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  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D453/06—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing isoquinuclidine ring systems

Definitions

• This invention relates to 2-Aza-bicyclo[2.2.2]octane-3-carboxylic acid (benzyl-cyano-methyl)- amides of formula 1
• Dipeptidyl-aminopeptidase I (DPPI or Cathepsin C; EC3.4.141), is a lysosomal cysteine protease capable of removing dipeptides from the amino terminus of protein substrates.
• DPPI was first discovered by Gutman and Fruton in 1948 (J. Biol. Chem 174: 851-858, 1948).
• the cDNA of the human enzyme has been described in 1995 (Paris et al.; FEBS Lett 369: 326-330, 1995).
• the DPPI protein is processed into a mature proteolytically active enzyme consisting of a heavy chain, a light chain, and a propeptide that remains associated with the active enzyme (Wo Iters et al.; J. Biol.
• inhibitors of Cathepsin C could potentially be useful therapeutics for the treatment of neutrophil- dominated inflammatory diseases such as chronic obstructive pulmonary disease (COPD), pulmonary emphysema, asthma, multiple sclerosis, and cystic fibrosis (Guay et al.; Curr. Topics Med. Chem. 10: 708-716, 2010; Laine and Busch-Petersen; Expert Opin. Ther. Patents 20: 497-506, 2010).
• COPD chronic obstructive pulmonary disease
• pulmonary emphysema asthma
• multiple sclerosis multiple sclerosis
• cystic fibrosis cystic fibrosis
• Rheumatoid arthritis is also another chronic inflammatory disease where DPPI appears to play a role.
• Cathepsin K and in general desirable pharmacokinetic properties.
• Ci_6-alkyl- is independently selected from among H, Ci_6-alkyl-, halogen, HO-, Ci_6-alkyl-0-, H 2 N-, Ci_ 6 -alkyl-HN- and (d_ 6 -alkyl) 2 N-, Ci_ 6 -alkyl-C(0)HN-;
• R 1 are together Ci_4-alkylene; is selected from among
• C 5 _io-heteroaryl- containing one, two, three or four heteroatoms independently selected from among S, S(O), S(0)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 ; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R 2'2 ; wherein a carbon atom of the ring is optionally substituted with one R 2'3 ; a nitrogen atom of the ring is optionally substituted with one R 2 - 4 ; and
• R 2 and R 4 are together with two adjacent carbon atoms of the phenyl ring a 5- or
• H-A-Ci_ 6 -alkylene- R 2 1 1 -A-, Ci_ 6 -alkyl-A-, C 3 - 8 -cycloalkyl-A-, Ci_ 6 -haloalkyl-A-, R 2 1 1 -Ci_6-alkylene-A-, C i_ 6 -alkyl- A-C i_ 6 -alkylene-,
• R 2' 1'1 is independently selected from among
• R 2'3' 1 is independently selected from among H, Ci_6-alkyl-, Ci_6-haloalkyl-;
• R 2'4 and R 4 are together selected from
• R 4 is independently selected from among H, F, CI, phenyl- H 2 C-0-, HO-, Ci_6-alkyl-,
• R 5 is independently selected from among H, Ci_6-alkyl-- and NC-; or a salt thereof.
• R 1 is R l a and R l a is independently selected from among H, Ci_4-alkyl-, F- and HO-.
• R 1 is R l b and R l b is H.
• R 2 is R 2 a and R 2 a is R 2'1 .
• R 2 is R 2 b and R 2 b is R 2 1 a .
• R 2 is R 2 c and R 2 c is aryl-; optionally substituted with one, two or three residues independently selected from R 2 1 ; optionally substituted with one R 2'3 .
• R 2 is R 2 d and R 2 d is phenyl; optionally substituted with one, two or three residues independently selected from R 2 1 ; optionally substituted with one R 2'3 .
• R 2 is R 2 e and R 2 e is C 5 or 6-heteroaryl-, containing one, two, three or four heteroatoms independently selected from among S, S(O), S(0)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 ; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R 2'2 ; wherein a carbon atom of the ring is optionally substituted with one R 2'3 ; a nitrogen atom of the ring is optionally substituted with one R 2 4 .
• C 7 _io-heteroaryl- each containing one, two, three or four heteroatoms independently selected from among S, S(O), S(0)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 ; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R 2 2 ; wherein a carbon atom of the ring is optionally substituted with one R 2 3 ; a nitrogen atom of the ring is optionally substituted with one R 2'4 .
• R is R 8 and R 8 is selected from among
• 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 ; wherein a carbon atom of the ring is optionally substituted with one R 2'3 ; a nitrogen atom of the ring is optionally substituted with one R 2'4 .
• R 2 is R 2'8 and R 2'8 is selected from among
• H-A-Ci_ 4 -alkylene- R 2 1 1 -A-, Ci_ 4 -alkyl-A-, C 3 _ 6 -cycloalkyl-A-, Ci_ 4 -haloalkyl-A-, R 2 1 1 -Ci_4-alkylene-A-, Ci_4-alkyl-A-Ci_4-alkylene-, C3_6-cycloalkyl-A-Ci_4-alkylene-, Ci_4-haloalkyl-A-Ci_4-alkylene-, R 2 -Ci_4-alkylene-A-Ci_4-alkylene-,
• R 2 1 1 -A-Ci_ 4 -alkylene-, HO-Ci_ 4 -alkylene-A-, HO-Ci_ 4 -alkylene-A-Ci_ 4 -alkylene-,
• R 2.1.1 is R 2.1.1.a R 2.1.1.a ⁇ se J ecte( J g. Qm among
• C 5 _io-heteroaryl- containing one, two, three or four heteroatoms selected independently from S, S(O), S(0)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 ;
• R 2'2 is R 2'2 a and R 2'2 a is independently selected from among H-A-Ci_4-alkylene-, C3_6-cycloalkyl-, Ci_4-alkyl-A-Ci_4-alkylene-, C 3 _6-cycloalkyl-A-Ci_4-alkylene-, Ci_4-haloalkyl-A-Ci_4-alkylene-, R 2 -A-Ci_4-alkylene-, Ci_ 4 -alkyl-S(0) 2 -, Ci_ 4 -alkyl-C(0)- - and R 2 -A-.
• R 2 is R 2 h and R 2 h is selected from among pyrazole, thiophene- and furane, 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 ; wherein a carbon atom of the ring is optionally substituted with one R 2'3 ; a nitrogen atom of the ring is optionally substituted with one R 2'4 .
