U.S. patent number RE46,630 [Application Number 14/858,408] was granted by the patent office on 2017-12-12 for substituted 4-pyridones and their use as inhibitors of neutrophil elastase activity.
This patent grant is currently assigned to Boehringer Ingelhelheim International GmbH. The grantee listed for this patent is Boehringer Ingelheim International GmbH. Invention is credited to Dennnis Fiegen, Christian Gnamm, Sandra Handschuh, Thorsten Oost, Stefan Peters, Gerald Juergen Roth.
United States Patent |
RE46,630 |
Oost , et al. |
December 12, 2017 |
Substituted 4-pyridones and their use as inhibitors of neutrophil
elastase activity
Abstract
This invention relates to substituted 4-pyridones of formula 1
##STR00001## and their use as inhibitors of neutrophil elastase
activity, pharmaceutical compositions containing the same, and
methods of using the same as agents for treatment and/or prevention
of pulmonary, gastrointestinal and genitourinary diseases,
inflammatory diseases of the skin and the eye and other auto-immune
and allergic disorders, allograft rejection, and oncological
diseases.
Inventors: |
Oost; Thorsten (Biberach an der
Riss, DE), Fiegen; Dennnis (Biberach an der Riss,
DE), Gnamm; Christian (Biberach an der Riss,
DE), Handschuh; Sandra (Biberach an der Riss,
DE), Peters; Stefan (Biberach an der Riss,
DE), Roth; Gerald Juergen (Biberach an der Riss,
DE) |
Applicant: |
Name |
City |
State |
Country |
Type |
Boehringer Ingelheim International GmbH |
Ingelheim am Rhein |
N/A |
DE |
|
|
Assignee: |
Boehringer Ingelhelheim
International GmbH (Ingelheim am Rhein, DE)
|
Family
ID: |
46963418 |
Appl.
No.: |
14/858,408 |
Filed: |
September 18, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
Reissue of: |
13971369 |
Aug 20, 2013 |
9102624 |
Aug 11, 2015 |
|
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Foreign Application Priority Data
|
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|
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Aug 23, 2012 [EP] |
|
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12181539 |
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P
17/00 (20180101); C07D 409/12 (20130101); C07D
401/14 (20130101); C07D 213/80 (20130101); C07D
401/12 (20130101); A61P 29/00 (20180101); C07D
413/12 (20130101); C07D 405/12 (20130101); C07D
409/12 (20130101); A61P 31/00 (20180101); A61P
37/08 (20180101); C07D 213/82 (20130101); A61P
43/00 (20180101); A61P 1/04 (20180101); C07D
405/14 (20130101); C07D 493/08 (20130101); A61P
11/06 (20180101); C07D 213/82 (20130101); C07D
413/12 (20130101); C07D 493/08 (20130101); C07D
405/12 (20130101); C07D 213/80 (20130101); C07D
401/12 (20130101); C07D 401/14 (20130101); C07D
405/14 (20130101); A61P 11/00 (20180101) |
Current International
Class: |
A61K
31/54 (20060101); C07D 413/12 (20060101); C07D
409/12 (20060101); C07D 493/08 (20060101); A61K
38/00 (20060101); A61P 11/06 (20060101); A61P
17/00 (20060101); A61P 29/00 (20060101); C07D
213/80 (20060101); C07D 213/82 (20060101); C07D
401/12 (20060101); C07D 401/14 (20060101); C07D
405/12 (20060101); C07D 405/14 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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1562902 |
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Aug 2005 |
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EP |
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2261211 |
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Dec 2010 |
|
EP |
|
03013528 |
|
Feb 2003 |
|
WO |
|
2006098683 |
|
Sep 2006 |
|
WO |
|
2009094417 |
|
Jul 2009 |
|
WO |
|
Other References
International Search Report, Form PCT/ISA/210, and Written Opinion,
Form PCT/ISA/237, For Corresponding Application PCT/EP2013/067426,
dated Oct. 2, 2013. cited by applicant.
|
Primary Examiner: Kunz; Gary
Attorney, Agent or Firm: Began; Marc Datlow; Philip I.
Claims
What we claim:
.[.1. A compound of formula 1 ##STR00445## wherein R.sup.1 is
H.sub.2N--, R.sup.1.1HN--, R.sup.1.2HN--,
H(O(CH.sub.2).sub.2).sub.2--HN--, H(O(CH.sub.2).sub.2).sub.3--HN--,
or H(O(CH.sub.2).sub.2).sub.4HN--; R.sup.1.1 is
C.sub.3-6-cycloalkly or a four-, five- or six-membered,
non-aromatic heteroring, wherein one, two or three elements are
replaced by an element selected independent from each other from
the group consisting of N, O, S, (O)S and (O).sub.2S; wherein each
element of one of the above mentioned rings is optionally
substituted with a residue selected from the group consisting of
HO--, O.dbd., C.sub.1-4-alkyl-, C.sub.1-4-cycloalkyl-,
C.sub.1-4-haloalkyl-, halogen, NC--; and if the rings contains
nitrogen, it is optionally substituted with C.sub.1-4-alkyl-,
C.sub.3-6-cycloalkyl-, C.sub.1-4-haloalkyl-,
C.sub.1-4-alkyl-(O)C--, C.sub.1-4-haloalkyl-(O)C--,
C.sub.3-6-cycloalkyl-(O)C--, C.sub.1-4-alkyl-O(O)C--,
C.sub.1-4-alkyl-HN(O)C--, (C.sub.1-4-alkyl).sub.2N(O)C--,
C.sub.1-4-alkyl-(O).sub.2S--; R.sup.1.2 is a branched or unbranched
C.sub.1-6-alkyl-, C.sub.2-6-alkenyl or C.sub.2-6-alkynyl,
optionally substituted independently from each other with one, two
or three residues selected from the group consisting of HO--,
O.dbd., HO--, halogen, NC--, C.sub.1-4-alkyl-O--, H.sub.2N--,
(C.sub.1-4-alkyl)-HN--, (C.sub.1-4-alkyl).sub.2N--,
C.sub.1-4-alkyl-O(O)C--, HO(O)C--, H.sub.2N--(O)C--,
(C.sub.1-4-alkyl)-HN--(O)C--, (C.sub.1-4-alkyl).sub.2N(O)C--,
(C.sub.1-4-alkyl)-(O)C--HN--,
(C.sub.1-4-alkyl)-(O)C--(C.sub.1-4-alkyl)N--,
(C.sub.1-4-alkyl)-O(O)C--HN--,
(C.sub.1-4-alkyl)-O(O)C--(C.sub.1-4-alkyl)N--, H.sub.2N--(O)
C--NH--, (C.sub.1-4-alkyl)-NH--(O)C--NH--,
(C.sub.1-4-alkyl).sub.2N--(O)C--HN--,
H.sub.2N--(O)C--(C.sub.is-alkyl)N--,
(C.sub.1-4-alkyl)-HN--(O)C--(C.sub.1-4-alkyl)N--,
(C.sub.1-4-alkyl).sub.2N--(O)C--(C.sub.1-4-alkyl) N--,
C.sub.1-4-alkyl-(O)S--, C.sub.1-4-alkyl-(O).sub.2S--,
C.sub.1-4-alkyl-(HN)(O)S--, C.sub.1-4-alkyl-(C.sub.1-4-alkyl-N)(O)
S--, C.sub.1-4 alkyl (NC--N)(O)S--,
C.sub.1-4-alkyl-(O).sub.2S--HN--,
C.sub.1-4-alkyl-(O).sub.2S--(C.sub.1-4-alkyl) N--;
Azetidinyl-(O)C--, Pyrrolidinyl-(O)C--, Piperidinyl-(O)C--,
Morpholinyl-(O)C--; Azetidinyl-(O)C--HN--, Pyrrolidinyl-(O)C--HN--,
Piperidinyl-(O)C--HN--, Morpholinyl-(O)C--HN--;
Azetidinyl-(O)C--(C.sub.1-4-alkyl)N--, Pyrrolidinyl-(O)
C--(C.sub.1-4-alkyl)N--, Piperidinyl-(O)C--(C.sub.1-4-alkyl)N--,
Morpholinyl-(O)C--(C.sub.1-4-alkyl)N--; a ring selected from
C.sub.1-6-cycloalkly, phenyl, a five- or six-membered, aromatic or
non-aromatic heteroring, wherein one, two or three elements of the
ring are replaced by an element selected independent from each
other from the group consisting of N, (O.sup.-)--N.sup.+, O, S,
(O)S and (O).sub.2S; or a ring system of two fused aromatic or
non-aromatic heterorings, wherein one or two elements of the rings
are replaced by an element selected independent from each other
from the group consisting of N, O, S, (O)S and (O).sub.2S; wherein
each element of one of the above mentioned rings and fused rings is
optionally substituted with a residue selected from the group
consisting of O.dbd., C.sub.1-4-alkyl-, C.sub.1-4-alkyl-(O)C--,
C.sub.1-4-alkyl-O(O)C--, C.sub.1-4-haloalkyl-,
C.sub.3-6cycloalkyl-, HO--, C.sub.1-4-alkyl-O--, NC--, halogen,
C.sub.1-4alkyl-S--, C.sub.1-4-alkyl-(O)S--,
C.sub.1-4-alkyl-(O).sub.2S--, Me.sub.2N--CH.sub.2--(O)C--; R.sup.2
is R.sup.2.1R.sup.2.2R.sup.2.3C--; R.sup.2.1 is phenyl or a five-
or six-membered, aromatic heteroring, wherein one, two or three
elements are replaced by an element selected independent from each
other from the group consisting of N, O and S; wherein each element
of one of the above mentioned rings is optionally substituted with
a residue selected from the group consisting of O.dbd.,
C.sub.1-4-alkyl-, C.sub.3-6-cycloalkyl-, C.sub.1-4-haloalkyl-,
halogen, NC--, C.sub.1-4-alkyl-O--, C.sub.1-4-alkyl-(O).sub.2S--,
C.sub.3-6cycloalkyl-(O).sub.2S--, C.sub.1-4-alkyl-(HN)(O)S--,
C.sub.1-4-alkyl-(C.sub.1-4-alkyl-N)(O)S--,
C.sub.1-4-alkyl-(NC--N)(O)S--; R.sup.2.2 is H or C.sub.1-4-alkyl-;
R.sup.2.3 is H, C.sub.1-4-alkyl-, C.sub.1-4-haloalkyl or
C.sub.3-6-cycloalkyl-; or R.sup.2.2 and R.sup.2.3 are forming
together a C.sub.2-5-alkylene; or R.sup.2.1 is phenyl, optionally
substituted with NC--, and R.sup.2.2 is C.sub.2-3-alkylene forming
together with the ortho position of the phenyl ring a fused ring
system, wherein optionally one element is replaced by an element
selected independent from each other from the group consisting of 0
and (O).sub.2S; R.sup.3 is of C.sub.1-4-alkyl-; R.sup.4 is phenyl
or a five- or six-membered, aromatic heteroring, wherein one or two
elements are replaced by an element selected independent from each
other from the group consisting of N, O and S; wherein each element
of one of the above mentioned rings is optionally substituted with
a residue selected from the group consisting of O.dbd.,
C.sub.1-4-alkyl-, C.sub.1-4-alkyl-O--, C.sub.1-4-haloalkyl-,
halogen; R.sup.5 is selected from the group consisting of H,
C.sub.1-4-alkyl-, C.sub.1-4-haloalkyl- or halogen; or a salt
thereof..].
.[.2. A compound of formula 1, according to claim 1, wherein
R.sup.1 is H.sub.2N--, R.sup.1.1HN--, R.sup.1.2HN--,
H(O(CH.sub.2).sub.2).sub.3--HN--; R.sup.1.1 is C.sub.3-6-cycloalkly
or a four-, five- or six-membered, non-aromatic heteroring, wherein
one or two elements are replaced by an element selected independent
from each other from the group consisting of N, O, S, (O)S and
(O).sub.2S; wherein each element of one of the above mentioned
rings is optionally substituted with a residue selected from the
group consisting of HO--, O.dbd., C.sub.1-4-alkyl-,
C.sub.1-4-cycloalkyl-, NC--; R.sup.1.2 is a branched or unbranched
C.sub.1-4-alkyl-, optionally substituted independently from each
other with one, two or three residues selected from the group
consisting of --HO--, F, NC--, C.sub.1-4-alkyl-O--,
(C.sub.1-4-alkyl).sub.2-N--, C.sub.1-4-alkyl-O(O)C--, HO(O)C--,
(C.sub.1-4-alkyl).sub.2-N(O)C--, (C.sub.1-4-alkyl)-(O)S--,
(C.sub.1-4-alkyl)-(O).sub.2S--; a ring selected from
C.sub.3-6-cycloalkly, phenyl, a five- or six-membered, aromatic or
non-aromatic heteroring, wherein one, two or three elements are
replaced by an element selected independent from each other from
the group consisting of N, (O.sup.-)--N.sup.+ and O; wherein each
element of one of the above mentioned rings is optionally
substituted with a residue selected from the group consisting of
O.dbd., halogen, C.sub.1-4-alkyl-, C.sub.1-4-haloalkyl-,
C.sub.3-6-cycloalkyl-, HO--, C.sub.1-4-alkyl-O--, NC--,
C.sub.1-4-alkyl-S--, C.sub.1-4-alkyl-(O)S--,
C.sub.1-4-alkyl-(O).sub.2S--, Me.sub.2N--CH.sub.2--(O)C--; R.sup.2
is R.sup.2.1R.sup.2.2R.sup.2.3C--; R.sup.2.1 is phenyl or a five-
or six-membered, aromatic heteroring, wherein one or two elements
are replaced by an element selected independent from each other
from the group consisting of N, O and S; wherein one or two
elements of one of the above mentioned rings are optionally
substituted with a residue selected from the group consisting of
halogen, NC--, C.sub.1-4-alkyl-, C.sub.1-4-haloalkyl-,
C.sub.1-4-alkyl-O--, C.sub.1-4-alkyl-(O).sub.2S--,
C.sub.3-6cycloalkyl-(O).sub.2S--; R.sup.2.2 is H or
C.sub.1-4-alkyl-; R.sup.2.3 is H or C.sub.1-4-alkyl-; R.sup.3 is
C.sub.1-4-alkyl-; R.sup.4 is phenyl or a six-membered, aromatic
heteroring, wherein one or two elements are replaced by N; wherein
one or two elements of one of the above mentioned rings are
substituted with a residue selected from the group consisting of
C.sub.1-4-alkyl-, C.sub.1-4-haloalkyl-, halogen; R.sup.5 is H; or a
salt thereof..].
.[.3. A compound of formula 1, according to claim 1, wherein
R.sup.1 is H.sub.2N , R.sup.1.1HN--, R.sup.1.2HN--,
H(O(CH.sub.2).sub.2).sub.3--HN--; R.sup.1.1 is cyclopropyl,
cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl,
pyrrolidin-2-onyl, piperidin-2-onyl,
tetrahydrothiophen-1,1-dioxidyl, each optionally substituted with
methyl, HO-- or NC--; R.sup.1.2 is a branched or unbranched
C.sub.1-4-alkyl-, optionally substituted independently from each
other with one, two or three residues selected from the group
consisting of HO--, F, NC--, C.sub.1-4-alkyl-O--,
(C.sub.1-4-alkyl).sub.2-N--, C.sub.1-4-alkyl-O(O)C--, HO(O)C--,
(C.sub.1-4-alkyl).sub.2-N (O)C--, C.sub.1-4-alkyl-(O)S--,
C.sub.1-4-alkyl-(O).sub.2S--; a ring selected from
C.sub.3-6-cycloalkly, phenyl, a five- or six-membered, aromatic or
non-aromatic heteroring, wherein one, two or three elements are
replaced by an element selected independent from each other from
the group consisting of N, (O.sup.-)--N.sup.+ and O; wherein each
element of one of the above mentioned rings is optionally
substituted with a residue selected from the group consisting of
O.dbd., halogen, C.sub.1-4-alkyl-, C.sub.1-4-haloalkyl-,
C.sub.3-6-cycloalkyl-, HO--, C.sub.1-4-alkyl-O--, NC--,
C.sub.1-4-alkyl-S--, C.sub.1-4-alkyl-(O)S--,
C.sub.1-4-alkyl-(O).sub.2S--, Me.sub.2N--CH.sub.2--(O)C--; R.sup.2
is R.sup.2.1R.sup.2.2R.sup.2.3C--; R.sup.2.1 is phenyl, a five- or
six-membered, aromatic heteroring, wherein one or two elements are
replaced by an element selected independent from each other from
the group consisting of N, O and S; wherein one or two elements of
one of the above mentioned rings are substituted with a residue
selected from the group consisting of halogen, NC--,
C.sub.1-4-alkyl-, C.sub.1-4-haloalkyl-, C.sub.1-4-alkyl-(O)--,
C.sub.1-4-alkyl-(O).sub.2S--, C.sub.3-6-cycloalkyl-(O).sub.2S--;
R.sup.2.2 is H or C.sub.1-4-alkyl-; R.sup.2.3 is H or
C.sub.1-4-alkyl-; R.sup.3 is C.sub.1-4-alkyl-; R.sup.4 is phenyl or
pyridinyl, substituted with C.sub.1-4-haloalkyl-; R.sup.5 is H; or
a salt thereof..].
.[.4. A compound of formula 1, according to claim 1, wherein
R.sup.1 is H.sub.2N--, R.sup.1.1HN--, R.sup.1.2HN--,
H(O(CH.sub.2).sub.2).sub.3--HN--; R.sup.1.1 is cyclopropyl,
cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl,
pyrrolidin-2-onyl, piperidin-2-onyl,
tetrahydrothiophen-1,1-dioxidyl, each optionally substituted with
methyl, HO-- or NC--; R.sup.1.2 is a branched or unbranched
C.sub.1-4-alkyl-, optionally substituted independently from each
other with one or two residues selected from the group consisting
of HO--, MeO--, EtO--, Me.sub.2N--, MeO(O)C--, Me.sub.2N(O)C--,
Me(O)S--, Me(O).sub.2S--; oxetanyl, tetrahydropyranyl,
tetrahydrofuranyl, dioxanyl, morpholinyl, imidazolidin-2-onyl,
pyrrolidin-2-onyl, pyridin-2-onyl; azetidinyl, pyrrolidinyl,
piperidinyl, optionally substituted with methyl,
Me.sub.2N--CH.sub.2--(O)C--; phenyl, thiophenyl, pyridinyl,
pyridazinyl, pyrid-2-onyl pyridin-1-oxidyl, each optionally
substituted with methyl, MeO--, H.sub.3C(O)S--,
H.sub.3C(O).sub.2S--; imidazolyl, pyrazolyl, oxadiazolyl,
isoxazolyl each optionally substituted with methyl; R.sup.2 is
R.sup.2.1R.sup.2.2R.sup.2.3C--; R.sup.2.1 is phenyl, pyridinyl,
each optionally substituted with one residue selected from the
group consisting of NC--, F--, Cl-- in para-position and optionally
another residue selected from the group consisting of Cl--, F--,
MeO--, Me(O).sub.2S--; R.sup.2.2 is H; R.sup.2.3 is H or methyl;
R.sup.3 is methyl; R.sup.4 is phenyl or pyridinyl, each substituted
with a residue selected from the group consisting of Me, Cl--,
F.sub.2HC--, F.sub.3C--; R.sup.5 is H; or a salt thereof..].
.[.5. A compound of formula 1, according to claim 1, wherein
R.sup.1 is R.sup.1.1HN--, R.sup.1.2HN--; R.sup.1.1 is cyclopropyl
or oxetanyl; wherein each element of one of the above mentioned
rings is optionally substituted with NC--; R.sup.1.2 is methyl or
ethyl, optionally substituted independently from each other with
one or two residues selected from the group consisting of halogen,
NC or oxadiazolyl, substituted with methyl; R.sup.2 is
R.sup.2.1R.sup.2.2R.sup.2.3C--; R.sup.2.1 is phenyl or pyridinyl;
wherein each element of one of the above mentioned rings is
optionally substituted with a residue selected from the group
consisting of NC--; R.sup.2.2 is methyl; R.sup.2.3 is H; R.sup.3 is
methyl; R.sup.4 is phenyl or pyridinyl; wherein each element of one
of the above mentioned rings is optionally substituted with a
residue selected from the group consisting of FH.sub.2C--,
F.sub.2HC--, F.sub.3C--; R.sup.5 is H; or a salt thereof..].
.[.6. A pharmaceutical composition comprising a compound of formula
1 according to claim 1 or a pharmaceutically active salt thereof
and a pharmaceutically acceptable carrier..].
.Iadd.7. A compound according to claim 1, wherein the compound is
Example 2.3 having the following structure: ##STR00446## wherein
R.sup.c is: ##STR00447## .Iaddend.
.Iadd.8. A compound according to claim 1, wherein the compound is
Example 2.5 having the following structure: ##STR00448## wherein
R.sup.c is: ##STR00449## .Iaddend.
.Iadd.9. A compound according to claim 1, wherein the compound is
Example 2.8 having the following structure: ##STR00450## wherein
R.sup.c is: ##STR00451## .Iaddend.
.Iadd.10. A compound according to claim 1, wherein the compound is
Example 2.9 having the following structure: ##STR00452## wherein
R.sup.c is: ##STR00453## .Iaddend.
.Iadd.11. A compound according to claim 1, wherein the compound is
Example 2.12 having the following structure: ##STR00454## wherein
R.sup.c is: ##STR00455## .Iaddend.
.Iadd.12. A compound according to claim 1, wherein the compound is
Example 4.1 having the following structure: ##STR00456## wherein
R.sup.e is: ##STR00457## .Iaddend.
.Iadd.13. A compound according to claim 1, wherein the compound is
Example 4.7 having the following structure: ##STR00458## wherein
R.sup.e is: ##STR00459## .Iaddend.
.Iadd.14. A compound according to claim 1, wherein the compound is
Example 4.9 having the following structure: ##STR00460## wherein
R.sup.e is: ##STR00461## .Iaddend.
.Iadd.15. A compound according to claim 1, wherein the compound is
Example 4.10 having the following structure: ##STR00462## wherein
R.sup.e is: ##STR00463## .Iaddend.
.Iadd.16. A compound according to claim 1, wherein the compound is
Example 6.8 having the following structure: ##STR00464## wherein
R.sup.g is: ##STR00465## .Iaddend.
.Iadd.17. A compound according to claim 1, wherein the compound is
Example 6.10 having the following structure: ##STR00466## wherein
R.sup.g is: ##STR00467## .Iaddend.
.Iadd.18. A compound according to claim 1, wherein the compound is
Example 6.11 having the following structure: ##STR00468## wherein
R.sup.g is: ##STR00469## .Iaddend.
.Iadd.19. A compound according to claim 1, wherein the compound is
Example 7.18 having the following structure: ##STR00470## wherein
R.sup.hR.sup.iN-is: ##STR00471## .Iaddend.
.Iadd.20. A compound according to claim 1, wherein the compound is
Example 11 having the following structure: ##STR00472##
.Iaddend.
.Iadd.21. A compound according to claim 1, wherein the compound is
Example 14 having the following structure: ##STR00473##
.Iaddend.
.Iadd.22. A compound according to claim 1, wherein the compound is
Example 39 having the following structure: ##STR00474##
.Iaddend.
.Iadd.23. A compound according to claim 1, wherein the compound is
Example 40 having the following structure: ##STR00475##
.Iaddend.
.Iadd.24. A compound according to claim 1, wherein the compound is
Example 41 having the following structure: ##STR00476## .Iaddend.
Description
FIELD OF THE INVENTION
This invention relates to substituted 4-pyridones and their use as
inhibitors of neutrophil elastase activity, pharmaceutical
compositions containing the same, and methods of using the same as
agents for treatment and/or prevention of pulmonary,
gastrointestinal and genitourinary diseases, inflammatory diseases
of the skin and the eye and other auto-immune and allergic
disorders, allograft rejection, and oncological diseases.
BACKGROUND INFORMATION
The following references describe neutrophil elastase inhibitors
with a 2-pyridone central core: WO04043924, WO05026123, WO05026124,
WO06098683, WO06098684, WO07129962, WO10094964, WO11039528. The
following references describe neutrophil elastase inhibitors with a
2-pyrazinone central core: WO07129963, WO09061271, WO09058076,
WO11110852. For a review on various inhibitors of neutrophil
elastase see: P. Sjo (Future Med. Chem. 2012, 4, 651-660).
BRIEF SUMMARY OF THE INVENTION
Neutrophil elastase is a 29 kDa serine protease. It is expressed in
bone marrow precursor cells, stored in the granula of peripheral
blood granulocytes at high concentrations and it is released upon
cellular activation. To the substrates of NE belong major elements
of the extracellular matrix: elastin, fibronectin, laminin,
collagen and proteoglycans. Neutrophil elastase activity leads to
ECM degradation, increases migration and chemotaxis of monocytes
and vascular smooth muscle cells and directly effects components of
the coagulation and fibrinolytic pathways (PAI-1 and TFPI.
Increased activity of neutrophil elastase is associated with
chronic inflammatory and fibrotic diseases of several organs.
Inhibitors of neutrophil elastase will therefore have an important
role for the treatment of different diseases like COPD, fibrosis,
cancer and others.
