Tertiary amines, medicaments containing said amines, use thereof and processes for the preparation thereof

Patent metadata

Field	Value
Publication number	US-9078909-B2
Application number	US-201313899762-A
Country	US
Kind code	B2
Filing date	May 22, 2013
Priority date	May 25, 2012
Publication date	Jul 14, 2015
Grant date	Jul 14, 2015

Abstract

The present invention relates to compounds of general formula (I)

and the tautomers and the salts thereof, particularly the pharmaceutically acceptable salts thereof with inorganic or organic acids and bases, which have valuable pharmacological properties, particularly an inhibitory effect on epithelial sodium channels, the use thereof for the treatment of diseases, particularly diseases of the lungs and airways.

First claim

The invention claimed is:

1. A compound of formula (I),

characterized in that
X denotes Cl or Br,
R 1 denotes H or methyl,
m and n denote 1,
R 2 denotes H or is selected from the group consisting of
methyl, —C(O)OR 2.1 and —C(O)NR 2.2 R 2.3 ,
wherein,
R 2.1 denotes H or is selected from the group consisting of optionally substituted C 1-8 -alkyl-, optionally substituted C 3-8 -cycloalkyl- and optionally substituted phenyl-C 1-4 -alkyl-,
R 2.2 , R 2.3 independently from each other denote H or are selected from the group consisting of optionally substituted C 1-8 -alkyl-, optionally substituted C 3-8 -cycloalkyl- and optionally substituted —C 1-4 -alkyl-C 6-10 -aryl,

R 3 denotes H or is selected from the group consisting of
—CN, —C 1-4 -alkyl-non aromatic heterocycle, —CH 2 —O—(C 2 H 4 —O) q —CH 3 ,
—CH 2 —O—(C 2 H 4 —O) q —H, —PO(OR 3.4 )(O—R 3.5 ), —C 1-4 -alkyl-S(O) 2 OH, —C 1-4 -alkyl-S(O) r —C 1-6 -alkyl, —C 1-4 -alkyl-COOH, —C 1-4 -alkyl-C(O)OR 3.8 ,
C 1-8 -alkyl, optionally substituted C 3-8 -cycloalkyl-, R 3.1 —OC(O)—, R 3.2 N(R 3.3 )C(O)—, optionally substituted C-linked-nonaromatic heterocycle-C 1-3 -alkyl, and —(CH 2 ) p —NR 3.6 R 3.7 ,
wherein,
p is 1, 2, 3 or 4,
q is 1, 2, 3 or 4,
r is 0, 1 or 2,
R 3.1 is selected from the group consisting of H, optionally substituted C 1-8 -alkyl-, optionally substituted C 3-8 -cycloalkyl-, hydroxyethoxy-C 2-4 -alkyl-, methoxyethoxy-C 2-4 -alkyl-, —C 1-4 -alkyl-S(O) s —C 1-4 -alkyl, optionally substituted phenyl-C 1-2 -alkyl-, optionally substituted heteroaryl-C 1-2 -alkyl-, C-linked 5-7-membered nonaromatic heterocycle, and 5-7-membered nonaromatic heterocycle-C 1-4 -alkyl-
R 3.1 , R 3.3 independently from each other denote H or are selected from the group consisting of optionally substituted C 1-8 -alkyl-, optionally substituted C 3-8 -cycloalkyl-, —C 2-8 -alkyl-O—C 1-4 -alkyl, hydroxy-C 2-4 -alkyl-, methoxyethoxy-C 2-4 -alkyl-,
—C 1-8 -alkyl-S(O) s —C 1-6 -alkyl, —CH 2 —COOH, —CH 2 —COO—C 1-4 -alkyl, —CH 2 —CO—NH—C 1-4 -alkyl, —C 1-4 -alkyl-5-to 7-membered nonaromatic heterocycle-R 3.3.3 , —C 1-4 -alkyl-5-to 7-membered heteroaryl-R 3.3.4 , -5- to 8-membered nonaromatic heterocycle-R 3.3.5 , -5-to 7-membered heteroaryl-R 3.3.6 ,
optionally substituted —C 1-4 -alkyl-phenyl-R 3.3.1 and
optionally substituted -phenyl-R 3.3.2 ,
wherein
s is 0, 1 or 2
R 3.3.1 denotes H or is selected from the group consisting of
—COOH, —COO—C 1-4 -alkyl, —O—C 1-4 -alkyl, —S—CF 3 , —SO 2 —C 1-3 -alkyl, —SO 2 —NH 2 , —CONH 2 , optionally substituted 5-to 7-membered nonaromatic heterocycle- and -5-to 7-membered nonaromatic heterocycle-C 1-3 -alkyl,
R 3.3.2 denotes H or is selected from the group consisting of
—CO—N(C 1-3 -alkyl)nonaromatic heterocycle-C 1-4 -alkyl, —N(SO 2 —C 1-3 -alkyl)(CH 2 CONH C 1-3 -alkyl), —N(CO C 1-3 -alkyl)(C 1-4 -alkyl-N(C 1-3 -alkyl) 2 ),
—N(C 1-3 -alkyl)CO—C 1-4 -alkyl-N(C 1-3 -alkyl) 2 , —C 1-3 -alkyl-nonaromatic heterocycle,
—SO 2 —N(C 1-3 -alkyl)C 1-3 -alkyl-N(C 1-3 -alkyl) 2 , —SO 2 NH 2 , —SO 2 OH, —COOH, —COO—C 1-3 -alkyl, —CONH 2 , —CONH—C 1-3 -alkyl-N(C 1-3 -alkyl) 2 , —O—C 2-3 -alkyl-N(C 1-3 -alkyl) 2 , —N(SO 2 CH 3 )—C 1-3 -alkyl-N(C 1-3 -alkyl) 2 , and —C 1-3 -alkyl-N(R 3.3.3.1 )R 3.3.2.2 ,
wherein,
R 3.3.2.1 denotes H, C 1-4 -alkyl-, C 1-4 -alkyl-CO— or C 1-4 -alkyl-SO 2 —,
R 3.3.2.2 denotes H or C 1-4 -alkyl-, or
R 3.3.2.1 and R 3.3.2.2 together with the nitrogen atom they are attached to form an optionally substituted 4-7-membered heterocycle containing at least one N-atom,