• R 2 is R 2'1 and R 2'1 is selected from among C6-heterocyclyl- - and C 7 _io-heterocyclyl-, each containing one, two, three or four heteroatoms independently selected from among S, O and N and 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 R 2'1 ; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R 2'2 ; wherein a carbon atom of the ring is optionally substituted with one R 2 3 or one R 2'5 ; a nitrogen atom of the ring is optionally substituted with one R 2 - 4 .
• R 2 is R 2 j and R 2 j is selected from among
• 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 ; wherein a carbon atom of the ring is optionally substituted with one R 2 3 or one R 2'5 ; a nitrogen atom of the ring is optionally substituted with one R 2 - 4 .
• R 2 is R 2j and R 2j is selected from among
• 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
• H-A-Ci_ 4 -alkylene- R 2 1 1 -A-, Ci_ 4 -alkyl-A-, C 3 _ 6 -cycloalkyl-A-, Ci_ 4 -haloalkyl-A-, R 2 1 1 -Ci_4-alkylene-A-, Ci_4-alkyl-A-Ci_4-alkylene-, C3_6-cycloalkyl-A-Ci_4-alkylene-, Ci_4-haloalkyl-A-Ci_4-alkylene-, R 2 -Ci_4-alkylene-A-Ci_4-alkylene-,
• R 2 1 1 -A-Ci_ 4 -alkylene-, HO-Ci_ 4 -alkylene-A-, HO-Ci. 4 -alkylene-A-Ci. 4 -alkylene-, Ci_4-alkyl-0-Ci_4-alkylene-A— and Ci.4-alkyl-0-Ci.4-alkylene-A-Ci.4-alkylene-;
• R 2.1.1 is R 2.1.1.a R 2.1.1.a ⁇ se J ecte( J g. Qm among
• C 5 _io-heteroaryl- containing one, two, three or four heteroatoms selected independently from S, S(O), S(0)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
• R 2'2 is R 2'2 a and R 2'2 a is independently selected from among H-A-Ci_4-alkylene-, C3_6-cycloalkyl-, Ci_4-alkyl-A-Ci_4-alkylene-, C3_6-cycloalkyl-A-Ci_4-alkylene-, Ci_4-haloalkyl-A-Ci_4-alkylene-, R 2 -A-Ci_4-alkylene-, Ci_ 4 -alkyl-S(0) 2 -, Ci_ 4 -alkyl-C(0)- - and R 2 -A-.
• R 2 is R 2 k and R 2 k is selected from among
• 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 ; wherein a carbon atom of the ring is optionally substituted with one R 2 3 or one R 2'5 ; a nitrogen atom of the ring is optionally substituted with one
• R is R 2 1 and R 1 is selected from among wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two, three or four R 2 1 ; wherein possibly available nitrogen atoms of the ring are optionally and independently from each other substituted with R 2 2 ; wherein a carbon atom of the ring is optionally substituted with one R 2 3 or one R 2'5 ; a nitrogen atom of the ring is optionally substituted with one R 2 - 4 .
• R 2 is R 2 m and R 2 m is together with R 4 and two adjacent carbon atoms of the phenyl ring a 5- or 6-membered aryl or heteroaryl, containing one, two or three heteroatoms independently selected from among S, S(O), S(0)2, O and N, preferably pyrazole- and naphtene, 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 one, two or three R 2'2 .
• R 2 is R 2 m and R 2 m is together with R 4 and two adjacent carbon atoms of the phenyl ring a 5- or 6-membered aryl or heteroaryl, containing one, two or three heteroatoms independently selected from among S, S(O), S(0)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 , wherein possibly available nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R 2'2 ; and
• H-A-Ci_ 4 -alkylene- R 2 1 1 -A-, Ci_ 4 -alkyl-A-, C 3 _ 6 -cycloalkyl-A-, Ci_ 4 -haloalkyl-A-, R 2 1 1 -Ci_4-alkylene-A-, Ci_4-alkyl-A-Ci_4-alkylene-, C3_6-cycloalkyl-A-Ci_4-alkylene-, Ci_4-haloalkyl-A-Ci_4-alkylene-, R 2' -Ci_4-alkylene-A-Ci_4-alkylene-,
• R 2.1.1 is R 2.1.1.a R 2.1.1.a ⁇ se J ecte( J g. Qm among
• R 2'2 is R 2'2 a and R 2'2 a is independently selected from among H-A-Ci_4-alkylene-, C3_6-cycloalkyl-, Ci_4-alkyl-A-Ci_4-alkylene-, C3_6-cycloalkyl-A-Ci_4-alkylene-, Ci.4-haloalkyl-A-Ci.4-alkylene-, R 2 -A-Ci_4-alkylene-, Ci_ 4 -alkyl-S(0) 2 -, Ci_ 4 -alkyl-C(0)- - and R 2 -A-.
• R 2 is R 2 n and R 2 n is selected from among aryl-, pyrazole, thiophene- and furane; wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two, three or four R 2 1 ; wherein possibly available nitrogen atoms of the ring are optionally and independently from each other substituted with R 2'2 ; wherein a carbon atom of the ring is optionally substituted with one R 2'3 ; a nitrogen atom of the ring is optionally substituted with one R 2'4 ; or R 2 n is selected from among
• carbon atoms of the ring are optionally and independently from each other substituted with one, two, three or four R 2 1 ; wherein possibly available nitrogen atoms of the ring are optionally and independently from each other substituted with R 2'2 ; wherein a carbon atom of the ring is optionally substituted with one R 2 3 or one R 2'5 ; a nitrogen atom of the ring is optionally substituted with one R 2 - 4 .
• R 2 is R 2 n and R 2 n is selected from among aryl-, pyrazole, thiophene- and furane; wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two, three or four R 2'1 ; wherein possibly available nitrogen atoms of the ring are optionally and independently from each other substituted with R 2'2 ; wherein a carbon atom of the ring is optionally substituted with one R 2'3 ; a nitrogen atom of the ring is optionally substituted with one R 2'4 ; or R 2 n is selected
• carbon atoms of the ring are optionally and independently from each other substituted with one, two, three or four R 2 1 ; wherein possibly available nitrogen atoms of the ring are optionally and independently from each other substituted with R 2'2 ; wherein a carbon atom of the ring is optionally substituted with one R 2 3 or one R 2'5 ; a nitrogen atom of the ring is optionally substituted with one R 2 - 4 ; and
• H-A-Ci_ 4 -alkylene- R 2 1 1 -A-, Ci_ 4 -alkyl-A-, C 3 _ 6 -cycloalkyl-A-, Ci_ 4 -haloalkyl-A-, R 2 1 1 -Ci_4-alkylene-A-, Ci_4-alkyl-A-Ci_4-alkylene-, C3_6-cycloalkyl-A-Ci_4-alkylene-, Ci_4-haloalkyl-A-Ci_4-alkylene-, R 2' -Ci_4-alkylene-A-Ci_4-alkylene-,
• R 2.1.1 is R 2.1.1.a R 2.1.1.a ⁇ se J ecte( J g. Qm among
• R 2'2 a and R 2'2 a is independently selected from among H-A-Ci_4-alkylene-, C3.
