IMIDAZOPYRIDINE COMPOUNDS

• US 20100069431A1
• Filed: 09/01/2006
• Published: 03/18/2010
• Est. Priority Date: 09/01/2005
• Status: Active Grant

• Current Assignee: Takeda San Diego, Inc. (Takeda Pharmaceutical Company Limited)
• Original Assignee: Takeda Pharmaceutical Company Limited
• Inventors: Throop, Beverly, Iwata, Hidehisa, Gwaltney, Stephen L., Hosfield, David J., Stafford, Jeffrey A., Kohara, Yasuhisa, Cao, Sheldon X., Guntupalli, Prasuna, Liu, Yan
• Granted Patent: US 8,124,617 B2
• Time in Patent Office: Days
• US Class Current: 514/303
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• 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 1/12 Antidiarrhoeals
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• 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 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/06 Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 : for peripheral neuropathies
• CPC Class Codes: A61P 25/26 : Psychostimulants, e.g. nicotine, cocaine
• 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 3/04 : Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 : Antihyperlipidemics
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 : Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 37/04 : Immunostimulants
• 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 5/00 : Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 5/28 : Antiandrogens
• CPC Class Codes: A61P 5/30 : Oestrogens
• CPC Class Codes: A61P 5/48 : of the pancreatic hormones
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• 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 9/08 : Vasodilators for multiple indications
• 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 471/02 : in which the condensed system contains two hetero rings
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C12N 9/1205 : Phosphotransferases with an alcohol group as acceptor (2.7.1), e.g. protein kinases
• CPC Class Codes: C12Y 207/01001 : Hexokinase (2.7.1.1)

Abstract

Compounds, pharmaceutical compositions, kits and methods are provided for use with glucokinase that comprise a compound selected from the group consisting of formula (I) wherein the variables are as defined herein.

Claims

1. A glucokinase activator comprising a compound represented by the formula (I):

wherein

ring A is an optionally substituted phenyl group; and

R¹, R², R³ and R⁴ are the same or different and each is a hydrogen atom or a substituent, a salt thereof or a prodrug thereof.

16. A method for activating glucokinase in a mammal in need thereof, which comprises administering to the mammal a compound according to claim 1, or a salt or prodrug thereof.

17. Use of a compound according to claim 1, or a salt or prodrug thereof, for the production of a glucokinase activator.

2. An agent for activating glucokinase, which comprises a compound represented by the formula (Ip):

wherein

m is 1, 2 or 3;

each L is independently absent or a linker providing 1, 2, 3, 4, 5 or 6 atom separation between R⁷ and the ring to which L is attached, wherein the atoms of the linker providing the separation are selected from the group consisting of carbon, oxygen, nitrogen, and sulfur;

R¹ is a hydrogen atom or a substituent convertible in vivo to hydrogen;

R², R³ and R⁴ are independently a hydrogen atom or a substituent; and

each R⁷ is independently selected from the group consisting of hydrogen, (C_1-3)alkyl, aryl(C_1-3)alkyl, (C_3-12)cycloalkyl, hetero(C_3-12)cycloalkyl, heteroaryl(C_1-3)alkyl, aryl and heteroaryl, each substituted or unsubstituted, a salt thereof or a prodrug thereof.

3. A compound represented by the formula (II):

wherein

R¹, R², R³ and R⁴ are the same or different and each is a hydrogen atom or a substituent; and

R⁵ and R⁶ are the same or different and each is an optionally substituted C_1-6 alkyl group, provided that when the alkyl group is a C_1-2 alkyl group, then the C_1-2 alkyl group should be substituted by optionally substituted cyclic group(s), or a salt thereof.

