example, for the potential treatment of diseases associated with P2X purinergic receptors. In certain aspects, the present disclosure provides P2X3 and/or P2X2/3 antagonists which are useful, for example, for the potential treatment of visceral organ, cardiovascular and pain-related diseases, conditions and disorders.

Beta adrenergic agonist and methods of using the same

The present disclosure is directed to chemical compounds and to the use of such compounds in the treatment of diseases associated with an adrenergic receptor. An advantage of the compounds provided herein is that a broad range of pharmacological activities is possible, consistent with modulation of beta-adrenergic receptors. In addition, the disclosure provides methods of using the compounds described herein for the treatment of diseases associated with an adrenergic receptor, including but not limited to neurodegenerative diseases and disorders.

Alpha1a-adrenergic receptor agonists and methods of use

The present disclosure relates generally to chemical compounds and, in some embodiments, to α1A-adrenergic receptor agonists and uses of such agonists in the treatment of diseases associated with an adrenergic receptor. Disclosed herein is a compound according to Formula (I) or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug thereof.

Agonista beta adrenergico y metodos de uso del mismo.

La presente revelación está dirigida a compuestos químicos y al uso de dichos compuestos en el tratamiento de enfermedades asociadas con un receptor adrenérgico.

Beta adrenergic agonist and methods of using the same

Compositions and methods involving isolated compounds

In various aspects and embodiments provided are compositions and methods for treating subjects in need thereof. In some embodiments, the compositions and methods involve purified or isolated isomers of nadolol. In one aspect, the disclosure provides a method including identifying a subject desiring improvement of cognitive function and/or treatment of a neurodegenerative disease or disorder and administering to said subject a pharmaceutical composition of the present disclosure.

Compositions and methods involving isolated compounds

In various aspects and embodiments provided are compositions and methods for treating subjects in need thereof. In some embodiments, the compositions and methods involve purified or isolated isomers of nadolol. In one aspect, the disclosure provides a method of identifying a subject desiring improvement of cognitive function and/or treatment of a neurodegenerative disease or disorder and administering to said subject a pharmaceutical composition as described herein.

Compositions and methods for treating patients with amyotrophic lateral sclerosis (als)

In various aspects and embodiments provided are compositions and methods for treating a patient that has ALS (or Lou Gehrig's disease or motor neuron disease). More specifically, the disclosure in some embodiments includes administration of a β-AR agonist (such as a β-agent) and optionally a peripherally acting β-blocker (PABRA) to a patient in need thereof.

Methods for improving neurological diseases and disorders

In various aspects and embodiments provided are compositions and methods for improving cognition and/or treating a neurodegenerative disease in a patient. In some embodiments the compositions and methods include identifying a patient in need of, or desiring improvement of, cognitive function and/or treatment of a neurodegenerative disease and administering to the patient a β agonist and optionally a peripherally acting β-blocker (PABRA).

Compositions and methods for treating patients with amyotrophic lateral sclerosis (als)

In various aspects and embodiments provided are compositions and methods for treating a patient that has ALS (or Lou Gehrig's disease or motor neuron disease). More specifically, the disclosure in some embodiments includes administration of a ß-AR agonist (such as a β-agent) and optionally a peripherally acting ß-blocker (PABRA) to a patient in need thereof.

Methods for improving neurological diseases and disorders

Methods for diagnosing, monitoring and treating neurological diseases and disorders

In various aspects and embodiments provided are compositions and methods for identifying patients in need of improving cognition and/or treating a neurodegenerative disease in a patient and treating such patient.

Methods for treating neurological disorders with alpha 1a-ar partial agonists

Methods for improving neurological diseases and disorders

In various aspects and embodiments provided are compositions and methods for improving cognition and/or treating a neurodegenerative disease in a patient. In some embodiments the compositions and methods include identifying a patient in need of, or desiring improvement of, cognitive function and/or treatment of a neurodegenerative disease and administering to the patient a β agonist and optionally a peripherally acting β-blocker (PABRA).