• R 2'3'1 is independently selected from among H, Ci_4-alkyl-, Ci.4-haloalkyl-, C3.
• 6-cycloalkyl- HO-Ci.4-alkylene-, (Ci_4-alkyl)-0-Ci_4-alkylene-, H 2 N-Ci_4-alkylene-, (Ci_4-alkyl)HN-Ci_ 4 -alkylene-- and (Ci.4-alkyl) 2 N-Ci. 4 -alkylene-;
• R 2'3'2 is independently selected from among H, Ci_4-alkyl-, Ci_4-haloalkyl-, C3.
• R 2A1 is independently selected from among H, Ci_4-alkyl-, Ci.4-haloalkyl-, C3.
• R 2'4'2 is independently selected from among H, Ci_4-alkyl-, Ci_4-haloalkyl-, C3.
• 6-cycloalkyl- HO-Ci.4-alkylene-, (Ci_4-alkyl)-0-Ci_4-alkylene-, H 2 N-Ci_4-alkylene- (Ci_4-alkyl)HN-Ci_4-alkylene— and (Ci_4-alkyl) 2 N-Ci_4-alkylene-; and
• R 2'5'1 is independently selected from among H, Ci_4-alkyl-, Ci.4-haloalkyl-, C3.
• R 2 is R 2 ° and R 2 ° is selected from among aryl-, pyrazole, thiophene- and furane; wherein carbon atoms of the ring are optionally and independently from each other substituted with one, two, three or four R 2 1 ; wherein possibly available nitrogen atoms of the ring are optionally and independently from each other substituted with R 2 2 ; wherein a carbon atom of the ring is optionally substituted with one R 2 3 ; a nitrogen atom of the ring is optionally substituted with one R 2'4 .
• R 2 is R 2 p and R 2 p is selected from among
• carbon atoms of the ring are optionally and independently from each other substituted with one, two, three or four R 2 1 ; wherein possibly available nitrogen atoms of the ring are optionally and independently from each other substituted with R 2'2 ; wherein a carbon atom of the ring is optionally substituted with one R 2 3 or one R 2'5 ; a nitrogen atom of the ring is optionally substituted with one R 2 - 4 .
• R 2' 1'1 is R 2 1 1 a and R 2 1 1 a i s selected from among
• C 5 _io-heteroaryl- containing one, two, three or four heteroatoms selected independently from S, S(O), S(0)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
• R 2' 1'1 is R 2 1 1 b and R 2 1 1 b i s phenyl or selected from among
• carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R 2'1'1 , wherein possibly available nitrogen atoms of the ring are optionally and independently from each other substituted with R 2' 1'1'2 ;
• R 2' 1'1 is R 2 1 1 c and R 2 1 1 c i s phenyl or selected from among 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 possibly available nitrogen atoms of the ring are optionally and independently from each other substituted with R 2' 1'1'2 ; and
• R 2'1'1'1 is independently selected from among F, CI, Me, MeO— and cyclopropyl-;
• R 2' 1'1'2 is independently selected from among Me, tetrahydroftiranylmethyl— and
• R 2' 1'2 is R 2 1 2 a and R 2 1 2 a i s
• R 2' 1'2 is R 2 1 2 b and R 2 1 2 b i s selected from among H, Ci_4-alkyl- and C3_6-cycloalkyl-;
• R 2'2 is R 2 2 a and R 2 2 a is independently selected from among H-A-Ci_4-alkylene-, C3_6-cycloalkyl-, Ci_4-alkyl-A-Ci_4-alkylene-, C3.
• R 2'3 is together with R 4 a group R 2 3 a and R 2'3 a is selected from
• R 2'3'1 is independently selected from among H, Ci_4-alkyl-, Ci_4-haloalkyl-, C3_6-cycloalkyl-,
• R 2'3'2 is independently selected from among H, Ci_4-alkyl-, Ci.4-haloalkyl-, C3_6-cycloalkyl-,
• R 2'4 is together with R 4 a group R 2Aa and R 2Aa is selected from
• R 2A 1 is independently selected from among H, Ci_4-alkyl-, Ci.4-haloalkyl-, C3_6-cycloalkyl-,
• R 2'4'2 is independently selected from among H, Ci_4-alkyl-, Ci.4-haloalkyl-, C3_6-cycloalkyl-,
• R 2'5'1 is independently selected from among H, Ci_4-alkyl-, Ci_4-haloalkyl-, C3_6-cycloalkyl-, H0-Ci_4-alkylene-, (Ci.4-alkyl)-0-Ci_4-alkylene-, H 2 N-Ci_4-alkylene-,
• R 2 - Embodiments of the invention for R 2 , R 2 - 1 , R 2 - , R 2 2 , R 2 3 , R 24 and R 2 5 (if present):
• R 2 can also be read as a group R 2 , wherein is R e and R e is C 5 or 6-heteroaryl-, containing one, two, three or four heteroatoms independently selected from among S, S(O), S(0)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 ; wherein nitrogen atoms of the ring are optionally and independently from each other substituted with one, two or three R 2'2 ; and
• H-A-Ci_4-alkylene- R 211 -A-, Ci_ 4 -alkyl-A-, C 3 . 6 -cycloalkyl-A-, Ci_ 4 -haloalkyl-A-, R 2' -Ci_ 4 -alkylene-A-, Ci_ 4 -alkyl-A-Ci_ 4 -alkylene-, C 3 _
• R 2' 1'1 i 2 1 1 c and R 2 1 1 c i s phenyl or selected from among
• carbon atoms of the ring are optionally and independently from each other substituted with one, two or three R 2 1 1 1 , wherein possibly available nitrogen atoms of the ring are optionally and independently from each other substituted with R 2' 1'1'2 ; and is independently selected from among F, CI, Me, MeO— and cyclopropyl-; and
• R is R ' a and R ' a is independently selected from among H-A-Ci_4-alkylene-, 6-cycloalkyl-, Ci_4-alkyl-A-Ci_4-alkylene-, C3_6-cycloalkyl-A-Ci_4-alkylene-, Ci_4-haloalkyl-A-Ci_ 4 -alkylene-, R 2 -A-C M -alkylene-, Ci. 4 -alkyl-S(0) 2 -, Ci_4-alkyl-C(0)- - and R 2 1 1 -A-.