The compounds according to the present invention, including the
physiologically acceptable salts, are effective as inhibitors of
neutrophil elastase and exhibit favourable inhibitory potency, as
determined by the half maximal inhibitory concentration
(IC.sub.50), in an enzymatic inhibition assay.
Some compounds according to the present invention, including the
physiologically acceptable salts, exhibit favourable inhibitory
potency, as determined by the half maximal effective concentration
(EC.sub.50), in a plasma or whole-blood assay, for instance as
described in T. Stevens et al., J. Pharm. Exp. Ther. 339, 313-320
(2011).
Some compounds according to the present invention, including the
physiologically acceptable salts, exhibit favourable in vivo
potency, as determined, for example, by the half maximal effective
dose (ED.sub.50), in a model of human neutrophil elastase-induced
lung injury in mice, for instance as described in Tremblay et al.,
Chest 121, 582-588 (2002) or T. Stevens et al. (J. Pharm. Exp.
Ther. 2011, 339, 313-320).
Some compounds according to the present invention, including the
physiologically acceptable salts, exhibit favourable in vivo
potency, as determined, for example, by the half maximal effective
dose (ED.sub.50), in a model of LPS/FMLP-induced lung injury in
hamster, for instance as described in Mitsuhashi et al. (Br. J.
Pharmacol. 1999, 126, 1147-1152).
Some compounds according to the present invention, including the
physiologically acceptable salts, exhibit favourable metabolic
stability in an in vitro microsomal assay for metabolic stability
as described in E. Kerns & L. Di, Drug-like properties:
concepts, structure design and methods: from ADME to toxicity
optimization, Elsevier, 1.sup.st ed, 2008, chapter 29 and
references therein.
Some compounds according to the present invention, including the
physiologically acceptable salts, exhibit favourable metabolic
stability in an in vitro hepatocytes assay for metabolic stability
as described in E. Kerns & L. Di, Drug-like properties:
concepts, structure design and methods: from ADME to toxicity
optimization, Elsevier, 1.sup.st ed, 2008, chapter 29 and
references therein.
An improved metabolic stability in an in vitro test system is
expected to translate into a reduced in vivo clearance (CL),
because the metabolic conversion in the liver is reduced. Based on
the pharmacokinetic equation CL/F.sub.oral=Dose/AUC (F.sub.oral:
oral bioavailability, AUC: area under the curve), a reduced in vivo
clearance is expected lead to higher dose-normalized systemic
exposure (AUC) of the drug.
Some compounds according to the present invention, including the
physiologically acceptable salts, exhibit favourable permeability
in an in vitro Caco-2 cell layer method for permeability as
described in E. Kerns & L. Di, Drug-like properties: concepts,
structure design and methods: from ADME to toxicity optimization,
Elsevier, 1.sup.st ed, 2008, chapter 26 and references therein. For
an oral drug, improved permeability is expected to translate into a
higher fraction of the drug absorbed in the intestinal tract, thus,
resulting in higher dose-normalized systemic exposure (AUC).
Some compounds according to the present invention, including the
physiologically acceptable salts, exhibit favourable aqueous
solubility in a kinetic or thermodynamic solubility method as
described in E. Kerns & L. Di, Drug-like properties: concepts,
structure design and methods: from ADME to toxicity optimization,
Elsevier, 1.sup.st ed, 2008, chapter 25 and references therein. For
an oral drug, improved aqueous solubility is expected to translate
into a higher fraction of the drug absorbed in the intestinal tract
resulting in higher dose-normalized systemic exposure (AUC).
Comparatively higher dose-normalized systemic exposure (AUC) can be
advantageous in several ways: (1) If a certain systemic exposure
(AUC) needs to be achieved for efficacy, the drug can be dosed in a
lower amount. Lower dosages have the advantages of lower drug load
(parent drug and metabolites thereof) for the patient causing
potentially less side effects, and lower production costs for the
drug product. (2) Comparatively higher dose-normalized systemic
exposure (AUC) can lead to increased efficacy or longer duration of
action of the drug when the same dose is applied.
Some compounds according to the present invention, including the
physiologically acceptable salts, exhibit favourable metabolic
stability, favourable permeability and favourable aqueous
solubility. Accordingly, some compounds of the present invention
are expected to exhibit favourable pharmacokinetic (PK) properties,
in particular favourable systemic exposure (area under the curve,
AUC).
Some compounds according to the present invention, including the
physiologically acceptable salts, exhibit favourable
pharmacokinetic (PK) properties. The PK properties can be
determined in pre-clinical animal species, for example mouse, rat,
dog, guinea pig, mini pig, cynomolgus monkey, rhesus monkey. The PK
properties of a compound can be described, for example, by the
following parameters: Mean residence time (MRT), elimination
half-live (t.sub.1/2), volume-of-distribution (V.sub.D), area under
the curve (AUC), clearance (CL), bioavailability after oral
administration (F.sub.oral).
DETAILED DESCRIPTION OF THE INVENTION
Compounds of formula 1
##STR00002## wherein R.sup.1 is H.sub.2N--, R.sup.1.1HN--,
R.sup.1.2HN--, R.sup.1.2HN--, H(O(CH.sub.2).sub.2).sub.2--HN--;
H(O(CH.sub.2).sub.2).sub.3--HN--; H(O(CH.sub.2).sub.2).sub.4--HN--,
C.sub.1-4-alkyl-O--; preferably R.sup.1.1HN--, R.sup.1.2HN--;
R.sup.1.1 is C.sub.3-6-cycloalkyl or a four-, five- or
six-membered, non-aromatic heteroring, wherein one, two or three,
preferably one or two elements are replaced by an element selected
independent from each other from the group consisting of N, O, S,
(O)S and (O).sub.2S; wherein each element of one of the above
mentioned rings is optionally substituted with a residue selected
from the group consisting of HO--, O.dbd., C.sub.1-4-cycloalkyl-,
C.sub.1-4-haloalkyl-, halogen, NC--; and if the rings contains
nitrogen, it is optionally substituted with C.sub.1-4-alkyl-,
C.sub.3-6cycloalkyl-, C.sub.1-4-haloalkyl-, C.sub.1-4-alkyl-(O)C--,
C.sub.1-4-haloalkyl-(O)C--, C.sub.3-6-cycloalkyl-(O)C--,
C.sub.1-4-alkyl-O(O)C--, C.sub.1-4-alkyl-HN(O)C--,
(C.sub.1-4-alkyl).sub.2N(O)C--, C.sub.1-4-alkyl-(O).sub.2S--;
R.sup.1.2 is a branched or unbranched C.sub.1-6-alkyl-,
C.sub.2-6-alkenyl or C.sub.2-6-alkynyl, optionally substituted
independently from each other with one, two or three residues
selected from the group consisting of O.dbd., HO--, halogen, NC--,
C.sub.1-4-alkyl-O--, H.sub.2N--, (C.sub.1-4-alkyl)-HN--,
(C.sub.1-4-alkyl).sub.2N--, C.sub.1-4-alkyl-O (O)C--, HO(O)C--,
H.sub.2N--(O)C--, (C.sub.1-4-alkyl)-HN--(O)C--,
(C.sub.1-4-alkyl).sub.2N(O)C--, (C.sub.1-4-alkyl)-(O)C--HN--,
(C.sub.1-4-alkyl)-(O)C--(C.sub.1-4-alkyl)N--,
(C.sub.1-4-alkyl)-O(O)C--HN--,
(C.sub.1-4-alkyl)-O(O)C--(C.sub.1-4-alkyl)N--,
H.sub.2N--(O)C--NH--, (C.sub.1-4-alkyl)-NH--(O)C--NH--,
(C.sub.1-4-alkyl).sub.2N--(O)C--HN--,
H.sub.2N--(O)C--(C.sub.1-4-alkyl)N--,
(C.sub.1-4-alkyl)-HN--(O)C--(C.sub.1-4-alkyl)N--,
(C.sub.1-4-alkyl).sub.2N--(O)C--(C.sub.1-4-alkyl)N--,
C.sub.1-4-alkyl-(O)S--, C.sub.1-4-alkyl-(O).sub.2S--,
C.sub.1-4-alkyl-(HN)(O)S--,
C.sub.1-4-alkyl-(C.sub.1-4-alkyl-N)(O)S--,
C.sub.1-4-alkyl-(NC--N)(O)S--, C.sub.1-4-alkyl-(O).sub.2S--HN--,
C.sub.1-4-alkyl-(O).sub.2S--(C.sub.1-4-alkyl) N--;
Azetidinyl-(O)C--, Pyrrolidinyl-(O)C--, Piperidinyl-(O)C--,
Morpholinyl-(O)C--; Azetidinyl-(O)C--HN--, Pyrrolidinyl-(O)C--HN--,
Piperidinyl-(O)C--HN--, Morpholinyl-(O)C--HN--;
Azetidinyl-(O)C--(C.sub.1-4-alkyl)N--,
Pyrrolidinyl-(O)C--(C.sub.1-4-alkyl)N--,
Piperidinyl-(O)C--(C.sub.1-4-alkyl)N--,
Morpholinyl-(O)C--(C.sub.1-4-alkyl) N--; a ring selected from
C.sub.1-6-cycloalkyl-, phenyl, a five- or six-membered, aromatic or
non-aromatic heteroring, wherein one, two or three elements of the
ring are replaced by an element selected independent from each
other from the group consisting of N, (O.sup.-)--N.sup.+, O, S,
(O)S and (O).sub.2S; or a ring system of two fused aromatic or
non-aromatic heterorings, wherein one or two elements of the rings
are replaced by an element selected independent from each other
from the group consisting of N, O, S, (O)S and (O).sub.2S; wherein
each element of one of the above mentioned rings and fused rings is
optionally substituted with a residue selected from the group
consisting of O.dbd., C.sub.1-4-alkyl-O(O)C--,
C.sub.3-6-cycloalkyl-, HO--, C.sub.1-4-alkyl-O--, NC--, halogen,
C.sub.1-4-alkyl-S--, C.sub.1-4-alkyl-(O).sub.2S--,
Me.sub.2N--CH.sub.2--(O)C--; preferably methyl, HO--, MeO--, NC--,
H.sub.3CS--, H.sub.3C(O)S--, H.sub.3C(O).sub.2S--; wherein tertiary
amines in principal can also be quaternary together with
(H.sub.3C).sup.+Y.sup.- and Y is an anion; preferably a
pharmaceutically acceptable anion; preferably Cl.sup.- R.sup.2 is
R.sup.2.1R.sup.2.2R.sup.2.3C--; R2.1 is phenyl or a five- or
six-membered, aromatic heteroring, wherein one, two or three
elements are replaced by an element selected independent from each
other from the group consisting of N, O and S; wherein each element
of one of the above mentioned rings is optionally substituted with
a residue selected from the group consisting of O.dbd.,
C.sub.1-4-alkyl-, C.sub.3-6-cycloalkyl-, C.sub.1-4-haloalkyl-,
halogen, NC--, C.sub.1-4-alkyl-O--, C.sub.1-4-alkyl-(O).sub.2S--,
C.sub.3-6-cycloalkyl-(O).sub.2S--, C.sub.1-4-alkyl-O--HN--S--,
C.sub.1-4-alkyl-HN--S--,
C.sub.1-4-alkyl-O--(C.sub.1-4-alkyl)N--S--,
C.sub.1-4-alkyl-O--HN(O)S--,
(C.sub.1-4-alkyl-(C.sub.1-4-alkyl-N)(O)S--,
C.sub.1-4-alkyl-(NC--N)(O)S--; R.sup.2.2 is H or C.sub.1-4-alkyl-;
R.sup.2.3 is H or C.sub.1-4-alkyl-; or R.sup.2.2 and R.sup.2.3 are
forming together a C.sub.2-5-alkylene; or R.sup.2.1 is phenyl,
optionally substituted with NC--, and R.sup.2.2 is
C.sub.2-3-alkylene forming together with the ortho position of the
phenyl ring a fused ring system, wherein optionally one element is
replaced by an element selected independent from each other from
the group consisting of O and (O).sub.2S; e.g. R.sup.2 is a group
of one of the following formulas
##STR00003## R.sup.3 is H or C.sub.1-4-alkyl-; R.sup.4 is phenyl or
a five- or six-membered, aromatic heteroring, wherein one or two
elements are replaced by an element selected independent from each
other from the group consisting of N, O and S; wherein each element
of one of the above mentioned rings is optionally substituted with
a residue selected from the group consisting of O.dbd.,
C.sub.1-4-haloalkyl-, halogen; R.sup.5 is selected from the group
consisting of H, C.sub.1-4-alkyl-, C.sub.1-4-alkyl-O--,
C.sub.1-4-haloalkyl- or halogen; or a salt thereof.
Preferred Embodiments
Preferred are the above compounds of formula 1, wherein R.sup.1 is
H.sub.2N , R.sup.1.1HN--, R.sup.1.2HN--,
H(O(CH.sub.2).sub.2).sub.3--HN--; R.sup.1.1 is
C.sub.3-6-cycloalkyl- or a four-, five- or six-membered,
non-aromatic heteroring, wherein one or two elements are replaced
by an element selected independent from each other from the group
consisting of N, O, S, (O)S and (O).sub.2S; wherein each element of
one of the above mentioned rings is optionally substituted with a
residue selected from the group consisting of HO--, NC--, O.dbd.,
C.sub.1-4-cycloalkyl-; R.sup.1.2 is a branched or unbranched
C.sub.1-4-alkyl-, optionally substituted independently from each
other with one, two or three, preferably one or two residues
selected from the group consisting of HO--, NC--, F,
C.sub.1-4-alkyl-O--, (C.sub.1-4-alkyl).sub.2-N--,
C.sub.1-4-alkyl-O(O)C--, HO(O)C--, (C.sub.1-4-alkyl).sub.2-N(O)
C--, C.sub.1-4-alkyl-(O)S--, C.sub.1-4-alkyl-(O).sub.2S--; a ring
selected from C.sub.1-6-cycloalkyl-, phenyl, a five- or
six-membered, aromatic or non-aromatic heteroring, wherein one, two
or three elements are replaced by an element selected independent
from each other from the group consisting of N, (O.sup.-)--N.sup.+
and O; wherein each element of one of the above mentioned rings is
optionally substituted with a residue selected from the group
consisting of O.dbd., C.sub.1-4-alkyl-, C.sub.1-4-haloalkyl-,
C.sub.3-6-cycloalkyl-, HO--, C.sub.1-4-alkyl-O--, NC--,
C.sub.1-4-alkyl-S--, C.sub.1-4-alkyl-(O)S--,
C.sub.1-4-alkyl-(O).sub.2S--, Me.sub.2N--CH.sub.2--(O)C--; R.sup.2
is R.sup.2.1R.sup.2.2R.sup.2.3C--; R.sup.2.1 is phenyl or a five-
or six-membered, aromatic heteroring, wherein one or two elements
are replaced by an element selected independent from each other
from the group consisting of N, O and S; wherein one or two
elements of one of the above mentioned rings are optionally
substituted with a residue selected from the group consisting of
halogen, NC--, C.sub.1-4-alkyl-, C.sub.1-4-haloalkyl-,
C.sub.1-4-alkyl-O--, C.sub.1-4-alkyl-(O).sub.2S--,
C.sub.3-6-cycloalkyl-(O).sub.2S--; R.sup.2.2 is H or
C.sub.1-4-alkyl-; preferably H; R.sup.2.3 is H or C.sub.1-4-alkyl-;
preferably H or methyl; or R.sup.2.2 and R.sup.2.3 are forming
together a C.sub.2-5-alkylene; R.sup.3 is C.sub.1-4-alkyl-; R.sup.4
is phenyl or a six-membered, aromatic heteroring, wherein one or
two elements are replaced by N; wherein one or two elements of one
of the above mentioned rings are optionally substituted with a
residue selected from the group consisting of C.sub.1-4-alkyl-,
C.sub.1-4-haloalkyl-, halogen; R.sup.5 is H; or a salt thereof.
Preferred are the above compounds of formula 1, wherein R.sup.1 is
R.sup.1.1HN--, R.sup.1.2HN--; R.sup.1.1 is C.sub.3-6-cycloalkyl or
a four-membered, non-aromatic heteroring, wherein one element is
replaced by an O; wherein each element of one of the above
mentioned rings is optionally substituted with NC--; R.sup.1.2 is a
branched or unbranched C.sub.1-4-alkyl-, preferably methyl or
ethyl; each optionally substituted with a ring selected from phenyl
or a five- or six-membered, aromatic or non-aromatic heteroring,
wherein one, two or three elements are replaced by an element
selected independent from each other from the group consisting of
N, (O.sup.-)--N.sup.+ and O; wherein each element of one of the
above mentioned rings is optionally substituted with a residue
selected from the group consisting of O.dbd., C.sub.1-4-alkyl-,
C.sub.1-4-haloalkyl-, C.sub.3-6-cycloalkyl-, HO--,
C.sub.1-4-alkyl-O--, NC--, C.sub.1-4-alkyl-S--,
C.sub.1-4-alkyl-(O)S--, C.sub.1-4-alkyl-(O).sub.2S--,
Me.sub.2N--CH.sub.2--(O)C--; preferably
C.sub.1-4-alkyl-(O).sub.2S--; preferably H.sub.3C--(O).sub.2S--;
R.sup.2 is R.sup.2.1R.sup.2.2R.sup.2.3C--; R.sup.2.1 is phenyl, a
five- or six-membered, aromatic heteroring, wherein one or two
elements, preferably one element, are replaced by an element
selected independent from each other from the group consisting of
N, O and S, preferably phenyl or pyridinyl; wherein one or two
elements of one of the above mentioned rings are substituted with a
residue selected from the group consisting of halogen, NC--,
C.sub.1-4-alkyl-, C.sub.1-4-haloalkyl-, C.sub.1-4-alkyl-O--,
C.sub.1-4-alkyl-(O).sub.2S--, C.sub.3-6-cycloalkyl-(O).sub.2S--;
preferably F, NC--, MeO--, H.sub.3C--(O).sub.2S--; R.sup.2.2 is H
or C.sub.1-4-alkyl-; preferably H; R.sup.2.3 is H or
C.sub.1-4-alkyl-; preferably H or methyl; R.sup.3 is
C.sub.1-4-alkyl-; preferably methyl; R.sup.4 is phenyl or
pyridinyl, substituted with C.sub.1-4-haloalkyl-; preferably
FH.sub.2C--, F.sub.2HC-- or or F.sub.3C--; preferably FH.sub.2C--,
F.sub.2HC-- or F.sub.3C-- in meta position; R.sup.5 is H; or a salt
thereof.
Preferred are the above compounds of formula 1, wherein R.sup.1 is
R.sup.1.1 HN--, R.sup.1.2HN--; R.sup.1.1 is C.sub.3-6-cycloalkyl or
a four-membered, non-aromatic heteroring, wherein one element is
replaced by an O; wherein each element of one of the above
mentioned rings is optionally substituted with NC--; R.sup.1.2 is a
branched or unbranched C.sub.1-4-alkyl-, preferably methyl,
substituted with a phenyl ring which is substituted with
C.sub.1-4-alkyl-(O)S--; R.sup.2 is R.sup.2.1R.sup.2.2R.sup.2.3C--;
R.sup.2.1 is phenyl or pyridinyl substituted with NC--; R.sup.2.2
is H; R.sup.2.3 is H or C.sub.1-4-alkyl-; preferably H or methyl;
R.sup.3 is C.sub.1-4-alkyl-; preferably methyl; R.sup.4 is phenyl,
substituted with C.sub.1-4-haloalkyl-; preferably FH.sub.2C--,
F.sub.2HC-- or F.sub.3C--; preferably FH.sub.2C--, F.sub.2HC-- or
F.sub.3C-- in meta position; R.sup.5 is H; or a salt thereof.
Preferred are the above compounds of formula 1, wherein R.sup.1 is
R.sup.1.1HN--, R.sup.1.2HN--; R.sup.1.1 is C.sub.3-6-cycloalkyl or
a four-membered, non-aromatic heteroring, wherein one element is
replaced by an O; wherein each element of one of the above
mentioned rings is optionally substituted with NC--; R.sup.1.2 is a
branched or unbranched C.sub.1-4-alkyl-, preferably methyl,
substituted with a phenyl ring which is substituted with
C.sub.1-4-alkyl-(O).sub.2S--; R.sup.2 is
R.sup.2.1R.sup.2.2R.sup.2.3C--; R.sup.2.1 is phenyl or a five- or
six-membered, aromatic heteroring, wherein one or two elements are
replaced by an element selected independent from each other from
the group consisting of N, O and S, preferably phenyl or pyridinyl;
wherein one or two elements of one of the above mentioned rings are
substituted with a residue selected from the group consisting of
halogen, NC--, C.sub.1-4-alkyl-, C.sub.1-4-haloalkyl-,
C.sub.1-4-alkyl-O--, C.sub.1-4-alkyl-(O).sub.2S--; preferably F,
NC--, MeO--; R.sup.2.2 is H; R.sup.2.3 is H or C.sub.1-4-alkyl-;
preferably H or methyl; R.sup.3 is C.sub.1-4-alkyl-; preferably
methyl; R.sup.4 is phenyl, substituted with C.sub.1-4-haloalkyl-;
preferably FH.sub.2C--, F.sub.2HC-- or F.sub.3C--; preferably
FH.sub.2C--, F.sub.2HC-- or F.sub.3C-- in meta position; R.sup.5 is
H; or a salt thereof.
Preferred are the above compounds of formula 1, wherein R.sup.1 is
R.sup.1.1HN--, R.sup.1.2HN--; R.sup.1.1 is C.sub.3-6-cycloalkyl or
a four-membered, non-aromatic heteroring, wherein one element is
replaced by an O; wherein each element of one of the above
mentioned rings is optionally substituted with NC--; R.sup.1.2 is a
branched or unbranched C.sub.1-4-alkyl-; preferably methyl or ethyl
each optionally substituted with one NC-- or one, two or three F;
R.sup.2 is R.sup.2.1R.sup.2.2R.sup.2.3C--; R2.1 is phenyl or
pyridinyl substituted with a residue selected from the group
consisting of NC--, C.sub.1-4-alkyl-(O).sub.2S--; preferably NC--,
H.sub.3C--(O).sub.2S--; R.sup.2.2 is H; R.sup.2.3 is H or
C.sub.1-4-alkyl-; preferably H or methyl; R.sup.3 is
C.sub.1-4-alkyl-; preferably methyl; R.sup.4 is phenyl or
pyridinyl, substituted with C.sub.1-4-haloalkyl-; preferably
FH.sub.2C--, F.sub.2HC-- or F.sub.3C--; R.sup.5 is H; or a salt
thereof.
Preferred are the above compounds of formula 1, wherein R.sup.1 is
R.sup.1.1HN--, R.sup.1.2HN--; R.sup.1.1 is C.sub.3-6-cycloalkyl or
a four-membered, non-aromatic heteroring, wherein one element is
replaced by an O; wherein each element of one of the above
mentioned rings is optionally substituted with NC--; R.sup.1.2 is a
branched or unbranched C.sub.1-4-alkyl-, preferably methyl,
substituted with a five- or six-membered, aromatic or non-aromatic
heteroring, wherein one, two or three elements are replaced by an
element selected independent from each other from the group
consisting of N, (O.sup.-)--N.sup.+ and O; which is substituted
with O.dbd. or C.sub.1-4-alkyl-(O).sub.2S--; R.sup.2 is
R.sup.2.1R.sup.2.2R.sup.2.3C--; R.sup.2.1 is phenyl or a five- or
six-membered, aromatic heteroring, wherein one or two elements are
replaced by an element selected independent from each other from
the group consisting of N, O and S, preferably phenyl or pyridinyl;
wherein one or two elements of one of the above mentioned rings are
substituted with a residue selected from the group consisting of
halogen, NC--, C.sub.1-4-alkyl-, C.sub.1-4-haloalkyl-,
C.sub.1-4-alkyl-O--, C.sub.1-4-alkyl-(O).sub.2S--; preferably F,
NC--, MeO--; R.sup.2.2 is H or C.sub.1-4-alkyl-; preferably H;
R.sup.2.3 is H or C.sub.1-4-alkyl-; preferably H or methyl; R.sup.3
is C.sub.1-4-alkyl-; preferably methyl; R.sup.4 is phenyl,
substituted with C.sub.1-4-haloalkyl-; preferably F.sub.3C--;
preferably F.sub.3C-- in meta position; R.sup.5 is H; or a salt
thereof.
Preferred are the above compounds of formula 1, wherein R.sup.1 is
R.sup.1.1HN--, R.sup.1.2HN--; R.sup.1.1 is cyclopropyl or oxetanyl;
wherein each element of one of the above mentioned rings is
optionally substituted with NC--; R.sup.1.2 is a branched or
unbranched C.sub.1-4-alkyl-, preferably methyl, substituted with a
phenyl ring which is substituted with C.sub.1-4-alkyl-(O).sub.2S--;
R.sup.2 is R.sup.2.1R.sup.2.2R.sup.2.3C--; R.sup.2.1 is phenyl or a
five- or six-membered, aromatic heteroring, wherein one or two
elements are replaced by an element selected independent from each
other from the group consisting of N, O and S, preferably phenyl or
pyridinyl; wherein one or two elements of one of the above
mentioned rings are substituted with a residue selected from the
group consisting of halogen, NC--, C.sub.1-4-alkyl-,
C.sub.1-4-haloalkyl-, C.sub.1-4-alkyl-O--,
C.sub.1-4alkyl-(O).sub.2S--; preferably F, NC--, MeO--; R.sup.2.2
is H or C.sub.1-4-alkyl-; preferably H; R.sup.2.3 is H or
C.sub.1-4-alkyl-; preferably H or methyl; R.sup.3 is
C.sub.1-4-alkyl-; preferably methyl; R.sup.4 is pyridinyl,
substituted with C.sub.1-4-haloalkyl-; preferably F.sub.3C--;
preferably F.sub.3C-- in meta position; R.sup.5 is H; or a salt
thereof.
