IP Library › Granted Patent US 7,179,823
Granted Patent B1
US 7,179,823 · App. 10/129,702 · Granted Feb 20, 2007

5-membered n-heterocyclic compounds with hypoglycemic and hypolipidemic activity

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Quick Facts
Patent No.
US 7,179,823
App. No.
10/129,702
Granted
Feb 20, 2007
Kind
B1
Abstract

A compound of formula (I) F wherein R 1 represents a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted; x represents a bond, an oxygen atom, a sulfur atom, or a group of the formula: —CO—, —CS—, —CR 4 (OR 5 )— or —NR 6 — wherein each of R 4 and R 6 represents a hydrogen atom or a hydrocarbon group which may be stubstituted, R 5 represents a hydrogen atom or a protective group for a hydroxyl group; m represents an integer of 0 to 3; Y represents an oxygen atom, a sulfur atom, or a group of the formula: —SO—, —SO 2 —, —NR 7 —, —CONR 7 — or —NR 7 CO— wherein R 7 represents a hydrogen atom or a hydrocarbon group which may be substituted; ring A represents an aromatic ring which may further have 1 to 3 substituents; n represents an integer of 1 to 8; ring B represents a nitrogen-containing 5-membered hetero ring which may further be substituted by an alkyl group.

Claims (69)

1. A compound of the formula:

wherein R 1 represents a hydrocarbon group which is optionally substituted or a heterocyclic group which is optionally substituted;

X represents a bond, an oxygen atom, a sulfur atom, or a group of the formula: —CO—, —CS—, —CR 4 (OR 5 )— or —NR 6 — wherein each of R 4 and R 6 represents a hydrogen atom or a hydrocarbon group which is optionally substituted, R 5 represents a hydrogen atom or a protective group for a hydroxyl group;

m represents an integer of 0 to 3;

Y represents an oxygen atom, a sulfur atom, or a group of the formula: —SO—, —SO 2 —, —NR 7 —, —CONR 7 — or —NR 7 CO— wherein R 7 represents a hydrogen atom or a hydrocarbon group which is optionally substituted;

ring A represents benzene, naphthalene or pyridine, each of which optionally has 1 to 3 substituents;

n represents an integer of 1 to 8;

ring B represents pyrrole or pyrazole, each of which is optionally substituted by an alkyl group;

X 1 represents a bond, an oxygen atom, a sulfur atom, or a group of the formula: —SO—, —SO 2 —, —O—SO 2 — or —NR 16 — wherein R 16 represents a hydrogen atom or a hydrocarbon group which is optionally substituted;

R 2 represents a hydrogen atom, a hydrocarbon group which is optionally substituted or a heterocyclic group which is optionally substituted;

W represents a bond or a divalent hydrocarbon group having 1 to 20 carbon atoms;

R 3 represents a group of the formula: —OR 8 (R 8 represents a hydrogen atom or a hydrocarbon group which is optionally substituted) or —NR 9 R 10 (each of R 9 and R 10 , whether identical or not, represents a hydrogen atom, a hydrocarbon group which is optionally substituted, a heterocyclic group which is optionally substituted, or an acyl group which is optionally substituted; or R 9 and R 10 may bind together to form a 5- to 7-membered cyclic amino group);

provided that R 1 is a heterocyclic group which is optionally substituted or R 2 is an aromatic hydrocarbon group which is optionally substituted or a heterocyclic group which is optionally substituted, when ring A is benzene which is optionally substituted, and Y is an oxygen atom, a sulfur atom, —NH— or —CONH—; or a salt thereof.

2. A compound according to claim 1 , wherein X 1 is a bond.

3. A compound according to claim 1 , wherein R 1 is a heterocyclic group which is optionally substituted or a cyclic hydrocarbon group which is optionally substituted.