• R 4 is R 4 a and R 4 a is H, F, CI,
• Ci_4-haloalkyl-0- Preferred are the above compounds of formula 1, wherein R 4 is R 4 b and R 4 b is H or F.
• R 4 is R 4 c and R 4 c is F; preferably in ortho position.
• R 5 is R 5 a and R 5 a is independently selected from among H, Ci_4-alkyl ⁇ and NC-.
• H-A-Ci_ 4 -alkylene- R 2 1 1 -A-, Ci_ 4 -alkyl-A-, C 3 _ 6 -cycloalkyl-A-, Ci_ 4 -haloalkyl-A-, R 2 1 1 -Ci_4-alkylene-A-, Ci_4-alkyl-A-Ci_4-alkylene-, C3_6-cycloalkyl-A-Ci_4-alkylene-, Ci_4-haloalkyl-A-Ci_4-alkylene-, R 2 -Ci_4-alkylene-A-Ci_4-alkylene-,
• R 2 1 1 -A-Ci_ 4 -alkylene-, HO-Ci_ 4 -alkylene-A-, HO-Ci. 4 -alkylene-A-Ci. 4 -alkylene-,
• C 5 _io-heteroaryl- containing one, two, three or four heteroatoms selected independently from S, S(0), S(0)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 ;
• R 2 is R 2 d and R 2 d is phenyl; optionally substituted with one, two or three residues independently selected from R 2 1 and
• R 2 1 1 -A-Ci_ 4 -alkylene-, HO-Ci_ 4 -alkylene-A-, HO-Ci_ 4 -alkylene-A-Ci_ 4 -alkylene-,
• C 5 _io-heteroaryl- containing one, two, three or four heteroatoms selected independently from S, S(O), S(0)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 ;
• R 1 is independently selected from among H, Ci_4-alkyl-, halogen, HO-, Ci_4-alkyl-0-, H 2 N-, Ci_6-alkyl-HN-, (Ci_ 6 -alkyl) 2 N- and Ci_ 6 -alkyl-C(0)HN-; or two R 1 are together Ci.4-alkylene;
• R 2 is selected of the examples of the Table 1 R 2 - Embodiments of the invention; preferably examples (E#) 7-51, preferably one of the groups selected from among 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40, 41, 42,43,44, 45, 45, 46, 47, 48, 49, 50- and 51 ;
• R 3 is Hor F
• R 4 is independently selected from among H, F, CI, phenyl- H 2 C-0-, HO-, Ci_6-alkyl-,
• A is a bond or independently selected from
• R 5 is independently selected from among H, Ci_6-alkyl-- and NC-; or a salt thereof.
• R 1 is R l a and R l a is independently selected from among H, Ci_4-alkyl-, F- and HO- or two R 1 are together Ci.4-alkylene;
• R 2 is selected of the examples of the Table 1 R 2 - Embodiments of the invention; preferably examples (E#) 7-51, preferably one of the groups selected from among 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40, 41, 42,43,44, 45, 45, 46, 47, 48, 49, 50- and 51 ;
• R 3 is H, F
• R 4 is R 4 a and R 4 a is H, F, CI, phenyl-H 2 C-0-, HO-, Ci_ 4 -alkyl-, Ci_ 4 -haloalkyl-, C 3 .
• A is a bond or independently selected from
• R 5 is independently selected from among H, Ci_6-alkyl— and NC-; or a salt thereof.
• R 1 is R l a and R l a is independently selected from among H, Ci_4-alkyl-, F- and HO-. or two R 1 are together Ci_4-alkylene;
• R 2 is selected of the examples of the Table 1 R 2 - Embodiments of the invention; preferably examples (E#) 7-51, preferably one of the groups selected from among 13, 14, 15, 16, 17, 18 or 25, 26, 27, 28, 29, 30, 34, 35, 36, 37, 38, 39 or 43, 44 ,45, 46, 47- and 48;
• R 3 is H or F
• R 4 is R 4 a and R 4 a is H, F, CI, phenyl-H 2 C-0-, HO-, Ci_ 4 -alkyl-, Ci_ 4 -haloalkyl-, C 3 .
• A is A a and A a is a bond or independently selected from
• R 5 is R 5 a and R 5 a is independently selected from among H, Ci_4-alkyl- and NC-; or a salt thereof.
• R 1 is R l b and R l b is H; or two R 1 are together -CH 2 -;
• R 2 is selected of the examples of the Table 1 R 2 - Embodiments of the invention; preferably examples (E#) 7-51, preferably one of the groups selected from among 13, 14, 15, 16, 17, 18 or 25, 26, 27, 28, 29, 30, 34, 35, 36, 37, 38, 39 or 43, 44 ,45, 46, 47- and 48;
• R 3 is H or F
• R 4 is R 4 b and R 4 b is H or F;
• A is A a and A a is a bond or independently selected from
• R 5 is R 5 a and R 5 a is independently selected from among H, Ci_4-alkyl- and NC-; or a salt thereof.
• Preferred is a compound of formula 1, wherein
• R 2 is selected of the examples of the Table 1 R 2 - Embodiments of the invention; preferably examples (E#) 7-51, preferably one of the groups selected from among 13-15, 16-18 or 25-30, 34-39 - and 43-48;
• R 3 is H or F
• R 4 is R 4 b and R 4 b is H or F;
• A is A a and A a is a bond or independently selected from
• R 5 is R 5 a and R 5 a is independently selected from among H, Ci_4-alkyl- and NC-; or a salt thereof.
• R 1 is R l b and R l b is H; or two R 1 are together -CH 2 -;
• R 2 is selected from among
• HO-Ci_4-alkylene-A-Ci_ 4 -alkylene-; preferably F, NC-, 0 H-A-, H-A-CH 2 -, R 2 -A-, H 3 C-A-, H 3 C-CH 2 -A-, Cyclopropyl-A-, R 2 -CH 2 -CH 2 -A-,
• R 2' 1'1 is independently selected from among
• R 2'2 is independently selected from among H- A-C 1.4-alkylene-, C3_6-cycloalkyl-,
• R 2'3 and R 4 are together a group selected from
• R 2'3' 1 is independently selected from among H- and H 3 C-; is H or F; R 4
• R 4 b is H or F
• R 2 is R 2 t and R 2 t is selected from among the substituents (al) to (fl), ), particularly preferred (al) and (bl),
• R is R r and R r is selected from amonj the substituents (a2) and (b2)
• R is R s and R s is selected from among the substituents (a3) and (b3)
• Ci_6-alkyl means an alkyl group or radical having 1 to 6 carbon atoms.