Preferred are the above compounds of formula 1, wherein R.sup.1 is
R.sup.1.1HN--, R.sup.1.2HN--; R.sup.1.1 is cyclopropyl or oxetanyl;
wherein each element of one of the above mentioned rings is
optionally substituted with NC--; R.sup.1.2 is a branched or
unbranched C.sub.1-4-alkyl-, preferably methyl, substituted with a
phenyl ring which is substituted with C.sub.1-4-alkyl-(O).sub.2S--;
R.sup.2 is R.sup.2.1R.sup.2.2R.sup.2.3C--; R.sup.2.1 is phenyl
substituted with NC--; R.sup.2.2 is H; R.sup.2.3 is H or
C.sub.1-4-alkyl-; preferably H or methyl; R.sup.3 is
C.sub.1-4-alkyl-; preferably methyl; R.sup.4 is phenyl or a
six-membered, aromatic heteroring, wherein one or two elements are
replaced by N; preferably phenyl or pyridinyl; wherein one or two
elements of one of the above mentioned rings are substituted with a
residue selected from the group consisting of C.sub.1-4-alkyl-,
C.sub.1-4-haloalkyl-, halogen; preferably methyl, Cl--,
HF.sub.2C--, F.sub.3C--; R.sup.5 is H; or a salt thereof.
Preferred are the above compounds of formula 1, wherein R.sup.1,
R.sup.2, R.sup.3 and R.sup.5 as described above and R.sup.4 is
phenyl or a six-membered, aromatic heteroring, wherein one or two
elements are replaced by N; preferably phenyl or pyridinyl; wherein
one or two elements of one of the above mentioned rings are
optionally substituted with a residue selected from the group
consisting of C.sub.1-4-alkyl-, C.sub.1-4-haloalkyl-, halogen;
preferably methyl, Cl--, HF.sub.2C--, F.sub.3C--; preferably
F.sub.3C--; preferably F.sub.3C-- in meta position; or a salt
thereof.
Preferred are the above compounds of formula 1, wherein R.sup.1,
R.sup.3, R.sup.4 and R.sup.5 as described above and R.sup.2 is
R.sup.2.1R.sup.2.2R.sup.2.3C--; R.sup.2.1 is phenyl or pyridinyl
substituted with NC--; R.sup.2.2 is H; R.sup.2.3 is H or methyl;
preferably methyl; or a salt thereof.
Also preferred are the above compounds of formula 1, wherein
R.sup.1 is H.sub.2N--, R.sup.1.1HN--, R.sup.1.2HN--,
H(O(CH.sub.2).sub.2).sub.3--HN--; R.sup.1.1 is cyclopropyl,
cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl,
pyrrolidin-2-onyl, piperidin-2-onyl,
tetrahydrothiophen-1,1-dioxidyl, each optionally substituted with
methyl, NC-- or HO--, preferably NC-- or methyl; R.sup.1.2 is a
branched or unbranched C.sub.1-4-alkyl-, optionally substituted
independently from each other with one or two residues selected
from the group consisting of HO--, NC--, F, MeO--, EtO--,
MeO(O)C--, Me.sub.2N (O)C--, Me(O)S--, Me(O).sub.2S--; preferably
NC--, F; oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, dioxanyl,
morpholinyl, imidazolidin-2-onyl, pyrrolidin-2-onyl,
pyridin-2-onyl; azetidinyl, pyrrolidinyl, piperidinyl, optionally
substituted with methyl, Me.sub.2N--CH.sub.2--(O)C--; phenyl,
thiophenyl, pyridinyl, pyridazinyl, pyrid-2-onyl pyridin-1-oxidyl,
each optionally substituted with methyl, MeO--, H.sub.3C(O)S--,
H.sub.3C(O).sub.2S--; imidazolyl, pyrazolyl, oxadiazolyl,
isoxazolyl each optionally substituted with methyl; R.sup.2 is
R.sup.2.1R.sup.2.2R.sup.2.3C--; R.sup.2.1 is phenyl, pyridinyl,
each optionally substituted with one residue selected from the
group consisting of NC--, F--, Cl-- in para-position, preferably
NC-- in para-position and optionally another residue selected from
the group consisting of Cl--, F--, MeO--, Me(O).sub.2S--; R.sup.2.2
is H; R.sup.2.3 is H or methyl; R.sup.3 is methyl; R.sup.4 is
phenyl or pyridinyl, each substituted with a residue selected from
the group consisting of Me, Cl--, F.sub.2HC--, F.sub.3C--; R.sup.5
is H; or a salt thereof.
Also preferred are compounds of formula 1 wherein R.sup.1 is
R.sup.1.1HN--, R.sup.1.2HN--; R.sup.1.1 is C.sub.3-6-cycloalkyl or
a four-membered, non-aromatic heteroring, wherein one element is
replaced by an O; wherein each element of one of the above
mentioned rings is optionally substituted with NC--; R.sup.1.2 is a
branched or unbranched C.sub.1-6-alkyl-, optionally substituted
independently from each other with one or two residues selected
from the group consisting of halogen, NC or a ring selected from
C.sub.1-6-cycloalkyl- or oxadiazolyl; wherein each element of one
of the above mentioned rings is optionally substituted with a
residue selected from the group consisting of C.sub.1-4-alkyl-,
NC--; R.sup.2 is R.sup.2.1R.sup.2.2R.sup.2.3C--; is R.sup.2.1 is
phenyl or pyridinyl; wherein each element of one of the above
mentioned rings is optionally substituted with a residue selected
from the group consisting of NC--; R.sup.2.2 is H or
C.sub.1-4-alkyl-; R.sup.2.3 is H or C.sub.1-4-alkyl-; R.sup.3 is H
or C.sub.1-4-alkyl-; R.sup.4 is phenyl or pyridinyl; wherein each
element of one of the above mentioned rings is optionally
substituted with a residue selected from the group consisting of
C.sub.1-4-alkyl-, C.sub.1-4-alkyl-O--, C.sub.1-4-haloalkyl-,
halogen; R.sup.5 is selected from the group consisting of H,
C.sub.1-4-alkyl-, C.sub.1-4-haloalkyl- or halogen; or a salt
thereof.
Also preferred are compounds of formula 1 wherein R.sup.1 is
R.sup.1.1HN--; R.sup.1.1 is C.sub.3-6-cycloalkyl or a
four-membered, non-aromatic heteroring, wherein one element is
replaced by an O; wherein each element of one of the above
mentioned rings is optionally substituted with NC--; R.sup.2 is
R.sup.2.1R.sup.2.2R.sup.2.3C--; R.sup.2.1 is phenyl or pyridinyl;
wherein each element of one of the above mentioned rings is
optionally substituted with a residue selected from the group
consisting of NC--; R.sup.2.2 is H or C.sub.1-4-alkyl-; R.sup.2.3
is H or C.sub.1-4-alkyl-; R.sup.3 is H or C.sub.1-4-alkyl-; R.sup.4
is phenyl or pyridinyl; wherein each element of one of the above
mentioned rings is optionally substituted with a residue selected
from the group consisting of C.sub.1-4-alkyl-, C.sub.1-4-alkyl-O--,
C.sub.1-4-haloalkyl-, halogen; R.sup.5 is selected from the group
consisting of H, C.sub.1-4-alkyl-, C.sub.1-4-haloalkyl- or halogen;
or a salt thereof.
Also preferred are compounds of formula 1 wherein R.sup.1 is
R.sup.1.2HN--; R.sup.1.2 is a branched or unbranched
C.sub.1-6-alkyl-, optionally substituted independently from each
other with one or two residues selected from the group consisting
of halogen, NC or a ring selected from C.sub.1-6-cycloalkyl- or
oxadiazolyl; wherein each element of one of the above mentioned
rings is optionally substituted with a residue selected from the
group consisting of C.sub.1-4-alkyl-, NC--; R.sup.2 is
R.sup.2.1R.sup.2.2R.sup.2.3C--; R.sup.2.1 is phenyl or pyridinyl;
wherein each element of one of the above mentioned rings is
optionally substituted with a residue selected from the group
consisting of NC--; R.sup.2.2 is H or C.sub.1-4-alkyl-; R.sup.2.3
is H or C.sub.1-4-alkyl-; R.sup.3 is H or C.sub.1-4-alkyl-; R.sup.4
is phenyl or pyridinyl; wherein each element of one of the above
mentioned rings is optionally substituted with a residue selected
from the group consisting of C.sub.1-4-alkyl-, C.sub.1-4-alkyl-O--,
C.sub.1-4-haloalkyl-, halogen; R.sup.5 is selected from the group
consisting of H, C.sub.1-4-alkyl-, C.sub.1-4-haloalkyl- or halogen;
or a salt thereof.
Also preferred are compounds of formula 1 wherein R.sup.1 is
R.sup.1.1HN--; R.sup.1.1 is C.sub.3-6-cycloalkyl or a
four-membered, non-aromatic heteroring, wherein one element is
replaced by an O; wherein each element of one of the above
mentioned rings is optionally substituted with NC--; R.sup.2 is
R.sup.2.1R.sup.2.2R.sup.2.3C--; R.sup.2.1 is phenyl or pyridinyl;
wherein each element of one of the above mentioned rings is
optionally substituted with a residue selected from the group
consisting of NC--; R.sup.2.2 is methyl; R.sup.2.3 is H; R.sup.3 is
methyl; R.sup.4 is phenyl or pyridinyl; wherein each element of one
of the above mentioned rings is optionally substituted with a
residue selected from the group consisting of FH.sub.2C--,
F.sub.2HC--, F.sub.3C--; R.sup.5 is H; or a salt thereof.
Also preferred are compounds of formula 1 wherein R.sup.1 is
R.sup.1.2HN--; R.sup.1.2 is a branched or unbranched
C.sub.1-6-alkyl-, optionally substituted independently from each
other with one or two residues selected from the group consisting
of halogen, NC or a ring selected from C.sub.1-6-cycloalkyl- or
oxadiazolyl; wherein each element of one of the above mentioned
rings is optionally substituted with a residue selected from the
group consisting of C.sub.1-4-alkyl-, NC--; R.sup.2 is
R.sup.2.1R.sup.2.2R.sup.2.3C--; R.sup.2.1 is phenyl or pyridinyl;
wherein each element of one of the above mentioned rings is
optionally substituted with a residue selected from the group
consisting of NC--; R.sup.2.2 is methyl; R.sup.2.3 is H; R.sup.3 is
methyl; R.sup.4 is phenyl or pyridinyl; wherein each element of one
of the above mentioned rings is optionally substituted with a
residue selected from the group consisting of FH.sub.2C--,
F.sub.2HC--, F.sub.3C--; R.sup.5 is H; or a salt thereof.
Also preferred are compounds of formula 1 wherein R.sup.1 is
R.sup.1.1HN--, R.sup.1.2HN--; R.sup.1.1 is cyclopropyl or oxetanyl;
wherein each element of one of the above mentioned rings is
optionally substituted with NC--; R.sup.1.2 is methyl or ethyl,
optionally substituted independently from each other with one or
two residues selected from the group consisting of halogen, NC or
oxadiazolyl, substituted with methyl; R.sup.2 is
R.sup.2.1R.sup.2.2R.sup.2.3C--; R.sup.2.1 is phenyl or pyridinyl;
wherein each element of one of the above mentioned rings is
optionally substituted with a residue selected from the group
consisting of NC--; R.sup.2.2 is methyl; R.sup.2.3 is H; R.sup.3 is
methyl; R.sup.4 is phenyl or pyridinyl; wherein each element of one
of the above mentioned rings is optionally substituted with a
residue selected from the group consisting of FH.sub.2C--,
F.sub.2HC--, F.sub.3C--; R.sup.5 is H; or a salt thereof.
Also preferred are the above compounds of formula 1, wherein
R.sup.1 is selected from a group consisting of
##STR00004## ##STR00005## ##STR00006## ##STR00007## ##STR00008##
R.sup.2 is selected from a group consisting of
##STR00009## R.sup.3 is methyl; R.sup.4 is selected from a group
consisting of
##STR00010## R.sup.5 is H; or a salt thereof.
Also preferred are the above compounds of formula 1, wherein
R.sup.1 is R.sup.1.1HN--, R.sup.1.2HN--; R.sup.1.1 is cyclopropyl
or oxetanyl; wherein each element of one of the above mentioned
rings is optionally substituted with NC--; R.sup.1.2 is methyl or
ethyl, optionally substituted independently from each other with
one or two residues selected from the group consisting of halogen,
NC or oxadiazolyl, substituted with methyl; wherein tertiary amines
in principal can also be quaternary together with
(H.sub.3C).sup.+Y.sup.- and Y is an anion; preferably a
pharmaceutically acceptable anion; preferably Cl.sup.- R.sup.2 is
selected from a group consisting of
##STR00011## R.sup.3 is methyl; R.sup.4 is selected from a group
consisting of
##STR00012## R.sup.5 is H; or a salt thereof.
From the above mentioned compounds those are preferred wherein
R.sup.2 is
##STR00013##
From the above mentioned compounds those are preferred wherein
R.sup.2 is
##STR00014##
From the above mentioned compounds those are preferred wherein
R.sup.2 is
##STR00015##
In a preferred embodiment of the invention R.sup.4 is one of the
above mentioned rings carrying the above mentioned optional
substituted in meta-position to the element connection R.sup.4 with
the compound of formula 1.
From the above mentioned compounds those are preferred wherein
R.sup.4 is
##STR00016##
From the above mentioned compounds those are preferred wherein
R.sup.4 is
##STR00017##
From the above mentioned compounds those are preferred wherein
R.sup.4 is
##STR00018##
As seen from above the compounds of formula 1 can contain one or
more nitrogen atoms and maybe from salts with one or more of them.
Thus compounds of formula 1 comprise a pharmaceutically acceptable
anion Y associated with the positive charge on a quaternary
nitrogen atom. The anion Y may be any pharmaceutically acceptable
anion of a mono or polyvalent (e.g. bivalent) acid. As will be
realized when Y is polyvalent for example a divalent anion
Y.sup.2'' the compound of formula 1 may form a hemi-salt with the
divalent anion of the formula 1
In an embodiment of the invention Y may be an "pharmaceutically
acceptable anion" of a mineral acid, preferred are chloride,
bromide, iodide, sulfate, nitrate or phosphate; or an anion of a
suitable organic acid, for example acetate, maleate, fumarate,
citrate, oxalate, succinate, tartrate, saccharinate, cinnamate,
mandelate, lactate, malonate, malate, methanesulphonate (mesylate),
p-toluenesulphonate, benzenesulfonate, napadisylate
(naphthalene-1,5-disulphonate) (e.g. a heminapadisylate),
1-hydroxy-2-naphthoate, 1-hydroxynaphthalene-2-sulphonate. In
another embodiment Y represents, for example, halide, acetate,
mesylate or benzenesulfonate. In one embodiment of the invention Y
represents halide, for example chloride, bromide or iodide. In
another embodiment Y represents iodide. In another embodiment Y
represents bromide. In another embodiment Y represents chloride. In
another embodiment Y represents acetate. In another embodiment Y
represents mesylate. In another embodiment Y represents
benzenesulfonate (besylate).
USED TERMS AND DEFINITIONS
Terms not specifically defined herein should be given the meanings
that would be given to them by one of skill in the art in light of
the disclosure and the context. As used in the specification,
however, unless specified to the contrary, the following terms have
the meaning indicated and the following conventions are adhered
to.
In the groups, radicals, or moieties defined below, the number of
carbon atoms is often specified preceding the group, for example,
C.sub.1-6-alkyl means an alkyl group or radical having 1 to 6
carbon atoms.
In general in single groups like HO, H.sub.2N, OS, O.sub.2S, NC
(cyano), HOOC, F.sub.3C or the like, the skilled artisan can see
the radical attachment point(s) to the molecule from the free
valences of the group itself. For combined groups comprising two or
more subgroups, the last named subgroup is the radical attachment
point, for example, the substituent "aryl-C.sub.1-3-alkyl-" means
an aryl group which is bound to a C.sub.1-3-alkyl-group, the latter
of which is bound to the core or to the group to which the
substituent is attached.
In case a compound of the present invention is depicted in form of
a chemical name and as a formula in case of any discrepancy the
formula shall prevail. An asterisk, a dashed or a dotted line may
be used in sub-formulas to indicate the bond which is connected to
the core molecule as defined.
For example, the term "3-carboxypropyl-group" represents the
following substituent:
##STR00019## wherein the carboxy group is attached to the third
carbon atom of the propyl group. The terms "1-methylpropyl-",
"2,2-dimethylpropyl-" or "cyclopropylmethyl-" group represent the
following groups:
##STR00020##
The asterisk, dashed or dotted line may be used in sub-formulas to
indicate the bond which is connected to the core molecule as
defined.
Many of the followings terms may be used repeatedly in the
definition of a formula or group and in each case have one of the
meanings given above, independently of one another.
The term "substituted" as used herein, 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.
The expressions "prevention", "prophylaxis", "prophylactic
treatment" or "preventive treatment" used herein should be
understood synonymous and in the sense that the risk to develop a
condition mentioned hereinbefore is reduced, especially in a
patient having elevated risk for said conditions or a corresponding
anamnesis, e.g. elevated risk of developing metabolic disorder such
as diabetes or obesity or another disorder mentioned herein. Thus
the expression "prevention of a disease" as used herein 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.
The expression "treatment" or "therapy" 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. Thus
the expression "treatment of a disease" as used herein 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.
Unless specifically indicated, throughout the specification and the
appended claims, 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.
The term halogen generally denotes fluorine, chlorine, bromine and
iodine.
As used herein the term "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).
The terms "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). Such 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).
In general, prodrugs themselves have weak or no biological activity
and are stable under ordinary conditions. Prodrugs can be readily
prepared from the parent compounds using methods known in the art,
such as those described in A Textbook of Drug Design and
Development, Krogsgaard-Larsen and H. Bundgaard (eds.), Gordon
& Breach, 1991, particularly Chapter 5: "Design and
Applications of Prodrugs"; Design of Prodrugs, H. Bundgaard (ed.),
Elsevier, 1985; Prodrugs: Topical and Ocular Drug Delivery, K. B.
Sloan (ed.), Marcel Dekker, 1998; Methods in Enzymology, K. Widder
et al. (eds.), Vol. 42, Academic Press, 1985, particularly pp.
309-396; Burger's Medicinal Chemistry and Drug Discovery, 5th Ed.,
M. Wolff (ed.), John Wiley & Sons, 1995, particularly Vol. 1
and pp. 172-178 and pp. 949-982; Pro-Drugs as Novel Delivery
Systems, T. Higuchi and V. Stella (eds.), Am. Chem. Soc., 1975;
Bioreversible Carriers in Drug Design, E. B. Roche (ed.), Elsevier,
1987, each of which is incorporated herein by reference in their
entireties.
The term "pharmaceutically acceptable prodrug" as used herein 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.
The phrase "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 commensurate with a
reasonable benefit/risk ratio.
As used herein, "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. For example, 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, ethylene-diamine, N-ethyl-glucamine, hydrabamine,
1H-imidazole, lysine, magnesium hydroxide,
4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide,
1-(2-hydroxyethyl)-pyrrolidine, sodium hydroxide, triethanolamine
(2,2',2''-nitrilotris(ethanol)), tromethamine, zinc hydroxide,
acetic acid, 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, ethane-sulfonic acid,
2-hydroxy-ethanesulfonic acid, ethylenediaminetetraacetic acid,
formic acid, fumaric acid, galactaric acid, gentisic acid,
D-glucoheptonic acid, D-gluconic acid, D-glucuronic acid, glutamic
acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid,
glycine, glycolic acid, hexanoic acid, hippuric acid, hydrobromic
acid, hydrochloric acid, isobutyric acid, DL-lactic acid,
lactobionic acid, lauric acid, lysine, maleic acid, (-)-L-malic
acid, malonic acid, DL-mandelic acid, methanesulfonic acid,
galactaric acid, naphthalene-1,5-disulfonic acid,
naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic
acid, nitric acid, octanoic acid, oleic acid, orotic acid, oxalic
acid, palmitic acid, pamoic acid (embonic acid), phosphoric acid,
propionic acid, (-)-L-pyroglutamic acid, salicylic acid,
4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid,
sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid,
p-toluenesulfonic acid and undecylenic acid. Further
pharmaceutically acceptable salts can be formed with cations from
metals like aluminium, calcium, lithium, magnesium, potassium,
sodium, zinc and the like. (also see Pharmaceutical salts, Berge,
S. M. et al., J. Pharm. Sci., (1977), 66, 1-19).
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.
The term "C.sub.1-n-alkyl", wherein n is an integer from 2 to 4 or
6 (preferably 4), either alone or in combination with another
radical denotes an acyclic, saturated, branched or linear
hydrocarbon radical with 1 to n C atoms. For example the term
C.sub.1-5-alkyl embraces the radicals H.sub.3C--,
H.sub.3C--CH.sub.2--, H.sub.3C--CH.sub.2--CH.sub.2--,
H.sub.3C--CH(CH.sub.3)--, H.sub.3C--CH.sub.2--CH.sub.2--CH.sub.2--,
H.sub.3C--CH.sub.2--CH(CH.sub.3)--, H.sub.3C--CH
(CH.sub.3)--CH.sub.2--, H.sub.3C--C(CH.sub.3).sub.2--,
H.sub.3C--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--,
H.sub.3C--CH.sub.2--CH.sub.2--CH(CH.sub.3)--,
H.sub.3C--CH.sub.2--CH(CH.sub.3)--CH.sub.2--,
H.sub.3C--CH(CH.sub.3)--CH.sub.2--CH.sub.2--,
H.sub.3C--CH.sub.2--C(CH.sub.3).sub.2--,
H.sub.3C--C(CH.sub.3).sub.2--CH.sub.2--,
H.sub.3C--CH(CH.sub.3)--CH(CH.sub.3)-- and H.sub.3C--CH.sub.2--CH
(CH.sub.2CH.sub.3)--.
The term "C.sub.2-n-alkylene" wherein n is an integer 3 to 5,
either alone or in combination with another radical, denotes an
acyclic, straight or branched chain divalent alkyl radical
containing from 2 to 5 carbon atoms. For example the term
C.sub.2-5-alkylene includes --CH.sub.2--CH.sub.2--,
--CH(CH.sub.3)--, --CH.sub.2--CH.sub.2--CH.sub.2--,
--C(CH.sub.3).sub.2--, --CH(CH.sub.2CH.sub.3)--,
--CH(CH.sub.3)--CH.sub.2--, --CH.sub.2--CH(CH.sub.3)--,
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--,
--CH.sub.2--CH.sub.2--CH(CH.sub.3)--, --CH
(CH.sub.3)--CH.sub.2--CH.sub.2--,
--CH.sub.2--CH(CH.sub.3)--CH.sub.2--,
--CH.sub.2--C(CH.sub.3).sub.2--, --C(CH.sub.3).sub.2--CH.sub.2--,
--CH(CH.sub.3)--CH(CH.sub.3)--, --CH.sub.2--CH(CH.sub.2CH.sub.3)--,
--CH(CH.sub.2CH.sub.3)--CH.sub.2--,
--CH(CH.sub.2CH.sub.2CH.sub.3)--, --CH(CH(CH.sub.3)).sub.2-- and
--C(CH.sub.3)(CH.sub.2CH.sub.3)--.
The term "C.sub.2-n-alkenyl", is used for a group as defined in the
definition for "C.sub.1-n-alkyl" with at least two carbon atoms, if
at least two of those carbon atoms of said group are bonded to each
other by a double bond.
The term "C.sub.2-n-alkynyl", is used for a group as defined in the
definition for "C.sub.1-n-alkyl" with at least two carbon atoms, if
at least two of those carbon atoms of said group are bonded to each
other by a triple bond.
The term "C.sub.3-n-cycloalkyl", wherein n is an integer from 4 to
6, either alone or in combination with another radical denotes a
cyclic, saturated, unbranched hydrocarbon radical with 3 to 6 C
atoms. For example the term C.sub.3-6-cycloalkyl includes
cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
By the term "halo" added to a "alkyl", "alkylene" or "cycloalkyl"
group (saturated or unsaturated) is such a alkyl or cycloalkyl
group meant 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.sub.2FC--, HF.sub.2C--,
F.sub.3C--.
The term "aryl" as used herein, either alone or in combination with
another radical, 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.
With the elements of a ring the atoms forming this ring are meant.
So, a phenyl ring contains 6 elements which are all carbon atoms, a
pyrrol ring contains 5 elements, wherein 4 elements are carbon
atoms and the remaining element is a nitrogen atom.