R 3.3.3 denotes H or C 1-3 -alkyl,
R 3.3.4 denotes H or C 1-3 -alkyl,
R 3.3.5 denotes H, C 1-3 -alkyl, oxo or —C 1-3 -alkyl-COO—C 1-3 -alkyl,
R 3.3.6 denotes H, oxo, C 1-3 -alkyl or —C 1-3 -alkyl-COO—C 1-3 -alkyl,

R 3.2 and R 3.3 together with the nitrogen atom they are attached to form an optionally substituted 5- to 7-membered heterocycle,
R 3.4 , R 3.5 independently from each other denote H or C 1-4 -alkyl,
R 3.6 denotes H, C 1-4 -alkyl-, C 1 -C 4 -alkyl—CO— or C 1-4 -alkyl-SO 2 —
R 3.7 denotes H or C 1-4 -alkyl-, or
R 3.6 and R 3.7 together with the nitrogen atom they are attached to form an optionally substituted 4-7-membered heterocycle containing at least one N-atom,
R 3.8 denotes H or is selected from the group consisting of optionally substituted C 1-8 -alkyl-, optionally substituted C 3-8 -cycloalkyl- and optionally substituted phenyl-C 1-4 -alkyl-,

or tautomers or optionally the pharmaceutically acceptable acid addition salts thereof.

2. The compound of formula (I) according to claim 1 , characterized in that
X denotes Cl or Br,
R 1 denotes H,
R 2 denotes H or is selected from the group consisting of
methyl, —C(O)OR 2.1 and —C(O)NR 2.2 R 2.3
wherein,
R 2.1 denotes C 1-3 -alkyl-,
R 2.2 , R 2.3 independently from each other denote H or phenyl-C 1-4 -alkyl-,

