Quinoline derivatives as neutrophil elastase inhibitors and their use

• US 20070010551A1
• Filed: 08/25/2004
• Published: 01/11/2007
• Est. Priority Date: 08/28/2003
• Status: Abandoned Application

• Current Assignee: Astrazeneca AB (Astrazeneca PLC)
• Original Assignee: Astrazeneca AB (Astrazeneca PLC)
• Inventors: Larsson, Joakim, Bladh, Hakan
• Application Number:
  US10/569,571
• Publication Number:
  US 20070010551A1
• Time in Patent Office: Days
• US Class Current: 514/312
• 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 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/04 for non-specific disorders of the connective tissue
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• 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 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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: C04B 35/632 Organic additives
• CPC Class Codes: C07D 215/54 attached in position 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 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links

Abstract

There are provided novel compounds of formula (I) wherein R¹, R³, R⁴, R⁵, G¹, G², L 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

R¹ represents H, halogen, CN, C1 to 6 alkyl, C1 to 6 alkoxy, CO₂R⁷ or CONR⁸R⁹;

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;

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

said alkyl being 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

G² 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 a bond, G² may also represent H;

p, q, s and t independently represent an integer 0, 1 or 2;

R⁸ and R⁹ independently represent H or C1 to 6 alkyl;

or the group NR⁸R⁹ together represents a 5 to 7 membered azacyclic ring optionally incorporating one further heteroatom selected from O, S and NR²⁸;

R¹⁸ and R¹⁹ independently represent H, C1 to 6 alkyl, formyl, C2 to 6 alkanoyl, S(O)_tR³ 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)_sR²⁵ or NHCOCH₃;

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

R⁷, R¹⁶, R¹⁷, R²⁰, R²¹, R²², R²³, R²⁴, R²⁶, R²⁷, R²⁸, R²⁹, R³¹, R³³, R³⁴, R³⁵, R³⁶, R³⁷, R³⁸, R³⁹, R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁴, R⁴⁵ and R⁴⁶ independently represent H or C1 to 6 alkyl;

and pharmaceutically acceptable salts thereof.

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

3. A compound of formula (I), according to claim 1, wherein R⁴ represents H.

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

6. A pharmaceutical formulation comprising a compound of formula (I), as defined in claim 1 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 claim 1, or a pharmaceutically acceptable salt thereof.

9. A method of treating or preventing an inflammatory disease or condition, the method comprising administering a therapeutically effective amount of a compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable salt thereof.

10. A process for the preparation of a compound of formula (I), as defined in claim 1, and optical isomers, racemates and tautomers thereof and pharmaceutically acceptable salts thereof, which comprises reacting a compound of formula (II)

wherein R¹, R³, R⁵, G¹ and n are as defined in claim 1 and L¹ represents a leaving group, with an amine of formula (III) or a salt thereof

wherein R⁴, G² and L are as defined in claim 1,

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.

5. (canceled)

8. (canceled)