The term "non-aromatic heteroring" means a saturated, partially
saturated or unsaturated monocyclic-ring systems containing one,
two, three or four heteroatoms selected from N, (O.sup.-)N.sup.+, 0
or (O).sub.rS, wherein r=0, 1 or 2, consisting of four, five or six
ring atoms. If the term is connected with a more detailed
definition of the amount or kind of heteroatoms and the possible
size of the non-aromatic heteroring, the detailed definition is
restricting the above mentioned definition.
Furthermore the term is intended to include all possible isomeric
forms. Thus, the term includes (if not otherwise restricted) 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:
##STR00021## ##STR00022##
The term "aromatic heteroring" means a unsaturated monocyclic-ring
systems containing one, two, three or four heteroatoms selected
from N, (O.sup.-)N.sup.+, O or (O).sub.rS, wherein r=0, 1 or 2,
consisting of four, five or six ring atoms. If the term is
connected with a more detailed definition of the amount or kind of
heteroatoms and the possible size of the aromatic heteroring, the
detailed definition is restricting the above mentioned
definition.
Furthermore the term is intended to include all possible isomeric
forms. Thus, the term includes (if not otherwise restricted) 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:
##STR00023##
The term "ring system of two fused aromatic or non-aromatic
heterorings" means a saturated or unsaturated polycyclic-ring
systems including aromatic heteroring system containing one or more
heteroatoms selected from N, O or S(O).sub.r, wherein r=0, 1 or 2,
consisting of 8 to 14 ring atoms, preferably 8 to 10 ring atoms,
wherein none of the heteroatoms is part of the aromatic heteroring.
If the term is connected with a more detailed definition of the
amount or kind of heteroatoms and the possible size of the aromatic
heteroring, the detailed definition is restricting the above
mentioned definition.
Furthermore the term is intended to include all possible isomeric
forms. Thus, the term includes (if not otherwise restricted) 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:
##STR00024## ##STR00025##
The following examples are also part of the term group defined with
the term "ring system of two fused aromatic or non-aromatic
heterorings", but are also a subgroup called "ring system of two
fused aromatic heterorings"
##STR00026##
Preparation
The compounds according to the present invention and their
intermediates may be obtained using methods of synthesis which are
known to the one skilled in the art and described in the literature
of organic synthesis. Preferably, the compounds are obtained in
analogous fashion to the methods of preparation explained more
fully hereinafter, in particular as described in the experimental
section. In some cases, the order in carrying out the reaction
steps may be varied. Variants of the reaction methods that are
known to the one skilled in the art but not described in detail
here may also be used. The general processes for preparing the
compounds according to the invention will become apparent to the
one skilled in the art studying the following schemes. Starting
materials are commercially available or may be prepared by methods
that are described in the literature or herein, or may be prepared
in an analogous or similar manner. Any functional groups in the
starting materials or intermediates may be protected using
conventional protecting groups. These protecting groups may be
cleaved again at a suitable stage within the reaction sequence
using methods familiar to the one skilled in the art.
##STR00027##
Starting material I can be prepared as described in
US2003/87940.
Intermediates II can be prepared as described in WO10133973 and
US2003/87940 by heating starting material I with amines R--NH.sub.2
in the presence of a strong base, for example sodium tert-butoxide
or sodium ethoxide, in an organic solvent, for example ethanol. The
reaction usually takes place within 2 to 72 hours. Preferred
reaction temperatures are between 50.degree. C. and 150.degree.
C.
The amide coupling (Step B, intermediates II.fwdarw.intermediates
III, intermediates IV.fwdarw.intermediates V, intermediates
VI.fwdarw.compounds of the invention) can be achieved by reacting
carboxylic acid intermediates II, IV or VI with amines R'--NH.sub.2
in the presence of an amide coupling reagent, for example
O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HBTU),
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HATU), 1-propanephosphonic acid cyclic
anhydride (PPA) or
O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate (TBTU), and in the presence of a base, for
example triethylamine, diisopropyl-ethylamine (DIPEA, Hunig's base)
or N-methyl-morpholine, in an organic solvent, for example
N,N-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP),
dichloromethane, acetonitrile or dimethylacetamide (DMA) or
mixtures thereof. The reaction usually takes place within 1 to 72
hours. Preferred reaction temperatures are between 0.degree. C. and
50.degree. C., most preferred room temperature. Alternatively, the
carboxylic acid intermediates can be activated first as described
in US2003/87940, for example with 1,1'-carbonyldiimidazole (CDI) in
DMF, followed by reaction with the amine R'--NH.sub.2.
The bromination (Step C, X.dbd.Br, intermediates
II.fwdarw.intermediates IV, intermediates III.fwdarw.intermediates
V) can be achieved by reacting intermediates II or III with
bromination agents, for example bromine or N-bromosuccinimide, in
an organic solvent, for example acetic acid, dichloromethane,
methanol, acetonitrile, tetrahydrofuran or mixtures thereof. The
iodination (Step C, X.dbd.I, intermediates II.fwdarw.intermediates
IV, intermediates III.fwdarw.intermediates V) can be achieved by
reacting intermediates II or III with iodination agents, for
example iodine, iodinechloride (I--Cl) or N-iodosuccinimide, in an
organic solvent, for example acetic acid, methanol, ethanol,
dichloromethane, acetonitrile, N,N-dimethylformamide,
tetrahydrofuran or mixtures thereof. The halogenation reaction
usually takes place within 1 to 72 hours. Preferred reaction
temperatures are between 0.degree. C. and 50.degree. C., most
preferred room temperature.
The Suzuki coupling (Step D, intermediates IV.fwdarw.intermediates
VI, intermediates V.fwdarw.compounds according to the invention)
can be achieved by reacting intermediates IV or V with aryl or
heteroaryl boronic acids R''--B (OH).sub.2 or the corresponding
boronic esters in the presence of a palladium catalyst, for example
tetrakis(triphenylphosphine)palladium(0) or
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), and in
the presence of a base, for example, potassium carbonate, barium
dihydroxide or cesium carbonate, in an organic solvent, for example
toluene, benzene, ethanol, ethylene glycol dimethyl ether,
acetonitrile, dioxane or mixtures thereof, optionally in the
presence of water. The reaction usually takes place within 1 to 72
hours. Preferred reaction temperatures are between 50.degree. C.
and 150.degree. C.
Compounds according to the present invention can also be prepared
according to the following scheme starting from
4-hydroxy-6-methyl-nicotinic acid. Halogenation (Step C) as
described above, followed by Suzuki coupling (Step D) as described
above, followed by amide coupling (Step B) as described above,
yields intermediates VII. The alkylation of the pyridone nitrogen
(Step E) can be achieved by reacting intermediate VII with
alkylating agents, for example alkyl bromides, alkyl iodides, alkyl
tosylates, alkyl mesylates or dialkyl sulfates, in the presence of
a base, for example sodium carbonate, potassium carbonate,
potassium hydroxide, sodium hydroxide or cesium carbonate, in an
organic solvent, N,N-dimethylformamide (DMF),
N-methyl-2-pyrrolidone (NMP) or dimethylacetamide (DMA). The
reaction usually takes place within 1 to 72 hours. Preferred
reaction temperatures are between 50.degree. C. and 150.degree.
C.
##STR00028##
The intermediates for compounds according to the present invention
with 2-alkyl substituents can be prepared according to Venkatramani
et al., J. Het. Chem. 30, 723-738 (1993).
Preliminary Remarks:
The HPLC data given are measured under the following
conditions:
TABLE-US-00001 Method Name: V003_003 Column: XBridge C18, 4.6
.times. 30 mm, 3.5 .mu.m Column Supplier: Waters % Sol
Gradient/Solvent [H2O, 0.1% % Sol Flow Temp Time [min] NH.sub.4OH]
[Methanol] [ml/min] [.degree. C.] 0.0 95 5 4 60 0.2 95 5 4 60 1.5 0
100 4 60 1.75 0 100 4 60 Method Name: Z002_002 Column: Sunfire C18,
3 .times. 30 mm, 2.5 .mu.m Column Supplier: Waters % Sol
Gradient/Solvent [H2O, % Sol Flow Temp Time [min] 0.1% TFA]
[Methanol] [ml/min] [.degree. C.] 0.0 95 5 2.2 60 0.05 95 5 2.2 60
1.40 0 100 2.2 60 1.80 0 100 2.2 60 Method Name: Z002_005 Column:
Sunfire C18, 3 .times. 30 mm, 2.5 .mu.m Column Supplier: Waters %
Sol Gradient/Solvent [H2O, % Sol Flow Temp Time [min] 0.1% TFA]
[Methanol] [ml/min] [.degree. C.] 0.0 95 5 1.8 60 0.25 95 5 1.8 60
1.70 0 100 1.8 60 1.75 0 100 2.5 60 1.90 0 100 2.5 60 Method Name:
Z002_007 Column: Sunfire C18, 3 .times. 30 mm, 2.5 .mu.m Column
Supplier: Waters % Sol Gradient/Solvent [H2O, % Sol Flow Temp Time
[min] 0.1% TFA] [Methanol] [ml/min] [.degree. C.] 0.0 95 5 1.9 60
0.20 95 5 1.9 60 1.55 0 100 1.9 60 1.60 0 100 2.4 60 1.80 0 100 2.4
60 Method Name: Z003_001 Column: XBridge C18, 3 .times. 30 mm, 2.5
.mu.m Column Supplier: Waters % Sol Gradient/Solvent [H2O, % Sol
Flow Temp Time [min] 0.1% NH.sub.4OH] [Methanol] [ml/min] [.degree.
C.] 0.0 95 5 2.2 60 0.05 95 5 2.2 60 1.40 0 100 2.2 60 1.80 0 100
2.2 60 Method Name: Z003_003 Column: XBridge C18, 3 .times. 30 mm,
2.5 .mu.m Column Supplier: Waters % Sol Gradient/Solvent [H2O, %
Sol Flow Temp Time [min] 0.1% NH.sub.4OH] [Methanol] [ml/min]
[.degree. C.] 0.0 95 5 2.2 60 0.30 95 5 2.2 60 1.50 0 100 2.2 60
1.55 0 100 2.9 60 1.70 0 100 2.9 60 Method Name: Z011_S03 Column:
XBridge C18, 3 .times. 30 mm, 2.5 .mu.m Column Supplier: Waters %
Sol % Sol Gradient/Solvent [H2O, [Aceto- Flow Temp Time [min] 0.1%
NH.sub.4OH] nitrile] [ml/min] [.degree. C.] 0.00 97 3 2.2 60 0.20
97 3 2.2 60 1.20 0 100 2.2 60 1.25 0 100 3 60 1.40 0 100 3 60
Method Name: Z018_S04 Column: Sunfire, 3 .times. 30 mm, 2.5 .mu.m
Column Supplier: Waters % Sol % Sol Gradient/Solvent [H2O, [Aceto-
Flow Temp Time [min] 0.1% TFA] nitrile] [ml/min] [.degree. C.] 0.00
97 3 2.2 60 0.20 97 3 2.2 60 1.20 0 100 2.2 60 1.25 0 100 3 60 1.40
0 100 3 60 Method Name: 001_CA04 Column: XBridge C18_4.6 .times. 30
mm, 3.5 .mu.m Column Supplier: Waters % Sol Gradient/Solvent [H2O,
0.1% % Sol Flow Temp Time [min] NH.sub.4OH] [Methanol] [ml/min]
[.degree. C.] 0.0 80 20 2.0 60 1.7 0 100 2.0 60 2.5 0 100 2.0 60
Method Name: 002_CA04 Column: XBridge C18_4.6 .times. 30 mm, 3.5
.mu.m Column Supplier: Waters % Sol % Sol Gradient/Solvent [H2O,
[Aceto- Flow Temp Time [min] 0.1% NH.sub.4OH] nitrile] [ml/min]
[.degree. C.] 0.0 98 2 2.5 60 1.5 0 100 2.5 60 1.8 0 100 2.5 60
Method Name: 004_CA05 Column: XBridge C18_3.0 .times. 30 mm, 2.5
.mu.m Column Supplier: Waters % Sol % Sol Gradient/Solvent [H2O,
[Aceto- Flow Temp Time [min] 0.1% NH.sub.4OH] nitrile] [ml/min]
[.degree. C.] 0.0 98 2 2.0 60 1.2 0 100 2.0 60 1.4 0 100 2.0 60
Method Name: 004_CC_ZQ4 Column: Sunfire C18_4.6 .times. 50 mm, 3.5
.mu.m Column Supplier: Waters % Sol Gradient/Solvent [H2O, % Sol
Flow Temp Time [min] 0.1% TFA] [Methanol] [ml/min] [.degree. C.]
0.0 80 20 2.0 60 1.7 0 100 2.0 60 2.5 0 100 2.0 60 2.6 80 20 2.0 60
Method Name: 015_CC_SQD1 Column: BEH C18_2.1 .times. 30 mm, 1.7
.mu.m Column Supplier: Waters % Sol % Sol Gradient/Solvent [H2O,
[Aceto- Flow Temp Time [min] 0.1% NH,OH] nitrile] [ml/min]
[.degree. C.] 0.0 95.0 5.0 1.5 60 0.8 0.1 99.9 1.5 60 0.9 0.1 99.9
1.5 60 Method Name: Z002_006 Column: Sunfire C18, 3 .times. 30 mm,
2.5 .mu.m Column Supplier: Waters % Sol Gradient/Solvent [H2O, %
Sol Flow Temp Time [min] 0.1% TFA] [Methanol] [ml/min] [.degree.
C.] 0.0 95 5 1.9 60 0.20 95 5 1.9 60 1.55 0 100 1.9 60 1.60 0 100
2.4 60 1.80 0 100 2.4 60 Method Name: 005_CA01 Column: Sunfire
C18_3.0 .times. 30 mm, 2.5 .mu.m Column producer: Waters % Sol %
Sol Gradient/Solvent [H2O, 0.1% [Aceto- Flow Temp Time [min] TFA]
nitrile] [ml/min] [.degree. C.] 0.0 98.0 2.0 2.0 60.0 1.2 0.0 100.0
2.0 60.0 1.4 0.0 100.0 2.0 60.0 Method Name: 002_CA03 Column:
Sunfire C18_3.0 .times. 30 mm, 2.5 .mu.m Column producer: Waters %
Sol % Sol Gradient/Solvent [H2O, [Aceto- Flow Temp Time [min] 0.1%
TFA] nitrile] [ml/min] [.degree. C.] 0.0 99.0 1.0 2.0 60.0 0.9 0.0
100.0 2.0 60.0 1.1 0.0 100.0 2.0 60.0 Method Name: 001_CA07 Column:
Sunfire C18 2.1 .times. 50 mm, 2.5 .mu.m Column producer: Waters %
Sol % Sol Gradient/Solvent [H2O, [Acetonitrile Flow Temp Time [min]
0.1% TFA] 0.08% TFA] [ml/min] [.degree. C.] 0.0 95.0 5.0 1.5 60.0
0.75 0.0 100.0 1.5 60.0 0.85 0.0 100.0 1.5 60.0 Method Name:
Z012_S04 Column: XBridge C18, 3 .times. 30 mm, 2.5 .mu.m Column
Supplier: Waters % Sol Gradient/Solvent [H2O, % Sol Flow Temp Time
[min] 0.1% TFA] [Acetonitril] [ml/min] [.degree. C.] 0.00 97 3 2.2
60 0.20 97 3 2.2 60 1.20 0 100 2.2 60 1.25 0 100 3 60 1.40 0 100 3
60 Method Name: Z017_S04 Column: Stable Bond, 3 .times. 30 mm, 1.8
.mu.m Column Supplier: Agilent % Sol Gradient/Solvent [H2O, % Sol
Flow Temp Time [min] 0.1% TFA] [Acetonitril] [ml/min] [.degree. C.]
0.00 97 3 2.2 60 0.20 97 3 2.2 60 1.20 0 100 2.2 60 1.25 0 100 3 60
1.40 0 100 3 60
Preparation 1:
1-(4-Cyano-benzyl)-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydr-
o-pyridine-3-carboxylic acid
##STR00029##
3-Dimethylaminomethylene-6-methyl-pyran-2,4-dione
##STR00030##
To a solution of 4-hydroxy-6-methyl-2-pyrone (11.50 g, 91.2 mmol)
in toluene (30 mL) is added N,N-dimethylformamide dimethyl acetal
(13.00 mL, 97.9 mmol). After stirring for 2 h at room temperature,
the reaction mixture is evaporated under reduced pressure and
co-evaporated with toluene several times. Yield: 18.5 g; ESI mass
spectrum: [M+H].sup.+=182; Retention time HPLC: 0.72 min
(Z002_007).
1b
1-(4-Cyano-benzyl)-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic
acid
##STR00031##
A solution of 3-dimethylaminomethylene-6-methyl-pyran-2,4-dione
(preparation 1a, 2.00 g, 9.38 mmol based on 85% purity),
4-cyanobenzylamine hydrochloride (4.00 mL, 23.7 mmol) and sodium
tert-butoxide (2.74 g, 28.5 mmol) in ethanol (11 mL) is heated for
48 h at 90.degree. C. The reaction mixture is acidified with 4N
aqueous HCl and extracted several times with dichloromethane. The
combined organic layer is dried over Na.sub.2SO.sub.4, evaporated
under reduced pressure and purified by preparative reversed-phase
HPLC (Sunfire, gradient of methanol in water, 0.1% TFA, 60.degree.
C.). Yield: 0.94 g (37% of theory); ESI mass spectrum:
[M+H].sup.+=269; Retention time HPLC: 0.86 min (Z002_005).
1c
5-Bromo-1-(4-cyano-benzyl)-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carbox-
ylic acid
##STR00032##
To a solution of
1-(4-cyano-benzyl)-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic
acid (preparation 1b, 12.9 g, 48.2 mmol) in glacial acetic acid (50
ml) is added at room temperature bromine (5.0 mL). The reaction
mixture is stirred for 1 day at room temperature, then additional
bromine (3.0 mL) is added. After stirring for an additional 4 days
at room temperature, water is added to the reaction mixture and the
formed precipitate is filtered off and dried. Yield: 14.0 g (84% of
theory); ESI mass spectrum: [M+H].sup.+=347 (bromine isotope
pattern); Retention time HPLC: 1.07 min (Z002_005).
1d
1-(4-Cyano-benzyl)-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihy-
dro-pyridine-3-carboxylic acid
##STR00033##
A mixture of
5-bromo-1-(4-cyano-benzyl)-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxyl-
ic acid (preparation 1c, 2.55 g, 7.34 mmol),
3-(trifluoromethyl)phenylboronic acid (1.65 g, 8.69 mmol),
1,1'-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (340
mg, 0.47 mmol) and Cs.sub.2CO.sub.3 (4.20 g, 12.9 mmol) in dioxane
(20.0 mL) is heated for 72 h at 80.degree. C. The reaction mixture
is filtered over silica, the filtrate is concentrated under reduced
pressure and purified by preparative reversed-phase HPLC (first
purification: Sunfire, gradient of methanol in water, 0.1% TFA;
second purification: Xbridge, gradient of methanol in water, 0.1%
NH.sub.4OH, 60.degree. C.). Yield: 514 mg (17% of theory); ESI mass
spectrum: [M+H].sup.+=413; Retention time HPLC: 1.37 min
(Z002_005).
Preparation 2:
1-[1-(4-Cyano-phenyl)-ethyl]-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)--
1,4-dihydro-pyridine-3-carboxylic acid
##STR00034##
2a
1-[1-(4-Cyano-phenyl)-ethyl]-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carb-
oxylic acid
##STR00035##
Preparation 2a is prepared following the procedure described for
preparation 1b, substituting 4-cyanobenzylamine hydrochloride with
4-(1-aminoethyl)benzonitrile. ESI mass spectrum: [M+H].sup.+=283;
Retention time HPLC: 0.78 min (Z018_S04).
2b
5-Bromo-1-[1-(4-cyano-phenyl)-ethyl]-6-methyl-4-oxo-1,4-dihydro-pyridin-
e-3-carboxylic acid
##STR00036##
Preparation 2b is prepared following the procedure described for
preparation 1c, substituting preparation 1b with preparation 2a as
starting material. ESI mass spectrum: [M+H].sup.+=361 (bromine
isotope pattern); Retention time HPLC: 0.91 min (Z018_S04).
2c
1-[1-(4-Cyano-phenyl)-ethyl]-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl-
)-1,4-dihydro-pyridine-3-carboxylic acid
##STR00037##
Preparation 2c is prepared following the procedure described for
preparation 1d, substituting preparation 1c with preparation 2b as
starting material. ESI mass spectrum: [M+H].sup.+=427; Retention
time HPLC: 1.07 min (Z018_S04).
Preparation 3:
1-[1-(4-Cyano-phenyl)-ethyl]-5-(3-difluoromethyl-phenyl)-6-methyl-4-oxo-1-
,4-dihydro-pyridine-3-carboxylic acid
##STR00038##
Preparation 3 is prepared following the procedure described for
preparation 1d, substituting 3-(trifluoromethyl) phenylboronic acid
with 2-(difluoromethyl)phenylboronic acid and substituting
preparation 1c with preparation 2b as starting material. ESI mass
spectrum: [M+H].sup.+=409; Retention time HPLC: 1.00 min
(Z018_S04).
Preparation 4:
1-[1-(4-Cyano-phenyl)-ethyl]-2-methyl-4-oxo-2'-trifluoromethyl-1,4-dihydr-
o-[3,4']bipyridinyl-5-carboxylic acid
##STR00039##
Preparation 4 is prepared following the procedure described for
preparation 1d, substituting 3-(trifluoromethyl) phenylboronic acid
with 2-(trifluoromethyl)pyridine-4-boronic acid and substituting
preparation 1c with preparation 2b as starting material. ESI mass
spectrum: [M+H].sup.+=428; Retention time HPLC: 0.99 min
(Z018_S04).
Preparation 5:
6-Methyl-4-oxo-5-(3-trifluoromethylphenyl)-1,4-dihydro-pyridine-3-carboxy-
lic acid 4-methanesulfonyl-benzylamide
##STR00040##
5a 5-Bromo-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic
acid
##STR00041##
To a solution of 4-hydroxy-6-methyl-nicotinic acid (10.00 g, 65.3
mmol) in glacial acetic acid (35 mL) is added bromine (4.00 mL,
78.1 mmol). After stirring for 18 h at room temperature, additional
bromine (0.5 mL) is added and the reaction mixture is stirred for
an additional 24 h. The reaction mixture is evaporated under
reduced pressure and the remaining residue is co-evaporated with
toluene. The remaining residue is treated with a small amount of
MeOH and then triturated with water. The precipitate is filtered
off and dried. Yield: 13.8 g (92% of theory); ESI mass spectrum:
[M+H].sup.+=232 (bromine isotope pattern); Retention time HPLC:
0.61 min (Z002_002).
5b
6-Methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridine-3-carb-
oxylic acid
##STR00042##
To a solution of
5-bromo-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid
(preparation 5a, 12.05 g, 51.9 mmol),
3-(trifluoromethyl)phenylboronic acid (13.6 g, 71.6 mmol),
1,1'-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (3.60
g, 4.92 mmol) in acetonitrile (100 mL) is added 2 M aqueous
K.sub.2CO.sub.3 solution (47 mL, 94 mmol). After stirring for 6 h
at 75.degree. C., the reaction mixture is filtered and the filtrate
is concentrated under reduced pressure. The resulting residue is
dissolved in dichloromethane and extracted several times with
water. The combined aqueous layer is acidified with 4 N aqueous
HCl. The formed precipitate is filtered off, washed with 50 mL
hexanes/ethyl acetate (4:1) and dried. Yield: 13.5 g (88% of
theory); ESI mass spectrum: [M+H].sup.+=298; Retention time HPLC:
0.80 min (Z003_001).
5c
6-Methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridine-3-carb-
oxylic acid 4-methanesulfonyl-benzylamide
##STR00043##
A solution of
6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridine-3-carbox-
ylic acid (preparation 5b, 3.00 g, 10.1 mmol), HBTU (4.00 g, 10.5
mmol), DIPEA (5.00 mL, 29.4 mmol) in NMP (15 mL) is stirred for 30
min. Then, 4-methylsulfonylbenzylamine hydrochloride (2.46 g, 11.1
mmol) is added and the reaction mixture is stirred for 72 h at room
temperature. Water is added to the reaction mixture. The formed
gummy precipitate is dissolved in MeOH and purified by preparative
reversed-phase HPLC (Gilson, XBridge, gradient of methanol in
water, 0.3% NH.sub.4OH, 60.degree. C.). Yield: 1.50 g (32% of
theory); ESI mass spectrum: [M+H].sup.+=465; Retention time HPLC:
0.89 min (Z003_001).
Preparation 6:
6-Methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridine-3-carbox-
ylic acid methylamide
##STR00044##
A solution of
6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridine-3-carbox-
ylic acid (preparation 5b, 0.800 g, 2.69 mmol), HBTU (1.07 g, 2.81
mmol), DIPEA (0.78 mL, 4.59 mmol) in NMP (5 mL) is stirred for 30
min. Then, methylamine (5.00 mL of 2M solution in THF, 10.0 mmol)
is added and the reaction mixture is stirred for 18 h at room
temperature. The reaction mixture is concentrated under reduced
pressure and purified by preparative reversed-phase HPLC (XBridge,
gradient of methanol in water, 0.3% NH.sub.4OH, 60.degree. C.).
