Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity

Patent metadata

Field	Value
Publication number	US-9458113-B2
Application number	US-201514809314-A
Country	US
Kind code	B2
Filing date	Jul 27, 2015
Priority date	Jul 31, 2014
Publication date	Oct 4, 2016
Grant date	Oct 4, 2016

Abstract

Substituted dihydropyrimidinones of formula 1

which are neutrophil elastase inhibitors and useful as medicaments for the treatment of, inter alia, COPD. Exemplary is

First claim

What we claim:

1. A compound of formula 1

wherein
R 1 is selected from the group consisting of
CO—R 1.1 , R 1.11 and —CH 2 —R 1.12
R 1.1 is selected from the group consisting of
—NH 2 , —NH—C 1-4 -alkyl, —NH—R 1.6 , —NH—CH 2 —R 1.6 , —NH—CH(CH 3 )—R, 1.9 —NH—CH 2 —CH 2 —R 1.4 , —NH—CH 2 —CH 2 —CH 2 —R 1.7 , —N(CH 3 )—CH 2 —CH 2 —CH 2 —R 1.8 , —N(C 1-3 -alkyl) 2 , —N(C 3-6 -cycloalkyl)(C 1-3 -alkyl), —N(CH 3 )—CH 2 —CH 2 —R 1.5 , —N(CH 3 )—CH 2 —R 1.10 —NH—R 1.2 , R 1.3 , —OH, —OCH 3 and —NH—CH 2 —C≡CH,
R 1.2 is selected from the group consisting of
C 3-6 -cycloalkyl and 4- to 6 membered heterocyclic ring containing one, two, three or four heteroatoms independently selected from among N, O and S, each ring optionally substituted by one or two C 1-3 alkyl, —NH2, —OH or ═O,

R 1.3 denotes a 4- to 10-membered heterocyclic or heteroaryl ring, containing one, two, three or four heteroatoms independently selected from among N and O, each of the rings optionally substituted with one or two substituents independently selected from among morpholinyl, —NHCOCH 3 , —N(CH 3 )COCH 3 , —COCH 3 , —OH, —NH 2 , —N(CH 3 ) 2 and C 1-3 alkyl,
R 1.4 , R 1.5 are independently selected from the group consisting of morpholinyl, —NH 2 , —OH, F, —N(CH 3 ) 2 , —O—CH 3 and —SO 2 —CH 3 ,
R 1.6 , R 1.9 , R 1.10 are independently selected from the group consisting of —CO-morpholinyl, —CN, —CF 3 , —CHF 2 , —C(CH 3 ) 2 OH, —C(CH 3 ) 2 NH 2 and —C(CH 3 ) 2 CN
or are independently selected from the group consisting of
phenyl and a 4- to 10-membered heterocyclic or heteroaryl ring, containing one to four heteroatoms independently selected from among N and O, each of the rings optionally substituted with C 1-3 alkyl or CN,
R 1.7 is —OH or —O—CH 3 ,
R 1.8 is —O—CH 3 ,
R 1.11 denotes a 5- to 10-membered heterocyclic or 5- to 10-membered heteroaryl ring, containing one to four heteroatoms independently selected from among N, O and S, each of the rings optionally substituted with a group independently selected from among C 1-3 alkyl, C 1-3 -cycloalkyl, OH, ═O, —COO—C 1-4 -alkyl, —O—C 1-3 -alkyl, —O—C 1-3 -cycloalkyl, —CN, halogen, —CO—C 1-3 -alkyl, —CO—C 1-3 -cycloalkyl and —N(CH 3 ) 2 ,
R 1.12 is selected from the group consisting of, —NH—R 1.13 , —N(CH 3 )—R 1.13 , and
a 5- to 6-membered N-containing heterocyclic ring, bound via N-atom to the —CH 2 —, optionally containing additional to the N-atom one to 3 heteroatoms independently selected from among N, O and S, each of the rings optionally substituted with a group independently selected from among C 1-3 alkyl, C 1-3 -cycloalkyl, OH, ═O, —COO—C 1-4 -alkyl, —O—C 1-3 alkyl, —O—C 1-3 -cycloalkyl, —CN, halogen, —CO—C 1-3 -alkyl and —CO—C 1-3 -cycloalkyl, —N(CH 3 ) 2 ,

R 1.13 denotes a group selected from among C 3-6 -cycloalkyl, C 1-4 -alkyl, each optionally substituted by a group selected from among halogen and OH, and
a 6-membered heterocyclic ring, containing one to four heteroatoms independently selected from among N, O and S, optionally substituted by a group selected from among halogen, —OCH 3 and OH,

n is 1 or 2,

R 2 is phenyl or pyridinyl, each substituted with CF 3 , —CHF 2 , C 1-4 alkyl and halogen
R 3 is selected from the group consisting of R 3.1 , R 3.1 —CO—, R 3.1 —O—CO—, R 3.1 SO 2 —, R 3.1 R 3.2 N—CO— and R 3.1 R 3.2 N—CO—CH 2 —,
R 3.1 is selected from the group consisting of H, —C 1-4 alkyl, —C 3-6 cycloalkyl, -4-haloalkyl and —C 3-6 -halocycloalkyl,
each optionally substituted with one substituent independently selected from the group consisting of OH, CN, NH 2 , (C 1-4 -alkyl)NH—, (C 1-4 -alkyl)(C 1-4 -alkyl)N—, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, N—C 1-4 -alkyl-piperazinyl, C 1-4 -alkoxy, oxetanyl, tetrahydrofuranyl and tetrahydropyranyl;

R 3.2 is selected from the group consisting of H and C 1-4 -alkyl;
or,
in case R 3 is selected from the group consisting of R 3.1 R 3.2 N—CO— and R 3.1 R 3.2 N—CO—CH 2 —,
R 3.2 and R 3.1 may form, together with the nitrogen atom to which they are bound, a ring independently selected from the group consisting of azetidine, pyrrolidine, piperidine, piperazine and N—C 1-4 -alkyl-piperazine

or a pharmaceutically acceptable salt thereof.

