Pyrazolo[3,4-b]pyridine compound, and its use as a PDE4 inhibitor

• US 7,709,497 B2
• Filed: 03/15/2005
• Issued: 05/04/2010
• Est. Priority Date: 03/16/2004
• Status: Expired due to Fees

• Current Assignee: Glaxo Group Limited (Glaxosmithkline Holdings Ltd.)
• Original Assignee: Glaxo Group Limited (Glaxosmithkline Holdings Ltd.)
• Inventors: Cook, Caroline Mary, Sayani, Amyn Pyarali, Lindvall, Mika Kristian, Christensen, Siegfried Benjamin IV, Johnson, Martin Redpath, Trivedi, Naimisha, Jones, Paul Spencer, Edlin, Christopher David, Trottet, Lionel
• Primary Examiner(s): Seaman; D. Margaret
• Assistant Examiner(s): Rahmani; Niloofar
• Application Number:
  US10/598,838
• Publication Number:
  US 20070280971A1
• Time in Patent Office: 1,876 Days
• Field of Search: 546/120, 514/303
• US Class Current: 514/303
• 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 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 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/24 Antidepressants
• 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 27/16 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 31/04 Antibacterial agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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: C07D 471/04 : Ortho-condensed systems

Abstract

The invention provides 4-{[1-(aminocarbonyl)-4-piperidinyl]amino}-N-[(3,4-dimethylphenyl)methyl]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide, which is the compound of formula (I):

or a salt thereof.

Claims

1. 4-{[1-(Aminocarbonyl)-4-piperidinyl]amino}-N-[(3,4-dimethylphenyl)methyl]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide or a pharmaceutically acceptable salt thereof.

13. A composition of matter according to claim 1 which is

4-{[1-(aminocarbonyl)-4-piperidinyl]amino}-N-[(3,4-dimethylphenyl)methyl]-1-ethyl-1H-pyrazolo [3,4-b]pyridine-5-carboxamide hydrobromide,

4-{[1-(aminocarbonyl)-4-piperidinyl]amino}-N-[(3,4-dimethylphenyl)methyl]-1-ethyl-1H-pyrazolo [3,4-b]pyridine-5-carboxamide sulfate,

4-{[1-(aminocarbonyl)-4-piperidinyl]amino}-N-[(3,4-dimethylphenyl)methyl]-1-ethyl-1H-pyrazolo [3,4-b]pyridine-5-carboxamide nitrate,

4-{[1-(aminocarbonyl)-4-piperidinyl]amino}-N-[(3,4-dimethylphenyl)methyl]-1-ethyl-1H-pyrazolo [3,4-b]pyridine-5-carboxamide phosphate,

4-{[1-(aminocarbonyl)-4-piperidinyl]amino}-N-[(3,4-dimethylphenyl)methyl]-1-ethyl-1H-pyrazolo [3,4-b]pyridine-5-carboxamide p-toluenesulfonate,

4-{[1-(aminocarbonyl)-4-piperidinyl]amino}-N-[(3,4-dimethylphenyl)methyl]-1-ethyl-1H-pyrazolo [3,4-b]pyridine-5-carboxamide benzenesulfonate,

4-{[1-(aminocarbonyl)-4-piperidinyl]amino}-N-[(3,4-dimethylphenyl)methyl]-1-ethyl-1H-pyrazolo [3,4-b]pyridine-5-carboxamide methanesulfonate,

4-{[1-(aminocarbonyl)-4-piperidinyl]amino}-N-[(3,4-dimethylphenyl)methyl]-1-ethyl-1H-pyrazolo [3,4-b]pyridine-5-carboxamide ethanesulfonate, or

4-{[1-(aminocarbonyl)-4-piperidinyl]amino}-N-[(3,4-dimethylphenyl)methyl]-1-ethyl-1H-pyrazolo [3,4-b]pyridine-5-carboxamide naphthalenesulfonate.

2. 4-{[1-(Aminocarbonyl)-4-piperidinyl]amino}-N-[(3,4-dimethylphenyl)methyl]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide.

3. 4-{[1-(Aminocarbonyl)-4-piperidinyl]amino}-N-[(3,4-dimethylphenyl)methyl]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide hydrochloride.