Yield: 0.20 g (24% of theory); ESI mass spectrum: [M+H].sup.+=311;
Retention time HPLC: 1.10 min (V003_003).
Preparation 7:
6-Methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridine-3-carbox-
ylic acid (5-methanesulfonyl-pyridin-2-ylmethyl)-amide
##STR00045##
A solution of
6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridine-3-carbox-
ylic acid (preparation 5b, 0.800 g, 2.69 mmol), HBTU (1.07 g, 2.81
mmol), DIPEA (1.37 mL, 8.08 mmol) in NMP (5 mL) is stirred for 30
min. Then, C-(5-methanesulfonyl-pyridin-2-yl)-methylamine (0.55 g,
2.95 mmol) is added and the reaction mixture is stirred for 18 h at
room temperature. The reaction mixture is diluted with a small
amount of MeOH. Upon addition of water a precipitate forms which is
collected by filtration and dried. Yield: 0.78 g (62% of theory);
ESI mass spectrum: [M+H].sup.+=466; Retention time HPLC: 1.09 min
(V003_003).
Preparation 8:
5-Bromo-1-(4-cyano-benzyl)-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxyl-
ic acid 4-methanesulfonyl-benzylamide
##STR00046##
A solution of
5-bromo-1-(4-cyano-benzyl)-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxyl-
ic acid (preparation 1c, 1.00 g, 2.88 mmol), TBTU (0.925 g, 2.88
mmol), DIPEA (1.50 mL, 8.67 mmol) in DMF (7 mL) is stirred for 30
min. Then, 4-(methylsulfonyl)benzylamine hydrochloride (0.766 g,
3.46 mmol) is added and the reaction mixture is stirred for 18 h at
room temperature. The reaction mixture is diluted with MeOH,
basified with NH.sub.4OH, filtered and purified by preparative
reversed-phase HPLC (XBridge, gradient of methanol in water, 0.3%
NH.sub.4OH, 60.degree. C.). Yield: 0.66 g (29% of theory); ESI mass
spectrum: [M+H].sup.+=514 (bromine isotope pattern); Retention time
HPLC: 0.88 min (Z003_001).
Preparation 9:
5-Bromo-1-[1-(4-cyano-phenyl)-ethyl]-6-methyl-4-oxo-1,4-dihydro-pyridine--
3-carboxylic acid methylamide
##STR00047##
A solution of
5-bromo-1-[1-(4-cyano-phenyl)-ethyl]-6-methyl-4-oxo-1,4-dihydro-pyridine--
3-carboxylic acid (preparation 2b, 0.51 g, 1.41 mmol), HBTU (0.620
g, 1.64 mmol), DIPEA (0.50 mL, 2.93 mmol) in DMF (2.7 g) is stirred
for 30 min. Then, methylamine (1.6 mL of 2M solution in THF, 3.20
mmol) is added and the reaction mixture is stirred for 18 h at room
temperature. The reaction mixture is diluted with MeOH and purified
by preparative reversed-phase HPLC (XBridge, gradient of
acetonitrile in water, 0.3% NH.sub.4OH, 60.degree. C.). Yield: 0.31
g (59% of theory); ESI mass spectrum: [M+H].sup.+=374 (bromine
isotope pattern); Retention time HPLC: 0.70 min (Z011_S03).
Preparation 10:
5-Bromo-1-[1-(4-cyano-phenyl)-ethyl]-6-methyl-4-oxo-1,4-dihydro-pyridine--
3-carboxylic acid ethylamide
##STR00048##
5-Bromo-1-[1-(4-cyano-phenyl)-ethyl]-6-methyl-4-oxo-1,4-dihydro-pyridine--
3-carboxylic acid ethylamide is prepared as described for
preparation 9, substituting methylamine with ethylamine. ESI mass
spectrum: [M+H].sup.+=388 (bromine isotope pattern); Retention time
HPLC: 0.92 min (Z018_S04).
Preparation 11:
5-Bromo-1-[1-(4-cyano-phenyl)-ethyl]-6-methyl-4-oxo-1,4-dihydro-pyridine--
3-carboxylic acid 4-methanesulfonyl-benzylamide
##STR00049##
5-Bromo-1-(4-cyano-benzyl)-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxyl-
ic acid 4-methanesulfonyl-benzylamide can be prepared as described
for preparation 9, substituting methylamine with
4-methylsulfonylbenzylamine hydrochloride; ESI mass spectrum:
[M+H].sup.+=528 (bromine isotope pattern); Retention time HPLC:
0.95 min (Z018_S04).
Preparation 12:
1-(4-Cyano-benzyl)-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridin-
e-3-carboxylic acid
##STR00050##
12a 1-(4-Cyano-benzyl)-4-oxo-1,4-dihydro-pyridine-3-carboxylic
acid
##STR00051##
To a solution of 4-hydroxynicotinic acid (2.00 g, 14.4 mmol) in DMF
(30 mL) is added sodium hydride (0.62 g, 55% dispersion in mineral
oil, 14.2 mmol). After stirring for 10 min at room temperature,
4-cyanobenzyl bromide (2.88 g, 14.7 mmol) is added. After stirring
for 2 h at room temperature, DMF (15 mL) is added and the reaction
mixture is diluted with water. The formed precipitate is filtered
off and dried. Yield: 2.57 g (56% of theory); ESI mass spectrum:
[M+H].sup.+=255; Retention time HPLC: 0.68 min (Z002_002).
12b
5-Bromo-1-(4-cyano-benzyl)-4-oxo-1,4-dihydro-pyridine-3-carboxylic
acid
##STR00052##
To a solution of
1-(4-cyano-benzyl)-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid
(preparation 12a, 2.57 g, 10.1 mmol) in glacial acetic acid (10 ml)
is added bromine (2 mL). The reaction mixture is stirred for 6 days
at room temperature and additional bromine (1 mL) is added on the
first 2 days, respectively. The reaction mixture is evaporated
under reduced pressure and co-evaporated with toluene twice. The
remaining residue is purified by preparative reversed-phase HPLC
(XBridge, gradient of methanol in water, 0.3% NH.sub.4OH,
60.degree. C.). Yield: 566 mg (17% of theory); ESI mass spectrum:
[M+H].sup.+=333 (bromine isotope pattern); Retention time HPLC:
0.84 min (Z002_002).
12c
1-(4-Cyano-benzyl)-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyri-
dine-3-carboxylic acid
##STR00053##
A mixture of
5-bromo-1-(4-cyano-benzyl)-4-oxo-1,4-dihydro-pyridine-3-carboxylic
acid (preparation 12b, 0.56 g, 1.68 mmol),
3-(trifluoromethyl)phenylboronic acid (0.39 g, 2.05 mmol),
1,1'-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (75 mg,
0.10 mmol) and Cs.sub.2CO.sub.3 (0.82 g, 2.51 mmol) in dioxane (4
mL) is heated for 24 h at 60.degree. C. The reaction mixture is
acidified with acetic acid and purified by preparative
reversed-phase HPLC (Sunfire, gradient of methanol in water, 0.1%
TFA, 60.degree. C.). Yield: 186 mg (28% of theory); ESI mass
spectrum: [M+H].sup.+=399; Retention time HPLC: 1.22 min
(Z002_002).
Preparation 13:
2-Methyl-4-oxo-2'-trifluoromethyl-1,4-dihydro-[3,4']bipyridinyl-5-carboxy-
lic acid 4-methanesulfonyl-benzylamide
##STR00054##
13a
2-Methyl-4-oxo-2'-trifluoromethyl-1,4-dihydro-[3,4']bipyridinyl-5-carb-
oxylic acid
##STR00055##
Preparation 13a is prepared as described for preparation 5b,
replacing 3-(trifluoromethyl)phenylboronic acid with
2-(trifluoromethyl)pyridine-4-boronic acid. ESI mass spectrum:
[M+H].sup.+=299; Retention time HPLC: 0.81 min (Z018_S04).
13b
2-Methyl-4-oxo-2'-trifluoromethyl-1,4-dihydro-[3,4']bipyridinyl-5-carb-
oxylic acid 4-methanesulfonyl-benzylamide
##STR00056##
Preparation 13b is prepared as described for preparation 5c,
replacing preparation 5b with preparation 13a as starting material
and NMP with DMF as solvent. ESI mass spectrum: [M+H].sup.+=466;
Retention time HPLC: 0.88 min (Z018_S04).
Example 1.1
1-(4-Cyano-benzyl)-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-
-pyridine-3-carboxylic acid (2-hydroxy-ethyl)-amide
##STR00057##
A solution of
1-(4-cyano-benzyl)-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydr-
o-pyridine-3-carboxylic acid (preparation 1, 70 mg, 0.102 mmol),
TBTU (37 mg, 0.115 mmol), DIPEA (40 .mu.L, 0.234 mmol) in DMF (0.5
mL) is stirred for 15 min at room temperature. Ethanolamine (7
.mu.L, 0.116 mmol) is added and the reaction mixture is stirred for
1.5 h at room temperature. The reaction mixture is purified by
preparative reversed-phase HPLC (Sunfire, gradient of methanol in
water, 0.1% TFA, 60.degree. C.). Yield: 16 mg (34% of theory); ESI
mass spectrum: [M+H].sup.+=456; Retention time HPLC: 1.34 min
(Z002_005).
The following examples are prepared as described for Example 1.1,
employing the appropriate amines instead of ethanolamine,
respectively.
##STR00058##
TABLE-US-00002 MS Retention Ex- [M + time ample R.sup.aR.sup.bN--
H].sup.+ HPLC/Method 1.2 ##STR00059## 523 1.19 min Z002_005 1.3
##STR00060## 484 1.45 min Z002_005 1.4 ##STR00061## 497 1.17 min
Z002_005 1.5 ##STR00062## 470 1.42 min Z002_005 1.6 ##STR00063##
483 1.16 min Z002_005 1.7 ##STR00064## 594 1.21 min Z002_005 1.8
##STR00065## 539 1.19 min Z003_003 1.9 ##STR00066## 470 1.16 min
Z003_003 1.10 ##STR00067## 564 1.02 min Z003_001 1.11 ##STR00068##
426 1.18 min Z003_003 1.12 ##STR00069## 495 0.79 min Z011_S03 1.13
##STR00070## 502 0.80 min Z011_S03 1.14 ##STR00071## 504 0.82 min
Z011_S03 1.15 ##STR00072## 508 0.84 min Z011_S03 1.16 ##STR00073##
532 0.83 min Z011_S03
Example 1.17
1-(4-Cyano-benzyl)-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-
-pyridine-3-carboxylic acid (2,3-dihydroxy-propyl)-amide
##STR00074##
The carboxylic acid (preparation 1, 41 mg, 0.1 mmol) is dissolved
in DMF (1 mL) and TBTU (32 mg, 0.1 mmol) and NEt.sub.3 (42 .mu.L,
0.3 mmol) are added. The mixture is shaken for 15 min and then
added to a solution of 3-amino-1,2-propanediol (11 mg, 0.12 mmol)
dissolved in DMF (0.1 mL). The reaction mixture is shaken overnight
and purified by preparative reversed phase HPLC (XBridge, gradient
of methanol in water+0.3% NH.sub.4OH, 60.degree. C.). Yield: 16 mg
(30% of theory); ESI mass spectrum: [M+H].sup.+=486; Retention time
HPLC: 1.59 min (004_CC_ZQ4).
The following examples are prepared as described for Example 1.17,
employing the appropriate amines instead of
3-amino-1,2-propanediol, respectively.
TABLE-US-00003 Exam- MS Retention time ple R.sup.aR.sup.bN-- [M +
H].sup.+ HPLC/Method 1.18 ##STR00075## 454 1.5 min 001_CA04 1.19
##STR00076## 486 1.2 min 001_CA04 1.20 ##STR00077## 484 1.7 min
004_CC_ZQ4 1.21 ##STR00078## 524 1.6 min 004_CC_ZQ4 1.22
##STR00079## 470 1.3 min 001_CA04 1.23 ##STR00080## 470 1.3 min
001_CA04 1.24 ##STR00081## 484 1.4 min 001_CA04 1.25 ##STR00082##
544 1.3 min 001_CA04 1.26 ##STR00083## 506 1.4 min 001_CA04 1.27
##STR00084## 510 1.4 min 001_CA04 1.28 ##STR00085## 523 1.3 min
001_CA04 1.29 ##STR00086## 496 1.3 min 001_CA04 1.30 ##STR00087##
506 1.7 min 004_CC_ZQ4 1.31 ##STR00088## 506 1.3 min 001_CA04 1.32
##STR00089## 506 1.3 min 001_CA04 1.33 ##STR00090## 506 1.4 min
001_CA04 1.34 ##STR00091## 506 1.4 min 001_CA04 1.35 ##STR00092##
512 1.4 min 001_CA04 1.36 ##STR00093## 523 1.3 min 001_CA04 1.37
##STR00094## 482 1.4 min 001_CA04 1.38 ##STR00095## 468 1.3 min
001_CA04 1.39 ##STR00096## 495 1.3 min 001_CA04 1.40 ##STR00097##
519 1.3 min 001_CA04 1.41 ##STR00098## 504 1.3 min 001_CA04 1.42
##STR00099## 519 1.3 min 001_CA04 1.43 ##STR00100## 517 1.4 min
001_CA04 1.44 ##STR00101## 517 1.4 min 001_CA04 1.45 ##STR00102##
517 1.4 min 001_CA04 1.46 ##STR00103## 503 1.4 min 001_CA04 1.47
##STR00104## 496 1.4 min 001_CA04 1.48 ##STR00105## 503 1.4 min
001_CA04 1.49 ##STR00106## 525 1.4 min 001_CA04 1.50 ##STR00107##
503 1.4 min 001_CA04 1.51 ##STR00108## 440 1.4 min 001_CA04 1.52
##STR00109## 412 0.82 min Z11_S03 1.53 ##STR00110## 509 1.0 min
002_CA04 1.54 ##STR00111## 523 1.1 min 002_CA04 1.55 ##STR00112##
509 1.0 min 002_CA04 1.56 ##STR00113## 533 1.2 min 002_CA04 1.57
##STR00114## 509 1.0 min 002_CA04 1.58 ##STR00115## 495 1.0 min
002_CA04 1.59 ##STR00116## 495 1.0 min 002_CA04 1.60 ##STR00117##
508 1.1 min 002_CA04 1.61 ##STR00118## 509 1.0 min 002_CA04 1.62
##STR00119## 523 1.0 min 002_CA04 1.63 ##STR00120## 484 1.1 min
002_CA04 1.64 ##STR00121## 530 1.1 min 002_CA04 1.65 ##STR00122##
497 1.0 min 002_CA04 1.66 ##STR00123## 518 1.0 min 002_CA04 1.67
##STR00124## 508 0.9 min Z011_S03
Example 2.1
1-Benzyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridine--
3-carboxylic acid 4-methanesulfonyl-benzylamide
##STR00125##
A mixture of
6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridine-3-carbox-
ylic acid 4-methane-sulfonyl-benzylamide (preparation 5, 50 mg,
0.108 mmol), K.sub.2CO.sub.3 (27 mg, 0.193 mmol) and benzyl bromide
(0.015 mL, 0.129 mmol) in DMF (0.5 mL) is stirred for 30 min at
80.degree. C. (microwave). The reaction mixture is diluted with
MeOH, filtered and purified by preparative reversed-phase HPLC
(XBridge, gradient of methanol in water, 0.3% NH.sub.4OH,
60.degree. C.). Yield: 28 mg (47% of theory); ESI mass spectrum:
[M+H].sup.+=555; Retention time HPLC: 1.16 min (Z003_001).
The following examples are prepared as described for Example 2.1,
employing the appropriate aryl- or heteroaryl-methyl bromides
instead of benzyl bromide, respectively.
##STR00126##
TABLE-US-00004 MS Retention time Example R.sup.c [M + H].sup.+
HPLC/Method 2.2 ##STR00127## 573 1.17 min Z003_001 2.3 ##STR00128##
581 1.03 min Z003_001 2.4 ##STR00129## 581 1.04 min Z003_001 2.5
##STR00130## 594 1.09 min Z003_001 2.6 ##STR00131## 610 1.12 min
Z003_001 2.7 ##STR00132## 589 1.23 min Z003_001 2.8 ##STR00133##
598 1.11 min Z003_001 2.9 ##STR00134## 598 1.12 min Z003_001 2.10
##STR00135## 580 1.10 min Z003_001 2.11 ##STR00136## 556 1.01 min
Z003_001 2.12 ##STR00137## 580 1.03 min Z003_001
Example 2.5A and Example 2.5B
Enantiomers of Example 2.5
90 mg of racemic example 2.5 are separated by chiral HPLC (Daicel
IB, 250 mm.times.20 mm, 20% MeOH+0.2% diethylamine in supercritical
CO.sub.2, 40.degree. C.).
Early eluting enantiomer (Example 2.5A): Retention time chiral
HPLC=4.086 min (Daicel Chiralpak.RTM.IB, 4.6 mm.times.250 mm 5
.mu.m, 4 ml/min, 10 min, 20% MeOH+0.2% diethylamine in
supercritical CO.sub.2, 40.degree. C., 150 bar back pressure); ESI
mass spectrum: [M+H].sup.+=594. Yield: 37 mg
Late eluting enantiomer (Example 2.5B): Retention time chiral
HPLC=5.952 min (Daicel Chiralpak.RTM.IB, 4.6 mm.times.250 mm 5
.mu.m, 4 ml/min, 10 min, 20% MeOH+0.2% diethylamine in
supercritical CO.sub.2, 40.degree. C., 150 bar back pressure); ESI
mass spectrum: [M+H].sup.+=594. Yield: 34 mg
The following examples are prepared as described for Example 2.1,
substituting preparation 5 with preparation 6 and employing the
appropriate aryl- or heteroaryl-methyl bromides instead of benzyl
bromide, respectively.
##STR00138##
TABLE-US-00005 Exam- MS Retention time ple R.sup.d [M + H].sup.+
HPLC/Method 3.1 ##STR00139## 440 1.09 min Z003_001_A05 3.2
##STR00140## 427 1.02 min Z003_001_A05 3.3 ##STR00141## 419 1.18
min Z003_001_A05 3.4 ##STR00142## 435 1.23 min Z003_001_A05 3.5
##STR00143## 444 1.13 min Z003_001_A05 3.6 ##STR00144## 444 1.08
min Z003_001_A05 3.7 ##STR00145## 456 1.11 min Z003_001_A05 3.8
##STR00146## 557 0.93 min Z011_S03 3.9 ##STR00147## 427 1.04 min
Z003_001_A05
Example 3.1A and Example 3.1B
Enantiomers of Example 3.1
100 mg of racemic example 3.1 are separated by chiral HPLC (Daicel
IB, 250 mm.times.20 mm, 20% MeOH+0.2% diethylamine in supercritical
CO.sub.2, 40.degree. C.).
Early eluting enantiomer (Example 3.1A): Retention time chiral
HPLC=1.759 min (Daicel Chiralpak.RTM.IB, 4.6 mm.times.250 mm 5
.mu.m, 4 ml/min, 10 min, 20% MeOH+0.2% diethylamine in
supercritical CO.sub.2, 40.degree. C., 150 bar back pressure); ESI
mass spectrum: [M+H].sup.+=440. Yield: 43 mg
Late eluting enantiomer (Example 3.1B): Retention time chiral
HPLC=2.459 min (Daicel Chiralpak.RTM.IB, 4.6 mm.times.250 mm 5
.mu.m, 4 ml/min, 10 min, 20% MeOH+0.2% diethylamine in
supercritical CO.sub.2, 40.degree. C., 150 bar back pressure); ESI
mass spectrum: [M+H].sup.+=440. Yield: 36 mg
The following examples are prepared as described for Example 2.1,
substituting preparation 5 with preparation 7 and employing the
appropriate aryl- or heteroaryl-methyl bromides instead of benzyl
bromide, respectively.
##STR00148##
TABLE-US-00006 MS Retention time Example R.sup.c [M + H].sup.+
HPLC/Method 4.1 ##STR00149## 581 1.06 min Z003_001 4.2 ##STR00150##
590 1.46 min V003_003 4.3 ##STR00151## 557 1.23 min V003_003 4.4
##STR00152## 581 1.32 min V003_003 4.5 ##STR00153## 599 1.34 min
V003_003 4.6 ##STR00154## 573 1.17 min Z003_001 4.7 ##STR00155##
611 1.09 min Z003_001 4.8 ##STR00156## 582 1.01 min Z003_001 4.9
##STR00157## 599 1.09 min Z003_001 4.10 ##STR00158## 595 1.07 min
Z003_001
The following examples are prepared as described for Example 2.1,
substituting preparation 5 with preparation 13 and employing the
appropriate aryl- or heteroaryl-methyl bromides instead of benzyl
bromide, respectively.
##STR00159##
TABLE-US-00007 MS Retention time Example R.sup.f [M + H].sup.+
HPLC/Method 5.1 ##STR00160## 582 0.95 min Z018_S04 5.2 ##STR00161##
599 1.01 min Z018_S04 5.3 ##STR00162## 599 0.99 min Z018_S04
Example 6.1
1-(4-Cyano-benzyl)-6-methyl-4-oxo-5-phenyl-1,4-dihydro-pyridine-3-carboxyl-
ic acid 4-methanesulfonyl-benzylamide
##STR00163##
To a solution of
5-bromo-1-(4-cyano-benzyl)-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxyl-
ic acid 4-methane-sulfonyl-benzylamide (preparation 8, 80 mg, 0.156
mmol), phenylboronic acid (27 mg, 0.22 mmol),
1,1'-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (11 mg,
0.016 mmol) in acetonitrile (2 mL) is added 2 M aqueous
K.sub.2CO.sub.3 solution (0.16 mL, 0.32 mmol). After stirring for
72 h at 75.degree. C., the reaction mixture is filtered, basified
with aqueous NH.sub.4OH solution and purified by preparative
reversed-phase HPLC (XBridge, gradient of methanol in water, 0.3%
NH.sub.4OH, 60.degree. C.). Yield: 59 mg (74% of theory); ESI mass
spectrum: [M+H].sup.+=512; Retention time HPLC: 0.98 min
(Z003_001).
The following examples are prepared as described for Example 6.1,
employing the appropriate aryl- or heteroaryl-boronic acids instead
of phenylboronic acid.
##STR00164##
TABLE-US-00008 MS Retention time Example R.sup.g [M + H].sup.+
HPLC/Method 6.2 ##STR00165## 526 1.05 min Z003_001 6.3 ##STR00166##
527 0.85 min Z003_001 6.4 ##STR00167## 527 0.82 min Z003_001 6.5
##STR00168## 530 0.99 min Z003_001 6.6 ##STR00169## 543 0.91 min
Z003_001 6.7 ##STR00170## 543 0.86 min Z003_001 6.8 ##STR00171##
546 1.06 min Z003_001 6.9 ##STR00172## 547 0.95 min Z003_001 6.10
##STR00173## 562 0.93 min Z003_001 6.11 ##STR00174## 581 0.97 min
Z003_001 6.12 ##STR00175## 581 0.94 min Z003_001 6.13 ##STR00176##
581 0.99 min Z003_001
The following examples are prepared as described for Example 1.17,
replacing preparation 1 with preparation 2 as starting material and
employing the appropriate amines, respectively.
##STR00177##
TABLE-US-00009 MS Retention time Example R.sup.hR.sup.iN-- [M +
H].sup.+ HPLC/Method 7.1 ##STR00178## 511 0.5 min 015_CC_SQD1 7.2
##STR00179## 522 0.5 min 015_CC_SQD1 7.3 ##STR00180## 546 0.4 min
015_CC_SQD1 7.4 ##STR00181## 484 0.4 min 015_CC_SQD1 7.5
##STR00182## 522 0.4 min 015_CC_SQD1 7.6 ##STR00183## 532 0.4 min
015_CC_SQD1 7.7 ##STR00184## 509 0.4 min 015_CC_SQD1 7.8
##STR00185## 516 0.4 min 015_CC_SQD1 7.9 ##STR00186## 470 0.4 min
015_CC_SQD1 7.10 ##STR00187## 523 0.4 min 015_CC_SQD1 7.11
##STR00188## 417 0.5 min 015_CC_SQD1 7.12 ##STR00189## 509 0.4 min
015_CC_SQD1
Examples 7.13-7.20 are prepared as described for Example 1.17,
replacing preparation 1 with preparation 2 as starting material and
employing the appropriate amines, respectively.
