Substituted 4-pyridones and their use as inhibitors of neutrophil elastase activity

• US RE46,630 E1
• Filed: 09/18/2015
• Issued: 12/12/2017
• Est. Priority Date: 08/23/2012
• Status: Active Grant

• Current Assignee: Boehringer Ingelheim Pharma GmbH & Company Kg (C.H. Boehringer Sohn AG & Co. KG)
• Original Assignee: Boehringer Ingelheim Pharma GmbH & Company Kg (C.H. Boehringer Sohn AG & Co. KG)
• Inventors: Oost, Thorsten, Fiegen, Dennnis, Gnamm, Christian, Handschuh, Sandra, Peters, Stefan, Roth, Gerald Juergen
• Primary Examiner(s): KUNZ, GARY L
• Application Number:
  US14/858,408
• Time in Patent Office: 816 Days
• CPC Class Codes: C07D 213/80 in position 3
• CPC Class Codes: C07D 213/82 in position 3
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• 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 409/12 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 493/08 Bridged systems

Abstract

This invention relates to substituted 4-pyridones of formula 1

and their use as inhibitors of neutrophil elastase activity, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and/or prevention of pulmonary, gastrointestinal and genitourinary diseases, inflammatory diseases of the skin and the eye and other auto-immune and allergic disorders, allograft rejection, and oncological diseases.

Claims

1. A compound of formula 1

2. A compound of formula 1, according to claim 1, wherein

R¹ is H₂N—

, R^1.1HN—

, R^1.2HN—

, H(O(CH₂)₂)₃—

HN—

;

R^1.1 is C_3-6-cycloalkly or a four-, five- or six-membered, non-aromatic heteroring, wherein one or two elements are replaced by an element selected independent from each other from the group consisting of N, O, S, (O)S and (O)₂S;

wherein each element of one of the above mentioned rings is optionally substituted with a residue selected from the group consisting of HO—

, O═

, C_1-4-alkyl-, C_1-4-cycloalkyl-, NC—

;

R^1.2 is a branched or unbranched C_1-4-alkyl-, optionally substituted independently from each other with one, two or three residues selected from the group consisting of

—

HO—

, F, NC—

, C_1-4-alkyl-O—

, (C_1-4-alkyl)₂-N—

, C_1-4-alkyl-O(O)C—

, HO(O)C—

, (C_1-4-alkyl)₂-N(O)C—

, (C_1-4-alkyl)-(O)S—

, (C_1-4-alkyl)-(O)₂S—

;

a ring selected from C_3-6-cycloalkly, phenyl, a five- or six-membered, aromatic or non-aromatic heteroring, wherein one, two or three elements are replaced by an element selected independent from each other from the group consisting of N, (O⁻

)—

N⁺ and O;

wherein each element of one of the above mentioned rings is optionally substituted with a residue selected from the group consisting of O═

, halogen, C_1-4-alkyl-, C_1-4-haloalkyl-, C_3-6-cycloalkyl-, HO—

, C_1-4-alkyl-O—

, NC—

, C_1-4-alkyl-S—

, C_1-4-alkyl-(O)S—

, C_1-4-alkyl-(O)₂S—

, Me₂N—

CH₂—

(O)C—

;

R² is R^2.1R^2.2R^2.3C—

;

R^2.1 is phenyl or a five- or six-membered, aromatic heteroring, wherein one or two elements are replaced by an element selected independent from each other from the group consisting of N, O and S;

wherein one or two elements of one of the above mentioned rings are optionally substituted with a residue selected from the group consisting of halogen, NC—

, C_1-4-alkyl-, C_1-4-haloalkyl-, C_1-4-alkyl-O—

, C_1-4-alkyl-(O)₂S—

, C_3-6cycloalkyl-(O)₂S—

;

R^2.2 is H or C_1-4-alkyl-;

R^2.3 is H or C_1-4-alkyl-;

R³ is C_1-4-alkyl-;

R⁴ is phenyl or a six-membered, aromatic heteroring, wherein one or two elements are replaced by N;

wherein one or two elements of one of the above mentioned rings are substituted with a residue selected from the group consisting of C_1-4-alkyl-, C_1-4-haloalkyl-, halogen;

R⁵ is H;

or a salt thereof.

3. A compound of formula 1, according to claim 1, wherein

R¹ is H₂N , R^1.1HN—

, R^1.2HN—

, H(O(CH₂)₂)₃—

HN—

;

R^1.1 is cyclopropyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidin-2-onyl, piperidin-2-onyl, tetrahydrothiophen-1,1-dioxidyl, each optionally substituted with methyl, HO—

or NC—

;

R^1.2 is a branched or unbranched C_1-4-alkyl-, optionally substituted independently from each other with one, two or three residues selected from the group consisting of

HO—

, F, NC—

, C_1-4-alkyl-O—

, (C_1-4-alkyl)₂-N—

, C_1-4-alkyl-O(O)C—

, HO(O)C—

, (C_1-4-alkyl)₂-N (O)C—

, C_1-4-alkyl-(O)S—

, C_1-4-alkyl-(O)₂S—

;

a ring selected from C_3-6-cycloalkly, phenyl, a five- or six-membered, aromatic or non-aromatic heteroring, wherein one, two or three elements are replaced by an element selected independent from each other from the group consisting of N, (O⁻

)—

N⁺ and O;

wherein each element of one of the above mentioned rings is optionally substituted with a residue selected from the group consisting of O═

