Pyrazolo pyridine derivatives as NADPH oxidase inhibitors

• US 9,073,919 B2
• Filed: 01/04/2013
• Issued: 07/07/2015
• Est. Priority Date: 03/22/2007
• Status: Active Grant

• Current Assignee: Calliditas Therapeutics Suisse SA
• Original Assignee: Genkyotex SA (Calliditas Therapeutics AB)
• Inventors: Page, Patrick, Orchard, Mike, Fioraso-Cartier, Laetitia, Mottironi, Bianca
• Primary Examiner(s): VAJDA, KRISTIN ANN
• Application Number:
  US13/734,205
• Publication Number:
  US 20130123256A1
• Time in Patent Office: 914 Days
• Field of Search: 514/234.2, 514/303, 514/253.04, 544/127, 544/362, 546/119
• US Class Current: 1/1
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/16 Emollients or protectives, e.g. against radiation
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 25/00 : Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 : Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/28 : for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 : Ophthalmic agents
• CPC Class Codes: A61P 27/12 : for cataracts
• CPC Class Codes: A61P 27/16 : Otologicals
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 29/02 : without antiinflammatory effect
• CPC Class Codes: A61P 3/00 : Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/06 : Antihyperlipidemics
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/16 : for influenza or rhinoviruses
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 39/02 : Antidotes
• CPC Class Codes: A61P 39/06 : Free radical scavengers or antioxidants
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/04 : Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems

Abstract

The present invention is related to pyrazolo pyridine derivatives of Formula (I), pharmaceutical composition thereof and to their use for the treatment and/or prophylaxis of disorders or conditions related to Nicotinamide adenine dinucleotide phosphate oxidase (NADPH Oxidase).

Claims

1. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent or excipient and at least one pyrazolo pyridine derivative according to Formula (I):

2. The pharmaceutical composition according to claim 1, wherein G₂ is selected from phenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-nitrophenyl, 2-chlorophenyl, 2-methyl phenyl, 4-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl, 2,5-difluorophenyl and 2-methoxyphenyl.

3. The pharmaceutical composition according to claim 1, wherein G₃ is optionally substituted alkyl.

4. The pharmaceutical composition according to claim 1, wherein G₃ is methyl.

5. The pharmaceutical composition according to claim 1, wherein G₃ is optionally substituted phenyl.

6. The pharmaceutical composition according to claim 1, wherein G₄ is selected from optionally substituted alkyl, optionally substituted alkenyl and optionally substituted alkynyl.

7. The pharmaceutical composition according to claim 1, wherein G₄ is selected from optionally substituted aryl alkyl and optionally substituted heteroaryl alkyl.

8. The pharmaceutical composition according to claim 1, wherein G₄ is selected from optionally substituted morpholinyl alkyl, optionally substituted piperazinyl alkyl, optionally substituted pyrrolidinyl alkyl and optionally substituted tetrahydrofuranyl alkyl.

9. The pharmaceutical composition according to claim 1, wherein G₄ is selected from optionally substituted morpholinyl propyl, optionally substituted morpholinyl ethyl, optionally substituted piperazinyl ethyl, optionally substituted pyrrolidinyl propyl and optionally substituted tetrahydrofuranyl methyl.

10. The pharmaceutical composition according to claim 1, wherein said pyrazolo pyridine derivative is selected from:

4-methyl-2-phenyl-5-(thiophen-2-ylmethyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

5-(furan-2-ylmethyl)-4-methyl-2-phenyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

4-methyl-2-phenyl-5-(pyridin-3-ylmethyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

4-methyl-2-phenyl-5-(2-phenylethyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

5-[2-(1H-indol-3-yl)ethyl]-4-methyl-1-(3-methylbenzyl)-2-phenyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

1-(4-fluorobenzyl)-5-[2-(1H-indol-3-yl)ethyl]-4-methyl-2-phenyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

1-(2-chlorobenzyl)-4-methyl-5-[3-(2-oxopyrrolidin-1-yl)propyl]-2-phenyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

1-(4-chlorobenzyl)-5-[2-(1H-imidazol-4-yl)ethyl]-4-methyl-2-phenyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

5-(1,3-benzodioxol-5-ylmethyl)-4-methyl-2-phenyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

5-benzyl-4-methyl-2-phenyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

5-benzyl-2-(4-fluorophenyl)-4-methyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

5-benzyl-2-(4-methoxyphenyl)-4-methyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

5-benzyl-4-methyl-2-(4-nitrophenyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

4-methyl-2-phenyl-5-(tetrahydrofuran-2-ylmethyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

5-[2-(1H-indol-3-yl)ethyl]-4-methyl-2-phenyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

