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CN-121991127-A - Phosphate compounds for detection of neurological diseases

CN121991127ACN 121991127 ACN121991127 ACN 121991127ACN-121991127-A

Abstract

Provided herein are compounds, methods, and compositions for determining whether a patient has a neurological disease or disorder, comprising detecting the presence of a detectable target protein, or a cumulative mass thereof, e.g., the presence of amyloid beta protein or phosphorylated tau protein, in a tissue or sample of the patient. The detecting can include contacting the target protein with a compound described herein.

Inventors

  • S. Saraf
  • L M Randolph
  • S. Rasul

Assignees

  • 阿米达斯公司

Dates

Publication Date
20260508
Application Date
20191101
Priority Date
20181102

Claims (20)

  1. 1. A compound of formula I or a pharmaceutically acceptable salt thereof: I Wherein R 1 is selected from 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 And ; Each X is independently O or S; Each R 11 is independently selected from the group consisting of hydrogen, C 1-10 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 5 to 10 membered heteroaryl, and 4 to 10 membered heterocyclyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are optionally substituted with 1-4R 21 , or each XR 11 may independently be-XP (X) (R 12 ) 2 ; each R 12 is independently selected from hydroxy, mercapto, -XP (X) (R1 3 ) 2 、C 1-10 alkyl, -OC 1-10 alkyl, and-SC 1-10 alkyl; Each R 13 is independently selected from hydroxy, mercapto, C 1-10 alkyl, -OC 1-10 alkyl, and-SC 1-10 alkyl; Each R 21 is independently selected from halogen, hydroxy, mercapto, -NO 2 、-N 3 , cyano, C 1-10 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 1-8 haloalkyl, C 6-10 aryl, 5 to 10 membered heteroaryl, 4 to 10 membered heterocyclyl, -OC 1-10 alkyl, -OC 2-6 alkenyl, -OC 2-6 alkynyl, -OC 3-10 cycloalkyl, -OC 1-8 haloalkyl, -O-aryl, -O-heteroaryl, -O-heterocyclyl 、-NH 2 、-NH(R 31 )、-N(R 31 ) 2 、-C(O)(R 31 )、-C(O)O(R 31 )、-C(O)OH、-C(O)NH 2 、-C(O)NH(R 31 )、-C(O)N(R 31 ) 2 、-NHC(O)(R 31 )、-NHC(O)O(R 31 )、-NHC(O)NH(R 31 )、-S(R 31 )-NHS(O) y (R 31 )、-N(C1-10 alkyl) S (O) y (R 31 )、-S(O) y N(R 31 ) 2 、-S(O)NH(R 31 ), and-S (O) y (R 31 ); each R 31 is independently selected from the group consisting of C 1-10 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 1-8 haloalkyl, aryl, heteroaryl, and heterocyclyl, and Each y is independently 1 or 2.
  2. 2. The compound of claim 1, wherein R 1 is 。
  3. 3. A compound according to claim 1 or 2, wherein each X is independently O.
  4. 4. The compound of claim 1, wherein R 1 is 。
  5. 5. The compound of claim 1, wherein R 1 is 。
  6. 6. A compound according to any one of claims 1 to 5 which is a monobasic salt.
  7. 7. A compound according to any one of claims 1 to 5 which is a dibasic salt.
  8. 8. A compound according to any one of claims 1 to 7 which is a salt selected from sodium, potassium, lithium, ammonium, calcium, magnesium or zinc salts.
  9. 9. The compound according to any one of claims 1 to 7, which is a sodium salt.
  10. 10. The compound according to any one of claims 1 to 7, which is a potassium salt.
  11. 11. The compound according to any one of claims 1 to 7, which is an ammonium salt or a diammonium salt.
  12. 12. A compound Or a pharmaceutically acceptable salt thereof.
  13. 13. The compound of claim 11 which is an ammonium salt or a diammonium salt.
  14. 14. A compound Or a pharmaceutically acceptable salt thereof.
  15. 15. A pharmaceutical composition comprising a compound according to any one of the preceding claims and a pharmaceutically acceptable carrier.
  16. 16. A method of determining whether a patient has a neurological disease or disorder comprising administering to the patient a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 15.
  17. 17. The method of claim 16, wherein the compound is administered intravenously.
  18. 18. The method of claim 16, wherein the compound is administered to the eye of the patient.
  19. 19. The method of any one of claims 16 to 18, further comprising detecting the presence or absence of binding of the compound or a parent compound thereof to a detectable target protein.
  20. 20. The method of claim 19, wherein the detecting comprises activating tissue of a patient to be examined with light, thereby generating emission of a detectable signal, and detecting the detectable signal.

Description

Phosphate compounds for detection of neurological diseases The application is a divisional application of Chinese patent application of which the application date is 2019, 11, 1, 201980087229.4 and the application name is 'phosphate compound used for detecting nerve diseases'. Cross Reference to Related Applications The present application claims the benefit of U.S. provisional application Ser. No. 62/755,331, filed on Ser. No. 62/755,331, and U.S. provisional application Ser. No. 62/855,442, filed on Ser. No. 31, 5, 2019, chapter 35 (e), each of which is incorporated herein by reference in its entirety. Background Neurological diseases are diseases of the brain, spinal cord and peripheral nervous system. In terms of epidemiology and individual morbidity, the greatest social costs are caused by neurological diseases. The most prominent of these neurological diseases are Alzheimer's disease and Parkinson's disease. Other neurological disorders include age-related conditions (e.g., parkinson's dementia, vascular dementia, amyotrophic lateral sclerosis), genetic syndrome (e.g., down's syndrome), injury-related conditions (e.g., traumatic brain injury, chronic traumatic brain disease), and conditions that are generally considered to be purely psychotic in nature, such as schizophrenia and depression. Compounds useful for the detection of these and other neurological disorders are useful in the detection, diagnosis, monitoring and treatment of these diseases. Disclosure of Invention The present disclosure provides compounds for the detection and treatment of neurological diseases or disorders. Certain diagnostic compounds that are useful in the detection of neurological diseases have been found to have less than ideal physicochemical properties, such as low water solubility and high crystallinity. Disclosed herein are compounds having improved physicochemical properties that are useful in the diagnosis and treatment of neurological diseases. In some embodiments, a method for determining whether a patient has a neurological disease or disorder is provided, the method comprising administering to the patient a compound described herein. In some embodiments, a method for detecting a neurological disease or disorder in a patient is provided, the method comprising administering to the patient a compound described herein that is capable of binding to a detectable target protein or that, upon isolation, generates a compound capable of binding to a detectable target protein, determining the presence or absence of the binding, wherein the presence of the binding indicates that the patient has or is at risk of developing a neurological disease or disorder. The compound may be a compound of formula I. In some embodiments, the compound is compound 7, compound 8, compound 9, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is compound 7, compound 8, compound 9, or compound 10. Accordingly, provided herein are methods and compositions for determining whether a patient has a neurological disease or disorder, the methods comprising detecting the presence of a detectable target protein or a cumulative mass thereof (e.g., amyloid β protein or phosphorylated tau protein or a cumulative mass thereof) in a tissue or sample of the patient. The detection may comprise contacting the target protein with a compound described herein. In some embodiments, the patient is free of any symptoms of the disease or disorder to be detected. In some embodiments, the patient has one or more symptoms of the disease or disorder to be detected. In some embodiments, the methods comprise administering a compound described herein to a patient. In some embodiments, the administration is intravenous or is located in the retina of the eye. In some embodiments, the administration is bolus injection. In some embodiments, the administration is topical. In some embodiments, the neurological disease or disorder is selected from the group consisting of an age-related disease or disorder, a genetic disease or disorder, a disease or disorder associated with injury, and a psychosis or disease. In some embodiments, the age-related disease or disorder is selected from the group consisting of parkinson's disease, vascular dementia, and amyotrophic lateral sclerosis, the genetic disease or disorder is down's syndrome, the disease or disorder associated with injury is selected from the group consisting of traumatic brain injury and chronic traumatic brain disease, and the mental disease or disorder is selected from the group consisting of schizophrenia and depression. In some embodiments of the method, the neurological disease or disorder is alzheimer's disease or Traumatic Brain Injury (TBI). In some embodiments of the method, the neurological disease or disorder is prion disease. Accordingly, a method for detecting prion deposition in a patient is provided. In certain embodiments, the detection is performed in the retina. In certain embodi