, halogen, C_1-4-alkyl-, C_1-4-haloalkyl-, C_3-6-cycloalkyl-, HO—

, C_1-4-alkyl-O—

, NC—

, C_1-4-alkyl-S—

, C_1-4-alkyl-(O)S—

, C_1-4-alkyl-(O)₂S—

, Me₂N—

CH₂—

(O)C—

;

R² is R^2.1R^2.2R^2.3C—

;

R^2.1 is phenyl, a five- or six-membered, aromatic heteroring, wherein one or two elements are replaced by an element selected independent from each other from the group consisting of N, O and S;

wherein one or two elements of one of the above mentioned rings are substituted with a residue selected from the group consisting of halogen, NC—

, C_1-4-alkyl-, C_1-4-haloalkyl-, C_1-4-alkyl-(O)—

, C_1-4-alkyl-(O)₂S—

, C_3-6-cycloalkyl-(O)₂S—

;

R^2.2 is H or C_1-4-alkyl-;

R^2.3 is H or C_1-4-alkyl-;

R³ is C_1-4-alkyl-;

R⁴ is phenyl or pyridinyl, substituted with C_1-4-haloalkyl-;

R⁵ is H;

or a salt thereof.

4. A compound of formula 1, according to claim 1, wherein

R¹ is H₂N—

, R^1.1HN—

, R^1.2HN—

, H(O(CH₂)₂)₃—

HN—

;

R^1.1 is cyclopropyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidin-2-onyl, piperidin-2-onyl, tetrahydrothiophen-1,1-dioxidyl, each optionally substituted with methyl, HO—

or NC—

;

R^1.2 is a branched or unbranched C_1-4-alkyl-, optionally substituted independently from each other with one or two residues selected from the group consisting of

HO—

, MeO—

, EtO—

, Me₂N—

, MeO(O)C—

, Me₂N(O)C—

, Me(O)S—

, Me(O)₂S—

;

oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, dioxanyl, morpholinyl, imidazolidin-2-onyl, pyrrolidin-2-onyl, pyridin-2-onyl;

azetidinyl, pyrrolidinyl, piperidinyl, optionally substituted with methyl, Me₂N—

CH₂—

(O)C—

;

phenyl, thiophenyl, pyridinyl, pyridazinyl, pyrid-2-onyl pyridin-1-oxidyl, each optionally substituted with methyl, MeO—

, H₃C(O)S—

, H₃C(O)₂S—

;

imidazolyl, pyrazolyl, oxadiazolyl, isoxazolyl each optionally substituted with methyl;

R² is R^2.1R^2.2R^2.3C—

;

R^2.1 is phenyl, pyridinyl, each optionally substituted with one residue selected from the group consisting of NC—

, F—

, Cl—

in para-position and optionally another residue selected from the group consisting of Cl—

, F—

, MeO—

, Me(O)₂S—

;

R^2.2 is H;

R^2.3 is H or methyl;

R³ is methyl;

R⁴ is phenyl or pyridinyl, each substituted with a residue selected from the group consisting of Me, Cl—

, F₂HC—

, F₃C—

;

R⁵ is H;

or a salt thereof.

5. A compound of formula 1, according to claim 1, wherein

R¹ is R^1.1HN—

, R^1.2HN—

;

R^1.1 is cyclopropyl or oxetanyl;

wherein each element of one of the above mentioned rings is optionally substituted with NC—

;

R^1.2 is methyl or ethyl, optionally substituted independently from each other with one or two residues selected from the group consisting of halogen, NC or oxadiazolyl, substituted with methyl;

R² is R^2.1R^2.2R^2.3C—

;

R^2.1 is phenyl or pyridinyl;

wherein each element of one of the above mentioned rings is optionally substituted with a residue selected from the group consisting of NC—

;

R^2.2 is methyl;

R^2.3 is H;

R³ is methyl;

R⁴ is phenyl or pyridinyl;

wherein each element of one of the above mentioned rings is optionally substituted with a residue selected from the group consisting of FH₂C—

, F₂HC—

, F₃C—

;

R⁵ is H;

or a salt thereof.

6. A pharmaceutical composition comprising a compound of formula 1 according to claim 1 or a pharmaceutically active salt thereof and a pharmaceutically acceptable carrier.

7. A compound according to claim 1, wherein the compound is Example 2.3 having the following structure:

8. A compound according to claim 1, wherein the compound is Example 2.5 having the following structure:

9. A compound according to claim 1, wherein the compound is Example 2.8 having the following structure:

10. A compound according to claim 1, wherein the compound is Example 2.9 having the following structure:

11. A compound according to claim 1, wherein the compound is Example 2.12 having the following structure:

12. A compound according to claim 1, wherein the compound is Example 4.1 having the following structure:

13. A compound according to claim 1, wherein the compound is Example 4.7 having the following structure:

14. A compound according to claim 1, wherein the compound is Example 4.9 having the following structure:

15. A compound according to claim 1, wherein the compound is Example 4.10 having the following structure:

16. A compound according to claim 1, wherein the compound is Example 6.8 having the following structure:

17. A compound according to claim 1, wherein the compound is Example 6.10 having the following structure:

18. A compound according to claim 1, wherein the compound is Example 6.11 having the following structure:

19. A compound according to claim 1, wherein the compound is Example 7.18 having the following structure:

20. A compound according to claim 1, wherein the compound is Example 11 having the following structure:

21. A compound according to claim 1, wherein the compound is Example 14 having the following structure:

22. A compound according to claim 1, wherein the compound is Example 39 having the following structure:

23. A compound according to claim 1, wherein the compound is Example 40 having the following structure:

24. A compound according to claim 1, wherein the compound is Example 41 having the following structure: