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CN-121986104-A - PDE1 inhibitors

CN121986104ACN 121986104 ACN121986104 ACN 121986104ACN-121986104-A

Abstract

The present invention provides compounds of formula I or a pharmaceutically acceptable salt thereof for use as human PDE1 inhibitors: Wherein R 1 、R 2 、R 3 、R 4 and R 5 are each as defined herein.

Inventors

  • R.D. Johnston
  • K. M. Luli

Assignees

  • 伊莱利利公司

Dates

Publication Date
20260505
Application Date
20240916
Priority Date
20230914

Claims (16)

  1. 1. A compound of the formula: Wherein R 1 、R 2 and R 3 are each independently H, halogen or C1-C3 alkyl optionally substituted by one or more halogens; R 4 is H, halogen, C1-C4 alkyl optionally substituted by one or more halogens, cyclopropyl or CH=CH-CH 3 , and R 5 is C1-C3 alkyl optionally substituted by one or more halogen or cyclopropyl; or a pharmaceutically acceptable salt thereof.
  2. 2. The compound or salt of claim 1, wherein R 1 、R 2 、R 3 is H.
  3. 3. A compound or salt according to claim 1 or claim 2, wherein R 4 is C1-C4 alkyl.
  4. 4. A compound or salt according to any one of claims 1 to 3, wherein R 4 is ethyl.
  5. 5. The compound or salt of any one of claims 1 to 4, wherein R 5 is C1-C3 alkyl.
  6. 6. A compound or salt according to any one of claims 1 to 5, wherein R 5 is methyl.
  7. 7. The compound or salt of any one of claims 1 to 6, wherein the compound is in free base form.
  8. 8. The compound or salt of claim 1, wherein the compound is: , or a pharmaceutically acceptable salt thereof.
  9. 9. The compound or salt of claim 8, wherein the compound is 。
  10. 10. The compound or salt of claim 8, which is a pharmaceutically acceptable salt of a compound of 。
  11. 11. A method of treating diabetic nephropathy, chronic kidney disease, acute kidney injury, hypertension, refractory hypertension, parkinson's disease, atherosclerotic cardiovascular disease, angina, myocardial infarction, heart failure, pulmonary hypertension, ischemic stroke, cognitive deficits associated with schizophrenia, cognitive disorders associated with alzheimer's disease, dyskinesia, or attention deficit and hyperactivity disorder in a patient in need thereof, comprising administering to the patient an effective amount of a compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.
  12. 12. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, for use in therapy.
  13. 13. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, for use in the treatment of diabetic nephropathy, chronic kidney disease, acute kidney injury, hypertension, refractory hypertension, parkinson's disease, atherosclerotic cardiovascular disease, angina pectoris, myocardial infarction, heart failure, pulmonary hypertension, ischemic stroke, cognitive deficit associated with schizophrenia, cognitive deficit associated with alzheimer's disease, dyskinesia, or attention deficit and hyperactivity disorder.
  14. 14. Use of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of diabetic nephropathy, chronic kidney disease, acute kidney injury, hypertension, refractory hypertension, parkinson's disease, atherosclerotic cardiovascular disease, angina pectoris, myocardial infarction, heart failure, pulmonary hypertension, ischemic stroke, cognitive deficit associated with schizophrenia, cognitive deficit associated with alzheimer's disease, dyskinesia or attention deficit and hyperactivity disorder.
  15. 15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  16. 16. A method of preparing a pharmaceutical composition comprising mixing a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable carriers, diluents or excipients.