2. A compound of formula 1 according to claim 1 , wherein
R 1 is selected from the group consisting of —CO—R 1.1 , R 1.11 and —CH 2 —R 1.12 ,
R 1.1 is selected from the group consisting of
—NH 2 , —NH—C 1-4 -alkyl, —NH—CH 2 —R 1.6 , —NH—CH(CH 3 )—R 1.9 , —NH—CH 2 —CH 2 —R 1.4 , —NH—CH 2 —CH 2 —CH 2 —R 1.7 , —NH—CH 2 —CH 2 —CH 2 —R 1.8 , —N(C 1-3 -alkyl) 2 , —N(CH 3 )—CH 2 —CH 2 —R 1.5 , —N(CH 3 )—CH 2 —R 1.10 , —NH—R 1.2 , R 1.3 , —OH, —OCH 3 and —NH—CH 2 —C≡CH,
R 1.2 is selected from the group consisting of
C 3-6 -cycloalkyl and 4- to 6 membered heterocyclic ring containing one, two, three or four heteroatoms independently selected from among N, O and S, each ring optionally substituted by C 1-3 alkyl, —OH or ═O,

R 1.3 denotes a 4- to 6-membered heterocyclic or heteroaryl ring, containing one, two or three heteroatoms independently selected from among N and O, each of the rings optionally substituted with one or two substituents independently selected from among morpholinyl, —NHCOCH 3 , —N(CH 3 )COCH 3 , —COCH 3 , —OH, —NH 2 ,
—N(CH 3 ) 2 and C 1-3 alkyl,

R 1.4 is selected from the group consisting of
morpholinyl, —NH 2 , —OH, F, —NH—CH 3 , —N(CH 3 ) 2 , —O—CH 3 and —SO 2 —CH 3 ,

R 1.5 is selected from the group consisting of
morpholinyl, —NH 2 , —OH and —NH—CH 3 ,

R 1.6 , R 1.9 , R 1.10 are independently selected from the group consisting of —CO-morpholinyl, —CN, —CF 3 , CHF 2 , —C(CH 3 ) 2 OH and —C(CH 3 ) 2 NH 2
or are independently selected from the group consisting of phenyl and a 4- to 6-membered heterocyclic or heteroaryl ring, containing one, to four heteroatoms independently selected from among N and O, each of the rings optionally substituted with C 1-3 alkyl or CN,
R 1.7 is —OH or —O—CH 3 ,
R 1.8 is —O—CH 3 ,
R 1.11 denotes a 5- to 6-membered heterocyclic or 5- to 6-membered heteroaryl ring, containing one to four heteroatoms independently selected from among N, O and S, each of the rings optionally substituted with a group independently selected from among C 1-3 alkyl, ═O and —COO—C 1-4 -alkyl,
R 1.12 is selected from the group consisting of —NH—C 1-4 -alkyl, —NH—R 1.13 and
a 6-membered N-containing heterocyclic ring, bound via N-atom to the —CH 2 —, optionally containing additional to the N-atom 1 to 3 heteroatoms independently selected from among N, O and S,
R 1.13 denotes a 6-membered heterocyclic ring, containing one to four heteroatoms independently selected from among N, O and S,

n is 1 or 2

R 2 is phenyl or pyridinyl, each substituted with CF 3 or CHF 2 ,
R 3 is H or methyl
or a pharmaceutically acceptable salt thereof.

3. A compound of formula 1 according to claim 1 , wherein
R 1 is selected from the group consisting of
—CO—R 1.1 , R 1.11 and —CH 2 —R 1.12 ,
R 1.1 is selected from the group consisting of
—NH 2 , —NH—C 1-4 -alkyl, —NH—R 1.6 —NH—CH 2 —R 1.6 , —NH—CH(CH 3 )—R 1.9 , —NH—CH 2 —CH 2 —R 1.4 , —NH—CH 2 —CH 2 —CH 2 —R 1.7 , —NH—CH 2 —CH 2 —CH 2 —R 1.8 , —N(CH 3 )—CH 2 —CH 2 —CH 2 —R 1.8 , —N(CH 3 ) 2 —N(CH 3 )—CH 2 —CH 2 —R 1.5 , —N(CH 3 )—CH 2 —R 1.10 , —NH—R 1.2 , R 1.3 , —OH, —OCH 3 and —NH—CH 2 —C≡CH,
R 1.2 is selected from the group consisting of
Formulas a.1 to a.14

R 1.3 is selected from the group consisting of formulas b.1 to b.37

Assignees

• Boehringer Ingelheim Int

Inventors

• Peters Stefan
• Anderskewitz Ralf
• Gnamm Christian
• Hoesch Holger
• Morschhaeuser Gerd
• Oost Thorsten
• Ries Uwe Joerg

Classifications

• A61P37/08

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

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title