Pyrazine amide compounds

Patent metadata

Field	Value
Publication number	US-9096548-B2
Application number	US-201414453642-A
Country	US
Kind code	B2
Filing date	Aug 7, 2014
Priority date	Aug 8, 2013
Publication date	Aug 4, 2015
Grant date	Aug 4, 2015

Abstract

The present invention relates to compounds of formula 1 or pharmaceutically acceptable salt thereof,

wherein R 1 , R 2 , R 3 , R 5 , R 4 , R 5 , R 6 and X − have the meanings as indicated in the specification, to their use as a medicament, to their use in the treatment of a disease selected from among respiratory diseases or complaints and allergic diseases of the airways, to pharmaceutical composition comprising at least one of said compound or a pharmaceutically acceptable salt thereof, as well as to medicament combinations containing one or more of said compounds or a pharmaceutically acceptable salt thereof.

First claim

What we claim:

1. A compound of formula 1,

wherein
R 6 is selected from H or C 1-4 -alkyl;
R 2 is selected from C 1-4 -alkyl;
R 3 is selected from C 1-4 -alkyl, optionally substituted with one or two groups selected from C 5-6 -cycloalkyl, indolyl, HO(O)C—, C 1-4 -alkyl-O(O)C—, C 5-6 -cycloalkyl-O(O)C—, aryl-O— optionally substituted with C 1-4 -alkyl-O—, aryl-C 1-4 -alkyl optionally substituted with C 1-4 -alkyl-O—, or aryl optionally substituted with one or two R 3.1 —, R 3.1 —O—, R 3.1 —CH 2 —, R 3.1 —CH 2 —O—, halogen or NC—, wherein
R 3.1 is selected independently from H, C 1-4 -alkyl, benzyl, HO(O)C—,
C 1-4 -alkyl-O(O)C—, HO—CH 2 —, C 1-4 -alkyl-O—CH 2 —, (C 1-4 -alkyl) 2 N—CH 2 —,
C 1-4 -alkyl-(O) 2 S, H[O—CH 2 —CH 2 ] n —, R 3.1.1 HN(O)C—, (R 3.1.1 ) 2 N(O)C—, R 3.1.2 HN(O)C— or (R 3.1.2 ) 2 N(O)C—, wherein
n is 3, 4 or 5,
R 3.1.1 is selected independently from H, H—[O—CH 2 —CH 2 ] 2 —, H—[O—CH 2 —CH 2 ] 3 — or a five-, six- or nine-membered heterocyclyl, wherein one, two or three elements are replaced by an element independently selected from N, O or S; each five-, six- or nine-membered heterocyclyl optionally substituted with one or two substituents independently selected from C 1-4 -alkyl-, HO—, HO—C 1-4 -alkyl- or O═ or two substituents R 3.1.1 together with the nitrogen atom they are bound to form a five-, six- or nine-membered heterocyclyl, wherein one or two further elements are replaced by an element independently selected from N, O or S; each five-, six- or nine-membered heterocyclyl is optionally substituted with one or two substituents independently selected from C 1-4 -alkyl, C 1-4 -alkyl-O— or O═, and R 3.1.2 is independently branched or unbranched C 1-4 -alkyl, optionally substituted with one or two substituents selected independently from O═, NC—, HO—, C 1-4 -alkyl-O—, (C 1-4 -alkyl) 2 N—, Cl(C 1-4 -alkyl) 3 N—, HO(O)C—, C 1-4 -alkyl-O(O)C—, HO(O) 2 S—, C 1-4 -alkyl-(O) 2 S—, C 1-4 -alkyl-(O) 2 S—, (C 1-4 -alkyl) 2 OP— or a five- or six-membered heterocyclyl or heteroaryl, wherein one or two elements are replaced by an element independently selected from N or O; each five- or six-membered heterocyclyl or heteroaryl being optionally substituted with one or two substituents independently selected from C 1-4 -alkyl or O═;

R 4 is selected from C 1-4 -alkyl, optionally substituted with one or two groups selected from C 5-6 -cycloalkyl, indolyl, HO(O)C—, C 1-4 -alkyl-O(O)C—,
C 5-6 -cycloalkyl-O(O)C—, aryl-O— optionally substituted with C 1-4 -alkyl-O—, aryl-C 1-4 -alkyl optionally substituted with C 1-4 -alkyl-O—, or aryl optionally substituted with one or two R 4.1 —, R 4.1 —O—, R 4.1 —CH 2 —,
R 4.1 —CH 2 —O—, halogen or NC—, wherein R 4.1 is selected independently from H, C 1-4 -alkyl, benzyl, HO(O)C—, C 1-4 -alkyl-O(O)C—, HO—CH 2 —, C 1-4 -alkyl-O—CH 2 —, (C 1-4 -alkyl) 2 N—CH 2 —, C 1-4 -alkyl-(O) 2 S, H—[O—CH 2 —CH 2 ] n —, R 4.1.1 HN(O)C—, (R 4.1.1 ) 2 N(O)C—, R 4.1.2 HN(O)C— or (R 4.1.2 ) 2 N(O)C—, wherein
n is 3, 4 or 5,
R 4.1.1 is selected independently from H, H—[O—CH 2 —CH 2 ] 2 —, H—[O—CH 2 —CH 2 ] 3 — or a five-, six- or nine-membered heterocyclyl, wherein one, two or three elements are replaced by an element independently selected from N, O or S; each five-, six- or nine-membered heterocyclyl being optionally substituted with one or two substituents independently selected from C 1-4 -alkyl-, HO—, HO—C 1-4 -alkyl-, O═ or two substituents R 4.1.1 together with the nitrogen atom they are bound to form a five-, six- or nine-membered heterocyclyl, wherein one or two further elements are replaced by an element independently selected from N, O or S; each five-, six- or nine-membered heterocyclyl being optionally substituted with one or two substituents independently selected from C 1-4 -alkyl-, HO—, HO—C 1-4 -alkyl-, O═, and R 4.1.2 is branched or unbranched C 1-4 -alkyl, optionally substituted with one or two substituents selected independently from O═, NC—, HO—, C 1-4 -alkyl-O—, (C 1-4 -alkyl) 2 N—, Cl(C 1-4 -alkyl) 3 N—, HO(O)C—, C 1-4 -alkyl-O(O)C—, HO(O) 2 S—, C 1-4 -alkyl-(O) 2 S—, C 1-4 -alkyl-(O) 2 S—, (C 1-4 -alkyl) 2 OP— or a five- or six-membered heterocyclyl or heteroaryl, wherein one or two elements are replaced by an element independently selected from N or O; each five- or six-membered heterocyclyl or heteroaryl being optionally substituted with one or two substituents independently selected from C 1-4 -alkyl or O═;