Composiciones y metodos para mejorar enfermedades y trastornos neurologicos.

En varios aspectos y formas de modalidad se proporcionan composiciones y métodos para identificar pacientes que necesitan mejorar la cognición y/o tratar una enfermedad neurodegenerativa en un paciente y tratar a dicho paciente. Más específicamente, la divulgación en algunas formas de modalidad incluye la administración de un agonista ß-AR (tal como un agente ß) y un ß-bloqueante de acción periférica (PABRA) a un paciente que lo necesite.

Verwendung von nk-1-rezeptorantagonisten gegen benigne prostatahyperplasie

Compositions and methods for improving neurological diseases and disorders

In various aspects and embodiments provided are compositions and methods for identifying patients in need of improving cognition and/or treating a neurodegenerative disease in a patient and treating such patient. More specifically, the disclosure in some embodiments includes administration of a β-AR agonist (such as a β-agent) and a peripherally acting β-blocker (PABRA) to a patient in need thereof.

METHODS FOR TREATING NEUROLOGICAL DISORDERS WITH α1A-AR PARTIAL AGONISTS

In various aspects and embodiments provided are compositions and methods for a disease or disorder in a patient such as a disease or disorder that affects the brain in a patient and treating such patient.

Agonistas del receptor adrenérgico a1a y métodos de uso.

La presente divulgación se refiere en general a compuestos químicos y, en algunas formas de realización, a agonistas del receptor a1A-adrenérgico y usos de tales agonistas en el tratamiento de enfermedades asociadas con un receptor adrenérgico. Se divulga aquí un compuesto según la fórmula (I) o un estereoisómero ópticamente puro, sal farmacéuticamente aceptable, solvato o profármaco del mismo.

Beta adrenergic agonist and methods of using the same

The present disclosure is directed to chemical compounds and to the use of such compounds in the treatment of diseases associated with an adrenergic receptor. An advantage of the compounds provided herein is that a broad range of pharmacological activities is possible, consistent with modulation of beta-adrenergic receptors. In addition, the disclosure provides methods of using the compounds described herein for the treatment of diseases associated with an adrenergic receptor, including but not limited to neurodegenerative diseases and disorders.

Methods for diagnosing, monitoring and treating neurological diseases and disorders

In various aspects and embodiments provided are compositions and methods for identifying patients in need of improving cognition and/or treating a neurodegenerative disease in a patient and treating such patient.

Compositions and methods for improving neurological diseases and disorders

In various aspects and embodiments provided are compositions and methods for identifying subjects in need of improving cognition and/or treating a neurodegenerative disease in a subject and treating such subject. More specifically, the disclosure in some embodiments includes administration of a β-AR agonist (such as a β-agent) and a peripherally acting β-blocker (PABRA) to a subject in need thereof.

Methods for treating various conditions and indications with agonists and antagonists

In various aspects and embodiments provided are compositions and methods for identifying subjects in need of improving cognition and/or treating a neurodegenerative disease in a subject and treating such subject. More specifically, the disclosure in some embodiments includes administration of a β-AR agonist and a peripherally acting β-blocker (PABRA) to a subject in need thereof.

Compositions and methods for improving neurological diseases and disorders

In various aspects and embodiments provided are compositions and methods for identifying patients in need of improving cognition and/or treating a neurodegenerative disease in a patient and treating such patient. More specifically, the disclosure in some embodiments includes administration of a β-AR agonist (such as a β-agent) and a peripherally acting β-blocker (PABRA) to a patient in need thereof.

α1A-ADRENERGIC RECEPTOR AGONISTS AND METHODS OF USE

The present disclosure relates generally to chemical compounds and, in some embodiments, to α1A-adrenergic receptor agonists and uses of such agonists in the treatment of diseases associated with an adrenergic receptor. Disclosed herein is a compound according to Formula (I) or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug thereof.

Agonista beta adrenergico y metodos de uso del mismo.