• radical attachment point(s) to the molecule from the free valences of the group itself.
• the last named subgroup is the radical attachment point, for example, the substituent "aryl-Ci_4-alkyl-" means an aryl group which is bound to a Ci_4-alkyl- group, the latter of which is bound to the core or to the group to which the substituent is attached.
• substituted means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound.
• prevention means the management and care of an individual at risk of developing the disease prior to the clinical onset of the disease.
• the purpose of prevention is to combat the development of the disease, condition or disorder, and includes the administration of the active compounds to prevent or delay the onset of the symptoms or complications and to prevent or delay the development of related diseases, conditions or disorders. Success of said preventive treatment is reflected statistically by reduced incidence of said condition within a patient population at risk for this condition in comparison to an equivalent patient population without preventive treatment.
• treatment means therapeutic treatment of patients having already developed one or more of said conditions in manifest, acute or chronic form, including symptomatic treatment in order to relieve symptoms of the specific indication or causal treatment in order to reverse or partially reverse the condition or to delay the progression of the indication as far as this may be possible, depending on the condition and the severity thereof.
• treatment of a disease means the management and care of a patient having developed the disease, condition or disorder.
• the purpose of treatment is to combat the disease, condition or disorder.
• Treatment includes the administration of the active compounds to eliminate or control the disease, condition or disorder as well as to alleviate the symptoms or complications associated with the disease, condition or disorder.
• a given chemical formula or name shall encompass tautomers and all stereo, optical and geometrical isomers (e.g. enantiomers, diastereomers, E/Z isomers etc%) and racemates thereof as well as mixtures in different proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms where such isomers and enantiomers exist, as well as salts, including pharmaceutically acceptable salts thereof and solvates thereof such as for instance hydrates including solvates of the free compounds or solvates of a salt of the compound.
• prodrug refers to (i) an inactive form of a drug that exerts its effects after metabolic processes within the body converting it to a usable or active form, or (ii) a substance that gives rise to a pharmacologically active metabolite, although not itself active (i.e. an inactive precursor).
• prodrug or prodrug derivative mean a covalently-bonded derivative, carrier or precursor of the parent compound or active drug substance which undergoes at least some biotransformation prior to exhibiting its pharmacological effect(s).
• prodrugs either have metabolically cleavable or otherwise convertible groups and are rapidly transformed in vivo to yield the parent compound, for example, by hydrolysis in blood or by activation via oxidation as in case of thioether groups.
• Most common prodrugs include esters and amide analogs of the parent compounds.
• the prodrug is formulated with the objectives of improved chemical stability, improved patient acceptance and compliance, improved bioavailability, prolonged duration of action, improved organ selectivity, improved formulation (e.g., increased hydrosolubility), and/or decreased side effects (e.g., toxicity).
• prodrugs themselves have weak or no biological activity and are stable under ordinary conditions.
• pharmaceutically acceptable prodrug means a prodrug of a compound of the invention which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible.
• phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, and
• pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
• examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
• such salts include salts from ammonia, L-arginine, betaine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine (2, 2'-iminobis(ethanol)), diethylamine, 2-(diethylamino)-ethanol, 2-aminoethanol, ethylenediamine, N-ethyl-glucamine, hydrabamine, lH-imidazole, lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1 -(2-hydroxyethyl)-pyrrolidine, sodium hydroxide,
• 2.2-dichloro-acetic acid adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 2, 5-dihydroxybenzoic acid, 4-acetamido-benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, decanoic acid, dodecylsulfuric acid, ethane- 1, 2-disulfonic acid, ethanesulfonic acid,
• the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a sufficient amount of the appropriate base or acid in water or in an organic diluent like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof. Salts of other acids than those mentioned above which for example are useful for purifying or isolating the compounds of the present invention (e.g. trifluoro acetate salts, ) also comprise a part of the invention.
• halogen generally denotes fluorine, chlorine, bromine and iodine.
• Ci_ n -alkyl wherein n is an integer selected from among 2, 3, 4, 5 or 6, either alone or in combination with another radical denotes an acyclic, saturated, branched or linear hydrocarbon radical with 1 to n C atoms.
• Ci_ 5 -alkyl embraces the radicals H 3 C-,
• Ci_ n -alkylene wherein n is an integer selected from among 2, 3, 4, 5 or 6, preferably 4 or 6, either alone or in combination with another radical, denotes an acyclic, straight or branched chain divalent alkyl radical containing from 1 to n carbon atoms.
• n is an integer selected from among 2, 3, 4, 5 or 6, preferably 4 or 6, either alone or in combination with another radical, denotes an acyclic, straight or branched chain divalent alkyl radical containing from 1 to n carbon atoms.
• C 3 . n -cycloalkyl wherein n is an integer selected from among 4, 5, 6, 7 or 8, preferably 4, 5 or 6, either alone or in combination with another radical denotes a cyclic, saturated, unbranched hydrocarbon radical with 3 to 8 C atoms.
• C 3 .g-cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.
• halo added to a “alkyl”, “alkylene” or “cycloalkyl” group (saturated or unsaturated) is such a alkyl or cycloalkyl group wherein one or more hydrogen atoms are replaced by a halogen atom selected from among fluorine, chlorine or bromine, preferably fluorine and chlorine, particularly preferred is fluorine. Examples include: H 2 FC-, HF 2 C-, F 3 C-.
• aryl denotes a carbocyclic aromatic monocyclic group containing 6 carbon atoms which may be further fused to a second five- or six-membered, carbocyclic group which may be aromatic, saturated or unsaturated.
• Aryl includes, but is not limited to, phenyl, indanyl, indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl and dihydronaphthyl.
• heterocyclyl is intended to include all the possible isomeric forms.
• the term “heterocyclyl” includes the following exemplary structures which are not depicted as radicals as each form may be attached through a covalent (single or double) bond to any atom so long as appropriate valences are maintained:
• heteroaryl is intended to include all the possible isomeric forms.
• heteroaryl includes the following exemplary structures which are not depicted as radicals as each form may be attached through a covalent bond to any atom so long as appropriate valences are maintained:
• the invention also provides processes for making a compound of Formula I.
• R 1 , R 2 and n in the formulas below shall have the meaning of R 1 , R 2 and n m Formula I of the invention described herein above.