R 3 is selected from the group consisting of
—CN, —CH 2 -morpholinyl, —CH 2 —O—(C 2 H 4 —O) 3 —CH 3 , —PO(O—R 3.4 )(O—R 3.3 ), —C 1-3 -alkyl-S(O) 2 OH, —C 1-3 -alkyl, —C 1-3 -alkyl-COOH, —C 1-3 -alkyl-COOCH 3 , C 3-8 -cycloalkyl-, R 3.1 —OC(O)—, R 3.2 N(R 3.3 )C(O)— and —C-linked nonaromatic heterocycle-R 3.3.6 ,
wherein
r is 0, 1 or 2,
R 3.1 denotes H, C 1-8 -alkyl- or phenyl-C 1-2 -alkyl-,
R 3.2 , R 3.3 independently from each other denote H or are selected from the group consisting of C 1-8 -alkyl-, C 3-8 -cycloalkyl-, —C 2-8 -alkyl-O—C 1-4 -alkyl, —C 1-8 -alkyl-S—C 1-4 -alkyl, —C 1-4 -alkyl-S(O) s —C 2-6 -alkyl, —CH 2 —COOH, —CH 2 —COO—C 1-4 -alkyl, —CH 2 —CO—NH—C 1-4 -alkyl, optionally substituted —CH 2 -phenyl-R 3.3.1 ,
optionally substituted -phenyl-R 3.3.2 , —C 1-4 -alkyl-5- to 7-membered nonaromatic heterocycle-R 3.3.3 ,
—C 1-4 -alkyl-5-to 7-membered heteroaryl-R 3.3.4 , -5-to 8-membered nonaromatic heterocycle-R 3.3.5 ,
and -5-to 7-membered heteroaryl-R 3.3.6 ,
wherein
s is 0, 1 or 2,
R 3.3.1 denotes H or is selected from the group consisting of —SO 2 —C 1-3 -alkyl, —SO 2 —NH 2 , —CONH 2 , -5-to 7-membered nonaromatic heterocycle-R 3.3.7 , -OMe, —S—CF 3 and —COO—C 1-4 -alkyl,
R 3.3.2 denotes H or is selected from the group consisting of
—CO—N(CH 3 )(nonaromatic heterocycle-C 1-4 -alkyl), —N(SO 2 —CH 3 )(CH 2 CONHCH 3 ), —N(COCH 3 )(C 1-4 -alkyl-N(CH 3 ) 2 ), —N(CH 3 )CO C 1-4 -alkyl-N(CH 3 ) 2 , —C 1-3 -alkyl-nonaromatic heterocycle, —SO 2 —N(CH 3 )(C 1-3 -alkyl-N(CH 3 ) 2 ), —SO 2 NH 2 , —SO 2 OH,
—COOH, —COO—C 1-3 -alkyl, —CONH 2 , —CONH—C 1-3 -alkyl-N(CH 3 ) 2 , —O—C 2-3 -alkyl-N(CH 3 ) 2 and —N(SO 2 CH 3 )(C 1-3 -alkyl-N(CH 3 ) 2 ),

R 3.3.3 denotes H or methyl,
R 3.3.4 denotes H or methyl,
R 3.3.5 denotes H, C 1-3 -alkyl or oxo,
R 3.3.6 denotes H, oxo, —CH 3 or —CH 2 —COO—CH 3 ,

R 3.3.7 H, C 1-3 -alkyl or oxo,
R 3.2 and R 3.3 together with the nitrogen atom they are attached to form an optionally substituted 5- to 7-membered heterocycle, and
R 3.4 , R 3.3 independently from each other denote H or C 1-4 -alkyl.

3. The compound of formula (I) according to claim 1 , characterized in that
X denotes Cl,
R 1 denotes H,
and
R 2 denotes H.

4. The compound of formula (I) according to claim 1 ,
characterized in that
R 2 denotes H,
R 3 is selected from the group consisting of
—CN, —CH 2 -morpholinyl, —PO(O—R 3.4 )(O—R 3.5 ), —C 1-3 -alkyl-S(O) 2 OH, —C 1-4 -alkyl-S(O) r —C 1-6 -alkyl, —C 1-3 -alkyl-COOH, —C 1-3 -alkyl-COOCH 3 and —CH 2 —COO—C 1-3 -alkyl,
wherein
R 3.4 , R 3.5 independently from each other denote H or C 1-4 -alkyl.

5. The compound of formula (I) according to claim 1 ,
characterized in that
R 2 denotes H,
R 3 is selected from the group consist

Assignees

• Hamprecht Dieter
• Heckel Armin
• Kley Joerg
• Boehringer Ingelheim Int

Inventors

• Hamprecht Dieter
• Heckel Armin
• Kley Joerg

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/08

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

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title