Heterocyclic Amide Compound and Use Thereof as an Mmp-13 Inhibitor(Amended Ex Officio)

• US 20080027050A1
• Filed: 04/28/2005
• Published: 01/31/2008
• Est. Priority Date: 04/30/2004
• Status: Active Grant

• Current Assignee: Takeda Pharmaceutical Company Limited
• Original Assignee: Takeda Pharmaceutical Company Limited
• Inventors: Oki, Hideyuki, Kuno, Haruhiko, Terauchi, Jun, Nara, Hiroshi, Sato, Kenjiro
• Granted Patent: US 9,212,149 B2
• Time in Patent Office: Days
• US Class Current: 514/233.8
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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 239/90 with acyclic radicals attached in position 2 or 3
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 491/04 Ortho-condensed systems
• CPC Class Codes: C07D 495/04 Ortho-condensed systems

Abstract

The present invention provides a novel amide derivative having a matrix metalloproteinase inhibitory activity, and useful as a pharmaceutical agent, which is a compound represented by the formula (I) wherein ring A is an optionally substituted, nitrogen-containing heterocycle, ring B is an optionally substituted monocyclic homocycle or an optionally substituted monocyclic heterocycle, Z is N or NR¹ (R¹ is a hydrogen atom or an optionally substituted hydrocarbon group), is a single bond or a double bond, R² is a hydrogen atom or an optionally substituted hydrocarbon group, X is an optionally substituted spacer having 1 to 6 atoms, ring C is (1) an optionally substituted homocycle or (2) an optionally substituted heterocycle other than a ring represented by (II) (X′ is S, O, SO, or CH₂), and at least one of ring B and ring C has substituent(s), provided that N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5,6-dimethyl-4-oxo-1,4-dihadrothieno[2,3-d]pyrimidine-2-carboxamide is excluded, or a salt thereof.

Claims

1. A compound represented by the formula

wherein ring A is an optionally substituted, nitrogen-containing heterocycle, ring B is an optionally substituted monocyclic homocycle or optionally substituted monocyclic heterocycle, Z is N or NR¹ (R¹ is a hydrogen atom or an optionally substituted hydrocarbon group), is a single bond or a double bond, R² is a hydrogen atom or an optionally substituted hydrocarbon group, X is an optionally substituted spacer having 1 to 6 atoms, ring C is (1) an optionally substituted homocycle or optionally substituted (2) an optionally substituted heterocycle other than a ring represented by the formula

(X′

is S, O, SO or CH₂), and at least one of ring B and ring C has substituent(s), provided that N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5,6-dimethyl-4-oxo-1,4-dihydrothieno[2,3-d]pyrimidine-2-carboxamide and 6-chloro-N-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)-4-oxo-1,4-dihydroquinazoline-2-carboxamide are excluded, or a salt thereof.

2. The compound of claim 1, wherein, when the partial structure represented by the formula

X is an optionally substituted spacer having 1, 3 or 4 atoms or a salt thereof.

3. The compound of claim 1, wherein ring A is

wherein R¹ is a hydrogen atom or an optionally substituted hydrocarbon group or a salt thereof.

4. The compound of claim 1, wherein ring A is

or a salt thereof.

5. The compound of claim 1, wherein ring B is an optionally substituted 5- or 6-membered monocyclic heterocycle containing, besides carbon atom, 1 to 3 hetero atoms selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom or a salt thereof.

6. The compound of claim 1, wherein ring B is an optionally substituted benzene ring or a salt thereof.

7. The compound of claim 1, wherein the partial structure represented by the formula

wherein R¹ is a hydrogen atom or an optionally substituted hydrocarbon group or a salt thereof.

8. The compound of claim 1, wherein the partial structure represented by the formula

or a salt thereof.

9. The compound of claim 1, wherein the partial structure represented by the formula

or a salt thereof.

10. The compound of claim 1, wherein the substituent of ring B is selected from (1) a C_1-6 alkyl group, (2) a C_1-6 alkyl group substituted by a C_7-16 aralkyloxy optionally substituted by a carboxyl group, (3) a C_1-6 alkyl group substituted by a C_6-14 aryl-aminocarbonyl optionally substituted by a carboxyl group, (4) a C_1-6 alkyl group substituted by a C_6-14 aryl-carbonylamino optionally substituted by a carboxyl group, (5) a C_1-6 alkyl group substituted by a C_6-14 aryloxy optionally substituted by a carboxyl group, (6) a C_6-14 aryloxy group optionally substituted by a carboxyl group, (7) a C_7-16 aralkyloxy group optionally substituted by a carboxyl group, (8) a C_6-14 aryl group optionally substituted by a carboxyl group, (9) a carbamoyl group optionally substituted by a C_7-16 aralkyl optionally substituted by a carboxyl group, (10) an amino group optionally substituted by C_7-16 aralkyl-carbonyl and (11) halogen atoms, or a salt thereof.

