Novel 6-substituted 2-aminopyridine derivatives

• US 20060194847A1
• Filed: 03/30/2004
• Published: 08/31/2006
• Est. Priority Date: 03/31/2003
• Status: Abandoned Application

• Current Assignee: Astrazeneca AB (Astrazeneca PLC)
• Original Assignee: Astrazeneca AB (Astrazeneca PLC)
• Inventors: Connolly, Stephen, Luker, Timothy, Cheshire, David
• Application Number:
  US10/551,494
• Publication Number:
  US 20060194847A1
• Time in Patent Office: Days
• US Class Current: 514/352
• 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: C07D 213/73 Unsubstituted amino or imino radicals

Abstract

There are provided novel compounds of formula (I) wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, L¹, L², L³ and Q are are as defined in the specification, and pharmaceutically acceptable salts thereof; together with processes for their preparation, compositions containing them and their use in therapy. The compounds are inhibitors of nitric oxide synthase and are thereby particularly useful in the treatment or prophylaxis of inflammatory disease and pain.

Claims

1. A compound of formula (I)

wherein

R¹, R² and R³ independently represent H, halogen, C1to 4 alkyl, C1to 4 alkoxy, CN, MeS(O)_m or NR¹⁰R¹¹;

said alkyl group being optionally further substituted by OH or one or more halogen atoms;

L¹ and L² independently represent a bond or CR¹²R¹³ wherein R¹² and R¹³ independently represent H or C1to 4 alkyl;

said alkyl being optionally further substituted by OH, C1to 2 alkoxy, CN or one or more halogen atoms;

L³ represents —

CH₂—

or a bond;

R⁴, R⁵, R⁶ and R⁷ independently represent H, C1to 6 alkyl, Ar¹ or Ar¹—

C1 to 4 alkyl;

or R⁴ and R⁵, or R⁶ and R⁷, may be joined together such that the group CR⁴R⁵ or the group CR⁶R⁷ represents a C3 to 6 cycloalkyl ring;

Q represents O, S(O)_n or NR¹⁶;

R¹⁶ represents H, C1 to 6 alkyl, C1 to 6 alkanoyl, C1 to 6 alkyl-SO₂—

,

C1 to 6 alkyl-O—

CO—

, Ar² or Ar²—

CH₂—

;

Ar¹ and Ar² independently represents phenyl or a 5- or 6-membered heteroaromatic ring containing one to three heteroatoms independently selected from O, S and N;

said phenyl or heteroaromatic ring being optionally substituted by one or more substituents independently selected from halogen, CN, CF₃, C1to 3 alkyl, C1to 3 alkoxy, hydroxy, C1to 3 thioalkoxy or NR¹⁴R¹⁵;

m and n independently represent an integer 0, 1 or 2;

R⁸ represents H or C1to 4 alkyl;

said alkyl being optionally further substituted by OH, C1to 2 alkoxy, CN or one or more halogen atoms;

R⁹ represents H or C1 to 4 alkyl;

R¹⁰ and R¹¹ independently represent H, C1to 2 alkyl, C1to 2 alkanoyl or C1to 2 alkylsulfonyl;

R¹⁴ and R¹⁵ independently represent H, C1to 4 alkyl, C1to 2 alkylsulfonyl or C1 to 4 alkanoyl;

said alkyl being optionally further substituted by OH, C1to 2 alkoxy, CN or one or more halogen atoms;

and pharmaceutically acceptable salts thereof

2. A compound according to claim 1 wherein Q represents S.

3. A compound of formula (I), according to claim 1, which is:

S-[(6-amino-4-methyl-2-pyridinyl)methyl]-L-cysteine;

S-[2-(6-amino-4-methyl-2-pyridinyl)ethyl]-L-cysteine;

S-[(6-amino-4-methyl-2-pyridinyl)methyl]-L-homocysteine;

S-[(6-amino-4-methyl-2-pyridinyl)methyl]-2-methyl-L-cysteine;

(3R)-S-[(6-amino-4-methyl-2-pyridinyl)methyl]-3-methyl-L-cysteine;

O-[(6-amino-4-methyl-2-pyridinyl)methyl]-L-serine;

O-[(6-amino-4-methyl-2-pyridinyl)methyl]-D-serine;

3-[[(6-amino-4-methyl-2-pyridinyl)methyl](methylsulfonyl)amino]-L-alanine;

3-[[(6-amino-4-methyl-2-pyridinyl)methyl]amino]-L-alanine;

(3S)-S-[(6-amino-4-methyl-2-pyridinyl)methyl]-3-methyl-L-cysteine;

or a pharmaceutically acceptable salt thereof.

5. A pharmaceutical composition comprising a compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

13. A method of treating, or reducing the risk of, a human disease or condition in which inhibition of nitric oxide synthase activity is beneficial which comprises administering a therapeutically effective amount of a compound of formula (I), as defined in claim 1, or a pharmaceutically acceptable salt thereof, to a person suffering from, or at increased risk of, said disease or condition.

14. A method of treating, or reducing the risk of, inflammatory disease in a person suffering from, or at risk of, said disease, wherein the method comprises administering to the person a therapeutically effective amount of a compound of formula (I), as defined in claim 1, or a pharmaceutically acceptable salt thereof.

15. A process for the preparation of a first compound of formula (I), as defined in claim 1, or a pharmaceutically acceptable salt, enantiomer or racemate thereof, wherein the process comprises:

(a) reaction of a compound of formula (II)

wherein LG represents a leaving group,

with a compound of formula (III)

or

(b) reaction of a compound of formula (IV)

with a compound of formula (V)

wherein LG is a leaving group;

or

(c) when Q represents S, reacting a compound of formula (VI)

with a compound of formula (VII)

under Mitsunobu conditions;

wherein the variable groups shown above are, unless otherwise specified, as defined in claim 1;

and where desired or necessary converting the first compound of formula (I), or another salt thereof, into a pharmaceutically acceptable salt thereof;

or converting the first compound of formula (I) into a second compound of formula (I); and

where desired converting the first compound of formula (I) into an optical isomer thereof.

16. The method as claimed in claim 13, wherein it is predominantly inducible nitric oxide synthase that is inhibited.

17. The method as claimed in claim 14, wherein the disease is rheumatoid arthritis.

18. The method as claimed in claim 14, wherein the disease is osteoarthritis.

19. A method for the treatment or prophylaxis of pain, comprising administering a therapeutically effective amount of a compound of formula (I), as defined in claim 1, or a pharmaceutically acceptable salt thereof.

20. A method for the treatment or prophylaxis of inflammatory disease, comprising administering a therapeutically effective amount of a compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable salt thereof, in combination with a COX-2 inhibitor.

4. (canceled)

6-12. -12. (canceled)