##STR00190##
TABLE-US-00010 Exam- MS Retention time ple R.sup.hR.sup.iN-- [M +
H].sup.+ HPLC/Method BI01290664 7.13 ##STR00191## 484 0.78 min
005_CA01 BI01289587 7.14 ##STR00192## 484 0.77 min 002_CA03
BI01289640 7.15 ##STR00193## 498 0.81 min 005_CA01 BI01289946 7.16
##STR00194## 496 0.73 min 004_CA05 BI01252544 7.17 ##STR00195## 426
1.03 min 002_CA04 BI01229575 7.18 ##STR00196## 465 1.04 min
Z018_S04 BI01278675 7.19 ##STR00197## 482 0.87 min Z018_S04
BI01299522 7.20 ##STR00198## 490 0.93 min Z018_S04
Example 8
1-[1-(4-Cyano-phenyl)-ethyl]-5-(3-difluoromethyl-phenyl)-6-methyl-4-oxo-1,-
4-dihydro-pyridine-3-carboxylic acid methylamide
##STR00199##
To a solution of
5-bromo-1-[1-(4-cyano-phenyl)-ethyl]-6-methyl-4-oxo-1,4-dihydro-pyridine--
3-carboxylic acid methylamide (preparation 9, 100 mg, 0.267 mmol),
3-difluoromethyl-phenylboronic acid (67 mg, 0.390 mmol), palladium
(0) tetrakis(triphenylphosphine) (25 mg, 0.022 mmol) in
acetonitrile (2 mL) is added 2 M aqueous K.sub.2CO.sub.3 solution
(0.30 mL, 0.60 mmol). After stirring for 18 h at 75.degree. C., the
reaction mixture is purified by preparative reversed-phase HPLC
(XBridge, gradient of methanol in water, 0.1% NH.sub.4OH,
60.degree. C.). Yield: 80 mg (71% of theory); ESI mass spectrum:
[M+H].sup.+=422; Retention time HPLC: 0.99 min (Z018_S04).
Example 8A and Example 8B
Enantiomers of Example 8
80 mg of racemic example 8 are separated by chiral HPLC (Daicel IB,
250 mm.times.20 mm, 20% MeOH+0.2% diethylamine in supercritical
CO.sub.2, 40.degree. C.).
Early eluting enantiomer (Example 8A): Retention time chiral
HPLC=2.143 min (Daicel Chiralpak.RTM.IB, 4.6 mm.times.250 mm 5
.mu.m, 4 ml/min, 10 min, 20% MeOH+0.2% diethylamine in
supercritical CO.sub.2, 40.degree. C., 150 bar back pressure); ESI
mass spectrum: [M+H].sup.+=422. Yield: 27 mg
Late eluting enantiomer (Example 8B): Retention time chiral
HPLC=3.136 min (Daicel Chiralpak.RTM.IB, 4.6 mm.times.250 mm 5
.mu.m, 4 ml/min, 10 min, 20% MeOH+0.2% diethylamine in
supercritical CO.sub.2, 40.degree. C., 150 bar back pressure); ESI
mass spectrum: [M+H].sup.+=422. Yield: 31 mg
The following examples are prepared as described for Example 1.17,
replacing preparation 1 with preparation 3 as starting material and
employing the appropriate amines, respectively.
##STR00200##
TABLE-US-00011 Exam- MS Retention time ple R.sup.jR.sup.kN-- [M +
H].sup.+ HPLC/Method 8.1 ##STR00201## 493 0.5 min 015_CC_SQD1 8.2
##STR00202## 504 0.4 min 015_CC_SQD1 8.3 ##STR00203## 528 0.4 min
015_CC_SQD1 8.4 ##STR00204## 466 0.4 min 015_CC_SQD1 8.5
##STR00205## 504 0.4 min 015_CC_SQD1 8.6 ##STR00206## 514 0.4 min
015_CC_SQD1 8.7 ##STR00207## 491 0.4 min 015_CC_SQD1 8.8
##STR00208## 498 0.4 min 015_CC_SQD1 8.9 ##STR00209## 452 0.4 min
015_CC_SQD1 8.10 ##STR00210## 505 0.4 min 015_CC_SQD1 8.11
##STR00211## 479 0.4 min 015_CC_SQD1 8.12 ##STR00212## 491 0.4 min
015_CC_ SQD1 8.13 ##STR00213## 480 0.7 min 004_CA05 8.14
##STR00214## 502 0.7 min 004_CA05 8.15 ##STR00215## 502 0.7 min
004_CA05 8.16 ##STR00216## 502 0.7 min 004_CA05 8.17 ##STR00217##
489 0.7 min 004_CA05 8.18 ##STR00218## 499 0.7 min 004_CA05 8.19
##STR00219## 499 0.7 min 004_CA05 8.20 ##STR00220## 499 0.7 min
004_CA05 8.21 ##STR00221## 436 0.7 min 004_CA05 8.22 ##STR00222##
408 0.6 min 004_CA05 8.23 ##STR00223## 504 0.84 min Z011_S03
Examples 8.24-8.28 are prepared as described for Example 1.17,
replacing preparation 1 with preparation 3 as starting material and
employing the appropriate amines, respectively.
##STR00224##
TABLE-US-00012 Ex- MS Retention am- [M + time HPLC/ ple
R.sup.jR.sup.kN-- H].sup.+ Method B101213073 8.24 ##STR00225## 480
1.05 min Z018_S04 B101213074 8.25 ##STR00226## 480 1.02 min
Z018_S04 B101213072 8.26 ##STR00227## 466 1.00 min Z018_S04
B101237203 8.27 ##STR00228## 450 0.89 min Z011_S03 B101237199 8.28
##STR00229## 502 0.83 min Z011_S03
Example 9
1-[1-(4-Cyano-phenyl)-ethyl]-2-methyl-4-oxo-2'-trifluoromethyl-1,4-dihydro-
-[3,4']bipyridinyl-5-carboxylic acid methylamide
##STR00230##
To a solution of
5-bromo-1-[1-(4-cyano-phenyl)-ethyl]-6-methyl-4-oxo-1,4-dihydro-pyridine--
3-carboxylic acid methylamide (preparation 9, 240 mg, 0.641 mmol),
2-(trifluoromethyl)pyridine-4-boronic acid (148 mg, 0.78 mmol),
palladium (0) tetrakis(triphenylphosphine) (79 mg, 0.068 mmol) in
acetonitrile (4 mL) is added 2 M aqueous K.sub.2CO.sub.3 solution
(0.60 mL, 1.20 mmol). After stirring for 72 h at 75.degree. C., the
reaction mixture is diluted with methanol and purified by
preparative reversed-phase HPLC (XBridge, gradient of methanol in
water, 0.1% NH.sub.4OH, 60.degree. C.). Yield: 48 mg (17% of
theory); ESI mass spectrum: [M+H].sup.+=441; Retention time HPLC:
0.78 min (Z011_S03).
Example 9A and Example 9B
Enantiomers of Example 9
48 mg of racemic example 9 are separated by chiral HPLC (Daicel IB,
250 mm.times.20 mm, 20% MeOH+0.2% diethylamine in supercritical
CO.sub.2 40.degree. C.).
Early eluting enantiomer (Example 9A): Retention time chiral
HPLC=1.832 min (Daicel Chiralpak.RTM.IB, 4.6 mm.times.250 mm 5
.mu.m, 4 ml/min, 10 min, 20% MeOH+0.2% diethylamine in
supercritical CO.sub.2, 40.degree. C., 150 bar back pressure); ESI
mass spectrum: [M+H].sup.+=441. Yield: 23 mg
Late eluting enantiomer (Example 9B): Retention time chiral
HPLC=2.710 min (Daicel Chiralpak.RTM.IB, 4.6 mm.times.250 mm 5
.mu.m, 4 ml/min, 10 min, 20% MeOH+0.2% diethylamine in
supercritical CO.sub.2, 40.degree. C., 150 bar back pressure); ESI
mass spectrum: [M+H].sup.+=441. Yield: 24 mg
The following examples are prepared as described for Example 1.17,
replacing preparation 1 with preparation 4 as starting material and
employing the appropriate amines, respectively.
##STR00231##
TABLE-US-00013 Ex- MS Retention time ample R.sup.lR.sup.mN-- [M +
H].sup.+ HPLC/Method 9.1 ##STR00232## 485 0.6 min 004_CA55 9.2
##STR00233## 533 0.6 min 004_CA55 9.3 ##STR00234## 517 0.6 min
004_CA55 9.4 ##STR00235## 510 0.6 min 004_CA55 9.5 ##STR00236## 523
0.7 min 004_CA05 9.6 ##STR00237## 547 0.6 min 004_CA05 9.7
##STR00238## 523 0.6 min 004_CA05 9.8 ##STR00239## 510 0.6 min
004_CA05 9.9 ##STR00240## 471 0.6 min 004_CA05 9.10 ##STR00241##
498 0.7 min 004_CA05 9.11 ##STR00242## 512 0.7 min 004_CA05 9.12
##STR00243## 524 0.8 min Z011_S03
Example 9.5A and Example 9.5B
Enantiomers of Example 9.5
155 mg of racemic example 9.5 are separated by chiral HPLC (Daicel
IB, 250 mm.times.20 mm, 20% MeOH+0.2% diethylamine in supercritical
CO.sub.2, 40.degree. C.).
Early eluting enantiomer (Example 9.5A): Retention time chiral
HPLC=2.106 min (Daicel Chiralpak.RTM.IB, 4.6 mm.times.250 mm 5
.mu.m, 4 ml/min, 10 min, 20% MeOH+0.2% diethylamine in
supercritical CO.sub.2, 40.degree. C., 150 bar back pressure); ESI
mass spectrum: [M+H].sup.+=523. Yield: 61 mg
Late eluting enantiomer (Example 9.5B): Retention time chiral
HPLC=3.017 min (Daicel Chiralpak.RTM.IB, 4.6 mm.times.250 mm 5
.mu.m, 4 ml/min, 10 min, 20% MeOH+0.2% diethylamine in
supercritical CO.sub.2, 40.degree. C., 150 bar back pressure); ESI
mass spectrum: [M+H].sup.+=523. Yield: 57 mg
Examples 9.13-9.55 are prepared according to one of the following
procedures (Procedure A or Procedure B) employing the appropriate
amines.
Procedure A
The carboxylic acid (preparation 4, 43 mg, 100 .mu.mol) is
dissolved in acetonitrile (1 mL) and N-methylmorpholine (55 .mu.L,
0.500 mmol) is added. The mixture is cooled to 0.degree. C., then
the amine (250 .mu.mol) and 1-propanephosphonic acid cyclic
anhydride (50% in ethyl acetate, 200 .mu.L, 343 .mu.mol) are added.
The reaction mixture is shaken overnight and purified by
preparative reversed phase HPLC (XBridge, gradient of acetonitrile
in water).
Procedure B
The carboxylic acid (preparation 4, 40 mg, 94 .mu.mol) is dissolved
in DMF (1 mL) and NEt.sub.3 (41 .mu.L, 0.29 mmol) is added. The
mixture is shaken for 15 min and then HATU (36 mg, 94 .mu.mol) is
added. The mixture is shaken for 15 min and then the amine (187
.mu.mol) is added. The reaction mixture is shaken overnight and
purified by preparative reversed phase HPLC (XBridge, gradient of
acetonitrile in water).
##STR00244##
TABLE-US-00014 Ex- Retention time am- MS HPLC/ Proce- ple
R.sup.jR.sup.kN-- [M + H].sup.+ Method dure 9.13 ##STR00245## 466
0.92 min Z011_S03 A 9.14 ##STR00246## 469 0.98 min Z011_S03 A 9.15
##STR00247## 497 0.90 min Z011_S03 A 9.16 ##STR00248## 521 0.92 min
Z011_S03 B 9.17 ##STR00249## 483 0.91 min Z011_S03 A 9.18
##STR00250## 484 0.84 min Z011_S03 A 9.19 ##STR00251## 521 0.91 min
Z011_S03 A 9.20 ##STR00252## 481 0.99 min Z011_S03 A 9.21
##STR00253## 511 0.93 min Z011_S03 A 9.22 ##STR00254## 491 0.96 min
Z011_S03 A 9.23 ##STR00255## 495 1.04 min Z011_S03 A 9.24
##STR00256## 537 0.97 min Z011_S03 A 9.25 ##STR00257## 511 0.93 min
Z011_S03 A 9.26 ##STR00258## 511 0.95 min Z011_S03 A 9.27
##STR00259## 497 0.91 min Z011_S03 A 9.28 ##STR00260## 525 0.95 min
Z011_S03 A 9.29 ##STR00261## 525 0.96 min Z011_S03 B 9.30
##STR00262## 537 0.95 min Z011_S03 A 9.31 ##STR00263## 527 1.00 min
Z011_S03 A 9.32 ##STR00264## 511 0.95 min Z011_S03 A 9.33
##STR00265## 513 1.01 min Z18_S04 A 9.34 ##STR00266## 497 0.92 min
Z011_S03 A 9.35 ##STR00267## 511 0.94 min Z011_S03 B 9.36
##STR00268## 511 0.93 min Z011_S03 B 9.37 ##STR00269## 525 0.99 min
Z011_S03 A 9.38 ##STR00270## 511 0.93 min Z011_S03 A 9.39
##STR00271## 523 0.95 min Z011_S03 A 9.40 ##STR00272## 513 0.86 min
Z011_S03 B 9.41 ##STR00273## 511 0.92 min Z011_S03 B 9.42
##STR00274## 513 0.87 min Z011_S03 B 9.43 ##STR00275## 509 1.01 min
Z011_S03 A 9.44 ##STR00276## 473 0.93 min Z011_S03 A 9.45
##STR00277## 492 0.95 min Z011_S03 A 9.46 ##STR00278## 494 0.98 min
Z011_S03 A 9.47 ##STR00279## 511 0.89 min Z011_S03 A 9.48
##STR00280## 511 0.89 min Z011_S03 A 9.49 ##STR00281## 524 0.98 min
Z011_S03 A 9.50 ##STR00282## 480 0.96 min Z011_S03 A 9.51
##STR00283## 467 0.97 min Z011_S03 A 9.52 ##STR00284## 497 1.05 min
Z011_S03 A 9.53 ##STR00285## 483 1.02 min Z011_S03 A 9.54
##STR00286## 480 0.91 min Z011_S03 A 9.55 ##STR00287## 465 0.95 min
Z011_S03 A
Examples 9.56-9.59 are prepared in two steps: (1) Amide coupling as
described for Example 1.17, replacing preparation 1 with
preparation 2b and employing the appropriate amines, respectively;
(2) Suzuki coupling as described for preparation 5b, substituting
3-s (trifluoromethyl)phenylboronic acid with
2-(trifluoromethyl)pyridine-4-boronic acid and substituting
preparation 5a with the appropriate intermediates from step 1,
respectively.
Intermediates from Step 1 (Amide Coupling)
##STR00288##
TABLE-US-00015 Intermediate Retention for MS time HPLC/ Example . .
. R.sup.jR.sup.kN-- [M + H].sup.+ Method 9.56 ##STR00289## 388 (Br
pattern) 0.75 min Z011_S03 9.57 ##STR00290## 418 (Br pattern) 0.73
min Z011_S03 9.58 ##STR00291## 432 (Br pattern) 0.78 min Z011_S03
9.59 ##STR00292## 432 (Br pattern) 0.74 min Z011_S03
##STR00293##
TABLE-US-00016 MS Retention time Example R.sup.jR.sup.kN-- [M +
H].sup.+ HPLC/Method 9.56 ##STR00294## 455 1.00 min Z018_S04 9.57
##STR00295## 485 0.81 min Z011_S03 9.58 ##STR00296## 499 1.02 min
Z018_S04 9.59 ##STR00297## 499 0.83 min Z011_S03
Example 9.56A and Example 9.56B
Enantiomers of Example 9.56
35 mg of racemic example 9.56 are separated by chiral HPLC (Daicel
IB, 250 mm.times.20 mm, 15% MeOH+0.2% diethylamine in supercritical
CO.sub.2, 40.degree. C.).
Early eluting enantiomer (Example 9.56A): Retention time chiral
HPLC=2.426 min (Daicel Chiralpak.RTM.IB, 4.6 mm.times.250 mm 5
.mu.m, 4 ml/min, 10 min, 15% MeOH+0.2% diethylamine in
supercritical CO.sub.2, 40.degree. C., 150 bar back pressure); ESI
mass spectrum: [M+H].sup.+=455. Yield: 12 mg
Late eluting enantiomer (Example 9.56B): Retention time chiral
HPLC=3.599 min (Daicel Chiralpak.RTM.IB, 4.6 mm.times.250 mm 5
.mu.m, 4 ml/min, 10 min, 15% MeOH+0.2% diethylamine in
supercritical CO.sub.2, 40.degree. C., 150 bar back pressure); ESI
mass spectrum: [M+H].sup.+=455. Yield: 11 mg
Examples 9.60-9.63 are prepared in two steps: (1) Amide coupling as
described for preparation 13b employing the appropriate amines,
respectively; (2) Alkylation as described for example 2.1,
substituting benzyl bromide with 4-(1-bromo-ethyl)-benzonitrile and
substituting preparation 5 with the appropriate intermediates from
step 1, respectively. Intermediates from Step 1 (Amide
Coupling)
##STR00298##
TABLE-US-00017 Intermediate Retention for MS time Example . . .
R.sup.jR.sup.kN-- [M + H].sup.+ HPLC/Method 9.60 ##STR00299## 370
0.51 min Z018_S04 9.61 ##STR00300## 356 0.46 min Z011_S03 9.62
##STR00301## 356 0.49 min Z011_S03 9.63 ##STR00302## 370 0.51 min
Z011_S03
##STR00303##
TABLE-US-00018 MS Retention time Example R.sup.jR.sup.kN-- [M +
H].sup.+ HPLC/Method 9.60 ##STR00304## 499 0.95 min Z018_S04 9.61
##STR00305## 485 0.61 min 004_CA55 9.62 ##STR00306## 485 0.93 min
Z018_S04 9.63 ##STR00307## 499 0.96 min Z018_S04
Example 10
1-[1-(4-Cyano-phenyl)-ethyl]-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1-
,4-dihydro-pyridine-3-carboxylic acid ethylamide
##STR00308##
To a solution of
5-bromo-1-[1-(4-cyano-phenyl)-ethyl]-6-methyl-4-oxo-1,4-dihydro-pyridine--
3-carboxylic acid ethylamide (preparation 10, 50 mg, 0.129 mmol),
3-trifluoromethyl-phenylboronic acid (29 mg, 0.155 mmol),
1,1'-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (9 mg,
0.012 mmol) in acetonitrile (1 mL) is added 2 M aqueous
K.sub.2CO.sub.3 solution (0.20 mL, 0.40 mmol). After stirring for
24 h at 75.degree. C., the reaction mixture is diluted with
methanol and purified by preparative reversed-phase HPLC (XBridge,
gradient of methanol in water, 0.1% NH.sub.4OH, 60.degree. C.).
Yield: 56 mg (96% of theory); ESI mass spectrum: [M+H].sup.+=454;
Retention time HPLC: 0.93 min (Z011_S03).
Example 10A and Example 10B
Enantiomers of Example 10
56 mg of racemic example 10 are separated by chiral HPLC (Daicel
IB, 250 mm.times.20 mm, 20% MeOH+0.2% diethylamine in supercritical
CO.sub.2, 40.degree. C.).
Early eluting enantiomer (Example 10A): Retention time chiral
HPLC=1.62 min (Daicel Chiralpak.RTM.IB, 4.6 mm.times.250 mm 5
.mu.m, 4 ml/min, 10 min, 20% MeOH+0.2% diethylamine in
supercritical CO.sub.2, 40.degree. C., 150 bar back pressure); ESI
mass spectrum: [M+H].sup.+=454. Yield: 22 mg
Late eluting enantiomer (Example 10B): Retention time chiral
HPLC=1.99 min (Daicel Chiralpak.RTM.IB, 4.6 mm.times.250 mm 5
.mu.m, 4 ml/min, 10 min, 20% MeOH+0.2% diethylamine in
supercritical CO.sub.2, 40.degree. C., 150 bar back pressure); ESI
mass spectrum: [M+H].sup.+=454. Yield: 20 mg
Example 11
1-[1-(4-Cyano-phenyl)-ethyl]-5-(3-difluoromethyl-phenyl)-6-methyl-4-oxo-1,-
4-dihydro-pyridine-3-carboxylic acid
4-methanesulfonyl-benzylamide
##STR00309##
To a solution of
5-bromo-1-[1-(4-cyano-phenyl)-ethyl]-6-methyl-4-oxo-1,4-dihydro-pyridine--
3-carboxylic acid 4-methanesulfonyl-benzylamide (preparation 11,
110 mg, 0.208 mmol), 3-difluoromethyl-phenylboronic acid (48 mg,
0.28 mmol), palladium (0) tetrakis(triphenylphosphine) (32 mg,
0.028 mmol) in acetonitrile (2 mL) is added 2 M aqueous
K.sub.2CO.sub.3 solution (0.21 mL, 0.42 mmol). After stirring for
18 h at 75.degree. C., the reaction mixture is diluted with
methanol, acidified with acetic acid and purified by preparative
reversed-phase HPLC (XBridge, gradient of methanol in water, 0.1%
TFA, 60.degree. C.). Yield: 90 mg (75% of theory); ESI mass
spectrum: [M+H].sup.+=576; Retention time HPLC: 1.03 min
(Z018_S04).
Example 11A and Example 11B
Enantiomers of Example 11
105 mg of racemic example 11 are separated by chiral HPLC (Daicel
IB, 250 mm.times.20 mm, 30% MeOH+0.2% diethylamine in supercritical
CO.sub.2, 40.degree. C.).
Early eluting enantiomer (Example 11A): Retention time chiral
HPLC=2.519 min (Daicel Chiralpak.RTM.IB, 4.6 mm.times.250 mm 5
.mu.m, 4 ml/min, 10 min, 30% MeOH+0.2% diethylamine in
supercritical CO.sub.2, 40.degree. C., 150 bar back pressure); ESI
mass spectrum: [M+H].sup.+=576. Yield: 33 mg
Late eluting enantiomer (Example 11B): Retention time chiral
HPLC=3.480 min (Daicel Chiralpak.RTM.IB, 4.6 mm.times.250 mm 5
.mu.m, 4 ml/min, 10 min, 30% MeOH+0.2% diethylamine in
supercritical CO.sub.2, 40.degree. C., 150 bar back pressure); ESI
mass spectrum: [M+H].sup.+=576. Yield: 26 mg
Example 12.1
(2-{[1-(4-Cyano-benzyl)-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-di-
hydro-pyridine-3-carbonyl]-amino}-ethyl)-trimethyl-ammonium
chloride
##STR00310##
To a solution of example 1.6 (19 mg, 0.032 mmol) in acetonitrile (1
mL) is added K.sub.2CO.sub.3 (9 mg, 0.065 mmol) and methyl iodide
(10 .mu.L, 0.162 mmol). After stirring for 2 h at 55.degree. C.,
the reaction mixture is acidified with glacial acetic acid and
purified by preparative reversed-phase HPLC (Sunfire, gradient of
methanol in water, 0.1% TFA, 60.degree. C.). The product-containing
fraction is acidified with 1N aqueous HCl, evaporated, re-dissolved
in acetonitrile/1N aqueous HCl and lyophilized Yield: 17 mg
(quantitative); ESI mass spectrum: [M+H].sup.+=497; Retention time
HPLC: 1.16 min (Z002_005).
Example 12.2
(3-{[1-(4-Cyano-benzyl)-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-di-
hydro-pyridine-3-carbonyl]-amino}-propyl)-trimethyl-ammonium
chloride
##STR00311##
Example 12.2 is prepared as described for example 12.1, replacing
example 1.6 with example 1.4 as starting material. ESI mass
spectrum: [M+H].sup.+=511; Retention time HPLC: 1.16 min
(Z002_005).
Example 12.3
4-({[1-(4-Cyano-benzyl)-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-di-
hydro-pyridine-3-carbonyl]-amino}-methyl)-1,1-dimethyl-piperidinium
chloride
##STR00312##
Example 12.3 is prepared as described for example 12.1, replacing
example 1.6 with example 1.2 as starting material. ESI mass
spectrum: [M+H].sup.+=537; Retention time HPLC: 1.18 min
(Z002_005).
Example 12.4
{2-[4-({[1-(4-Cyano-benzyl)-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,-
4-dihydro-pyridine-3-carbonyl]-amino}-methyl)-piperidin-1-yl]-2-oxo-ethyl}-
-trimethyl-ammonium chloride
##STR00313##
Example 12.4 is prepared as described for example 12.1, replacing
example 1.6 with example 1.7 as starting material. ESI mass
spectrum: [M+H].sup.+=608; Retention time HPLC: 1.21 min
(Z002_005).
Example 13.1
1-(4-Cyano-benzyl)-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridine-
-3-carboxylic acid 4-methanesulfonyl-benzylamide
##STR00314##
A solution of
1-(4-cyano-benzyl)-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-m
pyridine-3-carboxylic acid (preparation 12, 90 mg, 0.226 mmol),
TBTU (74 mg, 0.231 mmol), DIPEA (100 .mu.L, 0.585 mmol) in DMF (1
mL) is stirred for 15 min at room temperature.
4-Methylsulfonylbenzylamine hydrochloride (55 mg, 0.248 mmol) is
added and the reaction mixture is stirred for 18 h at room
temperature. The reaction mixture is purified by preparative
reversed-phase HPLC (XBridge, gradient of methanol in water, 0.1%
NH.sub.4OH, 60.degree. C.). Yield: 41 mg (32% of theory); ESI mass
spectrum: [M+H].sup.+=566; Retention time HPLC: 1.04 min
(Z003_001).
Example 13.2
1-(4-Cyano-benzyl)-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridine-
-3-carboxylic acid (5-methanesulfonyl-pyridin-2-ylmethyl)-amide
##STR00315##
Example 13.2 is prepared as described for example 13.1, replacing
4-methylsulfonylbenzylamine hydrochloride with
C-(5-methanesulfonyl-pyridin-2-yl)-methylamine. ESI mass spectrum:
[M+H].sup.+=567; Retention time HPLC: 0.99 min (Z003_001).