• reaction conditions and reaction times may vary depending on the particular reactants used. Unless otherwise specified, solvents, temperatures, pressures, and other reaction conditions may be readily selected by one of ordinary skill in the art. Specific procedures are provided in the Synthetic Examples section. Typically, reaction progress may be monitored by thin layer chromatography (TLC) or LC-MS, if desired, and intermediates and products may be purified by chromatography on silica gel, HPLC and/or by recrystallization.
• TLC thin layer chromatography
• LC-MS LC-MS
• intermediates and products may be purified by chromatography on silica gel, HPLC and/or by recrystallization.
• the examples which follow are illustrative and, as recognized by one skilled in the art, particular reagents or conditions could be modified as needed for individual compounds without undue experimentation. Starting materials and intermediates used, in the methods below, are either commercially available or easily prepared from commercially available materials by those skilled in the art.
• a compound of Formula V, VII and IX may be made by the method outlined in Scheme 1 :
• a compound of Formula II wherein PG represents a protecting group (e.g. teri-butoxycarbonyl), may be reacted with an aqueous ammonia solution, using standard literature procedures for the formation of an amide.
• PG represents a protecting group (e.g. teri-butoxycarbonyl)
• a base such as N-methyl-morpholine or N-ethyl-morpholine
• an activating agent such as 0-(7- Azabenzotriazol-l-yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate (HATU) or O- (Benzotriazol-l-yl)- N, N, N', N'-tetramethyluroniumtetrafluoroborate (TBTU).
• HATU 0-(7- Azabenzotriazol-l-yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate
• HATU 0-(7- Azabenzotriazol-l-yl)-N, N, N', N'-te
• Reacting an acid of Formula VI using standard literature procedures for the formation of an amide for example in the presence of a base such as N, N-diisopropylethylamine (DIPEA) and an activating agent such as HATU or TBTU, with an amine of Formula V or VIII in a suitable solvent, provides a compound of Formula VII or IX.
• DIPEA N, N-diisopropylethylamine
• an activating agent such as HATU or TBTU
• tert-butoxycarbonyl an acid such as formic acid, trifluoroacetic acid, p-toluenesulfonic acid or HC1 may be used in a suitable solvent such as water, DCM or dioxane.
• a suitable solvent such as water, DCM or dioxane.
• Another method to deprotect tert-butoxycarbonyl is the reaction with trimethyliodosilane or trimethylchlorosilane in combination with sodium iodide in an appropriate solvent like acetonitrile, DMF or DCM.
• a suitable catalyst such as bis-(triphenylphosphin)- palladiumchloride
• a suitable solvent such as dimethylformamide (DMF)
• an additive such as tetraethylammonium chloride
• reaction of a compound of Formula VII or IX, wherein X is I or Br may be reacted with an amine in the presence of a suitable catalyst such as Cu(I)I and a suitable base such as caesium carbonate and a suitable promotor such as L-
• compounds of formula VII or IX (X: I, Br, CI, OTf) can be converted into the corresponding boronic acid derivatives Vila or IXa, wherein R can be H or lower alkyl independently and the residues R can form a ring.
• VII or IX can be reacted with bis- pinacolato-diboron in the presence of a suitable catalyst such as 1, 1 -bis(di-tert- butylphosphino)ferrocene palladium dichloride and a suitable base such as potassium acetate or sodium, potassium or cesium carbonate or phosphate, in a suitable solvent such as dioxan, dimethylformamide (DMF), or dichloromethane (DCM) to yield the boronic esters Vila or IXa, respectively.
• a suitable catalyst such as 1, 1 -bis(di-tert- butylphosphino)ferrocene palladium dichloride and a suitable base such as potassium acetate or sodium, potassium or cesium carbonate or phosphate
• a suitable solvent such as dioxan, dimethylformamide (DMF), or dichloromethane (DCM)
• reaction of a compound of Formula VII or IX, wherein X is N 3 with an alkyne in the presence of a suitable catalyst such as copper(II)sulfate pentahydrate and a suitable reducing agent such as L-ascorbic acid in a suitable solvent such as dimethyl sulfoxide (DMSO) / water provides a compound of Formula X or XL
• reaction of a compound of Formula IV wherein X is I, Br, cl or OTf provides a compound of Formula XII.
• a boronic acid or the corresponding boronic acid ester in a suitable solvent such as acetonitrile, in the presence of a suitable catalyst such as 1 , 1 -bis(di-tert-butylphosphino)ferrocene palladium dichloride and a suitable base such as K 2 CO 3 provides a compound of Formula XII.
• Step 1 Synthesis of Intermediate 1-8.1 To 4-cyano-3-fluoroboronic acid (0.16 g, 0.97 mmol) in dioxane (10 mL) is added 1-1.1.1 (0.3 g, 0.81 mmol) and Bis(bis(l,2-diphenylphosphino)ethane)palladium(0) (10 mg, 0.01 mmol) and degassed with nitrogen for 15min. A solution of potassium carbonate (0.23 g, 1.63 mmol) in water (1 mL) is added and again degassed for 15 min . The reaction mixture is stirred at 80°C overnight and afterwards concentrated in vacuo.
• Step 2 Synthesis of Intermediate 1-5.2 1-5.1 (15.0 g, 63 mmol) and hydrazine hydrate (30 niL, 618 mmol) are heated to 125 °C for 72 h. To the cool reaction mixture DCM is added and extracted with water and 1 M HCl. The organic layer is dried over MgS0 4 and concentrated. The crystallized residue is dissolved in DCM, methanol is added and the DCM is removed under vacuum. The crystallized product is filtered with sunction and washed with cold methanol. Yield 63%, m/z 226/228 [M+H]+, rt 1.16 min, LC-MS Method V001 003.
• TSA toluene sulfonic acid cf. Example 2
• SI trimethylsilyl iodide cf. example 3
• FA formic acid cf. example 1
• TFA trifluoroacetic acid
• Microtiterplates (Optiplate-384 F) were purchased from PerkinElmer (Prod.No.
• the substrate Gly-Arg-AMC was from Biotrend (Prod.-No.808756 Custom peptide).
• Bovine serum albumin (BSA; Prod.No. A3059) and Dithiothreitol (DTT; Prod.No D0632) were from Sigma.
• TagZyme buffer was from Riedel-de-Haen (Prod. -No. 04269), NaCl was from Merck (Prod. -No. 1.06404.1000) and morpholinoethane sulfonic acid (MES), was from Serva (Prod. -No. 29834).
