Methods for treating pulmonary emphysema using substituted 2-Aza-bicyclo[2.2.1]heptane-3-carboxylic acid (benzyl-cyano-methyl)-amides inhibitors of cathepsin C

Patent metadata

Field	Value
Publication number	US-9713606-B2
Application number	US-201514955379-A
Country	US
Kind code	B2
Filing date	Dec 1, 2015
Priority date	Mar 14, 2013
Publication date	Jul 25, 2017
Grant date	Jul 25, 2017

Abstract

This invention relates to 2-Aza-bicyclo[2.2.1]heptane-3-carboxylic acid (benzyl-cyano-methyl)-amides of formula 1

and their use as inhibitors of Cathepsin C, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and/or prevention of diseases connected with dipeptidyl peptidase I activity, e.g. respiratory diseases.

First claim

The invention claimed is:

1. A method of treating pulmonary emphysema comprising administering to a patient a therapeutically effective amount of a compound of formula 1

wherein
R 1 is independently selected from H, C 1-6 -alkyl-, halogen, HO—, C 1-6 -alkyl-O—, H 2 N—, C 1-6 -alkyl-HN—, C 1-6 -alkyl) 2 N— and C 1-6 -alkyl-C(O)HN—;
or two R 1 are together C 1-4 -alkylene;
R 2 is selected from

wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1 ; wherein possibly available nitrogen atoms of the ring are optionally and independently from each other substituted with R 2.2 ; and
R 2.1 is independently selected from H, halogen, NC—, O═, HO—, H-A-, H-A-C 1-4 -alkylene-, R 2.1.1 -A-, C 1-4 -alkyl-A-, C 3-6 -cycloalkyl-A-, C 1-4 -haloalkyl-A-, R 2.1.1 —C 1-4 -alkylene-A-, C 1-4 -alkyl-A-C 1-4 -alkylene-, C 3-6 -cycloalkyl-A-C 1-4 -alkylene-, C 1-4 -haloalkyl-A-C 1-4 -alkylene-, R 2.1.1 —C 1-4 -alkylene-A-C 1-4 -alkylene-, R 2.1.1 -A-C 1-4 -alkylene, HO—C 1-4 -alkylene-A-, HO—C 1-4 -alkylene-A-C 1-4 -alkylene-, C 1-4 -alkyl-O—C 1-4 -alkylene-A- and C 1-4 -alkyl-O—C 1-4 -alkylene-A-C 1-4 -alkylene-; and
R2.1.1 is independently selected from
aryl-; optionally substituted independently from each other with one, two or three R 2.1.1.1 ;
C 5-10 -heteroaryl-; containing one, two, three or four heteroatoms independently selected from S, S(O), S(O) 2 , O and N, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1.1.1 ; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1.1.2 ; and
C 5-10 -heterocyclyl-; containing one, two, three or four heteroatoms independently selected from S, S(O), S(O) 2 , O and N, wherein the ring is fully or partially saturated, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three or four R 2.1.1.1 ; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1.1.2 ;
R2.1.1.1 is independently selected from halogen, HO—, O═, C 1-4 -alkyl-, C 1-4 -alkyl-O—, C 1-4 -haloalkyl-, C 1-4 -haloalkyl-O—and C 3-6 -cycloalkyl-; and
R2.1.1.2 is independently selected from C 1-4 -alkyl-, C 1-4 -haloalkyl-; C 3-6 -cycloalkyl-, C 1-4 -alkyl-O—C 1-4 -alkyl-, H(O)C—, C 1-4 -alkyl-(O)C—, tetrahydrofuranylmethyl- and tetrahydropyranylmethyl-; and

