2-Pyridone derivatives as neutrophil elastase inhibitors and their use

• US 20070043036A1
• Filed: 09/15/2004
• Published: 02/22/2007
• Est. Priority Date: 09/18/2003
• Status: Abandoned Application

• Current Assignee: Astrazeneca AB (Astrazeneca PLC)
• Original Assignee: Astrazeneca AB (Astrazeneca PLC)
• Inventors: Hansen, Peter, Lawitz, Karolina, Lonn, Hans, Nikitidis, Antonios
• Application Number:
  US10/572,640
• Publication Number:
  US 20070043036A1
• Time in Patent Office: Days
• US Class Current: 514/227.500
• 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 213/82 in position 3
• CPC Class Codes: C07D 213/85 in position 3
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond

Abstract

There are provided novel compounds of formula (I), wherein R¹, R², R⁴, R⁵, G¹, G², L, Y and n are as defined in the Specification and optical isomers, racemates and tautomers thereof, and pharmaceutically acceptable salts thereof; together with processes for their preparation, compositions containing them and their use in therapy. The compounds are inhibitors of neutrophil elastase.

Claims

1. A compound of formula (I)

wherein:

Y represents CR³ or N;

R¹ represents H or C1 to 6 alkyl;

R² represents;

i) CN, NO₂, OH, OSO₂R⁴⁷, O—

C2 to 6 alkanoyl, CO₂R⁴⁷, CHO or C2 to 6 alkanoyl;

or

ii) C1 to 6 alkoxy optionally substituted by OH, C1 to 6 alkoxy, CN, NR⁵⁴R⁵⁵, CONR⁵⁴R⁵⁵, OCOR⁴⁷ or one or more F atoms;

or

iii) C3 to 6 saturated or partially unsaturated cycloalkyl optionally further substituted by C1 to 6 alkyl;

or

iv) C4 to 7 saturated or partially unsaturated heterocyclic ring containing 1 to 3 heteroatoms independently selected from O, S(O)_m and NR⁶² optionally further substituted by C1 to 6 alkyl;

or

v) CONR⁴⁸R⁴⁹, CONR⁵⁰NR⁴⁸R⁴⁹, C(═

NOR⁵²)R⁵³, C(═

NH)NHOR⁵² or NR⁴⁸R⁴⁹;

or

vi) C2 to 6 alkenyl or C2 to 6 alkynyl;

said alkenyl or alkyl group being optionally further substituted by C1 to 6 alkoxy or phenyl or a five- or six-membered heteroaromatic ring containing 1 to 3 heteroatoms independently selected from O, S and N;

said phenyl or heteroaromatic ring being optionally further substituted by halogen, CN, C1 to 6 alkyl or C1 to 6 alkoxy;

or

vii) C1 to 6 alkyl substituted by one or more F atoms;

or

viii) C1 to 6 alkyl substituted by one or more groups selected from halogen, OH, oxo, azido, NR⁴⁸R⁴⁹, C1 to 6 alkoxy and C1 to 6 alkoxy substituted by one or more F atoms;

or

ix) C1 to 6 alkyl substituted by phenyl or a five- or six-membered heteroaromatic ring containing 1 to 3 heteroatoms independently selected from O, S and N;

said phenyl or heteroaromatic ring being optionally further substituted by halogen, CN, C1 to 6 alkyl or C1 to 6 alkoxy;

R⁴⁸ and R⁴⁹ independently represent H, OH, C1 to 6 alkoxy, C3 to 6 cycloalkyl, CHO, C2 to 6 alkanoyl, CO₂R⁵⁰, C(X)NR⁶³R⁶⁴ or C1 to 6 alkyl;

said alkyl being optionally further substituted by OH, C1 to 4 alkoxy, C3 to 6 cycloalkyl, CN or phenyl or a five- or six-membered heteroaromatic ring containing 1 to 3 heteroatoms independently selected from O, S and N;

said alkanoyl being optionally further substituted by CN;

X represent O or S;

or the group NR⁴⁸R⁴⁹ together represents a saturated or partially unsaturated 5 to 7 membered azacyclic ring optionally incorporating one further heteroatom selected from O, S and NR⁵⁶;

said azacyclic ring being optionally further substituted by one or more substituents selected from OR⁵⁷ and C1 to 4 alkyl;

said alkyl being optionally further substituted by OR⁵⁷;

R³ represents H or F;

G¹ represents phenyl or a five- or six-membered heteroaromatic ring containing 1 to 3 heteroatoms independently selected from O, S and N;

R⁵ represents H, halogen, C1 to 6 alkyl, CN, C1 to 6 alkoxy, NO₂, NR¹⁴R¹⁵, C1 to 3 alkyl substituted by one or more F atoms or C1 to 3 alkoxy substituted by one or more F atoms;

R¹⁴ and R¹⁵ independently represent H or C1 to 3 alkyl;

said alkyl being optionally further substituted by one or more F atoms;

n represents an integer 1, 2 or 3 and when n represents 2 or 3, each R⁵ group is selected independently;

R⁴ represents H or C1 to 6 alkyl;

said alkyl being optionally further substituted by OH or C1 to 6 alkoxy;

or R⁴ and L are joined together such that the group —

NR⁴L represents a 5 to 7 membered azacyclic ring optionally incorporating one further heteroatom selected from O, S and NR¹⁶;

said ring being optionally further substituted by C1 to 6 alkyl or NR⁶⁰R⁶¹;

said alkyl being optionally further substituted by OH;

L represents a bond, O, NR²⁹ or C1 to 6 alkyl;

said alkyl optionally incorporating a heteroatom selected from O, S and NR¹⁶; and

said alkyl being optionally further substituted by OH or OMe;