4. A compound of claim 3, wherein R¹ is a hydrogen atom.

5. A compound of claim 3, wherein R² is a hydrogen atom.

6. A compound of claim 3, wherein R³ is

(1) a hydrogen atom;

(2) a C_6-14 aryl group optionally substituted by 1 to 3 substituents selected from

(a) a halogen atom,

(b) a C_1-6 alkyl group optionally substituted by 1 to 3 halogen atoms,

(c) a C_1-6 alkoxy group, and

(d) a hydroxy group;

(3) a C_1-6 alkyl group optionally substituted by 1 to 3 substituents selected from

(a) an amino group optionally substituted by 1 or 2 substituents selected from

(i) a C_1-6 alkyl group optionally substituted by 1 to 3 substituents selected from a C_1-6 alkoxy group, a C_6-14 aryloxy group, a carboxyl group and a C_1-6 alkoxy-carbonyl group, and

(ii) a C_7-13 aralkyl group, and

(b) a hydroxy group;

(4) an optionally substituted aromatic heterocyclic group;

(5) a formyl group;

(6) a carboxyl group;

(7) a C_1-6 alkoxy-carbonyl group;

or

(8) a halogen atom.

7. A compound of claim 3, wherein R⁴ is

(1) a hydrogen atom;

(2) a C_1-6 alkyl group optionally substituted by 1 to 3 substituents selected from

(a) a hydroxy group,

(b) a carboxyl group,

(c) a C_1-6 alkoxy-carbonyl group,

(d) a halogen atom, and

(e) a cyano group;

(3) a cyano group;

(4) a carboxyl group;

or

(5) a C_1-6 alkoxy-carbonyl group.

8. A compound of claim 3, wherein R⁵ and R⁶ are the same or different and each is

(1) a C_1-6 alkyl group substituted by 1 to 3 substituents selected from

(a) a C_6-14 aryl group,

(b) a C_3-10 cycloalkyl group,

(c) a 5- or 6-membered aromatic heterocyclic group, and

(d) a 5- or 6-membered non-aromatic heterocyclic group

(each of the above-mentioned (a) to (d) is optionally substituted by 1 to 3 substituents selected from a halogen atom, a C_1-6 alkyl group, a C_1-6 alkoxy group, a thiol group, a C_1-6 alkyl-carbonyl group, a C_1-6 alkylsulfonyl group, a C_6-14 aryloxy group, a mono- or di-C_1-6 alkyl-amino group);

or

(2) a C_3-6 alkyl group optionally substituted by 1 to 3 substituents selected from a C_1-6 alkoxy group and a C_6-14 aryloxy group optionally substituted by 1 to 3 substituents selected from a cyano group and a halogen atom.

14. A prodrug of a compound according to claim 3.

15. A pharmaceutical agent comprising a compound according to claim 3 or a prodrug thereof.

9. A compound represented by the formula (Iq):

wherein R¹ is a hydrogen atom or a substituent convertible in vivo to hydrogen;

R², R³ and R⁴ are independently a hydrogen or a substituent; and

R⁸ is selected from the group consisting of (C_1-3)alkyl, aryl(C_1-3)alkyl, (C_3-12)cycloalkyl, hetero(C_3-12)cycloalkyl, heteroaryl(C_1-3)alkyl, aryl and heteroaryl, each substituted or unsubstituted, or a salt thereof.

10. A compound represented by the formula (Ir):

wherein R¹ is a hydrogen atom or a substituent convertible in vivo to hydrogen;

R², R³, R⁴ and each R¹¹ are independently a hydrogen or a substituent;

R⁵ is an optionally substituted C_1-6 alkyl group; and

n is 0, 1, 2, 3, 4 or 5, or a salt thereof.

11. A compound represented by the formula (Is):

wherein R¹ is a hydrogen atom or a substituent convertible in vivo to hydrogen;

R², R³ and R⁴ are independently a hydrogen or a substituent;

each R¹¹ is independently selected from the group consisting of (C_1-3)alkyl, aryl(C_1-3)alkyl, (C_3-12)cycloalkyl, hetero(C_3-12)cycloalkyl, heteroaryl(C_1-3)alkyl, aryl and heteroaryl, each substituted or unsubstituted; and

n is 0, 1, 2, 3, 4 or 5, or a salt thereof.

12. A compound represented by the formula (It):

wherein R¹ is a hydrogen atom or a substituent convertible in vivo to hydrogen;

R², R³ and R⁴ are independently a hydrogen or a substituent; and

R⁹ and R¹⁰ are independently an optionally substituted C_1-6 alkyl, acyl or sulfonyl group, or a salt thereof.