La presente divulgación se refiere a compuestos químicos y al uso de estos compuestos en el tratamiento de enfermedades asociadas con un receptor adrenérgico. Se divulga en la presente un compuesto de acuerdo con la Fórmula (I) o un estereoisómero ópticamente puro, una sal, un solvato o un profármaco del mismo farmacéuticamente aceptable. Se divulga en la presente, además, un compuesto de acuerdo con la Fórmula (II) o un estereoisómero ópticamente puro, una sal, un solvato o un profármaco del mismo farmacéuticamente aceptable.

Beta adrenergic agonist and methods of using the same

The present disclosure is directed to chemical compounds and to the use of such compounds in the treatment of diseases associated with an adrenergic receptor. An advantage of the compounds provided herein is that a broad range of pharmacological activities is possible, consistent with modulation of beta-adrenergic receptors. In addition, the disclosure provides methods of using the compounds described herein for the treatment of diseases associated with an adrenergic receptor, including but not limited to neurodegenerative diseases and disorders.

Agonista adrenérgico beta e métodos para usar o mesmo

agonista adrenérgico beta e métodos para usar o mesmo. a presente invenção refere-se a compostos químicos e ao uso de tais compostos no tratamento de doenças associadas a um receptor adrenérgico. em certas modalidades dos métodos descritos neste documento, os métodos incluem a administração ao indivíduo de um composto conforme descrito neste documento e um bloqueador p de ação periférica (pabra).

Alpha 1a-adrenergic receptor agonists and methods of use

The present disclosure is based at least in part on the identification of compounds that modulate adrenergic receptor and methods of using the same to treat diseases associated with an adrenergic receptor. For example, disclosed herein is a compound according to Formula (I) or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug thereof.

Beta adrenergic agonist and methods of using the same

The present disclosure is directed to chemical compounds and to the use of such compounds in the treatment of diseases associated with an adrenergic receptor. Disclosed herein is a compound according to Formula (I) or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug thereof. Further disclosed herein is a compound according to Formula (II) or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug thereof.

Agonista beta adrenergico y metodos de uso del mismo.

La presente descripción está dirigida a compuestos químicos y al uso de tales compuestos en el tratamiento de enfermedades asociadas con un receptor adrenérgico. Una ventaja de los compuestos proporcionados en este documento es que es posible una amplia gama de actividades farmacológicas, consistentes con la modulación de los receptores beta adrenérgicos. Además, la descripción proporciona métodos para usar los compuestos descritos en el presente documento para el tratamiento de enfermedades asociadas con un receptor adrenérgico, incluyendo, entre otros, enfermedades y trastornos neurodegenerativos.

Beta adrenergic agonist and methods of using the same

The present disclosure is directed to chemical compounds and to the use of such compounds in the treatment of diseases associated with an adrenergic receptor. An advantage of the compounds provided herein is that a broad range of pharmacological activities is possible, consistent with modulation of beta-adrenergic receptors. In addition, the disclosure provides methods of using the compounds described herein for the treatment of diseases associated with an adrenergic receptor, including but not limited to neurodegenerative diseases and disorders.

Diaminopyrimidine P2x3 and P2x 2/3 Receptor Modulators for Treatment of Acute, Sub-Acute or Chronic Cough

This invention pertains to diaminopyrimidine compounds having activity as antagonists of P2X purinergic receptors, and to methods for treatment of diseases associated with P2X receptors comprising administering an effective amount of a diaminopyrimidine compound. More particularly, methods are provided for using P2X3 and/or P2X2/3 antagonists in the treatment of cough, chronic cough and urge to cough in respiratory conditions and disorders.

Compositions and methods for improving neurological diseases and disorders

Beta adrenergic agonist and methods of using the same

The present disclosure is directed to chemical compounds and to the use of such compounds in the treatment of diseases associated with an adrenergic receptor. Disclosed herein is a compound according to Formula (I) or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug thereof. Further disclosed herein is a compound according to Formula (II) or an optically pure stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug thereof.