G² represents a monocyclic ring system selected from;

i) phenyl or phenoxy,

ii) a 5 or 6 membered heteroaromatic ring containing one to three heteroatoms independently selected from O, S and N,

iii) a C3 to 6 saturated or partially unsaturated cycloalkyl, or

iv) a C4 to 7 saturated or partially unsaturated heterocyclic ring containing one or two heteroatoms independently selected from O, S(O)_p and NR¹⁷ and optionally further incorporating a carbonyl group;

or

G represents a bicyclic ring system in which each of the two rings is independently selected from;

i) phenyl,

ii) a 5 or 6 membered heteroaromatic ring containing one to three heteroatoms independently selected from O, S and N,

iii) a C3 to 6 saturated or partially unsaturated cycloalkyl, or

iv) a C4 to 7 saturated or partially unsaturated heterocyclic ring containing one or two heteroatoms independently selected from O, S(O)_p and NR¹⁷ and optionally further incorporating a carbonyl group;

and the two rings are either fused together, or are bonded directly together or are separated by a linker group selected from O, S(O)_q or CH₂,

said monocyclic or bicyclic ring system being optionally further substituted by one to three substituents independently selected from CN, OH, C1 to 6 alkyl, C1 to 6 alkoxy, halogen, NR¹⁸R¹⁹, NO₂, OSO₂R³⁸, CO₂R²⁰, C(═

NH)NH₂, C(O)NR²¹R²², C(S)NR²³R²⁴, SC(═

NH)NH₂, NR³¹C(═

NH)NH₂, S(O)_sR²⁵, SO₂NR²⁶R²⁷, C1 to 3 alkoxy substituted by one or more F atoms and C1 to 3 alkyl substituted by SO₂R³⁹ or by one or more F atoms;

or

when L does not represent an bond, G² may also represent H;

at each occurrence, m, p, q, s and t independently represent an integer 0, 1 or 2;

R¹⁸ and R¹⁹ independently represent H, C1 to 6 alkyl, formyl, C2 to 6 alkanoyl, S(O)_tR³² or SO₂NR³³R³⁴;

said alkyl group being optionally further substituted by halogen, CN, C1 to 4 alkoxy or CONR⁴¹R⁴²;

R²⁵ represents H, C1 to 6 alkyl or C3 to 6 cycloalkyl;

said alkyl group being optionally further substituted by one or more substituents selected independently from OH, CN, CONR³⁵R³⁶, CO₂R³⁷, OCOR⁴⁰, C3 to 6 cycloalkyl, a C4 to 7 saturated heterocyclic ring containing one or two heteroatoms independently selected from O, S(O)_p and NR⁴³ and phenyl or a 5 or 6 membered heteroaromatic ring containing one to three heteroatoms independently selected from O, S and N;

said aromatic ring being optionally further substituted by one or more substituents selected independently from halogen, CN, C1 to 4 alkyl, C1 to 4 alkoxy, OH, CONR⁴⁴R⁴⁵, CO₂R⁴⁶, S(O)_sR⁶⁵ and NHCOCH₃;

R³² represents H, C1 to 6 alkyl or C3 to 6 cycloalkyl;

R¹⁶, R¹⁷, R²⁰, R²¹, R²², R²³, R²⁴, R²⁶, R²⁷, R²⁹, R³¹, R³³, R³⁴, R³⁵, R³⁶, R³⁷, R³⁸, R³⁹, R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁷, R⁵⁰, R⁵², R⁵³, R⁵⁴, R⁵⁵, R⁵⁶, R⁵⁷, R⁶⁰, R⁶¹, R⁶², R⁶³, R⁶⁴ and R⁶⁵ independently represent H or C1 to 6 alkyl;

and pharmaceutically acceptable salts thereof.

2. A compound of formula (I), according to claim 1, wherein Y represents CR³.

3. A compound of formula (I), according to claim 1 or claim 2, wherein G¹ represents phenyl.

4. A compound of formula (I), according to any one of claims 1 to 3, wherein R⁵ represents Cl, CH₃, CN or CF₃.

5. A compound of formula (I), according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, for use as a medicament.

6. A pharmaceutical formulation comprising a compound of formula (I), as defined in any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, optionally in admixture with a pharmaceutically acceptable diluent or carrier.

7. A method of treating, or reducing the risk of, a human disease or condition in which inhibition of neutrophil elastase activity is beneficial which comprises administering to a person suffering from or susceptible to such a disease or condition, a therapeutically effective amount of a compound of formula (I), as defined in any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

8. The use of a compound of formula (I) as defined in any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prophylaxis of human diseases or conditions in which inhibition of neutrophil elastase activity is beneficial.

9. The use of a compound of formula (I) as defined in any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prophylaxis of inflammatory diseases or conditions.

10. A process for the preparation of a compound of formula (I), as defined in any one of claims 1 to 4, and optical isomers, racemates and tautomers thereof and pharmaceutically acceptable salts thereof, which comprises:

a) reacting a compound of formula (II)

with a nucleophilic equivalent of R², such as Cu(I)CN, an alkyl vinyl ether, an organo-tin compound, an organo boronic acid, a terminal alkyne or an alcohol and carbon monoxide;

wherein R¹, R², R⁴, R⁵, Y, G¹, G², L and n are as defined in formula (I) and Hal represents a halogen atom, preferably bromo or iodo;

or

b) reacting a compound of formula (XV)

wherein R¹, R², R⁵, n, G¹ and Y are as defined in formula (I) and L¹ represents a leaving group,

with a compound of formula (IX) or a salt thereof

wherein R⁴, G² and L are as defined in formula (I);

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

or converting one compound of formula (I) into another compound of formula (I); and

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