R2.2 is independently selected from H-A-C 1-4 -alkylene-, C 3-6 -cycloalkyl-, C 1-4 -alkyl-A-C 1-4 -alkylene-, C 3-6 -cycloalkyl-A-C 1-4 -alkylene-, C 1-4 -haloalkyl-A-C 1-4 -alkylene-, R 2.1.1 -A-, C 1-4 -alkyl-S(O) 2 — and C 1-4 -alkyl-C(O)—, R2.1.1-A-;
R 2.3 and R 4 are together selected
from —O—, —S—, —N(R 2.3.1 )—, —C(O)N(R 2.3.1 )—, —N(R 2.3.1 )C(O)—, —S(O) 2 N(R 2.3.1 )—, —N(R 2.3.1 )S(O) 2 —, —C(O)O—, —OC(O)—, —C(O)—, —S(O)—, —S(O) 2 —, R 2.3 , R 2.3 , —C(R 2.3.2 )═C(R 2.3.2 )—, —C═N—, —N═C—, —C(R 2.3.2 ) 2 —O—, —O—C(R 2.3.2 ) 2 —, —C(R 2.3.2 ) 2 N(R 2.3.1 )—, and —N(R 2.3.1 )C(R 2.3.2 ) 2 — and —C 1-4 -alkylene-;
R 2.3.1 is independently selected from H, C 1-6 -alkyl-, C 1-6 -haloalkyl-; C 3-8 -cycloalkyl-, HO—C 1-4 -alkylene-, (C 1-4 -alkyl)-O—C 1-4 -alkylene-, H 2 N—C 1-4 -alkylene-, (C 1-4 -alkyl)HN—C 1-4 -alkylene- and (C 1-4 -alkyl) 2 N—C 1-4 -alkylene-;
R 2.3.2 is independently selected from H, C 1-6 -alkyl-, C 1-6 -haloalkyl-; C 3-8 -cycloalkyl-, HO—C 1-4 -alkylene-, (C 1-4 -alkyl)-O—C 1-4 -alkylene-, H 2 N—C 1-4 -alkylene-, (C 1-4 -alkyl)HN—C 1-4 -alkylene- and (C 1-4 -alkyl) 2 N—C 1-4 -alkylene-;

R 2.4 and R 4 are together selected
from —N(R 2.4.1 )—, —C(O)N(R 2.4.1 )—, —N(R 2.4.1 )C(O)—, —S(O) 2 N(R 2.4.1 )—, —N(R 2.4.1 )S(O) 2 —, —C(O)—, —S(O)—, —S(O) 2 —, —C(R 2.4.2 )═C(R 2.4.2 )—, —C═N—, —N═C—, —C(R 2.4.2 ) 2 N(R 2.4.1 )— and —N(R 2.4.1 )C(R 2.4.2 ) 2 —, —C 1-4 -alkylene-; and
R 2.4.1 is independently selected from H, C 1-6 -alkyl-, C 1-6 -haloalkyl-; C 3-8 -cycloalkyl-, HO—C 1-4 -alkylene-, (C 1-4 -alkyl)-O—C 1-4 -alkylene-, H 2 N—C 1-4 -alkylene-, (C 1-4 -alkyl)HN—C 1-4 -alkylene- and (C 1-4 -alkyl) 2 N—C 1-4 -alkylene-;
R 2.4.2 is independently selected from H, C 1-6 -alkyl-, C 1-6 -haloalkyl-; C 3-8 -cycloalkyl-, HO—C 1-4 -alkylene-, (C 1-4 -alkyl)-O—C 1-4 -alkylene-, H 2 N—C 1-4 -alkylene-, (C 1-4 -alkyl)HN—C 1-4 -alkylene- and (C 1-4 -alkyl) 2 N—C 1-4 -alkylene-;

R 2.5 and R 4 are together selected from —C(R 2.5.1 )═, ═C(R 2.5.1 )—, —N═; and
R 2.5.1 is independently selected from H, C 1-6 -alkyl-, C 1-6 -haloalkyl-; C 3-8 cycloalkyl, HO—C 1-4 -alkylene-, (C 1-4 -alkyl)-O—C 1-4 -alkylene-, H 2 N—C 1-4 -alkylene-, (C 1-4 -alkyl)HN—C 1-4 -alkylene- and (C 1-4 -alkyl) 2 N—C 1-4 -alkylene-;