13. A compound selected from the group consisting of:

2-[5-(benzyloxy)-2-isopropoxyphenyl]-6-(3-fluorophenyl)-3H-imidazo[4,5-b]pyridine;

2-(3-(benzyloxy)-5-isopropoxyphenyl)-3H-imidazo[4,5-b]pyridine;

2-(3-isopropoxy-5-(3-phenylpropoxy)phenyl)-3H-imidazo[4,5-b]pyridine;

2-(3-isopropoxy-5-phenethoxyphenyl)-3H-imidazo[4,5-b]pyridine;

2-(3-(benzyloxy)-5-((1-methyl-1H-imidazol-2-yl)methoxy)phenyl)-3H-imidazo[4,5-b]pyridine;

2-(3-(benzyloxy)-5-((1-methyl-1H-imidazol-2-yl)methoxy)phenyl)-6-bromo-3H-imidazo[4,5-b]pyridine;

6-bromo-2-(3-((1-methyl-1H-imidazol-2-yl)methoxy)-5-(2-(thiophen-3-yl)ethoxy)phenyl)-3H-imidazo[4,5-b]pyridine;

2-(3-(2-fluorobenzyloxy)-5-((1-methyl-1H-imidazol-2yl)methoxy)phenyl)-3H-imidazo[4,5-b]pyridine;

6-chloro-2-(3-(2-fluorobenzyloxy)-5-((1-methyl-1H-imidazol-2-yl)methoxy)phenyl)-3H-imidazo[4,5-b]pyridine;

6-bromo-2-(3-(2-fluorobenzyloxy)-5-((1-methyl-1H-imidazol-2-yl)methoxy)phenyl)-3H-imidazo[4,5-b]pyridine;

3-(2-(3-(2-fluorobenzyloxy)-5-((1-methyl-1H-imidazol-2-yl)methoxy)phenyl)-3H-imidazo[4,5-b]pyridin-6-yl)propan-1-ol;

(R)-2-(3-(2-fluorobenzyloxy)-5-(1-methoxypropan-2-yloxy)phenyl)-3H-imidazo[4,5-b]pyridine;

(R)-6-chloro-2-(3-(2-fluorobenzyloxy)-5-(1-methoxypropan-2-yloxy)phenyl)-3H-imidazo[4,5-b]pyridine;

(R)-6-bromo-2-(3-(2-fluorobenzyloxy)-5-(1-methoxypropan-2-yloxy)phenyl)-3H-imidazo[4,5-b]pyridine;

(S)-3-(2-(3-(2-fluorobenzyloxy)-5-(1-methoxypropan-2-yloxy)phenyl)-3H-imidazo[4,5-b]pyridin-6-yl)propan-1-ol;

(S)-methyl 2-(3-(2-fluorobenzyloxy)-5-(1-methoxypropan-2-yloxy)phenyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate;

(S)-2-(3-(2-fluorobenzyloxy)-5-(1-methoxypropan-2-yloxy)phenyl)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid

(S)-2-(3-(1-methoxypropan-2-yloxy)-5-(4-(methylsulfonyl)phenoxy)phenyl)-3H-imidazo[4,5-b]pyridine;

6-bromo-2-(2-phenoxyphenyl)-3H-imidazo[4,5-b]pyridine;

(E)-2-(2-isopropoxy-5-styrylphenyl)-3H-imidazo[4,5-b]pyridine;

N-(3-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)-5-((1-methyl-1H-imidazol-2-yl)methylamino)phenyl)benzenesulfonamide;

N-(3-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)-5-((1-methyl-1H-imidazol-2-yl)methylamino)phenyl)methanesulfonamide;

2-(5-(benzyloxy)-2-methoxyphenyl)-6-bromo-3H-imidazo[4,5-b]pyridine;

6-bromo-2-(2-(pyridin-3-yloxy)phenyl)-3H-imidazo[4,5-b]pyridine;

6-bromo-2-(3-(2-fluorobenzyloxy)-5-(pyrimidin-2-yloxy)phenyl)-3H-imidazo[4,5-b]pyridine; and

(E)-2-(2-methoxy-5-(2-(pyridin-4-yl)vinyl)phenyl)-3H-imidazo[4,5-b]pyridine.