• the DPPl inhibitor Gly-Phe-DMK was purchased from MP Biomedicals
• MES buffer 25 mM MES, 50 mM NaCl, 5 mM DTT, adjusted to pH 6.0, containing 0.1% BSA
• TAGZyme Buffer 20 mM NaH 2 P0 4 , 150 mM NaCl adjusted to pH 6.0 with HC1
• Assay conditions The recombinant human DPPI was diluted in TAGZyme buffer to 1 U/ml (38.1 ⁇ g/ml, respectively), and then activated by mixing in a 1 :2 ratio with a Cysteamine aqueous solution ( 2mM) and incubating for 5 min at room temperature.
• test compound final concentration 0.1 nM to 100 ⁇
• aqua bidest containing 4% DMSO, final DMSO concentration 16%
• 10 ⁇ of DPPI in MES buffer final concentration 0.0125 ng/ ⁇
• substrate final concentration 50 ⁇
• the microtiter plates were then incubated at room temperature for 30 min. Then, the reaction was stopped by adding 10 ⁇ of Gly-Phe-DMK in MES-buffer (final concentration 1 ⁇ ).
• the fluorescence in the wells was determined using a Molecular Devices SpectraMax M5 Fluorescence Reader (Ex 360 nm, Em 460 nm) or an Envision Fluorescence Reader (Ex 355 nm, Em 460 nm).
• Each assay microtiter plate contained wells with vehicle controls (1% DMSO in bidest + 0.075% BSA) as reference for non- inhibited enzyme activity (100%) Ctl; high values) and wells with inhibitor (Gly-Phe-DMK, in bidest + 1% DMSO + 0.075%BSA, final concentration ⁇ ⁇ ) as controls for background fluorescence (0%> Ctl; low values).
• Microtiterplates (Optiplate-384 F were purchased from PerkinElmer (Prod.No.
• the substrate Z-Gly-Pro-Arg-AMC was from Biomol (Prod. -No. P-142).
• L-Cysteine (Prod.No. 168149) was from Sigma.
• Sodium actetate was from Merck (Prod. -No. 6268.0250), EDTA was from Fluka (Prod. -No. 03680).
• the inhibitor E-64 was purchased from Sigma (Prod. -No. E3132).
• the recombinant human Cathepsin K proenzyme was purchased from Biomol (Prod.No. SE-367). All other materials were of highest grade commercially available.
• Assay conditions To activate the proenzyme, 5 ⁇ procathepsin K were mixed with lul activation buffer, and incubated at room temperature for 30 min.
• test compound final concentration 0.1 nM to 100 ⁇
• aqua bidest containing 4% DMSO, final DMSO concentration 16%
• 10 uL of Cathepsin K in assay buffer final concentration 2 ng/ ⁇
• substrate final concentration 12.5 ⁇
• the plates were then incubated at room temperature for 60min.
• the reaction was stopped by adding 10 ⁇ of E64 in assay buffer (final concentration 1 ⁇ ).
• the fluorescence in the wells was determined using a Molecular Devices SpectraMax M5 Fluorescence Reader (Ex 360 nm, Em 460 nm).
• Each assay microtiter plate contains wells with vehicle controls (1% DMSO in bidest) as reference for non- inhibited enzyme activity (100% Ctl; high values) and wells with inhibitor (E64 in bidest + 1%) DMSO, final concentration 1 ⁇ ) as controls for background fluorescence (0% Ctl; low values).
• vehicle controls 1% DMSO in bidest
• inhibitor E64 in bidest + 1%) DMSO, final concentration 1 ⁇
• background fluorescence 0% Ctl; low values
• Optiplate 384F were purchased from PerkinElmer (Prod. No. #6007270). 24well Nunclon cell culture plates (No. 142475) and 96well plates (No. 267245) were from Nunc. Dimethylsulfoxid (DMSO) was from Sigma (Prod.No. D8418). Nonidet-P40 (NP40) was from USBiological (Prod.No. N3500)
• Substrate specific for Neutrophil elastase, was from Bachem (MeOSuc- Ala- Ala-Pro- Val-AMC; Prod.No. 1-1270).
• Tris-buffer (lOOmM Tris; 1M NaCL; pH 7.5)
• Serine-protease buffer (20mM Tris; lOOmM NaCL; pH 7.5) + 0.1%HSA
• Serine protease lysis buffer 20mM Tris-HCL; lOOmM NaCl pH 7.5; + 0.2% Nonidet-P40; PBS: phosphate buffered saline, without Ca and Mg, from Gibco
• centrifugation 400 X g; 5min ; RT); wash cells twice with PBS.
• Frozen lysates were thawn at 37°C for 10 minutes and stored on ice. Protein content was determined with Bradford protein assay. Lysates were diluted to 0.2-0.5mg/ml protein in serine protease buffer + HSA.
• a test compound will give values between 0% and 100% inhibition of neutrophil elastase.
• IC50 is calculated using Graphpad Prism; nonlinear fitting (log(inhibitor) vs. response - Variable slope). The IC50 value is interpolated as the concentration of test compound which leads to a neutrophil elastase activity reduction of 50%> (relative to the DMSO-treated control).
• the metabolic degradation of the test compound is assayed at 37 °C with pooled human liver microsomes.
• the final incubation volume of 100 ⁇ per time point contains TRIS buffer pH 7.6 (0.1 M), magnesium chloride (5 mM), microsomal protein (1 mg/ml) and the test compound at a final concentration of 1 ⁇ .
• the reactions are initiated by addition of beta-nicotinamide adenine dinucleotide phosphate, reduced form (NADPH, 1 mM) and terminated by transfering an aliquot into acetonitrile after different time points. Additionally, the NADPH-independent degradation is monitored in incubations without NADPH, terminated at the last time point.
• the compounds of general formula I may be used on their own or combined with other active substances of formula I according to the invention.