4. A pharmaceutical composition comprising 4-{[1-(aminocarbonyl)-4-piperidinyl]amino}-N-[(3,4-dimethylphenyl)methyl]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

5. A pharmaceutical composition as claimed in claim 4, which is suitable for external topical administration to a human.

6. A pharmaceutical composition as claimed in claim 5, which is an ointment comprising:

4-{[1-(aminocarbonyl)-4-piperidinyl]amino}-N-[(3,4-dimethylphenyl)methyl]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide or a pharmaceutically acceptable salt thereof present at 0.1% to 3% w/w;

an oil phase present at 25% to 99% w/w;

one or more surfactants present in total at 0.5% to 10% w/w; and

one or more agents acting as a skin-penetration enhancer present in total at 0.5% to 50% w/w.

7. A pharmaceutical composition as claimed in claim 6, which is an ointment comprising:

4-{[1-(aminocarbonyl)-4-piperidinyl]amino}-N-[(3,4-dimethylphenyl)methyl]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide or a pharmaceutically acceptable salt thereof present at 0.2% to 1.5% w/w;

an oil phase present at 50% to 80% w/w, comprising white petrolatum present at 45 to 75% w/w, and also comprising mineral oil present at 2.5% to 15% w/w;

one or more surfactants present in total at 3% to 10% w/w; and

one or more hydrophilic agents acting as both a solubiliser and skin-penetration enhancer, present in total at 5% to 50% w/w;

wherein, in the ointment composition, the oil phase and the hydrophilic solubiliser/penetration-enhancer phase have been emulsified to form an ointment emulsion.

8. A pharmaceutical composition as claimed in claim 5, which is a water-in-oil cream comprising:

4-{[1-(aminocarbonyl)-4-piperidinyl]amino}-N-[(3,4-dimethylphenyl)methyl]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide or a pharmaceutically acceptable salt thereof present at 0.1% to 3% w/w;

an oil phase present at 25% to 85% w/w;

water present in 2% to 30% w/w;

one or more surfactants present in total at 0.5% to 12% w/w; and

one or more agents acting as a skin-penetration enhancer present in total at 0.5% to 50% w/w.

9. A pharmaceutical composition as claimed in claim 8, which is a water-in-oil cream emulsion comprising:

4-{[1-(aminocarbonyl)-4-piperidinyl]amino}-N-[(3,4-dimethylphenyl)methyl]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide or a pharmaceutically acceptable salt thereof present at 0.2% to 1.5% w/w;

an oil phase present at 35% to 70% w/w, comprising white petrolatum present at 30% to 65% w/w and mineral oil present at 2.5% to 15% w/w;

water present in 5% to 25% w/w;

one or more surfactants present in total at 3% to 10% w/w; and

one or more hydrophilic agents acting as both a solubiliser and skin-penetration enhancer, present in total at 5% to 50% w/w.

10. A pharmaceutical composition as claimed in claim 5, which is an oil-in-water cream comprising:

4-{[1-(aminocarbonyl)-4-piperidinyl]amino}-N-[(3,4-dimethylphenyl)methyl]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide or a pharmaceutically acceptable salt thereof present at 0.1% to 3% w/w;

an oil phase containing one or more ingredients capable of acting as emollients, the oil phase being present at 20% to 60% w/w;

water present in 15% to 75% w/w;

one or more surfactants present in total at 0.5% to 12% w/w; and

one or more agents acting as a skin-penetration enhancer, present in total at 0.5% to 50% w/w.

11. A pharmaceutical composition as claimed in claim 10, which is an oil-in-water cream emulsion comprising:

4-{[1-(aminocarbonyl)-4-piperidinyl]amino}-N-[(3,4-dimethylphenyl)methyl]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide or a pharmaceutically acceptable salt thereof present at 0.2% to 3% w/w;

an oil phase containing one or more ingredients capable of acting as emollients, the oil phase being present at 30% to 55% w/w;

water present in 15% to 50% w/w;

one or more surfactants present in total at 3% to 10% w/w; and

one or more hydrophilic agents acting as both a solubiliser and skin-penetration enhancer, present in total at 5% to 50% w/w;

wherein the oil phase comprises mineral oil present at 20% to 45% w/w, and/or microcrystalline wax present at 5% to 25% w/w, and/or a silicone present at 0.5% to 10% w/w.

12. A method for the treatment of atopic dermatitis in a patient comprising administering a therapeutically effective amount of 4-{[1-(aminocarbonyl)-4-piperidinyl]amino}-N-[(3,4-dimethylphenyl)methyl]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide or a pharmaceutically acceptable salt thereof alone, or in admixture with a pharmaceutically acceptable excipient.