11. The compound of claim 1, wherein the partial structure represented by the formula

wherein R^a and R^b are each (1) a C_1-6 alkyl group, (2) a C_1-6 alkyl group substituted by a C_7-16 aralkyloxy optionally substituted by a carboxyl group, (3) a C_1-6 alkyl group substituted by a C_6-14 aryl-aminocarbonyl optionally substituted by a carboxyl group, (4) a C_1-6 alkyl group substituted by a C_6-14 aryl-carbonylamino optionally substituted by a carboxyl group, (5) a C_1-6 alkyl group substituted by a C_6-14 aryloxy optionally substituted by a carboxyl group, (6) a C_6-14 aryloxy group optionally substituted by a carboxyl group, (7) a C_7-16 aralkyloxy group optionally substituted by a carboxyl group, (8) a C_6-14 aryl group optionally substituted by a carboxyl group, (9) a carbamoyl group optionally substituted by a C_7-16 aralkyl optionally substituted by a carboxyl group or (10) an amino group optionally substituted by a C_7-16 aralkyl-carbonyl or a salt thereof.

12. The compound of claim 1, wherein X is an optionally substituted group represented by the formula —

(CH₂)_n—

X¹—

(CH₂)_m—

wherein X¹ is O, NR³ (R³ is a hydrogen atom or an optionally substituted lower alkyl group), SO₂ or CH₂, n and m are each an integer of 0 to 3 and n+m<

6 or a salt thereof.

13. The compound of claim 1, wherein X is an optionally substituted methylene group or a salt thereof.

14. The compound of claim 1, wherein ring C is an optionally substituted benzene ring or optionally substituted pyridine ring or a salt thereof,

16. A prodrug of the compound of claim 1 or a salt thereof.

17. A pharmaceutical agent comprising the compound of claim 1 or a salt thereof or a prodrug thereof.

18. A pharmaceutical agent of claim 17, which is an agent for the prophylaxis or treatment of osteoarthritis or rheumatoid arthritis.

19. A production method of the compound of claim 1 or a salt thereof, which comprises [1] reacting a compound represented by the formula

wherein L is a leaving group, and other symbols are as defined in claim 1, or a salt thereof, with a compound represented by the formula

wherein each symbol is as defined in claim 1, or a salt thereof, or

[2] reacting a compound represented by the formula

wherein L² is a leaving group, and other symbols are as defined in claim 1, or a salt thereof, with a compound represented by the formula R—

H wherein R is a substituent of ring B, or a salt thereof.

15. 4-[2-({6-fluoro-2-[({[3-(methoxy)phenyl]methyl}amino)carbonyl]-4-oxo-3,4-dihydroquinazolin-5-yl}oxy)ethyl]benzoic acid, 4-[({[2-({[(3-chloro-4- fluorophenyl)methyl]amino}carbonyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-5-yl]methyl}oxy)methyl]benzoic acid, 4-[({[2-({[(4-fluoro-3-methylphenyl)methyl]amino}carbonyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-5-yl]methyl}oxy)methyl]benzoic acid, 4-{[({2-[({[3-(methoxy)phenyl]methyl}amino)carbonyl]-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-5-yl}methyl)oxy]methyl}benzoic acid or a salt thereof.

20. A matrix metalloproteinase inhibitor comprising a compound represented by the formula

wherein Z is N or NR¹ (R¹ is a hydrogen atom or an optionally substituted hydrocarbon group), ring A′

is an optionally substituted, nitrogen-containing heterocycle, ring B′ and

ring C′

are each an optionally substituted homocycle or heterocycle, is a single bond or a double bond, R² is a hydrogen atom or an optionally substituted hydrocarbon group, and Y is a bond or an optionally substituted spacer having 1 to 6 atoms, or a salt thereof or a prodrug thereof.

21. The inhibitor of claim 20, wherein the matrix metalloproteinase is matrix metalloproteinase-13 (MMP-13).

22. A method of inhibiting a matrix metalloproteinase, which comprises administering, to a mammal, an effective amount of a compound represented the formula

wherein Z is N or NR¹ (R¹ is a hydrogen atom or an optionally substituted hydrocarbon group), ring A′

is an optionally substituted, nitrogen-containing heterocycle, ring B′ and

ring C′

are an optionally substituted homocycle or an optionally substituted heterocycle, is a single bond or a double bond, R² is a hydrogen atom or an optionally substituted hydrocarbon group, and Y is a bond or an optionally substituted spacer having 1 to 6 atoms, or a salt thereof or a prodrug thereof.

23. Use of a compound represented by the formula

wherein Z is N or NR¹ (R¹ is a hydrogen atom or an optionally substituted hydrocarbon group), ring A′

is an optionally substituted, nitrogen-containing heterocycle, ring B′ and

ring C′

are an optionally substituted homocycle or an optionally substituted heterocycle, is a single bond or a double bond, R² is a hydrogen atom or an optionally substituted hydrocarbon group, and Y is a bond or an optionally substituted spacer having 1 to 6 atoms, or a salt thereof or a prodrug thereof, for the production of a matrix metalloproteinase inhibitor.