Example 14
Pyridin-N-oxide of example 4.1
##STR00316##
To a solution of
1-(4-cyano-benzyl)-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydr-
o-pyridine-3-carboxylic acid
(5-methanesulfonyl-pyridin-2-ylmethyl)-amide (example 4.1, 34 mg,
0.059 mmol) in dichloromethane (2 mL) is added
3-chloroperoxybenzoic acid (MCPBA, 69 mg, 0.28 mmol). After
stirring for 2 days at room temperature, the reaction mixture is
purified by preparative reversed-phase HPLC (XBridge, gradient of
methanol in water, 0.1% NH.sub.4OH, 60.degree. C.). Yield: 17 mg
(49% of theory); ESI mass spectrum: [M+H].sup.+=597; Retention time
HPLC: 1.13 min (Z003_003).
Example 15
1-[1-(5-Cyano-pyridin-2-yl)-ethyl]-2-methyl-4-oxo-2'-trifluoromethyl-1,4-d-
ihydro-[3,4']bipyridinyl-5-carboxylic acid methylamide
##STR00317##
15a 6-(1-Bromo-ethyl)-nicotinonitrile
##STR00318##
A solution of 5-bromo-2-ethylpyridine (500 mg, 2.69 mmol),
N-bromosuccinimide (484 mg, 2.69 mmol) and
2,2'-azo-bis(isobutyronitrile) (5 mg, 0.03 mmol) in chloroform is
heated at reflux for 2 h. After stirring over night at room
temperature, the reaction mixture is filtered, evaporated under
reduced pressure and purified by preparative reversed-phase HPLC
(Gilson, XBridge, gradient of acetonitrile in water, 0.1% HCOOH).
Yield: 37 mg (5% of theory); Retention time HPLC: 0.89 min
(Z011_S03).
15b
1-[1-(5-Bromo-pyridin-2-yl)-ethyl]-2-methyl-4-oxo-2'-trifluoromethyl-1-
,4-dihydro-[3,4']bipyridinyl-5-carboxylic acid methylamide
##STR00319##
Preparation 15b is prepared as described for example 2.1,
substituting benzyl bromide with preparation 15a, substituting
preparation 5 with preparation 6 and DMF with NMP. ESI mass
spectrum: [M+H].sup.+=494 (bromine pattern); Retention time HPLC:
1.51 min (Z002_006).
15c 6-(1-Bromo-ethyl)-nicotinonitrile
##STR00320##
A solution of 6-ethyl-nicotinonitrile (synthesis described in
WO2008/71404, 1000 mg, 7.57 mmol), N-bromosuccinimide (1632 mg,
9.08 mmol) and 2,2'-azo-bis(isobutyronitrile) (62 mg, 0.38 mmol) in
chloroform (12 mL) is heated at reflux for 7 min. After cooling to
room temperature, the reaction mixture is filtered and the
volatiles are removed under reduced pressure (260 mbar, 55.degree.
C.) to yield the product which was used without further
purification. Yield: 1597 mg (quant.); ESI mass spectrum:
[M+H].sup.+=211 (Br pattern); Retention time HPLC: 0.92 min
(Z018_S04).
Example 15
1-[1-(5-Cyano-pyridin-2-yl)-ethyl]-2-methyl-4-oxo-2'-trifluoromethyl-1,4-d-
ihydro-[3,4']bipyridinyl-5-carboxylic acid methylamide
##STR00321##
A solution of preparation 15b (42 mg, 85 .mu.mol), zinc cyanide (13
mg, 111 .mu.mol) and Pd-tetrakis(triphenylphosphine) (5 mg) in DMF
(0.5 mL) is heated overnight at 110.degree. C. After cooling to
room temperature, the reaction mixture is filtered and purified by
preparative reversed-phase HPLC (Gilson, XBridge, gradient of
acetonitrile in water, 0.1% HCOOH). Yield: 9 mg (37% of theory);
ESI mass spectrum: [M+H].sup.+=441; Retention time HPLC: 1.37 min
(Z002_006).
Alternatively, example 15 is prepared as described for example 2.1,
substituting benzyl bromide with preparation 15c, substituting
preparation 5 with preparation 6 and DMF with NMP.
Example 15A and Example 15B
Enantiomers of Example 15
58 mg of racemic example 15 are separated by chiral HPLC (Daicel
IB, 250 mm.times.20 mm, 20% MeOH+0.2% diethylamine in supercritical
CO.sub.2, 40.degree. C., 10 mL/min)
Early eluting enantiomer (Example 15A): Retention time chiral
HPLC=1.858 min (Daicel Chiralpak.RTM.IB, 4.6 mm.times.250 mm 5
.mu.m, 4 ml/min, 10 min, 20% MeOH+0.2% diethylamine in
supercritical CO.sub.2, 40.degree. C., 150 bar back pressure); ESI
mass spectrum: [M+H].sup.+=441. Yield: 15 mg
Late eluting enantiomer (Example 15B): Retention time chiral
HPLC=2.633 min (Daicel Chiralpak.RTM.IB, 4.6 mm.times.250 mm 5
.mu.m, 4 ml/min, 10 min, 20% MeOH+0.2% diethylamine in
supercritical CO.sub.2, 40.degree. C., 150 bar back pressure); ESI
mass spectrum: [M+H].sup.+=441. Yield: 13 mg
Example 16
1-[1-(5-Cyano-pyridin-2-yl)-ethyl]-5-(3-difluoromethyl-phenyl)-6-methyl-4--
oxo-1,4-dihydro-pyridine-3-carboxylic acid methylamide
##STR00322##
16a
5-(3-Difluoromethyl-phenyl)-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carb-
oxylic acid
##STR00323##
Preparation 16a is prepared as described for preparation 5b,
substituting 3-(trifluoromethyl)phenylboronic acid with
3-(difluoromethyl)phenylboronic acid. ESI mass spectrum:
[M+H].sup.+=280; Retention time HPLC: 1.51 min (Z018_S04).
16b
5-(3-Difluoromethyl-phenyl)-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carb-
oxylic acid methylamide
##STR00324##
A solution of
5-(3-difluoromethyl-phenyl)-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxy-
lic acid (preparation 16a, 931 mg, 3.33 mmol), TBTU (1.17 g, 3.64
mmol), triethylamine (0.94 mL, 6.70 mmol) in DMF (3 mL) is stirred
for 30 min. Then, methylamine (5.23 mL of 2M solution in THF, 10.5
mmol) is added and the reaction mixture is stirred for 18 h at room
temperature. The reaction mixture is concentrated under reduced
pressure and purified by preparative reversed-phase HPLC (XBridge,
gradient of acetonitrile in water, 0.3% NH.sub.4OH, 60.degree. C.).
Yield: 0.25 g (25% of theory); ESI mass spectrum: [M+H].sup.+=293;
Retention time HPLC: 0.59 min (Z011_S03).
16c
1-[1-(5-Bromo-pyridin-2-yl)-ethyl]-5-(3-difluoromethyl-phenyl)-6-methy-
l-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid methylamide
##STR00325##
Preparation 16c is prepared as described for example 2.1,
substituting benzyl bromide with preparation 15a, substituting
preparation 5 with preparation 16b and DMF with NMP. ESI mass
spectrum: [M+H].sup.+=476 (bromine pattern); Retention time HPLC:
1.02 min (Z018_S04).
Example 16
1-[1-(5-Cyano-pyridin-2-yl)-ethyl]-5-(3-difluoromethyl-phenyl)-6-methyl-4--
oxo-1,4-dihydro-pyridine-3-carboxylic acid methylamide
##STR00326##
Example 16 is prepared as described for Example 15, substituting
preparation 15b with preparation 16c. ESI mass spectrum:
[M+H].sup.+=423; Retention time HPLC: 0.94 min (Z018_S04).
Example 16A and Example 16B
Enantiomers of Example 16
86 mg of racemic example 16 are separated by chiral HPLC (Daicel
IB, 250 mm.times.20 mm, 20% MeOH+0.2% diethylamine in supercritical
CO.sub.2, 40.degree. C., 10 mL/min)
Early eluting enantiomer (Example 16A): Retention time chiral
HPLC=2.351 min (Daicel Chiralpak.RTM.IB, 4.6 mm.times.250 mm 5
.mu.m, 4 ml/min, 10 min, 20% MeOH+0.2% diethylamine in
supercritical CO.sub.2, 40.degree. C., 150 bar back pressure); ESI
mass spectrum: [M+H].sup.+=423. Yield: 31 mg
Late eluting enantiomer (Example 16B): Retention time chiral
HPLC=3.507 min (Daicel Chiralpak.RTM.IB, 4.6 mm.times.250 mm 5
.mu.m, 4 ml/min, 10 min, 20% MeOH+0.2% diethylamine in
supercritical CO.sub.2, 40.degree. C., 150 bar back pressure); ESI
mass spectrum: [M+H].sup.+=423. Yield: 32 mg
Example 17
1-[1-(5-Cyano-pyridin-2-yl)-ethyl]-6-methyl-4-oxo-5-(3-trifluoromethyl-phe-
nyl)-1,4-dihydro-pyridine-3-carboxylic acid ethylamide
##STR00327##
17a
6-Methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridine-3-car-
boxylic acid ethylamide
##STR00328##
Preparation 17a is prepared as described for preparation 6 and
substituting methylamine with ethylamine. ESI mass spectrum:
[M+H].sup.+=325; Retention time HPLC: 0.70 min (Z011_S03).
17b
1-[1-(5-Bromo-pyridin-2-yl)-ethyl]-6-methyl-4-oxo-5-(3-trifluoromethyl-
-phenyl)-1,4-dihydro-pyridine-3-carboxylic acid ethylamide
##STR00329##
Preparation 17b is prepared as described for example 2.1,
substituting benzyl bromide with preparation 15a, substituting
preparation 5 with preparation 17a and DMF with NMP. ESI mass
spectrum: [M+H].sup.+=508 (bromine pattern); Retention time HPLC:
1.26 min (Z018_S04).
Example 17
1-[1-(5-Cyano-pyridin-2-yl)-ethyl]-6-methyl-4-oxo-5-(3-trifluoromethyl-phe-
nyl)-1,4-dihydro-pyridine-3-carboxylic acid ethylamide
##STR00330##
Example 17 is prepared as described for Example 15, substituting
preparation 15b with preparation 17b. ESI mass spectrum: [M+H]=455;
Retention time HPLC: 1.03 min (Z018_S04).
Example 18
1-[1-(5-Cyano-pyridin-2-yl)-ethyl]-5-(3-difluoromethyl-phenyl)-6-methyl-4--
oxo-1,4-dihydro-pyridine-3-carboxylic acid ethylamide
##STR00331##
18a
5-(3-Difluoromethyl-phenyl)-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carb-
oxylic acid ethylamide
##STR00332##
Preparation 18a is prepared as described for preparation 6,
substituting preparation 5b with preparation 16a and methylamine
with ethylamine. ESI mass spectrum: [M+H].sup.+=307; Retention time
HPLC: 0.62 min (Z011_S03).
18b
1-[1-(5-Bromo-pyridin-2-yl)-ethyl]-5-(3-difluoromethyl-phenyl)-6-methy-
l-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid ethylamide
##STR00333##
Preparation 18b is prepared as described for example 2.1,
substituting benzyl bromide with preparation 15a, substituting
preparation 5 with preparation 18a and DMF with NMP. ESI mass
spectrum: [M+H].sup.+=490 (bromine pattern); Retention time HPLC:
1.06 min (Z018_S04).
Example 18
1-[1-(5-Cyano-pyridin-2-yl)-ethyl]-5-(3-difluoromethyl-phenyl)-6-methyl-4--
oxo-1,4-dihydro-pyridine-3-carboxylic acid ethylamide
##STR00334##
Example 18 is prepared as described for Example 15, substituting
preparation 15b with preparation 18b. ESI mass spectrum:
[M+H].sup.+=437; Retention time HPLC: 0.76 min (002_CA03).
Example 19
1-[1-(5-Cyano-pyridin-2-yl)-ethyl]-2-methyl-4-oxo-2'-trifluoromethyl-1,4-d-
ihydro-[3,4']bipyridinyl-5-carboxylic acid ethylamide
##STR00335##
19a
2-Methyl-4-oxo-2'-trifluoromethyl-1,4-dihydro-[3,4']bipyridinyl-5-carb-
oxylic acid ethylamide
##STR00336##
Preparation 19a is prepared as described for preparation 16b,
substituting preparation 16a with preparation 13a and methylamine
with ethylamine. ESI mass spectrum: [M+H].sup.+=326; Retention time
HPLC: 0.84 min (Z018_S04).
19b 1-[1-(5-Bromo
-pyridin-2-yl)-ethyl]-2-methyl-4-oxo-2'-trifluoromethyl-1,4-dihydro-[3,4'-
]bipyridinyl-5-carboxylic acid ethylamide
##STR00337##
Preparation 19b is prepared as described for example 2.1,
substituting benzyl bromide with preparation 15a, substituting
preparation 5 with preparation 19a and DMF with NMP. ESI mass
spectrum: [M+H].sup.+=509 (bromine pattern); Retention time HPLC:
1.04 min (Z018_S04).
Example 19
1-[1-(5-Cyano-pyridin-2-yl)-ethyl]-2-methyl-4-oxo-2'-trifluoromethyl-1,4-d-
ihydro-[3,4']bipyridinyl-5-carboxylic acid ethylamide
##STR00338##
Example 19c is prepared as described for Example 15, substituting
preparation 15b with preparation 19b. ESI mass spectrum:
[M+H].sup.+=456; Retention time HPLC: 0.96 min (Z018_S04).
Examples 20-24. are prepared in three steps: (1) Amide coupling as
described for preparation 6, employing the appropriate amines,
respectively; (2) Alkylation as described for example 2.1,
substituting preparation 5 with the corresponding intermediates
from step 1 and substituting DMF with NMP; (3) Cyanation as
described for Example 15, substituting preparation 15b with the
corresponding intermediates from step 2.
Intermediates from Step 1 (Amide Coupling)
##STR00339##
TABLE-US-00019 Intermediate Retention time for MS HPLC/ Example . .
. R.sup.jR.sup.kN-- [M + H].sup.+ Method 20 (Preparation 6)
##STR00340## 311 1.10 min V003_003 21 ##STR00341## 325 0.70 min
Z011_S03 22 ##STR00342## 393 0.64 mi Z011_S03 23 ##STR00343## 355
0.63 min Z011_S03 24 ##STR00344## 393 0.65 min Z011_S03
Intermediates from Step 2 (Alkylation)
##STR00345##
TABLE-US-00020 Intermediate Retention time for MS HPLC/ Example...
R.sup.jR.sup.kN-- [M + H].sup.+ Method 20 ##STR00346## 557 0.93 min
Z011_S03 21 ##STR00347## 571 0.96 min Z011_S03 22 ##STR00348## 639
0.91 min Z011_S03 23 ##STR00349## 601 0.90 min Z011_S03 24
##STR00350## 639 0.95 min Z011_S03
##STR00351##
TABLE-US-00021 MS Retention time Example R.sup.jR.sup.kN-- [M +
H].sup.+ HPLC/Method 20 ##STR00352## 504 0.85 min Z011_S03 21
##STR00353## 518 1.01 min Z012_S04 22 ##STR00354## 586 0.91 min
Z011_S03 23 ##STR00355## 548 1.36 min Z002_006 24 ##STR00356## 586
1.39 min Z002_006
Example 25
1-[4-Cyano-2-(propane-1-sulfonyl)-benzyl]-6-methyl-4-oxo-5-(3-trifluoromet-
hyl-phenyl)-1,4-dihydro-pyridine-3-carboxylic acid methylamide
##STR00357##
25a
1-(2-Bromo-4-cyano-benzyl)-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-
-1,4-dihydro-pyridine-3-carboxylic acid methylamide
##STR00358##
Preparation 25a is prepared as described for example 2.1,
substituting benzyl bromide with 2-bromo-4-cyanobenzyl bromide and
DMF with NMP. ESI mass spectrum: [M+H].sup.+=504 (bromine pattern);
Retention time HPLC: 1.06 min (Z018_S04).
Example 25
1-[4-Cyano-2-(propane-1-sulfonyl)-benzyl]-6-methyl-4-oxo-5-(3-trifluoromet-
hyl-phenyl)-1,4-dihydro-pyridine-3-carboxylic acid methylamide
##STR00359##
A mixture of preparation 25a (70 mg, 139 .mu.mol), sodium
1-propylsulfinate (54 mg, 415 .mu.mol), L-proline (20 mg, 174
.mu.mol), CuI (7 mg, 37 .mu.mol), K.sub.2CO.sub.3 (24 mg, 174
.mu.mol) in DMSO (0.7 mL) is heated 60 min at 110.degree. C. The
reaction mixture is purified by preparative reversed-phase HPLC
(XBridge, gradient of methanol in water, 0.3% NH.sub.4OH,
60.degree. C.). Yield: 11 mg (15% of theory); ESI mass spectrum:
[M+H].sup.+=532; Retention time HPLC: 1.06 min (Z003_001).
Examples 26 and 27 are prepared as described for example 25,
employing the appropriate sulfinates, respectively.
##STR00360##
TABLE-US-00022 MS Retention time Example R [M + H].sup.+
HPLC/Method 26 Ethyl 518 1.03 min Z018_504 27 Cyclopropyl 530 0.59
min 001_CA07
Examples 28-30 are prepared as described for example 9,
substituting 2-(trifluoromethyl)pyridine-4-boronic acid with the
boronic acids or esters indicated in the table below.
##STR00361##
TABLE-US-00023 Ex- Retention time am- MS HPLC/ ple Boronic Acid or
Boronic Ester [M + H].sup.+ Method 28 ##STR00362## 440 0.84 min
Z011_S03 29 ##STR00363## 386 0.98 min Z018_S04 30 ##STR00364## 458
1.04 min Z018_S04
Example 31
1-[1-(4-Cyano-phenyl)-ethyl]-5-(3-fluoromethyl-phenyl)-6-methyl-4-oxo-1,4--
dihydro-pyridine-3-carboxylic acid methylamide
##STR00365##
31a
1-[1-(4-Cyano-phenyl)-ethyl]-5-(3-hydroxymethyl-phenyl)-6-methyl-4-oxo-
-1,4-dihydro-pyridine-3-carboxylic acid methylamide
##STR00366##
Preparation 31a is prepared as described for example 9,
substituting 2-(trifluoromethyl)pyridine-4-boronic acid with
3-(hydroxymethyl)phenylboronic acid. ESI mass spectrum:
[M+H].sup.+=402; Retention time HPLC: 0.69 min (Z011_S03).
Example 31
1-[1-(4-Cyano-phenyl)-ethyl]-5-(3-fluoromethyl-phenyl)-6-methyl-4-oxo-1,4--
dihydro-pyridine-3-carboxylic acid methylamide
##STR00367##
A solution of preparation 31a (60 mg, 149 .mu.mol) and
[bis(2-methoxyethyl)amino]sulfur trifluoride (50% in toluene, 74
.mu.L, 202 .mu.mol) in dichloromethane (1 mL) is stirred for 3 h at
room temperature. The reaction mixture is quenched with 1N HCl,
extracted twice with dichloromethane and the organic phase is
concentrated under reduced pressure. The remaining residue is
purified by preparative reversed-phase HPLC (Stable Bond, gradient
of acetonitrile in water, 0.1% TFA, 60.degree. C.). Yield: 30 mg
(50% of theory); ESI mass spectrum: [M+H].sup.+=404; Retention time
HPLC: 0.95 min (Z017_504).
xample 31A and Example 31B
Enantiomers of Example 31
25 mg of racemic example 31 are separated by chiral HPLC (Daicel
IB, 250 mm.times.20 mm, 25% MeOH+0.2% diethylamine in supercritical
CO.sub.2, 40.degree. C., 10 mL/min)
Early eluting enantiomer (Example 31A): Retention time chiral
HPLC=4.172 min (Daicel Chiralpak.RTM.IB, 4.6 mm.times.250 mm 5
.mu.m, 4 ml/min, 10 min, 25% MeOH+0.2% diethylamine in
supercritical CO.sub.2, 40.degree. C., 150 bar back pressure); ESI
mass spectrum: [M+H].sup.+=404. Yield: 11 mg
Late eluting enantiomer (Example 31B): Retention time chiral
HPLC=5.707 min (Daicel Chiralpak.RTM.IB, 4.6 mm.times.250 mm 5
.mu.m, 4 ml/min, 10 min, 25% MeOH+0.2% diethylamine in
supercritical CO.sub.2, 40.degree. C., 150 bar back pressure); ESI
mass spectrum: [M+H].sup.+=404. Yield: 10 mg
Examples 32-34 are prepared as described for example 2.1,
substituting benzyl bromide with the appropriate aryl- or
heteroaryl-methyl bromides and substituting preparation 5 with
preparation 16b.
##STR00368##
TABLE-US-00024 MS Retention time Example R [M + H].sup.+
HPLC/Method 32 ##STR00369## 426 0.98 Z018_S04 33 ##STR00370## 426
0.99 min Z018_S04 34 ##STR00371## 409 0.99 min Z018_S04
Example 35
1-[1-(4-Cyano-phenyl)-propyl]-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)--
1,4-dihydro-pyridine-3-carboxylic acid ethylamide
##STR00372##
35a 1-[1-(4-Bromo -phenyl)-propyl]-6-methyl-4-oxo
-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridine-3-carboxylic
acid ethylamide
##STR00373##
Preparation 35a is prepared as described for example 2.1,
substituting benzyl bromide with 1-bromo-4-(1-bromopropyl)benzene
and substituting preparation 5 with preparation 17a. ESI mass
spectrum: [M+H].sup.+=521 (bromine pattern); Retention time HPLC:
1.21 min (Z018_S04).
Example 35
1-[1-(4-Cyano-phenyl)-propyl]-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)--
1,4-dihydro-pyridine-3-carboxylic acid ethylamide
##STR00374##
Example 35 is prepared as described for Example 15, substituting
preparation 15b with preparation 35a. ESI mass spectrum:
[M+H].sup.+=468; Retention time HPLC: 0.51 min (Z011_S03).
Example 36
1-[1-(4-Cyano-phenyl)-propyl]-2-methyl-4-oxo-2'-trifluoromethyl-1,4-dihydr-
o-[3,4']bipyridinyl-5-carboxylic acid methylamide
##STR00375##
36a
2-Methyl-4-oxo-2'-trifluoromethyl-1,4-dihydro-[3,4']bipyridinyl-5-carb-
oxylic acid methylamide
##STR00376##
Preparation 36a is prepared as described for preparation 16b,
substituting preparation 16a with preparation 13a. ESI mass
spectrum: [M+H].sup.+=312.
36b
1-[1-(4-Bromo-phenyl)-propyl]-2-methyl-4-oxo-2'-trifluoromethyl-1,4-di-
hydro-[3,4']bipyridinyl-5-carboxylic acid methylamide
##STR00377##
Preparation 36b is prepared as described for example 2.1,
substituting benzyl bromide with 1-bromo-4-(1-bromopropyl)benzene
and substituting preparation 5 with preparation 36a. ESI mass
spectrum: [M+H].sup.+=508 (bromine pattern); Retention time HPLC:
1.08 min (Z018_S04).
Example 36
1-[1-(4-Cyano-phenyl)-propyl]-2-methyl-4-oxo-2'-trifluoromethyl-1,4-dihydr-
o-[3,4']bipyridinyl-5-carboxylic acid methylamide
##STR00378##
Example 36 is prepared as described for Example 15, substituting
preparation 15b with preparation 36b. ESI mass spectrum:
[M+H].sup.+=455; Retention time HPLC: 0.85 min (Z011_S03).
Example 37
1-(5-Cyano-indan-1-yl)-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dih-
ydro-pyridine-3-carboxylic acid methylamide
##STR00379##
37a
1-(5-Bromo-indan-1-yl)-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxyli-
c acid
##STR00380##
Preparation 37a is prepared as described for preparation 1b,
substituting 4-cyanobenzylamine hydrochloride with
5-bromo-2,3-dihydro-1H-inden-1-amine. ESI mass spectrum:
[M+H].sup.+=348 (bromine pattern); Retention time HPLC: 0.93 min
(Z018_S04).
37b
1-(5-Cyano-indan-1-yl)-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxyli-
c acid
##STR00381##
Preparation 37b is prepared as described for Example 15,
substituting preparation 15b with preparation 37a. ESI mass
spectrum: [M+H].sup.+=295; Retention time HPLC: 0.34 min
(Z011_S03).
37c
5-Bromo-1-(5-cyano-indan-1-yl)-6-methyl-4-oxo-1,4-dihydro-pyridine-3-c-
arboxylic acid
##STR00382##
Preparation 37c is prepared as described for preparation 1c,
substituting preparation 1b with preparation 37b. ESI mass
spectrum: [M+H].sup.+=373; Retention time HPLC: 0.91 min
(Z018_S04).
37d
1-(5-Cyano-indan-1-yl)-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-
-dihydro -pyridine-3-carboxylic acid
##STR00383##
Preparation 37d is prepared as described for preparation 5b,
substituting preparation 5a with preparation 37c. ESI mass
spectrum: [M+H].sup.+=439; Retention time HPLC: 1.05 min
(Z018_S04).