Description

PDE1 inhibitors The present invention relates to certain human PDE1 inhibitors, to pharmaceutical compositions comprising the compounds, to methods of using the compounds to treat physiological disorders, and to intermediates and methods useful in the synthesis of the compounds. Phosphodiesterases (PDEs) are enzymes that regulate the cellular levels of these cyclic nucleotides by controlling the rate of hydrolysis of cAMP and cGMP. PDE1 is a calcium and calmodulin dependent PDE, one of at least 11 known PDE families. PDE1 is expressed in many tissues including brain, heart, lung, kidney and smooth muscle. Furthermore, PDE1 consists of a family of three known isoforms PDE1A, PDE B and PDE 1C. Patients with diabetes often develop a form of chronic kidney disease, known as diabetic kidney disease (or diabetic nephropathy). It has been estimated that diabetic kidney disease can affect up to 40% of diabetics. Treatment options for diabetic kidney disease are limited and include the use of blood pressure lowering drugs, management of blood glucose levels, diet and weight, and regular physical activity. Thus, patients suffering from chronic kidney disease, particularly diabetic kidney disease, require additional treatment options. U.S. patent No. 8,299,080 discloses certain quinoxaline derivatives useful in the treatment of various disorders such as dysuria and hypertension. Furthermore, european patent No. 0 404 401 discloses certain substituted triazoloquinoxalin-4-ones having antihypertensive activity. Certain other PDE1 inhibitor compounds are disclosed in WO 2018/039051, WO 2017/139186, WO 2019/032383, WO 2019/156861 and WO 2019/027783. There remains a need for PDE1 inhibitor therapy using a compound that exhibits desirable potency, minimizes induction of cytochrome P450 (cyp) enzymes in patients, and minimizes toxicity to patients, e.g., with respect to undesirable cardiac effects. The present invention provides certain novel compounds that are inhibitors of human PDE 1. Furthermore, the present invention provides certain novel compounds that are selective inhibitors of human PDE1A, PDE1B and PDE1C relative to other human PDEs (e.g., PDE3A, PDE4D and PDE6 AB). Furthermore, the present invention provides certain novel compounds that may have antihypertensive effects and may also improve renal blood flow. In addition, certain compounds of the invention may reduce renal fibrosis. Accordingly, the present invention provides compounds of formula I: Wherein R 1、R2 and R 3 are each independently H, halogen or C1-C3 alkyl optionally substituted by one or more halogens; R 4 is H, halogen, C1-C4 alkyl optionally substituted by one or more halogens, cyclopropyl or CH=CH-CH 3, and R 5 is C1-C3 alkyl optionally substituted by one or more halogen or cyclopropyl; or a pharmaceutically acceptable salt thereof. PDE1 pathway and disorders and diseases such as kidney disease, cardiovascular disease, hypertension, pulmonary hypertension, parkinson's disease, atherosclerosis, neurocognitive disorders, schizophrenia, cognitive deficits associated with Alzheimer's disease, dyskinesias, and attention deficit and hyperactivity disorder (Samidurai A et al, pharmacol Ther.2021, month 10; 226: 107858. Doi:10.1016/j. Pharmathera.2021.107858). Accordingly, the present invention also provides a method of treating chronic kidney disease, diabetic nephropathy, acute kidney injury, hypertension, intractable hypertension, parkinson's disease, atherosclerotic cardiovascular disease, angina pectoris, myocardial infarction, heart failure, pulmonary hypertension, ischemic stroke, cognitive deficits associated with schizophrenia, cognitive deficits associated with alzheimer's disease, dyskinesia, or attention deficit and hyperactivity disorder in a patient, the method comprising administering to a patient in need of such treatment an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof. Furthermore, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in therapy. The invention further provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment of diabetic nephropathy, chronic kidney disease, acute kidney injury, hypertension, refractory hypertension, parkinson's disease, atherosclerotic cardiovascular disease, angina pectoris, myocardial infarction, heart failure, pulmonary hypertension, ischemic stroke, cognitive deficit associated with schizophrenia, cognitive deficit associated with alzheimer's disease, dyskinesia or attention deficit and hyperactivity disorder. Furthermore, the present invention provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of diabetic nephropathy, chronic kidney disease, acute kidney injury, hypertension, refractory hypertension, parkinson's disease, atherosclerotic cardiovascular disease, ang