4-methyl-5-morpholin-4-yl-2-phenyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

5-benzyl-4-ethyl-2-(4-fluorophenyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

4-ethyl-2-(4-fluorophenyl)-5-(2-phenylethyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

4-ethyl-2-(4-fluorophenyl)-5-morpholin-4-yl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

4-methyl-5-(2-morpholin-4-ylethyl)-2-phenyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

4-ethyl-5-morpholin-4-yl-2-phenyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-(2-chlorophenyl)-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

4-methyl-2-(2-methylphenyl)-5-(3-morpholin-4-ylpropyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

4-ethyl-2-(4-fluorophenyl)-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

4-ethyl-2-(4-fluorophenyl)-5-(3-morpholin-4-ylpropyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

4-ethyl-2-(4-fluorophenyl)-5-(2-methoxyethyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2,4-diphenyl-5-(pyridin-3-ylmethyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-(2-chlorophenyl)-4-ethyl-5-(pyridin-3-ylmethyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

4-methyl-2-(2-methylphenyl)-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

4-ethyl-5-(3-morpholin-4-ylpropyl)-2-[4-(trifluoromethyl)phenyl]-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

4-ethyl-5-(3-morpholin-4-ylpropyl)-2-[4-(trifluoromethoxy)phenyl]-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-(2,5-difluorophenyl)-4-ethyl-5-(3-morpholin-4-ylpropyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione; and

4-ethyl-2-(2-methoxyphenyl)-5-(3-morpholin-4-ylpropyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione, tautomers, geometrical isomers, optically active forms, enantiomers, diastereomers and racemate forms.

11. A method of preparing a pharmaceutical composition comprising combining a pyrazolo pyridine derivative according to Formula (I):

12. A method for the treatment of a patient suffering from a disease or condition selected from the group consisting of diabetic nephropathy, renal failure, glomerulonephritis, nephrotoxicity of aminoglycosides and platinum compounds, hyperactive bladder, liver fibrosis, alcohol induced fibrosis, steatosis, non-alcoholic steatohepatitis, bronchial asthma, bronchitis, allergic rhinitis, adult respiratory syndrome, viral lung infection, pulmonary hypertension, chronic obstructive pulmonary diseases (COPD), pulmonary fibrosis, erectile dysfunction, fertility disorders, prostatic hypertrophy, benign prostatic hypertrophy, pain, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endothelium sarcoma, lymphangiosarcoma, lymphangioendothelioma, periosteoma, mesothelioma, Ewing'"'"'s tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostatic carcinoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms'"'"' tumor, cervical cancer, orchioncus, lung cancer, small-cell lung cancer, bladder cancer, epithelial cancer, gastric mucosa disorders, ischemic bowel disease management, enteritis/colitis, cancer chemotherapy, neutropenia, a disease or a state characterized by a central nervous system (CNS) degeneration or alteration, and arthritis, comprising administering a pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent or excipient and at least one pryazolo pyridine derivative according to Formula (I):

13. The method according to claim 12, wherein said disease or disorder is selected from diabetic nephropathy, renal failure, glomerulonephritis, nephrotoxicity of aminoglycosides and platinum compounds and hyperactive bladder.

14. The method according to claim 12, wherein said disease or disorder is selected from liver fibrosis, alcohol induced fibrosis, steatosis and non-alcoholic steatohepatitis.

15. The method according to claim 12, wherein said disease or disorder is selected from bronchial asthma, bronchitis, allergic rhinitis, adult respiratory syndrome, viral lung infection pulmonary hypertension and chronic obstructive pulmonary diseases (COPD).

16. The method according to claim 12, wherein said disease or disorder is pulmonary fibrosis.

17. The method according to claim 12, wherein said disease or disorder is selected from erectile dysfunction, fertility disorders, prostatic hypertrophy and benign prostatic hypertrophy.

18. The method according to claim 12, wherein said pain is an inflammatory pain.

19. The method according to claim 12, wherein said disease or condition is selected from the group consisting of fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endothelium sarcoma, lymphangiosarcoma, lymphangioendothelioma, periosteoma, mesothelioma, Ewing'"'"'s tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostatic carcinoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, broncho genic carcinoma, renal cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms'"'"' tumor, cervical cancer, orchioncus, lung cancer, small-cell lung cancer, bladder cancer and epithelial cancer.

20. The method according to claim 12, wherein said disease or disorder is selected from the group consisting of gastric mucosa disorders, ischemic bowel disease management, enteritis/colitis, cancer chemotherapy, and neutropenia.

21. The method according to claim 12, wherein said disease or disorder is a disease or a state characterized by a central nervous system (CNS) degeneration or alteration.