• the compounds of general formula I may optionally also be combined with other pharmacologically active substances. These include, B2-adrenoceptor-agonists (short and long-acting), anti-cholinergics (short and long-acting), anti- inflammatory steroids (oral and topical corticosteroids), cromoglycate, methylxanthine, dissociated-glucocorticoidmimetics, PDE3 inhibitors, PDE4- inhibitors, PDE7- inhibitors, LTD4 antagonists, EGFR- inhibitors, Dopamine agonists, PAF antagonists, Lipoxin A4 derivatives, FPRLl modulators, LTB4-receptor (BLTl, BLT2) antagonists, Histamine HI receptor antagonists, Histamine H4 receptor antagonists, dual Histamine H1/H3 -receptor antagonists, PI3 -kinase inhibitors
• 5-Lipoxygenase (5-LO) inhibitors cPLA2 inhibitors, Leukotriene A4 Hydrolase inhibitors or FLAP inhibitors
• Non-steroidal anti-inflammatory agents NSAIDs
• CRTH2 antagonists DPI -receptor modulators
• Thromboxane receptor antagonists CCR3 antagonists, CCR 4 antagonists, CCR1 antagonists, CCR5 antagonists, CCR6 antagonists, CCR7 antagonists, CCR8 antagonists, CCR9 antagonists, CCR30 antagonists, , CXCR 3 antagonists, CXCR 4 antagonists, CXCR 2 antagonists, CXCR 1 antagonists, CXCR5 antagonists, CXCR6 antagonists, CX3CR 3 antagonists, Neurokinin (NK1, NK2) antagonists, Sphingosine 1 -Phosphate receptor modulators, Sphingosine 1 phosphate lyase inhibitors, Adenosine receptor modulators as for example
• NSAIDs Non-steroidal anti
• A2a-agonists modulators of purinergic rezeptors as for example P2X7 inhibitors, Histone Deacetylase (HDAC) activators, Bradykinin (BK1, BK2) antagonists, TACE inhibitors, PPAR gamma modulators, Rho-kinase inhibitors, interleukin 1 -beta converting enzyme (ICE) inhibitors, Toll-Like receptor (TLR) modulators, HMG-CoA reductase inhibitors, VLA-4 antagonists, ICAM-1 inhibitors, SHIP agonists, GAB Aa receptor antagonist, ENaC-inhibitors,
• Prostasin- inhibitors Matriptase-inhibitors, Melanocortin receptor (MCIR, MC2R, MC3R, MC4R, MC5R) modulators, CGRP antagonists, Endothelin antagonists, TNFa antagonists, anti-TNF antibodies, anti-GM-CSF antibodies, anti-CD46 antibodies, anti-IL-1 antibodies, anti-IL-2 antibodies, anti-IL-4 antibodies, anti-IL-5 antibodies, anti-IL-13 antibodies, anti-IL-4/IL-13 antibodies, anti-TSLP antibodies, anti-OX40 antibodies, mucoregulators, immunotherapeutic agents, compounds against swelling of the airways, compounds against cough, VEGF inhibitors, NE-inhibitors, MMP9 inhibitors, MMP12 inhibitors, but also combinations of two or three active substances.
• MCIR Melanocortin receptor
• SYK- inhibitors SYK- inhibitors, NE-inhibitors, MMP9 inhibitors, MMP12 inhibitors, but also combinations of two or three active substances, i.e.:
• the compounds of the invention and their pharmaceutically acceptable salts have activity as pharmaceuticals, in particular as inhibitors of dipeptidyl peptidase I activity, and thus may be used in the treatment of:
• respiratory tract obstructive diseases of the airways including: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and
• NSAID-induced and dust-induced asthma both intermittent and persistent and of all severities, and other causes of airway hyper-responsiveness; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; alphal -antitrypsin deficiency, bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases;
• COPD chronic obstructive pulmonary disease
• bronchitis including infectious and eosinophilic bronchitis; emphysema; alphal -antitrypsin deficiency, bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases;
• lung fibrosis including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitic and thrombotic disorders of the lung vasculature, polyangiitis (Wegener Granulomatosis) and pulmonary hypertension; antitussive activity including treatment of chronic cough associated with inflammatory and secretory conditions of the airways, and iatrogenic cough; acute and chronic rhinitis including rhinitis medicamentosa, and vasomotor rhinitis; perennial and seasonal allergic rhinitis including rhinitis nervosa (hay fever); nasal polyposis; acute viral infection including the common cold, and infection due to respiratory syncytial virus, influenza, coronavirus (including SARS) and adenovirus;
• skin psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses, and delayed-type hypersensitivity reactions; phyto- and photodermatitis; seborrhoeic dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosus et atrophica, pyoderma gangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitides, toxic erythemas, cutaneous eosinophilias, alopecia areata, male-pattern baldness, Sweet's syndrome, Weber-Christian syndrome, erythema multiforme; cellulitis, both infective and non-infective; panniculitis;cutaneous lymphomas, non-melanoma
• eyes blepharitis; conjunctivitis, including perennial and vernal allergic conjunctivitis; ulceris; anterior and posterior uveitis; choroiditis; autoimmune, degenerative or inflammatory disorders affecting the retina; ophthalmitis including sympathetic ophthalmitis; sarcoidosis; infections including viral , fungal, and bacterial; 4. genitourinary: nephritis including interstitial and glomerulonephritis; nephrotic syndrome;
• cystitis including acute and chronic (interstitial) cystitis and Hunner's ulcer; acute and chronic urethritis, prostatitis, epididymitis, oophoritis and salpingitis; vulvo-vaginitis; Peyronie's disease; erectile dysfunction (both male and female);
• allograft rejection acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea or following blood transfusion; or chronic graft versus host disease;
• oncology treatment of common cancers including prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain tumors and malignancies affecting the bone marrow (including the leukaemias) and lymphoproliferative systems, such as Hodgkin's and non-Hodgkin's lymphoma; including the prevention and treatment of metastatic disease and tumour recurrences, and paraneoplastic syndromes; and,
• infectious diseases virus diseases such as genital warts, common warts, plantar warts, hepatitis B, hepatitis C, herpes simplex virus, molluscum contagiosum, variola, human immunodeficiency virus (HIV), human papilloma virus (HPV), cytomegalovirus (CMV), varicella zoster virus (VZV), rhinovirus, adenovirus, coronavirus, influenza, para-influenza; bacterial diseases such as tuberculosis and mycobacterium avium, leprosy; other infectious diseases, such as fungal diseases, chlamydia, Candida, aspergillus, cryptococcal meningitis, Pneumocystis carnii, cryptosporidiosis, histoplasmosis, toxoplasmosis, trypanosome infection and leishmaniasis.
• virus diseases such as genital warts, common warts, plantar war
• a therapeutically effective dose will generally be in the range from about 0.01 mg to about 100 mg/kg of body weight per dosage of a compound of the invention; preferably, from about 0.1 mg to about 20 mg/kg of body weight per dosage.
• the dosage range would be from about 0.7 mg to about 7000 mg per dosage of a compound of the invention, preferably from about 7.0 mg to about 1400 mg per dosage. Some degree of routine dose optimization may be required to determine an optimal dosing level and pattern.
• the active ingredient may be administered from 1 to 6 times a day.
• the actual pharmaceutically effective amount or therapeutic dosage will of course depend on factors known by those skilled in the art such as age and weight of the patient, route of administration and severity of disease.
• the active ingredient will be administered at dosages and in a manner which allows a pharmaceutically effective amount to be delivered based upon patient's unique condition.

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• 2014
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