4. A compound according to claim 1 , wherein R 1 is a heterocyclic group which is optionally substituted.

5. A compound according to claim 1 , wherein X is a bond.

6. A compound according to claim 1 , wherein m is 1 or 2.

7. A compound according to claim 1 , wherein Y is an oxygen atom.

8. A compound according to claim 1 , wherein ring A is benzene or pyridine, each of which optionally has 1 to 3 substituents.

9. A compound according to claim 1 , wherein n is an integer of 1 to 3.

10. A compound according to claim 1 , wherein X 1 is a bond or an oxygen atom.

11. A compound according to claim 1 , wherein W is a divalent hydrocarbon group having 1 to 8 carbon atoms.

12. A compound according to claim 1 , wherein R 3 is a group of the formula: —OR 8 (R 8 represents a hydrogen atom or a hydrocarbon group which is optionally substituted).

13. A compound according to claim 1 , which is

3-[3-ethoxy-1-[4-(2-phenyl-4-thiazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid,

3-[3-ethoxy-1-[4-(2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid,

3-[3-ethoxy-1-[4-[3-methyl-1-(2-pyridyl)-1H-pyrazol-4-ylmethoxy]benzyl]-1H-pyrazol-4-yl]propionic acid,

3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazol-4-yl]propionic acid,

3-[1-[4-(2-phenyl-4-thiazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazol-4-yl]propionic acid, or

3-[1-[4-(2-phenyl-4-oxazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazol-4-yl]propionic acid.

14. A prodrug of a compound of the formula:

wherein R 1 represents a hydrocarbon group which is optionally substituted or a heterocyclic group which is optionally substituted;

X represents a bond, an oxygen atom, a sulfur atom, or a group of the formula: —CO—, —CS—, —CR 4 (OR 5 )— or —NR 6 — wherein each of R 4 and R 6 represents a hydrogen atom or a hydrocarbon group which is optionally substituted, R 5 represents a hydrogen atom or a protective group for a hydroxyl group;

m represents an integer of 0 to 3;

Y represents an oxygen atom, a sulfur atom, or a group of the formula: —SO—, —SO 2 —, —NR 7 —, —CONR 7 — or —NR 7 CO— wherein R 7 represents a hydrogen atom or a hydrocarbon group which is optionally substituted;

ring A represents benzene, naphthalene or pyridine, each of which optionally has 1 to 3 substituents;

n represents an integer of 1 to 8;

ring B represents pyrrole or pyrazole, each of which is optionally substituted by an alkyl group;

X 1 represents a bond, an oxygen atom, a sulfur atom, or a group of the formula: —SO—, —SO 2 —, —O—SO 2 — or —NR 16 — wherein R 16 represents a hydrogen atom or a hydrocarbon group which is optionally substituted;

R 2 represents a hydrogen atom, a hydrocarbon group which is optionally substituted or a heterocyclic group which is optionally substituted;

W represents a bond or a divalent hydrocarbon group having 1 to 20 carbon atoms;

R 3 represents a group of the formula: —OR 8 (R 8 represents a hydrogen atom or a hydrocarbon group which is optionally substituted) or —NR 9 R 10 (each of R 9 and R 10 , whether identical or not, represents a hydrogen atom, a hydrocarbon group which is optionally substituted, a heterocyclic group which is optionally substituted, or an acyl group which is optionally substituted; or R 9 and R 10 may bind together to form a 5- to 7-membered cyclic amino group);

provided that R 1 is a heterocyclic group which is optionally substituted or R 2 is an aromatic hydrocarbon group which is optionally substituted or a heterocyclic group which is optionally substituted, when ring A is benzene which is optionally substituted, and Y is an oxygen atom, a sulfur atom, —NH— or —CONH—; or a salt thereof.

