Amido compounds and their use as pharmaceuticals

• US 7,776,874 B2
• Filed: 06/10/2008
• Issued: 08/17/2010
• Est. Priority Date: 05/07/2004
• Status: Active Grant

• Current Assignee: Incyte Corporation, Incyte Holdings Corporation (Incyte Corporation), Incyte Holdings Corporation And Incyte Corporation
• Original Assignee: Incyte Corporation
• Inventors: Zhang, Colin, Xu, Meizhong, Zhuo, Jincong, Metcalf, Brian W., Yao, Wenqing, Qian, Ding-Quan, He, Chunhong
• Primary Examiner(s): Kosack; Joseph R
• Application Number:
  US12/136,529
• Publication Number:
  US 20080255154A1
• Time in Patent Office: 798 Days
• Field of Search: 514/278, 514/409, 514/462, 546/15, 548/411, 549/265
• US Class Current: 514/278
• CPC Class Codes: A61K 31/407 condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61P 11/04 for throat disorders
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 19/10 for osteoporosis
• 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 27/06 Antiglaucoma agents or miotics
• 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 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/48 of the pancreatic hormones
• CPC Class Codes: A61P 5/50 for increasing or potentiating the activity of insulin
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• 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: A61P 9/14 : Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07D 207/06 : with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 207/08 : with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 207/10 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 207/12 : Oxygen or sulfur atoms
• CPC Class Codes: C07D 207/14 : Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 207/16 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 207/27 : with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 209/08 : with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 209/42 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 209/44 : Iso-indoles; Hydrogenated iso-indoles
• CPC Class Codes: C07D 209/52 : condensed with a ring other than six-membered
• CPC Class Codes: C07D 209/62 : Naphtho [c] pyrroles; Hydrogenated naphtho [c] pyrroles
• CPC Class Codes: C07D 209/70 : containing carbocyclic rings other than six-membered
• CPC Class Codes: C07D 211/16 : with acylated ring nitrogen atom
• CPC Class Codes: C07D 211/18 : with substituted hydrocarbon radicals attached to ring carbon atoms
• CPC Class Codes: C07D 211/22 : by oxygen atoms
• CPC Class Codes: C07D 211/34 : with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 211/46 : having a hydrogen atom as the second substituent in position 4
• CPC Class Codes: C07D 211/48 : having an acyclic carbon atom attached in position 4
• CPC Class Codes: C07D 211/52 : having an aryl radical as the second substituent in position 4
• CPC Class Codes: C07D 211/58 : attached in position 4
• CPC Class Codes: C07D 211/64 : having an aryl radical as the second substituent in position 4
• CPC Class Codes: C07D 211/66 : having a hetero atom as the second substituent in position 4
• CPC Class Codes: C07D 211/70 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 213/38 : having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
• CPC Class Codes: C07D 217/06 : with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 217/26 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 221/20 : Spiro-condensed ring systems
• CPC Class Codes: C07D 295/185 : from aliphatic carboxylic acids
• CPC Class Codes: C07D 333/34 : Sulfur atoms
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 403/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings
• CPC Class Codes: C07D 413/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 471/10 : Spiro-condensed systems
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C07D 487/08 : Bridged systems
• CPC Class Codes: C07D 487/10 : Spiro-condensed systems
• CPC Class Codes: C07D 491/10 : Spiro-condensed systems
• CPC Class Codes: C07D 491/107 : with only one oxygen atom as ring hetero atom in the oxygen-containing ring
• CPC Class Codes: C07D 491/20 : Spiro-condensed systems
• CPC Class Codes: C07D 493/10 : Spiro-condensed systems
• CPC Class Codes: C07D 495/04 : Ortho-condensed systems
• CPC Class Codes: C07D 498/20 : Spiro-condensed systems
• CPC Class Codes: C07D 513/10 : Spiro-condensed systems

Abstract

The present invention relates to inhibitors of 11-β hydroxyl steroid dehydrogenase type 1, antagonists of the mineralocorticoid receptor (MR), and pharmaceutical compositions thereof. The compounds of the invention can be useful in the treatment of various diseases associated with expression or activity of 11-β hydroxyl steroid dehydrogenase type 1 and/or diseases associated with aldosterone excess.

Claims

1. A compound which is N-methyl-5-[4-(1-{[3-oxo-1′

H,3H-spiro[2-benzofuran-1,3′

-pyrrolidin]-1′

-yl]carbonyl}cyclopropyl)phenyl]pyridine-2-carboxamide, or a pharmaceutically acceptable salt thereof.

4. A pharmaceutical composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

5. A method of treating a disease in a patient, wherein the disease is selected from obesity, diabetes, glucose intolerance, insulin resistance, hyperglycemia, hyperlipidemia, glaucoma, hypertension, osteoporosis inflammation, renal disease, atherosclerosis, arteriosclerosis, coronary artery disease, thrombosis, angina, vascular wall damage, stroke, dyslipidemia, hyperlipoproteinemia, diabetic dyslipidemia, mixed dyslipidemia, hypercholesterolemia, hypertriglyceridemia, metabolic syndrome or general aldosterone-related target organ damage, the method comprising administering to said patient a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

6. A method of treating Type II diabetes in a patient comprising administering to said patient a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

9. A method according to claim 5, wherein the disease is obesity.

10. A method according to claim 5, wherein the disease is diabetes.

11. A method according to claim 5, wherein the disease is glucose intolerance.

12. A method according to claim 5, wherein the disease is insulin resistance.

13. A method according to claim 5, wherein the disease is hyperglycemia.

14. A method according to claim 5, wherein the disease is hypertension.

15. A method according to claim 5, wherein the disease is hyperlipidemia.

2. A compound which is N-methyl-5-[4-(1-{[(1R)-3-oxo-1′

H,3H-spiro[2-benzofuran-1,3′

-pyrrolidin]-1′

-yl]carbonyl}cyclopropyl)phenyl]pyridine-2-carboxamide, or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition comprising a compound according to claim 2, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

16. A method of treating a disease in a patient, wherein the disease is selected from obesity, diabetes, glucose intolerance, insulin resistance, hyperglycemia, hyperlipidemia, glaucoma, hypertension, osteoporosis inflammation, renal disease, atherosclerosis, arteriosclerosis, coronary artery disease, thrombosis, angina, vascular wall damage, stroke, dyslipidemia, hyperlipoproteinemia, diabetic dyslipidemia, mixed dyslipidemia, hypercholesterolemia, hypertriglyceridemia, metabolic syndrome or general aldosterone-related target organ damage, wherein the method comprises administering to said patient a therapeutically effective amount of a compound of claim 2, or a pharmaceutically acceptable salt thereof.

17. A method of treating type II diabetes in a patient comprising administering to said patient a therapeutically effective amount of a compound of claim 2, or a pharmaceutically acceptable salt thereof.

18. A method according to claim 16, wherein the disease is obesity.

19. A method according to claim 16, wherein the disease is diabetes.

20. A method according to claim 16, wherein the disease is glucose intolerance.

21. A method according to claim 16, wherein the disease is insulin resistance.

22. A method according to claim 16, wherein the disease is hyperglycemia.

23. A method according to claim 16, wherein the disease is hypertension.

24. A method according to claim 16, wherein the disease is hyperlipidemia.

3. A compound which is N-methyl-5-[4-(1-{[(1R)-3-oxo-1′

H,3H-spiro[2-benzofuran-1,3′

-pyrrolidin]-1′

-yl]carbonyl}cyclopropyl)phenyl]pyridine-2-carboxamide.

8. A pharmaceutical composition comprising a compound according to claim 3 and at least one pharmaceutically acceptable carrier.