Example 37
1-(5-Cyano-indan-1-yl)-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dih-
ydro-pyridine-3-carboxylic acid methylamide
##STR00384##
Example 37 is prepared as described for example 1.17, substituting
3-amino-1,2-propanediol with methylamine. ESI mass spectrum:
[M+H].sup.+=452; Retention time HPLC: 0.90 min (Z011_S03).
Example 38
1-[1-(4-Cyano-phenyl)-ethyl]-2'-difluoromethyl-2-methyl-4-oxo-1,4-dihydro--
[3,4']bipyridinyl-5-carboxylic acid ethylamide
##STR00385##
38a 2-(Difluoromethyl)pyridine-4-boronic acid
##STR00386##
A mixture of 4-bromo-2-(difluoromethyl)pyridine (2.50 g, 12.0
mmol), bis-(pinakolato)-diboron (3.80 g, 15.0 mmol),
(1,1'-Bis-(diphenylphosphino)-ferrocen)-dichlorpalladium (II) (26
mg, 36 .mu.mol) and potassium acetate (2.90 g, 30.0 mmol) in
dioxane is stirred for 48 h at 80.degree. C. The volatiles are
removed under reduced pressure. After addition of water, the
mixture is extracted with dichloromethane. The combined organic
layer is dried over Na.sub.2SO.sub.4 and evaporated under reduced
pressure. The remaining residue is purified by preparative reversed
phase HPLC (Sunfire, gradient of acetonitrile in water, 0.1%
HCOOH). Yield: 599 mg of the desired boronic acid (60% pure, 17% of
theory).
Example 38
1-[1-(4-Cyano-phenyl)-ethyl]-2'-difluoromethyl-2-methyl-4-oxo-1,4-dihydro--
[3,4']bipyridinyl-5-carboxylic acid ethylamide
##STR00387##
Example 38 is prepared as described for example 10, substituting
3-trifluoromethyl-phenylboronic acid with preparation 38a. ESI mass
spectrum: [M+H].sup.+=437; Retention time HPLC: 0.77 min
(Z011_S03).
Example 39
1-(4-Cyano-3-fluoro-benzyl)-5-(3-difluoromethyl-phenyl)-6-methyl-4-oxo-1,4-
-dihydro-pyridine-3-carboxylic acid
4-methanesulfonyl-benzylamide
##STR00388##
39a
5-(3-Difluoromethyl-phenyl)-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carb-
oxylic acid 4-methane-sulfonyl-benzylamide
##STR00389##
Preparation 39a is prepared as described for preparation 5c,
substituting preparation 5b with preparation 16a. ESI mass
spectrum: [M+H].sup.+=447; Retention time HPLC: 0.66 min
(Z011_S03).
Example 39
1-(4-Cyano-3-fluoro-benzyl)-5-(3-difluoromethyl-phenyl)-6-methyl-4-oxo-1,4-
-dihydro-pyridine-3-carboxylic acid
4-methanesulfonyl-benzylamide
##STR00390##
Example 39 is prepared as described for example 2.1, substituting
benzyl bromide with 4-bromomethyl-2-fluorobenzonitrile and
substituting preparation 5 with preparation 39a. ESI mass spectrum:
[M+H].sup.+=580; Retention time HPLC: 1.03 min (Z018_S04).
Example 40
1-(5-Cyano-pyridin-2-ylmethyl)-5-(3-difluoromethyl-phenyl)-6-methyl-4-oxo--
1,4-dihydro-pyridine-3-carboxylic acid
4-methanesulfonyl-benzylamide
##STR00391##
Example 40 is prepared as described for example 2.1, substituting
benzyl bromide with 6-bromomethyl-nicotino-nitrile and substituting
preparation 5 with preparation 39a. ESI mass spectrum:
[M+H].sup.+=563; Retention time HPLC: 0.99 min (Z018_S04).
Example 41
1-(4-Cyano-2-fluoro-benzyl)-5-(3-difluoromethyl-phenyl)-6-methyl-4-oxo-1,4-
-dihydro-pyridine-3-carboxylic acid
4-methanesulfonyl-benzylamide
##STR00392##
Example 41 is prepared as described for example 2.1, substituting
benzyl bromide with 4-bromomethyl-3-fluoro-benzonitrile and
substituting preparation 5 with preparation 39a. ESI mass spectrum:
[M+H].sup.+=580; Retention time HPLC: 1.02 min (Z018_S04).
Example 42
1-(4-Cyano-2-fluoro-benzyl)-2-methyl-4-oxo-2'-trifluoromethyl-1,4-dihydro--
[3,4']bipyridinyl-5-carboxylic acid methylamide
##STR00393##
Example 42 is prepared as described for example 2.1, substituting
benzyl bromide with 4-s bromomethyl-3-fluoro-benzonitrile and
substituting preparation 5 with preparation 36a. ESI mass spectrum:
[M+H].sup.+=445; Retention time HPLC: 0.96 min (Z018_S04).
Example 43
1-(4-Cyano-3-fluoro-benzyl)-2-methyl-4-oxo-2'-trifluoromethyl-1,4-dihydro--
[3,4']bipyridinyl-5-carboxylic acid methylamide
##STR00394##
Example 43 is prepared as described for example 2.1, substituting
benzyl bromide with 4-bromomethyl-2-fluorobenzonitrile and
substituting preparation 5 with preparation 36a. ESI mass spectrum:
[M+H].sup.+=445; Retention time HPLC: 0.97 min (Z018_S04).
Example 44
1-(5-Cyano-pyridin-2-ylmethyl)-2-methyl-4-oxo-2'-trifluoromethyl-1,4-dihyd-
ro-[3,4']bipyridinyl-5-carboxylic acid methylamide
##STR00395##
Example 44 is prepared as described for example 2.1, substituting
benzyl bromide with 6-bromomethyl-nicotino-nitrile and substituting
preparation 5 with preparation 36a. ESI mass spectrum:
[M+H].sup.+=428; Retention time HPLC: 0.99 min (Z018_S04).
Example 45
1-[1-(4-Cyano-phenyl)-cyclopropyl]-6-methyl-4-oxo-5-(3-trifluoromethyl-phe-
nyl)-1,4-dihydro-pyridine-3-carboxylic acid
4-methanesulfonyl-benzylamide
##STR00396##
45a
1-[1-(4-Cyano-phenyl)-cyclopropyl]-6-methyl-4-oxo-1,4-dihydro-pyridine-
-3-carboxylic acid
##STR00397##
Preparation 45a is prepared as described for preparation 1b,
substituting 4-cyanobenzylamine hydrochloride with
4-(1-aminocyclopropyl)-benzonitril hydrochloride. ESI mass
spectrum: [M+H].sup.+=295; Retention time HPLC: 0.95 min
(Z002_005).
45b
1-[1-(4-Cyano-phenyl)-cyclopropyl]-6-methyl-4-oxo-1,4-dihydro-pyridine-
-3-carboxylic acid 4-methanesulfonyl-benzylamide
##STR00398##
Preparation 45b is prepared as described for Example 9,
substituting preparation 2b with preparation 45a and methylamine
with 4-(methylsulfonyl)benzylamine. ESI mass spectrum:
[M+H].sup.+=462; Retention time HPLC: 0.89 min (Z018_S04).
45c
5-Bromo-1-[1-(4-cyano-phenyl)-cyclopropyl]-6-methyl-4-oxo-1,4-dihydro--
pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide
##STR00399##
Preparation 45c is prepared by bromination of preparation 45b with
N-bromosuccinimide in dichloromethane (1 h, room temperature) and
subsequent purification by reversed-phase HPLC (Sunfire, gradient
of methanol in water, 0.1% TFA, 60.degree. C.). ESI mass spectrum:
[M+H].sup.+=540 (bromine pattern); Retention time HPLC: 0.96 min
(Z018_S04).
Example 45
1-[1-(4-Cyano-phenyl)-cyclopropyl]-6-methyl-4-oxo-5-(3-trifluoromethyl-phe-
nyl)-1,4-dihydro-pyridine-3-carboxylic acid
4-methanesulfonyl-benzylamide
##STR00400##
Example 45 is prepared as described for example 6.1, substituting
phenylboronic acid with 3-(trifluoromethyl)phenylboronic acid. ESI
mass spectrum: [M+H].sup.+=606; Retention time HPLC: 1.09 min
(Z018_S04).
Example 46
1-(4-Cyano-benzyl)-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-
-pyridine-3-carboxylic acid cyanomethyl-amide
##STR00401##
To a solution of
1-(4-cyano-benzyl)-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydr-
o-pyridine-3-carboxylic acid (preparation 1, 60 mg, 90% purity,
0.131 mmol), aminoacetonitrile (15 mg, 0.262 mmol) and
N-methylmorpholine (66 mg, 0.66 mmol) in dichloromethane (2 mL) is
added at 0.degree. C. 1-propanephosphonic acid cyclic anhydride in
ethyl acetate (250 mg, 50%, 0.39 mmol). The reaction mixture is
stirred for 3 h at room temperature. The volatiles are evaporated
under reduced pressure and the remaining residue is purified by
preparative reversed-phase HPLC (Sunfire, gradient of acetonitrile
in water, 0.1% TFA, 60.degree. C.). Yield: 5 mg (9% of theory); ESI
mass spectrum: [M+H].sup.+=451; Retention time HPLC: 0.87 min
(Z011_S03).
Examples 47.1-47.20 are prepared in two steps: (1) Amide coupling
as described for preparation 9.13 (Procedure A), substituting
preparation 4 with preparation 5b and substituting
aminoacetonitrile with the appropriate amines, respectively; (2)
Alkylation as described for example 2.1, substituting benzyl
bromide with preparation 15c, substituting preparation 5 with the
intermediates from step 1, and substituting DMF with NMP.
Intermediates from Step 1 (Amide Coupling)
##STR00402##
TABLE-US-00025 Intermediate Retention for MS time HPLC/ Example . .
. R.sup.jR.sup.kN-- [M + H].sup.+ Method 47.1 ##STR00403## 355 0.68
min Z011_S03 47.2 ##STR00404## 380 0.61 min Z011_S03 47.3
##STR00405## 379 1.01 min Z018_S043 47.4 ##STR00406## 369 0.88 min
Z012_S04 47.5 ##STR00407## 351 0.75 min Z011_S03 47.6 ##STR00408##
343 0.66 min Z011_S03 47.7 ##STR00409## 367 0.64 min Z011_S03 47.8
##STR00410## 391 0.66 min Z011_S03 47.9 ##STR00411## 367 0.65 min
Z011_S03 47.10 ##STR00412## 381 0.67 min Z011_S03 47.11
##STR00413## 369 0.65 min Z011_S03 47.12 ##STR00414## 394 0.63 min
Z011_S03 47.13 ##STR00415## 465 0.71 min Z011_S03 47.14
##STR00416## 353 0.65 min Z011_S03 47.15 ##STR00417## 393 0.69 min
Z011_S03 47.16 ##STR00418## 350 0.66 min Z011_S03 47.17
##STR00419## 364 0.68 min Z011_S03 47.18 ##STR00420## 362 0.65 min
Z011_S03 47.19 ##STR00421## 361 0.96 min Z018_S04 47.20
##STR00422## 336 0.92 min Z018_S04
##STR00423##
TABLE-US-00026 Exam- MS Retention time ple R.sup.jR.sup.kN-- [M +
H].sup.+ HPLC/Method 47.1 ##STR00424## 485 1.02 min Z018_S04 47.2
##STR00425## 510 0.94 min Z018_S04 47.3 ##STR00426## 509 1.10 min
Z018_S04 47.4 ##STR00427## 499 0.99 min Z018_S04 47.5 ##STR00428##
481 1.09 min Z018_S04 47.6 ##STR00429## 473 1.01 min Z017_S04 47.7
##STR00430## 497 1.00 min Z018_S04 47.8 ##STR00431## 521 0.99 min
Z018_S04 47.9 ##STR00432## 497 0.99 min Z017_S04 47.10 ##STR00433##
511 1.02 min Z018_S04 47.11 ##STR00434## 499 0.99 min Z018_S04
47.12 ##STR00435## 524 0.97 min Z018_S04 47.13 ##STR00436## 595
1.04 min Z018_S04 47.14 ##STR00437## 483 0.99 min Z018_S04 47.15
##STR00438## 523 1.03 min Z018_S04 47.16 ##STR00439## 480 1.06 min
Z018_S04 47.17 ##STR00440## 494 1.08 min Z018_S04 47.18
##STR00441## 492 1.05 min Z018_S04 47.19 ##STR00442## 491 1.06 min
Z018_S04 47.20 ##STR00443## 466 1.01 min Z018_S04
EXAMPLES
Other features and advantages of the present invention will become
apparent from the following more detailed examples which
illustrate, by way of example, the principles of the invention.
Human Neutrophil Elastase Assay
Materials: Human neutrophil elastase was purchased from Calbiochem
(Cat. No.: 324681) and the elastase substrate
MeOSuc-Ala-Ala-Pro-Val-AMC from Bachem (Cat. No.: I-1270). All
other materials were of the highest grade commercially
available.
The following buffers were used: Compound buffer: 100 mM Tris, 500
mM NaCl, adjusted to pH 7.5; Assay buffer: 100 mM Tris, 500 mM
NaCl, adjusted to pH 7.5, containing 0.01% BSA.
Assay conditions: Test compounds were prediluted in DMSO and
subsequently in compound buffer (5% DMSO final). 5 .mu.L of these
compound dilutions were mixed with 10 .mu.l Neutrophil elastase (9
ng/ml in assay buffer) in a black 384 well OptiPlate (Perkin Elmer,
Cat No.: 6007270) and incubated for 15 min at room temperature.
Subsequently 10 .mu.L substrate solution in assay buffer were added
(250 .mu.M final concentration) and the plates were incubated for
60 min at room temperature. After inactivation of the enzyme,
fluorescence intensities were measured at 380 nm excitation and 460
nm emission wavelengths.
Each plate contains wells with a high value control
(DMSO+enzyme+substrate) and wells with a low value control
(DMSO+inactivated enzyme+substrate). 1050 values were estimated
using a sigmoidal concentration response curve with variable slope.
Means of low values were taken as 0%, means of high values as 100%.
1050 values of selected compound in the Neutrophil Elastase
assay:
TABLE-US-00027 Example IC50 [nM] 1.1 15.2 1.2 48.3 1.3 13.0 1.4
27.6 1.5 10.4 1.6 30.5 1.7 15.8 1.8 83.0 1.9 8.4 1.10 1.1 1.11 14.4
1.12 12.1 1.13 6.6 1.14 1.8 1.15 7.9 1.16 7.4 1.17 21.0 1.18 23.8
1.19 48.1 1.20 10.6 1.21 14.4 1.22 44.6 1.23 19.0 1.24 10.0 1.25
10.9 1.26 13.2 1.27 46.4 1.28 21.8 1.29 31.6 1.30 17.1 1.31 13.7
1.32 23.0 1.33 3.7 1.34 8.9 1.35 31.4 1.36 47.1 1.37 95.7 1.38 36.9
1.39 6.2 1.40 2.1 1.41 3.2 1.42 5.2 1.43 8.9 1.44 7.9 1.45 7.6 1.46
5.9 1.47 22.0 1.48 4.1 1.49 10.4 1.50 1.4 1.51 10.7 1.52 9.6 1.53
9.0 1.54 41.5 1.55 4.9 1.56 4.6 1.57 6.8 1.58 8.1 1.59 10.5 1.60
13.3 1.61 11.4 1.62 10.4 1.63 22.5 1.64 17.2 1.65 38.5 1.66 6.2
1.67 6.5 2.1 55.3 2.2 1.9 2.3 <1 2.4 1.4 2.5 <1 2.6 1.6 2.7
6.9 2.8 <1 2.9 <1 2.10 83.8 2.11 38.9 2.12 <1 2.5A <1
2.5B 20.1 3.1 2.9 3.2 53.7 3.3 51.0 3.4 29.1 3.5 19.3 3.6 20.3 3.7
26.4 3.8 14.0 3.9 25.7 3.1A <1 3.1B 225.5 4.1 <1 4.2 2.1 4.3
58.0 4.4 63.8 4.5 1.0 4.6 1.5 4.7 <1 4.8 1.4 4.9 <1 4.10
<1 5.1 2.8 5.2 1.2 5.3 1.4 6.1 44.5 6.2 1.5 6.3 9.1 6.4 19.3 6.5
9.6 6.6 38.6 6.7 75.3 6.8 <1 6.9 3.8 6.10 <1 6.11 <1 6.12
3.8 6.13 2.5 7.1 4.1 7.2 2.5 7.3 1.3 7.4 1.8 7.5 1.4 7.6 1.2 7.7
2.4 7.8 1.3 7.9 2.3 7.10 2.0 7.11 4.4 7.12 1.5 7.13 4.0 7.14 4.7
7.15 10.3 7.16 17.9 7.17 18.5 7.18 <1 7.19 4.1 7.20 3.6 8A 1.2
8B 522.0 8.1 4.1 8.2 1.9 8.3 1.3 8.4 1.8 8.5 1.2 8.6 1.2 8.7 1.7
8.8 1.1 8.9 1.9 8.10 1.6 8.11 4.3 8.12 1.4 8.13 3.2 8.14 3.6 8.15
4.4 8.16 2.4 8.17 3.1 8.18 2.4 8.19 1.7 8.20 1.0 8.21 3.0 8.22 21.6
8.23 3.4 8.24 1.7 8.25 1.8 8.26 1.8 8.27 3.0 8.28 3.3 9A 3.7 9B
1505.0 9.1 4.5 9.2 3.3 9.3 3.9 9.4 4.1 9.5 5.7 9.5A 2.8 9.5B 878.5
9.6 3.2 9.7 7.0 9.8 4.2 9.9 7.6 9.10 12.4 9.11 18.3 9.12 4.6 9.13
1.7 9.14 7.0 9.15 5.7 9.16 6.7 9.17 10.1 9.18 7.5 9.19 8.9 9.20
10.9 9.21 9.5 9.22 7.3 9.23 14.4 9.24 9.8 9.25 11.4 9.26 12.1 9.27
13.7 9.28 12.8 9.29 22.3 9.30 16.3 9.31 18.7 9.32 19.4 9.33 23.1
9.34 23.5 9.35 26.2 9.36 33.9 9.37 32.9 9.38 33.3 9.39 58.3 9.40
69.4 9.41 100.0 9.42 29.9 9.43 11.5 9.44 9.8 9.45 5.3 9.46 94 9.47
14.9 9.48 17.3 9.49 150 9.50 4.6 9.51 6.0 9.52 420 9.53 23 9.54 4.1
9.55 5.1 9.56 6.1 9.56A 2.3 9.56B 1299.3 9.57 5.2 9.58 5.4 9.59 7.5
9.60 5.7 9.61 8.6 9.62 12.0 9.63 37.5 10A <1 10B 289.5 11A <1
11B 19.5 12.1 35.9 12.2 49.5 12.3 59.7 12.4 14.4 13.1 6.6
13.2 5.2 14 <1 15 10.5 15A 3.8 15B 67.8 16 9.9 16A 4.2 16B 371.5
17 4.5 18 5.4 19 22.2 20 8.6 21 4.6 22 2.8 23 4.4 24 4.8 25 14.0 26
10.8 27 8.1 28 13.3 29 14.4 30 5.3 31 7.8 31A 1885.0 31B 4.2 32
11.8 33 14.0 34 31.2 35 7.8 36 18.4 37 13.7 38 11.0 39 <1 40
<1 41 <1 42 46.0 43 48.4 44 94.6 45 4.6 46 2.3 47.1 12.9 47.2
7.3 47.3 10.7 47.4 12.2 47.5 16.7 47.6 12.0 47.7 30.1 47.8 13.1
47.9 67.2 47.10 19.2 47.11 63.5 47.12 7.3 47.13 <1 47.14 26.4
47.15 13.4 47.16 6.2 47.17 139 47.18 6.4 47.19 10.3 47.20 2.5
Surprisingly, it was found that for compounds with a single methyl
group attached to the methylene group connecting the 4-pyridone
nitrogen with the 4-cyano-phenyl or 4-cyano-pyridyl moiety,
typically there is a strong discrimination in neutrophil elastase
inhibitory potency observed for the two enantiomers.
##STR00444##
For instance, in the case of example 2.5, the enantiomer example
2.5A (eutomer) is much more active than enantiomer example 2.5B
(distomer); wherein the absolute configuration of compound 2.5A can
be determined to be (R) by x-ray analysis.
Similar observations were made for the following examples: example
3.1, example 8, example 9, example 10, example 11, example 9.5,
example 9.56, example 15, example 16, example 31, thus from the
above mentioned examples the more active enantiomers (eutomers) are
preferred; furthermore based on the x-ray analysis of eutomers the
(R) configuration is preferred for the benzylic carbon atom.
Combinations
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, .beta.2-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, FPRL1 modulators, LTB4-receptor (BLT1, BLT2)
antagonists, Histamine H1 receptor antagonists, Histamine H4
receptor antagonists, dual Histamine H1/H3-receptor antagonists,
PI3-kinase inhibitors, inhibitors of non-receptor tyrosine kinases
as for example LYN, LCK, SYK, ZAP-70, FYN, BTK or ITK, inhibitors
of MAP kinases as for example p38, ERK1, ERK2, JNK1, JNK2, JNK3 or
SAP, inhibitors of the NF-.kappa.B signalling pathway as for
example IKK2 kinase inhibitors, iNOS inhibitors, MRP4 inhibitors,
leukotriene biosynthese inhibitors as for example 5-Lipoxygenase
(5-LO) inhibitors, cPLA2 inhibitors, Leukotriene A4 Hydrolase
inhibitors or FLAP inhibitors, MMP9-inhibitors, MMP12-inhibitors
Non-steroidale anti-inflammatory agents (NSAIDs), Cathepsin C (or
DPPI/Dipeptidyl-aminopeptidase I) inhibitors, CRTH2 antagonists,
DP1-receptor modulators, Thromboxane receptor antagonists, CCR3
antagonists, CCR4 antagonists, CCR1 antagonists, CCR5 antagonists,
CCR6 antagonists, CCR7 antagonists, CCR8 antagonists, CCR9
antagonists, CCR30 antagonists, CXCR3 antagonists, CXCR4
antagonists, CXCR2 antagonists, CXCR1 antagonists, CXCR5
antagonists, CXCR6 antagonists, CX3CR3 antagonists, Neurokinin
(NK1, NK2) antagonists, Sphingosine 1-Phosphate receptor
modulators, Sphingosine 1 phosphate lyase inhibitors, Adenosine
receptor modulators as for example A2a-agonists, modulators of
purinergic receptors 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, GABAa receptor
antagonist, ENaC-inhibitors, Prostasin-inhibitors, Melanocortin
receptor (MC1R, MC2R, MC3R, MC4R, MC5R) modulators, CGRP
antagonists, Endothelin antagonists, TNF.alpha. 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,
but also combinations of two or three active substances.
Preferred are betamimetics, anticholinergics, corticosteroids,
PDE4-inhibitors, LTD4-antagonists, EGFR-inhibitors, Cathepsin C
inhibitors, CRTH2 inhibitors, 5-LO-inhibitors, Histamine receptor
antagonists and SYK-inhibitors, especially Cathepsin C inhibitors,
but also combinations of two or three active substances, i.e.:
Betamimetics with corticosteroids, PDE4-inhibitors,
CRTH2-inhibitors or LTD4-antagonists, Anticholinergics with
betamimetics, corticosteroids, PDE4-inhibitors, CRTH2-inhibitors or
LTD4-antagonists, Corticosteroids with PDE4-inhibitors,
CRTH2-inhibitors or LTD4-antagonists PDE4-inhibitors with
CRTH2-inhibitors or LTD4-antagonists CRTH2-inhibitors with
LTD4-antagonists. Indications
The compounds of the invention and their pharmaceutically
acceptable salts have activity as pharmaceuticals, in particular as
inhibitors of neutrophil elastase, and thus may be used in the
treatment of:
1. 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; alpha1-antitrypsin deficiency; bronchiectasis; cystic
fibrosis; sarcoidosis; farmer's lung and related diseases;
hypersensitivity pneumonitis; 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, 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; acute lung injury
(ALI); acute respiratory distress syndrome (ARDS).
2. 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 greata, male-pattern baldness, Sweet's syndrome,
Weber-Christian syndrome, erythema multiforme; cellulitis, both
infective and non-infective; panniculitis; cutaneous lymphomas,
non-melanoma skin cancer and other dysplastic lesions; drug-induced
disorders including fixed drug eruptions;
3. eyes: blepharitis; conjunctivitis, including perennial and
vernal allergic conjunctivitis; iritis; 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);
5. 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;
6. other auto-immune and allergic disorders including rheumatoid
arthritis, irritable bowel syndrome, systemic lupus erythematosus,
multiple sclerosis, Hashimoto's thyroiditis, Graves' disease,
Addison's disease, diabetes mellitus, idiopathic thrombocytopaenic
purpura, eosinophilic fasciitis, hyper-IgE syndrome,
antiphospholipid syndrome and Sazary syndrome;
7. 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,
8. 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.
For treatment of the above-described diseases and conditions, 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. For Example, for administration
to a 70 kg person, 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. In any case 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.
* * * * *