15. A pharmaceutical composition comprising a compound of the formula:

wherein R 1 represents a hydrocarbon group which is optionally substituted or a heterocyclic group which is optionally substituted;

X represents a bond, an oxygen atom, a sulfur atom, or a group of the formula: —CO—, —CS—, —CR 4 (OR 5 )— or —NR 6 — wherein each of R 4 and R 6 represents a hydrogen atom or a hydrocarbon group which is optionally substituted, R 5 represents a hydrogen atom or a protective group for a hydroxyl group;

m represents an integer of 0 to 3;

Y represents an oxygen atom, a sulfur atom, or a group of the formula: —SO—, —SO 2 —, —NR 7 —, —CONR 7 — or —NR 7 CO— wherein R 7 represents a hydrogen atom or a hydrocarbon group which is optionally substituted;

ring A represents benzene, naphthalene or pyridine, each of which optionally has 1 to 3 substituents;

n represents an integer of 1 to 8;

ring B represents pyrrole or pyrazole, each of which is optionally substituted by an alkyl group;

X 1 represents a bond, an oxygen atom, a sulfur atom, or a group of the formula: —SO—, —SO 2 —, —O—SO 2 — or —NR 16 — wherein R 16 represents a hydrogen atom or a hydrocarbon group which is optionally substituted;

R 2 represents a hydrogen atom, a hydrocarbon group which is optionally substituted or a heterocyclic group which is optionally substituted;

W represents a bond or a divalent hydrocarbon group having 1 to 20 carbon atoms;

R 3 represents a group of the formula: —R 8 (R 8 represents a hydrogen atom or a hydrocarbon group which is optionally substituted) or —NR 9 R 10 (each of R 9 and R 10 , whether identical or not, represents a hydrogen atom, a hydrocarbon group which is optionally substituted, a heterocyclic group which is optionally substituted, or an acyl group which is optionally substituted; or R 9 and R 10 may bind together to form a 5- to 7-membered cyclic amino group); or a salt thereof or a prodrug thereof, and a pharmaceutically acceptable carrier.

16. A composition according to claim 15 , wherein X 1 is a bond.

17. A method for treating diabetes mellitus in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of the formula:

wherein R 1 represents a hydrocarbon group which is optionally substituted or a heterocyclic group which is optionally substituted;

X represents a bond, an oxygen atom, a sulfur atom, or a group of the formula: —CO—, —CS—, —CR 4 (OR 5 )— or —NR 6 — wherein each of R 4 and R 6 represents a hydrogen atom or a hydrocarbon group which is optionally substituted, R 5 represents a hydrogen atom or a protective group for a hydroxyl group;

m represents an integer of 0 to 3;

Y represents an oxygen atom, a sulfur atom, or a group of the formula: —SO—, —SO 2 —, —NR 7 —, —CONR 7 — or —NR 7 CO— wherein R 7 represents a hydrogen atom or a hydrocarbon group which is optionally substituted;

ring A represents benzene, naphthalene or pyridine, each of which optionally has 1 to 3 substituents;

n represents an integer of 1 to 8;

ring B represents pyrrole or pyrazole, each of which is optionally substituted by an alkyl group;

X 1 represents a bond, an oxygen atom, a sulfur atom, or a group of the formula: —SO—, —SO 2 —, —O—SO 2 — or —NR 16 — wherein R 16 represents a hydrogen atom or a hydrocarbon group which is optionally substituted;

R 2 represents a hydrogen atom, a hydrocarbon group which is optionally substituted or a heterocyclic group which is optionally substituted;

W represents a bond or a divalent hydrocarbon group having 1 to 20 carbon atoms;

R 3 represents a group of the formula: —OR 8 (R 8 represents a hydrogen atom or a hydrocarbon group which is optionally substituted) or —NR 9 R 10 (each of R 9 and R 10 , whether identical or not, represents a hydrogen atom, a hydrocarbon group which is optionally substituted, a heterocyclic group which is optionally substituted, or an acyl group which is optionally substituted; or R 9 and R 10 may bind together to form a 5- to 7-membered cyclic amino group); or a salt thereof or a prodrug thereof.