R 5 is H;
or R 1 and R 2 are together R 12 , wherein R 12 is selected from C 2-4 -alkylene each optionally partially or fully substituted with R 12.1 , wherein R 12.1 is selected from phenyl, optionally substituted with C 1-4 -alkyl;
or R 1 , R 2 and R 4 together with the atoms connecting them form an aza-bicyclo [2.2.2] octane;
or R 1 and R 5 are together —CH 2 —; and
X − is selected from chloride, bromide, iodide, hydroxide, hydrogensulfate, nitrate, formiate, acetate, trifluoroacetate, methanesulfonate or p-toluenesulfonate;
or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 wherein R 1 and R 2 are together R 12 and R 12 is selected from C 2-4 -alkylene each optionally partially or fully substituted with R 12.1 wherein R 12.1 is selected from phenyl, optionally substituted with C 1-4 -alkyl.

3. The compound according to claim 2 wherein R 1 and R 2 are together R 12 , wherein R 12 is selected from —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —CH 2 — each optionally partially or fully substituted with R 12.1 , wherein R 12.1 is selected from phenyl, optionally substituted with CH 3 —.

4. The compound according to claim 1 wherein R 1 , R 2 and R 4 together with the atoms connecting them form an aza-bicyclo[2.2.2]octane, wherein said compound is selected from compounds of formula (2)

wherein R 3 , R 5 , R 6 and X − are as defined in claim 1 .

5. The compound according to claim 1 wherein R 1 and R 5 are together —CH 2 —.

6. The compound according to claim 1 wherein R 6 is selected from H or CH 3 .

7. The compound according to claim 6 wherein R 6 is H.

8. The compound according to claim 1 wherein R 2 is selected from C 1-4 -alkyl.

9. The compound according to claim 8 wherein R 2 is CH 3 .

10. The compound according to claim 1 wherein R 3 is selected from C 1-4 -alkyl optionally substituted with one or two groups selected from C 5-6 -cycloalkyl, indolyl, HO(O)C—, C 1-4 -alkyl-O(O)C—CH 2 —, C 5-6 -cycloalkyl-O(O)C—CH 2 —, phenyl-O-optionally substituted with C 1-4 -alkyl-O—,
phenyl substituted with two halogen, phenyl optionally substituted with one R 3.1 —, R 3.1 —O—, R 3.1 —CH 2 —, R 3.1 —CH 2 —O—, halogen or NC—,
wherein R 3.1 is independently selected from H, C 1-4 -alkyl, benzyl, HO(O)C—,
C 1-4 -alkyl-O(O)C—, HO—CH 2 —, C 1-4 -alkyl-O—CH 2 —, (C 1-4 -alkyl) 2 N—CH 2 —, H—[O—CH 2 —CH 2 ] n —, R 3.1.1 HN(O)C—, (R 3.1.1 ) 2 N(O)C—, R 3.1.2 HN(O)C— or (R 3.1.2 ) 2 N(O)C—,
n is 3, 4 or 5,
R 3.1.1 is independently selected from H, H—[O—CH 2 —CH 2 ] 2 — or H—[O—CH 2 —CH 2 ] 3 — or a five or six-membered heterocyclyl selected from piperidinyl optionally substituted with C 1-4 -alkyl, pyrrolidinyl optionally substituted with one or two substituents selected independently from C 1-4 -alkyl or O═, tetrahydrofuranyl optionally substituted with C 1-4 -alkyl-O—, or tetrahydrothiophenyl optionally substituted with two O═, or
two substituents R 3.1.1 together with th

Assignees

• Wiedenmayer Dieter
• Heckel Armin
• Hamprecht Dieter
• Boehringer Ingelheim Int

Inventors

• Wiedenmayer Dieter
• Heckel Armin
• Hamprecht Dieter

Classifications

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P11/06

  Antiasthmatics · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D241/26 Primary

  with nitrogen atoms directly attached to ring carbon atoms · CPC title