R 3 is H or F;
R 4 is independently selected from F, Cl, phenyl-H 2 C—O—, HO—, C 1-6 -alkyl-, C 1-6 -haloalkyl-, C 3-8 -cycloalkyl-, C 1-6 -alkyl-O—, C 1-6 -haloalkyl-O—, C 1-6 -alkyl-HN—, (C 1-6 -alkyl) 2 -HN—, C 1-6 -alkyl-HN—C 1-4 -alkylene- and (C 1-6 -alkyl) 2 -HN—C 1-4 -alkylene-;
A is a bond or independently selected
from —O—, —S—, —N(R 5 )—, —C(O)N(R 5 )—, —N(R 5 )C(O)—, —S(O) 2 N(R 5 )—, —N(R 5 )S(O) 2 —, —S(O)(═NR 5 )—N(R 5 )—, —N(R 5 )(NR 5 ═) S(O)—, —S(═NR 5 ) 2 —N(R 5 )—, —N(R 5 )(NR 5 ═) 2 S—, —C(R 5 )═C(R 5 )—, C≡C—, —C(O)O—, —OC(O)—, —C(O)—, —S(O)—, —S(O) 2 —, —S(═NR 5 )—, —S(O)(═NR 5 )—, —S(═NR 5 ) 2 —, —(R 5 )(O)S═N—, —(R 5 N═)(O)S—, and —N═(O)(R 5 )S—;

R 5 is independently selected from H, C 1-6 -alkyl- and NC—;
or a salt thereof.

2. The method according to claim 1 , wherein R 1 is R 1.a and R 1.a is independently selected from H, C 1-4 -alkyl-, F and HO—.

3. The method according to claim 1 , wherein R 4 is R 4.a and R 4.a is F, Cl, phenyl-H 2 C—O—, HO—, C 1-4 -alkyl-, C 1-4 -haloalkyl-, C 3-6 -cycloalkyl-, C 1-4 -alkyl-O— and C 1-4 -haloalkyl-O—.

4. The method according to claim 1 , wherein R 4 is R 4.b and R 4.b is F.

5. The method according to claim 1 , wherein A is A a and A a is a bond or independently selected from —O—, —C(O)N(R 5 )—, —N(R 5 )C(O)—, —S(O) 2 N(R 5 )—, —N(R 5 )S(O) 2 —, —C(O)O—, —OC(O)—, —C(O)—, —S(O) 2 —, —(R 5 )(O)S═N—, —(R 5 N═)(O)S—, —N═(O)(R 5 )S— and R 5 is R 5.a and R 5.a is independently selected from H, C 1-4 -alkyl- and NC—.

6. The method according to claim 1 , wherein R 2 is R 2.1 and
R 2.1 is R 2.1.a and R 2.1.a is selected from H, halogen, NC—, O═, HO—, H-A-, H-A-C 1-4 -alkylene-, R 2.1.1 -A-, C 1-4 -alkyl-A-, C 3-6 -cycloalkyl-A-, C 1-4 -haloalkyl-A-, R 2.1.1 —C 1-4 -alkylene-A-, C 1-4 -alkyl-A-C 1-4 -alkylene-, C 3-6 -cycloalkyl-A-C 1-4 -alkylene-, C 1-4 -haloalkyl-A-C 1-4 -alkylene-, R 2.1.1 —C 1-4 -alkylene-A-C 1-4 -alkylene-, R 2.1.1 -A-C 1-4 -alkylene-, HO—C 1-4 -alkylene-A-, HO—C 1-4 -alkylene-A-C 1-4 -alkylene-, C 1-4 -alkyl-O—C 1-4 -alkylene-A- and C 1-4 -alkyl-O—C 1-4 -alkylene-A-C 1-4 -alkylene-; and
R 2.1.1 is R 2.1.1.a and R 2.1.1.a is selected from
aryl-, optionally substituted independently from each other with one, two or three residues independently selected from R 2.1.1.1 ;
C 5-10 -heteroaryl-, containing one, two, three or four heteroatoms selected independently from S, S(O), S(O) 2 , O and N, wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1.1.1 ; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R 2.1.1.2 ; and
C 5-10 -heterocyclyl-, containing one, two, three or four hete

Assignees

• Boehringer Ingelheim Int

Inventors

• Anderskewitz Ralf
• Binder Florian
• Grauert Matthias
• Grundl Marc
• Haebel Peter Wilhelm
• Oost Thorsten
• Pautsch Alexander
• Peters Stefan
• Vintonyak Viktor

Classifications

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P43/00

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

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P37/08

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