22. The method according to claim 12, wherein said disorder or disease is arthritis.

25. The method according to claim 21, wherein said patient is treated for a disease or a state characterized by a central nervous system (CNS) degeneration or alteration at the neuronal level.

28. The method according to claim 12, wherein said patient is treated for a viral lung infection caused by influenza.

23. A pyrazolo pyridine derivative according to Formula (I):

24. A method for the treatment of a patient suffering from a disease or condition selected from the group consisting of diabetic nephropathy, renal failure, glomerulonephritis, nephrotoxicity of aminoglycosides and platinum compounds, hyperactive bladder, liver fibrosis, alcohol induced fibrosis, steatosis, non-alcoholic steatohepatitis, bronchial asthma, bronchitis, allergic rhinitis, adult respiratory syndrome, viral lung infection, pulmonary hypertension, chronic obstructive pulmonary diseases (COPD), pulmonary fibrosis, erectile dysfunction, fertility disorders, prostatic hypertrophy, benign prostatic hypertrophy, pain, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endothelium sarcoma, lymphangiosarcoma, lymphangioendothelioma, periosteoma, mesothelioma, Ewing'"'"'s tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostatic carcinoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms'"'"' tumor, cervical cancer, orchioncus, lung cancer, small-cell lung cancer, bladder cancer, epithelial cancer, gastric mucosa disorders, ischemic bowel disease management, enteritis/colitis, cancer chemotherapy, neutropenia, a disease or a state characterized by a central nervous system (CNS) degeneration or alteration and arthritis, comprising administering a compound selected from:

benzyl-4-ethyl-2-(4-fluorophenyl)-1H-pyrazolo[4,3c]pyridine-3,6(2H,5H)-dione;

4-ethyl-2-(4-fluorophenyl)-5-(2-phenylethyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

4-ethyl-2-(4-fluorophenyl)-5-morpholin-4-yl-1 H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-(2-chlorophenyl)-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-c] pyridine-3,6(2H,5H)-dione;

4-methyl-2-(2-methylphenyl)-5-(3-morpholin-4-ylpropyl)-1H-pyrazolo[4,3-c] pyridine-3,6(2H,5H)-dione;

2-{1,3-benzothiazol-2-yl)-4-methyl-1-(pyridin-2-ylmethyl)5-(tetrahydrofuran-2-ylmethyl)-1H-pyrazolo[4,3-c] pyridine-3,6(2H,5H}-dione;

2-(1,3-benzothiazol-2-yl)-4-ethyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-c] pyridine-3,6(2H,5H)-dione;

2-(1,3-benzothiazol-2-yl)-4-ethyl-5-(3-morpholin-4ylpropyl)-1H-pyrazolo[4,3-c] pyridine-3,6(2H,5H)-dione;

2-(1,3-benzothiazol-2-yl)-4-ethyl-5-(2-methoxyethyl)-1H-pyrazolo[4,3-c] pyridine-3,6(2H,5H)-dione;

2-(1,3-benzothiazol-2-yl)-4-ethyl-5-(4-methylpiperazin-1yl)-1H-pyrazolo[4,3-c] pyridine-3,6(2H,5H)-dione;

4-ethyl-2-(4-fluorophenyl)-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

4-ethyl-2-(4-fluorophenyl)-5-(3-morpholin-4-ylpropyl)-1H-pyrazolo[4,3-c] pyridine-3,6(2H,5H)-dione;

4-ethyl-2-(4-fluorophenyl)-5-(2-methoxyethyl)-1H-pyrazolo[4,3-c]pyridine-3,6 (2H,5H)-dione;

5-(2-morpholin-4-ylethyl)-2-pyridin-2-yl-1H-pyrazolo[4,3c]pyridine-3,6(2H,5H)-dione;

4-ethyl-5-(3-morpholin-4-ylpropyl)-2-[4-(trifluoromethyl)phenyl)-1H-pyrazolo [4,3-c]pyridine-3,6(2H,5H)-dione;

4-ethyl-5-(3-morpholin-4-ylpropyl)-2-[4-(trifluoromethoxy)phenyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

or

2-(2,5-difluorophenyl)-4-ethyl-5-(3-morpholin-4-ylpropyl)-1H-pyrazolo[4,3-c] pyridine-3,6(2H,5H)-dione; and

pharmaceutically acceptable salts, tautomers, geometrical isomers, optically active forms, enantiomers, diastereomers and racemate forms thereof, to a patient in need of treatment of said disease or condition.

26. The method according to claim 24, wherein said patient is treated for a disease or a state characterized by a central nervous system (CNS) degeneration or alteration at the neuronal level.

27. The method according to claim 24, wherein said patient is treated for a viral lung infection caused by influenza.